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Presenting Faculty : Tomas Villanueva, DO, MBA, FACPE, SFHM

Presenting Faculty : Tomas Villanueva, DO, MBA, FACPE, SFHM Clinical Assistant Professor of Medicine College of Osteopathic Medicine Nova Southeastern University Medical Director, Hospital Medicine Program Baptist Health System of Miami Miami, FL

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Presenting Faculty : Tomas Villanueva, DO, MBA, FACPE, SFHM

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  1. Presenting Faculty: Tomas Villanueva, DO, MBA, FACPE, SFHM Clinical Assistant Professor of Medicine College of Osteopathic Medicine Nova Southeastern University Medical Director, Hospital Medicine Program Baptist Health System of Miami Miami, FL Dr. Villanueva has disclosed that he is a consulting editor for Hospital Medicine Program Management and a reviewer for Hospital Medicine. He is also on the speakers’ bureaus for American Regent, AstraZeneca, Forest, Novo Nordisk, and Pfizer.

  2. Pre-test

  3. 67 year old man with history of DM and GI bleed six months ago is admitted with NSTE-ACS. Initial ECG showed anterolateral ST depressions and troponin levels rose to 1.3. He undergoes stenting of the LAD with a drug-eluting stent (DES). He is discharged to your care for further management.

  4. What is the most appropriate daily dose of aspirin to treat him with long-term? • 81 mg QD • 325 mg (enteric coated) QD • 325 mg BID (to better prevent stent thrombosis) • It doesn’t matter 10 Countdown

  5. How long should his P2Y12 inhibitor therapy (clopidogrel, ticagrelor, or prasugrel) be continued? • One month • 3-6 months • At least 12 months • It depends on which P2Y12 inhibitor he was placed on 10 Countdown

  6. Should the patient be placed on a PPI? • It depends • Yes • No • Maybe 10 Countdown

  7. Pathophysiology of Plaque Rupture and Acute Coronary Syndromes

  8. Coronary Atherosclerotic Plaque • Coronary artery smooth muscle thickening • Foam cells accumulate in smooth muscle • Core of extracellular lipid accumulates

  9. Ruptured Vulnerable Plaque with Thrombus Formation Ruptured Vulnerable Fibrous Cap Thrombus Plaque Core

  10. Plaque Rupture with Coronary Thrombus

  11. Platelet Aggregation

  12. Platelet Cascade in ACS Activation Adhesion 2 1 Thrombin von Willebrand Factor/GP lb Bind ADP Platelets 5 HT Collagen GP la/lla Bind TXA2 Lipid Core Aggregation Platelet Plug 4 3 Activated GP llb/llla Fibrinogen Schafer AI. Am J Med. 1996.

  13. 16 12 8 4 0 % Mortality 0 30 60 90 120 150 180 Days Mortality in the Global Registry of Acute Coronary Events (GRACE) STEMI Mortality from D/C to six months STEMI – 4.8% NSTEMI – 6.2% Unstable – 3.6% NSTEMI UA N=43,810 Fox KA, et al. BMJ. 2006; Goldberg RJ, et al. Am J Cardiol. 2004.

  14. Aspirin for ACS and Secondary Prevention

  15. Aspirin in Acute Coronary Syndromes (ACS) Acute MI Unstable Angina P<.0001 Death or MI P=.001 Reocclusion P=.012 MI P<.001 Vascular Death 20 30 4 15 17.1 25.0 3.3 11.8 15 3 9.4* 20 10 1.9* Patients (%) 10 2 11.0* 6.5* 10 5 5 1 0 0 0 0 Placebo ASA Placebo Placebo Placebo ASA ASA ASA N= 397 399 513 419 8,5878,6008,5878,600 MI=myocardial infarction ASA=acetylsalicylic acid RISC=Research on Instability in Coronary Artery Disease • RISC Group. Lancet. 1990; • Roux S, et al. J Am Coll Cardiol. 1992; ISIS-2. Lancet. 1988.

  16. Chronic ASA Doses and Vascular Events in High Risk Patients • Antithrombotic Trialists Collaboration. Br Med J. 2002.

  17. Relationship Between Major Bleeding and ASA Dose in ACS Patients Post-hoc Analysis from CURE ASA + Clopidogrel ASA + Placebo 4.9% 5.0 3.7% 4.0 3.4% 3.0% 2.8% Incidence of Major Bleeding (%) 3.0 1.9% 2.0 1.0 0 ≤100 mg (N=5,320) ≥200 mg (N=4,110) 101–199 mg (N=3,109) ASA dose (range 75-325 mg) Peters RJ, et al. Circulation. 2003.

