15 years of heart-failure trials: what have we learned?
1998; Elsevier BV; Volume: 352; Linguagem: Inglês
10.1016/s0140-6736(98)90016-2
ISSN1474-547X
Autores Tópico(s)Blood Pressure and Hypertension Studies
ResumoIn the past 15 years, several trials in patients with chronic heart failure have revolutionised the management of this disorder and our understanding of its pathophysiology. Furthermore, these studies have provided important lessons about design and interpretation that will impact trials well into the next century. This paper is intended to place them in perspective and discuss their implications.Overview of heart-failure trials 1983-98We have listed 26 important heart-failure trials (table). This listing is not meant to be a complete listing, nor will all of the cited studies meet everyone's definition of a clinical trial. However, all these trials are randomised, controlled, double-blind studies. The results, alone or in conjunction with other results, have significantly influenced our thinking and practices.TableMajor clinical trials, 1986-98, and their implicationsDrug classTreatmentsOutcomeCommentsVasodilatorsV-HeFT-I1Cohn JN Archibald DG Ziesche S et al.Effect of vasodilator therapy on mortality in chronic congestive heart failure: results of a Veterans Administration Cooperative Study.N Engl J Med. 1986; 314: 1547-1552Crossref PubMed Scopus (2042) Google ScholarH+I vs prazosin vs placebo in ∼NYHA II/IIIIm proved survival with H+IFirst RCT in CHF with survival endpointV-HeFT-II14Cohn JN Johnson G Ziesche S et al.A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure.N Engl J Med. 1991; 325: 303-310Crossref PubMed Scopus (2520) Google ScholarH+I vs enalapril in NYHA II/IIIEnalapril superior for HI for survivalShowed differences between vasodilators and AcE FIRST6Califf RM Adams KF McKenna WJ et al.A randomized controlled trial of epoprostenol therapy for severe congestive heart failure: the Flolan International Randomized Survival Trial (FIRST).Am Heart J. 1997; 134: 44-54Summary Full Text Full Text PDF PubMed Scopus (549) Google ScholarPROFILE5Packer M Rouleau J Swedberg K Pitt B Fisher L Klepper M Effect of flosequinan on survival in chronic heart failure: preliminary results of the PROFILE study.Circulation. 1993; 88 (abstr): I, 310Google ScholarFlosequinan vs placebo in NYHA III/IVPoorer survival with flosequinanShowed importance of long-term follow-up and possible dissociation between symptoms and survivalMDPT2Goldstein RE Boccuzzi SJ Cruess D Nattel S Diltiazem increases late-onset congestive heart failure in post-infarction patients with early reduction of ejection fraction.Circulation. 1991; 83: 52-60Crossref PubMed Scopus (403) Google ScholarDiltiazem vs placebo in post-MI patients with LV dysfunctionPoorer outcome with diltiazem in subgroup with LV dysfunctionFirst to show adverse outcome with calcium antagonist in randomised controlled trialPRAISE4Amiedipine vs placebo in NYHA Ill/IVAmlodipine equal to placebo for survivalFirst to show safety of calcium antagonist in CHFACE inhibitorsCaptopril multicentre7Captopril Multicenter Research GroupA placebo controlled trial of captopril in refractory chronic congestive heart failure.J Am Coll Cardiol. 1983; 2: 755-763Summary Full Text PDF PubMed Scopus (588) Google ScholarCaptopril vs placebo in NYHA II/IIICaptopril superior to placebo for exercise toleranceFirst multicentre trial to show improvement in exerciseCONSENSUS-I9The CONSENSUS Trial study groupEffects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS).N Engl J Med. 1987; 316: 1429-1435Crossref PubMed Scopus (4692) Google ScholarEnalapril vs placebo in NYHA IVEnalapril superior to placebo for survivalFirst to show improved survival with an ACE inhibitorSOLVD-P10The SOLVD InvestigatorsEffect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure.N Engl J Med. 1991; 325: 293-302Crossref PubMed Scopus (6640) Google ScholarEnalapril vs placebo in NYHA II/IIIEnalapril superior to placebo for survivalFirst large simple trial in CHFSOLVD-P11The SOLVD InvestigatorsEffect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions.N Engl J Med. 1992; 327: 685-691Crossref PubMed Scopus (3494) Google ScholarEnalapril vs placebo in NYHA I/II CHFEnalapril superor to placebo for onset ofFirst trial to show prevention of CHFSAVE12Pfeffer MA Braunwald E Moyé LA et al.Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction.N Engl J Med. 1992; 327: 669-677Crossref PubMed Scopus (5427) Google ScholarCaptopril vs placebo for post-MI left-ventricular dysfunctionCaptopril better than placebo for survival and onset of CHFFirst trial to test the remodelling hypothesisAIRE13The Acute Infarction Ramipril Efficacy (AIRE) Study InvestigatorsEffects of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure.Lancet. 1993; 342: 821-828Summary PubMed Scopus (2339) Google ScholarRamipril vs placebo in heart failure after myocardial infarctionImproved survival with ramiprilConfirms SAVE results in patients with heart failurePositive inotropic drugsMilrinone-digoxin17DiBianco R Shabetai R Kostuk W Moran J Schlant RC Wright R A comparison of oral milrinone, digoxin, and their combination in the treatment of patients with chronic heart failure.N Engl J Med. 1989; 320: 677Crossref PubMed Scopus (438) Google ScholarMilrinone-digoxin vs placebo in NYHA II/IIIDigoxin superior to placebo and milrinone for exercise and clinical statusFirst large rigorous trial to show efficacy of digoxinRADIANCE19Packer M Gheorghiade M Young JB et al.Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors.N Engl J Med. 1993; 329: 1-7Crossref PubMed Scopus (669) Google ScholarDigoxin vs placebo in NYHA II/IIIDigoxin superior to placebo for clinical statusPositive studies but limited by withdrawal designPROVED18Uretsky BF Young JB Shahidi FE Yellen LG Harrison MC Jolly MK Randomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: results of the PROVED Trial.J Am Coll Cardiol. 1993; 22: 955-962Summary Full Text PDF PubMed Scopus (510) Google ScholarDIG Trial20The Digitalis Investigation GroupThe effect of digoxin on mortality and morbidity in patients with heart failure.N Engl J Med. 1997; 336: 525-533Crossref PubMed Scopus (2670) Google ScholarDigoxin vs placebo in NYHA I/II/IIIDigoxin equal to placebo for survival; digoxin decreased CHF hospital admissionsDefinitive safety study for digoxinXamoterol Trial21The Xamoterol in Severe Heart Study GroupXamoterol in severe heart failure.Lancet. 1990; 336: 1-6Summary PubMed Scopus (491) Google ScholarXamoterol vs placebo in NYHA III/IVPoorer survival with xamoterolFirst to show increased mortality with inotropic drug and specifically with a 13-receptor agonistPRIME-II23Hampton JR van Veldhuisen DJ Kleber FX et al.Randomized study of effect of ibopamine on survival in patients with advanced severe heart failure: Second Prospective Randomised Study of Ibopamine on Mortality and Efficacy (PRIME II) Investigators.Lancet. 1997; 349: 971-977Summary Full Text Full Text PDF PubMed Scopus (323) Google ScholarIbopamine vs placebo in NYHA III/IVPoorer survival with ibopamineDopamine receptor agoniet also has adverse effectPROMISE24Packer M Carver JR Rodeheffer RJ et al.Effect of oral milrinone on mortality in severe chronic heart failure: the PROMISE Study Research Group.N Engl J Med. 1991; 325: 1468-1475Crossref PubMed Scopus (1932) Google ScholarMilrinone vs placebo in NYHA IIII/IVPoorer survival with milrinonePossibly the final blow for pure phosphodiesterase inhibitorsVEST25Ferguson JJ Meeting highlights: American Heart Association 69th Scientific Session, New Orleans, LA, November 10–13, 1996 Circulation. 95. 1997: 761-764Google ScholarVesnarinone vs placebo NYHA III/IVPoorer survival with vesnarinoneSuggests that no positive inotropic agent is safe (except digoxin) in CHFPICO26Lubsen J Just H Hjalmarsson AC Framboise D et al.Effect of pimobendan on exercise capacity in patients with heart failure: main results from the Pimobendan in Congestive Heart Failure (PICO) trial.Heart. 