A Prospective, Randomized A Prospective, Randomized Comparison of Bivalirudin vs. Comparison of Bivalirudin vs. Heparin Plus Glycoprotein IIb/IIIa Heparin Plus Glycoprotein IIb/IIIa Inhibitors During Primary Inhibitors During Primary Angioplasty in Acute Myocardial Angioplasty in Acute Myocardial Infarction Infarction – – One Year Results – One Year Results – Roxana Mehran MD Roxana Mehran MD For the HORIZONS-AMI Investigators For the HORIZONS-AMI Investigators
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A Prospective, Randomized Comparison of Bivalirudin vs. Heparin Plus Glycoprotein IIb/IIIa Inhibitors During Primary Angioplasty in Acute Myocardial Infarction.
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A Prospective, Randomized Comparison of A Prospective, Randomized Comparison of Bivalirudin vs. Heparin Plus Glycoprotein Bivalirudin vs. Heparin Plus Glycoprotein
IIb/IIIa Inhibitors During Primary IIb/IIIa Inhibitors During Primary Angioplasty in Acute Myocardial InfarctionAngioplasty in Acute Myocardial Infarction
– – One Year Results –One Year Results –
Roxana Mehran MDRoxana Mehran MDFor the HORIZONS-AMI InvestigatorsFor the HORIZONS-AMI Investigators
A Prospective, Randomized Comparison of A Prospective, Randomized Comparison of Bivalirudin vs. Heparin Plus Glycoprotein Bivalirudin vs. Heparin Plus Glycoprotein
IIb/IIIa Inhibitors During Primary IIb/IIIa Inhibitors During Primary Angioplasty in Acute Myocardial InfarctionAngioplasty in Acute Myocardial Infarction
– – One Year Results –One Year Results –
Roxana Mehran MDRoxana Mehran MDFor the HORIZONS-AMI InvestigatorsFor the HORIZONS-AMI Investigators
Background Numerous studies have demonstrated a strong Numerous studies have demonstrated a strong
association between hemorrhagic complications and association between hemorrhagic complications and subsequent mortality in pts with ACS and after PCIsubsequent mortality in pts with ACS and after PCI
In the HORIZONS-AMI trial, In the HORIZONS-AMI trial, among high risk pts among high risk pts with STEMI undergoing primary PCI, randomization with STEMI undergoing primary PCI, randomization to bivalirudin monotherapy compared to UFH + GPI to bivalirudin monotherapy compared to UFH + GPI resulted in reduced rates of bleeding, thrombo-resulted in reduced rates of bleeding, thrombo-cytopenia, and blood transfusions; non significantly cytopenia, and blood transfusions; non significantly different rates of reinfarction, stent thrombosis and different rates of reinfarction, stent thrombosis and TVR; and improved survival at 30 daysTVR; and improved survival at 30 days
Whether these benefits are maintained at 1-year is Whether these benefits are maintained at 1-year is unknownunknown
HHarmonizing armonizing OOutcomes with utcomes with RRevascularevascularizizatiationon and and SStents in tents in AMIAMI
3602 pts with STEMI with symptom onset ≤12 hours3602 pts with STEMI with symptom onset ≤12 hours
UFH + GP IIb/IIIa inhibitorUFH + GP IIb/IIIa inhibitor(abciximab or eptifibatide)(abciximab or eptifibatide)
Bivalirudin monotherapyBivalirudin monotherapy(± provisional GP IIb/IIIa)(± provisional GP IIb/IIIa)
Aspirin, thienopyridineAspirin, thienopyridine R 1:1
Emergent angiography, followed by triage to primary PCI, CABG or medical therapyEmergent angiography, followed by triage to primary PCI, CABG or medical therapy
3006 pts eligible for stent randomization3006 pts eligible for stent randomization
R 3:1
Bare metal EXPRESS stentBare metal EXPRESS stentPaclitaxel-eluting TAXUS stentPaclitaxel-eluting TAXUS stent
Clinical FU at 30 days, 6 months,1 year, and then yearly through 5 years
Clinical FU at 30 days, 6 months,1 year, and then yearly through 5 years
HHarmonizing armonizing OOutcomes with utcomes with RRevascularevascularizizatiationon and and SStents in tents in AMIAMI
3602 pts with STEMI with symptom onset ≤12 hours3602 pts with STEMI with symptom onset ≤12 hours
UFH + GP IIb/IIIa inhibitorUFH + GP IIb/IIIa inhibitor(abciximab or eptifibatide)(abciximab or eptifibatide)
Bivalirudin monotherapyBivalirudin monotherapy(± provisional GP IIb/IIIa)(± provisional GP IIb/IIIa)
Aspirin, thienopyridineAspirin, thienopyridine R 1:1
Pharmacology ArmPharmacology ArmPrimary and Secondary EndpointsPrimary and Secondary Endpoints
1-Year1-YearIntention to Treat PopulationIntention to Treat Population
Outcomes in the 4 randomized groupsOutcomes in the 4 randomized groups
Study Medications (i)Study Medications (i) Unfractionated heparinUnfractionated heparin– 60 U/kg IV*; subsequent boluses titrated by nomogram to 60 U/kg IV*; subsequent boluses titrated by nomogram to
ACT 200-250 secs; terminated at procedure end unless ACT 200-250 secs; terminated at procedure end unless prolonged antithrombin neededprolonged antithrombin needed
BivalirudinBivalirudin– Bolus 0.75 mg/kg IV**, infusion 1.75 mg/kg/h, not titrated to Bolus 0.75 mg/kg IV**, infusion 1.75 mg/kg/h, not titrated to
ACT; terminated at procedure end unless prolonged ACT; terminated at procedure end unless prolonged antithrombin needed (0.25 mg/kg/hr infusion)antithrombin needed (0.25 mg/kg/hr infusion)
Glycoprotein IIb/IIIa inhibitorsGlycoprotein IIb/IIIa inhibitors– Routine use in UFH arm; recommended only for giant Routine use in UFH arm; recommended only for giant
