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Ann Thorac Surg 2003;75:S86-S92
© 2003 The Society of Thoracic Surgeons
a Department of Surgery, The University of Iowa, Iowa City, Iowa, USA
b Department of Surgery, Columbia University, New York, New York, USA
j Columbia University, New York, New York, USA
c Bryan LGH Heart Institute, Lincoln, Nebraska, USA
d Department of Surgery, Texas Heart Institute, Houston, Texas, USA
e Division of Cardiovascular Surgery, Brigham & Women’s Hospital, Boston, Massachusetts, USA
f Section of Cardiac Surgery, University of Michigan, Ann Arbor, Michigan, USA
g Thoratec Corporation, Pleasanton, California, USA
h Department of Thoracic & CV Surgery and Transplantation, Ochsner Medical Foundation, New Orleans, Louisiana, USA
i Department of Cardiothoracic Surgery, Allegheny General Hospital, Pittsburgh, Pennsylvania, USA
k Department of Surgery, LDS Hospital, Salt Lake City, Utah, USA
* Address reprint requests to Dr Richenbacher, Division of Cardiothoracic Surgery, Department of Surgery, The University of Iowa Hospitals and Clinics, 200 Hawkins Drive, 1613B-JCP, Iowa City, IA 52242, USA.
e-mail: wayne-richenbacher{at}uiowa.edu
Published as part of the supplement on the Heart Failure & Circulatory Support Summit, Cleveland, OH, Aug 22–25, 2002.
Abstract
The donor shortage makes cardiac transplantation a less than ideal treatment for end-stage heart failure. The utility of the left ventricular assist device (LVAD) as a permanent form of circulatory support has recently been established in the REMATCH (Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure) trial. In this report, we describe the surgical management of LVAD patients in REMATCH and their short-term outcomes. Between 1998 and 2001, 129 patients with end-stage heart failure, who were excluded from consideration for transplantation, were enrolled in the REMATCH clinical trial. Patients were randomized to two treatment arms: optimal medical management or HeartMate vented electric LVAD implantation. The primary end point of the study was death from any cause. Secondary end points included the incidence of serious adverse events, the duration of hospitalization, quality of life, and functional status. Sixty-eight patients received an LVAD, 55 (81%) of whom survived for longer than 1 month. The median intensive care unit and hospital lengths of stay (LOS) for those that survived at least 1 month were 15 and 34 days, respectively. Sixty-seven (99%) patients had a serious adverse event. The rates of perioperative bleeding, late bleeding, right heart failure, and sepsis were 0.42, 0.53, 0.15, and 0.53 events/patient-year, respectively. Factors predictive of a longer LOS for the implant hospitalization included sepsis, age, and late bleeding (p < 0.0001). The patients’ New York Heart Association functional class improved significantly at 1 month compared with base line (p < 0.001). Functional class improved in LVAD-supported patients despite a high adverse event rate. Most adverse events occurred within 30 days of device implantation. Sepsis, age, and late bleeding were the major determinants of LOS.
| Laura Damme, RN, MPH, discloses that she has a financial relationship with Thoratec Corporation.
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The economic and public health burdens of end-stage congestive heart failure are well described. Approximately 4.9 million Americans, slightly less than 2% of the population, have been diagnosed with heart failure [1]. More than 400,000 new cases are diagnosed annually [1]. More importantly, both the incidence and prevalence of this disease increase exponentially with advancing age. Projections are that in the next 30 years the number of Americans older than 65 years will double. As the prevalence of heart failure doubles with each decade after age 45 years, the number of individuals at risk for the development of heart failure is expected to increase dramatically in the foreseeable future. Due to its high prevalence and intensive medical resource usage, heart failure has become the most costly cardiovascular disorder in the United States. Estimated annual expenditures exceed $20 billion [1].
Cardiac transplantation remains the gold standard for the surgical treatment of end-stage heart failure that is refractory to medical therapy. Despite legislative efforts and public education programs, however, the utility of this therapy is limited by a shortage of donors. Estimates are that 30,000 to 60,000 persons die of heart failure, whereas fewer than 2,400 heart transplants are performed in the United States each year [2]. Thus, there is a readily recognizable need for an alternative surgical therapy for patients with end-stage heart failure.
