1

Replace Heparin and Improve OutcomesNew Antithrombotic Strategies in ACS Patients Undergoing PCI

ANG-PSL-XXX-XXX

2

Overview

• Thrombin’s critical role

• Clot burden in the ACS patient

• Mechanistic rationale for switching patients to ANGIOMAX®

(bivalirudin) for PCI

• Why is there concern about switching anticoagulants in ACS treatment?– Lessons from SYNERGY

• Clinical evidence in support of switching to ANGIOMAX

• ACUITY PCI Subgroup Analysis: 1-Year Mortality Results

ACS=acute coronary syndromes; ACUITY=Acute Catheterization and Urgent Intervention Triage strategY; AT=antithrombin; PCI=percutaneous coronary intervention; SYNERGY=Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors.

3

Why ANGIOMAX® (bivalirudin)?The Critical Role of Thrombin• Thrombin is the link between vessel injury, coagulation,

and platelet response

Vessel Injury

Platelet activation

Platelet aggregation

Fibrinogen

Fibrin

Thrombin

Plasma clotting factors

Prothrombin

Tissue factor

Collagen

ADPplatelet

activation

ADP TXA2=adenosine diphosphate/thromboxane A2.

Coughlin SR. Nature. 2000;407:258-264; Monroe DM et al. Arterioscler Thromb Vasc Biol. 2002;22:1381-1389.

4

Thrombin Promotes Platelet Activation and Clotting

• Thrombin is the link between tissue injury, coagulation, and platelet response

Coughlin SR. Nature. 2000;407:258-264; Monroe DM et al. Arterioscler Thromb Vasc Biol. 2002;22:1381-1389.

Platelet activation

Platelet Aggregation

Fibrinogen

Fibrin

Thrombin is a critical mediator in hemostasis and thrombosis

Thrombinbegetsthrombin

Thrombin is a platelet agonist;

elicits multiple responses in

plateletsThrombin

Plasma clotting factors

Prothrombin

5

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

Indirect Versus Direct Thrombin Inhibition

ANGIOMAX® (bivalirudin) inhibits thrombin directly with high affinity and specificity.

ANGIOMAX provides rapid, effective thrombin inhibition to prevent thrombosis and thrombin-mediated platelet effects.

AT=antithrombin.Hirsh J et al. Chest. 2001;119(1 suppl):64S-94S.Weitz JI et al. Thromb Res. 2002;106:V275-V284.

6

Clot Burden in ACS

• Many ACS patients already have significant clot burden– 94% of patients with UA have angioscopic-evident clot

– Only 13% of clots are identified by angiography

Brummel KE et al. Blood. 2002;100:148-152.White CJ et al. In: Textbook of Interventional Cardiology. 2003:873-891.

T=red, globular mass of thrombus (clot); UA=unstable angina; W=guidewire within the lumen.

• Clot contains activated platelets and active thrombin, which continues to activate and recruit more platelets – 96% of thrombin is still being generated after the clot is visible

7

0

50

100

0.1 0.2 0.4 1.0 2.0 3.0 4.0

Soluble thrombin Clot-bound thrombin

Heparin Fails to Effectively Inhibit Clot-Bound Thrombin• Therapeutic levels of UFH inhibit only 20% to 60% of clot-bound

thrombin

Heparin concentration (units/mL)

Inh

ibit

ion

(%

)

Weitz JI et al. J Clin Invest. 1990;86:388. Reproduced with permission. ©1990 American Society for Clinical Investigation.

UFH=unfractionated heparin.

8

87

10096 100

0

20

40

60

80

100

Solublethrombin

Clot-boundthrombin

0.5 M ANGIOMAX

1.0 M ANGIOMAX

Mean inhibition of fibrinopeptide A production by ANGIOMAX

Data on file. The Medicines Company, Parsippany, NJ.

ANGIOMAX® (bivalirudin) Inhibits Clot-Bound and Circulating Thrombin

Inh

ibit

ion

(%

)

• ANGIOMAX is 100% effective against clot-bound thrombin

9

Heparin (long strand) binds to other plasma proteins (colored molecules) and platelets, reducing the availability of heparin to bind to AT.

Heparin-binding proteins are elevated in ACS.

Heparin Binds to Plasma Proteins; ANGIOMAX® (bivalirudin) Binds Specifically to Thrombin

ANGIOMAX (bright blue) binds onlyto thrombin (orange).

ANGIOMAX is not neutralized by other plasma proteins or platelets; it remains fully active near thrombus.

