The PASTIS trial: Testing tadalafil for possible use in vascular cognitive impairment

Abstract

Introduction: There are few randomized clinical trials in vascular cognitive impairment (VCI). This trial tested the hypothesis that the PDE5 inhibitor tadalafil, a widely used vasodilator, increases cerebral blood flow (CBF) in older people with symptomatic small vessel disease, the main cause of VCI.

Methods: In a double-blind, placebo-controlled, cross-over trial, participants received tadalafil (20 mg) and placebo on two visits ≥7 days apart (randomized to order of treatment). The primary endpoint, change in subcortical CBF, was measured by arterial spin labelling.

Results: Tadalafil increased CBF non-significantly in all subcortical areas (N = 55, age: 66.8 (8.6) years) with greatest treatment effect within white matter hyperintensities (+9.8%, P = .0960). There were incidental treatment effects on systolic and diastolic blood pressure (-7.8, -4.9 mmHg; P < .001). No serious adverse events were observed.

Discussion: This trial did not identify a significant treatment effect of single-administration tadalafil on subcortical CBF. To detect treatment effects may require different dosing regimens.

Trial registration: ClinicalTrials.gov NCT02450253.

Keywords: PDE5; cerebral blood flow; clinical trials; small vessel disease; tadalafil; vascular cognitive impairment; vascular cognitive impairment and dementia.

FIGURE 1

PASTIS trial design and recruitment. A, Trial design. For Group 1, Treatment 1 was tadalafil and Treatment 2 placebo, for Group 2 vice versa. B, Recruitment to PASTIS. C, CONSORT diagram. CONSORT, Consolidated Standards of Reporting Trials; MRI, magnetic resonance imaging; PASTIS, Perfusion by Arterial Spin Labelling Following Single Dose Tadalafil in Small Vessel Disease

FIGURE 2

Example of anatomical and cerebral blood flow (CBF) mapping, with tissue segmentation. A, Fluid‐attenuated inversion recovery (FLAIR) image at full resolution. B, FLAIR image co‐registered to the CBF map, with voxels re‐sized to be equivalent to the pseudo‐continuous arterial spin labelling (pCASL) map. C, CBF map, derived from pCASL. Calibration bar shows 0.0–80.0 mL/min/100 g. D, Tissue segmentation map for CBF computation. Each voxel has been defined as either: cerebrospinal fluid (CSF), gray matter (GM), normal‐appearing white matter (WM), or white matter hyperintensity (WMH). E, F, Probability density functions of CBF values in voxels assigned as gray matter (E) or normal‐appearing white matter (F). For this participant, median CBF was 51.3 mL/min/100 g in gray matter and 21.8 mL/min/100 g in normal‐appearing white matter

FIGURE 3

Distributions of change (after–before) after placebo or tadalafil for cerebral blood flow (CBF) and blood pressure. A‐D, Change in CBF (mL/min/100 g) in deep gray nuclei (A), normal‐appearing white matter (B), white matter hyperintensities (C), and total gray matter (D). E,F, Change in systolic blood pressure (SBP; E) and diastolic blood pressure (DBP; F) (mmHg). Box‐whisker plots show median, interquartile range (IQR), and full range. Asterisks indicate mean values. For each of the parameters presented, mean values are listed in Table 2. Individual data points shown are > 3 IQR from the median

FIGURE 4

Change in cerebral blood flow (CBF) after placebo or tadalafil as a function of age. Change in CBF in total gray matter (A), and normal‐appearing white matter (B). Lines of best fit are shown for placebo (solid line), or tadalafil (dashed line) or for all data points (gray line)