DOI: 10.1161/CIRCEP.114.001623
1
Mortality Reduction In Relation To ICD Programming In MADIT-RIT
Running title: Ruwald et al.; Mortality and ICD Programming
Anne-Christine Ruwald, MD1,2; Claudio Schuger, MD3; Arthur J. Moss, MD1; Valentina
Kutyifa, MD, PhD1; Brian Olshansky, MD4; Henry Greenberg, MD5; David S. Cannom, MD6,7;
N.A. Mark Estes, MD8; Martin H. Ruwald, MD, PhD1,2; David T. Huang, MD1; Helmut Klein,
MD1; Scott McNitt, MS1; Christopher A. Beck, MA, PhD1; Robert Goldstein, MD9; Mary W.
Brown, MS1; Josef Kautzner, MD, PhD10; Morio Shoda, MD11; David Wilber, MD12;
Wojciech Zareba, MD, PhD1; James P. Daubert MD13
1University of Rochester Medical Center, Heart Research Follow-up Program, Rochester, NY; 2Department of Cardiology, Gentofte University Hospital, Hellerup, Denmark; 3Division of Cardiology, Henry Ford Hospital,
Detroit, MI; 4Department of Medicine, University of Iowa Health Care, Iowa City, IA; 5St. Luke's and Roosevelt Hospitals, Departments of Medicine and Epidemiology, Columbia University, New York, NY; 6Division of Cardiology, Hospital of the Good Samaritan; 7Cedars-Sinai Heart Institute, Los Angeles, CA; 8New England
Cardiac Arrhythmia Center, Tufts-New England Medical Center, Boston, MA; 9Department of Medicine,Uniformed Services University of the Health Sciences, Bethesda, MD; 10Cardiology Department, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; 11Department of Cardiology, Tokyo Women’s
Medical University, Tokyo, Japan; 12Cardiovascular Institute, Loyola University Medical Center, Chicago, IL; 13Cardiology Division, Department of Medicine, Duke University Medical Center, Durham, NC
Correspondence
James P. Daubert, MD
Division of Cardiology, Department of Medicine
Duke Clinical Research Institute
Duke University Medical Center
Box 3174-DUMC
Durham, NC 27710
Tel: (919) 681-4294
Fax: (919) 681-9260
E-mail: [email protected]
Journal Subject code: [110] Congestive, [121] Primary prevention, [22] Ablation/ICD/surgery
MDMDMDMD1313
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DOI: 10.1161/CIRCEP.114.001623
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Abstract:
Background - The benefit of novel ICD programming in reducing inappropriate ICD therapy
and mortality was demonstrated in MADIT-RIT. However, the cause of the mortality reduction
remains incompletely evaluated. We aimed to identify factors associated with mortality, with
focus on ICD therapy and programming in the MADIT-RIT population.
Methods and Results - In MADIT-RIT, 1500 patients with a primary prophylactic indication for
ICD or CRT-D were randomized to one of three different ICD programming arms: conventional
programming (VT- -rate programming (VT-
programming (60 sec. delay before therapy ). Multivariate Cox models were used to
assess the influence of time-dependent appropriate and inappropriate ICD therapy (shock and/or
antitachycardia pacing [ATP]) and randomized programming arm on all-cause mortality.
During an average follow-up of 1.4±0.6 years, 71 of 1500 (5%) patients died: cardiac in 40
patients (56.3 %), non-cardiac in 23 patients (32.4%), and unknown in 8 patients (11.3%).
Appropriate shocks (Hazard Ratio [HR] = 6.32 [95% CI: 3.13-12.75], p<0.001) and
inappropriate therapy (HR=2.61 [1.28-5.31], p=0.01) were significantly associated with an
increased mortality risk. There was no evidence of increased mortality risk in patients who
experienced appropriate ATP only (HR=1.02 [0.36-2.88], p=0.98). Randomization to
conventional programming was identified as an independent predictor of death when compared
to patients randomized to high-rate programming (HR=2.0 [1.06-3.71], p=0.03).
Conclusions - In the MADIT-RIT trial, appropriate shocks, inappropriate ICD therapy, and
randomization to conventional ICD programming were independently associated with an
increased mortality risk. Appropriate ATP was not related to an adverse outcome.
Clinical Trial Registration - clinicaltrials.gov; Unique Identifier: NCT00947310.
Key words: mortality, implanted cardioverter defibrillator, arrhythmia, MADIT-RIT, ICD therapy, inappropriate ATP, ICD programming
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DOI: 10.1161/CIRCEP.114.001623
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Introduction
An implantable cardioverter defibrillator (ICD) and cardiac resynchronization therapy
defibrillator (CRT-D) have been shown to reduce mortality in patients at high risk for ventricular
tachycardia or fibrillation (VT or VF).1-4 However, many patients experience inappropriate
defibrillator therapy, defined as therapy delivered for a non-ventricular arrhythmia. Inappropriate
shocks have been associated with reduced quality of life,5, 6 myocardial injury,7-9 rare fatal
proarrhythmia,10 and increased mortality in some studies,11-13 whereas in other studies, no
association between mortality and inappropriate shocks has been found.14-16 Whether
inappropriate shocks are causally related to increased mortality or indirectly related to mortality
by the supraventricular arrhythmias triggering them,16-18 has been difficult to establish.11-14, 19
Increasingly, device therapy programming considerations have emphasized antitachycardia
pacing (ATP).20 While ATP may reduce shocks, and improve quality of life, the effect of ATP
on mortality, if any, remains unknown.21
In the Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate
Therapy22, 23 (MADIT-RIT) study, we investigated the effect of two novel ICD programming
strategies on inappropriate therapy. Randomization of patients to high-rate ICD device
programming with ICD therapy beginning at 200 beats per minute (bpm) or to delayed
programming (12-60 seconds before ATP or shock) was associated with reductions in
inappropriate therapy when compared to conventional programming. Mortality was higher with
conventional programming than in the other two programming arms. In the current MADIT-RIT
sub-study, we investigated the factors associated with mortality in the three treatment arms of
this randomized trial. Based on potentially harmful consequences of inappropriate therapies, we
hypothesized that the higher mortality rate seen with conventional programming was due in part
d.14 16 Whether
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lyyyy, ddded vice therrappy prpprogrararammmmininini g cconssiddderatatiionsnns hhhavaava e emememphasasizededede antititiitaaachyhycardrdrdia
TP).2020202 WhWhWhWhiiile ATATATA PPPP may redudududuccce shohoockckckcks,ss, anddd iiimpmpmprorororoveee quaaalililil tyy offf f lifeff , ththththe effffffe ttct offff AAAA
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DOI: 10.1161/CIRCEP.114.001623
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to the high frequency of inappropriate ICD therapies in this treatment arm when compared to the
other two treatment arms.
