1. Adjunctive Antithrombotic for PCI Theodore A Bass, MD FSCAI President SCAI Professor of Medicine, University of Florida Medical Director UF Shands CV Center,Jacksonville SCAI Fellows Course December 9, 2013

2. Disclosures Consulting: none Adjunctive Antithrombotic Therapy for PCI: Theodore A. Bass MD, FSCAI The following relationships exist related to this presentation

3. ANTITHROMBOTIC DRUGS USED IN ACS/PCI I. ANTIPLATELET DRUGS II. ANTICOAGULANT DRUGS COX-1 inhibitor (aspirin) P2Y 12 inhibitors (ticlopidine; clopidogrel; prasugrel; ticagrelor) Glycoprotein IIb/IIIa inhibitors (abciximab; eptifibatide; tirofiban) Anti-Factor II (anti-thrombins) - Indirect Thrombin Inhibitors (UFH & LMWH) - Direct Thrombin Inhibitors (Bivalirudin) Anti-Factor X - Fondaparinux

4. ANTITHROMBOTIC DRUGS USED IN PCI Many options! Who wins?

5. Optimal Antithrombotic PCI “Cocktail” Stable CAD UA/NSTEMI STEMI

6. What’s MY Antithrombotic “Cocktail” Stable CAD elective PCI Aspirin 325mg LD / 81mg maintenance + Clopidogrel 600mg LD / 75mg maintenance + UFH (70-100 IU/kg)

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

8. Early termination of TRIGGER-PCI at March 18, 2011  236 patients completed 6 months follow-up  Only 1 clinical endpoint (peri-procedural MI) observed → rate 0.4% Hazard Ratio 1.517 (95% CI, 0.428-5.376) p=0.516 Clopidogrel Prasugrel 0306090120150180210240 Days from randomization 0.0 0.5 1.5 1.0 2.0 2.5 3.0 3.5 4.0 Event rate, % Non-CABG TIMI major, minor or minimal bleeding Trenk D. JACC 2012

9. Optimal Antithrombotic “Cocktail” Stable CAD UA/NSTEMI STEMI

10. Optimal Antithrombotic “Cocktail” When to consider: 1.GP IIb/IIIa inhibitors 2. Bivalirudin 3. New P2Y12 receptor antagonists

11. Major Considerations: 1)Trials performed in the “good old days” - Less experience; not all with stents; devices 2)Antiplatelet therapy -1 st generation thienopyridine (ticlopidine) -300mg LD clopidogrel 3)Anticoagulant therapy - indirect thrombin inhibitors William Shakespeare (1564- 1616) “IIb or not IIb?” NSTEMI: The Role of GP IIb/IIIa inhibitors in the era of clopidogrel and direct thrombin inhibitors Shifting the paradigm !!

12. 0 5 10 15 20 051015202530 Days after randomization Abciximab vs. Placebo Troponin-Positive: RR=0.71 [0.54-0.95] Troponin-Negative: RR=0.99 [0.56-1.76] Death/MI/UTVR, % Kastrati et al. JAMA. 2006;295:1531-8. ISAR-REACT 2: Abciximab vs. Placebo in ACS All patients pretreated with 600mg clopidogrel at least 2 hrs prior to PCI.

13. Mortality (%) Days From Randomization 0306090120150180210240270300330360390 0 5 15 30 10 25 20 Mehran R, et al. Eur Heart J. 2009;30(12):1457-1466. Impact of MI and Major Bleeding (Non-CABG) in the First 30 Days on Risk of Death Over 1 Year ACUITY 1 Year Estimate Both MI and Major Bleed (N=94) Major Bleed Only (Without MI) (N=551) MI Only (Without Major Bleed) (N=611) No MI or Major Bleed (N=12,557) 28.9% 12.5% 8.6% 3.4%

14. ACUITY: Primary Results UFH/Enox + GP IIb/IIIa Bivalirudin + GP IIb/IIIa Bivalirudinalone ObservedRateRate PValue Rate PValue Endpoint Net clinical outcome11.7%11.8% <0.001 NI 10.1% 0.015 Sup Ischemic events7.3%7.7% 0.007 NI 7.8% 0.011 NI Major bleeding5.7%5.3% 0.001 NI 3.0% <0.001 Sup NI = non-inferiority; Sup = superiority

15. Primary endpoint Death, large MI, uTVR, major bleeding Days since Randomization 0 5 10 15 20 051015202530 Cumulative Incidence (%) Relative risk, 0.99 (95% CI, 0.74–1.32) P=0.94 Bivalirudin Abciximab 10.9% 11.0% Kastrati et al. NEJM 2011 ISAR-REACT 4

16. Secondary safety endpoint Major bleeding 0 5 10 15 20 051015202530 Cumulative Incidence (%) Days since Randomization Relative risk, 1.82 (95% CI, 1.10–3.07) P=0.02 Bivalirudin Abciximab 4.6% 2.6% Kastrati et al. NEJM 2011 ISAR-REACT 4

17. What’s MY Antithrombotic “Cocktail” UA/NSTEMI PCI GPI: -Already on upstream GPI -Not pre-treated w/clopidogrel (especially if high thrombotic burden) -ACS while on DAPT Bivalirudin: -High bleeding risk (elderly, CKD, diabetes) -Pre-treated w/clopidogrel -Unclear prior anticoagulation (safe to switch)

