Archives of Internal Medicine

Ewy, Gordon A.

doi: 10.1001/archinte.159.12.1279pmid: 10386503

THE ROLE of low-density lipoprotein (LDL) cholesterol in the pathogenesis of coronary artery disease and the importance of statin therapy in lowering LDL cholesterol in individuals with symptomatic1,2 and asymptomatic3,4 coronary artery disease is now well established. The relatively recent but already classic trials in patients with symptomatic coronary artery disease (the Scandinavian Simvastatin Survival Study1 and the Coronary Atherosclerosis and Recurrent Events trial2) and in asymptomatic individuals with increased risk because of elevated LDL cholesterol levels (the West of Scotland Coronary Prevention Study3) or because of low high-density lipoprotein cholesterol levels (the Air Force/Texas Coronary Artery Prevention Studies4 [AFCAPS/TexCAPS]) have shown that lowering LDL cholesterol level is the key to decreasing total mortality1,2 and preventing the complications of coronary artery disease.1-4 One of the remaining questions is how far should the LDL cholesterol level be lowered? The recent Atorvastatin Versus Revascularization Treatments trial5 suggests that the answer may be much lower than most of us would have predicted only a year ago. In that trial, 341 patients with significant coronary artery disease (≥1 defined narrowing of a major coronary artery; LDL cholesterol level >2.9 mmol/L [114 mg/dL]; and ability to exercise ≥4 minutes) were randomized to receive the indicated catheter-based revascularization (percutaneous transluminal coronary angioplasty [PTCA]) and conventional care or 80 mg of atorvastatin calcium.5,6 At 18 months, the incidence of unstable angina was 25 (14.0%) of 178 for the PTCA group and 11 (6.7%) of 163 in the atorvastatin group.6 The LDL cholesterol level was 3.1 mmol/L (119 mg/dL) in the PTCA group and 2.0 mmol/L (77 mg/dL) in the atorvastatin group.6 These results are so exciting that if the results are confirmed, PTCA may well soon stand for "Put That Catheter Away." The evolution of the evidence of lowering LDL cholesterol levels is reminiscent of the evolution of evidence of lowering the blood pressure. The landmark Veterans Affairs Cooperative Study was necessary to convince our profession that antihypertensive therapy was beneficial. During the ensuing decades, studies showed the benefit of lowering the diastolic blood pressure to 110 mm Hg, then 100 mm Hg, and then 90 mm Hg. The latest, the Hypertension Optimal Treatment trial,7 showed that a diastolic blood pressure treatment goal of 80 mm Hg decreased the incidence of heart attacks and strokes. Although smoking cessation, lowering LDL cholesterol levels, controlling blood pressure, a Mediterranean diet, and regular exercise (walking 3.2 km/d) have all been shown to reduce mortality, antioxidant therapy has not. As Spencer and colleagues8 review in this issue of the ARCHIVES, the 3 prospective randomized trials evaluating vitamin E administration showed no improvement in mortality. Like aspirin, which has not been shown to decrease mortality, but which has been shown in many studies to decrease the incidence of myocardial infarction, the Cambridge Heart Antioxidant Study9 found that vitamin E therapy decreased the incidence of myocardial infarction, but not mortality; there was 1 more death in the vitamin E–treated group. Why then might one hesitate to prescribe vitamin E and the other antioxidant vitamins? There are at least 3 reasons. The first is possible disequilibrium induced by excess vitamin supplements. The second is that the oxidative hypothesis of LDL cholesterol in the pathogenesis of coronary atherosclerosis has recently been questioned. The third is that the findings from the Cambridge Heart Antioxidant Study need to be confirmed. Beta carotene (vitamin A) is another of the so-called antioxidant vitamins.10-13 A lower risk for cancer and heart disease has been shown not only in observational studies of individuals with diets that contained more fruits and vegetables, but also in epidemiological studies of individuals with higher serum beta carotene levels. These findings suggested that beta carotene supplementation would be beneficial. There was some concern when, in the Alpha-Tocopherol, Beta Carotene Cancer Prevention Study,10 a study of 29,000 Finnish male smokers, beta carotene supplementation showed no significant effect on coronary mortality or on the incidence of new angina pectoris, but was associated with an 8% increase in total mortality and an 18% increase in lung cancer. This concern was justified, as the Beta Carotene and Retinol Efficacy Trial11 also found a higher incidence of lung cancer in individuals who smoked and were taking beta carotene supplements. In that study, 18,314 smokers, former smokers, and workers exposed to asbestos were randomized to a combination of 30 mg of beta carotene per day and 25,000 IU of retinol (vitamin A) or placebo. The active treatment group had a relative risk for lung cancer of 1.28 compared with the placebo group. The study was stopped 21 months early.11 In the Physicians' Health Study (a randomized, double-blind, placebo-controlled trial of 22,071 male physicians),12 50 mg of beta carotene on alternate days for 12 years showed no effect on coronary heart disease events. The results of these 3 studies led to the discontinuation of the beta carotene therapy arm of the Women's Health Initiative. One hypothesis that has been advanced is that harm can result from a disequilibrium induced by excess beta carotene supplementation.13 Beta carotene is only 1 of more than 500 carotenoids, and there are numerous other plant compounds that may be responsible for the beneficial effects of a diet high in carotenoids.13 Unfortunately, many alternative medicine advocates still recommend high-dose beta carotene. Alpha tocopherol is also only 1 of the many forms of vitamin E.8 Are we creating another disequilibrium by prescribing high doses of alpha tocopherol? It is probable that a high dose of vitamins will not compensate for a poor diet or other activities that place one's health at risk, such as smoking, nor are vitamins a substitute for a healthy diet. The theoretical basis of antioxidant therapy is the oxidative modification hypothesis, or oxidative modification of LDL hypothesis advocated by Steinberg et al.14 Simply stated, the hypothesis assumes that unoxidized LDL is not very harmful, as the apolipoprotein B receptors of the cells are saturable. However, once the LDL apolipoprotein B proteins are altered by oxidation, they are not recognized by the LDL receptors but are taken up by scavenger receptors, and the scavenger receptors are not saturable. Cells with scavenger receptors become overloaded with LDL cholesterol and become foam cells, the hallmark of atherosclerotic lesions. If the oxidative modification hypothesis were true, logically one would not have to worry about cholesterol intake or cholesterol levels if one took enough antioxidants. Thus, the current antioxidant megavitamin regimens. The problem is that the oxidative modification hypothesis of atherosclerosis is just a hypothesis and may not be correct. Bhakdi15 and others16 from Mainz, Germany, have made a series of observations that call into question the entire oxidative modification hypothesis of atherogenesis. These investigators have found several problems with the oxidized LDL hypothesis. They found that atherosclerotic plaques contain a very small amount of oxidized LDL, but contain large amounts of activated complement and enzymatically altered LDL.16 This immune complex alteration of LDL is compatible with all of the known observations of the pathogenesis of atherosclerosis, including uptake of enzymatically modified LDL by scavenger receptors. If these new studies are correct, the entire basis of antioxidant therapy lacks scientific support. The major limitation of alternative medicine is that it is based on theory, hearsay, and hope, but not fact. The "scientific" studies that support many of alternative therapies are observational and do not stand up to scientific rigor. Alternative medicine is seductive, however, in that it promises empowerment of the individual—an approach that is even more attractive as our health care systems become more expensive, more technological, and more impersonal. It is ironic that patients want the best and most scientifically proven therapy when they are ill with serious diseases, yet trust their health to salespeople at the local health food store, magazines, newspaper, radio and television testimonials or commercials, recommendations from "alternative medicine authorities," and some health resorts. Prevention is too important not to be under the auspices of the scientific medical profession. The cholesterol hypothesis of atherosclerosis is no longer a hypothesis, but a fact. The oxidative modification of LDL cholesterol hypothesis is still just that—a yet-to-be-proven hypothesis. The evidence that lowering LDL cholesterol with a statin decreases the complications of coronary artery disease is overwhelming. Antioxidant therapy is far from proven, yet many individuals are taking antioxidants, thinking that they are protecting themselves from the ravages of atherosclerosis and not taking therapy that has been proven to be beneficial; they are painting the walls without treating the termites. References 1. The Scandinavian Simvastatin Survival Study Group, Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;3441383- 1389Google Scholar 2. Sacks FMPfeffer MAMoye LA et al. Cholesterol and Recurrent Events Trial Investigators, The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;3351001- 1009Google ScholarCrossref 3. Shepherd JCobbe SMFord I et al. West of Scotland Coronary Prevention Study Group, Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995;3331301- 1307Google ScholarCrossref 4. Downs JRClearfield MWeis S et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA. 1998;2741615- 1622Google ScholarCrossref 5. McCormick LSBlack DMWaters DBrown WVPitt BAVERT Investigators, Rationale, design, and baseline characteristics of a trial comparing aggressive lipid lowering with atorvastatin versus revascularization treatments (AVERT). Am J Cardiol. 1997;801130- 1133Google ScholarCrossref 6. Pitt BWaters DBrown V et al. Results of the Atrovastatin Versus Revascularization Treatments (AVERT) Study: an 18-month study of aggressive lipid lowering in patients with stable coronary artery disease indicated for a catheter-based revascularization (CR) [abstract]. Circulation. 1998;98I- 636Google ScholarCrossref 7. Hansson LZanchetti ACarruthers SG et al. HOT Study Group, Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1998;3511755- 1762Google ScholarCrossref 8. Spencer APCarson DSCrouch MA Vitamin E and coronary artery disease. Arch Intern Med. 1999;1591313- 1320Google ScholarCrossref 9. Stephens NGParsons ASchofield PMKelly FCheeseman KMitchinson MJ Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet. 1996;347781- 786Google ScholarCrossref 10. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group, The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med. 1994;3301029- 1035Google ScholarCrossref 11. Omenn GSGoodman GEThornquist MD et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996;3341150- 1155Google ScholarCrossref 12. Hennekens CHBuring JEManson JE et al. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med. 1996;3341145- 1149Google ScholarCrossref 13. Rowe PM Beta-carotene takes a collective beating [editorial]. Lancet. 1996;347249Google ScholarCrossref 14. Steinberg DParthasarathy SCarew TEKhoo JCWitztum JL Beyond cholesterol: modification of low density liporotein that increase its atherogenicity. N Engl J Med. 1998;320915- 924Google Scholar 15. Bhakdi S An alternative hypothesis of the pathogenesis of atherosclerosis. Herz. 1998;23163- 167Google ScholarCrossref 16. Torzewski MKlouche MHock J et al. Immunohistochemical demonstration of enzymatically modified human LDL and its colocalization with the terminal complement complex in early atherosclerotic lesions. Atheroscler Thromb Vasc Biol. 1998;18369- 378Google ScholarCrossref

Goldberger, Jeffrey J.

doi: 10.1001/archinte.159.12.1281pmid: 10386504

Abstract Tremendous strides have been made in recent years in the treatment and prevention of sudden cardiac death. Large scale trials have now established several interventions that may improve survival in patients susceptible to sudden cardiac death. In patients who have had a sustained ventricular tachyarrhythmia, the current therapy of choice is an implantable cardioverter defibrillator. For prophylaxis of sudden cardiac death in patients without a previous event, several approaches should be considered. β-Adrenergic blocking agents are an effective pharmacologic therapy in patients following myocardial infarction, and their efficacy has also most recently been demonstrated in patients with congestive heart failure. There is no Vaughan Williams class I or III antiarrhythmic drug that has demonstrated efficacy as a prophylactic agent to reduce mortality in these populations, with the possible exception of amiodarone. The best therapeutic approach for prophylactic therapy to prevent sudden cardiac death appears to be the implantable cardioverter defibrillator; however, its use can be justified only in patients at high risk for developing sudden cardiac death. Further work is needed to identify the high risk populations in which this therapy is warranted. The problem of sudden cardiac death has commanded the attention of the medical community. In its classic depiction, a patient who has been clinically stable dies unexpectedly either during sleep or within a short time after the onset of terminal symptoms. Frequently, the cause of such an event is an arrhythmia; timely treatment may prevent death. Because adequate treatment is rarely readily available, the survival rate from a sudden cardiac death episode is dismal. Thus, tremendous efforts have been expended along 2 fronts. First, effective treatment strategies need to be identified that prevent episodes in patients who are known to be at high risk for sudden cardiac death (such as those with previously documented episodes). Second, it would be ideal to identify the high-risk populations who should be treated before an episode of sudden cardiac death occurs. Although many early therapeutic studies have been disappointing, recent clinical studies have charted a favorable course in this field. This review will summarize the advances made in the therapeutic approach to these patients and the identification of appropriate patients in whom to consider these approaches. Whereas many of the recent large-scale studies have been criticized for various pitfalls, when viewed as pieces of a larger puzzle, they provide a perceptibly clearer image of how to deal with the problem than has been available in the past. This review will present a coherent summary of the lessons learned from these trials. Because most of the patients at risk have coronary artery disease, most studies have focused on this subgroup. Thus, the best information available is on the treatment and prevention of sudden cardiac death in patients with coronary artery disease. Background About 400,000 episodes of sudden cardiac death occur per year in the United States. Less than 20% of these are due to acute transmural myocardial infarction (MI).1,2 Although myocardial ischemia may be an important precipitant for sudden cardiac death, a substantial fraction of cases likely result from reversible arrhythmia. Several studies3,4 have addressed the precision of the diagnosis of sudden cardiac death. Despite expert classification, the mechanism of sudden cardiac death is not always arrhythmia. Pratt et al3 evaluated autopsy findings and the results of interrogating implantable defibrillators in 17 patients classified clinically as having had sudden cardiac death. Seven patients had autopsy-proven nonarrhythmic causes of sudden cardiac death, and only 7 had any evidence of a defibrillator discharge (indicating a detected tachycardia) near the time of death. Thus, the classification "sudden cardiac death" encompasses diverse causes, including arrhythmias. For this reason, recent studies have focused on the end point of total mortality. Where possible, I will also highlight total mortality. Because no placebo-controlled trials have been done of the treatment of patients with a history of sudden cardiac death, the literature has to be examined carefully to identify appropriate benchmarks against which to measure the success of interventions designed to prevent recurrent sudden cardiac death. Cobb et al2 reported on the survival of patients who were successfully resuscitated from out-of-hospital ventricular fibrillation. These patients received either no therapy or empiric medical therapy. The authors noted a 1-year mortality of 32% and a 2-year mortality of 47% in patients who had no evidence of myocardial necrosis associated with their episode of ventricular fibrillation; presumably in these patients, the out-of-hospital ventricular fibrillation was primarily arrhythmic. The mortality in this subgroup of patients was similar to that noted in the larger group of patients who did not have an acute transmural MI on electrocardiography. Of note, at least 60% of these patients had been prescribed an antiarrhythmic medication. This study was done when clinical practice differed from current standards; differences in the use of cardiac medications, such as β-adrenergic blocking agents, may affect survival. In a smaller, more recent study,5 54 patients with clinical sustained ventricular tachyarrhythmias and inducible ventricular tachycardia during electrophysiologic studies were treated with only β-adrenergic blocking agents. The rate of either recurrence or sudden death was approximately 42% at 1 year and 46% at 2 years. It is, therefore, reasonable to estimate the 1-year mortality as 30% and to use this as a benchmark by which strategies to prevent recurrent sudden cardiac death can be measured. Treatment of life-threatening ventricular arrhythmias Given the high recurrence rate following an episode of sudden cardiac death, treatment has been considered mandatory. One approach that has been considered in patients with severe coronary artery disease who have had an episode of ventricular fibrillation is revascularization. Myocardial ischemia may serve as the main precipitant of ventricular fibrillation or may be a contributing factor.6 Because most patients who have had an episode of sudden cardiac death have substantial coronary artery disease, it is critically important to evaluate the clinical scenario to determine whether the primary cause of sudden cardiac death was myocardial ischemia. In a retrospective study7 that described the outcomes of 300 patients with coronary artery disease who had presented with ventricular fibrillation and were treated with an implantable cardioverter defibrillator (ICD), the incidence of appropriate ICD shocks was the same in the group who had undergone concomitant coronary artery bypass grafting as in the group who had not. This suggests that in many patients with ventricular fibrillation, a distinct arrhythmogenic substrate exists, independent of myocardial ischemia, that needs to be addressed therapeutically. The main treatment options for ventricular arrhythmias include empiric medical therapy, Holter-guided medical therapy, electrophysiologic testing–guided medical therapy, ICD, or catheter ablation. Despite its usefulness in many patients, including some with ventricular tachycardia, catheter ablation has not been assessed as a therapeutic strategy to prevent recurrent sudden cardiac death due to lethal ventricular arrhythmias. Because of the high recurrence rate, empiric medical therapy has, in general, been abandoned as an approach to patients with aborted sudden cardiac death. The one agent that has been considered to have some promise as empiric therapy is amiodarone (Table 11,5,8-16). Herre et al8 evaluated 427 patients treated with amiodarone for either sustained ventricular tachycardia or an episode of resuscitated sudden cardiac death not associated with acute MI. They noted a 1-year mortality of about 20% and a 2-year mortality of about 35%. Although this may represent a substantial improvement over historic control groups, the high recurrence rate of arrhythmia—19% at 1 year and 26% at 2 years—suggests that there may be an opportunity for other therapeutic approaches to enhance survival. This concept is supported by the Antiarrhythmics Versus Implantable Defibrillators trial9 in which 1016 patients with hemodynamically significant ventricular tachycardia or ventricular fibrillation were randomly assigned to receive either an ICD or antiarrhythmic drug therapy. Most of the group treated with antiarrhythmic drugs received empiric amiodarone therapy. The 1- and 2-year mortality rates in this group were 17.7% and 25.3%, respectively. The ICD-treated group had a significantly better survival rate. Thus, therapeutic approaches are available, in addition to empiric amiodarone therapy, that can be implemented to improve survival. Regarding the use of other antiarrhythmic drugs for the treatment of ventricular tachyarrhythmias, there are 2 major issues. First, the strategic choice of guiding antiarrhythmic drug therapy by either noninvasive monitoring or invasive electrophysiologic testing has been the subject of considerable debate. The noninvasive monitoring approach includes documentation that the use of an antiarrhythmic drug suppresses a substantial portion of the patient's ventricular ectopy. This has sometimes been supplemented by the documentation of efficacy with the results of a stress test. The invasive approach includes documentation that treatment with an antiarrhythmic drug suppresses the inducibility of sustained ventricular tachycardia with programmed ventricular stimulation. The other important issue affecting the use of antiarrhythmic drugs is the end point considered to identify a drug that would be considered effective. The largest study to directly compare the invasive and noninvasive approaches was the Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM).11 In this study, 486 patients were randomly assigned to receive therapy based on one of the approaches, although each patient was eligible for treatment guided by either approach. In the invasive approach, only 13% of all drug trials resulted in an efficacy rating, and in the noninvasive approach, only 38% of all drug trials resulted in an efficacy rating, suggesting that it is difficult to find an "efficacious" antiarrhythmic drug by either approach. The study revealed similar outcomes in the 2 groups. Further evaluation of the actual outcomes in each of the groups indicates that, using the ESVEM method, neither approach is acceptable; 1-year recurrence rates were 32% to 41% in the 2 groups. Even the use of sotalol hydrochloride, which was identified as the most efficacious of the drugs tested, was associated with a 1-year recurrence rate of 20%.17 As the shortcomings of the ESVEM have been hotly debated, the investigators reanalyzed their data to adjust for some of these critiques, with no significant change in the findings.18 Given the high recurrence rate using both strategies, it is questionable whether either strategy provides adequate control of life-threatening ventricular arrhythmias. The only other randomized study19 to compare these 2 approaches was a small study that demonstrated that electrophysiologic testing–guided therapy is superior to the noninvasive strategy. Although neither Holter-guided nor electrophysiologic testing–guided antiarrhythmic drug therapy may yield optimal results, data suggest that the latter may result in better outcomes under certain conditions ( Table 1). Specifically, focusing on the results of using an antiarrhythmic drug that has been shown by serial electrophysiologic testing12-15 to be effective shows that mortality seems to be significantly reduced. This may be even more pronounced with the use of sotalol. The recurrence rate remains significant, however (Table 1). In addition, another notable drawback to this approach is that a drug that prevents the inducibility of ventricular tachycardia during electrophysiologic testing can be identified in only a fraction of eligible patients. An approach not tested in the ESVEM study is amiodarone therapy guided by electrophysiologic testing. In a study of 100 patients, Horowitz et al20 found no recurrences in 20 patients in whom the inducibility of ventricular tachycardia was suppressed; however, sudden death has been reported in patients who have had no inducible ventricular tachycardia while taking amiodarone.21 Despite promising results with the use of amiodarone, the value of this strategy is likely to be limited because ventricular tachycardia is rendered noninducible with amiodarone in only 10% to 20% of patients,20,21 and large-scale studies8,22-24 have demonstrated a rate of withdrawal from active treatment of 30% to 40% within 5 years. Thus, the overall clinical experience with antiarrhythmic drug therapy for life-threatening ventricular arrhythmias has been disappointing for several possible reasons. First, patients taking these medications are plagued by proarrhythmia—the development of new, potentially life-threatening arrhythmias or aggravation of the underlying arrhythmia. Whereas this occurs in few patients treated with these medications, the patients at highest risk for proarrhythmia are precisely those who are most likely to need treatment of life-threatening ventricular arrhythmias. Another major drawback of medications is that they represent a fixed therapy that must be effective under a wide variety of conditions, such as changes in the underlying substrate, in the autonomic tone, and in coronary perfusion or ischemia. The techniques available to evaluate the efficacy of medications cannot assess all of the effects of these conditions. Finally, the medications may intrinsically have low efficacy for the treatment of life-threatening ventricular arrhythmias. These problems may be difficult to overcome. The ICD has emerged as a promising alternative to antiarrhythmic drug therapy. Although it is not designed to prevent recurrences, it has been highly effective at terminating ventricular tachycardia or fibrillation. Observational studies16 have demonstrated excellent survival in patients with previous sudden cardiac death or ventricular tachycardia treated with an ICD; the 1-year mortality for 1478 patients treated with an epicardial ICD system was 12.2%, and for 1356 patients treated with the less-invasive endocardial system (current preferred approach), the 1-year mortality was 6.9%. Bocker et al14 used a case-control study design to compare the outcomes of patients with coronary artery disease and sustained ventricular tachycardia or fibrillation treated with either an ICD (n=50) or sotalol (n=50). All patients treated with sotalol had inducible sustained ventricular tachyarrhythmias at baseline electrophysiologic testing, but these were not inducible during treatment. Survival in the ICD group was significantly better ( Table 1). Wever et al25 randomly assigned 60 survivors of cardiac arrest to either early ICD implantation or electrophysiologic testing–guided antiarrhythmic drug therapy. Because of the inefficacy of antiarrhythmic drug therapy, only a few patients were treated with this approach, and those who were had a substantial mortality or recurrence rate of 67%. More than half the patients assigned to the antiarrhythmic drug therapy group were ultimately treated with an ICD. In addition to the better outcomes in the ICD group, this group underwent fewer invasive procedures, fewer therapy changes, and had fewer days in a hospital. Thus, the use of ICD was recommended as first-choice therapy for survivors of sudden cardiac death. The lack of large-scale randomized clinical trials comparing the efficacy of ICD therapy with antiarrhythmic drug therapy prompted the Antiarrhythmics Versus Implantable Defibrillators trial.9 In this study, patients with hemodynamically significant ventricular tachycardia or ventricular fibrillation were randomly assigned to either the use of ICD or antiarrhythmic drug therapy. The 2 drugs studied were amiodarone and sotalol. In the antiarrhythmic drug therapy group, however, 356 of 509 patients were considered to have a contraindication to the use of sotalol and were therefore treated empirically with amiodarone. Of the remaining 153 patients, 137 received empiric amiodarone, and only 13 received either Holter- or electrophysiologic testing–guided sotalol therapy. Thus, 97% of the antiarrhythmic drug therapy group was treated with amiodarone. This trial can, therefore, be considered a trial of empiric amiodarone therapy vs ICD therapy. The study demonstrated a 38% reduction in total mortality at 1 year and 25% reductions in years 2 and 3 in the ICD group. The 1- and 2-year mortality rates in the ICD group were 10.7% and 18.4%, respectively. Preliminary results of the Cardiac Arrest Study Hamburg and the Canadian Implantable Defibrillator Study were recently presented. Both studies found significantly improved survival in the ICD group. Thus, these trials have established the ICD as the premier therapy for patients with life-threatening ventricular arrhythmias. Furthermore, ICD therapy should now be the benchmark by which to measure any other therapeutic strategy. As the Antiarrhythmics Versus Implantable Defibrillators study9 compared ICD therapy with that of empiric amiodarone, it is not possible to conclude that ICD therapy is better than amiodarone therapy when efficacy is established by electrophysiologic testing. However, the low rate of efficacy, the need for prolonged hospitalization for drug loading, and the high rate of discontinuation remain significant problems that will limit the widespread applicability of amiodarone in these patients. Sudden cardiac death prophylaxis Having established the therapeutic options in the group at highest risk for sudden cardiac death, it is now reasonable to consider whether there are viable strategies to prevent sudden cardiac death in other patient groups. Given the poor survival of patients with out-of-hospital sudden cardiac death, it is critically important to identify strategies that can be implemented to prevent the initial episode of sudden death. The groups that have been most extensively studied are patients who have had MIs and those with congestive heart failure. Myriad studies have established that various clinical factors can identify subgroups in these populations who are at particularly high risk for sudden cardiac death. Two of these factors have been left ventricular dysfunction and frequent ventricular ectopic activity.26-28 Despite the identification of these factors, therapeutic trials have, in general, been disappointing. Interventions designed to have salutary effects may, in fact, result in excess mortality.29 The possible therapeutic options are similar to those discussed previously and include empiric medical therapy, Holter-guided medical therapy, electrophysiologic testing–guided medical therapy, and the ICD. When considering medical therapy for the prevention of sudden cardiac death, the initial agent of choice should be a β-adrenergic blocking agent. In a meta-analysis30 including more than 53,000 patients, these agents were shown to be associated with a significant improvement in survival in patients following an MI (relative risk reduction, 19%; 95% confidence interval [CI], 13%-25%). β-Adrenergic blocking agents are also emerging as important agents in patients with congestive heart failure31; in this group, carvedilol—a new nonselective β-adrenergic blocking agent and α1-receptor blocker, has been shown to reduce mortality. Given the demonstrated efficacy of β-adrenergic blocking agents, it is important to consider whether treatment with β-adrenergic blocking agents is enough for the prophylaxis of sudden cardiac death. No data are available to answer this question adequately, but some data are available on the efficacy of β-adrenergic blocking agents in patients with ventricular tachycardia. Steinbeck et al5 randomly assigned 115 patients with ventricular tachycardia to receive β-adrenergic blocking agent therapy or electrophysiologic testing–guided therapy. Although the overall results for the 2 groups were similar, the 1-year recurrence or sudden death rate in the group that received β-adrenergic blocking agents exceeded 40%. Furthermore, this was significantly greater than the recurrence or sudden death rate (10% at 1 year) noted in patients treated with an antiarrhythmic drug proved to be efficacious by electrophysiologic testing. This suggests that there is considerable room for improvement in the treatment of serious ventricular arrhythmias beyond what can be achieved with β-adrenergic blocking agents. In addition, in both the European Myocardial Infarct Amiodarone Trial22 and Canadian Amiodarone Myocardial Infarction Arrhythmic Trial,23 there appeared to be an interaction between the use of β-adrenergic blocking agents and amiodarone; amiodarone therapy appeared to have a greater effect on reducing mortality in those patients taking β-adrenergic blocking agents. This, again, supports the concept that therapeutic options can be added to β-adrenergic blocking agents to reduce mortality due to tachyarrhythmias. Given the important role of β-adrenergic blocking agents in reducing mortality, it is important to consider how the choice of additional therapies affects the use of β-adrenergic blocking agents. For example, in the Antiarrhythmics Versus Implantable Defibrillators trial,9 more patients in the ICD group than in the antiarrhythmic drug therapy group were taking β-adrenergic blocking agents. Because of the strong evidence that frequent ventricular ectopy is associated with an increased risk of sudden cardiac death, the use of antiarrhythmic drug therapy to suppress ventricular ectopy in patients with a history of MI was widespread. The Cardiac Arrhythmia Suppression Trial29 definitively demonstrated that not only is this strategy ineffective it is also dangerous. Patients treated with antiarrhythmic drugs that were effective in suppressing their ventricular ectopy had an increased mortality compared with patients given placebo (relative risk, 2.5). Combined results30 of multiple studies of Vaughan Williams class I antiarrhythmic agents used following MI have confirmed this. The Survival With Oral D-Sotalol trial32 evaluating the class III antiarrhythmic drug, sotalol, had similar findings. The only agent that has demonstrated some promise as a prophylactic agent following MI is amiodarone. In a compilation of several studies,30 there was a survival benefit, albeit with wide confidence intervals (relative risk reduction, 29%; 95% CI, 3%-49%). The recent European Myocardial Infarct Amiodarone Trial22 and Canadian Amiodarone Myocardial Infarction Arrhythmic Trial23 have shed further light on this question. Both studies evaluated the prophylactic use of amiodarone following an MI, the former using an ejection fraction criterion for entry and the latter using a ventricular ectopy criterion for entry. In both trials, despite a reduction in the combined end points of resuscitated cardiac arrest and arrhythmia mortality, no differences in total mortality were noted between the group receiving placebo and the one receiving amiodarone. A meta-analysis24 of all trials of amiodarone therapy was recently performed that included 5101 patients who had had an MI and 1452 patients with congestive heart failure. With one type of analytic approach, there was a 13% reduction in the relative risk for total mortality (95% CI, 1%-22%) in favor of amiodarone therapy. This was due to a 29% reduction in the relative risk for arrhythmic or sudden death (95% CI, 15%-41%) in favor of amiodarone. Using a more conservative analytic approach, however, only a trend remained for a reduction in total mortality (15% reduction; P=.08). Furthermore, when the patients who had had an MI and those who had congestive heart failure were evaluated in subgroup analyses, no significant reduction in total mortality was noted in the subgroup who had had an MI. In this subgroup, there was a 35% reduction in the relative risk for arrhythmic or sudden death (95% CI, 16%-50% in favor of amiodarone). In the subgroup with congestive heart failure, there was a 17% reduction in total mortality (95% CI, 1%-30%). Thus, amiodarone use may be associated with a mild protective effect, but the magnitude of its effect is unclear. Clearly, however, its use does not increase mortality—an important consideration in the use of antiarrhythmic drugs in these patients. A large-scale trial of antiarrhythmic drug therapy guided by electrophysiologic test results in patients who have not previously had ventricular tachycardia or fibrillation has not yet been completed. Early studies33-36 have suggested that the inducibility of ventricular tachycardia in patients without previous sustained ventricular tachycardia or syncope identifies a high-risk population for the development of ventricular tachycardia or sudden cardiac death. Furthermore, antiarrhythmic drug therapy guided by the results of electrophysiologic testing has been suggested to be beneficial. Data to support this therapeutic approach are insufficient, however. Several factors have propelled the ICD to the forefront of prophylactic therapy to prevent sudden cardiac death. These include the technological achievements allowing the ICD to be implanted transvenously in the pectoral area and the clinical success of the device in the higher risk patients with a previous episode of a life-threatening ventricular arrhythmia. The Multicenter Automatic Defibrillator Implantation Trial (MADIT)37 was the first large-scale randomized trial to evaluate the concept of prophylactic ICDs. For inclusion, patients had to have an ejection fraction of less than 36%, nonsustained ventricular tachycardia, and inducible ventricular tachycardia that was not suppressed with the use of procainamide hydrochloride. Patients were randomly assigned to receive either an ICD or other therapy directed by their physician; in most patients (74 of 93 one month after enrollment), this was amiodarone. In this subset of patients, the ICD group had a substantially lower mortality (hazard ratio, 0.46; 1-year survival of approximately 96% vs 76%). Although there have been several important critiques of this study, it nevertheless establishes the ICD as a benchmark by which other options may be measured. Another recently completed trial is the Coronary Artery Bypass Graft Patch study38 in which patients with coronary artery disease, an ejection fraction of less than 36%, and an abnormal signal-averaged electrocardiogram at the time of coronary artery bypass surgery were randomly assigned to an ICD or no therapy. In this trial, the 2 groups had no significant difference in survival. The 1-year survival was approximately 87%. Of particular interest, the probability of a first shock in the cardiac defibrillator group was approximately 50% at 1 year, a finding that is similar to that published in the MADIT.37 The fraction of these shocks that were appropriate—ie, used for the treatment of ventricular tachycardia or fibrillation—is unknown. Inappropriate shocks for supraventricular arrhythmias, such as those given following cardiac surgery, may account for a substantial portion of these shocks. There are several explanations for the divergent findings of the MADIT37 and the Coronary Artery Bypass Graft Patch study.38 First, the test used to identify a high-risk population differed between the studies. It is possible that inducible ventricular tachycardia at electrophysiologic study is a better test for identifying patients at risk for life-threatening ventricular arrhythmias than signal-averaged electrocardiography. Next, coronary artery bypass surgery may reduce the incidence of ischemia, which may be an important trigger for ventricular tachyarrhythmias in these patients; thus, the benefit of ICD therapy may be delayed until ischemia resurfaces. Although there may be multiple explanations for the divergent findings of these 2 studies, the most appropriate conclusion is that the Coronary Artery Bypass Graft Patch trial did not select a population at high enough risk to demonstrate a benefit of intervention with an ICD. Several other large-scale ICD trials are in progress that should shed further light on which populations may benefit from this therapy. The MADIT investigators39 recently reported the cost-effectiveness of the ICD in that trial. The cost of the defibrillator was about $20,000, with a total cost for the initial hospital stay in the ICD group of about $45,000. This compared with a total cost of about $19,000 in the conventional therapy group. The incremental cost-effectiveness ratio for the ICD group was $27,000 per life-year saved, which is similar to the cost-effectiveness of ICD therapy reported in other studies.40,41 Figure 1 demonstrates the current role of the ICD. There is clearly a continuum of patients in whom the probability of sudden cardiac death steadily increases. When this probability crosses a certain threshold, the risk-benefit ratio and cost-effectiveness of ICD implantation become favorable. The goal for the next few years is to better define the appropriate level of risk within the shaded area that justifies implanting an ICD. This will be determined by the relative risks, benefits, and costs of implanting this device. Conclusions For many years, there has been much frustration among physicians and investigators involved in the treatment and prevention of sudden cardiac death. Tremendous strides have been made in the past several years in this area. Large-scale trials have now established several interventions that may improve survival in patients susceptible to sudden cardiac death. In patients who have had a sustained ventricular tachyarrhythmia, the current therapy of choice is an ICD. For the prophylaxis of sudden cardiac death in patients without a previous event, several approaches should be considered. It has become increasingly clear that β-adrenergic blocking agents are an effective pharmacologic therapy in patients following MI and in patients with congestive heart failure and that, when possible, they should be used. No class I or III antiarrhythmic drug has demonstrated efficacy as a prophylactic agent to reduce mortality in these populations, with the possible exception of amiodarone. The best therapeutic approach for prophylactic therapy against sudden cardiac death appears to be the ICD; however, its use can be justified only in patients at high risk for this event. New strategies and approaches may be developed to target drug therapy in specific populations using either a current or newly developed antiarrhythmic drug. Given the efficacy of the ICD and the low morbidity and mortality rate from implantation, any new approach to treat high-risk populations should be compared with the ICD. Finally, further work is needed to identify the high-risk patients in whom therapy is warranted. Accepted for publication October 8, 1998. Corresponding author: Jeffrey J. Goldberger, MD, Northwestern Memorial Hospital, Wesley Pavilion, 250 E Superior St, Suite 520, Chicago, IL 60611 (e-mail: [email protected]). References 1. Baum RSAlvarez H IIICobb LA Survival after resuscitation from out-of-hospital ventricular fibrillation. Circulation. 1974;501231- 1235Google ScholarCrossref 2. Cobb LABaum RSAlvarez H IIISchaffer WA Resuscitation from out-of-hospital ventricular fibrillation: 4 years' follow-up. Circulation. 1975;52(suppl)III223- III235Google Scholar 3. Pratt CMGreenway PSSchoenfeld MHHibben MLReiffel JA Exploration of the precision of classifying sudden cardiac death: implications for the interpretation of clinical trials. Circulation. 1996;93519- 524Google ScholarCrossref 4. Epstein ACarlson MFogoros RHiggins SVenditti F Classification of death in antiarrhythmia trials. J Am Coll Cardiol. 1996;27433- 442Google ScholarCrossref 5. Steinbeck GAndresen DBach P et al. A comparison of electrophysiologically guided antiarrhythmic drug therapy with beta-blocker therapy in patients with symptomatic, sustained ventricular tachyarrhythmias. N Engl J Med. 1992;327987- 992Google ScholarCrossref 6. Wiesfeld ACCrijns HJHillege HLTuininga YSLie KL The clinical significance of coronary anatomy in post-infarct patients with late sustained ventricular tachycardia or ventricular fibrillation. Eur Heart J. 1995;16818- 824Google Scholar 7. Lessmeier TJLehmann MHSteinman RT et al. Implantable cardioverter-defibrillator therapy in 300 patients with coronary artery disease presenting exclusively with ventricular fibrillation. Am Heart J. 1994;128211- 218Google ScholarCrossref 8. Herre JMSauve MJMalone P et al. Long-term results of amiodarone therapy in patients with recurrent sustained ventricular tachycardia or ventricular fibrillation. J Am Coll Cardiol. 1989;13442- 449Google ScholarCrossref 9. Antiarrhythmics Versus Implantable Defibrillators Investigators, A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. N Engl J Med. 1997;3371576- 1583Google ScholarCrossref 10. Myers MPeter TWeiss D et al. Benefit and risks of long-term amiodarone therapy for sustained ventricular tachycardia/fibrillation: minimum of three-year follow-up in 145 patients. Am Heart J. 1990;1198- 14Google ScholarCrossref 11. Mason JW A comparison of electrophysiologic testing with Holter monitoring to predict antiarrhythmic-drug efficacy for ventricular tachyarrhythmias: Electrophysiologic Study Versus Electrocardiographic Monitoring Investigators. N Engl J Med. 1993;329445- 451Google ScholarCrossref 12. Mitchell LBSheldon RSGillis AM et al. Definition of predicted effective antiarrhythmic drug therapy for ventricular tachyarrhythmias by the electrophysiologic study approach: randomized comparison of patient response criteria. J Am Coll Cardiol. 1997;301346- 1353Google ScholarCrossref 13. Wilber DJGaran HFinkelstein D et al. Out-of-hospital cardiac arrest: use of electrophysiologic testing in the prediction of long-term outcome. N Engl J Med. 1988;31819- 24Google ScholarCrossref 14. Bocker DHaverkamp WBlock MBorggrefe MHammel DBreithardt G Comparison of D,L-sotalol and implantable defibrillators for treatment of sustained ventricular tachycardia or fibrillation in patients with coronary artery disease. Circulation. 1996;94151- 157Google ScholarCrossref 15. Haverkamp WMartinez-Rubio AHief C et al. Efficacy and safety of D,L-sotalol in patients with ventricular tachycardia and in survivors of cardiac arrest. J Am Coll Cardiol. 1997;30487- 495Google ScholarCrossref 16. Zipes DRoberts D Results of the international study of the implantable pacemaker cardioverter-defibrillator. Circulation. 1995;9259- 65Google ScholarCrossref 17. Mason JW A comparison of seven antiarrhythmic drugs in patients with ventricular tachyarrhythmias: Electrophysiologic Study Versus Electrocardiographic Monitoring Investigators. N Engl J Med. 1993;329452- 458Google ScholarCrossref 18. Reiffel JAReiter MJFreedman RA et al. Influence of Holter monitor and electrophysiologic study methods and efficacy criteria on the outcome of patients with ventricular tachycardia and ventricular fibrillation in the ESVEM trial. Prog Cardiovasc Dis. 1996;38359- 370Google ScholarCrossref 19. Mitchell LBDuff HJManyari DEWyse DG A randomized clinical trial of the noninvasive and invasive approaches to drug therapy of ventricular tachycardia. N Engl J Med. 1987;3171681- 1687Google ScholarCrossref 20. Horowitz LNGreenspan AMSpielman SR et al. Usefulness of electrophysiologic testing in evaluation of amiodarone therapy for sustained ventricular tachyarrhythmias associated with coronary heart disease. Am J Cardiol. 1985;55367- 371Google ScholarCrossref 21. Weinberg BAMiles WMKlein LS et al. Five-year follow-up of 589 patients treated with amiodarone. Am Heart J. 1993;125109- 120Google ScholarCrossref 22. Julian DGCamm AJFrangin G et al. Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT: European Myocardial Infarct Amiodarone Trial Investigators [published corrections appeared in Lancet. 1997;349:1180; 1776]. Lancet. 1997;349667- 674Google ScholarCrossref 23. Cairns JAConnolly SJRoberts RGent M Randomised trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarisations: CAMIAT: Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Investigators [published correction appears in Lancet. 1997;349:1776]. Lancet. 1997;349675- 682Google ScholarCrossref 24. Connolly SJCairns JAGent MRoberts RYusuf S Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: meta-analysis of individual data from 6500 patients in randomised trials. Lancet. 1997;3501417- 1424Google ScholarCrossref 25. Wever EFHauer RNvan Capelle FL et al. Randomized study of implantable defibrillator as first-choice therapy versus conventional strategy in postinfarct sudden death survivors. Circulation. 1995;912195- 2203Google ScholarCrossref 26. Multicenter Postinfarction Research Group, Risk stratification and survival after myocardial infarction. N Engl J Med. 1983;309331- 336Google ScholarCrossref 27. Maggioni APZuanetti GFranzosi MG et al. Prevalence and prognostic significance of ventricular arrhythmias after acute myocardial infarction in the fibrinolytic era: GISSI-2 results. Circulation. 1993;87312- 322Google ScholarCrossref 28. Doval HCNul DRGrancelli HOPerrone SVBortman GRCuriel R Randomised trial of low-dose amiodarone in severe congestive heart failure: Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina. Lancet. 1994;344493- 498Google ScholarCrossref 29. Cardiac Arrhythmia Suppression Trial Investigators (CAST), Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med. 1989;321406- 412Google ScholarCrossref 30. Teo KKYusuf SFurberg CD Effects of prophylactic antiarrhythmic drug therapy in acute myocardial infarction: an overview of results from randomized controlled trials. JAMA. 1993;2701589- 1595Google ScholarCrossref 31. Packer MBristow MRCohn JN et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure: U.S. Carvedilol Heart Failure Study Group. N Engl J Med. 1996;3341349- 1355Google ScholarCrossref 32. Waldo ALCamm AJdeRuyter H et al. Effect of D-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction: The SWORD Investigators: Survival With Oral D-Sotalol [published correction appears in Lancet. 1996;348:416]. Lancet. 1996;3487- 12Google ScholarCrossref 33. Wilber DJOlshansky BMoran JFScanlon PJ Electrophysiological testing and nonsustained ventricular tachycardia: use and limitations in patients with coronary artery disease and impaired ventricular function. Circulation. 1990;82350- 358Google ScholarCrossref 34. Gomes JAHariman RIKang PSEl-Sherif NChowdhry ILyons J Programmed electrical stimulation in patients with high-grade ventricular ectopy: electrophysiologic findings and prognosis for survival. Circulation. 1984;7043- 51Google ScholarCrossref 35. Buxton AEMarchlinski FEFlores BTMiller JMDoherty JVJosephson ME Nonsustained ventricular tachycardia in patients with coronary artery disease: role of electrophysiologic study. Circulation. 1987;751178- 1185Google ScholarCrossref 36. Klein RCMachell C Use of electrophysiologic testing in patients with nonsustained ventricular tachycardia: prognostic and therapeutic implications. J Am Coll Cardiol. 1989;14155- 161Google ScholarCrossref 37. Moss AJHall WJCannom DS et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia: Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med. 1996;3351933- 1940Google ScholarCrossref 38. Bigger JT JrCoronary Artery Bypass Graft (CABG) Patch Trial Investigators, Prophylactic use of implanted cardiac defibrillators in patients at high risk for ventricular arrhythmias after coronary-artery bypass graft surgery. N Engl J Med. 1997;3371569- 1575Google ScholarCrossref 39. Mushlin AIHall WJZwanziger J et al. The cost-effectiveness of automatic implantable cardiac defibrillators: results from MADIT: Multicenter Automatic Defibrillator Implantation Trial. Circulation. 1998;972129- 2135Google ScholarCrossref 40. Kupersmith JHogan AGuerrero P et al. Evaluating and improving the cost-effectiveness of the implantable cardioverter-defibrillator. Am Heart J. 1995;130 ((pt 1)) 507- 515Google ScholarCrossref 41. Wever EFHauer RNSchrijvers G et al. Cost-effectiveness of implantable defibrillator as first-choice therapy versus electrophysiologically guided, tiered strategy in postinfarct sudden death survivors: a randomized study. Circulation. 1996;93489- 496Google ScholarCrossref

