HEART FAILURE
Trials of Interest
Recent Trials of Interest

The RALES study (Randomized Aldactone Evaluation Study)¹ was designed to examine the effect of adding spironolactone to an established drug therapy regimen for heart failure. Since even high doses of ACE inhibitors may not be able to completely suppress the renin-angiotensin-aldosterone system, the addition of the spironolactone further suppressed the system by blocking aldosterone, The study was concluded 18 months early, in June 1998, because the results were so clinically significant; it was considered unethical to continue. The trial included 1663 patients with NYHA Class III or IV heart failure, who were followed for a mean of 24 months. The patients that were randomized to receive the spironolactone therapy showed a 27% decrease in mortality as compared to those patients receiving placebo.

ACE INHIBITORS
A study by van Velduisen and colleagues² examined the effects of low dose vs. high dose imidapril therapy in heart failure patients. 244 patients with mild to moderate heart failure were stabilized on digoxin and diuretics. The patients were randomized into four groups, a placebo group and three imidapril groups, each receiving a different dose. Within three months of initiation of treatment, the patients in the highest dose group (10 mg) showed greatest improvement in exercise capacity.

The NETWORK investigators³ compared the effect of high dose ACE inhibition on clinical outcomes of heart failure. 1532 heart failure patients were randomized to receive one of three doses of enalapril, 2.5mg, 5mg, or 10mg twice daily. The patients were followed for 24 weeks. The combined primary endpoint included death, heart failure-related hospitalization and worsening heart failure. The study results did not show any significant differences between the three groups in relation to the combined primary endpoint of the study.

The ATLAS (Assessment of Treatment with Lisinopril and Survival)⁴ trial was designed to address low dose vs. high dose lisinopril therapy, using the primary endpoint of all-cause mortality. This trial utilized a double-blind, randomized design and enrolled 3164 patients. Inclusion criteria required patients to have NYHA Class II-IV heart failure, LVEF ² 30%, and standard treatment with digoxin, diuretic, and/or ACE inhibitor. Patients were randomized to low-dose (2.5 to 5 mg/day) or high-dose (32.5 to 35 mg/day) lisinopril, then followed for a median of 46 months. High-dose lisinopril resulted in a statistically significant 14% reduction in the composite endpoint of death or hospitalization for heart failure and a 24% reduction in hospitalization due to heart failure compared to low-dose therapy. The frequency of adverse effects did not statistically differ between the groups. The study investigators concluded that these results strongly support the use of the higher doses of ACE inhibitors that have been used in clinical trials.

Luzier and colleagues⁵ retrospectively examined the effect of underdosing of ACE inhibitors in heart failure patients. 314 patients were included in the study. The endpoints were time-to readmission and 90-day readmission rate. Time-to-readmission was increased in patients receiving ACE inhibitor, but not in those patients taking diuretics or digoxin (p=0.002). With low ACE inhibitor doses (i.e. enalapril 5mg/day), readmission rate was not reduced; however, with high doses (10mg daily), 90-day readmission rates were reduced as compared to digoxin and diuretic (p0.05). Only 22% of the patients receiving ACE inhibitors were taking the higher dose of the drug.

DIGOXIN

The primary objective of the DIG (Digitalis Investigation Group)⁶ study was to assess the long-term effect of digoxin on mortality from any cause and on hospitalization for heart failure. Patients with left ventricular ejection fractions of 0.45 or less were randomized to digoxin (3397 patients, median dose 0.25 mg/day) or placebo (3403 patients). Patients were followed for an average of 37 months. Results of this study indicate a modest but significant reduction in hospitalization for any cause and a 10% reduction in hospitalizations due to cardiovascular causes. The primary endpoint measured was death from any cause and the investigators found that mortality rates were nearly identical in the two groups. The investigators concluded that digoxin therapy in heart failure patients is likely to affect the frequency of hospitalization but not survival.

Young and colleagues⁷ further evaluated the PROVED and RADIANCE trials to determine if "triple" drug therapy, consisting of digoxin, ACE inhibitor, and diuretic, was superior in clinical endpoints of heart failure than diuretic alone, diuretic + ACE inhibitor, or diuretic + digoxin. In the areas of frequency of treatment failure and likelihood of deterioration in heart failure status, triple drug therapy was significantly superior to the other three drug therapy combinations. Exercise capacity and maintenance of LVEF was significantly greater in the groups treated with digoxin as opposed to those not receiving digoxin. The authors conclude that patients with symptomatic heart failure due to severe systolic dysfunction can significantly benefit with triple drug therapy in the initial management of their disease.

