Prevention of stroke: risk stratification and targeted and novel therapies

Stroke is a common disorder with dire consequences for the patient and for society and will increase in prevalence over the coming years. Following stroke, many patients unfortunately suffer a further stroke, and recurrent strokes account for approximately 25% of the total. Considerable scope therefore exists to improve both primary and secondary stroke prevention. This thesis has addressed several areas at key stages in the prevention of stroke by developing strategies to better identify those at highest risk, attempting to better target pre-existing anti-platelet therapy and by beginning the evaluation of xanthine oxidase reduction and uric acid lowering therapy in the prevention of stroke. A clinical scoring system to aid diagnostic recognition in those with suspected transient ischaemic attack (TIA) was successfully developed and has the ability to reduce the referral of those without cerebrovascular disease to busy TIA clinics. The score was developed on data from 3216 patients and included 9 clinically useful predictive variables. After adjustment to reflect the greater seriousness of missing true TIA patients, 97% of TIA and 22% of non-TIA patients were accurately identified. The results were confirmed during prospective validation. Use of the score could have a substantial effect on waiting times for assessment; there is potential double the numbers seen within the timeframe recommended by guidelines with no other change to services. This would be an important advance given the recent evidence that rapid assessment and treatment of those with TIA greatly reduces stroke risk. Aspirin resistance was found to be higher in those with cerebrovascular microembolic signals (MES) and carotid disease compared to those with equivalent carotid disease and no MES. This study included sixty-two patients who mostly had symptomatic carotid disease. Approximately a quarter had MES. The rate of aspirin resistance on at least one test was 25.8% (16 patients), with 13 (21%) resistant on PFA-100 testing, 8 (12.9%) using the Verify-Now system and 5 (8.1%) resistant on both. Aspirin resistance was more common in patients with MES (50% compared to 17.4% without, p=0.018 on Fishers exact test). This provides a link to a well established and robust surrogate marker of outcome and thus a useful model to further study the benefits of guided anti-platelet strategies. An interventional clinical anti-platelet trial based upon individual aspirin responsiveness in high risk individuals such as those with MES is now warranted. Aspirin resistance was also confirmed to be a common phenomenon in a case-control study of 180 patients. It was present in 34% of those with recent stroke and in 18% of those with risk factors but no established disease. However, the role of poor compliance with therapy as a cause in a substantial number of cases was established; it accounted for approximately half of those labelled resistant in the stroke group. Further, when only those with objective evidence of recent aspirin ingestion were considered, the prevalence of aspirin resistance was similar in both groups (at 26%). This suggests that objective measures to confirm compliance with aspirin therapy should be mandatory in future studies of aspirin resistance. Increasing serum uric acid was found to be a predictor of poor functional outcome following acute stroke but not in an independent fashion. In total, 852 patients were included in this study and greater uric acid levels were associated with increased odds of poor outcome on univariate but not multivariate analysis (OR 1.3, 95% CI 0.73-2.31). However, there was no evidence of an association with favourable outcome as other groups have found. Increasing serum uric acid was also shown to be predictive of increased risk of stroke, total, vascular and coronary mortality in treated hypertensive patients but interestingly, the relationship between stroke mortality and serum uric acid appears J-shaped and most apparent in females. A study of the use of allopurinol in those with diabetes showed that xanthine oxidase inhibition improves cerebral nitric oxide bioavailability suggesting a beneficial effect of allopurinol on cerebrovascular health. This study included 14 participants who had impaired baseline cerebrovascular nitric oxide bioavailability. Allopurinol led to a significant improvement in responses to NG-monomethyl-L-arginine (L-NMMA) when compared to placebo (p=0.032, median improvement in ICA flow reduction following L-NMMA of 3144 (95% CI 375 to 7143)) mls). L-NMMA is an inhibitor of endothelial nitric oxide synthase which reduces cerebral blood flow in healthy volunteers; the bigger the reduction, the greater the endothelial health. However, a study of the effect of allopurinol treatment on cerebrovascular reactivity (as measured by response to acetazolamide infusion) in a group of patients with recent subcortical stroke revealed no positive effect. Cerebrovascular reactivity was unchanged by treatment with allopurinol. This raises interesting questions regarding the longevity of any positive effect of allopurinol as this, and other studies of 3 month duration, have revealed no benefit. Further, subjects in this study did not, on balance, have elevated serum uric acid and it has recently been suggested that only those with significantly elevated levels benefit in the setting of congestive cardiac failure. Whether this is also true in those with stroke also requires to be clarified. A large study of the effect of allopurinol on carotid intima-media thickness, a robust and modifiable marker of vascular risk, in those with recent stroke is planned to address these questions. The studies in this thesis therefore include a number of pragmatic findings which could improve care at all stages in the prevention of stroke. The TIA scoring system could improve recognition of the high risk condition TIA, a useful model has been developed in which to study a population of patients truly resistant to aspirin and important lessons have been learned to aid further evaluation of xanthine oxidase inhibition; a promising therapy for the prevention of stroke