Special Feature
Beta Blockers In Heart Failure: An Update
By Jonathan Abrams, MD
The recent resurgence of the concept that the beta-adrenergic blockers are useful in patients with depressed left ventricular (LV) systolic function and congestive heart failure (CHF) is a remarkable story. The original observations from Scandinavia many years ago were never sufficiently convincing for most clinicians. However, the more recent science behind beta-adrenergic blockade in CHF is robust. Thus, with the advent of the major positive clinical trials using three different beta blockers (metoprolol, carvedilol, bisoprolol), it became clear that these drugs impart substantial benefit, including a decrease in all-cause as well as CHF mortality, sudden death, and hospitalization for CHF. In addition, functional improvements have been documented, with the very important observation of reverse remodeling: an increase in LV ejection fraction (EF) and decrease in LV cavity size. Nevertheless, the use of beta blockers in patients with stable heart failure in the United States remains very low, probably well under 20%. Carvedilol was the first (and only) drug approved by the FDA for use in heart failure. This drug is costly, has vasodilator properties, and remains relatively unfamiliar to many physicians. Metroprolol CR used in MERIT-HF is available.1 Initiation of therapy with standard metroprolol is a problem because of the difficulty in providing very small doses during drug initiation. Bisoprolol, the agent used in CIBIS I and CIBIS II, is clearly effective but is a little used drug in the United States.2,3 Numerous guidelines and recommendations over the past several years have been consistent in recommending consideration of beta blockers in any patient with stable congestive heart failure, NYHA class II-III, who is already on an ACE inhibitor. This approach is still uncommonly used by physicians.
There has been a recent spate of publications dealing with these issues. The Heart Failure Society of America has formally recommended that a beta blocker be used in all stable patients with class II-III symptoms. The choice of which beta blocker, how to initiate beta-blocker therapy, and whether class I or class IV patients should be considered for this treatment, remain important unanswered issues.
Two recent studies of metoprolol (1 placebo trial, 1 comparison to carvedilol) reach similar conclusions. The RESOLVD Trial was a complex study in symptomatic CHF subjects investigating an ACE inhibitor, angiotensin II receptor blocker, or the combination, with a second-phase protocol whereby all enrolled individuals were randomized to metoprolol CR or placebo, and followed for an additional six months.4 A total of 426 stable patients were randomized to beta blocker or placebo. Metoprolol improved a number of parameters, including an increase in LVEF and prevention of an increase in LV volumes seen in placebo patients. Clinical findings were relatively unimpressive; there was no difference from placebo in the six-minute walk test results, quality of life, or NYHA functional class. There were actually more hospitalizations for CHF in the metoprolol patients, but a trend for fewer deaths (3.7% vs 8.1%) than with placebo. Assessment of neurohormones suggested that the beta blocker suppressed renin and angiotensin II levels, but not aldosterone. The EF changes were modest, but this study was short-term. The mean LVEF in metoprolol patients rose from 28% to 31%, while placebo EF remained relatively flat. Catecholamine levels did not decrease with metoprolol, but atrial and brain naturetic peptide levels did rise over the six-month study, findings of uncertain significance. The investigators emphasize that the small number of individuals and short-study duration made it difficult to detect important differences in clinical end points, although the trend to a reduction in mortality echoed the MERIT-HF trial results.
A more important study compared metoprolol to carvedilol.5 In this Italian trial, 150 patients with heart failure and severely depressed EF were randomized to either agent for two years. Class II-IV patients were eligible. The overall group had moderate to severe heart failure with a reduced peak O2 consumption of 13.6 mLs/kg/min, and a mean EF of 21%. The primary end point of LVEF on therapy increased in both groups, but more so with carvedilol (11% vs 7%; P = 0.04). LV volumes diminished in both, with a trend favoring carvedilol. A number of hemodynamic indices were measured with right-heart catheterization at rest and exercise. These were relatively comparable. Of potential importance, carvedilol patients had a greater decrease in peak exercise heart rate. NYHA class, six-minute walk test, and quality of life scores were no different between the two drugs; metoprolol increased peak VO2 and carvedilol did not. Adverse reactions were substantial, including hospitalization for heart failure in 17% of metoprolol patients and 8% of the carvedilol cohort; marked dizziness was noted in 15% of the carvedilol patients but only one metoprolol patient. Metra and associates concluded that carvedilol resulted in a greater improvement in cardiac performance than with metoprolol, with a greater increase in LVEF, although exercise capacity augmented to a lesser degree with carvedilol than with metoprolol. Metra et al conclude that the differences were related to a greater degree of anti-adrenergic activity with carvedilol, a third-generation inhibitor of beta-1, beta-2, and alpha-1 adrenergic receptor. Prior studies have shown a greater decrease in cardiac norepinephrine with carvedilol than with metoprolol; carvedilol down-regulates beta-receptors regulation, as opposed to metoprolol. Thus, greater overall adrenergic blockade is likely to be the mechanism for an enhanced efficacy of carvedilol.
