European Journal of Radiology 82 (2013) 1633 1637

Contents lists available at ScienceDirect

European Journal of Radiology

jo ur nal ho me page: www.elsev ier .co

Endovascular treatment of aneurisms: Pre, intra amanagement

S. Bracar ,1

a Universit de b INSERM U 94c Department od Department o pital C

a r t i c l

Article history:Received 29 NReceived in reAccepted 7 Feb

Keywords:Cerebral aneurEndovascular ComplicationsAnticoagulatioAntiplatelet thThrombo-embolism

lar afocusmorr

eitherd ra

h clin

1. Introduction

There isliterature cendovasculcussion to amedicationno recomm

Several mment to excRisks vary within whicthus be tail

Among intra and pthromboemThus adjuvaand treatin

Corresponradiology, BatiFrance. Tel.: +3

E-mail add(C. Barbier), al(R. Anxionnat)

1 DepartmeLepoire. Hopit

of subarachnoid hemorrhage (SAH) and treatments to avoid

0720-048X/$ http://dx.doi.o no identiable consensus across teams or in theoncerning the pharmacological accompaniment ofar aneurysm treatment. We will limit the present dis-

review of the principles and rationale of the use of theses; any discussion of protocols is strictly illustrative withendatory intent.ethods are available in endovascular aneurysm treat-

lude the affected vascular section from the circulation.according to the treatment option and the conditionsh the surgery is performed. Associated treatments mustored on a case-by-case basis.the most frequent risks of endovascular repair areostoperative hemorrhagic rupture, a rare event, andbolic complications, which are much more frequent.nt pharmaceuticals are largely focused on preventingg these latter. Additionally symptomatic treatment

ding author at: Department of Diagnostic and Interventional Neuro-ment Jean Lepoire. Hopital Central, CHU Nancy, 54035 Nancy cedex,33 83851773.resses: s.bracard@chu-nancy.fr (S. Bracard), c.barbier@chu-nancy.fr.derelle@chu-nancy.fr (A.L. Derelle), r.anxionnat@chu-nancy.fr.nt of Diagnostic and Interventional Neuroradiology, Batiment Jeanal Central, CHU Nancy, 54035 Nancy cedex, France.

vasospasm will enter into play in cases of ruptured aneurisms.

2. Thromboembolic complications

The most frequent risk in endovascular aneurysm treatmentis thromboembolic complications. Their analysis in the literaturevaries according to how they are considered: only symptomaticcomplications, intraoperative occlusions, probable ischemic abnor-malities on systematic postoperative MRIs, etc. Thromboemboliccomplications have become less frequent and the management oftheir consequences has improved. Nonetheless, they remain themain risk in endovascular approaches.

The frequency of intraoperative thromboembolic complicationsin multicenter series can vary, ranging for example from 7% inthe ATENA study (considering only non-ruptured aneurisms) [1]to 12.5% in the CLARITY study [2]; morbidity and mortality was3.8% in this latter.

The inuence of employed techniques varies across assess-ments. Sluzewski et al. [3,4] found that remodeling resulted inlarger risks but this tendency was not detected in Altay et al.s metaanalysis [5] and Pierot et als recent review of the literature [6]. Theuse of stents increased the risk of stroke per operative and in therst 48 h by 10% [710].

The size of the aneurysm and its neck are risk factors, withthromboembolic events being more frequent in large and giant

see front matter 2013 Elsevier Ireland Ltd. All rights reserved.rg/10.1016/j.ejrad.2013.02.012da,b,c,, C. Barbierd, A.L. Derelled, R. Anxionnata,b,c

Lorraine, France7, Francef Diagnostic and Interventional Neuroradiology. CHU Nancy cedex, Francef Diagnostic and Interventional Neuroradiology. CHU Nancy, Batiment Jean Lepoire. Ho

e i n f o

ovember 2012vised form 5 February 2013ruary 2013

ismstreatment

nerapy

a b s t r a c t

The most frequent risk in endovascuadjuvant pharmaceuticals are largely tomatic treatment of subarachnoid heplay in cases of ruptured aneurisms.

