1. The Time Dependence of Anti-thrombin Initiation in Patients with Non-ST-segment –elevation Acute Coronary Syndrome: Subgroup Analysis form the ACUITY Trial
Deborah B. Diercks, MD
Associate Professor of Emergency Medicine
University of California, Davis Medical Center
Sacramento, CA

2. Authors Andra L. Blomkalns, MD Charles L. Emerman, MD
Ivan C. Rokos, MD
David M. Larson, MD
James W. Hoekstra, MD
Charles V. Pollack, MD
ACUITY EM Study Group

3. Disclosure
All authors participated as a consultant to The Medicines Company as part of the EM Study Group
Authors speak or consult for Sanofi-Aventis, Schering-Plough

4. Antithrombin Therapy Non-ST elevation acute coronary syndrome
Class 1 A recommendation
Acute therapy within 24 hours
No emphasis based on time from symptom onset
CRUSADE data
86% receive treatment within 24 hours

5. Antithrombin Therapy Multiple Options
Synergy
Oasis-5
ACUITY
Time frame looked at is from randomization
Limited data on time from presentation or symptom onset
Differences in preference may result in delay of treatment as decision on which agent to start are made

6. Hypothesis
Initiating an antithrombin agent soon after symptom onset improves outcome.

7. Methods Subgroup analysis of the ACUITY trial ACUITY methods
The ACUITY trial enrolled patients (pts) with high or intermediate risk NSTEACS.
All patients received an antithrombin treatment (UFH, LMWH, or bivalirudin) in addition to other agents (ASA, clopidogrel, +/- glycoprotein 2b-3a inhibitors) with an early intervention strategy.
In the ACUITY trial 2722 of the 13,819 pts were enrolled in a formal ED substudy
The purpose of which was to collect detailed baseline and treatment data related to ED processes.

8. ED substudy
3/2005 ED steering committee created and met to discuss trial
Data entry for ACUITY trial was amended to include ED pertinent variables to exam the following in pre-specified analysis
Time of agent initiation
Bleeding complications
Time from symptom onset

9. Methods Inclusion criteria Exclusion criteria
Patients with data from the ED page
Exclusion criteria
No time of symptom onset or treatment

10. Methods
Observed frequency (%)s by the time duration from symptom onset to initiation of any antithrombin (AT) treatment:
0-6 hrs
>6 hrs-12 hrs
>12-24 hrs
>24 hrs
The treatment initiation was from the combination of any pre-randomization AT treatment and any post-randomization AT treatment (UFH, LMWH or Bivalirudin).
Since no date was collected for any use of pre-randomization medications, imputation on date of initial use of AT pre-randomization was applied for any pre-randomization AT treatment.

11. Methods
Net clinical outcome was defined as death, myocardial infarction, major bleeding, and unplanned revascularization at any time during the 30 day follow-up period.
Ischemic outcome was defined as death, myocardial infarction, and unplanned revascularization at any time during the 30 day follow-up period

12. Methods
Stepwise logistic regression model on ischemic endpoint adjusted for the confounding risk factors
Age
Gender
baseline diabetes
baseline troponin(I/T) or CPK-MB >3 ULN
prior PCI or CABG
ECG changes
post-randomization GPI use (upstream, during PCI, no GPI)
actual procedure (PCI, CABG, MM)
baseline lab CrCl >=60
baseline blood pressure
ED admission to intervention (PCI or angiogram) < 8 hrs
ED symptom onset to ED admission < 6hrs,
ASA pre-/post-rand prior to intervention
Thienopyridine pre-/post-rand prior to intervention
duration of initiation of AT treatment

13. Methods
A significance level of 0.15 is required to allow a variable into logistic model
Expected ischemic rates from the final model by duration will be presented

14. Results
Of the 2741 patients in the ED substudy 2603 (96%) were included in the analyses
2494 were included in the logistic regression
109 excluded for missing variables
Time groups
0-6 hrs N=436 (17%)
>6 hrs-12 hrs N=524 (20%)
>12-24 hrs N=657 (25%)
>24 hrs N=986 (38%)

