Summary of Safety and Effectiveness

# General Information

  -------------------- --------------------------------------------------
  Device Generic Name: Automatic Implantable CardioDefibrillator (AICD)

  Device Trade Name:   See Table 1 Below

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

  PMA Number:          P910077/S037 and P960040/S026

  Date of Panel        None
  Recommendation:      

  Date of Notice of    July 18, 2002
  Approval to          
  Applicant            
  -------------------- --------------------------------------------------

The Ventak AICDs were originally approved on July 18, 1997 under PMA
P960040 and on June 17, 1994 under PMA P910077. The sponsor submitted
the current supplement to further expand the indication for use
statement and to refine the original indication for use statement. The
updated clinical data to support the expanded indication, i.e., for
prophylactic treatment of patients with a prior myocardial infarction
and an ejection fraction (EF) ≤ 30% (as defined in the clinical
section). are provided in this summary. The pre-clinical test results
were presented in the original PMA application and subsequent
supplements as shown in Table I below. Written requests for copies of
the SSEDs can be obtained from the Dockets Management Branch (HFA-305),
Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD
20857. The summary for P960040 can also be found on the FDA CDRH
Internet Home Page located
[**http:/www.fda.gov/cdrh/pmapage.html**](http://www.fda.gov/cdrh/pmapage.html)

Table 1: MADIT II Applicable Devices

+--------------------------------+-------------------------------------+
| Device Family / Model          | Submission / Approval Date          |
+--------------------------------+-------------------------------------+
| VENTAK PRIZM 2 VR/DR           | P960040_S015 /                      |
|                                |                                     |
| (1860/1861)                    | approved 8/4/00                     |
+--------------------------------+-------------------------------------+
| VENTAK PRIZM VR/DR             | P960040_S012 /                      |
|                                |                                     |
| (1850/1851/1855/1856)          | approved 1/21/00                    |
+--------------------------------+-------------------------------------+
| VENTAK PRIZM VR/DR HE          | P960040_S016 /                      |
|                                |                                     |
| (1852/1853)                    | approved 8/7/00                     |
+--------------------------------+-------------------------------------+
| VENTAK MINI IV                 | P910077_S025 /                      |
|                                |                                     |
| (1790/1793/1796)               | approved 12/2/98                    |
+--------------------------------+-------------------------------------+
| VENTAK MINI III HE             | P910077_S025 /                      |
|                                |                                     |
| \(1789\)                       | approved 12/2/98                    |
+--------------------------------+-------------------------------------+

# Indications For Use

Guidant implantable cardioverter defibrillators (ICDs) are indicated in
patients who have had spontaneous and/or inducible life-threatening
ventricular arrhythmias and those who are at high risk for developing
such arrhythmias. In addition, this device is indicated for prophylactic
treatment of patients with a prior myocardial infarction and an ejection
fraction (EF) \<= 30% (as defined in the Clinical Study section).

# System Description

Reference the Physician's System Guide specific to the pulse generator
being implanted. Also reference the Model 2920 ZOOM programming manual
for use of the programmer.

# Contraindications

Use of ICD pulse generators are contraindicated in:

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

-   Patients who have a unipolar pacemaker

# Warnings and Precautions

Reference the Physician's System Guide specific to the device that is
being implanted for the complete list of warnings and precautions.

# Adverse Events

## Observed Adverse Events

The Multicenter Automatic Defibrillator Implantation Trial II (MADIT II)
was a prospective, randomized, controlled, multicenter, unblinded study
conducted at 76 sites (71 in the United States and 5 in Europe) and
enrolled a total of 1,232 patients. Patients were randomly assigned in a
3:2 ratio to receive an ICD (742 patients) or conventional medical
therapy (490 patients). There were a total of 22 conventional therapy
patients that were crossed over to the ICD group and a total of 32
patients randomized to the ICD arm that were considered crossovers. Of
these 32 crossovers, 11 were due to subsequent device explants.

There were no unanticipated adverse events reported in the MADIT II
study. There were no patient deaths that occurred during implantation.
Table 2 provides information on all adverse events reported from implant
through the randomization period in patients attempted or implanted with
the MADIT II criteria. The table includes a total of 3,161 events
reported for a total of 1,206 patients as of the data cutoff date of
January 16, 2002. The number of patients is less than the total enrolled
1,232 patients because not all patients had reached the point of the
one-month follow-up. The observed adverse events do not reflect an
intention-to-treat analysis.

Table 2: Adverse Events Through the Randomization Period

(3,161 Events in 1,206 patients who reached one month follow-up prior to
data cutoff date (1-16-02); 24,814 total device months)

  -------------------------------------------------------------------------------------------------------
  Adverse Event           \#           % Complic-ations\   Complications   % \             Observations
                          Of Events\   (Patients)          per\            Observations\   per\
                          (# of                            100 Device\     (Patients)      100  Device\
                          pts)^2^                          Months\                         Months
                                                           (Events)                        (Events)
  ----------------------- ------------ ------------------- --------------- --------------- --------------
  **Total of All Adverse  **3161       **49.7 (599)**      **7.9 (1761)**  **46.9 (566)**  **6.3 (1400)**
  Events (AE)**           (813^2^)**                                                       

  **ICD Therapy (Total    **2105       **51.5 (376)**      **8.4 (1172)**  **49.9 (364)**  **6.7 (933)**
  AEs-treatment group)**  (503)**                                                          

  **Conventional Therapy  **1056       **46.8 (223)**      **7.0 (589)**   **42.4 (202)**  **5.5 (476)**
  (Total AEs-control      (310)**                                                          
  group)**                                                                                 

  **TOTAL CARDIOVASCULAR                                                                   
  RELATED ADVERSE                                                                          
  EVENTS**                                                                                 

  **Device-Related                                                                         
  Events^1^**                                                                              

  Prophylactic            7 (7)        0.6 (7)             0.0 (7)         0.0 (0)         0.0 (0)
  replacement                                                                              

  Lead related problem    14 (13)      0.8 (10)            0.0 (10)        0.3 (3)         0.0 (4)

  Battery depletion --    2 (2)        0.2 (2)             0.0 (2)         0.0 (0)         0.0 (0)
  normal (at EOL)                                                                          

  Electromagnetic         2 (2)        0.0 (0)             0.0 (0)         0.2 (2)         0.0 (2)
  interference (EMI)                                                                       

  Nonconversion of        3 (3)        0.2 (3)             0.0 (3)         0.0 (0)         0.0 (0)
  arrhythmia                                                                               

  Sense time prolonged /  5 (5)        0.2 (3)             0.0 (3)         0.2 (2)         0.0 (2)
  inappropriate                                                                            

  Generator manufacturing 2 (2)        0.2 (2)             0.0 (2)         0.0 (0)         0.0 (0)
  problem                                                                                  

  Pacemaker mediated      79 (47)      0.0 (0)             0.0 (0)         3.9 (47)        0.4 (79)
  tachycardia                                                                              

  Individual events that  18 (18)      1.0 (10)            0.0 (10)        0.8 (8)         0.0 (8)
  occurred one time                                                                        

  **Subtotal Device       **132        **2.9 (35)**        **0.2 (37)**    **4.9 (59)**    **0.4 (95)**
  Related Events**        (91^2^)**                                                        

