BACKGROUND: Beta-blockers improve left ventricular (LV) systolic function and prognosis in patients with chronic heart failure (CHF), but their different pleiotropic properties may influence their cardiovascular effects. This open-label study compared the effects of long-term treatment with nebivolol versus carvedilol on LV ejection fraction (LVEF), in hypertensive CHF patients. Secondary end points were to assess the effect of the 2 beta-blockers on exercise capacity and clinical outcome.
METHODS AND RESULTS: A total of 160 hypertensive CHF patients, with LVEF <40% and in New York Heart Association (NYHA) functional class I, II, or III, were randomly assigned to receive nebivolol or carvedilol for 24 months. At baseline and at the end of treatment, all patients underwent clinical evaluation, echocardiography, and 6-minute walking test. The target doses were 10 mg/d for nebivolol and 50 mg/d for carvedilol. Compared with baseline values, LVEF increased by a similar extent in the carvedilol (C) and nebivolol (N) groups (C from 36.1% (SD 1.5%) to 40.9% (SD 1.9%), P < .001; N from 34.1% (SD 1.8%) to 38.5% (SF 2.2%), P < .001). Heart rate and NYHA functional class decreased significantly in both groups, and the 6-minute walking distance increased (C from 420 m (SD 104 m) to 490 m (SD 115 m), P < .001; N from 421 m (SD 118 m) to 487 m (SD 138 m), P < .001). During 24 months, 21 carvedilol recipients (26%) and 18 nebivolol recipients (22%) had cardiac events, including 3 and 4 deaths, respectively.
CONCLUSION: In the long term, nebivolol and carvedilol appear to be similarly effective in the treatment of hypertensive patients with CHF.
<b>AIMS: </b>Various beta-blockers with distinct pharmacological profiles are approved in heart failure, yet they remain underused and underdosed. Although potentially of major public health importance, whether one agent is superior in terms of tolerability and optimal dosing has not been investigated. The aim of this study was therefore to compare the tolerability and clinical effects of two proven beta-blockers in elderly patients with heart failure.<b>METHODS AND RESULTS: </b>We performed a double-blind superiority trial of bisoprolol vs. carvedilol in 883 elderly heart failure patients with reduced or preserved left ventricular ejection fraction in 41 European centres. The primary endpoint was tolerability, defined as reaching and maintaining guideline-recommended target doses after 12 weeks treatment. Adverse events and clinical parameters of patient status were secondary endpoints. None of the beta-blockers was superior with regards to tolerability: 24% [95% confidence interval (CI) 20-28] of patients in the bisoprolol arm and 25% (95% CI 21-29) of patients in the carvedilol arm achieved the primary endpoint (P= 0.64). The use of bisoprolol resulted in greater reduction of heart rate (adjusted mean difference 2.1 b.p.m., 95% CI 0.5-3.6, P= 0.008) and more, dose-limiting, bradycardic adverse events (16 vs. 11%; P= 0.02). The use of carvedilol led to a reduction of forced expiratory volume (adjusted mean difference 50 mL, 95% CI 4-95, P= 0.03) and more, non-dose-limiting, pulmonary adverse events (10 vs. 4%; P < 0.001).<b>CONCLUSION: </b>Overall tolerability to target doses was comparable. The pattern of intolerance, however, was different: bradycardia occurred more often in the bisoprolol group, whereas pulmonary adverse events occurred more often in the carvedilol group. This study is registered with controlled-trials.com, number ISRCTN34827306.
BACKGROUND: Carvedilol has previously been demonstrated to be beneficial in patients with acute myocardial infarction (AMI) and left ventricular (LV) dysfunction. However, metoprolol has not to date been randomly evaluated in the same patient population. The objective of this study was to compare the effects of treatment with carvedilol versus metoprolol in patients with LV dysfunction after AMI.
METHODS: The study enrolled 313 high-risk patients with anterior AMI and LV ejection fraction of <45%, randomly assigned to treatment with carvedilol or metoprolol. Patients were followed-up for a mean period of 13.4 months. The primary end point was time to composite adverse events (t-CAE). The secondary end points were time to composite hard events (t-CHE) and health-related quality of life.
