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Ann Thorac Surg 2004;78:2123-2130
© 2004 The Society of Thoracic Surgeons
a USA
b USA
c Sharp Memorial Hospital, San Diego, California; St. Luke's Medical Center, Milwaukee, Wisconsin, USA
d California Pacific Medical Center, San Francisco, California, USA
e International Center for Health Outcomes and Innovation Research (InCHOIR); Columbia University, New York, New York, USA
f Rush Presbyterian, Chicago, Illinois, USA
g University of Alabama at Birmingham, Birmingham, Alabama, USA
h Temple University Hospital, Philadelphia, Pennsylvania, USA
i Thoratec Corp, Pleasanton, California, USA
j Latter-Day Saints (LDS) Hospital, Salt Lake City, Utah, USA
Accepted for publication February 10, 2004.
* Address reprint requests to Dr Gelijns, International Center for Health Outcomes and Innovation Research, Columbia University, 600 W 168th St, 7th Floor, New York, NY 10032, USA
acp10{at}columbia.edu
Presented at the Thirty-ninth Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Jan 31–Feb 2, 2003.
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Abstract |
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METHODS: REMATCH is a randomized trial that compares optimal medical management with LVAD implantation for patients with end-stage heart failure. An independent committee adjudicated patient outcomes. The primary endpoint—survival—was analyzed by intention to treat using the log-rank statistic. Frequency of event occurrence was analyzed by Poisson regression. The time to first event was analyzed by the product limit method. Device performance was disaggregated into confirmed malfunctions and system failures. The latter were events in which patients could not be rescued with backup circulatory support measures.
RESULTS: The 1-year survival rate was 52% (95% confidence limit [CL]; 40%–63%) for LVAD patients versus 28% (95% CL; 17%–39%) for medical patients and the 2-year survival rate was 29% (95% CL; 19%–40%) for LVAD patients versus 13% (95% CL; 5%–22%) for medical patients. System failure was 0.13 per patient per year and the confirmed LVAD malfunction rate was 0.90. Freedom from device replacement was 87% at 1 year and 37% at 2 years.
CONCLUSIONS: Despite the observed rates of device malfunction and replacement, LVAD implantation confers clinically significant improvement with regard to survival as compared with medical management. Device modifications and innovations for infection management exhibit great promise of improving device performance in the near future.
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Introduction |
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TopAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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| Ms Damme and Mr Poirier and Heatley disclose that they have a financial relationship with Thoratec Corp.
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In 2003 the Food and Drug Administration (FDA) approved the Thoratec HeartMate (Thoratec Corp, Pleasanton, CA) vented electric (VE) left ventricular assist device (LVAD) for long-term support of patients with end-stage heart failure, which was followed by reimbursement approval for this indication from the Center for Medicare and Medicaid Services (CMS). These approvals were based upon data collected in the multicenter randomized evaluation of mechanical assistance for the treatment of congestive heart failure (REMATCH) trial. Meeting its primary endpoint in July 2001, the trial demonstrated that LVAD implantation decreased the 1-year mortality by a third (from 75% down to 51%) compared with medical management [1]. This survival advantage was associated with a considerable improvement in the quality of life and functional status of these patients, as compared with their medical counterparts. However, these benefits were not without disadvantage: LVAD patients experienced considerably more adverse events than medically managed patients. Next to sepsis, LVAD failure was the leading cause of death among LVAD patients. As such LVAD failure and device malfunction rates are critical parameters for establishing LVADs as a long-term therapy for end-stage heart failure patients.
To date these device performance measures have been inadequately characterized in the bridge-to-transplantation (BTT) literature. Such implantations offer only a short period of observation that is rarely long enough to appropriately assess the durability of these mechanical devices. Moreover the published BTT trials typically have not been independently adjudicated and, for the most part, different device manufacturers employ unique definitions of failure and malfunction. The REMATCH trial collected detailed data on device performance that were adjudicated by an independent morbidity and mortality (M&M) committee and monitored by an independent Data Safety and Monitoring Board (DSMB) the latter of which was constituted by the National Heart, Lung, and Blood Institute (Bethesda, MD). To date these data have not been published. This paper characterizes the long-term experience with regard to device performance in the REMATCH trial and provides an additional 375 patient months of LVAD experience over the initial publication in 2001 [1]. Such a characterization can provide critical insights into future opportunities for improving patient management and device design as well as a standard for comparison.
