dual antiplatelet therapy with aspirin and a p2y12 inhibitor is standard of care in acute coronary syndromes ( acs ) . as opposed to clopidogrel and prasugrel , it does not require enzymatic activation , and causes faster , greater , and more consistent platelet inhibition compared with clopidogrel . the platelet inhibition and patient outcomes ( plato ) trial compared ticagrelor with clopidogrel in patients with acs . ticagrelor was superior in preventing ischaemic events ( the composite of death from vascular causes , myocardial infarction , and stroke ) , as well as death from any cause , without a significant increase in all - cause major bleeding . the third - generation thienopyridine prasugrel is , like clopidogrel , an irreversible p2y12 inhibitor , but with faster and more consistent platelet inhibition . prasugrel , when compared with clopidogrel , reduced ischaemic events in patients with acs planned for pci in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel ( triton ) , but in non - st - elevation acute coronary syndrome ( nste - acs ) patients planned for management without revascularization , prasugrel showed no benefit over clopidogrel in the targeted platelet inhibition to clarify the optimal strategy to medically manage acute coronary syndromes ( trilogy - acs ) trial . the aim of the present study was to explore the effect of ticagrelor vs. clopidogrel in the total nste - acs subgroup of the plato trial and also stratified by initial management with or without revascularization . nct00391872 ) was an international randomized double - blind , double - dummy phase iii study comparing ticagrelor with clopidogrel in acs . briefly , a total of 18 624 patients were randomized to receive either ticagrelor or clopidogrel on background treatment with aspirin . the study included patients with st - elevation mi intended for primary pci , as well as patients with non - st - elevation acs , regardless if aimed for an initial invasive or non - invasive treatment strategy . it adhered to the declaration of helsinki , to the specifications of the international conference of harmonization , and to good clinical practice ; and was approved by national and institutional regulatory authorities and ethics committees . two or more of the following inclusion criteria were required for patients enrolled without st - elevation acs at admission : ( 1 ) st - segment changes on ecg indicating ischaemia [ st - segment depression or transient elevation ( 1 mm ) in at least two contiguous leads ] ; ( 2 ) positive biomarker indicating myocardial necrosis ( troponin i or t or ck - mb above the upper limit of normal ) ; ( 3 ) one of the following : 60 years of age , previous myocardial infarction or coronary artery bypass surgery , coronary artery disease with 50% stenosis in 2 vessels , previous ischaemic stroke , transient ischaemic attack ( tia ) , carotid stenosis , cerebral revascularization , diabetes mellitus , peripheral artery disease , or chronic renal dysfunction . in the current analysis , nste - acs was in the data - base defined as absence of either persistent st - segment elevation of 1 mv for 20 min in two contiguous leads or new ( or presumed new ) left bundle branch block in entry ecg . in addition to the overall nste - acs population , we also analysed outcomes in the subgroups of nste - acs patients who initially underwent revascularization and those who were treated without early revascularization . both cohorts required endpoint - free survival for 10 days post - randomization to determine revascularization status . the no - revascularization subgroup was defined as nste - acs patients who did not undergo any revascularization procedure ( pci or cabg ) with or without angiography during the first 10 days . the primary efficacy endpoint of the present study was the composite of cardiovascular death , myocardial infarction , ( excluding silent infarctions ) and stroke . major bleeding by plato criteria and life - threatening / fatal bleeding were the primary safety endpoints . secondary safety endpoints were cabg - related major bleeding , non - cabg - related major bleeding , minor bleeding , intracranial bleeding , and fatal bleeding . additional secondary safety outcomes were bleeding events as defined by timi ( major , minor , and non - cabg related major ) and gusto ( severe and moderate ) . major bleeding as defined by timi was recorded from the electronic case report form , where a drop of 50 g / l in haemoglobin was used as a cut - off , but this did not necessarily require clinical evidence of bleeding . patient characteristics and medical history , in - hospital procedures and medications , discharge acs status , and post - discharge medications are presented by treatment in the nste - acs patient cohort as well as by revascularization status subgroup . continuous variables are presented as median and 25th75th percentiles ; categorical variables are presented as number and percentage . the treatment effect of ticagrelor vs. clopidogrel on the primary and secondary endpoints was compared within the subgroup of nste - acs patients . meier estimated event rates at 360 days and total number of observed events during the study were presented for each endpoint . hazard ratios ( hr ) , confidence intervals ( ci ) , and p - values from unadjusted cox proportional hazards regression models were presented . meier estimated event rates were plotted by treatment for the primary efficacy endpoint , all - cause death , major bleeding , and non - cabg related major bleeding . to examine whether the effect of ticagrelor in patients with nste - acs differed based on early revascularization , cox proportional hazards models were fitted for each endpoint using a treatment - by - revascularization interaction term . in these models , we adjusted for region of the world to account for differences in revascularization practice and the time - to - event was measured from a landmark at 10 days post - randomization . meier rates 350 days post - landmark are presented for each treatment / revascularization category along with hr for ticagrelor vs. clopidogrel in the revascularization and medical management subgroups . interaction p - values assess whether the treatment effect is different depending on revascularization status . meier event rates adjusted for region are plotted by the four treatment / revascularization categories for the primary efficacy endpoint , all - cause death , major bleeding , and non - cabg related major bleeding . for consistency with the plato design paper , we also performed a 30-day landmark analysis ; and as a sensitivity analysis , we also performed a 10-day landmark analysis of the full study population . finally , the association of treatment with the primary efficacy endpoint was evaluated within several patient cohorts using cox proportional hazards models , separately within the revascularization and non - revascularization subgroups . endpoints are defined using intent to treat and a p - value of 0.05 is used to denote statistical significance . nct00391872 ) was an international randomized double - blind , double - dummy phase iii study comparing ticagrelor with clopidogrel in acs . briefly , a total of 18 624 patients were randomized to receive either ticagrelor or clopidogrel on background treatment with aspirin . the study included patients with st - elevation mi intended for primary pci , as well as patients with non - st - elevation acs , regardless if aimed for an initial invasive or non - invasive treatment strategy . it adhered to the declaration of helsinki , to the specifications of the international conference of harmonization , and to good clinical practice ; and was approved by national and institutional regulatory authorities and ethics committees . two or more of the following inclusion criteria were required for patients enrolled without st - elevation acs at admission : ( 1 ) st - segment changes on ecg indicating ischaemia [ st - segment depression or transient elevation ( 1 mm ) in at least two contiguous leads ] ; ( 2 ) positive biomarker indicating myocardial necrosis ( troponin i or t or ck - mb above the upper limit of normal ) ; ( 3 ) one of the following : 60 years of age , previous myocardial infarction or coronary artery bypass surgery , coronary artery disease with 50% stenosis in 2 vessels , previous ischaemic stroke , transient ischaemic attack ( tia ) , carotid stenosis , cerebral revascularization , diabetes mellitus , peripheral artery disease , or chronic renal dysfunction . in the current analysis , nste - acs was in the data - base defined as absence of either persistent st - segment elevation of 1 mv for 20 min in two contiguous leads or new ( or presumed new ) left bundle branch block in entry ecg . in addition to the overall nste - acs population , we also analysed outcomes in the subgroups of nste - acs patients who initially underwent revascularization and those who were treated without early revascularization . both cohorts required endpoint - free survival for 10 days post - randomization to determine revascularization status . the no - revascularization subgroup was defined as nste - acs patients who did not undergo any revascularization procedure ( pci or cabg ) with or without angiography during the first 10 days . the primary efficacy endpoint of the present study was the composite of cardiovascular death , myocardial infarction , ( excluding silent infarctions ) and stroke . major bleeding by plato criteria and life - threatening / fatal bleeding were the primary safety endpoints . secondary safety endpoints were cabg - related major bleeding , non - cabg - related major bleeding , minor bleeding , intracranial bleeding , and fatal bleeding . additional secondary safety outcomes were bleeding events as defined by timi ( major , minor , and non - cabg related major ) and gusto ( severe and moderate ) . an independent central adjudication committee , unaware of treatment assignments , assessed all endpoints . major bleeding as defined by timi was recorded from the electronic case report form , where a drop of 50 g / l in haemoglobin was used as a cut - off , but this did not necessarily require clinical evidence of bleeding . patient characteristics and medical history , in - hospital procedures and medications , discharge acs status , and post - discharge medications are presented by treatment in the nste - acs patient cohort as well as by revascularization status subgroup . continuous variables are presented as median and 25th75th percentiles ; categorical variables are presented as number and percentage . the treatment effect of ticagrelor vs. clopidogrel on the primary and secondary endpoints was compared within the subgroup of nste - acs patients . meier estimated event rates at 360 days and total number of observed events during the study were presented for each endpoint . hazard ratios ( hr ) , confidence intervals ( ci ) , and p - values from unadjusted cox proportional hazards regression models were presented . meier estimated event rates were plotted by treatment for the primary efficacy endpoint , all - cause death , major bleeding , and non - cabg related major bleeding . to examine whether the effect of ticagrelor in patients with nste - acs differed based on early revascularization , cox proportional hazards models were fitted for each endpoint using a treatment - by - revascularization interaction term . in these models , we adjusted for region of the world to account for differences in revascularization practice and the time - to - event was measured from a landmark at 10 days post - randomization . meier rates 350 days post - landmark are presented for each treatment / revascularization category along with hr for ticagrelor vs. clopidogrel in the revascularization and medical management subgroups . interaction p - values assess whether the treatment effect is different depending on revascularization status . meier event rates adjusted for region are plotted by the four treatment / revascularization categories for the primary efficacy endpoint , all - cause death , major bleeding , and non - cabg related major bleeding . for consistency with the plato design paper , we also performed a 30-day landmark analysis ; and as a sensitivity analysis , we also performed a 10-day landmark analysis of the full study population . finally , the association of treatment with the primary efficacy endpoint was evaluated within several patient cohorts using cox proportional hazards models , separately within the revascularization and non - revascularization subgroups . endpoints are defined using intent to treat and a p - value of 0.05 is used to denote statistical significance . the plato trial included 18 624 patients with acs , of which 11 080 patients were classified as nste - acs at randomization . of these , 5581 were randomized to ticagrelor and 5499 to clopidogrel ( figure  1 ) . the baseline and in - hospital characteristics were similar between groups in the overall nste - acs population ( table  1 ) . in the overall nste - acs group , 74% of patients had a coronary angiography performed , 46% underwent pci , and 5% cabg . the discharge diagnosis ( in this population categorized as nste - acs at admission ) was nstemi in 65% , stemi in 8% , and unstable angina / other in 27% . table  1baseline characteristics and invasive procedures by randomized treatment in the overall nste - acs population , and by initial treatment strategy ( within the first 10 days after randomization )  overall nste - acsnste - acs with revascularizationnste - acs without revascularizationticagrelor ( n = 5581)clopidogrel ( n = 5499)ticagrelor ( n = 2873)clopidogrel ( n = 2841)ticagrelor ( n = 2708)clopidogrel ( n = 2658)demographics  age , median ( 25th75th percentile ) , years64 ( 5672)64 ( 5672)63 ( 5571)63 ( 5571)65 ( 5773)65 ( 5773 )  age  75 years , n ( % ) 955 ( 17.1)1024 ( 18.6)420 ( 14.6)460 ( 16.2)535 ( 19.8)564 ( 21.2 )  female gender , n ( % ) 1746 ( 31.3)1746 ( 31.8)706 ( 24.6)716 ( 25.2)1040 ( 38.4)1030 ( 38.8 )  body weight < 60 kg , n ( % ) 398 ( 7.2)389 ( 7.1)165 ( 5.8)172 ( 6.1)233 ( 8.6)217 ( 8.2 )  