1. STEMI, Bleeding & Outcomes in Seniors: What Are the Issues? Ron Waksman, MD Joshua P, Loh, MD July 29, 2013 Trans –Radial Education and Therapeutics (TREAT IV

2. Overview Challenges of treating STEMI in elderly PPCI in the elderly Increased bleeding risk in STEMI Increased bleeding risk in the elderly Bleeding avoidance strategies

3. STEMI in the elderly: Challenges Eligibility for reperfusion decreases in the elderly (contraindications, cognition, comorbidities). Elderly STEMI patients less likely to receive reperfusion (PCI or fibrinolysis) even if eligible. Many elderly present with atypical symptoms, abnormal baseline ECGs, or comorbidities that contribute to clinical uncertainty, delayed diagnosis and delayed treatment. PCI success rates lower, with higher complication rates in the elderly. Higher mortality after STEMI. Limited data from clinical trials Alexander et al. Acute coronary care in the elderly, part II: ST-segment-elevation myocardial infarction: a scientific statement for healthcare professionals from the American Heart Association Council on Clinical Cardiology: in collaboration with the Society of Geriatric Cardiology. Circulation. 2007;115:2570-89.

4. Primary PCI vs. Fibrinolysis in the Elderly Few trials enrolled adequate numbers of older patients TrialTypeAge (yrs)NoPCI vs fibrinolysis PAMI-I NEJM 1993 Subgroup≥ 65150Lower in-hosp death or MI GUSTO IIb NEJM 1997 Subgroup≥ 70300Trend toward lower 30-day mortality DANAMI-2 NEJM 2003 Subgroup≥ 63Lower 30-day death, MI or stroke De Boer et al. JACC2002 RCT>7587Lower 30-day death, MI or stroke Goldenberg et al. AHJ 2003 RCT≥ 70130Lower death, MI or revascularization Senior PAMI TCT 2005 RCT≥ 70481Lower death, stroke or reinfarction

5. Primary PCI vs. Fibrinolysis in the Elderly: Absolute mortality advantage of PCI increases with age Boersma E; Primary Coronary Angioplasty vs. Thrombolysis Group. Eur Heart J. 2006;27:779-788.

6. Challenges of Primary PCI in the Elderly: High-risk subset ELDERLY ≥ 75 yrs More comorbidities HTN, COPD, stroke, CHF, CKD, prior revasc, higher KILLIP class on presentation Lower procedural success More peri-procedural complications Less ST resolution Mechanical Electrical Bleeding (3% in 75 yrs)

7. Challenges of Primary PCI in the Elderly: outcomes according to age On multivariable adjustment, age was the strongest independent predictor of 90-day mortality (HR 2.07 per 10-year increase; 95% CI 1.84-2.33). APEX-AMI CADILLAC Guagliumi G, et al. Outcome in elderly patients undergoing primary coronary intervention for acute myocardial infarction: CADILLAC. Circulation 2004;110:1598-604.

8. Primary PCI in the very elderly Salinas et al. (n=38) Eurointerv 2011 Koutouzis et al. (n=22) Clin cardiol 2010 Antoniucci et al. (n=55) AHJ 1999 Valente et al. (n=88) Circ J 2008 Median age/yrs91.5928488 Procedural mortality 9% In-hospital mortality 34.2%27%17% 30 day mortality32%16% Factors associated with mortality Killip class >I vs. I 53.3% vs. 21.7% TIMI flow <3 vs. 3 71.4% vs. 22.7% Major bleeding vs. none 100% vs. 31.4% Killip class III/IV vs. I/II 100% vs. 21% Cardiogenic shock vs. none 70% vs. 4% Cardiogenic shock vs. none 90% vs. 7% Killip class III/IV vs. I/II 40% vs. 12.3% Major bleeding5.4%0NA11%

9. Bleeding after PCI Elderly STEMI Comorbidities e.g. renal failure Increased Risk

10. Post PCI bleeding increases mortality: NCDR Chhatriwalla et al; NCDR. Association between bleeding events and in-hospital mortality after percutaneous coronary intervention. JAMA 2013;309:1022-9.  CathPCI registry: analyzed 3 million PCIs in the US between 2004 and 2011  Bleeding events occurred in 1.7%  In-hospital deaths occurred in 0.65%

11. Bleeding after Primary PCI: Sustained effect of bleeding on mortality and MACE up to 3 years Suh JW, et al. Impact of in-hospital major bleeding on late clinical outcomes after primary percutaneous coronary intervention in acute myocardial infarction the HORIZONS-AMI trial. J Am Coll Cardiol. 2011;58:1750-6.