ACS=acute coronary syndromes.

Hirsh J et al. Chest. 2001;119(suppl 1):64S-94S.Weitz JI et al. Thromb Res. 2002;106:V275-V284.Wittkowsky AK. Pharmacotherapy. 2002;22(6 Pt 2):97S-104S.

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Heparin is neutralized by PF4, which is present in high concentrations near vascular injury.

Thrombin continues activating platelets.

PF4/heparin complex antibodies activate platelets, causing thrombocytopenia as well as HIT/TS.

ANGIOMAX® (bivalirudin) does not bind to PF4, and remains fully active.

There is no risk of HIT/TS or other thrombotic events associated with PF4/heparin antibodies.

Consequences of Nonspecific Binding

HIT/TS=heparin-induced thrombocytopenia thrombosis syndrome; PF4=platelet factor 4.Weitz JI et al. Thromb Res. 2002;106:V275-V284.Williams RT et al. Circulation. 2003;107:2307-2312.

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Heparin Increases Platelet Activation

Heparin makes platelets more reactive to activation by other agonists such as ADP. Heparin binds to the platelet GP IIb/IIIa receptor.

Given the various ways heparin increases platelet activation, its use may actually increase the need for antiplatelet agents.

ADP=adenosine diphosphate.Becker R et al. J Invasive Cardiol. 2003;(suppl):1-15. Sobel M et al. J Vasc Surg. 2001;33:587-594.Xiao Z et al. Circulation. 1998;97:251-256.

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ANGIOMAX® (bivalirudin): No Platelet Activation

*All scanning electron micrographs were acquired at a magnification of 4,000x with the investigator blinded to treatment.

Control platelets

• Direct platelet activation by UFH but not ANGIOMAX*

Anand SX et al. Am J Cardiol. 2007;100:417-424. Reproduced with permission. ©2007 Elsevier Health Science Journals.

Platelets treated with UFH

Platelets treated with ANGIOMAX

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ANGIOMAX® (bivalirudin) Inhibits Platelets Via Thrombin• Thrombin is the most potent known physiologic platelet agonist

• Platelet inhibition occurs well below therapeutic levels of ANGIOMAX

Adapted from Weitz J et al. Am J Cardiol. 2001;88(5 suppl 1):83G.

110

90

70

50

30

100.01 0.1 1 10 100 1000

Concentration of ANGIOMAX (μg/mL)

Thrombin

Therapeutic plasma level range

Ag

gre

gat

ion

in

resp

on

se t

o t

hro

mb

in

(%)

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Return to Hemostasis—Safety Advantage

ANGIOMAX® (bivalirudin) is cleaved by thrombin, allowing thrombin to quickly recover hemostatic activity upon discontinuation of ANGIOMAX.2

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

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

1. Hirsh J et al. Chest. 2001;119(suppl 1):64S-94S.2. Weitz JI et al. Thromb Res. 2002;106:V275-V284.3. ANGIOMAX (bivalirudin) [prescribing information]; December 6, 2005.

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ANGIOMAX® (bivalirudin) Has Predictable Pharmacology

ANGIOMAX (bivalirudin) [prescribing information]; December 6, 2005.Robson R. J Invasive Cardiol. 2000;12(suppl F):33F-36F. Data on file. The Medicines Company, Parsippany, NJ.

*Modeled data. PCI=percutaneous coronary intervention.

0

2

4

6

8

10

12

14

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 8

Infusion 2.5 mg/kg/hour

Est

imat

ed (

AN

GIO

MA

X)

mea

n (μ

g/m

L)

Time from start of bolus of ANGIOMAX (h)

Infusion 1.75 mg/kg/hour*

Bolus 1 mg/kg

Bolus 0.75 mg/kg*

25-minutehalf-life1

Plasma level of ANGIOMAX shown to

reduce risk of ischemia in PCI2

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ANGIOMAX® (bivalirudin)—Unique Mechanism of Action Overcomes the Limitations of Heparin

• Direct thrombin inhibitor that is reversible via thrombin yielding a 25-minute half-life– Heparin requires antithrombin to be able to deactivate thrombin

• Inhibits clot-bound and circulating thrombin– Heparin fails to effectively inhibit clot-bound thrombin

• Inhibits thrombin-mediated platelet aggregation and does not activate platelets– Heparin activates platelets

• Provides predictable pharmacology and linear pharmacokinetics– Heparin is unpredictable and has nonlinear pharmacokinetics

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Switching to ANGIOMAX® (bivalirudin) for PCI Delivers Improved Outcomes

ANG-PSL-484-XXX

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SYNERGY: Switching Between Heparins

• SYNERGY overall primary end point results– No difference in the composite of death/MI with enoxaparin

compared with UFH

– Significant increase in bleeding (TIMI major) with enoxaparin compared with UFH

• Patients who crossed over after randomization from UFH to enoxaparin or vice versa had– Increased rates of death/MI at 30 days compared with those who

did not cross over

– More bleeding complications (transfusions)

Ferguson JJ et al. JAMA. 2004;292:45-54.

