Oral Anticoagulation

Oral Anticoagulation
How to Manage
Bleeding Complications
on Novel Oral
Anticoagulants
Carlos Aguiar
Albufeira, 28 April 2014
Bleeding on NOACs
2
Important Considerations
 In RCTs: despite the unavailability of antidotes, NOACs reduced ICH
and hemorrhagic stroke by 33%-74%, regardless of how well
warfarin was managed
 Real world post-marketing data collected by FDA and EMA suggest
that NOACs have similar performance regarding safety as observed in
their RCTs
 Knowlegde on pharmacology is an important step to avoid bleeding:
 influence of renal function on dosing (Cockgraft-Gault)
 clinically relevant drug interactions
 Dabi: potent P-gp inhibitors (more bleeding) and P-gp
inducers (less efficacy)
 Xa inhibitors: strong inhibitors/inducers of both CYP3A4 and
P-gp
Strong CYP3A4 and P-gp inhibitors: systemic azole-antimycotics, HIV PIs
Strong CYP3A4 and P-gp inducers: rifampicin, phenytoin, carbamazepine, Hypericum
Other strong P-gp inhibitors: cyclosporine, dronaderone, tacrolimus
Bleeding on NOACs
3
Non Life-Threatening Bleeding
 Identify source of bleeding and control with local measures (such
as mechanical compression, surgical haemostasis)
 Standard supportive measures



Fluid replacement and other haemodynamic support
 Crystalloids or fresh frozen plasma (not as a reversal agent)
RBC if necessary
Platelets if thrombocytopenia ≤60000 or thrombopathy
 Time is the most important antidote because of short half-life



Inquire last intake and dosing regimen
Expect restoration of haemostasis 12-24 h after last taken dose (Xa inh)
For Dabi, time frame of drug elimination depends alot on renal function
 CrCl 50-80: 24-36 h; CrCl 30-50: 36-48 h; CrCl <30: ≥48h
 Maintain adequate diuresis (Dabi)
 Consider pro-coagulants such as antifibrinolytics (e.g. aminocaproic
acid) or desmopressin (special situations of thrombopathy) as adjunctive
measures
Heidbuchel H et al. Eur Heart J 2013; 34: 2094
Bleeding on NOACs
4
Life-Threatening Bleeding
 Measures for non life-threatening bleeding + suspend OAC
 Consider reversal of anticoagulation (e.g. bleeding into a closed
space or vital organ)






Limited data from preclinical experiments and studies of coagulation
parameters in healthy volunteers
Prothrombin complex concentrate (PCC) 25 U/kg (may repeat 1-2x)
Activated PCC 50 IE/kg (max 200 IE/kg/day)
Activated factor VII (rFVIIa; 90 mg/kg): ?additional benefit + expensive
Antifibrinolytics and desmopressin do not substitute the above
Vit K and protamine do not reverse NOAC-associated bleeding
 Consider dialysis for Dabi (?followed by CVVHD) (renal failure or
dangerous bleed requiring rapid removal of drug)



