HEART FAILURE

Outcomes Trials

This section will more closely examine trials that specifically look at clinical outcomes as an endpoint of their study. While some trials may only examine physiological endpoints, such as a laboratory value or diagnostic test, clinical outcome trials determine how a new treatment can impact a patient's life. This impact may be the ability to walk an extra block, or to have another six months of a comfortable life. Many patients do not recognize an increase in their ejection fraction (an objective parameter), but a patient does know when their quality of life has improved; it is easier to get dressed in the morning, takes less time to finish the grocery shopping, or they can sleep better at night.(See Minnesota Living with Heart Failure Questionnaire)

ACE inhibitor therapy has persuasively shown to improve outcomes in heart failure patients in clinical trials. Philbin and colleagues¹compared clinical outcomes of heart failure patients with and without preserved left ventricular systolic function and the use of ACE inhibitor therapy. After identification of study subjects (hospital survivors of heart failure), they were followed for 6 months following discharge with endpoints of death, hospital readmission and quality of life. Results were compared between subjects with ejection fraction(EF) 40% and EF < 40%. ACE inhibitors were prescribed as treatment significantly more often in patients with LV dysfunction (p<0.0001). ACE inhibitor therapy in the patients with normal LV function was associated with a lower risk of death and delayed time to readmission. In those patients with LV dysfunction, ACE inhibitor therapy was associated with lower risk of death and lower rates of rehospitalization. Thus, this study showed that positive outcomes from ACE inhibitor therapy were observed in heart failure patients with and without LV dysfunction.

Several studies have examined the magnitude of the ACE inhibitor dose on the clinical outcomes of heart failure patients. Clinical guidelines recommend ACE inhibitor therapy for all heart failure patients who can tolerate it. However, some studies have determined that lower doses of ACE inhibitors are actually sub-therapeutic.

The NETWORK² investigators randomized heart failure patients 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.

However, the ATLAS (Assessment of Treatment with Lisinopril and Survival)³ trial, which addressed low dose vs. high dose lisinopril therapy, did show improved patient outcomes with high-dose lisinopril. Patients were followed for a median of 46 months following randomization to a lisinopril dose. High-dose lisinopril resulted in a statistically significant reduction in the composite endpoint of death or hospitalization for heart failure and a reduction in hospitalization due to heart failure. 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. They went on to state that if all patients in the US with depressed left-ventricular systolic function and NYHA class II-IV heart failure were treated with high-dose ACE inhibitors, there would be 100,000 fewer deaths and 250,000 fewer hospital admissions for heart failure annually.

Luzier and colleagues⁴ retrospectively examined the effect of underdosing of ACE inhibitors in heart failure patients. Readmission rates were reduced only with high doses of ACE inhibitors (equivalent to >10mg enalapril daily).

The ACHIEVE study⁵ is further examining this question of ACE inhibitor dosing in heart failure.

The MDC (Metoprolol in Dilated Cardiomyopathy) trial⁷ examined the effect of the beta blocker metoprolol in patients with idiopathic dilated cardiomyopathy (IDC). In this placebo controlled trial, patients treated with metoprolol showed a significant improvement in exercise capacity and an improvement in ejection fraction. The metoprolol group also demonstrated a significant risk reduction in overall hospitalizations. A 34% risk reduction (not significant) in the combined endpoint of need for cardiac transplantation and mortality was also demonstrated by the treatment group. When examining mortality alone, no difference in total number of deaths was demonstrated between the treatment and placebo groups.

CIBIS (Cardiac Insufficiency Bisoprolol Study)^8,9 randomized ischemic heart disease (IHD) and IDC heart failure patients to receive bisoprolol or placebo and followed them for a mean of 1.9 years. The mortality in the bisoprolol group was reduced by 20% as compared to the placebo group. Patients without a history of MI showed a significant reduction in mortality when treated with bisoprolol. Those receiving bisoprolol had significantly improved functional status and significantly more subjects in the bisoprolol group had at least one NYHA functional class improvement. The 15-month CIBIS-2 study⁹ also randomized heart failure patients 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 U.S. Carvedilol Heart Failure Study¹⁰was one of the major determinants for FDA approval of carvedilol for heart failure. 1094 patients with chronic heart failure were enrolled in this double-blind, placebo-controlled study. The Data and Safety Monitoring board recommended early termination of the study because of the dramatic results. The reduction in risk of overall mortality in the carvedilol group was 65%. There was a 27% reduction in the risk of hospitalization for cardiovascular causes in the carvedilol treatment group.

In the Australia and New Zealand Carvedilol Study¹¹ , patients with mild to moderate heart failure were randomized to receive treatment with carvedilol or placebo. After 18 months or more of treatment, the carvedilol group showed a 26% lower rate of death or hospitalization as compared to the placebo group. However, the carvedilol group showed no significant advantage over the placebo group in treadmill exercise duration, 6 minutes walk distance, NYHA class or specific activity scale score.

The Metoprolol CR/XL (Controlled Release) Randomized Intervention Trial in Heart Failure (MERIT-HF)¹² 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.

