Alastair J S Webb, Jacqueline S Birks, Karolina A Feakins, Amy Lawson, Jesse Dawson, Alexander M K Rothman, David J Werring, Osian Llwyd, Catriona R Stewart, James Thomas
{"title":"西地那非对小血管疾病的脑血管效应：OxHARP 试验","authors":"Alastair J S Webb, Jacqueline S Birks, Karolina A Feakins, Amy Lawson, Jesse Dawson, Alexander M K Rothman, David J Werring, Osian Llwyd, Catriona R Stewart, James Thomas","doi":"10.1161/CIRCRESAHA.124.324327","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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<sub>2</sub> 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.</p><p><strong>Results: </strong>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; <i>P</i>=0.18), or versus cilostazol (-0.01, -0.04 to 0.02; <i>P</i>=0.36), despite increased blood flow (∆ peak systolic velocity, 6.3 cm/s, 3.5-9.07; <i>P</i><0.001; ∆ end-diastolic velocity, 1.98, 0.66-3.29; <i>P</i>=0.004). Secondary outcomes improved on sildenafil versus placebo for CVR-transcranial ultrasound (0.83 cm/s per mm Hg, 0.23-1.42; <i>P</i>=0.007), CVR-WMH (0.07, 0-0.14; <i>P</i>=0.043), CVR-normal-appearing white matter (0.06, 0.00-0.12; <i>P</i>=0.048), perfusion (WMH: 1.82 mL/100 g per minute, 0.5-3.15; <i>P</i>=0.008; and normal-appearing white matter, 2.12, 0.66-3.6; <i>P</i>=0.006) and cerebrovascular resistance (sildenafil-placebo: 0.08, 0.05-0.10; <i>P</i>=4.9×10<sup>-8</sup>; cilostazol-placebo, 0.06, 0.03-0.09; <i>P</i>=5.1×10<sup>-5</sup>). Both drugs increased headaches (<i>P</i>=1.1×10<sup>-4</sup>), while cilostazol increased moderate-severe diarrhea (<i>P</i>=0.013).</p><p><strong>Conclusions: </strong>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.</p><p><strong>Registration: </strong>URL: https://www.clinicaltrials.gov/study/NCT03855332; Unique identifier: NCT03855332.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":null,"pages":null},"PeriodicalIF":16.5000,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11227301/pdf/","citationCount":"0","resultStr":"{\"title\":\"Cerebrovascular Effects of Sildenafil in Small Vessel Disease: The OxHARP Trial.\",\"authors\":\"Alastair J S Webb, Jacqueline S Birks, Karolina A Feakins, Amy Lawson, Jesse Dawson, Alexander M K Rothman, David J Werring, Osian Llwyd, Catriona R Stewart, James Thomas\",\"doi\":\"10.1161/CIRCRESAHA.124.324327\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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<sub>2</sub> 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.</p><p><strong>Results: </strong>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; <i>P</i>=0.18), or versus cilostazol (-0.01, -0.04 to 0.02; <i>P</i>=0.36), despite increased blood flow (∆ peak systolic velocity, 6.3 cm/s, 3.5-9.07; <i>P</i><0.001; ∆ end-diastolic velocity, 1.98, 0.66-3.29; <i>P</i>=0.004). Secondary outcomes improved on sildenafil versus placebo for CVR-transcranial ultrasound (0.83 cm/s per mm Hg, 0.23-1.42; <i>P</i>=0.007), CVR-WMH (0.07, 0-0.14; <i>P</i>=0.043), CVR-normal-appearing white matter (0.06, 0.00-0.12; <i>P</i>=0.048), perfusion (WMH: 1.82 mL/100 g per minute, 0.5-3.15; <i>P</i>=0.008; and normal-appearing white matter, 2.12, 0.66-3.6; <i>P</i>=0.006) and cerebrovascular resistance (sildenafil-placebo: 0.08, 0.05-0.10; <i>P</i>=4.9×10<sup>-8</sup>; cilostazol-placebo, 0.06, 0.03-0.09; <i>P</i>=5.1×10<sup>-5</sup>). Both drugs increased headaches (<i>P</i>=1.1×10<sup>-4</sup>), while cilostazol increased moderate-severe diarrhea (<i>P</i>=0.013).</p><p><strong>Conclusions: </strong>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.</p><p><strong>Registration: </strong>URL: https://www.clinicaltrials.gov/study/NCT03855332; Unique identifier: NCT03855332.</p>\",\"PeriodicalId\":10147,\"journal\":{\"name\":\"Circulation research\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":16.5000,\"publicationDate\":\"2024-07-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11227301/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Circulation research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1161/CIRCRESAHA.124.324327\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/6/4 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"CARDIAC & CARDIOVASCULAR SYSTEMS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Circulation research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1161/CIRCRESAHA.124.324327","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/6/4 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
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% 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.
期刊介绍：
Circulation Research is a peer-reviewed journal that serves as a forum for the highest quality research in basic cardiovascular biology. The journal publishes studies that utilize state-of-the-art approaches to investigate mechanisms of human disease, as well as translational and clinical research that provide fundamental insights into the basis of disease and the mechanism of therapies.
Circulation Research has a broad audience that includes clinical and academic cardiologists, basic cardiovascular scientists, physiologists, cellular and molecular biologists, and cardiovascular pharmacologists. The journal aims to advance the understanding of cardiovascular biology and disease by disseminating cutting-edge research to these diverse communities.
In terms of indexing, Circulation Research is included in several prominent scientific databases, including BIOSIS, CAB Abstracts, Chemical Abstracts, Current Contents, EMBASE, and MEDLINE. This ensures that the journal's articles are easily discoverable and accessible to researchers in the field.
Overall, Circulation Research is a reputable publication that attracts high-quality research and provides a platform for the dissemination of important findings in basic cardiovascular biology and its translational and clinical applications.
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