Bivalirudin: Optimising

Antithrombotic Therapy in

Acute Coronary Syndromes

Jonathan Briers MB; ChB

Medical Director – Northern Europe

The Medicines Company

PCI – Therapeutic targets in

adjunctive pharmacotherapy

Limit

ischaemic

complications

Minimize

bleeding

Re-establish flow

The critical roles of thrombin

ADP

+

TXA2

Neutrophils Monocytes

Activated

platelets

Endothelial cells

Activated

platelets

Resting

platelets

Monocyte

Resting

platelets

II Tenase complex

Thrombin

Prothrombin

Prothrombinase

complex

TF

Activated

platelets

Fibrin

Croce K et al. Curr Opin Hematol. 2007;14:55–61; Coughlin SR. Nature. 2000;407:258–64; Mann KG. Chest. 2003;124:4S–10S; Monroe DM et al. Arterioscler Thromb Vasc Biol. 2002;22:1381–89.

THROMBIN

ADP: adenosine diphosphate;

TxA2: thromboxane A2.

Bivalirudin mechanism of action

● Bivalirudin exhibits direct and reversible binding to thrombin (both circulating and clot bound thrombin)

Maraganore J et al Biochemistry 1990;30:7095-101

(Gly)4

D-Phe-Pro-Arg-Pro

(active-site-binding portion)

C-terminal dodecapeptide

(Substrate recognition / Exosite 1-binding portion)

Thrombin

Bivalirudin binds to active site and

substrate recognition site of thrombin

Bivalirudin is cleaved by thrombin; allowing

thrombin to resume its physiological function

NICE STEMI

● Recommendation (July 2011)

“Bivalirudin in combination with aspirin and clopidogrel is recommended for the

treatment of adults with ST-segment-elevation myocardial infarction undergoing

primary percutaneous coronary intervention.”

“In the base-case analysis the bivalirudin strategy dominated the heparin plus

glycoprotein IIb/IIIa inhibitor strategy because it was cheaper and more

effective… sensitivity analysis presented for the base-case 1-year analysis

showed that the bivalirudin strategy was dominant (that is, it was cost-saving

and showed a QALY gain).”

http://www.nice.org.uk/guidance/TA230

Guidelines for the management of

acute myocardial infarction in

patients presenting with

ST segment elevation

The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC)

Steg G et al Eur Heart J. 2012;33:2569-619.

ESC 2012 Guidelines: Management of

STEMI

Class Level

An injectable anticoagulant must be used in primary PCI I C

Bivalirudin (with use of GP IIb/ IIIa blocker restricted to bail out) is recommended over unfractionated

heparin and a GP IIb/ IIIa blocker I B

Enoxaparin (with or without routine GP IIb/ IIIa blocker) may be preferred over unfractionated heparin IIb B

Unfractionated heparin with or without routine GP IIb/ IIIa blocker must be used in patients not receiving

bivalirudin or enoxaparin I C

Fondaparinux is not recommended for primary PCI III B

The use of fibrinolysis before planned primary PCI is not recommended III A

● Peri-procedural antithrombotic medication in primary PCI – Anticoagulant Therapy

Steg G et al Eur Heart J. 2012;33:2569-619.

30-day Clinical Outcomes

P=0.95 P<0.001 P=0.005

30-d

ay e

vent ra

tes (

%)

*93% of bivalirudin patients received monotherapy without provisional GP IIb/IIIa.

MACE=all-cause death, reinfarction, ischemic TVR, or stroke; NACE=net adverse clinical events=major bleeding + MACE

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

12.1

8.3

5.5

9.2

4.9 5.4

0

5

10

15

20

NACE Non-CABG major bleeding MACE

Heparin + GP IIb/ IIIa inhibitor (n = 1,802) Bivalirudin (n= 1800)*

30-day MACE Components†

Stone GW. New Engl J Med. 2008;358:2218–30.

