Is the Heart a Continuous Pump
Introduction
Advances in design and patient management have made left ventricular assist device (LVAD) therapy an indispensable tool in the management of advanced heart failure. One fourth of all US heart transplant recipients are supported with these devices before transplantation, and their use for permanent therapy is increasing.1 The large size and limited durability of pulsatile-flow pumps2 led to the development of a smaller, continuous-flow, axial design pump with improved durability and long-term survival.3,4 Although the incremental benefits of the second-generation pump have been substantial, complications, including bleeding, infection, and stroke, continue to pose challenges. A third-generation, continuous-flow, centrifugal pump has been developed that may offer additional advantages.5,6 Like the commercially available axial-flow pump, this pump has only 1 moving part. However, this pump has no mechanical bearings, is implanted directly in the left ventricle, and is positioned in the pericardial space.
Editorial see p 3069
Clinical Perspective on p 3200
We conducted a multicenter, prospective study of this novel, continuous-flow, centrifugal LVAD, comparing success and survival against a contemporaneous control group from a national registry of commercially approved ventricular assist devices.7 We also assessed functional and quality-of-life outcomes and adverse events in the investigational device group.
Methods
Study Design
The study of the investigational device was conducted at 30 centers in the United States between August 2008 and August 2010 and was supervised by the sponsor (HeartWare) and a clinical research organization (Novella Clinical, Durham, NC). The study was designed by the sponsor's clinical affairs group in consultation with the Food and Drug Administration (FDA) and clinical investigators. Coordinators at each site collected all study data electronically and submitted them to the data analysis center of the clinical research organization. The academic authors had independent access to the data; they vouch for the completeness and accuracy of the data and the analyses.
A Data Safety Monitoring Board monitored and reviewed study compliance, adverse events, quality of life, and outcomes for the investigational device group. A Clinical Events Committee reviewed, classified, and adjudicated the causes of deaths and all adverse events of the patients who received the investigational device on a continuous basis, supplemented with quarterly teleconferences. Adverse events were classified by Interagency Registry for Mechanical Assisted Circulatory Support (INTERMACS) criteria.7
The study was conducted in compliance with FDA regulations for good clinical practices. The protocol was approved by the FDA and by an institutional review board designated by each participating clinical site.
Study Subjects
Adults with advanced heart failure who were eligible for heart transplantation at each center and were believed to be unable to survive without mechanical circulatory support were eligible for enrollment in the study. For enrollment, patients had to be eligible for United Network for Organ Sharing 1A or 1B status listing and not be supported by any other mechanical circulatory support device other than an intra-aortic balloon pump. (Complete inclusion and exclusion criteria are included in the online-only Data Supplement.)
Baseline data were obtained on patient consent and enrollment into the study. Assessments included demographics; health history; medications; INTERMACS patient profile8 (determined by an independent assessor); quality-of-life surveys (Kansas City Cardiomyopathy Questionnaire and EuroQoL EQ-5D questionnaire); 6-minute walk test distance; hematologic, biochemical, and hemodynamic data; and neurological and neurocognitive status.
Investigational Device
The HeartWare system consists of an implantable continuous-flow pump with centrifugal design (HeartWare ventricular assist device [HVAD]), an external controller, and external power sources (Figure 1). The pump is surgically placed within the pericardial space with the integrated inflow cannula positioned in the left ventricle, avoiding abdominal pump placement. The impeller, the only moving part within the pump, is suspended by passive magnetic and hydrodynamic thrust bearings to create contact-free rotation. The normal operating speed of the pump is 2000 to 3000 rpm, with a maximum flow rate of 10 L/min. The pump is connected to external system components by a driveline that is tunneled subcutaneously and exits the patient's abdominal wall. A controller operates the pump, regulates power, monitors system performance, and displays alarm notifications. The system can be powered by the following: a pair of rechargeable direct-current lithium-ion batteries, alternating-current power from an electric wall outlet, or a 12-V direct-current power source. A monitor displays pump performance, is used to set and adjust the operating parameters, and provides a means to download data from the controller. Details of device design, function, and surgical implantation technique have been described previously.5,9
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Figure 1. Components of the HeartWare left ventricular assist system. The continuous flow of blood through the centrifugal pump is shown. The inflow cannula is surgically implanted into the left ventricle. Blood is conveyed through the pump via an impeller that is suspended by a combination of magnetic and hydrodynamic forces, allowing frictionless rotation at operating speeds of 1800 to 2400 rpm. Blood exits the pump into a flexible, gel-impregnated outflow cannula that is connected to the ascending aorta by means of surgical anastomosis. The percutaneous lead is tunneled subcutaneously and carries wires from the pump to an external controller. The controller regulates power and operating signals to the pump and collects information about operations that can be downloaded for analyses. Two lithium ion batteries provide power with the combined capacity of >10 hours of use. The batteries are both rechargeable and replaceable.
