Arrhythmia and Sudden Death in Hemodialysis Patients: Protocol and Baseline Characteristics of ...

15 Pages·2016·1.06 MB·English

CJASN ePress. Published on January 13, 2016 as doi: 10.2215/CJN.09350915
Special Feature
Arrhythmia and Sudden Death in Hemodialysis Patients:
Protocol and Baseline Characteristics of the Monitoring
in Dialysis Study
DavidM.Charytan,*RobertFoley,†PeterA.McCullough,‡§JohnD.Rogers,|PeterZimetbaum,¶
CharlesA.Herzog,†andJamesA.Tumlin,**onbehalfoftheMiDInvestigatorsandCommittees
*Departmentof
Abstract
Medicine,Brigham&
BackgroundDialysispatientshavehighratesofcardiovascularmorbidityandmortality,butdataonarrhythmia Women’sHospital,
burden,arrhythmiatype,arrhythmiatriggers,andtheidentityofterminalarrhythmiashavehistoricallybeen Boston,
limitedbyaninabilitytomonitorheartrhythmforprolongedperiods. Massachusetts;
†Departmentof
Medicine,Hennepin
ObjectivesToinvestigatearrhythmiaanditsassociationwithsuddendeathindialysis-dependentESRD,
CountyMedical
describethepotentialforimplantabledevicestoadvancestudyofdialysisphysiology,reviewtheethical Center,Universityof
implicationsofusingimplantabledevicesinclinicalstudies,andreportontheprotocolandbaselineresultsofthe Minnesota,
MonitoringinDialysisStudy(MiD). Minneapolis,
Minnesota;
‡Departmentof
Design,setting,participants,&measurementsInthismulticenter,interventional-observational,prospective Medicine,Baylor
cohortstudy,weplacedimplantablelooprecordersinpatientsundergoinglong-termhemodialysis.The UniversityMedical
proportionofpatientsexperiencingclinicallysignificantarrhythmiaswastheprimaryendpoint.For6months, Center,BaylorHeart
andVascularInstitute,
wecaptureddetaileddataontheprimaryendpoint,symptomaticarrhythmias,otherelectrocardiographic
BaylorJackandJane
variables,dialysisprescription,electrolytes,dialysis-relatedvariables,andvitalsigns.Wecollectedadditional
HamiltonHeartand
electrocardiographicdataforupto1year. VascularHospital,
Dallas,Texas;
ResultsOverall,66patientsunderwentimplantationinsitesintheUnitedStatesandIndia.Diabeteswaspresent §Departmentof
in63.6%ofpatients,12.1%wereage$70years,69.7%weremen,and53.0%wereblack.Primaryandsecondary Medicine,Divisionof
Cardiology,TheHeart
endpointdataareexpectedin2016. Hospital,Plano,
Texas;|Departmentof
ConclusionsCardiacarrhythmiaisanimportantcontributortocardiovascularmorbidityandmortalityin Cardiology,Scripps
Clinic,TorreyPines,
dialysispatients,butavailabletechnologyhaspreviouslylimitedtheabilitytoestimateitstrueburdenand
triggersandtodefineterminalrhythmsinsuddendeath.Useofimplantabletechnologyinobservationalstudies C¶Daleipfoarrntmiae;ntof
raisescomplexissuesbutmaygreatlyexpandunderstandingofdialysisphysiology.Theuseofimplantableloop Medicine,BethIsrael
recordersinMiDisamongthefirstexamplesofsuchatrial,andtheresultsareexpectedtoprovidenovelinsights DeaconessMedical
intothenatureofarrhythmiainhemodialysispatients. CenterandHarvard
ClinJAmSocNephrol▪:ccc–ccc,2016.doi: 10.2215/CJN.09350915 MedicalSchool,
Boston,
Massachusetts;and
**Departmentof
Medicine,University
Introduction as sudden deaths (4), resolving speculation on the ofTennessee,
Dialysis patients experience high cardiovascular and relative importance of (presumed) sudden cardiac ChattanoogaCollege
all-causemortality.ThedeathrateforallUnitedStates death (SCD) in HD patients (Figures 1 and 2) (1,4). ofMedicine,
dialysis patients in 2011 was 198 per 1000 patient- The underlying mechanisms of SCD, particularly Chattanooga,
years, with cardiac disease accounting for roughly the specific type of terminal arrhythmia (which has Tennessee
40% (1). In the US Renal Data System database, two profound implications for prevention), remain con-
Correspondence:
thirdsofcardiacdeathsareattributedto arrhythmia, troversial. Nearly 5 years ago, the Kidney Disease Dr.DavidM.
makingup26%ofmortality.Similarly,intheHemo- ImprovingGlobalOutcomesClinicalUpdateConfer- Charytan,Renal
dialysis Study and Die Deutsche Diabetes Dialyse ence on cardiovascular disease in CKD presciently Division,Brigham&
Studie trials, 22% and 26% of deaths, respectively, concluded, “Implantable loop recorders (ILRs) used Women’sHospital,
1620TremontStreet,
were sudden (2,3). The most convincing validation to identify terminal arrhythmias could prove useful,
3rdFloor,Boston,MA
of registry data is provided by the EValuation Of but a coordinated effort would be necessary given 02115.Email:
Cinacalcet HCl Therapy to Lower CardioVascular low enrollment rates anticipated in such studies” (5). Dcharytan@partners.