1996; 76: 223-231Crossref PubMed Scopus (198) Google ScholarPimobendan vs placebo in NYHA II/IIIPimobendan better than placebo for exercise tolerance but tendency toward increased mortalitySafety concerns continueb-blockersMDC23Hampton JR van Veldhuisen DJ Kleber FX et al.Randomized study of effect of ibopamine on survival in patients with advanced severe heart failure: Second Prospective Randomised Study of Ibopamine on Mortality and Efficacy (PRIME II) Investigators.Lancet. 1997; 349: 971-977Summary Full Text Full Text PDF PubMed Scopus (323) Google ScholarMetoprolol vs placebo in NYHA II/IIIMetoprolol equal to placebo for survival but improves clinical statusFirst multicentre clinical trial to assess a b-blockerCIBIS-I29CIBIS Investigators and CommitteesA randomized trial of β-blockade in heart failure.in: The Cardiac Insufficiency Bisoprolol Study (CIBIS). Circulation. 90. 1994: 1765-1773Google ScholarBisoprolol vs placebo in NYHA II/IIIBisoprolol shows trend toward improved survivalApparent difference in effect in patients with and without previous myocardial infarctionCarvedilol US30Packer M Bristow MR Cohn IN et al.Effect of carvedilol on morbidity and mortality in chronic heart failure.N Engl J Med. 1996; 334: 1349-1355Crossref PubMed Scopus (4175) Google ScholarCarvedilol vs placebo in NYHA II/IIICarvedilol superior to placebo for morbidity and mortalityNot designed as a mortality study; follow-up sort and few NHYA IV patients includedANZTrial31Australia/New Zealand Heart Failure Research Collaborative GroupRandomized, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease.Lancet. 1997; 349: 375-380Summary Full Text Full Text PDF PubMed Scopus (711) Google ScholarCarvedilol vs placebo in NYHA I/IICarvedilol superior to placebo for morbidity and mortalityb-blocker beneficial in mild CHF due to coronary diseaseCIBIS-IIBisoprolol vs placebo in NYHA III/IVBisoprolol superior to placebo for survivalTrial stopped early for significant survival benefitRCT=randomised controlled trial; CHF=chronic heart failure; ACE=angiotensin-converting enzyme; CAD=coronary artery disease; DCM=dilated cardiomyopathy; H+l=hydralazine lus isosorbide dinitrate; NYHA=New York Heart Association. Open table in a new tab VasodilatorsThe first major heart-failure trial, the Veterans Administration Heart Failure Trial (V-HeFT-I),1Cohn JN Archibald DG Ziesche S et al.Effect of vasodilator therapy on mortality in chronic congestive heart failure: results of a Veterans Administration Cooperative Study.N Engl J Med. 1986; 314: 1547-1552Crossref PubMed Scopus (2042) Google Scholar a randomised survival trial of hydralazine plus isosorbide dinitrate and prazosin compared with placebo, was published in 1986. This landmark study showed the feasibility of mortality trials for heart failure and, for the first time, suggested that survival could be improved with drug treatment. The mechanism of benefit was assumed to be haemodynamic, with hydralazine and nitrates leading a balanced decrease in left-ventricular afterload and preload.It has, however, subsequently become clear that direct-acting vasodilators are not consistently beneficial for symptoms or survival in heart-failure patients, as became apparent with the calcium antagonists, which worsened outlook in patients with heart failure or left-ventricular dysfunction after myocardial infarction.2Goldstein RE Boccuzzi SJ Cruess D Nattel S Diltiazem increases late-onset congestive heart failure in post-infarction patients with early reduction of ejection fraction.Circulation. 1991; 83: 52-60Crossref PubMed Scopus (403) Google Scholar, 3The Danish Study Group on Verapamil in Myocardial InfarctionVerapamil in acute myocardial infarction.Eur Heart J. 1984; 5: 516-528PubMed Google Scholar Even a vasoselective agent, amlodipine, failed to improve survival,4Packer M O'Connor CM Ghali JK et al.Effect of amlodipine on morbidity and mortality in severe chronic heart failure.N Engl J Med. 1996; 335: 1107-1114Crossref PubMed Scopus (1061) Google Scholar although the absence of an adverse effect in patients with advanced heart failure makes this agent a therapeutic option for angina. The worsening survival seen with two other vasodilators, fiosequinan and epoprostenol, was noteworthy,5Packer M Rouleau J Swedberg K Pitt B Fisher L Klepper M Effect of flosequinan on survival in chronic heart failure: preliminary results of the PROFILE study.Circulation. 