Phosphodiesterase-5 Inhibitors Improve Clinical Outcomes, Exercise Capacity and Pulmonary Hemodynamics in Patients With Heart Failure With Reduced Left Ventricular Ejection Fraction: A Meta-Analysis

Background: Several studies have compared the use of phosphodiesterase-5 (PDE5) inhibitors sildenafil or udenafil with the placebo in patients suffering from pulmonary hypertension (PH) due to left chronic heart failure (CHF), corresponding to group 2 (PH due to left heart disease) of the PH classification (according to 2015 ESC/ERS guidelines for the diagnosis and treatment of PH). The results of the use of PDE5 inhibitors in the PH due to left heart disease were inconsistent and heterogeneous. Therefore, we carried out a meta-analysis to assess the effect of PDE5 inhibitors in this clinical setting, i.e., patients with left CHF.

Methods: A systematic search was conducted using the PubMed and Embase electronic archives. Studies had to be prospective randomized controlled trials (RCTs). In each of the RCTs admitted to meta-analysis, a comparison was made between a group of CHF patients taking a PDE5 inhibitor and a second group assigned a placebo. Studies were incorporated in the meta-analysis provided that they had sufficient information about two or more of the following clinical, ergospirometric or hemodynamic outcomes: the composite of all-cause death and hospitalization, adverse events, peak VO₂, 6-min walking distance (6MWD), left ventricular ejection fraction (LVEF), E/e' ratio, mean pulmonary arterial pressure (mPAP), pulmonary arterial systolic pressure (PASP), and pulmonary vascular resistance (PVR).

Results: Fourteen studies enrolling a total of 928 patients were incorporated in the meta-analysis. Among them,13 were RCTs and one was a subgroup analysis. Among patients with CHF with reduced left ventricular ejection fraction (HFREF, n = 555), a significant benefit was conferred by PDE5 inhibitors against the risk of the composite endpoint of death and hospitalizations (odds ratio (OR): 0.28; 95% confidence interval (CI): 0.10 - 0.74; P = 0.03). Furthermore, among HFREF patients, PDE5 inhibitors were associated with a significant improvement in peak VO₂ (difference in means (MD): 3.76 mL/min/kg; 95% CI: 3.27 - 4.25) as well as in 6MWD (MD: 22.7 m; 95% CI: 8.19 - 37.21) and LVEF (MD: 4.30%; 95% CI: 2.18% to 6.42%). For patients with HFREF, PDE5 inhibitors caused a non-significant reduction in mPAP, while PASP was significantly reduced (MD: -11.52 mm Hg; 95% CI: -15.56 to -7.49; P < 0.001). By contrast, in the RCTs of patients with CHF with preserved left ventricular ejection fraction (HFpEF, n = 373), no benefit ensued from PDE5 inhibitor use regarding all of the investigated clinical, ergospirometric or hemodynamic endpoints.

Conclusions: PDE5 inhibitors improved clinical outcomes, exercise capacity and pulmonary hemodynamics in patients with HFREF, but not in HFpEF. However, considering the relatively small size of the HFpEF subset enrolled so far in the RCTs that explored the PDE5 inhibitor effects, further research in this field is undoubtedly warranted.