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The Economics of Therapeutic Advances: The Paradigm of Sympathetic Suppression in Chronic Heart Failure

The Economics of Therapeutic Advances: The Paradigm of Sympathetic Suppression in Chronic Heart... THE IMPACT of a newly introduced therapeutic approach is mostly determined by 2 facts: (1) it addresses a common condition that affects large numbers of people and defines their functional status and quality of life for long periods of time; (2) it is inexpensive and readily available not only to those who live in technologically advanced societies, but also to those who live in the developing countries, where most of the world's population resides. While death rates from other cardiovascular diseases are decreasing, the incidence of death rates from heart failure has been increasing in recent years. Several factors account for this trend, including, ironically, the successful management of inflammatory or ischemic heart disease, hypertension, and other conditions that lead to heart failure, as well as increasing life expectancy. Indeed, today, heart failure is estimated to affect about 5 million people in the United States, of whom more than 75% are older than 65 years.1 Similar trends are observed worldwide, partly as a result of successful implementation of various health measures and better living standards, which ensure that the incidence and prevalence of cardiovascular disease will continue to increase in aging populations. As a chronic, inexorably progressing condition, heart failure requires lifelong maintenance with multiple drugs. Even with state-of-the-art therapy, which today includes angiotensin-converting enzyme (ACE) inhibitors, with or without the standard diuretics and inotropes of the previous era, the death rate associated with heart failure still includes approximately 10% to 20% of patients within the first year of diagnosis and 50% within 5 years. Furthermore, the incapacitating symptoms of the disease and the adverse effects of the drugs diminish the productivity and enjoyment of these years. Clearly, there is room for improvement, and this has become apparent to both research scientists and the pharmaceutical industry. Intensive research over the past few decades into the pathogenic mechanisms of heart failure has gradually altered our perception of this condition: A generation ago, it was viewed mostly as pump failure leading to fluid volume overload and was treated with digitalis and diuretics. Even after Kelly et al2 introduced, and Cohn3 promoted, the concept of afterload rather than preload reduction to relieve pump failure and enhance tissue perfusion, the mainstay of treatment continued to be diuresis and inotropic stimulation. There is no evidence that either of these treatments prolongs life, but clinical experience shows that they offer immediate symptomatic relief. Several vasodilators have been tried briefly and abandoned for various reasons over the years. Today, it is recognized that the progressive deterioration of myocardial remodeling and function is attributable not so much to the hemodynamic burden per se, but rather to the neurohormonal activation accompanying the hemodynamic decompensation. Exposure of the myocardium to high levels of angiotensin II and norepinephrine was shown to produce widespread necrotic lesions,4,5 and sympathetic activation was proposed as both cause and marker of worsening heart failure.6,7 Although many humoral factors are now known to contribute to the phenomenon referred to as neurohormonal activation (eg, autacoids such as cytokines and tumor necrosis factors), it is the harnessing of the 2 major systemic pressor systems—the renin-angiotensin system and the sympathetic nervous system (SNS)—that has produced clinically significant results. Recent research has revealed that their deleterious effects result not only from their systemic pressor actions but also from their local autocrine/paracrine/intracrine effects on cardiomyocytes and adjacent tissues.8,9 Inhibition of the renin-angiotensin system as treatment for congestive heart failure was first proposed in 1977 with the angiotensin II receptor antagonist saralasin acetate,10 and was subsequently corroborated by clinical experiments with parenteral and oral ACE inhibitors. These first clinical studies were mostly observational, with hemodynamic, electrocardiographic, and other clinical parameters