JAMA

Russell, James A.

doi: 10.1001/jama.2010.183pmid: 20197525

To the Editor: The randomized controlled trial by Dr Taccone and colleagues1 studied prone positioning in patients with acute respiratory distress syndrome (ARDS). The article raises questions about cardiovascular alterations and treatment of sepsis in study patients. Shock and hemodynamic instability make prone positioning more difficult and potentially less safe. Furthermore, hemodynamic alterations and vasoactive agents (such as α- and β-adrenergic agents used clinically, including norepinephrine, dopamine, and dobutamine) can change perfusion distribution in the lung, alter gas exchange, and worsen oxygenation. Thus, over time a patient could move out of a state of being ineligible for the trial, and could also move from a classification of moderate to severe hypoxemia, with no change in the underlying ARDS pathology. Furthermore, it is likely that more patients in the severe hypoxemia group had hemodynamic instability. Previous trials of prone positioning found that 75.9% of supine-positioned and 70.7% of prone-positioned patients had vasopressor or inotropic support,2 that 35% of supine-positioned and 29% of prone-positioned patients had cardiovascular dysfunction,3 and that the mean number of days of vasopressor infusion was 6.35 days (supine group) and 5.43 days (prone group) or was not reported.4 Thus, cardiovascular alterations and need for cardiovascular support have been common in patients in previous randomized controlled trials of prone positioning in patients with ARDS. Accordingly, it would be valuable to know the cardiovascular characteristics and support given (eg, heart rate, mean arterial pressure, central venous pressure, and use of inotropic and vasopressor agents) for the supine vs prone group (and moderate vs severe hypoxemia subgroups) at baseline and over time. In addition, approximately 59% of patients had pneumonia and 5% had sepsis, so 64% could have been managed using Surviving Sepsis Campaign guidelines,5 which (if not balanced between groups) could have altered outcomes. Therefore it would also be valuable to have information about activated protein C levels, as well as the use of early antibiotics, early goal-directed therapy, corticosteroids, and intensive insulin, in each group at baseline and over time. Back to top Article Information Financial Disclosures: Dr Russell reported being an inventor on a patent application for the use of vasopressin in septic shock that the University of British Columbia has submitted; having received consulting fees from Ferring and Sirius Genomics; having received grants from Novartis, Ferring, and Eli Lilly; having received speaking honoraria from Eli Lilly; and holding stock in Sirius Genomics, which has submitted patents owned by the University of British Columbia and licensed to Sirius Genomics related to the genetics of vasopressin and activated protein C. References 1. Taccone P, Pesenti A, Latini R, et al; Prone-Supine II Study Group. Prone positioning in patients with moderate and severe acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2009;302(18):1977-198419903918PubMedGoogle ScholarCrossref 2. Guerin C, Gaillard S, Lemasson S, et al. Effects of systematic prone positioning in hypoxemic acute respiratory failure: a randomized controlled trial. JAMA. 2004;292(19):2379-238715547166PubMedGoogle ScholarCrossref 3. Mancebo J, Fernandez R, Blanch L, et al. A multicenter trial of prolonged prone ventilation in severe acute respiratory distress syndrome. Am J Respir Crit Care Med. 2006;173(11):1233-123916556697PubMedGoogle ScholarCrossref 4. Gattinoni L, Tognoni G, Pesenti A, et al; Prone-Supine Study Group. Effect of prone positioning on the survival of patients with acute respiratory failure. N Engl J Med. 2001;345(8):568-57311529210PubMedGoogle ScholarCrossref 5. Dellinger RP, Levy MM, Carlet JM, et al; International Surviving Sepsis Campaign Guidelines Committee; American Association of Critical-Care Nurses; American College of Chest Physicians; American College of Emergency Physicians; Canadian Critical Care Society; European Society of Clinical Microbiology and Infectious Diseases; European Society of Intensive Care Medicine; European Respiratory Society; International Sepsis Forum; Japanese Association for Acute Medicine; Japanese Society of Intensive Care Medicine; Society of Critical Care Medicine; Society of Hospital Medicine; Surgical Infection Society; World Federation of Societies of Intensive and Critical Care Medicine. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008;36(1):296-32718158437PubMedGoogle ScholarCrossref

Albert, Nancy M.;Fonarow, Gregg C.;Hernandez, Adrian F.

