Role of More Potent Antiplatelet in ACS Management

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Dr. Jajang Sinardja, SpJP, FIHA. 3rd Pekanbaru Cardiology Update, August 24th 2013.
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Role of More Potent Antiplatelet in ACS Management

  1. 1. Jajang Sinardja
  2. 2. The Standard Dual Antiplatelet Therapy for ACS Clopidogrel : loading dose 300 mg, followed by 75 mg daily ASA: 160 mg non-enteric chewed tablet, followed by 80 mg daily
  3. 3. Trial & population Comparison Primary Endpoint Bleeding CURE (2001) NSTE-ACS patients n = 12,562 Clopidogrel 75 mg (300 mg loading) vs. placebo CV death, MI, CVA Clopidogrel 9.3% Placebo 11.4% (P < 0.001) ARR 2.1%; RRR 20%; NNT 48 Major bleeding* Clopidogrel 3.7% Placebo 2.7% (P = 0.001) NNH: 100 PCI Cure (2001) NSTE-ACS undergoing PCI n = 2,658 Like CURE (after PCI clopidogrel in both groups for 1 month) CV death, MI, or urgent TVR in 30 days Clopidogrel 4.5% Placebo 6.4% ARR 1.9%; RRR 30%; NNT 53 Major bleeding* Clopidogrel 2.7% Placebo 2.5% (P = 0.69 CURRENT OASIS 7 (2010) NSTE-ACS - 63% STEMI - 37% n = 25,086 Clopidogrel double dose (600 mg loading, 150 mg day 2–7, then 75 mg) vs. standard dose 75 mg (150 mg loading) CV death, MI, CVA (at 30 days) Double 4.2% Standard 4.4% (P = 0.30) Major bleeding Double 2.5% Standard 2.0% (P = 0.01) NNH: 200 Clopidogrel Trials Hamm CW et al. Eur Heart J 2011;32:2999 – 3054 * CURE Definition
  4. 4. Potential Limitations of Clopidogrel Moderate overall levels of platelet inhibition Average IPA ~50% High variability response within a population 4-34% with very low levels of platelet inhibition Slow onset of antiplatelet effect Requiring 300 – 600 mg loading doses in acute phase Gurbel et al. Circulation 2009;120:2577-2585 O’ Donoghue M. Wiviott SD . Circulation 2006;114:e600-e606
  5. 5. Inhibition of ADP-Induced Platelet Function Following 600mg Clopidogrel in 1,001 patients Hochholzer W. Circulation 2005;111: 2560-2564 Variability in Clopidogrel Responsiveness
  6. 6. Angiolillo DJ & Ueno M. JACC: Cardiology Interventions 2011;4 (4):411–414
  7. 7. Trial & population Comparison Primary Endpoint Bleeding TRITON (2007) Undergoing PCI NSTE-ACS 74% STEMI 26% n = 13 608 Prasugrel 10 mg (60 mg loading) vs. clopidogrel 75 mg (300 loading) CV death, MI, CVA Prasugrel 9.9% Clopidogrel 12.1% (P < 0.001) ARR 2.2%; RRR 27%; NNT 45 Non–CABG-related major bleeding:# Prasugrel 2.4% Clopidogrel 1.8% (P = 0.03) NNH: 167 CABG-related major bleeding Prasugrel 13.4% Clopidogrel 3.2% (P < 0.001) NNH: 10 (CABG Prasugrel Trial Hamm CW et al. Eur Heart J 2011;32:2999 – 3054 * TIMI Criteria
  8. 8. Ticagrelor is a cyclo-pentyl- triazolo-pyrimidine (CPTP) OH OH O OH N F S N H N N N N F • Direct-acting – Not a pro drug: does not require metabolic activation – Rapid onset of inhibitory effect on the P2Y12 receptor than clopidogrel • Reversibly bound – Faster offset than clopidogrel – Functional recovery of circulating platelets within ~ 48 hours Ticagrelor Deeks ED. Drugs 2011;71(7):909-933 Husted S. Van Giezen JJJ. Cardiovascular Therapeutics 2009;27:259-274
  9. 9. Adapted from Schomig A. N Engl J Med. 2009;361:1108–1111. Ticagrelor: Does NOT require metabolic activation to become active drug Clopidogrel: A prodrug; requires metabolism to become active drug CYP-dependent oxidation CYP1A2 CYP2B6 CYP2C19 CYP-dependent oxidation CYP2C19 CYP3A4/5 CYP2B6 Active compound Intermediate metabolite Prodrug Ticagrelor Clopidogrel Binding P2Y12 Ticagrelor: Does Not Require Hepatic Metabolism for Activation Platelet
