Presentation on theme: "JOURNAL REVIEW Dr RAJESH K F"— Presentation transcript:
1JOURNAL REVIEW Dr RAJESH K F NEWER ANTIPLATELETSJOURNAL REVIEWDr RAJESH K F
2Adenosine diphosphate (ADP) plays a key role in the genesis of physiological platelet-rich hemostatic plugs and of pathological arterial thrombi
3Gq-coupled P2Y1 receptor and Gi-coupled P2Y12 receptor Transduction of ADP signal involves interaction with 2 platelet receptorsGq-coupled P2Y1 receptor and Gi-coupled P2Y12 receptorConcomitant activation of both Gq and Gi pathways by ADP elicit normal platelet aggregationP2Y1
4PrasugrelRapid and consistent inhibitory effects on platelet aggregation than clopidogrelDistinct chemical structure permits conversion to its active metabolite with less dependence on CYP enzymes than clopidogrel
5Different metabolismAppearance of active metabolite in circulation within 15 minReaches max plasma concentration at 30 minHigher mean area under concentration-time curve of active metabolite of prasugrel 60 mg than that of clopidogrel 600 mg
6Faster 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 clopidogrelNo influence of CYP genotype on its pharmacokinetics and pharmacodynamicsLower interindividual variability in inhibition of P2Y12Low prevalence of subjects who display resistance to prasugrel
7TRITON TIMI 38Randomized, double-blind, parallel-group, multinational trialEvaluated high-risk patients with ACS who required PCIPatients 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
8Prasugrel associated with Fewer ischemic events (HR, 0.81; 95% CI, 0.73 to 0.90; P<0.001)Significant reductions inRates 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)
9Major bleeding observed in 2. 4% of prasugrel and in 1 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)
10Posthoc analysis3 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 treatmentDIABETIC SUBGROUP
11TRILOGY ACSTrial 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)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 elderly16.013.9%ConclusionsAmong medically treated patients with NSTE-ACS, prasugrel did not reduce adverse outcomes compared with clopidogrelMajor bleeding was similar between groupsPrasugrelClopidogrelRoe MT, et al. N Engl J Med 2012;367:
13Comparison with Higher Dose Clopidogrel IPA (%; 20 mM ADP)IPA (%; 20 mM ADP)N=201P< for eachP<0.0001Prasugrel 60 mgClopidogrel 600 mgClopidogrel 150 mgPrasugrel 10 mgHours14 DaysWiviott et al Circ 2007 (In Press)13
14CANGRELOR Belongs to family of analogs of ATP Display high affinity for P2Y12 receptorPotent inhibitor of ADP-induced aggregation of human washed platelets (PIC509.4 with 30 mol/L ADP)Does not require conversion to an active metaboliteImmediately active after IV infusionHalf-life of 3 to 6 minutes
15Clinical Pharmacology IV infusion well tolerated in healthy volunteersResult in dose-dependent inhibition of ADP-induced platelet aggregation at doses up to 4 microg/kg/minAt highest dose 3.2- and 2.9-fold increase in bleeding time in men and women, respectivelyShort half-life result in rapid reversal of both platelet-inhibitory effect and effect on bleeding timeReverse within 20 minutes after cessation of infusion
17Double-blind randomized trial in PCI 2-part phase II study Assessed safety and pharmacodynamics in PCIFirst part of study enrolled 200 patients undergoing PCIRandomized 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 procedureGreenbaum 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.
18Second part of study 199 patients Randomized to receive either cangrelor (4 microg / kg/ min1) or abciximab before PCIIncidence of combined major and minor bleeding - not significant differenceAfter termination of infusion platelet aggregation returned to baseline values much faster in cangrelor treated group10 DAY EVENTS
19STEP-AMI Safety, Tolerability and Effect on Patency in Acute MI Angiographic trialAssessed safety and efficacy of cangrelor as an adjunct to tpa in 92 patients with AMIAll patients were treated with aspirin and heparinRandomized to cangrelor alone (280micro g/min), full-dose tpa alone, or cangrelor 35, 140, or 280micro g/min in conjunction with half-dose tpaCombination 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
204 to 7 days of clopidogrel treatment resulted in only 60% inhibition Study directly compared effects of clopidogrel and cangrelor administration in patients with IHDCangrelor (2 and 4micro g/mL/min) almost completely inhibited 10 mol/L ADP induced platelet aggregation4 to 7 days of clopidogrel treatment resulted in only 60% inhibitionStorey 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.
