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.

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.

Streamlined mail-based methods for large randomised trials: lessons learnt from the ASCEND study.

Reliable assessment of the effects of an intervention usually requires large randomised trials but such studies are becoming increasingly complex and costly to run. 'Streamlined' trials are needed in which every aspect of the trial design and conduct is simplified, retaining only those elements needed to answer the research question and ensure the safety of the individual participants. In this review we discuss how the trial 'A Study of Cardiovascular Events iN Diabetes' (ASCEND) was streamlined. The study included a two-by-two factorial design: it assessed the effects of low-dose aspirin and, separately, supplementation with n-3 fatty acids on serious vascular events in 15,480 people with diabetes but no overt cardiovascular disease. Other key streamlined design features, such as mail-based recruitment and follow-up, mainly by post, with no in-person visits and use of a run-in period, are also described. We go on to discuss the success of the study and other studies that have employed a similar mail-based approach, and the type of clinical trials that are suitable for mail-based design. Finally, we consider the limitations of the study, and how these could be circumvented in future studies. ASCEND randomised large numbers of eligible participants, achieved good adherence rates and almost complete follow-up at a fraction of the cost of traditional clinic-based trials. Such studies are necessary if researchers are to address the important clinical questions most relevant to improving health.

Effects of n-3 Fatty Acid Supplements in Diabetes Mellitus.

BACKGROUND: Increased intake of n-3 fatty acids has been associated with a reduced risk of cardiovascular disease in observational studies, but this finding has not been confirmed in randomized trials. It remains unclear whether n-3 (also called omega-3) fatty acid supplementation has cardiovascular benefit in patients with diabetes mellitus. METHODS: We randomly assigned 15,480 patients with diabetes but without evidence of atherosclerotic cardiovascular disease to receive 1-g capsules containing either n-3 fatty acids (fatty acid group) or matching placebo (olive oil) daily. The primary outcome was a first serious vascular event (i.e., nonfatal myocardial infarction or stroke, transient ischemic attack, or vascular death, excluding confirmed intracranial hemorrhage). The secondary outcome was a first serious vascular event or any arterial revascularization. RESULTS: During a mean follow-up of 7.4 years (adherence rate, 76%), a serious vascular event occurred in 689 patients (8.9%) in the fatty acid group and in 712 (9.2%) in the placebo group (rate ratio, 0.97; 95% confidence interval [CI], 0.87 to 1.08; P=0.55). The composite outcome of a serious vascular event or revascularization occurred in 882 patients (11.4%) and 887 patients (11.5%), respectively (rate ratio, 1.00; 95% CI, 0.91 to 1.09). Death from any cause occurred in 752 patients (9.7%) in the fatty acid group and in 788 (10.2%) in the placebo group (rate ratio, 0.95; 95% CI, 0.86 to 1.05). There were no significant between-group differences in the rates of nonfatal serious adverse events. CONCLUSIONS: Among patients with diabetes without evidence of cardiovascular disease, there was no significant difference in the risk of serious vascular events between those who were assigned to receive n-3 fatty acid supplementation and those who were assigned to receive placebo. (Funded by the British Heart Foundation and others; Current Controlled Trials number, ISRCTN60635500 ; ClinicalTrials.gov number, NCT00135226 .).

ASCEND: A Study of Cardiovascular Events iN Diabetes: Characteristics of a randomized trial of aspirin and of omega-3 fatty acid supplementation in 15,480 people with diabetes.

OBJECTIVES: The use of aspirin for the secondary prevention of cardiovascular disease (CVD) is firmly established, and the proportional reductions in heart attacks and strokes appear to be similar in people with and without diabetes. Uncertainty remains about the role of antiplatelet treatments for primary prevention of CVD, and guidelines vary in their recommendations. It has also been hypothesized that long-term aspirin can prevent gastro-intestinal and other cancers. Observational studies suggest associations between higher intakes of omega-3 fatty acids (FA) and lower rates of CVD, but there is no large-scale randomized evidence to support using prophylactic omega-3 FA supplementation in primary prevention. ASCEND is a randomized trial assessing whether 100 mg daily aspirin safely prevents CVD and cancer in patients with diabetes without known arterial disease. It is also assessing whether supplementation with 1 g omega-3 FA daily prevents CVD. This paper describes the methods and baseline characteristics of the randomized participants. METHODS AND RESULTS: Between 2005 and 2011, using mail-based methods, 15,480 people with diabetes were randomized to aspirin versus placebo and, in a factorial design, to omega-3 FA supplementation versus placebo. Blood and urine samples were collected to allow baseline stratification by biochemical prognostic variables (e.g. HbA1c, blood lipids). Follow-up is for a median of at least 7 years. CONCLUSIONS: Demonstrating that prophylactic aspirin safely reduces the risk of CVD or cancer in the primary prevention setting, or that omega-3 FA supplementation prevents CVD, would be relevant to hundreds of millions of people worldwide who are currently not receiving such therapies. The results of ASCEND will be reported in 2018.

