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Antiplatelet therapy for acute coronary syndrome treated with PCI: New developments

Antiplatelet therapy for acute coronary syndrome treated with PCI: New developments. Amber Malik Director Cath Lab Services Shaikh Zayed Hospital, Lahore. Platelet aggregation contributes to atherothrombosis which in turn is associated with Acute Coronary Syndromes

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Antiplatelet therapy for acute coronary syndrome treated with PCI: New developments

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  1. Antiplatelet therapy for acute coronary syndrome treated with PCI: New developments Amber Malik Director Cath Lab Services Shaikh Zayed Hospital, Lahore

  2. Platelet aggregation contributes to atherothrombosis which in turn is associated with Acute Coronary Syndromes ACS often precipitates cardiovascular death

  3. Complete obstruction Partial flow Acute coronary syndrome No ST elevation ST elevation UA/NSTEMI STEMI Antithrombin Rx Antiplatelet Rx

  4. FGN X XI TF/ VIIa Fibrin IXa Xa VIIIa VaCa ++ Thrombin Prothrom Plt FGN FGN

  5. Platelet adhesion: Binding to collagen Platelet activation: Release of contents,surface receptor expression Inactive platelet GP Ia/IIa GP VI Collagen fibrils

  6. Platelet Activation RBCs Endothelial cells ­Ca++ ADP Collagen AA release Thrombin COX Epinephrine PGG2-PGH2 Tx A2 Tx Syn Serotonin Tx A2 Tx A2

  7. Glycoprotein IIb/IIIa Receptor: Final Pathway of Platelet Aggregation IIb/IIIa Thrombin FGN Collagen ADP GP IIb/IIIa receptor activation Epinephrine Tx A2 Serotonin Shear forces IIb/IIIa inhibitor

  8. Risk during and after ACS can be reduced by optimal anticoagulation and antiplatelet treatment in conservatively treated as well as revascularised patients • In PCI with stents effective AP inhibition is highly mandatory as the processes themselves are thrombogenic and add to the risk

  9. X Xa LMWH, pentasaccharide UFH Va,Ca2+ LMWH Thrombin UFH Prothrombin DTIs Clopidogrel ASA Platelet GP IIb/IIIa inhibitor

  10. Current Guidelines (2007,2008) recommend : • DAPT ( aspirin and clopidogrel) for NSTEMI for 1 year (CURE trial ) • DAPT for STEMI for at least 30 days (CLARITY- TIMI 28 trial ) • DAPT mandatory post PCI with stents • BMS at least 1 month • DES at least 1 year

  11. Even though CURE shows a RRR of 20% of composite end point which occurred in 9.3% vs 11.4 % on placebo . • The 9.35 % event rate is still quite high inspite of DAPT, which rose to 16.3% when recurrent ischemia was included. • Hence the desire to improve outcome even further

  12. Current options for antiplatelets Cox inhibitors : Aspirin ADP receptor antagonist : Ticlopidine Clopidogrel Prasugrel Cangrelor Ticagrelor(AZD6140)

  13. Current options for antiplatelets Phosphodiesterase inhibitors : Cilostazol Dipyridamole Thrombin inhibitor : Bivalirudin Glycoprotein IIb/IIIA inhibitors : Abciximab Eptifibatide Tirofiban

  14. COOCH3 N N S S Cl Cl Thienopyridines Ticlopidine (1st generation) Clopidogrel (2nd generation) Prasugrel (CS-747) (LY640315) (3rd generation) O N C H O 3 S F O

  15. Limitations of Current thienopyridines • Slow onset: requires prolonged pretreatment for PCI efficacy • Optimal interval from delivery to max drug effect is >15 hrs • Bleeding (especially related to CABG) • Modest levels of platelet inhibition • Variability of response is upto 30% depending on the measure of platelet aggregation used

  16. Critical timing of antiplatelet response • ESC guidelines recommend 300mg loading dose > 6 hrs pre PCI • Reality is very different • Common practise CAG is often followed by ad hoc PCI with very little time for optimal dosing etc and exposing patients to an increased risk of bleeding • PRAGUE 8 concluded that non selective treatment of pts with high dose clopidogrel should not be routinely undertaken

  17. Clinical Importance of Response Variability ? Failure of Therapy Successful Therapy Lesser Response Greater Response Failure of Therapy = Drug Resistance

  18. Sem Vasc Med 3:113, 2003 Sankyo Ann Report 51:1,1999 O CH3 O C O O O CH3 CH3 O O C C N N O O C S S N N F Cl C H S S 3 Cl Cl 85% Inactive MetabolitesEsterases O O O N N HOOC N HOOC O O * HS S F OCH3 * HS F Cl Active Metabolite Active Metabolite Change the agent? Pro-drug Clopidogrel Prasugrel Hydrolysis (Esterases) Oxidation (Cytochrome P450)

  19. Inhibition of Platelet Aggregation(IPA) at 24 Hours (Healthy Volunteers) 100.0 80.0 Interpatient Variability 60.0 Inhibition of Platelet Aggregation (%) 40.0 Interpatient Variability 20.0 0.0 Clopidogrel Responder Clopidogrel Non-responder -20.0 Response to Prasugrel Response to Clopidogrel *Responder =  25% IPA at 4 and 24 h Brandt, Payne, Wiviott et al AHJ 2007

  20. Fast , potent , and reliable inhibition of platelet aggregation • PRASUGREL • Faster and more potent IPA : • Less dependent on CYP450 for metabolism • More extensively metabolised to its active metabolite • Reaches higher concentrations with a 60mg LD and 10mg MD vs 300mgLD and 75mg MD as well as high dose 600mg LD and 150 mg MD clopidogrel • Less variabilty of response • Benefits demonstrated in both healthy volunteers and CAD pts.

