Sildenafil therapy in patients with sickle cell disease and pulmonary hypertension

Abstract

SummaryPulmonary hypertension is a frequent complication of sickle cell disease that is associated with haemolysis, impaired nitric oxide bioavailability and high mortality. We sought to evaluate the safety and efficacy of selective pulmonary vasodilators and antiproliferative agents in this at‐risk population. After optimising sickle cell disease therapy to stabilise haemoglobin and fetal haemoglobin levels, we evaluated the safety and efficacy of sildenafil in 12 patients with sickle cell disease and pulmonary hypertension. Sildenafil therapy (mean duration 6 ± 1 months) decreased the estimated pulmonary artery systolic pressure [50 ± 4 to 41 ± 3 mmHg; difference 9 mmHg, 95% confidence interval (CI): 0·3–17, P = 0·043] and increased the 6‐min walk distance (384 ± 30 to 462 ± 28 m; difference 78 m, 95% CI: 40–117, P = 0·0012). Transient headaches occurred in two patients and transient eye‐lid oedema in four patients. No episodes of priapism occurred in the three men in the study; two of them were on chronic exchange transfusions and one had erectile dysfunction. In conclusion: (1) sickle cell disease patients with anaemia and pulmonary hypertension have significant exercise limitation; (2) the 6‐min walk distance may be a valid endpoint in this population; (3) therapy with sildenafil appears safe and improves pulmonary hypertension and exercise capacity. Additional phase I studies in males with sickle cell disease followed by phase II/III placebo controlled trials evaluating the safety and efficacy of sildenafil therapy in sickle cell disease patients with pulmonary hypertension are warranted.

Hospitalization for pain in patients with sickle cell disease treated with sildenafil for elevated TRV and low exercise capacity

“…on April 3, 2019. by guest www.bloodjournal.org From prevented or minimized the development of pain episodes requiring hospitalization is unknown. 20 In the current 16-week trial, sildenafil therapy did not improve exercise capacity nor did it decrease Doppler-defined estimated right ventricular systolic pressure, as had been suggested in previous nonrandomized, uncontrolled studies. It is possible that by increasing pain, sildenafil interfered with subjects' ability to perform the 6MW test, although post hoc analysis did not demonstrate a relationship between report of pain by Brief Pain Inventory and 6MW distance.…”

“…This observation of an increased rate of subjects experiencing serious SCD pain episodes was not reported previously in 2 open-label studies, most likely due to the absence of control groups or to differences in patient selection. 19,20 In one of the prior studies, subjects underwent maximization of SCD specific therapy with hydroxyurea and/or red blood cell transfusions before initiation of sildenafil. Whether this *Statistics for the 6MWD test were based on an ANCOVA model with treatment as a fixed effect and baseline 6MWD distance, TRV stratum, and study site as covariates.…”

“…18 Two uncontrolled case series have suggested that sildenafil treatment for patients with SCD and an increased right ventricular systolic pressure estimated by an increased TRV appeared to be well tolerated, improved exercise capacity, and decreased TRV. 19,20 Based on these observations, we sought to determine whether sildenafil would also be efficacious in patients with SCD and an elevated TRV. We designed a double-blind, placebo-controlled trial to assess the safety, tolerability, and efficacy of sildenafil in patients with SCD who had both an elevated TRV and decreased exercise capacity.…”

Pulmonary Complications of Sickle Cell Disease

“…NO exerts its vascular effects principally by binding and activating soluble guanylyl cyclase, boosting intracellular cyclic guanosine monophosphate (cGMP) levels (87,88). In pulmonary vasculature, this is counterbalanced by the phosphodiesterase-5 (PDE-5) enzyme, which hydrolyzes cGMP.…”

Genética das doenças hematológicas: as hemoglobinopatias hereditárias

“…81 Certain agents that reduce production of ROS, 81 such as xanthine oxidase, or others that reduce cell-endothelium adhesion, may be of benefit. Sildenafil amplifies the response of vascular musculature to NO and is being used in clinical trials for the treatment of pulmonary hypertension in SCA, 82 but the greatest concern related to the use of this type of medication is the possibility of male patients developing priapism. Recently, Canalli et al demonstrated that in vitro adhesion of neutrophils to fibronectin and the ICAM-1 protein, which is increased in SCD, is significantly reduced in the presence of pharmacological NO donation agents, such us sodium nitroprusside and diethylamine NONOate (DEANO).…”