Isosorbide Mononitrate in Heart Failure with Preserved Ejection Fraction

Abstract

Background: Nitrates are commonly prescribed to enhance activity tolerance in patients with heart failure and a preserved ejection fraction. We compared the effect of isosorbide mononitrate or placebo on daily activity in such patients.

Methods: In this multicenter, double-blind, crossover study, 110 patients with heart failure and a preserved ejection fraction were randomly assigned to a 6-week dose-escalation regimen of isosorbide mononitrate (from 30 mg to 60 mg to 120 mg once daily) or placebo, with subsequent crossover to the other group for 6 weeks. The primary end point was the daily activity level, quantified as the average daily accelerometer units during the 120-mg phase, as assessed by patient-worn accelerometers. Secondary end points included hours of activity per day during the 120-mg phase, daily accelerometer units during all three dose regimens, quality-of-life scores, 6-minute walk distance, and levels of N-terminal pro-brain natriuretic peptide (NT-proBNP).

Results: In the group receiving the 120-mg dose of isosorbide mononitrate, as compared with the placebo group, there was a nonsignificant trend toward lower daily activity (-381 accelerometer units; 95% confidence interval [CI], -780 to 17; P=0.06) and a significant decrease in hours of activity per day (-0.30 hours; 95% CI, -0.55 to -0.05; P=0.02). During all dose regimens, activity in the isosorbide mononitrate group was lower than that in the placebo group (-439 accelerometer units; 95% CI, -792 to -86; P=0.02). Activity levels decreased progressively and significantly with increased doses of isosorbide mononitrate (but not placebo). There were no significant between-group differences in the 6-minute walk distance, quality-of-life scores, or NT-proBNP levels.

Conclusions: Patients with heart failure and a preserved ejection fraction who received isosorbide mononitrate were less active and did not have better quality of life or submaximal exercise capacity than did patients who received placebo. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02053493.).

Figure 1. Primary and Secondary End Points for Activity Levels

Shown are the absolute values and differences between the two treatments (isosorbide mononitrate minus placebo) for the average daily arbitrary accelerometer units (Panel A) and hours of activity per day (Panel B) during the 120-mg phase and for daily arbitrary accelerometer units for all three doses (30 mg, 60 mg, and 120 mg) combined (Panel C). The arbitrary accelerometer units were stored as 15-minute cumulative accelerometer units (96 data points per day) and were totaled over a 24-hour period to provide daily accelerometer units. The I bars indicate 95% confidence intervals.

Figure 2. Change in Activity Levels with Increasing Doses of Isosorbide Mononitrate or Placebo

Shown are the changes from baseline in the average daily arbitrary accelerometer units according to the dose of iso-sorbide mononitrate and placebo in the two study groups and the corresponding treatment differences (dose value minus baseline value). Among the patients who received placebo, 89 received the 30-mg dose, 91 received the 60-mg dose, and 93 received the 120-mg dose. Among the patients who received isosorbide mononitrate, 85 received the 30-mg dose, 87 received the 60-mg dose, and 89 received the 120-mg dose. The I bars indicate 95% confidence intervals.

Figure 3. Average Daily Arbitrary Accelerometer Units, According to Subgroup

Shown are the average daily arbitrary accelerometer units in each of the prespecified subgroups and the between-group treatment differences and 95% confidence intervals. The term “nitrate tolerance” refers to the decreasing effect of nitrates in patients after long-term exposure to this drug class. Inhibitors of nitrate tolerance include renin–angiotensin–aldosterone antagonists, carvedilol, statins, and hydralazine. Since only four patients were treated with hydralazine, the subgroup analysis for this variable alone is not shown. ACE denotes angiotensin-converting enzyme, ARB angiotensin-receptor blocker, ECG electrocardiography, and NT-proBNP N-terminal pro–brain natriuretic peptide.