MI=myocardial infarction; TIMI=Thrombosis in Myocardial Infarction.

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SYNERGY: 30-Day Death/MI

• Patients who crossed over from UFH to enoxaparin or vice versa had increased rates of death/MI within 30 days compared with those on consistent therapy*

14.2 13.5

22.0

17.4

0

10

20

30

40

UFH Enoxaparin

Consistent Crossover

Dea

th/M

I a

t 30

day

s (%

)

n=677 n=45 n=593 n=103

*Postrandomization crossovers.

Ferguson JJ et al. JAMA. 2004;292:45-54.

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SYNERGY: 30-Day Transfusions

• The rate of transfusion doubled in patients who crossed over from UFH to enoxaparin or vice versa within 30 days compared with those on consistent therapy*

15.1 15.3

35.1

30.2

0

10

20

30

40

UFH Enoxaparin

Consistent Crossover

Tra

nsf

usi

on

s at

30

day

s (%

)

n=724 n=72 n=671 n=179

*Postrandomization crossovers.

Ferguson JJ et al. JAMA. 2004;292:45-54.

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SYNERGY: Switching Between Heparins

• The SYNERGY trial suggested that changing therapies between UFH and enoxaparin (or vice versa) resulted in an increased risk of bleeding

• Do these findings apply to ANGIOMAX® (bivalirudin)? Is it better to switch to ANGIOMAX or stay on consistent heparin therapy?

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Evidence to Support Switching to ANGIOMAX® (bivalirudin)• BAT analysis (Bittl)

– Evaluate switching in era of conservative management

– Switching to ANGIOMAX improved ischemic and bleeding outcomes

– Improvements more profound in higher risk strata

• SWITCH study (Waksman)– Impact (safety) of switching, relative to last enoxaparin dose

– Switching outcomes consistent with other ANGIOMAX trials

• REPLACE-2 analysis (Gibson)– Data in patients undergoing PCI

– Switching to ANGIOMAX associated with improved bleeding outcomes

• ACUITY analysis (White)– Data in ACS patients undergoing PCI

– Switching to ANGIOMAX yielded improved bleeding outcomes

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PTCA

Stratify

Randomize Randomize

Measure death, MI, revascularization, bleeding in hospital2

Prespecified analysis: Patients on UFH infusion (n=1,006)1

Non post-MI(n=765)2

Post-MI(n=241)2

Switch toANGIOMAX®

(bivalirudin)Heparin

Switch toANGIOMAXHeparin

UA patients without UFH infusion (n=3,306)1

1. Henry TD. J Invasive Cardiol. 2002;14(suppl B):19B-29B.2. Data on file. The Medicines Company, Parsippany, NJ.

Overall population: Patients with new onset severe, accelerating or rest angina (N=4,312)1

PTCA=percutaneous transluminal coronary angiography.

Bivalirudin Angioplasty Trial (BAT): Switch B•A•T

24

BAT: Switch Analysis

• Among 4,312 patients, there were1,2

– 1,006 patients who had a UFH infusion during the hour prior to randomization and were switched to ANGIOMAX® (bivalirudin) or continued on UFH

– 241 in the post-MI patient group (<2 weeks) who received UFH during the hour prior to randomization and were switched to ANGIOMAX or continued on UFH

• In patients receiving UFH prior to PTCA, infusion was discontinued at least 30 minutes prior to switching

1. Bittl J. Circulation. 2000;102(suppl 2):813. Abstract 3927.2. Henry TD. J Invasive Cardiol. 2002;14(suppl B):19B-29B.

B•A•T

25

10.3%

7.4%

9.1%

7.9%

14.0%

5.8%3.3%

16.5%

4.3%

10.5%

4.1%

11.9%

Death/MI/revascularization

Heparin

ANGIOMAX

Heparin

Heparin

ANGIOMAX

ANGIOMAX

UA/UFH prior to PTCA & <14 days post-MI1,2

(n=241)

In patients receiving UFH prior to PTCA, infusion was discontinued at least 30 minutes prior to switching.

