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Dr Jonathan Day Senior Director Global Medical The Medicines Company

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Bivalirudin Advancing Anticoagulation in ACS . Dr Jonathan Day Senior Director Global Medical The Medicines Company . MY CONFLICTS OF INTEREST ARE The Medicines Company (Employee) . ANGIOX ® (bivalirudin) indication.

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slide1
Bivalirudin

Advancing Anticoagulation in ACS

Dr Jonathan Day

Senior Director Global Medical

The Medicines Company

slide2
MY CONFLICTS

OF INTEREST ARE

The Medicines Company (Employee)

angiox bivalirudin indication
ANGIOX® (bivalirudin) indication
  • Bivalirudin is indicated as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI)
  • Bivalirudin is indicated for the treatment of adult patients with acute coronary syndromes (unstable angina/non-ST segment elevation myocardial infarction (UA/NSTEMI)) planned for urgent or early intervention.
  • Bivalirudin should be administered with aspirin and clopidogrel

Please see full Prescribing Information.

indirect versus direct thrombin inhibition
Indirect versus direct thrombin inhibition

Indirect inhibition by heparin requires the presence of antithrombin, the actual inhibitor.1

ANGIOX inhibits thrombin directly with high affinity and specificity.2

ANGIOX provides effective thrombin inhibition to prevent thrombosis and thrombin-mediated platelet effects.2

2. Weitz JI et al. Thromb Res. 2002;106:V275-V284.

Please see full Prescribing Information.

angiox bivalirudin effectively inhibits clot bound thrombin
ANGIOX® (bivalirudin) effectively inhibits clot-bound thrombin

The heparin-antithrombin complex is not effective against clot-bound thrombin.1

This reservoir of active thrombin continues to activate platelets and trigger further clotting.1

ANGIOX, with a high affinity for thrombin, displaces thrombin from fibrin.2

ANGIOX effectively inhibits clot-bound and circulating thrombin.2

1. Hirsh J et al. Chest. 2001;119(1 suppl):64S-94S.

2. Weitz JI et al. Thromb Res. 2002;106:V275-V284.

Please see full Prescribing Information.

return to haemostasis safety advantage
Return to haemostasis—safety advantage

When heparin dissociates from cells/proteins, there can be an anticoagulant effect even when it is not needed. This may explain the prolonged bleeding risk after discontinuation of heparin.1

ANGIOX is cleaved by thrombin, allowing thrombin to quickly recover hemostatic activity upon discontinuation of ANGIOX.2

The natural reversibility and the short, 25-minute half-life may explain the significantly lower bleeding rates seen in clinical trials.3

1. Hirsh J et al. Chest. 2001;119(suppl 1):64S-94S.

2. ANGIOX Prescribing Information. The Medicines Company; UK Ltd. 2008.

Please see full Prescribing Information.

broad spectrum of experience with bivalirudin in clinical trials
Broad spectrum of experience with bivalirudin in clinical trials

27,735 patients undergoing invasive management of CAD

Increasing risk of ischemic complications

REPLACE-2

(N=6,002)

CAD

Planned PCI

BAT

(N=4,312)

UA, NQWMI

Planned PTCA

ACUITY

(N=13,819)

NSTE-ACS

PCI <72h

HORIZONS

(N=3,602)

STEMI

Emergency PCI

Lincoff et al

JAMA, 2003

Bittl et al

AHJ, 2001

Stone et al

NEJM, 2006

Stone et al

NEJM, 2007

ischemic protection less major bleeding and reduced mortality in acute management of cad
Ischemic protection, less major bleeding and reduced mortality in acute management of CAD

14,407 patients in REPLACE-2, ACUITY and HORIZONS†

Bivalirudin alone better

Heparin + GP IIb/IIIa better

† All patients administered ASA and clopidogrel

*includes stroke for HORIZONS patients

Data on file: The Medicines Company

significant reduction in all cause mortality
Significant reduction in all-cause mortality

