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NEWER ANTIPLATELETS JOURNAL REVIEW Dr RAJESH K F.

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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 Gq and Gi pathways 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 Prasugrel associated 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 clopidogrel vs. 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 prasugrel and 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 yrs and <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 Conclusions Among medically treated patients with NSTE- ACS, prasugrel did not reduce adverse outcomes compared with clopidogrel Major bleeding was similar between groups Roe MT, et al. N Engl J Med 2012;367:1297-1309 (p = 0.21) Prasugrel % 13.9 16.0 Clopidogrel

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13 PRINCIPLE – TIMI 44 Comparison with Higher Dose Clopidogrel P<0.0001 for each IPA (%; 20  M ADP) Hours14 Days IPA (%; 20  M ADP) P<0.0001 Prasugrel 10 mg Clopidogrel 150 mg Wiviott et al Circ 2007 (In Press) N=201 Prasugrel 60 mg Clopidogrel 600 mg

14 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

15  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 Clinical Pharmacology

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17  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 Greenbaum AB, Grines CL, Bittl JA, Becker RC, Kereiakes DJ, Gilchrist IC, Clegg J, Stankowski JE, Grogan DR, Harrington RA, Emanuelsson H,Weaver WD. Initial experience with an intravenous P2Y12 platelet receptor antagonist in patients undergoing percutaneous coronary intervention:results from a 2-part, phase II, multicenter, randomized, placeboand active-controlled trial. Am Heart J. 006;151:689.e1– 689.e10.

18  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 infusion platelet aggregation returned to baseline values much faster in cangrelor treated group 10 DAY EVENTS

19  Safety, Tolerability and Effect on Patency in Acute MI  Angiographic trial  Assessed safety and efficacy of cangrelor as an adjunct to tpa in 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 tpa resulted 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 STEP-AMI

20  Study directly compared effects of clopidogrel and cangrelor administration 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 Storey RF, Wilcox RG, Heptinstall S. Comparison of the pharmacodynamic effects of the platelet ADP receptor antagonists clopidogrel and AR-C69931MX in patients with ischaemic heart disease. Platelets. 2002;13:407– 413.

21 CHAMPION PCI  Comparing Treatment With Cangrelor (With Usual Care) to Usual Care, in Subjects Who Require PCI N=8877

22 Clopidogrel maintenance (at the discretion of the physician) Subjects who require PCI (with or without stent) 1:1 randomization to main treatment groups Double blind, double dummy Cangrelor bolus (30 µg/kg) & infusion (4 µg/kg/min) Clopidogrel capsules (600 mg) Placebo capsules (to match) Placebo bolus & infusion (to match) ++ Subjects Index Procedure Endpoints Subjects who require PCI Study drug infusion: for at least 2 hours or the duration of the procedure, whichever is longer Clopidogrel capsules (600 mg) Placebo capsules (to match) 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

23  Cangrelor not 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 clopidogrel effect

24 Efficacy Endpoints at 48 hours *mITT= modified intent to treat population (patients with PCI and study drug) CangrelorClopidogrel Efficacy 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) MI7.1%6.6%1.09 (0.91, 1.29)0.36 IDR0.3%0.6%0.56 (0.28, 1.11)0.10 All-cause mortality0.2%0.1%1.59 (0.52, 4.87)0.42 Stent thrombosis0.2%0.3%0.63 (0.25, 1.63)0.34 Stroke0.2%0.2%0.85 (0.29, 2.54)0.77 Q-wave MI0.1%0.3%0.40 (0.12, 1.27)0.12 Death/Q-wave MI/0.6%0.9%0.67 (0.39, 1.14)0.14 IDR Death/Q-wave MI/0.5%0.6%0.78 (0.42, 1.44)0.42 Stent thrombosis

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

26 CHAMPION PLATFORM

27 Efficacy Endpoints at 48 Hours Efficacy mITT* (SA/UA/NSTEMI) Cangrelor N=2654 Comparator N=2641 OR [95% CI]P value Death/MI/IDR**7.0%8.0%0.87 (0.71,1.07) 0.17 MI6.7%7.2%0.92 (0.74,1.13) 0.42 Non QMI**6.5%6.9%0.94 (0.76,1.16) 0.55 QMI0.2%0.3%0.50 (0.15,1.65) 0.25 IDR0.7%0.9%0.79 (0.43,1.44) 0.44 Stent Thrombosis0.2%0.6%0.31 (0.11,0.85) 0.02 Death0.2%0.7%0.33 (0.13,0.83) 0.02 Death/QMI/IDR0.9%1.6%0.55 (0.33,0.93) 0.02 Cangrelor Better 5.02.01.00.20.5 Comparator (placebo) Better * *Primary Analysis ** mITT= modified intent to treat population (patients with PCI and study drug), QMI= Q-wave myocardial infarction

28  Difference in primary endpoint not statistically significant  Lower rates of stent thrombosis, mortality

29  No significant effect on transfusions, even in high risk subgroups  Groin hematomas increased, not unexpected versus placebo