BETA BLOCKERS

The 15-month CIBIS-2⁸ study examined 4647 heart failure patients randomized to take placebo or bisoprolol. Patients continued to take diuretic and ACE inhibitor throughout the trial. The trial was stopped early because of the obvious benefit of the study drug. By the end of the study, the mortality rate of the placebo group was 17.3% versus 11.8% in the bisoprolol group. The number of sudden deaths and hospital admissions were also lower in the bisoprolol patients.

The Metoprolol CR/XL (Controlled Release) Randomized Intervention Trial in Heart Failure (MERIT-HF)⁹ included almost 4000 patient with moderate to severe heart failure randomized to receive metoprolol or placebo. The study was stopped early due to the great beneficial effect that was found in the metoprolol group. The patients taking metoprolol had a 35% lower rate of mortality than the placebo group.

Kukin¹⁰ compared the action of metoprolol and carvedilol on heart failure patients. 67 patients were randomized to receive one of the drugs after being stabilized on digoxin, ACE inhibitor or angiotensin II antagonist, and a diuretic. The trial continued for 12 months with 47 patients completing the study. All these patients demonstrated significant improvements in clinical and exercise parameters. Heart rate declined significantly more in the carvedilol patients than the metoprolol patients. However, the metoprolol group showed a significant decrease in their Minnesota Living with Heart Failure Questionnaire score, whereas the carvedilol groups decrease in score was not significant. Both groups showed improvement in exercise capacity and ejection fraction over the course of the study.

Exner, et al.¹¹ retrospectively analyzed the SOLVD - Prevention and Treatment trials for effects of combining ACE inhibitors with beta-blockers in the treatment of heart failure. They found that 1015 subjects in the Prevention arm and 197 subjects in the Treatment arm received beta-blockers. In the Prevention arm, beta-blocker use resulted in a lower rate of arrhythmic and pump failure death and a decreased progression from asymptomatic to symptomatic heart failure. Also in the Prevention arm, the combined use of a beta-blocker and an ACE inhibitor showed a synergistic effect in reducing mortality.

The tolerability and efficacy of carvedilol in patients with severe heart failure was examined by Macdonald et al.¹²in a recent study. Of the 230 heart failure patients retrospectively analyzed, 63 of the patients had NYHA class IV heart failure. Nonfatal adverse events were more frequent with the severe HF patients than the other patient groups. 59% of the 63 severe HF patients improved by one or more functional classes after 3 months of carvedilol therapy. The authors concluded that carvedilol is useful as adjunctive therapy in class IV heart failure patients, but they must be closely monitored through the initiation and titration of the drug.

Meta-analysis of beta blocker trials¹³

A meta-analysis of completed beta blocker trials in heart failure patients was conducted by Heidenreich and colleagues. An overall reduction in mortality of 31% was seen. However, carvedilol had a large impact on the mortality reduction since 55% of the subjects included in the meta-analysis participated in carvedilol trials. It was found that the etiology of the heart failure did not have any impact on the effectiveness of the beta blockers. The improvement in nonsudden cardiac death was more significant than the reduction of sudden cardiac death, implying that beta blockers do not have a primary antiarrhythmic effect, but rather the beta blockers prevent and/or delay the progression of heart failure.

ANGIOTENSIN II RECEPTOR ANTAGONISTS

The ELITE (Evaluation of Losartan in the Elderly) Study Investigators¹⁴ randomized 722 ACE inhibitor naive heart failure patients to receive losartan or captopril. All subjects were aged 65 years or more with an average age of 73.5 years. At the conclusion of the 48 week study, the secondary endpoints of death and/or heart failure hospital admission, was 9.4% in the losartan group and 13.2% for the captopril group, which was not a statistically significant difference. However, when looking at the mortality rate alone, the losartan group had significantly lower all-cause mortality (4.8%) than the captopril group (8.7%) with a p-value of 0.035. In addition, significantly fewer subjects in the losartan group discontinued their drug treatment due to adverse effects as compared to the captopril treated group.

