Cerebrovascular Effects of Sildenafil in Small Vessel Disease: The OxHARP Trial

Background: Vascular cognitive impairment due to cerebral small vessel disease is associated with cerebral pulsatility, white matter hypoperfusion, and reduced cerebrovascular reactivity (CVR), and is potentially improved by endothelium-targeted drugs such as cilostazol. Whether sildenafil, a phosphodiesterase-5 inhibitor, improves cerebrovascular dysfunction is unknown.

Methods: OxHARP trial (Oxford Haemodynamic Adaptation to Reduce Pulsatility) was a double-blind, randomized, placebo-controlled, 3-way crossover trial after nonembolic cerebrovascular events with mild-moderate white matter hyperintensities (WMH), the most prevalent manifestation of cerebral small vessel disease. The primary outcome assessed the superiority of 3 weeks of sildenafil 50 mg thrice daily versus placebo (mixed-effect linear models) on middle cerebral artery pulsatility, derived from peak systolic and end-diastolic velocities (transcranial ultrasound), with noninferiority to cilostazol 100 mg twice daily. Secondary end points included the following: cerebrovascular reactivity during inhalation of air, 4% and 6% CO on transcranial ultrasound (transcranial ultrasound-CVR); blood oxygen-level dependent-magnetic resonance imaging within WMH (CVR-WMH) and normal-appearing white matter (CVR-normal-appearing white matter); cerebral perfusion by arterial spin labeling (magnetic resonance imaging pseudocontinuous arterial spin labeling); and resistance by cerebrovascular conductance. Adverse effects were compared by Cochran Q.

Results: In 65/75 (87%) patients (median, 70 years;79% male) with valid primary outcome data, cerebral pulsatility was unchanged on sildenafil versus placebo (0.02, -0.01 to 0.05; =0.18), or versus cilostazol (-0.01, -0.04 to 0.02; =0.36), despite increased blood flow (∆ peak systolic velocity, 6.3 cm/s, 3.5-9.07; <0.001; ∆ end-diastolic velocity, 1.98, 0.66-3.29; =0.004). Secondary outcomes improved on sildenafil versus placebo for CVR-transcranial ultrasound (0.83 cm/s per mm Hg, 0.23-1.42; =0.007), CVR-WMH (0.07, 0-0.14; =0.043), CVR-normal-appearing white matter (0.06, 0.00-0.12; =0.048), perfusion (WMH: 1.82 mL/100 g per minute, 0.5-3.15; =0.008; and normal-appearing white matter, 2.12, 0.66-3.6; =0.006) and cerebrovascular resistance (sildenafil-placebo: 0.08, 0.05-0.10; =4.9×10; cilostazol-placebo, 0.06, 0.03-0.09; =5.1×10). Both drugs increased headaches (=1.1×10), while cilostazol increased moderate-severe diarrhea (=0.013).

Conclusions: Sildenafil did not reduce pulsatility but increased cerebrovascular reactivity and perfusion. Sildenafil merits further study to determine whether it prevents the clinical sequelae of small vessel disease.

Registration: URL: https://www.clinicaltrials.gov/study/NCT03855332; Unique identifier: NCT03855332.