Title: Comprehensive ascertainment of bleeding in patients prescribed different combinations of dual antiplatelet therapy (DAPT) and triple therapy (TT, DAPT plus an anticoagulant) after coronary interventions in the UK: a population based cohort study The ADAPTT Study
Funder: Department of Health and Social Care

Abstract: Design: Retrospective population-based cohort study. We will derive three patient cohorts from Hospital Episode Statistics (HES): percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), and acute coronary syndrome (ACS) treated by medication only. We will follow all patient cohorts through the UK Clinical Practice Research Datalink (CPRD). Setting: Primary and secondary care (for minor and major bleeding events, respectively). Target population: Patients discharged from hospital following PCI, CABG or admission for ACS. Patients will be identified in HES using OPCS intervention codes for PCI (K49, K50 & K75) and CABG (K40, K45 & K46) and ICD-10 diagnosis codes for ACS (I20, I21, I22 without an OPCS intervention code for PCI and CABG within 12 months of cohort entry). Time frame: April 2010 to March 2016 (or the latest dataset available at the project start date). Inclusion criteria: Patients will be included if they are: labelled as ‘acceptable’ for use in research by CPRD (a process that identifies and excludes patients with non-continuous follow up or patients with poor data recording that raises suspicion as to the validity of that patient’s record); are over 18 years of age; have one year of medical history in CPRD before cohort entry (time of index procedure or event); have a record of aspirin monotherapy (Asp) or dual antiplatelet therapy (DAPT: aspirin and clopidogrel, AC; aspirin and prasugrel, AP; aspirin and ticagrelor, AT) in the year following the index procedure or event; and have no record of DAPT in the 3 months prior to the index procedure or event. Exclusion criteria: None. Health technologies being assessed: For the PCI cohort we will compare AC (reference) vs. AP or AT. For the CABG and ACS cohorts we will compare Asp (reference) vs. AC. For all three cohorts we will also compare Asp or DAPT (reference) vs. triple therapy (TT, DAPT + an oral anticoagulant such as warfarin, dabigatran, rivaroxaban, or apixaban). Measurement of cost and outcomes: The primary outcome will be any bleeding event (classified as minor or major by WHO bleeding scale, see section 6, Aims and objectives). Secondary outcomes will be all-cause mortality; cardiovascular mortality; mortality from bleeding; hospital admission. Sample size: Based on the minimum number of patients in the three cohorts (7580 PCI, 3151 CABG, and 11230 ACS, Table 1) and estimated rates of bleeding of 5% (Asp), 9% (AC), and 12% (AP and AT), we expect approximately 700 (PCI), 180 (CABG) and 680 (ACS) bleeding events. In these circumstances, the study will have 80% power (90% power) to detect adjusted hazard ratios of 1.47 (1.56), 1.87 (2.06) and 1.33 (1.39) respectively at the 5% level (2-sided), assuming a squared multiple correlation with other covariates of 0.3. Planned analysis: We will calculate crude and adjusted rates of bleeding (events/person time) with 95% confidence intervals (CIs) for each exposure group and use Cox proportional hazards models to estimate adjusted hazard ratios (HRs) with 95% CIs for time to first bleeding event. We will classify bleeding as major or minor (using the WHO bleeding scale) since adverse events of each type have different health and resource use consequences and carry out separate analyses, and will account for the competing risks in our analyses. Project timetable: The study will run over 30 months: month 1-3, application to the Independent Scientific Advisory Committee (ISAC) for project approval; month 1-6, literature review (to estimate QALY in patients taking DAPT); month 4-6, dataset specification and signing of data sharing agreement by University of Bristol and CPRD; month 7-8, write study protocol and protocol paper for publication; month 10-24, cohort study analysis; month 18 -27, update existing cost-effectiveness models; month 27-30, project report. Expertise in team: The team has patient representatives, clinicians (cardiologist, cardiac surgeon, haematologist, general practitioner), statisticians, methodologists and clinicians with expertise in analysis of administrative datasets including CPRD, and epidemiologists with expertise in cohort study methodology, a pharmaco-epidemiologist with expertise in adverse effects of drugs and a health economist.

Lay abstract: Antiplatelet drugs are used to prevent heart disease and stroke. They work by preventing the formation of blood clots in arteries. Blood clots happen when platelets (cells in the blood) clump together at the site of an injury to stop bleeding. Diseased arteries, such as those affected by fatty deposits (atherosclerosis), are particularly susceptible to blood clots. In people who have had a heart attack or have diseased arteries, low-dose aspirin (75 mg daily) is recommended indefinitely to prevent another heart attack or a stroke. People who have had a coronary stent put in one or more of their arteries or have had coronary artery bypass grafting (CABG) surgery following a heart attack are prescribed low-dose aspirin and an additional antiplatelet drug, most commonly clopidogrel (Plavix), less commonly prasugrel (Effient) and ticagrelor (Brilinta) for up to 12 months following the event. After this period of combined treatment, antiplatelet treatment is continued with low-dose aspirin alone. Combined treatment with aspirin and another antiplatelet drug is called dual antiplatelet therapy (DAPT). Some patients (e.g. those with atrial fibrillation) are also prescribed an anticoagulant (e.g. warfarin, dabigatran, rivaroxaban, or apixaban) in addition to DAPT. Antiplatelet therapies increase the risk of bleeding. Taking an anticoagulant on top of DAPT further increases bleeding risk. About 1 in 100 people on aspirin and 2 in 100 people on DAPT have a major bleeding event that requires hospitalisation. However, many more people (about 9 in 100) experience minor bleeding, such as bleeding in the stomach or bowel, and nuisance bleeding, such as nosebleeds, bleeding from gums, and excessive bruising. These minor bleeding events cause discomfort and anxiety, take up consultations with GPs and may cause patients to stop taking their tablets as prescribed. Few studies have assessed how often bleeding events happen in people taking DAPT. Hospital doctors (cardiolgists and surgeons) are increasingly prescribing more potent antiplatelet therapy to people who have had a stent or CABG surgery, without taking into account the risk of minor bleeding. They are doing this mainly because they do not know the extent of minor bleeding and the effect that it has on patients. This information is not known because most minor bleeding events are treated by GPs and patients do not go to hospital. Currently, decision-makers such as the National Institute for Clinical Excellent (NICE) are uncertain about the risk of minor and nuisance bleeding in people who take DAPT. Therefore, they cannot take it into account when making recommendations about which antiplatelet drugs should be used in people with heart disease and how long these drugs should taken for. We propose to use a large GP database of routinely collected data, and a database of describing patients’ attendances and admissions to hospital, to determine how many people experience bleeding after being prescribed DAPT or DAPT and an anticoagulant. We will compare patients who take aspirin only with patients taking different combinations of DAPT (with or without an anticoagulant). We will do this for different patient groups (treated with stent, CABG surgery or medication only). We will revise existing economic models of the cost-effectiveness of DAPT to take into account the rate of all bleeding events in people who take these medications. We will also review the literature to determine how bleeding affects quality of life in these individuals. Information from our study will help doctors to choose drugs that are more appropriate for individual patients’ specific needs, which will reduce the risk of bleeding and increase adherence to treatment.

Research activity codes: 6.1 PHARMACEUTICALS;6.4 SURGERY;8.2 HEALTH AND WELFARE ECONOMICS
Health categories: CARDIOVASCULAR