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Updated: Jun 24, 2025
Evaluation of the Cognitive Performance of Hypertensive Patients with Silent Cerebrovascular Lesions
Published on: April 23, 2021
Cerebrovascular Effects of Sildenafil in Small Vessel Disease: The OxHARP Trial
Alastair J S Webb1,2, Jacqueline S Birks3, Karolina A Feakins1
1Wolfson Centre for Prevention of Stroke and Dementia (A.J.S.W., K.A.F., A.L., O.L., C.R.S., J.T.), University of Oxford, United Kingdom.
Insights
Sildenafil did not reduce cerebral pulsatility in patients with small vessel disease but improved cerebrovascular reactivity and perfusion. Further research is needed to see if sildenafil can prevent clinical issues related to this condition.
Area of Science:
- Neurology
- Vascular Medicine
- Pharmacology
Background:
- Cerebral small vessel disease is linked to impaired cerebrovascular function, including reduced cerebrovascular reactivity (CVR) and hypoperfusion.
- Endothelium-targeted drugs like cilostazol may improve these deficits, but the effect of sildenafil, a phosphodiesterase-5 inhibitor, on cerebrovascular dysfunction is unknown.
Purpose of the Study:
- To investigate the efficacy of sildenafil in improving cerebrovascular dysfunction in patients with cerebral small vessel disease.
- To compare the effects of sildenafil and cilostazol on cerebral pulsatility and CVR.
Main Methods:
- The Oxford Haemodynamic Adaptation to Reduce Pulsatility (OxHARP) trial was a randomized, placebo-controlled, 3-way crossover study.
- Participants received sildenafil, cilostazol, or placebo for 3 weeks, with primary outcome being middle cerebral artery pulsatility measured by transcranial ultrasound.
- Secondary outcomes included CVR, cerebral perfusion, and cerebrovascular conductance, assessed via transcranial ultrasound and MRI.
Main Results:
- Sildenafil did not significantly alter cerebral pulsatility compared to placebo or cilostazol, despite increasing blood flow.
- Sildenafil significantly improved CVR (transcranial ultrasound and MRI), cerebral perfusion, and reduced cerebrovascular resistance compared to placebo.
- Both drugs increased headache incidence; cilostazol also increased moderate-severe diarrhea.
Conclusions:
- Sildenafil effectively enhances cerebrovascular reactivity and perfusion in patients with cerebral small vessel disease.
- While not reducing pulsatility, sildenafil's positive effects on CVR and perfusion warrant further investigation for potential clinical benefits in preventing small vessel disease sequelae.
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% CO2 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.
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