I Nuovi anticoagulanti orali Pistoia 23 gennaio 2016

I Nuovi anticoagulanti orali
Domenico Prisco
DMSC Università di Firenze
SOD Medicina Interna Interdisciplinare
AOU Careggi Firenze
Pistoia 23 gennaio 2016
Anticoagulanti e coagulazione
inibitori indiretti:
fondaparinux LMWH
inibitori diretti:
rivaroxaban
apixaban
betrixaban
edoxaban
antagonisti
vitamina K:
warfarin
acenocumarolo
dabigatran argatroban
ximelagatran hirudin,
bivalirudin
Prisco D, J Cardiovasc Med 2015
Vantaggi dei NAO
• Rapido effetto terapeutico
Non necessario “bridging”
• Target su specifico enzima coagulazione Basso rischio di eventi avversi
• Bassa interferenza con i cibi
No restrizioni dietetiche
• Basse interazioni con farmaci
Meno restrizioni farmacologiche
• Effetto anticoagulante NON necessario
prevedibile
monitoraggio di
laboratorio
I risultati nei trial sulla FA
E’ tempo per uno screening (opportunistico ) della FA?
Stroke or systemic embolic events
Dabigatran 150 mg bid
Rivaroxaban 20 mg od
Apixaban 5 mg bid
Edoxaban 60 mg od
Ruff C, Lancet 2013
Secondary efficacy and safety outcomes
Dabigatran 150 mg bid
Rivaroxaban 20 mg od
Apixaban 5 mg bid
Edoxaban 60 mg od
Ruff C, Lancet 2013
Major bleeding
Dabigatran 150 mg bid
Rivaroxaban 20 mg od
Apixaban 5 mg bid
Edoxaban 60 mg od
Ruff C, Lancet 2013
Stroke or systemic embolic events subgroups
Ruff C, Lancet 2013
Major bleeding subgroups
Ruff C, Lancet 2013
La stratificazione del rischio
CHA2DS2VASc
HAS-BLED bleeding risk score
> 3 high risk: attentionbothwith ASA and OAT
Pisters The Euro HeartSurvey. Chest 2010
Necessità di terapia antiaggregante
National Swedish Patient register, matched with data from the National Prescribed Drugs register
Concomitant Use of Antiplatelet Therapy with Dabigatran or
Warfarin in the RELY Trial
Dans Al et al, Circulation 2013
Dabigatran 110mg might be a safer alternative
to warfarin in patients requiring antiplatelet
therapy
Post hoc analysis: use of antiplatelet therapy was not
randomized or stratified.
Antiplatelet therapy left at the discretion of the physician.
Most patients were taking ASA (80mg or more), 1,9%
Clopidogrel, 4,5% DAPT (median duration, 66% of the
study period).
Adding a single anti-platelet drug increased the risk of major
bleeding by 60%.
Clinical contexts from which evidence regarding triple therapy of
OAC, aspirin and clopidogrel is derived
Rubboli A , TR 2015
Thromb Haemost 2014
Thromb Haemost 2014
2014 ESC/EACTS Guidelines on
myocardial revascularization
The dose intensity of oral anticoagulation should be
carefully monitored with a target INR of 2.0–2.5 in the
case of vitamin K antagonists and use of lower tested
dose for stroke prevention in the case of NOACs
(dabigatran 110 mg b.i.d.; rivaroxaban 15 mg once
daily, apixaban 2.5 mg).