Follow-Up After Investigational Device Implantation
Scheduled clinical assessments were performed until transplantation or until 60 days beyond device explantation for recovery or until 180 days after implantation while the subject was on LVAD support. Subjects remaining on LVAD support will be followed beyond 180 days for a total of 5 years. Assessments included physical examination, medications, functional assessments, serum chemistry and hematology, and LVAD system management information. Neurological assessments and quality-of-life questionnaires were administered at week 4, months 3 and 6, annually, and at device explantation.
Anticoagulation was individualized and differed among centers. As patients tolerated oral medication, warfarin and aspirin were started to transition from heparin (see the online-only Data Supplement).
Control Subjects
The control group for testing the primary study hypothesis was drawn from INTERMACS, which collects data on patients who receive FDA-approved durable mechanical circulatory support device therapy in the United States (Figure 2 and the online-only Data Supplement).7 The comparability of this control cohort and the interventional group and the criteria for comparison of the outcomes of the interventional group were determined in a prespecified manner with the use of only baseline characteristics (see the online-only Data Supplement).
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Figure 2. Creation of the populations for analysis. The control group included all adult patients enrolled in Interagency Registry for Mechanical Assisted Circulatory Support (INTERMACS) during the study enrollment period who met these additional criteria: only left ventricular assist device (LVAD) implanted, first ventricular assist device implantation, done as a bridge to transplantation, patient currently listed for heart transplantation, body surface area ≥1.2 m2, creatinine <5.0 mg/dL, not on dialysis within 24 hours of implantation, prospectively included in the registry, and not on ventilator support within 24 hours of implantation.
Outcomes
The primary outcome was a between-group comparison of success, with success prespecified as survival on the originally implanted LVAD for 180 days after implantation or explantation to receive a heart transplantation or for recovery10–12 before 180 days. For those explanted for recovery, survival 60 days after explantation was required for the outcome to be considered a success. Explantation for device exchange was considered a failure.
The main secondary end point was a between-group comparison of overall survival, defined as survival through 180 days after implantation on an implanted LVAD or explantation to receive a heart transplantation or for recovery. Any subject explanted for device exchange continued to be followed through day 180 for death or a censoring event.
Other secondary end points included incidence of all serious adverse events, including neurocognitive status and unanticipated adverse device effects; incidence of all device failures and device malfunctions; change in quality of life, as measured by the Kansas City Cardiomyopathy Questionnaire and the EQ-5D; and change in functional status, as measured by the 6-minute walk test and New York Heart Association functional class. All serious adverse events and those meeting INTERMACS criteria were adjudicated with respect to classification and device relatedness.
Statistical Analysis
For the investigational group, the intent-to-treat and safety populations both consisted of all patients who provided informed consent and who were anesthetized for implantation, and the per-protocol population included all such patients who did not have a prespecified major protocol violation (see the online-only Data Supplement). For the control group, the safety and per-protocol populations coincided, being by definition all patients as defined above. Analysis of the primary outcome was performed on the safety and per-protocol populations; analyses of secondary end points and safety outcomes other than mortality were performed on the safety population of the interventional group only.
A prespecified stratified analysis of the success/failure outcomes in the investigational and control groups was performed to determine the upper 95% confidence limit of the difference in success rates. The strata were the quartiles of the propensity scores derived from baseline characteristics of the investigational and control subjects (see the online-only Data Supplement). The upper 95% confidence limit on the weighted average of the stratum-specific differences in proportions, computed with the use of minimum risk weights,13 was compared with the prespecified 15% noninferiority margin. Subjects with an undeterminable outcome at 180 days were excluded from the analysis. A secondary analysis of the principal outcome examined success rates stratified by INTERMACS patient profiles only.
Differences between the investigational and control groups with respect to the overall survival end point were reported descriptively through Kaplan–Meier plots and through the estimated hazard ratio from a Cox proportional hazards regression, with treatment group as the independent variable and follow-up censored at the time of heart transplantation, device explantation for recovery, withdrawal of consent, or loss to follow-up. The separate components of the survival end point were also evaluated with the competing outcomes methodology.14 To provide more informative intermediate-term outcome results, the Kaplan–Meier and competing outcome results were reported with follow-up to 360 days after implantation.
