CONCERTO/INSYNC SENTRY/INSYNC MAXIMO IMPLANTABLE CARDIOVASCULAR DEFIBRILLATORS WITH CARDIAC RESYNCHICNIZATION

P010031 · Medtronic Cardiac Rhythm Disease Management · NIK · Jun 26, 2002 · Cardiovascular

Device Facts

Record IDP010031
Device NameCONCERTO/INSYNC SENTRY/INSYNC MAXIMO IMPLANTABLE CARDIOVASCULAR DEFIBRILLATORS WITH CARDIAC RESYNCHICNIZATION
ApplicantMedtronic Cardiac Rhythm Disease Management
Product CodeNIK · Cardiovascular
Decision DateJun 26, 2002
DecisionAPPR
Device ClassClass 3
AttributesTherapeutic, Expedited Review

Intended Use

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.

Device Story

The InSync® ICD Model 7272 is a multi-programmable, implantable cardioverter defibrillator (ICD) providing biventricular pacing for cardiac resynchronization therapy (CRT). It monitors heart rate and delivers ventricular tachyarrhythmia therapy (VT/VF) and bradycardia pacing. The system uses an LV lead (placed via coronary sinus) and RV/RA leads to provide simultaneous biventricular electrical stimulation, synchronizing ventricular contractions to improve heart failure symptoms. The device is implanted by a physician; it is programmed using external programmers (Models 9790C/2090) and Model 9969 application software. The device continuously monitors cardiac signals; if a tachyarrhythmia is detected, it delivers appropriate pacing or defibrillation shocks. For heart failure, it provides continuous biventricular pacing. The output helps synchronize the heart, potentially reducing heart failure symptoms and improving exercise capacity. The device is intended for long-term implantation to manage both lethal arrhythmias and chronic heart failure.

Clinical Evidence

Prospective, multi-center, randomized, double-blind, parallel-arm trial (n=434 NYHA Class III/IV patients). Primary endpoints: NYHA class, Quality of Life (MLWHF), and 6-minute hall walk. Results: Treatment group (CRT ON) showed significant improvement in QOL (p=0.02) and NYHA class (p=0.01) compared to control (CRT OFF). 6-minute hall walk showed no significant difference (p=0.43). Secondary endpoint peak VO2 significantly improved in treatment group (p=0.03). Safety: 81.1% freedom from system-related complications at 6 months. No difference in all-cause mortality between groups.

Technological Characteristics

Implantable pulse generator; titanium housing; lithium-silver vanadium oxide (Li/SVO) batteries; high-voltage capacitors. Materials: titanium, silicone adhesive, silicone rubber, polyurethane. Sensing/pacing: multi-programmable, biventricular pacing (CRT), ventricular tachyarrhythmia therapy. Connectivity: bi-directional telemetry via external programmer. Sterilization: 100% ethylene oxide (EtO). Standards: IS-1 (ISO 5841-3) and DF-1 (ISO 11318) for connectors; AAMI Pacemaker Standard for EMI.

Indications for Use

Indicated for patients with life-threatening ventricular arrhythmias requiring antitachycardia pacing or defibrillation, and symptomatic heart failure (NYHA Class III or IV) despite optimal medical therapy, with LVEF ≤ 35% and QRS ≥ 130 ms. Contraindicated in patients with transient/reversible causes of arrhythmias (e.g., acute MI, electrolyte imbalance, sepsis), incessant VT/VF, or unipolar pacemakers.

Regulatory Classification

Identification

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

Reference Devices

Related Devices

Submission Summary (Full Text)

