Cerebrovascular effects of sildenafil in small vessel disease: the OxHARP trial
File(s)
Author(s)
Type
Journal Article
Abstract
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.
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.
Date Issued
2024-07-05
Date Acceptance
2024-05-14
Citation
Circulation Research, 2024, 135 (2), pp.320-331
ISSN
0009-7330
Publisher
American Heart Association
Start Page
320
End Page
331
Journal / Book Title
Circulation Research
Volume
135
Issue
2
Copyright Statement
© 2024 The Authors. Circulation Research is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/38832504
Subjects
BLOOD-PRESSURE
Cardiac & Cardiovascular Systems
Cardiovascular System & Cardiology
CEREBRAL ARTERIAL PULSATILITY
cerebral small vessel diseases
cilostazol
CILOSTAZOL
COGNITIVE FUNCTION
Hematology
LACUNAR INFARCTION
LEUKOARAIOSIS
Life Sciences & Biomedicine
perfusion
Peripheral Vascular Disease
REACTIVITY
Science & Technology
STIFFNESS
STROKE
white matter
WHITE-MATTER
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2024-06-04