  18. Aspirin Dosing After ACS/PCI: Current ACCF/AHA Recommendations • UA/NSTEMI (2011 Focused Update):1 • 75-162 mg indefinitely • STEMI (2004 Guideline):2 • 75-162 mg indefinitely • Secondary Prevention (2011 Update):3 • 75-162 mg indefinitely • PCI (2011 Guideline):4 • Aspirin indefinitely (class I; LOE A) • Reasonable to use 81 mg/day in preference to higher maintenance doses (class IIa; LOE B) 1Wright RS, et al. Circulation. 2011; 2Antman EM, et al. J Am Coll Cardiol. 2004; 3Smith S, et al. J Am Coll Cardiol. 2011; 4Levine GN. J Am Coll Cardiol. 2011.

  19. Clopidogrel After NSTE-ACS

  20. CURE Trial: Primary Composite Endpoint (MI/CVA/CV Death) • at 12 Months in Patients with NSTE-ACS 11.4% 20% RRR P=.00009 Placebo + Aspirin 14 12 9.3% 10 Clopidogrel + Aspirin 8 % With Event 6 4 2 0 3 6 9 12 Follow-up (Months) Yusuf S, et al. N Engl J Med. 2001.

  21. Clopidogrel For Primary and Secondary Prevention

  22. CHARISMA Trial Design(Clopidogrel in Addition to Aspirin in Patients Without Recent ACS) Clopidogrel75 mg/day (N=7,802) Patients age ≥45 years at high risk of atherothrombotic events* Low dose ASA 75-162 mg/day R Double-blind treatment up to 1040 primary efficacy events (CV death, MI or CVA) (N=15,603) Low dose ASA 75-162 mg/day Placebo 1 tablet/day (N=7,801) *Documented CAD, CVD, symptomatic PAD or >=2 CRF 1-month visit 3-month visit Final visit (Fixed study end date) Visitsevery 6 months Bhatt DL, et al. Am Heart J. 2004.

  23. CHARISMA: Overall Population: Primary Efficacy Outcome (MI, Stroke, or CV Death)† 8 6 4 2 0 Placebo + ASA* 7.3% Clopidogrel + ASA* 6.8% Cumulative event rate (%) RRR: 7.1% [95% CI: -4.5%, 17.5%] P=.22 0 6 12 18 24 30 Months since randomization§ † First Occurrence of MI (fatal or non-fatal), stroke (fatal or non-fatal), or cardiovascular death *All patients received ASA 75-162 mg/day §The number of patients followed beyond 30 months decreases rapidly to zero and there are only 21 primary efficacy events that occurred beyond this time (13 clopidogrel and 8 placebo) Bhatt DL, et al. N Engl J Med.2006.

  24. CHARISMA Primary Efficacy Results (MI/Stroke/CV Death) by Pre-Specified Entry Category Population RR (95% CI) Pvalue Qualifying CAD, CVD or PAD 0.88 (0.77, 0.998) .046 (N=12,153) Multiple Risk Factors 1.20 (0.91, 1.59) .20 (N=3,284) Overall Population* 0.93 (0.83, 1.05) .22 (N=15,603) 1.2 1.4 1.6 0.4 0.6 0.8 Clopidogrel Better Placebo Better *A statistical test for interaction showed marginally significant heterogeneity (P=.045) in treatment response for these pre-specified subgroups of patients Bhatt DL, et al. N Engl J Med.2006.

  25. CHARISMA– Prior MI 10 N=3,846 8.3% 8 Placebo + ASA Clopidogrel + ASA 6.6% 6 Primary Outcome Event Rate (%) 4 2 HR=0.774 (95% CI [0.613–0.978]) P=.031 0 0 6 12 18 24 30 Months Since Randomization Bhatt DL, et al.J Am Coll Cardiol.2007.

  26. Clopidogrelshould be considered in a non-diabetic patient with high risk for atherosclerosis but has not had an episode of ACS. • True • False 10 Countdown

  27. P2Y12 Inhibitor Therapy After Stenting

  28. Coronary Stenting Lesion crossed with guidewire Lesion dilated with balloon Stent aligned in lesion Deployed stent In artery

  29. Post-Balloon Pre-PTCA Post-Stent Coronary Stenting

  30. CREDO: One Year Primary Outcome Stable CAD and ACS Patients Rx with Bare Metal Stents (BMS) 27% RRR P=.02 15 Placebo N=1063 11.5% 10 8.5% Death, MI, or Stroke Clopidogrel N=1,053 5 0 0 3 6 9 12 Months Steinhubl SR, et al. JAMA. 2002.

