**summary of safety and effectiveness**

I. General Information

**Device Generic Name:** Dual Chamber Implantable\
Cardioverter Defibrillator (ICD) with Cardiac Resynchronization Therapy

**Device Trade Name:** InSync^®^ ICD Model 7272 Dual Chamber Implantable
Cardioverter Defibrillator with Cardiac Resynchronization Therapy and
the Model 9969 Application Software

**Applicant's Name and Address**: Medtronic, Inc.

710 Medtronic Parkway

Minneapolis, MN 55432-5604

**PMA Number:** P010031

**Date of Panel Recommendation:** March 5, 2002

**Date of Notice of Approval to Applicant:** June 26, 2002

II\. Indications for Use

InSync^®^ ICD Model 7272 Device

The InSync^®^ ICD Model 7272 is indicated for ventricular
antitachycardia pacing and ven­tricu­lar defibrillation for automated
treatment of life threatening ventricular arrhyth­mias. The system is
also indicated for the reduction of the symptoms of moderate to severe
heart failure (NYHA Func­tional Class III or IV) in those patients who
remain symptomatic despite stable, optimal medical therapy (as defined
in the clinical trials section), and have a left ventricu­lar ejec­tion
fraction less than or equal to 35% and a QRS duration greater than or
equal to 130 ms.

III\. System Description

Description of InSync^®^ ICD Model 7272

The InSync^®^ ICD Model 7272 Dual Chamber Implantable Cardioverter
Defibrillator (ICD) System is a multi-programmable, implantable
cardioverter defibrillator with biventricular pacing for cardiac
resynchronization therapy (CRT) that monitors and regulates a patient's
heart rate by providing ventricular tachyarrhythmia therapy and single
or dual chamber bradycardia pacing. Ventricular tachyarrhythmias
therapies are for the treatment of ventricular tachycardia (VT) and
ventricular fibrillation (VF), arrhythmias associated with sudden
cardiac death (SCD). Cardiac resynchronization therapy uses simultaneous
biventricular electrical stimulation to synchronize ventricular
contractions.

The Model 7272 InSync^®^ ICD System consists of:

1.  InSync^®^ ICD Model 7272

2.  Model 9969 Application Software for use with the previously
    approved:

    1.  Model 9790C Programmer

    2.  Model 2090 Programmer

3.  Commercially Available Components

    1.  Attain LV Model 2187 Cardiac Vein Pacing Lead

    2.  Attain CS Model 2188 Coronary Sinus Pacing Lead

    3.  Attain Model 6215 Venogram Balloon

    4.  Attain Models 6216 and 6218 Left Heart Delivery Systems

    5.  Right Atrial, Right Ventricular and Cardioversion/Defibrillation
        leads, implant support instruments and accessories

IV\. Contraindications

InSync^®^ ICD Model 7272 Device

Do not use the InSync^®^ ICD system in:

1.  Patients whose ventricular tachyarrhythmias may have transient or
    reversible causes, such as:

    1.  Acute myocardial infarction

    2.  Digitalis intoxication

    3.  Drowning

    4.  Electrocution

    5.  Electrolyte imbalance

    6.  Hypoxia

    7.  Sepsis

2.  Patients with incessant VT or VF

3.  Patients who have a unipolar pacemaker

V. Warnings and Precautions

See device labeling.

VI\. Adverse Events

Per the investigational plan, an *adverse event* is defined as any
undesirable experience (sign, symptom, illness, or other medical event)
occurring to a patient whether it is considered to be device related or
not. Adverse events were classified as complications or observations
based on the following definitions:

-   A *complication* is defined as an adverse event that results in
    invasive intervention, or directly results in the death or serious
    injury to the patient, the explant or repositioning of the ICD or
    lead, or the termination of significant device function regardless
    of other treatments.

-   An *observation* is defined as an adverse event that does *not*
    result in invasive intervention, the death or serious injury to the
    patient, the explant or repositioning of the ICD or lead, or the
    termination of significant device function.

    On the following pages, Table 1 summarizes all reported adverse
    events in NYHA Class III and IV patients; and Table 2 summarizes
    NYHA Class III and IV patient deaths.

    The InSync^®^ ICD study was a prospective, multi-center, randomized
    double-blind, parallel arm, controlled clinical trial to assess the
    safety and effectiveness of biventricular pacing for heart failure
    therapy in ICD patients.

A. Adverse Events

Table 1 provides a summary of all adverse events that occurred in NYHA
Class III and IV patients from implant through the 6-month randomization
period who had an implant attempt or were implanted with an InSync^®^
ICD system. 1499 events were reported in 351 of 424 patients implanted
or attempted with an InSync^®^ ICD system (1861 total device months). Of
the events, 459 were complications and 1040 were observations.

**Table 1**. Adverse Events During the Randomization Period

  ----------------------------------------------------------------------------------------------------------
                            **\# of       **%              **Complications   **%            **Observations
                            Events\       Complications\   per 100           Observations   per 100
                            (# of         (# of            device-months\    (# of          device-months\
                            patients)**   patients)**      (# of events)**   patients)**    (# of events)**
  ------------------------- ------------- ---------------- ----------------- -------------- ----------------
  **Total Adverse Events**  **1499        **49.4 (208)**   **24.7 (459)**    **75.8 (319)** **55.9 (1040)**
                            (351)**                                                         

  **ICD related events**                                                                    

  Abnormal impedance        2 (2)         0.2 (1)          0.1 (1)           0.2 (1)        0.1 (1)
  measurement                                                                               

  Atrial or ventricular     4 (4)         0.0 (0)          0.0 (0)           1.0 (4)        0.2 (4)
  arrhythmias                                                                               

  Electrical reset of ICD   1 (1)         0.2 (1)          0.1 (1)           0.0 (0)        0.0 (0)

  ICD discharge             1 (1)         0.0 (0)          0.0 (0)           0.2 (1)        0.1 (1)

  Inappropriate VT/VF       5 (5)         0.0 (0)          0.0 (0)           1.2 (5)        0.3 (5)
  detection                                                                                 

  Pacemaker mediated        1 (1)         0.2 (1)          0.1 (1)           0.0 (0)        0.0 (0)
  tachycardia                                                                               

  Phantom shocks            1 (1)         0.0 (0)          0.0 (0)           0.2 (1)        0.1 (1)

  Pocket infection/         2 (2)         0.2 (1)          0.1 (1)           0.2 (1)        0.1 (1)
  seroma/hematoma                                                                           

  **Subtotal: ICD related   **19 (17)**   **1.0 (4)**      **0.2 (4)**       **3.3 (14)**   **0.8 (15)**
  events^1^**                                                                               

  **LV lead related                                                                         
  events**                                                                                  

  Cardiac perforation       2 (2)         0.5 (2)          0.1 (2)           0.0 (0)        0.0 (0)

  Coronary Sinus dissection 5 (5)         0.7 (3)          0.2 (3)           0.5 (2)        0.1 (2)

  Elevated pacing           12 (11)       2.1 (9)          0.5 (9)           0.7 (3)        0.2 (3)
  thresholds/ Failure to                                                                    
  capture, loss of capture                                                                  

  Lead dislodgment          33 (31)       6.7 (28)         1.6 (30)          0.7 (3)        0.2 (3)

  Muscle stimulation        32 (29)       2.9 (12)         0.6 (12)          4.5 (19)       1.1 (20)
  (diaphragm, chest wall,                                                                   
  pectoral)                                                                                 

  Pain (chest; neck)        2 (2)         0.0 (0)          0.0 (0)           0.5 (2)        0.1 (2)

  Palpitations              1 (1)         0.0 (0)          0.0 (0)           0.2 (1)        0.1 (1)

  Pericardial effusion      2 (2)         0.2 (1)          0.1 (1)           0.2 (1)        0.1 (1)

  Ventricular arrhythmias   1 (1)         0.2 (1)          0.1 (1)           0.0 (0)        0.0 (0)

  **Subtotal: LV lead       **90 (77)**   **12.6 (53)**    **3.1 (58)**      **7.1 (30)**   **1.7 (32)**
  related events**                                                                          

  **RA lead related                                                                         
  events**                                                                                  

  Atrial arrhythmias        2 (2)         0.2 (1)          0.1 (1)           0.2 (1)        0.1 (1)

  Atrial standstill         1 (1)         0.0 (0)          0.0 (0)           0.2 (1)        0.1 (1)

  Elevated pacing           7 (6)         1.0 (4)          0.2 (4)           0.7 (3)        0.2 (3)
  thresholds/ Failure to                                                                    
  capture, loss of capture                                                                  

  Far-field R-wave sensing  1 (1)         0.2 (1)          0.1 (1)           0.0 (0)        0.0 (0)

  Lead dislodgment          6 (6)         1.4 (6)          0.3 (6)           0.0 (0)        0.0 (0)

  Oversensing, undersensing 2 (2)         0.0 (0)          0.0 (0)           0.5 (2)        0.1 (2)

  **Subtotal: RA lead       **19 (18)**   **2.9 (12)**     **0.6 (12)**      **1.7 (7)**    **0.4 (7)**
  related events**                                                                          

  **RV lead related                                                                         
  events**                                                                                  

  Cardiac perforation       1 (1)         0.2 (1)          0.1 (1)           0.0 (0)        0.0 (0)

  Elevated pacing           2 (2)         0.5 (2)          0.1 (2)           0.0 (0)        0.0 (0)
  thresholds/ Failure to                                                                    
  capture, loss of capture                                                                  

  Heart block               3 (3)         0.5 (2)          0.1 (2)           0.2 (1)        0.1 (1)

  Lead dislodgment          1 (1)         0.2 (1)          0.1 (1)           0.0 (0)        0.0 (0)

  Muscle stimulation        2 (2)         0.5 (2)          0.1 (1)           0.2 (1)        0.1 (1)
  (diaphragm, pectoral)                                                                     

  Oversensing               4 (4)         0.0 (0)          0.0 (0)           1.0 (4)        0.2 (4)

  PVCs                      1 (1)         0.0 (0)          0.0 (0)           0.2 (1)        0.1 (1)

  Poor DFTs                 1 (1)         0.2 (1)          0.1 (1)           0.0 (0)        0.0 (0)

  **Subtotal: RV lead       **15 (15)**   **1.9 (8)**      **0.4 (8)**       **1.7 (7)**    **0.4 (7)**
  related events**                                                                          

  **System related events**                                                                 

  Elevated pacing           1 (1)         0.2 (1)          0.1 (1)           0.0 (0)        0.0 (0)
  thresholds/ Failure to                                                                    
  capture, loss of capture                                                                  

  Inappropriate VT/VF       2 (1)         0.0 (0)          0.0 (0)           0.2 (1)        0.1 (2)
  detection                                                                                 

  Muscle stimulation -      2 (2)         0.0 (0)          0.0 (0)           0.5 (2)        0.1 (2)
  diaphragm                                                                                 

  Phantom shocks            2 (1)         0.0 (0)          0.0 (0)           0.2 (1)        0.1 (2)

  Programmer malfunction    1 (1)         0.0 (0)          0.0 (0)           0.2 (1)        0.1 (1)

  Twiddler's syndrome       1 (1)         0.2 (1)          0.1 (1)           0.0 (0)        0.0 (0)

  **Subtotal: System        **9 (7)**     **0.5 (2)**      **0.1 (2)**       **1.2 (5)**    **0.4 (7)**
  related events^1^**                                                                       

  **Implant tools related                                                                   
  events**                                                                                  

  Cardiac                   4 (4)         0.7 (3)          0.2 (3)           0.2 (1)        0.1 (1)
  perforation/pericardial                                                                   
  effusion                                                                                  

  Chest pressure/tightness  1 (1)         0.0 (0)          0.0 (0)           0.2 (1)        0.1 (1)

  Coronary Sinus dissection 8 (8)         1.4 (6)          0.3 (6)           0.5 (2)        0.1 (2)

  Guide catheter damage     1 (1)         0.2 (1)          0.1 (1)           0.0 (0)        0.0 (0)

  Guidewire fracture        1 (1)         0.2 (1)          0.1 (1)           0.0 (0)        0.0 (0)

  Heart block               7 (7)         0.2 (1)          0.1 (1)           1.4 (6)        0.3 (6)

  Hemo/Pneumothorax         1 (1)         0.2 (1)          0.1 (1)           0.0 (0)        0.0 (0)

  Lead stylet stuck         1 (1)         0.0 (0)          0.0 (0)           0.2 (1)        0.1 (1)

  Ventricular arrhythmias   1 (1)         0.2 (1)          0.1 (1)           0.0 (0)        0.0 (0)

  **Subtotal: Implant tools **25 (22)**   **3.1 (13)**     **0.8 (14)**      **2.4 (10)**   **0.6 (11)**
  related events**                                                                          

  **Possibly device                                                                         
  related**                                                                                 

  Atrial arrhythmias        12 (11)       0.5 (2)          0.1 (2)           2.1 (9)        0.5 (10)

  Bradycardia/heart block/  3 (3)         0.0 (0)          0.0 (0)           0.7 (3)        0.2 (3)
  junctional rhythm                                                                         

  Chest pain/angina         7 (7)         0.5 (2)          0.1 (2)           1.2 (5)        0.3 (5)
  pectoris                                                                                  

  Dizziness                 4 (4)         0.0 (0)          0.0 (0)           1.0 (4)        0.2 (4)

  Fever                     1 (1)         0.0 (0)          0.0 (0)           0.2 (1)        0.1 (1)

  Hypertension              1 (1)         0.0 (0)          0.0 (0)           0.2 (1)        0.1 (1)

  Hypotension               3 (3)         0.7 (3)          0.2 (3)           0.0 (0)        0.0 (0)

  Ventricular arrhythmias   9 (8)         0.2 (1)          0.1 (1)           1.7 (7)        0.4 (8)

  **Subtotal: Possibly      **49 (36)**   **2.1 (9)**      **0.6 (11)**      **6.9 (29)**   **2.0 (38)**
  device related**                                                                          

  **Procedure                                                                               
  related/Possibly                                                                          
  procedure related**                                                                       

  Arm/hand numbness/        6 (6)         0.0 (0)          0.0 (0)           1.4 (6)        0.3 (6)
  swelling                                                                                  

  Atrial arrhythmias        6 (6)         0.5 (2)          0.1 (2)           1.0 (4)        0.2 (4)

  Coronary Sinus dissection 1 (1)         0.0 (0)          0.0 (0)           0.2 (1)        0.1 (1)

  Dizziness                 2 (2)         0.2 (1)          0.1 (1)           0.2 (1)        0.1 (1)

  Drainage, pocket site     3 (3)         0.2 (1)          0.1 (1)           0.5 (2)        0.1 (2)

  Eccymosis, groin          1 (1)         0.0 (0)          0.0 (0)           0.2 (1)        0.1 (1)

  Eccymosis, pocket site    2 (2)         0.0 (0)          0.0 (0)           0.5 (2)        0.1 (2)

  Fatigue, tiredness        3 (3)         0.2 (1)          0.1 (1)           0.5 (2)        0.1 (2)

  Fever                     6 (5)         0.5 (2)          0.2 (3)           0.7 (3)        0.2 (3)

  ICD migration             1 (1)         0.0 (0)          0.0 (0)           0.2 (1)        0.1 (1)

  Heart failure             5 (5)         1.2 (5)          0.3 (5)           0.0 (0)        0.0 (0)
  decompensation                                                                            

  Hematoma, groin           2 (2)         0.0 (0)          0.0 (0)           0.5 (2)        0.1 (2)

  Hemo/Pneumothorax         3 (3)         0.5 (2)          0.1 (2)           0.2 (1)        0.1 (1)

  Hypotension               8 (7)         1.7 (7)          0.4 (8)           0.0 (0)        0.0 (0)

  Inadequate cardiac output 1 (1)         0.2 (1)          0.1 (1)           0.0 (0)        0.0 (0)

  Junctional rhythm         1 (1)         0.0 (0)          0.0 (0)           0.2 (1)        0.1 (1)

