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 ₂ 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; P =0.18), or versus cilostazol (-0.01, -0.04 to 0.02; P =0.36), despite increased blood flow (∆ peak systolic velocity, 6.3 cm/s, 3.5-9.07; P <0.001; ∆ end-diastolic velocity, 1.98, 0.66-3.29; P =0.004). Secondary outcomes improved on sildenafil versus placebo for CVR-transcranial ultrasound (0.83 cm/s per mm Hg, 0.23-1.42; P =0.007), CVR-WMH (0.07, 0-0.14; P =0.043), CVR-normal-appearing white matter (0.06, 0.00-0.12; P =0.048), perfusion (WMH: 1.82 mL/100 g per minute, 0.5-3.15; P =0.008; and normal-appearing white matter, 2.12, 0.66-3.6; P =0.006) and cerebrovascular resistance (sildenafil-placebo: 0.08, 0.05-0.10; P =4.9×10 ^-8 ; cilostazol-placebo, 0.06, 0.03-0.09; P =5.1×10 ^-5 ). Both drugs increased headaches ( P =1.1×10 ^-4 ), while cilostazol increased moderate-severe diarrhea ( P =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.
Competing Interests: A.J.S. Webb has received related funding from the Wellcome Trust, Alzheimer Society and British Heart Foundation and has received consulting fees from Woolsey Pharmaceuticals. J. Dawson is on advisory boards and has received speakers fees from AstraZeneca and Medtronic. D.J. Werring reports grant funding from the Stroke Association and British Heart Foundation; speaking honoraria from Bayer; speaking and chairing honoraria from Alexion and NovoNordisk; and consultancy fees from Alnylam, Bayer and NovoNordisk. The other authors report no conflicts.