Download The Novel Oral Anticoagulants - Adelaide Emergency Physicians

The Novel Oral
Anticoagulants
Fawaz Altuwaijri
ACEM trainee
 Introduction
 Characteristics of novel anticoagulants
 Laboratory Testing
 Reversal in the bleeding patient
Introduction
 Prevalence atrial fibrillation
 3.03 million in 2005
 7.56 million by 2050
 VTE = 900K/yr in US
 1-2% of adults take warfarin
WARFARINWisconsin Alumni Research Foundation
Coumarin
 1920s – Outbreak hemorrhagic disease in cattle in
northern US and Canada
 1933 – Isolated by Karl Link
 1948 – Rodenticde
 1954 – Approved in humans
Warfarin Disadvantages
 Bridging
 Drug and food interactions
 Long half-life
 Close monitoring required
Why New Anticoagulants
 Rapid onset/shorter half-life
 Fewer drug and no food interactions
 No lab monitoring
 Equivalent to warfarin
 Prevention of stroke, VTE
 Bleeding rates
 Also known as Target specific Oral Anticoagulant –
TSOAC.
New Anticoagulant
Disadvantages
 Limited experience treating bleeding
 No proven reversal agent
 No monitoring
New Anticoagulants
 Direct Thrombin (Factor
IIa) inhibitor
 Dabigatran (Pradaxa®)
 Selective, direct, factor Xa
inhibitors
 Rivaroxaban (Xarelto®)
 Apixaban (Eliquis®)
Dabigatran
 Indications:
 FDA approved
• Stroke prevention in non-valvular afib
 Under FDA review
• VTE prophylaxis in hip or knee replacement
• Approved in Europe/Canada
Dabigatran
 Mechanism:
• Direct Thrombin (Factor IIa) inhibitor
• Blocks conversion of fibrinogen to fibrin
Dabigatran
 Pharmacology:
 Dabigatran etexilate = inactive pro-drug
 Rapidly absorbed
 Active form binds active site of thrombin
 Inhibits free and clot-bound thrombin
Dabigatran
 Pharmacokinetics:
 Rapid onset
 Peak plasma level at 2 hours
 Half-life 14-17 hours
 No food interactions, few drug interactions
 No need for routine monitoring or dose adjustment
Dabigatran
 Metabolism:
 85% excreted via the kidneys
 Use caution with renal dysfunction
 Low protein binding (dialyzable)
FACTOR Xa INHIBITORS
 Indications:
 Rivaroxaban/Apixaban
 Stroke prevention in non-valvular atrial fib
 Rivaroxaban only
 VTE prophylaxis post-joint replacement
 DVT/PE prophylaxis and treatment
FACTOR Xa INHIBITORS
 Mechanism:
 Selective, direct, factor Xa inhibitors
FACTOR Xa INHIBITORS
 Pharmacology:
 Highly protein bound
 Not easily dialyzed
 Few drug interactions
FACTOR Xa INHIBITORS
 Pharmacokinetics:
 Rapid onset
 Predictable
 Not affected by age, sex, body weight
 Fixed dose
 Peak at 2 – 3h
 Half life 7-14h
Metabolism:
Rivaroxaban
 Excretion
 2/3rd renal
 1/3rd liver
 Dose adjusted for reduced
CrCl
Apixaban
 Excretion


