Based on the information provided: - Her stroke risk can be assessed using CHA2DS2-VASc score: C = 1 (Congestive heart failure) H = 1 (Hypertension) A = 1 (Age 65-74) D = 1 (Diabetes) S = 1 (Stroke/TIA/TE) V = 0 A = 0 S = 1 (Sex category) c = 1 (CKD with eGFR 30-59) Total score = 6 - A score of 6 corresponds to high risk of stroke (>4%/year) - Given her high stroke risk, anticoagulation would be recommended. -

1. Anticoagulation in Chronic
Kidney Disease
Mohsen El Kossi
Consultant Renal Physician
Doncaster Royal Infirmary

2. Indications
• Thromboembolic prophylaxis in non valvular
AF
• Treatment and prophylaxis for VTE
• Acute coronary syndrome
• Extracorporeal dialysis circulation
• Miscellaneous

3. AF and CKD
• Inverse relationship between eGFR and AF (ARIC and
REGARDS studies)
• Increased risk of AF with micro and
macroalbuminuria
• Prevalence between 18-22% in CKD
• Coexistence of well recognised risk factors for AF in
general population with CKD (DM, Hypertension,
heart failure)

4. AF in CKD-5D
AF prevalence is around 7.7% in HD patients (Winkelmayer et al 2011)

5. • Prevalence among HD patients 11.6%
• Incidence in HD patients 2.6/100 patient-years
• Risk of stroke 5.2 vs 1.9/100 patient-years
• Risk of mortality 26.9 vs 13.4/100 patients-years
• There was no protective effect of warfarin on stroke
risk

6. Risk of Stroke in CKD-5D
Wang et al; AJKD 2014
Herzog et al; KI 2011
Mortality rate from stroke is X3 higher in dialysis patients compared to the
general population

7. AF Associated Mortality in HD Population
Winkelmayer et al JASN 2011

8. CHADS2 Score and Stroke Risk
General Population
Gage et al JAMA 2001

9. Stroke Risk Assessment
CHADS-VASC Score

10. Stroke Risk
• Low: <2%/year
• Medium: 2-4%/year
• High risk: >4%/year

11. Stroke Risk Assessment in CKD
• All schemes were not validated in dialysis
patients
• ATRIA and R2CHADS2incorporate CKD as a risk
factor
• 80% of CKD-5D have score of >2 on CHADS2
score

12. Bleeding Risk Calculation

13. HAS-BLED Score
• Hypertension: systolic BP>160mmhg
• Abnormal kidney function:
– Dialysis, kidney transplant, sCr >200 umol/l
• Abnormal liver function:
– Chronic hepatitis, Bilirubin>X2, ALT/AST/ALP>X3
• Age>65 years
• Labile INR:
– Unstable/high INR, <60% in range
• Concomitant drugs: NSAIDs, antiplatlets..etc.
Pisters et al Chest, 2010

14. Risk of Bleeding in CKD
• Increased risk of GI and intracerebral bleeding in
CKD-5D (20% have major GI bleed in the first 4 years
of dialysis)
• Interestingly warfarin use was not associated with
increased risk of bleeding
• Bleeding risk assessment in CKD-5D is not validated
• Risk of bleeding in CKD-ND is less clear
• SCr>1.5 mg/dl and eGFR <60ml/min increased risk of
major bleed or haemorrhagic stroke respectively
• Bleeding risk was more common in CKD patients in
ROCKET-AF and ARISTOTLE trials
Ng et al AJKD, 2013

15. Anti-coagulants in Practice
• Vitamin K dependent agents (warfarin)
• NOACS/DOACS
• UFH
• LMWH

16. Mechanism of Oral Anticoagulation

17. Anti-coagulation in
(Parenteral)Haemodialysis

18. LMWH versus UFH
• APTT monitoring is required for UFH
• Lower risk of osteoporosis with LMWH
• Lower risk of HIT with LMWH
• Protamine sulphate is antidote for heparin not
for LMWH
• Heparin blocks both thrombin and factor Xa
versus factor Xa only with LMWH
• LMWH reduces 20% of clinical events in
ACS/non ST elevation myocardial infarction
• Less risk of hypertriglyceredemia with LMWH

19. Mechanism of Action of LMWH vs UFH

20. UFH-1
• Affordability, availability, short half life and presence
of antidote
• Potential problems: bleeding, anaphylaxis,
thrombocytopenia, osteoporosis, hyperkalaemia and
hypertriglyceredemia
• Alternatives: LMWH, direct thrombin inhibitors,
regional heparinization, heparinioids, citrate, and
heparin coated dialyzers.
Shen and Winklemayer AJKD, 2012

