Long-term Dual Antiplatelet Therapy for Prevention of Cardiovascular Events

Collaborative meta-analysis explores the efficacy of long-term dual antiplatelet therapy in preventing cardiovascular events in patients with previous myocardial infarction. Trials show heterogeneous results on the benefits and safety of prolonged therapy, with varying recommendations based on patient populations and risk factors. Guidelines recommend different durations of therapy based on the type of coronary syndrome and stenting, highlighting the importance of individualized treatment plans.

• Antiplatelet therapy
• Cardiovascular events
• Myocardial infarction
• Meta-analysis
• Guidelines

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1. Long-term Dual Antiplatelet Therapy for 2 Prevention of Cardiovascular Events in Patients with Previous Myocardial Infarction A Collaborative Meta-Analysis of Randomized Trials Jacob A. Udell, MD, MPH, Marc P. Bonaca, MD, MPH, Jean-Philippe Collet, MD, PhD, A. Michael Lincoff, MD, Dean J. Kereiakes, MD, Francesco Costa, MD, Cheol Whan Lee, MD, Laura Mauri, MD, MSc, Marco Valgimigli, MD, PhD, Seung-Jung Park, MD, PhD, Gilles Montalescot, MD, PhD, Marc S. Sabatine, MD, MPH, Eugene Braunwald, MD, Deepak L. Bhatt, MD, MPH European Society of Cardiology, London August 31, 2015

2. Disclosures for Dr. Udell There was no funding source for this study Advisory Board: Merck, Novartis, Sanofi Pasteur Research Grants: Support through Women s College Hospital from Novartis, NYU, Brigham & Women s Hospital This presentation discusses off-label and/or investigational uses of platelet ADP receptor antagonist drugs, including clopidogrel, prasugrel, and ticagrelor

3. Duration of DAPT following MI Recent trials have examined the effect of prolonged dual antiplatelet therapy (DAPT) in a variety of patient populations Heterogeneous results regarding benefit and safety, specifically regarding CV and non-CV mortality Do patients with a history of MI, who are at high risk for major adverse CV events with persistent platelet activation, benefit more from DAPT versus stable PCI patients? Bhatt DL, et al. JAMA 2010;304:1350-7. Jernberg T, et al. EHJ 2015;36:1163-70.

4. Guideline Recommendations Population Acute Coronary Syndrome (BMS or DES) ESC Guidelines Maximum of 12 months (Class I-A) ACCF/AHA/SCAI Guidelines At least 12 months (Class I-B) Longer durations may be considered in pts w/ DES (Class IIb-C) Longer durations may be considered (Class IIb-A) Stable Ischemia and BMS At least 1 month At least 1 month, ideally up to 12 months (Class I-B) At least 12 months (Class I-B) May be considered (Class IIb-B) (Class I-A) Stable Ischemia and DES 6 months (Class I-B) Selected patients at high ischemic risk Secondary Prevention Roffi M, et al. 2015 ESC Guidelines for Management of ACS. EHJ 2015 (Online Aug 29, 2015). Windecker S, et al. 2014 ESC/EACTS Guidelines on Myocardial Revascularization. EHJ 2014;35:3541-619. Amsterdam EA, et al. 2014 AHA/ACC Guideline for Management of NSTE-ACS. JACC 2014;64:e139-228. Montalescot G, et al. 2013 ESC Guidelines on Management of Stable CAD. EHJ 2013;34:2949-3003. Levine GN, et al. 2011 ACCF/AHA/SCAI Guidelines for PCI. JACC 2011;58:e44-122. Smith SC Jr, et al. 2011 AHA/ACCF Secondary Prevention Guidelines. JACC 2011;58:2342-46.

5. Objective / Hypothesis Need for definitive longer-term data on the CV benefit and safety of extended DAPT beyond one year for secondary prevention in patients following an MI We evaluated with a meta-analysis of RCTs whether long-term DAPT reduces CV risk compared with aspirin alone in patients with a history of previous MI Udell JA, et al. Eur Heart J 2015 at eurheartj.oxfordjournals.org.

6. Methods Systematic review and random-effects meta- analysis of RCTs that compared >1 y of DAPT with aspirin alone in patients that presented with, or had a history of, a prior MI PROSPERO 2015:CRD42015019657 Investigators of eligible trials were contacted to provide relevant unpublished data; CV endpoints underwent blinded adjudication Primary Endpoint: CV death, MI, or stroke (MACE) Secondary Endpoints: CV death MI Stroke Non-CV death All-cause mortality Major bleeding Stent thrombosis

