Recruiting patients to medical research: double blind randomised trial of "opt-in" versus "opt-out" strategies

Objective To evaluate the effect of opt-in compared with opt-out recruitment strategies on response rate and selection bias. Design Double blind randomised controlled trial. Setting Two general practices in England. Participants 510 patients with angina. Intervention Patients were randomly allocated to an opt-in (asked to actively signal willingness to participate in research) or opt-out (contacted repeatedly unless they signalled unwillingness to participate) approach for recruitment to an observational prognostic study of patients with angina. Main outcome measures Recruitment rate and clinical characteristics of patients. Results The recruitment rate, defined by clinic attendance, was 38% (96/252) in the opt-in arm and 50% (128/258) in the opt-out arm (P = 0.014). Once an appointment had been made, non-attendance at the clinic was similar (20% opt-in arm v 17% opt-out arm; P = 0.86). Patients in the opt-in arm had fewer risk factors (44% v 60%; P = 0.053), less treatment for angina (69% v 82%; P = 0.010), and less functional impairment (9% v 20%; P = 0.023) than patients in the opt-out arm. Conclusions The opt-in approach to participant recruitment, increasingly required by ethics committees, resulted in lower response rates and a biased sample. We propose that the opt-out approach should be the default recruitment strategy for studies with low risk to participants

Underuse of coronary revascularization procedures in patients considered appropriate candidates for revascularization.

Background: Ratings by an expert panel of the appropriateness of treatments may offer better guidance for clinical practice than the variable decisions of individual clinicians, yet there have been no prospective studies of clinical outcomes. We compared the clinical outcomes of patients treated medically after angiography with those of patients who underwent revascularization, within groups defined by ratings of the degree of appropriateness of revascularization in varying clinical circumstances.Methods: This was a prospective study of consecutive patients undergoing coronary angiography at three London hospitals. Before patients were recruited, a nine-member expert panel rated the appropriateness of percutaneous transluminal coronary angioplasty (PTCA) and coronary-artery bypass grafting (CABG) on a nine-point scale (with 1 denoting highly inappropriate and 9 denoting highly appropriate) for specific clinical indications. These ratings were then applied to a population of patients with coronary artery disease. However, the patients were treated without regard to the ratings. A total of 2552 patients were followed for a median of 30 months after angiography.Results: Of 908 patients with indications for which PTCA was rated appropriate (score, 7 to 9), 34 percent were treated medically; these patients were more likely to have angina at follow-up than those who underwent PTCA (odds ratio, 1.97; 95 percent confidence interval, 1.29 to 3.00). Of 1353 patients with indications for which CABG was considered appropriate, 26 percent were treated medically; they were more likely than those who underwent CABG to die or have a nonfatal myocardial infarction - the composite primary outcome (hazard ratio, 4.08; 95 percent confidence interval, 2.82 to 5.93) - and to have angina (odds ratio, 3.03; 95 percent confidence interval, 2.08 to 4.42). Furthermore, there was a graded relation between rating and outcome over the entire scale of appropriateness (P for linear trend = 0.002).Conclusions: On the basis of the ratings of the expert panel, we identified substantial underuse of coronary revascularization among patients who were considered appropriate candidates for these procedures. Underuse was associated with adverse clinical outcomes. (N Engl J Med 2001;344:645-54.) Copyright (C) 2001 Massachusetts Medical Society

Data Resource Profile: Cardiovascular disease research using linked bespoke studies and electronic health records (CALIBER)

The goal of cardiovascular disease (CVD) research using linked bespoke studies and electronic health records (CALIBER) is to provide evidence to inform health care and public health policy for CVDs across different stages of translation, from discovery, through evaluation in trials to implementation, where linkages to electronic health records provide new scientific opportunities. The initial approach of the CALIBER programme is characterized as follows: (i) Linkages of multiple electronic heath record sources: examples include linkages between the longitudinal primary care data from the Clinical Practice Research Datalink, the national registry of acute coronary syndromes (Myocardial Ischaemia National Audit Project), hospitalization and procedure data from Hospital Episode Statistics and cause-specific mortality and social deprivation data from the Office of National Statistics. Current cohort analyses involve a million people in initially healthy populations and disease registries with ∼105 patients. (ii) Linkages of bespoke investigator-led cohort studies (e.g. UK Biobank) to registry data (e.g. Myocardial Ischaemia National Audit Project), providing new means of ascertaining, validating and phenotyping disease. (iii) A common data model in which routine electronic health record data are made research ready, and sharable, by defining and curating with meta-data >300 variables (categorical, continuous, event) on risk factors, CVDs and non-cardiovascular comorbidities. (iv) Transparency: all CALIBER studies have an analytic protocol registered in the public domain, and data are available (safe haven model) for use subject to approvals. For more information, e-mail [email protected]