{0} # 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. {1} 2 # 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: - InSync® ICD Model 7272 - Model 9969 Application Software for use with the previously approved: - Model 9790C Programmer - Model 2090 Programmer - Commercially Available Components - Attain LV Model 2187 Cardiac Vein Pacing Lead - Attain CS Model 2188 Coronary Sinus Pacing Lead - Attain Model 6215 Venogram Balloon - Attain Models 6216 and 6218 Left Heart Delivery Systems - 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: - Patients whose ventricular tachyarrhythmias may have transient or reversible causes, such as: - Acute myocardial infarction - Digitalis intoxication - Drowning - Electrocution - Electrolyte imbalance - Hypoxia - Sepsis - Patients with incessant VT or VF - Patients who have a unipolar pacemaker # V. Warnings and Precautions See device labeling. {2} # 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 Events (# of patients) | % Complications (# of patients) | Complications per 100 device-months (# of events) | % Observations (# of patients) | Observations per 100 device-months (# of events) | | --- | --- | --- | --- | --- | --- | | Total Adverse Events | 1499 (351) | 49.4 (208) | 24.7 (459) | 75.8 (319) | 55.9 (1040) | | ICD related events | | | | | | | Abnormal impedance measurement | 2 (2) | 0.2 (1) | 0.1 (1) | 0.2 (1) | 0.1 (1) | | Atrial or ventricular arrhythmias | 4 (4) | 0.0 (0) | 0.0 (0) | 1.0 (4) | 0.2 (4) | | 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 detection | 5 (5) | 0.0 (0) | 0.0 (0) | 1.2 (5) | 0.3 (5) | | Pacemaker mediated tachycardia | 1 (1) | 0.2 (1) | 0.1 (1) | 0.0 (0) | 0.0 (0) | | Phantom shocks | 1 (1) | 0.0 (0) | 0.0 (0) | 0.2 (1) | 0.1 (1) | | Pocket infection/seroma/hematoma | 2 (2) | 0.2 (1) | 0.1 (1) | 0.2 (1) | 0.1 (1) | | Subtotal: ICD related events^{1} | 19 (17) | 1.0 (4) | 0.2 (4) | 3.3 (14) | 0.8 (15) | | LV lead related events | | | | | | | Cardiac perforation | 2 (2) | 0.5 (2) | 0.1 (2) | 0.0 (0) | 0.0 (0) | {3} | | # of events (6 of patients) | # of complications (6 of patients) | Complications per 100,000 patients (6 of events) | # of live patients (6 of patients) | Disease that per 100,000 patients (6 of events) | | --- | --- | --- | --- | --- | --- | | Coronary Sinus dissection | 5 (5) | 0.7 (3) | 0.2 (3) | 0.5 (2) | 0.1 (2) | | Elevated pacing thresholds/Failure to capture, loss of capture | 12 (11) | 2.1 (9) | 0.5 (9) | 0.7 (3) | 0.2 (3) | | Lead dislodgment | 33 (31) | 6.7 (28) | 1.6 (30) | 0.7 (3) | 0.2 (3) | | Muscle stimulation (diaphragm, chest wall, pectoral) | 32 (29) | 2.9 (12) | 0.6 (12) | 4.5 (19) | 1.1 (20) | | 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 related events | 90 (77) | 12.6 (53) | 3.1 (58) | 7.1 (30) | 1.7 (32) | | 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 thresholds/Failure to capture, loss of capture | 7 (6) | 1.0 (4) | 0.2 (4) | 0.7 (3) | 0.2 (3) | | 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 related events | 19 (18) | 2.9 (12) | 0.6 (12) | 1.7 (7) | 0.4 (7) | | RV lead related events | | | | | | | Cardiac perforation | 1 (1) | 0.2 (1) | 0.1 (1) | 0.0 (0) | 0.0 (0) | | Elevated pacing thresholds/Failure to capture, loss of capture | 2 (2) | 0.5 (2) | 0.1 (2) | 0.0 (0) | 0.0 (0) | | 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 (diaphragm, pectoral) | 2 (2) | 0.5 (2) | 0.1 (1) | 0.2 (1) | 0.1 (1) | | 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 related events | 15 (15) | 1.9 (8) | 0.4 (8) | 1.7 (7) | 0.4 (7) | | System related events | | | | | | | Elevated pacing thresholds/Failure to capture, loss of capture | 1 (1) | 0.2 (1) | 0.1 (1) | 0.0 (0) | 0.0 (0) | | Inappropriate VT/VF detection | 2 (1) | 0.0 (0) | 0.0 (0) | 0.2 (1) | 0.1 (2) | | Muscle stimulation - diaphragm | 2 (2) | 0.0 (0) | 0.0 (0) | 0.5 (2) | 0.1 (2) | | 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) | {4} | | # of Events (# of patients) | Complications (# of patients) | Complications per 100 device months (# of events) | Observations (# of patients) | Observations per 100 device months (# of events) | | --- | --- | --- | --- | --- | --- | | Subtotal: System related events^{1} | 9 (7) | 0.5 (2) | 0.1 (2) | 1.2 (5) | 0.4 (7) | | Implant tools related events | | | | | | | Cardiac perforation/pericardial effusion | 4 (4) | 0.7 (3) | 0.2 (3) | 0.2 (1) | 0.1 (1) | | 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 related events | 25 (22) | 3.1 (13) | 0.8 (14) | 2.4 (10) | 0.6 (11) | | Possibly device related | | | | | | | Atrial arrhythmias | 12 (11) | 0.5 (2) | 0.1 (2) | 2.1 (9) | 0.5 (10) | | Bradycardia/heart block/ junctional rhythm | 3 (3) | 0.0 (0) | 0.0 (0) | 0.7 (3) | 0.2 (3) | | Chest pain/angina pectoris | 7 (7) | 0.5 (2) | 0.1 (2) | 1.2 (5) | 0.3 (5) | | 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 device related | 49 (36) | 2.1 (9) | 0.6 (11) | 6.9 (29) | 2.0 (38) | | Procedure related/Possibly procedure related | | | | | | | Arm/hand numbness/ swelling | 6 (6) | 0.0 (0) | 0.0 (0) | 1.4 (6) | 0.3 (6) | | 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 decompensation | 5 (5) | 1.2 (5) | 0.3 (5) | 0.0 (0) | 0.0 (0) | | 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) | {5} | | 1 of Events (# of patients) | Complications (# of patients) | Complications per 100 device months (# of