Methods
MADIT-RIT randomization, programming and interrogation
MADIT-RIT22, 23 enrolled 1500 patients with guideline-indicated,24 primary prevention ICD or
CRT-D devices at 98 centers in the United States, Canada, Europe, Israel, and Japan from
September 15th 2009 to October 10th 2011 . Commercially available dual-chamber ICD or CRT-
D Boston Scientific devices were used as appropriate. Dual-chamber ICD devices were used to
permit the same programming discriminators in patients with CRT-D and ICD devices, and to
optimize arrhythmia adjudication. Subjects were randomized to one of three different
programming arms. Arm A, conventional programming, used VT-detection 170-199 bpm with a
2.5 sec. delay before therapy (ATP or shock) and a faster VT and/or VF zone above 200 bpm
with a 1 sec. delay before therapy. Arm B, high-rate programming, had a monitor-only zone
from 170-199 bpm and a therapy zone at 200 bpm and above with a 2.5 sec. delay before
therapy. Arm C, delayed therapy, consisted of 3 therapy zones; Zone 1 provided therapy from
170-199 bpm after a 60 sec. delay; Zone 2, 200-249 bpm, used a 12 sec. delay before therapy;
and Zone 3 treated VT/VF above 250 bpm after a 2.5 sec. delay. Atrial discriminators were
turned “on” in all arms. For the conventional and high-rate programming arms, onset and
stability detection were used, whereas in the delayed programming arm Rhythm ID detection
algorithms were used. Physician investigators were encouraged to follow optimal
pharmacological treatment for the enrolled patients according to current guidelines.25
The protocol allowed reprogramming of the devices after an inappropriate ICD therapy.
Device interrogations were conducted every three months the first year and every six months
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same programming discriminators in patients with CRT-D and ICD devices and
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c. delay before therapy. Arm B, high- p g g, had a monitor-only zon
same ee prprprogogograrr mmmmmmmming discriminators in patiiienenents with CRT-DDD aaaand ICD devices, and
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ing gg arararmsmsmsms. AAAArmmmm AAAA,,, cocococonvnnn ennnntititionononnalaa prprprp ogogogograrararammmmmmmminnnng,g,g,, uuuseseseed d dd VTVTVTVT-d-d-d- eeeetttet ctctctctiooon n n n 17171770000-1-1-1999999 bbbbpmpmpmpm w
lay bebebeb fofoforerere tttheheherarararapypypypy (((ATATATP PP orororor shohohoockckck) )) anananand a aaa fafafaststststererer VVVVTT T T ananannd/d/d/d/orororo VVVF F F F zozozozonenene aaaaboboboovevevev 2220000000 bp
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DOI: 10.1161/CIRCEP.114.001623
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thereafter. Post-mortem device interrogation was encouraged.
The current data represents version 2 of the MADIT-RIT data, with follow-up conducted
until July 10th 2012.
The MADIT-RIT study was approved by an institutional review committee and all
patients gave informed consent before being enrolled in the study.
End points
The primary end point of MADIT-RIT was first occurrence of inappropriate therapy; all-cause
mortality was a secondary end point.22, 23 For the current analysis, all-cause mortality was
utilized as the primary end point. An independent morbidity and mortality committee adjudicated
and classified deaths as cardiac, non-cardiac or unknown based on an assessment of all the
information provided by the enrolling centers, including; medical history, description of the
circumstances surrounding the death from family members and/or hospital personnel, the
physician’s determination of the cause of death, death records and when available post-mortem
ICD interrogation.
ICD therapy and arrhythmia definitions
All ICD therapies from in-clinic and available post-mortem interrogations (18 of 71 death, 25%)
were adjudicated by an independent device interrogation committee. Appropriate ICD therapy
was defined as any ICD therapy rendered for VT or VF. Inappropriate ICD therapy was defined
as any ICD therapy delivered where VT or VF was not present.22 Appropriate and inappropriate
ICD therapies were subdivided as ATP or shock. If both ATP and shock occurred in an episode it
was considered a shocked episode.
Pharmacotherapy
Cardiovascular pharmacotherapy, including beta-blockers, statins, diuretics, digitalis,
cause mortality y wawaaassss
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n provided by the enrolling centers, including; medical history, descr tion of the
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s determinii atioioionnn n offf thheh cause of fff dddeath,hhh dea hhth recordddsd andndndnd whehehen nnn availalll blblb e popopopostststs -mor
tatiio
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DOI: 10.1161/CIRCEP.114.001623
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angiotensin-II-receptor blocker (ARB), angiotensin converting enzyme inhibitor (ACE),
aldosterone antagonists, and amiodarone, was recorded at each visit. The influence of
pharmacotherapy on all-cause mortality was investigated by incorporating either baseline or in-
trial use into multivariate Cox proportional- hazard regression models. Time-dependent
pharmacotherapy throughout the study period was adjusted for by creating variables for each
drug taking into account the time each patient was either “on” or “off” the specific drug.
