according to the current guidelines of the european society of cardiology ( esc ) for patients with acute myocardial infarction with persistent st - segment elevation , intravenous anticoagulation is recommended in all patients undergoing primary percutaneous coronary intervention ( pci ) .
unfractionated heparin ( ufh ) has traditionally been used in the catheterization laboratory as the anticoagulant of choice during primary pci to prevent thrombosis and ischaemic events .
however , ufh has several pharmacological limitations including a high intra- and inter - individual variability .
bivalirudin is a thrombin - specific anticoagulant , which has the ability to inactivate both free and fibrin - bound thrombin . in several randomized clinical trials ,
bivalirudin has demonstrated efficacy and safety in patients undergoing pci . in the horizons trial ,
bivalirudin reduced the primary combined endpoint including death , myocardial infarction and bleeding complications compared to heparin plus routine glycoprotein iib / iiia inhibitors ( gpi ) in patients undergoing primary pci .
moreover , cardiovascular mortality was reduced after 30 days and at 3-year follow - up .
however , the use of gpi is not always routine in clinical practice anymore and might have contributed to the increase in bleeding complications seen in the control arm . in the euromax trial ,
the use of gpi was not mandated , but was left to the standard practice of participating centres .
the euromax study design has been previously described in detail . in brief , the study enrolled patients 18 years of age or older , presenting within 12 h after the onset of symptoms with a presumed diagnosis of st - segment elevation myocardial infarction ( stemi ) .
all patients had to be scheduled for angiography with the intention of performing primary pci within 2 h after the first medical contact .
patients were identified , initial consent was obtained , randomization was performed , and study drug administration was initiated in the ambulance or in a non - pci hospital .
patients were transported urgently to the primary pci hospital , where treatment was continued and outcomes data collected .
all patients provided written , informed consent and the study was approved by local ethics committees and health authorities .
bivalirudin was to be administered as a bolus of 0.75 mg / kg , followed by an infusion of 1.75 mg / kg / h .
the protocol specified that the infusion should be continued for at least 4 h after pci at a dose of be 0.25 mg / kg / h ; however , continuation of the full dose ( 1.75 mg / kg / h ) used during pci was also permitted .
both the decision for the use and the selection of gpi agent were left up to the investigator 's discretion and preference .
the use of gpi was classified as routine when treatment commenced before or during angiography but not after the start of pci .
bailout use of gpi was permitted after the commencement of pci in both bivalirudin- and heparin - treated patients , but was limited according to the protocol only for the presence of giant thrombus or no - reflow during or after the index procedure .
patients who were assigned to the heparins group ( control group ) were to receive either ufh or low - molecular - weight heparin ( lmwh ) .
unfractionated heparin was to be administered at a dose of 100 iu / kg without a gpi or 60 iu / kg with a gpi ; lmwh was to be given as a bolus of 0.5 mg / kg .
all patients received aspirin and an approved p2y12 inhibitor as early as possible after the first medical contact
. decisions regarding access site , performance of thrombus aspiration , and stent type were left to physician preference .
the primary outcome was the composite of death from any cause or protocol major bleeding not related to coronary - artery bypass grafting ( cabg ) at 30 days .
the principal secondary 30-day outcome was a composite of death from any cause , myocardial re - infarction , or non - cabg major bleeding .
pre - specified secondary endpoints included major adverse cardiovascular events [ mace ; death , reinfarction , ischaemia - driven revascularization ( idr ) , or stroke ] , net adverse clinical events ( nace ; composite of major adverse cardiovascular events and non - cabg major bleeding ) , each of the components of the primary and principal secondary outcomes , idr , and stent thrombosis ( as defined by the academic research consortium ) .
protocol - defined major bleeding was characterized as bleeding unrelated to cabg surgery that included intracranial , retroperitoneal , or intraocular bleeding ; access - site haemorrhage requiring radiological or surgical intervention ; a reduction in the haemoglobin level of more than 4 g / dl ( 2.5 mmol / l ) without an overt source of bleeding ; a reduction in the haemoglobin level of > 3 g / dl ( 1.8 mmol / l ) with an overt source of bleeding ; reintervention for bleeding ; or use of any blood - product transfusion .
note that access - site haematomas which did not require surgical or radiological intervention were not counted as major bleeds regardless of their size .
all cases of deaths , bleeding events , reinfarction , idr , stent thrombosis , and stroke were adjudicated by a blinded , independent clinical - events committee . in the present pre - specified analysis
, we compared outcomes among patients with routine bivalirudin treatment to patients in the control arm according to gpi use ( heparin plus routine gpi vs. heparin without routine gpi ) . in patients randomized to the control arm ,
routine ( treatment of patients before or during angiography but not once pci has commenced ) or 
analyses were performed in the intention - to - treat ( itt ) population , which was defined as all patients who underwent randomization and provided written informed consent . the chi - square test was used for comparisons of event rates or , in the case of sparse data , fisher 's exact test was used .
log - rank test was used to compute the significance of time - to - event data .
continuous variables are reported as medians and interquartile ranges . a p - value of < 0.05 was considered significant .
