Boston Scientific CRMN11906 Implantable Defibrillator User Manual Cognis Part 4 Manual

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CLINICAL STUDY - COMPANION B-15

Sub-study Primary Endpoint and Additional Tertiary Endpoints

Exercise performance––the co-primary endpoint, which consists of Peak VO2

and Six-Minute Walk, is designed to demonstrate improvement in exercise

performance with CRT (CONTAK TR and CONTAK CD pooled data) compared

to OPT at six months post-baseline.

Additional tertiary endpoints included Quality of Life as measured by the

Minnesota Living with Heart Failure Questionnaire®and NYHA Class.

FOLLOW-UP SCHEDULE

The follow-up schedule included the following:

• Enrollment––initial assessment of patient eligibility; taking of patient history

• Baseline screening––special testing (included a Symptom-Limited Treadmill

Test with measurement of oxygen uptake (Peak VO2), a Six-Minute Walk,

Quality of Life [QOL] questionnaire and NYHA Classiﬁcation)

• Randomization––randomization status (OPT, CRT-P, or CRT-D) was

assigned

• Implant (CRT-P or CRT-D arm)––implant of investigational devices and

acute device testing for those randomized to a CRT therapy arm

• Routine follow-up––routine evaluation of device function and patient

condition at pre-discharge, one week, and one month post-implant

• Three- and six-month visits––evaluation of randomized therapy with special

testing and device function at three and six months after the Post-Recovery

Visit

• Quarterly Visits––after the six-month visit, patients were seen for routine

evaluation of device function and patient condition

DEMOGRAPHIC DATA

All baseline patient characteristics are presented in Table B-5 on page B-16.

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B-16 CLINICAL STUDY - COMPANION

Table B-5. Patient population characteristics for COMPANION (OPT and CRT-D)

Characteristic OPT

(N = 308)

CRT-D

(N = 595)

P-value

Age (years) Mean ± SD 66.7 ± 10.7 65.6 ± 11.2 0.14

Female 97 (31.4) 194 (32.6) 0.73

Gender [N (%)]

Male 211 (68.5) 401 (67.3) 0.73

Class III 253 (82.1) 512 (86.1) 0.12

NYHA Classiﬁcation [N (%)]

Class IV 55 (17.8) 83 (13.9) 0.12

Ischemic 58.7 54.6 0.13

Ischemic Etiology (%)

Non-ischemic 41.3 45.4 0.13

LVEF (%) Mean ± SD 22.8 ± 7.2 22.5 ± 6.8 0.47

Resting Heart Rate (bpm) Mean ± SD 72 ± 12 73 ± 13 0.37

QRS Width (ms) Mean ± SD 156 ± 24 159 ± 24 0.09

LBBB 69.8 72.9 0.21

Non-speciﬁc21.4 16.8 0.21

Conduction Abnormality (%)

RBBB 8.77 10.2 0.21

Duration of Heart Failure (years) Mean ± SD 4.86 ± 4.41 4.44 ± 3.83 0.43

Diuretic 94.4 96.6 0.12

ACE inhibitor or ARB 88.6 89.6 0.66

Beta Blockers 66.2 67.6 0.69

Aldosterone Antagonist 54.8 55.1 0.94

Heart Failure Medications [(%)]

Digoxin 67.2 70.9 0.25

PATIENT ACCOUNTABILITY AND FOLLOW-UP DURATION

The COMPANION study enrolled 1638 patients, with 1520 patients randomized

to a treatment group and one hundred eighteen patients (118) not randomized

due to changes in patient condition or consent between time of enrollment and

time of randomization, such that the inclusion criteria were no longer satisﬁed.

Of the 1520 patients, 595 were randomized to CRT-D with a mean follow-up of

1.3 years and 308 were randomized to OPT with a mean follow-up of 1.1 years.

Figure B-1 on page B-18 provides an overview of patient enrollment.

Table B-6 on page B-17 gives a summary (by treatment group) of patient

disposition over time through 12 months after randomization. This does not

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CLINICAL STUDY - COMPANION B-17

account for patients that had a hospitalization or death event that contributed to

the primary endpoint or secondary endpoint of all-cause mortality.

Table B-6. Patient follow-up disposition 12 months post-randomization

CRT-D OPT

#of

Withdrawn

Patients

#of

Deceased

Patients

(N =

595) #

Reached

end of

study

(Nov. 30,

2002)

#of

Active

Patients

at end

of time

interval

#of

Withdrawn

Patients

#of

Deceased

Patients

(N = 308)#

Reached

end of

study

(Nov. 30,

2002)

#of

Active

Patients

at end

of time

interval

1Day-

7Days

4 3 0 588 6 0 0 302

7Days-

1 Month

435576 10 3 1 288

1Month-

3 Months

4 15 6 551 11 11 1 265

3 Months

9 Months

12 28 49 462 26 22 29 188

9 Months

-12

Months

1 12 35 414 11 11 19 147

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B-18 CLINICAL STUDY - COMPANION

COMPANION

Enrolled

n = 1638

Fall out prior to

Randomization

n = 118

Randomized

n = 1520

Randomized to

OPT

n = 308

Randomized to

CRT-D

n = 595

Randomized to

CRT-P

n = 617

CRT-D Implant

Intents

n = 7 CRT-D Implant

Attempts

n = 47

Implanted CRT-D

Devices

n = 541

System Safety Endpoint

n = 541

All-cause mortality endpoint through 12/1/02 for OPT and CRT-D

n = 903

All adverse events through 11/26/03 for OPT and CRT-D

n = 903

All-cause mortality or first hospitalization and cardiac morbidity endpoints

through 12/1/02 for OPT and CRT-D

n = 903

Figure B-1. Study patient enrollment and randomization for CRT-D and OPT

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CLINICAL STUDY - COMPANION B-19

Event Contributing to Primary Endpoint and Secondary Endpoint of

All-cause Mortality

A total of 903 COMPANION patients in the CRT-D (595) and OPT (308) groups

were eligible for the primary endpoint. Figure B-2 on page B-19 provides patient

randomization and status for the primary endpoint and Figure B-3 on page B-19

provides patient randomization and status for the secondary mortality endpoint.

Randomized

n = 903 of 1520

OPT

n = 308

CRT-P

n = 595

Hospitalization

n = 196

Death

n = 20

Unknown

n = 15

No event

n = 77

Hospitalization

n = 372

Death

n = 18

Unknown

n = 5

No event

n = 200

No event

n = 92

Event

n = 216

No event

n = 205

Event

n = 390

Figure B-2. CRT-D and OPT patient randomization for primary endpoint

Randomized

n = 903

Alive

n = 218

Unknown

n = 15

Dead

n = 77

Alive

n = 484

Unknown

n = 6

Dead

n = 105

OPT

n = 308

CRT-D

n = 595

Figure B-3. CRT-D and OPT patient randomization for mortality endpoint

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B-20 CLINICAL STUDY - COMPANION

DATA ANALYSIS AND RESULTS FOR PRIMARY ENDPOINT AND

SECONDARY ALL-CAUSE MORTALITY ENDPOINT

Sequential Monitoring

The COMPANION DSMB met approximately every six months to review the

trial’s progress and to review the safety and effectiveness data collected. An

“O’Brien-Fleming” type boundary as implemented by Lan and DeMets was

used in monitoring the trial. The Group sequential procedure ensured that

the total alpha spent across repeated analyses did not exceed the total type I

error, in this case a=0.03.

On November 18, 2002 the DSMB reviewed the study progress for the ﬁnal

time. The CRT-D arm of the Study had reached the target number of events

for both the combined mortality and hospitalization endpoint as well as the

all-cause mortality endpoint prompting the DSMB to recommend to the Steering

Committee that enrollment be stopped. All effectiveness follow-ups ended

on December 1, 2002.

Results

Primary Endpoint: All-cause Mortality or First Hospitalization

The Kaplan-Meier curves illustrate the time to all-cause mortality or ﬁrst

hospitalization (Figure B-4 on page B-21). There were 216 primary endpoint

events observed in the OPT arm and 390 in the CRT-D arm (p = 0.010; p =

0.011 after adjustment for interim analyses). The median time to ﬁrst event was

209 days in the OPT group and 269 days in the CRT-D group. The annual

event rates for OPT and CRT-D, respectively, were 68.0% and 55.9%, with a

hazard ratio of 0.80; 95% CI (0.68, 0.95). This result demonstrated that CRT-D

signiﬁcantly reduced the relative risk of all-cause mortality or ﬁrst hospitalization

by 20% when compared to OPT alone.

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CLINICAL STUDY - COMPANION B-21

1080 960 840 720 600 480 360 240 120 0

100

% of Patients Event-Free

Days from Randomization

All-cause Mortality or First Hospitalization

CRT-D vs. OPT: p = 0.010

Number of Events

OPT: 216

CRT-D: 390

OPT

CRT-D

308

595

Number of

Patients at Risk

OPT

CRT-D

176

385

115

283

217

128

HR = 0.80. 95% CI (0.68, 0.95)

Figure B-4. Primary Endpoint: All-cause mortality or ﬁrst hospitalization

In addition to the hazard ratio, point estimates of risk reduction were also

calculated (Table B-7 on page B-21). These estimates will vary with time from

the true treatment effect, and thus should be interpreted with caution.

Table B-7. Risk reduction point estimates

% Failure Absolute Risk

Reduction

Relative Risk

Reduction

OPT CRT-D

6months 44.9%

(38.9%, 50.3%)

42.9%

(38.7%, 46.7%)

2.0% 4.5%

12 months 68.0%

(61.7%, 73.2%)

55.9%

(51.6%, 59.8%)

12.1% 17.8%

18 months 77.8%

(71.6%, 82.7%)

69.0%

(64.5%, 73.1%)

8.8% 11.3%

Secondary Endpoints

All-cause Mortality––deaths from any cause were reported in 77 patients

randomized to OPT and 105 patients randomized to CRT-D (p = 0.003, p

= 0.004 after adjusting for interim analyses). The Kaplan-Meier curves are

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B-22 CLINICAL STUDY - COMPANION

depicted in Figure B-5 on page B-22. These numbers correspond to an annual

mortality rate of 19% in the OPT arm and 12% in the CRT-D arm, with a hazard

ratio of 0.64, 95% CI (0.48, 0.86). These results demonstrated that CRT-D

was associated with a 36% reduction in the risk of all-cause mortality when

compared to OPT alone.

1080 720 630 540 450 360 270 180 90 0

100

% of Patients Event-Free

Days from Randomization

All-cause Mortality

CRT-D vs. OPT: p = 0.003

Number of Events

OPT: 77

CRT-D: 105

OPT

CRT-D

308

595

Number of

Patients at Risk

OPT

CRT-D

284

555

255

517

217

470

186

420

141

331

219

148

HR = 0.64. 95% CI (0.48, 0.86)

810 900 990

Figure B-5. Secondary Endpoint: All-cause mortality

In addition to the hazard ratio, point estimates of risk reduction were also

calculated (Table B-8 on page B-22). These estimates will vary with time from

the true treatment effect, and thus should be interpreted with caution.

Table B-8. Mortality endpoint risk reduction point estimates

% Failure Absolute Risk

Reduction

Relative Risk

Reduction

OPT CRT-D

6months 9.0%

(5.7%, 12.2%)

7.3%

(5.1%, 9.3%)

1.7% 18.9%

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CLINICAL STUDY - COMPANION B-23

Table B-8. Mortality endpoint risk reduction point estimates (continued)

% Failure Absolute Risk

Reduction

Relative Risk

Reduction

OPT CRT-D

12 months 18.9%

(14.1%, 23.5%)

12.1%

(9.3%, 14.8%)

6.8% 36.0%

18 months 28.4%

(22.3%, 34.1%)

18.0%

(14.4%, 21.5%)

10.4% 36.6%

Results for Secondary Cardiac Morbidity Endpoint

During a hospitalization more than one of the pre-speciﬁed cardiac morbid

events could occur. The Anderson-Gill extension to the Cox proportional

hazard model was used to analyze time to multiple cardiac morbid events.

Caution must be used in interpreting p-values in this analysis because this

analysis does not account for the competing risk of death.

In Figure B-6 on page B-24, the frequency and duration of cardiac morbid

events are illustrated. CRT-D was associated with a 36% reduction (p <

0.0001) in the proportion of patients with at least one event, a 52% reduction

(p < 0.0001) in events on an annual basis, and a 41% reduction (p < 0.0001)

in the hospital duration on an annual basis. These reductions are primarily

due to the reduction of hospitalizations for acute decompensation of heart

failure, worsening heart failure resulting in IV inotrope or vasoactive therapy

> 4 hours (during an inpatient hospitalization) and cardiac surgery (including

percutaneous intervention) (Figure B-7 on page B-24).

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B-24 CLINICAL STUDY - COMPANION

55% 1.08 7.6

1.2

1.0

0.8

0.4

0.2

0.6

0.0

35%

Proportion of Patients with ≥ 1 Event (%)

0.52

Event Rate (Events/Patient-Year)

4.5

Duration (Days/Patient-Year)

Frequency (per Patient)

36% reduction

p < 0.0001

Duration

41% reduction

p < 0.0001

Frequency (per Patient Year)

52% reduction

p < 0.0001

OPT (n = 308) CRT-D (n = 595)

Figure B-6. Secondary Endpoint: cardiac morbidity

Caution must be used in interpreting p-values; analysis does not account for

competing risk of death.

0.68

0.8

0.6

0.4

0.2

0.0

0.42

Events per Patient Year

0.57

0.31

0.38

0.06 0.06

0.08 0.04 0.05

0.02 0.02

OPT

CRT-D

Hospitalization

for acute

decompensation

of HF

Worsening HF

resulting in IV

inotrope or

vasoactive > 4

hours

Cardiac surgery,

including

percutaneous

intervention

Hospitalization

resulting in

death from

cardiac causes

Mechanical

respiratory or

cardiac support

Resuscitated

cardiac arrest or

sustained VT

requiring

external

intervention

38% reduction

p < 0.0001

46% reduction

p < 0.0001

84% reduction

p < 0.0001

50% reduction

p = 0.016

17% reduction

p = 0.54

No change

p = 0.55

Figure B-7. Cardiac morbidity by major component

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CLINICAL STUDY - COMPANION B-25

For a given cardiac hospitalization, patients may have events in more than

one category, and if there are multiple occurrences in a single category, then

only the ﬁrst occurrence was counted.