Statistics
Baseline characteristics were compared between patients who died and survivors. Comparisons
between groups used chi-square or Fisher’s exact tests for categorical variables, and Wilcoxon
rank-sum test for continuous measures.
The cumulative proportion of all-cause mortality was calculated using the method of
Kaplan-Meier. In-trial mortality risk was analyzed in all 1500 patients by multivariate Cox
proportional-hazards regression models, adjusting for baseline predictors of death found by best
subset analysis, setting the limit for inclusion in the model at p<0.05. The selected model was
then used to analyze the influence of: 1) ICD therapy throughout the study, 2) pharmacotherapy
throughout the study, and 3) randomized programming arm on the end point of all-cause
mortality.
We created time-dependent variables for appropriate shock, appropriate ATP-only,
inappropriate shock, and inappropriate ATP-only. The shock and ATP-only groups were defined
based on the assumption that appropriate and inappropriate ICD therapies were two different
entities, and therefore any potential overlaps between appropriate and inappropriate ICD
therapies were not included in the definition. Furthermore, shocks were assumed to be more
detrimental than ATP, and therefore patients in the ATP-only groups were defined as ATP
d survivors. Compmppparararari
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est t t t fofofforr cocooontntntinuouououous measures.
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DOI: 10.1161/CIRCEP.114.001623
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without prior shock. They contributed with risk time in the ATP-only group until they received a
shock, and afterward they contributed with risk time in the shock groups.
The proportional hazards assumption was checked in the multivariate models by the use
of time-dependent covariates created by interacting survival time with the various covariates and
testing for statistical significance using the likelihood ratio test.
Covariate interactions were systematically investigated between programming arms and
baseline variables, ICD therapies, and pharmacotherapies. Interactions were also checked
between the specific types of ICD therapy (appropriate therapy [ATP-only or shock] and
inappropriate therapy [ATP-only or shock]), baseline variables, and pharmacotherapy. A
significance limit for interactions was set at p<0.01, in order to account for multiple
comparisons. No significant interactions were found.
Hazard ratios (HR) with their 95% confidence intervals (CI) and two-sided p-values are
reported. A two-tailed p-value below 0.05 was considered statistically significant.
Analyses were performed using SAS software version 9.3 (SAS Institute, Cary, NC).
Results
During a mean follow-up period of 1.4±0.6 years, 71 of 1500 (5%) enrolled patients died with
34, 16, and 21 deaths in the conventional, high-rate and delayed programming arms, respectively
(Figure 1). The 2.5-year cumulative probability of death was 9%. The adjudicated cause of death
was cardiac in 40 patients (56.3 %), non-cardiac in 23 patients (32.4%) and unknown in 8
patients (11.3%) (Figure 1). The majority of the cardiac deaths were due to heart failure (HF),
closely followed by SCD (Figure 1). The proportions of cardiac deaths were equally distributed
among the programming arms, whereas the percentage of non-cardiac deaths were higher in the
only y or shock]] annd d d d
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nns.ss No significcaant ininintttteraaactctctionss wwwerre ffouuundd.
zarddd rrrrataatioiooios (H(HHHR)R)R) wititithhhh theiiiirrr r 95959595% cococoonfnfnfnfididdidence iiiintnttterererervaaalslslsls (CICICICI))) anddd d two-ooo sisisis dddded ddd p-valllues
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ll ffo ded isi SSASAS ftft re iio 99 33 (S(SASAS II tititt tte CCa NCNC
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conventional and delayed programming arms compared to the high-rate programming arm. Most
of the non-cardiac death in the conventional programming arm were related to cancer (n=8).
Baseline factors and all-cause mortality
Patients who died were significantly older, had lower left ventricular ejection fraction (LVEF),
lower diastolic blood pressure, and were more likely to have ischemic cardiomyopathy, diabetes,
and to receive amiodarone and/or digitalis at baseline than patients who survived (Table 1).
Similarly, in multivariate analysis, older age, lower diastolic blood pressure, NYHA class III
(compared to lower NYHA class), lower LVEF, ischemic cardiomyopathy, diabetes, and
implantation of an ICD (compared to a CRT-D) were significantly associated with an increased
risk of all-cause mortality (Table 2).
ICD therapy and all-cause mortality
During follow-up, appropriate ICD therapy occurred in 186 of 1500 patients (12.4%).
Inappropriate ICD therapy, largely due to atrial tachyarrhythmia, occurred in 152 of 1500
patients (10.1%). Patients in the conventional programming arm received a higher frequency of
both appropriate and inappropriate therapies than patients in the other two treatment arms. Figure
2 shows the breakdown of patients who died with known antecedent appropriate or inappropriate
ICD therapies.
In multivariate analyses, both appropriate and inappropriate therapies were significantly
associated with increased risk of all-cause mortality (Table 3a). Increased risk of mortality was
associated with the delivery of appropriate shock, inappropriate shock, and/or inappropriate
ATP-only (Table 3a). No increased risk of mortality was found in the 112 patients who
experienced appropriate ATP-only (Table 3a). The significant associations persisted after
adjustment for programming arm and time-dependent pharmacotherapy (results not shown).
athy,y, diabetes, andnddd
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caususususe e e e momomoortrtrtr alaa itttyyyy (Table 2).
ppppy and all-caaause momm rtalalality
low-uuuuppp, aaaapppropriaiii ttte ICICICI D ththththeererapy ocococo cuuurreddd iiin 18181818666 6 ofofofof 150505050000 papatitititientstststs ((((12121212.4444%)%)%)).
ate ICICICDDD thhherapapappy,y,y lllargegg lylyly ddddue to at iriiallll tachyhyhyar hhrhytytythmhhh iaii , oooco currrrrrr deddd iiin 1515151 2 22 ofofofof 1111505050500
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Over the course of the follow-up, a total of 7 inappropriate therapies (in 6 patients)
induced VT/VF requiring appropriate device therapy. Three patients experienced such an
induced VT/VF event in conventional arm, 3 in high-rate arm, and 1 in the delayed arm. None of
these patients died during the trial.