Events study, the largest randomized dialysis trial, Furthermore,thepotentialvalueofILRsisnotrestricted org
which enrolled 3883 hyperparathyroid hemodialysis tolethalarrhythmias—thedetectionofclinicallyunsus-
(HD)patients.Overall,25%ofdeathswereadjudicated pected bradyarrhythmia and atrial fibrillation (AF)
www.cjasn.orgVol▪▪▪▪,2016 Copyright©2016bytheAmericanSocietyofNephrology 1
2 ClinicalJournaloftheAmericanSocietyofNephrology
within an hour of symptom onset, or unwitnessed, unex-
pected death without obvious non-cardiac cause in patients
knowntobewellwithinthepast24hours.”Whatexactlyis
“unexpected death” in a population with a high burden of
comorbid illness who spend a disproportionate amount of
time in health care facilities? Furthermore, following with-
drawal from dialysis, patients ultimately die of terminal ar-
rhythmias, but this is death due to withdrawal. Without
patient-centeredcontext,onecouldeasily(andwrongly)infer
SCD as the “primary” event from an ILR. Similarly, such
diseases as subarachnoid hemorrhage or aortic dissection
maymimicSCDintheabsenceofrhythmtracings.
Many publications have highlighted strategies for risk
Figure1.|Causesofdeathinprevalentdialysispatients,2009–2011. stratificationtopredictSCDindialysispatients.Forexample,
AMI,acutemyocardialinfarction;CHF,congestiveheartfailure;CVA, biomarkers indicating inflammation and malnutrition (e.g.,
cerebrovascularaccident.Dataobtainedfromreference1.Thedata
albumin) are associated with SCD risk (7,8). Additionally
reported here have been supplied by the United States Renal Data
System(USRDS).Theinterpretationandreportingofthesedataarethe (but perhaps not surprisingly), there may be heritability to
responsibilityoftheauthor(s)andinnowayshouldbeseenasanofficial SCD propensity in dialysis patients. Chan et al. recently re-
policyorinterpretationoftheU.S.government. ported that genetically related family members on dialysis
hada1.7-foldincreaseintheoddsofcardiacarrestcompared
markedlywidenstheirpotentialutility.Inthismanuscript, with matched, unrelated controls (9). In the general popula-
wereviewdataonarrhythmiainHDpatientsandpresent tion, rare mutations in ionic channels cause several distinct
the protocol and baseline data from the Monitoring in Di- long-QT syndromes, which are associated with a markedly
alysisTrial(MiD),whichusedILRtodetectarrhythmiain higherriskofSCD(10).However,polymorphismsinlong-QT
the setting of HD. syndromegenesarerelativelycommon(approximately1%of
general population) (11). These genetic polymorphisms may
SCD behighlyrelevantandmoredangerousinthecontextofcon-
Hemodialysis initiation is a time of markedly increased ventional HD given the rapid declines in serum potassium,
risk.HealthyPeople(HP)isafederallymandatedprogram magnesium,andcalcium,coupledwithfrequentexposureto
establishedtoimprovethehealthofAmericans;onemajor drugsthatcauseQTprolongation(suchasfluoroquinolones).
goalofHP2020isto“reducenewcasesofCKDanditscom- Conventional 12-lead electrocardiography is a reason-
plications, disability, death, and economic costs” (1). Com- ablemethodforassessmentoftheQTintervalandtheQT
mensurate with the singularly high mortality rate in incident intervalcorrectedforheartrate(avalue.460msecforthe
dialysis patients, the HP2020 CKD-14.2 goal is to reduce the latterisconsideredprolonged).Althoughmeasurementof
deathratewithinthefirst3monthsofdialysisinitiationto319.9 QT dispersion as a predictor of risk has been studied in
deathsper1,000patient-years(fromthe2011rateof335.4per dialysispatients,itsroleinclinicalpracticeisstilluncertain.
1000 patient-years). Figure 3 shows the early hazard of SCD Although ventricular arrhythmias (primarily premature
(andothercause-specificmortality)at dialysisinitiation(6). ventricular contractions) are common in dialysis patients
One major knowledge gap in understanding of SCD in (based on 48-hour Holter monitoring), a prospective study
dialysispatientsisambiguityregardingthe“terminalevent,” of127ItalianHDpatientsfollowedfor4yearsshowedthey
particularly in distinguishing between sudden death due to werenot predictiveofoverallmortality(12,13).
arrhythmia and sudden death not preventable with cardiac Fewdataareavailableonthetypesoflethalarrhythmias
devices.KidneyDiseaseImprovingGlobalOutcomes(5)iden- indialysispatients.Onepaperdetailed84suddencardiacar-
tifiedthepaucityofautopsydataindialysis-relatedSCDasa resteventsindialysispatientswithwearablecardioverter-
majorknowledgegapandhighlightedtheproblematicnature defibrillators (14). In this selected cohort, 78% of initial
of conventional definitions: “sudden, unexpected death rhythms were ventricular tachycardia (VT; 64.3%) or
Figure2.|AdjudicatedcauseofdeathintheEValuationOfCinacalcetHClTherapytoLowerCardioVascularEventsstudypopulation.
CV,cardiovascular.Modifiedwithpermissionfromreference4.
ClinJAmSocNephrol▪:ccc–ccc,▪▪▪,2016 DesignoftheMonitoringinDialysisStudy,Charytanetal. 3
Figure3.|Cause-specificmortalityin2011incidentdialysispatientsfollowingafirstdialysissessioninafree-standingfacilityaccordingto
thedeathnotificationform.Modifiedfromreference6.
ventricularfibrillation(VF;14.3%),and21.4%wereasystole RoleofDialysisBaths
(i.e.,notshockable).Unpublisheddata(kindlysuppliedby Low-potassiumdialysateof0or1mEq/L(17)or,2mEq/L
Linda Becker) covering emergency medical services data (18) and lower calcium dialysate (,2.5 mEq/L) (19) have
on47cardiacarrestsinnineoutpatientdialysiscentersin been implicated as risk factors for SCD in large database
Seattle/KingCountybetween1990and1996showedthat studies. Similarly, low serum magnesium levels were asso-
in 29 (62%) arrests the rhythm was VT or VF. A recent ciated with higher all-cause mortality in Japanese dialysis
Australian study using ILRs, however, implicates brady- patients(20),butfewdataexistonSCDriskandmagnesium
cardia and asystole as the major contributors to SCD in dialysatelevels.
