DISCUSSION
In this study, we sought to define and quantify the VA burden
ascertained from CIED monitoring in ESRD patients on HD and age,
sex-matched controls. Our key findings were 1) utilization of CIED
monitoring in HD patients to define arrhythmia burden is feasible and
easily accessible, 2) no significant differences existed between groups
in VA prevalence, though control patients experiencing VA were more
likely to require device therapy, and 3) in HD patients experiencing VA,
events were most likely to occur within 12 hours of HD end, with the
vast majority being NSVT.
Over 720,000 Americans are living with ESRD, and the vast majority of
incident cases (87.3%) will pursue renal replacement therapy in the
form of HD [1]. The high rate of mortality observed in this
population has been an area of active interest, as ESRD patients on
dialysis exhibit an annual mortality of 16% [1]. The average
expected remaining lifespan of patients initiated on HD is six years,
less than one-third that of their age-matched counterparts in the
general population [1]. Non-white patients are at particular risk of
ESRD development, with African-Americans and Native Americans 3.4 times
and 1.6 times more likely, respectively, to progress to ESRD compared to
white patients [1], a trend reflected in our cohort as well.
Cardiovascular disease is the primary driver of mortality in patients on
dialysis, with the specific etiologies of arrhythmia and cardiac arrest
accounting for 40% of deaths overall [2-6]. Comparatively, patients
with congestive heart failure (CHF) have a projected mortality
approaching 50% over five years [12]. Over 70% of ESRD patients on
HD have at least one cardiovascular comorbidity, which might be expected
as they share several common risk factors [1].
Historically, the majority of fatal sudden cardiac death (SCD) events in
patients on HD were assumed to be fatal VA. One study of 75 patients on
HD with a wearable cardioverter defibrillator found that 79% of sudden
cardiac arrhythmias (SCA) were attributable to VT or VF [13].
Additionally, unpublished emergency medical services data across nine
ambulatory hemodialysis centers found that 62% of cardiac arrests were
attributable to VT or VF [5]. In our cohort, we found that 10 HD
patients (45%) experienced any VA, with a substantial portion of total
ventricular events (18.4%) representing VT or VF.
However, our study also demonstrated that the VA burden between ESRD
patients on HD and controls was similar. Though nearly half of HD
patients (45.4%) experienced VA events, the vast majority of events
were NSVT (81.6%), and there were no differences in VA subtype between
the two groups. Despite similar rates of VT and VF, HD patients were
less likely than controls to require CIED therapy in the form of ATP or
ICD shock. The fact that the vast majority of events experienced by HD
patients were NSVT, and that control patients were more likely to
actually require device therapy for ventricular events, might suggest
that ventricular ectopy in the HD population may not be
clinically-actionable.
Similar observations have been described elsewhere. For example, in one
study of HD patients prescribed a wearable cardioverter defibrillator
(WCD), the type of SCA experienced seemed to predict future survival.
Specifically, though 79% of total SCAs were VT/VF (compared to 21% of
events being asystole), 91% of patients with VT/VF were alive within 24
hours of their SCA event, and over half were alive at thirty days. By
comparison, only one patient with asystole survived more than three days
post-SCA [13]. Thus, though VT/VF events may have been more common,
asystole events were more likely to be fatal.
The notion that VA events may not play a major role in the mortality of
HD patients has also been supported by recent interventional studies.
For example, the recently-published ICD2 trial, a prospective randomized
study which implanted primary prevention ICDs in 188 ESRD patients on HD
with LVEF ≥35%, found no difference in SCD between the ICD and non-ICD
groups. In fact, the trial was ultimately stopped early due to futility
of the intervention [14]. Similarly, data derived from over 700
in-center cardiac arrests across more than 500 ambulatory dialysis
clinics found that survival after such events does not appear to be
impacted by the presence or absence of an automated external
defibrillator [15]. Taken together, these findings suggest that
primary prevention against VA events may not significantly impact
mortality in ESRD patients on HD.
In contrast, there is increasing evidence that bradyarrhythmias and
asystole may be the major contributors to SCD in the HD population. In a
study performed in the United Kingdom during which 30 patients on HD
received an implantable loop recorder, bradyarrhythmias, rather than
tachyarrhythmias, emerged as the commonest and most significant
arrhythmic events, with 17% of participants meeting the combined
primary outcome of either SCD or implantation of a pacing device
[16]. More recently, outcomes data for the Monitoring in Dialysis
(MiD) Study examined implantable loop recorder data in 66 patients over
a six month period, and found that 87% of the clinically-significant
arrhythmias detected were bradycardic events [6]. Of note, a high
degree of cardiovascular comorbidity was observed in this particular
cohort. These data raise the important question of whether implantable
cardiac pacemakers, rather than ICDs, may impact survival in HD
patients, especially given their demonstrated reduction in mortality
among bradycardic non-HD patients [5, 17].
