Individualizing Treatment Duration of Dual Antiplatelet Therapy after PCI: Analysis from DAPT Study

1. Individualizing Treatment Duration of Dual Antiplatelet Therapy after Percutaneous Coronary Intervention: An Analysis from the DAPT Study Robert W. Yeh, Eric A. Secemsky, Dean J. Kereiakes, Sharon-Lise T. Normand, Anthony H. Gershlick, David J. Cohen, John A. Spertus, P. Gabriel Steg, Donald E. Cutlip, Michael J. Rinaldi, EdoardoCamenzind, William Wijns, Patricia K. Apruzzese, Yang Song, Joseph M. Massaro, and Laura Mauri, for the Dual Antiplatelet Therapy (DAPT) Study Investigators

2. Background Risk Difference (Continued Thienopyridine – Placebo), 12-30M Stent Thrombosis Death, MI, Or Stroke (MACCE) Myocardial Infarction GUSTO Mod/Severe Bleed Death HR 0.47 (0.37–0.61) P<0.001 HR 0.71 (0.59–0.85) P<0.001 Mauri, Kereiakes, Yeh et al. NEJM. 2014 Dec 4:371:2155-66. • In the DAPT Study, continuation of dual antiplatelet therapy beyond 12 months reduced ischemic complications after coronary stenting compared with aspirin alone, yet increased moderate or severe bleeding.

3. Objective • To develop a decision tool to identify whether an individual patient is more likely to derive benefit or harm from continuation of dual antiplatelet therapy beyond 1 year. • Based on composite of individual patient characteristics • Simultaneously accounting for patient risks of ischemia AND bleeding events with continued therapy.

4. Design Inclusion: FDA-approved DES or BMS, candidates for thienopyridine Excluded: Oral anticoagulant therapy; life expectancy < 3y Randomized: Free from MI, stroke, repeat revascularization, moderate/severe bleeding, and adherent with therapy at 12 months Mauri, Kereiakes et al. AHJ. 2010;160(6): 1035-41. ClinicalTrials.gov number NCT00977938 4 4

5. Methods – Models to Predict Ischemic and Bleeding Events Development of 2 Prediction Models within the randomized DAPT Study population (N=11648). • Ischemic Model: Stent thrombosis of myocardial infarction between 12-30 months after index PCI. Includes fatal events. • Bleeding Model: GUSTO moderate or severe bleeding between 12-30 months after index PCI. Includes fatal events. • Cox regression, stepwise selection among 37 candidate variables, including randomized treatment arm. In addition, several interaction terms with treatment arm evaluated. P value of 0.05 for retention. • Validated internally via bootstrap resampling, and externally within the PROTECT trial population (excluding randomized treatment arm).* *Camenzind, Wijns, Mauri et al. Lancet. 380;9851:1396-1405.

6. Methods – Predicting Combined Ischemic and Bleeding Treatment Effects Predicted Risk in Ischemic Events Predicted Risk Difference in Bleeding Events Predicted Combined Treatment Effect • Predictors of combined treatment effect with continued thienopyridine determined from linear regression and simplified to an integer point score (DAPT Score) • Kaplan Meier of observed rates of ST, MI, MACCE, mortality, and bleeding by treatment arm, according to DAPT Score strata, with test of interaction across strata. Sensitivity analysis without paclitaxel-eluting stent treated subjects. Lower DAPT Score Greater increase in bleeding Smaller reduction ischemia Higher DAPT Score Greater reduction in ischemia Small increase in bleeding

7. Baseline Characteristics; All Randomized Patients With vs. Without Ischemic or Bleeding Events

8. Baseline Characteristics; All Randomized Patients With vs. Without Ischemic or Bleeding Events

9. Prediction Models *The ischemia model C-statistic: 0.70 in DAPT Study; 0.64 in PROTECT **The bleeding model C-statistic: 0.68 in DAPT Study; 0.64 in PROTECT