categorical variables are reported as frequencies and percentages . to account for differences in baseline characteristics in this post - randomization subgroup analysis ,
variables in the logistic regression model included : age over 65 years , female sex , anaemia , hypertension , hyperlipidaemia , diabetes , smoking , creatinine clearance 60 ml / min , choice of p2y12 inhibitor , prior myocardial infarction , prior cabg , prior pci , killip class ii , access - site ( femoral vs. radial ) , pre - pci timi flow 0/1 , single - vessel disease , placement of a drug - eluting stent , and treatment with bivalirudin vs. heparins with routine gpi vs. heparins with bailout gpi only .
the euromax study design has been previously described in detail . in brief , the study enrolled patients 18 years of age or older , presenting within 12 h after the onset of symptoms with a presumed diagnosis of st - segment elevation myocardial infarction ( stemi ) .
all patients had to be scheduled for angiography with the intention of performing primary pci within 2 h after the first medical contact .
patients were identified , initial consent was obtained , randomization was performed , and study drug administration was initiated in the ambulance or in a non - pci hospital .
patients were transported urgently to the primary pci hospital , where treatment was continued and outcomes data collected .
all patients provided written , informed consent and the study was approved by local ethics committees and health authorities .
bivalirudin was to be administered as a bolus of 0.75 mg / kg , followed by an infusion of 1.75 mg / kg / h .
the protocol specified that the infusion should be continued for at least 4 h after pci at a dose of be 0.25 mg / kg / h ; however , continuation of the full dose ( 1.75 mg / kg / h ) used during pci was also permitted .
both the decision for the use and the selection of gpi agent were left up to the investigator 's discretion and preference .
the use of gpi was classified as routine when treatment commenced before or during angiography but not after the start of pci .
bailout use of gpi was permitted after the commencement of pci in both bivalirudin- and heparin - treated patients , but was limited according to the protocol only for the presence of giant thrombus or no - reflow during or after the index procedure .
patients who were assigned to the heparins group ( control group ) were to receive either ufh or low - molecular - weight heparin ( lmwh ) .
unfractionated heparin was to be administered at a dose of 100 iu / kg without a gpi or 60 iu / kg with a gpi ; lmwh was to be given as a bolus of 0.5 mg / kg .
all patients received aspirin and an approved p2y12 inhibitor as early as possible after the first medical contact
. decisions regarding access site , performance of thrombus aspiration , and stent type were left to physician preference .
the primary outcome was the composite of death from any cause or protocol major bleeding not related to coronary - artery bypass grafting ( cabg ) at 30 days .
the principal secondary 30-day outcome was a composite of death from any cause , myocardial re - infarction , or non - cabg major bleeding .
pre - specified secondary endpoints included major adverse cardiovascular events [ mace ; death , reinfarction , ischaemia - driven revascularization ( idr ) , or stroke ] , net adverse clinical events ( nace ; composite of major adverse cardiovascular events and non - cabg major bleeding ) , each of the components of the primary and principal secondary outcomes , idr , and stent thrombosis ( as defined by the academic research consortium ) .
protocol - defined major bleeding was characterized as bleeding unrelated to cabg surgery that included intracranial , retroperitoneal , or intraocular bleeding ; access - site haemorrhage requiring radiological or surgical intervention ; a reduction in the haemoglobin level of more than 4 g / dl ( 2.5 mmol / l ) without an overt source of bleeding ; a reduction in the haemoglobin level of > 3 g / dl ( 1.8 mmol / l ) with an overt source of bleeding ; reintervention for bleeding ; or use of any blood - product transfusion .
note that access - site haematomas which did not require surgical or radiological intervention were not counted as major bleeds regardless of their size .
all cases of deaths , bleeding events , reinfarction , idr , stent thrombosis , and stroke were adjudicated by a blinded , independent clinical - events committee . in the present pre - specified analysis
, we compared outcomes among patients with routine bivalirudin treatment to patients in the control arm according to gpi use ( heparin plus routine gpi vs. heparin without routine gpi ) . in patients randomized to the control arm ,
routine ( treatment of patients before or during angiography but not once pci has commenced ) or 
analyses were performed in the intention - to - treat ( itt ) population , which was defined as all patients who underwent randomization and provided written informed consent . the chi - square test was used for comparisons of event rates or , in the case of sparse data , fisher 's exact test was used .
log - rank test was used to compute the significance of time - to - event data .
categorical variables are reported as frequencies and percentages . to account for differences in baseline characteristics in this post - randomization subgroup analysis ,
variables in the logistic regression model included : age over 65 years , female sex , anaemia , hypertension , hyperlipidaemia , diabetes , smoking , creatinine clearance 60 ml / min , choice of p2y12 inhibitor , prior myocardial infarction , prior cabg , prior pci , killip class ii , access - site ( femoral vs. radial ) , pre - pci timi flow 0/1 , single - vessel disease , placement of a drug - eluting stent , and treatment with bivalirudin vs. heparins with routine gpi vs. heparins with bailout gpi only .
a total of 2198 patients ( 1089 in the bivalirudin group and 1109 in the control group ) provided formal informed consent and comprised the itt population .
a breakdown of gpi use by treatment arm is presented in figure  1 . in the control arm , 649 ( 58.5% )
patients received routine gpi and 460 ( 41.5% ) did not . in the routine gpi group ,
gpi treatment was initiated in the ambulance in 68% and during coronary angiography in 32% of patients .
of the 460 patients who did not receive routine use of a gpi , 117 ( 25.4% ) patients received it as bailout during pci and most frequently due to the presence of giant thrombus . in the bivalirudin group , 1047 ( 96% )
patients did not receive a routine gpi , while 42 ( 3.9% ) patients did , despite the fact that this was a deviation from the protocol . of
the 1047 patients who did not receive routine gpi , 83 ( 7.9% ) received it as bailout also more commonly due to the presence of giant thrombus . 