Clinical contexts from which evidence regarding triple therapy of
OAC, aspirin and clopidogrel is derived
Rubboli A , TR 2015
Suggested algorithm for the selection of OAC, and dose, to be
combined with DAPT in patients recently submitted to PCI-S
who develop AF
Rubboli A , TR 2015
Future trials evaluating the optimal antithrombotic regimen in patients
undergoing percutaneous coronary intervention with stent implantation
on chronic oral anticoagulation
Jagrohe D, Curr Opin Cardiol 2015
La terapia del TEV
Acute and chronic treatment of VTE with NOAs
Phase III trials
Drug/Trial
Clinical Condition
DABIGATRAN
RE-COVER studies
Treatment of acute VTE
RE-MEDY and
RE-SONATE studies
Secondary prevention of VTE
RIVAROXABAN
EINSTEIN program
Treatment of acute DVT
Treatment of acute PE
Secondary prevention of VTE
APIXABAN
AMPLIFY program
Treatment of acute VTE
Secondary prevention of VTE
EDOXABAN
HOKUSAI study
Acute and long term treatment of VTE
First VTE or VTE-related death
Major bleedings
Major bleedings (2)
La profilassi del TEV
VALUTAZIONE DEL RISCHIO TROMBOEMBOLICO
INDIVIDUALE
A
RISCHIO DOVUTO ALL’ EVENTO
B
RISCHIO DOVUTO A FATTORI
PERSONALI PREDISPONENTI
A+B
RISCHIO GLOBALE
VALUTARE RISCHIO EMORRAGICO
NAO e profilassi del TEV nel paziente internistico
Trial di fase III DOAC,
dosaggio e
durata
MAGELLAN
Farmaco
comparato,
dosaggio e
durata
Principali risultati
Rivaroxaban 10 Enoxaparina 40 ↔ efficacia a 10 giorni, ↑ efficacia a 35 giorni
mg x 35 giorni mg x 10 giorni
↓sicurezza a 10 giorni, ↓ sicurezza a 35 giorni
↓ beneficio clinico netto
ADOPT
Apixaban 2,5
mg x 2 x 30
giorni
Enoxaparina 40 ↔ efficacia a 30 giorni
mg x 6-14 giorni
↓ sicurezza a 30 giorni
↓ beneficio clinico netto
APEX
Betrixaban
Enoxaparina
IN CORSO
ADOPT and MAGELLAN: main results
Imberti D , Intern Emerg Med 2013
Results of a meta-analysis of ADOPT and
MAGELLAN studies
Imberti D , Intern Emerg Med 2013
Conclusion
The evidence of this analysis confirms that in acute medically
ill patients, prolonged thromboprophylaxis with an oral FXa
inhibitor is more protective than regular short-term treatment
with enoxaparin, even if the results of only one study
(MAGELLAN) could have influenced those of the metaanalysis itself.
However, treatment with FXa inhibitors is associated with
significant major bleeding, both in long- and short-term
treatment compared with enoxaparin
Imberti D , Intern Emerg Med 2013
Conclusion
Physicians guidelines recommend short-term parenteral
anticoagulant prophylaxis with UFH, LMWH or fondaparinux
for all high-risk medical patients during hospitalization.
The results of the MAGELLAN and ADOPT studies
should not change our daily clinical practice of VTE
prophylaxis in medical patients and, at least at the
moment, new OACs should not be recommended in this
clinical setting.
Imberti D , Intern Emerg Med 2013
ACCP recommendations
Initiate low-dose unfractionated heparin two or three times
daily, low molecular- weight heparin (LMWH), or
fondaparinux in acutely ill hospitalized medical patients with
an increased risk of thrombosis (grade: 1B).
Avoid chemical prophylaxis in acutely ill hospitalized patients
at low risk of thrombosis (grade: 1B).
Avoid chemical prophylaxis in acutely ill hospitalized patients
who are bleeding or have a high risk of bleeding (grade: 1B).
Initiate mechanical prophylaxis with graduated compression
stockings or intermittent pneumatic compression in acutely ill
hospitalized patients who have compelling risk factors for
both thrombosis and major bleeding or are currently bleeding
(grade: 2C).
Kahn SR, Chest 2012
Le indicazioni delle linee guida della regione
toscana
I mezzi di Profilassi
Raccomandazioni
• Le CCG sono indicate per la profilassi dei pazienti chirurgici
con controindicazione assoluta a profilassi farmacologica per
alto rischio emorragico (prova I A).
• Nei pazienti chirurgici le CCG possono essere utilizzate in
combinazione con la profilassi farmacologica allo scopo di
ridurre l’incidenza di TVP (prova I A).
• L’uso delle CCG potrebbe essere considerato nei pazienti ad
altissimo rischio di TVP ricoverati in terapia intensiva in
associazione alla profilassi farmacologica (prova VI B).
LG Regione Toscana
I mezzi di Profilassi
Raccomandazione
La CPI è indicata nella profilassi della TVP nei pazienti chirurgici e in
quelli ricoverati in terapia intensiva (prova I A).
