ticagrelor versus clopidogrel in patients with acute...

DOI: 10.1161/CIRCULATIONAHA.111.082727

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Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes

and a History of Stroke or Transient Ischemic Attack

Running title: James et al.; Ticagrelor in acute coronary syndromes and stroke

Stefan K. James, MD, PhD1; Robert F. Storey, MD, DM2; Nardev Khurmi, MD3;

Steen Husted, MD, Dsc4; Matyas Keltai, MD, PhD5; Kenneth W. Mahaffey, MD6;

Juan Maya, MD, MS3; Joao Morais, MD7; Renato D. Lopes, MD, PhD6; Jose C. Nicolau, MD,

PhD8; Prem Pais, MD9; Dimitar Raev, MD, ScD10; Jose L. Lopez Sendon, MD, PhD11;

Susanna R. Stevens, MS6; Richard C. Becker, MD6 for the PLATO study group

1Dept of Med Sciences & Uppsala Clinical Rsrch Ctr, Uppsala University, Uppsala, Sweden; 2Dept of Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom; 3AstraZeneca R&D, Wilmington, DE; 4Dept of Cardiology, Århus University Hospital, Århus, Denmark; 5Semmelweis

University, Hungarian Inst of Cardiology, Budapest, Hungary; 6Duke Clinical Rsrch Inst, Durham, NC; 7Santo Andre’s Hospital, Leiria, Portugal; 8University of São Paulo Med School, São Paolo, Brazil; 9St. John’s Med College & Rsrch Inst, Bangalore, India; 10Medical Inst-Ministry of Interior, Sofia, Bulgaria;

11Cardiology Dept, Universidad Autonoma de Madrid, Hospital Universitario La Paz, Madrid, Spain

Correspondence:

Stefan James, MD, PhD

Department of Medical Sciences

Uppsala Clinical Research Center

Uppsala University, Uppsala, Sweden

Tel: +46 18 611 91 28

Fax: +46 18 51 55 70

E-mail: [email protected]

Journal Subject Codes: [3] Acute coronary syndromes, [13] Cerebrovascular disease/stroke, [71] Antiplatelets, [186] Platelet function inhibitors

Susanna R. Stevens, MS6; Richard C. Becker, MD6 for the PLATO studyy g ggroror upupp

Dept of Med Sciences & Uppsala Clinical Rsrch Ctr, Uppsala University, Uppsala, Sweden; 2Dept oCardiovascular Science, University of Sheffield,, Sheffield, United Kingdom; 3AstraZeneca R&D, WiWiWilmlmlmininingtgtgtonoo , DEDEDE;; 4Dept of Cardiology, Århus Unnniviviveerrsity Hospital, ÅÅrhususs,, , DDDenmark; 5Semmelweis

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Abstract:

Background - Patients with acute coronary syndromes (ACS) and history of stroke or transient

ischemic attack (TIA) have an increased rate of recurrent cardiac events and intracranial

hemorrhages.

Methods and Results - We evaluated treatment effects of ticagrelor versus clopidogrel in ACS

patients with and without a history of prior stroke or TIA in the PLATelet inhibition and patient

Outcomes (PLATO) trial. Of the 18,624 randomized patients, 1,152 (6%) had history of stroke or

TIA. They had higher rates of myocardial infarction (11.5 % versus 6.0 %), death (10.5 % versus

4.9 %), stroke (3.4 % versus 1.2%), and intracranial bleeding (0.8 % versus 0.2 %) when

compared to patients without prior stroke or TIA. Among patients with a history of stroke or TIA

the reduction of the primary composite outcome and total mortality at one year with ticagrelor

vs. clopidogrel was consistent with the overall trial results: 19.0% vs. 20.8% (Hazard ratio, HR

0.87; 95% Confidence Interval, CI; 0.66-1.13, interaction p-value=0.84) and 7.9% vs. 13.0%,

HR. 0.62 (95% CI; 0.42, 0.91). The overall PLATO defined bleeding rates were similar; 14.6%

vs. 14.9%, HR 0.99 (95% CI; 0.71, 1.37) and intracranial bleeding occurred infrequently (4 vs. 4

cases, respectively).

Conclusions - ACS patients with prior history of ischemic stroke or TIA had higher rates of

clinical outcomes when compared to patients without prior stroke and TIA. However, the

efficacy and bleeding results of ticagrelor in these high risk patients were consistent with the

overall trial population with a favourable clinical net benefit and associated impact on mortality.

Clinical Trial Registration Information - clinicatrials.gov; Identifier: NCT00391872.

Key words: acute coronary syndrome; antiplatelet; cardiovascular diseases; stroke; Ticagrelor

compared to patients without prior stroke or TIA. Among patients with a history y ofofof sstrrrokokokee e ororor T TIA

he reduction of the primary composite outcome and total mortality at one year with ticagrelor

vss. . clclclopopopidididogogogreel wawawas s consistent with the overall trrriaiaiall results: 19.0%%% v s. 2 2200.0.8% (Hazard ratio, HR

00..8777; ; 95% Coonfnffiidi eenencecee IInnntetetervrvrvalalal, , CICICI;; ; 0.0 6666-1.113,, intteerraacttioioion n ppp-vvavaluluue===0.0 848484) anand dd 77.7.9%9%% vvvs.s. 1 3.3.3.0%0%0%,

HRHRR. . 0.00.62626 ( ((959595%% CCICI; ;; 0.0.44242, ,, 0.0 91911).).). TT Thehehe o ovveverararallllll P PLALALATOTOTO ddeeefifiineneneddd blblbleeeeedidiingngng rrrattees s wewewererer s ssimimimillaaar; ; 1414..6.6%%%

vs. 14.9%, HHR R R 0.0.0 999999 ( ( (95959 % %% CICICI; ; ; 0.0..717171,, 1.11 373737) ) ananand d d ininntrtrracacacrararanniaiaal ll blblb eeeeeedididingngn oooccccccurururrerered dd ininnfrfrfreqeqequeueuentn ly (4 vs. 444


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Introduction

Patients with acute coronary syndromes (ACS) with a history of stroke or transient ischemic

attacks (TIA) are at particularly high risk for recurrent cardiovascular events including death and

myocardial infarction. Clopidogrel combined with aspirin has been used successfully to prevent

thrombotic events in patients with ACS, but patients with prior stroke continue to have a high

risk of ischemic complications and bleeding complications including an increased risk of

intracranial bleeding1, 2.

Ticagrelor is an oral non-thienopyridine P2Y12 inhibitor active upon absorption that binds

directly and reversibly to the receptor, providing faster, greater and more consistent platelet

inhibition than clopidogrel3. The PLATelet inhibition and patient Outcomes (PLATO) trial

showed that ticagrelor was superior to clopidogrel for the prevention of cardiovascular death,

myocardial infarction (MI) or stroke without a significant increase in overall major bleeding in a

broad population of patients with ACS4. A higher rate of major bleeding unrelated to coronary

artery bypass graft surgery (CABG) with ticagrelor was observed. The rates of fatal bleeding

were similar (0.3%) in both the ticagrelor and clopidogrel groups but more patients had fatal

intracranial bleeding in the ticagrelor group (11 of 9,235) compared to the clopidogrel group (1

of 9,186)4.

