Dr Jonathan Day

Senior Director Global Medical

The Medicines Company

Bivalirudin

For patients with STEMI undergoing primary PCI

MY CONFLICTS OF INTEREST ARE

The Medicines Company (Employee)

New Indication for STEMI

– Approved in the European Union in 2004As an anticoagulant in patients undergoing percutaneous coronary intervention (PCI)

– Type II variation approved in 2008For the treatment of patients with ACS undergoing early or urgent intervention

– Type II variation approved in 2009As an anticoagulant in patients undergoing percutaneous coronary intervention (PCI) including primary PCI

“The only anticoagulant approved for patients undergoing PPCI”

Broad spectrum of experience with bivalirudin in clinical trials27,735 patients undergoing invasive management of CAD

REPLACE-2(N=6,002)

CADPlanned PCI

BAT(N=4,312)

UA, NQWMIPlanned PTCA

ACUITY(N=13,819)

NSTE-ACSPCI <72h

HORIZONS(N=3,602)

STEMIEmergency PCI

Increasing risk of ischaemic complications

Lincoff et alJAMA, 2003

Bittl et alAHJ, 2001

Stone et alNEJM, 2006

Stone et alNEJM, 2007

0 1 2

Consistent trial results

● Meta-analysis of REPLACE-2, ACUITY and HORIZONS

● 14,258 patients given aspirin, clopidogrel prior to angio/intervention

Risk ratio ±95% CI P-value

Death, MI or revasc 30d 1.0 (0.88-1.13) 0.941

All cause death 30d 0.73 (0.54-0.99) 0.043

All cause death 1y 0.80 (0.66-0.96) 0.015

Major bleeding 30d 0.54 (0.4-.63) <0.0001

Bivalirudin better Heparin+GPI better

Data on file The Medicines CompanyMehran ESC 2009

●The data source for the analysis is the Premier Perspective Database

●A total of 127,185 PCI procedures were identified from the database between June 2003 through December 2006

●Patients received either bivalirudin plus provisional GPI or the comparator, heparin plus GPIIb/IIIa

Rassen JA et al Eur Heart J 2009

PREMIER Dataset

Hazard Ratio ± 95% CI OR (95% CI)

Fully adjusted HR for transfusion 0.67 (0.61–0.73)

Fully adjusted HR for repeat PCI 0.96 (0.90–1.03)

Fully adjusted HR for death 0.51 (0.44–0.60)

0 1 2

Bivalirudin Better

Bivalirudin Better

Heparin + GP IIb/IIIa Inhibitor Better

Heparin + GP IIb/IIIa Inhibitor Better

7

ANGIOX is Effective in Routine Care

● Angiox reduced the risk of in-hospital death and blood transfusions

Rassen JA et al Eur Heart J 2009

Primary PCI Strategy

Aspirin, thienopyridine

3,000 pts eligible for stent randomisation

Bare metal stent paclitaxel-eluting stent

Clinical FU at 30 days, 1 yr, 2 years Clinical FU at 30 days, 1 yr, 2 years

HORIZONS AMI Trial Design● Open-label, randomised, prospective, multicenter trial

FU=follow-up; pts=patients; R=randomised; UFH=unfractionated heparin.

Stone GW. NEJM 2008;358:2218-30.

UFH + GP IIb/IIIa inhibitor(abciximab or eptifibatide)

Bivalirudin monotherapy(± provisional GP IIb/IIIa)

3,602 pts with STEMI with symptom onset ≤12 hours

R 1:3

R 1:1

8

30-day Clinical Outcomes30

-day

eve

nt

rate

s (%

)

NACE Major Bleeding† MACE‡

*In HORIZONS AMI, 93% of bivalirudin patients received monotherapy, without provisional GP IIb/IIIa.

†Not related to CABG.

‡MACE=all-cause death, reinfarction, ischaemic TVR, or stroke.