Hemorrhage

BAT: Outcomes for ACS Patients With Prior Heparin• Patients in prestratified high-risk groups switched to ANGIOMAX® (bivalirudin)

1. Henry TD. J Invasive Cardiol. 2002;14(suppl B):19B-29B.2. Data on File. The Medicines Company, Parsippany, NJ.

UA/UFH prior to PTCA1,2

(n=1,006)

UA/UFH prior to PTCA non post-MI2

(n=765)

B•A•T

26

31

30

30

Primary end point:

major bleeding

91 ACSpatients

undergoing PCI

(3 US sites)

Open-label, prospective, 3-arm study

LMWH1 mg/kg SC

0-4 h before PCI

LMWH1 mg/kg SC

4-8 h before PCI

LMWH1 mg/kg SC

8-12 h before PCI

ANGIOMAX® (bivalirudin)during PCI

0.75 mg/kg bolus

1.75 mg/kg/h IV infusion

Arms switched

SWITCH: Study Design

Waksman R et al. J Invasive Cardiol. 2006;18:370-375.

IV=intravenous; LMWH=low-molecular-weight heparin; SC=subcutaneous.

27

EVENT All

(N=91)

SWITCH0-4 h

(n=30)

SWITCH4-8 h

(n=30)

SWITCH8-12 h(n=31)

P value

All major bleeding 8% (7) 13% (4)* 3% (1) 7% (2)* .39

Transfusion ≥2 units 4% (4) 3% (1) 3%(1) 7% (2) 1.00

Intracranial bleed 0 0 0 0 --

Retroperitoneal bleed 0 0 0 0 --

Drop in Hg >4 g/dL, no site 2% (2) 7% (2) 0 0 .21

All transfusions 4% (4) 7% (2) 0% (0) 7% (2) 1.00

Minor bleeding 4% (4) 7% (2) 7% (2) 0 (0) .39

*One patient received postprocedural enoxaparin and/or heparin.Hg=hemoglobin.

SWITCH: Bleeding Outcomes in Patients Switched to ANGIOMAX® (bivalirudin)

Reproduced with permission. Waksman R et al. J Invasive Cardiol. 2006;18:370-375. ©2006 The Journal of Invasive Cardiology.

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SWITCH: Conclusions

• There were no significant differences in major bleeding between the various enoxaparin pretreatment groups when switched over to ANGIOMAX® (bivalirudin) for PCI

• For patients on LMWH, ANGIOMAX can be started 8 hours after the last LMWH dose

Waksman R et al. J Invasive Cardiol. 2006;18:370-375.

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REPLACE-2: SWITCH Analysis

• The goal of this analysis was to evaluate whether a hazard existed when UFH or LMWH was administered prior to ANGIOMAX® (bivalirudin)

• This analysis compared bleeding among patients treated with or without UFH or LMWH in the 48 hours before study treatment

Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.

30

Randomize

Protocol major/minor bleeding, TIMI bleeding, transfusion, mortality

ANGIOMAX® (bivalirudin)0.75 mg/kg bolus/1.75 mg/kg/h infusion with

“provisional” GP IIb/IIIa (n=2,994)1

Prior UFH (n=287)2

Naïve – no prior AT

(n=2,345)2

Overall population: Urgent or elective PCI patients (N=6,002)1

UFH 65 U/kg with planned GP IIb/IIIa

(n=3,008)1

Prior LMWH

(n=258)2

Naïve – no prior AT

(n=2,325)2

Prior UFH (n=349)2

Prior LMWH

(n=313)2

REPLACE-2: SWITCH Analysis

AT=antithrombin.1. Lincoff ML et al. JAMA. 2004;292:696-703.2. Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.

31

Protocol Major/Minor Bleed by SWITCH and Randomized Therapy• Regardless of prior heparin or not, patients administered ANGIOMAX® (bivalirudin) had decreased bleeding

• There was a significant increase in major/minor protocol bleeding in patients administered UFH with prior heparin therapy

*P=NS for all 3-way comparisons versus ANGIOMAX alone; †P<.05 vs prior treatment with UFH or enoxaparin; ‡naïve=no prior AT therapy in preceding 48 hours.

