Stratifying stroke severity: towards a personalised medicine application for primary care

Abstract

Stroke remains a major cause of death and disability worldwide, despite advances in prevention and treatment. Improvements in acute care have led to many surviving after an incident stroke event. However, the prognosis after surviving remains compromised. This is due to the high risk of recurrent adverse cardiovascular events, greatest during the first year but persisting over one’s lifetime. Reducing long-term residual cardiovascular risk and improving quality of life are primary goals for clinical practice and research. Identifying patients at the greatest risk of subsequent major adverse cardiovascular events (MACE) could help clinicians and policymakers determine which patients need to be prioritised. This thesis research aimed to identify clinical phenotypes (that is, patient characteristics and distinct patient clusters) that correlate with subsequent MACE outcomes (defined as a diagnosis of either CHD, recurrent stroke, PVD, heart failure, or CVD-related mortality) in adults with an incident stroke diagnosis. Firstly, a systematic review was completed to identify and summarise the available evidence on prognostic models and assess their accuracy for predicting MACE outcomes in an adult with established stroke. Forty (40) full-text articles with 23 distinct prognostic models for predicting MACE outcomes in adults with established stroke were identified by the systematic review. There were 11 prognostic model developments and 77 external validations of models reported. Among the 23 models, the most frequently used predictors were age, sex, history of transient ischaemic attack, hypertension (blood pressure), and diabetes. Critical appraisal identified methodological limitations, in particular: inadequate sample size, improper handling of missing data, and incomplete evaluation of model performance. The Clinical Practice Research Datalink (CPRD GOLD), a longitudinal database of anonymised electronic health records (UK primary care data) linked to Hospital Episode Statistics (HES APC), national death registry, and social deprivation data was then used to undertake a series of data-related studies. Four cohort studies were completed using patients aged ³18 years with an incident stroke diagnosis between 1 January 1998 and 31 December 2017, and no prior history of either CHD, PVD or heart failure, to assess the risk of subsequent cardiovascular morbidity and mortality outcomes. In the analysis of 9,997,376 individual records in CPRD GOLD database, there were 82,774 non-fatal incident stroke events recorded in either primary care or hospital data – a stroke incident rate of 109.20 per 100,000 person-years (95% CI: 108.46 – 109.95). Of the 82,774 patients, 13,879 (16.8%) patients had a prior history of major adverse outcomes (CHD, PVD, and heart failure) and were excluded. Subsequent MACE was recorded in 47,500 (69.0%) of the remaining 68,877 patients. In the UK, the incidence of stroke and subsequent major adverse cardiovascular morbidity and mortality outcomes were higher in women, older populations, and people living in socially deprived areas. After excluding patients with stroke not-otherwise specified (n=36,551) and adjusting for potential confounders, patients with incident haemorrhagic stroke (n=6,535, 20.4%) had no significantly different risk of subsequent cardiovascular morbidity, compared with patients with incident ischaemic stroke (n=25,556, 79.6%) – CHD [HR 0.86, 95% CI 0.56 – 1.32], recurrent stroke [HR 0.92, 95% CI 0.83 – 1.02], PVD [HR 1.15, 95% CI 0.56 – 2.38], or heart failure [HR 1.03, 95% CI 0.61 – 1.74]. However, patients with incident haemorrhagic stroke had a significantly higher risk of subsequent CVD-related mortality [HR 2.35, 95% CI 2.04 – 2.72] and all-cause mortality [HR 2.16, 95% CI 1.94 – 2.41]. Propensityscore matched analysis of 1,039 patients with haemorrhagic stroke and 1,039 with ischaemic stroke showed similar risk in subsequent cardiovascular morbidity outcomes – CHD, recurrent stroke, PVD and heart failure. Obesity, a risk factor for stroke and is also a risk factor for hypertension and diabetes (known risk factors for CVD), is commonly measured using body mass index (BMI). In a multivariable analysis of a cohort of 30,702 patients with incident stroke and BMI record, individuals in higher BMI categories were associated with lower risk of subsequent: • MACE [overweight (BMI: 25.0-29.9 kg/m2): HR 0.96, 95% CI 0.93 – 0.99)], • PVD [overweight: HR 0.65, 95% CI 0.49 – 0.85; obesity class III (BMI: ³40 kg/m2): HR 0.19, 95% CI 0.50 – 0.77], • CVD-related mortality [overweight: HR 0.80, 95% CI 0.74 – 0.86; obesity class I (BMI: 30.0-34.9 kg/m2): HR 0.79, 95% 0.71 – 0.88; class II (BMI: 35.0-39.9 kg/m2): HR 0.80, 95% CI 0.67 – 0.96]; and • all-cause mortality [overweight: HR 0.75, 95% CI 0.71 – 0.79; obesity class I: HR 0.75, 95% CI 0.70 – 0.81; class II: HR 0.77, 95% CI 0.68 – 0.86] when compared with those with normal BMI. The results were similar irrespective of sex, smoking status, history of diabetes mellitus or cancer at the time of incident stroke. Using a combination of data-driven feature selection approaches and clinical expert opinion, 39 out of 336 characteristics (clinical features including sociodemographic, biochemical, comorbid conditions, and prescribed medications related to stroke or CVD) at the time of incident stroke were selected. An unsupervised machine learning approach [clustering algorithm for mixed (both categorical and continuous) data] was used to identify 4 phenotypic clusters for a cohort of 48,114 patients with incident stroke and subsequent outcomes occurring 30 days after incident stroke. Cluster 1 (n=5,201, 10.8%) was a cohort with high prevalence of CHD-related risk factors and prescribed medications; cluster 2 (n=18,655, 38.8%) a cohort with low prevalence of multiple long-term conditions (MLTC); cluster 3 (n=10,244, 21.3%) a cohort with high prevalence of MLTC; and cluster 4 (n=14,014, 29.1%), the oldest population cohort and predominantly female. The phenotypic clusters had different incidences and risks for subsequent cardiovascular morbidity and mortality outcomes. For instance, the incidence of the composite outcome of recurrent stroke and CVD-related mortality was lowest in cluster 1 and highest in cluster 4 (15.13 and 23.17 per 100 person-years, respectively). The risk of subsequent recurrent stroke + CVD-related mortality was significantly increased in cluster 2 (HR 1.07, 95% CI 1.02 – 1.12); cluster 3 (HR 1.20, 95% CI 1.14 – 1.26), and cluster 4 (HR 1.29, 95% CI 1.26 – 1.33), when compared with cluster 1. Findings from this thesis research indicate patients with incident stroke experience considerable heterogeneity in subsequent clinical outcomes. In particular, women, older patients, and those living in socially deprived areas are at greater risk of subsequent major adverse outcomes. Additionally, age at incident stroke, blood pressure, LDL cholesterol level, a diagnosis of hypertension and potency of prescribed statin were identified as key indicators of patients’ phenotypic clusters and associated risk for subsequent clinical outcomes. The studies add to growing and wider evidence to identify those who may most benefit from, and be least likely to be harmed by, preventive treatment. Stratifying patients with stroke early, could lower the burden of subsequent adverse clinical outcomes, improve patients’ long-term outcomes, and reduce the associated economic burden. This should, therefore, be a continuing research and public health priority