Tadalafil Treatment in Patients With Cerebral Small Vessel Disease: The ETLAS-2 Randomized Clinical Trial.

IF 8.9 1区医学 Q1 CLINICAL NEUROLOGY

Stroke Pub Date : 2025-10-01 Epub Date: 2025-07-28 DOI:10.1161/STROKEAHA.125.051602

Joakim Ölmestig, Kristian Nygaard Mortensen, Marie Bjerregaard Thomas, Birgitte Fagerlund, Nadia Naveed, Mette Maria Nordling, Marie Katrine Klose Nielsen, Brian Schou Rasmussen, Hanne Christensen, Helle Klingenberg Iversen, Mai Bang Poulsen, Hartwig Roman Siebner, Christina Kruuse

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Abstract

Background: White matter hyperintensities and reduced cerebral blood flow are hallmarks of cerebral small vessel disease (CSVD). We tested the feasibility of daily treatment with the vasoactive drug tadalafil in patients with CSVD and its effects on cognition and imaging markers of CSVD.

Methods: The ETLAS-2 trial (Effect of Tadalafil in Lacunar Stroke) was a randomized, placebo-controlled, double-blind, parallel phase II trial testing 3 months of daily tadalafil 20 mg versus placebo in patients with CSVD and previous stroke or transient ischemic attack. Participants were included from the Capital Region of Denmark from 2022 to 2024. Outcomes were assessed at baseline and after 3 months. A binary logistic regression model with the treatment group as a covariate was used to calculate the primary outcome of feasibility (≥90% study drug compliance). Secondary outcomes included the Montreal Cognitive Assessment, magnetic resonance imaging markers of CSVD (Standards for Reporting Vascular Changes on Neuroimaging criteria), blood pressure, and adverse events.

Results: We included 76 participants (20 female, mean age, 68.0±8.9 years). Seventy-one initiated treatment, and 26 of 38 participants with tadalafil were ≥90% compliant versus 31 of 33 with placebo (odds ratio, 0.13 [95% CI, 0.03-0.69]; P=0.030). There was a female preponderance in tadalafil dropouts, with 46% of females stopping treatment, compared with only 16% of males. Adverse events occurred in 76% of participants with tadalafil versus 36% with placebo (odds ratio, 5.49 [95% CI, 1.81-18.07]; P=0.001). A trend toward lower white matter hyperintensity volume at follow-up was observed in the tadalafil group in the unadjusted per-protocol analysis (relative change, 0.939 [95% CI, 0.881-1.001]; P=0.054). No differences were observed in cognition, mental well-being, or blood pressure.

Conclusions: In participants with CSVD, adherence to tadalafil was significantly lower than to placebo and did not meet the prespecified compliance threshold. We observed a nonsignificant reduction in white matter hyperintensity volume after tadalafil, which warrants larger and prolonged studies with reduced tadalafil doses to explore potential benefits in CSVD.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05173896.

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他达拉非治疗脑血管病患者：ETLAS-2随机临床试验

背景：脑白质高信号和脑血流减少是脑小血管疾病（CSVD）的标志。我们测试了血管活性药物他达拉非每日治疗CSVD患者的可行性及其对CSVD认知和影像学指标的影响。方法：etas -2试验是一项随机、安慰剂对照、双盲、平行的II期试验，对患有CSVD且既往卒中或短暂性脑缺血发作的患者进行为期3个月的每日20mg他达拉非与安慰剂的对照试验。参与者来自丹麦首都地区，时间为2022 - 2024年。在基线和3个月后评估结果。采用以治疗组为协变量的二元logistic回归模型计算可行性的主要结局（≥90%的研究药物依从性）。次要结果包括蒙特利尔认知评估、CSVD的磁共振成像标记物（神经影像学标准血管变化报告标准）、血压和不良事件。结果：纳入76例受试者，其中女性20例，平均年龄68.0±8.9岁。71人开始治疗，38名他达拉非患者中有26人依从性≥90%，而33名安慰剂患者中有31人依从性≥90%(优势比0.13 [95% CI, 0.03-0.69]；P = 0.030)。退出他达拉非的女性占多数，46%的女性停止治疗，而只有16%的男性停止治疗。他达拉非组不良事件发生率为76%，安慰剂组为36%(优势比5.49 [95% CI, 1.81-18.07]；P = 0.001)。在未调整的方案分析中，他达拉非组随访时白质高强度体积有降低的趋势(相对变化，0.939 [95% CI, 0.881-1.001]；P = 0.054)。在认知、心理健康或血压方面没有观察到差异。结论：在CSVD患者中，他达拉非的依从性明显低于安慰剂，并且未达到预先规定的依从性阈值。我们观察到他达拉非后白质高强度体积的不显著减少，这需要更大规模和更长时间的研究，减少他达拉非剂量，以探索心血管疾病的潜在益处。注册：网址：https://www.clinicaltrials.gov；唯一标识符：NCT05173896。

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来源期刊

Stroke 医学-临床神经学

CiteScore

13.40

自引率

6.00%

发文量

2021

审稿时长

3 months

期刊介绍： Stroke is a monthly publication that collates reports of clinical and basic investigation of any aspect of the cerebral circulation and its diseases. The publication covers a wide range of disciplines including anesthesiology, critical care medicine, epidemiology, internal medicine, neurology, neuro-ophthalmology, neuropathology, neuropsychology, neurosurgery, nuclear medicine, nursing, radiology, rehabilitation, speech pathology, vascular physiology, and vascular surgery. The audience of Stroke includes neurologists, basic scientists, cardiologists, vascular surgeons, internists, interventionalists, neurosurgeons, nurses, and physiatrists. Stroke is indexed in Biological Abstracts, BIOSIS, CAB Abstracts, Chemical Abstracts, CINAHL, Current Contents, Embase, MEDLINE, and Science Citation Index Expanded.