events) | Observations (# of patients) | Observations per 100 device months (# of events) | | --- | --- | --- | --- | --- | --- | | Pain pocket site | 101 (96) | 1.7 (7) | 0.5 (9) | 21.4 (90) | 4.9 (92) | | Pain (arm, back, chest, groin, head, shoulder) | 62 (61) | 1.0 (4) | 0.1 (2) | 13.5 (57) | 3.1 (58) | | Pericardial effusion/Pericarditis | 4 (4) | 0.2 (1) | 0.2 (1) | 0.7 (3) | 0.2 (3) | | 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/hematoma/swelling | 38 (38) | 2.4 (10) | 0.5 (10) | 6.7 (28) | 1.5 (28) | | Rash | 3 (3) | 0.2 (1) | 0.1 (1) | 0.5 (2) | 0.1 (2) | | Renal insufficiency/failure | 4 (4) | 0.7 (3) | 0.2 (3) | 0.2 (1) | 0.1 (1) | | Respiratory arrest/ failure | 2 (2) | 0.5 (2) | 0.1 (2) | 0.0 (0) | 0.0 (0) | | Thrombosis | 2 (2) | 0.5 (2) | 0.1 (2) | 0.0 (0) | 0.0 (0) | | Atrial or ventricular arrhythmias | 6 (6) | 1.0 (4) | 0.2 (4) | 0.5 (2) | 0.1 (2) | | Subtotal: Procedure related/Possibly procedure related^{1} | 317 (208) | 13.3 (56) | 4.0 (74) | 42.5 (179) | 13.1 (243) | | 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 decompensation | 127 (88) | 14.3 (60) | 4.4 (82) | 9.7 (41) | 2.4 (45) | | Pleural effusion | 2 (2) | 0.5 (2) | 0.1 (2) | 0.0 (0) | 0.0 (0) | | Renal insufficiency/failure; elevated creatinine | 13 (12) | 1.4 (6) | 0.4 (7) | 1.4 (6) | 0.3 (6) | | Respiratory related^{4} | 26 (25) | 1.9 (8) | 0.5 (9) | 4.0 (17) | 0.9 (17) | | Subtotal: Heart failure decompensation^{1} | 202 (120) | 17.1 (72) | 6.3 (118) | 16.2 (68) | 4.5 (84) | | Not device or procedure related | 754 (259) | 21.9 (92) | 8.5 (158) | 56.3 (237) | 32.0 (596) | 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. {6} 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. {7} 8 # 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 - 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). {8} 9 # 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* 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. *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. {9} 10 # 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 | | --- | --- | --- | | Connector Module | • Polyurethane module that contains lead ports. The module is bonded to device can • Similar to Model 7271 GEM DR. LV lead port added to the connector module | • InSync® ICD Model 7272 Connector Qualification Testing | | Battery (2) | • Same lithium-silver vanadium oxide cells (Li/SVO) developed by the Promeon Division of Medtronic | • Qualified with Model 7271 GEM DR | | High Voltage Capacitors (2) | • Two HV output capacitors provide energy for cardioversion and defibrillation therapies. Same as Model 7271 | • Qualified with Model 7271 GEM DR | | Antenna | • The antenna sends/receives device communications through bi-directional telemetry • Same component used in Model 7271 GEM DR | • Qualified with Model 7271 GEM DR | | Transformer | • The transformer converts low voltage from the battery to high voltage for the HV capacitors • Same component used in Model 7271 GEM DR | • Qualified with Model 7271 GEM DR | | Reedswitch | • The reedswitch is a magnetically controlled mechanical switch that, once closed, signals the device that telemetry communications with the external programmer can occur • Same component used in Model 7271 GEM DR | • Qualified with Model 7271 GEM DR | | Biocompatibility | • The materials used in the InSync® ICD device are identical to those used in the 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. | • Qualified with Model 7271 GEM DR | {10} 11 # 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 | Sample Size | Acceptance Criteria | Result | | --- | --- | --- | --- | | 1. Insertion / Withdrawal (Go Gauge & Lead Connector) | 22 | ≤ 2.0 lbf, Go Gauge), ≤ 13.15 lbf, Lead Connector) | Passed Passed | | 2. IS-1 Electrical Leakage Impedance | 22 | ≥ 50 K ohms | Passed | | 3. DF-1 Electrical Isolation | 22 | ≤ 50 mA | Passed | | 4. DF-1 Current Carrying | NA | ≤ 65 V | Qualified by Similarity | | 5. Suture Hole Pull Force | 22 | ≥ 6 lbs | Passed | {11} 12 # 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 | Sample Size | Acceptance Criteria | Results | | --- | --- | --- | --- | | Environmental | 10 | Temperature Storage: Meets Section 26.2 of European Standard 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. | Meets Acceptance Criteria | | Electromagnetic Compatibility | 22 | Electromagnetic Interference: Meets requirements of the 1975 AAMI Pacemaker Standard. Also meets requirements at additional frequencies, including radiated continuous wave and pulsed electromagnetic fields and conducted continuous wave sinusoidal currents. | Meets Acceptance Criteria | | | 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 Verification Testing | 3 | Because of hardware similarity between InSync® ICD and GEM DR, verification 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. | Meets Acceptance Criteria | {12} 13 # 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 Testing | Sample Tested | Result | | --- | --- | --- | | Firmware verification testing was performed as defined by the Verification Test Plan Rev. 003 | Firmware | Passed | ## 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 Testing | Sample Tested | Result | | --- | --- | --- | | Software verification testing was performed as defined by the Verification Test Plan. Testing consisted of functional