La CPI è indicata nei pazienti con ictus emorragico in fase acuta
(prova IIA) e nei pazienti con ictus ischemico ad alto rischio di
trasformazione emorragica (prova VI A)
LG Regione Toscana
I pazienti con insufficienza renale
L’uso di fondaparinux e dabigatran è assolutamente controindicato per clearance
della creatinina rispettivamente <20 e <30 ml/min rispettivamente, in base alla
scheda tecnica. L’uso di apixaban e rivaroxaban è controindicato per clearance
della creatinina < 15 ml/min. Nei pazienti con clearance fra 20 e 50 ml/min, la
scheda tecnica di fondaparinux consiglia di utilizzare la dose di 1,5 mg/dì. Nei
pazienti con clearance della creatinina fra 30 e 50 ml/min la scheda tecnica di
dabigatran suggerisce la dose di 75 mg due volte al giorno.
LG Regione Toscana
La Profilassi nei pazienti con Insufficienza Renale
Nei pazienti con clearance della creatinina <30 ml/min, i livelli plasmatici di
rivaroxaban possono aumentare in misura significativa; ciò può aumentare il
rischio emorragico. Le schede tecniche controindicano l’uso di apixaban
rivaroxaban in pazienti con clearance della creatinina <15 ml/min, mentre
suggerisce un uso prudente nei pazienti con clearance della creatinina 15-29
ml/min. Cautela è suggerita anche nei pazienti con insufficienza renale moderata
(clearance della creatinina 30-49 ml/min) trattati contemporaneamente con
farmaci che inducono un aumento delle concentrazioni plasmatiche di apixaban e
rivaroxaban.
LG Regione Toscana
La Profilassi nei pazienti con Insufficienza Renale
•
valutare la funzione renale ogni qual volta si deve decidere sull’uso e/o il
dosaggio di EBPM, fondaparinux e altri farmaci antitrombotici che sono eliminati
per via renale, soprattutto in pazienti anziani, con diabete mellito e con rischio
emorragico elevato (prova I A);
•
seguire, in rapporto ai diversi quadri clinici, una delle seguenti opzioni:
evitare l’uso di anti- coagulanti che si accumulano in presenza di IRC, utilizzare
una dose più bassa o monitorare le concentrazioni del farmaco o la sua efficacia
terapeutica (prova I B).
LG Regione Toscana
Profilassi del tromboembolismo venoso in
chirurgia ortopedica
LG Regione Toscana
Gestione perioperatoria
The question of whether antithrombotic therapy
should be suspended in a patient who
will be undergoing an invasive procedure
involves balancing the risk of postprocedural
bleeding with continued treatment against the
thrombotic risk with suspension of treatment and
use of bridging anticoagulation therapy
Invasive procedures where the bleeding risk is low and oral
anticoagulation can often be continued
Patel J, Br J of Hematol 2013
Classification of surgical interventions
according to bleeding risk
LG EHRA ESC 2013
ACCP risk stratification of patients treated with oral anticoagulant
(Douketis, 2012)
Patel J, Br J of Hematol 2013
Guidelines applied at King’s College Hospital for oral
VKA therapy
Patel J, Br J of Hematol 2013
Bridging Therapy
Siegal D, Circulation 2012
Forest plot of thromboembolic events
Siegal D, Circulation 2012
Forest plot of Forest plot of overall bleeding
events
Siegal D, Circulation 2012
Forest plot of Forest plot of major bleeding events
Siegal D, Circulation 2012
Conclusion
We found that VKA-treated patients who require an elective
surgical or invasive procedure and receive periprocedural
bridging anticoagulation with LMWH appear to be at increased
risk of overall and major bleeding and at similar risk
of thromboembolic events compared with non bridged patients.
The ACCP and other antithrombotic guidelines advocate
that bridging anticoagulation should be undertaken with
consideration of individual patient thromboembolic risk and
procedural bleeding risk by balancing expected benefits and
harms.
Siegal D, Circulation 2012
Douketis J, NEJM 2013
Douketis J, NEJM 2015
Study Outcome
Douketis J, NEJM 2015
Conclusion
In the BRIDGE trial, we found that for patients with
atrial fibrillation who require temporary interruption of
warfarin treatment for an elective operation or other
elective invasive procedure, a strategy of forgoing
bridging anticoagulation was noninferior to
perioperative bridging with low-molecular-weight
heparin for the prevention of arterial
thromboembolism.