Pro

toc

ol

ma

jor/

min

or

ble

ed

15.6% 15.3%16.7%

28.6%

33.8% 34.8%

0%

5%

10%

15%

20%

25%

30%

35%

Naïve→ANGIOMAX‡

(n=2,345)

LMWH→ANGIOMAX

(n=258)

UFH→ANGIOMAX

(n=287)

LMWH→UFH + GP IIb/IIIa

(n=313)

Naïve→ UFH +

GP IIb/IIIa‡

(n=2,325)

UFH→UFH + GP IIb/IIIa

(n=349)

*

†

Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.

32

TIMI Major/Minor Bleed bySWITCH and Randomized Therapy• Patients switched from UFH or enoxaparin to ANGIOMAX® (bivalirudin) had the lowest rates of TIMI bleeding

• Patients administered UFH had higher rates of bleeding, with highest rates in patients switching between heparins

TIM

I m

ajo

r/m

ino

r b

lee

d

1.9%1.4%

4.3%

5.4%

1.9%

3.5%

0%

1%

2%

3%

4%

5%

6%

Naïve→ANGIOMAX†

(n=2,345)

LMWH → ANGIOMAX

(n=258)

UFH→ANGIOMAX

(n=287)

LMWH→UFH+ GP IIb/IIIa

(n=313)

Naïve→UFH + GP IIb/IIIa†

(n=2,325)

UFH→UFH + GP IIb/IIIa

(n=349)

*

*P=NS for all 3-way comparisons versus ANGIOMAX alone; †naïve=no prior AT therapy in preceding 48 hours.

Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.

33

Transfusion by SWITCH and Randomized Therapy• Patients switched to ANGIOMAX® (bivalirudin) had lower rates of transfusions

• UFH continued on UFH + GP IIb/IIIa had twice the rate of transfusions than naïve UFH group

• Enoxaparin switched to UFH + GP IIb/IIIa had 3 times the rate of transfusions than naïve UFH group

0.8%

1.1%

2.3%

2.9%

1.2%1.0%

0%

1%

2%

3%

No

n-C

AB

G t

ran

sfu

sio

n ≥

2 u

nit

s

Naïve→ANGIOMAX‡

(n=2,345)

UFH→ ANGIOMAX

(n=287)

UFH→UFH + GP IIb/IIIa

(n=349)

LMWH→UFH+ GP IIb/IIIa

(n=313)

Naïve→ UFH +

GP IIb/IIIa‡

(n=2,325)

LMWH → ANGIOMAX

(n=258)

*†

*P=NS for all 3-way comparisons versus ANGIOMAX alone; †P<.05 versus prior treatment with UFH or enoxaparin; ‡naïve=no prior AT therapy in preceding 48 hours.CABG=coronary artery bypass graft surgery.Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.

34

2.1%2.2% 2.1%

3.8%

4.9%

3.3%

0%

1%

2%

3%

4%

5%

UFH pretreatment*(n=685)

LMWH pretreatment*(n=591)

Any heparinpretreatment* (n=1,228)

ANGIOMAX with "provisional" GP IIb/IIIa Heparin + GP IIb/IIIa

1-Year Mortality: Prior UFH or LMWH

• Patients switched to ANGIOMAX® (bivalirudin) with “provisional” GP IIb/IIIa experienced a 33%-57% relative risk reduction in mortality at 1 year

Lincoff AM et al. JAMA 2004;292:696-703.Data on file. The Medicines Company, Parsippany, NJ.

Cu

mu

lati

ve d

eath

s at

12

mo

nth

s

*Pretreatment within prior 48 hours.

P=.38 P=.07 P=.07

33% 57% 45%

35

• Moderate- and high-risk UA or NSTEMI patients undergoing an earlyinvasive strategy

• Prospective, randomized, active-controlled trial

ACUITY Study Design

*Stratified by preangiography thienopyridine use or administration. †UFH or enoxaparin. ‡ ANGIOMAX alone = ANGIOMAX monotherapy with GP IIb/IIIa reserved for severe breakthrough ischemia and procedural complications during PCI. NSTEMI=non-ST–segment elevation myocardial infarction; R=randomized.The safety and effectiveness of ANGIOMAX have not been established in patients with ACS who are not undergoing PCI.

CABG

Moderate-and high-risk ACS

(N=13,819)

An

gio

gra

ph

y w

ith

in 7

2 h

Aspirin in all;clopidogrel

dosing and timingper local practice

Heparin(s)† + GP IIb/IIIa(n=4,603)

ANGIOMAX®

(bivalirudin)+ GP IIb/IIIa(n=4,604)

ANGIOMAXalone‡

(n=4,612)

R*

Medicalmanagement

PCI

Stone GW et al. N Engl J Med. 2006;355:2203-2216.

