Introduction
Patients with chronic kidney disease (CKD) are predisposed to heart rhythm disorders,
including atrial fibrillation (AF)/atrial flutter, supraventricular tachycardias,
ventricular arrhythmias, and sudden cardiac death (SCD). While treatment options,
including drug, device, and procedural therapies, are available, their use in the
setting of CKD is complex and limited. Patients with CKD and end-stage kidney disease
(ESKD) have historically been under-represented or excluded from randomized trials
of arrhythmia treatment strategies,
1
although this situation is changing.
2
Cardiovascular society consensus documents have recently identified evidence gaps
for treating patients with CKD and heart rhythm disorders.
3–7
To identify key issues relevant to the optimal prevention, management, and treatment
of arrhythmias and their complications in patients with kidney disease, Kidney Disease:
Improving Global Outcomes (KDIGO) convened an international, multidisciplinary Controversies
Conference in Berlin, Germany, titled CKD and Arrhythmias in October 2016. The conference
agenda and discussion questions are available on the KDIGO website (http://kdigo.org/conferences/ckd-arrhythmias/;
13 February 2018).
Atrial fibrillation and stroke in kidney disease
Epidemiology
Atrial fibrillation is the most common sustained arrhythmia.
8
Chronic kidney disease affects 10% of adults worldwide,
9
and patients with CKD have an increased burden of AF compared with those without CKD
(Supplementary material online, Table S1
). The prevalence of AF is high: estimates range from 16% to 21% in CKD patients not
dependent on dialysis
10–12
and 15% to 40% in patients on dialysis (Supplementary material online, Table S1
).
13–18
Chronic kidney disease and AF share many risk factors, making it difficult to discern
the contributions of individual factors to either condition or associated outcomes
(Figure 1
). For non-dialysis CKD, there seems to be an independent relationship between CKD
and the risk of AF,
19–25
although this association has not been well characterized across the spectrum of estimated
glomerular filtration rate (eGFR) or proteinuria.
13
,
14
,
26
,
27
In the USA, both incidence and prevalence of AF are increasing among haemodialysis
patients,
27
,
28
which could be because of older age of patients, better ascertainment of AF, and improved
survival after vascular events.
Figure 1
Relationship between chronic kidney disease and atrial fibrillation: shared risk factors
and outcomes. Chronic kidney disease and atrial fibrillation share a number of risk
factors and conditions that promote their incidence, possibly via systemic processes
such as inflammation, oxidative stress, or fibrosis. It is established that chronic
kidney disease increases the incidence of atrial fibrillation and there is some evidence
to suggest that atrial fibrillation also increases chronic kidney disease progression.
When examining the strength of these associations, we acknowledge the potential impact
of detection bias in observational studies where more frequent exposure to healthcare
likely prompts more clinical findings in this comorbid population. AF, atrial fibrillation;
CKD, chronic kidney disease; CVD, cardiovascular disease.
Consequences of atrial fibrillation in chronic kidney disease
The risk of stroke is elevated in non-dialysis
29–32
and dialysis
29
,
31
,
33
CKD (Supplementary material online, Table S2
). Separately, both CKD and AF are risk factors for stroke, but it is currently unknown
whether the prognostic significance of CKD markers and AF is independent or interdependent.
The association between AF and CKD may be bidirectional; AF may predict new-onset
low GFR and proteinuria.
21
In CKD, the adjusted risk ratios of stroke with AF have varied considerably across
CKD subpopulations, ranging from 4.2 in women in the general population,
34
1.3 in dialysis patients,
33
,
35
and with modestly significant (1.4)
36
and non-significant
37
associations after kidney transplantation. These differences may be due to greater
competing risk of death in more advanced CKD,
35
a higher baseline risk of stroke in CKD without AF, or a higher prevalence of unrecognized
AF.
AF increases the risk of incident CKD and progression to ESKD
21
,
38–40
(Supplementary material online, Table S3
), and increases risk of death in patients with non-dialysis CKD and those on dialysis.
13
,
35
,
41
,
42
Other outcomes related to AF, including heart failure, SCD, and myocardial infarction
(MI), require further research. The contribution of AF as a mediator of stroke in
CKD, as well as the stroke subtypes observed, requires further study. The competing
risk of death in CKD may reduce the importance of the contribution of AF to stroke,
which could mitigate the effectiveness of some stroke prevention strategies.
35
Stroke risk scores
The predictive value and calibration of the CHADS2 and CHA2DS2-VASc stroke prediction
scores have only been evaluated in dialysis patients, in which performance appears
to be similar to their performance in the general population.
16
,
33
,
43
,
44
Inclusion of CKD in risk scores to improve stroke prediction has demonstrated variable
results. Adding two points for creatinine clearance < 60 mL/min to CHADS2 (called
R2CHADS2) improved net reclassification index (NRI) but not C-statistic in one large
study using external validation
30
but did not improve NRI or C-statistic in other studies.
45
,
46
The ATRIA score, which includes terms for GFR < 45 mL/min/1.73 m2 and proteinuria,
demonstrated improved NRI and borderline improvement in C-statistic compared with
CHADS2 and CHA2DS2-VASc in external validation,
47
although NRI may not be clinically meaningful.
48
For these reasons and for the potential for categorically recommending oral anticoagulant
(OAC) to most patients with CKD without regard to competing risks, CHA2DS2-VASc remains
the most commonly recommended score for risk stratification,
5
,
49
and observational data have shown that a treatment threshold of CHA2DS2-VASc ≥ 2 is
associated with OAC benefit, even in CKD.
50
Bleeding risk scores
The HAS-BLED, ORBIT, HEMORR2HAGES, and ATRIA bleeding risk scores all include CKD
measures. Although the formal use of these bleeding risk scores has not been recommended
by the majority of professional society guidelines,
49
,
51
the increased risk of bleeding with and without OAC in CKD is well described and should
be considered in clinical decision making.
Stroke prevention and oral anticoagulation
The pathophysiologic mechanisms responsible for stroke/thromboembolism in patients
with CKD and AF are multifactorial and poorly understood; the precise contribution
of cardio-embolic vs. non-cardioembolic factors is unclear. Atrial fibrillation may
be a direct cause of cardio-embolic stroke, a risk marker of ischaemic stroke including
atherothrombotic subtypes, and in rare cases, a consequence of stroke.
