J.C. WAUTRECHT Service de Pathologie Vasculaire , Hôpital ERASME

Université Libre de Bruxelles

CARDIO ‘016LIGUE

CARDIOLOGIQUEBELGEASBL

THE HOTEL BRUSSELS

21 MAI 2016

VEINES

§  Traitement de la TVP §  Traitement de l’IVC MI §  Bas de compression

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VEINES

§  Traitement de la TVP §  Traitement de l’IVC MI §  Bas de compression

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VTE : quelques données…

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and PE, the limitations of administrative databases, andthe regional and racial specifıcity of community-basedstudies, VTE may be vastly under-reported.12,13

Morbidity and MortalityVenous thromboembolism is often fatal. Depending oncase ascertainment and the use of autopsy data, studiesestimate that 10%–30% of all patients suffer mortalitywithin 30 days; the majority of deaths occur among thosewith PE, as an estimated 20%–25% of all PE cases presentas sudden death.6,8–10 Other serious complications ofDVT and PE include increased risks of recurrent throm-boembolism and chronic morbidity (e.g., venous insuffı-ciency, pulmonary hypertension). Following a standardcourse of anticoagulant therapy, about one third of allVTE patients experience a recurrencewithin 10 years of theinitial event, with the highest risk occurring within the fırstyear, yet they remain at risk throughout their lives.6,14 Onethird to one half of lower-extremity DVT patients developpost-thrombotic syndrome and chronic venous insuffı-ciency, lifelong conditions characterized by pain, swelling,skin necrosis, and ulceration.6,15

Quality of life has been reported to be adversely af-fected up to 4 months after DVT, and for those withpost-thrombotic syndrome, quality of life actually de-clines further during this period, with changes similar tothose seen in individuals with chronic heart, lung, orarthritic disease.15 In addition, subsets of VTE patientsrequire long-term anticoagulation to prevent additional

clots, which also decreases quality of life and places themat an increased risk for adverse bleeding episodes.

Economic BurdenVenous thromboembolism is complex and presents inboth inpatient and outpatient settings, and although manycases have been attributed to hospitalization, about twothirds of cases occur in outpatients.16 Although data arelacking on the exact cost attributed toVTE, a recent analysisof healthcare claims estimated that the total annual health-care cost for VTE ranges from $7594 to $16,644 per pa-tient.17 With estimates of 300,000–600,000 incident casesper year, this cost equates to a total annual cost of $2 billionto $10 billion attributable to VTE.

Etiology and Risk FactorsThe etiology of VTE is not fully understood. It is a multi-factorial condition involving genetic and both constantand transient acquired risk factors (Table 2). A thresholdseems to exist, as the presence of one risk factor does notalways result in disease status; however, an interactiveeffect of multiple triggers and events can lead to clotformation. Yet, in about 50% of cases there is no acquiredrisk factor identifıed (idiopathic), and in 10%–20% there isno acquired or genetic risk identifıed, signifying the effect ofstill unknown genetic and/or acquired risk factors.12,13,18

Known acquired risks include chronic disease, can-cer, obesity, antiphospholipid antibodies, and advancedage.6,9,11,19–21 Other acquired risks can be thought of astransient states, which include surgery, trauma, immobi-lization, infection, and hospitalization.6,8,19–21 Womenalso have increased risk during pregnancy and the post-partumperiod andwhile taking hormonal contraceptivesand hormone replacement therapy.11,22–25 Hospitaliza-tion is an especially important risk factor as it provides aunique period in which multiple risk factors may be

Table 2. Identified risk factors for venousthromboembolism

Genetic Acquired Transient acquired

Family history Advanced age Pregnancy

Factor V Leiden Antiphospholipidantibodies

Oral contraceptives

ProthrombinG20210A

Cancer Hormone therapy

Protein C deficiency Chronic disease Hospitalization

Protein S deficiency Obesity Surgery

Antithrombindeficiency

— Trauma

Sickle cell trait — Immobilization

Table 1. Estimated incidence of venousthromboembolism by age, race, and gender

Characteristics Annual incidence per 1000

Race/ethnicity

White 1.173

Black 0.776–1.415

Asian 0.297

Hispanic 0.617

Age (years)

!15 !0.53,8

15–44 1.493

45–79 1.929

!80 5–63,4,8,9

Gender

Male 1.33

Female 1.13

Overall 1–23–5

S496 Beckman et al / Am J Prev Med 2010;38(4S):S495–S501

www.ajpm-online.net

and PE, the limitations of administrative databases, andthe regional and racial specifıcity of community-basedstudies, VTE may be vastly under-reported.12,13

