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P2Y12

Inhibitors - 1 P2Y12

Inhibitors - 2 GPIIb/IIIa Anticoagulants Studies

10 10 10 10 10

20 20 20 20 20

30 30 30 30 30

40 40 40 40 40

50 50 50 50 50

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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

*