The prognosis remains poor for many patients with congestive heart failure (CHF) despite the addition of angiotensin converting enzyme (ACE) inhibitors to the traditional medical therapy of diuretics and digitalis.^1–4 Even with the addition of ACE inhibitors, the overall one-year mortality rate remains at 10 percent in patients with mild or moderate heart failure; at 26 percent in patients with New York Heart Association (NYHA) functional class III impairment; and at 42 percent in patients with NYHA functional class IV impairment (Table 1). Moreover, patients with CHF tend to experience progressive declines in exercise tolerance and functional ability.¹ Thus, there is a need for new therapies that will improve symptoms and survival rates in patients with CHF.

Use of Beta Blockers

CHF is a progressive syndrome resulting from the heart's inability to adequately perfuse and oxygenate peripheral tissues. This syndrome is manifested by symptoms of fatigue, dyspnea and congestion.^1,5 Chronic heart failure is associated with worsening ventricular dysfunction and pathologic ventricular remodeling, resulting in adverse hemodynamic changes.⁶ It is not surprising, therefore, that physicians have chosen therapies aimed primarily at reversing these changes. Physicians treating patients with heart failure have traditionally selected agents with positive inotropic or peripheral vasodilatory effects and have avoided agents such as beta blockers, which exert negative inotropic effects.⁷ Until recently, beta blockers were contraindicated in the treatment of CHF, largely because heart failure was viewed primarily as a hemodynamic disorder.^7–9

It has become increasingly apparent that the view of heart failure as primarily a hemodynamic disorder is incomplete. Although drugs with positive inotropic effects can produce short-term symptomatic improvements in patients with heart failure,^10,11 their long-term use does not prolong life. In fact, some positive inotropic agents, such as beta agonists (e.g., dobutamine [Dobutrex]) and phosphodiesterase inhibitors (e.g., milrinone [Primacor]), have actually been shown to decrease survival rates.^7,10,11

In addition to the familiar hemodynamic changes, heart failure also results in widespread neurohumoral activation. Aortic and ventricular baroreceptors are reset to permit less sympathetic inhibition, ultimately resulting in increased adrenergic tone. Decreased glomerular flow also activates the renin-angiotensin system. Both of these systems—adrenergic and renin-angiotensin—activate each other.

Initially, these neurohumoral changes are compensatory, functioning to retain fluid and maintain cardiac output. Unfortunately, with prolonged activation, such neurohumoral changes have detrimental effects on the heart.^1,12 The benefits of ACE inhibitors on disease progression are well documented, and survival in patients with heart failure is believed to be due in large part to the effects of these drugs on the neurohumoral changes of CHF.^13–15

Activation of the sympathetic nervous system has been described as “one of the cardinal pathophysiologic abnormalities in patients with congestive heart failure”¹⁶ and as “one of the most important mechanisms that may be responsible for progression of heart failure.”¹⁷ Catecholamine levels are known to increase in proportion to the severity of symptoms in patients with heart failure. Patients with the highest levels of norepinephrine have the least favorable prognosis.^18,19 In animal models, interference with the actions of norepinephrine has been shown to retard the progression of heart failure.^12,16

Moreover, because the sympathetic nervous system is the principal neurohumoral system activated in patients with mild symptoms of heart failure, the use of medications such as beta blockers, which inhibit sympathetic activity, might reduce the risk of disease progression in patients with mildly symptomatic heart failure.¹⁷

Recent controlled studies of patients with heart failure who received beta blockers have indeed shown that, with long-term use, these agents can improve left ventricular function^20–22 and symptoms of CHF.^20,23 Results of the Metoprolol in Dilated Cardiomyopathy (MDC) trial,²⁰ which included 383 patients with ejection fractions of less than 40 percent, showed that patients treated with metoprolol had improved exercise time, decreased left ventricular filling pressures and a reduced need for heart transplantation.

