Diego Ardissino, MD

1. Orlando, March 10-12 2018, • American College of Cardiology • 67°Annual Scientific Session & Expo ThePHARMCLOstudy A prospective, randomised, multicentre study of a pharmacogenomic approach to the selection of antiplatelet therapy in acute coronary syndromes Diego Ardissino, MD

2. ThePHARMCLOstudy Disclosures All authors have no relationships relevant to this presentation to disclose. Division of Cardiology Parma

3. ThePHARMCLOstudy - Background Clopidogrel Response Variability Baseline - 2hr (5mol ADP) Resistance = 63% Number of patients ≤ -30 -20, -10 0, 10 20, 30 40, 50 60, 70 > 80 Division of Cardiology Parma -30, -20 -10, 0 10, 20 30, 40 50, 60 70, 80 ∆ percent aggregation Gurbel PA et al. Circulation 2003; 107:2908-13

4. ThePHARMCLOstudy - Background Genetic targets modulating Clopidogrel antiplatelet effects O COOCH3 N O N S Cl S Cl O N HOOC * HS Cl Pro-drug Pre-hepatic metabolismEsterases in blood (Small Intestine) ABCB1 Clopidogrel 2 step: CYP3A CYP2C9 CYP2C19 CYP2B6 1 step: CYP1A2 CYP2C19 CYP2B6 OCH3 Hepatic Metabolism OCH3 Platelet membrane receptors P2Y12, GP IIb/IIIa, GPIa Platelet inhibition Marín F et al. J Am Coll Cardiol. 2009;54:1041-57

5. ThePHARMCLOstudy Study design Unselected patients hospitalized for STEMI or NSTEMI ACS R n ≈ 3,612 Pharmacogenomic arm Standard of care arm ABCB1, 2C19*2, 2C19*17 Clinical data Clinical data Follow-up visits at 1,6 and 12 ±1 months Division of Cardiology Parma Primary end-point: the composite of cardiovascular death and the first occurrence of non-fatal MI, non-fatal stroke and BARC 3 to 5-defined major bleeding

6. ThePHARMCLOstudy Patient population • Inclusion Criteria: • The diagnosis of acute coronary syndromes was based on the presence of at least two of the following criteria: • ischemic symptoms at rest lasting >20 minutes • electrocardiographic changes • ST-segment elevation • ST-segment depression • the typical rise and fall of cardiac biomarker troponin I or T levels • Exclusion criteria: • an inability to provide informed consent or follow study procedures • any contraindication to the use of P2Y12 receptor antagonists • a life expectancy of <1 year • thrombolytic therapy within the previous 24 hours • enrolment in another randomised trial or observational registry • prior knowledge of the patients’ ABCB1, CYP2C19*2 or CYP2C19*17 genotype Division of Cardiology Parma

7. ThePHARMCLOstudy ST Q3 system Division of Cardiology Parma

8. ThePHARMCLOstudy Algorithm for the selection of P2Y12 receptor antagonist CT / CC T T ABCB1 3435 Clinical data *2 / *2 *2 / *1 *1 / *1 *2 / *2 *2 / *1 • age • weight • Grace score • Crusade score *1 / *1 • diabetes • prior history of stroke/TIA • intracranial bleeding • history of bleeding • active bleeding • anemia • chronic kidney disease • warfarin treatment CYP2C19*2 *17 / *17 *17 / *1 *1 / *1 CYP2C19*17 *17 / *17 *17 / *1 *17 / *17 *17 / *1 *1 / *1 *1 / *1 ABCB1, 2C19*2, 2C19*17 clopidogrel prasugrel / ticagrelor clopidogrel prasugrel / ticagrelor Division of Cardiology Parma

9. ThePHARMCLOstudy Participating Centres • PARMA • PIACENZA • FIDENZA • GUASTALLA • CARPI • RAVENNA • RIMINI • CESENA • MODENA • REGGIO EMILIA TORINO SAVONA NUORO Division of Cardiology Parma

10. ThePHARMCLOstudy Premature discontinuation A total of 888 patients were recruited between 12 June 2013 and 18 February 2015; 448 patients were randomised to the pharmacogenomic arm and 440 to the standard of care arm. This represents 24.6% of the pre-specified sample size because, on 18 February 2015, the Ethics Committee of Modena (Italy) required that the trial should be prematurely stopped and all of the patients followed up as planned because of the lack of in vitro diagnosis (IVD) certification for the ST Q3 instrument. Notice: Q3-Evo Reader is for use in research and for all other fields except the field of in vitro diagnostics. Therefore, while waiting for more information, the Ethics Committee orders the immediate stopping of enrolment and asks the PI for an urgent update on study progress, including the number of patients enrolled and their clinical condition during follow-up. Division of Cardiology Parma

11. The PHARMCLOstudy Demographic and clinical characteristics Division of Cardiology Parma

12. ThePHARMCLOstudy Clinical and revascularization characteristics Division of Cardiology Parma

13. ThePHARMCLOstudy Frequency distribution of selected P2Y12 receptor antagonist Clopidogrel Prasugrel Ticagrelor No P2Y12 Division of Cardiology Parma

14. ThePHARMCLOstudy Primary composite end-point Standard of care H.R.: 0.58 95% confidence interval: 0.43 – 0.78 P < 0.001 Pharmacogenomic Standard of care Pharmacogenomic Division of Cardiology Parma

15. ThePHARMCLOstudy Individual components of the primary composite end-point Division of Cardiology Parma

16. ThePHARMCLOstudy Primary composite end-point in clopidogrel-treated patients Standard of care H.R.: 0.68 95% confidence interval: 0.47 – 0.97 P = 0.03 Pharmacogenomic Standard of care Pharmacogenomic Division of Cardiology Parma

17. ThePHARMCLOstudy Conclusions • The implementation of multiple genotyping to guide the antiplatelet therapy in acute coronary syndromes is feasible across different institutions • A more personalised approach to the selection of antiplatelet therapy may lead to a clinically meaningful reduction in ischemic and bleeding complications • Future studies of genotype-guided antiplatelet therapy are required to confirm these data and clarify the cost-efficacy of genotyping in the challenging setting of acute coronary syndromes before implementing it in everyday clinical practice Division of Cardiology Parma

18. ThePHARMCLOstudy JACC cover page Division of Cardiology Parma