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, MD 1,2 ; Claudio Schuger, MD 3 ; Arthur J. Moss, MD 1 ; Valentina Kutyifa, MD, PhD 1 ; Brian Olshansky, MD 4 ; Henry Greenberg, MD 5 ; David S. Cannom, MD 6,7 ; N.A. Mark Estes, MD 8 ; Martin H. Ruwald, MD, PhD 1,2 ; David T. Huang, MD 1 ; Helmut Klein, MD 1 ; Scott McNitt, MS 1 ; Christopher A. Beck, MA, PhD 1 ; Robert Goldstein, MD 9 ; Mary W. Brown, MS 1 ; Josef Kautzner, MD, PhD 10 ; Morio Shoda, MD 11 ; David Wilber, MD 12 ; Wojciech Zareba, MD, PhD 1 ; James P. Daubert MD 13 1 University of Rochester Medical Center, Heart Research Follow-up Program, Rochester, NY; 2 Department of Cardiology, Gentofte University Hospital, Hellerup, Denmark; 3 Division of Cardiology, Henry Ford Hospital, Detroit, MI; 4 Department of Medicine, University of Iowa Health Care, Iowa City, IA; 5 St. Luke's and Roosevelt Hospitals, Departments of Medicine and Epidemiology, Columbia University, New York, NY; 6 Division of Cardiology, Hospital of the Good Samaritan; 7 Cedars-Sinai Heart Institute, Los Angeles, CA; 8 New England Cardiac Arrhythmia Center, Tufts-New England Medical Center, Boston, MA; 9 Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD; 10 Cardiology Department, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; 11 Department of Cardiology, Tokyo Women’s Medical University, Tokyo, Japan; 12 Cardiovascular Institute, Loyola University Medical Center, Chicago, IL; 13 Cardiology 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 MD MD MD MD 13 13 ty of Rochester Medical Center, Heart Research F ollow up Program Rochester NY; Departme g p I l n g l c n e e a e U o C ty of Ro Ro Roch ch ches e e te te ter Me Me M Medical Center, Heart Research F F F ol ol ollow - up Program, Ro Ro Ro Rochester, NY; Departme gy , , Ge Ge Ge G ntofte e U U University Hospital, Hellerup , Denm mar ark; 3 D ivision of f of f Cardi di di d ology, Henry Ford Hosp I ; ; 4 D D De D partment o o of f f f Me Me Me M di di di dici ci ci cin ne ne, , , Un Un Un Univ iv iv iver er er e si si si s ty ty ty o of Io Io Iow w wa H Hea alth h h h Ca Ca C Care re re e, Io owa wa wa C C Cit it it i y y y, IA ; 5 St St St S . Lu Lu Lu Luke e e e's s 's a a and nd nd nd R R R Roo ls s, s, , D D De D partments o of Med di ic i ine e a a and Ep E E E idem e emiolo og g gy, Co Columb b bia ia ia U U U Un nive e ersity, N N ew w w w Y Y Y Y ork , NY NY NY; ; 6 D Divi i isi i ion gy y y, H H Hospital o o o of th he e Go o ood d Sam m mar a a itan n n n ; ; ; ; 7 Ce C Cedars s - S Sina ai He He ear ar ar a t t In n nst titut t te, , , Los s A Ang g g gel l eles e , CA CA CA C ; 8 Ne New En En Engl c Ar rrh rh rh rhyt yt yt ythm hm hm hmia ia ia C C C Cen en en e te te ter, r r r T T T Tuf uf uf ufts t t - Ne Ne Ne ew w w w En En En E g la a and nd nd nd M M M Med ed ed edic ic ic cal al al C C C Cen en en ente te te ter r, r, r B B B Bos os os osto to to on n n, n, M M M MA; A; A; 9 9 De D D D pa pa pa art rt rt rtme me me ment of of of Me Me Me Medi di di d ci ci ci c n ed Serv rv rv vices Un Un Univ ersi si sity ty ty of th e He He H Hea lth Sc ie nces es es e , Be Be Be Beth th th he esda , MD M M ; 10 C ar di i i iol o o og y De De e Depa rt t t tme me ment, In stitute and E E Exp xp xper e erim m men e enta ta tal l l l Me Me Me M di d dici ci cine ne ne, Pr Pr Prag a ag ague, , , Cz Cz Czec ec ech h h h R Repu pu pu bl bl blic ic c ; ; ; 11 11 11 11 De De De D pa pa pa rt rt rtme me ment nt nt o o of f Ca Ca Ca ard rd rd rdio io io i lo lo logy gy gy , , , To To Toky ky ky k o o o W Wo W W me Un Un Univ iver er ersi sity ty ty, , , To To Toky kyo, o, o, J J J ap ap apan an an ; ; ; 12 Ca Ca Card rdio iova va vasc sc scul ular ar ar I I Ins ns nsti titu tu tute te te, , , Lo Lo Lo yo yo yola la U U Uni nive ve vers rs rsit ity y y Me Me Medi dica ca cal l Ce Ce Cent nt nter er er, , , Ch Ch Chic ic ag ag ago o o Cardiology D D D Div i iv ivis i is isio io o ion, n, n, n, De De De Depa pa pa part rt rt rtme me m m nt nt nt o o o of f f Me Me Me Medi di di dici ci i cine ne ne ne, , , , Du Du Du Duke ke ke ke U U Uni ni nive ve ve vers rs rs rsit i it ity y y y Me Me Me e di di di d ca ca ca cal l l l Ce Ce Ce Cent nt nt nter er er e , , , Du Du Du Durh rh rh rham, NC by guest on August 19, 2015 http://circep.ahajournals.org/ Downloaded from
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Mortality Reduction In Relation To ICD Programming In MADIT-RIT
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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
ate thhhereee apppy y y y ((HR===2.22.2 61 [[[1...282828-5.31]],,, p=p=p==0.0101001)))) were sssigggnificantntntn lyyy asssssssococoociaiaiaatett d with an
mortallliiti y yy irii kskk. ThThThThere was no eviiidddence offff iiincreas ddedd morttaalaa itii y y y rirrr skkkk iiin papp tiiiiennnntststss wwwwho
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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
d.14 16 Whether
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raveveveventntntntriririricucuuulalalaar arararrrrrhythmias triggering them,m,m,161616-18 has beennn difffffifificult to establish.fffff 11-14
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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
ICCD D ddddeveveveviciciciceseseses wwwwerererereeee ususususeeee
same programming discriminators in patients with CRT-D and ICD devices and
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same ee prprprogogograrr mmmmmmmming discriminators in patiiienenents with CRT-DDD aaaand ICD devices, and
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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
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,
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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mmmmpaaaared with fififirsst ICDCDCD eeevevv nts,s mummulltipleee ICDCD theheheh rarararapippip es of thee ssamemm typpppe e diidd nooot re
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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
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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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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
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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
thth tat iri lal hh thth imi ibiblle ff tt iri iin thth iin iri tat itit ii
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DOI: 10.1161/CIRCEP.114.001623
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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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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
c
c z
n t
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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
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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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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
* 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.
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
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)
3.3.3.3.13131313-1-1-1-12.2.22 75757575
e ATP only 4/112 0 36-2 881 02
rat , NYHA class III com red to lower NYHA class and im anted device ICD/CRT
e ATP onononlyyy 4/112 1.02 0.36-2.88
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Table 4: Frequency of different ICD Therapies per Treated Episode
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.
intervalinterval
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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
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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