Cangrelor: an emerging therapeutic option for patients with coronary artery disease

Current Medical Research & Opinion 2014, 1–16

0300-7995 Article ST-0296.R1/880050

doi:10.1185/03007995.2014.880050 All rights reserved: reproduction in whole or part not permitted

Review articleCangrelor: an emerging therapeutic option forpatients with coronary artery disease

Jacek KubicaMarek KozinskiEliano Pio NavareseCollegium Medicum, Nicolaus Copernicus University,

Bydgoszcz, Poland

Udaya TantrySinai Hospital of Baltimore, Baltimore, Maryland, USA

Aldona KubicaCollegium Medicum, Nicolaus Copernicus University,

Bydgoszcz, Poland

Jolanta Maria Siller-MatulaMedical University of Vienna, Vienna, Austria

Young-Hoon JeongGyeongsang National University Hospital, Jinju,

Republic of Korea

Tomasz FabiszakAnna AndruszkiewiczCollegium Medicum, Nicolaus Copernicus University,

Bydgoszcz, Poland

Paul Alfred GurbelSinai Hospital of Baltimore, Baltimore, Maryland, USA

Address for correspondence:Marek Kozinski MD PhD, Department of Cardiology

and Internal Medicine, Collegium Medicum, Nicolaus

Copernicus University, 9 Curie-Skłodowskiej Street,

85-094 Bydgoszcz, Poland.

Tel: +48 52 5854023; Fax: +48 52 5854024;

[email protected]

Keywords:Antiplatelet therapy – AR-C69931MX – Cangrelor –

P2Y12 inhibitor

Accepted: 31 December 2013; published online: 24 January 2014

Citation: Curr Med Res Opin 2014; 1–16

Abstract

Objectives:

To perform a systematic up-to-date review and critical discussion of potential clinical applications of

cangrelor based on its pharmacologic properties and the main findings from randomized clinical studies.

Methods:

A database search (PubMed, CENTRAL and Google Scholar) by two independent investigators, including

proceedings from scientific sessions of ACC, AHA, ESC, TCT and EuroPCR, from January 1998 through

December 2013.

Results:

Cangrelor is a potent, intravenous, direct-acting P2Y12 antagonist with rapid onset and quickly reversible

action. In contrast to ticagrelor, cangrelor’s interaction with thienopiridines requires termination of cangrelor

infusion before switching to clopidogrel or prasugrel. According to randomized trials, a cangrelor–

clopidogrel combination is relatively safe and more effective than the standard clopidogrel regimen in

both urgent and elective percutaneous coronary intervention (PCI) settings, with the advantage of this

drug combination fully evident when the universal definition of myocardial infarction is applied. In

contrast to available antiplatelet drugs with delayed onset and offset of action, its favorable properties

make cangrelor a desirable agent for ad hoc elective PCI, high risk acute coronary syndromes treated with

immediate coronary stenting and for bridging those surgery patients who require periprocedural P2Y12

inhibition. Current evidence on cangrelor therapy is limited by the lack of adequately powered studies

assessing cangrelor co-administration either with prasugrel or ticagrelor, suboptimal design of some of the

trials favoring cangrelor, potentially attenuated benefits with modern stent design, and finally, by the lack of

survival advantage.

Conclusions:

With its pharmacokinetic and pharmacodynamic advantages, allowing consistent and strong P2Y12

inhibition, and with its rapid onset and swift reversal of action devoid of need for an antidote, cangrelor

might improve clinical outcomes in clopidogrel-treated patients by reducing ischemic events, while

maintaining a favorable safety profile. However, further studies, addressing the safety and efficacy of

cangrelor on top of novel oral P2Y12 inhibitors, are warranted.

Introduction

The discovery of the critical role of the P2Y12 receptor in platelet activationand thrombus formation has led to development of its inhibitors and theirsubsequent widespread use in treatment and secondary prevention in acutecoronary syndromes (ACS) and percutaneous coronary interventions(PCI)1–3. P2Y12 receptor blockade prevents initial activation and amplificationof responses to platelet stimuli, while leaving the final common pathway ofplatelet aggregation intact4.

! 2014 Informa UK Ltd www.cmrojournal.com Cangrelor in coronary artery disease Kubica et al. 1

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mailto:[email protected]

The P2Y12 receptor is the molecular target for thieno-pyridines: ticlopidine, clopidogrel and prasugrel, whoseactive metabolites, formed in the liver, covalently bindto the P2Y12 receptor5,6, as well as for direct, reversibleantagonists, such as ticagrelor, cangrelor, and elinogrel7–9.The latter two, potentially very attractive, are still underclinical evaluation. In contrast to currently availableP2Y12 inhibitors administered only orally, cangrelor isan intravenous agent, while elinogrel may be administeredeither orally or intravenously. Conversely to relativelysparse clinical experience with elinogrel, cangrelor hasalready completed the CHAMPION (Cangrelor versusstandard therapy to acHieve optimal Managementof Platelet InhibitiON) program consisting of threephase III trials including together more than 25,000patients10–12. Based on their results, particularly on thesuperiority of cangrelor combined with clopidogrel overclopidogrel alone, proven in the recent CHAMPIONPHOENIX trial12, it faces a real chance to soon beimplemented in clinical practice.

The aim of this systematic review was to criticallydiscuss potential clinical applications of cangreloraccording to currently available knowledge based on thepharmacologic properties of this new cardiovascular drugand on the main findings of randomized clinical studies.

Methods

A systematic investigation of all published andunpublished literature including oral presentations wasconducted to minimize the risk of bias. Briefly, we followedthe PRISMA statement for reporting systematic reviews inhealth care interventions13. A database search includingPubMed, CENTRAL and Google Scholar databases, cov-ering the period from January 1998 through December2013 was conducted by two independent investigators(J.K. and M.K.), neither involved in any of the retrievedstudies. Proceedings from the Scientific Sessions of theAmerican College of Cardiology (http://www.acc.org),American Heart Association (http://www.heart.org),European Society of Cardiology (http://www.escar-dio.org), Transcatheter Cardiovascular Therapeutics(http://www.tctmd.com) and EuroPCR (http://www.eur-opcr.com) were also considered. The following keywordswere applied: ‘cangrelor’ and ‘AR-C69931MX’. Referencesof retrieved studies were searched manually for additionalstudies and reviews. No language restrictions were applied.Data were abstracted on prespecified forms. Alldivergences were resolved by discussion with a third inves-tigator (E.P.N.). Both preclinical and clinical studiesreporting on pharmacokinetics, pharmacodynamics, inter-actions, adverse effects, safety and efficacy of cangrelorwere considered eligible only if full-text publication wasavailable. Studies were included in the systematic review

as long as they clearly reported study design, participantor animal characteristics, cangrelor regimen, durationof therapy, reason for treatment, and adverse effects orevents. Data was extracted regarding the above mentionedcharacteristics of the included studies. Reviews were alsoconsidered a source of citations of relevant studies andinterpretation of their results.

After a systematic search 13,563 citations wereidentified: 590 in PubMed, 15 in CENTRAL, 12,860 inGoogle Scholar, and 98 in other databases. Duplicate/multiple citations and reviews not containing any relevantinformation were excluded. Eventually, 89 papers oncangrelor or providing a rationale for therapy withcangrelor were considered eligible for inclusion in thesystematic review.

