Antiplatelet Therapy in ACS and PCI: current state of the art and future therapies Stephen D Wiviott MD Cardiovascular Division Brigham and Women’s Hospital

Antiplatelet Therapy in ACS and PCI: current Antiplatelet Therapy in ACS and PCI: current state of the art and future therapiesstate of the art and future therapies

Stephen D Wiviott MDStephen D Wiviott MDCardiovascular DivisionCardiovascular Division

Brigham and Women’s HospitalBrigham and Women’s HospitalAssistant Professor of MedicineAssistant Professor of Medicine

Harvard Medical SchoolHarvard Medical School Investigator, TIMI Study Group Investigator, TIMI Study Group

DisclosuresDisclosuresCME Honoraria: Eli Lilly, Daiichi Sankyo; CME Honoraria: Eli Lilly, Daiichi Sankyo;

Accumetrics, Astra-Zeneca, Pfizer, Merck. Accumetrics, Astra-Zeneca, Pfizer, Merck. Consultancies: Sanofi-Aventis, BMS, Portola, Consultancies: Sanofi-Aventis, BMS, Portola,

Astra-Zeneca Astra-Zeneca

TIMI Study GroupTIMI Study Group Receives Research Funding Receives Research Funding From: Eli Lilly, Daiichi Sankyo, Merck, Schering From: Eli Lilly, Daiichi Sankyo, Merck, Schering

Plough, Sanofi-Aventis, AstraZeneca, AccumetricsPlough, Sanofi-Aventis, AstraZeneca, Accumetrics

History of Present IllnessHistory of Present IllnessCC: CC: Chest painChest pain

73 yo F with a h/o HTN, HL, strong FH of CAD 73 yo F with a h/o HTN, HL, strong FH of CAD admitted with new onset CP. admitted with new onset CP.

• 4 days prior to admission: CP radiating to both 4 days prior to admission: CP radiating to both arms while walking & relieved with restarms while walking & relieved with rest

• Sxs continued with minimal exertion over Sxs continued with minimal exertion over subsequent dayssubsequent days

• Morning of admission, pt developed CP radiating to Morning of admission, pt developed CP radiating to both arms at rest. Recurred 3x during am. both arms at rest. Recurred 3x during am.

• Denied SOB, N/V, lightheadedness or diaphoresisDenied SOB, N/V, lightheadedness or diaphoresis

Day of presentationDay of presentation

• Seen in urgent care clinic at PCP’s officeSeen in urgent care clinic at PCP’s office

• Referred to ED. CP-free on arrival.Referred to ED. CP-free on arrival.

• BP 123/68, P95 regular, OBP 123/68, P95 regular, O22 sat 99% RA sat 99% RA

Past Medical HistoryPast Medical History: : CholesterolCholesterol

HTNHTN

Breast CA: s/p left breast lumpectomy 12/05, s/p XRT, ER+ on Breast CA: s/p left breast lumpectomy 12/05, s/p XRT, ER+ on tamoxifentamoxifen

Psoriasis Psoriasis

Meds on admissionMeds on admission: :

ASA 81mg PO QDASA 81mg PO QD

Tamoxifen 20mg PO QDTamoxifen 20mg PO QD

Irbisartan 150mg PO QDIrbisartan 150mg PO QD

Pravastatin 20mg PO QDPravastatin 20mg PO QD

DataDataBP 117/73 both arms, P68 reg, R 14, OBP 117/73 both arms, P68 reg, R 14, O22 97%, T97.6 97%, T97.6

NADNAD

JVP 6 cm HJVP 6 cm H220, nl contours0, nl contours

No carotid bruitsNo carotid bruits

CV: non-displaced discrete PMICV: non-displaced discrete PMI

Ext: warm, no edema or tenderness bilaterallyExt: warm, no edema or tenderness bilaterally

2+ DP bilat2+ DP bilat

141 110 11 96141 110 11 96

4.2 26 0.8 4.2 26 0.8 10.410.4

38.738.7328328

Troponin I = 0.12 (ULN = 0.04)Troponin I = 0.12 (ULN = 0.04)

CK = 105, CK-MB = 5.2 (ULN =5)CK = 105, CK-MB = 5.2 (ULN =5)

STRIVE TM

8

ACUTE CORONARY SYNDROMES

No ST elevation ST elevation

Unstableangina

NSTEMI STEMI

Spectrum of CAD

Stableangina

Reprinted with permission from Davies MJ. Heart. 2000;83:361-366.American Heart Association. Heart Disease and Stroke Statistics—2007 Update. Circulation. 2007; 115:69-171.

CAD = coronary artery disease; NSTEMI = non–ST-segment elevation myocardial infarction;STEMI = ST-segment elevation myocardial infarction.

~0.33 MillionDischarges Per Year

~1.24 MillionDischarges Per Year

Decision MakingDecision Making

DiagnosisDiagnosis

Risk AssessmentRisk Assessment

Early Invasive/Early Conservative Early Invasive/Early Conservative Managment?Managment?

Antithrombin?Antithrombin?

GP IIB/IIIA?GP IIB/IIIA?

Oral Antiplatelets?Oral Antiplatelets?

10

Risk Assessment Dependent on Risk Assessment Dependent on Contingent ProbabilitiesContingent Probabilities

Does this patient have Does this patient have symptoms due to acute symptoms due to acute ischemia from obstructive ischemia from obstructive CAD?CAD?

Likelihood of obstructive CAD Likelihood of obstructive CAD as cause of symptomsas cause of symptoms Dominated by acute findingsDominated by acute findings

– ExaminationExamination– SymptomsSymptoms– MarkersMarkers

Traditional risk factors are of Traditional risk factors are of limited utilitylimited utility

What is the likelihood of What is the likelihood of death, MI, heart failure?death, MI, heart failure?

Risk of bad outcomeRisk of bad outcome Dominated by acute Dominated by acute

findingsfindings– Older age very Older age very

importantimportant– Hemodynamic Hemodynamic

abnormalities criticalabnormalities critical– ECG, markersECG, markers

2007 ACC/AHA UA/NSTEMI Guideline Revision

Anderson JL, et al. http://cardiosource.com/guidelinefocus/gfc_acs.asp. Accessed August 8, 2007. Reproduced by STRIVE with permission from Cardiosource.com.

STRIVE TM

11

TIMI Risk Score for UA/NSTEMI:7 Independent Predictors

1. Aged ≥65 y

2. ≥3 CAD risk factors (high cholesterol, family history, hypertension, diabetes, smoking)

3. Prior coronary stenosis ≥50%

4. Aspirin in last 7 days

5. ≥2 anginal events ≤24 h

6. ST-segment deviation

7. Elevated cardiac markers (CK-MB or troponin)

Antman EM, et al. JAMA. 2000;284:835-842.