body mass index , median ( 25th75th percentile ) , kg / m27.5 ( 24.830.8)27.4 ( 24.830.5)27.5 ( 24.930.8)27.5 ( 24.930.5)27.5 ( 24.730.6)27.3 ( 24.630.5 )  grace risk score nomogram130 ( 112150)130 ( 112149)128 ( 110145)127 ( 110145)133 ( 114154)134 ( 116153)cardiovascular risk factors , n ( % )  current smoking1636 ( 29.4)1640 ( 29.9)1000 ( 34.8)960 ( 33.8)636 ( 23.6)680 ( 25.6 )  hypertension3915 ( 70.2)3835 ( 69.8)1881 ( 65.5)1886 ( 66.4)2034 ( 75.3)1949 ( 73.4 )  dyslipidaemia2885 ( 51.8)2852 ( 51.9)1515 ( 52.8)1569 ( 55.2)1370 ( 50.7)1283 ( 48.3 )  diabetes mellitus1608 ( 28.9)1520 ( 27.7)756 ( 26.3)747 ( 26.3)852 ( 31.6)773 ( 29.1)medical history , n ( % )  angina pectoris2932 ( 52.6)2890 ( 52.6)1337 ( 46.5)1356 ( 47.7)1595 ( 59.1)1534 ( 57.8 )  myocardial infarction1400 ( 25.1)1410 ( 25.7)609 ( 21.2)608 ( 21.4)791 ( 29.3)802 ( 30.2 )  congestive heart failure397 ( 7.1)429 ( 7.8)99 ( 3.4)103 ( 3.6)298 ( 11.0)326 ( 12.3 )  percutaneous coronary intervention ( pci)944 ( 16.9)918 ( 16.7)537 ( 18.7)517 ( 18.2)407 ( 15.1)401 ( 15.1 )  coronary artery bypass graft ( cabg)434 ( 7.8)474 ( 8.6)214 ( 7.4)218 ( 7.7)220 ( 8.1)256 ( 9.6 )  transient ischaemic attack185 ( 3.3)189 ( 3.4)82 ( 2.9)74 ( 2.6)103 ( 3.8)115 ( 4.3 )  non - hemorrhagic stroke246 ( 4.4)243 ( 4.4)81 ( 2.8)98 ( 3.5)165 ( 6.1)145 ( 5.5 )  peripheral arterial disease400 ( 7.2)413 ( 7.5)174 ( 6.1)204 ( 7.2)226 ( 8.4)209 ( 7.9 )  chronic renal disease273 ( 4.9)279 ( 5.1)117 ( 4.1)108 ( 3.8)156 ( 5.8)171 ( 6.4)physical findings , median ( 25th75th percentile )  heart rate ( bpm)72 ( 6480)72 ( 6481)71 ( 6280)72 ( 6380)72 ( 6482)72 ( 6482 )  systolic blood pressure ( mmhg)135 ( 120150)134 ( 120150)135 ( 120150)135 ( 120150)134 ( 120150)132 ( 120150 )  diastolic blood pressure ( mmhg)80 ( 7089)80 ( 7087)80 ( 7089)80 ( 7087)80 ( 7089)80 ( 7087)risk indicators , n ( % )  troponin positive , n ( % ) 4356 ( 80.8)4323 ( 81.3)2522 ( 89.6)2486 ( 89.3)1834 ( 71.3)1837 ( 72.4 )  st depression ( 1 mm)3158 ( 56.8)3201 ( 58.4)1547 ( 54.0)1535 ( 54.2)1611 ( 59.8)1666 ( 62.8 )  timi risk score > 24838 ( 89.7)4785 ( 89.8)2584 ( 91.3)2566 ( 91.8)2254 ( 88.0)2219 ( 87.7)type of acs at discharge , n ( % )  stemi449 ( 8.1)437 ( 8.0)330 ( 11.5)305 ( 10.7)119 ( 4.4)132 ( 5.0 )  nstemi3605 ( 64.8)3525 ( 64.3)2045 ( 71.2)2025 ( 71.3)1560 ( 58.0)1500 ( 56.7 )  ua / other1509 ( 27.1)1524 ( 27.8)497 ( 17.3)510 ( 18.0)1012 ( 37.6)1014 ( 38.3)antithrombotic treatment during index hospitalization , n ( % )  aspirin5386 ( 96.6)5316 ( 96.8)2797 ( 97.4)2779 ( 97.8)2589 ( 95.9)2537 ( 95.8 )  unfractionated heparin2910 ( 52.1)2856 ( 51.9)1845 ( 64.2)1845 ( 64.9)1065 ( 39.3)1011 ( 38.0 )  low molecular weight heparin3181 ( 57.0)3084 ( 56.1)1568 ( 54.6)1501 ( 52.8)1613 ( 59.6)1583 ( 59.6 )  fondaparinux194 ( 3.5)191 ( 3.5)87 ( 3.0)76 ( 2.7)107 ( 4.0)115 ( 4.3 )  bivalirudin140 ( 2.5)133 ( 2.4)135 ( 4.7)122 ( 4.3)5 ( 0.2)11 ( 0.4 )  gp iib / iiia inhibitor1170 ( 21.0)1117 ( 20.3)982 ( 34.2)963 ( 33.9)188 ( 6.9)154 ( 5.8)other drug from randomization to end of study , n ( % )  beta - blocker4768 ( 85.4)4685 ( 85.2)2536 ( 88.3)2512 ( 88.4)2232 ( 82.4)2173 ( 81.8 )  ace - inhibitor and/or arb4693 ( 84.2)4602 ( 83.8)2447 ( 85.2)2433 ( 85.6)2246 ( 83.2)2169 ( 81.9 )  statin5196 ( 93.1)5109 ( 92.9)2777 ( 96.7)2745 ( 96.6)2419 ( 89.3)2364 ( 88.9 )  proton - pump inhibitor2776 ( 49.7)2613 ( 47.5)1618 ( 56.3)1536 ( 54.1)1158 ( 42.8)1077 ( 40.5 )  calcium channel inhibitor1553 ( 27.8)1515 ( 27.6)720 ( 25.1)723 ( 25.4)833 ( 30.8)792 ( 29.8 )  diuretic2393 ( 42.9)2280 ( 41.5)1073 ( 37.3)1037 ( 36.5)1320 ( 48.9)1243 ( 46.9)invasive procedures  coronary angiography  during first 10 days , n ( % ) 4143 ( 74.5)4072 ( 74.2)2873 ( 100.0)2841 ( 100.0)1270 ( 47.2)1231 ( 46.6 )  after first 10 days , n ( % ) 357 ( 6.4)335 ( 6.1)0 ( 0)0 ( 0)357 ( 13.3)335 ( 12.7 )  pci  during first 10 days , n ( % ) 2590 ( 46.4)2550 ( 46.4)2590 ( 90.1)2550 ( 89.8)0 ( 0)0 ( 0 )  after first 10 days , n ( % ) 279 ( 5.0)291 ( 5.3)11 ( 0.4)3 ( 0.1)268 ( 9.9)288 ( 10.8 )  cabg  during first 10 days , n ( % ) 296 ( 5.3)305 ( 5.5)296 ( 10.3)305 ( 10.7)0 ( 0)0 ( 0 )  after first 10 days , n ( % ) 382 ( 6.8)375 ( 6.8)55 ( 1.9)55 ( 1.9)327 ( 12.1)320 ( 12.0 ) 
 figure  1trial profile  patients classified by entry ecg and by treatment during the first 10 days after randomization . baseline characteristics and invasive procedures by randomized treatment in the overall nste - acs population , and by initial treatment strategy ( within the first 10 days after randomization ) trial profile  patients classified by entry ecg and by treatment during the first 10 days after randomization . at 10 days post - randomization , there were regional differences in the proportion of patients undergoing revascularization during the initial 10 days ( asia / australia 44% , central / south america 40.3% , europe / middle east / africa 49.8% , north america 71.6% ) . non - revascularized and revascularized patients were of similar age ( 63 vs. 65 ) , but patients who did not undergo revascularization were more likely to be of female gender ( 39 vs. 25% ) , and more likely to have comorbidities ( e.g. previous myocardial infarction , heart failure , renal disease ) . although non - revascularized patients had more comorbidities , they were less likely to be troponin i positive ( table  1 ) . the proportion of patients with timi risk score > 2 was slightly higher in the revascularization group ( 92 vs. 88% ) . during the first 10 days , 47% of non - revascularized patients underwent coronary angiography . when including only those who had angiography during the initial 10 days , female gender was more common in the non - revascularized ( 36% ) than revascularized ( 25% ) . no significant coronary artery disease at angiography was noted in 32 and 0.7% of the non - revascularized and revascularized , respectively . efficacy and safety outcomes of the overall nste - acs population are summarized in table  2 , and kaplan  meier curves are shown in supplementary material online . the incidence of the primary composite endpoint was reduced with ticagrelor vs. clopidogrel ( 10.0 vs. 12.3% ; hr 0.83 ; 95% ci = 0.740.93 ; p = 0.0013 ) ( see supplementary material online , figure s1a ) . cardiovascular death occurred less often in the ticagrelor group than in the clopidogrel group ( 3.7 vs. 4.9% ; hr 0.77 ; 95% ci = 0.640.93 ; p = 0.0070 ) , and myocardial infarction was also less common with ticagrelor vs. clopidogrel ( 6.6 vs. 7.7% ; hr 0.86 ; 95% ci = 0.740.99 ; p = 0.0419 ) , whereas stroke incidence did not differ significantly between treatment arms ( 1.3 vs. 1.4% ; hr 0.95 ; 95% ci 0.691.33 ; p = 0.79 ) . all - cause death was reduced in those treated with ticagrelor vs. clopidogrel ( 4.3 vs. 5.8% ; hr 0.76 ; 95% ci = 0.640.90 ; p = 0.0020 ) ( see supplementary material online , figure s1b ) . table  2efficacy and safety outcomes in patients with nste - acsticagrelor % ( n)clopidogrel % ( n)hr ( 95% ci)p - valueefficacy endpoints  cv death / mi ( excluding silent)/stroke10.0 ( 533)12.3 ( 630)0.83 ( 0.74 , 0.93)0.0013  all - cause death / mi(excl . silent)/stroke10.5 ( 557)13.0 ( 664)0.82 ( 0.73 , 0.92)0.0006  cv death / mi(all)/stroke / severe recurrent ischaemia / recurrent ischaemia / tia / arterial thrombotic event15.5 ( 824)17.8 ( 918)0.88 ( 0.80 , 0.96)0.0058 myocardial infarction ( excluding silent)6.6 ( 345)7.7 ( 392)0.86 ( 0.74 , 0.99)0.0419  cardiovascular death ( includes vascular and unknown deaths)3.7 ( 194)4.9 ( 247)0.77 ( 0.64 , 0.93)0.0070  stroke1.3 ( 69)1.4 ( 71)0.95 ( 0.69 , 1.33)0.79  all - cause death4.3 ( 224)5.8 ( 290)0.76 ( 0.64 , 0.90)0.0020safety endpoints  major bleeding ( study criteria)13.4 ( 660)12.6 ( 618)1.07 ( 0.95 , 1.19)0.26  major or minor bleeding ( study criteria)18.2 ( 900)16.3 ( 794)1.14 ( 1.03 , 1.25)0.0078  non - cabg related major bleeding ( study criteria)4.8 ( 225)3.8 ( 176)1.28 ( 1.05 , 1.56)0.0139  fatal bleeding0.3 ( 13)0.4 ( 18)0.72 ( 0.35 , 1.47)0.37  life threatening or fatal bleeding ( study criteria)6.6 ( 331)6.5 ( 315)1.05 ( 0.90 , 1.22)0.56  intracranial bleeding0.3 ( 14)0.2 ( 7)2.01 ( 0.81 , 4.99)0.13  other major bleeding7.2 ( 344)6.6 ( 318)1.08 ( 0.93 , 1.25)0.34  major bleeding ( timi criteria)9.2 ( 452)8.7 ( 422)1.07 ( 0.94 , 1.22)0.33  major or minor bleeding ( timi criteria)13.2 ( 653)12.3 ( 602)1.08 ( 0.97 , 1.21)0.16  non - cabg related major bleeding ( timi criteria)2.9 ( 137)2.2 ( 99)1.39 ( 1.07 , 1.80)0.0131  gusto severe bleeding3.1 ( 146)3.2 ( 151)0.96 ( 0.77 , 1.21)0.74  gusto moderate or severe bleeding8.6 ( 416)7.8 ( 382)1.08 ( 0.94 , 1.25)0.25each treatment group is summarized as kaplan  meier rates at 360 days and total number of events during the study . p - values and hazard ratios ( 95% ci ) come from unadjusted cox models testing ticagrelor vs. clopidogrel . efficacy and safety outcomes in patients with nste - acs each treatment group is summarized as kaplan  meier rates at 360 days and total number of events during the study . p - values and hazard ratios ( 95% ci ) come from unadjusted cox models testing ticagrelor vs. clopidogrel . with ticagrelor when compared with clopidogrel , there was no significant difference in plato major bleeding ( 13.4 vs. 12.6% ; hr 1.07 ; 95% ci = 0.951.19 ; p = 0.26 ) , but a higher rate of non - cabg - related major bleeding ( 4.8 vs. 3.8% ; hr 1.28 ; 95% ci = 1.051.56 ; p = 0.0139 ) ( see supplementary material online , figure s2a and b ) . there was no significant difference in the rate of life - threatening or fatal bleeding ( 6.6 vs. 6.5% ; hr 1.05 ; 95% ci = 0.901.22 , p = 0.56 ) , nor any significant difference in the rate of intracranial bleeding with ticagrelor compared with clopidogrel ( 0.3 vs. 0.2% ; hr 2.01 ; 95% ci = 0.814.99 ; p = 0.13 ) . the composite of major or minor bleeding ( by plato criteria ) occurred more often in the ticagrelor group ( 18.2 vs. 16.3% ; hr 1.14 ; 95% ci = 1.031.25 , p = 0.0078 ) . when assessed by timi criteria , there was no significant difference in major or minor bleeding ( 13.2 vs. 12.3% ; hr 1.08 ; 95% ci = 0.971.21 ; p = 0.16 ) . timi major bleeding , gusto severe , and gusto moderate or severe bleeding also did not appear to differ significantly between ticagrelor and clopidogrel , whereas timi non - cabg - related major bleeding was more common in the ticagrelor group ( table  2 ) . event rates were considerably higher in nste - acs patients treated without revascularization compared with patients undergoing revascularization during the initial 10 days . for both revascularized and non - revascularized patients , there were similar proportional reductions of the primary endpoint with ticagrelor compared with clopidogrel ( hr 0.86 vs. 0.85 , interaction p = 0.93 ) ( figure  2a , table  3 ) consistent with the overall trial . there was also a consistent reduction in all - cause death ( hr 0.75 vs. 0.73 ; interaction p = 0.89 ) ( figure  2b ) . no significant difference in overall major bleeding was seen with ticagrelor vs. clopidogrel within each treatment strategy ( revascularization / no revascularization ) ( figure  3a ) . there was a higher incidence of non - cabg - related major bleeding with ticagrelor vs. clopidogrel in patients with nste - acs with no significant interaction by invasive treatment strategy ( hr 1.32 vs. 1.07 ; interaction p = 0.43 ) ( figure  3b ) . the primary outcome was reduced in major subgroups in both revascularized and non - revascularized patients ( see supplementary material online , figures s3 and s4 ) . the results were consistent with a 30-day landmark for revascularization ( see supplementary material online , table s1 ) , as well as in the full study population ( see supplementary material online , table s2 ) . in patients who underwent angiography during the initial 10 days with or without significant coronary disease , the effect of ticagrelor vs. clopidogrel was consistent ( see supplementary material online , table s3 ) . table  3interaction of ticagrelor treatment and revascularization within 10 days ( adjusting for region )  nste - acs with revascularizationnste - acs without revascularizationinteraction pnticagrelor km rateclopidogrel km ratehr ( 95% ci)nticagrelor km rateclopidogrel km ratehr ( 95% ci)efficacy endpoints  cv death / mi ( excluding silent)/stroke54165.116.100.86 ( 0.68 , 1.09)51899.6311.600.85 ( 0.72 , 1.01)0.93  all - cause death / mi silent)/stroke54165.446.600.85 ( 0.67 , 1.06)518910.1512.530.84 ( 0.71 , 0.99)0.94  cv death / mi ( all)/stroke / severe recurrent ischaemia / recurrent ischaemia / tia / arterial thrombotic event52908.7310.310.86 ( 0.71 , 1.03)510914.1415.160.97 ( 0.84 , 1.13)0.29  myocardial infarction ( excluding silent)54383.523.880.90 ( 0.68 , 1.21)52016.046.680.94 ( 0.75 , 1.17)0.85  cardiovascular death ( includes vascular and unknown deaths)56481.642.330.76 ( 0.52 , 1.13)52174.075.440.75 ( 0.58 , 0.98)0.95  stroke56320.670.591.18 ( 0.60 , 2.34)52091.481.690.92 ( 0.58 , 1.46)0.56  all - cause death56482.032.880.75 ( 0.53 , 1.07)52174.776.650.73 ( 0.57 , 0.93)0.89safety endpoints  major bleeding ( study criteria)49835.254.681.10 ( 0.84 , 1.44)493111.8311.431.05 ( 0.88 , 1.26)0.82  major or minor bleeding ( study criteria)48427.766.351.22 ( 0.97 , 1.54)484714.5913.961.07 ( 0.91 , 1.25)0.34  non - cabg major bleeding ( study criteria)52703.142.381.32 ( 0.92 , 1.90)49332.782.791.07 ( 0.74 , 1.56)0.43  fatal or life - threatening major bleeding ( study criteria)51732.252.011.18 ( 0.79 , 1.76)49625.776.110.95 ( 0.75 , 1.22)0.37  other major bleeding ( study criteria)51783.102.851.02 ( 0.72 , 1.45)49456.505.681.16 ( 0.91 , 1.49)0.55  major bleeding ( timi criteria)51023.422.791.21 ( 0.86 , 1.70)49528.048.390.97 ( 0.79 , 1.20)0.28  major or minor bleeding ( timi criteria)49905.244.561.12 ( 0.85 , 1.47)493311.7811.161.08 ( 0.91 , 1.29)0.85  non - cabg major bleeding ( timi criteria)53161.881.191.66 ( 1.01 , 2.72)49522.051.841.19 ( 0.76 , 1.87)0.34  gusto severe bleeding52861.161.490.75 ( 0.45 , 1.26)49462.752.461.13 ( 0.77 , 1.65)0.22  gusto moderate or severe bleeding51343.933.301.13 ( 0.82 , 1.55)49457.185.961.19 ( 0.95 , 1.51)0.78kaplan  meier ( km ) rates 350 days after day 10 post - randomization . 
