Effect of Switching Antithrombin Agents for Primary Angioplasty in Acute Myocardial Infarction The HORIZONS-SWITCH Analysis HORIZONS AMI Dangas G, et al JACC 2011;57:2309–16

Background and Methods ● The safety and efficacy of switching anticoagulants in the early treatment of STEMI is unknown. ● In the HORIZONS-AMI randomized trial, 65.4% of patients in HORIZONS -AMI received pre-randomization heparin ● The subgroup of HORIZONS-AMI patients (n=2357) treated with heparin before randomization was analyzed according to subsequent assignment to bivalirudin (Switch group, n=1178) or to heparin plus GPI (Control group, n=1179). ● Randomization was stratified according to pre-randomization UFH administration, therefore the present analysis reflects a stand-alone randomized comparison less subject to confounding than a nonrandomized subgroup analysis Dangas G, et al JACC 2011;57:2309–16

Results Dangas G, et al JACC 2011;57:2309–16 ● Patients received heparin in a transfer facility (n=650), ambulance (n=876), the enrolling hospital (n=797), or multiple locations (n=37). ● Most patients (n=1934) received a UFH bolus only, the rest received a bolus plus infusion (n=399) or infusion only (n=22). ● The mean UFH bolus dose was 4,912 ±1,684 IU and 4,892 ± 883 IU in the switch versus control groups (p =0.72) ● Study antithrombin was given in the cath lab to 85% of patients, and in the ED to15% of patients ● The duration from pre-randomization UFH bolus to study drug initiation was 64 ± 61 min vs 59 ± 55 min in the switch vs control groups (p=0.05). ● The mean baseline activated clotting time (ACT) levels were 205 ± 95 s vs 183 ± 85 s in the switch versus control groups (p<0.001).

P= P=0.007 P= day event rates (%) P=0.18 Dangas G, et al JACC 2011;57:2309–16 HORIZONS-AMI Switch 30-day Outcomes MACE= Major Adverse Cardiovascular Events (death, reinfarction, target vessel revascularization for ischemia, or stroke), NACE= Net Adverse Clinical Events (MACE plus non-CABG major bleeding)

P=0.01 P=0.007 P= year event rates (%) P=0.06 Dangas G, et al JACC 2011;57:2309–16 HORIZONS-AMI Switch 2-Year Outcomes MACE= Major Adverse Cardiovascular Events (death, reinfarction, target vessel revascularization for ischemia, or stroke), NACE= Net Adverse Clinical Events (MACE plus non-CABG major bleeding)

P=0.001 P=0.002 P= day event rates (%) P=0.48 Dangas G, et al JACC 2011;57:2309–16 HORIZONS-AMI Switch 30-day Outcomes (Target Vessel Revascularization)

P=0.001 P=0.002 P= year event rates (%) P=0.48 Dangas G, et al JACC 2011;57:2309–16 HORIZONS-AMI Switch 2-Year Outcomes (Target Vessel Revascularization)

HORIZONS-AMI Switch 2-Year Net Adverse Clinical Events (%) Time (months) Switch to Bivalirudin alone (n=1178) Control Heparin plus GP IIb/IIIa (n=1179) 25.3% 21.4% 30-day HR [95%CI] = 0.63 [0.49, 0.80] p < year HR [95%CI] = 0.81 [0.68, 0.96] p=0.01 Dangas G, et al JACC 2011;57:2309–16 Net adverse clinical events = Death/MI/target vessel revascularization, stroke. non-CABG major bleeding.

HORIZONS-AMI Switch 2-Year Cardiac Mortality (%) Time (months) 3.8% 2.3% 30-day HR [95%CI] = 0.56 [0.32, 0.98] p= year HR [95%CI] = 0.61 [0.38, 0.99] p=0.04 Dangas G, et al JACC 2011;57:2309–16 Switch to Bivalirudin alone (n=1178) Control Heparin plus GP IIb/IIIa (n=1179)

HORIZONS-AMI Switch 2-Year Major Bleeding (%) Time (months) 13.0% 8.4% 30-day HR [95%CI] = 0.60 [0.46, 0.79] p < year HR [95%CI] = 0.63 [0.49, 0.81] p < Dangas G, et al JACC 2011;57:2309–16 Switch to Bivalirudin alone (n=1178) Control Heparin plus GP IIb/IIIa (n=1179)

HORIZONS-AMI Switch 2-Year Stent Thrombosis (%) Time (months) 4.3% 3.1% 30-day HR [95%CI] = 1.17 [0.68, 2.02] p= year HR [95%CI] = 0.73 [0.46, 1.15] p=0.17 Dangas G, et al JACC 2011;57:2309–16 Switch to Bivalirudin alone (n=1178) Control Heparin plus GP IIb/IIIa (n=1179)

HORIZONS-AMI Switch Group NACEMACEMajor Bleeding (non-CABG-related) p=0.59 p=0.78 p=0.65 Dangas G, et al JACC 2011;57:2309–16 Baseline ACT <200 s (n=637) median 158 s Baseline ACT ≥200 s (n=362) median 257 s ACT= Activated Clotting Time; MACE= Major Adverse Cardiovascular Events (death, reinfarction, target vessel revascularization for ischemia, or stroke), NACE= Net Adverse Clinical Events (MACE plus non-CABG major bleeding) ●30-day outcomes by ACT at the start of PCI before bivalirudin administration

HORIZONS-AMI Switch Group Mortality, All Cause ReinfarctionStent Thrombosis p=0.35 p=0.60 p=0.39 Dangas G, et al JACC 2011;57:2309–16 ●30-day outcomes by ACT at the start of PCI before bivalirudin administration Baseline ACT <200 s (n=637) median 158 s Baseline ACT ≥200 s (n=362) median 257 s ACT= Activated Clotting Time

HORIZONS-AMI Switch Group NACEMACEMajor Bleeding (non-CABG-related) p=0.36 p=0.76 p=0.32 Baseline ACT <200 s (n=637) median 158 s Baseline ACT ≥200 s (n=362) median 257 s Dangas G, et al JACC 2011;57:2309–16 ACT= Activated Clotting Time; MACE= Major Adverse Cardiovascular Events (death, reinfarction, target vessel revascularization for ischemia, or stroke), NACE= Net Adverse Clinical Events (MACE plus non-CABG major bleeding) ●2-year outcomes by ACT at the start of PCI before bivalirudin administration

HORIZONS-AMI Switch Group p=0.80 p=0.72 p=0.79 Mortality, All Cause ReinfarctionStent Thrombosis Dangas G, et al JACC 2011;57:2309–16 Baseline ACT <200 s (n=637) median 158 s Baseline ACT ≥200 s (n=362) median 257 s ACT= Activated Clotting Time ●2-year outcomes by ACT at the start of PCI before bivalirudin administration

Limitations ● Despite the randomized treatment assignment, this substudy of the HORIZONS-AMI trial should be considered exploratory and hypothesis-generating due to limited statistical power. ● A switch strategy from UFH to bivalirudin vs continuing UFH without a GPI was not tested. ● However, previous studies showed that adding a GPI to UFH reduces mortality and reinfarction after primary PCI, and thus before the HORIZONS-AMI trial, 90% of patients with STEMI undergoing primary PCI were treated with UFH plus GPI.

Conclusions ● STEMI patients who receive early treatment with UFH may be safely switched to bivalirudin, a strategy that results in reduced hemorrhagic complications and cardiac mortality and enhanced event-free survival compared with UFH continuation and initiation of a GPI Dangas G, et al JACC 2011;57:2309–16