ADDITIONAL STUDY DATA

Implant Disposition

Table B-9 on page B-25 identiﬁes the number of initial and subsequent implant

procedures attempted in patients randomized to CRT-D and the rate of success

for each additional implant procedure. There were 81 CRT-D patients that

had an unsuccessful initial implant for the CRT-D system. Fifty (50) of these

patients had a second implant procedure, of which 33 were successful and 17

were unsuccessful. Three patients had a third implant procedure, of which one

was successful. Therefore, there were 541 patients implanted with the CRT-D

system.

Table B-9. CRT-D system implant disposition

Attempt

successful

Failed implant Reattempt not

done after this

procedure

Initial implants 588 (98.8%) 507 (85.0%) 81 (14.0%) 31 (5.2%)

First reattempt 50 (8.4%) 33 (5.5%) 17 (2.9%) 14 (2.3%)

Second reattempt 3 (0.5%) 1 (0.2%) 2 (0.3%) 2 (0.34%)

ADDITIONAL OUTCOME MEASURES

First Heart Failure Hospitalizations

An additional outcome that was not pre-speciﬁed in the protocol provides

further insight into the results observed in the composite primary endpoint.

This post-hoc analysis was conducted using cause-speciﬁc hospitalizations as

adjudicated by the morbidity and mortality committee and therefore should

be interpreted with caution.

The outcome of all-cause mortality or ﬁrst heart failure hospitalization was

analyzed on an intention-to-treat basis and time to ﬁrst event.

Hospitalizations were deﬁned per any of the following:

• Care provided at a hospital for any reason in which the duration is

associated with a date change

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B-26 CLINICAL STUDY - COMPANION

• Use of intravenous inotropes and/or vasoactive drugs for a duration > 4

hours (inpatient or outpatient)

NOTE: Hospitalizations associated with a device implant attempt or

re-attempt are excluded.

Those contributing to the heart failure hospitalization outcome were required

by the Morbidity and Mortality committee to meet at least one of the following

additional criteria:

•IVdiuretics

• IV inotrope/vasoactive therapy

• Other parenteral therapy for the treatment of heart failure

•Signiﬁcant alterations in oral therapy for the treatment of heart failure

All-cause Mortality or First Heart Failure Hospitalization

The Kaplan-Meier curves for all-cause mortality or ﬁrst heart failure

hospitalization is shown in Figure B-8 on page B-27. OPT and CRT-D had

annual event rates of 45% and 29%, respectively with a hazard ratio of 0.60,

95% CI (0.49-0.75), p < 0.001. Therefore, CRT-D was associated with a

40% relative reduction in the risk of all-cause mortality or ﬁrst heart-failure

hospitalization when compared to OPT alone.

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CLINICAL STUDY - COMPANION B-27

10809608407206004803602401200

100

% of Patients Event-Free

Days from Randomization

All-cause Mortality or First Heart Failure Hospitalization

CRT-D vs. OPT: p < 0.001

Number of Events

OPT: 145

CRT-D: 212

OPT

CRT-D

308

595

Number of

Patients at Risk

OPT

CRT-D

216

497

161

411

118

470

228

131

HR = 0.60. 95% CI (0.49, 0.75)

Figure B-8. All-cause mortality or ﬁrst heart failure hospitalization

Disposition of Hospitalization

Implantation of the CRT-D system generally requires hospitalization. To

differentiate between the hospitalization required to implant the system and

those hospitalizations that occurred after the system was implanted, the

following terms are used:

• Implant hospitalization––the elective hospitalization associated with either

the implant procedure or a repeat implant procedure if the initial procedure

was unsuccessful.

• All other hospitalizations––patients who required a revision for an implanted

system (e.g., lead dislodgment or infection) were included in this category

as were hospitalizations for non-elective device related implants.

The hospitalizations analysis (Figure B-9 on page B-28) and hospitalization

days analysis (Figure B-10 on page B-28) depicts hospitalization data

stratiﬁed by implant and non-elective hospitalizations. This analysis was on

an intention-to-treat basis and includes patients who underwent an attempted

implant procedure. Patients randomized to CRT-D had a follow-up duration

approximately 30% longer than OPT patients. Thus, hospitalization data

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B-28 CLINICAL STUDY - COMPANION

are normalized per patient-year of follow-up. An additional comparison of

hospitalization days for heart failure hospitalizations is shown in Figure B-11

on page B-29.

NOTE: CRT-D was associated with a reduction in all-cause mortality and

therefore there is a competing risk for hospitalizations. This data should be

interpreted with caution.

2.5

2.0

1.0

0.5

1.5

0.0

Initial

Implant 0.07

Non-elective

1.55

1.62 Initial

Implant 0.83

Non-elective

1.18

2.01

OPT

(n = 308)

CRT-D

(n = 595)

Hospitalizations (In-patient)

per Patient-Year of Follow-up

Figure B-9. Hospitalizations per patient year

Initial

Implant 0.2

Non-elective

10.9

11.2

Initial

Implant 2.4

Non-elective

8.6

11.1

OPT

(n = 308)

CRT-D

(n = 595)

All-cause Hospitalization (In-patient)

Days per Patient-Year of Follow-up

Figure B-10. Hospitalization days per patient year

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CLINICAL STUDY - COMPANION B-29

5.9

3.8

OPT

(n = 308)

CRT-D

(n = 595)

Heart Failure Hospitalization Days

per Patient-Year of Follow-up

Figure B-11. Heart failure hospitalization days per patient year

DATA ANALYSIS AND RESULTS - CRT-D SYSTEM SAFETY

The system-related complication-free rate analysis was not a predeﬁned

endpoint in the protocol. The intent of this analysis is to provide reasonable

assurance of safety of the CONTAK CD system in this patient population.

The system-related complication-free rate was deﬁned over a six-month

follow-up period as the proportion of patients who are free of complications

attributed to:

• Any implanted component (e.g, pulse generator, coronary venous lead,

right atrial pace/sense lead, cardioversion/deﬁbrillation lead)

• The surgical procedure required to implant the CRT-D system

In the COMPANION study, this analysis was performed on an intention-to-treat

basis and also extends to those patients who underwent an implant procedure

but did not ultimately receive a device. Of the 595 patients analyzed, 522

(87.7%) were free of system-related complications.

Of the 73 (12.3%) patients who experienced a system-related complication,

the most common were loss of left ventricular capture (25 patients, 4.2%),

loss of right atrial capture (9 patients, 1.5%), and phrenic nerve/diaphragmatic

stimulation (8 patients, 1.3%).

When analyzed on a time-to-event basis, the system-related complication-free

rate was 87.7%. The safety performance of the CONTAK CD system compares

favorably with the safety performance observed in the prior CONTAK CD study

(P010012, May 2, 2002).

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B-30 CLINICAL STUDY - COMPANION

DATA ANALYSIS AND RESULTS - COMPANION SUB-STUDY

The Exercise Performance Sub-study consisted of the following components.

CRT Effectiveness

Primary Co-primary endpoint consisting of Peak VO2derived from a

symptom-limited exercise test and Six-Minute Walk, with CRT results pooled

from the CONTAK TR and CONTAK CD arms.

Effectiveness was determined by assessing both Peak VO2and Six-Minute

Walk distance improvements with CRT compared to OPT.

Prospectively, success was deﬁned as occurring if either of the following

occurred:

•PeakVO

2improved ≥0.7 ml/kg/min (p < 0.05) and 6 MWD improvement

resulted in p < 0.10

•PeakVO

2improved ≥0.5 ml/kg/min (p < 0.10) and 6 MWD improvement

resulted in p < 0.05

Additional: Quality of Life as measured by the Minnesota Living with Heart

Failure Questionnaire®‚ and NYHA Class

- DRAFT -

CLINICAL STUDY - COMPANION B-31

Patient Accountability (Figure B-12 on page B-31)

OPT

Baseline Visit

Peak VO2

Assessable for

effectiveness

6MW

Assessable for

effectiveness

Patient related

Crossover

Withdrawn

Death

Other

Peak VO2

Assessable for

effectiveness

231

6MW

Assessable for

effectiveness

261

Patient related

Mode Change

Withdrawn

Death

Other

CRT

Baseline Visit

318

Randomized

448

Met Exclusion Criteria 6

Intent/Attempt 37

Figure B-12. Enrollment and follow-up of randomized patients

Baseline Characteristics— (Table B-10 on page B-31)

Table B-10. Patient population characteristics

Characteristic CRT

(N = 318)

OPT

(N = 87)

P-valuea

Age (years) Mean ± SD 62.1 ± 11.8 63.1 ± 10.6 0.48

Range 32.0–86.0 27.0–85.0

Gender [N (%)] Female 109 (34.3) 24 (27.6) 0.24

Male 209 (65.7) 63 (72.4)

NYHA Classiﬁcation [N (%)] III 294 (92.5) 79 (90.8) 0.61

IV 24 (7.5) 8 (9.2)

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B-32 CLINICAL STUDY - COMPANION

Table B-10. Patient population characteristics (continued)

Characteristic CRT

(N = 318)

OPT

(N = 87)

P-valuea

Ischemic Etiology Ischemic 141 (44.3) 42 (48.3) 0.51

Non-ischemic 177 (55.7) 45 (51.7)

LVEF (%) Mean ± SD 22.5 ± 6.9 22.2 ± 8.0 0.79

Range 5.0–35.0 5.0–35.0

Resting Heart Rate (bpm) Mean ± SD 73.1 ± 12.8 73.5 ± 11.5 0.78

Range 46.0–122.0 54.0–103.0

QRS Width (ms) Mean ± SD 159.2 ± 25.0 155.7 ± 25.8 0.26

Range 120.0–276.0 120.0–224.0

LBBB/NSIVCD (%) LBBB 230 (72.3) 62 (71.3) 0.60

Nonspeciﬁc 54 (17.0) 18 (20.7)

RBBB 34 (10.7) 7 (8.0)

Peak VO2(ml/kg/min) Mean ± SD 12.7 ± 3.3 12.4 ± 3.3 0.42

Range 3.0–21.2 4.8–21.5

Six-MInute Walk Distance (m) Mean ± SD 292.4 ± 65.5 291.6 ± 70.5 0.92

Range 152.0–411.5 162.4–414.0

Quality of Life Score (points) Mean ± SD 59.8 ± 23.1 55.4 ± 23.3 0.12

Range 0.0–105.0 0.0–97.0

Heart Failure Medications [N (%)] Diuretic 300 (94.3) 82 (94.3) 0.98

ACE Inhibitor or ARB 286 (89.9) 82 (94.3) 0.22

Beta Blockers 240 (75.5) 60 (69.0) 0.22

Aldosterone Antagonist 178 (56.0) 51 (58.6) 0.66

Digoxin 239 (75.2) 65 (74.7) 0.93

a. Continuous data were analyzed using a two-tailed t-test procedure, and categorical data were analyzed using a two-tailed

chi-square procedure. A p-value < 0.05 is considered signiﬁcant.

CRT Effectiveness

Peak VO2—Peak VO2was determined from a standardized protocol for

exercise testing as a means of measuring a patient’s capacity for performing

physical activity (Figure B-13 on page B-33, Table B-11 on page B-33).

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CLINICAL STUDY - COMPANION B-33

2.0

1.0

0.5

1.5

0.0

Time (months)

∆ Peak VO2 (ml/kg/min)

3 6

CRT

OPT

∆ = 0.8

p = 0.026

∆ = 0.6

p = 0.074

(Critical boundary = 0.10)

Mean ± SE

Figure B-13. Maximal Oxygen Consumption Results

Table B-11. Maximal Oxygen Consumption Results

CRT OPT

Peak VO2(ml/kg/min)

N Mean ±

S.E.

N Mean ±

S.E.

P-valuea

Change at 3 months 247 1.1 ± 0.2 52 0.3 ± 0.4 0.026

Change at 6 months 230 1.2 ± 0.2 46 0.6 ± 0.4 0.074

a. P-values obtained using one-tailed longitudinal analysis methods.

The longitudinal analysis was performed on all available data. The percentages

of missing data at the six-month endpoints for Peak VO2and Six-Minute Walk

were 36 percent and 28 percent for the CRT arm and 47 percent and 34 percent

for the OPT arm. The longitudinal analysis performed is most appropriate when

missing data occurs at the percentages found in this trial.

Six-Minute Walk––the Six-Minute Walk test is a measure of a patient’s ability

to sustain exercise during an activity similar to that which a patient may typically

perform on a daily basis. For this test, patients are instructed to walk as far as

possible in 6 minutes in a level corridor (Figure B-14 on page B-34, Table B-12

on page B-34).

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B-34 CLINICAL STUDY - COMPANION

Time (months)

∆ Six Minute Walk Distance (m)

3 6

CRT

OPT

∆ = 24

p = 0.016

∆ = 24

p = 0.017

(Critical boundary = 0.05)

Mean ± SE

Figure B-14. Change in six-minute walk

Table B-12. Change in six-minute walk

CRT OPT

Six-Minute Walk (m)

N Mean ±

S.E.

NMean±

S.E.

P-valuea

Change at 3 months 274 37 ± 5 63 13 ± 10 0.016

Change at 6 months 260 41 ± 5 57 17 ± 10 0.017

a. P-values obtained using one-tailed longitudinal analysis methods.

NYHA Class––the determination for New York Heart Association (NYHA) Class

is based on mutual assessment, by the patient and physician, of the patient’s

heart failure symptoms both at rest and while performing ordinary physical

activity(FigureB-15onpageB-35,TableB-13onpageB-35).

- DRAFT -

CLINICAL STUDY - COMPANION B-35

100

CRT OPT

NYHA Class (%)

CRT OPT

Improve 2 Classes

Improve 1 Class

No Change

Worsen 1 Class

Time (months)

Figure B-15. Change in NYHA

Table B-13. Change in NYHA

CRT OPT

NYHA

Classiﬁcation

Change

N Patients N Patients

P-valuea

3 months Improve 2 Classes 294 22 (7.5%) 69 3 (4.4%) <0.01

Improve 1 Class 142

(48.3%)

13 (18.8%)

No Change 122

(41.5%)

48 (69.6%)

Worsen 1 Class 8 (2.7%) 5 (7.3%)

6 months Improve 2 Classes 291 20 (6.9%) 65 2 (3.1%) 0.032

Improve 1 Class 149

(51.2%)

28 (43.1%)

No Change 118 (40.6%) 34 (52.3%)

Worsen 1 Class 4 (1.4%) 1 (1.5%)

a. P-values are not adjusted for multiplicity and were obtained using a one-tailed Mantel-Haenszel chi-square method.

Quality of Life (QOL)––Quality of Life was assessed using the 21-question

Minnesota Living with Heart Failure questionnaire. Each question, answered

by the patient, is ranked on a scale ranging from 0 to 5. A lower total score

indicatesanimprovedqualityoflife(FigureB-16onpageB-36,TableB-14on

page B-36).

