CAMOIn COPACAMU 2015 - Alti sitessites.altilab.com/files/11/communications2015/JEUDI/HA1/11h15... · Pic 1-3h 0,5-4h 1-3h ... Rivaroxaban 20 mg qd Patients with AF 274† 30† (33)

Troubles de la coagula.on observés au cours de hémorragies sous AOD

L Camoin Lab.Hématologie -‐ CHU Timone -‐ APHM

Troubles de la coagula.on observés au cours de hémorragies sous AOD

L Camoin – Jau Lab.Hématologie CHU Timone

APHM Marseille

Voie orale Voie

parentérale

Facteurs II, VII, IX, X hypo-‐γ-‐carboxylés

FT/VIIa

X IX

IXa VIIIa

Complexe prothrombinase

Va

Xa rivaroxaban Apixaban

AT

AT

AT

fondaparinux

danaparoïde

II

IIa

HBPM HNF

argatroban bivalirudine

dabigatran

Fibrinogène Fibrine

AVK

dabigatran etexilate

rivaroxaban

apixaban

Prodrogue Oui (estérases) Non Non

Cible Anti-IIa direct sélectif Anti-Xa direct sélectif Anti-Xa direct sélectif

Biodispo. 6,5% 80% 50%

Pic 1-3h 0,5-4h 1-3h

Demi-vie 7-17h 7-11h 8-15h

Liaison prot. 35% 90-95% 85%

Métabolisme Transport

Non P-gp

CYP3A4, CYP2J2 P-gp

CYP3A4, CYP1A1/2 P-gp

Elimination 80% rénale inchangée 20% fèces

(glycuroconjuguée)

1/3 rénale inchangée 1/ 3 rénale métabolisée

1/3 fèces

25% rénale inchangée 75% fèces (inchangée)

Interactions Inhib P-gp : amiodarone, vérapamil,

(quinidine)

Antifongiques azolés, Inhibiteurs protéases VIH

CYP3A4, P-gP

CYP3A4

Antidote Non Non Non

Des tests d’Hémostase: Quand ?

ABSENCE DE SURVEILLANCE DE LEUR EFFET ANTI COAGULANT EN ROUTINE

Bilan d ‘Hémostase si : •  Saignements •  Thrombose sous traitement •  Overdose •  Acte invasif urgent quand le pa.ent a pris sa dernière dose dans les 24 heures (ou avant si clairance Creat <50 ml/min)

•  Insuffisance rénale

Des tests d’Hémostase: Lesquels ?

Dabigatran Rivaroxaban Apixaban

TP î îî -‐ TCA ìì ì -‐

Temps de Thrombine

ìì -‐ -‐

An.-‐Xa -‐ ++ ++ An.-‐IIa ++ -‐ -‐

Varia.on des paramètres au cours de 24h

With Persistent Atrial Fibrillation) study, the range(5th to 95th percentile) in peak and trough con-centrations in patients taking 150 mg twice dailywas 64 to 443 ng/ml and 31 to 225 ng/ml, respec-tively (9,10).

Study se lect ion . Our literature search yielded 160articles. Nine additional references were identifiedfrom bibliographies. A total of 152 articles wereexcluded: 135 did not report an original researchstudy, 14 did not report drug levels measured byLC-MS/MS, and 3 were published as abstracts only.The remaining 17 articles (11–27) met eligibilitycriteria (Figure 1). Eligible studies were collectivelyconducted in 9 different countries across a range ofdabigatran concentrations from 0 to 1,886 ng/ml.Only 4 studies used ex vivo plasma from dabigatran-treated patients; the remainder involved ex vivohealthy volunteer plasma or normal plasma spikedin vitro with dabigatran as the test material(Table 2).Act ivated part ia l thromboplast in t ime. Twelveeligible studies reported a relationship betweenthe activated partial thromboplastin time (APTT)and dabigatran levels. Three used ex vivo patient

TABLE 1 Expected Steady-State Peak and Trough Concentrationsof Dabigatran, Rivaroxaban, and Apixaban Derived FromPharmacokinetic Studies

Drug DoseStudy

PopulationPeak,ng/ml

Trough,ng/ml Ref. #

Dabigatran 150 mg bid Patients with AF 184* 90* (9,10)

Rivaroxaban 20 mg qd Patients with AF 274† 30† (33)

Apixaban 5 mg bid Healthy malevolunteers

129‡ 50‡ (52)

Only standard doses approved for AF are shown. *Median. †Median estimated bymathematical modeling. ‡Mean.

AF ! atrial fibrillation; bid ! twice daily; qd ! once daily.

