1. 1 PERIPROCEDURAL PHARMACOTHERAPHY IN PRIMARY ANGIOPLASTY SM Ashraf PROFESSOR MD DM FSCAI FESC FACC Sahakarana Hrudayalaya Pariyaram Medical College Hospital

2. 2 Causes of death worldwide *Population: Age ≥60 years; CHD is the second leading cause of death in persons 15-59 years. Deaths (2002)* Mackay J, et al. Deaths from coronary heart disease. In: The Atlas of Heart Disease and Stroke. Geneva: World Health Organization; 2004:46-49.

3. 3 CHD and mortality in high-, middle- and low-income countries [WHO 2008:A] World Health Organization. The top 10 causes of death, Fact sheet Number 310. November 2008.

4. 4 Essential Principals in STEMI Interventions 1. To balance Ischemia and Bleeding 2. Control | Speed | Urgency

5. 5 Five Best Strategies to PAMI Success Improving Procedure 1. Culprit Lesion Identification & Parameters of success 2. Standardized techniques 3. Understanding thrombus dynamics/ Selective strategy for thrombus management 4. Intracoronary Vasodilators 5. Better anti-coagulant & anti platelet drugs

6. 6 6

7. 7 Unfractionated Heparin  Indirect thrombin inhibitor (does not inhibit clot-bound thrombin)  Nonspecific binding to: ―Plasma proteins ―Endothelial cells (variable anticoagulation level)  Inhibited by platelet factor 4 ―reduced effect in ACS  Causes platelet aggregation  Risk of HIT Disadvantages  Multiple sites of action in coagulation cascade (IIa,Xa)  Long history of successful clinical use  Readily monitored by aPTT and ACT  Very inexpensive Advantages Hirsh J, et al. Circulation. 2001;103:2994-3018

8. 8 Binds to plasma proteins Interpatient variability Indirect action; needs antithrombin (AT) to exert effect Unpredictable anticoagulant response Neutralized by platelet factor 4 (PF4) Heparin/AT complex has limited activity on clot-bound thrombin vs. free thrombin Limited activity in the presence of platelet-rich clot Non-linear pharmacokinetics/ pharmacodynamics (PK/PD) Narrow therapeutic window Heparin-induced platelet activation via GPIIb/IIIa receptors Procoagulant effect Heparin-PF4 antibody complex formation Heparin-induced thrombocytopenia Heparin characteristics 8

9. 9 LMWH LMWH Indirect thrombin inhibitor Lack of binding to plasma proteins No reversible agent Difficult to monitor (no aPTT or ACT) Higher rates of major and minor bleeding in PCI ( Potent thrombin inhibitor ) Long half-life (4 -6 hours) Risk of HIT 9

10. 10 Antman EM: Circulation 1996; 94: 911; Théroux P: N Engl J Med 1992; 327: 141; Cohen M: Circulation 1994; 89:81 Limitations of UFH Unpredictable anticoagulant effect Non-specific protein binding and saturable clearance mechanism Inactivation by platelet factor 4 Platelet activation and aggregation

11. 11 Advantages of LMWH vs UFH No platelet activation Inhibits von Willebrand factor release Augments TFPI release Inhibits thrombin generation No rebound hypercoagulability

12. 12 IIa S C Direct antithrombin LMWH AT Xa AT Xa Pentasaccharide Bivalirudin = saccharide unit. Konkle BA, Schafer AI. In: Zipes DP, Libby P, Bonow RO, Braunwald E, eds. Braunwald’s Heart Disease. 7th ed, vol 2. Philadelphia: Elsevier Saunders; 2005:2067-2092. UFH

13. 13 Bivalirudin

14. 14 Bivalirudin overcomes the risks and limitations of heparin ACT= activated clotting time; IV=intravenous. 1. Bivalirudin Prescribing Information. The Medicines Company; Parsippany, NJ, December 6, 2005. 2. Bates SM et al. J Invasive Cardiol. 2000;12(suppl F):27F-32F. 3. Mehta S et al. Cath Lab Digest. 2004;12:1-4. 4. Minutello RM et al. Poster abstract 340. Presented at: 15th Transcatheter Cardiovascular Therapeutics Meeting; Washington, DC; 2003. 5. Schussler JM et al. Am J Cardiol. 2004;94:1417-1419. 6. Xiao Z et al. Circulation. 1998;97:251-256. Antithrombotic feature BivalirudinHeparinBenefits 100% bioavailable Provides a predictable dose response; no continuous ACT monitoring required 1 IV, 25-minute half-life Enables fast-on, fast-off activity 1 Does not require antithrombin as a binding cofactor Inhibits thrombin directly, and effectively inactivates clot-bound thrombin 2 Binds reversibly to thrombin Thrombin is able to resume normal hemostatic functions 1,3 Sheath removal* 2 hours after discontinuation in most patients Reduces access-site bleeding complications and time spent in the recovery area after PCI 3-5 No heparin/PF4 cross- reactivity No risk of HIT/HITTS 1 Does not activate platelets Does not promote platelet activation or aggregation 6 *Sheath removal has not been studied in dialysis-dependent patients treated with Bivalirudin. Follow standard hospital protocol for this population. 1