gpi , glycoprotein iib / iiia inhibitor ; itt , intent - to - treat ; lmwh , low - molecular - weight heparin ; ufh , unfractionated heparin .
gpi , glycoprotein iib / iiia inhibitor ; itt , intent - to - treat ; lmwh , low - molecular - weight heparin ; ufh , unfractionated heparin .
the baseline characteristics of patients in the three groups were generally well matched between the groups , although there was a higher rate of hypertension and lower rates of killip class ii 
iv and creatinine clearance 60 ml / min in the heparins with routine gpi use treatment group compared with the heparins with bailout gpi use group ( table  1 ) . 

heparins + routine gpi(n = 649)n / n ( % ) heparins + bailout gpi(n = 460)n / n ( % ) bailout gpi83/1046 ( 7.9)n / a117/460 ( 25.4)age , median ( iqr ) , years61 ( 52 , 71)61 ( 52 , 71)62 ( 53 , 73)age > 65 years394 ( 36.2)245 ( 37.8)189 ( 41.1)female275 ( 25.3)144 ( 22.2)104 ( 22.6)diabetes127 ( 11.7)89/648 ( 13.7)80 ( 17.4)current smoker ( within past 30 days)453 ( 41.6)271/648 ( 41.8)201 ( 43.7)hypertension459 ( 42.2)261/648 ( 40.3)243 ( 52.8)previous myocardial infarction80 ( 7.4)65/648 ( 10.0)48 ( 10.4)previous ptca / pci97 ( 8.9)57/648 ( 8.8)51 ( 11.1)previous cabg18 ( 1.7)14/648 ( 2.2)15 ( 3.3)hyperlipidaemia398 ( 36.6)222/648 ( 34.3)195 ( 42.4)killip class ii  iv77/996 ( 7.7)27/568 ( 4.8)42/432 ( 9.7)creatinine clearance 60 ml / min147/1001 ( 14.7)81/617 ( 13.1)84/381 ( 22.0)creatinine clearance > 60 ml / min854/1001 ( 85.3)536/617 ( 86.9)297/381 ( 78.0)anaemia129/987 ( 13.1)86/606 ( 14.2)62/383 ( 16.2)cabg , coronary artery bypass graft surgery ; gpi , glycoprotein iib / iiia inhibitor ; iqr , interquartile range ; n / a , not applicable ; pci , percutaneous coronary intervention ; ptca , percutaneous transluminal coronary angioplasty.data are provided for patients who were eligible for bailout use of a gpi ( i.e. those who did not receive the drug routinely).known hyperlipidaemia or on lipid - lowering drugs.p < 0.05 .
baseline characteristics cabg , coronary artery bypass graft surgery ; gpi , glycoprotein iib / iiia inhibitor ; iqr , interquartile range ; n / a , not applicable ; pci , percutaneous coronary intervention ; ptca , percutaneous transluminal coronary angioplasty .
data are provided for patients who were eligible for bailout use of a gpi ( i.e. those who did not receive the drug routinely ) . known hyperlipidaemia or on lipid - lowering drugs .
enoxaparin was used in 51/649 ( 8% ) and 43/460 ( 9% ) of patients treated with routine or with bailout gpi , respectively .
a similar percentage of patients in each group received a loading dose of a p2y12 inhibitor , with clopidogrel as the most frequently given agent .
a significantly higher percentage of patients in the heparins plus bailout gpi group received prasugrel compared with the heparins plus routine gpi group .
conversely , ticagrelor was more commonly given to patients in the heparins plus routine gpi compared with heparins with bailout gpi group . 

table  2treatment and procedural characteristicsvariablebivalirudin(n=1089)n / n ( % ) heparins + routine gpi(n = 649)n / n ( % ) heparins + bailout gpi(n = 460)n / n ( % ) p2y12 loading dose1048/1066 ( 98.3)629/643 ( 97.8)429/440 ( 97.5 )  clopidogrel524/1048 ( 50.0)329/627 ( 52.5)216/429 ( 50.3 )  prasugrel*323/1048 ( 30.8)119/627 ( 19.0)187/429 ( 43.6 )  ticagrelor*201/1048 ( 19.2)179/627 ( 28.5)26/429 ( 6.1)p2y12 maintenance dose958/1065 ( 90.0)585/643 ( 91.0)384/439 ( 87.5 )  clopidogrel377/955(39.5)220/583 ( 37.7)187/381 ( 49.1 )  prasugrel*321/955 ( 33.6)135/583 ( 23.2)163/381 ( 42.8 )  ticagrelor*257/955(26.9)228/583 ( 39.1)31/381 ( 8.1)catheter access site  femoral*558/1069 ( 52.2)374/631 ( 59.3)208/453 ( 45.9 )  radial510/1069 ( 47.7)257/631 ( 40.7)245/453 ( 54.1)single - vessel disease*591/1069 ( 55.3)348/631 ( 55.2)208/453 ( 45.9)pre - pci timi flow  0 to 1 * 593/931 ( 63.7)319/563 ( 56.7)244/369 ( 66.1 )  2143/931 ( 15.4)112/563 ( 19.9)46/369 ( 12.5 )  3195/931 ( 20.9)132/563 ( 23.4)79/369 ( 21.4)post - pci timi flow  0 to 118/930 ( 1.9)7/563 ( 1.2)9/369 ( 2.4 )  229/930 ( 3.1)22/563 ( 3.9)9/369 ( 2.4 ) 
3883/930 ( 94.9)534/563 ( 94.8)351/369 ( 95.1)drug - eluting stent*538/943 ( 57.1)364/573 ( 63.5)165/373 ( 44.2)thrombectomy304/943 ( 32.2)192/573 ( 33.5)106/373 ( 28.4)balloon angioplasty only48/943 ( 5.1)29/573 ( 5.1)13/373 ( 3.5)gpi , glycoprotein iib / iiia inhibitor ; pci , percutaneous coronary intervention ; timi , thrombolysis in myocardial infarction.*p < 0.05 .