1993; 88 (abstr): I, 310Google Scholar, 6Califf RM Adams KF McKenna WJ et al.A randomized controlled trial of epoprostenol therapy for severe congestive heart failure: the Flolan International Randomized Survival Trial (FIRST).Am Heart J. 1997; 134: 44-54Summary Full Text Full Text PDF PubMed Scopus (549) Google Scholar since these agents had previously been found to improve haemodynamic measurements, symptoms, and exercise tolerance. The V-HeFT-I results, therefore, represent the only evidence of vasodilator benefit in heart failure, which raises the concern that vasodilators may not be as beneficial as once thought and shows that improved outcomes are not likely to be mediated exclusively by haemodynamic effects.Angiotensin-converting-enzyme (ACE) inhibitorsThe largest proportion of trials have involved ACE inhibitors. The Captopril-Multicenter Study7Captopril Multicenter Research GroupA placebo controlled trial of captopril in refractory chronic congestive heart failure.J Am Coll Cardiol. 1983; 2: 755-763Summary Full Text PDF PubMed Scopus (588) Google Scholar started the present era of heart-failure trials and showed for the first time in a rigorously designed protocol that endpoints such as exercise capacity and symptoms could be improved. Mortality was not assessed in that study, and only in a post-hoc analysis was a favourable effect recognised.8Newman TJ Maskin CS Dennick LG Meyer JH Hallows BG Cooper WH Effects of captopril on survival in patients with heart failure.Am J Med. 1988; 84: 140-144Summary Full Text PDF PubMed Scopus (68) Google Scholar Subsequently, improved survival with ACE-inhibitor therapy has been documented in patients with mild, moderate, and severe heart failure9The CONSENSUS Trial study groupEffects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS).N Engl J Med. 1987; 316: 1429-1435Crossref PubMed Scopus (4692) Google Scholar, 10The SOLVD InvestigatorsEffect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure.N Engl J Med. 1991; 325: 293-302Crossref PubMed Scopus (6640) Google Scholar ACE inhibitors were found also to prevent the onset of heart failure in patients with chronic symptomless left-ventricular dysfunction and in those with decreased ejection fractions after infarction.11The SOLVD InvestigatorsEffect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions.N Engl J Med. 1992; 327: 685-691Crossref PubMed Scopus (3494) Google Scholar, 12Pfeffer MA Braunwald E Moyé LA et al.Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction.N Engl J Med. 1992; 327: 669-677Crossref PubMed Scopus (5427) Google Scholar In the latter group, as well as in patients already with heart failure after infarction,12Pfeffer MA Braunwald E Moyé LA et al.Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction.N Engl J Med. 1992; 327: 669-677Crossref PubMed Scopus (5427) Google Scholar, 13The Acute Infarction Ramipril Efficacy (AIRE) Study InvestigatorsEffects of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure.Lancet. 1993; 342: 821-828Summary PubMed Scopus (2339) Google Scholar survival was improved. Importantly, VHeFT-II found that treatment with an ACE inhibitor was associated with a better prognosis than a hydralazinenitrate and direct-acting vasodilator combination.14Cohn JN Johnson G Ziesche S et al.A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure.N Engl J Med. 1991; 325: 303-310Crossref PubMed Scopus (2520) Google ScholarThe Assessment of Treatment with Lisinopril and Survival (ATLAS) trial15Results of the Assessment Trial of Lisinopril and Survival Trial (ATLAS). Presented at the 47th Annual Scientific Session of the American College of Cardiology, Atlant, GA. April 29, 1998Google Scholar highlighted that even a therapy that consistently exerts positive effects in clinical trials, such as ACE inhibitors, may not be effective in clinical practice if the doses in the study are not used. The target ACE-inhibitor doses in studies (eg, enalapril 20–40 mg or captopril 150–300 mg daily), as have been seen with many