Authors' objectives: Bleeding among populations undergoing percutaneous coronary intervention or coronary artery bypass grafting and among conservatively managed patients with acute coronary syndrome exposed to different dual antiplatelet therapy and triple therapy (i.e. dual antiplatelet therapy plus an anticoagulant) has not been previously quantified. The objectives were to estimate hazard ratios for bleeding for different antiplatelet and triple therapy regimens, estimate resources and the associated costs of treating bleeding events, and to extend existing economic models of the cost-effectiveness of dual antiplatelet therapy. Dual antiplatelet therapy (DAPT), a combination of aspirin and clopidogrel, prasugrel or ticagrelor, is recommended for up to 12 months for secondary prevention of ischaemic events (heart attack and stroke) among people undergoing coronary interventions [coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI)] and people with acute coronary syndrome (ACS) who are medically managed. Randomised controlled trials (RCTs) in these populations suggest that DAPT increases the risk of bleeding compared with aspirin monotherapy, and that more potent DAPT (with prasugrel and ticagrelor) increases the risk of bleeding compared with less potent DAPT (with clopidogrel). Adding an anticoagulant to DAPT (e.g. for the management of atrial fibrillation), known as triple therapy (TT), increases risk further. Real-world bleeding among populations exposed to different DAPT and TT regimens has not been previously quantified. The economic impact of bleeding events is poorly characterised, in particular for minor bleeding, as is their impact on health-related quality of life (HRQoL). 1.Estimate rates of major and minor bleeding events with different DAPT (and TT) exposures among CABG, PCI and conservatively treated ACS patients. 2.Estimate hazard ratios (HRs) for bleeding for different antiplatelet regimens: for the PCI cohort, we compared aspirin and clopidogrel (AC) with aspirin and prasugrel (AP) or aspirin and ticagrelor (AT); for the CABG and ACS no-procedure cohorts, we compared aspirin with AC. 3.Review the literature to estimate the deterioration in utility (quality-adjusted life-years) of patients who have minor or major bleeding events. 4.Revise/extend existing economic models of the cost-effectiveness of different DAPT regimens to include estimates of the incidence of minor and major bleeding events and associated impacts on utility in the general population. 5.Estimate the resources required and associated costs incurred of treating major and minor events of the alternative DAPT (TT) exposures in the three specified patient populations. 6.Understand patients' perspectives of DAPT, and the factors that influence responses to nuisance bleeding focusing on adherence and information-seeking (this objective was identified through the patient and public involvement work after the start of the ADAPTT study). We conducted a study to identify confounders systematically by performing a systematic review of RCTs and cohort studies; conducting semistructured interviews with six cardiac surgeons, six cardiologists and five general practitioners (GPs); and conducting a survey of 79 cardiologists and 31 cardiac surgeons. We used linked Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES) data to assemble populations (CABG, PCI and conservatively managed ACS patients) eligible for three target trials. Inclusion criteria for the target trial were as follows: 18 years of age, 1 year of data in CPRD before the index event, no prescription for DAPT or anticoagulants in the preceding 3 months and a prescription for aspirin or DAPT within 2 months of discharge after the index event. The primary outcome was any bleeding event (CPRD or HES data) up to 12 months after the index event. We described rates of bleeding among patients prescribed different DAPT regimens and TT. We estimated adjusted HRs for time to first bleed comparing DAPT with AC (reference) versus aspirin monotherapy for CABG and conservatively managed ACS patient, and, in the emergency PCI population, DAPT with prasugrel versus DAPT with clopidogrel for ST-elevation myocardial infarction (STEMI) patients only and DAPT with ticagrelor versus DAPT with clopidogrel for all the emergency PCI population. We prespecified five sensitivity analyses and conducted three: sensitivity analysis 1 - multiple imputation for eligible patients for whom we had no data to assign an intervention; sensitivity analysis 3 - restricted to patients at low risk of bleeding; and sensitivity analysis 4 -repeating primary outcome analysis without censoring of any CPRD or HES bleed events at transfer-out or last collection date. The transfer-out or last collection date reflect the date that a patient leaves the general practice or the date that the last capture from CPRD was made. A systematic review was conducted of primary research and decision-analytic modelling studies reporting utility decrements for bleeds related to DAPT through a search of MEDLINE, PubMed and references of included studies. A health elicitation study was undertaken, comprising 21 participants (PCI, CABG and conservatively managed ACS) who completed an elicitation exercise involving vignettes describing minor and major bleeds and the EuroQol-5 Dimensions, three-level version (EQ-5D-3L), and the EuroQol-5 Dimensions, five-level