Ticagrelor With Asp Irin or ALone In Hi

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Ticagrelor With Asp. Irin or ALone In Hi. GH-Risk Pa. Tients With Diabetes Mellitus

Ticagrelor With Asp. Irin or ALone In Hi. GH-Risk Pa. Tients With Diabetes Mellitus After Coronary Intervention: The TWILIGHT-DM Study Dominick J. Angiolillo, MD, Ph. D on behalf of Roxana Mehran, MD / Usman Baber, MD and the TWILIGHT Investigators University of Florida College of Medicine, Jacksonville, FL, USA Icahn School of Medicine at Mount Sinai, New York, NY, USA

Declaration of Interest The TWILIGHT Trial Sponsoring organization: Icahn School of Medicine at Mount

Declaration of Interest The TWILIGHT Trial Sponsoring organization: Icahn School of Medicine at Mount Sinai, NY Funded by Astra. Zeneca Coordinated by Icahn School of Medicine at Mount Sinai, NY

Presenter Disclosure Information Name: Dominick J Angiolillo Within the past 12 months, the presenter

Presenter Disclosure Information Name: Dominick J Angiolillo Within the past 12 months, the presenter or their spouse/partner have had a financial interest/arrangement or affiliation with the organization listed below. Received payment as an individual for: a) Consulting fee or honorarium from Amgen, Aralez, Astra. Zeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, Phase. Bio, PLx Pharma, Pfizer, Sanofi, and The Medicines Company. b) Honorarium for participation in review activities (DSMB member) from Celo. Nova. c) Honorarium from the American Board of Internal Medicine (Interventional Cardiology Subspecialty Exam Writing Committee Member) Institutional payments for: a) Grant support industry: Amgen, Astra. Zeneca, Bayer, Biosensors, Celo. Nova, CSL Behring, Daiichi-Sankyo, Eisai, Eli-Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co. , Merck, Novartis, Osprey Medical, and Renal Guard Solutions. b) Grant in gift: Spartan; Scott R. Mac. Kenzie Foundation c) Federal agency: NIH

Background • DAPT with aspirin and a P 2 Y 12 inhibitor is the

Background • DAPT with aspirin and a P 2 Y 12 inhibitor is the standard of care for the prevention of thrombotic complications in patients undergoing PCI. However, this occurs at the expense of enhanced bleeding, the risk of which increases with prolonged exposure to DAPT 1. • These observations underscore the need to identify antithrombotic regimens that can reduce the risk of bleeding while maintaining efficacy post-PCI. Among these, maintaining P 2 Y 12 inhibitor monotherapy, after a brief period of DAPT, has emerged as a promising strategy 2. • The TWILIGHT trial showed that among high-risk PCI patients, after 3 months of DAPT, ticagrelor monotherapy reduced bleeding without increasing ischemic harm 3. • Understanding the benefit of this antithrombotic strategy in patient cohorts who are at particularly high -risk for adverse events is of utmost clinical interest. 1. Capodanno et al. J Am Coll Cardiol. 2018; 72: 2915 -31. 2. Capodanno et al. Nat Rev Cardiol. 2018; 15: 480 -96. 3. Mehran et al. N Engl J Med. 2019; 381: 2032 -42.

Background • Patients with DM are known to be at high-risk for both ischemic

Background • Patients with DM are known to be at high-risk for both ischemic and bleeding complications post-PCI. A number of factors contribute to these observations, including the complexity of coronary interventions, endothelial dysfunction, concomitant comorbidities, and dysregulation of hemostatic and thrombotic processes 4. • Importantly, the prevalence of DM (mostly type 2) in the past decade has increased by 30% globally and is projected to markedly increase in the upcoming decades, highlighting the importance of defining optimal post-PCI pharmacotherapy in these patients 5. 4. Ferreiro et al. Circulation. 2011; 123: 798 -813. 5. Ogurtsova et al. Diabetes Res Clin Pract. 2017; 128: 40 -50.

