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NEWER ANTIPLATELETS

NEWER ANTIPLATELETS. JOURNAL REVIEW Dr RAJESH K F. Adenosine diphosphate (ADP) plays a key role in the genesis of physiological platelet-rich hemostatic plugs and of pathological arterial thrombi. T ransduction of ADP signal involves interaction with 2 platelet receptors

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  1. NEWER ANTIPLATELETS JOURNAL REVIEW Dr RAJESH K F

  2. Adenosine diphosphate (ADP) plays a key role in the genesis of physiological platelet-rich hemostatic plugs and of pathological arterial thrombi

  3. Transduction of ADP signal involves interaction with 2 platelet receptors • Gq-coupled P2Y1 receptor and Gi-coupled P2Y12 receptor • Concomitant activation of both Gqand Gipathways by ADP elicit normal platelet aggregation P2Y1

  4. Prasugrel • Rapid and consistent inhibitory effects on platelet aggregation than clopidogrel • Distinct chemical structure permits conversion to its active metabolite with less dependence on CYP enzymes than clopidogrel

  5. Different metabolism • Appearance of active metabolite in circulation within 15 min • Reaches max plasma concentration at 30 min • Higher mean area under concentration-time curve of active metabolite of prasugrel 60 mg than that of clopidogrel 600 mg

  6. Faster and greater mean inhibition of P2Y12-dependent platelet function after 60-mg LD and 10-mg maintenance dose than after a 300- or 600-mg LD and 75- or 150-mg maintenance dose of clopidogrel No influence of CYP genotype on its pharmacokinetics and pharmacodynamics Lower interindividual variability in inhibition of P2Y12 Low prevalence of subjects who display resistance to prasugrel

  7. TRITON TIMI 38 • Randomized, double-blind, parallel-group, multinational trial • Evaluated 13 608 high-risk patients with ACS who required PCI • Patients randomized to receive 60-mg prasugrel followed by 10 mg/d or a 300-mg clopidogrel followed by 75 mg/d for 6 to 15 months

  8. Prasugrelassociated with • Fewer ischemic events (HR, 0.81; 95% CI, 0.73 to 0.90; P<0.001) • Significant reductions in • Rates of MI (9.7% for clopidogrelvs. 7.4% for prasugrel; P<0.001), • Urgent TVR(3.7% vs. 2.5%; P<0.001) • Stent thrombosis (2.4% vs. 1.1%; P<0.001)

  9. Major bleeding observed in 2.4% of prasugreland in 1.8% of clopidogrel(hazard ratio, 1.32; 95% CI, 1.03 to 1.68; P = 0.03) • Rate of life-threatening bleeding (1.4% vs. 0.9%;P= 0.01) • Nonfatal bleeding (1.1% vs. 0.9%; HR, 1.25; P = 0.23) • Fatal bleeding (0.4% vs. 0.1%; P = 0.002)

  10. Posthoc analysis • 3 subgroups appeared to have less net clinical benefit(≥75 yrsand <60 kg) or greater harm(previous CVA) • More effective antithrombotic drug than clopidogrel in patients with diabetes mellitus, STEMI, coronary stents, or recurrent cardiovascular events on treatment DIABETIC SUBGROUP

  11. TRILOGY ACS At 30 months, among patients <75 years of age: CV death, MI, or stroke: 13.9% of the prasugrel group vs. 16.0% of the clopidogrel group (HR = 0.91, p = 0.21) All-cause death: 7.8% vs. 8.1% (HR = 0.96, p = 0.63 ) Non-CABG TIMI major bleeding: 2.1% vs. 1.5% (HR = 1.31, p = 0.27) Outcomes were similar in the overall population, including the elderly Trial design:NSTE-ACS patients <75 years of age selected for medical management without PCI (n = 7,243) were randomized to prasugrel 10 mg daily vs. clopidogrel 75 mg daily. Patients ≥75 years of age (n = 2,083) were randomized to prasugrel 5 mg daily vs. clopidogrel 75 mg daily. Results (p = 0.21) 16.0 13.9 % Conclusions • Among medically treated patients with NSTE-ACS, prasugreldid not reduce adverse outcomes compared with clopidogrel • Major bleeding was similar between groups Prasugrel Clopidogrel Roe MT, et al. N Engl J Med 2012;367:1297-1309

  12. Comparison with Higher Dose Clopidogrel IPA (%; 20 mM ADP) IPA (%; 20 mM ADP) P<0.0001 N=201 P<0.0001 for each Prasugrel 60 mg Clopidogrel 600 mg Clopidogrel 150 mg Prasugrel 10 mg Hours 14 Days Wiviott et al Circ 2007 (In Press)