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B-36 CLINICAL STUDY - COMPANION

Time (months)

∆ Quality of Life Score (points)

3 6

CRT

OPT

∆ = 17 ∆ = 13

Mean ± SE

Figure B-16. Quality of Life score

TableB-14. QualityofLifescore

CRT OPT

Quality of Life

(points) NMean ± S.E. (95% CI) NMean ± S.E. (95% CI)

P-valuea

Change at 3 months 289 23 ± 1 (20.1, 25.7) 72 6±3(0.6,11.3) < 0.001

Change at 6 months 279 23 ± 1 (19.7, 25.4) 66 10 ± 3 (4.2, 15.2) < 0.001

a. P-values are not adjusted for multiplicity and were obtained using one-tailed longitudinal analysis methods.

Additional Functional Capacity Data

In addition to the Exercise Performance sub-study, functional capacity was

evaluated by means of NYHA Class, six-minute walk distance, and Minnesota

Living with Heart Failure Questionnaire QOL for the all patients randomized

to OPT and CRT-D through 6-months of follow up.

NYHA Class, six-minute walk distance, and QOL scores were signiﬁcantly

improved in the CRT-D group compared to the OPT group at 3 and 6 months

(Table B-15 on page B-36). These ﬁndings are similar to those presented in

the exercise performance sub-study and previous cardiac resynchronization

therapy trials.

Table B-15. Changes in six-minute walk, QOL, and NYHA

CRT-D OPT P-valuea

Six Minute Walk Distance NMean ± SD NMean ± SD

Change at 3 months 420 42 ± 98 172 8 ± 82 < 0.0001

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CLINICAL STUDY - COMPANION B-37

Table B-15. Changes in six-minute walk, QOL, and NYHA (continued)

CRT-D OPT P-valuea

Change at 6 months 377 45 ± 98 141 2 ± 92 < 0.0001

QOL NMean ± SD NMean ± SD

Change at 3 months 514 -24 ± 28 243 -8 ± 21 < 0.0001

Change at 6 months 479 -23 ± 28 207 -12 ± 23 < 0.0001

NYHA N % Improved N% Improved

Change at 3 months 543 55 242 24 < 0.0001

Change at 6 months 498 57 199 38 < 0.0001

a. P-values are not adjusted for multiplicity and were obtained using t-tests for continuous data and chi-square for categorical data.

- DRAFT -

B-38 CLINICAL STUDY - COMPANION

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C-1

CLINICAL STUDY - DECREASE HF

APPENDIX C

SUMMARY

The DECREASE-HF study was designed to determine if LV-CRT and LV Offset

are safe and effective as compared to the control treatment (BiV-CRT) in

patients with heart failure and an indication for an implantable cardioverter

deﬁbrillator (ICD). The primary effectiveness endpoint was a composite of

peak VO2and left ventricular end systolic diameter (LVESD). The primary

safety endpoints were heart failure related adverse event free rate and system

related adverse event free rate. The LV Offset arm supports the safety and

effectiveness of the LV Offset feature.

The DECREASE-HF Study design has been previously described in medical

literature.1

STUDY DESIGN

Patients were randomized (1:1:1) to receive one of these three therapies.

Patients who could not be randomized due to their inability to complete baseline

testing or because Expert Ease recommended BiV-CRT were followed for

safety data only in a separate “safety arm.” Available data for all patients were

analyzed by randomization group assignment, regardless of actual therapy

received (i.e., intent to treat).

The DECREASE-HF clinical investigation used CONTAK RENEWAL 2/4/4HE

devices to study the LV Offset feature as well as other features that are not

available in the CONTAK RENEWAL 1/3/3HE devices. The 2/4/4HE devices

are physically and mechanically identical to the 1/3/3HE devices and they both

contain the LV Offset feature. As such, the data from the DECREASE-HF

clinical study regarding the LV Offset feature, studied by using the 2/4/4HE

devices, applies to the CONTAK RENEWAL 1/3/3HE devices. The LV Offset

arm supports the safety and effectiveness of the LV Offset feature.

1.De Lurgio D, Foster E, Higginbotham M, Larntz K, Saxon L. A Comparison of cardiac

resynchronization by sequential biventricular pacing and left ventricular pacing to simultaneous

biventricular pacing: Rationale and design of the DECREASE-HF clinical trial. J Card Fail.

2005;11(3):233-239

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C-2 CLINICAL STUDY - DECREASE HF

FOLLOW-UP SCHEDULE

The follow-up schedule for the DECREASE HF study is detailed below

(Table C-1 on page C-2).

Table C-1. DECREASE HF follow-up schedule

Follow-up period Follow-up schedule

Pre-implant Initial assessment of patient eligibility; taking of patient history.

Administration of baseline Quality of Life (QOL) questionnaire.

Implant Implant of investigational devices and acute device testing.

Two-week visit Physical assessment, including NYHA assessment, and device evaluation.

Special Testingato establish the patient’s baseline condition, after which the randomization

assignment was assigned.

Three- and six-month

visit

Evaluation of randomized therapy with Special Testing and device functionb.

Quarterly visits After the six-month visit, patients were seen for routine evaluation of device function

and patient condition.

a. Special Testing included a Symptom-Limited Treadmill Test with measurement of oxygen uptake (Peak VO2), Echocardiography,

QOL questionnaire.

b. Holter monitor recordings were taken at the three-month visit for patients in the Holter Substudy.

INCLUSION/EXCLUSION CRITERIA

Patients enrolled in the investigation were required to meet the following

inclusion criteria:

• Must meet the general indications for a CRT-D implant

• Moderate or severe heart failure, deﬁned as NYHA Class III-IV despite

optimal pharmacological heart failure therapy

• A 12-lead electrocardiogram (ECG) obtained no more than 90 days prior to

enrollment documenting a sinus rate > 50 bpm, QRS duration ≥150 ms,

PR interval ≤320 ms measured from any two leads and a P-wave duration

< 150 ms measured from lead V1

• Creatinine ≤2.5 mg/dL obtained no more than 14 days prior to enrollment

• Left ventricular ejection fraction ≤35% [measured by echo, multiple gated

acquisition (MUGA) scan, cardiac catheterization, etc.] no more than 14

days prior to enrollment

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CLINICAL STUDY - DECREASE HF C-3

• Willing and capable of undergoing a device implant and participating in all

testing associated with this clinical investigation

• Have a life expectancy of more than 180 days, per physician discretion

• Age 18 or above, or of legal age to give informed consent speciﬁc to state

and national law

Patients were excluded from the investigation if they met any one of the

following exclusion criteria:

• Right bundle branch block morphology (per World Health Organization

Guidelines), on a 12-lead ECG obtained no more than 90 days prior to

enrollment

• Had previous cardiac resynchronization therapy, a previous coronary

venous lead, or met the general indications for antibradycardia pacing

• Had a neuromuscular, orthopedic, or other non-cardiac condition that

prevented normal, unsupported walking

• Had an atrial tachyarrhythmia that was permanent (i.e., did not terminate

spontaneously and could not be terminated with medical intervention) or

persistent (i.e., could be terminated with medical intervention, but did not

terminate spontaneously) within 180 days prior to enrollment

• Had a hypersensitivity to a 0.7 mg dose of dexamethasone acetate

• Had surgically uncorrected primary valvular heart disease

• Required dialysis at the time of enrollment

• Had chronic obstructive pulmonary disease (COPD), deﬁned as FEV1/FVC

<60%

• Had a myocardial infarct, unstable angina, percutaneous coronary

intervention, or coronary artery bypass graft during the 30 days prior to

enrollment

• Had hypertrophic obstructive cardiomyopathy or inﬁltrative cardiomyopathy

(e.g., amyloidosis, sarcoidosis)

• Had a mechanical tricuspid prosthesis

- DRAFT -

C-4 CLINICAL STUDY - DECREASE HF

• Were enrolled in any concurrent study, without Guidant written approval,

that may confound the results of this study

DEMOGRAPHIC DATA

Patient enrollment (Figure C-1 on page C-4) and baseline characteristics

(Table C-2 on page C-4) are detailed below.

Enrolled

360

Implant

342

Attempt

Death

Intent

Death

3 Received

Randomization

Assignment

325

Withdrawal

Incomplete

Baseline

Testing

Expert Ease

BiV Suggestion

Randomized

306

LV-CRT

101

LV Offset

104

BiV-CRT

101

Safety Arm

Figure C-1. DECREASE-HF Study Patient Enrollment and Randomization

Table C-2. DECREASE-HF study patient characteristics

Characteristic Measurement LV-CRT

(N=101)

LV Offset

(N=104)

BiV-CRT

(N=101)

P-valuea

Age at Implant (years) N 101 104 101

Mean ± SD 67.4 ± 9.6 66.6 ± 10.5 66.2 ± 10.6 0.69

Range 45.4 - 87.3 32.4 - 85.6 40.6 - 86.2

Gender [N (%)] Male 66 (65) 70 (67) 69 (68) 0.90

Female 35 (35) 34 (33) 32 (32)

NYHA Class [N (%)] III 98 (97) 100 (96) 101 (100) 0.16

IV 3(3) 4(4) 0(0)

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CLINICAL STUDY - DECREASE HF C-5

Table C-2. DECREASE-HF study patient characteristics (continued)

Characteristic Measurement LV-CRT

(N=101)

LV Offset

(N=104)

BiV-CRT

(N=101)

P-valuea

LVEF (%) N 101 104 100

Mean ± SD 22.6 ± 6.6 22.4 ± 6.7 23.2 ± 7.1 0.67

Range 8.0 - 35.0 9.0 - 35.0 5.0 - 35.0

QRS Duration (ms) N 101 104 101

Mean ± SD 165 ± 15 167 ± 16 168 ± 15 0.29

Range 150 - 220 150 - 220 150 - 218

PR Interval (ms) N 101 104 101

Mean ± SD 195 ± 42 195 ± 42 194 ± 39 0.98

Range 120 - 318 100 - 320 88 - 320

P-Wave Duration (ms) N 101 104 101

Mean ± SD 91 ± 22 96 ± 22 95 ± 24 0.21

Range 39 - 140 40 - 140 40 - 145

Concomitant Medicationsb[N

(%)]

ACE Inhibitor/ARB 88 (87) 88 (85) 91 (90) 0.50

Beta Blocker 84 (83) 84 (81) 82 (81) 0.89

Digoxin 47 (47) 55 (53) 46 (46) 0.52

Diuretic 89 (88) 93 (89) 82 (81) 0.19

Loop Diuretic 87 (86) 91 (88) 80 (79) 0.22

Nonloop Diuretic 8(8) 8(8) 8(8) 1.00

Aldosterone Antagonist 40 (40) 37 (36) 40 (40) 0.79

Antiarrhythmic 21 (21) 14 (13) 13 (13) 0.22

Etiology [N (%)] Ischemic 67 (66) 70 (67) 58 (57) 0.27

Nonischemic 34 (34) 34 (33) 43 (43)

Conduction Disorder [N (%)] Left Bundle Branch

Block

94 (93) 95 (91) 97 (96) 0.68

Nonspeciﬁc

Intraventricular

Conduction

6(6) 8(8) 4(4)

Right Bundle Branch

Block

1(1) 1(1) 0(0)

a. P-values for continuous variables were calculated from a Student’s t-test; p-values for discrete variables were calculated from

a Chi-squared test.

b. Patients may appear in more than one category.

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C-6 CLINICAL STUDY - DECREASE HF

STUDY RESULTS

Therapy Effectiveness

Primary Endpoint

Composite Score––Effectiveness of LV Offset was measured using a

Composite Score that combines six-month changes in Peak VO2and LVESD

(FigureC-2onpageC-6,TableC-3onpageC-7).Basedontheseestimatesof

clinically meaningful improvement (1 ml/kg/min and -5 mm, for Peak VO2and

LVESD, respectively), a scaling factor of 5 was chosen to give each component

approximately equal weight, as follows: Composite Score = (5 x change in

peak VO2) - (change in LVESD).

To evaluate the effectiveness of LV Offset, the Composite Score was compared

to the control arm using a longitudinal analysis. The null hypothesis was to be

rejected if the upper one-sided conﬁdence bound of the difference were less

than 10 points.

The observed mean differences from the BiV-CRT control arm was 3.6 ± 2.4

in the LV Offset arm, with upper one-sided conﬁdence bound of 8.2 showing

statistical equivalence to BiV-CRT.

LV Offset BiV-CRT

6-month Composite Score

LV Offset

Difference from BiV-CRT in a 6-month Score

Acceptable

Boundary

All patients with peak VO2 and LVESD data at a minimum of one visit, N=189

Figure C-2. Composite Score Equivalence to BiV-CRT at Six Months

- DRAFT -

CLINICAL STUDY - DECREASE HF C-7

Table C-3. Composite score equivalence to BiV-CRT at six months

Statistic LV Offset BiV-CRT

NaEstimate ± SE NaEstimate ± SE

3-Month Composite Score 71 12.4 ± 1.5 70 16.0 ± 1.5

6-Month Composite Score 70 12.8 ± 1.7 76 16.4 ± 1.7

Difference at 6 Months

(BiV-CRT - LV Offset)

3.6 ± 2.4

Conﬁdence Interval Upper Bound 8.2

a. N refers to the number of patients with paired data.

Secondary Endpoints

Peak VO2––A patient’s capacity for performing physical activity was assessed

using six-month change in Peak VO2achieved during CPX testing. The

endpoint analysis includes only CPX tests that are representative of maximal

patient effort, deﬁned as achievement of a Borg RPE ≥16 or RER ≥1.1.

As deﬁned in the Protocol, patients with a baseline Peak VO2greater than

20 ml/kg/min were excluded from the analysis. A longitudinal analysis that

included all patients with data at a minimum of one visit was performed to

estimate six-month change from baseline in each group.

As shown in (Figure C-3 on page C-8) and Table C-4 on page C-8, both

treatment arms showed a statistically signiﬁcant and clinically meaningful (≥

1.0 ml/kg/min) improvement in Peak VO2, an endpoint considered clinically

meaningful in previous randomized controlled trials of CRT. The null hypothesis

was to be rejected if the lower one-sided 95% conﬁdence bound were greater

than zero. The observed lower one-sided conﬁdence bound for LV Offset is

1.1 ml/kg/min.

