Effect of Isosorbide-5-Mononitrate on Exercise Performance and Clinical Status in Patients with Congestive Heart Failure

Abstract

Background and Aims: Nitrate therapy improves hemodynamics in patients with heart failure, but the chronic effects of oral nitrates on exercise performance and clinical status have not been well studied. Methods: Oral isosorbide-5-mononitrate (ISMN) (50 mg once daily) or placebo was administered to 136 patients (NYHA Class 2–3) treated for heart failure, all receiving captopril and most also furosemide. Endpoints were treadmill exercise time at 12 weeks by modified Naughton protocol (primary), with an additional 12-week follow-up period. Secondary endpoints included left ventricular dimensions, ejection fraction, cardiothoracic ratio, functional class, quality of life, hospitalizations and plasma norepinephrine and atrial natriuretic peptide in a four-center substudy. Results: Intention-to-treat analysis showed that mean change in treadmill exercise duration tended to be greater in patients receiving ISMN than placebo (treatment difference +42 s, 95% CI –5, +90 s at 12 weeks and +21 s, 95% CI –25, +74 s after 24 weeks) (NS). Treatment difference was greater in the prespecified subgroup with ejection fraction 31–40% (+55 s, 95% CI –11, +136 s at 12 weeks and +65 s, 95% CI +3, +147 s) (p = 0.035) at 24 weeks. No deleterious effects (i.e. hypotension) were observed with ISMN, although headache was reported in 19% of the active treatment group (p = 0.0001). Conclusions: ISMN added to captopril increased treadmill exercise time in patients with heart failure and a lesser reduction in baseline ejection fraction, although for the group as a whole, the increase in treadmill time was not significant.

Effects of Chronic Nitrate Therapy on Left-Ventricular Volume in Patients with Heart Failure Secondary to Coronary Disease Already Treated with Captopril: A Withdrawal Study

“…We have demonstrated that the addition of nitrates to a baseline therapy with captopril and diuretics does not improve exercise tolerance of patients with mild-to-moderate heart failure from coronary disease [5]. This is in agreement with a study by Lewis et al [6]who found no effect of isosorbide-5-mononitrate on treadmill exercise time in their study group as a whole while patients with a lesser reduction in left-ventricular ejection fraction might benefit from the addition of nitrates. The objective of this substudy of our preceding study [5]was to evaluate the effects of stopping nitrate therapy on left-ventricular volume at rest and during exercise.…”

Effect of nitrate treatment on functional capacity and exercise time in patients with heart failure: a systematic review and meta-analysis

“…A total of 14 studies were included in the meta-analysis of adverse events. All-cause mortality was reported in 10 studies, 18 – 20 , 22 – 25 , 27 , 29 , 30 which all compared nitrate with control treatments. A low heterogeneity between studies was found.…”

“…Arrhythmia was reported in three studies. 24,29,32 No significant heterogeneity between studies was found. Therefore, the fixed-effects model was used.…”

“…23 Several studies have compared nitrates with control treatments for HF, but no consistent outcomes have been reported. [24][25][26][27][28][29][30][31][32][33][34][35][36] Therefore, this meta-analysis was conducted to assess the efficacy and safety of nitrates compared with control treatment for HF.…”

A Sustained Release Formulation of Isosorbide‐5‐mononitrate With a Rapid Onset of Action

“…In a double‐blind, placebo‐controlled study of 136 patients with NYHA functional class II‐III cardiac failure, 31 ISMN‐SR 50 mg was added to captopril for 12 weeks. Patients were subdivided into those with entry LVEF of 20‐30% or 31‐40%.…”