The effects of phosphodiesterase 5 inhibition on hemodynamics, functional status and survival in advanced heart failure and pulmonary hypertension: A case–control study

Abstract

Background

The goal was to examine the hemodynamic and clinical effects of long-term therapy with PDE5 inhibitor sildenafil (SILD) in patients with advanced, pre-transplant heart failure (HF) and severe pulmonary hypertension (PH), in comparison to a similar control group (CON).

Methods

In this non-randomized, retrospective case–control study, 32 middle-aged patients (81% males) with advanced systolic HF (80% ≥ NYHA III, 56% ischemic) and severe pre-capillary PH (transpulmonary pressure gradient > 15 mm Hg) were studied before and after initiation of SILD (dose 73 ± 25 mg/day) and were compared to 15 CON patients, matched for key clinical characteristics (including PH severity, age and co-morbidities), not exposed to SILD. Changes at 3 months and the long-term outcome were compared between groups.

Results

SILD significantly reduced pulmonary vascular resistance (− 32% vs. baseline), transpulmonary gradient (− 25%) and increased cardiac output (+ 15%) compared to controls, without affecting systemic or ventricular filling pressures. SILD-treated subjects experienced an improvement in NYHA class and had a steady body weight which contrasted with significant weight loss in the CON group (by − 4.8%, absolutely by 4.3 ± 6 kg). During follow-up (median 349 days from baseline), 60% of patients underwent heart transplantation. Two patients in CON group had severe post-transplant failure of the right ventricle, none in SILD group. Overall pre- and peritransplant survival (censored 30 days after transplantation) was significantly better in SILD than CON group (93.7 vs 60%, p = 0.0048).

Conclusions

In patients with advanced HF and severe PH, SILD therapy has beneficial effects on hemodynamics, clinical status, cardiac cachexia, and contributes to improved peri-transplant survival.

Introduction

Pulmonary hypertension (PH) develops in 60% of patients with moderate-to-severe heart failure (HF) [1], [2] and is predominantly a consequence of elevated left atrial pressure transmitted backward into pulmonary circulation. However, structural remodelling [3] and endothelial dysfunction [4], [5] in the pulmonary vascular tree result in an increase of pulmonary vascular resistance in some HF patients, leading to severe PH that is “out-of proportion” to left atrial pressure. By overloading the right ventricle, PH causes right ventricular dysfunction and promotes the transition of left heart disease into biventricular failure which has high mortality [2]. Increased pulmonary vascular resistance, particularly if not reversible with a vasodilator challenge, is a crucial predictor of poor results of heart transplantation [6]. The underlying cause of such an adverse outcome is mainly acute post-transplant failure of the right ventricle of the graft suddenly exposed to vascular bed with elevated resistance [6]. Management of PH in the heart transplant candidates is therefore an issue of a critical importance.

Experimental animal studies have demonstrated that phosphodiesterase 5 (PDE5) is upregulated in the pulmonary vasculature in the HF state [7]. The inhibition of PDE5 enhances attenuated cGMP signalling and causes pulmonary vasodilatation in patients with HF and PH [5]. In several small clinical studies, long-term therapy with PDE5 inhibitor sildenafil was shown to decrease pulmonary vascular resistance, increase right ventricular function and improve exercise tolerance in patients with moderate heart failure without having serious adverse effects [8], [9]. Based on these positive preliminary findings, many heart transplant centers adopted off-label use of sildenafil in selected heart transplant candidates with severe PH as a salvage approach to achieve transplantability [10], [11], [12], [13], [14], despite the fact that long-term, randomized outcome studies are not available. In this study, we report on the hemodynamics and clinical course of the largest ever-published cohort of sildenafil-treated advanced HF patients and severe PH who are compared to similar control patients without PDE5 inhibitor therapy.