Kidney specific mechanisms leading to atrial fibrillation Possible mechanism of CKD progression in atrial fibrillation Atherosclerosis Risk in Communities (ARIC) study Guidelines Pulmonary embolism & deep vein thrombosis Nephrotic syndrome Problems with Vit K antagonists in CKD Non Vit K oral anticoagulants Site of action of NOACs and VKAs Pharmacology of Direct Oral Anticoagulants Trials for NOACs Dose NOACs according to renal function Laboratory monitoring of NOACs Anticoagulant reversal of NOACs

1. Newer Oral Anticoagulant in
Chronic Kidney Disease
Dr Abdullah Ansari
SR Nephrology
SGPGI Lucknow

2. Kidney specific mechanisms leading to atrial
fibrillation
• Cardiac structure
• Concentric LVH with pronounced myocardial fibrosis
• Larger left atrial and left ventricular size than patients without CKD
• Endothelial dysfunction
• Premature atherosclerosis
• Low-grade inflammation
• Renin-angiotensin-aldosterone and adrenergic system activation
• Vascular calcification
• Abnormalities in mineral metabolism
• Deficiency of active vitamin D in CKD

3. Possible mechanism of CKD progression in
atrial fibrillation
• Pronounced myocardial fibrosis
• Decline in left ventricular systolic and diastolic function
• Altered hemodynamics, venous congestion, activation of the RAAS
and adrenergic system
• Renal microinfarcts that result from a postulated systemic
prothrombotic state that is associated with AF

4. Atherosclerosis Risk in Communities (ARIC)
study
• Reduced GFR and albuminuria were strongly associated with incident
AF after extensive adjustment for other cardiovascular risk factors
• The risk of incident AF gradually increased with decreasing cystatin-C
based eGFR and increasing albuminuria
• Incident AF was associated with a threefold increased risk of CKD
progression to ESRD

5. Guidelines
• The KDIGO guidelines 2011 do not recommend VKA therapy for
primary prevention of stroke in dialysis patients with AF
• The AHA/ACC guidelines 2014 recommend VKA therapy for patients
with ESRD and AF with CHA2DS2-VASc score of minimum 2 points

6. Pulmonary embolism & deep vein thrombosis
• CKD is associated with hypercoagulable state
• CKD patients are at increased risk for developing venous thrombosis
and pulmonary embolism
• CKD patients have higher risk for recurrent thromboembolic events
and mortality as compared to normal renal function
• These should be treated with anticoagulants urgently

7. Nephrotic syndrome
• Nephrotic syndrome patients are at increased risk for thromboembolic
events due to renal loss of albumin and other coagulation factors
• The KDIGO guidelines recommend anticoagulation with VKA when
serum albumin is below 2.0–2.5 g/dl and additional thrombosis risk
factors are present until serum albumin rises to above 3 g/dl

8. Problems with Vit K antagonists in CKD
• No data from randomized trials of VKAs exist for patients with ESRD and AF,
and observational studies in this population have yielded conflicting results
• A mean time in the therapeutic range (TTR) of ≥65-70% is difficult to
maintain, due to reduced nonrenal and renal clearance of warfarin,
impaired drug metabolism and fluctuations in volume status
• The risks of stroke and bleeding in warfarin inexperienced patients with AF
and CKD are particularly high in the first 30 days of warfarin treatment
• Increased vascular calcification mediated through inactivation of matrix Gla
protein
• Warfarin-related nephropathy in patients with supratherapeutic INR levels

9. Problems with Vit K antagonists in CKD
• No data from randomized trials of VKAs exist for patients with ESRD
and AF, and observational studies in this population have yielded
conflicting results
• A mean time in the therapeutic range (TTR) of ≥65-70% is difficult to
maintain, due to reduced nonrenal and renal clearance of warfarin,
impaired drug metabolism and fluctuations in volume status
• The risks of stroke and bleeding in warfarin inexperienced patients
with AF and CKD are particularly high in the first 30 days of warfarin
treatment

10. Problems with Vit K antagonists in CKD
• Increased vascular calcification mediated through inactivation of
matrix Gla protein
• Warfarin-related nephropathy in patients with supratherapeutic INR
levels

11. Non Vit K oral anticoagulants
• In RCTs, they were either superior or noninferior to warfarin for stroke
prevention and exhibited better safety profiles than warfarin
• Fixed-dose regimens
• No requirement for routine laboratory monitoring
• A low probability for food and drug interactions

12. Site of action of NOACs and VKAs

13. Pharmacology of Direct Oral Anticoagulants
Dabigatran Rivaroxaban Apixaban Edoxaban
Target Thrombin Factor Xa Factor Xa Factor Xa
Half-Life (h) 12-17 5-9 12 10-14
Renal Excretion (%) 80 66 27 50
Fecal Excretion (%) Not Applicable 7 50 50
Hepatic metabolism No CYP3A4/5, CYP2J2 CYP3A4/5, others CYP3A4/5 minimal
Protein Binding (%) 35 92-95 87 55
Dialyzable Yes No No No
Reversal Agent Idarucizumab Andexanet Alfa Andexanet Alfa Andexanet Alfa