  **Procedure Related                                                                      
  Events^1^**                                                                              

  Infection               13 (13)      0.8 (9)             0.0 (9)         0.3 (4)         0.0 (4)

  Lead problem            2 (2)        0.1 (1)             0.0 (1)         0.1 (1)         0.0 (1)

  Patient bleeding        2 (2)        0.1 (1)             0.0 (1)         0.1 (1)         0.0 (1)

  Pulse generator flipped 2 (2)        0.0 (0)             0.0 (0)         0.2 (2)         0.0 (2)
  (Twiddler)                                                                               

  Pocket                  15 (15)      0.9 (11)            0.0 (11)        0.3 (4)         0.0 (4)
  inflammation/hematoma                                                                    

  Pain                    10 (10)      0.1 (1)             0.0 (1)         0.7 (9)         0.0 (9)

  Fibrillation, atrial    2 (2)        0.0 (0)             0.0 (0)         0.2 (2)         0.0 (2)

  Deep Vein Thrombosis    3 (3)        0.1 (1)             0.0 (1)         0.2 (2)         0.0 (2)

  Anxiety                 2 (2)        0.0 (0)             0.0 (0)         0.2 (2)         0.0 (2)

  Individual events that  17 (17)      0.8 (8)             0.0 (8)         0.9 (9)         0.0 (9)
  occurred one time                                                                        

  **Subtotal Procedure    **68         **2.2 (26)**        **0.1 (32)**    **3.0 (36)**    **0.2 (36)**
  Related Events**        (59^2^)**                                                        

  **Cardiovascular                                                                         
  Related Events(n=730                                                                     
  pts): ICD Therapy                                                                        
  (treatment group)**                                                                      

  Arrhythmia, atrial      78 (66)      4.2 (31)            0.2 (34)        5.3 (39)        0.3 (44)

  Arrhythmia, ventricular 64 (49)      5.3 (39)            0.4 (53)        1.4 (10)        0.1 (11)

  Mitral valve            1 (1)        0.1 (1)             0.0 (1)         0.0 (0)         0.0 (0)
  regurgitation                                                                            

  Congestive heart        444 (227)    22.9 (167)          2.2 (304)       14.1 (103)      1.0 (140)
  failure                                                                                  

  Palpitation, pounding   21 (18)      1.0 (7)             0.1 (7)         1.5 (11)        0.1 (14)
  heart                                                                                    

  Syncope                 62 (50)      4.7 (34)            0.3 (40)        2.5 (18)        0.2 (22)

  Infarction, myocardial  34 (28)      3.8 (28)            0.2 (34)        0.0 (0)         0.0 (0)

  Angina pectoris         166 (110)    10.0 (73)           0.8 (112)       6.0 (44)        0.4 (54)

  Bradycardia, sinus      8 (8)        1.0 (7)             0.1 (7)         0.1 (1)         0.0 (1)

  Tachycardia             7 (7)        0.3 (2)             0.0 (2)         0.7 (5)         0.0 (5)

  AV Block, Complete      1 (1)        0.1 (1)             0.0 (1)         0.0 (0)         0.0 (0)

  Cardiac allograft       2 (2)        0.3 (2)             0.0 (2)         0.0 (0)         0.0 (0)
  rejection                                                                                

  Hypotension             28 (26)      1.4 (10)            0.1 (10)        2.2 (16)        0.1 (18)

  Hypertension            6 (6)        0.1 (1)             0.0 (1)         0.7 (5)         0.0 (5)

  Claudication            10 (7)       0.8 (6)             0.1 (9)         0.1 (1)         0.0 (1)

  Carotid stenosis        5 (5)        0.5 (4)             0.0 (4)         0.1 (1)         0.0 (1)

  Aneurysm                1 (1)        0.1 (1)             0.0 (1)         0.0 (0)         0.0 (0)

  Deep vein thrombosis    9 (9)        1.0 (7)             0.1 (7)         0.3 (2)         0.0 (2)

  Pulmonary Embolus       4 (4)        0.5 (4)             0.0 (4)         0.0 (0)         0.0 (0)

  Individual events that  5 (5)        0.5 (4)             0.0 (4)         0.1 (1)         0.0 (1)
  occurred one time                                                                        

  Subtotal Cardiovascular 956 (354)    36.8 (269)          4.6 (637)       26.8 (196)      2.3 (319)
  Related Events: ICD                                                                      
  Therapy (treatment                                                                       
  group)                                                                                   

  **Cardiovascular                                                                         
  Related Events (n=476                                                                    
  pts): Conventional                                                                       
  Therapy (control                                                                         
  group)**                                                                                 

  Arrhythmia, atrial      31 (29)      3.2 (15)            0.2 (16)        3.2 (15)        0.2 (15)

  Arrhythmia, ventricular 33 (26)      4.6 (22)            0.3 (27)        1.1 (5)         0.1 (6)

  Arrhythmia, general     3 (3)        0.4 (2)             0.0 (2)         0.2 (1)         0.0 (1)
  report                                                                                   

  Mitral valve            1 (1)        0.2 (1)             0.0 (1)         0.0 (0)         0.0 (0)
  regurgitation                                                                            

  Congestive heart        212 (128)    16.6 (79)           1.5 (126)       14.3 (68)       1.0 (86)
  failure                                                                                  

  Palpitation, pounding   6 (5)        0.4 (2)             0.0 (3)         0.6 (3)         0.0 (3)
  heart                                                                                    

  Syncope                 35 (31)      4.8 (23)            0.3 (24)        2.1 (10)        0.1 (11)

  Infarction, myocardial  19 (17)      3.6 (17)            0.2 (19)        0.0 (0)         0.0 (0)

  Angina pectoris         93 (71)      10.7 (51)           0.8 (64)        5.5 (26)        0.3 (29)

  Bradycardia, sinus      8 (8)        1.7 (8)             0.1 (8)         0.0 (0)         0.0 (0)

  AV Block, Complete      4 (2)        0.4 (2)             0.0 (3)         0.2 (1)         0.0 (1)

  Bundle branch block     4 (4)        0.4 (2)             0.0 (2)         0.4 (2)         0.0 (2)

  Hypotension             17 (13)      1.9 (9)             0.1 (12)        1.1 (5)         0.1 (5)

  Hypertension            2 (2)        0.0 (0)             0.0 (0)         0.4 (2)         0.0 (2)

  Claudication            6 (4)        0.6 (3)             0.1 (5)         0.2 (1)         0.0 (1)

  Carotid stenosis        5 (5)        1.1 (5)             0.1 (5)         0.0 (0)         0.0 (0)

  Aneurysm                3 (3)        0.6 (3)             0.0 (3)         0.0 (0)         0.0 (0)

  Deep vein thrombosis    3 (3)        0.6 (3)             0.0 (3)         0.0 (0)         0.0 (0)

  Pulmonary Embolus       2 (2)        0.4 (2)             0.0 (2)         0.0 (0)         0.0 (0)

  Tachycardia             2 (2)        0.2 (1)             0.0 (1)         0.2 (1)         0.0 (1)

  Individual events that  7 (7)        1.1 (5)             0.1 (5)         0.4 (2)         0.0 (2)
  occurred one time                                                                        

  Subtotal Cardiovascular 496 (222)    34.7 (165)          3.9 (331)       25.0 (119)      2.0 (165)
  Related Events:                                                                          
  Conventional Therapy                                                                     
  (control group)                                                                          

  **Subtotal              **1452       **36.0 (434)**      **4.3 (968)**   **26.1 (315)**  **2.2 (484)**
  Cardiovascular Related  (576^2^)**                                                       
  Events: Both groups**                                                                    
  -------------------------------------------------------------------------------------------------------

^1^ Events include only patients in the ICD treatment group.

