Venous Thrombo-Embolism (VTE) Therapy

current challenges & opportunities

Asher Winder M.D.Director, Department of HematologyWolfson Medical Center

כנס האיגוד הישראלי

2012לפרמקולוגיה קלינית

Direct Oral AntiCoagulantsבעידן VTE-טיפול ב (DOAC)

0–14

Age group (yr)

60–64 80–8420–24 70–7430–34 40–44 50–5415–19 65–69 8525–29 75–7935–39 45–49 55–59

800

600

0

400

200

1000

1200

An

nu

al

incid

en

ce /

100,0

00

All DVT or PE

PE ± DVT

DVT alone

Silverstein, M.D. et al. Arch Intern Med 1998; 158:585-593.

Annual Incidence of VTE by Event Type (PE vs. DVT)

Venous Thrombo-Embolism (VTE) Therapy

current challenges & opportunities

• Common – preventable?

• Diagnosis

• Therapy - anticoagulation

– Efficacy

– Side effects – bleeding• Management of bleedings

– Burden, Compliance & adherence• Monitoring & measuring

– Special populations

– For how long

Recurrence Rate in Patients With A First Unprovoked VTE

Eichinger S, et al. Circulation. 2010;121:1630-1636.

95% CIs (dotted lines)

VTE Therapy – Anticoagulation

What is the optimal duration of oral anticoagulant therapy after an episode of VTE?

Common policy:

Provoked VTE – 3-6 months

Unprovoked VTE – 6-12 months

Recurrent VTE – life long

The objective of treating venous thrombosis

--to prevent local extension of the thrombus --to prevent the thrombus from embolizing--to induce accelerated fibrinolysis.

… and then to stop anticoagulation?Kearon C. Circulation 2003;107:I22–I30

Ginsberg JS, et al. Arch Intern Med 2000;160:669–672

Kearon C et al. Chest 2012;141:e419S-e494S

treatment prevention

Duration of Anticoagulation for Secondary Prevention after First Unprovoked DVT

Years

Recu

rren

ce (

%)

1 2 3

10

20

30

3 months (INR 2-3)

Indefinite (INR 2-3)

12 months (INR 2-3)

Bauer. JAMA. 2011. 305 (13): 1336-45

Conclusion: give anticoagulants life time ?

Coagulation

ThrombosisBleeding

treatment duration does not seem to influence recurrent VTE risk in patients with unprovoked VTE; longer anticoagulation seems to simply delay recurrence

Annual major hemorrhage rates in trials of long-term full-intensity and low-intensity warfarin therapy in the prevention of recurrent VTE

Ridker P.M. J Thrombos Haemos 2004;2(7):1034

Emergency Hospitalizations for Adverse Drug Events in Older U.S. Adults, 2007–2009.

Budnitz DS et al. N Engl J Med 2011;365;21

VTE and bleeding in elderly patients: RIETE registry

López-Jiménez et al .Haematologica 2006;91:1046-51

Outcomes < 80 years ≥ 80 years

VTE recurrence 2.8% 2.1%

Major bleeding2.1% 3.4%

(OR 1.7, 95% CI 1.3-2.1)

Fatal PE1.1% 3.7%

(OR 3.6, 95% CI 2.7-4.7)

Fatal bleeding 0.4% 0.8%

(OR 2.0, 95% CI 1.2-3.4)

Of 13,011 patients with VTE, 2890 (22%) were aged ≥80 years

OR, odds ratio

An international, multicentre, observational registry of patients with symptomatic, objectively

confirmed acute VTE. Enrollment between March 2001 and September 1, 2005

included 13 011 patients.

What strategies for optimal duration of oral anticoagulant therapy after an episode of VTE?

• Thrombophilia

• Provocation

• Location of thrombus

• Residual thrombus

• Age

• Gender

• D-dimer

• Bleeding risk

• Patient preference

Do positive thrombophilia tests predict increased risk of recurrent VTE?

