MADIT-RIT: Frequently Asked Questions & Answers

USAGE NOTES:
 Distribution of this document is limited to Internal Use Only.
 This document is intended to provide a background on the MADIT RIT study and serve as a
resource for questions regarding the MADIT-RIT study.
Most Common Anticipated Questions on MADIT RIT:
Q1: What were the results of this study and were they significant?
Q1a: Results showed that:
 The Primary Endpoint was time to first inappropriate therapy (ATP or shock therapy): The
alternate programming in Arm C (Duration Delay) and Arm B (High Rate Cutoff) reduced the risk of
inappropriate therapy by 76-79% when compared to conventional programming in Arm A (Arm C vs
A: p<0.001;HR=0.24 and Arm B vs A: p<0.001;HR= 0.21)

 The Secondary Endpoints were all cause mortality and syncope: Risk of death was decreased
by 44-55% for patients who received the alternate programming (Arm B and Arm C) when compared
to conventional programming ( Arm C vs A, p=0.06 HR=0.56 and Arm B vs A, p=0.01 HR=0.45
respectively). See question below for results on syncope.

Q2: Was there a difference is syncope between study Arms?

Q2a: No, syncope was evaluated in this study and the incidence of syncope was similar between all groups; #
of events below:
 Arm A = 23 events (514 patients);
 Arm B = 22 events (500 patients); B vs A HR =1.32 (p=0.39)
 Arm C = 23 events (486 patients); C vs A HR =1.09 (p=0.80)

Q3: Was there a difference in the primary endpoint result between Arms B and C?
Q3a: The study was not designed to evaluate Arms B vs C, however there were no clinically meaningful
differences between outcomes in patients in Arm B and C.

Q4: How does MADIT RIT build on the other MADIT landmark trial results?
Q4a: In MADIT II we saw a 31% reduction in all-cause mortality with a number needed to treat of 8. MADIT
RIT demonstrated that alternate (improved) programming reduced the risk of inappropriate therapy by
close to 80% and can further improve patient survival. This nicely complements the results of MADIT
CRT which demonstrated that CRT-D therapy reduces the relative risk of all-cause mortality or first heart
failure event by 57% when compared to ICD therapy (p < 0.001).² Remind customers that this research
is sponsored exclusively by Boston Scientific.


MADIT II 8-year Results:

 Save Lives: NNT of 8
 ICD patients experienced a 34% relative reduction in the risk of death at 8 years, showing a sustained ICD
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benefit.

Q5: What caused the reduction in mortality in this study?

Q5a: The cause of the significant difference in all-cause mortality is not known. A significant difference in
mortality was observed between Arm B and Arm A (p=0.01) and a directionally favorable mortality
reduction was observed between Arm C and A (p=0.06).

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Q6: Do we know how ATP contributed to the higher mortality?
Q6a: No. While in this trial there was a correlation between more ATP and higher mortality, we do not
understand the mechanism. It is possible that giving unnecessary therapy (specifically ATP), may have
an adverse hemodynamic consequence that requires further study.

Q7: Do we believe this study will change how physicians program therapy for primary prevention
patients?
Q7a: In the past some physicians have been reluctant to use MADIT RIT Arm B and Arm C programming
because of the concern that patients could become syncopal or the programming might miss treating an
arrhythmia. We believe that this study will bring awareness and help educate physicians on the
importance of programming to prevent inappropriate therapy in primary prevention patients.

Q8: Can competitor devices be programmed to follow the MADIT RIT programming?
Q8a: Arm B programming will be relatively simple for all manufacturers; however, it is important to note
that only BSC devices were used in this study and we cannot speculate how other devices would
have performed. Arm C programming will be more challenging for all other manufacturers who use
NID (number of intervals to detect) vs “duration” to program the extended delay. In BSC devices,
programming a 60 second, 12 second and 2.5 second duration is very easy, but with other
companies, it will be challenging to duplicate this as the NID will change with the patients’ heart rate
changes. Competitors may be able to come close to Arm C programming, but will not be able to be
identical with their current algorithms.

Q9: Should we expect these results to be the same for secondary prevention patients?
Q9a: No, the study results are limited to primary prevention patients, secondary prevention patients were
excluded from trial participation. In this study the patients also has to be at least 21 years of age with
normal sinus rhythm and no history of permanent atrial fibrillation, CABG, PCI or enzyme positive MI
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within past 3 months. All inclusion and exclusion criteria can be found in the MADIT RIT design paper.

Q10: What other programming studies should I be aware of?

Q10a: Other well-known programming studies are listed below. These were different studies, with
6,7,8,9,10,11,12
different patient populations and inclusion/exclusion criteria so outcomes cannot be compared.

