By Michael Crawford, MD
Professor of Medicine, Chief of Clinical Cardiology, University of California San Francisco
Dr. Crawford reports no financial relationships relevant to this field of study.
SYNOPSIS: Investigators from the Outcome of Beta-blocker Therapy After Myocardial Infarction (OBTAIN) study hypothesized that the higher the dose of beta-blocker the lower the mortality.
SOURCES: Goldberger JJ, el al. Effect of beta-blocker dose on survival after acute myocardial infarction. J Am Coll Cardiol 2015;66:1431-1441.
Taqueti VR, O’Gara PT. Beta-blocker therapy after myocardial infarction: More questions than answers. J Am Coll Cardiol 2015;66:1442-1444.
Beta-blocker therapy after acute myocardial infarction (MI) was retired as a hospital performance measure because its almost universal acceptance removed its discriminating value. However, it is well known that clinically used doses are significantly lower than those achieved in the randomized trials that established their mortality-reducing benefits. Thus, the investigators from the Outcome of Beta-blocker Therapy After Myocardial Infarction (OBTAIN) study hypothesized that the higher the dose of beta-blocker the lower the mortality. The OBTAIN study was a multicenter registry that recorded beta-blocker dosing information and tracked survival. The beta-blocker and the dose were determined by the treating physician. More than 90% of the subjects were on either metoprolol or carvedilol and 91.5% of the subjects were prescribed a beta-blocker. Almost 86% were on doses < 50% of the trial target doses. After a median follow-up of 2 years, there was a 12% all-cause mortality, which was the primary endpoint. The unadjusted data showed that survival was significantly higher for any dose of beta-blockers vs no beta-blockers. The multivariate adjustment of the data showed that higher doses were not associated with better survival. In fact, the lowest mortality was observed at 25% of the target dose. The authors concluded that they had failed to demonstrate that higher doses of beta-blockers approximating those used in randomized trials improved survival compared to lower doses.
COMMENTARY
This retrospective, observational study tends to support what most clinicians are doing with post-MI beta-blockade: Titrate the dose to reduce the heart rate to < 70 bpm and avoid adverse effects. This practice results in reduced mortality compared to no beta-blocker use, but fails to identify an optimal dose. Most patients end up on 25% or less of the target doses achieved in the randomized trials or ≤ 50mg/day of metoprolol or ≤ 12.5 mg/day of carvedilol. Interestingly, perhaps realizing the wisdom of this approach, the various society guidelines do not recommend a particular dose. It is always nice to have a study validate what we are practicing rather than vilifying it.
Why the disconnect between the randomized trials and today’s practice? The authors advanced several possibilities. First, perhaps the hypothesis is correct, but they couldn’t demonstrate it in this study due to unmeasured confounders. Second, there may be a beta-blocker dose threshold and once you exceed it, you cannot show increased benefits with higher doses. Third, perhaps there is no optimal dose and it varies by patient depending on their adrenergic tone, left ventricular performance, and sensitivity to adverse effects.
Beta-blockers in the randomized trials were thought to reduce post-MI mortality by reducing ischemia, recurrent MI, and sudden death. However, these trials were conducted before widespread use of reperfusion therapy. Early reperfusion probably abrogates ischemia and re-infarction, leaving sudden arrhythmic death as the only effect left for beta-blockers. Recent studies of post-MI sudden death note that compared to the pre-reperfusion era, patients today are more likely to present with pulseless electrical activity rather than ventricular tachycardia. So widespread beta-blocker use post-MI may be affecting ventricular arrhythmias. Recent analyses suggest that unlike the 25% reduction in death post-MI observed during the trials, beta-blocker use today reduces these endpoints by 15%, which would be at the margin of statistical significance.
The randomized trials also showed that beta-blockers were most beneficial in large ST elevation MIs or patients with reduced left ventricular performance. We know beta-blockers are good for heart failure, so with less post-MI heart failure in the current era, their effectiveness may be less. This is in line with other trends in beta-blocker use, as is pointed out by Drs. Taqueti and O’Gara. Their value in hypertension, perioperative care, and chronic stable ischemic heart disease has been questioned by recent studies. It may be that modern therapy is reducing the value of beta-blockers in cardiovascular disease. Until researchers conduct a randomized, dose-ranging trial of beta-blockers in post-MI patients in the current therapeutic milieu, we should continue doing what we are doing and not worry that we are underdosing beta-blockers in post-MI patients.