Snow, Christopher F.

doi: 10.1001/archinte.159.12.1289pmid: 10386505

Abstract At one time, the diagnosis of a deficiency of vitamin B12 or folate was considered to be relatively straightforward. As knowledge has accumulated, the limitations of such tests as serum vitamin level measurements and the Schilling test have become apparent. With the development of newer tests, atypical and subclinical deficiency states have been recognized. In this review, available tests used in the diagnosis of vitamin B12 and folate deficiency are discussed, and a rational approach to the diagnosis of these deficiency states is presented. VITAMIN B12 (COBALAMIN) Strictly speaking, vitamin B12 refers to only cyanocobalamin, but several other Cobalamins have identical nutritional properties, and in the hematology literature, the terms cobalamin (Cbl) and vitamin B12 are used interchangeably. Cobalamin is synthesized by bacteria and is found in soil and in contaminated water. Foods of animal origin (meat, eggs, and milk) are the primary dietary sources. The amount of Cbl in the average Western diet (5-15 µg/d) is more than sufficient to meet the recommended dietary allowance of 2 µg/d. Therefore, except in strict vegetarians, the presence of Cbl deficiency implies the presence of an absorptive problem. The body stores a large amount of Cbl (2-5 mg) relative to daily requirements. Therefore, it takes 2 to 5 years to develop Cbl deficiency even in the presence of severe malabsorption. Table 1 summarizes the steps in Cbl absorption and transport. Folic acid (folate) The term folic acid can designate a specific compound, pteroylglutamic acid, but more commonly it is used as a general term for a class of related compounds (also called folates) with similar nutritional activity. Folates are synthesized by microorganisms and by plants and are widely distributed in the diet. Vegetables, fruits, dairy products, and cereals are the most important sources. Americans ingest an average of 200 to 300 µg/d, which is close to the recommended dietary allowance. Unlike Cbl, the body stores of folate (5-10 mg) are small relative to daily requirements. Table 2 summarizes the steps in folate absorption and distribution. BIOCHEMICAL ASPECTS OF Cbl AND FOLATE DEFICIENCIES In mammals, only 2 Cbl-dependent enzymatic reactions have been identified. One involves the conversion of methylmalonyl–coenzyme A (CoA) to succinyl-CoA using adenosyl-Cbl (Ado-Cbl) as a cofactor ( Figure 1). It can be seen that a deficiency of Cbl will lead to an increase in methylmalonyl-CoA and in its hydrolysis product methylmalonic acid (MMA). The other Cbl-dependent reaction involves the synthesis of methionine from homocysteine (Hcy) using methyl-Cbl as a cofactor (Figure 2). This reaction is believed to be of primary importance in explaining the pathophysiological aspects of Cbl and folate deficiencies. The following points should be noted: A deficiency of either Cbl or folate will impair the production of tetrahydrofolate. In patients with megaloblastic anemia, this causes a defect in DNA synthesis that prevents cell division in the marrow, whereas RNA synthesis and the synthesis of cytoplasmic components remain unaffected. The result is the production of large erythrocytes. In addition, a deficiency of either vitamin will result in accumulation of the substrate Hcy. The production of S-adenosylmethionine (SAM) from methionine is thought to be critical to nervous system function, which probably explains the neuropathic effects of Cbl deficiency. Although it would seem that folate should be required for the production of SAM, neurologic complications are unusual in folate deficiency, probably because the cell has developed alternate mechanisms that preserve the supply of SAM in times of folate deprivation.6 Unlike dietary folate, synthetic folic acid (pteroylglutamic acid) is reduced directly to tetrahydrofolate without the need for Cbl as a cofactor. For this reason, the administration of supplemental amounts of folic acid to a Cbl-deficient patient may correct megaloblastic hematologic changes and still allow neurologic disease to progress. CLINICAL ASPECTS OF Cbl AND FOLATE DEFICIENCY Cobalamin deficiency is usually suspected because of the presence of unexplained anemia, macrocytosis, or neurologic disease. The more common neurologic symptoms are paresthesias, numbness, and ataxia, although dementia and psychosis may occur.7 Although hematologic abnormalities frequently develop before the onset of neurologic disease, more than one quarter of patients with neurologic manifestations of Cbl deficiency have either a normal hematocrit or a normal mean corpuscular volume (MCV); sometimes both values are normal.8 Causes of Cbl deficiency are listed in Table 3. Although pernicious anemia has been considered to be the most common disorder leading to the development of Cbl deficiency, many patients with suspected deficiency in recent series have normal Schilling test results. Controversy exists as to whether these patients represent cases of protein-bound Cbl malabsorption caused by relative achlorhydria (Table 1) or in fact are being incorrectly diagnosed as Cbl deficient in the first place.9,10 Folate deficiency is usually suspected because of the presence of unexplained anemia or macrocytosis. When neuropsychiatric disorders are encountered in folate-deficient patients, they are perhaps more likely to be caused by coexisting Cbl deficiency or other disorders.11 However, there is some evidence that, on occasion, depression, dementia, and other neurologic syndromes may be caused by folate deficiency.12 Causes of folate deficiency are listed in Table 4. SPECIFIC TESTS USED IN THE DIAGNOSIS OF Cbl AND FOLATE DEFICIENCIES Mean Corpuscular Volume Macrocytosis (mean corpuscular volume [MCV] >100 fl) with or without anemia is a common finding in adults undergoing automated complete blood cell counts. Patients with an elevated MCV may have a megaloblastic disorder, defined by the presence of morphologic changes in the bone marrow that reflect defective DNA synthesis, or a nonmegaloblastic disorder. The presence of megaloblastic changes in the marrow usually implies a diagnosis of Cbl or folate deficiency. However, some myelodysplastic disorders are associated with similar morphologic changes, and the administration of zidovudine or of certain chemotherapeutic agents that affect DNA synthesis can induce a megaloblastic marrow. Nonmegaloblastic causes of macrocytosis are listed in Table 5. In patients with either Cbl or folate deficiency, the MCV tends to increase before the hemoglobin level decreases significantly.13,14 However, even when there is biochemical evidence of vitamin deficiency, the MCV often remains within the reference range,15 especially if concurrent iron deficiency or thalassemia is present. The MCV also lacks specificity for the diagnosis of Cbl or folate deficiency. In a study of 100 patients with an MCV greater than 115 fl (much higher than the usual upper limit of the reference range), only 50% had subnormal values of serum Cbl, erythrocyte folate, or both; only an MCV of 130 fl or higher was found to reliably predict the presence of low vitamin levels.16 Peripheral Blood Smear In discussions concerning the evaluation of macrocytic anemia, the importance of examining the peripheral smear is often emphasized.11,17 However, compliance with this recommendation is poor among physicians other than hematologists. To the skilled examiner, a variety of smear findings may provide diagnostic clues. For example, the presence of oval macrocytes suggests a megaloblastic disorder, whereas the presence of stomatocytes is significantly more common among patients with macrocytosis caused by alcoholism than among Cbl-deficient patients.18 The presence of hypersegmented neutrophils has been said to be highly sensitive and specific for the diagnosis of megaloblastic anemia.11,19 For example, in one study20 in which hypersegmentation was defined as the presence of at least 1 neutrophil with 6 lobes or more, the sensitivity of this finding for the diagnosis of megaloblastic anemia was 98%. However, patients in this study had unequivocal megaloblastic changes on bone marrow examination and low serum vitamin concentrations. In more recent studies21,22 of patients with mild Cbl deficiency, the finding of neutrophil hypersegmentation was neither sensitive nor specific. It is doubtful that examination of the smear, especially by physicians other than hematologists, will avoid the need for use of less observer-dependent tests in the evaluation of macrocytic anemia. Serum Cbl Measurement Depending on the technique used in measurement, the lower limit of normal for serum Cbl is variable; usually it is set at about 148 pmol/L (200 pg/mL). Published estimates of the sensitivity and specificity of the test in the diagnosis of Cbl deficiency vary widely. This relates in part to the lack of a consistently defined gold standard for the diagnosis and in part to varying study designs. For example, in considering the sensitivity of the test, one study23 estimated that 90% to 95% of patients with Cbl deficiency had levels of less than 148 pmol/L (200 pg/mL), 5% to 10% had levels of 148 to 221 pmol/L (200-300 pg/mL), and less than 1% had levels greater than 221 pmol/L (300 pg/mL). Patients were considered to be Cbl deficient if they had characteristic clinical features that responded to Cbl therapy, although for some patients follow-up data after therapy were lacking. Because the authors did not systematically evaluate most patients with normal serum Cbl values, they recognized that the 90% to 95% figure for test sensitivity was probably an overestimate. At the other end of the spectrum are prospective studies of elderly outpatients in which elevations of serum and urine metabolite levels (see below) are used as evidence of Cbl deficiency. With this design, only about half of ostensibly Cbl-deficient patients have serum levels below 148 pmol/L (200 pg/mL),24,25 with 14% having levels above 258 pmol/L (350 pg/mL).25 However, there has been concern that the use of metabolite assays as a gold standard for the diagnosis of Cbl deficiency may lead to overdiagnosis and overtreatment.10,26 Causes of falsely normal serum Cbl levels are listed in Table 6. Note that intestinal bacterial overgrowth, a cause of Cbl deficiency, may also cause falsely normal serum Cbl levels because of the production of biologically inactive Cbl analogues by the bacteria.27 The reported specificity of a low serum Cbl level in predicting Cbl deficiency is also variable.28,29 In a study of unselected patients with suspected Cbl deficiency and levels below 148 pmol/L (200 pg/mL), 60% of evaluable patients had a hematologic or neurologic response to parenteral Cbl administration.28 The specificity of a serum Cbl level below 74 pmol/L (100 pg/mL) was 90% in this study. In most cases, the reason for a falsely low serum Cbl is not apparent, although there are recognized causes (Table 6). It is important to note that as many as one third of patients with folate deficiency will have low serum Cbl levels (some with levels <74 pmol/L [100 pg/mL]) that return to normal with folate therapy.14 The mechanism for reduced serum Cbl levels in some folate-deficient patients is poorly understood; this finding is less frequent in alcoholic populations because of the tendency of liver disease to increase serum Cbl levels. If after administration of folate low serum Cbl levels do not return to normal, concurrent Cbl deficiency may be present.30 Serum Folate and Erythrocyte (Red Blood Cell) Folate The lower limit of the reference range for serum folate varies depending on technical factors but is usually set at about 6.8 nmol/L (3 ng/mL). Serum folate levels decrease within a few days of dietary folate restriction,31 although tissue stores may be normal. This is perhaps why serum folate levels are low in about one third of hospitalized patients.32 Serum folate levels increase with feeding, and the use of fasting determinations has been recommended.33 However, the contention that a brief period of adequate feeding will normalize levels in deficient patients has been questioned.34,35 Folate concentrations within erythrocytes are much higher than in serum, and even a slight degree of hemolysis will cause a falsely elevated serum folate level. The sensitivity of serum folate measurement for the diagnosis of clinically significant folate deficiency is uncertain; it is known that in some patients with clear-cut megaloblastic anemia caused by folate deficiency, the serum folate level is normal or only slightly low.35,36 Serum folate measurement is also nonspecific; low levels are often seen in patients without other evidence of deficiency. Alcohol intake in particular may cause a short-term decrease in serum levels in patients with adequate tissue stores (Table 2). Serum folate levels tend to increase in patients with Cbl deficiency, presumably because impairment of the methionine synthetase pathway leads to the accumulation of methyltetrahydrofolate, the principal form of folate in the serum. Serum folate levels are above normal in 20% of patients with pernicious anemia but inexplicably are low in up to 10% of affected patients.32 Because of the limitations of the assay for serum folate, the determination of red blood cell (RBC) folate levels has been advocated as a better measure of folate tissue stores. As noted previously, erythrocytes incorporate folate as they are formed, and levels remain constant throughout the life span of the cell; RBC folate levels are less sensitive to short-term dietary effects than are serum folate levels. In addition, the RBC folate level has been shown to correlate more strongly than the serum folate level with the presence of megaloblastic changes in the peripheral blood smear and bone marrow.37 However, as with serum folate testing, limitations of sensitivity and specificity reduce the value of RBC folate measurement. For example, only 76% of pregnant women38 and 69% of alcoholic persons35 with megaloblastic erythropoiesis believed to be caused by folate deficiency had low RBC folate levels (<340 nmol/L [150 ng/mL]). Most falsely normal values were in the borderline range of 340 to 567 nmol/L (150-250 ng/mL), but values in many patients with normal erythropoiesis also fall within this range. The test also lacked specificity in these studies; 19% of pregnant women and 31% of alcoholics had RBC folate levels less than 340 nmol/L without evidence of megaloblastic erythropoiesis. Although it can be argued that such patients have early folate deficiency, it is difficult to be certain in the absence of a well-defined gold standard for the diagnosis. An important cause of falsely low RBC folate levels is Cbl deficiency; 60% of patients with pernicious anemia have low RBC folate levels,32 presumably because Cbl is required for the normal transfer of methyltetrahydrofolate from plasma to cells.39 Most studies of the performance of RBC folate measurement have used microbiologic assays that are no longer available in clinical laboratories today; instead, the same radioassays used for serum Cbl and serum folate measurement are used to determine RBC folate concentration. Serious questions have been raised about the reliability of these isotopic methods for determination of RBC folate, and one recent review recommended against their use in diagnostic testing.14 Methylmalonic Acid and Homocysteine The use of metabolite measurements for the diagnosis, confirmation, and differentiation of Cbl and folate deficiencies has been made possible by the development of accurate assays for serum and urine MMA and serum Hcy. As discussed previously, elevations of both metabolite levels are anticipated in patients with Cbl deficiency, whereas only Hcy levels would be expected to increase in patients with folate deficiency. Factors other than Cbl or folate status can increase serum MMA levels ( Table 7). Renal insufficiency causes serum levels of both metabolites to increase, although the elevations are typically modest compared with those caused by Cbl deficiency.36 Antibiotic drug therapy–related reductions in bowel flora may decrease the serum MMA level. Measurement of urinary MMA levels adjusted for creatinine excretion may be a useful alternative to serum MMA measurement, especially for patients with renal disease.24 Serum MMA and Hcy levels also increase with age, although this may be caused by an increased prevalence of subclinical vitamin deficiency in the elderly.40 The reference range for these tests is variable depending on the laboratory. Serum MMA and Hcy measurement seems to be sensitive for the diagnosis of Cbl deficiency. In a study28 using a response to Cbl therapy as evidence of deficiency, 86% of Cbl-responsive patients had elevated levels of MMA and 85% had elevated levels of Hcy; 94% had elevated levels of at least 1 serum metabolite. Data from another study36 that looked at the sensitivity of metabolite tests in the diagnosis of Cbl and folate deficiencies are summarized in Table 8. Patients had either low serum Cbl or low serum folate levels and clinical evidence of deficiency based on hematologic findings or a hematologic response to replacement therapy. Serum MMA and Hcy levels were highly sensitive for the diagnosis of Cbl deficiency, although some patients had elevated levels of only 1 metabolite (usually MMA). The sensitivity of the serum Hcy level for the diagnosis of folate deficiency was somewhat lower. Also, in 15 of 123 patients with folate deficiency, the serum MMA level was elevated. However, 11 of these patients had renal insufficiency and 3 had severe volume depletion, which are known causes of elevated levels of serum MMA. The sensitivity of metabolite measurements for milder deficiency states is uncertain. In Cbl deficiency, it seems likely that elevated levels of serum MMA and Hcy usually precede the development of hematologic abnormalities and reductions in the serum Cbl level.34 One screening study of geriatric outpatients found that 14.5% had serum Cbl levels of 221 pmol/L (300 pg/mL) or less and elevated levels of at least 1 serum metabolite.25 These patients were believed to be Cbl deficient despite the relative absence of hematologic or neurologic findings based on their response to Cbl therapy: all treated patients had a marked decrease in metabolite levels, and a significant number had a decrease of 2 fl or more in their MCV. It is difficult to estimate the specificity of metabolite tests for the diagnosis of Cbl or folate deficiency. There are several known causes of false-positive results, especially for serum Hcy ( Table 7). Particularly in the elderly, the prevalence of an elevated serum MMA or Hcy level is much higher than the prevalence of low serum vitamin levels or of clinically evident vitamin deficiency.25,41 Is this because the tests are nonspecific or because subclinical deficiencies of Cbl, folate, and pyridoxine are highly prevalent in older patients? The answer is uncertain, but caution has been urged in the interpretation of elevated metabolite levels in the absence of other evidence of deficiency.10,26 In patients with Cbl or folate deficiency, metabolite levels tend to normalize 7 to 14 days after the onset of replacement therapy.34 As noted previously, treatment-related reductions in levels of serum MMA and Hcy have been equated with evidence of deficiency.25 In addition, it has also been reported that in folate-deficient patients who are inappropriately treated with Cbl, the serum Hcy remains elevated, whereas in Cbl-deficient patients who are inappropriately treated with folate, the serum MMA level remains elevated.42 Therefore, measurement of metabolite levels before and after initiation of treatment has been proposed as a means of distinguishing Cbl deficiency from folate deficiency in cases in which both serum vitamin levels are low. However, other reports43,44 suggest that normalization of metabolite levels after initiation of folate and Cbl supplement use is a nonspecific response that may occur in nondeficient subjects. Antiparietal Cell and Anti–Intrinsic Factor Antibodies A variety of autoantibodies can be detected in serum samples from patients with pernicious anemia, including antibodies to gastric parietal cells and to intrinsic factor (IF). Antiparietal cell antibodies may have a causative role in the autoimmune gastritis of pernicious anemia45 and are present in about 85% of affected patients.32,46 Antiparietal cell antibodies are nonspecific; they are often present in patients with autoimmune endocrinopathies and are present in 3% to 10% of healthy persons, depending on age.47 Compared with the antiparietal cell assay, the anti–IF antibody test is relatively insensitive; only about half of the patients with pernicious anemia have detectable anti-IF antibody.32,48 However, anti-IF antibody is highly specific; it is rarely present in healthy patients or in patients with other autoimmune disorders,11 although it may be detected in some patients with Graves disease. In such cases, a nonprogressive atrophic gastritis (with normal production of IF) has been described.49 Schilling Test The Schilling test is used in patients with Cbl deficiency to document defects in absorption of the orally administered vitamin. In the stage 1 test, a dose of crystalline Cbl labeled with radioactive cobalt is given by mouth, and the subsequent percentage of ingested radiolabeled Cbl excreted during 24-hour urine collection is measured. If the results of the first stage of the Schilling test are abnormal, a second stage is performed 3 to 7 days later, using oral administration of labeled Cbl and IF. Possible interpretations of the results of the Schilling test are listed in Table 9. It is important to note the following: With a partial deficiency of IF or gastric hypochlorhydria, there may be sufficient absorption of the crystalline Cbl administered in stage 1 to yield a normal result, although malabsorption of dietary Cbl may be present. A significant percentage of patients with pernicious anemia may malabsorb the Cbl-IF complex (resulting in an abnormal stage 2 test result) because of ileal dysfunction, which is induced by Cbl deficiency and reversible with prolonged Cbl administration.50 However, in this setting it is likely that the stage 2 result would increase compared with the stage 1 result, even if still abnormal. Inadequate urine collection is a significant cause of falsely abnormal Schilling test results,51 particularly if the urine aliquot produced 8 to 12 hours after administration of the radiolabeled Cbl is lost. Renal insufficiency may delay excretion of the labeled Cbl and cause falsely abnormal results; extending urine collection for an additional 24 hours or measuring radiolabeled Cbl in plasma samples may be required to document normal absorption of Cbl.11,52 A variation of the standard Schilling test is the dual isotope (or "single-stage") Schilling test, which combines the stage 1 and stage 2 tests. However, use of this test has been discouraged because of a high rate of indeterminate results compared with the standard protocol.50 Because of its many limitations, the Schilling test is probably overused in the evaluation of Cbl deficiency; often the result does not alter clinical management.9 Arguments in favor of performing the Schilling test (especially if relevant antibody tests are negative) include the ability to confirm a diagnosis of pernicious anemia, which may affect the risk of the development of other autoimmune disorders and some cancers, and the occasional ability to diagnose occult intestinal or pancreatic disease. Also, a normal Schilling test result, which may indicate dietary deficiency or protein-bound Cbl malabsorption, increases the likelihood of successful oral Cbl replacement therapy. Therapeutic Trials If a trial of therapy is elected as a diagnostic tool, a control period of 7 to 10 days before therapy is started is recommended to ensure stability of the RBC and reticulocyte counts because apparently "spontaneous" hematologic responses may occur without specific therapy.53 In patients with megaloblastic anemia, replacement therapy with the appropriate vitamin will result in an increase in the reticulocyte count in 2 to 3 days, with a peak reticulocyte count in 5 to 8 days.32 The RBC count will increase appreciably within 1 week and will normalize within 4 to 8 weeks.11 Typically, the MCV increases for the first 3 to 4 days (presumably because of reticulocytosis) then begins to decrease, reaching the reference range in 25 to 78 days.54 Several points of caution should be noted: In patients with Cbl or folate deficiency, the response to appropriate therapy may be absent or incomplete if concurrent iron deficiency is present or in the presence of other acute or chronic diseases that impair reticulocyte response. Results of the therapeutic trial may be ambiguous in patients who are only mildly anemic because the degree of the response is proportional to the severity of the anemia. For example, the reticulocyte count peaks at 50% to 70% in patients with an initial RBC count of less than 1×1012/L but only increases to 4% to 9% in patients with an initial RBC count of 3.0 to 3.6×1012/L.32 As discussed earlier, administration of therapeutic doses of folate may correct the hematologic abnormalities of Cbl deficiency and still allow neurologic damage to progress. Although administration of therapeutic doses of Cbl to folate-deficient patients does not usually result in hematologic improvement, it has been reported to do so on occasion.55 Because of this potential for "cross-reactivity" of responses, a therapeutic trial may be of most value if the patient does not respond.14 It has been proposed that the use of small ("physiologic") intramuscular doses of Cbl (3 µg/d) or folate (0.1-0.2 mg/d) can improve the specificity of the therapeutic trial.56 However, low-dose trials are difficult to perform because often the vitamins are not available at the required dosage levels, and concurrent dietary restriction is necessary. In nonanemic patients, a response to therapy of nonhematologic clinical parameters is sometimes cited as evidence of Cbl or folate deficiency despite the often subjective nature of the response. Neurologic disease related to Cbl deficiency may improve within weeks, especially if the symptoms are of short duration.32 In some patients, however, neurologic manifestations will not improve despite appropriate Cbl replacement, although in all cases progression of disease is halted. As discussed previously, in patients suspected of Cbl or folate deficiency who are not anemic (or who have only a mild anemia), measurement of metabolite levels (MMA and Hcy) before and during the therapeutic trial may be useful. Other Tests The fasting serum gastrin level is elevated in 80% to 90% of patients with pernicious anemia.32,57 Levels also tend to be elevated in patients with lesser degrees of gastric atrophy who may have malabsorption of protein-bound Cbl despite a normal Schilling test result. Therefore, the presence of an elevated serum gastrin level may be used as indirect evidence of protein-bound Cbl malabsorption. However, the test has limited sensitivity and specificity when used to detect subclinical gastric abnormalities.58,59 Bone marrow examination is rarely necessary or useful in the diagnosis of Cbl or folate deficiency. In mild deficiency states, it may be hard to identify unequivocal megaloblasts in the marrow.11 For example, in a study8 of nonanemic patients with neurologic abnormalities caused by Cbl deficiency, 2 of 10 marrow smears with evidence of megaloblastic changes were initially read as normoblastic by a consulting hematologist. The test also lacks specificity; as discussed above, "megaloblastoid" changes can be seen in patients with myelodysplastic disorders. Approach to diagnosis in patients with hematologic abnormalities In patients with hematologic findings suggestive of Cbl or folate deficiency, it is reasonable to start the evaluation by measuring serum Cbl and fasting serum folate levels. In patients with at least several days of poor dietary folate intake, one may choose to measure the erythrocyte folate level, although the limitations of radioassays for RBC folate should be kept in mind. Table 10 summarizes the initial diagnostic approach based on serum vitamin levels. Patients with low serum Cbl levels (<74 pmol/L [100 pg/mL]) usually have Cbl deficiency. Figure 3 summarizes the diagnostic approach. Because the serum folate level is more likely to increase than to decrease in patients with Cbl deficiency, patients with low levels of both vitamins are likely to have a mixed deficiency. However, if RBC folate level rather than serum folate level is measured, the finding of low levels of both vitamins may be explained by isolated Cbl deficiency because of the propensity of the RBC folate level to decrease in Cbl-deficient patients. Patients with slightly low or borderline serum Cbl levels (74-221 pmol/L [100-300 pg/mL]) may have Cbl deficiency, but a higher standard of proof is required than for patients with a serum Cbl level of less than 74 pmol/L (100 pg/mL). It is reasonable to order serum MMA and Hcy determinations in this setting and to use the results of the serum folate and metabolite measurements to determine the course of action. Table 11 summarizes the diagnostic approach. If the serum folate level is also low, isolated folate deficiency is a diagnostic consideration because serum Cbl levels tend to decrease in folate-deficient patients. Patients with serum Cbl levels greater than 221 pmol/L (300 pg/mL) are unlikely to be Cbl deficient. If the serum folate level is low, it should be replaced. If the serum folate level is normal or if replacement therapy in a patient with a low serum folate level does not result in hematologic improvement, alternative diagnoses should be sought. If an alternative explanation for the hematologic findings cannot be found, one may consider the measurement of metabolite levels (see previously). If serum MMA or Hcy levels are elevated, a therapeutic trial of vitamin replacement therapy may be undertaken. Approach to diagnosis in patients with isolated neurologic findings As discussed above, patients with Cbl deficiency may have overt neurologic disease in the absence of hematologic findings. Patients with neurologic symptoms and signs and a normal complete blood cell count require a modified diagnostic approach because of several considerations. First, folate deficiency is an unlikely cause of neurologic disease. Second, the neurologic disease of Cbl deficiency may be irreversible if treatment is withheld or delayed; because Cbl therapy is nontoxic, the risk-benefit ratio favors treatment in questionable cases. Finally, an apparent response to therapy (or lack of response to therapy) is less definitive in ruling in or ruling out Cbl deficiency than is the serial measurement of abnormal initial hematologic parameters. Even in patients with a normal complete blood cell count, it may be worthwhile to monitor the MCV after treatment because a significant decline within the normal range provides additional evidence of Cbl deficiency. An approach to the diagnosis of Cbl deficiency in patients with isolated neurologic findings is outlined in Figure 4. Relevant to the development of this algorithm is a study23 of 419 patients with Cbl deficiency, 12 of whom had serum Cbl levels greater than 148 pmol/L (200 pg/mL). All 12 had elevated levels of serum Hcy and serum MMA. Five patients with normal serum Cbl levels had neurologic disease, and 1 of the 5 had a level greater than 221 pmol/L (300 pg/mL). All 5 patients had a clinical neurologic response to Cbl therapy and normalization of metabolite levels. Conclusions The accurate diagnosis of Cbl and folate deficiency is a complex task. No easily performed test can reliably serve as a diagnostic gold standard. Consequently, the performance characteristics of the available laboratory tests are difficult to ascertain. In each case, the primary physician must integrate clinical information, laboratory test results, and response to specific treatment and keep in mind the relative risks and benefits of administering or withholding vitamin replacement therapy. The algorithms in this article should not be considered rigid guides; if diagnostic uncertainty exists, consultation with a hematologist is advisable. Accepted for publication October 1, 1998. I thank Patrick Kearns, MD, and William Grove, MD, for their review of the manuscript and Louise Leprohon for her assistance in the preparation of the manuscript. Corresponding author: Christopher F. Snow, MD, Suite 212, 2400 Moorpark Ave, San Jose, CA 95128. References 1. 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Lee, Francis Y. W.;Mossad, Sherif B.;Adal, Karim A.

