John H. Alexander, MD, MHScDuke Clinical Research Institute, Durham, NC, USA

Lars Wallentin, MD, PhDUppsala Clinical Research Center, Uppsala, Sweden

On behalf of the APPRAISE Investigators

John H. Alexander, MD, MHScDuke Clinical Research Institute, Durham, NC, USA

Lars Wallentin, MD, PhDUppsala Clinical Research Center, Uppsala, Sweden

On behalf of the APPRAISE Investigators

Safety of the factor Xa inhibitor, apixaban, in combination with antiplatelet therapy

after acute coronary syndromes: Results from the APPRAISE-1 dose guiding trial

Safety of the factor Xa inhibitor, apixaban, in combination with antiplatelet therapy

after acute coronary syndromes: Results from the APPRAISE-1 dose guiding trial

DisclosuresDisclosuresAPPRAISE-1 was supported by Bristol-Myers Squibb

John Alexander Research Support: Bristol-Myers Squibb, Medicure, Medtronic Japan,

Millennium, NIH, Regado Biosciences, Schering Plough

Consulting: Adolor, Daiichi Sankyo, Medicure, NIH, Novartis

Lars Wallentin Research Support: Astra-Zeneca, Bristol-Myers Squibb, Boehringer-

Ingelheim, Lilly, GlaxoSmithKlein, Schering-Plough

This presentation discusses the unapproved use of apixaban in patients with acute coronary syndromes

BackgroundBackground Patients with acute coronary syndromes continue to have recurrent ischemic

events despite contemporary evidence based care including revascularization and potent antiplatelet therapy.

Oral anticoagulation (warfarin and the direct thrombin inhibitor, ximelagatran) is superior to aspirin following acute coronary syndromes, however warfarin is rarely used because of its narrow therapeutic window and requirement for monitoring.

No placebo controlled trial of oral anticoagulation has been performed in patients taking dual antiplatelet therapy.

Novel anticoagulants offer an opportunity to reduce recurrent ischemic events beyond dual antiplatelet therapy but also pose a risk of bleeding.

Direct, selective inhibitor of Factor Xa Potent with high oral bioavailability Concentration-dependent

anticoagulation Effective in preclinical models of venous

and arterial thrombosis No QTc prolongation No organ toxicity in toxicology studies Elimination ~70% GI tract, ~25% renal Half-life ~12 hrs Ongoing phase 3 clinical programs

venous thromboembolismatrial fibrillation

ApixabanApixaban

X

Thrombin (IIa)

Fibrin

IX

XI

XII

VIII

VII

Prothrombin

FibrinogenV

Prothrombinase

Complex

TF

APPRAISE ObjectivesAPPRAISE Objectives

To evaluate the effect on bleeding of 4 doses of apixaban vs. placebo given over 26 weeks in patients with a recent acute coronary syndrome receiving current evidence based care.

To determine the optimal dose of apixaban for further investigation.

Inclusion CriteriaInclusion Criteria Age 18–90 years Recent (7 days) acute coronary syndrome

Symptoms of myocardial ischemia lasting at least 10 minutes Elevated cardiac markers (Tn T or I, CK-MB) or ST elevation / depression (≥1.0 mm)

Clinically stable, receiving standard post-ACS care At least 1 additional risk factor for recurrent ischemic event

Age 65 years Both elevated cardiac markers and ST deviation Diabetes mellitus Prior MI within the past 12 months Prior ischemic stroke, TIA, or asymptomatic carotid stenosis Peripheral vascular disease Prior symptomatic CHF or a left ventricular EF <40% Non-revascularized multivessel CAD Mild to moderate renal insufficiency (CrCl <90 ml/min)

Exclusion CriteriaExclusion Criteria Planned catheterization, PCI, CABG or other invasive procedure Persistent severe HTN (SBP ≥180, DBP ≥110 mmHg) Severe renal dysfunction (CrCl <30 ml/min) Active bleeding or at high risk for bleeding Acute pericarditis or pericardial effusion Recent stroke (3 months) Severe heart failure (NYHA Class IV) Platelet count 100,000/mm3, hemoglobin 10g/dl Need for ongoing parenteral or oral anticoagulant Chronic NSAID or high-dose (>325 mg/day) aspirin

Phase B = 1168

Study DesignStudy DesignRecent (7 days) Acute Coronary Syndrome

plus at least one additional risk factor

Apixaban20 mg QD

n=221

Apixaban20 mg QD

n=221

Apixaban10 mg BID

n=248

Apixaban10 mg BID

n=248

Phase A = 547

Apixaban 10 mg QD

n=184

Apixaban 10 mg QD

n=184

Placebon=184

Placebon=184

•Randomized, double-blind. •Study drug for 6 months. •Aspirin 165 mg/d. •Clopidogrel per MD discretion (stratified randomization)

