Is it time to deprescribe lifetime beta-blockers for chronic coronary disease?
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Key takeaways:
- Beta-blockers have traditionally been prescribed for chronic coronary syndromes.
- Recent guidelines have reconsidered beta-blockers in chronic coronary disease, raising questions about when to discontinue them.
Over the last 50 years, revascularization and pharmacotherapeutic innovations have led to significant reductions in major adverse CV events associated with both acute and chronic coronary diseases.
In historic acute MI trials, long-term use of beta-blockers has led to large reductions in major adverse CV events (MACE). These trials laid the foundation for the widespread and often lifelong use of beta-blockers in many patients with CAD.
In the era of early reperfusion and advancing secondary prevention pharmacotherapies (antiplatelets, renin-angiotensin-aldosterone-system antagonists and statins), the ongoing role of chronic beta-blockers in all patients with chronic coronary diseases (CCD) has been challenged.
Contemporary use
Beta-blockers have a clearly defined role in the treatment of many CV conditions, such as left ventricular systolic dysfunction (LVSD), including after acute MI, atrial fibrillation and chronic angina. Unfortunately, there remains a gap in evidence to support the role of beta-blockers for patients without LVSD after an acute MI or in those with coronary disease but without other compelling indications. Nearly all of the historic beta-blocker randomized controlled trials (RCTs) were conducted before routine reperfusion (now standard of care) and were conducted in patients experiencing a recent or previous ACS event with event-related HF symptoms or with LVSD.
To address the growing uncertainties of widespread beta-blocker use in the contemporary era, Troels Yndigegn, MD, an interventional cardiologist currently serving as the chief of the department of cardiology at Skåne University Hospital, Lund, Sweden, and colleagues conducted the REDUCE-AMI trial. REDUCE-AMI was a contemporary, registry-based, open-label, parallel-group trial designed to evaluate the effect of long-term beta-blocker use (median follow-up, 3.5 years) on the composite endpoint of all-cause mortality or new MI in post-MI patients without LVSD (LV ejection fraction 50%). All patients received early coronary angiography and other evidence-based CV medications in accordance with modern acute MI treatment. After angiography with or without coronary revascularization, patients were randomly assigned to receive a beta-1-selective beta-blocker (metoprolol or bisoprolol) or no beta-blocker.
Importantly, although no treatment effect of beta-blockers was observed on the primary endpoint of death or new MI or on any secondary efficacy endpoints (Table 1), the trial enrolled generally low-risk patients (35.2% with STEMI, 46.2% with hypertension, 14% with diabetes, 7.1% with prior MI). There were also no differences in safety endpoints (hospitalization for bradycardia, heart block, hypotension, syncope, pacemaker implantation, asthma/coronary obstructive pulmonary disease exacerbations or stroke) observed between those assigned beta-blockers vs. those not assigned beta-blockers.
There has only been one other contemporary, prospective, open-label trial, CAPITAL-RCT, to evaluate the effects of long-term beta-blocker use in patients with preserved EF after STEMI managed with PCI. This trial did not find a survival benefit associated with the use of carvedilol over a 4-year follow-up period, but unfortunately this study was underpowered and terminated early due to slow enrollment.
Until the results of REDUCE-AMI were published, there had been a lack of prospective data available for decades. Thus, several population-based studies were conducted to evaluate the role of lifetime beta-blocker use on CV outcomes after an uncomplicated MI in the modern era.
For example, Park and colleagues conducted an analysis of the KAMIR-NIH registry data from 3,177 patients and found beta-blocker use to be associated with a survival benefit, but only among patients who had a persistently low LVEF ( 50%) 1 year after the initial MI. A survival benefit was not observed in those with an EF more than 50%.
Using the SWEDEHEART registry, Desta and colleagues described the effect of adherence vs. nonadherence to beta-blocker therapy after MI on long-term outcomes such as HF and death among 38,608 patients. Adherence to therapy in the first year after MI was associated with lower risk for all-cause mortality and lower risk for HF readmissions in the full 4-year follow-up period; however, the lower risk for death was only observed in patients with HF or EF of 50% or less, and not in those with EF more than 50% or without HF. Still, there was a trend toward more favorable outcomes in all medication-adherent groups, regardless of EF. A more recent analysis of the same registry data found similar results, with no observable survival benefit or improvement on CV outcomes in patients without HF even with more than 1 year of adherence to beta-blocker therapy.
Additionally, meta-analyses and large cohort studies have investigated contemporary data in which most patients included in the analyses have received PCI/reperfusion and appropriate secondary prevention regimens. Several of these meta-analyses did not find an association with beta-blocker use after an MI and the rates of cardiac death, MI or HF readmissions. In other recent cohort studies, survival benefits associated with long-term beta-blocker use were either limited to 1 year or less and/or in those with reduced LV function. However, one cohort found beta-blocker use of 1 year or more after MI to be associated with reduced all-cause death among patients with MI without HF. These conflicting data have added a layer of complexity when coupled with all other data that have been published to date.
