CONTAK CD,EASYTRAK, LIVIAN, COGNIS AND ACUITY SPIRIAL AUTOMATIC IMPLANTABLE CARDIAC RESYNCHRONIZATION THERAPY DEFIBRILLL

P010012 · Boston Scientific Corp · NIK · May 2, 2002 · Cardiovascular

Device Facts

• Record ID: P010012
• Device Name: CONTAK CD,EASYTRAK, LIVIAN, COGNIS AND ACUITY SPIRIAL AUTOMATIC IMPLANTABLE CARDIAC RESYNCHRONIZATION THERAPY DEFIBRILLL
• Applicant: Boston Scientific Corp
• Product Code: NIK · Cardiovascular
• Decision Date: May 2, 2002
• Decision: APPR
• Device Class: Class 3
• Attributes: Therapeutic, Expedited Review

Intended Use

The CONTAK CD CRT-D System is indicated for use in the following: Patients who are at high risk of sudden cardiac death due to ventricular arrhythmias and who have moderate to severe heart failure [New York Heart Association (NYHA) Class III/IV] including left ventricular dysfunction (ejection fraction (EF) ≤ 35%) and QRS duration ≥120 ms and remain symptomatic despite stable, optimal heart failure drug therapy. Patient populations at high risk of sudden cardiac death due to ventricular arrhythmias include, but are not limited to, those with: - Survival of at least one episode of cardiac arrest (manifested by the loss of consciousness) due to a ventricular tachyarrhythmia. - Recurrent, poorly tolerated sustained ventricular tachycardia (VT). NOTE: The clinical outcome of hemodynamically stable, sustained-VT patients is not fully known. Safety and effectiveness studies have not been conducted. - Prior myocardial infarction, left ventricular ejection fraction of ≤35%, and a documented episode of nonsustained VT, with an inducible ventricular tachyarrhythmia. Patients suppressible with IV procainamide or an equivalent antiarrhythmic (drug) have not been studied. The Guidant EASYTRAK coronary venous, steroid-eluting, single-electrode pace/sense leads, Models 4510/4511/4512/4513, are transvenous leads intended for chronic left ventricular pacing and sensing via the coronary veins when used in conjunction with a compatible Guidant cardiac resynchronization therapy (CRT) device that accepts the LV-1 connector.

Device Story

The CONTAK CD CRT-D system is an implantable cardioverter-defibrillator (ICD) with cardiac resynchronization therapy (CRT) capabilities. It uses an atrial lead, a right ventricular lead, and an EASYTRAK coronary venous lead to provide biventricular pacing and defibrillation. The pulse generator (Model 1823) monitors cardiac signals; it uses accelerometer-based adaptive-rate bradycardia pacing and antitachycardia pacing (ATP) to treat arrhythmias. If VT/VF is detected, it delivers biphasic or monophasic shocks. The system is programmed externally via the ZOOM Programming System (Model 2920 PRM with Version 3.1 software). Physicians use the programmer to interrogate the device, adjust therapy parameters, and review diagnostic history. The EASYTRAK lead is placed transvenously through the coronary sinus into a cardiac vein to provide chronic left ventricular pacing and sensing. The system synchronizes ventricular contractions to improve cardiac function in heart failure patients, while simultaneously providing life-saving defibrillation therapy for sudden cardiac death prevention.

Clinical Evidence

Evidence includes a prospective, randomized, multicenter, double-blind study (CONTAK CD Study, N=581) and a Focused Confirmatory Study (N=127). Primary endpoints for the CONTAK CD Study (composite of mortality, HF hospitalization, VT/VF) failed to show statistical significance for the overall population. However, subgroup analysis of NYHA Class III/IV patients showed functional improvements. The Focused Confirmatory Study confirmed effectiveness in this subgroup, showing significant improvements in Peak VO2 (0.94 ml/kg/min), Six-Minute Walk distance (50.9 m), and Quality of Life scores (23.9 points) at 6 months. Safety endpoints (lead-related adverse events, operative mortality) met performance criteria.

Technological Characteristics

Pulse generator: Titanium housing, silicone rubber/polyurethane components. EASYTRAK lead: Silicone rubber, polyurethane, PTFE, platinum electrode, dexamethasone acetate drug collar. Sensing/Pacing: Biventricular pacing via coronary venous lead (LV-1 connector) and right ventricular lead. Energy: Biphasic/monophasic shocks. Connectivity: Telemetry via external programmer. Software: Firmware identical to VENTAK AV III DR. Sterilization: Ethylene oxide (EtO). Standards: ANSI/AAMI PC69:2000, ISO 5841-3, ISO 11318, ISO 10993.

Indications for Use

Indicated for patients ≥18 years with moderate to severe heart failure (NYHA Class III/IV), LVEF ≤35%, and QRS duration ≥120 ms who remain symptomatic despite optimal drug therapy and are at high risk of sudden cardiac death due to ventricular arrhythmias (e.g., history of cardiac arrest, recurrent sustained VT, or prior MI with nonsustained VT). Contraindicated in patients with reversible or transient causes of ventricular tachyarrhythmias.

Regulatory Classification

Identification

These devices will be indicated for patients needing an ICD who also have moderate to severe heart failure and are indicated for cardiac resynchronization therapy.

Predicate Devices

• VENTAK AV III DR (PMA P960040)
• ENDOTAK (PMA P910073)

Reference Devices

• VENTAK CHF AICD (Model 1822)

Submission Summary (Full Text)

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# Summary of Safety and Effectiveness

## Original PMA P010012

CONTAK CD® CRT-D System

and

EASYTRAK® Coronary Venous Steroid-Eluting Single-Electrode

Pace/Sense Lead, Models 4510, 4511, 4512, 4513

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Summary of Safety and Effectiveness

# Summary of Safety and Effectiveness

## 1 GENERAL INFORMATION

Device Generic Name: Cardiac Resynchronization Therapy Defibrillator (CRT-D) System

Device Trade Name: Guidant CONTAK CD® CRT-D system including the:
- CONTAK CD CRT-D pulse generator Model 1823
- Software Application Model 2848 (Version 3.1)

EASYTRAK® Coronary Venous Steroid-Eluting Single Electrode
Pace/Sense Lead, Models 4510, 4511, 4512, 4513

System accessories:
- Finishing Wire, Models 6730, 6731, 6732, 6733
- Suture Sleeve, Model 6741
- LV®-1 Lead Cap, Model 6742
- LV®-1 Lead Port Plug, Model 6743
- Lead Adapter, Model 6744

Applicant's Name and Address: GUIDANT Corporation, Cardiac Rhythm Management
4100 Hamline Avenue North
St. Paul, Minnesota 55112-5798

PMA Number: P010012

Preapproval Inspection: April 29, 2002

Date of Panel Recommendations: July 10, 2001

Date of Notice of Approval to Applicant: May 02, 2002

## 2 INDICATIONS FOR USE

### 2.1 CONTAK CD CRT-D SYSTEM

The CONTAK CD CRT-D System is indicated for use in the following:

Patients who are at high risk of sudden cardiac death due to ventricular arrhythmias and who have moderate to severe heart failure [New York Heart

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Summary of Safety and Effectiveness
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Association (NYHA) Class III/IV] including left ventricular dysfunction (ejection fraction (EF) ≤ 35%) and QRS duration ≥120 ms and remain symptomatic despite stable, optimal heart failure drug therapy.

Patient populations at high risk of sudden cardiac death due to ventricular arrhythmias include, but are not limited to, those with:

- Survival of at least one episode of cardiac arrest (manifested by the loss of consciousness) due to a ventricular tachyarrhythmia.
- Recurrent, poorly tolerated sustained ventricular tachycardia (VT).

