Pall* T. Onundarson, M.D.National Hospital and University of Iceland School of Medicine

ReykjavikIceland

Monitoring oral anticoagulationPhilosophy and controversies

*Paul, Paolo, Pablo….

Non-adherence is a problem

Size of problemFactors promoting adherence in medical practice

� Non-adherence of cardiovascular drug intake in USA is up to 50%

� 125,000 deaths in USA

� Patients perceive symptom reduction

� Monitoring/feedback

Bosworth HB, Granger BB, Mendys P, et alAm Heart J. 2011 Sep; 162(3):412-24.

ADHERENCE TO LONG-TERM THERAPIESEvidence for actionWorld Health Organization 2003

“Despite the availability of effective treatment, over half of the patients being treated for hypertension drop out of care entirely within a year of diagnosis (15)…

… of those who remain under medical supervision only about 50% take at least 80% of their prescribed medications (16).

Consequently, because of poor adherence to antihypertensive treatment, approximately 75% of patients with a diagnosis of hypertension do not achieve optimum blood-pressure control (13,18).”

Holland

“Since cardiologists will not keep the majority of AF patients under regular surveillance, unless there are complicating factors, the patients […on DOACs…] may lack proper surveillance with regard to side effects, complications, adherence etc.

This situation is disturbing given the fact that long term medication is prone not to be used properly by ± 50% of the patients! ”

Hugo ten Cate. New oral anticoagulants: discussion on monitoring and adherence should start now! Thromb J. 2013; 11: 8. doi: 10.1186/1477-9560-11-8 (editorial)

What happens when a patient taking a VKA with high INR variability is switched to an unmonitored oral anticoagulant that has:

� short half-life?� 50% adherence?

Switched to NOAC:

Risk of bleeding may be reduced but is there any benefit?

Drug monitoring; when is it useful?

Answer: When there is a dose response relationship with a relatively narrow therapeutic window between efficacy and harm, monitoring is useful:

- Factor VIII during surgery

- Insulin

- Gentamicin

- Vitamin K antagonists

- Why not direct oral anticoagulants?

… we don´t monitor DOACs� DOACs are approved in certain doses, not to be titrated� Pharmaceutical companies contend monioring is not needed

� -Why?

� Does this withstand scrutiny?

Anticoagulant monitoring

Useful: Tailored dose Not useful: Fixed dose

� Dose response effect important� LMWH

� VKA

� DOACs?

� Food and drug interactions� VKA

� DOACs?

� All or none effect

� Predictable pharmacokinetics with little inter- and intraindividual variation

� LMWH, dosed by weight

� DOACs???

Aim of measuring VKA

Therapeutic effect levels Assure adherence/compliance� Tailoring of dose to achieve ideal

risk/benefit

� Emergencies� TE or bleeding� Safe levels pre-operatively� Overdose� Confirm effective reversal

� Monitoring improves adherence� Aherence may be up to 80% with VKA

� What is adherence with DOACs?

Aim of measuring DOACs

Therapeutic levels Adherence/compliance� Tailoring vs fixed doses

� Difficult

� Emergencies� TE or bleeding� Safe levels pre-operatively� Effective reversal� Overdose?

� Elderly?

� Comorbidities?� Impaired renal function; monitor creatinine

x 2-3 annually� Impaired liver function

� Unmonitored: 50%?

All the same reasons to monitor exist as with

warfarin/VKA!

What to monitor?

Monitoring antithrombotics;

What to monitor?

Drug concentration Biological effect� Antiplatelet agents

� no

� Anticoagulants� VKA

� no

� DOACs?� possibly

� Renal function

� All or none effect� Antiplatelet agents; arguable

� Platelet aggregation and release� Multiplate®

� Dose-response effect; useful� Anticoagulants

� Warfarin� INR

� DTI� Ecarin clotting time� Hemoclot dTT

� aXA agents� Chromogenic anti-Xa assays

Is there a dose-response effect?