recorded before and during administration of the ACE inhibitor. The results were encouraging and consistent, so they caught the attention of the pharmaceutical industry. Several pharmaceutical companies were coming up with their own ACE inhibitors, and all were interested in taking advantage of this potential new indication for their antihypertensive drugs. Accordingly, they organized numerous meetings, satellite symposia at national or international meetings, and other occasions for exchange of information. They were also keen to initiate and fund large controlled multicenter trials to prove the benefit of their product in terms of patient outcome. The first such trial, the Cooperative North Scandinavian Enalapril Survival Study,11 demonstrated that this treatment could decrease the morbidity and mortality of heart failure. Further comparative trials with various ACE inhibitors against inotropes, diuretics, and vasodilators in various combinations have now established ACE inhibition as the standard therapy for left ventricular dysfunction, especially after a myocardial infarct, and mandate initiation of therapy even before the onset of overt systolic failure. The recent introduction of oral angiotensin II receptor antagonists indicates that these agents may be at least as effective hemodynamically and possibly more effective in terms of prevention of sudden death12 in such patients. This finding led to a resurgence of interest on the part of the pharmaceutical industry, with multiple meetings, symposia, and multicenter controlled trials to establish and propagate this new therapeutic approach. There is no doubt that this active generation and dissemination of information must have helped to improve and prolong the life of many patients with heart failure. Inhibition of the SNS as treatment for heart failure has followed a somewhat different course. Initially, it was attempted by use of a ganglionic blocker2 or an α-adrenoceptor blocker,13 both of which were viewed mostly as vasodilators, but was soon abandoned for various reasons, including lack of sustained benefits. It was then attempted with clonidine,14,15 which was also viewed as a vasodilator, but was abandoned for fear of a negative inotropic effect at a time when positive inotropes were still the standard therapy for myocardial pump failure. Use of β-adrenergic blockade was shunned for years because of its immediate negative inotropic action, although some clinical studies suggested a later benefit in cardiac economy.16,17 However, accumulating evidence from clinical and basic research led gradually to the realization that β-adrenergic inhibition may indeed be beneficial in the long run in most cases, despite the risk of an early hemodynamic reversal. As with ACE inhibition, these encouraging results caught the attention of the pharmaceutical industry, especially those companies that manufactured the second and third generation of β-adrenoceptor blockers, such as bisoprolol, bucindolol hydrocholoride, and carvedilol, in the 1990s. The pharmaceutical companies have funded large multicenter controlled trials,18,19 organized numerous scientific meetings and satellite symposia, and facilitated publication of the proceedings in journal supplements and newsletters, thus ensuring wide dissemination of this information. Even though the outcome data have not always been positive (eg, the Australia-New Zealand data regarding carvedilol failed to demonstrate a decrease in mortality, as did some of the earlier bisoprolol data), they have generated a great deal of enthusiasm, which mostly appears to be justified. Nevertheless, some experienced clinical researchers have added a note of caution, especially as to the selection of appropriate subjects as candidates for this treatment.20 But there is another way to inhibit the SNS in heart failure, a way that can restore autonomic balance and may actually be devoid of the immediate risk of left ventricular depression seen with β-blockade: the central SNS suppression with clonidine. A series of investigator-initiated clinical studies by us and others over the last 3 to 4 years,21-26 some observational only, others placebo controlled with or without ACE inhibitors, and some of many months' duration, have given consistently encouraging results: they indicate that clonidine improves functional capacity (as assessed by prolonged exercise tolerance), while improving or leaving unaffected