New and more potent antithrombotic agents need to be evaluated regarding the balance

between efficacy and safety, particularly in the most vulnerable patients. Establishing the clinical

efficacy and safety of ticagrelor versus clopidogrel in patients with prior stroke or TIA was a pre-

specified subgroup analysis of the PLATO trial.

Methods

The PLATO trial randomized 18,624 patients admitted to hospital with ST-segment elevation or

nhibition than clopidogrel3. The PLATelet inhibition and patient Outcomes (PLALAATOTOT ) ) ) trtrtriaiaial ll

howed that ticagrelor was superior to clopidogrel for the prevention of cardiovascular death,

mymyyoococararardididialalal i i innnfarrrctctctioion (MI) or stroke without a sisiigngng iificant increasesee in oooveveverar ll major bleeding in a

bbrroaaad d populatitiononn ooof ppaatiienenenttsts w wwitith h ACACACSSS4.. A hhhigggherrr r raate ooff m mmajjoror b bbleeeedidiinngng uunrnrnreleelatatededed ttto o o cccorororonanaaryyy

arrteteteryryry b b bypypypasasasss s grgraafaftt t susurrrgeereryy (C(CCABABABG)G)G) wwwitith hh tititicccagrgrgrelelororor wwasasa oo obbsbsererrvevev d.d. TT Thehee raatatesess o o ff f fafaatatatall l blbleeeeedidingngng

were similarr ( ( (0.0.0.3%3%%) ) ) ininn b bbotth h h thththe titit cacacagrgrg elellororor a a andndnd c c cloloopipipidodod grgrrelele g ggroror upupups ss bububut t momomorerere p ppatattieieentntn ss s hahah d fatal


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non–ST- segment elevation ACS, with onset during the previous 24 hours, to ticagrelor or

clopidogrel as soon as possible after admission. Details of study design, inclusion and exclusion

criteria, outcome definitions, and results have been published5. For non-ST-segment elevation

ACS, carotid artery disease, previous ischemic stroke, TIA, carotid stenosis or cerebral

revascularization were among the risk factors that were required for inclusion in addition to

either biomarker elevation indicating myocardial necrosis or ST changes on electrocardiogram.

Medical history including any prior stroke or TIA was assessed at the time of randomization and

reported in the clinical report form.

Ticagrelor was given in a loading dose of 180 mg followed by 90 mg twice daily.

Patients randomized to clopidogrel were given a maintenance dose of 75 mg daily. Those who

were clopidogrel naive received a 300 mg loading dose. All patients received acetylsalicylic acid

unless intolerant. The randomized treatment continued for a minimum of 6 to a maximum of 12

months with a median duration of study treatment of 9.1 months.

The primary efficacy variable was time to first occurrence of any event from the

composite of death from vascular causes, MI, or stroke and the first secondary efficacy outcome

was the primary outcome in patients who were intended for an invasive treatment management at

the time of randomization. The primary safety variable was the time to first occurrence of any

PLATO-defined major bleeding. Medical history including any prior stroke or TIA was assessed

at the time of randomization and reported in the clinical report form. A neurologic deficit caused

by an ischemic or hemorrhagic central nervous system event with symptoms lasting at least 24h

after onset or leading to death, constituted a stroke. A focal neurologic deficit that resolved

spontaneously without evidence of residual deficit 24h after onset constituted a TIA. The study

was approved by appropriate national and institutional regulatory authorities and ethics

Patients randomized to clopidogrel were given a maintenance dose of 75 mg daililyy.y TTThohohosesese w wwhhoho

were clopidogrel naive received a 300 mg loading dose. All patients received acetylsalicylic acid

unnleleesssss ii i tntntolololererrant.t. T TTheh randomized treatment contntntinini uued for a miniimumm m m ofofof 6 to a maximum of 12

mmonntnths with a a mmmedddianann d durururatatatioioionnn ofoff ss ttutuddydy treaaatmmmenttt ooof 99.9.111 mmoonntnthshss. fff

TThehee p p pririmmmaryryry e effffiiccacacy y vavaariririabababllele w wwasasas t t tiimime ee totoo f fiirirsttt o occccccuuurrererencncnce ofofof a anynyny eeveveventntnt f froroommm ththhe

composite off d ddeaeae ththth f ffroroom mm vavaascsccululararar c c auaua sesees,s,s, M M MI,I,, o oor r stststrororokeke a aandndnd ttthehee f f firii ststt s s secececooondndndarara y y y efefeffifificacacacyc outcomee


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committees, and all participants gave written informed consent.

Statistical analyses

Patient characteristics were compared by prior history of stroke or TIA status using chi-square

and Wilcoxon rank sum tests. Outcomes were compared for those with and without a history of

stroke using proportional hazards regression models. Hazard ratios (HR) and confidence

intervals (CI) are for prior stroke or TIA versus no prior stroke or TIA. For the primary efficacy

and safety endpoints and all cause death, the time to event is presented by treatment/stroke

history group with Kaplan-Meier curves.

We tested whether the effect of ticagrelor on the primary efficacy and safety endpoints

was different in patients with and without a history of stroke with Cox proportional hazards

regression models that included treatment group, stroke history, and the treatment-by-stroke

history interaction. These models were repeated with the addition of covariates from previously

developed models in the PLATO population6 (Supplemental Table 1). We also tested for

treatment-by-stroke history interactions for other efficacy and safety endpoints. Results are

presented as hazard ratios and 95% confidence intervals for ticagrelor versus clopidogrel

(unadjusted and adjusted where available) for those with and without a stroke history. Event

rates are presented as Kaplan-Meier rate at 360 days and total number of events during the trial.

All analyses were performed according to the intention-to-treat principle, utilizing SAS®

version 9.1. A two-sided p-value of 0.05 was regarded statistically significant for overall

treatment differences.

Results

Patients

was different in patients with and without a history of stroke with Cox proportioonnnal l hahaazazazardrdrds s s

egression models that included treatment group, stroke histord y, and the treatment-by-stroke rr

hiiststtorororyy y iininteteteraractc iooonn.n. TThese models were repeated d wwiwitth the addition n ofo ccovovovaariates from previously

ddedevveveloped moodeded lsl in n ththt ee e PLPLPLATATATO O popopopupuulaaationnn6 (Suuppppplememem ntnttaall TTaabablee 111).)) WWWe e e alalalsoso tttesese tetet dd d fofoforr

rreaeaatmtmmenene t-t-bybyby-s-strtrokokoke e hihiisttororo yy inininteteerararactctctiioionnsns fffororor o oththherere eeffffficccacaccyy y aanand d d sasaafeeetytyty e endndndpopop ininintststs. . RReRessusultltts aararee

presented as hhhazazazararrd d d rararatitit ooos ananand dd 959595% %% cocc nfnfnfididdenenencecece i innnteteervrvrvalalss s fofofor rr titit cacacagrgg elelelororor v vvererersususus s clclc opopopididdogogogrelrrr


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Among the 18,624 patients randomized in the PLATO study, 1,152 (6.2%) were reported as

having a history of stroke or TIA by the investigators (Table 1). Patients with a history of stroke

or TIA were older, more often female, and had more cardiovascular risk factors than patients

without a history of stroke or TIA. One quarter of the patients was above the age of 75 years.

