Continuing Education Activity

Carvedilol is a nonselective adrenergic blocker indicated for the chronic therapy of heart failure with reduced ejection fraction, hypertension, and left ventricular dysfunction following myocardial infarction in clinically stable patients. Carvedilol is utilized off-label for stable angina, atrial fibrillation, prophylaxis against cirrhotic esophageal variceal bleeding, and the management of ventricular arrhythmias. This activity reviews the mechanism of action, adverse event profile, toxicity, dosing, pharmacodynamics, and monitoring of carvedilol. This activity also provides essential insights for clinicians and other members of the interprofessional healthcare team, facilitating the appropriate utilization of carvedilol for its indicated conditions.

Objectives:

• Identify the diverse indications for carvedilol, including its off-label uses in stable angina, atrial fibrillation, and prophylaxis against cirrhotic esophageal variceal bleeding.

• Screen patients for potential contraindications, such as severe hypotension, second or third-degree AV block, and other conditions that may necessitate caution or alternative therapies.

• Apply knowledge of carvedilol's mechanism of action to optimize therapeutic outcomes in cardiovascular conditions, balancing its beta-blocking properties and peripheral vasodilating effects.

• Collaborate with other healthcare professionals to ensure a holistic approach to patient care, incorporating carvedilol into a comprehensive treatment plan that addresses cardiovascular conditions.

Indications

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

The 2017 guidelines from the American College of Cardiology/American Heart Association Task Force on Clinical Practice and the Heart Rhythm Society recommend carvedilol (immediate- or extended-release capsule) as a beta blocker for treating heart failure with reduced ejection fraction (HFrEF).[1] Several studies support this recommendation, with noteworthy endorsement from the 2002 COPERNICUS trial. This pivotal study demonstrated that carvedilol significantly reduces the risk of death and hospitalizations for heart failure by 31%, as compared to a placebo group, in patients with New York Heart Association classes III and IV heart failure with an ejection fraction of less than 25%.[2]

In addition, the 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America (AHA/ACC/HFSA) guidelines advocate for the use of 3 beta blockers—carvedilol, bisoprolol, and sustained-release metoprolol succinate—in patients with HFrEF. This recommendation aims to reduce both mortality and hospitalizations effectively. In addition, prescribing carvedilol upon discharge is associated with a decrease in 60- to 90-day mortality and rehospitalization rates.[3]

Another important study worth noting is the 2003 COMET trial, which compared carvedilol to metoprolol tartrate. The findings revealed that carvedilol, in contrast to metoprolol tartrate, reduced all-cause mortality in patients with HFrEF and an ejection fraction equal to 35%.[4] Criticism is directed at these findings. Notably, a comparison between carvedilol and metoprolol was made in the COMET trial. However, it should be acknowledged that patients randomized to receive metoprolol were administered metoprolol tartrate at 50 mg twice daily. This represented an alternative and underdosed form of metoprolol, differing from the metoprolol succinate at 200 mg daily used in the MERIT-HF trial, which demonstrated a reduction in all-cause mortality.[4][5] This result highlights a common topic in the treatment of heart failure with these 2 beta blockers. Subsequent investigations have revealed no difference in all-cause mortality or hospitalizations between carvedilol and metoprolol succinate, with some studies favoring metoprolol succinate. However, these findings stem from meta-analyses and observational studies rather than randomized trials.[6][7][8]

The CAPRICORN trial, published in 2001, provided substantial evidence endorsing the use of carvedilol in cases of left ventricular dysfunction following a myocardial infarction. The study reported a significant reduction in all-cause mortality among patients with left ventricular dysfunction following an acute myocardial infarction.[9]

Off-Label Uses

Off-label indications for carvedilol include stable angina, atrial fibrillation, cirrhotic esophageal variceal bleeding prophylaxis, and ventricular arrhythmias. These off-label uses can generally be extrapolated to most beta blockers rather than being specific to carvedilol alone. For example, stable angina is commonly addressed with beta blockers, and anti-anginal therapy aims for a target heart rate of 55 to 60, irrespective of the specific beta blocker used by clinicians. Similarly, effective rate control therapy for atrial fibrillation can be accomplished with nearly any beta blocker.

