Cardio-embolic stroke accounts for nearly a third of all ischaemic strokes. The most clinically important cardio-embolic sources are non-valvular atrial fibrillation (AF) and chronic heart failure. Strokes due to these conditions are associated with greater disability and more mortality, as compared to stroke of other aetiology. This thesis is aimed at addressing some of the challenges faced by clinicians when dealing with stroke in patients with AF or heart failure, using an extensive range of historical data.
Chapter 1 provides an introduction to stroke, AF and heart failure, including current prevalences, aetiology, and their complex intertwine relationship. The current acute stroke management in patients with AF or heart failure is also outlined within the chapter.
In chapter 2, the data sources and statistical methods that were common to the studies in the thesis are outlined. The justifications of using historical data in the absence of evidence from robust clinical trials are also detailed.
Chapter 3 explores the relevance of antithrombotic treatment on patterns and outcomes of acute stroke patients with AF. A non-randomised cohort analysis was conducted using data from the Virtual International Stroke Trials Archive (VISTA). The associations of antithrombotic treatment with the modified Rankin scale (mRS) outcome, and the occurrence of recurrent stroke and symptomatic intracerebral haemorrhage, at 90 days after stroke were described. Combined sequential antithrombotic therapy (i.e. oral anticoagulant and antiplatelet treatment), was associated with favourable outcome on ordinal mRS and significantly lower risk of recurrent stroke, symptomatic intracerebral haemorrhage and mortality by day 90, compared to the patients who did not receive any antithrombotic treatment. The relative-risk of recurrent stroke and symptomatic intracerebral haemorrhage appeared highest in the first 2 days after stroke before attenuating to become constant over time. Thus, early introduction of oral anticoagulant treatment (2-3 days after stroke), and to a lesser extent antiplatelet agents, was associated with substantially fewer recurrent stroke events over the following weeks but with no excess risk of symptomatic intracerebral haemorrhage.
Chapter 4 seeks to describe the current prescribing patterns in stroke survivors with AF, with particular emphasis on socio-demographic associations. A cross-sectional analysis of city-wide Glasgow primary care data for the year 2010, was conducted. This chapter highlights that oral anticoagulant treatment was under-used in this high risk population, especially those of older age and affected by deprivation. Strategies need to be developed to improve prescription of oral anticoagulant treatment.
Chapter 5 investigates the incidence of stroke within the available heart failure trials spanning a 30 year period, according to AF status at baseline. Individual patient data were pooled from 11 trials conducted in patients with heart failure and reduced ejection fraction (HF-REF); and, 3 trials performed in patients with heart failure and preserved ejection fraction (HF-PEF). Stroke incidence has not significantly declined over time in patients with HF-REF enrolled to trials, despite greater use of evidence-based heart failure and oral anticoagulant therapies. However, anticoagulation proportions remain under 70% among HF-REF patients with documented AF. Similar trends of stroke incidence were observed for patients enrolled in HF-PEF trials.
Some patients with heart failure but without atrial fibrillation may be at high risk of stroke and may potentially benefit from oral anticoagulant treatment.
Chapter 6 provides a comprehensive description of the current incidence of and risk factors for stroke in patients with HF-REF but without AF. Data from two large and contemporary heart failure trials, the Controlled Rosuvastatin in Multinational Trial Heart Failure (CORONA) and the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza cardiac- Heart Failure trial (GISSI-HF), were pooled to enable the analysis. The new simple clinical predictive model for stroke showed that about one-third of patients without AF have a risk of stroke similar to patients with AF. The predictive model was also validated in an independent large data set. The high risk of stroke in patients without AF might be reduced by individualised and safer oral anticoagulant treatment.
Correspondingly, Chapter 7 explores the risk-model for stroke in a contemporary cohort of patients with HF-PEF but without AF. Data were pooled from the Candesartan in Heart failure Assessment of Reduction in Mortality and Morbidity- Preserved trial (CHARM-Preserved) and the Irbesartan in Heart Failure with Preserved Systolic Function trial (I-Preserve), for patients with ejection fraction ≥45% only. The analysis showed that the simple clinical model developed in Chapter 6, for patients with HF-REF, is also applicable to patients with HF-PEF.
There are concerns that systemic thrombolysis might not achieve clinically-important outcome among chronic heart failure patients with acute ischaemic stroke. Chapter 8 evaluates the relevance of chronic heart failure on the outcome of acute stroke patients who received thrombolysis. A non-randomised cohort analysis was conducted using data obtained from the Virtual International Stroke Trials Archive (VISTA). The associations of outcome among chronic heart failure patients with thrombolysis treatment using the mRS distribution at day 90, stratified by presence of AF, were evaluated. Chronic heart failure was associated with a worse outcome with or without thrombolysis. However, acute stroke patients who received thrombolysis had more favourable outcome regardless of heart failure status, compared to their untreated peers. The findings should reassure clinicians considering systemic thrombolysis treatment in hyper-acute ischaemic stroke patients with chronic heart failure.
This thesis has summarised and extended our knowledge of the complex relationship between stroke and the heart, focusing on atrial fibrillation and heart failure. It has answered many questions and generated many more. The reported studies may assist clinicians who are dealing with stroke in patients with atrial fibrillation or heart failure. These conditions are common and each carry poor prognosis. Thus, even small advances in their treatment may have a useful societal impact
