{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T16:22:41Z","timestamp":1792513361109,"version":"4.5.0"},"reference-count":39,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2024,7,5]],"date-time":"2024-07-05T00:00:00Z","timestamp":1720137600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2024,7,5]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:sub>2<\/jats:sub>\n                      on transcranial ultrasound (transcranial ultrasound-CVR); blood oxygen-level dependent\u2013magnetic 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      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, \u22120.01 to 0.05;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.18), or versus cilostazol (\u22120.01, \u22120.04 to 0.02;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.36), despite increased blood flow (\u2206 peak systolic velocity, 6.3 cm\/s, 3.5\u20139.07;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt;0.001; \u2206 end-diastolic velocity, 1.98, 0.66\u20133.29;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.004). Secondary outcomes improved on sildenafil versus placebo for CVR-transcranial ultrasound (0.83 cm\/s per mm\u2005Hg, 0.23\u20131.42;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.007), CVR-WMH (0.07, 0\u20130.14;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.043), CVR-normal-appearing white matter (0.06, 0.00\u20130.12;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.048), perfusion (WMH: 1.82 mL\/100 g per minute, 0.5\u20133.15;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.008; and normal-appearing white matter, 2.12, 0.66\u20133.6;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.006) and cerebrovascular resistance (sildenafil-placebo: 0.08, 0.05\u20130.10;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =4.9\u00d710\n                      <jats:sup>\u22128<\/jats:sup>\n                      ; cilostazol-placebo, 0.06, 0.03\u20130.09;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =5.1\u00d710\n                      <jats:sup>\u22125<\/jats:sup>\n                      ). Both drugs increased headaches (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =1.1\u00d710\n                      <jats:sup>\u22124<\/jats:sup>\n                      ), while cilostazol increased moderate-severe diarrhea (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =0.013).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>REGISTRATION:<\/jats:title>\n                    <jats:p>\n                      URL:\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.clinicaltrials.gov\/study\/NCT03855332\">https:\/\/www.clinicaltrials.gov\/study\/NCT03855332<\/jats:ext-link>\n                      ; Unique identifier: NCT03855332.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.124.324327","type":"journal-article","created":{"date-parts":[[2024,6,4]],"date-time":"2024-06-04T05:37:27Z","timestamp":1717479447000},"page":"320-331","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":37,"title":["Cerebrovascular Effects of Sildenafil in Small Vessel Disease: The OxHARP Trial"],"prefix":"10.1161","volume":"135","clinical-trial-number":[{"clinical-trial-number":"nct03855332","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0630-8204","authenticated-orcid":true,"given":"Alastair J.S.","family":"Webb","sequence":"first","affiliation":[{"name":"Wolfson 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."},{"name":"Department of Brain Sciences, Imperial College London, United Kingdom (A.J.S.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8310-9911","authenticated-orcid":true,"given":"Jacqueline S.","family":"Birks","sequence":"additional","affiliation":[{"name":"Centre for Statistics in Medicine, Botnar Research Centre (J.S.B.), University of Oxford, United 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