^2^ Identifies number of unique patients. Patients may have one or more
adverse events.

## Mortality 

## 

## *Note: For additional information see Section 10, Summary of MADIT II Clinical Study*

There were a total of 202 deaths that occurred during the trial and
recorded as of the stop date, November 20, 2001. These deaths occurred
during the study periods as shown in Table 3 along with the cause of
death as adjudicated by an independent events committee.

Table 3: Cause of Death During the Treatment Period

+--------------------------+-----------+----------------+-------------+
| Cause of Death           | ICD       | Conventional   | Total       |
|                          | Therapy   | Therapy        |             |
| (as a percent of total   |           |                | (N=202)     |
| pts)                     | (N=742)   | (N=490)        |             |
|                          |           |                |             |
|                          | Patients  | Patients (%)   |             |
|                          | (%)       |                |             |
+--------------------------+-----------+----------------+-------------+
| Non-Cardiac              | 25 (3.4%) | 21 (4.3%)      | 46 (3.7%)   |
+--------------------------+-----------+----------------+-------------+
| Cardiac: Arrhythmic      | 28 (3.8%) | 48 (9.8%)      | 76 (6.2%)   |
+--------------------------+-----------+----------------+-------------+
| Cardiac: Non-arrhythmic  | 45 (6.1%) | 22 (4.5%)      | 67 (5.4%)   |
+--------------------------+-----------+----------------+-------------+
| Cardiac: Undetermined    | 1 (0.1%)  | 2 (0.4%)       | 3 (0.2%)    |
| cause                    |           |                |             |
+--------------------------+-----------+----------------+-------------+
| Unknown                  | 6 (0.8%)  | 4 (0.8%)       | 10 (0.8%)   |
+--------------------------+-----------+----------------+-------------+
| Total Deaths             | 105       | 97 (19.8%)     | 202 (16.3%) |
|                          | (14.2%)   |                |             |
+--------------------------+-----------+----------------+-------------+

## Potential Adverse Events

Based on the literature and implantable cardioverter defibrillator (ICD)
implant experience, the following alphabetical list includes possible
adverse events associated with implantation of an ICD system.

+------------------------------+---------------------------------------+
| Possible Adverse Events      |                                       |
+------------------------------+---------------------------------------+
| -   Acceleration of          | -   Keloid formation                  |
|     arrhythmias              |                                       |
+------------------------------+---------------------------------------+
| -   Air embolism             | -   Lead abrasion                     |
+------------------------------+---------------------------------------+
| -   Bleeding                 | -   Lead discontinuity                |
+------------------------------+---------------------------------------+
| -   Chronic nerve damage     | -   Lead migration/dislodgement       |
+------------------------------+---------------------------------------+
| -   Erosion                  | -   Myocardial damage                 |
+------------------------------+---------------------------------------+
| -   Excessive fibrotic       | -   Pneumothorax                      |
|     tissue growth            |                                       |
+------------------------------+---------------------------------------+
| -   Extrusion                | -   Potential mortality due to        |
|                              |     inability to defibrillate or pace |
+------------------------------+---------------------------------------+
| -   Fluid accumulation       | -   Shunting current or insulating    |
|                              |     myocardium during defibrillation  |
|                              |     with internal or external paddles |
+------------------------------+---------------------------------------+
| -   Formation of hematomas   | -   Thromboemboli                     |
|     or cysts                 |                                       |
+------------------------------+---------------------------------------+
| -   Inappropriate shocks     | -   Venous occlusion                  |
+------------------------------+---------------------------------------+
| -   Infection                | -   Venous or cardiac perforation     |
+------------------------------+---------------------------------------+
| Patients susceptible to      |                                       |
| frequent shocks despite      |                                       |
| antiarrhythmic medical       |                                       |
| management may develop       |                                       |
| psychologic intolerance to   |                                       |
| an ICD system that may       |                                       |
| include the following:       |                                       |
+------------------------------+---------------------------------------+
| -   Dependency               | -   Fear of shocking while conscious  |
+------------------------------+---------------------------------------+
| -   Depression               | -   Fear that shocking capability may |
|                              |     be lost                           |
+------------------------------+---------------------------------------+
| -   Fear of premature        | -   Imagined shocking                 |
|     battery depletion        |                                       |
+------------------------------+---------------------------------------+

# Alternate Practices and Procedures

Alternative therapies for the treatment of life-threatening ventricular
arrhythmias include the use of antiarrhythmic medication, electrical
ablation, cardiac surgery and electronic devices including pacemakers
and other legally marketed ICD systems, or a combination thereof.

# Marketing History

All Guidant devices for this indication used during the MADIT II
clinical study are legally distributed within the United States and
outside the United States. These devices are approved for sale in the
European Economic Community, Australia, New Zealand, Canada, Hong Kong,
Singapore, Indonesia, Lebanon, Malaysia, Malta, Mexico, Israel, Egypt,
Saudi Arabia, Turkey, Czech Republic, Slovakia, Slovenia, India, South
Africa, and Latin America (Argentina, Bolivia, Chile, Columbia,
Dominican Republic, Ecuador, Panama, Venezuela, Uruguay).

None of these devices and/or leads have been withdrawn from the market
in any country for any reason related to their safety and effectiveness.

# Summary of Pre-Clinical Studies

All Guidant devices used in the MADIT II study were legally marketed
(See Table 1, page 1 and Table 2 below). The devices included in Table 2
were used during the study but are no longer manufactured by the
sponsor. As such, only devices shown in Table 1 are the subject of this
PMA supplement. All ICD systems were previously tested via nonclinical
laboratory testing including bench testing, biocompatibility evaluation
and animal studies. Device design and system compatibility involved
verification and validation of each system. The test results were
previously found acceptable.