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Device Nominals

Q11: How does the Arm A MADIT RIT programming compare to the nominal settings for BSC devices?
Q11a: Arm A (Conventional Programming Arm) used the nominal tachy detection and therapy
parameters for COGNIS® and TELIGEN® devices with the following exceptions:
• VT zone was 170 bpm versus the nominal of 160 bpm
• Rhythm Detection Enhancement used was Onset/Stability versus Rhythm ID®

Q12: Do we know what ATP scheme was used in the study?

Q12a: While there was a recommended ATP protocol (below), physicians were not required to use this
ATP protocol. The recommended protocol was for 8 bursts of ATP versus the 3 bursts that are
nominally on in our devices for ATP 1 (2 bursts) and ATP 2 (1 burst).

ATP Programming recommended within the study protocol for Arms A and C (not
protocol required):
ATP 1 Scan ATP 2 Ramp
 Number of Bursts 4  Number of Bursts 4
 Pulses per Burst  Pulses per Burst
o Initial 8 o Initial 10
o Increment 1 o Increment 1
o Maximum 16 o Maximum 15
 Coupling Interval 81%  Coupling Interval 81%
o Decrement 0 ms o Decrement 0 ms
 Burst cycle Length 81%  Burst Cycle Length 81%
o Ramp Decrement 0 ms o Ramp Decrement 10 ms
o Scan Decrement 20 ms o Scan Decrement 0 ms
 Minimum Interval 200 ms  Minimum Interval 200 ms
 ATP Time-out 360 seconds

 It is recommended that brady programming parameters for ICD devices include the use of the AV
Search+ algorithm for optimization of AV delay and AV Search Hysteresis ON to prevent
unnecessary RV pacing
 It is recommended that brady programming parameters for CRT-D devices include the use of the
SMARTDelay algorithm for optimization of AV delay and VRR and BiV Trigger ON to maximize
biventricular pacing

Q13: What percent of COGNIS & TELIGEN and Progeny devices are programmed to nominals?
Q13a: We are working on getting this information for patients who are being monitored on LATITUDE.
Our nominal settings provide a good starting point for physicians and can easily be adjusted to match the
MADIT RIT programming in Arm B or Arm C if your physician requests this for the patient.

Q14: Does BSC plan to change nominal settings or programmer options for future devices?
Q14a: This is currently under evaluation within BSC and with our advisory boards.

Education Tools on MADIT RIT

Q15: What tools do we have available to make my physicians aware of this study?
Q15a: Send customers to www.bostonscientific.com/MADIT-RIT for a complimentary e-print of
the online study publication in NEJM. On this website they will also find:
 MADIT RIT programming cards
 Slide deck adapted from the presentation that Dr. Moss gave during the late
breaking sessions at AHA on Nov 6th, 2012
 Link to press release
 Media resources

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Q16: Will we have MADIT RIT programming cards to give to customers if requested?
Q16a: Yes. Copies of the MADIT RIT programming cards can be printed from the MADIT RIT
website by going to www.bostonscientific.com/MADIT-RIT. In the U.S. copies of the
MADIT RIT programming cards will be sent to sales reps and additional copies can be
ordered through customer service.

Q17: Can customers use the MADIT RIT slides to educate their peers?
Q17a: Yes

Q18: Will this data be included in our Medical Educations programs?

Q18a: Yes, it will be incorporated into our BSC sponsored MedEd programs beginning on
November 18th, 2012

Programming Questions

Q19: Should I be recommending this programming for all primary prevention patients?
Q19a: No. Your responsibility is to make your physicians aware of the data from MADIT RIT and
if they decide they want to program patients to match the programming in MADIT RIT, you
can provide them with the programming information on the MADIT RIT programming card.

Caution: Regarding MADIT RIT programming:

 You cannot recommend or prescribe programming for a patient.
 You cannot imply or promise an improved outcome for patients programmed with
MADIT RIT programming.

Q20: Was programming changed if the patient received inappropriate therapy during the trial?
Q20a: The MADIT-RIT protocol allowed for physicians to reprogram patients after they received their first
inappropriate therapy. If reprogramming was done it was changed to what the physician requested. We
are unaware at this time the number of patients that were ultimately reprogrammed.

Q21: What was done to assure that programming was done correctly as prescribed in the protocol?
Q21a: Strong effort was made to prevent initial programming errors in all arms of the study. Additionally, this
study was monitored by BSC in efforts to ensure correct programming remained throughout the study. It
was noted that Arm C experienced the most programming related deviations, however those deviations
were corrected as quickly as possible.

Q22: Why was Onset/Stability used as the rhythm discriminator in Arm A instead of Rhythm ID?
Q22a: The intention of Arm A was to use the generic conventional therapy, and historically Onset and
Stability had been used as discriminators for many years. Onset and Stability was also used as the
discriminator in the MADIT II trial. This study was not intended to evaluate Rhythm ID or Onset and
Stability.