  10. 10. Ticagrelor P2Y12 receptor binding ADP, adenosine diphosphate Adapted from Husted S. Van Giezen JJJ. Cardiovascular Therapeutics 2009;27:259-274 ADP P2Y12 receptor ADP binds and activates the receptor Conformational change and signalling Ticagrelor binds away from ADP pocket ADP can bind reversibly but no conformational change or signalling Receptor remains intact upon dissociation
  11. 11. ONSET/OFFSET: Pharmacodynamics in Stable CAD Patients Onset 100 90 80 70 60 50 40 30 20 10 0 IPA% // Ticagrelor (n=54) Clopidogrel (n=50) 0 0.5 1 2 4 8 24 6 weeks 0 2 4 8 24 48 72 120 168 240 Maintenance Offset Time (Hours) Loading Dose 180 mg 600 mg * * * * * ‡ † ** † Last Maintenance Dose 90 mg bid 75 mg qd // * * // * P<0.0001 † P<0.005 ‡ P<0.05 Time (Hours) Gurbel PA et al. Circulation 2009;120:2577-2585
  12. 12. PLATO Study PLATO Study2: • 43 countries • 862 sites • 18,624 patients 43 countries862 sites PLATO study tested the hypothesis that… ticagrelor will result in a lower risk of recurrent thrombotic events in a broad patient population with ACS as compared to clopidogrel and this would be achieved with a clinically acceptable bleeding rate and overall safety profile1 18,624 patients 1. James S et al. Am Heart J 2009;157: 599 – 605 2. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
  13. 13. PLATO: Study Population ACS Patient STEMI Primary PCI No Reperf Fibrinolytic Rx UA/NSTEMI Initial Invasive Management PCI No revascularisation CABG Initial Non-Invasive Management PCI CABG No revascularisation Only STEMI patients intended for primary PCI included Adapted from James S, et al. Am Heart J. 2009;157:599–605.
  14. 14. 180-mg loading dose Ticagrelor (n=9,333) *STEMI patients scheduled for primary PCI were randomised; however, they may not have received PCI. †A loading dose of 300-mg clopidogrel was permitted in patients not previously treated with clopidogrel, with an additional 300 mg allowed at the discretion of the investigator. ‡The PLATO study expanded the definition of major bleeding to be more inclusive compared with previous studies in ACS patients. The primary safety endpoint was the first occurrence of any major bleeding event. 90 mg bid + ASA maintenance dose 300-mg loading dose† 75 mg qd + ASA maintenance dose Clopidogrel (n=9,291) Primary efficacy endpoint: Composite of CV death, MI (excluding silent MI), or stroke Primary safety endpoint: Total PLATO major bleeding‡ N=18,624 Patients with ACS (UA, NSTEMI, or STEMI*) <24h Month 1 Month 3 Month 6 Month 9 Month 12Screening Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Initial Treatment approaches • Medically managed (n=5,216 — 28.0%) • Invasively managed (n=13,408 — 72.0%) Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. James S, et al. Am Heart J. 2009;157:599–605. Randomisation • All patients were hospitalised with symptom onset <24 hours • Patients could be taking clopidogrel at time of randomisation PLATO: Study Design
  15. 15. PLATO Main: Inclusion Criteria • Hospitalisation for STEMI or NSTEMI/UA ACS, with onset during previous 24 hours • With STEMI, the following 2 inclusion criteria were required – Persistent ST elevation of at least 0.1 mV in ≥2 contiguous leads or new LBBB – Primary PCI planned James S, et al. Am Heart J. 2009;157:599–605.
