²-Adrenergic Blocking Agents in Heart Failure

ORIGINAL INVESTIGATION ␤-Adrenergic Blocking Agents in Heart Failure Benefits of Vasodilating and Nonvasodilating Agents According to Patients’ Characteristics: A Meta-analysis of Clinical Trials

Sara Bonet, MD; Anto`nia Agustı´, MD; Josep M. Arnau, MD; Xavier Vidal, MD; Eduard Dioge`ne, MD; Enrique Galve, MD; Joan-Ramon Laporte, MD

Background: In patients with heart failure, ␤-adrener- diovascular mortality, and mortality due to pump fail- gic blocking agents reduce overall and cardiovascular mor- ure and sudden death by 34% to 39%. The decrease in tality. This meta-analysis aimed at clarifying their effect overall mortality in patients with ischemic heart disease on sudden death, the magnitude of their benefit accord- (IHD) (30%) was no different from that among patients ing to the cause of heart failure, and whether there is any with non-IHD (26%) (P = .08). The reduction in overall difference between vasodilating and nonvasodilating mortality was greater with vasodilating than with non- agents. vasodilating agents (45% vs 27%; P = .007), particularly in patients without IHD (62%), compared with those with Methods: Randomized, clinical trials were included if they IHD (22%; P = .03). evaluated a ␤-adrenergic blocking agent without intrinsic sympathomimetic activity, included a control group re- Conclusions: In patients with heart failure, ␤-blockers ceiving placebo or standard treatment, evaluated mortal- reduce total and cardiovascular mortality at the expense ity on an intention-to-treat basis, and lasted at least 8 weeks. of a decrease in mortality due to pump failure and sudden death. The magnitude of the benefit is similar in pa- Results: Twenty-one trials with 5849 patients (3130 tients with IHD and in those with non-IHD. Vasodilat- receiving ␤-blockers) were included. Median length of ing ␤-blockers have a greater effect on overall mortality treatment was 6 months. Most patients had mild or mod- than nonvasodilating agents, particularly in patients with erate heart failure and were treated with angiotensin- non-IHD. converting enzyme inhibitors, diuretics, and digitalis. The ␤-blockers significantly reduced overall mortality, car- Arch Intern Med. 2000;160:621-627

ESPITE MAJOR advances in the myocardium, through direct myocar- knowledge about heart dial toxic effects and arrhythmogenesis failure, it remains a seri- caused by excess of catecholamines, and ous public health prob- through indirect stimulation of the renin- lem,withagrowingpreva- angiotensin system.9-11 The results of sev- lenceD of 0.2% to 4% in the general popu- eral clinical trials suggest that ␤-adrener- lation and about 10% in patients older than gic blocking agents improve symptoms, left 80 years.1 Case-fatality rate is 10% to 20% ventricular function, and the rate of hos- within 1 year of diagnosis and 50% or more pital admission.12-21 For carvedilol, a ben- within 5 years.1,2 Although death rates due eficial effect on mortality has also been re- to other cardiovascular diseases are falling, ported.22 Three meta-analyses23-25 have advanced heart failure progresses to rapid indicated that ␤-blockers reduce overall From the Fundacio´ Institut deterioration and is a cause of rising mor- and cardiovascular mortality. However, it Catala` de Farmacologia, tality rates.3-6 This has stimulated research is not known whether they reduce sud- Service of Clinical into a more intensive treatment of less ad- den death, whether their efficacy is influ- Pharmacology, Department vanced stages of the disease and treatments enced by the cause of heart failure, or of Pharmacology and based on new pathophysiological targets. whether there is any difference in the ef- Therapeutics (Drs Bonet, In patients with heart failure, the re- fect of vasodilating and nonvasodilating Agustı´, Arnau, Vidal, Dioge`ne, and Laporte), and the Service nin-angiotensin and sympathetic ner- agents. Our study addressed these ques- of Cardiology (Dr Galve), vous systems are activated and contrib- tions, including additional information Hospitals Vall d’Hebron, ute to progressive deterioration of the from the recently published Cardiac In- Universitat Auto`noma de patient’s condition.7,8 Long-term sympa- sufficiency Bisoprolol Study II (CIBIS-II) Barcelona, Barcelona, Spain. thetic activation has detrimental effects on trial.26