doi: 10.1001/jama.2010.187pmid: N/A

In Reply: Dr Fayssoil raises a question regarding whether the strength of associations of study variables with aldosterone antagonist therapy prescription differed in the subsets of patients with ischemic and nonischemic HF. Our multivariable model included ischemic etiology, which was not predictive of aldosterone antagonist prescription (adjusted odds ratio [aOR], 0.98; 95% confidence interval [CI], 0.89-1.07; P = .64). We performed subgroup analyses of patients with ischemic and nonischemic etiology of HF to determine factors associated with aldosterone antagonist prescription. Patient and hospital factors associated with aldosterone antagonist use were similar in the subgroups of patients with ischemic and nonischemic etiology for HF. The exceptions were that African American race (aOR, 1.29; 95% CI, 1.08-1.55; P = .005), female sex (aOR, 1.13; 95% CI, 1.01-1.26; P = .03), depression (aOR, 1.23; 95% CI, 1.05-1.44; P = .009), and pacemaker implantation (aOR, 1.25; 95% CI, 1.08-1.46; P = .003) were associated with aldosterone antagonist use only in the ischemic subgroup; alcohol history (aOR, 1.29; 95% CI, 1.03-1.61; P = .03) was associated with aldosterone antagonist use only in the nonischemic subgroup. Fayssoil also suggests that hypotension may be an explanation for lack of prescription of aldosterone antagonists. Only a very small portion of patients hospitalized with HF have low systolic blood pressure at the time of admission.1 Moreover, discharge blood pressure values were available and were lower in patients prescribed an aldosterone antagonist vs those not receiving treatment at discharge (mean systolic blood pressure, 117.8 mm Hg [95% CI, 117.4-118.3] vs 125.0 mm Hg [95% CI, 124.8-125.3], respectively; P < .001). Our findings suggest that a low blood pressure at admission or discharge was not a common rationale for nonprescription of aldosterone antagonist therapy in patients who met inclusion criteria. Regarding a relationship between arrhythmia onset and aldosterone use, clinical trials have demonstrated lower risk of sudden death with aldosterone antagonists in HF.2 Data from our study were available for some procedures (such as implantable cardioverter-defibrillator or pacemaker placement during the hospital episode) that may reflect arrhythmias requiring treatment; however, timing of aldosterone antagonist prescription in relation to procedures or clinical events was not captured. Dr Ghali comments about current evidence for using aldosterone antagonist therapy in African American individuals with HF. We agree that additional evidence would be helpful to guide decisions for important patient groups who were underrepresented in pivotal trials. Professional guidelines generally do not distinguish therapeutic recommendations based on race, ethnicity, or sex unless there is significant evidence to do so, such as prospective clinical trials or well-validated analyses. Ghali notes a post hoc analysis from the A-HeFT, in which patients in the placebo group who received baseline therapy with spironolactone did not have improved survival but those who were randomized to hydralazine-isosorbide dinitrate therapy did.3 We agree that clinicians should follow recommendations for evidence-based HF therapies in eligible patients. Back to top Article Information Financial Disclosures: Dr Albert reported serving on the speakers' bureau of GlaxoSmithKline, Medtronic, Nitromed, and Scios (since 2004; speakers' bureau relationships with Nitromed, Medtronic, and Scios ended in 2007); serving as a consultant for ARCA biopharma (2008); and currently serving as a consultant for Medtronic, Merck, and Impedance Cardiology Systems Inc. Dr Fonarow reported receiving research grants or other research support from GlaxoSmithKline, Pfizer, and the National Institutes of Health; receiving honoraria from Amgen, AstraZeneca, Boston Scientific/Guidant, GlaxoSmithKline, Medtronic, Merck, Novartis, Pfizer, Schering-Plough, and St Jude Medical; serving as a consultant for ARCA, Boston Scientific/Guidant, DebioPharm, GlaxoSmithKline, Medtronic, Merck, Novartis, Pfizer, Relypsa, Scios, and St Jude Medical; and serving as chair of the American Heart Association Get With The Guidelines Steering Committee. Dr Fonarow holds the Eliot Corday Chair of Cardiovascular Medicine at UCLA and is also supported by the Ahmanson Foundation (Los Angeles, California). Dr Hernandez reported receiving research grants from GlaxoSmithKline, Johnson & Johnson (Scios Inc), Medtronic, Merck, and Roche Diagnostics and serving on the speakers' bureau for or receiving honoraria within the past 5 years from AstraZeneca, Medtronic, Novartis, Sanofi-Aventis, and Thoratec Corporation. Dr Hernandez has made detailed listings of financial disclosures available online at http://www.dcri.duke.edu/research/coi.jsp. References 1. Gheorghiade M, Abraham WT, Albert NM, et al; OPTIMIZE-HF Investigators and Coordinators. Systolic blood pressure at admission, clinical characteristics, and outcomes in patients hospitalized with acute heart failure. JAMA. 2006;296(18):2217-222617090768PubMedGoogle ScholarCrossref 2. Pitt B, Zannad F, Remme WJ, et al; Randomized Aldactone Evaluation Study Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341(10):709-71710471456PubMedGoogle ScholarCrossref 3. Ghali JK, Tam SW, Sabolinski ML, et al. Exploring the potential synergistic action of spironolactone on nitric oxide-enhancing therapy: insights from the African American Heart Failure Trial. J Card Fail. 2008;14(9):718-72318995175PubMedGoogle ScholarCrossref

