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Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
Antiplatelet agents in acute coronary syndrome
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Antiplatelet agents in acute coronary syndrome

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  • Platelet AdhesionPlatelet ActivationPlatelet AggregationPAR-1 protease activated receptorTRACER, stopped early due to excess bleedingAPPRAISE-2, stopped early due to bleeding complications including stroke, used the A fib anticoagulation dose 5mg BIDATLAS ACS TIMI 51, less ischemic events but more bleeding, used a lower dose 2.5mg BID, 5mg BID ; approved europeChamp trial, no benefit, more bleedingAcquity, bivalirudinvs heparin Iib/IIIavsbivalirudin / IIbIIIa
  • Composite endpoint of death from cardiovascular cause, non fatal MI, Stroke
  • Major bleeding according to TIMI definition
  • NNT = 50
  • Patients undergoing PCI , 1/3 stable angina, ½ unstable angina, 15% NSTEMIs300mg dose of plavix
  • Carriers of the CYP2C19 loss of function
  • Patients undergoing PCI who were on one year dual antiplatelet, VerifyNow Assay to assess platelet reactivity1 arm reload with 600mg and maintain on 150mg1 arm main
  • Minority need C
  • 2 adult doses of plateletsRepeated platetet transfusion for 4-5 days
  • 2 RCTs, 1 observerational cohort
  • Similar to mechanism of action to Clopidogrel
  • Randomized to prasugrel and clopidogrel
  • Composite endpoint of death due to cardiovascular cause, non fatal MI, ischemic stroke
  • Lives saved 0.3%
  • Lives lost 0.3%
  • Prasugrel Lesson: More platelet inhibition not necessarily better outcomes
  • 4 hours from loading dose to Cath
  • Full antiplatelet activity at sheath insertion, if you go to CABG17% major bleeding in pretreated compared to 10%
  • Criticized for not giving a loading dose of 600mg
  • Major bleeding 11.6, 11.2% vs. 5, 3.8% in TRITON vs. 3.7, 2.7% in CURE
  • FDA approval came with a boxed warning
  • Most events in 2 countries Hungary and Poland
  • Transcript

    • 1. Antiplatelet Agents in Acute Coronary Syndrome LHH Cardiology Grand Rounds January 27th 2014 Salaheldin Abusin Interventional Cardiology Fellow
    • 2. Outline • 3 FDA approved Oral Agents – Clopidogrel – Prasugrel – Ticagrelor • IV Agents – Cangrelor • Evidence • Discerning the differences
    • 3. Vorapaxar TRACER, NEJM 2012 Apixaban, APPRAISE-2 Rivoraxaban, ATLAS ACS TIMI 51, 2012 Warfarin, CHAMP,Circulaation 2002 ACCSAP8 Acquity trial, NEJM 2006
    • 4. Oral P2Y12 Agents Schomig, NEJM 2009
    • 5. Clopidogrel • Oral thienopyridine • Irreversible ADP P2Y12 receptor blocker • Is a prodrug that is converted to active metabolites through oxidation by the hepatic cytochrome P-450 system
    • 6. Clopidogrel • CURE 2001 – Patients with non STE ACS who had presented within 24 hours after the onset of symptoms. – Clopidogrel vs Placebo – ~ 6000 in each arm – Primary outcome a composite endpoint of death, non fatal MI, Stroke – 21% PCI rate (conservative therapy) CURE investigators NEJM 2001
    • 7. • ARR 2.1% in the composite endpoint • Reduction in non fatal MI, with a favorable trend towards benefit with Clopidogrel in death from cardiovascular causes and stroke • More major bleeding in the Clopidogrel group ARI 1% • Predominantly in patients who underwent CABG less than 5 days after stopping Clopidogrel
    • 8. AHA/ACC 2007 • All patients with ACS should receive Clopidogrel, loading dose followed by maintenance, regardless of choice selective invasive or invasive (Class I) • For a duration of 1 month minimum, ideally one year (Class I) • Stop Clopidogrel 5-7 days before CABG
    • 9. Benefit from Clopidogrel and Timing of PCI 300mg dose Steinhubl et al. JAMA 2002 ; CREDO trial
    • 10. Non responders to clopidogrel Carriers of CYP2C19 loss of function Hulot et al. Circ: Cardiovasc Interv 2011; CLOVIS trial
    • 11. Platelet Reactivity Testing Hulot et al. Circ: Cardiovasc Interv 2011; Gravitas trial
    • 12. CABG in ACS with clopidogrel on board • 30% of patients undergoing CABG have received clopidogrel • 90% of them get CABG in less than 5 days • Operating in less than 5 days with clopidogrel on board – More blood transfusion rates, and more blood given – 1% additional risk of MI while waiting for CABG Mehta et al JACC 2006 ; CRUSADE Registry