NOTE: The clinical outcome of hemodynamically stable, sustained-VT patients is not fully known. Safety and effectiveness studies have not been conducted.

- Prior myocardial infarction, left ventricular ejection fraction of ≤35%, and a documented episode of nonsustained VT, with an inducible ventricular tachyarrhythmia. Patients suppressible with IV procainamide or an equivalent antiarrhythmic (drug) have not been studied.

## 2.2 EASYTRAK LEAD

The Guidant EASYTRAK coronary venous, steroid-eluting, single-electrode pace/sense leads, Models 4510/4511/4512/4513, are transvenous leads intended for chronic left ventricular pacing and sensing via the coronary veins when used in conjunction with a compatible Guidant cardiac resynchronization therapy (CRT) device that accepts the LV-1 connector.

## 3 SYSTEM DESCRIPTION

## 3.1 CONTAK CD CRT-D PULSE GENERATOR

The Guidant CONTAK CD CRT-D pulse generator, Model 1823, provides ventricular tachyarrhythmia and cardiac resynchronization therapies. Ventricular tachyarrhythmia therapy is for the treatment of VT and ventricular fibrillation (VF), rhythms that are associated with sudden cardiac death (SCD). Cardiac resynchronization therapy uses simultaneous biventricular electrical stimulation to synchronize ventricular contractions. The device uses accelerometer-based adaptive-rate bradycardia therapy similar to Guidant's commercially available VENTAK® family of implantable cardioverter defibrillators (ICDs). The pulse generator, an atrial lead, and two ventricular leads connected in parallel configuration constitute the implantable portion of the CRT-D

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system. The pulse generator accepts one atrial lead (IS-1 connector type), one coronary venous lead (LV-1 connector type) (EASYTRAK®), and one cardioversion/ defibrillation lead (DF-1/IS-1 connector type).

Cardioversion/defibrillation therapies include a range of low- and high-energy shocks using either a biphasic or monophasic waveform. The CONTAK CD CRT-D pulse generator uses the Guidant TRIAD® electrode system for defibrillation energy delivery. By using the metallic housing of the pulse generator as an active electrode, combined with the Guidant ENDOTAK (approved in P910073) two-electrode defibrillation lead, energy is sent via a dual-current pathway from the distal shocking electrode to the proximal electrode and to the pulse generator case. The CONTAK CD CRT-D system also offers a variety of antitachycardia pacing (ATP) schemes to terminate slower, more stable ventricular tachyarrhythmias. Bradycardia pacing with resynchronization therapy, including adaptive-rate features, is available to detect and treat bradyarrhythmias and to support the cardiac rhythm after defibrillation therapy.

The ZOOM® Programming System, which includes the Model 2920 Programmer/ Recorder/ Monitor (PRM) (approved in P840068/S039, P910077/S031, P940031/S023, and P960040/S013), the Model 2848 Software Application (Version 3.1), and an accessory telemetry wand, constitutes the external portion of the CONTAK CD CRT-D system. The external components allow interrogation and programming of the pulse generator as well as access to the device's diagnostic features. The CONTAK CD CRT-D system can be programmed to provide a variety of therapy options. It also can provide noninvasive diagnostic testing and therapy history data.

## 3.2 EASYTRAK LEAD

The EASYTRAK coronary venous, steroid-eluting single-electrode pace/sense leads, Models 4510/4511/4512/4513, provide chronic pacing and sensing of the left ventricle. The lead is placed by inserting it through the coronary sinus and into a branch of the cardiac veins. The over-the-wire design has an open inner lumen which allows passage over a guide wire.

The lead features a single pacing electrode. Distal to the electrode is a drug collar with an anti-inflammatory glucocorticosteroid. The distal end of the lead has passive fixation tines, and the tip is constructed of soft silicone rubber.

The electrode is connected by a multifilar conductor coil to the terminal pin on the proximal end of the lead. The LV-1 terminal pin is hollow to allow for insertion of the guide wire and is streamlined to facilitate guide catheter removal. The LV-1 lead port in

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Summary of Safety and Effectiveness
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the header of a compatible heart failure device has sealing rings that electrically insulate the terminal pin. The EASYTRAK lead is constructed of silicone rubber tubing, which electrically insulates the coil. Additionally, an abrasion-resistant polyurethane sleeve over the silicone insulation covers all but the terminal and distal-most portion of the lead body.

The EASYTRAK lead is used in conjunction with the CONTAK CD CRT-D Model 1823 pulse generator, or a compatible Guidant CRT device, that accepts the LV-1 connector.

Implant accessory devices are available for use with the EASYTRAK lead. Implant accessory devices include guiding catheters, guide wires, finishing wires, and balloon catheters that are labeled for use with the EASYTRAK lead.

# 4 CONTRAINDICATIONS

The CONTAK CD CRT-D system is contraindicated for use in the following:

- Patients whose ventricular tachyarrhythmias may have a reversible cause such as 1) digitalis intoxication, 2) electrolyte imbalance, 3) hypoxia, 4) sepsis, or
- Patients whose ventricular tachyarrhythmias may have a transient cause, such as 1) acute myocardial infarction, 2) electrocution, or 3) drowning.

# 5 WARNINGS AND PRECAUTIONS

See device labeling.

# 6 ADVERSE EVENTS

## 6.1 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 EASYTRAK lead. An additional 510 patients initially underwent an implant procedure to receive the Model 1823 CONTAK CD CRT-D pulse generator 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.

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Summary of Safety and Effectiveness

Table 1 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.

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Summary of Safety and Effectiveness

(765 Events in 517 patients implanted or attempted with the EASYTRAK lead, 2559 total device months)

Table 1: Adverse Events Through the Randomization Period

| | # Of Events (# of pts)a | % Complic- ations (Patients) | Complications per 100 Device Months (Events) | % Observations (Patients) | Observatrions 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 countingb | 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 | | | | | |
| 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) |
| Non-conversion of VF | 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) |
| Otherc | 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) |
| Cardiovascular Related Events | | | | | |

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Summary of Safety and Effectiveness
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| | # Of Events (# of pts)^{a} | % Complications (Patients) | Complications per 100 Device Months (Events) | % Observations (Patients) | Observatrions per 100 Device Months (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) |
| Subtotal Cardiovascular Related Events | 358 (200) | 7.7 (40) | 1.6 (42) | 35.6 (184) | 12.2 (316) |
| Total Non-cardiovascular Related Events | 142 (92) | 6.2 (32) | 1.5 (39) | 13.5 (70) | 4.0 (103) |

a. The total number of patients for a given event represents the unique number of patients who experienced that event. The total may not be equal to the sum of patients with complications or observations because some patients experienced more than one event that fell into both categories.

b. Sensing of two ventricular intrinsic events when only one intrinsic event is present due to intraventricular conduction delay.

c. Other procedure related events occurred in three patients or fewer: Guide wire fracture (1), Hemorrhage (3), Finishing wire left in lead (1), Non-conversion of VF (1), Perforation, arterial (1), Perforation, cardiac (1), Perforation, venous (2), Pericardial effusion (3), Pericarditis (1), Physiological reaction (1).

A total of 109 deaths occurred during the study. These deaths occurred during the study periods as shown in Table 2 along with the cause of death as adjudicated by an independent events committee.

