Medtronic 1403US Instructions for Use

HeartWareHeartWare™™ HVADHVAD™™ SystemSystem

Instructions for Use

Table of Contents

1.0 Introduction ..............................................................................................................................................................1

1.1 Introduction ........................................................................................................................... 2

1.2 Indications for Use ................................................................................................................. 2

1.3 Contraindications ................................................................................................................. 2

1.4

1.5 Precautions .................................................................................................................... 7

1.6 Potential Complications ..................................................................................................... 10

1.7 Pivotal US Clinical Study: Bridge-to-Transplant ................................................................ 11

1.8 Post Approval Study Follow-up of the Pivotal US Clinical Study: Bridge-to-Transplant ........... 20

1.9 US Clinical Study: Destination Therapy ............................................................................. 30

1.10 Destination Therapy Supplemental Study ........................................................................ 47

1.11 North American Clinical Study: LATERAL .......................................................................... 64

Warnings ......................................................................................................................... 3

2.0 HeartWare™ HVAD™ System Overview ...................................................................................................75

2.1 HVAD™ Pump and Surgical Tools ...................................................................................... 75

2.2 HVAD™ Controller ................................................................................................................ 76

2.3 HeartWare™ Monitor ........................................................................................................... 77

2.4 HVAD™ Controller Power Sources ..................................................................................... 77

2.5 HeartWare™ Battery Charger ............................................................................................ 78

2.6 Carrying Cases and Shower Bag ...................................................................................... 78

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3.0 HeartWare™ HVAD™ System Pump ............................................................................................................81

3.1 Principles of Operation ....................................................................................................... 81

3.2 Physiologic Control Algorithms .......................................................................................... 83

3.2.1 Flow Estimation .......................................................................................................... 83

3.2.2 [Ventricular Suction Detection] Alarm ................................................................... 84

3.2.3 LavareTM Cycle........................................................................................................... 86

3.3 HVAD™ Pump Operating Guidelines ................................................................................ 87

3.4 Expected Useful Life of the HVAD™ Pump ........................................................................ 87

3.5 Device Tracking and Reporting Requirements ............................................................... 87

4.0 HeartWare™ HVAD™ System Peripherals and Accessories ......................................................89

4.1 HVAD™ Controller Connections ....................................................................................... 89

4.2 HVAD™ Controller .............................................................................................................. 93

4.3 Using the HeartWare™ Batteries ....................................................................................... 97

4.4 Using the HeartWare™ Battery Charger ........................................................................ 103

4.5 Using the HVAD™ Controller AC Adapter or DC Adapter ........................................... 106

4.6 Carrying Cases ................................................................................................................ 107

4.7 Recommended Equipment for Use at Home .............................................................. 108

Patient

Management

Alarms and

Emergencies

Reference

Guides

Appendix

Table of Contents

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5.0 Using the HeartWare™ Monitor ................................................................................................................109

5.1 General Overview ............................................................................................................ 109

5.2 Informational Screens ....................................................................................................... 111

5.3 System Screens .................................................................................................................. 113

5.4 Downloading Controller Log Files ................................................................................... 125

5.5 Updating Software on the HVAD™ Controller ................................................................ 125

5.6 Monitor Shutdown ............................................................................................................. 129

5.7 HeartWare™ Monitor Care ............................................................................................... 130

6.0 Surgical Implant and Explant of the HVAD™ Pump .....................................................................133

6.1 Preparing for Implantation ..............................................................................................133

6.2 Programming HVAD™ Controllers .....................................................................................135

6.3 HVAD™ Pump Pre-Implant Test and Pump Assembly ...................................................137

6.4 Surgical Implant Procedure ..............................................................................................142

6.5 HVAD™ Pump Explant ........................................................................................................148

7.0 Patient Management and Education ...................................................................................................151

7.1 Postoperative Management ............................................................................................151

7.1.1 Setting Speed with HVAD™ Pump ..........................................................................152

7.1.2 Blood Pressure Maintenance .................................................................................153

7.1.3 Anticoagulation .......................................................................................................153

7.1.4 Right Heart Failure ....................................................................................................154

7.1.5 Arrhythmias ...............................................................................................................154

7.1.6 Infection Control Guidelines ...................................................................................154

7.2 Driveline Care .................................................................................................................... 155

7.3 Emergency Management ............................................................................................... 156

7.4 Physical Rehabilitation .................................................................................................... 156

7.5 Patient Education ............................................................................................................. 156

Patient

Alarms and

Reference

Appendix

Management

Emergencies

Guides

8.0 HeartWare™ HVAD™ System Alarms and Emergencies............................................................. 157

8.1 Alarm Overview ................................................................................................................ 157

8.2 High Priority Alarms ............................................................................................................ 158

8.3 Medium Priority Alarms ..................................................................................................... 160

8.4 Low Priority Alarms ............................................................................................................ 162

8.5 Multiple Alarms .................................................................................................................. 163

8.6 How to Silence (Mute) Alarms ......................................................................................... 164

8.7 How to Change the Controller ........................................................................................ 165

9.0 Quick Reference Guide for Alarms ........................................................................................................169

10.0 Appendix ..................................................................................................................................................................173

Appendix A System Components ............................................................................................ 173

Appendix B Product Specications ........................................................................................ 174

Appendix C EMC Manual Requirements Guidance Document ......................................... 176

Appendix D Symbol Denitions ............................................................................................... 180

HVAD™ Instructions for Use

1.0 Introduction

1.1 Introduction ..................2

1.2 Indications for Use .......2

1.3 Contraindications .........2

1.4 Warnings ......................3

1.5 Precautions ..................7

1.6 Potential

Complications............... 10

1.7 Pivotal US Clinical Study: Bridge-to-Transplant ..11

1.8 Post Approval Study Follow-up of the Pivotal US Clinical Study: Bridge-to-Transplant .. 20

Foreword

The HeartWare™ HVAD™ 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 qualied cardiac

surgeon trained by HeartWare-authorized personnel. Clinical users of the HVAD System should attend HeartWare training, should have a working knowledge of the principles of ventricular assist devices (VADs), and should be aware of the physical and psychological needs of patients undergoing VAD support. Patients and caregivers should complete a user training program and demonstrate their ability to use the system prior to independence.

Clinicians should read the entire Instructions for Use

before system operation. This manual may serve

as a reference for detailed information including

specic 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.

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1.9 US Clinical Study:

Destination Therapy ....30

1.10 Destination Therapy

Supplemental Study 47

1.11 North American Clinical

Study: LATERAL ........64

Introduction

Reference

Guides

Appendix

Introduction

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1.0 Introduction

In this manual, there will be the following symbols:

Indicates there is more information available in the manual and the location in

the manual

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.

Identies information

as a Warning

A Warning is a statement

about the possibility of

injury, death or other serious

adverse reaction that is

associated with the use or

misuse of the device

Identies information

as a Caution or Precaution

A Caution is a statement

that not following the

instruction may lead to

device misuse, malfunction

or damage

Indicates there is

a quick reference

guide available

1.1 Introduction

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The HVAD System is designed to assist a weakened, poorly functioning left ventricle. The HVAD System is designed for in-hospital and out-of-hospital settings, including transportation via

xed wing aircraft or helicopter. The HVAD 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. The inow

conduit, which is partially sintered, is integrated with the pump and

Explant

a 10 mm gel impregnated outow 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 a 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 HVAD 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:

HVAD System

1.2 Indications for Use

The HVAD System is indicated for hemodynamic support in patients with advanced, refractory left ventricular heart failure; either as a Bridge to Cardiac Transplantation (BTT), myocardial recovery, or as Destination Therapy (DT) in patients for whom subsequent transplantation is not planned.

Reference

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Appendix

1.3 Contraindications

The HVAD System is contraindicated in patients who cannot tolerate anticoagulation therapy.

2 HVAD™ Instructions for Use

1.4 Warnings

WARNINGS

1. WARNING! Serious and life threatening adverse events, including stroke, have been

associated with use of this device. The risk of death as a result of stroke has been observed in randomized clinical trials to be higher with the HVAD than with alternative treatment options. The HVAD has been associated with a rate of stroke of 22% at one year and 29.7% at two years. A blood pressure management protocol may reduce the overall incidence of stroke to 16.9% at one year and may reduce the incidence of disabling strokes at one year from 8.1% to 6.5%. A user must fully consider the risks of this device with that of other treatment modalities before deciding to proceed with device implantation. Please refer to section 1.8 (“Safety and Effectiveness Results”) for a summary of the stroke data. To mitigate the risk of stroke, please adhere to the following patient management guidelines:

• Monitor and treat mean arterial pressure. Maintain MAP less than 85 mmHg as tolerated.

• Speed on the HVAD Pump should be set to maintain adequate pump ow index, this generally does not need exceed 2.6 L/min/m2.

• Maintain anticoagulation within the recommended INR range of 2.0-3.0.

• Daily aspirin dose should be > 81 mg and platelet inhibition should be evaluated 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.

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! DO NOT use the HVAD System in pregnant women. Any woman receiving an HVAD 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. 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 an HVAD System product training program. A thorough understanding of technical principles, clinical applications and risks associated with the HVAD 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.

5. WARNING! ALWAYS connect an AC Adapter to the controller before relaxing or sleeping. Power from an electrical outlet (AC Adapter) provides power for an unlimited period of time.

6. 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.

7. 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.

8. WARNING! DO NOT allow hearing impaired patients to shower unless their caregiver is close by to hear alarms.

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3Introduction

Introduction

1.4 Warnings (continued)

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WARNINGS

9. 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.

10. WARNING! DO NOT allow patients to take a bath or swim, as this may damage HVAD System components and/or result in driveline exit site infection.

11. WARNING! DO NOT submerge HVAD System components in water or other uid as this may damage them. If this happens, contact HeartWare.

12. WARNING! DO NOT allow water or other uids to enter the controller, power adapters,

batteries, battery charger or connectors, as this may damage HVAD System components. If this happens, contact HeartWare.

13. WARNING! DO NOT use any components other than those supplied by HeartWare with the HVAD System, as this may affect HVAD System operation.

14. WARNING! Damaged equipment should be reported to HeartWare and replaced.

15. WARNING! DO NOT rely only on ow estimation to assess cardiac output. An average

estimated ow on the monitor or Controller Display of less than 2.0 L/min, or greater than

10.0 L/min may indicate an electrical fault, incorrect hematocrit entry or an occlusion and/or thrombus or other materials (e.g. tissue fragments) in the device. Inaccurate assessment of HVAD Pump ow may lead to less than optimal treatment.

16. WARNING! DO NOT grasp the driveline cable as this may damage the driveline. To

remove the driveline from the controller, rst pull back the driveline cover then grasp and

pull the driveline connector.

17. 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.

18. WARNING! DO NOT plug the HeartWare™ Battery Charger or monitor AC adapter into an electrical outlet which is not properly grounded or you may receive a serious electrical shock.

19. 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.

20. WARNING! AVOID devices and conditions that may induce strong static discharges (e.g., television or computer monitor screens) as electrostatic discharges can damage the electrical parts of the system and cause the VAD to perform improperly or stop.

21. WARNING! The HVAD System components should not be used adjacent to or stacked with

equipment other than specied in the IFU. If adjacent to or stacked use is necessary, the

HVAD System and other equipment should be observed to verify normal operation.

22. WARNING! ALWAYS have a back-up controller handy and, whenever possible, a caregiver nearby when changing power sources or controllers. Be watchful for unusual

changes in power or ow alarms for a period of time following equipment changes.

23. 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.

24. 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.

Appendix

4 HVAD™ Instructions for Use

1.4 Warnings (continued)

WARNINGS

25. WARNING! NEVER clean the battery charger with the power on, as this may lead to an

electrical shock.

26. WARNING! AVOID areas with high magnetic forces such as theft detection devices or airport security systems, as this may affect HVAD System operation.

27. WARNING! Keep mobile phones at least 20 inches (50 centimeters) away from the controller, as mobile phones may interfere with controller operation.

28. 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.

29. WARNING! DO NOT apply high power electrical treatment (e.g., deep tissue heating which can be used for treatment of arthritis and/or some injuries) directly to the patient, as this may affect HVAD System operation.

30. WARNING! AVOID therapeutic levels of ultrasound energy, as the device may

inadvertently concentrate the ultrasound eld and cause harm.

31. WARNING! AVOID therapeutic ionizing radiation since it may damage the device. This damage may not be immediately detectable.

32. WARNING! ALWAYS investigate, and if possible, correct the cause of any alarm. Silencing an alarm does not resolve the alarm condition.

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33. 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.

34. 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.

35. WARNING! Keep power connected to the controller after setting up the primary controller to minimize the risk of air embolus during implant. Disconnecting and then reconnecting power will result in the controller starting the pump as soon as the driveline is connected.

36. 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.

37. 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.

38. 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 uid during the pre-implant test and prior to implantation: The HVAD Pump must be completely

submerged in uid before being turned on.

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5Introduction

Introduction

1.4 Warnings (continued)

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WARNINGS

39. 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.

40. WARNING! The manufacturing process for gelatin sealed vascular grafts uses the cross-

linking agent formaldehyde to achieve the graft performance. All gelatin sealed grafts are thoroughly rinsed with reverse osmosis water to reduce residual formaldehyde,

however residual amounts may be present in the nished graft. Formaldehyde is

also found at low levels naturally in the body, some of which is derived from food. Formaldehyde is known to be mutagenic and carcinogenic. The risks of these potential harms from the product have not been established clinically.

41. WARNING! DO NOT allow the Gelweave™ prostheses non-sterile foil pouch or outer tray

to be introduced to the sterile eld or the sterile eld will be contaminated. Only the

innermost tray is sterile.

42. WARNING! DO NOT preclot the outow graft. Preclotting may disrupt the gel matrix,

resulting in bleeding. Gelweave™ prostheses are sealed grafts and must not be preclotted.

43. 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.

44. WARNING! DO NOT allow anyone but a surgeon, physician’s assistant or surgical assistant

trained in the procedure to attach the outow graft to the pump, as a loose graft connection may lead to bleeding and/or an air embolus.

45. WARNING! ALWAYS position the clamp screw so that it is located on the inner side of the

outow conduit to avoid tissue irritation or damage.

46. WARNING! DO NOT over-loosen the sewing ring’s screw or it may fall off the sewing ring

and be lost in the sterile eld.

47. WARNING! DO NOT cut the outow 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

outow graft may lead to reduced ow and/or thrombus formation.

48. 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.

49. WARNING! ALWAYS position the driveline exit site so that the tunneler does not contact

any vital organs or structures.

50. 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.

51. WARNING! ALWAYS remove all air from the HVAD Pump and its conduits to reduce risk of

air embolus.

52. WARNING! DO NOT de-air the HVAD Pump when there is inadequate blood volume in

the HVAD Pump or leaks in the inow/outow connections, as air may enter the HVAD

Pump and outow graft resulting in a delay in de-airing and possible air embolism.

53. WARNING! At HVAD Pump explant the percutaneous driveline is not sterile; therefore

ensure that the driveline does not contaminate the sterile eld.

54. 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.

55. WARNING! ALWAYS replace a controller with a blank display or no audible alarms. This

condition is predictive of a controller failure.

56. WARNING! ALWAYS switch to the back-up controller if there is a [Controller Failed] alarm

since the HVAD Pump may not be running.

57. WARNING! ALWAYS respond to low battery alarms. Silencing an alarm does not resolve

the alarm condition and will eventually deplete the batteries.

Appendix

6 HVAD™ Instructions for Use

1.4 Warnings (continued)

WARNINGS

58. WARNING! DO NOT attach the alarm adapter to a controller that is connected to a

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 running pump.

59. WARNING! ALWAYS keep a spare controller and fully-charged spare batteries at a temperature between 0°C and 50°C (+32°F to 122°F) available at all times in case of an emergency.

60. WARNING! DO NOT remove the driveline cover from the driveline. Maintaining proper driveline cover attachment prevents accidental disconnection which will lead to a pump stop.

1.5 Precautions

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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 HVAD System has had limited use in patients with articial mitral or

aortic valves and therefore the risks are currently unknown. Caution should be used

in selecting patients with articial mitral or aortic valves for HVAD System therapy.

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

4. CAUTION: The HeartWare™ Waist Pack and the HeartWare™ Shoulder Pack contain

magnetic closures. Patients with an internal cardiac debrillator (ICD) or pacemaker

should keep the pack away from their chest, including when sleeping. Per pacemaker and ICD manufacturer guidelines, magnets should be kept at least 6 inches (15 centimeters) away from the pacemaker or ICD (please refer to manufacturer guidelines for additional information).

5. 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.

6. CAUTION: DO NOT attempt to repair or service any components of the HVAD System. If HVAD System equipment malfunctions, contact HeartWare.

7. 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.

8. 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.

9. CAUTION: ALWAYS keep all connectors free of liquid, dust and dirt, or the HVAD System may not function as intended.

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Appendix

7Introduction

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1.5 Precautions (continued)

PRECAUTIONS

10. CAUTION: DO NOT force connectors together without proper alignment. Forcing

together misaligned connectors may damage the connectors.

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

13. CAUTION: DO NOT expose batteries to temperatures outside the storage and operational ranges or they may provide less runtime or may be unable to start a pump in an emergency. To preserve battery life, batteries should be stored at room temperature.

Battery operating and storage temperatures:

a. Operating: discharge (normal use with the HVAD System): 0°C to +50°C (+32°F to

+122°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.

14. CAUTION: ALWAYS keep batteries away from children. Children may be harmed by damaged batteries or components.

15. CAUTION: DO NOT disassemble, crush, or puncture a battery.

16. CAUTION: DO NOT use a damaged battery. Battery function is unknown if the battery

is damaged.

17. CAUTION: DO NOT short circuit the external contacts on a battery since this may result in battery damage.

18. CAUTION: DO NOT touch the uid if a battery pack is leaking uid. Dispose of a leaking battery pack. In case of eye contact with uid, DO NOT rub eyes. Immediately ush

eyes thoroughly with water for at least 15 minutes, lifting upper and lower lids, until no

evidence of the uid remains. Seek medical attention.

19. CAUTION: DO NOT expose batteries to excessive shock or vibration since this may affect battery operation.

20. CAUTION: DO NOT dispose of a battery in re or water. Dispose of batteries according

to federal, state, and local regulations.

21. CAUTION: DO NOT place batteries in water or liquid.

22. CAUTION: ONLY use the HeartWare™ Battery Charger to charge HeartWare™ Batteries.

Other battery chargers will not charge the batteries and may damage them.

23. 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.

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

25. CAUTION: DO NOT allow patients to touch the monitor, as this may lead to the entering

of unwanted HVAD System parameters.

Appendix

8 HVAD™ Instructions for Use

1.5 Precautions (continued)

PRECAUTIONS

26. CAUTION: DO NOT use the “Set Defaults” button on monitor REF1510 when a

controller is connected to a patient. Pressing it will erase all patient VAD parameter information from the controller.

27. CAUTION: DO NOT use HeartWare equipment in the presence of a ammable anesthetic mixture with air or with oxygen or nitrous oxide. (NOTE: Flammable anesthetics are typically ether based).

28. CAUTION: A back-up controller should always be available and programmed identically to the primary controller.

29. CAUTION: DO NOT exert excessive tension or force on the Gelweave™ prostheses as it will damage the polyester bers and the gelatin impregnation, which may result in bleeding.