Fayssoil, Abdallah

doi: 10.1001/jama.2010.185pmid: 20197527

To the Editor: Dr Albert and colleagues1 studied the prescription of aldosterone antagonists for patients with heart failure (HF). Among the patients studied, 46% had nonischemic HF. It would be helpful to know whether the strength of the associations with aldosterone antagonist use found in the study differed between the nonischemic group and the ischemic group. Because the use of aldosterone antagonists together with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or β-blockers can lead to hypotensive episodes,2 I would like to know if the authors assessed whether this reaction could explain interruption in aldosterone antagonists use. Also, because new-onset arrhythmia may be influenced by the renin-angiotensin-aldosterone system,3 I would like to know whether the authors assessed correlation between onset of arrhythmia and aldosterone antagonist use. Back to top Article Information Financial Disclosures: None reported. References 1. Albert NM, Yancy CW, Liang L, et al. Use of aldosterone antagonists in heart failure. JAMA. 2009;302(15):1658-166519843900PubMedGoogle ScholarCrossref 2. Mak G, Murphy NF, Ali A, et al. Multiple neurohumoral modulating agents in systolic dysfunction heart failure: are we lowering blood pressure too much? J Card Fail. 2008;14(7):555-56018722320PubMedGoogle ScholarCrossref 3. Makkar KM, Sanoski CA, Spinler SA. Role of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and aldosterone antagonists in the prevention of atrial and ventricular arrhythmias. Pharmacotherapy. 2009;29(1):31-4819113795PubMedGoogle ScholarCrossref

Ghali, Jalal K.

doi: 10.1001/jama.2010.186pmid: 20197526

To the Editor: In their report on the use of aldosterone antagonists in HF, Dr Albert and colleagues1 observed that being African American was an independent predictor of aldosterone antagonist prescription. This is somewhat surprising considering the limited evidence for the efficacy of aldosterone antagonists in African American individuals with HF. The representation of African American individuals in the 2 survival studies with aldosterone antagonists was small, less than 1% in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS)2 and 13% in the Randomized Aldactone Evaluation Study (RALES).3 In the latter, only 11% of all patients received β-blockers. Furthermore, a retrospective analysis of the African American Heart Failure Trial (A-HeFT) demonstrated lack of benefit of spironolactone in African American patients with HF who were not concomitantly receiving the combination of hydralazine and isosorbide dinitrate.4 There should be a focus on recommendations based on proven effectiveness in improving outcomes. Back to top Article Information Financial Disclosures: None reported. References 1. Albert NM, Yancy CW, Liang L, et al. Use of aldosterone antagonists in heart failure. JAMA. 2009;302(15):1658-166519843900PubMedGoogle ScholarCrossref 2. Pitt B, Remme WJ, Zannad F, et al; Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348(14):1309-132112668699PubMedGoogle ScholarCrossref 3. Pitt B, Zannad F, Remme WJ, et al; Randomized Aldactone Evaluation Study Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341(10):709-71710471456PubMedGoogle ScholarCrossref 4. Ghali JK, Tam SW, Sabolinski ML, et al. Exploring the potential synergistic action of spironolactone on nitric oxide-enhancing therapy: insights from the African American Heart Failure Trial. J Card Fail. 2008;14(9):718-72318995175PubMedGoogle ScholarCrossref

Hingorani, Aroon D.;Psaty, Bruce M.

doi: 10.1001/jama.2010.189pmid: N/A

In Reply: We agree with Dr Pletcher and colleagues that development of policy for the primary prevention of CVD in the United States and elsewhere will require the explicit integration of the best available evidence from population studies, intervention trials, and studies evaluating the comparative performance of the available screening strategies. Although many of the estimates needed to populate decision models are already available, there has been relatively little comparative work on the performance and cost-effectiveness of available screening tests and risk scores. Also, the preferences of populations that might be targeted for primary prevention have yet to be adequately evaluated. The wide cost differential between generic and proprietary statins also needs to be considered. A dialogue is now needed among the relevant investigators—epidemiologists, trialists, and modelers—and other stakeholders to ensure that gaps in knowledge are filled and that patients, physicians, and policy makers have the information needed to make an informed choice on the optimal approach for primary prevention. Back to top Article Information Financial Disclosures: Dr Hingorani reported that he is on the editorial board of Drug and Therapeutics Bulletin, a BMJ Group Publication; has provided nonremunerated advice to GlaxoSmithKline, and London Genetics; and has received honoraria for speaking at educational meetings relating to risk factor management and primary prevention. These have been donated in whole or large part to medical charities. No other disclosures were reported.