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Downloaded From: https://jamanetwork.com/ on 10/02/2021 MATERIALS AND METHODS knowledge of the title, authors, and publishing journal. Differences were resolved by consensus. The information on each trial included in the meta-analysis usually was Clinical trials were identified through a computerized biblio- obtained from the corresponding publication. For each graphicsearchoftheMEDLINE(fromJanuary1,1966,toJanu- trial, the following information was independently col- ary 31, 1998) and EMBASE (from January 1, 1974, to May 30, lected by two of us (S.B., A.A.), using a standard form: sex, 1997) databases and by browsing the bibliography from re- age, New York Heart Association (NYHA) functional clas- view articles on heart failure. A letter, asking about any un- sification, ejection fraction, standard treatments, duration published or unknown trial on ␤-blockers in heart failure, was of the study, ␤-adrenergic agent tested, number of with- also sent to the first author of identified clinical trials, to ex- drawals and deaths during the run-in phase, and mortality perts in heart failure, and to the pharmaceutical companies during the double-blind phase of each trial. When some of manufacturing ␤-blocking agents. Furthermore, since Janu- these items were missing in the article, the first investiga- ary 1998, we have been following the progress and possible tor of the study was asked for them. When information on termination of a number of ongoing clinical trials. a particular variable ultimately was not obtained, the trial Clinical trials were included if they (1) were random- was excluded from the analysis of that particular variable. ized and tested a ␤-adrenergic blocking agent devoid of Heterogeneity of treatment effects between studies was intrinsic sympathomimetic activity in patients with heart tested by using a ␹2 test for heterogeneity.27 Relative risks (RR) failure; (2) had a control group treated with placebo or and their 95% confidence intervals (CIs) were calculated us- standard treatment; (3) had a parallel or crossover design ing the DerSimonian and Laird random-effects methods28 with (from the latter, only the results of the first part of the the Rev-man program developed by the Cochrane Collabo- study before the crossover were included); (4) evaluated ration.28 The random effects model was chosen because, in mortality on an intention-to-treat basis; and (5) had a absence of heterogeneity, the results are the same as those minimum duration of 8 weeks. Trials with and without obtained with the fixed effects model, and they can be more run-in phase were included. confidently generalized, as they are also more conservative. Three investigators (A.A., J.M.A., X.V.) indepen- Comparisons between relative risk estimates were per- dently considered the inclusion of each trial without formed using the method described by Schlesselman.29

RESULTS als (1839 patients, of whom 1658 were included in trials with carvedilol) tested a ␤-blocker with vasodilating prop- CLINICAL TRIALS INCLUDED IN THE erties, and 10 (4010 patients) tested a nonvasodilating agent META-ANALYSIS (3288 patients in trials with bisoprolol). Heart failure due to ischemic heart disease (IHD) Thirty-nine studies12-22,26,30-56 were evaluated, but only resulted in 3 trials,16,21,39 to non-IHD (idiopathic) in 2112-21,26,30-39 met the preestablished criteria and were in- 8,12,14,15,18,19,34,36,37 and to mixed in 9*; cause was not stated cluded in the study (Table 1). Four studies were ex- in 1 study.31 In total, heart failure was judged to be is- cluded because they lasted less than 8 weeks40-43; 6 stud- chemic in 2841 patients (48.6%) and nonischemic in 2903 ies because they did not include a control group receiving (49.6%). Patients with NYHA class II or III disease con- placebo or standard treatment44-49; 1 study because it was stituted 88.7%. In trials that included information on con- a subanalysis of patients with heart failure in the ␤-Blocker comitant treatment, 70% to 100% of patients received an Heart Attack Trial50; 1 study because labetalol hydro- angiotensin-converting enzyme (ACE) inhibitor (15 tri- chloride, the agent used, has some intrinsic sympatho- als); 75% to 100%, a diuretic (14 trials); and 34% to 100%, mimetic activity51; 1 study because the assignment pro- digitalis (16 trials). cedure was suboptimal52; 1 study because it only described the design of a study53; 1 study because it did not report TOTAL AND CARDIOVASCULAR MORTALITY on mortality54; and 2 studies because of discrepancies in the numerical data.55,56 Finally, 1 was the summary re- Seven hundred eighty-three patients died, 333 (10.6%) port22 of 4 randomized trials with carvedilol,30,31,33,38 and of 3130 treated with ␤-blockers, and 450 (16.6%) of 2719 its results were used only when data were not available in the control group (RR, 0.71; 95% CI, 0.63-0.80) from the individual trials. (Table 2). Thus, 1 death can be prevented by treating 17 patients for 6 months. In 14 trials, a trend toward re- BASELINE CHARACTERISTICS OF PATIENTS duced mortality was seen, but only in 3 was this statistically significant (Figure). Including deaths during the A total of 5849 patients were studied (75% male; 3130 ran- run-in phase of trials (n = 15) in the analysis did not ma- domized to ␤-blocking agents and 2719 to the control terially change the estimate of mortality reduction (OR, group). The median duration of treatment was 6 months 0.71; 95% CI, 0.63-0.80). (range, 3-32 months). In 8 trials, the drug under study was Information on cardiovascular mortality was ob- carvedilol17,18,21,30-33,38; in 7 studies, metoprolol (metopro- tained from 18 studies.† There were 262 (9.0%) of 2913 lol tartrate in three studies15,16,19; nonspecified salt in the cardiovascular deaths among patients treated with others)12,14-16,19,34,36; in 3 studies, bucindolol hydrochlo- ride13,35,37; in 2 studies, bisoprolol fumarate20,26; and in 1 *References 13, 17, 20, 26, 30, 32, 33, 35, 38. study, propranolol hydrochloride39 (Table 1). Eleven tri- †References 12-21, 26, 30, 32, 34-36, 38, 39.