30. CAUTION: ALWAYS ensure the inow cannula position is pointed toward the mitral valve

and parallel to the interventricular septum to optimize HVAD Pump operation.

31. CAUTION: ALWAYS position the sewing ring to permit access to its screw after cannulation.

32. CAUTION: ALWAYS use round body taper point needles when implanting Gelweave™

prostheses to minimize ber damage. A kinked or compressed outow graft may lead to reduced ow and/or thrombus formation.

33. CAUTION: The driveline connector is made of nickel-coated brass which may cause a rash in patients with a nickel allergy.

34. 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.

35. CAUTION: ALWAYS use the smallest possible needle for de-airing; 19-gauge is normally

sufcient. Hypodermic needles have a cutting point which may result in blood leakage

and may require repair by suturing.

36. CAUTION: DO NOT rely on HVAD Pump ow estimation during the de-airing procedure. Flow estimation may not be accurate.

37. 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 HVAD System performance.

38. CAUTION: DO NOT expose the driveline to direct or indirect sunlight. ALWAYS keep the driveline completely covered when in the sun. Instruct patients not to use tanning lights or black lights. The light from these sources contains ultraviolet radiation which may damage the outer sheath of the driveline.

39. CAUTION: DO NOT use prophylactic topical antibiotic ointments such as silver sulfadiazine, povidone iodine (betadine), or polymyxin-neomycin-bacitracin ointment on the exit site. These ointments can injure the tissue next to the driveline.

40. CAUTION: Chest compressions may pose a risk due to pump location and position of

the outow graft on the aorta - use clinical judgment. If chest compressions have been administered, conrm function and positioning of HVAD Pump.

41. CAUTION: Speeds below 2400 RPM or above 3200 RPM should be used with caution.

42. CAUTION: The safety and effectiveness of the Lavare™ Cycle has not been evaluated

clinically.

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1.6 Potential Complications

Implantation of a VAD is an invasive procedure requiring general anesthesia and entry into the thoracic cavity. These surgical procedures are associated with numerous risks. Risks associated with the implant procedure and use of the device may include, but are not limited to, the following1:

• Death

• Arterial Non-CNS Thromboembolism

– Air Embolism

• Bleeding

– Bleeding, perioperative or late

– GI bleeding / AV malformations

• Burn

• Cardiac Arrhythmias

• Device Malfunction

– Device Thrombus – Electrostatic Discharge (ESD) damage

to device

• Hemolysis

• Hepatic Dysfunction

• Hypertension

• Major Infection

– Driveline Infection

– Internal Pump Component, Inow or

Outow Tract Infection

– Local Infection – Sepsis

• Myocardial Infarction

• Neurological Dysfunction

– Transient Ischemic Attack (TIA) – Stroke

∙ Ischemic Cerebral Accident (ICVA) ∙ Hemorrhagic Cerebral Accident

(HCVA)

• Pericardial Effusion/ Tamponade

• Psychiatric Episodes

– Suicide

• Pneumothorax

• Renal Dysfunction

• Respiratory Dysfunction

• Right Ventricular Failure

• Venous Thromboembolism

• Wound Dehiscence

• Other

– Aortic Insufciency

– Cardiopulmonary Arrest – Multi-organ failure – Platelet Dysfunction – Pleural Effusion

∙ Organ damage during driveline

tunneling

∙ Pain

– Syncope

– Tissue Erosion and other tissue damage

– Worsening Heart Failure

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Emergencies

Guides

10 HVAD™ Instructions for Use

Other than death, the adverse events are listed in alphabetical order according to INTERMACS categories.

1.7 Pivotal US Clinical Study: Bridge-to-Transplant

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 specied 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 rst.

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.

Study Objectives

Primary Objective

The purpose of the HVAD System study was to evaluate the safety and effectiveness of the HVAD 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 dened 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.

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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)

classication and 6-minute walk.

Safety measures included the frequency and rates of adverse events, overall and for each

specic event, which were collected throughout HVAD System support.

Study Population Demographics and Baseline Parameters

There were three analysis populations dened for this trial. These are the intent-to-treat population, (ITT), the Safety population (SAF) and the Per Protocol population (PP).

Intent to Treat Population

N=140

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Safety Population

N=140

Per Protocol Population

N=137

Major Protocol Violations

N=3

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Subjects were predominately male (72.1%) and 53.3 ± 10.3 years of age. BSA and BMI were

2.1 ± 0.3 m2 and 28.6 ± 6.1 kg/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 classied 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 HVAD 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 HVAD 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 HVAD treatment and control groups were not statistically signicantly different (Table 1).

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Table 1: Select Baseline Characteristics for HVAD and INTERMACS® Groups

Characteristics

Age (years) 53.3 ± 10.3 52.2 ± 12.2 0.19

Female Gender, n (%) 39 (28%) 120 (24%) 0.36

Explant

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)

Serum creatinine (mg/dL)

HeartWare™

HVAD™ System

N=140

10.8 ± 3.3 11.5 ± 5.0 0.53

1.3 ± 0.4 1.4 ± 0.6 0.89

INTERMACS

N=499

p-value

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% non-inferiority 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-specied primary endpoint was achieved.

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1.7 Pivotal US Clinical Study: Bridge-to-Transplant (continued)

Table 2: Success Rates and Inference on Non-Inferiority

Implanted

(N)

Safety Cohort

HVAD™ 140 127 (90.7)

Controls 497 448 (90.1)

Per Protocol Cohort

HVAD™ 137 126 (92.0)

Controls 497 448 (90.1)

P-value: From signicance test of non-inferiority

UCL: 95% one-sided upper condence 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.

Successes

N (%)

UCL (%) p-value

4.5 <0.0001

0.9 <0.0001

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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.

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This study was not randomized and used a contemporaneous control for the sole purpose of

comparing a pre-dened success outcome. The adverse events reported here are unique to the

HVAD System and have no randomized comparator arm.

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Exposure

The total support (exposure) on the original HVAD 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® dened specic 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.

Table 3: Summary of All Investigator-Reported Adverse Events

Event Total %

INTERMACS® dened Events 437 56.3%

INTERMACS® “Other” AE’s 338 43.6%

UADE 1 0.1%

Total 776 100%

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INTERMACS® Events

The INTERMACS® dened 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. Bleeding,

Explant

infections and arrhythmia were the most common. Most bleeding events qualied due to transfusions (see denition below). On the other hand, all reoperations due to bleeding were in the rst 30-days post-op (23 vs. 0 events post-30 days).

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1.7 Pivotal US Clinical Study: Bridge-to-Transplant (continued)

Table 4: INTERMACS® Events by Type and Time of Onset (HVAD System N=140)

Day of Event Onset

INTERMACS® dened AEs

Bleeding

Re Op

Transfusion Criteria2 >4 Units within 7 Days

Any Units at > 7 Days 31 25 (17.9) 46 20 (14.3)

Infections

Local (Non-device) 20 20 (14.3) 17 17 (12.1)

Driveline Exit 5 5 (3.6) 14 11 (7.9)

Sepsis 3 3 (2.1) 8 7 (5.0)

Neurological Events

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)

Respiratory Dysfunction 26 22 (15.7) 8 5 (3.6)

Arrhythmia

Ventricular 15 14 (10.0) 14 11 (7.9)

Supraventricular 25 21 (15.0) 7 6 (4.3)

Right Heart Failure

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 Event

0-30 Days 31-180 Days

Events

23 20 (14.3) 0 0

10 10 (7.1) 0 0

1 1 (0.7) 1 1 (0.7)

Subjects

N (%)

Events

Subjects

N (%)

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4 procedures were not included: elective hysterectomy, elective repair of hemorrhoids, HVAD™ exchange and RVAD placement.

Transfusion criteria include: ≥ 20cc/kg packed red blood cells (PRBC) within any 24 hour period during the rst 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.

Two cases were excluded: 1 case hemolysis < 72 hours post-implant; 1 case hemolysis occurring in the presence of tPA/Integrillin for VAD thrombosis.

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1.7 Pivotal US Clinical Study: Bridge-to-Transplant (continued)

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 brillation, 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 0-30 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).

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 inow 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).

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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® dened events met the denition of an SAE, and 164

INTERMACS® “other” events met the denition of an SAE.

16 HVAD™ Instructions for Use

1.7 Pivotal US Clinical Study: Bridge-to-Transplant (continued)

Table 5: Summary of Serious Adverse Events (HVAD System N=140)

Serious Adverse Events (SAEs) Number of SAEs

Total Serious Adverse Events 452 118 (84.3)

INTERMACS 287 98 (70.0)

“Other” 164 75 (53.6)

UADE 1 1 (0.7)

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 dened as a failure of one or more of the components of the HVAD

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).

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Table 6: Malfunctions by Suspected Component

HVAD System N=140

Device Component ID

Pump 7 (5.0) *

Controller 7 (5.0)

Battery 1 (0.7)

Battery Charger 0

Monitor 0

Driveline 2 (1.4)

Controller AC Adapter 6 (4.3)

Other Component 3 (2.1)

*Described in Pump Exchange section

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Quality of Life: KCCQ And EuroQol

Kansas City Cardiomyopathy Questionnaire (KCCQ): At baseline, 128/140 (91.4%) patients were able to complete the KCCQ and at month 6 there were 88 patients available to complete the test (39 had received a transplant, six had died, seven had met an endpoint receiving a device exchange) (Table 7), Of the 88 patients available for assessment, 74 patients had data at month 6, Reasons for missing the month 6 data included: 9 of 14 with poor compliance/missed visit (8 of 9 of these from a single site and 1 of 9 had a prior ICVA with mRS score of 2), 2 were too sick, 1 had no form available, 1 had been transplanted within the 14 day visit window, and 1 had refused. Seventy patients (70) had both baseline and month 6 data. For these 70 patients who were on HVAD™ therapy continuously for 180 days had a 31 point improvement in KCCQ Overall Summary Score, over the 180 day period.

Table 7: KCCQ - Overall Summary Score

KCCQ Baseline Month 6 Change from Baseline

N 128 74 70

Mean (SD) 34.9 (18.9) 67.5 (20.4) 30.9 (26.5)

Median 31.5 71.4 34.5

Min, Max 0.0, 84.1 19.3, 100.0 -49.4, 80.5

95% CI 31.6, 38.2 62.8, 72.2 24.6, 37.3

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European Quality of Life (EuroQol): At baseline, 130/140 (92.9%) of patients were able to complete the test, and at month 6 there were 88 patients available to complete the test, (39 had received a transplant, six had died, seven had met an endpoint receiving a device exchange) (Table 8). Of the 88 patients available 75 had data at month 6. Reasons for missing the month 6 data included: 9 of 13 with poor compliance/missed visit (8 of 9 of these from a single site and 1 of 9 had a prior ICVA with mRS score of 2), 2 were too sick, 1 had been transplanted within the 14 day visit window, and 1 had refused. Seventy-two patients (72) had both baseline and month 6 data showing an improvement of 30 points over the 180 day period.

Table 8: EuroQol (EQ-5D) - Summary of Quality of Life

EuroQol Baseline Month 6 Change from Baseline

Overall Summary Score

N 130 75 72

Mean (SD) 39.7 (23.5) 69.8 (19.8) 29.5 (25.2)

Median 40.0 75.0 30.0

Min, Max 0.0, 92.0 4.0, 100.0 -36.0, 80.0

95% CI 35.6, 43.7 65.2, 74.4 23.6, 35.4

Functional Analyses: 6 Minute Walk

6 Minute Walk: Of the 132 patients assessed for the 6-minute walk test, the mean distance walked was 89.4 meters. Seventy-Five (75) of the 88 patients on pump at month 6 completed the test (Table 9 and Figure 3). Reasons for missing the 6 minute walk test at month 6 included: 9 of 14 with poor compliance/missed visit (8 of 9 of these from a single site and 1 of 9 had a prior ICVA with mRS score of 2), 2 were too sick, 1 had no form available, 1 had been transplanted within the 14 day visit window, and 1 had refused. These 75 patients showed a mean distance walked of 246 meters, a mean change of 150 meters from baseline.

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1.7 Pivotal US Clinical Study: Bridge-to-Transplant (continued)

Table 9: Functional Status – 6 Minute Walk

6 Minute Walk Baseline Month 6 Change from Baseline

Distance Walked in Meters

N 132 75 74

Mean (SD) 89.4 (141.3) 246.0 (203.9) 150.1 (214.1)

Median 0.0 274.0 108.3

Min, Max 0.0, 600.2 0.0, 991.8 -273.1, 700.9

95% CI 65.1, 113.7 199.1, 292.9 100.5, 199.8

Figure 3:

6 Minute Walk Test

Table 10 shows a breakdown of results of patients who walked at both baseline and at 6 months

as well as those patients that did not walk at baseline but did walk at 6 months.

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Table 10: 6 Minute Walk – Breakdown of Patients Walking vs. Not Walking at Baseline

HVAD System Patients Baseline (m) Month 6 (m)

Patients walking at baseline and at 6 months

Patients NOT walking at baseline (for any reason) but walking at 6 months

Overall Conclusions from Clinical Data

The HVAD System bridge-to-transplant study (ADVANCE) was a multi-center, prospective, contemporaneous control trial. The purpose of this study was to evaluate the safety and effectiveness in patients listed for cardiac transplantation with refractory, advanced heart failure at risk of death. The primary endpoint was success at 180 days which is dened as alive on the originally implanted HVAD Pump or transplanted or explanted for recovery.

The analysis of the primary endpoint yielded non-inferiority of the HVAD System to the INTERMACS® control. The 95% one-sided UCL on the difference in success rates was 4.5% for the Safety Group and 0.9% for the Per Protocol Group. Each of these limits was less than the 15% non-inferiority margin (p-value <0.0001).

• The pre-specied primary endpoint was achieved.

• Both quality of life and functional capacity showed improvements following implant of the HVAD Pump.

260 ± 140 (n=25) 338 ± 202 (n=25)

N/A 333 ± 125 (n=30)

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• The HVAD System has an adverse event prole that supports its safe use for bridge to transplant

patients.

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1.8 Post Approval Study Follow-up of the Pivotal US Clinical Study: Bridge-to-Transplant

Summary of the Post-Approval Study Methods

Study Objective

The purpose of the HW-PAS-03 follow-up study was to continue the evaluation of the longer-term safety and effectiveness of the HeartWare Ventricular Assist System through 5 years in patients who were enrolled in the ADVANCE pivotal study presented above in Section 1.7.

Study Design

This was an observational, prospective study, conducted at multiple study sites with no new enrollment. As, no new patients were screened or implanted with the HeartWare VAS for this study; it is a continued follow-up study only. HW-PAS-03 included, patients who were enrolled from the ADVANCE Trial, and a continuation of that study, known as the continuous access protocol (CAP).

Study Population and Data Source

Patient population

The original ADVANCE cohort implanted 140 bridge-to-transplant (BTT) patients, and the Continued Access from the ADVANCE trial (CAP) implanted 242 additional patients using the same inclusion criteria.

Patients who participated in the prior (BTT and CAP) were approached for participation in this continued follow-up PAS if eligible according to the HW-PAS-03 protocol version 3.0 04Sep2013.

BTT and CAP patients eligible for participation in HW-PAS-03 were:

• Patients who were alive at the start of enrollment for the PAS who either

• were on continued HeartWare VAS support (original or exchange device), or

• had been explanted for transplant or recovery and had not yet completed six months of follow-up.

At the time of enrollment, all surviving patients from the BTT cohort had been followed for at least

37.7 months, and all surviving patients from the CAP cohort had been followed for at least 4.4 months.

A total of 152 subjects (39.8% of the original combined BTT and CAP cohorts) survived to the Premarket approval of the HeartWare VAS, were still enrolled in the original BTT or CAP trials and were therefore eligible for enrollment into HW-PAS-03.

The PAS results below include three main cohorts:

• On Device: Patients in this cohort (N=84) were still on the HeartWare HVAS device upon enrollment into the HW-PAS-03 study.

• All Enrolled: This cohort includes all 101 patients who enrolled into the HW-PAS-03 study. It includes On Device patients (N=84), as well as Off Device patients.

• Off Device patients (N=17) were enrolled into HW-PAS-03 less than six months posttransplant or explant for recovery (no device in the body upon enrollment). These patients only participated in the study through completion of their 6 months’ follow-up.

This PAS does not include 51 patients (33.6% of eligible subjects) from the total BTT+CAP population who were eligible but declined. See Table 11 below for specic reasons.

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1.8 Post Approval Study Follow-up of the Pivotal US Clinical Study:

Bridge-to-Transplant (continued)

Table 11: Reason for Not Participating in HW-PAS-03

Reason

Patients whose eligibility expired: they completed the required 6-month post-explant visit between approval and enrollment

Patient declined participation 12

Patient died between approval and enrollment 8

Site declined participation 7

Patient is lost to follow-up 3

Patient transferred to another non HW-PAS-03 site/moved to another city 2

Patient’s condition did not allow enrollment per PI 1

Enrollment visit could not be performed within the enrollment period 1

Total 51

Key Study Endpoints

Endpoints for this study were observational only. The endpoints assessed included:

• Overall survival on device

• Final patient status

• Re-hospitalizations

• INTERMACS® adverse events

• Quality of Life measures

• Functional Status

Safety measures included the frequency of adverse events, which were collected throughout HeartWare Ventricular Assist System support.

Total Number of

Patients

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Total number of Enrolled Study Sites and Subjects, Follow-up Rate

Summary of Study Progress

HW-PAS-03 protocol approval was received on November 20, 2012.

Enrollment into the study started on January 23, 2013 and was completed on May 23, 2013. A

total of 101 BTT and CAP subjects from 25 sites were enrolled. The study collected its nal data

and was closed on December 20, 2017.

Patient

Management

Alarms and

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Reference

Guides

Appendix

21Introduction

382 BTT+CAP

subjects implanted

27* subjects

explanted

95 subjects

sll on device

157 subjects transplanted

103 subjects

died on device

152 BTT+CAP

subjects eligible

51 subjects

not included

101 subjects

enrolled

84 subjects

sll on device

17 subjects < 6 months

post-transplant

Introduction

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™

HVAD

Peripherals

and

1.8 Post Approval Study Follow-up of the Pivotal US Clinical Study: Bridge-to-Transplant (continued)

Figure 4. Flowchart for Enrollment into HW-PAS-03 Trial

Accessories

*2 subjects had withdrawn consent.

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Surgical

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Patient

Management

Alarms and

Emergencies

Number of Eligible Sites

All 30 sites that participated in BTT and CAP were eligible for participation in HW-PAS-03 . Twenty-

ve of those sites enrolled at least one eligible subject and participated in HW-PAS-03.

The remaining ve centers did not participate in HW-PAS-03. The most frequent reason for not

participating was lack of center resources.

Study visits and length of follow-up

Assessments were conducted at enrollment into HW-PAS-03 and at visits according to the following schedule:

• Subjects enrolled on device (either original device or HeartWare device exchange):

every six months until outcome or ve years post-initial implant of the original device.

• Subjects who were enrolled after being explanted for transplant or recovery: until six months post-explant to record subject status only, at which point participation in the study was considered complete.

Summary of the Post Approval Study Results

A total of 152 subjects were eligible for participation in the HW-PAS-03 study. Of those, 101 (66%) were enrolled; 84 subjects enrolled while still on the HeartWare device, and 17 enrolled posttransplant. Subjects in the All Enrolled cohort (N=101) had rates of complete study visit follow-up between 90.9% - 100%.