In addition, results of the Cardiac Insufficiency Bisoprolol Study (CIBIS)²³ demonstrated a significant reduction in hospital readmissions due to worsening CHF among patients treated with this beta blocker. However, neither the MDC trial nor the CIBIS study were able to demonstrate reductions in overall mortality.^20,23

Carvedilol (Coreg) is the first beta blocker labeled in the United States specifically for the treatment of mild to moderate (NYHA class II or III) heart failure of ischemic or cardiomyopathic origin. The benefits of using carvedilol in patients with CHF have been demonstrated in both single-center^24–26 and multicenter^2,16,17,27 trials. The Australia–New Zealand Research Collaborative Group²⁸ studied 415 patients with stable heart failure of ischemic origin and found that treatment with carvedilol improved left ventricular function and decreased the risk of the combined end points of death or hospitalization over a 19-month period. However, the use of carvedilol was not shown to significantly reduce either mortality or hospitalization.²⁸

The U.S. Carvedilol Study Group¹⁶ enrolled 1,094 patients with chronic heart failure who were stratified into one of four groups on the basis of their performance on a six-minute walking test. This study was terminated early after researchers concluded that treatment with carvedilol resulted in a 65 percent relative reduction in the mortality rate among patients with heart failure. Although this conclusion has been challenged,^11,29,30 even critics of this study have acknowledged that the results of carvedilol trials are “promising.”¹¹ Thus, findings to date suggest that carvedilol, and quite possibly other beta blockers, may not only improve left ventricular ejection fraction in patients with heart failure, but also reduce their risk of hospitalization and death.

Pharmacology

Carvedilol is a nonselective beta-adreno-receptor antagonist and an alpha₁-adreno-receptor antagonist. It has no intrinsic sympathomimetic activity.³¹ Like many other classes of medications, beta blockers can be divided into three distinct groups. The first group consists of nonselective beta blockers without ancillary properties and includes such drugs as propranolol (Inderal) and timolol maleate (Blocadren).

The second group consists of selective blockers of beta receptor subtypes without ancillary properties. This group includes metoprolol (Lopressor) and atenolol (Tenormin). The third group consists of nonselective beta blockers that have the ancillary property of vasodilation. Included in this group are labetalol (Normodyne), carvedilol and bucindolol (currently in phase 3 trials). Bucindolol and carvedilol produce less “inverse agonism” than most other beta blockers. Inverse agonism is the ability of a beta blocker to inactivate active state receptors. The beta blockers with the most inverse agonism, like propranolol, produce the greatest negative chronotropic and inotropic effects. Thus, bucindolol and carvedilol produce relatively fewer negative chronotropic and inotropic effects when compared with beta blockers like propranolol.⁶

The beta-blocking actions of carvedilol are generally evident in humans within one hour of administration, and the alpha-mediated vasodilatory effects, manifested by decreased peripheral resistance and decreased blood pressure, are evident within about 30 minutes of administration. The clinical significance of alpha blockade in conjunction with beta blockade in the treatment of CHF is not known. The use of alpha blockers alone, however, does not appear to reduce mortality in patients with symptomatic CHF.³²

At high dosages, carvedilol exerts calcium channel blocking activity.³³ It also has significant antioxidant properties.^34,35 Carvedilol inhibits the generation of oxygen free radicals and prevents low-density lipoprotein (LDL) oxidation, which, in turn, reduces the uptake of LDL into the coronary vasculature. This antioxidant activity may contribute to carvedilol's cardioprotective effects.³⁶ In fact, compared with captopril, carvedilol has demonstrated similarly favorable effects on the lipid profiles of hypertensive patients with dyslipidemia.³⁷

Carvedilol is rapidly absorbed following oral administration, achieving peak plasma concentrations within one to two hours. The apparent mean terminal elimination half-life of carvedilol generally ranges from seven to 10 hours. The rate of absorption is delayed by taking carvedilol with food. Carvedilol is metabolized by the liver and undergoes extensive first-pass metabolism. Three active metabolites of carvedilol have been identified, but none of these compounds appears to contribute to carvedilol's beta-blocking activity. Carvedilol is primarily metabolized by the liver, with less than 2 percent of a given dose excreted unchanged in the urine. Plasma concentrations of carvedilol are nevertheless increased in patients with renal failure. Carvedilol is highly bound to plasma proteins and is, therefore, not cleared significantly by hemodialysis.^13,31

Precautions and Contraindications

Carvedilol is contraindicated in patients with bronchial asthma or related bronchospastic conditions, decompensated NYHA functional class IV heart failure requiring intravenous inotropic therapy, severe liver impairment, second- or third-degree atrioventricular block, sick sinus syndrome (unless a permanent pacemaker is in place), cardiogenic shock, severe bradycardia or known hypersensitivity to the drug.

