Novel secondary preventative strategies in the management of ischaemic stroke and transient ischaemic attack

Higgins, Peter (2014) Novel secondary preventative strategies in the management of ischaemic stroke and transient ischaemic attack. MD thesis, University of Glasgow.

Abstract

Stroke represents the second leading cause of global mortality. Despite improvements in acute stroke management in recent years, many patients suffer a poor outcome and stroke represents a leading cause of adult disability. Beyond the human impact of disease, societal costs are huge. Stroke is principally a disease of the elderly population, which is increasing in size. Incidence is increasing in the younger population and the developing world. Accordingly, the global burden of stroke is anticipated to increase substantially in the coming decades.

Fatal and disabling strokes are frequently preceded by either a milder, non-disabling stroke or a transient ischaemic attack (TIA). The optimised implementation of effective preventative strategies and the evaluation of potentially novel therapeutic agents, both represent crucial strategies in reducing the burden of cerebrovascular disease. This thesis addresses two aspects of secondary prevention following ischaemic stroke: Firstly, improved identification and optimised use of anticoagulant based secondary prevention for an established but frequently occult risk factor for recurrent stroke; paroxysmal atrial fibrillation (PAF). Secondly, the evaluation of xanthine oxidase inhibition (XOI), as a potential therapeutic strategy for the prevention of stroke and cardiovascular disease.

Chapter 1 highlights the importance of optimising secondary preventative strategies following ischaemic stroke and TIA. The anticipated increase in the global burden of cerebrovascular disease is described, together with review of stroke outcomes in the context of contemporary acute stroke management. The risk of stroke recurrence following ischaemic stroke and TIA is reviewed, followed by discussion of available secondary preventative strategies.

In Chapter 2, the role of AF in the aetiology of stroke disease is reviewed in greater detail. The early and subsequent risk of stroke recurrence in patients with AF is considered, together with review of the evidence for antithrombotic therapy. The potential for increased detection of paroxysmal AF in the ischaemic stroke and TIA population is discussed, with particular reference to the therapeutic implications and potential for reduced stroke recurrence.

In Chapter 3, details of a randomised, open-label trial with objective outcome assessment, in patients with recent (< 7 days) ischaemic stroke or TIA, are presented. This study evaluated the use of non-invasive cardiac event monitoring to detect AF, in patients with ischaemic stroke or TIA presenting with sinus rhythm, an area of management for which a robust evidence base is lacking. The primary endpoint was the difference in AF detection at 14 days, between patients randomised to receive supplemental cardiac event monitoring of 7 days duration, compared to those receiving standard guideline based investigation alone. Detection of AF was defined as evidence of “sustained” PAF and “any duration” PAF episodes. Secondary endpoints were the difference in AF detection at 90 days and the difference in AF-thromboembolic prophylaxis-related anticoagulation (e.g. warfarin) at 14 & 90 days. 100 patients were enrolled and completed 90 day follow up. “Sustained” and “any duration” PAF episodes were detected, respectively, in 16% (95% CI, 7.2 – 29.1%) and 42% (95% CI, 28.2 – 56.8%) of patients through 7 days non-invasive cardiac event monitoring. Supplementation of standard guideline based investigation with 7 days’ cardiac event monitoring resulted in detection of “sustained” and “any duration” PAF episodes in an additional 16% (4.7 – 27.3%) and 40% (25.2 – 54.8%) of patients, respectively, at 14 days follow up. These differences persisted at 90 days. Anticoagulant therapy was commenced within 14 days in 16% of the group randomised to receive supplemental monitoring, versus none randomised to standard investigation alone (p<0.01). This difference persisted to 90 days (22% versus 6%, p<0.05). This study provided the first randomised controlled evidence for a specific investigation strategy for the detection of occult PAF in unselected patients with ischaemic stroke and TIA. These data should support guidelines regarding the management of this patient group. In addition, the study provided evidence that this strategy is not reliant on specialist electrocardiological service support, with very good agreement [(96%; 95% CI, 86.3 – 99.5%), Fleiss’ Kappa 0.86, p < 0.00001] observed between non-cardiology trained stroke clinicians and the independent reporting electrocardiology laboratory for “sustained” PAF detection.

In a related observational study, the predictive value of detection of AF in the period immediately following ischaemic stroke or TIA was examined, relative to interval evaluation for AF by non-invasive cardiac event monitoring, performed 90 days following the index event. This study demonstrated that identification of AF immediately following stroke holds strong positive predictive value for subsequent AF detection following a 90 day interval, supporting treatment decisions being based on the findings of early monitoring. Negative predictive value of failure to identify AF through early monitoring was only modest, suggesting that repeated investigation may be of value.

