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Impact of advances in therapy for heart failure on secular trends in mortality
Journal of Cardiac Failure Vol. 2 No. 1 1996
Editorial Comment
Impact of Advances in Therapy for Heart Failure on Secular Trends in Mortality During the past 15 years, controlled clinical trials have clearly established that certain treatments for heart failure can improve survival. Numerous survival studies have documented that increased use of angiotensin-converting enzyme (ACE) inhibitors in clinical practice would lead to improved survival in populations of patients with heart failure. The expected magnitude of reductions in mortality would depend on the population's prognostic profile. For example, in the Studies of Left Ventricular Dysfunction Treatment Trial, enalapril reduced mortality compared to a placebo by 4%, from approximately 16 to 12% after 1 year, whereas in the Cooperative North Scandinavian Enalapril Survival Study, after 1 year the mortality in patients with more severe heart failure was reduced by 16%, from 52 to 36% (1,2). Many clinical trials also have indicated that the use of ACE inhibitors in patients with left ventricular dysfunction subsequent to myocardial infarction would be expected to lower mortality, albeit to a smaller extent since these patients have less risk of death than patients with chronic heart failure (3). In addition, therapy with oral nitrates in combination with hydralazine has been shown to lower mortality in patients with chronic heart failure (4). Few studies have examined the impact of these recent therapeutic advances on mortality rates in populations. There are many reasons why treatments may not produce the same degree of benefit in clinical practice as was estimated in clinical trials. Different disease characteristics, comorbidities, concurrent treatments, and treatment regimens may lead to different treatment outcomes. Epidemiologic investigations may yield important insights through examinations of the variation in the application of therapies in clinical practice and how it relates to variation in patient outcomes. Comparisons of the efficacy of medical practice during different time periods are susceptible to many confounding factors. Differences in referral patterns, diagnostic criteria, disease severity, and outcomes assessment, as well as inadequate documentation of treatments, often make interpretation of observational studies difficult. Nevertheless, studies of trends in mortality may raise important issues that need further investigation. In this issue, Messner and Petersson compare survival of patients in rural Sweden who experienced their first hospital admission for heart failure from 1987 to 1990 to a cohort from 1991 to 1994. They did not observe a significant improvement in survival during this time period. This report lacks sufficient information, however, to clearly establish that the two time cohorts had similar prognostic profiles at baseline and that there were differences in exposure to treatment regimens known to alter survival. Lack of prognostic information also prevents comparisons to patients enrolled in previous clinical trials. For example, left ventricular ejection fraction is a well-established prognostic variable that was used as a patient selection criterion in many survival studies. Ejection fraction was apparently not used in this practice setting to characterize either the type or severity of heart failure. If these cohorts included large subgroups with primarily diastolic dysfunction, one might not expect estimates of survival benefits from clinical trials conducted in patients with documented systolic dysfunction to apply. In addition, if therapies that improve survival were applied to some patients in the earlier cohort or if the treatments and dosage regimens used in the clinical trials were not applied consistently in the later cohort, one would expect less difference in survival between the two time cohorts than
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Journal of Cardiac Failure Vol. 2 No. 1 March 1996
were observed in clinical trials. Estimated 95% confidence intervals for the risk of death in the 1991-1994 cohort relative to the 1987-1990 cohort ranged from 0.66 to 1.12. Expected survival benefits based on generalization of clinical trials results to the studied population would be within this interval. Therefore, these data do not provide conclusive evidence that the use of new treatments, such as ACE inhibitors, did not reduce mortality rates in this rural Swedish population with heart failure. The data should inspire investigations to ask why the expected effects were not observed, however. In a previous issue of the Journal of Cardiac Failure, Keeling and associates suggested that new treatments have improved survival in patients with idiopathic dilated cardiomyopathy (5). Patients referred to their center from 1989 to 1993 were evaluated by extensive diagnostic tests. Many therapeutic options were applied as clinically indicated, including ACE inhibitors titrated to doses with demonstrated survival benefits in clinical trials (90%), cardiac transplantation (27%), and amiodarone (30%). A