Adverse events and device failures were reported both as the percentage of subjects affected and the rate per subject-year of follow-up, with follow-up to 180 days on the last subject. Descriptive statistics were provided for the other secondary end points and safety measures. Predicted survival with medical therapy for the investigational cohort, as predicted by the Seattle Heart Failure Model, was calculated as described previously.15
Results
Study Groups
For the investigational device group, 157 patients provided informed consent, and 17 were screening failures. Thus, 140 patients met study enrollment criteria and were implanted with the investigational pump between August 18, 2008, and February 26, 2010. Three patients were excluded from the per-protocol population because of major protocol violations at the time of implantation: 2 for liver enzymes >3 times normal and 1 for participation in another clinical trial (Figure 2).
During this same period, 544 adults had a commercially available LVAD placed as a bridge to transplantation and were enrolled in INTERMACS. Forty-five patients were excluded for meeting 1 or more exclusion criteria, leaving 499 control patients. Two of these patients had follow-up consent withdrawn before 180 days, leaving 497 controls for the primary analysis; all 499 were used for other analyses (Figure 2).
Although INTERMACS policy prevents disclosure of the precise breakdown of pump types in the control group, an estimate can be inferred from publicly available information.16 Of all implanted pumps entered in INTERMACS, continuous-flow implantable pumps comprised 95.0% of implanted pumps between January 2008 and June 2010, and we take this to represent a conservative estimate of the proportion of LVADs in the INTERMACS control group that were continuous flow. Thus, the comparison presented in this study is between a centrifugal design, continuous-flow, investigational device group and a control group likely comprised almost exclusively of patients who received an axial design, continuous-flow device.
Baseline Characteristics
Baseline data from the limited categories available from INTERMACS for the control group were compared with those of the investigational device group in Table 1. There were no differences between groups in these baseline characteristics, with the exception of INTERMACS profiles, which were lower for control subjects, suggesting their greater severity of illness by this metric. Additional data available only for the investigational group are shown in Table 2. Despite high doses of loop diuretics (oral furosemide equivalent 6.8±1.8 mg/kg per day), maximal oral medical therapy had failed in all subjects, with 83% receiving 1 or more intravenous inotropic agents and 25% supported with an intra-aortic balloon pump. Predicted 1-year survival with medical therapy for the investigational cohort by the Seattle Heart Failure Model was 43±5%.15
| Investigational (n=140) | Control (n=499) | P | |
|---|---|---|---|
| Age, n (%) | 0.19 | ||
| 0–18 y | 0 | 2 (0.4) | |
| 19–39 y | 13 (9.3) | 78 (15.6) | |
| 40–59 y | 82 (58.6) | 256 (51.3) | |
| 60–79 y | 45 (32.1) | 163 (32.7) | |
| ≥80 y | 0 | 0 | |
| Mean (SD) age, y | 53.3±10.3 | 52.2±12.2 | |
| Gender, n (%) | 0.36 | ||
| Male | 101 (72) | 379 (76) | |
| Female | 39 (28) | 120 (24) | |
| Race, n (%)* | 0.86 | ||
| White | 102 (73) | 325 (65) | |
| Black | 32 (23) | 142 (29) | |
| Asian | 1 (0.7) | 4 (0.8) | |
| Pacific Islander | 0 | 2 (0.4) | |
| American Indian/Alaska Native | 1 (0.7) | 2 (0.4) | |
| Other | 4 (2.9) | 17 (3.4) | |
| Prior cardiac surgery, n (%) | 0.2902 | ||
| Yes | 33 (23.6) | 139 (27.9) | |
| No | 107 (76.4) | 360 (72.1) | |
| INTERMACS patient profile, n (%) | <0.0001 | ||
| INTERMACS 1 | 7 (5) | 39 (7.8) | |
| INTERMACS 2 | 34 (24.3) | 259 (51.9) | |
| INTERMACS 3 | 73 (52.1) | 103 (20.6) | |
| INTERMACS 4 | 13 (9.3) | 60 (12) | |
| INTERMACS 5 | 6 (4.3) | 15 (3) | |
| INTERMACS 6 | 2 (1.4) | 9 (1.8) | |
| INTERMACS 7 | 5 (3.6) | 14 (2.8) | |
| Body mass index, kg/m2 | 28.6±6.1 | 28.3±6.3 | 0.63 |
| Body surface area, m2 | 2.06±0.28 | 2.07±0.3 | 0.59 |