Number of Predictors

0

5

10

15

20

25

30

35

40

45

0/1 2 3 4 5 6/7

% D

ea

th /

MI

/ R

ev

as

c

I IIa IIb III

STRIVE ®

12

Our Patient’s GRACE Prediction Score for All-Cause Mortality From Discharge to6 Months

Reprinted with permission from Eagle KA, et al. JAMA. 2004;291(22):2727-2733.

NSTEMI 6-Month Postdischarge Mortality

Risk GRACE ProbabilityCategory Score of DeathLow 1-88 <3%Medium 89-118 3-8%High 119-263 >8%

http://www.outcomes-umassmed.org/grace/grace_risk_table.cfm.

1258%

STRIVE TM

13

0.2 0.5 1 2 5

Favors Invasive

Favors Conservative

Odds RatioDeath or MI

OR 0.82, P=.001

Trial

TIMI 3B

VANQWISH

MATE

FRISC II

TACTICS

RITA 3

TOTAL

Invasive Management of UA/NSTEMI Meta-analysis: Death/MI at 17-Month F/U

5.1% 8.1%

27.2% 28.0%

12.0% 8.9%

4.3% 11.4%

4.0% 5.3%

7.4% 10.9%

VINO 4.8% 14.8%

Inv Cons

7.4% 11.0%

Adapted with permission from Mehta S, et al. JAMA. 2005;293:2908-2917.

Anderson JL, et al. J Am Coll Cardiol. 2007;50:1-157.

ACC/AHA UA/NSTEMI Guidelines: High-risk Indicators for Early Invasive Strategy

Coronary angiography needs to be performed within 48 hoursACC = American College of Cardiology; AHA = American Heart Association; CABG = coronary artery bypass graft surgery; GRACE = Global

Registry of Acute Coronary Events; HF = heart failure; LVEF = left ventricular ejection fraction; PCI = percutaneous coronary intervention; TnI = troponin I; TnT = troponin T

Preferred Strategy Patient Characteristics

Invasive •Recurrent angina or ischemia at rest or with low-level activities despite intensive medical therapy•Elevated cardiac biomarkers (TnT or TnI)•New or presumably new ST-segment depression•Signs or symptoms of HF or new or worsening mitral regurgitation•High-risk findings from noninvasive testing•Hemodynamic instability•Sustained ventricular tachycardia•PCI within 6 months•Prior CABG•High-risk score (eg, TIMI, GRACE)•Reduced left ventricular function (LVEF of <40%)

Conservative •Low-risk score (eg, TIMI, GRACE)•Patient or physician preference in the absence of high-risk features

TIMACS: GRACE Score and Primary End Point

De

ath

, MI,

or

Str

oke

at 6

Mo

nth

sHR=0.65

(0.48-0.89)P=0.006

HR=1.12(0.81-1.56)

P=0.48

Low/Intermediate RiskScore ≤140

N=2,070

High RiskScore >140

N=961

GRACE=Global Registry of Acute Coronary Events; HR=hazard ratio; MI=myocardial infarction.Mehta SR, et al. N Engl J Med. 2009;360(21):2165-2175.

Delayed

Early

I IIa IIb III

STRIVE ®

16

It is reasonable for initially stabilized high-risk patients with UA/NSTEMI (GRACE risk score >140) to undergo an early invasive strategy within 12 to 24 hours of admission. For patients not at high risk, an early invasive approach is also reasonable

B

Kushner FG, et al. J Am Coll Cardiol. 2009;54(23):2205-2241.

Timing of Angiography in UA/NSTEMI

2009 ACC/AHA STEMI/PCI Guidelines Focused Updates

New Recommendation

17

Algorithm for Patients with UA/NSTEMI Managed by an Initial Invasive Strategy

Proceed to Diagnostic Angiography

ASA (Class I, LOE: A)Clopidogrel if ASA intolerant (Class I,

LOE: A)

Diagnosis of UA/NSTEMI is Likely or Definite

Invasive StrategyInit ACT (Class I, LOE: A)

Acceptable options: enoxaparin or UFH (Class I, LOE: A) bivalirudin or fondaparinux (Class I, LOE: B)

Select Management StrategyProceed with an

Initial Conservative

Strategy

Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1-e157, Figure 7. ACT = anticoagulation therapy; LOE = level of evidence.

A

B

B1

B2

Prior to AngiographyInit at least one (Class I, LOE: A) or

both (Class IIa, LOE: B) of the following:

ClopidogrelIV GP IIb/IIIa inhibitor

Factors favoring admin of both clopidogrel and GP IIb/IIIa inhibitor include:

Delay to AngiographyHigh Risk Features

Early recurrent ischemic discomfort

STRIVE®

Initial Invasive Strategy: Antiplatelet, Anticoagulant Therapy

Aspirin Initiate anticoagulant therapy as soon as possible after presentation

(I, A). Regimens with established efficacy:– Enoxaparin or UFH (I, A)– Bivalirudin or fondaparinux (I, B)

Prior to angiography, initiate one (I, A) or both (IIa, B)– Clopidogrel – IV GP IIb/IIIa inhibitor

Use both if: Delay to angiography High-risk features Early recurrent ischemic syndromes


Anderson JL, et al. J Am Coll Cardiol. 2007;50(7):e1-e157.

STRIVE TM

19

CURE: Primary Outcome by Type of Intervention

Adapted with permission from Fox KAA, et al. Circulation. 2004;110:1202-1208.

Cu

mu

lati

ve H

azar

d R

ates 0.20

0.15

0.10

0.05

0.00

Medical Rx Group

Days of Follow-up0 100 200 300

Placebo

Clopidogrel

RR:0.80 (0.69-0.92)

Days of Follow-up

Cu

mu

lati

ve H

azar

d R

ates 0.20

0.15

0.10

0.05

0.00

Any Revascularization Group

0 100 200 300

Placebo

Clopidogrel

RR:0.82 (0.69-0.96)

Cu

mu

lati

ve H

azar

d R

ates 0.20

0.15

0.10

0.05

0.00

PCI Group


Placebo

Clopidogrel

RR:0.72 (0.57-0.90)

Cu

mu

lati

ve H

azar

d R

ates 0.20

0.15

0.10

0.05

0.00

CABG Group


Placebo

Clopidogrel

RR:0.89 (0.71-1.11)

I IIa IIb III

STRIVE ®

20

Patients with definite or likely UA/NSTEMI selected for an invasive approach should receive dual antiplatelet therapy.