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Summary of Safety and Effectiveness

Table 2: Deaths that Occurred During the Study
All patients enrolled, $\mathrm{N} = {581}$

| | | Cause of Death | | | | |
| --- | --- | --- | --- | --- | --- | --- |
| Study Period | # of pt deaths | Cardiac: Pump Failure | Cardiac: Arrhythmic | Cardiac: Other | Non-Cardiac | Unknown |
| After unsuccessful implant procedure | 2 | 1 | 1 | 0 | 0 | 0 |
| Peri-operative (<= 30 days) | 10 | 5 | 2 | 0 | 2 | 1 |
| Randomized therapy phase*: No CRT | 16 | 9 | 0 | 1 | 3 | 3 |
| Randomized therapy phase*: CRT | 11 | 4 | 1 | 2 | 2 | 2 |
| Post-randomized therapy phase** | 70 | 28 | 5 | 1 | 16 | 20 |
| Total | 109 | 47 | 9 | 4 | 23 | 26 |

* Day 31 to 120 for Phase I patients, day 31 to 210 for Phase II patients
** Day 121 and beyond for Phase I patients, day 211 and beyond for Phase II patients

# 6.2 POSSIBLE ADVERSE EVENTS

Based on the literature and ICD implant experience, the following alphabetical list includes possible adverse events associated with implantation of an ICD system:

- Acceleration of arrhythmias
- Air embolism
- Allergic reaction
- Bleeding
- Cardiac tamponade
- Chronic nerve damage
- Conductor coil fracture
- Death
- Elevated thresholds
- Erosion/extrusion
- Extracardiac stimulation (e.g., phrenic, diaphragm, chest wall)
- Fibrotic tissue formation (e.g., keloid formation)
- Fluid accumulation
- Formation of hematomas or cysts
- Heart block
- Inability to defibrillate or pace
- Inappropriate therapy (e.g., shocks, ATP, pacing)
- Incomplete lead connection with pulse generator

- Infection
- Lead displacement/dislodgment
- Lead insulation breakage or abrasion
- Lead tip deformation and/or breakage
- Local tissue reaction
- Muscle and nerve stimulation
- Myocardial trauma (e.g., cardiac perforation, irritability, injury)
- Myopotential sensing
- Oversensing/undersensing
- Pacemaker mediated tachcardia
- Pericardial rub, effusion
- Pneumothorax
- Random component failures
- Shunting current or insulating myocardium during defibrillation with internal or external paddles
- Thrombosis/thromboemboli
- Valve damage
- Venous occlusion
- Venous trauma (e.g., perforation, dissection, erosion)

Patients susceptible to frequent shocks despite antiarrhythmic medical management may develop psychological intolerance to an implantable system that may include the following:

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- Dependency
- Depression
- Fear of premature battery depletion
- Fear of shocking while conscious
- Fear that shocking capability may be lost
- Imagined shocking

In addition to the implantation of an ICD system, possible adverse events associated with implantation of a coronary venous lead system are listed below in alphabetical order:

- Allergic reaction to contrast media
- Breakage/failure of implant tools
- Coronary venous occlusion
- Coronary venous trauma (e.g., perforation, dissection, erosion)
- Prolonged exposure to fluoroscopic radiation
- Renal failure from contrast media used to visualize coronary veins

# 7 ALTERNATE PRACTICES AND PROCEDURES

Patients who require an ICD and also have heart failure are routinely treated with a commercially available ICD and medications. Medications include both those to treat arrhythmias and medications to treat heart failure. Additional medical treatments for heart failure include, but are not limited to, exercise and nutrition programs. Alternative therapies for the treatment of ventricular arrhythmias, as deemed appropriate by the physician based upon electrophysiological (EP) testing and other diagnostic evaluation, include antiarrhythmic medication, electrical ablation, cardiac surgery, and electronic devices including pacemaker and other commercially available ICD systems, or a combination thereof.

# 8 MARKETING HISTORY

The CONTAK CD CRT-D System and the EASYTRAK lead (Models 4510/4511/4512/4513) are distributed commercially outside the United States. These devices are approved for sale in the European Economic Community, Australia, New Zealand, Canada, Hong Kong, Singapore, Indonesia, Lebanon, Malaysia, Malta, Mexico, Israel, Egypt, Saudi Arabia, Turkey, Czech Republic, Slovakia, Slovenia, India, South Africa, and Latin America (Argentina, Bolivia, Chile, Columbia, Dominican Republic, Ecuador, Panama, Venezuela, Uruguay).

Neither the CONTAK CD CRT-D System nor the EASYTRAK leads have been withdrawn from market in any country for any reason related to the safety and effectiveness.

# 9 SUMMARY OF PRE-CLINICAL STUDIES

Prior to initiation of clinical studies, Guidant conducted the following bench testing (i.e., components, assemblies, device system and software tests), biocompatibility evaluation,

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Summary of Safety and Effectiveness

sterilization validation, and animal studies on the CONTAK CD CRT-D System. These studies were performed in accordance with established national and international industry standards such as ANSI/AAMI PC69:2000; ISO 5841-3: 1992(E); ISO 11318:1993(E); prEN45502 Active Implantable Medical Devices, Part 2-1 (Requirements for active implantable medical devices intended to treat bradyarrythmia), (draft) November 1996; and the Association for the Advancement of Medical Instrumentation (AAMI) Pacemaker Standard, August 1975; or Guidant's product specification. The test results demonstrated that the CONTAK CD CRT-D pulse generator, EASYTRAK lead and the entire CONTAK CD CRT-D system met the requirements set by these standards (sections that apply, as outlined in the following tables), and Guidant's specifications. The following tables provide brief descriptions of the verification and validation tests conducted on the CONTAK CD CRT-D system and EASYTRAK® lead.

# 9.1 PULSE GENERATOR: DESIGN VERIFICATION TESTING (DVT)

The design verification testing of the CONTAK CD CRT-D Model 1823 pulse generator included component, electronic and mechanical tests (including packaging and shipping), electromagnetic compatibility evaluation, battery capacity test, pulse generator software design verification and programmer software application tests as described below:

Component Testing: Except for the lead connector assembly, the major components for the CONTAK CD CRT-D pulse generator are identical to the legally marketed VENTAK AV III DR (PMA P960040). The lead connector assembly was modified to include three new components, the header, the outer lead seals, and the IS-1/LV-1 Connector Block. These new components were tested and passed (Table 3).

Table 3: Component Testing

| Summary of Component Testing* | Sample Size | Test Results (Pass/Fail) |
| --- | --- | --- |
| Header: Visual inspection, dimensional analysis, thermal shock, high temp/high humidity storage, cytotoxicity, pyrogenicity, material analysis. | 1 to 35 | Pass |
| Outer Lead Seals: Visual inspection, dimensional inspection; cytotoxicity, pyrogenicity, material analysis. | 1 to 105 | Pass |
| IS-1/LV-1 Connector Block: Visual inspection, dimensional inspection, material analysis. | 1 to 32 | Pass |
| *Materials used in these components were tested and met the requirements of ISO-10993, “Biological Evaluation of Medical Devices Part 1: Evaluation and Testing (1997) | | |

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Summary of Safety and Effectiveness

Electronic and Mechanical Design Verification Tests: Because of the similarity (same electronics and firmware) between the legally marketed VENTAK AV III DR and the CONTAK CD CRT-D pulse generator, electrical design verification testing for the VENTAK AV III DR applies to the CONTAK CD CRT-D pulse generator and was not repeated. Mechanical design verification test was performed on CONTAK CD CRT-D devices that were exposed to a representative manufacturing process, including sterilization cycles and vibration tests (Table 4).