160 articlesidenti!ed by

databasesearch


databasesearch

9 articlesidenti!ed by bibliography

review

169 articles screened

34 articles reviewedby full-text



135 excluded:

17 excluded:

17 articles includedin analysis



13 excluded: 1 excluded:Abstract only (n=3)Relationship withreference methodnot reported (n=14)

Abstract only (n=1) Abstract only (n=1)Relationship withreference methodnot reported (n=12)

Review (n=114)Case report (n=9)Guideline (n=7)Editorial (n=5)

Review (n=98)Case report (n=2)Guideline (n=4)Editorial (n=1)Other (n=3)

Review (n=55)Guideline (n=2)Editorial (n=7)Other (n=4)

108 excluded: 68 excluded:


Dabigatran

••

••

••

•

••

•••••

••••

Includ

edEligibility

Screen

ing

Iden

ti!catio

n Rivaroxaban Apixaban



review


databasesearch


review

FIGURE 1 PRISMA Diagram

This PRISMA (Preferred Reporting Items of Systematic Reviews and Meta-Analyses) flow diagram illustrates dabigatran, rivaroxaban, andapixaban literature searches.

Cuker et al. J A C C V O L . 6 4 , N O . 1 1 , 2 0 1 4

Laboratory Testing of Anticoagulants S E P T E M B E R 1 6 , 2 0 1 4 : 1 1 2 8 – 3 9

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Pharmacociné.que des AOD

JACC VOL. 64, NO. 11, 2014

Quels tests pour le dabigatran ? Reference Range of drug

concenra3ons (ng/ml)

Indica3on Dose Coagula3on test

R 2

Van Ryn et al, Am J Med 2012, 125

<0.5-‐ 586 AF (n=70) APTT DILUTE TT PT/INR

0.58 0.97 0.48

Antovic et al, Eur J Pharmacol 2013,69

AF 150 bid DILUTE TT 0.96-‐0.97

Gosselin et al, Ann Pharmacother 2013, 47

18-‐487 AF APTT DILUTE TT

0.64-‐0.72 0.92

Quels tests pour le rivaroxaban ? Reference Range of drug

concenra3ons (ng/ml)

Indica3on Dose Coagula3on test R 2

Asmis et al, Thromb Res 2012, 129

1.9-‐283 MOS 10 qd An.-‐Xa 1

Dinkelaar et al, J Thromb Haemost 2013,11

AT, VTE An.-‐Xa PT

1 0.5

Quels tests pour l’Apixaban ?

Reference Range of drug concenra3ons (ng/ml)

Indica3on Coagula3on test R 2

Mueck et al, Clin

Pharmacokinet 2011, 50

<10-‐>1000 VTE An.-‐Xa PT

0.88-‐0.89 0.36

Barret et la, Cli Appl Thromb Haemost 2013,

19

1-‐933 ACS An.-‐Xa 0.97

Becker et al, J Thromb

Thrombolysis 2011,32

0-‐2500 PT 0.41

Laboratory Measurement of the An.coagulant Ac.vity of the Non–Vitamin

K Oral An.coagulants

activity (whether the standard curve is establishedwith apixaban or LMWH) likely excludes the presenceof physiologically important apixaban activity.

SUGGESTIONS AND COMPARISONS WITH GUIDANCE

DOCUMENTS. Recommendations for laboratory mea-surement of the NOACs differ by drug and clinicalobjective. The findings of our systematic reviewsupport the suggestions summarized in Table 6.These suggestions align with recommendationsprovided in drug labels and published guidancedocuments, with 2 notable exceptions. First, wefound strong evidence from studies of ex vivo pa-tient samples that a normal APTT does not defini-tively exclude on-therapy dabigatran concentrations(23,25). This observation is at variance with guide-lines from the American Society of Hematology(ASH) and the British Committee for Standards inHaematology (BCSH), which state that a normalAPTT is likely to exclude therapeutic intensitydabigatran (58) or contribution of dabigatran tobleeding (59). Second, we found that a normal PTdoes not exclude clinically relevant rivaroxabanlevels. The BCSH statement, in contrast, commentsthat a normal PT ratio with most reagents excludestherapeutic intensity rivaroxaban (58). The ASH andBCSH statements were published in 2011 and 2012,respectively. Discrepancies between our findings andthese statements may reflect availability of new in-formation since their publication regarding a widervariety of test reagents and their sensitivity to theNOACs.

STUDY LIMITATIONS. Quality assessment high-lighted several key limitations of eligible studies(Table 5). First, on-therapy ranges (Table 1) were

derived from pharmacokinetic analyses. We resistedthe term “therapeutic range” because data on howthese ranges correlate with clinical outcomes aresparse, although they are beginning to emerge (57).Second, many eligible studies used either ex vivo orspiked plasma samples from healthy controls ratherthan ex vivo samples from NOAC-treated patients.Reassuringly, results obtained with patient samplesgenerally aligned with those from healthy controls.Third, we identified only 4 eligible apixaban studies,just 2 of which used ex vivo patient samples. Becauseapixaban was the most recent NOAC to receive reg-ulatory approval, we expect that additional studiesof its laboratory measurement will be forthcoming.Such studies are also needed for NOACs not yetapproved in North America and Europe (e.g.,edoxaban).