7. Trials Evaluating Prolonged DAPT following MI Subgroup /Population Duration (months) MACE Events Trial N Drug Bleeding EP Stable prior MI (mean 24 mo.) GUSTO mod/severe 3846 Clopi 28 287 CHARISMA PCI for ACS 1465 Clopi 6 vs. 24 132 TIMI major PRODIGY PCI for ACS (excluded STEMI) Clopi or Pras STEEPLE major ARCTIC- Interruption 323 12 vs. 24 7 Clopi or Pras GUSTO mod/severe PCI for MI 3576 12 vs. 30 167 DAPT PCI for ACS 3063 Clopi 12 vs. 24 122 TIMI major DES-LATE Stable prior MI (median 20 mo.) PEGASUS TIMI-54 Total 21162 Ticag 33 1558 TIMI major 33435 30 2273 Abbreviations: Clopi: clopidogrel; Pras: prasugrel; Ticag: ticagrelor

8. Baseline Characteristics Characteristic Age Weight Female Index MI Overall (N = 33435) 64 yr 81 kg 24% 49% 39% 7% 18 months 84% 30% 21% 19% 3% 7% 16% STEMI NSTEMI UA Time from MI Prior PCI Diabetes Current Smoker CKD or eGFR <60 mL/min Prior Stroke/TIA Prior CABG Hx of Additional MI

9. Primary Endpoint CV Death, MI, or Stroke Extended DAPT Aspirin Alone Risk Ratio (95% CI) Study Events Total Events Total CHARISMA 125 1903 162 1943 0.77 (0.61 - 0.98) PRODIGY 63 732 69 733 0.91 (0.65 - 1.28) ARCTIC-Int n 3 156 4 167 0.79 (0.18 - 3.51) DAPT 59 1805 108 1771 0.52 (0.38 - 0.72) DES-LATE 56 1512 66 1551 0.85 (0.60 - 1.21) PEGASUS 980 14095 578 7067 0.84 (0.76 - 0.94) TOTAL 1286 20203 987 13232 6.4% 7.5% 0.78 (0.67 - 0.90) 0.2 0.5 1 2 P = 0.001 Aspirin Alone Better Extended DAPT Better Udell JA, et al. Eur Heart J 2015 at eurheartj.oxfordjournals.org.

10. Cardiovascular Death Extended DAPT Aspirin Alone Risk Ratio (95% CI) Study Events Total Events Total CHARISMA 53 1903 65 1943 0.82 (0.57 - 1.18) PRODIGY 31 732 31 733 1.00 (0.61 - 1.64) ARCTIC-Int n 0 156 1 167 0.36 (0.01 - 8.69) DAPT 11 1805 16 1771 0.67 (0.31 - 1.44) DES-LATE 21 1512 21 1551 1.00 (0.55 - 1.83) PEGASUS 356 14095 210 7067 0.85 (0.71 - 1.00) TOTAL 472 20203 344 13232 2.3% 2.6% 0.85 (0.74 - 0.98) 0.2 0.5 1 2 P = 0.03 Aspirin Alone Better Extended DAPT Better Udell JA, et al. Eur Heart J 2015 at eurheartj.oxfordjournals.org.

11. Individual CV Endpoints Extended DAPT Aspirin Alone 10 RR 0.78 P = 0.001 9 8 7.5 7 Event Rate (%) 6.4 RR 0.70 P = 0.003 6 RR 0.85 P = 0.03 5 4.4 RR 0.81 P = 0.02 4 3.5 RR 0.50 P = 0.02 2.6 3 2.3 1.7 2 1.4 1.4 0.6 1 0 MACE CV Death MI Stroke Stent Thrombosis (Def/Prob) Udell JA, et al. Eur Heart J 2015 at eurheartj.oxfordjournals.org.

12. Major Bleeding Extended DAPT Aspirin Alone Risk Ratio (95% CI) Study Events Total Events Total CHARISMA 45 1903 39 1943 1.17 (0.76 - 1.79) PRODIGY 9 732 6 733 1.50 (0.53 - 4.20) ARCTIC-Int n 2 156 0 167 5.35 (0.26 - 110.6) DAPT 34 1805 14 1771 2.38 (1.27 - 4.43) DES-LATE 39 1512 31 1551 1.27 (0.79 - 2.03) PEGASUS 242 13946 54 6996 2.50 (1.86 - 3.36) TOTAL 371 20054 144 13161 1.9% 1.1% 1.73 (1.19 - 2.50) 0.5 1 Extended DAPT Better 2 5 P = 0.004 Aspirin Alone Better Udell JA, et al. Eur Heart J 2015 at eurheartj.oxfordjournals.org.

13. Major Bleeding Events and Safety Extended DAPT Aspirin Alone 10 9 8 Event Rate (%) 7 RR 0.92 P = NS 6 5 4.2 RR 1.73 P = 0.004 4.0 RR 1.03 P = NS 4 3 1.9 1.7 P = NS 1.6 2 P = NS 1.1 1 0.4 0.3 0.2 0.1 0 Major Bleeding ICH Fatal Bleeding Non-CV Death All-Cause Death Udell JA, et al. Eur Heart J 2015 at eurheartj.oxfordjournals.org.