Table 4: Pulse Generator Design Verification Testing

| Summary of Pulse Generator DVT | Sample Size | Test Results (Pass/Fail) |
| --- | --- | --- |
| Electronic Design Verification Testing | | |
| Tests were conducted on the VENTAK AV III DR at three different stages of the pulse generator: welded PG assembly, PG assembly with external battery connections, and hybrid system board. Tests were conducted in the following functional areas: Telemetry operation, sensing, pacing, shocking, magnet, beeper, electrograms, device clock, battery status, and faults/error handling. | 5 | Pass |
| Mechanical Design Verification Testing | | |
| Tests were conducted on the CONTAK CD CRT-D in the main functional areas: mechanical requirements, environmental tests, and package and shipping tests. Such tests included internal atmosphere and hermeticity, connector assembly lead and adapter compatibility, thermal shock and cycling, vibration, and dimensional analysis. The IS-1/DF-1/LV-1 connector assembly met requirements of ISO 5841-3: 1992(E) and ISO 11318: 1993(E). | 1 to 10 | Pass |
| Packaging and Shipping tests were done to ensure that the device remains damage free and that the package remains functional while in transit and storage mode prior to implant. Labeling must remain legible. | 4 | Pass |

Electromagnetic Compatibility (EMC) Evaluation: The CONTAK CD CRT-D Model 1823 pulse generator was evaluated to ensure that the device will operate safely in the presence of commonly encountered electromagnetic interference (EMI) such as cellular phones, cordless phones, electronic article surveillance systems (EASS), and radios designed for the home (provided labeled guidances are adhered to). Testing was based on prEN45502 Active Implantable Medical Devices, Part 2-1: Requirements for active implantable medical devices intended to treat bradyarrythmia (cardiac pacemakers) Version 9.0, draft Nov. 1996 and the AAMI Pacemaker Standard, August 1975. Since the CONTAK CD CRT-D pulse generator uses the same electronics and device firmware as the legally marketed VENTAK AV III DR, test results from the VENTAK AV III DR apply to the CONTAK CD CRT-D. A subset of tests was repeated on the CONTAK CD CRT-D to evaluate the effects of adding the left ventricular lead (Table 5).

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Summary of Safety and Effectiveness

Table 5: Electromagnetic Compatibility (EMC) Testing

| Summary of Electromagnetic Compatibility (EMC) Testing | Sample Size | Test Results (Pass/Fail) |
| --- | --- | --- |
| VENTAK AV III DR pulse generator performance was evaluated when subjected to the following: | 3 | Pass* |
| • Radiated radio frequency; pulsed and continuous wave up to 200 V/m field strength, (27, 72, 450, 900, 1800, 2450, and 3100 MHz) based on the AAMI pacemaker standard, Aug 1975. • Testing at 27 & 72 MHz was repeated for the CONTAK CD CRT-D.* | | |
| • Conducted frequency from 16.6 Hz to 50 MHz as defined in prEN45502 Active Implantable Medical Devices. Part 2-1Requirements for active implantable medical devices intended to treat bradyarrythmia (cardiac pacemakers). Version 9.0. | | |
| • High voltage external defibrillation shocks. | | |
| • Exposure to electrostatic discharge pulses. | | |
| • Exposure to Electronic Article Surveillance Systems (EASS) per Georgia Technical Institute EASS test protocol for Implantable Medical Devices, Version 2.0. | | |
| • Exposure to electrocautery | | |
| • Exposure to static magnetic fields up to 10mT (the reed switch is activated/deactivated when the field is maintained at >1.0mT.) | | |
| Summary of Cellular Telephone Testing for VENTAK AV III DR | | |
| Resistance to Interference from Cellular Telephones (450 MHZ to 1100 MHz) | 1 | Pass |
| Resistance to Interference from Cellular Telephones (850 MHZ to 2500 MHz) | 1 | Pass |
| Resistance to Interference from Cellular Telephones U. S. Cellular telephones. (NADC = TDMA-50) (MIRS = TDMA-11) | 1 | Pass |
| The CONTAK CD CRT-D was also tested for EMI simulating cellular phone emissions per the ANSI/AAMI PC69:2000 (Active Implantable Medical Devices - Electromagnetic Compatibility (EMC) test protocols for Implantable Cardiac Pacemakers and Implantable Cardioverter Defibrillators.) | 3 | Pass |

*Guidant reported that there were no instances of memory errors, parameter changes, reset conditions or damage from any test. Three devices showed the expected reversion to noise mode in the presence of conducted signals of sufficient amplitude and frequency. Three devices showed susceptibility to pulsed RF at 27 MHz and slight susceptibility to pulsed RF at 72 MHZ; these levels are comparable to other legally marketed implantable defibrillator devices.

Battery Capacity Test: The CONTAK CD CRT-D battery is identical to the VENTAK AV III DR battery; therefore, the VENTAK AV III DR battery testing applies to the CONTAK CD CRT-D and was not repeated. However, a Battery Capacity Test was performed for the CONTAK CD CRT-D pulse generator to establish the usable capacity of the cell (battery) and the reserve capacity between ERI (Elective Replacement Indicator) and EOL (End Of Life) when used with the pulse generator's electronics (Table 6).

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Summary of Safety and Effectiveness

Table 6: Battery CapacityTesting

| Summary of Battery CapacityTesting | Sample Size | Test Results (Pass/Fail) |
| --- | --- | --- |
| The Battery Capacity Test used a set of calculations, with data provided by the battery manufacturer and data measured in Guidant's laboratory, to calculate usable battery capacity. The battery met Guidant specification. | 6 flex assemblies and 6 sets of batteries | Pass |

Pulse Generator Software Design Verification Test: The CONTAK CD CRT-D pulse generator software (also known as firmware) is identical to the VENTAK AV III DR pulse generator software. Design verification testing of the software incorporated in the CONTAK CD CRT-D pulse generators encompassed two different areas: the Flash EPROM and the Read-Only Memory on the chip (microcontrol) (Table 7).

Table 7: Pulse Generator Software Design Verification Test

| Summary of Pulse Generator Software Design Verification Test: (from VENTAK AV III DR) | Sample Size | Test Results (Pass/Fail) |
| --- | --- | --- |
| Using an automated test system, the testing verified the proper operation and interaction of the various tasks to be executed by the software (according to the test requirements specification) to ensure proper function, timing, and data exchange. The firmware version number is 1.0.02. | PG Software | Pass |

Model 2848 Software Application Design Verification Test: Design verification testing of the Model 2848 Programmer Software Application (the PRM Software, Version 3.1) was performed to ensure that the software meets the functional software requirements specifications. Testing was conducted with either a CONTAK CD CRT-D system including a CONTAK CD CRT-D Model 1823 pulse generator and a Model 2920 PRM (Programmer, Recorder, Monitor) with the Model 2909 Multiple Application Utility (MAU) and Model 2848 Software Application installed on it, or the same system with a pulse generator simulator replacing the CONTAK CD CRT-D pulse generator (Table 8).

Table 8: Model 2848 Software (Version 3.1) Application DVT

| Summary of Model 2848 Software Application DVT | Sample Size | Test Results (Pass/Fail) |
| --- | --- | --- |
| Testing includes the functional software requirements associated with each window/feature. The software version number is Version 3.1 for use with the Model 2920 PRM. | PG Software | Pass with 2 anomalies* |

*1) Under certain circumstances at the end of a pacing threshold test, after pulling the telemetry wand out of range, a text box indicating "Out of Range/Telemetry Noise" remains and threshold values will not display on the dialog window until the wand is replaced; this is not expected to occur under actual use. 2) Under certain circumstances when

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Summary of Safety and Effectiveness

the PRM is in disk mode, the Last Interrogation Date field is blank on the Battery Status screen and in the printed report. These anomalies have no effect on therapy or patient safety.

