dr trevor baglin department of haematology addenbrookes
TRANSCRIPT
Thromboembolic disease – new medications
Dr Trevor Baglin
Department of Haematology
Addenbrookes Hospital Cambridge
• New medications - Direct Oral Anticoagulants – DOACs Dabigatran – Pradaxa
Rivaroxaban – Xarelto
Apixaban – Eliquis
Edoxaban - Lixiana
• How long should the initial treatment of VTE with a DOAC be?
• Is there a preferred DOAC for long-term treatment?
• Is there a place for aspirin in long-term treatment?
• Cancer-associated VTE
Thromboembolic disease – new medications
Dr Trevor Baglin
Department of Haematology
Addenbrookes Hospital Cambridge
Declarations of interests
Dr Trevor Baglin
Department of Haematology
Addenbrookes Hospital Cambridge
No current consultancies or funding from:
Boehringer Ingelheim
Bayer
Pfizer
Daiichi Sankyo
In past: Consultancy payments for Advisory Board meetings and
unrestricted educational support to attend ISTH from Boehringer Ingelheim
Founder-Director of XO1 Ltd and remain a shareholder
Direct Oral Anticoagulants DOACs
better or just more convenient?
• DOACs versus warfarin – efficacy and safety
• Pharmacokinetics & pharmacodynamics
• How to and when to measure DOACs in the laboratory
• Selection of patients & patient safety
DOACs –
Direct Oral AntiCoagulants
Dissociated pharmacokinetic & pharmacodynamic
response with slow on and off rates
Variable dose response (inter and intra-individual)
Multiple drug interactions
Affected by dietary vitamin K intake
Poor adherence to loading protocols by doctors
with high incidence of over-anticoagulation during
loading
Requirement for heparin during loading contributes
to early bleeding risk
Individual time within target range in patients treated with vitamin K antagonists: main determinant of quality of anticoagulation
and predictor of clinical outcome
Veeger et al: Brit J Haematol 2005;128:513
Predictability Safe and effective anticoagulation
from the first dose
Wide therapeutic window Broad safety margin (at a wide range of
effective doses)
Fixed dose No need for dose adjustment
No monitoring No need for routine laboratory monitoring:
saves healthcare costs & compliance
Low risk of food and drug Ease of use regardless of concomitant
interactions medications and diet
Reversible Control of bleeding
In search of better anticoagulant drugs
Dissociation of antithrombotic Effective prevention and treatment of
& bleeding effects thrombosis without anticoagulant-related
bleeding
Bleeding
effect
Antithrombotic
effect
The Anticoagulant Paradigm
dose
Bleeding
effect
Antithrombotic
effect
The Anticoagulant Paradigm
dose
3% major bleeding rate
is the limiter of antithrombotic
efficacy
Properties of traditional & new anticoagulants
Predictable Fixed No routine No food/drug no HITT reversible
response dosing monitoring interactions
Ideal (no bleeding) + + + + + +
VKA + +
UF heparin + +
LMWH + + + + +/-
fondaparinux + + + + +
argatroban + + +
dabigatran + + + + + +
rivaroxaban + + + + +
apixaban + + + + +
edoxaban + + + + +
• predictable dose response
• no need for routine monitoring
• reduced need for dose adjustment
• no food interactions
• limited drug interactions
DOACs – more convenient, ultimately probably easier to use
Bleeding
effect
Antithrombotic
effect
The Anticoagulant Paradigm - DOACs
dose
annualised primary outcome major bleeding
warfarin 1.7% 3.4%
dabigatran 110mg 1.5% 2.7%
dabigatran 150mg 1.1% 3.1%
months
RELY: Dabigatran versus warfarin in patients with atrial fibrillation
Connolly et al NEJM 2009;361:1139
Annualised major bleeding in recent trials
VKA versus DOACs
Clinical Trial Bleeding Rate % (warfarin) Bleeding rate % (NOAC)
RELY 3.4 3.1
ROCKET-AF 3.5 3.6
ARISTOTLE 3.1 2.1
Van Es et al Blood 2014;124:1968
DOACs compared with VKA for acute VTE:
evidence from phase 3 trials
First recurrent VTE or VTE-related death
Effectiveness and safety of NOACs as compared with VKAs in the
treatment of acute symptomatic VTE: a systematic review and meta-
analysis
Van der Hulle et al J Thromb Haemostas 2014;12;320
Recurrent VTE
Fatal PE
Mortality
0.88
0.97
1.02
Effectiveness and safety of NOACs as compared with VKAs in the
treatment of acute symptomatic VTE: a systematic review and meta-
analysis
Van der Hulle et al J Thromb Haemostas 2014;12;320
Non-fatal bleeding at a critical site
Major bleeding
0.39
0.38
0.60
0.76 Clinically relevant non-major bleeding
Non fatal ICH
Major GI bleeding 0.68
Fatal bleeding 0.36
Van Es et al Blood 2014;124:1968
DOACs compared with VKA for acute VTE:
evidence from phase 3 trials
RR 95%CI
Major bleeding 0.61 0.45 to 0.83
Intracranial bleeding 0.37 0.21 to 0.68
Fatal bleeding 0.36 0.15 to 0.84
CRNM bleeding 0.73 0.58 to 0.93
Major GI bleeding 0.78 0.0.47 to 1.31
Analysis of lowest effective intensity of anticoagulation for AF
Ruff et al Lancet 2014;383:955
Gomez-Outes et al Thrombosis 2013 article ID 640723
Efficacy & bleeding: DOACs v warfarin