Specific beta blockers, other than carvedilol, are recommended to prevent esophageal variceal bleeding. However, certain studies have indicated that carvedilol might exhibit greater efficacy in reducing hepatic venous pressure or preventing variceal bleeding than other beta blockers.[10][11][12] The American Association for the Study of Liver Diseases recommends the use of nonselective beta blockers (NSBBs), including propranolol, carvedilol, or nadolol, for pharmacotherapy in the primary prophylaxis of first variceal hemorrhage in cases of medium or large varices.[13]

Mechanism of Action

Carvedilol is a nonselective adrenergic blocker, specifically categorized as an NSBB with alpha-1–adrenergic receptor antagonist properties.[14][15] This medication is a nonselective cardiac beta blocker with peripheral vasodilating effects, which improve blood flow throughout the body.[16] Due to its distinctive mechanism, carvedilol maintains cardiac output by decreasing afterload with a cardiac beta blockade. Carvedilol exerts a lesser effect on heart rate than pure selective beta blockers.

Additional benefits of carvedilol include antioxidant effects, reduced neutrophil infiltration, apoptosis inhibition, diminished vascular smooth muscle migration, and enhanced myocardial remodeling following an acute myocardial infarction.[14] Carvedilol can potentially treat atherosclerotic disease by preventing the formation of oxidized low-density lipoproteins and inhibiting vascular smooth muscle cell proliferation and migration, thus impeding its progression.[17] 

Carvedilol primarily lowers blood pressure by diminishing arterial vascular resistance through its alpha-1–blocking properties, resulting in a decrease in afterload. The efficacy of the drug is notable in the management of hypertension, particularly in patients with renal impairment, where caution is advised against the use of diuretics and angiotensin-converting enzyme inhibitors (ACEI).[16] Compared to other classes of antihypertensive medications, carvedilol shows similar efficacy to other beta blockers, calcium channel blockers, ACEI, and diuretics.[15]

Pharmacokinetics

Absorption: Carvedilol exhibits rapid absorption, reaching peak plasma concentration (Cmax) within 1 to 2 hours after administration. Administration with food slows the absorption rate, although the bioavailability remains unaffected. Although carvedilol is well absorbed in the body, it experiences significant first-pass metabolism, resulting in poor systemic bioavailability of 25%.[18]

Distribution: Carvedilol is a highly lipophilic drug that undergoes extensive distribution into tissues, leading to a substantial volume of distribution (Vd) of 1.5 L/kg.

Metabolism: Carvedilol undergoes hepatic metabolism, initially through oxidation, followed by glucuronidation and conjugation. The primary mediators of its metabolism are cytochromes P450, specifically CYP2D6 and CYP2C9. In addition, carvedilol acts as an inhibitor of P-glycoprotein.[19]

Elimination: Carvedilol is primarily excreted into the bile and eliminated via feces, with only 16% accounted for by urinary excretion. The elimination half-life of carvedilol typically ranges between 6 and 7 hours.[20]

Administration

Available Dosage Forms and Strengths

Carvedilol is an oral medication administered either twice daily in an immediate-release formulation or once daily in a controlled-release formulation. The dosage is tailored to each individual, considering their blood pressure and heart rate response. However, for heart failure, it is recommended to follow guideline-directed medical therapy (GDMT). The carvedilol dosage ranges from 3.125 mg twice daily to 25 mg twice daily.[21]

Adult Dosage

According to the FDA product insert, the recommended dosing based on the indication is as follows:

Heart failure: In managing heart failure, the initial dosage is initiated at 3.125 mg twice daily, with subsequent increments to 6.25 mg, 12.5 mg, and then 25 mg twice daily over at least 2 weeks intervals. Clinicians are advised to maintain lower doses if higher doses are not well-tolerated by the patient.

Left ventricular dysfunction following myocardial infarction: Initiation of dosing for this condition begins at 6.25 mg twice daily, with subsequent increments to 12.5 mg and then 25 mg twice daily, following intervals of 3 to 10 days. A lower starting dose or slower titration is considered an alternative option.

Hypertension: The recommended approach for treating hypertension is to initiate dosing at 6.25 mg twice daily, with adjustments permissible based on the necessity for blood pressure control, escalating to 12.5 mg, and eventually 25 mg twice daily, following intervals of 1 to 2 weeks. (2.3)

A maximum permissible dose of up to 100 mg daily is applicable for patients with a body weight of over 85 kg. GDMT for heart failure dictates the up-titration of carvedilol to 25 mg twice daily, as tolerated.[1][4]

Specific Patient Populations

Hepatic impairment: In cases of hepatic impairment, NSBBs, such as carvedilol, may be used for primary prophylaxis in patients with ascites and are also recommended for secondary prophylaxis of variceal bleeding. However, close monitoring for hypotension, worsening renal function, and potential infection is essential, and cessation of NSBB may be warranted if such complications arise. Due to the increased risk of hypotension, the use of carvedilol is contraindicated in patients with severe or refractory ascites.[22] Dosage adjustments are not required for mild-to-moderate hepatic impairment. However, due to carvedilol's extensive hepatic metabolism, it is contraindicated in patients with severe hepatic impairment.[23]

Renal impairment: No dosage adjustments are necessary for patients with renal impairment. 