Stone GW. NEJM 2008;358:2218-30:9

Diff = 0.0% [-1.6, 1.5] RR = 0.99 [0.76, 1.30]

Psup = 0.95

Diff = -3.3% [-5.0, -1.6] RR = 0.60 [0.46, 0.77]

PNI ≤ 0.0001Psup ≤ 0.0001

Diff = -2.9% [-4.9, -0.8]RR = 0.76 [0.63, 0.92]

PNI ≤ 0.0001Psup = 0.005

30-day MACE Components

10

Bivalirudin(n=1,800)*

UFH + GP IIb/IIIa(n=1,802) P value

Mortality† 2.1% 3.1% 0.047

- Cardiac 1.8% 2.9% 0.03

- Noncardiac 0.3% 0.2% 0.75

Reinfarction 1.8% 1.8% 0.90

- Q-wave 1.4% 1.2% 0.66

- Non–Q-wave 0.4% 0.7% 0.37

Ischaemic TVR 2.6% 1.9% 0.18

Stroke 0.7% 0.6% 0.68

*In HORisONS AMI, 93% of bivalirudin patients received monotherapy, without provisional GP IIb/IIIa. †Adjudicated. TLR=target lesion revascularisation.

Stone GW. NEJM 2008;358:2218-30

2-Year Reinfarction

1800 1644 1603 1554 12981802 1621 1576 1500 1244

p= 0.038

HR [95%CI]=0.75 [0.56, 0.98]

5.1%

6.9%

Re

infa

rcti

on

(%

)

0

1

2

3

4

5

6

7

8

9

10

0 3 6 9 12 15 18 21 24

Number at riskBivalirudin aloneHeparin+GPIIb/IIIa

Bivalirudin alone (n=1800)

Heparin + GPIIb/IIIa (n=1802)

Months

Stone GW TCT 2009

HORIZONS 2 year follow-up

● Cardiac mortality in ITT population

↓41%*

2.5%

4.2%

0

1

2

3

4

5

Months0 3 6 9 12 15 18 21 24

Ca

rdia

c m

ort

alit

y (%

)

2.1%

3.7 %

↓43%*

1.8%

2.9%

↓38%*

All p≤0.03

*Relative risk reduction

Bivalirudin UFH+GPI

Stone et al TCT 2009

HORIZONS

Stent thrombosis

30 Day Stent Thrombosis (N=3,124)

UFH + GP IIb/IIIa

(N=1553)

Bivalirudin(N=1571)

PValue

ARC definite or probable* 1.9% 2.5% 0.33

- definite 1.4% 2.2% 0.11

- probable 0.5% 0.3% 0.26

- acute (≤24 hrs) 0.3% 1.3% 0.0009

- subacute (>24 hrs – 30d) 1.7% 1.2% 0.30

*Protocol definition of stent thrombosis, CEC adjudicated*Protocol definition of stent thrombosis, CEC adjudicated

HORIZONS ST to 30 days

● Increase in acute ST offset by decrease in sub-acute ST

Bivalirudin UFH+GPI

Est

ima

ted

eve

nt

rate

(%

)

Days from randomisation

0

1

2

3

4

5

5 10 15 20 25 300 0.5 1

24 acute ST

4 acute ST

30 sub-acute ST

20 sub-acute ST

Stone et al NEJM, 2008

GPIIb/IIIa and stent thrombosis● Cumulative distribution for time to development of ST according to GPIIb-IIIa

inhibitor exposure. Among patients who received GPIIb-IIIa blockade, the median time to development of ST was increased from 2 to 5 days (P = .002).

0 5 10 15 20 25 30

1.0

0.8

0.6

0.4

0.2

0

Cum

ulat

ive

Fre

quen

cy o

f ST

Days

No GP IIb/IIIa Pretreatment

GP IIb/IIIa Pretreatment

P = .002

Rinaldi Am Heart J 2008;155:654-60

Timing of Stent Thrombosis in Patients Treated with Tirofiban.

Assali AR J Invasive Cardiol. 2000 Sep;12(9):460-3

Retrospective analysis of a single-center intervention database between January1997 and October 1999 . 13 patients identified with

acute or subacute stent thrombosis

The median time from stent deployment to ST was 7 hours (IQR, 2.5-33 hours) in patients not receiving a GPIIb/IIIa antagonist compared to 84.5 hours (IQR, 56-124.5 hours) in patients receiving one.