doi: 10.1001/archinte.159.12.1301pmid: 10386506

Abstract Pulmonary mucormycosis is relatively uncommon but an important opportunistic fungal infection in immunocompromised persons. The literature on the subject is sparse. We describe a recent case and review the literature to delineate the clinical characteristics of this infection. We searched the MEDLINE database for articles published in the English-language literature since 1970 and carefully analyzed 87 cases. The main risk factors were diabetes mellitus, hematologic cancers, renal insufficiency, and organ transplantation. Several patients had no apparent immune compromise. There was a predilection for involvement of the upper lobes. Air crescent signs on chest x-ray films were predictors of pulmonary hemorrhage and death from hemoptysis. Fiberoptic bronchoscopy was a useful diagnostic method, and histopathologic examination was more sensitive than fungal cultures. The overall survival rate was 44%. Patients treated with a combined medical-surgical approach had a better outcome than patients who did not undergo surgery. Thus, this relatively rare but often fatal disease should be suspected in immunocompromised patients who fail to respond to antibacterial therapy. Early recognition and aggressive management are warranted to maximize chances for cure. Optimal therapy requires systemic antifungal therapy, surgical resection, and, when possible, control of the patient's underlying disease. Pulmonary mucormycosis is a relatively uncommon infection that occurs mostly in immunocompromised persons. The first case of pulmonary mucormycosis was described in 1876 by Furbringer.1 In a classic review in 1971, Baker2 thoroughly describes all cases of mucormycosis previously reported. Since then, only scattered reports have been published, except for a review by Tedder et al,3 who describe 30 patients treated at their institution and 225 additional patients described in the literature. They include many patients with disseminated mucormycosis in their analysis, thus weakening the applicability of their findings and conclusions to isolated pulmonary disease. In this article, we describe an immunocompromised patient with localized pulmonary mucormycosis and review 86 other cases reported in the literature since 1970, when bronchoscopy became widely available. Because a high index of suspicion, earlier diagnosis, and aggressive management, often involving surgical resection, can lead to a cure in selected patients, the goal of our review is to better characterize the population at risk, presenting symptoms, radiological appearance, diagnostic methods, therapy, and outcome. Illustrative case The patient, a 39-year-old white man with a medical history of hypertension, myelodysplastic syndrome, and type 1 diabetes mellitus of 18 years' duration complicated by retinopathy and renal failure, had received a cadaveric renal transplant in 1991. He was seen in the outpatient clinic September 15, 1995, with a 2-week history of sore throat, nonproductive cough, dyspnea on exertion, fever, chills, generalized malaise, and myalgias. Medications at presentation included prednisone, 5 mg daily; cyclosporine, 125 mg twice a day; ofloxacin, 400 mg daily; ferrous polysaccharide; and insulin. On physical examination on admission to the hospital, he had a temperature of 38.4°C, and his lung fields were normal to auscultation. His chest radiograph revealed a new right upper lobe infiltrate that was not present on a radiograph taken 10 days before. His white blood cell count was 4.19×109/L; hemoglobin level, 69 g/L; and platelet count, 52×109/L; with serum levels of urea nitrogen, 9.3 mmol/L (26 mg/dL), and creatinine, 133 µmol/L (1.5 mg/dL). He had defervescence, with lessening of his symptoms, with the administration of intravenous vancomycin and ceftazidime. Blood and sputum cultures remained negative for pathogens. He was discharged from the hospital 4 days later with oral clarithromycin. The patient returned to the emergency department 4 days later with recrudescence of his previous symptoms and pleuritic chest pain. He was again febrile to 38.2°C, with bronchial breath sounds and a localized wheeze heard over the right upper lung. His blood pressure on admission was 132/64 mm Hg; respirations, 20/min; and oxygen saturation, 100% with the patient breathing room air. His chest radiograph revealed persistence of the right upper lobe infiltrate, which now extended to the right hilum, with volume loss and the development of a hilar mass (Figure 1). His white blood cell count was 5.8×109/L with 0.74 neutrophils. The intravenous administration of a combination of ticarcillin and clavulanate, and erythromycin was started. Flexible fiberoptic bronchoscopy performed on day 3 of his second hospital admission revealed narrowing of the anterior and posterior segments of the right upper lobe associated with mucosal edema. Computed tomography of the sinuses revealed no abnormalities. Computed tomography of the chest on the same day revealed right upper lobe consolidation and necrosis extending to the right hilum (Figure 2). The right upper lobe and right main bronchi were both narrowed. A small right pleural effusion was also noted. Cytologic analysis of endobronchial brushings and histological examination of a biopsy specimen revealed broad nonseptate hyphae with right-angle branching, consistent with mucormycosis. His absolute neutrophil cell count fell to 1.02×109/L. A course of intravenous amphotericin B (1 mg/kg of body weight) was initiated that evening. At thoracotomy on September 29, the right main pulmonary artery was found to be invaded by a fungating mass, and a pneumonectomy was performed. Histopathologic analysis of the lung confirmed widespread angioinvasive infection with Mucorales (Figure 3 and Figure 4). The organism grew and was found to be Rhizopus arrhizus. His postoperative course was complicated by a rise in the serum creatinine level to 212 µmol/L (2.4 mg/dL). His amphotericin preparation was changed on October 3 to a colloidal dispersion (Amphotec; 4 mg/kg) to minimize nephrotoxic effects. A nosocomial left lower lobe pneumonia developed that progressed despite broad-spectrum antibiotic therapy, necessitating mechanical ventilation. He died of sepsis on October 9. An autopsy revealed pneumonitis of the left lower lobe, with silver staining failing to show fungi. There was no evidence of disseminated mucor. Methods Our retrospective review focuses on patients with localized pulmonary mucormycosis who did not have evidence of dissemination. Pulmonary mucormycosis was defined as disease localized to the lungs or mediastinum. Disease was defined as disseminated when 2 or more noncontiguous organ systems were involved or blood cultures grew the causative organism. The presence of sinus disease in addition to pulmonary disease was not considered dissemination because it reflected focal involvement of the respiratory tract, and a case of rhinocerebral disease in the presence of pulmonary lesions was accepted only if it was obvious that the cerebral lesion was due to direct extension from the sinuses. The diagnosis was accepted only if it was established by histological or cytologic examination or by a culture positive for the causative organism. We searched the MEDLINE database for articles published in the English-language literature since 1970 using mucormycosis and pulmonary as keywords or text words. We used 1970 as a cutoff because of the year of publication of Baker's article (1971) and because of the introduction of flexible fiberoptic bronchoscopy. Where applicable, we reviewed references cited in the above studies. Care was taken to ensure that the same patient was not included twice in our analysis, as some patients were described more than once in the literature. Incomplete case reports with limited clinical information were not included in our analysis. The data were analyzed with a database program (Reflex 2.0; Borland [now Inprise Corp], Scotts Valley, Calif). Results Eighty-six cases in the literature met our criteria for localized pulmonary mucormycosis without evidence of dissemination, 4-4041-80 leading to a total of 87 cases when our patient's case is added. Demographics and underlying conditions Sixty-five patients were male and 22 were female, for a male-female ratio of 3:0. The mean age was 44 years (range, 2 months to 83 years). The ethnic group was not recorded consistently in the literature, being reported for only 36 of 87 patients, with the following distribution: 16 whites, 10 African Americans, 7 Asians, 2 Hispanics, and 1 Middle Eastern patient. When we analyzed underlying conditions in our study population, the largest group consisted of 49 patients (56%) with diabetes mellitus, of whom 10 (20%) presented with ketoacidosis. The next largest group consisted of 28 patients (32%) with hematologic cancers, of whom 13 (46%) had neutropenia. Of the 28 patients, 17 (61%) had acute leukemia (8 with acute myeloid leukemia, 7 with acute lymphocytic leukemia, and 2 with acute promyelocytic leukemia), whereas 7 (25%) had chronic leukemia (5 with chronic lymphocytic leukemia and 2 with chronic myeloid leukemia), and 1 each had hairy cell leukemia, Hodgkin lymphoma, myelodysplastic syndrome, and agammaglobulinemia. Of the 11 patients (13%) with renal insufficiency, 6 were receiving dialysis. Ten patients (11%) were organ transplant recipients. Of these, 6 received renal transplants, 2 bone marrow transplants, 1 a heart transplant, and 1 a liver transplant. Of note, 8 patients (9%) had metabolic acidosis, including 1 patient with long-term salicylate ingestion, 1 with renal insufficiency, 2 with diabetes mellitus without ketosis, and 2 diabetic patients receiving dialysis. One patient was taking deferoxamine and another was taking iron supplements. Finally, 11 patients (13%) had no apparent underlying illness. Clinical presentation Table 1 summarizes presenting symptoms and physical findings. These were mostly nonspecific. Cough was present in 53 patients (61%) only, and 23 (26%) presented with hemoptysis. The most prominent physical finding was fever in 55 patients (63%). The findings otherwise were sparse, including 8 patients with normal findings on clinical examination. Unusual presentations included 1 patient with superior vena cava obstruction who was found at autopsy to have lung infarcts and invasion of the superior vena cava and pulmonary artery by mucor37 and another patient with cervical lymphadenopathy who died of stridor due to granulomatous and fibrous mediastinitis.48 One patient was seen because of left shoulder pain due to the Pancoast syndrome.67 Two patients were reportedly asymptomatic at presentation.29,54 One had diabetes mellitus and the other did not have an underlying condition. Both had a right upper lobe solitary pulmonary nodule and survived surgical resection of the lesions. We arbitrarily defined onset as acute if symptoms were present for 30 days or less before presentation and chronic if present for more than 30 days. Most patients (68 [78%]) had an acute onset, but a substantial number (16 [18%]) had chronic symptoms. Both groups had similar bacterial coinfection rates (34% vs 29%) and survival rates (44% vs 41%). Microbiologic assessment A total of 59 specimens were submitted to the microbiology laboratory for culture. Only 29 (49%) were positive for the causative organism. Of these, the most common isolates belonged to the genus Rhizopus in 12 patients (41%). Our patient's organism was identified as R arrhizus. Mucor was identified in 7 patients (24%), although it is unclear whether these organisms truly belonged to the genus Mucor or if this was simply a generic designation. Cunninghamella bertholletiae was identified in 6 patients (21%), and in 1 patient, the pathogen was Cunninghamella elegans,45 now reclassified as Apophysomyces elegans. Two patients grew organisms belonging to the genus Absidia and 1 to the genus Syncephalastrum. Coinfection was a feature in 28 patients (32%) only. Of these, 27 had bacterial pneumonia, and 1 patient had Pneumocystis carinii pneumonia.60 All 28 patients had received chemotherapy or steroids for their underlying condition, and 23 patients (82%) presented with acute symptoms. Radiological presentation Table 2 outlines the radiographic manifestations of pulmonary mucormycosis. Most patients (37 [43%]) had involvement of the upper part of the chest, with the right upper lobe (23 patients) more commonly implicated than the left upper lobe (16 patients), followed by the lower part of the chest (21%)—equally divided between right and left lungs (9 patients each)—and, rarely, the middle part of the chest (3 patients). The findings of a chest radiograph were rarely normal: 1 patient had tracheal mucor presenting with stridor,66 another had endobronchial disease with right pulmonary artery involvement at autopsy,77 and a third died of multiple mucor-related pulmonary infarcts.73 Thirty-four patients (39%) were described as having an infiltrate or consolidation, and 23 (26%) had a cavitary lesion. An air crescent sign was described on chest radiograph in 7 patients, all with upper lobe disease. The presence of an air crescent sign seems to be significantly associated with an increased risk for massive hemoptysis. Chest pain, hemoptysis, or both were a feature in 10 patients (43%) with a cavity only on chest radiograph, as opposed to 5 patients (71%) with an air crescent sign, suggesting that the latter may herald the onset of pulmonary infarction and the erosion of pulmonary vessels.34 More specifically, only 1 patient (5%) with a cavity, but 3 patients (43%) with an air crescent sign, died of massive hemoptysis. Pleural effusions seem to be relatively uncommon in pulmonary mucormycosis, with only 7 patients (8%) exhibiting this finding on chest radiograph. One report described only bilateral effusions on chest radiograph, but a computed tomographic scan of the thorax revealed a left lower lobe cavity, illustrating the value of computed tomographic imaging in selected cases.58 Fistulas were uncommon, occurring in 5 patients (6%) only, but they were fatal in 3 of the patients. The types of fistulas described include bronchocutaneous,61 bronchopleural,51,55,74 and bronchoarterial with pseudoaneurysm.16 Diagnosis The most common method used to make the diagnosis of pulmonary mucormycosis in our review was flexible fiberoptic bronchoscopy, which was used in 35 (40%) of 87 patients, and 34 of these had visible endobronchial disease. Our review also confirms the hypothesis of Donahue et al20 that diabetic patients have a predilection for endobronchial disease because the most common predisposing factor was diabetes mellitus in 29 (85%) of these 34 patients. Table 3 outlines the variety of features seen with bronchoscopy in these 34 patients. Stenosis and obstruction were seen in 12 patients (35%). Seventeen patients (20%) required open lung biopsy or surgical resection for diagnosis. Transthoracic needle aspiration and thoracentesis were successfully used for diagnosis in 6 and 3 patients, respectively. Sputum culture was a remarkably insensitive method, leading to the diagnosis in only 2 patients. Direct laryngoscopy was used in a diabetic patient with tracheal mucormycosis who eventually required laryngotracheal resection and primary reanastomosis.66 The diagnosis was made at autopsy in 23 patients. The diagnosis was established by histological examination in 71 (93%) of 76 patients for whom it was done and by cytologic examination in 18 (62%) of 29 patients for whom it was done, whereas cultures were positive for fungi in only 29 (49%) of 59 specimens submitted. In one report,43 "dicing" or homogenizing of the specimen was noted to result in a negative culture result because of the aseptate nature of the fungus. This may explain, at least in part, why fungal cultures provided the lowest yield among the 3 modalities. Therapy and outcome Of the 87 patients, 38 (44%) survived. Twenty-two patients (25%) died of the infection, and 15 (17%) died of massive hemoptysis. The remaining 12 patients (14%) died of unrelated causes. If we exclude deaths unrelated to the fungal infection or hemoptysis, the overall survival rate was 51% (38 of 75 patients). We also looked at the effects of predisposing factors on the outcome (Table 4). Patients with renal insufficiency or metabolic acidosis did the worst, with no survivors. Patients with hematologic conditions had a survival rate of only 25% (7 of 28 patients). Within this group, only 1 (8%) of 13 patients with neutropenia survived, compared with 6 (40%) of 15 patients without neutropenia. Diabetic patients, organ transplant recipients, and patients with no predisposing factors had similar survival rates—between 45% and 60%. Table 5 summarizes the therapeutic choices for all patients in our series and outlines the overall mortality in each group. A total of 55 patients received antifungal therapy, but medical therapy was the only form of treatment in 31 patients. Amphotericin B was used in almost all patients. Seven patients also received an azole. Of the 31 patients receiving medical therapy alone, 17 patients (55%) died: 6 with massive hemoptysis, 7 of overwhelming fungal sepsis, and the remaining 4 of unrelated causes. Thirty patients were treated surgically with or without antifungal therapy, and 3 underwent an adjunctive drainage procedure. Patients who underwent surgery had a mortality of 27%, with 5 of the 8 deaths due to unrelated causes. Twenty-three patients, most of whose diagnosis was made at autopsy, received no specific antifungal therapy or surgery. All but 1 died: 12 of the infection, 8 of massive hemoptysis, and 2 of unrelated causes. Comment The review by Baker2 in 1971 thoroughly describes all cases of mucormycosis previously reported. He reports on 49 cases of primary pulmonary mucormycosis, although, from our criteria, some of these could be classified as disseminated mucormycosis. This leaves 39 patients with mucormycosis limited to the lungs, with a mean age of 44 years (range, 112-72 years). In his series, 24 patients were male and 10 female (5 were not specified), for a male-female ratio of 2.4:1. Hematologic conditions were the most frequent underlying disease, occurring in 18 (46%) of the 39 patients, and 17 of these had leukemia. Eleven patients (28%) were taking steroids, but 10 of these had an underlying hematologic condition. Nine patients (23%) had diabetes mellitus, 6 (15%) had sarcoma or carcinoma, and 4 (10%) had uremia. Only 4 (12%) of 32 patients for whom an outcome is reported were cured. The review by Tedder et al3 in 1994 combines 30 patients treated at their institution with 225 cases from the literature. Again, they do not restrict their review to pulmonary cases and include patients with disseminated disease. We limited our review to patients with localized pulmonary mucormycosis because we thought that it represents a different disease in outcome and therapeutic options. This strengthens the conclusions that can be deduced from such a series, with the recognition, of course, that the retrospective nature of the study has unavoidable inherent limitations, including incomplete data and selection bias in the literature to report successes more than failures. To minimize the former, we limited our series to patients with sufficient data reported. In all 3 reviews, the mean age is in the 40s, and the male-female ratio is between 2.4:1 and 3:1. This preponderance of male patients is difficult to explain, and none of the risk factors explain it. These remain the same over the years, except for the emergence of organ transplantation as a significant underlying predisposing disease. Diabetes mellitus and hematologic cancers continue to lead the list. The finding of 12 patients with no apparent underlying illness was unexpected because mucormycosis has been traditionally considered a disease of immunocompromised patients and suggests that a heightened level of suspicion may be warranted in immunocompetent patients as well. None of the patients in our series or that of Tedder et al3 had the acquired immunodeficiency syndrome. We found only 1 case report81 in the German-language literature of a patient who had diffuse infiltrates and whose condition was diagnosed at autopsy. Patients infected with the human immunodeficiency virus are at risk for infections with Aspergillus species, another angioinvasive fungal disease,82,83 but it is unclear why more cases of mucormycosis have not been reported. Whether this reflects that such patients are not at increased risk for this particular infection or simply that mucormycosis is less common than aspergillosis remains to be determined. The association of mucormycosis with deferoxamine therapy and iron overload states is well recognized, and several such cases have been reported.84-90 Iron availability is critical for the growth of mucor, and when transferrin is saturated with iron and more free iron becomes available to the fungus, the fungistatic capacity of serum is decreased.91 To explain why deferoxamine, an iron chelator, paradoxically increases susceptibility to mucormycosis, it has been hypothesized that the fungi use deferoxamine as a siderophore. The iron chelate of deferoxamine abolishes the fungistatic effect of serum on Rhizopus species and increases the in vitro growth of the fungus, much more than iron alone and more than the effect on Aspergillus species.92 Part of the reason that acidosis increases the susceptibility of the host to mucormycosis may be by temporarily disrupting the capacity of transferrin to bind iron.93 Not surprisingly, the clinical presentation of pulmonary mucormycosis is not specific. The presence of hemoptysis should bring mucormycosis to mind because it is one of the angioinvasive fungi. The chronicity of the symptoms (>30 days) in no way helped rule out mucormycosis, and the duration of symptoms at the time of presentation should not be used to exclude pulmonary mucormycosis from the differential diagnosis in any patient. Similarly, none of the radiological findings were characteristic, although we found a predilection for the upper lobes, a finding not previously described on plain radiography. The presence of an air crescent sign is noteworthy and should increase the urgency of the workup because massive hemoptysis and death were more common in these patients. This sign appears to be a useful diagnostic clue for fungal infection, and aspergillosis and cryptococcosis need to be considered as well.94,95 Computed tomography appears to have some benefit in the diagnosis of angioinvasive fungal infections, especially mucor and Aspergillus species. Jamadar et al96 reviewed the computed tomographic appearance of 8 patients with pulmonary mucormycosis and found a predilection for the upper lobes in 16 (84%) of 19 patients, in agreement with our findings. They also cite cavitation, air crescent sign, halo sign, and rim enhancement as radiological evidence of necrosis in these patients. Noninvasive diagnosis with sputum cultures is difficult to achieve, and, in fact, even when culturing surgical specimens, false-negative culture results can be obtained. This may be due in part to sampling error when highly necrotic tissue is submitted for culture and no viable fungus is present or that the microbiology laboratory usually processes specimens for fungal culture after initially homogenizing the specimen. This dicing decreases the sensitivity of the sputum culture because this microorganism is aseptate and is killed by this process. This is an important concept and reinforces the high level of suspicion that one must have to notify the laboratory when submitting a specimen for appropriate processing. For that purpose, we summarize the various appearances of mucormycosis at bronchoscopy, in the hope of educating our pulmonary and surgical colleagues in that regard. Endobronchial features seen with mucormycosis may provide important clues for selecting the appropriate methods for specimen collection, preparation, and staining. Finally, the high incidence of obstruction may help explain the frequent occurrence of bacterial coinfection, likely due to postobstructive pneumonia. Survival seems to have increased. Substantially more patients are now being diagnosed premortem, which may help explain the better outcome. In Baker's article,2 12% (4/32) of the patients survived. In 1977, Murray97 noted in an editorial that only 6 (9%) of 70 patients with localized pulmonary involvement survived in the first 100 years since the disease was originally described. In our series, 44% of all patients (n=38) survived, and if we exclude patients who died of unrelated causes, this percentage increases to 51% (38 of 75 patients). A premortem diagnosis was made in 62 (71%) of 87 patients. Of these, 38 patients (61%) survived, and, if we exclude deaths unrelated to mucormycosis, we come up with a survival rate of 72%. These figures compare favorably with the data by Tedder et al,3 where there was only a 35% survival in patients with disease confined to the lungs. In both series, renal failure portended a poor outcome, and neutropenia was clearly a predictor of death in our series. As noted by Tedder et al, although not as strikingly as in ours, the survival of patients treated only medically was much worse than for patients who underwent a surgical procedure. These observations have a great potential for bias because patients more fit for surgery and with a better possible outcome may well be the ones undergoing surgery. Despite this, the contrast between the group treated medically alone and the group treated surgically is impressive. Surgical resection is important in the treatment of pulmonary mucor because of the angiocentric nature of the fungus, with its propensity toward invading the pulmonary vasculature, often resulting in massive hemoptysis. Conclusions Pulmonary mucormycosis is a relatively rare disease, but with a growing number of immunosuppressed patients, it may become more common. Maintaining a high level of suspicion is important in any patient in the right clinical setting with a pneumonic process that fails to respond to antibacterial agents, either clinically or radiologically. In some patients, an apparent initial improvement is followed by recrudescence of symptoms shortly after, maybe due to a transient response of a postobstructive bacterial pneumonitis secondary to endobronchial disease. These scenarios should heighten concerns about the possibility of a fungal infection. The diagnosis is rarely obtained by cultures because of processing in microbiology laboratories, and more aggressive bronchoscopic or surgical approaches should be pursued to obtain histopathologic specimens. The presence of an air crescent sign on radiological imaging often portends a poor prognosis if surgical therapy is delayed. 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Spencer, Anne P.;Carson, Deborah Stier;Crouch, Michael A.