testing, Software Install testing, stress testing, and regression testing. | Software | Passed | ## 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 Tested | Result | | --- | --- | --- | | System testing evaluates the compatibility, interaction and functional operation of the InSync® ICD system components when used together as a system. | InSync® ICD System Components | Passed | {13} 14 ## 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. {14} 15 # 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* 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. ![img-0.jpeg](img-0.jpeg) Figure 1. InSync® ICD Study Design *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. {15} 16 # Patient Selection Criteria ## Inclusion Criteria ### ICD Indication - Patients who have had at least one episode of cardiac arrest (manifested by loss of consciousness) due to ventricular tachyarrhythmia; or - Patients having recurrent, poorly tolerated, sustained VT that occurs spontaneously or can be induced; or - **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: - Patients having symptomatic congestive heart failure (NYHA Class II, III, IV) with evidence of ventricular dysynchrony demonstrated by: - QRS duration ≥ 130 ms, - LV Ejection Fraction ≤ 35%, - LV End Diastolic Diameter ≥ 55 mm. - 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. - 18 years of age or older. {16} 17 # Exclusion Criteria - Baseline Six Minute Hall Walk distance greater than 450 meters (Class III and IV only). - Unstable angina, or acute MI, CABG, or PTCA within the past 3 months. - Recent CVA or TIA (within the previous 3 months). - Intermittent positive inotropic drug therapy (intermittent is defined as more than two infusions per week). - Patients having indications or contraindications for standard cardiac pacing. - Systolic blood pressure of less than 80 mm or greater than 170 mm. - Resting heart rate greater than 140 bpm. - Serum Creatinine greater than 3 mg/dl. - Hepatic function (serum) greater than 3 times the upper limit of normal. - Primary valvular disease. - Severe primary pulmonary disease. - Chronic atrial arrhythmias (or cardioversion for afib within the past month) or paroxysmal atrial fib event within the previous month. - Post heart transplant (patients who are waiting for a heart transplant are allowed entry into the study). - Enrolled in any concurrent study that may confound the results of this study. - Patients who are not expected to survive for 6 months of study participation. - Women who are pregnant or with child bearing potential and who are not on a reliable form of birth control. - Patients with mechanical right heart valves. - 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. {17} 18 # 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* 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. * 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. {18} ![img-1.jpeg](img-1.jpeg) Figure 2 provides summary information on the study patient population. Figure 2. InSync® ICD Study Patient Population {19} 20 # Patients Enrolled But Implant Not Attempted 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 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) {20} # 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: - Worsening heart failure requiring CRT (11) - Inadvertent programming (2) - Bradycardia (1) - 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: - Inadvertent programming (6) - LV lead dislodgment (2) - Diaphragmatic stimulation (2) {21} # 2. Baseline Demographic Data Baseline demographic data for randomized NYHA Class III and IV patients are summarized in Table 10. P-values &lt; 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 (OFF) (n=177) | Treatment (ON) (n=187) | P-value | | Gender (n,%) | | | | | Male | 136 (76.8%) | 142 (75.9%) | 0.90 | | Female | 41 (23.2%) | 45 (24.1%) | | | Age (years) | | | | | Mean ± Standard deviation | 67.4 ± 9.4 | 66.6 ± 11.3 | 0.88 | | n(%) | 177 (100.0%) | 187 (100.0%) | | | New York Heart Classification (n,%) | | | | | III | 158 (89.3%) | 165 (88.2%) | 0.87 | | IV | 19 (10.7%) | 22 (11.8%) | | | QRS Width (ms) | | | | | Mean ± Standard deviation | 162 ± 22 | 165 ± 22 | 0.15 | | n (%) | 177 (100.0%) | 187 (100.0%) | | | Ejection Fraction (%) | | | | | Mean ± Standard deviation | 20.1 ± 6.1 | 20.5 ± 7.0 | 0.74 | | n (%) | 176 (99.4%) | 187 (100.0%) | | | LVEDD (mm) | | | | | Mean ± Standard deviation | 70.9 ± 9.1 | 70.4 ± 9.0 | 0.51 | | n (%) | 174 (98.3%) | 186 (99.5%) | | | MN Living with HF Score | | | | | Mean ± Standard deviation | 55.2 ± 22.9 | 56.5 ± 22.9 | 0.56 | | n (%) | 174 (98.3%) | 185 (98.9%) | | | 6-Minute Hall Walk (meters) | | | | | Mean ± Standard deviation | 245 ± 118 | 243 ± 130 | 0.87 | | n (%) | 175 (98.9%) | 183 (97.9%) | | | Peak VO₂/kg (ml/kg/min.) | | | | | Mean ± Standard deviation | 13.5 ± 3.9 | 13.4 ± 3.6 | 0.96 | | n (%) | 135 (76.3%) | 144 (77.0%) | | | Exercise Time (seconds) | | | | | Mean ± Standard deviation | 511 ± 229 | 473 ± 213 | 0.27 | | n (%) | 136 (76.8%) | 143 (76.5%) | | | Supine Heart Rate (bpm) | | | | | Mean ± Standard deviation | 71.5 ± 12.9 | 70.9 ± 12.4 | 0.82 | | n (%) | 171 (96.6%) | 186 (99.5%) | | | Baseline CV Medical History (n, %) (non-exclusive) | | | | | n recorded | 177 | 186 | | | Coronary Artery Disease | 135 (76.3%) | 122 (65.6%) | 