# 9.2 EASYTRAK LEAD: DESIGN VERIFICATION TESTING

Electrical and mechanical integrity of the EASYTRAK lead were performed to demonstrate conformance to a battery of lead tests and are summarized below (Table 9). All leads were preconditioned with shelf life, temperature cycling, and shipping test conditions prior to functional testing.

Table 9: EASYTRAK Lead DVT

| Summary of EASYTRAK Lead DVT | Sample Size | Test Results (Pass/Fail) |
| --- | --- | --- |
| Full Lead Testing: | | |
| Packaging visual verified that the packaging met the requirements of the sterile pack and final pack engineering documents. | 12 | Pass |
| Guide Catheter Compatibility testing verified that the EASYTRAK Lead passed through the EASYTRAK guide catheters with no damage to the lead or guide catheter. | 48 | Pass |
| Guide Wire Compatibility testing verified that all 0.014" guide wires indicated for use with the EASYTRAK Lead passed through the lead and guide catheter and could be withdrawn from the lead with no damage to the lead or guide wire. | 48 | Pass |
| Finishing Wire Compatibility testing verified that the finishing wire could track to the transition of the lead and was able to be withdrawn from the lead with no damage to the lead or finishing wire. | 48 | Pass |
| Axial Load testing verified that the lead can withstand implant forces and demonstrated compliance to the requirements defined by prEN 45502-2-1, section 23.3. (draft Nov. 96). | 48 | Pass |
| Electrical Resistance: DC Resistance was required to be between 10 and 22 ohms. | 12 | Pass |
| Insulation Integrity Pressure testing verified the integrity of the insulation. Leads were pressurized to 14 ± 2 PSI with dry nitrogen; leads must not exhibit evidence of nitrogen leakage. | 12 | Pass |
| Pacing Impedance: was tested per the prEN 45502-Part 2-1, (draft Nov. 96). | 12 | Pass |
| LV-1 Terminal Testing: The LV-1 connector is a proprietary connector designed for compatibility with Guidant pulse generators with an LV-1 port. | | |
| LV-1 Insertion/Withdrawal: this test verified that the LV-1 terminal meets maximum insertion/withdrawal requirements per ISO 11318:1993(E). | 12 | Pass |
| LV-1 Pin Setscrew Deformation: this test verified that set screw forces can not deform the lead connector to the extent that insertion and withdrawal forces become excessive. | 12 | Pass |
| LV-1 Low Voltage Seal Integrity: this test verified that the LV-1 connector seal rings could electrically isolate the pin and the external environment. | 12 | Pass |
| LV-1 High Voltage Seal Integrity: this test verified that the LV-1 connector seal rings could electrically isolate the pin and the external environment under high voltage conditions. | 12 | Pass |

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Summary of Safety and Effectiveness

| Summary of EASYTRAK Lead DVT | Sample Size | Test Results (Pass/Fail) |
| --- | --- | --- |
| Flex Fatigue Testing: | | |
| LV-1 Connector Flex Fatigue testing assessed the fatigue resistance of the LV-1 terminals and demonstrated conformance to the prEN 45502 Part 2-1 Connector Flex Test, Section 23.5 Test 2 (draft Nov. 1996). | 12 | Pass |
| Bell Mouth Flex Fatigue Test of Lead Conductor verified compliance of the lead conductor with the requirements of prEN 45502 Section 23.5 Test 1 (draft Nov. 1996). | 12 | Pass |
| Buckle Flex Fatigue Test of Lead Body Conductor verified the ability of the lead body conductor to withstand ten years (420 million cycles) of flexing. | 12 | Pass |
| Manufacturing Process Validation for Bond/Weld/Strength Testing: | | |
| All welded electro-mechanical connections must withstand a minimum assembly joint pull force. All load-bearing molded and bonded connections must have a minimum dry pull strength. The dry retention force between the steroid collar and electrode molding must also meet the minimum force per specifications. | 12 | Pass |

# 9.3 SYSTEM: DESIGN VALIDATION TESTING

Design validation testing that was conducted on the CONTAK CD CRT-D system included system features tests and a simulated use test (field study). In addition, an animal study carried out under Good Laboratory Practices was also conducted preclinically (Table 10).

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Summary of Safety and Effectiveness

Table 10: System Design Validation Testing

| System Design Validation Testing | Sample Size | Test Results (Pass/Fail) |
| --- | --- | --- |
| System Features Tests: Tests were conducted to exercise major features of the CONTAK CD CRT-D system. Each test demonstrated the functionality of a given feature and verified that the programmer had properly loaded parameters into the pulse generator. Feature groups tested included device family, programmer support, lead support, tachy modes, tachyarrhythmia detection, tachyarrhythmia therapy, bradycardia modes, bradycardia therapy, diagnostics, and faults/errort handling. The system performed as expected based on the specifications. | 2 systems consisting of CONTAK CD CRT-D PG and programmer software. | Pass |
| Simulated Use Test: From a field user perspective, Guidant field clinical engineers evaluated the performance of the CONTAK CD CRT-D system and EASYTRAK lead and verified that the labeling/manuals were easily understood and the entire CONTAK CD CRT-D system and EASYTRAK lead performed as expected during clinical use. Clinical scenarios were simulated using the pulse generator, programmer (PRM), PRM software, a cardiac signal simulator, and the EASYTRAK lead and accessories (guide catheter, guidewire, and finishing wire). | 2 users performed tests. | Pass |
| Animal Study: Study verified that the CONTAK CD CRT-D system and EASYTRAK leads including CONTAK CD CRT-D Model 1823 pulse generator, EASYTRAK lead, guide catheter, occluding guiding catheter, guidewire, finishing wire, lead stabilizer, LV-1 Port Plug, LV-1 Adapter, and Model 2848 software, along with a commercially available atrial pace/sense lead and a ventricular pace/sense/shocking lead, were compatible and performed safely in an in-vivo canine model. Testing demonstrated that the system performed safely in an in-vivo animal model. | 3 animals | Pass |

# 9.4 CONTAK CD CRT-D SYSTEM &amp; EASYTRAK LEAD: SAFETY AND RISK ANALYSIS

The safety and risk analysis of the CONTAK CD CRT-D system was conducted to identify potential hazards and their causes, and to take appropriate actions to minimize patient and user risk. Analysis included the following:

Hazard Analysis: Hazard Analysis identified potential hazards with using the system devices and documented the response taken to control the probability of occurrence or to minimize the risk. Potential hazards were peer reviewed for adequacy of the mitigation; residual risk was deemed acceptable.

Failure Modes and Effects Criticality Analysis (FMECA): FMECA identified potential design, test, or process inadequacies that could adversely affect the safety and performance of the device and recommended corrective actions to eliminate or minimize

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Summary of Safety and Effectiveness
p. 17

these inadequacies. Three recommendations were identified and were incorporated into device testing scheme.

**Reliability Prediction Analysis**: The Reliability Prediction Analysis was performed using field performance failure rates of similar pulse generators along with the “Parts Stress Analysis Prediction” procedure in MIL-HDBK-217F in the absence of field performance data. The analysis resulted in an expected field performance of 0.1461% failures/month.

## 9.5 BIOCOMPATIBILITY EVALUATION

The biocompatibility of the tissue contacting materials used in the CONTAK CD CRT-D pulse generator, and the EASYTRAK lead and lead accessories was established in previous PMA applications (P890061, P910077, P960040 and P910073, P950001, P960060 respectively). Pulse generator materials include: polyurethane, titanium, and silicone rubber that are all currently used in Guidant's commercially available ICD devices.