the various hemodynamic parameters. More importantly, clonidine appears to correct autonomic imbalance and to ameliorate most indices of arrhythmogenic potential (such as heart rate variability and related parameters derived from Holter monitoring) and indeed seems to decrease the incidence and complexity of ventricular ectopy, which is the main cause of sudden death in heart failure. Yet, despite multiple efforts, there has been no interest so far from anyone to fund large controlled studies to demonstrate the long-term impact of these alterations on patient outcome.27 The clinically observed benefits of clonidine in heart failure are known to a small circle of academic cardiologists, but the primary care physicians who treat 90% of patients with chronic heart failure are totally unaware of them. TWENTY OR 30 years ago, journals addressed to general clinical readership would accept manuscripts from investigators who conducted small clinical trials as long as the trials were properly conducted and met rigorous scientific standards. Today, these journals will only accept manuscripts that report the results of large, double-blind, placebo-controlled trials, which are very expensive and can only be conducted with support from the pharmaceutical industry. But, naturally, companies will only fund trials assessing their own patented products that promise large returns. Partnership between industry and academia is driven by the expectation of profit. Clonidine has few commercial prospects: it is an old and inexpensive drug, long out of patent, that is now finding a new use and may have the potential to ameliorate and prolong lives. This is of particular interest to physicians in parts of the world where the newest ACE inhibitors, angiotensin II receptor antagonists, and β-blockers—those proved to help patients with heart failure—are out of reach to large segments of the population. However, there are no symposia or journal supplements or newsletters to help disseminate this information, and it does not have the eye-catching appeal of miraculous technological accomplishments, such as genetic engineering, to make it newsworthy. Is there a solution to this problem? The story of aspirin as an antiplatelet agent and the renaissance of spironolactone as an adjunct to ACE inhibition in heart failure suggest that an old, inexpensive, widely available drug that is now proposed to have a new role may yet generate enough interest on the part of policymakers, if not industry, to permit its formal testing. On the other hand, the pharmaceutical industry may fund studies using similar drugs that are still under patent, eg, α2-agonists with a central SNS suppressant effect, such as moxonidine or rilmenidine, provided, of course, that they will turn out to be as effective as clonidine. Such studies would at least allow dissemination of the relevant information that may then be extrapolated to all members of that class. It may also be of interest to insurers or government agencies to sponsor trials designed to assess whether this treatment is not only clinically effective but cost-effective as well. Decision makers are usually under the dual pressures of adopting expensive new technologies and considering budgetary constraints.28 Pharmacoeconomic evaluation of an old drug with a known safety profile and promising value in terms of patient outcomes should be appealing to such organizations, as both acquisition costs and follow-up costs should compare favorably with alternative treatments. References 1. Not Available, Morbidity and Mortality Chartbook on Cardiovascular, Lung and Blood Disease, 1990-1994. Bethesda, Md National Institutes of Health, National Heart, Lung, and Blood Institute, US Dept of Health and Human Services1994; 2. Kelly RTFreis EDHiggins TH The effects of hexamethonium on certain manifestations of congestive heart failure. Circulation. 1953;7169- 174Google ScholarCrossref 3. Cohn JN Vasodilator therapy for heart failure. Circulation. 1973;485- 8Google ScholarCrossref 4. Gavras HBrown JJLever AFMacadam RFRobertson JIS Acute renal failure, tubular necrosis and myocardial infarction induced in the rabbit by intravenous angiotensin II. Lancet. 