New Option of Antiplatelet and Controversies in ACS Treatment

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dr. Isfanuddin N Kaoy, SpJP (K), FIHA. 3rd Pekanbaru Cardiology Update, August 25th 2013. Pangeran Hotel, Pekanbaru. Learn more at PerkiPekanbaru.com

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New Option of Antiplatelet and Controversies in ACS Treatment

  1. 1. New Option and Controversies in ACS Treatment
  2. 2. Evolving landscape of antithrombotic treatment in ACS Aspirin dose Heparin LMWH GP IIb/IIIa timing Direct thrombin inhib Clopidogrel dose Fonda Prasugrel Ticagrelor
  3. 3. ANTI PLATELET ASPIRIN TICLOPIDINE Clopidogrel standard Dose PRASUGREL TICAGLEROL CLOPIDOGREL High Dose PLATO TRITON TRILOGI ACS GRAVITAS CURRENT CURE, CALRITY CREDO, COMMIT
  4. 4. Atherothrombosis: A Generalized and Progressive Disease Unstable angina MI Ischemic stroke/TIA Critical leg ischemia Intermittent claudication CV death ACS Atherosclerosis Stable angina/Intermittent claudication Atherothrombosis MI = Myocardial infarction ACS = Acute coronary syndromes CV = Cardiovascular Adapted from Libby P. Circulation 2001; 104: 365–372
  5. 5. CURRENT OASIS 7: A 2X2 Factorial Randomized Trial of Optimal Clopidogrel and Aspirin Dosing in Patients with ACS Undergoing an Early Invasive Strategy with Intent For PCI OASIS-7 Shamir R. Mehta on behalf of the CURRENT Investigators Disclosures: CURRENT OASIS 7 was funded by a grant from sanofi-aventis and Bristol Myers Squibb. All data were managed independently of the sponsor at the PHRI, McMaster University and the trial was overseen by an international steering committee of experts.
  6. 6. Study Design, Flow and Compliance 25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%) Planned Early (<24 h) Invasive Management with intended PCI Ischemic ECG ∆ (80.8%) or ↑cardiac biomarker (42%) 25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%) Planned Early (<24 h) Invasive Management with intended PCI Ischemic ECG ∆ (80.8%) or ↑cardiac biomarker (42%) PCI 17,232 (70%) Angio 24,769 (99%) Angio 24,769 (99%) No PCI 7,855 (30%) No Sig. CAD 3,616 CABG 1,809 CAD 2,430 Randomized to receive (2 X 2 factorial): CLOPIDOGREL: Double-dose (600 mg then150 mg/d x 7d then 75 mg/d) vs Standard dose (300 mg then 75 mg/d) ASA: High Dose (300-325 mg/d) vs Low dose (75-100 mg/d) Efficacy Outcomes: CV Death, MI or stroke at day 30 Stent Thrombosis at day 30 Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TIMI Major) Key Subgroup: PCI v No PCI Clop in 1st 7d (median) 7d 7 d 2 d 7d Complete Followup 99.8% Compliance:
  7. 7. Days CumulativeHazard 0.00.010.020.030.04 0 3 6 9 12 15 18 21 24 27 30 Clopidogrel: Double vs Standard Dose Primary Outcome: PCI Patients Clopidogrel Standard Clopidogrel Double HR 0.85 95% CI 0.74-0.99 P=0.036 15% RRR CV Death, MI or Stroke
  8. 8. Days CumulativeHazard 0.00.0040.0080.012 0 3 6 9 12 15 18 21 24 27 30 Clopidogrel Standard Dose Clopidogrel Double Dose 42% RRR HR 0.58 95% CI 0.42-0.79 P=0.001 Clopidogrel: Double vs Standard Dose Definite Stent Thrombosis (Angio confirmed)
  9. 9. CLOPIDOGREL vs. PRASUGREL
  10. 10. TRITON: Primary Efficacy Results in Entire ACS Cohort at 15 Months Wiviott SD, et al. N Engl J Med 2007;357:2001-15 0 5 10 15 0 30 60 90 180 270 360 450 HR 0.81 (0.73-0.90) P<0.001 Prasugrel Clopidogrel HR 0.80 P=0.0003 HR 0.77 P=0.0001 Days PrimaryEndpoint%(N) 12.1% (781) 9.9% (643) NNT= 46 ITT= 13,608 LTFU = 14 (0.1%) LTFU = Lost to follow-up ITT = Intention to treat
  11. 11. TRITON: Primary Efficacy and Safety Endpoints in Entire ACS Cohort at 15 Months Wiviott SD, et al. N Engl J Med 2007;357:2001-15 0 5 10 15 0 30 60 90 180 270 360 450 Prasugrel Clopidogrel Days Endpoint(%) 12.1 9.9 Prasugrel Clopidogrel 1.8 2.4 CV Death / MI / Stroke TIMI Major NonCABG Bleeds HR 0.81 (0.73-0.90) P<0.001 138 events NNT = 46 HR 1.32 (1.03-1.68) P=0.03 35 events NNH = 167