Table 4: Devices Implanted / No Longer Manufactured

+-------------------------------+--------------------------------------+
| Devices Implanted During      |                                      |
| MADIT II Study but no longer  |                                      |
| Manufactured by Guidant       |                                      |
+===============================+======================================+
| VENTAK MINI III---1782        | P910077_S022, approved 1/23/98       |
|                               |                                      |
| VENTAK MINI III+---1783       | P910077_S022, approved 1/23/98       |
|                               |                                      |
| VENTAK MINI III               | P910077_S025, approved 12/2/98       |
| HE---1786/1788                |                                      |
+-------------------------------+--------------------------------------+
| VENTAK MINI II (1762/1763)    | P910077_S012, approved 4/29/96       |
+-------------------------------+--------------------------------------+
| VENTAK VR (1774/1775)         | P960040_S09, approved 5/3/99         |
+-------------------------------+--------------------------------------+
| VENTAK MINI I                 | P910077_S012, approved 4/29/96 and   |
| (1742/1743/1748)              | P910077_S022, approved 1/23/98       |
+-------------------------------+--------------------------------------+
| VENTAK AV III DR (1831/1836)  | P960040_S06, approved 8/31/98        |
+-------------------------------+--------------------------------------+
| VENTAK AV II DDD/DR           | P960040_S03, approved 3/13/98        |
| (1820/1821/1826)              |                                      |
+-------------------------------+--------------------------------------+
| VENTAK AV (1810/1815)         | P960040, approved 7/18/97            |
+-------------------------------+--------------------------------------+

# Summary of MADIT II Clinical Study

The Multicenter Automatic Defibrillator Implantation Trial II (MADIT II)
was designed to determine if implantation of an ICD in high-risk cardiac
patients with advanced left ventricular dysfunction could improve
overall survival. The previous MADIT I trial demonstrated improved
overall survival with an ICD in high-risk patients with coronary heart
disease, left ventricular dysfunction, asymptomatic non-sustained
ventricular tachyarrhythmias and an inducible nonsuppressible
ventricular tachycardia at EP study.

## MADIT II Summary of Clinical Study

The MADIT II Clinical Study was conducted to evaluate the potential
survival benefit of a prophylactically implanted ICD in patients with a
prior myocardial infarction and a left ventricular ejection of
[\<]{.underline} 30 percent. Unlike MADIT I ^(^[^1]^)^, patients
enrolled in MADIT II were not required to undergo electrophysiologic
testing to induce arrhythmias prior to implant. Patients were randomized
to either ICD or conventional therapy. All cause mortality was the
primary endpoint of the study.

The MADIT II trial was monitored using a sequential design and on
November 20, 2001, after review of the data by the Data and Safety
Monitoring Board, the study was stopped. Results of the trial data
indicated a 31% decrease in the mortality rate in patients implanted
with an ICD device compared to patients randomized to the conventional
therapy group, thus meeting its effectiveness endpoint.

The trial began July 11, 1997 and was conducted over a period of four
years at 76 investigational centers both within and outside the United
States. The inclusion and exclusion criteria for the study have been
included in Section 10.1.2.

### Study Design

MADIT II was a prospective, randomized \[3:2 ICD to conventional
(non-ICD) therapy\], controlled, unblinded, multi-center trial**.**
Randomization to the ICD group consisted of implantation of a legally
marketed Guidant ICD device. Randomization to the conventional therapy
group consisted of beta-adrenergic blocking drugs and
angiotensin-converting enzyme (ACE) inhibitors when indicated.

Patients provided written informed consent and received a baseline
reference examination that included prior clinical history, physical
examination and a 12-lead ECG. Following completion of the baseline
evaluation, patients were randomized by the Coordination and Data Center
(CDC) in a 3:2 fashion to receive either an ICD or conventional medical
therapy; randomization was done separately for each center, with
blocking, to assure proper balance between the two treatment groups
within each center. Each randomized patient remained counted as a member
of the original randomization assignment (intention-to-treat) regardless
of subsequent crossover or protocol adherence.

Patients randomized to the ICD arm were implanted with Guidant
transvenous defibrillator devices by MADIT II investigators. All Guidant
ICD systems used during the trial were legally approved devices.
Following randomization, patients were seen at a 1-month follow-up visit
in the clinic and at 3-month intervals thereafter until termination of
the study.

Primary Endpoint

The primary endpoint for MADIT II was all cause mortality.

Primary Objective

The primary objective of the trial was to determine if implantation of
ICDs in moderately high-risk coronary patients would result in
significant reduction in death when compared to patients treated without
an ICD.

### Inclusion/Exclusion Criteria

Study **[inclusion]{.underline}** criteria were as follows:

-   Patients must have an ejection fraction [\<]{.underline} 0.30
    obtained [\<]{.underline} 3 months prior to enrollment by
    angiographic, radionuclide, or echocardiographic methods. This
    ejection fraction must be obtained at least 30 days following the
    most recent myocardial infarction, coronary artery bypass graft
    surgery, or coronary revascularization procedure.

-   Patients must have had at least one or more documented Q-wave or
    other enzyme positive infarctions. If enzyme information is not
    available, then there must be clear evidence of an infarct
    identified as a Q-wave on an ECG, fixed defect (scar) on a thallium
    scan, or infarcted area on a coronary angiogram or echocardiography.

-   Patients must be men or women greater than 21 years of age (no upper
    cut-off).

Study **[exclusion]{.underline}** criteria were as follows:

-   Previous cardiac arrest or syncopal ventricular tachycardia
    unassociated with an acute myocardial infarction (existing ICD
    indication)

-   Patients meeting MADIT I criteria with EF[\<]{.underline} 0.35,
    nonsustained VT, and inducible-nonsuppressible VT at
    electrophysiologic study (existing ICD indication)

-   Cardiogenic shock, symptomatic hypotension while in a stable
    baseline rhythm

-   NYHA functional Class IV

-   Current use of antiarrhythmic agents except when indicated for
    atrial arrhythmias

-   Coronary artery bypass graft surgery or PTCA within the past 3
    months

-   Enzyme-positive myocardial infarction [\<]{.underline} 30 days prior
    to enrollment

-   Patients with angiographic evidence of coronary disease who are
    candidates for coronary revascularization and are likely to undergo
    coronary artery bypass graft surgery or PTCA in the foreseeable
    future

-   Patients with irreversible brain damage from preexisting cerebral
    disease

-   Women of childbearing potential not using medically prescribed
    contraceptive measures

-   Presence of any disease, other than the patient's cardiac disease,
    associated with a reduced likelihood of survival for the duration of
    the trial, e.g. cancer, uremia (BUN [\>]{.underline} 70 mg% and/or
    creatinine [\>]{.underline} 30 mg%

-   Patients participating in other clinical heart disease trials

-   Patients unwilling or unable to cooperate with the study due to
    dementia, psychological or other related reasons

-   Patients who were unable to participate due to one or more
    logistical considerations

-   Patient's primary care physician refuses to allow patient to
    participate

-   Patients who are on the heart transplant list. If the patient is
    pending evaluation for the heart transplant list, the patient cannot
    be enrolled in MADIT II until it is definitively determined that the
    patient will NOT be placed on the transplant list

-   ICD cannot be implanted due to anatomical abnormality or other
    medical problem

### Follow-up schedule

Following randomization, patients were seen at a 1-month follow-up visit
in the clinic and at 3-month intervals thereafter until termination of
the study. During each clinic visit, an appropriate clinical evaluation
was completed. Patients with an ICD device underwent device testing
according to an agreed-upon protocol at the investigational center.
Patients were followed from between 6 days and 53 months averaging 20
months.

### Patient Status

There were a total of 1,232 patients with a prior myocardial infarction
and a left ventricular ejection fraction of [\<]{.underline} 0.30
enrolled in the MADIT II trial. A total of 742 patients were randomized
to receive an ICD and 490 patients were randomized to conventional
therapy. provides an overview of the patient enrollment.

