Nuovi anticoagulanti orali (NOA): dalla farmacologia alla pratica clinica

Caratteristiche farmacologiche e farmacodinamiche

Prof. Alberto CorsiniUniversità degli Studi di Milano

2S1618

Principali caratteristiche farmacocinetiche di warfarin e dei nuovi anticoagulanti orali

Rapid Absorption

A single 150 mg dose in 12 healthy males.

• Rapid absorption (Cmax in up to 2 hours)

• Food delayed Cmax by 2 hours

• Surgery delayed Cmax by 4 hours

Stangier J.: Clin Pharmacokinet 2008:47:285-295

Foods does not affect the pharmacokinetic profile of apixaban

Foods does not affect the pharmacokinetic profile of apixaban

, ◊ Fasted (n = 23); ■ Fed (n = 22

Frost C et al Br J Clin Pharmacol. 2013 Nov;76(5):776-86

6S1618

Summary of absorption, metabolism, and excretion of dabigatran, rivaroxaban, and apixaban

Gong IY and Kim RB Canadian Journal of Cardiology 29 (2013) S24eS33

FDA 2012

P-GP InhibitorsAmiodarone: Dabigatran exposure in healthy subjects was

increased by 60 % in the presence of amiodarone

Verapamil: When dabigatran 150 mg was coadministered with oral verapamil, the Cmax and AUC of dabigatran were

increased,but the magnitude of this change differs, depending on

timing of administration and formulation of verapamil

Clarithromycin: Dabigatan exposure (AUC) in healthy subjects

was increased by about 19 % in the presence of clarithromycin

without any clinical safety concern

Current US labeling for dabigatran with rifampicin a P-GP inducers should be avoided

Pradaxa® – Summary of Product Characteristics

Semin Thromb Hemost. 2015 Mar;41(2):195-207

JA C C VO L . 6 4, 2 0 1 4 Flaker et al.O C T O B E R 1 4 , 2 0 1 4 : 1 5 4 1 – 5 0

Efficacy and Safety of apixaban vs. warfarin in patients with and without amiodarone on Stroke or Systemic Embolism

Adjusted outcomes of rivaroxaban vs warfarin stratified by amiodarone use at baseline

Adjusted outcomes of rivaroxaban vs warfarin stratified by amiodarone use at baseline

Steinberg BA et al. Heart Rhythm 2014;11:925–932)

12S1618

Principali caratteristiche farmacocinetiche di warfarin e dei nuovi anticoagulanti orali

Plasma concentration profiles of rivaroxaban and apixaban in atrial fibrillation patients

Plasma concentration profiles of rivaroxaban and apixaban in atrial fibrillation patients

Gong IY and Kim RB Canadian Journal of Cardiology 29 (2013) S24eS33

NOAC - Differences

l Mechanism of action l Pharmacokineticsl Pharmacodynamicsl Documentation of health benefits and long-term safety

15S1618

Comparative pharmacodynamicsof warfarin and of

NOAs

Desai J et al Gast End 78:227-239 2013

Rivaroxaban: similar onset and offset of action to enoxaparin

Kubitza et al, 2005

0 4 8 12 16 20 24 28 32 36 40 44 48

0

1

2

3

4

Ant

i-Fac

tor X

a ac

tivity

(cha

nge

from

bas

elin

e; n

g/m

l eno

xapa

rin)

Rivaroxaban 10 mg

Enoxaparin 40 mg

Time (hours)

Stroke or systemic embolic events by age and sex (A) and major bleeding subgroups (B)

Lancet 2014; 383: 955–62

Andreotti F et akl Eur Heart J. 2015 Dec 7;36(46):3238-49

Clin Pharmacokinet.2015;54(6):651-62

The effect of apixaban vs. warfarin on major study outcomes according to age

The effect of apixaban vs. warfarin on major study outcomes according to age

Halvorsen S et al European Heart Journal (2014) 35, 1864–1872• Results were also consistent for the 13% of patients ≥80 years (2436 patients)

Heidbuchel H et al. Europace. 2015 Oct;17(10):1467-507

Chest. 2016 Jan 18

Major bleeding, difference between the specific medications in patients witheCrCL 50-80 mL/min (A) and eCrCL <50mL/min (B)

Heidbuchel H et al. Europace. 2015 Oct;17(10):1467-507

Apixaban mean (+ SD) plasma concentration–time profiles in subjects with low, reference and high body weights. Body weight group: low (50 kg), reference (65–85 kg), high (120 kg)

Uprett VV et al Br J Clin Pharmacol. 2013 Dec;76(6):908-16.

