Study Questions Incremental Benefit of Beta-Blockers After Acute MI

Patients who adhere to statins and ACE inhibitors or angiotensin receptor blockers (ARBs) following an acute MI do not appear to gain any additional benefit from treatment with beta-blockers, the results of a new study suggest.

In an analysis of older Medicare patients who had prescriptions for all guideline-recommended therapies, those who adhered only to ACE inhibitors/ARBs and statins had similar mortality rates when compared with patients who adhered to those same drugs plus beta-blockers.

Researchers say the results raise “intriguing” questions for the long-term medical management of older patients after acute MI.

“Most heart attack patients are elderly patients,” senior investigator Gang Fang, PharmD, PhD (University of North Carolina at Chapel Hill), told TCTMD. “In our study cohort, the Medicare cohort, two-thirds are 75 years and older. On average, they are taking more than 10 different medications at the same time, which increases the risk of side effects and drug-drug interactions. We began to ask if a patient can’t take all three recommended therapies, what combination of medications they were able to take would result in better health outcomes? If they took two, would they have the same outcomes?”

The bottom line, said Fang, is that if elderly patients are consistently taking an ACE inhibitor or ARB and statin therapy, but are unable to take the beta-blocker as prescribed, there is not a significant impact on mortality.

In an editorial accompanying the study, Eric Peterson, MD, and Ann Marie Navar, MD, PhD (Duke University Medical Center, Durham, NC), state that while the results should be considered preliminary, the study raises a “provocative” hypothesis.

“The first beta-blocker trials in MI are over 3 decades old and much has changed in the clinical management of MI patients in the interim,” they write. “This includes better short-term management of MI, new concomitant drugs, and quicker and more durable revascularization options. These advances have halved MI mortality rates and may have reduced the incremental effectiveness of beta-blockers in the modern era.”

Sripal Bangalore, MD (NYU Langone Medical Center, New York, NY), who first questioned the benefit of beta-blockers in patients with MI back in 2012, told TCTMD the present analysis is a unique way of addressing the value of beta-blockers in the modern era. Prior to 2012, the benefit of beta-blockers was unquestioned in the post-MI setting.

“There seems to be more and more data questioning the benefits of beta-blockers today,” he said. “The broader issue is this, though: the guidelines strongly recommend beta-blockers. Although there are a number of analyses now questioning the utility of beta-blockers after an MI, the problem is that you also having other observational studies showing a benefit.”

With the conflicting studies, the only way to address the question head-on is with a randomized controlled clinical trial of beta-blockers in post-MI patients treated with contemporary therapies, such as ACE inhibitors/ARBs and statins, said Bangalore.  

Relative Benefit of Adding Beta-Blockers

The study, which is published in the September 26, 2017, issue of the Journal of the American College of Cardiology, included 90,869 Medicare beneficiaries 65 years and older who had prescriptions for an ACE inhibitor/ARB, statin, and beta-blocker after acute MI. Overall adherence to all three medications—which was defined as the proportion of days covered ≥ 80% in the first 6 months after MI hospitalization—was just 49%. Almost 31% were nonadherent to ACE inhibitors/ARBs, 23.8% were nonadherent to beta-blockers, and 23.0% were nonadherent to statins.

At 1-year follow-up, the adjusted mortality rate for those adherent to all three medications was 9.3%. For those taking an ACE inhibitor/ARB and statin, the adjusted mortality rate was 9.1%. Among patients taking beta-blockers alone, the 1-year mortality rate was 11.6%. Comparatively, the adjusted mortality rate for those nonadherent to all three medications was 14.3%.

For those who didn’t adhere to any of the medications, the risk of death was significantly elevated compared with those who took all three medications (HR 1.65; 95% CI 1.54-1.76). The risk of death was also significantly elevated when individuals adhered to beta-blockers alone, statins alone, and ACE inhibitors/ARBs alone. 

When compared with individuals who adhered to all three therapies, patients who adhered to ACE inhibitors/ARBs and statins had a similar risk of death at 1 year (adjusted HR 0.98; 95% CI 0.91-1.07). In contrast, those who adhered to beta-blockers and statins had an increased risk of death at 1 year compared with those who adhered to all three medications (HR 1.17; 95% CI 1.10-1.22). For those who took ACE inhibitors/ARBs and beta-blockers, the risk was also increased (HR 1.12; 95% CI 1.04-1.21).

“We’re not saying beta-blockers have no benefit,” said Fang. “Our data actually support the benefit of beta-blockers, but this is really about the additional benefit when patients are already taking an ACE inhibitor or ARB and statins.”

Like the editorialists, Fang said the clinical trials testing beta-blockers took place in the era before ACE inhibitors, ARBs, and statins, and weren’t tested in combination with other medical therapies.

“Clinical practice has changed dramatically since then,” he told TCTMD.

In a subgroup analysis, the findings were largely consistent, said Fang. In patients with heart failure, though, there was no increased risk of death at 1 year among those who adhered to ACE inhibitors/ARBs alone when compared with those who adhered to all three therapies. They also observed a significantly increased risk of death at 1 year among patients with diabetes and dementia who adhered to beta-blockers alone. 

Adherence Rates Drop Off Sharply

The researchers have been studying medication adherence following MI for a number of years, noting that adherence rates to guideline-recommended therapy declines very quickly. In the first year, more than half of patients are nonadherent to therapy, although the present analysis showed that more than half of patients stopped within the first 6 months.

For Peterson and Navar, a randomized clinical trial is needed to confirm whether or not the incremental effectiveness of beta-blockers is reduced in the modern era, although such a trial is unlikely to be done. “The current paradigm of randomized controlled trials is not suited to trials of ‘less’ medication,” they write. “Nor are most trials able to truly determine when patients can ‘stop’ therapy.”

Bangalore is more optimistic, noting they are hoping to design and launch a clinical trial testing whether beta-blockers are useful in “a similar group of patients.” Because there is little interest in funding from the pharmaceutical industry, the money will need to come from the National Heart, Lung, and Blood Institute or another national organization, he added. “We do need an answer and hopefully we can do a trial.”

As for his clinical practice, Bangalore said he will typically start most patients who have had an MI on beta-blockers, at least in the short term. If there is left ventricular dysfunction, these patients will stay on the drug longer. For those without left ventricular dysfunction, it’s a question of “whether they truly need it, particularly if they have side effects.” He said he has a very low threshold for stopping treatment when patients have side effects.   

Regarding the overall low rates of adherence following acute MI, Peterson and Navar said there is also unlikely to be a “silver bullet” that yields better results, but patient education, behavior counseling, electronic and mobile reminders, financial and nonfinancial incentives, and family/peer engagement can help. They point out that even modest improvements in adherence rates can result in clinically significant improvements in patient outcomes.