• Factor V Leiden (+/-) NO

• Prothrombin 20210 (+/-) NO

• APLA (LAC) YES

• AT, PC,PS, multiple risks excluded/too rare

Eichinger et al. Arch.Int. Med. 2002

Sabine Eichinger

Recurrent VTE is Common after A First Episode of Symptomatic DVT

Idiopathic vs Secondary VTE

Adjusted HR = 2.30

(95% CI, 1.82 - 2.90)

P. Prandoni et al. Haematologica. 2007;92:199-205.

A prospective cohort study in 1626 patients

Paolo Prandoni

Padua

Risk of recurrent VTE after stopping anticoagulant therapy

provocation after 1 year % after 5 years %

surgery 1 3

nonsurgical

reversible risk

factor *5 15

Unprovoked 10 30

Cancer ** 15

* nonsurgical trigger : eg, estrogen therapy, pregnancy, leg injury, flight of > 8 h

** cancer: vary according to whether the cancer is metastatic, being treated

with chemotherapy, or rapidly progressing

CHEST 2012;141 suppl e419S-e494S

Residual Thrombosis on Ultrasonography to Guide the Duration of Anticoagulation

flexible-duration, ultrasonography-guided anticoagulation (no further anticoagulation in

patients with recanalized veins and continued anticoagulation in all other patients for up

to 9 months for secondary DVT and up to 21 months for unprovoked thrombosis)

Cumulative incidence of recurrent thromboembolism

Prandoni P. et al. Ann Intern Med 2009;150:577-585

OAT = oral anticoagulant therapy

Paolo Prandoni

Padua

Age as risk factor for recurrence after idiopathic venous thromboembolismThe Prolong study

Cosmi B., et al. J Thrombosis Haemostasis 2010;8:1933–1942.

Likelihood of Recurrent Venous Thromboembolism According to Sex.

Kyrle PA. et al. NEJM 2004;350:2558-2563

Unprovoked events excluding studies

enrolling patients with hormonal risk factors

McRae S. et al. Lancet 2006;368:371-8.

n=number of events (episodes of recurrent venous thromboembolism);

N=number of participants.

Risk factors for recurrent VTE with relative strength of association

Giancarlo Agnelli and Cecilia Becattini Hematology 2013;2013:471-477

Hazard for recurrent VTE by D-dimer status

Douketis A. et al. Ann Intern Med. 2010;153:523-531.

Ability of D-Dimer Testing to Assess

Recurrence Risk After Unprovoked VTE

timing of D-dimer testing

D-dimer status in

patient subgroups

defined by age.

HR for recurrent

VTE 2.4 [CI, 1.1-5.1]

Risk Assessment of Recurrence in

Patients With Unprovoked VTEThe Vienna Prediction Model

Eichinger S, et al. Circulation. 2010;121:1630-1636.

Sabine Eichinger

If one has a positive d-Dimer but refuse resuming anticoagulation?

DULCIS (D-dimer and ULtrasonography in Combination Italian Study)

Palareti G et al. Blood 2014;124:196-203

Recurrent VTE and death caused by VTE in pts with negative D-dimer results in whom anticoagulation was stopped and in those with positive D-dimer results who refused to resume anticoagulation

Is it really safe to stop anticoagulation if d-Dimer is negative?

d-Dimer Testing to Select Pts with a First Unprovoked VTE Who

Can Stop Anticoagulant Therapy

A Cohort Study (D-Dimer Optimal Duration Study)

Kearon, C, et al. Ann Intern Med. 2015;162(1):27-34.

“positive d-dimer result” - receiving anticoagulant therapy

All others had negative d-dimer test results at baseline and 1 mo after

anticoagulant withdrawal and did not restart anticoagulant therapy

Clive Kearon

In patients with a first VTE that is an unprovoked

VTE bleeding risk duration grade

proximal DVT low or

moderate

extended 2B

high 3 months 1B

PE low or

moderate

extended 2B

high 3 months 1B

CHEST 2012; 141(2)(Suppl)

Phases of anticoagulation.

Kearon C et al. Chest 2012;141:e419S-e494S

“We use the term extended anticoagulation to refer to

anticoagulation that is continued beyond 3 months

without a scheduled stop date.

Regular (yearly) reassessments are needed to assess

whether a patient’s risk of bleeding increased or the

patient’s preferences changed.”