version (EQ-5D-5L). Utility decrements were derived using linear regression, and were compared with existing estimates. No formal cost-effectiveness evaluation was undertaken. Data on health-care use were derived from the linked HES data set. The total health-care costs associated with the different antiplatelet regimens in the three target trials were measured at 1, 2 and 3 years after the start of follow-up. We used inverse probability of treatment weighting to adjust for the same confounders identified for the main ADAPTT analysis. The total health-care costs at 1, 2 and 3 years of follow-up were estimated by fitting weighted generalised linear models with gamma distribution and log-link. Two focus groups were conducted with patients at the early stages of treatment (3 months, nine participants), and two with patients coming to the end of treatment (12 months, 12 participants), to explore their experiences with DAPT. Recordings were transcribed verbatim, anonymised and analysed using framework analysis. Confounders study A total of 70 potential confounders were identified by systematic review, clinician interviews and surveys; of these, 34 (49%) were classified as true confounders (factors that influence both the assigned intervention and the outcome), of which 31 (91%) were identified by systematic review and three (9%) by clinician interview, and 31 (91%) were confirmed by the survey. The clinician interviews identified hard-to-measure factors not identified in the review (drug potency, resistance to antiplatelet medication and clinician concerns about adherence). Data that would enable the characterisation of risk, including presentation risk and procedural risk factors, were unavailable for 17 of the 34 confounders (50%). Twelve eligible studies were included for review. Reported utility decrements ranged from 0.002 to 0.03 for minor bleeds and 0.007 to 0.05 for major bleeds. Data sources used to estimate the decrements lacked relevance to our population group, and few studies adequately reported details of their measurement and valuation approaches. Our patient health elicitation study elicited utility decrements that overlapped existing estimates, ranging from 0.000848 to 0.00828 for minor bleeds and from 0.0187 to 0.0621 for major bleeds. However, the magnitude of difference depended on the instrument (EQ-5D-5L or EQ-5D-3L), estimation method and valuation approach applied. The mean total health-care cost in the year prior to the index event was much higher for CABG patients (13,601) than for conservatively managed ACS (3528) or emergency PCI patients (3625). For CABG patients, mean costs were similar between different antiplatelet regimens (13,623 for aspirin monotherapy and 13,537 for DAPT with clopidogrel). For conservatively managed ACS, patients on DAPT with clopidogrel had a lower mean total health-care cost in the year prior to the index date than patients on aspirin monotherapy (3317 vs. 3857, respectively). Among emergency PCI patients, those initiated on DAPT with clopidogrel had a higher mean total health-care cost in the year prior to the index event (4492) than those initiated on DAPT with prasugrel (STEMI patients only) (£1660) or ticagrelor (£2829). Among the CABG population, there was no difference in mean cumulative health-care costs between initiation of DAPT with clopidogrel and initiation of aspirin monotherapy; the mean difference at 1, 2 and 3 years was £94 (95% CI –£555 to £763), £236 (95% CI –£831 to £1223) and £113 (95% CI –£1318 to £1102), respectively. Among the conservatively managed ACS population, the mean cumulative health-care costs were estimated to be slightly higher if all patients were treated with DAPT with clopidogrel than if all were treated with aspirin monotherapy; the mean difference at 1, 2 and 3 years was £610 (95% CI –£626 to £1516), £1118 (95% CI –£226 to £2206) and £1225 (95% CI –£426 to £2423), respectively, although there was considerable overlap between CIs. For emergency PCI patients, the estimated cumulative health-care costs were comparable under the different antiplatelet regimens among patients not receiving concurrent proton pump inhibitor (PPI) prescriptions, but were higher for patients receiving DAPT with ticagrelor than for patients receiving DAPT with clopidogrel. At 1 year, for example, the predicted mean difference in health-care costs if all patients received DAPT with ticagrelor rather than DAPT with clopidogrel was £72 (95% CI –£532 to £762) among those not receiving concurrent PPI therapy and £1145 (95% CI £269 to £2195) among those receiving concurrent PPI therapy. Among STEMI patients receiving concurrent PPI therapy, DAPT with prasugrel was associated with higher costs than DAPT with clopidogrel or DAPT with ticagrelor. Participants would adhere to DAPT when they believed that DAPT was important to ACS outcomes. Those who had experienced nuisance bleeding reported symptoms to be mild and manageable and did not report the bleed to their GP. Adherence was influenced by participants’ and their families’ understanding of the risks and benefits of DAPT, and their ability to manage symptoms. Factors influencing knowledge about DAPT included access to medication counselling; processing of and engaging with information communicated during medication counselling; and access to timely, relevant and expert information and advice after discharge from hospital.

