Giancarlo Antonucci

EO Galliera SC medicina /SSD Area critica Genova

II Sessione EMOSTASI E TROMBOSI Terapia antitrombotica nella fibrillazione atriale

>65 yrs 9%

2018: 67%-88% of A F patients are on anticoagulation

Bungard TJ et al. Arch Intern Med. 2000;160:41–46.

Why do patients with atrial fibrillation not receive warfarin?

•  unpredictable response •  slow onset and offset of the

pharmacological effect •  narrow therapeutic window •  numerous interactions with

other drugs and foods

Dabigatran Rivaroxaban

2008 Apixaban 2011 Edoxabann 2015

  prevention of stroke and systemic embolism

in patients with NVAF

Different mechanisms of action

Y. Ingrasciotta et al.(2018) Pharmacokinetics of new oral anticoagulants: implications for use in routine care, Expert Opinion on Drug Metabolism & Toxicology, 14:10, 1057

Reproduced from Ruff et al.36 with permission. Ruff et al. Lancet 2014;383:955-62

(A)Stroke or systemic embolic events - (B) Major bleeding. Data are n/N, unless otherwise indicated. Heterogeneity: I2 = 47%; P = 0·13. NOAC, new oral anticoagulant; RR, risk ratio. *, dabigatran 150 mg twice daily; †, rivaroxaban 20 mg once daily; ‡, apixaban 5 mg twice daily; §, edoxaban 60 mg once daily.

DOAC Trials Efficacy and Safety outcomes

Recommendations for Selecting an Anticoagulant Regimen

“Superiorità” dei DOACs

1.  Farmacocinetica e farmacodinamica lineare

2.  Finestra terapeutica più ampia

3.  Non necessario monitoraggio

“Superiorità” dei DOACs

1.  Farmacocinetica e farmacodinamica lineare

Frost et al. Br J Clin Pharmacol. 2013;76:776–86

Cinetica lineare

Peak

Trough

The effect of dabigatran plasma concentrations and patient characteristics on the frequency of

ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial.

Reilly PA et al. J Am Coll Cardiol2014;63:321-8.

-28%

Le differenze nella struttura chimica causano diversi effetti farmacocinetici e farmacodinamici

Le differenze nella struttura chimica causano diversi effetti farmacocinetici e farmacodinamici

Biodisponibilità ridotta PgP Attivazione epatica Eliminazione renale 80%

Le differenze nella struttura chimica causano diversi effetti farmacocinetici e farmacodinamici

Biodisponibilità PgP Attivazione epatica Eliminazione renale 80%

PgP CYTP450 (CYT3A4) Minor eliminazione renale

Assunzione con il cibo

Dose-Normalized Plasma Concentrations (ng/ml/mg) of Dabigatran According to Demographic Characteristics in the RE-LY Trial.

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

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

Estimated drug half lives and effect on AUC NOAC plasma concentrationin different stages of CKD compared to healthy

controls

Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in

patients with atrial fibrillation treated for stroke prevention.

Mueck W. Mis-selwitz F. Clin Pharmacokinet 2011;50:675-86.

Plas

ma R

ivaro

xaba

n Con

centr

ation

(g/l)

Effect of Specific Populations on the Pharmacokinetics of Apixaban

* Dashed vertical lines illustrate pharmacokinetic changes that were used to inform dosing recommendations Apixaban Label 2018 US

Effect of Coadministered Drugs on the Pharmacokinetics of Apixaban

Apixaban Label 2019 US

Salazar DE et alThro b Haemost 2012;107:925-36

Modelling and simulation of edoxaban exposure and response relationships in patients with atrial fibrillation.