One third of the patients had reported diabetes mellitus. The majority (70.6%) of patients with a

prior stroke or TIA underwent coronary angiography during the initial hospitalization and they

received guideline-recommended concomitant medical therapy to a high degree (Table 2).

Sixty-nine patients reported both prior TIA and prior stroke, 653 had prior non-

hemorrhagic stroke only and 430 had a prior TIA only. Most patients (52%) had their

cerebrovascular event more than 12 months prior to enrolment into PLATO. Five percent had

their event between 6-12 months prior to and 5% of patients within 6 months of enrolment. The

interval was unknown in the remaining 39% of patients.

Outcomes in relation to prior stroke status

Patients with prior stroke or TIA presented higher rates at one year of the primary composite

endpoint, myocardial infarction, death, stroke, major bleeding and intracranial bleeding when

compared to those patients without prior stroke or TIA. After multivariable adjustment, prior

stroke or TIA remained significantly correlated with the primary composite endpoint, total

mortality, and major bleeding not related to coronary artery bypass surgery (Table 3). Endpoint

events with low event rates or for which models have not been previously developed in the

PLATO population were not included in the multivariable analyses.

Outcomes in relation to stroke status and randomized treatment

The overall results for the randomized groups were consistent with the overall PLATO trial

results (Figure 1 and 2). The relative reduction of the primary endpoint with ticagrelor compared

cerebrovascular event more than 12 months prior to enrolment into PLATO. Fivevee p peree cececentntnt h hhadadad

heir event between 6-12 months prior to and 5% of patients within 6 months of enrolment. The

nnteteervrvrvalalal w wwasasas uuunkknononownw in the remaining 39% of pppaata iients.

OOOuttctcomes in rerelalal ttiononn ttoo o prpprioioiorr ststtrororokekee ssttatuuus

PaPatititienenntstst w wititith h h prpriioorr r ststrorokkeke oor TITITIAAA prprpreseseenentetetedd d hhihighghghererr rrata eees aaattt oonone ee yeyeeararr o o off tttheee p priririmmamaryryry c ccomommpooosisitetee ff

endpoint, mymyyocococarara dididialala i iinfnfn arcrcrctitiiononon,, , deded atata h,h,, s s strtrtrokokke,e,e, m mmajajajororr b bleleeedededininingggaa a a andnn iiintntntrararacrcrcranananiaiall l blblbleeeeeedididingn when


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with clopidogrel was consistent in patients with (13%) and without (16%) prior stroke or TIA

(Figure 1A). After multivariable adjustment the HR for patients with prior stroke/TIA was 0.97;

95% CI (0.72, 1.31) with no significant treatment-by-stroke history interaction test (p=0.39).

This reduction was 34% in the subset of patients with a history of stroke or TIA who were

intended for an invasive management at the time of randomization.

For all-cause death, the relative reduction with ticagrelor versus clopidogrel was 38% and

19% in patients with or without a prior history of stroke, respectively (Figure 1B) with no

significant treatment-by-stroke history interaction test (Figure 2). After multivariable adjustment

the HR for patients with prior stroke/TIA was 0.85; 95% CI (0.56, 1.30) with no significant

treatment-by-stroke history interaction (p=0.98). Neither overall stroke rates nor hemorrhagic

stroke rates displayed a significant treatment by subgroup interaction. The number of fatal stroke

events was small with a HR point estimates for ticagrelor versus clopidogrel of 0.43 in patients

with prior stroke or TIA, as compared to 2.23 in patients without prior stroke or TIA. The

treatment-by-stroke history interaction was nominally significant, p=0.029.

Among patients with a prior stroke or TIA, the rate of PLATO defined major bleeding

and non CABG related major bleeding were not significantly different between patients assigned

ticagrelor and clopidogrel (Figure 1C and 2) with adjusted HR of 1.11; 95% CI (0.77, 1.59) and

1.10; 95% CI (0.63, 1.90) respectively. Intracranial bleeding occurred infrequently and with no

difference between the ticagrelor and clopidogrel groups (4 patients each).

These results were consistent with those of patients with prior ischemic stroke alone

(N=653) (data not shown).

Discussion

The present study confirms the findings from several other clinical trials and databases that

reatment-by-stroke history interaction (p=0.98). Neither overall stroke rar tes nor r hehehemomomorrrrrrhahahagigigic c

troke rates displayed a significant treatment by subgroup interaction. The number of fatal stroke

evvenenentststs ww wasasas s s mmmalllll w wwiti h a HR point estimates for ttticicicaaggrelor versust ccclol pipidododoggrel of 0.43 in patients

wwithhh p rior strokokkee oor TTIAIAIA, asasas c ccoomompapaarereredd tooo 2.2223 in pppaattienntntss s wwiwithhhououtt pprprioior r sttrorokekeke oor r TTITIA.A.A. T T Thehehe

rreaeaatmtmmenene t-t-bybyby-s-strtrokokoke e hihiisttororo yy inininteteerararactctctiioionn n wawawass s nonoomimim nnanallly y y sisiigngngniiificiccananant,t ppp=0=0= ..022929.

Amoongngng p ppatatatieieientntts s wiwiiththth a aa pppriririororor s strrrokokokee e ororor T T TIAIAA, , ththhe e rararatetete o o of f PLPLPLATATTO O O dededefififinenen d d d mamamajojoor r r blb eeding


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patients admitted with ACS and a history of stroke or TIA have an increased risk of adverse

ischemic events7, mortality8 and bleeding9 also after multivariable adjustment for baseline

differences. Despite good adherence to guidelines concerning pharmacological therapies and

invasive procedures, patients with prior stroke or TIA demonstrated a doubled mortality rate and

a three and four times higher risk for stroke and intracerebral bleeding, respectively. Therefore,

patients with a history of stroke constitute a real treatment challenge. Most factors indicating

high ischemic risk also indicate high bleeding risk. In this high risk population, the balance

between safety and efficacy of antithrombotic treatment is therefore particularly important.

The reduction of the primary ischemic endpoint, cardiovascular and total mortality of

ticagrelor over clopidogrel in aspirin treated ACS patients with prior stroke or TIA was

consistent with the overall PLATO population with no apparent increase in overall bleeding and

low rates of hemorrhagic stroke and intracranial bleeding.