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C-8 CLINICAL STUDY - DECREASE HF

Peak VO2 (ml/kg/min)

Baseline 3-Month 6-Month

LV Offset BiV-CRT

All patients with data at a minimum of one visit, N=189

Figure C-3. Improvement in Peak V02 at Six Months

Table C-4. Improvement in Peak VO2 at six months

Statistic LV Offset BiV-CRT

NaEstimate ± SE NaEstimate ± SE

Baseline 89 12.7 ± 0.2 88 12.7 ± 0.2

3 Months 72 14.2 ± 0.3 71 14.5 ± 0.3

6 Months 71 14.3 ± 0.3 76 14.2 ± 0.3

Improvement at 6 Months 1.6 ± 0.3 1.5 ± 0.3

Conﬁdence Interval Lower Bound 1.1 1.0

a. N refers to the number of patients with paired data.

Left Ventricular End Systolic Diameter (LVESD)––TheeffectofLV

Offset was also assessed using six-month change in LVESD. A recorded

echocardiographic examination was performed at the randomization visit (prior

to CRT initiation) and subsequently at the three-month and six-month visits. A

longitudinal analysis that included all patients with data at a minimum of one

visit was performed to estimate six-month change from baseline in each group.

Both arms showed a statistically signiﬁcant and clinically meaningful

improvement (≤-5 mm) in LVESD (Figure C-4 on page C-9, Table C-5 on

page C-9). The null hypothesis was to be rejected if the upper one-sided 95%

conﬁdence bound were less than zero. The observed upper one-sided bound

for LV Offset is -4.2 mm.

- DRAFT -

CLINICAL STUDY - DECREASE HF C-9

LVESD (mm)

Baseline 3-Month 6-Month

LV Offset BiV-CRT

All patients with data at a minimum of one visit, N=205

Figure C-4. Improvement in LVESD at Six Months

Table C-5. Improvement in LVESD at six months

Statistic LV Offset BiV-CRT

NaEstimate ± SE NaEstimate ± SE

Baseline 104 55.7 ± 0.5 100 55.7 ± 0.5

3 Months 97 50.5 ± 0.9 97 48.9 ± 0.9

6 Months 92 50.3 ± 0.9 91 47.1 ± 0.9

Improvement at 6 Months -5.4 ± 0.7 -8.7 ± 0.7

Conﬁdence Interval Upper Bound -4.2 -7.5

a. N refers to the number of patients with paired data.

Quality of Life (QOL)––The effect of CRT on the patient’s perceived quality

of life was assessed using six-month change in QOL score. The Minnesota

Living with Heart Failure Questionnaire‚ was administered prior to implant and

subsequently at the three-month and six-month visits. A longitudinal analysis

that included all patients with data at a minimum of one visit was performed to

estimate six-month change from baseline in each group.

Both arms showed a statistically signiﬁcant and clinically meaningful

improvement (≤-10 points) in QOL, an endpoint considered clinically

meaningful in previous randomized controlled trials of CRT (Figure C-5 on page

C-10, Table C-6 on page C-10). The null hypothesis was to be rejected if the

- DRAFT -

C-10 CLINICAL STUDY - DECREASE HF

upper one-sided 95% conﬁdence bound were less than zero. The observed

upper one-sided conﬁdence bound for LV Offset was -19.4 points.

QOL Score

Baseline 3-Month 6-Month

LV Offset BiV-CRT

All patients with data at a minimum of one visit, N=205

Figure C-5. Improvement in Quality of Life at Six months

Table C-6. Improvement in QOL at six months.

Statistic LV Offset BiV-CRT

NaEstimate ± SE NaEstimate ± SE

Baseline 100 54.6 ± 1.4 98 54.6 ± 1.4

3 Months 94 33.5 ± 2.4 95 34.0 ± 2.3

6 Months 88 31.3 ± 2.4 91 32.5 ± 2.4

Improvement at 6 Months -23.4 ± 2.4 -22.1 ± 2.4

Conﬁdence Interval Upper Bound -19.4 -18.1

a. N refers to the number of patients with paired data.

NYHA Class––The effect of CRT on the patient’s heart failure related

symptoms (as measured by NYHA Class) was assessed prior to implant and

subsequently at the three-month and six-month visits. The analysis of NYHA

Class included all patients with data at enrollment and six months.

As shown in Figure C-6 on page C-11 and Table C-7 on page C-11, both arms

showed a statistically signiﬁcant percentage of patients who improved at least

one NYHA Class, an endpoint considered clinically meaningful in previous

randomized controlled trials of CRT. The null hypothesis was to be rejected

- DRAFT -

CLINICAL STUDY - DECREASE HF C-11

if the lower one-sided 95% conﬁdence bound of the percentage of patients

improving one or more NYHA Class were greater than zero. The observed

lower one-sided conﬁdence bound for LV Offset was 47.9%.

100

Percent of Patients Improved

LV Offset BiV-CRT

All patients with data at a minimum of one visit, N=187

Figure C-6. Improvement in NYHA Class at Six Months

Table C-7. Improvement in NYHA Class at six months

Statistic LV Offset BiV-CRT

Total Patients 95 92

Number (Percent) of Patients Improved 54 (56.8%) 54 (58.7%)

Lower Bound of One-Sided Exact 95% Conﬁdence Interval 47.9% 49.6%

Table C-8 on page C-11 provides additional detail, showing the percent of

patients who improved two or three classes, as well as the percent of those

who had no change or worsened.

Table C-8. Six-month change in NYHA by treatment group

6-Month Change in NYHAaLV Offset (N=95) BiV-CRT (N=92) Total (N=187)

Improved 3 Classes 1 (1.1) 0 (0.0) 1 (0.5)

Improved 2 Classes 16 (16.8) 8 (8.7) 24 (12.8)

Improved 1 Class 37 (38.9) 46 (50.0) 83 (44.4)

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C-12 CLINICAL STUDY - DECREASE HF

Table C-8. Six-month change in NYHA by treatment group (continued)

6-Month Change in NYHAaLV Offset (N=95) BiV-CRT (N=92) Total (N=187)

No Change 35 (36.8) 36 (39.1) 71 (38.0)

Worsened 1 Class 6 (6.3) 2 (2.2) 8 (4.3)

a. All patients with paired data; N=187.

Device Effectiveness

Primary Endpoint

Ventricular Tachycardia/Fibrillation Detection Time––The objective of this

endpoint was to demonstrate that CRT does not affect the ability to detect

VT/VF. The results for VT/VF detection time are shown in Table C-9 on page

C-12.

Table C-9. VT/VF detection time

Number of PatientsaMean SD Upper Bound of One-Sided

95% Conﬁdence Interval

338 2.46 0.58 2.50

a. All patients implanted with non-missing data; N=338.

The null hypothesis was to be rejected if the upper one-sided 95% conﬁdence

bound for mean VF detection time were less than 6 seconds. The observed

upper one-sided 95% conﬁdence bound for VF detection time was 2.50

seconds. These data demonstrate device effectiveness in the detection of

VT/VF.

Therapy Safety

Primary Endpoint

Heart Failure-Related Adverse Event Free Rate––Therapy safety was

assessed by the heart failure related adverse event free rate observed

through six months of therapy delivery (randomization visit through six months

post-randomization). The heart failure related adverse event free rate is

deﬁned as the number of patients who do not experience a heart failure related

adverse event divided by the total number of patients implanted and active

at the randomization visit. All patients who were successfully implanted and

remained active at the randomization visit were included in the analysis.

- DRAFT -

CLINICAL STUDY - DECREASE HF C-13

Table C-10 on page C-13 summarizes the heart failure related adverse event

rates through the six-month visit. A Kaplan-Meier analysis is also presented in

FigureC-7onpageC-14toshowtimetoevents.

Table C-10. Heart failure-related adverse event free rate at six months

Adverse EventaNumber

Events

Number of

Patients

Heart Failure

Adverse

Event Free Rate

Lower One-Sided 95%

Conﬁdence Bound

Multiple heart failure symptoms 38 29 91.4 88.5

Dyspnea - Heart failure 13 13 96.2 94.0

Heart failure symptoms -

Unspeciﬁed

13 12 96.4 94.3

Hypotension - Heart failure 10 9 97.3 95.4

Weight gain - Heart failure 54 98.8 97.3

Fatigue - Heart failure 4 4 98.8 97.3

Pulmonary edema - Heart failure 4 4 98.8 97.3

Renal insufﬁciency - Heart failure 4 3 99.1 97.7

Gastrointestinal - Heart failure 3 3 99.1 97.7

Multi-system failure - Heart failure 2 2 99.4 98.1

Peripheral edema - Heart failure 2 2 99.4 98.1

Chest pain - Heart failure 1 1 99.7 98.6

Dehydration - Heart failure 1 1 99.7 98.6

Dizziness - Heart failure 1 1 99.7 98.6

Elevated BNP - Heart Failure 1 1 99.7 98.6

Total 102 67 80.2 76.3

a. All patients implanted and active at the randomization visit; N=338.

The null hypothesis was to be rejected if the lower one-sided 95% conﬁdence

bound for heart failure adverse event free rate through six months post-implant

were greater than 50%. The heart failure related adverse event free rate at six

months was 80.2% with a lower one-sided 95% conﬁdence bound of 76.3%.

- DRAFT -

C-14 CLINICAL STUDY - DECREASE HF

Months from Randomization Visit

Percent Free from HF AE

All patients implanted and active at the randomization follow-up; N=338.

100

Acceptance Boundary

338 313 300 290 279 267 258

0123456

Event-Free Rate

Lower One-Sided 95% Confidence Bound

Figure C-7. Time to Heart Failure Related Adverse Event

Device Safety

Primary Endpoint

System-Related Complication Free Rate––The safety of the investigational

system was assessed by the system related complication free rate observed

in the period between implant and six months post-implant in all patients

attempted or implanted. System related complication free rate is deﬁned

as the proportion of patients without a system related complication within

six months post-implant. All patients who underwent an implant procedure

were included in the analysis. Table C-11 on page C-14 shows the system

related complication free rates by event type. A Kaplan-Meier analysis is also

presented in (Figure C-8 on page C-15) to show time to events.

Table C-11. System-related complication free rate at six months

ComplicationaNumber

ofEvents

Number

of Patients

Complication

Free Rate

Lower One-Sided

95% Conﬁdence

Bound

LV Lead 35 31 91.3 88.5

RA Lead 11 9 97.5 95.7

RV Lead 3 3 99.2 97.8

PG 14 14 96.1 94.0

Procedure 17 16 95.5 93.3

Tota l b80 60 83.2 79.7

a. All patients implanted or attempted; N=358.

b. Includes patients in the Safety Arm.

- DRAFT -

CLINICAL STUDY - DECREASE HF C-15

The null hypothesis was to be rejected if the lower one-sided 95% conﬁdence

bound for system related complication rate through six months post-implant

were greater than 70%. The system related complication free rate at six months

was 83.2% with a lower 95% conﬁdence bound of 79.7%.

Months from Implant

0 1 2 3 4 5 6

100

N 358 287 285 280 272 268 265

Acceptance Boundary

Percent Free from System Comp

All patients implanted or attempted; N=358.

Event-Free Rate

Lower One-Sided 95% Confidence Bound

Figure C-8. Time to System Related Complication

The Holter Substudy

Ancillary Endpoints

Sixty-nine patients at nine centers were included in the Holter Substudy. Data

were collected at the three-month visit at centers participating in the Holter

Substudy. Holter recordings were analyzed by a Holter core laboratory.

Continuous Appropriate Pacing During Activities of Daily Living––The

safety of CRT therapy provided by the investigational system was assessed by

the percent of time a patient is appropriately paced over a 24-hour period, as

recorded with a Holter monitor at the three-month visit. The appropriateness

of CRT delivery is deﬁned by whether the device delivers CRT in accordance

with the physician’s programming. The objective of this endpoint was to

demonstrate that patients receive continuous appropriate pacing from the

device during activities of daily living.

It is expected that patients will receive pacing approximately 95% of the time on

average. The null hypothesis was to be rejected if the lower one-sided 95%

conﬁdence bound of the mean time paced were greater than 90%. Due to the

non-normality of the data, a non-parametric test of the median was performed,

which compared the median to 90% instead of comparing the lower 95%

conﬁdence bound of the mean to 90%.

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C-16 CLINICAL STUDY - DECREASE HF

The mean percentage of appropriately paced beats during activities of daily

living was 99.5 ± 1.3 with a median of 100.0% (p <0.01) (Table C-12 on page

C-16).

Table C-12. Continuous appropriate pacing during activities of daily living

StatisticaResult

N69

Mean ± SD 99.5 ± 1.3

Median 100.0

Range 93.1 - 100.0

P-valueb<0.01

a. All patients in the Holter Substudy; N=69.

b. P-value calculated from a signed-rank test.

Continuous Appropriate Pacing During Exercise––The safety of CRT

therapy provided by the investigational system was assessed by the percent

of time a patient receives appropriate pacing during the patient’s three-month

CPX test, as recorded with a Holter monitor. The appropriateness of CRT

delivery is deﬁned by whether or not the device delivers CRT in accordance

with the physician’s programming. The objective of this endpoint was to

demonstrate that patients receive continuous appropriate pacing from the

device during exercise.

It is expected that patients will receive pacing approximately 95% of the time on

average. The null hypothesis was to be rejected if the lower one-sided 95%

conﬁdence bound of the mean time paced were greater than 90%. Due to the

non-normality of the data, a non-parametric test of the median was performed

comparing the median to 90% instead of comparing the lower 95% conﬁdence

bound to 90%.

The mean percentage of appropriately paced beats during exercise was 99.4 ±

1.9 with a median of 100.0% (p < 0.01) (Table C-13 on page C-16).

Table C-13. Continuous appropriate pacing during exercise

StatisticaResult

N67

Mean ± SD 99.4 ± 1.9

Median 100.0

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CLINICAL STUDY - DECREASE HF C-17

Table C-13. Continuous appropriate pacing during exercise (continued)

StatisticaResult

Range 90.3 - 100.0

P-valueb<0.01

a. All patients in the Holter Substudy; N=67.

b. P-value calculated from a signed-rank test.

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C-18 CLINICAL STUDY - DECREASE HF

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D-1

CLINICAL STUDY - CONTAK CD

APPENDIX D

CLINICAL STUDY POPULATIONS

Guidant CRT-Ds, when compared to OPT alone, have been demonstrated with

reasonable assurance, to be safe and effective in signiﬁcantly reducing: the

risk of a composite of all-cause mortality or ﬁrst hospitalization by 20%, the

risk of all-cause mortality by 36%, and heart failure symptoms in patients who

have moderate to severe heart failure (NYHA III/IV) including left ventricular

dysfunction (EF ≤35%) and QRS duration ≥120 ms and remain symptomatic

despite stable, optimal heart failure drug therapy, based on the Guidant

sponsored COMPANION clinical study. (Guidant devices were the only devices

studied in the COMPANION clinical trial.)

