HeartWare Ventricular Assist System Instructions for Use Rev 15 Nov 2012

HeartWare® Ventricular Assist System Instructions for Use

TABLE OF CONTENTS 1.0

INTRODUCTION ... 1

2.0

INDICATIONS FOR USE ... 2

3.0

CONTRAINDICATIONS ... 2

4.0

WARNINGS ... 2

5.0

PRECAUTIONS ... 6

6.0

POTENTIAL COMPLICATIONS ... 8

7.0

CLINICAL TRIAL RESULTS ... 9

7.1

PIVOTAL CLINICAL STUDY DESIGN ... 9

7.2

STUDY OBJECTIVES ... 9

7.3

STUDY POPULATION DEMOGRAPHICS AND BASELINE PARAMETERS ... 9

7.4

SAFETY AND EFFECTIVENESS RESULTS ... 11

7.5

OVERALL CONCLUSIONS FROM CLINICAL DATA ... 24

8.0

SYSTEM COMPONENT OVERVIEW ... 24

8.1

HEARTWARE® VENTRICULAR ASSIST SYSTEM ... 24

8.2

HEARTWARE® CONTROLLER ... 25

8.3

HEARTWARE® MONITOR ... 25

8.4

HEARTWARE® CONTROLLER POWER SOURCES ... 25

8.5

HEARTWARE® BATTERY CHARGER ... 26

8.6

EQUIPMENT FOR IMPLANT ... 26

9.0

PRINCIPLES OF OPERATION ... 27

9.1

BACKGROUND ... 27

9.2

BLOOD FLOW CHARACTERISTICS ... 28

9.3

PHYSIOLOGICAL CONTROL ALGORITHMS ... 28

9.3.1

Flow Estimation ... 29

9.3.2

Ventricular Suction Detection Alarm ... 29

9.4

HVAD® PUMP OPERATING GUIDELINES ... 31

10.0 USING THE HEARTWARE® MONITOR ... 33 10.1 CLINICAL (HOME) SCREEN ... 34 10.2 ALARM SCREEN ... 35 10.3 TREND SCREEN ... 36 10.4 SYSTEM SCREEN ... 36 10.4.1

Speed/Control Tab ... 37 i

HeartWare® Ventricular Assist System Instructions for Use

10.4.2

Setup Tab ... 38

10.4.3

Alarm Settings Tab ... 44

10.5 MONITOR SHUT DOWN... 47

11.0 USING THE HEARTWARE® CONTROLLER ... 47 11.1 CONTROLLER CONNECTOR LAYOUT ... 47 11.2 CONTROLLER DISPLAY AND OPERATION ... 48 11.3 HOW TO CHANGE THE CONTROLLER ... 49

12.0 USING THE HEARTWARE® BATTERIES ... 51 12.1 CHANGING A BATTERY ... 52 12.2 CARE OF BATTERIES ... 53

13.0 USING THE HEARTWARE® BATTERY CHARGER ... 54 13.1 CONNECTING THE BATTERY TO THE BATTERY CHARGER... 55 13.2 DISCONNECTING THE BATTERY FROM THE BATTERY CHARGER ... 55

14.0 USING THE HEARTWARE® CONTROLLER AC ADAPTER OR DC ADAPTER ... 56 14.1 CONNECTING THE AC ADAPTER OR DC ADAPTER TO THE CONTROLLER ... 56 14.2 DISCONNECTING FROM THE AC ADAPTER OR DC ADAPTER ... 57

15.0 ALARMS ... 58 15.1 HIGH ALARMS ... 58 15.2 MEDIUM ALARMS ... 59 15.3 LOW ALARMS ... 62 15.4 MULTIPLE ALARMS ... 62 15.5 HOW TO SILENCE (MUTE) ALARMS ... 63 15.6 STATUS MESSAGE DISPLAY ... 64

16.0 SURGICAL IMPLANT PROCEDURE... 64 16.1 HEARTWARE® VENTRICULAR ASSIST SYSTEM SETUP ... 65 16.2 HVAD® PUMP PRE-IMPLANT TEST ... 67 16.3 OUTFLOW GRAFT ATTACHMENT ... 69 16.4 PUMP IMPLANTATION PREPARATION ... 71 16.5 LEFT VENTRICLE (LV) APEX CANNULATION ... 71 16.6 OUTFLOW GRAFT ANASTOMOSIS ... 72 16.7 DRIVELINE PLACEMENT ... 73 16.8 DE-AIRING PROCEDURE ... 74 16.9 PROGRAMMING THE BACKUP CONTROLLER TO MATCH THE PRIMARY CONTROLLER ... 75 ii

HeartWare® Ventricular Assist System Instructions for Use

17.0 HVAD® PUMP EXPLANT ... 75 17.1 AT TRANSPLANT ... 75 17.2 MYOCARDIAL RECOVERY/ PUMP EXCHANGE ... 76

18.0 PATIENT MANAGEMENT ... 76 18.1 POSTOPERATIVE MANAGEMENT ... 76 18.2 EMERGENCY MANAGEMENT ... 77 18.3 ANTICOAGULATION ... 77 18.4 INFECTION CONTROL GUIDELINES* ... 78 18.5 DRIVELINE CARE* ... 78 18.6 ARRHYTHMIAS ... 79 18.7 RIGHT HEART FAILURE ... 79 18.8 BLOOD PRESSURE MAINTENANCE ... 80 18.9 PHYSICAL REHABILITATION ... 80 18.10 PATIENT EDUCATION ... 80 18.11 EXTERNAL ACCESSORIES ... 80 18.11.1