21CHAMPION PCIComparing Treatment With Cangrelor (With Usual Care) to Usual Care, in Subjects Who Require PCIN=8877
22+ + Subjects Index Procedure Endpoints Subjects who require PCI (with or without stent)1:1 randomization to main treatment groups Double blind, double dummyPlacebo 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 PCI Study drug infusion: for at least 2 hours or the duration of the procedure, whichever is longerIndex ProcedureClopidogrel capsules (600 mg)Placebo capsules (to match)Clopidogrel maintenance (at the discretion of the physician)EndpointsAt 48 hours after randomization—1° efficacy endpoint: composite incidence of all-cause mortality, MI, and IDR2° efficacy endpoint: incidence of individual components, stroke & abrupt vessel closureSafety endpoints: hemorrhage and transfusionSafety: AEs/SAEs
23Cangrelor 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 clopidogrelPlatelet function testing - cangrelor provides very rapid ADP blockade and did not interfere with post PCI clopidogrel effect
24Efficacy Endpoints at 48 hours Cangrelor Clopidogrel Efficacy mITT* (N=3897) (N=3871) OR (95% CI) P ValueDeath/MI/IDR 7.5% 7.1% 1.05 (0.88, 1.24) (primary endpoint)MI 7.1% 6.6% 1.09 (0.91, 1.29) 0.36IDR 0.3% 0.6% 0.56 (0.28, 1.11) 0.10All-cause mortality 0.2% 0.1% 1.59 (0.52, 4.87) 0.42Stent thrombosis 0.2% 0.3% 0.63 (0.25, 1.63) 0.34Stroke 0.2% 0.2% 0.85 (0.29, 2.54) 0.77Q-wave MI 0.1% 0.3% 0.40 (0.12, 1.27) 0.12Death/Q-wave MI/ 0.6% 0.9% 0.67 (0.39, 1.14) 0.14 IDRDeath/Q-wave MI/ 0.5% 0.6% 0.78 (0.42, 1.44) 0.42 Stent thrombosis*mITT= modified intent to treat population (patients with PCI and study drug)
25Increase in ACUITY minor and GUSTO mild bleeding with cangrelor though no increase in the need for blood transfusion
27Efficacy Endpoints at 48 Hours Efficacy mITT*(SA/UA/NSTEMI)CangrelorN=2654ComparatorN=2641OR [95% CI]P valueDeath/MI/IDR**7.0%8.0%0.87 (0.71,1.07)0.17MI6.7%7.2%0.92 (0.74,1.13)0.42Non QMI**6.5%6.9%0.94 (0.76,1.16)0.55QMI0.2%0.3%0.50 (0.15,1.65)0.25IDR0.7%0.9%0.79 (0.43,1.44)0.44Stent Thrombosis0.6%0.31 (0.11,0.85)0.02Death0.33 (0.13,0.83)Death/QMI/IDR1.6%0.55 (0.33,0.93)0.20.51.02.05.0Cangrelor BetterComparator (placebo) Better* *Primary Analysis** mITT= modified intent to treat population (patients with PCI and study drug), QMI= Q-wave myocardial infarction
28Difference in primary endpoint not statistically significant Lower rates of stent thrombosis, mortality
29No significant effect on transfusions, even in high risk subgroups Groin hematomas increased, not unexpected versus placebo
30CHAMPION PHOENIX Randomized, double-blind, double-dummy, superiority Primary efficacy endpoint: Death/MI/IDR/ST at 48 hoursKey secondary endpoint: Stent Thrombosis at 48 hoursEfficacy endpoints also examined at 30 daysPrimary safety endpoint: GUSTO Severe Bleeding at 48 hours
