Metoprolol CR/XL in Female Patients With Heart Failure
Analysis of the Experience in Metoprolol Extended-Release Randomized Intervention Trial in Heart Failure (MERIT-HF)
Background— Underrepresentation of women in heart failure clinical trials has limited conclusions regarding the effect of various management strategies on survival in women with heart failure and decreased left ventricular ejection fraction (LVEF).
Methods and Results— MERIT-HF (Metoprolol Extended-Release Randomized Intervention Trial in Heart Failure) was a randomized, placebo-controlled study, the purpose of which was to evaluate the effect of metoprolol controlled-release/extended-release (CR/XL) in 3991 patients with New York Heart Association class II to IV heart failure and LVEF ≤0.40. We performed a post hoc analysis to evaluate the effect of metoprolol CR/XL on outcome in women (n=898), including the outcome in 183 women with severe heart failure (New York Heart Association class III/IV and LVEF <0.25). Treatment with metoprolol CR/XL in women resulted in a 21% reduction in the primary combined end point of all-cause mortality/all-cause hospitalizations (164 versus 137 patients; P=0.044). The number of cardiovascular hospitalizations was reduced by 29% (164 versus 120; P=0.013), and hospitalization for worsening heart failure was reduced by 42% (95 versus 56; P=0.021). Similar results were noted in the subgroup of women with severe heart failure, with a 57% reduction in cardiovascular hospitalizations (63 versus 30; P=0.005) and a 72% reduction in hospitalization due to worsening heart failure (46 versus 14; P=0.0004). A pooling of mortality results from MERIT-HF, the Cardiac Insufficiency Bisoprolol Study (CIBIS II), and the Carvedilol Prospective Randomized Cumulative Survival Study (COPERNICUS) showed very similar survival benefits in women and men.
Conclusions— The beneficial effects of metoprolol CR/XL extend to women with heart failure, including women with clinically stable severe heart failure.
Received December 12, 2001; revision received January 28, 2002; accepted January 28, 2002.
Recent randomized clinical trials have clearly established the beneficial effects of β-blockers in a broad spectrum of patients with heart failure (HF) and impaired left ventricular ejection fraction (LVEF).1–5⇓⇓⇓⇓ This information has led to the universal recommendations by clinical guidelines to use this class of medications in all symptomatic patients with HF and impaired LVEF.6,7⇓ Underrepresentation of women in these trials, however, has led to uncertainty about the effect of β-blockers in women, including whether their well-documented benefits in men would extend to women.8,9⇓
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The Metoprolol CR/XL Randomized Intervention Trial in Heart Failure (MERIT-HF) provides the second-largest database of women with HF and the largest that includes treatment with a β-blocker. The present analysis was undertaken to assess the response of women with HF and impaired LVEF to metoprolol succinate controlled-release/extended-release (CR/XL). We also pooled mortality data for women from the 3 large trials that evaluated the effect of β-blockers on survival in patients with HF and impaired LVEF: MERIT-HF, the Cardiac Insufficiency Bisoprolol Study (CIBIS-II),2,10⇓ and the Carvedilol Prospective Randomized Cumulative Survival Study (COPERNICUS).5 In view of the recently published data about the safety and efficacy of β-blockers in advanced HF,5,11⇓ we also analyzed separately the effect of metoprolol CR/XL in women with severe HF as defined by New York Heart Association (NYHA) functional class III/IV with LVEF <0.25.
The MERIT-HF study randomized 3991 patients. The 2 primary outcome events were total mortality and the combined end point of all-cause mortality or all-cause hospitalization (time to first event). The results of MERIT-HF have been published previously.3,4⇓ The present post hoc analysis focused on the female patients (n=898). Patients enrolled in MERIT-HF were 40 to 80 years of age, had LVEF ≤0.40 and were in NYHA class II to IV HF for ≥3 months before enrollment, had a heart rate ≥68 bpm, and were receiving optimum standard therapy of diuretics and an ACE inhibitor. If an ACE inhibitor was not tolerated, other vasodilators, preferably angiotensin II receptor blockers, were used. Digitalis could also be prescribed.
