Oral Antiplatelet Therapy

Scott Davis, MD, FACC BHHI Primary Care Symposium

February 28, 2014

Financial Disclosures

Boston ScientificGilead

Thrombus Formation

Tissue Factor

Thrombin

Prothrombin

Collagen

TXA2

PlateletactivationADP

Plasma Clotting cascade

THROMBUS

Fibrinogen Fibrin

Platelet aggregation

Two key elements: cellular (platelets) and plasmatic (coagulation factors)

ANTITHROMBOTIC DRUGS USED IN ACS/PCI

I. ANTIPLATELET DRUGS

• Glycoprotein IIb/IIIa inhibitors (abciximab; eptifibatide; tirofiban)

II. ANTICOAGULANT DRUGS• Anti-Factor II (anti-thrombins)

- Indirect Thrombin Inhibitors (UFH & LMWH)- Direct Thrombin Inhibitors (Bivalirudin)

• Anti-Factor X- Fondaparinux

• COX-1 inhibitor (aspirin)• P2Y12 inhibitors (ticlopidine; clopidogrel; prasugrel; ticagrelor)

ORAL

1. Which drugs do we use?

2. When to start and at which dose?

3. Length of therapy?

Oral Antiplatelet Therapy in ACS/PCI

The combination of aspirin and a P2Y12

receptor inhibitor represents the treatment

of choice for the prevention of recurrent

ischemic events, including stent thrombosis.

Oral Antiplatelet Therapy in ACS/PCI

ADP = adenosine diphosphate, TXA2 = thromboxane A2, COX = cyclooxygenase.

Adapted from Schafer AI. Am J Med. 1996;101:199-209.

CollagenThrombin

TXA2

ADP

TXA2

ADP P2Y12

Aspirin

ADP

cAMP

ActivationGP IIb/IIIa

(fibrinogen receptor)

COX-1

Mechanisms of Action of Oral AntiplateletTherapies

Clopidogrel

Ticlopidine

PrasugrelTicagrelor

12

10

8

6

4

2

0MATTISISAR

n:517 n:350STARSn:1653

FANTASTIC

n:485

MA

CE

(%)

Ticlopidine during PCI with use of Coronary Stents

- Schomig et al, N Engl J Med 1996- Urban et al, Circulation 1998

- Bertrand et al, Circulation 1998- Leon et al, Circulation 1998

CoumadinASA+TicloASA

Ticlopidine(1st generation)

N

S Cl

The Thienopyridine Family

Cl Clopidogrel

(2nd generation)

NS

O

O CH3C

Delayed time frame to achieve full antiplateleteffects

Solution to these problems:Better Safety profile - Fewer side effects

P2Y12 ADP receptor antagonism: antithrombotic treatment of choice for coronary stenting

Side effects: neutropenia, thrombocytopenia, rash, diarrhea, etc

(CLASSICS trial. Bertrand NE et al. Circulation 2000; 102: 624–9).

Rapid onset of action with a loading dose(Cadroy Y et al. Circulation. 2000;101:2823-28).

Better clinical outcomes(Bhatt DL et al. J Am Coll Cardiol 2002; 39: 9–14.).

CUREPrimary Endpoint—MI/Stroke/CV Death

6 9

Months of Follow-Up

*Other standard therapies were used as appropriate. Yusuf S et al. N Engl J Med. 2001;345:494-502.

0.00

0.02

0.06

0.04

0.08

0.10

0.12

0.14

Cum

ulat

ive

Haz

ard

Rat

e

Clopidogrel+ ASA*

3

Placebo+ ASA*

P=0.00009 N=12,562 20% RRR

0 12

The primary outcome occurred in 9.3% of pts in the clopidogrel + ASA group and

11.4% in the placebo + ASA group.

Strategies of ADP P2Y12 mediated platelet inhibition

0

5

10

15

0 30 60 90Wiviott et al. NEJM 2007

180 270 360 450

HR 0.81(0.73-0.90) P=0.0004NNT = 46

Prasugrel

Clopidogrel

Days

Endp

oint

(%)

12.1

9.9

35eventsHR 1.32(1.03-1.68)

P=0.03NNH =

167

Prasugrel

Clopidogrel

2.41.8

138events

Balance of Efficacy and Safety

CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

////

LastMaintenance

DoseLoading Dose

Time (hours)Onset Maintenance Offset

100

90

80

70

60

50

40

30

20

10

0

IPA

%Ticagrelor (n=54) Clopidogrel (n=50) Placebo (n=12)

0 .5 1 2 4 8 24 6 weeks 0 2 4 8 24 48 72 120 168 240

*

*

****

*

*

*

‡

†

†

//

//20 µM ADP- Final Extent

ONSET/OFFSET STUDY

Gurbel PAet al. Circulation 2010

Novel P2Y12 receptor antagonists:When “NOT to Use” or “Use with Caution”?