Patient Pack ... 80

18.11.2

HeartWare® Shower Bag ... 81

18.12 RECOMMENDED EQUIPMENT FOR USE AT HOME... 81

19.0 EQUIPMENT INSPECTION, CLEANING AND MAINTENANCE ... 82 19.1 GENERAL CARE ... 82 19.2 CONTROLLER ... 82 19.3 BATTERIES ... 83 19.4 BATTERY CHARGER ... 83 19.5 HEARTWARE® MONITOR ... 83 19.6 EXPECTED USEFUL LIFE OF HEARTWARE COMPONENTS ... 84 19.7 PRODUCT DISPOSAL... 84

20.0 DEVICE TRACKING AND REPORTING REQUIREMENTS ... 84 APPENDIX A: QUICK REFERENCE GUIDE FOR ALARMS ... 85 APPENDIX B: SYSTEM COMPONENTS ... 87 APPENDIX C: PRODUCT SPECIFICATIONS... 88 APPENDIX D: EMC MANUAL REQUIREMENTS GUIDANCE DOCUMENT ... 91 APPENDIX E: SYMBOL DEFINITIONS ... 95

iii

HeartWare® Ventricular Assist System Instructions for Use

iv

HeartWare® Ventricular Assist System Instructions for Use

FOREWORD The HeartWare® Ventricular Assist System is indicated for use under the direct supervision of a licensed healthcare practitioner or by personnel trained in its proper use. Clinical users include physicians, registered nurses, perfusionists and biomedical engineers. Implant of the device must be performed by a qualified cardiac surgeon trained by HeartWare-authorized personnel. Clinical users of the HeartWare® System should attend HeartWare clinical operator training, should have a working knowledge of the principles of left ventricular assist devices (LVADs), and should be aware of the physical and psychological needs of patients undergoing LVAD support. Patients and caregivers should complete a user training program and demonstrate their ability to use the system. Clinicians should read the entire Instructions for Use before system operation. This manual may serve as a reference for detailed information including specific information on device function, system setup, implant and maintenance. This manual is not intended to replace comprehensive educational programs or to supersede acquired knowledge or proper medical judgment. WARNING! Carefully read this entire manual prior to implanting or operating the device. Improper operation of the system and potential harm to the patient and to the user could result.

1.0

INTRODUCTION STERILE: All HeartWare components used at implant including surgical tools are provided sterile. The HeartWare® Ventricular Assist System (HeartWare® System) is designed to assist a weakened, poorly functioning left ventricle. The HeartWare® System utilizes a centrifugal blood pump, the HVAD® Pump (the “pump”), which is implanted in the pericardial space with left ventricular apex to ascending aortic cannulation for left ventricular support (Figure 1). The inflow conduit, which is partially sintered, is integrated with the pump and a 10mm gel impregnated outflow graft with a strain relief is attached to the pump. A percutaneous driveline connects the pump to an external controller. The controller, powered by two batteries or by one battery and electricity from the wall or car outlet, regulates pump function and monitors the system. The monitor is used to display system performance and to change controller operating parameters. A battery charger is also included. All components of the HeartWare® System are designed to be used only in conjunction with each other. They are neither compatible nor intended to be used with other manufacturer’s devices.

Figure 1: HeartWare® Ventricular Assist System 1. Monitor 4. Controller 2. HVAD® Pump 5. Battery 3. AC Adapter 1

HeartWare® Ventricular Assist System Instructions for Use

2.0

INDICATIONS FOR USE The HeartWare® Ventricular Assist System is indicated for use as a bridge to cardiac transplantation in patients who are at risk of death from refractory end-stage left ventricular heart failure. The HeartWare® System is designed for in-hospital and out-of-hospital settings, including transportation via fixed wing aircraft or helicopter.

3.0

CONTRAINDICATIONS The HeartWare® System is contraindicated in patients who cannot tolerate anticoagulation therapy. WARNING! Serious and life threatening adverse events, including stroke, have been associated with use of this device. A user must fully consider the risks of this device with that of other treatment modalities before deciding to proceed with device implantation. Please see Section 6.4 for a summary of the stroke data.

WARNING! Do not use the HeartWare System in pregnant women. Any woman receiving a HeartWare System who is of childbearing age and sexually active should use a reliable method of birth control. Use of anticoagulants during pregnancy has been associated with birth defects and bleeding.