1971;219- 22Google ScholarCrossref 5. Gavras H.Kremer DBrown JJ et al. Angiotensin- and norepinephrine-induced myocardial lesions: experimental and clinical studies in rabbits and man. Am Heart J. 1975;89321- 332Google ScholarCrossref 6. Cohn JNLevine TBOlivari MT et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med. 1984;311819- 823Google ScholarCrossref 7. Bristow MR The adrenergic nervous system in heart failure. N Engl J Med. 1984;311850- 851Google ScholarCrossref 8. Dostal DEBaker KM Biochemistry, molecular biology, and potential roles of the cardiac renin-angiotensin system. Dhalla NSTakeda NNagano Meds. The Failing Heart. Philadelphia, Pa Lippincott-Raven Publishers1995;275- 294Google Scholar 9. Newling RPFletcher PJCoutis MShaw J Noradrenaline and cardiac hypertrophy in the rat: changes in morphology, blood pressure and ventricular performance. J Hypertens. 1989;7561- 567Google ScholarCrossref 10. Gavras HFlessas ARyan TJBrunner HRFaxon DPGavras I Angiotensin II inhibition: treatment of congestive cardiac failure in a high-renin hypertension. JAMA. 1977;238880- 882Google ScholarCrossref 11. The CONSENSUS Trial Study Group, Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987;3161429- 1435Google ScholarCrossref 12. Pitt BSegal RMartinez FA et al. Randomized trial of losartan versus captopril in patients over 65 with heart failure. Lancet. 1997;349747- 752Google ScholarCrossref 13. Packer MMeller JCorlin RHerman MV Hemodynamic and clinical tachyphylaxis to prazosin-mediated afterload reduction in severe chronic congestive heart failure. Circulation. 1979;59531- 539Google ScholarCrossref 14. Giles TDIteld BJMautner RKRognoni PADillenkoffer RL Short-term effects of intravenous clonidine in congestive heart failure. Clin Pharmacol Ther. 1981;30724- 728Google ScholarCrossref 15. Hermiller BMagorien RDLeithe MEUnverferth DVLeier CV Clonidine in congestive heart failure: a vasodilator with negative inotropic effects. Am J Cardiol. 1983;51791- 795Google ScholarCrossref 16. Eichhorn EJBedotto JBMalloy CR et al. Effect of beta-adrenergic blockade on myocardial function and energetics in congestive heart failure: improvements in hemodynamic, contractile and diastolic performance with bucindolol. Circulation. 1990;82473- 483Google ScholarCrossref 17. Hjalmarson AWaasgstein F New therapeutic strategies in chronic heart failure: challenge of long-term beta-blockade. Eur Heart J. 1991;12(suppl F)63- 69Google ScholarCrossref 18. CIBIS Investigators and Committees, A randomized trial of beta-blockade in heart failure: the Cardiac Insufficiency Bisoprolol Study (CIBIS). Circulation. 1994;901765- 1773Google ScholarCrossref 19. Packer MBristow MRCohn JN et al. The Effect of Carvedilol on Morbidity and Mortality in Patients with Chronic Heart Failure. N Engl J Med. 1996;3341349- 1355Google ScholarCrossref 20. Pfeffer MAStevenson LW β-Adrenergic blockers and survival in heart failure. N Engl J Med. 1996;3341396- 1397Google ScholarCrossref 21. Manolis AJOlympios CSifaki M et al. Suppressing sympathetic activation in congestive heart failure. Hypertension. 1995;26719- 724Google ScholarCrossref 22. Manolis AJOlympios CSifaki M et al. Combined sympathetic suppression and angiotensin-converting enzyme inhibition in congestive heart failure. Hypertension. 1997;29 ((pt 2)) 525- 530Google ScholarCrossref 23. Manolis AJOlympios CSifaki M et al. Chronic sympathetic suppression in the treatment of chronic congestive heart failure. Clin Exp Hypertens. 1998;20717- 731Google ScholarCrossref 24. You-hu ZYou-cheng SJun ZXian-qi Y Sympathetic inhibition with clonidine improves autonomic balance in congestive heart failure. Int J Cardiol. 1997;59139- 144Google ScholarCrossref 25. Lang CCRayos GHChomsky DBWood AJWilson JR Effect of sympathoinhibition on exercise performance in patients with heart failure. Circulation. 1997;96238- 245Google ScholarCrossref 26. Girgis IChakko Sde Marchena E et al. Effect of clonidine on heart rate variability in congestive heart failure. Am J Cardiol. 1998;82335- 337Google ScholarCrossref 27. Giles TD Clonidine and heart failure [letter]. Hypertension. 1996;271187Google Scholar 28. Szucs TD Pharmacoeconomics of angiotensin converting enzyme inhibitors in heart failure. Am J Hypertens. 1997;10 ((10 Pt 2)) 272S- 279SGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Internal Medicine American Medical Association

The Economics of Therapeutic Advances: The Paradigm of Sympathetic Suppression in Chronic Heart Failure

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References (34)

Publisher
American Medical Association
Copyright
Copyright © 1999 American Medical Association. All Rights Reserved.