  Nausea/vomiting           11 (11)       1.4 (6)          0.3 (6)           1.2 (5)        0.3 (5)

  Pain pocket site          101 (96)      1.7 (7)          0.5 (9)           21.4 (90)      4.9 (92)

  Pain (arm, back, chest,   62 (61)       1.0 (4)          0.1 (2)           13.5 (57)      3.1 (58)
  groin, head, shoulder)                                                                    

  Pericardial               4 (4)         0.2 (1)          0.2 (1)           0.7 (3)        0.2 (3)
  effusion/Pericarditis                                                                     

  Phlebitis                 1 (1)         0.0 (0)          0.0 (0)           0.2 (1)        0.1 (1)

  Pleural effusion          6 (6)         0.2 (1)          0.1 (1)           1.2 (5)        0.3 (5)

  Pocket infection/seroma/  38 (38)       2.4 (10)         0.5 (10)          6.7 (28)       1.5 (28)
  hematoma/swelling                                                                         

  Rash                      3 (3)         0.2 (1)          0.1 (1)           0.5 (2)        0.1 (2)

  Renal                     4 (4)         0.7 (3)          0.2 (3)           0.2 (1)        0.1 (1)
  insufficiency/failure                                                                     

  Respiratory arrest/       2 (2)         0.5 (2)          0.1 (2)           0.0 (0)        0.0 (0)
  failure                                                                                   

  Thrombosis                2 (2)         0.5 (2)          0.1 (2)           0.0 (0)        0.0 (0)

  Atrial or ventricular     6 (6)         1.0 (4)          0.2 (4)           0.5 (2)        0.1 (2)
  arrhythmias                                                                               

  **Subtotal: Procedure     **317 (208)** **13.3 (56)**    **4.0 (74)**      **42.5 (179)** **13.1 (243)**
  related/Possibly                                                                          
  procedure related^1^**                                                                    

  **Heart failure                                                                           
  decompensation**                                                                          

  Atrial arrhythmias        3 (3)         0.7 (3)          0.2 (3)           0.0 (0)        0.0 (0)

  Cardiac related^2^        12 (12)       1.9 (8)          0.4 (8)           1.0 (4)        0.2 (4)

  Edema                     6 (5)         0.2 (1)          0.1 (1)           1.2 (5)        0.3 (5)

  Electrolyte imbalance^3^  3 (3)         0.2 (1)          0.1 (1)           0.5 (2)        0.1 (2)

  Elevated liver enzymes    1 (1)         0.0 (0)          0.0 (0)           0.2 (1)        0.1 (1)

  Heart failure             127 (88)      14.3 (60)        4.4 (82)          9.7 (41)       2.4 (45)
  decompensation                                                                            

  Pleural effusion          2 (2)         0.5 (2)          0.1 (2)           0.0 (0)        0.0 (0)

  Renal                     13 (12)       1.4 (6)          0.4 (7)           1.4 (6)        0.3 (6)
  insufficiency/failure;                                                                    
  elevated creatinine                                                                       

  Respiratory related^4^    26 (25)       1.9 (8)          0.5 (9)           4.0 (17)       0.9 (17)

  **Subtotal: Heart failure **202 (120)** **17.1 (72)**    **6.3 (118)**     **16.2 (68)**  **4.5 (84)**
  decompensation^1^**                                                                       

  **Not device or procedure **754 (259)** **21.9 (92)**    **8.5 (158)**     **56.3 (237)** **32.0 (596)**
  related**                                                                                 
  ----------------------------------------------------------------------------------------------------------

^1^The following adverse events were reported in three or fewer
patients: ICD related: Pain pocket site, shoulder pain/discomfort.
Possibly device related: Back pain/discomfort, diaphoresis,
dyspnea/shortness of breath, palpitations, peripheral edema, renal
insufficiency/failure, shoulder pain/discomfort. Procedure
related/possibly procedure related: Adrenal insufficiency, anemia,
anxiety, bloody sputum, COPD, confusion, decreased oxygen saturation,
density on chest x-ray, drainage of old device pocket site, dysphagia,
electromechanical dissociation (transient), elevated white blood cell
count, eye abrasion, headache, nose bleed, occluded brachiocephalic
vein, palpitations, sinus tachycardia, sleep problems, subclavian vein
collapse, urinary problems. Heart failure decompensation: Anxiety,
decreased appetite, fatigue, heart block, heart transplant, syncope,
ventricular arrhythmias, weight gain.

^2^ Reported cardiac related events: cardiac arrest, cardiogenic shock,
cardiomyopathy, chest pain/angina pectoris, inadequate\
cardiac output.\
^3^ Reported electrolyte imbalances: hyperkalemia, hyponatremia.\
^4^ Reported respiratory events: Bloody sputum, dyspnea/shortness of
breath, COPD, respiratory failure.

A total of 82 deaths were reported in the 434 enrolled NYHA Class III
and IV patients. Of these deaths, 59 occurred in 364 patients who were
implanted with an InSync^®^ ICD system and randomized to either the
control (CRT OFF) or treatment group (CRT ON) **Table 2** summarizes the
investigator's death classifications.

> **Table 2. Summary of Death Classifications for Randomized NYHA Class
> III and IV Patients**

  --------------------------- ------------------- ------------------------
  Investigator Classification Control             Treatment

  Sudden Cardiac              5                   4

  Non-sudden Cardiac          17                  20

  Non-Cardiac                 7                   3

  Unknown                     1                   2

  Total                       **30**              **29**
  --------------------------- ------------------- ------------------------

In addition, 23 deaths occurred in patients who were not randomized: 3
deaths in patients in whom an implant was not attempted; 14 deaths in
patients in whom an implant attempt was unsuccessful; and 6 deaths in
patients who were implanted with an InSync^®^ ICD system but were not
randomized. Of these 23 deaths, 4 were classified by the investigator as
sudden cardiac, 12 as non-sudden cardiac, 3 as non-cardiac and 4 as
unknown.

B. Possible Adverse Events

Possible adverse events associated with ICD systems with Cardiac
Resynchronization Therapy include (in alphabetical order):

-   acceleration of arrhythmias (caused by ICD)

-   air embolism

-   bleeding

-   chronic nerve damage

-   erosion

-   exacerbation of heart failure

-   excessive fibrotic tissue growth

-   extrusion

-   fluid accumulation

-   formation of hematomas or cysts

-   inappropriate shocks

-   infection

-   keloid formation

-   lead abrasion and discontinuity

-   lead migration / dislodgment

-   myocardial damage

-   pneumothorax

-   potential mortality due to inability to defibrillate or pace

-   shunting current or insulating myocardium during defibrillation;
    thromboemboli

-   venous occlusion

-   venous or cardiac perforation.

    The adverse events related to the use of transvenous leads include,
    but are not limited to, the follow patient-related conditions when
    the lead is being inserted and/or repositioned

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-   cardiac dissection

-   cardiac perforation

-   cardiac tamponade

-   coronary sinus dissection

-   endocarditis

-   fibrillation or other arrhythmias

-   heart block

-   heart wall or vein wall rupture

-   infection, muscle or nerve stimulation

-   myocardial irritability

-   pericardial effusion

-   pericardial rub

-   pneumothorax

-   thrombolytic and air embolism

-   thrombosis

-   valve damage (particularly in fragile hearts).

VII\. Alternative Practices and Procedures

The present established therapies for the treatment of heart failure and
sudden cardiac death and the associated signs and symptoms include
pharmacological therapy, heart transplantation, other approved
biventricular ICDs or other surgical procedures.

VIII\. Marketing History

The InSync^®^ ICD device and Attain Models 2187/2188/4189[^1] leads are
currently distributed commercially outside the United States.
Specifically, these devices are approved for sale in the European
Community, Australia, Canada, and Latin America (Argentina, Uruguay).

Neither the device nor leads have been withdrawn from the market in any
country for any reason related to the safety and effectiveness of the
device.

IX. Summary of Pre-clinical Studies InSync^®^ ICD System

A. Safety and Risk Analysis

A safety and risk analysis of the InSync^®^ ICD system was conducted to
identify potential system hazards and to identify appropriate mitigating
actions. This analysis included:

Hazard Analysis

Hazard analysis identifies possible hazards from use of the InSync^®^
ICD system, determines the probability of occurrence and documents
mitigating actions to minimize risk. Hazard analysis was performed on
the InSync^®^ ICD system, including review of all hazards and mitigating
actions, and the remaining risk was determined to be acceptable.

Failure Modes Effects Analysis (FMEA)

FMEA was performed on the InSync^®^ ICD system to identify and mitigate
any potential design, test, or process issues that could adversely
influence the safety and/or performance of the device.

Reliability Prediction Analysis

An analysis of the expected field performance on the InSync^®^ ICD was
performed based on the field performance of similar Medtronic devices.
The predicted field performance of the InSync^®^ ICD is a failure rate
of 0.035% per month at a 90% confidence level.

B.  Non-clinical Laboratory Studies -- InSync^®^ ICD Model 7272

Major Components

The InSync^®^ ICD Model 7272 is a derivation of the GEM DR Model 7271
and GEM II DR Model 7273 systems with biventricular pacing capability
added for cardiac resynchronization. The InSync^®^ ICD Model 7272
components are identical or similar to those used in the GEM DR Model
7271.

**Table 3. Major Components of the InSync^®^** ICD Model 7272

+-----------+--------------------------------------+-------------------+
| Component | Comparison to Model 7271 GEM DR      | Qualification     |
+===========+======================================+===================+
| **        | -   Polyurethane module that         | -   InSync^®^ ICD |
| Connector |     contains lead ports. The module  |     Model 7272    |
| Module**  |     is bonded to device can          |     Connector     |
|           |                                      |     Qualification |
|           | -   Similar to Model 7271 GEM DR. LV |     Testing       |
|           |     lead port added to the connector |                   |
|           |     module                           |                   |
+-----------+--------------------------------------+-------------------+
| **        | -   Same lithium-silver vanadium     | -   Qualified     |
| Battery** |     oxide cells (Li/SVO) developed   |     with Model    |
| **(2)**   |     by the Promeon Division of       |     7271 GEM DR   |
|           |     Medtronic                        |                   |
+-----------+--------------------------------------+-------------------+
| **High    | -   Two HV output capacitors provide | -   Qualified     |
| Voltage   |     energy for cardioversion and     |     with Model    |
| C         |     defibrillation therapies. Same   |     7271 GEM DR   |
| apacitors |     as Model 7271                    |                   |
| (2)**     |                                      |                   |
+-----------+--------------------------------------+-------------------+
| **        | -   The antenna sends/receives       | -   Qualified     |
| Antenna** |     device communications through    |     with Model    |
|           |     bi-directional telemetry         |     7271 GEM DR   |
|           |                                      |                   |
|           | -   Same component used in Model     |                   |
|           |     7271 GEM DR                      |                   |
+-----------+--------------------------------------+-------------------+
| **Tran    | -   The transformer converts low     | -   Qualified     |
| sformer** |     voltage from the battery to high |     with Model    |
|           |     voltage for the HV capacitors    |     7271 GEM DR   |
|           |                                      |                   |
|           | -   Same component used in Model     |                   |
|           |     7271 GEM DR                      |                   |
+-----------+--------------------------------------+-------------------+
| **Ree     | -   The reedswitch is a magnetically | -   Qualified     |
| dswitch** |     controlled mechanical switch     |     with Model    |
|           |     that, once closed, signals the   |     7271 GEM DR   |
|           |     device that telemetry            |                   |
|           |     communications with the external |                   |
|           |     programmer can occur             |                   |
|           |                                      |                   |
|           | -   Same component used in Model     |                   |
|           |     7271 GEM DR                      |                   |
+-----------+--------------------------------------+-------------------+
| **        | -   The materials used in the        | -   Qualified     |
| Biocompat |     InSync^®^ ICD device are         |     with Model    |
| ibility** |     identical to those used in the   |     7271 GEM DR   |
|           |     Medtronic GEM DR Model 7271.     |                   |
|           |     These materials include:         |                   |
|           |     titanium, silicone adhesive,     |                   |
|           |     silicone rubber, and             |                   |
|           |     polyurethane. No new materials   |                   |
|           |     or processes were introduced     |                   |
|           |     with the InSync^®^ ICD Model     |                   |
|           |     7272 that would introduce new    |                   |
|           |     issues of biocompatibility.      |                   |
+-----------+--------------------------------------+-------------------+

Connector Module

Qualification activities performed on the InSync^®^ ICD Model 7272
tested the electrical and physical integrity of the connector module,
adhesive interfaces, and block / MBC-to-feedthrough welds (qualified by
similarity to GEM Model 7227Cx). The connector design met all
connector-specific requirements specified in the InSync^®^ ICD product
specification and the IS-1 and DF-1 international standards for
connectors (ISO 5841-3 and ISO 11318, respectively). Qualification
demonstrated that the connector module met these requirements with 90%
reliability at a 90% confidence level.

> **Table 4**. Connector Test

+-------------------------------+------+-----------------+------------+
| Connector Test                | Sa   | Acceptance      | Result     |
|                               | mple | Criteria        |            |
|                               | Size |                 |            |
+-------------------------------+------+-----------------+------------+
| 1.  Insertion / Withdrawal    | 22   | [               | Passed     |
|     (Go Gauge & Lead          |      | \<]{.underline} |            |
|     Connector)                |      | 2.0 lbf, Go     | Passed     |
|                               |      | Gauge),         |            |
|                               |      |                 |            |
|                               |      | [               |            |
|                               |      | \<]{.underline} |            |
|                               |      | 13.15 lbf, Lead |            |
|                               |      | Connector)      |            |
+-------------------------------+------+-----------------+------------+
| 2.  IS-1 Electrical Leakage   | 22   | [               | Passed     |
|     Impedance                 |      | \>]{.underline} |            |
|                               |      | 50 K ohms       |            |
+-------------------------------+------+-----------------+------------+
| 3.  DF-1 Electrical Isolation | 22   | [               | Passed     |
|                               |      | \<]{.underline} |            |
|                               |      | 50 mA           |            |
+-------------------------------+------+-----------------+------------+
| 4.  DF-1 Current Carrying     | NA   | [               | Qualified  |
|                               |      | \<]{.underline} | by         |
|                               |      | 65 V            | Similarity |
+-------------------------------+------+-----------------+------------+
| 5.  Suture Hole Pull Force    | 22   | [               | Passed     |
|                               |      | \>]{.underline} |            |
|                               |      | 6 lbs           |            |
+-------------------------------+------+-----------------+------------+

Device Qualification

Device qualification testing was performed to ensure that the InSync^®^
ICD Model 7272 performs acceptably in typical shipping, handling and
operating environments. The device qualification testing is summarized
below. The results demonstrated that the InSync^®^ ICD Model 7272 will
perform acceptably in typical shipping, handling, and operating
environments and is qualified for its intended use.