31Primary Efficacy Outcomes at 48 Hours, MITT Cangrelor (N=5472)Clopidogrel(N=5470)OR (95% CI)P-valuePrimary Analysis Adjusted1Death/MI/IDR/ST257/5470 (4.7%)322/5469 (5.9%)(0.66, 0.93)0.005Secondary Efficacy Outcomes at 48 Hours, MITTStent thrombosis (key secondary endpoint)46/5470(0.8%)74/5469(1.4%)0.62 (0.43,0.90)0.01MI207/5470 (3.8)255/5469 (4.7)0.80 (0.67,0.97)0.02Q-wave MI11/5470 (0.2)18/5469 (0.3)0.61 (0.29,1.29)0.19IDR28/5470 (0.5)38/5469 ( 0.7)0.74 (0.45,1.20)0.22Death18/5470 (0.3)1.00 (0.52,1.92)>0.99CV Death1. The logistic model was adjusted for baseline status and clopidogrel dose. P value of shown on the KM curve is log rank p value.Bhatt DL, Stone GW, Mahaffey KW, et al…. Harrington RA. NEJM 2013 at
32IV cangrelor significantly (p=0 IV cangrelor significantly (p=0.005) reduced composite of death, MI, ischemia-driven revascularization, or stent thrombosis at 48 hours, with a 22% odds reductionkey secondary endpoint of stent thrombosis significantly reduced with 38% odds reductionBenefit sustained through 30 days
33No 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.
34BRIDGE STUDYTo evaluate the use of cangrelor, an IV, reversible P2Y12 platelet inhibitor, for bridging thienopyridine-treated patients to CABGStage II Randomized, Double-Blind, Placebo-Controlled
35Bridging 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 eventsWithout increased risk of bleeding before or during CABG, although with a numerical increase in minor pre-CABG bleedingIndependent of prior thienopyridine dose & time of discontinuationConsistent pharmaocdynamic effect during IV infusionRapid offset after IV discontinuation prior to surgeryNo increased incidence of adverse events (e.g. dyspnea) or laboratory abnormalities despite extended dosing
36TICAGRELOR Not a prodrug; does not require metabolic activation Rapid onset of inhibitory effect on P2Y12 receptorGreater inhibition of platelet aggregation than clopidogrelDegree of inhibition reflects plasma concentrationFaster offset of effect than clopidogrelFunctional recovery of all circulating plateletsDisplays no significant affinity for other P2 receptorsP2Y12 receptor is targeted by ticagrelor via noncompetitive mechanism suggesting existence of an independent receptor binding site
37DISPERSE TRIALDose-Finding Investigative Study to Assess the Pharmakodynamic Effects in Atherosclerotic DiseaseComparison of Ticagrelor With ClopidogrelRandomized, double-blind, parallel-group dose-finding study200 stable atherosclerotic outpatients on treatment with aspirin 75 to 100 mg once dailyReceived ticagrelor (50, 100, or 200 mg BID or 400 mg QD) or clopidogrel 75 mg once daily for 28 days
38Ticagrelor (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 therapyOnly 1 major, nonfatal hemorrhage occurred in ticagrelor 400 mg QD groupModerate and minor bleeding events - dose related (from 29% to 51%) in ticagrelor and 32% in clopidogrelOther adverse events- dyspnea,dizziness, headache, and hematuriaDyspnea-dose related(10%-50mg BID, 16% mg BID and 20% mg QD)None of dyspnea was seriousNone associated with congestive heart failure or bronchospasm.
