TY - JOUR
T1 - Tadalafil Treatment in Patients With Cerebral Small Vessel Disease
T2 - The ETLAS-2 Randomized Clinical Trial
AU - Ölmestig, Joakim
AU - Mortensen, Kristian Nygaard
AU - Thomas, Marie Bjerregaard
AU - Fagerlund, Birgitte
AU - Naveed, Nadia
AU - Nordling, Mette Maria
AU - Nielsen, Marie Katrine Klose
AU - Rasmussen, Brian Schou
AU - Christensen, Hanne
AU - Iversen, Helle Klingenberg
AU - Poulsen, Mai Bang
AU - Siebner, Hartwig Roman
AU - Kruuse, Christina
PY - 2025/10
Y1 - 2025/10
N2 - 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.
AB - 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.
KW - Aged
KW - Cerebral Small Vessel Diseases/drug therapy
KW - Denmark
KW - Double-Blind Method
KW - Female
KW - Humans
KW - Magnetic Resonance Imaging
KW - Male
KW - Middle Aged
KW - Tadalafil/therapeutic use
KW - Treatment Outcome
KW - White Matter/diagnostic imaging
UR - http://www.scopus.com/inward/record.url?scp=105011960886&partnerID=8YFLogxK
U2 - 10.1161/STROKEAHA.125.051602
DO - 10.1161/STROKEAHA.125.051602
M3 - Journal article
C2 - 40718899
SN - 0039-2499
VL - 56
SP - 2846
EP - 2857
JO - Stroke
JF - Stroke
IS - 10
ER -