doi: 10.1001/archinte.159.12.1313pmid: 10386507

Abstract Various studies have evaluated the antioxidant effects of vitamin E in the prevention or treatment of coronary artery disease (CAD). In vitro data suggest that vitamin E protects against oxidation of low-density lipoprotein and decreases the deposition of atherogenic oxidized low-density lipoprotein in arterial walls. Various observational and epidemiological studies also suggest a relationship between vitamin E serum concentrations or intake and CAD. One prospective, randomized trial suggested that low-dosage vitamin E supplementation (50 IU/d) decreases the risk of angina in patients without previously diagnosed CAD. Another study, using high-dosage vitamin E supplementation (400 or 800 IU/d), demonstrated a decrease in the combined end point of nonfatal myocardial infarction and cardiovascular death in patients with established CAD. Discordant data, however, have been published that imply no cardiovascular benefit of low-dosage vitamin E supplementation (50 IU/d) and detrimental effects if vitamin E is combined with beta carotene. At this point, clinicians should emphasize a low-fat diet with high intake of fruits and vegetable sources containing vitamin E. Supplemental vitamin E may be considered in patients at high risk for CAD or with documented CAD, but the potential beneficial effects should be weighed against possible long-term adverse effects. If vitamin E supplementation is initiated, the literature suggests dosages of 100 to 400 IU/d, with the higher dosage considered in patients with documented CAD. Additional investigation is warranted to further define the role of vitamin E supplementation in CAD and to critically evaluate the optimal dosage, duration of use, and method of consumption (dietary vs supplemental). In recent years, there has been a surge of interest regarding the use of vitamins to prevent or treat disease. Vitamin E, in particular, has been studied for various conditions, including hot flashes, hypercholesterolemia, fibrocystic disease, and hemolytic anemia. This vitamin has also been promoted to increase sexual potency, diminish wound scarring, augment resistance to infection, and decrease aging.1,2 Lately, researchers have placed specific emphasis on the effects of vitamin E in coronary artery disease (CAD). Acute myocardial infarction (MI) is a leading cause of morbidity and mortality among adults in the United States. Acute MI occurs in more than 1.5 million people annually and is fatal in one third of these cases.3 In the last 40 years, much progress has occurred in the management of CAD and mortality has decreased. This progress is likely due to the impact of drug therapy and lifestyle modifications on people with hypertension and hyperlipidemia, as well as the widespread use of thrombolytic drugs, angioplasty, and coronary artery bypass surgery.4,5 Traditional risk factors, such as hypertension, hypercholesterolemia, and smoking, explain some but not all CAD risk.6,7 Recent studies provide insight into the contribution of antioxidants, particularly vitamin E, in CAD prevention and treatment. The purpose of this review is to critically evaluate the role of vitamin E in the management of CAD. Oxidative modification hypothesis Recent evidence demonstrates that oxidation of low-density lipoprotein (LDL) plays an important role in the development of atherosclerosis. This theory, termed the oxidative modification hypothesis, has fueled numerous epidemiological studies and clinical trials to determine the role of antioxidants in the prevention and treatment of CAD.8 Normally functioning LDL provides vital nutrients, such as vitamins and cholesterol, to peripheral cells to maintain cellular function. The entry of LDL into cells is regulated by external receptors. When the cell has received sufficient cholesterol, these receptors down-regulate and prevent further LDL uptake. Through this mechanism, cells avoids excess LDL accumulation.9 The development of atherosclerosis is characterized by the deposition of large amounts of lipids in arterial walls, primarily derived from LDL. Macrophages residing in the endothelial wall are the site of lipid deposition and accumulation.9 Macrophages possess 2 types of LDL receptors: one that recognizes native LDL and down-regulates after sufficient LDL has entered the cell, and another receptor that recognizes modified, or oxidized, LDL. The latter receptor is termed the scavenger receptor and is not subject to feedback inhibition by the cellular cholesterol content. This inability to terminate the uptake of oxidized LDL permits excessive accumulation of LDL in tissue macrophages and the subsequent formation of a foam cell in the arterial wall. These lipid-laden foam cells are believed to be the primary contributor to atherosclerotic CAD (Figure 1).10 In addition to its role in foam cell production, oxidized LDL has effects on platelet and endothelial function that further promote cardiovascular events.9-11 The theory that oxidized LDL promotes the development of atherosclerosis has prompted investigations of augmented antioxidant activity. Some believe oxidative damage occurs when the protective antioxidant systems are depleted or when these systems are inadequate to cope with increased levels of oxidative stress. The endogenous antioxidant system includes several enzymes and many lipophilic antioxidants, including α-tocopherol, beta carotene, and γ-tocopherol.9 These antioxidants prevent the oxidation of polyunsaturated fatty acids (PUFAs) that are bound to LDL. The primary component of vitamin E, α-tocopherol, is the most prevalent antioxidant in LDL.11 In vitro data suggest that endogenous vitamin E and beta carotene concentrations decline prior to lipoprotein oxidation and that vitamin E supplementation prevents this destructive oxidative reaction.12 Vitamin e Vitamin E exists as at least 8 naturally occurring compounds, including α-, β-, γ-, and δ-tocopherol and α-, β-, γ-, and δ-tocotrienol; α-tocopherol is the most active component in vitamin E and naturally occurs as 1 isomer. Dietary vitamin E is expressed in milligrams of α-tocopherol equivalents. The recommended dietary allowances (RDA) of vitamin E according to the National Research Council are 10 and 8 mg daily of α-tocopherol equivalents for men and women, respectively (approximately 13.5 and 10.8 IU/d).13 The reference daily intake (RDI), formerly the US recommended daily allowance (USRDA), is based on the activity of racemic synthetic α-tocopherol, the form in vitamin E supplements. The RDI for vitamin E is 30 IU.14 The National Research Council RDA is generally considered the more authoritative body; however, the RDI is used to determine vitamin supplements.14 In general, 60% of dietary vitamin E is derived from vegetable and seed oils, such as margarine, salad dressings, and shortenings. Soybean and wheat germ oils are particularly high in vitamin E, while corn, cottonseed, and sunflower oils are of intermediate content. Animal fats, such as butter and milk, contain negligible vitamin E, although eggs and liver are substantial sources of this nutrient. Grains, fruits, and leafy green vegetables account for the remaining dietary intake.1,2 Interestingly, olive oil, a major component of the "Mediterranean diet" that is associated with a decreased risk of CAD, contains minimal vitamin E compared with other vegetable oils.15 This diet is rich in fruit, vegetables, legumes, and grains, and olive oil is the primary source of fat. As a whole, this diet is high in monosaturated fatty acids and low in saturated fatty acids, and it is rich in natural antioxidants.16,17 In vitro, olive oil has been shown to decrease LDL oxidation; however, this activity is not mediated by vitamin E but rather is attributed to polyphenol antioxidant compounds.17 Although small, short-term studies using vitamin E supplementation (100-800 IU/d) have shown no evidence of toxicity,18,19 recent findings warrant attention. A study involving α-tocopherol supplementation (50 IU/d) and its effects on the incidence of cancer found a higher mortality rate due to hemorrhagic stroke in patients receiving α-tocopherol supplementation than in patients receiving placebo (7.8 vs 5.2 deaths per 10,000 person-years).20 Additionally, high vitamin E intake is contraindicated in patients with coagulation defects caused by vitamin K deficiency, as it may promote hemorrhage.18 Therefore, caution should be exercised in patients receiving warfarin or who have a malabsorption syndrome that may decrease vitamin K absorption. While vitamin E supplementation is often stated to be safe, this finding is frequently based on either small, short-term studies or long-term studies with inadequate end points to address the health consequences of vitamin E supplementation. The true long-term safety of vitamin E supplementation is unknown. Cross-sectional studies An early study analyzed the lipid-adjusted serum concentrations of vitamin E from various European communities in relation to each area's CAD mortality.21 Vitamin E concentrations were adjusted for serum lipid concentrations because this vitamin is highly bound to lipoproteins (micromoles of vitamin E per millimole of cholesterol). It is important to lipid-adjust serum vitamin E concentrations to accurately compare antioxidant activity. Eastern Finland, southwest Finland, Scotland, and southern Italy were included; 80 to 131 healthy men aged 40 to 49 years participated from each region. Eastern Finland had the highest CAD mortality rate (212 deaths per 100,000 men per year), southwest Finland and Scotland had intermediate mortality rates (146 and 140 deaths per 100,000, respectively), and southern Italy had the lowest mortality rate (43 deaths per 100,000). The 3 areas with intermediate to high CAD mortality (eastern Finland, Scotland, and southwest Finland) all had similar median lipid-adjusted serum vitamin E concentrations (3.41-3.53 µmol/mmol). On the other hand, Italy, which had the lowest CAD mortality rate, had a significantly higher median vitamin E concentration (4.81 µmol/mmol, P<.001). The lack of difference between vitamin E concentrations in the 3 areas with higher CAD mortality rates may be related to other CAD risk factors in eastern Finland, such as blood pressure, serum cholesterol level, smoking, and obesity. Of note, eastern Finland has one of the highest CAD mortality rates worldwide. The term Finland factor has been coined to encompass the yet undiscovered reason for this marked CAD increase. A cross-cultural study examined the relationship between ischemic heart disease (IHD) mortality and lipid-adjusted serum vitamin E concentrations. Other classic coronary risk factors, such as blood pressure, cholesterol, and smoking, were also evaluated.22 Approximately 100 healthy men from 16 different European communities with different incidences of IHD mortality were studied. Through regression analysis, the inverse correlation of lipid-standardized vitamin E levels and mortality from IHD was r2=0.62 (cholesterol, 5.7 mmol/L [220 mg/dL]; triglycerides, 1.25 mmol/L; P=.002) (Figure 2). In other words, 62% of the IHD mortality was attributable to variation in the standardized vitamin E concentrations. In this investigation, IHD mortality was more strongly correlated with vitamin E concentration than with blood pressure (r2=0.24), cholesterol level (r2=0.29), number of cigarettes per day (r2=0.02), serum vitamin A level (r2=0.26), and vitamin C concentration (r2=0.11). This study suggests that an individual's vitamin E concentration may be more indicative of IHD mortality than classic risk factors. Epidemiological data Epidemiological studies have examined the relationship between vitamin E intake or serum vitamin E concentration and the rate of CAD (Table 1 and Table 2). Initial studies found no correlation between serum or plasma vitamin E concentrations and CAD death.23,24 The results from these studies, however, may be unreliable because samples were not stored in suitable environments for vitamin E stability.10,25 In addition, vitamin E measurements were not adjusted for cholesterol levels, which may result in overestimation of vitamin E levels in patients with elevated cholesterol concentrations. One of the studies was in a Finnish population, and the influence of the Finland factor may overshadow any vitamin E effect. Further epidemiological studies examined lipid-adjusted serum vitamin E concentrations in patients who experienced some type of coronary event.26-28 Each study recruited matched controls. A study in Finnish men found no association between lipid-adjusted serum vitamin E level and a coronary end point, which was a positive stress test.26 One investigation reported an odds ratio of 2.68 (95% confidence interval [CI], 1.07-6.70) for a positive response on a chest pain questionnaire in the lowest vs the highest quintile of lipid-adjusted vitamin E concentration.27 The actual presence of angina was not verified following a positive response on the questionnaire, possibly resulting in the inclusion of some false-positive results. A third study found significantly decreased lipid-adjusted vitamin E concentrations in patients with a first acute MI as compared with controls (P=.001).28 All 3 studies were relatively small (64-175 cases) and included only men. Two case-control studies evaluated the rate of MI in relation to serum vitamin E concentration.29,30 Both studies included male and female subjects who were monitored for 6 to 14 years for the occurrence of MI. In 1 investigation, which included 46 German cases, no difference in mean lipid-adjusted serum vitamin E concentration was observed between cases and controls. A larger sample size may have been necessary to detect a difference between groups. Furthermore, the authors suggest that the relatively high concentrations of vitamin E (4.89 and 4.82 µmol/mmol in cases and controls, respectively) may have been at the level of maximum protective effect of vitamin E.29 This threshold effect means that low vitamin E levels constitute a risk factor for CAD, while levels above a certain threshold confer no additional protection. Based on several cross-sectional studies, it has been proposed that a lipid-adjusted vitamin E concentration of 4.8 µmol/mmol is the threshold above which there is no further decrease in CAD risk.31 Street and colleagues30 performed a similar study with 123 cases from the United States. They found no difference between cases and controls in lipid-adjusted serum α-tocopherol levels. They did report, however, that low non–lipid-adjusted α-tocopherol levels (less than the median of 24.4 µmol/L [105 mg/dL]) were associated with an increased risk of MI compared with matched controls when cholesterol levels were greater than 6.21 µmol/L (240 mg/dL). Without lipid adjustment, it is difficult to interpret these data. A similar study evaluated men in the United States for the development of fatal coronary heart disease (CHD) or nonfatal MI over a period of approximately 20 years. Again, no association was found between serum vitamin E level and coronary events. Interestingly, the investigators reported α-, γ-, and total tocopherol levels; however, these were not lipid-adjusted, rendering the applicability of the results unclear.32 Subsequent longitudinal epidemiological studies evaluated the role of vitamin E intake in large patient populations. A study on vitamin E intake among 87,425 female nurses in the US Nurses' Health Study was published in 1993.33 A dietary questionnaire was used to estimate vitamin E intake, and levels of intake were divided into quintiles. This study found an adjusted coronary disease relative risk (RR) of 0.66 (95% CI, 0.50-0.87; P<.001) for women consuming the highest vs lowest amount of vitamin E (median, 208 vs 2.8 IU/d). This study also found that the benefit was only evident with greater than 2 years of continued consumption. The benefit of vitamin E intake appeared to occur with both supplemental and dietary vitamin E. A similar study in 39,910 men, the Health Professions Follow-up Study, reported an adjusted RR for CAD of 0.64 (95% CI, 0.49-0.83; P<.003) for men with a median vitamin E intake of 419 vs 6.4 IU/d.34 The decrease in cardiovascular mortality was primarily evident in men who consumed supplemental sources of vitamin E. Both the US Nurses' Health Study and the Health Professions Follow-up Study found evidence that cardiovascular protection is maximized at 100 IU/d, with little benefit derived with higher intake.33,34 It is important to realize that these 2 studies included only health care professionals, who may have healthier lifestyles in terms of diet, exercise, and health care access; this may introduce numerous confounding variables into the study results. A 14-year study in a Finnish population found RRs of 0.68 and 0.35 for CHD-related death in men and women, respectively, in the tertiles of greatest vs lowest vitamin E consumption.35 The tertile boundaries are relatively close and indicate only a 25% difference in vitamin E consumption. These data are difficult to interpret, as the breadth of consumption represented within the tertiles is unknown. However, this result may indicate that cardiovascular benefit is seen with small increases of vitamin E consumption. A final investigation regarding vitamin E intake evaluated postmenopausal women with no cardiovascular disease who completed questionnaires regarding vitamin E intake and supplementation.36 Compared with women in the lowest quintile of intake, women in the highest quintile of vitamin E intake had an RR of 0.38 (P=.004 for the trend) for death from CHD. In contrast to the US Nurses' Health Study, this benefit was seen in women who consumed vitamin E in their diet, but not in those who used vitamin E supplementation. These longitudinal studies suggest that vitamin E intake and cardiovascular disease are related, yet raise additional questions: (1) What is the most appropriate dosage? Benefits have been associated with a very large range of vitamin E intake, from 7.1 to 419 IU/d, but intake of 100 IU/d or greater is most consistently associated with benefit. (2) How long must increased vitamin E be consumed to realize a benefit? Supplementation for greater than 2 years has most consistently been associated with a benefit, yet this has not been rigorously studied. (3) Which is better, dietary or supplemental vitamin E? Whether dietary or supplemental sources or both confer protection against CAD has not been answered, as conflicting results have been reported. Dietary vitamin E is primarily found in foods high in PUFAs,2 which are susceptible to lipid oxidation. It has been shown in both animals and humans that vitamin E requirements increase with increased PUFA intake. A ratio of milligrams of vitamin E to grams of PUFA has been suggested to quantify vitamin E dietary requirements more appropriately. While vitamin E intake increases with vegetable oil use, fish oils are remarkably low in vitamin E, although high in PUFAs. Theoretically, supplemental vitamin E will improve the vitamin E–PUFA ratio more effectively than dietary consumption of foods high in vitamin E and more effectively decrease lipid oxidation. Unfortunately, the available data have not clarified the relative importance of dietary vs supplemental vitamin E, as benefits of each method of consumption have been found. Furthermore, data suggest that γ-tocopherol, present in dietary but not supplemental vitamin E, plays a role in the oxidation of LDL.37,38 This adds confusion to the issue of dietary (all vitamin E components) vs supplemental (α-tocopherol only) vitamin E.37,38 Prospective trials One study evaluated the effect of vitamin E intake (supplemental and dietary, nonrandomized) on coronary artery lesion progression.39 Subjects were men who had previously undergone coronary artery bypass graft surgery and were randomized into a cholesterol-lowering diet and colestipol-niacin group or a placebo group. Although the vitamin E aspect of the study was not randomized and the dosages were not consistent, the investigators found decreased coronary artery lesion progression, as assessed with angiography, in patients consuming 100 IU/d or more of supplemental vitamin E compared with patients who had lower vitamin E intake (P=.04). Dietary vitamin E consumption was not found to have an effect on lesion progression. Two prospective, randomized trials have evaluated coronary outcomes following vitamin E supplementation (Table 3). One study, the Alpha-Tocopherol, Beta Carotene Cancer Prevention Study, was designed to evaluate the development of lung cancer, but also documented the coronary outcomes in several subgroups of Finnish men who were randomized to receive either placebo or α-tocopherol (50 IU/d).20 Several analyses have been performed based on this initial study.40-43 In the men initially free of CHD, a very modest decrease in the incidence of angina was noted over 4.7 years in patients taking vitamin E supplementation (RR, 0.91; 95% CI, 0.83-0.99; P=.04), while no effect was seen on the occurrence of major coronary events (fatal CHD or nonfatal MI).40,41 Similarly, in patients with a history of angina, vitamin E supplementation had no effect on the recurrence or progression of angina, or on the incidence of major coronary events.42 In patients with a previous myocardial infarction, α-tocopherol supplementation produced no change in major coronary events, and α-tocopherol in combination with beta carotene actually resulted in increased mortality.43 The small decrease in the incidence of angina and the lack of apparent benefit in the above analyses could be related to the low dosage of vitamin E (50 IU/d) used in the study, which is lower than the 100 IU/d suggested by epidemiological studies. The follow-up periods ranged from 4 to 6.1 years, which may have been too short a period to detect a difference in the development of the various cardiac end points, especially in the primary prevention analyses. In addition, all subjects were Finnish male smokers, and these factors may have influences that render the data not applicable to the general population. As a whole, these results indicate that supplemental vitamin E at this dosage appears to have no clinically relevant effect for primary or secondary prevention of CAD and may be harmful if used in combination with beta carotene. A second trial, the Cambridge Heart Antioxidant Study, evaluated higher dosages of vitamin E (400 or 800 IU/d).44 This trial included 2002 patients in the United Kingdom with angiographically proven CAD. Patients were randomized to receive a placebo or vitamin E supplementation and were evaluated for a mean of 1.4 years. End points were nonfatal MI, cardiovascular death, and death from any cause. This trial demonstrated a significant decrease in the combined end point of cardiovascular death and nonfatal MI (41 vs 64 events, P=.005) in patients who received vitamin E. The RR for cardiac events was 0.53 (95% CI, 0.34-0.83) for patients receiving supplementation. The beneficial effects of vitamin E appeared to occur after 200 days of supplementation; however, there was no difference in overall mortality between groups. The Cambridge Heart Antioxidant Study trial provided the most substantial evidence that vitamin E supplementation may decrease cardiac events in high-risk patients. Baseline data regarding coronary vessel stenosis and left ventricular impairment were provided, yet there was no information regarding past MIs, angina, or arrhythmias, which may have influenced the risk of cardiac events. The 2 groups were not equal at baseline with regard to gender, serum cholesterol level, systolic blood pressure, diabetes, and β-blocker use. The first patients randomized into the vitamin E group received 800 IU/d, while later patients received 400 IU/d. The reason for this dosage change was decreased drug availability, and all patients who received vitamin E were analyzed as a homogeneous group. There was an increase in noncardiovascular deaths in the vitamin E group compared with the placebo group (9 vs 3), but this was not analyzed or discussed. Although the decrease in the combined end point was marked, additional investigation is required to further explore the effects of vitamin E, since overall mortality was unaffected. Conclusions Epidemiological evidence supports the hypothesis that a relationship exists between vitamin E consumption and the incidence of CAD. In particular, data imply that a low vitamin E serum concentration is correlated with the development of CAD. Despite some epidemiological and in vitro data supporting the use of vitamin E, the findings of prospective, controlled trials are limited and inconclusive. Thus far, studies suggest that increased intake of this vitamin may attenuate the development of CAD; however, the optimum dosage, duration of use, and method of consumption (dietary vs supplemental) remain undetermined. The incidence of adverse effects and long-term outcomes associated with vitamin E supplementation have not been carefully investigated, and some data suggest possible detrimental effects. While it is too early to provide definitive guidelines for vitamin E intake, we feel that the following are reasonable recommendations based on the current data. A low-fat diet with high intake of fruit and vegetable sources containing vitamin E should be emphasized for all patients. Vitamin E supplementation may be considered in those at increased risk for CAD or with documented CAD, although this should be weighed against possible unknown long-term adverse effects. If vitamin E supplementation is initiated, a dosage of at least 100 IU/d appears necessary to derive cardiovascular benefit. Additional data from a prospective trial imply that a dosage of 400 IU/d is more appropriate in patients with documented CAD. Importantly, recommendation of the higher dosage of vitamin E is based on only 1 study, and this dosage has not been compared with a lower dosage (eg, 100 IU/d). The outcomes of additional prospective, randomized trials are necessary to more appropriately define the role of vitamin E in CAD and to critically evaluate the optimal dose, duration of use, and method of consumption (dietary vs supplemental). Accepted for publication January 6, 1999. Corresponding author: Anne P. Spencer, PharmD, Medical University of South Carolina, College of Pharmacy, 280 Calhoun St, QF309B, PO Box 250140, Charleston, SC 29425. References 1. Gaby SKMachlin LJ Vitamin E. Gaby SKBendich ASingh VNMachlin LJeds. Vitamin Intake and Health A Scientific Review. New York, NY Marcel Dekker1991;71- 95Google Scholar 2. Whitney ENHamilton EMNRolfes SR The fat soluble vitamins A, D, E, and K. Understanding Nutrition. 5th ed. St Paul, Minn West Publishing Co1990;Google Scholar 3. Antman EMBraunwald E Acute myocardial infarction. Braunwald Eed. Heart Disease A Textbook of Cardiovascular Medicine. Philadelphia, Pa WB Saunders Co1997;1184- 1288Google Scholar 4. Farmer JAGotto AMPhil D Risk factors for coronary artery disease. Braunwald Eed. Heart Disease A Textbook of Cardiovascular Medicine. Philadelphia, Pa WB Saunders Co1997;1125- 1160Google Scholar 5. Hunink MGGoldman LTosteson AN et al. 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Knekt PReunanen AJarvinen RSeppänen RHeliövaara MAromaa A Antioxidant vitamin intake and coronary mortality in a longitudinal population study. Am J Epidemiol. 1994;1391180- 1189Google Scholar 36. Kushi LHFolsom ARPrineas RJMink PJWu YBostick RM Dietary antioxidant vitamins and death from coronary artery disease in postmenopausal women. N Engl J Med. 1996;3341156- 1162Google ScholarCrossref 37. Öhrvall MSundlöf GVessby B Gamma, but not alpha, tocopherol levels in serum are reduced in coronary heart disease patients. J Intern Med. 1996;239111- 117Google ScholarCrossref 38. Christen SWoodall AAShigenaga MKSouthwell-Keely PTDuncan MWAmes BN Gamma-tocopherol traps mutagenic electrophiles such as NO(X) and complements alpha-tocopherol: physiological implications. Proc Natl Acad Sci U S A. 1997;943217- 3222Google ScholarCrossref 39. Hodis HNMack WJLaBree L et al. Serial coronary angiographic evidence that antioxidant vitamin intake reduces progression of coronary artery atherosclerosis. 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Gulløv, Annette Lemche;Koefoed, Birgitte Gade;Petersen, Palle

