Covariates
The covariates for the GARFIELD-AF models are: age, sex, pulse, systolic blood pressure and diastolic blood pressure, weight, height, ethnicity, current smoking, and paroxysmal AF; history of vascular disease, diabetes, cirrhosis, peripheral vascular disease, stroke, bleeding, heart failure, chronic kidney disease, sleep apnoea, dementia, and/or carotid occlusive disease; and anticoagulant use and antiplatelet use. The covariates and coefficients for the 2017 and 2021 models are detailed in Supplementary Tables S1 and S2.
The main difference between the 2017 and the 2021 models is that the 2021 models have a wider range of variables. For example, the 2017 GARFIELD-AF model for stroke includes the variables age, history of stroke, bleeding, heart failure, chronic kidney disease, region, ethnicity, and anticoagulant use. The 2021 GARFIELD- AF model for stroke has the additional variables female sex, history of carotid occlusive disease, dementia, and smoking. For the GARFIELD-AF 2017 models for death, there exists a full version and a simpler version that comprises a reduced set of variables (age, pulse, systolic blood pressure, history of vascular disease, history of bleeding, heart failure, renal disease, and anticoagulant use), whereas the 2021 death model has just one version.
The covariates for the CHA2DS2VASc score are: history of congestive heart failure, hypertension, age, diabetes, prior stroke, vascular disease, and sex. The covariates for the HAS-BLED score are: hypertension, abnormal liver or renal function, history of stroke, bleeding history, labile international normalised ratio, age, drug use at time of diagnosis (antiplatelets or non-steroidal anti-inflammatory drugs), or alcohol use.
The baseline variables for the GARFIELD- AF models and CHA2DS2VASc and HAS-BLED scores were defined from CPRD data using Medical Code IDs. Details are provided in Supplementary Box S1.
Definition of endpoints
The study endpoints were all-cause mortality; ischaemic stroke/systemic embolism, defined as the combined endpoint of any ischaemic stroke, transient ischaemic attack, or systemic embolism; and major bleeding (including haemorrhagic stroke), defined as bleeding requiring admission to hospital. The first occurrence of an ischaemic stroke/systemic embolism after AF diagnosis was the endpoint for ischaemic stroke/systemic embolism, and the first occurrence of major bleeding after AF diagnosis was the endpoint for major bleeding.
Statistical analysis
The GARFIELD-AF models were applied to the CPRD dataset to obtain the predicted risks for each outcome. The performance of the tool was measured in terms of calibration using calibration-in-the-large regression and calibration plots, and in terms of discrimination using the area under the receiver operating characteristic curve (AUC), also referred to as the C-statistic. The performance of the models was compared with the CHA2DS2VASc and HAS- BLED scores by comparing the AUC of each model. The CHA2DS2VASc score, in addition to predicting the risk of stroke in patients with AF, has been shown to predict mortality in patients with several diseases, regardless of the presence of AF.13 The performance of the CHA2DS2VASc score for predicting stroke and death was compared with the GARFELD-AF models for stroke and death, and the performance of the HAS-BLED score for predicting bleeding was compared with the GARFIELD-AF bleeding models. The treatment effect was estimated by running separate Cox regression models for each outcome (death, stroke, and bleeding) and adjusting each model for all the variables that contribute to the GARFIELD-AF 2021 score for that outcome.
Each variable was assessed for the degree of missingness. The assessment for discrimination and calibration was performed on the whole dataset and repeated in patients without missing data in any score. Subgroup analysis was conducted according to risk stratification of stroke (high, moderate, and low according to CHA2DS2VASc) and bleeding (HAS- BLED <2 or >2), and for individuals receiving anticoagulation or no anticoagulation at baseline.