21. UFH-2
• Half life is 1 hour in HD which is 30 minutes normally
• Dialyzer type and Epo dose can alter this time
• Sources porcine (higher risk of anaphylaxis) or bovine
(risk of mad cow disease)
• 80 reported cases of death in HD because of over
sulphated chondritin sulphate
• USA: no recommended dosing in HD, weight based,
fixed or APTT guided (X1.5)

22. Warfarin
• Rodent Pesticide (1948)
• Inhibits production of vitamin K dependent
factors (II,VII,IX,X)
• Prevents activation of factor X into Xa
• Slow onset of action
• Unpredictable anticoagulation effect
• Narrow therapeutic window
• Cheap, there is antidote

23. NOACS/DOACS

24. Salient RCTs of NOACs and Warfarin
RE-LY Dabigatran (Pradaxa)
ROCKET-AF Rivaroxaban (Xarelto)
ARISTOTLE Apixaban (Eliquis)

26. Risk of Bleeding
Message
NOACS have a favourable risk/benefit profile versus warfarin
Significant reductions in stroke, intracranial bleeding, mortality
Similar major bleeding except with slightly increased GI ones.

27. Antidote for NOACS
Haemodialysis can help with Dabigatran clearance but none of the others

28. Exclusion Criteria in NOAC RCTs
• CrCl<30 ml/min
– RE-LY Dabigatran (Pradaxa)
– ROCKET-AF Rivaroxaban (Xarelto)
• CrCl<25 ml/min
– ARISTOTLE Apixaban (Eliquis)
• Others: active liver disease, prosthetic heart
valves, pregnancy, valvular AF, higher Aspirin
dose

29. Warfarin and AF in HD
• Wizemann V1
, Tong L, Satayathum S, Disney A, Akiba T, Fissell RB, Kerr PG, Young EW, Robinson BM. Atrial fibrillation in
hemodialysis patients: clinical features and associations with anticoagulant therapy. Kidney Int. 2010 Jun;77(12):1098-
106
• Writing group Members; Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics-2016 update: a
report from American Heart Association. Circulation. 2016;133(4):e38-e360.
• Genovesi S1
, Vincenti A, Rossi E, Pogliani D, Acquistapace I, Stella A, Valsecchi MG. Atrial fibrillation and morbidity and
mortality in a cohort of long-term hemodialysis patients. Am J Kidney Dis. 2008 Feb;51(2):255-62.
• Bonde AN1
, Lip GY2
, Kamper AL3
, Hansen PR1
, Lamberts M1
, Hommel K3
, Hansen ML1
, Gislason GH4
, Torp-Pedersen C5
, Olesen
JB6
. Net clinical benefit of antithrombotic therapy in patients with atrial fibrillation and chronic kidney disease: a
nationwide observational cohort study. J Am Coll Cardiol. 2014 Dec 16;64(23):2471-82.
• Elliott MJ1
, Zimmerman D, Holden RM. Warfarin anticoagulation in hemodialysis patients: a systematic review of bleeding
rates. Am J Kidney Dis. 2007 Sep;50(3):433-40.
• McAlister FA, Wiebe N, Jun M, Sandhu R, James MT, McMurtry MS, Hemmelgarn BR, Tonelli M.
Are Existing Risk Scores for Nonvalvular Atrial Fibrillation Useful for Prediction or Risk Adjustment in Patients With Chronic
Kidney Disease? Can J Cardiol. 2017 Feb;33(2):243-252.

30. RCTs For AF Anticoagulation in CKD-5D
Stroke risk with warfarin in HD with AF varies 0.95-1.5
2.3 fold of increased haemorrhagic stroke with warfarin
No difference for ischaemic stroke

31. Guidelines Recommendations
Bansal et al AJKD 2017

32. Different Equations for CrCl and eGFR
MDRD equation: GFR (mL/min/1.73 m2
)
175 × (Scr)-1.154
× (Age)-0.203
× (0.742 if female) × (1.212
if African American)
CKD-EPI equation: GFR (mL/min/1.73 m2
)
GFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 ×
0.993Age × 1.018 [if female] × 1.159 [if black]

33. Oral Anticoagulant Dosing in CKD with AF
• Dabigatran 110mg BD
– Renal impairment (CrCl between 49-30)
– Age≥80 or 75 with 1 or more risk of bleeding
• Apixaban 2.5 mg BD if two or more of the following
– Cr ≥ 133 umol/l, age ≥ 80 and weight ≤60 Kg
• Rivaroxaban 15 mg (CrCl between 49-30)