Authors' results and conclusions: The incidence of any bleeding was 5% among coronary artery bypass graft patients, 10% among conservatively managed acute coronary syndrome patients and 9% among emergency percutaneous coronary intervention patients, compared with 18% among patients prescribed triple therapy. Among coronary artery bypass grafting and conservatively managed acute coronary syndrome patients, dual antiplatelet therapy, compared with aspirin, increased the hazards of any bleeding (coronary artery bypass grafting: hazard ratio 1.43, 95% confidence interval 1.21 to 1.69; conservatively-managed acute coronary syndrome: hazard ratio 1.72, 95% confidence interval 1.15 to 2.57) and major adverse cardiovascular events (coronary artery bypass grafting: hazard ratio 2.06, 95% confidence interval 1.23 to 3.46; conservatively-managed acute coronary syndrome: hazard ratio 1.57, 95% confidence interval 1.38 to 1.78). Among emergency percutaneous coronary intervention patients, dual antiplatelet therapy with ticagrelor, compared with dual antiplatelet therapy with clopidogrel, increased the hazard of any bleeding (hazard ratio 1.47, 95% confidence interval 1.19 to 1.82), but did not reduce the incidence of major adverse cardiovascular events (hazard ratio 1.06, 95% confidence interval 0.89 to 1.27). Among ST elevation myocardial infarction percutaneous coronary intervention patients, dual antiplatelet therapy with prasugrel, compared with dual antiplatelet therapy with clopidogrel, increased the hazard of any bleeding (hazard ratio 1.48, 95% confidence interval 1.02 to 2.12), but did not reduce the incidence of major adverse cardiovascular events (hazard ratio 1.10, 95% confidence interval 0.80 to 1.51). Health-care costs in the first year did not differ between dual antiplatelet therapy with clopidogrel and aspirin monotherapy among either coronary artery bypass grafting patients (mean difference £94, 95% confidence interval –£155 to £763) or conservatively managed acute coronary syndrome patients (mean difference £610, 95% confidence interval –£626 to £1516), but among emergency percutaneous coronary intervention patients were higher for those receiving dual antiplatelet therapy with ticagrelor than for those receiving dual antiplatelet therapy with clopidogrel, although for only patients on concurrent proton pump inhibitors (mean difference £1145, 95% confidence interval £269 to £2195). This study suggests that more potent dual antiplatelet therapy may increase the risk of bleeding without reducing the incidence of major adverse cardiovascular events. These results should be carefully considered by clinicians and decision-makers alongside randomised controlled trial evidence when making recommendations about dual antiplatelet therapy. There is underascertainment of minor/nuisance bleeding in the CPRD, probably as a result of under-reporting of nuisance bleeding by patients to their GPs. In three retrospective population-based cohort studies emulating target trials, there was an increased risk of bleeding among patients receiving DAPT compared with those receiving aspirin monotherapy (CABG and conservatively managed ACS patients) and among patients receiving more potent DAPT than among those receiving less potent DAPT (emergency PCI patients), but not the expected decrease in MACEs. We identified several potential biases that may have influenced the results of the ADAPTT study as a result of imperfect emulation of the defined target trials: (1) selection bias – we excluded a subgroup of the eligible population because they could not be assigned an intervention; (2) confounding – we had no data for half of the confounders identified, including procedure-related characteristics and disease complexity, and evidence from clinician interviews and surveys that clinicians balance bleeding and ischaemic risk when prescribing DAPT to their patients; and (3) non-adherence to DAPT, which was substantial, and generally higher in the stronger antiplatelet treatment groups. Medication knowledge and understanding, and confidence in dealing with symptoms facilitate positive attitudes towards adherence to DAPT, but may be hindered by opportunities to access relevant, timely and appropriate medication counselling. Although we derived relevant utility decrements for the included population using a patient elicitation exercise, based on standardised definitions of minor and major bleeding events, using a validated HRQoL instrument and valued using general population tariffs, we could not conduct a formal cost-effectiveness analysis given the uncertainty around the estimates for bleeding. Nevertheless, the results using routinely collected data need to be carefully considered by clinicians and decision-makers, given that the increased risk of bleeding we observed with more potent DAPT was not offset by a reduced risk of cardiovascular events and that several recent large meta-analyses of RCTs have also failed to show a conclusive benefit of more potent antiplatelet therapy on cardiovascular events.