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Downloaded From: https://jamanetwork.com/ on 10/02/2021 Table 1. Main Characteristics of Trials of ␤-Blockers in Patients With Heart Failure*

NYHA Functional Class, % Run-in Duration, Male, Ischemic Heart Deaths, Source ␤-Blocker mo % I II III IV Disease, % Primary End Point No. (%)† Anderson et al12 Metoprolol‡ 19 66 . . .§ 0 Mortality . . . Australia/New Zealand Carvedilol 19 80 30 54 16 0 100 Left ventricular function 3 (0.007) Heart Failure Research Collaborative Group21 Bristow et al13 Bucindolol 3 61 1 42 56 1 29 Left ventricular function 0 hydrochloride Bristow et al30࿣ Carvedilol 6 76 0 46 52 2 52 Exercise tolerance 1 (0.003) CIBIS Investigators and Bisoprolol fumarate 23 83 0 0 95 5 55 Mortality . . . Committees20 CIBIS-II Investigators Bisoprolol 16 80 0 0 83 17 50 Mortality . . . and Committees26 Cohn et al31࿣ Carvedilol 6 NS NS NS Mortality NS Fisher et al16 Metoprolol tartrate 6 96 0 40 46 14 100 Left ventricular function . . . Krum et al17 Carvedilol 3 78 0 27 63 10 26 Left ventricular function 4 (0.7) Packer et al33࿣ Carvedilol 6 73 0 40 56 4 52 Exercise tolerance 5 (0.02) Waagstein et al19 Metoprolol tartrate 15 73 2 45 49 4 0 Mortality 0 Gilbert et al37 Bucindolol 3 70 0 44 56 0 0 Left ventricular function 0 Colucci et al38࿣ Carvedilol 7 85 0 86 14 0 41 Symptoms 1 (0.0025) Eichhorn et al14 Metoprolol‡ 3 100 0 67 29 2 0 Left ventricular function . . . Engelmeier et al15 Metoprolol tartrate 10 64 . . .¶ 0 Left ventricular function . . . Metra et al18 Carvedilol 4 90 0 28 72 0 0 Heart rate . . . Olsen et al32 Carvedilol 4 93 0 50 50 0 28 Symptoms 0 Pollock et al35 Bucindolol 3 79 0 5 74 21 37 Exercise tolerance 1 (0.05) Paolisso et al34 Metoprolol‡ 3 60 0 40 60 0 0 Metabolic variables . . . Sano et al36 Metoprolol‡ 12 86 0 64 36 0 0 NS . . . Aronow et al39 Propranolol 32 30 0 52 48 0 100 Mortality . . . hydrochloride

*NYHA indicates New York Heart Association; NS, not stated. †Ellipses indicate that a run-in phase was not performed. ‡Salt not specified. §Mean of the NYHA functional class in treatment and control groups was 2.7 and 2.8, respectively. ࿣The results of these 4 trials were also included in a combined analysis.22 ¶Mean of the NYHA functional class in treatment and control groups was 2.4 and 2.4, respectively.