VKA DOACs

What to monitor (2)Vitamin K antagonists

VKA concentration cannot be used� A surrogate for biological effect is used;

� prothrombin time (PT-INR)

Influence of VKD factors on the PT

0.1 1 10 1000

20

40

60

80

FII

FVIIFIX

FX

A

Coagulation factor activity (%)

Qui

ck P

roth

rom

bin

time

(sec

onds

)

Gudmundsdottir BR, Francis CW, Bjornsdottir A, Nellbring M, Onundarson PT. Thromb Res 2012;130:674-81

VKA biological effect is not correctly reflected by PT-INRThe INR needs Fiix-ing

Thrombin generation in relation to vitamin K factor deficiency

The sensitivity of the INR to FVII causes instability of anticoagulation

PT-INRmonitoring

Fiix-INRmonitoring

Jonsson PI et al. The Fiix-trial, submitted 2016Onundarson PT et al .The Fiix-trial. www.thelancet.com/haematology 2015Gudmundsdottir BR et al. Thromb Research 2012.

Fiix-trial: Total thromboembolism reduced with Fiix-INR monitoring(Stroke + SE + MI + TIA + VTE)Intention to monitor analysis

d1-720

2.3% ppy

d181-720

1.2% ppy

d181-720

2.2%

d181-720

1.1%*

d181-720

2.2% ppy

d181-720

2.5% ppy Major bleeding (all patients)

Per protocol analysis

Onundarson PT et al www.thelancet.com/haematology

Published online May 26, 2015 http://dx.doi.org/10.1016/S2352-

3026(15)00073-3

What to monitor (3)DOACs

DOAC levels in relation to TE or MBAre the tested doses in trials the best doses?

Concentrations in relation to untoward events

� We don´t know but they are the only approved doses!

� Tailored doses are not approved (like with VKA)

� Available for dabigatran etixilate (RE-LY) and edoxaban (ENGAGE trial)

� Not available for rivaroxaban or apixaban

Date of download: 5/1/2016 Copyright © The American College of Cardiology. All rights reserved.

From: The Effect of Dabigatran Plasma Concentrations and Patient Characteristics on the Frequency of Ischemic Stroke and Major Bleeding in Atrial Fibrillation Patients: The RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy) Reilly PA, et al. J Am Coll Cardiol. 2014;63(4):321-328.

Probability of Major Bleeding Event and Ischemic Stroke/SEE Versus Trough Plasma Concentration of DabigatranCalculated for 72-year-old male atrial fibrillation patient with prior stroke and diabetes. Lines and boxes at the top of the panel indicate median dabigatran concentrations in the RE-LY trial with 10th and 90th percentiles. Conc. = concentration; DE = dabigatran etexilate; SEE = systemic embolic event(s).

Figure Legend:

Worse efficacy outcome than warfarin in AF

Concentrations of DOAC and biological effect may be interchangeable

Calbrated dilute thrombin time Calibrated chromogenic anti Xa assay

What to monitor (4)Single assay for all OACs?Calibrated or not

Dilute PT or dilute Fiix-PT to measure all oral anticoagulants, UFH and enoxaparin

Increasing thromboplastin dilutions make the PT sensitive

Patient samples

Dabigatran (ng/mL)

Clot

ting

time

(s)

0 100 200 300 400 5000

50

100

150

200

250

300

dPT

A)TPdil 1/1500

TPdil 1/750

TPdil 1/300

TPdil 1/150

TPdil 1/15

TPdil 10/15

Dabigatran (ng/mL)

Clot

ting

time

(s)

0 100 200 300 400 5000

50

100

150

200

250

300

dFiix-PT

B)

TPdil 1/2313

TPdil 1/1156

TPdil 1/463

TPdil 1/231

TPdil 1/23TPdil 16/37

Rivaroxaban (ng/mL)

Clot

ting

time

(s)

0 100 200 300 400 5000

50

100

150

200

250

300

dPT

C)

TPdil 1/1500

TPdil 1/750

TPdil 1/300

TPdil 1/150

TPdil 1/15

TPdil 10/15

Rivaroxaban (ng/mL)