| Weight, kg | 88.1±21.2 | 87.2±21.5 | 0.66 |
| Height, cm | 175.3±9.6 | 175.5±10.3 | 0.86 |
| Blood urea nitrogen, mg/dL | 25.3±13.5 | 28.9±20.9 | 0.03 |
| Right atrial pressure, mm Hg | 10.8±3.3 | 11.5±5.0 | 0.11 |
| Serum creatinine, mg/dL | 1.3±0.4 | 1.4±0.6 | 0.06 |
| Characteristics | |
|---|---|
| Age, y | 53.3±10.3 |
| Ischemic cause of heart failure, % | 41 |
| Left ventricular ejection fraction, % | 17.8±7.1 |
| Arterial blood pressure, mm Hg | |
| Systolic | 104±16 |
| Diastolic | 64±11 |
| Mean | 77±13 |
| Pulmonary capillary wedge pressure, mm Hg | 23±9 |
| Cardiac index, L/(min · m2) | 2±0.5 |
| Pulmonary artery pressure, mm Hg | |
| Systolic | 49±15 |
| Diastolic | 25±9 |
| NYHA class, % | |
| III | 3.6% |
| IV | 96.4% |
| Laboratory values | |
| Serum sodium, mmol/L | 135±4.3 |
| Serum albumin, g/dL | 3.4±0.9 |
| Serum cholesterol, mg/dL | 136±35 |
| Blood urea nitrogen, mg/dL | 26±14 |
| Serum alanine aminotransferase, U/L | 35±36 |
| Serum aspartate aminotransferase, U/L | 31±19 |
| Serum bilirubin, mg/dL | 1.1±0.9 |
| Hematologic values | |
| Hematocrit, % | 34±5.8 |
| White cell count, ×109/L | 7.5±2.5 |
| Platelets, ×109/L | 216±76 |
| International normalized ratio | 1.3±0.4 |
| Concomitant medications, n (%) | |
| Intravenous inotropic agents | |
| 1 inotrope | 115 (82) |
| ≥2 inotropes | 16 (11) |
| Diuretic | 119 (85) |
| Oral furosemide dose, mg/(kg · d) | 6.8±1.8 |
| ACE inhibitor | 43 (31) |
| Angiotensin II receptor antagonist | 20 (14) |
| β-blocker | 84 (60) |
| Digoxin | 50 (36) |
| Hydralazine | 28 (20) |
| Amiodarone | 99 (71) |
| Heparin | 70 (50) |
| Warfarin | 4 (3) |
| Aspirin | 41 (29) |
| Mechanical device, n (%) | |
| Implantable cardioverter-defibrillator | 119 (85) |
| Intra-aortic balloon pump | 35 (25) |
| Mechanical ventilation | 1 (1) |
Clinical Course for the Investigational Group
Operative time was 203 (160, 249) (median [25th, 75th percentiles]) minutes, with a cardiopulmonary bypass time median of 71 (58, 98) minutes. Day 1 pump settings were as follows: speed, 2700 (2500, 2800) rpm; power, 3.85 (3.40, 4.50) W; estimated flow, 4.7 (4.1, 5.3) L/min. Recipients spent 6 (4, 11) days in the intensive care unit after implantation, and total hospitalization time was 20 (16, 31) days. Five patients required right ventricular assist device support: 4 in the first 30 days after implantation and 1 additional patient at 75 days.
At 6 months, functional capacity, global quality of life, and heart failure–specific quality of life each improved markedly (Table 3).
| All at Baseline | Baseline, No Follow-Up | Baseline, With Follow-Up | At 6-mo Follow-Up | Change From Baseline | P, Change From Baseline | |
|---|---|---|---|---|---|---|
| 6-min walk, m† | n=132 | n=58 | n=74 | n=74 | n=74 | |
| 0, 0, 189.6 | 0, 0, 151.5 | 0, 0, 204.2 | 0, 274.2, 365.8 | 0, 128.5, 313.3 | <0.001 | |
| EQ-5D Visual Analog Scale‡ | n=130 | n=58 | n=72 | n=72 | n=72 | |
| 40±24 | 37±24 | 42±23 | 70±20 | 28±25 | <0.001 | |
| Kansas City Cardiomyopathy Questionnaire overall summary score‡ | n=128 | n=58 | n=70 | n=70 | n=70 | |
| 35±19 | 33±16 | 36±21 | 67±21 | 30±26 | <0.001 | |
| Kansas City Cardiomyopathy Questionnaire clinical summary score‡ | n=128 | n=58 | n=70 | n=70 | n=70 | <0.001 |
| 44±22 | 43±20 | 45±23 | 74±21 | 29±28 |
Outcomes
All 140 investigational device patients were followed for at least 180 days or until transplantation or death (Table 4). Eighty-eight patients (62.9%) remained on the originally implanted study device at 180 days, and 39 (27%) were transplanted during this period. Death on the originally implanted device and device exchanges at ≤180 days each occurred in 6 patients (4.3%) in the safety population (5 patients [3.6%] of the per-protocol population). Deaths were the result of multisystem organ failure (in 3 patients), hemorrhagic stroke (in 2 patients), and right heart failure (in 1 patient). With the use of competing outcomes methodology, these results are displayed for the investigational device safety population in Figure 3. Two additional deaths at ≤180 days occurred after device exchange, both as a result of multisystem organ failure.