2/3rd liver, biliary
1/3rd renal
Laboratory testing
 NOAC do not require monitoring when used for
thromboprophylaxis or for therapeutic anticoagulation.
 The anticoagulant effect of NOAC should be measured
in the following clinical situations:
 Bleeding
 Change in clinical scenario: urgent surgery, renal failure
Laboratory testing
 Recommended Assays in the presence of bleeding:
Since specific assays for quantitation of drug levels may not
be available in many laboratories, routine coagulation
assays may be utilized to provide qualitative information
about the presence of some NOACs.
Laboratory testing
 Dabigatran:
 The TT is the most sensitive routine coagulation assay
for determining if any dabigatran is present.
 A normal aPTT suggests that it is unlikely that a high
level of dabigatran is contributing to bleeding
 A normal TT excludes the presence of dabigatran
 Rivaroxaban:
 The PT (INR) is the most sensitive routine coagulation assay
for detecting rivaroxaban.
 A normal PT/INR value suggests that the rivaroxaban level
is not high, but does not exclude its presence.
 As with the low molecular weight heparins (LMWH), the
APTT and PT cannot estimate the intensity of the
anticoagulant effect.
 Rivaroxaban does not prolong the TT.
 Apixaban:
 There are limited data available for apixaban.
 A normal PT and APTT does not rule out significant
anticoagulant effect
 The drug specific anti-factor Xa chromogenic assay is
necessary to estimate accurately the anticoagulant
effect of apixaban.
NOACs Reversal
 Randomized trial data to support this practice are
lacking.
 Based on clinical experience and data from case series
 There are no specific antidotes or reversal agents for
NOACs
 Available strategies for reversing the anticoagulant
effect of NOACs:
 Drug discontinuation.
 Drug removal from the circulation and/or gastrointestinal
tract.
 Pro-hemostatic therapies such as antifibrinolytic agents.
 Prothrombin complex concentrates (PCCs), which may
be prothrombotic.
 Abnormal coagulation testing is consistent with the presence
of continued NOAC effect, but normal testing does not
necessarily eliminate the possibility of clinically important
concentrations of these agents.
 Therefore, the results of coagulation tests, or their trends
over time, do not meaningfully inform reversal of NOACassociated bleeding.
 Management is based on the patient's presentation and
change in their status over time rather than on the results of
coagulation testing in most cases
General principles in management of
patients
bleeding while receiving NOAC
 Drug discontinuation:
 Anticoagulant should be ceased at least temporarily in all patients
presenting with significant bleeding.
 The timing of recommencement will be influenced by the severity of
the bleeding event, the presence of ongoing risk factors for bleeding
 Baseline laboratory assessment:
 Haemoglobin- assess bleed severity
 Standard coagulation testing

Creatinine level; allow prediction of the expected rate of anticoagulant drug
clearance.
 General supportive care measures:
 Surgical and radiological procedures to identify the source of
bleeding and to limit ongoing bleeding should be performed
as appropriate, taking into account the risk of procedurerelated bleeding in an anticoagulated patient.
 Adequate hydration to enhance renal clearance
 RBC’s and platelets as indicated.
 Activated charcoal: within 2 h of the last oral dose of NOAC.
 Administration of haemostatic agents:
 Current evidence on the use of pro-haemostatic agents is
limited and conflicting.
 aPCC (FEIBA) and four-factor PCC have been shown to reduce
bleeding in animal models with variable effect on coagulation
parameters in animals, healthy volunteers, with recombinant
factor VIIa (rFVIIa) demonstrating a less consistent effect.
 Due to the limited data supporting efficacy and potential
for thrombotic complications, use of these prohaemostatic agents should be restricted to patients
with life-threatening bleeding unable to be managed
with supportive measures alone.
 PCC have been demonstrated to be able to reverse the
laboratory anticoagulant effect of rivaroxaban, but in a small
series appeared ineffective in patients with bleeding on
dabigatran.
 In Australia and New Zealand, only three-factor PCC
(Prothrombinex-VF) is available and its efficacy in the new
anticoagulant drugs has not been evaluated.
 Did not recommend the use of rFVIIa, based on less consistent
data on its ability to reverse anticoagulant effect, and its
association with risk of thrombosis when used outside patients
with haemophilia.
 Dialysis:
 patients receiving dabigatran with life-threatening
bleeding,particularly if renal function is impaired or
dabigatran is present in excess (APTT > 80 s or
dabigatran level >500 ng/mL).
 62% in 2 hours, 68% in 4hours. (6 healthy volunteers)
 There is no role for dialysis in factor X inhibitors related
bleeding.
Tran et al, New oral anticoagulants: a practical guide,IMJ 44 (2014)
UpToDate
 Charcol: Dabigatran 2hr, Rivaroxaban 8 hr, Apixaban
6hr.
 Antifibrinolytic agents including tranexamic acid and
aminocaproic acid can be used for severe bleeding.
 Recommended PCC’s for both dabigatran and
rivaroxaban in “ imminent risk of death” bleeding.
New oral anticoagulants: An emergency department overview, Emergency
Medicine Australasia (2013) 25, 503–514
New oral anticoagulants: An emergency department overview, Emergency
Medicine Australasia (2013) 25, 503–514
RAH Dabigatran Guidlines
Thank you