36

*ANGIOMAX monotherapy with GP IIb/IIIa reserved for severe breakthrough ischemia and procedural complications during PCI.

P=.47 P<.001

48%

Adv

erse

eve

nts

(%)

30-day

9.0%

3.5%

8.2%

6.7%

0

5

10

15

Composite ischemia Non-CABG major bleeding

P=.75

Adv

erse

eve

nts

(%)

1-year

2.7%2.9%

0

1

2

3

4

5

Mortality

Data on file. The Medicines Company, Parsippany, NJ.

Switch to ANGIOMAX* vs consistent heparin + GP IIb/IIIa outcomes

Switching to ANGIOMAX® (bivalirudin) Improves Bleeding Outcomes

• Ischemic suppression was maintained and bleeding significantly reduced at 30 days

• Long-term efficacy in both groups was consistent at 1 year

ANGIOMAX* (n=1,292)switch arm

UFH/enoxaparin + GP IIb/IIIa (n=1,236)consistent arm

PCI Subgroup

37

ANGIOMAX* (n=1,014)switch arm

P=.36 P=.003

45%

*ANGIOMAX monotherapy with GP IIb/IIIa reserved for severe breakthrough ischemia and procedural complications during PCI. †76% of ACUITY PCI patients had raised cardiac biomarkers and/or ST-segment deviation at baseline.

9.3%

3.9%

8.1%7.1%

UFH/enoxaparin + GP IIb/IIIa (n=974)consistent arm

0

5

10

15P=.97

3.1% 3.1%

0

1

2

3

4

5

30-dayComposite ischemia Non-CABG major bleeding

1-yearMortality

Adv

erse

eve

nts

(%)

Adv

erse

eve

nts

(%)

Data on file. The Medicines Company, Parsippany, NJ.

In High-Risk Patient Subset, Switching to ANGIOMAX® (bivalirudin) Improves Bleeding Outcomes

• Ischemic suppression was maintained and major bleeding significantly reduced at 30 days

• Long-term efficacy in both groups was consistent at 1 year

Switch to ANGIOMAX* vs consistent heparin + GP IIb/IIIa outcomes†

PCI Subgroup

38

How to Switch from Heparin(s) to ANGIOMAX® (bivalirudin) for PCI

Reed MD et al. Pharmacotherapy. 2002;22(6 pt 2):105S-111S.

UFH

LMWH

From UFH to ANGIOMAX, discontinue UFH for

30 minutes before starting ANGIOMAX for PCI

From LMWH to ANGIOMAX, discontinue LMWH for

8 hours before starting ANGIOMAX for PCI

39

ACUITY PCI Subgroup Analysis: 1-Year Mortality Results

PCI Subgroup

40

56% of Patients in ACUITY Underwent PCI

56.4%

11.1%32.5%CABG (n=1,539) Medical management

(n=4,491)

Heparin(s) + GP IIb/IIIa(n=2,561)

Heparin(s) + GP IIb/IIIa(n=2,561)

ANGIOMAX® (bivalirudin) +

GP IIb/IIIa(n=2,609)

ANGIOMAX® (bivalirudin) +

GP IIb/IIIa(n=2,609)

ANGIOMAX alone(n=2,619)

ANGIOMAX alone(n=2,619)

Stone GW et al. N Engl J Med. 2006;355:2203-2216.

PCI (n=7,789)

41

Baseline Characteristics

ANGIOMAX® (bivalirudin) alone

(n=2,619)

Heparin(s) + GP IIb/IIIa(n=2,561)

Age (median [range], y) 63 [30-92] 63 [25-91]

Male 73% 73%

Weight (median [IQR], kg) 84 [75,95] 84 [73,96]

Diabetes 28% 28%

- Insulin requiring 9% 8%

Hypertension 66% 66%

Hyperlipidemia 56% 56%

Current smoker 31% 31%

Prior MI 31% 30%

Prior PCI 40% 38%

Prior CABG 18% 17%

Renal insufficiency (CrCl <60 mL/min) 18% 19%

P=NS for all values.

Stone GW et al. Lancet. 2007;369:907-919.

PCI Subgroup

42

Baseline High-Risk Features

• 77% of the PCI patients had elevated cardiac biomarkers or ST-segment changes

ANGIOMAX® (bivalirudin) alone

(n=2,619)

Heparin(s) + GP IIb/IIIa(n=2,561)

Cardiac biomarker (MB or troponin) 66% 65%

- Troponin 66% 65%

ST-segment ≥1 mm 35% 35%

Cardiac biomarker or ST-segment 77% 77%

Stone GW et al. Lancet. 2007;369:907-919.