39DISPERSE-2 study Compared safety of ticagrelor with clopidogrel 990 patientsNSTEMI treated with aspirin and standard therapy for ACSRandomly assigned ticagrelor 90 mg BID or 180 mg BID and clopidogrel (300-mg LD 75-mg QD MD) for up to 12 weeksStatistically significant difference in major bleedings
40Posthoc analysisContinuous ECG- asymptomatic ventricular pauses 2.5 seconds were more common with ticagrelor 180 mg BIDDyspnea frequently with ticagrelorClinical impact appeared low, with few cases being considered serious or leading to discontinuation of treatmentPathogenesis of dyspnea is unclearHypothesis - may be mediated by adenosine
41SUBSTUDY OF DISPERSE-2Ticagrelor inhibition of platelet aggregation-dose dependentBoth doses achieved greater inhibition than clopidogrelTicagrelor produced further suppression of platelet aggregation in patients who were currently receiving clopidogrelStorey 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.
42PLATO Platelet Inhibition and Patient Outcomes Phase III randomized, double-blind, parallel group efficacy and safety studyTicagrelor (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 STEMI65% of enrolled patients underwent PCI
43After 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
44Major 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)<0.001Secondary objectives, n (%)Total death + MI + strokeCV death + MI + stroke +ischaemia + TIA + arterialthrombotic eventsMyocardial infarctionCV deathStroke901 (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)0.88 (0.81–0.95)0.84 (0.75–0.95)0.79 (0.69–0.91)1.17 (0.91–1.52)0.0050.0010.22Total death399 (4.5)506 (5.9)0.78 (0.69–0.89)The percentages are K-M estimates of the rate of the endpoint at 12 months.
45Stent thrombosis(evaluated in patients with any stent during the study)Ticagrelor (n=5,640)Clopidogrel(n=5,649)HR(95% CI)p valueStent thrombosis, n (%)DefiniteProbable or definitePossible, probable, definite71 (1.3)118 (2.1) (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)0.0090.020.01*Time-at-risk is calculated from first stent insertion in the study or date of randomisation
46Higher 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 - similarHigh 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
47PLATO - Dyspnoea *p values were calculated using Fischer’s exact test All patientsTicagrelor(n=9,235)Clopidogrel(n=9,186)p value*Dyspnoea, %AnyWith discontinuation of study treatment220.127.116.11.1<0.001*p values were calculated using Fischer’s exact test
48ELINOGREL Direct-acting, reversible P2Y12 inhibitor Can be administered both intravenously and orallyTerminal half-life of 12 hoursComplete inhibition of P2Y12-dependent ADP induced platelet aggregation was observed at the 20-mg dose.
49ERASE-MIEarly Rapid Reversal of Platelet Thrombosis With Intravenous PRT Before PCI to Optimize Reperfusion in Acute MIPhase II clinical trialRandomized trial evaluating the safety and tolerability of adjunctive antiplatelet therapy with intravenous elinogrel (10, 20, 40, and 60 mg) before PCI in patients with STEMIResults showed that incidence of bleeding events was infrequent and appeared to be similar in patients treated with all doses of elinogrel and in placeboERASE-MI, published in the December 2009 issue of the American Heart JournalDr Jeffrey Berger (Duke Clinical Research Institute, Durham, NC).
50INNOVATE-PCI Phase 2 Safety and Efficacy Study Evaluate use of both intravenous and oral formulationsMulticenter, randomized, double-blind, triple-dummy,clopidogrel-controlled study of intravenous and oral elinogrel compared with clopidogrel in non urgent (including elective) PCIAfter CAG randomized to clopidogrel or 1 of 3 doses of elinogrelStudy designed to understand clinical efficacy, biological activity, tolerability, and safety nonurgent PCI
51Death, MI, stroke, or revascularization INNOVATE PCITrial 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 mg, then 75 mg daily (n = 208).ResultsNo TIMI major bleeds in any groupNumerical increase in access bleeds requiring medical attention with higher doses of elinogrel compared with clopidogrelDeath, 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%(p = NS)%4.02.81.5ConclusionsAmong patients undergoing nonurgent PCI, the use of elinogrel is feasibleAccess site bleeds were numerically higher with increasing doses of elinogrelSimilar to ticagrelor, dyspnea was more common with study drugDeath, MI, stroke, or revascularizationElinogrel 150 mgElinogrel 100 mgClopidogrelPresented by Dr. Sunil Raul at ESC 2010