Carvedilol Produces Sustained Benefits Over 12 Years of Follow-Up
Carvedilol Produces Sustained Benefits Over 12 Years of Follow-Up
Presenters: John F. MacGregor, MD, University of Utah (Salt Lake City) and colleagues
Beta-blockers have been shown in clinical trials to improve outcomes in heart failure, but long-term follow-up has been limited. Now, 2-year follow-up of patients originally enrolled in a phase 2 trial has shown that carvedilol produces sustained benefits in mortality, left ventricular ejection fraction (LVEF), LV dimensions, and symptom scores in patients with chronic heart failure.
Trials of Beta-blockers in Heart Failure
Phase 2 trials of beta-blockers typically lasting 3-6 months have demonstrated that beta-blocker treatment in heart failure results in improvement in right heart hemodynamics, reversal of ventricular remodeling, and improvements in heart failure symptoms. Prospective controlled outcomes trials of carvedilol, bisoprolol, and metoprolol succinate in heart failure have shown significant reductions in mortality and hospitalizations, as well as an improvement in patient well-being. The superior efficacy of these agents compared with placebo resulted in premature termination of all these trials, however, and so the duration of follow-up was limited to the following:
CIBIS II = Cardiac Insufficiency Bisoprolol Study II; COPERNICUS = Carvedilol Prospective Randomized Cumulative Survival Study Group; MERIT-HF = Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure
Long-term Follow-up
The long-term safety, tolerability, and outcome associated with chronic carvedilol use were assessed in patients with heart failure due to LV systolic dysfunction who were enrolled between 1990 and 1992 in a 4-month, placebo-controlled, phase 2 trial. Fifty-seven patients completed the placebo-controlled trial. The majority of patients had nonischemic heart failure and were taking similar background medical therapies (Table 1).
Table 1. Baseline Clinical Characteristics
ACE = angiotensin-converting enzyme; NYHA = New York Heart Association
All patients continued with open-label carvedilol. Patients who had been randomized to carvedilol in the original trial continued at their highest achieved dose, and patients who had been randomized to placebo started on a dose equivalent to 6.25 mg orally every 12 hours, uptitrated in weekly intervals to a maximum of 25 mg twice daily (patients weighing < 75 kg) or 50 mg twice daily (patients weighing > 75 mg).
LV internal dimension-diastole (LVIDd) and systole (LVIDs), LV fractional shortening by echocardiogram, rest and peak exercise radionuclide ventriculogram, and DiBianco symptom scores were evaluated at 4, 6, 12, and 24 months after initiation of carvedilol in patients. Survival was assessed for all subjects, censored as of January 1, 2004.
Mortality
Median follow-up in these patients was 12.89 years (range: 11.14-13.82 years) and mean dose of carvedilol dose 85 ± 3 mg/day. Five patients had died at 2 years and 29 at last follow-up; 2 and 6 patients, respectively, had been transplanted at the same timepoints. Mortality benefit was most pronounced in the group with nonischemic cardiomyopathy (Table 2).
Table 2. Etiology and Outcomes
Kaplan-Meier analysis for death in ischemic vs nonischemic patients showed a significant difference (log rank test P = .002).
LV Remodeling
Investigators found that treatment with carvediolol increased resting LVEF, decreased LVIDs, and improved DiBianco symptom scores at both 4- and 24-month follow-up compared with baseline measures (Table 3).
Table 3. Resting LVEF, LVIDs, and DiBianco Symptom Score*
*P = < .05 for all comparisons between baseline and each time period
LVEF = left ventricular ejection fraction; LVIDs = left ventricular internal dimension systole
In a multivariate analysis, only ischemic etiology and baseline LVEF were significant predictors of outcome (Table 4).
Table 4. Multivariable Cox Regression Models for Death Outcome
*Since LVEF at baseline and New York Heart Association (NYHA) are correlated, they appear nonsignificant in the same model.
LVEF = left ventricular ejection fraction; NYHA = New York Heart Association Conclusions
At 2 years after initiation of carvedilol in this heart failure population, improvements in remodeling and symptoms were maintained. There was a difference in the time course for improvement in LVEF and LV dimensions; near maximal improvements were in LVEF observed at 4 months, whereas reductions in LVIDd continued during the 2 years of follow-up. This suggests that different biologic mechanisms may be impacting these measures of the remodeling process.
There did not appear to be a significant increase in the year-specific risk of death over the total duration of follow-up, suggesting maintenance of the beneficial effects of carvedilol. Etiology, NYHA functional class, and LVEF appeared to be predictors of survival.
References
Beta-blockers have been shown in clinical trials to improve outcomes in heart failure, but long-term follow-up has been limited. Now, 2-year follow-up of patients originally enrolled in a phase 2 trial has shown that carvedilol produces sustained benefits in mortality, left ventricular ejection fraction (LVEF), LV dimensions, and symptom scores in patients with chronic heart failure.
Trials of Beta-blockers in Heart Failure
Phase 2 trials of beta-blockers typically lasting 3-6 months have demonstrated that beta-blocker treatment in heart failure results in improvement in right heart hemodynamics, reversal of ventricular remodeling, and improvements in heart failure symptoms. Prospective controlled outcomes trials of carvedilol, bisoprolol, and metoprolol succinate in heart failure have shown significant reductions in mortality and hospitalizations, as well as an improvement in patient well-being. The superior efficacy of these agents compared with placebo resulted in premature termination of all these trials, however, and so the duration of follow-up was limited to the following:
| Trial | Follow-up duration |
| US Carvedilol Trial | 6-12 months |
| CIBIS II | 1.3 years |
| MERIT-HF | 12 months |
| COPERNICUS | 10.4 months |
The long-term safety, tolerability, and outcome associated with chronic carvedilol use were assessed in patients with heart failure due to LV systolic dysfunction who were enrolled between 1990 and 1992 in a 4-month, placebo-controlled, phase 2 trial. Fifty-seven patients completed the placebo-controlled trial. The majority of patients had nonischemic heart failure and were taking similar background medical therapies (Table 1).
