Chronic damage to small blood vessels deep in the brain is seen in half of patients over the age of 60 and almost all patients over the age of 80, and is responsible for up to a third of strokes and almost half of patients with dementia. However, there is limited evidence for how small vessel disease develops and no specific treatment. One potential explanation is that greater pulsations in blood pressure are transmitted to the brain through stiff blood vessels, resulting in increased pressure hitting the brain each time the heart beats and reduced blood flow between heart beats.

Sildenafil is used to open up blood vessels (a vasodilator) in patients with erectile difficulties or poor blood supply to the lungs. This trial will test sildenafil (50mg, thrice daily) against placebo and a similar drug (cilostazol 100mg, twice daily) in 75 patients with previous stroke or mini-stroke and small vessel disease, given in random order to every participant for 3 weeks each. It will primarily assess changes in pulsations of blood flow to the brain on each tablet, measured with an ultrasound scanner (transcranial ultrasound). To understand why any changes occur, we will also measure the stiffness of arteries, the blood pressure at the heart and how much blood vessels in the brain open up when participants breathe air with added carbon dioxide (6%), using ultrasound in all participants and on MRI brain scans in 30 patients.

This study will test whether a vasodilator used in other conditions with a good safety profile can reduce pulsations in blood flow to the brain, to assess whether it is a good candidate drug to reduce the progression of small vessel disease in future clinical trials. This would be the first effective treatment for a condition associated with a very high burden of disability.

Inclusion Criteria:

• Participant is willing and able to give informed consent for participation in the study.
• Male or Female, aged 18 years or above.
• Can record MCA waveform on at least one side ('useable TCD window')
• Non-disabling, ischaemic stroke or TIA, >1 month prior to randomisation, of either cryptogenic or lacunar aetiology, confirmed clinically or on brain imaging
• White matter hyperintensities on MRI (Fazekas scale) or CT (Blennow scale) consistent with cerebral small vessel disease
• Age below 60 MRI Fazekas score 1 to 3 (max 2 points in periventricular or deep score) or CT Blennow score 1 to 3 (max 2 points in periventricular or deep score)
• Age above 60 MRI Fazekas score 1 to 4 (max 2 points in periventricular or deep score) or CT Blennow score 1 to 4 (max 2 points in periventricular or deep score)

Exclusion Criteria:

• Pregnant or breastfeeding women, women of childbearing age not taking contraception.

• Other major neurological or psychiatric conditions affecting the brain and interfering with the study design (e.g. multiple sclerosis)

• Other causes of stroke such as

  • ≥50% luminal stenosis (NASCET) in large arteries supplying the infarct area
  • major-risk cardioembolic source of embolism (permanent or paroxysmal atrial fibrillation, sustained atrial flutter, intracardiac thrombus, prosthetic cardiac valve, atrial myxoma or other cardiac tumours, mitral stenosis, recent (<4 weeks) myocardial infarction, left ventricular ejection fraction less than 30%, valvular vegetations, or infective endocarditis)
  • other specific causes of stroke (e.g. arteritis, dissection, drug misuse)

• Large vessel occlusion on MRA or CTA (carotid, basilar or MCA)

• Modified Rankin Score >3

• Unable to swallow

• Renal impairment (eGFR <35ml/min)

• Significant biochemical abnormalities (sodium <130, K+ <2.5 or >5.5, LFTs >3 x upper limit of normal range)

• Life expectancy <2 years

• Contraindication to active agents

  • Concurrent use of alphablocker
  • Regular use of nitrate (ISMN, GTN, other)
  • Heart failure (NYHA 2-4)
  • Severe aortic stenosis
  • Bilateral renal artery stenosis
  • Uncontrolled arrhythmias
  • Previous priapism
  • Anatomical deformation of the penis
  • Recent myocardial infarction (within 6 months)
  • Unstable angina
  • History of non-arteritic ischaemic optic neuropathy
  • Hypotension: BP <90/60
  • Haemodynamically significant aortic / mitral valve disease
  • Sickle cell disease, myeloma, leukaemia
  • Uncontrolled hypertension (BP >180/110 despite treatment with 3 antihypertensives)

• Scheduled elective surgery or other procedures requiring general anaesthesia during the study.

• Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the study or the participant's ability to participate in the study.

• Participants who have participated in another research study involving an investigational product in the past 12 weeks.

• Use of an anticoagulant (warfarin, dabigatran, rivaroxaban etc) or more than one antiplatelet drug.

• Predisposition to intracerebral haemorrhage (previous ICH, likely cerebral amyloid angiopathy) or intraocular haemorrhage (uncontrolled diabetic retinopathy or neovascularisation)

• Allergy to constituents of medications or components of placebo / overencapsulation

• Use of CYP inducers that interact with study medications (ketoconazole, erythromycin).

Exclusion criteria specific for MRI substudy

• Not able to transfer to MRI scanner
• Active respiratory illness (such as moderate to severe asthma or COPD) such that they are unable to tolerate MRI or unable to lie flat
• Claustrophobia
• Contraindication to MRI scan (pacemaker, aneurysm clip etc)

This will be determined on specific request