Clive Kearon

Patients with VTE who should be treated for 3 months and who should be treated indefinitely.

Kearon C , and Akl E A Blood 2014;123:1794-1801

Clive Kearon

If we only had an anticoagulant agent effective as warfarin but with less risk for bleeding!

New horizons for VTE therapyDirect oral anticoagulants (DOACs)

Current standard of careVKA

Heparin

RECOVER I/II (2009, 2013) DabigatranHeparin

EINSTEIN DVT/PE (2010) Rivaroxaban

AMPLIFY (2013) Apixaban

HOKUSAI (2013) EdoxabanHeparin

6 months

3, 6, 12 months

6 months

3-12 months

Current standard of care

RECOVER I/II (2009, 2013)

EINSTEIN DVT/PE (2010)

AMPLIFY (2013)

HOKUSAI (2013)

Schulman S et al. N Engl J Med 2009;361:2342–52; Schulman S et al. Circulation 2014; 129:764–72The Hokusai-VTE Investigators. N Engl J Med 2013;369:1406–15; EINSTEIN Investigators. N Engl J Med 2010;363:2499–2510;

EINSTEIN–PE Investigators. N Engl J Med 2012;366:1287–97; Agnelli G et al. N Engl J Med 2013;369:799–808

What should we measure in clinical trials and in real life?

• Efficacy end points

• Safety end points

– Major bleeding

– Clinically relevant non-major bleeding (CRNMB):

• spontaneous skin hematoma of at least 25 cm2

• spontaneous nose bleed of more than 5 minutes duration

• macroscopic hematuria (spontaneous or, if associated with

intervention, lasting more than 24 hours)

• spontaneous rectal bleeding (more than spotting on toilet paper)

• gingival bleeding for more than 5 minutes

• bleeding leading to hospitalization and/or requiring surgical

treatment

• bleeding leading to a transfusion of less than 2 units of blood

• or any other bleeding considered clinically relevant by the

investigator

Acute VTE treatment

Phase 3 Trials with New Oral Anticoagulants (NOACs)

Wells PS, et al. JAMA 2014;311(7):717-728.

Clinically relevant non-major bleeding: spontaneous skin haematoma of at least 25 cm2, spontaneous nose bleed of more

than 5 minutes’ duration, macroscopic haematuria (spontaneous or, if associated with intervention, lasting more than 24

hours), spontaneous rectal bleeding (more than spotting on toilet paper), gingival bleeding for more than 5 minutes, bleeding

leading to hospitalisation and/or requiring surgical treatment, bleeding leading to a transfusion of less than 2 units of blood, or

any other bleeding considered clinically relevant by the investigator.

Recurrent VTE and VTE-related deathin phase 3 trials comparing NOACs with conventional therapy for acute VTE treatment

Yeh C H et al. Blood 2014;124:1020-1028Hazard ratios (HR) for recurrent VTE and VTE-related

death and their 95% confidence intervals (CI)

Major bleeding and clinically relevant nonmajor bleedingin phase 3 trials comparing NOACs with conventional therapy for acute VTE treatment

Yeh C H et al. Blood 2014;124:1020-1028

Hazard ratios (HR) for major bleeding or major plus

clinically relevant nonmajor bleeding (CRNB) and their

95% confidence intervals (CI)

Safety of NOACs versus standard care in acute VTE

T van der Hulle. J Thromb Haemost 2014;12:320-8

NOACs have comparable efficacy to that

of VKAs and are associated with

significantly lower risk of bleeding

complications

Aspirin for Preventing the Recurrence of Venous Thromboembolism (WARFASA )

Becattini C, et al. N Engl J Med 2012; 366:1959-1967.

Clinical trials of DOACs and aspirin for extended treatment of VTE

Giancarlo Agnelli, and Cecilia Becattini Hematology 2013;471-477

Results of Phase 3 Trials With New Oral Anticoagulants (NOACs)—Extended VTE

Wells PS, et al. JAMA 2014;311(7):717-728.