Although carvedilol has not been demonstrated to have adverse effects on lipids, beta blockers without intrinsic sympathomimetic activity can worsen lipid profiles. Family physicians should, therefore, pay careful attention to lipid levels in patients with hyperlipidemia who are treated with carvedilol. Parameters of glycemic control should also be monitored. Patients with diabetes or thyroid disease should be warned that carvedilol, like other beta blockers, can mask the signs and symptoms of hypoglycemia and hyperthyroidism, including tachycardia. Moreover, nonselective beta blockers, like carvedilol, can potentiate insulin-induced hypoglycemia. Carvedilol should be used with caution in patients with peripheral vascular disease because beta blockers can precipitate or aggravate symptoms of arterial insufficiency.

Finally, carvedilol therapy should be avoided in patients with known hepatic impairment, since mild hepatocellular injury has occurred, although rarely, among patients treated with the drug.^13,31,38

Adverse Reactions

Carvedilol is generally well-tolerated. In clinical trials comparing carvedilol monotherapy with placebo, 4.9 percent of patients treated with less than 50 mg of carvedilol and 5.2 percent of patients taking placebo discontinued use because of adverse effects. Discontinuation of therapy because of postural hypotension was more common among patients treated with carvedilol (1 percent versus zero percent).³¹ Dizziness, hypotension and fatigue were the most frequently reported adverse effects.^13,16,31 Less common adverse effects included diarrhea (2.2 percent in patients taking carvedilol versus 1.3 percent in patients taking placebo), bradycardia (2.1 percent versus 0.2 percent), edema (1.4 percent versus 0.4 percent), insomnia (1.6 percent versus 0.6 percent), dyspnea (1.4 percent versus 0.9 percent), pharyngitis (1.5 percent versus 0.6 percent) and urinary tract infections (1.8 percent versus 0.6 percent).³¹ Rare reports of liver function abnormalities have been noted; however, no deaths have been reported, and the mild hepatic injury appears to have been reversed once the drug was discontinued. Rare cases of thrombocytopenia have also been reported.^13,31,38

Much of the initial study of carvedilol's tolerability did not include patients with heart failure. Nevertheless, the U.S. Carvedilol Heart Failure Study Group¹⁶ also found that dizziness and fatigue were the most common adverse reactions reported by patients treated with carvedilol. They also noted increased reports of dyspnea (25 percent with carvedilol versus 22 percent with placebo), heart failure (21 percent versus 16 percent) and cough (10 percent versus 8 percent). The Australia–New Zealand Heart Failure Research Collaborative Group² reported the following as the most frequent reasons for withdrawal from treatment during the double-blind phase of their study: worsening heart failure (5 percent in patients taking carvedilol versus 2 percent in patients taking placebo), dizziness/hypotension (3 percent versus zero percent), bradycardia/heart block (3 percent versus zero percent), headache, tiredness, irritability and worsening control over diabetes (1 percent versus zero percent).

Drug Interactions

Because of carvedilol's extensive oxidative liver metabolism, its pharmacokinetics can be profoundly affected by certain drugs that significantly induce or inhibit oxidation. Rifampin (Rifadin), an inducer of hepatic metabolism, can reduce plasma concentrations of carvedilol by 70 percent when these drugs are coadministered. In contrast, cimetidine (Tagamet), an inhibitor of the cytochrome P₄₅₀ 2D6 isoenzyme (the same isoenzyme involved in the metabolism of carvedilol), can increase carvedilol's plasma concentration by 30 percent. Other inhibitors of the cytochrome P₄₅₀ 2D6 isoenzyme, such as quinidine, fluoxetine (Prozac), paroxetine (Paxil) and propafenone (Rythmol), could be expected to have similar effects on carvedilol's plasma concentrations.^13,31