Ideally, we would have hoped to compare bradyarrhythmia events between
HD patients and controls, but were unable to do so given the
compensatory pacing ability of CIEDs. Therefore, we chose to compare
ventricular pacing burden between groups as a surrogate for
bradyarrhythmia burden. However, comparing ventricular pacing burden
between populations is challenging. Device interrogations report percent
time since last device interrogation spent ventricular pacing. There
exists a high degree of variability 1) in the number of interrogations
between patients, 2) the amount of time between interrogations for a
single patient, and 3) the absolute pacing percentage reported by the
device. We therefore utilized a quartile method, and found that control
patients were more likely to pace in the 26-50% quartile compared to HD
patients. This finding does not appear to be clinically-significant.
Overall, we interpret this data as demonstrating no significant increase
in pacing burden in HD patients, which suggests no difference in
clinically-relevant bradycardic episodes between dialysis patients and
controls.
However, an important question generated by the similar pacing trends
observed in our HD and control cohorts is whether bradyarrhythmias in HD
patients reflect an end-stage myocardial failure (as suggested by prior
studies), or true electrophysiological malfunction. For example, the
longest pause duration among patients studied by Wong et al. [7] was
2 seconds, which generally would not be considered relevant in clinical
practice. In the CRASH-ILR study [16], pauses ranged between 3 and 7
seconds. Trends in arrhythmia subtype prevalence may be a function of
dialysis vintage, with VA more common following HD initiation and
bradycardic events becoming more common after a long period of dialysis
dependence. However, a large degree of variation in dialysis vintage
exists both between and within studies, making relationships between
dialysis vintage and documented pause and/or asystole duration difficult
to interpret. For example, the mean HD vintage in our population was
3.36 ± 2.5 years, while those in the MiD study [5, 6], Wong et. al
[7], and CRASH-ILR [16] were 2.4 years (no SD given), 6 ± 4
years, and 3.75 ± 3.3 years, respectively. Interestingly, the cohort
with the longest mean dialysis vintage [7] also demonstrated the
shortest maximal pause duration (2 seconds). Thus, additional research
is needed to clarify the relationships between clinically-significant
bradycardia in HD patients and how this might relate to dialysis
vintage.
Finally, beyond the questions of arrhythmia type and potential impact of
cardiac device interventions, there have also been interesting temporal
relationships demonstrated between arrhythmia burden, SCD, and HD
schedule. Both all-cause mortality and mortality due to cardiovascular
disease peak in the second month following HD initiation, then downtrend
[1]. Similarly, arrhythmia burden is not evenly distributed across
intervals of the HD schedule. In ESRD patients on HD, three
interdialytic periods exist: one long interdialytic period (LIDP, 72
hours) and two short interdialytic periods (SIDP, 48 hours each). The
final hours of the LIDP as well as during the first weekly dialysis
session itself have each been shown to be critical periods during which
overall arrhythmia burden is greatest [6-11]. A recent study in the
United Kingdom demonstrated that the LIDP is associated with higher
rates of hospital admission, all-cause mortality, and out-of-hospital
death rates [5, 11]. More specifically, bradycardic events appear to
occur with significantly greater frequency toward the end of the
inter-dialytic period compared to other intervals throughout the week
[6].
In our cohort, we found that VA were most likely to occur within 12
hours of dialysis end. No other intervals reached statistical
significance. These findings are inconsistent with available studies
implicating the end of the LIDP as the most arrhythmogenic interval
[8, 9]. This discrepancy in findings may be due in part to the fact
that our cohort was maintained on variable dialytic schedules. However,
our results do support previous studies suggesting that the highest
rates of SCD appear to cluster around HD sessions and diminish during
nocturnal hours [13]. A small retrospective review of 80 HD patients
also demonstrated a 1.7-fold increase in SCD risk in the 12 hours
following dialysis [18]. These findings may be explained by rapid
fluid and electrolyte shifts during HD which — while correcting
pre-dialysis hypertension and hyperkalemia due to significant
volume-overload — may also trigger hemodynamic instability and
arrhythmogenic episodes.
