Improving Cerebral Blood Flow and Cognition in Patients with Cerebral Small Vessel Disease. the ETLAS-2 Trial

Prior treatment

• Concomitant use of PDE5 inhibitors e.g. sildenafil, tadalafil, and vardenafil during trial period
• Patients receiving nicorandil and nitrates e.g. isosorbide mononitrate, isosorbide dinitrate, glyceryl trinitrate
• History of acute myocardial infarction in the last three months before trial intervention

Other illness

• Known diagnosis of dementia, medically treated dementia, or under investigation for dementia
• Known carotid or vertebral dissection as a cause of stroke
• Stroke after carotid or heart surgery
• Known hypercoagulable disease
• Known severe hepatic impairment (Child-Pugh \> B)
• History of non-arthritic anterior ischemic optic neuropathy
• Known cardiac failure (NYHA ≥ II)
• History of "sick sinus syndrome" or other supraventricular cardiac conduction conditions such as sinoatrial or atrioventricular block (2nd of 3rd degree)
• Other known cardiogenic cause of stroke
• Contraindication to CO2 challenge, eg severe respiratory disease
• Known monogenic causes of stroke i.e. CADASIL

Lab values

• Known severe renal impairment (eGFR \< 30ml/min)

Age

• Women of childbearing age not taking contraception

Other

• Pregnancy or nursing
• Known cortical infarction (\> 1.5 cm maximum diameter)
• Known carotid artery stenosis ≥ 50 % with Doppler ultrasound, CT angiography, or MRI angiography diagnosed within the last five years
• Systolic BP \< 90 and/or diastolic BP \< 50
• Body weight \> 130kg
• Known persistent or paroxysmal atrial fibrillation/flutter
• MRI not tolerated or contraindicated
• Unable to provide informed consent
• The participant does not wish to be informed about results from the MRI

• MRI/computed tomography (CT) evidence of small vessel occlusion stroke(s)/lacunar stroke(s) (involving ≤2 cm in the acute phase and ≤1.5cm in the late phase) and/or confluent deep white matter hyperintensities (≥ grade 2 on Fazekas's scale).
• Clinical evidence of cerebral small vessel disease can be: a) small vessel occlusion stroke (lacunar stroke) syndrome with symptoms lasting \> 24 hours, occurring \< 5 years ago; OR b) transient ischemic attack (TIA) with symptoms lasting \< 24 hours AND with MR-DWI imaging performed acutely showing small vessel occlusion stroke, occurring \< 5 years ago; OR c) TIA with symptoms lasting \< 24 hours AND no acute MRI-DWI lesion but MRI/CT evidence of CSVD with old small vessel occlusion stroke(s) (involving ≤1.5cm) and/or confluent deep white matter hyperintensities (≥ grade 2 on Fazekas's scale).
• Age ≥ 50 years.