52
Chronic kidney disease patients with estimated creatinine clearance of 30–50 mL/min
Pivotal randomized controlled trials (RCTs) have established that direct oral anticoagulants
(DOACs) are non-inferior to warfarin among patients with Cockroft–Gault estimated
creatinine clearance (eCrCl) of 30–50 mL/min (for apixaban, 25–50 mL/min).
53–56
However, there is insufficient evidence to recommend any one DOAC over any other in
this population because no head-to-head trials have directly compared individual DOACs
57–62
(Table 1
). Indirect comparisons are challenging because these trials differed in inclusion
criteria and outcome definitions.
Table 1
Evidence from randomized trial data regarding therapeutic anticoagulation on the basis
of kidney function
4
,
63
,
64
eCrCl (mL/min)
a
Warfarin
Apixaban
b
Dabigatran
Edoxaban
c
Rivaroxaban
>95
Adjusted dose (INR 2–3)
5
mg b.i.d.
150
mg b.i.d.
60
mg QD
d
20
mg QD
51–95
Adjusted dose (INR 2–3)
5
mg b.i.d.
150
mg b.i.d.
60
mg QD
20
mg QD
31–50
Adjusted dose (INR 2–3)
5
mg b.i.d.(eCrCl cut-off 25 mL/min)
150
mg b.i.d. or 110
mg b.i.d.
e
30
mg QD
15
mg QD
INR, international normalized ratio.
a
Cockcroft-Gault estimated creatinine clearance (eCrCl).
b
Apixaban dose modification from 5
mg b.i.d. to 2.5
mg b.i.d. if patient has any two of the following: serum creatinine ≥1.5
mg/dL, age ≥80
years, or body weight ≤60
kg.
c
In the ENGAGE-AF TIMI 48 study, the dose was halved if any of the following: eCrCl
of 30–50
mL/min, body weight ≤60
kg, or concomitant use of verapamil or quinidine (potent P-glycoprotein inhibitors).
d
This dose has not been approved for use by the US Food and Drug Administration in
this category of kidney function.
e
In countries where 110 mg b.i.d. is approved, clinicians may prefer this dose after
clinical assessment of thromboembolic vs bleeding risk. This dose has not been approved
for use by the US Food and Drug Administration.
Although efficacy (prevention of stroke and systemic embolism) may merely be non-inferior
to warfarin, the safety profile of DOACs compared to warfarin does appear to be superior.
In all pivotal RCTs, DOACs have been associated with a significant reduction (about
50%) in risk of intracranial haemorrhage compared to warfarin. Among patients with
eCrCl between 25 and 50 mL/min, treatment with apixaban and edoxaban resulted in significantly
fewer major bleeding events compared with warfarin (Figure 2
).
63
Although these observations do not necessarily indicate the superiority of apixaban
and edoxaban relative to other DOACs, it may be helpful to clinicians when treating
patients at particularly high-bleeding risk or low time in therapeutic range (TTR)
values while receiving warfarin or other vitamin K antagonists (VKAs).
Figure 2
Efficacy and safety of direct oral anticoagulants (DOACs) vs. warfarin in the subgroup
of patients with moderate chronic kidney disease from randomized controlled trials
in atrial fibrillation. Comparison of hazard ratios and 95% confidence intervals for
primary efficacy and safety outcomes for 150 and 110 mg dabigatran twice daily, 15 mg
rivaroxaban once daily, 5 mg apixaban twice daily, and 30 mg edoxaban once daily.
Chronic kidney disease was defined as estimated creatinine clearance of 30 to 49 mL/min
or as 25 to 49 mL/min for apixaban. aApixaban 2.5 mg twice daily if patient had any
two of the following: age ≥ 80 years, body weight ≤ 60 kg, or serum creatinine ≥1.5 mg/dL.
Reproduced from Qamar and Bhatt
63
with permission from the publisher.
Chronic kidney disease G4, G5, and G5D
In the absence of trial data, the results from observational studies on the efficacy
and safety of anticoagulation for stroke prevention in CKD patients with eCrCl < 30 mL/min
not on dialysis are conflicting as they are for CKD G5D (Table 2
).
65
There is insufficient high-quality evidence to recommend warfarin or other VKAs for
prevention of stroke in CKD G5D patients with AF, especially when balancing the significant
risks of bleeding, accelerated vascular calcification, and calcific uraemic arteriopathy
associated with VKA therapy.
66
A pooled meta-analysis of 56 146 CKD G5D patients with AF from 20 observational cohort
studies demonstrated an increase in all-cause bleeding associated with VKA therapy
without benefit in reduction of all-cause stroke or ischaemic stroke.
65
Yet, a well-conducted observational analysis of acute MI patients with AF from the
SWEDEHEART registry (2003–2010) found that VKA therapy was associated with a reduced
risk of a composite of death, MI, and ischaemic stroke with no increase in bleeding
risk across the spectrum of CKD.
67
The high time in international normalized ratio (INR) TTR in Sweden (>75%) likely
contributed to these findings and has been difficult to replicate in other health
systems.
68
A large US health care system analysis found that CKD severity is associated with
decreased TTR despite similar INR monitoring intensity.
69
These findings suggest that TTR is more likely to be poor in CKD and can mediate the
increased stroke and bleeding risk in CKD.
70
VKAs may lead to CKD via repeated subclinical glomerular haemorrhages
71
or through accelerated tissue or vascular calcification.
72
Table 2
Chronic kidney disease categories lacking randomized clinical trial data on the utility
of anticoagulation
4
,
63
,
64
eCrCl (mL/min)
a
Warfarin
Apixaban
b
Dabigatran
Edoxaban
Rivaroxaban
15–30
Adjusted dose for INR 2–3 could be considered
2.5
mg PO b.i.d. could be considered
Unknown (75
mg PO b.i.d.)c,d
30
mg QD
e
could be considered
15
mg QD could be considered
<15 not on dialysis
Equipoise based on observational data and meta-analysis
Unknown (2.5
mg PO b.i.d.)
c
Not recommended
Not recommended
Unknown (15
mg QD)
c
<15 on dialysis
Equipoise based on observational data and meta-analysis
Unknown (2.5
mg PO b.i.d.)
c
Not recommended
Not recommended
Unknown (15
mg QD)
c
INR, international normalized ratio.