Figure 1: MADIT II Patient Enrollment Cascade\
Primary Endpoint

![](media/image1.wmf)

### Primary Endpoint

The primary endpoint for MADIT II was death from any cause. Analysis was
performed according to the intention-to-treat principle. The trial was
designed to have 95 percent power to detect a 38 percent reduction in
the two-year mortality rate among the patients in the ICD group, given a
postulated two-year mortality rate of 19 percent among patients assigned
to conventional therapy, with a two-sided significance level of 5%. For
proportional-hazards modeling, power was maintained for a true hazard
ratio of 0.63, after allowance for crossovers. A triangular sequential
design was used, which was modified for two-sided alternatives. The data
was corrected to account for any lag in obtaining data accrued (during
weekly monitoring), but not reported before the termination of the
trial, with preset boundaries to permit termination of the trial if the
ICD therapy was found to be superior to, inferior to, or equal to
conventional medical therapy.

Secondary analyses were performed with use of the Cox proportional
hazards regression model. Survival curves were determined according to
the Kaplan and Meier method, with comparisons of cumulative mortality
based on logarithmic transformation. The p-values were termed nominal
when they were not adjusted for sequential monitoring. All p-values were
two-tailed.

At the recommendation of the Data and Safety Monitoring Board (DSMB),
the trial was stopped on November 20, 2001, when it was revealed that
the difference in mortality between the two groups had reached the
prespecified efficacy boundary (p=0.027) (See Figure 2).

Figure 2: Sequential Monitoring in the Triangular Design

![](media/image2.png){width="5.7in" height="3.9770833333333333in"}

### Study Results

####  Study Duration

Study duration, measured in months, is displayed in Table 5. The mean
duration was similar between the ICD group and the conventional therapy
group. As expected, the ICD group accumulated \>15,000 months of
follow-up.

Table 5: MADIT II Study Duration in months

+----------------+------+------+------+---------+---------+----------+
| Therapy        | No.  | Mean | [    | Minimum | Maximum | Cu       |
|                |      |      | +]{. |         |         | mulative |
|                | (P   |      | unde |         |         |          |
|                | ts.) |      | rlin |         |         |          |
|                |      |      | e}SD |         |         |          |
+----------------+------+------+------+---------+---------+----------+
| ICD Therapy    | 742  | 20.5 | 12.9 | 0.2     | 51.7    | 15,190   |
+----------------+------+------+------+---------+---------+----------+
| Conventional   | 490  | 19.6 | 12.6 | 0.2     | 52.3    | 9,624    |
| Therapy        |      |      |      |         |         |          |
+----------------+------+------+------+---------+---------+----------+

**Baseline Characteristics**

**Table 6** provides a summary of the general characteristics of the
enrolled MADIT II patient population. Characteristics were balanced
across therapy groups and no statistical differences were found during
data analysis as indicated by the p-values in the table.

Table 6: Patient Population Characteristics

+-------------------------------+-----------+--------------+----------+
| Characteristic                | ICD       | Conventional | p-value  |
|                               |           | Therapy      |          |
|                               | Patients  | Patients     |          |
|                               |           |              |          |
|                               | (n=742)   | (n=490)      |          |
+===============================+===========+==============+==========+
| Age at Enrollment             | 397       | 262 (53.5%)  | 0.99     |
|                               | (53.5%)   |              |          |
| -   [\>]{.underline} 65 years |           | 64.6 +/-     |          |
|     (patients, %)             | 64.4 +/-  | 10.3         |          |
|                               | 10.4      |              |          |
| -   Mean +/- Standard         |           |              |          |
|     Deviation (years)         |           |              |          |
+-------------------------------+-----------+--------------+----------+
| Gender (patients, %)          | 623       | 417 (85.1%)  | 0.59     |
|                               | (83.9%)   |              |          |
| -   Male                      |           |              |          |
+-------------------------------+-----------+--------------+----------+
| LVEF (%)                      | 23.1 +/-  | 23.2 +/- 5.6 | 0.93     |
|                               | 5.4       |              |          |
| -   Mean +/- Standard         |           |              |          |
|     Deviation                 |           |              |          |
+-------------------------------+-----------+--------------+----------+
| LVEF\*                        | 502       | 330 (67.3%)  | 0.91     |
|                               | (76.7%)   |              |          |
| -   [\<]{.underline} 25%      |           |              |          |
|     (patients, %)             |           |              |          |
+-------------------------------+-----------+--------------+----------+
| New York Heart Association    | 179       | 129 (26.3%)  | 0.64     |
| Classification                | (24.1%)   |              |          |
|                               |           | 58 (11.8%)   |          |
| 3 months before enrollment    | 75        |              |          |
| (patients, %)                 | (10.1%)   | 162 (33.1%)  |          |
|                               |           |              |          |
| -   No CHF                    | 258       | 111 (22.7%)  |          |
|                               | (34.8%)   |              |          |
| -   Class I                   |           | 20 (4.1%)    |          |
|                               | 187       |              |          |
| -   Class II                  | (25.2%)   | 10 (2.0%)    |          |
|                               |           |              |          |
| -   Class III                 | 33 (4.5%) |              |          |
|                               |           |              |          |
| -   Class IV                  | 10 (1.4%) |              |          |
|                               |           |              |          |
| -   Unknown                   |           |              |          |
+-------------------------------+-----------+--------------+----------+
| Canadian Heart Association    | 126       | 81 (16.5%)   | 0.62     |
| Classification                | (16.9%)   |              |          |
|                               |           | 120 (24.4%)  |          |
| -   Class I                   | 168       |              |          |
|                               | (23.1%)   | 15 (3.1%)    |          |
| -   Class II, III, IV         |           |              |          |
|                               | 35 (4.7%) | 268 (54.7%)  |          |
| -   Angina Decubitus          |           |              |          |
|                               | 402       | 6 (1.2%)     |          |
| -   No Angina Pectoris        | (54.1%)   |              |          |
|                               |           |              |          |
| -   Unknown                   | 11 (1.4%) |              |          |
+-------------------------------+-----------+--------------+----------+
| Ventricular arrhythmias       | 74        | 64 (13.1%)   | 0.24     |
| requiring treatment           | (10.0%)   |              |          |
| (patients, %)                 |           |              |          |
+-------------------------------+-----------+--------------+----------+
| Atrial Arrhythmias requiring  | 201       | 120 (24.4%)  | 0.56     |
| treatment                     | (27.1%)   |              |          |
|                               |           |              |          |
| (patients, %)                 |           |              |          |
+-------------------------------+-----------+--------------+----------+
| History of Hypertension       | 411       | 277 (56.5%)  | 0.71     |
| (patients, %)                 | (55.3%)   |              |          |
|                               |           |              |          |
| -   Hypertension              |           |              |          |
+-------------------------------+-----------+--------------+----------+
| Blood Urea Nitrogen           | 213       | 153 (31.2%)  | 0.52     |
| (patients, %)                 | (28.7%)   |              |          |
|                               |           |              |          |
| -   \> 25 mg %                |           |              |          |
+-------------------------------+-----------+--------------+----------+
| Diabetes Mellitus (patients,  | 246       | 184 (37.6%)  | 0.45     |
| %)                            | (33.2%)   |              |          |
+-------------------------------+-----------+--------------+----------+
| Non-CABG Revascularization    | 331       | 205 (41.8%)  | 0.56     |
| Procedures (patients, %)      | (44.6%)   |              |          |
+-------------------------------+-----------+--------------+----------+
| CABG Surgery (patients, %)    | 428       | 274 (55.9%)  | 0.53     |
|                               | (57.7%)   |              |          |
+-------------------------------+-----------+--------------+----------+
| Permanent Pacemaker           | 62 (8.4%) | 30 (6.1%)    | 0.22     |
| (patients, %)                 |           |              |          |
+-------------------------------+-----------+--------------+----------+
| EP Study prior to enrollment  | n=150     | n=112        | 0.27     |
| (262 patients)                | (20.2%)   | (22.8%)      |          |
|                               |           |              | 0.25     |
| -   Inducible                 | 8 (5.3%)  | 2 (1.8%)     |          |
+-------------------------------+-----------+--------------+----------+

\*Two patients enrolled with EF \> 30%.