HD patients; this finding suggests pump failure or non-
cardiac causes for the final sequence of clinical events DialyticCycle
leadingtodeath (15,16).Animportantcaveatwastheex- Although great enthusiasm exists among nephrology
ceptionally long dialysis vintage of the study patients professionals for more frequent maintenance HD, most
(mean6SD, 664 years); the type of arrhythmia (and termi- patients dialyze three times weekly, necessitating two gaps
nal event) might be different in patients of newer versus of1dayandonegapof2days.Thishaslongbeenviewedas
olderdialysisvintage. physiologicallychallenginginpatientswithlimitedcapacity
4 ClinicalJournaloftheAmericanSocietyofNephrology
to maintain homeostasis in the presence of metabolic and and accelerated cardiac fibrosis, appear to contribute to
volume-related excursions from normality, where back- arrhythmiapathogenesisinESRD(25).Althougharrhythmia
groundcardiovasculardiseaseisthenorm. and ultimately sudden cardiac death can occur in patients
In a nationally representative United States sample (inthegeneralpopulation)withapparentlystructurallynor-
between2004and2007,onestudycomparedratesofdeath mal hearts, most patients (particularly those with CKD)
and cardiovascular admissions on the day after the 2-day have underlying structural heart disease, and sometype of
interdialyticintervalwithratesonotherdays(21).Asshown acute event interacts with the underlying substrate to pro-
inFigure4,althoughoverallmortality,cardiovascularmor- ducethefatalarrhythmia(26,27).
tality, and cardiovascular admission rates were higher on Althoughmanytriggershavebeenidentified,acutemyo-
the day after the long interval, relative event disparities cardial ischemia is felt to be the most common initiating
were especially marked for congestive heart failure (by a event in the general population (28). In patients with
factorof1.8) anddysrhythmia(byafactorof1.9). advancedCKD(particularlythoseundergoingdialysis),
Similarassociationshavebeenseeninseverallargestudies myocardial ischemia is likely to be a contributor, but it
(22–24).Forexample,inarecentstudyofnewlyincidentHD is also plausible that myocardial ischemia (of the type
patients in the United Kingdom between 2002 and 2006, mediatedbyepicardialcoronaryarterydisease)mayplaya
hospital admission rates after the 2-day gap were 1.7-fold lesspredominantroleandthatotherfactors,suchasinflam-
higher, whereas all-cause mortality rates were 1.22 times mation and autonomic imbalance or increased sympathetic
higher.Aswithalmostalloftheliteraturetodate,thisstudy activity (including sleep apnea), may be important contrib-
was not specifically configured to compare rates of SCD. utorstosuddencardiacdeath(29,30).Hypertrophicmyocar-
Nevertheless, out-of-hospital death rates were 1.59 times dium is predisposed to both atrial and ventricular
higher after the long interval than after the shorter interval arrhythmia through the induction of prolonged action
andonly1.06timeshigherforin-hospitaldeath(23). potentials and increased repolarization defects in areas
ofischemia,withunderlingfibrosisservingasafavorable
substrate for propagation of arrhythmia. While hyperten-
Pathophysiology of Arrhythmia in CKD sion, diabetes, and other typical risk factors undoubtedly
Multiple cardiovascular risk factors, including athero- contribute,dialysisanduremiamaydirectlycontributeto
scleroticheartdisease,leftventricularhypertrophy(LVH), LVH and fibrosis, which appears to accelerate after
Figure4.|Associationofdialyticintervalscyclewithmortalityandcardiovascularhospitalizations.Annualizedmortality(A)andcardio-
vascularadmissionrates(B)per100patient-years,ondifferentdaysofthedialysisweek.Errorbarsrepresent95%confidenceintervals.CHF,
congestiveheartfailure;CVD,cardiovasculardisease;HD,hemodialysis(session);MI,myocardialinfarction.Adaptedfromreference21.
ClinJAmSocNephrol▪:ccc–ccc,▪▪▪,2016 DesignoftheMonitoringinDialysisStudy,Charytanetal. 5
dialysis initiation. In a prospective study of 596 patients DialysisasaTrigger
withESRDwhohadnohistoryofcardiovasculardisease, MostevidencethatHDtriggersAFisindirect.Echocar-
for example, serial echocardiography demonstrated that diographicintra-atrialandinteratrialactivationtimes,for
left ventricular mass index increased significantly during example,correlatewithultrafiltrationvolumeandshorten
the first 2 years of dialysis (31). significantly toward the end of HD (47). Similarly, there
ProcessesuniquetoCKDandESRDmaylargelyaccount are peridialytic changes in P-wave dispersion (standard
forincreasingleftventricularmassindex.Malletal.analyzed electrocardiography), P-wave duration, and the root
myocardial histology in patients with advanced renal dis- mean square voltage of the final 20 ms of the filtered P
easeandnotedthat.90%ofpatientsexhibiteddiffuseand wave (signal-averaged electrocardiography)—parameters
uniform cardiac fibrosis with significantly greater levels of that measure atrial conduction delay and are associated
myocardialcollagenthanobservedinhypertensiveandval- with AF (48,49). In several studies, intradialytic changes
vularcardiomyopathiesanddiffuseratherthanthe“patchy” were prominent and were attenuated at the conclusion of
fibrosis characterizing other conditions (32). Amann et al. dialysis (50,51). In others, changes were not detected or
subsequently demonstrated that myocardial matrix ex- wereseenonlyattheconclusionofdialysisandthenquickly
pansion was associated with a reduction of capillary attenuated(52).However,inonestudy,P-wavedurationde-
density (33). Low capillary density may partly explain creasedandrootmeansquarevoltageofthefinal20msofthe
sudden reductions in myocardial perfusion induced filtered P wave decreased from the beginning to the end of
duringdialysis.Forexample,McIntyreetal.studiedpatients dialysis, changes suggesting a reduced risk of AF after HD
with ESRD who did not have significant coronary disease (53). Changes in electrolytes were associated with P-wave
usingintradialyticpositionemissiontomographyandnoted parameters in several studies (51,52), but associations with
marked,regionalreductionsinmyocardialperfusionduring ultrafiltration appear more robust (50,51). On balance, this
dialysis. Changes in perfusion were accompanied by re- literature suggests that rapid ultrafiltration or other factors
gionalwall-motionabnormalities,suggestingthatfunctional during HD acutely affect conduction in a way that could
ischemia during dialysis is not caused by flow-limiting triggerAFbutthateffectsrapidlyattenuateafterHD.
