Safety and Efficacy of Bivalirudin in Patients with Non-ST Elevation

Acute Coronary Syndromes Undergoing Medical Management:

One Year Results from the Randomized ACUITY Trial

Walter Desmet, Lars Rasmussen, A. Michael Lincoff, Angel Cequier, Hans-Jürgen Rupprecht, Bernard Gersh, Steven Manoukian, Michel Bertrand, Gregg Stone

FINANCIAL DISCLOSURE: no disclosure to make

Walter Desmet, MD, PhDSafety and Efficacy of Bivalirudin in Patients With Non-ST Elevation Acute Coronary Syndromes Undergoing Medical Management:One Year Results from the Randomized ACUITY Trial

UNLABELED/UNAPPROVED USES DISCLOSURE:Bivalirudin is not approved for the indication discussed

Presenter Disclosure Information

Background: Current Management of ACS

1 Braunwald et al JACC 2002; 2 Bassand et al. EHJ 2007; 3www.crusade.org; 4SYNERGY. JAMA 2004;292:45-54

• Early invasive strategy if moderate-high risk1,2

– Median time to cath 21 hours3

• Revascularization with PCI or CABG1,2

– 55% PCI, 12% CABG, 33% medical mgt3

• Triple anti-platelet therapy1,2

– Aspirin

– Clopidogrel (initiated pre or post angiography)

– GP IIb/IIIa inhibitors

- started upstream in all pts or in the CCL for PCI

• Unfractionated or LMW heparin1,2,4

Bivalirudin as an Alternative to UFH/LMWH

• Advantages of the direct thrombin inhibitor bivalirudin– No requirement for anti-thrombin III

– Effective on clot-bound thrombin

– Inhibits thrombin-mediated platelet activation

– No interactions with PF- 4

– Plasma half-life 25 minutes

– No requirement for anticoagulant monitoring

• Clinical results with bivalirudin in PCI– Similar protection from ischemic events as UFH +

GP IIb/IIIa inhibitors, with markedly reduced bleeding1

• Not previously tested in contemporary ACS patients

REPLACE 2. Lincoff AM et al. JAMA 2003;289:853-863

7851 (56.8%) USA

438 (3.2%) Canada

499 (3.6%) Australia

547 (4.0%) Spain

155 (1.1%) France162 (1.2%) UK

89 (0.6%) Norway

Finland 51 (0.4%)

Poland 14 (0.1%) Germany 2561 (18.5%)

Austria 356 (2.6%)

132 (1.0%) Netherlands198 (1.4%) Belgium

Italy 238 (1.7%)

Sweden 175 (1.3%)

203 (1.5%) New Zealand

150 (1.1%) Denmark

ACUITY Enrollment13,819 pts randomized at 448 centers in 17 countries

Moderate-high risk

ACS

Study Design – Primary Randomization

An

gio

gra

ph

y w

ith

in 7

2h

Aspirin in allClopidogrel

dosing and timingper local practice

UFH orEnoxaparin+ GP IIb/IIIa

Bivalirudin+ GP IIb/IIIa

BivalirudinAlone

R*

*Stratified by pre-angiography thienopyridine use or administration

Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819)

ACUITY Design. Stone GW et al. AHJ 2004;148:764–75

Medicalmanagement

PCI

CABG

Major Entry Criteria

Age ≥18 years Chest pain ≥10’ within 24h At least one of:

New ST depression or transient ST elevation ≥1 mm

Troponin I, T, or CKMB Documented CAD All other 4 TIMI risk criteria

- Age ≥65 years- Aspirin within 7 days- ≥2 angina episodes w/i 24h- ≥3 cardiac risk factors

Written informed consent

Inclusion Criteria Exclusion Criteria No angiography within 72h Acute STEMI or shock Bleeding diathesis or major

bleed within 2 weeks Platelet count ≤100,000/mm3

INR >1.5 control CrCl ≤30 ml/min Abcx or ≥2 prior LMWH doses

Prior UFH, LMWH (1 dose), eptifibatide and tirofiban were allowed

Allergy to drugs, contrast

Moderate-high risk unstable angina or NSTEMI

ACUITY Design. Stone GW et al. AHJ 2004;148:764–75

Composite Ischemia: Death from any cause Myocardial infarction

During medical Rx: Any biomarker elevation >ULN Post PCI: CKMB >ULN with new Q waves or >3x ULN w/o Q waves Post CABG: CKMB >5x ULN with new Q waves, >10x ULN w/o Q waves