SUMMARY

Guidant conducted the CONTAK CD Study to demonstrate the safety and

effectiveness of the CONTAK CD system and to demonstrate a reasonable

assurance of the safety and effectiveness of biventricular stimulation, or cardiac

resynchronization therapy (CRT), using the Guidant Model 1822 VENTAK CHF

AICD and Model 1823 CONTAK CD CRT-D along with the EASYTRAK (Models

4510/4511/4512/4513) coronary venous, steroid-eluting, single-electrode

pace/sense lead.

The CONTAK CD Study failed to prospectively demonstrate effectiveness of the

CRT portion of the device. The CONTAK CD Study met the Lead and System

Effectiveness endpoints as well as the Lead and System Safety endpoints.

Subgroup analysis revealed a population of patients that had Class III/IV heart

failure at the time of randomization that appeared to have improvements on

certain functional endpoints, including the Peak VO2and the Six-Minute Hall

walk. A second study was performed (Focused Conﬁrmatory Study) using this

subgroup of patients to conﬁrm the effectiveness of CRT.

OBSERVED ADVERSE EVENTS

The VENTAK CHF/CONTAK CD/EASYTRAK Biventricular Pacing Study

(hereafter referred to as the CONTAK CD Study) was a prospective,

randomized, controlled, multicenter, double-blind study conducted at 47 sites in

the United States and enrolled a total of 581 patients. Of these, 57 patients

initially underwent a thoracotomy procedure to receive the Guidant Model 1822

VENTAK CHF AICD; 7 patients underwent a repeat procedure to receive an

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D-2 CLINICAL STUDY - CONTAK CD

EASYTRAK lead. An additional 510 patients initially underwent an implant

procedure to receive the Model 1823 CONTAK CD CRT-D along with the

EASYTRAK (Models 4510/4511/4512/4513) coronary venous, single-electrode

pace/sense lead for a total of 517 patients who underwent an EASYTRAK

lead implant procedure. In 69 patients the EASYTRAK lead implant attempt

was unsuccessful.

Table D-1 on page D-2 provides information on all adverse events reported

from implant through the randomization period in patients attempted or

implanted with the EASYTRAK lead. During this period, a total of 765 events

were reported in 310 patients. Of these, 155 were classiﬁed as complications,

and 610 were classiﬁed as observations.

Table D-1. Adverse events through randomization period

# Of Events

(# of pts)

Complications

(Patients)

Complications

per 100

Device Months

(Events)

Observations

(Patients)

Observations

per 100

Device Months

(Events)

Total Adverse

Events

765 (310) 23.4 (121) 6.0 (155) 51.8 (268) 23.5 (610)

PG-Related Events

Migration of device 1 (1) 0.0 (0) 0.0 (0) 0.2 (1) 0.0 (1)

Pacemaker-mediated

tachycardia (PMT)

3 (3) 0.0 (0) 0.0 (0) 0.6 (3) 0.1 (3)

Telemetry difﬁculty 1 (1) 0.2 (1) 0.0 (1) 0.0 (0) 0.0 (0)

LV Lead-Related Events

Loss of capture 43 (41) 5.6 (29) 1.1 (29) 2.5 (13) 0.5 (14)

Inappropriate shock

due to oversensing

1 (1) 0.0 (0) 0.0 (0) 0.2 (1) 0.0 (1)

Insulation breach

observed

1 (1) 0.2 (1) 0.0 (1) 0.0 (0) 0.0 (0)

Multiple counting 31 (22) 1.0 (5) 0.2 (5) 3.9 (20) 1.0 (26)

Phrenic

nerve/diaphragm

stimulation

15 (15) 0.4 (2) 0.1 (2) 2.5 (13) 0.5 (13)

RA Lead-Related Events

Loss of capture 6 (6) 1.0 (5) 0.2 (5) 0.2 (1) 0.0 (1)

Oversensing 3 (3) 0.0 (0) 0.0 (0) 0.6 (3) 0.1 (3)

Undersensing 1 (1) 0.2 (1) 0.0 (1) 0.0 (0) 0.0 (0)

RV Lead-Related Events

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CLINICAL STUDY - CONTAK CD D-3

Table D-1. Adverse events through randomization period (continued)

# Of Events

(# of pts)

Complications

(Patients)

Complications

per 100

Device Months

(Events)

Observations

(Patients)

Observations

per 100

Device Months

(Events)

Loss of capture 10 (9) 0.6 (3) 0.1 (3) 1.2 (6) 0.3 (7)

Elevated DFTs 6 (6) 0.4 (2) 0.1 (2) 0.8 (4) 0.2 (4)

Inappropriate shock

above rate cutoff

49 (38) 0.4 (2) 0.1 (2) 7.2 (37) 1.8 (47)

Inappropriate shock

due to oversensing

5 (4) 0.0 (0) 0.0 (0) 0.8 (4) 0.2 (5)

Nonconversion of

1 (1) 0.2 (1) 0.0 (1) 0.0 (0) 0.0 (0)

Oversensing 2 (2) 0.0 (0) 0.0 (0) 0.4 (2) 0.1 (2)

Phantom shock 2 (2) 0.0 (0) 0.0 (0) 0.4 (2) 0.1 (2)

Phrenic

nerve/diaphragm

stimulation

5 (5) 0.4 (2) 0.1 (2) 0.6 (3) 0.1 (3)

Subtotal

Device-Related

Events

186 (135) 9.5 (49) 2.1 (54) 19.0 (98) 5.1 (132)

Procedure-Related Events

AV block 7 (7) 0.0 (0) 0.0 (0) 1.4 (7) 0.3 (7)

Coronary sinus

dissection

5 (5) 0.0 (0) 0.0 (0) 1.0 (5) 0.2 (5)

Coronary venous

perforation

5 (5) 0.2 (1) 0.0 (1) 0.8 (4) 0.2 (4)

Hematoma 11 (10) 0.8 (4) 0.2 (4) 1.2 (6) 0.3 (7)

Hypotension 7 (7) 0.0 (0) 0.0 (0) 1.4 (7) 0.3 (7)

Infection,

post-operative

wound

7 (7) 0.6 (3) 0.1 (3) 0.8 (4) 0.2 (4)

Pneumothorax 7 (7) 0.8 (4) 0.2 (4) 0.6 (3) 0.1 (3)

Post surgical

wound discomfort

10 (9) 0.2 (1) 0.0 (1) 1.5 (8) 0.3 (9)

Renal failure 5 (5) 0.2 (1) 0.0 (1) 0.8 (4) 0.2 (4)

Other 18 (18) 1.2 (6) 0.2 (6) 2.3 (12) 0.5 (12)

Subtotal

Procedure-Related

Events

79 (71) 3.9 (20) 0.7 (17) 10.0 (51) 2.2 (56)

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D-4 CLINICAL STUDY - CONTAK CD

Table D-1. Adverse events through randomization period (continued)

# Of Events

(# of pts)

Complications

(Patients)

Complications

per 100

Device Months

(Events)

Observations

(Patients)

Observations

per 100

Device Months

(Events)

Cardiovascular-Related Events

AV Block 3 (3) 0.0 (0) 0.0 (0) 0.6 (3) 0.1 (3)

Arrhythmia - SVT 49 (42) 0.2 (1) 0.0 (1) 7.9 (41) 1.8 (48)

Arrhythmia - VT 20 (17) 1.0 (5) 0.2 (5) 2.7 (14) 0.6 (15)

Arrhythmia - brady 16 (14) 0.2 (1) 0.0 (1) 2.5 (13) 0.6 (15)

Cardiac arrest 2 (2) 0.4 (2) 0.1 (2) 0.0 (0) 0.0 (0)

Chest pain 30 (20) 1.0 (5) 0.2 (5) 3.1 (16) 1.0 (25)

Coagulopathy 3 (3) 0.2 (1) 0.0 (1) 0.4 (2) 0.1 (2)

Congestive heart

failure

140 (91) 3.5 (18) 0.7 (18) 16.1 (83) 4.7 (122)

Distal

thromboemboli

3 (2) 0.0 (0) 0.0 (0) 0.4 (2) 0.1 (3)

Dizziness 17 (17) 0.0 (0) 0.0 (0) 3.3 (17) 0.7 (17)

Dyspnea

(shortness of

breath)

16 (13) 0.0 (0) 0.0 (0) 2.5 (13) 0.6 (16)

Fatigue 10 (10) 0.0 (0) 0.0 (0) 1.9 (10) 0.4 (10)

Hypertension 1 (1) 0.0 (0) 0.0 (0) 0.2 (1) 0.0 (1)

Hypotension 11 (9) 0.2 (1) 0.0 (1) 1.7 (9) 0.4 (10)

Myocardial

infarction

2 (2) 0.0 (0) 0.0 (0) 0.4 (2) 0.1 (2)

Pacemaker

syndrome

1 (1) 0.0 (0) 0.0 (0) 0.2 (1) 0.0 (1)

Palpitations 2 (2) 0.0 (0) 0.0 (0) 0.4 (2) 0.1 (2)

Pulmonary edema 6 (6) 0.4 (2) 0.1 (2) 0.8 (4) 0.2 (4)

Shock 4 (4) 0.2 (1) 0.0 (1) 0.6 (3) 0.1 (3)

Stroke syndrome or

CVA

4 (4) 0.0 (0) 0.0 (0) 0.8 (4) 0.2 (4)

Syncope 9 (9) 0.0 (0) 0.0 (0) 1.7 (9) 0.3 (9)

Thrombosis 3 (3) 0.0 (0) 0.0 (0) 0.6 (3) 0.1 (3)

Vascular related 6 (6) 1.0 (5) 0.2 (5) 0.2 (1) 0.0 (1)

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CLINICAL STUDY - CONTAK CD D-5

Table D-1. Adverse events through randomization period (continued)

# Of Events

(# of pts)

Complications

(Patients)

Complications

per 100

Device Months

(Events)

Observations

(Patients)

Observations

per 100

Device Months

(Events)

Subtotal

Cardiovascular-

Related Events

358 (200) 7.7 (40) 1.6 (42) 35.6 (184) 12.2 (316)

Tota l

Noncardiovascular-

Related Events

142 (92) 6.2 (32) 1.5 (39) 13.5 (70) 4.0 (103)

Deaths

A total of 109 deaths occurred during the study. These deaths occurred during

the study periods as shown in Table D-2 on page D-5 along with the cause of

death as adjudicated by an independent events committee.

Table D-2. Deaths that occurred during CONTAK CD study

Cause of Death

Study Perioda#ofpt

deaths Cardiac:

Pump

Failure

Cardiac:

Arrhythmic

Cardiac:

Other

Non-

cardiac

Unknown

After unsuccessful implant

procedure

21 1 0 0 0

Peri-operative (≤30 days) 10 52021

Randomized therapy phase: No

CRTb

16 9 0 1 3 3

Randomized therapy phase: CRTb11 4 1 2 2 2

Post-randomized therapy phasec70 26 511620

Total 109 47 9 4 23 26

a. All patients enrolled, N = 581.

b. Day 31 to 120 for Phase I patients, day 31 to 210 for Phase II patients.

c. Day 121 and beyond for Phase I patients, day 211 and beyond for Phase II patients.

STUDY DESIGN

The CONTAK CD Study was a prospective, randomized, controlled,

multi-center, double-blind study conducted at 47 sites in the United States

and enrolled a total of 581 patients. All patients enrolled were intended to be

implanted with a device capable of delivering both CRT and treating ventricular

tachyarrhythmias. Patients were randomized to CRT Off (VVI lower rate 40)

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D-6 CLINICAL STUDY - CONTAK CD

or CRT On (VDD). The study began as a crossover design (called "Phase I")

and enrolled 248 patients with a primary endpoint of functional status with

three months of follow-up. The study was later modiﬁed to a parallel design

(called "Phase II") and enrolled 333 patients with a longer, six-month follow-up.

Thedatafromtheﬁrst three months of the crossover phase were pooled

with data obtained from the six-month parallel phase. The visit schedule

and testing requirements remained the same. Additionally, while the study

originally used the VENTAK CHF ICD in conjunction with epicardial leads

placed via thoracotomy, the CONTAK CD CRT-D and EASYTRAK lead (placed

transvenously) were added to the protocol later in the study.

INCLUSION/EXCLUSION CRITERIA

Patients enrolled in the study were required to meet the following inclusion

criteria:

• Meet the general indication for ICD implant

• Symptomatic heart failure despite optimal drug therapy (ACE inhibitors with

diuretic and/or digoxin, as determined to be indicated and tolerated by

the patient’s physician-investigator)

• Left ventricular ejection fraction ≤35%

• QRS duration ≥120 ms

•Age≥18 years

• Normal sinus node function

Patients were excluded from the investigation if they met any of the following

criteria:

• Meet the general indications for permanent antibradycardia pacing,

including pacemaker dependence

• Have chronic, medically refractory atrial tachyarrhythmias

• Require concomitant cardiac surgery

• Are unable to undergo device implant, including general anesthesia if

required

• Are unable to comply with the protocol and follow-up requirements,

including exercise testing

• Have a life expectancy of less than six months due to other medical

conditions

• Have amyloid disease (amyloidosis)

• Have hypertrophic obstructive cardiomyopathy

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CLINICAL STUDY - CONTAK CD D-7

• Require in-hospital continuous intravenous inotropes

• Have pre-existing cardioversion/deﬁbrillation leads other than those

speciﬁed in this investigational plan (unless the investigator intends to

replace them with permitted cardioversion/deﬁbrillation leads)

• Women who are pregnant or not using medically accepted birth control

• Have a mechanical tricuspid prosthesis

• Involved in other cardiovascular clinical investigations of active therapy

or treatment

FOLLOW-UP SCHEDULE

The follow-up schedule for the clinical study consisted of the following

components:

• Pre-implant visit––initial assessment of patient eligibility; taking of patient

history.

• Implant––implant of investigational devices and acute device testing.

Randomization status (CRT or No CRT) was assigned for implementation

after a 30-day recovery period.

• Recovery period––minimum 30-day period over which the patient recovered

from the implant procedure and had his/her heart failure medications

adjusted, but with no CRT, regardless of the randomization assignment.

• Post-recovery visit––ﬁrst visit after the Recovery Period in which patients

underwent Special Testing to establish their baseline condition, after which

the randomization assignment was implemented (CRT or No CRT).

• Three- and six-month visit––evaluation of randomized therapy with Special

Testing and device function at three- and six-months after the post-recovery

visit.

• Quarterly visits––After the six-month visit, patients were seen for routine

evaluation of device function and patient condition.