ISSN
0003-9926
eISSN
1538-3679
DOI
10.1001/archinte.159.22.2634
Publisher site
See Article on Publisher Site

Abstract

THE IMPACT of a newly introduced therapeutic approach is mostly determined by 2 facts: (1) it addresses a common condition that affects large numbers of people and defines their functional status and quality of life for long periods of time; (2) it is inexpensive and readily available not only to those who live in technologically advanced societies, but also to those who live in the developing countries, where most of the world's population resides. While death rates from other cardiovascular diseases are decreasing, the incidence of death rates from heart failure has been increasing in recent years. Several factors account for this trend, including, ironically, the successful management of inflammatory or ischemic heart disease, hypertension, and other conditions that lead to heart failure, as well as increasing life expectancy. Indeed, today, heart failure is estimated to affect about 5 million people in the United States, of whom more than 75% are older than 65 years.1 Similar trends are observed worldwide, partly as a result of successful implementation of various health measures and better living standards, which ensure that the incidence and prevalence of cardiovascular disease will continue to increase in aging populations. As a chronic, inexorably progressing condition, heart failure requires lifelong maintenance with multiple drugs. Even with state-of-the-art therapy, which today includes angiotensin-converting enzyme (ACE) inhibitors, with or without the standard diuretics and inotropes of the previous era, the death rate associated with heart failure still includes approximately 10% to 20% of patients within the first year of diagnosis and 50% within 5 years. Furthermore, the incapacitating symptoms of the disease and the adverse effects of the drugs diminish the productivity and enjoyment of these years. Clearly, there is room for improvement, and this has become apparent to both research scientists and the pharmaceutical industry. Intensive research over the past few decades into the pathogenic mechanisms of heart failure has gradually altered our perception of this condition: A generation ago, it was viewed mostly as pump failure leading to fluid volume overload and was treated with digitalis and diuretics. Even after Kelly et al2 introduced, and Cohn3 promoted, the concept of afterload rather than preload reduction to relieve pump failure and enhance tissue perfusion, the mainstay of treatment continued to be diuresis and inotropic stimulation. There is no evidence that either of these treatments prolongs life, but clinical experience shows that they offer immediate symptomatic relief. Several vasodilators have been tried briefly and abandoned for various reasons over the years. Today, it is recognized that the progressive deterioration of myocardial remodeling and function is attributable not so much to the hemodynamic burden per se, but rather to the neurohormonal activation accompanying the hemodynamic decompensation. Exposure of the myocardium to high levels of angiotensin II and norepinephrine was shown to produce widespread necrotic lesions,4,5 and sympathetic activation was proposed as both cause and marker of worsening heart failure.6,7 Although many humoral factors are now known to contribute to the phenomenon referred to as neurohormonal activation (eg, autacoids such as cytokines and tumor necrosis factors), it is the harnessing of the 2 major systemic pressor systems—the renin-angiotensin system and the sympathetic nervous system (SNS)—that has produced clinically significant results. Recent research has revealed that their deleterious effects result not only from their systemic pressor actions but also from their local autocrine/paracrine/intracrine effects on cardiomyocytes and adjacent tissues.8,9 Inhibition of the renin-angiotensin system as treatment for congestive heart failure was first proposed in 1977 with the angiotensin II receptor antagonist saralasin acetate,10 and was subsequently corroborated by clinical experiments with parenteral and oral ACE inhibitors. These first clinical studies were mostly observational, with hemodynamic, electrocardiographic, and other clinical parameters recorded before and during administration of the ACE inhibitor. The