Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial

Abstract

Importance: Studies in experimental and human heart failure suggest that phosphodiesterase-5 inhibitors may enhance cardiovascular function and thus exercise capacity in heart failure with preserved ejection fraction (HFPEF).

Objective: To determine the effect of the phosphodiesterase-5 inhibitor sildenafil compared with placebo on exercise capacity and clinical status in HFPEF.

Design: Multicenter, double-blind, placebo-controlled, parallel-group, randomized clinical trial of 216 stable outpatients with HF, ejection fraction ≥50%, elevated N-terminal brain-type natriuretic peptide or elevated invasively measured filling pressures, and reduced exercise capacity. Participants were randomized from October 2008 through February 2012 at 26 centers in North America. Follow-up was through August 30, 2012.

Interventions: Sildenafil (n = 113) or placebo (n = 103) administered orally at 20 mg, 3 times daily for 12 weeks, followed by 60 mg, 3 times daily for 12 weeks.

Main outcome measures: Primary end point was change in peak oxygen consumption after 24 weeks of therapy. Secondary end points included change in 6-minute walk distance and a hierarchical composite clinical status score (range, 1-n, a higher value indicates better status; expected value with no treatment effect, 95) based on time to death, time to cardiovascular or cardiorenal hospitalization, and change in quality of life for participants without cardiovascular or cardiorenal hospitalization at 24 weeks.

Results: Median age was 69 years, and 48% of patients were women. At baseline, median peak oxygen consumption (11.7 mL/kg/min) and 6-minute walk distance (308 m) were reduced. The median E/e' (16), left atrial volume index (44 mL/m2), and pulmonary artery systolic pressure (41 mm Hg) were consistent with chronically elevated left ventricular filling pressures. At 24 weeks, median (IQR) changes in peak oxygen consumption (mL/kg/min) in patients who received placebo (-0.20 [IQR, -0.70 to 1.00]) or sildenafil (-0.20 [IQR, -1.70 to 1.11]) were not significantly different (P = .90) in analyses in which patients with missing week-24 data were excluded, and in sensitivity analysis based on intention to treat with multiple imputation for missing values (mean between-group difference, 0.01 mL/kg/min, [95% CI, -0.60 to 0.61]). The mean clinical status rank score was not significantly different at 24 weeks between placebo (95.8) and sildenafil (94.2) (P = .85). Changes in 6-minute walk distance at 24 weeks in patients who received placebo (15.0 m [IQR, -26.0 to 45.0]) or sildenafil (5.0 m [IQR, -37.0 to 55.0]; P = .92) were also not significantly different. Adverse events occurred in 78 placebo patients (76%) and 90 sildenafil patients (80%). Serious adverse events occurred in 16 placebo patients (16%) and 25 sildenafil patients (22%).

Conclusion and relevance: Among patients with HFPEF, phosphodiesterase-5 inhibition with administration of sildenafil for 24 weeks, compared with placebo, did not result in significant improvement in exercise capacity or clinical status.

Trial registration: clinicaltrials.gov Identifier: NCT00763867.

Conflict of interest statement

Conflicts of Interest

Potential conflicts of interest including financial disclosures are listed below:

MMR: Receives financial support from the NIH and royalties from Annexon.

HHC: Has received funding for patents that his institution has licensed to Nile Therapeutics and Annexon with other patents pending at the U.S. patent office; has royalties with Nile Therapeutics, Annexon and Up To Date.

BAB: Consults for Medscape, Amgen and GlaxoSmithKline; and receives financial support from Atcor Medical and Gilead.

MJS: Receives financial support from the NIH for participation in the HFN, and from Bayer, Inc.

KLL: Receives financial support from the NIH for participation in the HFN.

GDL: None reported.

MML: Receives financial support from the NIH for participation in the HFN.

JLR: None reported.

DAB: Receives financial support from the NIH for participation in the HFN.

DLM: None reported.