Assessing the risk of mortality associated with ICD therapies by heart rate range revealed
that inappropriate ICD therapy in the 170-199 bpm range was associated with a significantly
increased risk of death, whereas appropriate ICD therapy in the same heart rate range had no
associated mortality risk (Table 3b). The risk of mortality was increased in patients who
although we were unable to show an increased
risk of mortality with inappropriate ICD th 200 bpm (Table 3b).
Compared with first ICD events, multiple ICD therapies of the same type did not result in
an additional increase in mortality risk considering either appropriate shocks, inappropriate
shocks, inappropriate ATP-only, or appropriate ATP-only (p=0.30-0.75). However, only limited
numbers of deaths were present in patients with multiple ICD therapies (Events: appropriate
shock=5, inappropriate shock=1, appropriate ATP=1, inappropriate ATP=2) When considering
number of specific ICD therapies within each ICD therapy episode, the number of rendered
inappropriate therapies was twice as high as the number of rendered appropriate ICD therapies
(Table 4).
Pharmacotherapy and all-cause mortality
In multivariate analysis, after adjusting for baseline predictors of death and for ICD therapy, the
time-dependent use of amiodarone (HR=2.52 [1.34-4.74], p=0.004) and the lack of ACE/ARB
use (HR=2.59 [1.56-4.31], p<0.001) were associated with increased mortality risk. No other
pharmacological treatment was significantly associated with mortality. No differential anti-
ed in ppatients who o o o
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f deaths ere present in patients ith m ltiple ICD therapies (E ents: appropriat
rtalllititity yy y wiwiwiwithththth iiinaaaappppp ropriate ICD th 2020200 00 bpm (Tableee 3b)b)b))...
mmmmpaaaared with fififirsst ICDCDCD eeevevv nts,s mummulltipleee ICDCD theheheh rarararapippip es of thee ssamemm typpppe e diidd nooot re
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apppprpp oppp iriiate ATATATTPPP-P onlylyly, or apppppproprpp iiiate ATTTTPPP-only yy (p(p(p=000 33.30-0-0-0 0.00 7575755)))). HHHHowever, ononono lylylyl lim
ff dd thth tnt iin titi tts itithh ltltiiplle IICDCD tthhe ipies ((EE tts iri tat
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arrhythmic treatment throughout the study was evident between the programming arms. This was
confirmed in multivariate analysis where the results were consistent within each programming
arm (interaction p-values: range=0.12-0.78). Importantly, the influence of ICD therapy on
mortality was not altered when adjusting for time-dependent amiodarone and ACE/ARB use, and
the results were similar when further adjustments were made for randomized programming arm
(results not shown).
ICD programming and all-cause mortality
Randomization to conventional programming compared to high-rate programming remained
significantly associated with increased risk of mortality even after further adjustment for time-
dependent ICD therapies and time-dependent use of amiodarone and ACE/ARB (Table 5). A
significant mortality risk was not present when comparing conventional programming to delayed
programming (Table 5). The results were consistent when considering cardiac mortality (Table
5).
During follow-up, 166 patients (11%) deviated from the allocated randomized
programming arm on the parameters of rate cut-off, delay before therapy and ATP on/off, with
70 patients randomized to conventional programming, 54 randomized to high-rate programming
and 42 randomized to delayed programming. Of the patients who deviated within the above
mentioned parameters only 9 patients died, with equal distribution among the programming arms
(3 events in each arm).
Discussion
In the MADIT-RIT trial, randomization to conventional ICD programming, inappropriate ICD
therapy, and appropriate ICD shocks were each independently associated with increased
mortality risk after adjustment for relevant risk covariates.
rogrg ammingg remmaiaiaiainenenn
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ICCCD D D D ththththererrrapapapa iesss aanaa d time-dependent use ooof fff aamiodarone aaand AAAACE/ARB (Table 5).
momomomortality riskk wwwasss nnot prprpresennttt t whwwhen cooompaparingngngg cocococonnvenenentionnaal ppproogrammmmmmim nng too de
ing (T(T(TTababablelelele 5).))) TTThhheh results wwwweere coonsnsnsn iisissttttenttt whehhh nnnn coconnnsnsiddddererereriiing cardidididiacacacac morttt llallititiity (T(T(T(T
iri ff lolllo 116666 tatiie tnt (1(11%1%)) dde ii tat ded ff thth lalllo ttedd dnd ii ded
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11
Several mechanisms could potentially explain the association of conventional
programming to increased mortality. Inappropriate therapy may have contributed to the
differential mortality rates between arms. The sum total of inappropriate and appropriate shocks
in the conventional treatment arm was almost twice the number of delivered shock therapies in
the high-rate and delayed-treatment arms.23 Thus, the increased frequency of shocks in the
conventional treatment arm could contribute additional myocardial injury to an already
compromised myocardium with increase in the subsequent risk for heart failure and/or life-
threatening ventricular tachyarrhythmias, as previously suggested.9 However, inappropriate ATP
and/or shock therapy cannot be the only factor responsible for the increased mortality in the
conventional arm. Total deaths numbered 34 in conventional, versus 16 in the high rate and 21 in
the delayed therapy arm. However, the number of patients dying after experiencing a confirmed
inappropriate therapy was 8 versus 0 versus 2 respectively, and therefore other factors must have
contributed to the increased mortality. In multivariate analyses, when adjusted for appropriate
and inappropriate therapy, assignment to conventional programming remained an independent
predictor of mortality, indicating the presence of an unknown entity in patients programmed to
conventional programming that contributed to increased mortality. As seen in Figure 1, there was
a sizable difference in non-cardiac deaths between the programming arms, and this was mostly
due to cancer-related deaths as adjudicated by the Mortality Review Committee. Although an
element of chance might be involved in the higher frequency of cancer-related deaths in the
conventional programming arm, it is also possible that cancer patients are especially vulnerable
to the increased occurrence of adverse appropriate and inappropriate shocks in the 170-199 bpm
range potentially compromising their limited medical reserve.