4.0

WARNINGS 1. WARNING! The Instructions for Use (IFU) is intended to be used by physicians, nurses, and other clinical professionals. Setup and operation of this device should only be undertaken by personnel who have completed a HeartWare product training program. A thorough understanding of technical principles, clinical applications and risks associated with the HeartWare® System is required before using this product. Failure to understand these principles, applications and risks may result in improper operation of the system and potential harm to the patient or to the user. 2. WARNING! Carefully read this entire manual prior to implanting or operating the device. Improper operation of the system and potential harm to the patient and to the user could result. 3. WARNING! Serious and life threatening adverse events, including stroke, have been associated with use of this device. A user must fully consider the risks of this device with that of other treatment modalities before deciding to proceed with device implantation. Please see Section 6.4 for a summary of the stroke data. To mitigate the risk of stroke, please adhere to the following patient management guidelines:  

Maintain MAP at <85 mm Hg as tolerated. The HVAD® Pump is sensitive to both preload and afterload. Ramp speed and flows more slowly during the first few weeks (e.g. 30 days) post-implant to avoid excessive hemodynamic forces that may damage fragile blood vessels that have undergone remodeling secondary to the lower pressures and reduced flow associated with medically-treated heart failure. There is no apparent need to exceed a cardiac index of 2.6 L/min/m2 until patients have fully recovered from the implant surgery and physical 2

HeartWare® Ventricular Assist System Instructions for Use

 

performance improves. A cardiac index of 2.6 L/min/m2 is the lower limit of normal for a healthy adult. Maintain anticoagulation within the recommended INR range of 2.0-3.0. Check for ASA resistance with a reliable test (e.g. VerifyNow®) and adjust ASA mono-therapy accordingly or consider combination therapy such as ASA 81 mg plus Aggrenox® (ASA plus extended –release dipyridamole) or daily ASA 81 mg plus Plavix 75 mg. In general, monotherapy with ASA is not encouraged in the absence of testing for resistance.

4. WARNING! Do not use the HeartWare System in pregnant women. Any woman receiving a HeartWare System who is of childbearing age and sexually active should use a reliable method of birth control. Use of anticoagulants during pregnancy has been associated with birth defects and bleeding. 5. WARNING! NEVER disconnect both power sources (batteries and AC or DC adapter) at the same time since this will stop the pump. At least one power source must be connected at all times. 6. WARNING! DO NOT rely only on flow estimation to assess cardiac output. An average estimated flow on the monitor or controller display of less than 2 L/min, or greater than 10 L/min may indicate an electrical fault, incorrect hematocrit entry or an occlusion due to thrombus or other materials (e.g. tissue fragments) in the device. Inaccurate assessment of HVAD® Pump flow may lead to less than optimal treatment. 7. WARNING! ALWAYS investigate, and if possible, correct the cause of any alarm. Silencing an alarm does not resolve the alarm condition. 8. WARNING! DO NOT grasp the driveline cable as this may damage the driveline. To remove the driveline from the controller, first pull back the driveline cover then grasp and pull the driveline connector. 9. WARNING! DO NOT disconnect the driveline from the controller or the pump will stop. If this happens, reconnect the driveline to the controller as soon as possible to restart the pump. 10. WARNING! DO NOT operate the controller in temperatures less than -20°C (-4°F) or greater than 50°C (122°F) or the controller may fail. 11. WARNING! DO NOT attach the alarm adapter to a controller connected to the running pump. The alarm adapter silences the “No Power” alarm and should only be attached to a controller that has failed or malfunctioned and is no longer connected to a pump. 12. WARNING! ALWAYS keep a spare controller and fully charged spare batteries available at all times in case of an emergency. 13. WARNING! DO NOT plug the AC adapter into an electrical outlet which is not properly grounded or you may receive a serious electrical shock. 14. WARNING! ALWAYS check the controller display for any information regarding an alarm when using loud machinery or in the vicinity of loud noises as the alarms may not be audible. 15. WARNING! ALWAYS replace a controller with a blank display or no audible alarms. This condition is predictive of a controller failure. 16. WARNING! ALWAYS switch to the backup controller if there is a “Controller Failed” alarm since the HVAD® Pump may not be running. 17. WARNING! The HVAD® Pump may cause interference with AICDs. If electromagnetic interference occurs, it may lead to inappropriate shocks, arrhythmia and possibly death. The occurrence of electromagnetic interference with AICD sensing may require adjustment of lead sensitivity, proximal placement of new leads or replacement of an existing sensing lead. 3

HeartWare® Ventricular Assist System Instructions for Use

18. WARNING! Keep both power supplies connected to the controller after setting up the primary controller to minimize the risk of air embolus during implant. Disconnecting and then reconnecting both power supplies will result in the controller starting the pump as soon as the driveline is connected. 19. WARNING! DO NOT use if package is damaged or opened. Sterile components are intended for single use only. DO NOT re-sterilize or re-use as this will increase the risk of infection. 20. WARNING! ALWAYS check for an audible click when connecting the driveline to the controller or driveline extension cable. Failure to ensure a secure connection may cause an electrical fault. 21. WARNING! NEVER turn on the HVAD® Pump in air as this may damage the pump. DO NOT use an HVAD® Pump that was turned on without total submersion in fluid during the pre-implant test and prior to implantation: The HVAD® Pump must be completely submerged in fluid before being turned on. 22. WARNING! DO NOT implant gel impregnated vascular prostheses in patients who exhibit sensitivity to polyester or materials of bovine origin, as severe reactions may occur. 23. WARNING! DO NOT allow the Gelweave prostheses non-sterile foil pouch or outer tray to be introduced to the sterile field or the sterile field will be contaminated. Only the innermost tray is sterile. 24. WARNING! DO NOT preclot the outflow graft. Preclotting may disrupt the gel matrix, resulting in bleeding. Gelweave prostheses are sealed grafts and must not be preclotted. 25. WARNING! DO NOT implant the Gelweave prostheses more than one month after removal from the foil pouch. This may disrupt the gel matrix, resulting in bleeding. 26. WARNING! DO NOT allow anyone but a surgeon, physician’s assistant or surgical assistant trained in the procedure to attach the outflow graft to the pump, as a loose graft connection may lead to bleeding and/or an air embolus. 27. WARNING! ALWAYS rotate the strain relief so that the clamp screw is located on the inner side of the outflow conduit to avoid tissue irritation or damage. 28. WARNING! DO NOT use excessive force when tightening the clamp screw because this could damage the graft clamp or graft clamp screw and a loose connection may result in bleeding and/or an air embolus. Replace components if required. 29. WARNING! DO NOT over-loosen the sewing ring’s screw or it may fall off the sewing ring and be lost in the sterile field. 30. WARNING! DO NOT cut the outflow graft too short or too long, or it may kink. Prior to chest closure, ensure that the graft is not kinked or compressed. A kinked or compressed outflow graft may lead to reduced flow and/or thrombus formation. 31. WARNING! DO NOT immerse the Gelweave grafts in saline for longer than 5 minutes. Longer periods of soaking in saline may disrupt the gel matrix, resulting in bleeding. 32. WARNING! ALWAYS position the driveline exit site so that the tunneler does not contact any vital organs or structures. 33. WARNING! DO NOT grasp the driveline and pull as this may damage the driveline. To remove the driveline cap from the driveline, unscrew the outer sleeve, then pull back on the grooved part of the connector.