Materials used in the EASYTRAK lead that have direct long-term tissue or blood contact include: titanium, platinum, silicone rubber (including silicone rubber with titanium oxide pigment), polyurethane, and polytetrafluoroethylene (PTFE). In addition, the drug collar contains Dexamethasone Acetate in liquid silicone rubber. The biocompatibility of titanium, platinum, silicone rubber, and Dexamethasone Acetate has been established in previous PMA applications (P910073, P950001, P960060). Materials that have a new use in the EASYTRAK lead include silicone rubber with titanium oxide pigment, polyurethane, and PTFE. Guidant performed biocompatibility testing on these materials and all were determined to be biocompatible. Biocompatibility testing included cytotoxicity, hemolysis, Ames Mutagenicity, and acute and chronic system toxicity.

Materials used in the CONTAK CD CRT-D pulse generator, and the EASYTRAK lead and lead accessories were tested and met the requirements of ISO-10993, "Biological Evaluation of Medical Devices Part 1: Evaluation and Testing (1997).

## 9.6 STERILIZATION VALIDATION

Sterilization assessments were performed and validated that the CONTAK CD CRT-D Model 1823 pulse generator, EASYTRAK leads, and system accessories can be effectively sterilized with the Getinge Oxyfume 2000® or the 100% ethylene oxide (EtO) sterilization process. These processes are identical to those used for Guidant's commercially available ICD pulse generators and leads.

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Summary of Safety and Effectiveness
p. 18

For the CONTAK CD CRT-D Model 1823 pulse generator, the sterility assurance factor (SAL) was estimated to be $10^{-24}$. For the EASYTRAK lead, suture sleeve, LV-1 Lead Cap, LV-1 Lead Port Plug, and Model 6744 Lead Adapter the SAL was estimated to be $10^{-16}$. For the Finishing Wire, the SAL was estimated to be $10^{-37}$.

## 9.7 ANIMAL STUDIES

Guidant conducted an animal study in compliance with Good Laboratory Practice (GLP) regulations (21 CFR, Part 58) with the CONTAK CD CRT-D system in an *in-vivo* canine model to demonstrate that the system meets user needs and intended uses. The animal study also addressed the compatibility of the system components and verified that the components of the CONTAK CD CRT-D system were compatible, and the system performed safely for its intended use.

In addition to the system study described above, Guidant conducted a series of animal studies to verify that the EASYTRAK lead is safe for chronic implantation. These studies demonstrated that the EASYTRAK lead is biocompatible and biostable after chronic (six months) implantation in canines and that the lead remains in position once implanted.

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Summary of Safety and Effectiveness

# 9.8 SHELF LIFE FOR PMA DEVICES

Table 11: Device Shelf Life

| Device | Shelf Life |
| --- | --- |
| CONTAK CD CRT-D pulse generator, Model 1823 | Expiration dating for this device has been established and approved at 1 year from the battery-attach date. |
| EASYTRAK Lead, 4510, 4511, 4512, 4513 | Expiration dating for this device has been established and approved at 2 years from the date of sterilization. |
| Accessory: · Finishing Wire, Models 6730, 6731, 6732, 6733 | Expiration dating for this device has been established and approved at 2 years from the date of sterilization. |
| Accessories: · Suture Sleeve, Model 6741 · LV-1 Lead Cap, Model 6742 · LV-1 Lead Port Plug, Model 6742 · Lead Adapter, Model 6744 | Expiration dating for these devices has been established and approved at 4 years from the date of sterilization. |

# 10 SUMMARY OF CLINICAL STUDIES

Guidant conducted the CONTAK CD Study to demonstrate the safety and effectiveness of the CONTAK CD CRT-D 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 pulse generator 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 function of the device. The CONTAK CD Study met the Lead and System Effectiveness endpoints as well as the Lead and System Safety endpoints (as defined on page 22). 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 VO2 and the six minute hall walk. A second study was performed (Focused Confirmatory Study) using this subgroup of patients to confirm the effectiveness of CRT.

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Summary of Safety and Effectiveness
p. 20

# 10.1 CONTAK CD STUDY

## 10.1.1 STUDY DESIGN

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. 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) 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. The data from the first three months of the crossover phase were pooled with data from the six-month parallel phase. The visit schedule and testing requirements remained the same. Additionally, while the study originally used the VENTAK CHF AICD 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.

## 10.1.2 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

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p. 21

- 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
- Require in-hospital continuous intravenous inotropes
- Have pre-existing cardioversion/defibrillation leads other than those specified in the 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

## 10.1.3 FOLLOW-UP SCHEDULE

| 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 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. |

* 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.

## 10.1.4 PATIENT GROUPS

The CONTAK CD Study included patients with symptomatic heart failure despite optimal drug therapy as defined in the inclusion criteria. This population included patients who were NYHA Class II, III, or IV at the time of implant.

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Summary of Safety and Effectiveness
p. 22

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 pre-selected covariates with the functional status endpoints.

## 10.1.5 ENDPOINTS

The CONTAK CD Study had three investigational elements consisting of:

### CRT Effectiveness:

**Primary:** Composite endpoint consisting of all-cause mortality, hospitalization for heart failure, and ventricular tachyarrhythmia requiring device intervention.

**Secondary:** Peak VO₂ derived 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.

### Lead and System Effectiveness:

**Lead:** Left ventricular pacing thresholds, biventricular sensing, biventricular lead impedance, and lead placement success rate.

**System:** VF detection time, biventricular antitachycardia pacing (ATP) efficacy.

### Lead and System Safety:

**Lead:** Incidence of lead-related adverse events.

**System:** Incidence of severe, device-related adverse events and operative mortality.

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Summary of Safety and Effectiveness

# 10.1.6 STUDY RESULTS

# 10.1.6.1 PATIENT ACCOUNTABILITY

Figure 1: Enrollment and Follow-Up of Randomized Patients

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Summary of Safety and Effectiveness

# 10.1.6.2 BASELINE CHARACTERISTICS

Table 12: Pre-Implant Assessment
All patients implanted, $\mathbf{N} = {501}$

| | | All Patients | | | NYHA Class III/IV | | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Characteristic | | CRT (N=248) | No CRT (N=253) | P-val* | CRT (N=117) | No CRT (N=110) | P-val* |
| Age at Implant (years) | N | 248 | 253 | | 117 | 110 | |
| | Mean +/- SD | 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 +/- SD | 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 Interval** (ms) | N | 224 | 222 | | 107 | 91 | |
| | Mean +/- SD | 205 +/- 42 | 202 +/- 49 | 0.44 | 204 +/- 41 | 200 +/- 54 | 0.60 |
| | Range | 88 - 336 | 104 - 400 | | 136 - 336 | 110 - 400 | |
| Qualifying QRS Duration** (ms) | N | 226 | 224 | | 109 | 93 | |
| | Mean +/- SD | 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 | |
| | Mean +/- SD | 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 +/- SD | 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 +/- SD | 67 +/- 12 | 69 +/- 12 | 0.27 | 68 +/- 12 | 67 +/- 14 | 0.85 |
| | Range | 31 - 100 | 40 - 109 | | 31 - 100 | 40 - 109 | |

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

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Summary of Safety and Effectiveness

Table 13: Pre-Implant History
All patients implanted, $\mathrm{N} = {501}$

| | | All Patients | | | NYHA Class III/IV | | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Characteristic | | CRT (N=248) | No CRT (N=253) | P-val* | CRT (N=117) | No CRT (N=110) | P-val* |
| Primary Tachy Arrhythmia [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 VT | 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 Fib. | 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 |
| 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) | |

* P-values were calculated with Pearson's chi-squared test

# 10.1.6.3 CRT EFFECTIVENESS

# 10.1.6.3.1 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. 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 14: Composite Index
All patients implanted and active 31 days post-implant

| Group | Heart Failure Mortality or Morbidity Event | CRT | | No CRT | | Relative Reduction with CRT |
| --- | --- | --- | --- | --- | --- | --- |
| | | N | % | N | % | |
| All Patients (NYHA II/III/IV) (n=490) | Death from any cause | 11 | 4.5 | 16 | 6.5 | 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 | |

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Summary of Safety and Effectiveness

Twenty-seven patients died during the therapy phase. Mortality stratified by treatment group and cause, as adjudicated by the Events Committee, is shown in Table 15. The Kaplan-Meier (Figure 2) shows total survival by treatment group.