  12. 12. %Events TIMI Major Bleeds ARR 0.6% HR 1.32 P=0.03 Clopidogrel Prasugrel Life Threatening ARR 0.5% HR 1.52 P=0.01 Nonfatal ARR 0.2% P=0.23 ICH ARR 0% P=0.74 Fatal ARR 0.3% P=0.002 ICH in Pts w Prior Stroke/TIA (N=518) Clop 0 (0) % Pras 6 (2.3)% (P=0.02) 1.8 0.9 0.9 0.1 0.3 2.4 1.4 1.1 0.4 0.3 0 2 4 TRITON: Prasugrel increase Significant Major & Life Threatening Bleeding Results in Entire ACS Cohort at 15 Months Adapted Wiviott SD, et al. N Engl J Med 2007;357:2001-15 NNH=167 NNH = Number needed to harm ARR = Absolute risk reduction HR = hazard ratio ICH = intracranial hemorrhage
  13. 13. CURRENT PCI N=17,232 TRITON N=13,608 CV Death, MI or Stroke ↓ 15% ↓ 21% (w high dose ASA) ↓ 19% Definite Stent Thrombosis ↓ 42% ↓ 51% (w high dose ASA) ↓ 58% TIMI Major Bleed No increase ↑ 32% CABG-related Bleeding No increase ↑ 4-fold Fatal bleeding No increase ↑ 4-fold Comparison of CURRENT and TRITON
  14. 14. CLOPIDOGREL Vs. TICAGLEROL
  15. 15. Primary efficacy endpoint: Death from vascular causes/MI/stroke Secondary efficacy endpoints: Primary endpoint in patients undergoing PCI; all cause mortality/MI/stroke,vascular death/MI/stroke/severe recurrent ischemia/TIA/arterial thrombotic event; stent thrombosis; all-cause mortality Primary safety endpoint: PLATO-defined major bleeding 12-month maximum exposure (Min = 6 mo, Max = 12 mo, Mean = 11 mo) (N>18,000) ASA* + Clopidogrel 300-mg LD/75 mg qd† Additional 300-mg LD allowed in PCI ASA* + AZD6140 180-mg LD/90 mg bid† Additional 90 mg LD allowed in PCI >24 h after randomization ACS patients (UA/NSTEMI/STEMI, PCI, medically managed, or CABG) *All patients received ASA 75-100 mg qd unless intolerant. ASA = acetylsalicylic acid; LD = loading dose; PLATO = PLATelet inhibition and patient Outcomes trial. James S et al. Am Heart J. 2009;157:599-605. PLATO Study Design Dose of study drug assigned as soon as possible (≤ 24 h) after index event
  16. 16. 4 8 2 6 Primary efficacy endpoint over time (composite of CV death, MI or stroke) *Excludes patients with any primary event during the first 30 days 0 Clopidogrel Cumulativeincidence(%) Ticagrelor HR 0.88 (95% CI 0.77–1.00), p=0.045 0 10 20 30 Days after randomisation 5,43 4.77 No. at risk Ticagrelor 9,333 8,942 8,827 8,763 Clopidogrel 9,291 8,875 8,763 8,688 8 0 Clopidogrel 2 4 6 Cumulativeincidence(%) Ticagrelor 0 90 150 330 Days after randomisation 8,673 8,543 8,397 7,028 6,480 4,822 8,688 8,437 8,286 6,945 6,379 4,751 210 270 6.60 5.28 HR 0.80 (95% CI 0.70–0.91), p<0.001 Wallentin L et al. New Engl J Med.2009;361:DOI:10.1056/NEJMoa0904327. http://www.clinicaltrialresults.org/
  17. 17. PLATO : No Significant different in Sub Analysis for UA
  18. 18. US PLATO: Clopidogrel Better than Ticagrelor
  19. 19. Ticaglerol Better Vs. Clopi Ticaglerol Non Significant and Clopi better
  20. 20. PLATO : Ticaglerol significantly increase Non- CABG Bleeding 7 0 K-Mestimatedrate(%peryear) 9 8 6 5 4 3 2 1 Non-CABG PLATO major bleeding 4.5 3.8 P=0.03 HR 1.19 (1.02- 1.38) 2.8 2.2 P=0.03 HR 1.25 (1.03- 1.53) 7.4 7.9 NS 5.3 5.8 NS Ticagrelor Clopidogrel Non-CABG TIMI major bleeding CABG PLATO major bleeding CABG TIMI major bleeding Wallentin L et al. N Engl J Med. 2009 Sep 10;361(11):1045-57. NNH = 143
  21. 21. PLATO : Ticaglerol Increase Intracranial bleeding & Fatal ICH P=0.06 HR 1.87 P=0.02 HR=5.47 K-Mestimatedrate(%peryear) ICH 0.35 0.3 0.25 0.2 0.15 0.1 0.05 0 Fatal ICH 0.28 0.15 0.12 0.01 Ticagrelor Clopidogrel Ticagrelor (N=9235) 26 11 Clopidogrel (N=9186) 14 1 Wallentin L et al. N Engl J Med. 2009 Sep 10;361(11):1045-57. FDA website CardiovascularandRenalDrugsAdvisoryCommittee/ucm192863.htm. Accessed on August 23rd, 2010.
