Carvedilol

Article Author:
Shashank Singh
Article Editor:
Charles Preuss
Updated:
9/30/2019 3:59:43 PM
PubMed Link:
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 HeartAssociation 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 it is most importantly supported by 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 is a common topic between these 2 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 an 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 is treated with beta blockers an anti-anginal therapy to a target heart rate of 55 to 60, regardless of which beta blocker is used. Rate control therapy in atrial fibrillation can also be achieved with nearly any beta blockers. Note that specific beta-blockers other than carvedilol are preferred in uses of 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 a1-adrenergic receptor antagonist properties.[10][11] Simply put, 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 a1-blocking properties, causing a reduction in afterload. It is highly useful in the management of hypertension in patients with renal impairment where diuretics and angiotensin-converting enzyme inhibitors (ACEI) are avoided.[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 is 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 may be used 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 are 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. This includes 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 have also been related to 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. Caution should be used in a patient with a history of asthma or reactive airway disease, and use should be avoided in patients with active wheezing due to 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 should be monitored 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 is treated with isotonic fluid and intravenous (IV) atropine administration. Depending on the extent of hemodynamic instability, it may require the insertion of a pacemaker or 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 therapy.For cases involving bronchospasm, beta-sympathomimetics (as aerosol or IV) or IV aminophylline can be administered. In the event of seizures, slow IV injection of diazepam or clonazepam is recommended.

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. The pharmacist, nurse, and clinician should work together to watch for signs and symptoms of toxicity. (Level V)


References

[1] Yancy CW,Jessup M,Bozkurt B,Butler J,Casey DE Jr,Colvin MM,Drazner MH,Filippatos GS,Fonarow GC,Givertz MM,Hollenberg SM,Lindenfeld J,Masoudi FA,McBride PE,Peterson PN,Stevenson LW,Westlake C, 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017 Aug 8     [PubMed PMID: 28455343]
[2] Packer M,Fowler MB,Roecker EB,Coats AJ,Katus HA,Krum H,Mohacsi P,Rouleau JL,Tendera M,Staiger C,Holcslaw TL,Amann-Zalan I,DeMets DL, 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 Oct 22     [PubMed PMID: 12390947]
[3] Poole-Wilson PA,Swedberg K,Cleland JG,Di Lenarda A,Hanrath P,Komajda M,Lubsen J,Lutiger B,Metra M,Remme WJ,Torp-Pedersen C,Scherhag A,Skene A, Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet (London, England). 2003 Jul 5     [PubMed PMID: 12853193]
[4] Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF) Lancet (London, England). 1999 Jun 12     [PubMed PMID: 10376614]
[5] Briasoulis A,Palla M,Afonso L, Meta-analysis of the effects of carvedilol versus metoprolol on all-cause mortality and hospitalizations in patients with heart failure. The American journal of cardiology. 2015 Apr 15     [PubMed PMID: 25708861]
[6] Fröhlich H,Zhao J,Täger T,Cebola R,Schellberg D,Katus HA,Grundtvig M,Hole T,Atar D,Agewall S,Frankenstein L, Carvedilol Compared With Metoprolol Succinate in the Treatment and Prognosis of Patients With Stable Chronic Heart Failure: Carvedilol or Metoprolol Evaluation Study. Circulation. Heart failure. 2015 Sep     [PubMed PMID: 26175538]
[7] Church KM,Henalt R,Baker E,Smith GL Jr,Brennan MT,Joseph J, Comparison of metoprolol succinate versus carvedilol in time to cardiovascular admission in a Veterans Affairs healthcare system: An observational study. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists. 2015 Dec 1     [PubMed PMID: 26582307]
[8] Dargie HJ, Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. Lancet (London, England). 2001 May 5     [PubMed PMID: 11356434]
[9] Li T,Ke W,Sun P,Chen X,Belgaumkar A,Huang Y,Xian W,Li J,Zheng Q, Carvedilol for portal hypertension in cirrhosis: systematic review with meta-analysis. BMJ open. 2016 May 4     [PubMed PMID: 27147389]
[10] Chen-Scarabelli C,Saravolatz L Jr,Murad Y,Shieh WS,Qureshi W,Di Rezze J,Abrencillo R,Gardin T,Gidwani UK,Saravolatz L,Faggian G,Scarabelli TM, A critical review of the use of carvedilol in ischemic heart disease. American journal of cardiovascular drugs : drugs, devices, and other interventions. 2012 Dec 1     [PubMed PMID: 23061698]
[11] Dunn CJ,Lea AP,Wagstaff AJ, Carvedilol. A reappraisal of its pharmacological properties and therapeutic use in cardiovascular disorders. Drugs. 1997 Jul     [PubMed PMID: 9211087]
[12] McTavish D,Campoli-Richards D,Sorkin EM, Carvedilol. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. Drugs. 1993 Feb     [PubMed PMID: 7681374]
[13] Feuerstein GZ,Ruffolo RR Jr, Carvedilol, a novel vasodilating beta-blocker with the potential for cardiovascular organ protection. European heart journal. 1996 Apr     [PubMed PMID: 8733068]