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TRANSCRIPT
8/15/2014
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P2Y12
Inhibitors - 1 P2Y12
Inhibitors - 2 GPIIb/IIIa Anticoagulants Studies
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Question 1 - 10
Time to 50% platelet inhibition if a clopidogrel 600 mg loading dose is administered
Answer 1 – 10
What is 2 – 4 hours?
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Question 1 - 20
Duration of clopidogrel for a NSTEMI patient who received a BMS
Answer 1 – 20
What is 1 month, ideally up to a year?
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Bare metal stent or drug-eluting stent for ACS indication
Aspirin 81mg* daily lifelong plus Clopidogrel 75mg daily or prasugrel 10mg daily or ticagrelor 90mg twice daily for at least 12 months
Bare metal stent for Non-ACS indication
Aspirin 81 mg daily lifelong plus Clopidogrel 75mg daily for a minimum of 1 month, and ideally up to 12 months**
Drug-eluting stent for Non-ACS indication
Aspirin 81mg daily lifelong plus Clopidogrel 75mg daily for at least 12 months
*Only 81mg of aspirin should be used with ticagrelor.
**A minimum of 1 month is preferred; but if the patient is at high risk for
bleeding, a minimum of 2 weeks can be considered.
DAPT Recommendations
Curfman GD, et al. NEJM 2007;356:1059-1060
*
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Question 1 - 30
Maximal platelet inhibition with prasugrel
Answer 1 – 30
What is 80%?
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P2Y12 Receptor Inhibitors
Clopidogrel
(Plavix®)
Prasugrel
(Effient®)
Ticagrelor
(Brilinta®)
Loading Dose
Maintenance
300-600mg
75 mg
60mg
10mg
180mg
90mg bid
Route Oral Oral Oral
Prodrug Yes Yes No
Reversible No No Yes
Hepatic
Metabolism
2C19, 1A2 3A, 2B6 3A4/5
Max Platelet
Inhibition (%)
35 79 88
Time to 50% platelet
inhibition (min)
120-240 60 30
*
Question 1 - 40
P2Y12 inhibitor which is a reversible inhibitor of platelets
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Answer 1 – 40
What is ticagrelor?
*
Novel Mechanism of Action
P2Y12
Receptor
ADP
GP IIb/IIIa
GP IIb/IIIa
Fibrinogen
Clopidogrel
Prasugrel
Ticagrelor
Platelet
*
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Question 1 - 50
P2Y12 inhibitor which exhibits adenosine related side-effects
Answer 1 – 50
What is ticagrelor?
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Bradycardia
• PLATO excluded:
– ↑ risk of bradycardia (SSS, 2nd or 3rd degree
AV block, syncope d/t bradycardia, not
pacemaker protected)
• 3,000 Holter substudy
– More patients with ventricular pauses
• Ticagrelor 6% vs Clopidogrel 3.5% (acute)
• Ticagrelor 2.2% vs Clopidogrel 1.6% (>1
month)
Scirica et al. J Am Coll Cardiol 2011;57:1908-16
Dyspnea
• Dyspnea
– Ticagrelor 14% vs Clopidogrel 8%
• Mild to moderate intensity
• Resolved during continued therapy
Storey et al. Am J Cardiol 2011;108:1542-46
*
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Question 2 - 10
Loading dose of prasugrel for a STEMI
Answer 2 – 10
What is 60 mg?
*
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Question 2 - 20
Absolute contraindication for prasugrel
Answer 2 – 20
What is history of TIA/Stroke?
*
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Question 2 - 30
Loading dose of ticagrelor for an ACS
Answer 2 – 30
What is 180 mg?
*
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Question 2 - 40
Onset of prasgurel if an appropriate loading dose is administered.
Answer 2 – 40
What is 60 minutes?
*
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Question 2 - 50
Mechanism of metabolism and elimination for ticagrelor
Answer 2 – 50
What is CYP 3A4 and P-glycoprotein?