10. Predictors of Combined Treatment Effect

11. Continued Thienopyridine vs. Placebo Treatment Effect by DAPT Score Quartile Quartile 1st 2nd 3rd 4th N 2729 3002 3011 2906 Score 1 2 > 2 -2 to 0 Risk Difference (Continued Thienopyridine – Placebo), 12-30M Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4

12. Continued Thienopyridine vs. PlaceboTreatment Effect by DAPT Score Quartile Risk Difference (Continued Thienopyridine – Placebo), 12-30M Mortality Net Adverse Events Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 DAPT Score < 2 DAPT Score ≥ 2 12

13. Continued Thienopyridine vs. Placebo DAPT Score <2 (Low); N=5731 Stent Thrombosis or MI MACCE 10% 10% Continued ThienopyridinePlacebo Continued ThienopyridinePlacebo 8% 8% 6% 6% Cumulative Incidence of ST/MI Cumulative Incidence of MACCE 1.7% vs. 2.3% P=0.07 3.7% vs. 3.8% P=0.73 4% 4% 2% 2% 0% 0% 27 27 12 15 18 21 24 30 12 15 18 21 24 30 Months After Enrollment Months After Enrollment 10% Continued ThienopyridinePlacebo 8% GUSTO Moderate/ Severe Bleeding 6% Cumulative Incidence of GUSTO Moderate/ Severe Bleed 3.0% vs. 1.4% P<0.001 4% 2% 0% 27 12 15 18 21 24 30 Months After Enrollment

14. Continued Thienopyridine vs. Placebo DAPT Score ≥ 2 (High); N=5917 Stent Thrombosis or MI MACCE 10% 10% Continued ThienopyridinePlacebo Continued ThienopyridinePlacebo 8% 8% 4.9% vs. 7.6% P<0.001 6% 6% Cumulative Incidence of ST/MI 2.7% vs. 5.7% P<0.001 Cumulative Incidence of MACCE 4% 4% 2% 2% 0% 0% 27 27 12 15 18 21 24 30 12 15 18 21 24 30 Months After Enrollment Months After Enrollment 10% Continued ThienopyridinePlacebo 8% GUSTO Moderate/ Severe Bleeding 6% 1.8% vs. 1.4% P=0.26 Cumulative Incidence of GUSTO Moderate/ Severe Bleed 4% 2% 0% 27 12 15 18 21 24 30 Months After Enrollment

15. Continued Thienopyridine vs. Placebo High vs. Low DAPT Score Stent Thrombosis or MI GUSTO Moderate Or Severe Bleed Net Adverse Events Risk Difference (Continued Thienopyridine – Placebo), 12-30M NNT 153 NNT 34 NNH 64 NNH 272 NNH 109 NNT 37 P<0.001 P=0.02 P<0.001 P values are for comparison of risk differences across DAPT Score category (interaction).

16. Continued Thienopyridine vs. Placebo, by DAPT Score, Excluding Paclitaxel-Eluting Stent Stent Thrombosis or MI GUSTO Moderate Or Severe Bleed Net Adverse Events Risk Difference (Continued Thienopyridine – Placebo), 12-30M NNT 192 NNT 53 NNH 70 NNH 264 NNH 97 NNT 60 P=0.07 P=0.003 P=0.06 P values are for comparison of risk differences across DAPT Score category (interaction).

17. Model Limitations • Post hoc analysis, not powered to examine differences in outcomes between subgroups for individual outcomes • Limited ability to identify rare but important predictors of benefit or risk • Inability to identify unmeasured but potentially important predictors • Models not evaluated in patients receiving ticagrelor or other antiplatelet combinations

18. Conclusions Low DAPT Score (< 2) NNT to prevent ischemia = 153 NNH to cause bleeding 64 High DAPT Score ≥ 2 NNT to prevent ischemia = 34 NNH to cause bleeding = 272 • The DAPT Score accurately identifies patients with the greatest anticipated benefit vs. harm from continuing dual antiplatelet therapy beyond 12 months among randomized patients in the DAPT Study

19. Conclusions • The DAPT Score, when combined with clinical judgment, can be a useful tool to help individualize dual antiplatelet duration in patients who have not had a major ischemic or bleeding event within the first year after PCI.