Nitrates in Congestive Heart Failure (NICE) Study - NICE

Description:

NICE was a randomized, multicenter, clinical trial designed to determine whether nitrate therapy in patients with congestive heart failure (CHF) is associated with improved exercise tolerance.

Hypothesis:

Oral isosorbide-5-mononitrate (ISMN) therapy will be associated with increased duration of treadmill exercise.

Study Design

Study Design:

Patients Enrolled: 136
NYHA Class: II-III
Mean Follow Up: 24 weeks
Mean Patient Age: 37-74
Female: 5.9
Mean Ejection Fraction: 20-40%

Patient Populations:

NYHA class II-III heart failure due to coronary artery disease, documented prior myocardial infarction (>6 months ago), therapy with ACE inhibitors for at least eight weeks prior to enrollment, and LVEF 20-40%

Exclusions:

Therapy with beta-blockers, digoxin, or calcium antagonists, or insulin-dependent diabetes

Primary Endpoints:

Treadmill exercise time at 12 weeks

Secondary Endpoints:

Left ventricular dimensions, EF, cardiothoracic ratio, functional class, quality of life, hospitalizations, plasma norepinephrine, and atrial natriuretic peptide

Drug/Procedures Used:

Subjects with left ventricular ejection fraction (LVEF) of 20-40% and New York Heart Association (NYHA) class II-III CHF were randomly assigned to receive ISMN at a goal dose of 50 mg once daily or placebo.

Treadmill exercise testing was performed at baseline and two weeks of a single-blinded placebo run-in period. Subjects who performed 4-18 minutes of exercise and had <15% difference between the two exercise tests were randomly assigned to receive ISMN 25 mg once daily or matching placebo. The dose of ISMN was increased to 50 mg once daily after one week. Treatment was continued for 12 weeks in the primary study, and an additional 12 weeks in the follow-up part of the study.

Symptom-limited treadmill exercise testing was performed at 12 weeks.

Concomitant Medications:

Loop diuretics (primarily furosemide) and angiotensin-converting enzyme (ACE) inhibitors

Principal Findings:

A total of 136 subjects were enrolled in the study. Data concerning the primary endpoint were available in 126 subjects. Baseline treadmill time was similar in the two groups (mean of 587 seconds vs. 570 seconds for the ISMN vs. placebo group, p=NS). After 12 weeks of randomized therapy, treatment with ISMN was associated with a trend toward longer exercise time (advantage in the treatment group of 42 seconds, p=0.087). After 24 weeks of randomized treatment, the same trend was observed (advantage in the treatment group of 21 seconds, p=0.32). The overall treatment difference was not significant after adjustment for baseline exercise time, EF, or research center.

In a subgroup analysis of the follow-up study, treatment with ISMN was associated with a significant increase in exercise at 24 weeks' time among subjects with higher EF (treatment advantage 65 seconds, p=0.035).

There were no significant differences between ISMN and placebo study groups in NYHA functional class, quality of life, LVEF, plasma norepinephrine levels, or plasma atrial natriuretic peptide levels.

Interpretation:

In a population of patients with class II-III CHF treated with ACE inhibitors and diuretics, therapy with long-acting isosorbide mononitrate was not associated with longer exercise time, improved quality of life, or decrease in neurohormonal markers of heart failure. In a subset of patients with higher EF, therapy with ISMN was associated with a small, but statistically significant improvement in exercise duration after 24 weeks.

References:

Lewis BS, Rabinowitz B, Schlesinger Z, et al. Effect of isosorbide-5-mononitrate on exercise performance and clinical status in patients with congestive heart failure. Results of the Nitrates in Congestive Heart Failure (NICE) Study. Cardiology 1999;91:1-7.

Clinical Topics: Heart Failure and Cardiomyopathies, Atherosclerotic Disease (CAD/PAD), Acute Heart Failure

Keywords: Exercise Tolerance, Coronary Artery Disease, Myocardial Infarction, Follow-Up Studies, Diuretics, Norepinephrine, Vasodilator Agents, Isosorbide Dinitrate, Quality of Life, Nitrates, Heart Failure, Stroke Volume, Nitric Oxide Donors, Atrial Natriuretic Factor, Exercise Test


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