#### Medications

Table 7 provides a summary of the medication utilization for the
patients enrolled. The two treatment groups were balanced and
appropriately treated with standard cardiac therapy. There were no
differences in ACE inhibitors, beta blockers or digitalis therapy
between the ICD therapy group and the conventional therapy patients.

Table 7: Patient Population Medication Therapy

+-------------------------------+-----------+--------------+----------+
| Medication                    | ICD       | Conventional | p-value  |
|                               |           | Therapy      |          |
|                               | Patients  | Patients     |          |
|                               |           |              |          |
|                               | (n=742)   | (n=490)      |          |
+===============================+===========+==============+==========+
| **ACE inhibitor use           | 574       | 377 (76.9%)  | 0.47     |
| (patients, %)**               | (77.4%)   |              |          |
|                               |           | 363 (74.1%)  | 0.31     |
| Baseline/Enrollment           | 533       |              |          |
|                               | (71.8%)   |              |          |
| Last Follow-up                |           |              |          |
+-------------------------------+-----------+--------------+----------+
| **Amiodarone use (patients,   | 49 (6.6%) | 36 (7.3%)    | 0.41     |
| %)**                          |           |              |          |
|                               | 94        | 51 (10.4%)   | 0.23     |
| Baseline/Enrollment           | (12.7%)   |              |          |
|                               |           |              |          |
| Last Follow-up                |           |              |          |
+-------------------------------+-----------+--------------+----------+
| **Antiarrhythmic use          | 18 (2.4%) | 15 (3.1%)    | 0.37     |
| (patients, %)**               |           |              |          |
|                               | 21 (2.8%) | 12 (2.4%)    | 0.43     |
| Baseline/Enrollment           |           |              |          |
|                               |           |              |          |
| Last Follow-up                |           |              |          |
+-------------------------------+-----------+--------------+----------+
| **Aspirin use (patients, %)** | 503       | 344 (70.2%)  | 0.30     |
|                               | (67.8%)   |              |          |
| Baseline/Enrollment           |           | 332 (67.8%)  | 0.20     |
|                               | 477       |              |          |
| Last Follow-up                | (64.3%)   |              |          |
+-------------------------------+-----------+--------------+----------+
| **Beta blocker use (patients, | 469       | 295 (60.2%)  | 0.28     |
| %)**                          | (63.2%)   |              |          |
|                               |           | 351 (71.6%)  | 0.46     |
| Baseline/Enrollment           | 529       |              |          |
|                               | (71.3%)   |              |          |
| Last Follow-up                |           |              |          |
+-------------------------------+-----------+--------------+----------+
| **Digitalis use (patients,    | 441       | 277 (56.5%)  | 0.29     |
| %)**                          | (59.4%)   |              |          |
|                               |           | 290 (59.2%)  | 0.41     |
| Baseline/Enrollment           | 451       |              |          |
|                               | (60.8%)   |              |          |
| Last Follow-up                |           |              |          |
+-------------------------------+-----------+--------------+----------+
| **Diuretics use (patients,    | 541       | 379 (77.3%)  | 0.09     |
| %)**                          | (72.9%)   |              |          |
|                               |           | 396 (80.8%)  | 0.04     |
| Baseline/Enrollment           | 562       |              |          |
|                               | (75.7%)   |              |          |
| Last Follow-up                |           |              |          |
+-------------------------------+-----------+--------------+----------+
| **Lipid Lowering use          | 492       | 315 (64.3%)  | 0.37     |
| (patients, %)**               | (66.3%)   |              |          |
|                               |           | 339 (69.2%)  | 0.04     |
| Baseline/Enrollment           | 556       |              |          |
|                               | (74.9%)   |              |          |
| Last Follow-up                |           |              |          |
+-------------------------------+-----------+--------------+----------+
| **Sotalol use (patients, %)** | 7 (0.9%)  | 3 (0.6%)     | 0.38     |
|                               |           |              |          |
| Baseline/Enrollment           | 18 (2.4%) | 4 (0.8%)     | 0.05     |
|                               |           |              |          |
| Last Follow-up                |           |              |          |
+-------------------------------+-----------+--------------+----------+

####  All Cause Mortality 

The Kaplan-Meier mortality curves depicting mortality for the two groups
are shown below in Figure 3. Although the conventional and ICD survival
curves remain close during the first nine months, they progressively
separate thereafter. Table 8 presents information derived from these
curves, with the conclusion that 3-year cumulative all-cause mortality
is estimated to be reduced by 29% in those with an ICD.

Figure 3: Kaplan-Meier Mortality Curves Conventional vs. ICD Groups

![](media/image3.wmf){width="5.990277777777778in"
height="3.847916666666667in"}

Table 8: Cumulative Mortality and Percentage Reduction

+------+-----------+--------+----------+----------+--------+--------+
| Year | Con       | ICD    | Di       | R        | CI^\*^ | p-va   |
|      | ventional | Arm    | fference | eduction |        | lue^†^ |
|      | Arm       |        |          |          | \%     |        |
+------+-----------+--------+----------+----------+--------+--------+
| 1    | 9.9       | 8.8    | 1.1      | 11%      | -29,   | 0.53   |
| Year |           |        |          |          | 39     |        |
+------+-----------+--------+----------+----------+--------+--------+
| 2    | 21.5      | 15.5   | 6.0      | 28%      | 5, 46  | 0.02   |
| Y    |           |        |          |          |        |        |
| ears |           |        |          |          |        |        |
+------+-----------+--------+----------+----------+--------+--------+
| 3    | 30.4      | 21.6   | 8.8      | 29%      | 6, 46  | 0.02   |
| Y    |           |        |          |          |        |        |
| ears |           |        |          |          |        |        |
+------+-----------+--------+----------+----------+--------+--------+

> ^\*Indicates\ Confidence\ Interval\ for\ the\ percentage\ reduction\ in\ cumulative\ mortality.\ The\ cumulative\ mortality\ (and\ associated\ standard\ errors)\ is\ taken\ from\ the\ Kaplan-Meier\ analyses;\ percentage\ reduction\ analyses\ are\ based\ on\ a\ log\ transform\ method.^
>
> ^†\ For\ null\ hypothesis\ that\ the\ percentage\ (%)\ reduction\ is\ zero.^

The pre-specified primary analysis of the trial was based on computation
of a hazard ratio, based on an assumption that the two survival curves
satisfy a proportional hazards condition (one is a power \-- the
\`hazard ratio\' \-- of the other), and recognizing the sequential
stopping rule of the trial. The hazard ratio is interpreted as the ratio
of instantaneous risks of dying, at each point in time, in the two
treatment groups. The hazard ratio for the ICD group relative to the
conventional therapy group was found to be 0.69, indicating a 31%
reduction in instantaneous risk (95% confidence interval, 0.51 to 0.93;
p=0.016, reduced from p=0.027 when reaching the stopping boundary, by
incorporation of lagged data). The Cox regression analyses used for this
purpose were stratified by enrollment centers, thus allowing for
somewhat different patient pools at differing locations.

