OVATIO CRT SYSTEM
Device Facts
| Record ID | P060027 |
|---|---|
| Device Name | OVATIO CRT SYSTEM |
| Applicant | MicroPort CRM USA, Inc. |
| Product Code | NIK · Cardiovascular |
| Decision Date | May 15, 2008 |
| Decision | APPR |
| Device Class | Class 3 |
| Attributes | Therapeutic |
Intended Use
Ovatio CRT-D is indicated for ventricular antitachycardia pacing and ventricular defibrillation for automated treatment of life threatening arrhythmias. The device is also indicated for the reduction of heart failure symptoms in medically optimized NYHA Functional Class III and IV patients with left ventricular ejection fraction of 35% or less, and a QRS duration of 150 ms or longer. Situs OTW is designed to pace the left ventricle through a coronary vein. It is intended to be used in conjunction with ELA Medical cardiac resynchronization therapy pulse generators.
Device Story
Ovatio CRT-D is a rate-responsive implantable cardioverter defibrillator (ICD) providing biventricular pacing for cardiac resynchronization therapy (CRT). It monitors cardiac electrical activity; detects life-threatening tachyarrhythmias; delivers antitachycardia pacing (ATP) or defibrillation shocks. The Situs OTW lead, a steroid-eluting unipolar lead with a vitreous carbon electrode, is implanted via coronary vein to pace the left ventricle. The system is programmed using the Orchestra programmer with Elaview 1.34 UG2 software. Physicians use the programmer to set pacing parameters, including AV and VV delays, to optimize cardiac resynchronization. By correcting ventricular dyssynchrony and providing ICD therapy, the device reduces heart failure symptoms and prevents sudden cardiac death. The device is intended for long-term implantation in patients with severe heart failure and arrhythmia risk.
Clinical Evidence
Prospective, randomized, double-blinded, multi-center trial (Alto MSP Study) of 182 implanted patients (114 CRT, 63 control). Primary safety endpoints (6-month complication-free rate) met: 89.5% for system (lower CI 84.1%) and 94.8% for lead (lower CI 90%). Primary effectiveness endpoint (composite of Peak VO2 and LHFQ score) showed 24.9% improvement in CRT group vs 15.5% in control (p=0.046). Mean chronic pacing threshold 1.83V; mean chronic impedance 390 Ohms.
Technological Characteristics
Rate-responsive ICD with biventricular pacing. Features two DF-1 and three IS-1 ports. Situs OTW lead: unipolar, silicone-insulated, steroid-eluting, vitreous carbon electrode, polyurethane sheath. Materials: silicone, stainless steel, vitreous carbon, polyurethane. Sterilization: Ethylene Oxide (EtO). Connectivity: Programmed via Orchestra programmer. Software: Elaview 1.34 UG2.
Indications for Use
Indicated for patients with life-threatening arrhythmias requiring ventricular antitachycardia pacing and defibrillation, and medically optimized NYHA Class III/IV heart failure patients with LVEF ≤ 35% and QRS duration ≥ 150 ms. Contraindicated in patients with transient/reversible arrhythmia causes, incessant tachyarrhythmia, existing pacemakers, primary bradyarrhythmia/atrial tachyarrhythmia, or dexamethasone hypersensitivity.
Regulatory Classification
Identification
These devices will be indicated for patients needing an ICD who also have moderate to severe heart failure and are indicated for cardiac resynchronization therapy.
Predicate Devices
Related Devices
- P010031 — CONCERTO/INSYNC SENTRY/INSYNC MAXIMO IMPLANTABLE CARDIOVASCULAR DEFIBRILLATORS WITH CARDIAC RESYNCHICNIZATION · Medtronic Cardiac Rhythm Disease Management · Jun 26, 2002
- P010012 — CONTAK CD,EASYTRAK, LIVIAN, COGNIS AND ACUITY SPIRIAL AUTOMATIC IMPLANTABLE CARDIAC RESYNCHRONIZATION THERAPY DEFIBRILLL · Boston Scientific Corp · May 2, 2002
- P030054 — ST JUDE MEDICAL EPIC HF SYSTEM · ABBOTT MEDICAL · Jun 30, 2004
- P070008 — STRATOS LV CRT-P AND STRATOS LV-T CRT-P, COROX OTW BP LEAD AND COROX OTW-S BP LEAD · Biotronik, Inc. · May 12, 2008
- P050023 — TUPOS LV/ATX & KRONOS LV-T CRT-D & COROX OWT STEROID LV PACING LEAD · Biotronik, Inc. · Aug 10, 2006
Submission Summary (Full Text)
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SUMMARY OF SAFETY AND EFFECTIVENESS (SSED)
I. GENERAL INFORMATION
Device Generic Name: Implantable Cardioverter Defibrillator with Cardiac Resynchronization Therapy
Steroid-eluting endocardial left ventricular pacing lead Programmer
Device Trade Name: Ovatio CRT-D Model 6750
Situs OTW Left Ventricular Over-the-Wire Lead Model UW28D
Situs OTW Stylet kit
Elaview 1.34 UG2 programming software
Applicant’s Name and Address:
ELA Medical, Inc.
2950 Xenium Lane North, Suite 120
Plymouth, MN 55441
Date(s) of Panel Recommendation: None
Premarket Approval Application (PMA) Number: P060027
Date of FDA Notice of Approval: May 15, 2008
Expedited: Not applicable
II. INDICATIONS FOR USE
Ovatio CRT-D is indicated for ventricular antitachycardia pacing and ventricular defibrillation for automated treatment of life threatening arrhythmias. The device is also indicated for the reduction of heart failure symptoms in medically optimized NYHA Functional Class III and IV patients with left ventricular ejection fraction of 35% or less, and a QRS duration of 150 ms or longer.
Situs OTW is designed to pace the left ventricle through a coronary vein. It is intended to be used in conjunction with ELA Medical cardiac resynchronization therapy pulse generators.
III. CONTRAINDICATIONS
Ovatio CRT-D is contraindicated in:
- Patients whose ventricular tachyarrhythmias may have transient or reversible causes such as: acute myocardial infarction, digitalis intoxication, drowning,
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electrocution, electrolyte imbalance, hypoxia, sepsis, or unstable ischemic episodes.
- Patients with incessant tachyarrhythmia.
- Patients who already have an implanted pacemaker.
- Patients whose primary disorder is bradyarrhythmia or atrial tachyarrhythmias.
- Dual-chamber and single-chamber atrial pacing is contraindicated in patients with chronic refractory atrial tachyarrhythmias.
Situs OTW is contraindicated in patients for whom a single dose (1 mg) of dexamethasone sodium phosphate may be contraindicated.
## IV. WARNINGS AND PRECAUTIONS
The warnings and precautions can be found in the Ovatio CRT-D, Situs OTW, Situs OTW stylet kit, and Elaview 1.34 UG2 programming software labeling.
## V. DEVICE DESCRIPTION
### Ovatio CRT-D implantable cardioverter defibrillator description
Ovatio CRT-D is a rate responsive implantable cardioverter defibrillator with biventricular pacing for cardiac resynchronization therapy (CRT). The device has five ports: two DF-1 and three IS-1 ports.
Ovatio CRT-D is based on the marketed Ovatio DR ICD (P980049/S20). Both devices have the same circuitry and hybrids. The tachyarrhythmia detection and therapy and bradycardia pacing parameters are identical to those in the marketed Ovatio DR. The only difference between Ovatio CRT-D and the Ovatio DR is its ability to pace the left ventricle, which is accomplished through software and a third IS-1 port. Ovatio CRT-D has a maximum stored energy of 34 J.
Ovatio CRT-D is programmed with the Orchestra programmer using Elaview 1.34 UG2 or higher programming software.
### Situs OTW lead description
The Situs OTW left ventricular lead model UW28D is an IS-1 compliant, unipolar, silicone-insulated, steroid eluting pacing lead with a vitreous carbon electrode. The distal portion of the lead has a silicone molded helix. A polyurethane sheath is intended to provide abrasion resistance.
### Situs OTW stylet kit description
The Situs OTW stylet kit contains accessories used for implanting the Situs OTW. The kit contains two straight stylets, one flat-tipped (or screwdriver) stylet, one anchoring sleeve, one vein lifter and a funnel. All of the items, except the screwdriver stylet, are identical to those included in the Situs package.
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# VI. ALTERNATIVE PRACTICES AND PROCEDURES
There are several other alternatives for the treatment of heart failure and sudden cardiac death: pharmacological therapy, heart transplantation, other marketed biventricular ICDs or other surgical procedures. Each alternative has its own advantages and disadvantages. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle.
# VII. MARKETING HISTORY
Ovatio CRT-D, Situs OTW, and Situs OTW stylet kit are currently distributed in the European Community. None of the devices have been withdrawn from the market in any country for any reason related to safety and effectiveness.
# VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH
Below is a list of the potential adverse effects (e.g., complications) associated with the use of the device.