 figure  2efficacy endpoints stratified by management strategy kaplan  meier estimates of time to first occurrence of : ( a ) primary endpoint , ( b ) all - cause death , from 10 days post - randomization onward . figure  3bleeding stratified by revascularization  kaplan  meier estimate of ( a ) time to major bleeding according to the plato criteria from day 10 post - randomization , and ( b ) time to non - cabg major bleeding . interaction of ticagrelor treatment and revascularization within 10 days ( adjusting for region ) kaplan  meier ( km ) rates 350 days after day 10 post - randomization . efficacy endpoints stratified by management strategy  kaplan  meier estimates of time to first occurrence of : ( a ) primary endpoint , ( b ) all - cause death , from 10 days post - randomization onward . meier estimate of ( a ) time to major bleeding according to the plato criteria from day 10 post - randomization , and ( b ) time to non - cabg major bleeding . the plato trial included 18 624 patients with acs , of which 11 080 patients were classified as nste - acs at randomization . of these , 5581 were randomized to ticagrelor and 5499 to clopidogrel ( figure  1 ) . the baseline and in - hospital characteristics were similar between groups in the overall nste - acs population ( table  1 ) . in the overall nste - acs group , 74% of patients had a coronary angiography performed , 46% underwent pci , and 5% cabg . the discharge diagnosis ( in this population categorized as nste - acs at admission ) was nstemi in 65% , stemi in 8% , and unstable angina / other in 27% . table  1baseline characteristics and invasive procedures by randomized treatment in the overall nste - acs population , and by initial treatment strategy ( within the first 10 days after randomization )  overall nste - acsnste - acs with revascularizationnste - acs without revascularizationticagrelor ( n = 5581)clopidogrel ( n = 5499)ticagrelor ( n = 2873)clopidogrel ( n = 2841)ticagrelor ( n = 2708)clopidogrel ( n = 2658)demographics  age , median ( 25th75th percentile ) , years64 ( 5672)64 ( 5672)63 ( 5571)63 ( 5571)65 ( 5773)65 ( 5773 )  age  75 years , n ( % ) 955 ( 17.1)1024 ( 18.6)420 ( 14.6)460 ( 16.2)535 ( 19.8)564 ( 21.2 )  female gender , n ( % ) 1746 ( 31.3)1746 ( 31.8)706 ( 24.6)716 ( 25.2)1040 ( 38.4)1030 ( 38.8 )  body weight < 60 kg , n ( % ) 398 ( 7.2)389 ( 7.1)165 ( 5.8)172 ( 6.1)233 ( 8.6)217 ( 8.2 )  body mass index , median ( 25th75th percentile ) , kg / m27.5 ( 24.830.8)27.4 ( 24.830.5)27.5 ( 24.930.8)27.5 ( 24.930.5)27.5 ( 24.730.6)27.3 ( 24.630.5 )  grace risk score nomogram130 ( 112150)130 ( 112149)128 ( 110145)127 ( 110145)133 ( 114154)134 ( 116153)cardiovascular risk factors , n ( % )  current smoking1636 ( 29.4)1640 ( 29.9)1000 ( 34.8)960 ( 33.8)636 ( 23.6)680 ( 25.6 )  hypertension3915 ( 70.2)3835 ( 69.8)1881 ( 65.5)1886 ( 66.4)2034 ( 75.3)1949 ( 73.4 )  dyslipidaemia2885 ( 51.8)2852 ( 51.9)1515 ( 52.8)1569 ( 55.2)1370 ( 50.7)1283 ( 48.3 )  diabetes mellitus1608 ( 28.9)1520 ( 27.7)756 ( 26.3)747 ( 26.3)852 ( 31.6)773 ( 29.1)medical history , n ( % )  angina pectoris2932 ( 52.6)2890 ( 52.6)1337 ( 46.5)1356 ( 47.7)1595 ( 59.1)1534 ( 57.8 )  myocardial infarction1400 ( 25.1)1410 ( 25.7)609 ( 21.2)608 ( 21.4)791 ( 29.3)802 ( 30.2 )  congestive heart failure397 ( 7.1)429 ( 7.8)99 ( 3.4)103 ( 3.6)298 ( 11.0)326 ( 12.3 )  percutaneous coronary intervention ( pci)944 ( 16.9)918 ( 16.7)537 ( 18.7)517 ( 18.2)407 ( 15.1)401 ( 15.1 )  coronary artery bypass graft ( cabg)434 ( 7.8)474 ( 8.6)214 ( 7.4)218 ( 7.7)220 ( 8.1)256 ( 9.6 )  transient ischaemic attack185 ( 3.3)189 ( 3.4)82 ( 2.9)74 ( 2.6)103 ( 3.8)115 ( 4.3 )  non - hemorrhagic stroke246 ( 4.4)243 ( 4.4)81 ( 2.8)98 ( 3.5)165 ( 6.1)145 ( 5.5 )  peripheral arterial disease400 ( 7.2)413 ( 7.5)174 ( 6.1)204 ( 7.2)226 ( 8.4)209 ( 7.9 )  chronic renal disease273 ( 4.9)279 ( 5.1)117 ( 4.1)108 ( 3.8)156 ( 5.8)171 ( 6.4)physical findings , median ( 25th75th percentile )  heart rate ( bpm)72 ( 6480)72 ( 6481)71 ( 6280)72 ( 6380)72 ( 6482)72 ( 6482 )  systolic blood pressure ( mmhg)135 ( 120150)134 ( 120150)135 ( 120150)135 ( 120150)134 ( 120150)132 ( 120150 )  diastolic blood pressure ( mmhg)80 ( 7089)80 ( 7087)80 ( 7089)80 ( 7087)80 ( 7089)80 ( 7087)risk indicators , n ( % )  troponin positive , n ( % ) 4356 ( 80.8)4323 ( 81.3)2522 ( 89.6)2486 ( 89.3)1834 ( 71.3)1837 ( 72.4 )  st depression ( 1 mm)3158 ( 56.8)3201 ( 58.4)1547 ( 54.0)1535 ( 54.2)1611 ( 59.8)1666 ( 62.8 )  timi risk score > 24838 ( 89.7)4785 ( 89.8)2584 ( 91.3)2566 ( 91.8)2254 ( 88.0)2219 ( 87.7)type of acs at discharge , n ( % )  stemi449 ( 8.1)437 ( 8.0)330 ( 11.5)305 ( 10.7)119 ( 4.4)132 ( 5.0 )  nstemi3605 ( 64.8)3525 ( 64.3)2045 ( 71.2)2025 ( 71.3)1560 ( 58.0)1500 ( 56.7 )  ua / other1509 ( 27.1)1524 ( 27.8)497 ( 17.3)510 ( 18.0)1012 ( 37.6)1014 ( 38.3)antithrombotic treatment during index hospitalization , n ( % )  aspirin5386 ( 96.6)5316 ( 96.8)2797 ( 97.4)2779 ( 97.8)2589 ( 95.9)2537 ( 95.8 )  unfractionated heparin2910 ( 52.1)2856 ( 51.9)1845 ( 64.2)1845 ( 64.9)1065 ( 39.3)1011 ( 38.0 )  low molecular weight heparin3181 ( 57.0)3084 ( 56.1)1568 ( 54.6)1501 ( 52.8)1613 ( 59.6)1583 ( 59.6 )  fondaparinux194 ( 3.5)191 ( 3.5)87 ( 3.0)76 ( 2.7)107 ( 4.0)115 ( 4.3 )  bivalirudin140 ( 2.5)133 ( 2.4)135 ( 4.7)122 ( 4.3)5 ( 0.2)11 ( 0.4 )  gp iib / iiia inhibitor1170 ( 21.0)1117 ( 20.3)982 ( 34.2)963 ( 33.9)188 ( 6.9)154 ( 5.8)other drug from randomization to end of study , n ( % )  beta - blocker4768 ( 85.4)4685 ( 85.2)2536 ( 88.3)2512 ( 88.4)2232 ( 82.4)2173 ( 81.8 )  ace - inhibitor and/or arb4693 ( 84.2)4602 ( 83.8)2447 ( 85.2)2433 ( 85.6)2246 ( 83.2)2169 ( 81.9 )  statin5196 ( 93.1)5109 ( 92.9)2777 ( 96.7)2745 ( 96.6)2419 ( 89.3)2364 ( 88.9 )  proton - pump inhibitor2776 ( 49.7)2613 ( 47.5)1618 ( 56.3)1536 ( 54.1)1158 ( 42.8)1077 ( 40.5 )  calcium channel inhibitor1553 ( 27.8)1515 ( 27.6)720 ( 25.1)723 ( 25.4)833 ( 30.8)792 ( 29.8 )  diuretic2393 ( 42.9)2280 ( 41.5)1073 ( 37.3)1037 ( 36.5)1320 ( 48.9)1243 ( 46.9)invasive procedures  coronary angiography  during first 10 days , n ( % ) 4143 ( 74.5)4072 ( 74.2)2873 ( 100.0)2841 ( 100.0)1270 ( 47.2)1231 ( 46.6 )  after first 10 days , n ( % ) 357 ( 6.4)335 ( 6.1)0 ( 0)0 ( 0)357 ( 13.3)335 ( 12.7 )  pci  during first 10 days , n ( % ) 2590 ( 46.4)2550 ( 46.4)2590 ( 90.1)2550 ( 89.8)0 ( 0)0 ( 0 )  after first 10 days , n ( % ) 279 ( 5.0)291 ( 5.3)11 ( 0.4)3 ( 0.1)268 ( 9.9)288 ( 10.8 )  cabg  during first 10 days , n ( % ) 296 ( 5.3)305 ( 5.5)296 ( 10.3)305 ( 10.7)0 ( 0)0 ( 0 )  after first 10 days , n ( % ) 382 ( 6.8)375 ( 6.8)55 ( 1.9)55 ( 1.9)327 ( 12.1)320 ( 12.0 ) 