Inappropriate ATP-only was very frequent in the conventional programming arm,23
owever, inapppproprprrriaiaiaiat
easeedd dd momorttrtt llalalitititity y y inininn tttthhhehe
n d
d r
ate therapy was 8 versus 0 versus 2 respectively, and therefore other factors must
d
opriate therap assignment to con entional programming remained an independ
nal aaaarmrmrmrm. ToToToT tatt l dededed aths numbered 34 in connnvevev ntional, versssus 111166 6 in the high rate and
d thhhherapy arm. HHowwweeverrr, the nun mbmmber ooof paattiennntststs ddddyiyyiy nggg aaafterr eexpppeerienccccininingg aa cooonnnfir
ate thththhereerappapapy y was 8888 versus 0000 vvversus 222 2 reeespspectititiivelylylyly, ananananddd d thththheeere efffore ottttheheheherrr r factttors must
d to thehh increasasassedddd mortalililitytyty. In m lulltiiiivariiiiate anallllysyy es, wwheheheh n adadaddjujujust deddd fffor aaaapppppppprorororoprpp i
iri tat thth iig tt tto tntiio ll iin iin ded iindde dnd
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12
consistent with the increased risk of mortality associated with inappropriate therapy in the 170-
199 bpm range. This association between inappropriate ATP and increased mortality risk was
also reported in a recent sub-study of the MADIT-CRT trial.14 However, the mechanism by
which inappropriate ATP, by itself, contributed to increased mortality risk is still unclear, since
in both the current study and in MADIT-CRT trial14, appropriate ATP was not associated
directly with any harm. In the current study, inappropriate ATP-only was not a marker for risk
related to supraventricular tachyarrhythmias, since device interrogations revealed that the
cumulative frequency of these arrhythmias in the 170-199 bpm range, was almost identical (21-
22%) in the conventional and high-rate treatment arms.26 Inappropriate ATP can be
proarrhythmic,27 but such episodes of direct and immediate harm were very infrequent, and no
fatal ICD-proarrhythmic events10 (from ATP or shock) were documented in MADIT-RIT. As
compared with appropriate ATP, when inappropriate ATP was delivered approximately twice as
many pacing sequences resulted. Given that inappropriate therapy is rarely effective in
terminating the atrial arrhythmias responsible for triggering the inappropriate response, it is
possible, that the larger number of sequences may have exerted an adverse influence on the
myocardium. However, in summary, based on analysis of the available data, it is not currently
possible to determine the mechanism by which inappropriate ATP was significantly associated
with increased mortality.
Since MADIT-RIT was designed for analysis as two parallel trials, it is intriguing that
both high-rate and delayed therapy intervention arms exhibited both a 75-80% lower incidence
of first inappropriate therapy and also a 44-55% mortality reduction. Although the mortality
difference was significant only for the conventional versus the high-rate programming arm, the
results from the two arms are nevertheless mutually supportive. Moreover, the two-fold higher
was almost identticicicicalaaa
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mic,c,cc 272727 bbbbutututut sssucucch hh episodes of direct and immmmmemem diate harm werrrree ee very infrequent, and
prrrroaaaarrhythmic eevennntss10000 (f(f(f( rrom m ATATATA PP orr ssshockck) wewewerererere dddocucucumenntededd innnn MADADADA ITIT-RIIITTT. A
with hh apapaapprrprproppriiii ttate ATATAATPPPP, whehehehennn inapprprprpropopp iiriattte ATATATATPPPP wawawawassss dededed lilililivered ddd appprprprproooxo im ttatellly tttw
nggg seqqquences rrrrees llulteddd. GiGiGiven ththhhat iiinapppppproprpp iaiii te thehhh rapypypy iiis raaaarerrr lylylyl effffffffectiiiiveeee iiiinnn
thth tat iri lal hh thth imi ibiblle ff tt iri iin thth iin iri tat itit ii
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13
cardiac mortality in the conventional programming arm compared to the other two arms supports
the link between ICD therapy and mortality risk. We do however, acknowledge the risk of
confounding by the use of a common comparator group.
