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

 Since post stroke we need lots of CBF(cerebral blood flow) along with extra oxygen delivery by our red blood cells. That should mean our stroke leadership should initiate research into both immediately. But without survivors in charge nothing will be done and your children and grandchildren will be screwed when they have strokes.

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

 

Mathilde M.H. Pauls, Lauren R. Binnie, Philip Benjamin, Shai Betteridge, Brian Clarke, Mohani-Preet K. Dhillon, Rita Ghatala, Fearghal A.H. Hainsworth … See all authors

First published: 08 February 2022

https://doi.org/10.1002/alz.12559

Clinical Trial Registration: . http://www.clinicaltrials.gov. Unique identifier: NCT02450253. https://eudract.ema.europa.eu. Unique identifier: 2015-001235-20.

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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(but maybe it will for stroke patients) (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(will multiple administrations work better?) on subcortical CBF. To detect treatment effects may require different dosing regimens.

1 BACKGROUND

Small vessel disease (SVD) is a common cause of lacunar stroke and vascular contributions to cognitive impairment and dementia.^{1, 2} SVD is common in older people, seen on brain magnetic resonance imaging (MRI) as diffuse white matter hyperintensities (WMH), focal ischemic lesions, and micro-hemorrhages.² SVD is associated with reduced cerebral blood flow (CBF) particularly in subcortical areas, including deep grey nuclei, subcortical white matter, and within WMH.^3-7 There is currently no disease-modifying therapy for SVD.^{2, 8}

CBF is regulated by multiple factors, including nitric oxide (NO). Tonic endothelial NO activates guanylyl cyclase in overlying vascular myocytes, to drive cyclic guanosine monophosphate (cGMP) formation, leading to myocyte relaxation and vasodilation. Cytoplasmic cGMP is degraded by phosphodiesterase enzymes, in particular PDE5. Potent, selective PDE5 inhibitors (PDE5i) such as sildenafil (Viagra) and tadalafil (Cialis) are in routine use as vasodilators in erectile dysfunction and pulmonary arterial hypertension. PDE5i augment blood flow in peripheral tissues and are well tolerated across dosing regimens.^{9, 10} This study addressed the hypothesis that PDE5i increase CBF in older people, particularly in the subcortical regions affected by SVD.¹¹

PDE5 is present in human brain neurons¹² and in vascular myocytes within subcortical white matter.¹³ Among PDE5i, tadalafil has a relatively long plasma half-life (16 hours in healthy adults)^{14, 15} with evidence of brain penetration in rodents and primates.^{16, 17} Tadalafil is well tolerated and has been widely prescribed worldwide.^{9, 10, 14, 15} This article presents primary outcomes from a clinical trial with cross-over design^{8, 18} to determine whether a single administration of tadalafil increases subcortical CBF.