Neurovascular effects of tadalafil in patients with cerebral small vessel disease: ETLAS-2 substudy

Cerebral small vessel disease is a major contributor to stroke and cognitive impairment, often associated with reduced cerebral blood flow and cerebrovascular reactivity. In this study, we used MRI to investigate if daily treatment with the phosphodiesterase-5 inhibitor tadalafil over 3 months improved cerebral blood flow and cerebrovascular reactivity in patients with cerebral small vessel disease. Using a randomized, placebo-controlled, parallel-group design, this MRI sub-study was prospectively performed as part of the Effect of Tadalafil in Lacunar Stroke 2 trial, which included a total of 76 participants, of whom 60 were included in the per-protocol analysis. Patients with cerebral small vessel disease and prior stroke or transient ischaemic attack received either tadalafil (20 mg/day) or placebo for 3 months and completed the study. Neurovascular outcomes were assessed at baseline and at the 3-month follow-up using dual-echo pseudo-continuous arterial spin labelling MRI to evaluate reactivity to hypercapnia and visual stimulation. Endpoints included changes in whole-brain baseline cerebral blood flow and cerebrovascular reactivity, visual stimulation response, and neurovascular coupling index. In addition, we investigated arterial transit time measured using diffusion-prepared pseudo-continuous arterial spin labelling and changes in event-related sensory blood-oxygen-level-dependent responses in the primary somatosensory cortex (S1) after stimulation of the index finger. In total, 60 participants (median age: 66.5, 14 females) were included in this per-protocol sub-study analysis (28 on tadalafil and 32 on placebo). Forty-two pseudo-continuous arterial spin labelling datasets (20 on tadalafil and 22 on placebo), 53 blood-oxygen-level-dependent functional MRI datasets (26 on tadalafil and 27 on placebo), and 45 arterial transit time datasets (22 on tadalafil and 23 on placebo) were of sufficient quality to be included in the analysis. Baseline whole-brain cerebral blood flow was 25.4 ± 5.1 ml/100 g/min. Compared to placebo, tadalafil significantly increased whole-brain cerebral blood flow with a mean group difference of 3.33 ± 0.97 ml/100 g/min at follow-up (P = 0.001). None of the other MRI-based outcome metrics differed between groups. Three months of tadalafil treatment significantly enhanced whole-brain cerebral blood flow in patients with cerebral small vessel disease without altering cerebrovascular reactivity, neurovascular coupling, arterial transit time, and event-related blood-oxygen-level-dependent responses. The clinical significance of a tadalafil-induced increase in cerebral blood flow remains to be determined in prospective studies covering longer treatment periods.