 figure  1trial profile  patients classified by entry ecg and by treatment during the first 10 days after randomization . baseline characteristics and invasive procedures by randomized treatment in the overall nste - acs population , and by initial treatment strategy ( within the first 10 days after randomization ) trial profile  patients classified by entry ecg and by treatment during the first 10 days after randomization . at 10 days post - randomization , there were regional differences in the proportion of patients undergoing revascularization during the initial 10 days ( asia / australia 44% , central / south america 40.3% , europe / middle east / africa 49.8% , north america 71.6% ) . non - revascularized and revascularized patients were of similar age ( 63 vs. 65 ) , but patients who did not undergo revascularization were more likely to be of female gender ( 39 vs. 25% ) , and more likely to have comorbidities ( e.g. previous myocardial infarction , heart failure , renal disease ) . although non - revascularized patients had more comorbidities , they were less likely to be troponin i positive ( table  1 ) . the proportion of patients with timi risk score > 2 was slightly higher in the revascularization group ( 92 vs. 88% ) . during the first 10 days , 47% of non - revascularized patients underwent coronary angiography . when including only those who had angiography during the initial 10 days , female gender was more common in the non - revascularized ( 36% ) than revascularized ( 25% ) . no significant coronary artery disease at angiography was noted in 32 and 0.7% of the non - revascularized and revascularized , respectively . efficacy and safety outcomes of the overall nste - acs population are summarized in table  2 , and kaplan  meier curves are shown in supplementary material online . the incidence of the primary composite endpoint was reduced with ticagrelor vs. clopidogrel ( 10.0 vs. 12.3% ; hr 0.83 ; 95% ci = 0.740.93 ; p = 0.0013 ) ( see supplementary material online , figure s1a ) . cardiovascular death occurred less often in the ticagrelor group than in the clopidogrel group ( 3.7 vs. 4.9% ; hr 0.77 ; 95% ci = 0.640.93 ; p = 0.0070 ) , and myocardial infarction was also less common with ticagrelor vs. clopidogrel ( 6.6 vs. 7.7% ; hr 0.86 ; 95% ci = 0.740.99 ; p = 0.0419 ) , whereas stroke incidence did not differ significantly between treatment arms ( 1.3 vs. 1.4% ; hr 0.95 ; 95% ci 0.691.33 ; p = 0.79 ) . all - cause death was reduced in those treated with ticagrelor vs. clopidogrel ( 4.3 vs. 5.8% ; hr 0.76 ; 95% ci = 0.640.90 ; p = 0.0020 ) ( see supplementary material online , figure s1b ) . table  2efficacy and safety outcomes in patients with nste - acsticagrelor % ( n)clopidogrel % ( n)hr ( 95% ci)p - valueefficacy endpoints  cv death / mi ( excluding silent)/stroke10.0 ( 533)12.3 ( 630)0.83 ( 0.74 , 0.93)0.0013  all - cause death / mi(excl . silent)/stroke10.5 ( 557)13.0 ( 664)0.82 ( 0.73 , 0.92)0.0006  cv death / mi(all)/stroke / severe recurrent ischaemia / recurrent ischaemia / tia / arterial thrombotic event15.5 ( 824)17.8 ( 918)0.88 ( 0.80 , 0.96)0.0058  myocardial infarction ( excluding silent)6.6 ( 345)7.7 ( 392)0.86 ( 0.74 , 0.99)0.0419  cardiovascular death ( includes vascular and unknown deaths)3.7 ( 194)4.9 ( 247)0.77 ( 0.64 , 0.93)0.0070  stroke1.3 ( 69)1.4 ( 71)0.95 ( 0.69 , 1.33)0.79  all - cause death4.3 ( 224)5.8 ( 290)0.76 ( 0.64 , 0.90)0.0020safety endpoints  major bleeding ( study criteria)13.4 ( 660)12.6 ( 618)1.07 ( 0.95 , 1.19)0.26  major or minor bleeding ( study criteria)18.2 ( 900)16.3 ( 794)1.14 ( 1.03 , 1.25)0.0078  non - cabg related major bleeding ( study criteria)4.8 ( 225)3.8 ( 176)1.28 ( 1.05 , 1.56)0.0139  fatal bleeding0.3 ( 13)0.4 ( 18)0.72 ( 0.35 , 1.47)0.37  life threatening or fatal bleeding ( study criteria)6.6 ( 331)6.5 ( 315)1.05 ( 0.90 , 1.22)0.56  intracranial bleeding0.3 ( 14)0.2 ( 7)2.01 ( 0.81 , 4.99)0.13  other major bleeding7.2 ( 344)6.6 ( 318)1.08 ( 0.93 , 1.25)0.34  major bleeding ( timi criteria)9.2 ( 452)8.7 ( 422)1.07 ( 0.94 , 1.22)0.33  major or minor bleeding ( timi criteria)13.2 ( 653)12.3 ( 602)1.08 ( 0.97 , 1.21)0.16  non - cabg related major bleeding ( timi criteria)2.9 ( 137)2.2 ( 99)1.39 ( 1.07 , 1.80)0.0131  gusto severe bleeding3.1 ( 146)3.2 ( 151)0.96 ( 0.77 , 1.21)0.74  gusto moderate or severe bleeding8.6 ( 416)7.8 ( 382)1.08 ( 0.94 , 1.25)0.25each treatment group is summarized as kaplan  meier rates at 360 days and total number of events during the study . p - values and hazard ratios ( 95% ci ) come from unadjusted cox models testing ticagrelor vs. clopidogrel . efficacy and safety outcomes in patients with nste - acs each treatment group is summarized as kaplan  meier rates at 360 days and total number of events during the study . p - values and hazard ratios ( 95% ci ) come from unadjusted cox models testing ticagrelor vs. clopidogrel . with ticagrelor when compared with clopidogrel , there was no significant difference in plato major bleeding ( 13.4 vs. 12.6% ; hr 1.07 ; 95% ci = 0.951.19 ; p = 0.26 ) , but a higher rate of non - cabg - related major bleeding ( 4.8 vs. 3.8% ; hr 1.28 ; 95% ci = 1.051.56 ; p = 0.0139 ) ( see supplementary material online , figure s2a and b ) . there was no significant difference in the rate of life - threatening or fatal bleeding ( 6.6 vs. 6.5% ; hr 1.05 ; 95% ci = 0.901.22 , p = 0.56 ) , nor any significant difference in the rate of intracranial bleeding with ticagrelor compared with clopidogrel ( 0.3 vs. 0.2% ; hr 2.01 ; 95% ci = 0.814.99 ; p = 0.13 ) . the composite of major or minor bleeding ( by plato criteria ) occurred more often in the ticagrelor group ( 18.2 vs. 16.3% ; hr 1.14 ; 95% ci = 1.031.25 , p = 0.0078 ) . when assessed by timi criteria , there was no significant difference in major or minor bleeding ( 13.2 vs. 12.3% ; hr 1.08 ; 95% ci = 0.971.21 ; p = 0.16 ) . timi major bleeding , gusto severe , and gusto moderate or severe bleeding also did not appear to differ significantly between ticagrelor and clopidogrel , whereas timi non - cabg - related major bleeding was more common in the ticagrelor group ( table  2 ) . event rates were considerably higher in nste - acs patients treated without revascularization compared with patients undergoing revascularization during the initial 10 days . for both revascularized and non - revascularized patients , there were similar proportional reductions of the primary endpoint with ticagrelor compared with clopidogrel ( hr 0.86 vs. 0.85 , interaction p = 0.93 ) ( figure  2a , table  3 ) consistent with the overall trial . there was also a consistent reduction in all - cause death ( hr 0.75 vs. 0.73 ; interaction p = 0.89 ) ( figure  2b ) . no significant difference in overall major bleeding was seen with ticagrelor vs. clopidogrel within each treatment strategy ( revascularization / no revascularization ) ( figure  3a ) . there was a higher incidence of non - cabg - related major bleeding with ticagrelor vs. clopidogrel in patients with nste - acs with no significant interaction by invasive treatment strategy ( hr 1.32 vs. 1.07 ; interaction p = 0.43 ) ( figure  3b ) . the primary outcome was reduced in major subgroups in both revascularized and non - revascularized patients ( see supplementary material online , figures s3 and s4 ) . the results were consistent with a 30-day landmark for revascularization ( see supplementary material online , table s1 ) , as well as in the full study population ( see supplementary material online , table s2 ) . in patients who underwent angiography during the initial 10 days with or without significant coronary disease , the effect of ticagrelor vs. clopidogrel was consistent ( see supplementary material online , table s3 ) . table  3interaction of ticagrelor treatment and revascularization within 10 days ( adjusting for region )  nste - acs with revascularizationnste - acs without revascularizationinteraction pnticagrelor km rateclopidogrel km ratehr ( 95% ci)nticagrelor km rateclopidogrel km ratehr ( 95% ci)efficacy endpoints  cv death / mi ( excluding silent)/stroke54165.116.100.86 ( 0.68 , 1.09)51899.6311.600.85 ( 0.72 , 1.01)0.93  all - cause death / mi silent)/stroke54165.446.600.85 ( 0.67 , 1.06)518910.1512.530.84 ( 0.71 , 0.99)0.94  cv death / mi ( all)/stroke / severe recurrent ischaemia / recurrent ischaemia / tia / arterial thrombotic event52908.7310.310.86 ( 0.71 , 1.03)510914.1415.160.97 ( 0.84 , 1.13)0.29  myocardial infarction ( excluding silent)54383.523.880.90 ( 0.68 , 1.21)52016.046.680.94 ( 0.75 , 1.17)0.85  cardiovascular death ( includes vascular and unknown deaths)56481.642.330.76 ( 0.52 , 1.13)52174.075.440.75 ( 0.58 , 0.98)0.95  stroke56320.670.591.18 ( 0.60 , 2.34)52091.481.690.92 ( 0.58 , 