Chronic Heart Failure
Conditions
Brief summary
This is a prospective, randomized, controlled, unblinded, multi-center evaluation of safety and efficacy in patients implanted with a HeartWare® HVAD who receive improved blood pressure management. Subjects have chronic Stage D or NYHA Class IIIB/IV left ventricular failure who have received and failed optimal medical therapy, and who are ineligible for cardiac transplantation.
Detailed description
The study will evaluate non-inferiority of neurologic injury incidence in a new cohort of subjects receiving improved blood pressure management to a control group (i.e., any FDA-approved LVAD for destination therapy). Secondary endpoints include: a comparison of stroke/TIA incidence to a reference observed in the original IDE clinical trial (HW004) that did not specify improved blood pressure management; and non-inferiority of stroke-free success on the originally implanted device to the control group. Subjects will be randomized to HeartWare® HVAD or control LVAD in a 2:1 ratio. Each subject receiving the HeartWare® HVAD or control LVAD is followed to the primary and secondary endpoints at 12 months, with a subsequent follow-up period extending to 60 months post-implant.
Interventions
DEVICEHeartWare® VAS (HVAD)
The HeartWare® VAS is an implantable centrifugal pump that was designed to provide flows up to 10 L/min in a small device that is both lightweight and simple to use.
DEVICEControl LVAD
Any FDA-approved LVAD for destination therapy.
Sponsors
Medtronic Cardiac Rhythm and Heart Failure
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Must be ≥18 years of age at consent 2. Body Surface Area (BSA) ≥ 1.2 m2 3. Patients with advanced heart failure symptoms (Class IIIB or IV) who are: (patient must meet one of the following)a. On optimal medical management, including dietary salt restriction and diuretics, for at least 45 out of the last 60 days and are failing to respond; or b. In Class III or Class IV heart failure for at least 14 days, and dependent on intra-aortic balloon pump (IABP) for 7 days and/or inotropes for at least 14 days 4. Left ventricular ejection fraction ≤ 25% 5. LVAD implant is intended as destination therapy 6. Must be able to receive either the HeartWare® HVAD or control LVAD 7. Patient must agree to participate in and comply with an improved blood pressure management program, including maintenance of a patient diary. 8. Female patients of childbearing potential must agree to use adequate contraceptive precautions (defined as oral contraceptives, intrauterine devices, surgical contraceptives or a combination of condom and spermicide) for the duration of the study. 9. The patient or legally authorized representative has signed the informed consent form
Exclusion criteria
1. Body Mass Index (BMI) \> 40 2. Existence of any ongoing mechanical circulatory support (MCS) other than an intra-aortic balloon pump (IABP) 3. Prior cardiac transplant. 4. History of confirmed, untreated abdominal or thoracic aortic aneurysm \> 5 cm. 5. Cardiothoracic surgery within 30 days of randomization. 6. Acute myocardial infarction within 14 days of implant as diagnosed by ST or T wave changes on the ECG, diagnostic biomarkers, ongoing pain and hemodynamic abnormalities as described (Figure 2) in the guidelines published in ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction ;. 7. Patients eligible for cardiac transplantation 8. On ventilator support for \> 72 hours within the four days immediately prior to randomization and implant. 9. Pulmonary embolus within three weeks of randomization as documented by computed tomography (CT) scan or nuclear scan. 10. Symptomatic cerebrovascular disease, stroke within 180 days of randomization or \> 80% stenosis of carotid or cranial vessels. 11. Uncorrected moderate to severe aortic insufficiency. Correction may include repair or bioprosthesis at the time of implant. 12. Severe right ventricular failure as defined by the anticipated need for right ventricular assist device (RVAD) support or extracorporeal membrane oxygenation (ECMO) at the time of screening/randomization or right atrial pressure \> 20 mmHg on multiple inotropes or right ventricular ejection fraction (RVEF) \<15% with clinical signs of severe right heart failure (e.g. Lower extremity edema, ascites or pleural effusions refractory to treatment with diuretics and two inotropic drugs). 13. Active, uncontrolled infection diagnosed by a combination of clinical symptoms and laboratory testing, including but not limited to, continued positive cultures, elevated temperature and white blood cell (WBC) count, hypotension, tachycardia, generalized malaise despite appropriate antibiotic, antiviral or antifungal treatment. 14. Uncorrected thrombocytopenia or generalized coagulopathy (e.g., platelet count \< 75,000, INR \> 2.0 or PTT \> 2.5 times control in the absence of anticoagulation therapy). 15. Intolerance to anticoagulant or antiplatelet therapies or any other peri- or postoperative therapy that the investigator may administer based upon the patient's health status. 16. Serum creatinine \> 3.0 mg/dL within 72 hours of randomization or requiring dialysis or ultrafiltration. 17. Specific liver enzymes \[AST (SGOT) and ALT (SGPT\] \> 3 times upper limit of normal within 72 hours of randomization. 18. A total bilirubin \> 3 mg/dl within 72 hours of randomization, or biopsy proven liver cirrhosis or portal hypertension. 19. Pulmonary vascular resistance is demonstrated to be unresponsive to pharmacological manipulation and the PVR \> 6 Wood units. 20. Patients with a mechanical heart valve. 21. Etiology of heart failure is due to, or associated with, uncorrected thyroid disease, obstructive cardiomyopathy, pericardial disease, amyloidosis, active myocarditis or restrictive cardiomyopathy 22. History of severe COPD or severe restrictive lung disease (e.g. FEV1 \<50%) 23. Participation in any other study involving investigational drugs or devices 24. Severe illness, other than heart disease, which would limit survival to \< 3 years 25. Peripheral vascular disease with rest pain or ischemic ulcers of the extremities 26. Pregnancy 27. Patient unwilling or unable to comply with study requirements 28. Technical obstacles, which pose an inordinately high surgical risk, in the judgment of the investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Neurologic Injury | Implant to 12 Months | The primary endpoint is the percent of participants at 12 months on the originally implanted device with neurologic injury, defined as a stroke with Modified Rankin Scale (MRS) \> 0 at 24-weeks post-stroke, or a transient ischemic attack (TIA), or a spinal cord infarction (SCI). The Modified Rankin Scale is scored from 0 to 6, where 0 indicates an absence of symptoms and 6 indicates death. A score of 4 or higher indicates moderately severe or greater disability. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of HeartWare VAS Participants With Stroke/TIA | Implant to 12 Months | The first secondary endpoint is the number of HeartWare VAS participants with stroke/TIA at 12 months on the originally implanted device. |
| Number of Participants With Stroke-Free Success | Implant to 12 Months | Success is defined as alive on the originally implanted device, electively transplanted or explanted due to subject recovery and free from disabling stroke (Modified Rankin Scale \>=4). |
Countries
United States
Participant flow
Pre-assignment details
Subjects were considered enrolled upon signing informed consent. 19 enrolled subjects weren't randomized as they were considered screen failures. 10 subjects were randomized but didn't receive a device due to death (with 1 subject dying post anesthesia but prior to Left Ventricular Assist Device (LVAD) implant) or screen failure prior to implant.