AMPLIFY-EXT: Apixaban for Extended Treatment of VTE

Symptomatic Recurrent VTE or VTE-Related Death

Agnelli G., et al. N Engl J Med 2013; 368:699-708

Giancarlo Agnelli

Perugia

Major or Clinically Relevant Non major Bleeding

AMPLIFY-EXT: Apixaban for Extended Treatment of VTE

Agnelli G., et al. N Engl J Med 2013; 368:699-708

Treatment of DVT and PEPrevention of recurrent

DVT and PE

10 mg

twice daily

5 mg

twice daily

2.5 mg

twice daily

for the first

7 days>7 days to 3–6 months After 6 months of AC

Apixaban for treatment and secondary prevention of VTE

Vitamin K antagonistParenteral

heparin

Initial(0 to ~7days)

Extended(~3 months to indefinite)

Long-term(~7 days to ~3 months)

Phases of anticoagulation

LMWH, dabigatran, rivaroxaban, apixaban, EdoxabanRivaroxaban/Apixaban

Anticoagulation registries

StudyPatient type Start date Number of patients Duration of patient

follow-up

XAMOS phase IV study

Elective hip or knee replacement

surgery or hip-fracture surgery

Early 2009 17,701 Enrolment to 3

months post-surgery

XALIA phase IV study

Objectively confirmed acute DVT

treated with rivaroxaban

June 2012 ~4800 planned

(ongoing)

1 year from the final

date of patient

enrolment

RIETE registryAcute DVT or PE March 2001 >40,000 to date

(ongoing)

Minimum of 3 months

XANTUS phase IV study

Non-valvular AF prescribed

rivaroxaban, irrespective of stroke

risk

June 2012 ~6000 1 year

GARFIELD-AF registry

Newly diagnosed non-valvular AF

and ≥1 investigator-defined stroke

risk factor

December 2009 55,000 planned

(ongoing)

At least 2 years

PREFER in AF registry

Patients with a diagnosis of AF in

Europe

January 2012 7243 1 year

GLORIA-AF registryNewly diagnosed with AF at risk

of stroke

May 2011 Up to 56,000 (ongoing) 3 years

ORBIT-AF registryCommunity-based outpatients

with AF

June 2010 10,098 ³2 years

RE-LY AF registryPatients presenting to emergency

department with AF

Sep 08 15,4 1.5 years

Dresden NOAC registry

Patients treated with novel OACs October 2011 1776 treated with

rivaroxaban

2 years

Sylvia Haas, May 2015

Physician-cited reasons for not prescribing warfarin

Hylek et al. Stroke. 2006; 2006;37:1075–1080

28%

41%

11%

4%

10%

7%

42%

18%

17%

1%

5%

5%

11%

Patients <80 years (n=76) Patients ≥80 years (n=123)

Hemorrhage

FallsPatient refusal/ non-compliance

Cognitive impairment

Active alcohol abuse

Advanced illness

Other

Being at risk of falls is not a valid reason to avoid oral anticoagulants in medical patients

prospective cohort, patients on oral anticoagulants

hazard ratio for high falls risk and a risk of major bleeds -1.09 (95% confidence interval, 0.54-2.21)

Donzé J, Clair C, Hug B, et al. Am J Med 2012:125,773–778

New Oral Anticoagulants in Elderly Adults (aged 75 and older): venous thromboembolism (VTE) or VTE‐related death

Sardar P, Chatterjee S, Chaudhari S, Lip GYH. J Am Geriatr Soc 2014: 62:857-864.

Barco S, Cheung YW, Eikelboom JW, Michiel Coppens. Best Practice & Research Clinical Haematology 2013:26:215–224

New Oral Anticoagulants in Elderly Adults (aged 75 and older): recurrent VTE & Major bleeding

recurrent VTE

Major bleeding

ARISTOTLE: Efficacy and safety of apixaban in the elderly

Halvorsen S, et al. Eur Heart J. 2014;35:1864–72;

Major bleedingNo of

patients

≥ 75 years

Apixaban Warfarin

Hazard ratio(95% CI)

Interaction P value

No. of events/patients

(%/year)

eGFR >80 ml/min 596 11 (2.10) 15 (3.39)

