DOACs: QUANDO DOSARNE L’ATTIVITA’ E COME INTERPRETARE I RISULTATI

Sophie Testa Centro Emostasi e Trombosi

Dipartimento di Medicina di Laboratorio e Radiologia ASST Cremona

PUNTI DI DISCUSSIONE

• Perché parliamo di misurazione dell’attività anticoagulante dei DOACs

• Quando misurare

• Come misurare

• Come interpretare i risultati

DOACs

At present, DOACs are administered at fixed dose in relation to clinical

indications, individual characteristics and renal function without need for

laboratory monitoring, because:

1. Pharmacologycal studies have shown that DOAC have predictable

anticoagulant response in “standard” clinical condition

2. Clinical trials have been successfully conducted at fixed-dose regimen, without

laboratory controls and without the availability of specific antidotes, in two

clinical conditions (NVAF and VTE)

DOAC CHARACTERISTICS

Gosselin R et al, Thromb Haemost 2018

DOACs DOSAGE

DOSING ADJUSTEMENT IS

BASED ON PHARMACOKINETIC CONSIDERATIONS

(Clinical characteristics and

renal function)

BASED ON PK MODELS, “A PRIORI” DOAC PLASMA LEVELS ARE SUPPOSED AS FOLLOW

Therapeutic ranges for the DOACs have not been established. The “on-therapy” range is defined as the

interval from the 5th to 95th percentile of DOAC concentration. Drug levels below this range may be regarded

as “below on-therapy”, those exceeding this range as “above on-therapy”.

Cuker A, Siegal D, Haematology 2015

BUT, THE REALITY IS THAT …

• High inter/intra individual variability has been demonstrated in the real

world patient population

• Pharmacological modifications have been showed in relation to: drug

interaction, liver and renal function, age , weight, comorbidities….

• After DOAC introduction in clinical practice specific antidotes have been

requested and are now available

• Laboratory measurements are recommended, at the moment, at least in

particular clinical conditions

VARIABILITY

Drug interactions, renal and liver function, age, weight, genetic polymorphisms…

dabigatran rivaroxaban

apixaban

Gong IY et al, 2013

EXPECTED PEAK AND TROUGH DOAC LEVELS IN NVAF AND VTE PATIENTS ENROLLED

IN PHASE II-III CLINICAL STUDIES

Gosselin R et al, Thromb Haemost 2018

aMean (25th–75th percentile); bMean (5th–95th percentile); cMedian (5th–95th percentile); dMedian (1.5 x IQR); eMedian (IQR).

DOACs INTER-INDIVIDUAL VARIABILITY

Population CV%

Healthy and young volunteers ~ 20

Phase III randomized clinical studied ~ 40

“Real world” patients ~ up to 100

Testa S et al, Thromb Res 2016, 2019

WHAT WE KNOW AND OUR ASSUMPTIONS IN DAILY CLINICAL PRACTICE

1. We know the biological variability of

DOACs (NOT the therapeutic range), in

population enrolled in phase II-III studies

and few data are available in real life patient

populations

2. DOAC biological variability differs

between NVAF and VTE patients

3. It has been assumed that DOAC levels,

“individually” and “a priori” , also during

time, are “acceptable” and do not occur

persistent accumulation or absence of drug

ARE THESE PHARMACOLOGICAL

INFORMATIONS USEFUL FROM A

CLINICAL POINT OF VIEW?

FDA REPORTS: DOACs EXPOSURE-RESPONSE ASSOCIATION FOR EFFICACY AND SAFETY

dabigatran rivaroxaban

apixaban edoxaban

Eikelboom JW et al, JAMA Cardiol 2017

DOACs AND THE LAB

Test Recommendation Comments

ClCr 1.Before starting DOACs and in the follow up to continue treatments (or adapt posology).