Consensus exists in the literature nto be administered. The principles andiscussion of protocols according witm/locate /e j rad

nd post operative

entral, CHU Nancy, 54035 Nancy cedex, France

neurysm treatment is thromboembolic complications. Thused on preventing and treating these latter. Additionally symp-hage (SAH) and treatments to avoid vasospasm will enter into

for the necessity of heparin or antiplatelets nor for the dosestionale of the use of these medications are reviewed with aical situations and technical choices.

2013 Elsevier Ireland Ltd. All rights reserved.

1634 S. Bracard et al. / European Journal of Radiology 82 (2013) 1633 1637

aneurysms. In the Clarity study [2], risks were 28% for aneurysmsover 10 mm vs. 10.7% for those under 10 mm.

Finally, an increased frequency of thromboembolic events isassociated with SAH [2,5].

The intantiplateletof thrombo

3. Interest

Consensof heparin recommendintravascul

In publisgenerally lereported. Mboluses rancontinuousbetween 20boembolic risks in theor extracran

Protocoland often ccontrols.

The Wororadiologythe results ding teams in a continuthen 1000 U

There arthe eld of ithe endova

Heparinare not accemonitoringmonly betwof the hepa

Loading weight to rinterventio80 U/kg areor cardiolomaintaineding to reguadaptation bosis treatmAfter a bo18 U/kg/h agram.

Preoperabefore the advantage aneurism rdose in the

At the enmally stoppinfusion forarin (LMWHbe falling oanticoagula

Any rationo convincilogical pers

However, LMWH is relevant for the prevention of deep veinthrombosis (DVT). DVT risks are elevated after a SAH (18% in theRay et al. study) and vary according to the severity of bleeding andthe duration of hospitalization [16]. This rate justies the use of

at pity r

iplat

reat charassocationt andons.

inte ofteenterantipent, ed rativeliograceiv(1.6%iplatn), cl

antip

e rol

actious ftimulatelgen aationiplat

of tboxaagreatidetudi

pirin

irin ambo

path 40ect ise n

caseomotmennt. Homp

onlo clicts atelet

opido

owingrelra and postoperative use of anticoagulants ands has been proposed to reduce the frequency and gravityembolic complications.

and use of heparin

us exists in the literature neither for the necessitynor for the quantities to be administered. Heparin ised during interventions due to the use of multiplear tools in procedures that can last several hours.hed multicenter studies, the use of anticoagulants wasft to the judgment of the investigators and thus notajor monocenter studies [1113] have reported initialging from 3000 to 5000 IU followed by 2040 IU/kg/hly to maintain a monitored activated clotting time (ACT)0 and 300 s. This tactic is a compromise between throm-and hemorrhagic risks, noting that thromboembolicse procedures are lesser than those found in stentingial angioplasty.s found in the literature or proposed by institutions varyomprise a standardized loading dose and no specied

rld Federation of Interventional and Therapeutic Neu- (WFITN) surveyed its members in 2006 and publishedand its recommendations on its website. Most respon-reported the use of intraoperative heparin but only 69%ous infusion. The WFITN recommends a 5000 U bolus,/h continuously, with (monitored) ACT at about 200 s.e a number of recommendations for heparin use outsidenterventional neuroradiology that may be adaptable toscular treatment of aneurisms [14].

use must be monitored. Blood heparin concentrationsssible during our interventions. The normally employed

method is ACT, with guideline values >200 s, most com-een 250 and 300 s. It is recommended to test the efcacyrin regularly during the intervention.and continuous doses must be adapted to the patientsapidly attain and maintain ACT objectives during then, which may take several hours. Doses from 70 to

proposed in heparin use protocols in intensive caregy to obtain efcacious anticoagulation. This is then

via infusion, with doses adjusted as needed accord-lar (at least hourly) ACT monitoring. A practical dosetable is frequently used to manage heparin in throm-ent and can be adapted for use in aneurisms [15].