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Material and Methods |
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Patient Population and Treatment Modalities
The trial targeted patients with chronic end-stage heart failure in New York Heart Association (NYHA) class IV for at least 60 of the last 90 days before enrollment despite adequate medical therapy. Detailed eligibility criteria are documented elsewhere [2]. All device patients received the HeartMate VE LVAD and associated medical care. A surgical management committee developed guidelines and monitored adherence. The LVAD recipients (n = 68) were compared with patients receiving OMM (n = 61), which included the use of angiotensin-converting enzyme inhibitors (ACEI), diuretics, digoxin, and ß-blockers if not contraindicated. OMM guidelines were established and adherence was monitored by a medical management committee.
Endpoints, Adjudication, and Monitoring
The primary endpoint was all-cause mortality. Quality of life was assessed using the Minnesota Living with Heart Failure (MLHF) questionnaire [3]. This survey instrument contains 21 questions regarding the patients' perceptions of the effects of heart failure on their daily lives. The best score is 0 and the worst score is 105. Adverse events were adjudicated by an external M&M committee (independent of the trial investigators and sponsors) and designated as serious if heart failure caused death, permanent disability, threatened life, or required prolonged hospitalization. The device evaluation committee, composed of engineers from the device manufacturer, evaluated device malfunctions and failures.
The focus of this current paper is device performance and the following definitions of performance were used. Device malfunction was defined as any instance when any component of the system failed to perform for its intended function. Loss of the display, inability to operate batteries, and temporary loss of life support caused by the device are examples. All device malfunctions were designated as suspect until confirmed by the device evaluation committee. The device evaluation committee was composed of engineers from the manufacturer and their analyses were forwarded to the morbidity and mortality committee for final adjudication.
LVAD system failure is defined as the inability of the device system (including either pneumatic backup or redundant components) to maintain adequate circulatory support. Inadequate circulatory support is defined as the presence of two of the following three conditions: (1) an acute reduction in cognitive function, (2) hemodynamic instability defined as a sustained systolic blood pressure less than 80 mm Hg and pulse greater than 120 beat/min, and (3) acute development of oliguria (< 30 mL/h) without evidence of urinary obstruction.
Thus if the LVAD failed but the patient could be maintained on pneumatic backup, the investigator would designate the event as a device malfunction and not an LVAD failure. However if the patient subsequently died while undergoing surgery, the M&M committee in adjudicating the causes of death would reclassify the patient as having died from a LVAD system failure. In this paper, therefore, we focus on presenting LVAD failures as a cause of death.
An independent DSMB monitored the progress of the trial. The trial met its primary endpoint in June 2001. At that point enrollment was discontinued and, based on the trial results, LVAD therapy was offered to the medical management patients. Three of the 5 remaining patients in the OMM arm of the trial opted for LVAD implantation. Data collection is ongoing.
Statistical Analysis
The primary endpoint—survival—was analyzed by intention to treat using the log-rank statistic. The adjudicated clinical and engineering dataset used for this analysis was closed in July 2003. The trial follow-up included 24 visits, which equaled 672 days. Adverse events were truncated after that time, but mortality and causes of death were followed for the life of the cohort as were device replacements. The frequency of event occurrence was analyzed by Poisson regression and expressed as rates per patient per year. Time to first event (eg, device failure) was analyzed by the product limit method of Kaplan and Meier [4]. Because of the inherent within patient correlation, we used a mixed model approach to analyze longitudinal quality of life [5].
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Results |
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Adverse Events: The Role of Device Malfunctions
Table 2 summarizes the five most common serious adverse events for LVAD recipients. The main adverse events for LVAD recipients included (1) sepsis, (2) bleeding, (3) neurologic dysfunction that subsumed stroke, (4) neurologic dysfunction that subsumed transient ischemic attacks (TIA), and (5) neurologic dysfunction that subsumed metabolic encephalopathy. The majority of neurologic events were transient in nature; 16% of LVAD patients experienced a stroke [6]. Table 3 breaks down the device-specific adverse events with confirmed device malfunctions being the leading source of such adverse events.
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Table 4 depicts the implantable component malfunctions. The pump component malfunctions included two diaphragm fractures, 13 bearing failures, and three motor component failures. The inflow conduit malfunctions included 32 events of inflow valve incompetence in 29 patients and one event of inflow graft perforation. Outflow conduit malfunctions included three graft kinks, one perforation, two instances of outflow valve incompetence, and one distorted washer (noted during pump explantation). In the majority of the external component malfunction cases (Table 5), the patients and/or caregivers resolved the problem by exchanging the components.