In Chapter 4, the hypothetical role of uric acid (UA) in the pathogenesis of cardiovascular disease is reviewed. Conflicting data are discussed, including those which support the hypothesis that serum UA represents a surrogate marker of elevated cardiovascular risk attributable to either its association with established cardiovascular risk factors or, alternatively, as a surrogate marker for a novel mechanism of vascular injury: harmful oxidative stress produced by the xanthine oxidase enzymatic system. XOI is discussed as a potential novel therapeutic strategy in the prevention and management of cardiovascular disease.

In chapter 5 a systematic review and meta-analysis of studies evaluating the effect of XOI on cardiovascular health in humans are presented. This study identified a body of heterogeneous studies, reporting largely positive results. In meta-analysis, improvement in brachial artery flow mediated dilatation, [2.50% increase (95% CI, 0.15 – 4.84%)] and venous occlusion plethysmography derived forearm blood flow response to acetylcholine, [69% increase relative to control arm (95% CI, 18 – 119%)], indicated that XOI improves endothelial function amongst patients with, or at risk of, cardiovascular disease. In addition, XOI reduces vascular oxidative stress, Malondialdehyde reducing by 0.56 nmol/ml (95% CI 0.26 – 0.87 nmol/ml). Several studies indicated that the benefits of treatment may be limited to patients with hyperuricaemia. Definitive clinical endpoint studies were lacking. The study confirmed that XOI has beneficial effects within the cardiovascular system, providing supportive evidence for further study in the stroke patient population and in relation to more definitive clinical endpoints.

In Chapter 6, three surrogate measures of cardiovascular risk: Carotid intima media thickness (CIMT); blood pressure pulse wave analysis (BP-PWA); and endothelial function are reviewed. Each is considered with respect to their independent predictive value for risk of cardiovascular disease, and utility as surrogate outcome measures in clinical trials. Together with chapter 4 and the systematic review reported in chapter 5, this chapter provides additional background to the randomised controlled trial reported in chapter 7.

In Chapter 7, the details of a double blind, randomised placebo-controlled trial, evaluating XOI (with Allopurinol 300 mg once daily) in a population with recent (< 12 months) ischaemic stroke or TIA, are presented. Patients were followed up at 1, 3, 6 & 12 months in relation to several prognostically important surrogate measures of cardiovascular function. End points included differences in CIMT progression, change in central blood pressure (BP) and change in arterial stiffness at one year and change in endothelial function at 6 months. Data regarding safety and tolerability were also collected. Eighty participants were recruited, mean age 67.8 (SD 9.4) years. Progression in mean common CIMT at one year was less in allopurinol treated patients compared with placebo [between group difference, -0.097mm (95% CI, -0.175, -0.019), p=0.015]. Mean maximum CIMT progression did not differ between treatment groups at one year [between group difference, -0.060mm (95% CI, -0.146, 0.027), p=0.17]. Central aortic systolic BP [-6.6 mmHg (95% CI -13.0 to -0.3), p=0.042] and augmentation index [-4.4% (95% CI -7.9, -1.0), p=0.013], were each reduced following allopurinol treatment compared with placebo at 12 months. No significant difference was observed for measures of endothelial function. This study extends the evidence of sustained beneficial effects of allopurinol on the vasculature to the stroke population and to endpoints including CIMT progression and central BP. The study confirmed that a previously reported benefit of reduced arterial stiffness represents a sustained treatment effect. These data provide evidence in support of the hypothesis that the therapeutic strategy of XOI has the potential to reduce the risk of cardiovascular events.

The studies presented in this thesis provide a combination of clinically relevant and novel scientific findings. The two randomised controlled clinical trials were robustly conducted studies, adhering to vigorous regulatory standards and provide prospective data obtained in clinical patient populations. The evidence from the non-invasive cardiac event monitoring study should immediately support the optimisation of care of patients with acute ischaemic stroke or TIA for the detection of occult paroxysmal AF, thereby optimising use of anticoagulant therapy. The systematic review and clinical trial evaluation of XOI, respectively, provide confirmatory evidence of beneficial effects within the vasculature and extend this to the stroke patient population, including to the surrogate markers of CIMT progression and central BP. Together they provide supportive evidence for more definitive study to evaluate whether XOI reduces the risk of cardiovascular disease.

• Item Type: Thesis (MD)
• Qualification Level: Doctoral
• Subjects: R Medicine > R Medicine (General); R Medicine > RC Internal medicine; R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry; R Medicine > RM Therapeutics. Pharmacology; R Medicine > RS Pharmacy and materia medica
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health > Stroke/Cerbovascular Disease and Care of the Elderly
• Supervisor's Name: Walters, Professor Matthew R and Lees, Professor Kennedy R
• Date of Award: 2014
• Depositing User: Dr Peter Higgins
• Unique ID: glathesis:2014-5152
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 19 Jun 2014 13:12
• Last Modified: 19 Jun 2014 13:13
• URI: https://theses.gla.ac.uk/id/eprint/5152