  16. 16. PLATO Main: Inclusion Criteria • With NSTEMI, at least 2 of the following 3 were required – ST changes on ECG indicating ischaemia – Positive biomarker indicating myocardial necrosis – One of the following risk indicators • ≥60 years of age • Previous MI or CABG • CAD with ≥50% stenosis in ≥2 vessels • Previous ischaemic stroke, TIA, carotid stenosis (≥50%), or cerebral revascularisation • Diabetes mellitus • Peripheral artery disease • Chronic renal dysfunction (creatinine clearance <60 mL/min) James S, et al. Am Heart J. 2009;157:599–605.
  17. 17. PLATO Main: Key Exclusion Criteria • Contraindication to clopidogrel • Fibrinolytic therapy within 24 hours • Oral anticoagulation therapy that cannot be stopped • ACS event was a complication of previous PCI • PCI after index event (initial clinical signs and symptoms) and before first study dose • Increased risk for bradycardic events • Concomitant therapy with strong CYP3A inhibitors/inducers • Patients requiring dialysis James S, et al. Am Heart J. 2009;157:599–605.
  18. 18. Efficacy Results
  19. 19. PLATO: Baseline Characteristics Characteristic Ticagrelor (n=9,333) Clopidogrel (n=9,291) Median age, years 62.0 62.0 Age ≥75 years, n (%) 1,396 (15.0) 1,482 (16.0) Women, n (%) 2,655 (28.4) 2,633 (28.3) CV risk factors, n (%) Habitual smoker 3,360 (36.0) 3,318 (35.7) Hypertension 6,139 (65.8) 6,044 (65.1) Dyslipidemia 4,347 (46.6) 4,342 (46.7) Diabetes mellitus 2,326 (24.9) 2,336 (25.1) History, n (%) MI 1,900 (20.4) 1,924 (20.7) PCI 1,272 (13.6) 1,220 (13.1) CABG 532 (5.7) 574 (6.2) ECG at study entry, n (%) ST-segment elevation, persistent 3,497 (37.5) 3,511 (37.8) ST-depression 4,730 (50.7) 4,756 (51.2) T-wave inversion 2,970 (31.8) 2,975 (32.0) Troponin-I positive, n (%) 7,965 (85.3) 7,999 (86.0) Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
  20. 20. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. Both groups included aspirin. *NNT at one year. PLATO: Primary Efficacy Endpoint (Composite of CV Death, MI, or Stroke) No. at risk Clopidogrel Ticagrelor 9,291 9,333 Months After Randomization 8,521 8,628 8,362 8,460 8,124 6,650 6,743 5,096 5,161 4,047 4,1478,219 0 2 4 6 8 10 12 12 11 10 9 8 7 6 5 4 3 2 1 0 13CumulativeIncidence(%) 11.7 Clopidogrel 9.8 Ticagrelor ARR=0.6% RRR=12% P=0.045 HR: 0.88 (95% CI, 0.77−1.00) 0–30 Days 4.8 5.4 Clopidogrel Ticagrelor ARR=1.9% RRR=16% NNT=54* P<0.001 HR: 0.84 (95% CI, 0.77–0.92) 0–12 Months
  21. 21. PLATO: Predefined Testing of Primary and Major Secondary Efficacy Endpoints Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. All Patients* Ticagrelor (n=9,333) Clopidogrel (n=9,291) HR for Ticagrelor (95% CI) P Value** Primary endpoint, n (%/year) Death from vascular cause + MI† + stroke 864 (9.8) 1,014 (11.7) 0.84 (0.77–0.92) <0.001 Secondary endpoints, n (%/yr) Death from any cause + MI† + stroke 901 (10.2) 1,065 (12.3) 0.84 (0.77–0.92) <0.001 Death from vascular causes + MI† + stroke + severe recurrent ischemia + recurrent ischemia + TIA + arterial thrombus 1,290 (14.6) 1,456 (16.7) 0.88 (0.81–0.95) <0.001 MI† 504 (5.8) 593 (6.9) 0.84 (0.75–0.95) 0.005 Death from vascular causes 353 (4.0) 442 (5.1) 0.79 (0.69–0.91) 0.001 Stroke 125 (1.5) 106 (1.3) 1.17 (0.91–1.52) 0.22 Death from any cause 399 (4.5) 506 (5.9) 0.78 (0.69–0.89) <0.001‡ Nominal Significance Both groups included aspirin. The percentages presented are Kaplan-Meier estimates of the rate of the endpoint at 12 months. * Patients could have had more than one type of endpoint. Death from CV causes and fatal bleeding, as only traumatic fatal bleeds were excluded from the CV death category. ** By Cox regression analysis using treatment as factor; †Excluding silent MI; ‡Death from any cause was tested after stroke, which was non-significant, so the results should be considered nominally significant.