| Population | ||
|---|---|---|
| Safety (n=140) | Per Protocol (n=137) | |
| Outcome | ||
| Principal outcomes to 180 d, n (%) | ||
| Heart transplantation | 39 (27) | … |
| Recovery with explantation | 0 | … |
| Ongoing device support on original device | 88 (62.9) | … |
| Waiting list for transplantation | 73 (52.1) | … |
| Eligible for transplantation* | 13 (9.3) | … |
| Adverse outcomes, n (%) | ||
| Death on original device at | 6 (4.3) | 5 (3.6) |
| Patients withdrawn from study | 0 | 0 |
| Device exchange at | 7 (5) | 6 (4.3) |
| Death on second device at | 2 (1.4) | 2 (1.4) |
| Evaluation of primary study outcome | ||
| Success (transplantation, recovery, or ongoing support on original device at 180 d), n (%)† | 127 (90.7) | 126 (92.0) |
| Upper 95% confidence limit on difference of success (INTERMACS vs investigational pump), % | 4.5 | 0.9 |
| P (1-sided) with respect to noninferiority hypothesis‡ | <0.001 | <0.001 |
| P (1-sided) with respect to superiority | 0.47 | 0.11 |
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Figure 3. Outcomes for the investigational pump group (safety population, n=140) displayed with the use of competing outcomes methodology. At any point in time, the sum of the probabilities of each outcome event totals 100%. HVAD indicates HeartWare ventricular assist device.
Success on the primary end point occurred in 92.0% of the investigational device patients in the per-protocol study population, 90.7% of the investigational device patients in the safety study population, and 90.1% of INTERMACS control patients. Success for the investigational device cohort was found to be noninferior to that of the controls for both the per-protocol and safety populations (P<0.001); the upper confidence limits on the differences were 4.5% (per-protocol populations) and 0.9% (safety populations), both within the 15% prespecified noninferiority margin. Superiority could not be established (Table 4). Success rates were very similar for the 2 groups when stratified by INTERMACS profile (see the online-only Data Supplement).
As shown in Figure 4, Kaplan–Meier survival estimates at 30, 60, 180, and 360 days were 99%, 96%, 94%, and 86% for the investigational device group and 97%, 95%, 90%, and 85% for the INTERMACS control group.
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Figure 4. Kaplan–Meier survival censored at transplantation or explantation for recovery for the investigational pump group (safety population, n=140) and for Interagency Registry for Mechanical Assisted Circulatory Support (INTERMACS) controls (n=499). Follow-up for 360 days for patients not experiencing an earlier event is shown. HVAD indicates HeartWare ventricular assist device; BTT, bridge to transplantation.
Adverse Events
Adverse events experienced by investigational pump patients are shown in Table 5. The event types are typical of those reported previously for an axial design, continuous-flow pump.3,4,17,18 Bleeding, infections, and perioperative right heart failure were the most frequent complications. Inotropic support for >14 days was required by 16.4% of patients. Driveline exit site infections and sepsis occurred in 12.1% and 11.4% of recipients, respectively. One patient developed intercostal arterial bleeding secondary to erosive contact of the device with the left chest wall. Electromagnetic interference with sensing in implantable cardioverter-defibrillators was reported for 2 subjects in ADVANCE, resulting in inappropriate shocks. The sensing leads in the 2 subjects were replaced and positioned at the mid right septum with complete resolution of the electromagnetic interference.