2. CrCl is also considered as surrogate of good anticoagulant action

- ClCr not validated in older population

- CrCl>30ml/min not correlate with aXa drugs

AST/ALT 1. Before starting DOACs and in the follow up to continue treatments

No clear timing of controls

Blood Cell Count

Should be recommended Before starting and during the follow up

PT/aPTT Not recommended to assess levels of anticoagulation

Should be recommended before starting DOAC to assess haemostatic status

DOAC specific

test

In special clinical conditions There is still no unanimous consensus

Tromb Res, 2016

EDOXABAN PLASMA LEVELS IN PATIENTS WITH NON-VALVULAR ATRIAL FIBRILLATION: INTER AND INTRA-INDIVIDUAL VARIABILITY, CORRELATION WITH

COAGULATION SCREENING TEST AND RENAL FUNCTION

Thromb Res, 2019

DOACs MEASUREMENT

1. PERIODICAL MEASUREMENT (MONITORING) TO FREQUENT DOSE-

ADJUSTEMENT (currently no evidences…)

2. MEASUREMENT (CONTROL) TO HIGHLIGHT UNDER/OVER ANTICOAGULATION IN RELATION TO RISK OF BLEEDING AND THROMBOSIS

3. MEASUREMENT IN SPECIAL CLINICAL CONDITIONS (Patients presenting in emergency with bleeding/thrombosis, immediate reverse of anticoagulation, perioperative management, renal disease, liver disease, suspicion or known interaction with other drugs, elderly patients, under/over weight….but no still unanimous consensus)

Eikelboom JW et al, 2017

IN RECENT LITERATURE

These retrospective observational studies, conducted on small cohort of patient

population, highlighted :

1. A role in drug monitoring in the management of patients in selected

circumstances (surgery, bleeding thromboembolic complications, renal

failure, drug interactions, overweight)

2. No current indications in routine (frequent) drug level monitoring because it

rarely affected clinical management

3. The necessity of studies to further establish association between drug-

specific DOAC levels and clinical outcomes, to define appropriate indications

for testing

Thromb Res 2016; Int J Lab Hem 2017; JTH 2018

1. PERIODICAL MEASUREMENTS

(MONITORING) TO

DRUG DOSE-ADJUSTMENT

Drug Trough (ng/ml)‏

mean (min-max)

Peak (ng/ml)‏

media (min-max)

Dabigatran 110 mgx2/die 93 (14-386) 190 (31-651)

Dabigatran 150mgx2/die 91 (16-494) 210 (43-538)

Rivaroxaban 15mg/die 27 (0-88) 208 (77-393)

Rivaroxaban 20mg/die 41 (5-119) 235 (61-449)

Apixaban 2,5mgx2/die 79 (26-248) 192 (55-300)

Apixaban 5 mgx2/die 113 (42-283) 200 (102-416)

Thrombosis Research, 2016

Drug Trough (ng/ml)‏

mean (min-max)

Peak (ng/ml)‏

media (min-max)

Edoxaban 60 mg/die 39 (13-114) 294 (136-569)

Edoxaban 30 mg/die 37 (11-147) 184 (10-529)

Thrombosis Research 2019

Ejkelboom JW, 2017

Ejkelboom JW, 2017

2.

PERIODICAL MEASUREMENT

(CONTROL) TO HIGHLIGHT

UNDER/OVER ANTICOAGULATION

Recurrent venous thrombosis under rivaroxaban and carbamazepine for symptomatic epilepsy

A 55-year-old male was admitted because of pain and swelling of his right leg spontaneously since 2 days. He was on rivaroxaban 20mg/die since 4 months because of an unprovoked venous thrombosis of his right leg. He had a history of poliomyelitis, structural epilepsy treated with carbamazepine (900mg/d). He reported to be highly adherent to his anticoagulant and antiepileptic medication. Anti-Xa activity was <20ng/ml. Therapy with rivaroxaban was stopped, and low-molecular-weight heparin, followed by phenprocoumon, was started.

The combination of DOACs with carbamazepine, an inducer of P-gp and CYP3A4-activity, should be avoided since the anticoagulant effect is decreased. There is an urgent need to increase our knowledge and physicians' awareness about the potential of drug-drug interactions of DOACs.