**Table 5. Device Qualification Testing**

+---------------+--------+------------------------------+-------------+
| **Test**      | **     | **Acceptance Criteria**      | **Results** |
|               | Sample |                              |             |
|               | Size** |                              |             |
+---------------+--------+------------------------------+-------------+
| **En          | 10     | **Temperature Storage:**     | Meets       |
| vironmental** |        | Meets Section 26.2 of        | Acceptance  |
|               |        | European Standard            | Criteria    |
|               |        | prEN45502-2-2                |             |
|               |        |                              |             |
|               |        | **Mechanical Vibration:**    |             |
|               |        | Meets Section 23.2 of        |             |
|               |        | European Standard            |             |
|               |        | prEN45502-2-2.               |             |
|               |        |                              |             |
|               |        | **Mechanical Shock:** Show   |             |
|               |        | no visible signs of damage   |             |
|               |        | which affects function of    |             |
|               |        | device after a shock having  |             |
|               |        | a change in velocity (dV) of |             |
|               |        | 118 inches per second and a  |             |
|               |        | duration of 1ms in each of   |             |
|               |        | six axes. Simulates a drop   |             |
|               |        | of 45cm (18") to a hard      |             |
|               |        | surface.                     |             |
+---------------+--------+------------------------------+-------------+
| **El          | 22     | **Electromagnetic            | Meets       |
| ectromagnetic |        | Interference:** Meets        | Acceptance  |
| Co            |        | requirements of the 1975     | Criteria    |
| mpatibility** |        | AAMI Pacemaker Standard.     |             |
|               |        | Also meets requirements at   |             |
|               |        | additional frequencies,      |             |
|               |        | including radiated           |             |
|               |        | continuous wave and pulsed   |             |
|               |        | electromagnetic fields and   |             |
|               |        | conducted continuous wave    |             |
|               |        | sinusoidal currents.         |             |
+---------------+--------+------------------------------+-------------+
|               | 3      | **Cellular Phone:** Not      |             |
|               |        | susceptible to interference  |             |
|               |        | from analog or digital       |             |
|               |        | cellular telephones at       |             |
|               |        | distances \>=8 cm, including |             |
|               |        | the following systems: AMPS, |             |
|               |        | TDMA-50 (NADC), GSM, DCS,    |             |
|               |        | and CDMA.                    |             |
+---------------+--------+------------------------------+-------------+
|               | 22     | **X-ray:** Testing waived    |             |
|               |        | based on similarity to GEM   |             |
|               |        | DR Model 7271.               |             |
+---------------+--------+------------------------------+-------------+
|               | 22     | **Electrosurgical Cautery:** |             |
|               |        | Must withstand spark         |             |
|               |        | cutting, spark coagulating,  |             |
|               |        | and sine cutting modes and   |             |
|               |        | energies.                    |             |
+---------------+--------+------------------------------+-------------+
|               | 22     | **Transthoracic              |             |
|               |        | Defibrillation:** must       |             |
|               |        | withstand 1000V and 1500V.   |             |
+---------------+--------+------------------------------+-------------+
| **Design      | 3      | Because of hardware          | Meets       |
| Verification  |        | similarity between InSync^®^ | Acceptance  |
| Testing**     |        | ICD and GEM DR, verification | Criteria    |
|               |        | testing was conducted only   |             |
|               |        | on hardware components       |             |
|               |        | (tests on the CRT therapy,   |             |
|               |        | unmodified circuits and      |             |
|               |        | device immunity to noise and |             |
|               |        | ESD). Testing confirmed      |             |
|               |        | conformance with product     |             |
|               |        | specifications.              |             |
+---------------+--------+------------------------------+-------------+

C. Non-clinical Laboratory Testing -- Firmware/Software

1\. Firmware Verification Testing

Firmware verification testing functionally verifies that each firmware
requirement for the Model 7272 InSync^®^ ICD is met. The verification
test plan is developed in parallel with the firmware design and firmware
implementation phases.

> **Table 6**. Summary of Firmware Verification Testing

  ----------------------------------------- --------------- --------------
  **Summary of Firmware Verification        **Sample        **Result**
  Testing**                                 Tested**        

  Firmware verification testing was         Firmware        Passed
  performed as defined by the Verification                  
  Test Plan Rev. 003                                        
  ----------------------------------------- --------------- --------------

2\. Software Verification Testing

Software verification testing was performed on the Model 9969
Application Software on both the Model 9790 and 2090 Programmers.

> **Table 7**. Summary of Software Verification Testing

  ----------------------------------------- --------------- --------------
  **Summary of Software Verification        **Sample        **Result**
  Testing**                                 Tested**        

  Software verification testing was         Software        Passed
  performed as defined by the Verification                  
  Test Plan. Testing consisted of                           
  functional testing, Software Install                      
  testing, stress testing, and regression                   
  testing.                                                  
  ----------------------------------------- --------------- --------------

3\. System Testing

System testing of the InSync^®^ ICD system (InSync^®^ ICD Model 7272,
Model 9969 Software, Model 9790 and 2090 programmers, and accessories)
was performed to ensure that all system components work together
appropriately under simulated clinical situations.

> **Table 8**. Summary of System Testing

  ----------------------------------------- --------------- --------------
  **Summary of System Testing**             **Sample        **Result**
                                            Tested**        

  System testing evaluates the              InSync^®^ ICD   Passed
  compatibility, interaction and functional System          
  operation of the InSync^®^ ICD system     Components      
  components when used together as a                        
  system.                                                   
  ----------------------------------------- --------------- --------------

D. Biocompatibility Testing

All blood-contacting materials used in the InSync^®^ ICD pulse generator
are identical to those used in PMA-approved Medtronic pulse generators.
These currently-marketed pulse generators have previously been subject
to standard biocompatibility evaluations which conform to FDA Tripartite
Biocompatibility Guidance (4/87), FDA Blue Book Memorandum #95-1 (5/95),
and the International Standard ISO-10993.

All biocompatibility testing was conducted in compliance with Good
Laboratory Practices (GLP).

E. Sterilization Information

The 100% ethylene oxide (EtO) sterilization process used to sterilize
the implantable pulse generator has been previously approved in other
PMA applications. All processes used to sterilize a product are
validated and qualified according to the major guidelines and standards.
Package qualification testing was performed on both the device to ensure
suitability for their intended purpose.

F. Animal Studies

GLP studies were conducted in 3 canines with the InSync^®^ ICD Model
7272. The purpose of the Model 7272 InSync^®^ ICD study was to determine
that the device provided acceptable performance for sensing and
detection of cardiac rhythms, appropriate rejection of sinus
arrhythmias, and correct delivery of appropriate programmed therapy. In
each of the studies, appropriate pacing, sensing, and thresholds were
documented.

G. Conclusion Concerning Non-clinical Laboratory Testing

Medtronic conducted a hazard analysis on all new features and critical
components and then conducted testing to evaluate these and other device
features. All test results were found to be acceptable.

H. Shelf Life

Based on battery longevity testing, the shelf life for the InSync^®^ ICD
pulse generator was established and approved at 18 months from battery
attachment date.

X. Summary of Clinical Study

A. Study Design

The InSync^®^ ICD study was a prospective, multi-center, randomized,
double-blind, parallel arm, controlled clinical trial to assess the
safety and effectiveness of transvenous atrial-based synchronous
biventricular pacing for heart failure therapy (cardiac
resynchronization therapy -- CRT) in patients who are indicated for an
ICD. Patients in NYHA Classes II, III and IV were enrolled in the
clinical study (for the purposes of FDA approval, only data from NYHA
Class III and IV patients are presented unless otherwise noted). The
products being evaluated include the Model 7272 InSync^®^ ICD and the
Model 9969 application software for use with the Model 9790C and 2090
programmers and the commercially available Models 2187 and 2188 Attain
LV leads and the Model 4189[^2] Attain LV Lead.

**Note:** The 4189 Attain Lead is not currently market approved in the
U.S. Lead performance data in the clinical trial did not support
reasonable assurance of the safety and effectiveness of the 4189 Lead.
However, the data obtained with the 4189 Lead are presented for
completeness here. Based on similarities in the design and function of
the 4189 and 2187/2188, these two sets of leads are equally compatible
with the Model 7272 InSync^®^ ICD to deliver biventricular pacing.

**\
Figure 1** depicts the InSync^®^ ICD study design. Patients were
randomized within 7 days of a successful implant and were in
double-blind follow-up for 6 months. After the six-month follow up, all
patients had CRT turned on.

![](media/image1.wmf)

**Figure 1. InSync^®^ ICD Study Design**

Patient Selection Criteria

Inclusion Criteria

**ICD Indication**

1.  Patients who have had at least one episode of cardiac arrest
    (manifested by loss of consciousness) due to ventricular
    tachyarrhythmia;

    or

2.  Patients having recurrent, poorly tolerated, sustained VT that
    occurs spontaneously or can be induced;

    or

3.  ***Canada Only:*** Patients who have had a prior myocardial
    infarction, left ventricular ejection fraction less than or equal to
    35%, a documented episode of non-sustained VT and inducible
    ventricular tachyarrhythmia.

    **And Heart Failure as defined by:**

4.  Patients having symptomatic congestive heart failure (NYHA Class II,
    III, IV) with evidence of ventricular dysynchrony demonstrated by:

5.  QRS duration ≥ 130 ms,

6.  LV Ejection Fraction ≤ 35%,

7.  LV End Diastolic Diameter ≥ 55 mm.

8.  Stable medical regimen for at least 1 month prior to enrollment (to
    include at least ACE inhibitors, or ACE inhibitor substitute)
    patients currently on stable beta blockade regimes for at least 3
    months prior to enrollment were allowed in the study. Patients may
    not be started on beta-blockers during the 6-month randomization
    period.

9.  18 years of age or older.

Exclusion Criteria

10. Baseline Six Minute Hall Walk distance greater than 450 meters
    (Class III and IV only).

11. Unstable angina, or acute MI, CABG, or PTCA within the past 3
    months.

12. Recent CVA or TIA (within the previous 3 months).

13. Intermittent positive inotropic drug therapy (intermittent is
    defined as more than two infusions per week).

14. Patients having indications or contraindications for standard
    cardiac pacing.

15. Systolic blood pressure of less than 80 mm or greater than 170 mm.

16. Resting heart rate greater than 140 bpm.

17. Serum Creatinine greater than 3 mg/dl.

18. Hepatic function (serum) greater than 3 times the upper limit of
    normal.

19. Primary valvular disease.

20. Severe primary pulmonary disease.

21. Chronic atrial arrhythmias (or cardioversion for afib within the
    past month) or paroxysmal atrial fib event within the previous
    month.

22. Post heart transplant (patients who are waiting for a heart
    transplant are allowed entry into the study).

23. Enrolled in any concurrent study that may confound the results of
    this study.

24. Patients who are not expected to survive for 6 months of study
    participation.

25. Women who are pregnant or with child bearing potential and who are
    not on a reliable form of birth control.

26. Patients with mechanical right heart valves.

27. Patients with VT associated with reversible causes.

Study Blind

The InSync^®^ ICD trial was double-blinded to reduce the effect of bias.
Implanting physicians and staff responsible for programming the
InSync^®^ ICD were required to be aware of the mode to which the device
was programmed. The EP staff (electrophysiologist, EP nurses, etc.)
performed all tests that required viewing of the programmed pacing mode
or the patient's ECG. The heart failure staff (heart failure physician,
nurses, etc.) and the patients remained blinded and did not view these
materials. Neither the patient nor the heart failure physician had
knowledge of the pacing mode assigned. Because of their blinded status,
the evaluations of QOL, NYHA classification, and 6-minute hall walk were
conducted by the heart failure staff. All non-electrophysiological
patient management decisions were made by the blinded heart failure
physicians and nurses.

B. Clinical Study Results

1\. Patient Population

Study Enrollment

The first successful implant of the Model 7272 InSync^®^ ICD cardiac
resynchronization system was performed on October 4, 1999. Fifty-three
centers provided data for this clinical report (48 in USA, 5 in Canada)
and 638 patients (Class II, III and IV) had implant attempts. There were
570 patients with successful implants, of which 555 were randomized. The
patients received the commercially available LV Lead Models 2187 or 2188
or the Model 4189[^3] LV Lead which is not a subject of this PMA
approval. In total, there were 283 patients randomized to the control
arm (OFF), and 272 patients randomized to the treatment arm (ON). Of the
283 control patients, 106 were NYHA Class II and 177 were NYHA Class III
and IV. Of the 272 treatment patients, 85 were NYHA Class II and 187
were NYHA Class III and IV treatment patients. For the purposes of FDA
approval, results from NYHA Class III and IV patients only will be
presented unless otherwise noted.

Figure 2 provides summary information on the study patient population.

^1^ Refer to page [20](#no_impl_attempt) for additional information.\
^2^ Refer to page [33](#unsuccessful_implants) for detailed
information.\
^3^ Refer to page [20](#not_randomized) for detailed information.

**\
Figure 2. InSync^®^ ICD Study Patient Population**

Patients Enrolled But Implant Not Attempted[]{#no_impl_attempt .anchor}

Of the 434 NYHA Class III and IV patients enrolled in the InSync^®^ ICD
study, 10 NYHA Class III and IV patients were consented, entailing
enrollment, but an implant was not attempted. **Table 9** summarizes the
reasons that an implant was not attempted in these patients.

**Table 9**. Patients Enrolled But Implant Not Attempted --\
NYHA Class III and IV Patients

  ---------------------------------------------------------- ------------
  Reason implant was not attempted                           Total

  Did not satisfy VT inclusion criterion                     2

  Did not satisfy LVEF inclusion criterion                   2

  Unable to obtain venous access                             2

  Death prior to implant attempt                             2

  Developed indications for standard cardiac pacing          1

  Cancer diagnosed; chemotherapy initiated                   1
  ---------------------------------------------------------- ------------

Patients Not Randomized[]{#not_randomized .anchor}

Reasons for ten NYHA Class III and IV patients who were implanted with
an InSync^®^ ICD system but not randomized are summarized below:

-   Patient unstable/pacing required (4)

-   LV lead dislodgement (3)

-   Respiratory arrest (1)

-   Heart transplant prior to randomization (1)

-   Patient death prior to randomization (1)

Crossovers

Biventricular Pacing OFF to ON

Fifteen NYHA Class III and IV patients were randomized to biventricular
pacing OFF and had an early crossover to biventricular pacing ON prior
to the 6-month follow-up visit. The reasons for the programming changes
are described below:

1.  Worsening heart failure requiring CRT (11)

2.  Inadvertent programming (2)

3.  Bradycardia (1)

4.  AV nodal ablation (1)

Biventricular Pacing ON to OFF

Ten NYHA Class III and IV patients were randomized to biventricular
pacing ON and had an early crossover to biventricular pacing OFF prior
to the 6-month follow-up visit. The reasons for the programming changes
are described below:

5.  Inadvertent programming (6)

6.  LV lead dislodgment (2)

7.  Diaphragmatic stimulation (2)

2\. Baseline Demographic Data

Baseline demographic data for randomized NYHA Class III and IV patients
are summarized in Table 10. P-values \< 0.05 are noted with an asterisk.