NOTE: Special Testing included a Symptom-Limited Treadmill Test

with measurement of oxygen uptake (Peak VO2), a Six-Minute Walk,

Echocardiography, Holter monitoring, blood chemistry testing, and a Quality

of Life (QOL) questionnaire

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D-8 CLINICAL STUDY - CONTAK CD

DEMOGRAPHIC DATA

The CONTAK CD Study included patients with symptomatic heart failure

despite optimal drug therapy as deﬁned in the inclusion criteria. The population

included patients who were NYHA Class II, III, or IV at the time of implant.

Based upon the clinical results from the covariate analyses in this study and the

internal consistency of these clinical ﬁndings with those from other completed

CRT studies, the patient subgroup with NYHA Class III/IV heart failure in this

study was examined further.

• All Patients––all patients (NYHA Class II/III/IV at the time of implant)

implanted with an investigational system (N = 501). Ten patients died

and one withdrew before the post-recovery visit. Therefore, therapy

effectiveness analyses used N = 490.

• NYHA Class III/IV (Advanced Heart Failure)––this subgroup was deﬁned

as those patients with moderate to severe heart failure at the time of the

Post-Recovery Visit (N = 227). A percentage of patients either had an

improvement or worsening of their NYHA Class during the post-implant

recovery period. The patients in the Advanced Heart Failure subgroup

were only those who remained in NYHA Class III/IV at the end of the

post-recovery period. This subgroup was determined from interaction

analysis of preselected covariates with the functional status endpoints.

ENDPOINTS

The CONTAK CD Study had three investigational elements consisting of the

following components:

• CRT effectiveness

– Primary––composite endpoint consisting of all-cause mortality,

hospitalization for heart failure, and ventricular tachyarrhythmia

requiring device intervention

– Secondary–Peak VO2derived from a symptom-limited exercise test

and Quality of Life as measured by the Minnesota Living with Heart

Failure Questionnaire®

– Additional––Six-Minute Walk, NYHA Class, Echocardiographic

Analysis, Change in Norepinephrine, and Change in Heart Rate

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CLINICAL STUDY - CONTAK CD D-9

• Lead and System Effectiveness

– Lead––left ventricular pacing thresholds, biventricular sensing,

biventricular lead impedance, and lead placement success rate

– System––VF detection time and biventricular ATP effectiveness

• Lead and System Safety

– Lead––incidence of lead-related adverse events

– System––incidence of severe, device-related adverse events and

operative mortality

STUDY RESULTS

Patient Accountability (Figure D-1 on page D-10)

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D-10 CLINICAL STUDY - CONTAK CD

Control (No CRT)

n = 245

Assessable for

effectiveness

n = 224

Assessable for

effectiveness

n = 232

CRT

n = 245

Randomized

n = 490

Death

Uncorrected lead dislodgement

Heart transplant

Withdrew

Six months

n = 125

Three months

n = 99

Six months

n = 126

Three months

n = 106

Death

Withdrew

Implanted

n = 501

Withdrew prior to surgery (“Intent”)

Unable to implant lead (“Attempt”)

Enrolled

n = 581

Figure D-1. Enrollment and follow-up of randomized patients

Baseline Characteristics––Includes all patients implanted; N = 501(Table D-3

on page D-11, Table D-4 on page D-12).

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CLINICAL STUDY - CONTAK CD D-11

Table D-3. Pre-implant assessment

All Patients NYHA Class III/IV

Characteristic

CRT

(N = 248)

No CRT

(N = 253)

P-valueaCRT

(N = 117)

No CRT

(N = 110)

P-valuea

Age at Implant

(years)

N 248 253 117 110

Mean ±

66.0 ± 10.5 66.3 ± 10.5 0.73 66.1 ±

10.5

65.8 ± 10.5 0.80

Range 26.1 - 82.6 29.5 - 86.3 26.1 - 82.5 38.3 - 85.3

Gender [N (%)] Male 210 (84.7) 211 (83.4) 0.70 90 (76.9) 86 (78.2) 0.82

Female 38 (15.3) 42 (16.6) 27 (23.1) 24 (21.8)

NYHA Class [N

(%)]

II 80 (32.3) 83 (32.8) 0.66 20 (17.1) 11 (10.0) 0.08

III 148 (59.7) 144 (56.9) 85 (72.6) 78 (70.9)

IV 20 (8.1) 26 (10.3) 12 (10.3) 21 (19.1)

Concomitant

Medications [N

(%)]

ACE or

ARB

212 (85.5) 224 (88.5) 0.31 95 (81.2) 98 (89.1) 0.10

Beta

Blocker

119 (48.0) 117 (46.2) 0.70 53 (45.3) 44 (40.0) 0.42

Digoxin 172 (69.4) 171 (67.6) 0.67 84 (71.8) 75 (68.2) 0.55

Diuretic 217 (87.5) 210 (83.0) 0.16 108 (92.3) 95 (86.4) 0.15

Qualifying LVEF

(%)

N 248 253 117 110

Mean ±

21.4 ± 6.6 21.5 ± 6.7 0.74 20.6 ± 6.4 21.1 ± 6.2 0.61

Range 5.0 - 35.0 10.0 - 35.0 8.0 - 35.0 10.0 - 35.0

PR Intervalb(ms) N 224 222 107 91

Mean ±

205± 42 202 ± 49 0.44 204 ± 41 200 ± 54 0.60

Range 88 - 336 104 - 400 136 - 336 110 - 400

Qualifying QRS

Durationb(ms)

N 226 224 109 93

Mean ±

160 ± 27 156 ± 26 0.06 164 ± 27 152 ± 24 < 0.01

Range 120 - 240 120 - 264 120 - 240 120 - 222

Resting Heart Rate

( bpm)

N 248 253 117 110

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D-12 CLINICAL STUDY - CONTAK CD

Table D-3. Pre-implant assessment (continued)

All Patients NYHA Class III/IV

Characteristic

CRT

(N = 248)

No CRT

(N = 253)

P-valueaCRT

(N = 117)

No CRT

(N = 110)

P-valuea

Mean ±

73 ± 12 75 ± 14 0.37 75 ± 13 74 ± 15 0.61

Range 43 - 108 48 - 120 43 - 108 50 - 120

Systolic Blood

Pressure (mmHg)

N 247 253 116 110

Mean ±

118 ± 21 118 ± 21 0.95 116 ± 20 117 ± 23 0.72

Range 79 - 197 70 - 190 79 - 191 74 - 190

Diastolic Blood

Pressure (mmHg)

N 247 253 116 110

Mean ±

67 ± 12 69 ± 12 0.27 68 ± 12 67 ± 14 0.85

Range 31 - 100 40 - 109 31 - 100 40 - 109

a. P-values for comparing means were calculated with Student’s t-test; p-values for comparing proportions were calculated with

Pearson’s chi-squared test.

b. PR interval and QRS duration were not obtained for thoracotomy patients.

Table D-4. Pre-implant history

All Patients NYHA Class III/IV

Characteristic

CRT

(N = 248)

No CRT

(N = 253)

P-valueaCRT

(N = 117)

No CRT

(N = 110)

P-valuea

Primary

Tachyarrhythmia [N

(%)]

Monomorphic

VT (MVT)

148

(59.7)

136

(53.8)

0.44 72 (61.5) 48 (43.6) 0.03

Polymorphic

VT (PVT)

16 (6.5) 20 (7.9) 7 (6.0) 7 (6.4)

Nonsustained

58 (23.4) 63 (24.9) 30 (25.6) 35 (31.8)

Ventricular

Fibrillation

(VF)

26 (10.5) 32 (12.6) 8 (6.8) 18 (16.4)

Other 0 (0.0) 2 (0.8) 0 (0.0) 2 (1.8)

Other Arrhythmias [N

(%)]

Paroxysmal

Atrial

Fibrillation

43 (17.3) 62 (24.5) 0.05 21 (17.9) 29 (26.4) 0.13

Atrial Flutter 10 (4.0) 13 (5.1) 0.55 3 (2.6) 7 (6.4) 0.16

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CLINICAL STUDY - CONTAK CD D-13

Table D-4. Pre-implant history (continued)

All Patients NYHA Class III/IV

Characteristic

CRT

(N = 248)

No CRT

(N = 253)

P-valueaCRT

(N = 117)

No CRT

(N = 110)

P-valuea

Arrhythmia/Conduction

Disorder [N (%)]

LBBB 133

(53.6)

138

(54.5)

0.83 59 (50.4) 59 (53.6) 0.55

RBBB 35 (14.1) 31 (12.3) 21 (17.9) 14 (12.7)

Non-Speciﬁc 80 (32.3) 84 (33.2) 37 (31.6) 37 (33.6)

Etiology [N (%)] Ischemic 167

(67.3)

178

(70.4)

0.47 76 (65.0) 78 (70.9) 0.34

Non-Ischemic 81 (32.7) 75 (29.6) 41 (35.0) 32 (29.1)

a. P-values were calculated with Pearson’s chi-squared test.

CRT Effectiveness

Heart Failure Progression (Composite Index)––the Composite Index

(primary endpoint) was a combination of three events: all-cause mortality,

hospitalization for heart failure, and VT/VF event requiring therapy (Table D-5

on page D-13). A committee consisting of three heart failure specialists and

an electrophysiologist reviewed and adjudicated all patient deaths and all

hospitalizations, deﬁned as an admission greater than 23 hours. Outpatient

care, emergency room care, and clinic visits less than 23 hours were collected

but not considered to be hospitalizations for the purposes of analysis.

Table D-5. Heart Failure Progression (Composite Index)

CRT No CRT

GroupaHeart Failure Mortality

or Morbidity Event N%N%

Relative Reduction

with CRT

All Patients

(N = 490)

Death from any cause 114.5166.5 15% p = 0.35

HF hospitalization 32 13.1 39 15.9

VT/VF 36 14.7 39 15.9

NYHA Class III/IV

(N = 227)

Death from any cause 11 9.4 11 10.0 22% p = 0.23

HF hospitalization 23 19.7 27 24.5

VT/VF 21 17.9 22 20.0

a. All patients implanted and active 31 days post-implant.

Twenty-seven patients died during the therapy phase. Mortality stratiﬁed by

treatment group and cause, as adjudicated by the Events Committee, is shown

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inTable D-6 on page D-14. The Kaplan-Meier curve, showing total survival by

treatment group, is shown in Figure D-2 on page D-14.

TableD-6. Mortalitystratiﬁed by treatment group and cause

DeathsaPatients with CRT

(N = 245)

Patients with No CRT

(N = 245)

Cardiac, pump failure 4 (1.6%) 9 (3.7%)

Cardiac, arrhythmic 1 (0.4%) 0 (0.0%)

Cardiac, other 2 (0.8%) 1 (0.4%)

Noncardiac 2 (0.8%) 3 (1.2%)

Unknown 2 (0.8%) 3 (1.2%)

Tota l 11 (4.5%) 16 (6.5%)

a. All patients implanted and active at 31 days post-implant; N = 490.

630

100

Total Survival (%)

Time Post-randomization (Months)

No CRT

CRT

245

242

241

239

233

127

130

125

129

123

126

122

125

p = 0.32

CRT

No CRT

Patients at Risk

Figure D-2. Kaplan-Meier curve

Table D-7 on page D-15 presents the reasons for hospitalization within the

treatment period as determined by the Events Committee. This table represents

the number of patients with each category of hospitalization. Patients may have

multiple hospitalizations that fall into different categories.

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Table D-7. Patients hospitalized during treatment period

All Patients NYHA Class III/IV

Reason for Hospitalizationa

CRT

(N = 245)

No CRT

(N = 245)

Total

(N = 490)

CRT

(N = 117)

No CRT

(N = 110)

Total

(N = 227)

Heart failure 32 39 71 23 27 50

Cardiac, other 20 25 45 14 14 28

Noncardiac 26 19 45 14 14 28

Total Hospitalizations 66 70 136 40 46 86

a. All patients implanted and active at 31 days post-implant; N = 490.

Peak VO2––the Peak VO2was determined from a standardized protocol for

exercise testing as a means of measuring a patient’s capacity for performing

physical activity. Figure D-3 on page D-15 and Table D-8 on page D-15 provide

the change in Peak VO2.

Time (months)

Peak VO2 (ml/kg/min)

All Patients

∆ = 0.8 ± 0.4

p = 0.030

Mean ± SE

CRT (n = 216)

No CRT (n = 201)

Time (months)

NYHA Class III/IV

∆ = 1.8 ± 0.6

p = 0.003

CRT (n = 96)

No CRT (n = 80)

Figure D-3. Change in Peak VO2

Table D-8. Change in Peak VO2

All Patients NYHA Class III/IV

Peak VO2

(ml/kg/min) CRT

(N = 216)

No CRT

(N = 201)

P-valueaCRT

(N = 96)

No CRT

(N = 80)

P-valuea

Post-recovery Visit 13.5 ± 0.2 13.5 ± 0.2 –– 12.0 ± 0.3 12.0 ± 0.3 ––

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Table D-8. Change in Peak VO2 (continued)

All Patients NYHA Class III/IV

Peak VO2

(ml/kg/min) CRT

(N = 216)

No CRT

(N = 201)

P-valueaCRT

(N = 96)

No CRT

(N = 80)

P-valuea

3 Months 14.3 ± 0.2 13.9 ± 0.2 0.206 12.8 ± 0.4 12.1 ± 0.4 0.084

6 Months 14.4 ± 0.3 13.6 ± 0.3 0.030 13.8 ± 0.5 12.0 ± 0.5 0.003

a. P-values reﬂect the between-group differences with respect to baseline.

Six-Minute Walk––the Six-Minute Walk test is a measure of a patient’s ability

to sustain exercise during an activity similar to that which a patient may typically

perform on a daily basis. For this test, patients are instructed to walk as far

as possible in 6 minutes in a level corridor. Figure D-4 on page D-16 and

Table D-9 on page D-16 provide the change in Six-Minute Walk.

375

325

275

350

250

Time (months)

Six Minute Walk Distance (m)

All Patients

∆ = 21 ± 10

p = 0.043

Mean ± SE

CRT (n = 224)

No CRT (n = 220)

Time (months)

NYHA Class III/IV

∆ = 39 ± 18

p = 0.029

CRT (n = 99)

No CRT (n = 90)

300

Figure D-4. Change in Six-Minute Walk

Table D-9. Change in Six-Minute Walk

All Patients NYHA Class III/IV

SixMinuteWalkDistance(meters)

CRT

(N = 224)

No CRT

(N = 200)

P-valueaCRT

(N = 99)

No CRT

(N = 90)

P-valuea

Post-recovery Visit 317 ± 5 317 ± 5 –– 268 ± 9 268 ± 9 ––

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Table D-9. Change in Six-Minute Walk (continued)

All Patients NYHA Class III/IV

SixMinuteWalkDistance(meters)

CRT

(N = 224)

No CRT

(N = 200)

P-valueaCRT

(N = 99)

No CRT

(N = 90)

P-valuea

3 Months 348 ± 7 331 ± 8 0.058 312 ± 12 280 ± 12 0.028

6 Months 353 ± 8 332 ± 8 0.043 327 ± 14 288 ± 15 0.029

a. P-values reﬂect the between-group differences with respect to baseline.

