Novel oral anticoagulants in CKD review, Moh'd sharshir

Moh’d Sharshir, MD
Nephrology Fellow

INTRODUCTION
• Chronic kidney disease (CKD) and cardiovascular morbidity and mortality are intricately linked posing
unique challenges in the clinical setting.
• Atrial fibrillation is the most common arrhythmia in the CKD and dialysis populations and affects 15–
20% of patients.
• Declining estimated glomerular filtration rate (eGFR) and proteinuria are independently associated with
the risk of developing atrial fibrillation.

INTRODUCTION
• The combination of atrial fibrillation and CKD can lead to a four-fold to five-fold higher risk of stroke.
• CKD is also highly associated with venous thromboembolism (VTE) including deep vein thrombosis
(DVT), and pulmonary embolism.
• The reported relative risk for VTE was higher in patients with CKD, increasing with CKD severity,
compared with patients with normal kidney function [mild CKD – relative risk (RR) 1.28, 95% CI 1.02–
1.59; CKD stage 3/4 – RR 2.09, 95% CI 1.47–2.96].

INTRODUCTION
• Vitamin K antagonists (VKA) such as warfarin are the mainstay for stroke prevention in atrial fibrillation
and VTE.
• However, multiple drug and dietary interactions with warfarin compounded by vitamin K deficiency in the
CKD population limits the time in therapeutic range (TTR).
• This significantly affects warfarin’s safety and efficacy.

INTRODUCTION
• There is little evidence of the effectiveness of VKAs in stroke reduction in patients with advanced CKD
or on dialysis.
• In fact, there may be an increased bleeding risk.

INTRODUCTION
• Nonvitamin K oral anticoagulants (novel oral anticoagulants; NOAC)
are a group of anticoagulants that directly antagonize either factor II or
Xa in the coagulation cascade.
• Dabigatran: a direct thrombin inhibitor, inhibits the protease enzyme
that is responsible for the conversion of fibrinogen to fibrin (the final
step in the coagulation cascade).
• Rivaroxaban, Apixaban, and Edoxaban: work by inhibiting factor Xa,
the rate-limiting step in the coagulation cascade.

INTRODUCTION
• Multiple randomized controlled trials and real-world studies have identified NOACs as safer (i.e. lower
risk of bleeding and all cause mortality) and more efficacious (i.e. lower risk of ischemic stroke and
embolic events) medications in the general population whenever compared with warfarin.

INTRODUCTION
• NOACs still have clinical challenges:
 First, Unlike warfarin, NOACs do not have a standardized test to monitor drug levels.
 Secondly, all NOACs are renally excreted to various degrees (Table1).
• Accordingly, as patient’s eGFR decline the effects of NOACs become less predictable consequently
increasing bleeding risk. To address this, NOACs often have standard and reduced dosing to reflect
patients with normal and reduced eGFRs (Table 1).

INTRODUCTION
• NOACs still have clinical challenges:
 First, Unlike warfarin, NOACs do not have a
standardized test to monitor drug levels.
 Secondly, all NOACs are renally excreted to various
degrees .

Novel oral anticoagulants in CKD review, Moh'd sharshir

INTRODUCTION
• Understanding of the efficacy and safety of NOACs in CKD and end-stage kidney disease (ESKD) is still
underdeveloped:
 First, The major trials that evaluated NOACs excluded patients with a creatinine clearance (CrCl) less than 25–30ml/
min and on dialysis; patients that are at the highest risk of atrial fibrillation, stroke, and VTE.
 Secondly, little data is available regarding, which anticoagulant is most appropriate for patients with CKD and ESKD.

RECENT TRIALS

 The landmark trials assessing the efficacy and safety NOAC have led to a paradigm shift of the
management of atrial fibrillation and VTE from VKAs to NOACs.
 The American Heart Association (AHA) and the Canadian Cardiovascular Society recognize NOACs as preferable or
equivalent therapies to warfarin for the management of nonvalvular atrial fibrillation.
 The American College of Chest Physicians (CHEST) identifies NOACs as preferable long-term anticoagulants in
noncancer related DVT and pulmonary embolism.

RECENT TRIALS
• Recent studies have re-analysed data from these landmark trials focusing on reduced eGFRs and its
effects on the efficacy and safety of NOACs.

RECENT TRIALS
(ROCKET-AF) TRIAL.

RECENT TRIALS
(ROCKET-AF) TRIAL.
A recent study conducted a post hoc analysis of The Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation
(ROCKET-AF) trial.
 The investigators reanalyzed the patients with at least four creatinine measurements at set intervals.
 Worsening renal function was defined as a deterioration of more than 20% of CrCl from screening measurement at any time during the study period.