Stöllberger C et al, Neurol Neurochir Pol. 2017

Breuer L, N Engl J Med 2013

LEVELS

• During 1 year follow up we

observed 10 thromboembolic

events (1.8%), all occurred after

the first 6 months of treatment

• All events were recorded in

patients whose C-trough drug

levels were in the lowest level

class, calculated for each drug

Patients with thromboembolic events are identified as filled circles

THROMBOEMBOLIC RISK IN PATIENTS WITH LOW DOACs LEVEL AND HIGHER CHA2DS2-VASc

CHA2DS2-VASc >3.0

(291/595pts; 51.5%)

Class I n°

(Lower drug levels)

Class II, III,IV n°

(Highest drug levels)

Total

(n)

Thrombosis

10

0

10

No Thrombosis

117

164

281

10/127

(7.9%)

0/164

(0%)

CONCLUSION

• Our data show a relationship between low DOACs trough plasma levels and subsequent thrombotic events

• Especially in high cardiovascular risk patients with low DOACs levels

• DOACs measurement seems particularly indicated in these patients

DRUG LEVELS AND BLEEDING COMPLICATIONS

IN ATRIAL FIBRILLATION PATIENTS TREATED WITH DIRECT ORAL ANTICOAGULANTS

• To evaluate a possible relationship between DOACs C-trough and C-

peak anticoagulant levels, measured at steady state within the first

month of treatment, and bleeding events observed during one year

follow up.

JTH, 2019

The MAS study (“Measure And See”)

Measurement of the anticoagulant levels in patients treated with Direct

Oral Anticoagulants (DOACs) and observation of bleeding and thrombotic complications during follow up.

Promoted and funded by the «Arianna Anticoagulazione Foundation» (Bologna, Italy), Coordinator: prof. Gualtiero Palareti In collaboration with: FCSA (Federation of Italian Anticoagulation Clinics)

To confirm this preliminary results a large prospective, multicenter, observational study - The MAS (Measure And See) Study, conducted within FCSA and the START Registry- has been planned and is started in June 2018.

The question: Is DOAC testing usefull to highlight patient at higher risk of complication? The answer: The MAS Study

Powell JR, JAMA 2015

• Patients presenting in emergency with adverse events (Thrombosis, Bleeding)

• Immediate reverse of anticoagulation

• Perioperative management

• Renal Disease

• Liver Disease

• Suspicion or known interaction with other drugs

• Elderly patients

• Under/over weight

3. DOAC MEASUREMENT IN SPECIAL

CLINICAL CONDITIONS

Pengo V et al, 2011

DOACs MEASUREMENT

=

HELPFUL TO GUIDE APPROPRIATE

MANAGEMENT

Caso 1: Stroke ischemico in donna di 58 anni trattata con dabigatran 150 mg 1cpx2/die per FANV, ultima dose assunta 1 ora prima del ricovero. Dosaggio dabigatran (dTT) <15 ng/mL a due controlli successivi. Si procedeva quindi a terapia trombolitica, profilassi eparinica e terapia con AVK. Caso 2: Emorragia cerebrale post-traumatica in pz trattato con dabigatran 150mgx2die per FANV . Dosaggio dabigatran = 189 ng/mL (6 ore dopo l’ultima assunzione del farmaco). Praticata infusione di idarucizumab (Praxbind®) 2.5 g 1flx2. Al termine dell’infusione dosaggio dabigatran (dTT)=2.28 ng/mL ( sempre negativo nelle 24 ore successive). TC encefalo a distanza di un mese evidenziava pressochè completo riassorbimento dell’emorragia.Ripresa terapia con dabigatran.

• Laboratory measurements were performed centrally and were

not used to guide therapy.

• dTT results were normal in ¼ of the study population. This group

of patients would not be expected to benefit from the

administration of idarucizumab.

