Thrombosis, Kidney disease & Cancer Brussels, Belgium 14 - 15 April 2015 TKC Working Group Thrombosis, Kidney disease & Cancer

C-KIN Working Group Thrombosis, Kidney disease & Cancer Dr. Vincent LAUNAY-VACHER C-KIN President Service ICAR Pitié-Salpêtrière University Hospital Paris, France

C-KIN Working Group TKC Dr. Christine Ribic – Ontario, Canada – Nephrology recently joined Contact at C-KIN: Marie Mahieux marie.mahieux@c-kin.org

Rationale Why focusing on Thrombosis in patients with kidney disease and cancer ? Cancer VTE CKD

Rationale Why focusing on Thrombosis in patients with kidney disease and cancer ? Cancer VTE CKD

Cancer patients are at risk for VTE Cancer-related risk factors: Metastatic disease at the time of diagnosis Increased hypercoagulability due to tumour production of procoagulant proteins or inflammatory cytokines Compromised venous blood flow due to tumour mass …/… Cancer treatment-related risk factors: Surgery Long-term central venous catheters Some chemotherapies, hormone therapies, and angiogenesis inhibitors Scotté F, et al. Support Care Cancer 2012

Cancer patients are at risk for VTE Cancer and VTE/PE: A frequent situation 20% of VTE/PE occur in cancer patients 20% of cancer patients experience VTE/EP (up to 50% on post-mortem autopsies) The risk of VTE/PE recurrence in 4-fold higher in cancer patients The risk of major bleeding under anticoagulant therapy is doubled The risk of PE is 2 to 3-fold higher Lyman GH et al. Cancer 2011; Farge D et al. Thromb Res 2010

Cancer patients are at risk for VTE VTE/PE is associated with high mortality rates VTE/PE is the second cause of death in cancer patients Lyman GH et al. Cancer 2011; Scotté F et al. Supp Care Cancer 2011; Farge D et al. Thromb Res 2010; Pruemer J et al. Am J Health Syst Pharm 2005

VTE impacts cancer patients’ survival Cancer patients with VTE vs. Cancer patients without Higher risk of metastasis: 44% vs. 35.1%, HR 1.26, 95%CI [1.13-1.40] Reduced survival: 1-year survival rate of 12% vs. 36%, p<0.001 Sorensen HT, et al.. N Engl J Med 2000

VTE impacts cancer patients’ survival VTE patients with cancer within a year vs. no cancer Higher risk of metastasis: 44% vs. 35.1%, HR 1.23, 95%CI [1.08-1.40] Reduced survival: 1-year survival rate of 38% vs. 47%, p<0.001 Sorensen HT, et al.. N Engl J Med 2000

Rationale Why focusing on Thrombosis in patients with kidney disease and cancer ? Cancer VTE CKD

CKD is highly prevalent in cancer France1,2: IRMA studies (IRMA-1 and IRMA-2) 4’684 et 4’945 patients (all types of solid tumours) eGFR<60 : 12.0% et 11.8% (MDRD) Belgium3: BIRMA study 1’218 patients (all types of solid tumours) eGFR<60 : 16.1% (MDRD) United States4: 1’114 patients (kidney cancer) eGFR<60 : 22,0% (MDRD) Japan5: 231 patients (all types of solid tumours) eGFR<60 : 25.0% (MDRD) Austria6: 1’100 patients (all types of solid tumours) eGFR<60 : 14.7% (MDRD) and 16.1% (CKD-EPI) Prevalence of CKD in cancer patients 12 to 25% 1Launay-Vacher V et al. Cancer 2007; 2Launay-Vacher V et al. Semin Nephrol 2010; 3Janus N et al. Br J Cancer 2010; 4Canter D et al. Urology. 2011; 5Nakamura Y et al. Nihon Jinzo Gakkai Shi. 2011; 6Königsbrügge O et al. Thromb Res 2014

CKD is highly prevalent in cancer 1Launay-Vacher V et al. Breast Cancer Res Treat 2010; 2Launay-Vacher V et al. Lung 2009; 3Launay-Vacher V et al. Clinical Genit Cancer 2009; 4Personal data IRMA-1

CKD impacts cancer patients’ survival France1: eGFR<60 => reduced overall survival HR 1.27 (p=0.0002) Japan2: eGFR<60 = independent risk factor for death at 1 year Korea3: 30<eGFR<60 => HR 1.12 (p=0.04) for cancer-related mortality eGFR<30 => HR 1.75 (p<0.001) for cancer-related mortality Australia4: eGFR<60 => increased cancer-related mortality HR 1.27 Each ⬊ in eGFR of 10 ml/min/1.73m2 = 18% ⬈ of cancer mortality (p<0.001) 1Launay-Vacher V et al. Semin Nephrol 2010; 2Nakamura Y et al. Nihon Jinzo Gakkai Shi. 2011; 3Na SY, et al. Am J Nephrol. 2011; Iff S, et al. Am J Kidney Dis 2014

Rationale Why focusing on Thrombosis in patients with kidney disease and cancer ? Cancer VTE CKD

Higher risk of VTE in CKD patients RR for venous thromboembolism increases as eGFR decreases RR becomes significant when eGFR is below 88 mL/min/1.73m2 Especially when eGFR < 60 mL/min/1.73m2 A: Mahmoodi BK. Circulation 2012

CKD impacts VTE patients survival B Reduced survival in CKD patients experiencing venous thromboembolism / pulmonary embolism B: Parikh AM. Am J Kidney Dis 2011

Rationale Cancer patients with CKD are VERY HIGH-RISK patients Cancer VTE CKD

Rationale Cancer patients with CKD are VERY HIGH-RISK patients What do we have in Clinical Practice Guidelines ?

