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?