4

HeartWare® Ventricular Assist System Instructions for Use

34. WARNING! ALWAYS remove all air from the HVAD® Pump and its conduits to reduce risk of air embolus. 35. WARNING! DO NOT de-air the HVAD® Pump when there is inadequate blood volume in the HVAD® Pump or leaks in the inflow/outflow connections, as air may enter the HVAD® Pump and outflow graft resulting in a delay in de-airing and possible air embolism. 36. WARNING! DO NOT allow patients to shower until they have received permission from their clinician to do so. Patients who shower must use the HeartWare® Shower Bag. 37. WARNING! DO NOT allow hearing impaired patients to shower unless their caregiver is close by to hear alarms. 38. WARNING! DO NOT plug the controller into an AC wall outlet during showers; to eliminate the possibility of a severe electrical shock, it should be connected to two batteries. 39. WARNING! DO NOT allow patients to take a bath or swim, as this may damage HeartWare® System components and/or result in driveline exit site infection. 40. WARNING! DO NOT submerge HeartWare® System components in water or other fluid as this may damage them. If this happens, contact HeartWare. 41. WARNING! DO NOT allow water or other fluids to enter the controller, power adapters, batteries, battery charger or connectors, as this may damage HeartWare® System components. If this happens, contact HeartWare. 42. WARNING! AVOID areas with high magnetic forces such as theft detection devices or airport security systems, as this may affect HeartWare® System operation. 43. WARNING! Keep mobile phones at least 20 inches (50 centimeters) away from the controller, as mobile phones may interfere with controller operation. 44. WARNING! DO NOT let the patient have a magnetic resonance imaging (MRI) procedure while implanted with the HVAD® Pump. Doing so could cause harm to the patient or could cause the pump to stop. 45. WARNING! DO NOT apply high power electrical treatment (e.g. application of diathermy) directly to the patient, as this may affect HeartWare® System operation. 46. WARNING! AVOID therapeutic levels of ultrasound energy, as the device may inadvertently concentrate the ultrasound field and cause harm. 47. WARNING! AVOID therapeutic ionizing radiation since it may damage the device. This damage may not be immediately detectable. 48. WARNING! DO NOT use any components other than those supplied by HeartWare with the HeartWare® System, as this may affect HeartWare® System operation. 49. WARNING! DO NOT drop the controller or other equipment. Dropping the controller could cause sudden stoppage of the pump. Dropped equipment should be reported to HeartWare and inspected. 50. WARNING! Damaged equipment should be reported to HeartWare and inspected. 51. WARNING! NEVER clean the battery charger with the power on, as this may lead to an electrical shock. 52. WARNING! NEVER clean the monitor with the power on, as this may lead to an electrical shock. DO NOT use alcohol or detergent on the monitor display. Gently wipe the display with a soft, lint free cloth. 5

HeartWare® Ventricular Assist System Instructions for Use

53. WARNING! DO NOT disconnect the driveline or power sources from the controller while cleaning it or the pump will stop. If this happens, reconnect the driveline to the controller as soon as possible to restart the pump.

5.0

PRECAUTIONS 1.

CAUTION: Safety and effectiveness in persons less than 18 years of age and in persons with a BSA of less than 1.5 m2 have not been established.

2.

CAUTION: The HeartWare® Ventricular Assist System has had limited use in patients with artificial mitral or aortic valves and therefore the risks are currently unknown. Caution should be used in selecting patients with artificial mitral or aortic valves for HeartWare® System therapy.

3.

CAUTION: ONLY use HeartWare® Controllers on one patient to avoid risks associated with an inadvertent mismatch of controller pump speed settings.

4.

CAUTION: Manual changes to the speed will immediately disable the ventricular suction detection alarm. An “Sx Off” will be displayed on the monitor screen below the “Fixed” mode display. The ventricular suction detection alarm will have to be re-activated.

5.

CAUTION: DO NOT enable the ventricular suction detection alarm while the patient is in a suction condition. To optimize operation of the suction detection the patient should be hemodynamically stable prior to enabling the ventricular suction detection alarm.

6.