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Ticagrelor Pharmacokinetics
Bioavailability 36% (take w or w/o food)
Median tmax
Ticagrelor 1.5h (1 – 4)
Active metabolite 2.5 (1.5 – 5)
Vd 88 L
Metabolism Hepatic CYP 3A4
Elimination Biliary secretion
t½
Ticagrelor – 7h
Active metabolite – 9 h
Protein binding >99%
Mean IPA following 6 weeks on placebo,
ticagrelor 90mg twice a day, or clopidogrel 75mg daily
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Strong CYP 3A
inhibitors
CYP 3A inducers CYP 3A substrates
Antiretrovirals Carbamazepine Cyclosporine
Clarithromycin Rifampin Tacrolimus
Ketoconazole Phenytoin Amlodipine
Itraconazole Dexamethasone Diltiazem, Verapamil
Voriconazole Phenobarbital Ator, simva, lovastatin*
↑ serum concentrations of simvastatin and lovastatin. Avoid doses >40mg.
*
Question 3 - 10
Trial showing bivalirudin was as efficacious and and caused less bleeding than GPIIb/IIIa
inhibitors plus heparin for STEMI patients
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Answer 3 – 10
What is HORIZONS-AMI?
HORIZONS - AMI
Hypothesis There is no difference between bivalirudin and GP IIb/IIIa inhibitors plus heparin
Population • >18 years, present within 12 hrs after onset of symptoms, ST-elevation >1mm in >2 contiguous leads, New LBBB, true posterior MI • N = 3,602
Intervention •Primary – open-label 1:1 randomization of bival or GP IIb/IIIa + heparin •Secondary – 3:1 randomization of paclitaxel or BMS
Endpoints • 1° = major bleeding (not related to CABG) and combined adverse CV events (death, reinfarction, TVR and stroke)
Limitations • Open-label
Stone et al. NEJM 2008;358:2218-2230
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HORIZONS AMI Results 30-Day Event Rates
* Primary Endpoint
% o
f P
ati
en
ts
PNI <0.0001
Psup = 0.006
PNI <0.0001
Psup <0.001 Psup = 1.00
*
12.1%
5.5%
8.3%
5.4% 4.9%
9.2%
0%
5%
10%
15%
20%
Net Clinical
Outcome
Major Bleeding Ischemic
Outcomes
Heparin+GPI Bivalirudin Alone
*
Question 3 - 20
Glycoprotein IIb/IIIa inhibitor that is not renally eliminated and does not require dose
adjustment for renal dysfunction.
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Answer 3 – 20
What is abciximab or reopro?
Glycoprotein IIb/IIIa Inhibitors Agent Molecule Dose Elimination Platelet
Binding
Bleeding
Integrilin®
(eptifibatide)
Peptide Bolus
180 mcg/kg X2
IV gtt
2mcg/kg/min X 18-24h
Renal (CI – dialysis)
CrCl<50mL/min
1 mcg/kg/min
Reversible 9-11%
Reopro®
(Abciximab)
Monoclonal
Antibody
Bolus
0.25 mg/kg
IV gtt
0.125 mcg/kg/min X 12
hours
Plasma Irreversible 14%
Aggrastat®
(Tirofiban)
Non-
Peptide
Bolus
0.4 mcg/kg/min X 30 min
IV gtt
0.1 mcg/kg/min up to 4
days
Renal CrCl <30mL/min
0.2mcg/kg/min
0.05mcg/kg/min
Reversible 10-12%
*
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Question 3 - 30
Glycoprotein IIb/IIIa inhibitor that is a reversible inhibitor of platelets.
Answer 3 – 30
What is eptifibatide or integrilin?
*
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Question 3 - 40
Trial illustrating upstream use of GP IIb/IIIa inhibitors increases the risk of bleeding.
Answer 3 – 40
What is EARLY - ACS?
