Assessment of the high risk and unmet need in patients with CAD and type 2 diabetes (ATHENA): US healthcare resource utilization, cost and burden of illness in the Diabetes Collaborative Registry

Abstract Background THEMIS (NCT01991795) showed that in patients with type 2 diabetes (T2D) and stable coronary artery disease (CAD) but with no prior myocardial infarction (MI) or stroke, ticagrelor plus acetylsalicylic acid (ASA) decreased the incidence of ischaemic cardiovascular events compared with placebo plus ASA. To complement these findings, we assessed disease burden and healthcare resource utilization (HRU) in US patients with CAD and T2D, but without a prior MI or stroke. Methods This observational study used 2013‐2014 data from the Diabetes Collaborative Registry linked to Medicare administrative claims. Two cohorts of patients with T2D were studied: patients at high cardiovascular risk (THEMIS‐like cohort; N = 56 040) and patients at high cardiovascular risk or taking P2Y12 inhibitors (CAD‐T2D cohort; N = 69 790). Outcomes included the composite of all‐cause death, MI and stroke; the individual events from the composite endpoint; HRU; and costs. Results Median age was 73.0 years, and median follow‐up was 1.3 years in both cohorts. Event rates of the composite outcome were 16.34 (95% confidence interval: 16.31‐16.37) and 17.64 (17.61‐17.67) per 100 person‐years for the THEMIS‐like and CAD‐T2D cohorts, respectively. The incidence rate of bleeding events was 0.13 events per 100 person‐years in both cohorts. Healthcare costs per patient‐year were USD 8741 and USD 9150 in the THEMIS‐like and CAD‐T2D cohorts, respectively. Conclusions Patients in the THEMIS‐like cohort and the broader CAD‐T2D population had similarly substantial cardiovascular event rates and healthcare costs, indicating that patients with CAD and T2D similar to the THEMIS population are at an increased cardiovascular risk.


| INTRODUC TI ON
Cardiovascular (CV) disease is a major cause of morbidity and mortality in patients with type 2 diabetes (T2D), and reduction of CV risk is an important goal of treatment. [1][2][3] Long-term (up to 12 months) dual antiplatelet therapy, comprising acetylsalicylic acid (ASA) and a P2Y12 inhibitor (clopidogrel, prasugrel or ticagrelor), is widely used to prevent recurrent ischaemic events in patients with T2D and acute coronary syndrome. [3][4][5] However, although the magnitude of the independent CV risk conferred by the presence of T2D in the absence of prior ischaemic events has been documented, 1 The present analysis, Assessment of The High Risk and Unmet Need in Patients with CAD and Type 2 Diabetes (ATHENA), was designed to complement the clinical data from THEMIS, by providing real-world insights into the burden of disease in patients with CAD and T2D but without a history of MI or stroke. ATHENA is an observational study, which aimed to assess and describe the fol-

| Data sources and study population
The DCR is a real-world, quality-oriented registry led by the American College of Cardiology in partnership with the American Diabetes Association, the American College of Physicians, the American Association of Clinical Endocrinologists, and the Joslin Diabetes Center. 14 The registry collects real-world data from a diverse range of care providers, including primary care physicians, endocrinologists and cardiologists. Patients eligible for enrolment in the DCR include those with a diagnosis of diabetes identified through International Classification of Diseases 9th/10th Revision (ICD-9/10) diagnostic codes. As of 31 March 2016, the DCR included data from 1 029 807 patients across 374 sites and 5114 providers.
General practice (including internal medicine, primary care or family practices), cardiology, endocrinology and obstetrics/gynaecology practices were self-identified in 50.1%, 74.9%, 2.1% and 9.4% of sites, respectively; sites could contain practices with more than one specialty. DCR participation requires no data collection beyond that of routine clinical care and poses no additional risks to clinical providers or their patients; therefore, a waiver of written informed consent and authorization for this study were granted by Chesapeake Research Review, Inc.
The CMS collects data from patients who are enrolled in Medicare or Medicaid healthcare plans in the USA. Available data include records of clinical services used by enrolees, including source of care, dates of admission and discharge, and diagnosis and procedure codes. CMS data can be linked with other databases and registries to create comprehensive data sets. 15 Selection of the study cohorts is shown in Figure 1. Adults who were seen in a DCR-participating practice during the time period for which linked CMS administrative claims data were available (1 January 2013 to 31 December 2014), and whose data could be linked with CMS administrative claims data, were eligible for inclusion. Patients were also required to have a diagnostic code for T2D in the DCR and have at least one dispensed prescription for any glucose-lowering medication.
Two cohorts were defined within the overall set of patients who met these eligibility criteria: THEMIS-like and T2D-CAD. The THEMIS-like cohort (N = 56 040) included patients with a high risk of CV events, defined as having a prior PCI or prior coronary artery bypass graft (CABG), or the presence of a code for angina (ICD-10-CM I20. 8

T2D-CAD cohort N = 69 790
Exclusion criteria were the same as for the THEMIS-like cohort, with the exception that, regarding stroke, only patients with ischaemic stroke (with the exception of TIA) were excluded. As a consequence of these different criteria, the CAD-T2D cohort consisted of a broader population of patients with T2D than the THEMIS-like cohort, due to the inclusion of patients with a history of nonischaemic (haemorrhagic) stroke, as well as patients with baseline use of P2Y12 inhibitors.