The proportional hazards assumption was evaluated by several standard
statistical methods, all providing support. One method is derived from
finding parallelism in so-called log (-log) plots of the cumulative
hazards. Another is from fitting models that allow for differing hazard
ratios in differing intervals of time, and demonstrating that any
apparent differences among the period-specific hazard ratios can be
attributed to chance. One such analysis is summarized in Table 9.

Table 9: Year-Specific Hazard Ratios (HR)

  -------------------- ----------------------- --------------------------
  Year                 Estimate                CI

  1 Year               0.87                    0.59, 1.29

  2 Years              0.56                    0.29, 1.07

  3+ Years             0.61                    0.28, 1.34

  Overall              0.69                    0.51, 0.93
  -------------------- ----------------------- --------------------------

The p-value = 0.16 for differences among the 3 HRs, and the p-value =
0.016 for the overall HR. The exponential mortality curves fit the data
very well, with risks of mortality of 0.0100 each month for patients in
the conventional therapy group and 0.0069 each month in the ICD group,
with the ratio, 0.69, in agreement with that reported above.

#### Verification of ICD Shock Therapy Treatment

Of the 710 patients that were implanted with an ICD, 134 received
appropriate therapy for ventricular tachycardia/ventricular fibrillation
(VT/VF) and the probability of therapy increased over time. There was a
34% cumulative probability that ICD patients received therapy from the
device for VT/VF within three years (see Figure 4). The probability of
first appropriate shock for VF only at one year was 4% and increased to
10% after four years. These percentages are closely related to the
survival probability differences observed between the ICD and
conventional therapy groups (1% and 11%, respectively) as shown in
Figure 3.

Figure 4: Probability of First Therapy Due to VT/VF

> ![](media/image4.png)

The probability of appropriate ICD shocks for ventricular fibrillation
() correlates closely to the difference in the cumulative number of
deaths between the ICD and conventional groups as shown in .

#### Hospitalization Results

The rate of occurrence of adverse events requiring hospitalization was
0.29 per year of observation in both the conventional therapy patients
and in the ICD patients. Table 10 provides the summary of all
hospitalizations that occurred as a result of adverse events. Adverse
events that resulted in hospitalizations do not differ significantly
between groups.

Table 10: Adverse Events Requiring Hospitalizations (Rate/Year)\
(excludes adverse events that resulted in death)

  -------------- ------------- ---------------- ---------------- ----------
  Treatment      Cumulative    Total Number of  Rate per Year of p-value
  Group          Years of      Individuals with Individuals with 
                 Observation   Adverse Events   Adverse Events   

  Conventional   703.6         201 (41%)        0.29             0.85
  (n=490)                                                        

  ICD Therapy    1155.97       337 (45%)        0.29             
  Group (n=742)                                                  
  -------------- ------------- ---------------- ---------------- ----------

Table 11 provides a summary of hospitalizations that were required as a
result of congestive heart failure (CHF) related adverse events. There
were 78 of the 490 patients in the conventional group and 161 of the 742
ICD patients who had one or more hospitalizations that did not result in
death. The annual rate of hospitalization for CHF for each treatment
group was calculated by dividing the number of patients with one or more
hospitalizations for new or worsening CHF by the cumulative years of
observation. The rate of hospitalization for CHF per year was somewhat
higher in the ICD group (161/1155.97 = 0.14) compared to the
conventional therapy group (78/703.6 = 0.11); however, this difference
in the rate of hospitalization for CHF was not statistically significant
(p=0.11).

Table 11: Heart Failure Adverse Events Requiring Hospitalization
(Rate/Year)\
(excludes adverse events that resulted in death)

  -------------- ------------- ---------------- ---------------- ----------
  Treatment      Cumulative    Total Number of  Rate per Year of p-value
  Group          Years of      Individuals with Individuals with 
                 Observation   Adverse Events   Adverse Events   

  Conventional   703.6         78 (16%)         0.11             0.11
  (n=490)                                                        

  ICD Therapy    1155.97       161 (22%)        0.14             
  Group (n=742)                                                  
  -------------- ------------- ---------------- ---------------- ----------

### Reasons For Crossover

The MADIT II study was an intention-to-treat analysis, therefore, any
patient receiving therapy outside of their randomized therapy group was
counted as a crossover. Table 12 details crossovers by treatment group.

Table 12: Reasons for Crossovers by Treatment Group

+--------------------------+------------------+------------------------+
| Description              | ICD Therapy      | Conventional Therapy   |
|                          |                  |                        |
|                          | (n=742)          | (n=490)                |
+--------------------------+------------------+------------------------+
| Refusal of therapy       | 21               | 0                      |
+--------------------------+------------------+------------------------+
| Met ICD implant criteria | N/A              | 21                     |
+--------------------------+------------------+------------------------+
| Heart transplant         | 9                | 0                      |
+--------------------------+------------------+------------------------+
| Sepsis related to CABG   | 1                | 0                      |
| surgery                  |                  |                        |
+--------------------------+------------------+------------------------+
| Non-conversion of        | 1                | 0                      |
| arrhythmia               |                  |                        |
+--------------------------+------------------+------------------------+
| Physician Discretion     | 0                | 1                      |
+--------------------------+------------------+------------------------+
| **Total Crossovers       | 32               | 22                     |
| (54)**                   |                  |                        |
+--------------------------+------------------+------------------------+

A crossover patient was defined as a patient who, at the time of a
specified data cutoff date, was receiving treatment that was different
than their originally randomized assignment. Crossovers from the
conventional therapy group to the ICD group were strongly discouraged
unless a patient was determined to have a strong clinical justification
such as positive inducibility during EP testing or spontaneous
ventricular arrhythmia event(s) requiring hospitalization that would be
an approved indication for receiving an ICD.

### Follow-Up Compliance

The compliance rate is calculated by dividing the number of successful
visits by the sum of the visits expected for the designated month
sequence. Table 13 details reported visit compliance in six month
intervals. Compliance to follow-up was [\>]{.underline} 88% at the
majority of required visits. There was no difference in the follow-up
rates between the two groups.

Table 13. Follow-Up Compliance

  ------------------------------------------------------------------------
  Follow-up Sequence      \% Compliant\          \% Compliant\
  Month                   ICD Group              Conventional Therapy
                                                 Group
  ----------------------- ---------------------- -------------------------
  1-6 months              98                     96

  7-12 months             97                     95

  13-18 months            96                     93

  19-24 months            95                     93

  25-30 months            93                     89

  31-36 months            97                     90

  37-42 months            95                     85

  43-51 months            96                     100

  Total Average           96                     94
  ------------------------------------------------------------------------

## Subgroup Analysis Of MADIT II Patient Population 

Figure 5 provides the hazard ratios and 95 percent confidence intervals
for death from any cause in the ICD group as compared to the
conventional therapy group according to selected clinical
characteristics.