doi: 10.1001/archinte.159.12.1322pmid: 10386508

Abstract Background Treatment with warfarin sodium is effective for stroke prevention in atrial fibrillation but many physicians hesitate to prescribe it to elderly patients presumably because of the associated risk for bleeding and the inconvenience of frequent blood tests for the patients. Methods In the Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation (AFASAK 2) Study, we studied the rate of bleeding events associated with the incidence of thromboembolic events in patients receiving warfarin sodium, 1.25 mg/d; warfarin sodium, 1.25 mg/d, plus aspirin, 300 mg/d; aspirin, 300 mg/d; or adjusted-dose warfarin therapy aiming at an international normalized ratio of the prothrombin time ratio (INR) of 2.0 to 3.0. The study was scheduled for 6 years from May 1, 1993, but owing to evidence of inefficiency of low-intensity therapy plus aspirin from another study it was prematurely terminated on October 2, 1996. Minor and major bleeding events were recorded prospectively. The rate of bleeding was calculated using the Kaplan-Meier method and risk factors were identified by the Cox proportional hazards model. Results Of 677 included patients, 130 (median age, 77 years; range, 67-89 years) experienced bleeding. One woman and 12 men experienced major bleeding. Four had intracranial bleeding: 2 cases were fatal and 2 were nonfatal. During treatment with mini-dose warfarin, warfarin plus aspirin, aspirin, and adjusted-dose warfarin, the annual rate of major bleeding was 0.8%, 0.3%, 1.4%, and 1.1%, respectively (P=.20). After 3 years of treatment the cumulative rate of any bleeding was 24.7%, 24.4%, 30.0%, and 41.1% (P=.003), respectively. Increasing INR value (P<.001) and prior myocardial infarction (P=.001) were independent risk factors for bleeding, whereas increasing age was not. Conclusions Fixed mini-dose warfarin and aspirin alone or in combination were associated with both minor and major bleeding. The small number of major bleeding events in patients receiving adjusted-dose warfarin therapy as compared with those receiving less intensive antithrombotic treatments and the finding of no significant influence of age on the risk for bleeding indicate that even elderly patients with atrial fibrillation tolerate adjusted-dose warfarin therapy (INR, 2.0-3.0). TREATMENT WITH warfarin sodium is effective for stroke prevention in atrial fibrillation but many physicians hesitate to prescribe it to elderly patients.1-5 This reluctance may be ascribed to the associated risk for bleeding complications, to inconvenience for the patients, and to expected poor compliance in the elderly.1-5 The safety and tolerability of long-term oral anticoagulation therapy is not entirely clear in elderly patients, who have the highest risk for stroke6 and who may have an increased risk for bleeding complications.7 Less intensive antiplatelet and anticoagulation strategies have been investigated to find an antithrombotic regimen with a smaller risk for bleeding and fewer requirements for laboratory monitoring than adjusted-dose warfarin therapy.8-12 In the present trial we studied the rate of bleeding in patients treated with mini-dose warfarin, aspirin, both drugs in combination, or adjusted-dose warfarin aiming at the intensity of the international normalized ratio of prothrombin time ratio (INR) of 2.0 to 3.0.7 The trial was conducted from May 1, 1993, to October 2, 1996. For ethical reasons it was prematurely terminated due to the publication of other studies stressing the superiority of adjusted-dose warfarin therapy for stroke prevention in atrial fibrillation as compared with less intensive antithrombotic treatments.8,13,14 The primary outcome events of this Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation (AFASAK 2) Study have already been reported.15 Subjects and methods The AFASAK 2 Study was a randomized controlled trial conducted from a single center recruiting outpatients with chronic atrial fibrillation. The design and methods of the study have been described elsewhere.8 Subjects Patients older than 18 years with nonvalvular chronic atrial fibrillation were eligible. In summary, exclusion criteria were lone atrial fibrillation in patients younger than 60 years, recent stroke or transient ischemic attack, concomitant disease or other conditions increasing the risk for bleeding, and ongoing or planned oral anticoagulant therapy. Participants were recruited from general practices in Copenhagen, Denmark, and the surrounding areas. Before randomization, patients were interviewed and examined by 1 of 3 investigators. Baseline characteristics were recorded in standardized case record forms. The study protocol was approved by the regional ethics committees and the Danish National Board of Health, and the trial was performed according to the Second Declaration of Helsinki. All patients received oral and written information about the background and procedures of the trial, and signed informed consent was obtained. Randomization and study treatments According to computer-generated randomization, eligible patients were assigned to treatment with (1) warfarin sodium, 1.25 mg/d; (2) warfarin sodium, 1.25 mg/d, plus aspirin, 300 mg/d; (3) aspirin, 300 mg/d; or (4) adjusted-dose warfarin therapy in the intensity of INR 2.0 to 3.0. Warfarin (tablets of 2.5 mg and 1.25 mg; Marevan) and aspirin (non–enteric-coated tablets of 150 mg; Hjertemagnyl) were supplied by Nycomed DAK A/S, Roskilde, Denmark. The treatment was not blinded. Discontinuation of the study treatment was allowed for a maximum of 4 weeks per year. Therapy monitoring Treatment with adjusted-dose warfarin sodium was initiated with a loading dose of 10 mg and during the following days dose adjustments were made to achieve an INR of 2.0 to 3.0. When the intended anticoagulation level was reached, INR determinations were performed with a maximum interval of 4 weeks. After an introduction with weekly monitoring, INR values in patients receiving 1.25-mg/d warfarin sodium with or without aspirin were monitored once every 3 months. Blood samples were analyzed with the automatic coagulation analyzers Nycomatic (Nycomed Pharma A/S, Oslo, Norway), Thrombolyser (Behringwerke AG, Marburg, Germany), and ACL 200 (Instrumentation Laboratory, Milan, Italy). The thromboplastins used were Nycotest PT (Nycomed Pharma A/S) with an international sensitivity index of 0.97 and SPA (Diagnostica Stago, Asnieres sur-Seine, France) with an international sensitivity index of 1.04. Aspirin therapy was not monitored by blood tests. Follow-up Patients receiving treatment were followed up with physical examinations 3 and 6 months after inclusion, and then at 6-month intervals until termination of the trial. By the end of the study all patients were interviewed concerning major bleeding events and end points that might have occurred since the last evaluation in the study center. Hemorrhagic events Hemorrhagic events were classified as minor or major according to the loss of blood and the severity and rate of bleeding. A major bleeding event was defined as being fatal, life-threatening, or potentially life-threatening. Bleeding leading directly to death was characterized as fatal; bleeding requiring surgical or angiographic intervention to stop the loss of blood and bleeding leading to cardiopulmonary arrest or irreversible damage such as myocardial infarction, stroke, or blindness was characterized as life-threatening. Hemorrhagic events leading to 2 of the following 3 consequences were considered potentially life-threatening: (1) severe loss of blood requiring transfusion of more than 3 U of erythrocytes (1 U equals 250-300 g of erythrocytes), (2) decline in systolic blood pressure to below 90 mm Hg, or (3) critical anemia, ie, a hemoglobin substance concentration below 6.0 mmol/L. All reports on major bleeding events were confirmed by hospital records. Minor bleeding events were nonthreatening and included overt or occult gastrointestinal tract bleeding, hemoptysis, gross hematuria, nose bleeding, bruising, symptomatic anemia ascribed to bleeding, and chronic bleeding with minor or moderate loss of blood. Outcome events The primary end point was a stroke (ischemic and hemorrhagic) or a systemic thromboembolic event. The secondary end points were acute myocardial infarction, transient ischemic attack, and death not due to other end points. These events have been defined elsewhere.8 Statistical analyses Sample size estimations have been reported elsewhere.15 Baseline comparisons among the 4 groups were performed using the χ2 test for categorical data and analysis of variance for continuous data. Patients who experienced both major and minor bleeding events were categorized as patients with major bleeding. For the 4 groups the cumulative rates of total hemorrhagic events were calculated using the Kaplan-Meier method,16 and the log-rank statistics were used for comparison of the event rates in the 4 groups. Time until a hemorrhagic event was analyzed using the Cox regression model.17 In patients with more bleeding events, the time to the first hemorrhagic event was used in the analysis. Backward selection was used to identify significant risk factors. The INRs were calculated using linear interpolation for days on which INR was not observed and were consequently included as time-dependent covariates in the risk factor analysis. Because of the small number of major bleeding events, the risk factor analysis was performed for all bleeding events together. The mean rate of major and minor bleeding (the number of patients with bleeding per patient-year, ie, from randomization to a hemorrhagic or thromboembolic event or to termination of the trial) was calculated to facilitate comparison with other studies. Results A total of 887 patients were examined by the investigators. Of these, 210 were ineligible and 677 were eligible. Baseline data characteristics of the patients are presented according to assigned treatment in Table 1. Of the 677 randomized patients, 130 (19.2%) experienced bleeding (Table 2). The male-female ratio in patients with bleeding was 3:2 and the mean age was 74.4 years (median age, 77 years; range, 67-87 years). A total of 13 major and 139 minor bleeding events were noted. In 3 patients a minor bleeding event was succeeded by a major bleeding event, and 16 patients had more than 1 minor hemorrhagic event. No hemorrhagic events were reported in withdrawn patients. Major bleeding Thirteen patients (1 woman and 12 men) had a major hemorrhagic event. The patients were aged between 69 and 87 years (median, 79 years; mean±SD, 78.2 years) and major bleeding occurred from 14 to 830 days (median, 202 days; mean±SD, 235 days) after initiation of treatment. Detailed information on the major hemorrhagic events is reported in Table 3. Four hemorrhagic events were intracerebral, 8 were gastrointestinal, and 1 was retinal. In 1 patient receiving aspirin (patient 5) and in 1 receiving adjusted-dose warfarin therapy (patient 11) intracerebral bleeding occurred spontaneously, whereas the fatal intracerebral bleeding in patient 12 and the nonfatal intracerebral bleeding in patient 3 were traumatic. Four patients receiving aspirin monotherapy who experienced major gastrointestinal tract bleeding all had a lesion in the stomach. Only 1 patient receiving combined warfarin and aspirin therapy (patient 4) had a major gastrointestinal bleeding event, which was ascribed to diverticulitis in the colon. In 2 patients receiving low-dose therapy (patients 1 and 2) with lower gastrointestinal tract bleeding and anemia, the source of bleeding was not identified. Only 1 patient with major bleeding (patient 13) had a neoplasm. Retinal bleeding resulting in permanent blindness in 1 eye occurred in 1 patient receiving adjusted-dose warfarin therapy. Minor bleeding A total of 139 minor hemorrhagic events were noted in 120 patients. Twenty-nine cases of gastrointestinal tract bleeding, 52 cases of nose bleeding, 23 cases of gross hematuria, 21 subcutaneous hematomas, and 14 other minor hemorrhages occurred. There was no significant difference between the number of gastrointestinal, nose, and skin bleeding events in the 4 groups. Gross hematuria, however, was significantly more frequent in patients receiving adjusted-dose warfarin therapy than in patients receiving any of the other treatments (P=.01), and more nose bleedings were noted in patients receiving adjusted-dose warfarin or aspirin therapies than in the other groups (P=.025). Anemia was the first sign of bleeding in 3 patients with minor bleeding. They were all evaluated in the hospital. A total of 10 patients with minor nose bleeding had acute treatment in the hospital emergency department, but the events did not fulfill the criteria of major bleeding. Rate of bleeding After 3 years of treatment, the cumulative rate of bleeding was 24.7%, 24.4%, 30.0%, and 41.1% in patients receiving mini-dose warfarin, warfarin plus aspirin, aspirin, and adjusted-dose warfarin, respectively. The cumulative incidence was significantly higher in patients receiving adjusted-dose warfarin than in the other groups (P=.003), but the difference was ascribed only to a higher rate of minor bleeding. The probability of survival on treatment without any bleeding in the 4 groups is illustrated in Figure 1. The annual risk for minor respective major bleeding events according to assigned treatment are listed in Table 2. The rate of major bleeding ranged from 0.3% to 1.4% per year among the 4 groups. The very small number of major events and consequently the low incidence rates do not allow for statistical comparison, but the events seem equally distributed among the 4 groups. Minor bleeding, however, was significantly more frequent in patients receiving adjusted-dose warfarin than any of the other treatments (P=.02). Anticoagulant intensity prior to bleeding Patients treated with adjusted-dose warfarin had an INR between 2.0 and 3.0 for 73% of the time of treatment, above this range for 9%, and below this range for 18%. None of the patients who experienced major bleeding during warfarin therapy had an INR above 2.8 at the last evaluation in the study laboratory, but 1 patient who was severely injured after a fall down a staircase had an INR of 3.9 at admission to the hospital. One patient receiving fixed low-dose warfarin therapy had an INR of 1.5 five days before a major gastrointestinal bleeding event. He had a prothrombin time ratio of 0.11 at admission to the hospital. The sudden pronounced anticoagulant effect of 1.25-mg/d warfarin sodium was ascribed to interaction with aspirin, of which the patient had taken 3 to 4 g/d for 1 week. The bleeding was caused by gastric ulcers. In the 4 patients who experienced a major bleeding episode during adjusted-dose therapy, the intensity of anticoagulation was stable with the last 3 INR values within or just below the intended range. Risk factors for bleeding Prior myocardial infarction (P=.001) and allocation to adjusted-dose warfarin therapy (P<.001) were the only independent risk factors for bleeding. The risk for bleeding increased by increasing INR value. There was no significant impact of age, sex, history of stroke or transient ischemic attack, diabetes, cigarette smoking, left ventricular fractional shortening, or arterial hypertension on the occurrence of bleeding. Risk factor analysis for only patients receiving adjusted-dose warfarin therapy did not identify increasing age as a risk factor for bleeding. Interestingly, a bleeding complication related to the study treatment was identified as an independent risk factor for a thromboembolic event later in the study period (P=.006) in patients who did not stop taking the study treatment after the bleeding event. Therapeutic consequences of bleeding In all patients with major bleeding the antithrombotic treatment was discontinued and the patients were permanently withdrawn from the study. All patients who reported minor bleeding were encouraged to visit their primary care physician for further examination and 7 patients were admitted to the hospital for examination and/or treatment of an underlying disorder. These examinations, however, were not coordinated with the study center, and follow-up information on minor bleeding events was not systematically recorded. The study treatment was permanently discontinued in 4 (19%) of 21 patients who experienced a minor bleeding event while receiving mini-dose warfarin therapy, in 12 (43%) of 28 receiving combined warfarin and aspirin therapy, in 6 (23%) of 26 receiving aspirin therapy, and in 15 (36%) of 42 receiving adjusted-dose warfarin therapy (P=.22). Comment In the AFASAK 2 Study the number of major bleeding events was very small, with no significant difference among the 4 groups. Considering all minor and major hemorrhagic events, the cumulative rate of bleeding was significantly higher in patients receiving adjusted-dose warfarin than in those receiving the other antithrombotic treatments. In patients receiving adjusted-dose warfarin therapy in the present study, the annual incidence of major bleeding of 1.1% was comparable to the rate of major bleeding in the first trials on stroke prevention in atrial fibrillation.18-23 In the Stroke Prevention in Atrial Fibrillation (SPAF) II Study, the overall risk of major bleeding in patients receiving warfarin aiming at an INR of 2.0 to 4.5 was 2.3% per year,24 which was slightly higher than in the previous trials. The higher rate of bleeding events may partly be ascribed to the relatively high intensity of anticoagulation therapy used in that study.7 The rate of bleeding in the SPAF II subgroup of patients older than 75 years will be discussed later. For comparison, the rates of major bleeding during antithrombotic therapy in various atrial fibrillation trials are listed in Table 4. The relatively large number of major hemorrhagic events in patients receiving aspirin in the present study is important to note as aspirin is suggested as an alternative treatment for patients in whom warfarin is considered inappropriate.26 The risk for gastrointestinal tract bleeding has been shown to be proportional with the dose of aspirin,27 and in the AFASAK 2 Study a relatively large dose of non–enteric-coated aspirin was used. Other studies, however, have indicated that neither coating nor a small dose of aspirin ensures a small risk for gastrointestinal tract bleeding.28,29 As aspirin may be associated with a risk for major bleeding very close to that of adjusted-dose warfarin therapy,9,18,20 we find that the only reason for choosing aspirin instead of warfarin should be expected poor compliance during oral anticoagulant therapy. In our study the combination of warfarin and aspirin was associated with a risk for major bleeding of 0.3% per year. This was unexpectedly low as compared with both adjusted-dose warfarin therapy (1.1% per year) and aspirin monotherapy (1.4% per year) and indicates that combined low-intensity warfarin and aspirin therapy can be safe even in the elderly. It should, however, be noted that 1 patient receiving mini-dose warfarin therapy who unaware took aspirin 3 to 4 g/d for approximately 1 week developed pronounced hypoprothrombinemia and had a major gastrointestinal bleeding event. Our experience with combined warfarin and aspirin therapy in respect to major bleeding is in accordance with the findings in other recent trials.30,31 In patients with prosthetic heart valves treated with warfarin alone aiming at INR of 2.5 to 4.0 or in combination with 100 mg of aspirin, the combined treatment increased the risk for minor bleeding but not for major bleeding.30 In the SPAF III Study, excretion of fecal hemoglobin was increased in patients receiving combined therapy compared with those receiving adjusted-dose warfarin therapy,32 whereas no difference in the rate of major bleeding was found.9 In contrast to this, patients with intracoronary stent placement receiving combined warfarin and aspirin therapy had a high risk for upper gastrointestinal tract bleeding as compared with patients receiving aspirin monotherapy.33 In the present study, the incidence of minor bleeding of 11.8% per year in patients receiving adjusted-dose warfarin therapy was significantly higher than in the other study groups but it was comparable to the rate of minor bleeding in prior atrial fibrillation trials,23 in which the rate ranged from 1.5% to 14.0% per year in the warfarin groups. The large spread in the incidences of minor bleeding may be explained by different operational definitions and follow-up schedules and by the patients' susceptibility to report harmless bleeding such as bruising and nose bleeding rather than by a real difference in the number of minor bleeding events. We found it important, however, to obtain data on even minimal bleeding events, as such events were expected to reflect compliance and to influence withdrawal and dropout from the trial. In fact, bleeding was a major reason for both withdrawal and dropout. Although insignificant, the dropout ratio seemed elevated in patients receiving warfarin plus aspirin or adjusted-dose warfarin, suggesting that a complicated treatment and polypharmacy influence the patients' willingness to continue the treatment after even minor adverse events. By stepwise multiple regression analysis we found that prior myocardial infarction and allocation to adjusted-dose warfarin therapy were the only independent risk factors for bleeding. The risk for bleeding increased with increasing INR. The finding of myocardial infarction as a risk factor for bleeding was surprising. An explanation could be that some of these patients previously had been told always to take aspirin and maybe still took it in addition to the study medication. The literature does not explain this finding. A risk factor analysis for only major bleeding events was not performed as the number of events was considered insufficient, but it is remarkable that only 1 of 13 patients with major bleeding was female. An explanation for this is not evident, but compliance may have been better or comorbidity less frequent in female participants. Older age as a potential risk factor for bleeding is an important issue of debate as many patients may be withheld from relevant warfarin therapy only because of their age. In the SPAF II Study, the risk of major bleeding was high in the elderly, ie, 4.2% per year in the subgroup of patients older than 75 years.7 When interpretating the results of the SPAF II Study, however, it should be kept in mind that increasing age was identified as an independent risk factor for bleeding for the entire study population. Thus, it is not surprising that a subgroup of the study population consisting of only persons older than 75 years had a very high risk for hemorrhage. Since the publication of the SPAF II Study, many physicians have been reluctant to prescribe warfarin therapy to the elderly, who may, however, benefit most from the treatment.6 Among other investigators, Launbjerg et al34 also noted that age over 75 years was an individual risk factor for bleeding. In a recent prospective cohort study of patients with various diseases receiving oral anticoagulant therapy, the rate of bleeding was higher in patients older than 75 years than in those younger, and more bleeding events were major or fatal in the elderly.35 Opposite to these findings, the present and other studies have shown that it may be safe to treat even elderly patients with warfarin.36-39 The intensity and variability of anticoagulation therapy have also been determined as risk factors for bleeding.7,40,41 In our study the last 3 control INRs were below 3.0 in all patients who experienced major bleeding during adjusted-dose warfarin therapy, but at admission to the hospital the level of anticoagulation was more intense than intended in 2 of the patients. In 1 case it was a consequence of accidental interaction between low-dose warfarin and high-dose aspirin and in the other case the patient was severely traumatized. Prior studies have demonstrated that a history of stroke or arterial hypertension increases the risk for intracerebral bleeding during oral anticoagulant treatment.40-42 Such a relationship could not be confirmed by the AFASAK 2 Study, but it should be remembered that patients with uncontrolled arterial hypertension and recent stroke were not included in the study. In the European Atrial Fibrillation Trial, which included patients with a recent stroke or transient ischemic attack,25 no intracranial bleeding was noted in 225 patients with atrial fibrillation receiving oral anticoagulant therapy—a result contradicting that a history of stroke increases the risk for warfarin-associated bleeding. In both the AFASAK 2 Study and the European Atrial Fibrillation Trial, however, the cause of death was not clarified in several patients who unexpectedly died at home. We did not find that minor bleeding could predict the risk for major bleeding, as only 3 patients experienced both minor and major hemorrhage, but the finding of bleeding as a risk factor for thromboembolic events should be noticed as it may indicate unsteady intake of the study medication. Drug interaction caused major bleeding in only 1 patient, but in more patients without bleeding elevated INRs could be ascribed to drug interaction. Aspirin was the most frequent interacting agent, but amiodarone, cimetidine, and nalidixic acid43 also were recorded. This study showed that treatment with mini-dose warfarin given alone or in combination with aspirin implies a nonnegligible risk for bleeding. Traditional warfarin therapy was not associated with a higher risk for major bleeding than aspirin and the other "low-risk" antithrombotic treatments, and increasing age was not a risk factor for bleeding. Thus, this study indicates that even elderly patients with atrial fibrillation tolerate and should receive adjusted-dose warfarin therapy (INR, 2.0-3.0) provided there are no contraindications for the treatment and patients are carefully monitored. Accepted for publication October 22, 1998. This study was supported by grants from the Danish Heart Foundation, Copenhagen, Denmark; Nycomed DAK A/S; Du Pont Pharma, Wilmington, Del; Danish Foundation for Medical Research for the Region of Copenhagen, the Faroe Islands, and Greenland, Copenhagen; Danish General Practitioners Foundation for the Municipalities of Copenhagen, Frederiksberg, and Dragør, Copenhagen; Danish Medical Research Foundation, Copenhagen; Sophus and Astrid Jacobsen Foundation, Virum, Denmark; Jacob and Olga Madsen Foundation, Copenhagen; Kathrine and Vigo Skovgård Foundation, Roskilde; Danish National Stroke and Aphasia Foundation, Copenhagen; Beckett Foundation, Copenhagen; Leo Pharmaceuticals Research Foundation, Ballerup, Denmark; Hede Nielsen Family Foundation, Copenhagen; Director E. Danielsen Foundation, Lyngby, Denmark; Therese Maria Hansen Grant, Bagsvaerd, Denmark; Michael Hermann Nielsen Grant, Copenhagen; and Mimi and Victor Larsen Foundation, Birkerød, Denmark. We thank Helle Vilhelmsen, Käthe Rasmussen, and Isabella Frederiksen for their enthusiastic work during the trial; the general practitioners in Copenhagen, Frederiksberg, and the counties of Roskilde and Copenhagen for their cooperation; the staff and the laboratory technicians of Copenhagen General Practitioners Laboratory for accommodation and support; Sissel Vorstrup, MD, DMSc, Per Sidenius, MD, DMSc, Jan Kyst Madsen, MD, DMSc, and Jens Kastrup, MD, DMSc, for attending the end point committee; and Jørgen Hilden, MD, Kai Jensen, MD, DMSc, and Knud Skagen, MD, DMSc, for attending the safety committee. Reprints not available from the authors. References 1. Kutner MNixon GSilverstone F Physicians' attitudes toward oral anticoagulants and antiplatelet agents for stroke prevention in elderly patients with atrial fibrillation. Arch Intern Med. 1991;1511950- 1953Google ScholarCrossref 2. Lip GYHTean KNDunn F Treatment of atrial fibrillation in a district general hospital. Br Heart J. 1994;7192- 95Google ScholarCrossref 3. McCrory DCMatchar DBSamsa GSanders LLPrichett ELC Physician attitudes about anticoagulation for nonvalvular atrial fibrillation in the elderly. Arch Intern Med. 1995;155277- 281Google ScholarCrossref 4. Whittle JWickenheiser LVenditti LN Is warfarin underused in the treatment of elderly persons with atrial fibrillation? Arch Intern Med. 1997;157441- 445Google ScholarCrossref 5. Stafford RSSinger DE National patterns of warfarin use in atrial fibrillation. Arch Intern Med. 1996;1562537- 2541Google ScholarCrossref 6. Atrial Fibrillation Investigators, Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials. Arch Intern Med. 1994;1541449- 1457Google ScholarCrossref 7. Stroke Prevention in Atrial Fibrillation Investigators, Bleeding during antithrombotic therapy in patients with atrial fibrillation. 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Davidson, Michael H.;Hunninghake, Donald;Maki, Kevin C.;Kwiterovich, Peter O.;Kafonek, Stephanie