Dosing of direct oral anticoagulants (DOACs) based solely on limited pharmacokinetic
and pharmacodynamic data (no randomized efficacy or safety data exist).
a
Cockcroft-Gault estimated creatinine clearance.
b
Apixaban dose needs modification to 2.5
mg b.i.d. if patient has any two of the following: serum creatinine ≥1.5
mg/dL, age ≥80
years, or body weight ≤60
kg.
c
DOAC doses listed in parenthesis are doses that do not currently have any clinical
safety or efficacy data. The doses of DOACs apixaban 5
mg b.i.d.b, rivaroxaban 15
mg QD and dabigatran 75
mg b.i.d. are included in the United States Food and Drug Administration approved
labelling based on limited dose pharmacokinetic and pharmacodynamics data with no
clinical safety data. We suggest consideration of the lower dose of apixaban 2.5
mg PO b.i.d. in CKD G5/G5D to reduce bleeding risk until clinical safety data are
available.
d
Dabigatran 75
mg available only in the USA.
e
The dose was halved if any of the following: estimated CrCl of 30–50
mL/min, body weight of ≤60
kg, or concomitant use of verapamil or quinidine (potent P-glycoprotein inhibitors).
The US Food and Drug Administration recently approved mention of the doses of apixaban
5 mg twice daily (with contingent dose modifications) and rivaroxaban 15 mg daily
in CKD G5 and G5D (and dabigatran 75 mg orally twice daily for eCrCl 15–30 mL/min)
on the respective labels based on single/limited dose pharmacokinetic and pharmacodynamic
data with no clinical safety data.
73–76
The conference attendees suggest consideration of the lower dose of apixaban 2.5 mg
orally twice daily in CKD G5/G5D to reduce bleeding risk until clinical safety data
are available, an approach supported by a recent pharmacokinetic study comparing the
two doses.
77
Recognizing that many CKD patients would likely qualify for a dose reduction to apixaban
2.5 mg orally twice daily anyway (if age ≥80 years or body weight ≤ 60 kg), this suggestion
honours the ‘first do no harm’ principle, while acknowledging the lack of clinical
efficacy or safety data in this regard (Table 2
).
Randomized clinical trials are particularly needed to evaluate VKA use in patients
with CKD G5D. A clinical trial evaluating VKAs vs. no oral anticoagulation (AVKDIAL,
NCT02886962) is planned. It is not known whether DOACs have an advantage over VKAs
in CKD G5D patients with AF. The AXADIA (NCT02933697) and RENAL-AF (NCT02942407) trials
of apixaban vs. VKAs in ESKD are enrolling in Germany and USA.
Pragmatic considerations while managing anticoagulation in chronic kidney disease
In pivotal RCTs, study eligibility and DOAC dose assignments were based on kidney
function as assessed using eCrCl (Cockcroft-Gault). However, in clinical practice,
other measures such as eGFR are routinely used. Given the imprecision in measures
for estimating kidney function, individualization of DOAC dosing based on either method
is reasonable.
78–80
Important safety concerns, mainly increased fatal or non-fatal bleeding, emerged after
the early ‘off-label’ prescriptions of dabigatran and rivaroxaban in patients with
CKD G5D.
81–83
A recent study of 1473 AF patients with renal indication for dose reduction found
that 43% were potentially overdosed with DOACs, resulting in higher bleeding risk.
84
These adverse signals suggest the need for systemic measures focused on patient safety
to guide clinicians regarding the use of DOACs.
85
Team-based, multidisciplinary active communication, particularly involving the nephrologist,
cardiologist (or cardiac electrophysiologist), primary care physician, and when possible,
clinical pharmacist, may be useful to evaluate the risk–benefit of any decision regarding
choice of VKA or a DOAC.
5
,
85
For CKD patients receiving DOAC therapy, we recommend periodic monitoring of kidney
function because decline over time may necessitate dose modification.
86
There are no data to indicate the optimal frequency of monitoring, but it may be clinically
reasonable to assess kidney function every 6 to 12 months, (or at least yearly, consistent
with professional society guidelines),
5
with more or less frequent monitoring as appropriate based on recency of DOAC initiation,
CKD severity, and CKD trajectory. For all CKD patients on anticoagulant therapy, annual
re-evaluation of treatment goals and discussion of pros and cons of anticoagulant
therapy should be considered.
Periprocedural/perioperative management of DOACs is contingent upon individual agents
and eCrCl, for which recommended parameters exist (Table 3
).
4
,
87
For patients with CKD G5D on anticoagulants, strategies to reduce bleeding warrant
systematic research but may include minimizing heparin with dialysis, use of citrate
locks for catheters,
88
consideration of prophylaxis for gastrointestinal bleeding when clinically indicated,
tight blood pressure control, and discontinuation of concurrent antiplatelet agents
if clinically reasonable.
Table 3
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)
Dabigatran
Apixaban–Edoxaban–Rivaroxaban
No important bleeding risk and/or adequate local haemostasis possible: perform at
trough level (i.e. ≥12 or 24
h after last intake)
Low risk
High risk
Low risk
High risk
CrCl ≥ 80
mL/min
≥24
h
≥48
h
≥24
h
≥48
h
CrCl 50–80
mL/min
≥36 h
≥72 h
≥24
h
≥48
h
CrCl 30–50
mL/min
a
≥48 h
≥96 h
≥24
h
≥48
h
CrCl 15–30
mL/min
a
No official indication
No official indication
≥36 h
≥48 h
CrCl
<
15
mL/min
No official indication for use
There is no need for bridging with LMWH/UFH
Bold values deviate from the common stopping rule of ≥24
h low risk, ≥48
h high risk. Low risk is defined as a low frequency of bleeding and/or minor impact
of a bleeding. High risk is defined as a high frequency of bleeding and/or important
clinical impact. Adapted from Heidbuchel et al.
4
CrCl, creatinine clearance; DOAC, direct oral anticoagulant; LMWH, low molecular weight
heparin; UFH, unfractionated heparin.
a
Many of these patients may be on the lower dose of dabigatran (110
mg b.i.d.) or apixaban (2.5
mg b.i.d.), or have to be on the lower dose of rivaroxaban (15
mg OD) or edoxaban (30 mg OD). Dabigatran 110 mg b.i.d. has not been approved for
use by the US Food and Drug Administration.
