COME ORIENTARSI TRA I NUOVI. Maria Rosa Conte H. Mauriziano Torino

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1 COME ORIENTARSI TRA I NUOVI ANTIPIASTRINIC I Maria Rosa Conte H. Mauriziano Torino Sulle sponde del Ticino- Novara 10 maggio 2013

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3 NEW ORAL ANTIPLATET AGENT PRASUGREL TICAGRELOR (Cangrelor)

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5 Death/ MI/ IDR/ Stent Thrombosis within 48 Hours Event Rate (%) clopidogrel cangrelor Log Rank P Value = Bhatt DL, Stone GW, Mahaffey KW, et al. Harrington RA. NEJM 2013 at

6 Demographics, MITT

7 NSTEMI

8 Recommendations for oral antiplatelet agents 2011 ESC Guidelines on NSTEMI ACS Management European Heart Journal doi: /eurheartj/ehr236

9 2011 ESC Guidelines on NSTEMI ACS Management d Prasugrel is in the Guidelines on Revascularization 148 given a IIa recommendation as the overall indication including clopidogrel-pre-treated patients and/or unknown coronary anatomy. The class I recommendation here refers to the specifically defined subgroup.

10 STEMI

11 PRASUGREL Montalescot, Lancet 09

12 TRITON-TIMI TIMI 38: STEMI Cohort Primary Efficacy Endpoint at 15 Months (CV Death, NF MI, NF Stroke) ts (%) ,4 * 11, ,2 14,1 * 9,6 Clopidogrel Prasugrel Patient 5 the test for heterogeneity showed the effect was not significant *p < All STEMI Primary PCI Secondary PCI CV = cardiovascular; NF = non-fatal; MI = myocardial infarction; PCI = percutaneous coronary intervention; STEMI = ST-segment elevation myocardial infarction Montalescot G et al. Lancet 2009;373(9665):

13 PLATO STEMI P=0.07 P=0.07 P=0.03 P=0.02 ISO 9001 Steg PG, et al. Circulation 2010;122:

14 Deaths by PCI within or more than 10h

15 Comparison between the trials Timing of drug efficacy Mortality Safetyy Bleeding Subgroups Stent Thrombosis Conservative approach

16 A cmparison between TRITON and PLATO TRITON TIMI 38 PLATO Mean age TnI + > 70% > 70% PCI (%) DM (%) Clopidogrel administration before randomization Nobody 46% CABG precoce 1% 4.7%

17 Comparison of the Pivotal Trials

18 Timing of Drug Efficacy TRITON Study PLATO Study 3days All pts clopidogrel-naive 46% pts pre-treated with clopidogrel Wiovitt SD, et al. N Engl J Med. 2007;357:2001 Wallentin L, et al. N Engl J Med 2009;361:1045

19 KM curves for the adjudicated primary composite endpoint of CV death, nonfatal MI, or nonfatal stroke over time in the STEMI populations in PLATO and TRITON trials PLATO TRITON The main effects of ticagrelor may not relate to the rapidity or the completeness of acute Steg PG et al - Circulation. 2010;122: FDA Cardio-Renal Advisory Committee Meeting reperfusion, but rather the prevention of recurrent vascular events by more powerful platelet July 28, 2010 inhibition or other mechanisms

20 The FABOLUS PRO Trial Valgimigli M et al. J Am Coll Cardiol Intv 2012;5:268 77

21 MORTALITY PLATO: Secondary Efficacy Endpoints Over Time Wallentin L et al. N Engl J Med 2009

22 Potential ti explanations for the reduced CV mortality observed in PLATO Potent antithrombotic effect without increased bleeding- risk Characteristics of study population

23 CHARACTERISTICS OF THE PLATO POPULATION All Pts (n=18624) (ref 1) Pts with planned Invasive strategy (n= 13408) (ref 8 ) Conservatively treated pts (n=5216) Significance* Age >75 yrs (%) 2878 (15.5) 1770 (13.2) 1108 (21.2) P<.0001 Women (%) 5288 (28.4) 3382 (25.2) 1906 (36.5) P<.0001 Prior MI (%) 3824 (20.5) 2279 (17) 1545 (29.6) P<.0001 Diabetes (%) 4662 (25) 3109 (23.2) 1553 (29.8) P<.0001 Prior non-hemorragic 722 (3.9) 427 (3.2) 295 (5.6) P<.0001 stroke (%) NSTEMI (%) 7955 (42.7) 5045 (37.6) 2910 (55.8) P<.0001 STEMI (%) 7026 (37.8) 6575 (49) 451 (8.6) P<.0001

24 CONSERVATIVE TREATMENT IN PLATO (N=5216) N= 3176 (60%) PCI N= 1514 (30%) PCI CABG MEDICAL MANAGEMENT Medical theraphy N= 559 (10%) CABG STEMI = 9% NSTEMI = 56% Unst. Ang.= 35%