Table 1. Baseline Clinical Characteristics
| Characteristic | Patients (N = 57) |
|---|---|
| Age (yrs) | 53 ± 2 |
| Male (n) | 53 |
| Disease etiology (n) | |
| Ischemic | 15 |
| Nonischemic | 42 |
| NYHA functional class (n) | |
| II | 33 |
| III | 23 |
| IV | 1 |
| Medical therapy (%) | |
| ACE inhibitors | 93 |
| Digoxin | 82 |
| Diuretics | 79 |
| Warfarin | 75 |
| Vasodilators | 10 |
| Antiarrhythmic agents | 19 |
All patients continued with open-label carvedilol. Patients who had been randomized to carvedilol in the original trial continued at their highest achieved dose, and patients who had been randomized to placebo started on a dose equivalent to 6.25 mg orally every 12 hours, uptitrated in weekly intervals to a maximum of 25 mg twice daily (patients weighing < 75 kg) or 50 mg twice daily (patients weighing > 75 mg).
LV internal dimension-diastole (LVIDd) and systole (LVIDs), LV fractional shortening by echocardiogram, rest and peak exercise radionuclide ventriculogram, and DiBianco symptom scores were evaluated at 4, 6, 12, and 24 months after initiation of carvedilol in patients. Survival was assessed for all subjects, censored as of January 1, 2004.
Mortality
Median follow-up in these patients was 12.89 years (range: 11.14-13.82 years) and mean dose of carvedilol dose 85 ± 3 mg/day. Five patients had died at 2 years and 29 at last follow-up; 2 and 6 patients, respectively, had been transplanted at the same timepoints. Mortality benefit was most pronounced in the group with nonischemic cardiomyopathy (Table 2).
Table 2. Etiology and Outcomes
| Ischemic | Nonischemic | |||
|---|---|---|---|---|
| No. | % | No. | % | |
| Living | 4 | 26.7 | 24 | 57.1 |
| Dead | 11 | 73.3 | 18 | 42.9 |
Kaplan-Meier analysis for death in ischemic vs nonischemic patients showed a significant difference (log rank test P = .002).
LV Remodeling
Investigators found that treatment with carvediolol increased resting LVEF, decreased LVIDs, and improved DiBianco symptom scores at both 4- and 24-month follow-up compared with baseline measures (Table 3).
Table 3. Resting LVEF, LVIDs, and DiBianco Symptom Score*
| Endpoint | Baseline | 4 months | 24 months |
|---|---|---|---|
| Resting LVEF (%) | 20 ± 1 | 30 ± 1 | 31 ± 2 |
| LVIDs (mm) | 62 ± 1 | 58 ± 2 | 54 ± 2 |
| DiBianco symptom score | 4.5 ± 0.4 | 2.8 ± 0.3 | 3.3 ± 0.4 |
LVEF = left ventricular ejection fraction; LVIDs = left ventricular internal dimension systole
In a multivariate analysis, only ischemic etiology and baseline LVEF were significant predictors of outcome (Table 4).
Table 4. Multivariable Cox Regression Models for Death Outcome
| Baseline Predictor Variables | HR | 95% CI | P Value |
|---|---|---|---|
| Model 1 | |||
| Ischemic (present/absent) | 2.81 | 1.26-6.29 | .011 |
| LVEF baseline, per 1 additional unit | 0.95 | 0.90-1.01 | .080* |
| NYHA (III/II) | 2.05 | 0.93-4.51 | .075* |
| Model 2 | |||
| Ischemic (present/absent) | 2.99 | 1.34-6.66 | .007 |
| LVEF baseline, per 1 additional unit | 0.94 | 0.89-0.99 | .027 |
| Model 3 | |||
| Ischemic (present/absent) | 3.03 | 1.39-6.65 | .006 |
| NYHA III/II | 2.54 | 1.18-5.43 | .017 |
LVEF = left ventricular ejection fraction; NYHA = New York Heart Association Conclusions
At 2 years after initiation of carvedilol in this heart failure population, improvements in remodeling and symptoms were maintained. There was a difference in the time course for improvement in LVEF and LV dimensions; near maximal improvements were in LVEF observed at 4 months, whereas reductions in LVIDd continued during the 2 years of follow-up. This suggests that different biologic mechanisms may be impacting these measures of the remodeling process.
There did not appear to be a significant increase in the year-specific risk of death over the total duration of follow-up, suggesting maintenance of the beneficial effects of carvedilol. Etiology, NYHA functional class, and LVEF appeared to be predictors of survival.
References
MacGregor JF, Munger M, Stoddard G, et al. Carvedilol produces sustained benefits over 12 years of follow-up. J Cardiac Fail. 2004;10(suppl 4):S85. Abstract 249.
Packer M, Bristow MR, Cohn JR, et al, for the US Carvedilol Heart Failure Study Group. The effect of carvedilol on morbidity and mortality inpatients with chronic heart failure. N Engl J Med. 1996;334:1349-1355.
CIBIS Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS II): a randomized trial. 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.
Packer M, Costa A, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344:1651-1658.
Olsen SL, Gilbert EM, Renlund DG, et al. Carvedilol improves left ventricular function and symptoms in chronic heart failure: A double blind randomized study. J Am Coll Cardiol. 1995;25:1225-1231.
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