0.1635

eGFR >50–80 ml/min

2912 85 (3.53) 104 (4.45)

eGFR >30–50 ml/min

1898 47 (3.32) 87 (6.27)

eGFR 30 ml/min 221 7 (4.64) 17 (13.4)

ARISTOTLE: Major bleeding rates in the elderly(≥75 years) in relation to renal function

Halvorsen S, et al. Eur Heart J. 2014;35:1864–72;

0.1 1.31.0

Favors apixaban Favors warfarin

1

Efficacy and safety of DOACs versus warfarin when eGFR is ≤50mL/min

Stroke

or SE 0.77 (0.45–1.32)

0.98 (0.67–1.42)

0 2

Favours

warfarin

0.54 (0.30–0.98)

1.01 (0.70–1.46)

0 1 2

0.84 (0.57–1.23)

0.95 (0.72–1.26)

0 1 2

0.79 (0.55–1.14)

0.50 (0.38–0.66)*

0 1 2

Major

bleeding

Dabigatran 110 mg

HR (95% CI)

Dabigatran 150 mg

HR (95% CI)

Rivaroxaban

HR (95% CI)

Apixaban

HR (95% CI)

Favours

dabigatran

Favours

warfarin

Favours

dabigatran

Favours

warfarin

Favours

rivaroxaban

Favours

warfarin

Favours

apixaban

Capranzano P, et al. Expert Rev Cardiovasc Ther 2013;11:959-73.

*p for interaction = 0.03.

eGFR, estimated glomerular filtration rate.

Head-to-head studies do not exist, and direct comparisons between agents may not be made

Am J Cardiovasc Drugs, 2013, Nov

Dabigatran (150 mg bid) Rivaroxaban (20 mg bid)

Circulation 2011; 124: 1573-1579

Lehmann T., et al. Thrombosis and Haemostasis 2014;112:834-836

Course of rivaroxaban plasma concentration

Rivaroxaban plasma concentration measured by anti- FXa assay (red), by

HPLCMS/ MS (blue) and prothrombin time (green) over 24 h after ingestion of

an oral overdose. s = second, L = liter, h = hour.

No bleeding

occurred at any

time during the

clinical course.

Dabigatran-

associated

massive

postcardiac

surgery

bleeding.

Warkentin T E et al. Blood 2012;119:2172-2174

A 79-year-old male

underwent elective aortic

valve replacement and

single-vessel coronary

artery bypass grafting

unintentionally with

therapeutic dabigatran

levels

Reversal of new oral anticoagulants

General measures Specific antidotes

Anti-IIa Anti-Xa

Activated charcoal,

hemofiltration & hemodialysis

Fab fragment

idarucizumab

Factor Xa

decoy

Andexanet

alfaPCCs

(e.g., Beriplex, Octaplex)

Activated PCCs

(e.g., FEIBA)

Recombinant factor VIIa

(Novoseven)

Antifibrinolytic agents

(e.g., TXA)

Andexanet Alfa for the Reversal of Factor Xa

Lu, G. et al. Nat. Med 2013;19, 446–451; Siegal DM, et al. N Engl J Med 2015; 373:2413-2424

modified recombinant

enzymatically inactive

factor Xa that traps

circulating Xa inhibitor

Healthy volunteer with an

age range of 50 to 75 years

Idarucizumab: Antidote for dabigatranaDabi-Fab reverses the anticoagulative effects of dabigatran

Glund S et al. Lancet 2015; 386:680–690; Pollack CV, et al. N Engl J Med 2015; 373:511-520

The antidote shares structural features

with thrombin in the mode of binding but

has no activity in coagulation tests. It has

an affinity for dabigatran that is ∼350

times stronger than its affinity for thrombin

51 patients median

age 77 (48-93) who

had serious bleeding

Significant hematoma growth despite INR

correction with PCC. The patient was treated

with 1000 U of PCC and 10 mg vitamin K 98

minutes after baseline CT scan.

Dowlatshahi D et al. Stroke 2012;43:1812-1817

Poor Prognosis in Warfarin-Associated Intracranial

Hemorrhage Despite Anticoagulation Reversal

prospective multicenter

registry of patients

treated with PCC for

ICH in Canada (2008-

2010, n=141)

PCC therapy rapidly

corrected INR in the

majority of patients, yet

mortality and morbidity

rates remained high.