Potential adverse events Ovatio CRT-D
- Acceleration of arrhythmia (caused by device)
- Air embolism
- Bleeding
- Chronic nerve damage
- Erosion
- Excessive fibrotic tissue growth
- Extrusion
- Fluid accumulation
- Formation of hematoma or cysts
- Inappropriate shocks
- Infection
- Keloid formation
- Lead abrasion and discontinuity
- Lead migration/dislodgment
- Myocardial damage
- Pneumothorax
- Shunting current or insulating myocardium during defibrillation with internal or external paddles
- Potential mortality due to inability to defibrillate or pace
- Thromboemboli
- Venous occlusion
- Venous or cardiac perforation
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Patients susceptible to frequent shocks despite medical management may develop psychological intolerance to an ICD system that may include the following:
- Dependency
- Depression
- Fear of premature battery depletion
- Fear of shocking while conscious
- Fear that shocking capability may be lost
- Imagined shocking (phantom shock).
Potential adverse events Situs OTW left ventricular lead
- Air embolism
- Allergic reaction
- Arrhythmia at implant
- Bleeding
- Cardiac or venous perforation
- Cardiac tamponade
- Coronary sinus or venous trauma
- Death
- Extracardiac stimulation
- Infection
- Lead conductor fracture
- Lead dislodgement
## IX. SUMMARY OF PRECLINICAL STUDIES
### Ovatio CRT ICD
Pre-clinical testing of the Ovatio CRT ICD is summarized in the table below. Ovatio CRT-D uses all of the same components, except for the connector, as the marketed Ovatio DR ICD (P980049/S20). The Ovatio DR ICD uses some components from previously marketed devices. Testing was performed on the components, finished device, and software. A result of "Pass" indicates that the component, device, or software met required pass/fail criteria.
| COMPONENT DEVICE TESTING | | |
| --- | --- | --- |
| Bench Test Performed | Sample Size* | Test Result (Pass/Fail) |
| Capacitor qualification: dimensional inspection, electrical measurements, terminal strength, thermal shocks, pull testing, burn-in | 2-140 | Pass |
| Shielded inductor: life test, electrical measurements, burn-in under bias, visual inspection, dimensional inspection | 5 | Pass |
| Transformer: incoming inspection, high temperature storage, burn-in under bias, visual inspection, dimensional inspection | 5 | Pass |
* When a range of values is given, the exact sample size is determined based on the requirements for a specific component or a specific test.
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| COMPONENT DEVICE TESTING | | |
| --- | --- | --- |
| Bench Test Performed | Sample Size* | Test Result (Pass/Fail) |
| Shock capacitors: extended charge/discharge, surge voltage and current, short circuit, thermal shock, high temperature storage, low temperature storage, high pressure, low pressure, mechanical shock, mechanical vibration, reverse charge, visual inspection, hermeticity, dimensional inspection, electrical measurements | 10 | Pass |
| Flex circuits: dimensional inspection, bending stress, thermal stress, soldering, detachment | 1-5 | Pass |
| Low-power module with integrated circuits and electronic components: probe card test, visual inspection, heating, thermal cycling, electrical testing, humid heat under bias, burn-in | 5-6 | Pass |
| PROT6 module: probe card test, visual inspection, heating, thermal cycling, burn-in under bias, heating, electrical measurements | 5 | Pass |
| High-voltage module: probe card test, visual inspection, heating, thermal cycling, electrical measurements, humid heat under bias, burn-in under bias | 5 | Pass |
| Connector: visual inspection, dimensional inspection, insertion/extraction of gages, low voltage electrical isolation, electrical resistance of the circuits, variation of resistance, maximum insertion force of competitor leads, mechanical stresses, connector-case attachment strength, bending of the connector-case assembly, angular stress on the IS-1/DF-1 cavity, low voltage electrical isolation after immersion, setscrew cover punching, high voltage electrical isolation | 1-4 | Pass |
| Feedthrough: visual inspection, hermeticity, electrical characterization, thermal shocks, mechanical stresses, burn-in, dielectric breakdown, shocks | 3-6 | Pass |
| Batteries: high pressure, low pressure, mechanical shock, vibration, high temperature exposure, low temperature exposure, temperature shock, storage temperature, short circuit, short circuit in series, forced overdischarge, temperature shock, varying orientation pulse test, accelerated pulse test, slow dent puncture, crushing, charge, end-of-life discharge | 4-23 | Pass |
| Antenna: visual inspection, high temperature storage, electrical measurements, stress testing, cleaning | 10 | Pass |
| Crystal: visual inspection, dimensional inspection, electrical measurements, burn-in, thermal shocks, humid heat, vibration, mechanical shocks, soldering, pull testing, hermeticity | 12-296 | Pass |
| SOFTWARE DEVICE TESTING | |
| --- | --- |
| Bench Test Performed | Test Result (Pass/Fail) |
| Device software testing | Pass |
| Programmer software testing | Pass |
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| FINISHED DEVICE TESTING | | | |
| --- | --- | --- | --- |
| Bench Test Performed | Source | Minimum Sample Size | Test Result (Pass/Fail) |
| Measurement of Pulse Generator electrical characteristics | EN 45502-2-2.6.1† | 1 | Pass |
| Shocks and ATP shipped OFF | EN 45502-2-2.7.3 | 1 | Pass |
| Shock, compression, vibration, temperature | EN 45502-1.10.1‡ | 6 | Pass |
| Humidity during storage | EN 45502-1.10.2 | 1 | Pass |
| Markings indelible on sales package | EN 45502-1.10.3 | 1 | Pass |
| Microbiological impermeability | EN 45502-1.12.x | 6 | Pass |
| Markings indelible on sterile package | EN 45502-1.12.3 | 1 | Pass |
| Markings indelible on implant | EN 45502-1.13.1 | 1 | Pass |
| Radio-opaque identification | EN 45502-1.13.3 | 6 | Pass |
| Sterilization Validation | EN 45502-1.14.1 / EN 550§ / EN 556** | According to Standard | Pass |
| Sterility Test | EN 45502-1.14.1 USP <71>†† / ISO 11737-2‡‡ | 6 | Pass |
| Bioburden | ISO 11797-1 NF EN 1174§§ | 6 | Pass |
| Endotoxins | LAL test | 6 | Pass |
| Particulates | EN 45502-2-2.14.2 | 6 | Pass |
| Biocompatibility | EN 45502-1.14.3 / ISO 10993-x*** | According to Standard | Pass |
| EtO residuals | ISO 10993-7 | According to Standard | Pass |
| DC leakage | EN 45502-2-2.16.2 | 1 | Pass |
| AC leakage | EN 45502-2-2.16.4 | 1 | Pass |
| DC leakage, charged | EN 45502-2-2.16.5 | 1 | Pass |
| Protect patient from heat | EN 45502-2-2.17.1 | 6 | Pass |
† EN 45502-2-2: Active Implantable Medical Devices Part 2-2: Particular Requirements for Active Implantable Medical Devices Intended to Treat Tachyarrhythmia (Includes Implantable Defibrillators)
‡ EN 45502-1: Active implantable medical devices. Part 1: General requirements for safety, labeling and information to be provided by the manufacturer
§ Sterilization of Medical Devices - Validation and Routine Control of Ethylene Oxide Sterilization
** Sterilization of Medical Devices - Requirements for Medical Devices to Be Designated "Sterile" - Part 1: Requirements for Terminally Sterilized Medical Devices
†† Bacteriostasis and Fungistasis test
‡‡ Sterilization of medical devices -- Microbiological methods -- Part 2: Tests of sterility performed in the validation of a sterilization process
§§ Sterilization of medical devices - Estimation of the population of micro-organisms on product.