Reference

Guides

Appendix

22 HVAD™ Instructions for Use

1.8 Post Approval Study Follow-up of the Pivotal US Clinical Study:

Bridge-to-Transplant (continued)

Table 12: Subject Baseline Demographics

Demographics

Age at enrollment into PAS03 (years)

Gender

Male 73.3% (74/101) 69.0% (58/84) 94.1% (16/17)

Female 26.7% (27/101) 31.0% (26/84) 5.9% (1/17)

Ethnicity

Hispanic or Latino 5.9% (6/101) 6.0% (5/84) 5.9% (1/17)

Non-Hispanic or Non-Latino 94.1% (95/101) 94.0% (79/84) 94.1% (16/17)

Race

White 58.4% (59/101) 54.8% (46/84) 76.5% (13/17)

Black/African American 36.6% (37/101) 40.5% (34/84) 17.6% (3/17)

Asian 1.0% (1/101) 1.2% (1/84) 0.0% (0/17)

American Indian/Native Alaskan 1.0% (1/101) 0.0% (0/84) 5.9% (1/17)

Other 3.0% (3/101) 3.6% (3/84) 0.0% (0/17)

Note: Data is from the original ADVANCE and CAP trials for gender, ethnicity and race. Age is as of consent into the HW-PAS-03 study.

For the All Enrolled cohort, 67 subjects (66%) were alive at the time of completion/exit; 26 (26%) were still implanted with an HVAD (21 on original and 5 post-exchange). 41 (41%) subjects were alive after being explanted for transplant. 34 (34%) subjects had died. On Device subjects spent

42.7 months on average implanted with the device through completion of study follow up (Table

14).

All Enrolled

(N=101)

54.4 ± 12.62 (101)

(22.0, 57.0, 74.0)

On Device

(N=84)

54.8 ± 12.35 (84)

(24.0, 56.0, 74.0)

Off Device

(N=17)

52.3 ± 14.08 (17)

(22.0, 58.0, 67.0)

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Figure 5: Subject Status

Patient

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Reference

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23Introduction

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Explant

1.8 Post Approval Study Follow-up of the Pivotal US Clinical Study: Bridge-to-Transplant (continued)

Table 13: Subject Disposition (all enrolled through 5 years)

Disposition

Alive

On Original Device 21 (20.8%)

Post-Exchange 5 (5.0%)

Post-Explant for Transplant

Post-Explant for Recovery

Dead

On Original Device

Post-Exchange

Post-Explant for Transplant

Post-Explant for Recovery

Table 14: Summary of Duration on Device and In Study (all enrolled)

Parameter

Duration on Original Devicea (months)

Duration on Device (months)

Duration in Study (months)

Note: Numbers are mean ± SD (min, median, max).a Duration on Original Device (months) = date of rst explant/transplant/exchange or last follow up – date of original implant + 1b Duration on Device (months) = date of last explant/transplant or last follow up – date of original implant + 1c Duration on Study (months) = date the subject exited from the study – date of original implant +1

HW-PAS-03

(N=101)

33.6 ± 19.0

(0.1, 31.6, 62.1)

38.1 ± 18.3

(2.5, 41.5, 62.4)

40.5 ± 17.1

(7.8, 44.4, 65.4)

HW-PAS-03

(N=101)

67 (66.3%) 14 (63.6%) 53 (67.1%)

41 (40.6%) 6 (27.3%) 35 (44.3%)

0 (0.0%) 0 (0.0%) 0 (0.0%)

34 (33.7%) 8 (36.4%) 26 (32.9%)

22 (21.8%) 4 (18.2%) 18 (22.8%)

6 (5.9%) 3 (13.6%) 3 (3.8%)

6 (5.9%) 1 (4.5%) 5 (6.3%)

0 (0.0%) 0 (0.0%) 0 (0.0%)

BTT Cohort

(N=22)

39.9 ± 20.0

(0.2, 45.2, 61.5)

53.5 ± 6.9

(41.7, 56.9, 62.4)

55.2 ± 6.6

(43.4, 57.1, 63.4)

BTT Cohort

(N=22)

5 (22.7%) 16 (20.3%)

3 (13.6%) 2 (2.5%)

CAP Cohort

(N=79)

CAP Cohort

(N=79)

31.8 ± 18.4

(0.1, 30.3, 62.1)

33.8 ± 18.2

(2.5, 31.6, 62.1)

36.4 ± 16.8

(7.8, 33.6, 62.1)

Patient

Alarms and

Reference

Appendix

The Kaplan-Meier survival estimates at 5 years for all implanted BTT and CAP subjects (N=382) was 37.1%.

Management

Emergencies

Guides

24 HVAD™ Instructions for Use

1.8 Post Approval Study Follow-up of the Pivotal US Clinical Study:

Bridge-to-Transplant (continued)

Figure 6: Kaplan-Meier Survival on device

Note: Of the 51 subjects who did not rollover into the HW-PAS-03 trial from Table 11, 26 subjects were still eligible to

participate in the post market study at the time exit from the original trials (did not die or complete 6 months posttransplant).Their follow up was censored at the time of last follow up from the pre-market trials.

There was no statistically signicant difference in survival between the BTT and CAP Cohorts,

between males and females, or between white and non-white patients when analyzing the All Enrolled (N=101) cohort, which only includes subjects who enrolled into the HW-PAS-03 trial. The two most common causes of death were device malfunction (seven subjects) and neurological dysfunction (four subjects).

Survival on device from time of consent into HW-PAS-03 for the On Device subjects (N=84) is presented for the subject who were from the BTT cohort (N=21) and CAP cohort (N=63) separately, as all subjects were enrolled into HW-PAS-03 after implant and given the difference between implant times prior to enrollment. Time 0 was the date of consent for the HW-PAS-03 trial and subjects were censored at the earlier time of their last follow up or the end of LVAD support.

Figure 7: Kaplan-Meier Survival on device from enrollment into HW-PAS-03, BTT cohort

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Appendix

25Introduction

Introduction

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Peripherals

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1.8 Post Approval Study Follow-up of the Pivotal US Clinical Study: Bridge-to-Transplant (continued)

Figure 8: Kaplan-Meier Survival on device from enrollment into HW-PAS-03, CAP cohort

Accessories

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Surgical

Implant and

Patient

Management

Alarms and

Emergencies

Quality of life and functional status assessments demonstrated sustained improvements over time. The overall summary score for KCCQ had an average improvement of at least 20 points from baseline at all follow up visits, and the average EQ-5D-5L Visual Analog Scale was greater than 65 at all visits. The 6-minute walk test showed an average increase of at least 90 meters from baseline at all follow-up timepoints. At most timepoints for NYHA, over 80% of the subjects who completed the assessment were improved to a NYHA classes I or II.

For the On Device subjects in this PAS (n=84), the three most common adverse events were infection, device malfunction/failure and bleeding.

Explant

Reference

Guides

Appendix

26 HVAD™ Instructions for Use

1.8 Post Approval Study Follow-up of the Pivotal US Clinical Study:

Bridge-to-Transplant (continued)

Table 15: INTERMACS® adverse events while on a HeartWare device during PAS03* (On Device Subjects)

HW-PAS-03

(N=84)

INTERMACS®

Category Adverse

Events

Total Adverse Events

UADE 0 0 0 0 0 0 0 0 0

Bleeding

ReHospitalization

Re-Operation 1 (1.2%) 1 0.01 1 (4.8%) 1 0.05 0 0 0

Cardiac Arrhythmia

Ventricular 8 (9.5%) 11 0.08 1 (4.8%) 1 0.05

Supraventricular 7 (8.3%) 7 0.05 0 0 0

Device Malfunction/ Failure

Hemolysis 3 (3.6%) 4 0.03 2 (9.5%) 3 0.14 1 (1.6%) 1 0.01

Hepatic Dysfunction

Hypertension 2 (2.4%) 5 0.04 1 (4.8%) 1 0.05 1 (1.6%) 4 0.03

Infection

Localized NonDevice

Sepsis

Driveline Exit Site

Myocardial Infarction

Neurological Dysfunction

Ischemic CVA 6 (7.1%) 7 0.05 2 (9.5%) 2 0.09 4 (6.3%) 5 0.04

Hemorrhagic CVA

TIA 4 (4.8%) 4 0.03 2 (9.5%) 2 0.09 2 (3.2%) 2 0.02

Pericardial Fluid Collection

Psychiatric 8 (9.5%) 8 0.06 1 (4.8%) 1 0.05

Subjects

with

Event

(%)

(89.3%)

(25.0%)

(19.0%)

(21.4%)

(42.9%)

2 (2.4%) 3 0.02 0 0 0 2 (3.2%) 3 0.03

(51.2%)

(14.3%)

(10.7%)

(32.1%)

1 (1.2%) 1 0.01 1 (4.8%) 1 0.05 0 0 0

(19.0%)

(10.7%)

1 (1.2%) 1 0.01 0 0 0 1 (1.6%) 0 0.01

No. of

Events

503 3.67

38 0.28 5 (23.8%) 9 0.42

31 0.23 4 (19.0%) 8 0.38

24 0.17 3 (14.3%) 5 0.24

23 0.17 5 (23.8%) 5 0.24

49 0.36

89 0.65

17 0.12 3 (14.3%) 4 0.19

12 0.09 3 (14.3%) 4 0.19 6 (9.5%) 8 0.07

35 0.26 6 (28.6%) 9 0.42

23 0.17 5 (23.8%) 7 0.33

12 0.09 3 (14.3%) 3 0.14 6 (9.5%) 9 0.08

Event

Rate

per PY

(137.22)

Subjects

Event (%)

(90.5%)

(47.6%)

(66.7%)

with

BTT Cohort

(N=21)

No. of

Events

120 5.65

12 0.57

23 1.08

Event

Rate

per PY

(21.22)

Subjects

with

Event

(%)

(88.9%)

(22.2%)

(17.5%)

(20.6%)

(11.1%)

(41.3%)

(46.0%)

(14.3%)

(33.3%)

(17.5%)

(11.1%)

CAP Cohort

(N=63)

No. of

Events

383 3.30

29 0.25

23 0.20

19 0.16

18 0.16

10 0.09

7 0.06

37 0.32

66 0.57

13 0.11

26 0.22

16 0.14

7 0.06

Event

Rate

per PY

(115.99)

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27Introduction

Introduction

1.8 Post Approval Study Follow-up of the Pivotal US Clinical Study: Bridge-to-Transplant (continued)

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Explant

Table 15: INTERMACS adverse events while on a HeartWare device during PAS03* (On Device Subjects) (continued)

HW-PAS-03

(N=84)

INTERMACS®

Category Adverse

Events

Renal Dysfunction 7 (8.3%) 7 0.05 3 (14.3%) 3 0.14 4 (6.3%) 4 0.03

Acute 7 (8.3%) 7 0.05 3 (14.3%) 3 0.14 4 (6.3%) 4 0.03

Chronic 0 0 0 0 0 0 0 0 0

Respiratory Dysfunction

Right Heart Failure 8 (9.5%) 9 0.07 5 (23.8%) 6 0.28 3 (4.8%) 3 0.03

Inotropic Therapy

RVAD 1 (1.2%) 1 0.01 1 (4.8%) 1 0.05 0 0 0

Inhaled Nitric Oxide

Arterial Non-CNS Thromboembolism

Venous Thromboembolism

Wound Dehiscence

Other

Note: Percentages are based on the number of subjects in the group. Subjects are counted once within each INTERMACS® dened adverse event term. Summarized AEs include emergent AEs, and AEs that occurred while on any HeartWare device (including pre and post-exchange AEs). *Adverse Events that occurred and were not ongoing in the Premarket duration of the BTT and CAP studies are not included in this table.

Subjects

with

Event

(%)

(16.7%)

7 (8.3%) 8 0.06 4 (19.0%) 5 0.24 3 (4.8%) 3 0.03

0 0 0 0 0 0 0 0 0

1 (1.2%) 1 0.01 0 0 0 1 (1.6%) 1 0.01

3 (3.6%) 3 0.02 0 0 0 3 (4.8%) 3 0.03

0 0 0 0 0 0 0 0 0

(72.6%)

No. of

Events

15 0.11 4 (19.0%) 4 0.19

224 1.63

Event

Rate

per PY

(137.22)

Subjects

Event (%)

(76.2%)

with

BTT Cohort

(N=21)

No. of

Events

45 2.12

Event

Rate

per PY

(21.22)

Subjects

with

Event

(%)

(15.9%)

(71.4%)

CAP Cohort

(N=63)

No. of

Events

11 0.09

179 1.54

Event

Rate

per PY

(115.99)

Patient

Alarms and

Reference

Appendix

Management

Emergencies

Guides

Neurological dysfunction in subjects on a HeartWare device included 16 subjects (19.0%)

who had 23 events. Of those, 6 subjects (7.1%) had 7 CT-conrmed ischemic cerebrovascular event’s, 9 subjects (10.7%) had 12 CT-conrmed hemorrhagic cerebrovascular event’s, and 4

subjects (4.8%) had 4 TIAs. The proportion of On Device subjects who experienced neurological dysfunction adverse events was higher in the BTT cohort (23.84%) than the CAP cohort (17.5%).

A total of 89 infection events occurred in 43 subjects (51.2%) while on a HeartWare device. Of those, driveline infections occurred in 27 subjects (32.1%) who had 35 events and 9 subjects (10.7%) experienced 12 sepsis events.

A total of 49 device malfunctions/failure events occurred in 35 subjects (42.9%) while on a HeartWare device during HW-PAS-03 follow up. The most frequent events were related to the

pump, including outow graft and inow cannula issues (18 events, 23.1%) and suspected/ conrmed pump thrombus (9 events, 11.5%). The second most common event type was

controller faults and damage (17 events, 21.8%). Less frequent events included power disconnection, connector issues, electrical faults, and battery issues.

Eight subjects (9.5%) had nine exchanges, with one subject having two exchanges, during HWPAS-03 follow up.

28 HVAD™ Instructions for Use

1.8 Post Approval Study Follow-up of the Pivotal US Clinical Study:

Bridge-to-Transplant (continued)

Most subjects had at least one re-hospitalization, with more than half having three or more re-hospitalizations. The mean cumulative LOS was 45.8 days. The two most common primary reasons for re-hospitalization were adverse event (23 subjects, 77.4%) and explant (8 subjects,

27.4%).

Final safety ndings (key endpoints)

This post approval study followed the long-term safety and effectiveness of IDE trial subjects up

to ve years post original implant. All subjects had at least one re-hospitalization during the HW-

PAS-03 study. The longer term follow up for these subjects (more than three years on average) were associated with, with infections, device malfunctions/failures and bleeding events as the most common type of adverse event.

Final effectiveness ndings (key endpoints)

Of the 101 enrolled subjects, about two-thirds (67 subjects, 66.3%), were still alive at the time of their study exit or HW-PAS-03 study completion/exit. Of those, 41 subjects were alive posttransplant (40.6% of the enrolled subjects) and 26 were alive on support (25.7% of those enrolled). Fewer than 10% of subjects had an exchange during the HW-PAS-03 trial (8 subjects,

9.5%), 27.7% died while on the device (28 subjects), and 5.9% (6 subjects) died less than 6 months post-transplant. Quality of life and functional status measurements improved over time.

Study Strengths and Limitations

There were several strengths to this study. It provided continued follow-up for patients who had received an HVAD System, allowing observation of long-term outcomes in an initial bridge to

transplant approach. Additionally, the nal data demonstrated consistent results regarding

adverse event rate outcomes. A limitation of the study was that only subjects who were still alive on a HeartWare device or post-transplant for less than 6 months were eligible for the HW-PAS-03 trial. Subjects also had varying follow up times prior to enrollment into HW-PAS-03. Additionally, of the 152 eligible subjects, 33% (51/152) of those who potentially could have enrolled into HWPAS-03 did not (e.g., site declined participation, subject declined participation, lost to follow up, etc.). These factors limit the interpretability of longer-term survival and adverse event results, as

the potential for selection bias and the inuence of competing risks must be considered.

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29Introduction

Introduction

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Accessories

1.9 US Clinical Study: Destination Therapy

A. Study Design

Patients in the ENDURANCE trial were enrolled between August 4, 2010 and May 8, 2012. The

database for this Panel Track Supplement reected data collected through June 06, 2016, as

well as some additional updated data from March 27, 2017, and included 451 subjects enrolled at 48 investigational sites.

The trial was a prospective, randomized, controlled, multicenter clinical trial. Subjects were randomly assigned using a permuted block, central randomization scheme, in a 2:1 ratio, to receive either the study (HVAD) or control (HeartMate II) device.

The objective of the trial was to compare the safety and effectiveness of HVAD for destination therapy to the HeartMate II, which is legally marketed in the U.S. for destination therapy, in patients with end-stage heart failure who are ineligible for heart transplantation.

The sample size for formal hypothesis testing was to be determined adaptively. Subjects were to be randomized until 450 subjects were randomized and implanted.

It was pre-specied that after the rst 300 randomized subjects reached the two-year primary

endpoint, the success rate from the control subjects would be assessed. If the observed control

success rate was at least 55%, then the data from the rst 300 subjects would be analyzed. If the

observed control success was less than 55%, then no interim analysis would be performed and the full 450 subjects would be subsequently analyzed. This adaptive sample size for statistical analysis provides at least 90% power to establish non-inferiority.

The ENDURANCE trial was conducted under the oversight of an independent Clinical Events Committee, which adjudicated all the adverse events according to the Interagency Registry of Mechanically Assisted Circulatory Support (INTERMACS®) denitions; and an independent Data Safety Monitoring Board reviewed study compliance and monitored adverse events and outcomes.

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Management

Emergencies

Guides

1. Clinical Inclusion and Exclusion Criteria

Enrollment in the ENDURANCE trial was limited to patients who met the following inclusion criteria:

- Patients ≥18 years old with chronic, advanced left ventricular failure with New York Heart Association (NYHA) functional class IIIB or IV limitations despite optimal medical therapy and were transplant ineligible at the time of enrollment in whom informed consent was obtained.

Patients were not permitted to enroll in the ENDURANCE trial if they met any of the following exclusion criteria:

- Patients eligible for cardiac transplant or with prior cardiac transplant.

- Patients with recent (within 14 days) acute myocardial infarction or stroke within 180 days.

- Patients with a mechanical heart valve.

- Patients with severe right heart failure in whom right ventricular support is anticipated.

- Patients who might be unwilling or unable to comply with the study criteria.

- Additional exclusion criteria available in the Clinical Study Report.

Appendix

30 HVAD™ Instructions for Use

1.9 US Clinical Study: Destination Therapy (continued)

2. Follow-up Schedule

All patients were scheduled to return for follow-up examinations at 3, 6, 12, 18, and 24 months with a window of ± 7days, and at 30, 36, 42, 48, 54, and 60 months with a window of ± 14 days postoperatively.

Preoperative baseline assessments included demographics, medical history, physical examination, concurrent medications, laboratory tests, electrocardiogram (ECG), New

York Heart Association (NYHA) classication, The National Institutes of Health (NIH) stroke

scale, neurocognitive exam, quality of life, and functional status. Postoperative assessments included LVAD parameters, hemodynamics, concurrent medications, laboratory tests, neurocognitive exam, six-minute walk test, NYHA status, and health status.

