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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

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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
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
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
Apixaban
  • Direct, selective inhibitor of Factor Xa
  • Potent with high oral bioavailability
  • Concentration-dependent

anticoagulation

  • Effective in preclinical models of venous and arterial thrombosis
  • 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

XII

TF

XI

VII

IX

VIII

Prothrombinase

Complex

X

V

Fibrinogen

Thrombin (IIa)

Prothrombin

Fibrin

appraise objectives
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
Inclusion Criteria
  • Age18–90 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
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
Study Design

Recent (7 days)Acute Coronary Syndrome

plus at least one additional risk factor

Phase A = 547

Phase A

1:1:1

  • Randomized, double-blind.
  • Study drug for 6 months.
  • Aspirin 165 mg/d.
  • Clopidogrel per MD discretion (stratified randomization)

Apixaban

10 mg QD

n=184

Apixaban

2.5 mg BID

n=179

Placebo

n=184

Discontinued early due to excess bleeding in patients receiving apixaban and dual antiplatelet therapy

Interim analysis (DSMB review)

Phase B =1168

Phase B

3:1:1:2:2

Placebo

n=427

Apixaban

2.5 mg BID

n=138

Apixaban

10 mg QD

n=134

Apixaban

10 mg BID

n=248

Apixaban

20 mg QD

n=221

Apixaban

10 mg BID

n=248

Apixaban

20 mg QD

n=221

Total = 1715

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
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
APPRAISE Enrollment

Enrollment

Europe (plus)1305

  • Austria 14
  • Belgium 62
  • Denmark 54
  • France 56
  • Germany 95
  • Israel 163
  • Italy 2
  • Poland 166
  • Russia 442
  • Spain 99
  • Sweden 111
  • United Kingdom 41

North America410

  • Canada 219
  • United States 191
baseline characteristics
Baseline Characteristics

Placebo Apixaban

2.5 mg BID 10 mg QD

N 611 317 318

Median (IQR) Age, yrs 60 (52,69) 62 (53,69) 61 (52,69)

Age ≥75 yrs, % 11.0 14.2 12.3

Female, % 25.7 23.7 27.0

Mean weight, kg 81.8 81.3 82.5

Diabetes mellitus, % 23.2 21.8 22.3

Recent prior MI, % 4.7 7.9 5.7

Cerebrovascular disease, % 4.9 4.1 5.0

Peripheral vascular disease, % 3.9 6.6 4.4

CHF or LVEF < 40%, % 9.7 18.0 15.7

Residual multivessel CAD, % 25.0 26.8 25.8

Mild or moderate renal insufficiency, % 32.1 33.4 28.6

index event and concomitant medications
Index Event and Concomitant Medications

Placebo Apixaban

2.5 mg BID 10 mg QD

N 599 315 315

Index Event

ST-elevation MI, % 61.6 62.2 67.0

PCI, % 64.8 62.2 64.8

Clopidogrel, % 75.6 73.0 76.5

Mean time to study drug, days 4.3 4.2 4.1

Concomitant Medications During Trial

Aspirin, % 100.0 99.7 99.7

Clopidogrel, % 78.1 77.1 77.5

Beta blockers, % 92.0 92.7 92.1

Ace-Inhibitors or ARBs, % 87.3 85.1 82.9

Calcium blockers, % 20.5 25.1 19.7

Nitrates, % 36.7 41.3 41.3

Statins, % 88.3 87.0 87.9

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

ISTH Major or CRNM Bleeding

Apix 2.5 mg BID

Placebo

Weeks

bleeding by clopidogrel status
Bleeding by Clopidogrel Status

N 599 315 315 453 230 241 146 85 74

ischemic outcome
Ischemic Outcome

Placebo

HR: 0.73

95% CI: 0.44 to 1.19

p = 0.21

Apix 2.5 mg BID

HR: 0.61

95% CI: 0.35 to 1.04

p = 0.07

CV Death, MI, SRI or Stroke

Apix 10 mg QD

Weeks

ischemic events by clopidogrel status
Ischemic Events by Clopidogrel Status

N 611 317 318 462 232 243 149 85 75

adverse events
Adverse Events

Placebo Apixaban

2.5 BID 10 QD 10 BID* 20 QD*

N 611 317 318 244 218

Any Adverse Event 74.1 73.0 77.1 64.8 60.1

Any Serious Adverse Event 20.9 23.2 22.9 22.5 16.5

Discontinuation Due to AE 8.3 8.3 9.2 9.4 8.7

Liver Function Testing

ALT/AST >3 x ULN, % 3.4 0.3 1.3 0.9 0.5

ALT/AST >5 x ULN, % 0.5 0.0 0.3 0.9 0.5

ALT/AST >10 x ULN, % 0.0 0.0 0.3 0.9 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
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
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 Lopez-Sendon (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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