VENOUS THROMBOEMBOLISM, CANCER AND CKD ANOTHER TRIAD TO MANAGE

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1 VENOUS THROMBOEMBOLISM, CANCER AND CKD ANOTHER TRIAD TO MANAGE I. ELALAMY Service d Hématologie Biologique HOPITAL TENON PARIS INSERM UMR U938

2 DISCLOSURES Conferences Clinical Studies Board Sanofi X X X Boehringer-Ingelheim X X Pfizer Bristol Myers Squibb X X X Bayer HealthCare X X X Leo-Pharma X X X

3 AGENDA 1. Cancer an acquired hypercoagulable state with multicellular interactions? 2. CKD a worse prognosis factor : vulnerable status? 3. Heparin heterogeneity : structure-activity relationship? 4. The optimal choice for clinical benefit : which one?

4 COMPLEX INTERACTIONS CANCER VASCULAR COMPARTMENT «Numerous Comorbidities» Gay et al Nat Rev Cancer 2011; 11: «Caution Care Cancer!»

5 TRIAD MAD TO MANAGE VTE and Cancer : worse prognosis and reduced survival CKD and Cancer : worse prognosis and reduced survival VTE and CKD : worse prognosis and reduced survival Cancer VTE CKD Arora et al Sem Thromb Haemost 2014; 40: TRIAD = MAFIA

6 CANCER ASSOCIATED-THROMBOSIS (CAT) AND CKD 1684 patients withvte and cancer (RIETE + Leiden) : 55% 19% 17% 9% KooimanJ et al J ThrombHaemost2013

7 CANCER ASSOCIATED-RENAL IMPAIRMENT 50% of cancer patients present a renal insufficiency 80% of cancer patients receive various treatments with potential nephrotoxicity => risk of antithrombotics accumulation => risk of bleeding F. Scotté et al, Support Care Cancer 2012 I Elalamy et al J Blood Disorders Transf 2014

8 Hunt N Engl J Med 2014; 370:

9 RENAL IMPAIRMENT AND THROMBOTIC RISK MEGA study N=2473 TVP N=2936 Témoins Ocak et al Circulation 2014; 129:

10 Bleeding Reduced Platelets Platelet dysfunction Granular Secretion Uremic Toxins Oxidative Stress PAL CD18 CD11b βtg TxA2 CD62-P sérotonine NO PGI2 MPO Elastase FVIII FW Thrombosis Fibrinolysis Inflammation Uremic Toxins Free Radicals

11 Thromb Haemost 2012 Renal Impairment Cancer = independent Risk Factors

12 VKA AND RENAL IMPAIRMENT : RISKY OPTION Limdi NA et al., J Am Soc Nephrol 2009

13 VKA AND RENAL IMPAIRMENT : RISKY OPTION Deaths per 100 pts.year from Stroke : Warfarin users 1.3 vs Non users 0.4 (n=746) (n=925) HR 4.31 ( )

14 HEPARINS STRUCTURE-ACTIVITY RELATIONSHIP 30% 30% Lai & Coppola Kidney International (2013) 84,

15 LMWH HETEROGENEITY Heparin Mean MW (Da) Anti-Xa/ anti-iia Anti-Xa activity/mg UFH UI Tinzaparin IU Dalteparin IU Enoxaparin IU Nadroparin IU Reviparin IU Bemiparin IU European Pharmacopoeia 2010

16 LMWH AND CAT IN RENAL IMPAIRMENT PATIENTS A SENSITIVE CHOICE 1. Better than VKA 2. Similar to VKA 3. Better than UFH 4. Similar to UFH

17 BEST ANTITHROMBOTIC OPTION Recurrent VTE Major Bleeding Akl et al Cochrane Database Syst Rev 2014; 7:CD

18 LMWH CLINICAL BENEFIT FOR VTE MANAGEMENT (RIETE REGISTRY) N= with 12% moderate RI and 6% severe RI Fatal PE at D15 Major Bleeding at D15 LMWH UFH Trujillo Santos et al, Am J Med 2013 ; 126 :

19 Lyman et al J Clin Oncol 2013; 31:

20 HEPARIN POLYSACCHARIDE CHAINS CLEARANCE UFH LMWH PentaS Reticuloendothelial system Kidney Long chains anti-xa & anti-iia Short chains Only anti-xa Holbrook A et al. Chest 2012; 141(2 Suppl): e152s-e184s)