Recently, Gasparini,28 et al., reported the findings from ADVANCE III, a randomized
trial involving 1902 primary and secondary prevention patients with ICD therapy. They
evaluated the use of prolonged (30 of 40) vs. standard (18 of 24) VT detection intervals and
observed a 38% lower rate of delivered therapies including inappropriate shocks and appropriate
ATP and shocks. However no decreased risk of mortality was found. In the MADIT-RIT trial,
the total delivered therapies in the high-rate arm was 66% lower than the delivered therapies in
the conventional therapy arm.23 This difference in delivered therapies between the control and
interventional arm of the two studies, as well as both the higher detection limit in the control
group, and the shorter follow-up time in ADVANCE III as compared to MADIT-RIT, may
explain the different findings regarding reduction in mortality between the two studies. Similar to
MADIT-RIT, a trend toward mortality reduction was seen in the shock-reduction programming
study PREPARE.29
Study Limitations
Since MADIT-RIT was designed to evaluate the primary end point of first inappropriate therapy,
we are limited in power for secondary analysis on the end point of mortality, with relatively few
mortality events in each of the programming arms over a comparatively short follow-up period
(1.4±0.6 years). This is evident from the p-value when comparing conventional programming to
high-rate programming (p=0.032). Given the number of statistical tests, the p-values reported
should be considered as nominal and it is noted that the difference in all-cause mortality would
not reach significance if we had corrected for the two comparisons A vs. B and A vs. C, although
In the MADIT-RIIT T T T ttrt
the ddddelelliivivi erer ddeded ttthehhheraraaappppiiieie
t 23 a
n o
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e m
IT a trend to ard mortalit red ction as seen in the shock red ction programm
tiononononalalall tttheheheerararapyyy aaaarm.23 This difference in dedededelil vered therapapappies ss bbbetween the control a
nnnnallll arm of thee ttwoo sttstudieieiees, ass weleell ass bbbothh ttheeee hhhigigiggher dededetecttioon n n liiimit ininin thehe cononontro
the shshsshorrororttetet r fofff llllllow-up timememee iiiin ADDDDVAVAVAVANCNCNCNCE EE IIIIIIIII asasasas comomomompapaaarrrer d ddd ttto MADADADADIITIT-RIRIRIR TT,TT may
e difffffff erent fffiini didididingggs regagg drddiniii g gg reddductiioii n iniii mortat lililitytyty bbbetetwewww ennn tttthheh two studidididiesesese . Sim
IITT ttr dd tto drd ttalilitt ded titi iin tthhe hho kck ded titi m
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it would be very close to significant (significance limit accounting for two comparisons:
p<0.025, actual p-value: p=0.032). Furthermore, by utilizing the conventional programming arm
as common comparator there is a risk of confounding. Secondly, the ICD device memory
capacity might have led to unavailability of electrograms for some repeat arrhythmia episodes
due to overwriting.22 Third, even though adjustments for multiple baseline variables were used to
investigate the association of ICD therapy and mortality, there is a possibility that other
unmeasured confounders, such as differential medical or surgical management, may have
affected the results. Furthermore, post-mortem interrogations were only available in 18 of 71
deaths (25%), which make it difficult to assess whether patients had ICD therapy prior to their
death. This limitation might have impacted our results on an unknown level. Lastly, information
regarding cancer at baseline was not reported, and cancer at baseline was not an exclusion
criterion according to the protocol. Therefore there is a chance that more patients randomized to
conventional programming had cancer at enrollment, as compared to patients randomized to
high-rate or delayed programming, which may have contributed to the mortality difference. As
previously mentioned, the cancer patients may have less medical reserve due to their chronic
illness and thus may be more vulnerable to the increased occurrence of adverse appropriate and
inappropriate shocks in the conventional treatment arm.
Conclusion
In the MADIT-RIT study, appropriate shock, inappropriate shock, and inappropriate ATP were
all independent predictors of all-cause mortality, whereas appropriate ATP was not.
Conventional ICD programming, beginning therapies at 170 bpm, was associated with an
increased risk of all-cause mortality as compared to ICD programming with a cut-off above 200
bpm, even when taking into account ICD therapies delivered. The explanation of the increased
lyy available in 18 oooof f ff 7
CD ththhhererapapy y prprioioii r totototo ttthh
s limitation might have impacted our results on an unknown level. Lastly, inform
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s limimiimitatatat tititiononono migigighthh have impacted our resulululultss on an unknonn wnnnn lllevel. Lastly, inform
caaaancncccer at basellinne wwwaas nnnototot reppoortttedd, anannd caanncererer aaaat t t baseeeliiine waw s nnot annnn eeexxcllusiiionnn
ccordrdddininininggg tttot thehhh protttocol. ThThThTheereforreeee thththere isii a chahahahanccceeee thhhhatatatat more paatititit enenene ts randoddd iiimiz
nal prpp ogggrammmminininng gg hahh dd d cancer at t enrollllllllment, as comppparedededed to papapaatititit ents randodododomimimim zezzz d t
ddella dd iin hhiichh hha ttribib tt ded tt thth trt lalitit didiffff
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mortality seen in MADIT-RIT patients randomized to conventional programming as compared to
high-rate programming appears to be multifactorial with contributing risk factors including the
higher frequency of inappropriate ATP-only therapies and inappropriate and unnecessary shock
therapies in the 170-199 bpm range. In addition, there could be one or more unknown
confounding factors as well as a chance effect in the distribution of deaths that may also
contribute to a higher mortality in the conventional programming arm.
Acknowledgments: The authors would like to acknowledge Bronislava Polonsky MS, Claire Zhang, Suneet Mittal MD, Ilan Goldenberg MD, Poul Erik Block Thomsen MD, PhD, Christian Jons MD, PhD, Mark Haigney MD, Emad Aziz MD, RN, Ted Dwyer MD, Jackson Hall PhD, and the all MADIT-RIT investigators and enrolling centers. We thank you for your contributions. This research was performed while Dr. AC Ruwald was a Mirowski-Moss Awardee, she has further received unrestricted travel grants from The Denmark-America Foundation, Falck Denmark,The Lundbeck-Foundation, Bønnelykkefonden, Carl and Ellen Hertz Grant and Torben and Alice Frimodts Foundation.
Funding Sources: The MADIT-RIT study was supported by a research grant from Boston Scientific to the University of Rochester, with funds distributed to the coordination and data center, enrolling centers, core laboratories, committees, and boards under subcontracts from the University of Rochester.