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Event and Bleeding Rates
Study GPI N Routine Stenting (%)
ADP Antag Pre-load
ADP Antag Post-PCI
GPI vs Placebo
Death or MI at 30 days
Major (%) Minor (%)
EPIC 1994
Abciximab 2,099 No (<2%) No N/A 6.6 vs 9.6 p = 0.01
14 vs 7 p=0.001
N/A
EPILOG 1997
Abciximab 2,792 No (15%) No N/A 4 vs 9.1 p<0.001
2 vs 3.1 p=NS
4 vs 3.7 p=NS*
ESPRIT 2000
Eptifibatide 2,064 Yes (95%) No Yes 6.4 vs 10.2 p=0.0014
1 vs 4 p=0.027
2.8 vs 1.7 p=NS
PURSUIT 1998
Eptifibatide 10,948 50% No N/A 14.2 vs 15.7 p=0.004
3 vs 1.3 p<0.001
11.1 vs 4.7 p<0.001
CADILLAC stent 2002
Abciximab 1,036 100 Yes Yes 4.4 vs 5.7 p=NS
0.8 vs 0.2 p=NS†
4.3 vs 2.5 p=NS†
*In EPILOG, GPI + high-dose UFH had ↑minor bleeding 7.4 vs 3.7% p<0.001. †GUSTO bleeding criteria was used in CADILLAC.
Adapted from J Am Coll Cardiol Intv 2010;3:1209-1210
Event and Bleeding Rates in the era of routine stenting and ADP antagonists
Study GPI N Routine Stenting (%)
ADP Antag Load
ADP Antag Post-PCI
GPI vs Placebo
Death, MI or urgent revasc.
at 30 days
Major (%) Minor (%) % requiring PRBCs
ISAR-React 2004
Abciximab 2,159 Stable CAD
Yes Yes Yes 4 vs 4 p = NS
1 vs 1 p=NS
2 vs 2 p=NS
2 vs 1 p=0.007
ISAR-Sweet 2004
Abciximab 701 DM w/ Stable CAD
Yes Yes Yes 5.7 vs 4.3 P=0.39
1.1 vs 0.9 p=NS
3.4 vs 1.4 p=0.09
2.3 vs 0.6 p=0.11
ISAR-React 2 2006
Abciximab 2022 ACS
Yes Yes Yes 8.9 vs 11.9 p=0.03*
1.4 vs 1.4 p=NS
4.2 vs 3.3 p=NS
2.5 vs 2 p=NS
Adapted from J Am Coll Cardiol Intv 2010;3:1209-1210
*In pt with ↑ troponins, events rates were lower with GPI: 13.1 vs 18.3% p=0.02
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EARLY ACS
Hypothesis Early, routine administration of eptifibatide would be superior
to delayed, provisional administration in reducing ischemic
complications among high risk pt
Population • >18 years, cardiac ischemia at rest >10 min within 12 hr of
randomization
•High risk = > 2 of the following: ↓ST or transient ↑ST, ↑ troponin
/CKMB, > 60 years or 50-59 w/known vascular disease
• N = 9,492
Intervention •1:1 randomization of early versus delayed therapy
•Early 180mcg/kg x 2 then 2 mcg/kg/min (1mcg/kg/min for
CrCl<50mL/min) continued for 18 – 24 hr
•Investigators could request IIb/IIIa kit for pt who would benefit
Giugliano et al. NEJM 2009;360:2176-2190
EARLY ACS
Additional
Therapy
•ASA 162-325mg or 150-500mg IV then 75mg daily
•UFH target ACT 250 sec
•Enoxaparin 0.3mg IV if last dose in 8-12 hr
•Early clopidogrel 300mg or 600mg at PCI then 75mg daily
Endpoints •1° = Death, MI, recurrent ischemia requiring revascularization, or
thrombotic bailout at 96 hrs
•2° = Death or MI within 30 days, rates of hemorrhage or
transfusion within 120 hr of randomization
Limitations •No restriction to a strict placebo group
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EARLY ACS
p=0.23
p=0.08
p=0.02
P<0.001
P<0.001
10 11.2
12.3
2.6 1.8
4.3
1.9
6.7
Reduce the risk of bleeding
with GP IIb/IIIa inhibitors
Strategy
Dosage and infusion •Minimize the infusion duration •Target ACTs of 200 – 250 sec •Adjust eptifibatide and tirofiban in pt with renal dysfunction
Patient selection •Avoid GP IIb/IIIa Inhibitors in pt >75 years of age or at high risk for bleeding •Careful upstream selection
•Elevated troponins •Not received a thienopyridine load
Access selection and management •Transradial approach •Smaller sheath size •Prompt sheath removal •Use of vascular closure devices
*
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Question 3 - 50
Platelets are not as effective to treat bleeding immediately after administration of this GP
IIb/IIIa inhibitor.