Rationale for therapy with cangrelor incoronary artery disease

Although the introduction of oral P2Y12 inhibitors to thecardiovascular armamentarium is regarded as a greatadvance, therapy with these drugs is flawed by several limi-tations. First of all, clopidogrel, the only currentlyapproved compound for elective PCI14, is a prodrug andrequires two-step activation of at least 2 hours’ duration toexert its full antiplatelet effect in this clinical scenario,even when administered at a high loading dose15. It is ofmajor importance that the onset and strength of clopido-grel action are further delayed in the setting of ST-segmentelevation myocardial infarction (STEMI)16. As shown inthe landmark TRITON-TIMI 38 (TRial to assessImprovement in Therapeutic Outcomes by optimizingplatelet InhibitioN with prasugrel Thrombolysis InMyocardial Infarction 38)1 and PLATO (PLATelet inhib-ition and patient Outcomes)2 trials, prasugrel and ticagre-lor – the novel P2Y12 receptor inhibitors, more potentthan clopidogrel – provide significant reductions in ather-othrombotic events in ACS patients when compared withclopidogrel, and therefore are recommended as first lineagents in this subset17,18. Despite this fact, the onset oftheir action is also substantially delayed in STEMIpatients19,20. According to recent pharmacodynamic stu-dies19,20, it takes 4 to 6 hours after administration of pra-sugrel and ticagrelor loading to achieve sufficient plateletinhibition in STEMI patients. For this reason, the majorityof STEMI patients treated with oral P2Y12 inhibitors areexposed to thrombogenic stent implantation into thethrombotic lesion without adequate platelet inhibition.Moreover, the release of atrial natriuretic peptide triggeredby elevated venous pressure in the course of STEMI inhi-bits gut permeability and intestinal motility21–24.Therefore, absorption of drugs from the digestive systemand their bioavailability may be impaired in STEMI

Current Medical Research & Opinion 2014

2 Cangrelor in coronary artery disease Kubica et al. www.cmrojournal.com ! 2014 Informa UK Ltd

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http://www.acc.org

http://www.heart.org

http://www.escardio.org

http://www.escardio.org

http://www.europcr.com



patients. Additionally, high pre-treatment plateletreactivity present in STEMI patients seriously affects theinhibition of platelets after a 600 mg loading dose of clo-pidogrel25,26. In contrast to currently available antiplateletdrugs with a delayed onset and offset of action, the favor-able properties of cangrelor make it a desirable agent in thesetting of high risk ACS, particularly STEMI, treated withimmediate coronary stenting or ad hoc elective PCI.Platelet inhibition at the time of PCI is supposed to beresponsible for mortality benefits associated with upstreamclopidogrel treatment when compared with in-hospitalinitiation of clopidogrel therapy in two large Europeanregistries including STEMI patients27,28. Similarly insome29,30, but not all31,32, studies pre-treatment withclopidogrel in the setting of elective PCI was associatedwith lower rates of ischemic events.

Furthermore, oral P2Y12 inhibitors cannot provide reli-able inhibition in those who are incapable of swallowing orof rapid gastro-intestinal absorption of medications, suchas patients in shock, presenting with nausea or vomiting,under sedation or after endotracheal intubation16,33,34.Morphine, frequently used in STEMI patients to relievechest pain, inhibits the normal activity of the gastro-intestinal musculature and induces nausea and vomitingas well as impairing drugs’ gastro-intestinal absorption20.Among STEMI patients nausea was reported in almost twothirds and vomiting in nearly one third of cases35,36.

Large interindividual variability of the pharmacoki-netic and pharmacodynamic response, widely describedfor clopidogrel37–40, and also reported for prasugrel-treatedpatients41, remains another major limitation of currentlyavailable P2Y12 inhibitors. Several studies have demon-strated that a substantial subset of patients treated withthese P2Y12 inhibitors do not reach adequate levels ofplatelet inhibition at the time of PCI41,42. Moreover,patients with high on-clopidogrel and on-prasugrel plate-let reactivity are at higher risk for atherothromboticevents43–46.

For safety issues, it is of major importance for an anti-platelet drug to have a rapid offset of activity47,48.Pretreatment with irreversible P2Y12 inhibitors in theACS setting, although possibly advantageous in compari-son with their downstream administration, can eitherexpose patients undergoing undeferrable coronary arterybypass grafting (CABG) to excessive bleeding risk orresult in a delay of cardiac surgery. Additionally, swiftreversal of the antiplatelet effect is of fundamental mean-ing in patients with an initial misdiagnosis of ACS andlife-threatening conditions requiring immediate surgicalintervention such as dissecting aortic aneurysm, acuteabdomen, pericarditis with cardiac tamponade, or spon-taneous pneumothorax.

Intravenous glycoprotein (GP) IIb/IIIa inhibitors, alsodiscussed in this review, show a rapid onset of action andcan efficiently prevent ischemic events, but their

prolonged effect of at least 4 hours (eptifibatide and tiro-fiban) or several days (abciximab) cannot be quicklyreversed49–51. In contrast to cangrelor – a selective inhibi-tor of adenosine diphosphate (ADP)-induced plateletaggregation – GP IIb/IIIa inhibitors, by blocking thefinal common pathway of platelet aggregation, preventplatelets from binding to fibrinogen in an agonist non-spe-cific manner. Thus, fewer bleeding complications arelikely to occur with cangrelor than with GP IIb/IIIa inhibi-tors. A 98-fold separation between the antithromboticeffect and increase in bleeding time for cangrelor hasbeen shown compared with GP IIb/IIIa inhibitors in athrombosis model in dogs52. The peak cangrelor-inducedinhibition of platelet aggregation was achieved at as low as1.4-fold extension of bleeding time, while with GP IIb/IIIainhibitors six- to seven-fold extension was mandatory52.Additionally, in contrast to glycoprotein IIb/IIIa inhibi-tors, therapy with cangrelor is not associated withthrombocytopenia53.

Cangrelor’s properties and mechanism ofaction

N6-[2-(methylthio)ethyl]-2-[3,3,3-triflouropropyl)thiol]-50-adenylic acid (cangrelor, formerly known as AR-C69931MX), is an adenosine triphosphate analog thatselectively and specifically blocks P2Y12-receptor-mediated platelet activation (Figure 1).

Cangrelor has multiple unique advantages over allorally administered agents of being a very potent, quicklyreversible and direct-acting P2Y12 antagonist, reachingoptimal platelet inhibition within minutes after the startof infusion38,54. The very rapid onset of action of cangreloris a result of intravenous administration and small initialvolume of distribution restricted to the blood compart-ment55. Importantly, cangrelor has a linear dose-dependent pharmacokinetic profile with predictableplasma levels56. ADP-induced platelet inhibition bycangrelor increases in a dose-dependent manner withinfusions of up to 4 mg/kg/min, resulting in plateletinhibition rate exceeding 80%55. The drug is rapidlymetabolized through dephosphorylation by an endonu-cleotidase located on the surface of vascular endothelialcells with an elimination half-life of 2.9 to 5.5 minutes57.Platelet function recovers within 60–90 minutes after

s

s

NH

N N

NNFF

FO

O

O O

O O

HO OH

OH OH OH

OH

CI CI

P P P

Figure 1. Cangrelor molecule.