doi: 10.1001/archinte.159.12.1331pmid: 10386509

Abstract Background Patients with hypercholesterolemia are often counseled to limit or eliminate intake of red meats, despite evidence that lean red meats (LRMs) are not hypercholesterolemic in comparison with lean white meats (LWMs). The objective of this study was to evaluate the long-term effects on serum lipids of incorporating LRM (beef, veal, and pork) vs LWM (poultry and fish) into a National Cholesterol Education Program (NCEP) Step I diet in free-living individuals with hypercholesterolemia. Methods Subjects included 191 men and women with a serum low-density lipoprotein cholesterol level of 3.37 to 4.92 mmol/L (130-190 mg/dL) and triglyceride level less than 3.96 mmol/L (350 mg/dL). After a 4-week baseline phase, subjects were counseled to follow an NCEP Step I diet including 170 g (6 oz) of lean meat per day, 5 to 7 days per week. Based on random assignment, subjects were instructed to consume at least 80% of their meat in the form of LRM or LWM. Fasting serum lipid levels were assessed 4, 12, 20, 28, and 36 weeks after randomization. Results After randomization, mean concentrations of total cholesterol (6.09 mmol/L [235.7 mg/dL] vs 6.08 mmol/L [235.2 mg/dL]) and low-density lipoprotein cholesterol (3.99 mmol/L [154.1 mg/dL] vs 4.01 mmol/L [154.7 mg/dL]) were nearly identical in the LRM and LWM groups (1%-3% below baseline) during treatment. Mean triglyceride levels remained similar to baseline values and high-density lipoprotein cholesterol concentrations increased by approximately 2% in both groups. Conclusions The NCEP Step I diets containing primarily LRM or LWM produced similar reductions in low-density lipoprotein cholesterol and elevations in high-density lipoprotein cholesterol levels, which were maintained thoughout 36 weeks of treatment. EPIDEMIOLOGICAL studies have shown a strong positive association between serum total and low-density lipoprotein cholesterol (LDL-C) levels and risk for coronary heart disease.1-4 Several large-scale clinical trials have also demonstrated that reducing elevated LDL-C lowers the risk of coronary heart disease morbidity and mortality.3,5 Diet intervention is recommended by the National Cholesterol Education Program (NCEP) guidelines as first-line therapy for the management of high blood cholesterol levels.6,7 The NCEP Step I diet limits intake of fat to 30% or less of energy intake, saturated fatty acids to 8% to 10% of energy, and cholesterol to less than 300 mg/d.6 To achieve NCEP dietary goals, individuals are often counseled to reduce the amount and frequency of red meat consumption.8-11 However, controlled feeding studies have shown that the cholesterol-raising influence of some red meats appears to result from the cholesterol-raising fatty acids they contain.8,12,13 Therefore, lean red meats (LRMs) that provide small amounts of these fatty acids would not be expected to adversely influence the blood lipid profile compared with lean white meats (LWMs). In fact, studies directly comparing the effects of lean beef with chicken, or with chicken and fish, indicate that these meats are interchangeable with regard to their influence on serum lipid levels.9,14 Since lean cuts of red meat are now readily available to consumers, the common practice of advising patients to avoid or severely limit red meat intake may be unnecessarily restrictive and adversely affect long-term dietary adherence. The present study was undertaken to compare the long-term effects of diets in which LRM (beef, veal, pork) or LWM (poultry and fish) comprised the principal meat sources within the context of an NCEP Step I diet among free-living subjects with mild to moderate hypercholesterolemia. Subjects and methods Screening and diet stabilization This was a randomized, multisite study with participants recruited from the Chicago, Ill (Chicago Center for Clinical Research); Minneapolis, Minn (The University of Minnesota Hospital and Clinics); and Baltimore, Md (The Johns Hopkins University Lipid Clinic), metropolitan areas. The study protocol was reviewed and approved by an institutional review board for each investigative site. Men and women aged 18 to 75 years were screened by telephone interview. Individuals who met the initial screening criteria were asked to discontinue all lipid-lowering drugs or therapies, with approval from their physicians, for at least 6 weeks prior to an orientation and screening visit at their respective clinical research center. Volunteers were excluded from the study if they were pregnant or lactating, vegetarians, current smokers, abused alcohol (>14 drinks per week), or used illicit drugs. At the time of the baseline measurements, eligible subjects were not allowed to be using hypolipidemic drugs, or therapeutic doses of fish oil supplements, niacin/nicotinic acid (>250 mg/d), psyllium (>10 g/d), or oat bran (>13 cup/d). At screening (week −4), the conditions and procedures of the study were explained and a written consent form was signed by each participant. Participants completed a medical history questionnaire and underwent a physical examination and laboratory procedures including hematological assessment, blood chemistry studies, urinalysis (including a urine pregnancy test for women of childbearing potential), and a blood lipid profile (total cholesterol, high-density lipoprotein cholesterol [HDL-C], LDL-C, and triglycerides). Persons with a body mass index (calculated as weight in kilograms divided by the square of height in meters) of 35 or greater; diabetes mellitus; atherosclerotic disease; cancer; hypothyroidism or other endocrine disorder; or any hematological, hepatic, gastrointestinal, or immune disorder were excluded from the study. All individuals who met the inclusion criteria were administered the Oregon Health Sciences Diet Habit Survey, an indicator of typical eating habits,15 and were instructed to maintain their usual diets throughout a 4-week diet stabilization period. Subjects returned to their respective clinical research center 2 weeks after the screening visit (week −2) to have vital signs and body weight checked, and for another blood lipid profile measurement. Lipid criteria for inclusion in the study, based on the average of the 2 measurements obtained at weeks −4 and −2, included LDL-C level between 3.37 and 4.92 mmol/L (130-190 mg/dL) and serum triglyceride level less than 3.96 mmol/L (<350 mg/dL). If LDL-C concentrations varied by more than 15% between visits at week −4 and −2 (larger value as the denominator), an additional lipid profile clinic visit at week −1 was scheduled. If values from week −2 and week −1 did not meet the lipid eligibility criteria, the subject was dropped from the study. At the week −2 visit, subjects were asked to continue their usual diets for the remaining 2 weeks of the diet stabilization period, and were instructed to complete a 3-day diet record (including 1 weekend day) during this period. A nutritionist instructed the subjects on how to complete the diet records, using Nasco food models to illustrate portion sizes. Randomization and diet instruction Of the 382 persons who were screened, 202 men and women met all inclusion criteria and were randomly assigned to either the LRM (n=95) or (LWM) (n=107) treatment group. At the randomization visit (week 0), subjects assigned to the LRM group were instructed to consume 170 g (6 oz) of meat, 5 to 7 days per week, for 36 weeks as part of an NCEP Step I diet. Subjects in the LRM group were instructed to consume at least 80% of their total meat in the form of lean beef, veal, or pork. Subjects randomized to the LWM group were similarly instructed, except that at least 80% of their meat consumption was to be LWMs defined as poultry or fish. Lamb was included in the 20% of other meat consumed by both groups during the treatment period. Baseline 3-day diet records and the results of the baseline Diet Habit Survey were reviewed with each subject at the randomization visit. Detailed instructions were provided on following an NCEP Step I diet. An American Heart Association booklet, food scales, handouts, and videotapes were also provided as aids to help subjects understand and comply with the prescribed diet. Participants were also counseled by a nutritionist on selection and preparation of appropriate meats and completion of meat consumption daily logs used to record information on meat intake, cuts of meat consumed, methods of preparation, and portion sizes. Treatment period Subjects returned to the clinic at weeks 4, 12, 20, 28, and 36 of the treatment period. Vital signs, body weight, and fasting serum lipid profiles were measured at each clinic visit. Additionally, at week 36, safety measurements (hematology, blood chemistry, and urinalysis) were obtained. Throughout the treatment period, subjects maintained meat consumption daily logs. Three-day diet records (2 weekdays and 1 weekend day) were collected and analyzed at baseline (week 0) and at each subsequent clinic visit. Diet records and results of the computerized analysis of the diet record from the previous clinic visit were reviewed with the subject at each visit. Counseling and feedback were provided to assist patients with dietary adherence. Between clinic visits at weeks 8, 16, 24, and 32, telephone interviews were conducted to further monitor and encourage subject compliance with the study protocol. The Diet Habit Survey was administered during the telephone interviews at weeks 16 and 32. Analyses Lipids and Lipoproteins Fasting (≥12 hours) blood collection was completed at each clinical research site according to previously described procedures.16 Serum total cholesterol, HDL-C, and triglyceride concentrations were measured enzymatically by a central laboratory (Medical Research Laboratories, Cincinnati, Ohio) that participates in the Centers for Disease Control and Prevention lipid measurement standardization program.17 Low-density lipoprotein cholesterol in milligrams per deciliter was calculated using the Friedewald equation: [LDL-C=total cholesterol−HDL-C−(triglycerides/5)].18 Results were blinded from investigators throughout the treatment period, though clinic sites were notified by the central laboratory if the LDL-C concentration of any subject exceeded 5.69 mmol/L (220 mg/dL). Compliance A subject was deemed compliant with their assigned treatment if at least 80% of total meat intake during each 1-month period came from the appropriate meat, and if the subject consumed an average of 795 to 1306 g (28-46 oz) of meat per week. Subjects whose average meat consumption was out of this range were not dropped from the study, but were strongly encouraged to follow the specified guidelines. Compliance with the fat and cholesterol recommendations of the NCEP Step I diet was determined using the cholesterol–saturated fat index of the Diet Habit Survey administered at baseline and at 16 and 32 weeks of the treatment period. A value of 60 or higher is consistent with the recommendations for intakes of less than 30% of total energy (calories) from fat and less than 300 mg/d of cholesterol. Three-day diet records were analyzed using the University of Minnesota Nutrition Data System, version 2.7 software. Three-day averages were calculated for intake of selected nutrients at weeks 0 (baseline), 4, 20, and 36. Nutrient analyses were completed at the Chicago Center for Clinical Research Nutrient Analysis Center according to standard operating procedures, including blinded reentry of data on a randomly selected portion of the records. Diet records from the Minnesota and Maryland sites were sent by facsimile to the Chicago site, and the nutrient intake results were sent back to each clinical site prior to the next clinic visit for use in dietary counseling. Statistical Procedures Analyses were conducted using the JMP 3.1 (SAS Institute, Cary, NC) and Statview 4.5 (Abacus Concepts, Berkeley, Calif) statistical analysis packages. P ≤.05 (2-sided) was used to denote statistical significance. Analysis of variance and χ2 tests were used to assess comparability of baseline characteristics between treatment groups. Outcome analyses were conducted using data from all subjects who provided at least 1 postrandomization blood specimen for lipid analysis. The initial statistical models contained terms for treatment, time, treatment×time interaction, study center, and treatment×study center interaction. No evidence of treatment×time or treatment×study center interactions was detected (P>.10). Therefore, data from the 3 sites were pooled and mean blood lipid levels during treatment were used in the final statistical models. Blood lipid variables examined were the mean concentrations of total cholesterol, LDL-C, HDL-C, triglycerides, and the total cholesterol/HDL-C ratio during treatment, as well as the changes in these values from baseline (mean of 3 or 4 baseline measurements) to treatment (mean of all postrandomization measurements). Results Subjects and demographics Two hundred two subjects met all inclusion criteria and were randomly assigned to the LRM (n=95) or LWM (n=107) treatment groups. Forty-two subjects dropped out of the study prior to its completion. Of these, 18 were in the LRM group and 24 in the LWM group. Reasons reported for study discontinuation included inability to follow the diet (n=15), scheduling problems (n=11), loss to follow-up (n=7), private medical advice or newly prescribed medications (n=5), personal reasons (n=2), surgery (n=1), and relocation (n=1). At least 1 postrandomization blood specimen was obtained from 191 subjects. Subjects for whom no postrandomization blood samples were obtained (n=11) were excluded from all analyses. Baseline anthropometric and demographic characteristics of each treatment group are shown in Table 1. Treatment groups did not differ significantly in mean age or body mass index at baseline and were comparable with respect to sex and race distribution, as well as median weekly consumption of alcoholic beverages. Serum lipids Serum lipid values at baseline and during treatment are summarized in Table 2. No differences between groups were observed for any of the serum lipid measures assessed at baseline. Mean baseline total cholesterol and LDL-C values were near the cut points for high-risk classification as defined by the NCEP, 6.20 mmol/L (240 mg/dL) and 4.13 mmol/L (160 mg/dL), respectively. During treatment, mean concentrations of total cholesterol (6.09 mmol/L [235.7 mg/dL] vs 6.08 mmol/L [235.2 mg/dL]) and LDL-C (3.99 mmol/L [154.1 mg/dL] vs 4.01 mmol/L [154.7 mg/dL]) were nearly identical in the LRM and LWM groups, respectively (Table 2 and Figure 1). Compared with baseline, total cholesterol concentration declined by 1.0% in the LRM group (P>.05) and 1.8% in the LWM group (P=.003). Levels of LDL-C decreased 1.7% in the LRM group (P=.01) and 2.9% in the LWM group (P<.001). No significant differences in total cholesterol or LDL-C responses were present between treatment groups. A pooled SD of 0.3 mmol/L (11.6 mg/dL) was observed for the absolute change in LDL-C. Accordingly, this study had approximately 80% power to detect a difference of 5 mg/dL (3%) in LDL-C response between treatment arms. No between-group differences were observed for HDL-C, although HDL-C concentration increased by approximately 2% relative to baseline in both the LRM (P=.01) and LWM (P=.004) groups (Table 2 and Figure 2). The total cholesterol/HDL-C ratio did not differ between groups, and was maintained at a level 3% to 4% below the baseline value in both groups (LRM, P=.002; LWM, P<.001). No significant differences were observed within or between groups for triglyceride concentration at baseline or during treatment. Dietary data Randomly selected consecutive 7-day periods between each clinic visit were chosen for evaluation of daily meat logs ( Table 3). During the first 4 weeks of the treatment phase, mean reported total meat intake was 167.7 g/d in the LRM group and 160.7 g/d in the LWM group. These values were not significantly different and suggest that subjects were generally meeting the treatment compliance goal of consuming an average of 120 to 170 g/d of meat. In both groups, 84.2% of the reported meat intake was in the form of red meat (LRM group) or white meat (LWM group). The mean proportion of meat consumed from the appropriate category did not vary significantly during the treatment period for either group and stayed above 80% at each measurement point. Total meat intake declined in both groups over time, but this trend was more pronounced in the LWM group. Compared with the first 4 weeks of the intervention period, reported meat intake had declined by approximately 5% in the LRM group and about 10% in the LWM group. During the final 16 weeks of the study, reported weekly meat intake was significantly lower in the LWM group than in the LRM group (P<.01). Mean values of the Diet Habit Survey cholesterol–saturated fat index in the 2 treatment groups were 64.9 (LRM group) and 62.1 (LWM group) at baseline and were not statistically different ( Table 4). After 16 and 32 weeks of treatment, scores were elevated significantly (P<.001) from baseline in both groups (LRM: 72.0 and 73.7; LWM: 72.0 and 75.0 for weeks 16 and 32, respectively) and values in the 2 treatment groups did not differ significantly from one another. Examination of the relationship between baseline scores and change in lipid levels during the treatment period indicated that subjects compliant with the NCEP Step I diet at baseline (score >60) had significantly smaller reductions of total cholesterol and LDL-C during treatment than did noncompliant subjects (score <60) (P<.05) ( Table 5). Results of diet record analysis at baseline and during treatment (mean of values from weeks 4 to 36) are shown in Table 6. No significant differences between groups were observed for intakes of any major dietary components at baseline (P>.05 for all comparisons). Both treatment groups had significantly lower intakes of energy (P=.006 and P<.001 for LRM and LWM groups, respectively), total fat (P=.001 and P < .001), monounsaturated fatty acids (P=.02 and P<.001), and protein (P<.001 for both) during the treatment period than at baseline. Additionally, the LWM group had reduced intake of 18:0 and 12:0-16:0 fatty acids (P<.001) and cholesterol (P=.02), whereas the LRM group had a reduction from baseline in polyunsaturated fatty acid intake (P<.001). Diet records collected during the treatment period suggest that daily consumption of fat (P=.003), stearic acid (18:0) (P<.001), cholesterol-raising (12:0-16:0) fatty acids (P<.001), and monounsaturated fatty acids (P<.001) were higher, and carbohydrate (P=.005) and polyunsaturated fatty acid intakes (P<.001) were lower during the treatment phase in the LRM group than in the LWM group. Total energy (P=.06) and cholesterol intakes (P=.10) tended to be lower in the LWM group. Reported consumption of protein, dietary fiber (including soluble fiber), and iron did not differ significantly between treatment groups. Body weight Mean body weight in the 2 treatment groups was similar at baseline and did not change significantly during the treatment period. The LRM group had a mean±SEM baseline body weight of 79.9±14.5 kg and the corresponding level in the LWM group was 80.2±14.6 kg. At the end of the treatment period, the mean body weight of the LRM group was 80.8±14.9 kg and the LWM group was 79.7±14.8 kg. Mean weight change during the treatment period was less than 1 kg in both groups (P>.05). Comment The participants of the present trial were free-living adult volunteers with hypercholesterolemia, for whom dietary modification is the first line of therapy. This long-term, randomized, multisite trial showed that serum lipid responses did not differ between groups consuming primarily LRM or LWM, as part of an NCEP Step I diet. In shorter studies conducted under highly controlled conditions, blood lipid responses to consuming lean beef were equivalent to responses to consumption of chicken, or chicken and fish.9,14 Scott and colleagues9,14 directly compared blood lipid responses with consumption of lean beef vs chicken and fish, or chicken alone, among men with hypercholesterolemia in 2 randomized, controlled feeding studies. These meats were incorporated into diets containing less than 30% of energy from fat and less than 10% of energy from saturated fatty acids, and all foods consumed by the participants were prepared by the investigators. In both trials, total cholesterol and LDL-C responses during the 4- to 5-week treatment periods were similar in the lean beef, chicken, and chicken and fish treatment groups. Similar findings have also been reported for normocholesterolemic subjects.8 Our trial extends these findings to a group of hypercholesterolemic men and women who were free to make their own choices regarding food selection and preparation over a 9-month period. Together, these studies provide compelling evidence to support the view that instructing patients with hypercholesterolemia to eliminate or markedly reduce all red meat intake is unnecessarily restrictive. Replacement of high-fat meats with leaner red or white meat selections has the potential to improve long-term dietary adherence by increasing food choices. Nearly all of the energy in meats is derived from protein and fat. The available data suggest that meat protein, per se, is not hypercholesterolemic.8,12,14 The blood cholesterol-raising potential of meat products appears to be a function of their fat and cholesterol contents. Red meats vary considerably in fat content. An 85-g (3-oz) serving of regular ground beef contains approximately 22 g of fat and 8 g of cholesterol-raising (12:0-16:0) fatty acids.8 The same size serving of ground round provides only 3 to 4 g of fat and less than 2 g of cholesterol-raising fatty acids. Therefore, substituting lean selections for higher fat cuts of red meat should favorably influence serum total cholesterol and LDL-C levels. Controlled feeding trials provide important information regarding the biological effects of dietary components. However, such information will have limited clinical utility if practical barriers exist that prevent translation into dietary choices for free-living persons. If, for example, LRMs were not readily available to consumers in supermarkets and restaurants, findings from controlled feeding studies would be of little relevance to patients and health care professionals. In recent years, consumers have had access to a wider variety of lean meat products. In the present study, the degree of lipid lowering after dietary counseling was modest for both treatment groups. Total cholesterol and LDL-C remained 1% to 3% below the baseline levels for the duration of the 36-week treatment period, suggesting that adherence to the NCEP Step I diet did not deteriorate over time. Participants were hypercholesterolemic on entry into the study while on a self-selected diet, although many had received prior counseling and were already consuming a diet similar to that recommended by the NCEP. Mean baseline cholesterol–saturated fat scores on the Diet Habit Survey were above 60 in both groups, suggesting that many subjects were consuming diets conforming to the NCEP recommendations.6 Further subgroup analysis of subjects with baseline scores above vs below 60 indicated that individuals compliant with the NCEP diet had less lipid lowering during treatment than did persons who were not compliant at baseline. In fact, noncompliant subjects (red and white combined) had a 3% to 5% LDL-C reduction from baseline. Thus, the lipid-lowering response in this group was close to the 5% to 10% lipid reduction expected from NCEP Step I diet intervention.6,19 Meat consumption logs indicated that both groups maintained their meat consumption according to their appropriate treatment; however, total meat consumption declined over time, particularly in the LWM group. During the final 12 weeks of the treatment period, the LWM group had a reported meat intake of approximately 10% less than during the first 4 weeks of the intervention period compared with the LRM group, which had only approximately a 5% decline. Many of the participants had been following a cholesterol-lowering diet prior to enrollment in the study and thus may have been restricting red meat intake at baseline. For these subjects, the LRM diet may have had higher palatability because it represented a greater change from the dietary pattern followed prior to entry into the trial. According to diet records, mean intakes (approximate) of total fat, saturated fats, and cholesterol at baseline were 32% of energy, 10.5% of energy, and 255 mg/d, respectively. Average fat consumption reported by US adults who participated in the third National Health and Nutrition Examination Survey was 34% of energy, while saturated fats comprised 12% of energy intake.20 Diet records suggest that subjects in the LRM group consumed more fat and cholesterol-raising fatty acids during the treatment phase. In addition, the LRM group showed a trend toward increased energy consumption compared with the LWM group. Although these differences were not large, they were statistically significant and are not fully consistent with the lack of difference in body weight and lipid responses between treatment groups. Food records are among the best tools for estimating dietary intake, particularly in a free-living population, yet subjects frequently underreport or overreport their intakes.21 Further difficulties arose from the Nutrition Data System assumptions for red meat selections, which may no longer be valid with the now widely available leaner cuts of meat. Red meats vary more in their fat content than do white meats. These variations may not be fully reflected by the Nutrition Data System, which has limited options for cuts of red meat and different external fat (trim) widths. Thus, limitations inherent in the methods available for collection of dietary data from free-living subjects may explain the differences observed. The data obtained from administration of the Diet Habit Survey suggest that there were no marked differences in cholesterol–saturated fat intakes between the 2 groups after 16 and 32 weeks of treatment. To further assess the potential impact of dietary differences between groups, predicted changes from baseline LDL-C concentration were calculated for each group using the equation published by Kris-Etherton and Yu22: ΔLDL-C (mmol/L or mg/dL)=1.46 Δ12:0-16:0+ 0.07 Δ18:0 – 0.69 ΔM – 0.96 ΔP, where 12:0-16:0 is the percentage of energy intake from cholesterol-raising fatty acids, 18:0 is the percentage of energy from stearic acid, M is the percentage of energy from monounsaturated fatty acids, and P is the percentage of energy from polyunsaturated fatty acids. Using this equation, the predicted change in LDL-C was −0.08 mmol/L (−3.0 mg/dL) for the LRM group compared with −0.13 mmol/L (−5.2 mg/dL) for the LWM group. Because this equation has no term for differences in cholesterol intake, an additional calculation was performed using a factor of 0.01 mmol/L (0.44 mg/dL) to account for the influence of each 1-mg/d difference of dietary cholesterol intake per 4184 kJ (1000 kcal) of energy, from the equation of Hegsted and colleagues.22 This resulted in predicted changes in LDL-C of −0.07 mmol/L (−2.9 mg/dL) vs −0.15 mmol/L (−5.7 mg/dL) for the LRM and LWM groups, respectively.22 Comparison of the mean actual vs predicted mean changes in LDL-C showed that they were nearly identical (P>.95). Therefore, these data support the view that differences between groups in the intake of nutritional components known to influence blood cholesterol levels were small and not clinically significant. Conclusions The results of this 36-week dietary intervention trial indicate that the serum lipid profile was similarly improved by implementation of an NCEP Step I diet when the primary sources of meat consumed were lean cuts of red meat (beef, veal, and pork) vs white meat (poultry and fish). Therefore, with instruction regarding meat selection and preparation, free-living persons can effectively incorporate LRMs into their diets on a long-term basis, without compromising the lipid-lowering benefits of the diet. Counseling patients to replace high-fat meats with leaner red and white meat selections allows a greater range of food choices, which may improve patient acceptance and long-term dietary adherence. Accepted for publication October 22, 1998. This research was funded by the National Cattlemen's Beef Association, Chicago, Ill. We thank Julie Kong, MS, RD; Julie Rink, RD; Cindy Miglieri, RD; Andrea Druetzler, MS, RD; Rebecca Westereng, RD, LD; Mary Patz, RD; Kathleen R. Shultz, RD, LD; and Liz Johnston, MPH, RD, LD, for their help with the conduct of the study. We also thank Mary R. Dicklin, PhD, and Penny Kris-Etherton, RD, PhD, for their assistance with the preparation and review of the manuscript. Reprints: Michael H. Davidson, MD, Chicago Center for Clinical Research, 515 N State St, Suite 2700, Chicago, IL 60610 (e-mail: [email protected]). References 1. Drexel HAmann FWBeran J et al. Plasma triglycerides and three lipoprotein cholesterol fractions are independent predictors of the extent of coronary atherosclerosis. Circulation. 1994;902230- 2235Google ScholarCrossref 2. Genest JMcNamara JSalem DSchaefer E Prevalence of risk factors in men with coronary artery disease. Am J Cardiol. 1991;671185- 1189Google ScholarCrossref 3. Holme I An analysis of randomized trials evaluating the effect of cholesterol reduction on total mortality and coronary heart disease incidence. Circulation. 1990;821916- 1924Google ScholarCrossref 4. Sarrett APatsch WSorlie PHeiss GBond MDavis C Associations of lipoprotein cholesterols, apolipoproteins A-I and B, and triglycerides with carotid atherosclerosis and coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study. Arterioscler Thromb. 1994;141098- 1104Google ScholarCrossref 5. Law MWald NThompson S By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease? BMJ. 1994;308367- 372Google ScholarCrossref 6. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, Second Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Washington, DC US Dept of Health and Human Services1993; 7. American Heart Association, Dietary guidelines for healthy American adults: a statement for physicians and health professionals by the nutrition committee. Circulation. 1988;77721A- 724AGoogle ScholarCrossref 8. Denke M Role of beef tallow, an enriched source of stearic acid, in a cholesterol-lowering diet. Am J Clin Nutr. 1994;60(suppl)1044S- 1049SGoogle Scholar 9. Scott LDunn JPownall H et al. Effects of beef and chicken consumption on plasma lipid levels in hypercholesterolemic men. Arch Intern Med. 1994;1541261- 1267Google ScholarCrossref 10. Hunt JKristal AWhite ELynch JFries E Physician recommendations for dietary change: their prevalence and impact in a population-based sample. Am J Public Health. 1995;85722- 726Google ScholarCrossref 11. McIntosh WFletcher RKubena KLandmann W Factors associated with sources of influence/information in reducing red meat by elderly subjects. Appetite. 1995;24219- 230Google ScholarCrossref 12. Morgan SSinclair AO'Dea K Effect on serum lipids of addition of safflower oil or olive oil to very-low-fat diets rich in lean beef. J Am Diet Assoc. 1993;93644- 648Google ScholarCrossref 13. Bonanome AGrundy S Effect of dietary stearate on plasma cholesterol and lipoprotein levels. N Engl Med J. 1988;3181244- 1248Google ScholarCrossref 14. Scott LKimball KWittels EH et al. Effects of a lean beef diet and of a chicken and fish diet on lipoprotein profiles. Nutr Metab Cardiovasc Dis. 1991;125- 30Google Scholar 15. Connor SGustafson JSexton GBecker NArtaud-Wild SConnor W The Diet Habit Survey: a new method of dietary assessment that relates to plasma cholesterol changes. J Am Diet Assoc. 1992;9241- 47Google Scholar 16. Maki KCBriones ERLangbein WE et al. Associations between serum lipids and indicators of adiposity in men with spinal cord injury. Paraplegia. 1995;33102- 109Google ScholarCrossref 17. Myers GCooper GWinn CSmith S The Centers for Disease Control-National Heart, Lung, and Blood Institute Lipid Standardization Program: an approach to accurate and precise lipid measurements. Clin Lab Med. 1989;9105- 135Google Scholar 18. Friedewald WLevy RFrederickson D Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18499- 502Google Scholar 19. Denke MAGrundy SM Individual responses to a cholesterol-lowering diet in 50 men with moderate hypercholesterolemia. Arch Intern Med. 1994;154317- 325Google ScholarCrossref 20. Ernst NDSempos CTBriefel RRClark MB Consistency between US dietary fat intake and serum total cholesterol concentrations: the National Health and Nutrition Examination Surveys. Am J Clin Nutr. 1997;66(4 suppl)965S- 972SGoogle Scholar 21. Lichtman SWPisarka KBerman ER et al. Discrepancy between self-reported and actual caloric intake and exercise in obese subjects. N Engl J Med. 1992;3271893- 1898Google ScholarCrossref 22. Kris-Etherton PMYu S Individual fatty acid effects on plasma lipids and lipoproteins: human studies. Am J Clin Nutr. 1997;65(suppl)1628S- 1644SGoogle Scholar

Psaty, Bruce M.;Furberg, Curt D.;Kuller, Lewis H.;Bild, Diane E.;Rautaharju, Pentti M.;Polak, Joseph F.;Bovill, Edwin;Gottdiener, John S.