Anticoagulation reversal protocols are well established for warfarin and VKAs. Idarucizumab
has been approved for reversing dabigatran, and andexanet alfa has been developed
for reversal of anti-Xa agents. Data specific to reversal in CKD patients are limited.
89
Antiplatelet therapy for stroke prevention for atrial fibrillation in chronic kidney
disease
In a general, mostly non-CKD population, the AVERROES trial of aspirin vs. apixaban
was stopped early due to a higher risk of stroke with aspirin but with similar bleeding
risk in both groups.
90
However, there is insufficient evidence to recommend single or dual antiplatelet therapy
for prevention of stroke/thromboembolism in AF among patients with CKD G4, G5, or
G5D, even when OAC is considered undesirable. Similarly, these patients should not
receive concomitant antiplatelet therapy while taking anticoagulants, unless there
is a specific secondary indication (e.g. recent coronary stent). The duration of concomitant
single or dual antiplatelet therapy in those receiving anticoagulants needs to be
minimized and individualized based on clinical factors and type of stent.
91
Left atrial appendage occlusion in chronic kidney disease
The left atrial appendage (LAA) is believed to be the site of thrombus formation for
most AF-related cardio-embolic strokes. Circulatory exclusion of the LAA represents
a non-pharmacological, device-based therapy for stroke prevention that could conceivably
be an option in moderate to high stroke risk in CKD, particularly with contraindications
to long-term OAC. Five-year data from two randomized trials of the Watchman® LAA occlusion
device demonstrated a reduction in stroke risk comparable to warfarin but with additional
reduction in major bleeding.
92
However, CKD prevalence or severity was not reported and could have been under-represented.
The majority of patients receiving the device in trials and in practice are continued
on dual- or single-antiplatelet drug therapy, which may be associated with higher
bleeding risk in CKD. Moreover, enrolled subjects were without contraindications and
hence randomized. Registry data of the Amplatzer Cardiac Plug, a similar device, has
shown comparable procedural safety in CKD vs. normal kidney function.
93
A randomized trial of LAA occlusion vs. VKAs in CKD Stages 4 and 5 (CKD G4 and G5)
is ongoing (https://clinicaltrials.gov/ct2/show/NCT02039167; 13 February 2018).
Rate vs. rhythm control of atrial fibrillation
Indications for a rhythm control strategy in CKD patients mirror those in the general
population. The major evidence-based indication for a rhythm-control strategy for
AF is symptom reduction, although many patients are asymptomatic.
5
,
49
Older randomized trials have demonstrated that rhythm and rate control strategies
are equivalent in terms of their effects on risks of heart failure, stroke, and survival.
94–97
Retrospective analyses have suggested rhythm control with ablation provides superior
outcomes, but the evidence is limited. Regardless of which strategy is pursued, anticoagulation
should also be continued based on stroke risk (as indicated by the CHADS2 or CHA2DS2-VASc
score), unless otherwise contraindicated. Additional factors that may favour attempts
at rhythm control include difficulty in achieving adequate rate control, younger patient
age, tachycardia-mediated cardiomyopathy, first episode of AF, AF that is precipitated
by an acute illness or surgery, and patient preference (Figure 3
).
5
,
49
Haemodialysis patients with haemodynamic instability due to AF during dialysis sessions
may benefit from rhythm control. The impact of its treatment on outcome is unknown.
98
Patients without clear indications for a rhythm control strategy should default to
rate control. In the general population of patients with permanent AF and preserved
ejection fraction, lenient rate control (i.e. resting heart rate < 110 beats per minute)
has been shown to be equivalent to a strict rate control for a combined endpoint including
stroke, heart failure, death, and need for pacemaker or implantable cardioverter-defibrillator
(ICD).
99
Figure 3
Algorithm for decision-making about rate vs. rhythm control in chronic kidney disease.
Especially since chronic kidney disease patients show a lot of specific characteristics
regarding history, comorbidities and personal preferences, in each patient an individualized
decision should be made. Many aspects should be taken into account: the duration of
atrial fibrillation, the symptom severity, renal clearance (risk of toxicity, dialyzability),
and potential contraindications for antiarrhythmic drugs due to structural heart disease,
which is very frequent in these patients (such as left ventricular hypertrophy, reduced
ejection fraction, obstructive coronary artery disease). Moreover, proarrhythmic effects
(such as QT prolongation) may be pronounced because of electrolyte imbalances in chronic
kidney disease. The figure suggests an algorithm presenting the most relevant criteria
that should be incorporated into a multidisciplinary decision-making process, including
the treating nephrologist, a heart rhythm specialist, and eventually also physicians
of other disciplines. Of note, regardless of which strategy is chosen, oral anticoagulation
should always be administered in early stages of chronic kidney disease and at least
be considered in advanced stages of chronic kidney disease (see section on Stroke
prevention and oral anticoagulation). AF, atrial fibrillation; CKD, chronic kidney
disease; EF, ejection fraction; eGFR, estimated glomerular filtration rate; HD, haemodialysis;
LA, left atrial; LVEF, left ventricular ejection fraction; LVH, left ventricular hypertrophy.
Adapted in part from Kirchhof et al.
5
No RCTs have specifically compared rate vs. rhythm control or strict vs. lenient rate
control in patients with CKD or ESKD. In a post hoc analysis of the GUSTO III trial,
treatment with a rhythm or rate control strategy did not significantly impact short-
or long-term mortality regardless of kidney disease status.
100
Considerations about rate control
Special considerations in CKD include alterations in symptomatology and a potentially
increased propensity to develop tachycardia-mediated cardiomyopathy, given the prevalence
of structural heart disease. Moreover, the pharmacokinetic and dialyzability of rate
control agents in CKD need to be considered (Table 4
). When the ventricular rate cannot be controlled with medical therapies alone, atrioventricular
nodal ablation and pacemaker implantation can be considered. However, the high rates
of complications from transvenous devices in haemodialysis patients should enter into
the decision-making process.
107
Whether leadless pacemakers have a role in this situation remains to be determined.