Only 35% Dabi is bound to plasma protein: 65% removal after 4h
? enhanced removal via haemoperfusion over a charcoal filter
Xa inhibitors have >90% albumin binding
 Overdose: consider activated charcoal (30-50 gr) to absorption if 2-4h
Kumar R et al. J Intensive Care Med 2014; epub ahead of print
after dose of any NOAC
Heidbuchel H et al. Eur Heart J 2013; 34: 2094
Bleeding on NOACs
5
Algorithm for Management of NOAC-Related Bleeding
Stratify by severity of bleed
epistaxis,
ecchymosis,
menorrhagia, …
Minor
Identify source of bleeding
Control with local measures
If bleeding continues, hold 1
or 2 NOAC doses
If bleeding persists or recurs:
Assess renal function
Stop NSAIDs and ASA (if
possible)
Consider lower NOAC dose
GI bleed
Moderate
Severe
Evaluate hemodynamic stability
Assess renal function
Establish time of last NOAC dose
Stop NOAC and antiplatelet drugs (if possible)
Identify source of bleed + control with local measures
Check Hb, platelet count and NOAC effect/level
Volume and blood products replacement as required
Activated charcoal if last NOAC dose within 2-4 h
If bleeding
continues
Consider:
Procoagulants
(PCC, aPCC or rfVIIa)
Hemodialysis for Dabi
Antifibrinolytics
Oral Anticoagulation
How to Manage
Bleeding Complications
on Novel Oral
Anticoagulants
Carlos Aguiar
Albufeira, 28 April 2014
Oral Anticoagulation
7
EMEA Dosing Recommendations (NVAF Indication)
DABIGATRAN
<30
Contraindicated
30-50
>50
Age <75
High
bleeding
risk
Age 75-80
Age >80
Low TE risk, but
high bleed risk
110
150
150
110
150
110
bid
bid
bid
bid
bid
bid
RIVAROXABAN
APIXABAN
eGFR (mL/min)
20 mg id; 15 mg id if eGFR 15-49 mL/min
5 mg bid; 2,5 mg bid if eGFR 15-29 mL/min
or if any 2 of: age ≥80, ≤60 Kg, creat ≥1,5 mg/dL
www.emea.europe.eu
Oral Anticoagulation
8
Properties of Warfarin and New Oral Anticoagulants
Pro-drug
Warfarin
Dabigatran
Rivaroxaban Apixaban
Edoxaban
No
Yes
No
No
No
3-7%
66% to 100%
50%
62%
Bioavailability 100%
Effect onset
3-5 days
2 hrs
2-4 hrs
3 hrs
1-2 hrs
Dosing
Variable,
1x day
Fixed, 2x day
Fixed, 1x day
Fixed, 2x day
Fixed, 1x day
Half-life
40 hrs
12-17 hrs
7-13 hrs
8-14 hrs
9-11 hrs
Drug
interactions
Multiple
CYP 2C9,
3A4, 1A2
Potent P-gp
inhibitors; P-gp
inducers
Strong dual
CYP3A4 and
P-gp
inhibitors/induc
ers
Strong dual
CYP3A4 and
P-gp
inhibitors/induc
ers
Elimination
Hepatic
80% renal
36% renal
25% renal
35% renal
Potent P-gp inhibitors: systemic ketoconazole, cyclosporine, itraconazole, dronaderone and tacrolimus
Strong inhibitors of both CYP3A4 and P-gp: systemic azole-antimycotics or HIV PIs
Strong inducers of both CYP3A4 and P-gp: rifampicin, phenytoin, phenobarbital, carbamazepine, Hypericum
Caterina R et al. J Am Coll Cardiol 2012; 59: 1413
Bauer K et al. Hematology Am Soc Hematol Educ Program 2013 2013; 1: 464
Heidbuchel H et al. Eur Heart J 2013; 34: 2094
Oral Anticoagulation
9
Safety of New Oral Anticoagulants
Major Bleed (%/yr)
Dabi 110
Dabi 150
Rivaroxa
Apixa
Edoxa60
ICH (%/yr)
Hem Stroke (%/yr)
NOAC
Warfarin
NOAC
Warfarin
NOAC
Warfarin
2,71
3,36
0,23
0,74
0,12
0,38
20% (P=0,003)
69% (P<0,001)
69% (P<0,001)
3,11
0,30
0,10
3,36
NS
3,6
3,4
3,09
0,38
60% (P<0,001)
74% (P<0,001)
0,5
0,26
0,7
33% (P=0,02)
NS
2,13
0,74
0,33
0,80
0,44
42% (P=0,012)
0,24
0,47
31% (P<0,001)
58% (P<0,001)
49% (P<0,001)
2,75
0,39
0,26
3,43
20% (P<0,001)
0,85
53% (P<0,001)
0,47
46% (P<0,001)
Connolly S et al. N Engl J Med 2009; 361: 1139
Patel MR et al. N Engl J Med 2011; 365: 883
Granger CB et al. N Engl J Med 2011; 365: 981
Giugliano RP et al. N Engl J Med 2013; 369: 2093
Oral Anticoagulation
10
Important Considerations
 Potent/Strong P-gp inhibitors: Dabi, Rivaro