• It will be useful to have activity measurements available for the

various direct oral anticoagulants in real time to help guide the

treatment of such patients and to prevent overutilization of

what will surely be a costly medication

Bauer KA , N Engl J Med 2015

PERIOPERATIVE MANAGEMENT: THE GUIDELINES

Schulman S, J Intern Med 2013

PERIPROCEDURAL MANAGEMENT OF DOAC SHOULD BE GUIDED BY

ACCURATE LABORATORY TESTS

Interruption of DOAC should not be based only on their respective

half-life but also on the residual drug concentration

• Poor correlation between renal function and plasma

concentration of apixaban and rivaroxaban was found except

dabigatran measured at trough (Testa S et al, TR 2016)

• Mass spectrometry measured dabigatran level greater than

20ng/ml in nearly 16% of patients undergoing high bleeding risk

procedures (Douketis JD et al JT&H 2016)

Douxfils J et al, Reg Anesthesia and Pain Medicine, Sept 2016

Douketis J et al, Jama Intern Med 2019

COMMENTS on JAMA • Altogether the study showed 3.43% of major and clinically

relevant, plus 5% of minor bleeding complications

• The adopted management algorithm was based on the DOACs pharmacokinetics, CrCl and the procedure-associate bleeding risk.

• However, DOACs plasma levels have a high inter-individual variability; furthermore, the drug elimination rate may not be constant in all patients

• Our question is: may we be really confident that a standardized model, which never takes into consideration the high drug level variability or the high risk of bleeding both from individual patients or from anesthesiology procedures, may be the best strategy to be adopted in all patients?

Testa S et al, JAMA 2019

1. At the beginning of DOAC treatment to confirm adsorption

and to know patient’s individual anticoagulant levels

2. Over-under weight

3. In case of potential interferences with co-medications

4. Co-morbidities

5. Bleeding and thromboembolic complications

6. Surgical and invasive procedures

Blood Transfusion, 2017

HOW TO MEASURE? 1. PT and aPTT react differently with DOACs in relation to type of

drug and type of reagent

2. Patients having the same DOAC plasma concentration may show

different PT or aPTT results

3. Normal PT/aPTT results cannot exclude significantly high

concentrations of DOACs, such as abnormal prolongation could

be caused by defects of coagulation other than those stemming

from the drug being taken by the patients

4. Specific test are easily available (dTT, Ecarin Tests, specified

calibrated aXa)

5. The use of PT or aPTT in clinical practice to evaluate DOAC

anticoagulant activity could cause dangerous misinterpretations.

Kitchen S et al, BJH 2015; Douxfils 2012, Douxfils 2013, Testa S et al, JTH 2016, Gosselin R 2018

COME INTERPRETARE I RISULTATI (I) • Considerare : tipo di farmaco, mono/bi-somminitrazione giornaliera,

orario dell’ultima assunzione

• Il laboratorio deve riportare sul referto i valori relativi all’assenza di farmaco, cioè i limiti inferiori di sensibilità analitica del test in uso

Test Negativo (ng/mL)*

dabigatran < 15

apixaban < 25

edoxaban < 20

rivaroxaban < 20 *ASST Cremona

COME INTERPRETARE I RISULTATI (II)

• I range pubblicati si riferiscono alla variabilità biologica osservata negli studi di fase II-III ma non sono ancora validati come range terapeutici

aMean (25th–75th percentile); bMean (5th–95th percentile); cMedian (5th–95th percentile); dMedian (1.5 x IQR); eMedian (IQR).

COME INTERPRETARE I RISULTATI (III)

In attesa dei risultati degli studi in corso, pragmaticamente :

1. DOACs Livelli bassi : valori compresi tra il limite inferiore di sensibilità analitica e 50 ng/ml

2. Livelli al di fuori del 10/90 percentile sono rispettivamente espressione di basse o elevate concentrazioni di farmaco.