atherosclerosis (34). More recently, implanted defibrillators were used to
The full pathogenesis of myocardial fibrosis and capil- monitor patients enrolledin the Implantable Cardioverter
laryrarefactioninESRDisbeyondthescopeofthisreview. Defibrillator-2 Trial. AF was detected in 14 of 40 dialysis
Further study is needed to fully elucidate the pathways patients—11receivingHD,3receivingperitonealdialysis,
involved. However, several circulating factors, including and9withoutknownAF(54).AFfrequencywasthree-fold
asymmetric dimethyl arginine (35,36), parathyroid hor- higher on dialysis days (P50.001) but did not differ with
mone (37), aldosterone (38), fibroblast growth factor-23 duration of the interdialytic interval. Intradialytic AF was
(39), angiotensin-2 (40), endogenous cardiac glycosides 13-fold more frequent than in the 7 hours before dialysis
(41), vitamin D (42), and circulating angiogenesis inhibi- (P50.03) and two-fold higher than in the 7 hours after di-
tors, have been implicated (35). alysis (P50.001), although results were largely driven by
Theseobservationssuggestthatinadditiontotheeffect two patients. Lower dialysate potassium concentration and
ofLVHandcoronarydisease,transientmyocardialischemia higher ultrafiltration volumes were associated with AF oc-
induced by a mismatch between capillary supply and the currence. More recently, a trial using an ILR in 50 HD pa-
hypertrophied myocardium may be critical to the gener- tientsfoundthatthelonginterdialyticintervalwasthemost
ation of arrhythmias (43). Conversely, myocardial fibro- frequent period of arrhythmia. AF was detected in 42% of
sis may slow or disrupt normal conduction, leading to patients,andnew-onsetAFwasasymptomaticin86%(16).
bradycardia, asystole, and reentrant arrhythmias (43).
Peridialytic changes in BP, volume status, sympathetic ConsequencesofAF
tone, and electrolytes are likely to further contribute to Associations with stroke are similar in the ESRD and
arrhythmogenesis, but their exact contributions remain general populations (44–46,55,56). In a recent study, for
largely unstudied. example, stroke incidence was 5.2/100 patient-years in
patients with AF compared with 1.9/100 patient-years in
dialysispatientswithoutAF(46).AFisalsostronglyasso-
AF ciatedwithmortalityduetofatalstrokeandothercauses,
IncidenceandPrevalenceofAF therateofwhichisroughlydoubled(26.9versus13.4/100
Although asystole or ventricular arrhythmias are the patient-years)whenAFispresent(44–46).Inaddition,AF
mostlikelytypesofarrhythmiatoresultinsuddendeath, is an independent risk factor for mesenteric ischemia, a
atrialarrhythmias,particularlyAF,mayresultinsignificant frequently fatal event (57), and amputation (58); although
morbidityinpatientswithESRD.AFisincreasinglycommon this has not been studied in the setting of ESRD, AF may
inHDpatients.Inastudyof258,605olderparticipants,the lead to tachyarrhythmia-induced cardiomyopathy when
AF incidence in incident dialysis patients was 14.8/100 sustained (59). Frequent AF could thus be an important
person-years, and adjusted probabilities of developing cause of an extended array of morbidity and mortality,
AFduringthefirstyearofdialysisincreasedfrom11.3% including fatal stroke, heart failure, and deterioration in
in1995to14.3%in2007(44).Similarly,theprevalenceof LV ejection fraction in HD patients.
AF(diagnosedfromadministrativeclaims)was10.7%in
2006—a three-fold increase from 1992 (45). Finally, the RelevanceofSubclinicalAF
overall AF prevalence in a meta-analysis of 25 dialysis Although associations of subclinical AF with clinical
studies was 11.6% (46). outcomeshavenotbeenstudiedinESRD,multiplestudies
6 ClinicalJournaloftheAmericanSocietyofNephrology
suggestthatclinicallysilentAFisanimportantstrokerisk expanding capabilities and decreasing size of wearable
factor in the general population. In one randomized or implantable technologies will facilitate capture of pre-
pacemaker trial, the pacemaker monitoring function was viously unmeasurable parameters and collection of more
used to record rapid atrial events (rate $220 beats/min granular physiologic data, thereby improving under-
[BPM] lasting $5 minutes) presumed to represent AF standing of dialysis physiology.
