VKA in Dialysis: Navigating between Scylla and Charybdis. An De Vriese Nephrology & Infectious Diseases AZ Sint-Jan Brugge

Transcription

1 VKA in Dialysis: Navigating between Scylla and Charybdis An De Vriese Nephrology & Infectious Diseases AZ Sint-Jan Brugge

2 AF in Dialysis DOPPS I ( ) and DOPPS II ( ) Wizeman V et al. Kidney Int 2010; 77: Prevalence in Belgium = 24.7%

3 AF in Dialysis Winkelmayer W et al. J Am Soc Nephrol 2011; 22: Fully adjusted = +dialysis vintage, Medicaid eligibility, all available indicators of comorbidity

4 The Relative Risks and Benefits of Anticoagulation Allon M. J Am Soc Nephrol 2013; 24: Warfarin in 1000 patients for 1 year prevents 23 strokes and causes 9 major hemorrhages

5

6 Major Bleeding in Patients taking Warfarin Wieloch et al. Thromb Res 2013; 131: 481-6

7 Warfarin and Vascular calcification Matrix Gla protein (MGP): Most potent local inhibitor of ectopic calcification Locally produced by VSMC ucmgp cmgp

8 Schurgers L et al. PLoS ONE 2012; 7(8): e43229

9 Warfarin and Vascular calcification Weijs et al. Eur Heart J 2011; 32:

10 1) Warfarin and Hemodialysis: Indirect Evidence Prevention of stroke: equivocal Major Bleeding: increased Vascular Calcifications: increased

11 2) Dialysis = Vitamin K-deficient state

12 Dp-uc-MGP correlates inversely with Menaquinone intake Caluwe R et al. Nephrol Dial Transplant 2013 Nov 26 Dutch Hemodialysis=118µg Normal=200µg Dutch Hemodialysis=21µg Cranenburg et al. Kidney Int 2012; 82: Normal=31µg

13 Circulating Inactive form of Matrix Gla Protein (dp-uc-mgp) increases with CKD stage Schurgers L et al. Clin J Am Soc Nephrol 2010; 5:

14 Vintage, Months Dp-uc-MGP increases with Dialysis Vintage Caluwe R et al. Nephrol Dial Transplant 2013 Nov uc-dp-mgp, pmol/l P < 0.001, r = 0.29

15 -glutamyl carboxylase (GGCX) activity is impaired by uremia Kaesleret al. Kidney Int 2014 Control CKD CKD +K2 CKD +High K2 CKD +High K1

16 Vitamin K and warfarin replacement: effect on VC in Hemodialysis: RCT Dialysis patients on warfarin for AF: Continue warfarin Replace warfarin Replace warfarin + supplement vitamin K CAC score SfygmoCor pulse wave analysis

17 First question: Which vitamin K?

18 MK µmol/d = 150 µg/d Vitamin K µmol/d = 100 µg/d Placebo

19 Second question: How much vitamin K2?

20 Second question: How much vitamin K2? Caluwe R et al. Nephrol Dial Transplant 2013 Nov 26 NB:Healthy population 31 µg/d Konakion = 10 mg

21 Second question: How much vitamin K2? Caluwe R et al. Nephrol Dial Transplant 2013 Nov 26 NB: Healthy Dutch population 25-80y = pmol/l

22 Third question: Replace warfarin with what? Harderet al. Eur J Clin Pharmacol 2013; 69: Anti-FXa Anti-FXa Anti-FXa Anti-FIIa

23 Stroke prevention in non-valvular AF: ROCKET-AF Patelet al. N Engl J Med 2011; 365:

24 Rivaroxaban RCTs CrClear > 30 ml/min!! Reference Indication Dose Comparator Result NEJM 2008 Lancet 2008 NEJM 2008 Lancet 2009 NEJM 2013 Prevention VTEhip arthroplasty Prevention VTEknee arthroplasty Prevention VTEacute ill medical pts NEJM 2010 Treatment VTE 15mg bid 21d- 20mg od NEJM 2012 Treatment PE 15mg bid 21d- 20mg od NEJM 2011 Prevention strokenon-valvular AF 10mg od Enoxaparin More Effective = Bleeding 10mg od Enoxaparin More Effective = Bleeding 10mg od Enoxaparin More Effective More Bleeding 20mg od 15mg od-ccl30-45 Enoxaparin + Vitamin K ATG Enoxaparin + Vitamin K ATG More Effective = Bleeding = Effective Less Bleeding Vitamin K ATG = Effective Less Bleeding NEJM 2012 ACS 2.5 bid Placebo More Effective More Bleeding

25 Rivaroxaban Clearance Kubitza et al. Brit J Clin Pharmacol 2010; 70: Tubular Secretion Glomerular Filtration Non-renal Clearance

26 Prevention DVT Knee replacement surgery Hip replacement surgery 10 mg od 2w 10 mg od 5w Treatment DVT/PE Prevention recurrent DVT 15 mg bid 3w 20 mg od Stroke prevention in AF CrCl 50 ml/min CrCl ml/min 20 mg od 15 mg od Mueck et al. Clin Pharmacokinet 2014; 53: 1-16

27 Fourth question: How much rivaroxaban? 12 chronic hemodialysis patients Single dose of 10 mg after dialysis Follow-up for 44h Mean of 3 AUC

28 Single dose of 10 mg rivaroxaban Kubitza et al. Brit J Clin Pharmacol 2010; 70: and our data Healthy Controls (n=8) CreaCl 67 ml/min (n=8) CreaCl 43 ml/min (n=8) CreaCl 22 ml/min (n=8) Hemo dialysis (n=12) AUC, µg/l/h, GM* % CV C max, µg/l, GM %CV T ½ **, h, GM % CV *Geometric mean **Terminal elimination half-life time

29 Single dose of rivaroxaban (1) Stampfuss et al. Int J Clin Pharmacol Ther 2013; 51: (2) Our data Healthy Controls 20 mg (1) AUC, µg/l/h 2294 (19) C max, µg/l (15) Hemodialysis 10 mg (2) 2072 (54.7) (45.5) Values are geometric mean (% coefficient of variation), range

30 Rivaroxaban: Effect of Dialysis

31 Trial Design Vitamin K antagonist INR 2-3 Vitamin K antagonist Rivaroxaban 10 mg od Rivaroxaban + MK µg 3x/w 0m 6m 12m 18m

32

33 What should we do in the mean time?

34 Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate Eerenberg L et al. Circulation 2011; 124: RIVAROXABAN DABIGATRAN

35

36 Warfarin and Vascular calcification Krüger T et al. Arterioscler Thromb Vasc Biol 2013; 33:

37 Warfarin and Vascular calcification Krüger T et al. Arterioscler Thromb Vasc Biol 2013; 33:

38 Warfarin and Vascular calcification Schurgers L et al. PLoS ONE 2012; 7(8): e43229