* 93% of bivalirudin patients received monotherapy, without provisional GP IIb/IIIa inhibitor. † Adjudicated by blinded CEC.

Bivalirudin

(n=1,800)*

UFH +

GP IIb/IIIa inhibitor

(n=1,802) P-value

Mortality† 2.1% 3.1% 0.047

- Cardiac 1.8% 2.9% 0.03

- Non-cardiac 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

Cardiac Mortality

30 days to 3 years*

'

Bivalirudin (n=1800) Heparin + GPIIb/IIIa (n=1802)

Stone GW et al NEJM 2008;358:2218-30; Mehran R et al Lancet. 2009;374:1149-59; Stone GW et al. Lancet 2011;377:2193-204

Card

iac M

ort

alit

y (

%)

3-yr† HR [95%CI]=

0.56 [0.40, 0.80]

P=0.001

2.9%

5.1% 1-yr† HR [95%CI]=

0.57 [0.38, 0.84]

P=0.005

0 12 15 18 21 24 27 30 33 36

Months

3 6 9

0

1

6

5

4

3

2

3.8%

2.1%

30-d† HR [95% CI]

0.62; [0.40,0.96]

P = 0.03

1.8%

2.9%

*All cause mortality at 3 years was also consistently lower with bivalirudin (5·9% vs 7·7%),

HR 0·75 [0·58–0·97]; p=0·03 †These timepoints were prespecified analyses

12

0

4

6

8

10

2

0

12 15 18 21 24 27 30 33 36

3-yr HR [95%CI]=

0.64 [0.51, 0.80]

P<0.001

6.9%

10.5%

Majo

r B

leedin

g,

non

-CA

BG

(%

)

Months

3 6 9

Δ=64

major bleeds

3-Year Major Bleeding*

* Intracranial intraocular, retroperitoneal, access site bleed requiring intervention/surgery, hematoma ≥5 cm, Hgb ↓ ≥3g/dL with or ≥4g/dL w/o overt source; reoperation for bleeding; or blood product transfusion

Stone GW et al. Lancet 2011;377:2193-204

Bivalirudin (n=1800) Heparin + GPIIb/IIIa (n=1802)

Day 0–1 after MI 14.1 (9.1-21.9) <.001

Day 2–7 after MI 6.0 (3.8-9.6) <.001

Day 8–30 after MI 2.1 (1.4-3.1) <.001

Day >35 after MI 1.1 (0.6-2.0) .77

Day 0–2 after major bleed* 3.5 (2.0-6.1) <.001

Day 3–7 after major bleed* 5.1 (3.3-7.8) <.001

Day 8–35 after major bleed* 2.8 (2.1-3.9) <.001

Day >35 after major bleed* 2.7 (1.9-3.9) <.001

p value HR ± 95% CI

0.5 1 2 4 8 16 32

HR (CI)

Association of MI and major

bleeding with 1-year mortality

● Time-updated Cox-proportional analysis,13819 ACUITY patients

● Risk of mortality after bleeding persists longer than after MI

Mehran R JACC. 2010;55:2556-66.

*Non-CABG major bleed.

Analysis of patients without

bleeding

● In the HORIZONS-AMI trial, treatment with bivalirudin compared to heparin +

a GP IIb/IIIa inhibitor in patients with STEMI undergoing primary PCI resulted

in significantly reduced 30-day rates of major bleeding and net adverse

clinical events

● Bivalirudin-treated patients had reduced rates of cardiac mortality, which is

usually attributed to decreased bleeding

● Whether the reduction in mortality with bivalirudin can be fully ascribed to

reduced bleeding is unknown

● Post-hoc analysis of STEMI patients with vs without major bleeding

● Time and covariate adjusted model

Stone GW TCT 2012 and JACC. 2012;60(17SupplB):B16.