Long-term excess mortality associated with diabetes following acute myocardial infarction: a population-based cohort study

The long-term excess risk of death associated with diabetes following acute myocardial infarction is unknown. We determined the excess risk of death associated with diabetes among patients with ST-elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) after adjustment for comorbidity, risk factors and cardiovascular treatments.Nationwide population-based cohort (STEMI n=281 259 and NSTEMI n=422 661) using data from the UK acute myocardial infarction registry, MINAP, between 1 January 2003 and 30 June 2013. Age, sex, calendar year and country-specific mortality rates for the populace of England and Wales (n=56.9 million) were matched to cases of STEMI and NSTEMI. Flexible parametric survival models were used to calculate excess mortality rate ratios (EMRR) after multivariable adjustment. This study is registered at ClinicalTrials.gov (NCT02591576).Over 1.94 million person-years follow-up including 120 568 (17.1%) patients with diabetes, there were 187 875 (26.7%) deaths. Overall, unadjusted (all cause) mortality was higher among patients with than without diabetes (35.8% vs 25.3%). After adjustment for age, sex and year of acute myocardial infarction, diabetes was associated with a 72% and 67% excess risk of death following STEMI (EMRR 1.72, 95% CI 1.66 to 1.79) and NSTEMI (1.67, 1.63 to 1.71). Diabetes remained significantly associated with substantial excess mortality despite cumulative adjustment for comorbidity (EMRR 1.52, 95% CI 1.46 to 1.58 vs 1.45, 1.42 to 1.49), risk factors (1.50, 1.44 to 1.57 vs 1.33, 1.30 to 1.36) and cardiovascular treatments (1.56, 1.49 to 1.63 vs 1.39, 1.36 to 1.43).At index acute myocardial infarction, diabetes was common and associated with significant long-term excess mortality, over and above the effects of comorbidities, risk factors and cardiovascular treatments

Excess mortality and guideline-indicated care following non-ST-elevation myocardial infarction

BACKGROUND: Adherence to guideline-indicated care for the treatment of non-ST-elevation myocardial infarction (NSTEMI) is associated with improved outcomes. We investigated the extent and consequences of non-adherence to guideline-indicated care across a national health system. METHODS: A cohort study (ClinicalTrials.gov identifier: NCT02436187) was conducted using data from the Myocardial Ischaemia National Audit Project (n = 389,057 NSTEMI, n = 247 hospitals, England and Wales, 2003-2013). Accelerated failure time models were used to quantify the impact of non-adherence on survival according to dates of guideline publication. RESULTS: Over a period of 1,079,044 person-years (median 2.2 years of follow-up), 113,586 (29.2%) NSTEMI patients died. Of those eligible to receive care, 337,881 (86.9%) did not receive one or more guideline-indicated intervention; the most frequently missed were dietary advice (n = 254,869, 68.1%), smoking cessation advice (n = 245,357, 87.9%), P2Y12 inhibitors (n = 192,906, 66.3%) and coronary angiography (n = 161,853, 43.4%). Missed interventions with the strongest impact on reduced survival were coronary angiography (time ratio: 0.18, 95% confidence interval (CI): 0.17-0.18), cardiac rehabilitation (time ratio: 0.49, 95% CI: 0.48-0.50), smoking cessation advice (time ratio: 0.53, 95% CI: 0.51-0.57) and statins (time ratio: 0.56, 95% CI: 0.55-0.58). If all eligible patients in the study had received optimal care at the time of guideline publication, then 32,765 (28.9%) deaths (95% CI: 30,531-33,509) may have been prevented. CONCLUSION: The majority of patients hospitalised with NSTEMI missed at least one guideline-indicated intervention for which they were eligible. This was significantly associated with excess mortality. Greater attention to the provision of guideline-indicated care for the management of NSTEMI will reduce premature cardiovascular deaths

Using electronic health records to predict costs and outcomes in stable coronary artery disease