Interestingly, the difference in arrhythmogenicity between the immediate
post-HD period and the other defined intervals was driven primarily by
an increased rate of NSVT, rather than the more malignant VA subtypes of
VT and VF. This again raises the important question of whether and to
what degree the ventricular ectopy observed in the post-HD period is
clinically-actionable and, if so, what might be the cardiovascular
sequela of this presumed electrophysiologic disarray both acutely and
chronically. Continuing to clearly define the temporal relationships
between arrhythmia burden and HD schedule may provide crucial insights
into the precise pathophysiologic links between the timing of HD
initiation, interdialytic period duration, arrhythmia risk, and SCD. In
addition, there is current interest in understanding the role of sensors
for dialysate which could impact arrhythmia development and burden.
Given that current dialysis prescriptions are fixed with monthly lab
monitoring, our data supports the development of dynamic electrolyte
sensors and personalized dialysis prescription customized for individual
patients. A better mechanistic understanding would lend more insight
into strategic research forward.
Our inclusion of only patients with CIEDs is a novel approach to
evaluating cardiac rhythms in HD patients. Existing studies
investigating the relationships between arrhythmia, SCD, and dialysis
schedule have prospectively analyzed HD patients with only ILRs, WCDs,
or short-duration cardiac event monitors (e.g. 48-hour Holter monitors).
To our knowledge, there have been no studies including patients with
CIEDs such as implantable pacemakers (IPMs) and implantable
cardioverter-defibrillators (ICDs), and these devices provide several
key advantages. First, CIEDs such as pacemakers and defibrillators have
much greater memory storage capacity. For example, ILRs generally only
store < 1 hour of arrhythmia data per event, and therefore may
underestimate highly-frequent arrhythmias [19]. Additionally, ILRs
possess only a single lead, which increases the rates of false-positive
transmissions and may make ECG interpretation difficult [18]. Not
only do CIEDs provide much greater memory capacity, a feature
particularly important in the long-term monitoring of patient arrhythmia
data, but they also demonstrate excellent discrimination between
arrhythmia types [20]. Finally, CIEDs allow for more sophisticated
data interpretation, with type, time, and duration data available for
each individual event, as well as rate histograms and overall burden of
both supraventricular and ventricular events.
Additionally, our study is unique in that it is the first to our
knowledge which includes HD patients with known baseline cardiac
disease. Given that over 70% of ESRD patients carry comorbid cardiac
diagnoses, our cohort seems representative of a real-world practice
scenario. Given the multiple shared risk factors between renal and
cardiac disease, the inclusion of these patients allows for the study of
an important subset of the HD population. Overall, there remains a
paucity of data to guide cardiologists in the management of ESRD
patients, who will continue to be an important and growing subset of the
cardiologist’s patient base. The potential for cardiac pharmacological
and procedural intervention to potentially improve survival in HD
patients first necessitates a deeper understanding of the relationships
between renal disease and cardiac arrhythmogenesis.
It should also be noted, however, that our study does have significant
limitations. First, our sample size is quite small (44 total patients,
22 of which were on HD), making it difficult to reach the statistical
power necessary to find significance for important outcomes such as
mortality. Additionally, though our study had excellent female
representation (50%), its generalizability is limited by including only
HD patients with CIEDs. We may have observed different results had we
included patients on peritoneal dialysis or those with other means of
monitoring cardiac rhythms (e.g. ILR, WCD, event monitor, etc.). The
evaluation of HD patients with CIEDs, though novel, may also introduce
an inherent selection bias. Previous studies [13] have demonstrated
that only 7.6% of eligible HD patients undergo ICD implantation, which
raises the question of whether our population may be skewed toward a
healthier population of dialysis patients. It should also be noted that
VA detection and therapy may be dependent on device programming, and
ideally groups would be analyzed in the context of prospective uniform
programming.
Another important consideration in our cohort is that potential
confounders existed between groups in that HD patients were more likely
to have OSA compared to controls, a known pro-arrhythmic comorbidity.
However, the fact that no significant differences existed between groups
in VA subtypes nor in AF burden suggests any potential confounding
effect was negligible. Finally, the role of dynamic shifts in
electrolytes and volume status is unable to be accounted for by the
retrospective nature of this study. Dialysis patients receive labs on a
monthly basis, yet undergo an average of 12 sessions per month. A better
understanding of the fluctuations in potassium and magnesium and the
role of dynamic fluid dialysate may portend a promising direction for
future research.