TWILIGHT-DM: Study Objective Pre-specified analysis of the TWILIGHT trial To examine the effect of

TWILIGHT-DM: Study Objective Pre-specified analysis of the TWILIGHT trial To examine the effect of ticagrelor monotherapy versus ticagrelor plus aspirin among patients with diabetes mellitus undergoing PCI with drug eluting stents after completing a 3 -month course of DAPT

TWILIGHT-DM: Study Design • Randomized, double-blind placebo controlled trial in 187 sites and 11

TWILIGHT-DM: Study Design • Randomized, double-blind placebo controlled trial in 187 sites and 11 countries. • High-risk PCI patients treated with ticagrelor plus aspirin for 3 months. • Event-free and adherent patients were randomized to aspirin versus placebo and continued ticagrelor for an additional 12 months. High-Risk PCI Patients (N = 9006) Ticagrelor + Aspirin Standard of Care Ticagrelor + Placebo Standard of Care Enrolled with DM (N = 3395) DM = 2620 Enrollment Period 3 Months 3 M Randomization Period 12 Months 15 M Observation Period 18 M 3 Months

TWILIGHT Inclusion/Exclusion Criteria Must meet at least one clinical AND one angiographic criterion Clinical

TWILIGHT Inclusion/Exclusion Criteria Must meet at least one clinical AND one angiographic criterion Clinical criteria Angiographic criteria Age ≥ 65 years Multivessel CAD Female gender Target lesion requiring total stent length >30 mm Troponin positive ACS Thrombotic target lesion Established vascular disease (previous MI, documented PAD or CAD/PAD revasc) Bifurcation lesion(s) with Medina X, 1, 1 classification requiring ≥ 2 stents DM treated with medications or insulin Left main (≥ 50%) or proximal LAD (≥ 70%) lesions CKD (e. GFR <60 ml/min/1. 73 m 2 or Cr. Cl <60 ml/min) Calcified target lesion(s) requiring atherectomy Key Exclusions: STEMI; Salvage PCI; need for chronic oral anticoagulation; prior stroke; planned coronary revascularization

TWILIGHT-DM: Methods Target Population Randomized TWILIGHT participants presenting with diabetes mellitus (DM) Endpoints Primary:

TWILIGHT-DM: Methods Target Population Randomized TWILIGHT participants presenting with diabetes mellitus (DM) Endpoints Primary: BARC 2, 3 or 5 bleeding between 0 - 12 months after randomization Secondary: All-cause death, non-fatal MI or stroke between 0 - 12 months after randomization Analytic Approach • Survival analyses for both primary and secondary endpoints using the Kaplan-Meier method • Hazard ratios and 95% confidence intervals (CI) generated using Cox regression • Analyses of bleeding were performed using the intention-to-treat cohort, while ischemic outcomes were • • analyzed using the per-protocol cohort Treatment effects were estimated according to presence of DM with formal interaction testing to assess for effect modification Exploratory analysis: a) clinical presentation (ACS vs. stable CAD); b) type of glucose lowering treatment (insulin vs. non-insulin); and c) net adverse clinical events (BARC 3 or 5 bleeding, death, MI, or stroke)

Adherence rates to ticagrelor at 1 to year were 87. 1% andof 84. 7%

Adherence rates to ticagrelor at 1 to year were 87. 1% andof 84. 7% amongrace, thosehave randomized to ticagrelor DM patients were more likely berandomization from North America and nonwhite more risk factors plus placebo and ticagrelor plus aspirin, respectively. Analogous rates for blinded study drug were 81. 5% and 79. 9%. (CKD, HTN, obesity), prior revascularization and multivessel CAD compared to non-DM patients.

TWILIGHT-DM: Patient Characteristics Baseline Demographics Tica + Placebo (N = 1319) Tica + Aspirin