25 SAFETY- BLEEDING

26 Balance of Efficacy and Safety Wiviott SD et al. N Engl J Med 2007; 2001

27 Balance of Efficacy and Safety in Patients <75 Yrs, 60 kg, and without Prior TIA/Stroke Adapted from Wiviott SD et al NEJM 357: 2001, 2007 Presented at TCT 2009, San Francisco, CA

28 PLATO Ticagrelor vs Clopidogrel: major bleeding K-M estim mated rat te (% per year) Ticagrelor Clopidogrel p= p= NS ICH T (n p.) C (n p.) p Fatal Non fatal Total NS HR IC Non-CABG PLATO major bleeding Non-CABG TIMI major bleeding CABG PLATO major bleeding CABG TIMI major bleeding Wallentin L, NEJM 2009;361:1045

29 Ticagrelor vs Prasugrel: bleedings rate Non-CABG TIMI Bleeding Fatal and Non-Fatal Intracranial Bleeding Modified from Wiviott SD, et al. NEJM 2007;357:2001 and Wallentin L, et al. NEJM 2009;361:1045

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31 SUBGROUPS DIABETES

32 PLATO diabetes: Primary composite endpoint CV death h, MI, or stro oke (%) Diabetes Ticagrelor (n=2326) Clopidogrel (n=2336) HR (95% CI) = 0.88( ) p for interaction = % 14.1% 10.2% 8.4% No diabetes Ticagrelor (n=6999) Clopidogrel (n=6952) HR (95% CI) = 0.83( ) Days after randomisation Primary endpoint benefit with ticagrelor was consistent with the overall PLATO trial results No interaction between diabetes status and treatment was observed (p=0.49) CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction. James S, et al. Eur Heart J 2010;31:

33 Diabetic Subgroup N=3146 PLATO, ticagrelor Wiviott SD et al. Circulation 2008; 118:1626

34 Efficacy in reducing adverse outcomes of new drugs in DM patients Study o % of events Hazard ratio [ 95% confidence interval] Standard New Drug /Approach TRITON-TIMI [ ] PLATO [ ] CURRENT-OASIS [ ] (PCI COHORT) New Drug Approach Standard Clopidogrel Better Better

35 PLATO vs TRITON : DM Hochtl T et al. European J Acute Cardiovasc Care 2012

36 SUBGROUPS RENAL FUNCTION

37 Pts with Chronic Kidney Disease (CKD) Data from clinical trial suggest that 35 to 40% of patients resenting with an ACS have some degree of renal insufficiency Patients with renal insufficiency are known to have a graded increased risk for thrombosis and bleeding Prasugrel: the levels of the active metabolite were not affected by moderate renal impairment, but decreased by 40% in end stage renal disease, although with similar platelet inhibition levels Ticagrelor: a subanalysis sis of the PLATO trial showed CKD pts (3237) have a greater reduction in events (17.3 vs 22%, HR 0,77) and mortality (10 vs 14%, HR 0.72) as compared to non CKD patients (4.7% per year vs 1% py)

38 Ticagrelor Versus Clopidogrel in ACS in Relation to Renal Function James S et al. Circulation 2010;122:

39 Ticagrelor vs Clopidogrel in ACS in Relation to Renal Function James S et al. Circulation 2010;122:1056

40 Old and New Oral P2Y12 Antagonists and CKD

41 STENT THROMBOSIS

42 CEC Adjudicated Stent Thrombosis Definite/Probable Wiviott SD et al. Lancet 2008;371:1

43 PLATO Invasive: Stent Thrombosis in BMS and DES BMS DES % ,8 Ticagrelor 3,1 Clopidogrel ,7 3,5 2,5 2 2,1 2,2 14 1,4 1,5 1,3 1 0,5 0 Definite Definite or probable Definite, probable or possible 4 3,5 3 2,5 2 1,5 1 0, ,8 Definite ,3 2,5 Definite or probable 31 3,1 3,8 Definite, probable or possible Cannon CP, et al. Lancet 2010;375:283

44 Stent Thrombosis in PLATO and TRITON PLATO-Invasive TRITON

45 CONSERVATIVE APPROACH

46 Ticagrelor versus clopidogrel in patients with ACS intended d for non-invasive i management James SK et al. BMJ. 2011;342:d3527

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48 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 clopidogrel given) 4% of total Medical Management Decision 10 days (Clopidogrel started 72 hrs in-hospital OR on chronic clopidogrel) 96% of total Clopidogrel mg LD + 75 mg MD Prasugrel 1 30 mg LD + 5 or 10 mg MD Clopidogrel 1 75 mg MD Prasugrel 1 5 or 10 mg MD Minimum Rx Duration: 6 months; Maximum Rx Duration: 30 months Primary Efficacy Endpoint: CV Death, MI, Stroke 1. 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;160:16-22.e1.

