Therapeutic potential of sildenafil in patients with heart failure and reactive pulmonary hypertension

Abstract

The PDE5 inhibitor sildenafil belongs to the established and approved therapies in pulmonary arterial hypertension (PAH) [1]. While PAH is a relatively rare disease, pulmonary hypertension (PH) due to left heart disease (postcapillary PH; group 2 of the Dana Point classification) is a frequent phenomenon, particularly in patients with congestive heart failure (CHF) [2]. Importantly, in patients with left heart disease the presence of PH and an impaired right ventricular (RV) function, indicating biventricular heart failure, is associated with a particularly poor prognosis [2]. Targeted PAH therapy is currently not recommended in postcapillary PH [1]. However, in patients with severe CHF who present with impaired RV function and PH despite optimized medical therapy, additional treatment of PH may improve exercise tolerance and outcome. Small uncontrolled studies indicate that sildenafil may be beneficial in patientswith CHF [3,4], but these studies did not consider the severity of PH and the extent of prevs. postcapillary pressure elevation. In this context, the current ESC/ERS guidelines on PH distinguish between passive and reactive postcapillary PH, depending on the transpulmonary gradient (TPG). The therapeutic consequence of this hemodynamic definition remains unclear, however patients with a predominant precapillary component of PH may benefit from targeted therapy. In the context of compassionate care, 9 highly selected patients with biventricular heart failure (LVEF b40%; impaired RV function, defined as TAPSE b17 mm; NYHA class III/IV) and reactive PH (PAPmean ≥25 mmHg), characterized by elevated left ventricular filling pressures (PCWP/LVEDP ≥15 mmHg) and an increased TPG (N12 mmHg) were treatedwith sildenafil (20 mg tid) in addition to pre-existing, guidelineoriented treatment of CHF which had been on a stable dose for at least one month. In all patients, right heart catheterization was performed before and after initiation of sildenafil. Additionally, echocardiographic parameters, serummarkers (NTproBNP) and exercise capacity (6MWD) were recorded. The mean age of the patients was 67.4±2.2 years (range 64–75 years). 7 patients were initially in NYHA class III, 2 patients in NYHA class IV. All patients had received best medical treatment for CHF according to current guidelines (β-blockers, ACE inhibitors and/or AT1-receptor antagonists, aldosterone antagonists, diuretics). The mean follow-up after initiation of sildenafil was 19.7±6.9 weeks. The effects of sildenafil on invasive hemodynamics, echocardiographic parameters, serum markers and exercise capacity are summarized in Table 1. Add-on sildenafil treatment particularly resulted in a significant decrease of PAPmean, TPG and PVR as well as a decrease of PCWP and a trend towards decreased SVR. These hemodynamic changes were associated with an improvement of prognostically relevant parameters including an increase of RV function, decreased right atrial and right ventricular dimensions, a reduction of NTproBNP serum levels, and a substantial improvement of the 6MWD by 91±54m. Consistently, the patients clinical status improved markedly, and there were no significant adverse events. In highly selected patients with CHF, PH and impaired RV function, who were characterized by a predominant precapillary component of PH, the PDE5 inhibitor sildenafil significantly improved clinical symptoms, exercise capacity and prognostically relevant parameters. Although these findings suggest a beneficial effect in this special group of patients, they have to be interpreted with great caution. While the extent of the precapillary component in such patients is highly variable and depends on the volume load, it is important to note that all measurements were performed in fully compensated condition, so that the body weight remained unchanged between the first and follow-up hemodynamic measurements (75.0±6.4 vs. 74.8±6.0 kg, n.s.). Furthermore, previous mortality data exist on the effects of pulmonary vasodilator therapy in patients with CHF. In the FIRST trial, treatment with epoprostenol was associated with a higher mortality compared to placebo [5], indicating that pulmonary vasodilationmay be detrimental in CHF. However, there are important differences between this observation and the findings presented