3. Clinical Endpoints

The primary endpoint was a composite of two-year survival free of disabling stroke (i.e.,

modied Rankin score ≥ 4 assessed 24 weeks post-event), while alive on the originally

implanted device, electively transplanted or explanted due to left ventricular recovery. Success in meeting the primary endpoint was tested for non-inferiority of the experimental group against the control device. The non-inferiority margin of 15% was based on the observed success rate of the control device at >55%. Estimates of stroke-free survival were performed for each treatment using Kaplan-Meier non-inferiority log-rank methodology, comparing study device to control using a one-sided alpha of 0.05; that is, non-inferiority will

be established if the one-sided upper condence limit on the difference in proportions is less

than the non-inferiority margin. Analysis of the primary endpoint was conducted on the Per Protocol (PP) population.

Patients were considered a success if at 730 days post implantation, the subject was alive,

did not have a stroke of mRS ≥ 4 assessed 24 weeks post-stroke, and remained on the

originally implanted device, unless the device was removed due to heart recovery, or the subject was electively transplanted. Patients were considered a failure if at 730 days post

implantation, they expired, had a stroke with a modied Rankin score ≥ 4 assessed 24 weeks

post-stroke, or were urgently transplanted or had surgery for LVAD removal or replacement due to failure of the original device.

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There were seven (7) secondary endpoints, of which the following three (3) were to be

assessed inferentially to test for superiority in a xed-sequence procedure if non-inferiority

was established for the primary endpoint: incidence of bleeding (per INTERMACS®

denition), incidence of major infections (per INTERMACS® denition), and overall survival (time to death). In addition, a number of subgroup analyses were pre-specied, including

gender and BSA (<1.5 m2 vs. ≥1.5 m2).

Alarms and

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Reference

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Appendix

31Introduction

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1.9 US Clinical Study: Destination Therapy (continued)

B. Accountability of PMA Cohort

Pre-specified Interim Analysis

Per the pre-specied analysis plan, the interim analysis cohort (N=300) was to serve as the

principal analysis cohort if the Control group success rate for the primary endpoint was at least 55%; as shown below, the observed success rate for the Control group was 59%. A total of 451 patients (inclusive of the initial 300 patients) were enrolled, of which 445 were implanted with a

device. This summary presents the ENDURANCE trial results using both the pre-specied interim

analysis and full enrollment cohorts. FDA considered the interim analysis to be the principal analysis of the ENDURANCE trial, but considered all analyses when evaluating the safety and effectiveness of the HVAD. The analyses from the full enrollment cohort are included in the Other Results section.

At the time of database lock for the interim analysis 100% of the pre-specied interim analysis

cohort (300 patients) had been followed through the 2-year primary endpoint time point. The disposition of the patients is shown in Figure 9.

The Randomized population (HVAD N=200 and Control N=100) included all subjects who were consented (Intent-to-Treat (ITT)) and then enrolled in the study.

The Anesthetized Population (AP) included all randomized subjects who receive induction of anesthesia for implantation.

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The Anesthetized and Implanted Population (AIP) population, equivalent to an As Treated population, consisted of all randomized subjects who received induction of anesthesia for implantation and received an implant of an LVAD. In the full cohort (N=445), four (4) patients crossed over from HVAD to Control and three (3) patients crossed over from Control to HVAD after randomization but before receiving a device, and one (1) patient in the Control arm did not receive any device. As such, the AT population for the interim analysis consists of 300 patients, 197 in the HVAD arm and 103 in the Control arm.

Explant

The Per Protocol (PP) population included all subjects in the AIP population analyzed according

to the LVAD to which they were randomized. This denition is more consistent with the ICH denition of what a modied ITT population would be.

The Inclusion Compliant (IC) population included all randomized subjects who received the LVAD to which they were randomized and who did not violate certain inclusion and exclusion criteria that would likely have an effect on outcome.

The primary analysis was performed on the Per Protocol (PP) population. All safety analyses were performed on the AIP population.

Reference

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Appendix

32 HVAD™ Instructions for Use

1.9 US Clinical Study: Destination Therapy (continued)

Figure 9: Disposition of First 300 Subjects in the ENDURANCE Trial

Randomized Subjects

N = 300

Received HeartWare

Device

N = 197

Did not complete

ﬁrst 2 Years

N = 85

Death

N = 83

HeartWare N = 200

(96 Non-Sintered,

104 Sintered)

Voluntary

Withdrawal

N = 2

Completed ﬁrst

2 Years

N = 115

Did not complete

ﬁrst 2 Years

N = 32

Death N = 32

Control N = 100

Voluntary

Withdrawal

N = 0

Received Control

Device

N = 103

Completed ﬁrst

2 Years

N = 68

C. Study Population Demographics and Baseline Parameters

The demographics and baseline characteristics, as summarized in Table 16, are typical for an

LVAD study performed in the U.S. The HVAD and Control groups did not differ signicantly.

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Table 16: Patient Demographics and Baseline Characteristics in the rst 300 Subjects in the

Explant

ENDURANCE Trial

Demographics and Baseline

Characteristics

Age (years) 64.4 ± 12.0 66.1 ± 10.4 0.25

Male gender (%) 77.5% 80.8% 0.66

Race (%)

White

Black or African American

Other

Height (cm) 173.5 ± 9.8 175.2 ± 9.3 0.15

Body Surface Area (m2) 2.0 ± 0.3 2.0 ± 0.3 0.98

INTERMACS Prole (%)

5-7

Ischemic Etiology of Heart Failure 59.5% 59.0% > 0.99

HVAD

(N=200)

79.5%

19.5%

1.0%

3.5%

27.5%

39.5%

21.5%

8.0%

Control

(N=100)

75.0%

25.0%

0.0%

1.0%

38.0%

41.0%

13.0%

7.0%

P-value

0.37

0.17

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D. Safety and Effectiveness Results

1. Primary Endpoint

The pre-specied interim analysis was conducted on the rst 300 patients to reach two (2)

years post implantation. The Kaplan-Meier estimate for stroke-free success at 2 years for the Control arm was 59.0%; as such, the interim analysis represented the primary analysis for the ENDURANCE trial. The Kaplan-Meier estimate for stroke-free success at 2 years for the HVAD arm was 51.1%. The results of the interim analysis are shown in Figure 10. The upper bound

of the condence interval around the difference exceeded the 15% non-inferiority margin

(17.9%), resulting in a p-value of 0.1219. The interim analysis showed that the trial failed to demonstrate non-inferiority of the HVAD to the Control.

Figure 10: ENDURANCE Trial Primary Endpoint. Survival at 2 years free from disabling stroke (mRS ≥ 4)

and alive on the originally implanted device, or transplanted or explanted for recovery.

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A binary analysis from the pre-specied interim analysis is presented in Table 17.

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34 HVAD™ Instructions for Use

1.9 US Clinical Study: Destination Therapy (continued)

Table 17: Binary Analysis of the Primary ENDURANCE Endpoint and its Components for Subjects

Receiving Study or Control Device

Event Free Survival at 2 years

Success 51.5% (103) 59 (59.0%)

Failure 48.5% (97) 41.0% (41)

If Failure, reason:

Patient dies 35.5% (71) 25.0% (25)

Device malfunction or failure requiring exchange, explant or urgent transplant

Exchange

Explant

Urgent Transplant

Disabling stroke

(mRS ≥ 4 at 24 weeks)

Imputed failure* 0.5% (1) 0.0% (0)

A subject may have multiple reasons for not completing the rst two (2) years, only the rst failure type for each subject is specied.

*Patient experienced a stroke prior to their 2-year endpoint, and died beyond the 2 year endpoint, but before the 24 week mRS assessment.

HVAD

(N=200)

11.0% (22)

9.5% (19)

0.0% (0)

1.5% (3)

1.5% (3) 0.0% (0)

Control

(N=100)

16.0% (16)

14.0% (14)

0.0% (0)

2.0% (2)

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2. Secondary Endpoints

Because the primary endpoint was not met per the pre-specied interim analysis, the

hypotheses associated with the secondary endpoints of incidence of bleeding (per INTERMACS® denition), incidence of major infections (per INTERMACS® denition), and overall survival (time to death) could not be tested. As such, the secondary endpoints were not reported.

3. Other Results - Adjunctive analysis: Primary Endpoint Using Expanded Dataset

Following the interim analysis at 300 patients, the trial was expanded to enroll additional patients to further investigate various device, procedural, and clinical changes introduced during the trial. A total of 451 patients (inclusive of the initial 300 patients) were enrolled, of which 445 were implanted with a device. The patient disposition is summarized in Figure

11.The results of the expanded dataset are summarized below.

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Figure 11: Disposition of Subjects in the ENDURANCE Expanded Dataset

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The demographics and baseline characteristics of the ENDURANCE expanded dataset is summarized in Table 18. The demographics and baseline characteristics are typical for an LVAD

study performed in the U.S. The HVAD and Control groups did not differ signicantly with respect

to severity of illness, baseline hemodynamic characteristics, or treatment with evidence-based

Explant

therapy for heart failure at the time of enrollment. However, subjects in the control group were slightly older (66.2 versus 63.9, control versus HVAD, P=0.04).

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1.9 US Clinical Study: Destination Therapy (continued)

Table 18: Patient Demographics and Baseline Characteristics of the ENDURANCE Expanded

Dataset

Demographics and Baseline

Characteristics

Age (years) 63.9 ± 11.6 66.2 ± 10.2 0.044

Male gender (%) 76.4% 82.4% 0.178

Race (%)

White

Black or African American

Other

Height (cm) 173.8 ± 9.4 175.5 ± 9.1 0.068

Body Surface Area (m2) 2.0 ± 0.3 2.0 ± 0.3 0.615

INTERMACS Prole (%)

5-7

Ischemic Etiology of Heart Failure 57.9% 60.1% 0.684

Smoker 68.0% 62.2% 0.243

Diabetic 44.4% 43.9% > 0.999

Previous Stroke/TIA 19.2% 16.2% 0.515

Hypertension requiring medication 65.3% 70.9% 0.241

Serum creatinine (mg/dL) 1.5 ± 0.5 1.4 ± 0.5 0.760

Severe tricuspid valve insufciency

Left ventricular ejection fraction (LVEF, %) 17.1 ± 4.6 16.2 ± 4.8 0.055

HVAD

(N=297)

76.8%

22.2%

1.0%

3.4%

29.0%

40.4%

19.9%

7.4%

12.0%

(N=292)

Control

(N=148)

77.7%

21.6%

0.7%

3.4%

31.1%

40.5%

18.2%

6.8%

5.5%

(N=146)

P-value

0.962

0.989

0.040

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Survival free from disabling stroke (mRS ≥4) and alive on the originally implanted device, or

transplanted or explanted for recovery for the complete ENDURANCE population is shown below in Figure 12. The expanded dataset includes a higher proportion of HVAD devices

having titanium-sintered inow cannulae, a device modication that was introduced during

ENDURANCE and designed to decrease thromboembolic adverse event rates. Post hoc oneyear comparisons of all sintered HVADs (pooled from both ENDURANCE and ENDURANCESupplemental) to pooled Control subjects were also performed, as shown in Figure 12.

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Figure 12: ENDURANCE Trial Expanded Dataset: Survival free from disabling stroke (mRS ≥4) and alive on

the originally implanted device, or transplanted or explanted for recovery in the overall study dataset.

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The post hoc comparison of sintered and non-sintered HVAD™ Pumps in the interim analysis cohort did not demonstrate markedly different results (See Figure 13A, 13B).

Figure 13: Comparison of Outcomes from the Interim analysis of Subjects with Sintered Pumps Compared to

Control: Survival free from disabling stroke (mRS ≥4) and alive on the originally implanted device,

or transplanted or explanted for recovery in A) the subset of subjects receiving a sintered HVAD ™ Pump, compared to Control, and in B) the subset of subjects receiving the non-sintered

Explant

HVAD™ Pump. This analysis is based on the as-treated population.

A) Sintered:

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38 HVAD™ Instructions for Use

1.9 US Clinical Study: Destination Therapy (continued)

B) Non-Sintered:

Table 19: Binary Analysis of ENDURANCE Expanded Dataset: Survival at 2 years free from

disabling stroke (mRS ≥4) and alive on the originally implanted device, or transplanted

or explanted for recovery.

Event Free Survival at 2 years

Success 55.2% (164) 57.4% (85)

Failure 44.8% (133) 42.6% (63)

If Failure, reason:

Patient dies 34.7% (103) 26.4% (39)

Device malfunction or failure requiring exchange, explant or urgent transplant

Exchange

Explant

Urgent Transplant

Disabling stroke

(mRS ≥ 4 at 24 weeks)

Imputed failure* 0.3% (1) 0

HVAD

(N=297)

8.8% (26)

7.7% (23)

0.0% (0)

1.0% (3)

1.0% (3) 0

Control

(N=148)

16.2% (24)

13.5% (20)

0.7% (1)

2.0% (3)

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A subject may have multiple reasons for not completing the rst two (2) years, only the rst failure type for each subject is specied.

*Patient experienced a stroke prior to their 2-year endpoint, and died beyond the 2 year endpoint, but before the 24 week mRS assessment.

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In the analyses presented on the entire ENDURANCE trial cohort, the secondary endpoints were analyzed and descriptive data include the following:

• The incidence of bleeding was 60.1% for the HVAD compared to 60.4% for the Control.

• The incidence of major infections was 69.3% for the HVAD and 62.4% for the Control.

• Overall survival was 60.2% for the HVAD and 67.6% for the Control.

The CEC adjudicated causes of death for the entire ENDURANCE trial cohort are shown in Table 20.

Table 20: ENDURANCE Expanded Dataset Cause of CEC Adjudicated on Device Death within 730

days (AIP as Received)

Cause of Death

Total 38.5% (114) 30.9% (46)

Bleeding 0.3% (1) 0.7% (1)

Cardiovascular procedure 1.4% (4) 1.3% (2)

Heart failure 16.2% (48) 14.8% (22)

Infection 3.0% (9) 2.7% (4)

Malignancy 1.4% (4) 0.7% (1)

Multisystem organ failure 0.0% (0) 0.7% (1)

Respiratory failure 0.0% (0) 0.7% (1)

Stroke 8.4% (25) 6.0% (9)

Sudden death 3.7% (11) 2.0% (3)

Trauma 0.7% (2) 0.0% (0)

Other cardiovascular 2.7% (8) 1.3% (2)

Other non-cardiovascular 0.7% (2) 0.0% (0)

HVAD

(N=296)

Control

(N=149)

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40 HVAD™ Instructions for Use

1.9 US Clinical Study: Destination Therapy (continued)

Overall survival for the ENDURANCE trial expanded dataset beyond the two (2) year timepoint is included below in Figure 14. Aggregate 5-year mortality results for all ENDURANCE subjects were similar.

Figure 14: Kaplan Meier Survival (Time to Death) in ENDURANCE through 5 years (PP, Per Protocol).

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Adverse events

The key safety/adverse event outcomes for the ENDURANCE trial expanded dataset are presented in Table 21 below. Patients in the HVAD arm had a higher rate of ischemic and hemorrhagic stroke, sepsis, and right heart failure compared to control. An analysis of the patient-level data indicated that elevated blood pressure appeared to be a risk factor for stroke, particularly hemorrhagic stroke.

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Table 21: Summary of INTERMACS® Adverse Events Occurring Through 2 Years in Subjects in the

ENDURANCE Trial Expanded Dataset

Adverse Event

Overall Bleeding events GI Bleed

Cardiac Arrhythmia 37.8% (112) 40.9% (61)

Hepatic Dysfunction 4.7% (14) 8.1% (12)

Hypertension 15.9% (47) 16.8% (25)

Sepsis 23.6% (70) 15.4% (23)

Driveline Exit Site Infection 19.6% (58) 15.4% (23)

Stroke

Ischemic Cerebrovascular Event

Hemorrhagic Cerebrovascular Event

TIA

Renal Dysfunction 14.9% (44) 12.1% (18)

Respiratory Dysfunction 29.1% (86) 25.5% (38)

Right Heart Failure Need for RVAD*

Pump Replacement Exchange for Pump Thrombosis

Device Malfunction or Failure 31.4% (93) 25.5% (38)

HVAD

(N=296)

60.1% (178)

35.1% (104)

29.7% (88)

17.6% (52)

14.9% (44)

8.4% (25)

38.5% (114)

2.7% (8)

7.8% (23)

6.4% (19)

Control

(N=149)

60.4% (90)

34.2% (51)

12.1% (18)

8.1% (12)

4.0% (6)

4.7% (7)

26.8% (40)

3.4% (5)

13.4% (20)

10.7% (16)

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*Site-reported event.

Abbreviations: GI - gastrointestinal; RVAD=right ventricular assist device; TIA= transient ischemic attack (<24 hours). Note: The event of device thrombosis reported is not an INTERMACS®-dened event.

Explant

Stroke-related Deaths

Per CEC adjudication, among the full AIP population 12.5% (37/296) of HVAD patients and

6.7% (10/149) of Control patients had stroke-related deaths (data lock date of May 30, 2017, all patients with follow-up > 4 years or censored). HVAD subjects in the ENDURANCE trial had a risk of death from stroke that was 87% greater than the risk of Control patients. The rate of strokerelated death within 2 years of implantation was 8.4% (25/296) for HVAD patients and 6.0% (9/149) for Control patients. The rate of later-onset stroke-related death (i.e., stroke occurring after 2 years of LVAD support) was 3.7% (11/296) for HVAD patients and 0.7% (1/149) for Control patients. The majority of HVADs which were involved with stroke-related deaths had sintered inlet cannulae.

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1.9 US Clinical Study: Destination Therapy (continued)

Device Failures and Malfunctions

The incidence of device failures and device malfunctions within 730 days was 31.4% in the HVAD arm vs. 25.5% in the Control arm. The rates of pump thrombosis were similar in both arms, though sintering of the HVAD did appear to decrease this event. Device malfunctions related to controller faults were substantially more frequent in the HVAD arm.

Table 22: Device Failure or Malfunctions in the ENDURANCE Trial Expanded Dataset

HVAD

Parameter

Based on CEC Adjudication Data

Device Failure 30.5% (61) 33.3% (32) 25.5% (38)

Type of Device Malfunction

Controller fault 10.0% (20) 7.3% (7) 2.7% (4)

Critical low battery 0.0% (0) 1.0% (1) 0.7% (1)

Damaged battery 1.0% (2) 0.0% (0) 0.0% (0)

Damaged cable 2.5% (5) 3.1% (3) 4.0% (6)

Damaged controller 2.0% (4) 3.1% (3) 0.0% (0)

Electrical fault 2.0% (4) 0.0% (0) 0.0% (0)

Iatrogenic/Recipient-Induced Failure

Insufcient battery charging 1.5% (3) 1.0% (1) 0.0% (0)

Power disconnect 2.5% (5) 0.0% (0) 1.3% (2)

Pump 0.0% (0) 0.0% (0) 2.7% (4)

Pump Thrombosis 10.0% (20) 22.9% (22) 11.4% (17)

Other 4.5% (9) 1.0% (1) 3.4% (5)

Sintered (N=200)

0.5% (1) 0.0% (0) 0.7% (1)

HVAD

Non-Sintered

(N=96)

Control

(N=149)

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Rehospitalizations

The average number of re-hospitalizations within 730 days after the initial hospitalization was similar between the HVAD arm and the Control arm, as shown in Figure 15. For the AIP population, the HVAD subjects were re-hospitalized on average, 4.1 times, compared to 3.6 times in the Control group.

