anticoagulants et cancer en 2016.

anticoagulants et cancer en 2016. Ludovic Drouet Université Paris VII EA 7334 REMES Centre de Référence et d Education des Antithrombotiques d Ile de France 50 e congrès du CFPV 16 au 18 mars 2016 Maison de la Chimie, 28 bis rue Saint Dominique, 75007 Paris

AC et K en 2016 On vivait sous des recommandations relativement anciennes du traitement AC des patients K Mais c est domaine évolutif Et jusqu à il y a très récemment Florilège de nouvelles recommandations / guidelines / Guidances Arrivée des nouveaux anticoagulants : quelle est leur place Et on commence à mieux comprendre pourquoi l hyperthrombogenicité des K Implications de mécanismes que l on ne soupçonnait pas jusqu à récemment Aidant en plus à comprendre pourquoi les héparines sont plus efficaces que les AVK Pourquoi les AODs ne sont pas forcement efficaces et qu on a besoin de les évaluer spécifiquement dans cette indication Pourquoi être actif sur la thrombose ne se traduit pas forcement en gain sur la mortalité!!

RECOMMANDATIONS

Recommandations recentes pour la MTEV associée au K For long-term anticoagulation, LMWH for at least 6 months is preferred because of improved efficacy over VKAs Evidence: strong Lyman et al. J Clin Oncol. 2013;31:2189-204 LMWHs are preferred over VKA for the early maintenance treatment (10 days to 3 months) and long-term treatment (>3 months) [Grade 1A]. Farge et al. J Thromb Haemost. 2013;11:56 70 In patients with DVT of the leg and cancer, we suggest LMWH over VKA therapy (Grade 2B). Kearon et al. Chest. 2012;141(2)(Suppl):e419S-e494S LMWH=Low-molecular weight heparin; VKA=Vitamin K antagonist; VTE=Venous thromboembolism; DVT=Deep vein thrombosis. 1. Lyman G, et al. J Clin Oncol. 2013;31:2189 204; 2. Farge D, et al. J Thromb Haemost. 2013;11:56 70; 3. Kearon C, et al. Chest. 2012;141(2)(Suppl):e419S e494s.

Comparison of extended (2-6 W) versus conventional (<2 W) thromboprophylaxis. Metaanalysis of all venous thromboembolic events A. Fagarasanu et al Ann Surg Oncol 2016

Comparison of extended (2-6 W) versus conventional (<2 W) thromboprophylaxis. Metaanalysis of all hemorrhagic events A. Fagarasanu et al Ann Surg Oncol 2016

Kearon C et al Antithrombotic Therapy for VTE Disease CHEST Guideline and Expert Panel Report CHEST 2016; 149(2):315-352 3. In patients with DVT of the leg or PE and cancer ( cancer-associated thrombosis ), as long-term (first 3 months) anticoagulant therapy, we suggest LMWH over VKA therapy (Grade 2C), dabigatran (Grade 2C), rivaroxaban (Grade 2C), apixaban (Grade 2C), or edoxaban (Grade 2C). 11. In patients with DVT of the leg or PE and active cancer ( cancer-associated thrombosis ) and who (i) do not have a high bleeding risk, we recommend extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 1B), or (ii) have a high bleeding risk, we suggest extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 2B).

Recommended duration of therapy for malignancyassociated VTE Streiff MG et al Guidance for the treatment of DVT and PE J Thromb Thrombolysis (2016) 41:32 67 Active K is associated with a 4 6 fold increased risk of VTE. This risk is modified by the primary site, type and extent of K and its treatment and concomitant pre-existing risk factors for VTE (e.g. thrombophilia). Patients with active K are at high risk for recurrent VTE as long as the K is present or under active treatment. Therefore, long term anticoagulation is indicated for as long as the K is present or under treatment. A risk model for assessing the risk of recurrent VTE in K patients has recently been developed. Guidance Statement Active K is a potent risk factor for VTE that varies with the type and extent of K and its treatment. Therefore, we suggest anticoagulation be continued as long as the underlying K is active or under treatment.

VTE traditional phases of treatment Streiff MG et al Guidance for the treatment of DVT and PE J Thromb Thrombolysis (2016) 41:32 67

1. What is the appropriate workup to search for occult malignancy in patients with idiopathic VTE? Khorana A et al Guidance for the prevention and treatment of K-associated VTE J Thromb Thrombolysis (2016) 41:81 91 Patients with unprovoked VTE should undergo a through medical history and physical examination, basic laboratory investigations (complete blood counts, metabolic profile and liver function tests) and chestx-ray We suggest that if not up-to-date, patients undergo age- and gender-specific cancer screening (i.e. cervical, breast, prostate and colon)

2. How can high-risk cancer patients be identified for primary thromboprophylaxis(tp)? Khorana A et al Guidance for the prevention and treatment of K-associated VTE J Thromb Thrombolysis (2016) 41:81 91 Recommendations are made assuming no existing contraindications CI to pharmacologic prophylaxis We suggest against routine TP in unselected and low-risk K outpatients. We also suggest against routine TP in patients with high risk for bleeding (e.g. primary brain tumors) We suggest consideration of outpatient TP with LMWH in high-risk (Khorana Score C3 or advanced pancreas) K outpatients receiving chemotherapy and with aspirin or LMWH in patients with myeloma receiving imidbased regimens We suggest routine consideration of inpatient TP with LMWH or UFH in K patients hospitalized with an acute medical illness We suggest inpatient TP with LMWH or UFH in K patients undergoing major surgery, We suggest post-operative TP with LMWH for up to 4 weeks in patients undergoing major abdominal or pelvic surgery for K with high-risk features such as immobility, obesity and history of VTE

