1. Measurement of Antiplatelet Therapeutic Efficacy Bonnie H. Weiner MD MSEC MBA FSCAI FACC FAHA Professor of Medicine Director, Interventional Cardiology Research St Vincent Hospital Worcester MA Bonnie H. Weiner MD MSEC MBA FSCAI FACC FAHA Professor of Medicine Director, Interventional Cardiology Research St Vincent Hospital Worcester MA

2. Disclosure No conflicts relative to this presentation General Disclosures – Ownership Imaging Core Lab Services AtheroMed Acclarent Stryker/Surpass/Cersys – Consulting Boston Biomedical Associates – Atricure – Atheromed – 480 Biomedical – Angiolight – Creganna – Cardiac Assist – GI Dynamics Cormend – Honoraria SCAI FAAC Accreditation for Cardiovascular Excellence Board Chair Chief Medical Officer No conflicts relative to this presentation General Disclosures – Ownership Imaging Core Lab Services AtheroMed Acclarent Stryker/Surpass/Cersys – Consulting Boston Biomedical Associates – Atricure – Atheromed – 480 Biomedical – Angiolight – Creganna – Cardiac Assist – GI Dynamics Cormend – Honoraria SCAI FAAC Accreditation for Cardiovascular Excellence Board Chair Chief Medical Officer

3. Antiplatelet Drug “Resistance” / “Response Variability” An Emerging Clinical Problem?

4. Does laboratory identification and treatment of high platelet reactivity benefit the patient? What Key Questions Would You Ask about Platelet Function Testing? What does high on-treatment platelet reactivity mean to the patient? High platelet reactivity: quantifiable and modifiable risk factor Can increasing anti-platelet agent doses affect high platelet reactivity? Can increasing anti-platelet agent doses affect high platelet reactivity? What is the anti-platelet effect of clopidogrel, asa, and emerging agents?

5. Tests of Aspirin Resistance Light transmission Aggregometry Arachadonic acid ADP Whole blood aggregometry PFA-100 ® (platelet function analyzer) VerifyNow Aspirin ® Urinary 11-dehydro-thromboxane B 2 Light transmission Aggregometry Arachadonic acid ADP Whole blood aggregometry PFA-100 ® (platelet function analyzer) VerifyNow Aspirin ® Urinary 11-dehydro-thromboxane B 2 European Heart Journal (2007) 28, 1702–1708 doi:10.1093/eurheartj/ehm226

6. Comparison in Patients with Stable CAD

7. Aspirin Resistance Lack of correlation between the different tests Measure different aspects of platelet function Lack of correlation between the different tests Measure different aspects of platelet function

8. Aspirin Resistance

9. HOPE Trial Heart Outcomes Prevention Evaluation Urinary 11-dehydro thromboxane B 2 levels 488 patients on aspirin who had CV events compared to case controlled patients without events Heart Outcomes Prevention Evaluation Urinary 11-dehydro thromboxane B 2 levels 488 patients on aspirin who had CV events compared to case controlled patients without events

10. HOPE

12. PCI and ASA Resistance Ultegra Rapid Platelet Function Assay (Accumetrics Inc., San Diego, California)

13. Krasopoulos, G. et al. BMJ 2008;336:195-198 Risk of any cardiovascular event in aspirin resistant patients

14. Point-of-Care Platelet Function Testing At least 7 studies involving more than 3,000 patients have concluded that high residual (on-clopidogrel) platelet reactivity measured by the VerifyNow P2Y12 test is associated with poor clinical outcomes after PCI. A treatment strategy for patients with high residual platelet reactivity has not been tested in a large, randomized, clinical trial.

15. Baseline Platelet Reactivity* Determines Outcomes Following Coronary Stenting 1.0 0.9 0.8 0.7 0.6 0.5 0 100 200 300 Low Reactivity Group High Reactivity Group Time (Days) Probability of Freedom from Event** *Fibrinogen binding in response to 0.2  M ADP **Composite MI, UR, Revascularization P = 0.01 P = 0.006 P = 0.043 Kabbani SS et al. Am J Cardiol. 2003;91:876-878.

16. Standard-Dose Clopidogrel † clopidogrel 75-mg daily X 6 months High-Dose Clopidogrel † clopidogrel 600-mg, then clopidogrel 150-mg daily X 6 months Elective or Urgent PCI with DES* VerifyNow P2Y12 Test 12-24 hours post-PCI PRU ≥ 230 R R GRAVITAS Study Design † placebo - controlled Primary Efficacy Endpoint: CV Death, Non-Fatal MI, Stent Thrombosis at 6 mo Key Safety Endpoint: GUSTO Moderate or Severe Bleeding at 6 mo Pharmacodynamics: Repeat VerifyNow P2Y12 at 1 and 6 months All patients received aspirin (81-162mg daily) *Peri-PCI clopidogrel per protocol-mandated criteria to ensure steady-state at 12-24 hrs

17. 5429 patients screened with VerifyNow P2Y12 12-24 hours post-PCI 2214 (41%) with high residual platelet reactivity (PRU ≥ 230) 3215 (59%) without high residual platelet reactivity (PRU < 230) Clopidogrel High Dose N=1109 Clopidogrel Standard Dose N=1105 GRAVITAS Patient Flow

18. Primary Endpoint: CV Death, MI, Stent Thrombosis Observed event rates are listed; P value by log rank test.

19. Secondary Comparison: High vs. Not High Reactivity Treated with Clopidogrel 75-mg daily Observed event rates are listed. P value by log-rank test.

