Studies Explore Post-MI Use of Beta-blockers, Mineralocorticoid Receptor Antagonists

If there is a benefit to continuing beta-blockers beyond 1 year after acute MI, it might come with a lower dose. And for patients with LV dysfunction after STEMI, mineralocorticoid receptor antagonists (MRA), which have a proven benefit in this scenario, continued to be underused.

Those are the conclusions of two studies published online this week in the Journal of the American Heart Association that explore the use of two older classes of drugs in patients who have had an MI and raise questions about where they fit into treatment plans in the current era, after decades of advancements in care.

Tying the results together, Ricky Turgeon, PharmD (University of British Columbia, Vancouver, Canada), senior author of the MRA analysis, told TCTMD that clinicians need to be continuously reevaluating what they’re doing in this setting, in which the mix of available treatments changes frequently.

“When we get newer therapies, we need to not forget about the old therapies and understand how these all interplay and interact together,” he said. “With all of the new interventions that are coming out for these patients, and with increasing complexity with the different antithrombotics and other therapies, we need to really not look at this as a sort of grocery list of therapies that we could use, but really see which combination is optimal for patients.”

Questions Around Beta-blocker Dose, Duration

Beta-blockers are a guideline-recommended post-MI therapy based on the results of trials published in the 1970s and 1980s, before many of the treatments that have resulted in big gains in outcomes after MI over the years—like widespread use of aspirin, acute angioplasty/thrombolysis, and statins—were available or popular, Jeffrey Goldberger, MD, MBA (University of Miami Miller School of Medicine, FL), lead author of the beta-blocker analysis, told TCTMD. That has led to some questions about whether beta-blockers remain beneficial in contemporary practice. Goldberger said he thinks they are still useful, pointing to the main results of the OBTAIN registry published in 2015, which also showed use of lower doses provided outcomes similar to those achieved with higher doses.

Aside from questions of dosing, how long patients need to be treated with beta-blockers after an MI remains uncertain, as the original trials studying these treatments varied in duration.

Goldberger et al set out to address some of these issues in a new landmark analysis of the OBTAIN registry, which focused on 3,004 patients (mean age 63-64; about two-thirds men) who survived for a year after their MI and who had information on beta-blocker dose available at 1 year. Dose was stratified by how it aligned with the target doses used in the randomized trials: > 0 to 12.5%, > 12.5% to 25%, > 25% to 50%, or > 50% of the target doses.

There was no difference in mortality over a median follow-up of 1.05 years when comparing any use of beta-blockers to none (adjusted HR 0.806; 95% CI 0.485–1.340).

Dose mattered, however, with the lowest mortality rate seen in patients who were taking beta-blockers at > 12.5% to 25% of the target dose. Compared with that group, in a propensity-score analysis, mortality rates were higher in those not taking beta-blockers (HR 1.997) and in those taking a dose of 12.5% of the target dose or less (HR 1.817) or > 25% to 50% of the target dose (HR 1.764). Risk was not significantly higher in patients receiving a dose > 50% of the target.

The findings “show that perhaps there’s a benefit” to extending beta-blocker therapy beyond 1 year after MI, according to Goldberger. “It’s not 100% clear, but if there is a benefit, we only found it in that one dosing group.”

These data are informative, but they’d have to be replicated in additional registry studies or confirmed in randomized trials before forming the basis for practice recommendations, he said, adding that further research is needed to sort out optimal dosing as well.

Additionally, Turgeon commented that this analysis adds to a beta-blocker literature that includes at least a dozen observational studies addressing post-MI treatment, which have yielded mixed results. That points to the need for a randomized trial to determine whether the drugs are beneficial in the contemporary era, he said. Some patients—including those with reduced EF, ongoing angina, or arrhythmias—still have a clear indication for beta-blockers, but, Turgeon added, “if we can find those patients who don’t need beta-blockers, we can reduce pill burden and then initiate therapies which may benefit those patients.”

While sorting out these issues, Goldberger said, “I believe very strongly that everybody with a heart attack should be on a beta-blocker at least at a moderate dose,” which would be 25% of the target doses used in the clinical trials. “If you achieve at least that dose, you’re deriving most of the benefit of the beta-blockers.” Then, when thinking about longer-term treatment, physicians should consider factors like how well the patient is tolerating the regimen, what other conditions that also serve as indications for beta-blocker therapy are present, and patient preference, he added.

Underuse of MRAs

Like beta-blockers, MRAs are also backed by strong guideline recommendations for use in patients who have LV dysfunction (LVEF 40% or lower) after MI plus heart failure or diabetes. That advice is based mainly on the mortality benefit seen in the 2003 EPHESUS trial of eplerenone.