While there is more information available now with regard to beta-blockers for uncomplicated MI, more prospective data will help to address other outstanding questions for this indication, such as optimal dosing, duration and beta-blocker and potential target populations. It is fortunate that other RCTs are still underway to investigate more specific aspects regarding the role of beta-blockers in the contemporary era of acute MI management with early revascularization and novel pharmacotherapy. These studies will aim to determine the role of beta-blockers (dose, duration, drug) for patients with uncomplicated ACS or MI and preserved LVEF [Ongoing: DANBLOCK (Denmark), BETAMI (Norway), REBOOT (Spain), REDUCE-SWEDEHEART (Sweden) and ABYSS (France)]. For example, in the pragmatic clinical trial REBOOT, patients discharged after MI, with LVEF more than 40%, will be prospectively randomly assigned at hospital discharge to either a beta-blocker or no beta-blocker.
Guidance from the guidelines?
Despite a lack of quality evidence, nearly all historic U.S. and European guidelines for the management of CAD, ACS and CCD have recommended unanimous use of beta-blockers as a primary and secondary prevention measure, regardless of previous ACS or the presence or absence of HF. With regard to treatment duration, guidelines for secondary prevention have recommended from 3 years to lifetime use of beta-blockers for most patients.
However, in the 2023 American Heart Association/American College of Cardiology/Multisociety Guideline for the Management of Chronic Coronary Disease, the recommended initial beta-blocker treatment duration is limited to 1 year for select patients with CCD. This guideline suggests that clinicians can reassess the need for ongoing beta-blocker use after the first year given the uncertainty of benefit beyond 1 year (Table 2).
These updates seem to acknowledge that past recommendations for lifetime beta-blocker use for both primary or secondary prevention of MACE for patients with CCD are no longer supported by contemporary data.
Risks associated with long-term use
In general, beta-blockers as a drug class are well tolerated. Despite the rarity of a true beta-blocker intolerance (ie, hemodynamic compromise, advanced atrioventricular nodal block) or a specific contraindication to use, many physicians are overly cautious and reluctant to initiate beta-blockers. Many of the concerns with beta-blockers are driven by historical anecdotes only applicable to beta-blockers no longer in use or with exceptionally high doses that are no longer commonly used in clinical practice.
Concerns have been raised about the long-term safety of beta-blockers, including the lifelong use of beta-blockers in certain populations such as those without a recent MI or compelling indication for beta-blocker use, in older patients and in patients at risk for metabolic complications.
In one meta-analysis, beta-blocker use for hypertension alone was associated with an elevated risk for stroke, having no impact on death or MI, compared with use of other antihypertensive agents. Similarly, another meta-analysis investigating beta-blocker use post-MI in the reperfusion era (where > 50% of patients will undergo reperfusion or receive aspirin/statin) found the long-term use of beta-blockers post-MI to be associated with increased risk for HF, cardiogenic shock and drug discontinuation.
In REDUCE-AMI, there were no apparent safety concerns with at least short-term (median, 3.5 years) use of beta-blockers in those without HF after MI.
Among older nursing home residents, especially for those with baseline moderate or severe cognitive impairment, the use of beta-blockers post-MI has been associated with more frequent functional decline. However, in the same study, beta-blocker use was also associated with a lower incidence of death and had no impact on the rates of rehospitalization.
Although various negative metabolic consequences of beta-blockers have been previously described, including new-onset diabetes and elevation of fasting blood glucose, the data are unclear whether these are clinically significant findings. Negative metabolic effects can also be mitigated. For example, carvedilol has been shown to have the most favorable metabolic profile, having little effect on glycemic control, and is generally the recommended beta-blocker for patients with diabetes and an indication for use.
Another concept that has been discussed relating to the lifetime beta-blocker use is long-term adherence to medical therapies. Both short- and long-term nonadherence to medical therapies is common among patients with CCD and is associated with poorer outcomes.
Less complex medication regimens can improve adherence to medication therapy if, by minimizing unnecessary drug treatments and reducing overall pill burden, it is possible to increase adherence with a simpler, less-overwhelming daily medication regimen.
Unanswered questions
Importantly, the significance of varied beta-blocker dosing strategies for ACS and other CCDs in clinical practice has recently been questioned. In the treatment of HF, beta-blocker selection and dose have proved to be vital to clinical outcomes, with benefits of beta-blockers only observed with specific beta-blockers and the effects being dose-dependent.
For now, it is unclear whether these concepts could also be applicable to beta-blocker dosing post-MI, with beta-blocker benefits not yet realized if suboptimal dosing strategies were employed.
Jumping off the bandwagon?
If deciding to discontinue or interrupt beta-blocker therapy in patients with CCD, a slow taper rather than abrupt discontinuation can be considered.
During the taper period, or after complete drug withdrawal, careful monitoring of BP and heart rate should be performed. Patients should be assessed for adverse events associated with beta-blocker withdrawal, including signs of rebound sympathetic activation such as increased BP, palpitations or chest pain. If withdrawal symptoms occur, either introduction of a non-beta-blocker alternative (when appropriate) or reintroduction of the previous beta-blocker at the same or lower dose can be considered.
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For more information:
Rebekka Adamson, PharmD, BCCP, is a clinical pharmacy specialist at Lexington Medical Center in Columbia, South Carolina.
Sarah A. Spinler, PharmD, FCCP, FAHA, FASHP, AACC, BCPS (AQ Cardiology), is the Healio | Cardiology Today Pharmacology Consult column editor. Spinler is professor and chair of the department of pharmacy services in the School of Pharmacy and Pharmaceutical Sciences at Binghamton University. Spinler can be reached at sspinler@binghamton.edu.
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