0.03* | | Congenital Heart Disease | 0 (0%) | 2 (1.1%) | 0.50 | {22} | InSync® ICD Comparison of Demographics by Treatment Assignment All Randomized NYHA Class III/IV Patients | | | | | --- | --- | --- | --- | | | Control (OFF) (n=177) | Treatment (ON) (n=187) | P-value | | HF etiology: ischemic | 133 (75.1%) | 119 (64.0%) | 0.02* | | HF etiology: non-ischemic | 49 (27.7%) | 67 (36.0%) | 0.09 | | Myocardial Infarction | 112 (63.3%) | 100 (53.8%) | 0.07 | | Anterior | 46 (26.0%) | 48 (25.8%) | 1.00 | | Lateral | 13 (7.3%) | 16 (8.6%) | 0.70 | | Posterior | 3 (1.7%) | 5 (2.7%) | 0.72 | | Inferior | 32 (18.1%) | 31 (16.7%) | 0.78 | | Non Q-wave | 15 (8.5%) | 6 (3.2%) | 0.04* | | Cardiomyopathy | 166 (93.8%) | 176 (94.6%) | 0.82 | | Primary electrical disease | 5 (2.8%) | 6 (3.2%) | 1.00 | | Valvular Disease | 0 (0%) | 0 (0%) | 1.00 | | Hypertension | 90 (50.8%) | 84 (45.2%) | 0.29 | | Chronotropic incompetence | 2 (1.1%) | 0 (0%) | 0.24 | | Syncope/presyncope | 46 (26.0%) | 49 (26.3%) | 1.00 | | Other | 28 (15.8%) | 31 (16.7%) | 0.89 | | Prior Cardiac Intervention (n, %) (non-exclusive) | | | | | n recorded | 173 | 182 | | | CABG | 87 (50.3%) | 82 (45.1%) | 0.34 | | Valve replacement | 9 (5.2%) | 13 (7.1%) | 0.51 | | Ablation | 7 (4.0%) | 6 (3.3%) | 0.78 | | Coronary Artery Intervention | 48 (27.7%) | 44 (24.2%) | 0.47 | | Repair/Correction of Cong. Abnormality | 0 (0%) | 2 (1.1%) | 0.50 | | ICD currently implanted | 51 (29.5%) | 54 (29.7%) | 1.00 | | None | 48 (27.7%) | 55 (30.2%) | 0.64 | | Spontaneous Arrhythmia History (non-exclusive) | | | | | n recorded | 177 | 187 | | | Atrial Fibrillation | 31 (17.5%) | 49 (26.2%) | 0.06 | | Atrial Flutter | 7 (4.0%) | 10 (5.3%) | 0.62 | | AV Nodal Reentrant Tachycardia | 0 (0%) | 0 (0%) | 0.62 | | Sustained Monomorphic VT | 67 (37.9%) | 64 (34.2%) | 0.51 | | Sustained Polymorphic VT | 10 (5.6%) | 7 (3.7%) | 0.46 | | Nonsustained VT | 52 (29.4%) | 73 (39.0%) | 0.06 | | Ventricular Flutter/Fibrillation | 28 (15.8%) | 26 (13.9%) | 0.66 | | Torsades de Pointes | 1 (0.6%) | 1 (0.5%) | 1.00 | | Long QT Syndrome | 0 (0%) | 0 (0%) | 1.00 | | Bradycardia¹ | 101 (57.1%) | 105 (56.2%) | 0.92 | | Right Bundle Branch Block | 24 (13.6%) | 24 (12.8%) | 0.88 | | Left Bundle Branch Block | 126 (71.2%) | 141 (75.4%) | 0.41 | | Others | 32 (18.1%) | 39 (20.9%) | 0.51 | | Other Medical History (n, %) (non-exclusive) | | | | | n recorded | 177 | 187 | | | Endocrine (includes diabetes) | 32 (18.1%) | 24 (12.8%) | 0.19 | | Pulmonary (includes COPD) | 37 (20.9%) | 49 (26.2%) | 0.27 | | Renal | 33 (18.6%) | 28 (15.0%) | 0.40 | {23} | InSync® ICD Comparison of Demographics by Treatment Assignment All Randomized NYHA Class III/IV Patients | | | | | --- | --- | --- | --- | | | Control (OFF) (n=177) | Treatment (ON) (n=187) | P-value | | Medications (n, %) (non-exclusive) n recorded | 177 | 187 | | | ACE Inhibitor | 155 (87.6%) | 172 (92.0%) | 0.17 | | Anti-Arrhythmic | 57 (32.2%) | 79 (42.2%) | 0.05 | | Anti-Depressant | 35 (19.8%) | 36 (19.3%) | 1.00 | | Anti-Coagulant | 143 (80.8%) | 144 (77.0%) | 0.44 | | Beta Blocker | 103 (58.2%) | 118 (63.1%) | 0.39 | | Ca++ Blocker | 10 (5.6%) | 13 (7.0%) | 0.67 | | Diuretic | 167 (94.4%) | 173 (92.5%) | 0.53 | | Positive Inotrope | 129 (72.9%) | 142 (75.9%) | 0.55 | | Nitrate | 59 (33.3%) | 68 (36.4%) | 0.58 | | Other Medication | 108 (61.0%) | 108 (57.8%) | 0.59 | * p &lt; 0.50 ¹ Includes sinus bradycardia, sick sinus syndrome, 1°, 2° and 3° atrioventricular block and bradycardia-tachycardia syndrome. {24} # 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 (CRT OFF) | Treatment Group (CRT ON) | P-value | | --- | --- | --- | --- | | 6-month change in QOL score | 153 patients with paired data | 162 patients with paired data | 0.02 | | | Baseline: median 57.0 | Baseline: median 55.0 | | | | Mean 55.1 ± 22.5 | mean 54.2 ± 23.1 | | | | 6-month: median 43.0 | 6-month: median 34.0 | | | | mean 42.0 ± 22.9 | mean 35.9 ± 23.4 | | | | Median Paired Difference: – 11.0 | Median Paired Difference: – 17.5 | | ![img-2.jpeg](img-2.jpeg) Figure 3 presents the median change in QOL for the control and treatment groups at baseline through 6 month follow up. Figure 3. MN Living With Heart Failure Data Summary {25} # 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 (OFF) | Treatment Group (ON) | P-value | | --- | --- | --- | --- | | 6-month change in NYHA Classification | 158 patients with paired data | 165 patients with paired data | 0.01 | | | Baseline: median 3.0 | Baseline: median 3.0 | | | | Mean 3.09 ± 0.29 | mean 3.10 ± 0.30 | | | | 6-month: median 3.0 | 6-month: median 2.0 | | | | mean 2.51 ± 0.6 | mean 2.31 ± 0.72 | | | | Median Paired Difference: – 0.5 | Median Paired Difference: – 1 | | ![img-3.jpeg](img-3.jpeg) Figure 4 presents the median change in NYHA class for the control and treatment groups at baseline through 6 month follow up. Figure 4. NYHA Classification Data Summary {26} # 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 (OFF) | Treatment Group (ON) | P-value | | --- | --- | --- | --- | | 6-month change in 6 minute hall walk (meters) | 150 patients with paired data | 153 patients with paired data | 0.43 | | | Baseline: median 275 | Baseline: median 254 | | | | Mean 254 ± 112 | mean 252 ± 128 | | | | 6-month: median 334 | 6-month: median 340 | | | | mean 324 ± 114 | mean 339 ± 106 | | | | Median Paired Difference: 53 | Median Paired Difference: 55 | | ![img-4.jpeg](img-4.jpeg) 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. Figure 5. 