142 CHAPTER 8 The percentage of male sex ranged from 47.4% to 78.0%; the mean age of study populations ranged from 67.2 to 78.7 years. Overall, hypertension was the most common reported comorbidity, ranging from 54.0% to 95.4%. The percentage of patients with a history of (ischaemic) stroke (and TIA and/or thromboembolism) ranged from 5.9% to 49.8%. The percentage of OLRD ranged from 8.9% to 53.0%. A detailed overview of all extracted study and patient characteristics can be found in Supplementary File S5. Risk of bias assessment An overview of the risk of bias assessment can be found in Supplementary File S6. In general, all studies scored well on the selection, comparability and outcome category of the NOS, except for demonstrating that the outcome of interest was not present at the start of the study and adequacy of the follow-up of the cohorts. Three out of 19 studies reported on the handling of missing data, all using multiple imputation. Meta-analysis of clinical outcomes associated with OLRD of NOACs Seven studies met the predefined criteria for meta-analysis (n=80,725) (see Supplementary File S7).35,36,38,44,47,48,51 The percentage of OLRD in these studies ranged from 9.6% to 53.0%. The pooled HR associated with OLRD of NOACs in AF patients was 1.04 (95% CI 0.83-1.29; 95% PI 0.60-1.79) for stroke/thromboembolism, 1.10 (95% CI 0.95-1.29; 95% PI 0.81-1.50) for bleeding, and 1.22 (95% CI 0.81-1.84; 95% PI 0.55-2.70) for all-cause mortality (see Figure 2). Of studies meeting our criteria for meta-analysis no study reported on all-cause hospitalisation, and only two studies reported on MACE, (HR of 1.2 (95% CI 1.05-1.37) and HR of 1.4 (95% CI 0.94-2.1)).44,48 When also including studies that used multivariate regression to adjust for confounding, we could meta-analyse one additional study that did not change our results (data not shown).33
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