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Figure 15: Average Number of Rehospitalizations over Two Years in the ENDURANCE Trial Expanded Dataset

Accessories

Functional Status

Functional status was assessed by the NYHA class and the 6-minute walk test (6MWT), as shown in Figures 16 and 17. Following LVAD implant, approximately 70-80% of subjects in both arms improved to NYHA class I or II by Month 12. The median baseline 6-minute walk distance (6MWD) was 0 meters for both study and control subjects. At 3 months following LVAD implant, 6MWD increased to a median of 210 meters and 201 meters for study and control subjects, respectively. These improvements were sustained through two (2) years.

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Figure 16: ENDURANCE Trial Expanded Dataset Six-Minute Walk Test

Explant

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1.9 US Clinical Study: Destination Therapy (continued)

Figure 17: ENDURANCE Trial Expanded Dataset NYHA Classication Improvement

Quality of Life

The quality of life was assessed by the EQ-5D-5L and the KCCQ questionnaires, as summarized in Figure 18. At baseline, subjects in both cohorts had poor quality of life and health status assessed by KCCQ and EuroQOL EQ-5D. At 3 months, median KCCQ score had improved by

27.3 points and 24.2 points for study and control subjects, respectively. EuroQOL EQ-5D VAS improved an average of 1.6 points at 3 months for subjects in the study arm and 1.7 points at 3 months for subjects in the control arm. Improvements in KCCQ and EuroQOL EQ-5D were sustained during the follow-up period.

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Figure 18: Improvements in Quality of Life and Functional Capacity in the ENDURANCE Trial Expanded

Dataset. A) Change over time of the KCCQ Overall Summary Score. B) Change over baseline in the EQ-5D Visual Analog Scale.

A. KCCQ

100.0

80.0

60.0

40.0

20.0

Overall Summary Score

0.0

HVAD

Control

3 monthBaseline

6 month 12 month 24 month

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B. EQ-5D

3.0

2.5

2.0

1.5

1.0

0.5

Change from Baseline

0.0

Subgroup Analyses

The following preoperative characteristics were evaluated for potential association with outcomes: gender, and BSA (< 1.5 m2, ≥ 1.5 m2). The pre-specied sub-group analyses showed no major clinical differences in outcomes based on gender or BSA.

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6 months 12 months 24 months

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Conclusions from the ENDURANCE Destination Therapy Trial

The ENDURANCE trial did not meet its pre-specied primary endpoint, a demonstration of non-

inferiority of the HVAD to the control device for patients alive on original device at two (2) years free from disabling stroke (mRS >4). However, an adjunctive analysis using the full-enrollment

Explant

dataset demonstrated similar endpoint results, with 57.4% success for control and 55% success for HVAD. Following LVAD implant, approximately 80% of subjects in both arms improved to NYHA class I or II symptomatology. At 3 months following LVAD implant, median 6 minute walk distance increased in both arms (210 meters and 201 meters for study and control subjects, respectively). Patients in both arms also showed comparable improvement in quality of life from baseline to 3 months as measured by EQ-5D-5L and KCCQ, and the results were sustained through 2 years.

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46 HVAD™ Instructions for Use

1.10 Destination Therapy Supplemental Study

A. Study Design

The objective of the ENDURANCE Supplemental trial was to evaluate the safety and effectiveness of a prospective blood pressure management strategy in HVAD DT patients. The purpose of implementing the prospective blood pressure management strategy was to investigate its effect on the stroke rates in HVAD subjects. The trial was a prospective, randomized, controlled, un-blinded, multicenter clinical study. Subjects were randomly assigned using a permuted block, central randomization scheme, in a 2:1 ratio, to receive either the study (HVAD) or control (HeartMate II) device. All HVAD subjects, in addition to receiving standard of care management, were required to adhere to a blood pressure management protocol

that aimed to maintain mean arterial pressure (MAP) ≤ 85 mmHg (automated pneumatic cuff

method) or < 90 mmHg (Doppler cuff method). Control patients were not managed with a blood pressure management protocol.

Patients in the ENDURANCE Supplemental trial were enrolled between October 25, 2013 and August 7, 2015. 475 subjects were randomized, with 465 patients implanted at 47 investigational sites.

Similar to the ENDURANCE trial, the ENDURANCE Supplemental trial was conducted under the oversight of an independent Clinical Events Committee and monitored by an independent Data Safety Monitoring Board.

1. Clinical Inclusion and Exclusion Criteria

Enrollment in the ENDURANCE Supplemental trial was limited to patients who met the same inclusion and exclusion criteria as in the ENDURANCE trial.

2. Follow-up Schedule

All patients were scheduled to return for follow-up examinations at 3 and 6 months with a window of ± 7 days, at 12 months with a window of + 7 days, and at 18, 24, 30, 36, 42, 48, 54, and 60 months with a window of ± 14 days postoperatively.

The pre- and post-operative assessments were the same the in the ENDURANCE trial.

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3. Clinical Endpoints

The primary endpoint was the incidence of neurologic injury at 12 months. Neurologic injury

was dened as an ICVA or HCVA with mRS > 0 at 24 weeks post-stroke, or a TIA, or as a

spinal cord infarct (SCI).

The HVAD was to be considered non-inferior to the HeartMate II if the upper bound of the

two-sided 90% exact binomial condence interval of the difference in the primary endpoint

between the HVAD arm and the control arm was less than 6%.

There were two secondary endpoints. The rst secondary endpoint was incidence of HVAD

stroke and TIA by 12 months on the originally implanted HVAD. Unlike the primary endpoint,

this secondary endpoint included those strokes that were classied as mRS=0 at 24 weeks

post-stroke. This endpoint was to be tested by comparison to a performance goal of 17.7%;

the performance goal was equivalent to the lower 95% condence interval of the one-year

stroke/TIA rate among sintered HVAD patients in the ENDURANCE trial.

The second secondary effectiveness endpoint was analogous to the ENDURANCE trial’s primary endpoint, in that it compared the composite of stroke-free (mRS < 4 at 24 weeks post-stroke) survival while on the original device between HVAD and Control arms; however, the time point for this endpoint was one year, unlike the ENDURANCE trial’s 2-year endpoint. This endpoint was to test for non-inferiority of the HVAD to the control device, with a non-inferiority margin of 15%.

Additional endpoints included adverse events, device malfunctions and failures, as well as health status and functional improvements.

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B. Accountability of PMA Cohort

At the time of database lock, of the 494 patients enrolled in the ENDURANCE Supplemental trial,

93.7% (463) patients were available for analysis of the primary objective at the completion of the study, the 12-month post-operative visit. The disposition of the patients is shown in Figure 19.

Figure 19: Disposition of Subjects in the ENDURANCE Supplemental Trial

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The Modied Intent-to-Treat Population (mITT; Total N=465; HVAD, N=308 and Control, N=157)

included all subjects who received a device. It was analyzed according to the device to which the subjects were randomized.

All safety analyses were performed on the safety population (SAF), which assigned subjects to the device they actually received. The SAF was equivalent to the mITT population.

The Complete Case Population includes all subjects in the mITT population except those who withdraw, are lost to follow-up, or have missing outcomes (any subject with missing post-event mRS) on original device. It differs for each objective. For the primary endpoint, the Complete

Case Population was dened as the mITT population excluding any subjects who withdrew or

were lost to follow-up, and any subjects who were missing CEC adjudicated mRS scores (both day of event and 24 weeks post-event) for the latest stroke event on original device. For the secondary endpoint of stroke/TIA incidence at 12 months on the originally implanted HVAD,

the Complete Case Population was dened as the mITT population excluding the subjects who

withdrew or were lost to follow-up. For the secondary endpoint of stroke-free success (mRS < 4

at 24 weeks post-stroke) at 12 months, the Complete Case Population was dened as the mITT

population excluding subjects who withdrew or were lost to follow-up, and those subjects who were missing a 24 week mRS score for their last stroke on original device (within 1 year post original implant).

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1.10 Destination Therapy Supplemental Study (continued)

C. Study Population Demographics and Baseline Parameters

The demographics and baseline characteristics of the study population, as summarized in Table 23, are typical for an LVAD study performed in the U.S. The baseline characteristics of the two

(2) arms were similar; there was no clinically signicant difference in the severity of illness or

treatments at the time of enrollment.

Table 23: Patient Demographics and Baseline Characteristics in the ENDURANCE Supplemental Trial.

Demographics and Baseline

Characteristics

Age (years) 63.3 ± 11.4 64.2 ± 11.1 0.39

Female gender (%) 18.2% 20.4% 0.62

Race (% White) 71.8% 75.2% 0.51

Height (cm) 175.0 ± 9.4 175.1 ± 9.8 0.91

Body Mass Index (kg/m2) 28.2 ± 5.5 27.4 ± 5.2 0.13

INTERMACS Prole (%)

4-7

Ischemic Etiology of Heart Failure 55.2% 58.0% 0.62

History of smoking 68.2% 65.6% 0.60

Diabetic 49.4% 48.4% 0.92

Previous Stroke 10.4% 8.3% 0.51

Hypertension requiring medication 75.0% 72.0% 0.50

Atrial Fibrillation 50.6% 51.0% > 0.99

Mean arterial blood pressure (mmHg)

Tricuspid regurgitation (≥ moderate)

Left ventricular ejection fraction (LVEF, %) 17.3 ± 5.1 18.2 ± 4.5 0.07

Previous intervention (%)

ICD

CRT

IABP

Abbreviations: CRT=cardiac resynchronization therapy; ICD=implantable cardioverter debrillator; LVEF=left

ventricular ejection fraction.

Note: P-values are post-hoc and are included for information purposes only.

P-values comparing categorical values are from the Fisher’s Exact Test. P-values comparing continuous values are from a two-sample t-test.

HVAD

(N=308)

3.9%

32.8%

43.3%

20.0%

78.9 ± 11.5 (N=296)

40.4%

(N=302)

80.8%

28.9%

19.2%

Control

(N=157)

2.5%

32.5%

43.3%

21.7%

77.6 ± 11.1 (N=153)

44.2%

(N=154)

82.2%

28.7%

15.9%

P-value

0.90

0.23

0.48

0.80

> 0.99

0.45

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1.10 Destination Therapy Supplemental Study (continued)

D. Safety and Effectiveness Results

1. Primary Endpoint

The outcome and analysis of the primary endpoint are shown in Table 24 and Figure 20.

The results show that 14.7% of the HVAD subjects experienced endpoint-dened neurologic

injury as compared to 12.1% of the control subjects, with a difference of 2.6% between the

two arms. The upper bound of the two-sided 90% exact binomial condence interval of the difference in the neurologic injury incidence was 10.7%, which was above the pre-specied

non-inferiority margin of 6%. Thus, the primary endpoint of the ENDURANCE Supplemental trial was not met.

Table 24: Analyses of the Primary Endpoint

HVAD

(N=306)

Number of subjects who had a stroke/TIA at 12 months 58 24

Number of subjects who had a stroke at 12 months 51 23

Number of subjects who had a TIA at 12 months

Number of subjects who had mRS > 0 at 24 weeks post-stroke

Number of subjects who had spinal cord infarction at 12 months

Number of subjects with endpoint-dened

neurologic injury events at 12 months

Difference of neurologic injury incidence

Two-sided 90% condence interval

Non-inferiority criteria

p-value

13 1

38 18

0 0

45 (14.7%) 19 (12.1%)

2.6%

[-5.5%, 10.7%]

Fail

0.1444

Control

(N=157)

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Figure 20: ENDURANCE Supplemental Trial Primary Endpoint Survival

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50 HVAD™ Instructions for Use

1.10 Destination Therapy Supplemental Study (continued)

2. Secondary Endpoints

Because the primary endpoint was not met, the hypotheses associated with the secondary endpoints of stroke/TIA incidence and stroke-free success rate could not be tested. Thus, only descriptive data are presented for the two secondary endpoints.

The incidence of stroke/TIA (inclusive of strokes with mRS = 0 at the 24 week time point) in HVAD patients was 19.2% at 12 months. The Time to event curve is shown in Figure 21.

Figure 21: ENDURANCE Supplemental Trial Survival Free from Stroke or TIA

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The proportion of subjects who survived to one year on the original device in the absence of

“disabling” stroke (mRS ≥4), death, device exchange or urgent transplantation was 75.3% in the

HVAD arm and 66.7% in the Control arm. A freedom from event analysis is shown in Figure 21, using data from March 27, 2017. The magnitude of the rate differential for this composite decreased with follow-up more analogous to the ENDURANCE trial’s 2-year endpoint time frame.

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Figure 22: ENDURANCE Supplemental Trial Survival Free from Death, Disabling Stroke or Device Malfunction/

Failure Requiring Exchange

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In the ENDURANCE Supplemental trial, freedom from ischemic stroke was numerically greater in the Control arm, as shown in Figure 22; freedom from hemorrhagic stroke was similar in HVAD and Control, as shown in Figure 23.

Figure 23: ENDURANCE Supplemental Trial Survival Free from Ischemic Stroke

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52 HVAD™ Instructions for Use

1.10 Destination Therapy Supplemental Study (continued)

Figure 24: ENDURANCE Supplemental Trial Survival Free from Hemorrhagic Stroke

3. Adverse Events

Table 25 lists all the adverse events that occurred in the safety cohort.

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Table 25: Summary of Adverse Events at 1 Year in the ENDURANCE Supplemental Trial.

Adverse Event

Major Bleeding 51.6% (159) 56.7% (89)

Cardiac Arrhythmia 34.1% (105) 31.2% (49)

Hepatic Dysfunction 3.9% (12) 3.8% (6)

Hypertension 13.0% (40) 12.7% (20)

Major Infection 53.9% (166) 59.2% (93)

Driveline Exit Site Infection 16.2% (50) 12.1% (19)

Device Malfunction/Failure 24.0% (74) 24.2% (38)

Hemolysis 1.3% (4) 5.7% (9)

Stroke

Ischemic Cerebrovascular Event

Hemorrhagic Cerebrovascular Event

TIA

Renal Dysfunction 10.4% (32) 14.6% (23)

Respiratory Failure 19.8% (61) 19.7% (31)

Right Heart Failure 35.4% (109) 38.2% (60)

Pump Replacement 5.2% (16) 11.5% (18)

Exchange for Pump Thrombosis 4.5% (14) 10.2% (16)

HVAD

(N=308)

16.9% (52)

13.0% (40)

5.2% (16)

4.2% (13)

Control

(N=157)

14.6% (23)

7.6% (12)

7.0% (11)

0.6% (1)

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1.10 Destination Therapy Supplemental Study (continued)

Stroke-related Deaths

Within the mITT population, the CEC-adjudicated rate of stroke-related death within 1 year of implantation was 3.2% (10/308) for HVAD patients and 2.5% (4/157) for Control patients.

Comparing the results of ENDURANCE and ENDURANCE Supplemental, the rates of strokerelated death decreased by the same proportions (approximately 58%) for both HVAD and Control arms; only the HVAD arm was exposed to the trial’s investigational intervention of a blood pressure management protocol. The stroke-related deaths are compared in Table 26. The MAP over time from the ENDURANCE Supplemental trial for the HVAD compared to the Control is shown in Figure 25.

Table 26: Stroke-related Deaths in ENDURANCE and ENDURANCE Supplemental Trials

HVAD

HMII (control)

ENDURANCE

Within 2 years of implant (AIP)

25/296 (8.4%) 10/308 (3.2%)

9/149 (6.0%) 4/157 (2.5%)

ENDURANCE Supplemental

Within 1 year of implant (mITT)

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Figure 25: ENDURANCE Supplemental Trial MAP over Time

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Health Status and Functional Improvements

The improvements in quality of life, as measured by the KCCQ and EQ-5D-5L, and functional capacity, as measured by the 6 minute walk test and NYHA Class improvement, in the ENDURANCE Supplement trial patients are presented in Figure 26.

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54 HVAD™ Instructions for Use

1.10 Destination Therapy Supplemental Study (continued)

Figure 26: Improvements in Quality of Life and Functional Capacity in ENDURANCE Supplemental Subjects.

A) Change over time of the KCCQ Overall Summary Score. B) Change over time in the EQ-5D Visual Analog Scale. C) Change over time of total distance walked in the Six Minute Walk Test. D)

Percent of patients with 2 or more class increase in NYHA Classication at 12 months compared

to baseline.

A. KCCQ

B. EQ-5D

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1.10 Destination Therapy Supplemental Study (continued)

C. Six-Minute Walk

D. NYHA Classication Improvement

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Figure 27: Average Number of Rehospitalizations in the First-Year Post Implant in the ENDURANCE

Supplemental Trial

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56 HVAD™ Instructions for Use

1.10 Destination Therapy Supplemental Study (continued)

Subgroup Analyses

The following preoperative characteristics were evaluated for potential association with outcomes: gender, BSA (<1.5 m2, ≥1.5 m2). No associations to outcomes of the primary and secondary endpoints were found for these two preoperative characteristics.

Conclusions from the ENDURANCE Destination Therapy Supplemental Trial

The ENDURANCE Supplemental trial did not meet its pre-specied primary endpoint, a

demonstration of non-inferiority of the HVAD to the control device for freedom from neurologic injury (stroke with mRS >0 at 24 weeks post stroke or a transient ischemic attack) at 12 months (HVAD: 14.7% vs control: 12.1%). The combined rate of stroke and TIA in HVAD patients at one year did not meet a performance goal derived from the rate observed in ENDURANCE. Survival at 1 year free from the composite of disabling stroke or device exchange favored the HVAD System (HVAD: 75.3% vs control: 66.7%), though the trend diminished in magnitude over time (at 2 years, HVAD: 59.2% vs Control: 55.2%). The HVAD System and Control both demonstrated

sustained improvements in quality of life, functional capacity, and NYHA classication. Finally,

although the HVAD failed to demonstrate non-inferiority compared to Control for incidence of neurological injury at one year, the implementation of a blood pressure management strategy for HVAD recipients did demonstrate a reduction in the overall stroke rates in patients receiving

an HVAD System in the ENDURANCE Supplemental trial as compared to the rst ENDURANCE

trial.

Additional long-term follow-up from the ENDURANCE Destination Therapy Supplemental Trial

As of July 30, 2018 additional long-term data from the ENDURANCE Supplemental trial showed the comparative incidences and event-rates for adverse events between the HVAD and Control groups remained similar to those observed in the initial data analysis. The incidence of TIA in the

HVAD cohort (9.1%) is signicantly higher than the Control cohort (3.8%). However, the overall

myocardial infarction event rate was statistically higher in the Control group, while the overall ICVA event rate was statistically higher in the HVAD group. So, while it appears that the number of subjects having ICVA events is similar, HVAD subjects are more frequently having multiple occurrences of these events.

There was no statistically signicant difference between treatments for freedom from thrombus

on original device, freedom from exchange, freedom from stroke on original device, freedom from ICVA on original device, or freedom from HCVA on original device.

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The Kaplan-Meier estimates for freedom from CEC adjudicated stroke, ICVA and HCVA on original device are shown in Figure 28, Figure 29, and Figure 30, below. The log-rank p-values

show no signicant differences between HVAD and Control for stroke, ICVA, or HCVA.