  13. CANGRELOR • Belongs to family of analogs of ATP • Display high affinity for P2Y12 receptor • Potent inhibitor of ADP-induced aggregation of human washed platelets (PIC509.4 with 30 mol/L ADP) • Does not require conversion to an active metabolite • Immediately active after IV infusion • Half-life of 3 to 6 minutes

  14. Clinical Pharmacology IV infusion well tolerated in healthy volunteers Result in dose-dependent inhibition of ADP-induced platelet aggregation at doses up to 4 microg/kg/min At highest dose 3.2- and 2.9-fold increase in bleeding time in men and women, respectively Short half-life result in rapid reversal of both platelet-inhibitory effect and effect on bleeding time Reverse within 20 minutes after cessation of infusion

  15. Greenbaum AB, Grines CL, Bittl JA, Becker RC, Kereiakes DJ, Gilchrist IC, Clegg J, Stankowski JE, Grogan DR, Harrington RA, EmanuelssonH,WeaverWD. Initial experience with an intravenous P2Y12 platelet receptor antagonist in patients undergoing percutaneous coronary intervention:resultsfrom a 2-part, phase II, multicenter, randomized, placeboand active-controlled trial. Am Heart J. 006;151:689.e1– 689.e10. Double-blind randomized trial in PCI 2-part phase II study Assessed safety and pharmacodynamics in PCI First part of study enrolled 200 patients undergoing PCI Randomized to 18- to 24-hour IV infusion of placebo or to 1, 2, or 4 microg/kg/min cangrelor in addition to aspirin and heparin before procedure

  16. Second part of study • 199 patients • Randomized to receive either cangrelor (4 microg / kg/ min1) or abciximab before PCI • Incidence of combined major and minor bleeding - not significant difference • After termination of infusionplatelet aggregation returned to baseline values much faster in cangrelortreated group 10 DAY EVENTS

  17. STEP-AMI Safety, Tolerability and Effect on Patency in Acute MI Angiographic trial Assessed safety and efficacy of cangrelor as an adjunct to tpain 92 patients with AMI All patients were treated with aspirin and heparin Randomized to cangrelor alone (280micro g/min), full-dose tpa alone, or cangrelor 35, 140, or 280micro g/min in conjunction with half-dose tpa Combination of cangrelor and half-dose tparesulted in 60-min coronary patency similar to that of full-dose tpa alone (55% versus 50%; PNS) and greater patency than with cangrelor alone (55% versus 18%; P0.05) Bleeding and adverse clinical events were comparable across groups

  18. Storey RF, Wilcox RG, Heptinstall S. Comparison of the pharmacodynamic effects of the platelet ADP receptor antagonists clopidogreland AR-C69931MX in patients with ischaemic heart disease. Platelets. 2002;13:407– 413. Study directly compared effects of clopidogreland cangreloradministration in patients with IHD Cangrelor(2 and 4micro g/mL/min) almost completely inhibited 10 mol/L ADP induced platelet aggregation 4 to 7 days of clopidogrel treatment resulted in only 60% inhibition

  19. CHAMPION PCI • Comparing Treatment With Cangrelor (With Usual Care) to Usual Care, in Subjects Who Require PCI N=8877

  20. Subjects Subjects who require PCI (with or without stent) 1:1 randomization to main treatment groupsDouble blind, double dummy Placebo capsules(to match) Cangrelor bolus (30 µg/kg) & infusion (4 µg/kg/min) Clopidogrel capsules(600 mg) Placebo bolus & infusion (to match) + + Subjects who require PCIStudy drug infusion: for at least 2 hours or the duration of the procedure, whichever is longer IndexProcedure Clopidogrel capsules(600 mg) Placebo capsules(to match) Clopidogrel maintenance (at the discretion of the physician) • At 48 hours after randomization— • 1° efficacy endpoint: composite incidence of all-cause mortality, MI, and IDR • 2° efficacy endpoint: incidence of individual components, stroke & abrupt vessel closure • Safety endpoints: hemorrhage and transfusion • Safety: AEs/SAEs Endpoints

  21. Cangrelornot superior to 600 mg clopidogrel in moderate to high risk patients undergoing PCI • Using standard methods cangrelor appears to be non-inferior to 600 mg clopidogrel • Platelet function testing - cangrelor provides very rapid ADP blockade and did not interfere with post PCI clopidogreleffect

