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, 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 interprofessional team members 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 recommends 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 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 of less than 25%.[2]

In addition, the 2022 AHA/ACC/HFSA(American Heart Association/American College of Cardiology and Heart Failure Society of America) In patients with HFrEF, the use of the three beta blockers proven to reduce mortality (carvedilol, bisoprolol, sustained-release metoprolol succinate) is recommended to reduce mortality and hospitalizations. In addition, prescribing carvedilol on discharge is associated with a decrease in 60- to 90-day mortality and rehospitalization.[3]

Another important 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 equal to 35%.[4] 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.[4][5] This result highlights a common topic between these two beta-blockers in treating heart failure. Further studies have shown no difference between carvedilol and metoprolol succinate in all-cause mortality or hospitalizations and a difference in favor of metoprolol succinate. However, these studies were not randomized trials but meta-analyses and observational studies.[6][7][8]

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.[9]

Off-label indications for carvedilol include stable angina, atrial fibrillation, 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 targeting a heart rate of 55 to 60, regardless of which beta-blocker a clinician uses. 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 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.[10]

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.[11][12] It is a non-selective cardiac beta-blocker with peripheral vasodilating effects.[13] Secondary to its unique action, carvedilol maintains cardiac output by decreasing afterload in conjunction with a cardiac beta-blockade. It 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.[11] Because carvedilol can prevent the formation of oxidized low-density lipoproteins and inhibit vascular smooth muscle cell proliferation and migration, it shows great promise in treating atherosclerotic disease formation and progression.[14] 

Carvedilol decreases blood pressure mainly by reducing arterial vascular resistance through its alpha1-blocking properties, causing a reduction in afterload. It is highly useful in managing hypertension in patients with renal impairment, where clinicians should avoid diuretics and angiotensin-converting enzyme inhibitors (ACEI).[13] Compared to other classes of antihypertensive medications, carvedilol shows similar efficacy to other beta-blockers, calcium channel blockers, ACEI, and diuretics.[12]

Pharmacokinetics

Absorption: Carvedilol is rapidly absorbed with peak plasma concentration (Cmax) in 1 to 2 hours after administration. The absorption rate is slower when the carvedilol is administered with food, but the bioavailability is unaffected. Carvedilol is well absorbed but has poor systemic bioavailability (25%) due to substantial first-pass metabolism.[15]

Distribution: Carvedilol is a highly lipophilic drug extensively distributed into tissues. The volume of distribution is high(approximate Vd=1.5 L/kg).

Metabolism: Carvedilol is metabolized by oxidation in the liver, followed by glucuronidation and conjugation. The metabolism is predominantly mediated by Cytochromes P450( CYP2D6 and CYP2C9).

Excretion: Carvedilol is primarily excreted into the bile and eliminated via feces, while urinary excretion accounts for only 16%. The elimination half-life of carvedilol is generally 6–7 hours.[16]

Administration

Carvedilol is an oral medication dosed twice daily for therapy in immediate-release form or once-daily dosing in a controlled release form. The dose is individualized based on blood pressure and heart rate response, although guideline-directed medical therapy (GDMT) is recommended for heart failure. Dose ranges include from 3.125 mg twice daily to 25 mg twice daily.[17]

Dosing by indication is as follows, per the FDA product insert:

• Heart failure: Start at 3.125 mg twice daily and increase to 6.25, 12.5, and then 25 mg twice daily over at least two weeks intervals. The clinicians should maintain lower doses if the patient does not tolerate higher doses.
• Left ventricular dysfunction following myocardial infarction: Initiate dosing at 6.25 mg twice daily and increase to 12.5 mg then 25 mg twice daily following 3 to 10 days intervals. A lower starting dose or slower titration is an option.
• Hypertension: Start at 6.25 mg twice daily and increase if needed for blood pressure control to 12.5 mg, then 25 mg twice daily over intervals of 1 to 2 weeks. (2.3)

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][4]

Use in Specific Patient Populations

Patients with Hepatic Impairment: Non-selective beta-blockers(NSBB), including carvedilol, can be used for primary prophylaxis in patients with ascites and should be used for secondary prophylaxis of variceal bleeding. However, hypotension, worsening renal function, and potential infection should be monitored, where NSBB may need to be stopped. Due to the increased risk of hypotension, carvedilol should not be used in patients with severe or refractory ascites.[18] There are no dosage adjustments for mild to moderate hepatic impairment. Due to carvedilol's extensive hepatic metabolism, it is contraindicated in patients with severe hepatic impairment.[19]

Patients with Renal Impairment: No dose adjustment is necessary. 