Participants by arm
| Arm | Count |
|---|---|
| HeartWare® VAS HeartWare® VAS: The HeartWare® VAS is an implantable centrifugal pump that was designed to provide flows up to 10 L/min in a small device that is both lightweight and simple to use. | 308 |
| Control LVAD Control LVAD: Any FDA-approved LVAD for destination therapy. | 157 |
| Total | 465 |
Baseline characteristics
| Characteristic | Control LVAD | Total | HeartWare® VAS |
|---|---|---|---|
| Age, Continuous | 64.2 years STANDARD_DEVIATION 11.14 | 63.6 years STANDARD_DEVIATION 11.34 | 63.3 years STANDARD_DEVIATION 11.44 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 23 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 154 Participants | 442 Participants | 288 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race American Indian/Alaska Native | 1 Participants | 3 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Asian | 2 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Black/African American | 33 Participants | 105 Participants | 72 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian/Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Other | 3 Participants | 14 Participants | 11 Participants |
| Race/Ethnicity, Customized Race White | 118 Participants | 339 Participants | 221 Participants |
| Sex: Female, Male Female | 32 Participants | 88 Participants | 56 Participants |
| Sex: Female, Male Male | 125 Participants | 377 Participants | 252 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 56 / 308 | 31 / 157 |
| other Total, other adverse events | 95 / 308 | 40 / 157 |
| serious Total, serious adverse events | 295 / 308 | 152 / 157 |
Outcome results
Primary
Number of Participants With Neurologic Injury
The primary endpoint is the percent of participants at 12 months on the originally implanted device with neurologic injury, defined as a stroke with Modified Rankin Scale (MRS) \> 0 at 24-weeks post-stroke, or a transient ischemic attack (TIA), or a spinal cord infarction (SCI). The Modified Rankin Scale is scored from 0 to 6, where 0 indicates an absence of symptoms and 6 indicates death. A score of 4 or higher indicates moderately severe or greater disability.
Time frame: Implant to 12 Months
Population: Subjects were excluded if they withdrew, were lost to follow-up or have missing outcomes on original device.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HeartWare® VAS | Number of Participants With Neurologic Injury | 45 Participants |
| Control LVAD | Number of Participants With Neurologic Injury | 19 Participants |
Comparison: The primary endpoint is a non-inferiority test comparing HeartWare® VAS to Control.p-value: 0.144490% CI: [-5.5, 10.7]Farrington-Manning asymptotic test
Secondary
Number of HeartWare VAS Participants With Stroke/TIA
The first secondary endpoint is the number of HeartWare VAS participants with stroke/TIA at 12 months on the originally implanted device.
Time frame: Implant to 12 Months
Population: Subjects were excluded if they withdrew or were lost to follow up on the original device.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HeartWare® VAS | Number of HeartWare VAS Participants With Stroke/TIA | 59 Participants |
Comparison: The first secondary endpoint is the percent of participants with stroke/TIA at 12 months on the originally implanted device. It will be compared to 17.7%, which is the lower bound of a pre-defined margin of superiority based on the Endurance clinical trial.p-value: 0.736390% CI: [15.6, 23.3]Exact Binomial Test
Secondary
Number of Participants With Stroke-Free Success
Success is defined as alive on the originally implanted device, electively transplanted or explanted due to subject recovery and free from disabling stroke (Modified Rankin Scale \>=4).
Time frame: Implant to 12 Months
Population: Subjects were excluded if they had no associated 24 week post-stroke Modified Rankin Scale value, or if the subject withdrew or was lost to follow-up on original device, and no other failure outcome occurred within 1 year post original implant.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| HeartWare® VAS | Number of Participants With Stroke-Free Success | 229 Participants |
| Control LVAD | Number of Participants With Stroke-Free Success | 105 Participants |
p-value: <0.000190% CI: [-17.2, -1.1]Farrington-Manning asymptotic test
p-value: 0.0354Chi-squared