␤-blockers, compared with 347 (13.7%) of 2530 in the (RR, 0.74 [95% CI, 0.64-0.86]), but the CIs were control group (RR, 0.71; 95% CI, 0.59-0.86). This cor- wide, and the difference was not statistically signifi- responds to 1 cardiac death prevented for every 21 pa- cant (P = .14). A similar nonsignificant trend was seen tients treated. Reduced cardiovascular mortality was the when the effect of vasodilating (RR, 0.33 [95% CI, result of a decrease in the number of deaths due to heart 0.08-1.35]) and nonvasodilating agents (RR, 0.72 failure (RR, 0.66 [95% CI, 0.47-0.92]) and sudden death [95% CI, 0.51-1.01]) (P = .24) on mortality due to (RR, 0.70 [95% CI, 0.54-0.89]). There were few deaths pump failure was considered. Both groups of drugs due to myocardial infarction (12 vs 14; RR, 0.81 [95% similarly reduced mortality due to sudden death (RR, CI, 0.38-1.72]) and other cardiovascular causes (41 vs 0.63 [95% CI, 0.35-1.12] vs RR, 0.76 [95% CI, 45; RR, 0.87 [95% CI, 0.48-1.57]). 0.53-1.10]). The inclusion of the CIBIS-II trial did not change Before the publication of the CIBIS-II trial, a trend the estimates of overall, cardiovascular, or heart failure toward a greater protective effect of vasodilating agents mortality (Table 2), but it did increase the estimate of on sudden death was seen (Table 5), but this disap- the benefit on sudden death. peared when the CIBIS-II was included.

VASODILATING VS NONVASODILATING CAUSES OF HEART FAILURE ␤-ADRENERGIC BLOCKING AGENTS Information on the causes of heart failure was avail- Both groups of drugs reduced overall mortality, and able from 15 trials.* Reduction in overall mortality this effect was greater with vasodilating agents (RR, with ␤-blockers was slightly greater in patients with 0.55 [95% CI, 0.38-0.78] vs RR, 0.73 [95% CI, 0.64- IHD (RR, 0.70 [95% CI, 0.60-0.81]) (Table 6) than 0.83]; P = .007) (Table 3 and Table 4). The point in those with non-IHD (RR, 0.74 [95% CI, 0.60-0.91]) estimate of the reduction in cardiovascular mortality (Table 7), but this difference was not statistically sig- was also greater with vasodilating agents (RR, 0.50 [95% CI, 0.22-1.17]) than with nonvasodilating agents *References 12, 14-16, 18-21, 26, 32, 34-37, 39.

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Downloaded From: https://jamanetwork.com/ on 10/02/2021 Table 2. Effect of ␤-Blockers on Mortality in Patients With Heart Failure*

No. of Deaths/Sample Size Mortality, RR (95% CI)