Pregnancy Considerations: The CHAP (Chronic Hypertension during Pregnancy) study indicated that targeting a blood pressure of less than 140/90 mm Hg decreases the incidence of adverse pregnancy consequences without compromising fetal growth.[20] ACOG guidelines (American College of Obstetricians and Gynecologists) suggest using 140/90 as the threshold for initiation or titration of pharmacological therapy for chronic hypertension in pregnancy. Guidelines recommend labetalol as the preferred antihypertensive agent during pregnancy.[21]

Breastfeeding Considerations: Carvedilol has approximately  95% plasma protein binding and a relatively long half-life with only 1% renal excretion; carvedilol doesn't appear to have significant exposure or accumulation in breastfed infants. There is no lack of clinical data with carvedilol during breastfeeding; consequently, other drugs may be preferred, especially in preterm infants.[22]

Adverse Effects

Carvedilol is a relatively well-tolerated drug with fewer frequent adverse events than other beta-blockers, and the adverse events are dose-related.[12] A post-marketing surveillance study reported that only 7% of patients taking carvedilol had to withdraw from treatment because of adverse events.[13] The most common adverse effect associated with carvedilol is undesired, excessive hypotension secondary to its vasodilating properties. These include dizziness, lightheadedness, fatigue, and headaches. Other adverse effects are related to the beta-blocking properties, including dyspnea, bronchospasm, bradycardia, malaise, and asthenia.[12] 

Adverse drug reactions include weight gain, depression, impotence, and memory loss. It is essential to recognize that abrupt discontinuation of carvedilol can lead to rebound hypertension. Hepatotoxicity from carvedilol is rare, but mild-to-moderate elevations in aminotransferase levels have been documented in < 2% of patients on carvedilol therapy, which are generally asymptomatic, resolving even with the continuance of therapy. Thus, clinically apparent liver injury from carvedilol is rare and perhaps associated with the idiosyncratic reaction to the carvedilol or its metabolites.[23]

Drug-Drug Interactions

Antidepressants such as fluoxetine, duloxetine, paroxetine, and bupropion are potent inhibitors of CYP2D6. They can increase the concentrations of β-blockers, including carvedilol, potentially increasing the risk of serious adverse events such as hypotension, bradycardia, and fall.[24]

Carvedilol and digoxin both slow atrioventricular conduction and decreases the heart rate. Concomitant use of carvedilol and digoxin can increase the risk of bradycardia.[25]

Contraindications

Absolute contraindications for using carvedilol include severe hypotension, second or third-degree AV block, sick sinus syndrome, 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 patients with a history of asthma or reactive airway disease; the recommendation is to avoid use in patients with active wheezing due to its beta-blocking properties.[26] Additionally, carvedilol is contraindicated in severe hepatic impairment, as discussed above.[19]

Monitoring

Vitals, including 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. A study also indicated that carvedilol is associated with an increased risk of hypoglycemia in hospitalized patients. Moreover, beta-blockers, including carvedilol, have been shown to prevent the autonomic response in the event of hypoglycemia. Hence it is essential to monitor blood glucose levels in patients treated with carvedilol therapy.[27] Carvedilol can increase exposure to digoxin; hence, it is suggested the monitoring serum digoxin levels in high-risk patients.[28]

Monitor response to therapy in heart failure patients with Kansas City Cardiomyopathy Questionnaire scores. In addition, predischarge NT-proBNP levels can be useful to monitor and indicate the patient's clinical course and determine a postdischarge prognosis.[3]

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. Beta-sympathomimetics (as aerosol or IV) or IV aminophylline are options for bronchospasm cases. Depending on the extent of hemodynamic instability, it may require the insertion of a temporary 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.[29] Severe cases of poisoning require intubation for respiratory insufficiency. Cardiopulmonary resuscitation should be carried out according to the AHA ACLS protocol.[30]

Beta-sympathomimetics (as aerosol or IV) or IV aminophylline are options for bronchospasm cases. Carvedilol is lipid soluble and can cause neuropsychiatric manifestations, including depression and seizures. Intravenous lorazepam is the recommended choice for generalized tonic-clonic seizures, according to the American epilepsy society.[31]

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. However, a pharmacist should be involved to ensure proper dosing for the condition and patient and verify 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 in inpatient and outpatient settings and should have 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 interprofessional team should work together to watch for signs and symptoms of toxicity, monitor treatment progress, and optimize outcomes. In addition, a study demonstrated that guideline-directed medical therapy (including carvedilol) could decrease mortality in patients suffering from HFrEF (heart failure with reduced ejection fraction).[32] [Level 3] This guideline-directed approach, in conjunction with an interprofessional team utilizing coordinated care and open communication, will help drive improved patient outcomes. [Level 5]