The hazard ratios in the various subgroups were similar, with no
statistically significant interactions. The dotted vertical line
represents the results for the entire study (nominal hazard ratio, 0.66,
without adjustment for the stopping rule). The horizontal lines indicate
nominal 95 percent confidence intervals.

Figure 5: Hazard Ratios and 95 Percent Confidence Intervals

![](media/image1.wmf)

### GENDER ANALYSIS

As seen above in the subgroup analysis, there is no significant
difference in the hazard ratios and 95 percent confidence intervals for
death from any cause in the ICD group as compared to the conventional
therapy group according gender. The 95% confidence interval crosses 1.0
because of the smaller number of female patients enrolled in the study.
The percentage of female patients enrolled is consistent with similar
ICD studies.

### Analysis of Inducibility as a Risk Factor

There were 583 patients enrolled in MADIT II who had EP testing
performed either prior to or during ICD implant. The definition for
inducibility was the same one used for the MADIT I study. Of these 583
patients, 373 (63%) were not inducible and the remaining 210 (36%) were
inducible. Of the 210 patients who were inducible, 180 (88%) had EP
testing performed at implant using a catheter method and 24 (12%) using
the ICD for induction; there was no data on the method of induction for
6 patients.

#### The occurrence of ICD therapy for VT, VF or VT/VF Combined

Therapy for VT was defined as antitachycardia pacing (ATP) or ICD shock
delivered by the device in an attempt to stop an arrhythmia as reported
by the enrolling center. Therapy for VF was defined as the delivery of
ICD shock therapy. The endpoint for VT/VF was defined by the occurrence
of either VT or VF therapy. The occurrence of therapy for each of these
groups is provided in Table 14. All analyses were Cox regression
analyses, stratified by enrollment center, with time to VT, time to VF
or time to VT/VF therapy as the respective endpoint.

Table 14: ICD Patients Receiving One or More Therapies\*

  ------------------------ ---------------- -----------------------------
  Type of ICD Therapy      Number of        Percent of Patients with
                           Patients         Therapy Episodes

  VT (ATP or shock)        89               15.4%

  VF (Shock only)          36               6.2%

  VT/VF VF (ATP + shock)   114              19.7%
  ------------------------ ---------------- -----------------------------

> \*Some patients received both types of therapy

#### Predictions of VT and VF Therapy in ICD Patients

A statistical analysis was performed to evaluate whether inducibility at
EP testing provides predictability of the potential effectiveness of an
ICD. To this end, the occurrence of each of the three endpoints defined
above (VT, VF and VT/VF), in ICD patients with EP testing were
evaluated. Analyses were done by Cox proportional hazards regression,
stratified by enrollment center. (See Table 15.)

A list of potential risk factors was considered for these endpoints,
such as age, gender, and standard cardiological variables like NYHA
class, EF, etc., and developed a parsimonious regression model in the
583 ICD patients identified above. GENDER and BUN (dichotomized at up to
25 versus 26 and over) were observed as potential risk factors for these
endpoints, with males and elevated BUN associated with increased
occurrence of these endpoints. Further analysis investigated whether
inducibility added any additional, independent predictive power for each
of these endpoints.

The conclusion was that inducibility increases the risk of VT events by
perhaps 60% (p=0.07) and decreases the risk of VF events by perhaps 50%
(p=0.08). As a consequence of these opposite directional effects of
similar magnitudes, there was no reliable evidence that inducibility
affects the frequency of VT/VF events (p=0.26); it may be associated
with a slight increase since VT events occur more frequently than VF.

Table 15: Therapy Predictability Based on Induced Arrhythmia

+----------------------+---------------------+------------------------+
| Therapy Delivered    | Inducible           |                        |
| for the following    |                     |                        |
| Type of Arrhythmia   |                     |                        |
+======================+=====================+========================+
|                      | **Yes**             | **No**                 |
+----------------------+---------------------+------------------------+
| **VF**               | 7                   | 29                     |
|                      |                     |                        |
| Yes                  | 202                 | 341                    |
|                      |                     |                        |
| No                   |                     |                        |
+----------------------+---------------------+------------------------+
| **VT**               | 43                  | 46                     |
|                      |                     |                        |
| Yes                  | 166                 | 324                    |
|                      |                     |                        |
| No                   |                     |                        |
+----------------------+---------------------+------------------------+
| **VT/VF**            | 48                  | 66                     |
|                      |                     |                        |
| Yes                  | 161                 | 304                    |
|                      |                     |                        |
| No                   |                     |                        |
+----------------------+---------------------+------------------------+

## Conclusions Drawn from the Studies

### Safety

Safety of the ICD systems used in the MADIT II study has been
established in previous PMA applications. In addition, analysis of the
system safety in the MADIT II patient population has been demonstrated,
as there were no unanticipated device-related adverse events. Use of the
ICD system in the defined MADIT II patient population is found to be
within the acceptance boundary for safety.

The rate of adverse events associated with the ICD in the MADIT II
population was within acceptable bounds and equivalent to that found in
other patient populations who receive ICDs. There were no deaths
associated with implantation of the device. There was no difference in
the overall number of hospitalizations for the two groups, however there
was a trend toward an increase in hospitalizations for congestive heart
failure in those patients treated with an ICD.

### Effectiveness

Guidant ICD systems have been proven effective in the prophylactic
treatment of patients who are at high risk for sudden cardiac death as
defined by the clinical trial. Results of the MADIT II study
demonstrated that ICD therapy provides a mortality benefit over current
conventional medical therapy in the treatment of patients with a history
of prior myocardial infarction and advanced left ventricular dysfunction
(EF [\<]{.underline} 0.30).

# CDRH Decision

FDA issued an approval order for P960040/S026 and P910077/S37 on July
19, 2002 to expand the indications for Guidant ICDs. This decision was
based on the entire results of the MADIT II study. In this clinical
study of patients with a previous myocardial infarction and an ejection
fraction of [\<]{.underline} 30%, those randomized to treatment with an
ICD had a better survival than those treated with conventional medical
therapy. The sponsor has demonstrated that the ICD itself is responsible
for the difference in mortality between the two treatment groups by
showing that the cumulative probability of receiving a shock for
ventricular fibrillation in the treatment group closely approximates the
difference in mortality between the two groups, suggesting that if the
patient did not have an ICD and had an episode of ventricular
fibrillation, they would have died. In addition, the subgroup analysis
shows there is approximately the same hazard ratio for death across
subgroups. Overall, the incidence of adverse events associated with the
ICD is small and there were no deaths associated with ICD implantation

# Approval Specifications

  --------------------------------------- -------------------------------
  Directions for Use:                     **See labeling.**

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

  Post-approval Requirements,             **See approval order.**
  Restrictions:                           
  --------------------------------------- -------------------------------

[^1]:  Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an
    implanted defibrillator in patients with coronary disease at high
    risk for ventricular arrhythmia. NEJM 1996;335:1993-40.