Therapeutic benefits of phosphodiesterase-5 inhibition in chronic heart failure: A meta-analysis RENATO DE VECCHIS 1, *, ARTURO CESARO 2 , CARMELINA ARIANO 1 1 Cardiology Unit, Presidio Sanitario Intermedio “Elena d’Aosta”, ASL Napoli 1 Centro, Napoli, Italy 2 Department of Cardiology, Second University of Napoli, Monaldi Hospital, Napoli, Italy *Corresponding author: Dr. Renato De Vecchis, MD; Cardiology Unit, Presidio Sanitario Intermedio “Elena d’Aosta”, via Cagnazzi 29, Napoli c.a.p. 80125, Italy. Home address: Renato De Vecchis, via P. Gaurico 21, Napoli 80125, Italy; Phone: +39 348 331 3530; Fax: +39 081 254 3144-45; E-mail: devecchis.erre@virgilio.it (Received: March 16, 2017; Revised manuscript received: June 9, 2017; Accepted: July 5, 2017) Abstract: Background: Phosphodiesterase-5 inhibitors (PDE5i) have been shown to be beneficial for patients with pulmonary arterial hyperten- sion. However, several studies would have documented a useful effect of PDE5i even for pulmonary hypertension secondary to left-sided chronic heart failure (CHF). Methods: We performed a meta-analysis including randomized controlled trials (RCTs) which had compared PDE5i (mostly sildenafil) and placebo in CHF patients. Results: Fourteen studies enrolling a total of 928 patients were incorporated in the meta-analysis. In heart failure with reduced left ventricular ejection fraction (HFREF), PDE5i, compared to placebo, significantly improved the composite of death and hospitalization (OR = 0.28; 95% CI: 0.10–0.74). They also improved peak VO 2 [difference in means (MD): 3.76; 95% CI: 3.27–4.25], six-minute walking distance test (MD: 22.7 m; 95% CI: 8.19–37.21), and pulmonary arterial systolic pressure (MD: -11.52 mmHg; 95% CI: -15.56 to -7.49). Conversely, in CHF with preserved left ventricular ejection fraction (HFpEF), PDE5i proved not to yield any significant improvement of the investigated outcomes. Conclusions: In HFREF, PDE5i showed beneficial effects on the composite of death and hospitalization, as well as on exercise capacity and pulmonary hemodynamics. Conversely, in HFpEF, no significant clinical, spiroergometric, or hemodynamic improvement was achieved using PDE5i therapy. Keywords: sildenafil, phosphodiesterase-5 inhibitors, heart failure, cardiovascular outcomes, meta-analysis Background The cardinal symptom of heart failure, i.e., the dyspnea, is largely attributable to pulmonary hypertension (PH) and congestion in the pulmonary vasculature [1]. So it is crucial to emphasize the very important role that PH plays in causing the symptoms and the clinical picture of heart failure either right-sided or left-sided or biven- tricular. PH associated with left heart disease (PH- LHD) coincides with the Group 2 of the most recent international classification of the PH [2] (Tables I and II). The favorable effects of phosphodiesterase-5 inhibitors (PDE5i), in particular sildenafil, in the treatment of PH are mainly attributed to the action exerted on the pulmonary arteriolar – precapillary district (so-called “precapillary pulmonary selectivity” of PDE5i) [3, 4]. In other words, the benefit of PDE5i in treating heart failure may originate from their hemodynamic effect for the combined post- and precapillary PH (Cpc-PH), but not for the isolated postcapillary PH (Ipc-PH) [5]. Aims In this study, to evaluate the effects exercised by sildenafil or other PDE5i on some functional, hemodynamic, or clinical endpoints, a number of meta-analyses were separately conducted in patients with chronic heart failure (CHF) with reduced left ventricular ejection fraction (HFREF) or preserved left ventricular ejection fraction (HFpEF), respectively. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium for non-commercial purposes, provided the original author and source are credited. Interventional Medicine & Applied Science, Vol. 9 (3), pp. 123–135 (2017) ORIGINAL PAPER DOI: 10.1556/1646.9.2017.26 123 ISSN 2061-1617 © 2017 The Author(s)