Aspirin should be initiated on presentation.

Clopidogrel (before or at the time of PCI)

or

prasugrel (at the time of PCI) is recommended as a second antiplatelet agent

A


Timing of Antiplatelet Therapy in UA/NSTEMI


New Recommendation

B

A

A

STRIVE®

21

a Use in UA/NSTEMI is off-label.

Adapted from Anderson JL, et al. J Am Coll Cardiol. 2007;50(7):e1-e157.


Bivalirudin 0.1 mg/kg bolus, 0.25 mg/kg/h infusiona

Enoxaparin 30 mg IV bolus may be givena

1 mg/kg SC every 12 h; extend dosing interval to 1 mg/kg every 24 h if estimated creatinine clearance <30 mL/min

Fondaparinux 2.5 mg SC once dailya

Avoid for creatinine clearance <30 mL/min

Unfractionated heparin

60 U/kg (max 4000 U) as IV bolus

IV infusion of 12 U/kg/h (max 1000 U/h) to maintain aPTT at 1.5-2.0 times control (approx. 50-70 s)

Initial Medical Treatment: Anticoagulant Dosing

STRIVE®

22

Moderate-to high-

riskACS

ACUITY Study: 30-Day Results

Aspirin in all;clopidogrel dosing

and timingper local practice

UFH or enox+ GP IIb/IIIa

n=4603

Bivalirudin+ GP IIb/IIIa

n=4604

Bivalirudinalone

n=4612

R*

Moderate- to high-risk patients with UA or NSTEMIundergoing an invasive strategy (N=13,819)

Stone GW, et al. N Engl J Med. 2006;355(21):2203-2216.

*Stratified by preangiography thienopyridine use or administration.

Ischemic Composite

BleedingNet Clinical

Outcome

7.3% 5.7% 11.7%

7.7% 5.3% 11.8%

7.8% 3.0% 10.1%

End points: death, MI, and unplanned revascularization for ischemia (30 days and 1 year); major bleeding (30 days); composite of the above (30 days)

23

ACUITY Composite Ischemia & Bleeding Outcomes

Absolute Risk Reduction -0.5 0.3 -2.0 2.7Hazard Ratio 1.08 0.97 1.29 0.5395% CI 0.93–1.24 0.80–1.17 1.03–1.63 0.43–0.65p 0.32 0.054 (for interaction) < 0.001

Stone GW, et al. N Engl J Med 2006;355:2203–16.

7.3 7.3 7.1

5.7

7.8

7.0

9.1

3.0

0

1

2

3

4

5

6

7

8

9

10

ACUITY Composite ischemiaendpoint at 30 days

Ischemia endpoint bythienopyridine loading before angiography or PCI YES

Ischemia endpoint bythienopyridine loading before

angiography or PCI No

ACUITY Major bleeding at 30days

UFH + GP IIb/IIIa

Bivalirudin alone

STRIVE®

24

Excess Dosing of Antithrombotic AgentsDose and Major Bleeding

Reproduced with permission from Alexander KP, et al. JAMA. 2005;294(24):3108-3116.

Unfractionated Heparin

Underdosed Recommended

Mild Excess Major Excess

(n=2074)

(n=2063)

(n=2073)

(n=714)

(n=2327)

(n=3998)

(n=922)

(n=237)

(n=5879)

(n=1955)

(n=178)

Low-Molecular-WeightHeparin

GlycoproteinIIb/IIIa Inhibitors

35

30

25

20

15

10

5

0

Maj

or

Ble

edin

g, %

Treatment Group

STRIVE®

25

New ACC/AHA 2008 Test Measures for STEMI and NSTEMIa

LDL assessment (formerly a performance measure)

Excessive initial UFH, enoxaparin, eptifibatide, tirofiban, or abciximab dose

Anticoagulant dosing protocol

Anticoagulant error tracking system

Clopidogrel prescribed at discharge for medically treated AMI patients

a For use in internal quality improvement programs only.

Krumholz HM, et al. J Am Coll Cardiol. 2008;52(24):2046-2099.

STRIVE TM

26

30-Day Death or Nonfatal MIRisk Ratio and 95% CI

Placebo BetterGP IIb/IIIa Inhibitor Better

Trial

Pooled 11.5%

PlaceboGP IIb/IIIa Inhibitor

10.7%29,855

n

0.92 (0.86, 0.995)P=.037

PRISM-PLUS 11.9% 10.2%1,915

PURSUIT 15.7% 14.2%9,461

PARAGON A 11.7% 11.3%2,282

7.1%PRISM 5.8%3,232

0.5 1.0 1.5

PARAGON B 11.4% 10.5%5,165

GUSTO-IV ACS

8.0% 8.7%7,800

GP IIb/IIIa Inhibition for Non–ST-Elevation ACS

Boersma E, et al. Lancet. 2002;359:189-198.

CI = confidence interval.

STRIVE TM

27

Benefits of GP IIb/IIIa by Troponin Status in Clinical Trials

Newby KL, et al. Circulation. 2001;103:2891-2896.

TnT-NegativeTnT-Positive

PARAGON-B

PRISM

CAPTURE

Combined

0.125 1 20.5 0.125 1 20.5GP IIb/IIIa

BetterGP IIb/IIIa

WorseGP IIb/IIIa

BetterGP IIb/IIIa

Worse

STRIVE TM

28

ISAR-REACT 2: Cumulative Incidence of Death, MI, or Urgent TVR in Subsets

With and Without Elevated Troponin levels (>0.03 µg/L)

ISAR-REACT 2 = Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 2. Adapted with permission from Kastrati A, et al. JAMA. 2006;295:1531-1538.

