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Prospective, Randomized Comparison of Routine Upfront Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes: The ACUITY Timing Trial. Gregg W. Stone MD for the ACUITY Investigators. Disclosure. Gregg W. Stone

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Gregg w stone md for the acuity investigators l.jpg

Prospective, Randomized Comparison of Routine Upfront Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes: The ACUITY Timing Trial

Gregg W. Stone MD

for the ACUITY Investigators


Disclosure l.jpg
Disclosure Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes:

  • Gregg W. Stone

    Consultant to The Medicines Company


Background i l.jpg
Background I Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes:

  • Optimal management of ACS1,2 consists of an early invasive strategy for moderate-high risk pts, followed by revascularization with PCI or CABG

    • Median time to cath 21 hours3

    • 55% PCI, 12% CABG, 33% medical mgt3

  • GP IIb/IIIa inhibitors are a class I indication1,2 (and are used in 80% of pts during PCI of ACS3)

    • Guidelines recommend that they be administered either upstream in all pts (PRISM PLUS and PURSUIT), or their use may be deferred for selective administration in the cath lab only for PCI

1 Braunwald et al JACC 2002; 2 Bertrand et al. EHJ 2002; 3www.crusade.org


Background ii l.jpg
Background II Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes:

  • However, the combination of invasive procedures with GP IIb/IIIa inhibitors, aspirin, clopidogrel, and antithrombin medications results in a high rate of hemorrhagic complications

  • The upstream use of GP IIb/IIIa inhibitors in all patients may further increase bleeding

    • Whether upstream GP IIb/IIIa use reduces ischemic complications sufficiently to justify such an increase is unknown


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The Question to Answer Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes:

  • When seeing a patient in the emergency department with moderate-high risk ACS in whom an invasive strategy is planned:

    • Should GP IIb/IIIa inhibitors be started immediately? Or

    • Should their use be withheld to

      • First perform coronary arteriography

      • And then only start GP IIb/IIIa inhibition if PCI is performed?


Optimal timing of gpi in acs hypotheses l.jpg
Optimal Timing of GPI in ACS: Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes: Hypotheses

  • In moderate-high risk patients with ACS undergoing an invasive strategy, compared to the routine upstream use of GP IIb/IIIa inhibitors in all patients, withholding upfront GP IIb/IIIa use for deferred administration in the cath lab only to patients undergoing PCI will result in:

    • Similar 30 day rates of death, MI or unplanned revascularization for ischemia

    • Reduced rates of major bleeding complications

    • Improved cost-effectiveness


Study design first randomization l.jpg

Medical Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes:

management

UFH or

Enoxaparin

+ GP IIb/IIIa

PCI

Bivalirudin

+ GP IIb/IIIa

Angiography within 72h

R*

Bivalirudin

Alone

CABG

Study Design – First Randomization

Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,800)

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


Study design second randomization l.jpg

UFH or Enoxaparin Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes:

Routine upstream

GPI in all pts

Routine upstream GPI in all pts

GPI started in CCL for PCI only

Bivalirudin

Routine upstream GPI in all pts

Deferred GPI

for PCI only

R

R

GPI started in CCL for PCI only

Bivalirudin

Alone

Secondary

analysis

Study Design – Second Randomization

Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,800)

UFH, Enoxaparin,

or Bivalirudin

VS.

Moderate-

high risk

ACS

Primary analysis

Aspirin in all

Clopidogrel

dosing and timing

per local practice

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


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Major Entry Criteria Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes:

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

  • ≥2 prior LMWH doses

  • Any prior abciximab

  • Prior tirofiban or eptifibatide if unable to be d/c for 4 hrs

  • Allergy to drugs, contrast

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


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3 Primary Endpoints (at 30 days) Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes:

1. Composite net clinical benefit =

2. Ischemic composite

or

3. Major bleeding

  • 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


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3 Primary Endpoints (at 30 days) Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes:

1. Composite net clinical benefit =

2. Ischemic composite

or

3. Major bleeding

  • Non CABG related bleeding

    • - Intracranial bleeding or intraocular bleeding

    • -Retroperitoneal bleeding

    • -Access site bleed requiring intervention/surgery

      • -Hematoma ≥5 cm

    • -Hgb ≥3g/dL with an overt source or ≥4g/dL w/o overt source

    • -Blood product transfusion

  • Reoperation for bleeding


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Power analysis and statistics Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes:

Routine upstream GP IIb/IIIa inhibition (n=4,600) vs. deferred GP IIb/IIIa inhibition in the CCL for PCI only (n=4,600)

  • The trial was powered to demonstrate non-inferiority for the composite ischemic endpoint at 30 days between the 2 groups (treatment strategy)