  31. Continued Risk of Drug Eluting Stent (DES) ThrombosisDES Stent Thrombosis In The Bern/Rotterdam Two Center Experience 4 Paclitaxel DES 3 Stent Thrombosis (%) 2 SirolimusDES 1 0 0 365 730 1,095 Days After Stenting P. Wenaweser and P.W. Serruys, ESC 2006. (Slide courtesy of Roxana Mehran, Columbia University)

  32. Newer P2Y12 Inhibitors ∙ Prasugrel∙ Ticagrelor

  33. Prasugrel • Thienopyridine • “Irreversible” platelet inhibition • Rapidly metabolized prodrug • Rapid onset of action • Greater and more reliable platelet inhibition than clopidogrel Bhatt DL. N Engl J Med.2009; van Giezen JJ. Eur Heart J Suppl. 2008.

  34. * Pras 10 mg * * * Clop 600 mg Pras 60 mg * * † * * † * * * * † § Clop 75 mg ! * ! Clop 75 mg Clop 300 mg * P<.001 vs. Clop 300 mg or 600 mg LD † P<.001 vs. Clop 300 ! P<.05 vs. Clop 300§P<.05 vs. Clop 300/75 • PRINCIPLE-TIMI 44 • Prasugrel vs. Clopidogrel Loading Dose Maintenance Doses 100 80 60 Inhibition of Platelet Aggregation (%) 40 20 mean ± SEM 20 μM ADP 0 0.5 0 0.25 1 2 4 6 24 3 4 5 6 7 8 9 Time Hours Days Wiviott SD, et al. Circulation. 2007.

  35. TRITON-TIMI 38: • Study Design ACS (STEMI or UA/NSTEMI) and Planned PCI N=13,600 ASA Double-blind CLOPIDOGREL 300 mg LD/75 mg MD PRASUGREL 60 mg LD/10 mg MD Median duration of therapy: 12 months 1o endpoint: CV death, MI, Stroke 2o endpoints: CV death, MI, Stroke, Rehospitalization for Recurrent IschemiaCV death, MI, UTVRStent Thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, Life-threatening bleedsKey Substudies: Pharmacokinetic, Genomic LD=loading dose; MD=maintenance dose Wiviott SD, et al. N Engl J Med. 2007.

  36. TRITON-TIMI 38 Timing of Benefit: Landmark Analysis 8 6.9 Clopidogrel Clopidogrel 5.6 5.6 6 4.7 Primary Endpoint (%) (CV death, MI, CVA) 4 Prasugrel Prasugrel HR 0.82P=.01 HR 0.80P=.003 2 1 0 0 1 2 3 30 60 90 180 270 360 450 0 Days Loading Dose Maintenance Dose Wiviott SD, et al. N Engl J Med. 2007.

  37. TRITON-TIMI 38: Definite and Probable Stent Thrombosis 2.5 2.4(142) Clopidogrel Any Stent at Index PCIN=12,844 2 Definite & Probable Stent Thrombosis (%) 1.1 (68) 1 Prasugrel HR 0.48P<.0001 NNT=77 0 0 30 60 90 180 270 360 450 Days Wiviott SD, et al. N Engl J Med. 2007.

  38. TRITON-TIMI 38: Bleeding Events Prasugrel Clopidogrel ICH in Pts with Prior Stroke/TIA (N=518) P=.03 Clopidogrel 0 (0%) Prasugrel 6 (2.3%) P=.02 P=.01 P=NS % Events P=.002 P=NS ARD 0.6%HR 1.32 ARD 0.5%HR 1.52 ARD 0.2% ARD 0.3% ARD 0% ARD=absolute risk difference Wiviott SD, et al. N Engl J Med. 2007.

  39. TRILOGY ACS Study Design Medically Managed UA/NSTEMI Patients Randomization Stratified by: Age, Country, Prior Clopidogrel Treatment (Primary analysis cohort — Age <75 years) Median Time to Enrollment=4.5 Days Medical Management Decision ≤72 hrs (No prior clopidogrelgiven) – 4% of total Medical Management Decision ≤ 10 days (Clopidogrel started ≤72 hrs in-hospital OR on chronic clopidogrel) – 96% of total Clopidogrel*300 mg LD + 75 mg MD Prasugrel*30 mg LD + 5 or 10 mg MD Clopidogrel* 75 mg MD Prasugrel*5or 10 mg MD Minimum Rx Duration: 6 months; Maximum Rx Duration: 30 months Primary Efficacy Endpoint: CV Death, MI, Stroke *All patients were on aspirin and low-dose aspirin (<100 mg) was strongly recommended. For patients <60 kg or ≥75 years, 5 mg MD of prasugrel was given Adapted from Chin CT, et al. Am Heart J. 2010.