lus injection of 70 U/kg, we used to continue withnd adjust according to ACT level and this kind of nomo-

tive oral anticoagulants are usually stopped 5 daysintervention and replaced by heparin, which has theof being easily antagonized in cases of intraoperativeupture. Administration of protamine sulfate dose forlast hour will rapidly terminate heparinization.d of aneurism treatment, heparin administration is nor-ed but not antagonized. Some teams continue heparin

2448 h. Follow-up with low molecular weight hep-) has been advised by certain teams, but this seems to

ut of favor. The WFITN does not recommend pursuingtion postoperatively.nale for postoperative use of heparin is unclear. Indeed,ng clinical results have been published, and from a bio-pective it seems more pertinent to use antiplatelets.

LMWHmorbid

4. Ant

To tspace ity of aaggregprevenplicati

Theevokedmulticing 3 treatmreportrespecof angwho redidnt

Ant(aspirinewer

4.1. Th

Theof varimore sfrom pbrinoaggreg

Antreleasethromand ticeptibbeing s

4.2. As

Aspof throCOX-1matelyThe effafter th50% oflacks hto treafrequebolic cdosagewith ntic effeantipla

4.3. Cl

Follclopidoreventative doses, especially as these latter present littleisk [17].

elets

an aneurism, a foreign body is placed within a vascularcterized by high-velocity blood ow and the possibil-iated intimal insults. These conditions activate platelet

mechanisms and thus justify the use of antiplatelets to treat intra and post-procedure thromboembolic com-

rest of the preventative use of antiplatelets has beenn, but has not yet been subjected to randomized or large,

studies to assess specic protocols. In a study involv-latelet protocols: no treatment, only post-procedurepre and post-procedure treatment, Yamada et al. [18]tes of symptomatic thromboembolic complications ofy 16%, 2.3% and 1.9%. They also reported a reduced ratephically visible clots during the procedure in patientsed pre-procedure antiplatelets compared to those who

and 4.5% respectively).elets employable in practice are acetylsalicylic acidopidogrel, and more rarely urbiprofen, as well as thelatelets prasugrel and ticagrelor.

e of platelets in thrombus formation

vation of platelets induces the formation and liberationactors including ADP and thromboxane A2, and further-lates the formation of thrombin. This reaction spreadset to platelet and a linking process begins involvingnd surface glycoprotein receptors, resulting in platelet.elet drugs are designed to inhibit the production andhese different factors: acetylsalicylic acid is the mainne inhibitor; clopidogrel and the newer drugs prasugrellor inhibit ADP receptors; and Abciximab, tiroban and

are glycoprotein IIb/IIIa inhibitors. Other molecules areed.

cts by inhibiting prostaglandin H synthase, a precursorxane A2, thus provoking a prolonged inhibition of theway. Aspirins antiplatelet activity will appear approxi-60 min after the administration of a dose of 75100 mg.

irreversible. Normal platelet activity will return 7 daysal dose. Resistance to acetylsalicylic acid in as much ass has been suggested, but the data behind this numbergeneity, and comprises in particular poor compliancet; truly insufcient response to aspirin is much lessowever, when it does occur, the risk of thromboem-lications is greatly augmented and increasing aspiriny increases the risk of aspirin-related complicationsnical benets. Aspirin and clopidogrel have synergis-nd thus their association generally results in efcacious

activity [19].

grel

g a loading dose of 300 mg, the antiplatelet effect of is observable after 2 h and remains stable for 48 h. As

S. Bracard et al. / European Journal of Radiology 82 (2013) 1633 1637 1635

for aspirin, normal platelet activity resumes 7 days after the naldose. Effects are obtained within 48 h with doses of 75 mg per day,but the objective of 50% inhibition is obtained only after 47 daysof treatment.

