Webb, A., Werring, D., Dawson, J. et al. (3 more authors) (2021) 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). European Stroke Journal, 6 (3). pp. 283-290. ISSN 2396-9873
Abstract
Background
Cerebral 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.
Methods
OxHARP 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 measures
The 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.
Discussion
Reduction 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
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | © European Stroke Organisation 2021. This article is distributed under the terms of the Creative Commons Attribution 4.0 License (https://creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). |
Keywords: | Vasodilator; protocol; cerebral pulsatility; cerebral reactivity; small vessel disease |
Dates: |
|
Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Sheffield Teaching Hospitals |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 08 Nov 2021 12:49 |
Last Modified: | 08 Nov 2021 12:49 |
Status: | Published |
Publisher: | SAGE Publications |
Refereed: | Yes |
Identification Number: | 10.1177/23969873211026698 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:180114 |