12. Bleeding after PCI in ≥65 yrs old: NCDR/Medicare/Medicaid Increased risks of MACE, mortality and future bleeding events Rao SV et al. Association between periprocedural bleeding and long-term outcomes following percutaneous coronary intervention in older patients. JACC Cardiovasc Interv 2012;5:958-65.

13. Bleeding increases mortality: proposed mechanisms Doyle BJ, et al. Bleeding, blood transfusion, and increased mortality after percutaneous coronary intervention: implications for contemporary practice. J Am Coll Cardiol 2009;53:2019-2027.

14. Access vs. non-access site bleed Chhatriwalla et al; NCDR. Association between bleeding events and in-hospital mortality after percutaneous coronary intervention. JAMA. 2013;309:1022-9. Verheugt et al. Incidence, prognostic impact, and influence of antithrombotic therapy on access and nonaccess site bleeding in percutaneous coronary intervention. JACC Cardiovasc Interv 2011;:191-7. Non-access site bleed confers higher mortality compared with access site bleed

15. Bleeding across clinical presentations Loh, Waksman. Impact Of Clinical Presentation On In-Hospital Bleeding Outcomes In Percutaneous Coronary Intervention. TCT 2013

16. Patients at highest bleeding risk (NCDR): pre-procedural factors Mehta SK, et al; NCDR. Bleeding in patients undergoing percutaneous coronary intervention: the development of a clinical risk algorithm from the NCDR. Circ Cardiovasc Interv. 2009;2:222-229. Many risk factors co-exist in the elderly patient

17. Patients at highest bleeding risk: HORIZONS-AMI Suh JW, et al. Impact of in-hospital major bleeding on late clinical outcomes after primary percutaneous coronary intervention in acute myocardial infarction the HORIZONS-AMI trial. J Am Coll Cardiol. 2011;58:1750-6.Impact of in-hospital major bleeding on late clinical outcomes after primary percutaneous coronary intervention in acute myocardial infarction the HORIZONS-AMI trial.

18. Elderly patients at increased bleeding risk: NCDR/Medicare/Medicaid Of patients who bled, access site bleed = 48.6% Predominantly femoral access PCI in 461311 patients ≥ 65 yrs old Post PCI bleeding in 3.1% Rao SV et al. JACC Cardiovasc Interv 2012;5:958-65.

19. Reduction in overall PCI bleeding complications: NCDR 2005-2009 (n=599524) (n=836103) (n=267632) Reduction in annual bleeding risk Reduction in in annual bleeding risk No change in annual bleeding risk Subherwal SSubherwal S, et al. Temporal trends in and factors associated with bleeding complications among patients undergoing percutaneous coronary intervention: a report from the NCDR. J Am Coll Cardiol. 2012;59:1861-9. J Am Coll Cardiol. Overall 20% reduction in post- PCI bleeding

20. Reduction in overall PCI bleeding complications: NCDR 2005-2009 (n=599524) (n=836103) (n=267632) Temporal decrease in heparin + GPI Increase in bivalirudin No change in anticoagulation/ thrombolytic use IABP use 10%

21. Reduction in overall PCI bleeding complications: NCDR 2005-2009 (n=599524) (n=836103) (n=267632) Only slight temporal increase in radial access and vascular closure device use

22. Bleeding avoidance strategies Dauerman et al. Bleeding avoidance strategies. Consensus and controversy. J Am Coll Cardiol 2011;58:1-10.

23. Bleeding avoidance strategies: Consensus and Controversy Dauerman et al. Bleeding avoidance strategies. Consensus and controversy. J Am Coll Cardiol 2011;58:1-10.

24. Pharmacology: Bivalirudin Stone GW, et al; HORIZONS-AMI Trial Investigators. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008;358:2218-30.

25. Pharmacology: Bivalirudin Reduction in both access and nonaccess site bleeding compared to Hep + GPI Verheugt FW, et al. Incidence, prognostic impact, and influence of antithrombotic therapy on access and nonaccess site bleeding in percutaneous coronary intervention. JACC Cardiovasc Interv 2011;4:191-7.