6-Minute Hall Walk Data Summary {27} 28 # 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 (in 6 patients) | 7 events (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 With ICD-Related Complications | # Implanted Patients | Estimated survival | Lower 95% confidence limit | 95% lower bound criterion | | --- | --- | --- | --- | --- | | 5 | 371 | 98.6% | 97.6% | 89.0% | {28} # Attain Model 4189 LV Lead-Related Complications Table 16 summarizes Model 4189* 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 In All Patients | Events In All 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 – pectoral | 1 | 1 | | Pericardial effusion | 1 | 1 | | TOTAL | 52 events (in 46 patients) | 49 events (in 44 patients) | Table 17. Freedom from Model 4189 Complications During First 6 Months – NYHA III/IV Patients | Number of Patients With Events | Number of Implanted Patients | Estimated Survival | Lower 95% Confidence Bound | 95% Lower Bound Criterion | | --- | --- | --- | --- | --- | | 44 | 315 | 85.1% | 81.7% | 75% | * 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. {29} 30 # 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 (in 8 patients) | 5 events (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 with complications | Number of Implanted Patients | Estimated survival | Lower 95% confidence limit | 95% Lower Bound Criterion | | --- | --- | --- | --- | --- | | 5 | 56 | 89.9% | 82.9% | 75% | {30} # 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 Relatedness | Event Type | # Events | # Events at 6 mo. | | --- | --- | --- | --- | | InSync® ICD related | Pain at pocket site | 1 | 1 | | | 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 (2187/88) | Lead dislodgment | 6 | 3 | | | Failure to capture | 1 | 1 | | | Elevated pacing thresholds | 1 | 1 | | | Subtotal: | 8 | 5 | | LV lead related (4189) | Lead dislodgment | 31 | 29 | | | 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 implanted in cardiac vein | 1 | 1 | | | Subtotal: | 4 | 4 | | System related | Pocket infection | 1 | 1 | | | Twiddler’s syndrome | 1 | 1 | | | Subtotal: | 2 | 2 | | Total | | 85 events (in 69 pts.) | 79 events (in 65 pts.) | {31} 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 System-Related Complications | # Implanted Patients | Estimated survival | Lower 95% confidence limit | 95% lower bound criterion | | --- | --- | --- | --- | --- | | 65 | 371 | 81.1% | 77.6% | 67.0% | {32} 33 # 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*, 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 Patients With Implant Attempts | Number of Successful Implants | Successful Implant Rate | Two-sided 95% Confidence Interval | 95% Lower Bound 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 (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 | *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. {33} # Model 4189 LV Lead Voltage Thresholds For all patients receiving a Model 4189* 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. ![img-5.jpeg](img-5.jpeg) Figure 6. Model 4189 Left Ventricular Voltage Threshold Data (@ 0.5 ms) *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. {34} 35 # 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. ![img-6.jpeg](img-6.jpeg) Figure 7. Model 2187/2188 Left Ventricular Voltage Threshold Data (@ 0.5 ms) {35} 36 # 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 Survival – 3 Months | | | | Estimated Survival – 6 Months | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | # of Deaths | Patients At Risk | Estimated Survival | 95% Confidence Interval | # of Deaths | Patients At Risk | Estimated Survival | 95% Confidence Interval | | Control Group (n=177) | 6 | 171 | 96.6% | 92.6%-98.5% | 14* | 87 | 92.0% | 86.8%-95.2% | | Treatment Group (n=187) | 7 | 178 | 96.2% | 92.3%-98.2% | 14 | 99 | 92.4% | 87.5%-95.4% | *One additional patient died after six months, but before their six-month follow-up ![img-7.jpeg](img-7.jpeg) Figure 8 depicts all-cause survival for control and treatment groups. Figure 8. Survival From All-cause Mortality During Randomization Period – NYHA Class III and IV {36} 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 Deaths | Estimated Survival | 95% Confidence 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. ![img-8.jpeg](img-8.jpeg) Figure 9. Survival From All-cause Mortality, NYHA Class III and IV {37} # Cardiopulmonary Exercise Peak VO₂, 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.