### Clinical Question
Does isosorbide mononitrate improve daily activity in patients with heart failure and a preserved ejection fraction?

### Bottom Line
Isosorbide mononitrate did not improve the daily activity level, submaximal exercise capacity, quality-of-life scores, or NT-proBNP levels, and actually decreased daily activity levels in patients with heart failure and a preserved ejection fraction.

### Major Points


### Guidelines


### Design
Multicenter, double-blind, crossover, randomized, placebo-controlled trial.

- **N** = 110 patients with HFpEF
- **Interventions**: Isosorbide mononitrate (30 mg to 120 mg once daily) vs placebo
- **Setting**: 20 US sites
- **Enrollment**: April 7, 2014, to October 30, 2014
- **Mean follow-up**: 6 weeks per treatment phase
- **Analysis**: Intention-to-treat
- **Primary outcome**: Average daily activity level assessed by accelerometry during 120-mg phase

### Population

#### Inclusion Criteria
- Heart failure diagnosis
- Age ≥50 years
- Ejection fraction ≥50%
- Objective evidence of heart failure (hospitalization for heart failure, elevated left ventricular end diastolic or pulmonary capillary wedge pressure, elevated NT-proBNP or BNP levels, or echocardiographic evidence of diastolic dysfunction)
- Heart failure symptoms as the primary reason for limited activity

#### Exclusion Criteria
- Systolic blood pressure <110 mm Hg or >180 mm Hg
- Adverse reaction or current use of long-term nitrate or phosphodiesterase type 5 inhibitor therapy

#### Baseline Characteristics
- Mean age 69 years, 57% female
- Majority were white and obese
- Majority had controlled blood pressure and multiple coexisting illnesses
- Most patients were on multiple cardiovascular medications
- Mean ejection fraction was 63%

### Interventions
- Isosorbide mononitrate - dose-escalation regimen 30 mg to 120 mg once daily for 6 weeks.
- Placebo for 6 weeks.
- Crossover design, so patients received both treatments sequentially with washout period.

### Outcomes

#### Primary Outcome
- No significant improvement in average daily activity levels during the 120-mg phase of isosorbide mononitrate vs placebo.

#### Secondary Outcomes
- Decrease in hours of activity per day with isosorbide mononitrate.
- No significant difference in 6-minute walk distance, quality-of-life scores, or NT-proBNP levels compared to placebo.

### Criticisms
- Rapid dose escalation of isosorbide mononitrate may have limited assessment of tolerability.
- Absence of longer-term outcomes assessment.
- No improvement in exercise tolerance and reduction of daily activity levels limits applicability.

### Funding
National Heart, Lung, and Blood Institute (NHLBI) grants.

### Further Reading
Full article and supplementary materials available at NEJM.org.