3. Valori di valle attesi (Derivati dagli studi fase IV 2016, 2019):

Farmaco Mean 10-90% (ng/ml)

Media Negativo (ng/mL)

dabigatran 50-170 80 < 15

apixaban 60-200 110 < 25

edoxaban 0-40 32 < 20

rivaroxaban 0-100 40 < 20

COME INTERPRETARE I RISULTATI (IV)

3. Livelli <50ng/ml consentono di procedere a Chirugia in Urgenza (According to ISTH, a drug concentration>30 ng mL in patients requiring an urgent intervention associated with a high risk of bleeding is likely to be sufficiently high to warrant antidote administration, whereas in patients with serious bleeding, antidote administration should be considered if the drug concentration exceeds 50 ng mL)

4. Livelli < 30 ng/ml sono auspicabili nella Chirugia Elettiva

5. La definizione dei cut-off per la trombolisi per i diversi DOAC non è ancora condivisa (In those requiring thrombolysis, plasma concentrations of 10 (apixaban), 50 (dabigatran) and 100 (rivaroxaban) ng/mL have been proposed as cut-offs)

Douxfils H et al, JTH 2017

CONCLUSIONI

• Il dosaggio dei DOACs è raccomandabile in molte situazioni cliniche • In considerazione dell’elevata variabilità dell’effetto anticoagulante, il dosaggio dei DOACs potrebbe essere auspicabile per ottimizzarne le posologie

Drug Trough (ng/ml)‏

mean (min-max)

Peak (ng/ml)‏

media (min-max)

Dabigatran 110 mgx2/die 93 (14-386) 190 (31-651)

Dabigatran 150mgx2/die 91 (16-494) 210 (43-538)

Rivaroxaban 15mg/die 27 (0-88) 208 (77-393)

Rivaroxaban 20mg/die 41 (5-119) 235 (61-449)

Apixaban 2,5mgx2/die 79 (26-248) 192 (55-300)

Apixaban 5 mgx2/die 113 (42-283) 200 (102-416)

Thrombosis Research, 2016

Drug Trough (ng/ml)‏

mean (min-max)

Peak (ng/ml)‏

media (min-max)

Edoxaban 60 mg/die 39 (13-114) 294 (136-569)

Edoxaban 30 mg/die 37 (11-147) 184 (10-529)

Thrombosis Research 2019

CARATTERISTICHE FARMACOLOGICHE

Gong IY et al 2013

Parameter

Dabigatran

Rivaroxaban

Apixaban

Edoxaban

Age

Yes, lower Cr/Cl as age increase

None

Yes, lower CL as age increase

None

Body weight

None None

Yes, higher exposure with

low body weight (<60kg)

Yes, higher exposure with

low body weight (<60kg)

Sex

Yes, lower CL in women

None

Yes higher exposure in

women

None

Ethnicity

None Yes, Lower dose in japanese pts

None Lower in Asian pts

DOACs AND WEIGHT: PHARMACOKINETIC AND PHARMACODYNAMIC STUDIES

DOAC PK/PD REFERENCES

DABIGATRAN Trough levels <21% for high body weight (>100 Kg) Reilly PA et al, J Am Coll Cardiol 2014

APIXABAN For body weight > 120 kg and BMI > 30: - Mean peak level < 31% - 24% higher volume of distribution and 23% lower drug

exposure - Mean half life 8.8 h ±3.2 vs 12±5.4

Upreti VV et al, Br J Clin Pharmacol 2013

EDOXABAN Body weight affected the non-renal clearence , with non renal decreasing with lower body weight (31-165kg)

Yin OQ et al, Eur J Clin Pharmacol 2014

RIVAROXABAN 1. Healthy volunteers with body weight > 120kg: No differencies for peak level and half life

2. No differencies in peak levels; volume of distribution directly correlated with body weight with a decrease of 0.8% per kg < 56 kg and increased Vd in higher weight pts .

1. Kubitza D et al, J Clin Pharmacol 2007

2. Mueck W et al, Clin Pharmacokinet 2011

Obese patients can show reduced DOAC exposure, but it doesn’t

mean that drug levels are “ a priori” low.