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Comment |
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In terms of patient management, sepsis is an obvious target for improvement. One year into the trial (Fall 1999) the REMATCH investigators began implementing guidelines for operating room and intensive care unit management to prevent infections that included antimicrobial prophylaxis and driveline immobilization with an abdominal binder [7]. Also they implemented a driveline infection management program that specified antimicrobial approaches to treatment. These guidelines were implemented based on the pilot trial preceding REMATCH (the PREMATCH trial) in that device-related infections developed in all device recipients, as well as during the early REMATCH experience. Given the limited sample size of the REMATCH trial, a full understanding of whether these measures are effective with regard to averting infection will require an analysis of postmarketing experience. An additional consideration, not addressed in the REMATCH protocol, is the necessity to reverse the long-term effects of malnutrition suffered by chronic heart failure patients as a means to restore normal immunological function that is likely to help avert infection. Although this is an important agenda item concerning the care of patients with advanced heart failure, therapeutic progress here has been slow. An additional nutritional consideration for LVAD patients is the added metabolic burden imposed by chronic inflammation from an indwelling intravascular device. Given the relationship of sepsis and survival that we observed, advancements in this area may exhibit a large impact with regard to the outcomes of LVAD recipients.
During REMATCH the most frequent malfunction was inflow valve incompetence. The inflow valve serves the same purpose as the mitral valve in the native heart partitioning the upstream chamber from the high systolic pressures generated by the LVAD. Intracavitary LVAD systolic pressure can be considerably increased by multiple factors including a kinking of the outflow graft, aortic outflow conduit anastomosis, and systemic hypertension. Outflow graft kinking can occur either during the initial implantation or after postoperative pump migration. Care must be taken when measuring the length of the outflow graft as well as placement. When making the anastomosis an elliptical or round opening should be created in the ascending aorta as opposed to a slit that only opens under pressure. Maintaining normal systemic pressures cannot be overemphasized as this aids in reducing increased pump pressures. Additionally valve distortion during implantation must be avoided because distortion can compromise the ability of the inflow valve to withstand pressures. Rotational deformity at the base of the valve, flexion deformity across the valve, and late axial excursion of the valve from high systolic pressures have created early unanticipated valve dysfunction in the clinical experience.
During the second half of the REMATCH trial, improvements to the pump were created that included "bend relief" for the outflow graft and locking screw rings. The outflow graft bend relief was designed to prevent kinking and abrasion of the outflow graft conduit, which was believed to cause graft erosion and blood loss as well as high pump chamber pressure that could contribute to increased stress on the inflow valve. The locking screw rings, a ratchet-type locking mechanism that secures the inflow and outflow valve conduits to the body of the LVAD pump, reduced the possibility of blood loss caused by accidental dislodgement.
Further pump improvements and system enhancements have been executed since the close of REMATCH enrollment. The HeartMate extended lead vented electric (XVE) LVAD, which was primarily designed to improve pump reliability and durability, became available for use in the Fall of 2001. Since that time nearly 500 BTT and DT patients have been implanted with this device and more than 100 years of patient experience has been accumulated. The new system includes a percutaneous tube that is longer, narrower, and more supple to assist in decreasing stress on existing site tissue and also includes new controller software to aid in controlling pump pressure levels that reduce the amount of stress on the inflow valve, diaphragm, and bearings. More recently the inflow valve was redesigned to facilitate inflow valve replacement without removal of the rigid titanium tube in the apex of the ventricle as well as to further reduce stress on the valve and reduce the risk of disconnection. These changes were approved by the FDA in November of 2003 and are currently being used.
With the introduction of changes in patient management and device design we anticipate improvement in the outcome of LVAD recipients. The current generation of pumps continue to undergo incremental improvement. At the same time new generations of LVADs, such as axial flow pumps or totally implantable devices, are being introduced in clinical trials that may more fundamentally address the device shortcomings observed in REMATCH. These devices exhibit smaller and more flexible drivelines or use a totally implantable design that eliminates a major portal for infection. Moreover as strategies for bridging to recovery using cell transplantation or gene therapy become more successful, issues regarding long-term device reliability may diminish in importance. Such advances could exact major economic implications. The mean total cost to insert an LVAD in the REMATCH patient population was $210,187, which includes a $60,000 charge for the device [8]. The average annual readmission cost per patient for the overall cohort was $105,326, the cost of which was considerably influenced by device reliability.