**Table 10**. Comparison of Control and Treatment Patients at Baseline
--\
NYHA Class III and IV Patients

+----------------------------------+------------+------------+--------+
| InSync^®^ ICD\                   |            |            |        |
| Comparison of Demographics by    |            |            |        |
| Treatment Assignment\            |            |            |        |
| All Randomized NYHA Class III/IV |            |            |        |
| Patients                         |            |            |        |
+==================================+============+============+========+
|                                  | Control\   | Treatment\ | P      |
|                                  | (OFF)      | (ON)       | -value |
|                                  |            |            |        |
|                                  | (n=177)    | (n=187)    |        |
+----------------------------------+------------+------------+--------+
| **Gender (n,%)**                 | 136        | 142        | 0.90   |
|                                  | (76.8%)    | (75.9%)    |        |
| > Male                           |            |            |        |
| >                                | 41 (23.2%) | 45 (24.1%) |        |
| > Female                         |            |            |        |
+----------------------------------+------------+------------+--------+
| **Age (years)**                  | 67.4 ± 9.4 | 66.6 ±     | 0.88   |
|                                  |            | 11.3       |        |
| > Mean ± Standard deviation      | 177        |            |        |
| >                                | (100.0%)   | 187        |        |
| > n(%)                           |            | (100.0%)   |        |
+----------------------------------+------------+------------+--------+
| **New York Heart Classification  | 158        | 165        | 0.87   |
| (n,%)**                          | (89.3%)    | (88.2%)    |        |
|                                  |            |            |        |
| > III                            | 19 (10.7%) | 22 (11.8%) |        |
| >                                |            |            |        |
| > IV                             |            |            |        |
+----------------------------------+------------+------------+--------+
| **QRS Width (ms)**               | 162 ± 22   | 165 ± 22   | 0.15   |
|                                  |            |            |        |
| > Mean ± Standard deviation      | 177        | 187        |        |
| >                                | (100.0%)   | (100.0%)   |        |
| > n (%)                          |            |            |        |
+----------------------------------+------------+------------+--------+
| **Ejection Fraction (%)**        | 20.1 ± 6.1 | 20.5 ± 7.0 | 0.74   |
|                                  |            |            |        |
| > Mean ± Standard deviation      | 176        | 187        |        |
| >                                | (99.4%)    | (100.0%)   |        |
| > n (%)                          |            |            |        |
+----------------------------------+------------+------------+--------+
| **LVEDD (mm)**                   | 70.9 ± 9.1 | 70.4 ± 9.0 | 0.51   |
|                                  |            |            |        |
| > Mean ± Standard deviation      | 174        | 186        |        |
| >                                | (98.3%)    | (99.5%)    |        |
| > n (%)                          |            |            |        |
+----------------------------------+------------+------------+--------+
| **MN Living with HF Score**      | 55.2 ±     | 56.5 ±     | 0.56   |
|                                  | 22.9       | 22.9       |        |
| > Mean ± Standard deviation      |            |            |        |
| >                                | 174        | 185        |        |
| > n (%)                          | (98.3%)    | (98.9%)    |        |
+----------------------------------+------------+------------+--------+
| **6 --Minute Hall Walk           | 245 ± 118  | 243 ± 130  | 0.87   |
| (meters)**                       |            |            |        |
|                                  | 175        | 183        |        |
| > Mean ± Standard deviation      | (98.9%)    | (97.9%)    |        |
| >                                |            |            |        |
| > n (%)                          |            |            |        |
+----------------------------------+------------+------------+--------+
| **Peak VO~2~/kg (ml/kg/min.)**   | 13.5 ± 3.9 | 13.4 ± 3.6 | 0.96   |
|                                  |            |            |        |
| > Mean ± Standard deviation      | 135        | 144        |        |
| >                                | (76.3%)    | (77.0%)    |        |
| > n (%)                          |            |            |        |
+----------------------------------+------------+------------+--------+
| **Exercise Time (seconds)**      | 511 ± 229  | 473 ± 213  | 0.27   |
|                                  |            |            |        |
| > Mean ± Standard deviation      | 136        | 143        |        |
| >                                | (76.8%)    | (76.5%)    |        |
| > n (%)                          |            |            |        |
+----------------------------------+------------+------------+--------+
| **Supine Heart Rate (bpm)**      | 71.5 ±     | 70.9 ±     | 0.82   |
|                                  | 12.9       | 12.4       |        |
| > Mean ± Standard deviation      |            |            |        |
| >                                | 171        | 186        |        |
| > n (%)                          | (96.6%)    | (99.5%)    |        |
+----------------------------------+------------+------------+--------+
| **Baseline CV Medical History    | 177        | 186        | 0.03\* |
| (n, %)**                         |            |            |        |
|                                  | 135        | 122        | 0.50   |
| (non-exclusive)                  | (76.3%)    | (65.6%)    |        |
|                                  |            |            | 0.02\* |
| n recorded                       | 0 (0%)     | 2 (1.1%)   |        |
|                                  |            |            | 0.09   |
| Coronary Artery Disease          | 133        | 119        |        |
|                                  | (75.1%)    | (64.0%)    | 0.07   |
| Congenital Heart Disease         |            |            |        |
|                                  | 49 (27.7%) | 67 (36.0%) | 1.00   |
| HF etiology: ischemic            |            |            |        |
|                                  | 112        | 100        | 0.70   |
| HF etiology: non-ischemic        | (63.3%)    | (53.8%)    |        |
|                                  |            |            | 0.72   |
| Myocardial Infarction            | 46 (26.0%) | 48 (25.8%) |        |
|                                  |            |            | 0.78   |
| Anterior                         | 13 (7.3%)  | 16 (8.6%)  |        |
|                                  |            |            | 0.04\* |
| Lateral                          | 3 (1.7%)   | 5 (2.7%)   |        |
|                                  |            |            | 0.82   |
| Posterior                        | 32 (18.1%) | 31 (16.7%) |        |
|                                  |            |            | 1.00   |
| Inferior                         | 15 (8.5%)  | 6 (3.2%)   |        |
|                                  |            |            | 1.00   |
| Non Q-wave                       | 166        | 176        |        |
|                                  | (93.8%)    | (94.6%)    | 0.29   |
| Cardiomyopathy                   |            |            |        |
|                                  | 5 (2.8%)   | 6 (3.2%)   | 0.24   |
| Primary electrical disease       |            |            |        |
|                                  | 0 (0%)     | 0 (0%)     | 1.00   |
| Valvular Disease                 |            |            |        |
|                                  | 90 (50.8%) | 84 (45.2%) | 0.89   |
| Hypertension                     |            |            |        |
|                                  | 2 (1.1%)   | 0 (0%)     |        |
| Chronotropic incompetence        |            |            |        |
|                                  | 46 (26.0%) | 49 (26.3%) |        |
| Syncope/presyncope               |            |            |        |
|                                  | 28 (15.8%) | 31 (16.7%) |        |
| Other                            |            |            |        |
+----------------------------------+------------+------------+--------+
| **Prior Cardiac Intervention (n, | 173        | 182        | 0.34   |
| %)**                             |            |            |        |
|                                  | 87 (50.3%) | 82 (45.1%) | 0.51   |
| **(non-exclusive)**              |            |            |        |
|                                  | 9 (5.2%)   | 13 (7.1%)  | 0.78   |
| n recorded                       |            |            |        |
|                                  | 7 (4.0%)   | 6 (3.3%)   | 0.47   |
| CABG                             |            |            |        |
|                                  | 48 (27.7%) | 44 (24.2%) | 0.50   |
| Valve replacement                |            |            |        |
|                                  | 0 (0%)     | 2 (1.1%)   | 1.00   |
| Ablation                         |            |            |        |
|                                  | 51 (29.5%) | 54 (29.7%) | 0.64   |
| Coronary Artery Intervention     |            |            |        |
|                                  | 48 (27.7%) | 55 (30.2%) |        |
| Repair/Correction of Cong.       |            |            |        |
| Abnormality                      |            |            |        |
|                                  |            |            |        |
| ICD currently implanted          |            |            |        |
|                                  |            |            |        |
| None                             |            |            |        |
+----------------------------------+------------+------------+--------+
| **Spontaneous Arrhythmia         | 177        | 187        | 0.06   |
| History**                        |            |            |        |
|                                  | 31 (17.5%) | 49 (26.2%) | 0.62   |
| **(non-exclusive)**              |            |            |        |
|                                  | 7 (4.0%)   | 10 (5.3%)  | 0.62   |
| n recorded                       |            |            |        |
|                                  | 0 (0%)     | 0 (0%)     | 0.51   |
| Atrial Fibrillation              |            |            |        |
|                                  | 67 (37.9%) | 64 (34.2%) | 0.46   |
| Atrial Flutter                   |            |            |        |
|                                  | 10 (5.6%)  | 7 (3.7%)   | 0.06   |
| AV Nodal Reentrant Tachycardia   |            |            |        |
|                                  | 52 (29.4%) | 73 (39.0%) | 0.66   |
| Sustained Monomorphic VT         |            |            |        |
|                                  | 28 (15.8%) | 26 (13.9%) | 1.00   |
| Sustained Polymorphic VT         |            |            |        |
|                                  | 1 (0.6%)   | 1 (0.5%)   | 1.00   |
| Nonsustained VT                  |            |            |        |
|                                  | 0 (0%)     | 0 (0%)     | 0.92   |
| Ventricular Flutter/Fibrillation |            |            |        |
|                                  | 101        | 105        | 0.88   |
| Torsades de Pointes              | (57.1%)    | (56.2%)    |        |
|                                  |            |            | 0.41   |
| Long QT Syndrome                 | 24 (13.6%) | 24 (12.8%) |        |
|                                  |            |            | 0.51   |
| Bradycardia^1^                   | 126        | 141        |        |
|                                  | (71.2%)    | (75.4%)    |        |
| Right Bundle Branch Block        |            |            |        |
|                                  | 32 (18.1%) | 39 (20.9%) |        |
| Left Bundle Branch Block         |            |            |        |
|                                  |            |            |        |
| Others                           |            |            |        |
+----------------------------------+------------+------------+--------+
| **Other Medical History (n, %)** | 177        | 187        | 0.19   |
|                                  |            |            |        |
| **(non-exclusive)**              | 32 (18.1%) | 24 (12.8%) | 0.27   |
|                                  |            |            |        |
| n recorded                       | 37 (20.9%) | 49 (26.2%) | 0.40   |
|                                  |            |            |        |
| Endocrine (includes diabetes)    | 33 (18.6%) | 28 (15.0%) |        |
|                                  |            |            |        |
| Pulmonary (includes COPD)        |            |            |        |
|                                  |            |            |        |
| Renal                            |            |            |        |
+----------------------------------+------------+------------+--------+
| **Medications (n, %)**           | 177        | 187        | 0.17   |
|                                  |            |            |        |
| **(non-exclusive)**              | 155        | 172        | 0.05   |
|                                  | (87.6%)    | (92.0%)    |        |
| n recorded                       |            |            | 1.00   |
|                                  | 57 (32.2%) | 79 (42.2%) |        |
| ACE Inhibitor                    |            |            | 0.44   |
|                                  | 35 (19.8%) | 36 (19.3%) |        |
| Anti-Arrhythmic                  |            |            | 0.39   |
|                                  | 143        | 144        |        |
| Anti-Depressant                  | (80.8%)    | (77.0%)    | 0.67   |
|                                  |            |            |        |
| Anti-Coagulant                   | 103        | 118        | 0.53   |
|                                  | (58.2%)    | (63.1%)    |        |
| Beta Blocker                     |            |            | 0.55   |
|                                  | 10 (5.6%)  | 13 (7.0%)  |        |
| Ca++ Blocker                     |            |            | 0.58   |
|                                  | 167        | 173        |        |
| Diuretic                         | (94.4%)    | (92.5%)    | 0.59   |
|                                  |            |            |        |
| Positive Inotrope                | 129        | 142        |        |
|                                  | (72.9%)    | (75.9%)    |        |
| Nitrate                          |            |            |        |
|                                  | 59 (33.3%) | 68 (36.4%) |        |
| Other Medication                 |            |            |        |
|                                  | 108        | 108        |        |
|                                  | (61.0%)    | (57.8%)    |        |
+----------------------------------+------------+------------+--------+

\* p \< 0.50

^1^ Includes sinus bradycardia, sick sinus syndrome, 1º, 2º and 3º
atrioventricular block and bradycardia-tachycardia syndrome.

3.  Primary Effectiveness Endpoint Results

The primary endpoints of the study were improvement in NYHA Class,
Quality of Life and 6-minute Hall Walk. The study results were analyzed
using the Hochberg criteria in that there would be a statistical success
for effectiveness if one of the three endpoints was statistically
significant at alpha =0.0167, if any two were significant at alpha =
0.025, or if all three were significant at alpha = 0.05.

Quality of Life

Patient quality of life (QOL) was assessed with the Minnesota Living
with Heart Failure (MLWHF) questionnaire. A lower score indicates an
improvement in quality of life. Both the patient and study personnel
administering the questionnaire were blinded to the randomization
assignment. Table 11 summarizes the paired baseline and 6 month QOL
results for NYHA Class III and IV patients. P-values were based on the
paired median difference.

> **Table 11**. MLWHF QOL Paired Baseline and 6-Month Data\
> NYHA III/IV Patients

+-------------+------------------------+-----------------------+------+
|             | **Control Group\       | **Treatment Group\    | **P- |
|             | *(CRT OFF)***          | *(CRT ON)***          | val  |
|             |                        |                       | ue** |
+-------------+------------------------+-----------------------+------+
| **6-month   | 153 patients with      | 162 patients with     | 0.02 |
| change in   | paired data            | paired data           |      |
| QOL score** |                        |                       |      |
|             | **Baseline:** median   | **Baseline:** median  |      |
|             | 57.0                   | 55.0                  |      |
|             |                        |                       |      |
|             | Mean 55.1              | mean 54.2             |      |
|             | [+]{.underline} 22.5   | [+]{.underline} 23.1  |      |
|             |                        |                       |      |
|             | **6-month:** median    | **6-month:** median   |      |
|             | 43.0                   | 34.0                  |      |
|             |                        |                       |      |
|             | mean 42.0              | mean 35.9             |      |
|             | [+]{.underline} 22.9   | [+]{.underline} 23.4  |      |
|             |                        |                       |      |
|             | **Median Paired        | **Median Paired       |      |
|             | Difference: -- 11.0**  | Difference: -- 17.5** |      |
+-------------+------------------------+-----------------------+------+

Figure 3 presents the median change in QOL for the control and treatment
groups at baseline through 6 month follow up.

![](media/image2.wmf)\
**Figure 3. MN Living With Heart Failure Data Summary**

NYHA Classification

NYHA functional classification was determined by a physician who was
blinded to the patient's randomization assignment. Table 12 summarizes
the paired baseline and 6 month NYHA results for NYHA Class III and IV
patients. The P-value was based on the median paired difference.

> **Table 12**. NYHA Paired Baseline and 6-Month Data-- NYHA III/IV
> Patients

+-------------+------------------------+-----------------------+------+
|             | **Control Group**      | **Treatment Group**   | **P- |
|             |                        |                       | val  |
|             | ***(OFF)***            | ***(ON)***            | ue** |
+-------------+------------------------+-----------------------+------+
| **6-month   | 158 patients with      | 165 patients with     | 0.01 |
| change in   | paired data            | paired data           |      |
| NYHA        |                        |                       |      |
| Class       | **Baseline:** median   | **Baseline:** median  |      |
| ification** | 3.0                    | 3.0                   |      |
|             |                        |                       |      |
|             | Mean 3.09              | mean 3.10             |      |
|             | [+]{.underline} 0.29   | [+]{.underline} 0.30  |      |
|             |                        |                       |      |
|             | **6-month:** median    | **6-month:** median   |      |
|             | 3.0                    | 2.0                   |      |
|             |                        |                       |      |
|             | mean 2.51              | mean 2.31             |      |
|             | [+]{.underline} 0.6    | [+]{.underline} 0.72  |      |
|             |                        |                       |      |
|             | **Median Paired        | **Median Paired       |      |
|             | Difference: -- 0.5**   | Difference: -- 1**    |      |
+-------------+------------------------+-----------------------+------+

Figure 4 presents the median change in NYHA class for the control and
treatment groups at baseline through 6 month follow up.

![](media/image3.wmf)

**Figure 4. NYHA Classification Data Summary**

6-Minute Hall Walk

Patients performed a 6-minute hall walk test in order to assess
sub-maximal exercise capacity. Study personnel administering the test
were blinded to the patient's randomization assignment. Table 13
summarizes the paired baseline and 6 month 6 minute hall walk results
for NYHA Class III and IV patients. The P-value was based on the median
paired difference.

**Table 13**. 6-Minute Hall Walk Paired Baseline and 6 Month Data--\
NYHA III/IV Patients

+-------------+------------------------+-----------------------+------+
|             | **Control Group**      | **Treatment Group**   | **P- |
|             |                        |                       | val  |
|             | ***(OFF)***            | ***(ON)***            | ue** |
+-------------+------------------------+-----------------------+------+
| **6-month   | 150 patients with      | 153 patients with     | 0.43 |
| change in 6 | paired data            | paired data           |      |
| minute hall |                        |                       |      |
| walk**      | **Baseline:** median   | **Baseline:** median  |      |
| (meters)    | 275                    | 254                   |      |
|             |                        |                       |      |
|             | Mean 254               | mean 252              |      |
|             | [+]{.underline} 112    | [+]{.underline} 128   |      |
|             |                        |                       |      |
|             | **6-month:** median    | **6-month:** median   |      |
|             | 334                    | 340                   |      |
|             |                        |                       |      |
|             | mean 324               | mean 339              |      |
|             | [+]{.underline} 114    | [+]{.underline} 106   |      |
|             |                        |                       |      |
|             | **Median Paired        | **Median Paired       |      |
|             | Difference: 53**       | Difference: 55**      |      |
+-------------+------------------------+-----------------------+------+

**Figure 5** presents the median change in 6-minute hall walk distance
for the control and treatment groups at baseline through 6 month follow
up.