  22. Efficacy Endpoints at 48 hours Cangrelor ClopidogrelEfficacy mITT* (N=3897) (N=3871) OR (95% CI) P Value Death/MI/IDR 7.5% 7.1% 1.05 (0.88, 1.24) 0.59(primary endpoint) MI 7.1% 6.6% 1.09 (0.91, 1.29) 0.36 IDR 0.3% 0.6% 0.56 (0.28, 1.11) 0.10 All-cause mortality 0.2% 0.1% 1.59 (0.52, 4.87) 0.42 Stent thrombosis 0.2% 0.3% 0.63 (0.25, 1.63) 0.34 Stroke 0.2% 0.2% 0.85 (0.29, 2.54) 0.77 Q-wave MI 0.1% 0.3% 0.40 (0.12, 1.27) 0.12 Death/Q-wave MI/ 0.6% 0.9% 0.67 (0.39, 1.14) 0.14IDR Death/Q-wave MI/ 0.5% 0.6% 0.78 (0.42, 1.44) 0.42Stent thrombosis *mITT= modified intent to treat population (patients with PCI and study drug)

  23. Increase in ACUITY minor and GUSTO mild bleeding with cangrelor though no increase in the need for blood transfusion

  24. CHAMPION PLATFORM

  25. Efficacy Endpoints at 48 Hours 0.2 0.5 1.0 2.0 5.0 Cangrelor Better Comparator (placebo) Better * *Primary Analysis ** mITT= modified intent to treat population (patients with PCI and study drug), QMI= Q-wave myocardial infarction

  26. Difference in primary endpoint not statistically significant • Lower rates of stent thrombosis, mortality

  27. No significant effect on transfusions, even in high risk subgroups • Groin hematomas increased, not unexpected versus placebo

  28. CHAMPION PHOENIX • Randomized, double-blind, double-dummy, superiority • Primary efficacy endpoint: Death/MI/IDR/ST at 48 hours • Key secondary endpoint: Stent Thrombosis at 48 hours • Efficacy endpoints also examined at 30 days • Primary safety endpoint: GUSTO Severe Bleeding at 48 hours

  29. Primary Efficacy Outcomes at 48 Hours, MITT 1. The logistic model was adjusted for baseline status and clopidogrel dose. P value of 0.006 shown on the KM curve is log rank p value. Bhatt DL, Stone GW, Mahaffey KW, et al…. Harrington RA. NEJM 2013 at www.nejm.org

  30. IV cangrelorsignificantly (p=0.005) reduced composite of death, MI, ischemia-driven revascularization, or stent thrombosis at 48 hours, with a 22% odds reduction • key secondary endpoint of stent thrombosis significantly reduced with 38% odds reduction • Benefit sustained through 30 days

  31. No excess in severe bleeding or transfusions • Intravenous cangrelor may be an attractive option across the full spectrum of PCI, including stable angina, NSTEMI, and STEMI.

  32. BRIDGE STUDY • To evaluate the use of cangrelor, an IV, reversible P2Y12 platelet inhibitor, for bridging thienopyridine-treated patients to CABG • Stage II Randomized, Double-Blind, Placebo-Controlled

  33. Bridging strategy to CABG after thienopyridinediscontinuation Cangrelor(at 0.75 µg/kg/min) achieves levels of platelet inhibition known to be associated with a low risk of thrombotic events Without increased risk of bleeding before or during CABG, although with a numerical increase in minor pre-CABG bleeding Independent of prior thienopyridine dose & time of discontinuation Consistent pharmaocdynamic effect during IV infusion Rapid offset after IV discontinuation prior to surgery No increased incidence of adverse events (e.g. dyspnea) or laboratory abnormalities despite extended dosing

  34. TICAGRELOR Not a prodrug; does not require metabolic activation Rapid onset of inhibitory effect on P2Y12 receptor Greater inhibition of platelet aggregation than clopidogrel Degree of inhibition reflects plasma concentration Faster offset of effect than clopidogrel Functional recovery of all circulating platelets Displays no significant affinity for other P2 receptors P2Y12 receptor is targeted by ticagrelor via noncompetitive mechanism suggesting existence of an independent receptor binding site

  35. DISPERSE TRIAL Dose-Finding Investigative Study to Assess the Pharmakodynamic Effects in Atherosclerotic Disease Comparison of Ticagrelor With Clopidogrel Randomized, double-blind, parallel-group dose-finding study 200 stable atherosclerotic outpatients on treatment with aspirin 75 to 100 mg once daily Received ticagrelor(50, 100, or 200 mg BID or 400 mg QD) or clopidogrel75 mg once daily for 28 days