Digoxin (Lanoxin) concentrations increase by approximately 15 percent in patients also taking carvedilol. Consequently, digoxin levels should be closely monitored when initiating, adjusting or discontinuing carvedilol therapy. As with other beta blockers, combining carvedilol with verapamil (Calan) or diltiazem (Cardizem) should be done with caution. When these agents are combined, it is recommended that blood pressure and electrocardiographic changes be closely monitored. Coadministration of beta blockers and catecholamine-depleting drugs, such as reserpine (Serpasil) or monoamine oxidase (MAO) inhibitors can result in severe hypotension. These agents should be combined with great caution, and patients taking these drugs should be closely monitored. Similarly, coadministration of carvedilol and clonidine (Catapres) should be undertaken carefully because beta blockers can potentiate blood pressure and heart rate reductions in such patients. When clonidine therapy is discontinued, it is recommended that the beta blocker be discontinued first. Then, after several days, clonidine can be gradually tapered and discontinued in the hope of avoiding reflex tachycardia and hypertensive crisis.^13,31 Drugs that interact with carvedilol are listed in Table 2.³¹

Dosing and Administration

Carvedilol is indicated for the treatment of heart failure in patients with clinically stable NYHA functional class II or III heart failure. Patients taking diuretics, digitalis or ACE inhibitors should be taking stable dosages of these medications before carvedilol therapy is initiated. Carvedilol may also be used in patients unable to tolerate an ACE inhibitor and in those not taking digoxin, hydralazine (Apresoline) or nitrate therapy. In most cases, however, ACE inhibitor therapy should be initiated and stabilized before the introduction of carvedilol therapy. Finally, it is important to remember that, initially, beta-blocker therapy causes negative inotropic and chronotropic effects while the improvements in left ventricular function develop over time. Therefore, patients hospitalized for heart failure, those in a fluid-overload state and those who are symptomatically hypotensive should not be given carvedilol.^6,13,38

The starting dosage of carvedilol is 3.125 mg orally twice daily for two weeks. This dosage is the same regardless of the patient's age or weight. Because food slows the rate (but not the extent) of absorption, carvedilol should be taken with food to reduce the incidence of orthostatic hypotension. Patients should be observed in the physician's office for adverse reactions, especially dizziness, light-headedness and hypotension, for one hour after the first dose and again after each dosage increase. Blood pressure should be measured with the patient standing. Patients should be instructed to weigh themselves every day and to contact their physician immediately if they experience a weight gain of 0.91 to 1.36 kg (2 to 3 lb) above their usual “dry” weight. If, after two weeks, the initial dosage of carvedilol has been well-tolerated, it should be doubled. The dosage should be doubled every two weeks to the maximum dosage or the highest tolerated dosage. The maximum recommended dosage for carvedilol is 25 mg twice daily in patients weighing less than 85 kg (187 lb) and 50 mg twice daily in patients weighing 85 kg (187 lb) or more.^6,13,36 Recommendations for the administration and titration of carvedilol are summarized in Tables 3 and 4.

It may also be necessary, based on clinical signs and symptoms, to adjust the dosages of the patient's other heart failure medications when carvedilol is introduced. When patients have signs and symptoms of excessive vasodilation, such as dizziness, lightheadedness or orthostatic hypotension, consideration should be given to decreasing diuretic, vasodilator or ACE inhibitor dosages. If these signs and symptoms persist, the dosage of carvedilol should be decreased. In patients with signs and symptoms of worsening heart failure, such as edema, weight gain or dyspnea, the dosage of diuretic therapy should be increased. If evidence of worsening heart failure persists, the dosage of carvedilol should be decreased. In patients with bradycardia or first-degree atrioventricular block, carvedilol should be titrated to maintain a heart rate greater than 55 beats per minute. Finally, patients should be advised not to stop taking carvedilol abruptly or without a physician's advice. When carvedilol therapy must be discontinued, the drug should be tapered slowly over seven to 14 days.^6,13,31,38

Cost and Available Forms

Carvedilol is supplied in tablet form and is available in four dosage strengths: 3.125 mg, 6.25 mg, 12.5 mg and 25 mg. The average wholesale price for all strengths is $1.55 per tablet.^13,38