Table 4
Characteristics of antiarrhythmic drugs for rate control in chronic kidney disease
Drug
Protein binding
Elimination
Dialyzable
Dosing in CKD
Atenolol
5%
Excreted unchanged in urine
Yes
Dose may need to be reduced
Propranolol
>90%
Hepatic metabolism
No
Serum creatinine may increase, but no dose adjustment is needed
Bisoprolol
30%
50% excreted unchanged in urine
No
Dose may need to be reduced in advanced CKD
Metoprolol
12%
Hepatic metabolism
Yes
No dosage reduction needed
Carvedilol
99%
Mainly biliary and 16% urinary
No
Specific guidelines for dosage adjustments in renal impairment are not available;
it appears no dosage adjustments are needed
Labetalol
50%
Inactive metabolites excreted in urine (5% unchanged) and bile
No
Dose reduction recommended in the elderly
Verapamil
90%
70% is excreted in the urine and 16% in faeces
No
Dose reduction by 20–25% if CrCl < 10 mL/min, not cleared by haemodialysis
Diltiazem
70–80%
2–4% unchanged drug excreted in the urine
No
Use with caution
Digoxin
20–30%
Main route of elimination is renal (closely correlated with the GFR) with 25–28% of
elimination by non-renal routes
No
Dosage adaptation is required, monitoring of serum digoxin levels
Modified from Potpara et al.
101
and Weir et al.
102
Metoprolol elimination data from Hoffman et al.
103
Labetalol protein binding data from Drugbank.ca
104
and dialyzability data from in vitro data by Daheb et al.
105
All other dialyzability data from Frishman.
106
CKD, chronic kidney disease; CrCl, creatinine clearance; GFR, glomerular filtration
rate.
Considerations about rhythm control
Direct current cardioversion (DCCV) is the most commonly used method of rhythm restoration
in patients with persistent AF. The success rate of DCCV been reported to be similar
regardless of kidney function.
108
However, the risk of recurrence of AF increases as eGFR decreases, although patients
with mild-to-moderate CKD in whom sinus rhythm is maintained may experience an improvement
in kidney function.
109
Direct current cardioversion alone is generally insufficient to maintain normal sinus
rhythm, and long-term antiarrhythmic drugs or ablation are necessary for rhythm control.
The use of antiarrhythmic drugs for rhythm control is limited in patients with CKD
because of issues with renal clearance and proarrhythmic risks in individuals with
structural heart disease (Table 5
). Amiodarone, the antiarrhythmic drug most commonly used to treat AF, does not appear
to negatively affect survival, regardless of eGFR function, even in ESKD.
111
Whether CKD patients treated with amiodarone are at higher risk for organ toxicity
is unknown.
Table 5
Characteristics of antiarrhythmic drugs for maintaining sinus rhythm in chronic kidney
disease
Drug
Protein binding
Elimination
Dialyzable
Dosing in CKD
Special considerations in CKD
Flecainide
40%
35% excreted unchanged in urine
No
Dose reduction if eGFR <35 mL/min/1.73 m2
Do not use if significant structural heart disease present
Propafenone
95%
38-50% excreted in urine as active metabolites (1% unchanged)
No
Careful monitoring recommended (in hospital initiation if advanced CKD)
Do not use if significant structural heart disease present
Amiodarone
99%
No renal elimination
No
No dosage requirements; not dialyzable; many drug-to-drug interactions
Dronedarone
98%
6% excreted in urine
Unlikely to be dialyzed
No dosage adaptation required in kidney failure
Do not use if EF <35% or recent CHF
Dofetilide
60–70%
80% renally excreted, as unchanged (80%) or inactive/minimally active metabolites
Unknown
Initial dose individualized on the basis of CrCl and subsequent dosing based on CrCl
and QTc monitoring
Contraindicated for CrCl <20 mL/min
Sotalol
Not protein bound
70% excreted unchanged in urine
Yes—give maintenance dose after dialysis or supplement with 80 mg after HD
A relative contraindication in view of the risk of proarrhythmic effects; in rare
and selected cases—dose to be halved or reduced to one quarter in CKD
A relative contraindication in view of the risk of proarrhythmic effects
CHF, congestive heart failure; CKD, chronic kidney disease; CrCl, creatinine clearance;
EF, ejection fraction; eGFR, estimated glomerular filtration rate; HD, haemodialysis.
Modified from Potpara et al.
101
Propafenone elimination data from Drugbank.ca.
110
Dialyzability data from Frishman.
106
Catheter ablation is more effective than antiarrhythmic drugs alone for maintenance
of sinus rhythm. The safety and efficacy of AF ablation in CKD was evaluated in 21 091
ablations, in which 1593 cases (7.6%) had CKD and 60 were on dialysis.
112
Among patients selected for AF ablation, those with and without CKD had similar rates
of post-procedural complications and subsequent AF hospitalization, DCCV, and repeat
ablation, although the patients with CKD were more likely to be re-admitted for heart
failure. A meta-analysis of four studies of pulmonary vein isolation using radiofrequency
ablation in patients with CKD showed a nearly two-fold increased risk of AF recurrence,
possibly as a result of larger pre-ablation left atrial volumes, which may serve as
a marker for non-pulmonary vein triggers of AF.
113
In a study of CKD patients undergoing cryoballoon ablation, patients with CKD G3 had
significantly higher rates of AF recurrence compared with those with CKD G1 and G2.
114
No cases of contrast-induced nephropathy were reported. In general, sinus rhythm maintenance
via ablation is associated with improved eGFR, while ablation failure is associated
with eGFR decline.
115
Atrial fibrillation ablation may potentially provide survival benefit in the setting
of reduced left ventricular ejection fraction (LVEF) and heart failure. A randomized
trial of catheter ablation compared to usual care in AF and LVEF < 35% recently reported
an improvement in survival associated with ablation
116
,
117
(https://clinicaltrials.gov/ct2/show/NCT00643188; 13 February 2018).
In contrast to atrial fibrillation, radiofrequency ablation for rhythm control of
atrial flutter should be considered as first-line therapy in CKD patients given the
high success and low complication rates of ablation. Patients with CKD are at higher
risk of long-term AF following ablation of atrial flutter and may require long-term
monitoring to survey for AF recurrences if a withdrawal of anticoagulation is being
considered.
