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
Secondary prevention
Rivaroxaban 20 mg o.d.
Secondary prevention
Apixaban 10 mg bid x 5 days Apixaban 5 mg bid
Acute phase
LMWH, fondaparinux at
therapeutic dose s.c. x 5 days
Secondary prevention
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;
VTE = venous thromboembolism.
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.
Palareti et al. Blood 2014;124:196-203
DULCIS: Primary efficacy outcome
Study outcome : confirmed recurrent VTE and death caused by VTE
who refused to resume anticoagulation
anticoagulation was definitively stopped
Palareti et al. Blood 2014;124:196-203
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;
VTE = venous thromboembolism.
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
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