(60). Overall, 51.3% of patients had events at a median
onset of 100 days. Atrial events were independently associ-
ated with stroke (hazard ratio, 2.8; P50.001). Other studies LINQ and Reveal XT System
have demonstrated similar associations between subclinical Subcutaneous ILRs have been clinically available since
AFandsubsequentovertAForstroke(61–63).Morerecently, 1998 (Medtronic Reveal; Medtronic, Minneapolis, MN), and
the Cryptogenic Stroke and Underlying AF (CRYSTAL AF) ILRusefordetectingheartrhythmabnormalitiesinpatients
(64)studyrandomlyassigned441strokepatientswithoutAF with syncope, palpitations, AF, and other conditions in
whowereundergoing24-hourmonitoringtoanILRorcon- which arrhythmia is suspected has been well described in
ventionalfollow-up.AFlasting.30secondswasdetectedin theliterature. These smalllooprecordersare placed inthe
30%ofinterventionversus3%ofcontrolpatientsat3years. subcutaneous space and are leadless. ILRs continuously
These data suggest that subclinical AF is an important record the heart rhythm, and when programmed alert
contributortostrokewhileillustratingthelimitsofclinical criteria are met for diagnosis of arrhythmia, the event is
observationandstandarddiagnosticsforadvancingscientific capturedandstoreduntilretrievedinpersonorviaremote
discovery. In CRYSTAL AF, newly developed implantable home monitoring. Most patients in the MiD study had a
technologies enabled long-term, continuous monitoring, MedtronicReveal XTILRimplanted,but recentlyenrolled
therebyfacilitatingdiscoveryofahighfrequencyof“silent” patientsreceivedanupdateddevice,theMedtronicReveal
AF and a paradigm shift in the understanding of crypto- LINQ (Figure 5). These monitors are implanted subcuta-
genicstroke.ImprovingunderstandingofSCDanditsasso- neously with a simple outpatient procedure using local
ciationwithdialysisisanobviousextension.Morebroadly, anesthesia.InpatientswithoutESRD,device-relatedcom-
CRYSTAL AF highlights a new paradigm in which the plications associated with ILR implantation include
Figure5.|RevealandMyCareLinksystems.(A)Reveal(bottom)andReveal(top)implantablemonitors.(B)MyCareLinkmonitor.Thepictured
deviceisusedwiththeLINQsystemandtransmitsstoredinformationwirelesslyfromtheimplantedmonitortocentralserverswhenitis
locatedwithinapproximately#30feetoftheimplantedmonitor.MyCareLinksystemsusedwiththeRevealXTdevicerequiredthatthe
transmitterbeconnectedtoalandlineandhelduptothechestwall.(C)Informationflowfromimplantablecardiacmonitortoweb-hosted
physicianinterface.
ClinJAmSocNephrol▪:ccc–ccc,▪▪▪,2016 DesignoftheMonitoringinDialysisStudy,Charytanetal. 7
infection(1.2%),devicemigration,andpainattheimplant StudyPopulation
site (,1%) (65).Batterylife isapproximately3 years,and Eligibility criteria were designed to maximize general-
bothdevicesareconditionallyapprovedformagneticres- izabilityandpatientsafety(Table1).Allresearchcomplied
onance imaging (1.5 and 3.0 T) without reprogramming, with the Declaration of Helsinki and was approved by
although waiting for 6 weeks after insertion with the XT applicable institutional review boards.
device is recommended (65,66). Medicare reimbursement
foranILRisgenerallyintherangeof$6000–$7000,which StudyProcedures
includes the device and insertion-related costs. Echocardiography(ifnotperformedwithinthepreceding
BothRevealXTandRevealLINQcandetectandrecordAF 6months),12-leadelectrocardiography,medicalhistory,and
aswellashomemonitoringcapabilities,buttheLINQdevice medications were obtained at baseline, and ILRs were
is 87% smaller (about a one third the size of a triple-A implanted within 14 days. For the first 6 months after
battery),offersmorememory(20%more),andprovides implantation,patientstransmittedRevealdataimmediately
automatic nightly downloads of detected arrhythmias. beforealldialysissessionsandaftereachsessionassociated
While Reveal XT required holding a landline-connected withastudyblooddraw.Postmortemtransmissionwasen-
transmitter over the chest wall, automatic nightly down- couraged but was not specifically required by the protocol.
loadsfromtheLINQmonitortoabedsidecellularphone–based Symptoms,dialysisprescription,ultrafiltrationvolumes,and
monitor (MyCareLink monitor [Medtronic, Minneapolis, peri- and postdialysis vital signs were collected at every
MN]), allow daily assessment of patient’s heart rhythms dialysissessionduringthefirst6months.Bloodwasdrawn
(Figure 5). This capability allows physicians to follow pa- bothbeforeandafterdialysis:twiceweeklyfor4weeksand
tients daily instead of receiving the data only when the once weekly thereafter through 6 months (Table 2 and 3).
patient has symptoms or at the time of scheduled interro- After 6 months, transmissions occurred at least weekly but
gation, as was the practice with the XT device. datacollectionwasotherwiselimitedtoadverseevents.