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termination of cangrelor’s infusion. A rapid on–off featureof cangrelor enables temporary suppression of platelet acti-vation on top of oral antiplatelet treatment during PCI.

Recent observations suggest that cangrelor may alsoexert P2Y12-receptor-independent actions on thrombingeneration due to its effects on intraplatelet signaling pos-sibly mediated through activation of a G-protein-coupledpathway separate from Gi and presumably involving Gs58.However, Xiang et al.59 demonstrated that cangrelor injec-tion inhibited thrombus formation in a thrombosis modelin wild-type mice, but it failed to affect thrombus forma-tion in P2Y12 deficient mice. Thus, it has been concludedthat cangrelor inhibits platelet function only through theP2Y12-dependent mechanism59. On the other hand,Ferreiro et al.60 observed a moderate inhibitory effect ofcangrelor on non-purinergic platelet signaling pathways,without modulation of platelet-derived thrombin gener-ation, in 90 patients with coronary artery disease.

Additionally, two recent experimental studies indi-cated that cangrelor may exert a cardioprotective effectbeyond the blockade of platelet aggregation61,62. Its mech-anism seems to be related to the same signal transductionpathway as involved in pre- and postconditioning.Administration of cangrelor shortly before reperfusion inrabbits reduced infarct size by approximately 50%61.Cangrelor-related myocardial salvage was dose dependentand correlated with the degree of inhibition of plateletaggregation. Cardioprotection was absent when cangrelorwas used in crystalloid-perfused isolated hearts, indicatinginvolvement of a so far undefined whole-blood componentin this process. This myocardium saving effect againstreperfusion injury may be a class effect and hencecommon for all P2Y12 inhibitors; however, with cangrelorthe protective effect develops within a short time – asusually clinically required in the target population ofpatients with myocardial infarction and occluded infarct-related arteries62.

Early phase clinical studies on cangrelor

Based on its favorable properties demonstrated in preclin-ical studies, i.e. inhibition of ADP-induced platelet aggre-gation and thrombus formation combined with a lowerincrease in bleeding time when compared with glycopro-tein IIb/IIIa inhibitors, cangrelor entered human studies54.

The safety profile, tolerability, and plasma concentra-tions of cangrelor have been assessed in a multicenter,double-blind, randomized study by Jacobsson et al.63.It included 91 patients with unstable angina or non-Q-wave-myocardial infarction, who received a 72 hinfusion of cangrelor at a dose of 4 mg/kg/min (n¼ 45) orplacebo (n¼ 46) as adjunctive treatment besides aspirinand low molecular weight heparin. No sign of study com-pound accumulation or interindividual variability in

clearance were distinct. Also, no serious bleeding eventswere seen during treatment. The incidence of minor bleed-ing was numerically higher with cangrelor than with pla-cebo (38% vs. 26%, respectively). The drug was welltolerated, and there were no significant changes in otherlaboratory values between groups63.

These findings are in line with observations publishedby Akers et al.64, who assessed the safety, tolerability,pharmacokinetics, and pharmacodynamics of cangreloradministered as an intravenous bolus plus a continuousinfusion at two different doses in healthy volunteers.Two dosages of cangrelor, 15 mg/kg bolus with subsequent2 mg/kg/min infusion and 30 mg/kg bolus followed by 4 mg/kg/min infusion, were studied and found to be well toler-ated. Both treatment doses of cangrelor achieved consist-ent and extensive inhibition of platelet aggregation within2 minutes of bolus administration. Almost complete recov-ery of baseline platelet activity was observed within 60 to90 minutes after termination of the infusion in both treat-ment arms. Moreover, it is interesting to note that thehigh-dose regimen of cangrelor may be associated with arebound effect demonstrated by an overshoot in baselineplatelet activity at later time points when cangrelor iscleared from the systemic circulation64.

Greenbaum et al. conducted a two-part multicentertrial on cangrelor including patients undergoing PCI dueto stable angina or non-ST-segment elevation ACS53. Part1 was a dose-finding study of cangrelor given intravenouslyfor 18 to 24 hours in addition to aspirin and heparin in 200participants. Patients were randomly assigned either toplacebo or to cangrelor infusion (1, 2 or 4 mg/kg/min)initiated just before the start of the revascularization pro-cedure. The mean percentage inhibition of platelet aggre-gation before the end of infusion was 13, 94, 87, and 99%respectively. Seventy one percent of patients receiving thehighest dose of cangrelor presented with complete plateletinhibition during infusion. Platelet inhibition with cangre-lor was maximal by 15 minutes after drug infusion andreturned toward baseline within 15 minutes of discontinu-ation of infusion in all treatment groups, except for thosereceiving the highest dose (4 mg/kg/min) of cangrelor,where platelet activity remained significantly inhibited.In contrast to the rebound phenomenon reported byAkers et al.64, the short-term effect of cangrelor was notassociated with any rebound or increase in thrombosis afterdiscontinuation of infusion53. In part 2, the authors per-formed a randomized, open label comparison of cangrelorwith abciximab in 199 patients before PCI. Completeplatelet inhibition was achieved before the end of infusionin 95% and 100% of patients, respectively (n¼ ns). Thebiggest differences in platelet aggregation between thesetwo active drugs occurred shortly after their termination(12–24 hours) when patients who received cangrelorreturned to baseline, whereas those having received abcix-imab showed persistent inhibition of platelet aggregation.



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Major or minor bleedings occurred in 7% of patientsreceiving cangrelor compared with 10% of patients rando-mized to abciximab (p¼ ns)53.

The primary objective of the STEP-AMI (the Safety,Tolerability and Effect on Patency in Acute MyocardialInfarction) trial was to assess the safety of cangrelor and itseffect on coronary artery patency in monotherapy and asan adjunct to tissue plasminogen activator (t-PA) inSTEMI patients65. Study participants were randomizedto an intravenous infusion of either cangrelor alone, full-dose of t-PA alone, or cangrelor along with half-dose oft-PA. The primary endpoint was TIMI grade 3 flow at 60minutes. Ninety two of an originally planned 180 patientswere enrolled. The decision of premature termination ofthe study was not related to data and safety monitoring.Angiographic data were available for 74 patients. Thecombination of cangrelor and half-dose of t-PA resultedin a similar 60 minute patency rate as full-dose of t-PAalone (55 vs. 50%; p¼ ns) and higher than with cangreloralone (55 vs. 18%, p50.05). The percentage of patientsachieving 470% ST-segment resolution at 60 minutestended to be greater with the combination therapy thanwith either cangrelor or t-PA alone (28 vs. 13% and 28 vs.14%, respectively). Bleeding and adverse clinical eventrates were comparable among the groups. The authors con-cluded that experience with cangrelor suggests a potentialof this compound as an adjunct to fibrinolysis duringSTEMI treatment. However, due to small sample sizescomparisons between the treatments are burdened withserious limitations65.