Figure 28: ENDURANCE Supplemental Trial Freedom from Stroke on Original Device

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Figure 29: ENDURANCE Supplemental Trial Freedom from ICVA on Original Device

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58 HVAD™ Instructions for Use

1.10 Destination Therapy Supplemental Study (continued)

Figure 30: ENDURANCE Supplemental Trial Freedom from HCVA on Original Device

Figure 31: ENDURANCE Supplemental Trial Time to Device Malfunction

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While the incidence of device malfunction/failure was numerically higher in the HVAD group (39.9% vs. 36.9%), the incidence of pump thrombosis and pump replacement was numerically higher in the Control group (21.0% vs. 20.1%, and 17.2% vs. 13.3%, respectively). Kaplan-Meier estimates for freedom from thrombus on original device are presented in Figure 32 below. There

is no signicant difference between the two groups.

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Figure 32: ENDURANCE Supplemental Trial Freedom from Thrombus on Original Device

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Figure 33: ENDURANCE Supplemental Trial Freedom From Exchange

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Overall, the incidences of the adverse events still appear similar between the two groups.

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60 HVAD™ Instructions for Use

1.10 Destination Therapy Supplemental Study (continued)

Table 27: Summary of Adverse Events on Original Device in the ENDURANCE Supplemental Trial

Adverse Event

Major Bleeding 63.6% (190) 66.2% (104)

Cardiac Arrhythmia 39.% (122) 36.3% (57)

Hepatic Dysfunction 5.8% (18) 5.1% (8)

Hypertension 14.3% (44) 15.9% (25)

Major Infection 73.7% (227) 73.2% (115)

Device Malfunction/Failure 39.9% (114) 36.9% (58)

Pump Thrombosis 20.1% (62) 21.0% (33)

Hemolysis 7.1% (22) 6.4% (10)

Stroke

Ischemic Cerebrovascular Event

Hemorrhagic Cerebrovascular Event

TIA

Renal Dysfunction 14.6% (45) 20.4% (32)

Respiratory Failure 24.0% (74) 28.7% (45)

Right Heart Failure 36.7% (113) 40.8% (64)

Pump Replacement 12.3% (38) 17.2% (27)

Additional post hoc one-year comparisons of all sintered HVADS (pooled from both ENDURANCE and ENDURANCE-Supplemental) to pooled Control subjects were also performed, and analyzed against the primary endpoint denition of the ENDURANCE Trial (at one year, Figure 34B) and against the primary endpoint of the ENDURANCE Supplemental Trial (Figure 34A).

An Analysis of Patients Receiving Sintered HVAD™ Pumps (Pooled ENDURANCE and ENDURANCE Supplemental) Compared to Control. A) the Primary Endpoint of the ENDURANCE Supplemental Trial, and B) the Primary Endpoint of the ENDURANCE Trial at 1 year.

HVAD

(N=308)

25.3% (78) 22.3% (35)

17.5% (54) 12.7% (20)

10.4% (32) 11.5% (18)

9.1% (28) 3.8% (6)

Control

(N=157)

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Figure 34A: Survival on Original Device Free from Neurologic Events (Strokes with mRS>0, TIA or SCI)

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Figure 34B: Survival on Original Device Free from Disabling Stroke (mRS ≥4)

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62 HVAD™ Instructions for Use

1.10 Destination Therapy Supplemental Study (continued)

Overall Conclusions

The overall safety comparisons in both the ENDURANCE and ENDURANCE Supplemental trials

resulted in similar mortality rates and adverse event proles. Pump thrombosis rates for the

sintered HVAD and the Control LVAD were similar, but a higher proportion of Control pump thrombosis events resulted in device exchange. The incidence of stroke was 2.5 times higher in the patients receiving an HVAD compared to control in the ENDURANCE trial. The ENDURANCE Supplemental trial, which included implementation of a blood pressure management strategy for HVAD recipients, demonstrated a reduction in the overall stroke rates in patients receiving an HVAD System, although a reduction in overall stroke rates was also demonstrated in Control patients who were not subject to the blood pressure management strategy. In ENDURANCE Supplemental, the HVAD failed to demonstrate non-inferiority compared to Control for incidence of neurological injury at one year.

The data supports the reasonable assurance of safety and effectiveness of the HVAD System for hemodynamic support in patients with advanced, refractory left ventricular heart failure; either as a bridge to cardiac transplantation (BTT), myocardial recovery, or as destination therapy (DT)

in patients for whom subsequent transplantation is not planned.

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1.11 North American Clinical Study: LATERAL

HeartWare™ HVAD™ System Clinical Trial Overview: LATERAL Trial

This was a multi-center, prospective, open-label non-randomized single arm trial conducted in collaboration with the InterAgency Registry for Mechanically Assisted Circulatory Support (INTERMACS®) to Evaluate the Thoracotomy Implant Technique of the HVAD System in Patients with Advanced Heart Failure. Enrollment in the study is complete, subjects have all reached

the primary endpoint as described and specied in the protocol, but follow-up of subjects is

ongoing.

A. Study Design

Patients were enrolled between January 15, 2015 and April 26, 2016. The study data was collected through June 15, 2017 and included 144 subjects treated per protocol who were enrolled at 26 investigational sites.

The study was a prospective, single arm, multi-center clinical study in collaboration with the InterAgency Registry for Mechanically Assisted Circulatory Support (INTERMACS®) to evaluate the thoracotomy implant technique of the HVAD System in patients with advanced heart failure. The study device was the HVAD (HeartWare Ventricular Assist Device) System. The treatment was open-label.

Following implantation, device performance, follow-up visits and visit windows for the LATERAL Study are dictated by the INTERMACS® protocol.

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Adverse events (AE) were reported through INTERMACS®, according to the INTERMACS® AE

denitions. An independent Data Safety Monitoring Board monitored and reviewed study

compliance, adverse events and outcomes.

An NHLBI-appointed (independent) Observational Study Monitoring Board (OSMB) was established in 2006 and meets, at minimum, on an annual basis. The principal role of the OSMB is to monitor data from the Registry, review and assess the performance of its operations, assure patient safety, and make recommendations to the NHLBI and INTERMACS® co-investigators.

Explant

1. Clinical Inclusion and Exclusion Criteria

Enrollment in the LATERAL Study was limited to subjects who met the following inclusion criteria:

- Subjects >19 years old with chronic, advanced left ventricular failure who were transplant eligible at the time of enrollment in whom informed consent was obtained.

Subjects were not permitted to enroll in the LATERAL Study if they met any of the following exclusion criteria:

- Subjects with a body surface area < 1.2 m

- Subjects with prior cardiac transplant

- Subjects with a mechanical heart valve

- Subjects with severe right heart failure or receiving biventricular or the device as a right ventricular assist device

- Subjects with a planned concurrent procedure

- Subjects with known LV thrombus

- Additional exclusion criteria are available in the Clinical Study Report.

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64 HVAD™ Instructions for Use

1.11 North American Clinical Study: LATERAL (continued)

2. Follow-up Schedule

Preoperative baseline assessments included demographics, medical history, concurrent medications, laboratory tests, echocardiogram, NYHA, neurocognitive status, quality of life, and functional status.

All patients were scheduled to return for follow-up examinations at Week 1 +/- 3 days, Month 1 +/- 7 days, Month 3 +/- 30 days, Month 6 +/- 60 days (primary endpoint), and every 6 months +/- 60 days through 5 years of follow-up.

Week 1 and Month 1 visits included clinical laboratory tests for hematology, chemistry and INR, LVAD parameters, concurrent medications, echocardiogram, and assessments of NYHA. Months 3, 6 and onward also included health status, six-minute walk and an assessment of neurocognitive status.

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

The primary endpoint was a composite of six-month survival free of disabling stroke (i.e.,

modied Rankin score ≥ 4 assessed 12 weeks post-event), while alive on the originally

implanted device, transplanted or explanted due to left ventricular recovery.

Success in meeting the primary endpoint was tested comparing to a performance goal (77.5%) using a one-sided exact binomial test. Success will be met if the lower bound of

the one-sided exact 95% condence limit is greater than 77.5%. Success at six months

is estimated to be 86% compared to a performance goal of 77.5%. The target success estimate was based on the primary endpoint observed in the ADVANCE BTT+CAP Trial, post-approval data on HVAD outcomes from the INTERMACS® Registry (through Q2 2014), and the INTERMACS® report from Q1 2014 indicating an 85% survival estimate with LVAD support. Using an exact binomial test, with a one-sided alpha of 0.05, and 80% Power, a sample size of 145 implanted subjects was planned.

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The prespecied secondary endpoint is an improvement in the mean length of initial

hospital stay as compared to a performance goal of median sternotomy subjects. The mean length of initial hospital stay is estimated to be 26.1 days with a standard deviation of 22.8 days and a median of 20 days based on data from the Bridge to Transplantation Continued Access Protocol (BTT CAP) population (N=242). Using a one sample t-test, with a one-sided alpha of 0.05, a sample of 145 implanted subjects with an average value of

21.3 days or less will result in Power greater than 80%.

Other secondary endpoints included the incidence of major adverse events (classied

according to the INTERMACS® denitions), overall survival, changes in quality of life and health status as assessed by the KCCQ and the EQ-5D VAS, and functional status, as measured by NYHA functional class and 6-minute walk distance. The safety analysis focused on adverse events. Survival analysis was performed using the Kaplan-Meier method.

With regards to safety, predetermined secondary endpoints included the incidence bleeding, major infections, and overall survival. Additionally, incidence of device malfunctions/failures, quality of life and health status changes, as well as major adverse

events (classied according to the INTERMACS® denitions) were analyzed.

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1.11 North American Clinical Study: LATERAL (continued)

B. Accountability of Cohort

At the time of the data cut-off for this analysis (June 15, 2017), of the 178 patients enrolled in the LATERAL study, with 158 subjects qualifying for the analysis population, 98.7% (156) subjects were available for analysis of the primary objective at the completion of the study, the 6-month post-operative visit. The disposition of patients is shown in Figure 35.

The primary analysis population is the Per Protocol (PP) population, including a total of 144 subjects implanted with an HVAD via a thoracotomy approach and meeting all inclusion criteria without violating any exclusion criteria. The mean duration of subjects on original device in the PP population is 12.1 months. Eleven (11) additional subjects were included in the intent-to-treat population. Of the 23 screen failures, 3 subjects were implanted via a thoracotomy and were thus included in additional secondary endpoint analyses.

Figure 35: Subject Enrollment and Study populations in the LATERAL study.

Signed Informed

Consent

(N=178)

Screen Failure (N=23)

12 = Excluded from

2 = Consent withdrawn for

1 = Transplant prior to implant 5 = Planned Sternotomy

3 = Other LATERAL

Analysis Poplulation N=158

All Enrolled (N=11)

Use of sternotomy and/or

descending aorta outow

graft placement

Intent to Treat

(N=155)

INTERMACS

LATERAL

exclusion criteria met, but implanted via thoracotomy

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Per Protocol (PP)

Study Population

(N=144)

The purpose of the LATERAL Study was to evaluate the safety and effectiveness of the implanting the HVAD System by a thoracotomy approach, therefore patients in whom an implant via sternotomy was planned were screen failed from the study. Additionally, subjects in whom thoracotomy was planned, but then were implanted via a sternotomy, or those in whom

the outow was implanted in the descending aorta rather than the ascending aorta were

included in the intent to treat population. Finally, those patients who violated one or more of the exclusion criteria, but in whom a thoracotomy implant was still completed, were included in the analysis population. All thoracotomy implant procedures were also recommended to be completed on cardiopulmonary bypass.

Study Population Demographics and Baseline Parameters

The demographics of the primary study population are typical for an advanced heart failure with LVAD therapy study performed in the US. The subjects in the trial had advanced heart

failure associated with a substantial risk of death, as evidenced by over 80% of subjects classied

as INTERMACS® Prole 1-3, almost 20% with chronic renal disease, and more than 60% with ejection fractions lower than 20%. See Table 28.

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1.11 North American Clinical Study: LATERAL (continued)

Table 28: Baseline Demographics and Parameters in LATERAL

Demographics and Baseline Characteristics Study Device N=144

Age (years) 54.2 ± 11.5

Male gender (%) 77.1%

Race (%)

White Black or African American Asian American Indian or Alaskan Native Other, none of the above

Unspecied, Undisclosed

Height (cm) 175.2 ± 8.8

Body Surface Area (m2) 2.0 ± 0.3

Intended use

Bridge to Transplant Possible Bridge to Transplant

INTERMACS® Prole (%)

1 2 3 4 5-7

Ischemic Etiology of Heart Failure 32.6%

Prior Cardiac Surgery 22.9%

Previous Major Stroke 4.9%

Chronic Renal Disease 18.8%

History of Atrial Arrhythmias 30.6%

Serum creatinine (mg/dL) 1.3 ± 0.74

Mean Arterial Blood Pressure (mmHg) 79.5 ± 10.5

Left ventricular ejection fraction <20% (LVEF, %) 61.1%

Cardiac Index (L/min/m2) 2.1 ± 0.54

62.5%

20.8%

4.9%

2.1%

4.9%

7.6%

73.6%

26.4%

3.5%

31.3%

47.2%

15.3%

2.8%

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C. Safety and Effectiveness Results

1. Primary Endpoint

The outcome and analysis of the primary endpoint are shown in Table 29. The primary

endpoint success in the LATERAL Study was dened as alive on original device, transplanted or explanted for recovery without a stroke with an mRS score of ≥ 4 (assessed ≥ three months post-stroke event). One subject had missing data for this endpoint, which

resulted in 143 evaluable subjects. The results show that 88.1% of the HVAD subjects

treated per protocol achieved primary endpoint success, which was signicantly greater

than the 77.5% performance goal (P=0.0012). The most common reason for primary endpoint failure was death on original device, seen in 7.7% (11/143) of subjects (Table 29). Protocol-mandated stroke assessments were not carried out in all subjects who experienced a stroke. In addition, 6 patients were reported as having a stroke within the

rst 6 months of implant. 3 of these 6 patients do not have sufcient data on mRS scores

and the severity of their strokes could not be determined. The Primary Endpoint for these 3 patients are based upon post hoc imputation of mRS scores.

Alarms and

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1.11 North American Clinical Study: LATERAL (continued)

Table 29: Primary Endpoint at Six Months*

Thoracotomy (N=143) N (%) 95% CI *

Primary Endpoint Success 126 (88.1%)

Alive on original device

Transplanted

Explanted for Recovery

Primary Endpoint Failure 17 (11.9%)

Death on original device

Stroke with mRS>=4 (as assessed >=3 Months post event)

Exchange

Explanted (not for recovery)

*Table is summarized by subjects’ rst failure event and includes all subjects with an endpoint event prior to 6

months or known to be alive on original device at 6 months.

**P-value of one-sided Binomial Exact test comparing to a performance goal of 77.5%

*** Subject considered a success if all strokes have day of and follow-up mRS scores <4.

97 (67.8%)

29 (20.3%)

0 (0.0%)

11 (7.7%)

4 (2.8%)

1 (0.7%)

0.0012

(82.7%, NA)

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2. Secondary Endpoints

For the PP population, the mean length of initial hospital stay (initial recovery and step

down unit) after the implant procedure (date of implant to rst discharge) was 18 ± 12.36 days, which is signicantly less than the 26.1 day performance goal estimate for median

sternotomy subjects. (P<0.0001). Additionally, the mean length of stay in the intensive care unit (ICU) was 8 ± 9.82 days. Results in the ITT population were similar.

Rehospitalization in the PP population was documented in 70.1% of subjects within 6

Explant

Figure 36: Time to Rehospitalization in LATERAL (PP Population, N=144)

months of initial hospitalization. The most common reasons for re-hospitalization were transplant (27.7%), anticoagulation adjustment (19.8%), and major bleeding (17.8%). A freedom from rehospitalization is presented in Figure 36.

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68 HVAD™ Instructions for Use

1.11 North American Clinical Study: LATERAL (continued)

Overall survival on the HVAD System was also assessed. A Kaplan-Meier estimate for freedom from death on original device for the PP population was 91.8% at 6 months, 88.8% at one year, and 87.4% at two years (Figure 37). The Kaplan-Meier estimates in the ITT population were similar.

Figure 37: Kaplan Meier Survival Analysis in the LATERAL Study (N=144)

Six of 11 deaths occurring within the rst 6 months post-implant were related to circulatory

causes, with two due to right heart failure (1.4%) and two due to sudden unexplained death (1.4%). The most common non-cardiovascular cause of death was neurological dysfunction, which occurred in three subjects (2.1%). Additionally, one subject died of multi-system organ failure and another after withdrawal of life support.

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1.11 North American Clinical Study: LATERAL (continued)

Health Status and Functional Improvements

The improvements in quality of life, as measured by the KCCQ and EQ-5D-5L, and functional capacity, as measured by the 6-Minute Walk Test and NYHA Class improvement, in the LATERAL Study subjects are presented in Figure 38A-D.

Figure 38: Improvements in Quality of Life and Functional Capacity in ENDURANCE Supplemental

Subjects. A) Change over time of the KCCQ Overall Summary Score. B) Change over time in the EQ-5D Visual Analog Scale. C) Change over time in subjects’ NYHA Classication.

D) Change over time of total distance walked in the Six Minute Walk Test.

A. KCCQ B. EQ-5D

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C. NYHA Classication

Improvement

Explant

3. Adverse Events

The analysis of safety was based on the per protocol cohort of 144 patients analyzed through the primary endpoint. A Clinical Events Committee (CEC) was not utilized in this study for adverse event adjudication. A total of 537 INTERMACS® adverse events were reported within 6 months on original device. Adverse events were most often reported

within the rst 30 days post-implant, with 87.5% (126/144) subjects having at least one

INTERMACS®-dened adverse event.

The most common adverse events were cardiac arrhythmia, bleeding, and infections. Adverse events are summarized in Table 30.

D. Six-Minute Walk

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70 HVAD™ Instructions for Use

1.11 North American Clinical Study: LATERAL (continued)

Table 30: Summary of INTERMACS® Adverse Events Occurring Through 6 Months

<=30 Days

(N=143)

INTERMACS® Category

Adverse Events

Total Adverse Events 126 (87.5) 89 (63.6)

Bleeding

Re-Hospitalization Re-Operation Transfusion: >=4 within 7 days GI

Cardiac Arrhythmia

Ventricular Supraventricular

Device Malfunction/Failure 9 (6.3) 10 (7.1)

Hepatic Dysfunction 1 (0.7) 0 (0.0)

Infection

Line Sepsis Driveline Exit Site

Myocardial Infarction 0 (0.0) 0 (0.0)

Neurological

Ischemic CVA Hemorrhagic CVA TIA

Psychiatric 3 (2.1) 2 (1.4)

Renal Dysfunction 8 (5.6) 6 (4.3)

Respiratory Dysfunction 11 (7.6) 2 (1.4)

Arterial non-CNS Thromboembolism

Venous Thromboembolism 4 (2.8) 1 (0.7)

Wound Dehiscence 1 (0.7) 2 (1.4)

Other 20 (13.9) 22 (15.7)

abbreviations: GI - gastrointestinal; TIA= transient ischemic attack (<24 hours)

Patients with

Event (%)

15 (10.4)

5 (3.5) 5 (3.5)

13 (9.0)

6 (4.2)

32 (22.2) 20 (13.9)

13 (9.0)

20 (13.9)

0 (0.0) 2 (1.4)

12 (8.3)

3 (2.1) 3 (2.1) 1 (0.7)

0 (0.0) 0 (0.0)

> 30 Days – 6 Months

(N=140)

Patients with

Event (%)

20 (14.3) 14 (10.0)

3 (2.1)

16 (11.4)

11 (7.9)

13 (9.3)

9 (6.4) 2 (1.4)

32 (22.9)

1 (0.7) 7 (5.0)

12 (8.6)

3 (2.1) 3 (2.1) 4 (2.9)

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Nineteen of 143 subjects were reported to have experienced a stroke within six months post-

implant, of which two were severely disabling with a mRS ≥ 4 at three months post-stroke. Functional assessment of stroke was specied in the protocol; degree of follow-ups is shown in

Table 31.

