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
Consultant to The Medicines Company
 Background I
 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
1
Braunwaldadministration
2
in the
et al JACC 2002; Bertrand cath
et al. EHJ
3
lab
2002; only for PCI
www.crusade.org
 Background II

 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
 The Question to Answer

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

UFH or Medical

Angiography within 72h

Enoxaparin management
+ GP IIb/IIIa

Moderate-
Bivalirudin
high risk R* + GP IIb/IIIa PCI
ACS

Aspirin in all
Clopidogrel Bivalirudin
dosing and timing Alone CABG
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
Moderate-high risk unstable angina or NSTEMI
undergoing an invasive strategy (N = 13,800)
UFH or Enoxaparin
Routine upstream
Routine upstream

UFH, Enoxaparin,
GPI in all pts
R GPI started in GPI in all pts

or Bivalirudin
CCL for PCI only
Bivalirudin VS.
Moderate- Routine upstream

high risk
GPI in all pts
R GPI started in Deferred GPI
ACS CCL for PCI only
for PCI only

Primary analysis
Aspirin in all
Clopidogrel Bivalirudin
dosing and timing Alone Secondary
per local practice analysis

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

 Major Entry Criteria
Moderate-high risk unstable angina or NSTEMI
Inclusion Criteria Exclusion Criteria
 Age ≥18 years  No angiography within 72h
 Chest pain ≥10’ within 24h  Acute STEMI or shock
 At least one of:  Bleeding diathesis or major
 New ST depression or bleed within 2 weeks
transient ST elevation ≥1 mm  Platelet count ≤100,000/mm3
 Troponin I, T, or CKMB
 INR >1.5 control
 Documented CAD
 CrCl ≤30 ml/min
 All other 4 TIMI risk criteria
- Age ≥65 years  ≥2 prior LMWH doses
- Aspirin within 7 days  Any prior abciximab
- ≥2 angina episodes w/i 24h  Prior tirofiban or eptifibatide
- ≥3 cardiac risk factors if unable to be d/c for 4 hrs
 Written informed consent  Allergy to drugs, contrast

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

 3 Primary Endpoints (at 30 days)
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
 3 Primary Endpoints (at 30 days)
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
 Power analysis and statistics
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 (α = 0.025, δ=25%)
• 2-sided confidence intervals used for superiority testing (α = 0.05)

Routine
Anticipated Deferred PCI
upstream
30-day event GP IIb/IIIa Power
GP IIb/IIIa
rates N = 4,600
N = 4,600
Ischemic 85% power for
5.9% 5.9%
composite non-inferiority
 ACUITY Enrollment
13,819 pts randomized at 448 centers in 17 countries
(4) Norway Sweden (6)
(5) Denmark
(4) Netherlands Finland (3)
Canada (26) (5) Belgium Poland (1)
(12) UK Germany (66)
USA (246) (8) France Austria (4)
(25) Spain Italy (15)

(4) New Zealand

(17) Australia
 ACUITY Enrollment
13,819 pts randomized at 448 centers in 17 countries
89 (0.6%) Norway Sweden 175 (1.3%)
150 (1.1%) Denmark
132 (1.0%) Netherlands Finland 51 (0.4%)
438 (3.2%) Canada 198 (1.4%) Belgium Poland 14 (0.1%)
162 (1.2%) UK Germany 2561 (18.5%)
7851 (56.8%) USA 155 (1.1%) France Austria 356 (2.6%)
547 (4.0%) Spain Italy 238 (1.7%)

203 (1.5%) New Zealand

499 (3.6%) Australia

 Study Design – Second Randomization
Moderate-high risk unstable angina or NSTEMI
undergoing an invasive strategy (N = 13,819)
UFH or Enoxaparin
Routine upstream Routine upstream

UFH, Enoxaparin,
GPI in all pts GPI in all pts
R GPI started in

or Bivalirudin
CCL for PCI only (4,605)
Bivalirudin VS.
Moderate- Routine upstream
high risk GPI in all pts
Deferred GPI
R GPI started in for PCI only
ACS
CCL for PCI only (n=4,602)
(n=13,819)
Aspirin in all Bivalirudin
Clopidogrel Alone
dosing and timing
(n=4,612)
per local practice

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

 Baseline Characteristics
Routine Upstream Deferred PCI
GP IIb/IIIa GP IIb/IIIa
(N=4,605) (N=4,602)
Age (median [range], yrs 63 [21-95] 63 [21-92]
Male 70.6% 69.9%
Diabetes 27.6% 28.6%
- Insulin requiring 8.1% 9.0%
Hypertension 67.0% 67.0%
Hyperlipidemia 57.2% 57.4%
Current smoker 28.5% 29.8%
Prior MI 30.4% 31.7%
Prior PCI 38.4% 38.3%
Prior CABG 18.4% 17.2%
Renal insufficiency 6.0% 5.7%
 Baseline High Risk Features
Routine Upstream Deferred PCI
GP IIb/IIIa GP IIb/IIIa
(N=4,605) (N=4,602)
Biomarker or ST ∆ 70.7% 70.6%
- Biomarker + 57.4% 57.6%
- ST-segment ∆ 35.1% 35.5%
Biomarker + ST ∆ 21.7% 22.4%
TIMI Risk Score
- Low (0-2) 16.1% 15.4%
- Intermediate (3-4) 53.7% 55.5%
- High (5-7) 30.3% 29.1%
 Invasive Management
Routine Upstream Deferred PCI
GP IIb/IIIa GP IIb/IIIa
(N=4,605) (N=4,602)