RESULTS: No differences were found either in the primary end point of t-CAE or in the secondary end point of t-CHE. A significant benefit was observed in 4 of 8 health-related quality of life domains in the carvedilol group, with fewer carvedilol group patients being withdrawn from therapy in the hospital.
CONCLUSIONS: Treatment with carvedilol, in comparison to that with metoprolol in patients with AMI and LV dysfunction, did not differ significantly in regard to the primary end point of t-CAE or to the secondary end point of t-CHE but resulted in better long-term quality of life and favorable early safety profile.
BACKGROUND: The value of early therapy with beta-blocking agents in acute myocardial infarction (AMI) undergoing reperfusion is not yet well established. Newer beta-blocking agents such as carvedilol offer potential advantages in the setting of ischemia and reperfusion injury.
METHODS: We randomized 100 patients with acute ST-elevation myocardial infarction (STEMI) to receive either 12.5 mg carvedilol or 50 mg metoprolol tartrate orally already before percutaneous coronary intervention (PCI) of the infarct-related artery, uptitrating to a daily target dose of 50 mg carvedilol or 150 mg metoprolol during the first week. Pts. were subjected to left ventricular (LV) angiography just before reperfusion and after 14 days to compare ejection fraction (EF) and regional wall motion abnormalities by quantitative LV analysis. Furthermore, kinetics of cardiac troponin T (cTnT), NT-proANP, NT-proBNP, endothelin, argenine vasopressin, epinephrine and norepinephrine were assessed during the first 12 hours and again at 2 weeks. In addition, reperfusion-induced rhythm abnormalities like VT, triplets, couplets, and bradycardic events were assessed continuously during the first 12 hours starting at reperfusion by Holter analysis.
RESULTS: Both groups did not differ with respect to onset of pain, target vessel, extent of coronary heart disease, age, gender, rate of stenting or use of a GP IIb/IIIa inhibitor, pre- and postinterventional TIMI flow grade, time course of heart rate or blood pressure. There were neither significant differences in the cardiac and neurohumoral markers nor in the occurrence of arrhythmias between both treatment groups. Within 14 days, EF improved by 5.8+/-2.0% (mean+/-SEM) in the metoprolol group and by 5.2+/-2.1% in the carvedilol group (n.s.). Area of infarction was reduced by 6.1+/-2.9% in the metoprolol group and by 12.8+/-3.6% of total LV outline in the carvedilol group (n.s.). Maximum hypokinesia in the central infarcted region was diminished by 0.40+/-0.11 standard deviation (SD) in the metoprolol group and by 0.34+/-0.13 SD in the carvedilol group (n.s.).
CONCLUSION: In the setting of direct PCI in acute STEMI, administration of carvedilol before reperfusion appears not to be superior to metoprolol with respect to myocardial injury and improvement of global and regional LV function. The study documents equivalent improvement of LV function and similar kinetics of cardiac and neurohumoral markers in pts. with acute STEMI undergoing direct PCI if the pts. were immediately treated with either carvedilol or metoprolol. Thus, superiority of carvedilol in experimental studies did not translate into a clinical benefit.
BACKGROUND: Beta-adrenoceptor antagonist (beta-blocker) therapy results in a significant improvement in left ventricular (LV) systolic function and prognosis in patients with chronic heart failure. Both carvedilol and nebivolol produce hemodynamic and clinical benefits in chronic heart failure, but it is unknown whether their peculiar pharmacologic properties produce different effects on LV function.
OBJECTIVE: To assess the effects on LV function of nebivolol compared with carvedilol in patients with chronic heart failure and reduced LV systolic function.
METHODS: Seventy patients with a LV ejection fraction <or=40% and in New York Heart Association (NYHA) functional class II or III were randomly assigned to receive carvedilol or nebivolol therapy for 6 months. At baseline and after 6 months of treatment, all patients were assessed clinically and by biochemical and hematological investigation, ECG, 24-hour Holter monitoring, echocardiogram, measurement of ventilatory function, and a 6-minute walk test.
