Guidelines for use of anticoagulant in ckd with atrial fibrillation

1. Guidelines for use of Anticoagulant
in CKD with AF

2. Topics
• Bidirectional Link Between CKD And AF
• Epidemiology
• CKD and AF share common risk factors
• Hypertension a stroke risk factor in AF
• Kidney-specific mechanisms that underlie the high burden of AF
among patients with CKD
• The pathophysiology of prothrombotic conditions in patients with AF
and CKD
• Consequences of AF In CKD
• Atrial Fibrillation And Stroke
• Kidney Disease and Atrial Fibrillation
• Atrial Fibrillation And CKD Progression
• Stroke In Patients With CKD And AF
• Stroke And Bleeding Risk Scores
• CHA2DS2-VASc score for stroke risk assessment in patients with AF
• HAS-BLED score for bleeding risk assessment in patients with AF.
• KDIGO recommendation for VKAs
• AHA /ACC recommendation for AKAs
• Stroke prevention and oral anticoagulation Management :
 non-vitamin K antagonist oral anticoagulants (NOACs) or direct oral
anticoagulants (DOACs)
• Dabigatran
• Rivaroxaban
• Apixaban
• Edoxaban
 Vitamin K antagonist
• warfarin
• phenprocoumon
• Site of action of NOACs and VKAs
• Disadvantages of vitamin K antagonists (VKAs)
• vitamin K antagonists (VKA) associated complications in CKD patients
• Advantages of NOACs
• Actions and pharmacokinetics of NOACs
• Dose adjustments of NOACs according to renal function
• Proposed Algorithm for Oral Anticoagulant Choices in Patients With
Atrial Fibrillation and Chronic Kidney Disease
• |Algorithm for the use of oral anticoagulant therapy in patients with AF
and CKD.
• Selection of appropriate oral anticoagulant for patients with AF and CKD
• Landmark clinical trials of NOACs versus warfarin in patients with AF
• Evidence from randomized trial data regarding therapeutic
anticoagulation on the basis of kidney function
• (DOACs) vs. warfarin
• Chronic kidney disease categories lacking randomized clinical trial data
on the utility of anticoagulation
• Recommendations for discontinuation of direct oral anticoagulant prior to
elective procedures, according to the risk of bleeding of any specific
procedure intervention (low vs. high risk procedures)
• DOACS IN PATIENTS WITH CKD G4–G5D
• 2016 ESC guidelines for the management of atrial fibrillation developed
in collaboration with EACTS
• Recommendations for patients wth Kidney disease and atrial fibrillation
• 2016 ESC guidelines Anticoagulation in patients with severe chronic
kidney disease
• Strategies to minimize bleeding on anticoagulant therapy
• Management of active bleeding in patients receiving anticoagulation
• Summary

3. CKD increases the risk of
incident AF, whereas AF
increases the risk of
development and
progression of CKD.
AF and CKD are associated
with an increased risk of
thromboembolic events;
patients with severe CKD
also exhibit a paradoxical
increase in bleeding risk.
Bidirectional Link Between CKD And AF

4. Atrial fibrillation is the most common sustained arrhythmia.
CKD affects 10% of adults worldwide
patients with CKD have an increased burden of AF compared
with those without CKD .
The prevalence of AF is high: estimates range from 16% to 21%
in CKD patients not dependent on dialysis10–12 and 15% to
40% in patients on dialysis .
Chronic kidney disease and AF share many risk factors
Epidemiology

5. CKD and AF share common risk factors

6. Hypertension a stroke risk factor in AF
• Hypertension is a stroke risk factor in AF
• good blood pressure control should form an integral part of the management of AF patients.
Inhibition of the renin–angiotensin–aldosterone system can prevent structural remodelling and
recurrent AF.
• ACE inhibitors or ARBs in patients with heart failure or LVH show a lower incidence of new-
onset AF.
• ACE inhibitors or ARBs may reduce recurrent AF after cardioversion when co-administered
with antiarrhythmic drug therapy compared with an antiarrhythmic drug alone.