Drug–drug interactions involvingcangrelor

As different P2Y12 receptor inhibitors, including cangre-lor, may be used in the same clinical setting, their potentialpharmacodynamic interactions are of interest. Ravnefjordet al.66 investigated possible interactions between theseagents in dogs. Mean maximum inhibition of plateletaggregation (IPA) was achieved at 6 minutes after drugadministration with cangrelor, at 3 hours with ticagrelorand at 4 hours with clopidogrel. Platelet function recov-ered after 1.5 hours, 12 hours, and 9 days, respectively. IPAat 2 hours post clopidogrel was reduced to 39% whenclopidogrel was given during cangrelor infusion versus69% for clopidogrel alone. However, after an initial IPAdecline during the first hour post cangrelor withdrawal,IPA apparently increased for approximately 24 hoursafter clopidogrel administration66. Cangrelor disappearsrapidly from the plasma after termination of infusion dueto its very short half life. Furthermore, because of its revers-ible binding, this drug would dissociate from the P2Y12receptors allowing them to become available for binding

clopidogrel active metabolite57. The observed IPAincrease in response to clopidogrel after cangrelor with-drawal suggests prolonged presence or formation of theactive metabolite of clopidogrel in the animal model66.In contrast to clopidogrel, no pharmacodynamic inter-action between ticagrelor and cangrelor was found. Theauthors concluded that the extent of the pharmacody-namic drug–drug interactions between clopidogrel andcangrelor apparently depends on the level of receptoroccupancy when clopidogrel is administered67. In contrast,Storey et al.67 reported an additive effect of cangrelor andclopidogrel on inhibition of platelet aggregation, asassessed by ADP-induced platelet aggregation in eightpatients undergoing intracoronary stent implantation.This intriguing finding suggesting interaction between clo-pidogrel and cangrelor was confirmed by Steinhubl et al.57.They investigated the effect of cangrelor administrationon the ability of clopidogrel to inhibit platelet functionwhen given concurrently with or immediately upon ter-mination of a cangrelor infusion in healthy volunteers(two groups consisting of 10 persons each). A bolus andinfusion of cangrelor provided immediate and almost com-plete inhibition of platelet aggregation, with a rapid rever-sal of activation upon termination of the infusion. Aloading dose of clopidogrel, given alone or started imme-diately after a cangrelor infusion, led to the anticipateddegree of platelet inhibition after approximately 2 h.However, when both drugs were administered simultan-eously clopidogrel was unable to inhibit platelet aggrega-tion57. These observations suggest that cangrelor’s highaffinity for the P2Y12 receptor prohibits clopidogrelactive metabolite from forming the necessary disulfidebridge with cysteine residues in the extracellular domainof this receptor57. Similar results have been reported byDovlatova et al.68. Preincubation of blood with cangrelorbefore adding active metabolites of clopidogrel or prasugrelresulted in a reduction of the ability of both these metab-olites to irreversibly inhibit the P2Y12 receptor. On theother hand, addition of cangrelor after preincubation withactive metabolites of clopidogrel or prasugrel led to sus-tained platelet inhibition68.

The mechanism of interaction between reversible andirreversible P2Y12 inhibitors may be explained by mech-anisms of the binding of these agents to the receptor(Figure 2). Cangrelor binds reversibly to a receptor sitedistinct from the ADP-binding site57. In contrast, clopido-grel’s active metabolite binds irreversibly to the P2Y12receptor, and is likely to involve cysteine-97. Subsequentreceptor assembly and membrane localization are therebydisrupted, preventing ADP binding5. It has been hypothe-sized that cangrelor binding to the P2Y12 receptor mayalter the accessibility of the cysteine-97 residue consideredto be involved in the inhibition of ADP-induced plate-let aggregation by clopidogrel5. The lack of inter-action between cangrelor and ticagrelor reported by



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Ravnefjord et al.66 is not unexpected, as the mechanism ofaction of reversible inhibitors is similar and IPA shouldreflect plasma concentrations of these agents. Thus,when a cangrelor infusion is stopped and rapidly clearedfrom the plasma, ticagrelor binds to the receptors as theybecome available, maintaining P2Y12 antagonism57.

These findings have potentially important clinical impli-cations, because patients treated with cangrelor, in par-ticular those undergoing PCI, would be expected tocontinue long-term oral platelet P2Y12 inhibition69,70.Initiation of oral therapy with a thienopyridine beforetermination of a cangrelor infusion may result in an

ADPADP

ADPADP

ADP ADP

P2Y12

P2Y12 P2Y12

P2Y12 P2Y12

P2Y12

GiGi

Gi Gi

AMClop

AMClop

AMClopCangCang

Figure 2. Effects of ADP, the active metabolite of clopidogrel and cangrelor on the platelet P2Y12 receptor and the proposed mechanism of the interactionbetween cangrelor and thienopiridines. ADP reversibly binds the Gi-linked P2Y12 receptor on platelets, which amplifies aggregation via adenylyl-cyclase-mediated cyclic AMP production (A). The active metabolite of clopidogrel forms an irreversible, covalent disulfide bond with the P2Y12 receptor, rendering thereceptor unable to respond to ADP, thus reducing platelet function (B). Cangrelor directly and competitively antagonizes ADP binding to the P2Y12 receptor,resulting in reversible, concentration-dependent inhibition of the receptor. Cangrelor binding to the P2Y12 receptor may impede the accessibility of thereceptor binding site for the active metabolite of clopidogrel, which is distinct from the cangrelor’s binding site (C). Due to reversible binding of cangrelor, thisdrug would dissociate from the P2Y12 receptor allowing it to become available for binding the active metabolite of clopidogrel rapidly after cessation ofcangrelor’s infusion. ADP – adenosine diphosphate; AMP – adenosine monophosphate.



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important gap in platelet inhibition. This might be par-ticularly critical following stent placement. Thus, toachieve sustained platelet inhibition in patients treatedwith cangrelor, administration of irreversible, oral P2Y12antagonists should be started after the cangrelor infusionhas been terminated56,57,67,68. These observations hadimplications in the design of subsequent clinical trials36.On the other hand, lack of interaction between cangrelorand ticagrelor may suggest choosing the latter for main-tenance treatment following cangrelor usage in the acutesetting.

Phase III studies on cangrelor

Results of three major, randomized, double-blind, placebo-controlled, clinical trials regarding the efficacy and safetyof cangrelor in a broad range of PCI-treated patients withcoronary artery disease are currently available:CHAMPION PLATFORM10, CHAMPION PCI11, andCHAMPION PHOENIX12. Patients pre-treated withGP IIb/IIIa inhibitors were excluded from these trials.In all the studies cangrelor-treated patients receiveda bolus of 30 mg/kg with a subsequent drug infusion of4 mg/kg/min10–12.

The population of the CHAMPION PLATFORM trialconsisted of 5362 patients requiring PCI due to myocardialinfarction without ST-segment elevation (59.4%;n¼ 1578) or unstable angina (35.4%; n¼ 939)10.Patients with stable angina (5.2%; n¼ 139) were also ini-tially eligible before a protocol amendment. STEMIpatients were excluded from the trial. Clopidogrel-naivepatients received either cangrelor or a placebo bolus andinfusion for the duration of the PCI procedure, with theinfusion duration ranging from 2 to 4 hours. Patients inthe cangrelor group were given 600 mg of clopidogrel afterthe end of the cangrelor infusion, and those in the placebogroup received 600 mg of clopidogrel at the end of theprocedure10. The occurrence of the primary efficacy end-point defined as a composite of death, myocardial infarc-tion, or ischemia-driven revascularization within 48 hoursafter PCI was numerically lower in the cangrelor group, butthe difference was not statistically significant (Table 1).However, the primary endpoint was significantly reducedin the subgroup of patients with normal troponin levels atbaseline in the cangrelor group compared with the placebogroup (4.6 vs. 7.2%; odds ratio [OR] 0.62; 95% confidenceinterval [CI] 0.41–0.95; p¼ 0.03)10. Furthermore, the rateof stent thrombosis at 48 hours was significantly lower inthe cangrelor group (Table 1), with the result sustainedat 30 days. Similarly, at 48 hours a significantly lowerall-cause mortality rate was seen in the cangrelor group,though this difference was no longer significant at 30 days.The results of comparison of bleeding rates were differentdepending on the choice of criteria to be used. The rates of

Tabl

e1.