doi: 10.1001/archinte.159.12.1339pmid: 10386510

Abstract Background Risk factors for myocardial infarction (MI) have not been well characterized in older adults, and in estimating risk, we sought to assess the individual and joint contributions made by both traditional risk factors and measures of subclinical disease. Methods In the Cardiovascular Health Study, we recruited 5888 adults aged 65 years and older from 4 US centers. At baseline in 1989-1990, participants underwent an extensive examination that included traditional risk factors such as blood pressure and fasting glucose level and measures of subclinical disease as assessed by electrocardiography, carotid ultrasonography, echocardiography, pulmonary function, and ankle-arm index. Participants were followed up with semiannual contacts, and all cardiovascular events were classified by the Morbidity and Mortality Committee. The main analytic technique was the Cox proportional hazards model. Results At baseline, 1967 men and 2979 women had no history of an MI. After follow-up for an average of 4.8 years, there were 302 coronary events, which included 263 patients with MI and 39 with definite fatal coronary disease. The incidence was higher in men (20.7 per 1000 person-years) than women (7.9 per 1000 person-years). In all subjects, the incidence was strongly associated with age, increasing from 7.8 per 1000 person-years in subjects aged 65 to 69 years to 25.6 per 1000 person-years in subjects aged 85 years and older. Glucose level and systolic blood pressure were associated with the incidence of MI, but smoking and lipid measures were not. After adjustment for age and sex, the significant subclinical disease predictors of MI were borderline or abnormal ejection fraction by echocardiography, high levels of intimal-medial thickness of the internal carotid artery, and a low ankle-arm index. Forced vital capacity and electrocardiographic left ventricular mass did not enter the stepwise model. Excluding subjects with clinical cardiovascular diseases such as prior angina or congestive heart failure at baseline had little effect on these results. Risk factors were generally similar in men and women. Conclusions After follow-up of 4.8 years, systolic blood pressure, fasting glucose level, and selected subclinical disease measures were important predictors of the incidence of MI in older adults. Uncontrolled high blood pressure may explain about one quarter of the coronary events in this population. IN MIDDLE-AGED adults, the major risk factors for a first myocardial infarction (MI) have been well characterized and include smoking, diabetes, lipid levels, and systolic and diastolic blood pressures.1-6 Drug treatment of hypertension and hyperlipidemia is known to reduce the risk of first coronary events.7,8 For several major risk factors in older adults, however, both the levels of risk and the benefits of intervention are in general less clearly established. While the benefits of the treatment of high blood pressure are clear,9,10 the risks associated with elevated levels of cholesterol and the potential benefits of therapy in older adults remain controversial.11-14 In recent years, advances in technology have also provided physicians with new diagnostic methods. Echocardiography is widely available, and early population-based studies suggested that echocardiographic left ventricular mass was an important predictor of MI.15 Ultrasound examination of the carotid arteries can be used to assess intima-to-media wall thickness (IMT) as a measure of atherosclerosis,16 and in a recent report from the Rotterdam Cohort Study, IMT of the common carotid artery was associated with increased risks of stroke and MI.17 In the assessment of the risk of MI, the individual and joint contributions of these subclinical disease measures and traditional risk factors have not been previously reported in population-based studies of older adults. The Cardiovascular Health Study (CHS) was designed to assess these risks. In this analysis, we sought to examine the association of incident MI with (1) traditional risk factors after adjustment for demographic factors, (2) subclinical disease measures before and after adjustment for traditional risk factors, and (3) the best overall set of predictors. Participants and methods Setting The CHS is a prospective cohort study of risk factors for coronary heart disease and stroke in men and women aged 65 years and older. In June 1990, 4 Field Centers completed recruitment of 5201 participants. In June 1993, the recruitment of an additional 687 African Americans was completed. Each community sample was obtained from random samples of the Medicare eligibility lists, and those eligible to participate included all persons who were living in the household of each individual sampled from the Health Care Financing Administration lists and who (1) were 65 years or older, (2) were noninstitutionalized, (3) expected to remain in the area for 3 years, and (4) gave informed consent and did not require a proxy respondent. Among those contacted and eligible, 57.3% were enrolled. The CHS design and recruitment experience are described in detail elsewhere.18,19 Baseline examination The baseline examination consisted of a home interview and a clinic examination. Participants answered standard questionnaires that assessed a variety of risk factors, including smoking, physical activity, and medical history of cardiovascular conditions.18 The self-reported medical conditions such as MI were validated.20 Medications were assessed by inventory at the home interview.21 Participants were asked to come to the clinic examination after a 12-hour overnight fast. Seated blood pressure, electrocardiography, and venipuncture were performed early in the examination as previously described.18 Duplicate measures of supine blood pressure in the right arm and both posterior tibial arteries were assessed by an 8-MHz Doppler probe attached to a stethoscope, and the ratio of systolic blood pressures was used to calculate the ankle-arm index. Anthropomorphic measures included weight and height. Electrocardiograms (ECGs) were read by the ECG Reading Center,22 and ECG left ventricular mass was estimated according to a new algorithm, which included the best predictors of echocardiographic left ventricular mass in the CHS population.23 The forced vital capacity and forced expiratory volume in 1 second were measured with a water-sealed spirometer (Collins Survey II; WE Collins, Braintree, Mass). Blood samples from the fasting venipuncture were analyzed at the Central Blood Analysis Laboratory for glucose; fibrinogen; factor VII, standardized to the World Health Organization reference materials; and total cholesterol, high-density lipoprotein cholesterol, and triglycerides, standardized according to the Centers for Disease Control and Prevention as previously described.18,24 Low-density lipoprotein cholesterol was calculated according to the Friedewald equation.25 Carotid sonography was performed with sonographic units (Toshiba SSA-270A; Toshiba America Medical Systems, Tustin, Calif). A single longitudinal lateral view with measurements taken at the distal 10 mm of the far wall of the right and left common carotid arteries and 3 views with measurements centered on the site of maximum wall thickening of the proximal right and left internal carotid arteries were recorded and read by the Ultrasound Reading Center.26 The IMT was the average of the discrete maximum separately for both common and both internal carotid arteries. Readers also estimated the maximum degree of luminal stenosis. The echocardiographic examinations included 2-dimensional and Doppler methods performed with the Toshiba SSH-160A sonographic units. The CHS Echocardiography Reading Center27 read M-mode left ventricular wall thicknesses and dimensions. Readers also classified the ejection fraction in qualitative terms as borderline or abnormal. The examination of the African American cohort in 1992-1993 was largely the same as the baseline examination of the main cohort in 1989-1990. Echocardiographic results were not available at baseline for the African American cohort, and based on the important predictors identified in the main cohort,28 ejection fraction was imputed.29-31 In sensitivity analyses, echocardiographic ejection fraction was an important predictor after excluding the African Americans recruited in 1992-1993. To include this subgroup of the cohort, we used the imputed ejection fraction for the African Americans recruited in 1992-1993. Subjects were excluded from the analysis if (1) they reported an MI prior to entry into CHS; (2) they had on their baseline ECG evidence of a previous MI defined as the presence of major Q waves or the combination of minor Q waves and ST-T wave changes32; or (3) during follow-up, they were found to have had an MI that predated their entry into CHS.33 Follow-up and classification of events Participants were contacted every 6 months, and the contacts alternated between a telephone interview and a clinic examination, which included an ECG. At each contact, participants were asked about cardiovascular events and all hospitalizations. Discharge summaries and diagnoses were obtained for all hospitalizations. For all potential incident cardiovascular events, additional information, including cardiac enzyme determinations and serial ECGs, was collected. The algorithm for classifying MI, which includes elements of chest pain, cardiac enzyme levels, and serial ECG changes, has been published.33 For participants whose fatal event did not meet the criteria for a definite fatal MI, deaths were classified as definite fatal coronary heart disease if the participants had chest pain within 72 hours of death or had a history of ischemic heart disease. Final classification of all cardiovascular events was determined by the consensus of the members of the Morbidity and Mortality Committee.33 To identify clinically unrecognized events, annual CHS clinic ECGs were read serially by the ECG Reading Center, and the development of new Q waves (major evolution of Q waves or moderate evolution of Q waves with major ST-T wave evolution; NOVACODES C1 and C222) in a patient without an intervening clinically recognized coronary event was counted as a new silent MI. Events that were judged by the Morbidity and Mortality Committee to be the consequence of a procedure such as surgery or angioplasty were eliminated from this analysis (n=5 for fatal events and n=45 for nonfatal events), and follow-up for these subjects was censored at the time of their procedure-related event. For subjects with an MI during follow-up, event times were computed as the time to the first definite event. For subjects with a silent MI during follow-up, the event times were set to the midpoint between the serial annual ECGs that identified the new Q waves. For subjects without events, censoring times were calculated as according to the last date of follow-up or the date of death. Definition of variables and statistical methods Although participants with a prebaseline MI were excluded, some had a history of coronary heart disease, which was defined as a history at baseline of angina, coronary angioplasty, coronary artery bypass surgery, or use of nitroglycerin at baseline. Clinical cardiovascular disease was defined as a history at baseline of coronary disease, congestive heart failure, stroke, or carotid endarterectomy. Several continuous variables were dichotomized: (1) systolic blood pressure less than 140 mm Hg vs 140 mm Hg or greater; (2) fasting glucose level less than 7 mmol/L vs 7 mmol/L or greater (<126 vs ≥126 mg/dL), which is the new recommended definition for diabetes34; (3) ankle-arm index less than 0.9 vs 0.9 or greater; and (4) internal carotid IMT less than 1.79 vs 1.79 mm or greater (80th percentile for subjects without clinical cardiovascular disease at baseline). We used SPSS-PC software for data analysis.35 Techniques included t tests for continuous variables, χ2 tests for categorical variables, and Cox proportional hazards models for multivariate analysis.36 Population attributable fraction was calculated according to the formula given by Rothman37 and uses information about the prevalence of a risk factor and its relative risk to estimate that risk factor's contribution to disease incidence in the population as a whole. All P values represent 2-sided tests. Approach to multivariate analysis The CHS has a large number of potential predictor variables, and in this analysis, we screened a representative sample of risk factors. The variables age, sex, race, and indicator variables for site were included in all models. Based on the initial bivariate screening, we selected a limited number of variables for multivariate analysis and submitted them to stepwise analysis in 2 separate groups. The first group included traditional major risk factors, which were systolic blood pressure, current smoking, fibrinogen level, fasting glucose level, and high-density lipoprotein cholesterol level. The second group included measures of subclinical disease, and for each examination component we selected a single predictor variable. The subclinical disease measures were ankle-arm index, maximum internal carotid IMT, ECG left ventricular mass, echocardiographic ejection fraction, and forced vital capacity. Data on left ventricular mass as assessed by echocardiography were missing for about one third of subjects, so we chose ECG left ventricular mass instead.23 Criteria for entry and exit in the stepwise models were P<.05 and P>.10, respectively. Results Excluded from this analysis were 403 men and 297 women who reported at baseline a previous history of MI; 97 men and 104 women with evidence of an MI on their baseline ECG; and 28 men and 13 women who, during follow-up, were found to have an MI that predated their entry into the CHS. Of 5888 participants, the 1967 men and 2979 women who were at risk of a first MI were included in this analysis and followed up for an average of 4.8 years. Among all events (Table 1), 29 (9.6%) of 302 were definite fatal MIs, and 39 (12.9%) represented definite fatal coronary heart disease. Another 40 (13.2%) MIs were detected only by the presence of new Q waves on annual in-clinic ECGs. The event rate in men was significantly higher than the rate in women (Table 2), and the incidence was strongly associated with age in both men and women (P<.01). Table 3 summarizes the baseline risk factors in men and women with and without clinical cardiovascular disease at baseline. In men and women, risk factors such as blood pressure and glucose level were generally higher in subjects with clinical cardiovascular disease. Lipid levels were similar in the 2 groups. The prevalence of smoking was actually lower in those with clinical cardiovascular disease at baseline. The subclinical disease measures, including ejection fraction, carotid IMT, and ankle-arm index, differed between those with and without clinical cardiovascular disease at baseline. Table 4 summarizes the bivariate associations between the incidence of MI and the risk factors that were considered for multivariate analysis. The unadjusted associations for many of the variables were strong and highly significant. With the exception of smoking, glucose level, and forced vital capacity, adjustment for age, sex, and clinical heart disease tended to reduce the strength of the associations. Table 5 summarizes the findings for traditional risk factors. After adjustment for age, sex, race, site, and clinical cardiovascular disease, the stepwise model included systolic blood pressure and fasting glucose level. The risk for current smoking was marginal (risk ratio, 1.41; 95% confidence interval, 0.99-2.00; P=.06). In analyses stratified on sex, the point estimates for the risk factors were similar in men and women. Table 6 summarizes the findings for subclinical disease measures after adjustment for demographic factors and traditional risk factors. Three variables—echocardiographic ejection fraction, ankle-arm index, and internal carotid IMT—entered the stepwise model. While internal carotid IMT was a significant predictor in both men and women, echocardiographic ejection fraction was a significant predictor only in women, and ankle-arm index only in men. Since the forced entry of all the traditional risk factors into the model in Table 6 may represent overadjustment, we repeated the analysis of subclinical disease measures after adjustment only for age, sex, race, site, and clinical cardiovascular disease (Table 7). Forced vital capacity and ECG left ventricular mass still did not enter the stepwise model. Ankle-arm index was primarily a predictor in participants who did not have clinical cardiovascular disease at baseline. In Table 8, we restricted the analysis to subjects without clinical cardiovascular disease at baseline. In this analysis, we adjusted for age, sex, race, and site, and permitted the traditional and subclinical disease measures to compete for entry into the stepwise model. Among all subjects, the significant predictors were the same—systolic blood pressure, fasting glucose level, ankle-arm index, echocardiographic ejection fraction, and internal carotid IMT. With the exception of ejection fraction, the point estimates for these risk factors were similar in men and women. In sex-specific stepwise models, systolic blood pressure, glucose level, ankle-arm index, and internal carotid IMT entered for men; and for women, systolic blood pressure, echocardiographic ejection fraction, and ankle-arm index. Figure 1 provides estimates of the population attribution fraction for these 5 predictors of MI among subjects free of clinical cardiovascular disease at baseline. Continuous variables were dichotomized. The range of prevalences was wide, from 5.2% for abnormal ejection fraction up to 39.5% for elevated systolic blood pressure. The population attributable fractions were highest for the traditional risk factors of elevated systolic blood pressure (24.0%) and fasting glucose level (12.8%). For each of the 3 subclinical disease measures, the population attributable fractions were less than 10%. In additional analysis, results were similar when we excluded the African American cohort recruited in 1992-1993. Systolic blood pressure was much more strongly associated with the incidence of MI than diastolic blood pressure, and after adjustment for systolic blood pressure, there was no association with diastolic blood pressure. None of the lipid measures (total, high-density lipoprotein, and low-density lipoprotein cholesterol or triglycerides) was associated with the risk of MI in this population. In the CHS, the maximum IMT of the internal but not the common carotid artery was associated with the incidence of MI. Analysis using quintiles for systolic blood pressure, ankle-arm index, and carotid IMT suggested generally linear trends in risk for these continuous variables while the elevated risk associated with glucose level was largely confined to those in the highest quintile (glucose level >6.3 mmol/L [>114 mg/dL]). There was no significant interaction between glucose level and drug treatment for diabetes (P=.79) or between systolic blood pressure and drug treatment for hypertension (P=.31). Excluding definite fatal coronary heart disease and excluding silent MI by annual ECG had little effect on the predictors or their estimated risk ratios. Comment During an average of 4.8 years of follow-up, we identified a first coronary event in 302 (6.1%) of 4946 older adults. The incidence was strongly associated with age, sex, and the presence of other clinical cardiovascular disease. Traditional risk factors, including systolic blood pressure and fasting glucose level, were strongly associated with the incidence of MI in this analysis. The results for smoking were marginal, and there was no association with lipid levels. Several measures of subclinical disease were also important predictors. Internal carotid IMT, ankle-arm index, and echocardiographic ejection fraction were associated with the incidence of MI. In this analysis, forced vital capacity and ECG left ventricular mass did not enter the stepwise models although they were associated with MI in bivariate analyses. In the CHS, the age-sex specific incidences of MI were 16.3 and 5.8 per 1000 person-years in men and women, respectively, aged 65 to 74 years at baseline and 28.7 and 12.9 in men and women aged 75 to 84 years at baseline. These rates are similar to those reported from 30 years of follow-up (through 1978) in the Framingham Heart Study.6 For the end point of coronary heart disease without angina,6 the respective age-sex specific incidences from Framingham were 18 and 8 per 1000 person-years in men and women aged 65 to 74 years and 27 and 14 in men and women aged 75 to 84 years. While mortality from coronary heart disease has declined precipitously in the past 30 years, the incidence in older adults appears to have changed little. The CHS findings of a relatively high incidence of coronary disease in older adults is consistent with the findings from other studies.38,39 In the Minnesota Heart Survey,39 mortality from coronary disease declined much more dramatically than the occurrence of hospitalizations. Both the improvements in medical care and the detection of less severe events in recent years may be responsible for these trends. Nonetheless, 13.2% of coronary events in the CHS remained clinically silent, detected only as Q wave changes on annual in-clinic ECGs. In general, the findings from the CHS for traditional risk factors are consistent with those of many previous studies. Although smoking was only marginally significant after adjustment for age, sex, race, clinical cardiovascular disease, systolic blood pressure, and fasting glucose level, the point estimate of a 41% increase in risk is consistent with estimates of other studies that have examined the effect of smoking in older adults.40-42 In the CHS, both systolic blood pressure and glucose level were strongly associated with the incidence of MI in older adults. Diabetes is a well-known risk factor in middle-aged adults,43,44 and several recent studies have given us a new appreciation for the importance of diabetes as a risk factor for ischemic heart disease in older adults.45,46 In older adults, systolic blood pressure is a major risk factor for coronary disease,9,47,48 and the data from the CHS suggest that even mild elevations above 140 mm Hg—an elevation present in about 40% of the population—may be important. There was little association between the incidence of coronary disease and plasma lipid levels in the CHS. Follow-up was relatively short in the CHS, and there is some evidence that the strength of the association between cholesterol level and risk increases with longer follow-up.49 While the level of risk appears to be smaller in the elderly than in the middle-aged, the general consensus seems to be that lipid levels are a risk factor for coronary disease in older adults.4,11-14,46 In this analysis, a number of measures of subclinical disease were also associated with the incidence of coronary disease in older adults. Internal carotid IMT, borderline or abnormal echocardiographic ejection fraction, and low ankle-arm index were all independently associated with coronary disease in the CHS cohort even after adjustment for demographic factors, systolic blood pressure, and fasting glucose level. It is interesting to speculate that since ejection fraction is depressed prior to infarction in some subjects, ischemic hibernation may antedate myocardial necrosis. The findings for subclinical disease are similar to the results of other studies. Low ankle-arm index is a strong predictor of mortality in older adults.50 In the Kuopio Ischemic Heart Disease Risk Factor Study,51 intimal-medial thickening of the common carotid artery was associated with a 2-fold increase in the risk of coronary heart disease. In the Atherosclerosis Risk in Communities Study, Chambless and colleagues52 also reported a strong graded association between carotid IMT and the incidence of coronary heart disease. Although echocardiographic left ventricular mass was also a risk factor in the Framingham Heart Study,15 ECG left ventricular mass was not an independent risk factor in this analysis from CHS. Forced vital capacity was an important predictor in Framingham,53 but did not enter the stepwise models in this analysis. At the outset, we identified a limited number of candidate variables, and by doing so, we did not examine the association between the incidence of MI and a large number of other variables that may be important predictors. Moreover, in stepwise analysis, the entry of additional variables and the estimates of their relative risks depend importantly on the variables that are already in the model. The CHS is a population-based study, and 57.3% of eligible subjects enrolled in the CHS. Population attributable fractions depend on estimates of both prevalence and risk level. The prevalences of hypertension and diabetes were actually lower in those who were eligible and enrolled than in those who were eligible but did not enroll.19 If, as seems likely, the associations of risk factors and disease incidence are similar between the enrolled and the unenrolled, the population attributable fractions for these risk factors in the CHS may be slightly underestimated. Compared with the measurement of blood pressure or fasting glucose, the subclinical disease measures represent more costly high-technology methods of assessing risk. Some of them, including echocardiographic ejection fraction and internal carotid maximum IMT, were important independent risk factors for coronary disease in this study, and clearly their use significantly improved the ability to predict coronary events in older adults. For the clinician seeing patients who have multiple risk factors, including those risk factors defined by subclinical disease measures, it is important to emphasize that these patients have high rates of coronary events.54,55 From the point of screening populations, however, these high-risk patients are uncommon. Among subjects without clinical cardiovascular disease at baseline, the prevalences of low ankle-arm index and borderline or abnormal ejection fraction were relatively low, found in only 9.5% and 5.2.% of the population at baseline, respectively (Figure 1). In this population, elevated levels of blood pressure and glucose clearly pose the greatest hazard to the health of the public ( Figure 1). Systolic blood pressure elevated above 140 mm Hg may explain one quarter of the coronary events in this study. For stroke in older adults, elevated systolic blood pressure may explain about one third of cerebrovascular events.31 While the health effects of the aggressive treatment of elevated glucose levels in patients with type 2 diabetes are currently under study,56 the effectiveness of antihypertensive therapy, especially low-dose diuretic therapy, is well established in older adults.7 The absolute risk reductions associated with the low-dose diuretic therapy to treat elevated systolic pressure are twice as high in diabetic as in nondiabetic individuals.57 Both in terms of the levels of risk and the prevalence of the conditions, the treatment of even modest levels of systolic hypertension and the prevention of glucose intolerance with diet and physical activity are likely to have the largest effects in preventing the incidence of coronary disease in older adults. Accepted for publication September 29, 1998. This research was supported by contracts N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, and N01-HC-85086 from the National Heart, Lung, and Blood Institute, and from the NWO (Nederlandse Organisatie voor Wetenschappelijk Onderzoek). Dr Psaty is a Merck/SER Clinical Epidemiology Fellow (sponsored by the Merck Co Foundation, Rahway, NJ, and the Society for Epidemiologic Research, Baltimore, Md). We appreciate the comments, criticisms, and suggestions that Teri Manolio, MD, MHS, provided on earlier drafts of the manuscript. Reprints: Cardiovascular Health Study, Coordinating Center, Century Square, Suite 2105, 1501 Fourth Ave, Seattle, WA 98101. Participating Institutions and Principal Staff Field Center in Forsyth County, North Carolina: Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, NC: Gregory L. Burke, Alan Elster, Walter H. Ettinger, Curt D. Furberg, Edward Haponik, Gerardo Heiss, Dalane Kitzman, H. Sidney Klopfenstein, Margie Lamb, David S. Lefkowitz, Mary F. Lyles, Cathy Nunn, Ward Riley, Maurice Mittelmark, Grethe S. Tell, James F. Toole, Beverly Tucker; Bowman Gray School of Medicine–ECG Reading Center: Farida Rautaharju, Pentti Rautaharju. Field Center in Sacramento County, California: University of California, Davis: William Bommer, Charles Bernick, Andrew Duxbury, Mary Haan, Calvin Hirsch, Paul Kellerman, Lawrence Laslett, Marshall Lee, Virginia Poirier, John Robbins, Marc Schenker, Nemat Borhani. Field Center in Washington County, Maryland: The Johns Hopkins University, Baltimore, Md: M. Jan Busby-Whitehead, Joyce Chabot, George W. Comstock, Linda P. Fried, Joel G. Hill, Steven J. Kittner, Shiriki Kumanyika, David Levine, Joao A. Lima, Neil R. Powe, Thomas R. Price, Jeff Williamson, Moyses Szklo, Melvyn Tockman; MRI Reading Center–The Johns Hopkins University: R. Nick Bryan, Carolyn C. Meltzer, Douglas Fellows, Melanie Hawkins, Patrice Holtz, Michael Kraut, Grace Lee, Larry Schertz, Earl P. Steinberg, Scott Wells, Linda Wilkins, Nancy C. Yue. Field Center in Allegheny County, Pennsylvania:University of Pittsburgh, Pittsburgh, Penn: Diane G. Ives, Charles A. Jungreis, Laurie Knepper, Lewis H. Kuller, Elaine Meilahn, Peg Meyer, Roberta Moyer, Anne Newman, Richard Schulz, Vivienne E. Smith, Sidney K. Wolfson. Echocardiography Reading Center (Baseline)–University of California, Irvine: Hoda Anton-Culver, Julius M. Gardin, Margaret Knoll, Tom Kurosaki, Nathan Wong; Echocardiography Reading Center (Follow-up)–Georgetown Medical Center, Washington, DC: John Gottdiener, Eva Hausner, Stephen Kraus, Judy Gay, Sue Livengood, Mary Ann Yohe, Retha Webb; Ultrasound Reading Center–Tufts, New England Medical Center, Boston, Mass: Daniel H. O'Leary, Joseph F. Polak, Laurie Funk; Central Blood Analysis Laboratory–University of Vermont, Colchester: Edwin Bovill, Elaine Cornell, Mary Cushman, Russell P. Tracy; Respiratory Sciences–University of Arizona-Tucson: Paul Enright; Coordinating Center–University of Washington, Seattle: Alice Arnold, Annette L. Fitzpatrick, Bonnie K. Lind, Richard A. Kronmal, Bruce M. Psaty, David S. Siscovick, Lynn Shemanski, Lloyd Fisher, Will Longstreth, Patricia W. Wahl, David Yanez, Paula Diehr, Maryann McBurnie; National Heart, Lung, and Blood Institute Project Office: Diane E. Bild, Robin Boineau, Teri A. Manolio, Peter J. Savage, Patricia Smith. References 1. Rosenberg LPalmer JRShapiro S Decline in the risk of myocardial infarction among women who stop smoking. N Engl J Med. 1990;322213- 217Google ScholarCrossref 2. Pan W-HCedres LBLiu KDryer ASchoenberger JAShekelle RB et al. Relationship of clinical diabetes and asymptomatic hyperglycemia to risk of coronary heart disease in men and women. 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Wu, Jin-Shang;Lu, Feng-Hwa;Yang, Yi-Ching;Chang, Chih-Jen