We need to really not look at this as a sort of grocery list of therapies that we could use, but really see which combination is optimal for patients. Ricky Turgeon

Prior research has shown, however, that most patients eligible for MRAs are not getting them. Anecdotally, Turgeon said, doctors want to minimize pill burden at the point of discharge, with the intention of prescribing MRAs at a later time. He and his colleagues note in their paper that concerns about hypotension, renal dysfunction, and hyperkalemia during the STEMI hospitalization might also be playing a role.

Turgeon and colleagues, led by Eric Wong, MD (University of British Columbia), wanted to see if underuse was still a problem. To do so, they looked at data from the population-based Vancouver Coastal Health Authority STEMI database linked to local outpatient cardiology records from patients treated between 2007 and 2018.

Of 2,691 patients with STEMI, 317 (12%) were deemed eligible for MRAs based on EPHESUS criteria (LVEF 40% or lower, clinical heart failure or diabetes, and no dialysis-dependent renal dysfunction). Of those, only 70 (22%) were prescribed an MRA at discharge. Moreover, of eligible patients who didn’t get an MRA at discharge, just 9.5% received a prescription for one within 3 months.

Overall, Turgeon said, only about one-quarter of eligible patients received an MRA within 3 months of STEMI. “If we’re really underusing this in this population, then we’re really kind of leaving a mortality benefit on the table,” he said.

The investigators also looked at factors associated with MRA prescription at discharge and found that use was higher when LVEF was worse (OR 1.55 per 5% decrease in LVEF; 95% CI 1.26-1.90) and with treatment in more-recent years (OR 1.23 per year; 95% CI 1.11-1.37). That shows improvement over time, but still only about half of eligible patients received an MRA at discharge in the last year of the study period, Turgeon noted.

Underuse of MRAs was also seen in the recently reported PARADISE-MI trial comparing sacubitril/valsartan (Entresto; Novartis) with the ACE inhibitor ramipril after acute MI, in which only about 42% of patients received one, he pointed out. “That really points to the fact that before we entertain the idea of these other newer therapies, which are quite expensive and [for which] access is a challenge, we really should still be optimizing these other therapies like MRAs, which are pennies a day and which can really help to improve outcomes.”

To that end, “we need more-effective decision support interventions for clinicians”—interactive online tools, for example—to help facilitate the multidisciplinary discussions that form the basis of decisions around initiating treatment, Turgeon said, adding that these therapies should be started when patients are still in the hospital.

Closing the Gap

Tobias Schupp, MD (University of Heidelberg, Mannheim, Germany), and colleagues write in an accompanying editorial that these two studies help close the gap when it comes to questions about whether older therapies like beta-blockers and MRAs still affect prognosis after so much improvement has been made in the treatment of MI since the pivotal trials were conducted.

The beta-blocker findings, they note, are consistent with those from an analysis of the SWEDEHEART registry showing that beta-blocker doses of 50% or more of the target doses were not associated with improved freedom from reinfarction or all-cause mortality.

Further research “will be necessary to provide robust data on the best duration of beta-blocker therapy, especially in patients with heart failure with preserved ejection fraction,” Schupp et al write. “The common indications for heart failure pharmacotherapies are based on the assessment of left ventricular ejection fraction and patients’ symptoms. However, one may wonder whether this is still appropriate in the complex heart failure patient with different underlying etiologies and multimodal treatments.”

As for MRAs, the editorialists point out that not only have low prescription rates been seen in prior studies of heart failure populations, but also there is a high discontinuation rate even when patients are started on them.

The inconsistency of MRA treatment raises questions as to whether it’s appropriate to study its impact on outcomes with a dichotomized approach (taking versus not taking), they write.

 “Therefore, the lack of endpoint-related data in the study by Wong and colleagues should not be considered as a major limitation. In contrast, it underlines the lack of optimal supply and guideline-adaption in daily clinical practice as well as in the setting of a clinical study.”

The study “underlines the necessity to further improve the clinical education of medical staff regarding indications and optimal use of MRA [along] with continuous and appropriate monitoring of renal function and serum potassium levels,” Schupp et al argue, adding the routine use of MRAs may be particularly important in certain high-risk subgroups, like patients with obesity, diabetes, and advanced symptoms.

But ultimately, they say, additional studies showing that MRAs are beneficial in contemporary heart failure populations are needed to boost adherence to the guidelines.

Goldberger, addressing both the beta-blocker and MRA studies, had a similar message about the need for additional research.

“The clinical science here is really, really important and requires a lot of continued research and support,” he said. “Sometimes that’s not very well appreciated because these are not necessarily going to be the breakthrough therapies that are highly desired. But yet these are things that are done every day for hundreds of thousands of patients and you need to invest to be able to decide what is the best approach to treatment.”