118
Lifestyle modifications
Weight loss and exercise, can reduce the burden of AF in the general population,
119
,
120
as does treatment for obstructive sleep apnoea.
121
,
122
Patients on haemodialysis have a four-fold higher risk of sleep-disordered breathing
compared with control patients matched for age, gender, race, and body mass index.
123
,
124
However, in a claims-based study of older patients in the USA, sleep-disordered breathing
in haemodialysis patients was not associated with AF.
125
Prevention of sudden cardiac death
Incidence and aetiology of sudden cardiac death in chronic kidney disease and end-stage
kidney disease populations
There is an increased risk of SCD in CKD (Supplementary material online, Table S4
).
126–132
SCD accounts for 25–29% of all-cause mortality in haemodialysis patients and around
30–35% of all-cause mortality in patients initiating dialysis.
133–139
Recent data indicate that although all-cause mortality rates in haemodialysis patients
have been decreasing, the rates of SCD remain the same, indicative of an increased
proportion of patients dying from SCD.
140
Risk of all-cause mortality is substantially higher in dialysis (15–20% at 1 year)
than in heart failure or post-infarction patients (3–8% at 1 year).
140–143
Annual risk of SCD is higher in haemodialysis patients in comparison to other patient
populations (Figure 4
): 5–7% in haemodialysis patients, 4% in heart failure patients, and 1.5–2.7% in non-dialysis
patients. The annual rates in non-dialysis patients are comparable to that of post-infarction
patients.
126
,
132
,
136
,
140
,
142–144
Nephrologists should be encouraged and educated to discuss risks and potential treatment
options with patients, and enhance participation in clinical trials.
Figure 4
Annual rates of sudden cardiac death. CKD, chronic kidney disease; GP, general population.
There is a significant gap of knowledge in the understanding of electrical and haemodynamic
mechanisms underlying SCD (Figure 5
). In a retrospective study of haemodialysis patients who were prescribed a wearable
cardioverter defibrillator, 80% of cardiac arrests were recorded as ventricular tachyarrhythmias
(ventricular tachycardia or ventricular fibrillation) compared to 20% bradyarrhythmias.
145
In a recent study with continuous electrocardiogram (ECG) monitoring, bradyarrhythmias
and asystole, rather than ventricular tachyarrhythmias, were important determinants
of SCD in ESKD patients.
146
Figure 5
Mechanisms of death in chronic kidney disease patients.
The definitions of sudden death and SCD in ESKD patients need to be refined. The unexpected
nature of sudden death needs to be emphasized to avoid misclassifications. Supplementary
material online, Table S5
proposes definitions of sudden death, SCD, and aborted cardiac arrest pertinent for
ESKD patients.
Risk factors for sudden cardiac death in chronic kidney disease and end-stage kidney
disease patients
The mechanisms of SCD in CKD and ESKD incorporate the long-standing, pathophysiologic
abnormalities that predispose to the arrhythmogenic conditions and the triggering
mechanisms which precipitate sudden cardiac arrhythmia (Figure 6
).
Figure 6
Potential predisposing factors of sudden cardiac death. CHF, congestive heart failure;
CKD-MBD, chronic kidney disease-mineral and bone disorders; LV, left ventricular;
LVH, left ventricular hypertrophy.
The roles of myocardial ischaemia, electrolyte, and volume shifts with haemodynamic
instability, left ventricular hypertrophy, fibrosis and dysfunction, as well as autonomic
dysregulation and sympathetic overactivity in the pathway leading to SCD, will all
need to be further evaluated.
Risk factors predisposing to SCD have been identified in ESKD patients (Supplementary
material online, Table S6
) and usually their combinations contribute to SCD.
136
,
147
Future studies need to determine whether SCD-specific risk factors could be recognized.
7
Since it is difficult to identify SCD-specific risk factors in patients without ESKD,
it might be that just cardiac death-specific risk factors will suffice to evaluate
life-saving interventions in ESKD patients.
148
The primary focus should be on modifiable risk factors which could be targets for
intervention (Supplementary material online, Table S6
).
147
The role of modifiable biomarkers (defined as laboratory tests that are measurable
in blood, urine, or saliva) has been investigated in risk stratification of CKD and
ESKD but requires further studies.
149
Troponins and brain natriuretic peptides could have an additive value and should be
further explored to assess their role in a comprehensive risk assessment for SCD.
150–153
There are very limited data regarding the prognostic significance of incidentally
detected arrhythmias in CKD and ESKD. Identification of episodes of non-sustained
ventricular tachycardia, frequent premature ventricular complexes, bradyarrhythmias
and pauses may be useful in identifying patients at risk of SCD.
154
Ongoing and upcoming studies with long-term ECG monitoring devices (implantable loop
recorders or external ECG monitoring patches worn over a few days to weeks) will provide
data regarding incidence and prognostic significance of these arrhythmias.
Syncope is yet another important and not infrequent event observed in CKD and ESKD
patients, but its prognostic significance is uncertain.
155
Transient loss of consciousness due to hypovolaemia or hypotension should be classified
as syncope and considered as such for prognostication and treatment.
The role of defibrillator therapies for primary and secondary prevention of sudden
cardiac death in end-stage kidney disease
Data regarding secondary prevention ICD therapy indicate some benefits but further
studies are needed to assess longer-term risk vs. benefit that account for competing
risks of death.
7
,
156
,
157
Primary prevention ICD therapy is indicated in patients with LVEF ≤ 35% although data
on benefits of primary prevention ICD therapy in patients with LVEF ≤ 35% and advanced
CKD are not encouraging,
158
as compromised by competing morbidity and mortality and high risk of complications.
Patients with LVEF ≤ 35% account for 10–15% of dialysis patients,
159
,
160
but no data exist for the majority of dialysis patients with LVEF > 35%. Available
data seem to suggest that the benefit of ICDs decreases with declining GFRs, in relationship
to competing risks of comorbidity and mortality and high risk of complications.
129
,
161
Studies with subcutaneous defibrillators, which do not have transvenous hardware,
are needed since this approach might be associated with fewer and less severe complications,
such as infection.
162
Wearable cardioverter defibrillators may provide protection for a limited high-risk
period.
145
Further assessment of pacing devices for bradyarrhythmias (including leadless pacemakers)
is needed.
