Safety and Efficacy of Bivalirudin
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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.

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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


Presenter disclosure information
Presenter Disclosure Information

Walter Desmet, MD, PhD

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

FINANCIAL DISCLOSURE: no disclosure to make

UNLABELED/UNAPPROVED USES DISCLOSURE:

Bivalirudin is not approved for the indication discussed


Background current management of acs
Background: Current Management of ACS

  • 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

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


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

Bivalirudin as an Alternative to UFH/LMWH

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


Acuity enrollment

89 (0.6%) Norway

Sweden 175 (1.3%)

150 (1.1%) Denmark

Finland 51 (0.4%)

132 (1.0%) Netherlands

438 (3.2%) Canada

198 (1.4%) Belgium

Poland 14 (0.1%)

162 (1.2%) UK

Germany 2561 (18.5%)

155 (1.1%) France

7851 (56.8%) USA

Austria 356 (2.6%)

Italy 238 (1.7%)

547 (4.0%) Spain

203 (1.5%) New Zealand

499 (3.6%)Australia

ACUITY Enrollment

13,819 pts randomized at 448 centers in 17 countries


Study design primary randomization

Medical

management

UFH or

Enoxaparin

+ GP IIb/IIIa

PCI

Bivalirudin

+ GP IIb/IIIa

Angiography within 72h

R*

Bivalirudin

Alone

CABG

Study Design – Primary Randomization

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

Moderate-

high risk

ACS

Aspirin in all

Clopidogrel

dosing and timing

per local practice

*Stratified by pre-angiography thienopyridine use or administration

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


Major entry criteria
Major Entry Criteria

Moderate-high risk unstable angina or NSTEMI

Inclusion Criteria

Exclusion 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

  • 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

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


Primary endpoints at 30 days
Primary Endpoints (at 30 days)

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

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


Primary endpoints at 1 year
Primary Endpoints (at 1 Year)

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


Invasive management
Invasive Management

*in patients receiving study antithrombin pre angiography

†median (IQR)


Overall 30 day results by treatment arm
Overall 30-day Results by Treatment Arm

†non-inferiority; ‡superiority

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


1 year composite ischemia by treatment arm

30 day

P

(log rank)

1 year

P

(log rank)

Estimate

Estimate

p=0.55

UFH/Enoxaparin + IIb/IIIa

7.4%

16.3%

0.36

0.38

Bivalirudin + IIb/IIIa

7.8%

16.5%

0.34

0.31

Bivalirudin alone

7.9%

16.4%

1 Year Composite Ischemia by Treatment Arm

Overall Population

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

25

20

15

Ischemic Composite (%)

10

Bivalirudin+GPI vs. Hep+GPI

HR [95% CI] = 1.05 (0.94-1.16)

5

Bivalirudin alone vs. Hep+GPI

HR [95% CI] = 1.05 (0.95-1.17)

0

0

30

60

90

120

150

180

210

240

270

300

330

360

390

Days from Randomization

Stone GW. ACC 2007 presentation


1 year mortality by treatment arm

UFH/Enoxaparin + IIb/IIIa

Bivalirudin + IIb/IIIa

Bivalirudin alone

P

(log rank)

1 year

P

(log rank)

Estimate

Estimate

1.4%

4.4%

0.53

0.93

1.6%

4.2%

0.39

0.66

1.6%

3.8%

1 Year Mortality by Treatment Arm

Overall Population

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

5

Bivalirudin+GPI vs. Hep+GPI

HR [95% CI] = 0.99 (0.80-1.22)

4

Bivalirudin alone vs. Hep+GPI

HR [95% CI] = 0.95 (0.77-1.18)

3

Mortality (%)

2

30 day

1

0

0

30

60

90

120

150

180

210

240

270

300

330

360

390

Days from Randomization

Stone GW. ACC 2007 presentation


Management strategy n 13 819

Heparin + IIb/IIIa

N = 1,493

Bivalirudin + IIb/IIIa

N = 1,496

Bivalirudin alone

N = 1,502

Management Strategy (N=13,819)

CABG (n=1,539)

PCI (n=7,789)

56.4%

11.1%

32.5%

MM (n=4,491)


Purpose of this post hoc analysis

MM

32.5 %

PCI

56.4 %

Angiography within 72h

R*

CABG

11.1%

Purpose of this post-hoc analysis

Compare clinical outcome of patients managed medically

1) to clinical outcome in

revascularized patients

2) between the 3

randomization groups

*Stratified by pre-angiography thienopyridine use or administration

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



30 day results by management strategy

Medical Management (MM)

Non-Medical Management (non-MM)

16

12

8

4

0

Net Clinical Outcome

Composite Ischemia

Major Bleeding

30-day Results by Management Strategy

P<0.001

14.0%

P<0.001

9.9%

30 day events (%)

P<0.001

5.5%

5.5%

3.1%

2.9%


30 day results by treatment arm

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

Bivalirudin + GPI (N = 1,496)

10

P=0.06

P=0.09

Bivalirudin (N = 1,502)

8

P=0.67

P=0.36

P<0.001

P=0.004

6

4

2

0

Net Clinical Outcome

Composite Ischemia

Major Bleeding

30 Day Results by Treatment Arm

Medical Management Population

6.5%

30 day events (%)

5.1%

4.9%

4.4%

3.4%

3.1%

2.8%

2.5%

1.9%


1 year results by management strategy

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

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

20

16

12

8

4

0

Composite Ischemia

Mortality

1 Year Results by Management Strategy

P<0.0001

19.0%

Percentage (%)

8.9%

P=0.65

3.9%

3.7%


1 year results by treatment arm

P=0.99

P=0.81

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

Bivalirudin + GPI (N = 1,496)

Bivalirudin (N = 1,502)

1 Year Results by Treatment Arm

Medical Management Population

10

9.0%

9.0%

8.7%

P=0.84

P=0.75

8

Percentage (%)

6

4.0%

3.9%

3.8%

4

2

0

Ischemic Composite

Mortality


Influence of major bleeding and mi in the first 30 days on risk of death over 1 year
Influence of Major Bleeding and MI in the First 30 Days on Risk of Death Over 1 Year

Medical Management Population

HR (95% CI)

P-value

HR ± 95% CI

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


Conclusions

Comprise a unique patient cohort with Risk of Death Over 1 Year

different demographic risk factors

fewer high-risk features (trop  / ECG ∆)

less major bleeding

fewer ischemic events

than patients requiring PCI or CABG

Conclusions

Patients triaged to medical management with

moderate and high risk NSTE-ACS


Conclusions1
Conclusions Risk of Death Over 1 Year

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

  • 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


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