other drugs, have generally been between two and four times higher than those used by most physicians. In ATLAS, fewer heart-failure patients randomly assigned high doses of lisinopril (32·5–35·0 mg) died or were admitted to hospital than patients treated with low doses (2·5–5·0 mg). Efficacy (and harm) in clinical trials is, therefore, determined not only by the agent studied but also by the dose used; physicians must begin by using the doses used in clinical trials to achieve the anticipated benefits.With the advent of specific blockers of angiotensin-II receptors, the question arose of whether these agents were suitable alternatives to ACE inhibitors. Only one published study, Evaluation of Losartan in the Elderly (ELITE), has compared these two classes of drugs (specifically, losartan vs, captopril).16Pitt B Segal R Martinez FA et al.Randomised trial of losartan versus captopril in patients over 65 with heart failure.in: Evaluation of Losartan in the Elderly Study, ELITE. Lancet. 349. 1997: 747-752Google Scholar The primary endpoint, change in serum creatinine, did not differ between treatments. Unexpectedly, however, there were significantly fewer deaths in the losartan group than in the captopril group, although symptoms or admissions to hospital for heart failure did not differ. Given the small number of deaths (49 of 722 patients) and the unexpected and non-specified nature of the mortality outcome, this result should be taken as hypothesisgenerating at best. A larger trial comparing losartan and captopril with a survival endpoint, ELITE-II, is underway.Positive inotropic agentsThe digitalis glycosides are the oldest recognised therapy for heart failure, but their efficacy in patients who are in sinus rhythm has long been controversial. Few studies of these agents, until the past decade, had been of sufficient size and done with sufficient rigour to provide convincing evidence of benefits. Three trials with a withdrawal design have shown that during periods of 3-6 months, fewer patients maintained on digoxin had worsening heart failure and are more likely to maintain their exercise capacity and ejection fraction than patients in whom digoxin is withdrawn,17DiBianco R Shabetai R Kostuk W Moran J Schlant RC Wright R A comparison of oral milrinone, digoxin, and their combination in the treatment of patients with chronic heart failure.N Engl J Med. 1989; 320: 677Crossref PubMed Scopus (438) Google Scholar, 18Uretsky BF Young JB Shahidi FE Yellen LG Harrison MC Jolly MK Randomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: results of the PROVED Trial.J Am Coll Cardiol. 1993; 22: 955-962Summary Full Text PDF PubMed Scopus (510) Google Scholar, 19Packer M Gheorghiade M Young JB et al.Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors.N Engl J Med. 1993; 329: 1-7Crossref PubMed Scopus (669) Google Scholar These findings provide no information, however, about the effect of digoxin on survival, and are consistent with either benefit or with findings of underlying progression of cardiac dysfunction concealed by ongoing digoxin treatment. The Digoxin Investigators Group (DIG) trial,20The Digitalis Investigation GroupThe effect of digoxin on mortality and morbidity in patients with heart failure.N Engl J Med. 1997; 336: 525-533Crossref PubMed Scopus (2670) Google Scholar in which most of the 6800 participants had not been given digoxin before randomisation, conclusively showed that digoxin has a neutral effect on survival. Although digoxin decreased the number of admissions to hospital for heart failure by 28%, the decrease in all-cause admissions to hospital was much lower at 6%. Among patients in sinus rhythm, therefore, dixogin seems to be most appropriate in patients with more advanced symptoms who have failed to respond to diuretics and ACE inhibitors.The digitalis glycosides have been recognised for many years to have weak positive inotropic actions. This weak effect has been thought to be a disadvantage, and discovery of more potent inotropic drugs has been a longstanding goal of drug development. Perhaps the most consistent result of heart-failure trials has been the adverse effects of these agents on survival, whether by adrenergic stimulation or phosphodiesterase inhibition. A β-1-adrenoreceptor agonist,21The Xamoterol in Severe Heart Study GroupXamoterol in severe heart failure.Lancet. 