PDF(Pubmed)
Abstract：
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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).
UNASSIGNED: 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.
UNASSIGNED: URL: https://www.clinicaltrials.gov/study/NCT03855332; Unique identifier: NCT03855332.
UNASSIGNED: 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.
UNASSIGNED: 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).
UNASSIGNED: 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.
UNASSIGNED: URL: https://www.clinicaltrials.gov/study/NCT03855332; Unique identifier: NCT03855332.
摘要：
■脑小血管病导致的血管性认知障碍与脑搏动有关，白质灌注不足,和降低脑血管反应性（CVR），并有可能通过内皮靶向药物如西洛他唑来改善。无论是西地那非,磷酸二酯酶-5抑制剂，改善脑血管功能障碍是未知的。
■OxHARP试验（牛津血液动力学适应降低搏动力）是一项双盲试验，随机化，安慰剂对照,无栓塞性脑血管事件伴轻度-中度白质高信号（WMH）后的3向交叉试验，脑小血管病最常见的表现。主要结果评估了3周西地那非50mg每日三次与安慰剂（混合效应线性模型）对大脑中动脉搏动的优越性，从峰值收缩压和舒张末期速度（经颅超声），与非劣效性西洛他唑100毫克，每日两次。次要终点包括：吸入空气期间的脑血管反应性，经颅超声（经颅超声-CVR）的4％和6％CO2；WMH（CVR-WMH）和正常出现的白质（CVR-正常出现的白质）内的血氧水平依赖性磁共振成像；通过动脉自旋标记（磁共振成像伪连续动脉自旋标记）进行脑灌注；和通过脑血管电导进行阻力。CochranQ.
■比较了65/75（87％）患者的不良反应（中位数，70岁；79%男性）具有有效的主要结果数据，与安慰剂相比，西地那非的脑搏动没有变化（0.02，-0.01至0.05；P=0.18），或与西洛他唑（-0.01，-0.04至0.02；P=0.36），尽管血流量增加(÷收缩期峰值速度，6.3cm/s,3.5-9.07；P<0.001；Δ舒张末期流速，1.98，0.66-3.29；P=0.004）。西地那非与安慰剂相比，CVR经颅超声的次要结果有所改善（0.83cm/s/mmHg，0.23-1.42；P=0.007），CVR-WMH(0.07,0-0.14;P=0.043),CVR-正常出现的白质(0.06,0.00-0.12;P=0.048),灌注（WMH：1.82mL/100g/分钟，0.5-3.15；P=0.008；外观正常的白质，2.12，0.66-3.6;P=0.006）和脑血管阻力（西地那非-安慰剂：0.08，0.05-0.10;P=4.9×10-8;西洛他唑-安慰剂，0.06,0.03-0.09;P=5.1×10-5)。两种药物都会增加头痛（P=1.1×10-4），西洛他唑增加了中重度腹泻（P=0.013）。
■西地那非不降低搏动性，但增加脑血管反应性和灌注。西地那非值得进一步研究，以确定它是否可以预防小血管疾病的临床后遗症。
■URL：https://www。clinicaltrials.gov；唯一标识符：NCT03855332。
■OxHARP试验（牛津血液动力学适应降低搏动力）是一项双盲试验，随机化，安慰剂对照,无栓塞性脑血管事件伴轻度-中度白质高信号（WMH）后的3向交叉试验，脑小血管病最常见的表现。主要结果评估了3周西地那非50mg每日三次与安慰剂（混合效应线性模型）对大脑中动脉搏动的优越性，从峰值收缩压和舒张末期速度（经颅超声），与非劣效性西洛他唑100毫克，每日两次。次要终点包括：吸入空气期间的脑血管反应性，经颅超声（经颅超声-CVR）的4％和6％CO2；WMH（CVR-WMH）和正常出现的白质（CVR-正常出现的白质）内的血氧水平依赖性磁共振成像；通过动脉自旋标记（磁共振成像伪连续动脉自旋标记）进行脑灌注；和通过脑血管电导进行阻力。CochranQ.
■比较了65/75（87％）患者的不良反应（中位数，70岁；79%男性）具有有效的主要结果数据，与安慰剂相比，西地那非的脑搏动没有变化（0.02，-0.01至0.05；P=0.18），或与西洛他唑（-0.01，-0.04至0.02；P=0.36），尽管血流量增加(÷收缩期峰值速度，6.3cm/s,3.5-9.07；P<0.001；Δ舒张末期流速，1.98，0.66-3.29；P=0.004）。西地那非与安慰剂相比，CVR经颅超声的次要结果有所改善（0.83cm/s/mmHg，0.23-1.42；P=0.007），CVR-WMH(0.07,0-0.14;P=0.043),CVR-正常出现的白质(0.06,0.00-0.12;P=0.048),灌注（WMH：1.82mL/100g/分钟，0.5-3.15；P=0.008；外观正常的白质，2.12，0.66-3.6;P=0.006）和脑血管阻力（西地那非-安慰剂：0.08，0.05-0.10;P=4.9×10-8;西洛他唑-安慰剂，0.06,0.03-0.09;P=5.1×10-5)。两种药物都会增加头痛（P=1.1×10-4），西洛他唑增加了中重度腹泻（P=0.013）。
■西地那非不降低搏动性，但增加脑血管反应性和灌注。西地那非值得进一步研究，以确定它是否可以预防小血管疾病的临床后遗症。
■URL：https://www。clinicaltrials.gov；唯一标识符：NCT03855332。
