Understanding Beta Blockers in HFrEF

Beta blockers are one of the four pillars of guideline-directed medical therapy (GDMT) for patients with heart failure with reduced ejection fraction (HFrEF). Their effectiveness in reducing mortality and heart failure-related hospitalizations is well established, making them an integral part of any HFrEF patient’s treatment plan.¹

The 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure recommends only three beta blocker agents: carvedilol, metoprolol succinate, and bisoprolol.¹ If all three of these agents reduce mortality, how do we determine which one is most appropriate for an individual patient?

Why Do We Use Beta Blockers in Heart Failure?

In HFrEF, the heart’s pumping ability declines. In response, the body activates the sympathetic nervous system. Short-term, rising norepinephrine levels raise heart rate and contractility to try to keep cardiac output up. As time goes on, this sustained high sympathetic stimulation becomes harmful. It increases myocardial oxygen demand, promotes ventricular remodeling, raises the risk of ventricular arrhythmias, and even worsens the heart’s pumping ability even more.

Beta blockers are used to interrupt this cycle by blocking the heart's response to chronic catecholamine exposure. Although it is counterintuitive, as these drugs have negative inotropic effects, over time these agents improve the heart’s pumping ability and reduce mortality.

Why These Agents?

Although carvedilol, metoprolol succinate, and bisoprolol are all beta blockers, they differ when it comes to their receptor selectivity, pharmacokinetics, hemodynamic effects, and dosing frequency. Despite these differences, each agent has proven mortality benefit in HFrEF patients as demonstrated in landmark clinical trials.¹

These trials and their findings established the role of these agents in HFrEF treatment. However, these trials compared the drugs against a placebo rather than head-to-head, so we don't have hard data proving that one agent is more effective than the others. Guidelines also emphasize that these benefits should not be assumed to be a class effect, so you cannot just substitute any beta blocker and expect the same survival outcomes.¹

Understanding the Agents

• Carvedilol is a non-selective beta blocker as well as an alpha blocker, meaning carvedilol antagonizes both β₁ and β₂ receptors in addition to α₁ receptors.⁵ This additional α₁ blockade results in peripheral vasodilation, contributing to greater blood pressure reduction. Because β₂ blockade can cause bronchoconstriction, carvedilol is contraindicated in asthma and requires caution in COPD.⁵ The starting dose is 3.125 mg twice daily. The target dose is weight-dependent: 25 mg twice daily for patients under 85 kg, and 50 mg twice daily for patients over 85 kg.^1,5
• Metoprolol succinate is a cardioselective beta blocker, meaning its antagonism is preferential for β₁ receptors.⁶ Metoprolol does not have the peripheral vasodilatory effects of α₁ blockade. The β₁ selectivity of metoprolol is only modest, and metoprolol does block β₂ receptors to some degree, particularly at higher doses, though the risk of β₂-related respiratory effects is lower than with carvedilol.⁷ Metoprolol succinate is the long-acting formulation of metoprolol, not to be confused with short-acting metoprolol tartrate, as mortality benefit data are limited to metoprolol succinate.¹ The starting dose is 12.5 to 25 mg once daily, with a target dose of 200 mg once daily.^1,6
• Bisoprolol is also a cardioselective beta blocker, similar to metoprolol. The difference between the two is that bisoprolol demonstrates greater β₁ selectivity, which is worth considering in patients with asthma or COPD.⁷ The starting dose is 1.25 mg once daily, with a target dose of 10 mg once daily.¹

Which Agent Should I Use?

Since we cannot rely on head-to-head efficacy data to pick a winner, pharmacists and providers must consider a patient’s specific comorbidities and hemodynamic profile to choose the right agent on a case-by-case basis.