Quality of Life (QOL)––QOL was assessed using the 21-question Minnesota

Living with Heart Failure Questionnaire®. Each question is answered by the

patient, ranking each item on a scale ranging from 0 to 5. A lower total score

indicates an improved quality of life. Figure D-5 on page D-17 and Table D-10

on page D-17 provide the change in QOL.

Time (months)

QOL Score (points)

All Patients

∆ = -2.1 ± 2.4

p = 0.40

Mean ± SE

CRT (n = 234)

No CRT (n = 225)

Time (months)

NYHA Class III/IV

∆ = -10.1 ± 4.2

p = 0.017

CRT (n = 107)

No CRT (n = 96)

Figure D-5. Change in Quality of Life

Table D-10. Change in Quality of Life

All Patients NYHA Class III/IV

QOL (points)

CRT

(N = 234)

No CRT

(N = 225)

P-valueaCRT

(N = 107)

No CRT

(N = 96)

P-valuea

Post-recovery Visit 41.8 ± 1.1 41.8 ± 1.1 –– 52.7 ± 1.5 52.7 ± 1.5 ––

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Table D-10. Change in Quality of Life (continued)

All Patients NYHA Class III/IV

QOL (points)

CRT

(N = 234)

No CRT

(N = 225)

P-valueaCRT

(N = 107)

No CRT

(N = 96)

P-valuea

3 Months 36.6 ± 1.5 37.3 ± 1.6 0.711 41.9 ± 2.4 47.5 ± 2.6 0.078

6 Months 34.8 ± 1.8 36.9 ± 1.8 0.395 37.2 ±- 3.1 47.3 ± 3.2 0.017

a. P-values reﬂect the between-group differences with respect to baseline.

NYHA Class––the determination of New York Heart Association (NYHA) Class

is based on mutual assessment by the patient and the patient’s physician of

the patient’s heart failure symptoms both at rest and while performing ordinary

physical activity. NYHA Class was determined at each follow-up visit by a

physician who was blinded to the patient’s randomized therapy. Figure D-6 on

pageD-18andTableD-11onpageD-18providethechangeinNYHAClass

results.

Change in NYHA Class (%)

CRT

(n = 109)

No CRT

(n = 116)

CRT

(n = 45)

No CRT

(n = 48)

Improve ≥ 2 Classes

Worsen ≥ 1 Class

Improve = 1 Class

No change

All Patients

(NYHA Class II / III / IV)

p = 0.10

NYHA Class III / IV

p = 0.006

Figure D-6. Change in NYHA Class

Table D-11. Change in NYHA Class

All Patients NYHA Class III/IV

CRT

(N = 109)

No CRT

(N = 116)

CRT

(N = 45)

No CRT

(N = 48)

Change in NYHA Class

N%N%

P-valuea

N%N%

P-valuea

Improve 2 or More Classes 12 11.0 2 1.7 0.10 12 26.7 2 4.2 0.006

Improve1Class 27 24.8 35 30.2 21 46.7 24 50.0

No Change 56 51.4 59 50.9 10 22.2 18 37.5

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Table D-11. Change in NYHA Class (continued)

All Patients NYHA Class III/IV

CRT

(N = 109)

No CRT

(N = 116)

CRT

(N = 45)

No CRT

(N = 48)

Change in NYHA Class

N%N%

P-valuea

N%N%

P-valuea

Worsen 1 Class 13 11.9 19 16.4 2 4.4 4 8.3

Worsen2orMoreClasses 10.910.9 00.000.0

a. P-value was calculated from Mantel-Haenszel test and reﬂects the between-group differences with respect to baseline.

Echocardiography––several echocardiography (echo) variables were

identiﬁed to assist in measuring the possible hemodynamic impact of CRT

(Table D-12 on page D-19). The limitation of this data is that patients

are measured while at rest, and therefore, the data may not reﬂect any

hemodynamic beneﬁt that may be observed when patients are exercising and

performing their daily activities.

Table D-12. Echocardiography results

CRT No CRT Between Groups

Parameter Timepoint

NMean ± SE NMean ± SE Mean ± SE P-value

All Patients

LVIDd (mm) Post-recovery

Visit

228 70.4 ± 0.5 219 70.4 ± 0.5 0 ––

Change at 6

Months

228 -3.4 ± 0.6 219 -0.3 ± 0.6 -3.1 ± 0.9 < 0.001

LVIDs (mm) Post-recovery

Visit

228 58.3 ± 0.5 219 58.3 ± 0.5 0 ––

Change at 6

Months

228 -4.0 ± 0.7 219 -0.7 ± 0.7 -3.3 ± 0.9 < 0.001

LVEF (%) Post-recovery

Visit

222 27.8 ± 0.3 216 27.8 ± 0.3 0 ––

Change at 6

Month

222 5.1 ± 0.7 216 2.8 ± 0.7 2.4 ± 1.0 0.020

NYHA Class III/IV

LVIDd (mm) Post-recovery

Visit

104 71.2 ± 0.7 92 71.2 ± 0.7 0 ––

Change at 6

Months

104 -4.9 ± 1.0 92 -0.2 ± 1.1 -4.7 ± 1.5 0.001

LVIDs (mm) Post-recovery

Visit

104 59.2 ± 0.7 92 59.2 ± 0.7 0 ––

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Table D-12. Echocardiography results (continued)

CRT No CRT Between Groups

Parameter Timepoint

NMean ± SE NMean ± SE Mean ± SE P-value

Change at 6

Months

104 -5.4 ± 1.1 92 -0.6 ± 1.1 -4.8 ± 1.5 0.002

LVEF (%) Post-recovery

Visit

99 26.9 ± 0.5 91 26.9 ± 0.5 0 ––

Change at 6

Months

99 6.0 ± 1.1 91 2.3 ± 1.2 3.7 ± 1.7 0.029

Measures of Sympathetic Tone––Mean Norepinephrine levels (Table D-13 on

page D-20) and Mean Heart Rate (Table D-14 on page D-20) were examined as

markers of how CRT may inﬂuence the excessive sympathetic drive associated

with chronic heart failure.

Table D-13. Mean Norepinephrine results

All Patients NYHA Class III/IV

Norepinephrine (pg/mL)

CRT

(N =

228)

No CRT

(N =

217)

P-value CRT

(N =

104)

No CRT

(N = 90)

P-value

Post-recovery Visit 663 ± 19 663 ± 19 –– 720 ± 31 720 ± 31 ––

3 Months 651 ± 31 681 ± 32 0.479 685 ± 55 743 ± 60 0.463

6 Months 658 ± 40 738 ± 41 0.143 681 ± 75 827 ± 79 0.163

Table D-14. Mean heart rate results

All Patients NYHA Class III/IV

Heart Rate (bpm)

CRT

(N = 240)

No CRT

(N = 233)

P-value CRT

(N = 113)

No CRT

(N = 101)

P-value

Post-recovery Visit 72.3 ± 0.6 72.3 ± 0.6 –– 74.5 ± 1.0 74.5 ± 1.0 ––

3 Months 70.8 ± 0.8 72.1 ± 0.8 0.20 74.1 ± 1.2 73.9 ± 1.3 0.94

6 Months 69.4 ± 1.0 70.2 ± 1.0 0.58 70.6 ± 1.6 72.5 ± 1.6 0.40

EASYTRAK Lead and System Effectiveness

It was hypothesized that the upper tolerance limit of the chronic left ventricular

pacing threshold of the EASYTRAK lead be less than 5.5 V to ensure that

an adequate safety margin exists. Chronic left ventricular pacing thresholds

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shown in Figure D-7 on page D-21 and Table D-15 on page D-21 are well

within this limit.

LV Pacing Threshold (V at 0.5 ms)

02418126

Acceptance Boundary

90% Tolerance Interval

Implant Duration (months)

Figure D-7. EASYTRAK lead threshold measurements

Table D-15. EASYTRAK lead threshold measurements

StatisticaImplant 3 Months 6 Months 12 Months 18 Months 24 Months

N 435 347 330 233 103 25

Mean ± SD 1.8 ± 1.2 1.7 ± 1.3 1.9 ± 1.5 1.8 ± 1.2 1.8 ± 1.1 2.0 ± 1.2

Range 0.2 - 7.5 0.2 - 7.5 0.2 - 7.5 0.4 - 7.5 0.6 - 7.5 0.6 - 5.0

Upper Tolerance Limit 3.8 3.8 4.3 3.8 3.7 3.9

a. EASYTRAK lead models: 4511, 4512, and 4513

Mean chronic biventricular R-wave amplitudes are measured as a combination

of the R-waves from both the right ventricle (commercially available ENDOTAK

lead) and left ventricle (EASYTRAK lead). It was hypothesized that the mean

biventricularR-waveamplitudebegreaterthan5mVtoensurepropersensing.

InFigureD-8onpageD-22andTableD-16onpageD-22,theperformanceof

the EASYTRAK lead system was signiﬁcantly above this value (p < 0.01).

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BiV R-wave Amplitude (mV)

02418126

Acceptance Boundary

Implant Duration (months)

Mean

Figure D-8. EASYTRAK biventricular-sensed R-wave amplitude

Table D-16. EASYTRAK biventricular-sensed R-wave amplitude

StatisticaImplant 3 Months 6 Months 12 Months 18 Months 24 Months

N 433 346 326 220 99 23

Mean ± SD 10.0 ± 5.2 9.9 ± 4.4 9.9 ± 4.5 9.8 ± 4.4 8.9 ± 3.5 8.5 ± 3.3

Upper Tolerance Limit 1.9 - 25.0 1.4 - 25.0 1.7 - 25.0 1.2 - 25.0 2.6 - 20.4 2.2 - 13.6

The impedance measured by the CONTAK CD device is the parallel

combination of the left ventricular (EASYTRAK) and right ventricular

(ENDOTAK) leads simultaneously. Therefore, the biventricular lead impedance

will be substantially less than that of either lead alone. It was hypothesized

that the lower limit of the 95% conﬁdence interval of the mean chronic

biventricular lead impedance would be greater than 200 Ωto ensure proper

pulse generator function. The lower limit of the 95% conﬁdence interval of the

chronic biventricular lead impedance exceeds this value (Figure D-9 on page

D-23, Table D-17 on page D-23).

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300

200

BiV Lead Impedance (Ω)

02418126

Acceptance Boundary

Implant Duration (months)

400

Lower Bound

of 95% CI

Figure D-9. EASYTRAK biventricular pacing impedance

Table D-17. EASYTRAK biventricular pacing impedance

StatisticaImplant 3 Months 6 Months 12 Months 18 Months 24 Months

N 436 355 336 237 107 26

Mean ± SD 340 ± 46 352 ± 47 349 ± 50 351 ± 51 347 ± 46 356 ± 67

Range 243 - 550 248 - 519 186 - 534 237 - 513 254 - 507 267 - 520

95% CI (336, 344) (347, 357) (344, 355) (345, 358) (338, 356) (329, 383)

EASYTRAK Lead Placement Success Rate––the EASYTRAK lead was

implanted in 448/517 (87%) of patients who underwent the implant procedure.

Table D-18 on page D-23 shows the reasons for inability to place the

EASYTRAK lead. Table D-19 on page D-24 provides the EASYTRAK lead

implant success rate.

Table D-18. Reasons for unsuccessful EASYTRAK lead implant

Reason #ofpts

Inability to locate or cannulate the coronary sinus 29 42

Dislodgment of EASYTRAK lead while removing guide catheter 13 18.8

Inability to advance the lead to a stable position 11 15.9

Inability to obtain adequate pacing thresholds 6 8.7

Procedure stopped due to coronary sinus dissection or perforation 57.2

Procedure stopped due to transient AV block 1 1.4

Procedure stopped due to venous perforation during subclavian stick 11.4

Reason not stated 11.4

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Table D-18. Reasons for unsuccessful EASYTRAK lead implant (continued)

Reason #ofpts

Extracardiac stimulation 1 1.4

Inability to place an atrial pace/sense lead 11.4

Tota l 69 100

a. Patients with unsuccessful attempt to implant EASYTRAK lead; N = 69.

Table D-19. EASYTRAK lead placement success rate

Measurement All Proceduresa

Number of patients implanted or attempted 517

Number of placements of the EASYTRAK Leadb448

Rate 87%

95% CI (84%, 90%)

a. All patients implanted or attempted with EASYTRAK lead; N = 517.

b. Deﬁned as an EASYTRAK implant procedure that is concluded with the implant of the investigational cardiac resynchronization

system.

Although some situations such as patient anatomy and poor thresholds cannot

be avoided, increased investigator experience with the EASYTRAK lead and

accessories was associated with improved success, decreased total procedure

time (measured skin-to-skin), and decreased ﬂuoroscopy exposure time

(FigureD-10onpageD-24).

Implant Success Rate (%)

8-15

>15

4-7

1-3

250

Mean Procedure Time (min)

200

150

100

8-15

>15

4-7

1-3

Mean Fluoroscopy Exposure Time (min)

8-15

>15

4-7

1-3

Mean ± SEMean ± SE

Implants (by order of enrollment)

Figure D-10. EASYTRAK success rate, procedure time, and ﬂuoroscopy exposure time

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Biventricular ATP Conversion Effectiveness Performance––the conversion

rate of induced monomorphic ventricular tachycardia (MVT) was 64% and

that of spontaneous MVT was 88%.

Ventricular Tachyarrhythmia Detection Time––the VENTAK CHF and

CONTAK CD devices sense events from both ventricles simultaneously.

Ventricular tachyarrhythmia detection time was analyzed to determine if the

additional lead had an adverse effect on sensing VT/VF. Guidant’s ICDs

typically have a detection time of two seconds. The VF detection time of 2.1

± 0.6 seconds was statistically signiﬁcantly lower than 6 seconds (p < 0.01),

demonstrating that there was no statistically signiﬁcant prolongation of induced

VF detection times with the additional left ventricular lead1.Therewerealso

no adverse events reported in which a VENTAK CHF or CONTAK CD failed to

detect a spontaneous ventricular tachyarrhythmia.

EASYTRAK Lead and System Safety

EASYTRAK Lead Safety––safety was established using the rate of adverse

events that are either related to the EASYTRAK lead or to the implant

procedure necessary to place the EASYTRAK lead.