Conflict of Interest Disclosures: This research was performed while Dr. Anne-Christine Ruwald was a Mirowski-Moss Awardee. Dr. Anne-Christine Ruwald has received travel grants from The Denmark-America Fundation, Falck Denmark,The Lundbeck-Foundatio, Bønnelykkefonden, Carl and Ellen Hertz grant and Torben and Alice Frimodts Fundation. She declares no other conflicts of interest. Dr. Moss reports receiving grant support from Boston Scientific and lecture fees from Boston Scientific, Medtronic and St. Jude Medical. Dr. Olshansky reports receiving consulting and/or speaking fee from Medtronic, Boston Scientific, Boehringer Ingelheim, Biocontrol and Amarin. Dr. Schuger reports receiving research grants from Boston Scientific. Dr. Estes reports receiving grant support from Boston Scientific and consulting fees from Boston Scientific, Medtronic, and St. Jude Medical. Dr. Kautzner reports receiving payment for board membership and lecture fees from Boston Scientific; payment for board membership and lecture fees from St. Jude Medical; lecture fees, as well as grant support through his institution, from Biotronik; and lecture fees, as well as grant support through his institution, from Medtronic. Dr. Shoda reports receiving consultate honoraria from Boston Scientific. Dr. Wilber reports receiving honoraria for lectures from Medtronic, St Jude and Boston Scientific. Dr. Zareba reports receiving grant support from Boston Scientific. Dr. Kleinreports receiving grant support from Boston Scientific and speaking honraria from Boston Scientific. Dr. Beck reports receiving grant support from Boston Scientific. Dr. Cannom reports
y ,msmsmsmsenenenen MMMMD,D,D,D, PPPPhDhDhDhD,,, ChChChChriririrMDMD,,,, JaJaJaJackckckcksosososon n n n HaHaHaHallllllll PPPPhhhhyou fffforororo yyyyouououour r rr
ons This research was performed while Dr AC Ruwald was a Mirowski Mosssn, Falck Denmark,The Lundbeck-Foundation, Bønnelykkefonden, Carl and Ellenn
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receiving speakers bureau from Medtronic, Boston Scientific, and Pfizer. Dr. Huang reports receiving consulting fees/honoraria from St. Jude Medical, speakers bureau from Biotronik, research grants and fellowship support from Medtronic Inc., Boston Scientific, St. Jude Medical and Biotronik. Dr. Daubert reports receiving grant support from Boston Scientific, Biosense-Webster, Medtronic, and Gilead; honoraria for lectures or consultation from Boston Scientific, Medtronic, Biosense-Webster, St. Jude Medical, Biotronik, Premier and Sorin. All others have none.
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DP, LLLLucucucerereri ii RMRMRM, , , , IpIpIpp JJJHH,H ttthehehe SSSSuududdededed n nn CaCaCaarrdr iaaaac cc DeDeDeDeatatath hhh inininin HHHHeaeaeaeartrtrtr FFFaiaiaiilulululurerrere TTTTriririr alalal IIII. AmAmAmAmiiioi daananantatatablbleee CaCaaardrdioiovevevertrtrtererer-DeDefifibrbrilillalatototorrr foforrr CoCongngngesesestitiveveve HHeaeaeartrtrt FFaiailulurerere. NN EnEnglglgg JJ MMeded.2255-23737..
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DP,, Packer DL, MaMaMaMarkrkrratatatatieieieientntntnts s ss wiwiwiwithththth hhhheaeaeaeartrt ffff iaiaiaillll
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N, Ruwald AC, Solomon S, Daubert JP, McNitt S, Polonsky B, Jons C, Clyne CA
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n AE, DiMarco JP, Ellenbogen KA, Estes NA, 3rd, Freedman RA, Gettes LS, Gio dStevenson LW, Sweeney MO. 2012 ACCF/AHA/HRS focused update incorporaCies: a report of the American College of Cardiolog Fo ndation/American Heart
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Table 1: Clinical characteristics at baseline in patients who died compared to those who survived
Clinical Characteristics DeathN=71
No DeathN=1429
Age at Time of Consent (years) 66±14 63±12* Female 17(24) 419(29) NYHA class III vs. class I-II 46(65) 734(52)* Left ventricular ejection Fraction 25 % 43(61) 683(48)* Body Mass Index (kg/m2) 29.5±9.0 29.3±6.7 Systolic Blood Pressure (mmHg) 120.8±21.5 123.7±19.1 Diastolic Blood Pressure (mmHg) 69.5±13.3 73.1±11.7* Resting Heart Rate (beats per min.) 72.1±12.0 72.1±12.5 Conventional programming arm 34(48) 480(34)* High-rate programming arm 16(23) 484(34)* Delayed programming arm 21(30) 465(33) Implanted Device Type: CRT-D (vs. ICD) 29(41) 728(51) Comorbidities at baselineIschemic cardiomyopathy 48(68) 743(52)* Diabetes Mellitus 34(48) 451(32)* Hypertension 51(73) 978(69) Myocardial Infarction 35(50) 603(44) Currently Smoking 10(15) 237(18)History of Ventricular Arrhythmias 1(1) 47(3) History of Atrial Arrhythmias 12(17) 191(13) Non-CABG Revascularization 27(40) 428(30) CABG Surgery 24(34) 344(24) Medication at baselineAmiodarone 13(18) 83(6)* ACE Inhibitor/ Angiotensin Receptor Blocker 58(82) 1254(88) Beta-blocker 64(90) 1340(94) Digitalis 15(21) 178(12)* Aldosterone antagonist 30(42) 514(36) Diuretic 55(77) 953(67) Calcium Channel Blocker 4(6) 118(8) Statins 41(58) 838(59) Values are presented as mean ± SD or frequencies with percentages in parenthesis. * p<0.05 CABG = coronary artery bypass graft surgery, CRT-D = Cardiac Resynchronization Therapy Defibrillator, ICD = Implantable Cardioverter Defibrillator
480((34)*) 484848484(4(4(4(34343434)*)*)*)* 464646465(5(5(5(33333333) ) ))
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Table 2. Baseline clinical characteristics associated with mortality*
Hazard ratios
95 % confidence interval P-value
Implanted device (ICD:CRT-D) 2.66 1.53-4.62 <0.001
NYHA class III vs. Class I-II 2.50 1.42-4.37 0.001
Ischemic cardiomyopathy 1.76 1.04-3.00 0.036
Lower ejection fraction (per 10 % reduction) 1.74 1.25-2.43 0.001
Diabetes 1.64 1.02-2.65 0.043
Increasing age (per decade) 1.36 1.08-1.72 0.009
Lower diastolic blood pressure (per 10 mmHg decrease) 1.28 1.03-1.60 0.029
* Based on a multivariate Cox model, with these seven covariates identified by best subset regression, setting the limit for entry into the model at p<0.05. ICD = Implantable Cardioverter Defibrillator, CRT-D = Cardiac Resynchronization Therapy with Defibrillator, NYHA= New York Heart Association.
