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Apixaban with Antiplatelet Therapy After Acute Coronary Syndrome: Results of the APPRAISE-2 Trial. John H. Alexander, MD, MHS on behalf of the APPRAISE-2 Investigators. Sponsored by Bristol-Myers Squibb and Pfizer. Disclosures for John H. Alexander.

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apixaban with antiplatelet therapy after acute coronary syndrome results of the appraise 2 trial

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

John H. Alexander, MD, MHS

on behalf of the APPRAISE-2 Investigators

Sponsored by Bristol-Myers Squibb and Pfizer

disclosures for john h alexander
Disclosures forJohn H. Alexander

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

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

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

Apixaban 2.5 mg BID, 10 mg QD, 10 mg BID, 20 mg QD, placeboApixaban 10 mg BID & 20 mg QD stopped due to excess bleeding

CV Death, MI, Stroke, Sev Recurrent Ischemia

ISTH Major or CRNM Bleeding

HR 2.45 (1.31-4.61)

p=0.005

HR: 0.73 (0.44-1.19)

p=0.21

HR: 0.61 (0.35-1.04)

p=0.07

HR 1.78 (0.91-3.48)

p=0.09

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

slide5

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

Recent (≤7days) Acute Coronary Syndrome

(STEMI or NSTE-ACS)

At Least 2 Additional Risk-Factors

Randomize 1:1

Double blind

N=10,800

  • Aspirin
  • Other antiplatelet therapy

Apixaban 5 mg BID

CrCl<40 ml/min 2.5 mg BID

Placebo

  • 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

Primary Outcome: CV Death, MI, Ischemic Stroke

Safety: TIMI Major Bleeding

objective
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
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%)
enrollment 7392 patients 858 sites 39 countries
Enrollment7392 patients, 858 sites, 39 countries

Poland: 353

Finland: 7

Slovak Republic: 59

Sweden: 105

Norway: 51

Hungary: 241

Romania: 158

Russia: 1082

Canada: 254

Ukraine: 258

Denmark: 71

U.K.: 45

Bulgaria: 202

Netherlands: 97

Turkey: 20

United States: 935

Japan: 186

Belgium: 97

China: 75

Korea: 177

Germany: 160

Mexico: 322

India: 794

France: 40

Spain: 160

Switzerland: 38

Czech Rep: 108

Colombia: 88

Austria: 114

Singapore: 25

Italy: 44

Brazil: 250

Peru: 132

Israel: 139

Chile: 56

Australia: 38

South Africa: 133

Argentina: 256

New Zealand: 22

primary outcome cv death mi ischemic stroke
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

primary outcome cv death mi stroke subgroups
Primary OutcomeCV Death, MI, Stroke — Subgroups

*HR not calculated for subgroups with ≤10 events

timi major bleeding
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
Other Bleeding Scales

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 bleeding subgroups
TIMI Major BleedingSubgroups

*HR not calculated for subgroups with ≤10 events

conclusions
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
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