TWILIGHT-DM: Patient Characteristics Baseline Demographics Tica + Placebo (N = 1319) Tica + Aspirin (N = 1301) p-value 64. 8 ± 9. 9 64. 8 ± 10. 2 0. 95 Female sex 308 (23. 4%) 310 (23. 8%) 0. 77 Nonwhite race 493 (37. 4%) 479 (36. 8%) 0. 77 29. 8 ± 5. 9 29. 8 ± 6. 0 0. 79 0. 27 North America 613 (46. 5%) 573 (44. 0%) Europe 371 (28. 1%) 402 (30. 9%) Asia 335 (25. 4%) 326 (25. 1%) Chronic Kidney Disease 256 (20. 3%) 278 (22. 0%) 0. 28 Anemia 323 (25. 6%) 322 (25. 6%) 1. 00 ACS presentation 810 (61. 4%) 804 (61. 8%) 0. 84 Current Smoker 219 (16. 6%) 255 (19. 6%) 0. 045 Previous MI 385 (29. 2%) 382 (29. 4%) 0. 92 Previous PCI 595 (45. 1%) 597 (45. 9%) 0. 69 Previous CABG 179 (13. 6%) 151 (11. 6%) 0. 97 12 (0. 9%) 0. 97 Variable Age, years [Mean ± SD] BMI, kg/m 2 [Mean ± SD] Enrolling region Previous major bleed

TWILIGHT-DM: Patient Characteristics Baseline Procedural Details Tica + Placebo (N = 1319) Tica +

TWILIGHT-DM: Patient Characteristics Baseline Procedural Details Tica + Placebo (N = 1319) Tica + Aspirin (N = 1301) p-value Radial access 920 (69. 8%) 900 (69. 2%) 0. 75 Multivessel CAD 915 (69. 4%) 883 (67. 9%) 0. 41 Variable Target vessel LAD 730 (55. 3%) 724 (55. 7%) 0. 88 RCA 460 (34. 9%) 457 (35. 1%) 0. 89 LCX 450 (34. 1%) 439 (33. 7%) 0. 84 Left Main Disease ≥ 50% 54 (4. 1%) 69 (5. 3%) 0. 14 Number of lesions treated [Mean ± SD] 1. 5 ± 0. 7 1. 6 ± 0. 8 0. 28 Thrombus 100 (7. 6%) 100 (7. 7%) 0. 92 Calcification, moderate/severe 217 (16. 5%) 192 (14. 8%) 0. 23 Any bifurcation 152 (11. 5%) 153 (11. 8%) 0. 85 Chronic total occlusion 79 (6. 0%) 94 (7. 2%) 0. 20 Total stent length [Mean ± SD] 39. 4 ± 23. 4 39. 7 ± 24. 6 0. 71 Lesion morphology

TWILIGHT-DM: BARC 2, 3 or 5 Bleeding Intention-To-Treat Cohort Ticagrelor + Aspirin Cumulative incidence

TWILIGHT-DM: BARC 2, 3 or 5 Bleeding Intention-To-Treat Cohort Ticagrelor + Aspirin Cumulative incidence (%) 10 Ticagrelor + Placebo 8 HR [95%CI]: 0. 65 [0. 47 – 0. 91] p = 0. 01 6. 7% 6 4 4. 5% 2 0 0 60 120 180 240 300 360 1184 1233 1169 1221 Days after randomization Number at risk Ticagrelor plus Aspirin Ticagrelor plus Placebo 1301 1319 1274 1297 1250 1285 1223 1270 1200 1246

Bleeding Events With and Without DM DM patients (N = 2620) Variable Tica +

Bleeding Events With and Without DM DM patients (N = 2620) Variable Tica + Placebo (N = 1319) Tica + Aspirin (N = 1301) HR (95% CI) Non-DM patients (N = 4499) p-value no. of patients (%) Tica + Placebo (N = 2236) Tica + Aspirin (N = 2263) Interaction p-value HR (95% CI) p-value no. of patients (%) BARC 2, 3 or 5 58 (4. 5%) 86 (6. 7%) 0. 65 (0. 47 – 0. 91) 0. 01 83 (3. 8%) 164 (7. 3%) 0. 50 (0. 39 – 0. 66) <0. 001 0. 23 BARC 3 or 5 14 (1. 1%) 40 (3. 1%) 0. 34 (0. 19 – 0. 63) 0. 001 20 (0. 9%) 29 (1. 3%) 0. 70 (0. 39 – 1. 23) 0. 22 0. 09 TIMI minor or major 58 (4. 5%) 86 (6. 7%) 0. 65 (0. 47 – 0. 91) 0. 01 83 (3. 8%) 164 (7. 3%) 0. 50 (0. 39 – 0. 66) <0. 001 0. 23 GUSTO moderate or severe 9 (0. 7%) 30 (2. 3%) 0. 29 (0. 14 – 0. 62) 0. 001 17 (0. 8%) 19 (0. 9%) 0. 91 (0. 47 – 1. 74) 0. 77 0. 03 ISTH major 18 (1. 4%) 40 (3. 1%) 0. 44 (0. 25 – 0. 77) 0. 004 21 (1. 0%) 32 (1. 4%) 0. 66 (0. 38 – 1. 15) 0. 15 0. 30