An EASYTRAK lead implant procedure was performed in 517 patients with 448

patients (86.7%) being successfully implanted with the EASYTRAK lead. The

upper boundary of the 95% conﬁdence interval was hypothesized to be less

than 23% at six months (Table D-20 on page D-25).

Table D-20. Lead-related adverse events at six months

Patient Population N Event Rate (%) 95% CI

All Patients 517 12.2 (9.4, 15.0)

NYHA Class III/IV 201 17.4 (12.7, 22.7)

Fifty-three lead-related adverse events were reported during the clinical

investigation of the EASYTRAK lead among the 448 patients who were

implanted with an EASYTRAK lead. Twenty-seven procedure-related adverse

events were reported among the 517 patients who underwent the implant

procedure for an EASYTRAK lead.2The overall lead-related adverse event

1. Detection time at implant with legally marketed Guidant ICD devices is typically two seconds,

and investigators have stated that an additional delay of 3 to 5 seconds would be a clinically

signiﬁcant event. The expected detection time is 2 seconds (95% CI: [0, 6 sec]).

2. For purposes of deﬁning event rates, a denominator of 448 will be used for those adverse

events that pertain to chronically implanted EASYTRAK leads, and a denominator of 517 will

be used for those adverse events that pertain to the implant procedure of the EASYTRAK lead.

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ratewas14.5%(95%CI[11.5–17.5%]). TableD-21onpageD-26reports

lead-related adverse events observed during the CONTAK CD Study.

Table D-21. EASYTRAK lead-related adverse events

Adverse EventsaTotal % of pts (95% Cl)

Lead-Related, N = 448

Loss of capture/lead dislodgment 31b6.9 (4.6–9.3)

Ventricular oversensing 11 2.5 (1.0–3.9)

Extracardiac stimulation 9 2.0 (0.7–3.3)

Insulation breach 2 0.4 (0.0–1.1)

Procedure-Related, N = 517

Transient AV block 6 1.2 (0.2–2.1)

Coronary venous dissection 51.0 (0.1–1.8)

Coronary venous perforation 51.0 (0.1–1.8)

Transient renal failure 51.0 (0.1–1.8)

Pericardial effusion 20.4 (0.0–0.9)

Finishing wire left in lead 10.2 (0.0–0.6)

Right ventricular lead dislodgment 1 0.2 (0.0–0.6)

Guide wire fracture 10.2 (0.0–0.6)

Hypotension due to blood loss 1 0.2 (0.0–0.6)

Total (unique patients) 75 14.5 (11.5–17.5)

a. All patients implanted, N = 448; All patients attempted, N = 517.

b. Twenty-six events were successfully corrected in a repeat procedure.

The most common of the 53 lead-related adverse events (>1% incidence)

included the following:

• Loss of left ventricular capture (31 patients, 6.9%)

• Ventricular oversensing (11 patients, 2.5%)

• Extracardiac stimulation (9 patients, 2.0%)

These events were typically resolved with surgical intervention.

The most common of the 27 procedure-related adverse events (> 1%

incidence) included the following:

• Coronary venous trauma (10 patients, 2.0%)

• Transient atrioventricular block (6 patients, 1.2%)

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• Transient renal failure (5 patients, 1.0%)

These events were typically resolved without intervention and no permanent

long-term sequelae were reported.

Severe, Device-Related Adverse Events and Operative Mortality––the

incidence of severe, device-related events was reported in 7 of 567 patients

(1.2%); this was signiﬁcantly less than the hypothesized rate of 20% (p <

0.01) (Table D-22 on page D-27). Table D-23 on page D-27 reports system,

device-related, severe adverse events observed during the CONTAK CD Study.

Table D-22. Adverse events and operative mortality

MeasurementaN%95%CI

Severe, Device-Related Adverse Events (Type I)b71.2 (0.3, 2.1)

All-Cause Operative Mortality (< = 30 Days Post Implant) 12 2.1 (0.9, 3.3)

a. All patients attempted or implanted, N = 567

b. Percent is of patients with at least one event.

Table D-23. System, device-related, severe adverse events

Adverse Eventa# of pts % of pts (95% CI)

Te l em e t ry d if ﬁculty; device explanted 20.4 (0.0–0.9)

Ventricular tachycardia during CPX testing 10.2 (0.0–0.5)

Coronary sinus perforation 10.2 (0.0–0.5)

Inappropriate shock due to oversensing 1 0.2 (0.0–0.5)

Lead dislodgment 1 0.2 (0.0–0.5)

Anaphylaxis in association with use of a pulmonary artery

catheter

10.2 (0.0–0.5)

a. All patients attempted or implanted, N = 567

Operative mortality, deﬁnedasdeathfromanycausewithin30daysofimplant,

was reported in 12 of 567 patients (2.1%) undergoing the implant procedure.

The outcome is signiﬁcantly less than the hypothesized rate of 9% (p < 0.01).

Table D-24 on page D-28 reports the cause of death for operative mortality.

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Table D-24. Cause of death for operative mortality

Cause of Death Implants

N=501

Attempts

N=66

Totala

N=567

Cardiac: pump failure 516

Cardiac: arrhythmic 213

Noncardiac 2 0 2

Unknown 1 0 1

Tota l 10 2 12

a. All patients attempted or implanted, N = 567.

System Safety Proﬁle––analysis of system safety was performed on the

complication-free rate of device-related adverse events, regardless of whether

or not they were related to the investigational device (Figure D-11 on page

D-29). Table D-25 on page D-28 outlines the device related complications. This

study used an acceptance criterion such that the lower boundary of the 95%

conﬁdence interval could not be less than 70%.

Table D-25. Device-related complications

Complicationa#ofpts %ofpts

All patients implanted (N = 448)

Loss of LV capture 31 6.9

Loss of right atrial capture 71.6

Ventricular oversensing 6 1.3

Extracardiac stimulation 51.1

All patients attempted or implanted (N = 517)

Infections 71.4

a. This table represents patients attempted or implanted with the EASYTRAK lead; most common (> 1%) device-related

complications reported.

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Complication-free Rate (%)

Acceptance Boundary

All Patients

(NYHA Class II / III / IV) NYHA Class III / IV

Figure D-11. System safety

Veriﬁcation of CRT Delivery

The delivery of biventricular pacing throughout the CONTAK CD Study was

conﬁrmed by comparing the programmed device output to the biventricular

pacing threshold and demonstrating that capture was maintained in daily

activities and during exercise.

The investigational plan recommended programming the device output to at

least twice the biventricular pacing voltage threshold. Electrocardiograms

(ECGs) from Holter Monitors during daily activities were received and analyzed

to verify that total capture was maintained at the 3-month and 6-month visits

and to ensure that the safety margin was adequate. Cardiopulmonary exercise

tests (CPX) were performed on patients who were randomized to receive CRT

therapy at 3- and 6- month visits.

• In 623 evaluations of safety margin at baseline, three-, and six-months, the

device output was programmed to deliver a voltage approximately three

times that necessary to stimulate both ventricles.

• A total of 1139 Holter monitors were placed throughout the study at

baseline, three-, and six-months. The tests indicated only 4 instances

(0.4%) of inappropriate pacing or sensing that were all corrected with

device programming.

• A total of 316 CPX tests at the three- and six-month follow-up visits were

performed in patients with CRT who also had interpretable ECG results. Of

these, 277 (88%) had continuous CRT delivery throughout exercise. The

remaining 39 patients (12%) had continuous CRT delivery until the sinus

rate exceeded the maximum tracking rate (MTR).

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D-30 CLINICAL STUDY - CONTAK CD

FOCUSED CONFIRMATORY STUDY

Study Design

The Focused Conﬁrmatory Study (FCS) was a prospective, multicenter study

conducted in the United States in 127 patients who participated in an exercise

performance study. The purpose of the FCS was to conﬁrm effectiveness

results related to functional capacity measures, speciﬁcally the Peak VO2and

6-Minute Hall Walk, previously reported in the NYHA Class III/IV subgroup of

the CONTAK CD Study.

CRT was provided in the same manner for the FCS as for the CONTAK CD

Study. The EASYTRAK lead, along with market approved right atrial and right

ventricular leads were used to provide biventricular stimulation.

Demographic Data

The patients in the FCS had the same heart failure indications as the patients

in the NYHA Class III/IV subgroup of the CONTAK CD Study; i.e., patient

inclusion criteria included NYHA Class III or IV while on drug therapy, QRS

duration ≥120 ms, and Left Ventricular Ejection Fraction (LVEF) ≤35%.

A baseline physical assessment and functional measures were performed prior

to CRT system implant. Patients were eligible for participation in the study if

they were capable of walking between 150 and 425 meters. In addition to

a Six-Minute Walk test, other special tests were performed prior to implant

consisting of a symptom-limited treadmill test and completion of the Minnesota

Living with Heart Failure Questionnaire®to assess Quality of Life. CRT therapy

was enabled immediately upon device implant. Patients were followed at one

week, one month, three months, six months and every three months thereafter

for a routine physical assessment and device evaluation. Special testing as

deﬁned above was repeated at three months and six months post-implant.

Prior to study entry, patients were stable on optimal heart failure medications

(ACE inhibitors or substitute > 1 month and beta blockers > 3 months). Patients

were excluded if they were indicated for either a pacemaker or ICD or if they

were hospitalized for heart failure in the month prior to enrollment.

The patient characteristics at study entry are summarized in Table D-26 on

page D-31.

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CLINICAL STUDY - CONTAK CD D-31

Table D-26. Pre-implant characteristics of study patients

Characteristics All Patients Receiving CRT

Age (years) 61 ± 12

Male Gender (%) 69

NYHA Class III (%) 94

Ischemic Etiology (%) 49

Resting heart rate (bpm) 73 ± 12

QRS width (ms) 159 ± 27

LBBB/NSIVCD (%) 91

Heart failure medications (%)

ACE inhibitor or ARB 91

Beta blockers 77

Digoxin 76

Diuretics 98

Inclusion Criteria

Inclusion criteria included:

• Moderate or severe heart failure, deﬁned as symptomatic heart failure

for at least six months with NYHA Class III or IV symptoms at the time

of enrollment, AND at least one of the following events in the previous

12 months:

– Hospitalization for heart failure management

– Outpatient visit in which intravenous (IV) inotropes or vasoactive

infusion were administered continuously for at least 4 hours

– Emergency room visit of at least twelve hours duration in which IV

heart failure medications were administered (including diuretics)

•QRS≥120 ms and PR interval > 150 ms from any two leads of a 12-lead

ECG

• Left ventricular ejection fraction ≤35%

• Left ventricular end diastolic dimension ≥60 mm (required only if LVEF

measured by echo)

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D-32 CLINICAL STUDY - CONTAK CD

•Age≥18 years

• Optimal pharmacologic therapy for heart failure

• Abletowalkbetween150and425minaSix-MinuteWalktest

Major Differences Between CONTAK CD and Focused Conﬁrmatory

Study Patients

The CONTAK RENEWAL 3, CONTAK RENEWAL, and CONTAK CD devices

provide the same cardiac resynchronization therapy (biventricular pacing) and

have the same Indications for Use. Therefore, the CONTAK CD clinical trial

data used to support CONTAK CD is also applicable to CONTAK RENEWAL

and CONTAK RENEWAL 3. The primary difference between CONTAK CD

devices and CONTAK RENEWAL and CONTAK RENEWAL 3 devices is that

CONTAK CD utilizes an electrically common RV and LV sensing/pacing circuit

whereas CONTAK RENEWAL and CONTAK RENEWAL 3 incorporate an

independent RV and LV sensing/pacing circuit. Additional clinical analysis

was also conducted with CONTAK RENEWAL to provide conﬁrmation that the

independent sensing and pacing capability did not adversely affect the ability

of the device to detect ventricular tachyarrhythmias or provide continuous

biventricular pacing therapy.

Some of the major differences between the study populations included:

• Patients were excluded from the FCS if they were indicated for either

a pacemaker or implantable cardioverter deﬁbrillator (ICD). Patients in

the CONTAK CD Study were excluded if they met the indications for a

pacemaker; however, they were required to meet the general indications

for an ICD.

• Patients were excluded from the FCS if they were hospitalized for heart

failure in the month prior to enrollment; whereas, there was no exclusion

for hospitalization for heart failure in the month prior to enrollment for the

CONTAK CD patients.

• Patients in the FCS must have been on stable, optimal heart failure

medications, including beta blocker therapy for three months, prior to study

entry. Patients in the CONTAK CD Study could be optimized on drug

therapy between the time from device implant until the treatment phase

(either CRT or No CRT) began.

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CLINICAL STUDY - CONTAK CD D-33

• Patients in the FCS had baseline measurements performed prior to implant.

Patients in the CONTAK CD Study had baseline measurements performed

post-implant, but before programming of the randomized therapy.

• Seventy-seven percent of patients in the FCS (98 of N = 127) were on beta

blockers compared to 42% in the CONTAK CD Study (95 of N = 227).

• Forty-nine percent of patients in the FCS (62 of N = 127) had ischemic

etiology compared to 68% in the CONTAK CD Study (154 of N = 227).

Endpoints

The primary endpoints of the study were Peak VO2and Six-Minute Walk

distance. The study was designed to show a mean change of at least

1ml/kg/min and a 95% lower conﬁdence bound (LCB) at least 0.5 ml/kg/min.

The study was also designed to detect a statistically signiﬁcant improvement

in the Six-Minute Walk distance at a one-sided signiﬁcance level of 0.10.

Additionally, two ancillary analyses of Quality of Life Score and NYHA Class

had to demonstrate a change that was directionally favorable towards CRT

using descriptive statistics.

Study Results

Study results for the Focused Conﬁrmatory Study include the following:

•PeakVO

2––a statistically signiﬁcant improvement from baseline of 0.94 ±

0.30 ml/kg/min with a 95% LCB of 0.45 was observed in Peak VO2after six

months of CRT

• Six-Minute Walk––statistically signiﬁcant improvements versus baseline

were observed in Six-Minute Walk distance after six months of CRT with an

observed mean improvement of 50.9 ± 10.4 m with a 95% LCB of 37.6 m

• Quality of Life––consistent with the other analyses, a statistically signiﬁcant

improvement of 23.9 ± 2.6 points was observed in the Quality of Life score

after six months of CRT with a 95% LCB of 19.7 points

• New York Heart Association Class––after six months of CRT, a statistically

signiﬁcant improvement in NYHA Class was observed with 60.4% of

patients improving one or more NYHA Class

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D-34 CLINICAL STUDY - CONTAK CD

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E-1

CLINICAL STUDY - CONTAK RENEWAL

APPENDIX E