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

Abstract

Aims: We 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 results: The 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.

Conclusion: Treatment 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.

Figure 1

Flow of patients. Asterisk indicates one patient died due to heart failure 20 days after the 6-month visit and was adjudicated as death.

Figure 2

Primary endpoint. The composite clinical score accounts for the combination of death due to any cause, hospitalization due to heart failure requiring intravenous diuretic treatment, change in the World Health Organisation (WHO) functional class or relevant changes in the patient global self-assessment. Total bars show the proportion of patients in each category, stacked bars show the criterion used to adjudication to each category, and the table shows the number of patients. Data are shown for the full analysis set. Odds ratio calculated using ordinal logistic regression under the proportionality assumption.

Figure 3

Key secondary endpoints. (A) Kaplan–Meier analysis for the incidence of major clinical events (any-cause mortality or admission for heart failure requiring intravenous diuretics). Hazard ratio calculated by proportional-hazard Cox model. P-value calculated by the log-rank test. (B) Identical analysis for the incidence of admission for heart failure. (C) Number of hospitalizations due to heart failure. Odds ratio and P-value calculated using ordinal logistic regression. (D) Changes from baseline to 6 months in the plasma levels of brain natriuretic peptide. (E) Proportion of patients in each category of World Health Organisation (WHO) functional class. Odds ratio and P-value calculated using a cumulative link mixed model for ordinal responses. (F) Changes from baseline in the 6-min walk test distance. (G) Changes in systolic pulmonary artery pressure as measured using Doppler-echocardiography. In (D, F, and G) the dots represent the least-square adjusted means, the bars represent their standard error, and P-values are shown for the effect of the interaction between visit (baseline or 6-month) and treatment group in a repeated-measure mixed-model design.

Figure 4

Interaction analysis. Odds ratios and P-values calculated using logistic-regression accounting for their interaction with the treatment group after binary categorization. PCWP, pulmonary capillary wedge pressure; PMAP, pulmonary mean arterial pressure; LV, left ventricle; PVR, pulmonary vascular resistance; TAPSE, tricuspid annular plane systolic excursion.

Figure 5

Secondary magnetic resonance imaging endpoints. Changes in end-diastolic volume index (EDVI; A and C) and end-systolic volume index (ESVI; B and D) for the right ventricle (RV; A and B) and the left ventricle (LV; C and D). Least-square (LS) adjusted means and standard error are shown for patients undergoing magnetic resonance imaging (n = 47 at baseline; n = 36 at follow-up). Symbols as in Figure 3D, F, and G.

Take home figure

Sildenafil is associated to impaired clinical outcomes, as demonstrated by a higher proportion of patients who worsen their clinical status (upper panel) mainly due to a higher risk of readmission due to heart failure in the following six months (lower panel).