Risultati di efficacia e sicurezza dei NAOA: ictus o eventi embolici sistemici; B: sanguinamenti maggiori

Risultati di efficacia e sicurezza dei NAOA: ictus o eventi embolici sistemici; B: sanguinamenti maggiori

Lancet 2014; 383: 955–62

Bleeding rates of newer anticoagulants

DeWald TA, Becker RCJ Thromb Thrombolysis. 2014 Feb;37(2):217-33

Reilly PA et al. J Am Coll Cardiol 2014;63:321–8

Major Bleeding Event and Ischemic Stroke/SEE Vs Trough Plasma Concentration of Dabigatran

with rivaroxaban or apixabanPlasma concentration over time at steady state after treatment with rivaroxaban or apixaban

Clinical Pharmacology: Advances and Applications 2014:6 179–187

Inset: Individual plasma concentration–time profiles

Anti-FXa activity over time at steady state on day 4 of treatment with rivaroxaban or apixaban

Clinical Pharmacology: Advances and Applications 2014:6 179–187

Inset: Individual plasma concentration–time profiles

Distribution of CV values calculated from DOAC concentrations in treated patients at trough and peak

Testa S et al Thrombosis Research 137 (2016) 178–183

Once-daily vs. twice-daily dosing: difference between intake and predicted biological impact in general

Once-daily vs. twice-daily dosing: difference between intake and predicted biological impact in general

Europace.2015 Feb 17. pii: euu311.

Major gastrointestinal bleedingMajor gastrointestinal bleeding

Gomez-Outes A et al Thrombosis. 2013;2013:640723

Warfarinvs.Apixaban: AdjustedHR:1.93(95%Cl:1.12–3.33)P=0.018Rivaroxabanvs.Apixaban:AdjustedHR:2.19(95%Cl:1.26–3.79)P=0.0052Dabigatranvs.Apixaban: AdjustedHR:1.71(95%Cl:0.94–3.10)P=0.079

Cumulativeincidenceofmajorbleeding

%ofP

atientsw

ithm

ajorbleeding

(Inpatie

ntbleeding)

TimefromAnticoagulation initiation (days)

0

0

1

2

3

4

5

30 60 90 120 150 180 210 240 270 300 330 360 390

WarfarinApixabanDabigatran Rivaroxaban

Dabigatran (N=4,173)

150 mg NR

N=3,768 N=405

Rivaroxaban (N=10,050)

20 mg NR

N=8,066 N=1,984

Apixaban (N=2,402)

5 mg NR

N=2,057 N=345

Warfarin (N=12,713)

Lipetal.Posterpresentation atESCAug/Sept2015;London, UKPoster/oral posterno.P6217

RealWorldComparisonofMajorBleedingRiskAmongNon-valvularAFPatientsNewlyInitiatedOnApixaban,Dabigatran,RivaroxabanOrWarfarin

DiscontinuationratesofNOACsinrealworld

Panetal. Presented attheESCCongress2014.Abstract #5112.

**Analysiscontrolled forother variablesincluding age,gender, onsetofembolic orprimaryischemicstroke, dyspepsiaorstomachdiscomfort, congestiveheartfailure, coronaryarterydisease,diabetes,hypertension, renaldisease,myocardialinfarction, historyofTIAorstrokeandhistoryofbleeding.

* Effectsizeisversusapixabanwhichactsasareferencecategory.

Retrospectivecohort studyNVAFpatientsnewlyprescribedaNOACornewlyprescribedwarfarinwithoutknee/hipreplacementsurgeriesinthetimeperiodofJan1– Dec31,2013

DiscontinuationratesofOACs

Dabigatranvs. apixaban*: HR**=1.581 (CI:1.451–1.721),P<0.0001Rivaroxabanvs. apixaban*: HR**=1.125(CI:1.121–1.317),P<0.0001Warfarinvs. apixaban*: HR**=1.638 (CI:1.514–1.772),P<0.0001

70

60

50

40

30

20

10

0

0 30 60 90 120 150 180 210 240 270 300 320 360 380Timefromanticoagulantinitiation(days)

%ofp

atientsw

ithdiscontin

uatio

n

Apixaban (n=2956)

Dabigatran (n=4495)

Rivaroxaban (n=12080)

Warfarin (n=14340)

Ip GYH and Lane DA J A C C V O L . 6 6 , N O. 2 1 , 2 0 1 5