  22. 22. Bleeding is a serious event Moscucci et al, Eur Heart J 2003 * * p<0.01 Bleeding associated with higher mortality after ACS
  23. 23. Ndrepepa et al, J Am Coll Cardiol 2008 5384 patients from 4 RCT’s, PCI studies, Stable CAD and ACS Bleeding is a serious event Same impact on long term mortality than new MI
  24. 24. Verheugt et al, JACC Cardiovasc Interv 2011 Recurrent events and Mortality 17393 PCI patients from 3 RCT’s (REPLACE 2, ACUITY and HORIZON) Bleeding is a serious event Greater impact on prognosis of non access site bleedings
  25. 25. All Access-site bleeding impact mortality ? Access-site bleeding impact mortality only if associated with Ht decrease Romaguera et al, Am J Cardiol 2012 7718 PCI patients, single center registry, femoral access
  26. 26. Two Types of Bleedings In Hospital Bleedings (Procedure/Antithrombotic therapy) Post Discharge Bleedings (Oral Antiplatelet Therapy)
  27. 27. After Discharge Low dose aspirin Individualized P2Y12 inhibitors Use of PPI Monitoring ? In Hospital - Radial Access +++ - Careful use of anticoagulant - Shorten Duration of Therapy - Selective use of GPIIbIIIa How to prevent bleedings in ACS/PCI patients ?
  28. 28. 0 108 Placebo APTC CURE Antiplatelet Therapy in ACS Single Antiplatelet Rx Dual Antiplatelet Rx Higher IPA ASA ASA + Clopidogrel ASA + New P2Y12 blockers - 22% - 20% - 19% + 60% + 38% + 32% Reduction in Ischemic Events Increase in Major Bleeds Placebo
  29. 29. 0 30 60 90 180 270 360 450 days 5 10 Endpoint(%) 0 9.8 11.7 Ticagrelor 90mg x2 HR 0.84 (0.77–0.92) p=0.0003* 12.1 9.9 Prasugrel 10mg Clopidogrel 75mg HR 0.81 (0.73-0.90) p=0.0004* TRITON and PLATO Primary endpoint = CV Death / MI / Stroke 12-15 months Wiviott et al, NEJM 2007, Wallentin et al, NEJM 2010
  30. 30. p=0.03* p=0.025* 7 6 5 4 3 2 1 0 2.8 2.2 Safety = Non-CABG related TIMI major bleedings 1.8 2.4 p=0.001* 2.7 3.7 450 days ASAonly 360 days360 days +38% +32% +27% Ticagrelor Clopidogrel 75 Prasugrel TRITON PLATOCURE Same Platelet InhibiƟon → Same Bleeding Risk NNH=167 NNH=167 Wiviott et al, NEJM 2007, Wallentin et al, NEJM 2010
  31. 31. High risk STEMI Diabetes mellitus, CKD High-risk NSTE ACS (Tn + and/or ST changes) Recurrent event on clopidogrel Stent Thrombosis Low risk No ST changes No Troponin elevation (Patients not in Triton / Plato) High risk: Prior stroke/TIA* Age > 75 y.o Weight < 60 kg Chronic OAC, Prior Bleeding Low risk No prior stroke/TIA/Bleeding Age < 75 y.o Weight > 60 kg No Chronic OAC Ischemic Risk Bleeding Risk P2Y12 Blockers Individual Decision Clopidogrel Clopidogrel ACS patients * CI Prasugrel Prevention of Post discharge Bleedings