Table 15: Mortality Stratified by Treatment Group and Cause
All patients implanted and active at 31 days post-implant, $\mathrm{N} = {490}$

| Deaths | CRT (N=245) | 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%) |
| Non-cardiac | 2 (0.8%) | 3 (1.2%) |
| Unknown | 2 (0.8%) | 3 (1.2%) |
| Total | 11 (4.5%) | 16 (6.5%) |

Figure 2: Kaplan Meier Curve

Patients at Risk

CRT 245 242 239 127 125 123 122

No CRT 245 241 233 130 129 126 125

{27}

Summary of Safety and Effectiveness

Table 16 presents the reasons for hospitalization within the treatment period as determined by the Events Committee.

All patients implanted and active at 31 days post-implant, $N = 490$

Table 16: Patients Hospitalized during Treatment Period*

| Reason for Hospitalization | All Patients | | | NYHA Class III/IV | | |
| --- | --- | --- | --- | --- | --- | --- |
| | 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 |

* Represents number of patients with each category of hospitalization. Patients may have multiple hospitalizations that fall into different categories

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Summary of Safety and Effectiveness

# 10.1.6.3.2 Peak VO2

Peak $\mathrm{VO}_2$ was determined from a standardized protocol for exercise testing as a means of measuring a patient's capacity for performing physical activity.

Figure 3: Change in Peak $\mathrm{VO}_2$

| | All Patients | | | NYHA Class III/IV | | |
| --- | --- | --- | --- | --- | --- | --- |
| Peak VO2(ml/kg/min) | CRT(N=216) | No CRT(N=201) | P-val | CRT(N=96) | No CRT(N=80) | P-val* |
| Post-recovery Visit | 13.5 +/- 0.2 | 13.5 +/- 0.2 | - | 12.0 +/- 0.3 | 12.0 +/- 0.3 | - |
| 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 |

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

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Summary of Safety and Effectiveness

# 10.1.6.3.3 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 4 provides the change in Six-Minute Walk.
Figure 4: Change in Six Minute Walk

| | All Patients | | | NYHA Class III/IV | | |
| --- | --- | --- | --- | --- | --- | --- |
| Six Minute Walk Distance (meters) | CRT (N=224) | No CRT (N=220) | P-val* | CRT (N=99) | No CRT (N=90) | P-val* |
| Post-recovery Visit | 317 +/- 5 | 317 +/- 5 | - | 268 +/- 9 | 268 +/- 9 | - |
| 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 |

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

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Summary of Safety and Effectiveness

# 10.1.6.3.4 Quality of Life

Quality of Life (QOL) (Figure 5) 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 5: Change in Quality of Life

| | All Patients | | | NYHA Class III/IV | | |
| --- | --- | --- | --- | --- | --- | --- |
| QOL (points) | CRT (N=234) | No CRT (N=225) | P-val* | CRT (N=107) | No CRT (N=96) | P-val* |
| Post-recovery Visit | 41.8 +/- 1.1 | 41.8 +/- 1.1 | - | 52.7 +/- 1.5 | 52.7 +/- 1.5 | - |
| 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 |

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

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Summary of Safety and Effectiveness

# 10.1.6.3.5 NYHA Class

The determination for 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 6: Changes in NYHA Class

| | All Patients | | | | | NYHA Class III/IV | | | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | CRT (N=109) | | No CRT (N=116) | | P-val* | CRT (N= 45) | | No CRT (N= 48) | | P-val* |
| Change in NYHA Class | N | % | N | % | | N | % | N | % | |
| Improve 2 or More Classes | 12 | 11.0 | 2 | 1.7 | 0.10 | 12 | 26.7 | 2 | 4.2 | 0.006 |
| Improve 1 Class | 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 | |
| Worsen 1 Class | 13 | 11.9 | 19 | 16.4 | | 2 | 4.4 | 4 | 8.3 | |
| Worsen 2 or More Classes | 1 | 0.9 | 1 | 0.9 | | 0 | 0.0 | 0 | 0.0 | |

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

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Summary of Safety and Effectiveness

# 10.1.6.3.6 Echocardiography

Several echocardiography (echo) variables were identified to assist in measuring the possible hemodynamic impact of CRT as shown in Table 17. 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 17: Echocardiography Results

| | | CRT | | No CRT | | Between Groups | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Parameter | Timepoint | N | Mean +/- SE | N | Mean +/- SE | Mean +/- SE | P-val |
| 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 | - |
| | 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 |

# 10.1.6.3.7 Measures of Sympathetic Tone

Mean Norepinephrine levels (Table 18) and Mean Heart Rate (Table 19) were examined as markers of how CRT may influence the excessive sympathetic drive associated with chronic heart failure.

Table 18: Mean Norepinephrine Results

| | All Patients | | | NYHA Class III/IV | | |
| --- | --- | --- | --- | --- | --- | --- |
| Norepinephrine (pg/mL) | CRT (N=228) | No CRT (N=217) | P-val | CRT (N=104) | No CRT (N=90) | P-val |
| 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 |

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Summary of Safety and Effectiveness

Table 19: Mean Heart Rate Results

| | All Patients | | | NYHA Class III/IV | | |
| --- | --- | --- | --- | --- | --- | --- |
| Heart Rate (bpm) | CRT (N=240) | No CRT (N=233) | P-val | CRT (N=113) | No CRT (N=101) | P-val |
| 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 |

# 10.1.6.4 EASYTRAK LEAD AND SYSTEM EFFECTIVENESS

# 10.1.6.4.1 Lead Measurements

Figure 7: EASYTRAK Lead Threshold Measurements
All patients implanted with an EASYTRAK lead at first implant, $N = 443$

| Statistic | Implant | 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 |

* EASYTRAK lead models: 4511, 4512, and 4513

It was hypothesized that the upper tolerance limit of the chronic left ventricular pacing threshold of the EASYTRAK lead be less than $5.5\mathrm{V}$ to ensure that an adequate safety margin exists. Chronic left ventricular pacing thresholds shown in Figure 7 are within this limit.

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Summary of Safety and Effectiveness

Figure 8: EASYTRAK Biventricular Sensed R-wave Amplitude
All patients implanted with an EASYTRAK lead at first implant, $N = 443$

| Statistic | Implant | 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 |
| Range | 1.9 - 25.0 | 1.4 - 25.0 | 1.7 - 25.0 | 1.2 - 25.0 | 2.6 - 20.4 | 2.2 - 13.6 |

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 the left ventricle (EASYTRAK lead). It was hypothesized that the mean biventricular R-wave amplitude be greater than $5\mathrm{mV}$ to ensure proper sensing (Figure 8). The performance of the EASYTRAK lead system was significantly above this value $(p &lt; 0.01)$ .

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Summary of Safety and Effectiveness

Figure 9: EASYTRAK Biventricular Pacing Impedance
All patients implanted with an EASYTRAK lead at first implant, $N = 443$

| Statistic | Implant | 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) |

The impedance measured by the CONTAK CD CRT-D 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 $200\Omega$ to ensure proper pulse generator function. The lower limit of the $95\%$ confidence interval of the chronic biventricular lead impedance exceeds this value (Figure 9).

