practical applications of biomarkers and risk...

Management of antithrombotic treatment in VTE

Practical applications of

biomarkers and risk stratification

Grigoris T Gerotziafas, MD, PhD, HDR

Unité d’Explorations Fonctionnelles et Génétiques du Risque VasculaireConsultation Thrombose – Oncologie

Service d'Hématologie BiologiqueHôpitaux Universitaires de l'Est Parisien – APHP

Group Thrombosis and Cancer

Cancer Biology and Therapeutics

Centre de Recherche Saint-Antoine

INSERM U938

Université Pierre et Marie Curie

DisclosuresResearch Support/P.I. Leo, Sanofi, Bayer HealthCare, Bristol-Myers

Squibb, GlaxoSmithKline, Leo-Pharma, Aspen,

LFB, Roche, Stago, RoviI, Siemens, Boehringer

Ingelheim, Astra Zeneca, Pfizer

Employee No relevant conflicts of interest to declare

Consultant Leo, Sanofi-aventis, Bayer HealthCare, Bristol-

Myers Squibb, GlaxoSmithKline, Leo-Pharma,

Aspen, LFB, Roche, Stago, RoviI, Siemens,

Boehringer Ingelheim, Astra Zeneca

Major Stockholder No relevant conflicts of interest to declare

Speakers Bureau No relevant conflicts of interest to declare

Scientific Advisory Board Leo, Sanofi, Bayer HealthCare, Bristol-Myers

Squibb, GlaxoSmithKline, Leo-Pharma, Aspen,

LFB, Roche, Stago, RoviI, Siemens, Boehringer

Ingelheim, Astra Zeneca, Pfizer

Agenda

Diagnostic and therapeutic protocols of VTE

Benefit/risk ratio in antithrombotic treatment of VTE

Predictors of VTE recurrence after treatment interruption

Factors influencing the risk of recurrence and bleeding

Take home messages

VTE: A major public health problem

Cohen AT, et al. (VITAE). Thromb Haemost 2007; 98:756–

764.

* Extrapolated from data from six EU countries:

France, Germany, Italy, Spain, Sweden and UK.

AIDS = acquired immunodeficiency syndrome;

VTE = venous thromboembolism.

12% of the

cumulative

mortality in EU*

TVP distale

Venous thromboembolism (VTE) = deep vein thrombosis (DVT) and/or pulmonary embolism

(PE)

TVP proximale Proximal DVT

La thrombose se situe au niveau des veines fémorales, iliaques,

pevliennes et veine cave inférieure

Maladie Thromboembolique Veineuse

Définitions

Embolie PulmonaireLa thrombose se situe au niveau

des arteres pulmonaires

70% des patients ont TVP + EP30% ont seulement une EP

THROMBOSIS

A multifactorial disease

VTE is a multifactorial and often

silent disease

Hypertension

Diabetes

Smoking

Age

PregnancyCancer

Antiphospholipids

Congenital

Thrombophilia

HIT

Acute

infection

Hyperlipidaemia

Others

Natural history of VTE without treatment

Kearon C,Semin Vasc Med 2001;1:2737

Buller et al. J Thromb Haemost 2005; 3: 1554–60

DVT = deep vein thrombosis;

PE = pulmonary embolism; VTE = venous thromboembolism.

In-hospital mortality

•20% in patients with PE

•3% in patients with DVT

1-year mortality

•39% in patients with initial PE

•21% in patients with DVT

The anticoagulant treatment reduces the

incidence of recurrent disease from 25% to 3%

during the first 6–12 months of therapy.

Phases and aims

of the anticoagulant treatment in VTE

Acute phase

Ris

k o

f re

cu

rre

nt

VTE

Start of active treatmentand secondary prevention

Completion of active treatment

Time since starting treatment

About 3 months

Treatment at the acute

phase of thrombosis

Improvement of acute symptoms

Prevention of thrombus extension

Reduction of the risk of early PE

Prevention of new episodes

of VTE that do not arise

directly from the acute

episode of thrombosis

Secondary prevention

Kearon C. J Thromb Haemost 2012; 10: 507–11.

Acute phase

D2 D3 D4 D5

INR: 2 - 3

Dx Dy 1/week to 1 month

VKA

UFH*, LMWH*, Fondaparinux

Platelet Number* D3* D5*

Classic protocol for VTE treatment

Monotherapy of VTE treatment

Acute phase

Rivaroxaban 15 mg bid x 3 weeks


Rivaroxaban 20 mg o.d.


Apixaban 10 mg bid x 5 days Apixaban 5 mg bid

Acute phase

LMWH, fondaparinux at

therapeutic dose s.c. x 5 days


Dabigatran 150 mg qd p.o.

or 110 mg bid p.o.