results were encouraging and consistent, so they caught the attention of the pharmaceutical industry. Several pharmaceutical companies were coming up with their own ACE inhibitors, and all were interested in taking advantage of this potential new indication for their antihypertensive drugs. Accordingly, they organized numerous meetings, satellite symposia at national or international meetings, and other occasions for exchange of information. They were also keen to initiate and fund large controlled multicenter trials to prove the benefit of their product in terms of patient outcome. The first such trial, the Cooperative North Scandinavian Enalapril Survival Study,11 demonstrated that this treatment could decrease the morbidity and mortality of heart failure. Further comparative trials with various ACE inhibitors against inotropes, diuretics, and vasodilators in various combinations have now established ACE inhibition as the standard therapy for left ventricular dysfunction, especially after a myocardial infarct, and mandate initiation of therapy even before the onset of overt systolic failure. The recent introduction of oral angiotensin II receptor antagonists indicates that these agents may be at least as effective hemodynamically and possibly more effective in terms of prevention of sudden death12 in such patients. This finding led to a resurgence of interest on the part of the pharmaceutical industry, with multiple meetings, symposia, and multicenter controlled trials to establish and propagate this new therapeutic approach. There is no doubt that this active generation and dissemination of information must have helped to improve and prolong the life of many patients with heart failure. Inhibition of the SNS as treatment for heart failure has followed a somewhat different course. Initially, it was attempted by use of a ganglionic blocker2 or an α-adrenoceptor blocker,13 both of which were viewed mostly as vasodilators, but was soon abandoned for various reasons, including lack of sustained benefits. It was then attempted with clonidine,14,15 which was also viewed as a vasodilator, but was abandoned for fear of a negative inotropic effect at a time when positive inotropes were still the standard therapy for myocardial pump failure. Use of β-adrenergic blockade was shunned for years because of its immediate negative inotropic action, although some clinical studies suggested a later benefit in cardiac economy.16,17 However, accumulating evidence from clinical and basic research led gradually to the realization that β-adrenergic inhibition may indeed be beneficial in the long run in most cases, despite the risk of an early hemodynamic reversal. As with ACE inhibition, these encouraging results caught the attention of the pharmaceutical industry, especially those companies that manufactured the second and third generation of β-adrenoceptor blockers, such as bisoprolol, bucindolol hydrocholoride, and carvedilol, in the 1990s. The pharmaceutical companies have funded large multicenter controlled trials,18,19 organized numerous scientific meetings and satellite symposia, and facilitated publication of the proceedings in journal supplements and newsletters, thus ensuring wide dissemination of this information. Even though the outcome data have not always been positive (eg, the Australia-New Zealand data regarding carvedilol failed to demonstrate a decrease in mortality, as did some of the earlier bisoprolol data), they have generated a great deal of enthusiasm, which mostly appears to be justified. Nevertheless, some experienced clinical researchers have added a note of caution, especially as to the selection of appropriate subjects as candidates for this treatment.20 But there is another way to inhibit the SNS in heart failure, a way that can restore autonomic balance and may actually be devoid of the immediate risk of left ventricular depression seen with β-blockade: the central SNS suppression with clonidine. A series of investigator-initiated clinical studies by us and others over the last 3 to 4 years,21-26 some observational only, others placebo controlled with or without ACE inhibitors, and some of many months' duration, have given consistently encouraging results: they indicate that clonidine improves functional capacity (as assessed by prolonged exercise tolerance), while improving or leaving