Cost-effective recruitment methods for a large randomised trial in people with diabetes: A Study of Cardiovascular Events iN Diabetes (ASCEND).

BACKGROUND: Clinical trials require cost-effective methods for identifying, randomising, and following large numbers of people in order to generate reliable evidence. ASCEND (A Study of Cardiovascular Events iN Diabetes) is a randomised '2 × 2 factorial design' study of aspirin and omega-3 fatty acid supplements for the primary prevention of cardiovascular events in people with diabetes; this study used central disease registers and a mail-based approach to identify, randomise, and follow 15,000 people. In collaboration with UK consultants and general practitioners (GPs), researchers identified potentially eligible people with diabetes from centrally held registers (e.g. for retinopathy screening) and GP-held disease registers. Permission was obtained under section 251 of the National Health Service Act 2006 (previously section 60 of the NHS act 2001) to allow invitation letters to be generated centrally in the name of the holder of the register. In addition, with the collaboration of the National Institutes for Health Research (NIHR) Diabetes and Primary Care Research Networks (DRN and PCRN), general practices sent pre-assembled invitation packs to people with a diagnosis of diabetes. Invitation packs included a cover letter, screening questionnaire (with consent form), information leaflet, and a Freepost envelope. Eligible patients entered a 2-month, pre-randomisation, run-in phase on placebo tablets and were only randomised if they completed a randomisation form and remained willing and eligible at the end of the run-in. Follow-up is ongoing, using mail-based approaches that are being supplemented by central registry data. RESULTS: Information on approximately 600,000 people listed on 58 centrally held diabetes registers was obtained, and 300,188 potentially eligible patients were invited to join the study. In addition, 785 GP practices mailed invitations to 120,875 patients. A further 2,340 potential study participants were identified via other routes. In total, 423,403 people with diabetes were invited to take part; 26,462 entered the 2-month, pre-randomisation, run-in phase; and 15,480 were randomised. CONCLUSION: If sufficient numbers of potentially eligible patients can be identified centrally and the trial treatments do not require participants to attend clinics, the recruitment and follow-up of patients by mail is feasible and cost-effective. Wider use of these methods could allow more, large, randomised trials to be undertaken successfully and cost-effectively. TRIAL REGISTRATION: Current Controlled Trials, ISRCTN60635500 , registered on 14 July 2005.

Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial.

CONTEXT: Blood homocysteine levels are positively associated with cardiovascular disease, but it is uncertain whether the association is causal. OBJECTIVE: To assess the effects of reducing homocysteine levels with folic acid and vitamin B(12) on vascular and nonvascular outcomes. DESIGN, SETTING, AND PATIENTS: Double-blind randomized controlled trial of 12,064 survivors of myocardial infarction in secondary care hospitals in the United Kingdom between 1998 and 2008. INTERVENTIONS: 2 mg folic acid plus 1 mg vitamin B(12) daily vs matching placebo. MAIN OUTCOME MEASURES: First major vascular event, defined as major coronary event (coronary death, myocardial infarction, or coronary revascularization), fatal or nonfatal stroke, or noncoronary revascularization. RESULTS: Allocation to the study vitamins reduced homocysteine by a mean of 3.8 micromol/L (28%). During 6.7 years of follow-up, major vascular events occurred in 1537 of 6033 participants (25.5%) allocated folic acid plus vitamin B(12) vs 1493 of 6031 participants (24.8%) allocated placebo (risk ratio [RR], 1.04; 95% confidence interval [CI], 0.97-1.12; P = .28). There were no apparent effects on major coronary events (vitamins, 1229 [20.4%], vs placebo, 1185 [19.6%]; RR, 1.05; 95% CI, 0.97-1.13), stroke (vitamins, 269 [4.5%], vs placebo, 265 [4.4%]; RR, 1.02; 95% CI, 0.86-1.21), or noncoronary revascularizations (vitamins, 178 [3.0%], vs placebo, 152 [2.5%]; RR, 1.18; 95% CI, 0.95-1.46). Nor were there significant differences in the numbers of deaths attributed to vascular causes (vitamins, 578 [9.6%], vs placebo, 559 [9.3%]) or nonvascular causes (vitamins, 405 [6.7%], vs placebo, 392 [6.5%]) or in the incidence of any cancer (vitamins, 678 [11.2%], vs placebo, 639 [10.6%]). CONCLUSION: Substantial long-term reductions in blood homocysteine levels with folic acid and vitamin B(12) supplementation did not have beneficial effects on vascular outcomes but were also not associated with adverse effects on cancer incidence. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN74348595.