doi: 10.1001/archinte.159.12.1350pmid: 10386511

Abstract Background Postural hypotension with a decline of 20 mm Hg or more in systolic blood pressure on standing is considered a potentially dangerous hypotensive response. Postural dizziness is often strongly associated with postural hypotension. However, there is conflicting evidence, and previous studies have been confined to the elderly, not specifically to patients with diabetes. Thus, we evaluated the association between postural hypotension and postural dizziness, and determined the factors most likely related to postural hypotension in patients with diabetes. Methods The subjects were 204 consecutive non–insulin-dependent patients with diabetes and 408 age- and sex-matched control subjects. Postural hypotension was defined as a decline of 20 mm Hg or more in systolic blood pressure 1 minute after standing. Postural dizziness was any feelings of dizziness, light-headedness, or faintness that occurred while standing during the examination. Results The prevalence of postural hypotension and postural dizziness in patients with diabetes was higher than in control subjects. Those patients with both diabetes and postural hypotension were older and had higher supine systolic blood pressures and higher plasma glycosylated hemoglobin and fasting glucose levels. They had higher prevalence of postural dizziness, hypertension, and cerebrovascular disease, and lower standing systolic blood pressures than those without postural hypotension. They also were more often being treated with antihypertensive agents. Only 32.8% of patients with diabetes with postural hypotension suffered from postural dizziness. Postural dizziness, hypertension, cerebrovascular disease, and plasma glycosylated hemoglobin levels were independently associated with postural hypotension in patients with diabetes. Conclusions Postural dizziness, glycemic control, hypertension, and cerebrovascular disease were important determinants of postural hypotension in patients with diabetes. Postural hypotension was associated with postural dizziness, but it cannot be determined clinically just from the presence of postural dizziness because the sensitivity for diagnosis of postural hypotension is low. POSTURAL hypotension is considered the most dramatic clinical manifestation and hallmark of diabetic autonomic neuropathy.1,2 In patients with diabetes, autonomic neuropathy with abnormal cardiovascular reflex tests has been associated with increased mortality from unexpected sudden death and renal failure.3,4 However, there is no uniform criterion for postural hypotension that may be symptomatic or asymptomatic.5 Although postural hypotension is most commonly defined as a drop of 20 mm Hg or more in systolic blood pressure from the lying posture to the upright posture,6-11 the lack of symptoms associated with postural hypotension raises a question about the clinical value of this definition. It is reasonable to define postural hypotension as a particular decline in blood pressure that can predict a poor outcome.10 A study of the Hypertension Detection and Follow-up Program6 revealed that a decline of 20 mm Hg or more in systolic blood pressure after standing was associated with a high 5-year mortality rate, which indicated a poor prognosis for patients with diabetes complicated with hypertension. Epidemiological evidence also suggested that postural change with a decrease of 20 mm Hg or more in systolic blood pressure was a significant risk factor for fall and syncope.7,8 Furthermore, a drop of more than 20 mm Hg in postural systolic blood pressure was a risk factor for symptomatic occlusive cerebrovascular disease.9 Therefore, Lipsitz10 thought that postural hypotension with a decline of 20 mm Hg or more in systolic blood pressure on standing should be used to define a potentially dangerous hypotensive response. Postural dizziness was believed to be due to reduced cerebral perfusion.8,12,13 However, Ohashi et al14 used single photon emission computed tomography to examine cerebral blood flow and showed that regional cerebral autoregulation was not associated with postural dizziness. Thus, the mechanism of postural dizziness may be heterogeneous.15 Clinically, postural dizziness is often strongly associated with postural hypotension, but the evidence is conflicted.11,16-18 Some people with minor drops in systemic blood pressure develop clinical signs of cerebral ischemia and complain of dizziness or faintness on standing, whereas others with greater drops in blood pressure remain asymptomatic.12 Thus, some reports indicate that postural hypotension is related to postural dizziness,16,18 while others show that there is no association between postural hypotension and postural dizziness.11,17 Certain medications, normal aging, and some pathological changes such as diabetes mellitus, hypertension, and cerebrovascular disease are believed to be associated with postural hypotension.10,19,20 Similarly, postural dizziness is also associated with age, medication use, and comorbid diseases such as diabetes and stroke.16,21,22 Some of these associated factors are interrelated and interdependent, which may confound the relationship between postural hypotension and postural dizziness. Studies on the factors most likely related to postural hypotension in subjects with diabetes have been few,23,24 and they did not examine postural hypotension as an outcome variable in multivariate analysis with adjustment for other confounding factors. One of the studies did not adjust for the use of medications, which was one of the important associated factors of postural hypotension.24 As for the association between postural hypotension and postural dizziness, some studies have examined their relationship,11,16-18,25 but the subjects were limited to the elderly, not specifically to patients with diabetes. Therefore, we have conducted a case-controlled study to evaluate the association between postural hypotension and postural dizziness in patients with diabetes. Subjects and methods The subjects were 204 consecutive non–insulin-dependent patients with diabetes and 408 age- and sex-matched nondiabetic control subjects who underwent physical examinations for preventive reasons at the National Cheng Kung University Hospital between October 1992 and September 1994. Subjects were excluded from the study for sympathectomy, anemia, thyroid disorder, pregnancy, chronic alcohol use, and/or use of anti-Parkinson drugs, narcotics, sedatives, antipsychotic agents, or antidepressants within 2 weeks of the study. The subjects with diabetes included 114 men and 90 women with a mean age ± SD of 57.9 ± 10.5 years. The nondiabetic control subjects were 228 men and 180 women with a mean age ± SD of 57.1 ± 9.5 years. Demographic characteristics, medical history, and use of medications were assessed using a standard structured questionnaire. All the subjects received a complete physical examination, measurement of seated blood pressure, body weight, height, and ophthalmic consultation. The laboratory tests included blood chemistry analysis, a 75-g oral glucose tolerance test after a 10-hour overnight fast, and standard 12-lead electrocardiography. Blood pressure and heart rate were measured based on the American Heart Association recommendations26 with a vital sign monitor (DINAMAP TM, model 1846SX; Critikon Inc, Irvine, Calif). The participants were instructed to not consume alcohol, coffee, or tea, or to smoke cigarettes on the day of the examination. Measurements were obtained at least 3 hours after a meal in a quiet room. The appropriate-sized cuff was wrapped around the right upper arm and blood pressure and heart rate were recorded after the subject had rested in a supine position for at least 5 minutes. The subject was then asked to stand, with the entire forearm relaxed and supported at the heart level (fourth intercostal space) on an adjustable table; measurements of blood pressure and heart rate were repeated after 1, 2, and 3 minutes of standing.5,26 The subjects were asked about any feelings of dizziness, light-headedness, or faintness during the standing procedure and a positive or negative response was recorded. Clinical diagnoses and definitions were determined as follows: (1) Diabetes mellitus was diagnosed with a fasting plasma glucose measurement of 7.8 mmol/L (140 mg/dL) or greater or 11.1 mmol/L (200 mg/dL) or greater 2 hours after a glucose load (75 g), when a history of diabetes was reported, or if the subject currently used insulin or an oral hypoglycemic agent.27 (2) Postural hypotension was defined as a drop in systolic blood pressure from the lying position to the upright position of 20 mm Hg or more after 1 minute of standing.11,16,25 (3) Postural dizziness was defined as any feelings of dizziness, light-headedness, or faintness while standing during the examination.11,16,25 (4) Body mass index (BMI or Quetelet index) was calculated as weight in kilograms divided by the square of the height in meters: weight (kg)/[height (m)]2. (5) Hypertension was defined as the average of 3 seated readings of systolic/diastolic blood pressure equal to or higher than 140/90 mm Hg or a positive response to a history of hypertension or current use of antihypertensive agents.28 (6) Cerebrovascular disease was defined as a previously documented stroke or transient ischemic attack, or presence of hemiparesis, asymmetric hyperreflexia, motor rigidity, or a positive Babinski reflex on physical examination.7 (7) Diabetic retinopathy included background and preproliferative and proliferative diabetic retinopathy.29 (8) Electrocardiography of left bundle-branch block or ischemic patterns were interpreted according to the Minnesota code.30 They included Q-QS abnormalities, various degrees of ST segment depression, T-wave changes, and left bundle-branch block (Minnesota code 1.1-3; 4.1-3; 5.1-3 and 7.1).30 Comparisons of categorical variables were analyzed using the χ2 test. Comparisons of continuous variables between the 2 groups were carried out using the Student t test or the Mann-Whitney U test, where appropriate. Analysis of variance was used for comparisons of blood pressure and levels of fasting plasma glucose, glycosylated hemoglobin, cholesterol, and triglycerides with covariance of age and BMI between the 2 groups. Stepwise multiple logistic regression analysis was used to assess the association of clinical variables with postural hypotension. P values of .05 or lower indicated statistical significance. Results Table 1 shows the clinical characteristics of subjects with diabetes and nondiabetic control subjects. Subjects with diabetes had significantly higher BMI, seated blood pressure, and heart rate; they had significantly higher plasma creatinine, cholesterol, triglyceride, fasting glucose, and glycosylated hemoglobin levels, and a significantly higher prevalence of hypertension and use of antihypertensive agents than nondiabetic control subjects. However, there were no significant differences between subjects with diabetes and nondiabetic control subjects in age, sex, prevalence of cerebrovascular disease, or left bundle-branch block or ischemic patterns on electrocardiography. Figure 1 reveals the prevalence of postural hypotension and postural dizziness in subjects with diabetes and nondiabetic control subjects. Subjects with diabetes had a significantly higher prevalence of postural hypotension and postural dizziness than nondiabetic control subjects (subjects with diabetes vs those without: postural hypotension, 28.4% vs 15.4%, P<.001; postural dizziness, 22.5% vs 15.4%, P=.03). If we used the criterion of decrease in systolic blood pressure of 20 mm Hg or greater within 3 minutes of standing as the diagnosis of postural hvpotension, subjects with diabetes also had significantly higher prevalence of postural hypotension and postural dizziness than nondiabetic control subjects (subjects with diabetes vs those without: postural hypotension, 36.3% vs 22.8%, P<.001; postural dizziness, 26.5% vs 19.1%, P=.04) (data not shown). Figure 2 illustrates the prevalence of postural dizziness in subjects with diabetes and nondiabetic control subjects with and without postural hypotension. Among subjects with diabetes, those with postural hypotension had a higher prevalence of postural dizziness than those without. However, only 19 (32.8%) of 58 subjects with both diabetes and postural hypotension suffered from postural dizziness. Among nondiabetic control subjects, there was no significant difference in the prevalence of postural dizziness between those with and those without postural hypotension. The prevalence of postural hypotension in subjects receiving different types of antihypertensive medications was as follows: calcium channel blockers, 18.8% (9/48); α-blockers, 26.3% (5/19); β-blockers, 13.6% (3/22); labetalol, 27.3% (3/11); angiotensin-converting enzyme inhibitors, 10.8% (4/37); diuretics, 30.0% (3/10); nitrates, 16.7% (2/12); and hydralazine, 33.3% (1/3). In univariate analysis, there was no association between postural hypotension and any of the above antihypertensive medications. Thus, we merged those subjects using the above antihypertensive medications into 1 group for analysis. Table 2 presents the comparisons of clinical variables in the subjects with diabetes and nondiabetic control subjects with and without postural hypotension. Subjects with both diabetes and postural hypotension were older and had higher supine systolic blood pressures, higher plasma glycosylated hemoglobin and fasting glucose levels, and higher prevalences of hypertension and cerebrovascular disease, and use of antihypertensive agents; they had lower standing systolic blood pressure than subjects with diabetes without postural hypotension. There were no statistical differences between subjects with diabetes who had postural hypotension and those who did not in sex, BMI, supine resting heart rate, heart rate change (heart rate after 1 minute of standing vs supine resting heart rate), or duration of diabetes. There were no statistical differences in plasma albumin, cholesterol, triglyceride, or creatinine levels or in the prevalence of left bundle-branch block or ischemic patterns on electrocardiographic studies; and there were no statistical differences in diabetic retinopathy or the use of insulin and oral hypoglycemic agents. In nondiabetic control subjects, those with postural hypotension were older and had higher supine systolic blood pressure and prevalence of hypertension, and lower standing systolic blood pressure than those without postural hypotension. As compared with nondiabetic control subjects with postural hypotension, subjects with both diabetes and postural hypotension had higher plasma cholesterol, triglyceride, fasting glucose, and glycosylated hemoglobin levels, and higher prevalences of hypertension, cerebrovascular disease, and use of antihypertensive agents. Subjects with diabetes but without postural hypotension had higher BMI, higher supine and standing systolic blood pressure, higher plasma cholesterol, triglyceride, fasting glucose, and glycosylated hemoglobin levels, and higher prevalence of hypertension and use of antihypertensive agents than nondiabetic control subjects without postural hypotension. To examine the relationship between postural hypotension and postural dizziness, the outcome variable was postural hypotension and the predictor variables included postural dizziness and other clinical variables in multiple logistic regression analysis (Table 3). For total study populations, the predictor variables included postural dizziness, age, BMI; plasma cholesterol, triglyceride, and creatinine levels; and diabetes mellitus, hypertension, cerebrovascular disease, and use of insulin or oral hypoglycemic and antihypertensive agents. The results show that an independently positive correlation existed between postural hypotension and the following variables: age (P=.005), diabetes mellitus (P=.005), and hypertension (P=.001). An increase in the number of these independently associated factors increased the likelihood of postural hypotension. In subjects with diabetes, the predictor variables of multiple logistic regression included postural dizziness, age, BMI; plasma cholesterol, triglyceride, creatinine, and glycosylated hemoglobin levels; and duration of diabetes, diabetic retinopathy, hypertension, cerebrovascular disease, and use of insulin or oral hypoglycemic and antihypertensive agents. The results demonstrated that postural dizziness (P=.02), glycosylated hemoglobin levels (P=.002), hypertension (P=.002), and cerebrovascular disease (P=.04) were independently associated with postural hypotension. In nondiabetic control subjects, the predictor variables included postural dizziness, age, and BMI; plasma cholesterol, triglyceride, creatinine, and glycosylated hemoglobin levels; and hypertension, cerebrovascular disease, and use of antihypertensive agents. The results indicated that age (P=.01) and hypertension (P=.01) were independently related to postural hypotension. If we used the criterion of decrease in systolic blood pressure of 20 mm Hg or greater within 3 minutes of standing as the diagnosis of postural hypotension, the relationships between postural hypotension and postural dizziness were not changed in the diabetic, nondiabetic, and total groups. For total study populations, age (P=.002), diabetes mellitus (P=.03), hypertension (P=.002), and cerebrovascular disease (P=.04) were independently associated factors of postural hypotension. In subjects with diabetes, postural dizziness (P=.03), glycosylated hemoglobin levels (P=.008), hypertension (P=.005), and cerebrovascular disease (P=.01) were independently associated with postural hypotension. In nondiabetic control subjects, age (P=.004) and hypertension (P=.04) were independently related to postural hypotension (data not shown). Comment There are varying criteria for the diagnosis of postural hypotension19,20,31; the most recent consensus is a drop in blood pressure of at least 20 mm Hg systolic or 10 mm Hg diastolic within 3 minutes of either standing or head-up tilt of at least 60°.5 However, several important studies have examined the relationship between postural dizziness and postural hypotension with the test of 1 minute of standing.11,16,25 For comparison with the above studies, we used the criterion of 1 minute of standing in this study. The impact of changing the criterion from 1 minute to 3 minutes of quiet standing was only that the prevalence of postural hypotension and postural dizziness increased in subjects both with and without diabetes. However, there was no change in the relationship between postural hypotension and postural dizziness in the 2 groups. Diabetes mellitus was an independently associated factor of postural hypotension in our study, which is consistent with the literature.1,3,19,32 Regarding the mechanism of postural hypotension in diabetes, there is more commonly a neurogenic cause usually associated with efferent involvement of the baroregulatory reflex arc with damaged sympathetic vasoconstrictor fibers in the splanchnic bed, muscle, and skin.5 In contrast, diminished cardiac acceleration may play a lesser role in the development of postural hypotension.33,34 Our patients with diabetes had a higher resting heart rate than nondiabetic control subjects, which is consistent with other reports.35,36 A higher resting heart rate is often observed in patients with diabetes, and this is due to cardiac vagal neuropathy.35,36 With progression of diabetic autonomic neuropathy, some patients experienced initial tachycardia that may be followed by a decreased heart rate and, ultimately, a fixed heart rate due to the progression of cardiac sympathetic nerve dysfunction.37-39 The increase in heart rate on standing results from the dual effects of inhibition in cardiac vagal tone and increase in sympathetic tone.40 The heart rate change after standing in those subjects with postural hypotension was lower than in those without because sympathetic abnormalities in patients with diabetes are detectable almost exclusively after cardiac vagal neuropathy is impaired.41-43 Although all of our subjects with postural hypotension, both with and without diabetes, had lower heart rate changes than those without postural hypotension, the difference was not significant. This may be due to the high fatality rate in subjects with postural hypotension3,4 and the minor role of diminished cardiac acceleration in the development of postural hypotension,33,34 thus causing an underestimate in the relationship between postural hypotension and heart rate change after standing. Reported studies have revealed that poor glycemic control of diabetes mellitus, which is shown by increasing plasma glycosylated hemoglobin levels, was vulnerable to postural hypotension.23,24 In our patients with diabetes, plasma glycosylated hemoglobin was an independently positive factor correlated with postural hypotension. Therefore, good glycemic control is important in the prevention of postural hypotension in subjects with diabetes, which is also suggested in other reports.1,23,24 Duration of diabetes has often been perceived as an associated factor of postural hypotension, but the evidence was sparse. The prevalence of postural hypotension (the criteria of postural hypotension with a systolic blood pressure change of 30 mm Hg or more) increased with duration of diabetes in a young group (aged 18-34 years).24 However, our study and another report23 showed that duration was not independently associated with postural hypotension. Because postural hypotension was associated with increased mortality,3,4 the prevalence of postural hypotension in survivors would be diminished.24 This may be the partial explanation for the discrepancy between the prevalence of postural hypotension and duration of diabetes. The prevalence of postural hypotension was 28.4% in our subjects with diabetes. Hilsted and Low1 reported 2 studies on diabetes mellitus complicated with postural hypotension in 19 (26%) of 73 patients and 7 (43%) of 16 patients. Tsutsu et al23 reported on 157 (18%) of 886 cases of patients with diabetes. The variation was considered to be due to the referral bias.1 The literature has revealed that cerebrovascular disease is a risk factor associated with postural hypotension,10,11,19 because it may interrupt the central nervous system pathways that control autonomic reflexes.32 Cerebrovascular disease was an independently associated factor of postural hypotension in our patients with diabetes. However, the Cardiovascular Health Study Collaborative Research Group did not find a positive association between postural hypotension and stroke,17 suggesting that a high fatality rate in strokes associated with postural hypotension (ie, the result of a survival effect) may explain the negative results in the association between stroke and postural hypotension.17 Our results suggest that hypertension is associated with postural hypotension in subjects with diabetes and in nondiabetic control and total subjects as well, which is consistent with the findings of other studies.11,16,18,25,44 Hypertension has been shown to be associated with impaired baroreflex sensitivity, which may be due to a decrease in vascular compliance and consequent diminution of baroreceptor stretch and relaxation during blood pressure changes.44,45 Moreover, an increase in blood pressure and the duration of hypertension may exacerbate the decline in baroreflex sensitivity, in part, causing postural hypotension.20,45 Although the literature has shown that antihypertensive medication was related to postural hypotension,10,19 our study and another report46 revealed that there was no significant association between postural hypotension and antihypertensive medication. Masuo et al47 showed that the incidence of postural hypotension decreased significantly followed by decreasing blood pressure and normalizing blood pressure with the use of antihypertensive drugs (especially calcium channel blockers, β-blockers, and angiotensin-converting enzyme inhibitors) in elderly patients with hypertension. This may be a partial explanation for the dissociation between postural hypotension and antihypertensive medication. Another factor could be due to an underestimation in a cross-sectional study if a past occurrence of a treatment adverse effect or related symptom led to an adjustment of the treatment regimen.46 The mechanism of postural dizziness remains obscure and may be heterogeneous.12 Some reports have suggested postural hypotension or cerebral ischemia may be involved in postural dizziness,12,13 and others have suggested vestibular dysfunction, vision impairment, and disorders in the proprioceptive system may be also involved.15,48 Thus, postural hypotension is just 1 of the causes of postural dizziness, and it is not surprising that only 19 (32.8%) of 58 subjects with diabetes and postural hypotension suffer from postural dizziness. This is consistent with other reports suggesting that postural hypotension may be a cause of postural dizziness, but most subjects with postural hypotension in the studies of the elderly16,18 did not suffer from postural dizziness. Thus, the sensitivity was low for the diagnosis of postural hypotension based solely on the presence of postural dizziness relative to the diagnosis based on the postural blood pressure changes. Therefore, postural hypotension cannot be clinically determined just from the presence of postural dizziness. In conclusion, the prevalence of postural hypotension and postural dizziness in patients with diabetes was higher than in nondiabetic control subjects. Only 32.8% of subjects with both diabetes and postural hypotension suffered from postural dizziness. Age, diabetes mellitus, and hypertension were independently associated with postural hypotension. Plasma glycosylated hemoglobin levels, postural dizziness, hypertension, and cerebrovascular disease are independent determinants of postural hypotension in subjects with diabetes. Clinically, older adults and patients with diabetes mellitus or hypertension should receive regular monitoring of supine and upright blood pressure changes. Good glycemic control is important in preventing postural hypotension in patients with diabetes. Postural hypotension was associated with postural dizziness in subjects with diabetes, but it cannot be diagnosed clinically just from the postural dizziness because of the low sensitivity in the diagnosis of postural hypotension based only on postural dizziness relative to the diagnosis based on postural systolic blood pressure changes. Accepted for publication October 15, 1998. This study was supported by grant NCKUH-R-85-50 from the Intramural Research Fund of the National Cheng Kung University Hospital, Tainan, Taiwan, Republic of China. Reprints: Chih-Jen Chang, MD, Department of Family Medicine, National Cheng Kung University Hospital, 138 Sheng Li Rd, Tainan, 70428, Taiwan, Republic of China (e-mail: [email protected]). References 1. Hilsted JLow PA Diabetic autonomic neuropathy. Low PAed. Clinical Autonomic Disorders Evaluation and Management. 2nd ed. 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Schein, Oliver D.;Hochberg, Marc C.;Muñoz, Beatriz;Tielsch, James M.;Bandeen-Roche, Karen;Provost, Thomas;Anhalt, Grant J.;West, Sheila

doi: 10.1001/archinte.159.12.1359pmid: 10386512

Abstract Background Symptoms of dry eye and dry mouth are common in the elderly and are often debilitating. Previous research on small populations has been inconsistent regarding the contribution to sicca symptoms of autoimmune markers, medication use, and other factors. The objective of this study was to determine the population prevalence of symptoms of dry eye and dry mouth and to evaluate possible risk factors. Methods This is a population-based study of 2481 individuals, aged 65 to 84 years, residing in Salisbury, Md, and identified by the Health Care Financing Medicare database. The main outcome measures included information on sicca symptoms, medical history, medication use, and joint examination results collected in a standardized manner. Autoimmune status was assessed in 1200 individuals by measuring antinuclear antibody, rheumatoid factor, and autoantibodies to the soluble nuclear antigens Ro/SS-A and La/SS-B by double immunodiffusion. Results Approximately 27% of the population reported dry eye or dry mouth symptoms to be present often or all the time and 4.4% reported both. The prevalence of dry mouth (but not dry eye) symptoms increased with age, female sex, and white race. No association of sicca symptoms was found with rheumatoid arthritis, smoking, alcohol consumption, reproductive hormonal status, or the presence of autoantibodies. A strong, dose-response relationship was observed between sicca symptoms and the use of certain medication classes. The proportion of the population prevalence of sicca symptoms attributable to the use of drying medications was estimated at 62% for dry eye and dry mouth and 38% for dry eye or dry mouth symptoms. Conclusions Sicca symptoms are common in the elderly, and medication side effects appear to be a major underlying factor. Our results do not indicate an association between autoimmune status and sicca symptoms and do not support immunologic testing in persons with sicca symptoms in the absence of other important systemic features. SYMPTOMS OF dry eye and dry mouth are common in the elderly and are frequently debilitating. When an individual presents with sicca symptoms, particularly if accompanied by musculoskeletal or other systemic complaints, considerations relating to the diagnosis of Sjogren syndrome arise, and an evaluation for evidence of an autoimmune process may ensue. In the United States, research on the epidemiology of sicca symptoms has largely been limited to selected populations such as outpatient clinics or nursing homes1-5 where a variety of selection biases are likely to play a significant role in both estimates of the prevalence of symptoms as well as their relationship to systemic disease or other factors. We have previously reported the relationship between tests (Schirmer and Rose Bengal) and symptoms of dry eye and the prevalence of dry eye by varying definitions.6-8 In summary, no significant association was seen between report of dry eye symptoms and either Rose Bengal or Schirmer testing nor was there any meaningful association between the results of Rose Bengal and Schirmer tests. Overall, 14.6% of the population reported symptoms of dry eye to be present often or all the time, and 3.5% were symptomatic and had either Rose Bengal scores or Schirmer test results in the lowest decile. Symptoms of dry mouth were found in 17% of the population and were closely associated with a measure of salivary production, the Saxon test.9,10 From a practical, clinical perspective, physicians are frequently presented with patient symptoms of dry eye, dry mouth, or vaginal dryness, particularly among the elderly. These symptoms are usually interpreted in the absence of physiologic tests of tear or salivary production. We report herein the population distribution of symptoms of dry eye and dry mouth and their association with putative risk factors. Participants and methods Population and setting The overall methodology for the Salisbury Eye Evaluation (SEE) Project has been previously described.11 Salisbury is located 106 miles from Baltimore on Maryland's eastern shore. The metropolitan area has a total population of 41,430, of whom 7004 are aged 65 years and older.12 Fifteen percent of the elderly population are African American. The SEE Project contains 4 research projects whose overall purpose is to study visual function in the elderly from a common population-based perspective. The goal of the population recruitment was to enroll a random sample of 2500 men and women aged 65 to 84 years from Salisbury to have a home interview and a clinical examination at the SEE Project headquarters. The study size was chosen based on estimates of the prevalence of visual disability, and the actual sample was selected from the Health Care Financing Administration Medicare database. Eligibility criteria stipulated the following: (1) age between 65 and 84 years as of July 1, 1993; (2) residence in the Salisbury metropolitan area and alive at the time of contact; (3) noninstitutionalized status, ability to communicate in English and travel to the clinic for the assessments (housebound or extremely ill subjects were considered ineligible); and (4) a score of 18 or higher on the Mini-Mental State Examination.13 Recruitment was based on initial contact by letter and a subsequent visit from a study interviewer. After the home interview, an appointment at the SEE facility was made where the participant completed a series of vision and functional status tests, questionnaires, and clinical assessments that included the dry eye and dry mouth evaluation described below. The representativeness of the cohort examined has been reported in detail elsewhere.11,14 Assessment of sicca symptoms A dry eye symptom questionnaire6 consisting of questions relating to 6 symptoms was administered in a standardized fashion by a trained technician. Symptoms of dry mouth were assessed by asking each participant the questions "Does your mouth feel dry?" and "Do you wake up at night feeling your mouth is so dry that you need to drink fluids?" Each time a respondent indicated the presence of a dry eye or dry mouth symptom, he or she was asked to indicate whether the symptom was experienced rarely, sometimes, often, or all the time. Tests of autoimmunity A total of 2199 (87.3%) of participants consented to blood drawing and the serum specimens from a sample of 1200 subjects were selected for immunologic testing. The sample was chosen to provide a population that included adequate representation from various subgroups selected on the basis of symptoms and test results. Specifically, the sample included (1) all subjects with at least 1 dry eye symptom or dry mouth symptom reported present often or all the time (n=350); (2) a random sample of 65% of subjects with a Rose Bengal score of 5 or more, or a Schirmer result of 5 mm or less (n=250); (3) a random sample of 38% of the subjects with no symptoms or signs of dry eye or dry mouth (n=600). Antinuclear antibodies were detected by incubating dilutions of sera with commercially prepared Hep-2 cells (Zeus Wampole, Raritan, NJ) followed by incubation with a polyvalent fluorescein isothiocyanate antihuman immunoglobulin. A quenching buffer containing 1 part 0.3-mol/L triethylenediamine, 0.1-mol/L Tris-hydrochloride (pH 9.0), and 9 parts glycerol (all from Sigma-Aldrich Corporation, St Louis, Mo) was applied, and slides were read under a Zeiss fluorescent microscope. A positive antinuclear antibody at a titer of 1:320 or greater is considered abnormal. Autoantibodies to soluble nuclear antigens Ro/SS-A and La/SS-B were detected by Ouchterlony double immunodiffusion against extracts of bovine spleen and rabbit thymus, prepared as described by Clark et al,15 and compared with control sera with known specificities. Titers of IgM rheumatoid factor were determined using latex agglutination. Other risk factors A standardized medical history and exposure (smoking, alcohol, etc) questionnaire was completed on each individual, and a trained physician examiner evaluated each subject for clinical evidence of rheumatoid arthritis. A medical comorbidity score from 0 to 15 was constructed for each participant based on the number of self-reported histories of the following 15 conditions: arthritis, hip fracture, back problems, myocardial infarction, angina, congestive heart failure, intermittent claudication, high blood pressure, diabetes, emphysema, asthma since age 50 years, stroke, Parkinson disease, cancer in the past 5 years, and vertigo. A complete list of currently used medications determined by self-report was recorded for each participant and entered into the database using either the Drug Products Information Coding system or the Iowa Nonprescription Drug Products Information Coding System. For analysis, all drugs were recorded according to the Iowa Drug Information System.16 Statistical methods Associations with potential risk factors for sicca symptoms are presented as crude and adjusted odds ratios. Adjustment for age, race, and sex was performed using logistic regression models with age as a continuous variable. Each medication class in the Iowa Drug Information System (eg, antihistamine) was examined to assess its association with sicca symptoms. To assess the correlation among medication classes, pairwise odds ratios were estimated. In the analysis, medication classes with all pairwise odds ratios less than 3 were considered to have low correlations (less likely to be taken simultaneously). Those medication classes that had only low correlation with other classes were tested in a univariate fashion for their associations with the presence of dry eye and/or dry mouth (symptoms reported often or all the time). Medications with pairwise odds ratios of 3 or higher were considered highly correlated (more likely to be taken simultaneously), and the associations with dry eye and/or dry mouth were tested jointly in a single model. Those medication classes that had an independent association with dry eye or dry mouth of P<.10 and were in current use by at least 2% of the population were retained for further analysis. Results Table 1 illustrates the distribution of sicca symptoms. Approximately 27% of the population reported (present often or all the time) dry eye or dry mouth symptoms, and 4.4% reported both. Report of dry eye or dry mouth symptoms was associated with increasing age, female sex, and white race. However, these associations were driven largely by symptoms of dry mouth, since no such associations were seen for dry eye alone. Table 2 summarizes the relationship between classes of medications and symptoms of dry eye and/or dry mouth. Only medications used by more than 2% of the population and associated with sicca symptoms at a level of P<.10 are listed. The accompanying odds ratios indicate the association of each class of medication with symptoms of dry eye and/or dry mouth, adjusted for other classes of medication that were commonly used in conjunction by subjects. Table 3 presents the association of potential risk factors with symptoms of dry eye and/or dry mouth. Each of the associations is presented in crude form and adjusted for age, sex, and race. No association of sicca symptoms was found for rheumatoid arthritis, smoking, alcohol, or the presence of autoantibodies (either individually or in combination). A strong association in a dose-response fashion was observed with both the number of reported comorbid medical conditions and use of certain medication classes. We explored the possibility that sicca symptoms are mediated through medication use rather than underlying medical comorbidities by computing the association (adjusted for age, sex, and race) of each medical comorbidity with dry eye and/or dry mouth. We reasoned that if the underlying comorbidities themselves were important risk factors on a population basis, that they should fall in order in a way that might reflect some biologic plausibility; however, they did not. For example, the medical conditions most closely associated with sicca symptoms were congestive heart failure and Parkinson disease. Arthritis ranked ninth of the 15 comorbidities assessed, and, as previously mentioned, a history of rheumatoid arthritis was also not associated with sicca symptoms. The proportion of the population prevalence of sicca symptoms attributable17 to the use of drying medications was estimated at 58% for dry eye and dry mouth symptoms and 37% for dry eye or dry mouth symptoms. Vaginal dryness was reported by 8.8% of the population and was associated with symptoms of dry eye and dry mouth (odds ratio, 3.7; 95% confidence interval, 2.1-6.4). No association was seen between vaginal dryness and medication use except for those using 6 or more of the "drying" medication classes. Potential risk factors for sicca symptoms relevant only to the female population were examined separately. No association (or protective effect) was found for oophorectomy, current estrogen use, age of menarche or menopause, or total reproductive years with reported symptoms of dry eye or dry mouth. Comment In the Salisbury elderly population, 27.4% reported experiencing dry eye or dry mouth symptoms often or all the time and 4.4% experienced both. An extrapolation to the US population for those aged 65 to 84 years18 yields an estimate of more than 8 million with symptoms of dry eye or dry mouth and 1.3 million with both. Our population-based sample does not support a significant association of autoimmunity (as assessed by rheumatoid factor, antinuclear antibody, and precipitins) with sicca symptoms. Of course, this does not mean that such an association does not exist for individuals with definite Sjögren syndrome or other connective tissue disease.19 However, in the general elderly population, sicca symptoms are unlikely to have an autoimmune basis, and our data do not provide a rationale for routine immunologic evaluation of elderly subjects who complain of sicca symptoms. Furthermore, the lack of association persisted after restricting the sicca group to those with both symptoms and test (Schirmer, Rose Bengal, Saxon10) results in the lowest deciles (data not shown). In the Salisbury population, a significant association between the current use of certain medications and sicca symptoms was observed. The strong dose-response relationship and biologic plausibility of this relationship suggest a causal association. The mechanisms by which medications may cause symptoms of dry eye and dry mouth are multifactorial (eg, direct effect on gland function or dehydration). It is possible that some of the medication classes listed in Table 2 may have only an indirect or confounded association with symptoms. However, we have attempted to minimize this possibility by using statistical techniques to separate out those medication classes with independent effects. The proportion of the population prevalence of sicca symptoms potentially attributable to drying medications was estimated at 62%, supporting the notion that medication side effect is a significant factor underlying sicca symptoms among the elderly. We also found a significant association of sicca symptoms and the number of comorbid medical conditions. It is likely that this association is mediated through the use of drugs rather than the comorbid conditions themselves since medical conditions known to cause dry eye and dry mouth were rare in this population and, when present (eg, rheumatoid arthritis), were not found to be independently associated with sicca symptoms. From a practical or public health perspective, however, one cannot choose one's comorbidities, but there may be an opportunity to reduce or alter medication therapy. The results of this epidemiological investigation suggest that elderly patients should be queried about sicca symptoms and their medications be reviewed. If the sicca symptoms are present and bothersome, consideration may be given to altering the medical regimen. Accepted for publication October 14, 1998. This work was supported by grant P01-A10184 from the National Institutes of Health, Bethesda, Md, and performed at the Johns Hopkins University School of Medicine, Baltimore, Md. Reprints: Oliver D. Schein, MD, 116 Wilmer Bldg, Johns Hopkins Hospital, 600 N Wolfe St, Baltimore, MD 21287-9019 (e-mail: [email protected]). References 1. Strickland RSTesar JTBerne BHHobbs BRLewis DMWelton RC The frequency of sicca syndrome in an elderly female population. J Rheumatol. 1987;14766- 771Google Scholar 2. Sreebny LMValdini A Xerostomia, part I: relationship to other oral symptoms and salivary gland hypofunction. Oral Surg Oral Med Oral Pathol. 1988;66451- 458Google ScholarCrossref 3. Drosos AAAndonopoulos APCostopoulos JSPapadimitriou CSMoutsopoulos HM Prevalence of primary Sjögren's syndrome in an elderly population. Br J Rheumatol. 1988;27123- 127Google ScholarCrossref 4. Whaley KWilliamson JWilson T et al. Sjögren's syndrome and autoimmunity in a geriatric population. 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