Pregnancy considerations: The Chronic Hypertension during Pregnancy (CHAP) study indicated that targeting a blood pressure below 140/90 mm Hg reduces the incidence of adverse pregnancy outcomes without compromising fetal growth.[24] The American College of Obstetricians and Gynecologists (ACOG) recommends initiating or titrating pharmacological therapy for chronic hypertension in pregnancy when blood pressure reaches or exceeds 140/90. However, guidelines recommend labetalol as the preferred antihypertensive agent during pregnancy.[25]

Breastfeeding considerations: Carvedilol, with approximately 95% plasma protein binding and a relatively long half-life, exhibits minimal renal excretion at only 1%. There is no significant evidence of exposure or accumulation in breastfed infants. However, due to insufficient clinical data on carvedilol during breastfeeding, alternative drugs may be preferred, particularly in the case of preterm infants.[26]

Pediatric patients: Carvedilol does not have FDA approval for use in pediatric patients. However, it has been used off-label in pediatric patients with heart failure.[27]

Older patients: As older patients may be more susceptible to adverse effects, caution is advised when transitioning from the immediate-release to the controlled-release formulation.

Adverse Effects

Carvedilol is a generally well-tolerated medication, exhibiting fewer frequent adverse events than other beta blockers, and adverse events are typically dose-related.[15] A post-marketing surveillance study reported that only 7% of patients taking carvedilol had to discontinue treatment due to adverse events.[16] The most prevalent adverse effect of carvedilol is undesired, excessive hypotension resulting from its vasodilating properties, leading to symptoms such as dizziness, lightheadedness, fatigue, and headaches. Additional adverse effects associated with the drug's beta-blocking properties include dyspnea, bronchospasm, bradycardia, malaise, and asthenia.[15] 

Adverse reactions to carvedilol include weight gain, depression, impotence, and memory loss. Moreover, it is crucial to acknowledge that abruptly discontinuing carvedilol can result in rebound hypertension. Although hepatotoxicity from carvedilol is rare, mild-to-moderate elevations in aminotransferase levels have been observed in less than 2% of patients on carvedilol therapy. These elevations are generally asymptomatic and resolve even with the continuation of treatment. Consequently, clinically apparent liver injury from carvedilol is rare and may be associated with an idiosyncratic reaction to carvedilol or its metabolites.[28]

Drug-Drug Interactions

Antidepressants: Antidepressants, including fluoxetine, duloxetine, paroxetine, and bupropion, serve as potent inhibitors of CYP2D6. Their use can increase the concentrations of beta blockers, including carvedilol, potentially increasing the risk of severe adverse events such as hypotension, bradycardia, and falls.[29]

Digoxin: Carvedilol and digoxin both slow atrioventricular conduction and decrease the heart rate. Concomitant use of carvedilol and digoxin can increase the risk of bradycardia.[30]

Clonidine: Patients taking a beta blocker with drugs that deplete catecholamines, such as reserpine and clonidine, should undergo close monitoring for indications of low blood pressure and severe bradycardia. In cases where discontinuation is necessary, carvedilol should be halted before clonidine, and the discontinuation of clonidine should be executed gradually.[31]

Cyclosporine: Carvedilol increases blood concentrations of cyclosporine by inhibiting P-glycoprotein–mediated transport in the intestine. Close monitoring of cyclosporine levels is recommended when initiating carvedilol.[32]

Amiodarone: Amiodarone and its metabolite inhibit CYP2C9 and P-glycoprotein, significantly increasing the concentration of carvedilol's S(-) enantiomer. This heightened concentration may enhance beta-blocking activity and potentially reduce heart rate or slow cardiac conduction. Furthermore, it is imperative to closely monitor for bradycardia or heart block, especially when coadministering amiodarone with carvedilol.

Nondihydropyridine calcium channel blockers: Coadministration of carvedilol with diltiazem or verapamil has been associated with bradycardia accompanied by hemodynamic compromise. Electrocardiogram and blood pressure monitoring are advised when using carvedilol in conjunction with calcium channel blockers, such as verapamil or diltiazem.[33]

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 severe hypersensitivity reaction. Clinicians should exercise caution in patients with a history of asthma or reactive airway disease, with the recommendation to refrain from using carvedilol in individuals with active wheezing due to its beta-blocking properties.[34] Additionally, as discussed earlier, carvedilol is contraindicated in cases of severe hepatic impairment.[23]

Warning and Precautions

Abrupt cessation of carvedilol: Patients with coronary artery disease undergoing carvedilol therapy should steer clear of abruptly discontinuing treatment to prevent the risk of severe angina exacerbation, myocardial infarction, and ventricular arrhythmias. A recommended approach is the gradual discontinuation over 1 to 2 weeks. This caution extends to patients treated for hypertension or heart failure alone.

