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Enrasentan Cooperative Randomized Evaluation - ENCOR
Description:
The goal of the trial was to compare the effect of the endothelin receptor antagonist enrasentan vs. placebo on a composite measure of clinical heart failure (HF) in patients with chronic HF.
Study Design
Study Design:
Patients Enrolled: 419
NYHA Class: II or III
Mean Follow Up: 3 months
Mean Patient Age: 65
Female: 25%
Mean Ejection Fraction: All had systolic HF (ejection fraction ≤ 35%). Ejection fractions averaged ~25%, which is moderately more impaired than some HF trials; baseline blood pressures and heart rates were typical for patients in NYHA class II and III populations.
Patient Populations:
419 patients with stable NYHA class II or III congestive HF (CHF) of ≥ 3 months duration. Standard background therapy included stable doses of digoxin, diuretics, beta blockers and vasodilators; patients also received stable "standard doses" of ACE inhibitors (equivalent to 5-10 mg of enalapril/day) 1 month prior to randomization. Overall the group was typical of patients with symptomatic HF: average age ~65 years, 75% male, and 65% had ischemic cardiomyopathy for an etiology of their disease. NYHA class was evenly split.
Primary Endpoints:
Clinical HF composite: Improved = improvement in either New York Heart Association (NYHA) functional class or global patient assessment or both; Worse = death, worsening HF leading to hospitalization, permanent withdrawal of therapy, worsening of NYHA class or global assessment; Unchanged = neither improvement nor worsening based on previous categories.
Drug/Procedures Used:
Enrasentan 30 mg (slow titration from 15 mg), 60 mg (slow and rapid titration from 20 mg), and 90 mg (slow titration from 30 mg); high-dose angiotensin-converting enzyme (ACE) inhibitor enalapril 10 mg above existing ACE-inhibitor therapy; and placebo (3x as many patients as other arms); for a total of 6 arms over a duration of 9 months (3-month titration phase plus 6-month maintenance phase).
Principal Findings:
No dose response was seen in the enrasentan-treated patients; fewer patients treated with enrasentan improved compared to placebo, and more patients were judged to worsen. In combining the enrasentan groups, there was a trend favoring placebo over study drug (p=0.0644). The same relationship remained for the endpoint components of NYHA class and patient global assessment measures, although there was slightly greater, but not significant, improvement in NYHA class in the enrasentan groups over placebo. In contrast, there was a significantly greater likelihood of being hospitalized for HF—almost 3-fold—for patients randomized to enrasentan. Likewise, active treatment patients were more likely to be withdrawn from study medication for worsening HF. Total drug withdrawals also were higher in the enrasentan-treated group. Although not statistically significant or definitive, enrasentan was associated with a trend towards more total mortality; in particular, more mortality attributable to progressive left ventricular dysfunction or progressive HF. In the combined endpoint of time to death, HF hospitalization, or withdrawal due to worsening HF (not a pre-defined study endpoint), there was a substantially worse outcome in the combined enrasentan groups (p=0.007). Adverse events were also more common in enrasentan-treated patients. Cardiac failure occurred at a substantially higher rate in enrasentan-treated patients (28.3% vs. 16.6% placebo) and there was a trend towards increased complaint of dyspnea among enrasentan patients. Additionally, there was a greater risk of anemia (16% vs. 5.1%). Enrasentan patients also had more incidents of all other events measured, including dizziness, upper respiratory infections, hypotension, and chest pain. Enrasentan was less well tolerated than placebo, with 21% vs. 8% of patients withdrawing due to an adverse event. The number of patients with at least 1 serious adverse event also was higher in the enrasentan group.
Interpretation:
Among patients with chronic heart failure, the addition of enrasentan to standard background therapy was not associated with improvements in clinical status, was actually associated with worsening clinical status, and was not well tolerated. Thus, treatment for symptomatic HF with mixed endothelin receptor antagonists may not represent a safe or effective approach to long-term treatment alternatives for HF.
Myocardial and plasma endothelin concentrations are elevated in patients with chronic HF, and these elevations correlate with HF disease severity and are associated with poor prognosis. Endothelin mediates its biological actions by binding to 2 membrane-bound receptors, the ETa and ETb receptors, leading to the development of both non-selective ETA and ETB antagonists and selective ETA antagonists.
Enrasentan is an orally active, mixed ETA/ETB receptor antagonist. It has 100-fold greater selectivity for the ETA receptors but substantially also blocks the ETB receptor, particularly in the doses used in this trial. In pre-clinical models of hypertension, long-term therapy improves survival and resting left ventricular function and dimensions and preserves cardiac reserves. It is pharmacologically active in normal subjects, patients with secondary pulmonary hypertension, and patients with systemic hypertension.
Dr. Abraham speculated that the mechanism for that worsening might be hemodynamic in nature; the curves articulated in the time-to-event analysis diverged practically from the first day of the trial.
References:
ACC '01, Late Breaking Clinical Trials, presented by William T. Abraham, MD, University of Kentucky, Lexington
Keywords: Respiratory Tract Infections, Enalapril, Ventricular Function, Left, Digoxin, Endothelins, Indans, Diuretics, Hypotension, Dyspnea, Vasodilator Agents, Receptors, Endothelin, Dizziness, Chest Pain, Carboxylic Acids, Cardiomyopathies, Hypertension, Pulmonary, Heart Failure, Ventricular Dysfunction, Left
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