Transcript 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
 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, parallelgroup, multinational trial
 Evaluated 13 608 high-risk patients
with ACS who required PCI
 Patients randomized to receive 60mg 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
TRILOGY ACS
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)
• At 30 months, among patients <75 years of age:
20
16.0
%
13.9
• 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 )
10
• 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
0
CV death, MI, or stroke
Prasugrel
Clopidogrel
Conclusions
• Among medically treated patients with NSTEACS, 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
PRINCIPLE – TIMI 44
IPA (%; 20 mM ADP)
N=201
P<0.0001 for each
Comparison with Higher
Dose Clopidogrel
IPA (%; 20 mM ADP)
P<0.0001
Prasugrel 60 mg
Clopidogrel 600 mg
Clopidogrel Prasugrel
150 mg
10 mg
Hours
Wiviott et al Circ 2007 (In Press)
14 Days
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
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
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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
10 DAY EVENTS
5.4%
5.7%
Abciximab (N=94)
Cangrelor (N=105)
2.1%
1.0%
Death, MI,
revascularization
Major bleed (TIMI criteria)
STEP-AMI
 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
 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
Subjects
Subjects who require PCI (with or without stent)
1:1 randomization to main treatment groups
Double 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 PCI
Study drug infusion: for at least 2 hours or the duration
of the procedure, whichever is longer
Index
Procedure
Clopidogrel capsules
(600 mg)
Placebo capsules
(to match)
Clopidogrel maintenance (at the discretion of the physician)
Endpoints
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
Cangrelor Clopidogrel
(N=3897)
(N=3871)
Efficacy mITT*
OR (95% CI)
P Value
Death/MI/IDR
(primary endpoint)
MI
7.5%
7.1%
1.05 (0.88, 1.24)
0.59
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/
IDR
Death/Q-wave MI/
Stent thrombosis
0.6%
0.9%
0.67 (0.39, 1.14)
0.14
0.5%
0.6%
0.78 (0.42, 1.44)
0.42
0.1
1
Cangrelor
Better
10
Clopidogrel
(600 mg) Better
*mITT= modified intent to treat population (patients with PCI and study drug)
 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)
Cangrelor Comparator
N=2654
N=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
0.7%
0.9%
0.79 (0.43,1.44)
0.44
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
IDR
Stent Thrombosis
0.2
0.5
Cangrelor Better
* *Primary Analysis
1.0
2.0
5.0
Comparator (placebo) Better
** 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
257/5470
(4.7%)
322/5469
(5.9%)
0.78
(0.66, 0.93)
0.005
Primary Analysis Adjusted1
Death/MI/IDR/ST
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
207/5470 (3.8)
255/5469 (4.7)
0.80 (0.67,0.97)
0.02
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
18/5470 (0.3)
18/5469 (0.3)
1.00 (0.52,1.92)
>0.99
MI
Q-wave MI
CV Death
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
 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 thienopyridinetreated patients to CABG
 Stage II Randomized, DoubleBlind, 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
TICAGRELOR
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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
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
clopidogrel 75 mg once daily for 28 days
 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.
DISPERSE-2 study

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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
 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
SUBSTUDY OF DISPERSE-2
 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
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 Clopidogrel
(n=9,333) (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
901 (10.2) 1,065 (12.3) 0.84 (0.77–0.92)
<0.001
1,290 (14.6) 1,456 (16.7) 0.88 (0.81–0.95)
<0.001
CV death + MI + stroke +
ischaemia + TIA + arterial
thrombotic events
Myocardial infarction
504 (5.8)
593 (6.9)
0.84 (0.75–0.95)
0.005
CV death
353 (4.0)
442 (5.1)
0.79 (0.69–0.91)
0.001
Stroke
125 (1.5)
106 (1.3)
1.17 (0.91–1.52)
0.22
399 (4.5)
506 (5.9)
0.78 (0.69–0.89)
<0.001
Total death
The percentages are K-M estimates of the rate of the endpoint at 12 months.
Stent thrombosis
(evaluated in patients with any stent during the study)
Ticagrelor Clopidogrel
(n=5,640)
(n=5,649)
HR
(95% CI)
p value
Stent thrombosis, n (%)
Definite
71 (1.3)
106 (1.9)
0.67 (0.50–0.91) 0.009
Probable or definite
118 (2.1)
158 (2.8)
0.75 (0.59–0.95)
0.02
Possible, probable, definite
155 (2.8)
202 (3.6)
0.77 (0.62–0.95)
0.01
*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 patients
Ticagrelor Clopidogrel
(n=9,235) (n=9,186)
p value*
Dyspnoea, %
Any
13.8
7.8
<0.001
With discontinuation of study treatment
0.9
0.1
<0.001
*p values were calculated using Fischer’s exact test
ELINOGREL

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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.
ERASE-MI
 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, published in the December 2009 issue of the American Heart JournalDr
Jeffrey Berger (Duke Clinical Research Institute, Durham, NC).
INNOVATE-PCI
 Phase 2 Safety and Efficacy Study
 Evaluate use of both intravenous and oral formulations
 Multicenter, randomized, double-blind, tripledummy,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
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 300600 mg, then 75 mg daily (n = 208).
Results
•
•
(p = NS)
6
•
%
4.0
2.8
3
•
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%
1.5
Conclusions
0
• Among patients undergoing nonurgent PCI, the use
of elinogrel is feasible
ischemic
Death, MI, stroke,
or revascularization
Elinogrel
150 mg
Elinogrel
100 mg
Clopidogrel
• 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
THANK U