A double-blind, randomized trial by Lang and colleagues¹⁵ compared losartan with enalapril in heart failure patients. Over 12 weeks, 116 patients were evaluated for functional capacity, symptom, and ejection fraction changes. All patients had a left ventricular ejection fraction 45% and had been receiving ACE inhibitors previous to the study. The study demonstrated similar results for both groups, showing that losartan may be as beneficial as enalapril in the treatment of heart failure. Further studies will need to evaluate the effects of losartan on survival of heart failure.

CALCIUM CHANNEL BLOCKERS

The V-HeFT III (Vasodilator-Heart Failure Trial III) trial¹⁶compared felodipine to placebo in patients with NYHA class II or III heart failure whose exercise tolerance was limited by dyspnea or fatigue. All patients were receiving diuretic and enalapril. After 18 months, no difference was seen in overall mortality between felodipine and placebo. The study shows that there is no benefit, but also no risk, in heart failure patients receiving felodipine if they have another condition that requires it.

The PRAISE (Prospective, Randomized Amlodipine Survival Evaluation) trial¹⁷examined the effects of amlodipine in patients with NYHA Class IV heart failure. All patients were receiving digoxin, diuretics, and an ACE inhibitor throughout the trial. The primary endpoint was cardiovascular mortality and morbidity; the secondary endpoint was all-cause mortality. After an average of 14 months, mortality and morbidity was reduced by 9% (not statistically significant) in the amlodipine group as compared to the placebo group. For the segment of patients who had nonischemic heart failure, a 31% reduction in mortality and morbidity and a 45% reduction in all-cause mortality was seen.

¹ Pitt B. Presentation of RALES Study at the 71st Meeting of the American Heart Association; November 11, 1998; Dallas, Texas.

² van Veldhuisen DJ, Genth-Zotz S, et al. High- versus low-dose ACE inhibition in chronic heart failure: a double-blind, placebo-controlled study of imidapril. J Amer Coll Cardiol 1998;32:1811-9.

³ The NETWORK Investigators. Clinical outcome with enalapril in symptomatic chronic heart failure; a dose comparison. Eur Heart J 1998;19:481-9.

⁴ Packer M. Presentation of ATLAS study at the Annual Scientific Meeting of the American College of Cardiology; March 16-19, 1998; Atlanta, Ga.

⁵ Luzier AB, et al. Impact of angiotensin-converting enzyme inhibitor underdosing on rehospitalization rates in congestive heart failure. Am J Cardiol 1998;82:465-469.

⁶ The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. NEJM 1997;336:525-33.

⁷ Young JB, Gheorghiade M, et al. Superiority of "triple" drug therapy in heart failure: insights from the PROVED and RADIANCE trials. J Am Coll Cardiol 1998;32:686-92.

⁸ CIBIS-ll Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999; 353: 9-13.

⁹ Metoprolol CR/XL improves survival in heart failure patients. 71st Meeting of the American Heart Association; November 11, 1998; Dallas, Texas

¹⁰ Kukin ML et al. Prospective, randomized comparison of effect of longterm treatment with metoprolol or carvedilol on symptoms, exercise, ejection fraction, and oxidative stress in heart failure. Circulation 1999;99:2645-2651.

¹¹ Exner DV, et al. Beta-adrenergic blocking agent use and mortality in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: A post hoc analysis of the Studies Of Left Ventricular Dysfunction. J Am Coll Cardiol 1999;33:916-23.

¹² Macdonald PS, Keogh AM, Aboyoun CL, et al. Tolerability and efficacy of carvedilol in patients with New York Heart Association class IV heart failure. J Am Coll Cardiol 1999;33 :924-931.

¹³ Heidenreich PA, Lee TT, Massie BM. Effect of beta-blockade on mortality in patients with heart failure: a meta-analysis of randomized clinical trials. J Am Coll Cardiol 1997;30:27-34.

¹⁴ Pitt B, et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly study, ELITE). Lancet 1997;349:747-752.

¹⁵ Lang RM, et al. Comparative effects of losartan and enalapril on exercise capacity and clinical status in patients with heart failure. J Am Coll Cardiol 1997;30:83-91.

¹⁶Cohn JN, et al. Effect of the calcium antagonist felodipine as supplementary vasodilator therapy in patients with chronic heart failure treated with enalapril: V-HeFT III. Vasodilator-Heart Failure Trial (V-HeFT) Study Group. Circulation 1997;96:856-63.

¹⁷Packer M, et al. Effect of amlodipine on morbidity and mortality in severe chronic heart failure (The PRAISE trial). NEJM 1996;335:1107-1114.

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