Dual therapy for VTE treatment

Principle of the diagnostic algorithm for VTE

(PE/DVT)

Tapson et al NEJM 2008

CUS or MDCTA

D-dimer

Low or intermediate High

Prior Clinical Probability

Below cutoff Above cutoff

Negative Positive

No Rx Rx

D-Dimers

Righini M et al. J Thromb Haemost. 2008; 6:1059-71CUS : Compression UltraSongography

MDCTA: Multidetector Computed Tomographic Angiography

*i.e. Wells score

Diagnosis of VTE in pregnancy

Geer I et al Royal College of Obstetricians and

Gynaecologists Recommendations 2015

CTPA: computed tomography pulmonary

angiogram

Clinical prediction rules used in the non-pregnant population, are not

validated for use in pregnancy

Measurement of D-dimer in pregnancy is not recommended

All pregnant women with suspected pulmonary embolism should

undergo bilateral duplex ultrasound scanning of the lower limbs prior to

any objective testing for pulmonary embolism

if a DVT is detected on ultrasound, then it would avoid further testing and

subsequent radiation exposure to both mother and fetus from either V/Q or

CTPA scanning

The choice of whether to proceed with CTPA or V/Q scanning to

investigate suspected pulmonary embolism in the pregnant population

will depend on local guidelines, availability and clinician/patient

preferences

Failure of VTE treatment

Incidence of VTEIncidence of clinically

relevant bleeding

LMWH LMWH/VKA DOAC LMWH LMWH/VKA DOAC

Non

cancer

patients

- 3% 2.5% - 9% 8%

Cancer

patients9% 20% 2.5%* 8% 10% 8%*

EINSTEIN DVT/PE, RECOVER, AMPLIFY

Lee AY. Hematology Am Soc Hematol Educ Program 2010:144-9

Prandoni P et al. Ann Intern Med 2002;137:955-60

Kearon C. Circulation 2003;107(23 Suppl 1):I22-30

Lee AY et al. N Engl J Med, 2003;349:146

Lee et al. JAMA 2015;314:677-686

Gerotziafas et al Ther Clin Risk Manag. 2014 Jun 13;10:423-36.

*data from small subgroup analysis

VKA initiation Early (D1) Delayed (D5) RR (CI95%)

VTE recurrence 3.4% 4.1% 0.83 (0.4-1.7)

Major bleeding 4.3% 3.0% 1.48 (0.7-3.2)

Mortality 3.4% 3.8% 0.9 (0.4-1.9)

Risk of bleeding and recurrence of

VTE at the acute phase

Early initiation: at least 5 days of parenteral treatment

Delayed initiation: at least 10 days of parenteral treatment

DOAC initiation

VTE recurrence 2%

Major bleeding 3%

C Kearon 2010

edoxaban Thrombus Reduction

Imaging Study, eTRIS Protocole

edoxaban 90 mg/day for 10 and then 60 mg/day (n=56)

LMWH/VKAfor 3 months (n=29)

End-point

MRV-quantified thrombus volume from baseline to Day 14-21

MRV: magnetic resonance venography

edoxaban LMWH/VKA p

Mean relative change in MRV-

quantified thrombus volume (D0-

D14/21)

-50% -59% >0.05

thrombus extension 14% 0 >0.05

Recurrent VTE 3.6% 3.6% >0.05

clinically relevant non-major bleeding 5.4% 7.1% >0.05

Piazza et al Vasc Med 2016

Inhibition of TG in patients treated

with VKA and LMWH

anti-Xa IU/ml

1,41,21,0,8,6,4,20,0

ET

P (

nMxm

in)

3000

2750

2500

2250

2000

1750

1500

1250

1000

750

500

250

0

-250

CLASINR

INR>5

3<1NR<5

2<INR<3

INR<2

!!!

Gerotziafas et al Thromb Haemost. 2009;102:42-8.

ETP (

nm

xm

in)

INR

0

200

400

600

800

1000

1200

1400

1600

1800

2000

0 1 2 3 4 5 6 7 8 9 10

Gerotziafas et al Thromb Haemost. 2009;102:42-8.

Pharmacodynamics and pharmacokinetics of

rivaroxaban (20 mg o.d.) in patients treated for

secondary prevention of VTE

anti-Xa activity assay Thrombin generation assay

Gerotziafas et al 2016

n=84 pts with VTE

Follow up = 12 months

Rivaroxaban 20 mg od for secondary prevention of VTE

Risk of Recurrent Venous Thromboembolism and

Major Haemorrhage in

Cancer-Associated Thrombosis

Incidental PE in Cancer patients (3,1%) conveys the same recurrence risk as symptomatic PE. LMWH=VKA (effectiveness). LMWH was safer than VKA (patients with high bleeding risk not excluded). Recurrence risk of Subsegmental incidental PE=other localisations incidental PE

Van Hulle T et al JTH. 2015 Oct 15. doi: 10.1111/jth.13172.

