Recent advances in the treatment of systolic congestive heart failure are based on the results of randomized, double-blind, placebo-controlled, multicenter trials. Heart failure is a complex condition, and its treatment requires consideration of two separate goals: symptom relief and tertiary prevention.
The goal of tertiary prevention may be achieved by altering the natural history of the progressive left ventricular remodeling process that leads to further increase in the size of the left ventricle, along with a decline in the ejection fraction. Remodeling is associated with a poor prognosis: it causes further deterioration of congestive heart failure along with a vicious circle of further remodeling.
Heart failure is currently considered to be the result of increased cardiac sympathetic drive that produces toxic effects on the heart and circulation (neurohormonal mechanism).1,2 Long-term neurohormonal activation has serious harmful biologic effects, such as pathologic growth and remodeling, cell death and phenotypical alterations. In experimental animals and patients with heart failure, beta-blocker therapy has been shown to reverse or prevent some of these undesirable processes and to prevent the progression of disease.1–6 Based on observations that the renin-angiotensin system and the sympathetic nervous system are activated in heart failure, it has been speculated that modulation of these systems could have an important role in modifying the pathophysiology of heart failure.
A meta-analysis7 of 39 published clinical trials of angiotensin-converting enzyme (ACE) inhibitor therapy in 8,308 patients with chronic heart failure revealed a 24 percent reduction in mortality (range: 13 to 33 percent). Despite the survival benefits of ACE inhibitors, these agents do not block chronic noradrenergic stimulation of the failing heart, and survival remains unacceptably poor among patients with heart failure.
Other clinically effective agents currently in use include the following: diuretics, which alleviate symptoms in patients with dyspnea; digoxin, administered in low dosages (0.125 to 0.25 mg per day), which provides improved relief of symptoms and reduces hospitalizations; and brief treatment with intravenously administered inotropic agents, which assists with diuresis or temporarily reverses low cardiac output in patients with advanced heart failure.8 Unfortunately, chronic use of positive inotropic agents other than digoxin increases long-term mortality in patients with chronic heart failure. Diuretics and digoxin have only a neutral or slightly favorable effect on mortality, and treatment with these agents is predominantly directed at relieving symptoms.
One investigative team recently reported that blockade of aldosterone receptors using spironolactone (Aldactone) in a low dosage (25 mg per day), in addition to standard therapy, diminished morbidity and mortality in patients with severe heart failure.9 Although the beneficial impact of spironolactone is promising, beta blockers have been established as the most effective treatment for reducing mortality in patients with heart failure. Several clinical trials found that all-cause mortality was reduced by 30 to 35 percent in patients with heart failure who were treated with beta blockers.4,8,10 The studies also showed consistent improvement in left ventricular function, symptoms and clinical status.
Data from controlled clinical trials have created a mandate to include beta blockers in the standard treatment of all patients with stable New York Heart Association (NYHA) class II or III heart failure caused by left ventricular systolic dysfunction.4,8 Beta blockers are predicted to have an even greater positive impact on mortality, particularly when they are given in addition to ACE inhibitors. It should be noted that beta blockers provide greater improvement of symptoms and clinical status (NYHA functional class and overall well-being) in patients with moderate to severe symptoms than in those with minimal to mild symptoms.
Although beta blockers may result in a transient decline in hemodynamics because of their negative inotropic effect, the left ventricular ejection fraction often increases by the third month.8,11–13 A meta-analysis10 of 18 published clinical trials of beta blockers in heart failure showed a significant increase in ejection fraction (from 23 to 31 percent) in patients treated with both selective and non-selective beta blockers. The same meta-analysis showed a 41 percent reduction in the risk of hospitalization and a 32 percent reduction of all-cause mortality in patients with mild to moderate heart failure.
Furthermore, as pointed out by Chavey14 in this issue of American Family Physician, the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II)11 and the Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF),12 which had primary end points of mortality, were stopped early because of significant survival benefits (44 percent and 41 percent reduction in sudden death, respectively, and a 34 percent reduction in total mortality in both studies) in patients with heart failure who were treated with beta1 blockers. In addition, the U.S. Carvedilol Heart Failure Study13 results revealed a 65 percent reduction in all-cause mortality.
Current data do not support a difference between beta1 blockers and nonselective beta blockers. Of note, the lipophilic beta blockers may be more beneficial than hydrophilic beta blockers in reducing the risk of sudden death.
At this time, carvedilol (Coreg) is the only beta blocker that the U.S. Food and Drug Administration has labeled for use in patients with NYHA class II or III heart failure. The Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial addressed the use of carvedilol in patients with more advanced heart failure (NYHA class IIIb to IV). Enrolled patients had a left ventricular ejection fraction of less than 25 percent and symptoms at rest or minimal exertion despite treatment with diuretics and ACE inhibitors for at least two months, but no or minimal evidence of fluid retention at study entry. This study was stopped prematurely by the data and safety steering committee because of significant mortality benefit seen early with carvedilol. The results were presented on August 29, 2000, at the European Society of Cardiologists 22nd annual congress in Amsterdam. All-cause mortality was 18.5 percent in the placebo group compared with 11.4 percent in the carvedilol group, representing a 35 percent reduction in the risk of death in patients receiving carvedilol (P = 0.00014). The study is undergoing final data analysis, and further study results are pending.
Available data strongly support the effectiveness of long-term beta blockade in improving morbidity and mortality in patients with systolic heart failure. As recommended by a panel of experts,“all patients with stable NYHA class II or III heart failure due to left ventricular systolic dysfunction should receive a beta blocker unless they have a contraindication to its use or have been shown to be unable to tolerate treatment with the drug; beta blockers are generally used together with diuretics and ACE inhibitors.”8 When the COPERNICUS trial has undergone the peer-review process and results have been published, patients with advanced systolic heart failure should also receive a beta-blocking agent in addition to standard therapy, if tolerated.