20

15

10

5

0

0 5 10 15 20 25 30Days After Randomization

Cu

mu

lati

ve R

ate

of

Pri

mar

y E

nd

Po

int,

%

Placebo Group (n=1010)Abciximab Group (n=1012)

Troponin >0.03 µg/LLog-Rank P=.02

Troponin ≤0.03 µg/LLog-Rank P=.98

Study DesignStudy Design

High-risk NSTE ACS

n = 10,500

High-risk NSTE ACS

n = 10,500

Primary Endpoint: 96-hr Death, MI, Recurrent ischemia requiring urgent revascularization, or Thrombotic bailout

Key Secondary Endpoint: 30-d Death or MI

Primary Endpoint: 96-hr Death, MI, Recurrent ischemia requiring urgent revascularization, or Thrombotic bailout

Key Secondary Endpoint: 30-d Death or MI

Placebo / delayed provisional eptifibatide pre-PCI

Placebo / delayed provisional eptifibatide pre-PCI

Routine, early eptifibatide (180/2/180)

Routine, early eptifibatide (180/2/180)

Randomize within 12 hours of presentation

Invasive strategy: 12 to 96 hours after randomization

Randomize within 12 hours of presentation

Invasive strategy: 12 to 96 hours after randomization

2 of 3 high-risk criteria:1. Age > 60 years2. + CKMB or TnT/I3. ST or transient ST (Or age 50-59, h/o CVDand + CKMB or TnT/I)

2 of 3 high-risk criteria:1. Age > 60 years2. + CKMB or TnT/I3. ST or transient ST (Or age 50-59, h/o CVDand + CKMB or TnT/I)

Safety Endpoints at 120 hrs: Bleeding (GUSTO and TIMI scales), Transfusions, Stroke, Non-hemorrhagic SAEsSafety Endpoints at 120 hrs: Bleeding (GUSTO and TIMI scales), Transfusions, Stroke, Non-hemorrhagic SAEs

Kaplan-Meier Curves for Primary EndpointKaplan-Meier Curves for Primary EndpointD

eath

, M

I, R

IUR

or

TB

O (

%)

Dea

th,

MI,

RIU

R o

r T

BO

(%

)

00

55

1010

1515

Time Since Randomization (Hours)Time Since Randomization (Hours)

10.0%10.0%

9.3%9.3%

P = 0.23P = 0.23(stratified for intended early

clopidogrel use)(stratified for intended early

clopidogrel use)

Delayed provisional eptifibatideDelayed provisional eptifibatide

Routine early eptifibatideRoutine early eptifibatide

00 88 1616 2424 3232 4040 4848 5656 6464 7272 8080 8888 9696

Initial TherapiesInitial Therapies

•In ED, patient received:•ASA 325mg PO x1•5mg IV metoprolol x1•IV unfractionated heparin w/ bolus and infusion (weight based)•Clopidogrel 300 mg•Referred for cardiac catheterization

Cardiac CatheterizationCardiac Catheterization•Single Vessel CAD•95% Proximal Hazy LAD lesion consistent with acute plaque rupture with thromboisis•TIMI 3 (Normal) Flow

33

Cardiac cath

CAD No Discharge from protocol

Yes

Left main disease Yes CABG

No

1- or 2- Vessel

Disease

3- or 2-vessel disease with proximal LAD involvement

LV dysfunction or treated diabetes*

No

PCI or CABG

Medial Therapy,

PCI or CABG

Yes CABG

*There is conflicting information about these patients. Most consider CABG to be preferable to PCI. Anderson JL, et al. J Am Coll Cardiol 2007;50:e1–e157, Figure 20.

Revascularization Strategy in UA/NSTEMI

Cardiac CatheterizationCardiac Catheterization

Drug Eluting Stent (2.5 x 15) to Drug Eluting Stent (2.5 x 15) to proximal LADproximal LAD

Drug Eluting Stent (2.25 x 12) to mid Drug Eluting Stent (2.25 x 12) to mid LADLAD

Both stents post-dilated and fully Both stents post-dilated and fully deployeddeployed

Heparin discontinuedHeparin discontinued

I IIa IIb III

STRIVE ®

In patients receiving a stent (BMS or DES) during PCI for ACS, clopidogrel 75 mg daily or prasugrel 10 mg daily should be given for at least 12 months

If the risk of morbidity from bleeding outweighs the anticipated benefit afforded by thienopyridine therapy, earlier discontinuation should be considered

B


Duration of Thienopyridine Therapy


Modified Recommendations

C

I IIa IIb III

STRIVE ®

Continuation of clopidogrel or prasugrel beyond 15 months may be considered in patients undergoing drug-eluting stent placement

C


Duration of Thienopyridine Therapy


Modified Recommendation

STRIVE®

37

Secondary Prevention: Additional Recommendations (cont)

Cardiac rehab BP control

– <140/90 mm Hg

– <130/80 mm Hg with diabetes or CKD

Diabetes management: HbA1c <7%

Smoking cessation/no environmental smoke exposure

– Education, referral programs, drug therapy

Physical activity (30-60 min, 7 d/wk; min 5 d/wk)

Weight management

– BMI 18.5-24.9 kg/m2

– Waist circumference: men, <40 in; women, <35 in

Discharge education/referral Stepped-care approach to

musculoskeletal pain management Annual influenza immunization HRT, antioxidant vitamin supplements

(C, E, beta carotene) and folic acid not recommended



Changes from (Post-ACS) Changes from (Post-ACS) Baseline in Median LDL-CBaseline in Median LDL-C

Note: Changes in LDL-C may differ from prior trials: Note: Changes in LDL-C may differ from prior trials: • 25% of patients on statins prior to ACS event25% of patients on statins prior to ACS event• ACS response lowers LDL-C from true baselineACS response lowers LDL-C from true baseline

LDL-C (mg/dL)

20

40

60

80

100

120

Rand. 30 Days 4 Mos. 8 Mos. 16 Mos. Final

Pravastatin 40mg

Atorvastatin 80mg49% 49%

21%21%

P<0.001P<0.001

Median LDL-C (Q1, Q3)Median LDL-C (Q1, Q3)

95 (79, 113)95 (79, 113)

62 (50, 79) 62 (50, 79)

<24h

All-Cause Death or Major CV Events in All Randomized Subjects

00 33 1818 2121 2424 2727 303066 99 1212 1515

% with Event

Months of Follow-up

Pravastatin 40mgPravastatin 40mg(26.3%)(26.3%)

Atorvastatin 80mgAtorvastatin 80mg(22.4%)(22.4%)

16% RR (P = 0.005)16% RR (P = 0.005)

3030

2525

2020

1515

1010

55

00

HD # 3 - DischargeHD # 3 - Discharge

Patient discharged to home to f/u in Patient discharged to home to f/u in cardiology clinic in 2 weekscardiology clinic in 2 weeks

Discharge regimen including:Discharge regimen including: ASA 162 mg POASA 162 mg PO Clopidogrel 75mg PO QDClopidogrel 75mg PO QD Metoprolol XL 50 mg/dMetoprolol XL 50 mg/d Lisinopril 10 mg/dLisinopril 10 mg/d Atorvastatin 80 mgAtorvastatin 80 mg

STRIVE®

41

Secondary Prevention: Additional Recommendations

β-blockers

ACE inhibitors/ARBs

Aldosterone blockade (low EF)

