XILO-FIST, the Effect of Allopurinol on the Brain Heart and Blood Pressure After Stroke

Overview

Recurrent stroke and cognitive decline are common after ischaemic stroke. Allopurinol, a drug usually used to treat gout, has been shown to reduce heart ischaemia, heart size, and arterial stiffness and to relax brain blood vessels and may reduce the blood pressure. All of these properties may be associated with a lower risk of second stroke and cognitive decline. We now aim to explore whether allopurinol will reduce further damage to the brain (called white matter hyper-intensities) after stroke and also whether it reduces heart size and blood pressure after stroke. We will conduct a multi-centre randomised, double-blind placebo controlled study to investigate whether two years allopurinol 300 mg twice per day (BD) improves these 3 outcomes, which are inextricably linked to risk of recurrence and cognitive decline after ischaemic stroke.

New strategies are needed to improve long-term outcomes after ischaemic stroke or transient ischaemic attack (TIA). Approximately 13% of participants suffered recurrent stroke in recent secondary preventative trials , 40% of patients with TIA experience recurrent cardiovascular (CV) events during long-term follow up and there is an additional substantial burden from incident post-stroke dementia (\~ 10% after first stroke and higher still after recurrent events) , cognitive decline (over 30%) and decline in physical function. Improving these outcomes is a recognised priority area for stroke research (as identified by stroke survivors through the recent James Lind Alliance priority setting workshops ). Such adverse outcomes are particularly common in those with brain white matter hyper-intensities (WMH) on brain magnetic resonance imaging (MRI) . WMH are seen in as many as 90% of patients with ischaemic stroke , , are at least moderately severe in 50%6 and such 'severe' WMH are associated with substantially higher stroke recurrence rates (43% in one study)6, death and increased cognitive and physical decline. The burden of WMH increases during longitudinal follow up and this is associated with increased incident stroke, dementia and cognitive decline5. In the longitudinal population based Rotterdam scan study, 39% of elderly participants had WMH progression (over a mean period of 3.4 years) , as did 50% in the recent PROFeSS MRI sub-study (over 2 years)7 and 74% (over 3 years) in the Leukoariosis and Disability study (LADIS) .Similarly, silent brain infarction (SBI) is also associated with recurrent stroke and 14% developed incident infarcts on brain MRI in the Rotterdam scan study9. Thus, treatments that reduce WMH progression and incident silent brain infarction could have potentially profound effects on a variety of outcomes after stroke including cognition, functional outcome and recurrent stroke. The pathological basis for WMH development and progression is poorly understood. Post mortem studies show presence of varied pathologies including demyelination, infarction, arteriosclerosis and breakdown of the blood-brain barrier. Key risk factors for development and progression of WMH are age, arterial hypertension and previous stroke9 and associations with other cardiovascular risk factors and left ventricular hypertrophy (LVH) have been demonstrated . Blood pressure (BP) lowering reduces WMH progression, as demonstrated by the PROGRESS MRI sub-study . In the PROFeSS MRI sub-study WMH progression was unaffected by the angiotensin receptor blocker telmisartan7 but unlike PROGRESS, there was no significant difference in BP between groups. In addition, WMH are less clearly related to hypertension in older patients with established cardiovascular disease meaning that novel strategies which reduce WMH progression and SBI would be particularly promising in this group. The association between WMH and LVH is of particular interest; it appears independent of arterial BP , and may be mediated by aortic stiffness . There are additional potential mechanisms for this association (e.g., LVH is the strongest predictor of left atrial appendage thrombi, stronger than any left atrial parameter) . Regression of LVH is associated with reduced risk of stroke. In a recent meta-analysis of 14 studies in 12,809 patients, LVH regression was independently associated with a 25% reduction in future strokes, whereas the composite endpoint of CV events/mortality was only 15% lower . Similar findings were seen in the LIFE echo sub-study which utilised measures of left ventricular mass (LVM) . LVH regression is thus a promising therapeutic target in devising new ways to prevent strokes, especially if the same treatment were found to reduce WMH.