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

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

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

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

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

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

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.

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

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

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.

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

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

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

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%)

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

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 6.2-11.7

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, 6.2-11.7) 4.1 0.2 6.4 >6, ≤12 N=524 10.5 7.6 (95% CI, 5.5-10.2) 3.6 1.7 4.4 2.5 >12, ≤24 N=657 11.6 7.3 (95% CI, 5.4-9.6) 5.8 2.1 4.6 >24 N=989 9.9 6.1 (95% CI, 4.7-7.7) 0.8 4.2 1.5 P trend value 0.35 0.07 0.58 0.75 0.12 0.003 6.2-11.7

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

Results Final selected model includes 5 variables: OR Age 1.11 (95% CI 1.0-1.03) actual procedure CABG Vs PCI 1.42 (95% CI 0.9-2.2) Med vs PCI 0.31 (95% CI 0.2-0.5) CrCl60 1.65 (95% CI 1.1-2.5) thienopyridine 2.14 (95% CI 1.4-3.3) duration group (forced in) 1 vs 4 1.62 (95% CI 1.0-2.5) 2 vs 4 1.28 (95% CI 0.8-2.0) 3vs 4 1.25 (95% CI 0.8-1.9) What does duration group mean? Is this treatment duration

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

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

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.