¹ 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 VO₂ – NYHA III/IV Patients | | Cardiopulmonary Exercise Testing - Results for NYHA Class III and IV Patients | | | | --- | --- | --- | --- | | | Control Group (CRT OFF) | Treatment Group (CRT ON) | P-value | | Peak VO₂ (ml/kg/min) | 118 patients with paired data | 118 patients with paired data | 0.03 | | | Baseline: median 13.4 | Baseline: median 13.4 | | | | Mean 13.7 ± 3.9 | mean 13.5 ± 3.5 | | | | 6-month: median 13.5 | 6-month: median 14.3 | | | | mean 14.0 ± 4.0 | mean 14.4 ± 3.7 | | | | Median Paired Difference: 0.0 | Median Paired Difference: 1.1 | | ![img-9.jpeg](img-9.jpeg) Figure 10 presents the median change in Peak VO₂ for the control and treatment groups at baseline and 6 month follow up. Figure 10. Peak VO₂ Data Summary ¹ Weber KT, Janicki JS. “Cardiopulmonary Exercise Testing: Physiologic Principles And Clinical Applications”. WB Saunders Company, 1986. {38} 39 Table 27. Cardiopulmonary Exercise Data – NYHA III/IV Patients | | Cardiopulmonary Exercise Testing - Results for NYHA Class III and IV Patients | | | | --- | --- | --- | --- | | | Control Group (CRT OFF) | Treatment Group (CRT ON) | P-value | | Exercise Time (sec) | 119 patients with paired data Baseline: median 494 Mean 518 ± 226 6-month: median 435 mean 483±265 Median Paired Difference: -9 | 118 patients with paired data Baseline: median 479 mean 494 ± 479 6-month: median 526 mean 537±219 Median Paired Difference: 56 | 0.0008 | | Respiratory Exchange Ratio (RER) Max | 112 patients with paired data Baseline: median 1.14 Mean 1.13 ± 0.10 6-month: median 1.09 mean 1.07 ±0.12 Median Paired Difference: -0.06 | 116 patients with paired data Baseline: median 1.14 mean 1.13±0.10 6-month: median 1.12 mean 1.11 ± 0.10 Median Paired Difference: -0.02 | 0.01 | | Ventilatory Exchange (VE) | 112 patients with paired data Baseline: median 47.3 Mean 48.3 ± 15.2 6-month: median 44.7 mean 47.6 ± 16.4 Median Paired Difference: -1.0 | 115 patients with paired data Baseline: median 47.8 mean 49.6 ± 17.9 6-month: median 48.5 mean 51.0 ± 16.1 Median Paired Difference: 0.9 | 0.13 | | VE/VCO2 | 112 patients with paired data Baseline: median 41.0 Mean 42.6 ± 10.4 6-month: median 40.9 mean 42.2 ± 10.6 Median Paired Difference: -0.6 | 115 patients with paired data Baseline: median 39.8 mean 41.8 ± 10.4 6-month: median 38.0 mean 39.9 ± 8.9 Median Paired Difference: -1.0 | 0.19 | | Anacrobic Threshold (AT) | 68 patients with paired data Baseline: median 8.90 Mean 9.11 ± 2.56 6-month: median 9.65 mean 10.30 ± 3.22 Median Paired Difference: 0.90 | 87 patients with paired data Baseline: median 9.80 mean 9.61 ± 2.20 6-month: median 10.30 mean 10.24 ± 2.02 Median Paired Difference: 0.70 | 0.41 | {39} # 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 (CRT OFF) | Treatment Group (CRT ON) | P-value | | Change in QRS duration from baseline through 6-months (ms) | 119 patients with paired data | 129 patients with paired data | 0.01 | | | Baseline: median 160 | Baseline: median 160 | | | | Mean 162 ± 22 | mean 163 ± 20 | | | | 6-month: median 160 | 6-month: median 150 | | | | mean 157 ± 37 | mean 146 ± 28 | | | | Median Paired Difference: –6 | Median Paired Difference: –20 | | # Health Care Utilization (Hospitalization) Emergency room, outpatient, clinic and hospital admission data were 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 (CRT OFF) | Treatment Group (CRT ON) | P-value | | Number of patients hospitalized | All-cause: n=176 | All-cause: n=186 | 0.40 | | | 79 (44.9%) | 75 (40.3%) | | | | CHF related: n=176 | CHF related: n=186 | 0.22 | | | 47 (26.7%) | 39 (21.0%) | | | Length of Stay (days) | All-cause: | All-cause: | 0.09 | | | 134 hospitalizations | 127 hospitalizations | | | | median; 7 days | median; 5 days | | | | mean: 8.9 ± 7.8 | mean: 7.6 ± 8.2 | | | | CHF related: | CHF related: | 0.04 | | | 70 hospitalizations | 54 hospitalizations | | | | median; 6 days | median; 3 days | | | | mean: 8.0 ± 7.0 | mean: 6.6 ± 7.4 | | {40} # 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 (CRT OFF) | Treatment Group (CRT ON) | P-value | | LV Ejection Fraction (%) | 98 patients with paired data Baseline: median 21.7 mean 23.3 ± 6.3 6-month: median 23.7 mean 24.4 ± 7.9 Median Paired Difference 1.6 | 97 patients with paired data Baseline: median 23.5 Mean 24.1 ± 6.7 6-month: median 25.5 mean 27.6 ± 8.9 Median Paired Difference 3.0 | 0.06 | | Mitral Regurgitation (cm², jet area) | 68 patients with paired data Baseline: median 7.1 mean 8.5 ± 7.6 6-month: median 5.9 mean 7.2 ± 6.8 Median Paired Difference -0.5 | 68 patients with paired data Baseline: median 7.0 mean 7.8 ± 5.9 6-month: median 4.9 mean 6.7 ± 5.6 Median Paired Difference -0.4 | 0.98 | | Cardiac Index (four chamber view) | 64 patients with paired data Baseline: median 2.45 mean 2.54 ± 0.90 6-month: median 2.34 mean 2.48 ± 0.88 Median Paired Difference -0.02 | 65 patients with paired data Baseline: 2.38 median mean 2.50 ± 0.78 6-month: 2.47 median mean 2.54 ± 0.79 Median Paired Difference 0.03 | 0.89 | | LV Systolic Volume (cm³) | 94 patients with paired data Baseline: median 230 mean 249 ± 88 6-month: median 225 mean 241 ± 80 Median Paired Difference -8 | 96 patients with paired data Baseline: median 232 mean 242 ± 84 6-month: median 212 mean 222 ± 94 Median Paired Difference -26 | 0.04 | | LV Diastolic Volume (cm³) | 94 patients with paired data Baseline: median 302 mean 320 ± 96 6-month: median 296 mean 315 ± 86 Median Paired Difference -5 | 96 patients with paired data Baseline: median 305 mean 315 ± 90 6-month: median 283 mean 298 ± 101 Median Paired Difference -25 | 0.046 | {41} | | Echocardiographic Indices – Results for NYHA Class III and IV Patients | | | | --- | --- | --- | --- | | | Control Group (CRT OFF) | Treatment Group (CRT ON) | P-value | | LV mass (g) | 58 patients with paired data Baseline: median 358 mean 367 ± 80 6-month: median 348 mean 365 ± 85 Median Paired Difference – 6 | 63 patients with paired data Baseline: median 353 mean 359 ± 83 6-month: median 339 mean 354 ± 87 Median Paired Difference – 3 | 0.97 | | Interventricular