Angiography performed 98.9% 99.0%

Adm. to angiography (h) 19.7 (6.8-28.4) 19.6 (7.1-29.0)

Rand. to angio/interv (h) 6.2 (2.1-23.1) 6.2 (2.1-23.2)
Actual procedure
- PCI 56.7% 55.6%
- CABG 11.6% 11.1%
- Medical therapy 31.6% 33.3%
 Study Medications: GP IIb/IIIa Inhibitors
Routine Upstream
Deferred PCI
GP
GP IIb/IIIa
IIb/IIIa
(N=4,602)
(N=4,605)
Pre randomization 8.1% 7.6%
Study GP IIb/IIIa – All patients
Initiated pre angiography 94.5% 5.8%
Overall exposure 98.3% 55.7%
Rand. to GP IIb/IIIa (h) 0.6 (0.3-1.0) 4.6 (1.7-19.8)*
Study GP IIb/IIIa – PCI patients
Initiated pre angiography 95.3% 6.1%
Any use during PCI 98.8% 94.0%
Initiated post PCI 0.2% 2.0%
Overall exposure 99.3%† 96.2%†
*In PCI pts only; †In a few patients the timing onset was not known
 GP IIb/IIIa Selection
Initiated Pre Angio (%)
Routine Upstream GP IIb/IIIa Deferred PCI GP IIb/IIIa
0.4
7.6
34.4 43.8

65.2 48.6

N=4,339 N=212

Use During PCI (%)

Routine Upstream GP IIb/IIIa Deferred PCI GP IIb/IIIa

33.5 1.1
4.5 33.4

65.4 62.1

N=2,559 N=2,405

Abciximab ■ Eptifibatide ■ Tirofiban ■

 Primary Endpoint Measures
Routine Upstream IIb/IIIa vs. Deferred PCI IIb/IIIa
Routine Upstream IIb/IIIa (N=4605) Deferred PCI IIb/IIIa (n=4602)

PNI <0.0001 PNI = 0.044 PNI < 0.0001

30 day events (%)

PSup = 0.93 PSup = 0.13 PSup = 0.009

11.7% 11.7%

7.1% 7.9%
6.1%
4.9%

Net clinical Ischemic composite Major bleeding

outcome
 Primary Endpoint Measures (ITT)
Routine Upstream IIb/IIIa vs. Deferred PCI IIb/IIIa
Primary Risk ratio Upstream Deferred p value
RR (95% CI) (non inferior)
endpoint ±95% CI IIb/IIIa IIb/IIIa (superior)

Upper boundary non-inferiority

Net clinical <0.001
11.7% 11.7% 1.00 (0.89-1.11)
outcome 0.93

Ischemic 0.06
composite 7.1% 7.9% 1.12 (0.97-1.29)
0.13

Major bleeding <0.001

6.1% 4.9% 0.80 (0.67-0.95)
0.01

0 1 2

Deferred PCI GPI better Routine Upstream GPI better

Components of the Ischemic Composite
Routine Upstream IIb/IIIa vs. Deferred PCI IIb/IIIa
Routine Upstream IIb/IIIa (N=4605) Deferred PCI IIb/IIIa (n=4602)

PSup = 0.13 PSup = 0.48 PSup = 0.70 PSup = 0.03

30 day events (%)

7.9%
7.1%
4.9% 5.0%
2.8%
2.1%
1.3% 1.5%

Ischemic Death Myocardial Unplanned

composite infarction revasc for
ischemia
 Ischemic Composite Endpoint
Routine Upstream IIb/IIIa vs. Deferred PCI IIb/IIIa
15
Estimate
Cumulative Events (%)