34. Can We Use VKA/NOACS in CKD&/or CKD-5D?
• Risk assessment as per current stroke schema
in the general population (evidence is B level)
• Warfarin is safe, effective but unclear to use it
with or without heparin during HD
• NOACS require further studies to be used in
the context of eGFR<15 ml/min/1.73 m2

35. Antiplatelets Vs Oral Anticoagulants in
IHD
Stable IHD no need to use both because of risk bleeding is high
without proven evidence of added benefit
Unclear how to treat patients with AF and recent ACS +/- PCI

36. Stroke Risk and VTE of NOACs vs VKA In
CKD
AF and Stroke
ARISTOTLE
J-ROCKET-AF
RE-LY
ROCKET-AF
Subtotal
Recurrent VTE
EINSTEIN-DVT
EINSTEIN-PE
RECOVER
REMEDY
Subtotal
Harel et al, JASN 2014
There was no significant difference in stroke or VTE risk in both groups with CrCl<50 ml/min

37. Bleeding Risk and VTE of NOACs vs VKA In
CKD
There was no significant difference in bleeding risk in both groups with CrCl<50 ml/min
Harel et al, JASN 2014

38. VTE in General Population
• Incidence 1-2/1000 patients-years
• Mortality rate is around 14% fatal in the first place
• PE mortality is around 17.5% in the first 3 month
• Postphlepitic syndrome 17-50% and is difficult to treat
• Pulmonary hypertension is around 1-3% in the first year after
PE
• $10000 and 14000 to manage initial DVT & PE respectively

39. VTE Risk in Five Population Cohorts
• PREVEND suggested a link between VTE and
albuminuria but ERIC suggested the risk with low
eGFR
• Combined data from PREVEND, HUNT, CHS, ERIC and
TORMSO confirmed the increased VTE risk with CKD
or albuminuria
• Increase risk was consistent for both provoked and
unprovoked VTE
• Increased risk was similar in both PE and DVT
Mahmoodi et al Circulation, 2012

40. Risk of VTE Recurrence
• Provoked 1-5% in the first year then 1% annually
• Unprovoked first VTE 10% in the first year then 5% in the
following years
• Unprovoked 2nd
VTE 15% risk in the first year then 7.5%
annually.
• Factors increase the risk, unprovoked ≥X2, male, DM, LL
paresis, IBD, Osterogen therapy, PE, proximal DVT, eGFR<30
ml/min, high D dimer after anticoagulant cessation,
thrompophilia screening for young patients.

41. VTE in CKD
• Observational study of 0.7 million patients over 10
years
• Risk of VTE is increased with increase in albuminuria
(HR 1.6)
• Risk of VTE is minimally increased with reduced eGFR
(15-29 ml/min) HR 1.23
Azmiouch et al AJKD, 2017

42. CKD and VTE Risk
Mahmoodi et al Circulation, 2012

43. ACR and VTE Risk
Mahmoodi et al Circulation, 2012

44. HR of VTE in CKD
Mahmoodi et al Circulation, 2012

45. Evidence of Efficacy and Side Effects of
NOACS in VTE
• RECOVER and RECOVER2 Dabigatran is non inferior to VKA
with non significant less risk of bleeding
• EINSTEIN DVT&PE: Rivaroxiban is non inferior to VKA with less
risk of bleeding
• AMPLIFY Apixaban: is non inferior to VKA with significant less
risk of bleeding
• Unclear effect in certain situations, pregnancy, lactation,
massive PE or DVT, active malignancy

46. Conclusions
• Not recommended to use both warfarin and
heparin in the dialysis circuit
• Not advisable to use antiplatelets and
anticoagulants for IHD unless recently placed
stents (eluting stents may be preferable)
• NOACS can use Apixaban at 2.5 mg BD up to
CrCl of 20 ml/min
• Use the current stroke risk assessment tool
used in the general population

47. Research Recommendations by KDOQI
Bansal et al AJKD 2017

48. Thank You

49. Cases

50. Cases
• 68 years old lady known insulin treated
diabetes, AF with previous history of TIA. Her
eGFR is 32 ml/min and currently on Aspirin 75
mg OD, Ramipril 2.5 mg OD, Bisoprolol 5
mg/day.
• What is her stroke risk?
• Would you recommend anticoagulation in her
case and which one?