treatment and procedural characteristics gpi , glycoprotein iib / iiia inhibitor ; pci , percutaneous coronary intervention ; timi , thrombolysis in myocardial infarction .
femoral artery access , drug - eluting stent use , and the presence of single - vessel disease were all more common in the heparins plus routine gpi group , while pre - pci timi flow of 0 or 1 was more frequent among the heparins with bailout gpi patients . comparisons of unadjusted event rates between the three treatment groups are shown in table  3 . among patients treated with heparins
, there were no significant differences observed in the rates of either the primary or key secondary outcomes according to the use of gpi .
the composite of ischaemic events ( mace ) , however , was significantly lower in patients treated with heparins plus routine gpi compared with patients treated with heparin and bailout gpi ( 4.3 vs. 7.2% , p = 0.04 ) . in the comparison between bivalirudin and either of the heparins arms the results were consistent with the overall results of the main trial .
specifically , bivalirudin resulted in significantly lower rates of the primary outcome and protocol major bleeding ( table  3 , figure  2 ) , as well as a higher rate of stent thrombosis . after adjustment ,
the benefit of bivalirudin over heparins with bailout gpi for the primary outcome , major bleeding , and nace was maintained ( figures  3 and 4 ) . 

table  3primary and secondary outcomes by treatment groupparameterbivalirudin(n = 1089)n ( % ) heparins + routine gpi(n = 649)n ( % ) relative risk(95% ci)p - valueheparins + bailout gpi(n = 460)n ( % ) relative risk(95% ci)p - valuerelative risk(95% ci)p - valueprimary endpoint : death or major bleeding55 ( 5.1)49 ( 7.6)0.67 ( 0.46 , 0.97)0.0345 ( 9.8)0.52 ( 0.35 , 0.75)0.00061.30 ( 0.88 , 1.91)0.19key secondary endpoint : death , mi , or major bleeding72 ( 6.6)54 ( 8.3)0.79 ( 0.57 , 1.12)0.1848 ( 10.4)0.63 ( 0.45 , 0.90)0.011.25 ( 0.87 , 1.82)0.23death32 ( 2.9)15 ( 2.3)1.27 ( 0.69 , 2.33)0.4419 ( 4.1)0.71 ( 0.41 , 1.24)0.231.79 ( 0.92 , 3.48)0.09cardiac cause27 ( 2.5)15 ( 2.3)1.07 ( 0.58 , 2.00)0.8318 ( 3.9)0.63 ( 0.35 , 1.14)0.131.69 ( 0.86 , 3.32)0.13protocol major bleeding28 ( 2.6)38 ( 5.9)0.44 ( 0.27 , 0.71)0.000729 ( 6.3)0.41 ( 0.25 , 0.68)0.00051.08 ( 0.67 , 1.72)0.76death , mi , idr , or stroke ( mace)65 ( 6.0)28 ( 4.3)1.38 ( 0.90 , 2.13)0.1433 ( 7.2)0.83 ( 0.56 , 1.25)0.371.66 ( 1.02 , 2.71)0.04death , mi , idr , stroke , or major bleeding ( nace)85 ( 7.8)62 ( 9.6)0.82 ( 0.60 , 1.12)0.2156 ( 12.2)0.64 ( 0.47 , 0.88)0.0061.27 ( 0.91 , 1.79)0.16myocardial infarction ( mi)19 ( 1.7)5 ( 0.8)2.26 ( 0.85 , 6.04)0.105 ( 1.1)0.61 ( 0.60 , 4.27)0.341.41 ( 0.41 , 4.85)0.58stent thrombosis17 ( 1.6)4 ( 0.6)2.53 ( 0.86 , 7.49)0.092 ( 0.4)3.59 ( 0.83 , 15.48)0.090.71 ( 0.13 , 3.84)0.69cabg , coronary artery bypass graft ; ci , confidence interval ; gpi , glycoprotein iib / iiia inhibitor ; idr , ischaemia - driven revascularization ; mace , major adverse cardiovascular events ; n / a , not applicable ; nace , net adverse clinical events.relative risk ( 95% ci ) and p - value comparing bivalirudin with heparins + routine gpi.relative risk ( 95% ci ) and p - value comparing bivalirudin with heparins + bailout gpi.relative risk ( 95% ci ) and p - value comparing heparins + bailout gpi with heparins + routine gpi . 
 figure  2kaplan  meier curves of the primary composite endpoint .
arc , academic research consortium ; gpi , glycoprotein iib / iiia inhibitor ; idr , ischaemia - driven revascularization ; mace , major adverse cardiac events ; mi , myocardial infarction ; nace , net adverse clinical events . 

