# Diabetes-Related Factors and the Effects of Ticagrelor Plus Aspirin in the THEMIS and THEMIS-PCI Trials

Lawrence A Leiter, Deepak L Bhatt, Darren K Mcguire, Hwee Teoh, Kim Fox, Tabassome Simon, Shamir R Mehta, Eli I Lev, Róbert G Kiss, Anthony J Dalby, et al.

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Lawrence A Leiter, Deepak L Bhatt, Darren K Mcguire, Hwee Teoh, Kim Fox, et al. Diabetes-Related Factors and the Effects of Ticagrelor Plus Aspirin in the THEMIS and THEMIS-PCI Trials. Journal of the American College of Cardiology, 2021, 77 (19), pp.2366-2377. 10.1016/j.jacc.2021.03.298. hal-03235076

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# Diabetes-Related Factors and the Effects of Ticagrelor Plus Aspirin in the THEMIS and THEMIS-PCI Trials

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Lawrence A. Leiter, MD,ᵃ,ᵇ Deepak L. Bhatt, MD, MPH,ᶜ Darren K. McGuire, MD, MHSc,ᵈ Hwee Teoh, PhD,ᵃ,ᵉ

Kim Fox, MD,ᵉ Tabassome Simon, MD, PhD, g, h Shamir R. Mehta, MD, MSc, i Eli I. Lev, MD, i, k Róbert G. Kiss, MD, PhD, l

Anthony J. Dalby, MB CHB, m Héctor Bueno, MD, PhD, n, o, p Wilhelm Ridderstråle, MD, PhD, q

Anders Himmelmann, MD, PhD,q Jayne Prats, PhD, r Yuyin Liu, PhD, s Jane J. Lee, PhD, s John Amerena, MBBS, t, u, v

Mikhail N. Kosiborod, MD, w, x, y, z Philippe Gabriel Steg, MD, f, g, aa on behalf of the THEMIS Steering Committee and Investigators

## ABSTRACT

**BACKGROUND** THEMIS (The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study) (n = 19,220) and its pre-specified THEMIS-PCI (The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study-Percutaneous Coronary Intervention) (n = 11,154) subanalysis showed, in individuals with type 2 diabetes mellitus (median duration 10.0 years; HbA1c 7.1%) and stable coronary artery disease without prior myocardial infarction (MI) or stroke, that ticagrelor plus aspirin (compared with placebo plus aspirin) produced a favorable net clinical benefit (composite of all-cause mortality, MI, stroke, fatal bleeding, and intracranial bleeding) if the patients had a previous percutaneous coronary intervention.

**OBJECTIVES** In these post hoc analyses, the authors examined whether the primary efficacy outcome (cardiovascular death, MI, stroke: 3-point major adverse cardiovascular events [MACE]), primary safety outcome (Thrombolysis In Myocardial Infarction-defined major bleeding) and net clinical benefit varied with diabetes-related factors.

**METHODS** Outcomes were analyzed across baseline diabetes duration, HbA1c, and antihyperglycemic medications.

**RESULTS** In THEMIS, the incidence of 3-point MACE increased with diabetes duration (6.7% for ≤5 years, 11.1% for >20 years) and HbA1c (6.4% for ≤6.0%, 11.8% for >10.0%). The relative benefits of ticagrelor plus aspirin on 3-point MACE reduction (hazard ratio [HR]: 0.90; p = 0.04) were generally consistent across subgroups. Major bleeding event rate (overall: 1.6%) did not vary by diabetes duration or HbA1c and was increased similarly by ticagrelor across all subgroups (HR: 2.32; p < 0.001). These findings were mirrored in THEMIS-PCI. The efficacy and safety of ticagrelor plus aspirin did not differ by baseline antihyperglycemic therapy. In THEMIS-PCI, but not THEMIS, ticagrelor generally produced favorable net clinical benefit across diabetes duration, HbA1c, and antihyperglycemic medications.

**CONCLUSION** Ticagrelor plus aspirin yielded generally consistent and favorable net clinical benefit across the diabetes-related factors in THEMIS-PCI but not in the overall THEMIS population. (J Am Coll Cardiol 2021;77:2366-77) © 2021 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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From the ᵃDivision of Endocrinology and Metabolism, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada; ᵇDepartments of Medicine and Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada; ᶜBrigham and Women's Hospital Heart and Vascular Center, Harvard Medical School Boston, Boston, Massachusetts, USA; ᵈDepartment of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA; ᵉDivision of Cardiac Surgery, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada; ṀNational Heart and Lung Institute, Imperial College, Royal Brompton Hospital, London, United Kingdom; ṲFrench Alliance for Cardiovascular Trials, Paris, France; ṩDepartment of Clinical Pharmacology, Unité de Recherche Clinique, Assistance Publique-Hôpitaux de Paris, Hôpital Saint Antoine, Sorbonne Université, site St. Antoine, Institut National de la Santé et de la Recherche Médicale U-698, Paris, France; ṛDivision of Cardiology, Population Health Institute, Hamilton Health Sciences Corporation, McMaster University, Hamilton, Ontario, Canada;
Individuals with both type 2 diabetes mellitus and coronary artery disease are at high risk for cardiovascular events (1-5). Among those with acute coronary syndrome (6) or a history of myocardial infarction (MI) (7), the addition of the reversible P2Y₁₂ receptor antagonist ticagrelor to background aspirin therapy can offer enhanced protection against cardiovascular events in patients both with and without diabetes. Before the reporting of THEMIS (The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study) (8), it was unknown if expanding antiplatelet therapy beyond aspirin would yield additional benefits in individuals who have type 2 diabetes mellitus and

coronary artery disease but without a prior cardiovascular event. In brief, THEMIS (n = 19,220) and the pre-specified THEMIS-PCI (Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study-Percutaneous Coronary Intervention) (n = 11,154) subgroup analysis (9) suggested that dual antiplatelet therapy (DAPT) with ticagrelor and low-dose aspirin may specifically benefit individuals with type 2 diabetes mellitus and stable atherosclerosis but without a history of MI or stroke and who had previously undergone a PCI. The U.S. Food and Drug Administration has since, based on THEMIS, additionally approved ticagrelor to reduce the risk of a first MI or stroke in patients with coronary artery disease who are at high risk for such events regardless of whether they have diabetes or not (10), and Health Canada, based on THEMIS-PCI, has expanded approval of ticagrelor more specifically in patients with coronary artery disease, type 2 diabetes, and a history of PCI (11).

The ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) investigators showed that duration of diabetes could influence cardiovascular responses to antihyperglycemic agents (12,13). More recently, an analysis from the DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis In Myocardial Infarction 58) study (14) demonstrated that in a contemporaneous type 2 diabetes mellitus population with well controlled risk factors, diabetes duration was again associated with increasing risk of atherosclerotic cardiovascular disease. Of note, meta-analyses of major trials investigating the potential benefit of glucose control on cardiovascular outcomes have revealed that although intensive glucose control had no overall benefit on major cardiovascular events, there was a modest reduction in MI (15,16). These collective findings led us to consider if diabetes duration and baseline HbA1c levels may have, in some way, driven the outcomes observed with the ticagrelor plus aspirin strategy adopted in THEMIS and its THEMIS-PCI subpopulation. Furthermore, the robust clinical trial evidence demonstrating that sodium-glucose cotransporter 2 (SGLT2) inhibitors and many glucagon-like peptide 1 (GLP-1) receptor agonists can offer clinically significant cardiovascular benefits (17-19) also led us to investigate whether any of the currently available pharmacotherapies for type 2 diabetes mellitus could have influenced the clinical outcomes evoked by the combination of ticagrelor and aspirin.