21 PROPHYLAXIS AND VULNERABLE PATIENTS 8 days Mahé I et al. Thromb Haemost 2007 ; 97 :

22 PROPHYLAXIS AND VULNERABLE PATIENTS Mahé I et al. Thromb Haemost 2007; 97:

23 TINZAPARIN AND VULNERABLE PATIENTS No accumulation of Tinzaparin was observed (Anti-Xa and Anti-IIa) N=30 pts (6M/24W), Tinzaparin 175 UI/kg during 10 days, 62.7 ± 14.6 kg (38-90) Mean age 87±5.9 yo (71-96) Clcr impaired 40.6 ± 15.3 ml/min (20-72) Siguret et al. Thromb Haemost 2000; 25 :

24 TINZAPARIN AND VULNERABLE PATIENTS N=200 patients 175 UI/kg # 1 month, Mean age 85,2 ± 6,9 yo Clcr 51,2 ± 22,9 ml/min 25% pts: Clcr ml/min Mean body weight 58 ± 14 kg No accumulation of Tinzaparin was observed (Anti-Xa and Anti-IIa) Only one fatal bleeding (0.5% - co-morbidities+++) Pautas E et al. Drug Saf 2002 ; 25 :

25 CURATIVE ENOXAPARIN AND VULNERABLE PATIENTS 100 UI/kg 2x/d DeCarolis D et al Arch Intern Med 2012 ; 172 (22) :

26 CURATIVE ENOXAPARIN AND VULNERABLE PATIENTS MAJOR BLEEDING 6/105 pts (5.7%) if Clcr 80 vs 13/59 pts (22.0%) if Clcr OR 4.7 (95% CI, ; p=0.002). DeCarolis D et al Arch Intern Med 2012 ; 172 (22) :

27 LMWH ARE NOT SIMILAR Enoxaparin: 20% Tinzaparin and Dalteparin: 60% of long chains Degré de polymérisation longues chaînes courtes Bisio A et al. Thromb Haemost

28 BLEEDING, ENOXAPARIN AND RENAL IMPAIRMENT Clcr <30 ml/min vs 30 ml/min Lim et al Ann InternMed 2006; 144:

29 BLEEDING, ENOXAPARIN AND RENAL IMPAIRMENT Clcr <30 ml/min vs 30 ml/min Lim et al Ann InternMed 2006; 144:

30 RECOMMENDATIONS FOR CAT 1) LMWH is recommended for the initial treatment of established VTE in cancer patients [Grade 1B]. Values and preferences : LMWHs are easier to use than UFH. 2) LMWHs are preferred over VKA for the early maintenance treatment (10 days to 3 months) and long-term treatment (beyond 3 months) [Grade 1A]. Farge D et al. J ThrombHaemost LMWH is preferred over UFH for the initial 5 to 10 days of anticoagulation for the cancer patient with newly diagnosed VTE who does not have severe renal impairment (defined as creatinin clearance < 30 ml/min). 4.2 For long term anticoagulation, LMWH for at least 6 months is preferred due to improved efficacy over Vitamin K antagonists. Kuderer N.M. and Lyman G.H. Thromb Res 2014

31 RECOMMENDATIONS FOR MEDICAL PROPHYLAXIS AND RENAL IMPAIRMENT 1) In hospitalized medical cancer patients with a creatinine clearance (Cockcroft- Gault) 30 ml/min, we recommend standard prophylactic doses of LMWH in the absence of other contraindications. 2) In cancer patients with a creatinine clearance below 30 ml/min, we suggest LMWH with a low degree of bioaccumulation or UFH. Di Nisio et al. ISTH Subcommitee. JTH E-pub 29 July ) In case of renal impairment, avoid antithrombotics with potential accumulation and determine anti-xa levels to adjust the dose and reduce the bleeding risk. However it is not well established that a reduced dose adjustment will allow the expected clinical benefit. Peak Values? Trough Levels? Targets?... Kearon et al Chest 2012

32 RENAL IMPAIRMENT, THROMBOSIS AND CANCER Select LMWH Smaller but Longer Seems Better TCK Working-Group

33 Aim of C-KIN TKC Working Group Develop Clinical Practice Guidelines Specifically aimed at cancer patients with CKD That would develop this section of ASCO guidelines Organisation: International expert group Preparation of an article «position paper» Follow-up: Develop education material Clinical research