Effic

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bleeding did not differ significantly between the twogroups according to TIMI and GUSTO (GlobalUtilization of Streptokinase and Tissue plasminogen acti-vator for Occluded coronary arteries) studies criteria.However, according to more sensitive ACUITY (AcuteCatheterization and Urgent Intervention TriagestrategY) trial derived criteria for major and minor bleed-ing and the criteria for mild bleeding from the GUSTOtrial, the rates of bleeding were significantly higher in thecangrelor group (Table 2). The difference in bleeding ratesin the cangrelor group, defined as major according to theACUITY criteria, was solely due to an excess of groinhematomas, with no contribution of more serious formsof bleeding. The rates of red-cell transfusion (0.9% inthe cangrelor group vs. 0.6% in the placebo group; OR1.67; 95% CI 0.88–3.17; p¼ 0.12) or any blood transfusion(Table 2) were not significantly different between thestudy arms10.

In another cangrelor trial - CHAMPION PCI - a totalof 8877 patients were randomly assigned in a 1:1 ratio toeither the experimental arm (cangrelor plus clopidogrel)or the active control arm (matching placebo plus clopido-grel)11. Study participants were treated with PCI due tostable angina (15.0%; n¼ 1333), unstable angina (24.6%;n¼ 2185), non-ST-segment elevation myocardial infarc-tion (49.2%; n¼ 4463), or STEMI (11.2%; n¼ 996).Patients on clopidogrel therapy were also allowed to berecruited in the trial. The infusion of cangrelor or placebobegan within 30 minutes before PCI and continued for 2–4hours or until the conclusion of the index procedure,whichever was longer. Patients in the clopidogrel armreceived 600 mg of clopidogrel, while patients assignedto the cangrelor arm received placebo at the time of infu-sion. To allow transition from intravenous cangrelor tooral clopidogrel, patients received another four capsules(either clopidogrel in patients receiving cangrelor or pla-cebo in patients receiving clopidogrel) at the discontinu-ation of the study-drug infusion. The primary endpoint ofdeath from any cause, myocardial infarction, or ischemia-driven revascularization at 48 hours occurred in similarproportions in both study arms (Table 1). No significantdifference between groups with regard to any single effi-cacy endpoint (all-cause mortality, myocardial infarction,ischemia-driven revascularization, stent thrombosis,stroke, and Q-wave myocardial infarction) at 48 hourswas found. Minor, but not major, bleedings occurredmore frequently in the cangrelor arm according to theACUITY and GUSTO criteria. According to theTIMI criteria, no increase in bleeding was seen, irrespec-tively of the magnitude of bleeding (Table 2). The ratesof any blood transfusion were comparable in bothgroups (Table 2).

In May 2009 both CHAMPION trials were discontin-ued, following a decision by the interim analysis reviewcommittee claiming that the studies would not show the

persuasive clinical efficacy needed for approval, although98% of planned 9000 patients for CHAMPION PCI and83% of scheduled 6000 patients for CHAMPIONPLATFORM had already been enrolled10,11. The earlytermination of both studies limited their statisticalpower. Taking into account observations regarding thepharmacodynamic limitations of clopidogrel, the lack ofcangrelor’s superiority over clopidogrel 600 mg in thesetrials was rather an unexpected finding, especially sincesignificantly higher levels of periprocedural platelet inhib-ition were achieved with cangrelor11. The mechanism,postulated to have contributed to the lack of superiorityof cangrelor, is an interaction between clopidogrel andcangrelor that could have limited the pharmacodynamiceffects of clopidogrel71. As suggested by previous studies,the effect of clopidogrel may be attenuated when clopido-grel or prasugrel is administered simultaneously with can-grelor57,68. A relatively short time-window of opportunityexists for thienopiridine active metabolites to bind to thereceptor and thereby exert antiplatelet effects before theyare inactivated and excreted. If cangrelor is occupying theP2Y12 receptor during this time-window, limited antipla-telet effects would be apparent during the transition fromcangrelor to clopidogrel or prasugrel71.

A prospectively designed platelet function substudy wasperformed in a selected cohort of patients to provideinsight into the pharmacodynamic effects of cangrelor,particularly in regard to whether cangrelor therapy mayinterfere with the inhibitory effects of clopidogrel71. Thispre-defined substudy was conducted in a subset of patientsundergoing PCI, randomized in the CHAMPIONPLATFORM10 and CHAMPION PCI11 trials. Thepatients were randomly assigned to receive either cangre-lor and clopidogrel (600 mg) or cangrelor and placebo in a1:1 fashion71. A total of 167 patients had valid pharmaco-dynamic assessments for the primary endpoint. The pro-portion of individuals achieving520% change in plateletreactivity units according to the VerifyNow P2Y12 assaybetween baseline and 410 h after PCI was higher withcangrelor plus clopidogrel (32/84; 38.1%) compared withplacebo plus clopidogrel (21/83; 25.3%), but the differencewas not statistically significant (12.79%; 95% CI 1.18–26.77%; p¼ 0.076). The planned target enrolment tothis substudy, estimated at 330 patients according to thesample size calculation, was not achieved due to prematureinterruption of the main trial. Thus, although no signifi-cant pharmacodynamic interaction was found when tran-sitioning to clopidogrel therapy, the results of this studyneed to be considered inconclusive due to the lack ofsufficient statistical power and further investigation iswarranted to reassess potential drug–drug interaction71.

Altogether, both CHAMPION trials may provideinsight into the optimal timing of periprocedural antipla-telet blockade with clopidogrel10,11,72. The examination ofsecondary composite endpoints suggests a more robust



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effect in the CHAMPION PLATFORM trial (600 mg ofclopidogrel at the end of the procedure in the controlarm)10 than in the CHAMPION PCI trial (600 mg ofclopidogrel at the beginning of the procedure in thecontrol arm)11, though it is only a speculative observation.Nevertheless, whenever clopidogrel is given – at the startor at the end of the procedure – the additional antiplateletblockade conferred by cangrelor may provide clinicalbenefit10,11,72.