TWILIGHT-DM: Death, MI or Stroke Per-Protocol Cohort Ticagrelor + Aspirin Cumulative incidence (%) 10

TWILIGHT-DM: Death, MI or Stroke Per-Protocol Cohort Ticagrelor + Aspirin Cumulative incidence (%) 10 Ticagrelor + Placebo 8 HR [95%CI]: 0. 77 [0. 55 – 1. 09] p = 0. 14 6 5. 9% 4 4. 6% 2 0 0 60 120 180 240 300 360 1204 1234 1190 1223 Days after randomization Number at risk Ticagrelor plus Aspirin Ticagrelor plus Placebo 1285 1308 1269 1288 1252 1273 1235 1261 1219 1242

Ischemic Events With and Without DM DM patients (N = 2620) Variable Tica +

Ischemic Events With and Without DM DM patients (N = 2620) Variable Tica + Placebo (N = 1319) Tica + Aspirin (N = 1301) HR (95% CI) Non-DM patients (N = 4499) p-value no. of patients (%) Death, MI or stroke 59 (4. 6%) 75 (5. 9%) Cardiovascular death, MI or ischemic stroke 57 (4. 4%) 70 (5. 5%) All-cause death 17 (1. 3%) 25 (2. 0%) Cardiovascular death 15 (1. 2%) 19 (1. 5%) MI 40 (3. 1%) 52 (4. 1%) Ischemic stroke 8 (0. 6%) 5 (0. 4%) Stent thrombosis (definite/probable) 6 (0. 5%) 9 (0. 7%) Tica + Placebo (N = 2236) Tica + Aspirin (N = 2263) HR (95% CI) Interaction p-value no. of patients (%) 0. 77 (0. 55 – 1. 09) 0. 80 (0. 56 – 1. 13) 0. 67 (0. 36 – 1. 23) 0. 78 (0. 39 – 1. 53) 0. 75 (0. 50 – 1. 14) 1. 58 (0. 52 – 4. 82) 0. 66 (0. 23 – 1. 84) 0. 14 76 (3. 5%) 62 (2. 8%) 0. 21 69 (3. 2%) 60 (2. 7%) 0. 20 17 (0. 8%) 20 (0. 9%) 0. 47 11 (0. 5%) 18 (0. 8%) 0. 18 55 (2. 5%) 43 (2. 0%) 0. 42 8 (0. 4%) 3 (0. 1%) 0. 42 8 (0. 4%) 10 (0. 5%) 1. 24 (0. 89 – 1. 73) 1. 16 (0. 82 – 1. 64) 0. 85 (0. 45 – 1. 63) 0. 62 (0. 29 – 1. 30) 1. 29 (0. 87 – 1. 92) 2. 69 (0. 71 – 10. 1) 0. 81 (0. 32 – 2. 04) 0. 21 0. 05 0. 39 0. 14 0. 64 0. 59 0. 21 0. 65 0. 21 0. 07 0. 14 0. 55 0. 65 0. 77

Net Adverse Clinical Events (ITT) BARC 3 or 5 Bleeding, Death, MI, or Stroke

Net Adverse Clinical Events (ITT) BARC 3 or 5 Bleeding, Death, MI, or Stroke Ticagrelor + Aspirin Cumulative incidence (%) 10 8. 7% Ticagrelor + Placebo 8 HR [95%CI]: 0. 61 [0. 45 – 0. 82] p = 0. 001 NNT = 30 6 5. 4% 4 2 not pre-specified and exploratory in nature 0 0 60 120 180 240 300 360 1186 1234 1169 1222 Days after randomization Number at risk Ticagrelor plus Aspirin Ticagrelor plus Placebo 1301 1319 1273 1293 1248 1278 1225 1263 1204 1242

Outcomes by Clinical Presentation HR (95% CI) BARC 2, 3 or 5 pint 0.