Unplanned revascularization for ischemia

Primary Endpoints (at 30 days)

Non CABG related bleeding Intracranial bleeding or intraocular bleeding Retroperitoneal bleeding Access site bleed requiring intervention/surgery Hematoma ≥5 cm Hgb ≥ 3 g/dL with , or ≥ 4 g/dL without overt source Blood product transfusion Reoperation for bleeding

Net Clinical Outcome (Composite Ischemia, Non-CABG Major Bleeding)

Composite Ischemia: Death from any cause Myocardial infarction

During medical Rx: Any biomarker elevation >ULN Post PCI: CKMB >ULN with new Q waves or >3x ULN w/o Q waves Post CABG: CKMB >5x ULN with new Q waves, >10x ULN w/o Q waves

Unplanned revascularization for ischemia

Primary Endpoints (at 1 Year)

Invasive Management

UFH/UFH/Enoxaparin + Enoxaparin +

GP IIb/IIIaGP IIb/IIIa(N=4,603)(N=4,603)

Bivalirudin Bivalirudin + GP IIb/IIIa + GP IIb/IIIa

(N=4,604)(N=4,604)

Bivalirudin Bivalirudin alone alone

(N=4,612)(N=4,612)

Angiography 99.2% 98.8% 98.9%

Adm. to angio (h) 19.7 (7.0-29.3)† 19.5 (7.0-28.2)† 19.8 (7.3-29.0)†

Drug* to angio/interv (h) 5.6 (1.6-22.5)† 5.0 (1.4-21.4)† 5.2 (1.5-22.5)†

Actual procedure

PCI 55.6% 56.7% 56.8%

CABG 11.9% 10.8% 10.6%

Medical therapy 32.4% 32.5% 32.6%

*in patients receiving study antithrombin pre angiography†median (IQR)

Overall 30-day Results by Treatment Arm

UFH/Enox + UFH/Enox + GP IIb/IIIa GP IIb/IIIa

Bivalirudin +Bivalirudin +GP IIb/IIIaGP IIb/IIIa

BivalirudinBivalirudinalonealone

Endpoint Rate RateRR (95% CI)

P ValueRate

RR (95% CI)P Value

Net clinical outcome

11.7% 11.8%1.01 (0.90-1.12)<0.001†, 0.93‡ 10.1%

0.86 (0.77-0.97)

<0.001†, 0.015‡

Composite Ischemia

7.3% 7.7%1.07 (0.92-1.23)

0.007†, 0.39‡ 7.8%1.08 (0.93-1.24)

0.01†, 0.32‡

Non-CABG Major Bleeding

5.7% 5.3%0.93 (0.78-1.10)<0.001†, 0.38‡ 3.0%

0.53 (0.43-0.65)<0.001†, 0.001‡

†non-inferiority; ‡superiority

Stone GW et al. NEJM 2006;355:2203-16

0 30 60 90 120 150 180 210 240 270 300 330 360 3900

5

15

25

Isch

emic

Co

mp

osi

te (

%)

Days from Randomization

10

20 UFH/Enoxaparin + IIb/IIIaBivalirudin + IIb/IIIa

Bivalirudin alone

EstimateP

(log rank)

30 day

7.4%0.367.8%0.347.9%

—

EstimateP

(log rank)

16.3%0.3816.5%0.3116.4%

1 year

—

p=0.55

Bivalirudin alone vs. H+GPIHR [95% CI] = 1.05 (0.95-1.17)

Bivalirudin+GPI vs. H+GPIHR [95% CI] = 1.05 (0.94-1.16)

UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone

1 Year Composite Ischemia by Treatment Arm

Overall Population

Stone GW. ACC 2007 presentation

0 30 60 90 120 150 180 210 240 270 300 330 360 3900

Mo

rtal

ity

(%)

Days from Randomization

2

1 UFH/Enoxaparin + IIb/IIIaBivalirudin + IIb/IIIa

Bivalirudin alone

EstimateP

(log rank)

1.4%0.531.6%0.391.6%

—

EstimateP

(log rank)

4.4%0.934.2%0.663.8%

1 year

—

p=0.90

UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone

1 Year Mortality by Treatment Arm

Overall Population

Stone GW. ACC 2007 presentation

3

4

5

Bivalirudin alone vs H+GPIHR [95% CI] = 0.95 (0.77-1.18)