Authors' recommendations: The incidence of any bleeding was 5% among coronary artery bypass graft patients, 10% among conservatively managed acute coronary syndrome patients and 9% among emergency percutaneous coronary intervention patients, compared with 18% among patients prescribed triple therapy. Among coronary artery bypass grafting and conservatively managed acute coronary syndrome patients, dual antiplatelet therapy, compared with aspirin, increased the hazards of any bleeding (coronary artery bypass grafting: hazard ratio 1.43, 95% confidence interval 1.21 to 1.69; conservatively-managed acute coronary syndrome: hazard ratio 1.72, 95% confidence interval 1.15 to 2.57) and major adverse cardiovascular events (coronary artery bypass grafting: hazard ratio 2.06, 95% confidence interval 1.23 to 3.46; conservatively-managed acute coronary syndrome: hazard ratio 1.57, 95% confidence interval 1.38 to 1.78). Among emergency percutaneous coronary intervention patients, dual antiplatelet therapy with ticagrelor, compared with dual antiplatelet therapy with clopidogrel, increased the hazard of any bleeding (hazard ratio 1.47, 95% confidence interval 1.19 to 1.82), but did not reduce the incidence of major adverse cardiovascular events (hazard ratio 1.06, 95% confidence interval 0.89 to 1.27). Among ST elevation myocardial infarction percutaneous coronary intervention patients, dual antiplatelet therapy with prasugrel, compared with dual antiplatelet therapy with clopidogrel, increased the hazard of any bleeding (hazard ratio 1.48, 95% confidence interval 1.02 to 2.12), but did not reduce the incidence of major adverse cardiovascular events (hazard ratio 1.10, 95% confidence interval 0.80 to 1.51). Health-care costs in the first year did not differ between dual antiplatelet therapy with clopidogrel and aspirin monotherapy among either coronary artery bypass grafting patients (mean difference £94, 95% confidence interval –£155 to £763) or conservatively managed acute coronary syndrome patients (mean difference £610, 95% confidence interval –£626 to £1516), but among emergency percutaneous coronary intervention patients were higher for those receiving dual antiplatelet therapy with ticagrelor than for those receiving dual antiplatelet therapy with clopidogrel, although for only patients on concurrent proton pump inhibitors (mean difference £1145, 95% confidence interval £269 to £2195). This study suggests that more potent dual antiplatelet therapy may increase the risk of bleeding without reducing the incidence of major adverse cardiovascular events. These results should be carefully considered by clinicians and decision-makers alongside randomised controlled trial evidence when making recommendations about dual antiplatelet therapy. There is underascertainment of minor/nuisance bleeding in the CPRD, probably as a result of under-reporting of nuisance bleeding by patients to their GPs. In three retrospective population-based cohort studies emulating target trials, there was an increased risk of bleeding among patients receiving DAPT compared with those receiving aspirin monotherapy (CABG and conservatively managed ACS patients) and among patients receiving more potent DAPT than among those receiving less potent DAPT (emergency PCI patients), but not the expected decrease in MACEs. We identified several potential biases that may have influenced the results of the ADAPTT study as a result of imperfect emulation of the defined target trials: (1) selection bias – we excluded a subgroup of the eligible population because they could not be assigned an intervention; (2) confounding – we had no data for half of the confounders identified, including procedure-related characteristics and disease complexity, and evidence from clinician interviews and surveys that clinicians balance bleeding and ischaemic risk when prescribing DAPT to their patients; and (3) non-adherence to DAPT, which was substantial, and generally higher in the stronger antiplatelet treatment groups. Medication knowledge and understanding, and confidence in dealing with symptoms facilitate positive attitudes towards adherence to DAPT, but may be hindered by opportunities to access relevant, timely and appropriate medication counselling. Although we derived relevant utility decrements for the included population using a patient elicitation exercise, based on standardised definitions of minor and major bleeding events, using a validated HRQoL instrument and valued using general population tariffs, we could not conduct a formal cost-effectiveness analysis given the uncertainty around the estimates for bleeding. Nevertheless, the results using routinely collected data need to be carefully considered by clinicians and decision-makers, given that the increased risk of bleeding we observed with more potent DAPT was not offset by a reduced risk of cardiovascular events and that several recent large meta-analyses of RCTs have also failed to show a conclusive benefit of more potent antiplatelet therapy on cardiovascular events.