| Overall | 0–30 Days | >30 Days | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Patients With Event | No. of Events | Event Rate PPY | Patients With Event† | No. of Events | Event Rate PPY | Patients With Event† | No. of Events | Event Rate PPY | |
| Bleeding | |||||||||
| Requiring surgery | 20 (14.3) | 23 | 0.26 | 20 (14.3) | 23 | 2.02 | 0 | 0 | 0.00 |
| ≥4 U PRBCs within 7 d after implant | 11 (7.9) | 11 | 0.12 | 11 (7.9) | 11 | 0.97 | NA | NA | NA |
| Gastrointestinal sites‡ | 15 (10.7) | 21 | 0.23 | 6 (4.3) | 6 | 0.53 | 9 (6.4) | 16 | 0.20 |
| Arrhythmias | |||||||||
| Supraventricular | 28 (20) | 36 | 0.40 | 21 (15) | 25 | 2.20 | 10 (7.1) | 11 | 0.14 |
| Ventricular† | 29 (20.7) | 35 | 0.39 | 14 (10) | 15 | 1.32 | 15 (10.7) | 20 | 0.26 |
| Infection | |||||||||
| Driveline exit | 17 (12.1) | 26 | 0.29 | 5 (3.6) | 5 | 0.44 | 14 (10.0) | 21 | 0.27 |
| Sepsis | 16 (11.4) | 21 | 0.24 | 3 (2.1) | 3 | 0.26 | 13 (9.3) | 18 | 0.23 |
| Respiratory failure | 28 (20.0) | 40 | 0.45 | 22 (15.7) | 27 | 2.38 | 8 (5.7) | 13 | 0.17 |
| Renal failure | 12 (8.6) | 14 | 0.16 | 8 (5.7) | 8 | 0.70 | 5 (3.6) | 6 | 0.08 |
| Right heart failure | |||||||||
| RVAD requirement | 4 (2.9) | 4 | 0.04 | 3 (2.1) | 3 | 0.26 | 1 (0.7) | 1 | 0.01 |
| Inotropic support | 23 (16.4) | 26 | 0.29 | 17 (12.1) | 17 | 1.49 | 8 (5.7) | 9 | 0.12 |
| Stroke | |||||||||
| Ischemic§ | 10 (7.1) | 10 | 0.11 | 7 (5.0) | 7 | 0.62 | 3 (2.1) | 3 | 0.04 |
| Hemorrhagic‖ | 8 (5.7) | 8 | 0.09 | 3 (2.1) | 3 | 0.26 | 5 (3.6) | 5 | 0.06 |
| Transient ischemic attack | 6 (4.3) | 7 | 0.08 | 2 (1.4) | 2 | 0.18 | 4 (2.9) | 5 | 0.06 |
| Psychiatric episodes | 13 (9.3) | 13 | 0.15 | 5 (3.6) | 5 | 0.44 | 8 (5.7) | 8 | 0.10 |
| Arterial thromboembolism | 5 (3.6) | 5 | 0.06 | 0 | 0 | 0 | 5 (3.6) | 5 | 0.06 |
| Venous thrombosis | 9 (6.4) | 9 | 0.10 | 5 (3.6) | 5 | 0.44 | 4 (2.9) | 4 | 0.05 |
| Device replacement | |||||||||
| Confirmed pump thrombus¶ | 3 (2.1) | 3 | 0.03 | 0 | 0 | 0 | 3 (2.1) | 3 | 0.04 |
| High power event# | 2 (1.4) | 2 | 0.02 | 0 | 0 | 0 | 2 (1.4) | 2 | 0.03 |
| Procedure related** | 3 (2.1) | 3 | 0.03 | 3 (2.1) | 3 | 0.26 | 0 | 0 | 0 |
| Infection†† | 1 (0.7) | 1 | 0.01 | 0 | 0 | 0 | 1 (1) | 1 | 0.01 |
| Exchange for BiVAD‡‡ | 1 (0.7) | 1 | 0.01 | 0 | 0 | 0 | 1 (1) | 1 | 0.01 |
| Hemolysis | 5 (3.6) | 5 | 0.06 | 2 (1.4) | 2 | 0.18 | 3 (2.1) | 3 | 0.04 |
| Hepatic dysfunction | 4 (2.9) | 4 | 0.04 | 3 (2.1) | 3 | 0.26 | 1 (0.7) | 1 | 0.01 |
Discussion
We have shown that a novel centrifugal design, continuous-flow pump implanted directly into the left ventricle and positioned within the pericardial space is associated with excellent outcomes when used as a bridge to transplantation. The investigational device yielded a 90.7% probability of success at 180 days, a result noninferior to that of contemporaneous control patients receiving commercially available implanted LVADs. Actuarial survival with the investigational device was 99% at 30 days, 94% at 180 days, and 86% at 1 year. These outcomes reflect incremental improvement in survival since the initial European bridge-to-transplantation trial of the same device.19 In properly selected patients with advanced heart failure, a LVAD can now be implanted with an exceptionally low perioperative mortality and excellent 1-year survival comparable to heart transplantation.