Pooled analysis of 926 patients

Failure of standard dose of enoxaparin to iacheive

predictable inhibition of thrombin generation in

patients with lung adenocarcinoma

*expressed as a pecentage of MRI values compared to T1,

Papageorgiou et al Thromb Res 2013;132: 584–591

0

1

2

3

4

5

6

>60 30 - 60 <30

od

ds

ratio

Creatinine clearance (ml/min)

fatal PE fatal bleeding

Renal failure and the risk of

fatal PE or fatal bleeding

ICTHIC Bergamo April 2016

Phase III VTE_EXT trials – recurrent VTE

95% CI: * 0.78–2.64.FUP = follow-up; HR = hazard ratio; NNT = number needed to treat; NOAC = novel oral anticoagulants

1. Einstein Investigators. NEJM. 2010; 363:2499–2510; 2. Agnelli G, et al. NEJM. 2013; 368:699–708; 3. Schulman S, et al. NEJM. 2013; 368:709–718.

HR 0.19

NNT 14HR 0.20

NNT 14

HR 1.44*

HR 0.08

HR 0.61

rivaroxaban

apixaban dabigatran

Phase III VTE_EXT trials – Major bleeding

95% CI: * 0.09–2.64; ** 0.03–2.24; *** 0.27–1.02; P = 0.06.

HR = hazard ratio; NOAC = novel oral anticoagulants;

RR = risk reduction.

RR = 0.49* RR = 0.25**

HR = 0.52***

P = 1.0

1. Einstein Investigators. NEJM 2010; 363:2499–2510;

2. Agnelli G, et al. NEJM 2013; 368:699–708;

3. Schulman S, et al. NEJM 2013; 368:709–718.

rivaroxaban apixaban dabigatran

A paradigm of benefit/risk balance in the secondary

prevention of VTE

EINSTEIN DVT/PE trial

EINSTEIN DVT

efficacy

Enoxaparin/VKA

(n=1,711)

Rivaroxaban

(n=1,718)EINSTEIN DVT

safety

Cu

mu

lativ

e e

ve

nt

rate

(%

)

Time to event (days)

EINSTEIN PE

efficacy

Time to event (days)

EINSTEIN PE

safety

A paradigm of benefit/risk balance in the secondary prevention of VTE

EINSTEIN DVT/PE trial

Agnelli G et al. N Engl J Med 2013;369:799-808

AMPLIFY trial

apixaban for the treatment of VTE

efficacy

safety

Extension of anticoagulant

treatment beyond 3 to 6 months

for VTE

Death by

PE recurrence80 VTE recurrences

Case-fatality rate 4–12%

3–10 deaths

Death by

major bleed20–60 bleeds

Case-fatality rate 10%

2–6 deaths

For 100 patient-years

PE = pulmonary embolism; VTE = venous thromboembolism.Douketis JD, et al. Ann Intern Med. 2007; 147:766–774;Linkins LA, et al. Ann Intern Med. 2003; 139:893–900.

The clinical course of 1,626 patients

with DVT and/or PE

DVT = deep vein thrombosis; PE = pulmonary embolism;


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

0 12 24 36 48 60 72 84 96 108 120

1,626 1,300 1,049 800 579 352 244 188 131 94

Time (months)Patients at risk

50

40

30

20

10

0

Cu

mu

lati

ve

% o

f V

TE

re

cu

rre

nc

e

Adjusted HR = 2.30

(95% CI: 1.82–2.90)

The clinical course of 1,626 patients

with DVT and/or PE

CI = confidence interval; DVT = deep vein thrombosis; HR = hazard ratio;

PE = pulmonary embolism; VTE = venous thromboembolism. Prandoni P, et al. Haematologica 2007; 92:199–205.

0 20 40 60 80 100 120

VTEidiopathic

secondary

Time (months)

60

50

40

30

20

10

0

Cu

mu

lati

ve

% o

f V

TE

re

cu

rre

nc

e

ICS International Angiology 2013

Risk of recurrence of VTE after

treatment interruption according

to the nature of the risk factor

Risk of recurrent VTE in relation to

the presence of known risk factors

Risk factors Increase of the Relative Risk

Active cancer >6

Homozygous mutation of FV Leiden 4

Hereditary deficiency of AT 3

Homozygous mutation of FIIG20210A 2-4

Mixed thrombophilia 4

Heterozygous FIIG20210A + Heterozygous FV

Leiden

2-5

Increased Ddimers after treatment interruption (>

500 ng / ml)