![](media/image4.wmf)

**Figure 5. 6-Minute Hall Walk Data Summary**

4\. Primary Safety Endpoint Results

ICD-Related Complications

Table 14 summarizes the 5 NYHA Class III and IV patients who experienced
7 complications at 3 months post-implant related to the Model 7272
InSync^®^ ICD.

**Table 14. InSync^®^** ICD-Related Complications -- NYHA III/IV
Patients

  --------------------------------- ----------------- --------------------
  Event Type                        Number of events  Events in the First\
                                                      3 Months

  Pain at pocket site               1                 1

  Pocket seroma/hematoma            2                 2

  Abnormal impedance measurement    1                 1

  Dizziness                         1                 1

  Electrical reset of ICD           1                 1

  Pocket infection                  1                 1

  Pacemaker-mediated tachycardia\*  1                 0

  **TOTAL**                         **8 events\       **7 events\
                                    (in 6 patients)** (in 5 patients)**
  --------------------------------- ----------------- --------------------

\*after 3 months

Table 15 summarizes the freedom from ICD-related complications at three
months post-implant.

**Table 15. Freedom from InSync^®^** ICD-Related Complications\
During First 3 Months -- NYHA III/IV Patients

  ---------------- ------------- ----------- --------------- ---------------
  \# Patients      \# Implanted  Estimated   Lower 95%       95% lower bound
  With\            Patients      survival    confidence      criterion
  ICD-Related                                limit           
  Complications                                              

  5                371           98.6%       97.6%           89.0%
  ---------------- ------------- ----------- --------------- ---------------

Attain Model 4189 LV Lead-Related Complications

Table 16 summarizes Model 4189[^4] LV lead-related complications in NYHA
Class III and IV patients at six months. The Model 4189^\*^ lead is not
the subject of this approval decision.

**Table 16**. Model 4189-Related Complications --\
NYHA III/IV Patients

+-------------------------------+------------------+------------------+
| Event Type                    | Number Of Events | Events In All    |
|                               | In All Patients  | Patients In The  |
|                               |                  | First 6 Months   |
+-------------------------------+------------------+------------------+
| Lead dislodgement             | 31               | 29               |
+-------------------------------+------------------+------------------+
| Extra cardiac stimulation     | 12               | 11               |
+-------------------------------+------------------+------------------+
| Elevated pacing thresholds    | 4                | 4                |
+-------------------------------+------------------+------------------+
| Failure to capture            | 3                | 3                |
+-------------------------------+------------------+------------------+
| Muscle stimulation --         | 1                | 1                |
| pectoral                      |                  |                  |
+-------------------------------+------------------+------------------+
| Pericardial effusion          | 1                | 1                |
+-------------------------------+------------------+------------------+
| **TOTAL**                     | **52 events**    | **49 events**    |
|                               |                  |                  |
|                               | **(in 46         | **(in 44         |
|                               | patients)**      | patients)**      |
+-------------------------------+------------------+------------------+

**Table 17**. Freedom from Model 4189\
Complications During First 6 Months -- NYHA III/IV Patients

  --------------- ------------ ------------- -------------- --------------
  Number of       Number of    Estimated     Lower 95%      95% Lower
  Patients With   Implanted    Survival      Confidence     Bound
  Events          Patients                   Bound          Criterion

  44              315          85.1%         81.7%          75%
  --------------- ------------ ------------- -------------- --------------

5\. Attain Models 2187 and 2188 LV Lead-Related Complications

The following table presents the summary of the market approved Model
2187 and 2188 complications in NYHA Class III and IV patients.

**Table 18**. Model 2187/2188 Related Complications\
NYHA III/IV Patients

  ---------------------------- --------------------- --------------------
  Event Type                   Number of Events      Events in the First
                                                     6 Months

  Lead dislodgment             6                     3

  Failure to capture           1                     1

  Elevated pacing thresholds   1\*                   1\*

  **TOTAL**                    **8\                  **5 events\
                               (in 8 patients)**     (in 5 patients)**
  ---------------------------- --------------------- --------------------

> \*Related to Model 2188

**Table 19**. Freedom from 2187/2188 Related Complications\
During First 6 Months -- NYHA III/IV Patients

  ------------------ ------------ ------------ ------------- -------------
  Number of patients Number of    Estimated    Lower 95%     95% Lower
  with complications Implanted    survival     confidence    Bound
                     Patients                  limit         Criterion

  5                  56           89.9%        82.9%         75%
  ------------------ ------------ ------------ ------------- -------------

System-Related Complications

Table 20 summarizes the system-related complications for NYHA Class III
and IV patients.

**Table 20**. System-Related Complications -- NYHA III/IV Patients

  -------------------------------------------------------------------------
  Device            **Event Type**                  **\#       **\# Events
  Relatedness                                       Events**   at 6 mo.**
  ----------------- ------------------------------- ---------- ------------
  InSync^®^ ICD     Pain at pocket site             1          1
  related                                                      

                    Abnormal impedance measurement  1          1

                    Pocket seroma/hematoma          2          2

                    Pocket infection                1          1

                    Dizziness                       1          1

                    Electrical reset of ICD         1          1

                    Pacemaker mediated tachycardia  1          1

                    **Subtotal:**                   **8**      **8**

  LV lead related   Lead dislodgment                6          3
  (2187/88)                                                    

                    Failure to capture              1          1

                    Elevated pacing thresholds      1          1

                    **Subtotal:**                   **8**      **5**

  LV lead related   Lead dislodgment                31         29
  (4189)                                                       

                    Muscle stimulation -- diaphragm 12         11

                    Elevated pacing thresholds      4          4

                    Failure to capture              3          3

                    Muscle stimulation -- pectoral  1          1

                    Pericardial effusion            1          1

                    **Subtotal:**                   **52**     **49**

  RA lead related   Lead dislodgment                6          6

                    Elevated pacing thresholds      2          2

                    Failure to capture              2          2

                    Far-field R-wave sensing        1          1

                    **Subtotal:**                   **11**     **11**

  RV lead related   Muscle stimulation -- diaphragm 1          1

                    Elevated pacing thresholds      1          1

                    Failure to capture              1          1

                    Chronic RV lead discovered      1          1
                    implanted in cardiac vein                  

                    **Subtotal:**                   **4**      **4**

  System related    Pocket infection                1          1

                    Twiddler's syndrome             1          1

                    **Subtotal:**                   **2**      **2**

  Total                                             **85       **79 events\
                                                    events\    (in 65
                                                    (in 69     pts.)**
                                                    pts.)**    
  -------------------------------------------------------------------------

Table 21 summarizes the freedom from system-related complications at six
months post-implant.

**Table 21**. Freedom from System-Related Complications During First 6
Months --\
NYHA III/IV Patients

  ------------------------- ----- ------------ ----------- --------- ------------ ----------- -----------
  \# Patients With                \# Implanted Estimated             Lower 95%                95% lower
  System-Related                  Patients     survival              confidence               bound
  Complications                                                      limit                    criterion

  65                        371                            81.1%                  77.6%       67.0%
  ------------------------- ----- ------------ ----------- --------- ------------ ----------- -----------

6\. Primary LV Lead Effectiveness Endpoint Results

LV Lead Implant Success

Four hundred and twenty-four NYHA Class III and IV patients underwent
implant attempts. 374 patients were successfully implanted with an
InSync^®^ ICD system (85% received a Model 4189[^5], 14% received a
Model 2187 and 1% received a Model 2188). Three hundred and sixty-five
patients were successfully implanted on their first attempt. Eleven of
the unsuccessful patients underwent a second implant attempt. Nine of
those patients were successfully implanted the second time.

**Table 22. Implant Success Rate** -- NYHA III/IV Patients

  ---------------- -------------- ------------ -------------- -------------
  Number of        Number of      Successful   Two-sided 95%  95% Lower
  Patients With    Successful     Implant Rate Confidence     Bound
  Implant Attempts Implants                    Interval       Criterion

  424              374            88.2%        84.8%-91.1%    83%
  ---------------- -------------- ------------ -------------- -------------

**Table 23** summarizes the reasons for the unsuccessful implants
(patients may have more than one reason).

**Table 23. Summary of Unsuccessful Implants**[]{#unsuccessful_implants
.anchor}\
(Model 2187, 2188 and 4189 LV Leads) -- NYHA III/IV Patients

  ---------------------------------------------- ------------------------
  Reason For Unsuccessful Implant                Number\
                                                 (not mutually exclusive)

  Dislodgement/unstable position                 31

  Unable to obtain adequate distal location      26

  Unable to cannulate coronary sinus ostium      23

  Unacceptable pacing thresholds                 21

  Dissection/perforation                         17

  Unable to access coronary vein                 12

  Coronary vein too small                        4

  Patient decompensation during implant          4

  Delivery system/tool problems                  4

  Patient venous anatomy                         3

  Diaphragmatic stimulation                      2

  Complete heart block                           1
  ---------------------------------------------- ------------------------

Model 4189 LV Lead Voltage Thresholds

For all patients receiving a Model 4189[^6] LV lead, the mean 6-month
voltage threshold measured at 0.5 ms was 1.5V; the two-sided 95%
confidence interval was (1.4V, 1.7V). The following table summarizes the
voltage thresholds measured at implant, 1-month, 3-month, and 6-month
follow-up visits, with two-sided 95% confidence intervals.

![](media/image5.wmf)\
**Figure 6. Model 4189 Left Ventricular Voltage Threshold Data (@ 0.5
ms)**

Models 2187 and 2188 LV Lead Voltage Thresholds

For all patients receiving a Model 2187 or 2188 lead, the mean 6-month
voltage threshold measured at 0.5 ms was 1.9V; the two-sided 95%
confidence interval was (1.7V, 2.2V). The following table summarizes the
voltage thresholds measured at implant, 1-month, 3-month, and 6-month
follow-up visits, with two-sided 95% confidence intervals.

![](media/image6.wmf)

**Figure 7. Model 2187/2188 Left Ventricular Voltage Threshold Data (@
0.5 ms)**

7\. Secondary Endpoint Results

Patient Survival

**Table 24** summarizes survival from all-cause mortality and the number
of patient deaths at 3 and 6 months in randomized NYHA Class III and IV
patients, comparing control and treatment groups. Survival from
all-cause mortality at\
6 months for the treatment group is 92.4%, and for the control group it
is 92.0%. There is no difference in survival from all-cause mortality
between treatment and control (p=0.72).

**Table 24**. Survival Estimates for Control vs. Treatment Groups --\
NYHA III/IV Patients

  ----------- ----------- ---------- ----------- ------------- ----------- ---------- ----------- -------------
              Estimated                                        Estimated                          
              Survival --                                      Survival --                        
              3 Months                                         6 Months                           

              \# of       Patients   Estimated   95%           \# of       Patients   Estimated   95%
              Deaths      At Risk    Survival    Confidence    Deaths      At Risk    Survival    Confidence
                                                 Interval                                         Interval

  Control     6           171        96.6%       92.6%-98.5%   14\*        87         92.0%       86.8%-95.2%
  Group                                                                                           
  (n=177)                                                                                         

  Treatment   7           178        96.2%       92.3%-98.2%   14          99         92.4%       87.5%-95.4%
  Group                                                                                           
  (n=187)                                                                                         
  ----------- ----------- ---------- ----------- ------------- ----------- ---------- ----------- -------------

> \*One additional patient died after six months, but before their
> six-month follow-up

Figure 8 depicts all-cause survival for control and treatment groups.

![](media/image7.wmf)

**Figure 8. Survival From All-cause Mortality\
During Randomization Period -- NYHA Class III and IV**

**Table 25** summarizes survival from all-cause mortality at 3, 6, 12,
and 18 months and number of deaths for all NYHA Class III and IV
patients receiving an InSync^®^ ICD system (n=374). Note that at the
conclusion of the 6-month follow-up visit, all patients had CRT turned
on.

**Table 25**. Estimated Survival From All Causes of Death --\
NYHA III/IV Patients

  ------------------------ ------------ --------------- -------------------
  Time Post-implant        Number of    Estimated       95% Confidence
                           Deaths       Survival        Interval

  3 Months                 18           95.2%           92.4%-96.9%

  6 Months                 34           90.8%           87.3%-93.3%

  12 Months                52           84.3%           79.8%-87.8%

  18 Months                62           76.2%           69.5%-81.7%
  ------------------------ ------------ --------------- -------------------

**Figure 9** depicts all-cause survival curve through 18 months for NYHA
Class III and IV patients.

![](media/image8.wmf)

**Figure 9. Survival From All-cause Mortality,\
NYHA Class III and IV**

Cardiopulmonary Exercise

Peak VO~2~, an indicator of a patient's exercise capacity, was the
secondary effectiveness endpoint specifically identified for NYHA Class
III and IV patients. Table 26 and Figure 10 summarize the peak VO2 data.
P-values were based on the median paired difference.

Cardiopulmonary exercise testing was performed on a treadmill using a
modified Naughton protocol.[^7] Data were analyzed by an independent
core lab. Table 27 summarizes the paired baseline and 6-month
cardiopulmonary exercise results for NYHA Class III and IV patients and
additional cardiopulmonary exercise data collected in the study.
P-values were based on the median paired difference.

**Table 26. Peak VO~2~** -- NYHA III/IV Patients

+-----------+------------------------+-------------------------+-------+
|           | **Cardiopulmonary      |                         |       |
|           | Exercise Testing -     |                         |       |
|           | Results for NYHA Class |                         |       |
|           | III and IV Patients**  |                         |       |
+===========+========================+=========================+=======+
|           | **Control Group *(CRT  | **Treatment Group *(CRT | P-    |
|           | OFF)***                | ON)***                  | value |
+-----------+------------------------+-------------------------+-------+
| Peak      | 118 patients with      | 118 patients with       | 0.03  |
| VO~2~\    | paired data            | paired data             |       |
| (m        |                        |                         |       |
| l/kg/min) | **Baseline:** median   | **Baseline:** median    |       |
|           | 13.4                   | 13.4                    |       |
|           |                        |                         |       |
|           | Mean 13.7              | mean 13.5               |       |
|           | [+]{.underline} 3.9    | [+]{.underline} 3.5     |       |
|           |                        |                         |       |
|           | **6-month:** median    | **6-month:** median     |       |
|           | 13.5                   | 14.3                    |       |
|           |                        |                         |       |
|           | mean 14.0              | mean 14.4               |       |
|           | [+]{.underline} 4.0    | [+]{.underline} 3.7     |       |
|           |                        |                         |       |
|           | **Median Paired        | **Median Paired         |       |
|           | Difference: 0.0**      | Difference: 1.1**       |       |
+-----------+------------------------+-------------------------+-------+

Figure 10 presents the median change in Peak VO~2~ for the control and
treatment groups at baseline and 6 month follow up.