Morbidity and MortalityVenous thromboembolism is often fatal. Depending oncase ascertainment and the use of autopsy data, studiesestimate that 10%–30% of all patients suffer mortalitywithin 30 days; the majority of deaths occur among thosewith PE, as an estimated 20%–25% of all PE cases presentas sudden death.6,8–10 Other serious complications ofDVT and PE include increased risks of recurrent throm-boembolism and chronic morbidity (e.g., venous insuffı-ciency, pulmonary hypertension). Following a standardcourse of anticoagulant therapy, about one third of allVTE patients experience a recurrencewithin 10 years of theinitial event, with the highest risk occurring within the fırstyear, yet they remain at risk throughout their lives.6,14 Onethird to one half of lower-extremity DVT patients developpost-thrombotic syndrome and chronic venous insuffı-ciency, lifelong conditions characterized by pain, swelling,skin necrosis, and ulceration.6,15

Quality of life has been reported to be adversely af-fected up to 4 months after DVT, and for those withpost-thrombotic syndrome, quality of life actually de-clines further during this period, with changes similar tothose seen in individuals with chronic heart, lung, orarthritic disease.15 In addition, subsets of VTE patientsrequire long-term anticoagulation to prevent additional

clots, which also decreases quality of life and places themat an increased risk for adverse bleeding episodes.

Economic BurdenVenous thromboembolism is complex and presents inboth inpatient and outpatient settings, and although manycases have been attributed to hospitalization, about twothirds of cases occur in outpatients.16 Although data arelacking on the exact cost attributed toVTE, a recent analysisof healthcare claims estimated that the total annual health-care cost for VTE ranges from $7594 to $16,644 per pa-tient.17 With estimates of 300,000–600,000 incident casesper year, this cost equates to a total annual cost of $2 billionto $10 billion attributable to VTE.

Etiology and Risk FactorsThe etiology of VTE is not fully understood. It is a multi-factorial condition involving genetic and both constantand transient acquired risk factors (Table 2). A thresholdseems to exist, as the presence of one risk factor does notalways result in disease status; however, an interactiveeffect of multiple triggers and events can lead to clotformation. Yet, in about 50% of cases there is no acquiredrisk factor identifıed (idiopathic), and in 10%–20% there isno acquired or genetic risk identifıed, signifying the effect ofstill unknown genetic and/or acquired risk factors.12,13,18Known acquired risks include chronic disease, can-

cer, obesity, antiphospholipid antibodies, and advancedage.6,9,11,19–21 Other acquired risks can be thought of astransient states, which include surgery, trauma, immobi-lization, infection, and hospitalization.6,8,19–21 Womenalso have increased risk during pregnancy and the post-partumperiod andwhile taking hormonal contraceptivesand hormone replacement therapy.11,22–25 Hospitaliza-tion is an especially important risk factor as it provides aunique period in which multiple risk factors may be

Table 2. Identified risk factors for venousthromboembolism

Genetic Acquired Transient acquired

Family history Advanced age Pregnancy

Factor V Leiden Antiphospholipidantibodies

Oral contraceptives

ProthrombinG20210A

Cancer Hormone therapy

Protein C deficiency Chronic disease Hospitalization

Protein S deficiency Obesity Surgery

Antithrombindeficiency

— Trauma

Sickle cell trait — Immobilization

Table 1. Estimated incidence of venousthromboembolism by age, race, and gender

Characteristics Annual incidence per 1000

Race/ethnicity

White 1.173

Black 0.776–1.415

Asian 0.297

Hispanic 0.617

Age (years)

!15 !0.53,8

15–44 1.493

45–79 1.929

!80 5–63,4,8,9

Gender

Male 1.33

Female 1.13

Overall 1–23–5

S496 Beckman et al / Am J Prev Med 2010;38(4S):S495–S501

www.ajpm-online.net

MG  Beckman  et  al.  Am  J  Prev  Med  2010;38:S495-­‐S501  

CONCEPT ACTUEL DE L ’ANTICOAGULATION SI TVP/EP

§  Traitement initial (anticoagulation rapide)

§  HBPM puis AOD (Dabigatran, Edoxaban) §  AODs seuls (Rivaroxaban, Apixaban)

§  Traitement prolongé (extended treatment) §  Minimum 3 mois

§  Traitement au long cours (long term treatment) §  Au-delà de 3 à 12 mois

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INCIDENCE CUMULÉE DE RÉCIDIVES DE VTE APRÈS ARRÊT DES ANTICOAGULANTS

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

FU  moyen  de  50  mois  de  1626  pa3ents  consécu3fs  avec  EP  ou  TVP  proximale  