14. Subgroup Analysis: Primary Endpoint Event Rate (%) Extended DAPT Aspirin Alone Hazard Ratio 0.83 Age < 75 years 5.9 6.8 0.88 11.1 12.9 75 years Male 6.6 7.7 0.84 Sex Female 6.9 7.7 0.84 0.82 DAPT Regimen Clopidogrel 5.8 NE 7.0 6.9 NE 0.84 Prasugrel Ticagrelor NE 8.2 3.3 Index ACS UA 4.6 0.68 7.6 0.88 NSTEMI 8.2 5.6 0.73 STEMI 7.1 6.1 7.3 0.76 Time from Index MI < 24 months 6.7 7.4 0.87 24 months History of PCI 0.78 Yes 5.7 6.7 0.83 No 9.9 11.3 6.4 0.78 (0.67 - 0.90) 7.5 Overall 0.2 0.5 1 2 All P-interactions >0.05 Abbreviations: NE: no estimate Extended DAPT Better Aspirin Alone Better

15. Summary Compared with aspirin alone, extended DAPT >1 year among stabilized high-risk patients with previous MI: - Decreased the risk of MACE, MI, stroke alone & CV death alone - Increased risk of major bleeding, but not fatal bleeding or ICH - No excess of non-CV causes of death Effect of extended DAPT consistent irrespective of: - DAPT regimen, time from MI, ST-elevation, or PCI status Who were high-risk pts at low risk of bleeding that derived benefit from extended DAPT? - High Risk: ~1-3 years after an MI with additional CV risk factors - Low Bleeding Risk: Excluded patients with anticoagulation, recent bleeding, recent surgery, or any history of ICH - Caution: Very few patients studied had prior stroke/TIA Udell JA, et al. Eur Heart J 2015 at eurheartj.oxfordjournals.org.

16. Conclusion These findings indicate that in patients with prior MI who are at low risk of bleeding, continuation of dual antiplatelet therapy beyond a year offers a substantial reduction in important cardiovascular outcomes, including cardiovascular death Udell JA, et al. Eur Heart J 2015 at eurheartj.oxfordjournals.org.

17. For Full Details, Please Go To eurheartj.oxfordjournals.org doi: 10.1093/eurheartj/ehv443 Slides available at hsrlce.utoronto.ca/research/nicr/

18. Back Up Slides

19. Primary Endpoint Sensitivity Analyses Extended DAPT Aspirin Alone Risk Ratio (95% CI) Study Events Total Events Total CHARISMA 125 1903 162 1943 0.77 (0.61 - 0.98) PRODIGY 63 732 69 733 0.91 (0.65 - 1.28) ARCTIC-Int n 3 156 4 167 0.79 (0.18 - 3.51) DAPT 59 1805 108 1771 0.52 (0.38 - 0.72) DES-LATE 56 1512 66 1551 0.85 (0.60 - 1.21) PEGASUS 980 14095 578 7067 0.84 (0.76 - 0.94) TOTAL 1286 20203 987 13232 6.4% 7.5% 0.78 (0.67 - 0.90) 0.2 0.5 1 2 P = 0.001 Aspirin Alone Better Extended DAPT Better Udell JA, et al. Eur Heart J 2015 at eurheartj.oxfordjournals.org.

20. Primary Endpoint Removal of PEGASUS Extended DAPT Aspirin Alone Risk Ratio (95% CI) Study Events Total Events Total CHARISMA 125 1903 162 1943 0.77 (0.61 - 0.98) PRODIGY 63 732 69 733 0.91 (0.65 - 1.28) ARCTIC-Int n 3 156 4 167 0.79 (0.18 - 3.51) DAPT 59 1805 108 1771 0.52 (0.38 - 0.72) DES-LATE 56 1512 66 1551 0.85 (0.60 - 1.21) TOTAL 306 6108 409 6165 5.0% 6.6% 0.75 (0.61 - 0.92) 0.2 0.5 1 2 P = 0.006 Aspirin Alone Better Extended DAPT Better Udell JA, et al. Eur Heart J 2015 at eurheartj.oxfordjournals.org.

21. Primary Endpoint Removed PEGASUS & DAPT Extended DAPT Aspirin Alone Risk Ratio (95% CI) Study Events Total Events Total CHARISMA 125 1903 162 1943 0.77 (0.61 - 0.98) PRODIGY 63 732 69 733 0.91 (0.65 - 1.28) ARCTIC-Int n 3 156 4 167 0.79 (0.18 - 3.51) DES-LATE 56 1512 66 1551 0.85 (0.60 - 1.21) TOTAL 247 4303 301 4394 5.7% 6.9% 0.82 (0.70 - 0.97) 0.2 0.5 1 2 P = 0.02 Aspirin Alone Better Extended DAPT Better Udell JA, et al. Eur Heart J 2015 at eurheartj.oxfordjournals.org.