![](media/image9.png)

> **Figure 10. Peak VO~2~ Data Summary**

**Table 27**. Cardiopulmonary Exercise Data -- NYHA III/IV Patients

+------------------+---------------------+---------------------+-----+
|                  | **Cardiopulmonary   |                     |     |
|                  | Exercise Testing -  |                     |     |
|                  | Results for NYHA    |                     |     |
|                  | Class III and IV    |                     |     |
|                  | Patients**          |                     |     |
+==================+=====================+=====================+=====+
|                  | **Control Group     | **Treatment Group   | P   |
|                  | *(CRT OFF)***       | *(CRT ON)***        | -va |
|                  |                     |                     | lue |
+------------------+---------------------+---------------------+-----+
| Exercise Time    | 119 patients with   | 118 patients with   | 0.0 |
| (sec)            | paired data         | paired data         | 008 |
|                  |                     |                     |     |
|                  | **Baseline:**       | **Baseline:**       |     |
|                  | median 494          | median 479          |     |
|                  |                     |                     |     |
|                  | Mean 518            | mean 494            |     |
|                  | [+]{.underline} 226 | [+]{.underline} 479 |     |
|                  |                     |                     |     |
|                  | **6-month:** median | **6-month:** median |     |
|                  | 435                 | 526                 |     |
|                  |                     |                     |     |
|                  | mean                | mean                |     |
|                  | 483[+]{.underline}  | 537[+]{.underline}  |     |
|                  | 265                 | 219                 |     |
|                  |                     |                     |     |
|                  | **Median Paired     | **Median Paired     |     |
|                  | Difference: -9**    | Difference: 56**    |     |
+------------------+---------------------+---------------------+-----+
| Respiratory      | 112 patients with   | 116 patients with   | 0   |
| Exchange Ratio   | paired data         | paired data         | .01 |
| (RER) Max        |                     |                     |     |
|                  | **Baseline:**       | **Baseline:**       |     |
|                  | median 1.14         | median 1.14         |     |
|                  |                     |                     |     |
|                  | Mean 1.13           | mean                |     |
|                  | [+]{.underline}     | 1.13[+]{.underline} |     |
|                  | 0.10                | 0.10                |     |
|                  |                     |                     |     |
|                  | **6-month:** median | **6-month:** median |     |
|                  | 1.09                | 1.12                |     |
|                  |                     |                     |     |
|                  | mean 1.07           | mean 1.11           |     |
|                  | [+]{.underline}0.12 | [+]{.underline}     |     |
|                  |                     | 0.10                |     |
|                  | **Median Paired     |                     |     |
|                  | Difference: -0.06** | **Median Paired     |     |
|                  |                     | Difference:**       |     |
|                  |                     |                     |     |
|                  |                     | **-0.02**           |     |
+------------------+---------------------+---------------------+-----+
| Ventilatory      | 112 patients with   | 115 patients with   | 0   |
| Exchange (VE)    | paired data         | paired data         | .13 |
|                  |                     |                     |     |
|                  | **Baseline:**       | **Baseline:**       |     |
|                  | median 47.3         | median 47.8         |     |
|                  |                     |                     |     |
|                  | Mean 48.3           | mean 49.6           |     |
|                  | [+]{.underline}     | [+]{.underline}     |     |
|                  | 15.2                | 17.9                |     |
|                  |                     |                     |     |
|                  | **6-month:** median | **6-month:** median |     |
|                  | 44.7                | 48.5                |     |
|                  |                     |                     |     |
|                  | mean 47.6           | mean 51.0           |     |
|                  | [+]{.underline}     | [+]{.underline}     |     |
|                  | 16.4                | 16.1                |     |
|                  |                     |                     |     |
|                  | **Median Paired     | **Median Paired     |     |
|                  | Difference: -1.0**  | Difference: 0.9**   |     |
+------------------+---------------------+---------------------+-----+
| VE/VCO2          | 112 patients with   | 115 patients with   | 0   |
|                  | paired data         | paired data         | .19 |
|                  |                     |                     |     |
|                  | **Baseline:**       | **Baseline:**       |     |
|                  | median 41.0         | median 39.8         |     |
|                  |                     |                     |     |
|                  | Mean 42.6           | mean 41.8           |     |
|                  | [+]{.underline}     | [+]{.underline}     |     |
|                  | 10.4                | 10.4                |     |
|                  |                     |                     |     |
|                  | **6-month:** median | **6-month:** median |     |
|                  | 40.9                | 38.0                |     |
|                  |                     |                     |     |
|                  | mean 42.2           | mean 39.9           |     |
|                  | [+]{.underline}     | [+]{.underline} 8.9 |     |
|                  | 10.6                |                     |     |
|                  |                     | **Median Paired     |     |
|                  | **Median Paired     | Difference: -1.0**  |     |
|                  | Difference: -0.6**  |                     |     |
+------------------+---------------------+---------------------+-----+
| Anaerobic        | 68 patients with    | 87 patients with    | 0   |
| Threshold (AT)   | paired data         | paired data         | .41 |
|                  |                     |                     |     |
|                  | **Baseline:**       | **Baseline:**       |     |
|                  | median 8.90         | median 9.80         |     |
|                  |                     |                     |     |
|                  | Mean 9.11           | mean 9.61           |     |
|                  | [+]{.underline}     | [+]{.underline}     |     |
|                  | 2.56                | 2.20                |     |
|                  |                     |                     |     |
|                  | **6-month:** median | **6-month:** median |     |
|                  | 9.65                | 10.30               |     |
|                  |                     |                     |     |
|                  | mean 10.30          | mean 10.24          |     |
|                  | [+]{.underline}     | [+]{.underline}     |     |
|                  | 3.22                | 2.02                |     |
|                  |                     |                     |     |
|                  | **Median Paired     | **Median Paired     |     |
|                  | Difference: 0.90**  | Difference: 0.70**  |     |
+------------------+---------------------+---------------------+-----+

QRS Duration

The change in patients' QRS duration from baseline to 6 months was
analyzed to assess the effects of cardiac resynchronization therapy.
Table 28 summarizes the paired baseline and 6-month peak QRS results for
NYHA Class III and IV patients. The P-values were based on the median
paired difference.

**Table 28**. QRS Duration -- NYHA III/IV Patients

+------------------+---------------------+---------------------+-----+
|                  | **QRS Duration --   |                     |     |
|                  | Results for NYHA    |                     |     |
|                  | Class III and IV    |                     |     |
|                  | Patients**          |                     |     |
+==================+=====================+=====================+=====+
|                  | **Control Group     | **Treatment Group   | P   |
|                  | *(CRT OFF)***       | *(CRT ON)***        | -va |
|                  |                     |                     | lue |
+------------------+---------------------+---------------------+-----+
| Change in QRS    | 119 patients with   | 129 patients with   | 0   |
| duration from    | paired data         | paired data         | .01 |
| baseline through |                     |                     |     |
| 6-months (ms)    | **Baseline:**       | **Baseline:**       |     |
|                  | median 160          | median 160          |     |
|                  |                     |                     |     |
|                  | Mean 162            | mean 163            |     |
|                  | [+]{.underline} 22  | [+]{.underline} 20  |     |
|                  |                     |                     |     |
|                  | **6-month:** median | **6-month:** median |     |
|                  | 160                 | 150                 |     |
|                  |                     |                     |     |
|                  | mean 157            | mean 146            |     |
|                  | [+]{.underline} 37  | [+]{.underline} 28  |     |
|                  |                     |                     |     |
|                  | **Median Paired     | **Median Paired     |     |
|                  | Difference: --6**   | Difference: --20**  |     |
+------------------+---------------------+---------------------+-----+

Health Care Utilization (Hospitalization)

Emergency room, outpatient, clinic and hospital admission data ware
collected in the study. An independent Adverse Events Review Committee
reviewed the hospitalization data and adjudicated hospitalizations as
either related or not related to heart failure. The analysis included
all admissions of at least 24 hours. Table 29 summarizes the
hospitalization (all-cause and heart failure (CHF) related) results for
NYHA Class III and IV patients. The P-values were based on the
comparison of the number of patients hospitalized in the two groups. For
the Length of Stay P-values were based on median number of days.

**Table 29**. Health Care Utilization -- NYHA III/IV Patients

+------------------+---------------------+---------------------+-----+
|                  | **Health Care       |                     |     |
|                  | Utilization -       |                     |     |
|                  | Results for NYHA    |                     |     |
|                  | Class III and IV    |                     |     |
|                  | Patients**          |                     |     |
+==================+=====================+=====================+=====+
|                  | **Control Group     | **Treatment Group   | P   |
|                  | *(CRT OFF)***       | *(CRT ON)***        | -va |
|                  |                     |                     | lue |
+------------------+---------------------+---------------------+-----+
| > Number of      | **All-cause:**      | **All-cause:**      | 0   |
| > patients       | n=176               | n=186               | .40 |
| > hospitalized   |                     |                     |     |
|                  | 79 (44.9%)          | 75 (40.3%)          | 0   |
|                  |                     |                     | .22 |
|                  | **CHF related:**    | **CHF related:**    |     |
|                  | n=176               | n=186               |     |
|                  |                     |                     |     |
|                  | 47 (26.7%)          | 39 (21.0%)          |     |
+------------------+---------------------+---------------------+-----+
| > Length of Stay | **All-cause:**      | **All-cause:**      | 0   |
| > (days)         |                     |                     | .09 |
|                  | 134                 | 127                 |     |
|                  | hospitalizations    | hospitalizations    | 0   |
|                  |                     |                     | .04 |
|                  | median; 7 days      | median; 5 days      |     |
|                  |                     |                     |     |
|                  | mean: 8.9 ± 7.8     | mean: 7.6 ± 8.2     |     |
|                  |                     |                     |     |
|                  | **CHF related:**    | **CHF related:**    |     |
|                  |                     |                     |     |
|                  | 70 hospitalizations | 54 hospitalizations |     |
|                  |                     |                     |     |
|                  | median; 6 days      | median; 3 days      |     |
|                  |                     |                     |     |
|                  | mean: 8.0 ± 7.0     | mean: 6.6 ± 7.4     |     |
+------------------+---------------------+---------------------+-----+

Echocardiographic Parameters

An echocardiographic study was performed to assess the effects of
cardiac resynchronization therapy on left ventricular structure and
function. Echo data were analyzed by an independent core lab. Table 30
summarizes the echocardiographic results from baseline and 6 months for
NYHA Class III and IV patients. P-values were based on the median paired
difference.

**Table 30**. Echocardiographic Parameters -- NYHA III/IV Patients

+------------------+---------------------+---------------------+-----+
|                  | **Echocardiographic |                     |     |
|                  | Indices -- Results  |                     |     |
|                  | for NYHA Class III  |                     |     |
|                  | and IV Patients**   |                     |     |
+==================+=====================+=====================+=====+
|                  | **Control Group     | **Treatment Group   | P   |
|                  | *(CRT OFF)***       | *(CRT ON)***        | -va |
|                  |                     |                     | lue |
+------------------+---------------------+---------------------+-----+
| > LV Ejection    | 98 patients with    | 97 patients with    | 0   |
| > Fraction (%)   | paired data         | paired data         | .06 |
|                  |                     |                     |     |
|                  | **Baseline:**       | **Baseline**:       |     |
|                  | median 21.7         | median 23.5         |     |
|                  |                     |                     |     |
|                  | mean 23.3           | Mean 24.1           |     |
|                  | [+]{.underline} 6.3 | [+]{.underline} 6.7 |     |
|                  |                     |                     |     |
|                  | **6-month:** median | **6-month:** median |     |
|                  | 23.7                | 25.5                |     |
|                  |                     |                     |     |
|                  | mean 24.4           | mean 27.6           |     |
|                  | [+]{.underline} 7.9 | [+]{.underline} 8.9 |     |
|                  |                     |                     |     |
|                  | **Median Paired     | **Median Paired     |     |
|                  | Difference 1.6**    | Difference 3.0**    |     |
+------------------+---------------------+---------------------+-----+
| > Mitral         | 68 patients with    | 68 patients with    | 0   |
| > Regurgitation\ | paired data         | paired data         | .98 |
| > (cm^2^, jet    |                     |                     |     |
| > area)          | **Baseline:**       | **Baseline:**       |     |
|                  | median 7.1          | median 7.0          |     |
|                  |                     |                     |     |
|                  | mean 8.5            | mean 7.8            |     |
|                  | [+]{.underline} 7.6 | [+]{.underline} 5.9 |     |
|                  |                     |                     |     |
|                  | **6-month:** median | **6-month:** median |     |
|                  | 5.9                 | 4.9                 |     |
|                  |                     |                     |     |
|                  | mean 7.2            | mean 6.7            |     |
|                  | [+]{.underline} 6.8 | [+]{.underline} 5.6 |     |
|                  |                     |                     |     |
|                  | **Median Paired     | **Median Paired     |     |
|                  | Difference --0.5**  | Difference -0.4**   |     |
+------------------+---------------------+---------------------+-----+
| > Cardiac Index  | 64 patients with    | 65 patients with    | 0   |
| > (four chamber  | paired data         | paired data         | .89 |
| > view)          |                     |                     |     |
|                  | **Baseline:**       | **Baseline:** 2.38  |     |
|                  | median 2.45         | median              |     |
|                  |                     |                     |     |
|                  | mean 2.54           | mean 2.50           |     |
|                  | [+]{.underline}     | [+]{.underline}     |     |
|                  | 0.90                | 0.78                |     |
|                  |                     |                     |     |
|                  | **6-month:** median | **6-month:** 2.47   |     |
|                  | 2.34                | median              |     |
|                  |                     |                     |     |
|                  | mean 2.48           | mean 2.54           |     |
|                  | [+]{.underline}     | [+]{.underline}     |     |
|                  | 0.88                | 0.79                |     |
|                  |                     |                     |     |
|                  | **Median Paired     | **Median Paired     |     |
|                  | Difference -0.02**  | Difference 0.03**   |     |
+------------------+---------------------+---------------------+-----+
| > LV Systolic\   | 94 patients with    | 96 patients with    | 0   |
| > Volume (cm^3^) | paired data         | paired data         | .04 |
|                  |                     |                     |     |
|                  | **Baseline:**       | **Baseline:**       |     |
|                  | median 230          | median 232          |     |
|                  |                     |                     |     |
|                  | mean 249            | mean 242            |     |
|                  | [+]{.underline} 88  | [+]{.underline} 84  |     |
|                  |                     |                     |     |
|                  | **6-month:** median | **6-month:** median |     |
|                  | 225                 | 212                 |     |
|                  |                     |                     |     |
|                  | mean 241            | mean 222            |     |
|                  | [+]{.underline} 80  | [+]{.underline} 94  |     |
|                  |                     |                     |     |
|                  | **Median Paired     | **Median Paired     |     |
|                  | Difference --8**    | Difference --26**   |     |
+------------------+---------------------+---------------------+-----+
| > LV\            | 94 patients with    | 96 patients with    | 0.  |
| > Diastolic      | paired data         | paired data         | 046 |
| > Volume (cm^3^) |                     |                     |     |
|                  | **Baseline:**       | **Baseline:**       |     |
|                  | median 302          | median 305          |     |
|                  |                     |                     |     |
|                  | mean 320            | mean 315            |     |
|                  | [+]{.underline} 96  | [+]{.underline} 90  |     |
|                  |                     |                     |     |
|                  | **6-month:** median | **6-month:** median |     |
|                  | 296                 | 283                 |     |
|                  |                     |                     |     |
|                  | mean 315            | mean 298            |     |
|                  | [+]{.underline} 86  | [+]{.underline} 101 |     |
|                  |                     |                     |     |
|                  | **Median Paired     | **Median Paired     |     |
|                  | Difference -5**     | Difference --25**   |     |
+------------------+---------------------+---------------------+-----+
| > LV mass (g)    | 58 patients with    | 63 patients with    | 0   |
|                  | paired data         | paired data         | .97 |
|                  |                     |                     |     |
|                  | **Baseline:**       | **Baseline:**       |     |
|                  | median 358          | median 353          |     |
|                  |                     |                     |     |
|                  | mean 367            | mean 359            |     |
|                  | [+]{.underline} 80  | [+]{.underline} 83  |     |
|                  |                     |                     |     |
|                  | **6-month:** median | **6-month:** median |     |
|                  | 348                 | 339                 |     |
|                  |                     |                     |     |
|                  | mean 365            | mean 354            |     |
|                  | [+]{.underline} 85  | [+]{.underline} 87  |     |
|                  |                     |                     |     |
|                  | **Median Paired     | **Median Paired     |     |
|                  | Difference -- 6**   | Difference -- 3**   |     |
+------------------+---------------------+---------------------+-----+
| >                | 63 patients with    | 79 patients with    | 0   |
| Interventricular | paired data         | paired data         | .12 |
| > mechanical     |                     |                     |     |
| > delay (IVMD)   | **Baseline**:       | **Baseline:**       |     |
| > (ms)           | median 31           | median 35           |     |
|                  |                     |                     |     |
|                  | mean 25.4           | mean 29.4           |     |
|                  | [+]{.underline}     | [+]{.underline}     |     |
|                  | 44.2                | 40.8                |     |
|                  |                     |                     |     |
|                  | **6-month:** median | **6-month:** median |     |
|                  | 25                  | 20                  |     |
|                  |                     |                     |     |
|                  | mean 19.1           | mean 15.4           |     |
|                  | [+]{.underline}     | [+]{.underline}     |     |
|                  | 34.4                | 30.1                |     |
|                  |                     |                     |     |
|                  | **Median Paired     | **Median Paired     |     |
|                  | Difference --2**    | Difference --18**   |     |
+------------------+---------------------+---------------------+-----+
| > E Wave /A Wave | 70 patients with    | 90 patients with    | 0   |
| > ratio          | paired data         | paired data         | .82 |
|                  |                     |                     |     |
|                  | **Baseline:**       | **Baseline:**       |     |
|                  | median 1.22         | median 1.12         |     |
|                  |                     |                     |     |
|                  | mean 1.54           | mean 1.50           |     |
|                  | [+]{.underline}     | [+]{.underline}     |     |
|                  | 1.08                | 1.08                |     |
|                  |                     |                     |     |
|                  | **6-month:** median | **6-month:** median |     |
|                  | 1.04                | 0.99                |     |
|                  |                     |                     |     |
|                  | mean 1.45           | mean 1.43           |     |
|                  | [+]{.underline}     | [+]{.underline}     |     |
|                  | 1.03                | 1.05                |     |
|                  |                     |                     |     |
|                  | **Median Paired     | **Median Paired     |     |
|                  | Difference -0.03**  | Difference -0.06**  |     |
+------------------+---------------------+---------------------+-----+
| > LV Diameter in | 45 patients with    | 56 patients with    | 0   |
| > Systole        | paired data         | paired data         | .98 |
|                  |                     |                     |     |
|                  | **Baseline:**       | **Baseline:**       |     |
|                  | median 6.8          | median 6.4          |     |
|                  |                     |                     |     |
|                  | mean 7.0            | mean 6.4            |     |
|                  | [+]{.underline} 1.0 | [+]{.underline} 1.0 |     |
|                  |                     |                     |     |
|                  | **6-month:** median | **6-month:** median |     |
|                  | 6.9                 | 6.3                 |     |
|                  |                     |                     |     |
|                  | mean 6.7            | mean 6.1            |     |
|                  | [+]{.underline} 1.0 | [+]{.underline} 1.2 |     |
|                  |                     |                     |     |
|                  | **Median Paired     | **Median Paired     |     |
|                  | Difference -0.3**   | Difference -0.2**   |     |
+------------------+---------------------+---------------------+-----+
| > LV Diameter in | 48 patients with    | 58 patients with    | 0   |
| > Diastole       | paired data         | paired data         | .85 |
|                  |                     |                     |     |
|                  | **Baseline:**       | **Baseline:**       |     |
|                  | median 7.8          | median 7.5          |     |
|                  |                     |                     |     |
|                  | mean 10.0           | mean 9.6            |     |
|                  | [+]{.underline}     | [+]{.underline}     |     |
|                  | 10.9                | 11.6                |     |
|                  |                     |                     |     |
|                  | **6-month:** median | **6-month:** median |     |
|                  | 7.6                 | 7.3                 |     |
|                  |                     |                     |     |
|                  | mean 7.6            | mean 7.3            |     |
|                  | [+]{.underline} 0.9 | [+]{.underline} 1.0 |     |
|                  |                     |                     |     |
|                  | **Median Paired     | **Median Paired     |     |
|                  | Difference -0.1**   | Difference -0.3**   |     |
+------------------+---------------------+---------------------+-----+