unaffected the various hemodynamic parameters. More importantly, clonidine appears to correct autonomic imbalance and to ameliorate most indices of arrhythmogenic potential (such as heart rate variability and related parameters derived from Holter monitoring) and indeed seems to decrease the incidence and complexity of ventricular ectopy, which is the main cause of sudden death in heart failure. Yet, despite multiple efforts, there has been no interest so far from anyone to fund large controlled studies to demonstrate the long-term impact of these alterations on patient outcome.27 The clinically observed benefits of clonidine in heart failure are known to a small circle of academic cardiologists, but the primary care physicians who treat 90% of patients with chronic heart failure are totally unaware of them. TWENTY OR 30 years ago, journals addressed to general clinical readership would accept manuscripts from investigators who conducted small clinical trials as long as the trials were properly conducted and met rigorous scientific standards. Today, these journals will only accept manuscripts that report the results of large, double-blind, placebo-controlled trials, which are very expensive and can only be conducted with support from the pharmaceutical industry. But, naturally, companies will only fund trials assessing their own patented products that promise large returns. Partnership between industry and academia is driven by the expectation of profit. Clonidine has few commercial prospects: it is an old and inexpensive drug, long out of patent, that is now finding a new use and may have the potential to ameliorate and prolong lives. This is of particular interest to physicians in parts of the world where the newest ACE inhibitors, angiotensin II receptor antagonists, and β-blockers—those proved to help patients with heart failure—are out of reach to large segments of the population. However, there are no symposia or journal supplements or newsletters to help disseminate this information, and it does not have the eye-catching appeal of miraculous technological accomplishments, such as genetic engineering, to make it newsworthy. Is there a solution to this problem? The story of aspirin as an antiplatelet agent and the renaissance of spironolactone as an adjunct to ACE inhibition in heart failure suggest that an old, inexpensive, widely available drug that is now proposed to have a new role may yet generate enough interest on the part of policymakers, if not industry, to permit its formal testing. On the other hand, the pharmaceutical industry may fund studies using similar drugs that are still under patent, eg, α2-agonists with a central SNS suppressant effect, such as moxonidine or rilmenidine, provided, of course, that they will turn out to be as effective as clonidine. Such studies would at least allow dissemination of the relevant information that may then be extrapolated to all members of that class. It may also be of interest to insurers or government agencies to sponsor trials designed to assess whether this treatment is not only clinically effective but cost-effective as well. Decision makers are usually under the dual pressures of adopting expensive new technologies and considering budgetary constraints.28 Pharmacoeconomic evaluation of an old drug with a known safety profile and promising value in terms of patient outcomes should be appealing to such organizations, as both acquisition costs and follow-up costs should compare favorably with alternative treatments. References 1. Not Available, Morbidity and Mortality Chartbook on Cardiovascular, Lung and Blood Disease, 1990-1994. Bethesda, Md National Institutes of Health, National Heart, Lung, and Blood Institute, US Dept of Health and Human Services1994; 2. Kelly RTFreis EDHiggins TH The effects of hexamethonium on certain manifestations of congestive heart failure. Circulation. 1953;7169- 174Google ScholarCrossref 3. Cohn JN Vasodilator therapy for heart failure. Circulation. 1973;485- 8Google ScholarCrossref 4. Gavras HBrown JJLever AFMacadam RFRobertson JIS Acute renal failure, tubular necrosis and myocardial infarction induced in the rabbit by intravenous angiotensin II. Lancet. 