HR [95%CI] =

5.81 [3.92, 8.62]

P<0.001

3.3%

11.6%

Years

Card

iac m

ort

alit

y (

%)

12% No major bleed (n=3296)

Major bleed (n=306)

10%

8%

6%

4%

2%

0%

0 1 2 3

Impact of Major Bleeding

Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16

14.6

3.8

5.8

2.6

0

5

10

15

Major bleeding No major bleeding

3-Y

ear

Card

iac

Mort

alit

y (

%)

Heparin + GPIIb/IIIa (n=1802) Bivalirudin (n=1800)

27/185 7/121 61/1617 43/1679

HR [95%CI] =

2.56 [1.12, 5.88]

P=0.02

HR [95%CI] =

1.47 [1.00, 2.17]

P=0.048

∆ = 20 deaths ∆ = 18 deaths # fewer cardiac

deaths with

bivalirudin

Pint = 0.34

3-Year Cardiac Mortality

Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16

● In patients with vs without major bleeding, according to treatment

0

5

10

15

20

Heparin + GPIIb/IIIa (n=1721)

Bivalirudin (n=1736)

13.2%

10.1%

P=0.004

3.1%

8.1%

HR [95%CI] =

2.76 [1.85, 4.14]

P<0.001

Thrombocytopenia Years

Card

iac m

ort

alit

y (

%)

Acquired thrombocytopenia (n=404)

No thrombocytopenia (n=3053)

0

10%

8%

6%

4%

2%

0%

1 2 3

Acquired thrombocytopenia,*

in-hospital

* Nadir platelet count <150,000 in patients w/o baseline thrombocytopenia

Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16

12.3

3.5

2.3 2.5

0

5

10

15

Thrombocytopenia No thrombocytopenia

3-Y

ear

Card

iac M

ort

alit

y (

%)

Heparin + GPIIb/IIIa (n=1721) Bivalirudin (n=1736)

HR (95%CI) =

5.56 (2.00, 16.67)

P=0.0001

HR (95%CI) =

1.41 (0.47 to 1.09)

P=0.12

4/176 39/1560 28/228 52/1493

Pint = 0.006

3-year Cardiac Mortality

Nadir platelet count <150,000 in patients w/o baseline thrombocytopenia

Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16

● In patients with and without thrombocytopenia, according to treatment

3-Year Cardiac Mortality

Excludes 145 patients with thrombocytopenia at baseline. Other variables in model: current smoker, female gender, prior MI, # vessels treated, hemoglobin

Risk factor Hazard ratio (95% CI) P-value

Age (per 5 years) 1.34 (1.23 to 1.46) <0.001

WBC (per 109 cells/L) 1.15 (1.09 to 1.21) <0.001

S. creatinine (per 0.1 mg/dl) 1.10 (1.05 to 1.16) <0.001

Killip class 2-4 2.17 (1.41 to 3.35) <0.001

LAD PCI 1.68 (1.13 to 2.50) 0.007

Diabetes, medically treated 1.50 (1.01 to 2.23) 0.045

Major bleeding 2.97 (1.88 to 4.69) <0.001

Acquired thrombocytopenia 2.10 (1.36 to 3.24) 0.001

Bivalirudin (vs UFH+GPIIb/IIIa) 0.54 (0.38 to 0.79) 0.002

Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16

● Multivariable model, including adverse events

Conclusions

● In HORIZONS-AMI, treatment with bivalirudin rather than UFH + GPIIb/IIIa resulted in a marked reduction in cardiac mortality in patients with STEMI undergoing primary PCI

– ~ Half of the reduction in cardiac deaths with bivalirudin occurred in patients without major bleeding

● In addition to reducing major bleeding, bivalirudin reduced the occurrence of thrombocytopenia, which contributed to the improved survival in patients with and without major bleeding

● The adverse effects of major bleeding and thrombocytopenia are mitigated in patients treated with bivalirudin rather than UFH + GPIIb/IIIa, and bivalirudin was strongly associated with reduced cardiac mortality even after accounting for bleeding and thrombocytopenia – further studies are required to identify the non-hematolgic benefits of bivalirudin

