John H. Alexander, MD, MHS

on behalf of the APPRAISE-2 Investigators

Apixaban with Antiplatelet Therapy After Acute Coronary Syndrome:Results of the APPRAISE-2 Trial

Sponsored by Bristol-Myers Squibb and Pfizer

Disclosures forJohn H. Alexander

In compliance with AMA requirements, ISTH makes the following disclosures to the session audience:

Research Support/P.I. Bristol-Myers Squibb, Pfizer, Merck-Schering Plough

Employee No relevant conflicts of interest to declare

Consultant Bristol-Myers Squibb, Pfizer, Polymedix

Major Stockholder No relevant conflicts of interest to declare

Speakers Bureau No relevant conflicts of interest to declare

Honoraria No relevant conflicts of interest to declare

Scientific Advisory Board

Bristol-Myers Squibb, Regado Biosciences, Ortho-McNeil-Jannsen

Presentation includes discussion of the following off-label use of a drug or medical device: Apixaban (Eliquis, Bristol-Myers Squibb)

Background

• Patients with ACS have recurrent ischemic events despite revascularization and antiplatelet therapy. Vitamin K antagonists have been shown to reduce recurrent events on a background of aspirin.

• Apixaban, an oral, direct, selective factor Xa inhibitor, reduces venous thromboembolism in patients undergoing orthopedic surgery and prevents thromboembolic events in patients with atrial fibrillation who are not candidates for oral vitamin K antagonists.

• The benefits of apixaban on a background of contemporary antiplatelet therapy following ACS are not known.

Wallentin L . N Engl J Med 2009;361:1045–57.Andreotti F. Eur Heart J 2006 Mar;27:519–26.Hansen ML. Arch Intern Med 2010;170:1433–41.Wong PC. J Thromb Haemost 2008;6:820–9.Lassen MR. Lancet 2010;375:807–15.Lassen MR. N Engl J Med 2010;363:2487–98.Connolly SJ. N Engl J Med 2011;364:806–17.

APPRAISE-1 TrialPhase 2, 1715 patients, recent acute coronary syndrome

Alexander JH. Circulation 2009;119:2877–85.

Apixaban 2.5 mg BID, 10 mg QD, 10 mg BID, 20 mg QD, placebo

Apixaban 10 mg BID & 20 mg QD stopped due to excess bleeding

ISTH Major or CRNM Bleeding CV Death, MI, Stroke, Sev Recurrent Ischemia

HR 2.45 (1.31-4.61)p=0.005

HR: 0.61 (0.35-1.04)p=0.07

HR: 0.73 (0.44-1.19)p=0.21

HR 1.78 (0.91-3.48)p=0.09

Apixaban 5 mg BID

CrCl<40 ml/min 2.5 mg BID

Primary Outcome: CV Death, MI, Ischemic Stroke

Safety: TIMI Major Bleeding

Randomize 1:1

Double blind• Aspirin

• Other antiplatelet therapy

N=10,800

Placebo

Recent (≤7days) Acute Coronary Syndrome(STEMI or NSTE-ACS)

At Least 2 Additional Risk-Factors

Risk Factors

• Age ≥65 years

• Diabetes mellitus

• Prior MI within 5 years

• Cerebrovascular disease

• Peripheral vascular disease

• Clinical heart failure or LV EF <40%

• Renal dysfunction (CrCl <60 mL/min)

• No revascularization for ACS event

Projected event rate: 8% / year, median f/u 1.25 years

Event driven: 938 patients with the primary outcome

• 80% power to detect a 20% risk reduction at a one-sided α of 0.005

• 93% power to detect a 20% risk reduction at a one-sided α of 0.025

Analysis: time to first event (stratified: single vs. dual antiplatelet therapy)

Key subgroups: single / dual antiplatelet therapy, revascularized / not revascularized

Objective

To determine whether apixaban 5mg twice daily reduces the composite of cardiovascular death, MI or stroke at an acceptable risk of bleeding in patients at high-risk for recurrent ischemic events receiving contemporary antiplatelet therapy following an acute coronary syndrome

Trial Stopped Prematurely

On November 15, 2010 the Data Monitoring Committee recommended that the trial be stopped due to an excess of clinically important bleeding in the apixaban arm without a counterbalancing reduction in ischemic events.

• Patients = 7048

• Median f/u = 3.5 months

• Primary Events = 412 (44%)

Enrollment7392 patients, 858 sites, 39 countries

Canada: 254

United States: 935

Mexico: 322

Finland: 7

Denmark: 71

Hungary: 241

Netherlands: 97

Ukraine: 258

Sweden: 105Norway: 51

U.K.: 45

Belgium: 97

France: 40

Spain: 160

Austria: 114

Italy: 44

Israel: 139

Poland: 353

Czech Rep: 108

Chile: 56

Peru: 132

Colombia: 88

Brazil: 250

Argentina: 256

South Africa: 133

Russia: 1082

China: 75

India: 794

Korea: 177

Singapore: 25

Australia: 38

Germany: 160

Japan: 186

Romania: 158

Turkey: 20Bulgaria: 202

Slovak Republic: 59

Switzerland: 38

New Zealand: 22

Baseline Characteristics

CharacteristicApixaban(n=3705)

Placebo(n=3687)

Age, years 67 (59, 73) 67 (58, 74)