Ischemic and bleeding outcomes have been evaluated in patients with a history of stroke

or TIA in several previous trials on antithrombotic agents. Clopidogrel compared with placebo

nominally reduced the primary endpoint of cardiovascular (CV) death, myocardial infarction and

stroke in the subgroup of patients with previous stroke and stable atherosclerotic disease in the

Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and

Avoidance (CHARISMA) trial10. Outcomes of clopidogrel vs. placebo in ACS patients with a

history of stroke have not been reported. Dual antiplatelet therapy with aspirin and clopidogrel in

high-risk patients with recent ischemic stroke or TIA was associated with numerical reduction of

major vascular events but increased the risk of life-threatening or major bleeding compared to

clopidogrel alone in the Management of ATherothrombosis with Clopidogrel in High-risk

patients (MATCH) trial11.

icagrelor over clopidogrel in aspirin treated ACS patients with prior stroke or TITIIAA A wawawas ss

consistent with the overall PLATO population with no apparent increase in overall bleeding and

oow w w raraatetetess ofofof h h hemmmorororrhrhagic stroke and intracranialll b b bleeeeding.

Ischemimiicc aannd dd bblb eeeeedididingngng o oututtcococommeess havveve beeen n evaalaluuauateteeddd inin paaatieientnnts wiwiththth aa hhisisistotooryry oof ff ststrrorokkke

orr T TTIAIAIA i inn sesesevveverarall pprprevevvioioousus triririalallsss ononon a antnttitithrhrhromomombobobotitiicc agagagenene tststs. . ClClClopopo iididogogogrerer lll ccoompmpmparararededd w w witithh h plllacaceeebooo

nominally reedududucecec d d d thththe e e prprp immmararary y enenendpdppoio ntntnt ooof f f cacacardrdrdioioovavavascscs ulululararar ( ((CVCVCV) ) ) dedeeatata h,h,h m mmyyyococo ararardididialalal i infnfn arction anddd


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In the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet

Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38)12,

prasugrel reduced the primary composite ischemic endpoint versus clopidogrel at a cost of more

frequent major bleeding events. The rate of intracranial bleeding and overall major bleeding with

prasugrel vs clopidogrel was increased in the cohort of patients with prior history of stroke or

TIA leading to an overall negative net clinical benefit. Prasugrel is therefore contraindicated for

this high-risk subset of patients by most regulatory authorities and guideline committees.

Recently, several trials of novel antithrombotic agents given in combination with other

antiplatelets or anticoagulants, have been terminated prematurely because of bleeding safety

issues in general and intracranial bleedings in particular. The Thrombin Receptor Antagonist –

secondary prevention (TRA-2ºP) trial13 stopped treatment during follow-up phase in patients

with a history of stroke or experienced stroke during the course of the study because the risk of

intracranial hemorrhage outweighed the potential benefit of vorapaxar in these patients.

(http://www.merck.com/newsroom/news-release-archive/research-and-

development/2011_0113.html). The follow-up phase of treatment with vorapaxar on top of mono

or dual antiplatelet therapy14 was also stopped prematurely by the Data Safety Monitoring Board

(DSMB) in the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary

Syndrome (TRACER) trial. The Apixaban for Prevention of Acute Ischemic Events 2

(APPRAISE 2) trial evaluated an oral direct coagulation factor Xa inhibitor apixaban compared

to placebo on top of mono or dual antiplatelet therapy for acute coronary syndromes and

included patients with a prior history of stroke and TIA. The trial was stopped prematurely by

the DSMB due to an increase in overall bleeding events including intracranial and fatal

hemorrhage15. The Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard

ssues in general and intracranial bleedings in particular. The Thrombin Receptoorr r AnAnA taaagogogonininiststst ––

econdary prevention (TRA-2ºP) trial13 stopped treatment during follow-up phase in patients

wiwiththh a aa hh hisisistototoryryy of ff stststroroke or experienced stroke durururiningg the course oof f f the e stststuuudy because the risk of

nntrraaca ranial hememorororrhrhagagge e ououtwtwtweieeiggheheheddd thhhee potteennntial bbeeneeefifiitt ofoff vvvororaapapaxaxarar i nnn ththhesesesee papaatitit eenentstss.

htttptp:/://w/ www.merrckk.comom/newwsrs oooom/m/newsws-r-releleaases --arrchihiveve/r/reeseaearcch-h-anand-d-

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Therapy in Subjects with Acute Coronary Syndrome (ATLAS) trial evaluated rivaroxaban,

another factor Xa inhibitor, but excluded patients with a prior history of stroke or TIA on dual

antiplatelet therapy16. Rivaroxaban reduced the primary ischemic endpoint and mortality but

increased the bleeding incidence considerably including intracerebral and fatal bleeding events.

Limitations

The present study is an underpowered subgroup analysis of the PLATO trial with its inherent

limitations. Due to small numbers significant interactions for the randomized treatment and

outcome cannot be excluded. However, the subgroup consists of over 1,000 patients and the

results are consistent with the overall trial results. For most of the ischemic endpoints and all

stroke related and bleeding endpoints the HR in fact tended to be lower for the ticagrelor vs.

clopidogrel comparison in patients with a history of stroke/TIA as compared to patients without

stroke/TIA. Thus, there was no signal of any particular increased risk with ticagrelor in this high-

risk subset of patients over other ACS patients. Randomization was not stratified for prior stroke

status why unbalances between the groups may exist. Results of this exploratory analysis appear

with nominal significance levels not corrected for multiplicity and should therefore be

interpreted with appropriate caution.

Conclusions

ACS patients with prior stroke or TIA constitute a sizeable subgroup, develop worse outcomes,

and challenge our clinical skills. This analysis of the high-risk subgroup of patients with a history

of stroke or TIA demonstrates that more potent and consistent inhibition of platelet aggregation

with the reversibly-binding P2Y12 receptor inhibitor ticagrelor reduced ischemic events with no

significant increase in overall major bleeding complications, consistent with the overall PLATO

troke related and bleeding endpoints the HR in fact tended to be lower for the titicccagrgg eelelororor vv vs.s.s.

clopidogrel comparison in patients with a history of stroke/TIA as compared to patients without

ttrorookekeke/T/T/TIAIAIA. . . ThTT ususs, , ththere was no signal of any parrrtititiccuular increased d rirr skk wwwiitith h ticagrelor in this high-kk

iiiskkk s subset of ppatattieeentntss ovvvererr o o ottthehher r ACACACSS ppaatiennntss. RRaannndomommiizazatit oonon wwwaaas nnooot ssstrratatatififfiieded ff fororr p prir ooror ssttrt oooke

ttatatatususus w w whyhyy u uunbnnbalallannncecesss bbebetwtweeeeeen n thththe e e grgroououpspsps m m mayayay e exxixissts . ReReesususullts ss ofofof thihihis s s exexxplpllororatata ororory y y anananalalyyysisiss aapppppeeear fff

with nominalal sssigiggnininififificacaancncn e lelelevevv lslss n n notott c orororrereectctctededed f ffororor mmmuluu titiipppliliicicicitytyty a a andnn ssshohohoululu dd d thththererrefefeforororee e bebeb


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trial results. In fact, despite the more potent antithrombotic effect, the risk of intracranial

haemorrhage or fatal stroke was low and total mortality was significantly reduced by ticagrelor.

In light of a favourable clinical net benefit and associated impact on mortality, treatment with

ticagrelor should not be withheld in ACS patients with a history of ischemic stroke or TIA for

safety concerns if otherwise indicated.