RECENT TRIALS
(ROCKET-AF) TRIAL.
A recent study conducted a post hoc analysis of The Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation
(ROCKET-AF) trial.
 Participants with worsening renal function on rivaroxaban had a reduction in stroke or systemic embolism
compared with worsening renal function on warfarin (hazard ratio 0.50, 95% CI 0.27–0.93; P=0.05).
 This was not observed in the stable renal function population.
 No significant difference between participants with worsening renal function on rivaroxaban or warfarin in regard to
safety was appreciated.

RECENT TRIALS
(ARISTOTLE) TRIAL

RECENT TRIALS
(ARISTOTLE) TRIAL
• A similar study re-analysed the data of the Apixaban for Reduction in Stroke and Other
Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial.
 The investigators divided participants into three groups based on renal function (eGFR >80ml/min, eGFR 50–80ml/min, eGFR <49ml/min) and a fourth group
for patients with worsening renal function (eGFR deterioration >20%).

RECENT TRIALS
(ARISTOTLE) TRIAL
 Patients randomized to apixaban had improved outcomes independent of renal function.
 Worsening renal function was associated with overall worse outcomes irrespective of baseline renal function.

RECENT TRIALS
(ARISTOTLE) TRIAL
 However, the relative risk of stroke or systemic embolism (hazard ratio 0.80, 95% CI 0.51–1.24; P=0.86), ischemic
or unspecified stroke (hazard ratio 0.88, 95% CI 0.52–1.48, P=0.94) and major bleeding (hazard ratio 0.76, 95% CI
0.54– 1.07, P=0.73) was lower in participants randomized to apixaban compared with warfarin.

RECENT TRIALS
ENGAGE AF-TIMI 48

RECENT TRIALS
ENGAGE AF-TIMI 48
The ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation –
Thrombolysis in Myocardial Infarction Study 48) trial assessed the efficacy and safety of edoxaban against
warfarin.
 Investigators conducted a subgroup analysis based on high-dose edoxaban (HDER) or low-dose edoxaban (LDER) regimens versus dose-adjusted warfarin
[target international normalized ratio (INR) 2.0–3.0] and kidney function (CrCl 30–50ml/min; CrCl 51–95ml/min; CrCl >95ml/min).

RECENT TRIALS
ENGAGE AF-TIMI 48
The ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation –
Thrombolysis in Myocardial Infarction Study 48) trial assessed the efficacy and safety of edoxaban against
warfarin.
 HDER and LDER versus warfarin was statistically significant in reducing composite outcomes of stroke, systemic
embolism, major bleeding, or death at CrCl 30–50ml/min and CrCl 51–95ml/min.
 Major bleeding was significantly reduced for both HDER and LDER whenever compared with warfarin for both the
reduced renal function groups.

RECENT TRIALS
 These post hoc analyses continue to demonstrate the efficacy and safety of NOACs in patients with
CKD or worsening kidney function.
 However, the relatively small numbers of the subgroup analyses and focus on only one NOAC per
study makes inferences about which NOAC is preferable in CKD a difficult task.

RESULTS FROM RECENT NETWORK
META-ANALYSES

RESULTS FROM RECENT NETWORK META-ANALYSES
• A recent meta-analysis assessed the efficacy of NOACs against warfarin in regards to efficacy in CKD.

 Investigators found a 21% reduction in the odds of stroke or systemic VTE for high-dose NOACs compared with warfarin (0.79, 95%
CI 0.67–0.94).
 A 29% reduction was found between high-dose NOACs and low-dose groups (0.71, 95% CI 0.57–0.89).
 NOACs were associated with lower incidence of major bleeding in a dose-dependent fashion.
 Dabigatran 150 mg was statistically superior to warfarin in reducing the efficacy outcome (OR 0.56, 95% CI 0.36–0.86).
 Other NOACs were comparable with VKA for stroke and VTE reduction.

 Two meta-analyses demonstrated NOACs to have a superior safety profile than warfarin in the CKD
population [33,51].
 One study [51] found the incidence of major bleeding was lower with NOACs than with warfarin in a dose-
dependent fashion (OR 0.61, 95% CI 0.50–0.74 for low-dose NOACs and OR 0.74, 95% CI 0.65–0.86 for full/single-
dose NOACs, both as compared with warfarin).

 Two meta-analyses demonstrated NOACs to have a superior safety profile than warfarin in the CKD
population [33,51].
 Other investigators [33] found that the composite risk of major bleeding was reduced by 19% in patients with
reduced eGFRs taking NOACs compared with VKAs (RR 0.81; 95% CI 0.71–0.93).

 One study [52] did not demonstrate a statistically significant difference between patients on NOACs
against VKAs in both minor kidney disease (CrCl 50–80 ml/min; RR 0.87 [95% CI 0.81–0.93]) and
moderate kidney disease (CrCl 25–49 ml/min; RR 0.83 [95% CI 0.68–1.02]) in regards to safety.

 However, whenever individual NOACs were analysed in subgroup analysis, apixaban and edoxaban
were associated with a decreased risk for major bleeding in patients with a CrCl less than 50ml/min
(apixaban – RR 0.52; CI 0.40–0.68; edoxaban – RR 0.77; CI 0.40–0.68) [52].