Answer 3 – 50
What is eptifibatide or Integrilin?
*
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Question 4 - 10
CrCl cut off for enoxaparin.
Answer 4 – 10
What is 30 mL/min?
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Low-Molecular Weight Heparin
• Dose – Enoxaparin
• 1mg/kg sq q12h • 0.3mg/kg IV should be given if
– <2 therapeutic SQ doses of enoxaparin – Last dose was 8 – 12hr before PCI
• Continue for 24 – 48 hr or until end of PCI
• Side Effects – Bleeding – Thrombocytopenia (HIT/HITT)
• Monitoring Parameters
– Not necessary when using for a short duration – Can not monitor aPTT or ACT – Caution in patients with renal impairment (CrCl<30mL/min)
*
Question 4 - 20
Anticoagulant that is usually only infused in the cath lab for PCI.
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Answer 4 – 20
Bivalirudin
Angiomax® (bivalirudin) • Alternative to heparin or LMWH + GP IIb/IIIa
inhibitors
• Mechanism of Action – Reversible inhibitor of thrombin
• Dose – Bolus 0.75 mg/kg
• Side Effects – Bleeding
Creatinine Clearance (mL/min) Dose (mg/kg/hr)
Greater than 30 1.75
Less than 30 but not dialysis 1
Dialysis patients (hemo-, peritoneal, CVVHD) 0.25
*
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Question 4 - 30
Anticoagulant which can not be given alone for PCI.
Answer 4 – 30
What is fondaparinux or arixtra?
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Factor Xa Inhibitors Dose
Fondaparinux 2.5mg sq q24h
Side Effects
Bleeding
Thrombocytopenia
Monitoring Parameters
Caution with renal impairment and
contraindication in SCr > 3.0 mg/dL
CrCl<30mL/min
Can not monitor aPTT or ACT
Note: Because of the risk of catheter thrombosis, fondaparinux should not be
used as the sole anticoagulant to support PCI.
*
Question 4 - 40
Anticoagulant contraindicated in dialysis patients.
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Answer 4 – 40
What is enoxaparin or lovenox?
*
Question 4 - 50
ACT goal for NSTEMI patients receiving a PCI when heparin plus a IIb/IIIa inhibitor are
administered
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Answer 4 – 50
200 - 250 seconds
Activated Clotting Time (ACT)
Goals
Goal ACT without a Glycoprotein IIb/IIIa
inhibitor
– 300 – 350 seconds (for Hemochron Signature Elite®)
Goal ACT with a Glycoprotein IIb/IIIa
inhibitor
– 200 seconds
Anderson JL. Circulation 2011;123:e246-e579
*
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Question 5 - 10
P2Y12 inhibitor which has been studied with thrombolytics.
Answer 5 – 10
What is clopidogrel?
*
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Question 5 - 20
Subgroup of patients in PLATO where ticagrelor did not show a benefit over clopidogrel
Answer 5 – 20
What is the North American subgroup?