CAUTION: ALWAYS fully charge the monitor’s internal battery prior to patient use.

7.

CAUTION: DO NOT allow patients to touch the monitor, as this may lead to the entering of unwanted HeartWare® System parameters.

8.

CAUTION: DO NOT use the “Set Defaults” button on the monitor when a controller is connected to a patient. Pressing it will erase all patient VAD parameter information from the controller.

9.

CAUTION: ALWAYS recharge fully depleted batteries within 24 hours to avoid permanent battery damage.

10. CAUTION: DO NOT force connectors together without proper alignment. Forcing together misaligned connectors may damage the connectors. 11. CAUTION: ALWAYS confirm that the power cables are properly locked on the controller by gently pulling the cable near the controller power connector or the power cables may come loose and result in an alarm or the pump stopping. 12. CAUTION: DO NOT expose batteries to temperatures outside the storage and operational ranges or they may provide less support than usual. To preserve battery life, batteries should be stored at room temperature. Battery operating and storage temperatures: a. Operating: discharge (normal use with the HeartWare® System) and charge (while on battery charger): 0°C to 45°C (+32°F to 113°F). Operation at temperatures below 0°C will temporarily reduce battery capacity but the battery will operate. b. Storage: -20°C to 25°C (-4°F to 77°F). Long term storage outside of this range may permanently reduce the battery capacity. Best condition for storage is at room temperature. 13. CAUTION: ALWAYS keep batteries away from children. Children may be harmed by damaged batteries or components. 6

HeartWare® Ventricular Assist System Instructions for Use

14. CAUTION: DO NOT disassemble, crush, or puncture a battery. 15. CAUTION: DO NOT use a damaged battery. Battery function is unknown if the battery is damaged. 16. CAUTION: DO NOT short circuit the external contacts on a battery since this may result in battery damage. 17. CAUTION: DO NOT touch the fluid if a battery pack is leaking fluid. Dispose of a leaking battery pack. In case of eye contact with fluid, DO NOT rub eyes. Immediately flush eyes thoroughly with water for at least 15 minutes, lifting upper and lower lids, until no evidence of the fluid remains. Seek medical attention. 18. CAUTION: DO NOT expose batteries to excessive shock or vibration since this may affect battery operation. 19. CAUTION: DO NOT dispose of a battery in fire or water. Dispose of batteries according to federal, state, and local regulations. 20. CAUTION: ONLY use the HeartWare® Battery Charger to charge HeartWare® Batteries. Other battery chargers will not charge the batteries and may damage them. 21. CAUTION: ALWAYS wait until the “Ready” light turns on to disconnect the battery from the battery charger. If this is not followed over consecutive charging cycles, the Battery Capacity Display will not function properly and may convey misleading battery capacity. 22. CAUTION: DO NOT use HeartWare equipment in the presence of a flammable anesthetic mixture with air or with oxygen or nitrous oxide. 23. CAUTION: A backup controller should always be available and programmed identically to the primary controller. 24. CAUTION: DO NOT exert excessive tension or force on the Gelweave prostheses as it will damage the polyester fibers and the gelatin impregnation, which may result in bleeding. 25. CAUTION: ALWAYS ensure the inflow cannula position is pointed toward the mitral valve and parallel to the interventricular septum to optimize HVAD® Pump operation. 26. CAUTION: ALWAYS position the sewing ring to permit access to its screw after cannulation. 27. CAUTION: ALWAYS use round body taper point needles when implanting Gelweave prostheses to minimize fiber damage. A kinked or compressed outflow graft may lead to reduced flow and/or thrombus formation. 28. CAUTION: The driveline connector is made of nickel-coated brass which may cause a rash in patients with a nickel allergy. 29. CAUTION: ALWAYS be aware of the position of the driveline to avoid damage by surgical instruments and needles during HVAD® Pump implantation and/or re-operation. 30. CAUTION: ALWAYS use the smallest possible needle for de-airing; 19-gauge is normally sufficient. Hypodermic needles have a cutting point which may result in blood leakage and may require repair by suturing. 31. CAUTION: DO NOT rely on HVAD® Pump flow estimation during the de-airing procedure. Flow estimation may not be accurate. 32. CAUTION: Chest compressions may pose a risk due to pump location and position of the outflow graft on the aorta - use clinical judgment. If chest compressions have been administered, confirm function and positioning of HVAD® Pump.

7

HeartWare® Ventricular Assist System Instructions for Use

33. CAUTION: ALWAYS examine the driveline for evidence of tears, punctures or breakdown of any of the material during exit site dressing changes. Driveline damage may affect HeartWare® System performance. 34. CAUTION: AVOID the use of prophylactic topical antibiotic ointments such as silver sulfadiazine, betadine or polymyxin-neomycin-bacitracin on the tissue around the driveline exit site as these ointments can injure the tissue. 35. CAUTION: DO NOT pull, kink or twist the driveline or the power cables, as these may damage the driveline. Special care should be taken not to twist the driveline while sitting, getting out of bed, adjusting controller or power sources, or when using the shower bag. 36. CAUTION: ALWAYS keep all connectors free of liquid, dust and dirt, or the HeartWare® System may not function as intended. 37. CAUTION: DO NOT attempt to repair or service any components of the HeartWare® System. If HeartWare® System equipment malfunctions, contact HeartWare. 38. CAUTION: DO NOT place batteries in water or liquid.