Studies iresulted in to a 300 mgperiprocedu

Insufcicases. The ffactors maythe treatmequantity ofand obesityhyper reactreduced bypatients. Th[22], whichand proton

Insufcirisks of throantiplateletare routinelpidogrel, an

The objealso be expVASP assayresponders

If initial may be condoubling ofies have sufrom 75 to 1

If neitheseveral new

4.4. New an

Prasugrediology whoptimizatioinhibition cprises a 60prodrug. Itsdrug takes attained in conrmed athe expense

Ticagrelopeak occursimen of 90PLATO studpidogrel in expense of

Unlike tprasugrel, trhagic compplatelets re

5. GPIIb/IIIeptibatide

GPIIb/IIIinvolved instrong anti

tiroban, and greater than 10 h for Abciximab. Reversibility isaverage to poor, necessitating the emergency use of concentratedplatelets in cases of hemorrhagic complications. Furthermore, aplatelet count in urgent conditions is necessary to rule out acute

bocyre uural mab ol cosion

sche

ptur

uch bal

use ural t befo

use is re

stop patieolecu

e anysmsmenion vpasmle fortoma

ome seveting telets ear

tecgrelstentards,eurisnes se is

rupt

For si use is re

stoptopeeckeFITent d

Coilinally, t

mg/ess idistereiplatgreln cardiology demonstrated that a 600 mg loading dosea more intense and rapid antiplatelet effect compared

loading dose (ISAR CHOICE [20]), and a reduction inral thromboembolic complications (ARMYDA-2 [21]).ent response to clopidogrel is observed in 5 to 11% ofactors resulting in this resistance are multiple. Genetic

result in faulty platelet receptors or in dysfunction ofnts metabolizing enzymes resulting in an insufcient

the active metabolite. Patient factors such as diabetes may play a role as may platelet-specic factors such asivity or increased turn-over. Clopidogrel efcacy is also

some medications commonly used in cardiovascularis includes statins, such as atorvastatin or simvastatin

decrease clopidogrel efcacy as their dosage increases,pump inhibitors such as omeprazole.ent antiplatelet activity is associated with increasedmboembolic events; thus, pre-operative evaluation of

response is recommended. Two platelet inhibition testsy used: the ow cytometric VASP assay, specic to clo-d the Verify Now P2Y12 assay [23].ctive is a >40% inhibition of platelet function; this mayressed as a residual platelet reactivity of

1636 S. Bracard et al. / European Journal of Radiology 82 (2013) 1633 1637

Fig. 1. Ruptured ICA aneurism before (A) and after coiling (B) with a platelet aggregation on the surface of coils (arrow). Complete disappearance 20 min after a standarddose of abciximab (C).

days before the intervention; less ideally: an additional loadingdose may be proposed. Efcacy is then reveried. If insufcientresponse persists, in place of clopidogrel, ideally: 10 mg/day of pra-sugrel should be administered for 4 days prior to the intervention;less ideally: a 60 mg loading dose of prasugrel should be adminis-tered at least 1 h before the intervention.

The use of heparin intraoperatively according to habitual pro-tocols is recommended. After the intervention, heparin infusionsmay be stopped but they should not be antagonized.

Postoperatively: aspirin 75 mg/day and clopidogrel 75 mg/dayare continued for 6 weeks to 3 months, then 75 mg/day of aspirinfor the patients lifetime.

6.3. Flow diverters

Flow diverting stents are made of tightly-spaced mesh and thuspresent a large metallic surface to blood, resulting in a greaterlikelihood of intra-stent thrombosis or acute thrombosis in theaneurysm sac with a risk of rupture [27].

Preparation is the same as with other stents, but postopera-tively a two-drug antiplatelet regimen is usually maintained for612 months and then replaced by clopidogrel.