14. RE-LY Rocket-AF Aristotle Engage AF TIMI
Agent
(mechanism of action)
Dabigatran (direct
thrombin inhibitor)
Rivaroxaban(direct inhibitor
of activated factor X)
Apixaban (direct inhibitor
of activated factor X)
Edoxaban (direct inhibitor
of activated factor X)
NOAC dose 150 mg or 110 mg twice
daily
20 mg once daily 5 mg twice daily 60 mg or 30 mg once daily
the dose was halved:
estimated CrCl 30-50 ml/
min, body weight ≤60 kg or
concomitant use of
verapamil or quinidine
Patients (n) 18,113 14,264 18,201 21,105
Renal function exclusion <30 ml/min/1.73 m2 <30 ml/min/1.73 m2 <25 ml/min/1.73 m2 <30 ml/min/1.73 m2
Safety and efficacy of
NOAC in comparison to
Warfarin
150 mg dose: lower rates
of stroke and similar rates
of major hemorrhage
110 mg dose: similar rates
of stroke and less major
bleeding
Similar rates of stroke and
major bleeding
Less stroke and major
bleeding
Both doses: similar rates of
stroke with less major
bleeding
Safety in patients with CKD
(risk of major bleeding)
No significant interaction
of adverse effects with
renal function
No significant interaction of
adverse effects with renal
function
Lower risk of major
bleeding events relative to
warfarin in patients with
CKD than without CKD
No significant interaction
of adverse effects with
renal function
Efficacy for stroke
prevention in patients with
CKD
No significant interaction
of treatment effects with
renal function
No significant interaction of
treatment effects with
renal function
No significant interaction
of treatment effects with
renal function
No significant interaction
of treatment effects with
renal function

15. Dose NOACs according to renal function

16. Drug
(renal excretion)
CrCl (ml/min) ≥50 CrCl (ml/min) 30-49 CrCl (ml/min) 15-29 CrCl (ml/min) <15 ESRD on RRT
Preferred class NOAC NOAC VKA or NOAC
VKA > NOAC
(use with caution)
VKA > NOAC
(use with caution)
Dabigatran (80%)
150 mg twice daily or
110 mg twice daily if
age ≥80 years or
receiving verapamil or
increased bleeding risk
150 mg twice daily or
110 mg twice daily if
age ≥80 years or
receiving verapamil or
increased bleeding risk
USA:75 mg
Other areas: do not
use
Do not use Do not use
Rivaroxaban (35%) 20 mg once daily 15 mg once daily 15 mg once daily Do not use Do not use
Apixaban (27%)
5 mg twice daily or 2.5
mg twice daily if ≥2 of
following: age ≥80
years, body weight ≤60
kg and Cr ≥1.5 mg/dl
5 mg twice daily or 2.5
mg twice daily if ≥2 of
following: age ≥80
years, body weight ≤60
kg and Cr ≥1.5 mg/dl
2.5 mg twice daily
USA: 2.5 mg twice
daily
Other areas: do not
use
USA: 2.5 mg twice
daily
Other areas: do not
use
Edoxaban (50%)
60 mg once daily or 30
mg once daily if ≥2
of the following: body
weight ≤60 kg, CrCl 30-
50 ml/min and therapy
with verapamil,
dronedarone, quinidine
30 mg once daily 30 mg once daily Do not use Do not use

17. Laboratory monitoring
• There may be need of coagulation monitoring in CKD patients,
despite the fact that NOACs do not need routinely monitoring
• INR testing is not suitable for monitoring of NOACs
• Chromogenic assays (eg Rotachrom) and drug-specific testing may be
more reliable and accurate, but not widely spread
• Quantitative testing, for example with Hemoclot for dabigatran

18. Anticoagulant reversal
• Specific reversal agents available for dabigatran (idarucizumab) and
for the oral direct factor Xa inhibitors - andexanet alfa
• Pro-hemostatic therapies such as antifibrinolytic agents and DDAVP
• Non-specific agents such as prothrombin complex concentrates (PCC)

19. Anticoagulant reversal
• Idarucizumab should not be administered in normal thrombin time
The dose is 5 grams, either as infusion or as a bolus
• Hemodialysis may remove dabigatran from the circulation
• Andexanet alfa is a recombinantly produced, catalytically inactive
form of factor Xa that acts as a “decoy” to bind and sequester the
anticoagulant. This drug was approved by the US FDA in May 2018

20. Conclusion
• Decisions on whether and which type of oral anticoagulant to use in
patients with CKD and AF are strongly affected by the CKD stage
• There is lacking evidence for the efficacy and safety of NOACs in ESRD
patients
• There is an urgent need of prospective studies in this field