RESULTS: Compared with baseline values LV end-systolic volume decreased and LV ejection fraction increased in both the carvedilol (from 79 +/- 38mL to 73 +/- 43mL and from 33% +/- 6% to 37% +/- 11%) and the nebivolol group (from 72 +/- 35mL to 66 +/- 32mL and from 34% +/- 7% to 38% +/- 10%), although the between-group differences were not statistically significant. ECG data showed a decrease in resting HR in both groups (from 83 +/- 20 bpm to 66 +/- 11 bpm for carvedilol and from 81 +/- 15 bpm to 65 +/- 11 bpm for nebivolol; p < 0.001 vs baseline for both groups) but no difference in the PQ, QRS, and QT intervals. Hematologic (in particular, N-terminal pro-brain natriuretic peptide), Holter monitoring (with the exception of HR), and respiratory functional data did not show any significant variation in either group after 6 months' therapy. SBP and DBP decreased in both groups. A small reduction in mean NYHA functional class from baseline was seen in both groups (from 2.5 +/- 0.5 to 2.2 +/- 0.5 for carvedilol [p < 0.05] and from 2.3 +/- 0.4 to 2.2 +/- 0.5 for nebivolol [not significant]). The 6-minute walk test showed a trend toward an increase in the walking distance in both groups. During 6 months of treatment no significant differences in adverse events were observed between the groups.
CONCLUSION: Nebivolol is as effective as carvedilol in patients with symptomatic chronic heart failure and reduced LV systolic function.
BACKGROUND: beta-Blockers have been found to reduce mortality and morbidity in postmyocardial infarction patients. However, it is not fully understood whether all beta-blockers have similar favourable cardiovascular effects. The aim of this study was to compare the effects of carvedilol and atenolol on global and regional left ventricular ejection fraction (LVEF) and on predefined cardiovascular endpoints.
METHODS: In a single-centre, randomized, open, endpoint-blinded, parallel group study, 232 patients with acute myocardial infarction were randomized to treatment with carvedilol or atenolol. LVEF was measured by gated blood pool scintigraphy during the first week and after 12 months. The treatment was given orally within 24 h. The mean dose was 36.2 and 72.1 mg in the carvedilol and atenolol groups, respectively.
RESULTS: No significant difference was found between the two study groups in the mean global and regional LVEF. There tended to be fewer first serious cardiovascular events in the carvedilol compared with the atenolol group (RR = 0.83, 95% CI 0.56-1.23, p = 0.39). Cold hands and feet were observed less frequently in the carvedilol group (20 vs. 33%, p = 0.025).
CONCLUSION: In patients following an acute myocardial infarction, no difference in either global or regional LVEF was observed between baseline and 12 months when treatment with carvedilol was compared with atenolol.
<b>BACKGROUND: </b>Beta blockers reduce mortality in patients who have chronic heart failure, systolic dysfunction, and are on background treatment with diuretics and angiotensin-converting enzyme inhibitors. We aimed to compare the effects of carvedilol and metoprolol on clinical outcome.<b>METHODS: </b>In a multicentre, double-blind, and randomised parallel group trial, we assigned 1511 patients with chronic heart failure to treatment with carvedilol (target dose 25 mg twice daily) and 1518 to metoprolol (metoprolol tartrate, target dose 50 mg twice daily). Patients were required to have chronic heart failure (NYHA II-IV), previous admission for a cardiovascular reason, an ejection fraction of less than 0.35, and to have been treated optimally with diuretics and angiotensin-converting enzyme inhibitors unless not tolerated. The primary endpoints were all-cause mortality and the composite endpoint of all-cause mortality or all-cause admission. Analysis was done by intention to treat.<b>FINDINGS: </b>The mean study duration was 58 months (SD 6). The mean ejection fraction was 0.26 (0.07) and the mean age 62 years (11). The all-cause mortality was 34% (512 of 1511) for carvedilol and 40% (600 of 1518) for metoprolol (hazard ratio 0.83 [95% CI 0.74-0.93], p=0.0017). The reduction of all-cause mortality was consistent across predefined subgroups. The composite endpoint of mortality or all-cause admission occurred in 1116 (74%) of 1511 on carvedilol and in 1160 (76%) of 1518 on metoprolol (0.94 [0.86-1.02], p=0.122). Incidence of side-effects and drug withdrawals did not differ by much between the two study groups.<b>INTERPRETATION: </b>Our results suggest that carvedilol extends survival compared with metoprolol.