1990; 336: 1-6Summary PubMed Scopus (491) Google Scholar, 22Dies F Knell MJ Whitlow P et al.Intermittent dobutamine in ambulatory outpatients with chronic cardiac failure.Circulation. 1986; 74 (abstr): II, 38Google Scholar a dopamine DA-1 agonist,23Hampton JR van Veldhuisen DJ Kleber FX et al.Randomized study of effect of ibopamine on survival in patients with advanced severe heart failure: Second Prospective Randomised Study of Ibopamine on Mortality and Efficacy (PRIME II) Investigators.Lancet. 1997; 349: 971-977Summary Full Text Full Text PDF PubMed Scopus (323) Google Scholar and several phosphodiesterase-III inhibitors (milrinone, vesnarinone, and probably enoximone and pimobendan)24Packer M Carver JR Rodeheffer RJ et al.Effect of oral milrinone on mortality in severe chronic heart failure: the PROMISE Study Research Group.N Engl J Med. 1991; 325: 1468-1475Crossref PubMed Scopus (1932) Google Scholar, 25Ferguson JJ Meeting highlights: American Heart Association 69th Scientific Session, New Orleans, LA, November 10–13, 1996 Circulation. 95. 1997: 761-764Google Scholar, 26Lubsen J Just H Hjalmarsson AC Framboise D et al.Effect of pimobendan on exercise capacity in patients with heart failure: main results from the Pimobendan in Congestive Heart Failure (PICO) trial.Heart. 1996; 76: 223-231Crossref PubMed Scopus (198) Google Scholar have been shown to have such adverse effects.The negative results with vesnarinone and pimobendan were especially disappointing since these agents were thought to enhance inotropy by facilitaton of sodium-channel transport and calcium sensitisation, respectively.27Feldman AM Classification of positive inotropic agents.J Am Coll Cardiol. 1993; 22: 1223-1227Summary Full Text PDF PubMed Scopus (45) Google Scholar Whether the adverse outcomes with these agents reflect their substantial phosphodiesterase-inhibiting activity or whether stimulation of contractility by any mechanism has an undesirable effect on prognosis is unclear. The magnitude of the adverse mortality effect with vesnarinone and pimobendan seem to be dose-dependent, which re-emphasises the importance of dose in clinical trials and practice.25Ferguson JJ Meeting highlights: American Heart Association 69th Scientific Session, New Orleans, LA, November 10–13, 1996 Circulation. 95. 1997: 761-764Google Scholar, 26Lubsen J Just H Hjalmarsson AC Framboise D et al.Effect of pimobendan on exercise capacity in patients with heart failure: main results from the Pimobendan in Congestive Heart Failure (PICO) trial.Heart. 1996; 76: 223-231Crossref PubMed Scopus (198) Google Scholar The cumulative effect of these results is to relegate non-glycoside-positive inotropic drugs to short-term or intermittent use in refractory patients or those awaiting cardiac transplantation. Even in these settings, however, neither the risks nor the benefits have been adequately defined.β-blockersAlthough β-blockers have been used to treat heart-failure patients in Scandinavia for more than two decades, their acceptance for this disorder elsewhere has been limited. In the Metroprolol in Dilated Cardiomyopathy (MDC) trial28Waagstein F Bristow MR Swedberg K et al.Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy: Metoprol in Dilated Cardiomyopathy (MDC) Trial Study Group.Lancet. 1993; 342: 1442-1446Summary Scopus (1187) Google Scholar and the Cardiac Insufficiency Bisoprolol Study (CIBIS-I) trial29CIBIS Investigators and CommitteesA randomized trial of β-blockade in heart failure.in: The Cardiac Insufficiency Bisoprolol Study (CIBIS). Circulation. 90. 