Patients entered this study with markedly impaired functional capacity and quality of life, and both improved markedly with the investigational device. The magnitude of these improvements is perhaps best appreciated in the context of achievements with other clinical interventions utilized in patients with advanced heart failure. The 128.5-m improvement in median 6-minute walk distance is nearly 3-fold greater than the improvement achieved with cardiac resynchronization therapy in New York Heart Association class IV patients in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial.20 Heart failure–related quality of life, as reflected in the 2 Kansas City Cardiomyopathy Questionnaire summary scales, increased 30 and 29 points; these are very large, clinically relevant improvements on these scales, in which an increase of 22±16 points represents a large improvement.21
The present generation of pumps has external drive lines, microprocessors, and power supplies; patients are restricted from bathing and swimming and must come to terms with their dependence on the technology. However, the EQ-5D Visual Analog Scale score, a grading in which patients rate their overall health state, rose 28±25 to 70±20 in study device subjects at 6 months, reaching a level similar to that of heart transplant recipients.22 Taken together, these findings confirm the substantial improvement in exercise capacity and quality of life that can be achieved with continuous-flow ventricular assist technologies in patients with advanced heart failure.23
These salutary effects of LVAD therapy must be weighed against the associated adverse events. The key adverse events that complicate device therapy are bleeding, infection, stroke, right heart failure, device replacement, kidney dysfunction, hemolysis, and arrhythmias.2–4,17,18 To provide a context for the adverse event rates in ADVANCE, it is instructive to contrast them with the corresponding rates observed with the use of the only commercially available intracorporeal, continuous-flow (axial design) ventricular assist device in the United States, the HeartMate II (Thoratec Corporation, Pleasanton, CA), in the most recent report of its US bridge-to-transplantation trial.3
Only 10.7% of patients (n=15) experienced gastrointestinal bleeding in this study. Bleeding has been more frequent with continuous-flow pumps than with pulsatile ventricular assist devices.2–4,17,18,24 Although anticoagulation is recommended for all continuous-flow pumps, bleeding is also thought to result in part from an acquired von Willebrand syndrome and a greater prevalence of arteriovenous malformations, consequent to reduced pulsatility and excessive fluid shear.17,24–26 The relatively low risk of reoperation for bleeding with the HVAD in this study (0.26/patient-year versus 0.45/patient-year for the HeartMate II) may reflect in part the smaller dissection required for an intrapericardial pump.3 Infection, right heart failure, device replacement, stroke, kidney dysfunction, hemolysis, and arrhythmia rates for the HVAD were similar to those reported previously for the HeartMate II.3
Electromagnetic interference between the HVAD and an implantable cardioverter-defibrillator occurred in 2 patients. Evaluation for electromagnetic interference before discharge is recommended. Adjustments in sensitivity of the implantable cardioverter-defibrillator (or pacemaker) may be required, or sensing leads may be replaced and repositioned.
Several limitations of our study should be noted. First, treatment assignment was not randomized. We compared success and survival outcomes with contemporaneous patients receiving FDA-approved ventricular assist device therapy for bridge to transplantation in INTERMACS. Lack of randomization increases the possibility that prognostically relevant baseline characteristics differed between groups and that selection bias influenced the results. However, the design of ADVANCE improved on previous FDA pivotal bridge-to-transplantation trials, which involved nonrandomized comparisons with ad hoc historical controls (patients at the implanting centers with similar characteristics who did not receive a ventricular assist device)27 or comparison with an objective performance criterion (ie, a prespecified probability of success).28 Because outcomes for bridge-to-transplantation ventricular assist device recipients have been improving continuously, the comparison with contemporaneous INTERMACS controls in ADVANCE removes a confounding factor in assessing treatment success. It also provides a more clinically relevant comparator than an objective performance criterion that might have been set too low.