thrombus or refractory no reflow in bivalirudin armthrombus or refractory no reflow in bivalirudin arm
– Abciximab or double bolus eptifibatide as per investigator Abciximab or double bolus eptifibatide as per investigator discretion – dosing per FDA label, renal adjusted; continued discretion – dosing per FDA label, renal adjusted; continued for 12for 12 (abcx) or 12-18 (abcx) or 12-18 (eptif) (eptif)
* If pre randomization UFH administered, ACT is checked first* If pre randomization UFH administered, ACT is checked first** If pre randomization UFH administered, started 30’ after last bolus** If pre randomization UFH administered, started 30’ after last bolus
GP IIb/IIIa in CCLGP IIb/IIIa in CCL 94.5%*94.5%* 7.2%*7.2%*
- Bail-out per protocol**- Bail-out per protocol** -- 4.4%4.4%
- Abciximab- Abciximab 49.9%49.9% 4.0%4.0%
- Eptifibatide- Eptifibatide 44.4%44.4% 3.1%3.1%
- Tirofiban- Tirofiban 0.2%0.2% 0.1%0.1%
*97.7% and 7.5% during PCI. ** For giant thrombus or refractory *97.7% and 7.5% during PCI. ** For giant thrombus or refractory no reflow after PCI. CCL = cardiac catheterization laboratoryno reflow after PCI. CCL = cardiac catheterization laboratory
*All Kaplan-Meier estimates except ≤24 hours; all CEC adjudicated*All Kaplan-Meier estimates except ≤24 hours; all CEC adjudicated
HHarmonizing armonizing OOutcomes with utcomes with RRevascularevascularizizatiationon and and SStents in tents in AMIAMI
R 1:1
3602 pts with STEMI3602 pts with STEMI
Stent rand.eligible
UFH + GP IIb/IIIaN=1802
N=1479
TAXUSN=1111
EXPRESSN=368
BivalirudinN=1800
N=1527
TAXUSN=1146
EXPRESSN=381
R 3:1
R 3:1Stratified by 1st rand.
Interaction Between Drug and Stent RandomizationInteraction Between Drug and Stent Randomization30 Day Pharmacology Endpoints (N=3006)30 Day Pharmacology Endpoints (N=3006)
*MACE or major bleeding; **Protocol defined (non *MACE or major bleeding; **Protocol defined (non CABG); ***Death, reinfarction, stroke or ischemic TVRCABG); ***Death, reinfarction, stroke or ischemic TVR
Interaction Between Drug and Stent RandomizationInteraction Between Drug and Stent Randomization1-Year Stent Endpoints (N=3006)1-Year Stent Endpoints (N=3006)
*Death, reinfarction, stroke or stent thrombosis*Death, reinfarction, stroke or stent thrombosis**1081 lesions in the TAXUS group, 332 in the EXPRESS group**1081 lesions in the TAXUS group, 332 in the EXPRESS group
LimitationsLimitations Open label designOpen label design
– Potential bias was mitigated by high Potential bias was mitigated by high protocol procedure compliance and use protocol procedure compliance and use of blinded clinical event adjudication of blinded clinical event adjudication committees and core laboratoriescommittees and core laboratories
Underpowered for low frequency safety Underpowered for low frequency safety endpoints and subgroup interactionsendpoints and subgroup interactions
– All such observations should be All such observations should be considered hypothesis-generatingconsidered hypothesis-generating
ConclusionsConclusions In this large scale, prospective, randomized In this large scale, prospective, randomized
trial of pts with STEMI undergoing a primary trial of pts with STEMI undergoing a primary PCI management strategy, bivalirudin PCI management strategy, bivalirudin monotherapy compared to UFH plus the monotherapy compared to UFH plus the routine use of GP IIb/IIIa inhibitors resulted in:routine use of GP IIb/IIIa inhibitors resulted in:
– A significant 16% reduction in the 1-year rate A significant 16% reduction in the 1-year rate of composite net adverse clinical events of composite net adverse clinical events
– A significant 39% reduction in the 1-year rate A significant 39% reduction in the 1-year rate of major bleeding of major bleeding
ConclusionsConclusions In this large scale, prospective, randomized trial In this large scale, prospective, randomized trial
of pts with STEMI undergoing a primary PCI of pts with STEMI undergoing a primary PCI management strategy, bivalirudin monotherapy management strategy, bivalirudin monotherapy compared to UFH plus the routine use of GP compared to UFH plus the routine use of GP IIb/IIIa inhibitors resulted in:IIb/IIIa inhibitors resulted in:
– Significant 31% and 43% reductions in the Significant 31% and 43% reductions in the
1-year rates of all-cause and cardiac mortality 1-year rates of all-cause and cardiac mortality
(absolute 1.4% and 1.7% reductions), (absolute 1.4% and 1.7% reductions), with non with non
significantly different rates of reinfarction, stent significantly different rates of reinfarction, stent
thrombosis, stroke and TVR at 1-year thrombosis, stroke and TVR at 1-year
Clinical ImplicationsClinical Implications HORIZONS has demonstrated that the HORIZONS has demonstrated that the
prevention of hemorrhagic complications prevention of hemorrhagic complications
after primary PCI in STEMI results in after primary PCI in STEMI results in
improved early and late survival improved early and late survival
– Optimal drug selection and technique to Optimal drug selection and technique to
minimize bleeding are essential to minimize bleeding are essential to
enhance outcomes for pts undergoing enhance outcomes for pts undergoing