Lipid management

– Statin regardless of baseline LDL-C initiated prior to discharge

– Goal LDL-C <100 mg/dL

– LDL <70 mg/dL reasonable

Treatment of triglycerides and non–HDL-C useful

– If TG 200-499 mg/dL, non–HDL-C should be <130 mg/dL

– TG 500 mg/dL, fibrate or niacin before LDL-C lowering to prevent pancreatitis

Encouraging consumption of omega-3 fatty acids for risk reduction reasonable

– For treatment of elevated triglycerides, higher doses may be used for risk reduction



Two days after discharge…Two days after discharge…

• Recurrent CP while cleaning her Recurrent CP while cleaning her basementbasement

• Returned to ED with 8/10 crushing Returned to ED with 8/10 crushing SSCPSSCP

• Patient reported compliance with her Patient reported compliance with her medicationsmedications

• IV UFH started in EDIV UFH started in ED

Cardiac CatheterizationCardiac Catheterization•Total Occlusion of LAD in previously stented segment consistent with STENT THROMBOSIS

Hospital CourseHospital Course

• 2 additional stents deployed bridging 2 additional stents deployed bridging

gap between prior stentsgap between prior stents

• IVUS showed no evidence of edge IVUS showed no evidence of edge

dissection, stents fully deployeddissection, stents fully deployed

• Reloaded with clopidogrel 600mg x1Reloaded with clopidogrel 600mg x1

• Peak CK 2100, CK-MB 150Peak CK 2100, CK-MB 150

• TTE: LVEF 40%, HK antero-septal wallTTE: LVEF 40%, HK antero-septal wall

Patient• Antiplatelet

noncompliance• Response variability

StentThrombosis

Adapted from Kereiakes DJ et al. Rev Cardiovasc Med. 2004;5:9-15.

Stent Thrombosis: Stent Thrombosis: A Multifactorial ProblemA Multifactorial Problem

Lesion • Long lesions • Small diameter• Multivessel • Acute myocardial

infarction (AMI)• Diabetes• Bifurcations

Technical • Underexpansion• Incomplete wall

apposition• Crush technique• Overlapping

Stent • Material• Polymer matrix• Antithrombotic

agent

Early Discontinuation of Antiplatelet Therapy Is an Important Risk Factor for ST

UA Thrombus Diabetes Unprotected left main

artery

Bifurcation lesion

Renal failure

Prior brachytherapy

Premature antiplatelet

therapy discontinuation

Inci

den

ce (

%)

Iakovou I, et al. JAMA. 2005;293:2126-2130.

Overall ST-elevation = 1.3% (P = .09, N=2229)

1.4 2.0 2.5 3.3 3.66.2

8.7

29.0

0

10

20

30

Clopidogrel Response Variability: Clopidogrel Response Variability: Increase the Dose (300 mg vs. 600 mg)Increase the Dose (300 mg vs. 600 mg)

Gurbel PA et al. J Am Coll Cardiol. 2005;45:1392-1396.

03

6

9

12

15

18

21

24

27

30

33

≤-30(-30,-20]

(-20,-10](-10,0]

(0,10](10,20]

(20,30](30,40]

(40,50](50,60]

(60,70]> 70

300 mg Clopidogrel

600 mg Clopidogrel

Aggregation (5 µM ADP-induced Aggregation) at 24 Hr

Pat

ien

ts (

%) Resistance = 28% (300 mg)

Resistance = 8% (600 mg)

P < 0.001

P < 0.001P < 0.001

Antoniucci D et al. Presented at ACC 2007.

The RECLOSE Study: 6-Month Outcomes After DES Implantation Stratified by Post-Clopidogrel ADP-mediated Platelet Reactivity

Non-responders defined as >70% aggregation by LTA 12 hours after 600 mg clopidogrel load

Platelet Function TestPlatelet Function Test

• Platelet response assessed on ASA Platelet response assessed on ASA 162mg QD and clopidogrel 75mg BID 162mg QD and clopidogrel 75mg BID using Accumetricsusing Accumetrics™™ device device

• Appropriate response to aspirin (ARU Appropriate response to aspirin (ARU 410, non-responder >550)410, non-responder >550)

• HOWEVERHOWEVER, only 0-3% platelet , only 0-3% platelet inhibition to clopidogrel 75mg BID inhibition to clopidogrel 75mg BID (PRU 253, baseline PRU 260)(PRU 253, baseline PRU 260)

Clinical ManagementClinical Management

• No guideline recommendationsNo guideline recommendations

• Aspirin increased to 325/dAspirin increased to 325/d

• Clopidogrel increased to 150 mg/d Clopidogrel increased to 150 mg/d (today may switch to prasugrel)(today may switch to prasugrel)

Study Design, Flow and Compliance

25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)Planned Early (<24 h) Invasive Management with intended PCIIschemic ECG Δ (80.8%) or ↑cardiac biomarker (42%)

25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)Planned Early (<24 h) Invasive Management with intended PCIIschemic ECG Δ (80.8%) or ↑cardiac biomarker (42%)

PCI 17,232(70%)

Angio 24,769(99%)

Angio 24,769(99%)

No PCI 7,855 (30%)

No Sig. CAD 3,616 CABG 1,809 CAD 2,430

Randomized to receive (2 X 2 factorial):

CLOPIDOGREL: Double-dose (600 mg then150 mg/d x 7d then 75 mg/d) vs Standard dose (300 mg then 75 mg/d)

ASA: High Dose (300-325 mg/d) vs Low dose (75-100 mg/d)

Efficacy Outcomes: CV Death, MI or stroke at day 30Stent Thrombosis at day 30

Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TIMI Major)Key Subgroup: PCI v No PCI

Efficacy Outcomes: CV Death, MI or stroke at day 30Stent Thrombosis at day 30

Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TIMI Major)Key Subgroup: PCI v No PCI

Clop in 1st 7d (median) 7d 7 d 2 d 7d

Complete Followup

99.8%

Complete Followup

99.8%

Compliance:Compliance:

Clopidogrel: Double vs Standard DosePrimary Outcome and Components

Standard Double HR 95% CI P Intn P

CV Death/MI/Stroke

PCI (2N=17,232) 4.5 3.9 0.85 0.74-0.99 0.0360.016

No PCI (2N=7855) 4.2 4.9 1.17 0.95-1.44 0.14

Overall (2N=25,087) 4.4 4.2 0.95 0.84-1.07 0.370

MI

PCI (2N=17,232) 2.6 2.0 0.78 0.64-0.95 0.0120.025

No PCI (2N=7855) 1.4 1.7 1.25 0.87-1.79 0.23

Overall (2N=25,087) 2.2 1.9 0.86 0.73-1.03 0.097

CV Death

PCI (2N=17,232) 1.9 1.9 0.96 0.77-1.19 0.681.0

No PCI (2N=7855) 2.8 2.7 0.96 0.74-1.26 0.77

Overall (2N=25,087) 2.2 2.1 0.96 0.81-1.14 0.628

Stroke

PCI (2N=17,232) 0.4 0.4 0.88 0.55-1.41 0.590.50

No PCI (2N=7855) 0.8 0.9 1.11 0.68-1.82 0.67

Overall (2N=25,087) 0.5 0.5 0.99 0.70-1.39 0.950

Clopidogrel Double vs Standard DoseBleeding Overall Population

Clopidogrel

Standard

N=12579

Double

N=12508

Hazard

Ratio

95% CI P

TIMI Major1 0.95 1.04 1.09 0.85-1.40 0.50

CURRENT Major2 2.0 2.5 1.25 1.05-1.47 0.01

CURRENT Severe3 1.5 1.9 1.23 1.02-1.49 0.03

Fatal 0.11 0.13 1.15 0.56-2.35 0.71

ICH 0.05 0.03 0.67 0.19-2.37 0.53

RBC transfusion ≥ 2U 1.76 2.21 1.26 1.06-1.51 0.01

CABG-related Major 0.9 1.0 1.10 0.85-1.42 0.48

1ICH, Hb drop ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal2Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units3Fatal or ↓Hb ≥ 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units

1ICH, Hb drop ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal2Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units3Fatal or ↓Hb ≥ 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units

Days

Cu

mu

lati

ve H

azar

d

0.0

0.00

40.

008

0.01

2

0 3 6 9 12 15 18 21 24 27 30

Clopidogrel Standard Dose

Clopidogrel Double Dose

42% RRR

HR 0.5895% CI 0.42-0.79

P=0.001

Clopidogrel: Double vs Standard DoseDefinite Stent Thrombosis (Angio confirmed)

Change the Agent?

PrasugrelPrasugrel

Pro-drugPro-drug

OxidationOxidation(Cytochrome (Cytochrome

P450)P450)

HOOCHOOC

* HS* HS

NN

OO

FF

Active MetaboliteActive Metabolite

NN

SS

OO

FF

OO

HydrolysisHydrolysis(Esterases)(Esterases)

NN

SS

OO

CC HH33

CCOO

FF

OONN

SS

OO

ClCl

OO CHCH33CC

ClopidogrelClopidogrel

85% Inactive 85% Inactive MetabolitesMetabolitesEsterasesEsterases

NN

SS

OO

ClCl

OO CHCH33CC

OONN

SS

OO

ClCl

OO CHCH33CC

Active MetaboliteActive Metabolite

HOOCHOOC

* HS* HS

NN

OO

ClCl

OCHOCH33

Herbert JM, Savi P. Sem Vasc Med. 2003;3:113-122.

Inhibition of Platelet AggregationInhibition of Platelet Aggregation(IPA) at 24 Hours (Healthy Volunteers)(IPA) at 24 Hours (Healthy Volunteers)

-20.0-20.0

0.00.0

20.020.0

40.040.0

60.060.0

80.080.0

100.0100.0

Inh

ibit

ion

of

Pla

tele

t A

gg

reg

atio

n (

%)

Inh

ibit

ion

of

Pla

tele

t A

gg

reg

atio

n (

%)

Response to PrasugrelResponse to PrasugrelResponse to ClopidogrelResponse to Clopidogrel

Clopidogrel Responder

Clopidogrel Non-responder

*Responder = 25% IPA at 4 and 24 h

Inte

rpat

ien

t V

aria

bil

ity

Inte

rpat

ien

t V

aria

bil

ity

Brandt JT et al. Am Heart J. 2007;153:66.e9-e16.

Study Design

Double-blind

ACS (STEMI or UA/NSTEMI) & Planned PCI

ASA

PRASUGREL60 mg LD/ 10 mg MD

CLOPIDOGREL300 mg LD/ 75 mg MD

1o endpoint: CV death, MI, Stroke2o endpoints: CV death, MI, Stroke, Rehosp-Rec Isch

CV death, MI, UTVR Stent Thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, Life-threatening bleeds

Median duration of therapy - 12 months

N= 13,600

Wiviott SD, AHJ 2006

0

5

10

15

0 30 60 90 180 270 360 450

HR 0.81(0.73-0.90)P=0.0004

Prasugrel

Clopidogrel

Days

En

dp

oin

t (%

)

12.1

9.9

HR 1.32(1.03-1.68)P=0.03

Prasugrel

Clopidogrel1.82.4

138 events

35 events

Balance of Balance of Efficacy and SafetyEfficacy and Safety

CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

NNT = 46

NNH = 167

Wiviott SD, Braunwald E, McCabe CH et al NEJM2007

Stent ThrombosisStent Thrombosis(ARC Definite + Probable)(ARC Definite + Probable)

0

1

2

3

0 30 60 90 180 270 360 450

HR 0.48P <0.0001

Prasugrel

Clopidogrel2.4

(142)

NNT= 77

1.1 (68)

Days

En

dp

oin

t (%

)

Any Stent at Index PCIAny Stent at Index PCI N= 12,844 N= 12,844

Wiviott SD, Braunwald E, McCabe CH et al NEJM2007 Antman EM, AHA2007

Definite/Probable ST: Definite/Probable ST: Any Stent (N=12844)Any Stent (N=12844)

0

0.5

1

1.5

2

2.5

0 5 10 15 20 25 300

0.5

1

1.5

2

2.5

30 90 150 210 270 330 390 450

% o

f S

ubje

cts

HR 0.41 [0.29-0.59]P<0.0001

HR 0.60 [0.37-0.97]P=0.03

DAYS

EARLY ST LATE ST

STENT ANALYSIS

1.56%

0.64%

59% 0.82%

0.49%

40%

CLOPIDOGREL

PRASUGREL

Wiviott SD, Braunwald E, McCabe CH, Lancet 2008

Antman EM, NYHA 2007

1.8

0.9 0.9

0.10.3

2.4

1.41.1

0.4 0.3

0

2

4

TIMI MajorBleeds

LifeThreatening

Nonfatal Fatal ICH

Bleeding EventsBleeding EventsSafety CohortSafety Cohort

(N=13,457)(N=13,457)