The first described case of

venous thrombosis (1271)

A young man from Normandy named

Raoul who, at the age of 20 years,

developed unilateral edema in the

right ankle that subsequently

extended up to the thigh

The great and much renowned

surgeon Henri du Perche advised him

to wait and see.

Raoul was advised to visit the tomb of

Saint Louis who was buried in the

church of Saint Denis, where the

patient spent several days confessing

his sins and praying to the saint.

Afterwards he chose to collect the

dust accumulating below the stone

that covered the tomb and apply it to

the fistulae and ulcers of his foot.

Clichè Bibliotèque National de France, Paris.

Clichè Bibliothèque Nationale de France, Paris

Vitamin K antagonistParenteral

heparin

Initial(0 to ~7days)

Extended(~3 months to indefinite)

Long-term(~7 days to ~3 months)

Phases of anticoagulation

LMWH, dabigatran, rivaroxaban, apixaban, EdoxabanRivaroxaban/Apixaban

Wells PS, et al. JAMA 2014;311(7):717-728.

Approach to Long-term and Extended Treatment of VTE

High D-dimer after surgery …

-נשלחת לPE-בחורה צעירה עם חשד נמוך ל

CT-בגלל אנגיוD-dimerגבוה

What do you do when duplex is

normal?

Potentially Lethal Misnomer SFV = deep

Duration of Anticoagulation forFirst Unprovoked DVT

Years

Recu

rren

ce (

%)

1 2 3

10

20

30

3 months (INR 2-3)

Indefinite (INR 2-3)

12 months (INR 2-3)

Indefinite (INR 1.5-2)

Bauer. JAMA. 2011. 305 (13): 1336-45

Anticoagulation registries (May 2015, Sylvia Haas)

StudyPatient type Start date Number of patients Duration of patient

follow-up

Key observations

XAMOS phase IV study

Elective hip or knee replacement

surgery or hip-fracture surgery

Early 2009 17,701 Enrolment to 3

months post-surgery

Confirmed favourable

benefit–risk profile of

rivaroxaban seen in phase III

studies

XALIA phase IV study

Objectively confirmed acute DVT

treated with rivaroxaban

June 2012 ~4800 planned

(ongoing)

1 year from the final

date of patient

enrolment

Results expected in 2015

RIETE registry

Acute DVT or PE March 2001 >40,000 to date

(ongoing)

Minimum of 3 months Both fatal PE and fatal

bleeding are more common

in cancer patients with VTE

than in patients without

cancer

In outpatients with DVT,

home treatment was

associated with a better

outcome than hospital

treatment

XANTUS phase IV study

Non-valvular AF prescribed

rivaroxaban, irrespective of stroke

risk

June 2012 ~6000 1 year Findings not yet reported

GARFIELD-AF registry

Newly diagnosed non-valvular AF

and ≥1 investigator-defined stroke

risk factor

December 2009 55,000 planned

(ongoing)

At least 2 years OACs frequently not used

according to guidelines

PREFER in AF registry

Patients with a diagnosis of AF in

Europe

January 2012 7243 1 year Frequent and possibly

inappropriate use of

combined oral anticoagulant

and antiplatelet agents

GLORIA-AF registryNewly diagnosed with AF at risk

of stroke

May 2011 Up to 56,000 (ongoing) 3 years Findings not yet reported

ORBIT-AF registry

Community-based outpatients

with AF

June 2010 10,098 ³2 years OAC use is high and driven

by bleeding risk as well as

stroke risk

RE-LY AF registry

Patients presenting to emergency

department with AF

Sep 08 15,4 1.5 years Large variations in

demographics and risk

factors exist between global

regions

Dresden NOAC registry

Patients treated with novel OACs October 2011 1776 treated with

rivaroxaban

2 years Rates of major bleeding with

rivaroxaban may be lower

and the outcome similar to

that seen with VKA

Effects of dabigatran on

coagulation

assays

John W. Eikelboom; Jeffrey I. Weitz. Thromb Haemost 2013; 110: 393–395

Measuring anticoagulation effect

Siegal DM et al. Blood. 2014;123(8):1152-1158

Dabi

Elective Interruption

Procedural

bleeding risk

Standard High

Hold

2-3 drug half-livesHold

4-5 drug half-lives

Elective Interruption

Procedural

bleeding risk

Standard High

Hold

2-3 drug half-livesHold

4-5 drug half-lives

Invasive procedures

?