beneficial effect of amiodarone on mortality in patients with idiopathic dilated cardiomyopathy is possible but not yet firmly established (6,7). Mortality during 2 years of follow-up study was only 7%, which was much less than was expected based on previous reports. There was no prior cohort, however, that met the same diagnostic criteria with documented similarities in prognostic characteristics and follow-up procedures and that had well-documented differences in exposure to treatments. Therefore, one cannot be assured that the lower than expected mortality rate truly reflected medical progress. The 1980s and early 1990s were an era of substantial progress in the treatment of heart failure. How are new therapies being used in clinical practice? Do therapies yield the expected benefits when applied in general practice where provider practices and patient characteristics exhibit more variation than clinical trials? Studies that address these important questions are very limited, although observational data are being collected in healthcare organizations to manage care. The scientific community should support creation and maintenance of uniform clinical databases that contain information on disease, treatments, outcomes, and important covariates to facilitate high quality observational studies of clinical practice. Thomas S. Rector, PhD
Department of Medicine University of Minnesota Medicai School Minneapolis, Minnesota
References 1. The SOLVD Investigators: Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325: 293-302 2. The CONSENSUS Trial Study Group: Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study. N Engl J Meal 1987;316:1429-35 3. Latini R, Maggioni AP, Flather M, Sleight P, Tognoni G: ACE inhibitor use in patients with myocardial infarction: summary of evidence from clinical trials. Circulation 1995;92:3132-7 4. Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FE, Dunkman WB, Jacobs WJ, Francis GS, Flohr KH, Goldman S, Cobb FR, Shah PM, Saunders R,
Fletcher RD, Loeb HS, Hughes VC, Baker B: Effect of vasodilator therapy on mortality in chronic congestive heart failure: results of a Veterans Administration Cooperative Study. N Engl J Med 1986;314:1547-52 5. Keeling PJ, Goldman JH, Siade AKB, Elliott PM, Caforio ALP, Poloniecki J, McKenna WJ: Prognosis of idiopathic dilated cardiomyopathy. J Card Failure 1995; 1:1-9 6. Doval HC, Nul DR, Grancelli HO, Pert'one SV, Bortman GR, Curiel R: Randomized trial of low dose amiodarone in severe congestive heart failure. Lancet 1994;344:493-8 7. Singh SN, Fletcher RD, Fisher SG, Singh BN, Lewis HD, Deedwania PC, Massie BM, Colling C, Lazzeri D: Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. N Engl J Meal 1995;333: 77-82
Editorial Comment
Impact of Advances in Therapy for Heart Failure on Secular Trends in Mortality During the past 15 years, controlled clinical trials have clearly established that certain treatments for heart failure can improve survival. Numerous survival studies have documented that increased use of angiotensin-converting enzyme (ACE) inhibitors in clinical practice would lead to improved survival in populations of patients with heart failure. The expected magnitude of reductions in mortality would depend on the population's prognostic profile. For example, in the Studies of Left Ventricular Dysfunction Treatment Trial, enalapril reduced mortality compared to a placebo by 4%, from approximately 16 to 12% after 1 year, whereas in the Cooperative North Scandinavian Enalapril Survival Study, after 1 year the mortality in patients with more severe heart failure was reduced by 16%, from 52 to 36% (1,2). Many clinical trials also have indicated that the use of ACE inhibitors in patients with left ventricular dysfunction subsequent to myocardial infarction would be expected to lower mortality, albeit to a smaller extent since these patients have less risk of death than patients with chronic heart failure (3). In addition, therapy with oral nitrates in combination with hydralazine has been shown to lower mortality in patients with chronic heart failure (4). Few studies have examined the impact of these recent therapeutic advances on mortality rates in populations. There are many reasons why treatments may not produce the same degree of benefit in clinical practice as was estimated in clinical trials. Different disease characteristics, comorbidities, concurrent treatments, and treatment regimens may lead to different treatment outcomes. Epidemiologic investigations may yield important insights through examinations of the variation in the application of therapies in clinical practice and how it relates to variation in patient outcomes. Comparisons of the efficacy of medical practice during different time periods are susceptible to many confounding factors. Differences in referral patterns, diagnostic criteria, disease severity, and outcomes assessment, as well as inadequate documentation of treatments, often make interpretation of observational studies difficult. Nevertheless, studies of trends in mortality may raise important issues that need further investigation. In this issue, Messner and Petersson compare survival of patients in rural Sweden who experienced their