Pletcher, Mark J.;Tice, Jeffrey A.;Pignone, Michael

doi: 10.1001/jama.2010.188pmid: 20197528

To the Editor: In their Commentary, Drs Hingorani and Psaty1 invoked the prevention paradox (a large proportion of cardiovascular disease [CVD] events occur among the many individuals with average risk factor values) in their discussion of whether to embrace new CVD risk markers as tools for targeting or personalizing statin therapy. They also described another well-known apparent paradox: even risk markers that are strongly associated with the outcome of interest (relative risks of 3 to 5 or even larger) often seem to contribute little in terms of discrimination or reclassification.2 Modeling the effect of different strategies for CVD prevention on population health is an approach to resolve these apparent paradoxes. By bringing together information about test performance, treatment efficacy, and population-level distributions of risk factors and disease rates, modeling can help provide answers to the question of who should receive preventive therapies such as statins and aspirin and can determine the role that novel risk factors may play in these decisions. In doing so, modeling goes beyond newer measures of test evaluation3 (eg, net reclassification improvement) because it can project and compare the actual health consequences of different strategies. When fiscal considerations are important, a cost component can be added to the model (cost-effectiveness analysis). Unlike randomized trials, which must limit the strategies compared to a small set for feasibility reasons, modeling allows consideration of the full range of strategies, including those intermediate to either treating all (the polypill strategy) or setting a very high treatment threshold (≥20% 10-year risk), and allows for identification of an optimal strategy for a given set of assumptions. For example, we have shown, using conservative estimates, that both aspirin and statins may be appropriate for CVD prevention at thresholds of less than 10%4 and that even lower-risk thresholds (approaching a polypill approach) may be reasonable for statins when statin costs are low.5 Hingorani and Psaty call for additional trials and studies to help decide whether to take a more or less personalized approach to CVD risk stratification. We suggest that careful decision modeling, with or without a cost component, followed by targeted trials or other studies only as needed to clarify key areas of uncertainty, should play a key role in this and other decisions about the viability of personalized medicine in the United States. Back to top Article Information Financial Disclosures: Dr Pignone reported having received research funding and licensing fees from Bayer. No other disclosures were reported. References 1. Hingorani AD, Psaty BM. Primary prevention of cardiovascular disease: time to get more or less personal? JAMA. 2009;302(19):2144-214519920239PubMedGoogle ScholarCrossref 2. Pepe MS, Janes H, Longton G, Leisenring W, Newcomb P. Limitations of the odds ratio in gauging the performance of a diagnostic, prognostic, or screening marker. Am J Epidemiol. 2004;159(9):882-89015105181PubMedGoogle ScholarCrossref 3. Pencina MJ, D'Agostino RB Sr, D'Agostino RB Jr, Vasan RS. Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med. 2008;27(2):157-17217569110PubMedGoogle ScholarCrossref 4. Pignone M, Earnshaw S, Tice JA, Pletcher MJ. Aspirin, statins, or both drugs for the primary prevention of coronary heart disease events in men: a cost-utility analysis. Ann Intern Med. 2006;144(5):326-33616520473PubMedGoogle ScholarCrossref 5. Pletcher MJ, Lazar L, Bibbins-Domingo K, et al. Comparing impact and cost-effectiveness of primary prevention strategies for lipid-lowering. Ann Intern Med. 2009;150(4):243-25419221376PubMedGoogle ScholarCrossref

Carney, Robert M.;Freedland, Kenneth E.;Steinmeyer, Brian C.