•Randomized, double-blind. •Study drug for 6 months. •Aspirin 165 mg/d. •Clopidogrel per MD discretion (stratified randomization)

Phase A1:1:1

Phase A1:1:1

Apixaban2.5 mg BID

n=179

Apixaban2.5 mg BID

n=179

Interim analysis (DSMB review)

Phase B3:1:1:2:2Phase B3:1:1:2:2

Placebon=427

Placebon=427

Apixaban2.5 mg BID

n=138

Apixaban2.5 mg BID

n=138

Apixaban10 mg QD

n=134

Apixaban10 mg QD

n=134Total = 1715Total = 1715

Apixaban20 mg QD

n=221

Apixaban20 mg QD

n=221

Apixaban10 mg BID

n=248

Apixaban10 mg BID

n=248

Primary safety outcome: ISTH major or clinically relevant non-major bleeding (ISTH)Secondary efficacy outcome: cardiovascular death, MI, severe recurrent ischemia or ischemic stroke

Discontinued early due to excess bleeding in patients receiving apixaban and dual antiplatelet therapy

ISTH* Bleeding DefinitionsISTH* Bleeding Definitions

Major Bleeding – Bleeding… with a fall in hemoglobin of ≥2 g/dL, or with transfusion of ≥2 units of PRBC or whole blood, or that occurs in a critical location, i.e., intracranial, intraspinal,

intraocular, retroperitoneal, intraarticular or pericardial, or that causes death

Clinically Relevant Non-Major Bleeding – Bleeding… that does not meet criteria for major bleeding, and that requires any medical or surgical intervention to treat the

bleeding

*ISTH – International Society of Thrombosis and Haemostasis

APPRAISE EnrollmentAPPRAISE EnrollmentEnrollment

Europe (plus) 1305 Austria 14 Belgium 62 Denmark 54 France 56 Germany 95 Israel 163 Italy 2 Poland 166 Russia 442 Spain 99 Sweden 111 United Kingdom 41

North America 410 Canada 219 United States 191

Baseline CharacteristicsBaseline CharacteristicsPlacebo Apixaban

2.5 mg BID 10 mg QD

N 611 317 318

Median (IQR) Age, yrs 60 (52,69) 62 (53,69) 61 (52,69)

Age ≥75 yrs, % 11.0 14.2 12.3

Female, % 25.7 23.7 27.0

Mean weight, kg 81.8 81.3 82.5

Diabetes mellitus, % 23.2 21.8 22.3

Recent prior MI, % 4.7 7.9 5.7

Cerebrovascular disease, % 4.9 4.1 5.0

Peripheral vascular disease, % 3.9 6.6 4.4

CHF or LVEF < 40%, % 9.7 18.0 15.7

Residual multivessel CAD, % 25.0 26.8 25.8

Mild or moderate renal insufficiency, % 32.1 33.4 28.6

Index Event and Concomitant MedicationsIndex Event and Concomitant MedicationsPlacebo Apixaban

2.5 mg BID 10 mg QDN 599 315 315Index Event ST-elevation MI, % 61.6 62.2 67.0 PCI, % 64.8 62.2 64.8 Clopidogrel, % 75.6 73.0 76.5 Mean time to study drug, days 4.3 4.2 4.1Concomitant Medications During Trial Aspirin, % 100.0 99.7 99.7 Clopidogrel, % 78.1 77.1 77.5 Beta blockers, % 92.0 92.7 92.1 Ace-Inhibitors or ARBs, % 87.3 85.1 82.9 Calcium blockers, % 20.5 25.1 19.7 Nitrates, % 36.7 41.3 41.3 Statins, % 88.3 87.0 87.9