gpi , glycoprotein iib / iiia inhibitor ; idr , ischaemia - driven revascularization ; mace , major adverse cardiac events ; mi , myocardial infarction ; nace , net adverse clinical events .
primary and secondary outcomes by treatment group cabg , coronary artery bypass graft ; ci , confidence interval ; gpi , glycoprotein iib / iiia inhibitor ; idr , ischaemia - driven revascularization ; mace , major adverse cardiovascular events ; n / a , not applicable ; nace , net adverse clinical events . relative risk ( 95% ci ) and p - value comparing bivalirudin with heparins + routine gpi .
relative risk ( 95% ci ) and p - value comparing bivalirudin with heparins + bailout gpi .
relative risk ( 95% ci ) and p - value comparing heparins + bailout gpi with heparins + routine gpi .
arc , academic research consortium ; gpi , glycoprotein iib / iiia inhibitor ; idr , ischaemia - driven revascularization ; mace , major adverse cardiac events ; mi , myocardial infarction ; nace , net adverse clinical events .
gpi , glycoprotein iib / iiia inhibitor ; idr , ischaemia - driven revascularization ; mace , major adverse cardiac events ; mi , myocardial infarction ; nace , net adverse clinical events .
a total of 94 patients in the control group received enoxaparin , 62 ( 66% ) of the latter were treated with routine gpi .
the rates of the primary endpoint were not different between the patients treated with enoxaparin and ufh ( 9.6 vs. 8.2% , odds ratio 1.16 , 95% ci 0.602.24 , p - value ) ( see supplementary material online , table s1 ) .
a total of 2198 patients ( 1089 in the bivalirudin group and 1109 in the control group ) provided formal informed consent and comprised the itt population .
a breakdown of gpi use by treatment arm is presented in figure  1 . in the control arm , 649 ( 58.5% )
patients received routine gpi and 460 ( 41.5% ) did not . in the routine gpi group ,
gpi treatment was initiated in the ambulance in 68% and during coronary angiography in 32% of patients .
of the 460 patients who did not receive routine use of a gpi , 117 ( 25.4% ) patients received it as bailout during pci and most frequently due to the presence of giant thrombus . in the bivalirudin group , 1047 ( 96% )
patients did not receive a routine gpi , while 42 ( 3.9% ) patients did , despite the fact that this was a deviation from the protocol . of
the 1047 patients who did not receive routine gpi , 83 ( 7.9% ) received it as bailout also more commonly due to the presence of giant thrombus . 

gpi , glycoprotein iib / iiia inhibitor ; itt , intent - to - treat ; lmwh , low - molecular - weight heparin ; ufh , unfractionated heparin .
gpi , glycoprotein iib / iiia inhibitor ; itt , intent - to - treat ; lmwh , low - molecular - weight heparin ; ufh , unfractionated heparin .
the baseline characteristics of patients in the three groups were generally well matched between the groups , although there was a higher rate of hypertension and lower rates of killip class ii 
iv and creatinine clearance 60 ml / min in the heparins with routine gpi use treatment group compared with the heparins with bailout gpi use group ( table  1 ) . 

heparins + routine gpi(n = 649)n / n ( % ) heparins + bailout gpi(n = 460)n / n ( % ) bailout gpi83/1046 ( 7.9)n / a117/460 ( 25.4)age , median ( iqr ) , years61 ( 52 , 71)61 ( 52 , 71)62 ( 53 , 73)age > 65 years394 ( 36.2)245 ( 37.8)189 ( 41.1)female275 ( 25.3)144 ( 22.2)104 ( 22.6)diabetes127 ( 11.7)89/648 ( 13.7)80 ( 17.4)current smoker ( within past 30 days)453 ( 41.6)271/648 ( 41.8)201 ( 43.7)hypertension459 ( 42.2)261/648 ( 40.3)243 ( 52.8)previous myocardial infarction80 ( 7.4)65/648 ( 10.0)48 ( 10.4)previous ptca / pci97 ( 8.9)57/648 ( 8.8)51 ( 11.1)previous cabg18 ( 1.7)14/648 ( 2.2)15 ( 3.3)hyperlipidaemia398 ( 36.6)222/648 ( 34.3)195 ( 42.4)killip class ii  iv77/996 ( 7.7)27/568 ( 4.8)42/432 ( 9.7)creatinine clearance 60 ml / min147/1001 ( 14.7)81/617 ( 13.1)84/381 ( 22.0)creatinine clearance > 60 ml / min854/1001 ( 85.3)536/617 ( 86.9)297/381 ( 78.0)anaemia129/987 ( 13.1)86/606 ( 14.2)62/383 ( 16.2)cabg , coronary artery bypass graft surgery ; gpi , glycoprotein iib / iiia inhibitor ; iqr , interquartile range ; n / a , not applicable ; pci , percutaneous coronary intervention ; ptca , percutaneous transluminal coronary angioplasty.data are provided for patients who were eligible for bailout use of a gpi ( i.e. those who did not receive the drug routinely).known hyperlipidaemia or on lipid - lowering drugs.p < 0.05 .