  21. TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel TRITON-TIMI 38AHA 2007Orlando, Florida Disclosure Statement: The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co.

  22. Publication of Primary Results www.NEJM.org NEJM 357: 2001-2015, 2007

  23. Antiplatelet Therapy for PCI • Dual antiplatelet Rx (ASA + thienopyridine) is standard of care: TiclopidineClopidogrel • Clinical need to improve on benefits observed with clopidogrel • Prasugrel Novel thienopyridine Efficient generation of active metabolite High levels of IPA achieved rapidly High IPA in clopidogrel“hyporesponders” Encouraging Phase 2 data

  24. Study Goals To test the hypothesis that higher and less variable IPA prevents clinical ischemic events. To evaluate the safety of a regimen that produces higher IPA. These goals were achieved by evaluating the efficacy and safety of prasugrel compared to clopidogrel in mod/high risk patients with ACS undergoing PCI on a background of ASA.

  25. Trial Organization Trial Leadership: TIMI Study Group Eugene Braunwald,Chairman, Elliott M. Antman,PI, Stephen D. Wiviott, Gilles Montalescot, Carolyn H. McCabe, Sabina A. Murphy, Susan McHale Sponsors: Daiichi Sankyo and Eli Lilly J. Anthony Ware, Jeffrey Riesmeyer, William Macias, James Croaning, GovindaWeerakkody, Francis Plat, Tomas Bocanegra Data Center and Site Management: Quintiles Inc Data Safety Monitoring Board David Williams (Chair) , Christophe Bode, Spencer King, Ulrich Sigwart, David DeMets

  26. Study Design ACS (STEMI or UA/NSTEMI) & Planned PCI N= 13,600 ASA Double-blind CLOPIDOGREL 300 mg LD/ 75 mg MD PRASUGREL 60 mg LD/ 10 mg MD Median duration of therapy - 12 months 1o endpoint: CV death, MI, Stroke 2o endpoints: CV death, MI, Stroke, Rehosp-Rec Isch,CV death, MI, UTVR Stent Thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, Life-threatening bleedsKey Substudies: Pharmacokinetic, Genomic

  27. Enrollment Criteria • Inclusion Criteria Planned PCI for : Mod-High Risk UA/NSTEMI (TRS > 3) STEMI: < 14 days (ischemia or Rx strategy) STEMI: Primary PCI • Major Exclusion Criteria: • Severe comorbidity • Increased bleeding risk • Prior hemorrhagic stroke or any stroke < 3 mos • Any thienopyridine within 5 days • No exclusion for advanced age or renal function KnownAnatomy

  28. Enrollment: Nov 2004 - Jan 2007N = 13,608 (ITT) 30 Countries 707 Sites LTFU = 14 (0.1%)

  29. Baseline Characteristics *P<0.05

  30. Index Procedure

  31. Primary EndpointCV Death,MI,Stroke 15 Clopidogrel 12.1(781) 9.9 (643) 10 Primary Endpoint (%) Prasugrel HR 0.81(0.73-0.90)P=0.0004 HR 0.80P=0.0003 HR 0.77P=0.0001 5 NNT= 46 LTFU = 14 (0.1%) ITT= 13,608 0 0 30 60 90 180 270 360 450 Days

  32. Primary EndpointCV Death,MI,Stroke This was primarily driven by a reduction in the rate of non-fatal MI 7.3 vs 9.5%; p<0.0001 at 6- 15 months There was no significant difference between the incidence of rates of CV death or nonfatal stroke

  33. Primary EndpointCV Death,MI,Stroke • Prasugrel compared to clopidogrel reduces the incidence of recurrent MI • Also reduces the severity of recurrent MI • Overall MI RRR – 24% • MI followed by death RRR - 42%

  34. Primary EndpointCV Death,MI,Stroke • The rapid onset time of prasugrel upto 30 mins means that the physician can afford to take the time to determine coronary anatomy ( rule out urgent CABG), yet still have time to achieve high levels of IPA for ?proceed PCI • LD and day 3 RRR 19 % • MD and day 450 RRR 31%

  35. Timing of Benefit(Landmark Analysis) 8 6.9 Clopidogrel Clopidogrel 5.6 5.6 6 Primary Endpoint (%) 4.7 4 Prasugrel Prasugrel HR 0.82P=0.01 HR 0.80P=0.003 2 1 0 0 1 2 3 0 30 60 90 180 270 360 450 Days Loading Dose Maintenance Dose