Clot

ting

time

(s)

0 100 200 300 400 5000

50

100

150

200

dFiix-PT

D)

TPdil 1/2313

TPdil 1/1156

TPdil 1/463

TPdil 1/231

TPdil 1/23TPdil 16/37

Apixaban (ng/mL)

Clot

ting

time

(s)

0 200 400 6000

50

100

150

dPT

E)

TPdil 1/1500

TPdil 1/750

TPdil 1/300

TPdil 1/150

TPdil 1/15

TPdil 10/15

Apixaban (ng/mL)

Clot

ting

time

(s)

0 200 400 6000

50

100

150

dFiix-PT

F)TPdil 1/2313

TPdil 1/1156

TPdil 1/463

TPdil 1/231

TPdil 1/23TPdil 16/37

0 50 100 150 200 250 300 350 400 450 5000

50

100

150

200

250

300

350

400

450

500

550

600

Dilute TT (ng/mL)

dPT

1:75

0 (n

g/m

L)

Y= 1.09x +73.0, R2 = 0.59, n= 63

A)

0 50 100 150 200 250 300 350 400 450 5000

50

100

150

200

250

300

350

400

450

500

550

600

Dilute TT (ng/mL)

dFiix

-PT,

TP

1:11

56 (n

g/m

L)

y = 0.94x +27.6, R2 = 0.77, n= 63

D)

0 50 100 150 200 250 300 350 400 450 500 550 6000

50

100

150

200

250

300

350

400

450

500

550

600

650

700

750

800

850

900

Chromogenic anti Xa (ng/mL)

dPT

1:75

0 (n

g/m

L)

Y = 0.78x + 66.2, R 2 = 0.72, n= 86

B)

0 50 100 150 200 250 300 350 400 450 500 550 6000

50

100

150

200

250

300

350

400

450

500

550

600

650

700

750

800

850

900

Chromogenic anti Xa (ng/mL)

dFiix

-PT,

TP

1:11

56 (n

g/m

L)

Y = 0.80x + 18.8, R2 = 0.81, n= 86

E)

0 50 100 150 200 250 300 350 400 450 500 550 6000

50

100

150

200

250

300

350

400

450

500

550

600

Chromogenic anti Xa (ng/mL)

dPT

1:75

0 (n

g/m

L)

Y = 0.74x + 46.2, R2 = 0.69, n= 10

C)

0 50 100 150 200 250 300 350 400 450 500 550 6000

50

100

150

200

250

300

350

400

450

500

550

600

Chromogenic anti Xa (ng/mL)

dFiix

-PT,

TP

1:11

56 (n

g/m

L)

Y = 1.03x + 30.7, R2 = 0.91, n= 10

F)

Loic R. Letertre*, Brynja R. Gudmundsdottir*, Charles W. Francis†, Robert C. Gosselin‡, Mika Skeppholm§, Rickard Malmstrom¶, Stephan Moll**, Emily Hawes**,††, Suzanne Francart††, and Pall T. Onundarson*,‡‡A single test to assay warfarin, dabigatran, rivaroxaban, apixaban, unfractionated heparin and enoxaparin in plasma. JTH 2016

Conclusions:

Should all oral anticoagulants be monitored?You bet!

Could improve outcome through individualization of doseCould improve adherence

Antithrombotic Therapy for VTE DiseaseCHEST Guideline and Expert Panel ReportCHEST 2016; 149(2):315-352Clive Kearon, MD, PhD; Elie A. Akl, MD, MPH, PhD; Joseph Ornelas, PhD; Allen Blaivas, DO, FCCP;David Jimenez, MD, PhD, FCCP; Henri Bounameaux, MD; Menno Huisman, MD, PhD;Christopher S. King, MD, FCCP; Timothy A. Morris, MD, FCCP; Namita Sood, MD, FCCP;Scott M. Stevens, MD; Janine R. E. Vintch, MD, FCCP; Philip Wells, MD; Scott C. Woller, MD;and COL Lisa Moores, MD, FCCP

Financial/nonfinancial disclosures: The authors have reported to CHEST the following: In the last 3 years:

� E. A. A. was an author on a number of systematic reviews on anticoagulation in patients with cancer.