3.0%

5.7%

7.9%

0.8%

1.6%1.9%

0.8%1.0%

1.3%

0.3%0.0%

1.0%

0%

2%

4%

6%

8%

10%

ISTH Major/CRNM ISTH Major TIMI Major/Minor TIMI Major

Placebo, n=599

Apixaban 2.5 mg BID, n=315

Apixaban 10 mg QD, n=315

Bleeding Bleeding ISTH and TIMI ScalesISTH and TIMI Scales

ISTH Major or CRNM BleedingISTH Major or CRNM BleedingIS

TH

Maj

or

or

CR

NM

Ble

edin

g

Weeks

HR 1.7895% CI 0.91 to 3.48p = 0.09

HR 2.4595% CI 1.31 to 4.61p = 0.005

Placebo

Apix 2.5 mg BID

Apix 10 mg QD

3.0%

5.7%

7.9%

3.1%

7.0%

9.1%

2.7%2.4%

4.1%

0%

2%

4%

6%

8%

10%

IST

H M

ajo

r o

r C

RN

M B

leed

ing

Overall Clopidogrel No Clopidogrel

Placebo

Apixaban 2.5 mg BID

Apixaban 10 mg QD

Bleeding by Clopidogrel StatusBleeding by Clopidogrel Status

N 599 315 315 453 230 241 146 85 74

8.7%

7.6%

6.0%

5.2%5.4%

3.1%

1.8%

3.5%

1.3%

0%

2%

4%

6%

8%

10%

CV Death, MI, SRI, Stroke CV Death, MI, Stroke CV Death

Placebo, n=611

Apixaban 2.5 mg BID, n=317

Apixaban 10 mg QD, n=318

Ischemic OutcomesIschemic Outcomes

Ischemic OutcomeIschemic OutcomeC

V D

eath

, M

I, S

RI

or

Str

oke

Weeks

HR: 0.73 95% CI: 0.44 to 1.19p = 0.21

HR: 0.6195% CI: 0.35 to 1.04p = 0.07

Placebo

Apix 2.5 mg BID

Apix 10 mg QD

8.7%

7.6%

6.0%6.5%

5.6%4.9%

15.4%

12.9%

9.3%

0%

4%

8%

12%

16%

CV

De

ath

, M

I, S

RI

or

Str

ok

e

Overall Clopidogrel No Clopidogrel

Placebo

Apixaban 2.5 mg BID

Apixaban 10 mg QD

Ischemic Events by Clopidogrel StatusIschemic Events by Clopidogrel Status

N 611 317 318 462 232 243 149 85 75

Adverse Events

Placebo Apixaban

2.5 BID 10 QD 10 BID* 20 QD*N 611 317 318 244 218

Any Adverse Event 74.1 73.0 77.1 64.8 60.1

Any Serious Adverse Event 20.9 23.2 22.9 22.5 16.5

Discontinuation Due to AE 8.3 8.3 9.2 9.4 8.7

Liver Function Testing

ALT/AST >3 x ULN, % 3.4 0.3 1.3 0.9 0.5

ALT/AST >5 x ULN, % 0.5 0.0 0.3 0.9 0.5

ALT/AST >10 x ULN, % 0.0 0.0 0.3 0.9 0.0

*Includes only patients who were randomized treated and events that occurred through October 1, 2007 when the 10mg BID and 20mg QD arms were discontinued.

ConclusionsConclusions This is the first experience using anticoagulation with a direct factor

Xa inhibitor for secondary prevention in patients with an acute coronary syndrome treated with dual antiplatelet therapy.

We found that the addition of apixaban to contemporary antiplatelet therapy for 6 months following an acute coronary syndrome results in a dose dependent increase in bleeding and a promising trend toward a reduction in clinically important ischemic events.

The relative increase in bleeding and reduction in ischemic events appears similar among patients taking single (aspirin) or dual (aspirin plus clopidogrel) antiplatelet therapy.

Apixaban, at a total daily dose of between 5 and 10 mg, appears promising in patients with recent acute coronary syndromes receiving either aspirin or dual antiplatelet therapy and deserves further clinical investigation.

Study OrganizationStudy Organization APPRAISE Investigators and Research Coordinators

Steering Committee (National Coordinators): Lars Wallentin and Robert Harrington (co-chairs), John Alexander (PI, USA), Richard Becker, Deepak Bhatt, Frank Cools (Belgium), Filippo Crea (Italy), Harald Darius (Germany), Mikael Dellborg (Sweden), Keith Fox (UK), Shaun Goodman (Canada), Kurt Huber (Austria), Steen Husted (Denmark), Basil Lewis (Israel), Jose Lopez-Sendon (Spain), Puneet Mohan (BMS), Giles Montalescot (France), Mikhail Ruda (Russia), Witold Ruzyllo (Poland), Freek Verheugt.

Data Monitoring Committee: Maarten Simoons (chair), Eric Boersma, James DeLemos, Fred Spencer

DCRI (CEC, Stats): Kenneth Mahaffey, Meredith Smith, Laura Melton, Robert Clare

CRO (PPD): Clark Weaver, Keven Griffith

Sponsor (BMS): Rajnish Saini, Leigh Townes, Heather Knowles, Helen He