3. What is the appropriate immediate and longterm treatment for people with K diagnosed with acute thromboembolism, including the role of DOACs? Khorana A et al Guidance for the prevention and treatment of K-associated VTE J Thromb Thrombolysis (2016) 41:81 91 We suggest that patients with active K (i.e. known disease or receiving some form of antiktherapy) and VTE be treated with LMWH for at least 6 months We suggest that patients with incidentally diagnosed DVT or PE be treated similarly to patients diagnosed with VTE based on symptoms i.e., with at least 6 months of LMWH monotherapy, with the exception of isolated subsegmental PE where decisions can be made on a case-by-case basis. We further suggest that treatment decisions in patients with incidentally diagnosed visceral vein thrombi be made on a case-by-case basis

4. What is the appropriate duration of anticoagulation? Khorana A et al Guidance for the prevention and treatment of K-associated VTE J Thromb Thrombolysis (2016) 41:81 91 Anticoagulation with LMWH monotherapy should be prescribed for a minimum period of 6 m after diagnosis of K- associated VTE. Anticoagulation therapy should be continued beyond 6 m if a patient has active malignancy (i.e. persistent malignant disease) or if ongoing anti K therapy is planned For patients at low risk of recurrence we suggest that anticoagulation be discontinued after 6 m in the absence of active malignancy (i.e. patients are cured or in complete remission), provided that no anti-cancer therapy is ongoing or planned For patients at high risk of recurrence we suggest that anticoagulation be continued but with periodic re-evaluation of risks and benefits

5. What is the appropriate treatment strategy in patients with recurrent VTE on anticoagulation? Khorana A et al Guidance for the prevention and treatment of K-associated VTE J Thromb Thrombolysis (2016) 41:81 91 We suggest that K patients with symptomatic recurrent VTE despite therapeutic anticoagulation with an agent other than LMWH be transitioned to therapeutic LMWH, assuming no contraindications to LMWH We suggest that K patients with symptomatic recurrent VTE despite optimal anticoagulation with LMWH continue with LMWH at a higher dose, starting at an increase of *25 % of the current dose or resuming the therapeutic weight-adjusted dose if the patient was receiving a nontherapeutic dose at the time of recurrence We suggest against the use of IVC filters except in the presence of absolute contraindications to pharmacologic anticoagulation (e.g. active bleeding). If necessary, retrievable filters should be used and a plan created to retrieve the filter when appropriate

Metanalyse AOD ETEV avec ou sans K Larsen TB, et al. PLoS ONE 9(12) December 5, 2014

ETEV /K AOD / AVK HBPM / K Khorana A et al Guidance for the prevention and treatment of K-associated VTE Thrombolysis (2016) 41:81 91 J Thromb

Incidence (% de patients) EINSTEIN TVP et XALIA : Résultats sous Rivaroxaban 3 Caractéristiques 3 * 2 2,1 55,8 Age (années) 57,3 57,4 % Sexe masculin 54,5 % 2 19,4 % ATCD de MTEV 24,1 % 1,4 1 0,8 6,8 % Cancer actif à l inclusion 5,6 % 1 0,7 0 Hémorragie majeure* (14/1 718) Récidive de TVP # (36/1 731) 6,2 % Thrombophilie connue 6,0 % 0 Hémorragie majeure* (19/2 619) Récidive de TVP* (37/2 619) # analyse en intention de traiter; *Population tolérance (patients prenant 1 dose de traitement étudié) Résultats en cours d évaluation par l EMA The EINSTEIN Investigators. N Engl J Med 2010;363:2499 510

Edoxaban / Dalteparine 1000 patients / arm

Streiff MG et al Guidance for the treatment of DVT and PE J Thromb Thrombolysis (2016) 41:32 67

Kearon C et al Antithrombotic Therapy for VTE Disease CHEST Guideline and Expert Panel Report CHEST 2016; 149(2):315-352 3. In patients with DVT of the leg or PE and cancer ( cancer-associated thrombosis ), as long-term (first 3 months) anticoagulant therapy, we suggest LMWH over VKA therapy (Grade 2C), dabigatran (Grade 2C), rivaroxaban (Grade 2C), apixaban (Grade 2C), or edoxaban (Grade 2C). 11. In patients with DVT of the leg or PE and active cancer ( cancer-associated thrombosis ) and who (i) do not have a high bleeding risk, we recommend extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 1B), or (ii) have a high bleeding risk, we suggest extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 2B).

Similar femoral vein But completely different thrombus

Demers M et Wagner DD. NETosis: a new factor in tumor progression and cancerassociated thrombosis Semin Thromb Hemost. 2014 April ; 40(3): 277 283

Thålin C et al, NETosis promotes cancerassociated arterial microthrombosis presenting as ischemic stroke with troponin elevation Thrombosis Research 139

l héparine non anticoagulante prévient in vitro la cytotoxicité induite par les histones et améliore la survie dans le sepsis Wildhagen KCAA et al Blood. 2014;123(7):1098-1101

l héparine non anticoagulante prévient in vitro la cytotoxicité induite par les histones et améliore la survie dans le sepsis Wildhagen KCAA et al Blood. 2014;123(7):1098-110 AADH histones ConA control CPL LPS

. The effect of LMWH on survival in K patients Sanford D, et al. J Thromb Haemost 2014; 12: 1076 85

Akl E A et al Cochrane Database of Systematic Reviews 2014, Issue 12.