Composite Response

The Heart Failure Clinical Composite Response[^8] provides an overall
assessment of a patient's condition. A patient is defined as "improved"
if they decrease NYHA functional class by one or more or if there is a
moderate or marked improvement in their global self-assessment score. A
patient is defined as "worsened" if they died, were hospitalized for
worsening heart failure. A patient is defined as "not changed" if the
"improved" or "worsened" conditions are not met.

Table 31 summarizes the composite response results for NYHA Class III
and IV patients. The P-value of 0.038 is an overall comparison of the
two distributions.

**Table 31**. Composite Response -- NYHA III/IV Patients

+-----------------+--------------------+----------------------+-------+
|                 | **Composite        |                      |       |
|                 | Response --        |                      |       |
|                 | Results for NYHA   |                      |       |
|                 | Class III and IV   |                      |       |
|                 | Patients**         |                      |       |
+=================+====================+======================+=======+
|                 | **Control Group    | **Treatment Group    | P-    |
|                 | *(CRT OFF)***      | *(CRT ON)***         | value |
+-----------------+--------------------+----------------------+-------+
| Composite       | n = 141            | n = 150              | 0.038 |
| Response        |                    |                      |       |
|                 | 40%                | 55%                  |       |
| > **Improved**  |                    |                      |       |
| >               | 26%                | 19%                  |       |
| > **Unchanged** |                    |                      |       |
| >               | 33%                | 26%                  |       |
| > **Worsened**  |                    |                      |       |
+-----------------+--------------------+----------------------+-------+

At their six-month follow-up patients were asked to rate their global
self assessment by answering the following question, "Specifically in
reference to your heart failure symptoms, how do you feel today as
compared to how you felt before having your InSync^®^ ICD system
implanted?"

69% of the treatment patients (n=131) reported at least mild improvement
vs. 60% of the control patients (n=121). The overall p-value comparing
the two distributions was 0.68. Note: Patients with global assessment
scores are a subset of the patients used in the clinical composite
response analysis.

Spontaneous VT/VF Therapy Efficacy

**Table 32** summarizes spontaneous VT/VF therapy efficacy of the
InSync^®^ ICD in all patients.

**Table 32. Spontaneous VT/VF Therapy Efficacy**

  --------------------- ------------------- ------------------------------
  Episode Detection     \# Patients         Percent Successfully
  Zone                                      Terminated

  FVT                   14                  98.5%

  VF                    41                  99.2%

  VT                    50                  99.2%

  OVERALL               78                  99.1%\*
  --------------------- ------------------- ------------------------------

> \*Of the episodes that did not satisfy the device's episode
> termination criteria, all episodes were eventually terminated.

Comparison of VT/VF Event Rates

Table 33 compares the VT/VF event rate during the randomization period
between NYHA Class III and IV control and treatment groups. The P-value
of 0.38 compares the number of episodes between the control and
treatment group.

**Table 33**. Comparison of VT/VF Event Rates -- NYHA III/IV Patients

+-------------+----------------------+----------------------+---------+
|             | **Control Group      | **Treatment Group    | P-value |
|             | *(CRT OFF)***        | *(CRT ON)***         |         |
+=============+======================+======================+=========+
| Comparison  | n=177                | n=187                | 0.38    |
| of VT/VF    |                      |                      |         |
| Event Rates | \# patients: 38      | \# patients: 35      |         |
|             | (21.6%)              | (18.8%)              |         |
|             |                      |                      |         |
|             | Total episodes: 321  | Total episodes: 356  |         |
|             |                      |                      |         |
|             | Episodes per month:  | Episodes per month:  |         |
|             | 0.39                 | 0.41                 |         |
+-------------+----------------------+----------------------+---------+

ATP Therapy Efficacy With Biventricular Pacing

**Table 34** summarizes the efficacy of biventricular and RV-only
anti-tachycardia pacing (ATP) therapy efficacy for induced and
spontaneous ventricular tachycardia (VT) episodes.

**Table 34. ATP Therapy Efficacy With Biventricular Pacing**

  ----------------- --------------------- ------------------- ------------
  ATP Site          Rhythm                ATP Success rate    P-value

  RV                Induced VT            11/20 (55%)         1.00

  RV+LV             Induced VT            12/20 (60%)         

  RV                Spontaneous VT        247/294 (84%)       \<0.0001

  RV+LV             Spontaneous VT        493/523 (94%)       

  RV                Spontaneous FVT       67/74 (91%)         0.05

  RV+LV             Spontaneous FVT       17/24 (71%)         
  ----------------- --------------------- ------------------- ------------

Plasma Neurohormone Levels

To characterize the effect of cardiac resynchronization, the following
plasma neurohormone levels were assessed: brain natriuretic peptide
(BNP), big endothelin (Big ET), epinephrine, norepinephrine and
dopamine. Neurohormone data were analyzed by an independent core lab.
Table 35 summarizes the neurohormone results from baseline and 6 months
for NYHA Class III and IV patients. P-Values were based on the median
paired difference.

**Table 35**. Plasma Neurohormones -- NYHA III/IV Patients

+-------------+------------------------+------------------------+-----+
|             | **Results for NYHA     |                        |     |
|             | Class III and IV       |                        |     |
|             | Patients**             |                        |     |
+=============+========================+========================+=====+
|             | **Control Group *(CRT  | **Treatment Group      | P   |
|             | OFF)***                | *(CRT ON)***           | -va |
|             |                        |                        | lue |
+-------------+------------------------+------------------------+-----+
| > Brain     | 70 patients with       | 83 patients with       | 0   |
| >           | paired data            | paired data            | .41 |
| Natriuretic |                        |                        |     |
| > Peptide   | **Baseline:** median   | **Baseline:** median   |     |
| > (BNP)     | 478.5                  | 450.0                  |     |
|             |                        |                        |     |
|             | Mean 889.8             | mean 813.0             |     |
|             | [+]{.underline} 1190.0 | [+]{.underline} 1063.6 |     |
|             |                        |                        |     |
|             | **6-month:** median    | **6-month:** median    |     |
|             | 357.0                  | 320.0                  |     |
|             |                        |                        |     |
|             | mean 799.9             | mean 568.9             |     |
|             | [+]{.underline} 1249.6 | [+]{.underline} 708.2  |     |
|             |                        |                        |     |
|             | **Median Paired        | **Median Paired        |     |
|             | Difference: -2.8**     | Difference: -38.0**    |     |
+-------------+------------------------+------------------------+-----+
| > Dopamine  | 73 patients with       | 79 patients with       | 0   |
|             | paired data            | paired data            | .56 |
|             |                        |                        |     |
|             | **Baseline:** median   | **Baseline:** median   |     |
|             | 9.0                    | 9.0                    |     |
|             |                        |                        |     |
|             | Mean 17.2              | mean 13.9              |     |
|             | [+]{.underline} 20.9   | [+]{.underline} 8.8    |     |
|             |                        |                        |     |
|             | **6-month:** median    | **6-month:** median    |     |
|             | 9.0                    | 9.0                    |     |
|             |                        |                        |     |
|             | mean 19.03             | mean 14.0              |     |
|             | [+]{.underline} 26.3   | [+]{.underline} 10.7   |     |
|             |                        |                        |     |
|             | **Median Paired        | **Median Paired        |     |
|             | Difference: 0.0**      | Difference: 0.0**      |     |
+-------------+------------------------+------------------------+-----+
| > Nor       | 74 patients with       | 80 patients with       | 0   |
| epinephrine | paired data            | paired data            | .24 |
|             |                        |                        |     |
|             | **Baseline:** median   | **Baseline:** median   |     |
|             | 454.5                  | 331.0                  |     |
|             |                        |                        |     |
|             | Mean 516.9             | mean 376.5             |     |
|             | [+]{.underline} 382.3  | [+]{.underline} 263.1  |     |
|             |                        |                        |     |
|             | **6-month:** median    | **6-month:** median    |     |
|             | 442.5                  | 339.5                  |     |
|             |                        |                        |     |
|             | mean 478.0             | mean 410.2             |     |
|             | [+]{.underline} 289.1  | [+]{.underline} 273.0  |     |
|             |                        |                        |     |
|             | **Median Paired        | **Median Paired        |     |
|             | Difference: -38.0**    | Difference: 10.5**     |     |
+-------------+------------------------+------------------------+-----+
| >           | 73 patients with       | 79 patients with       | 0   |
| Epinephrine | paired data            | paired data            | .03 |
|             |                        |                        |     |
|             | **Baseline:** median   | **Baseline:** median   |     |
|             | 25.0                   | 16.0                   |     |
|             |                        |                        |     |
|             | Mean 53.2              | mean 31.7              |     |
|             | [+]{.underline} 109.9  | [+]{.underline} 43.6   |     |
|             |                        |                        |     |
|             | **6-month:** median    | **6-month:** median    |     |
|             | 17.0                   | 17.0                   |     |
|             |                        |                        |     |
|             | mean 23.6              | mean 23.2              |     |
|             | [+]{.underline} 21.9   | [+]{.underline} 18.5   |     |
|             |                        |                        |     |
|             | **Median Paired        | **Median Paired        |     |
|             | Difference: -4.0**     | Difference: 0.0**      |     |
+-------------+------------------------+------------------------+-----+
| > Big       | 77 patients with       | 88 patients with       | 0   |
| >           | paired data            | paired data            | .88 |
|  Endothelin |                        |                        |     |
|             | **Baseline:** median   | **Baseline:** median   |     |
|             | 14.3                   | 12.3                   |     |
|             |                        |                        |     |
|             | Mean 26.6              | mean 19.5              |     |
|             | [+]{.underline} 34.9   | [+]{.underline} 21.6   |     |
|             |                        |                        |     |
|             | **6-month:** median    | **6-month:** median    |     |
|             | 16.4                   | 11.0                   |     |
|             |                        |                        |     |
|             | mean 21.3              | mean 18.1              |     |
|             | [+]{.underline} 23.0   | [+]{.underline} 20.0   |     |
|             |                        |                        |     |
|             | **Median Paired        | **Median Paired        |     |
|             | Difference: --0.5**    | Difference: -0.5**     |     |
+-------------+------------------------+------------------------+-----+

Attain LV Lead R-Wave Amplitude Sensing

The sensing performance of the LV leads was assessed by evaluating the
R-wave amplitudes from the Model 4189[^9], 2187 and 2188 leads. Table 36
summarizes the Model 4189^\*^ LV lead mean R-wave amplitude data and the
two-sided 95 percent confidence intervals on all patients receiving a
Model 4189^\*^ lead.

**Table 36. Model 4189 R-wave Amplitude Data**

  --------------------- ------------- --------------- --------------------
  Visit                 N             Mean (mV)       Two-sided 95% CI

  Implant               444           12.5 ± 4.6      12.1-13.0

  Pre-hospital          454           12.6 ± 4.6      12.2-13.0
  Discharge                                           

  1 Month               435           13.6 ± 4.5      13.1-14.0

  3 Months              412           13.8 ± 5.3      13.3-14.3

  6 Months              317           13.7 ± 5.4      13.1-14.3

  12 Months             130           14.2 ± 5.7      13.2-15.2

  18 Months             37            14.0 ± 5.4      12.2-15.8
  --------------------- ------------- --------------- --------------------

Table 37 summarizes the Model 2187 and 2188 LV lead R-wave amplitude
data from all patients receiving a Model 2187 or 2188 lead.

**Table 37**. Model 2187/2188 R-wave Amplitude Data

  --------------------- ------------- --------------- --------------------
  Visit                 N             Mean (mV)       Two-sided 95% CI

  Implant               88            12.7 ± 4.9      11.7-13.8

  Pre-hospital          90            12.4 ± 4.7      11.4-13.3
  Discharge                                           

  1 Month               85            13.3 ± 5.2      12.1-14.4

  3 Months              81            13.8 ± 4.8      12.7-14.8

  6 Months              63            13.5 ± 5.7      12.1-15.0

  12 Months             30            13.9 ± 5.1      12.0-15.8

  18 Months             18            12.0 ± 4.2      10.0-14.1
  --------------------- ------------- --------------- --------------------

8\. CS Dissections and Perforations

Table 38 summarizes the adverse events (complications and observations)
related to coronary sinus dissections and perforations in all patients.
Of the 33 patients with CS dissection/perforation, there were six deaths
(82, 263, 384, 415, 436 and 509 days post-implant). None of the deaths
was reported as related to the dissection or perforation. Two of the
patients that died received the InSync^®^ ICD system, and four of the
patients did not receive the InSync^®^ ICD system (two received the GEM
DR and two received the GEM III DR).

