Effects of sildenafil on symptoms and exercise capacity for heart failure with reduced ejection fraction and pulmonary hypertension (the SilHF study): a randomized placebo-controlled multicentre trial.

AIMS: Pulmonary hypertension (PHT) may complicate heart failure with reduced ejection fraction (HFrEF) and is associated with a substantial symptom burden and poor prognosis. Sildenafil, a phosphodiesterase-5 (PDE-5) inhibitor, might have beneficial effects on pulmonary haemodynamics, cardiac function and exercise capacity in HFrEF and PHT. The aim of this study was to determine the safety, tolerability, and efficacy of sildenafil in patients with HFrEF and indirect evidence of PHT. METHODS AND RESULTS: The Sildenafil in Heart Failure (SilHF) trial was an investigator-led, randomized, multinational trial in which patients with HFrEF and a pulmonary artery systolic pressure (PASP) ≥40 mmHg by echocardiography were randomly assigned in a 2:1 ratio to receive sildenafil (up to 40 mg three times/day) or placebo. The co-primary endpoints were improvement in patient global assessment by visual analogue scale and in the 6-min walk test at 24 weeks. The planned sample size was 210 participants but, due to problems with supplying sildenafil/placebo and recruitment, only 69 patients (11 women, median age 68 (interquartile range [IQR] 62-74) years, median left ventricular ejection fraction 29% (IQR 24-35), median PASP 45 (IQR 42-55) mmHg) were included. Compared to placebo, sildenafil did not improve symptoms, quality of life, PASP or walk test distance. Sildenafil was generally well tolerated, but those assigned to sildenafil had numerically more serious adverse events (33% vs. 21%). CONCLUSION: Compared to placebo, sildenafil did not improve symptoms, quality of life or exercise capacity in patients with HFrEF and PHT.

Relation of Longitudinal Changes in Quality of Life Assessments to Changes in Functional Capacity in Patients With Heart Failure With and Without Anemia.

Clinical status in heart failure is conventionally assessed by the physician's evaluation, patients' own perception of their symptoms, quality of life (QoL) tools, and a measure of functional capacity. These aspects can be measured with tools such as the New York Heart Association functional class, QoL tools such as the EuropeanQoL-5 dimension, the Kansas City Cardiomyopathy Questionnaire, patient global assessment (PGA), and by 6-minute walk test (6MWT), respectively. The ferric carboxymaltose in patients with heart failure and iron deficiency (FAIR-HF) trial demonstrated that treatment with intravenous ferric carboxymaltose in iron-deficient patients with symptomatic heart failure with reduced left ventricular function, significantly improved all 5 outcome measures. This analysis assessed the correlations between the longitudinal changes in the measures of clinical status, as measured by QoL tools and the changes in the measures of functional capacity as measured by the 6MWT. This analysis used the database from the FAIR-HF trial, which randomized 459 patients with chronic heart failure (reduced left ventricular ejection fraction) and iron deficiency, with or without anemia to ferrous carboxymaltose or placebo. The degree of correlation between QoL tools and the 6MWT was assessed at 4, 12, and 24 weeks. The data demonstrate highly significant correlations between QoL and functional capacity, as measured by the 6MWT, at all time points (p <0.001). Changes in PGA, Kansas City Cardiomyopathy Questionnaire, and EuroQoL-5D correlated increasingly over time with changes in 6MWT performance. Interestingly, the strongest correlation at 24 weeks is for the PGA, which is a simple numerical scale (r = -0.57, p <0.001). This analysis provides evidence that QoL assessment show a significant correlation with functional capacity, as measured by the 6MWT. The strength of these correlations increased over time.

Sildenafil in Heart failure (SilHF). An investigator-initiated multinational randomized controlled clinical trial: rationale and design.

AIMS: Heart failure (HF) is a major clinical problem and, despite advances in both pharmacological and device therapy, the mortality remains high and quality of life poor. Over the last decade there has been growing interest in using phosphodiesterase-5 (PDE-5) inhibitors in HF associated with group 2 pulmonary hypertension (PH), with benefits reported on pulmonary haemodynamic and functional status in single-centre trials Methods The Sildenafil in Heart Failure (SilHF) trial is a randomized, placebo-controlled multinational trial designed to assess efficacy and tolerability of PDE-5 inhibition with sildenafil (target dose 40 mg three times per day) in 210 patients with HF, New York Heart Association (NYHA) functional class II or III, and evidence of group 2 PH. The co-primary endpoints are patient global assessment and the 6 min walk test. Secondary endpoints include NYHA functional class and the quality of life tools Euro QoL 5D and the Kansas City questionnaire. Patients will be followed up for 6 months. PERSPECTIVE: The authors hypothesize that PDE-5 inhibition can improve exercise capacity and symptoms with acceptable tolerability in patients with HF and group 2 PH.