Carvedilol is used for the management of hypertension and heart failure. Carvedilol also is used to reduce the risk of cardiovascular mortality in clinically stable patients with left ventricular dysfunction (manifested as a left ventricular ejection fraction [LVEF] of 40% or less) with or without symptomatic heart failure following an acute myocardial infarction.
The choice of a β-adrenergic blocking agent (β-blocker) depends on numerous factors, including intended use, pharmacologic properties (e.g., relative β-selectivity, intrinsic sympathomimetic activity, membrane-stabilizing activity, lipophilicity), pharmacokinetics, and adverse effect profile, as well as the patient's coexisting disease states or conditions, response, and tolerance. While specific pharmacologic properties and other factors may appropriately influence the choice of a β-blocker in individual patients, evidence of clinically important differences among the agents in terms of overall efficacy and/or safety is limited. Patients who do not respond to or cannot tolerate a given β-blocker may be successfully treated with a different one.
Carvedilol is used alone or in combination with other classes of antihypertensive agents in the management of hypertension. Although a β-blocker was previously considered a drug of choice for the initial management of hypertension, most current guidelines no longer recommend these drugs as first-line therapy because of the lack of established superiority over other recommended drug classes and at least one study demonstrating that they may be less effective than angiotensin II receptor antagonists in preventing cardiovascular death, myocardial infarction, or stroke. However, β-blockers may still be considered in hypertensive patients who have a compelling indication (e.g., prior myocardial infarction, ischemic heart disease, heart failure) for their use or as add-on therapy in those who do not respond adequately to the preferred drug classes (angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, or thiazide diuretics). and in )
In general, black hypertensive patients tend to respond better to monotherapy with thiazide diuretics or calcium-channel blocking agents than to monotherapy with β-blockers. Although β-blockers have lowered blood pressure in all races studied, monotherapy with these agents has produced a smaller reduction in blood pressure in black hypertensive patients; however, this population difference in response does not appear to occur during combined therapy with a β-blocker and a thiazide diuretic. and in
For additional information on the role of nonselective β-adrenergic/selective α1-blocking agents in the management of hypertension, or on the role of β-blockers in the management of hypertension, and in . For information on overall principles and expert recommendations for treatment of hypertension, For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients,
Carvedilol is used (usually in conjunction with other heart failure therapies) in the management of mild to severe (New York Heart Association [NYHA] class II-IV) heart failure of ischemic or cardiomyopathic origin to increase survival and to reduce the risk of hospitalization. Current guidelines for the management of heart failure in adults generally recommend a combination of drug therapies to reduce morbidity and mortality, including neurohormonal antagonists (e.g., ACE inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs], β-blockers, aldosterone receptor antagonists), that inhibit the detrimental compensatory mechanisms in heart failure. Additional agents (e.g., cardiac glycosides, diuretics, sinoatrial modulators [i.e., ivabradine]) added to a heart failure treatment regimen in selected patients have been associated with symptomatic improvement of heart failure and/or reduction in heart failure-related hospitalizations. Experts recommend that all asymptomatic patients with reduced LVEF (American College of Cardiology Foundation [ACCF]/American Heart Association [AHA] stage B heart failure) receive therapy with an ACE inhibitor and a β-blocker to prevent symptomatic heart failure and reduce morbidity and mortality. In patients with prior or current symptoms of chronic heart failure and reduced LVEF (ACCF/AHA stage C heart failure), ACCF, AHA, and the Heart Failure Society of America (HFSA) recommend inhibition of the renin-angiotensin-aldosterone (RAA) system with an ACE inhibitor, angiotensin II receptor antagonist, or ARNI in conjunction with a β-blocker, and an aldosterone antagonist in selected patients, to reduce morbidity and mortality. While ACE inhibitors have been the preferred drugs for inhibition of the RAA system because of their established benefits in patients with heart failure and reduced ejection fraction, some evidence indicates that therapy with an ARNI (sacubitril/valsartan) may be more effective than ACE inhibitor therapy (enalapril) in reducing cardiovascular death and heart failure-related hospitalization in such patients. ACCF, AHA, and HFSA recommend that patients with chronic symptomatic heart failure and reduced LVEF (NYHA class II or III) who are able to tolerate an ACE inhibitor or angiotensin II receptor antagonist be switched to therapy containing an ARNI to further reduce morbidity and mortality.