The definitions of all endpoints used in theCHAMPION PLATFORM and CHAMPION PCI trialswere mutually consistent10,11. The primary compositeendpoint of these trials was negative; therefore, anysingle endpoint should be interpreted with caution.Interestingly, the primary endpoint in the CHAMPIONtrials was driven by the occurrence of myocardial infarc-tion. However, myocardial infarction is difficult to ascer-tain post-PCI, particularly when patients have elevatedbaseline cardiac biomarkers before the procedure. It isalso difficult to distinguish myocardial infarction occurringbefore from that occurring after randomization when thetime from hospital admission to PCI is short as in boththese trials10,11,73. The current universal definition of myo-cardial infarction was developed after initiation of theCHAMPION PCI and CHAMPION PLATFORM trials.This broad-consensus document addressed specifically theissue of baseline status assessment at the time of PCI andPCI-related myocardial infarction definition. As bothCHAMPION studies used similar inclusion/exclusion cri-teria and death, myocardial infarction, or ischemia-drivenrevascularization (including stent thrombosis) at 48 hoursas their primary endpoints, the studies were pooledtogether72. The clinical events committee adjudicatedall cases of myocardial infarction and the universal defin-ition was used. A total of 13,049 patients were included72.No effect of cangrelor with regard to the primary endpointwas revealed with the original definition of myocardialinfarction. However, after application of the universal def-inition of myocardial infarction a significant reduction ofthe primary endpoint with the cangrelor–clopidogrel com-bination, compared with clopidogrel alone, was observed(Table 1). In patients treated with cangrelor there was asignificant reduction in stent thrombosis, but not in therate of myocardial infarction (Table 1). Occurrence of Q-wave myocardial infarction tended to be lower in the can-grelor group (0.1 vs. 0.3%; OR 0.44; 95% CI 0.19–1.02;p¼ 0.054). Regarding safety measures, there was noincrease in blood transfusions or major bleeding assessedwith the TIMI or GUSTO bleeding scales with cangrelorcompared with clopidogrel (Table 2). However, using themore sensitive ACUITY scale, there was an increase inclinically significant major bleedings with cangrelor,mainly because of an increased occurrence of groinhematomas10,11,72.

The knowledge gained in CHAMPION PLATFORM10

and CHAMPION PCI11 resulted in new questions to beanswered in new trials. The CHAMPION PHOENIX trialwas designed to evaluate prospectively whether cangrelordoes indeed reduce ischemic complications of PCI12.A total of 10,942 clopidogrel-naive patients with coronaryartery disease requiring PCI for stable angina (56.1%;n¼ 6140), non-ST-segment elevation ACS (25.7%;n¼ 2810) or STEMI (18.2%; n¼ 1992), received a boluswith a subsequent infusion of cangrelor or placebo for atleast 2 hours or the duration of the procedure, whicheverwas longer. Patients treated with cangrelor obtained aloading dose of clopidogrel at the end of infusion, whilepatients receiving placebo obtained a loading dose of clo-pidogrel at the time of PCI procedure12. Treatment duringthe procedure was followed by a standard maintenancedose of oral P2Y12 inhibitor and aspirin. The rate of theprimary composite efficacy endpoint of death from anycause, myocardial infarction (according to the universaldefinition of myocardial infarction), ischemia-drivenrevascularization, or stent thrombosis at 48 hours was sig-nificantly lower in the cangrelor group than in the clopi-dogrel group (Table 1). Importantly, the benefit fromcangrelor with respect to the primary endpoint was con-sistent across multiple prespecified subgroups includingclinical diagnosis at presentation. Moreover, the rate ofstent thrombosis at 48 hours was also lower in the cangre-lor group than in the clopidogrel group (Table 1). Of note,the definition of stent thrombosis used in theCHAMPION PHOENIX trial was different from oneapplied in the CHAMPION PCI and CHAMPIONPLATFORM trials as cases of intraprocedural stent throm-bosis during PCI were also considered in the formerstudy74. The size of reduction in the risk of stent throm-bosis obtained with cangrelor versus clopidogrel in theCHAMPION PHOENIX trial was greater in the peripro-cedural setting than out of lab at 48 h (rates of intraproce-dural stent thrombosis: 35 [0.6%] vs. 54 [1.0%]; OR 0.65;95% CI 0.42–0.99; p¼ 0.04; rates of out-of-lab stentthrombosis: 11 [0.2%] vs. 20 [0.3%]; OR 0.55; 95% CI0.26–1.15; p¼ 0.11)12,75. Interestingly, the occurrence ofintraprocedural stent thrombosis was strongly predictive ofsubsequent adverse cardiovascular events both at 48 hoursand at 30 days in the CHAMPION PHOENIX trial (ratesof the composite endpoint including death, myocardialinfarction, ischemia-driven revascularization, or newonset out-of-lab stent thrombosis: 29.2 vs. 4.5% and 31.5vs. 5.7%, p50.0001 for both comparisons)75. Apart fromthe reduction in stent thrombosis, benefits of cangrelor inthe CHAMPION PHOENIX trial were mostly attributedto the decreased occurrence of myocardial infarction (ratesat 48 h – Table 1; rates at 30 days: 225 [4.1%] vs. 272[1.0%]; OR 0.82; 95% CI 0.68–0.98; p¼ 0.02)12,74. Theincidence of rescue therapy with GP IIb/IIIa inhibitors was2.3% with cangrelor and 3.5% with clopidogrel (OR 0.65;



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95% CI 0.52–0.82; p50.001)12. The observed reduction of22% in ischemic event odds in patients treated with can-grelor was not accompanied by a significant increase insevere bleeding or in the need for transfusions comparedwith patients on clopidogrel (Table 2). More sensitivemeasures showed an increase in bleeding with cangrelor,as it would be expected of a potent antiplatelet agent.The composite endpoint of the net rate of efficacy andsafety adverse clinical events was 4.8% in the cangrelorgroup and 6.0% in the clopidogrel group (OR 0.80; 95% CI0.68–0.94; p¼ 0.008)12.

Despite the important message based on the results ofthe trial, some weak points should be noted. The decisionregarding the loading dose of clopidogrel (300 mg or600 mg) as well as the choice of P2Y12 inhibitor for main-tenance therapy was allowed per investigator’s discretion.Thus, additional interfering factors have been introducedin the study. As a consequence, a substantial subset of ACSpatients in the trial received maintenance P2Y12 inhib-ition with ticagrelor or prasugrel, since these drugs aresuperior to clopidogrel in reducing PCI-related complica-tions76. In the cangrelor arm of the CHAMPIONPHOENIX trial the maximal antiplatelet effect was pre-sent during PCI, while in the clopidogrel arm it occurredlater and was weaker. Thus, as expected, the superiority ofcangrelor over clopidogrel in terms of the primary studyendpoint was proven12. However, despite the reductions inmyocardial infarction and stent thrombosis rates, the studyfailed to demonstrate any survival advantage of cangrelorover clopidogrel (mortality rates at 48 h: Table 1; mortalityrates at 30 days: 60 [1.1%] vs. 55 [1.0%]; OR 1.09; 95% CI0.76–1.58; p¼ 0.64)12,74. Finally, the real expected chal-lenge is a comparison between cangrelor and newer P2Y12inhibitors, such as prasugrel and ticagrelor. Such studiesthough are still lacking.

A recently published, prespecified, pooled analysis ofpatient-level data from three pivotal CHAMPIONtrials77 indicated that cangrelor, when compared with clo-pidogrel, reduces the risk of periprocedural thromboticcomplications during PCI at the expense of mild bleedings(Figure 3). Namely, the rates of stent thrombosis, myocar-dial infarction (including Q-wave myocardial infarction)and ischemia-driven revascularization were reduced in theexperimental group in comparison with the control group.The benefits of therapy with cangrelor, except for the sig-nificant difference in ischemia-driven revascularization,were maintained at 30 day follow-up77. Importantly, myo-cardial infarction was defined in this pooled analysisaccording to the universal definition, which was initiallyimplemented only in the CHAMPION PHOENIX trial.Additionally, all-cause mortality was similar in both armsat 48 h and at 30 days. The excess of mild bleedings seenwith cangrelor may be at least partially responsible for thelack of survival advantage74,78. However, the rates of fatal

bleedings were low and comparable between the cangrelorand clopidogrel groups (0.1 vs. 0.1%; p¼ 0.8054)77.