AD: Receives financial support from the NIH for participation in the HFN.

LWS: Receives financial support from the NIH for participation in the HFN.

MMG: Receives financial support from the NIH for participation in the HFN.

EOO: Receives financial support from the NIH; consults for Merck, Novartis and Arbor Pharmaceuticals; currently employed by the Morehouse School of Medicine; has grants pending from the NHLBI and NIMHD; and received lecture fees from Arbor Pharmaceuticals.

CMO: Consults for Roche Diagnostics, Amgen, Novartis, Ikaria, Acetlion Pharma, Heartware, ResMed, Pozen, GE Healthcare, Johnson & Johnson, Gilead, Critical Diagnostics, BG Medicine, Otsuka, Astellas, Novella, Cytokinetics, Capricor; holds stock options with Neurotronik/Intervential Automatics Corporation; edits the journal, American College of Cardiology, and co-owns Cardiology Consulting Associates.

GMF: Receives financial support from the NIH; consults for Novartis, Amgen, Trevena, Roche Diagnostics, Merck, Singulex and BG Medicine; and receives funding from Amgen, Otsuka and Roche Diagnostics.

SRG: None reported.

BAB: Receives financial support from the NIH for participation in the HFN.

SEM: None reported.

JCI: Receives financial support from the NIH for participation in the HFN.

GL: None reported.

JKO: Receives financial support as the Echo Core Lab, royalties for an Echo Lab Manual, and payment for ECHO tutorial DVDs; has been invited as a visiting professor for the Korean Society of Echo, Japanese Society of Echo, Sheba Medical Center in Israel, and Columbia Medical Center in NY; received Echo Core Lab projects from Medtronic for Core Valve, Neochord for Mitral valve, NIH for the Heart Failure Network; and collaborates with Samsung Medical Center, Korea.

MP: Consults for Genzyme, Baxter, Jensen and Bayer; and his financial institution receives financial support from Astra Zeneca, Johnson & Johnson, and Maquet.

RJK: Receives financial support from the NIH as the HFN DCC and MRI Core Lab, and funding for a patent with Northwestern University; and his institution has received a grant from Siemens.

RT: Receives financial support from the NIH for participation in the HFN; consults for Merck, Tibotec—Johnson & Johnson, and Abbott; and has given expert testimony about biomarkers in blood clotting.

EJV: Receives financial support from the NIH for participation in the HFN.

KJA: Receives financial support from the NIH for participation in the HFN.

AFH: Receives financial support from the NIH for participation in the HFN; consults for Astra Zenceca, Corthera, Janseen and BMS; and his institution has received funding from Amylin, Johnson & Johnson and BMS.

AMM: None reported.

EB: Consults for Merck & Co., Daiichi Sankyo, Genzyme, Amorcyte, Medicines Co., MC Communications, Ikaria, CardioRentis, Sanofi Aventis; has received funding (or pending) from Astra Zeneca, Johnson & Johnson, Merck & Co., Sanofi Aventis, Daiichi Sankyo, Glaxo Smith Kline, Bristol Myers Squibb, Beckman Coulter, Roche Diagnostics and Pfizer; has been compensated for lectures for Eli Lilly, Merck, CVRx (no compensation), CV Therapeutics (now Gilead), Daiichi Sankyo, MC Communications, Manarini International, Medscape and Bayer; and has received payment for development of educational presentations from MC Communications.

Figures

Figure 1. CONSORT Diagram

Reasons for study drug discontinuation included withdrawal of consent (placebo n=4, sildenafil n=5), adverse events (placebo n=1, sildenafil n=9), physician decision (placebo n=1, sildenafil n=1) and other (placebo n=2, sildenafil n=5). Note that some patients discontinued study drug for a specific reason but then subsequently withdrew from the study.

Figure 2. Change in peak VO2 from baseline to 24 weeks in placebo and sildenafil-treated patients

Median and interquartile range for the change in peak VO2 from baseline to 24 weeks are shown.