Continuing Education Activity

Carvedilol is a non-selective adrenergic blocker indicated for the chronic therapy of heart failure with reduced ejection fraction (HFrEF), hypertension, and left ventricular dysfunction following myocardial infarction (MI) in clinically stable patients. Off-label indications for carvedilol include stable angina, atrial fibrillation, and cirrhotic esophageal variceal bleeding prophylaxis, and ventricular arrhythmias. This activity reviews the mechanism of action, adverse event profile, toxicity, dosing, pharmacodynamics, and monitoring of carvedilol, pertinent for clinicians and other members of the interprofessional team to allow for appropriate utilization of carvedilol for indicated conditions.

Objectives:

• Identify the approved and off-label indications for carvedilol.
• Describe the mechanism of action of carvedilol.
• Review the adverse effects and contraindications of carvedilol.
• Summarize the importance of collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients receiving treatment with carvedilol.

Indications

Carvedilol is a non-selective adrenergic blocker indicated for the chronic therapy of heart failure with reduced ejection fraction (HFrEF), hypertension, and left ventricular dysfunction following myocardial infarction (MI) in clinically stable patients.

The 2017 ACC/AHA/HRS (American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society) guideline continues to recommend carvedilol (immediate or extended-release) as a beta-blocker of choice for HFrEF.[1] Several studies support this recommendation, but most importantly, it has support from the COPERNICUS trial published in 2002. This particular study found that carvedilol reduces the risk of death and hospitalizations for heart failure by 31% compared to a placebo group in patients with New York Heart Association class III and IV heart failure with an ejection fraction less than 25%.[2] Another paramount study is the COMET trial published in 2003, which compared carvedilol to metoprolol tartrate. This study showed that carvedilol reduced all-cause mortality compared to metoprolol tartrate in patients with HFrEF and an ejection fraction of equal to 35%.[3] Criticism revolves around these results. Although the COMET trial compared carvedilol to metoprolol, it should be understood that patients randomized to receive metoprolol received metoprolol tartrate at 50 mg twice daily; this was an alternate and underdosed form of metoprolol that was not used in the MERIT-HF trial that showed a reduction in all-cause mortality with metoprolol succinate at 200 mg daily.[3][4] This result highlights a common topic between these two beta-blockers in the treatment of heart failure. Further studies have shown no difference between carvedilol and metoprolol succinate in all-cause mortality or hospitalizations[5][6] and a difference in favor of metoprolol succinate,[7] although these were not randomized trials but meta-analysis and observational studies, respectively.

Evidence to support carvedilol’s use in left ventricular dysfunction following a myocardial infarction (MI) is established by the CAPRICORN trial published in 2001. This study found a decrease in all-cause mortality in patients with left ventricular dysfunction following an acute MI.[8]

Off-label indications for carvedilol include stable angina, atrial fibrillation, and cirrhotic esophageal variceal bleeding prophylaxis, and ventricular arrhythmias. These “off-label” uses can be extrapolated across most beta-blockers rather than just carvedilol alone. For example, stable angina gets treated with beta-blockers, with an anti-anginal therapy target heart rate of 55 to 60, regardless of which beta-blocker is used. Rate control therapy in atrial fibrillation is also achievable with nearly any beta-blocker. Note that specific beta-blockers other than carvedilol are preferable for use in esophageal variceal bleeding prevention; however, some studies have suggested that carvedilol may be more effective in decreasing hepatic venous pressure or preventing variceal bleeding than other beta-blockers.[9]

Mechanism of Action

As stated, carvedilol is a non-selective adrenergic blocker, and more specifically, is a non-selective beta-blocker with alpha1-adrenergic receptor antagonist properties.[10][11] It is a non-selective, cardiac beta-blocker with peripheral vasodilating effects.[12] Secondary to its unique action, carvedilol maintains cardiac output by decreasing afterload in conjunction with a cardiac beta-blockade and has a lesser effect on heart rate than pure selective beta-blockers. Other benefits include antioxidant effects, reduction in neutrophil infiltration, apoptosis inhibition, reduction of vascular smooth muscle migration, and improvement of myocardial remodeling post-acute myocardial infarction.[10] Being that carvedilol can prevent the formation of oxidized low-density lipoproteins and inhibit vascular smooth muscle cell proliferation and migration, it shows a great promise in the treatment of atherosclerotic disease formation and progression.[13] Carvedilol decreases blood pressure mainly by decreasing arterial vascular resistance through its alpha1-blocking properties, causing a reduction in afterload. It is highly useful in the management of hypertension in patients with renal impairment, where clinicians should avoid diuretics and angiotensin-converting enzyme inhibitors (ACEI).[12] Compared to other classes of antihypertensive medications, carvedilol shows similar efficacy to other beta-blockers, calcium channel blockers, ACEI, and diuretics.[11]