Acknowledgments: The complete list of PLATO investigators and main study committees has been published previously. We acknowledge Ebba Bergman, PhD, Uppsala Clinical Research Center for editorial support.

Funding Sources: The PLATO study was funded by AstraZeneca. Support for the analysis and interpretation of results and preparation of the manuscript was provided through funds to the Uppsala Clinical Research Center and Duke Clinical Research Institute as part of the Clinical Study Agreement.

Conflict of Interest Disclosures: Dr James receives institutional research grant and honoraria from AstraZeneca, Eli Lilly, Merck and Bristol-Myers Squibb. He also acts as an advisory board member for AstraZeneca, Eli Lilly and Merck. He also receives honoraria from The Medicines Company. Dr Storey receives research grant from AstraZeneca, Eli Lilly/Daiichi Sankyo, and Merck. He receives research support from Accumetrics and Dynabyte and honoraria from AstraZeneca, Eli Lilly/Daiichi Sankyo, Merck, Novartis, The Medicines company, Iroko, Sanofi-Aventis/Merck, GlaxoSmithKline, Accumterics, Medscape, and Eisai. He receives consultancy fees from AstraZeneca, Merck, Novartis, Accumterics, and Eisai. Drs. Khurmi and Maya are employees of AstraZeneca and having equity ownership in AstraZeneca. Dr. Husted receives advisory board fees from AstraZeneca, Bristol-Myers Squibb, and Bayer. Dr. Mahaffey receives consulting fees from AstraZeneca, Bayer, Boehringer Ingleheim, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Johnson and Johnson, Merck, Ortho/McNeill, Sanofi-Aventis, and Schering-Plough (now Merck). He receives grant support from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Johnson and Johnson, Merck, Novartis, Portola Pharmaceuticals, Pozen, Regado Biosciences, Sanofi-Aventis, Schering-Plough (now Merck), and The Medicines Company. Dr. Morais receives payments from speakers’ bureau from AstraZenecam, Bayer, and MSD, honoraria from AstraZeneca, Bayer, JABA Recordati, and MSD. Dr. Lopes receives research grant from Bristol-Myers Squibb and advisory board fees from Boehringer Ingelheim and Pfizer. Dr. Nicolau receives research grants, consultancy fees and payments from speakers’ bureau from Eli-Lilly and AstraZeneca. Dr. Raev receives honoraria from AstraZeneca. Dr. Lopez-Sendon receives research grants and honoraria from AstraZeneca, Eli-Lilly, Bayer, and Pfizer. Dr. Becker receives research grants from Johnson and Johnson, Bayer, and Redago Biosciences, honoraria and consultancy fees from Johnson and Johnson, Daiichi Sankyo, and Regardo Biosciences.

nterpretation of results and preparation of the manuscript was provided through ffununndsdsd t to o ththee Uppsala Clinical Research Center and Duke Clinical Research Institute as part ooff f ththhe ClClClinininicicicaalal Study Agreement.

Confnfflililictctct oo of f f InInInteerererestst Disclosures: Dr James receieieiveveves institutional reseearararchchc grant and honoraria frfromomom A AstraraZeZeZenecaca, , EEli LLilllyly, MeMerck k annd BrB istool--MyMyMyers SqSquiu bb. HHHee allsoso aca ts aas s ana advvissorry y boardmmmemmbm er forr AAAststtrraraZeZeZ nnenecacaa,, , ElElE i i LiLiLilllllly y ananand d d MeMeMercrcr k.k.k HHHe alssoo o rererececec ivivi eseses h honononorororararriia fffrororom mm ThThThe e MMeMedididicicicinnenes CCoC mmmpany. Dr Sttorororeey rrreccceiveees rer seeararchchh g ggranttt fffrrommm AAAstrraZaZaZeneneneecca, EElli Lillllyyy/D/DDaiaiicichii SSSaannkkyyooo, andnnd MeMeMercrcck.k. He rererececec ivivveeses r reeseeaearchh h susuuppppororort t t frfrroomm A AAccucummemetrtricccs ananddd DDyDynnnabybybyte annnd hhhononnoro ararriaaa frrrommm AsAstrtraZaZaZenenenecececaa, EEElilili LL Lilili lylyly/D/D/Daiaia ichihihi S S Sananankkykyo, M M Meererckckck,, NoNoNovavavarrtititiss,s, T TThehehe MM Medededicicicininneseses cc coompmpmpanananyy,y, I Irorookokoko, , SaSaSanononofifiAvAvAvenenentititis/s/s/MeMeMercrcrckkk, GG GlalalaxoxoxoSmSmSmititithKhKhKlililinenene, AcAcAccucucumtmtmtererericicicsss, MM Meeedsdsdscacacapepepe, anananddd EiEiEisasasaiii. HeHeHe rr recececeieieivevevesss ccconononsususultltltananancycycy fees from AsAsstrtrraZaZaZeneneneceecaaa, M Merererckckck, NNN vovovaartititisss, AA Accccccumumumteteririricsccs, ananandd d EiEiEissasaii.i DDDrsrsrs. KhKhKhururmimimi aandndnd MM Mayya are


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4. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Hea ld C, Horrrowowow J J,, , HuHuHustststededed S, ,James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Hararriririnngngtotoonnn RARARA, nvestigators P, Freij A, Thorsen M. Ticagrelor versus clopidogrel in patients with acute

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5.5. J Jaaames SS, AkAA ererblblblomom A AA, , , CaCaC nnnnononon C C P,P,, E Emamanunuelelsss ononon H,H, H HHususustet d S,S,S, KKKatatususs H H , SkSkenenenee e A,A, SSteteteg g g PGPGPG, , SStStorrreye RF, Hararririringggtoonnn R,R,R, B B Becececkkeker r R,R,R, W WWaalllennttinnn L. CCCompmpmpararisissoonn o off ttiiccagagrerelolor,r,, t thhehe f ffiririrststt r reeveerersiisiblbb eee ororrall p p 2y(12)) r recepepepttor ananntagogooniniist, wiwiiththt cllopidododogrelll iinn papapatititienenentsts wiitthh acuttte ccorroronanan ry ssyynyndddrooomess:RaRaatititionononalala e,e,e, d ddeesesigiggnnn, aandndd b basaseeliiinenen ccchahaharraractcttererrisisistititicscss o o of f ththee plplplatatateleleleeet iiinhnhn ibibitititioioi nnn aannd d papap titit enenntt t oououttccoomomesess plaatoto) ) triaial.l Amm HHeaearrt J. 220009;9;15157:7 599-60605.5.

66 JJamameses SS AnAngigiololilillolo DDJJ CCorornenell JHJH ErErlilingngee DD HHusustetedd SS KKonontntnyy FF MMayayaa JJ NNicicololauau JJCC


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16. Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, Burton P, Cohen M, Cook-Bruns N, Fox KA, Goto S, Murphy SA, Plotnikov AN, Schneider D, Sun X, Verheugt FW, Gibson CM, Investigators AAT. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012;366:9-19.

N Engl J Med. 2007;357:2001-2015.