18. What’s MY Antithrombotic “Cocktail” UA/NSTEMI PCI New P2Y12 Receptor Antagonists?

19. TRITON TIMI 38 (prasugrel vs clopidogrel) PLATO (ticagrelor vs clopidogrel)

20. Prasugrel and ticagrelor both showed favorable efficacy and safety profiles in their respective trials and only a head-to-head comparison will be able to define the winner. Prasugrel and ticagrelor both showed favorable efficacy and safety profiles in their respective trials and only a head-to-head comparison will be able to define the winner. Subgroup analysis will allow to define their best niche. Subgroup analysis will allow to define their best niche. –Prasugrel. Particularly efficacious in reducing stent thrombosis, MI, uTVR and great benefit in diabetics and STEMI. Contraindicated: high-risk bleeding; prior TIA/stroke Considerations: elderly, low-weight; CABG/surgery (7days). Considerations: elderly, low-weight; CABG/surgery (7days). –Ticagrelor. Particularly efficacious in reducing mortality (off- target effects), OK for patients with prior TIA/ ischemic stroke. Contraindicated: high-risk bleeding; prior hemorrhagic stroke Considerations: COPD/asthma, bradyarrythmia, gout syndromes, advanced CKD, compliance (b.i.d. administration), regional differences (North America?/ASA dose), CABG/surgery (5-7days). TRITON vs PLATO: Is there a winner?

21. Optimal Antithrombotic PCI “Cocktail” Stable CAD UA/NSTEMI STEMI

22. 3-Year All-Cause Mortality or Reinfarction Landmark analysis 5 4 3 2 1 0 0369121518212427303336 Heparin + GPIIb/IIIa (n=1802) Bivalirudin (n=1800) 3-year HR (95% CI) 0.72 (0.58 – 0.91) p=0.005 30-day HR (95% CI) 0.84 (0.61 – 1.16) p=0.30 10.6% 7.8% All-cause mortality or reinfarction (%) 3.8% 4.5% Months Stone, GW Lancet 2011 Published online June 13. DOI:10.1016/S0140-6736(11)60764-2

23. 2.2% 3.0% 1.5% 0.3% HR [95%CI] = 1.73 [0.47-1.13] 1.73 [0.47-1.13] P = 0.06 HR [95%CI] = 5.93 [2.06-17.04] P = 0.0002 1611 1591 160015621525150614851355 158715211495147614571315 Number at risk Bivalirudin UFH+GPIIb/IIIa Def/Prob Stent Thrombosis (%) 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Time in Days 013090180270365 Stent Thrombosis 1-Day Landmark Analysis: Impact of Antithrombin Bivalirudin monotherapy Heparin + GPIIb/IIIa inhibitor

24. Death, MI or Stroke in STEMI-PCI % P=0.11 P=0.07 P=0.02 DrugDouble dose clopidogrelTicagrelorPrasugrel Follow-up1 month6-12 months15 months N=6364 N=7544 N=3534

25. INFUSE-AMI: Infarct size at 30 days * - Primary endpoint - INFUSE-AMI: Infarct size at 30 days * - Primary endpoint - IC abciximab N=229 No abciximab N=223 Infarct size, %LV Median [IQR] 15.1% [6.8, 22.7] Median [IQR] 17.9% [10.3, 25.4] P=0.03 *Core laboratory assessed JAMA 2012

26. STEMI (# 1) What’s MY Antithrombotic Primary PCI “Cocktail” Aspirin 325mg LD + Prasugrel 60mg LD + UFH (4000 IU)

27. STEMI (# 2) What’s MY Antithrombotic Primary PCI “Cocktail” Bivalirudin in all my Primary PCI patients. Consider GPI: -STEMI while on DAPT -Already on upstream GPI -IC bolus only ? (INFUSE-AMI) -Bail-out

28. what’s not good for me, may be good for others… …….it’s a matter of taste! NOT in my Antithrombotic “Cocktail” LMWH (enoxaparin) – STEEPLE, ATOLL High maintenance dose clopidogrel - OASIS-7 Fondaparinux - OASIS-5, OASIS-6, OASIS-8

29. EMERGING ANTITHROMBOTIC DRUGS I. ANTIPLATELET DRUGS II. ANTICOAGULANT DRUGS Elinogrel – INNOVATE-PCI Vorapaxar – TRACER/TRA 2P Cangrelor – CHAMPION PHOENIX, BRIDGE Otamixaban – TAO Rivaroxaban - ATLAS 2

30. Current Controversies on DAPT in PCI Which drug? When to start? Which dose? How long? Testing?

31. Current Controversies on DAPT in PCI Which drug? When to start? Which dose? How long? Testing?

32. Genetic testing might be considered to identify whether a patient at high risk for poor clinical outcomes is predisposed to inadequate platelet inhibition with clopidogrel. When a patient predisposed to inadequate platelet inhibition with clopidogrel is identified by genetic testing, treatment with an alternate P2Y 12 inhibitor (e.g., prasugrel or ticagrelor) might be considered. The routine clinical use of genetic testing to screen clopidogrel-treated patients undergoing PCI is not recommended. Clopidogrel Genetic Testing I IIaIIbIII I IIaIIbIII I IIaIIbIII No Benefit

33. Platelet function testing may be considered in patients at high risk for poor clinical outcomes. In clopidogrel-treated patients with high platelet reactivity, alternative agents, such as prasugrel or ticagrelor, might be considered. The routine clinical use of platelet function testing to screen clopidogrel-treated patients undergoing PCI is not recommended. Platelet FunctionTesting I IIaIIbIII I IIaIIbIII I IIaIIbIII No Benefit

34. Thank You