Verapamil: Dabi 110 mg bid if concomitant; or take >2 hrs after Dabi
Systemic ketoconazole, cyclosporine, itraconazole, dronaderone and
tacrolimus are contra-indicated w/ Dabi
Co-administer Dabi w/ caution: amiodarone, quinidine, verapamil,
ticagrelor, clarithromicin
 P-gp inducers: Dabi, Apixa

Avoid co-adm w/ rifampicin, carbamazepine, phenytoin, Hypericum
 Strong CYP3A4 inhibitors: Rivaro, Apixa

concomitant systemic azole-antimycotics or PIs is not recommended
(strong inhibitors of both CYP3A4 and P-gp)
 Strong CYP3A4 inducers : Rivaro, Apixa

Co-administer with caution: rifampicin, phenytoin, phenobarbital,
carbamazepine, Hypericum (strong inducers of both CYP3A4 and P-gp)
 Due to lack of data, co-administration of Rivaro w/ dronaderone, or of
Dabi w/ PIs (inhibitors/inducers of P-gp) is not recommended
Oral Anticoagulation
11
Drug Interactions with New Oral Anticoagulants
3 Levels of Alert:
 RED – contra-indicated / not recommended
 ORANGE – adjust NOAC dose

dabigatran: 150 mg to 110 mg BID

rivaroxaban: 20 mg to 15 mg QD

apixaban:
5 mg to 2.5 mg BID
 YELLOW – consider dose reduction if ≥2 concomitant interactions
 When no data is available, use of NOAC is not recommended
Heidbuchel H et al. Eur Heart J 2013; 34: 2094
Oral Anticoagulation
12
Pharmacokinetic Drug Interactions
Atorvastatin
Digoxin
Verapamil
Diltiazem
Quinidine
Amiodarone
Dronedarone
Ketoconazole;
itraconazole;
voriconazole;
posaconazole;
Fluconazole
Cyclosporin;
tacrolimus
Clarithromycin;
erythromycin
HIV protease
inhibitors
Rifampicin;
St John’s wort;
carbamezepine;
phenytoin;
phenobarbital
Antacids
Interaction
Dabigatran
Apixaban
Edoxaban
Rivaroxaban
P-gp/ CYP3A4
P-gp
P-gp/ wk CYP3A4
P-gp/ wk CYP3A4
P-gp
P-gp
P-gp/CYP3A4
+18%
no effect
+12–180%
no effect
+50%
+12–60%
+70–100%
no data
no data
no data
+40%
no data
no data
no data
no effect
no effect
+ 53% (slow release)
No data
+80%
no effect
+85%
no effect
no effect
minor effect
minor effect
+50%
minor effect
no data
P-gp and BCRP/
CYP3A4
+140–150%
+100%
no data
up to +160%
CYP3A4
no data
no data
no data
+42%
P-gp
no data
no data
no data
+50%
+15–20%
no data
no data
+30–54%
P-gp and BCRP/
CYP3A4
no data
strong increase
no data
up to +153%
P-gp and BCRP/
CYP3A4/CYP2J2
-66%
-54%
-35%
up to -50%
-12-30%
no data
no effect
no effect
P-gp/ CYP3A4
GI absorption
Heidbuchel H et al. Eur Heart J 2013; 34: 2094
Oral Anticoagulation
13
Clinical Factors Affecting NOAC Metabolism or Effect
Dabigatran
Apixaban
Edoxaban
Aged ≥ 80 years
Increased plasma level
no data
Aged ≥ 75 years
Increased plasma level
no data
Weight ≤ 60 kg
Increased plasma level
Renal function
Increased plasma level
Other
increased
bleeding risk
Rivaroxaban
Pharmacodynamic interactions – antiplatelet drugs, NSAIDs
Systemic steroid therapy
Other anticoagulants
Recent surgery on critical organ (brain, eye)
Thrombocytopenia (e.g. chemotherapy)
HAS-BLED ≥ 3
Heidbuchel H et al. Eur Heart J 2013; 34: 2094
Oral Anticoagulation
14
EHRA Checklist During Follow Up Contacts
Interval
Comments
Compliance
Each visit
Note and calculate average adherence (Pt brings med)
Re-educate on importance of strict intake schedule
Inform about compliance aids (special boxes, Apps, …)
Thrombo-embolism
Each visit
Systemic or pulmonary
Bleeding
Each visit
Other side effects
Each visit
Co-medications
Each visit
Yearly
6 monthly
Blood sampling
3 monthly
On indication
‘Nuisance’ – preventive measures? (PPI; …). Motivate
Pt to diligently continue OAC
Bleeding w/ impact on QoL or w/ risk – preventive
measures? Need for revision of OAC indication or dose?
Carefully assess relation with NOAC: decide for
continuation (and motivate), temporary cessation (w/
bridging), or change of OAC drug
Prescription drugs, OTCs
Careful interval history: also temporary use can be risk!
Hemoglobin, renal and liver function
Renal function if CrCl 30-60 ml/min, or if on dabigatran +
>75 anos or fragile
If CrCl 15-30 ml/min
If intercurring state that may impact renal/liver function
Heidbuchel H et al. Eur Heart J 2013; 34: 2094
Oral Anticoagulation
15
Role of Monitoring: General Principles
 NOACs do not require routine monitoring of coagulation
 Do not change dose or dosing intervals in response to changes in
laboratory coagulation parameters
 Quantitative assessment of drug exposure and anticoagulant
effect may be needed in
 Emergency situations: serious bleeding and thrombotic events
 Need for urgent surgery
 Special clinical situations, e.g Pts who present with renal or
hepatic insufficiency
 Potential drug–drug interactions
 Suspected overdosing
 Assessment of treatment compliance
Bagler T et al. Br J Haematol 2012; 159: 427
Heidbuchel H et al. Eur Heart J 2013; 34: 2094
Oral Anticoagulation
16
Role of Monitoring: Warnings
 For correct interpretation of test result, need to know when was NOAC
administered relative to blood sampling (≠VKA)
 POC INR devices falsely elevate INR levels in Pts on NOACs
 Do not rely on POC INRs when switching from NOAC to VKA
 Method used to estimate renal function (CrCL in mL/min) during the
clinical development of Pradaxa and Xarelto was the Cockgroft-Gault
formula
 Use this formula prior to and during treatment
van Ryn J et al. Am J Med 2012; 125: 417
Baruch L et al. Ann Pharmacother 2013; 47: 1210
Oral Anticoagulation
17
Monitoring
 Qualitative assessment (for detection of excess anticoagulant effect)
 aPTT for dabigatran