doi: 10.1001/jama.2010.191pmid: N/A

In Reply: Dr Anghelescu offers 2 possible explanations for why our clinical trial found no difference in depression in patients with CHD after 10 weeks of treatment with a standard antidepressant (sertraline) and either 2 g/d of omega-3 fatty acids or a placebo. First, he notes that our measures of depression severity include somatic symptoms that may be confounded with symptoms of heart disease and that this may have made it more difficult to observe a treatment effect. We chose the HAM-D and the BDI-II because they are widely used measures of depression severity in clinical trials and have been recommended for use in assessing depression in patients with heart disease.1 Nevertheless, to investigate this possibility we reran the BDI-II analysis with the 5 somatic symptoms removed. The mean modified posttreatment BDI-II total score did not differ between the groups (9.5 [placebo] vs 10.7 [omega-3]; 95% confidence interval for the mean difference, −3.6 to 1.1; t116 = −1.06; P = .29). Thus, this analysis yielded no evidence that omega-3 improved the cognitive and affective symptoms of depression. Second, Anghelescu raises the possibility that because all patients were treated with sertraline in addition to either omega-3 or a placebo, there may have been a ceiling effect due to the efficacy of the antidepressant. This seems unlikely because the mean BDI-II scores at the end of treatment were in the mildly to moderately depressed range for both groups (14.8 and 16.1 for placebo and omega-3, respectively). Furthermore, the remission rate was less than 30% for both groups. Thus, there was ample room for further improvement in depression. Back to top Article Information Financial Disclosures: Dr Carney reported receiving an honorarium from Forest Laboratories Inc for participating in a symposium and completing a review of the literature concerning depression and heart disease. He or a member of his family is a stockholder in Pfizer Inc, Forest Laboratories, and Johnson & Johnson Inc. No other disclosures were reported. References 1. Davidson KW, Kupfer DJ, Bigger JT, et al; National Heart, Lung, and Blood Institute Working Group. Assessment and treatment of depression in patients with cardiovascular disease: National Heart, Lung, and Blood Institute Working Group report. Psychosom Med. 2006;68(5):645-65017012516PubMedGoogle ScholarCrossref

Anghelescu, Ion

doi: 10.1001/jama.2010.190pmid: 20197529

To the Editor: I am concerned about the choice of the rating scales in the study of omega-3 augmentation of sertraline for patients with coronary heart disease (CHD) and depression by Dr Carney and colleagues.1 The main inclusion criterion regarding severity of depression was related to the Beck Depression Inventory (BDI) II self-rating scale. Patients with scores of 16 or greater were included. The Montgomery-Asperg depression rating scale may have been more specific for depression in CHD patients, since it takes into account psychological signs and symptoms more than the BDI-II and the Hamilton Rating Scale for Depression (HAM-D) 17 scale,2 which comprise more of the physical symptoms that can also occur in association with a somatic disorder like CHD. Also, physically ill patients often respond well to antidepressant medication.3 Because of the potentially sufficient efficacy of sertraline as monotherapy, there might therefore have been a ceiling effect. This aspect of the study design could have contributed to the negative result of this study compared with 2 others that the authors cited.4,5 Investigating additional treatment with omega-3 in sertraline nonresponders could answer this question. Back to top Article Information Financial Disclosures: Dr Anghelescu reported being an employee of Johnson & Johnson Experimental Medicine Neuroscience and having received honoraria from AstraZeneca, Janssen, Lilly, Pfizer, Sanofi-Aventis, and Schwabe. References 1. Carney RM, Freedland KE, Rubin EH, Rich MW, Steinmeyer BC, Harris WS. Omega-3 augmentation of sertraline in treatment of depression in patients with coronary heart disease. JAMA. 2009;302(15):1651-165719843899PubMedGoogle ScholarCrossref 2. Demyttenaere K, De Fruyt J. Getting what you ask for: on the selectivity of depression rating scales. Psychother Psychosom. 2003;72(2):61-7012601223PubMedGoogle ScholarCrossref 3. Gill D, Hatcher S. Antidepressants for depression in people with physical illness. Cochrane Database Syst Rev. 2000;(2):CD00131210796770PubMedGoogle Scholar 4. Nemets B, Stahl Z, Belmaker RH. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry. 2002;159(3):477-47911870016PubMedGoogle ScholarCrossref 5. Peet M, Horrobin DF. A dose-ranging study of the effects of ethyl-eicosapentaenoate in patients with ongoing depression despite apparently adequate treatment with standard drugs. Arch Gen Psychiatry. 2002;59(10):913-91912365878PubMedGoogle ScholarCrossref

Fowkes, F. Gerald R.; Price, Jacqueline F.; Stewart, Marlene C. W.; Butcher, Isabella; Leng, Gillian C.; Pell, Alistair C. H.; Sandercock, Peter A. G.; Fox, Keith A. A.; Lowe, Gordon D. O.; Murray, Gordon D.

doi: 10.1001/jama.2010.221pmid:

Wunsch, Hannah; Guerra, Carmen; Barnato, Amber E.; Angus, Derek C.; Li, Guohua; Linde-Zwirble, Walter T.

doi: 10.1001/jama.2010.216pmid: 20197531