  22. 22. Months After Randomisation 0 2 4 6 8 10 12 6 5 4 3 2 1 0 7 CumulativeIncidence(%) Clopidogrel Ticagrelor 5.8 6.9 0 2 4 6 8 10 12 6 4 3 2 1 0 Clopidogrel Ticagrelor 4.0 5.1 7 5 Months After Randomisation Myocardial Infarction Cardiovascular Death CumulativeIncidence(%) PLATO: Secondary Efficacy Endpoints Rate of stroke for Ticagrelor was not different from clopidogrel (1.3% vs 1.1% ), P=0.225. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. Supplement. ARR=1.1% RRR=16% Calculated NNT=91 P=0.005 HR: 0.84 (95% CI, 0.75–0.95) ARR=1.1% RRR=21% NNT=91 P=0.001 HR: 0.79 (95% CI, 0.69–0.91) Both groups included aspirin.
  23. 23. PLATO Primary Endpoint: Initial Invasive vs Initial Non-Invasive Management James S, et al. ESC. 2010; Poster #1353. Cannon CP, et al. Lancet. 2010;375:283–293.
  24. 24. Stent Thrombosis ticagrelor vs clopidogrel 0,6% ARR 33% RRR P = 0.009 Ticagrelor n= 5640 Clopidogrel n = 5649 Wallentin L, et al. N Engl J Med 2009;361:1045-57 * Definition by Academic Research Consortium criteria
  25. 25. PLATO Efficacy Results Summary Ticagrelor significantly reduced the composite of CV death, MI or stroke vs clopidogrel at 1 year (1.9% ARR, 16% RRR, P<0.001, NNT=54) Ticagrelor significantly reduced CV mortality vs clopidogrel (1.1% ARR, 21% RRR, P=0.001) Risk of CV death and MI were both significantly reduced Risk of stroke was not significantly different Wallentin L, et al. N Engl J Med. 2009;361:1045-1057.
  26. 26. PLATO Efficacy Results Summary The absolute risk reduction with ticagrelor vs clopidogrel starts early and continues to build over the full 1 year treatment period For every 91 ACS patients treated with ticagrelor for 1 year, instead of clopidogrel, 1 CV death was prevented (NNT=91) The effect of ticagrelor over clopidogrel appears consistent across many subgroups Wallentin L, et al. N Engl J Med. 2009;361:1045-1057.
  27. 27. Safety Results
  28. 28. P=0.43 HR: 1.04 (95% CI, 0.95–1.13) PLATO: Primary Safety Endpoint PLATO-definedTotal MajorBleeding(%) Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. Days From First Dose 10 5 0 15 0 60 120 180 240 300 360 Clopidogrel Ticagrelor 11.2% 11.6% P=NS No. at risk Clopidogrel Ticagrelor 9,186 9,235 7,305 7,246 6,930 6,826 6,670 5,209 5,129 3,841 3,783 3,479 3,4336,545 Both groups included aspirin.
  29. 29. PLATO: Safety Endpoints - bleeding *Both groups included aspirin; **Proportion of patients (%) Wallentin L, et al. N Engl J Med. 2009;361:1045-1057.