1994: 1765-1773Google Scholar however, which studied two β-1 selective agents (metoprolol and bisoprolol), ejection fraction rose and the number of admissions to hospital were decreased but neither reached significance for the primary endpoint. Nonetheless, the 20% decrease in mortality with CIBIS-I is similar to that seen with ACE inhibitors and would have been signifiant in a larger trial.Carvedilol, a non-selective β-blocker with α-blocking activity, was the drug that paved the way to much wider use of β-bloqkers. Four studies, with a total of 1094 patients with ejection fractions of less than 35%, were done in the USA.30Packer M Bristow MR Cohn IN et al.Effect of carvedilol on morbidity and mortality in chronic heart failure.N Engl J Med. 1996; 334: 1349-1355Crossref PubMed Scopus (4175) Google Scholar Patients were entered into one of four similar protocols based on the distance travelled in a 6 min walk test. The primary endpoints were disease progression in patients with mild exercise limitation, exercise tolerance in those with moderate limitation, and quality of life in those with severe limitation. Only the first was positive for its main endpoint, but the combined experience, which averaged 6–8 months of follow-up, showed a substantial decrease in mortality and admissions to hospital for heart failure. These findings were corroborated to some degree by the Australia-New Zealand (ANZ) carvedilol trial,31Australia/New Zealand Heart Failure Research Collaborative GroupRandomized, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease.Lancet. 1997; 349: 375-380Summary Full Text Full Text PDF PubMed Scopus (711) Google Scholar which enrolled patients after infarctions with ejection fractions of less than 45% and New York Health Association class I-III symptoms, although the magnitude of this effect was substantially less than in the US studies. Nonetheless, the small number of deaths (105 of 1658), short duration of follow-up, and small number of patients with severe heart failure left substantial uncertainty about the effect of carvedilol on survival. In March, 1998, CIBIS-II was ended early by its Data Safety and Monitoring Board because of a significant decrease in mortality. Although the magnitude of benefit and its consistency across important subgroups have not been published, this result is likely to establish that β-blockade improves survival of heart-failure patients. Whether there are differences between β-blockers with different properties remains to be determined.Lessons from 15 years of heart-failure trialsInsights into mechanisms of drugsThere is much potential for benefit and harm in the treatment of heart failure. Increase of cardiac contractility with positive inotropic agents and improvement of cardiac performance by decrease of afterload and preload with vasodilators, together with diuresis, have long been taken as therapeutic targets in heart failure. These approaches may produce striking short-term haemodynamic improvement and may also improve symptoms and exercise tolerance. However, with the exception of hydralazine and nitrates in V-HeFT-I, positive iotropic drugs and direct-acting vasodialtors had no beneficial effect on prognosis. By contrast, most of these agents seem to worsen survival, often because of dose. These results clearly show that haemodynamic improvement is not the therapeutic target, nor should it be the criterion for drug or dose selection.Two explanations for these adverse outcomes come to mind. First, these agents may activate neurohormonal systems, either systemically or locally, with possible downstream consequences of accelerating cardiac remodelling, cell death, or both. Agents such as β-agonists and phosphodiesterase inhibitors may induce these processes by direct effects on the myocardium. Alternatively, either directly or indirectly, these agents may increase myocardial energy demands or decrease regional myocardial blood flow, leading to an imbalance in energy.By contrast, when studied with appropriate outcomes and statistical power, neurohormonal antagonists, including ACE inhibitors, β-blockers, and possibly angiotensin-II-receptor blockers, consistently improve prognosis. This finding occurs despite only slight haemodynamic improvement, or even short-term impairment. These outcomes suggest that these agents act by slowing progressiv
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