baseline characteristics cabg , coronary artery bypass graft surgery ; gpi , glycoprotein iib / iiia inhibitor ; iqr , interquartile range ; n / a , not applicable ; pci , percutaneous coronary intervention ; ptca , percutaneous transluminal coronary angioplasty .
data are provided for patients who were eligible for bailout use of a gpi ( i.e. those who did not receive the drug routinely ) . known hyperlipidaemia or on lipid - lowering drugs .
enoxaparin was used in 51/649 ( 8% ) and 43/460 ( 9% ) of patients treated with routine or with bailout gpi , respectively .
a similar percentage of patients in each group received a loading dose of a p2y12 inhibitor , with clopidogrel as the most frequently given agent . a significantly higher percentage of patients in the heparins plus bailout gpi group received prasugrel compared with the heparins plus routine gpi group .
conversely , ticagrelor was more commonly given to patients in the heparins plus routine gpi compared with heparins with bailout gpi group . 

table  2treatment and procedural characteristicsvariablebivalirudin(n=1089)n / n ( % ) heparins + routine gpi(n = 649)n / n ( % ) heparins + bailout gpi(n = 460)n / n ( % ) p2y12 loading dose1048/1066 ( 98.3)629/643 ( 97.8)429/440 ( 97.5 )  clopidogrel524/1048 ( 50.0)329/627 ( 52.5)216/429 ( 50.3 )  prasugrel*323/1048 ( 30.8)119/627 ( 19.0)187/429 ( 43.6 )  ticagrelor*201/1048 ( 19.2)179/627 ( 28.5)26/429 ( 6.1)p2y12 maintenance dose958/1065 ( 90.0)585/643 ( 91.0)384/439 ( 87.5 )  clopidogrel377/955(39.5)220/583 ( 37.7)187/381 ( 49.1 )  prasugrel*321/955 ( 33.6)135/583 ( 23.2)163/381 ( 42.8 )  ticagrelor*257/955(26.9)228/583 ( 39.1)31/381 ( 8.1)catheter access site  femoral*558/1069 ( 52.2)374/631 ( 59.3)208/453 ( 45.9 )  radial510/1069 ( 47.7)257/631 ( 40.7)245/453 ( 54.1)single - vessel disease*591/1069 ( 55.3)348/631 ( 55.2)208/453 ( 45.9)pre - pci timi flow  0 to 1 * 593/931 ( 63.7)319/563 ( 56.7)244/369 ( 66.1 )  2143/931 ( 15.4)112/563 ( 19.9)46/369 ( 12.5 )  3195/931 ( 20.9)132/563 ( 23.4)79/369 ( 21.4)post - pci timi flow  0 to 118/930 ( 1.9)7/563 ( 1.2)9/369 ( 2.4 )  229/930 ( 3.1)22/563 ( 3.9)9/369 ( 2.4 )  3883/930 ( 94.9)534/563 ( 94.8)351/369 ( 95.1)drug - eluting stent*538/943 ( 57.1)364/573 ( 63.5)165/373 ( 44.2)thrombectomy304/943 ( 32.2)192/573 ( 33.5)106/373 ( 28.4)balloon angioplasty only48/943 ( 5.1)29/573 ( 5.1)13/373 ( 3.5)gpi , glycoprotein iib / iiia inhibitor ; pci , percutaneous coronary intervention ; timi , thrombolysis in myocardial infarction.*p < 0.05 . treatment and procedural characteristics gpi , glycoprotein iib / iiia inhibitor ; pci , percutaneous coronary intervention ; timi , thrombolysis in myocardial infarction .
femoral artery access , drug - eluting stent use , and the presence of single - vessel disease were all more common in the heparins plus routine gpi group , while pre - pci timi flow of 0 or 1 was more frequent among the heparins with bailout gpi patients .
comparisons of unadjusted event rates between the three treatment groups are shown in table  3 . among patients treated with heparins
, there were no significant differences observed in the rates of either the primary or key secondary outcomes according to the use of gpi .
the composite of ischaemic events ( mace ) , however , was significantly lower in patients treated with heparins plus routine gpi compared with patients treated with heparin and bailout gpi ( 4.3 vs. 7.2% , p = 0.04 ) . in the comparison between bivalirudin and either of the heparins arms the results were consistent with the overall results of the main trial .
specifically , bivalirudin resulted in significantly lower rates of the primary outcome and protocol major bleeding ( table  3 , figure  2 ) , as well as a higher rate of stent thrombosis . after adjustment ,
the benefit of bivalirudin over heparins with bailout gpi for the primary outcome , major bleeding , and nace was maintained ( figures  3 and 4 ) . 

