By Van Selby, MD
Assistant Professor of Medicine, University of California San Francisco Advanced Heart Failure Section, San Francisco
Dr. Selby reports no financial relationships relevant to this field of study.
SYNOPSIS: In heart failure with preserved ejection fraction, the use of isosorbide mononitrate was associated with a nonsignificant decrease in physical activity level, and no improvement in symptoms or quality of life.
SOURCE: Redfield MM, et al. Isosorbide mononitrate in heart failure with preserved ejection fraction. N Engl J Med 2015;373:2314-2324.
No pharmacologic therapy has been proven to improve survival in heart failure with preserved ejection fraction (HFpEF). Long-acting nitrates are used frequently to improve symptoms, but the effectiveness of this practice has not been studied in a clinical trial.
The Nitrate’s Effect on Activity Tolerance in Heart Failure with Preserved Ejection Fraction (NEAT-HFpEF) trial tested the hypothesis that isosorbide mononitrate would increase patient activity level in HFpEF. One hundred and ten patients were randomized to isosorbide mononitrate vs placebo, using a crossover design. Inclusion criteria included age ≥ 50 years, New York Heart Association (NYHA) functional class II-IV symptoms, and at least one of the following criteria: history of heart failure (HF) hospitalization, elevated B-type natriuretic peptide (BNP) level, elevated pulmonary artery wedge pressure, or evidence of diastolic dysfunction on echocardiography. Additionally, all patients reported dyspnea, chest pain, or fatigue as the cause of their exercise limitation. Researchers administered isosorbide mononitrate at 30 mg and doubled the dose every week to a target dose of 120 mg daily. The primary outcome was daily activity level, measured using a patient-worn accelerometer.
Compared to patients receiving placebo, those taking isosorbide mononitrate 120 mg daily showed a nonsignificant trend toward lower daily activity (difference of -381 accelerometer units, 95% confidence interval [CI], -780 to 31; P = 0.06), with a significant decrease in the total hours of activity per day (P = 0.02). Activity levels decreased with increasing doses of isosorbide mononitrate in a stepwise manner. There were no statistically significant differences in 6-minute-walk distance, BNP, or quality of life scores.
Both adverse events and discontinuation of study drug were more common among the isosorbide mononitrate group. The authors concluded that in HFpEF, treatment with isosorbide mononitrate as compared to placebo is associated with decreased daily activity levels and no significant improvement in submaximal exercise capacity or quality of life.
COMMENTARY
Nitrates have been shown to improve symptoms in both heart failure with reduced ejection fraction (HFrEF) and ischemic heart disease. Based on these studies and our hemodynamic understanding of HF, long-acting nitrates are used frequently in the management of HFpEF as well. However, this strategy has never been evaluated rigorously in HFpEF. The authors of NEAT-HFpEF demonstrated that empiric use of long-acting nitrates is not beneficial and may actually be detrimental in this population.
These findings are somewhat surprising, and the authors offered several potential explanations. The pathophysiology of HFpEF is different from that of HFrEF or ischemic heart disease. Patients with HFpEF have more comorbidities as well as autonomic dysfunction, chronotropic incompetence, and vascular stiffness. All these comorbidities contribute to symptoms in HFpEF. Additionally, nitrates do not improve these conditions.
The observed difference in reported side effects between isosorbide mononitrate and placebo was insufficient to explain the decline in physical activity, but nitrates may cause subtle, unreported side effects that led patients to be less active. The dose of isosorbide increased at a faster rate than what is common in clinical practice. Patients may have better tolerated a slower dose escalation.
Another possible explanation is patient selection. As has been seen in other clinical trials, identifying patients who truly have HFpEF rather than dyspnea due to other etiologies can be challenging. Nitrates are particularly effective for relieving elevated left-sided filling pressures. Perhaps if the trial had been limited to patients with documented elevation in left-sided pressures, or at least symptoms of elevated pressure such as orthopnea, the authors could have identified a subset of HFpEF patients more likely to benefit from nitrate therapy. Alternatively, it is also possible the increased vascular stiffness in HFpEF makes the left-sided pressures less responsive to the hemodynamic effects of nitrates.
One particularly interesting aspect of this study is the use of patient-worn accelerometers for measuring the primary outcome. This provides continuous assessment of physical activity in a real-world setting, and may be a better measure of functional status than traditional measures such as NYHA class or 6-minute-walk distance. It would not be surprising to see increased use of mobile technology in future HF clinical trials.
Based on the findings of NEAT-HFpEF, nitrate therapy should not be used indiscriminately in HFpEF. That said, selected patients may still benefit, and a brief trial of long-acting nitrates in patients with clear evidence of elevated left-sided filling pressures, either by catheterization or symptoms, still seems reasonable. Patients with HFpEF and co-existing coronary artery disease may also benefit. Given the lack of mortality benefit and potential for harm, it would be reasonable to discontinue nitrate therapy in those who do not experience clear symptomatic improvement.
