CLARIFY: No Survival Benefit With Beta-Blockers Beyond 1 Year Post-MI in Stable CAD

MUNICH, Germany—Another study has concluded that beta-blockers have no impact on mortality beyond 1 year in post-MI stable CAD patients and offer no survival benefit in stable patients who have not had a myocardial infarction. The analysis, representing 5 years of follow-up in the large, multinational CLARIFY registry, also showed that calcium channel blockers (CCBs) offered no protection against mortality at any time point.

“After 1 year following an MI, or in patients without prior MI, both beta-blockers and calcium antagonists may be used for symptom relief, but a mortality benefit should not be assumed,” Emmanuel Sorbets, MD (Imperial College London, England), said in a late-breaking science session here at the European Society of Cardiology Congress 2018.

Current clinical practice guidelines in Europe recommend both beta-blockers and/or CCBs as first-line therapy for symptom relief in patients with stable CAD, a class IA indication. US guidelines, by contrast, recommend the beta-blockers preferentially, with CCBs used for symptom relief when beta-blockers are contraindicated or cause unacceptable side effects.

The problem, said Sorbets, is that there have never been large randomized trials to test the prognostic effects of beta-blockers in this patient group and instead, recommendations have been drawn from meta-analyses using data extracted from the acute MI setting or from observational studies. For the CCBs, the only randomized trials in stable CAD are outdated and there are no, large observational analyses.

Seeking to CLARIFY

CLARIFY is a prospective, longitudinal registry tracking stable CAD patients in 45 countries. The current analysis enrolled between 10 and 15 consecutive patients being treated by nearly 3,000 physicians between November 2009 and June 2010 then followed them for 5 years. In all, 22,006 patients were initiated on beta-blockers and 22,004 on a CCB. To be included, patients had to have had at least one of the following: prior MI (> 3 months), prior revascularization (> 3 months), proven symptomatic myocardial ischemia, and/or angiographic coronary stenosis >50%.

The trialists excluded patients with severe heart failure and other conditions “interfering with life expectancy.”

Over 5 years of follow-up, there were no differences in the rates of all-cause death (the primary endpoint) or of CV death/nonfatal MI according to whether or not patients were given baseline beta-blockers, or whether or not they were started on CCBs.

However, in further analyses that looked at time since MI, Sorbets and colleagues found a significant reduction in all-cause death, CV death, and CV death/nonfatal MI among patients whose MI had occurred within the previous year (7% versus 10.3%; 95% CI 0.50-0.91). For patients whose MIs had occurred beyond 1 year, no benefits of beta-blockers were seen.

By contrast, when the same time-since-MI model was used to compare CCB versus no-CCB use, no differences were seen for any of the endpoints, regardless of the number of months or years that had elapsed since myocardial infarction. In additional analyses that considered drug use over time, and that adjusted for additional risk factors, no benefits were seen for use of beta-blockers or CCBs versus nonuse.

Commenting on the study for TCTMD, Kim Williams Sr, MD (Rush University Medical Center, Chicago, IL), observed, “We have been using beta-blockers, for decades based on small amounts of data that they were good for a year after an MI, yet we’ve been using them forever after an event as if there is data to support it. Now, people are challenging that, particularly in the statin era. And this data, while observational, looks like it supports beta-blocker use for 1 year, but beyond that, we don’t know.”

Likewise, Eva Prescott, MD, DMSc (Bispebjerg Hospital, København, Denmark), one of the trial discussants, called the CLARIFY study “a very timely analysis because of discussion about beta-blockers and particularly after MI. The guidelines don’t agree, they’re not sure what they should recommend . . . and even for non-STEMI, there’s not a clear recommendation for beta-blockers.”

The problem with observational studies, she continued, is that it’s not possible to completely adjust for the reasons why patients were or were not given a beta-blocker to begin with. “Do you really think, based on observational data,” Prescott asked, “that we can conclude that we should be giving a beta-blocker, at least for the first year after a myocardial infarction? Are you actually sure that if you start a beta-blocker early after myocardial infarction that you should continue to have a benefit?”

In response, Sorbets conceded that only a randomized controlled trial could decisively settle this question but added that there are no such trials and little likelihood that one will ever be done. “I can ask also, why continue beta-blockers over time? There is no data to do that, yet we still do that. For now, there are several good registries that assessed the use of beta-blockers and they all say the same thing: after 1 year, it seems to be not that great,” he said.

Sorting Out the Heart Failure

During the discussion that followed the presentation by Sorbets, physicians zeroed in on the difficulty of distinguishing the “pure” post-MI, stable CAD patients from those who may have been taking beta-blockers for a different reason, namely heart failure. While the trialists excluded severe heart failure from the analysis and attempted to adjust for LV function, the data set did not permit an analysis that was restricted to patients with normal LV ejection fraction, Sorbets said.

Stephen Nicholls, MBBS, PhD (Royal Adelaide Hospital, Australia), pointed out that the type of beta-blockers used by CLARIFY patients suggests a mixed population. “It is important to note that nearly 50% of the beta-blockers used were those that are more conventionally used in heart failure patients—carvedilol and bisoprolol—despite the fact that you excluded severe HF from the analysis,” he said.

Likewise, Adam Timmis, MD (Barts and the London School of Medicine and Dentistry, London, England), who headed to the microphone following the presentation, commented: “It rather begs the question why these drugs were being prescribed in the first place.” An even more interesting question would be whether or not these drugs help in symptomatic ischemia, he continued. “That’s an unanswered question, but I suspect the answer is no.”