table  3primary and secondary outcomes by treatment groupparameterbivalirudin(n = 1089)n ( % ) heparins + routine gpi(n = 649)n ( % ) relative risk(95% ci)p - valueheparins + bailout gpi(n = 460)n ( % ) relative risk(95% ci)p - valuerelative risk(95% ci)p - valueprimary endpoint : death or major bleeding55 ( 5.1)49 ( 7.6)0.67 ( 0.46 , 0.97)0.0345 ( 9.8)0.52 ( 0.35 , 0.75)0.00061.30 ( 0.88 , 1.91)0.19key secondary endpoint : death , mi , or major bleeding72 ( 6.6)54 ( 8.3)0.79 ( 0.57 , 1.12)0.1848 ( 10.4)0.63 ( 0.45 , 0.90)0.011.25 ( 0.87 , 1.82)0.23death32 ( 2.9)15 ( 2.3)1.27 ( 0.69 , 2.33)0.4419 ( 4.1)0.71 ( 0.41 , 1.24)0.231.79 ( 0.92 , 3.48)0.09cardiac cause27 ( 2.5)15 ( 2.3)1.07 ( 0.58 , 2.00)0.8318 ( 3.9)0.63 ( 0.35 , 1.14)0.131.69 ( 0.86 , 3.32)0.13protocol major bleeding28 ( 2.6)38 ( 5.9)0.44 ( 0.27 , 0.71)0.000729 ( 6.3)0.41 ( 0.25 , 0.68)0.00051.08 ( 0.67 , 1.72)0.76death , mi , idr , or stroke ( mace)65 ( 6.0)28 ( 4.3)1.38 ( 0.90 , 2.13)0.1433 ( 7.2)0.83 ( 0.56 , 1.25)0.371.66 ( 1.02 , 2.71)0.04death , mi , idr , stroke , or major bleeding ( nace)85 ( 7.8)62 ( 9.6)0.82 ( 0.60 , 1.12)0.2156 ( 12.2)0.64 ( 0.47 , 0.88)0.0061.27 ( 0.91 , 1.79)0.16myocardial infarction ( mi)19 ( 1.7)5 ( 0.8)2.26 ( 0.85 , 6.04)0.105 ( 1.1)0.61 ( 0.60 , 4.27)0.341.41 ( 0.41 , 4.85)0.58stent thrombosis17 ( 1.6)4 ( 0.6)2.53 ( 0.86 , 7.49)0.092 ( 0.4)3.59 ( 0.83 , 15.48)0.090.71 ( 0.13 , 3.84)0.69cabg , coronary artery bypass graft ; ci , confidence interval ; gpi , glycoprotein iib / iiia inhibitor ; idr , ischaemia - driven revascularization ; mace , major adverse cardiovascular events ; n / a , not applicable ; nace , net adverse clinical events.relative risk ( 95% ci ) and p - value comparing bivalirudin with heparins + routine gpi.relative risk ( 95% ci ) and p - value comparing bivalirudin with heparins + bailout gpi.relative risk ( 95% ci ) and p - value comparing heparins + bailout gpi with heparins + routine gpi . 
 figure  2kaplan  meier curves of the primary composite endpoint .
arc , academic research consortium ; gpi , glycoprotein iib / iiia inhibitor ; idr , ischaemia - driven revascularization ; mace , major adverse cardiac events ; mi , myocardial infarction ; nace , net adverse clinical events . 

gpi , glycoprotein iib / iiia inhibitor ; idr , ischaemia - driven revascularization ; mace , major adverse cardiac events ; mi , myocardial infarction ; nace , net adverse clinical events .
primary and secondary outcomes by treatment group cabg , coronary artery bypass graft ; ci , confidence interval ; gpi , glycoprotein iib / iiia inhibitor ; idr , ischaemia - driven revascularization ; mace , major adverse cardiovascular events ; n / a , not applicable ; nace , net adverse clinical events .
relative risk ( 95% ci ) and p - value comparing bivalirudin with heparins + routine gpi .
relative risk ( 95% ci ) and p - value comparing bivalirudin with heparins + bailout gpi .
relative risk ( 95% ci ) and p - value comparing heparins + bailout gpi with heparins + routine gpi .
arc , academic research consortium ; gpi , glycoprotein iib / iiia inhibitor ; idr , ischaemia - driven revascularization ; mace , major adverse cardiac events ; mi , myocardial infarction ; nace , net adverse clinical events .
gpi , glycoprotein iib / iiia inhibitor ; idr , ischaemia - driven revascularization ; mace , major adverse cardiac events ; mi , myocardial infarction ; nace , net adverse clinical events .
a total of 94 patients in the control group received enoxaparin , 62 ( 66% ) of the latter were treated with routine gpi .
the rates of the primary endpoint were not different between the patients treated with enoxaparin and ufh ( 9.6 vs. 8.2% , odds ratio 1.16 , 95% ci 0.602.24 , p - value ) ( see supplementary material online , table s1 ) .
the main finding of this pre - specified subgroup analysis of the euromax trial is that a strategy of upstream bivalirudin with bailout use of gpi in < 10% of patients reduces the composite endpoint of death or major bleeding compared with a strategy of heparins plus bailout use of gpi and a strategy of heparins plus a routine upstream use of gpi in patients with stemi scheduled for primary pci .
although this analysis was pre - specified , it still represents a post - randomization subgroup comparison within an open - label trial and should therefore be considered as hypothesis generating rather than definitive . in the horizons - ami trial ,
bivalirudin administered in the hospital reduced the combined clinical endpoint of death , myocardial infraction , and major bleeding compared with ufh and routine use of gpi .
however , contemporary practice has since evolved to include earlier treatment with initiation in the pre - hospital phase , increasing use of prasugrel and ticagrelor and a rise in the adoption of the radial approach .