� H. B. has received compensation for participation on advisory committees with speaking engagements sponsored by Sanofi-Aventis, Bayer Healthcare, and Daiichi-Sankyo. His institution has received grant funding (no salary support) from Daiichi-Sankyo for studying VTE treatment. He has also served as a coauthor of original studies using rivaroxaban (EINSTEIN, EINSTEIN Pulmonary Embolism[PE]) and edoxaban (Hokusai-VTE study).

� M. H. has received grant funding and has delivered talks related to long-term and extended anticoagulation and treatment of subsegmental PE. He has also authored several papers related to long-term and extended anticoagulation, treatment of subsegmental PE, and compression stocking in preventing postthrombotic syndrome.

� D. J.’s institution has received grant funding (no salary support) from Instituto de salud Carlos III, Sociedad Española de Neumología y Cirugía Torácica, and NeumoMadrid for studying PE. He was a member of Steering

� Committee of the Pulmonary Embolism Thrombosis Study (PEITHO), a principal investigator of an original study related to the role of the inferior vena cava filter in addition to anticoagulation in patients with acute DVT or PE and has participated in the derivation of scores for identification of low-risk PE. He has delivered talks related to treatment of acute PE.

� C. K. has been compensated for speaking engagements sponsored by Boehringer Ingelheim and Bayer Healthcare related to VTE therapy. His institution has received grant funding (no salary support) from the National Institutes of Health related to the topic of catheter-assisted thrombus removal in patients with leg DVT. He has also published many studies related to longterm anticoagulation and compression stockings in preventing postthrombotic syndrome.

� L. M. has frequently lectured on the duration of long-term anticoagulation and is a coauthor on several risk-stratification papers. She has received honoraria from CHEST Enterprises for VTE talks.

� T. M. and C. S. K. have received honoraria from Chest Enterprises for VTE Prep Courses. T. M.’s institution has received grant funding (no salary support) from Portola Pharmaceuticals for the Acute Medically Ill VTE Prevention With Extended Duration Betrixaban Study (APEX) related to extended prophylaxis against VTE with betrixaban. T. M.’s institution received grant support from Bayer Pharmaceuticals for a research project concerning the etiology of chronic thromboembolic pulmonary hypertension. He has also authored textbook chapters related to thrombolytic interventions in patients with acute PE and pulmonary thromboendarterectomy in chronic thromboembolic pulmonary hypertension. S. M. S.’s and S. C. W.’s institution has received grant funding (no salary support) from the Canadian Institutes of Health for the D-dimer Optimal Duration Study Phase II (DODSExtension), from Washington University via the National Institutes of Health (Genetic Informatics Trial), Bayer related to VTE (EINSTEIN studies), and from Bristol-Myers Squibb related to apixaban for the Secondary Prevention of Thromboembolism (Apixaban for the Secondary prevention of Thromboembolism: A prospective Randomized Outcome pilot study among patients with the AntiphosPholipid Syndrome).

� J. R. E. V.’s institution has received grant funding (no salary support) from Bristol-Myers Squibb for evaluating the role of apixaban for long-term treatment of VTE.

� P. W. is a coinvestigator on a grant regarding the treatment of subsegmental

� PE. He has authored several studies and grants related to the longterm and extended anticoagulation (using vitamin K antagonists and the direct oral anticoagulants).

� P. W. has received grant funding from Bristol-Myers Squibb and has received honoraria for talks from Bayer. E. A. A., H. B., C. K., P. W., and S. C. W. participated in the last edition of the CHEST Antithrombotic Therapy for VTE Disease Guidelines (AT9).

� None declared (A. B., J. O., N. S.). Role of sponsors: This study was funded in total by internal funds from the American College of Chest Physicians.