The goal of ventricular assist device (VAD) development has been to create a blood pump that can serve as a reliable alternative to cardiac transplantation. Although VAD systems have become the standard of care for the bridge to transplant application, these devices have not been deliberately implanted as a permanent form of circulatory support. A recent clinical trial (REMATCH: Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure) was designed to test the efficacy and safety of the HeartMate vented electric left ventricular assist system (HeartMate VE LVAD, Thoratec Corporation, Pleasanton, CA) as destination therapy for patients with end-stage heart failure, who were excluded from consideration for cardiac transplantation [3]. Patients enrolled in this trial were randomized to one of two treatment arms: medical therapy or left VAD (LVAD) implantation. Our objective is to characterize the surgical management and short-term clinical outcomes of LVAD recipients in REMATCH.
Material and methods
Patient population
The prospective, randomized trial was conducted at 20 centers. Adult patients with chronic end-stage heart failure who were ineligible for cardiac transplantation were candidates for enrollment provided they presented with New York Heart Association (NYHA) class IV or IIIB symptomatology. The latter group of patients also had to be inotrope or intraaortic balloon pump dependent for more than 2 weeks. Remaining inclusion and exclusion criteria are summarized elsewhere [3, 4]. The institutional review board at each site approved the protocol. Informed consent was obtained from all patients.
Left ventricular assist device treatment
A surgical management committee, consisting of the surgical principal investigator from each participating institution, developed general guidelines for perioperative patient management. All patients who were assigned to the LVAD arm of the study received the device within 24 hours of randomization. The night before LVAD insertion, the patient’s indwelling intravenous and arterial catheters were moved to new locations. Initially, perioperative antibiotic coverage was left to the discretion of each investigator. In an effort to minimize infectious complications, the surgical management committee subsequently reached a consensus agreement regarding perioperative antibiotic coverage. It was suggested that the antibiotic regimen summarized in Table 1
be implemented in September 1999.
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After the operation, the patients were rapidly extubated and mobilized. Lines and tubes were removed as soon as the patient’s clinical condition permitted. As the study progressed, the importance of nutritional supplementation was recognized. Surgical investigators convened at a Nutrition Conference on June 6, 2001. The consensus at this conference was that patients should receive enteral supplements beginning immediately after LVAD insertion, if appropriate. If the patient’s condition precluded the use of enteral feedings, central venous hyperalimentation would be used. Guidelines suggested that all patients be enrolled in a cardiac rehabilitation program.
Left ventricular assist device educational programs varied among centers. In general, the patient and a family member, or any individual who might have the opportunity to participate in the patient’s care, were taught about the care and use of the ventricular assist system. Emphasis was placed on troubleshooting and managing controller alarms and potential device malfunction. In many instances, local health care providers and emergency medical services also received device management training.
Patients were discharged from the hospital when their surgical wounds had healed, their postoperative convalescence was complete, and they met the educational goals for the device-training program. The index hospitalization was defined as the hospital stay during which LVAD implantation was performed. The index hospitalization length of stay (LOS) started at randomization and ended when the patient was discharged to home or a rehabilitation facility. After discharge, patients were required to live within 2 hours’ travel time of the implant center. Patients returned to the outpatient clinic at 28-day intervals for the duration of the study. In addition, the VAD coordinator contacted the patient by telephone every 7 days.
End points
The primary end point of the study was death from any cause. Secondary end points included the incidence of serious adverse events, the duration of hospitalization, quality of life assessments, and functional status. Adverse events were defined as serious if they caused death or permanent disability, were life threatening, or required prolonged hospitalization. Perioperative bleeding was defined as blood loss resulting in death, reoperation, or red blood cell transfusion of at least 6 units within 24 hours of LVAD implantation. Late bleeding was defined as an episode of internal or external bleeding that caused death, hospitalization, permanent injury, or necessitated transfusion of red blood cells. Right ventricular failure was defined as symptoms or signs of right heart failure requiring either right VAD (RVAD) implantation or inotropic therapy for 14 days or more after LVAD implantation. A localized infection was defined as an infection of an organ system or region without evidence of systemic involvement. Sepsis was defined as a serious infection, manifested by fever, tachycardia, and leukocytosis. Sepsis may or may not be associated with a localized infection or a positive microbiological culture. A percutaneous site or pocket infection was defined as a positive culture from the skin or tissue surrounding the drive line, coupled with the need to treat with antimicrobial therapy because of clinical evidence of infection (pain, fever, drainage, and/or leukocytosis).