20. GRAVITAS: Possible Explanations Underpowered: patients low-risk, low event rates? Given HR of 1.01 with more than 2,200 patients, unlikely that a larger trial would show a clinically meaningful benefit Pharmacodynamic effect of the intervention was too weak? Stronger intervention and/or goal-directed therapy with serial measurements merit study (TRIGGER-PCI; ARCTIC; TARGET-PCI)

21. GRAVITAS: Summary Compared with standard-dose therapy, high-dose clopidogrel achieved a modest pharmacodynamic effect in patients with high residual reactivity. In patients with high residual reactivity measured after PCI, 6-months of high-dose clopidogrel did not reduce the rate of cardiovascular death, non- fatal MI, or stent thrombosis and did not increase GUSTO severe or moderate bleeding.

22. Primary Results of Testing platelet Reactivity In patients underGoing elective stent placement on clopidogrel to Guide alternative thErapy with pRasugrel TRIGGER-PCI Study

23. Study objective … to assess whether the outcome of patients with high on- clopidogrel platelet reactivity after elective PCI with drug- eluting stents can be improved by switching from clopidogrel to prasugrel. Primary efficacy endpoint:Cardiovascular death or myocardial infarction Key safety endpoint: Non-CABG TIMI major bleeding

24. “Standard Therapy” Clopidogrel 75 mg “Clopidogrel arm” Placebo LD Clopidogrel 75 mg MD + Prasugrel placebo “Prasugrel arm” Prasugrel 60 mg LD Prasugrel 10 mg MD + Clopidogrel placebo Successful PCI with DES without major complication and NO GPIIb/IIIa use Post-PCI VerifyNow P2Y12 Assay (PRU) 2 - 4 hours after 1 st MD of clopidogrel 75 mg at day 1 post-PCI Non-Responder Clinical Follow-up and VerifyNow Assessment at 90 days, 180 days Primary Endpoint: 6 month CV Death and MI Yes No N ~ 8800 N = 1075 A Random Selection TRIGGER-PCI “Clopidogrel arm” Placebo LD Clopidogrel 75 mg MD + Prasugrel placebo “Prasugrel arm” Prasugrel 60 mg LD Prasugrel 10 mg MD + Clopidogrel placebo Responder PRU ≥ 208? PRU ≥ 140? N = 1075 B N = 550 C DE Platelet function substudy: VerifyNow Assessment at day 2 (2 – 4 h after 1 st MD of study drug)

25.  6-month incidence of the composite endpoint of cardiovascular death or MI (including minor infarctions with elevated troponin) expected as 4.7%.  Randomization of 2,150 patients to provide 93% power to detect a 50 % relative risk reduction on prasugrel. Sample size and power calculation

26. Early termination of TRIGGER- PCI 236 patients completed 6 months follow-up Only 1 clinical endpoint (peri-procedural MI) observed → rate 0.4% Upper 95 %-confidence limit 1.25 %

27. Summary and conclusion:  High on-clopidogrel platelet reactivity (>208 PRU by VerifyNow P2Y12 test) was observed less frequently than expected.  Compared with standard-dose clopidogrel 75 mg QD, prasugrel 10 mg QD substantially decreased platelet reactivity in patients with high on-clopidogrel platelet reactivity after elective PCI.  Given the low event rate in elective PCI patients without peri-procedural complications it was not possible to assess the risk – benefit ratio with prasugrel treatment. Therefore, the study was terminated prematurely for futility.

28. ARCTIC MI, stroke, stent thrombosis, or urgent revascularization: 35% of the monitoring group vs. 31% of the usual care group (p = 0.10) Death or myocardial infarction: 32% vs. 29% (p = 0.15), respectively Stent thrombosis: 1.0% vs. 0.7% (p = 0.51), respectively Major bleeding: 2.3% vs. 3.3% (p = 0.15), respectively Trial design: Patients undergoing drug-eluting stent implantation were randomized to a strategy of platelet function monitoring with antiplatelet dose adjustments as necessary (n = 1,213) vs. usual care without monitoring or drug adjustments (n = 1,227). Results Conclusions Among a relatively high-risk cohort of patients undergoing drug-eluting stent implantation, a strategy to monitor platelet reactivity to guide antiplatelet dosing failed to improve clinical outcomes Collet JP, et al. N Engl J Med 2012;Nov 4:[Epub] (p = 0.10) Platelet function monitoring % 35 31 Usual care

29. ARCTIC

31. Conclusions Variability in platelet function testing Focus has been on P2Y12 resistance Newer more potent agents appear to be beneficial No clear correlation with clinical events or that correcting the laboratory finding affects clinical endpoints May be a relationship between ASA resistance and events Variability in platelet function testing Focus has been on P2Y12 resistance Newer more potent agents appear to be beneficial No clear correlation with clinical events or that correcting the laboratory finding affects clinical endpoints May be a relationship between ASA resistance and events