The strategy of forgoing bridging treatment also
decreased the risk of major bleeding
Douketis J, NEJM 2015
Pengo V, TH 2009
High thromboembolic risk:
mechanical mitral valve prostheses, monoleaflet mechanical aortic
prostheses or bileaflet aortic prostheses associated with AF or previous
arterial embolism,
AF associated with previous arterial thromboembolism or mitral valve
disease, previous cardiogenic or unexplained systemic embolism, and venous
thromboembolism in the previous 3 months.
All other cases were considered low to intermediate thromboembolic risk.
Anticoagulation Protocols Applied According
to Patient Thromboembolic Risk
Pengo V, TH 2009
Study Flow-Chart
Pengo V, TH 2009
Thromboembolic Event Details
Pengo V, TH 2009
Conclusion
The incidence of thromboembolic events was
low. All 5 thromboembolic events occurred in
high thromboembolic- risk patients resulting in
an incidence 1.7%.
We also found a low incidence of bleeding
events (major bleeding, 1.2%).
Pengo V, TH 2009
Approved European labels for NOACs and their
dosing in CKD
Heidbuchel H, Europace 2015
Profilassi nei pazienti che hanno sospeso gli
anticoagulanti orali inibitori della vitamina K
Alto rischio -> EBPM 70 U/kg x 2
Basso e medio rischio -> EBPM alla dose
profilattica elevata
LG Regione Toscana
BRIDGING Therapy in pazienti sotto
inibitori della vitamina K
LG Regione Toscana
Gestione dei pazienti in terapia con
NAO da sottoporre a chirurgia
d’elezione
LG Regione Toscana
Gestione dei pazienti in terapia con
NAO da sottoporre a chirurgia
d’elezione
LG Regione Toscana
La gestione delle emergenze: antidoti
Strategies for anticoagulation reversal in bleeding
associated with warfarin and new oral anticoagulants
Enriquez A, Europace 2015
Management of bleeding associated with NOACs
Enriquez A, Europace 2015
Comparison of specific antidotes for NOACs
Enriquez A, Europace 2015
DOAC-Antidotes
Pollack V, NEJM 2015
DOAC-Antidotes
Time Courses of Plasma Concentrations
of Unbound Dabigatran
before and after the Administration of Idarucizumab
patients who had serious bleeding
Pollack V, NEJM 2015
patients who required urgent surgery
Time Courses of Plasma Concentrations
of Idarucizumab
before and after the Administration of Idarucizumab
patients who had serious bleeding
Pollack V, NEJM 2015
patients who required urgent surgery
DOAC-Antidotes
Idarucizumab for dabigatran reversal
•Rapidly and complete reversal of the anticoagulant
activity of dabigatran in 88 to 98% of patients
•No safety concerns among the 90 patients involved
in this study — including patients who were given
idarucizumab on clinical grounds but were later
found to have had normal results on clotting tests at
baseline — or among the more than 200 volunteers
who were administered idarucizumab in previous
studies
Pollack V, NEJM 2015
DOAC-Antidotes
Siegal D, NEJM 2015
Time Courses of Anti–Factor Xa Activity
before and after Administration of Andexanet
Siegal D, NEJM 2015
Time Courses of Anti–Factor Xa Activity
before and after Administration of Andexanet
Siegal D, NEJM 2015
Time Courses of Plasma Concentrations of
Unbound Apixaban or Rivaroxaban before and
after Administration of Andexanet
Siegal D, NEJM 2015
Conclusion
Andexanet is a specific, rapidly
acting antidote that is being
developed for urgent reversal of
factor Xa inhibitor anticoagulant
activity.
Siegal D, NEJM 2015
Conclusion
In our studies, andexanet rapidly restored factor Xa activity
and thrombin generation and reduced unbound factor Xa
inhibitor concentrations in apixaban-treated and
rivaroxaban-treated older participants. The reversal of
anticoagulation with andexanet was not associated with
safety concerns or thrombotic events.
The ongoing ANNEXA-4 phase 3b–4 study
(ClinicalTrials.gov number, NCT02329327) is evaluating
the efficacy and safety of andexanet in patients with factor
Xa inhibitor–associated acute major bleeding
Siegal D, NEJM 2015
DOAC-Antidotes
In life-threatening situations, the possibility to barely
immediately reverse the anticoagulation effect of NOACs
could have importance.