• Blood Pressure Status: Because of its α₁ antagonistic properties, carvedilol produces a more pronounced drop in blood pressure compared to metoprolol or bisoprolol. If an HFrEF patient also has uncontrolled hypertension, carvedilol is an option that can address both conditions. Conversely, if a patient is borderline hypotensive, a cardioselective agent like metoprolol succinate or bisoprolol will lower the heart rate without as large a decrease in blood pressure.
• COPD and Asthma: Patients with asthma or COPD can be sensitive to β₂ blockade. Cardioselective agents have not been shown to worsen lung function or respiratory symptoms in COPD and should not be routinely withheld from these patients.⁸ Due to the higher β₁ selectivity, bisoprolol is a reasonable first pick, followed by metoprolol succinate.⁷ Carvedilol use should be avoided in asthma and used with caution in COPD.⁵
• Adherence and Pill Burden: Heart failure patients can easily feel overwhelmed by polypharmacy. As soon as a patient receives a diagnosis of HFrEF, there are four medication classes that the patient is recommended to start taking.¹ It is important to keep the patient’s overall pill burden and adherence risks in mind. Carvedilol requires twice-daily dosing, while metoprolol succinate and bisoprolol are dosed once daily. If a patient has a history of medication non-adherence or is expressing concerns over being able to keep up with all their medications, selecting a once-daily agent can significantly improve their chances of staying on therapy.

Pharmacist Takeaways

Dosing is the place where pharmacists in all practice settings can make the biggest impact. Initiating a beta blocker in an HFrEF patient requires two absolute rules: the patient must be “dry and stable,” and you must “start low and go slow.”

Because beta blockers have negative inotropic effects, starting them while a patient is in acute decompensated heart failure can acutely worsen their pumping ability. Once the patient is euvolemic, doses are typically doubled about every two weeks, closely monitoring the patient for signs of worsening fluid retention, symptomatic bradycardia, or hypotension. The ultimate goal is not just to have the patient on a beta blocker, but to titrate up to the target doses used in the clinical trials or the highest tolerated dose if the target cannot be reached.¹

This rule applies to starting therapy, not stopping it. For patients already on a beta blocker who are admitted with heart failure, the guideline recommends that preexisting GDMT be continued and optimized unless contraindicated. If GDMT must be held, it should be restarted as soon as possible.¹

A few counseling points that are also worth reinforcing with patients:

• Carvedilol should be taken with food to slow absorption and reduce the risk of orthostatic hypotension.⁵
• Metoprolol succinate tablets are scored and can be split, but should not be crushed or chewed.⁶
• Beta blockers should not be stopped abruptly. Sudden discontinuation can worsen angina and trigger myocardial infarction or arrhythmias, so when stopping is necessary, the dose should be tapered over 1 to 2 weeks.^5,6

While carvedilol, metoprolol succinate, and bisoprolol are all recommended agents in HFrEF, they are not interchangeable. By evaluating a patient’s baseline blood pressure, respiratory history, and daily routine, pharmacists can ensure that the right agent is chosen and titrated to the dose that will provide the most benefit to the patient.

References

1. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(18):e895-e1032. https://doi.org/10.1161/CIR.0000000000001063
2. MERIT-HF Study Group. 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. https://doi.org/10.1016/S0140-6736(99)04440-2
3. CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999;353(9146):9-13. https://doi.org/10.1016/S0140-6736(98)11181-9
4. Packer M, Coats AJ, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344(22):1651-1658. https://doi.org/10.1056/NEJM200105313442201
5. Coreg (carvedilol) tablets. Prescribing information. US Food and Drug Administration; 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/020297Orig1s039correctedlbl.pdf
6. Toprol-XL (metoprolol succinate) extended-release tablets. Prescribing information. Revised May 2023. https://www.drugs.com/pro/toprol-xl.html
7. Baker JG. The selectivity of β-adrenoceptor antagonists at the human β1, β2 and β3 adrenoceptors. Br J Pharmacol. 2005;144(3):317-322. https://doi.org/10.1038/sj.bjp.0706048
8. Salpeter SR, Ormiston TM, Salpeter EE. Cardioselective beta-blockers for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2005;(4):CD003566. https://doi.org/10.1002/14651858.CD003566.pub2

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