Study Design

Q23: Can you explain how the randomization was done?

Q23a: The patients enrolled in MADIT-RIT were randomized in a 1:1:1 scheme. This means that for every
one patient enrolled in Arm A there was also a patient enrolled in Arm B and Arm C. Patients were
equally distributed throughout the arms of the trial.

Q24: Why was a 3-arm trial design used?

Q24a: The study was designed to evaluate 2 different clinical questions. To evaluate these questions we had
2 groups of patients with a common control group. This study was designed to be conducted as though
there were 2 separate studies being performed.

Q25: Why were both ATP and Shocks evaluated?

Q25a:The intent was to evaluate all aspects of inappropriate therapy.

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Inappropriate and Unnecessary Therapy (ATP and Shock)

Q26: What percent of patients received an inappropriate shock in each group?

Q26a: Table 2 in the manuscript shows the number and % of patients who received inappropriate shocks over
a mean follow up time of 14 months. In Arms B and C, 3% of patients received at least one inappropriate
shock vs 6% of patients in Arm A, (conventional programming).

Q27: It appears that many appropriate ATPs in Arm A for VT were unnecessary, do we know why this
occurred?
Q27a: While appropriate and inappropriate therapy were defined in this study, necessary and unnecessary
were clinical descriptors used by the authors. The data reflects that there were many appropriate
therapies that were unnecessary. There appears to be more unnecessary ATP specifically, however we
are unable to define the mechanism at this time. See Table 2 above for details.

Q28: Was there a significant difference in incidence of inappropriate shocks between the groups?
Q28a: Yes, Arm A had a significantly higher number of inappropriate shocks when compared to both Arm B
and Arm C. This was seen in both first inappropriate therapy and total inappropriate therapy. See Table
2 above for details.

Q29: Were inappropriate shocks associated with mortality?

Q29a: Yes. The mechanism of death is still being analyzed and we need to further evaluate this association to
mortality.

Additional Questions on Mortality

Q30: Mortality was not the primary endpoint for the study, is this data valid?
Q30a: Yes. All-cause mortality was a prospectively defined secondary endpoint in the study. While the study
was not prospectively powered to detect a difference in all-cause mortality the magnitude of the
reduction was large enough for the observed difference to be statistically significant.

Q31: How does the mortality rate in the study compare to other ICD and CRT-D studies?
Q31a: Caution should be used when looking across other study results as patient populations and study
requirements varied greatly and outcomes cannot be compared. However, MADIT-RIT showed that 71
patients died (4.7%) during the 14 month mean follow up period for this study, with 6.6% of deaths in
Arm A, 3.2% of deaths in Arm B and 4.3% in Arm C. The authors indicated that the overall mortality rate
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in this study was low and was significantly lower in Arm B versus A (p=0.01). In the PainFree Rx II
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study the mortality rate was 10% in the ATP arm and 7% in the shock arm. In MADIT II the morality
rate was 14.2% in the defibrillator group vs 19.8% in the control group over a mean follow up of 20
5
months. In SCD-HeFT , the mortality rate was 22% in the ICD group vs 29% in the placebo group and
28% in the amiodarone group at 5 years.

Q32: Will there be further analysis on the mortality difference in this study?
Q32a: There will be further analysis related to the mortality difference noted in the primary results. We can
expect to see this information presented in future scientific conferences and/or upcoming publications.
To date we do not know the timing of this information.

Q33: Will there be further analysis of the ATP and mortality association in this study?
Q33a: There will be further analysis related to the therapy (both ATP and shock) difference noted in the
primary results. We can expect to see this information presented in future scientific conferences and/or
upcoming publication. To date we do not know the timing of this information.

Competitive Response

Q34: What do we think the competitive response will be to his study?

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Q34a: Medtronic will likely say that the results are similar to what was seen in the PREPARE study and
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the ADVANCE III study and that they were the first to suggest that longer duration was important in
reducing inappropriate therapy. They will likely downplay or criticize the results on ATP. STJ has
supported the use of ATP, but has been silent on long duration and has little clinical data to support
optimal programming with their devices. Biotronic has been a follower when it comes to
programming and appropriate therapy and will likely continue to take a fast follower position.
For Media Only
Q35: How would you describe shocks and ATP for the Media?
Q35a: ICDs constantly monitor the rate and rhythm of the heart and are designed to deliver electrical
shocks in response to very fast and potentially fatal heart rhythms. Shocks are highly effective in
returning the heart to a normal rhythm and provide life-saving therapy to patients. ATP or anti-
tachycardia pacing is effective in converting some types of fast heart rhythms and the device may be
programmed to deliver ATP first, and if this is successful, a painful shock can be avoided.

S-ICD
Notable differences between S-ICD System and transvenous ICDs:
 Lack of ATP in the S-ICD System
 Longer time to therapy averaging 16 seconds for induced VF and ~20 seconds for
spontaneous episodes
 Lack of transvenous ICD lead in the heart

Q36: Can these findings be applied to the S-ICD System?

Q36a: Because the MADIT-RIT study did not include the S-ICD System in it, its results cannot be applied to
the S-ICD System.

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Q37: ARM C used longer time to therapy. Doesn’t the S-ICD System have longer time to therapy?
QA: The S-ICD System provides a longer time to therapy which may allow arrhythmias to self-terminate
thereby preventing unnecessary therapy delivery. The S-ICD System delivers therapy for induced
arrhythmias in approximately 15 seconds and roughly 20 seconds for spontaneous events. In the US IDE
trial, the S-ICD System was shown to have avoided therapy delivery in over 50% of stored episodes due
to the arrhythmia being non-sustained. Because the MADIT-RIT study did not include the S-ICD System
in it, its results cannot be applied to the S-ICD System

Q38: Does the S-ICD System provide ATP?

Q38a: The S-ICD System does not provide ATP therapy. Therefore, it would be difficult to believe that
the correlation between higher rates of appropriate or inappropriate ATP and mortality would be seen in
the S-ICD System. In terms of ATP effectiveness, MADIT-RIT demonstrated that only 4% of patients
benefit from ATP in Arm C. Finally, is interesting to note that several events treated with ATP actually
accelerated and this must be balanced against the 4% of patients that may actually benefit from the
therapy.

Q39: What about concerns about syncope and the S-ICD System?
Q39a: Although the S-ICD System uses higher rate cutoffs (nominally) and longer time to therapy, the US IDE
trial for the S-ICD System demonstrated low rates of syncope.

Other questions
Q40: When did MADIT RIT start and end enrollment and was this study designed and executed prior
to the Cameron acquisition?
Q40a: The MADIT RIT study protocol was developed in 2008 and included a pre-IDE meeting with the
FDA. The first patient was enrolled in MADIT RIT in September of 2009 and the last patient was enrolled
in October of 2011. This all occurred well ahead of the Cameron acquisition.
Q41: What was Boston Scientific’s role in the study design, execution and publication?
Q41a: While Boston Scientific was the sole sponsor of this study, the study design, execution and
publication was run by Dr. Moss and the MADIT RIT executive board. In the paper the author’s state,
“The trial was designed by the MADIT-RIT Executive Committee, the data were gathered by the
participating center investigators, data were managed by the Coordinating and Data Center and were
analyzed by the Biostatistics Committee, both at the University of Rochester. The first draft of the
manuscript was written by the first author with revisions by the co-authors.
1
Moss AJ, Klein, H, Wilber DJ, Cannom DS, Daubert JP, Higgins SL et al. MADIT II. NEJM 2002; 346(12):877-883. 2Moss AJ,
Cannom DS, Klein, H, Daubert JP, Estes M, et al. Cardiac-Resynchronization Therapy for the Prevention of Heart-Failure Events.
NEJM, 2009;361(14):1329-1338. 3Goldenberg I, Gillespie J, Moss AJ, Klein H, Hall J, et al. Long-term Benefit of Primary Prevention
with an ICD: 8-year follow up MADIT II. Circulation 2010;122:1265-1271. 4Wathen MS, Sweeney MO, Volosin KJ, et al. PainFREE
Rx II Trial Results. Circulation. 2004;110:2591-2596. 5Bardy GH, Mark DB, Poole JE, Packer DL, Boineau R. et al. SCD-HeFT
NEJM 2005;352:3:225-237. 6Wilkoff BL, Williamson BD, Stern RS, Moore SL, Lu F. et al. Results from PREPARE. JACC
2008;52:541-550. 7Gasparini M. ADVANCE III Results presented during Late Breaking sessions at HRS, May 10 2012.
http://wwwp.medtronic.com/Newsroom/NewsReleaseDetails.do?itemId=1336655006810&lang=en_US.8Saeed M, et al. Results
from the PROVE Trial. J Cardiovasc Electrophysiol. 2010;21:1349-1354. 9Gilliam FR, Hayes DL, Boehmer JP, Day J, Saxon LA.
ALTITUDE REDUCES Study. J Cardiovasc Electrophysiol. 20ll;22:1023-1029. 10Moss AJ, Schuger C, Cannom DS, Daubert JP,
Estes M, et al. Reduction in Inappropriate Therapy and Mortality through ICD Programming. NEJM published on line Nov 6th 2012.
11
Gasparini, RELEVANT Eur Heart J (2009) 30(22): 2689-2692. 12Saeed. PROVIDE. Oral presentation at HRS 2012.

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