For example, when hemodynamic stability has been
compromised during hemorrhagic shock, stopping
active bleeding could be necessary in trying to
stabilize vital functions.
Proietti M, JTT 2015
DOAC-Antidotes
Dubbi sugli antidoti
La loro efficacia/sicurezza sarà valutata in RCT di
adeguata potenza e con sample size decisi su
end-point clinici (e non solo farmacologici)?
Quale l’appropriatezza del loro uso?
Quali i possibili effetti indesiderati?
Quale rapporto costo/efficacia?
La ripresa della terapia nei pazienti con NAO
Resumption of antithrombotic therapy
Baron T, NEJM 2013
Resumption of anticoagulant based on the peak effect
and onset of action
Benzon HT, British Journal of Anesthesia 2013
When to restart the non-vitamin K
antagonist anticoagulants?
For procedures with immediate and complete
haemostasis, the NOAC can be resumed 6–8 h after
the intervention. The same applies after atraumatic
spinal/epidural anaesthesia or clean lumbar puncture
(i.e. non-bloody tap).
For many surgical interventions, however, resuming
full dose anticoagulation within the first 48–72 h after
the procedure may carry a bleeding risk that could
outweigh the risk of cardio-embolism.
Heidbuchel H, Europace 2015
When to restart the non-vitamin K
antagonist anticoagulants?
For procedures associated with immobilization, it is
considered appropriate to initiate a reduced venous
thromboprophylactic (e.g. 0.5 mg/kg/day of
enoxaparin) or intermediate dose of LMWHs (e.g. 1
mg/kg/day of enoxaparin) 6–8 h after surgery if
adequate haemostasis has been achieved, whereas
full therapeutic anticoagulation by restarting NOACs
is deferred 48–72 h after the invasive procedure
Heidbuchel H, Europace 2015
I possibili pazienti su cui riflettere
Which patient subgroups do not benefit
from treatment with non-vitamin K
antagonist oral anticoagulants?
Dabigatran versus Warfarin in Patients
with Mechanical Heart Valves
Randomization 2:1 168 DE 84 warfarin
Eikelboom J et al NEJM 2013; 369:1206–14
Eikelboom JW et al, N Eng J Med,
September 2013
Conclusioni
…nessun beneficio ed un
eccesso di rischio nei pazienti
con protesi valvolari cardiache
meccaniche.
Apixaban in Comparison With Warfarin in Patients With Atrial
Fibrillation and Valvular Heart Disease
CLINICAL PERSPECTIVE
by Alvaro Avezum, Renato D. Lopes, Phillip J. Schulte, Fernando Lanas, Bernard
J. Gersh, Michael Hanna, Prem Pais, Cetin Erol, Rafael Diaz, M. Cecilia Bahit,
Jozef Bartunek, Raffaele De Caterina, Shinya Goto, Witold Ruzyllo, Jun Zhu,
Christopher B. Granger, and John H. Alexander
Circulation
Volume 132(8):624-632
August 25, 2015
Copyright © American Heart Association, Inc. All rights reserved.
Efficacy outcomes.
Alvaro Avezum et al. Circulation. 2015;132:624-632
Copyright © American Heart Association, Inc. All rights reserved.
Safety outcomes.
Alvaro Avezum et al. Circulation. 2015;132:624-632
Copyright © American Heart Association, Inc. All rights reserved.
Conclusions
In a large contemporary clinical trial in patients with atrial
fibrillation and an indication for oral anticoagulation, over
a quarter of patients have a history of moderate or severe
valvular heart disease or previous valvular surgery.