1.46)0.56  all - cause death56482.032.880.75 ( 0.53 , 1.07)52174.776.650.73 ( 0.57 , 0.93)0.89safety endpoints  major bleeding ( study criteria)49835.254.681.10 ( 0.84 , 1.44)493111.8311.431.05 ( 0.88 , 1.26)0.82  major or minor bleeding ( study criteria)48427.766.351.22 ( 0.97 , 1.54)484714.5913.961.07 ( 0.91 , 1.25)0.34  non - cabg major bleeding ( study criteria)52703.142.381.32 ( 0.92 , 1.90)49332.782.791.07 ( 0.74 , 1.56)0.43  fatal or life - threatening major bleeding ( study criteria)51732.252.011.18 ( 0.79 , 1.76)49625.776.110.95 ( 0.75 , 1.22)0.37  other major bleeding ( study criteria)51783.102.851.02 ( 0.72 , 1.45)49456.505.681.16 ( 0.91 , 1.49)0.55  major bleeding ( timi criteria)51023.422.791.21 ( 0.86 , 1.70)49528.048.390.97 ( 0.79 , 1.20)0.28  major or minor bleeding ( timi criteria)49905.244.561.12 ( 0.85 , 1.47)493311.7811.161.08 ( 0.91 , 1.29)0.85  non - cabg major bleeding ( timi criteria)53161.881.191.66 ( 1.01 , 2.72)49522.051.841.19 ( 0.76 , 1.87)0.34  gusto severe bleeding52861.161.490.75 ( 0.45 , 1.26)49462.752.461.13 ( 0.77 , 1.65)0.22  gusto moderate or severe bleeding51343.933.301.13 ( 0.82 , 1.55)49457.185.961.19 ( 0.95 , 1.51)0.78kaplan  meier ( km ) rates 350 days after day 10 post - randomization . meier estimates of time to first occurrence of : ( a ) primary endpoint , ( b ) all - cause death , from 10 days post - randomization onward . figure  3bleeding stratified by revascularization  kaplan  meier estimate of ( a ) time to major bleeding according to the plato criteria from day 10 post - randomization , and ( b ) time to non - cabg major bleeding . interaction of ticagrelor treatment and revascularization within 10 days ( adjusting for region ) kaplan  meier ( km ) rates 350 days after day 10 post - randomization . efficacy endpoints stratified by management strategy  kaplan  meier estimates of time to first occurrence of : ( a ) primary endpoint , ( b ) all - cause death , from 10 days post - randomization onward . meier estimate of ( a ) time to major bleeding according to the plato criteria from day 10 post - randomization , and ( b ) time to non - cabg major bleeding . in this subgroup analysis , ticagrelor compared with clopidogrel reduced the composite endpoint of cardiovascular death , myocardial infarction , and stroke as well as the individual endpoints of cardiovascular death , myocardial infarction , and all - cause death without any significant difference in major bleeding in patients with an entry diagnosis of nste - acs . the event curves for the primary composite endpoint and total mortality separated continuously for the duration of the trial . the benefits with ticagrelor were observed both in patients who underwent and in those who did not undergo early revascularization , regardless whether angiography was performed or not . these results are consistent with the previously reported subgroup analysis of all acs patients with an intended strategy ( prior to randomization ) of no revascularization , where about one - fifth still underwent pci and about 4% had cabg surgery before discharge . although current guidelines advocate early invasive management in nste - acs , a large proportion of patients are managed non - invasively . patients who are managed without revascularization usually have more comorbidities , higher risk of bleeding , and inferior outcome than patients who are revascularized . p2y12 inhibition has previously been shown to reduce ischaemic events in nste - acs patients managed without revascularization . in the clopidogrel in unstable angina to prevent recurrent events ( cure ) trial , which randomized nste - acs patients to receive either clopidogrel or placebo ( on background aspirin treatment ) , 64% of patients did not undergo revascularization after randomization . there were almost identical relative reductions in cv death / mi / stroke with clopidogrel in the non - invasive and invasive subgroups . the clopidogrel for high atherothrombotic risk and ischemic stabilization , management and avoidance ( charisma ) trial studied the addition of clopidogrel to aspirin in a stable , more heterogeneous population at risk for atherothrombotic events . overall , the combination was not more effective than aspirin monotherapy , but a trend towards benefit was noted in those with symptomatic atherosclerotic disease , whereas a trend towards harm was seen in those included based only on multiple cardiovascular risk factors . this issue was also recently studied in the trilogy - acs trial , in which nste - acs patients intended for management without revascularization were prospectively randomized to receive either prasugrel or clopidogrel ( both irreversible p2y12 inhibitors ) . the results showed no significant overall benefit of prasugrel over clopidogrel during 24 months , even though the kaplan  meier curves for the efficacy endpoints tended to separate after 1 year , and with a reduction of the primary outcome in the subgroup who underwent angiography . in the no revascularization subgroup of the current plato nste - acs substudy , there were consistent benefits with ticagrelor when compared with clopidogrel concerning both mortality and non - fatal ischaemic events . although the no revascularization subgroup of the present plato substudy seems similar to the trilogy - acs population , it is impossible to compare the effect of the respective new p2y12 inhibitor vs. clopidogrel across the two studies . patients with intention for treatment without revascularization were prospectively studied in trilogy - acs , while the present plato substudy was a post hoc stratification with subgroups of revascularization / no revascularization defined post randomization and post procedures . the trilogy - acs population also was of higher risk with more prevalent comorbidities such as hypertension , dyslipidaemia , and diabetes , and had higher rates of previous myocardial infarction and revascularization procedures . in acs patients managed with revascularization , more potent p2y12 inhibition has been associated with better outcomes , as shown in the intention for invasive management subgroup analysis of plato for ticagrelor and in triton for prasugrel . in the clopidogrel and aspirin optimal dose usage to reduce recurrent events  seventh organization to assess strategies in ischemic syndromes ( current oasis-7 ) trial also , intensified p2y12 inhibition with double dose clopidogrel for the first 7 days showed no significant difference in outcome in the overall population , but a reduction in cardiovascular events , including stent thrombosis in the pre - specified ( albeit post - randomization ) subgroup undergoing pci . with more potent platelet inhibition , 38 , where prasugrel vs. clopidogrel was evaluated in acs , prasugrel demonstrated a reduction in thrombotic events , but at the cost of significantly increased rates of major bleeding , including fatal bleeding , particularly in patients at high bleeding risk defined as high age and low body weight . in trilogy - acs on the other hand , which included a lower maintenance dose , prasugrel did not cause any increased major bleeding rate , including patients > 75 years of age . in the present analysis , there was no significant difference in plato - defined total major bleeding with ticagrelor compared with clopidogrel . however , the incidence of non - cabg - related major bleeding was significantly higher in the ticagrelor group . there was no significant difference in life - threatening or fatal bleeding or major bleeding as defined by the timi criteria , but the composite of plato major / minor bleeding was increased with ticagrelor . the sample size