Authors' methods: The study was designed as three retrospective population-based cohort studies emulating target randomised controlled trials. The study was set in primary and secondary care in England from 2010 to 2017. Participants were patients aged ≥ 18 years undergoing coronary artery bypass grafting or emergency percutaneous coronary intervention (for acute coronary syndrome), or conservatively managed patients with acute coronary syndrome. Data were sourced from linked Clinical Practice Research Datalink and Hospital Episode Statistics. Coronary artery bypass grafting and conservatively managed acute coronary syndrome: aspirin (reference) compared with aspirin and clopidogrel. Percutaneous coronary intervention: aspirin and clopidogrel (reference) compared with aspirin and prasugrel (ST elevation myocardial infarction only) or aspirin and ticagrelor. Primary outcome: any bleeding events up to 12 months after the index event. Secondary outcomes: major or minor bleeding, all-cause and cardiovascular mortality, mortality from bleeding, myocardial infarction, stroke, additional coronary intervention and major adverse cardiovascular events. The estimates for bleeding and major adverse cardiovascular events may be biased from unmeasured confounding and the exclusion of an eligible subgroup of patients who could not be assigned an intervention. Because of these limitations, a formal cost-effectiveness analysis could not be conducted. Objectives 1 and 2 We conducted a study to identify confounders systematically by performing a systematic review of RCTs and cohort studies; conducting semistructured interviews with six cardiac surgeons, six cardiologists and five general practitioners (GPs); and conducting a survey of 79 cardiologists and 31 cardiac surgeons. We used linked Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES) data to assemble populations (CABG, PCI and conservatively managed ACS patients) eligible for three ‘target trials’. Inclusion criteria for the target trial were as follows: ≥ 18 years of age, ≥ 1 year of data in CPRD before the index event, no prescription for DAPT or anticoagulants in the preceding 3 months and a prescription for aspirin or DAPT within 2 months of discharge after the index event. The primary outcome was any bleeding event (CPRD or HES data) up to 12 months after the index event. We described rates of bleeding among patients prescribed different DAPT regimens and TT. We estimated adjusted HRs for time to first bleed comparing DAPT with AC (reference) versus aspirin monotherapy for CABG and conservatively managed ACS patient, and, in the emergency PCI population, DAPT with prasugrel versus DAPT with clopidogrel for ST-elevation myocardial infarction (STEMI) patients only and DAPT with ticagrelor versus DAPT with clopidogrel for all the emergency PCI population. We prespecified five sensitivity analyses and conducted three: sensitivity analysis 1 – multiple imputation for eligible patients for whom we had no data to assign an intervention; sensitivity analysis 3 – restricted to patients at low risk of bleeding; and sensitivity analysis 4 – repeating primary outcome analysis without censoring of any CPRD or HES bleed events at transfer-out or last collection date. The transfer-out or last collection date reflect the date that a patient leaves the general practice or the date that the last capture from CPRD was made.

Project Status: Completed

URL for project: https://www.journalslibrary.nihr.ac.uk/programmes/hta/14/192/89

Year Published: 2023

URL for published report: https://www.journalslibrary.nihr.ac.uk/hta/MNJY9014

URL for additional information: English

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: England, United Kingdom

DOI: 10.3310/MNJY9014

Organisation Name: NIHR Health Technology Assessment programme

Contact Address: NIHR Journals Library, National Institute for Health and Care Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK

Contact Name: journals.library@nihr.ac.uk

Contact Email: journals.library@nihr.ac.uk