Routine Upstream IIb/IIIa (N=4605) 7.1% P = 0.14

(log rank)
Deferred PCI IIb/IIIa (n=4602) 7.9%
10

0
0 5 10 15 20 25 30 35

Days from Randomization

 Major Bleeding (Primary Endpoint)
Routine Upstream Deferred PCI
GP IIb/IIIa GP IIb/IIIa P value
(N=4,605) (N=4,602)
Major bleeding (ACUITY scale) 6.1% 4.9% 0.009
• Intracranial 0.04% 0.08% 0.41
• Intraocular 0.0% 0.0% 1.0
• Retroperitoneal 0.6% 0.5% 0.57
• Access site 2.7% 2.4% 0.36
- requiring intervention/surgery 0.4% 0.4% 0.62
- hematoma ≥5 cm 2.4% 2.0% 0.23
• Hgb ⇓ ≥3 g/dL with overt
2.3% 1.8% 0.09
source
• Hgb ⇓ ≥4 g/dL w/o overt source 1.0% 0.6% 0.02
• Blood transfusion 3.0% 2.3% 0.05
• Reoperation for bleed 0.1% 0.0% 0.26
 Bleeding Endpoints (Non-CABG)
Routine Upstream Deferred PCI
GP IIb/IIIa GP IIb/IIIa P value
(N=4,605) (N=4,602)
ACUITY Scale
- Any 26.0% 21.6% <0.001
- Major 6.1% 4.9% 0.009
- Minor 24.0% 19.3% <0.001
TIMI Scale
- Any 7.3% 5.7% 0.001
- Major 1.9% 1.5% 0.20
- Minor 7.2% 5.4% <0.001
Blood transfusion 3.0% 2.3% 0.05
 Actual Management
Routine Upfront IIb/IIIa vs. Deferred PCI IIb/IIIa
Risk ratio Upstream Deferred Pint
RR (95% CI) P
±95% CI IIb/IIIa IIb/IIIa
Net Clinical Outcome
PCI (n=5170) 13.7% 14.5% 1.06 (0.93-1.22) 0.38
CABG (n=1048) 18.5% 15.8% 0.85 (0.65-1.12) 0.25
0.34
Medical (n=2989) 5.8% 5.5% 0.96 (0.72-1.29) 0.80
Composite Ischemic
PCI (n=5170) 8.0% 9.5% 1.19 (1.00-1.42) 0.05
CABG (n=1048) 15.3% 13.5% 0.88 (0.65-1.18) 0.39
0.15
Medical (n=2989) 2.4% 3.3% 1.39 (0.91-2.12) 0.13
Major Bleeding
PCI (n=5170) 7.8% 6.5% 0.84 (0.69-1.02) 0.08
CABG (n=1048) 4.5% 3.3% 0.74 (0.40-1.34) 0.33
0.74
Medical (n=2989) 3.7% 2.6% 0.70 (0.47-1.05) 0.09

0 1 2
Deferred PCI GPI better Routine Upstream GPI better
 Primary Endpoint Measures - Timing Analysis
Duration from Initiation of GP IIb/IIIa to Angio/Interv
Upstream GPI group (N=4,342)

Short (<2.3 hrs) Intermediate (2.3-18.1 hrs) Long (>18.1 hrs)

30 day events (%)

14.8%

9.8% 9.7% 9.7%

6.0% 6.6%
5.3% 5.5% 5.4%

Net Clinical Outcome Ischemic Composite Major Bleeding

 Composite Ischemic - Timing Analysis
Randomization to Angio/Intervention within Index Hospitalization
25%
Routine Upstream GPI (N=4605) Deferred PCI GPI (n=4602)

20%
P = 0.06 P = 0.08 P = 0.60
30 day events (%)

15%

9.9% 9.3%
10%
7.3% 6.7%
5.6% 5.2%
5%

0%
Short Medium Long
(<3.0hrs) (3.0-19.7 hrs) (>19.7 hrs)
Median: 1.5 hrs 6.1 hrs 30.0 hrs
 Summary Conclusions
ACUITY Timing Trial
Routine upstream Deferred GPI
GPI in all pts for PCI only

Net Composite
11.7% 11.7% PNI <0.0001
Outcome

PNI = 0.044*
Ischemic Composite 7.1% 7.9% PSup = 0.13

Major Bleeding 6.1% 4.9% PSup = 0.009

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

 Net Clinical Outcome Composite Endpoint
Upstream IIb/IIIa vs. Deferred IIb/IIIa vs. Bivalirudin alone
15
Cumulative Events (%)

10

5 Estimate P
Routine Upstream IIb/IIIa (N=4605) 11.7% (log rank)
Deferred PCI IIb/IIIa (n=4602) 11.7% 0.88
Bivalirudin alone (N=4612) 10.1% 0.009
0
0 5 10 15 20 25 30 35

Days from Randomization

 Ischemic Composite Endpoint
Upstream IIb/IIIa vs. Selective IIb/IIIa vs. Bivalirudin alone
15
Estimate P
Cumulative Events (%)

Routine Upstream IIb/IIIa (N=4605) 7.1% (log rank)

Deferred PCI IIb/IIIa (n=4602) 7.9% 0.14
10 Bivalirudin alone (N=4612) 7.8% 0.28

0
0 5 10 15 20 25 30 35

Days from Randomization

 Major Bleeding Endpoint
Upstream IIb/IIIa vs. Selective IIb/IIIa vs. Bivalirudin alone
15
Estimate P
Cumulative Events (%)

Routine Upstream IIb/IIIa (N=4605) 6.1% (log rank)

Deferred PCI IIb/IIIa (n=4602) 4.9% 0.009
10 Bivalirudin alone (N=4612) 3.0% <0.001

0
0 5 10 15 20 25 30 35

Days from Randomization

 Clinical Implications

 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 Implications

 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