PCI Subgroup

43

ACUITY Patients Undergoing PCI30-Day Outcomes

Supplement to: Stone GW et al. N Engl J Med. 2006;355:2203-2216. http://content.nejm.org. Accessed December 21, 2006.Stone GW et al. Lancet. 2007;369(9565):907-919.

8.8%

3.5%

11.6%

13.3%

6.8%

8.2%

0%

2%

4%

6%

8%

10%

12%

14%

Composite ischemia Non-CABG majorbleeding

Net clinical outcome

ANGIOMAX (bivalirudin) alone* (n=2,619) Heparin(s) + GP IIb/IIIa (n=2,561)

P=.45 P<.001 P=.057

30-d

ay P

CI

resu

lts

*In the ANGIOMAX-alone group: 91% of PCI patients received ANGIOMAX monotherapy.

®

PCI Subgroup

44

0.1 1 10

Results at 1 Year

HR ±95% CI

HR (95% CI)

ANGIOMAX® (bivalirudin) alone

better

UFH/enoxaparin + GP IIb/IIIa better

Composite ischemia 1.09 (0.96–1.23)

Mortality 0.95 (0.70–1.30)

Data on file. The Medicines Company, Parsippany, NJ.

PCI Subgroup

45

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

0 30 60 90 120 150 180 210 240 270 300 330 360 390

Mo

rtal

ity

(%)

Days from randomization

Early and Late Mortality

UFH/Enoxaparin + GP IIb/IIIa vs ANGIOMAX® (bivalirudin) Alone

30-day

estimateP

(log rank) estimateP

(log rank)

ANGIOMAX alone .631.1% .482.2%

1-year

UFH/enoxaparin + IIb/IIIa 0.9% — 3.1% —

P=.78

Data on file. The Medicines Company, Parsippany, NJ.

PCI Subgroup

46

0.1 1 10

Age ≥75 years 2.63 (1.92-3.60) <.001

Anemia 1.45 (1.07-1.96) .016

Baseline CrCl <60 mL/min 1.43 (1.03-1.99) .033

Diabetes mellitus 1.74 (1.35-2.25) <.001

Male 1.46 (1.07-1.98) .017

History of CAD 1.97 (1.46-2.65) <.001

Baseline ST- deviation ≥1 mm 1.42 (1.08-1.86) .011

Baseline cardiac biomarker ↑ 2.05 (1.49-2.81) <.001

Revascularization within 30 days 1.70 (1.03-2.81) .039

MI within 30 days 2.31 (1.58-3.39) <.001

Major bleeding 3.20 (2.28-4.50) <.001

HR ±95% CI P valueHR (95% CI)

Predictors of 1-Year Mortality

• Major bleeding was associated with the highest risk followed by age ≥75 years and MI within 30 days

Cox model with major bleeding, MI, and revascularization as time-updated covariates

Data on file. The Medicines Company, Parsippany, NJ.

PCI Subgroup

47

Influence of 30-Day Major Bleeding and MI on Late Mortality

0.1 1 10

HR ±95% CI

30-day major bleeding 3.16 (2.25-4.42) <.001

HR (95% CI)

Cox model adjusted for baseline predictors, with non-CABG major bleeding and MI as time-updated covariates.

30-day MI 2.30 (1.57-3.36) <.001

P value

Data on file. The Medicines Company, Parsippany, NJ.

PCI Subgroup

48

Impact of Bleeding on Length of Stay

• Patients with a bleeding event had a significant increase of 2 days in their length of stay

Patients with bleeding event

(n=459)

Patients without bleeding event

(n=7,318)

Pvalue

Hospital length of stay, median days

5.0 3.0 <.001

Data on file. The Medicines Company, Parsippany, NJ.

PCI Subgroup

49

In High-risk Patients With Elevated Troponin Levels and/or ST-segment Changes

Risk Ratio±95% CI RR (95% CI)

HR±95% CI HR (95% CI)

UFH/enoxaparin + GP IIb/IIIa

better

0.1 1 10ANGIOMAX® (bivalirudin) alone

better

ANGIOMAX alone better

30-Day Results 1-Year Results

Composite ischemia 1.08 (0.88-1.32)

Major bleeding 0.55 (0.42-0.72)

Mortality 0.94 (0.67-1.31)

UFH/enoxaparin + GP IIb/IIIa

better

Data on file. The Medicines Company, Parsippany, NJ.