Potential specific clinical applications ofcangrelor

Approximately 5–10% of patients require some type ofsurgery within the first 12 months after stent implant oran ACS diagnosis2. In such cases the ability to restoreplatelet function is pivotal. Currently available oralP2Y12 inhibitors may increase the risk of bleedingshould urgent surgical revascularization be required. Onthe other hand, cessation of the antiplatelet therapy fornearly a week before surgery, necessary in patients on oralP2Y12 inhibitors, carries an excess risk of serious ischemicevents. The aim of the BRIDGE (maintenance of plateletinhiBition with cangreloR after dIscontinuation ofthienopyriDines in patients undergoing surGEry) study, aphase II clinical trial, was to evaluate the use of cangrelorfor bridging thienopyridine-treated patients to CABG sur-gery79. A total of 210 patients with ACS, or treated with acoronary stent, requiring bridging from oral thienopyridinetherapy to CABG surgery were randomly assigned in theblinded strata to either cangrelor (n¼ 106) or placebo(n¼ 104). The dose of cangrelor previously determinedin 10 patients in an open-label stage was 0.75 mg/kg/min.This infusion dose consistently allowed the achievementand maintainance of platelet inhibition at levels known tobe associated with a low risk of thrombotic events com-pared with placebo. Rapid recovery of platelet functionafter discontinuing cangrelor infusion was observed,achieving similar levels of platelet inhibition to thosewith placebo prior to CABG surgery. Bridging antiplatelettreatment with a prolonged infusion of cangrelor did notresult in an increase of major bleeding prior to surgery,although the rate of minor bleeding was numericallyhigher79. Moreover, there was no excess in CABG surgeryrelated bleeding with cangrelor versus placebo (relativerisk 1.1; 95% CI 0.5–2.5; p¼ 0.763). In addition, noincreased incidence of non-bleeding adverse events(including dyspnea) or laboratory abnormalities despiteextended dosing were found. A favorable safety profilewith prolonged infusion (up to 7 days) of cangrelor wasobserved at a dose shown to be below thresholds associatedwith thrombotic risk, but simultaneously not excessive, inorder to minimize the risk of bleeding. Nevertheless, theBRIDGE study was underpowered to assess whether treat-ment with cangrelor prior to CABG surgery would reducethe risk of ischemic events and/or increase the risk ofbleeding compared with placebo. The authors concludedthat the study results support the hypothesis that intraven-ous cangrelor is a feasible management strategy in patients



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Efficacy outcomesat 48 h

Death/MI/IDR/STDeathMI

STIDRQ-wave MI

Death/MI/IDR/STDeathMI

STIDRQ-wave MI

Cangrelor Clopidogrel Odds Ratio [95% CI] p Odds Ratio [95% CL]Events EventsTotal Total

Efficacy outcomesat 30 days

Cangrelor Clopidogrel Odds Ratio [95% CI] p Odds Ratio [95% CL]Events EventsTotal Total

Cangrelor Clopidogrel Odds Ratio [95% CI] p Odds Ratio [95% Cl]Events EventsTotal

Non-CABG-relatedbleedings at 48 h Total

473 57945

3692

453

105

33387196662

12459 124221242212422124221242212422

1245912459124591245912459

657 748141

51178

487

162

13741831

153113

12407 123571235712357123571235712357

1240712407124071240712407

12565

1256512565

12565

1256512565

1256512565

12542 0.48750.0828

0.61010.0218

<0.0001<0.0001

<0.0001<0.0001

125421254212542

1254212542

1254212542

12542

0.87 [0.78, 0.97]0.97 [0.76, 1.23]0.85 [0.74, 0.97]0.60 [0.39, 0.95]0.85 [0.69, 1.06]0.69 [0.54, 0.88]

0.81 [0.71, 0.91]0.73 [0.47, 1.15]0.85 [0.74, 0.97]0.53 [0.30, 0.92]0.71 [0.52, 0.98]0.59 [0.43, 0.80]

0.00990.78320.01650.02570.15550.0027

0.00070.16940.01820.02110.03630.0008

0.2 0.5 1 2 5Favours cangrelor Favours clopidogrel



GUSTO bleedingSevere/life threateningModerateMildAny GUSTO bleeding

2876

21092196

2356

28

3531381

16271696

1.22 [0.70, 2.11]1.36 [0.96, 1.92]1.35 [1.26, 1.45]1.35 [1.26, 1.45]

1.14 [0.69, 1.90]1.51 [1.06, 2.15]

1.53 [1.34, 1.76]1.30 [1.20, 1.40]

TIMI bleeding

ACUITY bleeding

MajorMinor

MajorMinor

3277 51

5341738

12565 0.11541254270 1.29 [0.94, 1.76]Any blood transfusion 90

Figure 3. Clinical efficacy and safety outcomes in the prespecified, pooled analysis of patient-level data from three phase III trials (CHAMPION-PCI,CHAMPION-PLATFORM and CHAMPION-PHOENIX) comparing cangrelor combined with clopidogrel (the cangrelor group on the figure) with clopidogrelalone (the clopidogrel group on the figure) for prevention of thrombotic complications during and after PCI77. Efficacy outcomes were reported at 48 h (A) and30 days (B), safety outcomes only at 48 h (C). The prespecified primary efficacy outcome comprised a composite of death, myocardial infarction, ischemia-driven revascularization or stent thrombosis at 48 h, while the primary safety outcome was non-CABG-related GUSTO severe or life-threatening bleeding at48 h. All p values for OR were calculated based on the �2 test. ACUITY – Acute Catheterization and Urgent Intervention Triage Strategy; CABG – coronary arterybypass grafting; CI – confidence interval; GUSTO – Global Use of Strategies to Open Occluded Coronary Arteries; IDR – ischemia-driven revascularization; MI –myocardial infarction defined according to the universal definition; OR – odds ratio; ST – stent thrombosis; TIMI – Thrombolysis In Myocardial Infarction.



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awaiting cardiac surgery who require prolonged plateletP2Y12 inhibition after thienopyridine discontinuation79.

Diabetes mellitus has been shown to be associatedwith impaired response to clopidogrel probably due toup-regulation of P2Y12 signaling80–82. Moreover,increased platelet-derived thrombin generation in diabeticpatients contributes to their pro-thrombotic status83,84.Ferreiro et al.60 evaluated the in vitro pharmacodynamiceffects of cangrelor in coronary artery disease with diabetes(n¼ 48) and without diabetes (n¼ 45). Cangrelor pro-vided potent and dose-dependent blockade of the plateletP2Y12 receptor with no differential effect in diabetic andnon-diabetic patients60. These results suggest that verypotent P2Y12 blockade may overcome the hyperreactiveplatelet phenotype and potentially contribute to favorableoutcomes in patients with diabetes83. On the other hand,the subgroup analyses of the CHAMPION PHOENIX trialrevealed a consistent reduction in the primary efficacyendpoint with cangrelor across multiple subgroups, withno significant interactions with diabetes12.