6.0

POTENTIAL COMPLICATIONS Implantation of a Ventricular Assist Device (VAD) is an invasive procedure requiring general anesthesia, a median sternotomy, a ventilator and cardiopulmonary bypass. These surgical procedures are associated with numerous risks. Adverse events that may be associated with the use of the HeartWare® System are listed below. Other than death, the adverse events are listed in alphabetical order.  Death

 Hemolysis

 Air embolism

 Hepatic dysfunction

 Aortic insufficiency

 Hypertension

 Platelet dysfunction

 Bleeding, perioperative or late

 Interference with/from other devices

 Psychiatric episodes  Renal dysfunction

 Local infection

 Re-operation

 Multi-organ failure

 Respiratory dysfunction

 Myocardial infarction

 Right ventricular failure

 Neurologic dysfunction

 Sensitivity to aspirin

 Organ damage during driveline tunneling

 Sepsis

 Pericardial effusion/ tamponade

 Worsening heart failure

 Cardiac arrhythmias  Death  Device malfunction  Device thrombosis  Driveline infection  Driveline perforation  Driveline wire damage  Erosions and other tissue damage  GI bleeding/ AV malformations

8

 Peripheral thromboembolism

 Stroke  Wound dehiscence

HeartWare® Ventricular Assist System Instructions for Use

7.0

CLINICAL TRIAL RESULTS

7.1

Pivotal Clinical Study Design This was a multi-center, prospective, contemporaneous control trial. The trial was non-randomized and open label. Enrollment in the study is complete, subjects have all reached the primary endpoint as described and specified in the protocol, but follow-up of subjects is ongoing. Subjects were consented for participation and then assessed against the inclusion and exclusion criteria for participation in the study and implantation of the HVAD® Pump. After the surgical recovery period, patients were allowed to leave the hospital if they met additional criteria for hospital discharge. Each patient was followed to 180 days, death, device explant for recovery, or cardiac transplantation, whichever occurred first. Patient outcomes were compared to a contemporaneously treated cohort of patients as recorded in the Interagency Registry for Mechanical Assisted Circulatory Support (INTERMACS). All patients enrolled in the INTERMACS registry over the same enrollment period as the trial that met the control group inclusion and exclusion criteria comprised the control group.

7.2

Study Objectives Primary Objective The purpose of the HeartWare® Ventricular Assist System study was to evaluate the safety and effectiveness of the HeartWare® System in patients listed for cardiac transplantation with refractory, advanced heart failure at risk of death. The primary endpoint is success at 180 days which was defined as alive on the originally implanted device or transplanted or explanted for recovery. If explanted for recovery patients must have survived 60 days post-explant to be considered successful. Effectiveness was measured by the primary endpoint. The proportion of study patients alive, transplanted, or explanted for recovery at 180 days was compared to the same proportion obtained from the INTERMACS registry cohort and tested for non-inferiority. Secondary Objectives Including Safety Secondary endpoints included: overall survival; incidence of all serious adverse events, including neurocognitive status and unanticipated adverse device effects; incidence of all device failures and device malfunctions; Quality of Life improvement, as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) and European Quality of Life Assessment (EuroQol) EQ-5D; and functional status improvement, as measured by New York Heart Association (NYHA) classification and 6-minute walk. Safety measures included the frequency and rates of adverse events, overall and for each specific event, which were collected throughout HeartWare® System support.

7.3

Study Population Demographics and Baseline Parameters There were three analysis populations defined for this trial. These are the intent-to-treat population, (ITT), the Safety population (SAF) and the Per Protocol population (PP).

9

HeartWare® Ventricular Assist System Instructions for Use

Intent to Treat Population N=140

Safety Population N=140

Per Protocol Population N=137

Major Protocol Violations N=3

Subjects were predominately male (72.1%) and 53.3 ± 10.3 years of age. BSA and BMI were 2.1 ± 0.3 kg/m2 and 28.6 ± 6.1 m2, respectively. The principal etiology of heart failure was ischemic heart disease (41%) and the average LVEF was 17.8 ± 7.1 %. Pulmonary Capillary Wedge Pressure (PCWP) was elevated at 23 ± 9 mm Hg and pulmonary artery pressures were also high: (49 ± 15)/(25 ± 9) mmHg. The majority of patients were classified as NYHA IV (95%). Laboratory values at baseline were, in general, unremarkable except for an elevated BUN (26 ± 14 mg/dL) and a depressed hematocrit (34 ± 5.8 %). Eighty percent of subjects in the HeartWare® System treatment group were on inotropic therapy at baseline. Some (23%) were on more than one inotrope. IABP therapy at baseline was reported for 25% of subjects and 85% presented with an AICD. Subjects received typical medications for congestive heart failure with diuretics (82%) most common.