  40. TRILOGY ACS: Primary Efficacy Endpoint* 20 Primary Efficacy Endpoint (%)** HR >1 Year: 0.72 (0.54, 0.97) HR ≤1Year: 0.99 (0.84, 1.16) 16.0% 15 13.9% 10 Clopidogrel Prasugrel HR: 0.91 P=.21 (NS) 5 Interaction P=.07 0 0 180 360 540 720 900 Time, days No. at risk Prasugrel: 3,620 3,248 2,359 1,611 953 389 Clopidogrel: 3,623 3,244 2,390 1,596 946 399 *Primary endpoint=CV death, nonfatal MI, nonfatal stroke **Primary analysis excludes age >75 yrs Roe MT, et al. N Engl J Med. 2012.

  41. Ticagrelor • Non-thienopyridine • “Reversible” binding of P2Y12 receptor • Active drug • Quick onset of action • Greater degree of and more reliable platelet inhibition than clopidogrel Bhatt DL. Nature Reviews Cardiology. 2009; van Giezen JJ. Eur Heart J Suppl. 2008.

  42. DISPERSE 2 Comparative Effectson PlateletAggregation of Ticagrelor vs.Clopidogrel 100 Ticagrelor 90 mg 75 Ticagrelor 180 mg Ticagrelor 270 mg 50 Clopidogrel 300 mg 25 0 0 2 4 6 8 10 12 Inhibition of Platelet Aggregation (IPA) IPA, % (mean ± SEM) Time Post Dose (Hours) Keeley EC, et al. Lancet. 2006.

  43. PLATO Study Design NSTEMI-ACS (moderate-to-high risk), STEMI (if primary PCI) Clopidogrel-treated or -naive; randomized within 24 hours of index event (N=18,624) Clopidogrel If pretreated, no additional loading dose; if naive, standard 300 mg loading dose, then 75 mg QD maintenance; (additional 300 mg allowed pre-PCI) Ticagrelor 180 mg loading dose, then 90 mg BID maintenance; (additional 90 mg pre-PCI) 6-12-month exposure Primary endpoint: CV death + MI + Stroke Primary safety endpoint: Total major bleeding Wallentin L, et al. N Engl J Med. 2009.

  44. PLATO: Time to Primary Efficacy Endpoint* 13 12 11.7% Clopidogrel 11 10 9.8% 9 Ticagrelor 8 7 Cumulative incidence (%) 6 5 HR 0.84 (95% CI 0.77-0.92) P=.0003 4 3 2 1 0 0 60 120 180 240 300 360 Days after Randomisation No. at risk Ticagrelor 9,333 8,628 8,460 8,219 6,743 5,161 4,147 Clopidogrel 9,291 8,521 8,362 8,124 6,650 5,096 4,047 *Composite of CV death, MI, or stroke Wallentin L, et al. N Engl J Med. 2009.

  45. PLATO: Secondary Efficacy Endpoints Myocardial infarction Cardiovascular death 7 7 6.9 Clopidogrel 6 6 5.8 Clopidogrel 5.1 5 5 Ticagrelor 4.0 4 4 Cumulative incidence (%) Cumulative incidence (%) Ticagrelor 3 3 HR 0.84 (95% CI 0.75-0.95) P=.005 2 2 HR 0.79 (95% CI 0.69-0.91) P=.001 1 1 0 0 0 60 120 180 240 300 360 0 60 120 180 240 300 360 Days after randomisation Days after randomisation Wallentin L, et al. N Engl J Med. 2009.

  46. PLATO: Overall, Non-CABG and CABG-related Major Bleeding P=.43 (NS) Ticagrelor Clopidogrel 13 11.6 12 11.2 11 P=.32 (NS) P=.57 (NS) 9 10 7.9 9 8 7.4 P=.32 (NS) 7.9 7.7 8 7 P=.026 7 5.8 Estimated Rate (% per year) 6 5.3 6 4.5 5 5 P=.025 3.8 4 4 2.8 3 3 2.2 2 2 1 1 0 0 Non-CABGPLATO majorbleeding Non-CABGTIMI major bleeding CABGPLATO major bleeding CABG TIMI major bleeding PLATO criteria major bleeding TIMI criteria major bleeding Wallentin L, et al. N Engl J Med. 2009.

  47. PLATO: Stent Thrombosis* *Evaluated in patients with any stent during the study Wallentin L, et al. N Engl J Med. 2009.

  48. PLATO: Initial Non-Invasive Strategy Subgroup Cardiovascular death, MI, or Stroke (%) 20 • N=5,216 (1/4 total study population, 1/3 NSTE-ACS population) • In-hospital procedures: cath 41.9%; PCI 20.4%; CABG 4.0% • By final follow-up: revascularization 40% (PCI only 72.6%; CABG only 25.8%; both 1.6%) 16 HR 0.85 P=.04 14.3% • Clopidogrel 12.0% 12 • Ticagrelor 8 4 0 0 60 120 180 240 300 360 Days after Randomization James SK, et al. BMJ. 2011.

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