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Beta-Blockers for Asymptomatic Left Ventricular Systolic Dysfunction
Abstract & Commentary
By Michael H. Crawford, MD, Professor of Medicine, and Chief of Clinical Cardiology, at the University of California, San Francisco. Dr. Crawford is on the speaker's bureau for Pfizer.
Source: Colucci W, et al. Metoprolol reverses left ventricular remodeling in patients with asymptomatic systolic dysfunction. Circulation. 2007:116:49-56.
Asymptomatic individuals with systolic left ventricular (LV) dysfunction have an increased mortality. Angiotensin converting enzymes inhibitors (ACEI) and angiotensin receptor blockers (ARB) favorably affect such patients, but little is known abut the effect of beta-blockers in this group. Thus, Colucci and coworkers hypothesized that beta-blockers would ameliorate LV remodeling in asymptomatic patients with LV systolic dysfunction and designed a randomized controlled trial, REversal of VEntricular Remodeling with Toprol-XL (REVERT) to test this hypothesis. Entry criteria included an LV ejection fraction (EF) < 40%, LV end-diastolic volume > 75 ml/m2 no symptoms during ordinary activity for 2 months, and ACEI or ARB therapy for 3 months. Unstable patients or those with other significant morbidities were excluded. Of the 164 patients randomized, 149 had at least one dose of drug and a follow-up echocardiogram and constituted the modified intention-to-treat study population. The subjects were randomized into 3 groups: metoprolol extended release 200 mg/day; 50 mg/day; or placebo for 12 months. The primary endpoint was end-systolic volume index at 12 months.
Results: At 12 months there was a 14 mL/m2 decrease in end-systolic volume index and a 6% increase in EF (P < 0.05 for both vs placebo) in the high-dose metoprolol group. Similar directional changes were observed in end-diastolic volume index, and with low-dose metoprolol and at 6 months, but they were not statistically different from placebo. Heart rate was significantly decreased by metoprolol, but blood pressure was not. The authors concluded that in asymptomatic patients with reduced LV systolic function, metoprolol ameliorates LV remodeling and improves systolic function.
The hypothesis chosen for this study is a surrogate endpoint for mortality and hospitalization for heart failure. In the MERIT-HF trial, symptomatic patients with heart failure due to systolic dysfunction treated with metoprolol exhibited improved survival and less hospitalizations vs placebo. An imaging sub-study showed reductions in LV volumes and an improvement in EF. Thus, the investigators in REVERT argue that similar changes in LV size and function seen in their study with metoprolol therapy in asymptomatic patients with LV systolic dysfunction would strongly support that mortality and morbidity would be reduced as well. They further argue that a large randomized trail to study metoprolol vs placebo in asymptomatic patients will not be done because of the large number of patients needed would make the cost prohibitive. They make a good point because despite an average EF of 27%, the death rate in REVERT was only 5% in 12 months. The implication is that asymptomatic patients with a low EF should receive beta-blockers. This is already recommended for post myocardial infarction patients with low EF. This study would extend such therapy to others with low EF.
Some might argue that the patients studied were similar to symptomatic patients because their definition of asymptomatic was no symptoms with ordinary activities. Their average BNP level was only 75 pg/Ml and only two-thirds were on any diuretic therapy. So, these were clearly different patients then those studied in MERIT-HF.
Another point worth noting was that 94% of their patients were on ACEI or ARBs, which are known to prolong life and reduce hospitalization in asymptomatic patients with systolic LV dysfunction. Thus, beneficial effects on LV remodeling in such a group seems more remarkable. Unfortunately, the patients were not studied again after stopping beta-blocker therapy to see if the effect persisted or was only present on therapy. Consequently, we have no idea how long to continue therapy if we elect to add beta-blockers to asymptomatic patients. Also, the effect seems dose related, since most endpoints were improved more on the higher doses of metoprolol. In addition, less patients in the high-dose group discontinued therapy because of adverse events. Thus, there is little downside to recommending beta-blockers for asymptomatic patients with LV systolic dysfunction.