Rationale Lyman GH, et al. J Clin Oncol 2013; Lyman GH, et al. J Clin Oncol 2015

Rationale Cancer patients with CKD are VERY HIGH-RISK patients What do we have in Clinical Practice Guidelines ? Lack of recommendations on how to treat these patients with Cancer and CKD

Kidney disease in ASCO CPG 2013 Lyman GH, et al. J Clin Oncol 2013

International definition and stratification of chronic kidney disease Stage Description eGFR (mL/min/1.73m²) At Increased Risk Risk factors for kidney disease (e.g., diabetes, high blood pressure, family history, older age, ethnic group) ≥ 90 1 Kidney damage (protein in the urine) and Normal GFR 2 Kidney damage and Mild decrease in GFR 60 to 89 3 Moderate decrease in GFR 30 to 59 4 Severe decrease in GFR 15 to 29 5 Kidney failure (dialysis or kidney transplant needed) Less than 15 What about Stage 1 to 3 ? ASCO CPG K/DOQI : National Kidney Foundation. Am J Kidney Dis 2002.; KDIGO : Levey AS, et al. Kidney Int 2005.

Kidney disease in ASCO CPG 2013 Lyman GH, et al. J Clin Oncol 2013

LMWH in CKD 2000 : « Enoxaparin may have resulted in increased bleeding complications and use of blood products in patients with renal insufficiency »1 2001 : « Excessive anticoagulation in patients with mild renal insufficiency receiving long-term therapeutic enoxaparin. Drug accumulation and clinical bleeding »2 2002 : 32% increase in anti-Xa activity in 40-80 vs. >80 mL/min (enoxaparin)3 121% increase in anti-Xa activity in <40 vs. >80 mL/min (+68% vs. 40-80 mL/min (enoxaparin)3 Increased Cmax and AUC of anti-Xa activity when eGFR ≤ 30 (+170%) (enoxaparin)4 1Gerlach AT et al. Pharmacotherapy 2000; 2Busby LT et al. Am J Hematol. 2001; 3Becker RC et al. American Heart Journal 2002; 4Sanderink GJCM et al. Thrombosis Research 2002

LMWH are a heterogeneous class of drugs Tinzaparin and Dalteparin: 60% long chains Enoxaparin: 20% long chains short Bisio A et al. Thromb Haemost 2009

LMWH are a heterogeneous class of drugs 2/3  in renal excretion No  in renal excretion Enoxaparin accumulation Tinzaparin does not accumulate Johansen KB et al. XXIst Congress of the International Society on Thrombosis and Haemostasis; Geneva 2007

LMWH are a heterogeneous class of drugs Delayed elimination => Accumulation Unchanged elimination => No accumulation Schmid P, et al. Swiss Med Wkly 2009

LMWH are a heterogeneous class of drugs Tinzaparin Enoxaparin PK param. Accumulation factor p Cmax D1 (UI/ml) 0.44 Ratio D8/D1 1.05 0.296 0.55 1.22 <0.001 Cmax D8 0.46 0.67 AUC D1 (UI/ml.min) 252 1.12 0.11 354 1.26 AUC D8 273 447 Trough D1 0.05 Difference D8-D1 0.01 0.17 0.06 0.013 Trough D8 Cmax: Maximal anti-Xa activity (peak) ; AUC: Area Under the Curve (body exposure) Mahé I et al. Thromb Haemost 2007

Anticoagulants and CKD Low-Molecular Weight Heparins: Enoxaparin accumulates in CKD Tinzaparin does not accumulate in CKD (dalteparin ?)

Kidney disease in ASCO CPG 2013 Lyman GH, et al. J Clin Oncol 2013

Vitamin K Antagonists in CKD eGFR>60 eGFR 30-60 p eGFR<30 Time under target range 8.7% 6.2% <0.001 5.5% 0.001 Time above target range 11.7% 15.2% 20.8% Kooiman J, et al. PLoS One 2014

Vitamin K Antagonists in CKD Canadian study: 12’403 patients : AF / Warfarin / ≥ 66 years eGFR < 60 mL/min/1,73m2 = 45% 11,6% experienced major bleeding over a median follow-up of 2.1 years 5,9 66,0 James T et al. American Society of Nephrology Annual Meeting 2014, Abstract TH-OR051

Anticoagulants and CKD Low-Molecular Weight Heparins: Tinzaparin can be used Vitamin K Antagonists Overdosage is frequent CKD patients under VKA are at higher risk of stroke, TIA (transient ischemic attack), and major bleeding

Anticoagulants and CKD Low-Molecular Weight Heparins: Tinzaparin can be used Vitamin K Antagonists: cannot be recommended Fondaparinux

« the optimal fondaparinux dosage in this population remains unknown » Fondaparinux in CKD « the optimal fondaparinux dosage in this population remains unknown » Cope J, et al. Ann Pharmacother Dec 2014

Anticoagulants and CKD Low-Molecular Weight Heparins: Tinzaparin can be used Vitamin K Antagonists: cannot be recommended Fondaparinux: cannot be recommended Direct anticoagulants: not recommended by ASCO Lyman GH, et al. J Clin Oncol 2013

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 First draft circulated via email with bibliography Comments and amendments from experts Second draft Approval Publication Follow-up: Develop education material Clinical research ?