13. Morrow DA, Scirica BM, Fox KA, Berman G, Strony J, Veltri E, Bonaca MMP,P FF Fiisish hh PPP, McCabe CH, Braunwald E; TRA 2(o)P-TIMI 50 Investigators. Evaluation of a novel antiplateletfagent for secoconddarary y prevention in patients with a a history of atherosclerototic disease: design and aatitionononalalalee fofofor r ttthe e ThThThrrombin-Receptor Antagonist tt inini SSecondary Preveve enntitiiononon of Atherothromboticfsschchcheemic EEveveentts s (T(T(TRARAA 2 2 d ddegege rereeseses P P P)-)-TITIMIMI 5 500 trtriaiall. AAm HHHeaeaeartrr JJ. . 2020200909;1;158585 :33535-3-3341414 .e.e3.3.

14144. TTrT icoci P,P,, H uauauanng ZZZ, Heelldd C,C,C MMololo itterernno DDDJJJ, Armrmrmststrororongngng P P PWWW, VaVaVan deee WWWeerf f F,F, WWWhiiitete HHDD, AyAyylwlwlwararardd PEPEE,, WaWaalllenentitiinn L,L,L CCheheh n nn E,E,E, L LLokokkhnhnhnygygyginnna aa YYY, PPeieii JJJ, , LLeLeonononararrddi ii S,S,S R RRoorricickk k TTLTL, , , KiKiKililiaanan AAAMMM, Jennninings L LH,H AAmbmbrorosis o G,G BBodode e C,C Ceqquiuierer A A, CoC rnnelel JJH,H, D Diaiaz RR, ErErkak n n A,A HHububer KK, HuHudsdsonn MP, Jiang L,L,, J JJukukukememema a JWJWJW, LeLeLewiwiwis s s BSBSBS, , LiLiLincncncofofoff f f AMAMAM,, MoMoM ntntntalalalesesescococot t t G,GG NNNicicicolololauauau J JC,C,C, OOOgagagawawaw H, PfPfisisteterererr MM PPririetetoo JCJC RuRuzyzylllloo WW SSininnanaevevee PRPR StStororeyey RRFF VValalgigimmigiglili MM WhWhelellalann DJDJ


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Table 1. Patient characteristics at baseline

Prior stroke or TIA*, N=1,152 Median (25th, 75th) or N (%)

No prior stroke or TIA*, N=17,458 Median (25th, 75th) or N (%)

Characteristic Ticagrelor Clopidogrel Ticagrelor Clopidogrel P†

Age (years) 67 (59 - 74) 68 (60 - 75) 62 (54 - 70) 62 (54 - 70) <0.0001 Age 75 years 136 (24.1) 152 (25.9) 1259 (14.4) 1329 (15.3) <0.0001 Gender, women 192 (34.0) 197 (33.5) 2462 (28.1) 2433 (28.0) <0.0001 Body weight (kg) 80 (70 - 88) 77 (68 - 86) 80 (70 - 90) 80 (70 - 90) 0.0024 Body weight <60 kg 39 (6.9) 45 (7.7) 613 (7.0) 615 (7.1) 0.7511 BMI (kg/m2) 27.5 (24.9 - 30.9) 27.3 (24.5 - 30.4) 27.4 (24.7 - 30.5) 27.3 (24.7 - 30.4) 0.5212 Race 0.0034 Black 7 (1.2) 16 (2.7) 108 (1.2) 98 (1.1) Caucasican 506 (89.7) 519 (88.3) 8053 (91.9) 7988 (91.8) Oriental 41 (7.3) 47 (8.0) 501 (5.7) 507 (5.8) Other 10 (1.8) 6 (1.0) 99 (1.1) 106 (1.2) Cardiovascular Risk Factors Habitual smoker 163 (28.9) 129 (21.9) 3197 (36.5) 3188 (36.7) <0.0001 Hypertension 495 (87.8) 490 (83.3) 5644 (64.4) 5553 (63.8) <0.0001 Dyslipidemia 321 (56.9) 350 (59.5) 4026 (46.0) 3991 (45.9) <0.0001 Medical History Angina Pectoris 315 (55.9) 335 (57.0) 3905 (44.6) 3802 (43.7) <0.0001 Myocardial Infarction 167 (29.6) 181 (30.8) 1733 (19.8) 1743 (20.0) <0.0001 Congestive Heart Failure 63 (11.2) 67 (11.4) 450 (5.1) 470 (5.4) <0.0001

Percutaneous coronary intervention 91 (16.1) 90 (15.3) 1181 (13.5) 1130 (13.0) 0.0169

Coronary Artery Bypass Graft 58 (10.3) 62 (10.5) 474 (5.4) 512 (5.9) <0.0001

Peripheral Artery Disease 86 (15.2) 70 (11.9) 480 (5.5) 507 (5.8) <0.0001

Chronic Renal Disease 31 (5.5) 45 (7.7) 348 (4.0) 361 (4.1) <0.0001 Treatment OL clopidogrel dose 600 mg before randomization

43 (7.6) 37 (6.3) 1113 (12.7) 1074 (12.3) <0.0001

Total clopidogrel (OL+IP) dose 600 mg, before randomization To 24h after first dose

79 (14.0) 73 (12.4) 1871 (21.4) 1822 (20.9) <0.0001

Intended invasive treatment 337 (59.8) 345 (58.7) 6388 (72.9) 6328 (72.7) <0.0001

Baseline labs Glucose, mmol 6.9 (5.7 - 8.7) 7.0 (5.7 - 9.4) 6.9 (5.7 - 8.8) 6.8 (5.7 - 8.7) 0.3288 Creatinine clearance, ml/min 74.4 (57.8 - 88.6) 73.4 (57.8 - 87.4) 83.2 (67.0 - 98.9) 82.3 (66.4 - 97.7) <0.0001

First central troponin I‡, umol/L 1.9 (0.2 - 10.2) 2.2 (0.2 - 11.5) 2.0 (0.2 - 11.9) 2.2 (0.2 - 12.2) 0.5325

*69 patients had both prior Transient Ischemic Attack (TIA) and prior stroke, 653 had prior non-hemorrhagic stroke only, and 430 had prior TIA only; †P-value from chi-square or Wilcoxon rank sum test comparing patients with and without stroke or TIA. BMI = Body Mass Index; OL = Open label; IP= Investigational product, ‡Advia Centaur TnI-Ultra Immunoassay (Siemens).

yAngina Pectoris 315 (55.9) 335 (57.0) 3905 (44.6) 38020202 ( (434343.7.77) ) ) <0.Myocardial Infarction 167 (29.6) 181 (30.8) 1733 (19.8) 11774743 (2(200.0.0)0)0) <0.0Congestive Heart Failure 63 (11.2) 67 (11.4) 450 (5.1) 470 (5.4) <0.

Percutaneous coronaryintetervrvenenntititionono 91 (16.1) 90 (15.3) 1181 (13.5)) 1130 (13.0) 0.0

CoCoorororonnanaryr AAArtrtrtereryy BBByppapass Graftf 5858 (100.3.3) 62 ( (100.5.55) 4 477474 (5..4)4) 5 512 (5.5.9)) <0.