  • 1-sided upper bound of the confidence interval of the observed difference was used for non-inferiority ( = 0.025, =25%)

  • 2-sided confidence intervals used for superiority testing ( = 0.05)


Acuity enrollment l.jpg

(4) Norway Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes:

Sweden (6)

(5) Denmark

Finland (3)

(4) Netherlands

Canada (26)

(5) Belgium

Poland (1)

(12) UK

Germany (66)

(8) France

USA (246)

Austria (4)

Italy (15)

(25) Spain

(4) New Zealand

(17) Australia

ACUITY Enrollment

13,819 pts randomized at 448 centers in 17 countries


Acuity enrollment14 l.jpg

89 (0.6%) Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes: 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 second randomization15 l.jpg

UFH or Enoxaparin Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes:

Routine upstream

GPI in all pts

(4,605)

Routine upstream GPI in all pts

GPI started in CCL for PCI only

Bivalirudin

Routine upstream GPI in all pts

Deferred GPI

for PCI only

(n=4,602)

R

R

GPI started in CCL for PCI only

Bivalirudin

Alone

(n=4,612)

Study Design – Second Randomization

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

UFH, Enoxaparin,

or Bivalirudin

VS.

Moderate-

high risk

ACS

(n=13,819)

Aspirin in all

Clopidogrel

dosing and timing

per local practice

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


Baseline characteristics l.jpg
Baseline Characteristics Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes:


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Baseline High Risk Features Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes:


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Invasive Management Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes:


Study medications gp iib iiia inhibitors l.jpg
Study Medications: GP IIb/IIIa Inhibitors Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes:

*In PCI pts only; †In a few patients the timing onset was not known


Gp iib iiia selection l.jpg

Use During PCI (%) Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes:

Routine Upstream GP IIb/IIIa

Deferred PCI GP IIb/IIIa

1.1

33.5

33.4

4.5

65.4

62.1

N=2,559

N=2,405

GP IIb/IIIa Selection

Initiated Pre Angio (%)

Routine Upstream GP IIb/IIIa

Deferred PCI GP IIb/IIIa

0.4

7.6

43.8

34.4

65.2

48.6

N=4,339

N=212

Abciximab ■ Eptifibatide ■ Tirofiban ■


Primary endpoint measures l.jpg
Primary Endpoint Measures Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes:

Routine Upstream IIb/IIIa vs. Deferred PCI IIb/IIIa

PNI <0.0001

PSup = 0.93

PNI = 0.044

PSup = 0.13

PNI < 0.0001

PSup = 0.009


Primary endpoint measures itt l.jpg
Primary Endpoint Measures (ITT) Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes:

Routine Upstream IIb/IIIa vs. Deferred PCI IIb/IIIa

p value(non inferior)(superior)

Deferred

IIb/IIIa

Primary

endpoint

Risk ratio

±95% CI

Upstream IIb/IIIa

RR (95% CI)

<0.001

0.93

Net clinical outcome

11.7%

11.7%

1.00 (0.89-1.11)

Ischemic composite

0.06

0.13

Upper boundary non-inferiority

7.1%

7.9%

1.12 (0.97-1.29)

<0.001

0.01

Major bleeding

6.1%

4.9%

0.80 (0.67-0.95)

Deferred PCI GPI better

Routine Upstream GPI better


Components of the ischemic composite l.jpg
Components of the Ischemic Composite Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes:

Routine Upstream IIb/IIIa vs. Deferred PCI IIb/IIIa

PSup = 0.13

PSup = 0.48

PSup = 0.70

PSup = 0.03


Ischemic composite endpoint l.jpg

P Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes:

(log rank)

= 0.14

Ischemic Composite Endpoint

Routine Upstream IIb/IIIa vs. Deferred PCI IIb/IIIa

15

Estimate

Routine Upstream IIb/IIIa (N=4605)

7.1%

Deferred PCI IIb/IIIa (n=4602)

7.9%

10

Cumulative Events (%)

5

0

0

5

10

15

20

25

30

35

Days from Randomization


Major bleeding primary endpoint l.jpg
Major Bleeding (Primary Endpoint) Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes:


Bleeding endpoints non cabg l.jpg
Bleeding Endpoints (Non-CABG) Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes:


Actual management l.jpg

Upstream Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes:

IIb/IIIa

Deferred

IIb/IIIa

14.5%

13.7%

15.8%

18.5%

5.5%

5.8%

9.5%

8.0%

13.5%

15.3%

3.3%

2.4%

6.5%

7.8%

3.3%

4.5%

2.6%

3.7%

Actual Management

Routine Upfront IIb/IIIa vs. Deferred PCI IIb/IIIa

Risk ratio

±95% CI

RR (95% CI)

