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

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
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.
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APPRAISE-1 Trial
Phase 2, 1715 patients, recent acute coronary syndrome
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
HR 2.45 (1.31-4.61)
p=0.005
CV Death, MI, Stroke,
Sev Recurrent Ischemia
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.
Risk Factors
• Age ≥65 years
• Diabetes mellitus
Recent (≤7days) Acute Coronary
Syndrome
• Prior MI within 5 years
(STEMI or NSTE-ACS)
• Cerebrovascular
At Least 2 Additional
Risk-Factors disease
• Peripheral vascular disease
N=10,800
Randomize 1:1
• Clinical heart failure or LV EF <40%
• Aspirin
Double blind
• Other antiplatelet therapy
• Renal dysfunction (CrCl <60 mL/min)
• No revascularization for ACS event
Projected event
rate: 8%5/ year,
median f/u 1.25 years
Apixaban
mg BID
Event driven:
938 patients with the primary outcome
CrCl<40 ml/min 2.5 mg BID
Placebo
• 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
Outcome:
Death,
Stroke
Analysis: time to Primary
first event
(stratified:CV
single
vs. MI,
dualIschemic
antiplatelet
therapy)
Safety: TIMI Major Bleeding
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%)
Enrollment
7392 patients, 858 sites, 39 countries
Norway: 51
Canada:
254
United States:
935
Mexico:
322
Colombia: 88
Peru: 132
Poland: 353
Sweden: 105
Denmark: 71
U.K.: 45
Netherlands: 97
Belgium: 97
Germany: 160
France: 40
Spain: 160
Switzerland: 38
Czech Rep: 108
Austria: 114
Brazil: 250
Italy: 44
Finland: 7
Slovak Republic: 59
Hungary: 241
Romania: 158
Ukraine: 258
Russia: 1082
Bulgaria: 202
Turkey: 20
Japan: 186
China: 75
Korea: 177
India:
794
Singapore: 25
Israel: 139
Chile: 56
Australia: 38
South Africa: 133
Argentina: 256
New Zealand: 22
Baseline Characteristics
Characteristic
Apixaban
(n=3705)
Placebo
(n=3687)
Age, years
67 (59, 73)
67 (58, 74)
Women, %
32.6
31.7
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
Hypertension
79.9
77.4
Revascularization
27.8
28.7
Inclusion criteria risk factors, %
History of…, %
Index ACS Event
Apixaban
(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
ST-elevation MI
39.8
39.4
Non-ST-elevation MI
Unstable angina
41.4
41.8
18.2
18.1
Coronary angiography
51.9
52.3
PCI
43.8
44.2
CABG
0.6
0.6
Medical therapy only
55.6
55.2
80.1
80.4
Characteristic
Index ACS event type
Index event ACS management
Dual antiplatelet therapy
Primary Outcome
CV 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
Apixaban
N=3705
Placebo
N=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 Outcome
CV 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
Apixaban
N=3705
Placebo
N=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 Bleeding
Subgroups
*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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