SEE PAGE 2378

ABBREVIATIONS AND ACRONYMS

**DAPT** = dual antiplatelet therapy

**DPP-4** = dipeptidyl peptidase 4

**GLP-1** = glucagon-like peptide 1

**HbA1c** = glycated hemoglobin

**MACE** = major adverse cardiovascular events

**MI** = myocardial infarction

**PCI** = percutaneous coronary intervention

**SGLT2** = sodium-glucose cotransporter-2

**THEMIS** = The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study

**THEMIS-PCI** = THEMIS-Percutaneous Coronary Intervention

**TIMI** = Thrombolysis In Myocardial Infarction

¹Department of Cardiology, Assuta Ashdod Medical Center, Ashdod, Israel; ²Faculty of Health Sciences, Ben-Gurion University, Be'er Sheva, Israel; ³Department of Cardiology, Military Hospital, Budapest, Hungary; ⁴Life Fourways Hospital, Randburg, Republic of South Africa; ⁵Department of Cardiology, Hospital Universitario 12 de Octubre, Madrid, Spain; ⁶Instituto de Investigación Sanitaria Hospital 12 de Octubre, Madrid, Spain; ⁷Late-Stage Development, Cardiovascular, Renal and Metabolic, Biopharmaceuticals Research & Development, AstraZeneca, Gothenburg, Sweden; ⁸ELYSIS-Med Scientific Solutions, Carlisle, Massachusetts, USA; ⁹Baim Institute for Clinical Research, Boston, Massachusetts, USA; ¹⁰Geelong Cardiology Research Unit, University Hospital Geelong, Barwon Health, Geelong, Victoria, Australia; ¹¹Department of Cardiology, Deakin University, Geelong, Victoria, Australia; ¹²Department of Epidemiology and Preventative Medicine, Monash University, Victoria, Australia; ¹³Department of Cardiology and Michael & Marlys Haverty Cardio Metabolic Center of Excellence, Saint Luke's Mid America Heart Institute, Kansas City, Missouri, USA; ¹⁴Department of Medicine, University of Missouri–Kansas City, Kansas City, Missouri, USA; ¹⁵The George Institute for Global Health, Sydney, New South Wales, Australia; ¹⁶University of New South Wales, Sydney, New South Wales, Australia; and the ¹⁷Université de Paris, Assistance Publique-Hôpitaux de Paris, Institut National de la Santé et de la Recherche Médicale 1148, Paris, France. Athena Poppas, MD, served as Guest Editor-in-Chief for this paper.

The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors' institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
## METHODS

The design, baseline characteristics, and main results of THEMIS and THEMIS-PCI have been reported (8,9,20). Briefly, enrollment for the phase 3b, double-blinded, placebo-controlled THEMIS trial took place at 1,315 sites in 42 countries from February 10, 2014, to May 24, 2016 (8). All of the trial centers obtained ethical approval according to local regulations. A total of 19,220 individuals (31.4% women) with angiographically proven coronary artery disease and type 2 diabetes mellitus (median duration at trial entry: 10.0 years: median baseline HbA1c: 7.1% [54 mmol/mol]), but no history of MI or stroke, were randomized 1:1 to either ticagrelor or placebo in addition to low-dose aspirin (75 to 150 mg) and other evidence-based therapies for a median follow-up of 39.9 months (8). At study initiation, participants allocated to the ticagrelor arm took 90 mg ticagrelor twice daily (orally). Approximately a year later, because the combination of 60 mg ticagrelor twice daily with low-dose aspirin was demonstrated in another trial of participants with stable atherosclerosis to have a better tolerability and similar efficacy profile than that of 90 mg ticagrelor twice daily plus low-dose aspirin (7), the ticagrelor study dose was amended to 60 mg twice daily for all participants.

The primary efficacy outcome was the time to first occurrence of a 3-point major adverse cardiovascular events (MACE) composite of cardiovascular death, MI, or stroke. The primary safety outcome was major bleeding per the TIMI definition. Net clinical benefit was a pre-specified exploratory endpoint consisting of irreversible harm events and was evaluated as time to first event of the composite of all-cause mortality, MI, stroke, fatal bleeding, or intracranial bleeding (8,20).

**STATISTICAL ANALYSES.** In these nonpre-specified and post hoc analyses, the THEMIS population and THEMIS-PCI subpopulation were examined according to the following baseline characteristics: duration of diabetes, HbA1c level and use of metformin, sulfonylurea, and insulin or any of the newer anti-hyperglycemic classes, namely, dipeptidyl peptidase-4 (DPP-4) inhibitors, SGLT2 inhibitors, and GLP-1 receptor agonists.

The efficacy analyses were conducted according to the intention-to-treat principle: All participants who underwent randomization were included; all events that occurred before or at the primary analysis censoring date (October 29, 2018) were entered into the analyses. The safety analyses were performed in the safety analysis population, which included all

participants who had been randomized and who had taken at least 1 dose of the assigned study drug; all events that occurred between randomization and through 7 days after the last dose was administered were included in the analyses. Participants randomized at sites closed by the sponsor before unblinding were excluded from all efficacy and safety analyses (20).

For time-to-event analyses, Cox proportional hazards models were used, with the treatment group as the explanatory variable and the Efron method for ties; confidence intervals (CIs) and p values were calculated with the use of Wald statistics. Given that the CIs for net clinical benefit were not adjusted for multiple comparisons, the inferences drawn from these intervals may not be reproducible. Follow-up data for participants without events were censored either on the censoring date for the primary analysis or on the date of the last clinical assessment, whichever came first. The results of Kaplan-Meier analyses are presented at 36 months. The p values for interaction between treatment groups and subgroups were calculated from the Cox proportional hazards model with treatment group, subgroup, and interaction term as explanatory variables. All analyses were conducted with SAS software version 9.4 (SAS Institute, Cary, North Carolina).

**ROLE OF THE FUNDER.** THEMIS (NCT01991795) was designed and governed by an academic Executive Committee that included nonvoting members who represented the sponsor, AstraZeneca. AstraZeneca funded the trial and was involved in the data collection and analysis. The data presented herein were independently analyzed by the Baim Clinical Research Institute, an academic research organization.

## RESULTS

As previously reported, the baseline characteristics of the participants in the ticagrelor plus aspirin and placebo plus aspirin arms of the full THEMIS cohort and THEMIS-PCI subcohort were balanced (8,9). The baseline characteristics of the full THEMIS population stratified by duration of diabetes and baseline HbA1c are summarized in Supplemental Tables 1 and 2. In contrast, there were clinically significant differences between those who had undergone a PCI procedure before study entry and those who had not (9).

