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.
Department of Brain Sciences, Imperial College London, United Kingdom (A.J.S.W.).
Circ Res. 2024 Jul 5;135(2):320-331. doi: 10.1161/CIRCRESAHA.124.324327. Epub 2024 Jun 4.
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.
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 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.
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; =0.18), or versus cilostazol (-0.01, -0.04 to 0.02; =0.36), despite increased blood flow (∆ peak systolic velocity, 6.3 cm/s, 3.5-9.07; <0.001; ∆ end-diastolic velocity, 1.98, 0.66-3.29; =0.004). Secondary outcomes improved on sildenafil versus placebo for CVR-transcranial ultrasound (0.83 cm/s per mm Hg, 0.23-1.42; =0.007), CVR-WMH (0.07, 0-0.14; =0.043), CVR-normal-appearing white matter (0.06, 0.00-0.12; =0.048), perfusion (WMH: 1.82 mL/100 g per minute, 0.5-3.15; =0.008; and normal-appearing white matter, 2.12, 0.66-3.6; =0.006) and cerebrovascular resistance (sildenafil-placebo: 0.08, 0.05-0.10; =4.9×10; cilostazol-placebo, 0.06, 0.03-0.09; =5.1×10). Both drugs increased headaches (=1.1×10), while cilostazol increased moderate-severe diarrhea (=0.013).
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.
URL: https://www.clinicaltrials.gov/study/NCT03855332; Unique identifier: NCT03855332.
由脑小血管病引起的血管性认知障碍与大脑脉动性、白质低灌注和脑血管反应性（CVR）降低有关，内皮靶向药物如西洛他唑可能会改善这些问题。磷酸二酯酶-5 抑制剂西地那非是否能改善脑血管功能障碍尚不清楚。
OxHARP 试验（牛津血液动力学适应以降低脉动性）是一项非栓塞性脑血管事件后伴有轻度至中度脑白质高信号（WMH）的双盲、随机、安慰剂对照、三向交叉试验，WMH 是脑小血管病最常见的表现。主要结局是评估西地那非 50mg 每日 3 次与安慰剂相比（混合效应线性模型）在经颅超声测量的大脑中动脉脉动性（从收缩期峰值速度和舒张末期速度得出）的优越性，以证明其不劣于西洛他唑 100mg 每日 2 次。次要终点包括以下内容：经颅超声（经颅超声-CVR）测量的空气吸入、4%和 6%CO 时的脑血管反应性；WMH 内（CVR-WMH）和正常表现白质内（CVR-正常表现白质）的血氧水平依赖性磁共振成像；动脉自旋标记（磁共振成像伪连续动脉自旋标记）的脑灌注；和脑血管传导率的阻力。通过 Cochran Q 比较不良反应。
在 65/75 名（中位数年龄 70 岁；79%为男性）具有有效主要结局数据的患者中，与安慰剂相比，西地那非对大脑脉动性没有影响（0.02，-0.01 至 0.05；=0.18），或与西洛他唑相比（-0.01，-0.04 至 0.02；=0.36），尽管血流增加（收缩期峰值速度增加 6.3cm/s，3.5-9.07；<0.001；舒张末期速度增加 1.98cm/s，0.66-3.29；=0.004）。与安慰剂相比，西地那非在经颅超声-CVR（每毫米汞柱增加 0.83cm/s，0.23-1.42；=0.007）、CVR-WMH（0.07，0-0.14；=0.043）、CVR-正常表现白质（0.06，0.00-0.12；=0.048）、灌注（WMH：每分钟每 100 克 1.82ml，0.5-3.15；=0.008；和正常表现白质，2.12，0.66-3.6；=0.006）和脑血管阻力（西地那非-安慰剂：0.08，0.05-0.10；=4.9×10；西洛他唑-安慰剂：0.06，0.03-0.09；=5.1×10）方面均有所改善。两种药物均增加了头痛（=1.1×10），而西洛他唑增加了中度至重度腹泻（=0.013）。
西地那非并没有降低脉动性，但增加了脑血管反应性和灌注。西地那非值得进一步研究，以确定它是否能预防小血管病的临床后果。
网址：https://www.clinicaltrials.gov/study/NCT03855332；独特标识符：NCT03855332。
