Objectives

The RELAX trial tested the hypothesis that chronic phosphodiesterase type-5 inhibitor therapy with sildenafil would improve exercise capacity and clinical status in heart failure patients with normal ejection fraction, as compared to placebo.

Background

Heart failure (HF) with preserved ejection fraction (HFpEF) is a common and highly morbid condition that is characterized by chronic exercise intolerance, progressive functional decline and a high rate of readmission. At the time of the RELAX trial, clinical trials of renin-angiotensin system antagonists had not demonstrated improvement in outcomes or clinical status in HFpEF, and effective therapies were needed. Phosphodiesterase type-5 (PDE-5) metabolizes the nitric oxide (NO) and natriuretic peptide (NP) systems’ second messenger cyclic guanosine monophosphate (cGMP), and thus may limit beneficial NO and NP actions in the heart, vasculature and kidney. Pre-clinical studies suggest that inhibition of PDE-5 reverses adverse cardiac structural and functional remodeling and enhances vascular, neuroendocrine and renal function. In clinical studies, PDE-5 inhibitor therapy improved exercise tolerance and clinical status in patients with idiopathic pulmonary arterial hypertension and in patients with HF and reduced ejection fraction (HFrEF). A small, single-center study in HFpEF observed improved hemodynamics, left ventricular (LV) diastolic function, right ventricular (RV) systolic function, LV hypertrophy and lung function with chronic PDE-5 inhibition as compared to placebo. In aggregate, these studies suggested the potential for PDE-5 inhibition to ameliorate several key pathophysiological perturbations in HFpEF, and thus improve exercise capacity and clinical status.

Participants

Eligible subjects included adult HF patients with normal (≥50%) left ventricular ejection fraction and New York Heart Association functional class II–IV symptoms. Objective evidence of HF was defined as at least one of the following occurring within 12 months: hospitalization for decompensated HF, acute HF therapy with intravenous diuretic or hemofiltration, chronic loop diuretic therapy for HF with left atrial enlargement, or invasively documented elevation in LV filling pressures. Patients must have been on stable medical therapy for 30 days, defined as no addition, removal, or change in dosage by more than 100% of angiotensin converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, or calcium channel blockers.

Additionally, patients were required to meet screening criteria, including a peak VO2 ≤ 60% of the normal value with a respiratory exchange ratio ≥ 1.0 and one of the following: elevated (≥400 pg/ml) N-terminal pro-brain natriuretic peptide (NT-proBNP) level, or mean pulmonary capillary wedge pressure > 20 mmHg at rest or > 25 mmHg with exercise within 2 weeks of an NT-proBNP level < 400 pg/ml.

A total of 216 patients were enrolled in the trial with 113 in the Sildenafil group and 103 in the placebo group.

Design

Subjects who met screening criteria underwent baseline studies including a history and physical examination, cardiopulmonary exercise test (CPXT), six-minute walk distance, Minnesota Living with Heart Failure Questionnaire (MLWHFQ), echocardiography, cardiac magnetic resonance imaging, and phlebotomy for biomarkers. Subjects were then randomly assigned, in a 1:1 ratio, to either the sildenafil or placebo intervention group.

The study drug was administered orally at 20 mg three times daily (TID) for 12 weeks. If the dose was well tolerated at 12 weeks, it was increased to 60 mg TID for another 12 weeks. If side effects developed, study staff could recommend discontinuation or return to a lower or previously tolerated dose of study drug. Sildenafil levels 2 hours after a scheduled dose of study drug were obtained at 12 and 24 weeks.

The primary endpoint was exercise capacity determined by change in peak oxygen consumption during the CPXT after 24 weeks of therapy. Secondary endpoints included change in six-minute walk distance at 12 and 24 weeks, change in peak oxygen consumption at 12 weeks, and a three tier score reflective of clinical status where patients were ranked based on time to death (lowest tier), time to cardiovascular or cardiorenal hospitalization (middle tier), and change in the MLWHFQ for patients alive without cardiovascular or cardiorenal hospitalization after 24 weeks (highest tier).

Conclusions

Chronic phosphodiesterase type-5 inhibitor therapy with sildenafil for 24 weeks did not alter exercise capacity or clinical status compared to placebo in patients with heart failure and preserved ejection fraction.

JAMA. 2013 Mar 27;309(12):1268-77.

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