| Analysis
The study index date was defined as the earliest date on which a participant satisfied all study inclusion criteria for either cohort on or

| Characteristics of the study cohorts
The THEMIS-like and CAD-T2D cohorts comprised 56 040 and 69 790 DCR patients with evaluable data who met the study inclusion criteria, respectively. Demographic and clinical characteristics of patients in the two cohorts were not markedly different (Table 1).
Men constituted 62.9% and 61.4% of the THEMIS-like and CAD-T2D cohorts, respectively, and the median age in both cohorts was

| Clinical events
The  Kaplan-Meier plots showing cumulative incidence of the composite outcome and the individual components over 2 years of follow-up are shown in Figure 2; the raw data are presented in Table   S1. After 360 days of follow-up, the cumulative incidence of the composite outcome was 8.3% and 8.9% in the THEMIS-like and CAD-T2D cohorts, respectively (Table S1). In both cohorts, the incidence of the composite outcome and each component event was higher in patients older than 75 years than in those aged 65-75 years, and this was also the case in patients with multi-vessel rather than single-vessel disease (Table 3). In both cohorts, the incidence of the composite outcome was higher in patients with a history of PCI or CABG than in patients without a history of these interventions, although the difference was more pronounced in the THEMIS-like cohort than in the CAD-T2D cohort.

| D ISCUSS I ON
The findings from this retrospective, observational, cohort study showed substantial rates of death, nonfatal MI and nonfatal stroke, as well as substantial HRU and healthcare costs, in DCR patients who were similar to those who would have been eligible for THEMIS. were not persistent with medications for CV prevention, which may have also contributed to high CV event rates.
Although the presence of T2D is a known risk factor for CV disease, there is a large gradient of CV risk among patients with T2D. 16    c Calculated by dividing the total costs over the study period by the mean duration of follow-up.
d Defined as continuation of a medication class over the study period without more than a 60-day gap in medication supply after the last fill, as determined by the date and days' supply dispensed. Denominators include patients with at least one claim for a given medication.
Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis In Myocardial Infarction 54 (PEGASUS-TIMI 54) trial, patients with T2D had a greater absolute reduction in the risk of major adverse CV events than patients without diabetes when treated with a combination of ticagrelor and ASA (1.5% vs 1.1%). 19 Moreover, a post hoc analysis of data from the Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial suggested that patients with diabetes derived a greater benefit from clopidogrel than from ASA therapy. 20 As a consequence of these trial findings, current clinical guidelines recommend the use of antiplatelet therapies in patients with T2D and prior MI or stroke, but not in those with low CV risk. 3,8 In particular, the 2019 guidelines from the American College of Cardiology (ACC) and the American Heart Association (AHA) advise against the use of ASA for the routine primary prevention of atherosclerotic CV disease, due to lack of net benefit in clinical trials. 10  In the present study, rates of ischaemic events during follow-up were high in both the THEMIS-like and the broader T2D-CAD cohorts. One-third of patients with an initial MI or stroke in both cohorts experienced recurrent events. In particular, the rates of the those observed in ATHENA, thus suggesting that T2D is associated with an increased CV risk in patients with CAD.
The costs associated with treating patients in both the THEMISlike and CAD-T2D cohorts were substantial, and a large proportion was attributable to inpatient stays. These findings concur with those from a 6-year, longitudinal analysis of claims data gathered from patients newly diagnosed with T2D in the USA, which also observed an increase in total healthcare costs of 33% over the study period. 23 In the present study of primarily elderly patients with mul- And Nutrition Examination Survey (NHANES). 24 Indeed, the DCR was highly enriched with cardiology practices during the years for which data were included. The high level of care of patients in the present analysis also gives rise to the possibility that the frequency of events and outcomes are lower than would be seen in comparable populations from other US data sources. For example, more than 80% of patients were using lipid-lowering medications, and median low-density lipoprotein cholesterol levels were close to those recommended by clinical guidelines for patients with diabetes and atherosclerotic CV disease. The study follow-up period was also relatively brief because linked data were only available for a 2-year period (from 1 January 2013 to 31 December 2014), so findings may change with longer follow-up. However, the findings from this analysis provide important preliminary data from comparable clinical practice-based cohorts in the USA to complement findings from THEMIS.
In conclusion, findings from this study demonstrated substantial rates of ischaemic events and all-cause death in patients with CAD and concomitant T2D, accompanied by considerable healthcare utilization and associated costs. This suggests a potential opportunity for improved management of these patients, which may include better persistence with CV prevention medications, better adherence to clinical guidelines and treatment with longterm dual antiplatelet therapy, to improve outcomes in this highrisk population.

ACK N OWLED G M ENTS
Medical writing support was provided by Lucy Ambrose, DPhil, of Oxford PharmaGenesis, Oxford, UK, and was funded by AstraZeneca.

E TH I C A L A PPROVA L
A waiver of written informed consent and authorization for this study were granted by Chesapeake Research Review, Inc., because DCR participation does not require data collection beyond that of routine clinical care and data are de-identified.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca's data sharing policy described at https://astra zenec agrou p-dt.pharm acm.com//DT/Home/ Index /.