% E

ven

ts%

Eve

nts

ARD 0.6%ARD 0.6%HR 1.32HR 1.32P=0.03P=0.03NNH=167 NNH=167

ClopidogrelClopidogrel

PrasugrelPrasugrel

ARD 0.5%ARD 0.5%HR 1.52HR 1.52P=0.01P=0.01

ARD 0.2%ARD 0.2%P=0.23P=0.23

ARD 0%ARD 0%P=0.74P=0.74

ARD 0.3%ARD 0.3%P=0.002P=0.002

ICH in Pts w ICH in Pts w Prior Stroke/TIA Prior Stroke/TIA (N=518)(N=518)

Clop 0 (0)%Clop 0 (0)% Pras 6 (2.3)%Pras 6 (2.3)% (P=0.02) (P=0.02)

Wiviott SD, Braunwald E, McCabe CH et al NEJM2007

Diabetic SubgroupDiabetic Subgroup

0

2

4

6

8

10

12

14

16

18

0 30 60 90 180 270 360 450

HR 0.70P<0.001

Days

En

dp

oin

t (%

)



NNT = 46

N=3146N=3146

17.0

12.2

Prasugrel

Clopidogrel

Prasugrel

Clopidogrel 2.6

2.5

Wiviott SD, Circulation 2008Wiviott SD, Circulation 2008

0

5

10

15

0 30 60 90 180 270 360 450

Per

cen

t (%

)

Days From Randomization

9.5%

6.5%

HR 0.68(0.54-0.87)

P=0.002

12.4%

10.0%

HR 0.79(0.65-0.97)

P=0.02

Clopidogrel

Prasugrel

NNT = 42



Clopidogrel

Prasugrel 2.4

2.1

STEMI CohortSTEMI CohortN=3534N=3534

Montalescot et al Lancet 2008

The first* adequately powered clinical trial to test and confirm the hypothesis:a drug with greater P2Y12 effect and less response variability reduces ischemic events compared to standard clopidogrel

*Now corroborated by PLATO and OASIS 7- PCI

Lesson

Ticagrelor (AZD 6140): an oral reversible P2Y12 antagonist

Ticagrelor is a cyclo-pentyl-triazolo-pyrimidine (CPTP)

OH

OH

O

OH

N

F

S

NH

NN

NN

F

• Direct acting – Not a prodrug; does not require metabolic activation

– Rapid onset of inhibitory effect on the P2Y12 receptor

– Greater inhibition of platelet aggregation than clopidogrel

• Reversibly bound– Degree of inhibition reflects plasma concentration– Faster offset of effect than clopidogrel – Functional recovery of all circulating platelets

LastMaintenance

Dose

Loading 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

PLATO study design

Primary endpoint: CV death + MI + Stroke Primary safety endpint: Total major bleeding

6–12-month exposure

ClopidogrelIf pre-treated, no additional loading dose;if naive, standard 300 mg loading dose,

then 75 mg qd maintenance;(additional 300 mg allowed pre PCI)

Ticagrelor180 mg loading dose, then

90 mg bid maintenance;(additional 90 mg pre-PCI)

NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)Clopidogrel-treated or -naive;

randomised within 24 hours of index event (N=18,624)

PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular; TIA = transient ischaemic attack

STRIVE®

69

PLATOPrimary End Point: CV Death, MI, or Stroke

0 1 2 3 4 5 6 7 8 9 10 11 12

12

11

10

9

8

7

6

5

4

3

2

1

0

Months

HR: 0.85 (95% CI, 0.74-0.97); P=.02

11.0

9.3

Clopidogrel

Ticagrelor

K-M

Est

imat

ed R

ate,

% p

er Y

ear

Steg PG. Presented at: the American Heart Association (AHA) Scientific Sessions; November 15, 2009; Orlando, Florida.

STRIVE®

70

PLATO: All-Cause Mortality

0 1 2 3 4 5 6 7 8 9 10 11 12

7

6

5

4

3

2

1

0

K-M

Est

imat

ed R

ate,

% p

er Y

ear

Months

Clopidogrel

Ticagrelor

4.9

6.0

HR 0.82 (95% CI, 0.68-0.99); P=.04

Steg PG Presented at: the American Heart Association (AHA) Scientific Sessions; November 15, 2009; Orlando, Florida.

Time to major bleeding – primary safety event

No. at risk

Clopidogrel

Ticagrelor

9,186

9,235

7,305

7,246

6,930

6,826

6,670

Days from first IP dose

5,209

5,129

3,841

3,783

3,479

3,433

0 60 120 180 240 300 360

10

5

0

15

Clopidogrel

Ticagrelor

11.2011.58

6,545

HR 1.04 (95% CI 0.95–1.13), p=0.434

K-M

est

imat

ed r

ate

(% p

er y

ear)

Adapted from Wallentin L, et al. N Engl J Med. 2009;361:1045-1057.

No. at risk

Clopidogrel

Ticagrelor

9,186

9,235

7,718

7,641

7,371

7,247

7,134

Days from first IP dose

5,597

5,496

4,147

4,067

3,764

3,698

0 60 120 180 240 300 360

3

2

1

0

4

Clopidogrel

Ticagrelor

2.31

3.06

6,979

HR 1.31 (95% CI 1.08–1.60), p=0.006

Time to non-procedure-related PLATO major bleeding

Completeness of follow-up 99.97% = five patients lost to follow-up

K-M

est

imat

ed r

ate

(% p

er y

ear)

GP IIb/IIIa receptor expression

P2Y12 receptor(irreversible inhibition)

Active metabolite

Hepatic metabolismCytochrome P450 pathway

Intestinal absorptionVariable absorption (Genetics – ABCB1)

Drug-drug interactions

Genetic polymorphisms CYP enzymes (2C19)

Drug-drug interactions (CYP 2C19)

Genetic polymorphisms P2Y12 receptor

Alternate pathways of platelet activation

↑ release of circulating ADP

Higher baseline platelet reactivity Genetic polymorphisms

Poor compliance

Inadequate administration (dose, generics?)

Potential Sites for Response VariabilityPotential Sites for Response Variability

Adapted from O’Donoghue M and Wiviott SD Circulation 2007

14

0

7

-log

10(P

V

alue

)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 2221

GWAS of Platelet Aggregation in Response to Clopidogrel

Shuldiner A et al. JAMA 2009; 302:849-857.