146
Potassium homeostasis and handling in chronic kidney disease and dialysis
Electrolyte abnormalities and risk for cardiovascular or arrhythmic events
Although definitive evidence for causality is lacking, both hyperkalaemia and hypokalaemia
have been associated with higher risk of all-cause and cardiovascular mortality in
patients with ESKD. In patients on haemodialysis, when pre-dialysis serum potassium
values (i.e. potassium values on blood drawn at the start of the haemodialysis procedure,
in keeping with clinical practice) rise or fall away from 5 mEq/L, the risk for sudden
cardiac arrest increases.
147
Among incident haemodialysis patients, higher mortality and hospitalization rates
have been documented to occur immediately after the 2-day interdialytic interval.
163
,
164
A contributing factor may be larger fluid accumulation followed by excessive ultrafiltration
and abrupt fluctuations in serum potassium concentrations (Supplementary material
online, Figure S1
).
165
In contrast, hypokalaemia is more common in patients on peritoneal dialysis, and hypokalaemia
has been associated with increased risk of all-cause, cardiovascular, and infectious
mortality in this subgroup of patients.
166
Treatment options for improving potassium homeostasis
Treatments for hyperkalaemia include dietary restriction, correction of acidosis,
increasing distal sodium load, and loop diuretics, and in the case of hypokalaemia,
potassium-sparing diuretics and potassium supplements could be used.
167
It may be possible to reduce the dose or stop drugs that interfere with potassium
homeostasis, such as nonsteroidal anti-inflammatory drugs, sulfamethoxazole-trimethoprim,
calcineurin inhibitors, and non-selective beta blockers. Pharmacologic treatments
for managing hyperkalaemia include the cation-exchange resin kayaexalate,
168
calcium-resin resonium,
169
the potassium-binding polymer patiromer,
170
and the potassium trap ZS-9.
167
Beyond the treatment of hyperkalaemia, these agents might also enable more patients
with concomitant CKD to be started on or maintained on guideline-recommended renin–angiotensin–aldosterone
system (RAAS) inhibitors, and this possibility is currently being investigated.
167
In addition to reducing serum potassium, patiromer has been shown to reduce serum
aldosterone levels in patients with CKD and hyperkalaemia taking RAAS inhibitors.
171
Other important questions regarding potassium binders relate to their safety and efficacy
in post-kidney transplant patients, patients with Type IV renal tubular acidosis,
or patients taking calcineurin inhibitors.
Data from three clinical trials have indicated that dual RAAS blockade therapy increases
the risk of hyperkalaemia in patients with CKD.
172–174
Meta-analysis data have indicated that mineralocorticoids can mediate hyperkalaemia
in patients undergoing dialysis, but large trials are needed to better evaluate this
process and its clinical significance.
175
In patients with Type 2 diabetes, a sodium-glucose cotransporter 2 (SGLT2) inhibitor
has been associated with small mean changes in serum electrolytes and less hyperkalaemia
compared to placebo, especially in patients taking anti-hypertensives that interfere
with potassium excretion.
176
Dialysate and dialysis parameters
For patients undergoing haemodialysis, both the potassium concentration in the dialysate
and the schedule of haemodialysis treatments affect the risk of sudden death (Figure
6
). Potential confounding factors, such as nutrition, treatment compliance, and comorbidities,
have not been thoroughly evaluated. It is also not clear whether or how much central
venous pressure, hypervolemia, and pulmonary hypertension predispose patients to arrhythmic
events. Three studies have indicated that a low potassium dialysate concentration
(<2 mEq/L) is associated with a higher incidence of sudden death, especially when
pre-dialysis patient serum levels are <5 mEq/L.
147
,
177
,
178
For patients with a pre-dialysis serum potassium concentration of >5 mEq/L, the risks
associated with low potassium dialysates have not been statistically significant.
In Dialysis Outcomes and Practice Patterns Study (DOPPS), mortality rates were similar
in patients prescribed 2 and 3 mEq/L dialysate.
179
Rapid correction of acidaemia, low serum or dialysate calcium, and high ultrafiltration
rates may contribute to the arrhythmogenic potential of low potassium dialysate.
147
,
180
In a study of 50 patients undergoing thrice-weekly dialysis, risk of SCD and significant
arrhythmias was greater during the 72-h vs. 48-h breaks. There were no analyses specifically
related to potassium levels in these studies.
146
Whether shortening the interval between haemodialysis sessions could result in clinically
significant reductions in sudden cardiac arrest and its relationship to potassium
levels is not clear and warrants further study. Dialysate concentrations of bicarbonate,
calcium, magnesium, and glutamic acid also are likely to be relevant to risk for arrhythmic
events. It is possible that personalizing dialysis parameters for individual patients
could reduce risk of SCD, but this is untested and would be logistically complicated
to implement.
Fluid control during dialysis
Ultrafiltration rates higher than 10 mL/h/kg have been associated with a higher likelihood
of intradialytic hypotension and risk of mortality.
181
Haemodynamic stress during dialysis induces cardiac stunning, which over time may
progress to the development of regional fixed systolic dysfunction, consistent with
underlying myocardial hibernation and fibrosis.
182
A retrospective analysis has indicated that greater interdialytic weight gain is associated
with an increased risk of cardiovascular morbid events
183
; therefore, strategies that mitigate interdialytic weight gain warrant investigation.
Conclusion
People with CKD have an increased burden from AF relative to those without CKD, and
an elevated risk of stroke. For preventing stroke in patients with eCrCl 30–50 mL/min,
DOACs are non-inferior to warfarin and have a more favourable safety profile. For
CKD G5D patients with AF, there are insufficient clinical efficacy and safety data
to routinely recommend VKA treatment for preventing stroke.
Evidence from older randomized trials indicates that pharmacological rhythm and rate
control strategies are equivalent in terms of their efficacy on risks of heart failure,
stroke, and survival. However, catheter ablation, which is superior to antiarrhythmic
drug therapy for freedom from AF recurrence, has comparable safety in CKD and non-CKD.
The role of AF ablation may continue to evolve, particularly among other co-morbid
conditions such as heart failure. Regardless of whether a rhythm or rate strategy
is pursued, anticoagulation should also be prescribed unless otherwise contraindicated
based on stroke risk.