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1.11 North American Clinical Study: LATERAL (continued)

Table 31: Summary of Stroke Events

Patient IDPrimary

End-point

Population

(Y/N)

102 899

103 374

103 481

103 573

103 799

103 825

103 984

105 103

105 184

105 534

105 799

106 048

106 239

106 358

106 667

107 394

107 558

108 106

108 131

108 257

* Grey indicates prior to stroke event

Primary

Success

Y N

Y Y

Y N Death 5

Y Y

Y N

Y Y

Y N

Y Y

Y N

Y Y

Y N

Y Y

Y N Death

Y Y

Y N Death

Y Y

End-

point

(Y/N)

Endpoint

Type

Stroke

with mRS >= 4

Alive

Original

Device

Alive

Original

Device

Alive

Original

Device

Stroke

with mRS >= 4

Trans-

planted

Stroke

with

Missing

mRS

Alive

Original

Device

Stroke

with

Missing

mRS

Explanted

for

Recovery

Stroke

with mRS >= 4

Alive

Original

Device

Alive

Original

Device

Alive

Original

Device

Alive

Original

Device

mRS at

Stroke

Event

Time to

Stroke

Event

(Months)

2.726 955

5 0 5 4 4 4 4 4 4

21.74 993

3.876 876

0.032

855

6.340 993

0.032

855

0.032

855

3.646

892

13.99

618

4.928 233

4.041 151

16.72

314

2.529 826

0.427

113

0.919 937

15.11 325

10.97 353

2.891

7.688 043

1 Week

Implant

up mRS

1 Month

Post

Implant

up mRS

0 0

4 0 0 0 0 0 0

0 0

1 2 0

0 0

2 3

1 1 1 1

Post

3 Months

Post

Implant

up mRS

6 Months

Post

Implant

up mRS

Months

Post

Implant

up mRS

Months

Post

Implant

up mRS

Months

Post

Implant

up mRS

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72 HVAD™ Instructions for Use

1.11 North American Clinical Study: LATERAL (continued)

INTERMACS® data collection methods for hemolysis, hypertension and right heart failure

(RHF) adverse events differ from other adverse events. Specically, events were triggered based on data entered at each patient visit rather than site-reporting of specic events as

they occur. This method results in a potential difference in reporting of event frequency. These events are no longer site-reported events per se.

A major hemolysis event was triggered in 11.2% (16/143) of subjects at one-week postimplant based on INTERMACS®-dened criteria, and to date this value has not changed substantially over the follow-up period. Severe hemolysis incidence appears greater than previously reported in HVAD studies, however, these are not site-reported events so comparisons cannot be made.

Moderate and severe right heart failure (RHF) events were triggered in 69.9% (100/143) and 0.7% (1/143) of subjects, respectively, at one-week post-implant based on INTERMACS®-dened criteria. Though the incidence of severe RHF was low, the incidence of moderate or severe RHF appears to be greater than RHF adverse events previously reported in HVAD studies. However, once again it should be noted that these are triggered events and not site- reported, so comparisons to previous reports cannot be appropriately made.

No unanticipated adverse device effects were reported in the LATERAL Study. The prevalence of device failure/malfunction in the per protocol population was 12.5%.

In a majority of these cases, no cause was identied. There were 5 cases of suspected or conrmed pump thrombosis identied by hemolysis (2/5) and/or abnormal pump parameters (4/5). One case was conrmed as pump thrombosis.

Table 32: Device Malfunction/Failure or Pump Thrombosis within 6 months

Adverse Event N=144 % (N)

Device Malfunction/Failure and/or Pump Thrombus

Outcome

Death 0% (0)

Serious Injury 0% (0)

Urgent Transplantation 0% (0)

Explant without Replacement 0% (0)

Exchange 2.8% (4)

Breach of Integrity of Driveline that Required Repair

None of the Above 9.7% (14)

Causative or Contributing Factors

Patient Accident 0.7% (1)

Patient Non-Compliance 0% (0)

Sub Therapeutic Anticoagulation 0.7% (1)

Prothrombotic States 0% (0)

End of Component Expected Life 0% (0)

Technical/Procedural Issues 2.8% (4)

No Cause Identied 9.0% (13)

Thrombus (Suspected or Conrmed) 3.5% (5)

12.5% (18)

0% (0)

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1.11 North American Clinical Study: LATERAL (continued)

4. Subgroup Analyses

Subgroup analyses were planned for analysis of the primary endpoint analysis using

stratication factors site, on- vs. off-cardiopulmonary bypass pump, and outow graft

location. An analysis of site homogeneity found that the primary endpoint results were

signicantly different by site (P = 0.035). Further analyses found no predictive factors.

Across all populations, only one ITT subject had alternative outow location. The subject

is currently alive on original device. Similarly, only one subject had no indication in his records regarding use of cardiopulmonary bypass, and that subject was transplanted. Due to the sparse nature of these data, no additional analyses were performed.

Overall Conclusions from the LATERAL Trial

The LATERAL Trial was a multi-center, prospective, contemporaneous controlled study. The purpose of this study was to evaluate the safety and effectiveness of HVAD implantation via the thoracotomy approach. The analysis of the primary endpoint suggested success of the HVAD System implanted via thoracotomy compared to the performance goal. The most common reason for primary endpoint failure was death on original device, seen in 7.7% (11/143) of subjects.

Accessories

An improvement in mean length of initial hospital stay was also observed, with a mean length of stay of 18 ± 12.36 days as compared to the 26.1 day performance goal.

HVAD implantation via thoracotomy appears to be safe, with adverse event rates that are comparable to previous HVAD studies, with the exception of hemolysis and right heart failure which may be partially related to data collection methods.

Overall, HVAD implantation via the thoracotomy approach appears to be effective, with

the achievement of statistical signicance in the LATERAL primary and secondary endpoints.

Additionally, overall quality of life and functional capacity were meaningfully improved in LATERAL subjects.

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74 HVAD™ Instructions for Use

2.0 HeartWare™ HVAD™ System Overview

2.1 HVAD™ Pump and

Surgical Tools .............75

2.2 HVAD™

Controller ....................76

2.3 HeartWare™

Monitor .......................77

2.4 HVAD™ Controller

Power Sources ...........77

2.5 HeartWare™

Battery Charger .........78

2.6 Carrying Cases and

Shower Bag ................78

System Component Overview

See Appendix A for a complete list of system components.

The primary components of the HVAD System (excluding the Monitor) are intended for single patient use.

STERILE: All HeartWare implantable components, surgical tools and accessories used at implant are provided sterile.

2.1 HVAD™ Pump and Surgical Tools

The HVAD System consists of a blood pump with an

integrated, partially sintered inow cannula; a 10 mm diameter gel impregnated polyester outow graft, and

a percutaneous driveline. A strain relief is used on the

outow graft to prevent kinking and secures the outow

graft to the pump. The driveline cable is wrapped with woven polyester fabric to encourage tissue in-growth at the skin exit site. The small, wearless pump has a displaced volume of 50cc and weighs 160 grams. The pump has one moving part, an impeller, which spins

blood to generate up to 10.0 L/min of ow. There are

two motors in the pump housing with one motor providing redundancy.

A short integrated inow cannula is inserted into the left ventricle and the outow graft connects the HVAD Pump

to the aorta. A sewing ring attaches to the myocardium and allows for pump orientation adjustments

intraoperatively. The device size and short inow cannula

allow for pericardial placement, which eliminates the need for abdominal surgery and device pockets

(Figure 39).

Figure 39: HVAD Pump and Left Ventricular (LV) Cannulation

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For additional information about the HVAD Pump, see Section 3.0.

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2.1 HVAD™ Pump and Surgical Tools (continued)

Surgical Tools and Accessories are Provided Sterile for Surgical Implantation.

Figure 40: Surgical Tools

1. Tunneler – to tunnel the pump’s percutaneous driveline

through the skin to the exit site

2. Sewing ring wrench – to tighten the screw on the sewing ring

3. Driveline cover – to cover the driveline connection to the controller

4. Apical coring tool – to core the LV apex

5. Strain relief wrench – to secure the strain relief and

outow graft to the HVAD Pump

All tools and accessories used during implantation are for single-use only.

Figure 41: Components used at Implant

1. HVAD Pump

2. Outow graft

3. Sewing ring

4. Driveline cap

Figure 40

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5. Strain relief

6. Inow cap

7. Driveline extension cable

For additional information on implantation, see Section 6.0.

2.2 HVAD™ Controller

The controller (Figure 42) is a microprocessor unit that controls and manages HVAD System operation. It sends power and operating signals to the blood pump and collects information from the pump. The percutaneous driveline is connected to the controller, which must always be connected to two power sources - an AC adapter or DC adapter and/or rechargeable batteries. The controller’s internal, non-replaceable, rechargeable battery is used to power an audible [No Power] alarm when both power sources are disconnected. The controller interfaces with the monitor through a data port.

Figure 41

Figure 42

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76 HVAD™ Instructions for Use

2.2 HVAD™ Controller (continued)

CAUTION: ONLY use HVAD™ Controllers on one patient to avoid risks associated with an

inadvertent mismatch of controller pump speed settings.

For additional information about the HVAD™ Controller, see Section 4.2.

2.3 HeartWare™ Monitor

The monitor (Figure 43) is a touch screen tablet that uses proprietary software to display system performance and to permit adjustment of selected controller parameters. When connected to a controller, the monitor receives continuous data from the controller and displays real-time and historical pump information. The monitor also displays alarm conditions and can provide

notication of available controller software updates.

Figure 43

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For additional information about the HeartWare™ Monitor, see Section 5.0.

2.4 HVAD™ Controller Power Sources

The controller requires two power sources for safe operation: either two batteries, or one battery (Figure 44) and an AC adapter (Figure 45) or DC adapter (Figure 46). While active, patients will typically use two batteries. While relaxing or sleeping, patients should use power from an electrical outlet (AC adapter) because it provides power for an unlimited period of time.

Figure 44 Figure 45

WARNING! ALWAYS connect an AC Adapter to the controller before relaxing or sleeping. Power from an

electrical outlet (AC Adapter) provides power for an unlimited period of time.

Figure 46

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77HeartWare™ HVAD™ System Overview

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2.4 HVAD™ Controller Power Sources (continued)

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.

For additional information on HeartWare™ Batteries, see Section 4.3. For additional information on the AC/DC adapter, see Section 4.5.

2.5 HeartWare™ Battery Charger

The battery charger (Figure 47) is used to simultaneously recharge up to four batteries. It takes approximately 5 to 6 hours to fully charge a depleted battery. Each battery slides into a bay and is connected to the battery charger. It is safe to leave the batteries in the charger.

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Figure 47

For additional information on the battery charger, see Section 4.4.

2.6 Carrying Cases and Shower Bag

The HeartWare™ Waist Pack, HeartWare™ Shoulder Pack, and HeartWare™ Convertible Patient Pack are used to safely secure, store and carry the controller and batteries. They can be used in

or out of the hospital, when resting, sleeping or ambulating. One controller and two batteries t

into each of the carrying cases.

The expected Useful Life of the HeartWare™ Shoulder Pack, Waist Pack, and Convertible Patient Pack is 12 months. Carry cases should always be inspected prior to use. DO NOT use a carry case if it shows signs of damage. Contact HeartWare for a replacement.

CAUTION: The HeartWare™ Waist Pack and the HeartWare™ Shoulder Pack contain magnetic closures.

Patients with an internal cardiac debrillator (ICD) or pacemaker should keep the pack away from their

chest, including when sleeping. Per pacemaker and ICD manufacturer guidelines, magnets should be kept at least 6 inches (15 centimeters) away from the pacemaker or ICD (please refer to manufacturer guidelines for additional information).

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78 HVAD™ Instructions for Use

2.6 Carrying Cases and Shower Bag (continued)

HeartWare™ Shower Bag

A shower bag is available for use in conjunction with the HVAD System. To ensure safe and appropriate use of the shower bag, all patients and caregivers should be trained on shower bag operation prior to use.

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.

WARNING! DO NOT allow hearing impaired patients to shower unless their caregiver is close by to hear alarms.

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.

WARNING! DO NOT allow patients to take a bath or swim, as this may damage HVAD System components and/or result in driveline exit site infection.

WARNING! DO NOT submerge HVAD System components in water or other uid as this may damage

them. If this happens, contact HeartWare.

WARNING! DO NOT allow water or other uids to enter the controller, power adapters, batteries,

battery charger or connectors, as this may damage HVAD System components. If this happens, contact HeartWare.

WARNING! DO NOT use any components other than those supplied by HeartWare with the HVAD System, as this may affect HVAD System operation.

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WARNING! Damaged equipment should be reported to HeartWare and replaced.

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.

CAUTION: DO NOT attempt to repair or service any components of the HVAD System. If HVAD System equipment malfunctions, contact HeartWare.

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80 HVAD™ Instructions for Use

3.0 HeartWare™ HVAD™ System Pump

3.1 Principles of

Operation ....................81

3.2 Physiologic Control

Algorithms ..................83

3.2.1 Flow Estimation .......... 83

3.2.2 [Ventricular Suction

Detection] Alarm .............. 84

3.2.3 LavareTM Cycle ............ 86

3.3 HVAD™ Pump Operating

Guidelines ...................87

3.4 Expected Useful Life

of the HVAD™ Pump ....87

3.5 Device Tracking and Reporting

Requirements .............87

3.1 Principles of Operation

Background

The HVAD Pump is a continuous ow pump. It contains a rotating impeller that adds energy to the blood by converting the rotational kinetic energy into mechanical energy (Figure 48). Impeller blades push the uid through the pump using hydrodynamic and centrifugal forces.

The net effect is to build up the uid pressure, sometimes

referred to as pump head (i.e., related to the differential pressure across the device) or just head, such that the

uid is moved from the inlet to the outlet of the pump.

Pump head is the difference between the afterload and the preload. Energy to rotate the impeller is provided through electromagnetic coupling between permanent magnets (rotor magnet) attached or enclosed within the impeller and the motor stators. The motor stators consist of coils of wire that are sequentially charged by electrical current, turning the coils into electromagnets. These electromagnets have the effect of spinning the rotor magnets around an axis of rotation. The HVAD

Pump is efcient at pumping moderate quantities of

blood against moderate amounts of resistance.

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Figure 48: Open View

of HVAD Pump

1. Inow Cannula

2. Impeller

3. Center Post

Emergencies

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3.1 Principles of Operation (continued)

Blood Flow Characteristics

The amount of ow a rotary pump can generate is dependent upon the diameter of the impeller, the geometry of the impeller blades, housing design, motor capacity, rotational speed, and pressure differential that exists across the pump. This allows for in-vitro pump

characterization for a specic pump and is the basis for blood ow estimation.

The HVAD System estimates blood ow rate using HVAD Pump characteristics (electrical current,

impeller speed) and blood viscosity. Viscosity is calculated from the patient’s hematocrit. To obtain the most accurate estimate of blood ow, the patient’s hematocrit must be entered into the HeartWare™ Monitor. Flow estimation should be used as a trending tool

only, as it cannot adapt to changing uid conditions.

For additional information on Flow Estimation, see Section 3.2.1.

Accessories

The volume of ow generated by the HVAD Pump is determined by the rotational speed of

the impeller and by the pressure differential across the pump. The pressure that the HVAD Pump must work against is similar to the mean arterial pressure. If the pump speed (RPM) is set too low then the device may not generate enough forward pressure. This can lead to retrograde

ow (ow from the aorta back through the device and into the left ventricle). The maximum rotational speed is determined by how much ow is available from the right heart. If the speed

is set too high and the pump attempts to pump more blood than is available, ventricular suction may occur.

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The controller operates in “Fixed” mode, which maintains a constant motor speed. The motor speed range is between 1800 and 4000 RPM. The appropriate speed should be determined based on the patient condition.

NOTE: Recommended HVAD Pump speeds are between 2400 RPM and 3200 RPM. HVAD Pump speeds outside this range may result in less than optimal HVAD Pump operation.

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82 HVAD™ Instructions for Use

3.2 Physiologic Control Algorithms

The HVAD Pump control algorithms provide clinicians information about device performance and HVAD Pump blood ow estimation.

3.2.1 Flow Estimation

Estimated HVAD Pump blood ow is calculated using VAD power, speed parameters, and hematocrit, based on a blood sample from the patient. The default hematocrit setting is 30%,

but for accurate ow estimation, the patient’s hematocrit should be entered into the monitor.

Adjustments to the hematocrit setting on the monitor should be made for hematocrit changes of ± 5% or greater.

NOTE: Update hematocrit settings on the monitor whenever hematocrit changes by plus or minus 5% or more.

The valid range of estimated blood ow is -2.0 to 10.0 L/min. The table below shows monitor and

Controller Display messages and what they mean.

Table 33: Monitor and Controller Display Messages

Monitor and Controller Display Estimated Flow Range

“--“ Invalid, not available

“< -2.0 L/min“ less than -2.0 L/min

“-2.0 L/min” up to “10.0 L/min” -2.0 to 10.0 L/min

“> 10.0 L/min” greater than 10.0 L/min

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The error of the estimated ow is the maximum of either 1.0 L/min or 20%, whichever is greater.

Flow estimation accuracy can be maintained only if accurate hematocrit values are entered.

Out of range values on the low side (less than -2.0 L/min), are invalid in terms of estimated ow but could indicate an incorrect hematocrit value used in the ow or occlusion of the inow or outow conduits. Out of range values on the high side (greater than 10.0 L/min), may occur due

to thrombus or other materials (e.g. tissue fragments) in the device, due to an incorrect

hematocrit value used in the ow or during an electrical fault.

NOTE: Flow estimation should only be used as a trending tool. Actual ow may differ from readout due

to variability of patient’s hematocrit.

WARNING! DO NOT rely only on ow estimation to assess cardiac output. An average estimated ow

on the monitor or Controller Display of less than 2.0 L/min, or greater than 10.0 L/min may indicate an electrical fault, incorrect hematocrit entry or an occlusion and/or thrombus or other materials (e.g. tissue fragments) in the device. Inaccurate assessment of HVAD Pump ow may lead to less than optimal treatment.

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3.2 Physiologic Control Algorithms (continued)

3.2.2 [Ventricular Suction Detection] Alarm

A suction condition may occur due to ventricular collapse or inow occlusion. Ventricular collapse occurs when a continuous ow VAD attempts to pump more blood from the left

ventricle than is available, resulting in considerable reduction in ventricular volume. Left ventricular collapse can be the result of clinical events affecting left ventricular preload, including hypovolemia

(bleeding), right heart failure, arrhythmia or pulmonary embolus. An inow occlusion occurs when the inow cannula is obstructed, causing a suction condition. Temporary inow obstruction can

occur as a result of surgical positioning, patient position or during straining (valsalva).

