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Safety and Efficacy of Switching from Either UFH or Enoxaparin Plus a GP IIb/IIIa Inhibitor to Bivalirudin Monotherapy in Patients with Non-ST Elevation ACS Managed with an Invasive Strategy: Results from the Randomized ACUITY Trial. Harvey D. White on behalf of the ACUITY investigators.

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Harvey d white on behalf of the acuity investigators

Safety and Efficacy of Switching from Either UFH or Enoxaparin Plus a GP IIb/IIIa Inhibitor to Bivalirudin Monotherapy in Patients with Non-ST Elevation ACS Managed with an Invasive Strategy: Results from the Randomized ACUITY Trial

Harvey D. White

on behalf of the ACUITY investigators


Disclosures
Disclosures Enoxaparin Plus a GP IIb/IIIa Inhibitor to Bivalirudin Monotherapy in Patients with Non-ST Elevation ACS Managed with an Invasive Strategy:

  • Research Grants:

    • Alexion, Fournier Laboratories, Sanofi Aventis, Johnson & Johnson, Eli Lilly, Proctor & Gamble, Merck Sharpe & Dohme, Schering Plough, Roche, The Medicines Company, Glaxo Smith Kline, Pfizer, Neuren Pharmaceuticals, NIH

  • Consultant:

    • Sanofi Aventis, The Medicines Company


Acuity study design

Medical Enoxaparin Plus a GP IIb/IIIa Inhibitor to Bivalirudin Monotherapy in Patients with Non-ST Elevation ACS Managed with an Invasive Strategy:

management

UFH or

Enoxaparin

+ GP IIb/IIIa

PCI

Bivalirudin

+ GP IIb/IIIa

Angiography within 72h

R*

Bivalirudin

Alone

CABG

ACUITY Study Design

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


Primary endpoints
Primary Endpoints Enoxaparin Plus a GP IIb/IIIa Inhibitor to Bivalirudin Monotherapy in Patients with Non-ST Elevation ACS Managed with an Invasive Strategy:

  • Net Clinical Outcomes

    • Death, MI, unplanned revascularization for ischemia or non-CABG major bleeding

  • Composite Ischemia

    • Death, MI or unplanned revascularization for ischemia

  • Major Bleeding (Non-CABG)

    • Intracranial, intraocular, or retroperitoneal bleeding

    • Access site bleed requiring intervention/surgery

    • Hematoma ≥5 cm

    • Hgb ≥4g/dL w/o overt source

    • Hgb ≥3g/dL with an overt source

    • Reoperation for bleeding

    • Any blood transfusion

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


Acuity primary results 30 days

UFH/Enox + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa vs. Bivalirudin Alone

PNI <0.001

PSup = 0.015

PNI = 0.01

PSup = 0.32

PNI <0.001

PSup <0.001

ACUITY: Primary results – 30 days

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


Ischemic composite endpoint death mi unplanned revascularization for ischemia
Ischemic Composite Endpoint Bivalirudin Alone(Death, MI, unplanned revascularization for ischemia)

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%

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


Mortality 524 total deaths at 1 year
Mortality: 524 total deaths at 1-year Bivalirudin Alone

p=0.90

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%

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


Background and objectives of the current analysis
Background and Objectives of the Current Analysis Bivalirudin Alone

  • Background

    • In prior studies, post-randomization crossover from UFH to enoxaparin or vice versa was associated with increased adverse events

    • In ACUITY, switching at randomization from prior UFH/enoxaparin to bivalirudin monotherapy was associated with significantly improved bleeding while preserving a similar rate of ischemia

  • Objective

    • Evaluate the effects of switching from pre-randomization UFH/Enox + GPI to bivalirudin monotherapy at randomization on 30-day and 1-year outcomes


Acuity overall switch from prior antithrombin
ACUITY Overall: Bivalirudin AloneSwitch from Prior Antithrombin

30 day Results

1 year Results

Risk Ratio±95% CI

Hazard Ratio±95% CI

RR (95% CI)

HR (95% CI)

Switch to

Bivalirudin better

Switch to

Bivalirudin better

Consistent UFH/Enox

+ IIb/IIIa better

Consistent UFH/Enox

+ IIb/IIIa better


Acuity pci switch from prior antithrombin
ACUITY PCI: Bivalirudin AloneSwitch from Prior Antithrombin

30 day Results

1 year Results

Risk Ratio±95% CI

Hazard Ratio±95% CI

RR (95% CI)

HR (95% CI)

Switch to

Bivalirudin better

Switch to

Bivalirudin better

Consistent UFH/Enox

+ IIb/IIIa better

Consistent UFH/Enox

+ IIb/IIIa better

* High risk = ↑Tn, CKMB or ECG Δ’s

White HD, ESC 2007.


Study population current analysis
Study Population – Current Analysis Bivalirudin Alone

Received UFH/Enox + GPI prior to Randomization

N=371

Randomized to bivalirudin monotherapy

(switched therapy)

N=164

Randomized to UFH/Enox + GPI (consistent therapy)

N=207


Baseline characteristics
Baseline Characteristics Bivalirudin Alone


Baseline characteristics1
Baseline Characteristics Bivalirudin Alone

*Prior to angiography or PCI


30 day outcomes
30-Day Outcomes Bivalirudin Alone

30 Day Events (%)


30 day composite ischemia outcomes
30-Day Composite Ischemia Outcomes Bivalirudin Alone

30 Day Events (%)


1 year outcomes
1-Year Outcomes Bivalirudin Alone


Study limitations
Study Limitations Bivalirudin Alone

  • Small, post-hoc analysis


Conclusions
Conclusions Bivalirudin Alone

  • In a small post-hoc analysis, switching from UFH/enoxaparin + a GP IIb/IIIa inhibitor to bivalirudin monotherapy was safe and effective, with an approximate 50% reduction in major bleeding and comparable ischemic events

  • Results of this analysis are consistent with overall ACUITY findings