    • 13. Emergency Reversal of Clopidogrel • No antidote • Platelet transfusion – Invitro studies of healthy volunteers • Recombinant Factor VII – Invitro studies of healthy volunteers – Renal transplant patients improved bleeding time • DDAVP ( n=1) – Severe epistaxis Beshay et al Journal of Neurosurgery 2010: Review
    • 14. Clopidogrel a good drug with drawbacks • • Proven benefit Drawbacks 1. Slow onset ;can be minimized by administering 600mg loading dose 2. Slow offset; (5 days wait before CABG can be safe to perform) 3. Variability in response up to 21% non responders, who will have higher risk of MI and stent thrombosis 4. No antidote
    • 15. May 17th 2012 Clopidogrel goes off patent Medication Price per day Clopidogrel Generic Clopidogrel Brand Prasugrel $0.37 Ticagrelor $7.11 $4.00 $5.78
    • 16. Is Generic Clopidogrel as good as Plavix? Caldiera et al. Journal of Cardiovascular Pharmacology 2013
    • 17. Prasugrel • Oral thienopyridine • Irreversible ADP P2Y12 receptor blocker • 2 step activation process without significant genetic polymorphism • Faster onset of action • More potent Higher rates of platelet aggregation
    • 18. LD and repeated pre-dose at days 14 and 29. Results: There was no significant difference in clinical characteristics o level at baseline. 106 patients completed the study (54 on prasugrel and clopidogrel). Treatment was well tolerated in both groups. As illustrated figure the mean MPA levels were significantly (p< 0.0001) lower with prasu all time-points after start of treatment. Faster, more potent Varenhorst et al. ESC 2007 Congress Abstract
    • 19. Prasugrel more reliable Proven efficacy in carriers of CYP2C19 Trenk et al. JACC 2012. Trigger PCI
    • 20. TRITON TIMI 38 • 13,608 patients with moderate-to-high-risk ACS planned for PCI (99% underwent PCI) • Prasugrel 60mg loading dose followed by 10mg maintenance • Clopidogrel 300 mg loading dose followed by 75mg maintenance dose for 6 to 15 months. • Difference from CURE population – – – – – 25% STEMIs compared to none 50% GPIIbIIIa compared to none Higher use of statins 92% vs. 25% at time of randomization Higher use of BBs 88% vs. 58% Higher use of ACEI 76% vs. 37% Wiviott et al. NEJM 2007
    • 21. • • • • • • • • ARR in composite endpoint 2.2% with Prasugrel ARR 2.3% in MI with Prasugrel ARR in Death from cardiovascular cause 0.3% NS Major bleeding ARI 0.6% Fatal bleeding ARI 0.3% So Prasugrel use contraindicated in PH of TIA/Stroke Caution in > 75, and low BMI Discontinue 7 days before CABG
    • 22. Timing of Prasugrel administration • On the table administration after diagnostic angiography and decision of PCI taken in TRITON TIMI 38 • FDA Package Insert/ Class IIb Recommendation – “it is reasonable to consider selective use of prasugrel before catheterization in subgroups of patients for whom a decision to proceed to angiography and PCI has already been established for any reason. “
    • 23. ACCOAST • • • • • N ~4000 NSTE ACS with +ve troponin PCI planned in 2-48 hours 30mg upfront then 30mg in Cath Lab vs 60mg in Cath Lab Montalescot et al. NEJM 2013
    • 24. More bleeding with pretreatment
    • 25. TRILOGY ACS • • • • Role of Prasugrel beyond PCI patients NSTE ACS, USA did not undergo PCI (< 75 yrs) Clopidogrel vs Prasugrel No difference in composite primary endpoint (Death, non fatal MI, Revasc) • Trend towards less ischemic events and more minor bleeding with prasugrel Roe et al. NEJM 2012
    • 26. Prasugrel • More reliable than clopidogrel • Higher efficacy • More bleeding – Avoid in bleeders • Initiate in Cath Lab • If CABG needed  7 day wait
    • 27. Ticagrelor • Ticagrelor, a reversible and direct-acting oral ADP receptor blocker (P2Y12) • faster, greater, and more consistent P2Y12 inhibition than Clopidogrel (possibly more than Prasugrel) • 90mg twice daily is the dose used in PLATO, higher doses were associated with more side effects (dyspnea, ventricular pauses)
    • 28. OFFSET/ONSET trial Gurbel et al. Circulation 2009
