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Randomized Controlled Trial
. 2021 Dec 1;4(12):e2139748.
doi: 10.1001/jamanetworkopen.2021.39748.

Comparison of the Accuracy and Completeness of Records of Serious Vascular Events in Routinely Collected Data vs Clinical Trial-Adjudicated Direct Follow-up Data in the UK: Secondary Analysis of the ASCEND Randomized Clinical Trial

Charlie Harper  1   2 , Marion Mafham  2 , William Herrington  1   2 , Natalie Staplin  1   2 , William Stevens  1   2 , Karl Wallendszus  1   2 , Richard Haynes  1   2 , Martin J Landray  1   2   3 , Sarah Parish  1   2 , Louise Bowman  1   2 , Jane Armitage  1   2
Affiliations
Randomized Controlled Trial

Comparison of the Accuracy and Completeness of Records of Serious Vascular Events in Routinely Collected Data vs Clinical Trial-Adjudicated Direct Follow-up Data in the UK: Secondary Analysis of the ASCEND Randomized Clinical Trial

Charlie Harper et al. JAMA Netw Open. .

Abstract

Importance: Routinely collected data could substantially decrease the cost of conducting trials.

Objective: To assess the accuracy and completeness of UK routine data for ascertaining serious vascular events (SVEs) compared with adjudicated follow-up data.

Design, setting, and participants: This was a secondary analysis of a randomized clinical trial. From June 24, 2005, to July 28, 2011, the ASCEND (A Study of Cardiovascular Events in Diabetes) primary prevention trial used mail-based methods to randomize people with diabetes without evidence of atherosclerotic vascular disease using a 2 × 2 factorial design to aspirin and/or ω-fatty acids vs matching placebo in the UK. Direct participant mail-based follow-up was the main source of outcome data, with more than 90% of the primary outcome events undergoing adjudication. Follow-up was completed on July 31, 2017. In parallel, more than 99% of participants were linked to routinely collected hospital admission and death registry data (ie, routine data), enabling post hoc randomized comparisons of different sources of outcome data (conducted from September 1, 2018, to October 1, 2021).

Interventions: Random allocation to 100 mg of aspirin once daily vs matching placebo and separately to 1 g of ω-3 fatty acids once daily vs placebo.

Main outcomes and measures: The primary outcome consisted of SVEs (a composite of nonfatal myocardial infarction, ischemic stroke, transient ischemic attack [TIA], or vascular death, excluding hemorrhagic stroke).

Results: A total of 15 480 participants were randomized (mean [SD] age, 63 [9] years; 9684 [62.6%] men) and followed up for a mean (SD) of 7.4 (1.8) years. For SVEs, agreement between adjudicated direct follow-up and routine data sources was strong (1401 vs 1127 events; κ = 0.78 [95% CI, 0.76-0.80]; sensitivity, 72.0% [95% CI, 69.7%-74.4%]; specificity, 99.2% [95% CI, 99.0%-99.3%]), and sensitivity improved for SVEs excluding transient ischemic attack (1129 vs 1026 events; sensitivity, 80.6% [95% CI, 78.3%-82.9%]). Rate ratios for the aspirin-randomized comparison for adjudicated direct follow-up vs follow-up solely through routine data alone were 0.88 (95% CI, 0.79-0.97) vs 0.91 (95% CI, 0.81-1.02) for the primary outcome and 0.92 (95% CI, 0.82-1.03) vs 0.91 (95% CI, 0.80-1.02) for SVEs excluding TIA. Results were similar for the ω-3 fatty acid comparison, and adjudication did not seem to markedly change rate ratios.

Conclusions and relevance: Post hoc analyses of the ASCEND trial suggest that routinely collected hospital admission and death registry data in the UK could be used as the sole method of follow-up for myocardial infarction, ischemic stroke resulting in hospitalization, vascular death, and arterial revascularization in primary prevention cardiovascular trials, without the need for verification by clinical adjudication.

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Conflict of interest statement