There was no evidence of a differential effect of
apixaban over warfarin in patients with and without valvular
heart disease in reducing stroke and systemic embolism,
causing less major bleeding, and reducing mortality With the
exception of those with clinically significant mitral stenosis
or mechanical prosthetic heart valves
Pazienti in cui i NAO vanno sicuramente o
probabilmente evitati
1. FA valvolare (protesi meccaniche, valvulopatia mitralica severa)
2. FA da cause reversibili (ipertiroidismo non trattato, intervento
cardiochirurgico, embolia polmonare…)
3. Ipertensione non controllata nonostante il trattamento
(>180/100 mmHg [RE-LY, ARISTOTLE], > 170/100 mmHg
[ENGAGE-AF])
4. Recente ictus: precedenti 14 giorni (RE-LY, ROCKET-AF), 7
giorni (ARISTOTLE), 30 giorni (ENGAGE-AF)
5. Recenti emorragie gastrointestinali: precedenti 12 mesi (RE-LY),
6 mesi (ROCKET-AF), 12 mesi (ENGAGE-AF), ‘recente’
(ARISTOTLE)
6. Insufficienza renale severa: VFG < 30 ml/h (RE-LY, ROCKETAF, ENGAGE-AF), < 25 ml/h (ARISTOTLE)
7. Intervento chirurgico maggiore già pianificato.
8. Hb < 9.0 g/dl (ARISTOTLE) o < 10 g/dl (altri trials)
9. Gravi malattie coesistenti
I condizionamenti normativi
Piani terapeutici AIFA per i NAO
Condizioni di ingresso
Apixaban
Dabigatran
Rivaroxaban
Paziente con Fibrillazione
Atriale Non Valvolare
(FANV) cronica o
parossistica
Paziente con Fibrillazione
Atriale Non Valvolare
(FANV)
Paziente con Fibrillazione
Atriale Non Valvolare
(FANV) permanente
Ai fini dell'eleggibilità bisogna rientrare in una delle seguenti condizioni (1, 2 o 3)
Gruppo 1
CHA2 DS 2 -VASc ≥1
e
HAS-BLED >3
CHA2 DS 2 -VASc ≥1
e
HAS-BLED >3
CHA2 DS 2 –VASc >3
e
HAS-BLED >3
Gruppo 2
TTR negli ultimi 6 mesi
<70%
TTR negli ultimi 6 mesi
<70%
TTR negli ultimi 6 mesi
<60%
Gruppo 3
Il trattamento
anticoagulante non è
attuabile per difficoltà
oggettive ad eseguire i
controlli di INR.
Il trattamento
anticoagulante non è
attuabile per difficoltà
oggettive ad eseguire i
controlli di INR.
Il trattamento
anticoagulante non è
attuabile per difficoltà
oggettive ad eseguire i
controlli di INR.
Having more effective or safer anticoagulants was not
the original hypothesis for their development

the original hypothesis was to find “noninferior” agents compared with warfarin, with
better acceptance because of the lack of need
of frequent coagulation testing
Suggerimenti per il follow-up
conclusioni
Effective use of NOACS in
clinical practice
1. Patient selection – ADHERENCE
2. Dose selection – creatinine clearance, age, weight
3. Determine interval follow-up – structured follow-up!!
4. Assess stability of renal function over time
5. Blood pressure control
6. Avoidance of concomitant antiplatelet therapy, when possible
7. Package insert – avoid potent drug interactions,
guidance on transitions
A possible guide for the choice of the best novel oral
anticoagulant
Prisco D, J Cardiovasc Med 2015
AVK nel 2015 ?
Sì, perché…
• Se ben monitorati, gli AVK sono efficaci e sicuri
come i NAO
• L’aderenza alla terapia con AVK è strettamente
controllata
• Rarissime complicanze anche a lungo termine (a
parte le emorragie)
• Molta esperienza clinica (antidoti, pazienti con
pluri-patologie….)
• Costano pochissimo (a molti sembra un pregio)
AVK nel 2015 ?
No, perché…
• Il monitoraggio può rivelarsi complicato e costoso
• Hanno un lento inizio di azione terapeutica = sono
spesso necessarie complicate procedure di
“bridging”
• Subiscono parecchie interferenze (farmaci, cibi,
malattie renali o epatiche…)
• Costano pochissimo (per alcuni è un difetto…)
NAO e medicina generale
VobisNewSMagazinE Anno IV 2014
Test di laboratorio qualitativi e quantitativi per monitorare
l’efficacia della terapia anticoagulante
VobisNewSMagazinE Anno IV 2014
Interazioni farmacologiche
VobisNewSMagazinE Anno IV 2014
Gestione degli imprevisti durante terapia
VobisNewSMagazinE Anno IV 2014
Interventi chirurgici o procedure diagnostiche invasive
VobisNewSMagazinE Anno IV 2014
Switching da una terapia anticoagulante ad un’altra
VobisNewSMagazinE Anno IV 2014