1. Thrombosis, Kidney disease & Cancer
Brussels, Belgium
April 2015
TKC Working Group
Thrombosis, Kidney
disease & Cancer

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

3. C-KIN Working Group TKC
Dr. Christine Ribic – Ontario, Canada – Nephrology
recently joined
Contact at C-KIN: Marie Mahieux

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

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

6. 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

7. 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

8. 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

9. 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 [ ]
Reduced survival: 1-year survival rate of 12% vs. 36%, p<0.001
Sorensen HT, et al.. N Engl J Med 2000

10. 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 [ ]
Reduced survival: 1-year survival rate of 38% vs. 47%, p<0.001
Sorensen HT, et al.. N Engl J Med 2000

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

12. 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

13. 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

14. 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

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

16. 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

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

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

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

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

21. 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

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

23. 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.

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

25. 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 vs. >80 mL/min (enoxaparin)3
121% increase in anti-Xa activity in <40 vs. >80 mL/min (+68% vs 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

26. 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

27. 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

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

29. 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

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

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

32. 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

33. 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

34. 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

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

36. « 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

37. 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

38. 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 with bibliography
Comments and amendments from experts
Second draft
Approval
Publication
Follow-up:
Develop education material
Clinical research ?