appraise-1 - Clinical Trial Results

Report
Safety of the factor Xa inhibitor, apixaban,
in combination with antiplatelet therapy
after acute coronary syndromes: Results
from the APPRAISE-1 dose guiding trial
John H. Alexander, MD, MHSc
Duke Clinical Research Institute, Durham, NC, USA
Lars Wallentin, MD, PhD
Uppsala Clinical Research Center, Uppsala, Sweden
On behalf of the APPRAISE Investigators
Disclosures
APPRAISE-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
Background

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.
Apixaban

Direct, selective inhibitor of Factor Xa

Potent with high oral bioavailability

Concentration-dependent
XII
TF
XI
anticoagulation

and arterial thrombosis

VII
Effective in preclinical models of venous
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 thromboembolism

atrial fibrillation
IX
VIII
Prothrombinase
Complex
V
Prothrombin
X
Fibrinogen
Thrombin
(IIa)
Fibrin
APPRAISE 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 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 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
Study Design
Recent (7 days) Acute Coronary Syndrome
plus at least one additional risk factor
Phase A = 547
Phase A
1:1:1
Placebo
n=184
Apixaban
2.5 mg BID
n=179
Apixaban
10 mg QD
n=184
Interim analysis (DSMB review)
Phase B = 1168
Placebo
n=427
Total = 1715
Phase B
3:1:1:2:2
Apixaban
2.5 mg BID
n=138
Apixaban
10 mg QD
n=134
Apixaban
10 mg BID
n=248
•Randomized, double-blind.
•Study drug for 6 months.
•Aspirin 165 mg/d.
•Clopidogrel per MD discretion
(stratified randomization)
Discontinued early due to
excess bleeding in patients
receiving apixaban and
dual antiplatelet therapy
Apixaban
20 mg QD
n=221
Primary safety outcome: ISTH major or clinically relevant non-major bleeding (ISTH)
Secondary efficacy outcome: cardiovascular death, MI, severe recurrent ischemia or ischemic stroke
ISTH* 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 Enrollment
Europe (plus)












Austria
Belgium
Denmark
France
Germany
Israel
Italy
Poland
Russia
Spain
Sweden
United Kingdom
Enrollment
1305
14
62
54
56
95
163
2
166
442
99
111
41
North America
410
Canada
United States
219
191


Baseline Characteristics
Placebo
N
611
Median (IQR) Age, yrs
60 (52,69)
Age ≥75 yrs, %
11.0
Female, %
25.7
Mean weight, kg
81.8
Diabetes mellitus, %
23.2
Recent prior MI, %
4.7
Cerebrovascular disease, %
4.9
Peripheral vascular disease, %
3.9
CHF or LVEF < 40%, %
9.7
Residual multivessel CAD, %
25.0
Mild or moderate renal insufficiency, % 32.1
Apixaban
2.5 mg BID
317
62 (53,69)
14.2
23.7
81.3
21.8
7.9
4.1
6.6
18.0
26.8
33.4
10 mg QD
318
61 (52,69)
12.3
27.0
82.5
22.3
5.7
5.0
4.4
15.7
25.8
28.6
Index Event and Concomitant Medications
Placebo
N
599
Index Event
ST-elevation MI, %
61.6
PCI, %
64.8
Clopidogrel, %
75.6
Mean time to study drug, days 4.3
Concomitant Medications During Trial
Aspirin, %
100.0
Clopidogrel, %
78.1
Beta blockers, %
92.0
Ace-Inhibitors or ARBs, %
87.3
Calcium blockers, %
20.5
Nitrates, %
36.7
Statins, %
88.3
Apixaban
2.5 mg BID
315
10 mg QD
315
62.2
62.2
73.0
4.2
67.0
64.8
76.5
4.1
99.7
77.1
92.7
85.1
25.1
41.3
87.0
99.7
77.5
92.1
82.9
19.7
41.3
87.9
Bleeding
10%
ISTH and TIMI Scales
7.9%
8%
Placebo, n=599
Apixaban 2.5 mg BID, n=315
Apixaban 10 mg QD, n=315
5.7%
6%
4%
3.0%
2%
1.6%
1.9%
0.8%
0.8%
1.0%
1.3%
1.0%
0.3%
0.0%
0%
ISTH Major/CRNM
ISTH Major
TIMI Major/Minor
TIMI Major
ISTH Major or CRNM Bleeding
ISTH Major or CRNM Bleeding
HR 2.45
95% CI 1.31 to 4.61
p = 0.005
Apix 10 mg QD
HR 1.78
95% CI 0.91 to 3.48
p = 0.09
Apix 2.5 mg BID
Placebo
Weeks
Bleeding by Clopidogrel Status
10%
ISTH Major or CRNM Bleeding
9.1%
Apixaban 2.5 mg BID
7.9%
8%
Placebo
7.0%
Apixaban 10 mg QD
5.7%
6%
4.1%
4%
3.0%
3.1%
2.7%
2.4%
2%
0%
N
Overall
599 315 315
Clopidogrel
453 230 241
No Clopidogrel
146 85 74
Ischemic Outcomes
10%
Placebo, n=611
8.7%
Apixaban 2.5 mg BID, n=317
8%
7.6%
Apixaban 10 mg QD, n=318
6%
6.0%
5.2%
5.4%
4%
3.5%
3.1%
1.8%
2%
1.3%
0%
CV Death, MI, SRI, Stroke
CV Death, MI, Stroke
CV Death
Ischemic Outcome
Placebo
CV Death, MI, SRI or Stroke
HR: 0.73
Apix 2.5 mg BID 95% CI: 0.44 to 1.19
p = 0.21
HR: 0.61
Apix 10 mg QD 95% CI: 0.35 to 1.04
p = 0.07
Weeks
Ischemic Events by Clopidogrel Status
CV Death, MI, SRI or Stroke
16%
15.4%
Placebo
Apixaban 2.5 mg BID
12%
12.9%
Apixaban 10 mg QD
9.3%
8.7%
8%
7.6%
6.0%
6.5%
5.6%
4.9%
4%
0%
N
Overall
Clopidogrel
611 317 318
462 232 243
No Clopidogrel
149
85
75
Adverse Events
Placebo
Apixaban
2.5 BID
10 QD
10 BID*
20 QD*
N
Any Adverse Event
Any Serious Adverse Event
Discontinuation Due to AE
611
74.1
20.9
8.3
317
73.0
23.2
8.3
318
77.1
22.9
9.2
244
64.8
22.5
9.4
218
60.1
16.5
8.7
Liver Function Testing
ALT/AST >3 x ULN, %
ALT/AST >5 x ULN, %
ALT/AST >10 x ULN, %
3.4
0.5
0.0
0.3
0.0
0.0
1.3
0.3
0.3
0.9
0.9
0.9
0.5
0.5
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.
Conclusions

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 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 LopezSendon (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

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