PPPerririppheral Arterry y DDiD sssease 8686 ( ((1555.22) 7770 ((11.999) 4 4800 (5.5 5)5) 550007 (((5.5 888) <0.

CCChrororonin c Renaal l DiDD seeasasee 3131 ( 55.5.5)5 4455 (7.77)) 3 3488 (4.0)) 36661 (((44.111) <0.TrTreaeaeatmtmmenenenttt tOLL cclolopidoogrgrel ddose 600 mg before e randomization n

4343 ( ((7.7 6)6)) 3 3 37 7 (6(6.3.3) ) 1111113 (1(1(12.2.7)7)) 1 107074 4 (1(1( 2.2 3) <00.


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Table 2. Medication and procedures during study and final diagnosis according to stroke status

Prior stroke or TIA*,

N=1,152

Median (25th, 75th) or N (%)

No prior stroke or TIA*,

N=17,458

Median (25th, 75th) or N (%)

Characteristic Ticagrelor Clopidogrel Ticagrelor Clopidogrel P†

Medication from index event to end

of hospitalization, % (n)

Aspirin 545 (96.6) 565 (96.1) 8514 (97.2) 8449 (97.3) 0.0752

Beta-blockers 474 (84.0) 485 (82.5) 7505 (85.7) 7476 (86.1) 0.0132

ACE-inhibitors and/or ARB 505 (89.5) 510 (86.7) 7255 (82.8) 7202 (82.9) <0.0001

Cholesterol lowering (Statin) 520 (92.2) 519 (88.3) 8232 (94.0) 8186 (94.2) <0.0001

Ca-channel blockers 192 (34.0) 187 (31.8) 1794 (20.5) 1850 (21.3) <0.0001

Diuretics 299 (53.0) 309 (52.6) 3260 (37.2) 3124 (36.0) <0.0001

Glycoprotein IIb/IIIa inhibitors 106 (18.8) 116 (19.7) 2407 (27.5) 2408 (27.7) <0.0001

Insulin 123 (21.8) 144 (24.5) 1559 (17.8) 1513 (17.4) <0.0001

Any anti-diabetic medication 186 (33.0) 199 (33.8) 2242 (25.6) 2183 (25.1) <0.0001

Procedures, % (n)

Coronary angiography before

discharge 402 (71.3) 411 (69.9) 7196 (82.1) 7159 (82.3) <0.0001

Coronary angiography during study 435 (77.1) 444 (75.5) 7572 (86.4) 7527 (86.5) <0.0001

PCI before discharge 264 (46.8) 270 (45.9) 5423 (61.9) 5405 (62.1) <0.0001

PCI during study 289 (51.2) 291 (49.5) 5689 (64.9) 5707 (65.6) <0.0001

Stenting 260 (46.1) 254 (43.2) 5380 (61.4) 5394 (62.0) <0.0001

With bare-metal stent only 157 (27.8) 170 (28.9) 3764 (43.0) 3721 (42.8) <0.0001

With 1 drug-eluding stent 103 (18.3) 84 (14.3) 1616 (18.4) 1673 (19.2) 0.0280

CABG before discharge 30 (5.3) 33 (5.6) 435 (5.0) 472 (5.4) 0.6853

CABG during study 62 (11.0) 67 (11.4) 869 (9.9) 901 (10.4) 0.2494

Final diagnosis, % (n) <0.0001

STEMI 149 (26.4) 156 (26.6) 3347 (38.3) 3374 (38.8)

NSTEMI 271 (48.0) 275 (46.9) 3734 (42.7) 3675 (42.3)

Unstable angina pectoris 128 (22.7) 140 (23.9) 1421 (16.2) 1422 (16.4)

Other 16 (2.8) 15 (2.6) 243 (2.8) 215 (2.5) *69 patients had both prior Transient Ischemic Attack (TIA) and prior stroke, 653 had prior non-hemorrhagic stroke only, and 430 had prior TIA only; †P-value from chi-square or Wilcoxon rank sum test comparing patients with and without stroke or TIA. PCI= Percutaneous Coronary Intervention, CABG=Coronary Artery Bypass Surgery

Glycoprotein IIb/IIIa inhibitors 106 (18.8) 116 (19.7) 2407 (27.5) 2424080808 ( (272727.7.7)) <0< .

Insulin 123 (21.8) 144 (24.5) 1559 (17.8) 111515113 (1(1(17.7.7.4)4)4) <<0.0

Any anti-diabetic medication 186 (33.0) 199 (33.8) 2242 (25.6) 2183 (25.1) <0.

Procedures, % (n)

CoCoorororonnanaryr aangngngioogrrapaphhyhy before

dddiscchah rge 40402 2 (7(71.1.3)3) 44111 (6969.9.9) ) ) 7719966 (8(8( 2.2 1)) 7 715159 9 (8(82.2 3)3)) <<0.

CCooronary anggiogrrrappphy dddurrring g sststuududy 434 555 ((777.1)) 444444 (75755.5.5.5) ) ) 75722 (8886.444) 7752525 77 (8866..5) <<0.

PCPCPCI II bebeb foforeree d d diisischchaaarggege 2 2264644 ( (464646.8.8.8)) 272770 0 (4(445.5.9)9)9) 5454542323 (66161.9.99)) ) 5454540005 ( (6262.1.1) ) <0< .

PCPCI I duduringngg stutudyyy 2 289 (((5151.2.2) ) ) 291 (4(4( 9.9.5)5)) 56568989 ( ((6464.9.9) )) 570707 ( ((6565.6.6) ) ) <0<0.

Stenting 22260600 (( (46466 1.11)) 252554 44 ((43.33 2)2)2) 535353808080 (((616161.444)) 53535 949494 (62.0) <00.


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Table 3. Association of prior stroke with endpoint

Unadjusted Adjusted

Endpoint

Prior stroke

or TIA

(n=1,152)

No prior

stroke or TIA

(n=17,460)

HR (95% CI) Chi-

Square p HR (95% CI)

Chi-

Square p

Primary Outcome: CV Death / MI

(excl. silent) / Stroke 19.9 (215) 10.1 (1663) 2.06 (1.78, 2.37) 98.9672 <0.0001 1.65 (1.40, 1.93) 36.7953 <0.0001

Cardiovascular Death (includes

vascular and unknown deaths) 9.7 (102) 4.2 (693) 2.29 (1.86, 2.82) 61.1987 <0.0001

All Cause Death 10.5 (111) 4.9 (794) 2.18 (1.79, 2.66) 59.1666 <0.0001 1.68 (1.33, 2.11) 19.7284 <0.0001

Myocardial Infarction (excluding

silent) 11.5 (119) 6.0 (978) 1.92 (1.59, 2.33) 45.3974 <0.0001

Major Bleeding (Study Criteria) 14.8 (144) 11.2 (1746) 1.31 (1.10, 1.55) 9.5022 0.0021 1.18 (0.98, 1.43) 2.9463 0.0861

Non-CABG Related Major Bleeding

(Study Criteria) 6.3 (60) 4.0 (608) 1.56 (1.20, 2.04) 10.8716 0.0010 1.38 (1.03, 1.85) 4.5464 0.0330