*** ISO 10993 - Biological Evaluation of Medical Devices Package
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| FINISHED DEVICE TESTING | | | |
| --- | --- | --- | --- |
| Bench Test Performed | Source | Minimum Sample Size | Test Result (Pass/Fail) |
| Battery ERI and EOL | EN 45502-2-2.19.2 | 11 | Pass |
| Protect implant from its own defibrillation | EN 45502-2-2.19.5† | 1 | Pass |
| Protect implant from external defibrillation | EN 45502-2-2.20.2 | 1 | Pass |
| Protect implant from diathermy | EN 45502-1.21.1‡ | 6 | Pass |
| Protect implant from HF surgical exposure | EN 45502-2-2.21.2 | 6 | Pass |
| Protect implant from ultrasound | EN 45502-1.22.1 | 6 | Pass |
| Protect implant from vibration | EN 45502-2-2.23.2 | 6 | Pass |
| Protect implant from mechanical shock | EN 45502-2-2.23.7 | 6 | Pass |
| Protect implant from pressure changes | EN 45502-1.25 | 6 | Pass |
| Protect implant from temperature changes | EN 45502-1.26.2 | 6 | Pass |
| Protect implant from EMI permanent damage | EN 45502-2-2.27.1 | 3 | Pass |
| Protect patient from EMI induced current | EN 45502-2-2.27.2 | According to Standard | Pass |
| Temporary response to EMI modulated fields | EN 45502-2-2.27.3 | According to Standard | Pass |
| Temporary response to EMI continuous fields | EN 45502-2-2.27.4 | According to Standard | Pass |
| Temporary response to EMI burst-modulated | EN 45502-2-2.27.5 | According to Standard | Pass |
| Protect patient from EMI radiated interference | ANSI/AAMI PC69††† | According to Standard | Pass |
| Temporary response to 1 mT magnetic field | EN 45502-2-2.27.6 | According to Standard | Pass |
| Permanent response to 10 mT magnetic field | EN 45502-2-2.27.7 | According to Standard | Pass |
| Permanent response to AC magnetic field | EN 45502-2-2.27.8 | According to Standard | Pass |
| Insertion: connector cavity GO gauge | FDA lead guidance 8‡‡‡ / ISO 5841-3.4.3.2.1§§§ | 6 | Pass |
| Maximum insertion force: gauge pin | FDA lead guidance 8 / ISO 5841-3.4.3.2.2 | 6 | Pass |
††† ANSI/AAMI Active implantable medical devices—Electromagnetic compatibility—EMC test protocols for implantable cardiac pacemakers and implantable cardioverter defibrillators
‡‡‡ Guidance for the Submission of Research and Marketing Applications for Permanent Pacemaker Leads and for Pacemaker Lead Adaptor 510(k) Submissions dated November 1, 2000
§§§ ISO 5841-3 - Implants for surgery -- Cardiac pacemakers -- Part 3: Low-profile connectors (IS-1) for implantable pacemakers
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| FINISHED DEVICE TESTING | | | |
| --- | --- | --- | --- |
| Bench Test Performed | Source | Minimum Sample Size | Test Result (Pass/Fail) |
| Insertion and withdrawal forces | FDA lead guidance 8‡‡‡ / ISO 11318.4.3.2.1§§§ | 6 | Pass |
| Current-carrying requirement | FDA lead guidance 8 / ISO 11318.4.3.2.2 | 6 | Pass |
## Ovatio CRT-D biocompatibility
All materials used in Ovatio CRT-D are currently used in marketed ELA Medical pulse generators for which biocompatibility has been previously demonstrated. Specifically, the tissue contacting materials that are used in the pulse generator are identical to those used in Ovatio DR Model 6550 ICD which was approved via P980049/S20 on April 28, 2006.
## Sterilization, packaging, and shelf life of Ovatio CRT-D
The sterilization process for Ovatio CRT-D is identical to that for the marketed Ovatio DR. Routine validation is performed according to the company’s approved sterilization validation protocol.
The packaging process and packaging materials for Ovatio CRT-D are identical to that for the marketed Ovatio DR ICD (P980049/S20).
Based on battery capacity testing and longevity projections, the shelf life for Ovatio CRT-D has been established at 12 months. This is the same as that for the Ovatio DR ICD (P980049/S20).
## Situs OTW left ventricular lead
The table below summarizes pre-clinical testing of the Situs OTW left ventricular lead. A result of “Pass” indicates that the component, device, or software met required pass/fail criteria.
| Bench Test Performed | Source | Minimum Sample Size | Test Result (Pass/Fail) |
| --- | --- | --- | --- |
| Measurement of lead electrical characteristics | EN 45502-2-1.6.2 † | 1 | Pass |
| Shock, compression, vibration, temperature | EN 45502-1.10.1 ‡ | 6 | Pass |
| Humidity during storage | EN 45502-1.10.2 | 1 | Pass |
| Markings indelible on sales package | EN 45502-1.10.3 | 1 | Pass |
| Microbiological impermeability | EN 45502-1.12.x | 1 | Pass |
| Markings indelible on sterile package | EN 45502-1.12.3 | 1 | Pass |
| Sterilization Validation (sample size from standard) | EN 45502-1.14.1 / EN 550§ / EN 556 ** | According to Standard | Pass |
| Sterility Test | EN 45502-1.14.1 / USP <71>†† ISO 11737-2 ‡‡/ | 6 | Pass |
| Particulates | EN 45502-2-1.14.2 | 6 | Pass |
| Biocompatibility (sample size from standard) | EN 45502-1.14.3 / ISO 10993-x*** | According to Standard | Pass |
| Ethylene Oxyde Degassing Curve | EN 45502-1.14.3 / ISO 10993-7 (Ethylene Oxyde Residuals) | According to Standard | Pass |
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| Bench Test Performed | Source | Minimum Sample Size | Test Result (Pass/Fail) |
| --- | --- | --- | --- |
| Ethylene Chlorhydrine Degassing Curve | EN 45502-1.14.3‡ / ISO 10993-7 (Ethylene Chlorhydrine Residuals) *** | According to Standard | Pass |
| Aging of implant | EN 45502-1.19.1 | 11 | Pass |
| Protect implant from tensile forces | EN 45502-2-1.23.3† | 6 | Pass |
| Protect implant from flexion, leads, body | EN 45502-2-1.23.5 test 1 | 11 | Pass |
| Protect implant from flexion, leads, connector | EN 45502-2-1.23.5 test 2 | 11 | Pass |
| Protect implant from stiffness gradients, leads, body | EN 45502-2-1.23.5 test 2 (Previous Edition) | 11 | Pass |
| Protect implant from temperature changes | EN 45502-1.26.2 / FDA lead guidance III.C-0‡‡‡ | 6 | Pass |
| Bioburden | ISO 11737 NF EN 1174§§ | 6 | Pass |
| Endotoxins | LAL test | 6 | Pass |
| Lead electrical continuity and DC resistance | FDA lead guidance III.C-1 | 1 | Pass |
| Lead leakage current (after soaking, before drying) | FDA lead guidance III.C-2 | 11 | Pass |
| Lead leakage current (after soaking, before drying) | Derived from FDA lead guidance III.C-2 | 6 | Pass |
| Lead bond strength, pull test on entire lead | FDA lead guidance III.C-3 | 6 | Pass |
| Lead leak proof | FDA lead guidance III.C-4 | 6 | Pass |
| Lead corrosion resistance | FDA lead guidance III.C-5 | 11 | Pass |
| Lead stylet insertion and removal | FDA lead guidance III.C-6 | 6 | Pass |
| Lead distal fatigue testing (400 M cycles) | FDA lead guidance III.C-7 | 11 | Pass |
| Dimensions | FDA lead guidance III.C-8 / ISO 5841-3.4.2.1.2 | 6 | Pass |
| Electrical continuity and function | FDA lead guidance III.C-8 / ISO 5841-3.4.2.1.3 | 6 | Pass |
| Maximum insertion and withdrawal force | FDA lead guidance III.C-8 / ISO 5841-3.4.2.2.1 | 6 | Pass |
| Electrical impedance | FDA lead guidance III.C-8 / ISO 5841-3.4.2.2.2 | 6 | Pass |
| Deformation due to set-screw forces | FDA lead guidance III.C-8 / ISO 5841-3.4.2.2.3§§§ | 6 | Pass |
| Effect of ring set screw | FDA lead guidance III.C-8 / ISO 5841-3.4.2.2.4 | 6 | Pass |
| Lead anchoring sleeve performance | FDA lead guidance III.C-9 | 6 | Pass |
| Lead tip pressure | FDA lead guidance III.C-10 | NA | NA: the lead lodges in the vein with a large-surface-area silicone helix, rather than with tip pressure |
| Lead helix extension, retraction, and seal | FDA lead guidance III.C-11 | NA | NA: no helix mecanism |
| Lead in vitro steroid elution rate | FDA lead guidance III.C-12 | 6 | Pass |
| Lead shelf life of steroid | FDA lead guidance III.C-13 | 6 | Pass |
| Lead steroid drug/matrix swelling | FDA lead guidance III.C-14 | 6 | Pass |
| Lead traction-torsion | ELA internal Reqt1 | 6 | Pass |
| Torque measurement with screwdriver stylet | ELA Internal Reqt2 | 1 | Pass |
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| Bench Test Performed | Source | Minimum Sample Size | Test Result (Pass/Fail) |
| --- | --- | --- | --- |
| Traction of the tip assembly | ELA Internal Reqt3 | 1 | Pass |
| Traction to rupture after 15-day at 100degC immersion | ELA Internal Reqt4 | 6 | Pass |
| Traction to rupture after 30-day at 100degC immersion | ELA Internal Reqt5 | 6 | Pass |
| Lead insertion into an introducer | ELA Internal Reqt6 | 6 | Pass |
## Abrasion resistance of the Situs OTW left ventricular lead
The Situs lead was evaluated for abrasion resistance under simulated use conditions. Based on these results, the lead is expected to withstand 50.25 years of use. A three-month animal implant study confirmed the simulated results.