Trough aPTT >2x is associated with bleeding risk
Normal aPTT ≈ no clinically relevant anticoagulant effect
 PT for rivaroxaban (no data for apixaban/edoxaban)
 INR is totally unreliable
 Quantitative assessment
 dTT (diluted thrombin time) for dabigatran (Hemoclot)


Trough dTT >65s is associated with bleeding risk
?dTT level below which elective or urgent surgery is ‘safe’
 Trough ECT >3x is associated with bleeding risk on dabigatran
 Anti-Xa chromogenic assays

no data that associate a coagulation parameter or a drug level at
trough/peak with bleeding/thromboembolism risk
 Dabigatran

DD may predict clinical response
Samama MM et al. Clin Chem Lab Med 2011; 49: 761
Freyburger G et al. Thromb Res 2011; 127: 457
Huisman MV et al. Thromb Haemost 2012; 107: 838
Oral Anticoagulation
18
Elective Surgery and Interventions
 RCTs: about ¼ Pts on OAC require
temporary cessation within 2 yrs
 Consider both Pt features (GFR,
age, hx of bleeding, concomitant
meds) and surgical factors for
deciding when to d/c and restart drug
 Bridging not necessary in NOACtreated Pts since the predictable
waning of the anticoagulation effect
allows properly timed short-term
cessation and reinitiation of NOAC
therapy before and after surgery
Heidbuchel H et al. Eur Heart J 2013; 34: 2094
Oral Anticoagulation
19
Elective Surgery and Interventions
Last intake of drug before elective surgical intervention


