NEWER ANTIPLATELETSJOURNAL 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

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

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

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

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

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

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)

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)

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

CV death, MI, or stroke0

10

20

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

% 13.916.0

Clopidogrel

PRINCIPLE – TIMI 44 Comparison with Higher Dose Clopidogrel

P<0.0001 for each

IPA (%; 20 mM ADP)

Hours 14 Days

IPA (%; 20 mM 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

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

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

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.

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

5.7%

2.1%

5.4%

1.0%

Death, MI,revascularization

Major bleed (TIMI criteria)

Abciximab (N=94)Cangrelor (N=105)

10 DAY EVENTS

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

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.

CHAMPION PCI

Comparing Treatment With Cangrelor (With Usual Care) to Usual Care, in Subjects Who Require PCI

N=8877

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

IndexProcedure

Endpoints

Subjects who require PCIStudy 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

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

Efficacy Endpoints at 48 hours

*mITT= modified intent to treat population (patients with PCI and study drug)

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) 0.14IDRDeath/Q-wave MI/ 0.5% 0.6% 0.78 (0.42, 1.44) 0.42Stent thrombosis

0.1 1 10Cangrelor

BetterClopidogrel

(600 mg) Better

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

CHAMPION PLATFORM

Efficacy Endpoints at 48 Hours

Efficacy mITT*(SA/UA/NSTEMI)

CangrelorN=2654

ComparatorN=2641

OR [95% CI] P value

Death/MI/IDR** 7.0% 8.0% 0.87 (0.71,1.07) 0.17

MI 6.7% 7.2% 0.92 (0.74,1.13) 0.42

Non QMI** 6.5% 6.9% 0.94 (0.76,1.16) 0.55

QMI 0.2% 0.3% 0.50 (0.15,1.65) 0.25

IDR 0.7% 0.9% 0.79 (0.43,1.44) 0.44

Stent Thrombosis 0.2% 0.6% 0.31 (0.11,0.85) 0.02

Death 0.2% 0.7% 0.33 (0.13,0.83) 0.02

Death/QMI/IDR 0.9% 1.6% 0.55 (0.33,0.93) 0.02

Cangrelor Better5.02.01.00.2 0.5

Comparator (placebo) Better

* *Primary Analysis ** mITT= modified intent to treat population (patients with PCI and study drug), QMI= Q-wave myocardial infarction

Difference in primary endpoint not statistically significant

Lower rates of stent thrombosis, mortality

No significant effect on transfusions, even in high risk subgroups

Groin hematomas increased, not unexpected versus placebo

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

Primary Efficacy Outcomes at 48 Hours, MITT

  Cangrelor(N=5472)

Clopidogrel(N=5470) OR (95% CI) P-value

Primary Analysis Adjusted1    

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, MITTStent thrombosis (keysecondary endpoint)

46/5470 (0.8%)

74/5469 (1.4%)

0.62 (0.43,0.90) 0.01

MI 207/5470 (3.8) 255/5469 (4.7) 0.80 (0.67,0.97) 0.02

Q-wave MI 11/5470 (0.2) 18/5469 (0.3) 0.61 (0.29,1.29) 0.19

IDR 28/5470 (0.5) 38/5469 ( 0.7) 0.74 (0.45,1.20) 0.22

Death 18/5470 (0.3) 18/5469 (0.3) 1.00 (0.52,1.92) >0.99

CV Death 18/5470 (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

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

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.

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

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

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

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

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.

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

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

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.

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

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

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 + stroke 864 (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

<0.001

0.005 0.001 0.22

Total death 399 (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.

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

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

PLATO - Dyspnoea

All patientsTicagrelor(n=9,235)

Clopidogrel(n=9,186)

p value*

Dyspnoea, % Any With discontinuation of study treatment

13.80.9

7.80.1

<0.001<0.001

*p values were calculated using Fischer’s exact test

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

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).

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

ischemic0

3

6• 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 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 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

THANK U