Women, % 32.6 31.7

Inclusion criteria risk factors, %

Age > 65 y 58.8 59.0

Diabetes mellitus 48.7 47.0

MI within 5 years 36.0 38.1

Cerebrovascular disease 10.1 9.9

Peripheral vascular disease 17.9 18.3

Heart failure or LVEF <40% 49.9 50.7

Impaired renal function 15.7 16.2

No revasc for index ACS event 55.6 55.2

History of…, %

Hypertension 79.9 77.4

Revascularization 27.8 28.7

Index ACS Event

CharacteristicApixaban (n=3705)

Placebo (n=3687)

Time from index ACS event to rand, days 6.0 (4.0, 7.0) 6.0 (4.0, 7.0)

Elevated biomarkers (CKMB or Troponin) 81.2 81.2

Index ACS event type

ST-elevation MI 39.8 39.4

Non-ST-elevation MI 41.4 41.8

Unstable angina 18.2 18.1

Index event ACS management

Coronary angiography 51.9 52.3

PCI 43.8 44.2

CABG 0.6 0.6

Medical therapy only 55.6 55.2

Dual antiplatelet therapy 80.1 80.4

Primary OutcomeCV Death, MI, Ischemic Stroke

Apixaban 279 (7.5%)Placebo 293 (7.9%)HR 0.95; 95% CI 0.80-1.11; p=0.509

Other Efficacy Outcomes

ApixabanN=3705

PlaceboN=3687

p-value

CV death, MI, ischemic stroke 7.5 7.9 0.509

CV death, MI, ischemic stroke, UA 9.5 10 0.430

Death 4.2 3.9 0.514

CV death 2.8 2.9 0.754

Myocardial infarction 4.9 5.3 0.509

Ischemic stroke 0.6 0.9 0.145

Unstable angina 2.3 2.4 0.670

Definite stent thrombosis 0.9 1.3 0.150

Primary OutcomeCV Death, MI, Stroke — Subgroups

*HR not calculated for subgroups with ≤10 events

TIMI Major Bleeding

Apixaban 48 (1.3%)Placebo 18 (0.5%) HR 2.59; 95% CI 1.50–4.46; p=0.001

Other Bleeding Scales

ApixabanN=3705

PlaceboN=3687

p-value

TIMI major 1.3 0.5 0.001

TIMI major or minor 2.2 0.8 <0.001

ISTH major 2.7 1.1 <0.001

ISTH major or clinically relevant non-major

3.2 1.2 <0.001

GUSTO severe 1.0 0.3 0.001

Intracranial 0.3 0.1 0.030

Fatal bleeding: Apixaban = 5 vs. Placebo = 0

ISTH major bleeding = bleeding leading to death, occurring in a critical location, or associated with a ≥2 g/dL drop in hemoglobin or transfusion of 2 or more units of PRBC.

TIMI Major BleedingSubgroups

*HR not calculated for subgroups with ≤10 events

Conclusions

• APPRAISE-2 Summary: The addition of apixaban to contemporary antiplatelet therapy increases major bleeding without any significant reduction in ischemic events in high-risk patients following an ACS.

• Limitations: Because of the early termination of the trial, with accrual of two-thirds of the expected events and a median follow-up of 8 months, some uncertainty regarding efficacy remains.

• Clinical Implications: The addition of an anticoagulant to currently recommended anti-platelet treatment post-ACS should be used cautiously and only in patients with clear indications for both an anticoagulant and antiplatelet therapy.

• Future Directions: Further research is needed to explore different antithrombotic combinations and doses that might have a different risk-benefit balance.

Acknowledgement

• Executive Committee: RA Harrington (co-chair), L Wallentin (co-chair), JH Alexander (PI), S James (co-PI), RD Lopes (CEC chair), P Mohan and D Liaw (BMS).

• Steering Committee: R Diaz, J Amerena, K Huber, F Cools, J Nicolau, D Raev, S Goodman, R Corbalan, Y Huo, M Urina-Triana, P Jansky, S Husted, K Niemela, G Montalescot, H Darius, M Keltai,; P Pais, B Lewis, R De Caterina, H Ogawa, SJ Park, JL Leiva-Pons, J Cornel, F Verheugt, H White, D Atar, A Gallegos-Cazorla, W Ramos, W Ruzyllo, D Vinereanu, M Ruda, RS Tan, V Fridrich, H Du Truit Theron, J Lopez-Sendon, T Jernberg, T Luscher, C Erol, M Flather, A Parkhomenko, D Bhatt, J Miller.

• Data Monitoring Committee: M Simoons (chair), P Armstrong, J DeLemos, T Kimura, A Maggioni, S Pocock.

• CEC: R Lopes, K Mahaffey, S Al-Khatib, A Hernandez, B Kolls, S Leonardi, R Mehta, C Melloni, LK Newby, M Roe, B Shah, L Szczech, P Tricoci, A Truffa, J Vavalle, AB Cavalcanti, L Echenique, C Gonzaga, HP Guimaraes, L Armaganijan.

• DCRI: L Hatch, M Banks, A Handler, L Perkins, A Heath, Y Lokhnygina, S Dickerson, A Stone, K Lee, J Garg.

• BMS / Pfizer: D Liaw, P Mohan, M Hanna, F Fiedorek, JM Bocquet, N Kolivodiakos, L Rossi, R Braceras, H Pouleur, N Jackson, D Hessinger.

• PPD: V Ponder-Lee, K Griffith, T Dremsizov, A Bevan, C Murphy, M Okabe, J Knoll, A Burr.

• The APPRAISE-2 Investigators, Coordinators and Patients

APPRAISE-2 Publication

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