5

Increased Thrombin Generation (CAT) 2-4

Significant residual clot after DVT 2-5

Antiphospholipide syndrome 3

Permanent risk factor >2

High risk or recurrence

Risk of recidivant VTE in relation to

the presence of known risk factors

Risk factors Increase of the

Relative Risk

Heterozygous mutation of FV Leiden 1-2

Hereditary deficiency of protein C 1.5-2

Heterozygous mutation FIIG20210A 1-2

Protein S deficiency 1.5

BMI> 30 1.9

FVIII> 150 UI / dL 1.3

Age : 11.1 increase of the risk for every 10 ys 1.1

Immobilisation 0.9

Transient risk factor <0.5

Low risk or recurrence

ICS International Angiology 2013

Recommendations from the

International Consensus Statement

DULCIS: D-dimer and residual thrombosis to

guide the duration of anticoagulation in

patients with VTE

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

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

Proximal DVT*

3–12 months VKA

Popliteal/femoral CUS

RVT Recanalisation

D-dimer

Continuing VKA up to

a maximum of 1 yearNegativePositive

Stop VKA

Repeat DD 5 times in 3 months

NegativePositive

No VKAResuming VKA

Continuing VKA

* In patients with isolated PE, proceed directly with D-dimer.

CUS = compression ultrasonography; DD = D-dimer; DVT =

deep vein thrombosis; RVT = recurrent venous thrombosis; VKA

= vitamin K antagonist.

D-dimer and residual thrombosis to guide the

duration of anticoagulation in patients VTE DULCIS

Prevalence of first-time-ever D-dimer result above the

predefined cutoff levels in the investigated study population at

the serial measurement days after VKA withdrawal.


DULCIS: Primary efficacy outcome

Study outcome : confirmed recurrent VTE and death caused by VTE

who refused to resume anticoagulation

anticoagulation was definitively stopped


D-dimer and ULtrasonography in

Combination Italian Study (DULCIS)

Palareti et al Eur Respir J. 2016 Feb 25. pii: ERJ-01126-2015.

Recurrent VTE

Recurent VTE in pts

who stopped AC

and had (-) DDi

Recurent VTE in pts

who stopped AC

and had (+) DDi

Isolated PE 4.8% 11.2%

Models to predict recurrence risk of VTE

* Men continue and HER DOO2 = men and women with ≥ 2 of the following are classified as having a high risk of recurrent VTE:

1. Post-thrombotic signs (any hyperpigmentation, oedema or redness in either leg

2. VIDAS® D-dimer level ≥ 250 μg/L

3. Obesity as defined by a BMI ≥ 30 kg/m2; 4. Age ≥ 65 years

BMI = body-mass index; PTS = post-thrombotic syndrome;


Rodger M, et al. CMAJ 2008; 179:417–426; Kyrle P & Eichinger S, Thromb Haemost 2012; 108:1061–1064;

Tosetto A, et al. J Thromb Haemost 2012; 10:1019–1025Ensor et al Health Technol Assess. 2016;20:1-190.

.

Men continue and HER DOO2

Vienna Prediction Model

DASH score

Author Rodger et al. 2008 Eichinger et al. 2010 Tosetto et al. 2012

Patients, n 646 929 1,818

Design Prospective cohort Prospective cohort Patient-level

meta-analysis

Predictive variables

• Men: none

• Women: age ≥ 65 years, signs of PTS,

• BMI ≥ 30 kg/m2,

• D-dimer ≥ 250 μg/l

during anticoagulation

• Location of first VTE

• D-dimer after anticoagulation

• Abnormal D-dimer after anticoagulation

• Age < 50 years

• Male sex

• Hormonal therapy

Recurrence risk

Low risk

• ≤ 1 point

• 1.6%

• 95% CI: 0.3%–4.6%

• ≤ 180 points (according to normogram)

• 4.4%• 95% CI: 2.7%–6.2%

• ≤ 1 point

• 3.1%

• 95% CI: 2.3–3.9

Take home messages

Tips for the management of VTE at the acute phase

1. Apply Clinical probability Score

2. Measure D-Dimers (ELISA) to identify low probability patients

3. Start AC treatment until objective confirmation of VTE

1. If VTE is excluded : stop the treatment

2. If VTE is confirmed : continue th treatment

Standard period of AC treatment : 3 – 6 months

Attention to special patients (cancer, pregnancy elderly, frigile)

Tips for the definition of the risk of recurrence in patients with VTE and prolongation of AC

1. Carefully evaluate of the presence of triggering risk factors for VTE

2. Do the recommended tests for hereditary and acquired thrombophilia to the suitable

patients

3. Evaluate the residual vein thrombus combined with the levels of D-Dimers one month

after treatment cessation

4. Follow up your patients with idiopathic VTE for one year to verify that a systemic

disease or cancer does not appear

practical applications of biomarkers and risk...

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