is large , which gives high power to detect even relatively small differences in effect that may or may not be clinically important . the revascularization / no revascularization analyses were post hoc investigations of subgroups identified post - randomization , which makes the analyses subject to potential bias . because landmark analyses were used , the risk of time - dependent confounding is acknowledged . as sensitivity analyses , we also performed landmark analyses at 30 days instead of 10 days , with consistent results . nevertheless , the findings reported with regard to revascularization status should be interpreted strictly as exploratory and hypothesis generating . the present results based on actual revascularization strategy support and complement those of our previous analysis based on pre - randomization intention to treat with invasive or conservative management , and the results based on performed revascularization or not are consistent with the overall nste - acs results , as well as the overall plato results . the sample size is large , which gives high power to detect even relatively small differences in effect that may or may not be clinically important . the revascularization / no revascularization analyses were post hoc investigations of subgroups identified post - randomization , which makes the analyses subject to potential bias . because landmark analyses were used , the risk of time - dependent confounding is acknowledged . as sensitivity analyses , we also performed landmark analyses at 30 days instead of 10 days , with consistent results . nevertheless , the findings reported with regard to revascularization status should be interpreted strictly as exploratory and hypothesis generating . the present results based on actual revascularization strategy support and complement those of our previous analysis based on pre - randomization intention to treat with invasive or conservative management , and the results based on performed revascularization or not are consistent with the overall nste - acs results , as well as the overall plato results . in this substudy of the plato trial , ticagrelor compared with clopidogrel consistently reduced the rates of ischaemic events and mortality without any difference in overall major bleeding in patients with an entry diagnosis of nste - acs , and this effect was independent of whether or not early revascularization was performed . these results harmonize with the european society of cardiology ( esc ) nste - acs guidelines , which recommend ticagrelor in all patients at moderate - to - high risk of ischaemic events , regardless of initial treatment strategy . funding to pay the open access publication charges for this article was provided by astra zeneca . conflicts of interest : d.l . : institutional research grant from astrazeneca to perform this research ; and lecture fees from astrazeneca . c.v . : research grant from astrazeneca to perform this research ; member of the speakers bureaus for astrazeneca , eli lilly & company , and the medicines company . : research grants / support from accumetrics , astrazeneca , csl behring , essentialis , glaxosmithkline , merck , regeneron , sanofi , and takeda ; on advisory boards for alnylam , bristol - myers squibb , lipimedix , and pfizer ( funds donated to charity ) ; and holds equity in automedics medical systems . consulting / advisory board fees from bristol - myers squibb , sanofi , portola pharmaceuticals , johnson & johnson and merck ; grant support from eli lilly / daiichi sankyo . , merck , portola pharmaceuticals , sanofi , johnson & johnson , bristol - myers squibb , the medicines company , and astrazeneca . reports being an employee of astrazeneca and having equity ownership . s.h . : advisory board member for astrazeneca , bristol - myers squibb , pfizer , and bayer ; research support from glaxosmithkline , pfizer , and sanofi - aventis . p.g.s . : research grant ( to inserm u698 ) : nyu school of medicine , sanofi , servier . speaking or consulting : amarin , astrazeneca , bayer , boehringer - ingelheim , bristol - myers - squibb , daiichi - sankyo , gsk , lilly , medtronic , otsuka , pfizer , roche , sanofi , servier , the medicines company , vivus . stockholding : aterovax . j.h.c . : advisory board fees from bms , astrazeneca , eli lilly / daiichi sankyo ; consultancy fees from merck and servier . r.f.s . : research grants from astrazeneca , eli lilly / daiichi sankyo , and merck ; research support from accumetrics ; honoraria from astrazeneca , eli lilly / daiichi sankyo , merck , iroko , accumetrics , and medscape ; consultancy fees from astrazeneca , merck , novartis , accumetrics , sanofi - aventis / regeneron , bristol - myers squibb , eisai , roche and daiichi sankyo . reports no conflict of interest . l.w . : research grants from astrazeneca , merck & co , boehringer - ingelheim , bristol - myers squibb / pfizer , glaxosmithkline ; consultant for merck & co , regado biosciences , evolva , portola , c.s.l . behring , athera biotechnologies , boehringer - ingelheim , astrazeneca , glaxosmithkline , and bristol - myers squibb / pfizer ; lecture fees from astrazeneca , boehringer - ingelheim , bristol - myers squibb / pfizer , glaxosmithkline , and merck & co. ; honoraria from boehringer ingelheim , astrazeneca , bristol - myers squibb / pfizer , glaxosmithkline , and merck & co. ; travel support from astrazeneca and bristol - myers squibb / pfizer . eli lilly , bristol - myers squibb , terumo inc , medtronic , and vascular solutions ; honoraria from the medicines company , astrazeneca , eli lilly , bristol - myers squibb , and iroko ; consultant / advisory board from astrazeneca , eli lilly , merck , medtronic , and sanofi .
aimsthe optimal platelet inhibition strategy for acs patients managed without revascularization is unknown.we aimed to evaluate efficacy and safety of ticagrelor vs. clopidogrel in the non - st - elevation acute coronary syndrome ( nste - acs ) subgroup of the plato trial , in the total cohort , and in the subgroups managed with and without revascularization within 10 days of randomization.methods and resultswe performed a retrospective analysis of the primary endpoint of cardiovascular death / myocardial infarction / stroke . among 18 624 plato patients , 11 080 ( 59% ) were categorized as nste - acs at randomization . during the initial 10 days , 74% had angiography , 46% pci , and 5% cabg . 
 in nste - acs patients , the primary endpoint was reduced with ticagrelor vs. clopidogrel [ 10.0 vs. 12.3% ; hazard ratio ( hr ) 0.83 ; 95% confidence interval ( ci ) = 0.740.93 ] , as was myocardial infarction ( 6.6 vs. 7.7% ; hr 0.86 ; 95% ci = 0.740.99 ) , cardiovascular death ( 3.7 vs. 4.9% ; hr 0.77 ; 95% ci = 0.640.93 ) , and all - cause death ( 4.3 vs. 5.8% ; hr 0.76 ; 95% ci = 0.640.90 ) . 
 major bleeding rate was similar between treatment groups ( 13.4 vs. 12.6% ; hr 1.07 ; 95% ci = 0.951.19 ) , but ticagrelor was associated with an increase in non - cabg major bleeding ( 4.8 vs. 3.8% ; hr 1.28 ; 95% ci = 1.051.56 ) . 
 within the first 10 days , 5366 ( 48.4% ) patients were managed without revascularization . 
 regardless of revascularization or not , ticagrelor consistently reduced the primary outcome ( hr 0.86 vs. 0.85 , interaction p = 0.93 ) , and all - cause death ( hr 0.75 vs. 0.73 , interaction p = 0.89 ) with no significant increase in overall major bleeding.conclusionin patients with nste - acs , benefit of ticagrelor over clopidogrel in reducing ischaemic events and total mortality was consistent with the overall plato trial , independent of actually performed revascularization during the initial 10 days .