Source ␤-Blocker Group Control Overall Cardiovascular Pump Failure Sudden Death Anderson et al12 5/25 6/25 0.83 (0.29-2.38) 0.83 (0.29-2.38) 1.50 (0.27-8.22) 0.50 (0.10-2.49) Australia/New Zealand 20/207 26/208 0.77 (0.45-1.34) 0.90 (0.49-1.66) 1.00 (0.25-3.96) 0.91 (0.40-2.10) Heart Failure Research Collaborative Group21 Bristow et al13 4/105 2/34 0.65 (0.12-3.38) 0.65 (0.12-3.38) . . . 0.65 (0.12-3.38) Bristow et al30 12/261 13/84 0.30 (0.14-0.63) 0.22 (0.10-0.50) 0.16 (0.04-0.63) 0.32 (0.11-0.97) CIBIS Investigators and 53/320 67/321 0.79 (0.57-1.10) 0.68 (0.47-0.98) 0.50 (0.25-1.02) 0.89 (0.45-1.74) Committees20 Cohn et al31 2/70 2/35 0.50 (0.07-3.40) NA NA NA Fisher et al16 1/25 2/25 0.50 (0.05-5.17) 0.20 (0.01-3.97) 0.20 (0.01-3.97) . . . Krum et al17 3/33 2/16 0.73 (0.13-3.93) 0.97 (0.09-9.92) . . . 0.97 (0.09-9.92) Packer et al33 6/133 11/145 0.59 (0.23-1.56) NA NA NA Waagstein et al19 23/194 21/189 1.07 (0.61-1.86) 1.18 (0.66-2.09) 0.97 (0.29-3.31) 1.46 (0.72-2.95) Gilbert et al37 0/14 1/9 0.22 (0.01-4.93) NA NA NA Colucci et al38 2/232 5/134 0.23 (0.05-1.17) 0.06 (0.00-1.19) 0.12 (0.01-2.40) 0.12 (0.01-2.40) Eichhorn et al14 0/15 0/9 ...... Engelmeier et al15 1/9 2/16 0.89 (0.09-8.50) 0.89 (0.09-8.50) 1.78 (0.13-25.13) 0.57 (0.03-12.63) Metra et al18 0/20 0/20 ...... Olsen et al32 1/36 0/24 2.03 (0.09-47.79) 2.03 (0.09-47.79) . . . 2.03 (0.09-47.79) Pollock et al35 0/12 0/7 ...... Paolisso et al34 0/5 0/5 ...... Sano et al36 0/8 2/14 0.33 (0.02-6.19) 0.33 (0.02-6.19) 0.56 (0.03-12.24) 0.56 (0.03-12.24) Aronow et al39 44/79 60/79 0.73 (0.58-0.93) 0.71 (0.55-0.93) NA NA All 177/1803 222/1399 0.73 (0.62-0.86) 0.70 (0.54-0.91) 0.56 (0.34-0.92) 0.85 (0.59-1.21) CIBIS-II Investigators 156/1327 228/1320 0.68 (0.56-0.82) 0.74 (0.59-0.92) 0.76 (0.50-1.17) 0.58 (0.41-0.81) and Committees26 Total including CIBIS-II 333/3130 450/2719 0.71 (0.63-0.80) 0.71 (0.59-0.86) 0.66 (0.47-0.92) 0.70 (0.54-0.89)

*RR indicates relative risk; CI, confidence interval; ellipses, not applicable because there were no deaths; and NA, not available.

non-IHD, the decrease in overall mortality was greater Source RR with vasodilating (RR, 0.38 [95% CI, 0.18-0.83]) than (95% CI Random) with nonvasodilating ␤-blockers (RR, 0.78 [95% CI, Anderson et al12 Australian/New Zealand Heart Failure 0.63-0.96]; P = .03) (Table 5). Research Collaborative Group21 Bristow et al13 HOSPITALIZATION Bristow et al30 CIBIS Investigators and Committees20 CIBIS-II Investigators and Committees26 Four trials gave information on all-cause hospital Cohn et al31 21,26,34,36 Fisher et al16 admissions, and 9 gave information on hospi- Krum et al17 talization for heart failure.* The ␤-blockers reduced Packer et al33 the rate of all-cause hospital admissions by 15% (RR, Waagstein et al19 Gilbert et al37 0.85 [95% CI, 0.77-0.92]), and the rate of hospital Colucci et al38 admissions for heart failure by 33% (RR, 0.67 [95% Eichhorn et al14 CI, 0.58-0.77]). Vasodilating (RR, 0.64 [95% CI, 0.43- Engelmeier et al15 Metra et al18 0.94]) and nonvasodilating agents (RR, 0.67 [95% CI, Olsen et al32 0.57-0.78]) similarly reduced hospitalization for heart Pollock et al35 Paolisso et al34 failure (Table 5). Sano et al36 39 Aronow et al COMMENT Total Previously published meta-analyses, which had each in- 0.1 0.2 1.0 5.0 10.0 cluded from 3023 to 3141 patients, had already sug- Favors Treatment Favors Control gested a protective effect of ␤-blocking agents on mor- 23-25 Effect of ␤-blockers on overall mortality in the 21 trials. RR indicates tality due to heart failure. Our study, which includes 23-25 relative risk; CI, confidence interval. 5849 patients, confirms previous estimates of the benefit of ␤-adrenergic blocking agents on total, cardiovascular, and pump failure mortality in patients with heart nificant (P = .08). In patients with IHD, overall mor- failure. In addition, our results indicate that reduced car- tality was similarly reduced by vasodilating (RR, 0.61 [95% CI, 0.35-1.06]) and nonvasodilating agents (RR, 0.71 [95% CI, 0.60-0.83]) (Table 5). In patients with *References 15, 18, 20, 21, 26, 30, 34, 36, 38.