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Table 3a: Influence of ICD therapy on the risk of mortality
Deaths/Total patients with the specific ICD therapy Hazard ratios 95 % confidence
interval P-value
Overall inappropriate therapy 10/152 2.61 1.28-5.31 0.008
Inappropriate shock 4/60 2.88 1.02-8.17 0.046
Inappropriate ATP-only 6/92 3.25 1.33-7.94 0.010
Overall appropriate therapy 15/186 2.66 1.45-4.88 0.002
Appropriate shock 11/74 6.32 3.13-12.75 <0.001
Appropriate ATP only 4/112 1.02 0.36-2.88 0.977
Adjusted for age, left ventricular ejection fraction, diastolic blood pressure, diabetes, ischemic cardiomyopathy, NYHA class III compared to lower NYHA class and implanted device (ICD/CRT-D)
Table 3b: Influence of ICD therapy by different heart rate ranges on mortality
Deaths/Total patients with the specific ICD therapy
Hazard ratio
95 % confidence
interval P-value
Inappropriate therapy 170-199 bpm 9/122 3.16 1.47-6.81 0.003
1/39 0.46 0.06-3.61 0.462
Appropriate therapy 170-199 bpm 5/97 0.98 0.37-2.55 0.961
11/123 3.22 1.59-6.54 0.001
Adjusted for age, left ventricular ejection fraction, diastolic blood pressure, diabetes, ischemic cardiomyopathy, NYHA class III compared to lower NYHA class and implanted device (ICD/CRT-D)
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Table 4: Frequency of different ICD Therapies per Treated Episode
Variable Total episodes
Mean therapies±standard
deviation
Median therapies
(IQR)
Minimum number of therapies
Maximum number of therapies
Appropriate ATP 169 1.28±0.89 1.00 (0.0) 1 6.5
Inappropriate ATP 149 2.52±2.32 1.67 (2.0) 1 15.0
Appropriate shock 74 1.29±0.72 1.00 (0.0) 1 4.0
Inappropriate shock 60 2.39±2.38 1.00 (2.0) 1 12.0
IQR= inter-quartile range, ATP=anti-tachycardia pacing
Table 5: Impact of randomized programming arm on mortality
All-Cause Mortality Cardiac Mortality
Hazard ratios
95 % confidence
intervalP-value Hazard
ratios
95 %confidence
intervalP-value
Conventional vs. High-Rate Programming 1.98 1.06-3.71 0.032 2.30 1.02-5.18 0.045
Conventional vs. Delayed Programming 1.34 0.75-2.40 0.322 1.86 0.83-4.17 0.134
Two different Cox models were fitted, one for the end point of all-cause mortality and one for the end point of cardiac mortality. All-Cause mortality: adjusted for age, left ventricular ejection fraction, diastolic blood pressure, diabetes, ischemic cardiomyopathy, NYHA class III compared to lower NYHA classes, implanted device (ICD/CRT-D), time-dependent appropriate and inappropriate ICD therapies, and time-dependent amiodarone usage and lack of ACE/ARB usage. Cardiac mortality: adjusted for left ventricular ejection fraction, diastolic blood pressure, ischemic cardiomyopathy, time-dependent appropriate and inappropriate ICD therapies, and time-dependent amiodarone usage and lack of ACE/ARB usage. Time-dependent variables represent the risk-time in on/off medication/ICD therapy groups throughout the follow-up period. All interaction p-values between programming arms and baseline characteristics or ICD therapies had p > 0.01.
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Figure Legends:
Figure 1: Mode of Death by programming arm. Bar-chart showing the number of patients who
died within each programming arm. All-cause mortality is shown along with the sub-division
into cardiac, non-cardiac and unknown cause of death.
Figure 2: Deaths in different programming arms according to prior ICD therapy. Bar-chart
showing the number of patients who died with or without antecedent ICD therapies by
programming arm.
p y
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Kautzner, Morio Shoda, David Wilber, Wojciech Zareba and James P. DaubertHelmut Klein, Scott McNitt, Christopher A. Beck, Robert Goldstein, Mary W. Brown, Josef
Henry Greenberg, David S. Cannom, N.A. Mark Estes III, Martin H. Ruwald, David T. Huang, Anne-Christine Ruwald, Claudio Schuger, Arthur J. Moss, Valentina Kutyifa, Brian Olshansky,
Mortality Reduction In Relation To ICD Programming In MADIT-RIT
Print ISSN: 1941-3149. Online ISSN: 1941-3084 Copyright © 2014 American Heart Association, Inc. All rights reserved.
Dallas, TX 75231is published by the American Heart Association, 7272 Greenville Avenue,Circulation: Arrhythmia and Electrophysiology
published online August 18, 2014;Circ Arrhythm Electrophysiol.
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