mechanical delay (IVMD) (ms) | 63 patients with paired data Baseline: median 31 mean 25.4 ± 44.2 6-month: median 25 mean 19.1 ± 34.4 Median Paired Difference –2 | 79 patients with paired data Baseline: median 35 mean 29.4 ± 40.8 6-month: median 20 mean 15.4 ± 30.1 Median Paired Difference –18 | 0.12 | | E Wave /A Wave ratio | 70 patients with paired data Baseline: median 1.22 mean 1.54 ± 1.08 6-month: median 1.04 mean 1.45 ± 1.03 Median Paired Difference -0.03 | 90 patients with paired data Baseline: median 1.12 mean 1.50 ± 1.08 6-month: median 0.99 mean 1.43 ± 1.05 Median Paired Difference -0.06 | 0.82 | | LV Diameter in Systole | 45 patients with paired data Baseline: median 6.8 mean 7.0 ± 1.0 6-month: median 6.9 mean 6.7 ± 1.0 Median Paired Difference -0.3 | 56 patients with paired data Baseline: median 6.4 mean 6.4 ± 1.0 6-month: median 6.3 mean 6.1 ± 1.2 Median Paired Difference -0.2 | 0.98 | | LV Diameter in Diastole | 48 patients with paired data Baseline: median 7.8 mean 10.0 ± 10.9 6-month: median 7.6 mean 7.6 ± 0.9 Median Paired Difference -0.1 | 58 patients with paired data Baseline: median 7.5 mean 9.6 ± 11.6 6-month: median 7.3 mean 7.3 ± 1.0 Median Paired Difference -0.3 | 0.85 | {42} # Composite Response The Heart Failure Clinical Composite Response² 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 (CRT OFF) | Treatment Group (CRT ON) | P-value | | Composite Response | n = 141 | n = 150 | 0.038 | | Improved | 40% | 55% | | | Unchanged | 26% | 19% | | | Worsened | 33% | 26% | | 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. ² Packer et al. J Cardiac Failure 2001;7:176-182. {43} # 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 Zone | # Patients | Percent Successfully 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 (CRT OFF) | Treatment Group (CRT ON) | P-value | | --- | --- | --- | --- | | Comparison of VT/VF Event Rates | n=177 | n=187 | 0.38 | | | # patients: 38 (21.6%) | # patients: 35 (18.8%) | | | | Total episodes: 321 | Total episodes: 356 | | | | Episodes per month: 0.39 | Episodes per month: 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%) | | {44} # 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 OFF) | Treatment Group (CRT ON) | P-value | | Brain Natriuretic Peptide (BNP) | 70 patients with paired data Baseline: median 478.5 Mean 889.8 ± 1190.0 6-month: median 357.0 mean 799.9 ± 1249.6 Median Paired Difference: -2.8 | 83 patients with paired data Baseline: median 450.0 mean 813.0 ± 1063.6 6-month: median 320.0 mean 568.9 ± 708.2 Median Paired Difference: -38.0 | 0.41 | | Dopamine | 73 patients with paired data Baseline: median 9.0 Mean 17.2 ± 20.9 6-month: median 9.0 mean 19.03 ± 26.3 Median Paired Difference: 0.0 | 79 patients with paired data Baseline: median 9.0 mean 13.9 ± 8.8 6-month: median 9.0 mean 14.0 ± 10.7 Median Paired Difference: 0.0 | 0.56 | | Norepinephrine | 74 patients with paired data Baseline: median 454.5 Mean 516.9 ± 382.3 6-month: median 442.5 mean 478.0 ± 289.1 Median Paired Difference: -38.0 | 80 patients with paired data Baseline: median 331.0 mean 376.5 ± 263.1 6-month: median 339.5 mean 410.2 ± 273.0 Median Paired Difference: 10.5 | 0.24 | | Epinephrine | 73 patients with paired data Baseline: median 25.0 Mean 53.2 ± 109.9 6-month: median 17.0 mean 23.6 ± 21.9 Median Paired Difference: -4.0 | 79 patients with paired data Baseline: median 16.0 mean 31.7 ± 43.6 6-month: median 17.0 mean 23.2 ± 18.5 Median Paired Difference: 0.0 | 0.03 | | Big Endothelin | 77 patients with paired data Baseline: median 14.3 Mean 26.6 ± 34.9 6-month: median 16.4 mean 21.3 ± 23.0 Median Paired Difference: -0.5 | 88 patients with paired data Baseline: median 12.3 mean 19.5 ± 21.6 6-month: median 11.0 mean 18.1 ± 20.0 Median Paired Difference: -0.5 | 0.88 | {45} # 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*, 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 Discharge | 454 | 12.6 ± 4.6 | 12.2-13.0 | | 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 Discharge | 90 | 12.4 ± 4.7 | 11.4-13.3 | | 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 | *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. {46} 47 # 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 (# pts.) | Observations (# pts.) | Total (# pts.) | | --- | --- | --- | --- | | CS dissection | 15 | 9 | 24 | | Cardiac vein/CS Perforation | 9 | 0 | 9 | | 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 indicated | Total | | --- | --- | --- | --- | --- | --- | | Lateral (marginal) cardiac | 6% | 31% | 2% | < 1% | 39% | | Posterior-lateral cardiac | 4% | 25% | 4% | < 1% | 33% | | 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% | | {47} 48 # 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%. ![img-10.jpeg](img-10.jpeg) Figure 11. Biventricular Pacing and Capture Margin {48} 49 # 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. {49} ![img-11.jpeg](img-11.jpeg) Figure 12. Biventricular Capture During Exercise Testing 1UTR programmed to a higher rate than their "normal" UTR setting during the CPX test for 2 patients. 2No biventricular pacing due to PVC initiated Vs-Ar-Vs-Ar... pattern. 3No biventricular pacing due to an intrinsic PR interval less than the programmed SAV interval at peak exercise (Rate Adaptive AV programmed OFF). {50} 51 # 3…
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