one point of criticism on horizons - ami has been the routine use of gpi , which is not recommended in the current esc - stemi guidelines and many operators have adopted a bailout only strategy for gpi .
it has been argued that the routine use of gpi may have contributed to the higher bleeding rate , without any benefit on ischaemic outcomes . however , several randomized trials have consistently shown the benefit of gpi when added to heparin in this setting . in the on time-2 trial , upstream tirofiban given in the ambulance was beneficial compared with selective use during primary pci .
the euromax trial tested the hypothesis that bivalirudin , started upstream before primary pci , is beneficial in the context of the use of the new antiplatelet drugs prasugrel and ticagrelor and a high use of radial access .
the results of this pre - specified subgroup analysis are consistent with the overall trial results and provide evidence that the benefits of bivalirudin over heparins are consistent regardless of the use of gpi .
interestingly , the strategy of upstream heparins alone with bailout gpi was associated even with higher ischaemic and bleeding complications compared with the routine use of heparin and upstream gpi , replicating the results of on - time 2 . in a previous randomized trial comparing bivalirudin vs. heparin during pci in patients with acute coronary syndromes ,
bivalirudin reduced ischaemic complications ( 6.2 vs. 7.9% , p = 0.039 ) and bleeding complications ( 3.5 vs. 9.3% , p < 0.001 ) compared with heparin .
a recent meta - analysis found a consistent reduction of bleeding complications of bivalirudin vs. heparin regardless of the bleeding risk of the patients .
the advantage of bivalirudin was observed regardless of the planned ( or = 0.58 , 95% ci 0.470.72 ) or provisional use ( or = 0.40 , 95% ci 0.320.51 ) .
importantly , patients treated with bivalirudin were at higher risk for acute stent thrombosis , an observation consistent with the results of horizons - ami .
the excess risk for acute stent thrombosis was limited to the first 4 h after the index procedure and was probably the result of the combination of the short half - life and rapid clearance of bivalirudin and the delayed bioavailability of the oral p2y12 inhibitors , including the newer agents prasugrel and ticagrelor .
possible treatments that could mitigate this risk could include co - administration of ufh , prolongation of the bivalirudin infusion at the pci dose for the first few hours after the procedure , or the use of an immediate acting p2y12 inhibitor such as cangrelor ; however , they will need to be tested in prospective trials .
the decision to use an upstream therapy with heparin only or heparin plus routine gpi was completely left to the discretion of the investigators and therefore , the equilibrium of randomization in baseline characteristics is potentially lost .
therefore , these results should be considered as hypothesis generating rather than definitive . since enoxaparin was given in only 94 ( 8.4% ) patients the results apply only to the use of ufh , which has been shown to be inferior to enoxaparin in the atoll trial .
euromax was an open - label trial due to the logistic difficulties related to implementation of complex antithrombotic regimens in the pre - hospital setting while rushing patients to primary pci .
however , all events were reviewed by a central adjudication committee blinded to treatment allocation .
in this pre - specified subgroup analysis from euromax , pre - hospital bivalirudin reduced the composite outcome of death or major bleeding compared with both heparins with routine gpi and heparins with only bailout gpi , an effect largely driven by marked reductions in major bleeding .
this work was supported by the medicines company , parsippany , nj , usa . funding to pay the open access publication charges for this article was provided by the medicines company , new york , usa .
 aimsin the horizons trial , in - hospital treatment with bivalirudin reduced bleeding and mortality in primary percutaneous coronary intervention ( pci ) compared with heparin and routine glycoprotein iib / iiia inhibitors ( gpi ) . 
 it is unknown whether this advantage of bivalirudin is observed in comparison with heparins only with gpi used as bailout.methods and resultsin the euromax study , 2198 patients with st - segment elevation myocardial infarction ( stemi ) were randomized during transport for primary pci to bivalirudin or to heparins with optional gpi . 
 primary and principal outcome was the composites of death or non - cabg - related major bleeding at 30 days . this pre - specified analysis compared patients receiving bivalirudin ( n = 1089 ) with those receiving heparins with routine upstream gpi ( n = 649 ) and those receiving heparins only with gpi use restricted to bailout ( n = 460 ) . 
 the primary outcome death and major bleeding occurred in 5.1% with bivalirudin , 7.6% with heparin plus routine gpi ( hr 0.67 and 95% ci 0.460.97 , p = 0.034 ) , and 9.8% with heparins plus bailout gpi ( hr 0.52 and 95% ci 0.350.75 , p = 0.006 ) . 
 following adjustment by logistic regression , bivalirudin was still associated with significantly lower rates of the primary outcome ( odds ratio 0.53 , 95% ci 0.330.87 ) and major bleeding ( odds ratio 0.44 , 95% ci 0.240.82 ) compared with heparins alone with bailout gpi . 
 rates of stent thrombosis were higher with bivalirudin ( 1.6 vs. 0.6 vs. 0.4% , p = 0.09 and 0.09).conclusionbivalirudin , started during transport for primary pci , reduces major bleeding compared with both patients treated with heparin only plus bailout gpi and patients treated with heparin and routine gpi , but increased stent thrombosis . 
Introduction
Methods
Study population
Study treatments
Study outcomes
Statistical analysis
Results
Patients
Procedures and treatments
Outcomes
Discussion
Limitations
Conclusion
Supplementary material
Funding
Supplementary Material