Design of a randomised, double-blind, crossover, placebo-controlled trial of effects of sildenafil on cerebrovascular function in small vessel disease: Oxford haemodynamic adaptation to reduce pulsatility trial (OxHARP).

Alastair Webb,Amy Lawson,David Werring,Alex Rothman,Jesse Dawson,Karolina Wartolowska

doi:10.1177/23969873211026698

Abstract

BackgroundCerebral small vessel disease (SVD) is associated with increased cerebrovascular pulsatility, endothelial dysfunction, and impaired vascular reactivity. Vasodilating phosphodiesterase inhibitors may improve cardiovascular pulsatility and reactivity, and potentially reduce progression of SVD.Hypothesis: Sildenafil, a PDE5 inhibitor, will reduce cerebrovascular pulsatility and increase cerebrovascular reactivity compared to placebo, and is non-inferior to cilostazol, a PDE3 inhibitor.MethodsOxHARP is a randomised, double-blind, crossover trial of sildenafil 50 mg thrice daily, cilostazol 100 mg twice daily and placebo in 75 patients with mild to moderate small vessel disease and a previous lacunar or cryptogenic stroke or TIA. Participants undergo a physiological assessment at baseline and on each treatment, including transcranial Doppler ultrasound (TCD, DWL DopplerBox) to assess cerebrovascular pulsatility and reactivity to 4–6% carbon dioxide. In up to 60 patients, cerebrovascular pulsatility, perfusion and reactivity will also be assessed by MRI.Outcome measuresThe primary outcome is difference in middle cerebral artery pulsatility (Gosling’s Pulsatility Index, PI) after 3 weeks of sildenafil versus placebo. Secondary outcomes including non-inferiority of sildenafil vs cilostazol in effects on PI, percentage increase in MCA blood flow velocity and BOLD-fMRI response during inhalation of 4–6% carbon dioxide.DiscussionReduction in cerebral pulsatility and increased cerebrovascular reactivity during treatment with sildenafil would indicate potential benefit to prevent progression of SVD, suggesting a need for trials with clinical outcomes.Trial Registration OxHARP is registered with ClinicalTrials.org, NCT03855332

Highlights

Chronic injury to the small vessels of the brain (‘small vessel disease’) is associated with acute lacunar stroke,[1] progressive cognitive decline,[2] late-onset refractory depression,[3] functional impairment in daily living[4] and increased mortality.[5]
Small vessel disease is associated with endothelial dysfunction, demonstrated by impaired cerebrovascular reactivity and breakdown of the blood-brain barrier.[10]
We aim to test the effect of sildenafil on cerebral pulsatility assessed by transcranial ultrasound (TCD) and reactivity compared to placebo, and its non-inferiority compared to cilostazol

Summary

Introduction

Chronic injury to the small vessels of the brain (‘small vessel disease’) is associated with acute lacunar stroke,[1] progressive cognitive decline,[2] late-onset refractory depression,[3] functional impairment in daily living[4] and increased mortality.[5]. The resulting enhanced pulsatility reaching the low resistance small vessels in the brain may cause increased shear stress during systole and potential hypoperfusion of tissues during diastole.[11] Increased aortic pulsatility may be modifiable by vasodilating medications that delay the site and severity of wave reflection Such medications may act upon muscular conduit vessels (distal internal carotid or middle cerebral arteries (MCA)) to increase elasticity, improve dampening of the aortic waveform and reducing pulsatility at distal vessels. Phosphodiesterase inhibitors such as sildenafil (a PDE5 inhibitor) and cilostazol (a PDE3 inhibitor) enhance the cGMP pathways downstream of nitric oxide-dependent endothelial signalling, potentially reducing wave reflection and enhancing cerebrovascular reactivity, but the effect of sildenafil on the intracranial vessels and brain vasculature has not been adequately assessed. We aim to test the effect of sildenafil on cerebral pulsatility assessed by transcranial ultrasound (TCD) and reactivity compared to placebo, and its non-inferiority compared to cilostazol

Study design

Discussion and conclusions

Findings

Ethical approval