OBJECTIVES: To use electronic health records (EHR) to predict lifetime costs and health outcomes of patients with stable coronary artery disease (stable-CAD) stratified by their risk of future cardiovascular events, and to evaluate the cost-effectiveness of treatments targeted at these populations. METHODS: The analysis was based on 94 966 patients with stable-CAD in England between 2001 and 2010, identified in four prospectively collected, linked EHR sources. Markov modelling was used to estimate lifetime costs and quality-adjusted life years (QALYs) stratified by baseline cardiovascular risk. RESULTS: For the lowest risk tenth of patients with stable-CAD, predicted discounted remaining lifetime healthcare costs and QALYs were £62 210 (95% CI £33 724 to £90 043) and 12.0 (95% CI 11.5 to 12.5) years, respectively. For the highest risk tenth of the population, the equivalent costs and QALYs were £35 549 (95% CI £31 679 to £39 615) and 2.9 (95% CI 2.6 to 3.1) years, respectively. A new treatment with a hazard reduction of 20% for myocardial infarction, stroke and cardiovascular disease death and no side-effects would be cost-effective if priced below £72 per year for the lowest risk patients and £646 per year for the highest risk patients. CONCLUSIONS: Existing EHRs may be used to estimate lifetime healthcare costs and outcomes of patients with stable-CAD. The stable-CAD model developed in this study lends itself to informing decisions about commissioning, pricing and reimbursement. At current prices, to be cost-effective some established as well as future stable-CAD treatments may require stratification by patient risk

Long-term healthcare use and costs in patients with stable coronary artery disease: a population-based cohort using linked health records (CALIBER)

AIMS: To examine long-term healthcare utilization and costs of patients with stable coronary artery disease (SCAD). METHODS AND RESULTS: Linked cohort study of 94 966 patients with SCAD in England, 1 January 2001 to 31 March 2010, identified from primary care, secondary care, disease, and death registries. Resource use and costs, and cost predictors by time and 5-year cardiovascular disease (CVD) risk profile were estimated using generalized linear models. Coronary heart disease hospitalizations were 20.5% in the first year and 66% in the year following a non-fatal (myocardial infarction, ischaemic or haemorrhagic stroke) event. Mean healthcare costs were £3133 per patient in the first year and £10 377 in the year following a non-fatal event. First-year predictors of cost included sex (mean cost £549 lower in females), SCAD diagnosis (non-ST-elevation myocardial infarction cost £656 more than stable angina), and co-morbidities (heart failure cost £657 more per patient). Compared with lower risk patients (5-year CVD risk 3.5%), those of higher risk (5-year CVD risk 44.2%) had higher 5-year costs (£23 393 vs. £9335) and lower lifetime costs (£43 020 vs. £116 888). CONCLUSION: Patients with SCAD incur substantial healthcare utilization and costs, which varies and may be predicted by 5-year CVD risk profile. Higher risk patients have higher initial but lower lifetime costs than lower risk patients as a result of shorter life expectancy. Improved cardiovascular survivorship among an ageing CVD population is likely to require stratified care in anticipation of the burgeoning demand

Prolonged dual anti-platelet therapy in stable coronary disease: a comparative observational study of benefits and harms in unselected versus trial populations

Objective: To estimate the potential magnitude in unselected patients of the benefits and harms of prolonged dual antiplatelet therapy after acute myocardial infarction seen in selected patients with high risk characteristics in trials. Design: Observational population based cohort study. Setting: PEGASUS-TIMI-54 trial population and CALIBER (ClinicAl research using LInked Bespoke studies and Electronic health Records). Participants: 7238 patients who survived a year or more after acute myocardial infarction. Interventions: Prolonged dual antiplatelet therapy after acute myocardial infarction. Main outcome measures: Recurrent acute myocardial infarction, stroke, or fatal cardiovascular disease. Fatal, severe, or intracranial bleeding. Results: 1676/7238 (23.1%) patients met trial inclusion and exclusion criteria (“target” population). Compared with the placebo arm in the trial population, in the target population the median age was 12 years higher, there were more women (48.6% v 24.3%), and there was a substantially higher cumulative three year risk of both the primary (benefit) trial endpoint of recurrent acute myocardial infarction, stroke, or fatal cardiovascular disease (18.8% (95% confidence interval 16.3% to 21.8%) v 9.04%) and the primary (harm) endpoint of fatal, severe, or intracranial bleeding (3.0% (2.0% to 4.4%) v 1.26% (TIMI major bleeding)). Application of intention to treat relative risks from the trial (ticagrelor 60 mg daily arm) to CALIBER’s target population showed an estimated 101 (95% confidence interval 87 to 117) ischaemic events prevented per 10 000 treated per year and an estimated 75 (50 to 110) excess fatal, severe, or intracranial bleeds caused per 10 000 patients treated per year. Generalisation from CALIBER’s target subgroup to all 7238 real world patients who were stable at least one year after acute myocardial infarction showed similar three year risks of ischaemic events (17.2%, 16.0% to 18.5%), with an estimated 92 (86 to 99) events prevented per 10 000 patients treated per year, and similar three year risks of bleeding events (2.3%, 1.8% to 2.9%), with an estimated 58 (45 to 73) events caused per 10 000 patients treated per year. Conclusions: This novel use of primary-secondary care linked electronic health records allows characterisation of “healthy trial participant” effects and confirms the potential absolute benefits and harms of dual antiplatelet therapy in representative patients a year or more after acute myocardial infarction