Stroke 3.4 (36) 1.2 (195) 2.90 (2.03, 4.14) 34.4170 <0.0001

Intracranial bleeding 0.8 (8) 0.2 (33) 3.95 (1.82, 8.55) 12.1333 0.0005

Event rates are presented as Kaplan-Meier rate at 360 days and total number of events during the trial. Variables included in the multivariable model; age, sex, prior myocardial infarction, heart failure, hypertension, smoking, height, weight, previous percutaneous coronary intervention, coronary artery by-pass surgery, ST elevation or left bundle branch block on ECG at entry, estimated creatinine clearance, heart rate, peripheral artery disease, prior tachyarrhythmia, blood pressure, and prior angina pectoris

ent) / Stroke

scular Death (includes

and unknown deaths) 9.7 (102) 4.2 (693) 2.29 (1.86, 2.82) 61.1987 <0.0001

e Death 10.5 (111) 4.9 (794) 2.18 (1.79, 2.66) 59.1666 <0.0001 1.68 (1.33, 2.11) 19.7284 <0.000

ial Infarction (excluding 11.5 (119) 6.0 (978) 1.92 (1.59, 2.33) ) 45.3974 <0.0001

eeeedidid gngng ( (StStudu y CrCrititit rere ia) 14.8 (144)) 11.2 (1746) 1.31 (1.10, 1.1. 5555 ) 9.5022 0.00021212 1.1.1818 (0.98, 1.43) 2.9463 0.0861

BGBGBG RR Relelated Majoror BBleeedededinii g g

iririte iiria)a) 6.6.6 3 (6(6(6 )0)0) 4.4 0 0 (6(6(6 8808) ) 1.1 56 ( (1.1 0202 , 2. 4040 ) 001 8.871716 6 0.0. 0000 0010 1. 8383 ((1...03030 , , 1.1.8585))) 4.4. 4545 6444 .0.030 30

.3.3 4 (3(( 6) 1.1 2 (1959595) ) 2.2 90 ( (2.2 3030 , 4. 441 ) 4343 44.417170 0 <0 00.0 0001 1

iialal b eleleedededining g 0.0.88 (8(8(8) ) 0.2 2 (3(3(33)3) 3.95955 ( (1.1.828282, 8.8..55555 )) ) 21212.1.13333333 3 00. 0000005050

rararatetetesss ararareee prprpresesesenenenteteteddd asasas KK Kapapaplalalann-n MeMeMeieieierrr rararatetete aa attt 363636000 dadadaysysys aa andndnd tt totototalalal nn numumumbebeberrr ofofof ee eveveventntntsss dududuririringngng tt thehehe tt triririalalal. VaVaVariririababablelelesss inininclclcludududededed ii innn ttthehehe mm mululultititivavavariririababablelele mm modododeeettttrior myocardial ininfafaarcrcr titit onnon, , heheheararrtt t fafaaili urre,e,e, h h hypypy rrertetetensnsn ioioon,n,n smomomokikikingngng, , heheeigigighthth , , weweweiggghthth , prprpreveve ioioioususus p p errercucucutat eneneououous s cococorororonananaryryr i intntntererervevevennntititionnon, , coronary artery y bururgegeryry, STST e elelevavatitionon o orr leleftft b bunundldlee brbrananchch b blolockck o onn ECECGG atat e entntryry, esestitimamatetedd crcreaeatitinininene c cleleararanancece, hehearartt raratete, pepeririphphereralal ararteteryry d disiseaeasese, prprioiorr


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Figure Legends:

Figure 1. Cumulative incidence of the primary composite of cardiovascular death, myocardial

infarction and stroke (A), total mortality (B) and major bleeding (C) in the ticagrelor (solid

lines) and clopidogrel (dotted lines) groups in patients with a history of prior stroke or TIA (blue

lines) and no previous stroke or TIA (red lines) at baseline. Event rates are presented as Kaplan-

Meier rate at 360 days and total number of events during the trial.

Figure 2. Association of randomized treatment with endpoint by prior stroke or TIA.


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L. Lopez Sendon, Susanna R. Stevens and Richard C. BeckerJoseMahaffey, Juan Maya, Joao Morais, Renato D. Lopes, Jose C. Nicolau, Prem Pais, Dimitar Raev,

Stefan K. James, Robert F. Storey, Nardev Khurmi, Steen Husted, Matyas Keltai, Kenneth W.Stroke or Transient Ischemic Attack

Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes and a History of

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 2012 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation published online May 9, 2012;Circulation.

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SUPPLEMENTAL MATERIAL

Table 1. Co- variates in the multivariable analyses

CV Death / MI (excl. silent) /

Stroke All-cause mortality Major bleeding Non-CABG Related Major

Bleeding (Study Criteria) Prior MI Prior MI Heart rate (linear spline for ≥75) Heart rate WBC count WBC count WBC count (linear spline for ≤5) WBC count Prior CABG Prior CABG Age Age Age (linear spline for ≤65) Age Killip class Killip class Killip class Hemoglobin (linear spline for

≤145) Hemoglobin (linear spline for



≤150) Prior PAD Prior PAD Prior PAD

Onset of symptoms to

randomization (2 linear splines

split at 18)

Onset of symptoms to

randomization (linear spline for

≤18)

Prior diabetes Prior diabetes Prior diabetes Log creatinine (linear spline for

≥4.4)

Changes in ECG at entry Changes in ECG at entry Region (Asia/Australia,

Central/South America, North

America, Europe/Middle

East/Africa)

Region (Asia/Australia,



East/Africa)

ACS diagnosis (STEMI, unstable

angina, NSTEMI/Other) ACS diagnosis (STEMI, unstable

angina, NSTEMI/Other) ACS diagnosis (STEMI, unstable

angina, NSTEMI/Other)

Ticagrelor Ticagrelor Ticagrelor

Systolic blood pressure (linear

spline for ≤140)

Prior CHF

Troponin

Female sex

Smoking status (habitual, former,

never)

Dyslipidemia

ST depression (≥1 mm)

Angina pectoris

Creatinine clearance (linear spline

for ≤80)

Glycoprotein IIb/IIIa inhibitors

Prior GI bleed

Prior CABG – by – changes in

ECG at entry interaction

Heart rate (linear spline for ≥75)

– by- WBC count interaction

Prior CABG –by- age interaction Hemoglobin (linear spline for

≤145) – by – prior PAD

interaction

Age – by – prior MI interaction

Age – by – heart rate interaction

WBC count – by - onset of

symptoms to randomization

(linear spline for ≤18)

Region (Asia/Australia,



East/Africa) – by - ACS diagnosis

(STEMI, unstable angina,

NSTEMI/Other) interaction

Sex – by - ACS diagnosis

(STEMI, unstable angina,

NSTEMI/Other) interaction

Age (linear spline for ≤65) – by -

ACS diagnosis (STEMI, unstable

angina, NSTEMI/Other)

interaction

Glycoprotein IIb/IIIa inhibitors –

by – Ticagrelor interaction

ticagrelor versus clopidogrel in patients with acute...

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