7. Management of intraoperative thromboemboliccomplications

The management of intraoperative thromboembolic eventsdemands the constant verication and correction of thepatients biological and clinical parameters, arterial pres-sure and the degree of anticoagulation if needed. ACT mustbe greater than 250 s. If this is not the case a 2000 IU bolusis indicated. IV nimodipine should be started (10 ml/h) andintra-arterial nimodipine or papaverine considered (Figs. 1and 2).

Fibrinolytics such as rTpa are rarely employed. GPIIb/IIIa recep-tor antagonists (Abciximab, tiroban and eptibatide) are widelyused and re-establish patency in approximately 80% of cases[28,29].

Fig. 2. Right abranches is deof the distal brzygo ACA aneurism on AP and oblique view before (9h45) and immediately at the end of creased (10h28) with a worsening on 10h34 control angio. Standard bolus injection of abanches on the late control angiogram.treatment (10h23). On nal AP control angiogram, the lling of distalciximab at 10h35 with progressive improvement and a normal lling

S. Bracard et al. / European Journal of Radiology 82 (2013) 1633 1637 1637

When clots are accessible in a proximal artery, a thrombectomymay also be considered as part of the approach.

Conict of interest

The authors conrm they have no conicts of interest.

References

[1] Pierot L, et al. Endovascular treatment of unruptured intracranial aneurysms:comparison of safety of remodeling technique and standard treatment withcoils. Radiology 2009;251(3):84655.

[2] Pierot L, et al. Ruptured intracranial aneurysms: factors affecting the rate andoutcome of endovascular treatment complications in a series of 782 patients(CLARITY study). Radiology 2010;256(3):91623.

[3] Sluzewski M, et al. Rupture of intracranial aneurysms during treatment withGuglielmi detachable coils: incidence, outcome, and risk factors. Journal ofNeurosurgery 2001;94(2):23840.

[4] van Rooij WJ, et al. Procedural complications of coiling of ruptured intracranialaneurysms: incidence and risk factors in a consecutive series of 681 patients.American Journal of Neuroradiology 2006;27(7):1498501.

[5] Altay T, et al. Thromboembolic events associated with endovasculartreatment of cerebral aneurysms. Journal of Neurointerventional Surgery2011;3(2):14750.

[6] Pierot L, et al. Safety and efcacy of balloon remodeling technique duringendovascular treatment of intracranial aneurysms: critical review of the lit-erature. American Journal of Neuroradiology 2012;33(1):125.

[7] Shapiro M, et al. Stent-supported aneurysm coiling: a literature survey of treat-ment and follow-up. American Journal of Neuroradiology 2012;33(1):15963.

[8] Golshani K, et al. Stent-assisted coil emboilization of ruptured intracranialaneurysms: A retrospective multicenter review. Surgical Neurology Interna-tional 2012;3:p84.

[9] Lodi YM, et al. Stent assisted coiling of the ruptured wide necked intracranialaneurysm. Journal of Neurointerventional Surgery 2012;4(4):2816.

[10] Bodily KD, et al. Stent-assisted coiling in acutely ruptured intracranialaneurysms: a qualitative, systematic review of the literature. American Journalof Neuroradiology 2011;32(7):12326.

[11] Park HK, et al. Periprocedural morbidity and mortality associated with endovas-cular trea2005;26(

[12] Qureshi Acomplicalogical an

[13] Hussein ulation mNeurorad

[14] Hirsh J, healthcar2001;103

[15] Raschke R, Reilly B. Monitoring heparin therapy. Annals of Internal Medicine1994;120:16970.

[16] Ray WZ, et al. incidence of deep venous thrombosis after subarachnoid hem-orrhage. Journal of Neurosurgery 2009;110:10104.

[17] Vance AZ, et al. Safety of intravenous heparin administration after endovasculartreatment for ruptured intracranial aneurysms. Journal of NeurointerventionalSurgery 2009;1(2):13641.

[18] Yamada NK, et al. Effect of antiplatelet therapy on thromboembolic complic-tions of elective coil embolization of cerebral aneurisms. American Journal ofNeuroradiology 2007;28:177882.