Extracorporeal circulation and hypothermia are rou-tinely used in cardiac surgery and in comatose survivorsof cardiac arrest today85. Both these procedures causeplatelet activation and dysfunction possibly followed bybleeding and thromboembolic complications. Krajewskiet al.86 analyzed the role of P2Y12 blockade in plateletactivation at normothermia and hypothermia in an exvivo extracorporeal circulation model. Cangrelor wasfound to inhibit platelet granule release (p50.01), plate-let-granulocyte binding (p50.05), and platelet loss(p50.001). The authors concluded that well controlledplatelet inhibition with cangrelor has the potential toreduce complications associated with extracorporeal circu-lation and hypothermia86.

Side effects of cangrelor

In general, side effects of cangrelor are not serious and donot impose limitation to its use. In fact, the only clinicallyrelevant side effect of cangrelor is the occurrence of a tran-sient sensation of dyspnea that we also reported afteradministration of ticagrelor and elinogrel8. Perhaps thiseffect reflects the similar mechanisms of these reversibleplatelet ADP-receptor antagonists. In the CHAMPIONPLATFORM trial a higher incidence of transient dyspneain the cangrelor group (1.4%) than in the placebo group(0.5%) was observed (p¼ 0.002)10. The same phenom-enon was reported in the CHAMPION PCI trial.Dyspnea occurred in 1.0% of patients who received can-grelor, compared with 0.4% of patients who received clo-pidogrel (p¼ 0.001)11. The CHAMPION PHOENIX trialconfirmed these observations. Dyspnea was reported in1.2% of patients treated with cangrelor and in only 0.3%of those on clopidogrel (p50.001)12. According to a

pooled analysis of patient-level data from three pivotalCHAMPION trials the occurrence of dyspnea was 1.1%and 0.4% in the cangrelor vs. clopidogrel group(p50.0001)77. Furthermore, the discontinuation rate ofthe investigated drug was slightly, but significantly,higher in the former group (0.6 vs. 0.4%; p¼ 0.04). Inthe BRIDGE study no difference in terms of dyspneaoccurrence was observed; however, this could be relatedto the limited size of study population79 as well as a reduceddose of cangrelor when compared with the CHAMPIONtrials10–12. The occurrence of dyspnea reported in thePLATO study was much higher than in theCHAMPION trials2,10–12. In ticagrelor-treated patientsdyspnea was observed in 14.5% versus 8.7% in clopido-grel-treated patients, with respectively 0.4% and 0.3%classified as severe in intensity2,87. Ticagrelor-related dys-pnea was usually mild or moderate in intensity and was notassociated with differences concerning any efficacy orsafety outcomes. It has been hypothesized that this sensa-tion in patients treated with ticagrelor is triggeredby increased adenosine concentration, as ticagrelor inhi-bits clearance of adenosine82. However, dipyridamole,which is an even stronger inhibitor of adenosine clearancethan ticagrelor, usually does not cause dyspnea. Onthe other hand, Cattaneo et al.88 speculated that theinhibition of the P2Y12 receptor on sensory neuronscauses the sensation of dyspnea, when its reversibleinhibitors are used.

According to data published by Balduini et al.89 P2Y12inhibitors, such as clopidogrel and prasugrel, do notinhibit proplatelet formation, but cangrelor does, byabout 50–60%. Proplatelet structure was not affectedby any of the tested P2Y12 inhibitors. Moreover, oraladministration of clopidogrel and prasugrel, at doses thateffectively inhibited ADP-induced platelet aggregation,did not affect circulating platelet counts. In contrast toclopidogrel and prasugrel, cangrelor inhibits not onlythe P2Y12, but also the P2Y13 receptor89. The impact ofcangrelor on in vivo platelet formation and count has notbeen reported. The short duration of infusion that has beeninvestigated would not be expected to change plateletcounts, however prolonged treatment may affect proplate-let formation. Therefore, this area needs furtherinvestigation.

Conclusions and future directions

The pharmacokinetic and pharmacodynamic features ofcangrelor allowing for consistent and strong P2Y12 inhib-ition, with a rapid onset and swift reversal of action devoidof the need for an antidote, offer a degree of control avail-able until now neither for oral P2Y12 inhibitors nor forintravenous GP IIb/IIIa antagonists. The landmark clin-ical trials demonstrated that cangrelor is capable of



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improving clinical outcomes in clopidogrel-treatedpatients by reducing ischemic events while holding afavorable safety profile. Cangrelor is a desirable agent forad hoc elective PCI and for high risk acute coronary syn-dromes treated with immediate coronary stenting. It seemsto be particularly useful in patients in shock, presentingwith nausea or vomiting, under sedation or after endotra-cheal intubation. Bridging therapy in patients undergoingundeferrable surgery who require periprocedural P2Y12inhibition is another attractive indication for cangrelor,but this approach warrants evaluation in large clinicaltrials. Based on data from preclinical studies indicatingthe cardioprotective effect of cangrelor, one could antici-pate particular benefits of cangrelor in STEMI patients.Worse than expected, but still favorable outcomes of can-grelor therapy achieved in phase III clinical trials may beassociated with a gap in platelet inhibition due to initi-ation of oral treatment with clopidogrel after terminationof cangrelor infusion. The lack of interaction betweencangrelor and ticagrelor may suggest choosing the latterfor maintenance treatment following cangrelor adminis-tration in the acute setting. However, these speculationsneed to be confirmed in clinical trials. Furthermore,advantages of cangrelor reported in the CHAMPIONtrials were particularly attributed to reduced rates ofstent thrombosis and myocardial infarction. Modernstent design, namely less thrombogenic and allowing amore feasible access for side branches, could potentiallyattenuate these benefits.

TransparencyDeclaration of fundingNo sources of funding were used to assist in the preparation of thisreview.

Declaration of financial/other relationshipsM.K. received a speaker’s fee from AstraZeneca. J.M.S.-M.received lecture fees from AstraZeneca, Daiichi Sankyo, EliLilly and Company, and a research grant from RocheDiagnostics. Y.-H.J. received honoraria for lectures fromSanofi-Aventis, Daiichi Sankyo and Eli Lilly and Company.P.A.G. served as a consultant for AstraZeneca, Daiichi Sankyo,Eli Lilly and Company, Pozen, Accumetrics, Nanosphere,Boehringer Ingelheim, Merck, CSL, and received researchgrants from the National Institutes of Health, AstraZeneca,Harvard Clinical Research Institute, Duke Clinical ResearchInstitute, CSL, Daiichi Sankyo, Eli Lilly and Company, andHaemonetics. J.K., E.P.N., U.T., A.K., T.F., and A.A. have dis-closed that they have no significant relationships with or finan-cial interests in any commercial companies related to this studyor article.

CMRO peer reviewers may have received honoraria fortheir review work. The peer reviewers on this manuscripthave disclosed that they have no relevant financialrelationships.

AcknowledgmentsThe present contribution is a project of Systematic Investigationand Research on Interventions and Outcomes (SIRIO)-MEDICINE, a group of senior scientists and fellows collaboratingworldwide to pursue research and innovation in medicine.

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