Dosing Issues
In both trials, the peak metoprolol dose was comparable to that in MERIT HF, and was considered to be optimal. Metoprolol CR results in 25-30% less bioavailabilty than the short-acting agent. In the RESOLVD trial, the mean dose was 156 ± 70 mg per day; 80% of patients received the maximal dose of 200 mg per day. In the Italian trial, the mean dose of metroprolol CR was 115-124 mg per day. The dose of carvedilol used in the Metra trial was 44-49 mg per day, similar to the United States and Australia/New Zealand carvedilol studies. Metra et al concludes, "it seems unlikely that the differencesin favor of carvedilol were due to underdosing or overdosing of metropolol."
Choice of Beta Blocker
A recent issue of the Medical Letter briefly discusses these issues and concludes that any of the three available beta blockers used in the large, positive, randomized clinical trials should be used in CHF subjects.6 All have been documented to decrease hospitalization and mortality rates in patients with heart failure. The Medical Letter also concludes that "all clinically stable patients with mild to moderate heart failure and no contraindications by beta blockade should take one of them."
Which Patients
The three major heart failure trials, MERIT HF, CIBIS-II, and the combined carvedilol studies, confirm a definite role for beta blockade in class II-III patients. Some studies have used beta blockers in class IV patients. Heart failure experts believe that with careful monitoring and experienced clinicians, stable class IV patients can be given a beta blocker. However, the caution remains that clinical instability, hypotension, large and/or changing diuretic requirements often preclude use of these agents. Furthermore, it is important to note that in the major trials as well as in RESOLVD, there was a small but substantial number of individuals who had to be hospitalized because of worsening heart failure during beta-blocker administration. Thus, the admonition is clear that very slow up titration with careful clinical monitoring remains mandatory.
Exner reviews the use of beta blockers in several of the older major ACE inhibitor trials, including SAVE, the Australian/New Zealand Heart Failure Trial, AIRE, and SOLVD Prevention Trial.7 These studies conducted retrospective analyses of the trial populations, all of whom were randomized to an ACE inhibitor and may or may not have received a beta blocker, based on clinician preference. These post-hoc analyses consistently show a benefit for the combination of an ACE inhibitor and a beta-blocker, but these findings do not achieve statistical power and represent retrospective data. Nevertheless, it is now clear that most CHF patients with an EF of less than 35% who are stable, should be treated with both an ACE inhibitor and a beta blocker, if there are no overt contraindications. This may be true for the class I, and possibly for class IV patients, who are stable, although clinical trial data are not yet available to confirm these recommendations. Bristow discusses the many mechanisms for beta-blocker efficacy in two elegant commentaries.8,9 The interested reader is urged to review these articles in order to better understand the pathophysiology of LV dysfunction and the role of cardiac and systemic sympathetic nervous system activity, as well as the potential differences among the beta blockers that might have clinical relevance. Bristow believes that greater adrenergic inhibition, such as provided by a drug like carvedilol, is likely to be more beneficial over the long haul, although there are no comparative data available other than several small trials and the Metra trial, which is modest in size and duration.5 COMET, an ongoing European study of patients with CHF randomized to carvedilol or metoprolol, may resolve the question as to which beta blocker is truly more effective in CHF.
Current clinical trial evidence should make the clinician comfortable in using either metoprolol or carvedilol. The carvedilol data may appear to be somewhat stronger, but the carvedilol database is based on a number of relatively small trials, and until head to head comparisons are available, there is no mandate for choice of agent at the present time. What is important is for physicians to get on the beta-blocker ball!
References
1. MERIT-HF Study Group. Lancet 1999;353:2001.
2. CIBIS Investigators. Circulation 1994;90:1765.
3. CIBIS-II Investigators. Lancet 1999;353:9.
4. The RESOLVD Investigators. Circulation 2000;101:378-384.
5. Metra M, et al. Circulation 2000;102:546-555.
6. Beta-Blockers in Heart Failure. Med Lett 2000;42: 54-55.
7. Exner DV. Congestive Heart Failure 2000;6:215-219.
8. Bristow MR. Circulation 2000;101:558-565.
9. Bristow MR. Circulation 2000;102:484-486.
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