The risk for SCD is increased in patients with CKD, and for those with ESKD on dialysis,
several factors that increase risk have been identified. Studies are needed to identify
risk factors for SCD in CKD non-dialysis patients. For preventing SCD in ESKD, primary
prevention ICD therapy is indicated in patients with LVEF ≤ 35%, although data on
its benefits in these patients are not encouraging. Data regarding secondary prevention
ICD therapy indicate some benefits, but further studies are needed to assess long-term
risk–benefit ratios in these patients. Available data seem to suggest that the benefit
of ICDs decreases with declining GFR.
For patients undergoing haemodialysis, both the potassium concentration in the dialysate
and the schedule of haemodialysis treatments affect the risk of sudden death. Whether
shortening the interval between haemodialysis sessions could result in clinically
significant reductions in sudden cardiac arrest is not yet clear and warrants further
study. It is possible that personalizing dialysis parameters for individual patients
could reduce risk of SCD, but this is untested and would be logistically complicated
to implement.
Recent guidelines include considerable practical and scientific detail on management
of these arrhythmias in CKD.
3–7
,
85
,
184
However, there remain substantial evidence gaps, which will require clinical trials,
and when not possible, robust observational data. We have outlined research recommendations
in the hopes that future investigations can better advance the evidence base in this
area (Table 6
). A multidisciplinary approach is vital for understanding the mechanisms of arrhythmias
in CKD as well as for evaluating therapies and improving clinical care. Nephrologists
and cardiologists should initiate and continue partnerships in designing and conducting
clinical trials as well as treating individual patients with CKD and AF.
Table 6
Arrhythmias and chronic kidney disease: current knowledge gaps and future research
recommendations
Should AF be a required secondary endpoint in future cardiovascular clinical trials
among CKD patients? This will enable future studies to examine the contribution of
AF to various outcomes (e.g. cognitive impairment).
Can we improve upon risk assessment in patients with CKD/CKD G5D by examining unique
risk factors for stroke (e.g. proteinuria) and bleeding (e.g. proteinuria, platelet
dysfunction, vascular access, dialysis anticoagulation)?
Based on a review of large observational studies, can we ascertain the combinations
of risk factors that predict competing SCD vs. non-SCD and cardiac vs. non-cardiac
death endpoints in patients with CKD/CKD G5D?
Are there modifiable risk factors (e.g. long chain omega-3 fatty acids) or pharmacological
therapies for SCD worth investigating?
What is the incidence and prognostic significance of syncope in dialysis patients
(on conventional or novel modalities) and transient hypotension, hypovolemia, and
bradycardia during and outside dialysis sessions?
Is there a role for biomarkers (e.g. troponins, BNP) and markers of autonomic dysregulation
and sympathetic overactivity in predicting cardiac death and SCD? Is there prognostic
significance in incidentally detected arrhythmias?
Among patients on dialysis, can we use modern imaging techniques (e.g. cardiac magnetic
resonance imaging with T1 mapping and speckle tracking imaging echocardiography both
during haemodialysis and on a non-dialysis day), long-term ECG monitoring, and emerging
biomarkers to ascertain predisposing factors to SCD?
Since patients with CKD G5D have consistently lower time in TTR values (despite comparable
intensity of monitoring) that may contribute to higher risk of bleeding, what is the
evidence regarding the role of TTR in decision-making and transitioning to DOAC therapy
with suboptimal TTR?
Estimates of kidney function using eGFR and eCrCl are not equivalent and can lead
to important dose discrepancies with DOACs. Both the conference participants and ESC
advocate the use of eGFR (over eCrCl) in future trials because of established superiority
in estimating kidney function and to reconcile the measure used in pragmatic clinical
practice. For adoption of this measure in future trials however, we recognize that
there would be need for upfront endorsement of eGFR as the preferred measure for estimating
kidney function by regulatory agencies.
Should serial measurements of kidney function be considered to determine if anticoagulation
(e.g. DOACs) is associated with changes in kidney function?
Does heparin use during haemodialysis alter the risk–benefit ratio when used with
concomitant oral anticoagulation? Are there clinical efficacy or safety data evaluating
whether the use of erythropoietin therapy influences stroke reduction with anticoagulant
therapy?
Is there utility in employing left atrial appendage occluder devices in patients with
CKD G5D who are already at high risk of bleeding and endovascular infections?
What is the role of DOACs among kidney transplant patients? Do specific drug–drug
interactions favour certain agents over others?
Is ICD therapy efficacious in the primary and secondary prevention of SCD in ESKD?
If so, what are the risk–benefit ratios? Utility of leadless pacemakers? Additional
studies examining transvenous, subcutaneous, and wearable defibrillators are needed
in CKD patients with EF >35% since they account for 90% of ESKD patients.
What are the long-term outcomes of rate vs. rhythm control in CKD or dialysis patients?
What should guide the selection of rate vs. rhythm control in this patient population?
For the former, what is the optimal rate control and what are the preferred rate-controlling
agents? Utility of transvenous vs. leadless permanent pacemaker following AV node
ablation? For rhythm control, what is benefit–risk ratio for ablation vs. antiarrhythmic
drugs?
What is the ideal ablation approach? For antiarrhythmic drugs, are there comparative
trials to provide information on safety, pharmacokinetics and efficacy on various
agents (especially amiodarone)? Is there a long-term need for oral anticoagulation
in patients with successful rhythm control?
Does personalizing dialysis prescription (e.g. electrolyte dialysate, close monitoring
of potassium levels or volume management) reduce the risk for SCD? Do changes in other
electrolytes associated with arrhythmic predisposition in haemodialysis patients (such
as magnesium) affect clinical outcomes?
AF, atrial fibrillation; AV, atrioventricular; BNP, B-type natriuretic peptide; CKD,
chronic kidney disease; DOAC, direct oral anticoagulant; ECG, electrocardiogram; eCrCl,
estimated creatinine clearance; EF, ejection fraction; eGFR, estimated glomerular
filtration rate; ESC, European Society of Cardiology; ESKD, end-stage kidney disease;
G5D, CKD stage G5 patients on dialysis therapy; ICD, implantable cardioverter-defibrillator;
SCD, sudden cardiac death; TTR, time in therapeutic range.
Supplementary material
Supplementary material is available at European Heart Journal online.
Supplementary Material
Supplementary Data
Click here for additional data file.