## Biocompatibility of the Situs OTW left ventricular lead
The steroid collar, silicone insulation, stainless steel pin, and vitreous carbon electrode are all materials that are identical to those in the approved Stelid II, Stelix, and Stelix II endocardial pacing leads (P020030). The only new material in the Situs lead is the polyurethane sleeve. Biocompatibility testing was performed according to ISO 10993 and all tests were passed.
## Sterilization, packaging, and shelf-life of Situs OTW left ventricular lead
The sterilization and packaging process of the Situs lead are identical to those used for the company's marketed Stelid II, Stelix, and Stelix II leads. Verification testing including sterility, bioburden, sterilization residues, LAL, and particulate contamination, was performed.
The packaging and packaging process used for the Situs lead is identical to the marketed Stelid II, Stelix, and Stelix II leads. Tests on the packaging for the marketed leads are applicable to the Situs OTW left ventricular lead.
Based on the above, the Situs OTW shelf-life has been established at 3 years, which is identical to that of the Stelid II, Stelix, and Stelix II leads.
## Situs OTW stylet kit
Testing of the items included in the stylet kit was performed with the Situs OTW lead. Additional bioburden and LAL tests were performed on the stylet kit. All tests passed. The shelf-life for this kit has been established at 2 years, which is the same as that for other marketed lead accessories having the same types of materials and packaging.
## X. SUMMARY OF PRIMARY CLINICAL STUDY
The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of its cardiac resynchronization system, with ELA Medical CRT-D, commercially available right atrial and ventricular leads, and a Situs UW28D left ventricular lead. Patients were ICD-indicated, New York Heart Association (NYHA)
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class III or IV congestive heart failure patients who do not have pacing indications, included in the US under IDE # G030019, as well as in France, Germany, Italy, Poland and UK.
## A. Study Design
Subjects were treated between December 17, 2003, and May 01, 2006. The database for this PMA reflects data collected through September 08, 2006. 210 patients consented to participate in the study, 196 patients were enrolled, and 182 patients were implanted. 177 patients were randomized, 114 to the treatment group and 63 to the control group. There were 27 investigational sites.
The study was an international, multi-center, prospective, randomized, double-blinded, parallel two-arm clinical trial with a six-month randomized treatment period. The treatment arm was programmed for CRT therapy. The control arm was not programmed with CRT therapy. Both arms were implanted with the study device.
Frequentist statistical analysis was employed. Sample sizes were calculated prospectively based on prior studies of similar therapies, with an alpha of 5% and a beta of 20%. Disjoint one-sided null and alternate hypotheses were defined quantitatively and prospectively for primary safety and effectiveness endpoints. Statistical analyses assumed a T-distribution for calculating p-values. Kaplan-Meyer actuarial survival tables were also presented. The table below summarizes primary objectives and prospectively-determined minimum sample sizes:
| Objective | Required sample size |
| --- | --- |
| CRT effectiveness composite (Peak V02, LHFQ) | 132 |
| System complication free rate | 61 |
| LV lead implant success rate | 93 |
| Chronic LV lead pacing threshold | 7 |
| Chronic biventricular impedance | 2 |
| LV lead-related complication free rate | 110 |
A central core laboratory analyzed all ventilatory gas exchange data collected during the study. This core laboratory was blinded. A second central core laboratory analyzed all echocardiographic data. Because of electrocardiograms collected along with these data, this second core laboratory could not be blinded.
The control group was placebo. After implant, patients were randomized following a 2:1 ratio, with two patients receiving cardiac resynchronization therapy (CRT) for every one patient that did not receive pacing (control group). In control patients, the device was programmed to VVI mode with a basic rate of 30 beats per minute (bpm) to eliminate pacing virtually. Any pacing that did occur was limited to the right ventricle. CRT patients' devices were programmed
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to DDD mode with a basic rate of 30 bpm, a short AV delay to promote atrial-synchronous biventricular pacing, and with BiV pacing enabled with an optimal delay between RV and LV pacing (VV delay). After the six-month randomized treatment period, all patients' devices might be programmed to provide biventricular pacing at the investigators' discretion. Throughout the study, ICD therapy was enabled for all patients.
## 1. Clinical Inclusion and Exclusion Criteria
Enrollment in the study was limited to patients who met the following inclusion criteria:
a. Accepted indication for ICD implant.
b. Severe heart failure (NYHA Class III or IV) at the time of enrollment.
c. If the patient has a pre-existing ICD, the patient must be on a stable, optimal (as determined by the enrolling physician) medical regimen
d. Sinus rhythm with spontaneous QRS duration ≥ 150 ms or, a QRS duration ≥ 130 ms with an interventricular mechanical delay (IVMD) ≥ 40 ms.
e. Left-ventricular ejection fraction (LVEF) of 35 % or less
Patients were not permitted to enroll in the study if they met any of the following exclusion criteria:
a. Any generally accepted indication for standard cardiac pacing, or any contraindication for standard cardiac pacing or ICD therapy.
b. Hypertrophic or obstructive cardiomyopathy, Acute myocarditis, unstable coronary symptoms, recent cardiac revascularization or coronary angioplasty.
c. Correctable valvular disease that is the primary cause of heart failure or mechanical tricuspid valve.
d. Receiving continuous IV infusion of positive inotropic therapy or intermittent therapy (IV infusion) more than twice per week
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# 2. Follow-up Schedule
All subjects were scheduled to return for follow-up examinations within the following time windows:
| Visit | Earliest | Latest |
| --- | --- | --- |
| Enrollment | -- | -- |
| Pre-implant baseline | 0 days post enrollment | 14 days post enrollment |
| Implant | 0 days post pre-implant baseline | 7 days post pre-implant baseline |
| Pre-discharge | 0 days post implant | Prior to CPX familiarization |
| CPX familiarization test | 0 days post enrollment | 24 hours prior to CPX baseline |
| CPX baseline | 2 days post implant | 14 days post implant |
| Randomization | 2 days post implant (and post CPX baseline) | 14 days post implant |
| 1-month follow-up | 23 days post randomization | 37 days post randomization |
| 3-month follow-up | 77 days post randomization | 105 days post randomization |
| 6-month follow-up | 160 days post randomization | 197 days post randomization |
| 9-month follow-up | 240 days post randomization | 300 days post-randomization |
| Recurring follow-ups | Every 6 months (± 30 days) after the 6-month follow-up | |
No subgroup population received additional types of evaluations.
Preoperatively, patients provided informed consent, were assessed for compliance with enrolment criteria and for current medications and medical history. Enrolled patients completed the Minnesota Living with Heart Failure Questionnaire (LHFQ) and performed symptom-limited cardiopulmonary exercise testing (CPX), for baseline data.
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Postoperatively, the objective parameters measured during the study included:
| Visit name | Purpose | Tests or assessments performed |
| --- | --- | --- |
| Implant | Implant CRT-D system and verify lead and ICD function. | Lead measurements
LVAS and Situs OTW handling assessments |
| Pre-discharge | Verify device function | Lead measurements
ATP therapy history |
| CPX familiarization | Familiarize patients with procedure and equipment for cardiopulmonary exercise testing. | |
| Baseline CPX | Collect baseline CPX data | CPX test |
| Randomization | Calculate optimal AV and VV delays, assign patient to randomized treatment group. | NYHA
Vitals
Lead measurements
ATP therapy history |
| One-month | Device and medical follow-up visit. | NYHA
Vitals
Lead measurements
ATP therapy history |
| Three-month | Device and medical follow-up visit. | NYHA
Vitals
Lead measurements
ATP therapy history
QOL |
| Six-month | Device and medical follow-up visit.
Collect six-month values. | NYHA
Vitals
Lead measurements
ATP therapy history
QOL
Echocardiography
CPX test |
| Nine-month | Device and medical follow-up visit for control patients to assess function of biventricular pacing | NYHA
Vitals
Lead measurements
ATP therapy history |
| Twelve-month and later | Device and medical follow-up visit. | NYHA
Vitals
Lead measurements
ATP therapy history |
Adverse events and complications were recorded at all visits. The key timepoints are shown below in the tables summarizing safety and effectiveness.
## 3. Clinical Endpoints
With regards to safety, the following endpoints were evaluated:
| Objective | Category |
| --- | --- |
| System complication-free rate ≥ 67 % at 6 months | System safety |
| Situs UW28D complication-free rate ≥ 75 % at 6 months | LV lead safety |
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With regards to effectiveness:
| Objective | Category |
| --- | --- |
| Composite endpoint combining %Peak VO_{2} improvement (increase) and %Minnesota Living with Heart Failure® Questionnaire score improvement (decrease) 6 months after randomization greater for CRT patients than for control patients | CRT effectiveness |
| Situs UW28D LV lead implant success rate ≥ 75 % | LV lead effectiveness |
| Mean chronic Situs UW28D LV lead pacing threshold ≤ 3.25 V | LV lead effectiveness |
| Mean chronic biventricular pacing impedance with Situs UW28D ≥ 100 Ohms | LV lead effectiveness |
With regard to success/failure criteria, the study was to be deemed successful if all primary safety and effectiveness endpoints listed above were demonstrated at the requisite alpha level (5 %).
## B. Accountability of PMA Cohort
At the time of database lock, of 197 subjects enrolled in PMA study, 77 % (152) subjects are available for analysis at the completion of the study, the six month post-operative visit. Please refer to the accountability summary table below. Intent-to-treat patients were defined by the protocol as “patients who leave the study prior to implant or in whom the system cannot be placed.” Only patients who were enrolled in the study and not successfully implanted with an ELA Medical CRT-D system are intent-to-treat patients. There were 15 intent-to-treat patients in the study.
| Consented to participate | 210 | |
| --- | --- | --- |
| Did not meet enrollment criteria | -10 | |
| Lost to follow-up | -2 | |
| Died before enrollment | -1 | |
| Enrolled | 197 | |
| Adverse event causing withdrawal from study | -3 | |
| Re-evaluation of enrollment criteria | -1 | |
| Patient withdrew informed consent | -1 | |
| Physician unwilling to randomize | -1 | |
| Lost to follow-up | -1 | |
| Unable to implant | -8 | |
| Implanted | 182 | |
| Unable to randomize (no LV lead implanted) | -1 | |
| Died before randomization | -4 | |
| Presented for randomization | 177 | |
| Randomization group (Test = CRT on, Control = off) | Test | Control |
| Randomized | 114 | 63 |
| Patients still in randomized treatment period | -8 | -6 |
| Withdrawn before six-month visit | -5 | -1 |
| Died before six-month visit | -1 | -4 |
| Presented for six-month visit | 100 | 52 |
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# C. Study Population Demographics and Baseline Parameters
The demographics of the study population are typical for a CRT-D study performed in the US.
Data were collected on age (first table below) and gender (22% women, 78% men) but not on race.
| All patients | CRT Off | CRT On | Not randomized | European Patients | U.S. Patients | Small sites*** | Large sites |
| --- | --- | --- | --- | --- | --- | --- | --- |
| 65.07 | 66.22 | 64.46 | 64.9 | 64.49 | 66.27 | 64.9 | 65.16 |
| (10.66) | (11.13) | (9.85) | (13.56) | (10.04) | (11.83) | (10.94) | (10.55) |
| N = 197 | N = 63 | N = 114 | N = 20 | N = 133 | N = 64 | N = 68 | N = 129 |
The table below shows the distribution of baseline parameters for clinically relevant variables important for understanding the treatment effect, and other population characteristics that have important implications for the extent to which the PMA study results can be generalized. The table below lists the average (± standard deviation) value and number of enrolled patients contributing for each variable.
| Variable | All patients | CRT Off | CRT On | Not randomized | European Patients | U.S. Patients | Small sites | Large sites |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Age | 65.07 | 66.22 | 64.46 | 64.9 | 64.49 | 66.27 | 64.9 | 65.16 |
| | (10.66) | (11.13) | (9.85) | (13.56) | (10.04) | (11.83) | (10.94) | (10.55) |
| | N = 197 | N = 63 | N = 114 | N = 20 | N = 133 | N = 64 | N = 68 | N = 129 |
| QRS duration | 164.49 | 165.03 | 162.63 | 173.4 | 166.24 | 160.86 | 169.09 | 162.07 |
| | (20.21) | (21.91) | (17.47) | (27) | (21.86) | (15.82) | (21.84) | (18.94) |
| | N = 197 | N = 63 | N = 114 | N = 20 | N = 133 | N = 64 | N = 68 | N = 129 |
| LVEF | 24.22 | 24.67 | 24.36 | 22 | 25.12 | 22.34 | 23.68 | 24.5 |
| | (6.71) | (6.82) | (6.33) | (8.27) | (6.7) | (6.37) | (6.8) | (6.67) |
| | N = 197 | N = 63 | N = 114 | N = 20 | N = 133 | N = 64 | N = 68 | N = 129 |
| LVEDD | 68.57 | 69.09 | 67.76 | 71.09 | 69.69 | 66.54 | 69.28 | 68.16 |
| | (9.34) | (9.14) | (8.43) | (13.59) | (9.27) | (9.22) | (9.82) | (9.07) |
| | N = 155 | N = 52 | N = 86 | N = 17 | N = 100 | N = 55 | N = 57 | N = 98 |
| Baseline | 51.82 | 47.37 | 52.32 | 63.02 | 53.77 | 47.82 | 47.4 | 54.18 |
| MN | (22.04) | (19.73) | (22.62) | (22.37) | (20.25) | (25.01) | (22.03) | (21.77) |
| LHFQ score | N = 195 | N = 63 | N = 112 | N = 20 | N = 131 | N = 64 | N = 68 | N = 127 |
| Baseline | 12.03 | 12.57 | 11.74 | | 12.06 | 11.97 | 12.28 | 11.88 |
| peak VO2 | (4.03) | (4.35) | (3.83) | | (4.38) | (3.15) | (4.32) | (3.85) |
| | N = 170 | N = 59 | N = 111 | | N = 117 | N = 53 | N = 64 | N = 106 |
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# D. Safety and Effectiveness Results
## 1. Safety Results
The analysis of safety was based on the control and test cohorts of patients available for the six month evaluation as specified below. For both primary objectives, the null hypothesis was rejected at the requisite level of significance:
| Parameter | Definition | Result |
| --- | --- | --- |
| Π | Six-month system complication-free Kaplan-Meier estimate | |
| Ho | π < 67 % | |
| Ha | π ≥ 67 % | |
| | Number of patients contributing to complication free rate | 190 |
| | Six-month complication-free Kaplan-Meier estimate | 89.5% |
| S0.95 | One-sided, 95% lower confidence level of Kaplan-Meier estimate | 84.1% |
| Parameter | Definition | Result |
| --- | --- | --- |
| Π | Six-month LV-lead complication-free Kaplan-Meier estimate | |
| Ho | π < 75% | |
| Ha | π ≥ 75% | |
| | Number of patients contributing to complication free rate | 152 |
| | Six-month complication-free Kaplan-Meier estimate | 94.8% |
| S0.95 | One-sided, 95% lower confidence level of Kaplan-Meier estimate | 90.0% |
## Adverse effects that occurred in the PMA clinical study:
The clinical study presented in this PMA was a prospective, multi-center, randomized, clinical trial to evaluate the safety and effectiveness of ELA’s cardiac resynchronization therapy (CRT) system in NYHA Class III or IV heart failure patients that were indicated for an ICD. The tables below summarize the adverse events observed in the study. The first table is for the CRT-D System and the second one is for the Situs lead. No deaths were related to the CRT-D system.
| Event | Number of patients | Percent of patients (%) | Number of events | Events per 100 device months |
| --- | --- | --- | --- | --- |
| Deaths not system related | 16 | 8.4 | 16 | 0.8 |
| Complications related to the system | 28 | 14.7 | 35 | 2.1 |
| Complications related to the implant procedure | 18 | 9.5 | 21 | 1.3 |
| Observations related to the system | 23 | 12.1 | 27 | 1.7 |
| Observations related to the implant procedure | 24 | 12.6 | 28 | 1.7 |
| Serious adverse events not related to the system | 85 | 44.7 | 176 | 10.8 |
| Not serious adverse events not related to the system | 58 | 30.5 | 121 | 7.4 |
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| Event | Number of patients | Percent of patients (%) | Number of events | Events per 100 device months |
| --- | --- | --- | --- | --- |
| Deaths not related to the lead | 10 | 6.6 | 10 | 0.6 |
| Complications related to the lead | 14 | 9.2 | 17 | 1.0 |
| Most common complications | | | | |
| Disfodgment | 6 | 3.95 | 7 | - |
| Extracardiac stimulation | 7 | 4.6 | 7 | - |
| Complications related to the implant procedure | 14 | 9.2 | 17 | 1.0 |
| Observations related to the lead | 12 | 7.9 | 14 | 0.9 |
| Most common observation: | | | | |
| Extracardiac stimulation | 10 | 6.58 | 12 | - |
| Observations related to the implant procedure | 20 | 13.2 | 24 | 1.5 |
| Serious adverse events not related to the lead | 69 | 45.4 | 142 | 8.7 |
| Not serious adverse events not related to the lead | 47 | 30.9 | 99 | 6.1 |
The following definitions were used to classify adverse events:
- Complication: Adverse device effect which cannot be treated or resolved by simple adjustments and requires intervention (surgery or external shock), or which results in loss of significant device function (e.g. lead dislodgement).
- Observation: A symptomatic or asymptomatic clinical event with potential adverse device effects that does not require intervention or can be corrected by simple adjustments (e.g. reprogramming).