14,407 patients in REPLACE-2, ACUITY and HORIZONS†

Bivalirudin alone better

Heparin + GP IIb/IIIa better

† All patients administered ASA and clopidogrel

Data on file: The Medicines Company

horizons 30 day mortality cardiac and non cardiac
HORIZONS 30 Day Mortality: Cardiac and Non Cardiac

HR [95%CI] =

0.62 [0.40, 0.96]

P=0.029

2.9%

Death (%)

Cardiac

1.8%

Non cardiac

0.3%

0.2%

Time in Days

Heparin + GPIIb/IIIa inhibitor (n=1802)

Bivalirudin monotherapy (n=1800)

slide11
30 Day MACE – GPI Choice

In the control arm (53%) received abciximab and (47%) received eptifibatide.

In the control arm MACE was independent of GP IIb/IIIa (interaction p-value for MACE = 0.5820).

slide12
30 Day MACE – 300 vs 600mg Clopidogrel

34.6% of patients received 300 mg and 65.2% of patients received 600 mg .

Outcomes were independent of the clopidogrel loading dose (interaction p-value = 0.7571).

horizons 1 year mortality cardiac and non cardiac
Bivalirudin alone (n=1800)

Heparin + GPIIb/IIIa (n=1802)

HORIZONS 1-Year Mortality: Cardiac and Non Cardiac

HR [95%CI] =

0.57 [0.38, 0.84] P=0.005

3.8%

Δ = 1.7%

2.9%

Cardiac

Mortality (%)

2.1%

Δ = 1.1%

P=0.03

Non Cardiac

1.3%

1.1%

Time in Months

Number at risk

Bivalirudin alone

1800

1705

1684

1669

1520

Heparin+GPIIb/IIIa

1802

1678

1663

1646

1486

Mehran R, TCT 2008

horizons subgroup analysis
HORIZONS Subgroup Analysis

Major Adverse Cardiovascular Events at 30 Days [ITT Population]

Data on file: The Medicines Company

horizons subgroup analysis16
HORIZONS Subgroup Analysis

Major Bleeding (non-CABG) at 30 Days [ITT Population]

Data on file: The Medicines Company

horizons subgroup analysis17
HORIZONS Subgroup Analysis

Death at 30 Days [ITT Population]

Data on file: The Medicines Company

horizons 30 day bleeding endpoints
HORIZONS 30 Day Bleeding Endpoints

*Primary endpoint; **Life threatening

## Intracranial bleeding, Intraocular, GI, GU, Pleural, Pulmonary, Head and Neck,Epistaxis, Haemoptysis, Haematemesis, Gingival, Malaena

Data on file: The Medicines Company

30 day stent thrombosis n 3 124
30 Day Stent Thrombosis (N=3,124)

*Protocol definition of stent thrombosis, CEC adjudicated

30 day stent thrombosis n 3 12420
Bivalirudin

UFH + GP IIb/IIIa

30 Day Stent Thrombosis (N=3,124)

5

4

3

Estimated Event Rate (%)

30

2

23

19

1

4

0

0

0.5

1

5

10

15

20

25

30

Days from Randomisation

Patients at Risk

slide21
30 Day Stent Thrombosis – Risk of Subsequent Death

Data on file: The Medicines Company

Analysis of safety population in all patients receiving stents

conclusions
Conclusions
  • In HORIZONS-AMI the significant reductions in cardiac-related death at 30-days and 1-year are important.
  • For every 96 patients with STEMI undergoing primary PCI with bivalirudin compared to conventional therapies one cardiac related death might be avoided (1 yr: NNT=58).
  • The important implications of the HORIZONS study are now reflected in the recently updated ESC guidelines for the management of patients with STEMI undergoing primary PCI where bivalirudin received a (Class IIa-B) recommendation [Van De Werf et al., 2008].
  • In conclusion, the favourable risk–benefit profile of bivalirudin, make it clinically important alternative to current treatments for the contemporary management of ACS patients undergoing PCI.
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