PCI Subgroup

50

Impact of Clopidogrel at 1 Year

0.1 1 10

PCI patients

1-year mortalityHR ±95% CI HR (95% CI)

ANGIOMAX®

(bivalirudin) alone better

UFH/enoxaparin + GP IIb/IIIa better

Groups based on first exposure to clopidogrel; excludes patients who received ticlopidine.

Pre-PCI clopidogrel (n=3,429) 1.02 (0.69-1.50)

Peri-PCI clopidogrel (n=1,044) 1.14 (0.59-2.22)

Post-PCI clopidogrel (n=519) 0.43 (0.17-1.11)

No clopidogrel (n=88) 3.24 (0.34-31.1)

Data on file. The Medicines Company, Parsippany, NJ.

PCI Subgroup

51

Impact of Clopidogrel at 1 Year:Troponin-Positive Patients

0.1 1 10

PCI troponin-positive patients1-year mortality

HR ±95% CIHR (95% CI)

ANGIOMAX®

(bivalirudin) alone better

UFH/enoxaparin + GP IIb/IIIa better

Groups based on first exposure to clopidogrel; excludes patients who received ticlopidine.

Pre-PCI clopidogrel (n=1,891) 1.07 (0.66-1.73)

Peri-PCI clopidogrel (n=649) 1.09 (0.46-2.58)

Post-PCI clopidogrel (n=307) 0.56 (0.17-1.93)

No clopidogrel (n=51) 3.07 (0.32-29.49)

Data on file. The Medicines Company, Parsippany, NJ.

PCI Subgroup

52

Additional ConsiderationsANGIOMAX® (bivalirudin) Important Safety Information, Dosing and Administration

53

Important Safety Information

• ANGIOMAX® (bivalirudin) with provisional use of GP IIb/IIIa inhibitor is indicated for use as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI), and in patients with or at risk for heparin-induced thrombocytopenia and thrombosis syndrome (HIT/HITTS) undergoing PCI

• ANGIOMAX is intended for use with aspirin and has been studied only in patients receiving concomitant aspirin

• ANGIOMAX is contraindicated in patients with active major bleeding or hypersensitivity to ANGIOMAX or its components

• The most common (≥10%) adverse events for ANGIOMAX were back pain, pain, nausea, headache, and hypotension

• An unexplained fall in blood pressure or hematocrit, or any unexplained symptom, should lead to serious consideration of a hemorrhagic event and cessation of ANGIOMAX administration

ANGIOMAX (bivalirudin) [prescribing information]; December 6, 2005.

54

Dosing and Administration

• The recommended dose for ANGIOMAX® (bivalirudin) is an intravenous (IV) bolus of 0.75 mg/kg

• This should be followed by an infusion of 1.75 mg/kg/hour for the duration of the PCI procedure or up to 4 hours per physician discretion

• After the 4 hours of the initial infusion, an additional infusion may be initiated at a rate of 0.2 mg/kg/hour for up to 20 hours, if needed

• If the low-rate infusion is used after the initial infusion, a lower concentration bag of 0.5 mg/mL should be prepared. See Prescribing information for diluting instructions

• Special precaution: It is important to note that the pre-PCI ANGIOMAX dose for patients with acute coronary syndromes in the ACUITY trial is not an approved dose and is much lower than the approved PCI dose discussed in these instructions

ANGIOMAX (bivalirudin) [prescribing information]; December 6, 2005.

55

Special Population: Patients With Renal Impairment• No reduction in the bolus dose of ANGIOMAX® (bivalirudin) is needed

• The infusion dose may need to be reduced– Severe renal impairment (CrCl <30 mL/minute): reduction in the infusion rate

to 1.0 mg/kg/hour should be considered

– On hemodialysis: infusion should be reduced to 0.25 mg/kg/hour

• Standard infusion dose for patients with normal to moderate renal impairment (CrCl ≥30 mL/minute)

• Anticoagulation status should be monitored in patients with renal impairment

ANGIOMAX (bivalirudin) [prescribing information]; December 6, 2005.

56

ANGIOMAX® (bivalirudin) in PCI

• ANGIOMAX improves bleeding outcomes while preserving ischemic suppression for UA/NSTEMI patients undergoing PCI even if the patients are switched from UFH or enoxaparin to ANGIOMAX

• Consistent results in low-, moderate-, and high-risk patients

For more information about ANGIOMAX, please see the representative for full ANGIOMAX Prescribing Information.