15. 15 Return to Hemostasis - Safety Advantage Bivalirudin is cleaved by thrombin, allowing thrombin to quickly recover hemostatic activity upon discontinuation of Bivalirudin. 2 The natural reversibility and the short, 25-minute half-life may explain the significantly lower bleeding rates seen in clinical trials. 3 When heparin dissociates from cells/proteins, there can be an anticoagulant effect even when it is not needed. This may explain the prolonged bleeding risk after discontinuation of heparin. 1 1. Hirsh J et al. Chest. 2001;119(suppl 1):64S-94S. 2. Weitz JI et al. Thromb Res. 2002;106:V275-V284. 3. Bivalirudin (bivalirudin) [prescribing information]; December 6, 2005. Why Bivalirudin ?

16. 16 Rationale on extended infusion

17. 17 Anticoagulants: Overview Established anticoagulants used in patients with ACS: –Heparin (inhibits thrombin by accelerating activity of antithrombin III) [Hirsch 1995] Low molecular weight heparins; unfractionated heparin Bivalurudin- Direct thrombin Inhibitor –Fondaparinux* (binds reversibly to antithrombin, potentiating its neutralising effect on factor Xa) [Garcia 2012] * Not approved for the treatment of ACS; † Approved in Europe for the treatment of patients with ACS; ‡ Phase III study terminated due to increased risk of bleeding in the absence of counterbalancing reduction in ischaemic events. ACS, acute coronary syndromes. Ansell J, et al. Chest 2008;133:160S–198S; Garcia D, et al. Chest 2012;141:e24S–e43S; Hamm CW, et al. Eur Heart J 2011;32:2999–3054; Hirsch J, et al. Chest 1995;108(Suppl. 4):258S–275S; Steg G, et al. Eur Heart J 2012;33:2569–2619. ACS: Acute Coronary Syndrome

18. 18 Role of New oral anticoagulants in the treatment of patients with ACS New oral anticoagulants were developed to improve CV clinical management limited by the disadvantages of traditional agents [Eikelboom 2010] Rivaroxaban, apixaban, and dabigatran target factor Xa or thrombin, key enzymes in the coagulation pathway [Eikelboom 2010; PRADAXA 2013] Only rivaroxaban 2.5 mg is approved for use in patients with ACS in Europe [XARELTO® 2013] –A Phase III study with apixaban was terminated early due to increased bleeding events with no concurrent reduction in CV events [Alexander 2011] –It is currently unknown whether a Phase III trial will be initiated with dabigatran Given the potential for a higher risk of bleeding, triple therapy with the newer P2Y 12 inhibitors plus a new oral anticoagulant in patients with ACS is still controversial ACS, acute coronary syndromes; CV, cardiovascular. Alexander J, et al. N Engl J Med 2011;365:699–708; Eikelboom J, Weitz J. Circulation 2010;121:1523–1532; PRADAXA® [Prescribing information] 2013; XARELTO ® [Summary of product characteristics] Berlin, Germany. Bayer 2013.

19. 19 Anti-Thrombins for PCI UFH is effective for PCI, especially when used with GP2b3a inhibition LMWH (enoxaparin) is safe and effective with PCI Bivalirudin is superior to heparin and non-inferior to heparin + GP 2b3a Rx Summary

20. 20 Recommended use of anticoagulants in STEMI- ACS Class I, LOE A–C In STEMI patients: –Must be implemented in addition to antiplatelet therapy in patients with clear indication for anticoagulation † LOE, level of evidence; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction; UA, unstable angina; UFH, unfractionated heparin. Hamm CW, et al. Eur Heart J 2011;32:2999–3054; Jneid H, et al. Circulation 2012;126:875–910; O’Gara PT, et al. Circulation 2013;127:e362–e425; Steg G, et al. Eur Heart J 2012;33:2569–2619. Class I, LOE C In STEMI patients: –UFH or Bivalirudin is recommended in those undergoing PCI ACC/ AHA ESC

21. 21 Storey RF Curr Pharm Des 2006;12:1255–1259 Targets for platelet inhibition GP, glycoprotein; PAR, protease-activated receptor; TP, thromboxane A 2 / prostaglandin H 2

22. 22 CPTP Ticagrelor ATP Analogues Cangrelor Elinogrel Theinopyridines Ticlopidine Clopidogrel Prasugrel Ant platelet's: Overview P2Y12 Receptor Antagonists Reversible Irreversible

23. 23 Clinical PharmacologyClopidogrelPrasugrelTicagrelor Chemical ClassThienopyridine Cyclopentatyltriazolopyrimidine Reversible inhibition of P 2 Y 12 receptor No Yes Pro drugYes No Mean IPA at 30 min8 % 31% 41 % Mean IPA at 2 Hours38 % 64% 89 % Variability with CYP 2 C 19 YesNo Comparison of P2Y12 Blockers Chin CT, et al. Am Heart J 2010;160:16–22; Montalescot G, et al. Lancet 2009;373:723–731; Roe MT, et al. N Engl J Med2012;367:1297–1309. Gurbel PA, et al. JAMA 2012;308:1785–1794. Gurbel PA et al. Thromb Haemost. 2012;108:12–20. Wiviott SD, et al. Circulation. 2007;116:2923-2932. Thomas J, et al. European Heart Journal (2006) 27, 1166–1173. IPA: Inhibition of Platelet Activation