Comparison of Selected Baseline Characteristics between Treatment and Control Groups The mean age of implant recipients in the HeartWare® System group was 53.3 (range 22-70) and for the control, 52.2. Other parameters available to compare included gender, BSA, BUN, right atrial pressure and creatinine. In all cases, the values for both the HeartWare treatment and control groups were not statistically significantly different (Table 1). Table 1: Select Baseline Characteristics for HeartWare and INTERMACS Groups HeartWare® System

INTERMACS

N=140

N=499

Age (years)

53.3 ± 10.3

52.2 ± 12.2

0.19

Female Gender, n (%)

39 (28%)

120 (24%)

0.36

BSA (m2)

2.06 ± 0.28

2.07 ± 0.30

0.59

BUN (mg/deciliter)

25.3 ± 13.5

28.9 ± 20.9

0.94

Right atrial pressure (mmHg)

10.8 ± 3.3

11.5 ± 5.0

0.53

Serum creatinine (mg/dL)

1.3 ± 0.4

1.4 ± 0.6

0.89

Characteristics

10

p-value

HeartWare® Ventricular Assist System Instructions for Use

7.4

Safety and Effectiveness Results EFFECTIVENESS RESULTS Primary Endpoint The analysis of the primary endpoint demonstrated HVAD® non-inferiority to the control group (Table 2). The difference in success rates between the HVAD® group and controls was less than the 15% noninferiority margin (p <0.0001). The 95% one-sided UCL on the difference in success rates was 4.5% for the Safety (SAF) population analysis and 0.9% for the Per Protocol (PP) population analysis. The pre-specified primary endpoint was achieved.

Table 2: Success Rates and Inference on non-Inferiority Implanted (N)

Successes N (%)

HVAD®

140

127 (90.7)

Controls

497

448 (90.1)

137

126 (92.0)

UCL (%)

p-value

4.5

<0.0001

0.9

<0.0001

Safety Cohort

Per Protocol Cohort HVAD® Controls

497

448 (90.1)

P-value: From significance test of non-inferiority UCL: 95% one-sided upper confidence limit on the difference in success rates Note: The table accounts for 497 of the 499 INTERMACS patients; the remaining 2 patients, who withdrew consent before 180 days, have a missing success/failure outcome.

Competing Outcomes A competing risks analysis was performed (Figure 2), estimating the time-related probability of experiencing each of the component events. These data are calculated from all events occurring during the study duration, including deaths, transplants and exchanges occurring after 180 days but ending with last-patient, last-visit.

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HeartWare® Ventricular Assist System Instructions for Use

Figure 2: Competing Risk Outcomes (HVAD® Safety Population)

Deaths There were eight subject deaths during the 180-day study period. Six deaths occurred in subjects with their originally implanted device and two deaths occurred after device exchange. Safety Results This study was not randomized and used a contemporaneous control for the sole purpose of comparing a pre-defined success outcome. The adverse events reported here are unique to the HeartWare® System and have no randomized comparator arm. Exposure The total support (exposure) on the original HeartWare® System was 20,698 days or 56.7 patient-years. The mean duration on device for the 140 subjects was 147.8 days (standard deviation 52.8) with a median 180 (range 6 – 180 days). The mean duration on study was 222.5 days (standard deviation 119) with a median of 196 (range 11 – 588 days). Duration on study exceeds duration on device, because the follow-up post-transplant is included. Adverse Events A total of 776 events (Table 3) were reported by investigators during the 180 day period on the original device. Of these 437 (437/776, 56.3%) were INTERMACS defined specific events, and 338/776 (43.6%) events were recorded under the INTERMACS category of “Other.” One UADE was reported during the 180-day primary endpoint period.

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HeartWare® Ventricular Assist System Instructions for Use

Table 3: Summary of All Investigator-Reported Adverse Events Event

Total

%

INTERMACS defined Events

437

56.3%

INTERMACS “Other” AE's

338

43.6%

UADE

1

0.1%

Total

776

100%

INTERMACS Events The INTERMACS defined adverse events for the 180-day primary endpoint on original device are summarized below and are separated into the perioperative (0-30 days) and post-perioperative (31-180 days) periods. Events meeting INTERMACS criteria are shown in Table 4 below. Bleeding, infections and arrhythmia were the most common. Most bleeding events qualified due to transfusions (see definition below). On the other hand, all reoperations due to bleeding were in the first 30-days post-op (23 vs. 0 events post-30 days).

Table 4: INTERMACS Events by Type and Time of Onset (HeartWare® System N=140) Day of Event Onset 0-30 Days 31-180 Days Events Subjects Events Subjects N N (%) N N (%)

INTERMACS defined AEs

BLEEDING Re op1

23

20 (14.3)

0

0

Transfusion criteria >4 units within 7 days

10

10 (7.1)

0

0

Any units at >7 days

31

25 (17.9)

46

20 (14.3)

Local (non-device)

20

20 (14.3)

17

17 (12.1)

Driveline exit

5

5 (3.6)

14

11 (7.9)

3

3

3 (2.1)

8

7 (5.0)

Ischemic CVA

7

7 (5.0)

3

3 (2.1)

Hemorrhagic CVA

2

2 (1.4)

2

2 (1.4)

TIA

2

2 (1.4)

5

4 (2.9)

26

22 (15.7)

8

5 (3.6)

2

Infections

Sepsis

Neurological Events

Respiratory Dysfunction Arrhythmia

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HeartWare® Ventricular Assist System Instructions for Use

INTERMACS defined AEs

Day of Event Onset 0-30 Days 31-180 Days Events Subjects Events Subjects N N (%) N N (%)

Ventricular

15

14 (10.0)

14

11 (7.9)

Supraventricular

25

21 (15.0)

7

6 (4.3)

Inotropes

17

17 (12.1)

8

7 (5.0)

RVAD

3

3 (2.1)

1

1 (0.7)

Arterial Thromboembolism

0

0

2

2 (1.4)