“Superiorità” dei DOACs

1.  Farmacocinetica e farmacodinamica lineare. Fattori condizionanti in maniera diversa per ogni farmaco:

–  Età –  Funzione renale –  Peso –  Farmaci –  Varie combinazioni

“Superiorità” dei DOACs

1.  Farmacocinetica e farmacodinamica lineare. 2.  Finestra terapeutica più ampia.   Ci sono soggetti possibilmente “fuori” dalla

finestra terapeutica? I trials registrativi

Challenges in comparing the non-vitamin K antagonist oral anticoagulants trials

A.Rubboli. G Ital Cardiol 2017;18(9 Suppl 2):3S-9S

Disegno degli studi registrativi con i nuovi anticoagulanti orali per la prevenzione di ictus e/o tromboembolia sistemica nella fibrillazione

atriale non valvolare

2008

X X

A.Rubboli. G Ital Cardiol 2017;18(9 Suppl 2):3S-9S

Disegno degli studi registrativi con i nuovi anticoagulanti orali per la prevenzione di ictus e/o tromboembolia sistemica nella fibrillazione

atriale non valvolare

Rimanere nella finestra terapeutica con sicurezza

X X

1.27% vs 1.6% ictus+embolismo 2.1% vs 3.1% sang.magg.

P <0,001

A.Rubboli. G Ital Cardiol 2017;18(9 Suppl 2):3S-9S

2008 2011 2015

Popolazione di pazienti trattata con dosi piene e ridotte dei NAO nei quattro mega-trial

Apixaban 5 mg twice daily and clinical outcomes in patients with atrial fibrillation and advanced age, low body weight, or high

creatinine: a secondary analysis of a randomized clinical trial.

Alexander JH et al. JAMA Cardiol.2016;1:673—81.

Rates of Major Bleeding

The effect of apixaban vs. warfarin on stroke or systemic embolism and major bleeding in patients ≥75 years in relation to apixaban dose.

Utilizzo di dosi piene e dosi ridotte dei quattro NAO (apixaban, dabigatran, edoxaban, rivaroxaban) nella vita reale in Italia negli

anni 2017 e 2018

The European Registry of Older Subjects With Atrial Fibrillation (EUROSAF)

INDICE PROGNOSTICO MULTIDIMENSIONALE (MPI)

Edoxaban versus warfarin in atrial fibrillation patients at risk of falling: ENGAGE AF-TIMI 48 analysis

Steffel J et al.. J Am Coll Cardiol 2016;68:1169-78.

Increased risk of falling: • major bleeding +30% • life-threatening bleeding +67% • all-cause death +45%

In the pivotal trials, NOACs were not tested in patients with a creatinine clearance < 30 mL/min.

European Heart Journal (2018) 00, 1–64

ESC guidelines do not recommend the introduction of NOACs in patients with a creatinine clearance < 30 mL/min

Stratified by age

Christina L. Fanola et al American Heart Journal 2017. 184:150-155

Incidence of severe renal dysfunction (CrCl<30 ml/min) among individuals taking warfarin and

implications for non-vitamin K oral anticoagulant

•  Moderate baseline CKD •  Coronary artery disease •  Use of RAAS inhibitors, •  Diuretics… •  Inpatient admission •  Heart failure •  Diarrhea •  Fever/Sepsis •  Hyperglycemia •  ……..

Risk Factors

*The median number of concomitant medications at baseline was 5 (25th, 75th percentiles, 4, 8).

Number of concomitant medications at baseline in the ROCKET AF study.

Piccini JP et al Circulation 2016;133:352-60.

Polypharmacy and the efficacy and safety of rivaroxaban versus warfarin in the prevention of stroke in patients with

nonvalvular atrial fibrillation.

Piccini JP et al Circulation 2016;133:352-60.

Polypharmacy and effects of apixaban versus warfarin in patients with atrial fibrillation: post-hoc analysis of the Aristotle trial.

Jaspers Focks J et al. BMJ 2016;353:i2868

0-5 drugs 6-8 drugs ≥9 drugs

0-5 drugs 6-8 drugs

≥9 drugs

Stroke or systemic embolism Major bleeding

Significant pharmacokinetic drug–drug interactions

Dabigatran

Edoxaban

Apixaban

Rivaroxaban

Dabigatran

Edoxaban

Apixaban

Rivaroxaban

Significant pharmacokinetic drug–drug interactions

I trials non hanno saggiato in maniera significativa l’interferenza dei farmaci

ESCLUSI

La strategia di evitare le associazioni con interazioni significative (inibitori e induttori forti) è tuttora l’unica proposta nelle LG

Y. Saito, Y. Kobayashi / Journal of Cardiology (2018)

after hospital

discharge?