**Table 38**. CS Dissections and Perforations

  --------------------- ------------------- -------------------- ----------
  Event                 Complications (#    Observations\        Total (#
                        pts.)               (# pts.)             pts.)

  CS dissection         15                  9                    24

  Cardiac vein/\        9                   0                    9
  CS Perforation                                                 

  Total                 **24**              **9**                **33**
  --------------------- ------------------- -------------------- ----------

9\. LV Lead Placement

Table 39 summarizes information related to LV lead placement and
positioning. The majority of LV leads (72%) were positioned in lateral
or posterior-lateral cardiac veins.

**Table 39. Final LV Lead Placement and Position**

  -------------------------- --------- --------- --------- ----------- ---------
  Vessel/Location            Basal     Mid       Apical    Not         Total
                                                           indicated   

  **Lateral (marginal)       6%        31%       2%        \< 1%       **39%**
  cardiac**                                                            

  **Posterior-lateral        4%        25%       4%        \< 1%       **33%**
  cardiac**                                                            

  **Anterior cardiac**       5%        10%       1%        \< 1%       **17%**

  **Posterior cardiac**      \< 1%     3%        1%        \< 1%       **5%**

  **Middle cardiac**         \< 1%     2%        1%        \< 1%       **4%**

  **Great cardiac**          \< 1%     \< 1%     \< 1%     \< 1%       **1%**

  **Not indicated**          \< 1%     \< 1%     \< 1%     1%          **1%**

  **Total**                  **16%**   **72%**   **10%**   **2%**      
  -------------------------- --------- --------- --------- ----------- ---------

C.  Confirmation of Biventricular Pacing and ICD Function

To confirm proper biventricular pacing and ICD function, percent
ventricular pacing, biventricular capture during cardiopulmonary
exercise (CPX), VT/VF detection efficacy and VF detection time were
assessed. To assess percent ventricular pacing, the percentage of time
that patients were paced was determined from the pace/sense counters of
the device at the 6- month follow-up. Electrocardiograms (ECGs) with
biventricular pacing ON from the 6-month follow-up visit were compared
to 12-lead ECGs at peak heart rate during the 6-month CPX test to
confirm that biventricular pacing and capture were maintained. The
incidence of inappropriate VT/VF episodes was analyzed to confirm that
there is nothing unique to a CHF ICD population that would increase the
risk of inappropriate detection. Analysis of VF detection times in
InSync^®^ ICD treatment vs. control patients was done to demonstrate
that VF detection is not compromised by the presence of the LV lead and
biventricular pacing.

1\. Percent Ventricular Pacing

The percentage of time patients were paced during their randomized
period was determined from each patient's six-month visit, using the
pace/sense counters over the lifetime of the device. All NYHA Class III
and IV randomized patients who did not cross over into the other group
(OFF to ON or ON to OFF) are included (116 control and 125 treatment
patients). Save-to-disk files were not available for 6 control and 7
treatment patients.

In Figure 11, the left-hand graph indicates that greater than 90% of the
treatment patients received ventricular pacing more than 90% of the
time, and conversely, greater than 90% of the control patients received
no ventricular pacing more than 90% of the time. The right-hand graph
indicates that more than 85% of the treatment patients had capture
margins greater than or equal to 100%.

![](media/image3.wmf)

**Figure 11. Biventricular Pacing and Capture Margin**

2\. Biventricular Capture During Exercise

NYHA Class III and IV patients with biventricular pacing randomized ON
and with paired baseline and 6-month cardiopulmonary exercise (CPX) data
(n=118) were included in the analysis. Of these 118 patients, 112 had
interpretable 12-lead electrocardiograms (ECGs). ECGs with biventricular
pacing ON from the 6-month follow-up visit (just prior to CPX testing)
were compared to 12-lead ECGs at peak heart rate during the 6-month CPX
test to confirm that biventricular pacing and capture was maintained.

Of the 112 NYHA Class III and IV patients with paired baseline and
6-month CPX data and interpretable 6-month pre- and peak exercise
12-lead ECGs, 83 patients had biventricular pacing at peak exercise. All
of these patients maintained biventricular capture at peak exercise.
Twenty-seven (27) patients lost biventricular pacing at maximum exercise
due to the intrinsic rate exceeding the programmed Upper Tracking Rate
(UTR). Two patients did not maintain pacing due to other unique
rhythm/programming conditions described in Figure 12. There were no
cases of LV-only or RV-only capture during biventricular pacing at any
pacing rate.

![](media/image4.wmf)

^1^UTR programmed to a higher rate than their "normal" UTR setting
during the CPX test for 2 patients.

^2^No biventricular pacing due to PVC initiated Vs-Ar-Vs-Ar... pattern.

^3^No biventricular pacing due to an intrinsic PR interval less than the
programmed SAV interval at peak exercise (Rate Adaptive AV programmed
OFF).

**Figure 12. Biventricular Capture During Exercise Testing**

3\. VT/VF Detection Efficacy

The incidence of inappropriate VT/VF episodes was similar in the
InSync^®^ ICD study population as compared to the Gem DR study
population (21.3% vs. 21.9%[^10]). The reasons for the inappropriate
detections were similar, and resulted from a similar proportion of
atrial fibrillation or flutter as compared to 1:1 SVTs. None of the
inappropriate detections in the InSync^®^ ICD study were related to
biventricular pacing or the LV lead, confirming that there is nothing
unique to a CHF ICD population that would increase the risk of
inappropriate detection. There were no VT/VF episodes for which therapy
was inappropriately withheld. The InSync^®^ ICD with its left
ventricular lead and possibility of biventricular pacing did not
adversely affect the device's ability to detect VT/VF or appropriately
withhold VT/VF therapy or delay detection time. 47% of the 135 episodes
were treated with at least one shock. No deaths, hospitalizations or
worsening of heart failure were attributed to inappropriate shocks.

**Table 40. Classification of VT/VF Episodes, Gem DR vs. InSync^®^** ICD

+------------------------------------+---------------+-----------------+
|                                    | GEM DR[^11]   | InSync^®^ ICD   |
+------------------------------------+---------------+-----------------+
| Total episodes in VT/VF log        | 3945 (278     | 950 (100 pts)   |
|                                    | pts)          |                 |
+------------------------------------+---------------+-----------------+
| Appropriate VT/VF episodes         | 3488 (232     | 815 (85 pts)    |
|                                    | pts)          |                 |
+------------------------------------+---------------+-----------------+
| Inappropriate VT/VF episodes:\     | 457 (86 pts)  | 135 (31 pts)    |
| GEE adjusted rate:                 | (12%)\        | (14%)\          |
|                                    | 21.9%         | 21.3%           |
| \- Atrial or RV sensing related    |               |                 |
|                                    | 93 (20%)      | 28 (21%)        |
| \- Ventricular rate during AF in   |               |                 |
| VF zone                            | 44 (10%)      | 5 (4%)          |
|                                    |               |                 |
| \- SVT Criteria programming (PR    | 68 (15%)      | 53 (39%)        |
| Logic)                             |               |                 |
|                                    | 252 (55%)     | 49 (36%)        |
| \- Detection algorithm             |               |                 |
| characteristics                    |               |                 |
+------------------------------------+---------------+-----------------+
| Total patients                     | 933           | 371             |
+------------------------------------+---------------+-----------------+
| Average follow-up time (months)    | 3.9           | 7.9             |
+------------------------------------+---------------+-----------------+

4\. VF Detection Time

Analysis of VF detection times in InSync^®^ ICD treatment vs. control
patients demonstrate that VF detection is not compromised by the
presence of the LV lead and biventricular pacing.

When the number of intervals to detect VF (VF NID) was programmed to
12/16 intervals, the mean VF detection time for the treatment group was
3.8 seconds, and the mean detection time for the control group was 3.4
seconds. These data demonstrate that there was no delay in detection
time compared to the theoretical time to detect (P=0.07) described
below:

1.  VF at a rate of 280 ms *x* 12 intervals to detect = 3360 ms = 3.4
    seconds

When the number of intervals to detect VF (VF NID) was programmed to
18/24 intervals, the mean VF detection time for the treatment group was
4.9 seconds, and the mean detection time for the control group was 5.3
seconds. These data demonstrate that there was no delay in detection
time compared to the theoretical time to detect described below:

2.  VF at a rate of 280 ms *x* 18 intervals to detect = 5040 ms = 5.0
    seconds

> **Table 41**. VF Detection Times in Treatment and Control Patients\
> During the Randomization Period

  ---------------- ------- ----------- ----------- ------- ----------- -----------
  Randomization    VF NID                          VF NID              
  Assignment       = 12/16                         = 18/24             

                   N       Mean Vent.  Mean        N       Mean Vent.  Mean
                           Cycle       Detection           Cycle       Detection
                           Length (ms) Time (sec)          Length (ms) Time (sec)

  Control          51      272         3.4         14      278         5.3

  Treatment        42      283         3.8         28      256         4.9

  p-value                              0.07                            0.84
  ---------------- ------- ----------- ----------- ------- ----------- -----------

D.  Programmed Parameters

Table 42 shows how Upper Tracking Rate was programmed in NYHA Class III
and IV treatment patients at the end of the randomization period (6
months).

> **Table 42**. Programmed Upper Tracking Rate (UTR)

+-------------------------------------+--------------------------------+
| **Programmed Value (ppm)**          | **% of Patients**              |
+-------------------------------------+--------------------------------+
| \<120                               | 5%                             |
|                                     |                                |
| 120                                 | 49%                            |
|                                     |                                |
| 125-130                             | 11%                            |
|                                     |                                |
| 136-140                             | 33%                            |
|                                     |                                |
| \>140                               | 2%                             |
+-------------------------------------+--------------------------------+

Table 43 demonstrates that the majority of NYHA Class III and IV
treatment patients were able to maintain over 90% ventricular pacing
regardless of their programmed Upper Tracking Rate.

> **Table 43**. Percent of Ventricular Pacing in Treatment Group\
> By Programmed UTR

+--------------+-----------------+-----------------+-------------------+
| \% Paced     | UTR \< 120      | UTR = 120       | UTR \> 120        |
|              |                 |                 |                   |
|              | (% of patients) | (% of patients) | (% of patients)   |
+--------------+-----------------+-----------------+-------------------+
| \<90%        |                 | 6%              | 2%                |
+--------------+-----------------+-----------------+-------------------+
| 90-94%       |                 | 21%             | 16%               |
+--------------+-----------------+-----------------+-------------------+
| 95-99%       | 100%            | 70%             | 71%               |
+--------------+-----------------+-----------------+-------------------+
| 100%         |                 | 4%              | 11%               |
+--------------+-----------------+-----------------+-------------------+

E. Gender Bias Analysis

A sub-group analysis was performed to evaluate the association of gender
with the primary effectiveness endpoints (NYHA functional class, quality
of life and 6-minute hall walk distance). Based on this analysis, gender
appears to be associated with an improvement in QOL scores, while gender
was not associated with NYHA class or 6-minute hall walk distance. The
InSync^®^ ICD study enrolled 75 percent males and 25 percent females.
There was no selection bias based on gender.

F. Conclusions Drawn from the Clinical Study

1\. Safety

> The InSync^®^ ICD pulse generator met the primary and secondary safety
> endpoints. Results were within protocol specified performance criteria
> for the rate of severe device related adverse events and operative
> mortality. The study additionally demonstrated that the ICD portion of
> the InSync^®^ ICD was not adversely affected by the addition of
> cardiac resynchronization as shown by adequate ventricular
> fibrillation detection times, antitachycardia pacing (ATP) conversion
> efficacy, and no increase in the amount of inappropriate ICD
> therapies.
>
> There was no difference in the mortality, number of hospitalizations,
> or incidence of malignant ventricular arrhythmias between the control
> and the treatment group.

2\. Effectiveness

The InSync^®^ ICD cardiac resynchronization system demonstrated a six-
month improvement in quality of life and a reduction in NYHA functional
class which were two of the three primary endpoints of the study. The
third endpoint, six-minute hall walk, showed no difference between the
treatment and the control group. Given this, results from the secondary
endpoint of cardiopulmonary exercise testing were used to show a
significant improvement in peak VO~2~ in the treatment group. Additional
supporting evidence included an improvement in heart failure status as
measured by a composite response assessment.

XI\. Panel Recommendation

FDA's advisory panel met on March 5, 2002 and voted 6 to 5 for
approvable with conditions. The conditions that were recommended by the
Panel included a post-approval study to obtain longer-term information
on mortality and performance of the device. They also requested
information regarding the administrative censoring of patients,
including documentation of the explicit original intent of the agreed
upon sample size of the study. Additional concerns were raised regarding
device programming and interaction issues between the ICD and CRT
portions of the device. The Panel requested that questions that were
raised on this issue be resolved by submitting additional information to
the Agency. There were significant concerns raised about the safety
profile of the Attain Model 4189[^12].

CDRH Decision

FDA found Medtronic's facilities in compliance with the Quality System
Requirements (21 CFR part 820).

FDA requested the additional information that was discussed at the panel
meeting. The approval decision was based on reviewing the entire cohort
of class III/IV patients that were enrolled in the study. Because of the
subjective nature of the successful primary endpoints of the study, FDA
specifically used data from the supporting secondary endpoints to
determine a reasonable level of effectiveness of the device.
Specifically, data from the cardiopulmonary exercise testing was used to
demonstrate a functional improvement in the treatment group. Subgroup
analysis did not delineate a specific group of patients that benefits
more from this device.

Data were provided to the agency regarding device performance that
included ICD/CRT interaction, percentage of time paced as well as other
programming issues that were used to further define the limitations of
the device. Lead performance data in the clinical trial did not support
reasonable assurance of the safety and effectiveness of the 4189 lead.

The conditions of approval include a 3-year evaluation of mortality and
chronic system performance, including adverse clinical events, on 1000
patients to assess the long-term safety of the device. Physicians will
be required to undergo training by the sponsor prior to implanting the
system.

FDA issued an approval order for P010031 on June 26, 2002. This decision
was based on a complete dataset as well as additional supporting
evidence regarding device functionality.

XII\. Approval Specifications

**Directions for Use:** See labeling.

**Hazards to Health from Use of the Device:** See Indications,
Contraindications, Warnings, Precautions and Adverse Events in the
labeling

[^1]: ^\*^ These data are included for completeness in reporting the
    results of the clinical study. The 4189 lead is not currently market
    approved in the U.S.

[^2]: ^\*^ These data are included for completeness in reporting the
    results of the clinical study. The 4189 lead is not currently market
    approved in the U.S.

[^3]: ^\*^ These data are included for completeness in reporting the
    results of the clinical study. The 4189 lead is not currently market
    approved in the U.S.

[^4]: ^\*^ These data are included for completeness in reporting the
    results of the clinical study. The 4189 lead is not currently market
    approved in the U.S.

[^5]: ^\*^ These data are included for completeness in reporting the
    results of the clinical study. The 4189 lead is not currently market
    approved in the U.S.

[^6]: ^\*^ These data are included for completeness in reporting the
    results of the clinical study. The 4189 lead is not currently market
    approved in the U.S.

[^7]: Weber KT, Janicki JS. "Cardiopulmonary Exercise Testing:
    Physiologic Principles And Clinical Applications". WB Saunders
    Company, 1986.

[^8]: Packer et al. J Cardiac Failure 2001;7:176-182.

[^9]: ^\*^ These data are included for completeness in reporting the
    results of the clinical study. The 4189 lead is not currently market
    approved in the U.S.

[^10]: Lee, EW and Dubin, N. Estimation and Sample Size Considerations
    for Clustered Binary Responses. *Statistics in Medicine*, Vol 13,
    1241-52 (1994).

[^11]: Wilkoff, BL, et al. Critical Analysis of Dual-Chamber Implantable
    Cardioverter-Defibrillator Arrhythmia Detection: Results and
    Technical Considerations. *Circulation*, Vol 103, 381-386 (2001).

[^12]: ^\*^ These data are included for completeness in reporting the
    results of the clinical study. The 4189 lead is not currently market
    approved in the U.S.