Incidence of subdural hematoma in patients with pulmonary arterial hypertension (PAH) in two randomized controlled clinical trials

Background: Recent reports have emerged of increased incidence of subdural haematoma in patients with PAH, a serious adverse event with high mortality and morbidity. We evaluate the event rate in two randomized controlled trials, SUPER-1/2 and PACES-1/2. Methods: In SUPER-1, 277 patients (IPAH, CTD-, CHD-PAH, WHO FC II-IV, mean baseline PVR 952.0 dyne.s/cm*5) naive to targeted therapy received placebo or sildenafil 20/40/80mg TID for 12 weeks. In the open-label extension (OLE) phase patients were up-titrated (as tolerated) to 80mg TID. In PACES-1, 267 patients (IPAH, CTD-PAH, WHO FC I-IV, mean baseline PVR 810.5 dyne.s/cm*5) stable on IV epoprostenol received placebo or sildenafil (up-titrated to 80mg TID, as tolerated) for 16 weeks. Patients in both OLE trials received sildenafil for ≥3 years. Treatment with conventional agents (anticoagulants, diuretics, digoxin, oxygen, calcium-channel blockers) was permitted. We determined the annual event rate of subdural haematoma by treatment exposure in person-years. Patient days on therapy does not include days on placebo. Results: 2 patients experienced subdural haematoma, both during OLE; one received placebo in PACES-1, one sildenafil 40mg TID in SUPER-1. Patients were female, aged 58 and 62 years, diagnosed with IPAH, WHO FC III, mean PVR 557 (PACES-1) and 1073 dyne.s/cm*5 (SUPER-1) at baseline. Both patients received oral anticoagulants. In SUPER-1 and PACES-1, 73 and 82% of patients were on anticoagulants, respectively. Incidence of subdural haematoma in these 2 studies was 0.0015 events/ patient-year. Conclusion: Subdural haematoma is a rare event in PAH patients in these 2 randomized controlled trials.