Beta-Blockers Post-MI Past Their Expiration Date: REDUCE-AMI

The REDUCE-AMI trial of beta-blockers post–myocardial infarction (MI) had a nonsignificant primary endpoint, yet it will probably be one of cardiology's most important modern-day trials.

Let's first review the results and then go over three teaching points.

The investigators, led by Troels Yndigegn, MD, from Lund University/Skane University Hospital, Sweden, asked a simple question: Do beta-blockers still reduce death and recurrent MI in patients with preserved left ventricular (LV) ejection fraction who just had an acute MI?

I modified the verb reduced with still because the trials that established the benefit of beta-blockers post-MI were done before acute revascularization was standard care. Contemporary MI care looks nothing like 1980s-era care. When an urgent percutaneous coronary intervention (PCI) opens an artery and limits myocardial injury, there may be little theoretical benefit from adrenergic blockade.

Yet, it wasn't just theory that stirred doubt about beta-blockers post-MI. There is also evidence. A meta-analysis of 60 trials of post-MI beta-blockers reported that the later trials (vs the early trials) no longer found any benefit from beta-blockers after MI.

The REDUCE-AMI Trial

REDUCE-AMI has special features. It was a registry-based, open-label, and pragmatic trial. Most of the patients were randomized from Sweden. The Swedish registry allowed for counting of outcomes. The trial also had no placebo arm; instead, patients were randomly assigned to beta-blocker (metoprolol or bisoprolol) or no beta-blocker.

After 3.5 years of follow-up, the primary endpoint of either death or MI occurred in 7.9% of the beta-blocker arm vs 8.3% of the control arm (HR, 0.96; 95% CI, 0.79-1.16; P = .64). Other secondary endpoints, such as cardiovascular death, hospital admission for atrial fibrillation, or heart failure also did not differ between the two groups. Neither did safety endpoints such as bradycardia, hypotension, or hospitalization for lung disease.

Most Evidence Should Have an Expiration Date

A beta-blocker pill exerts the same pharmacologic effect now as it did in the 1980s. Yet, nearly everything about MI care has changed. In REDUCE-AMI, more than 95% of patients were treated with PCI, dual-antiplatelet therapy, and a statin. Just over 80% received an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker. Few of these treatments existed in the 1980s.

The benefits of adrenergic blockade in the pre-revascularization era probably stemmed from reduction of arrhythmic death and wall-stress–related complications. Because modern therapy has dramatically reduced these complications, it follows that beta-blocker therapy may have little to add.

Pragmatic vs Standard Trials

One of the many impressive aspects of Scandinavian healthcare is its culture of randomization. Trials get embedded into routine medical care. The extensive registries, wherein citizens have a unique identifier number, allows investigators to monitor clinical endpoints.

The upside of such pragmatic trials is that it makes applying the results to routine care easier — because the trial is similar to routine care. The downside is that there may be less confidence in the effect estimates.

Consider a typical randomized trial of post-MI beta-blockers. This would include a placebo pill to maintain blinding and numerous trial-related follow-up visits. Though such a trial may be less prone to bias, it would be costly and more labor-intensive.

The results of REDUCE-AMI must be interpreted in light of its pragmatic nature. A major factor that lends confidence to the result is that hard endpoints such as death or CV death are unlikely to be influenced by an open-label design or miscounted in the registries.

Evidence of Absence vs Absence of Evidence

The yearly rate of primary outcome events was nearly identical in each arm (2.4% vs 2.5% for control). And the P value of .64 indicates that if we assumed no difference between the two groups, these data would not be surprising.

Because the confidence intervals range from 0.79 (21% benefit) to 1.16 (16% harm), statistical purists would argue that this does not allow us to conclude that there is evidence of an absent effect from beta-blockers. They would say that REDUCE-AMI is underpowered.

But understanding why this happened actually increases my confidence in the lack of benefit of post-MI beta-blockers. REDUCE-AMI had wide confidence intervals because the investigators overestimated the event rates and optimistically sought a 25% benefit.

The investigators expected an annual rate of events of 7% in the control arm; it was less than 3%. They were also overly optimistic to expect a 25% reduction in the primary endpoint with beta blockers. Had they expected a lower event rate and/or powered the trial for a benefit below 25%, they would have required many more patients. The problem, of course, with larger trials is cost, feasibility, and the risk of experimenting on too many patients. Enrolling the perfect number of patients is a high bar to hold trialists to.

I think the purist argument here is flawed. If you combine the pessimistic pretrial knowledge (no recent positive beta-blocker trial) with the fact that actual event rates are this low, then it makes sense that there is a no significant effect. Plus, there were no signals in the secondary outcomes. The results of REDUCE-AMI are like a negative stress test in a patient with no risk factors and atypical chest pain.

The good news is that there are at least three ongoing trials studying whether beta-blockade is beneficial after MI when LV function is preserved. The results from DANBLOCK, BETAMI, and REBOOT probably will add confidence to the results of REDUCE-AMI.

REDUCE-AMI Takeaways

The REDUCE-AMI investigators have begun the unwinding of a multidecade dogma of beta-blocker use after MI. We should remember that their data apply only to patients with preserved LV function — probably the majority of modern-day post-MI patients.

This trial teaches specific clinical and general evidentiary lessons. Clinically, after an artery is opened and an acute MI is aborted, all of our efforts turn to prevention of future events. The removal of a nonbeneficial medication (one with potential side effects) allows more focus on proven therapies. When ongoing trials confirm the results of REDUCE-AMI, the care of post-MI will have been greatly advanced.

For me, this trial opens a new chapter of modern cardiology: the extreme value in retesting old dogmas. In the future, the challenge of modern cardiology will be less about having a therapy available and more about whether we ought to use it.

The investigators have also shown the value in embedding randomization into routine care. No trial is perfect, but I would argue that the more we randomize, the more we learn. Evidence-based cardiology would do well to follow the lead of Scandinavia.

John Mandrola practices cardiac electrophysiology in Louisville, Kentucky, and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence.

Comments

Commenting is limited to medical professionals. To comment please Log-in.

Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.