Restart pf NOAC
For procedures with immediate and complete haemostasis, NOAC can be
resumed 6–8 h after intervention (same applies after atraumatic
spinal/epidural anaesthesia or clean lumbar puncture)
But for many surgical interventions, resuming full dose OAC within the first
48–72 h after the procedure may carry a bleeding risk that could outweigh the
risk of cardio-embolism
Heidbuchel H et al. Eur Heart J 2013; 34: 2094
Oral Anticoagulation
20
Urgent Surgery and Interventions
 If an emergency intervention is required, NOAC should be
discontinued
 Surgery or intervention should be deferred, if possible, until ≥12 h and
ideally 24 h after the last dose
 Qualitative and quantitative coagulation tests can be considered if
there is concern about the pharmacokinetic waning of the
anticoagulant effect (e.g. renal insufficiency), but such strategy has
never been evaluated, and therefore cannot be recommended and
should not be used routinely
 If surgery cannot be delayed, the risk of bleeding will be increased
and should be weighed against the urgency of the intervention
Heidbuchel H et al. Eur Heart J 2013; 34: 2094
Oral Anticoagulation
21
Switching Anticoagulant Drugs and Omitted Doses
DABIGATRANO
RIVA/APIXABAN
DabiVKA
GFR ≥50: start VKA 3 d prior to d/c
Dabi
GFR 30-49: start VKA 2 d prior to d/c
Dabi
VKADabi
Start Dabi when INR <2.0
Omitted Dose
May be taken up to 6 h prior to next
dose; do not take if <6 h to next dose;
never duplicate dose
RivaroAVK
Coadministrar até INR ≥2,0; não vigiar
INR nos 1ºs 2 d; a partir do 3º d, medir
INR imediatamente antes da próxima
toma de Rivaro
AVKRivaro
Iniciar Rivaro quando INR ≤3,0
Omissão de dose
Tomar logo que possível; manter
normalidade no dia seguinte; nunca
duplicar dose
Procedimento invasivo / Cirurgia
Parar Rivaro ≥24 h antes
Heidbuchel H et al. Eur Heart J 2013; 34: 2094
Anticoagulação Oral
22
Reversão do Efeito Anticoagulante
VKA
 Vit K iv
 Plasma fresco
congelado – reverte em
12-32h; risco de sobrecarga
de volume
 Concentrado de
complexo da
protrombina (II, VII, IX,
X) – reverte em 15 min após
infusão de 10 min a 1h;
coadministrar vit K para evitar
subida 2ª do INR
 r-FVIIa – opção cara
Dabigatran
 Plasma fresco
congelado
 Concentrado complexo
da protrombina
 FEIBA (fVIII inhibitor
bypass activity) –
protrombin, Xa e outros;
síntese de trombina
normaliza em 8-12 h
 r-FVIIa – reverte apenas
Rivaroxaban
 Concentrado de
complexo da
protrombina
 FEIBA (fVIII inhibitor
bypass activity)
 r-FVIIa
 Inibidor específico
GLAless-FXa – Xa sem
ácido glutâmico, logo inactivo;
decorrem estudos
parcialmente
 Hemodiálise – casos
excepcionais
Ansell J at al. Chest 2008; 133: 160S
Gersh BJ at al. Rev Esp Cardiol 2011; 64: 260
Anticoagulação Oral
23
Acidente Vascular Cerebral sob NOAC
 AVC hemorrágico

D/C NOAC, medidas de suporte, reversão da ACO

Retomar NOAC aos 10-14 dias se risco embólico elevado e
hemorrágico baixo (raro; off-label)

Prevenção tromboembólica não farmacológica a longo prazo
 AVC isquémico

Fibrinólise pode ser dada se última toma de NOAC há >48h

Se incerteza sobre última toma, fibrinólise só se aPTT (dabi) ou TP (Xa)
normais

Se última toma há <48h e testes de coagulação normais ou
indisponíveis, tentar reperfusão mecânica

Regra 1-3-6-12 (AIT, AVC pequeno e não incapacitante, AVC
moderado, AVC extenso)
Heidbuchel H et al. Eur Heart J 2013; 34: 2094

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