1971;219- 22Google ScholarCrossref 5. Gavras H.Kremer DBrown JJ et al. Angiotensin- and norepinephrine-induced myocardial lesions: experimental and clinical studies in rabbits and man. Am Heart J. 1975;89321- 332Google ScholarCrossref 6. Cohn JNLevine TBOlivari MT et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med. 1984;311819- 823Google ScholarCrossref 7. Bristow MR The adrenergic nervous system in heart failure. N Engl J Med. 1984;311850- 851Google ScholarCrossref 8. Dostal DEBaker KM Biochemistry, molecular biology, and potential roles of the cardiac renin-angiotensin system. Dhalla NSTakeda NNagano Meds. The Failing Heart. Philadelphia, Pa Lippincott-Raven Publishers1995;275- 294Google Scholar 9. Newling RPFletcher PJCoutis MShaw J Noradrenaline and cardiac hypertrophy in the rat: changes in morphology, blood pressure and ventricular performance. J Hypertens. 1989;7561- 567Google ScholarCrossref 10. Gavras HFlessas ARyan TJBrunner HRFaxon DPGavras I Angiotensin II inhibition: treatment of congestive cardiac failure in a high-renin hypertension. JAMA. 1977;238880- 882Google ScholarCrossref 11. The CONSENSUS Trial Study Group, Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987;3161429- 1435Google ScholarCrossref 12. Pitt BSegal RMartinez FA et al. Randomized trial of losartan versus captopril in patients over 65 with heart failure. Lancet. 1997;349747- 752Google ScholarCrossref 13. Packer MMeller JCorlin RHerman MV Hemodynamic and clinical tachyphylaxis to prazosin-mediated afterload reduction in severe chronic congestive heart failure. Circulation. 1979;59531- 539Google ScholarCrossref 14. Giles TDIteld BJMautner RKRognoni PADillenkoffer RL Short-term effects of intravenous clonidine in congestive heart failure. Clin Pharmacol Ther. 1981;30724- 728Google ScholarCrossref 15. Hermiller BMagorien RDLeithe MEUnverferth DVLeier CV Clonidine in congestive heart failure: a vasodilator with negative inotropic effects. Am J Cardiol. 1983;51791- 795Google ScholarCrossref 16. Eichhorn EJBedotto JBMalloy CR et al. Effect of beta-adrenergic blockade on myocardial function and energetics in congestive heart failure: improvements in hemodynamic, contractile and diastolic performance with bucindolol. Circulation. 1990;82473- 483Google ScholarCrossref 17. Hjalmarson AWaasgstein F New therapeutic strategies in chronic heart failure: challenge of long-term beta-blockade. Eur Heart J. 1991;12(suppl F)63- 69Google ScholarCrossref 18. CIBIS Investigators and Committees, A randomized trial of beta-blockade in heart failure: the Cardiac Insufficiency Bisoprolol Study (CIBIS). Circulation. 1994;901765- 1773Google ScholarCrossref 19. Packer MBristow MRCohn JN et al. The Effect of Carvedilol on Morbidity and Mortality in Patients with Chronic Heart Failure. N Engl J Med. 1996;3341349- 1355Google ScholarCrossref 20. Pfeffer MAStevenson LW β-Adrenergic blockers and survival in heart failure. N Engl J Med. 1996;3341396- 1397Google ScholarCrossref 21. Manolis AJOlympios CSifaki M et al. Suppressing sympathetic activation in congestive heart failure. Hypertension. 1995;26719- 724Google ScholarCrossref 22. Manolis AJOlympios CSifaki M et al. Combined sympathetic suppression and angiotensin-converting enzyme inhibition in congestive heart failure. Hypertension. 1997;29 ((pt 2)) 525- 530Google ScholarCrossref 23. Manolis AJOlympios CSifaki M et al. Chronic sympathetic suppression in the treatment of chronic congestive heart failure. Clin Exp Hypertens. 1998;20717- 731Google ScholarCrossref 24. You-hu ZYou-cheng SJun ZXian-qi Y Sympathetic inhibition with clonidine improves autonomic balance in congestive heart failure. Int J Cardiol. 1997;59139- 144Google ScholarCrossref 25. Lang CCRayos GHChomsky DBWood AJWilson JR Effect of sympathoinhibition on exercise performance in patients with heart failure. Circulation. 1997;96238- 245Google ScholarCrossref 26. Girgis IChakko Sde Marchena E et al. Effect of clonidine on heart rate variability in congestive heart failure. Am J Cardiol. 1998;82335- 337Google ScholarCrossref 27. Giles TD Clonidine and heart failure [letter]. Hypertension. 1996;271187Google Scholar 28. Szucs TD Pharmacoeconomics of angiotensin converting enzyme inhibitors in heart failure. Am J Hypertens. 1997;10 ((10 Pt 2)) 272S- 279SGoogle ScholarCrossref

Journal

Archives of Internal MedicineAmerican Medical Association

Published: Dec 13, 1999

Keywords: chronic heart failure,economics,psychological suppression,heart failure

There are no references for this article.