## Death Summary
A total of 16 deaths occurred in the Alto MSP Study. These are presented in the table below.
| Deaths, not device related | All Patients | Therapy On | Therapy Off | Not Randomized |
| --- | --- | --- | --- | --- |
| Cardiac arrest | 5 | 0 | 3 | 2 |
| Cardiomyopathy | 1 | 0 | 1 | 0 |
| Low output syndrome related to untreatable sepsis | 1 | 0 | 0 | 1 |
| Multi-organ dysfunction | 2 | 1 | 1 | 0 |
| Myocardial infarction | 1 | 0 | 1 | 0 |
| Pancreatic cancer | 1 | 1 | 0 | 0 |
| Unknown | 1 | 0 | 0 | 1 |
| Worsening CHF / CHF decompensation | 3 | 1 | 1 | 1 |
| Worsening CHF and atrial fibrillation | 1 | 0 | 0 | 1 |
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Adverse Event Detail:
The following table lists all adverse events observed during the Alto MSP Clinical Study. Adverse events occurring at a rate >1% or reported.
| Adverse Events | | Total (n=190) | | | Therapy on (n=114) | | | Therapy off (n=63) | | | Not randomized (n=2) | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Device Related | Final Diagnosis | Events | Patients | % of patients | Events | Patients | % of patients | Events | Patients | % of patients | Events | Patients | % of patients |
| Complications related to the system | | | | | | | | | | | | | |
| LV Lead | Dislodgment or migration | 9 | 8 | 4.2% | 7 | 6 | 5.3% | 2 | 2 | 3.2% | 0 | 0 | 0.0% |
| | Extracardiac stimulation | 9 | 9 | 4.7% | 5 | 5 | 4.4% | 4 | 4 | 6.3% | 0 | 0 | 0.0% |
| RA Lead | Undersensing/loss of sensing | 2 | 2 | 1.1% | 0 | 0 | 0.0% | 2 | 2 | 3.2% | 0 | 0 | 0.0% |
| RV Lead | Oversensing | 2 | 2 | 1.1% | 1 | 1 | 0.9% | 1 | 1 | 1.6% | 0 | 0 | 0.0% |
| ICD | Other | 2 | 2 | 1.1% | 2 | 2 | 1.7% | 0 | 0 | 0.0% | 0 | 0 | 0.0% |
| Complications related to the implant procedure | | | | | | | | | | | | | |
| ICD | Pocket infection | 3 | 2 | 1.1% | 3 | 2 | 1.7% | 0 | 0 | 0% | 0 | 0 | 0.0% |
| LV Lead | Dislodgment or migration | 2 | 2 | 1.1% | 1 | 1 | 0.9% | 1 | 1 | 1.6% | 0 | 0 | 0.0% |
| RV Lead | Undersensing/loss of sensing | 2 | 2 | 1.1% | 1 | 1 | 0.9% | 1 | 1 | 1.6% | 0 | 0 | 0.0% |
| RA Lead | Dislodgment or migration | 2 | 2 | 1.1% | 1 | 1 | 0.9% | 1 | 1 | 1.6% | 0 | 0 | 0.0% |
| Observations Related to the system | | | | | | | | | | | | | |
| LV Lead | Extracardiac stimulation | 13 | 11 | 6% | 9 | 8 | 7% | 4 | 3 | 4.8% | 0 | 0 | 0.0% |
| System | Inappropriate shock | 2 | 2 | 1.1% | 0 | 0 | 0.0% | 1 | 1 | 1.6% | 1 | 1 | 50.0% |
| Observations related to the implant procedure | | | | | | | | | | | | | |
| Implant | Heart block | 6 | 6 | 3.2% | 3 | 3 | 2.6% | 2 | 2 | 3.2% | 1 | 1 | 50.0% |
| Procedure | Cardiac perforation | 3 | 3 | 1.6% | 1 | 1 | 0.9% | 1 | 1 | 1.6% | 1 | 1 | 50.0% |
| LV Lead | Extracardiac stimulation | 5 | 3 | 1.6% | 5 | 3 | 2.6% | 0 | 0 | 0.0% | 0 | 0 | 0.0% |
| Serious adverse events not related to the system | | | | | | | | | | | | | |
| | Worsening CHF/CHF decompensation | 42 | 24 | 12.6% | 21 | 13 | 11.4% | 21 | 11 | 17.4% | 0 | 0 | 0.0% |
| | Other: Medical Non-Cardiac | 39 | 28 | 14.7% | 26 | 18 | 15.8% | 13 | 10 | 15.9% | 0 | 0 | 0.0% |
| | Atrial fibrillation/flutter | 14 | 14 | 7.4% | 8 | 8 | 7.0% | 6 | 6 | 9.5% | 0 | 0 | 0.0% |
| | Angina | 7 | 5 | 2.6% | 6 | 4 | 3.5% | 1 | 1 | 1.6% | 0 | 0 | 0.0% |
| | Pulmonary edema | 7 | 6 | 3.2% | 2 | 2 | 1.1% | 5 | 4 | 6.3% | 0 | 0 | 0.0% |
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| Adverse Events | | Total (n=190) | | | Therapy on (n=114) | | | Therapy off (n=63) | | | Not randomized (n=2) | | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Device Related | Final Diagnosis | Events | Patients | % of patients | Events | Patients | % of patients | Events | Patients | % of patients | Events | Patients | % of patients |
| | Ventricular tachycardia | 7 | 7 | 3.7% | 5 | 5 | 4.4% | 2 | 2 | 3.2% | 0 | 0 | 0.0% |
| | Heart block | 5 | 5 | 2.6% | 1 | 1 | 0.9% | 4 | 4 | 6.3% | 0 | 0 | 0.0% |
| | Renal dysfunction | 4 | 3 | 1.6% | 4 | 3 | 2.6% | 0 | 0 | 0.0% | 0 | 0 | 0.0% |
| | CVA/stroke | 3 | 3 | 1.6% | 2 | 2 | 1.7% | 0 | 0 | 0.0% | 1 | 1 | 50.0% |
| | Diabetes | 3 | 3 | 1.6% | 2 | 2 | 1.7% | 0 | 0 | 0.0% | 1 | 1 | 50.0% |
| | Infection | 3 | 2 | 1.1% | 1 | 1 | 0.9% | 2 | 1 | 1.6% | 0 | 0 | 0.0% |
| | Pneumonia | 3 | 3 | 1.6% | 3 | 3 | 2.6% | 0 | 0 | 0.0% | 0 | 0 | 0.0% |
| | Pocket infection | 3 | 3 | 1.6% | 2 | 2 | 1.7% | 1 | 1 | 1.6% | 0 | 0 | 0.0% |
| | Sepsis | 3 | 3 | 1.6% | 3 | 3 | 2.6% | 0 | 0 | 0.0% | 0 | 0 | 0.0% |
| | Anemia | 2 | 2 | 1.1% | 2 | 2 | 1.7% | 0 | 0 | 0.0% | 0 | 0 | 0.0% |
| | Ischemia | 2 | 2 | 1.1% | 1 | 1 | 0.9% | 1 | 1 | 1.6% | 0 | 0 | 0.0% |
| | Peripheral vascular disease | 2 | 2 | 1.1% | 1 | 1 | 0.9% | 1 | 1 | 1.6% | 0 | 0 | 0.0% |
| | Syncope | 2 | 2 | 1.1% | 2 | 2 | 1.7% | 0 | 0 | 0.0% | 0 | 0 | 0.0% |
| Not serious adverse events not related to the system | | | | | | | | | | | | | |
| | Other: Medical Non-Cardiac | 30 | 20 | 10.5% | 18 | 12 | 10.5% | 12 | 8 | 12.7% | 0 | 0 | 0.0% |
| | Worsening CHF/CHF decompensation | 16 | 13 | 6.8% | 8 | 7 | 6.1% | 8 | 6 | 9.5% | 0 | 0 | 0.0% |
| | Atrial fibrillation/flutter | 8 | 7 | 3.7% | 3 | 3 | 2.6% | 4 | 3 | 4.8% | 1 | 1 | 50.0% |
| | Ventricular tachycardia | 7 | 7 | 3.7% | 5 | 5 | 4.4% | 2 | 2 | 3.2% | 0 | 0 | 0.0% |
| | Peripheral edema | 6 | 6 | 3.2% | 3 | 3 | 2.6% | 3 | 3 | 4.8% | 0 | 0 | 0.0% |
| | Hypotension | 5 | 3 | 1.6% | 5 | 3 | 2.6% | 0 | 0 | 0.0% | 0 | 0 | 0.0% |
| | Angina | 4 | 3 | 1.6% | 3 | 2 | 1.7% | 1 | 1 | 1.6% | 0 | 0 | 0.0% |
| | Hypertension | 4 | 4 | 2.1% | 4 | 4 | 3.5% | 0 | 0 | 0.0% | 0 | 0 | 0.0% |
| | Peripheral vascular disease | 4 | 4 | 2.1% | 1 | 1 | 0.9% | 2 | 2 | 3.2% | 1 | 1 | 50.0% |
| | Atrial tachycardia | 3 | 2 | 1.1% | 2 | 1 | 0.9% | 1 | 1 | 1.6% | 0 | 0 | 0.0% |
| | Infection | 3 | 2 | 1.1% | 2 | 1 | 0.9% | 1 | 1 | 1.6% | 0 | 0 | 0.0% |
| | Other arrhythmia | 3 | 3 | 1.6% | 3 | 3 | 2.6% | 0 | 0 | 0.0% | 0 | 0 | 0.0% |
| | COPD | 2 | 2 | 1.1% | 1 | 1 | 0.9% | 0 | 0 | 0.0% | 1 | 1 | 50.0% |
| | Pleural effusion | 2 | 2 | 1.1% | 0 | 0 | 0.0% | 2 | 2 | 3.2% | 0 | 0 | 0.0% |
| | Shortness of breath | 2 | 2 | 1.1% | 2 | 2 | 1.7% | 0 | 0 | 0.0% | 0 | 0 | 0.0% |
{20}
The incidence of adverse events was as expected. There were no unanticipated adverse device effects or device-related deaths. It might be noted that in some instances the rate of specific adverse events was higher in the Therapy on group. This can be explained by the fact that the study was a 2:1 randomization; twice as many patients existed in the Therapy on group.