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Summary of Safety and Effectiveness

# 10.1.6.4.2 EASYTRAK Lead Placement Success Rate

The EASYTRAK lead was implanted in 448/517 (87%) of patients who underwent the implant procedure. Table 20 shows the reasons for inability to place the EASYTRAK lead. Table 21 provides the EASYTRAK lead implant success rate.

Table 20: Reasons for unsuccessful EASYTRAK Lead implant
Patients with unsuccessful attempt to implant EASYTRAK lead (N=69)

| Reason | # of pts | % |
| --- | --- | --- |
| Inability to locate or cannulate the coronary sinus | 29 | 42.0 |
| 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 | 5 | 7.2 |
| Procedure stopped due to transient AV block | 1 | 1.4 |
| Procedure stopped due to venous perforation during subclavian stick | 1 | 1.4 |
| Reason not stated | 1 | 1.4 |
| Extracardiac stimulation | 1 | 1.4 |
| Inability to place an atrial pace/sense lead | 1 | 1.4 |
| Total | 69 | 100% |

Table 21: EASYTRAK Lead Placement Success Rate
All patients implanted or attempted with EASYTRAK lead (N=517)

| Measurement | All Procedures |
| --- | --- |
| Number of patients implanted or attempted | 517 |
| Number of placements* of the EASYTRAK Lead | 448 |
| Rate | 87% |
| 95% CI | (84%, 90%) |

* 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 (Figure 10).

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Summary of Safety and Effectiveness

Figure 10: EASYTRAK Success Rate, Procedure Time, Fluoroscopy Exposure Time

Implants (by order of enrollment)


# 10.1.6.4.3 Biventricular Antitachycardia Pacing (ATP) Conversion Efficacy Performance

The conversion rate of induced monomorphic ventricular tachycardia (MVT) was $64\%$ and that of spontaneous MVT was $88\%$ .

# 10.1.6.4.4 Ventricular Tachyarrhythmia Detection Time

The VENTAK CHF AICD and CONTAK CD CRT-D 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 $2.1 \pm 0.6$ seconds was statistically significantly lower than 6 seconds $^{1}$ ( $p &lt; 0.01$ ), demonstrating that there was no statistically significant prolongation of induced VF detection times with the additional left ventricular lead. There were also no adverse events reported in which a VENTAK CHF AICD or CONTAK CD CRT-D device failed to detect a spontaneous ventricular tachyarrhythmia.

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Summary of Safety and Effectiveness

# 10.1.6.5 EASYTRAK LEAD AND SYSTEMSAFETY

# 10.1.6.5.1 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 22).

Table 22: Lead Related Adverse Events at Six Months

| Patient Population | N | Event Rate (%) | 95% Confidence Interval |
| --- | --- | --- | --- |
| 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. The overall lead-related adverse event rate was $14.5\%$ [95% CI (11.5–17.5%)]. Table 23 reports lead-related adverse events observed during the CONTAK CD Study.

Table 23: EASYTRAK Lead-Related Adverse Events throughout the Study
All patients implanted (N=448) All patients attempted (N=517)

| Adverse Events | Total | % of pts (95% CI) |
| --- | --- | --- |
| Lead-Related, N = 448 | | |
| Loss of capture/lead dislodgment | 31a | 6.9 (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 | 5 | 1.0 (0.1–1.8) |
| Coronary venous perforation | 5 | 1.0 (0.1–1.8) |
| Transient renal failure | 5 | 1.0 (0.1–1.8) |

{39}

Summary of Safety and Effectiveness

| Adverse Events | Total | % of pts (95% CI) |
| --- | --- | --- |
| Pericardial effusion | 2 | 0.4 (0.0–0.9) |
| Finishing wire left in lead | 1 | 0.2 (0.0–0.6) |
| Right ventricular lead dislodgment | 1 | 0.2 (0.0–0.6) |
| Guide wire fracture | 1 | 0.2 (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. Twenty-six events were successfully corrected in a repeat procedure

The most common of the 53 lead-related adverse events ( $&gt;1\%$ incidence) included loss of left ventricular capture (31 patients, $6.9\%$ ), ventricular oversensing (11 patients, $2.5\%$ ), and extracardiac stimulation (9 patients, $2.0\%$ ). These events were typically resolved with surgical intervention.

The most common of the 27 procedure-related adverse events ( $&gt;1\%$ incidence) included coronary venous trauma (10 patients, $2.0\%$ ), transient atrioventricular block (6 patients, $1.2\%$ ), and transient renal failure (5 patients, $1.0\%$ ). These events were typically resolved without intervention and no permanent long-term sequelae were reported.

# 10.1.6.5.2 Severe, Device-Related Adverse Events and Operative Mortality

Table 24: Adverse Events and Operative Mortality
All patients attempted or implanted (N=567)

| Measurement | N | % | 95% CI |
| --- | --- | --- | --- |
| Severe, Device-Related Adverse Events (Type I)* | 7 | 1.2 | (0.3%, 2.1%) |
| All-Cause Operative Mortality (<=30 Days Post Implant) | 12 | 2.1 | (0.9%, 3.3%) |

*Percent is of patients with at least one event

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 $20\%$ $(p &lt; 0.01)$ (Table 24). Table 25 reports system, device-related, severe adverse events observed during the CONTAK CD Study.

Table 25: System, device-related, severe adverse events
All patients attempted or implanted (N=567)

| Adverse Event | # of pts | % of pts (95% CI) |
| --- | --- | --- |
| Telemetry difficulty; device explanted | 2 | 0.4 (0.0–0.9) |
| Ventricular tachycardia during CPX testing | 1 | 0.2 (0.0–0.5) |
| Coronary sinus perforation | 1 | 0.2 (0.0–0.5) |

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Summary of Safety and Effectiveness
p. 40

| 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 | 1 | 0.2 (0.0–0.5) |

Operative mortality, defined as death from any cause within 30 days of implant, 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&lt;0.01). Table 26 reports the cause of death for operative mortality.

Table 26: Cause of Death for Operative Mortality
All patients attempted or implanted, N=567

| Cause of Death | Implants
N=501 | Attempts
N=66 | Total
N=567 |
| --- | --- | --- | --- |
| Cardiac: Pump Failure | 5 | 1 | 6 |
| Cardiac: Arrhythmic | 2 | 1 | 3 |
| Non-Cardiac | 2 | 0 | 2 |
| Unknown | 1 | 0 | 1 |
| Total | 10 | 2 | 12 |

## 10.1.6.5.3 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 11). Table 27 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 27: Device-related Complications*
All patients implanted (N=448) All patients attempted (N=517)

| Complication | # of pts | % of pts |
| --- | --- | --- |
| All patients implanted (N=448) | | |
| Loss of LV capture | 31 | 6.9 |
| Loss of right atrial capture | 7 | 1.6 |
| Ventricular oversensing | 6 | 1.3 |
| Extracardiac stimulation | 5 | 1.1 |
| All patients attempted or implanted (N=517) | | |
| Infections | 7 | 1.4 |

*This table represents patients attempted or implanted with the EASYTRAK lead, most common (&gt; 1%) device-related complications reported.

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Summary of Safety and Effectiveness

Figure 11: System Safety

System safety for the All Patients group and the NYHA Class III/IV subgroup as determined by the device-related complication-free rate was within the 70% acceptance boundary for safety.

## 10.1.6.6 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%)

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Summary of Safety and Effectiveness
p. 42

had continuous CRT delivery until the sinus rate exceeded the maximum tracking rate (MTR).

## 10.2 FOCUSED CONFIRMATORY STUDY

### 10.2.1 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 func…