Outcomes by Clinical Presentation HR (95% CI) BARC 2, 3 or 5 pint 0. 21 DM-ACS 0. 55 (0. 35 – 0. 85) DM-Stable CAD 0. 84 (0. 50 – 1. 42) BARC 3 or 5 DM-ACS 0. 16 0. 23 (0. 09 – 0. 55) DM-Stable CAD 0. 56 (0. 23 – 1. 33) Death, MI or Stroke DM-ACS 0. 74 0. 80 (0. 54 – 1. 20) DM-Stable CAD 0. 71 (0. 37 – 1. 34) 0. 1 Tica + Placebo Better 1 Tica + Aspirin Better 10

Outcomes by Management of DM HR (95% CI) BARC 2, 3 or 5 pint

Outcomes by Management of DM HR (95% CI) BARC 2, 3 or 5 pint 0. 84 IDDM 0. 62 (0. 34 – 1. 15) Non-IDDM 0. 67 (0. 45 – 1. 00) BARC 3 or 5 IDDM 0. 18 0. 61 (0. 22 – 1. 64) Non-IDDM 0. 26 (0. 12 – 0. 56) Death, MI or Stroke IDDM 0. 48 0. 92 (0. 53 – 1. 58) Non-IDDM 0. 71 (0. 46 – 1. 11) 0. 1 Tica + Placebo Better 1 Tica + Aspirin Better 10

Limitations • Although this was a pre-specified analysis, randomization was not stratified by DM

Limitations • Although this was a pre-specified analysis, randomization was not stratified by DM status and we did not account for multiplicity thereby increasing the chance for a type 1 error. • DM status was based upon physician diagnosis (serum glucose and hemoglobin A 1 c were not collected as part of the TWILIGHT trial). • Our findings may not generalize to patients treated with other oral P 2 Y 12 inhibitors, particularly clopidogrel. • Extrapolating results to STEMI patients not possible given trial design. • Lack of power to detect differences in the risk of important yet rare clinical events, such as stent thrombosis and stroke.

Conclusions • Compared with ticagrelor plus aspirin, the effect of ticagrelor monotherapy in reducing

Conclusions • Compared with ticagrelor plus aspirin, the effect of ticagrelor monotherapy in reducing the risk of clinically relevant bleeding without any increase in ischemic events was consistent among patients with or without DM undergoing PCI. • These findings support such a bleeding avoidance strategy, which can be implemented without any signals for harm even in high-risk patients such as those with DM.

Acknowledgement We thank all the country leaders, investigators, coordinators and study participants who made

Acknowledgement We thank all the country leaders, investigators, coordinators and study participants who made TWILIGHT possible!

Dominick J. Angiolillo, MD, Ph. D; Usman Baber, MD, MS; Samantha Sartori, Ph. D;

Dominick J. Angiolillo, MD, Ph. D; Usman Baber, MD, MS; Samantha Sartori, Ph. D; Carlo Briguori, MD, Ph. D; George Dangas, MD, Ph. D; David J. Cohen, MD, MSc; Shamir R. Mehta, MD, MSc; C. Michael Gibson, MD; Rishi Chandiramani, MD; Kurt Huber, MD; Ran Kornowski, MD; Giora Weisz, MD; Vijay Kunadian, MBBS, MD; Keith G. Oldroyd, MBCh. B, MD (Hons); Han Ya-Ling, MD, Ph. D; Upendra Kaul, MD; Bernhard Witzenbichler, MD; Dariusz Dudek, MD, Ph. D; Gennaro Sardella, MD; Javier Escaned, MD, Ph. D; Samin Sharma, MD; Richard A. Shlofmitz, MD; Timothy Collier, MSc; Stuart Pocock, Ph. D; Roxana Mehran, MD http: //www. onlinejacc. org/

THANK YOU!

THANK YOU!