Because of favorable effects on survival and disease progression, therapy with a clinical trial-proven β-blocker (bisoprolol, carvedilol, extended-release metoprolol succinate) should be initiated as soon as the patient is diagnosed with heart failure and reduced LVEF. While bisoprolol, carvedilol, and extended-release metoprolol have been effective in reducing the risk of death in patients with chronic heart failure, these positive findings should not be considered indicative of a β-blocker class effect. Even when symptoms are mild or improve with other therapies, β-blocker therapy should not be delayed until symptoms return or the disease progresses. Despite concerns about β-blockade potentially masking some signs of hypoglycemia, patients with diabetes mellitus may be particularly likely to experience a reduction in morbidity and mortality with the use of β-blockers. If a patient cannot tolerate a β-blocker or if increasing the β-blocker dosage to optimal levels is ineffective, ivabradine should be considered an alternative or additional treatment option. Some evidence suggests that ivabradine is effective in reducing hospitalizations related to heart failure, but unlike β-blockers, ivabradine has not been shown to reduce cardiovascular mortality.
In individualizing the decision to use a β-blocker, clinicians should consider that clinical studies establishing the effects of these drugs on morbidity and mortality excluded patients who were hospitalized or had unstable symptoms and enrolled few patients with current or recent NYHA class IV symptoms. The efficacy of β-blockers in such patients is not known, and they may be at particular risk of deterioration following initiation of therapy with β-blockers. In the Carvedilol Prospective Randomized Cumulative Survival Trial (COPERNICUS) evaluating such patients with severe but stable heart failure (patients with marked fluid retention or severe pulmonary disease or requiring intensive care, IV vasodilators, or positive inotropic agents were excluded), carvedilol decreased the rate of death and the combined risk of death and hospitalization for any reason compared with placebo.
The beneficial effects of β-blockers in the management of heart failure are thought to result principally from inhibition of the effects of the sympathetic nervous system.
(See Description.)Although the specific effects on the heart and circulation that are responsible for progression of heart failure remain to be established, sympathetic activity can increase ventricular volumes and pressure secondary to peripheral vasoconstriction and by impairing sodium excretion by the kidneys. Other sympathetic effects (e.g., induction of cardiac hypertrophy, arrhythmogenic activity) also may be involved. The beneficial effect of carvedilol in patients with severe heart failure may be the result of other effects (α-adrenergic blockade, antioxidant activity, antiendothelin effects) in addition to β-adrenergic blockade. Collective experience indicates that long-term therapy with β-blockers, like that with ACE inhibitors, can reduce heart failure symptoms and improve clinical status in patients with chronic heart failure and also can decrease the risk of death as well as the combined risk of death and hospitalization. These beneficial effects were demonstrated in patients already receiving an ACE inhibitor, suggesting that combined inhibition of the renin-angiotensin system and sympathetic nervous system can produce additive effects.
β-Blockers should not be used in patients with acutely decompensated heart failure requiring IV inotropic therapy and those with substantial fluid retention requiring intensive diuresis. In the absence of hemodynamic instability or contraindications, it has been recommended that patients with heart failure and a reduced ejection fraction who are hospitalized for a symptomatic exacerbation continue to receive maintenance treatment with standard oral therapy for heart failure (e.g., β-blocker, ACE inhibitor). Withholding of or reduction in β-blocker therapy should be considered only in patients hospitalized after recent initiation or increase in β-blocker therapy or in those with marked volume overload or low/marginal cardiac output. Initiation of β-blocker therapy in hospitalized patients is recommended once the patient's condition is stabilized (i.e., after optimization of volume status and successful discontinuance of IV diuretics, vasodilators, and inotropic agents). Caution should be used when initiating β-blockers in patients who have required inotrope therapy during hospitalization.
Carvedilol has been shown in controlled studies to improve left ventricular function, symptoms, and submaximal exercise tolerance (although not in all studies) in patients with wide-ranging severity of manifestations. Change in NYHA classification was a secondary endpoint in all of the studies, and a trend toward improvement in NYHA class was reported in all studies. Subjective quality-of-life determined by a standard questionnaire was not improved in patients receiving carvedilol compared with those receiving placebo; however, global assessments by patients and clinicians supported an improvement in such assessments in patients receiving carvedilol.
Left Ventricular Dysfunction after Acute Myocardial Infarction
Carvedilol is used to reduce the risk of cardiovascular mortality following myocardial infarction in clinically stable patients with left ventricular dysfunction (manifested as an ejection fraction of 40% or less) with or without symptomatic heart failure. In these patients, when compared with those receiving placebo, carvedilol therapy initiated within 21 days after an acute myocardial infarction reduced mortality from any cause by about 23%; all-cause mortality or cardiovascular hospitalization was reduced by 8%, which was not statistically significant. In addition, a 40% reduction in fatal and nonfatal myocardial infarction was observed in patients receiving carvedilol. This evidence of efficacy was obtained from a large, double-blind, placebo-controlled, multicenter long-term (about 16 months) study (Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction Study; CAPRICORN).