CONCLUSIONS

A relatively large number of published studies haveassessed the relationship between coagulation testsand levels of dabigatran, rivaroxaban, and apixaban.Each drug produces unique effects on coagulationassays. Our systematic review provides guidance tothe clinician on how to use and interpret coagulationtest results in NOAC-treated patients. Further studiesare needed to define the relationship between druglevels, coagulation test results, and clinical outcomes.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Adam Cuker, Hospital of the University of Pennsyl-vania, 3 Dulles, 3400 Spruce Street, Philadelphia,Pennsylvania 19014. E-mail: [email protected].

TABLE 6 Suggestions for Laboratory Measurement of Non–Vitamin K Oral Anticoagulants

Drug

Clinical Objective

Determine If Clinically Relevant BelowOn-Therapy Drug Levels Are Present

Estimate Drug Levels WithinOn-Therapy Range

Determine If AboveOn-Therapy Drug Levels Are Present

SuggestedTest Interpretation



Dabigatran TT Normal TT likely excludes clinicallyrelevant drug levels

Dilute TT,ECA, ECT

— APTT, dilute TT,ECA, ECT

Normal APTT likely excludesexcess drug levels; onlydilute TT, ECA, and ECTare suitable for quantitation

Rivaroxaban Anti-Xa Normal anti-Xa activity likely excludesclinically relevant drug levels

Anti-Xa — Anti-Xa, PT Normal PT likely excludes excessdrug levels; only anti-Xa issuitable for quantitation

Apixaban Anti-Xa Normal anti-Xa activity likely excludesclinically relevant drug levels

Anti-Xa — Anti-Xa —

Suggestions for laboratory measurement of the anticoagulant activity of dabigatran, rivaroxaban, and apixaban are based on the clinical objective. Typical on-therapy drug levels are shown in Table 1.

Abbreviations as in Table 2.

J A C C V O L . 6 4 , N O . 1 1 , 2 0 1 4 Cuker et al.S E P T E M B E R 1 6 , 2 0 1 4 : 1 1 2 8 – 3 9 Laboratory Testing of Anticoagulants

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JACC VOL. 64, NO. 11, 2014 < Zone thérapeu.que Zone thérapeu.que Surdosage

Interpréta.on •  Délai entre heure de prise et heure du prélèvement

•  Traitement et indica.on (posologie) •  Fonc.on rénale •  An. IIa /an.-‐Xa •  TP-‐TCA -‐TT •  Poids, fonc.on hépa.que

Saignement Pa3ent 1 Pa3ent 2 Pa3ent 3

Sexe/Age H/73 F/56 F/85

AOD Indica.on

Pradaxa 110*2 FA

Rivaroxaban 20 FA

Rivaroxaban 15 FA <1mois

Hémorragie Diges.ve Cérébrale Diges.ve

Pronos.c vital engagé? Oui Oui Non

Co-‐médica.on Chimio K poumon Non Zolpidem

Clairance (ml/min) 70 141 31

Ac.vité spécifique Délai/prise

3500 an.-‐IIa 5h

116 an.-‐Xa 9h

395 an.-‐Xa 22h

TP (%) 25 78 38

TCA (sec) Témoin : 33 sec

150 33 49

TT (sec) > 60 NR NR

Geste invasif Pa3ent 1 Pa3ent 2 Pa3ent 3

Sexe/Age F/79 H/78 H/ 77

AOD Indica.on

Rivaroxaban 15 FA

Rivaroxaban 20 FA

Dabigatran 110*2 FA

Chirurgie Diges.ve Neurochirurgie PTH

Saignement Non Non Non

Co-‐médica.on Non Aspirine Aspirine

Clairance (ml/min) 25 63 57

Ac.vité spécifique Délai/prise

356 25h

134 36h

287 26

TP (%) 57 82 74

TCA (sec) Témoin : 33 sec

38 33 45

TT (sec) >60

Dosage spécifique des ac.vités an.-‐IIa et an.-‐Xa

•  1 tube citraté ( bouchon bleu) •  Réalisa.on de l’analyse sur Timone 24/24h •  Délai rendu résultat : 40 minutes.`

Prescrip.on type : An.-‐IIa ou an.-‐Xa ++++

TP-‐ TT •  Au laboratoire de biochimie : Evalua.on de la fonc.on rénale

Conclusion

•  U.lisa.on des dosages spécifiques an.-‐II et an.-‐X

•  Limites d’interpréta.on des tests de première inten.on

•  Interpréta.on et évalua.on du risque à un instant donné

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CAMOIn COPACAMU 2015 - Alti sitessites.altilab.com/files/11/communications2015/JEUDI/HA1/11h15... · Pic 1-3h 0,5-4h 1-3h ... Rivaroxaban 20 mg qd Patients with AF 274† 30† (33)