ILRsoffertheabilitytomonitorpatientsforanextended Studycoordinatorsreviewedtransmissionsafterthedialysis
period (up to 3 years) (65). For patients with infrequent session to identify prespecified, potentially dangerous
symptoms or who require long-term rhythm evaluation, arrhythmias, which mandated investigator review:
these monitors provide more information than shorter- VT $180 BPM for .15 seconds, asystole .5 seconds,
termHoltermonitoring,wearablepatchtechnology,exter- waking(6a.m.–10p.m.)heartrate#40BPMfor$6seconds,
nallooprecorders,orintermittentmonitoringdevices(67). AFfor.24hoursorfor.12hoursoverconsecutivedays,or
Patientcompliancemayalsobeissuewithexternalmonitors, symptomaticarrhythmia.
whichlimitstheireffectiveness(68). During months 0–6, the study sponsor reviewed
patient-markedeventsandtransmissionswithpotential
arrhythmias. A core laboratory adjudicated those possibly
MiD Protocol consistentwiththeprimaryendpoint.Long-termfollow-up
Overview continued for a maximum of 12 months. The study con-
TheprimaryobjectiveoftheMiDstudy(NCT01779856) cluded when the last study participant had completed 6
wastoestimatetheproportionofHDpatientsexperiencing months of follow-up. ILR removal at study termination
clinicallysignificantarrhythmiasduringa6-monthprimary was optional.
observationperiodusingtheRevealILRsystem.Secondary
goalsweretobroadlycharacterizetheoccurrenceofarrhyth- Endpoints
miainHD-dependentESRDandquantifyassociationswith The primary study objective was to estimate the pro-
electrolytes,HD procedure,andvolumeparameters. portion of HD patients experiencing clinically significant
Table1. Inclusionandexclusioncriteria
InclusionCriteria ExclusionCriteria
Age$21yr Notsuitableforimplantation(e.g.,cachexia,severe
dermatologicconditions)
In-centerHD$3times/wkor Expectedsurvival,6mo
eGFR,15ml/minper1.73m2withexpectedHD Left-sidedHDcatheterinpositionexpectedtointerfere
initiationwithin2mo withimplantation
Abilitytocomplywithprotocol Thoracicsurgerywithin6mo
Infectionwith14d
Bacteremiawithin60d
Hemoglobin,10g/dlonconsecutivemeasurements
withinprior2mo
Transplantationexpectedwithin6mo
Modalitytransferexpectedwithin6mo
ExistingpacemakerorICD
HD,hemodialysis;ICD,implantablecardioverter-defibrillator.
8 ClinicalJournaloftheAmericanSocietyofNephrology
Table2. Scheduleforblooddraws
Weekly FirstSession FirstSession SecondorThirdSession SecondorThirdSession
Session Predialysis Postdialysis Predialysis Postdialysis
Wk1 A1B1LTS D1Ea C D
Wk2 C D C D
Wk3 C D C D
Wk4 C D C D
Wk5–26 BborC D
ForlaboratorytestsperformedinpanelsA–E,seeTable3.LTS,samplelong-termstorage.
aOptionalblooddraw.
bHemoglobin,hematocrit,andironcollectedmonthlyaccordingtostandardofcare.
cardiac arrhythmias (CSAs) over 6 months. CSAs are (2) recording health-related events, specifically death, car-
arrhythmias considered most likely to be associated with diovascularevents,andhealthcareutilization;(3)analyzing
syncope and cardiac arrest or to cause symptoms of the association of arrhythmic events with health-related
hypoperfusion. They were based on standard definitions eventsandHDtreatmentparameters(thisobjectiveincluded
(69–71), recommendations of an advisory panel, and the CSA, other arrhythmias [e.g., AF], and parameters such as
detection capabilities of the Reveal device and included heart rate variability and heart rate trend); (4) quantifying
the following: atrial arrhythmia burden and analyzing associations with
HD treatment parameters; and (5) assessing association of
c VT$115 BPM lasting $30 seconds (the rate limit was captured electrocardiographic morphology and pre- and
subsequently changed to $130 BPM with a protocol postdialysisserumelectrolytelevels.
amendment).
c Bradycardiawithheartrate#40BPMfor$6seconds. StatisticalAnalyses
c Asystolefor$3seconds. The planned sample size was 125 implanted patients.
c Patient-marked (symptomatic) events where electrocardio- With 10% attrition this would have enabled estimation of
graphicreviewshowedanarrhythmiaconsideredclinically the proportion of patients experiencing CSAs with a 95%
relevantinthejudgmentofthesitecardiologist. confidenceinterval(95%CI)half-widthoflessthan0.1for
anyproportion.Preliminarydatafromthefirst50enrolled
Secondary objectives were designed to assess device patients revealed CSA rates of$70%,which allowed esti-
safety,characterizecardiacrhythmandassociationswith mation of 95% CI half-widths #0.15 without additional
dialysis or clinical events, and assess the ability of the enrollment. Thus, recruitment of the full sample size was
Reveal device to detect short-term changes in electrocar- not necessary to reliably estimate CSA event rates or to
diographic morphology and their association with treat- determine whether there was a clinically relevant inci-
ment parameters. dence of CSA in the HD population. Given the financial
The following secondary objectives were specified: (1) andlogisticchallengesofrecruitmentandlimitedpotential
quantifying device and procedure-related adverse events; forqualitativeeffectfromadditionalenrollment,thestudy
Table3. Bloodcollectionpanels
A B C D E(Optionala)
Brainnatriureticpeptide Albumin Albumin Albumin Albumin
CK/CK-MB Bicarbonate Bicarbonate Bicarbonate Bicarbonate
HemoglobinA1c BUN BUN BUN Calcium
High-sensitivityC-reactiveprotein Calcium Calcium Calcium Creatinine
Parathyroidhormone Creatinine Creatinine Creatinine Magnesium
Troponin-T Hematocrit Magnesium Magnesium Phosphorous
Hemoglobin Phosphorous Phosphorous Potassium
Iron Potassium Potassium Sodium
Magnesium Sodium Sodium
Phosphorous
Potassium
Sodium
CK,creatinekinase;CK-MB,creatininekinasemusclebrain;BUN,bloodureanitrogen.
aOptionalbloodcollections15and30minutesafterdialysisonfirstsessionafterRevealimplantation.