P

Pint

Net Clinical Outcome

PCI (n=5170)

CABG (n=1048)

Medical (n=2989)

1.06 (0.93-1.22)

0.38

0.25

0.34

0.85 (0.65-1.12)

0.96 (0.72-1.29)

0.80

Composite Ischemic

PCI (n=5170)

CABG (n=1048)

Medical (n=2989)

1.19 (1.00-1.42)

0.05

0.39

0.15

0.88 (0.65-1.18)

1.39 (0.91-2.12)

0.13

Major Bleeding

PCI (n=5170)

CABG (n=1048)

Medical (n=2989)

0.84 (0.69-1.02)

0.08

0.33

0.74

0.74 (0.40-1.34)

0.70 (0.47-1.05)

0.09

Deferred PCI GPI better

Routine Upstream GPI better


Primary endpoint measures timing analysis l.jpg
Primary Endpoint Measures - Timing Analysis Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes:

Duration from Initiation of GP IIb/IIIa to Angio/Interv

Upstream GPI group (N=4,342)


Composite ischemic timing analysis l.jpg
Composite Ischemic - Timing Analysis Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes:

Randomization to Angio/Intervention within Index Hospitalization

P = 0.06

P = 0.08

P = 0.60

Short(<3.0hrs)

Medium(3.0-19.7 hrs)

Long(>19.7 hrs)

Median:

1.5 hrs

6.1 hrs

30.0 hrs


Summary conclusions acuity timing trial l.jpg

11.7% Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes:

11.7%

PNI <0.0001

PNI = 0.044*

PSup = 0.13

7.1%

7.9%

6.1%

4.9%

PSup = 0.009

Summary ConclusionsACUITY Timing Trial

Routine upstream

GPI in all pts

Deferred GPI

for PCI only

Net Composite

Outcome

Ischemic Composite

Major Bleeding

*RR [95%CI] = 1.12 [0.97-1.29]


Net clinical outcome composite endpoint l.jpg
Net Clinical Outcome Composite Endpoint Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes:

Upstream IIb/IIIa vs. Deferred IIb/IIIa vs. Bivalirudin alone

15

10

Cumulative Events (%)

Estimate

P

(log rank)

5

11.7%

Routine Upstream IIb/IIIa (N=4605)

0.88

11.7%

Deferred PCI IIb/IIIa (n=4602)

0.009

10.1%

Bivalirudin alone (N=4612)

0

0

5

10

15

20

25

30

35

Days from Randomization


Ischemic composite endpoint32 l.jpg
Ischemic Composite Endpoint Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes:

Upstream IIb/IIIa vs. Selective IIb/IIIa vs. Bivalirudin alone

15

Estimate

P

(log rank)

7.1%

Routine Upstream IIb/IIIa (N=4605)

0.14

7.9%

Deferred PCI IIb/IIIa (n=4602)

0.28

10

7.8%

Bivalirudin alone (N=4612)

Cumulative Events (%)

5

0

0

5

10

15

20

25

30

35

Days from Randomization


Major bleeding endpoint l.jpg

15 Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes:

10

5

0

0

5

10

15

20

25

30

35

Major Bleeding Endpoint

Upstream IIb/IIIa vs. Selective IIb/IIIa vs. Bivalirudin alone

Estimate

P

(log rank)

6.1%

Routine Upstream IIb/IIIa (N=4605)

0.009

4.9%

Deferred PCI IIb/IIIa (n=4602)

<0.001

3.0%

Bivalirudin alone (N=4612)

Cumulative Events (%)

Days from Randomization


Clinical implications l.jpg
Clinical Implications Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes:

  • In pts with moderate-high risk ACS undergoing an early invasive strategy, compared to the routine upstream use of GP IIb/IIIa inhibitors in all pts, withholding upfront IIb/IIIa inhibitor use for selective initiation in the cath lab only to pts undergoing PCI results in:

    • Similar rates of adverse ischemic events, though a slight increase cannot be excluded

    • Reduced rates of major and minor bleeding


Clinical implications35 l.jpg
Clinical Implications Initiation Versus Selective Use of Glycoprotein IIb/IIIa Inhibitors in Patients With Acute Coronary Syndromes:

  • The implications of these results will be further examined through detailed angiographic analysis, long-term clinical follow-up (to 1-year) and formal cost-effectiveness analysis

  • Regardless, in the context of the entire ACUITY trial, both upstream and selective GP IIb/IIIa inhibitor strategies (with either UFH, enoxaparin or bivalirudin) provided inferior net clinical outcomes compared to use of bivalirudin alone


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