TAUX CUMULÉ DE RÉCIDIVES DE VTE (TVP/EP) APRÈS ARRÊT DES ANTICOAGULANTS

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OPTIMEV.  Galanaud  JP  et  al.  J  Thromb  Haem  2014;12:436-­‐443  

TVP  prox  n=  259  TVP  dist  isolées  n=  490  

ACUTE AND EXTENDED (LONG-TERM) TREATMENT OF VTE

31/05/16 8 Adapted  from  P  Fontana  et  al.  Eur  Heart  J  2014;35:1836-­‐1843  

Dabigatran              LMWH  >  150  mg  bid                                                    150  mg  bid      Edoxaban                  LMWH  >  60  or  30  mg  od  

Rivaroxaban                15  mg  bid  21  days  >  20  mg  od                        20  mg  od  Apixaban                          10  mg  bid    7  days  >  5  mg  bid                              5  or  2.5  mg  bid                                                      

(vs  warfarin)  (vs  placebo)  

(vs  placebo)    

TRAITEMENT DE LA TVP/EP AVEC LES AODS (NOACS)

§  Apixaban (Eliquis®) §  Aigu : 2 x 10 mg /j (comp à 5 mg) pendant 7 jours §  Entretien : 2 X 5 mg/j 6 mois et si plus longtemps : 2 x 2,5 mg/j §  Précautions si Clearance créat 15-29 ml/min §  CI si Clearance créat < 15 ml/min

§  Dabigatran (Pradaxa®) §  Aigu : HBPM min 5 j puis 150 mg 2x/j §  Entretien : 2 x 150 mg/j §  Adaptation à 2 x 110 mg/j si ≥ 80 ans et/ou vérapamil et/ou risque

hémorragique individuel accru §  CI si Clearance créat < 30 ml/min

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TRAITEMENT DE LA TVP/EP AVEC LES AODS (NOACS)

§  Edoxaban (Lixiana®) : prévu septembre 2016 §  Aigu : HBPM min 5 j puis 60 mg/j §  Entretien : 60 mg/j §  Adaptation à 30 mg/j si Clearance créat 30-59 ml/min et/ou ≤ 60

kg §  Rivaroxaban (Xarelto®)

§  Aigu : 2 x 15 mg/j pendant 21 jours §  Entretien : 20 mg/j §  Prudence si Clearance créat 15-29 ml/min §  CI si clearance créat< 15 ml/min

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ELIQUIS® TVP ET EP

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XARELTO® TVP

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XARELTO EP

(glissé(e)s).pdf

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PRADAXA TVP

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PRADAXA EP

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LONG COURS : POSSIBILITE DE DIMINUER DOSES ? EINSTEIN CHOICE STUDY : CRITÈRES D’ INCLUSION

§  Patients ayant reçu un traitement anticoagulant de 6 à 12 mois (± 1 mois) et n’ayant pas interrompu leur traitement pendant plus d’une semaine

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EINSTEIN CHOICE STUDY

§  Etude multicentrique, en double-aveugle, en double insu, randomisée, guidée par les événements et contrôlée par comparateur actif

§  Randomisation : système réponse vocale automatique (IVRS) ou réponse web interactif (IWR)

§  Traitement pendant 12 mois §  10 mg Rivaroxaban OU §  20 mg Rivaroxaban OU §  100 mg ASA

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VEINES

§  Traitement de la TVP §  Traitement de l’IVC MI §  Bas de compression

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SUMMARY OF THE 2014 GUIDELINE RECOMMENDATIONS FOR THE USE OF VENO-ACTIVE DRUGS

Indication   Veno-active drug   Recommendation for use  

Quality of evidence   Grade  

Relief of symptoms associated with CVD (CEAP C0s to C6s) and those with venous edema (CEAP C3)  

MPFF  Nonmicronized diosmins or synthetic diosmins   Rutosides  Red-vine-leaf extracts  Calcium dobesilate  Horse chestnut seed extract  Ruscus extracts  Gingko biloba  Other veno-active drugs  

Strong  Weak  

   

Weak  Weak  Weak  Weak  Weak  Weak Weak  

Moderate  Poor  

   

Moderate  Moderate  Moderate  Moderate  Moderate  

Poor Poor  

1B  2C      

2B  2B  2B  2B  2B  2C 2C  

Healing of primary venous ulcer (CEAP C6), as an adjunct to comprehensive and local therapy  

MPFF   Strong   Moderate   1B  

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  CEAP  :  clinical,  etiological,  anatomical,  and  pathophysiological  classi7ication MPFF  :  micronized  puri7ied  7lavonoid  fraction

Int  Angiol  2014;33:126-­‐139  

VEINES

§  Traitement de la TVP §  Traitement de l’IVC MI §  Bas de compression

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POST THROMBOTIC SYNDROME (PTS)

§  PTS develops in 20 to 50 % of patients with DVT, even when appropriate anticoagulant therapy is prescribed.