All major GI bleeding
Upper GI bleeding
Lower GI bleeding
Pharmacokinetics of DOACs
Dabigatran Rivaroxaban Apixaban edoxaban
Target IIa Xa Xa Xa
Bioavailability 6% 60% - 80% 50% 62%
Peak action (tmax) < 3 hrs < 3 hrs < 3 hrs < 3 hrs
Half-life (t1/2) 14 8 15 12 hrs
Protein binding 35% 95% 85% 55%
Renal clearance 80% 33% 25% 35%
DOACs - treatment of VTE (according to SPCs)
initial dose maintenance dose initial heparin
Dabigatran 150mg bd 150mg bd 5 days
110mg bd considered for patients aged >75, or moderate renal
impairment of increased risk of bleeding
Rivaroxaban 15mg bd 20mg od No
21 days
Apixaban 10mg bd 5mg bd No
7 days
Edoxaban 60mg bd 60mg bd 5 days
DOACs - dose reductions
Dose reduction avoid
Dabigatran CrCl 30 to 50 mls/min CrCl < 30 mls/min
110mg bd age >75
increased risk of bleeding
Rivaroxaban CrCl 15 to 50 mls/min CrCl < 15 mls/min
15mg od increased risk of bleeding
Apixaban CrCl 15 to 30 mls/min CrCl < 15mls/min
2.5mg bd serum creatinine < 133umol/l
age > 80
body weight < 60kg
Edoxaban CrCl 15 to 50 mls/min CrCl < 15mls/min
30mg bd body weight < 60kg
use of P-gp inhibitors
DOACs - drug interactions
Increased levels with
1 P-gp inhibitors – amiodarone, verapamil, quinidine
2 azole antimycotics (ketoconazole, itraconazole, voriconazol,
posaconazole)
3 ciclosporin & tacrolimus
4 protease inhibitors (Xa inhibitors)
Decreased levels with
1 P-gp inducers – rifampacin, phenytoin, carbamazepine, phenobarbitol,
St John’s Wort
P-gp CYP3A4
Heparins, warfarin (VKA) & DOACs
PT APTT TT Fgn DD
warfarin +++ + Low
UF heparin + +++ +++ Low
LMWH + Low
fondaparinux + Low
dabigatran + ++ +++ -/+ Low
rivaroxaban ++ +/- Low
apixaban +/- +/- Low
edoxaban +/- +/-
Measurement of rivaroxaban in routine laboratory practice
PT – RecombiPlasTin IL – IL TOPS D
BIOPHEN DiXal rivaroxaban kit with BIOPHEN calibrators
Measurement of rivaroxaban in routine laboratory practice
APTT – SynthASil – IL TOPS D
BIOPHEN DiXal rivaroxaban kit with BIOPHEN calibrators
Dale et al J Thromb Haemostas 2014;12:1810
Comparison of apixaban and rivaroxaban on PT & APTT
using various reagents
• Semi-quantitative: readily available, easily performed
urgent / emergency situation – sub, therapeutic, supra-therapeutic level
Prothrombin Time / Activated Partial Thromboplastin Time
Each laboratory should be aware of the sensitivity of their PT / APTT
to each thrombin and factor Xa inhibitor
1 calibrate local PT/APTT with local quantitative assay
using patient plasmas
2 calibrate local PT/APTT with reference laboratory quantitative assay
using patient plasmas
3 calibrate local PT/APTT with calibrants
Measurement oral direct inhibitors of thrombin and factor Xa
• before surgery or invasive procedure when a patient has taken a drug in the
previous 24 hours (or longer if CrCl < 50ml/min),
• when a patient is bleeding
• when a patient has taken an overdose
• when a patient has developed renal failure (or impairment)
• when a patient is taking a drug that may interact
• assessment of dose in extremes of body weight
1 which DOAC
2 dose
3 when last taken
4 expected T1/2
5 factors influencing pharmacokinetics
When to measure anticoagulant effect of DOACs?
Measurement of DOACs
Qualitative assay Quantitative assay
dabigatran APTT / TT Hemoclot (dilute calibrated TT)
rivaroxaban PT calibrated anti-Xa
apixaban - calibrated anti-Xa
edoxaban - -
Idaruzicumab for dabigatran reversal
Pollack et al NEJM 2015;373:511
Andexanet alfa for the reversal of factor Xa inhibitor activity
Siegal et al NEJM 2015;373:2413
Preferred choice of anticoagulant?
Indication Preferred
CrCl < 15 warfarin
CrCl 15 – 30 Xa-inhibitor
Weight < 50 or > 120kg warfarin
Children warfarin
Heart valve prosthesis warfarin
Stroke or TIA on therapy dabigatran 150mg bd, apixaban 5mg bd
Cancer-associated
thrombosis LMWH
High GI bleed risk warfarin
Previous MI warfarin or Xa inhibitor
Checklist when starting DOAC
• check indication for anticoagulation – MHV, CHADS2VASC
• determine duration of therapy
• check renal function (CrCl), liver function (PT)
• check for interacting drugs
• review need for concurrent anti-platelet therapy
• assess GI bleeding risk and history of MI/CAD
• active education to achieve concordance and compliance
• provide written information to patient
• provide care plan to General Practitioner
• ensure arrangement for (annual) review
Duration of anticoagulant treatment after a first episode of VTE
ACCP: Chest 2008;133:454-545
provoked VTE with transient risk factor: 3 months
unprovoked VTE: 3 months then assess for long-term;
• proximal DVT (PE)
• absent risk factors for bleeding
• good anticoagulant control achievable
Agnelli et al NEJM 2013;368:699
Apixaban for extended treatment of venous thromboembolism
Aspirin for preventing the recurrence of VTE:
WARFASA & ASPIRE
Becattini et al NEJM 2012;366:1959 & Brighton et al NEJM 2012;367:1979
Cancer & thrombosis
LMWH or DOAC?