26. Pharmacology: Bivalirudin Does not reduce bleeding when used in conjunction with GPI Time to event curve of major bleeding Stone GW, et al. Bivalirudin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a subgroup analysis from the ACUITY trial. Lancet 2007;369:907-19.

27. Bleeding reductions maintained when compared to: Eptifibatide + 50U/kg heparin (PROTECT-TIMI 30. JACC 2006) Abciximab + heparin reversal with protamine post PCI (Parodi et al. J Thromb Thrombolysis 2010) Pharmacology: Bivalirudin

28. Bivalirudin vs. Heparin monotherapy Bertrand OF, et al. Meta-analysis comparing bivalirudin versus heparin monotherapy on ischemic and bleeding outcomes after percutaneous coronary intervention. Am J Cardiol 2012;110:599-606. Transfemoral Decrease in major bleeding Similar MACE Bleeding outcomes

29. Effect of radial access on bleeding: Clinical trials Crossover rates 4-6%, age 60-65 yrs old RIVAL (STEMI, n=1958): no difference in bleeding (0.84% vs. 0.61%) RIFLE-STEACS (n=1001): reduced bleeding (7.8% vs. 12.2%) STEMI-RADIAL (n=707):

30. Growth of transradial access in the US: NCDR 2007-2012 Adoption of radial access and comparison of outcomes to femoral access in percutaneous coronary intervention: an updated report from the NCDR (2007-2012). Circulation 2013;127:2295-306.

31. Reduced bleeding and vascular complications in key subgroups with transradial access Bleeding complications (unadjusted rates) Vascular complications (unadjusted rates)

32. New generation antiplatelet therapy: efficacy Newer generation antiplatelet agents significantly reduce adverse outcomes compared to clopidogrel up to 1-year in patients with ACS. TRITON TIMI-38 PLATO Wiviott et al. N Engl J Med 2007 15;357:2001-2015Wallentin et al. N Engl J Med 2009;361(11):1045-57

33. Balance of efficacy and safety: Ticagrelor Overall no difference in major bleeding as defined by the study criteria More fatal intracranial bleed, non-CABG related bleed Although no recommendation to dose- adjust in elderly, should take into consideration potential bleeding risks

34. Ticagrelor: Contraindications and Adverse Effects Contraindications – Active bleeding, severe hepatic failure, prior intracranial hemorrhage Adverse effects – Bradycardia No clinical sequelae in PLATO (patients at high risk excluded from the trial) – Dyspnea No objective effect on pulmonary function Unknown mechanism; adenosine?

35. Balance of efficacy and safety: Prasugrel Less clinical efficacy Greater absolute levels of bleeding

36. Dose adjust in the very elderly? Prasugrel 5mg in very elderly met non-inferiority criterion by MPA vs. Prasugrel 10mg in non-elderly Prasugrel 5mg resulted in fewer very elderly poor responders compared to clopidogrel 75mg Erlinge D, et al. Prasugrel 5-mg in the very elderly attenuates platelet inhibition but maintains non- inferiority to prasugrel 10-mg in non-elderly patients: The GENERATIONS trial, a pharmacodynamic and pharmacokinetic study in stable CAD patients. J Am Coll Cardiol 2013 Jun 6. [Epub ahead of print] Prasugrel 5mg suggested based on population pharmacokinetic substudy modeling in TRITON-TIMI 38.

37. Prasugrel: Summary of Boxed Warning Contraindications: Clinical hx of stroke/TIA Generally not recommended for age ≥ 75 yrs, except in high risk situations (prior MI, DM) where the ischemic benefit appears to be greater Greater risk of bleeding in patients weighing <60kg, can consider MD adjustment (5mg)

38. Summary The elderly STEMI patient presents an extremely challenging subset to treat due to presence of co- morbidities, high periprocedural mortality and significant morbidity. The elderly STEMI patients are at high risk of bleeding post PCI, and bleeding avoidance strategies should be employed as much as possible. There is still controversy towards certain strategies to reduce post-PCI bleed. The overall impact of transradial access on reduction of bleeding appears favorable,. However the greatest impact appears to be in the proper selection of antithrombotic therapy, especially in this high risk subpopulation.