§  PTS is the single most frequent complication of DVT. §  PTS is burdensome and potentially debilitating to patients. §  PTS has been shown to have significant, adverse effects

on quality of life and productivity, and is costly as measured by health resource utilization, directs costs, and indirect costs.

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SR  Kahn,  Blood  2009;114:4624-­‐4631  

POST THROMBOTIC SYNDROME (PTS)

§  « Syndrome » because various symptoms and clinical signs – PTS is a clinical diagnosis

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SR  Kahn,  Blood  2009;114:4624-­‐4631  

POST THROMBOTIC SYNDROME (PTS)

31/05/16 24 SR  Kahn,  Blood  2009;114:4624-­‐4631  

POST THROMBOTIC SYNDROME (PTS)

§  Risk factors §  Higher BMI §  No relationship between age, sex or thrombophilia and the

development of PTS §  No clear greater risk for proximal over distal DVT §  Strong association when ipsilateral recurrent DVT §  Role of venous reflux due to valvular incompetence and venous

hypertension due to thrombotic occlusion §  Persistent D-dimer level could be a predictor of PTS

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W  Ageno  et  al.  Thromb  Haemost  2003;89:305-­‐309  L  Spieza  et  al.  J  Thromb  Haemost  2010;8:211-­‐213  J  Latella  et  al.  J  Thromb  Haemost  2010;8:2169-­‐2175  

PREVENTION OF POST THROMBOTIC SYNDROME (PTS) WALKING

§  Several small studies and meta-analyses have shown that early ambulation does not increase the risk of recurrent or fatal PE

§  The risk of PE during more aggressive forms of exercise, physical therapy, or rehabilitation is unknown

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N  Aissaoui  et  al.  Int  J  Cardiol  2009;137;37-­‐41  

PREVENTION OF POST THROMBOTIC SYNDROME (PTS) COMPRESSION STOCKINGS

§  Evidence supporting the use of GCS for the prevention of PTS is conflicting.

§  3 small randomized trials of patients with acute proximal DVT that used the Villalta criteria for PTS suggested that GCS that apply an ankle pressure of 30 to 40 mm Hg started within 2 weeks and continued for 2 years reduced the risk of PTS by 50 %

§  Compliance was up to 90 %

§  A recent randomized placebo-controlled trial of 806 patients with a proximal DVT using the less stringent Ginsberg criteria reported no difference in the rate of PTS with GCS (14 vs 13 %). A similar lack of benefit was reported when the more rigorous Villalta criteria were applied.

§  Compliance was lower than in the 3 other studies : only 55.6 % of patients used GCS for 3 or more days a week after 2 years.

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DPM  Brandjes  et  al.  Lancet  1997;349:759-­‐762;JS  Ginsberg  et  al.  Arch  Intern  Med  2001;161:2105-­‐2109;  P  Prandoni  et  al.  Ann  Intern  Med  2004;141:249-­‐256    

RS  Kahn  et  al.  Lancet  2014;383:880-­‐888  

PTS AND GCS : META-ANALYSIS

31/05/16 28 AL  Skervin  et  al.,    Eur  J  Vasc  Endovasc  Surg  2016    h\p://dx.doi.org/10.1016/j.ejvs.2016.02.022  

TAKE HOME MESSAGE FOR THE DOCTOR PREVENTION OF PTS TODAY : COMPRESSION OR NOT ?

§  The role of compression stockings following DVT remains uncertain, with further evidence needed

§  It is presently reasonable to prescribe below-knee GCS with 30 to 40 mm Hg pressure to patients who have residual leg pain or swelling after proximal or distal DVT if they have benefit and if they are able to tolerate them.

§  GCS should be started after initiation of anticoagulant therapy, within 2 weeks of the diagnosis, during the day and for at least 2 years.

§  A multicentre randomised trial comparing usual care (ECS for 2 years) with individualised care based on Villalta scores is in progress (ClinicalTrials.gov, NCT01429714). This future study will hopefully give additional information on some open questions: is there any benefit of treatment with GCS, which patients benefit most, and what is the optimum treatment duration?

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TAKE HOME MESSAGE FOR THE PATIENT ABOUT COMPRESSION STOCKINGS

31/05/16 30 SR  Vazquez,SR  Kahn.  Circula`on  2010;121:e217-­‐e219