– Prasugrel.Contraindicated: high-risk bleeding; prior TIA/stroke;

hypersensitivity

Precautions: elderly (>75y), low-weight (<60kg); CABG/surgery (7days).

– Ticagrelor.Contraindicated: high-risk bleeding; prior hemorrhagic stroke;

severe hepatic dysfunction

Precautions: compliance (b.i.d. administration), drug interactions (CYP 3A4 interfering agents); regional differences (North America/ASA dose <100mg), COPD/asthma, bradyarrhythmia, gout syndromes, CABG/surgery (5 days).

1. Which drugs should we use?

2. When to start and at which dose?

3. Length of therapy?

Oral Antiplatelet Therapy in ACS/PCI

Patients already taking daily aspirin therapy should take 81 to 325 mg prior to PCI.

Patients not on aspirin therapy should be given nonenteric aspirin 325 mg prior to PCI.

Oral Antiplatelet Therapy

I IIa IIb III

I IIa IIb III

I IIa IIb III

2011ACCF/ AHA/ SCAI Guideline for PCI

After PCI, aspirin should be continued indefinitely.

After PCI, it is reasonable to use 81 mg per day of aspirin in preference to higher maintenance doses.

I IIa IIb III

2011ACCF/ AHA/ SCAI Guideline for PCI

Oral Antiplatelet Therapy (cont.)

Antithrombotic Trialists’ CollaborationDifferent Doses of Aspirin vs Control

Daily Dose Aspirin Control Reduction

Asp 500 -1500Asp 160 -325Asp 75-150Asp <75

14.5%11.5%11.0%17.3%

17.2% 19%±326%±332%±613%±8

14.8%15.2%19.4%

Any aspirin 12.9% 16.1% 23%±2 (2P<0.00001)

1.00.50.0 1.5 2.0BMJ 2002;324:71-86

Bleeding

P2Y12 Inhibitors

A loading dose of a P2Y12 receptor inhibitor should be given to patients undergoing PCI with stenting. Options include:

a.Clopidogrel 600 mg (ACS and non-ACS patients).b.Prasugrel 60 mg (ACS patients).c.Ticagrelor 180 mg (ACS patients).

I IIa IIb III

I IIa IIb III

2011ACCF/ AHA/ SCAI Guideline for PCI

Oral Antiplatelet Therapy

ACC/AHA/SCAI 2007 Focused Update for PCI

C

Oral Antiplatelet Adjunctive Therapies

(New Recommendation)

Use of warfarin in conjunction with aspirin and/or clopidogrel is associated with an increased risk of bleeding and should be monitored closely.

B

In patients requiring warfarin, clopidogrel, and aspirin therapy after PCI, an INR of 2.0 to 2.5 is recommended with low dose aspirin (75 mg to 81 mg) and a 75-mg dose of clopidogrel.

I IIa IIb III

%100

90

80

70

60

500 200 300 450

Days

600

Dual therapyTriple therapy (INR: 2.0-2.5)

Triple therapy (INR > 2.5)

95.1 %

95.1 %

Blee

ding

even

tfre

esu

rviv

al

66.7 %

†

‡

† Log Rank, p<0.0001 vs dual therapy

‡ Log Rank, p<0.0001 vs triple therapy (INR: 2.0-2.5)

Rossini & Angiolillo Am J Cardiol 2008

Bleeding risk in PCI patients on dual antiplatelettherapy requiring oral anticoagulation

PPI should be used in patients with history of prior GI bleeding who require DAPT (In patients in whom there is a clear indication for PPI therapy, some clinicians may choose to use a PPI other than omeprazole).

I IIa IIb IIIPPI use is reasonable in patients with increased risk of gastrointestinal bleeding (advanced age, concomitant use of warfarin, steroids, NSAIDS, H pylori infection, etc.) who require DAPT.

Routine use of a PPI is not recommended for patientsat low risk of gastrointestinal bleeding, who have muchless potential to benefit from prophylactic therapy.