Other predefined combined end points (time to first event) were total mortality or hospitalization for worsening HF; cardiac death or nonfatal myocardial infarction. Predefined end points were also total number of hospitalizations for cardiovascular causes and for worsening HF; and withdrawal of study drug for any cause and for worsening HF. The follow-up procedures and statistical analysis for MERIT-HF have been described previously.3,4,12⇓⇓
Data are provided separately for men and women for the above-mentioned end points. Similar data are also reported for patients with severe HF, defined as NYHA class III/IV and LVEF <0.25.
Cox proportional regression analysis was performed to determine the effect of sex on survival independent of baseline differences. The following variables were included in the analysis: age; LVEF; NYHA class; ischemic etiology; history of myocardial infarction, hypertension, and diabetes mellitus; blood pressures; heart rate; and smoking status. In addition, an interaction between sex and the effect of metoprolol CR/XL on the other end points was analyzed.
Relative risk and 95% CIs for total mortality for women and men in CIBIS II were calculated from raw data (e-mail communication from T. Simon, MD, March 2001, and Simon et al10) with EPI-INFO version 6. Pooling of total mortality data by sex and overall from CIBIS II,2 MERIT-HF,3 and COPERNICUS5 was performed with a meta-analysis technique based on the 95% CIs of the relative risks in the studies.
Baseline characteristics of patients by sex are presented in Table 1. Compared with men (n=3093), women (n=898) were older, were more often in NYHA class III and IV, less often were classified as previous or current smokers, had similar LVEF, and had a higher prevalence of hypertension and diabetes mellitus and a lower prevalence of ischemic etiology or history of myocardial infarction.
Baseline characteristics of patients with severe HF defined as NYHA class III or IV with LVEF <0.25 are presented in Table 2. Compared with men (n=612), female patients (n=183) were older; had higher systolic blood pressure; were less likely to have ischemia, history of myocardial infarction, or atrial fibrillation; and had a higher prevalence of third heart sound. Mean LVEF was 0.19.
In women, metoprolol CR/XL reduced all-cause hospitalizations by 19% (0.57 versus 0.46 per patient-year of follow-up; P=0.044), cardiovascular hospitalization by 29% (0.37 versus 0.27 per patient-year of follow-up; P=0.013), and hospitalization for worsening HF by 42% (0.22 versus 0.12; P=0.021; Figure 1, top panel, and Table 3). There were 33 deaths (7.5% per patient-year of follow-up) in the placebo group and 31 (6.9%) in the metoprolol CR/XL group (P=NS). The incidence of cardiovascular deaths (31 and 27), worsening HF deaths (10 and 5), and sudden deaths (18 and 17, respectively) was not significantly different. Metoprolol CR/XL decreased the combined end point of all-cause mortality/all-cause hospitalization (time to first event) by 21% (164 versus 137 patients; P=0.044; Figure 2).
In women with severe HF (n=183), significant reductions in hospitalizations were also noted. The number of all-cause hospitalizations was reduced by 44% (1.05 versus 0.59 per patient-year of follow-up; P=0.016); cardiovascular hospitalization was reduced by 57% (0.74 versus 0.32; P=0.005); and hospitalization for worsening HF was reduced by 72% (0.54 versus 0.15; P=0.0004; Figure 1, bottom panel, and Table 4). There were 12 deaths in the placebo group and 9 in the metoprolol CR/XL group (P=NS). Metoprolol CR/XL decreased the combined end point of all-cause mortality/all-cause hospitalization by 44% (95% CI 12% to 65%; P=0.010) and all-cause mortality/hospitalization because of worsening HF by 63% (95% CI 33% to 80%; P=0.0008).