49 Primary Efficacy Endpoint and TIMI Major Bleeding Through 30 Months (Overall population) HR (95% CI): 0.96 (0.86, 1.07) P = 0.45 HR (95% CI): 1.23 (0.84, 1.81) P = 0.29 Roe MT et al. NEJM DOI: /NEJMoa

50 TRILOGY ACS Primary Efficacy Endpoint to 30 Months (Age < 75 years) HR (95% CI) 1 Year: HR (95% CI) > 1 Year: 0.99 (0.84, 1.16) 0.72 (0.54, 0.97) HR (95% CI): 0.91 (0.79, 1.05) P = 0.21 Interaction P = 0.07

51 An indirect comparison between PLATO and TRITON results

52 Riflessioni conclusive Prasugrel attualmente approvato (da Linee Guida) con le limitazioni note: anatomia coronarica nota, età <75aa,pregresso ictus Prasugrel 5 mg >75aa safety OK efficacy? (Trilogy trial) Prasugrel superiorità nei pz diabetici e maggior efficace riduzione della stent thrombosis Ticagrelor non limitazioni Ticagrelor meglio nei pz con IRC Ticagrelor meglio nei pz con strategia conservativa Ticagrelor aumento emorragie intracraniche fatali, diminuzione emorragie CABG correlate

53 There is still room for clopidogrel: Bradycardia or rhythm disturbances in pts not suitable for prasugrel Previous stroke or TIA Pulmonary diseases associated with dyspnea in pts not suitable for prasugrel Current OAT or planned OAT

54 High bleeding risk OAC Fibrinolytici Therapy

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56 IIb/IIIa receptor inhibitors hb

57 2011 ESC Guidelines on NSTEMI ACS Management Recommendations for GP IIb/IIIa receptor inhibitors l European Heart Journal doi: /eurheartj/ehr236

58 Early ACS Trial: Early Routine vs Provisional y Eptifibatide

59 NEW ESC STEMI GUIDELINES 2012 European Heart Journal 2012

60 + No differences in death, recurrent MI, IRA revascularization or stroke

61 Ortolani et al. Eur Heart J 2009; 30: 33-43

62 Early vs Late Gp IIb-IIIa inhibitors EGYPT Abciximab De De Luca et al. Heart 2008; 94: trials 1662pz early arms better St resolution. Mortality NS except for abcximab p=0.026

63 The Efficacy and Safety of Prasugrel With and Without a GPIs in Patients With ACS Undergoing PCI A TRITON TIMI 38 Analysis O Donoghue M et al. J Am Coll Cardiol 2009;54:

64 Mean difference in infarct size size between treatment (Brave 3 Study) groups ) in various subgroups (Brave 3 Study) Mean difference in infarct size size between treatment groups in various subgroups

65 NSTEMI YES Prasugrel/Ticagrelor contraindication NO Clopidogrel Conservative Strategyt Prasugrel /Ticagrelor YES NO Ticagrelor Practice of pretreatment YES NO ISO 9001 Ticagrelor Exceptions: CrCL 60ml/min Prasugrel Excpecially if diabetics,

66 STEMI PPCI YES Prasugrel/Ticagrelor contraindication NO Clopidogrel HIGH ISCHEMIC RISK Prasugrel > Ticagrelor YES NO HIGH BLEEDING RISK HIGH BLEEDING RISK YES NO YES NO ISO 9001 GPI bolus only GPI bolus only NO GPI GPI bolus +/- short Radial access May consider infusion short infusion May omit GPI if bivaluridine or Prasugrel

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68 Two meta-analyses of randomized trials were published that compared small-molecule GP IIb/IIIa antagonists with abciximab in STEMI patients undergoing primary PCI.6,7 In each case, there was no statistically significant difference in 30-day mortality, reinfarction, or major TIMI bleeding, and there was no significant difference in death or reinfarction at 8 months between groups. There was also no statistically significant difference in postprocedural TIMI flow grade 3 or ST-segment resolution. On the basis of these studies, the present writing group judged that the totality of evidence indicates that the various GP IIb/IIIa antagonists demonstrate similar effectiveness in the setting of primary PCI. 6. Gurm H, Tamhane U, Meier P, et al. A comparison of abciximab and small molecule glycoprotein IIb/IIIa inhibitors in patients undergoing primary percutaneous coronary intervention: a meta-analysis of contemporary randomized controlled trials. Circ Cardiovasc Intervent. 2009;2: De Luca G, Ucci G, Cassetti E, et al. Benefits from small molecule administration as compared with abciximab among patients with ST-segment elevation myocardial infarction treated with primary angioplasty: a meta-analysis. J Am Coll Cardiol. 2009;53:

69 Ticagrelor vs Prasugrel: Fatal or life-threatening bleeding Modified from Wiviott SD, et al. NEJM 2007;357:2001 and Wallentin L, et al. NEJM 2009;361:1045