JOHN R. MCCONAGHY, MD STEVEN R. SMITH, MS, RPH, BCPS Toledo, Ohio From the Toledo Hospital Family Practice Residency, Toledo, Ohio. The authors report no competing interests. All requests for reprints should be addressed to John R. McConaghy, MD, Associate Director, Toledo Hospital Family Practice Residency, 2051 W. Central Ave, Toledo, OH 43606. E-mail: John.McConaghy.MD@ProMedica.org.
Dosage comparison studies demonstrate that HF patients can benefit from even moderate doses of ACE inhibitors. A recent multicenter trial comparing moderate dose enalapril (10 mg twice a day) with a higher dose (30 mg twice a day) in patients with a left ventricular ejection fraction (LVEF) of less than 20% found no differences in mortality at 1 year between the 2 groups.11 In addition, both groups achieved similar increases in functional status and LVEF.
Several trials have demonstrated good tolerability of ACE inhibitors.12-14 Dropout rates of 15% to 30% were similar between patients in the ACE inhibitor and placebo groups, mainly because of side effects, including dizziness, altered taste, hypotension, hyperkalemia, and cough.
Angiotensin-receptor blockers. Angiotensin-receptor blockers (ARBs) reduce all-cause mortality and HF-related hospitalizations in patients with NYHA class II and III HF at rates comparable with those of ACE inhibitors.15,16 Cough is not a side effect of ARBs. Although they are more expensive, ARBs offer a reasonable alternative for patients who do not tolerate ACE inhibitors.
Beta-blockers. The beta-blockers carvedilol, metoprolol, and bisoprolol have a proven mortality benefit for patients with HF.17-19 Pooled results of 6 randomized controlled trials (RCTs), including more than 9000 patients already taking ACE inhibitors, showed a significant reduction in total mortality (NNT = 24 over 1–2 years) and sudden death (NNT = 35), regardless of NYHA classification.20 The average dropout rate of 16% was similar in the betablocker and placebo groups.
Early beta-blocker studies included few NYHA class IV patients until a recent study of the use of carvedilol in severe chronic HF.21 In this study, all patients were taking diuretics plus either an ACE inhibitor or ARB and were permitted to take digoxin, nitrates, hydralazine, spironolactone, or amiodarone. Carvedilol at an average dose of 37 mg per day decreased mortality (NNT = 18 for 10 months) and lowered combined mortality and hospitalization for worsening HF (NNT = 13). Study patients taking carvedilol withdrew from the study at a lower rate (approximately 15%) than placebo.
Because the pharmacologic properties of betablockers vary, clinicians have wondered which are most beneficial. The investigators in a study comparing metoprolol (a beta-1 antagonist) with carvedilol (a beta-1, beta-2, and alpha-1 antagonist) in NYHA class II or III patients found no differences in quality-of-life measures or changes in NYHA classification.22
Spironolactone. The addition of spironolactone to standard care can help patients with severe HF.23 In NYHA class III and IV HF patients, spironolactone at doses ranging from 25 mg every other day to 50 mg per day reduces mortality (NNT = 9 for 2 years), reduces hospitalization from all cardiac causes (NNT = 4), and reduces hospitalization for worsening HF (NNT = 3). The most common serious adverse event in the spironolactone group was severe hyperkalemia (number needed to harm [NNH] = 195). Ten percent of men taking spironolactone experienced breast pain and gynecomastia.
Hydralazine and isosorbide dinitrate. The combination of hydralazine and isosorbide dinitrate (ISDN) reduces mortality in HF patients, but tolerability is an issue. In earlier trials, men with HF symptoms that were optimally controlled with digoxin and diuretics and treated with hydralazine (average dose = 270 mg/day) plus ISDN (average dose = 136 mg/day) had a decrease in all-cause mortality of 28% (NNT = 19 for 6 years).24 A more recent trial comparing hydralazine plus ISDN with enalapril25 (average daily doses of hydralazine = 300 mg/day; ISDN = 160 mg/day; enalapril = 20 mg/day) in NYHA class II–III patients showed no differences in mortality between the 2 groups over 3 years. Tolerability was a problem in these trials; more than 30% of patients stopped taking hydralazine, nitrate, or both.
Digoxin. Digoxin is effective for treating the symptoms of HF in the absence of dysrhythmias but there are no data demonstrating a mortality benefit. Digoxin increases functional capacity in NYHA class II–III patients and heart failure symptoms worsen if digoxin is withdrawn.26 Although there are no differences in all-cause mortality with the use of digoxin, there are fewer hospitalizations due to worsening HF (NNT = 27–114 over 3 years) and a lower rate of clinical deterioration (NNT = 4–75).27 In a randomized trial comparing digoxin and placebo, patients taking digoxin were twice as likely to be hospitalized for suspected digoxin toxicity (2.0% vs 0.9%; P < .001; NNH = 52).28
Diuretics. Diuretics are a mainstay of the symptomatic treatment of heart failure. Short-term studies have shown that diuretics improve the symptoms of sodium and fluid retention and increase exercise tolerance and cardiac function regardless of NYHA classification.29-32 No studies that examine their effects on morbidity and mortality are available.
