Mortality Reduction In Relation To ICD Programming In MADIT-RIT

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

2

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

3

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

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DOI: 10.1161/CIRCEP.114.001623

4

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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DOI: 10.1161/CIRCEP.114.001623

5

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,

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DOI: 10.1161/CIRCEP.114.001623

6

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

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DOI: 10.1161/CIRCEP.114.001623

7

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

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DOI: 10.1161/CIRCEP.114.001623

8

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).

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DOI: 10.1161/CIRCEP.114.001623

9

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-

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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

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DOI: 10.1161/CIRCEP.114.001623

10

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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ring follo p 166 patients (11%) de iated from the allocated randomi ed

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

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DOI: 10.1161/CIRCEP.114.001623

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


DOI: 10.1161/CIRCEP.114.001623

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

e ATTTTP PPP cacan n bbbebe

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n

g the atrial arrh thmias responsible for triggering the inappropriate response it is

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

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thth tat iri lal hh thth imi ibiblle ff tt iri iin thth iin iri tat itit ii


DOI: 10.1161/CIRCEP.114.001623

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

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IITT ttr dd tto drd ttalilitt ded titi iin tthhe hho kck ded titi m


DOI: 10.1161/CIRCEP.114.001623

14

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

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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


DOI: 10.1161/CIRCEP.114.001623

15

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

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ons This research was performed while Dr AC Ruwald was a Mirowski Mosssn, Falck Denmark,The Lundbeck-Foundation, Bønnelykkefonden, Carl and Ellenn

Sto the University of Rochester, with funds distributed to the coordination and datolling centers, core laboratories, committees, and boards under subcontracts fromof Rochester

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DOI: 10.1161/CIRCEP.114.001623

16

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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a

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GH,H LLLLeeeeeee KKKKL,L,LL, MMMMarararrk k k k DBDBDBDB, PoPoPooololole e e e JEJJEJE, ,, PaPaPaackckckckerererer DDDLL,L,L BBBBoioioinenenen auauauau RRRR,,, DDoDD mamamam nsnsnsskikikiki MMMM, TrTrTrououououtmtmtmtmanaaJ, Johnhnhnh son G,G,G MMMcNcNcNultyyy SSSSE,E,E, Clappppp-Chahhh nnnnnnnninininng gg N,, DDDavidson-n-n-n Ray yy LDLDDLD, ,, FrFrFrF aulo ES,

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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26. Zareba W, Kutyifa V, Rosero S, Tomkins C, Klein H, Goldenberg I, Beck C, McNitt S, Schuger C, Cannom D, Moss AJ. Clinical significance of supraventricular tachyarrhythmias in the 170-199 BPM range in MADIT-RIT patients. Heart Rhythm supplement. 2013;10:150-151 . "Abstract".

27. Pinski SL, Fahy GJ. The proarrhythmic potential of implantable cardioverter-defibrillators. Circulation. 1995;92:1651-1664.

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28. Gasparini M, Proclemer A, Klersy C, Kloppe A, Lunati M, Ferrer JB, Hersi A, Gulaj M, Wijfels MC, Santi E, Manotta L, Arenal A. Effect of long-detection interval vs standard-detection interval for implantable cardioverter-defibrillators on antitachycardia pacing and shock delivery: the ADVANCE III randomized clinical trial. JAMA. 2013;309:1903-1911.

29. Wilkoff BL, Williamson BD, Stern RS, Moore SL, Lu F, Lee SW, Birgersdotter-Green UM, Wathen MS, Van Gelder IC, Heubner BM, Brown ML, Holloman KK. Strategic programming of detection and therapy parameters in implantable cardioverter-defibrillators reduces shocks in primary prevention patients: results from the PREPARE (Primary Prevention Parameters Evaluation) study. J Am Coll Cardiol. 2008;52:541-550.


DOI: 10.1161/CIRCEP.114.001623

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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

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DOI: 10.1161/CIRCEP.114.001623

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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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DOI: 10.1161/CIRCEP.114.001623

22

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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DOI: 10.1161/CIRCEP.114.001623

23

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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DOI: 10.1161/CIRCEP.114.001623

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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.

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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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Mortality Reduction In Relation To ICD Programming In MADIT-RIT

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