Administration

Carvedilol is an oral medication used in a twice a day dosing therapy in immediate-release form or daily dosing in a controlled release form. The dose is individualized based on blood pressure and heart rate response, although if used in heart failure, the dose gets titrated up as directed by guideline-directed management and therapy. Dose ranges include from 3.125 mg twice daily to 25 mg twice daily. A total dose of up to 100 mg daily is permissible in patients weighing over 85 kg. Per guideline-directed management and therapy for heart failure, carvedilol is up-titrated to 25 mg twice daily as tolerated.[1][3]

Adverse Effects

Carvedilol is a relatively well-tolerated drug and appears to have less frequent adverse events than with other beta-blockers and is dose-related.[11] A post-marketing surveillance study reported that only 7% of patients taking carvedilol had to withdraw from treatment because of adverse events.[12] The most common adverse effect associated with carvedilol is related to undesired, excessive hypotension secondary to its vasodilating properties. These include dizziness, lightheadedness, fatigue, and headaches. Further adverse effects are related to the beta-blocking properties and include dyspnea, bronchospasm, bradycardia, malaise, and asthenia.[11] Additional symptoms of diarrhea, weight gain, headache, depression, impotence, and renal insufficiency also have correlations with carvedilol administration.

Contraindications

Absolute contraindications for the use of carvedilol include severe hypotension, second or third-degree AV block, sick sinus syndrome, and severe bradycardia in the absence of a functional pacemaker, severe decompensated heart failure requiring inotropic support, and a history of a serious hypersensitivity reaction. Clinicians should use caution in a patient with a history of asthma or reactive airway disease and should avoid use in patients with active wheezing due to its beta-blocking properties.

Monitoring

Blood pressure and heart rate should be monitored before initiation and at every dose, titration. Patients on treatment for heart failure require monitoring for any signs of decompensation. Monitoring the patient’s renal function should be considered if there are risk factors for renal impairment, and patients with diabetes mellitus should have adequate blood glucose monitoring.

Toxicity

Toxicity is treated primarily with supportive care and acute stabilization using the following therapies, depending on the clinical features. Symptomatic bradycardia or heart block requires treatment with isotonic fluid and intravenous (IV) atropine administration. Depending on the extent of hemodynamic instability, it may require the insertion of a pacemaker or the use of inotropic or vasopressor medications. Intravenous glucagon is commonly used to reverse the effects of beta-blocker toxicity as first-line therapy and adjunct to supportive treatment.

For cases involving bronchospasm, beta-sympathomimetics (as aerosol or IV) or IV aminophylline are options. In the event of seizures, a slow IV injection of diazepam or clonazepam is the recommendation.

Enhancing Healthcare Team Outcomes

Carvedilol is a non-selective adrenergic blocker indicated for the chronic therapy of heart failure with reduced ejection fraction (HFrEF), hypertension, and left ventricular dysfunction following myocardial infarction (MI) in clinically stable patients. Using this agent to manage these conditions requires the participation of an interprofessional team. The clinician or specialist will order/prescribe carvedilol when appropriate, but a pharmacist should have involvement to ensure proper dosing for the condition and patient, as well as verifying there are no potential drug interactions. Any concerns the pharmacist notes should be reported to the prescriber promptly so that they can consider alternative therapy. Nursing will administer the drug inpatient, and in outpatient settings should possess the knowledge to counsel the patient on proper administration, what side effects to watch for, and answer any questions. Nursing can also verify patient adherence, and note any potential adverse effects on follow-up visits, reporting concerns to the clinician. Thus, the entire interprofessional team should work together to watch for signs and symptoms of toxicity, monitor treatment progress, and optimize outcomes. [Level V]