Second, the modest number of pulsatile flow pumps in the INTERMACS cohort may have negatively affected the outcomes of this group. ADVANCE began before FDA approval of the Thoratec HeartMate II for bridge to transplantation, and therefore that device could not be prespecified as the comparator. However, the survival rate of the control group was virtually identical to that observed in the recent HeartMate II postmarket surveillance study (96%, 90%, and 85% at 30 days, 6 months, and 1 year), suggesting that the pumps of our control group were almost exclusively HeartMate IIs.29 Furthermore, outcomes of the INTERMACS cohort may have been modestly enhanced by the INTERMACS definition of "primary LVAD" that excludes patients who also received a right ventricular assist device during the initial operation. In addition, potential incomplete enrollment of eligible patients (≈11% of eligible patients are not enrolled in INTERMACS [D.C. Naftel, PhD, personal communication, October 17, 2010) and the opportunity for postimplantation enrollment of surviving patients up to 30 days after implantation represent differences in group enrollment with undetermined effects on survival and success. Therefore, in comparing investigational pump outcomes with those of control patients enrolled in INTERMACS, the study protocol conservatively prespecified that the investigational device be compared with the control with the use of a noninferiority criterion. Comparison of hard outcomes with those of a national registry provides a cost-effective method for device developers, clinical investigators, and regulators to more rapidly assess new technology while ensuring patient safety. However, in view of the aforementioned issues and because the protocols for adverse event reporting and adjudication in INTERMACS differ from those mandated by the FDA for a pivotal clinical trial, we could not compare adverse event rates between these groups, nor would it have been legitimate to compare ADVANCE adverse event rates with those in the HeartMate II postmarketing study, which evaluated outcomes and safety of the first 162 HeartMate II recipients enrolled in INTERMACS between April and August 2008.29 Rather, we contrasted adverse events rates for the HVAD in this trial with those of the HeartMate II in the latest report of its bridge-to-transplantation trial.3 Because the results derive from 2 separate trials, they should be viewed as solely hypothesis generating unless confirmed in a randomized clinical trial.
The design features of this pump provide grounds for anticipating long-term durability and reliability. However, an assessment of durability will require the much longer duration of follow-up that can only be achieved with the ongoing destination therapy trial. Finally, serial assessment of functional capacity and quality of life were limited by incomplete data on many subjects, including our inability to collect data on some critically ill patients, possibly leading to inaccurate estimation of the true benefits of investigational device therapy.
In summary, a small, continuous-flow, centrifugal pump with a single magnetically and hydrodynamically levitated moving part, implanted directly in the left ventricle and positioned within the pericardial space, was associated with high rates of 180-day success and survival and a favorable adverse event profile when used as a bridge to transplantation. Perioperative mortality was 1%, and survival at 1 year was 86%. Quality-of-life and functional capacity improvements were much larger than those seen with any drug or device therapy for advanced heart failure and were similar to those obtained with cardiac transplantation.
Sources of Funding
This study was funded by the sponsor, HeartWare, Inc. INTERMACS is funded under contracts from the
Disclosures
The authors report the following disclosures: Dr Aaronson: research grant (≥$10K),* speaker fees (<$10K) from HeartWare, and travel funds to HeartWare Investigator meetings (<$10K). Dr Aaronson's activities have been reviewed and approved by the University of Michigan Medical School Conflict of Interest Board, and a management plan is in place. Dr Slaughter: contract for services to HeartWare (≥$10K) and Thoratec (<$10K). Dr Miller: research grants from
Footnotes
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This study investigated a small, intrapericardially positioned, continuous-flow centrifugal pump, the HeartWare ventricular assist device, as a bridge to heart transplantation. The course of 140 investigational pump patients was compared with that of 499 patients implanted contemporaneously as a bridge to transplantation with commercially available ventricular assist devices and enrolled in a national registry. Perioperative mortality for the investigational pump group was 1%, and Kaplan–Meier estimated survival at 1 year was 90%. The primary outcome, defined as survival on the originally implanted device, transplantation, or explantation for ventricular recovery at 180 days, occurred in 92.0% of investigational pump patients and 90.1% of controls, establishing the noninferiority of the investigational pump. At 6 months, 6-minute walk test distance improved by 152 m, and both disease-specific and global quality-of-life scores improved substantially. The adverse event profile with the investigational pump was notable for relatively low rates of gastrointestinal bleeding and bleeding requiring surgery, with other adverse event rates similar to those reported previously for continuous-flow pumps in bridge-to-transplantation trials. Quality-of-life and functional capacity improvements were much larger than seen with any drug or device therapy for advanced heart failure and similar to those obtained with cardiac transplantation. This study demonstrates the excellent outcomes that are now achievable with the present generation of small, continuous-flow pumps.
Source: https://www.ahajournals.org/doi/10.1161/circulationaha.111.058412
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