  30. 30. PLATO: Bleeding 11.6 5.8 0.3 16.1 4.5 7.4 11.2 5.8 0.3 14.6 3.8 7.9 0 2 4 6 8 10 12 14 16 18 BRILINTA(n=9,235) Clopidogrel(n=9,186) Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. All values presented by PLATO criteria. Both groups included aspirin. Major Bleeding Non-CABG- Major Bleeding Major and Minor Bleeding Life-threatening/ Fatal Bleeding Fatal Bleeding CABG-Major Bleeding K-MEstimatedRate(%PerYear) NS P = 0.03 P = 0.008 NS NS NS
  31. 31. PLATO: Dyspnoea • Ticagrelor-associated dyspnoea was mostly mild to moderate in severity and did not reduce efficacy • Most events were reported as single episode occurring early after starting treatment • Not associated with new or worsening heart or lung disease BRILINTA. Indonesia Prescribing Information 2012. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. Storey R, et al. Eur Heart J 2011;32:2945-2953 Dyspnoea in the PLATO trial Ticagrelor Clopidogrel P Value Incidence of dyspnoea adverse events (%) 13.8 7.8 <0.001 Patients who discontinued treatment due to dyspnoea (%) 0.9 0.1 <0.001
  32. 32. PLATO: Bradycardia-related Events All Patients Ticagrelor (n=9,235) Clopidogrel (n=9,186) P Value Bradycardia-related event, n (%) Pacemaker insertion 82 (0.9) 79 (0.9) 0.87 Syncope 100 (1.1) 76 (0.8) 0.08 Bradycardia 409 (4.4) 372 (4.0) 0.21 Heart Block 67 (0.7) 66 (0.7) 1.00 • Ventricular pauses ≥3 seconds occurred in 5.8% of Ticagrelor-treated patients vs 3.6% of clopidogrel-treated patients in the acute phase, and 2.1% and 1.7% after 1 month, respectively • There were no differences in adverse clinical consequences (ie, pacemaker insertion, syncope, bradycardia, and heart block) 1. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.2. Scirica BM et al. J Am Coll Cardiol 2011;57:1908-1916 3. BRILINTA Indonesia Prescribing Information 2012.
  33. 33. PLATO: Laboratory Parameters All Patients Ticagrelor (n=9,235) Clopidogrel (n=9,186) P Value Mean % increase (± SD) in serum creatinine from baseline At 1 month 10 ± 22 8 ± 21 <0.001 At 12 months 11 ± 22 9 ± 22 <0.001 1 month after end of treatment 10 ± 22 10 ± 22 0.59 Mean % increase (± SD) in serum uric acid from baseline At 1 month 14 ± 46 7 ± 44 <0.001 At 12 months 15 ± 52 7 ± 31 <0.001 1 month after end of treatment 7 ± 43 8 ± 48 0.56 Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.
  34. 34. CI, confidence interval; CrCl, creatinine clearance; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction. James S, et al. Circulation 2010;122:1056–1067. Renal function and outcomes in PLATO: Primary composite endpoint by CrCl Ticagrelor better Clopidogrel better Risk of CV death, stroke or MI HR (95% CI) 30 40 50 60 70 80 90 100 CrCl (mL/min) 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.20.4 Increasingrenalimpairment
  35. 35. PLATO Safety Results Summary No increase in overall major bleeding with Ticagrelor vs clopidogrel Non-CABG major bleeding and major + minor bleeding were more frequent withTicagrelor vs clopidogrel No increase in overall fatal/life-threatening bleeding withTicagrelor vs clopidogrel Wallentin L, et al. N Engl J Med. 2009;361:1045-1057.
  36. 36. PLATO Safety Results Summary There are more dyspnoea-related events associated withTicagrelor vs clopidogrel, however most events were mild to moderate in intensity and often resolved without a need for treatment Wallentin L, et al. N Engl J Med. 2009;361:1045-1057.
  37. 37. Implicating New Guidelines into ACS Management
  38. 38. ESC Guidelines for the management of ACS in patients presenting without persistent ST-segment elevation Hamm CW et al. Eur Heart J 2011;32:2999 – 3054
  39. 39. LevelClass Steg PG, et al. European Heart Journal. 2012;33:2569-2619 Oral antiplatelet in ESC 2012 STEMI Guideline
  40. 40. ACCF/AHA 2013 STEMI Guideline Anderson JL, et al.Circulation. 2007;116:e148-e304.
  41. 41. Summary Ticagrelor is an active drug with reversible binding to P2Y12 receptor Ticagrelor provide fast onset and fast offset Ticagrelor significantly reduces the combined risk of CV death, MI, or stroke as compared to clopidogrel in patients with ACS
  42. 42. Summary Ticagrelor is effective in a broad spectrum of ACS patients There is no increase of overall major bleeding withTicagrelor as compared to clopidogrel Ticagrelor has been recommended in ACS guidelines both in initial management , before PCI procedure and at discharge

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