  36. Stent Thrombosis(ARC Definite + Probable) 3 Any Stent at Index PCI N= 12,844 2.4(142) Clopidogrel 2 Endpoint (%) 1.1 (68) 1 Prasugrel HR 0.48P <0.0001 NNT= 77 0 0 30 60 90 180 270 360 450 Days

  37. Balance of Efficacy and Safety 15 138 events Clopidogrel HR 0.81(0.73-0.90)P=0.0004 12.1 CV Death / MI / Stroke 9.9 10 NNT = 46 Prasugrel Endpoint (%) 5 35 events TIMI Major NonCABG Bleeds Prasugrel 2.4 HR 1.32(1.03-1.68)P=0.03 1.8 Clopidogrel 0 NNH = 167 0 30 60 90 180 270 360 450 Days

  38. Bleeding EventsSafety Cohort(N=13,457) ICH in Pts w Prior Stroke/TIA (N=518) Clopidogrel Prasugrel Clop 0 (0) %Pras 6 (2.3)% (P=0.02) % Events ARD 0.6%HR 1.32P=0.03NNH=167 ARD 0.5%HR 1.52P=0.01 ARD 0.2%P=0.23 ARD 0.3%P=0.002 ARD 0%P=0.74

  39. Events per 1000 pts + Major Bleed(non CABG) MI Net Clinical BenefitDeath, MI, Stroke, Major Bleed (non CABG) 15 Clopidogrel 13.9 ITT= 13,608 12.2 HR 0.87P=0.004 Prasugrel 10 Endpoint (%) All CauseMortality 5 Clop 3.2%Pras 3.0 %P=0.64 0 0 30 60 90 180 270 360 450 Days

  40. CV Death, MI, StrokeMajor Subgroups Reduction in risk (%) 18 UA/NSTEMI B 21 STEMI 21 Male 12 Female 25 <65 14 Age 65-74 6 >75 14 No DM 30 DM 20 BMS 18 DES 21 GPI 16 No GPI 14 CrCl < 60 20 CrCl > 60 Pinter = NS 19 OVERALL 0.5 1 2 Prasugrel Better Clopidogrel Better HR

  41. Net Clinical BenefitBleeding Risk Subgroups Post-hoc analysis Risk (%) + 37 Yes Prior Stroke / TIA -16 No Pint = 0.006 -1 >=75 Age -16 Pint = 0.18 < 75 +3 < 60 kg Wgt Pint = 0.36 -14 >=60 kg -13 OVERALL 0.5 1 2 Prasugrel Better Clopidogrel Better HR

  42. Bleeding Risk SubgroupsTherapeutic Considerations Reduced MDGuided by PKAge > 75 or Wt < 60 kg 16% Avoid PrasugrelPrior CVA/TIA 4% Significant Net Clinical Benefit with Prasugrel80% MD 10 mg

  43. ConclusionsHigher IPA to Support PCI Efficacy 1. A significant reduction in: CV Death/MI/Stroke19% Stent Thrombosis 52% uTVR 34%       MI 24% 2. An early and sustained benefit 3. Across ACS spectrum Safety Significant increase in serious bleeding(32%increase)Avoid in pts with prior CVA/TIA Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD Net clinical benefit significantly favored Prasugrel Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the benefit : risk balance

  44. Conclusion • Prasugrel compared with clopidogrel significantly reduced the incidence of ischemic events , both in the acute and long term • The increased efficacy of prasugrel was associated with an increased risk of bleeding. • The balance of efficacy and safety revealed an early and sustained net clinical benefit over the entire spectrum of ACS investigated • Avoid in pts with prior stroke / TIA • Very old and low body weight may require reduced dose

  45. Subgroup analyses Patients with DM and AMI derived the greatest net clincal benefit from prasugrel as compared to clopidogrel

  46. Subgroup analysis of STEMI pts STEMI 3534 pts Primary PCI 2438(69%) Secondary PCI 1094(31%) Baseline characteristics well matched More frequent use of Gp 11b111a inhibitorswith clopidogrel due to bail out

  47. Subgroup analysis of STEMI pts • Benefit of prasugrel across the overall spectrum of ACSs but particularly pronounced in STEMI pts. • Primary end point significant reduction • 6.5 vs 9.5%; p=0.002

  48. TRITON-TIMI 38: Myocardial infarction Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 6 Clopidogrel 5.24 4.79 Clopidogrel 4 Prasugrel 4.27 MI (%) 3.40 Prasugrel 2 HR 0.81(0. 70-0.95)P = 0.008 HR 0.69(0.58-0.83)P < 0.0001 0 0 1 2 3 60 180 270 360 450 Loading dose Maintenance dose Time (days) Antman EM et al. J Am Coll Cardiol. 2008;51:2028-33.

  49. Subgroup analysis of STEMI pts Secondary end point of CV death, MI and UTVR at 30 days was reduced 6.7%vs 8.8% p=0.02 Benefit persisted through 15 months

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