Hypotension: Hypotension and syncope were observed in heart failure trials, especially during initial dosing. Caution and gradual up-titration are advised, particularly in older patients.

Nonallergic bronchospasm: Beta blockers are generally avoided in bronchospastic diseases such as chronic obstructive pulmonary disease. Thus, caution should be exercised when using carvedilol in such cases.

Thyrotoxicosis: Beta blockers have the potential to mask symptoms of hyperthyroidism, and abrupt withdrawal may exacerbate hyperthyroidism.[35]

Floppy iris syndrome: Carvedilol's alpha-1–blocking property in cataract surgery may increase the risk of intraoperative floppy iris syndrome.[36]

Monitoring

Vital signs, such as blood pressure and heart rate, should be monitored before initiation and at each dose titration. Individuals undergoing heart failure treatment necessitate vigilant monitoring for any indications of decompensation. Assessing the patient's renal function is advisable, particularly in the presence of risk factors for renal impairment. A study also suggested an elevated risk of hypoglycemia in hospitalized patients receiving carvedilol. Furthermore, beta blockers, including carvedilol, have demonstrated the ability to prevent the autonomic response during hypoglycemia. Therefore, regular monitoring of blood glucose levels is imperative for patients undergoing carvedilol therapy.[37] 

In addition, it is recommended to monitor serum digoxin levels in high-risk patients taking carvedilol, as it can increase exposure to digoxin.[38] The response to therapy can be monitored by assessing Kansas City Cardiomyopathy Questionnaire scores in heart failure patients. Moreover, it is noteworthy that predischarge NT-proBNP levels can serve as valuable indicators for monitoring the patient's clinical course and determining postdischarge prognosis.[3]

Toxicity

Toxicity is primarily treated with supportive care and acute stabilization through specific therapies based on the clinical features. Treatment for symptomatic bradycardia or heart block involves isotonic fluid administration and intravenous (IV) atropine. In cases of bronchospasm, options include beta-sympathomimetic agents (administered as aerosol or IV) or IV aminophylline. Depending on the extent of hemodynamic instability, interventions may involve the insertion of a temporary pacemaker or using inotropic or vasopressor medications. IV glucagon is commonly utilized as a first-line therapy and adjunct to supportive treatment for reversing the effects of beta-blocker toxicity.[39] 

Severe cases of poisoning may require intubation due to respiratory failure. Cardiopulmonary resuscitation should be carried out according to the AHA advanced cardiac life support (ACLS) protocol.[40] The options for bronchospasm include beta-sympathomimetic agents (administered as aerosol or IV) or IV aminophylline. Notably, as carvedilol is a lipid-soluble drug, it has the potential to induce neuropsychiatric manifestations, such as depression and seizures. For generalized tonic-clonic seizures, the American Epilepsy Society recommends IV lorazepam as the preferred choice.[41] IV lipid emulsion therapy has been used to treat carvedilol toxicity due to its lipophilic nature.[42][43]

Enhancing Healthcare Team Outcomes

Carvedilol, a nonselective adrenergic blocker, is indicated for HFrEF, hypertension, and left ventricular dysfunction following myocardial infarction in clinically stable patients. Effective management of these conditions with this agent necessitates the coordinated involvement of an interprofessional healthcare team. The ordering or prescribing of carvedilol is typically done by a clinician or specialist as deemed appropriate. Nevertheless, the active participation of a pharmacist is crucial to guarantee accurate dosing tailored to the specific condition and patient, as well as to verify potential drug interactions. Any concerns the pharmacist identifies should be promptly communicated to the prescriber, enabling them to consider alternative therapy if necessary.

Nurses are responsible for administering a particular drug a clinician prescribes in both inpatient and outpatient settings. They provide counseling to the patient on appropriate administration, educate them about potential adverse effects to monitor, and address any questions they may have. Furthermore, nurses are critical in verifying patient adherence, observing potential adverse effects during follow-up visits, and reporting any concerns to the clinician. Therefore, interprofessional healthcare teams should collaborate to vigilantly watch signs and symptoms of toxicity, monitor treatment progress, and optimize outcomes. Furthermore, a study has shown that GDMT, including carvedilol, can significantly reduce mortality in patients with HFrEF.[44] An interprofessional team should implement this guideline-directed approach that utilizes coordinated care and open communication to drive improved patient outcomes.