  36. Ticagrelor(100 or 200 mg BID or 400 mg QD) inhibited platelet aggregation more rapidly and effectively and with less variability than clopidogrel after both first dose and 28 days of therapy Only 1 major, nonfatal hemorrhage occurred in ticagrelor400 mg QD group Moderate and minor bleeding events - dose related (from 29% to 51%) in ticagrelor and 32% in clopidogrel Other adverse events- dyspnea,dizziness, headache, and hematuria Dyspnea-dose related(10%-50mg BID, 16% - 200 mg BID and 20% - 400 mg QD) None of dyspnea was serious None associated with congestive heart failure or bronchospasm.

  37. DISPERSE-2 study Compared safety of ticagrelor with clopidogrel 990 patients NSTEMI treated with aspirin and standard therapy for ACS Randomly assigned ticagrelor90 mg BID or 180 mg BID and clopidogrel(300-mg LD 75-mg QD MD) for up to 12 weeks Statistically significant difference in major bleedings

  38. Posthoc analysis Continuous ECG- asymptomatic ventricular pauses 2.5 seconds were more common with ticagrelor 180 mg BID Dyspnea frequently with ticagrelor Clinical impact appeared low, with few cases being considered serious or leading to discontinuation of treatment Pathogenesis of dyspnea is unclear Hypothesis - may be mediated by adenosine

  39. SUBSTUDY OF DISPERSE-2 Storey RF, Husted S, Harrington RA, Heptinstall S, Wilcox RG, Peters G,WickensM, Emanuelsson H, Gurbel P, Grande P, Cannon CP. Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes. J Am CollCardiol. 2007;50:1852–1856. Ticagrelor inhibition of platelet aggregation-dose dependent Both doses achieved greater inhibition than clopidogrel Ticagrelorproduced further suppression of platelet aggregation in patients who were currently receiving clopidogrel

  40. PLATO • Platelet Inhibition and Patient Outcomes • Phase III randomized, double-blind, parallel group efficacy and safety study • Ticagrelor(180-mg LD 90-mg BID MD) compared with clopidogrel (300- to 600-mg LD 75-mg daily MD) for prevention of MACEs in patients with NSTEMI or STEMI • 65% of enrolled patients underwent PCI

  41. After 12 months of follow-up primary end point (a composite of vascular death,MI or stroke) - 9.8% in ticagrelor compared with 11.7% in patients receiving clopidogrel

  42. Major efficacy endpoints The percentages are K-M estimates of the rate of the endpoint at 12 months.

  43. Stent thrombosis (evaluated in patients with any stent during the study) *Time-at-risk is calculated from first stent insertion in the study or date of randomisation

  44. Higher incidence of TIMI major non–CABG related bleeding in ticagrelor(2.8%)compared with clopidogrel(2.2%;P0.03) • Incidence of TIMI major CABG related bleeding - similar • High incidence of CABG-related bleeding in both groups (446 of 931 [47.9%] in ticagrelor versus 476 of 968 [49.2%] in clopidogrel) incidence of total bleeding not significantly different

  45. PLATO - Dyspnoea *p values were calculated using Fischer’s exact test

  46. ELINOGREL Direct-acting, reversible P2Y12 inhibitor Can be administered both intravenously and orally Terminal half-life of 12 hours Complete inhibition of P2Y12-dependent ADP induced platelet aggregation was observed at the 20-mg dose.

  47. ERASE-MI ERASE-MI, published in the December 2009 issue of the American Heart JournalDrJeffrey Berger (Duke Clinical Research Institute, Durham, NC). Early Rapid Reversal of Platelet Thrombosis With Intravenous PRT060128 Before PCI to Optimize Reperfusion in Acute MI Phase II clinical trial Randomized trial evaluating the safety and tolerability of adjunctive antiplatelet therapy with intravenous elinogrel (10, 20, 40, and 60 mg) before PCI in patients with STEMI Results showed that incidence of bleeding events was infrequent and appeared to be similar in patients treated with all doses of elinogrel and in placebo

  48. INNOVATE-PCI Phase 2 Safety and Efficacy Study Evaluate use of both intravenous and oral formulations Multicenter, randomized, double-blind, triple-dummy,clopidogrel-controlled study of intravenous and oral elinogrel compared with clopidogrel in non urgent (including elective) PCI After CAG randomized to clopidogrelor 1 of 3 doses of elinogrel Study designed to understand clinical efficacy, biological activity, tolerability, and safety nonurgentPCI

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