30 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

31 Primary Efficacy Outcomes at 48 Hours, MITT Cangrelor (N=5472) Clopidogrel (N=5470) OR (95% CI)P-value Primary Analysis Adjusted 1 Death/MI/IDR/ST 257/5470 (4.7%) 322/5469 (5.9%) 0.78 (0.66, 0.93) 0.005 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. Secondary Efficacy Outcomes at 48 Hours, MITT Stent thrombosis (key secondary endpoint) 46/5470 (0.8%) 74/5469 (1.4%) 0.62 (0.43,0.90) 0.01 MI207/5470 (3.8)255/5469 (4.7)0.80 (0.67,0.97)0.02 Q-wave MI11/5470 (0.2)18/5469 (0.3)0.61 (0.29,1.29)0.19 IDR28/5470 (0.5)38/5469 ( 0.7)0.74 (0.45,1.20)0.22 Death18/5470 (0.3)18/5469 (0.3)1.00 (0.52,1.92)>0.99 CV Death18/5470 (0.3)18/5469 (0.3)1.00 (0.52,1.92)>0.99 Bhatt DL, Stone GW, Mahaffey KW, et al…. Harrington RA. NEJM 2013 at www.nejm.org

32  IV cangrelor significantly (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

33  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.

34 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

35  Bridging strategy to CABG after thienopyridine discontinuation  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

36  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 TICAGRELOR

37  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 clopidogrel 75 mg once daily for 28 days DISPERSE TRIAL

38  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 ticagrelor 400 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.

39  Compared safety of ticagrelor with clopidogrel  990 patients  NSTEMI treated with aspirin and standard therapy for ACS  Randomly assigned ticagrelor 90 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 DISPERSE-2 study

40  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

41  Ticagrelor inhibition of platelet aggregation-dose dependent  Both doses achieved greater inhibition than clopidogrel  Ticagrelor produced further suppression of platelet aggregation in patients who were currently receiving clopidogrel SUBSTUDY OF DISPERSE-2 Storey RF, Husted S, Harrington RA, Heptinstall S, Wilcox RG, Peters G,Wickens M, 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 Coll Cardiol. 2007;50:1852–1856.

42 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

43  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

44 Major efficacy endpoints All patients* Ticagrelor (n=9,333) Clopidogrel (n=9,291) HR for (95% CI)p value † Primary objective, n (%) CV death + MI + stroke864 (9.8)1,014 (11.7)0.84 (0.77–0.92) <0.001 Secondary objectives, n (%) Total death + MI + stroke CV death + MI + stroke + ischaemia + TIA + arterial thrombotic events Myocardial infarction CV death Stroke 901 (10.2) 1,290 (14.6) 504 (5.8) 353 (4.0) 125 (1.5) 1,065 (12.3) 1,456 (16.7) 593 (6.9) 442 (5.1) 106 (1.3) 0.84 (0.77–0.92) 0.88 (0.81–0.95) 0.84 (0.75–0.95) 0.79 (0.69–0.91) 1.17 (0.91–1.52) <0.001 0.005 0.001 0.22 Total death399 (4.5)506 (5.9)0.78 (0.69–0.89) <0.001 The percentages are K-M estimates of the rate of the endpoint at 12 months.

45 Stent thrombosis Ticagrelor (n=5,640) Clopidogrel (n=5,649) HR (95% CI)p value Stent thrombosis, n (%) Definite Probable or definite Possible, probable, definite 71 (1.3) 118 (2.1) 155 (2.8) 106 (1.9) 158 (2.8) 202 (3.6) 0.67 (0.50–0.91) 0.75 (0.59–0.95) 0.77 (0.62–0.95) 0.009 0.02 0.01 (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

46  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

47 PLATO - Dyspnoea All patients Ticagrelor (n=9,235) Clopidogrel (n=9,186) p value * Dyspnoea, % Any With discontinuation of study treatment 13.8 0.9 7.8 0.1 <0.001 *p values were calculated using Fischer’s exact test

48  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. ELINOGREL

49  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 ERASE-MI ERASE-MI, published in the December 2009 issue of the American Heart JournalDr Jeffrey Berger (Duke Clinical Research Institute, Durham, NC).

50  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 clopidogrel or 1 of 3 doses of elinogrel  Study designed to understand clinical efficacy, biological activity, tolerability, and safety nonurgent PCI INNOVATE-PCI

51 No TIMI major bleeds in any group Numerical increase in access bleeds requiring medical attention with higher doses of elinogrel compared with clopidogrel Death, MI, stroke, or revascularization: approximately 2.8% of the elinogrel 150 mg group, 4% of the elinogrel 100 mg group, and 1.5% of the clopidogrel group (p = NS) Dyspnea: 12.1%, 15.4%, and 4.3% INNOVATE PCI Trial design: Patients undergoing nonurgent PCI were randomized to one of four groups prior to PCI: 1) elinogrel 80 mg IV, then 150 mg oral twice daily (n = 207); 2) elinogrel 80 mg IV, then 100 mg oral twice daily (n = 201); 3) elinogrel 80 mg IV, then 50 mg oral twice daily; or 4) clopidogrel 300- 600 mg, then 75 mg daily (n = 208). Results Conclusions Among patients undergoing nonurgent PCI, the use of elinogrel is feasible Access site bleeds were numerically higher with increasing doses of elinogrel Similar to ticagrelor, dyspnea was more common with study drug Presented by Dr. Sunil Raul at ESC 2010 (p = NS) Elinogrel 150 mg Elinogrel 100 mg % Death, MI, stroke, or revascularization 2.8 4.0 1.5 Clopidogrel

52 THANK U


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