Bivalirudin+GPI vs. H+GPI HR [95% CI] = 0.99 (0.80-1.22)

Management Strategy (N=13,819)

56.4%

11.1%

32.5%

CABG (n=1,539) PCI (n=7,789)

MM (n=4,491)

Heparin + IIb/IIIaN = 1,493

Bivalirudin + IIb/IIIaN = 1,496

Bivalirudin aloneN = 1,502

Purpose of this post-hoc analysis

An

gio

gra

ph

y w

ith

in 7

2h

R*

Compare clinical outcome of patients managed medically

MM32.5 %

PCI56.4 %

CABG11.1%

1) to clinical outcome in revascularized patients1) to clinical outcome in revascularized patients

2) between the 3randomization groups2) between the 3randomization groups

*Stratified by pre-angiography thienopyridine use or administration

ACUITY Design. Stone GW et al. AHJ 2004;148:764–75

Patient Characteristics

Medical Revasc P

Age (mean ± SD) 61.8 ± 12.2 63.0 ± 11.4 < 0.001

Female (%) 38.1 26.2 < 0.001

Weight (mean ± SD) 84.7 ± 19.3 85.7 ± 18.0 < 0.001

Diabetes (%) 26.8 28.7 0.02

Current smoker (%) 26.2 30.5 < 0.001

R/ hypertension (%) 69.7 65.7 < 0.001

R/ hyperlip. (%) 60.8 55.5 <0.001

Fam. history CAD (%) 53.0 52.1 0.37

Previous MI (%) 35.2 29.4 < 0.001

Previous PCI (%) 45.0 35.9 < 0.001

Previous CABG (%) 23.1 15.4 < 0.001

History renal insuff. (%) 20.4 18.5 0.01

Baseline cardiac marker or ST ∆ 60.3 77.9 < 0.001

0

4

8

12

16

Net Clinical Outcome Composite Ischemia Major Bleeding

Medical Management (MM) Non-Medical Management (non-MM)

30-day Results by Management Strategy

P<0.001

P<0.001

P<0.001

5.5%

14.0%

3.1%

9.9%

2.9%

5.5%30 d

ay e

ven

ts (

%)

0

2

4

6

8

10

Net Clinical Outcome Composite Ischemia Major Bleeding

30 Day Results by Treatment Arm

Medical Management Population

Heparin + GP IIb/IIIa (N = 1,493)Bivalirudin + GPI (N = 1,496)

Bivalirudin (N = 1,502)

30 d

ay e

ven

ts (

%)

P=0.06 P=0.09

P=0.67 P=0.36

P<0.001 P=0.0046.5%

4.9% 5.1%

3.1% 3.4%2.8%

4.4%

1.9%2.5%

1 Year Results by Management StrategyP

erce

nta

ge

(%)

8.9%

19.0%

3.9% 3.7%

P=0.65

P<0.0001

0

4

8

12

16

20

Composite Ischemia Mortality

Medical Management (MM) (N = 4,491)

Non-Medical Management (non-MM) (N = 9,328)

1 Year Results by Treatment Arm

9.0% 8.7%

4.0% 3.9%Per

cen

tag

e (%

)

Medical Management Population

9.0%

3.8%

P=0.99 P=0.81

P=0.84 P=0.75

0

2

4

6

8

10

Ischemic Composite Mortality

Heparin + GP IIb/IIIa (N = 1,493)Bivalirudin + GPI (N = 1,496)

Bivalirudin (N = 1,502)

Influence of Major Bleeding and MI in the First 30 Days on Risk of Death Over 1 Year

30 Day Major Bleed 3.77 (2.33-6.11) <0.0001

30 Day Myocardial Infarction 3.39 (1.62-7.08) 0.0012

0.1 1 10

HR ± 95% CI P-valueHR (95% CI)

Medical Management Population

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

Conclusions

Comprise a unique patient cohort with

different demographic risk factors

fewer high-risk features (trop / ECG ∆)

less major bleeding

fewer ischemic events

than patients requiring PCI or CABG

Patients triaged to medical management with

moderate and high risk NSTE-ACS

Bivalirudin with or without a GPI results in marked reduction of bleeding at 30 days, while preserving the ischemic and mortality benefit at 1-year

Early iatrogenic bleeding complications are significantly associated with long-term prognosis

In moderate and high risk NSTE-ACS patients triaged to medical management

Conclusions