Relevant Disclosures for Dr. Mahaffey

1. Relevant Disclosures for Dr. Mahaffey • Research grants:Significant: Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Merck, Novartis, Portola Pharmaceuticals, Pozen, Regado, Sanofi-Aventis, Schering-Plough (now Merck), The Medicines Company • Consultant / advisory board:Significant: AstraZeneca; Modest: Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Merck, Ortho/McNeill, Sanofi-Aventis, Schering-Plough (now Merck) Full disclosures at: http://www.dcri.duke.edu/research/coi.jsp

2. Ticagrelor Compared with Clopidogrel by Geographic Region in the Platelet Inhibition and Patient Outcomes (PLATO) Trial Kenneth W. Mahaffey, MD Daniel M. Wojdyla, MS Kevin Carroll, MS Richard C. Becker, MD Robert F. Storey, MD, DM Dominick J. Angiolillo, MD, PhD Claes Held, MD, PhD Christopher P. Cannon, MD Stefan James, MD, PhD Karen S. Pieper, MS Jay Horrow, MD, MS Robert A. Harrington, MD Lars Wallentin, MD, PhD for the PLATO investigators

3. Background • PLATO trial • 18,624 patients with ACS from 43 countries • 16% reduction in CV death, MI, stroke (HR 0.84; 95% CI 0.77, 0.92; p<0.001) without increase in overall major bleeding (HR 1.04; 95% CI 0.95, 1.13; p=0.434) • 31 pre-specified subgroup analyses • Treatment by region interaction: p=0.045 • Less effect of ticagrelor in North America than in the rest of the world (ROW) • Exploratory analyses to understand basis of this result

4. Geographic RegionsCV Death, MI, Stroke KM at month 12 Geographicregion Totalpatients Interactionp-values Tic Clop HR (95% CI) Asia / Australia 1714 11.4 14.8 0.80 (0.61, 1.04) Central America / South America 1237 15.2 17.9 0.86 (0.65, 1.13) 0.045 Europe / Middle East / Africa 13859 8.8 11.0 0.80 (0.72, 0.90) 0.01 North America 1814 11.9 9.6 1.25 (0.93, 1.67) 0.5 1.0 2.0 Ticagrelor better Clopidogrel better

5. Methods • Independent evaluation by groups at AstraZeneca and the Duke Clinical Research Institute • Investigated systematic errors in trial conduct • Evaluated likelihood of the play of chance • 37 baseline and post-randomization variables identified • Cox regression analyses to quantitate the degree to which patient characteristics and concomitant treatments explain the regional interaction • Landmark Cox regressions at 8 time points evaluated the association of treatment outcomes with selected factors

6. No Systematic Errors • US and ROW exhibited similar data quality based on query rates • Pharmacokinetic substudy samples of US ticagrelor patients had ticagrelor in their plasma • US patients had lower study drug compliance (62% vs. 85%) and higher study drug discontinuation (31% vs. 22%) but similar by treatment group • No bias observed in event reporting

7. Play of Chance • Probability of at least 1 false positive treatment interaction (p<0.05) by chance among 31 independent variables is 79% (adjusted p=0.002) • Using overall trial result and distribution of patients and events across regions: • 32% probability of result favoring clopidogrel in 1 of 4 regions • 10% probability of result favoring clopidogrel in US and ticagrelor in other 3 regions • Distribution of HRs consistent with a common HR of 0.84 across 43 countries: • HR >1.0: expected in 13 countries; occurred in 12 • HR >1.25: expected in 6 countries; occurred in 3

8. Baseline Characteristics: US and Rest of the World Data are n (%) or * median (1st–3rd quartile).

9. Clinical OutcomesBy Region and Treatment KM, Kaplan-Meier; HR, hazard ratio; CI, confidence interval; CV, cardiovascular; ROW, rest of world; MI, myocardial infarction

10. High-dose Aspirin Use: Landmark Time Points ASA: <300 mg is low-dose; ≥300 mg is high-dose.

11. Effect Modifier Analysis Entire cohort analysis Day-4 landmark analysis

12. Primary Efficacy OutcomeUS and Non-US and by ASA Dose *Hazard ratio not calculated due to small number of events.

13. Primary Efficacy OutcomeASA Maintenance Dose Tic: ASA High 16 14 Clop: ASA High 12 Clop: ASA Low 10 Kaplan-Meier Estimated Rate (%) Tic: ASA Low 8 6 4 HR (95% CI), 0.79 (0.71, 0.88) ASA Low (<300mg): 2 ASA High (≥300mg): HR (95% CI), 1.45 (1.01, 2.09) 0 0 60 120 180 240 300 360 Days from Randomization

14. Landmark AnalysesPrimary Efficacy Outcome by ASA Dose ASA: <300 mg is low-dose; ≥300 mg is high-dose.

15. Landmark AnalysesRegion and ASA Dose ASA: <300 mg is low-dose; ≥300 mg is high-dose.

16. Limitations • Regions were pre-specified subgroups, but analyses for the US alone were not pre-specified • The US cohort was relatively small (n=1413), and few patients overall took high-dose maintenance ASA (n=958) • Large number of exploratory analyses and no adjustments for multiplicity increases the likelihood of spurious findings • Subgroups defined by post-randomization events are potentially biased and hazardous despite rigorous statistical methodology • Unknown or unmeasured factors may be contributory • No definitive biologic rationale yet explains the ASA finding

17. Summary • In PLATO, ticagrelor reduced CV death, MI, and stroke • In a pre-specified analysis of treatment effect across regions, the hazard ratio favored ticagrelor in the rest of the world but not in North America • Statistical analyses by two independent groups identified ASA maintenance dose as a potential explanation of the regional differences • The play of chance is another possible explanation • These analyses and current ACS treatment guideline recommendations support that, during potent P2Y12 inhibition with ticagrelor, low maintenance aspirin dose is likely associated with favorable outcomes