CYP2C18-CYP2C19-CYP2C9-CYP2C8

Genetic Effects on PK/PD

P value

-32.4 0.00006

-6.8 0.59

-15.7 0.035

5.6 0.59

11.2 0.45

Gene

CYP2C19

CYP2C9

CYP2B6

CYP3A5

CYP1A2

-15

Pharmacokinetics Pharmacodynamics

-10 -5 0 5 10 15-40 -20 200-50 -30 -10 3010

P value

-9.0 0.00054

-0.6 0.86

-5.7 0.012

7.5 0.012

0.5 0.90

-6.1 0.061

-5.3 0.27

-0.4 0.90

-0.8 0.82

-3.5 0.47

Gene

CYP2C19

CYP2C9

CYP2B6

CYP3A5

CYP1A2

-15 -10 -5 0 5 10 15-40 -20 200-50 -30 -10 3010

-1.3 0.63

-1.7 0.42

-0.6 0.65

1.3 0.38

-1.6 0.37

Relative percent difference in AUC0-t (95%CI)in carriers vs non-carriers of a reduced-function allele

CLOPIDOGREL

PRASUGREL

Mega JL et al. N Engl J Med. 2009;360:354-62.

Absolute difference in MPA (95% CI)in carriers vs non-carriers of a reduced-function allele

% Differencein AUC0-t

Absolute Difference in MPA

Mega JL et al. Circulation 2009

020

4060

8010

0R

educ

tion

in M

PA

(%

) at

24-

hour

UM EM IM PMn=47 n=43 n=27 n=3

Clopidogrel 75mg0

2040

6080

100

Red

uctio

n in

MP

A (

%)

at 2

4-ho

ur

UM EM IM PMn=22 n=31 n=29 n=8

Clopidogrel 300mg

CYP2C19 Extended Classification

CYP2C19 and Stent Thrombosis

* Carriers ~30% of the population

CYP2C19 Reduced-Function Allele Carriers

n=1477 n=1466

Mega JL et al. N Engl J Med. 2009;360:354-62/

Hazard Ratio, 0.58(95% CI 0.13-2.69)P=0.48

1.0

0.5

1000 992 990 969 870 764 550

379 374 371 363 323 276 189

0

1

2

3

4

0 30 90 180 270 360 450

Number at Risk:

Days after randomization

Non-Carrier

Carrier

Carriers

Hazard Ratio 3.09(95% CI 1.19-8.00)P=0.015

0.8

2.6

10141004 1001 989 885 765 547

375 368 366 359 316 279 186

Def

init

e o

r p

rob

able

ste

nt

thro

mb

osi

s (%

)

0

1

2

3

4

0 30 90 180 270 360 450

Number at Risk:

Days after randomization

Non-Carrier

Carrier

Clopidogrel Prasugrel

Non-carriers Non-carriers

Def

init

e o

r p

rob

able

ste

nt

thro

mb

osi

s (%

)

Mega JL et al. Circulation 2009

http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm203888.htm#ds

Major Adverse CV Events

Carriers vs Non-Carriers

Risk Higher withCYP2C19 Variant

Risk Lower withCYP2C19 Variant

Risk Ratio (95% CI) P Value

1.61 (1.28-2.02) <0.001

Heterozygotes vs Wildtype 1.50 (1.08-2.08) 0.016

Homozygotes vs Wildtype 1.81 (1.21-2.71) 0.004

Heterozygotes vs Wildtype

Homozygotes vs Wildtype

2.51 (1.59-3.98)

4.78 (2.01-11.39)

<0.001

<0.001

0.5 1.0 15.0

N=9,684

Stent Thrombosis

Carriers vs Non-Carriers 2.76 (1.77-4.30) <0.001

N=5,772

CYP2C19 and Treatment with Clopidogrel

Mega, J et al AHA 2009

Clopidogrel is a prodrug; requires conversion by the liver Clopidogrel is a prodrug; requires conversion by the liver primarily via CYP3A4 and CYP2C19 to an active metaboliteprimarily via CYP3A4 and CYP2C19 to an active metabolite

Some PPIs are strong inhibitors of CYP2C19 activitySome PPIs are strong inhibitors of CYP2C19 activity

Clopidogrel and PPIs – The OCLA studyClopidogrel and PPIs – The OCLA study

-32.6

-43.3-50-45-40-35-30-25-20-15-10-50

PR

I Var

iati

on

(%

)

Omeprazole (n=64)

Placebo (n=60)

PRI: Platelet Reactivity Index as measured by vasodilator stimulated phosphoprotein (VASP)

Gilard et al. J Am Coll Cardiol 2008;51:256-60.p<0.0001

Risk of Cardiovascular Events for Patients Taking Clopidogrel in Combination with a PPI

Ho PM, et al. JAMA. 2009;301:937

70

60

50

40

30

20

10

00 90 180 270 360 450 540 630 720 810 900 990 1080

Days Since Discharge

Dea

ths

or r

ecur

rent

AC

S (

%)

Clopidogrel + PPIClopidogrel without PPI

Adjusted OR 1.25 (95% CI 1.11-1.41)

14.816.2

13.2

9.210.8

7.7

0

5

10

15

20

PPI at baseline (N=374)

No PPI at baseline (N=1742)

Primary 1-Year Endpoint:Death, MI or Stroke

AllN=2116

PlaceboN=1063

ClopidogrelN=1053

Results – 1 Year Endpoint from CREDOResults – 1 Year Endpoint from CREDOUnadjusted DataUnadjusted Data

P=0.001

P=0.45

Dunn S.P. et al AHA 2008. Slide courtesy of Steve Steinhubl MDDunn S.P. et al AHA 2008. Slide courtesy of Steve Steinhubl MD

CV

dea

th,

MI

or s

trok

e

Days

CLOPIDOGREL PPI vs no PPI: Adj HR 0.94, 95% CI 0.80-1.11

PPI use at randomization (n= 4529)Clopidogrel

Prasugrel

PRASUGREL PPI vs no PPI: Adj HR 1.00, 95% CI 0.84-1.20

Observation from an RCT (TRITON-TIMI 38) Conducted for Another Purpose

O’Donoghue M, et al Lancet 2009

COGENT STUDY

CV Events

P=0.001

Bhatt TCT 2009

SummarySummary UA/NSTEMI is the most frequent manifestation of UA/NSTEMI is the most frequent manifestation of

ACSACS

Early risk assessment guides angiography Early risk assessment guides angiography strategy and medication choicesstrategy and medication choices

Dynamic evaluation based on angiogram and Dynamic evaluation based on angiogram and clinical course guides further therapyclinical course guides further therapy

Robust evidence base allows for rational care.Robust evidence base allows for rational care.

Future therapies in development may offer Future therapies in development may offer advantages over current standardsadvantages over current standards

Documents

Antiplatelet Therapy in ACS and PCI: current state of the art and future therapies Stephen D Wiviott MD Cardiovascular Division Brigham and Women’s Hospital