J Med July 2013 vol. 80 no. 7 443-451

Severe/life-threatening bleeding

Mortality after a major bleed: five Phase III trials N=27,419 (dabigatran n=16,755; warfarin

n=10,002; placebo n=662)

*Data combined from dabigatran 150 mg and 110 mg BID treatment groups. Only first major bleed included.

Analysis not adjusted for covariates

Reduced risk for death with dabigatran* vs warfarin during 30 days

from the bleeding (P=0.052)

Mo

rta

lity r

ate

(%

)

Time (days)

0

0.1

0.2

0.3

5 10 15 20 25 30 35

Warfarin

Dabigatran

Sam Schulman, ASH, Dec 2012

concern that major bleeding with dabigatran is associated with increased

risk due to the lack of antidote & established bleeding protocols

• Rivaroxaban

- specific anti-FXa activity

- PT and aPTT modified according

to the reagent (PT more sensitive)

• Apixaban

- specific anti-FXa activity

- PT and aPTT not really prolonged

• Dabigatran

- Ecarin clotting time, Haemoclot or anti-IIa

- PT, aPTT and TT modified according

to the reagent (aPTT more sensitive)

MM Samama et al. Clin Chem Lab Med 2011;49:761

Specific Tests (March 2015)

rFVIIa and PCC partially improved laboratory

parameters, but did not reverse rivaroxaban

induced-bleeding

Anesthesiology. 2012;116:94–102

Management of bleeding in patients taking

NOACs. Possible therapeutic measures in case of minor

or severe bleeding in patients on NOAC therapy. European

Society of Cardiology

Heidbuchel H et al. Europace 2013;15:625-651

Small, synthetic, water-soluble, cationic molecule that is designed to bind specifically to

unfractionated heparin and low-molecular-weight heparin through noncovalent hydrogen

bonding and charge–charge interactions.

It binds in a similar way to edoxaban, rivaroxaban, apixaban, and to dabigatran.

Edoxaban significantly

reduced the mean

fibrin-fiber diameted which

was restored to normal 30

minutes after

administration of PER977

aDabi-Fab reverses the anticoagulative effects of

dabigatran in vivo.

Schiele F et al. Blood 2013;121:3554-3562

Andexanet alfa

Dabigatran antidote

Human

MouseVL

CLCH

VH

Humanized

Fab

• Specific high affinity binding to dabigatran

• No homology of dabigatran to other endogenous

receptors/ligands

• Fab has shorter half life than full mAb (hrs vs

days for a full mAb)

van Ryn et al, JACC 2011; 57 (Suppl 1) abstr 1142-367

van Ryn et al, JTH 2011; 9 (suppl 2), 110, abstr P-MO-166

Efficacy and safety of DOACs versus LMWH/VKA

in acute VTE treatment

Extracted from: Cohen A, et al. Adv Ther 2014;31:473-93.

0

0

1

2

VT

E r

ecu

rre

nce (

HR

[9

5%

CI]

)

1 2Major or CRNM bleeding (HR [95% CI])

HOKUSAI-VTE

EINSTEIN-PE

EINSTEIN-DVT

AMPLIFY

RE-COVER RE-COVER II

Fewer

recurrences,

fewer bleeds

Fewer

recurrences,

more bleeds

More

recurrences,

more bleeds

More

recurrences,

fewer bleeds

VKA, vitamin K antagonist.

Incidence rates of VTE recurrence are

highest in the young

1. Martinez C, Cohen AT et al. Thromb Haem 2014; 112. ePub ahead of print.

1.0 1.5 2.0 3.0

EINSTEIN-PE

EINSTEIN-DVT

RECOVER I & II

HOKUSAI

Recurrent VTE in Patients with

Active Cancer

5.00.5

Favors DOAC Favors Warfarin

Schulman S, et al. Circulation, 2013; Agnelli G, et al. N Engl J Med, 2013; Prins M, et al.