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PLATO Hypothesis Ticagrelor is superior to clopidogrel for the prevention of
vascular events and death a broad ACS population
Population • >18 years, Ischemic sx >10 min within 24 hr of randomization
• UA/NSTEMI – > 2 of the following
• ST deviation >1mm
• ↑ cardiac biomarkers
• One risk factor (age >60, previous MI/CABG; CAD with
>50% stenosis in >2 vessels, previous CVA/TIA, carotid
stenosis > 50%, DM, PAD, CrCl<60 mL/min/1.73m2)
• STEMI – persistent ↑ ST-segment >1mm, new LBBB
Endpoints • 1° = CV death, nonfatal MI or stroke
• 2° = 30 and 90 day assessment of above composite endpoint,
stent thrombosis, TIMI bleeding
Wallentin L. NEJM 2009;361:1045-57
PLATO
Unstable Angina (Moderate/High Risk) (N=3112)
NSTEMI (N=7955)
STEMI (N=7026)
Other (N=531)
Clopidogrel
If pretreated no load
Or
300mg load, 75mg po qd
(300mg load allowed pre-PCI)
Ticagrelor
180mg load then
90mg po bid
(additional 90mg pre-PCI)
Wallentin L. NEJM 2009;361:1045-57
Aspirin loading dose 160-500mg then 75-100mg daily
Recommendations for CABG patients:
Study drugs withheld prior to surgery: 5 d for clopidogrel and 24–72 h for ticagrelor.
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Exclusion • Intracranial hemorrhage
• GI bleed w/in 6 months
• Other factors that predispose bleeding
• Major surgery within 30 days
• Fibrinolytics w/in 24 hours
• Need for oral anticoagulation
• Increased risk of bradycardia
• Concomitant tx with strong CYP 3A inhibitor or inducer
• Dialysis required
• Moderate severe liver disease
• Known clinically significant thrombocytopenia or anemia
Results
Wallentin L, et al. N Engl J Med 2009;361:1045-57
Outcome: n (%) Ticagrelor
(n=9333)
Clopidogrel
(n=9291)
HR for Ticagrelor
(95% CI) p value
Primary Composite: 864 (9.8) 1014 (11.7) 0.84 (0.77-0.92) <0.001
Death from
vascular causes 353 (4.0) 442 (5.1) 0.79 (0.69-0.91) 0.001
Non-fatal MI 504 (5.8) 593 (6.9) 0.84 (0.75-0.95) 0.005
Non-fatal stroke 125 (1.5) 106 (1.3) 1.17 (0.91-1.52) 0.22
Stent Thrombosis 118 (2.2) 158 (2.9) 0.75 (0.59-0.95) 0.02
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PLATO
Primary End Point
Wallentin L. NEJM 2009;361:1045-57
9.8
11.7%
9.8%
Concerns from PLATO: Effect by
Region
North America
(n=1814)
Central/South
America
(n=1237)
Europe, Middle
East, Africa
(n=13859)
Asia, Australia
(n=1714)
• Primary Efficacy in US (n=1413):
• Ticagrelor 12.6% vs. Clopidogrel 10.1%, HR=1.27 (0.92-1.75)
Wallentin L. NEJ M 2009;361:1045-57
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PLATO
Major Bleeding
Wallentin L et al. NEJM 2009;361:1045-57
11.6%
11.2%
*
Question 5 - 30
Trial supporting use of clopidogrel in patients who are medically managed with ACS for up
to a year
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Answer 5 – 30
What is CURE?
*
Question 5 - 40
Study showing high dose aspirin compared to low dose has the same benefit, but causes
more minor bleeding
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Answer 5 – 40
What is Current-Oasis - 7?