A time course of the occurrence of serious adverse events as compared to the control treatment, in relation to the initial treatment, is provided in the graph below:
No adverse events led to any device design modifications during the PMA clinical study.
## 2. Effectiveness Results
The analysis of effectiveness was based on the control and test cohorts evaluable at the six-month time point as specified in the tables below. Key effectiveness outcomes are presented below. In each case the null hypothesis was rejected in favor of the alternate at the requisite level of significance:
Objective: To demonstrate a greater improvement for patients receiving CRT in a composite endpoint combining percent peak VO2 improvement and percent Minnesota Living with Heart Failure Questionnaire® (LHFQ) score improvement measured six months after randomization. Results: The CRT group had a mean improvement in the composite endpoint of 24.9%. This is greater than that achieved by the control group, which was 15.5%. The table below shows the statistical analysis performed to evaluate the objective.
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The table below presents the percentage of patients in each group who improved, worsened, or remained unchanged in each element of the composite score and the composite score itself.
| | QOL Score | | VO2 Score | | Composite Score | |
| --- | --- | --- | --- | --- | --- | --- |
| | Control Group | Test Group | Control Group | Test Group | Control Group | Test Group |
| % Improved | 75.6 | 74.7 | 48.8 | 67.0 | 62.2 | 70.9 |
| % Worsened | 24.4 | 25.3 | 51.2 | 31.9 | 37.8 | 28.6 |
| % Unchanged | 0.0 | 0.0 | 1.1 | 0.0 | 0.0 | 0.0 |
To properly characterize the effect of the device, the following tables show the absolute changes in the endpoints.
Absolute difference between test and control groups' change in peak V02 over 6 months
| | QOL Score | | VO2 Score | | Difference within group | Difference between groups |
| --- | --- | --- | --- | --- | --- | --- |
| Change in Peak VO2 | Control group | Test Group | Control Group | Test Group | -0.28 | 1.85 |
| | (n=41) | 11.84 ± 3.90 | 13.41 ± 4.28 | 1.57 | | |
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Absolute difference between test and control groups' change in QOL score over 6 months
| | | Baseline
Mean ± SD
(range) | 6-month
Mean ± SD
(range) | Difference within
group | Difference between
groups |
| --- | --- | --- | --- | --- | --- |
| Change in QOL | Control group
(n=41) | 47.5 ± 19.29
(9, 90.3) | 31.21 ± 23.96
(0, 95) | 16.29 | 1.28 |
| | Test group
(n=91) | 52.81 ± 21.84
(9, 92) | 35.24 ± 23.73
(0, 93) | 17.57 | |
Objective: To demonstrate a Situs UW28D lead implant success rate that is greater than or equal to 75 %. Results: 149 patients were successfully implanted out of 177 attempts. The implant success rate for the Situs UW28D lead was 84%.
| Parameter | Definition | Result |
| --- | --- | --- |
| π | Population Situs UW28D implant success rate | |
| Ho | π < 75 % | |
| Ha | π ≥ 75 % | |
| | Number of patients contributing to implant success rate | 177 |
| | Number of patients successfully implanted | 149 |
| | Population Situs UW28D implant success rate | 84 % |
| CI95% | Exact, one-sided, 95% lower confidence level of implant success rate | 77.9% |
Objective: To demonstrate a mean chronic Situs UW28D lead pacing threshold less than or equal to 3.25 V. Results: The mean chronic (six months) pacing threshold observed in patients with Situs UW28D leads was 1.83 V.
| Parameter | Definition | Result |
| --- | --- | --- |
| μ | Population mean chronic Situs UW28D pacing threshold | |
| Ho | μ > 3.25 V | |
| Ha | μ ≤ 3.25 V | |
| | Number of patients contributing | 98 |
| | Mean chronic (six-month) pacing threshold | 1.83 V |
| | Standard deviation of chronic (six-month) pacing threshold | 1.04 V |
| CI95% | Upper one-sided 95% confidence interval | 2.00 V |
Objective: To demonstrate a mean chronic Situs UW28D biventricular pacing impedance greater than or equal to 100 Ohms. Results: The mean chronic biventricular pacing impedance for Situs UW28D observed during the study was 390 Ω.
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| Parameter | Definition | Result |
| --- | --- | --- |
| μ | Population mean chronic Situs UW28D biventricular pacing impedance | |
| Ho | μ < 100 Ohms | |
| Ha | μ ≥ 100 Ohms | |
| | One-sided, 95% lower confidence level of mean chronic biventricular pacing impedance | |
| | Number of patients contributing | 118 |
| | Mean chronic (six-month) biventricular pacing impedance | 390.0 |
| | Standard deviation of chronic (six-month) biventricular pacing impedance | 92.1 |
| CI95% | Lower one-sided 95% confidence interval | 376.05 |
## 4. Subgroup Analyses
### Per programming sub-analysis
A sub-analysis was performed of the effectiveness between the control and test cohorts up to the six month follow-up for patients programmed for the majority of the randomized treatment period.
Five patients crossed over before their one-month visit. Four patients were originally randomized to the control group and later had biventricular pacing enabled, and the other patient was originally randomized to the CRT group and had biventricular pacing disabled due to diaphragmatic stimulation. In the results of the per-programming analysis presented below, the four patients with biventricular pacing enabled have been analyzed with the CRT group, and the patient who had biventricular pacing turned off is analyzed with the control group.
| Parameter | Per programming |
| --- | --- |
| Ns | 38 |
| Ne | 95 |
| Average percent change in VO2, control group | 0.4 |
| Average percent change in VO2, CRT group | 18.0 |
| Average percent change in LHFQ, control group | 26.9 |
| Average percent change in LHFQ, CRT group | 32.1 |
| Standard deviation of percent change in VO2, control group | 22.9 |
| Standard deviation of percent change in VO2, CRT group | 36.2 |
| Standard deviation of percent change in LHFQ, control group | 53.8 |
| Standard deviation of percent change in LHFQ, CRT group | 44.4 |
| Is% | 13.6 |
| le% | 25.0 |
| D | 11.4 |
| SE(D) | 5.7 |
| T-statistic | 2.0 |
| p-value | 0.026 |
Conclusion: The effectiveness of ELA Medical's CRT system is confirmed by the statistically-significant difference between patients when they are analyzed according to their programming during the majority of the randomized treatment period.
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# VV delay optimization sub-analysis
Fifteen patients randomized to the CRT group did not undergo echo-guided optimization at randomization. The sub-analyses below compare how patients in the CRT group with and without optimized VV delays improved in the composite endpoint compared to the control group.
The first sub-analysis below (in the column entitled “With VV optimization”) compares the 41 control patients with the 77 test patients who underwent echo-guided optimization at randomization.
The second sub-analysis below (in the column entitled “Without VV optimization”) compares the same 41 control patients with the 15 test patients who did not undergo echo-guided optimization.
Consequently, the two sub-analyses below present data on $77 + 41 + 15 = 133$ patients, the same 133 patients who contributed to the per-randomization sub-analysis above.
| Parameter | With VV optimization | Without VV optimization |
| --- | --- | --- |
| Ns | 41 | 41 |
| Ne | 77 | 15 |
| Average percent change in VO2, control group | 0.9 | 0.9 |
| Average percent change in VO2, CRT group | 15.3 | 35.8 |
| Average percent change in LHFQ, control group | 30.2 | 30.2 |
| Average percent change in LHFQ, CRT group | 35.1 | 11.1 |
| Standard deviation of percent change in VO2, control group | 22.4 | 22.4 |
| Standard deviation of percent change in VO2, CRT group | 31.7 | 53.9 |
| Standard deviation of percent change in LHFQ, control group | 53.0 | 53.0 |
| Standard deviation of percent change in LHFQ, CRT group | 40.8 | 58.5 |
| Is% | 15.5 | 15.5 |
| le% | 24.8 | 23.4 |
| D | 9.3 | 7.9 |
| SE(D) | 5.5 | 11.2 |
| T-statistic | 1.7 | 0.7 |
| p-value | 0.05 | 0.24 |
Conclusion: The subset of CRT patients with optimized VV delays performed almost identically to all patients randomized to the CRT group.