In conclusion, despite the device-related problems observed in REMATCH, patients experienced a significantly greater survival and quality of life than those on medical management. Given the fact that current pumps are continuously being improved to enhance reliability and durability, it is imperative that we track the outcomes associated with LVAD DT throughout its dissemination to ensure that we discern what improvements are helpful and what improvements are not.
Discussion
DR CRAIG SMITH (New York, NY): Was the data you indicated regarding the total HeartMate experience only on patients implanted as destination therapy or were patients removed for transplant or censored in some other way?
DR DEMBITSKY: The original FDA approval for the HeartMate LVAD was for use as a bridge device. There were 68 destination pumps placed during the REMATCH study. These pumps are included in the 2,066 reported here. In the overall experience some of the non-REMATCH patients originally unintended to be a bridge-to-transplant have become destination patients for a variety of reasons.
DR SMITH: Then some of the decrement in the curve is due to patients explanted for transplant?
DR DEMBITSKY: I think 60% of them were transplanted.
DR MATTHIAS LOEBE (Houston, TX): Excellent presentation! If we want to consider mechanical assist devices as a real alternative to heart transplantation, we definitely have to improve their technical performance. An analysis like the one you presented is extremely important and very, very good for identifying technical issues and ways to improve these devices. My question is could you identify any impact regarding the way the device was implanted on the occurrence of the wear-out of the inflow graft of the valve in particular and, in addition, did the way the pump was run—in fixed rate or in auto mode—have any impact on the long-term performance and technical reliability of the pump?
DR DEMBITSKY: Implantation techniques and management styles do have an impact on pump performance. In the REMATCH population the null hypothesis that there were no institutional differences for infection rates was rejected. Intraperitoneal and extraperitoneal pump placement seemed to have the same outcomes. From the larger experience both outflow graft kinking and uncontrolled systemic hypertension increase wear on the LVAD valves, especially the inflow valve. Because the pumps have finite life, lower fixed pump rates, if tolerated by the patient, translate into longer implant times.
DR SMITH: One implication of your discussion, as you describe plans to redesign something to avoid a particular problem, is that you might be making tradeoffs that introduce the possibility of another problem. For example if you make the valve more robust, might you make it more thrombogenic? Are there tradeoffs of this sort that you know you will confront?
DR DEMBITSKY: One can only speculate because the only way to predict whether a valve is going to be thrombogenic or not is to implant it in humans. The thinking is that the way fluids are going to pass through this valve there will be less turbulence, shear stress, recirculation, and stasis. This should translate into less thrombogenicity. Hemolysis has not been a problem. There are ways to look at flow geometries with analytical micro-flow techniques that may predict design flaws that cause thrombolysis and hemolysis. These virtual and real techniques, including computational fluid dynamics and digital particle image velocimetry, have so far been more widely applied to the prosthetic valve field than to the VAD field and have been extensively used in the aerospace industry.
DR GLENN WHITMAN (Philadelphia, PA): How much did the LVAD arm lose versus optimal medical management? Secondly where are we with regard to reimbursement for these devices?
DR DEMBITSKY: Cost was analyzed as part of the REMATCH study. That data was recently presented in Florida by Mehmet Oz and will soon be published. The cost for the survivors in the surgical arm was approximately the cost of a heart transplant—around $200,000. The cost for patients who did not survive was over $300,000. The cost of the medical arm is currently being analyzed and will also be published. At this time the FDA has approved the Thoratec HeartMate device for use as destination therapy. Some private insurance companies have approved payment for these devices. The federal funding agency has yet to decide exactly how it is going to fund this therapy and they are also in the process of trying to decide how the technology will be distributed throughout our culture.
DR DUKE CAMERON (Baltimore, MD): If I read one of your early slides correctly, bleeding was still one of the most frequent problems. Has the REMATCH trial shed any light on management of that problem? Is it seen more as a surgical failure than device problem?
DR DEMBITSKY: Most of these patients underwent at least one previous surgery and most of them were quite ill—oftentimes with hepatic and renal dysfunction and inanition. Bleeding was common but was usually limited. Later bleeding was not common because most patients were not systemically anticoagulated.
DR PEER PORTNER (Stanford, CA): Given that the inflow valve conduit is essentially the equivalent of the mitral valve, when you make it more rigid, don't you increase the stress on the valve elevating the risk?
DR DEMBITSKY: There is reduced axial movement of the valve in the new design. During accelerated in vitro testing the valve seems to be more robust.
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Acknowledgments |
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TopAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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References |
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TopAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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