P 2 Y 12 Receptor Inhibitors

Transcription

1 P 2 Y 12 Receptor Inhibitors Clopidogrel, Prasugrel and Ticagrelor Which Drug and for Whom? Cheol Whan Lee, MD Professor of Medicine, University of Ulsan College of Medicine, Heart Institute, Asan Medical Center, Seoul, Korea

2 The Great Journey P2Y Receptor Blockers 12 A Miracle Drug!

3 P2Y Receptor: A Keyy Playery 12 Curr Pharm Des 2006;12:1255 Circulation 2010;121:171

4 The Inventor of Ticlopidine Jean Pierre Maffrand, 1972 (retire 2008) A New Chapter!

5 Clopidogrel monotherapy Cumulative Risk of Stoke, MI or Vascular Death in Patients in the CAPRIE Trial Cum mulative Event Rat te (%) 19,185 patients with atherosclerotic disease Event rate/year Aspirin 5.83% 5.32% Clopidogrel Months of Follow-Up P = Aspirin Clopidogrel 8.7%* Overall Relative Risk Reduction No major safety differences Aspirin Plavix Any bleed 9.28% 9.27% ICH 0.49% 0.35% GI bleed* 2.66% 1.99% *p<0.05 Lancet 1996;348:1329

6 Dual anti-platelet therapy STARS: P2Y12 Receptor Inhibitor N=1 1,965 ASA alone 3.5% vs. Dual 0.5% (ST 86% ) NEJM 1998;339: After coronary stenting, aspirin & ticlopidine should be considered for the prevention of the serious complication of stent thrombosis.

7 Superior Efficacy of ADP Receptor Antagonists in Coronary Stenting Ev vent rates (% death, MI, revasc.) 12 Coumadin + ASA Ticlopidine + ASA Clopidogrel ASA Clopidogrel + ASA Clopidogrel LD + ASA Dual therapy (aspirin & clopidogrel) PCI: BMS (1 month), DES (12 months) ACS: 12 months A P2Y12 1.6inhibitor should be added to aspirin as soon as possible and maintained over 12 months in ACS patients unless contraindication (IA, ESC2011) An alternative to aspirin ISAR FANTASTIC STARS MATTIS CLASSICS N=517 N=485 N=1653 N=350 N=1020

8 Further Drama The Challenge Which one is better?

9 P2Y 12 Antagonists Evolution Form follows function! Revolution N N COOCH 3 F S Cl Ticlopidine S Cl Clopidogrel Copdoge HO O N N N HN N N S F O HO OH CH 3 O O S N Prasugrel F AZD6140 (CPTP: Cyclo-Pentyl- Triazolo-Pyrimidine; orally active)

10 TRITON TIMI 38 ACS (STEMI or UA/NSTEMI) & Planned PCI (99%) ASA N = 13,000 Double-blind PRASUGREL CLOPIDOGREL Median duration of therapy 12 months 1 o endpoint: CV death, MI, Stroke 2 o endpoints: CV death, MI, Stroke, Rehosp Re-isch CV death, MI, UTVR

11 TRITON-TIMI TIMI 38 Prasugrel Lowers Events but Ups Bleeding versus Clopidogrel in ACS 13, 608 ACS patients scheduled for PCI (STEMI 26%) Early Benefits, Late Hazards! Primary Endpoint (%) HR 0.77 P= HR 0.80 P= ITT=13,608 Clopidogrel Prasugrel 12.1 (781) 9.9 (643) HR 0.81 ( ) P= NNT=46 LTFU=14(0.1%) Days Cardiovascular death/mi/stroke HR0.81 ( ), p<0.001 Nonfatal MI HR 0.76 ( ), p<0.001 Stent thrombosis (1.1% vs. 2.4%) HR 0.48 ( ), p<0.001 Fatal bleeding (0.4% vs 0.1%) HR 4.19 ( ), p=0.002 TIMI major/minor bleeding HR 1.31 ( ), p=0.002 Risk groups: age>75 & lean<60kg or history of stroke/tia NEJM 2007;357:2001

12 TRITON: Study Limitations Randomization after coronary angiogram (PCI trials) - clopidogrel naïve: Prasugrel any user within in 5 days ACS excluded - lower NSTE-ACS, loading ACCF/AHA dose Guideline of clopidogrel 2011 (300mg) - timing It is not of enrolment our recommendation (3 days vs 8 hours that in PLATO) prasugrel be administered routinely before angiography, Outcome such as in difference an emergency (<10 days): department, driven by non-fatal or be MI (half used of these in patients was non-clinical who have MI not [ biomarker undergone criterion]) PCI. Circulation2011;123: ACS, ESC Guideline 2011 Prasugrel in, Clopidogrel out for STEMI No difference in all cause mortality: balance between 0.3% absolute reduction in CV death, 0.3% fatal bleeding

