Sildenafil for improving outcomes in patients with corrected valvular heart disease and persistent pulmonary hypertension: a multicenter, double-blind, randomized clinical trial

Abstract

AimsWe aimed to determine whether treatment with sildenafil improves outcomes of patients with persistent pulmonary hypertension (PH) after correction of valvular heart disease (VHD).Methods and resultsThe sildenafil for improving outcomes after valvular correction (SIOVAC) study was a multricentric, randomized, parallel, and placebo-controlled trial that enrolled stable adults with mean pulmonary artery pressure ≥ 30 mmHg who had undergone a successful valve replacement or repair procedure at least 1 year before inclusion. We assigned 200 patients to receive sildenafil (40 mg three times daily, n = 104) or placebo (n = 96) for 6 months. The primary endpoint was the composite clinical score combining death, hospital admission for heart failure (HF), change in functional class, and patient global self-assessment. Only 27 patients receiving sildenafil improved their composite clinical score, as compared with 44 patients receiving placebo; in contrast 33 patients in the sildenafil group worsened their composite score, as compared with 14 in the placebo group [odds ratio 0.39; 95% confidence interval (CI) 0.22–0.67; P < 0.001]. The Kaplan–Meier estimates for survival without admission due to HF were 0.76 and 0.86 in the sildenafil and placebo groups, respectively (hazard ratio 2.0, 95% CI = 1.0–4.0; log-rank P = 0.044). Changes in 6-min walk test distance, natriuretic peptides, and Doppler-derived systolic pulmonary pressure were similar in both groups.ConclusionTreatment with sildenafil in patients with persistent PH after successfully corrected VHD is associated to worse clinical outcomes than placebo. Off-label usage of sildenafil for treating this source of left heart disease PH should be avoided.The trial is registered with ClinicalTrials.gov, number NCT00862043.

Haemodynamic mechanisms and long‐term prognostic impact of pulmonary hypertension in patients with severe aortic stenosis undergoing valve replacement

“…Importantly, there is no evidence for a beneficial effect of PAH‐specific therapies for the management of patients with PH due to left heart disease; the opposite may even be the case . Very recently, a randomized trial evaluating the effect of the phosphodiesterase‐5 inhibitor sildenafil in patients with persistent PH several months after valve replacement/repair (median mPAP 39 mmHg, median PVR 3.4 WU) found worse clinical outcomes (death, hospital admission, worsening functional class, global symptom burden) in patients treated with sildenafil compared to placebo . The study included patients with both IpcPH and CpcPH but the effect of sildenafil was similar in both groups.…”

Pulmonary hypertension associated with left heart disease: Updated Recommendations of the Cologne Consensus Conference 2018

“…Recent examples include the ENABLE and MELODY-1 studies, showing that the two ERAs bosentan and macitentan failed to improve clinical measures or outcome in patients with HFrEF or HFpEF, respectively, and in both studies ERA therapy was associated with an increased occurrence of fluid retention [91,92]. In addition, the SIOVAC trial has shown that the use of sildenafil was associated with an increased risk of clinical deterioration and worse outcome versus placebo in patients with PH after VHD intervention (aortic, mitral, or tricuspid) [93], thus indicating that such therapies may even be harmful in the context of LHD. When viewed together, there is currently no new evidence that would justify the general use of PAH therapies in PH-LHD, and potentially harmful effects have to be considered.…”

Pulmonary hypertension in chronic heart failure: definitions, advances, and unanswered issues

“…43 Recently, the SIOVAC trial results reported worse outcomes with sildenafil in patients with persistent PH after correction of valvular disease. 44 These last two studies suggest that sildenafil's induced lung vasodilatation increased pulmonary venous return and LV filling pressure causing haemodynamic damage to a flow-sensitive failing heart. Furthermore, sildenafil might also lead to hypoxemia in CHF by increasing ventilation-perfusion mismatching.…”

“…However, the most important randomized trial that tested the administration of PDE5‐I (sildenafil) in 216 patients with HFpEF for 24 weeks did not show any improvement in exercise capacity or clinical status . Recently, the SIOVAC trial results reported worse outcomes with sildenafil in patients with persistent PH after correction of valvular disease . These last two studies suggest that sildenafil's induced lung vasodilatation increased pulmonary venous return and LV filling pressure causing haemodynamic damage to a flow‐sensitive failing heart.…”