 Cumulatively, these studies continue to affirm that NOACs, as a class of drugs, offer either an
equivalent [52] or superior safety [33,51] and efficacy profile than VKAs in patients with impaired
kidney function.
 Further, network meta-analyses support NOACs as equivalent or superior to VKAs in preventing
stroke and systemic embolism [51].

In particular, dabigatran 150 mg daily and apixaban seem to be the most efficacious in patients with
atrial fibrillation and a CrCl of 25–30 to 50ml/ min and apixaban has been identified as a particularly
well tolerated medication in the CKD population for both atrial fibrillation and VTE.

REAL-WORLD SAFETY AND EFFECTIVENESS OF NOVEL
ORAL ANTICOAGULANTS IN CHRONIC KIDNEY DISEASE
• NOACs as patients with CKD were underrepresented in the major trials.
• Post-marketing surveillance or observational studies offer rigorous and complementary evidence to
RCTs as they provide real-world data on prescribing practices and safety.

• As the only Food and Drug Administration (FDA)-approved NOAC for use with CrCl less than 15ml/min,
apixaban is the only NOAC studied in the hemodialysis population.
A Multicenter Analysis of Factors Associated With Apixaban-Related Bleeding in Hospitalized Patients With End-Stage Renal Disease on Hemodialysis. Steuber TD

• Recent observational studies have continued to demonstrate rivaroxaban and dabigatran as similar or
superior alternatives to VKAs in the CKD population.
Impact of renal function on ischemic stroke and major bleeding rates in nonvalvular atrial fibrillation patients treated with warfarin or rivaroxaban: a retrospective cohort study using real-world evidence.

CONCLUSION
 The relationship between CKD, atrial fibrillation, stroke, and VTEs are intimately linked.
 This poses challenges for clinicians balancing risks of bleeding with stroke and systemic embolism.
 The evidence for supporting the use of NOACs in CKD is slowly increasing. In particular, apixaban has
been identified as an ideal alternative to VKAs such as warfarin.

CONCLUSION
 However, the conclusions are limited by the lack of RCTs studying patients with CrCl less than 30ml/
min as well as head-to-head comparisons of NOACs.
 Given their popularity, ease of use, and consistency in research settings, it is anticipated that NOAC
use will continue to rise in patients with CKD.

• Other observational studies, however, have found apixaban to be similar in efficacy and safety to
warfarin.
• In a small, retrospective cohort study, Stanton et al. [56] identified that patients with ESRD and NVAF
had equal rates of ischemic stroke (7.5% in both groups).
• No recurrent VTEs occurred between either group. Further, apixaban was associated with a lower rate
of bleeding (9.6 versus 17.8% in the VKA group). Investigators [57] compared apixaban and warfarin in
patients with ESRD undergoing chronic hemodialysis for the treatment or prevention of VTE.
• Again, there was no statistically significant difference between apixaban and warfarin regarding major
bleeding, clinically relevant nonmajor bleeding; or minor bleeding.
• These studies are limited by their small sample size and clinical context making the generalizability of
these studies difficult [56,57].

• A recent population-based nested case–control study focusing on the safety of dabigatran and
rivaroxaban versus warfarin in moderate CKD (median eGFR 38ml/min per 1.73m2) in Ontario, Canada
[59] could not find a statistical different risk of major hemorrhage compared with warfarin (dabigatran:
OR 1.15, 95% CI 0.91–0.45; rivaroxaban: OR 1.22, 95% CI 0.83–1.79) [59].

• The investigators conducted a nationwide cohort study of the rates of stroke prevention in dose-reduced
NOACs versus in the CKD population with NVAF versus warfarin and included a reduced dose
subgroup analysis based patients on age (age 80) and/or renal disease.
• Notably, researchers did not have access to eGFR or creatinine clearance at the time of treatment
initiation. A ‘reasonable clinical assumption’ was made as to why the NOAC was dose-reduced
participants (an assumption that would likely lead to significant misclassification).

• Apixaban was associated with higher 1-year rates of ischemic stroke or systemic embolism compared
with warfarin (hazard ratio 1.24,95% CI1.00– 1.55).
• Rivaroxaban was associated with a significant decrease in rates (hazard ratio 0.63, 95% CI 0.69– 1.24)
of stoke or systemic embolism.
• Dabigatran and apixaban had lower rates of composite bleeding in comparison with warfarin
(dabigatran: hazard ratio 078, 95% CI 0.61–0.99; apixaban: hazard ratio 0.81, 95% CI 0.69–0.94).
• Rivaroxaban had similar bleeding rates to warfarin (hazard ratio 1.00, 95% CI 0.81–1.24).
• The results of Nielsen et al. [60] continues to demonstrate NOACs, and in particular, rivaroxaban as well
tolerated alternatives to warfarin.

Novel oral anticoagulants in CKD review, Moh'd sharshir

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