The primary efficacy outcome (3-point MACE) was recorded for 8.1% of the overall THEMIS cohort and 7.3% of the THEMIS-PCI subcohort. In THEMIS, the event rates of the 3-point MACE were generally higher
<table><caption>TABLE 1 Primary Efficacy Outcome in the Overall THEMIS Cohort By Baseline Diabetes-Related Factors and Selected Baseline Antihyperglycemic Therapy</caption><thead><tr><th rowspan="2"></th><th colspan="3">Ticagrelor</th><th colspan="3">Placebo</th><th rowspan="2">p Value</th><th rowspan="2">Pinteraction</th><th rowspan="2">Risk Difference % (95% CI)</th><th rowspan="2">p Value</th><th rowspan="2">Pinteraction</th></tr><tr><th>N</th><th>Patients With Events</th><th>N</th><th>Patients With Events</th><th>Hazard Ratio (95% CI)</th><th>p Value</th></tr></thead><tbody><tr><td>Overall</td><td>9,619</td><td>736 (7.7)</td><td>9,601</td><td>818 (8.5)</td><td>0.90 (0.81-0.99)</td><td>0.0378</td><td></td><td>-0.9 (-1.6 to -0.1)</td><td>0.0281</td><td></td></tr><tr><td>Duration of type 2 diabetes mellitus at baseline, yrs</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.8255</td><td></td><td></td><td>0.8169</td><td></td></tr><tr><td>≤5</td><td>2,462</td><td>157 (6.4)</td><td>2,426</td><td>169 (7.0)</td><td>0.91 (0.74-1.14)</td><td>0.4189</td><td></td><td></td><td>-0.6 (-2.0 to 0.8)</td><td>0.4225</td><td></td></tr><tr><td>>5 to 10</td><td>2,353</td><td>146 (6.2)</td><td>2,461</td><td>182 (7.4)</td><td>0.84 (0.68-1.05)</td><td>0.1208</td><td></td><td></td><td>-1.2 (-2.6 to 0.2)</td><td>0.1091</td><td></td></tr><tr><td>>10 to 15</td><td>1,944</td><td>170 (8.7)</td><td>1,949</td><td>173 (8.9)</td><td>0.99 (0.80-1.23)</td><td>0.9477</td><td></td><td></td><td>-0.1 (-1.9 to 1.6)</td><td>0.9100</td><td></td></tr><tr><td>>15 to 20</td><td>1,293</td><td>100 (7.7)</td><td>1,250</td><td>116 (9.3)</td><td>0.84 (0.64-1.10)</td><td>0.2067</td><td></td><td></td><td>-1.5 (-3.7 to 0.6)</td><td>0.1765</td><td></td></tr><tr><td>>20</td><td>1,561</td><td>163 (10.4)</td><td>1,511</td><td>177 (11.7)</td><td>0.88 (0.71-1.09)</td><td>0.2371</td><td></td><td></td><td>-1.3 (-3.5 to 0.9)</td><td>0.2746</td><td></td></tr><tr><td>Baseline HbA1c, %</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.1567</td><td></td><td></td><td>0.1542</td><td></td></tr><tr><td>≤6</td><td>1,263</td><td>86 (6.8)</td><td>1,285</td><td>76 (5.9)</td><td>1.16 (0.85-1.57)</td><td>0.3549</td><td></td><td></td><td>0.9 (-1.0 to 2.8)</td><td>0.3724</td><td></td></tr><tr><td>>6 to 7</td><td>3,301</td><td>209 (6.3)</td><td>3,259</td><td>241 (7.4)</td><td>0.86 (0.71-1.04)</td><td>0.1119</td><td></td><td></td><td>-1.1 (-2.3 to 0.2)</td><td>0.0967</td><td></td></tr><tr><td>>7 to 8</td><td>2,334</td><td>184 (7.9)</td><td>2,449</td><td>215 (8.8)</td><td>0.90 (0.74-1.10)</td><td>0.3177</td><td></td><td></td><td>-0.9 (-2.5 to 0.7)</td><td>0.2722</td><td></td></tr><tr><td>>8 to 9</td><td>1,227</td><td>108 (8.8)</td><td>1,163</td><td>122 (10.5)</td><td>0.84 (0.65-1.09)</td><td>0.1891</td><td></td><td></td><td>-1.7 (-4.1 to 0.7)</td><td>0.1658</td><td></td></tr><tr><td>>9 to 10</td><td>633</td><td>51 (8.1)</td><td>615</td><td>75 (12.2)</td><td>0.64 (0.45-0.92)</td><td>0.0144</td><td></td><td></td><td>-4.1 (-7.5 to -0.8)</td><td>0.0185</td><td></td></tr><tr><td>>10</td><td>625</td><td>77 (12.3)</td><td>596</td><td>67 (11.2)</td><td>1.10 (0.79-1.52)</td><td>0.5748</td><td></td><td></td><td>1.1 (-2.5 to 4.7)</td><td>0.5948</td><td></td></tr><tr><td>Use of key antihyperglycemic agents</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Metformin</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.0695</td><td></td><td></td><td>0.0854</td><td></td></tr><tr><td>Yes</td><td>7,304</td><td>494 (6.8)</td><td>7,310</td><td>583 (8.0)</td><td>0.85 (0.75-0.95)</td><td>0.0065</td><td></td><td></td><td>-1.2 (-2.1 to -0.4)</td><td>0.0053</td><td></td></tr><tr><td>No</td><td>2,315</td><td>242 (10.5)</td><td>2,291</td><td>235 (10.3)</td><td>1.03 (0.86-1.24)</td><td>0.7194</td><td></td><td></td><td>0.2 (-1.6 to 2.0)</td><td>0.8467</td><td></td></tr><tr><td>Sulfonylurea</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.2290</td><td></td><td></td><td></td><td>0.2499</td><td></td></tr><tr><td>Yes</td><td>3,350</td><td>267 (8.0)</td><td>3,416</td><td>281 (8.2)</td><td>0.98 (0.83-1.16)</td><td>0.7943</td><td></td><td></td><td>-0.3 (-1.6 to 1.0)</td><td>0.7215</td><td></td></tr><tr><td>No</td><td>6,269</td><td>469 (7.5)</td><td>6,185</td><td>537 (8.7)</td><td>0.86 (0.76-0.97)</td><td>0.0174</td><td></td><td></td><td>-1.2 (-2.2 to -0.2)</td><td>0.0149</td><td></td></tr><tr><td>Dipeptidyl peptidase 4 inhibitor</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.6870</td><td></td><td></td><td></td><td>0.6646</td><td></td></tr><tr><td>Yes</td><td>1,819</td><td>124 (6.8)</td><td>1,795</td><td>130 (7.2)</td><td>0.94 (0.74-1.20)</td><td>0.6327</td><td></td><td></td><td>-0.4 (-2.1 to 1.2)</td><td>0.6489</td><td></td></tr><tr><td>No</td><td>7,800</td><td>612 (7.8)</td><td>7,806</td><td>688 (8.8)</td><td>0.89 (0.80-0.99)</td><td>0.0399</td><td></td><td></td><td>-1.0 (-1.8 to -0.1)</td><td>0.0298</td><td></td></tr><tr><td>Sodium-glucose cotransporter 2 inhibitor</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.7795</td><td></td><td></td><td></td><td>0.8611</td><td></td></tr><tr><td>Yes</td><td>189</td><td>9 (4.8)</td><td>174</td><td>10 (5.7)</td><td>0.78 (0.31-1.92)</td><td>0.5821</td><td></td><td></td><td>-1.0 (-5.6 to 3.6)</td><td>0.8144</td><td></td></tr><tr><td>No</td><td>9,430</td><td>727 (7.7)</td><td>9,427</td><td>808 (8.6)</td><td>0.90 (0.82-1.00)</td><td>0.0435</td><td></td><td></td><td>-0.9 (-1.6 to -0.1)</td><td>0.0310</td><td></td></tr><tr><td>Glucagon-like peptide 1 receptor agonist</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.9090</td><td></td><td></td><td></td><td>0.8206</td><td></td></tr><tr><td>Yes</td><td>203</td><td>15 (7.4)</td><td>210</td><td>16 (7.6)</td><td>0.92 (0.46-1.87)</td><td>0.8256</td><td></td><td></td><td>-0.2 (-5.3 to 4.9)</td><td>1.0000</td><td></td></tr><tr><td>No</td><td>9,416</td><td>721 (7.7)</td><td>9,391</td><td>802 (8.5)</td><td>0.90 (0.81-0.99)</td><td>0.0383</td><td></td><td></td><td>-0.9 (-1.7 to -0.1)</td><td>0.0265</td><td></td></tr><tr><td>Insulin</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.4562</td><td></td><td></td><td></td><td>0.4573</td><td></td></tr><tr><td>Yes</td><td>2,798</td><td>286 (10.2)</td><td>2,710</td><td>323 (11.9)</td><td>0.85 (0.73-1.00)</td><td>0.0515</td><td></td><td></td><td>-1.7 (-3.4 to -0.0)</td><td>0.0480</td><td></td></tr><tr><td>No</td><td>6,821</td><td>450 (6.6)</td><td>6,891</td><td>495 (7.2)</td><td>0.92 (0.81-1.05)</td><td>0.2145</td><td></td><td></td><td>-0.6 (-1.4 to 0.3)</td><td>0.1776</td><td></td></tr></tbody></table>

Values are n or n (%), unless otherwise indicated.

with increasing duration of diabetes (6.7% for ≤5 years and 11.1% for >20 years; p = 0.0001) and baseline HbA1c levels (6.4% for ≤6.0% [42 mmol/mol] and 11.8% for >10.0% [86 mmol/mol]; p = 0.0001). Similar observations were observed for THEMIS-PCI. The relative benefits of DAPT with ticagrelor plus low-dose aspirin on 3-point MACE in THEMIS (HR: 0.90; 95% CI: 0.81 to 0.99; p = 0.04) and THEMIS-PCI (HR: 0.85; 95% CI: 0.74 to 0.97; p = 0.013) did not differ across the duration of diabetes and HbA1c subgroups examined (Table 1 and Supplemental Table 3, respectively).