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Downloaded From: https://jamanetwork.com/ on 10/02/2021 Table 3. Effect of Vasodilating ␤-Blockers Table 4. Effect of Nonvasodilating ␤-Blockers on Overall Mortality* on Overall Mortality*

No. of Deaths/Sample Size No. of Deaths/Sample Size

Source ␤-Blocker Group Controls RR (95% CI) Source ␤-Blocker Group Controls RR (95% CI) Australia/New Zealand 20/207 26/208 0.77 (0.45-1.34) Anderson et al12 5/25 6/25 0.83 (0.29-2.38) Heart Failure Research CIBIS Investigators 53/320 67/321 0.79 (0.57-1.10) Collaborative Group21 and Committees20 Bristow et al13 4/105 2/34 0.65 (0.12-3.38) CIBIS-II Investigators 156/1327 228/1320 0.68 (0.56-0.82) Bristow et al30 12/261 13/84 0.30 (0.14-0.63) and Committees26 Cohn et al31 2/70 2/35 0.50 (0.07-3.40) Fisher et al16 1/25 2/25 0.50 (0.05-5.17) Krum et al17 3/33 2/16 0.73 (0.13-3.93) Waagstein et al19 23/194 21/189 1.07 (0.61-1.86) Packer et al33 6/133 11/145 0.59 (0.23-1.56) Eichhorn et al14 0/15 0/9 . . . Gilbert et al37 0/14 1/9 0.22 (0.01-4.93) Engelmeier et al15 1/9 2/16 0.89 (0.09-8.50) Colucci et al38 2/232 5/134 0.23 (0.05-1.17) Paolisso et al34 0/5 0/5 . . . Metra et al18 0/20 0/20 . . . Sano et al36 0/8 2/14 0.33 (0.02-6.19) Olsen et al32 1/36 0/24 2.03 (0.09-47.79) Aronow et al39 44/79 60/79 0.73 (0.58-0.93) Pollock et al35 0/12 0/7 . . . All 283/2007 388/2003 0.73 (0.64-0.83)† All 50/1123 62/ 716 0.55 (0.38-0.78) *Abbreviations are given in the footnote to Table 2. *Abbreviations are given in the footnote to Table 2. †Excluding CIBIS-II data, 0.78 (0.66-0.94).

Table 5. Summary Effects of Vasodilating and Nonvasodilating ␤-Adrenergic Blocking Agents on Mortality*

Nonvasodilating ␤-Blockers‡ Nonvasodilating ␤-Blockers Vasodilating ␤-Blockers,† Including CIBIS-II Data, Excluding CIBIS-II Data, Event RR (95% CI) RR (95% CI) P § RR (95% CI) P ሻ Overall mortality 0.55 (0.38-0.78) 0.73 (0.64-0.83) .007 0.78 (0.66-0.94) .004 IHD 0.61 (0.35-1.06) 0.71 (0.60-0.83) .18 0.77 (0.63-0.94) .11 Non-IHD 0.38 (0.18-0.83) 0.78 (0.63-0.96) .03 0.81 (0.57-1.16) .04 Cardiovascular mortality 0.50 (0.22-1.17) 0.74 (0.64-0.86) .14 0.75 (0.61-0.90) .14 Pump failure mortality 0.33 (0.08-1.35) 0.72 (0.51-1.01) .23 0.66 (0.38-1.13) .28 Sudden death 0.63 (0.35-1.12) 0.76 (0.53-1.10) .22 1.02 (0.65-1.62) .07 Hospitalization for heart failure 0.64 (0.43-0.94) 0.67 (0.57-0.78) .33 0.64 (0.49-0.85) Ͼ.99

*IHD indicates ischemic heart disease. Other abbreviations are given in the footnote to Table 2. †Includes carvedilol (1658 patients and bucindolol hydrochloride (181 patients). ‡Includes metoprolol (metoprolol tartrate in 3 studies15,16,19; salt not specified in the others12,14,34,36) (564 patients), bisoprolol fumarate (3288 patients), and propranolol hydrochloride (158 patients). §Vasodilating vs nonvasodilating ␤-blockers, including CIBIS-II data. ࿣Vasodilating vs nonvasodilating ␤-blockers, excluding CIBIS-II data.