Nursing home elderly with systolic heart failure were evaluated by Foreman et al.¹³ in regards to ACE inhibitor therapy. Heart failure classification, ACE inhibitor use, and ACE inhibitor dose were among the parameters measured in 819 nursing home residents. Of those residents, 119 had doclmented LV systolic dysfunction. Only 35% of these residents were receiving ACE inhibitor therapy, with a minority (22%) receiving the effective high doses needed in heart failure management.

The clinical effects of digoxin therapy in heart failure has become one of the more controversial subjects. Digoxin has been used as heart failure treatment for hundreds of years, yet the actual efficacy of this therapy in patients with milder forms of heart failure is still disputed. The PROVED (Prospective Randomized Study of Ventricular Failure and the Efficacy of Digoxin)¹⁴ study was designed to examine the effects of digoxin in mild to moderate heart failure in patients who were also receiving diuretic. A total of 88 patients were enrolled and randomized to continue digoxin or switch to placebo. After 12 weeks, the results demonstrated that patients on placebo were twice as likely to develop worsening heart failure and a decrease in exercise tolerance. Approximately one-third of those in the placebo group who had worsening of heart failure required hospitalization or emergency room visits. The RADIANCE (Randomized Assessment of Digoxin on Inhibitors of the Angiotensin-Converting Enzyme)¹⁵ study assessed the effects of digoxin in mild to moderate heart failure in patients who were also receiving diuretics and ACE inhibitors. Patients enrolled were randomized to continue to receive digoxin or change to placebo (diuretics and ACE inhibitors remained the same in both groups), and were followed for 12 weeks. All measures of functional capacity (exercise tolerance, exercise endurance) deteriorated in the placebo group compared to digoxin. Lower quality of life score were also seen in the placebo group. These findings indicated that withdrawal of digoxin can carry considerable risk in patients with heart failure who have remained clinically stable while receiving diuretics and ACE inhibitors.

Ward and colleagues¹⁶ examined the results of the PROVED and RADIANCE trials as they relate to economic outcomes. A decision-analytic model was used to approximate the outcomes of either 1)continuation of digoxin therapy in heart failure patients, or 2)discontinuing digoxin therapy in heart failure patients. The additional number of clinic visits, emergency room visits, and hospital admissions that would be required if digoxin was withdrawn were considered, as was the impact of digoxin toxicity cases in those patients that continued digoxin therapy. It was concluded that the continuation of digoxin therapy in heart failure patients would avoid approximately 185,000 clinic visits, 27,000 emergency visits, and 137,000 hospital admissions for heart failure. After an estimated 12,500 digoxin toxicity cases are taken into account, the approximate annual savings would be $406 million.

Young and colleauges¹⁷ 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.

Finally, the DIG (Digitalis Investigation Group)¹⁸ study assessed 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 or placebo. Patients were followed for an average of 37 months. Results indicate a significant reduction in hospitalization for any cause. 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.

REFERENCES

¹ Philbin EF and Rocco TA. Use of angiotensin-converting enzyme inhibitors in heart failure with preserved left ventricular systolic function. Am Heart J 1997;134:188-95.

² The NETWORK Investigators. Clinical outcome with enalapril in symptomatic chronic heart failure; a dose comparison. Eur Heart J 1998;19:481-9.

³ Packer M. Presentation of ATLAS study at the Annual Scientific Meeting of the American College of Cardiology; March 16-19, 1998; Atlanta, Ga.

⁴ 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.

⁵ O'Connor CM, Gattis WA, Swedberg K. Current and novel pharmacologic approaches in advanced heart failure. Am Heart J 1998;135:S249-S263.

⁶ 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.

⁷ Hjalmarson A, Kneider M, Waagstein F. The role of beta-blockers in left-ventricular dysfunction and heart failure. Drugs. 1997;54:501-10.

⁸ CIBIS Investigators and Committees. A randomized trial of beta-blockade in heart failure. The Cardiac Insufficiency Bisoprolol Study (CIBIS). Circulation 1994;90:1765-1773.

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

¹⁰ Packer M, Bristow MR, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. NEJM 1996;334:1349-55.

¹¹ Australia/New Zealand Heart Failure Research Collaborative Group. Randomised, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease. Lancet 1997; 349: 375-80.

¹² Metoprolol CR/XL improves survival in heart failure patients. 71st Meeting of the American Heart Association; November 11, 1998; Dallas, Texas

¹³ Forman DE, Chandler RB, Lapane KL et al. Evaluating the use on angiotensin-converting enzyme inhibitors for older nursing home residents with chronic heart failure. JAGS 199846:1550-1554.

¹⁴ Uretsky BF, Young JB, et al. Randomized study assessing the effect of digoxin withdrawal in patients with mild to moderate chronic congestive heart failure: results of the PROVED trial. PROVED Investigative Group. J Am Coll Cardiol 1993;22:955-62.

¹⁵ Packer M, Gheorghiade M, et al. Withdrawal of digoxin from patients with chronic heart failure treated with angiotensin-converting-enzyme inhibitors. RADIANCE Study. NEJM 1993;329:1-7.

¹⁶ Ward RE, et al. Economic outcomes of withdrawal of digoxin therapy in adult patients with stable congestive heart failure. J Am Coll Cardiol 1995;26:93-101.

¹⁷ 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.

¹⁸ The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. NEJM 1997;336:525-33.

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