Geographic variation in the treatment of non-ST-segment myocardial infarction in the English National Health Service: a cohort study

Objectives: To investigate geographic variation in guideline-indicated treatments for NSTEMI in the English National Health Service (NHS). Design: Cohort study using registry data from the Myocardial Ischaemia National Audit Project. Setting: All Clinical Commissioning Groups (CCGs) (n=211) in the English NHS. Participants: 357,228 patients with NSTEMI between 1st January, 2003 and 30th June, 2013. Main outcome measure: Proportion of eligible NSTEMI who received all eligible guideline-indicated treatments (optimal care) according to the date of guideline publication. Results: The proportion of NSTEMI who received optimal care was low (48,257/357,228; 13.5%) and varied between CCGs (median 12.8%, interquartile range 0.7 to 18.1%). The greatest geographic variation was for aldosterone antagonists (16.7%, 0.0 to 40.0%) and least for use of an electrocardiogram (96.7%, 92.5 to 98.7%). The highest rates of care were for acute aspirin (median 92.8%, interquartile range 88.6 to 97.1%), and aspirin (90.1%, 85.1 to 93.3%) and statins (86.4%, 82.3 to 91.2%) at hospital discharge. The lowest rates were for smoking cessation advice (median 11.6%, interquartile range 8.7 to 16.6%), dietary advice (32.4%, 23.9 to 41.7%) and the prescription of P2Y12 inhibitors (39.7%, 32.4 to 46.9%). After adjustment for case mix, nearly all (99.6%) of the variation was due to between hospitals differences (median 64.7%, interquartile range 57.4% to 70.0%; between hospital variance: 1.92, 95% confidence interval 1.51 to 2.44; interclass correlation 0.996, 0.976 to 0.999). Conclusions: Across the English NHS, the optimal use of guideline-indicated treatments for NSTEMI was low. Variation in the use of specific treatments for NSTEMI was mostly explained by between-hospital differences in care. Performance-based commissioning may increase the use of NSTEMI treatments and, therefore, reduce premature cardiovascular deaths

How Does Cardiovascular Disease First Present in Women and Men? Incidence of 12 Cardiovascular Diseases in a Contemporary Cohort of 1 937 360 People

Background—Given the recent declines in heart attack and stroke incidence, it is unclear how women and men differ in first lifetime presentations of cardiovascular diseases (CVDs). We compared the incidence of 12 cardiac, cerebrovascular, and peripheral vascular diseases in women and men at different ages. Methods and Results—We studied 1 937 360 people, aged ≥30 years and free from diagnosed CVD at baseline (51% women), using linked electronic health records covering primary care, hospital admissions, acute coronary syndrome registry, and mortality (Cardiovascular Research Using LInked Bespoke Studies and Electronic Records [CALIBER] research platform). During 6 years median follow-up between 1997 and 2010, 114 859 people experienced an incident cardiovascular diagnosis, the majority (66%) of which were neither myocardial infarction nor ischemic stroke. Associations of male sex with initial diagnoses of CVD, however, varied from strong (age-adjusted hazard ratios, 3.6–5.0) for abdominal aortic aneurysm, myocardial infarction, and unheralded coronary death (particularly >60 years), through modest (hazard ratio, 1.5–2.0) for stable angina, ischemic stroke, peripheral arterial disease, heart failure, and cardiac arrest, to weak (hazard ratio <1.5) for transient ischemic attack, intracerebral hemorrhage, and unstable angina, and inverse (0.69) for subarachnoid hemorrhage (all P<0.001). Conclusions—The majority of initial presentations of CVD are neither myocardial infarction nor ischemic stroke, yet most primary prevention studies focus on these presentations. Sex has differing associations with different CVDs, with implications for risk prediction and management strategies. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01164371