ClinJAmSocNephrol▪:ccc–ccc,▪▪▪,2016 DesignoftheMonitoringinDialysisStudy,Charytanetal. 9
was capped at 66 implanted patients. This final sample information) are not analyzed or interpreted until after the
size of 66 enables the estimation of the proportion of study,thisapproacheliminatestheethicalproblemsinherent
patients experiencing CSA with a 95% CI half-width of to withholding analyzed data; however, it imposes sub-
,0.13 for any proportion. stantialdatastoragerequirementsandmayinhibittheability
TheprimaryCSAproportionwillbecalculatedfromthe to optimally understand clinical features of events or to
cohortcompleting6-monthfollow-upwith95%CIbounds determinethebestclinicalresponse.Batchanalysisatregular
estimated by the Clopper–Pearson “exact” method using intervals offers a useful intermediate approach. Finally, it
theMiD-pmodification(72).Theanalysiswillberepeated maybepossibletoselectendpoints,monitoringtimeframes,
in two populations: (1) patients with complete follow-up, or data disclosures in order to limit biasing of important
plus those with incomplete data who experienced CSAs, endpoints while allowing clinical use of research data. In
and (2) all implanted patients, assuming that those with MiD,arrhythmiasfelttobedangerous,suchasasystoleand
incomplete follow-up and no CSAs while under observa- sustained VT, were reviewed in an ongoing manner and
tionhadnoeventsduringunobservedfollow-up.Thiswill sharedwithstudypatientsandtheirclinicians.Conversely,
be supplemented with Kaplan–Meier survivor plots of disclosure of arrhythmias of uncertain importance, such as
CSA-free survival. A negative binomial model, appropriate nonsustainedVT,wasnot required.
forrecurrenteventsandallowingforvariablefollow-up(73),
will be used to estimate mean and 95% CI of CSA per
patient-year. BaselineCharacteristics oftheStudyPopulation
PatientswereenrolledinIndia(23of66)andtheUnited
SpecialConsiderations States (43 of 66). Several characteristics of the study
Useofaninvasivemonitoringdeviceinaclinicalstudyis populationdifferedfromthoseoftheUnitedStatesdialysis
an unusual feature of MiD and raises unique issues by population(1).Meanagewaslower;only12.1%ofpatients
exposing patients to risk in an otherwise observational were$70yearsofage.Ahigherpercentageofpatientswere
study. The ethical issues are not unique to this design. black (53.0%), Asian (34.8%), and male (69.7%). Diabetes
Radiographicendpointsarefrequentlyusedinstudies,for was present in 63.6% of patients, while nearly half of the
example,andalsorequireradiationexposurewithoutclear patients (48.5%) had a history of ischemic heart disease. A
benefit; phase 1 drug studies or “first-in-human” device minority of patients had a history of arrhythmia (31.8%),
studies also expose people to risk without clear benefit. and 10.6% had a history of AF (Table 4). Use ofcardiovas-
GiventheneedtounderstandSCDandarrhythmiacause cularmedicationswascommon,with55%,33%,and48%of
inthedialysispopulation,theminimallyinvasivenatureof patients using b-blockers, angiotensin-converting enzyme
ILR devices, and the low rate of infections when used in inhibitors,orangiotensin-receptorblockersorstatins,respec-
otherpopulations,theuseofRevealXTandLINQinMiD tively.Laboratoryparameters(Table 5)suggestedadequate
wasfelttobeethicallyacceptable.Ingeneral,weadvocate deliveryofdialysiswithameansinglepoolKt/Vof1.560.4.
assessing “interventional-observational” research designs, Potassium (5.061.0 mEq/L), hemoglobin (10.6 61.2 g/dl),
withanethicalframeworkthatbalancestheimportanceof and phosphorous (5.562.0 mg/dl) were each mildly ele-
the knowledge gained against potential risks. High-risk, vatedbutwithintheexpectedrangeforpatientsundergoing
non–minimallyinvasivedeviceswouldrarelybeacceptable long-termdialysis.
without a potential for individual benefit. Conversely, as Several characteristics differed significantly between
devices become smaller and less invasive, they may enable United States and Indian patients. In particular, Indian
observational studies ofnonserious conditions. Use of non- patients weighed less (66.5 versus 97.6 kg), were more
invasivetoolsshouldgenerallybeconsideredasanalterna- likely to have diabetic kidney disease (56.5% versus
tive, and investigators are obligated to carefully review 34.9%), were more likely to dialyze via an arteriovenous
individualriskbeforeenrollingpatientsinanobservational fistula (91.3% versus 59.5%), had a shorter dialysis vin-
studyrequiringuseofanimplantablemonitor. tage (2.2 versus 3.5 years), and were less likely to have
A particularly thorny issue is that monitoring data can hypertension (60.9% versus 97.7%) than participants in
alter observed outcomes and bias estimated event rates. theUnitedStates.Laboratorycharacteristicsweregener-
DetectedarrhythmiasinMiD,forexample,couldmandate ally similar, but bicarbonate (18.8 versus 23.8 mEq/L)
changes in clinical care (e.g., pacemaker implantation, and sodium (134.1 versus 138.4 mEq/L) concentrations
change in dialysis prescription) that modify the risk of were lower in India.
subsequentarrhythmia,therebyreducingCSAsandresult- This regional variation and increased variability in labo-
ing in underestimation of the true population CSA rate. ratory and clinical characteristics present challenges and
Full disclosure to participants and clinicians maximizes opportunities.Analysisofcountry-specificarrhythmiarates
potential benefits to participants but also maximizes bias. isimportant,butthewiderangeofcharacteristics, suchas
Sequestering the monitoring data eliminates outcome body mass index, hypertension, and bicarbonate concen-
contamination,butnondisclosureofpotentiallyharmfuland trations, may provide a greater ability to analyze associa-
treatable conditions discovered during research is ethically tionsofthesefactorswitharrhythmiathanwouldhavebeen
unacceptable. possible had the study recruited only within the United
Withend-of-studybatchanalysisofrawmonitoringdata, States. Global enrollment should thus limit the effect of
results and interpretation of the monitoring data do not country-specificdialysispracticesonourfindingsandmay
becomeavailableuntilafterthestudyhasconcluded.Thisis enhance relevance to the global HD population while
similartostoringbloodsamplesforbatchanalysisattheend requiring more cautious extrapolation to the United States
of a study. Because the samples (in this case monitoring population.