North America Effect
• CURRENT-OASIS 7
– Double-blind random allocation of clopidogrel
• Standard dose (300 mg x1; 75 mg/day)
• Double dose (600 mg x1; 150 mg/day x 6; 75 mg/day)
– Open label aspirin
• High dose (300-325 mg/day)
• Low dose (75-100 mg/day)
The CURRENT-OASIS 7 Investigators. N Engl J Med 2010;363:930-42
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Outcomes
(30 days)
High
Dose
ASA
Low
Dose
ASA
HR for High
Dose
(95% CI)
p
value
All
Patients
(n=25,086)
CV Death, MI,
Stroke 4.2% 4.4%
0.97
(0.86-1.09) 0.61
Major Bleed 2.3% 2.3% 0.99
(0.84-1.17) 0.90
Minor Bleed 5.0% 4.4% 1.13
(1.00-1.27) 0.04
PCI
Patients
(n=17,263)
CV Death, MI,
Stroke 4.1% 4.2%
0.98
(0.84-1.13) 0.76
Major Bleed 1.5% 1.3% 1.18
(0.92-1.53) 0.20
Minor Bleed 5.0% 4.3% 1.18
(1.03-1.36) 0.019
The CURRENT-OASIS 7 Investigators. N Engl J Med 2010;363:930-42
*
Question 5 - 50
Patient population in Triton -TIMI 38 subgroup analysis where the benefit possibly outweighs
the risks even if a patient is greater than 75 years of age.
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Answer 5 – 50
What is diabetics?
Triton-TIMI 38 Hypothesis Prasugrel is superior to clopidogrel in addition to aspirin in patients
with ACS who undergo PCI.
Population • >18 years, ACS (10,074 UA/NSTEMI and 3534 STEMI)
•UA/NSTEMI – Ischemic sx >10 min within 72 hr of randomization, TIMI
score > 3, ST deviation >1mm or ↑ cardiac biomarkers
•STEMI – within 12 hrs of symptom onset or >12 hours, but <14 days from
onset
•Planned PCI
Intervention •Prasugrel 60mg, followed by 10mg daily
•Clopidogrel 300mg, followed by 75mg daily
•Aspirin 75 – 162mg daily
Endpoints •1° = CV death, nonfatal MI or stroke
•2° = 30 and 90 day assessment of above composite endpoint, stent
thrombosis, TIMI bleeding
Limitations •Load of clopidogrel 300mg
•Majority of patients (~70%) loaded at time of PCI
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TRITON-TIMI 38
Wiviott et al. NEJM 2007;357:2001-2015
Results
Outcome: n (%) Prasugrel
(n=6813)
Clopidogrel
(n=6795)
HR for Prasugrel
(95% CI) p value
Primary Composite: 643 (9.9) 781 (12.1) 0.81 (0.73-0.90) <0.001
Death from CV
causes 133 (2.1) 150 (2.4) 0.89 (0.70-1.12) 0.31
Non-fatal MI 475 (7.3) 620 (9.5) 0.76 (0.67-0.85) <0.001
Non-fatal stroke 61 (1.0) 60 (1.0) 1.02 (0.71-1.45) 0.93
Stent Thrombosis 68 (1.1) 142 (2.4) 0.48 (0.36-0.64) <0.001
Wiviott SD, et al. N Engl J Med 2007;357:2001-15
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Wiviott et al. NEJM 2007;357:2001-2015
End point Prasugrel
(N=6741)
Clopidogrel
(N=6716)
Hazard Ratio for
Prasugrel
(95%)
P Value
Life-threatening 85 (1.4) 56 (0.9) 1.52 (1.08 – 2.13) 0.01
Non-CABG-related
TIMI major bleeding
146 (2.4) 111 (1.8) 1.32 (1.03 – 1.68) 0.03
Major or Minor TIMI
bleeding
303 (5.0) 231 (3.8) 1.31 (1.11 – 1.56) 0.002
Bleeding requiring
transfusion
244 (4.0) 182 (3.0) 1.34 (1.11 – 1.63) <0.001
CABG-related TIMI
major bleeding
24 (13.4) 6 (3.2) 4.73 (1.90 – 11.82) <0.001
Diabetes Sub-Group Analysis
• Net Clinical Benefit: NNT = 22
Montalescot G. Eur Heart J 2009;11:18-24
*