15. Baseline Characteristics <6 hrs N=436 N (%) 6-12 hrs N=524
Age mean, (SD)
61.4 (SD 11.2)
61.1 (SD 12.3)
61.7 (SD 11.8)
62.2 (SD 11.8)
men
328 (75.2)
367 (70)
455 (69.3)
685 (69.5)
Planned Thienopytidines
259 (59.4)
290 (55.3)
381 (58.0)
581 (58.9)
Hx DM
101 (23.3)
136 (26.0)
205 (31.3)
307 (31.2)
Hx HTN
265 (60.8)
325 (62.3)
417 (64.0)
684 (69.4)
Hx CVA
19 (4.4)
26 (5.0)
42 (6.4)
54 (5.5)
Hx CAD
219 (54.9)
241 (51.0)
296 (49.3)
475 (52.2)
Hx CKD
21 (4.0)
43 (6.6)
Entry criteria (ECG and/or markers)
321 (73.6)
382 (72.9)
476 (72.5)
621 (63.0)
What is the red for ? The yellows differences between the groups

16. Net clinical outcome (%) Ischemic outcomes (%) Major bleeding (%)
Duration (hrs)
Net clinical outcome (%)
Ischemic outcomes (%)
Major bleeding (%)
Death (%)
MI (%)
UR (%)
≤6 N=436
11.9
8.7
4.1
0.2
6.4
>6, ≤12 N=524
10.5
7.6
3.6
1.7
4.4
2.5
>12, ≤24 N=657
11.6
7.3
5.8
2.1
4.6
>24 N=989
9.9
6.1
0.8
4.2
1.5
P trend value
0.35
0.07
0.58
0.75
0.12
0.003

17. Ischemic outcomes (%) UR (%) 8.7 (95% CI, 6.2-11.7) 7.6
Duration (hrs)
Net clinical outcome (%)
Ischemic outcomes (%)
Major bleeding (%)
Death (%)
MI (%)
UR (%)
≤6 N=436
11.9
8.7
(95% CI, )
4.1
0.2
6.4
>6, ≤12 N=524
10.5
7.6
(95% CI, )
3.6
1.7
4.4
2.5
>12, ≤24 N=657
11.6
7.3
(95% CI, )
5.8
2.1
4.6
>24 N=989
9.9
6.1
(95% CI, )
0.8
4.2
1.5
P trend value
0.35
0.07
0.58
0.75
0.12
0.003

18. Regression Model Baseline Characteristics
ED patients with dur. (N=2603)
N (%)
Included ED patients (N=2494)
Excluded ED patients (N=109)
Age mean, (SD)
61.7 (SD 11.8)
61.8 (SD 11.7)
60.3 (SD 12.8)
men
1835 (70.5)
1767 (70.9)
68 (62.4)
Planned Thienopytidines
1511 (58.0 )
1444 (57.9)
67 (61.5)
Hx DM
749 (28.8 )
712 (28.5)
37 (33.9)
Hx HTN
1691 (65.0)
1621 (65.0)
70 (64.2)
Hx CVA (Cerebrovascular)
141 (5.4)
133 (5.3)
8 (7.3)
Hx CAD
1231 (47.3)
1181 (47.4)
50 (45.9)
Hx CKD (renal insufficiency)
137 (5.3)
134 (5.4)
3 (2.8)
Entry criteria (ECG =/- markers)
1800 (69.2)
1724 (69.1)
76 (69.7)
No signficant differences

19. Results Final selected model includes 5 variables: OR
Age (95% CI )
actual procedure
CABG Vs PCI (95% CI )
Med vs PCI (95% CI )
CrCl (95% CI )
thienopyridine (95% CI )
duration group (forced in)
1 vs (95% CI )
2 vs (95% CI )
3vs (95% CI )
What does duration group mean? Is this treatment duration

20. Observed ischemic rate Expected ischemic rate (based on risk factors)
Duration (hrs)
Observed ischemic rate
Expected ischemic rate (based on risk factors)
Abs change (exp – obs) ≤6
8.7
9.2
0.5*
>6, ≤12
7.6
7.5
-0.1
>12, ≤24
7.3
>24
6.1
6.0
Run logistic regression model based on risk factors and calculate risk score and then able to calculate expected event rate. This means that we observed that treatment may be better because my early intervention helped. This is a very small benefit
*This indicates potential benefit of early treatment

21. Limitations Can not adjust for quality of history for ACS
Stuttering pain
Lack of consistency on how the question was asked
Can not adjust for clinical appearance
Outcome measure included unplanned revascularization which may is clinician dependant
We assumed no difference by treatment group

22. Conclusion
There is no difference in net clinical outcomes or ischemic outcomes by time interval.
Early treatment may improve ischemic outcomes in patients presenting within 6 hours of symptom onset.