first hospital admission for heart failure from 1987 to 1990 to a cohort from 1991 to 1994. They did not observe a significant improvement in survival during this time period. This report lacks sufficient information, however, to clearly establish that the two time cohorts had similar prognostic profiles at baseline and that there were differences in exposure to treatment regimens known to alter survival. Lack of prognostic information also prevents comparisons to patients enrolled in previous clinical trials. For example, left ventricular ejection fraction is a well-established prognostic variable that was used as a patient selection criterion in many survival studies. Ejection fraction was apparently not used in this practice setting to characterize either the type or severity of heart failure. If these cohorts included large subgroups with primarily diastolic dysfunction, one might not expect estimates of survival benefits from clinical trials conducted in patients with documented systolic dysfunction to apply. In addition, if therapies that improve survival were applied to some patients in the earlier cohort or if the treatments and dosage regimens used in the clinical trials were not applied consistently in the later cohort, one would expect less difference in survival between the two time cohorts than
31
32
Journal of Cardiac Failure Vol. 2 No. 1 March 1996
were observed in clinical trials. Estimated 95% confidence intervals for the risk of death in the 1991-1994 cohort relative to the 1987-1990 cohort ranged from 0.66 to 1.12. Expected survival benefits based on generalization of clinical trials results to the studied population would be within this interval. Therefore, these data do not provide conclusive evidence that the use of new treatments, such as ACE inhibitors, did not reduce mortality rates in this rural Swedish population with heart failure. The data should inspire investigations to ask why the expected effects were not observed, however. In a previous issue of the Journal of Cardiac Failure, Keeling and associates suggested that new treatments have improved survival in patients with idiopathic dilated cardiomyopathy (5). Patients referred to their center from 1989 to 1993 were evaluated by extensive diagnostic tests. Many therapeutic options were applied as clinically indicated, including ACE inhibitors titrated to doses with demonstrated survival benefits in clinical trials (90%), cardiac transplantation (27%), and amiodarone (30%). A beneficial effect of amiodarone on mortality in patients with idiopathic dilated cardiomyopathy is possible but not yet firmly established (6,7). Mortality during 2 years of follow-up study was only 7%, which was much less than was expected based on previous reports. There was no prior cohort, however, that met the same diagnostic criteria with documented similarities in prognostic characteristics and follow-up procedures and that had well-documented differences in exposure to treatments. Therefore, one cannot be assured that the lower than expected mortality rate truly reflected medical progress. The 1980s and early 1990s were an era of substantial progress in the treatment of heart failure. How are new therapies being used in clinical practice? Do therapies yield the expected benefits when applied in general practice where provider practices and patient characteristics exhibit more variation than clinical trials? Studies that address these important questions are very limited, although observational data are being collected in healthcare organizations to manage care. The scientific community should support creation and maintenance of uniform clinical databases that contain information on disease, treatments, outcomes, and important covariates to facilitate high quality observational studies of clinical practice. Thomas S. Rector, PhD
Department of Medicine University of Minnesota Medicai School Minneapolis, Minnesota
References 1. The SOLVD Investigators: Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325: 293-302 2. The CONSENSUS Trial Study Group: Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study. N Engl J Meal 1987;316:1429-35 3. Latini R, Maggioni AP, Flather M, Sleight P, Tognoni G: ACE inhibitor use in patients with myocardial infarction: summary of evidence from clinical trials. Circulation 1995;92:3132-7 4. Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FE, Dunkman WB, Jacobs WJ, Francis GS, Flohr KH, Goldman S, Cobb FR, Shah PM, Saunders R,
Fletcher RD, Loeb HS, Hughes VC, Baker B: Effect of vasodilator therapy on mortality in chronic congestive heart failure: results of a Veterans Administration Cooperative Study. N Engl J Med 1986;314:1547-52 5. Keeling PJ, Goldman JH, Siade AKB, Elliott PM, Caforio ALP, Poloniecki J, McKenna WJ: Prognosis of idiopathic dilated cardiomyopathy. J Card Failure 1995; 1:1-9 6. Doval HC, Nul DR, Grancelli HO, Pert'one SV, Bortman GR, Curiel R: Randomized trial of low dose amiodarone in severe congestive heart failure. Lancet 1994;344:493-8 7. Singh SN, Fletcher RD, Fisher SG, Singh BN, Lewis HD, Deedwania PC, Massie BM, Colling C, Lazzeri D: Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. N Engl J Meal 1995;333: 77-82