    • 29. Efficacy in clopidogrel non responders Gurbel et al. Circulation 2010: RESPOND study
    • 30. PLATO • Multicenter, randomized, double blind , double dummy clinical trial • 18,624 patients from 862 centers in 43 countries from October 2006 through July 2008 • The follow-up period ended in February 2009 Wallentin et al. NEJM 2009
    • 31. Study Design • Ticagrelor group – given in a loading dose of 180 mg followed by a dose of 90 mg twice daily. • Clopidogrel group – 300-mg loading dose followed by a dose of 75 mg – OR maintenance dose of 75 mg if already on Clopidogrel
    • 32. Results
    • 33. Safety
    • 34. What does PLATO brings to the table? 1. More platelet inhibition not necessarily more overall harm – CURE, TRITON TIMI 18 showed that more platelet inhibition equaled less MI, less urgent revascularization, – more bleeding, and in case of Prasugrel more life threatening, and fatal bleeding – Ticagrelor patients bled more (albeit not significantly) than Clopidogrel, but less during CABG
    • 35. 2. Ticagrelor saves lives  No significant mortality benefit in CURE with Clopidogrel in non ST ACS, or TRITON TIMI 38 with Prasugrel in all ACS, or the GPIIb/IIIa trials.  PLATO shows mortality benefit like aspirin in all ACS  ?play of chance as the trial not powered to detect difference in mortality,  but consistent benefit across MACE with less bleeding might be a possibility
    • 36. 3. New side effects with Ticagrelor  Dyspnea • •   Mild, early, transient with no changes on PFTs, Imaging Similar to adenosine reaction in non invasive stress testing Bradycardia Pauses
    • 37. ³75 Years Sex Male Female Weight Group <60 kg ³60 kg <80 kg ³80 kg Medical History of DM No Yes Region Asia/Australia Central/South America Europe/Middle East/Africa North America 2878 16.8 18.3 0.94 (0.78, 1.12) 0.82 13336 5288 9.2 11.2 1312 17256 9055 9513 13.1 9.5 11.4 8.3 11.1 13.2 0.85 (0.76, 0.95) 0.83 (0.71, 0.97) 17.3 11.2 12.8 10.5 0.75 (0.60, 0.99) 0.86 (0.78, 0.94) 0.90 (0.79, 1.01) 0.79 (0.69, 0.90) Subgroup analysis 0.36 0.17 0.49 • Benefits of Ticagrelor were 8.4 10.2 0.83 (0.74, 0.92) 14.1 16.2 0.88 (0.76, 1.03) seen across 62/66 subgroups 0.05 1714• 11.4 14.8 0.80 (0.61, 1.04) Trend towards harm in those 1237 15.2 17.9 0.86 (0.65, 1.13) enrolled in North America 13859 8.8 11.0 0.80 (0.72, 0.90) 13962 4662 1814 11.9 9.6 1.25 (0.93, 1.67) Antiplatelet Therapy Prior to Index Event 0.43 Clopidogrel ± ASA 1397 15.8 17.8 0.95 (0.73, 1.24) ASA 5024 11.8 14.0 0.84 (0.71, 0.98) None 12147 8.2 10.0 0.82 (0.73, 0.93) ASA on Day of Rand. No Yes 0.86 927 11.6 13.8 0.87 (0.60, 1.27) 17697 9.7 11.6 0.84 (0.77, 0.93) GPIIb/IIIa (IE to End of Index Hosp.) 0.41 No 13562 9.7 11.9 0.82 (0.74, 0.92) Yes 5062 10.0 11.1 0.90 (0.76, 1.07) Race Caucasian 0.66 17077 9.5 11.2 0.85 (0.77, 0.94)
    • 38. • 2 independent statistical analyses reached: Aspirin dose >300 in US (53.6%) compared to rest of the world (1.7%) may explain the geographic variation in outcomes
    • 39. Devil in the detail OR paranoid conspiracy theory
    • 40. Ticagrelor • • • • • More reliable than clopidogrel Superior to clopidogrel (?maybe) Less bleeding (?maybe) BID dosing issue Still 5 day wait for CABG
    • 41. Cangrelor • • • • • • Direct acting Parenteral Reversible P2Y12 very rapid onset half life 3-6 minutes Very rapid offset 30-60 minutes High efficacy similar to Abiciximab
    • 42. CHAMPION trials • Champion PCI – (Harrington, NEJM 2009) – Cangrelor vs clopidogrel 600mg (before PCI) – Negative trial • Champion Platform – (Bhatt, NEJM 2009) – Cangrelor vs clopidogrel 600mg (at end of PCI) – Negative Trial (less ST, less death trend) • Champion Phoenix (Bhatt, NEJM 2013) – Cangrelor vs clopidogrel 600mg or 300mg (start or end of PCI) – Changed periprocedural MI to include (ECG changes, new angio changes) – Positive trial – ARR 1.2 % driven by reduction in MI, also less ST
    • 43. Pooled Analysis of the Champion Trials Stegg et al. Lancet 2013
    • 44. Stegg et al. Lancet 2013
    • 45. Cangrelor • Patient cannot take orally • Superior onset (but does that matter?) • Comparison with newer agents
    • 46. Thanks

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