PPIs and Antiplatelet TherapyI IIa IIb III

I IIa IIb III

No Benefit

2009 Updated Labeling forClopidogrel–PPI Interaction

• FDA-required label changes:2

– Warning: “Co-administration of Plavix with omeprazole, a proton pump inhibitor that is an inhibitor of CYP2C19, reduces the pharmacological activity of Plavix if given concomitantly or if given 12 hours apart”

– Drug-Drug Interactions: “Avoid concomitant use of drugs that inhibit CYP2C19, including omeprazole, esomeprazole, cimetidine, fluconazole, ketoconazole, voriconazole, etravirine, felbamate, fluoxetine, fluvoxamine, and ticlopidine”

– Based on PK/PD studies showing concomitant omeprazole reduced clopidogrel active metabolite and effect on platelets1

• Did not include COGENT study data2

• EMEA warning extends to discourage concomitant use of all PPIs3

– Concomitant use of drugs that inhibit CYP2C19 discouraged; concomitant use of any PPI “should be avoided unless absolutely necessary”4

EMEA=European Medicines Agency; FDA=Food and Drug Administration; PD=pharmacodynamic; PK=pharmacokinetic.1Food and Drug Administration. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafety InformationforHeathcareProfessionals/ucm190787.htm. Published November 17, 2009. Accessed January 22, 2010. 2Plavix [package insert]. Bridgewater, NJ: Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; 2009. 3Wathion N. http://www.emea.europa.eu/humandocs/PDFs/ EPAR/Plavix/32895609en.pdf. Published May 29, 2009. Accessed January 22, 2010. 4Plavix [summary of product characteristics]. Paris, France: Sanofi Pharma Bristol-Myers Squibb SNC; 2009.

1. Which drugs should we use?

2. When to start and at which dose?

3. Length of therapy?

Oral Antiplatelet Therapy in PCI

After PCI, aspirin should be continued indefinitely.

The duration of P2Y12 inhibitor therapy after stent implantation should generally be as follows:

a) In patients receiving a stent (BMS or DES) during PCI for ACS, P2Y12 inhibitor therapy should be given for at least 12 months (clopidogrel 75 mg daily); prasugrel 10 mg daily; and ticagrelor90 mg twice daily.

b) In patients receiving a DES for a non–ACS indication, clopidogrel 75 mg daily should be given for at least 12 months if patients are not at high risk of bleeding.

c) In patients receiving a BMS for a non-ACS indication, clopidogrelshould be given for a minimum of 1 month and ideally up to 12 months (unless the patient is at increased risk of bleeding; then it should be given for a minimum of 2 weeks).

I IIa IIb III

I IIa IIb III

2011ACCF/ AHA/ SCAI Guideline for PCIPostprocedural Antiplatelet

Therapy

Patients should be counseled on the importance of compliance with DAPT, and that therapy should not be discontinued before discussion with the relevant cardiologist.

After PCI, it is reasonable to use 81 mg per day of aspirin in preference to higher maintenance doses.

If the risk of morbidity from bleeding outweighs the anticipated benefit afforded by a recommended duration of P2Y12 inhibitor therapy after stent implantation, earlier discontinuation (e.g., >12 months) of P2Y12 inhibitor therapy is reasonable.

Postprocedural Antiplatelet Therapy (cont.)

I IIa IIb III

I IIa IIb III

I IIa IIb III

2011 ACCF/AHA/SCAI Guideline for PCI

Continuation of clopidogrel, prasugrel or ticagrelor beyond 12 months may be considered in patients undergoing DES placement.

Postprocedural Antiplatelet Therapy (cont.)

I IIa IIb III

2011ACCF/ AHA/ SCAI Guideline for PCI

Platelet Function and Genetic Assays&

Antiplatelet Drug Response

Platelet function testing may be considered in patients at high risk for poor clinical outcomes.

In clopidogrel-treated patients with high plateletreactivity, alternative agents, such as prasugrelor ticagrelor, might be considered.

The routine clinical use of platelet function testing to screen clopidogrel-treated patients undergoing PCI is not recommended.

2011 ACCF/AHA/SCAI Guideline for PCI

I IIa IIb III

I IIa IIb III

I IIa IIb III

No Benefit

Platelet FunctionTesting

Genetic testing might be considered to identify whether a patient at high risk for poor clinical outcomes is predisposed to inadequate platelet inhibition with clopidogrel.

When a patient predisposed to inadequate platelet inhibition with clopidogrel is identified by genetic testing, treatment with an alternate P2Y12 inhibitor (e.g., prasugrelor ticagrelor) might be considered.

The routine clinical use of genetic testing to screen clopidogrel-treated patients undergoing PCI is not recommended.

2011 ACCF/AHA/SCAI Guideline for PCI

I IIa IIb III

I IIa IIb III

I IIa IIb III

No Benefit

Clopidogrel Genetic Testing

Aspirin Resistant Patient Management

• Educate patient on importance of compliance

• Eliminate interfering substances (ibuprofen)

• Increase aspirin dose (?) (increasing the dose of aspirin does not enhance COX-1 inhibition)

• Increase dose regimen from once to twice daily administration (?) (overcome platelet turnover)

• Add or switch antiplatelet treatment (?)

Questions?