β-Blockers: Big Role or Shrinking Spotlight in Cardiovascular Therapy?

β-blockers were first introduced in the1960s and quickly became a widespread treatment for cardiovascular problems. The Beta-Blocker Heart Attack Trial conducted in 1982 demonstrated that long-term treatment with propranolol significantly reduced total mortality, arteriosclerotic heart disease mortality, and sudden cardiac death. In the 2000s, the MERIT-HF trial suggested that metoprolol succinate extended-release tablets (CR/XL) improved survival, reduced the need for hospitalizations due to worsening heart failure (HF), improved New York Heart Association functional class, and improved patient well-being in patients with a left ventricular ejection fraction (LVEF) of less than 40%.¹ Based on these early findings from the pre-reperfusion therapy era, oral β-blocker therapy became recommended for all patients with acute myocardial infarction (AMI) for a minimum of 3 years, regardless of LV systolic function, provided there were no contraindications to β-blocker use.² In previous history, the benefit of β-blockers post-MI has been demonstrated in patients with reduced ejection fraction (EF; <40%).³

Recent evidence suggests that with advances in therapy for patients with HF and reperfusion as the standard of care treatment post-MI, the benefit of β-blockers may be more limited than current guidelines suggest. Image Credit: © G.Go - stock.adobe.com

While there are studies (performed more than 4 decades ago) that suggest β-blocker treatment is beneficial in patients with a normal LVEF, the majority of these trials were conducted before the introduction of modern treatment options, such as percutaneous coronary intervention, antithrombotic agents, high-intensity statins, and renin angiotensin-aldosterone system antagonists. Recent evidence suggests that with advances in therapy for patients with HF and reperfusion as the standard of care treatment post-MI, the benefit of β-blockers may be more limited than current guidelines suggest.

Current American Heart Association (AHA)/American College of Cardiology (ACC) guideline recommendations for pharmacologic treatment of HF with reduced EF(HFrEF): Three β-blockers have been shown to be effective in reducing the risk of death in patients with HFrEF: bisoprolol, sustained-release metoprolol (succinate), and carvedilol.^4-6 The favorable outcomes observed with these 3agents should not be interpreted as a class effect for all β-blockers in HFrEF and therefore there is no recommendation for the use of other β-blockers in HFrEF. β-blocker therapy remains a mainstay of therapy, even if patients are asymptomatic, have mild symptoms, or experience improvement with other treatments. It is recommended that therapy with β-blockers should not be postponed until symptoms reappear or disease progression is evident.

The 2023 AHA/ACC/American College of Clinical Pharmacy/American Society of Consultant Pharmacists/National Lipid Association/Preventive Cardiovascular Nursing Association guidelines for the management of patients with chronic coronary disease states that patients with this disease without history of LVEF at less than 50%, angina, arrhythmias, or uncontrolled hypertension, but with previous MI, may need continued β-blocker therapy after 1 year.¹ Previous MI guidelines have suggested β-blocker therapy be initiated within 24 hours of admission and continued for at least 3 years.⁷

Recently, there has been some emerging literature that suggest there is no benefit to the use of β-blockers post-MI in patients with preserved EFs (LV >50%).1 The REDUCE-AMI trial evaluated the benefit of β-blocker use post-MI in patients with preserved EF with a primary end point of a composite of death from any cause or new MI. A total of 5020 patients underwent randomization. Of the 2508 patients assigned to the β-blocker group, 1560 (62.2%) received metoprolol and 948 (37.8%) received bisoprolol. The primary end point—death from any cause or a new MI—occurred in 199 of 2508 patients (7.9%; annual event rate of 2.4%) in the β-blocker group and in 208 of 2512 patients (8.3%; annual event rate of 2.5%) in the non–β-blocker group (HR, 0.96; 95% CI, 0.79-1.16; P = .64).¹ The median follow-up period was 3.5 years for each group.

Despite the well-established benefits ofβ-blockers in HF and reduced EF, this study did not demonstrate a significant reduction in death or recurrent MI for patients with an LVEF of at least 50%. Instead, the trial concluded that in patients with preserved EF after an MI, β-blocker therapy did not significantly lower the risk of death or recurrent MI compared with those not receiving β-blockers. The findings of this study challenges the assumption that β-blockers are universally beneficial post-MI, particularly for those with preserved heart function.

The ABYSS trial was a multicenter, open-label, randomized, noninferiority trial conducted at 49sites in France. The trial randomized 3698 patients to either interruption of β-blocker therapy (n = 1846) or continuation (n = 1852). All patients had an LVEFof at least 40% and were receiving long-term β-blocker treatment, with no history of a cardiovascular event in the 6 months beforeenrollment. The primary end point was a composite of death, nonfatal MI, nonfatal stroke, or hospitalization for cardiovascular reasons at a minimum of 1 year. The authors concluded that in patients with a history of MI, interruption of long-term β-blocker treatment was not found to be noninferior to a strategy of β-blocker continuation.⁸

Other trials are currently ongoing to further assess β-blockers’ place in therapy after MI.^9,10 Results of the ABYSS, REDUCE-AMI, and these ongoing trials will likely lead to guideline changes in β-blocker treatment. While β-blockers remain a cornerstone of cardiovascular therapy, their role in certain patients may be limited, and long-term β-blockers are becoming less routinely recommended.¹⁰

Pharmacists should be aware that lifelong β-blocker use is becoming limited to patients withHFrEF, recent MI (1-3 years post-MI), arrhythmias, or uncontrolled hypertension (generally with other antihypertensive agents).

REFERENCES

1. Virani SS, Newby LK, Arnold SV, et al; Peer Review Committee Members. 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease: a report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation. 2023;148(9):e9-e119. doi:10.1161/CIR.0000000000001168

2. Packer M, Fowler MB, Roecker EB, et al; Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study Group. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation. 2002;106(17):2194-2199. doi:10.1161/01.cir.0000035653.72855.bf

3. Joo SJ. Beta-blocker therapy in patients with acute myocardial infarction: not all patients need it. Acute CritCare. 2023;38(3):251-260. doi:10.4266/acc.2023.00955

4. Yndigegn T, Lindahl B, Mars K, et al; REDUCE-AMI Investigators. Beta-blockers after myocardial infarction and preserved ejection fraction. N Engl J Med. 2024;390(15):1372-1381. doi:10.1056/NEJMoa2401479

5. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353(9169):2001-2007.

6. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999;353(9146):9-13.

7. Hjalmarson Å, Goldstein S, Fagerberg B, et al; MERIT-HF Study Group. Effects of controlled-release metoprolol on total mortality,hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). JAMA. 2000;283(10):1295-1302. doi:10.1001/jama.283.10.1295

8. Rosenson RS, Reeder RS, Kennedy HL. Acute myocardial infarction: role of beta blocker therapy.UpToDate. October 2024. Updated November 14, 2024. Accessed November 18, 2024. https://www.uptodate.com/contents/acute-myocardial-infarction-role-of-beta-blocker-therapy?search=beta%20block

9. Silvain J, Cayla G, Ferrari E, et al; ABYSS Investigators of the ACTION Study Group. Beta-blocker interruption or continuation after myocardial infarction. N Engl J Med. 2024;391(14):1277-1286. doi:10.1056/NEJMoa2404204

10. Steg PG. Routine beta-blockers in secondary prevention—on injured reserve. N Engl J Med. 2024;390(15):1434-1436. doi:10.1056/NEJMe2402731