Thromb J, 2013; Hokusai VTE, N Engl J Med, 2013

HR

(95% CI)

AMPLIFY

0.750.1

DOACs in Patients with

Active Cancer

• Few patients studied in the DOAC trials

(total of 962) – (however there were only 980 patients in the 3 main

LMWH studies)

• Comparator was VKA and not LMWH

Cancer and recurrences and major

bleeding – DOAC vs VKA

Van Es et al. Blood 2014

DVT and cancer – conclusions

• Cancer associated thrombosis (CAT) have high risk of recurrence

and bleeding and many can receive oral anticoagulants

• LMWH have an important role in active cancer patients with VTE

especially those who

– Can tolerate parenteral therapy

– Are not at increased risk of bleeding

• DOACs are an important advance in the safety of anticoagulation in

VTE (DVT and PE)

• DOACs can be used in benign and cancer associated VTE

• DOACs versus LMWH in active CAT awaited

Where is the INR?

No need for monitoring. But,

Should we measure DOACs levels?

How to measure?

Should we measure DOACs levels?

Expected plasma concentrations of

dabigatran or rivaroxaban

• ↵* Steady-state geometric mean dabigatran plasma concentration (25th-75th percentile range) measured around 2

hours (Cpeak) or 12 hours (Ctrough) after 150 mg dabigatran administration twice daily.10 Dilute thrombin clotting

time or ECT at Cpeak are approximately prolonged 2 or 3 times the baseline value, respectively.8 Between-reagent

variability should be considered when interpreting results.

• ↵† Steady-state geometric mean rivaroxaban plasma concentration (90% prediction interval) measured around 2

hours (Cpeak) or 24 hours (Ctrough) after 20 mg rivaroxaban administration once daily.17 PT at Cpeak is

approximately prolonged 1.5 times the baseline value.16,19 Between-reagent variability should be considered when

interpreting results.16,19,26,30

Blood 2013;121:4032-4035

Measurement of drug levels and anticoagulant effects

Test Dabigatran Rivaroxaban Apixaban

Specific

Assay

Drug

specificHemoclot Anti-Xa Anti-Xa

Non-specific

assays

aPTT ↑↑↑ ↑ ↑

PT ↑ ↑↑ ↑

TT ↑↑↑↑ No effect No effect

Four hours of haemodialysis removed 48.8% and 59.3% of total dabigatran from the

central compartment with 200 and 400 ml/minute targeted blood flow, respectively. The

anticoagulant activity of dabigatran was linearly related to its plasma levels.There was a

minor redistribution of dabigatran (<16%) after the end of the haemodialysis session.

Elderly healthy volunteer studies d

TT (

s)

DabigatranTime after end of infusion (hrs)

90

85

80

75

70

65

60

55

50

45

40

35

30

25

Minutes

24–2 0 120906030 20161284

65–80 years (n=16), dabigatran etexilate 220 mg

45–64 years (n=12), dabigatran etexilate 220 mg

+ idarucizumab 5 g

+ idarucizumab 5 g

End of idarucizumab injection (5 min infusion)

Idarucizumab

Glund S et al. ASH 2014

Mean baseline

Upper limit of normal

Mechanism of Action of Andexanet alfa

Yeh C et al., Circ. Res. 113:945, 2013

Actions of An Antidote to

Target-specific

AnticoagulantsAndexanet alfa (PRT4445, Portola

Pharmaceuticals)

(a) The prothrombin complex, consisting of

FXa and FVa, catalyzes the conversion

of prothrombin to thrombin

(b) FXa inhibitors such as rivaroxaban and

apixaban bind directly to FXa, preventing

the generation of enzymatically active

thrombin and clotting

(c) An antidote consisting of a modified

recombinant enzymatically inactive factor

FXa traps circulating Xa inhibitor, thus

allowing intrinsic FXa to escape inhibition

and participate in coagulation.

Lu, G. et al. Nat. Med. 19, 446–451 (2013)