10 ClinicalJournaloftheAmericanSocietyofNephrology
Table4. Baselinecharacteristicsofenrolledpatients
Characteristics AllPatients(n566) PaStiteantetssi(nn5U4n3it)ed Patie(nnt5si2n3)India PValue
Meanageatimplant6SD,yr(n/N) 56.3612.2(66/66) 55.8611.6(43/43) 57.2613.5(23/23) 0.66
Malesex 69.7(46/66) 62.8(27/43) 82.6(19/23) 0.16
Race ,0.001
Asian 34.8(23/66) 0.0(0/43) 100.0(23/23)
Black 53.0(35/66) 81.4(35/43) 0.0(0/23)
Other 1.5(1/66) 2.3(1/43) 0.0(0/23)
White 10.6(7/66) 16.3(7/43) 0.0(0/23)
Hispanicethnicity 0.0(0/66) 0.0(0/43) 0.0(0/23)
CauseofESRD
Diabetes 42.4(28/66) 34.9(15/43) 56.5(13/23) 0.01
GN 7.6(5/66) 7.0(3/43) 8.7(2/23)
Hypertension 37.9(25/66) 51.2(22/43) 13.0(3/23)
Other 12.1(8/66) 7.0(3/43) 21.7(5/23)
MedianESRDvintage 2.4(1.2–5.3)(65/66) 3.5(1.2–5.7)(42/43) 2.2(1.1–3.0)(23/23) ,0.001
(IQR),yr(n/N)
Priorkidneytransplant 13.6(9/66) 11.6(5/43) 17.4(4/23) 0.71
Previousperitonealdialysis 10.6(7/66) 14.0(6/43) 4.3(1/23) 0.41
Currentvascularaccess
AVfistula 70.8(46/65) 59.5(25/42) 91.3(21/23) 0.01
AVgraft 24.6(16/65) 35.7(15/42) 4.3(1/23)
Catheter 4.6(3/65) 4.8(2/42) 4.3(1/23)
Diabetes 0.61
None 36.4(24/66) 37.2(16/43) 34.8(8/23)
Type1 4.5(3/66) 7.0(3/43) 0.0(0/23)
Type2 59.1(39/66) 55.8(24/43) 65.2(15/23)
Meandiabetesduration6SD, 17.9612.8(37/66) 21.0613.6(24/43) 12.169.0(13/23) 0.04
yr(n/N)
Hyperlipidemia 60.6(40/66) 74.4(32/43) 34.8(8/23) 0.003
Hypertension 84.8(56/66) 97.7(42/43) 60.9(14/23) ,0.001
Ischemicheartdisease 48.5(32/66) 51.2(22/43) 43.5(10/23) 0.61
Congestiveheartfailure 25.8(17/66) 39.5(17/43) 0.0(0/23) ,0.001
Coronaryarterybypasssurgery 13.6(9/66) 11.6(5/43) 17.4(4/23) 0.71
Historyofarrhythmia 31.8(21/66) 48.8(21/43) 0.0(0/23) ,0.001
Atrialfibrillation 10.6(7/66) 16.3(7/43) 0.0(0/23) 0.09
Smoking 0.02
Current 7.6(5/66) 11.6(5/43) 0.0(0/23)
Never 69.7(46/66) 58.1(25/43) 91.3(21/23)
Past 22.7(15/66) 30.2(13/43) 8.7(2/23)
Meanweight6SD,kg(n/N) 86.7628.8(66/66) 97.6628.7(43/43) 66.5614.9(23/23) ,0.001
Bodymassindex$40kg/m2 9.1(6/66) 14.0(6/43) 0.0(0/23) 0.08
MeansystolicBP6SD,mmHg 140.8623.4(66/66) 139.6625.8(43/43) 143.0618.2(23/23) 0.57
(n/N)
MeandiastolicBP6SD,mmHg 76.8612.9(66/66) 75.5615.1(43/43) 79.166.7(23/23) 0.18
(n/N)
Medications
Nonaspirinanticoagulantsor 15(10/66) 16(7/43) 13(3/23) 1.00
antiplateletagents
b-Blockers 55(36/66) 58(25/43) 48(11/23) 0.45
Calciumchannelblockers 59(39/66) 51(22/43) 74(17/23) 0.11
ACEIorARB 33(22/66) 47(20/43) 9(2/23) 0.002
Statin 48(32/66) 47(20/43) 52(12/23) 0.80
Aspirin 45(30/66) 49(21/43) 39(9/23) 0.60
Unlessotherwisenoted,valuesarethenumber/numberofpatients(percentage).CategoricalPvalueisbasedonatwo-sidedFisher
exacttest.ContinuousPvalueisbasedonanunpairedttest.IQR,interquartilerange;AV,arteriovenous;ACEI,angiotensin-converting
enzymeinhibitor;ARB,angiotensin-receptorblocker.
MiDasa Paradigm clinical events in dialysis patients. From our experience, it
The MiD study illustrates the potential of invasive seems clear that when investigators are engaged, risks are
monitoring to improve understanding of the pathophysi- reasonably low, research questions are important, and
ology of ESRD and elucidate the true nature or cause of clinical benefit is possible, dialysis patients can be engaged