13 TRILOGY ACS Medically Managed NSTE-ACS Low-dose ASA N = 10,300 (<75y: ~7800) Randomization within 10 days of index event Stratified by age (75y), BWt (60kg), clopidogrel treatment (300mg LD within 72h of index event & daily MD; or MD 5 days) PRASUGREL CLOPIDOGREL 75mg/day 5 or 10mg/day 75mg/day Duration of therapy : minimum 6m, maximum30m 1 o endpoint: CV death, MI, Stroke

14 PLATO A Study of PLATelet Inhibition & Patient Outcomes ACS (STEMI/NSTEMI) (<24 h after chest pain) ASA N = 18,624 Double-blind IIbIIIa 27% Ticagrelor Clopidogrel Median duration of therapy: 6-12 months 1 o endpoint: CV death, MI, Stroke (15%RRR) 2 o endpoints: Death, CV death, MI, stroke, recurrent ischemia, arterial thrombotic events

15 Major Outcomes A Hard ACT to Follow Cumula ative Inc cidence(% %) 12 CV Death / MI / Stroke Clopidogrel 11.7 HR 0.84 ( ) P= In 1000 ACS patients, replacing9.8 NNT=54 Ticagrelor clopidogrel 8 with ticagrelor for 12 months, 6 14 fewer deaths Clopidogrel CV death 5.1 HR 0.79 (absolute risk reduction 1.4%) ( ) 91) P= fewer MI Ticagrelor NNT=90 2 6~8 fewer cases of stent thrombosis 0no increase in bleeding Definite ST33% p=0.009 Total death 22% 0 60 p< (NNT70) requiring ii transfusion Days After Randomization

16 Major Bleeding Ticagrelor in ACS ESC2011 Ticagrelor in, clopidogrel out

17 Adenosine Hypothesis? - vasodilation - preconditioning --immunomodulation -dyspnea -heart block -renal funtion

18 IC Adenosine for Myocardial Salvage in Patients t With STEMI - Adenosine 4mg -CMRI on day 2-3 -Salvage index= necrotic area/ risk area Eur Heart J 2011;32:867

19 AMI P2Y 12 R SMC CD31 P2Y 12 R SMC CD31 Stable angina

20 Summary Beyond Platelets ADP P2Y12 Receptor Platelets Endothelial Cells VSMCs Acute Coronary Syndrome P2Y12 receptor inhibitors may have a dual anti-ischemic ischemic effect by inhibiting both platelet activation and plaque destabilization.

21 P2Y12 Receptor Inhibitors King of kings Heart 2010;96:656

22 Unanswered Questions STEMI: thrombolytic or medical therapy AMI: 1 year after AMI (PEGASUS) Stable angina: after DES Ischemic stroke Primary prevention

23 Right Balance The Dilemma Bleeding is the key!

24 Trade-off, Dual Therapy Safety: More Potent, More Bleeding! bleedin ng (%) Sign nificant 10% 8% 6% 4% 2% 0% 3.7% P= % 8.8% P= % ASA + Clopidogrel ASA + Placebo P= % 2.6% CURE CREDO CHARISMA N=12,563 1 year FU CURE major bleed NEJM 2001;345: N=2,116 1 year FU TIMI major bleed NEJM 2001;345: N=15, year FU GUSTO major + moderate bleed NEJM 2001;345:

25 Fragile Brain vs. Tough Heart Intracranial Bleeding Patient history of stroke or TIA TRITON-TIMI 38: incidence of stroke in patients with a history of prior TIA or stroke greater with prasugrel + ASA (6.5% total: 4.2% thrombotic, 2.3% ICH) vs clopidogrel l + ASA(1.2% total, t all thrombotic) ti PLATO: Fatal ICH higher in ticagrelor vs clopidogrel (0.1 vs 0.01; P=.02)

26 TRACER, Gone without Any Trace Bleeding (p<0.001): GUSTO severe (HR1.66), TMIMI major(hr1.53), ICH (HR3.39) Total death: HR1.05 (P=0.52) In pts with ACS, the addition of vorapaxar to standard therapy did not significantly reduce the primary endpoint but significantly increased the risk of major bleeding.

27 End of the Chapter? Evolution of Anti-platelet Therapy tion events (%) Reduct emic e R in ische Placebo -22% -20% -19% -15% -8% (p=ns) +60% +38% +32% 0% +43% Aspirin Aspirin+ Aspirin+ Aspirin+ DAPT+ Clopidogrel Prasugrel Ticagrelol Vorapaxar

28 largely replaced by Newer Ones Small bleed becomes a big bleed! Old Soldiers Never Die. New P 2 Y 12 receptor inhibitors will be the key players in CV medicine. 감사합니다.