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# Peak VO2 sub-analyses
The table below presents the average baseline and six-month peak VO2 values for patients who completed CPX testing at both visits.
| Parameter | All patients | Control group | CRT group | Females | Males |
| --- | --- | --- | --- | --- | --- |
| Baseline average | 12.1 | 12.8 | 11.7 | 10.5 | 12.5 |
| Baseline standard deviation | 4.3 | 5.3 | 3.7 | 3.2 | 4.5 |
| Baseline number contributing | 135 | 43 | 92 | 29 | 106 |
| 6-month visit average | 13.1 | 13.0 | 13.2 | 12.4 | 13.3 |
| 6-month visit standard deviation | 4.0 | 3.9 | 4.0 | 3.0 | 4.2 |
| 6-month number contributing | 135 | 43 | 92 | 29 | 106 |
# Peak LHFQ sub-analyses
The table below presents the average baseline and six-month LHFQ scores for patients who completed questionnaires at both visits.
| Parameter | All patients | Control group | CRT group | Females | Males |
| --- | --- | --- | --- | --- | --- |
| Baseline average | 51.1 | 48.2 | 52.6 | 56.8 | 49.6 |
| Baseline standard deviation | 21.1 | 19.9 | 21.7 | 21.1 | 21.0 |
| Baseline number contributing | 149 | 52 | 97 | 31 | 118 |
| 6-month visit average | 34.8 | 33.2 | 35.7 | 34.5 | 34.9 |
| 6-month visit standard deviation | 23.9 | 24.2 | 23.9 | 24.3 | 23.9 |
| 6-month number contributing | 149 | 52 | 97 | 31 | 118 |
ELA performed an additional analysis on the LHFQ scores to determine if there was a difference between patients missing six-month scores and those who completed the questionnaire at their six-month visit. In this analysis the mean difference between baseline and three-month scores were compared using a Wilcoxon-Mann-Whitney test. No statistically significant difference was found between the two groups.
| | Value | |
| --- | --- | --- |
| Parameter | missing 6-month | not missing 6-month |
| Average change in LHFQ score at three months | 13.1 | 19.0 |
| Standard deviation of average change | 26.7 | 21.4 |
| Wilcoxon-Mann-Whitney p-value of difference | 0.12 | |
# XI. PANEL MEETING RECOMMENDATION AND FDA'S POST-PANEL ACTION
In accordance with the provisions of section 515(c)(2) of the act as amended by the Safe Medical Devices Act of 1990, this PMA was not referred to the Cardiovascular Panel, an FDA advisory committee, for review and recommendation because the information in the PMA substantially duplicates information previously reviewed by this panel.
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# XII. CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES
## A. Safety Conclusions
The adverse effects of the device are based on data collected in a clinical study conducted to support PMA approval as described above.
The primary safety objective required 6-month complication-free rate 67% or greater for the CRT-D system and 75% for the lead only (at alpha 5% level). The actual observed rate was 89.5% by K-M method for the system (one-sided lower confidence limit = 84.1%) and 94.8% for the lead (90%). The sum of clinical outcomes data, including reported deaths and adverse events did not suggest safety issues with the device itself in this high-risk patient population.
## B. Effectiveness Conclusions
The primary effectiveness objective for the CRT functionality required that a composite which was based on:
1. Change in % Peak V02
2. Change in % Minnesota Living with Heart Failure Questionnaire score showed greater improvements in the CRT (treatment) group than the control group (at alpha 5% level).
In summary, the composite averaged % change in each measure and found more improvement in the CRT treatment group by 9.4% when compared to the control group (24.9% vs. 15.5%). This was statistically significant, with a p-value of 0.046.
The primary effectiveness objective for the lead showed a mean pacing threshold of 1.83V in 98 patients and a mean chronic impedance of 390 Ω in 118 patients. Both of these values exceeded the hypothesis for these objectives.
## C. Overall Conclusions
The data in this application support the reasonable assurance of safety and effectiveness of this device when used in accordance with the indications for use.
The Alto MSP clinical trial examined CRT clinical outcomes using appropriately sized treatment and control groups, using endpoints that were clinically relevant, and which characterized CRT safety and effectiveness.
- Design: the trial was prospective, randomized and double-blinded, with randomization to a 6-month treatment arm of 114 receiving CRT using DDD mode, base rate 30 and a short AD delay versus a 6-month treatment arm of 63 who received VVI 30 pacing without LV stimulation
- Safety: The primary safety objective required 6-month complication-free rate 67% or greater for the CRT-D system and 75% for the lead only (at alpha 5% level). The actual observed rate was 89.5% by K-M method for the system (one-
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sided lower confidence limit = 84.1%) and 94.8% for the lead (90%). The sum of clinical outcomes data, including reported deaths and adverse events did not suggest safety issues with the device itself in this high-risk patient population. The rates of adverse events for the LV lead were comparable to market-approved leads and within acceptable limits for this type of device (9 dislodgements in 190 implants, 9 extracardiac stimulation). There were no unanticipated adverse events.
- Effectiveness: The primary effectiveness objective for the CRT functionality required that a composite which was based on the change in % Peak V02 and the change in % Minnesota Living with Heart Failure Questionnaire score showed greater improvements in the CRT (treatment) group than the control group (at alpha 5% level). In summary, the composite averaged % change in each measure and found more improvement in the CRT treatment group by 9.4% when compared to the control group (24.9% vs. 15.5%). This was statistically significant, with a p-value of 0.046. This improvement was primarily attributable to changes in Peak V02:
Control improvement in V02: 12.8→13.0 QOL questionnaire: 48.2→33.2
CRT improvement in V02: 11.7→13.2 QOL questionnaire: 52.6→35.7
- Compliance with the protocol: Of 197 enrollees, 152 (77%) had analyzable data through 6 months. This was because 15 patients could not be implanted or withdrew and one patient could not be implanted with an LV lead and 4 died before randomization, after implant. The 177 implanted patients were randomized 2:1 to test and control therapy but only 152 achieved 6-month follow-up due to either incomplete follow-up, withdrawal (5 test/1 control) or death (1 test/4 control).
- The study was successful overall since all primary safety and effectiveness endpoints were demonstrated successful at the requisite alpha level (5%).
# XIII. CDRH DECISION
CDRH issued an approval order on May 15, 2008. The final conditions of approval cited in the approval order are described below.
1. The sponsor has agreed to provide a test report including the results of 400 million cycle distal tip fatigue testing on 5 additional Situs UW28D lead samples no later than May 31, 2008. The report should include a copy of the results of the original 400 million cycle distal tip fatigue testing on 6 samples which was included in the original PMA submission.
2. The sponsor has also agreed to the following study outline for a post-approval study for the Situs LV Lead:
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i. a prospective study design to characterize chronic lead performance following device implant, as well as a robust process to retrospectively collect implant data for each study subject;
ii. a post-approval study duration of at least 5 years;
iii. a sample size that results in a 2-sided 95% upper confidence bound of no more than 1.0% for individual adverse event rates, assuming an expected rate of 0.4%, using the exact binomial method;
iv. a total enrollment which accounts for estimated attrition, and an enrollment plan which attempts to enroll 33% of all marketed devices in the US;
v. a primary safety endpoint as complication-free rate greater than 95% at 5 years, with any clinical adverse events omitted from the primary endpoint collected and reported as secondary data;
vi. a rigorous process to monitor the status of all study subjects, to actively follow-up missed visits, and to document the reason for all subject dropouts;
vii. inclusion of a trend analysis process in the protocol to provide a robust early warning mechanism to identify, characterize, and report adverse events, failure modes, and failure rates;
viii. post-approval study status reporting at least every 6 months and a mechanism for providing non-scheduled trend analysis reports for new information;
ix. inclusion of a full list of complications, failure modes, and definition of terms within the study protocol; and
x. collection of secondary data including implant data, demographic information, all cause adverse events, electrical performance, returned product analyses, extraction experience, and other parameters of interest.
The applicant’s manufacturing facilities were inspected and found to be in compliance with the device Quality System (QS) regulation (21 CFR 820).
## XIV. APPROVAL SPECIFICATIONS
Directions for use: See device labeling.
Hazards to Health from Use of the Device: See Indications, Contraindications, Warnings, Precautions, and Adverse Events in the device labeling.
Post-approval Requirements and Restrictions: See approval order.
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