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ST Type Bivalirudin (N=1800)

UFH + GPI

(N=1802)

Risk of death (n/N [%])

ST Death ST Death

Acute 23 1 4 1 2/27 (7.4)

Subacute 19 3 30 14 17/49 (34.7)

30 Day Stent Thrombosis – Risk of Subsequent Death

Deaths at 1 year subsequent to major events

Number of deaths

Major event BivalirudinUFH +

GP IIb/IIIa Total Delta

Acute ST 1 1 2 0

Subacute ST 3 16 19 13

Late ST 3 6 9 3

Major Bleeding 13 31 44 18

Re-Infarction 5 11 16 6

Stroke 5 4 9 1

HORIZONS Review

Did the dose of clopidogrel impact outcomes?

Clopidogrel 300mg versus 600mg

21

• The impact of bivalirudin was independent of the clopidogrel loading dose. Interaction P values = 0.48 (NACE) 0.41 (Major bleeding), and 0.75 (MACE).

• Significant decrease in MACE in patients treated with 600mg versus 300mg clopidogrel

MACE at 30 days

Clopidogrel 300mg Clopidogrel 600mg P-valueBivalirudin 43/595 (7.2) 46/1125 (4.1) 0.0052

UFH + GP IIb/IIIa 43/618 (7.0) 48/1091 (4.4) 0.0236

Dangas et al, JACC 2009

Clopidogrel and Stent Thrombosis

22

0

1

2

3

0 5 10 15 20 25 30

0

1

2

3

0 0.5 1

1204 1190 1188 1157 1147 1134

2203 2183 2181 2143 2124 2113

111 103 103 100 98 98

Days from RandomisationPatients at Risk

Clopidogrel 300mg:

Clopidogrel 600mg:

No Clopidogrel

Est

imat

ed E

vent

Rat

e (%

)

2.4%

Clopidogrel 300mg (A)

Clopidogrel 600mg (B)

No Clopidogrel (C)

1.2%

0%

Log Rank P–value24 hrs. A vs B: 0.939924 hrs. A vs C: 0.030624 hrs. B vs C: 0.0189

2.8%

0.7% 0.8%

Log Rank P–value30 days A vs B: 0.006730 days A vs C: 0.006730 days B vs C: 0.2803

Optimising outcomes with bivalirudin

● Early adjunctive therapy

Early adjunctive therapy with guideline recommended therapies (which should include aspirin and clopidogrel and may include UFH) was associated with a reduced rate of AST in both arms of HORIZONS

● Adequate PY12 inhibition

Treatment with Clopidogrel 600 mg vs. 300mg resulted in improved MACE in both arms

Prasugrel 60 mg may be better than clopidogrel

● Prolonged bivalirudin infusion

A post PCI infusion of bivalirudin at 0.25/mg/kg infusion for up to 4 hours does not increase bleeding (BAT) and does not affect sheath pull times (AFRICA)

Prolonged antithrombin therapy until such time that P2Y12 inhibition is effective may further reduce AST

23

Krumholz,. et al. JAMA 2009;302:767-773.

Trends in 30d mortality after AMI

● All-Cause risk-standardised mortality 1995-2006

Conclusion● In HORIZONS-AMI the significant reductions in cardiac-

related death at 30-days, 1-year and 2-years are important.

● For every 59 patients with STEMI undergoing primary PCI with bivalirudin compared to conventional therapies one cardiac related death might be avoided (NNT= 59 at 1 yr).

● The important implications of the HORIZONS study are now reflected in the recently updated ACC/AHA guidelines for the management of patients with STEMI undergoing primary PCI where bivalirudin received a (Class IB) recommendation [Kushner et al., 2009].

● In conclusion, the favourable risk–benefit profile of bivalirudin, make it clinically important alternative to current treatments for the contemporary management of STEMI patients undergoing primary PCI.