7. Kidney-specific mechanisms that underlie the high
burden of AF among patients with CKD
•Abnormalities in mineral metabolism (in particular, levels of phosphorus and fibroblast
growth factor 23 deficiency of active vitamin D in CKD affect cardiac structure and
function.
Effects on cardiac structure
•Premature atherosclerosis, and albuminuria is not only a sign of endothelial injury but
also a contributor to impaired endothelial function.
Effects on endothelial
•Low-grade inflammation and increased activity of the renin–angiotensin– aldosterone system
(RAAS) and the adrenergic system are associated with both CKD and AF, facilitating the
development of both conditions and likely underlying not only the occurrence of AF in patients
with CKD but also the development and/or progression of CKD in patients with AF.
Effects on function and vascular
calcification

8. The pathophysiology of prothrombotic conditions in patients with AF and CKD

9. Consequences of AF in CKD
• Risk of stroke elevated in both dialysis and non dialysis patients with AF.
• The association between AF and CKD is bidirectional:
– CKD increases risk of incident AF.
– AF may predict new-onset low GFR and proteinuria.
– AF increases the risk of progression to end-stage kidney disease.
• AF is associated with increased mortality in CKD.

10. Atrial Fibrillation and Stroke
AF increases risk of ischemic stroke 4- to 5-fold.
– Paroxysmal, persistent, and permanent AF all predispose to subsequent ischemic
stroke .
– Diagnosed AF responsible for at least 15% to 20% of all ischemic strokes.
– Subclinical AF increases subsequent risk of stroke or peripheral embolism 2.5-fold.
– Subclinical (undiagnosed) AF may be responsible for another 13% of ischemic
strokes .

11. Kidney Disease and Atrial Fibrillation
Alonso A, et al. Circula2on 2011;123:2946

12. Atrial Fibrillation and CKD Progression
Bansal N, et al. Circula2on 2013;127:569

13. Bansal N, et al. CJASN 2016;11:1189
Atrial Fibrillation and CKD Progression

14. Stroke in Patients with CKD and AF
Multifactorial mechanisms leading to
stroke that are poorly understood.
• AF may be:
• – a direct cause of cardioembolic
stroke
• – a risk marker of ischemic stroke
• – in rare cases, a consequence of
stroke
Direct oral anticoagulants (DOAC) are
preferred in comparison to warfarin for
prevention of stroke and systemic
embolism in patients with eCrCl 30–50
ml/min.

15. Stroke and Bleeding Risk Scores
The predictive value of stroke risk
scores (CHADS2, CHADS2VASC) in
CKD G5D is similar to that in the
general population.
The HAS-BLED, ORBIT,
HEMORR₂HAGES and ATRIA
bleeding risk scores all include CKD
measures.
Although formal use of bleeding risk
scores has not been recommended,
the increased risk of bleeding with and
without oral anticoagulants (OAC) in
CKD is well described and should be
considered in clinical decision making.

18. VKA do not seem to be the optimal treatment
strategy for CKD patients. Additionally, a
consensus protocol from the nephrological
KDIGO (Kidney Disease—Improving Global
Outcome) guideline group speaks out against
anticoagulation of dialysis patients with atrial
fibrillation for the primary prophylaxis of
ischemic stroke

19. considers VKA in
dialysis patients
with atrial
fibrillation as
useful

20. Management of AF in
CKD patients
non-vitamin
K antagonist oral
anticoagulants (NOACs)
or direct oral
anticoagulants (DOACs)
Dabigatran Rivaroxaban Apixaban Edoxaban
Vitamin K antagonist
warfarin phenprocoumon
Stroke prevention and oral Anticoagulation: Management

21. Site of Action of NOACs and VKAs

22. Disadvantages of vitamin K antagonists (VKAs)
• Relatively unpredictable pharmacokinetics and pharmacodynamics.
• Compared to patients with a glomerular filtration rate (GFR) >30mL/min, those with a GFR
<30mL/min :
o required significantly lower warfarin dosages.
o spent less time with their international normalized ratio (INR) within the target range.
o were more frequently over anticoagulated.
o increased number of bleeding episodes.
o accelerate progression of CKD via haemorrhage within tubules.

23. vitamin K antagonists (VKA) associated complications in CKD patients
• VKA prevent the activation of vitamin K dependent calcification inhibitors, especially matrix-gla proteins.
• Association of VKA intake with calciphylaxis (calcific uremic arteriopathy)—a rare but life-threatening
systemic disorder in dialysis patients suggests the possible clinical relevance .
• VKA administration in dosages exceeding the therapeutic measure (>target international normalized ratio
[INR] of 2.0–3.0) drives the progression of CKD, which may be explained with recurring subclinical bleeds
into the renal tubule system and subsequent tubular necrosis.

