Reliability of major bleeding events in UK routine data versus clinical trial adjudicated follow-up data

Abstract

Objective: To assess how reliable UK routine data are for ascertaining major bleeding events compared with adjudicated follow-up.

Methods: The ASCEND (A Study of Cardiovascular Events iN Diabetes) primary prevention trial randomised 15 480 UK people with diabetes to aspirin versus matching placebo. The primary safety outcome was major bleeding (including intracranial haemorrhage, sight-threatening eye bleeding, serious gastrointestinal bleeding and other major bleeding (epistaxis, haemoptysis, haematuria, vaginal and other bleeding)) ascertained by direct-participant mail-based follow-up, with >90% of outcomes undergoing adjudication. Nearly all participants were linked to routinely collected hospitalisation and death data (ie, routine data). An algorithm categorised bleeding events from routine data as major/minor. Kappa statistics were used to assess agreement between data sources, and randomised comparisons were re-run using routine data.

Results: When adjudicated follow-up and routine data were compared, there was agreement for 318 major bleeding events, with routine data identifying 281 additional-potential events, and not identifying 241 participant-reported events (kappa 0.53, 95% CI 0.49 to 0.57). Repeating ASCEND's randomised comparisons using routine data only found estimated relative and absolute effects of allocation to aspirin versus placebo on major bleeding similar to adjudicated follow-up (adjudicated follow-up: aspirin 314 (4.1%) vs placebo 245 (3.2%); rate ratio (RR) 1.29, 95% CI 1.09 to 1.52; absolute excess +6.3/5000 person-years (mean SE±2.1); vs routine data: 327 (4.2%) vs 272 (3.5%); RR 1.21, 95% CI 1.03 to 1.41; absolute excess +5.0/5000 (±2.2)).

Conclusions: Analyses of the ASCEND randomised trial found that major bleeding events ascertained via UK routine data sources provided relative and absolute treatment effects similar to adjudicated follow-up.

Trial registration number: ISRCTN60635500; NCT00135226.

Keywords: atherosclerosis; electronic health records; outcome assessment, health care; research design.

Conflict of interest statement

Competing interests: ASCEND (Current Controlled Trials number: ISRCTN60635500; ClinicalTrials.gov number: NCT00135226) was supported by grants to the University of Oxford from the British Heart Foundation and by Bayer (Germany and the USA), Solvay, Abbott and Mylan. The Clinical Trial Service Unit (CTSU) at the University of Oxford receives support from the U.K. Medical Research Council (which funds the MRC Population Health Research Unit in a strategic partnership with the University of Oxford), the British Heart Foundation and Cancer Research U.K. The Big Data Institute has received funding from the Li Ka Shing Foundation and Robertson Foundations, the U.K. Medical Research Council, British Heart Foundation and is supported by the NIHR Oxford Biomedical Research Centre and Health Data Research UK. WGH is supported by an MRC Kidney Research UK Professor David Kerr Clinician Scientist Award. CH is supported by a PhD studentship funded by the MRC Network of Hubs for Trials Methodology Research (HTMR) MR/L004933/2. MM is supported by a BHF CRE Intermediate Fellowship. NS is a Statistical Advisor for BMJ Heart. The CTSU has had an explicit policy for about 30 years of not accepting any personal payments directly or indirectly from industry. It only seeks reimbursement to the University of Oxford of the costs of travel and accommodation to participate in scientific meetings.

© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1

Effect of allocation to aspirin vs placebo on any major bleeding. Log-rank methods were used to calculate the rate ratio and 95% CIs. *The pre-adjudicated direct follow-up outcome included all eye bleeds.

Figure 2

Observed absolute effects of allocation to aspirin (A) vs placebo (P) for routine data follow-up. Data expressed as numbers of events per 5000 person-years. Plus-minus value are mean SEs. Serious vascular events include non-fatal myocardial infarction, ischaemic stroke, transient ischaemic attack or vascular death (excluding intracranial haemorrhage).