[19] Fox KA, et al. Benets and risks of the combination of clopidogreland aspirin in patients undergoing surgical revascularization for non-ST-elevation acute coronary syndrome: the Clopidogrel in Unstable angina toprevent Recurrent icchemic Event (CURE) trial. Circulation 2004;110(10):12028.

[20] von Beckerath N, et al. Absorption, metabolization, and antiplatelet effectsof 300-, 600-, and 900-mg loading doses of clopidogrel: results of theISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choosebetween 3 High Oral doses for Immediate Clopidogrel Effect) Trial. Circulation2005;112(19):294650.

[21] Patti G, et al. Outcome comparison of 600- and 300-mg loading doses of clo-pidogrel in patients undergoing primary percutaneous coronary interventionfor ST-segment elevation myocardial infarction: results from the ARMYDA-6 MI(Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty-Myocardial Infarction) randomized study. Journal of the American College ofCardiology 2011;58(15):15929.

[22] Lau WC, et al. Atorvastatin reduces the ability of clopidogrel to inhibit plateletaggregation: a new drug-drug interaction. Circulation 2003;107:327.

[23] van Werkum JW, et al. A head-to-head comparison between the Veri-fyNow P2Y12 assay and light transmittance aggregometry for monitoring theindividual platelet response to clopidogrel in patients undergoing electivepercutaneous coronary intervention. Journal of Thrombosis and Haemostasis2006;4(11):25168.

[24] Wiviott SD, et al. Prasugrel versus clopidogrel in patients with acute coronarysyndromes. New England Journal of Medicine 2007;357(20):200115.

[25] Wallentin WL, et al. Ticagrelor versus clopidogrel in patients with acute coro-nary syndromes. New England Journal of Medicine 2009;361:104557.

[26] Turmialan LM, et al. Intracranial hemorrhage associated with stent-assistedcoil embolization of cerebral aneurysms: a cautionary report. Journal of Neu-rosurgery 2008;108:11229.

csar Z, et al. Intra-aneurysmal thrombosis as a possible cause of delayedurysmiologys T, etplica

cases eningturedcoprot6;27:tment of intracranial aneurysms. American Journal of Neuroradiology3):50614.I, et al. Prevention and treatment of thromboembolic and ischemictions associated with endovascular procedures: Part I pathophysio-d pharmacological features. Neurosurgery 2000;46(6):134459.HM, Georgiadis AL, Qureshi AI. Point-of-care testing for anticoag-onitoring in neuroendovascular procedures. American Journal ofiology 2012;33(7):121120.et al. Guide to anticoagulant therapy: Heparin: a statement fore professionals from the American Heart Association. Circulation(24):29943018.

[27] Kulanerad

[28] Riecom42

[29] Brurupgly200 rupture after ow-diversion treatment. American Journal of Neuro- 2011;32(1):205.

al. Abciximab is a safe rescue yherapy in thromboembolic eventsting cerebral aneurysm coil embolization: single center experience inand review of the literature. Stroke 2009;40:17507.

R, et al. Intraprocedural thrombus formation during coil placementin intracranial aneurysms: treatment with systemic application of theein IIb/IIIa antagonist tiroban. American Journal of Neuroradiology132631.

Endovascular treatment of aneurisms: Pre, intra and post operative management1 Introduction2 Thromboembolic complications3 Interest and use of heparin4 Antiplatelets4.1 The role of platelets in thrombus formation4.2 Aspirin4.3 Clopidogrel4.4 New antiplatelet drugs

5 GPIIb/IIIa receptor antagonists (Abciximab, tirofiban and eptifibatide)6 Use schemas6.1 Ruptured aneurisms6.2 Unruptured aneurisms6.2.1 For simple coiling and possible remodeling6.2.2 Coiling and stenting

6.3 Flow diverters

7 Management of intraoperative thromboembolic complicationsConflict of interestReferences