Venous Thromboembolism

4

4( 2.9)

3

3 (2.1)

Renal Dysfunction

8

8 (5.7)

6

5(3.6)

Psychiatric event

5

5 (3.6)

4

4 (2.9)

Myocardial Infarction event

0

0

1

1 (0.7)

Hypertension

1

1 (0.7)

0

0

Hepatic dysfunction

3

3 (2.1)

1

1 (0.7)

Hemolysis event3

1

1 (0.7)

1

1 (0.7)

Right Heart Failure

1

4 procedures were not included: elective hysterectomy, elective repair of hemorrhoids, HVAD® exchange and RVAD placement. 2 Transfusion criteria include: ≥ 20cc/kg packed red blood cells (PRBC) within any 24 hour period during the first 7 day post implant and any transfusion of packed red blood cells (PRBC) after 7 days following implant with the Investigator recording the number of units given. 3 Two cases were excluded: 1 case hemolysis < 72 hours post-implant; 1 case hemolysis occurring in the presence of tPA/Integrillin for VAD thrombosis

The majority of infections did not involve the driveline or cause sepsis. The local, non-device category encompasses a host of sites, including the urinary tract, lungs, sinuses, IV punctures, colon and skin. Infections involving the driveline exit site were more common after hospital discharge (> 30 days). Similarly, subjects were somewhat more likely to experience sepsis from 31-180 days (5.0% of subjects) than perioperatively (2.1%). Nearly a third (11/32) of the supraventricular arrhythmias were bouts of atrial fibrillation, requiring drug therapy. Nearly all the ventricular arrhythmias were ventricular tachycardia. AICD shocks were recorded in 24/29 episodes of ventricular arrhythmia and 2/29 received external cardioversion. Nearly all patients with a reported episode of ventricular tachycardia were subsequently placed on amiodarone. Respiratory problems were more common in the perioperative period, declining from 26/34 events at 030 days to about one-third that number (8/34) from 31-180 days. Subjects were more likely to experience right heart failure events in the perioperative period (20/29). The most common treatment for right heart failure was the use of inotropic drugs and the pulmonary vascular dilator, nitric oxide (25/29). Three subjects required an RVAD and a fourth was exchanged for a pneumatic biVAD at 75 days post-implant. Ischemic strokes (ICVA) were more common overall (10/14 events) and occurred with greater frequency in the perioperative period (7/9 perioperative strokes). Four hemorrhagic strokes (HCVA) were recorded. Three of these resulted in deaths. TIAs were more common in the 31-180 day period (5/7 TIA events).While HCVAs were generally fatal (75%) they were most often associated with hypertension (MAP > 90 mm Hg). Three of the 4 HCVAs had a mean arterial pressure of ≥ 95 mm Hg at the time of the stroke and the one normotensive patient was septic and had an INR of 2.7 (high normal range).

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HeartWare® Ventricular Assist System Instructions for Use

Overall 70% of the patients who experienced ICVAs were transplanted or remained eligible. It is noteworthy that 6/10 ICVA events occurred within 48 hours of implant and may have been related to surgical procedural factors, such as ragged coring of the myocardium for inflow insertion or incomplete device de-airing. These issues were addressed by improvements to the coring tool and by site retraining. The overall stroke survival for the combined ICVAs and HCVAs on the original device was 77% (10/13 patients). Venous thrombosis occurred in 5% of subjects. Most of these were cases of DVT in the lower extremities. In the arterial thromboembolism category, a case of VAD thrombosis was treated with tPA and resolved and in another case a clot was removed from the left main coronary artery following cardiac catheterization. A third case appeared to involve a shower of small emboli to the periphery. No subject required permanent dialysis. Psychiatric events were recorded for nine subjects (6.4%). All recovered without sequelae. Two hemolysis events were detected by strict INTERMACS criteria in the absence of VAD thrombosis. These resolved spontaneously. One subject experienced a myocardial infarction and one subject had a hypertensive event during the perioperative period. Hepatic dysfunction was noted in four subjects. Adverse events were generally more common in the perioperative period. SERIOUS ADVERSE EVENTS A total of 452 serious adverse events on the original device occurred in 118 (84.3%) subjects (Table 5). A total of 287 INTERMACS defined events met the definition of an SAE, and 164 INTERMACS “other” events met the definition of an SAE. Table 5: Summary of Serious Adverse Events (HeartWare® System N=140) Number of SAEs

Subjects

452

118 (84.3)

INTERMACS

287

98 (70.0)

“Other”

164

75 (53.6)

UADE

1

1 (0.7)

Serious Adverse Events (SAEs) Total Serious Adverse Events

N (%)

Device Exchange Device exchange occurred in 7 patients (7/140, 5.0%) in the SAF population during the period 180 days post-implant. Of these 7 exchanges, 3 were resultant from retained tissue being pulled into the pump from the ventricle in the very early post-operative period and were deemed to be procedure related, 2 were exchanged due to thrombus inside the pump, one was exchanged for a high power event of unknown cause and one due to latent right heart failure which caused the patient to require a biventricular support system. Device Malfunctions A device malfunction is defined as a failure of one or more of the components of the HeartWare® System, which either directly causes or could potentially, cause or induce a state of inadequate circulatory support (low cardiac output state) or death. There was information on 26 malfunctions from 20 subjects entered into the clinical database during the study period (Table 6). 15