The [Ventricular Suction Detection] alarm functions by monitoring the estimated ow for sudden decreases in ow rate. A ow baseline is established by continuously tracking the minimum ow values. A trigger value is established at 40% below the estimated ow baseline. An indication of suction is obtained when the minimum ow falls below this trigger level. The alarm will be

triggered if this condition is maintained for 10 seconds.

The ow minimum that triggers the suction alarm is also used to dene the suction clear limit. The estimated ow baseline is continuously compared to this limit. The suction alarm will be cleared if the ow baseline is maintained above the trigger level for 20 seconds. (Figure 49) This is an

indication that the suction condition has cleared.

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Figure 49

The [Ventricular Suction Detection] alarm can only be activated from the System Screen of the monitor. Therefore, only the clinician has access to control the state of this alarm. The default setting for Suction Response is “Off”. In this mode, there will be no alarm during a ventricular suction condition. An “Sx Off” message will be displayed on the lower left-hand corner of the monitor screen below the “Fixed” mode display. When Suction Response is enabled (via the “Alarm” button), the “Sx On” message will be displayed on the lower left-hand corner of the monitor screen below the “Fixed” mode display.

For additional information on the monitor, see Section 5.0.

Reference

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Appendix

84 HVAD™ Instructions for Use

3.2 Physiologic Control Algorithms (continued)

3.2.2 [Ventricular Suction Detection] Alarm (continued)

The Suction Response “Alarm” mode must not be turned on if the patient is in a suction condition. If the mode is turned on during a suction condition, the “Sx On” message will be displayed on the monitor and the [Ventricular Suction Detection] alarm will be enabled but will be inaccurate due to the fact that normal baseline parameters could not be established during a suction condition. The algorithm attempts to establish a baseline detection level to distinguish abnormal conditions. This is not possible if the patient is experiencing ventricular suction when the algorithm is initiated. Once the suction condition clears, an accurate baseline will be obtained automatically and the suction detection will proceed.

NOTE: Ventricular suction detection may be activated once the patient’s intravascular volume and

pump ow have been stabilized.

If a [Ventricular Suction Detection] alarm is triggered, the clinician should evaluate whether the alarm was triggered by a transient, reversible condition which corrects itself, or whether the alarm is more serious and requires intervention. Transient alarms often occur at certain times during the day and/or under particular circumstances such as bending over or lying on one side. They usually resolve quickly without problems. If the [Ventricular Suction Detection] alarm is persistent and there are clinical symptoms of decreased blood ow, such as dizziness or hypotension, or if a [Low Flow] alarm is active, then the patient should be evaluated. This can be

accomplished by checking the pump ow waveform on the monitor for evidence of suction, or

if necessary, by visualizing the left ventricle with echocardiography. The clinician should attempt to identify and treat the underlying cause of the suction event. If the cause for the suction event cannot be determined, or if the cause is refractory to treatment, then the clinician should manually adjust the speed to resolve the suction condition. 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 clinician will have to reactivate the alarm after adjusting the speed.

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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.

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.

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3.2 Physiologic Control Algorithms (continued)

3.2.2 [Ventricular Suction Detection] Alarm (continued)

The ventricular suction detection function will temporarily deactivate if:

• The estimated ow value becomes invalid. Once the ow estimation is within valid range, the ventricular suction detection will resume.

• The baseline ow value is less than 1.8 L/min – the algorithm loses sensitivity if the baseline and, therefore, the suction detection level gets too low. Once the baseline value is above 1.8 L/min, then the ventricular suction detection will resume.

• The clinician changes the hematocrit input – the algorithm recognizes that a change in the uid viscosity will cause a change in the estimated ow. The ventricular suction detection reactivates once a new baseline is established.

• Lavare™ Cycle is active – the Lavare™ Cycle has a direct impact on the Suction Alarm tracking parameters, so the algorithm is temporarily disabled. The ventricular suction detection re-activates with the previous baseline once the Lavare™ Cycle is completed.

3.2.3 Lavare™ Cycle

The Lavare™ Cycle is a speed modulation algorithm designed to reduce areas of potential blood stasis within the left ventricle. As depicted in Figure 50, the Lavare™ Cycle decreases the pump speed by 200 RPM below the set speed for 2 seconds then increases the pump speed to 200 RPM above the set speed for 1 second followed by the return to the original set speed for 60 seconds. Once activated the Lavare™ Cycle continues until deactivated.

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Figure 50: Lavare™ Cycle Example: full cycle (left), close up of speed modulation (right)

Explant

Lavare™ Cycle is limited by pump speed range of 1800 – 4000 RPM during the low and high speed portions of the cycles. Accounting for the ±200 RPM change with respect to the set speed during the Lavare™ Cycle, set speeds below 2000 or above 3800 will not allow for the full ±200 RPM change. For example, if the set speed is 1900 RPM, the Lavare™ Cycle will operate between 1800 RPM and 2100 RPM, instead of 1700 RPM and 2100 RPM.

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86 HVAD™ Instructions for Use

3.2 Physiologic Control Algorithms (continued)

3.2.3 Lavare™ Cycle (continued)

The Lavare™ Cycle has two settings, OFF and ON which can be set by the clinician via the HeartWare™ Monitor. It is recommended that the Lavare™ Cycle be initiated once the patient

is hemodynamically stable and it is conrmed that the patient can tolerate the 2 seconds of

reduced support.

Hemodynamically Stable Suggests:

• HVAD Pump ow is maintained within the targeted range for each patient.

• The patient’s intravascular volume is stable requiring no serial blood product transfusions (no active bleeding).

• Inotropic, vasoactive and anti-arrhythmic drugs are at constant dosages or being decreased.

It is recommended that the “Lavare Cycle” be deactivated if use of the Lavare™ Cycle has a detrimental effect on the patient such as increased suction events or [Low Flow] alarms.

NOTE: If thrombus is suspected within the device, the Lavare™ Cycle should be turned “Off” until the thrombus is resolved.

3.3 HVAD™ Pump Operating Guidelines

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The HVAD Pump speed can be set between 1800 and 4000 RPM, however the recommended clinical operating speed range is 2400 to 3200 RPM. Speeds below 2400 RPM should only be used during the implant procedure when weaning from cardiopulmonary bypass. Speeds above 3200 RPM are seldom needed and may increase the risk of suction events. HVAD Pump power ranges from 2.5 to 8.5 Watts when operating within the recommended speed range. Power values > 8.5

Watts suggests a problem which should be evaluated by log le analysis. The table below shows the expected average values for speed, power and ow at 2400 and 3200 RPMs.

Table 34: Expected Average HVAD Pump Parameters

Speed (RPMs) Power (Watts) Flow (L/min)

2400 2.5 3.0

3200 8.5 8.0

3.4 Expected Useful Life of the HVAD™ Pump

The HVAD Pump was designed and tested to function for two years.

3.5 Device Tracking and Reporting Requirements

The HVAD Pump is considered a life-sustaining medical device and must be tracked per US Food and Drug Administration (FDA) and other foreign regulatory agency regulations. Compliance is mandatory. Accordingly, all device tracking paperwork must be completed and promptly returned to HeartWare. In addition, any device malfunctions must be reported to HeartWare by the implanting center.

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87HeartWare™ HVAD™ System Pump

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88 HVAD™ Instructions for Use

4.0 HeartWare™ HVAD™ System Peripherals and

Accessories

4.1 HVAD™ Controller Connections

4.1 HVAD™ Controller

Connections ...............89

4.2 HVAD™

Controller ....................93

Controller Connector Layout

There are four ports on the controller (Figure 51)

Data Cable Connection

• Usually covered with a dust cap

Driveline Connection

• Connects the pump driveline to the controller

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4.3 Using the HeartWare™

Batteries ....................97

4.4 Using the HeartWare™

Battery Charger .......103

4.5 Using the HVAD™ Controller AC Adapter or

DC Adapter ................106

4.6 Carrying Cases ......... 107

4.7 Recommended Equipment

for Use at Home ........108

• Accepts the data cable from the monitor or the red alarm adapter with the blue ring

Figure 51

Power Connection

• Connects the controller to the power source

• Accepts battery, AC, or DC adapter power

• Never disconnect both power sources at the same time or the pump will stop

• Should never be removed unless performing a controller exchange

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CAUTION: ALWAYS keep all connectors free of liquid, dust and dirt, or the HVAD System may not function as intended.

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89HeartWare™ HVAD™ System Peripherals and Accessories

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4.1 HVAD™ Controller Connections (continued)

Driveline Connection to the Controller:

To Disconnect the Driveline from the Controller:

1. Slide the driveline cover away from the controller so you can see

the whole silver connector.

2. Place your ngers on the silver connector, over the ringed area.

3. Pull back on the ringed area to release the locking mechanism.

DO NOT remove the driveline cover from the driveline.

NOTE: if you pull back on any other area of the driveline or

connector it will not release the driveline from the controller.

Figure 52

Figure 53

Figure 54

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WARNING! DO NOT remove the driveline cover from the driveline. Maintaining proper driveline cover attachment prevents accidental disconnection which will lead to a pump stop.

To Connect the Driveline:

Explant

1. Line up the red dots on the driveline connector and on the controller driveline port.

Figure 55

2. Push the driveline connector straight into the port.

NOTE: Verify the pump is running to ensure proper

connection.

Figure 56

3. Slide the driveline cover over the driveline connector.

Figure 57

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WARNING! DO NOT grasp the driveline cable as this may damage the driveline. To remove the driveline

from the controller, rst pull back the driveline cover then grasp and pull the driveline connector.

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.

90 HVAD™ Instructions for Use

4.1 HVAD™ Controller Connections (continued)

Connecting Power Sources and Monitor Cable to the Controller:

To Connect a Power Source:

1. To connect all power supplies (battery, AC adapter or DC

adapter) grasp the power cable near its connector. Leave the connector free to rotate.

2. Line up the solid white arrow on the cable connector with the dot on the controller (Figure 59).

3. Gently push the cable into the controller. DO NOT twist the connector, but allow it to naturally lock in place. A good connection will turn on the battery or AC/DC indicator on the controller, as well as beep. If an alarm is active or muted, the beep will not be heard.

Figure 58

Figure 59

Figure 60

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NOTE: When pushing the connector into the controller the white

arrow will shift slightly into the correct locking position.

4. Conrm that the power cable is properly locked to the controller by gently pulling on the cable

near the connector. Repeat steps above for second power source.

CAUTION: DO NOT force connectors together without proper alignment. Forcing together misaligned connectors may damage the connectors.

CAUTION: ALWAYS conrm 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.

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4.1 HVAD™ Controller Connections (continued)

Disconnecting Power Sources:

Disconnecting from the AC Adapter or DC Adapter

Before switching from AC or DC power to battery power, make sure that a fully charged battery is available. Connect the fully charged battery after disconnecting the AC or DC adapter. To disconnect power cables from the controller:

1. Turn the connector counterclockwise until it stops.

Figure 61

2. Pull the connector straight out from the controller.

NOTE: If another power source is not connected within 20 seconds,

the [Power Disconnect] message will be displayed on the Controller Display and an alarm will sound.

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Figure 62

NOTE: The alarm will automatically clear when another power

source is connected to the controller.

3. Connect a fully charged battery to the controller power connector.

Explant

4. If a charged battery is not connected to the controller within 20 seconds, the [Power Disconnect] message will be displayed on the Controller Display and an alarm will sound.

Reference

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92 HVAD™ Instructions for Use

4.2 HVAD™ Controller

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.

HVAD

Figure 63: The controller face incorporates a number of visual indicators and function buttons.

Alarm

Battery Indicator 1

Power Source 1 Alarm Mute Button

AC/DC Indicator

Controller Settings Menu

The Controller Settings Menu may be used to view controller information when a monitor is not available.

• To access the menu press and hold for two (2) seconds and then release.

• Press again to navigate through the controller settings. After the last setting in the menu, navigation will return to the top of the Settings Menu.

The controller will exit the settings menu automatically after 60 seconds.

Indicator

Controller Display

Battery Indicator 2

Power Source 2 Scroll Button

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• To exit the settings menu manually, press and hold for two (2) seconds.

• Once a user reaches the end of the menu, the next press will return to the Home screen on the Controller Display.

The Controller Settings Menu includes the following information:

1. Battery Cycles

2. [Low Flow] alarm (Setting)

3. [High Power] alarm (Setting)

4. Hematocrit (Setting)

5. RPM Setting

6. Suction Response (On/Off)

7. “Lavare Cycle”, if enabled

8. Peak Flow (L/min)

9. Trough Flow

10. Implant Date

11. Controller Date

12. VAD ID

13. Patient ID

14. Controller Software Version

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4.2 HVAD™ Controller (continued)

Table 35: Guide to Controller Display, Buttons, and Indicators

Accessories

The CONTROLLER DISPLAY gives pump information including impeller speed (RPM), power (Watts), and blood ow (L/min). When an alarm occurs, the pump information is replaced by two lines of text that tell you what the alarm is and what to do. The Controller Display also provides additional pump information in the controller settings menu.

For additional information on alarms, see Section 8.1.

The AC/DC INDICATOR will be green if you are using the AC adapter or DC adapter to power the controller.

The two BATTERY INDICATORS located on the top of the controller are labeled “1” and “2”. Either the “1” or “2” will be lit, depending upon which port is providing primary power. If an AC or DC adapter is connected, this will be the primary power source. The Battery Indicators tell you approximately how much power remains in each battery.

Note: If the AC adapter or DC adapter is connected to the controller, the corresponding Battery Indicator will not display lights but the corresponding “1” or “2” will be lit.

The ALARM INDICATOR lights when one or more alarms occur. The Alarm Indicator changes colors depending on the severity of the alarm and always displays the most severe alarm in the case of multiple alarms.

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For additional information on alarms, see Section 8.1.

The “ALARM MUTE” button will silence (mute) a low or medium alarm for 5 minutes or until a new alarm occurs. A high alarm cannot be silenced. Follow the instructions on the display screen, including to call your clinician for all medium and high alarms.

The “SCROLL” button on the right side of the controller has 4 functions:

1. used to see all active alarms as well as pump information (RPM, L/min, Watts) on the Controller Display.

2. will clear resolved medium alarms from the Controller Display.

3. will brighten the Controller Display.

4. will show additional information if pressed and held for 2 seconds.

Pressing and holding the “ALARM MUTE” button and the “SCROLL” button for 5 seconds at the same time will prevent the [No Power] alarm from sounding when power is removed during a controller exchange (use only on a controller not connected to a pump).

For additional information on changing controllers, see Section 8.7.

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4.2 HVAD™ Controller (continued)

Controller Power-up Sequence

When rst adding power to the controller the battery and alarm indicator lights will go on and then off. Both

the green and red lights will be turned on and then off. Although the red alarm indicator will turn on for 2.5 seconds, this is normal and does not mean there is a problem with the system. The power-up sequence is complete when the controller screen shows the pump information.

Electrostatic Discharge (ESD)

Static electricity is widely present and more so in certain conditions such as in drier environments and in the vicinity of certain materials and fabrics such as silk clothing and carpeting. Discharge of static electricity, commonly referred to as electrostatic discharge (ESD), may interfere with electronic equipment. The HVAD™ Controller, as a piece of electronic equipment, is susceptible to ESD. Be aware of ESD and its potential to cause disruptive and possibly fatal faults in susceptible patients.

The controller may alarm in certain situations as a result of ESD. These alarms include:

1. A [Controller Failed] alarm.

2. A high audible alarm without accompanying alarm text on the Controller Display.

• If either of those alarms occur: The controller should be switched to the back-up controller.

3. A [Controller Fault] alarm.

• If that alarm occurs: It should be treated as directed in Section 8.3 (“Medium Priority Alarms”), since there are a number of potential causes for this alarm.

WARNING! AVOID devices and conditions that may induce strong static discharges (e.g., television or computer monitor screens) as electrostatic discharges can damage the electrical parts of the system and cause the LVAD to perform improperly or stop.

WARNING! The HVAD System components should not be used adjacent to or stacked with equipment

other than specied in the IFU. If adjacent to or stacked use is necessary, the HVAD System and other

equipment should be observed to verify normal operation.

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WARNING! ALWAYS have a back-up controller handy and, whenever possible, a caregiver nearby when

changing power sources or controllers. Be watchful for unusual changes in power or ow alarms for a

period of time following equipment changes.

In order to avoid or minimize the potential for ESD occurrence, follow good power/battery connection techniques as described in the IFU and patient manual.

To reduce the chance of ESD damage to the controller instruct patients to:

1. Make good connections when changing power sources

• Do not touch the controller connector ports, or let foreign objects or materials come near a

disconnected controller power port.

• Have new battery within reach before disconnecting power source and when possible, have a

caregiver nearby in case an alarm occurs.

• Use 2 power sources. Only leave power source ports on controller open for the time it takes to change

the power sources.

2. Be careful near materials and electronic devices prone to static electricity, such as: carpeted oors, silk

clothing, TV screens, microwaves when in operation, and laptop or computer screens.

• Avoid changing power sources in these areas.

• Avoid vacuuming and removing clothes from the dryer.

• Use anti-static dryer sheets and fabric softener.

• Consider humidier in your house.

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4.2 HVAD™ Controller (continued)

In patients who may be at risk of catastrophic cardiovascular collapse associated with a pump shutdown (fused aortic valve, aortic valve that has been sewn shut due to aortic valve regurgitation, or patients with very poor endogenous ventricular function) ESD education is extremely important and controller exchanges should be performed in a controlled clinical setting whenever possible.

Controller Care

Once a week: Instruct the patient to inspect the controller power connections and connector pins for dirt. This inspection can be done while the patient is changing batteries or when changing from batteries to the AC adapter. Check the power connections on the controller one at a time. DO NOT disconnect both power sources to examine the connections. DO NOT disconnect the pump to examine the percutaneous lead/controller connection. This connector should be inspected only during a controller exchange. The patient should not attempt to clean the controller connectors, but should be instructed to contact their VAD coordinator if they notice the connectors are dirty. Exterior surfaces of the controller should be cleaned using a clean cloth. A damp cloth may be used but a wet cloth should not.

Accessories

Periodically or as needed:

The controller may be cleaned with the following agents:

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• Alcohol (Isopropyl 90% or Ethyl 70%)

• Hydrogen peroxide solution (1.4%)

• n-Alkyl Dimethyl Dibenzyl Ammonium Chloride combined with n-Alkyl Dimethyl Ethybenzyl Ammonium Chloride (active agent in some disinfecting wipes).

• Silver, ethanol, acetic acid, peroxyacetic acid, hydrogen peroxide solution (active ingredients of some sporicidal disinfecting wipes)

• UV-C disinfecting wand, one that radiates “short wave” UV-C band rays (100 to 280

Explant

nanometers) from a 4 watt bulb (or stronger)

Expected Useful Life of the HVAD™ Controller

The HVAD™ Controller was designed and tested to function for two years.

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.

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.

Reference

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Appendix

96 HVAD™ Instructions for Use

Medtronic 1403US Instructions for Use

Specifications and Main Features

Frequently Asked Questions

User Manual