diovascular mortality was the result of reduced mortal- ing ␤-blockers reduced overall mortality, but this effect ity due to heart failure and sudden death, that the ben- was greater with vasodilating agents, and mainly in efits in terms of mortality were of the same order in pa- patients with non-IHD cardiomyopathy. Our results tients with IHD and non-IHD, and that vasodilating agents suggest that the effect of vasodilating ␤-blockers could are more effective than nonvasodilating agents. be greater on cardiovascular mortality and on mortality The results of several clinical trials had suggested due to progressive pump failure. On the other hand, that patients with heart failure resulting from IHD did although a relative advantage of vasodilating ␤-blockers not benefit from ␤-blockers. In contrast, in 1 meta- on sudden death had been suggested,24 adding the analysis,24 overall mortality was similarly reduced in pa- results of the CIBIS-II trial suggests that the latter do tients with IHD and non-IHD heart failure. Our results not significantly differ from nonvasodilating ␤-blockers show that the magnitude of the benefit of ␤-blockers in in this respect. patients with IHD does not differ from that in patients A previously published meta-analysis25 had sug- with non-IHD. gested a greater effect of nonselective agents on overall Although ␤-adrenergic blocking agents are a rela- mortality compared with the selective agents. These re- tively heterogeneous group of drugs, pharmacological sults are in accord with ours, because, of 1600 patients differences rarely translate into therapeutic differences. treated with nonselective ␤-blocking agents and in- However, in patients with heart failure, the vasodilating cluded in that meta-analysis, 1564 had received carve- effect of certain ␤-blockers would compensate for the dilol or bucindolol, which are nonselective and vasodi- initial negative inotropic effect,57,58 and it has been sug- lating. The results of a recently early stopped trial with gested that this, rather than ␤-adrenergic blockade, metoprolol, where a 34% reduction in mortality was would account for their beneficial effect in heart fail- seen,61 are also in accord with our results regarding se- ure.59,60 In our analysis, vasodilating and nonvasodilat- lective nonvasodilating ␤-blockers.

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Downloaded From: https://jamanetwork.com/ on 10/02/2021 ure mortality and sudden death. Our results also show Table 6. Effect of ␤-Blockers on Overall Mortality in Patients that the effect of ␤-blockers in patients with IHD is at With Ischemic Heart Failure* least equal to that in patients with non-IHD. Compared with nonvasodilating agents, vasodilating ␤-blockers have No. of Deaths/Sample Size a greater effect on overall mortality, particularly in pa- Source ␤-Blocker Group Controls RR (95% CI) tients with non-IHD. This may be attributable to a greater ␤ Australia/New 20/207 26/208 0.77 (0.45-1.34) effect of vasodilating -blockers on cardiac and pump fail- Zealand Heart ure mortality, rather than on sudden death. Failure Research Collaborative Group21 Accepted for publication July 1, 1999. CIBIS Investigators 36/180 38/170 0.89 (0.60-1.34) This study was supported by grant 042996 from the and Committees20 Catalan Agency for Health Technology Assessment, Barce- CIBIS-II Investigators 75/662 121/654 0.61 (0.47-0.80) lona, Spain. and Committees26 We deeply acknowledge additional information on the 16 Fisher et al 1/25 2/25 0.50 (0.05-5.17) trials provided by Wilbert S. Aronow, MD; Eric J. Eich- Packer et al22† 13/332 17/189 0.44 (0.22-0.88) Olsen et al32 0/23 0/20 . . . horn, MD; John G. F . Cleland, MD; Jay N. Cohn, MD; Henry Pollock et al35 0/5 0/2 . . . J. Dargie, MD; Leif Erhardt, MD; Marc A. Pfeffer, MD; Wil- Aronow et al39 44/79 60/79 0.73 (0.58-0.93) lem J. Remme, MD; and Karl Swedberg, MD. All 189/1513 264/1347 0.70 (0.60-0.81)‡ Reprints: Joan-Ramon Laporte, MD, Fundacio´ Insti- tut Catala` de Farmacologia, Hospitals Vall d’Hebron, 08035, *Abbreviations are given in the footnote to Table 2. Barcelona, Spain (e-mail: [email protected]). †Information on mortality was not given in the original reports describing 4 individual trials with carvedilol, but was provided in this report. ‡Excluding CIBIS-II data, 0.74 (0.62-0.89). REFERENCES

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