  32. 32. STEMI: Oral antiplatelets What, when and how? WHAT? WHEN? HOW? Aspirin Clopidogrel / Prasugrel* / Ticagrelor* Aspirin Clopidogrel ASAP Aspirin: started at a dose of 150–300mg per os or 250– 500mg bolus iv followed by 75-100mg daily Prasugrel: 60mg LD followed by 10mg daily, or Ticagrelor: 180mg LD followed by 90mg twice daily, or Clopidogrel: 600mg LD followed by 75mg daily Aspirin: oral dose of 150-325mg or i.v. dose of 250mg if oral ingestion is not possible. Clopidogrel: loading dose of 300mg if age ≤75 years; 75mg if age >75 years 1. Wijns W et al Eur Heart J 2010;31:2501-55 2. Van de Werf F et al Eur Heart J 2008;29:2909-45 Primary PCI1 Thrombolysis2
  33. 33. Invasive 1,2 Conservative 2 WHAT? WHEN? HOW? Aspirin Ticagrelor* / Clopidogrel‡ Aspirin Ticagrelor* / Clopidogrel‡ Loading dose ASAP Aspirin: started at a dose of 150–300 mg and at a maintenance dose of 75–100 mg, plus Ticagrelor: 180 mg LD, 90 mg twice daily, or Clopidogrel: 300 or 600 mg LD, 75 mg daily Upstream GPIIbIIIa are not recommended in patients with high ischaemic risk Aspirin: started at 150–300 mg and at a maintenance dose of 75–100 mg, plus Ticagrelor 180 mg LD, 90 mg twice daily, or Clopidogrel: an immediate 300 mg LD, 75 mg daily dose 1. Wijns W et al Eur Heart J 2010;31:2501-55 2. Hamm CW et al ESC NSTE-ACS Guidelines EHJ 2011; doi:10.1093/eurheartj/ehr236 3. Anderson JL et al Circulation 2007;116:148-304 ‡All patient received clopidogrel LD before PCI in CURRENT * Ticagrelor has limited experience for prePCI loading Patients with low-likelihood of ACS, and lowest-risk ACS were excluded from clinical trials => Recommendations apply to NSTEMI for which the diagnosis is likely or definite 3 and should be adapted to patient risk level for thrombosis and bleeding 2,3 NSTE-ACS : Antiplatelets What, when and how?
  34. 34. New ESC and ACC Guidelines
  35. 35. ESC Guidelines
  36. 36. ACC AHA - PCI - Loading dose for all P2Y12 inhibitors is recommended (Class I-A) - 600 mg loading recommended for clopidogrel - Limitations imposed on prasugrel - Issue of compliance posed against ticagrelor
  37. 37. Plavix 300 mg = Improve Compliance Loading Dose 4 tabs 75 mg = 1 tab Plavix 300 mg Loading Dose 8 tabs 75 mg = 2 tabs Plavix 300 mg
  38. 38. Summary Clopidogrel Prasugrel Ticagrelor Major study CURE TRITON-TIMI 38 PLATO Population NSTEACS ACS - PCI ACS Loading dose 300 mg 60 mg 180 mg Maintenance dose 75 mg 10 mg 90 mg Maintenance schedule Daily Daily Twice daily Treatment arms Clopidogrel vs placebo Prasugrel vs clopidogrel Ticagrelor vs clopidogrel Duration of follow-up 9 months 14.5 months 9 months CV death, MI, stroke 9.3 vs 11.4% RR 0.80, p < 0.001 9.9 vs 12.1% HR 0.81, p < 0.001 9.8 vs 11.7% HR 0.84, p < 0.001 TIMI non-CABG major bleeding 1.1 vs 1.2%* RR 0.94, p = 0.7 2.4 vs 1.8% HR 1.32, p = 0.03 2.8 vs 2.2% HR 1.25, p = 0.03 Major bleeding per study definition 3.7 vs 2.7% RR 1.38, p = 0.001 2.4 vs 1.8% HR 1.32, p = 0.03 11.6 vs 11.2% HR 1.04, p = 0.43 Yusuf S et al. N Engl J Med. 2001;345:494-502. Wiviott SD et al. N Engl J Med 2007;357:2001-15 Wallentin L et al. N Engl J Med. 2009;361(11):1045-57. *TIMI major bleeding

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