Stone GW et al. TCT 2012 and JACC 2012;60(17SupplB):B16

ISAR REACT 4: Study Design

● Multi-centre, double-blind, double dummy drug design

* Abciximab: Bolus of 0.25 mg/kg, Infusion of 0.125 μg/kg/min for 12h UFH (=unfractionated heparin): Bolus of 70 U/kg Bivalirudin: Bolus of 0.75 mg/kg, Infusion of 1.75 mg/kg/hr for duration of PCI

Aspirin, 600mg clopidogrel

Randomised

1:1

Primary Endpoint: composite of death, large recurrent myocardial infarction, urgent target-vessel revascularisation, or major bleeding within 30 days after randomisation

Abciximab* plus UFH (n=861)

Bivalirudin* monotherapy

(n=860)

1,721 Patients with NSTEMI, Troponin +

No PCI in 2 patients No PCI in 2 patients

Kastrati A NEJM. 2011;365:1980-89.

ISAR-REACT 4: Primary endpoint

Kastrati A NEJM. 2011;365:1980-89.

0

5

10

15

20

0 5 10 15 20 25 30

Relative risk, 0.99 (95% CI, 0.74–1.32), p=0.94

Bivalirudin

UFH+Abciximab 10.9%

11.0%

Cum

ula

tive I

ncid

ence (

%)

Days since Randomization

● 30-day Death, large MI, uTVR, major bleeding

UFH=unfractionated heparin

ISAR-REACT 4: Secondary endpoints

● Major bleeding – safety secondary endpoint

Kastrati A NEJM. 2011;365:1980-89.

0

5

10

15

20

0 5 10 15 20 25 30

Days since Randomization

RR 1.82 (95% CI, 1.10–3.07), p=0.02

Bivalirudin UFH+Abciximab 4.6%

2.6%

UFH=unfractionated heparin

Cu

mu

lative

In

cid

en

ce

(%

)

Major bleeding (intracranial, intraocular, or retroperitoneal; Hb decrease >40g/L plus either overt bleeding or need for transfusion of 2 or more units)

Treatment Adjusted OR

± 95% CI Adj OR (95% Cl)

Heparin** alone

(n=1,365)

0.52 0.42, 0.65

Bivalirudin alone

(n=1,771)

0.48 0.39, 0.60

Bivalirudin + GP IIb/IIIa

(n=863)

1.23 0.98, 1.56

0 1 2

Comparisons relative to heparin** + GP IIb/IIIa (n=7086)

*Major bleeding was defined as intracranial haemorrhage, documented retroperitoneal bleed,

hematocrit (HCT) drop ≥12% (baseline to nadir ≥ 12%), any red blood cell (RBC) transfusion when

baseline HCT ≥ 28%, or any RBC transfusion when baseline HCT <28% with witnessed bleed.

**unfractionated or low molecular weight heparin

In-hospital major bleeding* by

antithrombotic strategy

Lopes RD JACC Cardiol Intv. 2010;3:669-77.

P < 0.001

In-hospital mortality by

antithrombotic strategy

Lopes RD J Am Coll Cardiol Intv. 2010;3:669-77.

Treatment Adjusted OR

± 95% CI Adj OR (95% Cl)

Heparin* alone

(n=1,365)

0.61 0.32, 1.16

Bivalirudin alone

(n=1,771)

0.39 0.21,0.71

Bivalirudin + GP IIb/IIIa

(n=863)

0.92 0.53, 1.60

0 1 2

Comparisons relative to heparin* +GP IIb/IIIa (n=7086)

P = 0.0035

*unfractionated or low molecular weight heparin

PCI – Therapeutic targets in

adjunctive pharmacotherapy

Limit

ischaemic

complications

Minimize

bleeding

Re-establish flow