john h. alexander, md, mhs on behalf of the appraise-2 investigators apixaban with antiplatelet...
TRANSCRIPT
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
Thank you to our hosts.Congratulations to the Soccer World
Cup Champions!