safety and efficacy of switching from either ufh or enoxaparin plus a gp iib/iiia inhibitor to...

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

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

Harvey D. White

on behalf of the ACUITY investigators

DisclosuresDisclosures

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

Moderate-high risk

ACS

ACUITY Study DesignACUITY Study Design

An

gio

gra

ph

y w

ith

in 7

2h

Aspirin in allClopidogrel

dosing and timingper local practice

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*Stratified by pre-angiography thienopyridine use or administration

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

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

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

Medicalmanagement

PCI

CABG

Primary EndpointsPrimary Endpoints

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

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

ACUITY: Primary results – 30 daysACUITY: Primary results – 30 daysUFH/Enox + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa vs. Bivalirudin AloneUFH/Enox + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa vs. Bivalirudin Alone

7.3%5.7%

11.7%

7.7%

11.8%

5.3%

3.0%

10.1%

7.8%

Net clinical outcome Composite ischemia Major bleeding (non-CABG)

30 d

ay e

ven

ts (

%)

UFH/Enox+ GP IIb/IIIa (N=4603) Bivalirudin+GP IIb/IIIa (N=4604) Bivalirudin alone (N=4612)

PNI <0.001PSup = 0.015

PNI = 0.01 PSup = 0.32

PNI <0.001PSup <0.001

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. Hep+GPIHR [95% CI] = 1.05 (0.95-1.17)

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

Ischemic Composite Endpoint(Death, MI, unplanned revascularization for ischemia)

Ischemic Composite Endpoint(Death, MI, unplanned revascularization for ischemia)

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

Stone GW. ACC 2007 presentation

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

4

5

Mo

rtal

ity

(%)

Days from Randomization

2

1

Mortality: 524 total deaths at 1-yearMortality: 524 total deaths at 1-yearUFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin AloneUFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone

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

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

30 day

3

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

Stone GW. ACC 2007 presentation

Background and Objectives of the Current Analysis

Background and Objectives of the Current Analysis

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

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: Switch from Prior Antithrombin

0.1 1 10 0.1 1 10

Switch to Bivalirudin better

Consistent UFH/Enox + IIb/IIIa better


Overall(N=4215)

Composite ischemia 0.93 (0.75-1.16)

Major bleeding 0.49 (0.36-0.66)

Overall(N=4215)

Mortality 0.75 (0.54-1.04)


RR (95% CI) HR (95% CI)

Risk Ratio±95% CI

Hazard Ratio±95% CI

30 day Results 1 year Results

ACUITY PCI: Switch from Prior Antithrombin

ACUITY PCI: Switch from Prior Antithrombin

Risk Ratio±95% CI

Hazard Ratio±95% CI

30 day Results 1 year Results

PCI (n=2528)



PCI HIGH RISK*(n=1988)



PCI (n=2528)

Mortality 0.93 (0.58-1.48)

PCI HIGH RISK*(n=1988)

Mortality 0.99 (0.60-1.63)

* High risk = ↑Tn, CKMB or ECG Δ’s White HD, ESC 2007.





RR (95% CI) HR (95% CI)

Study Population – Current AnalysisStudy Population – Current Analysis

Received UFH/Enox + GPI prior to

Randomization N=371

Randomized to UFH/Enox + GPI

(consistent therapy)N=207

Randomized to bivalirudin

monotherapy (switched therapy)

N=164

Baseline CharacteristicsBaseline CharacteristicsConsistent

UFH/Enox + GPI(N=207)

Switch to Bivalirudin

Monotherapy

(N=164)

P-value

Age (median [range]) 62 (33-83) 61 (31-88) 0.74

Age ≥75 years, % 14.0 12.8 0.74

Female, % 26.6 22.0 0.30

Diabetes, % 25.6 25.5 0.98

Current Smoker, % 35.0 38.7 0.46

Prior MI, % 30.2 26.7 0.46

Prior PCI, % 33.5 30.1 0.48

Prior CABG, % 18.8 15.3 0.38

Family History CAD, % 57.5 49.3 0.14

Anemia, % 19.5 20.0 0.91

Hypertension, % 63.8 60.4 0.50

Hyperlipidemia, % 53.0 48.8 0.43

Consistent UFH/Enox + GPI

(N=207)

Switch to Bivalirudin

Monotherapy

(N=164)

P-value

CKMB/Troponin or

ST-segment Deviation, %87.7 90.1 0.49

CKMB/Troponin

Elevation, %79.6 81.5 0.65

ST-segment deviation, % 42.0 37.2 0.35

Prior Thienopyridine exposure*, %

60.9 60.4 0.92

Baseline CharacteristicsBaseline Characteristics

*Prior to angiography or PCI

5.3%

12.6%

9.2%

7.3%

9.8%

2.4%

Net clinical outcome Composite ischemia Major bleeding (non-CABG)

Consistent UFH/Enox + GPI (n=207)

Switch to Bivalirudin Monotherapy (n=164)

30-Day Outcomes30-Day Outcomes30

Day

Eve

nts

(%

)

1.9%1.9%

6.8%6.1%

0.0%

1.8%

Death Myocardial Infarction Unplanned Revasc

Consistent UFH/Enox +GPI (n=207)


30-Day Composite Ischemia Outcomes30-Day Composite Ischemia Outcomes30

Day

Eve

nts

(%

)

16.4%

3.4%1.8%

12.2%

Composite Ischemia Mortality

1 ye

ar e

ven

ts (

%)

Consistent UFH/Enox + GPI (n=207)


1-Year Outcomes1-Year Outcomes

Study Limitations Study Limitations

Small, post-hoc analysis Small, post-hoc analysis

ConclusionsConclusions

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

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

safety and efficacy of switching from either ufh or enoxaparin plus a gp iib/iiia inhibitor to...

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