24. 24 Prasugrel comes with increased bleeding tendency in specific sub groups  Beneficial more in PCI pts  STEMI  Diabetes  Stent Thrombosis Black Box Warning of increased risk if severe bleed Dose Adjustment required in 75 years CI in stroke/ TIA CABG: d/c atleast 7d Effient PI; NEJM 357: 2001-2015, 2007  Overall ↑ in TIMI Major Bleed  Subgroup Analysis  > 75 yrs  <60 kg  h/o stroke/ TIA TIA – Transient ischemic attack ; STEMI : ST Elevation Myocardial Infarction ; TIMI: Thrombolytic in Myocardial Infarction

25. 25 Inhibition of platelet reactivity Gurbel PA, et al. Circulation. 2009;120:2577-2585. IPA, inhibition of platelet activity

26. 26

27. 27 GP IIb/IIIa Inhibitors in Acute MI Key questions regarding new adjuvant therapies –Can we improve reperfusion times? –Can we improve flow after reperfusion? –Can we limit infarct size and thus complications?

28. 28 GP IIb/IIIa Inhibitors in Acute MI Why a GP IIb/IIIa inhibitor could work –Early potent antiplatelet therapy –Adjunctive use in PCI improves outcomes –May improve flow –Relatively safe to use

29. 29 % GP IIb/IIIa in Acute MI Abciximab PCI in Acute MI Trials 30 Day Endpoint (D, Re-MI, Urg TVR) p=0.023 p<0.05 p=0.005 PTCA N = 483 Stent N = 401 Stent N = 301 PTCA or Stent N = 2082 Stent N = 400 p=0.038 p=0.01

30. 30 % platelet inhibition 0 20 40 60 80 100 BaselinePost Bolus20 min40 minEOC TIGER-PA Platelet Substudy – TIROFIBAN IN CATH LAB

31. 31 From: The Evolving Role of Glycoprotein IIb/IIIa Inhibitors in the Setting of Percutaneous Coronary Intervention: Strategies to Minimize Bleeding Risk and Optimize Outcomes J Am Coll Cardiol Intv. 2010;3(12):1209-1219. doi:10.1016/j.jcin.2010.09.015 Recommended Strategy of GPI Use in Patients Undergoing PCI and Routinely Treated With Stenting and Thienopyridines Flow chart of the recommended strategy for glycoprotein IIb/IIIa inhibitor use in patients undergoing percutaneous coronary intervention and who are routinely treated with stenting and thienopyridines. * Non–ST-segment elevation myocardial infarction (18). #The presence of 1 and particularly 2 or more of the following factors is associated with an increased bleeding risk: age > 75 years, female, chronic kidney disease stage 3 or worse, baseline anemia, history of prior bleeding, cardiogenic shock, or class IV heart failure. Also, adjust unfractionated heparin dose during percutaneous coronary intervention: use a starting bolus dose of ≤50 U/kg and achieve a target activated clotting time of low 200 s. †The need for a short infusion after percutaneous coronary intervention (≤2 h) depends on the timing of thienopyridine load. Adjust infusion dose to renal function. GPI = glycoprotein IIb/IIIa inhibitor(s); PCI = percutaneous coronary intervention; thieno = thienopyridine.

32. 32 Guidelines : ESC 2014 - STEMI

33. 33 Impact of Therapies on Outcomes in PPCI Bleeding/ Access and non access site bleeding Ischemic events: MI/CKMB↑/Stroke Stent Thrombosis EFFICACY SAFETY

34. 34 Relevance of bleeding as a clinical endpoint in contemporary PCI Availability of potent antithrombotic therapy including –ASA –P2Y 12 inhibitors (clopidogrel, prasugrel, ticagrelor) –heparin –GP IIb/IIIa inhibitors –direct thrombin inhibitors Has led to a reduction in ischemic events But is associated with an increased risk of bleeding The increase in bleeding is associated with worse clinical outcome

35. 35 Hypothetical Mechanisms associating Bleeding to Mortality Steg P G et al. Eur Heart J 2011;32:1854-1864

36. 36 Steg P G et al. Eur Heart J 2011;32:1854-1864

37. 37 How can Bleeding Increase Short and Long Term Mortality ? Hemodynamic compromise Hyper adrenergic state Transfusion induced micro circulatory disorder, NO depletion, immunological effects. Inflammatory response. Discontinuation of antiplatelet & antithrombotic regimens

38. 38 SUMMERY- PHARMACOTHERAPY IN STEMI INTERVENTIONS Optimal thrombus management is critical for STEMI Interventions With D2B<90 min, a fast acting OAP is mandatory – the role of Clopidogrel in these circumstances is fraught with issues of effectiveness from delayed onset of action Intravenous GP2b/3a is a non-ideal option Balancing Bleeding & Ischemic Benefits is Crucial in PPCI.

39. 39 THANK YOU