Conflict of Interest Disclosures: Mr Harper reported receiving grants from the Medical Research Council (MRC) Network of Hubs for Trials Methodology Research (for PhD studentship), UK MRC core funding, Cancer Research UK core funding, Health Data Research UK core funding, and the British Heart Foundation (3 Special Project grants for main study activity and a project grant for baseline blood and urine sampling exercise) and nonfinancial support from Bayer Healthcare AG, Bayer Shering Pharma AG, Bayer Pharma AG, Bayer Healthcare LLC, US, Solvay Pharmaceuticals GmbH, Abbott Product Operations AG, and Mylan EPD during the conduct of the study. Dr Mafham reported receiving grants from the UK MRC core funding, Cancer Research UK core funding, and the British Heart Foundation (3 Special Project grants for main study activity and a project grant for baseline blood and urine sampling exercise); nonfinancial support from Bayer Healthcare AG, Bayer Schering Pharma AG, Bayer Pharma AG, Bayer Healthcare LLC, US, Solvay Pharmaceuticals GmbH, Abbott Product Operations AG, and Mylan EPD; and funding from Bayer Healthcare AG, Bayer Schering Pharma AG, Bayer Pharma AG, Solvay Pharmaceuticals GmbH, Abbott Product Operations AG, and Mylan EPD for packaging and distribution of study drug during the conduct of the study and research grants from The Medicines Company/Novartis International AG and Novo Nordisk AG outside the submitted work. Dr Herrington reported receiving grants from MRC UK and Health Data Research UK during the conduct of the study. Dr Staplin reported receiving grants from the MRC Network of Hubs for Trials Methodology during the conduct of the study and grants from Boehringer Ingelheim and Novo Nordisk AG outside the submitted work. Dr Stevens reported receiving grants from the British Heart Foundation UK and the UK MRC and nonfinancial support from Bayer Healthcare AG, Bayer Shering Pharma AG, Bayer Pharma AG, Bayer Healthcare LLC, US, Solvay Pharmaceuticals GmbH, Abbott Product Operations AG, and Mylan EPD during the conduct of the study. Mr Wallendszus reported receiving grants from the British Heart Foundation UK and the UK MRC and nonfinancial support from Bayer Healthcare AG, Bayer Shering Pharma AG, Bayer Pharma AG, Bayer Healthcare LLC, US, Solvay Pharmaceuticals GmbH, Abbott Product Operations AG, and Mylan EPD during the conduct of the study. Dr Haynes reported receiving grants from Boehringer-Ingelheim and Novartis International AG outside the submitted work. Dr Landray reported receiving grants from Novartis International AG, Boehringer Ingelheim, and Merck & Co, Inc, outside the submitted work. Dr Parish reported receiving grants from the British Heart Foundation UK and the UK MRC and nonfinancial support from Bayer Healthcare AG, Bayer Shering Pharma AG, Bayer Pharma AG, Bayer Healthcare LLC, US, Solvay Pharmaceuticals GmbH, Abbott Product Operations AG, and Mylan EPD during the conduct of the study. Dr Bowman reported receiving grants from the British Heart Foundation and MRC during the conduct of the study; nonfinancial support from Bayer Pharma AG, Solvay Pharmaceuticals GmbH, Abbott Product Operations AG, and Mylan EPD during the conduct of the study; and grants from Novartis International AG outside the submitted work. Dr Armitage reported receiving grants from the UK MRC core funding, Cancer Research UK core funding, and British Heart Foundation (3 special project grants and 1 project grant) and nonfinancial support and grants for drug packaging from Bayer Healthcare AG, Solvay Pharmaceuticals GmbH, Mylan EPD, and Abbott Product Operations AG during the conduct of the study; and grants and nonfinancial support from The Medicines Company and Novartis International AG for the ORION4 trial outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flow Diagram of Post Hoc Analyses in ASCEND (A Study of Cardiovascular Events in Diabetes)
FA indicates fatty acids. aA complete breakdown of exclusions can be found in ASCEND’s main publications. bRandomization used a 2 × 2 factorial design. cAll 15 480 participants were included in both the aspirin and ω-3 FA comparisons.
Figure 2.
Figure 2.. Rate Ratios for Serious Vascular Events Using Routine Data and Adjudicated Direct Follow-up Data
Log-rank methods were used to calculate rate ratios (RRs) and 95% CIs. The size of the square for each RR is proportional to the amount of statistical information that was available; the horizontal lines represent 95% CIs. For composite outcomes, RRs and their corresponding 95% CIs are represented by diamonds. TIA indicates transient ischemic attack. aP = .01. bP = .10. cP = .55. dP = .32.
Figure 3.
Figure 3.. Rate Ratios for Serious Vascular Events Using Adjudicated and Preadjudicated Direct Follow-up Data
Log-rank methods were used to calculate rate ratios (RRs) and 95% CIs. The size of the square for each RR is proportional to the amount of statistical information that was available; the horizontal lines represent 95% CIs. For composite outcomes, RRs and their corresponding 95% CIs are represented by diamonds. TIA indicates transient ischemic attack. aP = .01. bP = .03. cP = .55. dP = .79.
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Comment in

  • Pragmatic Clinical Trials-Ready for Prime Time?
    Al Rifai M, Itchhaporia D, Virani SS. Al Rifai M, et al. JAMA Netw Open. 2021 Dec 1;4(12):e2140212. doi: 10.1001/jamanetworkopen.2021.40212. JAMA Netw Open. 2021. PMID: 34962564 No abstract available.

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