Chronic heart failure (CHF) is a risk factor for sudden death. Temporal and spatial changes in repolarization are among the most studied mechanisms for inducing fatal ventricular arrhythmias. Beta blockers effectively reduce the risk of sudden death in CHF. Our aim in this study was to investigate changes induced by metoprolol and carvedilol on the QT variability index (QTVI), a new measure reflecting the temporal heterogeneity of cardiac repolarization. A total of 82 subjects, who were in New York Heart Association functional class II or III, underwent short-term spectral analysis of RR and QT variability before and after a 1-year course of high-dose metoprolol (40 subjects) or carvedilol (42 subjects) at baseline (rest) and after sympathetic stress (head-up tilt). At rest, both drug-treated groups had lower QTVI (p <0.001) than after placebo, but during tilt patients treated with carvedilol had a lower QTVI than those treated with metoprolol (p <0.05). Although both beta-blocker treatments helped to normalize the QTVI measured in normal subjects at rest, they each differentially altered the index after tilt. Carvedilol seemed to improve the QTVI more than metoprolol.
BACKGROUND: Both metoprolol and carvedilol produce hemodynamic and clinical benefits in patients with chronic heart failure; carvedilol exerts greater antiadrenergic effects than metoprolol, but it is unknown whether this pharmacological difference results in hemodynamic and clinical differences between the 2 drugs.
METHODS AND RESULTS: We randomized 150 patients with heart failure (left ventricular ejection fraction </=0.35) to double-blind treatment with either metoprolol or carvedilol. When compared with metoprolol (124+/-55 mg/d), patients treated with carvedilol (49+/-18 mg/d) showed larger increases in left ventricular ejection fraction at rest (+10.9+/-11.0 versus +7.2+/-7.7 U, P=0.038) and in left ventricular stroke volume and stroke work during exercise (both P<0. 05) after 13 to 15 months of treatment. In addition, carvedilol produced greater decreases in mean pulmonary artery pressure and pulmonary wedge pressure, both at rest and during exercise, than metoprolol (all P<0.05). In contrast, the metoprolol group showed greater increases in maximal exercise capacity than the carvedilol group (P=0.035), but the 2 drugs improved symptoms, submaximal exercise tolerance, and quality of life to a similar degree. After a mean of 23+/-11 months of follow-up, 21 patients in the metoprolol group and 17 patients in the carvedilol group died or underwent urgent transplantation.
CONCLUSIONS: The present study demonstrates that during long-term therapy, carvedilol improves cardiac performance to a greater extent than metoprolol when administered to patients with heart failure in the doses shown to be effective in clinical trials. These differences were likely related to a greater antiadrenergic activity of carvedilol.
Beta-blockers improve left ventricular (LV) systolic function and prognosis in patients with chronic heart failure (CHF), but their different pleiotropic properties may influence their cardiovascular effects. This open-label study compared the effects of long-term treatment with nebivolol versus carvedilol on LV ejection fraction (LVEF), in hypertensive CHF patients. Secondary end points were to assess the effect of the 2 beta-blockers on exercise capacity and clinical outcome.
METHODS AND RESULTS:
A total of 160 hypertensive CHF patients, with LVEF <40% and in New York Heart Association (NYHA) functional class I, II, or III, were randomly assigned to receive nebivolol or carvedilol for 24 months. At baseline and at the end of treatment, all patients underwent clinical evaluation, echocardiography, and 6-minute walking test. The target doses were 10 mg/d for nebivolol and 50 mg/d for carvedilol. Compared with baseline values, LVEF increased by a similar extent in the carvedilol (C) and nebivolol (N) groups (C from 36.1% (SD 1.5%) to 40.9% (SD 1.9%), P < .001; N from 34.1% (SD 1.8%) to 38.5% (SF 2.2%), P < .001). Heart rate and NYHA functional class decreased significantly in both groups, and the 6-minute walking distance increased (C from 420 m (SD 104 m) to 490 m (SD 115 m), P < .001; N from 421 m (SD 118 m) to 487 m (SD 138 m), P < .001). During 24 months, 21 carvedilol recipients (26%) and 18 nebivolol recipients (22%) had cardiac events, including 3 and 4 deaths, respectively.
CONCLUSION:
In the long term, nebivolol and carvedilol appear to be similarly effective in the treatment of hypertensive patients with CHF.