24. Advantages of NOACs
More predictable effect by directly inhibiting the activation of coagulation factors that act late
in the coagulation cascade
Display more rapid onset of action
Shorter half-life
can be given in fixed doses without the need for monitoring
Lack the need for regular laboratory monitoring
Lack diet and drug interactions

25. Actions and pharmacokinetics of NOACs

26. Dose adjustments of NOACs according to renal function

31. Chronic kidney disease and arrhythmias: conclusions from a Kidney
Disease: Improving Global Outcomes (KDIGO) Controversies
Conference

32. DOAC VS. WARFARIN
Chronic kidney disease and arrhythmias: conclusions from a Kidney
Disease: Improving Global Outcomes (KDIGO) Controversies
Conference

33. Chronic kidney disease and arrhythmias: conclusions from a Kidney
Disease: Improving Global Outcomes (KDIGO) Controversies
Conference

34. Chronic kidney disease and arrhythmias: conclusions from a Kidney
Disease: Improving Global Outcomes (KDIGO) Controversies
Conference

35. Nephrol Dial Transplant (2017) 1–7

36. • Observational studies provide conflicting data on the safety and efficacy of DOACs in this population.
• Therapeutic range values (TTR) are more likely to be poor in CKD and can mediate the increased stroke
and bleeding risk in CKD.
• Warfarin may lead to CKD via repeated subclinical glomerular hemorrahages or through accelerated
tissue or vascular calcification.
• Low-dose apixaban (2.5 mg orally twice daily) in CKD G5/G5D is considered to reduce bleeding risk.
DOACS in Patients with CKD G4–G5D

37. Oral anticoagulant therapy in patients with mild or moderate CKD (CrCl 30 mL/min)
ARISTOTLE trial data analysis suggests that the bleeding benefit with apixaban compared with
warfarin becomes significantly more prominent at lower CrCl values, while the stroke reduction
benefit is maintained.
RE-LY trial data showed a significantly faster rate of decline in renal function during the trial in patients on warfarin
(especially at lower TTRs) compared with those on dabigatran200 suggesting that it may delay the decline in renal
function compared with warfarin. Warfarin use may be associated with increased vascular calcification and/or the
development of acute warfarin-related nephropathy with or without clinically overt haematuria.

38. Oral anticoagulant therapy in patients with a CrCl of 15–29 mL/min
There are no RCT data on the use of NOACs for stroke prevention in AF patients with severe CKD or on renal
replacement therapy (RRT) since all landmark NOACs trials essentially excluded patients with a CrCl of <30 mL/min
(except for a few patients on apixaban with CrCl 25–30 mL/min).
Rivaroxaban, apixaban, and edoxaban (but not dabigatran) are approved in Europe for the use in patients with
severe CKD (Stage 4, i.e. a CrCl of 15–29 mL/min), with the reduced dose regimen.
Contd….

39. • Apixaban is least renally cleared (27%), and the dose is reduced by 50% in rather stringent conditions according
to its dose reduction algorithm; furthermore the relative safety of apixaban vs. warfarin has been demonstrated to
increase with decreasing renal function.
• Edoxaban is 50% renally cleared, but its dose reduction to 50% is applied more rapidly and was tested in a large
subgroup.
• Rivaroxaban has an intermediate renal clearance (33%), and its dose is reduced less (by 25%) under similar
conditions as edoxaban.
• In the US (but not in Europe), a low dose dabigatran 75 mg BID regimen has been approved for patients with
severe CKD (a CrCl of 15–29 mL/ min), based on pharmacokinetic simulations.
Oral anticoagulant therapy in patients with a CrCl of 15–29 mL/min

40. Oral anticoagulant therapy in patients with a CrCl of 15 mL/min and on dialysis
• Significantly lower incidence of stroke and embolism under warfarin, but also a markedly increased bleeding risk.
• Use of warfarin in patients with end-stage renal failure may in some cases result in calciphylaxis, a painful and often
lethal condition caused by calcification and occlusion of cutaneous arteries and arterioles.
• Levels similar to those in patients with normal renal function on the respective NOACs were found for apixaban 2.5
mg BID in a small number of patients on dialysis, for edoxaban 15 mg OD (in Japanese patients with severe renal
insufficiency) and rivaroxaban 10 mg OD in endstage renal disease patients.