Among men, metoprolol CR/XL reduced the number of all-cause hospitalizations by 10% (0.58 versus 0.52 per patient-year of follow-up; P=0.044), cardiovascular hospitalizations by 14% (0.39 versus 0.34 per patient-year of follow-up; P=0.005), and hospitalization for worsening HF by 18% (0.23 versus 0.16 per patient-year of follow-up; P=0.0001; Table 4). Metoprolol CR/XL significantly reduced mortality (184 deaths, 12% per patient-year of follow-up, versus 114 deaths, 7.3% per patient-year of follow-up; P=0.0001), cardiovascular death (172 versus 101; P<0.0001), death caused by worsening HF (48 versus 25; P=0.006), and sudden death (114 versus 62; P=0.0001) in the placebo group and metoprolol CR/XL group, respectively. It also decreased the combined end point of all-cause mortality/all-cause hospitalization (time to first event) by 18% (95% CI 8% to 27%; P=0.001; Figure 2).
In men with severe HF (n=612), metoprolol CR/XL reduced the total number of all-cause hospitalizations by 20% (0.94 versus 0.75 per patient-year of follow-up; P=0.04). Cardiovascular hospitalizations were reduced by 25% (0.71 versus 0.53 per patient-year of follow-up; P=0.01) and hospitalizations for worsening HF by 35% (0.48 versus 0.31 per patient-year of follow-up, P=0.01). There were 60 deaths (20.6%) in the placebo group and 36 (12.4%) in the metoprolol CR/XL group. Total mortality was reduced by 40% (95% CI 9% to 60%; P=0.015), cardiovascular death (58 versus 32) by 45% (95% CI 15% to 64%; P=0.007), death due to worsening HF (22 versus 11) by 50% (95% CI −3% to 76%; P=0.056), and sudden death (33 versus 17) by 48% (95% CI 7% to 71%; P=0.025).
Withdrawal of Study Drug
Permanent withdrawal of study medicine in the placebo and metoprolol CR/XL groups, respectively, occurred in 59 and 52 women for any reason, of these 46 versus 35 patients because of an adverse event, and in 14 and 9 patients because of worsening HF. The mean dose of metoprolol CR/XL in women was 159 mg/d. In women with severe HF, discontinuation of study medication for any reason occurred in 18 versus 12 patients, of these discontinuation due to worsening HF occurred in 7 versus 1 for the placebo group and metoprolol CR/XL group, respectively.
In men, permanent withdrawal of study medicine for any reason occurred in 251 patients in the placebo group compared with 227 in the metoprolol CR/XL group; of these withdrawal because of adverse events occurred in 188 versus 161; and withdrawal because of worsening HF occurred in 71 and 55 patients, respectively. In the subgroup of men with severe HF, withdrawal of study medicine for any cause, adverse events, and worsening HF occurred in 68 versus 50, 53 versus 34, and 22 versus 17 patients in the placebo and metoprolol CR/XL groups, respectively.
Effect of Sex on Survival
After adjustment for baseline differences between women and men, the relative risk for total mortality was still significantly lower in women than in men (relative risk in placebo-treated women 0.63, 95% CI 0.43 to 0.91; P=0.015; Figure 3). Tests of sex-by-treatment interaction revealed a nonsignificant P value of 0.14 (unadjusted) for total mortality; tests were also nonsignificant for all other end points.
Pooling of Mortality Data From CIBIS II, MERIT-HF, and COPERNICUS
Pooling of total mortality by sex from CIBIS II, MERIT-HF, and COPERNICUS showed very similar and statistically significant survival benefits in women (relative risk 0.69; 95% CI 0.51 to 0.93) and men (0.66; 95% CI 0.58 to 0.75; Figure 4).
The relatively large number of women enrolled in MERIT-HF provides an opportunity to examine the effect of β-blockers in women with HF and impaired LVEF. There was a significant reduction in the primary combined end point of all-cause mortality/all-cause hospitalization and a significant reduction in hospitalizations for worsening HF. The β-blocker was well tolerated. Pooling of mortality data from MERIT-HF, CIBIS-II, and COPERNICUS showed similar survival benefits in women and men.
Reduction in Mortality in Women Versus Men
Underenrollment of women in clinical trials has been recognized for a decade,13,14⇓ and formal recommendations for adequate representation of women have been incorporated into the National Heart, Lung, and Blood Institute guidelines.15 In individual trials with β-blockers, mortality reduction in women may not be apparent, because women constitute <21% of those randomized, which limits the number of deaths available for analysis. In MERIT-HF, the point estimate for the mortality reduction in females was 0.92 (64 deaths) compared with 0.61 in men (298 deaths; Figure 4). Although 95% CIs for the hazard ratio were widely overlapping between women and men and no statistically significant sex interaction was observed, the question arises whether βS-blockade more effectively reduces the risk of death in men. To shed light on this question, sex data for mortality reduction have been illustrated for MERIT-HF, CIBIS II,2 and COPERNICUS5 (Figure 4).
In CIBIS II, which was a double-blind trial that randomized 2647 patients with symptomatic NYHA class III or IV HF and LVEF ≤35% to bisoprolol (a β1-selective β-blocker) or placebo and demonstrated a 34% reduction in all-cause mortality at a mean follow-up of 1.3 years, results opposite from those of MERIT-HF were observed, with a lower point estimate for the mortality reduction in women than in men (0.52 for women versus 0.71 for men). In COPERNICUS, a double-blind trial that randomized 2289 patients with severe HF and LVEF <25% to carvedilol (a nonselective β-blocker with weak α-blocking effects) or placebo and demonstrated a 35% reduction in all-cause mortality at a mean follow-up of 10.4 months, the same point estimate for mortality reduction was observed for women and men (0.65 in both sexes). Thus, with the larger number of deaths that the pooled data from the 3 survival studies provide, a very similar survival benefit was noted in women and men.
In the MERIT-HF data, women had a 37% lower risk of dying of any cause than men, even after adjustment for differences in baseline risk factors, which supports previous findings.11,16,17⇓⇓ Some earlier reports, however, suggested that a higher prevalence of nonischemic etiology could explain the difference in survival.16,17⇓ Although our data confirm a higher prevalence of nonischemic etiology in women, the fact that the survival advantage of women was significant even after adjustment for baseline differences including ischemic etiology indicates that the survival advantage of women should be explained by other confounders not identified by the measured baseline variables.
Another interesting finding was the absence of a sex effect on hospitalizations. The yearly rate for all-cause hospitalizations was 0.57 per patient-year of follow-up in women and 0.58 in men, with 43% of women and 41% of men being hospitalized at least once. Future studies should address the divergence between the risk of hospitalization and death in women.
Concomitant Treatment With ACE Inhibitors
The combination of the 2 arms of the largest study that proved the efficacy of ACE inhibitors in HF (Studies of Left Ventricular Dysfunction [SOLVD]) provided a total of 980 women, who did not appear to benefit from the ACE inhibitor.18 An overview of 30 randomized controlled trials of ACE inhibition in patients with HF identified a total of 5399 men and 1991 women who were studied.19 Significant reductions for mortality and for the combined end point of all-cause mortality and hospitalizations for HF were observed only in men. There was, however, no evidence of a statistical heterogeneity, and the apparent lack of response most likely reflects the small number of women. The proven clinical benefit observed with β-blockers in HF has been in patients already receiving optimal treatment with ACE inhibitors. Thus, the beneficial effect of β-blockers is in addition to ACE inhibition.
There has been reluctance among many physicians to use β-blockers in severe HF because of concern of decompensation and lack of published data about their benefit and safety. The publication of the COPERNICUS data,5 as well as the outcome of patients with severe HF in MERIT-HF,11 provided the needed evidence on the safety and efficacy of β-blockers in severe HF. Our data demonstrate that in women with severe HF and a mean LVEF of 0.19, metoprolol CR/XL resulted in a 44% reduction in the combined end point of all-cause mortality/all-cause hospitalization, as well as a highly significant reduction in hospitalizations due to worsening HF. Metoprolol CR/XL was well tolerated, as judged by fewer drug withdrawals for HF in comparison with the placebo group and on the basis of data on hospitalizations.
The beneficial effects of metoprolol CR/XL extend to women with HF, including women with clinically stable severe HF.
The MERIT-HF study was supported by grants from AstraZeneca. We wish to thank the CIBIS II Study Group for sharing with us the CIBIS II data for female patients with HF. We thank Georgina Bermann and Peter Johansson, AstraZeneca, Mölndal, and Hans Wedel, Nordic School of Public Health, Göteborg, Sweden, for data management and biostatistics.
Drs Ghali and Gottlieb have served as consultants to, and received grant support from, AstraZeneca; Dr Deedwania serves as a consultant to and speaker for AstraZeneca; Dr Piña serves on the Speaker’s Bureau and the Medical Advisory Committee of AstraZeneca; and Dr Wikstrand serves as Senior Medical Advisor to AstraZeneca. AstraZeneca is a manufacturer of metoprolol CR/XL.
Members of the MERIT-HF Study Group are given in Reference 3.
- ↵Packer M, Bristow MR, Cohn JN, et al, for the US Carvedilol Heart Failure Study Group. The effect of carvedilol on morbidity and morality in patients with chronic heart failure. N Engl J Med. 1996; 334: 1340–1355.
- ↵CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS II). Lancet. 1999; 353: 9–13.
- ↵MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999; 353: 2001–2007.
- ↵Hjalmarson A, Goldstein S, Fagerberg B, et al. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure. JAMA. 2000; 283: 1295–1302.
- ↵Packer M, Coats JS, Fowler MB, et al, for the Carvedilol Prospective Randomized Cumulative Survival Study Group (COPERNICUS). Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001; 344: 22: 1651–1658.
- ↵Task Force of the Working Group for Heart Failure of the European Society of Cardiology. The treatment of heart failure. Eur Heart J. 1997; 18: 736–753.
- ↵Heart Failure Society of America Committee Members and Executive Council. HFSA Guidelines for management of patients with heart failure caused by left ventricular dysfunction: pharmacological approaches. J Card Fail. 1999; 5: 357–82.
- ↵Ghali JK. The COHERE registry: hype or hope? J Card Fail. 2000; 6: 3: 272–275.
- ↵Ghali JK, A clinician’s perspective on clinical trials. J Card Fail. 2001; 7: 1: 1–3.
- ↵Simon T, Mary-Krause M, Funck-Brentano C, et al, on behalf of the CIBIS II Investigators. Sex differences in the prognosis of congestive heart failure: results from the Cardiac Insufficiency Bisoprolol Study (CIBIS II). Circulation. 2001; 103: 375–380.
- ↵Goldstein S, Fagerberg B, Hjalmarson Å, et al, for the MERIT-HF Study Group. Metoprolol CR/XL in patients with severe heart failure: analysis of the experience in MERIT-HF. J Am Coll Cardiol. 2001; 38: 4: 932–938.
- ↵Wikstrand J. MERIT-HF: description of the trial. Basic Res Cardiol. 2000; 95 (suppl 1): I-90–I-97.
- ↵Gurwitz JH, Col NF, Avorn J. The exclusion of the elderly and women from clinical trials in acute myocardial infarction. JAMA. 1992; 268: 1417–1422.
- ↵Wenger NK. Exclusion of the elderly and women from coronary trials: is their quality of care compromised? JAMA. 1992; 268: 1460–1461.Editorial.
- ↵NIH guidelines on the inclusion of women and minorities as subjects in clinical research. 59 Federal Register 14508–14513 (1994).
- ↵Adams KF, Dunlap SH, Sueta CA, et al. Relation between gender, etiology and survival in patients with symptomatic heart failure. J Am Coll Cardiol. 1996: 28: 7: 1781–1788.
- ↵Adams KF Jr, Sueta CA, Gheorghiade M, et al. Gender differences in survival in advanced heart failure: insights from the FIRST study. Circulation. 1999; 99: 1816–1821.
- ↵Limacher MC, Yusuf S, for the SOLVD Investigators. Gender differences in presentation, morbidity and mortality in the Studies of Left Ventricular Dysfunction (SOLVD): a preliminary report.In: Wenger NK, Sperof L, Packard B, eds. Cardiovascular Health and Disease in Women. Greenwich, Conn; 1993: 345–348.
- ↵Garg R, Yusuf S, for the Collaborative Group on ACE Inhibitor Trials. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA. 1995; 273: 1450–1456.