History of guideline recommendations for triple therapy vs. dual therapy in patients with AF undergoing PCI.

WOEST No trials

INR 2-2,5

ISAR- TRIPLE PIONEER AF-PCI

RE-DUAL PCI trial

Peri-PCI

*DOAC with the lowest tested dose for stroke prevention Trial underpowered to assess efficacy outcomes (?)

*

Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation

Lopes RD, et al. N Engl J Med 2019;380:1509-24

The primary safety outcome, major or clinically relevant non major bleeding (ISTH)

Influence of antidepressants on hemostasis

Halperin and Reber Dialogues in Clinical Neuroscience - Vol 9 . No. 1 . 2007

Fluoxetine Paroxetine Sertraline

“Superiorità” dei DOACs

1.  Farmacocinetica e farmacodinamica lineare. 2.  Finestra terapeutica più ampia

–  Indicate dosi ridotte –  Attenzione dosi basse

“Superiorità” dei DOACs

1.  Farmacocinetica e farmacodinamica lineare. 2.  Finestra terapeutica più ampia 3.  Non necessario monitoraggio.   Forse però in alcuni casi.

Why laboratories do not perform DOAC testing?

•  test availability, •  rapid result turn-around-time (TAT), •  difficulty in test performance and interpretation, •  result variability, •  lack of cutoff values, •  poor definition of tests •  lack of FDA approved methods for quantifying DOACs •  a general reluctance to provide tests that may be

infrequently used

Laboratory drug measurements may be warranted in certain populations

Emergent situations

•  bleeding •  acute stroke •  trauma •  surgery

Dose adjustement

•  the elderly •  those at extremes of body

weight •  those requiring drugs that

impact certain metabolic pathways

•  those with renal impairment •  poor responders

RC Gosselin. Int J Lab Hematol. 2019;41(Suppl. 1):33

ICSH Laboratory Measurements of DOAC recommendations

  Trough drug level assessment for non emergent situations, with results reported in ng/mL

International Council for Standardization in Haematology (ICSH) 2018

Plasma levels and coagulation assays in patients treated with non-vitamin K antagonist oral anticoagulants

?

Direct Oral Anticoagulant Plasma Levels for the Management of Acute Ischemic Stroke

Institutional standard operating procedure for IVT in patients on DOACs with acute ischemic stroke

11.5% on VKAs and 9.2% on DOACs received thrombolysis

>500 pts

Armin Marsch et al.Cerebrovasc Dis 2019. DOI: 10.1159/000502335

Management strategies of the interaction between direct oral anticoagulant and drug-metabolizing enzyme inducers

A. Perlman et al. Journal of Thrombosis and Thrombolysis 2019 https://doi.org/10.1007/s11239-018-01804-7

95th 5th percentiles

……..were much less likely to have one of the medications stopped and more often had the DOACs’ dose increased

1596 hospitalized patients 1.4% concomitant EIDs.

?

S.Moll et al. Res Pract Thromb Haemost. 2019;3:152–155.

Extreme obesity would not be predicted to significantly affect PK and PD of apixaban and rivaroxaban; however, available clinical data is scarce. For dabigatran and edoxaban, clinical efficacy and clinical pharmacology data are even much less clear.

Morbidly obesity?

Morbid obesity?

•  use warfarin •  if a DOAC is chosen, to obtain a trough drug concentration

after five or more doses (when the DOAC has reached a steady-state concentration), to determine whether concentrations are roughly within the range published for other patient or healthy volunteer populations.

S.Moll et al. Res Pract Thromb Haemost. 2019;3:152–155.

“Superiorità” dei DOACs

1.  Sono in aumento le prescrizioni in soggetti con un complesso profilo di rischio (nella maggior parte dei pazienti il rischio trombotico senza AC supera quello emorragico in corso di AC e i DOACs sono superiori al Warfarin)

2.  E’ necessario migliorare la nostra confidenza con i farmaci nelle diverse situazioni per essere appropriati con i dosaggi ridotti

3.  Il dosaggio al punto valle dell’anticoagulante allo steady state in alcune condizioni potrebbe in futuro rivelarsi utile