42. 9.2.4 Oral anticoagulation in atrial fibrillation patients with chronic kidney disease
• CKD is associated with stroke and bleeding in large data sets.
• Anticoagulation can be safely used in AF patients with moderate or moderate-to-severe CKD [glomerular filtration
rate (GFR) ≥15 mL/min]: the SPAF (Stroke Prevention in Atrial Fibrillation) III trial randomized 805/1936 participants
with stage 3 CKD (estimated GFR ,59 mL/min/1.73 m2 ), and reported good outcomes on warfarin (INR 2–3). This
finding is supported by a large Swedish database, in which stroke risk was lower in CKD patients with AF treated
with warfarin (adjusted HR 0.76; 95% CI 0.72–0.80), while bleeding was also slightly increased, especially during
therapy initiation.
• In a meta-analysis of the major NOAC trials, patients with mild or moderate CKD suffered fewer strokes, systemic
emboli, or major bleeding events on NOACs than on warfarin.

44. 15.5 Anticoagulation in patients with severe chronic kidney disease
The use of NOACs has not been tested in patients with creatinine clearance
,30 mL/min, and there is very little evidence on the effects of OAC in patients
on haemodialysis or on other forms of renal replacement therapy.

45. Strategies to minimize bleeding on anticoagulant therapy
•keeping systolic blood pressure well controlled is of particular relevance in anticoagulated patients with AF
Uncontrolled
hypertension
•History of bleeding events and the presence of anaemia are important parts of the assessment of all patients receiving OAC
•patients in whom the source of bleeding has been identified and corrected, OAC can be reinitiated.
Previous bleeding event
•targeting the INR between 2.0 and 3.0 in patients on VKAs, maintaining a high TTR (e.g. ≥70%494), and to consider
switching to a NOAC when a high TTR cannot be sustained
Labile international
normalized ratio and
adequate non-vitamin K
antagonist oral
anticoagulant dosing
•Alcohol excess is a risk factor for bleeding in anticoagulated patients, mediated by poor adherence, liver disease, variceal
bleeding, and risk of major trauma. Severe alcohol abuse and binge drinking habits should be corrected in patients eligible
for OAC.
Alcohol abuse
•Falls and dementia are associated with increased mortality in AF patients.
•Anticoagulation should only be withheld from patients with severe uncontrolled falls (e.g. epilepsy or advanced multisystem
atrophy with backwards falls), or in selected patients with dementia where compliance and adherence cannot be ensured by
a caregiver
Falls and dementia
•multiple genetic variations affect the metabolism of VKAs.Genetic testing
•percutaneous coronary intervention or pacemaker implantation) can be performed safely on continued OAC.
•OAC interruptions should be minimized to prevent stroke Previous bleeding event.
Bridging periods off oral
anticoagulation

47. • Atrial fibrillation (AF) and chronic kidney disease (CKD) share common risk factors, including older age,
hypertension and diabetes mellitus.
• CKD increases the risk of incident AF, whereas AF increases the risk of development and progression of
CKD.
• AF and CKD are associated with an increased risk of thromboembolic events; patients with severe CKD
also exhibit a paradoxical increase in bleeding risk.
• In trials that compared non-vitamin K antagonist oral anticoagulants (NOACs) with warfarin, the relative
efficacy and safety of NOACs were consistent in patients with and without mild or moderate CKD.
• In patients with ESRD, vitamin K antagonists might increase the risk of bleeding and thrombotic events;
however, good anticoagulation control might reduce the risk of ischaemic stroke without increasing
bleeding risk.
Summary

48. References
• European Heart Journal (2018) 39, 2314–2325
• Dtsch Arztebl Int. 2018 Apr; 115(17): 287–294.
• nefrologia. 2017;37(3):244–252
• Nature Reviews | Nephrology Volume 14 | May 2018 | 339
• https://www.uptodate.com/contents/management-of-thromboembolic-risk-in-patients-with-atrial-fibrillation-and-chronic-
kidney-disease
• J Am Coll Cardiol 2016;68:1452–64
• 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS