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DTBA1D4
Clinical Study / Summary
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Medtronic DTBA1D4 Clinical Study / Summary

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AdaptivCRT™ Clinical Study
Summary of clinical results
Clinical study
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The following list includes trademarks or registered trademarks of Medtronic in the United States and possibly in other countries. All other trademarks are the property of their respective owners.
AdaptivCRT, Consulta, Concerto II, Maximo II
Table of Contents
1 Study Purpose............................................................................................... 2
2 Study Scope, Design, and Methods .............................................................. 2
3 Subject Inclusion and Exclusion Criteria ....................................................... 2
4 Study Objectives ........................................................................................... 3
5 Results .......................................................................................................... 4
6 Adverse Events Summary ........................................................................... 16
7 Death Summary .......................................................................................... 29
8 Clinical Study Conclusion ............................................................................ 32
Summary of Clinical Results
1
The AdaptivCRT™ clinical study investigated the safety and efficacy of the AdaptivCRT feature, which provides patient-specific automatic and dynamic selection of left ventricular (LV) or biventricular (BiV) cardiac resynchronization therapy (CRT) pacing and adjustments of atrio-ventricular (AV) and inter­ventricular (VV) delays based on periodic evaluation of intrinsic electrical conduction. The study compared results from subjects using the AdaptivCRT feature to those of subjects with CRT using echocardiographic (echo) optimized CRT parameters. This study is also referred to as the Adaptive Cardiac Resynchronization Therapy (Adaptive CRT) Study in the medical literature.
1 Study Purpose
The purpose of the AdaptivCRT clinical study was to demonstrate safety and effectiveness of the AdaptivCRT feature.
2 Study Scope, Design, and Methods
The AdaptivCRT clinical study was a prospective, multi-site, randomized, double-blinded, worldwide Investigational Device Exemption (IDE) clinical study. Subjects were randomized in a 2:1 ratio to receive the AdaptivCRT feature (AdaptivCRT group) or echo-optimized CRT (Echo-Optimized Control group). Randomization occurred after a successful implant procedure, which was defined as implantation of market-released right atrial (RA), right ventricular (RV) and LV leads, and a Medtronic CRT defibrillator (CRT-D) device (Consulta®, Maximo II®, or Concerto II®).
Software for AdaptivCRT was provided via an enabling kit to install or remove the AdaptivCRT feature from the Medtronic 2090 Programmer. Once installed on a programmer, the AdaptivCRT software was used to inject the AdaptivCRT feature into study devices.
Clinical data were collected at baseline, implant, randomization and follow-up visits occurring at 1, 3, 6, and 12 months post-randomization, with further follow-up visits required every six months thereafter until approval is granted from the US FDA or official study closure, whichever is first. Data were also collected upon system modification, notification of adverse events or technical observations, study exits, deviations, and deaths. Data collected included demographics, medical history, device interrogations, Holter monitoring, echocardiograms (echo), assessment of clinical and functional status, as well as quality of life.
Primary objectives compared AdaptivCRT to echo-optimization using the Packer Clinical Composite Score1 (CCS) as a measure of patient outcome and aortic velocity time integral (AoVTI) as a measure of cardiac performance. AoVTI was measured under each of two parameter settings: AV and VV settings determined by AdaptivCRT and AV and VV settings determined by echo-optimization. The agreement between these paired AoVTI measurements was evaluated using the Concordance Correlation Coefficient (CCC) with each subject serving as his/her own control. Inappropriate AV or VV delay settings related to the AdaptivCRT feature served as the primary safety endpoint for this study. An AV or VV delay setting was evaluated for appropriateness if a delay varied by more than 60 ms during a 28-day period. The primary study objectives evaluated data from randomization through the 6 month follow-up visit.
3 Subject Inclusion and Exclusion Criteria
Subjects who satisfied all inclusion and no exclusion criteria were eligible to participate in the study.
Inclusion Criteria
Subject was willing to sign and date the study Informed Consent form.
Subject was at least 18 years of age (or older, if required by local law).
Subject was expected to remain available for at least six months of follow-up visits.
Packer M. Proposal for a new clinical end point to evaluate the efficacy of drugs and devices in the treatment of chronic heart
failure. Journal of Cardiac Failure 2001; 7:176-182.
2
Subject was indicated for a study device that would be implanted within 30 days after signing the
Informed Consent form.
Subject had an intrinsic QRS duration greater than or equal to 120 ms documented within 30 days
prior to enrollment.
Subject had a left ventricular ejection fraction less than or equal to 35% (method per physician
discretion) documented within 180 days prior to enrollment.
Subject was diagnosed with New York Heart Association (NYHA) class III or IV within 30 days prior to
enrollment despite optimal medical therapy which was defined as:
ACE-inhibitor (Angiotensin-Converting Enzyme) or Angiotensin II Receptor Blocker (ARB), if
tolerated, for at least one month prior to implant, and
Beta-blocker for at least three months preceding implant, if tolerated, and stable for one month.
Stable was defined as no upward titration of beta-blockers
OR
Subject had an urgent medical need for an ICD that precluded waiting the one or three months for
the medication requirements for ACE inhibitor, ARB or beta-blocker.
Exclusion Criteria
Subject had chronic (permanent) atrial arrhythmias for which pharmacological therapy and/or
cardioversion had been unsuccessful or had not been attempted.
Subject had existing CRT system.
Subject had non-intact or unstable leads.
Subject had medical conditions that would have limited study participation (per physician discretion).
Subject was enrolled in one or more concurrent studies that would have confounded the study results
as determined by Medtronic.
Subject had unstable angina, or experienced an acute myocardial infarction (MI) or received coronary
artery revascularization (CABG) or coronary angioplasty (PTCA) (documented within 30 days prior to enrollment).
Subject had a mechanical right heart valve or was scheduled to undergo valve repair or valve
replacement during the course of the study.
Subject was post-heart transplant (subjects on the heart transplant list for the first time were not
excluded).
Subject had a limited life expectancy that would not have allowed completion of the 6 month visit.
Subject was pregnant. (In the US, all women of child-bearing potential had to undergo a pregnancy
test within seven days prior to AdaptivCRT™ injection.)
Subject met the exclusion criteria required by local law.
4 Study Objectives
Primary Objectives
The three primary objectives of the AdaptivCRT clinical study were designed to demonstrate that:
The percent of AdaptivCRT subjects improved in their Clinical Composite Score was at least as
good as the percent of Echo-Optimized Control subjects improved.
Cardiac performance was similar when using AdaptivCRT versus echo-optimized settings.
AdaptivCRT did not result in inappropriate AV or VV delay settings.
3
Secondary Objectives
2
Secondary objectives focused on other clinically relevant outcomes for heart failure patients and were intended to corroborate the results of the primary objectives. Secondary objectives were planned to be tested in a hierarchical fashion, should all three primary objectives be met. The following secondary objectives were pre-specified to demonstrate that:
The right ventricular pacing percentage from implant to six months post-randomization was lower
in the AdaptivCRT™ group than in the Echo-Optimized Control group.
The change in left ventricular end systolic volume index (LVESVi) from baseline to six months in
the AdaptivCRT group was at least as good as the change in the Echo-Optimized Control group.
The change in left ventricular ejection fraction (LVEF) from baseline to six months in the
AdaptivCRT group was at least as good as the change in the Echo-Optimized Control group.
The change in NYHA classification from baseline to six months in the AdaptivCRT group was at
least as good as the change in the Echo-Optimized Control group.
The change in distance walked during the six minute hall walk from baseline to six months in the
AdaptivCRT group was at least as good as the change in the Echo-Optimized Control group.
The change in quality of life (QoL), measured by the Minnesota Living With Heart Failure
Questionnaire2 (MLWHF), from baseline to six months in the AdaptivCRT group was at least as good as the change in the Echo-Optimized Control group.
5 Results
The first enrollment occurred on November 16, 2009, and the first use of the AdaptivCRT feature occurred on November 24, 2009. Enrollments ended in December 2010. The results presented in this report include data collected at sites on or before July 8, 2011, with site data received in the database by August 3, 2011.
Patient Accountability
A total of 522 subjects were enrolled at 94 sites, including 291 enrollments at 55 sites in the United States, 162 enrollments at 25 sites in Europe/Central Asia, 30 enrollments at 6 sites in Australia, 29 enrollments at 5 sites in Canada, 7 enrollments at 2 sites in Japan, and 3 enrollments at 1 site in Hong Kong. Of the 522 enrolled subjects, 521 completed a baseline visit. Of these 521 subjects, 491 subjects had a successful implant. Of the 491 successfully implanted subjects, 478 were randomized. Of these, 318 subjects were randomized to the AdaptivCRT group and 160 subjects were randomized to the Echo­Optimized Control group. The distribution of subject enrollments and follow-up by randomized group is listed in Figure 1: The mean follow-up duration from enrollment for all 522 subjects was 9.2 ± 3.9 months (range from 0.0 to 19.7 months).
© University of Minnesota 1986
4
Figure 1: Subject Enrollments and Study Cohorts
Subjects Enrolled (n=522)
Baseline (n=521)
Completed (n=521)
Missing (n=0)
Pending (n=0)
Successful System Implant (n=491)
Completed (n=491)
Missing (n=0)
Pending (n=0)
Unsuccessful System Implant (n=14)*
Completed (n=14)
Missing (n=0)
Pending (n=0)
Randomization (n=478)
Completed (n=478)
Missing (n=0)
Pending (n=0)
1 Month Post-Randomization (n=316)
Completed (n=309)
Missing (n=7)
Pending (n=0)
1 Month Post-Randomization (n=160)
Completed (n=156)
Missing (n=4)
Pending (n=0)
3 Months Post-Randomization (n=307)
Completed (n=302)
Missing (n=5)
Pending (n=0)
6 Months Post-Randomization (n=299)
Completed (n=296)
Missing (n=3)
Pending (n=0)
18 Months Post-Randomization (n=147)
Completed (n=0)
Missing (n=0)
Pending (n=147)
12 Months Post-Randomization (n=291)
Completed (n=72)
Missing (n=1)
Pending (n=218)
18 Months Post-Randomization (n=291)
Completed (n=0)
Missing (n=1)
Pending (n=290)
12 Months Post-Randomization (n=148)
Completed (n=39)
Missing (n=0)
Pending (n=109)
6 Months Post-Randomization (n=155)
Completed (n=153)
Missing (n=2)
Pending (n=0)
3 Months Post-Randomization (n=157)
Completed (n=151)
Missing (n=6)
Pending (n=0)
Randomized to AdaptivCRT™
(n=318)
Randomized to Echo-Optimized Control
(n=160)
*All Subjects Exited
Exits (n=1) Deaths (n=0)
Exits (n=1) Deaths (n=0)
Exits (n=0) Deaths (n=0)
Exits (n=0) Deaths (n=0)
Exits (n=0) Deaths (n=2)
Exits (n=12) Deaths (n=1)
Exits (n=16) Deaths (n=0)
Exits (n=3) Deaths (n=4)
Exits (n=3) Deaths (n=5)
Exits (n=1) Deaths (n=1)
Exits (n=2) Deaths (n=6)
Exits (n=1) Deaths (n=2)
Exits (n=4) Deaths (n=5)
Note: A visit was considered
“missing” if the visit window had
closed and the visit was not entered
in the database. A visit was
considered “pending” if the visit
window had not yet opened or was
still open and a visit had not been
entered in the database.
5
Subject Demographics
Subject Demographics
AdaptivCRT
(n=318)
Echo-
Optimized
Control (n=160)
Total Subjects
(n=478)
Male, n (%)
221 (69%)
109 (68%)
330 (69%)
Age (years)
65.4 ± 11.2
66.2 ± 9.7
65.7 ± 10.7
Race/ Ethnic Origin, n (%)
Subject/physician chose not to provide information
2 (<1%)
2 (1%)
4 (<1%)
Not reportable per local laws or regulations
5 (2%)
3 (2%)
8 (2%)
American Indian or Alaska Native
1 (<1%)
0 (0%)
1 (<1%)
Asian
7 (2%)
3 (2%)
10 (2%)
Black or African American
29 (9%)
6 (4%)
35 (7%)
Hispanic or Latino
13 (4%)
5 (3%)
18 (4%)
Native Hawaiian or Pacific Islander
0 (0%)
1 (<1%)
1 (<1%)
White or Caucasian
256 (81%)
138 (86%)
394 (82%)
Two or more races3
3 (<1%)
1 (<1%)
4 (<1%)
Other race4
2 (<1%)
1 (<1%)
3 (<1%)
3
4
Table 1 and Table 2 summarize baseline demographics and clinical characteristics for all 478 randomized subjects. No significant differences were seen between the AdaptivCRT™ and Echo-Optimized Control group for these demographics and clinical characteristics. Mean and standard deviation are presented for continuous variables.
Table 1: Baseline Demographics
Multiple races are not individually specified. Other race includes: Arab, Turkish, Sri Lankan.
6
Table 2: Baseline Clinical Characteristics
Subject Demographics
AdaptivCRT
(n=318)
Echo-
Optimized
Control (n=160)
Total Subjects
(n=478)
Height (in.)
67.7 ± 3.8
67.5 ± 4.2
67.7 ± 3.9
Weight (lbs.)
190.4 ± 42.0
196.6 ± 54.2
192.5 ± 46.5
BMI (kg/m2)
29.1 ± 5.8
30.1 ± 7.1
29.4 ± 6.3
BSA (m2)
2.0 ± 0.2
2.0 ± 0.3
2.0 ± 0.3
LV Ejection Fraction (%)
24.7 ± 6.6
24.9 ± 6.5
24.8 ± 6.6
QRS Duration (ms)
154.3 ± 21.0
155.7 ± 21.4
154.8 ± 21.1
New York Heart Association, n (%)
Class I5
0 (0%)
1 (<1%)
1 (<1%)
Class II6
4 (1%)
1 (<1%)
5 (1%)
Class III
300 (94%)
153 (96%)
453 (95%)
Class IV
14 (4%)
5 (3%)
19 (4%)
5
6
Subject met eligibility for the study during the screening process and had a documented NYHA classification of Class III within 30
days prior to enrollment, and was assessed at the baseline visit as NYHA Class I.
Four of the five subjects met eligibility for the study during the screening process and had a documented NYHA classification of
Class III within 30 days prior to enrollment. One subject had a NYHA Class II documented prior to enrollment as well as at the baseline visit. Medtronic did not learn of this until after the subject had been randomized into the study, therefore this subject remained in the study and continued follow-up in accordance with intent-to-treat principles. A study deviation was reported.
7
Subjects Included in Analysis of Primary Objectives
Enrolled (n=522)
Randomized 2:1
A. Clinical Composite Score
Excluded (n=44)
Not meeting inc/exc criteria (n=12) Unsuccessful implant (n=14) Implant not performed (n=5) Subject withdrew (n=6) Medical reason (n=5) Rand cohort complete (n=1) Death (n=1)
Allocated to AdaptivCRT™ intervention (n=318)
Received intervention (n=311) Did not receive intervention (n=7) Unknown if received (n=0)
Allocated to echo-opt. intervention (n=160)
Received intervention (n=143) Did not receive intervention (n=16) Unknown if received (n=1)
Incomplete follow-up (n=19)
Death (n=13) Exited for medical reasons (n=3) Lost to follow-up (n=1) Subject withdrew (n=1) Non-study device replacement (n=1)
Clinical Composite Score at 6-months Analyzed by Intention to Treat (n=318)
Incomplete follow-up (n=4)
Death (n=2) Exited for medical reasons (n=1) Lost to follow-up (n=0) Subject withdrew (n=1) Non-study device replacement (n=0)
Clinical Composite Score at 6-months Analyzed by Intention to Treat (n=160)
B. Cardiac Performance
C. AdaptivCRT™ Safety
Randomized Subjects at Randomization (n=478) Not analyzed (n=79)
Echo not performed (n=1) Aortic VTI not readable (n=78)
Analyzed (n=399)
AdaptivCRT™ Subjects at 6-months (n=318) Not analyzed (n=83)
Incomplete follow-up (n=19) Visit missed (n=3) Echo not performed (n=3) Aortic VTI not readable (n=58)
AdaptivCRT™ Subjects at 6-months (n=318) Not analyzed (n=4)
Death prior to device data collection (n=2) Exited prior to device data collection (n=2)
Analyzed (n=314)
Complete device data (n=301) Partial device data (n=13)
Analyzed (n=235)
Figure 2 shows the number of subjects included in the analysis of the primary objectives. Every subject was assigned a CCS which by definition uses a last observation carried forward (LOCF) methodology. Clinical Composite Score values that were missing at 6-month post-randomization were determined by carrying forward an NYHA Class or Patient Global Assessment measurement made at a visit prior to the 6 month visit.
Figure 2: CONSORT Flow Diagram of Subjects Analyzed for Primary Objectives
8
Primary Objectives
14.2%
12.3%
73.6%
11.3%
16.3%
72.5%
Improved Unchanged Worsened
AdaptivCRT Echo-Optimized Control
Non-inferiority P = 0.0007
1. Clinical Composite Score - To demonstrate that the percent of AdaptivCRT™ subjects improved in
their CCS was at least as good as the percent of Echo-Optimized Control subjects improved in their CCS.
The Clinical Investigation Plan pre-specified that a comparison would be made between the two groups based on the percentage of subjects with an improved response. In the AdaptivCRT group 73.6% (234/318) of subjects had an improved CCS versus 72.5% (116/160) of subjects in the Echo-Optimized Control group. The p-value of the statistical test evaluating whether the AdaptivCRT group is non-inferior to the Echo-Optimized Control group within a 12% margin is 0.0007. Figure 3 shows the distribution of CCS by study group.
Figure 3: Clinical Composite Score Distribution at 6 Months
Figure 4 shows the non-inferiority comparison of the improved CCS with the AdaptivCRT group having a
1.1% higher percent of subjects with an improved CCS compared to the Echo-Optimized Control group. The 95% confidence interval for the difference was -6.9% to 9.1%. As demonstrated by the lower bound of the confidence interval being greater than the non-inferiority margin of -12%, the percent improved for AdaptivCRT subjects was non-inferior to the Echo-Optimized Control subjects and, therefore, this primary objective was met.
9
Figure 4: Non-inferiority Comparison of Proportion with Improved Clinical Composite Score
-25% -20% -15% -10% -5% 0% 5% 10% 15% 20% 25%
Difference in Clinical Composite Score
AdaptivCRT % Improved - Echo-Optimized Control % Improved
p=0.0007
Non-inferiority Margin (12%)
95% confidence interval
0
10
20
30
40
50
60
0 10 20 30 40 50 60
Echo-Optimized AoVTI (cm)
AdaptivCRT AoVTI (cm)
p<0.0001
CCC=0.93 (0.91-0.94)
n=399
2. Cardiac Performance - To demonstrate that cardiac performance was sufficiently similar when using
AdaptivCRT™ versus echo-optimized settings.
Two separate hypothesis tests were performed, one using randomization measurements and the other using 6-month measurements. Subjects randomized to the Echo-Optimized Control group only had manual echo-optimization at the 6-month visit and therefore are not included in the 6-month analysis.
At randomization, as seen in Figure 5, the paired AoVTI measurements follow the line of equality closely indicating the AoVTI measured with echo-optimized device settings and the AoVTI measured with AdaptivCRT device settings were similar. The CCC at randomization of 0.93 measures the agreement of the data with this ideal line of equality and has a lower confidence interval of 0.91 which is higher than the pre-specified minimum objective performance criteria of 0.82 (p<0.0001).
Figure 5: Concordance Correlation Coefficient at Randomization
10
0
10
20
30
40
50
60
0 10 20 30 40 50 60
Echo-Optimized AoVTI (cm)
AdaptivCRT AoVTI (cm)
p<0.0001
CCC=0.90 (0.87-0.92)
n=235
At 6 months post-randomization, as seen in Figure 6, the paired AoVTI measurements follow the line of equality closely indicating the AoVTI measured with echo-optimized device settings and the AoVTI measured with AdaptivCRT™ device settings were similar for subjects randomized to the AdaptivCRT group. The CCC at 6 months of 0.90 measures the agreement of the data with the ideal line of equality, and has a lower confidence interval of 0.87 which is higher than the pre-specified minimum objective performance criteria of 0.82 (p<0.0001).
Since the 95% lower confidence bound of the CCC at both randomization and six months exceeds the pre-specified limit of 0.82, it can be concluded that cardiac performance was sufficiently similar when using AdaptivCRT versus echo-optimized settings and, therefore, this primary objective was met.
Figure 6: Concordance Correlation Coefficient at 6 Months
3. AdaptivCRT™ Safety - To demonstrate that AdaptivCRT does not result in inappropriate AV or VV
delay settings.
All consecutive 28-day periods were evaluated for each subject to determine if any AV or VV delays had a range exceeding 60 ms. A medical review panel of independent physicians was in place to evaluate all occurrences of wide AV or VV delay ranges for appropriateness of the AV or VV delay variations. Information from device diagnostics and other study data were to be used for these evaluations. A subject experienced a safety event if the subject had an inappropriate AV or VV delay setting during a 28-day period with a wide delay range. Table 3 reports the results of this analysis for the subjects randomized to the AdaptivCRT group that had at least one post-randomization save-to-disk. No subjects had an AV or VV delay range that exceeded 60 ms within a 28-day period. Based on subjects’ AdaptivCRT feature data, no subjects were identified for further review by the medical review panel. There was no evidence that the AdaptivCRT feature resulted in inappropriate AV or VV delay settings and, therefore, this primary objective was met.
11
Table 3: AdaptivCRT Feature AV/VV Delay Range > 60 ms within 28-Day Period
AdaptivCRT
(n=314)
Sensed AV delay in LV mode
0 (0.0%)
Paced AV delay in LV mode
0 (0.0%)
Sensed AV delay in Bi-V mode
0 (0.0%)
Paced AV delay in Bi-V mode
0 (0.0%)
VV delay in Bi-V mode
0 (0.0%)
Total
0 (0.0%)
AdaptivCRT
(n=318)
Echo-Optimized
Control (n=160)
P-value
%Ventricular Pacing
n recorded Mean ± Standard Deviation
314
95.5 ± 5.7
160
95.1 ± 10.5
%LV Only Pacing n recorded Mean ± Standard Deviation
314
44.2 ± 38.0
160
0.1 ± 0.6
%BiV (RV + LV) Pacing n recorded Mean ± Standard Deviation
314
51.3 ± 37.9
160
95.1 ± 10.5
<0.0001
Secondary Objectives
1. Right Ventricular Pacing Percentage - To demonstrate that the right ventricular pacing percentage
from implant to six months post-randomization was lower in the AdaptivCRT™ group than in the Echo­Optimized Control group.
Subjects with the AdaptivCRT feature could be provided CRT therapy via two different types of ventricular pacing, with the algorithm dynamically selecting either adaptive BiV (RV+LV) pacing or adaptive LV only pacing that is synchronized to the intrinsic RV contraction. Subjects in the Echo-Optimized Control group received CRT therapy through BiV (RV+LV) pacing.
Table 4 provides the total percent ventricular pacing, percent LV only pacing, and percent BiV (RV+LV) pacing from implant to 6 months for all randomized subjects in each group of the analysis cohort. Subjects in both groups received CRT therapy a similar percentage of the time. The combination of adaptive BiV and adaptive LV pacing resulted in total percent ventricular pacing of 95.5% on average in the AdaptivCRT group versus 95.1% in the Echo-Optimized Control group. The observed mean percent BiV (RV+LV) pacing through 6 months was 51.3% in the AdaptivCRT group, and 95.1% in the Echo­Optimized Control group. The observed difference in mean percent BiV (RV+LV) pacing between the two groups was 43.8%, and the difference was significant (p < 0.0001). Thus, it can be concluded that subjects with the AdaptivCRT feature did, on average, have lower percent RV pacing over 6 months post­randomization than the Echo-Optimized Control subjects and, therefore, this secondary objective was met.
Table 4: Summary of Percent Pacing in First 6 Months
Figure 7 illustrates the distribution of LV-only pacing and BiV pacing for the subjects in the AdaptivCRT group with ventricular pacing data. The figure shows what percent of total ventricular pacing was adaptive BiV pacing and LV only pacing displayed as one stacked bar for each subject. The AdaptivCRT feature was effective at reducing RV pacing in a broad subset of subjects. There were 72% of subjects that experienced LV only pacing at least 1% of the time, 66% that experienced LV only pacing at least 10% of the time, and 47% that experienced LV only pacing at least 50% of the time.
12
Figure 7: Distribution of LV only and BiV Pacing in the AdaptivCRT Group
0
10
20
30
40
50
60
70
80
90
100
0 5 10 15 19 24 29 34 39 43 48 53 58 62 67 72 77 82 86 91 96
Percent (%) Ventricular Pacing
Percentage of Subjects
Total Percent LV Only Pacing in First 6 Months Total Percent BiV Pacing in First 6 Months
LVESVi (mL/m2)
AdaptivCRT
(n=318)
Echo-Optimized
Control
(n=160)
Difference
(95% CI)
Non-
inferiority
Margin
Non-
inferiority
P-value
Baseline
n recorded Mean ± Standard Deviation
291
71.7 ± 28.3
140
74.0 ± 30.9
6 Months n recorded Mean ± Standard Deviation
268
63.5 ± 31.9
137
64.7 ± 32.6
Paired Difference at 6 Months n recorded Mean ± Standard Deviation
250
-8.3 ± 23.3
123
-10.5 ± 24.2
2.3 (-2.8,
7.4)
15
<0.0001
2. Changes in Left Ventricular End Systolic Volume Index - To demonstrate that the change in LVESVi from baseline to six months in the AdaptivCRT™ group was at least as good as the change in the Echo-Optimized Control group.
Table 5 provides the LVESVi scores at baseline and 6 months for all randomized subjects in the analysis cohort as well as a comparison of the mean change in LVESVi over that time frame. In both the AdaptivCRT and Echo-Optimized Control groups, LVESVi, on average, was reduced over the 6-months post-randomization. The observed difference in mean change in LVESVi between the two groups was 2.3 with a 95% confidence interval of -2.8 to 7.4, and the difference was found to be below the non-inferiority margin of 15 mL/m2 (p <0.0001), therefore, this secondary objective was met.
Table 5: Change in LVESVi from Baseline to 6 Months
13
3. Changes in Left Ventricular Ejection Fraction - To demonstrate that the change in LVEF from
LVEF (%)
AdaptivCRT
(n=318)
Echo-Optimized
Control (n=160)
Difference
(95% CI)
Non-
inferiority
Margin
Non-
inferiority
P-value
Baseline
n recorded Mean ± Standard Deviation
291
29.6 ± 9.2
140
30.3 ± 8.4
6 Months n recorded Mean ± Standard Deviation
268
33.6 ± 10.4
137
32.9 ± 10.1
Paired Difference at 6 Months n recorded Mean ± Standard Deviation
250
3.9 ± 10.0
123
2.9 ± 9.8
1.0 (-1.2,
3.1)
-2.5
0.0009
AdaptivCRT
(n=318)
Echo-Optimized
Control (n=160)
Difference
(95% CI)
Non-
inferiority
Margin
Non-
inferiority
P-value
Baseline
n recorded Mean ± Standard Deviation
318
3.0 ± 0.2
160
3.0 ± 0.3
6 Months n recorded Mean ± Standard Deviation
296
2.0 ± 0.8
153
2.2 ± 0.8
Paired Difference at 6 Months n recorded Mean ± Standard Deviation
296
-1.0 ± 0.8
153
-0.8 ± 0.8
-0.15 (-0.3,
0.0)
0.3
<0.0001
baseline to six months in the AdaptivCRT™ group was at least as good as the change in the Echo­Optimized Control group.
Table 6 provides the LVEF measurements at baseline and 6 months for all randomized subjects in the analysis cohort as well as a comparison of the mean change in LVEF over that time frame. In both the AdaptivCRT and Echo-Optimized Control groups, LVEF, on average, tended to increase over the 6 months post-randomization. The observed difference in mean change in LVEF between the two groups was 1.0 with a 95% confidence interval of -1.2 to 3.1, and the difference was found to be above the non­inferiority margin of -2.5% (p = 0.0009), therefore, this secondary objective was met.
Table 6: Change in LVEF from Baseline to 6 Months
4. Changes in New York Heart Association Functional Class - To demonstrate that the change in
NYHA class from baseline to six months in the AdaptivCRT group was at least as good as the change in the Echo-Optimized Control group.
Table 7 provides the NYHA classification at baseline and 6 months for all randomized subjects in the analysis cohort as well as a comparison of the mean change in NYHA classification over that time frame. The observed difference in mean change in NYHA class (AdaptivCRT minus Echo-Optimized Control) was -0.15 with a 95% confidence interval of -0.30 to 0.00, and the difference was found to be below the non-inferiority margin of 0.30 (p < 0.0001), therefore, this secondary objective was met.
Table 7: Change in Mean NYHA Class from Baseline to 6 Months
14
5. Changes in Six-minute Hall Walk - To demonstrate that the change in distance walked during the six-
Distance (meters)
AdaptivCRT
(n=318)
Echo-Optimized
Control
(n=160)
Difference
(95% CI)
Non-
inferiority
Margin
Non-
inferiority
P-value
Baseline
n recorded Mean ± Standard Deviation
312
276.8 ± 127.5
156
277.7 ± 137.8
6 Months n recorded Mean ± Standard Deviation
288
325.5 ± 130.4
146
311.4 ± 152.0
Paired Difference at 6 Months n recorded Mean ± Standard Deviation
284
42.4 ± 103.3
142
29.0 ± 123.0
13.4 (-8.9,
35.7)
-30
0.0002
minute hall walk from baseline to six months in the AdaptivCRT™ group was at least as good as the change in the Echo-Optimized Control group.
Table 8 provides the six-minute hall walk performance for each group at baseline and 6 months, as well as a comparison of the mean change in performance over that time frame. Each group showed an observed mean improvement in hall walk distance (42.4 meters in the AdaptivCRT group and 29.0 meters in the Echo-Optimized Control group). The observed difference in mean performance between the two groups was 13.4 meters with a 95% confidence interval of -8.9 to 35.7 meters, and the difference was found to be above the non-inferiority margin of -30m (p = 0.0002), therefore, this secondary objective was met.
Table 8: Change in Six-minute Hall Walk from Baseline to 6 Months
6. Changes in Quality of Life - To demonstrate that the change in QoL, measured by the Minnesota
Living With Heart Failure Questionnaire, from baseline to six months in the AdaptivCRT group was at least as good as the change in the Echo-Optimized Control group.
Table 9 provides the MLWHF results for each group at baseline and 6 months, as well as a comparison of the mean change in overall score over that time frame. As a reduction in the MLWHF score indicates an improvement, both groups showed observed improvement in Quality of Life (QoL). The observed AdaptivCRT to Echo-Optimized Control group difference in mean change in score between groups was -
1.7 (meaning the observed reduction in QoL score was 1.7 units greater in the AdaptivCRT group than in the Echo-Optimized Control group) with a 95% confidence interval of -6.3 to 2.8, and the difference was found to be below the non-inferiority margin of 5.1 (p = 0.002), therefore, this secondary objective was met.
15
Table 9: Change in Minnesota Living With Heart Failure from Baseline to 6 Months
AdaptivCRT
(n=318)
Echo-Optimized
Control
(n=160)
Difference
(95% CI)
Non-
inferiority
Margin
Non-
inferiority
P-value
Baseline
n recorded Mean ± Standard Deviation
286
48.5 ± 24.1
142
46.3 ± 23.6
6 Months n recorded Mean ± Standard Deviation
263
28.2 ± 22.0
139
28.4 ± 23.0
Paired Difference at 6 Months n recorded Mean ± Standard Deviation
261
-19.3 ± 20.7
135
-17.6 ± 23.8
-1.7 (-6.3,
2.8)
5.1
0.002
Adverse Event Classification
Number of Events (# of Subjects, % of Subjects)
AdaptivCRT™
(n=318)
Echo-Optimized
Control (n=160)
Total Subjects
(n=478)
Total Adverse Events
374 (175, 55.0%)
285 (105, 65.6%)
659 (280, 58.6%)
Serious
195 (104, 32.7%)
140 (60, 37.5%)
335 (164, 34.3%)
Serious Adverse Device Effect (SADE)
16 (15, 4.7%)
18 (15, 9.4%)
34 (30, 6.3%)
Unanticipated Adverse Device Effect (UADE)
0 (0, 0.0%)
0 (0, 0.0%)
0 (0, 0.0%)
Complications/Observations
Complication
210 (116, 36.5%)
147 (65, 40.6%)
357 (181, 37.9%)
Observation
164 (105, 33.0%)
138 (80, 50.0%)
302 (185, 38.7%)
6 Adverse Events Summary
Adverse events were classified for Seriousness, Complications/Observations, and Relatedness. A complication was defined as an adverse event that results in death, involves any termination of significant device function, or requires invasive intervention. An observation was defined as any adverse event that is not a complication. System relatedness was assessed with respect to device, leads, implant tool, investigational algorithm, investigational software, and programmers. The Global Adverse Event Adjudication Committee (GAEAC) was permitted to select more than one relatedness for an individual adverse event. Therefore a single adverse event can contribute to multiple classifications.
There were a total of 280 subjects who experienced a total of 659 events after randomization. The GAEAC reviewed and adjudicated all of these adverse events in the subject cohort. Of the 659 events,
79.7% (525 events) were not related to the system or procedures for implanting or modifying the device and leads, and 45.8% (302 events) were classified as observations which required no invasive action. There were no unanticipated adverse device effects (UADEs) observed. Analysis comparing time to first event and time to first complication showed no statistical difference between the AdaptivCRT™ and Echo­Optimized Control groups for any adverse events or complications, respectively. Table 10 summarizes the adverse events by relatedness and Table 11 summarizes the adverse events by preferred term, by highest incidence of event rate, with cardiac failure the most frequently occurring event (107 events in 80 subjects).
Table 10: Classification of Adverse Events after Randomization
16
Adverse Event Classification
Number of Events (# of Subjects, % of Subjects)
AdaptivCRT™
(n=318)
Echo-Optimized
Control (n=160)
Total Subjects
(n=478)
Relatedness
Procedure or System Relatedness
Related
68 (57, 17.9%)
61 (46, 28.8%)
129 (103, 21.5%)
Not related
302 (145, 45.6%)
223 (90, 56.3%)
525 (235, 49.2%)
Unknown
4 (4, 1.3%)
1 (1, 0.6%)
5 (5, 1.0%)
Procedure Relatedness
Implant
Related
39 (35, 11.0%)
39 (33, 20.6%)
78 (68, 14.2%)
Not related
334 (156, 49.1%)
245 (94, 58.8%)
579 (250, 52.3%)
Unknown
1 (1, 0.3%)
1 (1, 0.6%)
2 (2, 0.4%)
System Modification
Related
2 (2, 0.6%)
3 (3, 1.9%)
5 (5, 1.0%)
Not related
372 (175, 55.0%)
282 (105, 65.6%)
654 (280, 58.6%)
Unknown
0 (0, 0.0%)
0 (0, 0.0%)
0 (0, 0.0%)
System Relatedness
Any System Component
Related
40 (35, 11.0%)
42 (33, 20.6%)
82 (68, 14.2%)
Not related
330 (157, 49.4%)
241 (97, 60.6%)
571 (254, 53.1%)
Unknown
4 (4, 1.3%)
2 (2, 1.3%)
6 (6, 1.3%)
Device
Related
9 (9, 2.8%)
11 (10, 6.3%)
20 (19, 4.0%)
Not related
363 (172, 54.1%)
272 (102, 63.8%)
635 (274, 57.3%)
Unknown
2 (2, 0.6%)
2 (2, 1.3%)
4 (4, 0.8%)
RA Lead
Related
8 (8, 2.5%)
7 (7, 4.4%)
15 (15, 3.1%)
Not related
366 (172, 54.1%)
277 (102, 63.8%)
643 (274, 57.3%)
Unknown
0 (0, 0.0%)
1 (1, 0.6%)
1 (1, 0.2%)
RV Lead
Related
5 (5, 1.6%)
7 (7, 4.4%)
12 (12, 2.5%)
Not related
367 (172, 54.1%)
277 (104, 65.0%)
644 (276, 57.7%)
Unknown
2 (2, 0.6%)
1 (1, 0.6%)
3 (3, 0.6%)
LV Lead
Related
22 (20, 6.3%)
24 (22, 13.8%)
46 (42, 8.8%)
Not related
352 (164, 51.6%)
260 (102, 63.8%)
612 (266, 55.6%)
17
Adverse Event Classification
Number of Events (# of Subjects, % of Subjects)
AdaptivCRT™
(n=318)
Echo-Optimized
Control (n=160)
Total Subjects
(n=478)
Unknown
0 (0, 0.0%)
1 (1, 0.6%)
1 (1, 0.2%)
Investigational Software
Related
0 (0, 0.0%)
0 (0, 0.0%)
0 (0, 0.0%)
Not related
371 (174, 54.7%)
285 (105, 65.6%)
656 (279, 58.4%)
Unknown7
3 (3, 0.9%)
0 (0, 0.0%)
3 (3, 0.6%)
Investigational Algorithm
Related
0 (0, 0.0%)
0 (0, 0.0%)
0 (0, 0.0%)
Not related
371 (174, 54.7%)
285 (105, 65.6%)
656 (279, 58.4%)
Unknown7
3 (3, 0.9%)
0 (0, 0.0%)
3 (3, 0.6%)
Implant or introduction tool(s)
Related
1 (1, 0.3%)
2 (2, 1.3%)
3 (3, 0.6%)
Not related
373 (175, 55.0%)
283 (104, 65.0%)
656 (279, 58.4%)
Unknown
0 (0, 0.0%)
0 (0, 0.0%)
0 (0, 0.0%)
Programmer
Related
1 (1, 0.3%)
0 (0, 0.0%)
1 (1, 0.2%)
Not related
373 (175, 55.0%)
285 (105, 65.6%)
658 (280, 58.6%)
Unknown
0 (0, 0.0%)
0 (0, 0.0%)
0 (0, 0.0%)
Other
Related
0 (0, 0.0%)
1 (1, 0.6%)
1 (1, 0.2%)
Not related
374 (175, 55.0%)
284 (105, 65.6%)
658 (280, 58.6%)
Unknown
0 (0, 0.0%)
0 (0, 0.0%)
0 (0, 0.0%)
Heart Failure Relatedness (N, %)
Related
98 (62, 19.5%)
48 (29, 18.1%)
146 (91, 19.0%)
Not related
276 (152, 47.8%)
237 (96, 60.0%)
513 (248, 51.9%)
Unknown
0 (0, 0.0%)
0 (0, 0.0%)
0 (0, 0.0%)
7
Two subjects had an AE associated with a crossover. GAEAC felt that this was unknown relatedness to the software and algorithm due to the fact that the subject was never re-challenged with the algorithm. One subject had an AE associated with a death. GAEAC felt that this was unknown relatedness to the software and algorithm due to a lack of data available. The last device interrogation collected from this subject was on the date of randomization so there was no additional algorithm data to review and thus no way to conclusively determine relatedness.
18
19
Adverse Event Preferred Term
Number of Events (# of Subjects, % of Subjects)
AdaptivCRT™
(n=318)
Total years of follow-up = 196.0
Echo-Optimized Control
(n=160)
Total years of follow-up = 103.6
Total Subjects
(n=478)
Total years of follow-up = 299.6
Events Complications
Events Complications
Events Complications
Cardiac failure
69 (54, 17.0%)
59 (46, 14.5%) 38 (26, 16.3%)
31 (20, 12.5%)
107 (80, 16.7%)
90 (66, 13.8%)
Device stimulation issue
13 (11, 3.5%)
2 (2, 0.6%)
12 (11, 6.9%)
2 (2, 1.3%)
25 (22, 4.6%)
4 (4, 0.8%)
Device dislocation
11 (11, 3.5%)
11 (11, 3.5%)
9 (6, 3.8%)
8 (5, 3.1%)
20 (17, 3.6%)
19 (16, 3.3%)
Pneumonia
12 (11, 3.5%)
10 (9, 2.8%)
8 (8, 5.0%)
8 (8, 5.0%)
20 (19, 4.0%)
18 (17, 3.6%)
Ventricular tachycardia
8 (7, 2.2%)
2 (2, 0.6%) 10 (8, 5.0%)
5 (3, 1.9%)
18 (15, 3.1%)
7 (5, 1.0%)
Atrial fibrillation
10 (8, 2.5%)
3 (1, 0.3%) 8 (8, 5.0%)
1 (1, 0.6%)
18 (16, 3.3%)
4 (2, 0.4%)
Chest pain
11 (10, 3.1%)
5 (5, 1.6%) 6 (6, 3.8%)
4 (4, 2.5%)
17 (16, 3.3%)
9 (9, 1.9%)
Urinary tract infection
6 (6, 1.9%)
5 (5, 1.6%) 6 (6, 3.8%)
3 (3, 1.9%)
12 (12, 2.5%)
8 (8, 1.7%)
Renal failure acute
6 (5, 1.6%)
6 (5, 1.6%) 5 (4, 2.5%)
4 (3, 1.9%) 11 (9, 1.9%)
10 (8, 1.7%)
Bronchitis
4 (4, 1.3%)
0 (0, 0.0%) 7 (6, 3.8%)
3 (2, 1.3%)
11 (10, 2.1%)
3 (2, 0.4%)
Dyspnoea
4 (4, 1.3%)
1 (1, 0.3%) 7 (6, 3.8%)
1 (1, 0.6%)
11 (10, 2.1%)
2 (2, 0.4%)
Anaemia
4 (4, 1.3%)
3 (3, 0.9%) 6 (5, 3.1%)
5 (4, 2.5%) 10 (9, 1.9%)
8 (7, 1.5%)
Chronic obstructive pulmonary
disease
5 (3, 0.9%)
5 (3, 0.9%) 5 (5, 3.1%)
2 (2, 1.3%) 10 (8, 1.7%)
7 (5, 1.0%)
Hypotension
6 (6, 1.9%)
0 (0, 0.0%) 2 (2, 1.3%)
0 (0, 0.0%) 8 (8, 1.7%)
0 (0, 0.0%)
Atrial flutter
5 (5, 1.6%)
3 (3, 0.9%) 2 (2, 1.3%)
0 (0, 0.0%) 7 (7, 1.5%)
3 (3, 0.6%)
Implant site hematoma
3 (3, 0.9%)
2 (2, 0.6%) 4 (4, 2.5%)
1 (1, 0.6%) 7 (7, 1.5%)
3 (3, 0.6%)
Implant site infection
3 (3, 0.9%)
1 (1, 0.3%) 4 (4, 2.5%)
2 (2, 1.3%) 7 (7, 1.5%)
3 (3, 0.6%)
Hyperglycemia
3 (3, 0.9%)
3 (3, 0.9%) 3 (3, 1.9%)
3 (3, 1.9%) 6 (6, 1.3%)
6 (6, 1.3%)
Dehydration
3 (3, 0.9%)
2 (2, 0.6%) 3 (3, 1.9%)
1 (1, 0.6%) 6 (6, 1.3%)
3 (3, 0.6%)
Syncope
2 (2, 0.6%)
1 (1, 0.3%) 4 (4, 2.5%)
2 (2, 1.3%) 6 (6, 1.3%)
3 (3, 0.6%)
Supraventricular tachycardia
6 (6, 1.9%)
2 (2, 0.6%) 0 (0, 0.0%)
0 (0, 0.0%) 6 (6, 1.3%)
2 (2, 0.4%)
Table 11: Adverse Events Occurring After Randomization
20
Adverse Event Preferred Term
Number of Events (# of Subjects, % of Subjects)
AdaptivCRT™
(n=318)
Total years of follow-up = 196.0
Echo-Optimized Control
(n=160)
Total years of follow-up = 103.6
Total Subjects
(n=478)
Total years of follow-up = 299.6
Events Complications
Events Complications
Events Complications
Device pacing issue
3 (3, 0.9%)
0 (0, 0.0%) 3 (3, 1.9%)
1 (1, 0.6%) 6 (6, 1.3%)
1 (1, 0.2%)
Cellulitis
2 (2, 0.6%)
1 (1, 0.3%) 3 (3, 1.9%)
3 (3, 1.9%) 5 (5, 1.0%)
4 (4, 0.8%)
Chest discomfort
4 (4, 1.3%)
1 (1, 0.3%) 1 (1, 0.6%)
0 (0, 0.0%) 5 (5, 1.0%)
1 (1, 0.2%)
Palpitations
5 (4, 1.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 5 (4, 0.8%)
1 (1, 0.2%)
Diarrhea
3 (3, 0.9%)
0 (0, 0.0%) 2 (1, 0.6%)
0 (0, 0.0%) 5 (4, 0.8%)
0 (0, 0.0%)
Sinusitis
4 (4, 1.3%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 5 (5, 1.0%)
0 (0, 0.0%)
Upper respiratory tract infection
1 (1, 0.3%)
0 (0, 0.0%) 4 (3, 1.9%)
0 (0, 0.0%) 5 (4, 0.8%)
0 (0, 0.0%)
Cardiac failure chronic
4 (2, 0.6%)
4 (2, 0.6%) 0 (0, 0.0%)
0 (0, 0.0%) 4 (2, 0.4%)
4 (2, 0.4%)
Gastrointestinal hemorrhage
1 (1, 0.3%)
1 (1, 0.3%) 3 (3, 1.9%)
3 (3, 1.9%) 4 (4, 0.8%)
4 (4, 0.8%)
Sepsis
3 (3, 0.9%)
3 (3, 0.9%) 1 (1, 0.6%)
1 (1, 0.6%) 4 (4, 0.8%)
4 (4, 0.8%)
Hypertension
1 (1, 0.3%)
1 (1, 0.3%) 3 (3, 1.9%)
1 (1, 0.6%) 4 (4, 0.8%)
2 (2, 0.4%)
Orthostatic hypotension
4 (4, 1.3%)
2 (2, 0.6%) 0 (0, 0.0%)
0 (0, 0.0%) 4 (4, 0.8%)
2 (2, 0.4%)
Angina pectoris
4 (4, 1.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 4 (4, 0.8%)
1 (1, 0.2%)
Device psychogenic complication
1 (1, 0.3%)
0 (0, 0.0%) 3 (3, 1.9%)
0 (0, 0.0%) 4 (4, 0.8%)
0 (0, 0.0%)
Gout
4 (3, 0.9%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 4 (3, 0.6%)
0 (0, 0.0%)
Hypothyroidism
1 (1, 0.3%)
0 (0, 0.0%) 3 (3, 1.9%)
0 (0, 0.0%) 4 (4, 0.8%)
0 (0, 0.0%)
Coronary artery disease
3 (3, 0.9%)
3 (3, 0.9%) 0 (0, 0.0%)
0 (0, 0.0%) 3 (3, 0.6%)
3 (3, 0.6%)
Osteoarthritis
2 (1, 0.3%)
2 (1, 0.3%) 1 (1, 0.6%)
1 (1, 0.6%) 3 (2, 0.4%)
3 (2, 0.4%)
Renal failure
2 (2, 0.6%)
2 (2, 0.6%) 1 (1, 0.6%)
1 (1, 0.6%) 3 (3, 0.6%)
3 (3, 0.6%)
Renal impairment
3 (3, 0.9%)
3 (3, 0.9%) 0 (0, 0.0%)
0 (0, 0.0%) 3 (3, 0.6%)
3 (3, 0.6%)
Deep vein thrombosis
1 (1, 0.3%)
1 (1, 0.3%) 2 (2, 1.3%)
1 (1, 0.6%) 3 (3, 0.6%)
2 (2, 0.4%)
Hyperkalemia
3 (3, 0.9%)
2 (2, 0.6%) 0 (0, 0.0%)
0 (0, 0.0%) 3 (3, 0.6%)
2 (2, 0.4%)
Implant site pain
2 (2, 0.6%)
2 (2, 0.6%) 1 (1, 0.6%)
0 (0, 0.0%) 3 (3, 0.6%)
2 (2, 0.4%)
21
Adverse Event Preferred Term
Number of Events (# of Subjects, % of Subjects)
AdaptivCRT™
(n=318)
Total years of follow-up = 196.0
Echo-Optimized Control
(n=160)
Total years of follow-up = 103.6
Total Subjects
(n=478)
Total years of follow-up = 299.6
Events Complications
Events Complications
Events Complications
Sinus tachycardia
2 (2, 0.6%)
1 (1, 0.3%) 1 (1, 0.6%)
1 (1, 0.6%) 3 (3, 0.6%)
2 (2, 0.4%)
Arthritis
1 (1, 0.3%)
0 (0, 0.0%) 2 (2, 1.3%)
1 (1, 0.6%) 3 (3, 0.6%)
1 (1, 0.2%)
Back pain
1 (1, 0.3%)
1 (1, 0.3%) 2 (2, 1.3%)
0 (0, 0.0%) 3 (3, 0.6%)
1 (1, 0.2%)
Ventricular arrhythmia
2 (2, 0.6%)
0 (0, 0.0%) 1 (1, 0.6%)
1 (1, 0.6%) 3 (3, 0.6%)
1 (1, 0.2%)
Diabetes mellitus
1 (1, 0.3%)
0 (0, 0.0%) 2 (2, 1.3%)
0 (0, 0.0%) 3 (3, 0.6%)
0 (0, 0.0%)
Dizziness
2 (2, 0.6%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 3 (3, 0.6%)
0 (0, 0.0%)
Influenza
1 (1, 0.3%)
0 (0, 0.0%) 2 (2, 1.3%)
0 (0, 0.0%) 3 (3, 0.6%)
0 (0, 0.0%)
Intracardiac thrombus
2 (2, 0.6%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 3 (3, 0.6%)
0 (0, 0.0%)
Non-cardiac chest pain
2 (2, 0.6%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 3 (3, 0.6%)
0 (0, 0.0%)
Oversensing
2 (2, 0.6%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 3 (3, 0.6%)
0 (0, 0.0%)
Presyncope
3 (3, 0.9%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 3 (3, 0.6%)
0 (0, 0.0%)
Ventricular fibrillation
1 (1, 0.3%)
0 (0, 0.0%) 2 (2, 1.3%)
0 (0, 0.0%) 3 (3, 0.6%)
0 (0, 0.0%)
Cardiac arrest
2 (2, 0.6%)
2 (2, 0.6%) 0 (0, 0.0%)
0 (0, 0.0%) 2 (2, 0.4%)
2 (2, 0.4%)
Device connection issue
0 (0, 0.0%)
0 (0, 0.0%) 2 (2, 1.3%)
2 (2, 1.3%) 2 (2, 0.4%)
2 (2, 0.4%)
Gastritis
0 (0, 0.0%)
0 (0, 0.0%) 2 (2, 1.3%)
2 (2, 1.3%) 2 (2, 0.4%)
2 (2, 0.4%)
Hypoglycaemia
0 (0, 0.0%)
0 (0, 0.0%) 2 (2, 1.3%)
2 (2, 1.3%) 2 (2, 0.4%)
2 (2, 0.4%)
Peptic ulcer
0 (0, 0.0%)
0 (0, 0.0%) 2 (2, 1.3%)
2 (2, 1.3%) 2 (2, 0.4%)
2 (2, 0.4%)
Pulmonary embolism
1 (1, 0.3%)
1 (1, 0.3%) 1 (1, 0.6%)
1 (1, 0.6%) 2 (2, 0.4%)
2 (2, 0.4%)
Sudden cardiac death
2 (2, 0.6%)
2 (2, 0.6%) 0 (0, 0.0%)
0 (0, 0.0%) 2 (2, 0.4%)
2 (2, 0.4%)
Tooth infection
0 (0, 0.0%)
0 (0, 0.0%) 2 (2, 1.3%)
2 (2, 1.3%) 2 (2, 0.4%)
2 (2, 0.4%)
Vomiting
0 (0, 0.0%)
0 (0, 0.0%) 2 (1, 0.6%)
2 (1, 0.6%) 2 (1, 0.2%)
2 (1, 0.2%)
Abdominal pain
0 (0, 0.0%)
0 (0, 0.0%) 2 (2, 1.3%)
1 (1, 0.6%) 2 (2, 0.4%)
1 (1, 0.2%)
Device capturing issue
1 (1, 0.3%)
0 (0, 0.0%) 1 (1, 0.6%)
1 (1, 0.6%) 2 (2, 0.4%)
1 (1, 0.2%)
22
Adverse Event Preferred Term
Number of Events (# of Subjects, % of Subjects)
AdaptivCRT™
(n=318)
Total years of follow-up = 196.0
Echo-Optimized Control
(n=160)
Total years of follow-up = 103.6
Total Subjects
(n=478)
Total years of follow-up = 299.6
Events Complications
Events Complications
Events Complications
Device electrical impedance issue
1 (1, 0.3%)
1 (1, 0.3%) 1 (1, 0.6%)
0 (0, 0.0%) 2 (2, 0.4%)
1 (1, 0.2%)
Fall
0 (0, 0.0%)
0 (0, 0.0%) 2 (2, 1.3%)
1 (1, 0.6%) 2 (2, 0.4%)
1 (1, 0.2%)
Gastroenteritis
0 (0, 0.0%)
0 (0, 0.0%) 2 (2, 1.3%)
1 (1, 0.6%) 2 (2, 0.4%)
1 (1, 0.2%)
Pericardial effusion
2 (2, 0.6%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 2 (2, 0.4%)
1 (1, 0.2%)
Transient ischaemic attack
1 (1, 0.3%)
0 (0, 0.0%) 1 (1, 0.6%)
1 (1, 0.6%) 2 (2, 0.4%)
1 (1, 0.2%)
Abdominal distension
1 (1, 0.3%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 2 (2, 0.4%)
0 (0, 0.0%)
Cough
1 (1, 0.3%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 2 (2, 0.4%)
0 (0, 0.0%)
Device misuse
8
1 (1, 0.3%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 2 (2, 0.4%)
0 (0, 0.0%)
Ecchymosis
0 (0, 0.0%)
0 (0, 0.0%) 2 (2, 1.3%)
0 (0, 0.0%) 2 (2, 0.4%)
0 (0, 0.0%)
Fatigue
1 (1, 0.3%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 2 (2, 0.4%)
0 (0, 0.0%)
Foot fracture
1 (1, 0.3%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 2 (2, 0.4%)
0 (0, 0.0%)
International normalized ratio
increased
1 (1, 0.3%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 2 (2, 0.4%)
0 (0, 0.0%)
Joint injury
1 (1, 0.3%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 2 (2, 0.4%)
0 (0, 0.0%)
Joint sprain
1 (1, 0.3%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 2 (2, 0.4%)
0 (0, 0.0%)
Nasopharyngitis
1 (1, 0.3%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 2 (2, 0.4%)
0 (0, 0.0%)
Pain in extremity
1 (1, 0.3%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 2 (2, 0.4%)
0 (0, 0.0%)
Abscess
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
1 (1, 0.6%) 1 (1, 0.2%)
1 (1, 0.2%)
Acute coronary syndrome
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
1 (1, 0.6%) 1 (1, 0.2%)
1 (1, 0.2%)
Acute myocardial infarction
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Acute respiratory failure
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Angioedema
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
8
For both events, Lowest Level Term was Inappropriate device therapy
23
Adverse Event Preferred Term
Number of Events (# of Subjects, % of Subjects)
AdaptivCRT™
(n=318)
Total years of follow-up = 196.0
Echo-Optimized Control
(n=160)
Total years of follow-up = 103.6
Total Subjects
(n=478)
Total years of follow-up = 299.6
Events Complications
Events Complications
Events Complications
Aortic aneurysm
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Aortic stenosis
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
1 (1, 0.6%) 1 (1, 0.2%)
1 (1, 0.2%)
Arrhythmia supraventricular
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Arthralgia
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Bronchopneumonia
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
1 (1, 0.6%) 1 (1, 0.2%)
1 (1, 0.2%)
Cardiogenic shock
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
1 (1, 0.6%) 1 (1, 0.2%)
1 (1, 0.2%)
Carotid artery stenosis
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Cataract
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Colitis
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Colonic polyp
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
1 (1, 0.6%) 1 (1, 0.2%)
1 (1, 0.2%)
Constipation
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Device lead damage
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
1 (1, 0.6%) 1 (1, 0.2%)
1 (1, 0.2%)
Diverticular perforation
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Duodenitis
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Dupuytren's contracture
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Dysphagia
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Dysuria
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
1 (1, 0.6%) 1 (1, 0.2%)
1 (1, 0.2%)
Embolism
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
1 (1, 0.6%) 1 (1, 0.2%)
1 (1, 0.2%)
Empyema
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
1 (1, 0.6%) 1 (1, 0.2%)
1 (1, 0.2%)
Encephalopathy
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Epistaxis
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Food poisoning
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Gallbladder cancer
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
24
Adverse Event Preferred Term
Number of Events (# of Subjects, % of Subjects)
AdaptivCRT™
(n=318)
Total years of follow-up = 196.0
Echo-Optimized Control
(n=160)
Total years of follow-up = 103.6
Total Subjects
(n=478)
Total years of follow-up = 299.6
Events Complications
Events Complications
Events Complications
Gastric hemorrhage
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Gastroenteritis viral
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
1 (1, 0.6%) 1 (1, 0.2%)
1 (1, 0.2%)
Hepatic neoplasm malignant
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
1 (1, 0.6%) 1 (1, 0.2%)
1 (1, 0.2%)
Hernia
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Hip fracture
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Hypernatremia
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
1 (1, 0.6%) 1 (1, 0.2%)
1 (1, 0.2%)
Hypersensitivity
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
1 (1, 0.6%) 1 (1, 0.2%)
1 (1, 0.2%)
Infection
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
1 (1, 0.6%) 1 (1, 0.2%)
1 (1, 0.2%)
Interstitial lung disease
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Intestinal ischemia
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Intestinal obstruction
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Joint dislocation
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
1 (1, 0.6%) 1 (1, 0.2%)
1 (1, 0.2%)
Laceration
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Liver abscess
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Lung infiltration
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
1 (1, 0.6%) 1 (1, 0.2%)
1 (1, 0.2%)
Metastases to gastrointestinal tract
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Multi-organ failure
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Myocardial infarction
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Neoplasm malignant
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Non-Hodgkin's lymphoma
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Pleural effusion
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
1 (1, 0.6%) 1 (1, 0.2%)
1 (1, 0.2%)
Pneumothorax
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Polyp
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
1 (1, 0.6%) 1 (1, 0.2%)
1 (1, 0.2%)
25
Adverse Event Preferred Term
Number of Events (# of Subjects, % of Subjects)
AdaptivCRT™
(n=318)
Total years of follow-up = 196.0
Echo-Optimized Control
(n=160)
Total years of follow-up = 103.6
Total Subjects
(n=478)
Total years of follow-up = 299.6
Events Complications
Events Complications
Events Complications
Post procedural hemorrhage
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
1 (1, 0.6%) 1 (1, 0.2%)
1 (1, 0.2%)
Pulmonary arterial hypertension
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Pulmonary fibrosis
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Pulmonary hemorrhage
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Pulmonary edema
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Pulseless electrical activity
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
1 (1, 0.6%) 1 (1, 0.2%)
1 (1, 0.2%)
Renal artery stenosis
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Rhabdomyolysis
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
1 (1, 0.6%) 1 (1, 0.2%)
1 (1, 0.2%)
Septic shock
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Spinal osteoarthritis
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Splenic infarction
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Staphylococcal infection
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Subarachnoid hemorrhage
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Thrombocytopenia
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
1 (1, 0.6%) 1 (1, 0.2%)
1 (1, 0.2%)
Tonsillitis
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Tympanic membrane perforation
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Undersensing
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
1 (1, 0.6%) 1 (1, 0.2%)
1 (1, 0.2%)
Urinary retention
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
1 (1, 0.6%) 1 (1, 0.2%)
1 (1, 0.2%)
Urosepsis
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
1 (1, 0.6%) 1 (1, 0.2%)
1 (1, 0.2%)
Vena cava thrombosis
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
1 (1, 0.6%) 1 (1, 0.2%)
1 (1, 0.2%)
Vocal cord paralysis
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
1 (1, 0.6%) 1 (1, 0.2%)
1 (1, 0.2%)
Wound infection pseudomonas
1 (1, 0.3%)
1 (1, 0.3%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
1 (1, 0.2%)
Acute prerenal failure
1 (1, 0.3%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
26
Adverse Event Preferred Term
Number of Events (# of Subjects, % of Subjects)
AdaptivCRT™
(n=318)
Total years of follow-up = 196.0
Echo-Optimized Control
(n=160)
Total years of follow-up = 103.6
Total Subjects
(n=478)
Total years of follow-up = 299.6
Events Complications
Events Complications
Events Complications
Angina unstable
1 (1, 0.3%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Anxiety
1 (1, 0.3%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Asthenia
1 (1, 0.3%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Cerebral hemorrhage
1 (1, 0.3%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Cerebral infarction
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Convulsion
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Dementia Alzheimer's type
1 (1, 0.3%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Dizziness postural
1 (1, 0.3%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Drug interaction
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Drug intolerance
1 (1, 0.3%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Eczema
1 (1, 0.3%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Enterocolitis
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Epilepsy
1 (1, 0.3%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Exercise tolerance decreased
1 (1, 0.3%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Flank pain
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Fluid overload
1 (1, 0.3%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Gait disturbance
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Gastrooesophageal reflux disease
1 (1, 0.3%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Headache
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Hyperparathyroidism secondary
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Hypertensive crisis
1 (1, 0.3%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Hyperthyroidism
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Hyperventilation
1 (1, 0.3%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
27
Adverse Event Preferred Term
Number of Events (# of Subjects, % of Subjects)
AdaptivCRT™
(n=318)
Total years of follow-up = 196.0
Echo-Optimized Control
(n=160)
Total years of follow-up = 103.6
Total Subjects
(n=478)
Total years of follow-up = 299.6
Events Complications
Events Complications
Events Complications
Implant site erosion
1 (1, 0.3%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Implant site inflammation
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Incision site complication
1 (1, 0.3%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Laryngitis
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Limb injury
1 (1, 0.3%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Medical device discomfort
1 (1, 0.3%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Mitral valve incompetence
1 (1, 0.3%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Muscle strain
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Musculoskeletal chest pain
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Musculoskeletal pain
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Neck pain
1 (1, 0.3%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Oedema
1 (1, 0.3%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Oedema peripheral
1 (1, 0.3%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Oral candidiasis
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Pain in jaw
1 (1, 0.3%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Pancytopenia
1 (1, 0.3%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Polycythaemia
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Procedural pain
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Prostatomegaly
1 (1, 0.3%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Rectal fissure
1 (1, 0.3%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Rectal hemorrhage
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Renal cyst
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Respiratory tract infection
1 (1, 0.3%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
28
Adverse Event Preferred Term
Number of Events (# of Subjects, % of Subjects)
AdaptivCRT™
(n=318)
Total years of follow-up = 196.0
Echo-Optimized Control
(n=160)
Total years of follow-up = 103.6
Total Subjects
(n=478)
Total years of follow-up = 299.6
Events Complications
Events Complications
Events Complications
Restless legs syndrome
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Rib fracture
1 (1, 0.3%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Skin ulcer
1 (1, 0.3%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Sunburn
1 (1, 0.3%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Supraventricular tachyarrhythmia
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Tachycardia
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Thyroid disorder
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Upper respiratory tract inflammation
1 (1, 0.3%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Ventricular extrasystoles
1 (1, 0.3%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Vertigo
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Viral infection
1 (1, 0.3%)
0 (0, 0.0%) 0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Visual impairment
0 (0, 0.0%)
0 (0, 0.0%) 1 (1, 0.6%)
0 (0, 0.0%) 1 (1, 0.2%)
0 (0, 0.0%)
Total Adverse Events (N, %)
374 (175, 55.0%)
210 (116, 36.5%) 285 (105, 65.6%)
147 (65, 40.6%) 659 (280, 58.6%)
357 (181, 37.9%)
7 Death Summary
A total of 26 deaths were observed in the study, 25 of which occurred after randomization where subjects were randomized in a 2:1 ratio to receive the AdaptivCRT™ feature (AdaptivCRT group) or echo­optimized CRT (Echo-Optimized Control group). The one death that occurred prior to randomization was considered related to the implant procedure due to the timing of death in proximity to the implant. Of the 25 total post-randomization deaths (18 AdaptivCRT group, 7 Echo-Optimized Control group), 2 were considered related to the implant procedure due to the timing of death in proximity to the implant and one was considered as having unknown relatedness to the device, RV lead, investigational software, and investigational algorithm. For that death, a device interrogation was not collected at the time of death or
after (most recent device interrogation was from the randomization visit). Additionally, the subject’s device
was not returned to Medtronic. Based on the limited available data, the Global Adverse Event Adjudication Committee could not conclusively determine the relatedness. Table 12 provides a full listing of all 26 subject deaths (1 prior to randomization and 25 post-randomization) organized by days post­randomization. Subject death rates were similar between the AdaptivCRT (9.8%) and Echo-Optimized Control (8.7%) groups over the total duration of follow-up. This difference was not statistically significant (log-rank p=0.47).
29
Table 12: Death Listing
Study
Arm
Randomization
Date
Death Date
(Days post-
randomization)
Cause of
Death*
Cardiac or Non-
Cardiac*
Sudden or Non-
Sudden*
None
Not randomized
28AUG2010
(3 days post­enrollment)
Sudden cardiac arrest
Cardiac
Sudden
AdaptivCRT
11NOV2010
17NOV2010
(6 days post­randomization)
Sudden cardiac death
Cardiac
Sudden
AdaptivCRT
20MAY2010
12JUN2010
(23 days post­randomization)
Sudden cardiac death
Cardiac
Sudden
AdaptivCRT
05MAY2010
08JUN2010
(34 days post­randomization)
Acute myocardial infarction
Cardiac
Sudden
Echo­Optimized Control
22JUL2010
14SEP2010
(54 days post­randomization)
Heart failure
Cardiac
Non-Sudden
AdaptivCRT
16DEC2010
21FEB2011
(67 days post­randomization)
Heart failure
Cardiac
Non-Sudden
AdaptivCRT
13OCT2010
13JAN2011
(92 days post­randomization)
Heart failure
Cardiac
Non-Sudden
AdaptivCRT
08DEC2010
11MAR2011
(93 days post­randomization)
Heart failure
Cardiac
Non-Sudden
Echo­Optimized Control
30OCT2010
04FEB2011
(97 days post­randomization)
Heart failure
Cardiac
Non-Sudden
AdaptivCRT
20JUL2010
01NOV2010
(104 days post­randomization)
Heart failure
Cardiac
Non-Sudden
AdaptivCRT
26OCT2010
07FEB2011
(104 days post­randomization)
Sudden cardiac death
Cardiac
Sudden
AdaptivCRT
12APR2010
27JUL2010
(106 days post­randomization)
Heart failure
Cardiac
Non-Sudden
AdaptivCRT
29SEP2010
03FEB2011
(127 days post­randomization)
Heart failure
Cardiac
Non-Sudden
AdaptivCRT
07DEC2010
16APR2011
(130 days post­randomization)
Sudden cardiac arrest due to ventricular fibrillation arrest
Cardiac
Sudden
30
Study
Arm
Randomization
Date
Death Date
(Days post-
randomization)
Cause of
Death*
Cardiac or Non-
Cardiac*
Sudden or Non-
Sudden*
AdaptivCRT
22JUL2010
16DEC2010
(147 days post­randomization)
Pneumonia
Non-Cardiac
Not Applicable
AdaptivCRT
17NOV2010
10MAY2011
(174 days post­randomization)
Cancer
Non-Cardiac
Not Applicable
Echo­Optimized Control
11FEB2010
07AUG2010
(177 days post­randomization)
Sepsis
Non-Cardiac
Not Applicable
Echo­Optimized Control
17NOV2010
30MAY2011
(194 days post­randomization)
Heart failure
Cardiac
Non-Sudden
Echo­Optimized Control
23NOV2010
15JUN2011
(204 days post­randomization)
Pneumonia
Non-Cardiac
Not Applicable
AdaptivCRT
19OCT2010
17JUN2011
(241 days post­randomization)
Heart failure
Cardiac
Non-Sudden
AdaptivCRT
22APR2010
19DEC2010
(241 days post­randomization)
Heart failure
Cardiac
Non-Sudden
Echo­Optimized Control
01JUN2010
07FEB2011
(251 days post­randomization)
Heart failure
Cardiac
Non-Sudden
Echo­Optimized Control
19AUG2010
03MAY2011
(257 days post­randomization)
Heart failure
Cardiac
Non-Sudden
AdaptivCRT
04FEB2010
16NOV2010
(285 days post­randomization)
Heart failure
Cardiac
Non-Sudden
AdaptivCRT
06APR2010
31JAN2011
(300 days post­randomization)
Heart failure
Cardiac
Non-Sudden
AdaptivCRT
06JUL2010
05MAY2011
(303 days post­randomization)
Progressive heart failure
Cardiac
Non-Sudden
* Cause of Death, Cardiac or Non-Cardiac, and Sudden or Non-Sudden categories are classified by the GAEAC and non-cardiac deaths are not classified as sudden or non-sudden.
31
8 Clinical Study Conclusion
The AdaptivCRT™ feature was designed to provide patient-specific automatic and dynamic selection of LV or BiV CRT pacing and adjustments of AV and VV delays based on periodic evaluation of intrinsic electrical conduction.
The AdaptivCRT clinical study evaluated the AdaptivCRT feature and passed all three of its primary objectives, demonstrating safety and effectiveness of the AdaptivCRT feature. Primary study objective results demonstrated the following:
The AdaptivCRT feature is effective as determined by the clinical non-inferiority results of the Clinical
Composite Score between the AdaptivCRT group and the Echo-Optimized Control group.
The AdaptivCRT feature is effective as determined by the clinical non-inferiority of the cardiac
performance results between the AdaptivCRT feature and the echo-optimized settings.
The AdaptivCRT feature is safe as determined by the results from AdaptivCRT feature data. No
inappropriate device AV or VV delays were found in the study.
Since all three primary endpoints were met, six pre-specified secondary endpoints were analyzed in a hierarchical fashion as planned. All six secondary endpoints were also met. The secondary objectives focused on other clinically relevant outcomes for heart failure patients and corroborated the results of the primary objectives. Furthermore, mortality and adverse event rates were similar between the two study groups.
In summary, the AdaptivCRT clinical study met all primary and secondary safety and efficacy endpoints demonstrating that the AdaptivCRT feature is safe and effective in the clinical environment.
32
World Headquarters
Medtronic, Inc. 710 Medtronic Parkway Minneapolis, MN 55432-5604 USA www.medtronic.com Tel. +1-763-514-4000 Fax +1-763-514-4879
Medtronic USA, Inc.
Toll-free in the USA (24-hour technical consultation for physicians and medical professionals) Bradycardia: 1-800-505-4636 Tachycardia: 1-800-723-4636
Europe/Africa/Middle East Headquarters
Medtronic International Trading Sàrl Route du Molliau 31 Case Postale 84 CH-1131 Tolochenaz Switzerland www.medtronic.com Tel. +41-21-802-7000 Fax +41-21-802-7900
Medtronic E.C. Authorized Representative
Medtronic B.V. Earl Bakkenstraat 10 6422 PJ Heerlen The Netherlands Tel. +31-45-566-8000 Fax +31-45-566-8668
Technical manuals: www.medtronic.com/manuals
© Medtronic, Inc. 2012 M951199A001A 2012-03-20
*M951199A001*
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