The primary safety outcome (TIMI-defined major bleeding) occurred in 1.6% of the overall THEMIS population (HR: 2.32; 95% CI: 1.82 to 2.94; for ticagrelor vs. placebo; p < 0.001) (Supplemental Figure 1) and 2.0% of the THEMIS-PCI subcohort (HR: 2.03; 95% CI: 1.48 to 2.76; for ticagrelor vs. placebo; p < 0.0001). Although the frequencies of major bleeding did not vary by diabetes duration or baseline HbA1c levels, they were consistently higher with ticagrelor plus aspirin across all the strata of diabetes duration and HbA1c evaluated (Table 2, Supplemental Table 4).
<table><caption>TABLE 2 Primary Safety Outcome in the Overall THEMIS Cohort By Baseline Diabetes-Related Factors and Selected Baseline Antihyperglycemic Therapy</caption><thead><tr><th rowspan="2"></th><th colspan="2">Ticagrelor</th><th colspan="2">Placebo</th><th rowspan="2">Hazard Ratio (95% CI)</th><th rowspan="2">p Value</th><th rowspan="2">Pinteraction</th></tr><tr><th>N</th><th>Patients With Events</th><th>N</th><th>Patients With Events</th></tr></thead><tbody><tr><td>Overall</td><td>9,562</td><td>206 (2.2)</td><td>9,531</td><td>100 (1.0)</td><td>2.32 (1.82-2.94)</td><td>&lt;0.001</td><td></td></tr><tr><td>Duration of type 2 diabetes mellitus at baseline, yrs</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.8275</td></tr><tr><td>≤5</td><td>2,445</td><td>47 (1.9)</td><td>2,406</td><td>25 (1.0)</td><td>2.04 (1.26-3.32)</td><td>0.0039</td><td></td></tr><tr><td>&gt;5 to 10</td><td>2,343</td><td>49 (2.1)</td><td>2,444</td><td>21 (0.9)</td><td>2.75 (1.65-4.59)</td><td>0.0001</td><td></td></tr><tr><td>&gt;10 to 15</td><td>1,931</td><td>43 (2.2)</td><td>1,933</td><td>18 (0.9)</td><td>2.72 (1.57-4.72)</td><td>0.0004</td><td></td></tr><tr><td>&gt;15 to 20</td><td>1,287</td><td>32 (2.5)</td><td>1,244</td><td>19 (1.5)</td><td>1.88 (1.07-3.32)</td><td>0.0291</td><td></td></tr><tr><td>&gt;20</td><td>1,550</td><td>35 (2.3)</td><td>1,501</td><td>16 (1.1)</td><td>2.39 (1.32-4.32)</td><td>0.0039</td><td></td></tr><tr><td>Baseline HbA1c, %</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.2227</td></tr><tr><td>≤6</td><td>1,260</td><td>27 (2.1)</td><td>1,281</td><td>12 (0.9)</td><td>2.55 (1.29-5.04)</td><td>0.0069</td><td></td></tr><tr><td>&gt;6 to 7</td><td>3,276</td><td>81 (2.5)</td><td>3,237</td><td>36 (1.1)</td><td>2.56 (1.73-3.78)</td><td>&lt;0.0001</td><td></td></tr><tr><td>&gt;7 to 8</td><td>2,324</td><td>41 (1.8)</td><td>2,437</td><td>23 (0.9)</td><td>2.13 (1.28-3.55)</td><td>0.0037</td><td></td></tr><tr><td>&gt;8 to 9</td><td>1,221</td><td>25 (2.0)</td><td>1,152</td><td>17 (1.5)</td><td>1.56 (0.84-2.89)</td><td>0.1561</td><td></td></tr><tr><td>&gt;9 to 10</td><td>629</td><td>20 (3.2)</td><td>613</td><td>3 (0.5)</td><td>6.91 (2.05-23.26)</td><td>0.0018</td><td></td></tr><tr><td>&gt;10</td><td>624</td><td>8 (1.3)</td><td>593</td><td>7 (1.2)</td><td>1.15 (0.42-3.16)</td><td>0.7920</td><td></td></tr><tr><td>Metformin use at baseline</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.6126</td></tr><tr><td>Yes</td><td>7,258</td><td>156 (2.1)</td><td>7,257</td><td>73 (1.0)</td><td>2.40 (1.82-3.17)</td><td>&lt;0.0001</td><td></td></tr><tr><td>No</td><td>2,304</td><td>50 (2.2)</td><td>2,274</td><td>27 (1.2)</td><td>2.08 (1.30-3.33)</td><td>0.0021</td><td></td></tr><tr><td>Sulfonylurea use at baseline</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.4937</td></tr><tr><td>Yes</td><td>3,333</td><td>81 (2.4)</td><td>3,394</td><td>36 (1.1)</td><td>2.59 (1.75-3.83)</td><td>&lt;0.0001</td><td></td></tr><tr><td>No</td><td>6,229</td><td>125 (2.0)</td><td>6,137</td><td>64 (1.0)</td><td>2.17 (1.60-2.93)</td><td>&lt;0.0001</td><td></td></tr><tr><td>Dipeptidyl peptidase 4 inhibitor use at baseline</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.6293</td></tr><tr><td>Yes</td><td>1,811</td><td>46 (2.5)</td><td>1,784</td><td>20 (1.1)</td><td>2.61 (1.55-4.42)</td><td>0.0003</td><td></td></tr><tr><td>No</td><td>7,751</td><td>160 (2.1)</td><td>7,747</td><td>80 (1.0)</td><td>2.24 (1.72-2.93)</td><td>&lt;0.0001</td><td></td></tr><tr><td>Sodium-glucose cotransporter 2 inhibitor use at baseline</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.8877</td></tr><tr><td>Yes</td><td>189</td><td>4 (2.1)</td><td>172</td><td>2 (1.2)</td><td>2.08 (0.38-11.36)</td><td>0.3985</td><td></td></tr><tr><td>No</td><td>9,373</td><td>202 (2.2)</td><td>9,359</td><td>98 (1.0)</td><td>2.32 (1.82-2.95)</td><td>&lt;0.0001</td><td></td></tr><tr><td>Glucagon-like peptide 1 receptor agonist use at baseline</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.2811</td></tr><tr><td>Yes</td><td>202</td><td>6 (3.0)</td><td>209</td><td>1 (0.5)</td><td>7.25 (0.87-60.23)</td><td>0.0667</td><td></td></tr><tr><td>No</td><td>9,360</td><td>200 (2.1)</td><td>9,322</td><td>99 (1.1)</td><td>2.27 (1.78-2.89)</td><td>&lt;0.0001</td><td></td></tr><tr><td>Insulin use at baseline</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.5452</td></tr><tr><td>Yes</td><td>2,779</td><td>56 (2.0)</td><td>2,685</td><td>23 (0.9)</td><td>2.65 (1.63-4.31)</td><td>&lt;0.0001</td><td></td></tr><tr><td>No</td><td>6,783</td><td>150 (2.2)</td><td>6,846</td><td>77 (1.1)</td><td>2.22 (1.69-2.92)</td><td>&lt;0.0001</td><td></td></tr></tbody></table>

Values are n or n (%), unless otherwise indicated.

Regardless of study drug assignment in THEMIS, insulin-using participants were at a relatively higher risk for 3-point MACE (HR: 1.65; 95% CI: 1.49 to 1.83; p < 0.0001) but had similar bleeding risks as those who were not on insulin (HR: 0.92; 95% CI: 0.71 to 1.19; p = 0.52) (Tables 1 and 2). In contrast, there was no difference in risk for 3-point MACE (HR: 1.00; 95% CI: 0.91 to 1.11; p = 0.93) or TIMI major bleeding (HR: 1.12; 95% CI: 0.89 to 1.41; p = 0.34) between those who were treated with a sulfonylurea and those who were not. There also did not appear to be any clinically relevant differences in risk for 3-point MACE or bleeding risk when the participants were classified in a similar fashion according to whether

they were treated or not treated with metformin, a DPP-4 inhibitor, SGLT2 inhibitor, or GLP-1 receptor agonist. We found similar results to those described above when the THEMIS-PCI subpopulation was stratified according to baseline antihyperglycemic regimens.

Using the irreversible harm pre-specified definition of net clinical benefit (composite of all-cause mortality, MI, stroke, fatal bleeding, or intracranial bleeding in the intention-to-treat population), net clinical benefit with ticagrelor add-on in the THEMIS cohort and THEMIS-PCI subcohort was similar across diabetes duration and HbA1c (Tables 3 and 4). Notably, ticagrelor was generally associated
<table><caption>TABLE 3 Net Clinical Benefit in the THEMIS Cohort By Baseline Diabetes-Related Factors and Selected Baseline Antihyperglycemic Therapy</caption><thead><tr><th rowspan="2"></th><th colspan="2">Ticagrelor</th><th colspan="2">Placebo</th><th rowspan="2">Hazard Ratio (95% CI)</th><th rowspan="2">p Value</th><th rowspan="2">Pinteraction</th><th rowspan="2">Risk Difference % (95% CI)</th><th rowspan="2">p Value</th><th rowspan="2">Pinteraction</th></tr><tr><th>N</th><th>Patients With Events</th><th>N</th><th>Patients With Events</th></tr></thead><tbody><tr><td>Overall</td><td>9,619</td><td>968 (10.1)</td><td>9,601</td><td>1,039 (10.8)</td><td>0.93 (0.86-1.02)</td><td>0.1249</td><td></td><td>-0.8 (-1.6 to -0.1)</td><td>0.0894</td><td></td></tr><tr><td>Duration of type 2 diabetes mellitus at baseline, yrs</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.5082</td><td></td><td></td><td>0.5109</td></tr><tr><td>≤5</td><td>2,462</td><td>198 (8.0)</td><td>2,426</td><td>213 (8.8)</td><td>0.92 (0.75-1.11)</td><td>0.3746</td><td></td><td>-0.7 (-2.3 to 0.8)</td><td>0.3541</td><td></td></tr><tr><td>>5 to 10</td><td>2,353</td><td>187 (7.9)</td><td>2,461</td><td>234 (9.5)</td><td>0.84 (0.69-1.02)</td><td>0.0738</td><td></td><td>-1.6 (-3.2 to 0.0)</td><td>0.0590</td><td></td></tr><tr><td>>10 to 15</td><td>1,944</td><td>222 (11.4)</td><td>1,949</td><td>211 (10.8)</td><td>1.07 (0.88-1.29)</td><td>0.5109</td><td></td><td>0.6 (-1.4 to 2.6)</td><td>0.5751</td><td></td></tr><tr><td>>15 to 20</td><td>1,293</td><td>147 (11.4)</td><td>1,250</td><td>152 (12.2)</td><td>0.95 (0.76-1.19)</td><td>0.6684</td><td></td><td>-0.8 (-3.3 to 1.7)</td><td>0.5388</td><td></td></tr><tr><td>>20</td><td>1,561</td><td>214 (13.7)</td><td>1,511</td><td>228 (15.1)</td><td>0.90 (0.75-1.08)</td><td>0.2596</td><td></td><td>-1.4 (-3.9 to 1.1)</td><td>0.2807</td><td></td></tr><tr><td>Baseline HbA<sub>1c</sub>, %</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.3597</td><td></td><td></td><td>0.3572</td></tr><tr><td>≤6</td><td>1,263</td><td>117 (9.3)</td><td>1,285</td><td>107 (8.3)</td><td>1.12 (0.86-1.45)</td><td>0.4038</td><td></td><td>0.9 (-1.3 to 3.1)</td><td>0.4416</td><td></td></tr><tr><td>>6 to 7</td><td>3,301</td><td>273 (8.3)</td><td>3,259</td><td>306 (9.4)</td><td>0.89 (0.75-1.05)</td><td>0.1533</td><td></td><td>-1.1 (-2.5 to 0.3)</td><td>0.1171</td><td></td></tr><tr><td>>7 to 8</td><td>2,334</td><td>249 (10.7)</td><td>2,449</td><td>276 (11.3)</td><td>0.96 (0.81-1.13)</td><td>0.6077</td><td></td><td>-0.6 (-2.4 to 1.2)</td><td>0.5173</td><td></td></tr><tr><td>>8 to 9</td><td>1,227</td><td>142 (11.6)</td><td>1,163</td><td>145 (12.5)</td><td>0.93 (0.74-1.17)</td><td>0.5446</td><td></td><td>-0.9 (-3.5 to 1.7)</td><td>0.5292</td><td></td></tr><tr><td>>9 to 10</td><td>633</td><td>73 (11.5)</td><td>615</td><td>96 (15.6)</td><td>0.72 (0.53-0.97)</td><td>0.0333</td><td></td><td>-4.1 (-7.9 to -0.3)</td><td>0.0386</td><td></td></tr><tr><td>>10</td><td>625</td><td>88 (14.1)</td><td>596</td><td>82 (13.8)</td><td>1.02 (0.76-1.38)</td><td>0.8733</td><td></td><td>0.3 (-3.6 to 4.2)</td><td>0.9341</td><td></td></tr><tr><td>Metformin use at baseline</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.0688</td><td></td><td></td><td>0.0843</td></tr><tr><td>Yes</td><td>7,304</td><td>664 (9.1)</td><td>7,310</td><td>750 (10.3)</td><td>0.89 (0.80-0.98)</td><td>0.0234</td><td></td><td>-1.2 (-2.1 to -0.2)</td><td>0.0174</td><td></td></tr><tr><td>No</td><td>2,315</td><td>304 (13.1)</td><td>2,291</td><td>289 (12.6)</td><td>1.06 (0.90-1.24)</td><td>0.4878</td><td></td><td>0.5 (-1.4 to 2.5)</td><td>0.6285</td><td></td></tr><tr><td>Sulfonylurea use at baseline</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.1735</td><td></td><td></td><td>0.1871</td></tr><tr><td>Yes</td><td>3,350</td><td>353 (10.5)</td><td>3,416</td><td>359 (10.5)</td><td>1.01 (0.88-1.17)</td><td>0.8516</td><td></td><td>0.0 (-1.4 to 1.5)</td><td>1.0000</td><td></td></tr><tr><td>No</td><td>6,269</td><td>615 (9.8)</td><td>6,185</td><td>680 (11.0)</td><td>0.89 (0.80-1.00)</td><td>0.0417</td><td></td><td>-1.2 (-2.3 to -0.1)</td><td>0.0321</td><td></td></tr><tr><td>Dipeptidyl peptidase 4 inhibitor use at baseline</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.8726</td><td></td><td></td><td>0.8426</td></tr><tr><td>Yes</td><td>1,819</td><td>166 (9.1)</td><td>1,795</td><td>173 (9.6)</td><td>0.95 (0.77-1.17)</td><td>0.6226</td><td></td><td>-0.5 (-2.4 to 1.4)</td><td>0.6080</td><td></td></tr><tr><td>No</td><td>7,800</td><td>802 (10.3)</td><td>7,806</td><td>866 (11.1)</td><td>0.93 (0.85-1.02)</td><td>0.1448</td><td></td><td>-0.8 (-1.8 to 0.2)</td><td>0.1027</td><td></td></tr><tr><td>Sodium-glucose cotransporter 2 inhibitor use at baseline</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.9862</td></tr><tr><td>Yes</td><td>189</td><td>11 (5.8)</td><td>174</td><td>11 (6.3)</td><td>0.83 (0.36-1.92)</td><td>0.6642</td><td></td><td>-0.5 (-5.4 to 4.4)</td><td>1.0000</td><td></td></tr><tr><td>No</td><td>9,430</td><td>957 (10.1)</td><td>9,427</td><td>1,028 (10.9)</td><td>0.94 (0.86-1.02)</td><td>0.1363</td><td></td><td>-0.8 (-1.6 to 0.1)</td><td>0.0921</td><td></td></tr><tr><td>Glucagon-like peptide 1 receptor agonist use at baseline</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.8186</td><td></td><td></td><td>0.9218</td></tr><tr><td>Yes</td><td>203</td><td>21 (10.3)</td><td>210</td><td>24 (11.4)</td><td>0.85 (0.47-1.53)</td><td>0.5964</td><td></td><td>-1.1 (-7.1 to 4.9)</td><td>0.7542</td><td></td></tr><tr><td>No</td><td>9,416</td><td>947 (10.1)</td><td>9,391</td><td>1,015 (10.8)</td><td>0.94 (0.86-1.02)</td><td>0.1379</td><td></td><td>-0.8 (-1.6 to 0.1)</td><td>0.0949</td><td></td></tr><tr><td>Insulin use at baseline</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.5819</td><td></td><td></td><td>0.5878</td></tr><tr><td>Yes</td><td>2,798</td><td>366 (13.1)</td><td>2,710</td><td>393 (14.5)</td><td>0.90 (0.78-1.04)</td><td>0.1492</td><td></td><td>-1.4 (-3.2 to 0.4)</td><td>0.1275</td><td></td></tr><tr><td>No</td><td>6,821</td><td>602 (8.8)</td><td>6,891</td><td>646 (9.4)</td><td>0.95 (0.85-1.06)</td><td>0.3380</td><td></td><td>-0.5 (-1.5 to 0.4)</td><td>0.2720</td><td></td></tr></tbody></table>

Values are n or n (%), unless otherwise indicated. Net clinical benefit was pre-specified as irreversible harms and evaluated as time to first event of the composite of all-cause mortality, myocardial infarction, stroke, fatal bleeding, or intracranial bleeding in the intention-to-treat population.

with greater net clinical benefit across the diabetes duration and HbA1c spectra in the THEMIS-PCI subcohort but not in the overall THEMIS cohort.

## DISCUSSION

The present analyses from the THEMIS cohort (8,20) revealed that although diabetes duration and HbA1c levels correlated positively with the incidence of MACE (Central Illustration), they did not influence major bleeding event rates. The favorable impact of ticagrelor plus aspirin had on MACE was consistent across the duration and HbA1c subgroups examined

albeit with an increase in major bleeding events and baseline antihyperglycemic therapy had no influence on the efficacy and safety of ticagrelor. Importantly, in the THEMIS-PCI but not the overall THEMIS population, the combination of ticagrelor plus aspirin resulted in generally consistent and favorable net clinical benefit across the various diabetes-related factors examined.

Current clinical guidelines consistently recommend aspirin as a secondary prevention strategy for cardiovascular events in type 2 diabetes mellitus (21-24). Contrary to the assumption that DAPT would provide protection beyond that offered by aspirin, results from DAPT studies with type 2 diabetes
<table><caption>TABLE 4 Net Clinical Benefit in the THEMIS-PCI Cohort By Baseline Diabetes-Related Factors and Selected Baseline Antihyperglycemic Therapy</caption><thead><tr><th rowspan="2"></th><th colspan="2">Ticagrelor</th><th colspan="2">Placebo</th><th rowspan="2">Hazard Ratio (95% CI)</th><th rowspan="2">p Value</th><th rowspan="2">Pinteraction</th><th rowspan="2">Risk Difference % (95% CI)</th><th rowspan="2">p Value</th><th rowspan="2">Pinteraction</th></tr><tr><th>N</th><th>Patients With Events</th><th>N</th><th>Patients With Events</th></tr></thead><tbody><tr><td>Overall</td><td>5,588</td><td>519 (9.3)</td><td>5,596</td><td>617 (11.0)</td><td>0.85 (0.75-0.95)</td><td>0.0052</td><td>0.012</td><td>-1.7 (-2.8 to -0.6)</td><td>0.003</td><td></td></tr><tr><td>Duration of type 2 diabetes mellitus at baseline, yrs</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.3450</td><td></td><td></td><td>0.3192</td></tr><tr><td>≤5</td><td>1,374</td><td>107 (7.8)</td><td>1,392</td><td>125 (9.0)</td><td>0.86 (0.67-1.12)</td><td>0.2581</td><td></td><td>-1.2 (-3.3 to 0.9)</td><td>0.2727</td><td></td></tr><tr><td>>5 to 10</td><td>1,383</td><td>101 (7.3)</td><td>1,446</td><td>152 (10.5)</td><td>0.70 (0.54-0.89)</td><td>0.0047</td><td></td><td>-3.2 (-5.3 to -1.1)</td><td>0.0030</td><td></td></tr><tr><td>>10 to 15</td><td>1,157</td><td>125 (10.8)</td><td>1,139</td><td>122 (10.7)</td><td>1.02 (0.79-1.30)</td><td>0.9035</td><td></td><td>0.1 (-2.4 to 2.6)</td><td>0.9464</td><td></td></tr><tr><td>>15 to 20</td><td>760</td><td>77 (10.1)</td><td>722</td><td>86 (11.9)</td><td>0.86 (0.63-1.17)</td><td>0.3371</td><td></td><td>-1.8 (-5.0 to 1.4)</td><td>0.2813</td><td></td></tr><tr><td>>20</td><td>881</td><td>109 (12.4)</td><td>894</td><td>132 (14.8)</td><td>0.82 (0.64-1.06)</td><td>0.1275</td><td></td><td>-2.4 (-5.6 to 0.8)</td><td>0.1461</td><td></td></tr><tr><td>Baseline HbA1c, %</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.3467</td><td></td><td></td><td>0.3262</td></tr><tr><td>≤6</td><td>702</td><td>62 (8.8)</td><td>744</td><td>72 (9.7)</td><td>0.90 (0.64-1.26)</td><td>0.5387</td><td></td><td>-0.8 (-3.8 to 2.1)</td><td>0.5876</td><td></td></tr><tr><td>>6 to 7</td><td>1,940</td><td>132 (6.8)</td><td>1,929</td><td>184 (9.5)</td><td>0.71 (0.57-0.89)</td><td>0.0031</td><td></td><td>-2.7 (-4.5 to -1.0)</td><td>0.0022</td><td></td></tr><tr><td>>7 to 8</td><td>1,380</td><td>149 (10.8)</td><td>1,419</td><td>166 (11.7)</td><td>0.94 (0.76-1.18)</td><td>0.5989</td><td></td><td>-0.9 (-3.2 to 1.4)</td><td>0.4731</td><td></td></tr><tr><td>>8 to 9</td><td>687</td><td>75 (10.9)</td><td>675</td><td>80 (11.9)</td><td>0.91 (0.67-1.25)</td><td>0.5758</td><td></td><td>-0.9 (-4.3 to 2.4)</td><td>0.6093</td><td></td></tr><tr><td>>9 to 10</td><td>363</td><td>41 (11.3)</td><td>360</td><td>55 (15.3)</td><td>0.72 (0.48-1.08)</td><td>0.1137</td><td></td><td>-4.0 (-8.9 to 1.0)</td><td>0.1254</td><td></td></tr><tr><td>>10</td><td>348</td><td>49 (14.1)</td><td>330</td><td>42 (12.7)</td><td>1.10 (0.73-1.67)</td><td>0.6391</td><td></td><td>1.4 (-3.8 to 6.5)</td><td>0.6527</td><td></td></tr><tr><td>Metformin use at baseline</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.1835</td><td></td><td></td><td>0.1955</td></tr><tr><td>Yes</td><td>4,253</td><td>364 (8.6)</td><td>4,311</td><td>457 (10.6)</td><td>0.80 (0.70-0.92)</td><td>0.0020</td><td></td><td>2.0 (-3.3 to -0.8)</td><td>0.0014</td><td></td></tr><tr><td>No</td><td>1,305</td><td>155 (11.9)</td><td>1,285</td><td>160 (12.5)</td><td>0.96 (0.77-1.20)</td><td>0.7174</td><td></td><td>-0.6 (-3.1 to 1.9)</td><td>0.6741</td><td></td></tr><tr><td>Sulfonylurea use at baseline</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.5999</td><td></td><td></td><td>0.5823</td></tr><tr><td>Yes</td><td>1,937</td><td>190 (9.8)</td><td>1,981</td><td>220 (11.1)</td><td>0.88 (0.73-1.07)</td><td>0.2110</td><td></td><td>-1.3 (-3.2 to 0.6)</td><td>0.1921</td><td></td></tr><tr><td>No</td><td>3,621</td><td>329 (9.1)</td><td>3,615</td><td>397 (11.0)</td><td>0.83 (0.72-0.96)</td><td>0.0111</td><td></td><td>-1.9 (-3.3 to -0.5)</td><td>0.0078</td><td></td></tr><tr><td>Dipeptidyl peptidase 4 inhibitor use at baseline</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.4293</td><td></td><td></td><td>0.4444</td></tr><tr><td>Yes</td><td>1,204</td><td>96 (8.0)</td><td>1,164</td><td>120 (10.3)</td><td>0.77 (0.59-1.00)</td><td>0.0533</td><td></td><td>-2.3 (-4.7 to -0.0)</td><td>0.0538</td><td></td></tr><tr><td>No</td><td>4,354</td><td>423 (9.7)</td><td>4,432</td><td>497 (11.2)</td><td>0.87 (0.76-0.99)</td><td>0.0313</td><td></td><td>-1.5 (-2.8 to -0.2)</td><td>0.0235</td><td></td></tr><tr><td>Sodium-glucose cotransporter 2 inhibitor use at baseline</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.7177</td><td></td><td></td><td>0.7814</td></tr><tr><td>Yes</td><td>117</td><td>6 (5.1)</td><td>99</td><td>7 (7.1)</td><td>0.63 (0.21-1.89)</td><td>0.4078</td><td></td><td>-1.9 (-8.4 to 4.5)</td><td>0.5785</td><td></td></tr><tr><td>No</td><td>5,441</td><td>513 (9.4)</td><td>5,497</td><td>610 (11.1)</td><td>0.85 (0.76-0.96)</td><td>0.0066</td><td></td><td>-1.7 (-2.8 to -0.5)</td><td>0.0041</td><td></td></tr><tr><td>Glucagon-like peptide 1 receptor agonist use at baseline</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.6596</td><td></td><td></td><td>0.6069</td></tr><tr><td>Yes</td><td>130</td><td>15 (11.5)</td><td>123</td><td>14 (11.4)</td><td>0.97 (0.47-2.02)</td><td>0.9435</td><td></td><td>0.2 (-7.7 to 8.0)</td><td>1.0000</td><td></td></tr><tr><td>No</td><td>5,428</td><td>504 (9.3)</td><td>5,473</td><td>603 (11.0)</td><td>0.84 (0.75-0.95)</td><td>0.0046</td><td></td><td>-1.7 (-2.9 to -0.6)</td><td>0.0029</td><td></td></tr><tr><td>Insulin use at baseline</td><td></td><td></td><td></td><td></td><td></td><td></td><td>0.4354</td><td></td><td></td><td>0.4846</td></tr><tr><td>Yes</td><td>1,541</td><td>204 (13.2)</td><td>1,495</td><td>222 (14.8)</td><td>0.89 (0.74-1.08)</td><td>0.2476</td><td></td><td>-1.6 (-4.1 to 0.9)</td><td>0.2099</td><td></td></tr><tr><td>No</td><td>4,017</td><td>315 (7.8)</td><td>4,101</td><td>395 (9.6)</td><td>0.81 (0.70-0.94)</td><td>0.0059</td><td></td><td>-1.8 (-3.0 to -0.6)</td><td>0.0046</td><td></td></tr></tbody></table>

Values are n or n (%), unless otherwise indicated. Net clinical benefit was pre-specified as irreversible harms and evaluated as time to first event of the composite of all-cause mortality, myocardial infarction, stroke, fatal bleeding, or intracranial bleeding in the intention-to-treat population.

mellitus cohorts that had well controlled traditional risk factors have been somewhat disappointing (7,25-28). Although clopidogrel is the most widely prescribed antithrombotic adjunct to aspirin, ticagrelor affords faster and more favorable antiplatelet outcomes (29,30). Furthermore, head-to-head comparisons have revealed that ticagrelor has superior benefits to clopidogrel in acute coronary syndrome (6,26). The benefits of ticagrelor over clopidogrel in individuals with type 2 diabetes mellitus may be attributed in part to impaired clopidogrel metabolism resulting in less exposure to the active clopidogrel metabolite (31) and the twice daily regimen of

ticagrelor that may be favorable in diabetes mellitus where platelet turnover rates are high (32). Of note, Capodanno et al. (33) found that 81 mg aspirin taken twice daily was more effective than 81 mg aspirin once daily at reducing platelet reactivity.

Unlike earlier outcome trials which evaluated secondary prevention with DAPT, THEMIS enrolled individuals who did not have a history of MI or stroke, resulting in a population that had a lower cardiovascular risk profile even though type 2 diabetes mellitus was a mandatory entry criterion. In addition and similarly to many of the earlier DAPT studies, the THEMIS participants were exceptionally well
managed and in accord with guideline recommendations; specifically, 90% were on a statin, 79% were taking either an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and 74% were using a β-blocker (8). Accordingly, the observations described herein further emphasize that individuals with type 2 diabetes mellitus and stable coronary artery disease without a history of MI or stroke, but who have undergone a PCI, and who are pharmacologically well managed can benefit significantly from the addition of ticagrelor on an aspirin background.

Like several studies that have previously investigated DAPT strategies with aspirin (34-37), THEMIS reported that decreases in the risk of the primary efficacy outcome occurred simultaneously with increases in bleeding events (8). This has, unsurprisingly, driven much discussion on the risk-benefit balance of applying DAPT approaches. That said, examination of data from the THEMIS-PCI subcohort showed that the rise in bleeding events was accompanied by a net clinical benefit among those who had previously undergone coronary revascularization relative to those without (9). In reviewing the present work, an important take-home message would be that the risk of a THEMIS-PCI participant experiencing a bleeding event with ticagrelor plus aspirin was not influenced by where they were positioned on the diabetes continuum. This is especially relevant given the burgeoning population with diabetes and the growing proportion of these individuals who are anticipated to require a PCI during their lifetime.

Previous studies have suggested that diabetes-related factors, such as diabetes duration, HbA1c levels, and background antihyperglycemic therapies, can influence cardiovascular risk and outcomes in populations with type 2 diabetes mellitus (14-17). Accordingly, the goal of the present nonprespecified analyses was to examine whether the efficacy, safety, and net clinical benefit observed with the combination of ticagrelor and low-dose aspirin in the THEMIS cohort and THEMIS-PCI subcohort varied across diabetes-related factors including duration of diabetes, baseline HbA1c, and baseline antihyperglycemic medications.

These analyses extend the findings of the overall THEMIS cohort (8) and smaller THEMIS-PCI subpopulation (9). The collective data remind us that type 2 diabetes mellitus is a progressive condition and that those who live with this disorder have a continuum of risk. The results indicate that the combination of ticagrelor and low-dose aspirin merits consideration alongside other guideline-recommended vascular

protective strategies in individuals with type 2 diabetes mellitus who have stable coronary artery disease, a prior PCI, and proven tolerance for DAPT with low bleeding risk. Importantly, these benefits are apparent regardless of diabetes-related factors (diabetes duration and HbA1c) or the baseline antihyperglycemic regimen.

The notion of expanding secondary prevention strategies beyond aspirin monotherapy, in cases of diabetes with stable atherosclerosis and acceptable bleeding risk, is not new and is supported by a recent pre-specified analysis from the COMPASS (Cardiovascular Outcomes for People Using Anti-coagulation Strategies) trial (38). Specifically, COMPASS demonstrated that when DAPT was not indicated, dual pathway inhibition with 2.5 mg rivaroxaban twice daily plus aspirin, compared with placebo plus aspirin, offered greater risk reduction of ischemic harm and all-cause mortality, as well as greater net clinical benefit in those with diabetes compared with those without diabetes. Of note, a pre-specified analysis from the TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention) trial revealed that ticagrelor monotherapy for 1 year following 3 months of DAPT with ticagrelor plus aspirin after PCI in participants with diabetes lowered the risk of clinically relevant bleeding in the absence of any increases of ischemic events (39). Whether the THEMIS-PCI participants would have experienced similar benefits by switching to a ticagrelor strategy that did not include aspirin is unknown and intriguing.

**STUDY LIMITATIONS.** It is important to recognize that the results reported herein have some limitations. First, the analyses were based on baseline HbA1c readings and the baseline antihyperglycemic regimens. In view of the median follow-up duration of 39.9 months, it is likely that there were at least some temporal fluctuations in HbA1c levels as well as modifications in glucose-lowering strategies, especially given evolving guideline recommendations during the study period. Second, rates of use of novel classes of antihyperglycemic agents were low and resulted in limited ability to ascertain potential treatment interactions. Third, net clinical benefit, which was a pre-specified exploratory endpoint in THEMIS and THEMIS-PCI, had a relatively restrictive definition of time to first event of the composite of all-cause mortality, MI, stroke, fatal bleeding, or intracranial bleeding.
**CENTRAL ILLUSTRATION** Primary Efficacy Outcome of 3-Point Major Adverse Cardiovascular Events (Cardiovascular Death, Myocardial Infarction, Stroke)

A

<figure><img src="image_5.png" /></figure>

B

<figure><img src="image_6.png" /></figure>

Leiter, L.A. et al. J Am Coll Cardiol. 2021;77(19):2366-77.
## CONCLUSIONS

Despite proactive management of traditional cardiovascular risk factors, ischemic events remain an ongoing concern among individuals with type 2 diabetes mellitus and established coronary artery disease who do not have a history of MI or stroke. The present results indicate that together, ticagrelor plus aspirin reduced the incidence of MACE regardless of baseline duration of diabetes and baseline HbA1c but at the expense of major bleeding events. Notably, the combination of ticagrelor plus aspirin resulted in generally consistent and favorable net clinical benefit across the various diabetes-related factors in THEMIS-PCI, but not in the overall THEMIS population.

**ACKNOWLEDGMENTS** The authors thank the THEMIS participants, investigators, and site staff who were involved in the conduct of the trial. The statistical analyses were conducted by independent statisticians at the Baim Institute for Clinical Research (Boston, MA).

## FUNDING SUPPORT AND AUTHOR DISCLOSURES

The THEMIS study was funded and sponsored by AstraZeneca Research & Development. The statistical analyses were conducted independently from but with funding from AstraZeneca. Dr. Leiter has received grants and personal fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, HLS, Janssen, Novartis, Novo Nordisk, and Sanofi; has received grants from Esperion, GSK, Kowa, Lexicon, Novartis, and The Medicines Company; and has received personal fees from Merck and Servier. Dr. Bhatt served as the co-chair and co-principal investigator of THEMIS and THEMIS-PCI with research funding from AstraZeneca to Brigham and Women's Hospital; and has served on the advisory board for Cardax, Cereno Scientific, Elsevier Practice Update Cardiology, Medscape Cardiology, PhaseBio, PLx Pharma, and Regado has served on the Biosciences; has served on the board of directors for Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; chair of American Heart Association Quality Oversight Committee; has served on the data monitoring committees for Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the

ExCEED trial, funded by Edwards), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi-Sankyo), Population Health Research Institute; has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; and Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim, and AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor-in-Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor-in-Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor, Associate Editor), Medtelligenge/ReachMD (CME steering committees), MJH Life Sciences, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), and WebMD (CME steering committees); Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry steering committee (Chair), VA CART Research and Publications Committee (Chair); has received research funding from Abbott, Afirmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi, Synaptic, and The Medicines Company; has received royalties from Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald's Heart Disease); site co-investigator for Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), and Svelte; has been a trustee of American College of Cardiology; and has performed unfunded research for FlowCo, Merck, Novo Nordisk, and Takeda. Dr. McGuire has received honoraria for clinical trials leadership from AstraZeneca, Boehringer Ingelheim, Eisai, Esperion, GlaxoSmithKline, Janssen, Lexicon, Lilly USA, Merck, Novo Nordisk, Pfizer, and Sanofi; and has received honoraria for consultancy from Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Lilly USA, Merck, Metavant, Novo Nordisk, and Sanofi. Dr. Teoh has received personal fees from Boehringer Ingelheim, Merck, and Servier. Dr. Fox has received fees, honoraria, and travel expenses from AstraZeneca, Broadview Ventures, Celixir, Servier, TaurX, and UCB; and has served as a director of Vesalius Trials. Dr. Simon has received grants to the institution from AstraZeneca, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, and Sanofi; and has received consulting fees or honoraria from AstraZeneca, Bristol Myers Squibb, Novartis, and Sanofi. Dr. Mehta has received research grants to Population Health Research Institute from AstraZeneca, Abbott, Boston Scientific, and Sanofi; and has received honoraria for consultancy from AstraZeneca, Bayer, Bio-

## CENTRAL ILLUSTRATION Continued

Outcomes were examined across groups of patients with type 2 diabetes mellitus (T2DM) duration ranging from ≤5 years to >20 years and separately by levels of baseline HbA1c ranging from ≤6% to >10%. In THEMIS, the incidence of the primary efficacy outcome was positively correlated with (A) increasing duration of type 2 diabetes mellitus and (B) the level of HbA1c at baseline. Ticagrelor plus aspirin treatment did not have a significant interaction with either parameter. Neither duration of type 2 diabetes mellitus nor baseline HbA1c influenced major bleeding rates (not shown). In THEMIS-PCI, ticagrelor plus aspirin yielded generally consistent and favorable net clinical benefit across the diabetes-related factors. THEMIS = The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study; THEMIS-PCI = The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study-Percutaneous Coronary Intervention.
sensors, and Sanofi. Dr. Kiss has received speaker honoraria from Bayer, Boehringer Ingelheim, Merck Sharp & Dohme, and Pfizer. Dr. Dalby has served on South African advisory boards for Aspen, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Sanofi, and Servier; has received honoraria from AstraZeneca and Servier; and has received travel sponsorship from Bayer, Boehringer Ingelheim, Novartis, and Sanofi. Dr. Bueno has received research funding from the Instituto de Salud Carlos III, Spain (PIE16/00021 and PI17/01799), Sociedad Española de Cardiología, AstraZeneca, Bayer, Bristol Myers Squibb, and Novartis; has received honoraria for consultancy from AstraZeneca, Bayer, Bristol Myers Squibb-Pfizer, and Novartis; and has received speaking fees or support for attending scientific meetings from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb-Pfizer, Novartis, and Medscape. Dr. Ridderstråle is an employee of AstraZeneca. Dr. Himmelmann is an employee of AstraZeneca. Dr. Kosiborod has received research support from AstraZeneca and Boehringer Ingelheim; and has received honoraria for clinical trial leadership and consultancy for Amarin, Applied Therapeutics, AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Eisai, Glytec, GlaxoSmithKline, Intacia, Janssen, Eli Lilly, Merck (Diabetes), Novartis, Novo Nordisk, Sanofi, and Vifor Pharma. Dr. Steg has received personal fees and nonfinancial support from AstraZeneca; has received grants and personal fees from Amarin, Bayer/Janssen, Merck, Sanofi, and Servier; and has received personal fees from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Idorsia, Lilly, Novartis, Novo Nordisk, Pfizer, and Regeneron. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

**ADDRESS FOR CORRESPONDENCE:** Dr. Lawrence A. Leiter, St. Michael's Hospital Medical Centre, 61 Queen Street East, Suite 6-121Q, Toronto, Ontario M5C 2T2, Canada. E-mail: lawrence.leiter@unityhealth.to. Twitter: @dlbhattmd, @gabrielsteg.

## PERSPECTIVES

**COMPETENCY IN PATIENT CARE:** In patients with type 2 diabetes mellitus and stable coronary artery disease without prior myocardial infarction or stroke, dual antiplatelet therapy with ticagrelor plus aspirin reduces the risk of ischemic events, independent of diabetes duration, baseline antihyperglycemic therapy or HbA1c, but increases the risk of bleeding.

**TRANSLATIONAL OUTLOOK:** Future studies should evaluate the safety and efficacy of dual anti-platelet therapy with ticagrelor plus aspirin in patients with diabetes taking new classes of antihyperglycemic agents.

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**KEY WORDS** aspirin, bleeding, diabetes mellitus, dual antiplatelet therapy, ticagrelor

**APPENDIX** For supplemental tables and a figure, please see the online version of this paper.