From the time that propranolol significantly lowered mortality after an acute myocardial infarction in the Beta-Blocker Heart Attack Trial in 1981, it took nearly 20 years for beta-blocker therapy to take hold as standard practice in AMI patients. Now, results of a recent trial may cause many to question the established therapy.
The Nov. 6, 1981, issue of JAMA announced that the National Heart, Lung, and Blood Institute had "taken the unusual step of curtailing" the Beta-Blocker Heart Attack Trial (BHAT) on the basis of findings that treatment of patients with the beta-adrenergic blocking agent, propranolol, resulted in a 26% decrease in all-cause mortality and a 23% decrease in sudden death (JAMA 1982;247:1707-14).
The study included 3,837 patients treated within 5-21 days of an acute myocardial infarction (AMI) and randomized to either propranolol 160-240 mg/day or placebo. Two-thirds of the patients had a ST-elevation MI; the remaining patients had symptoms compatible with an AMI with electrocardiographic changes accompanied by an increase in serum enzymatic elevations (serum glutamic oxaloacetic transaminase or creatine phosphokinase). This followed the report of similar results in Europe with the beta-blocker timolol in a similar group of patients. Since those early reports of randomized clinical trials, based on a subgroup analysis of BHAT, confirmed the benefit of beta-blocker therapy for both ischemic and nonischemic systolic heart failure. As steering committee chair of BHAT, I was excited about the result of our study and anticipated that beta-blocker therapy would rapidly become part of the treatment of AMI.
This was not to be. It took almost 20 years before beta-blocker therapy was incorporated into the standard treatment of AMI patients. In the interval, thousands of patients who could have benefited with this therapy died. As late as 1998, fewer than 50% of AMI patients without contraindication to therapy received that class of drug.
Why did it take so long? At the time of the BHAT results, many of the leading academic cardiologists were enamored with the use of calcium entry blocking agents for AMI, for which there were little data but a lot of encouragement by pharmaceutical companies. When propranolol went off patent and became available as a generic, there was little industrial support to publicize its benefit. Furthermore, there was little interest at the National Heart, Lung, and Blood Institute to educate physicians about the importance of BHAT. In 1996, beta-blocker therapy post-AMI was established as a quality standard by the National Committee for Quality Assurance (NCQA). At about the same time, it was incorporated in the American College of Cardiology guidelines. Not until 2000, 19 years after the initial report of beta-blocker therapy, did its usage reach 90% at discharge. A recent study from the NCQA indicated that 6 months after discharge only 71% of patients were taking the medication.
In the intervening 2 decades, the definition of an AMI has dramatically changed as a result of more sensitive, if less specific, enzyme measurements. In 1981, most of the patients in BHAT had a STEMI, whereas contemporary clinical trials include less than one-third STEMI patients. Therapy certainly has changed: first with the use of thrombolytic therapy and subsequently with the wide use of interventional angioplasty technology, particularly in the STEMI population. Aspirin, statins, and ACE inhibitors have also been added to the therapeutic mix.
Now, an observational study of almost 7,000 patients with a history of an AMI collected in 2004 and followed for 43 months, suggests that beta-blocker therapy is no longer necessary. Using a composite end point including cardiovascular death, nonfatal MI, or stroke, patients receiving propranolol had an event rate of 16.9%, compared with 18.6% not taking beta-blocker (hazard ratio, .90; P less than .14) (JAMA 2012;308:1340-9). It should be noted, however, that 74% of the patients in the study had a history of hypertension, 44% angina, and 22% heart failure, all clinical problems for which beta-blockers have been proven to be effective.
The most recent American College of Cardiology/American Heart Association guidelines suggest that beta-blocker therapy "is greatest (benefit) among patients with recent myocardial infarction [of up to 3 years prior] and/or left ventricular systolic dysfunction [left ventricular ejection fraction of 40% or less]. For those patient without these class I indication, [beta]-blocker therapy is optional (class IIa or IIb) (Circulation 2011;124:2458-73). I suppose that if you can find an AMI patient without hypertension, angina, or heart failure, discontinuing beta-blocker therapy could be justified. Until that rare patient appears in my office, I plan to maintain beta-blockers in my post-AMI patients.
Dr. Goldstein, medical editor of Cardiology News, is a professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.