Data analysis
The LVAD patient data summarized here are derived from the June 20, 2002, data set, which was adjudicated by an external morbidity and mortality committee. Information concerning concomitant operations was obtained by the first author’s retrospective review of operative notes. Multiple linear regression was used to discern predictors of LOS. A log transformation of LOS was used to normalize the data. For modeling the changes in hemodynamics and end-organ function for the three time points (base line, 1 month and 3 months after randomization), we used mixed modeling analyzed with the PROC MIXED procedure (the SAS System software, SAS Institute, Cary, NC). This approach estimates the standard errors by modeling the covariance structure of the repeated measures. These measures are inherently correlated within subject. Three of the common covariance structures include compound symmetry (cs), for correlations that are constant for any two points in time, autoregressive order one (ar1) for correlations that are smaller for time points further apart, and unstructured (un), which has no mathematical pattern within the covariance matrix. Other covariance structures tested included the Toplitz (toep) and the Heterogeneous Compound Symmetry structure (csh).
Results
Between May 15, 1998, and July 27, 2001, 129 patients were enrolled in REMATCH. Sixty-eight patients underwent LVAD implantation. When the trial reached its primary end point (July 2001), the 1-year survival in the LVAD population was 52% compared with 25% in the medical arm (p = 0.002) and 23% versus 8% at 2 years (p = 0.09). According to the most recent adjudicated (June 2002) data set, 16 LVAD and 5 medically managed patients remain alive (3 of the 5 medically managed patients received an LVAD after the study was completed). Patient demographics are shown in Table 2.
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In the REMATCH clinical trial, functional status in the LVAD cohort improved over base line, and this improvement persisted for at least 12 months. At enrollment, 97% of patients who received an LVAD were in NYHA class IV. Left ventricular assist device implantation normalized systemic perfusion. Although no formal rehabilitation protocol had been set for the LVAD patients in this trial, the ultimate goal was permanent discharge from the hospital. In most instances, patients received inpatient cardiac rehabilitative services with a goal of functional independence on hospital discharge. The observed improvement in NYHA functional class compares favorably with that reported in the HeartMate VE LVAD bridge to cardiac transplantation study [6]. In the latter trial, 153 of 160 (96%) patients enrolled were in NYHA class IV at base line. Seven (4%) patients were in NYHA class I to III. When these patients fulfilled the criteria for hospital discharge, 91 (57%) patients had improved to NYHA class II and 69 (43%) patients to NYHA class I.
In the present study the LVAD patient functional status improved despite a high rate of adverse events. Virtually all LVAD patients had a serious adverse event, the majority of which occurred within 30 days of LVAD implantation (Fig 2). The two most common perioperative adverse events were bleeding and right heart failure. The etiology of perioperative bleeding is multifactorial. Patients with end-stage heart failure suffer from end-organ hypoperfusion and central venous hypertension. The resultant hepatic dysfunction may produce a base line coagulopathic state. Initially, the trial protocol excluded patients with an international normalization ratio (INR) of more than 1.3 within 24 hours of randomization. However, the inability to correct even a mild elevation in INR in patients with hepatic dysfunction, and evidence that other major operations could be performed with higher INRs without major bleeding complications, led to a liberalization of this selection criterion. In January 1999, the INR entry criterion was raised to at least 1.5 within 24 hours of randomization. Nearly three-quarters of the patients received preoperative anticoagulation. More than half of the patients had undergone at least one sternotomy before LVAD implantation, and LVAD implantation was accompanied by a secondary cardiac operation in 28 (41%) patients. The pericardial adhesions and combined nature of many of the operations may well have contributed to excessive perioperative bleeding. Operative management of these patients who were at high risk for postoperative bleeding included liberal use of aprotinin [7] and a near universal need for a perioperative blood transfusion.
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Right heart failure is a relatively uncommon, but potentially catastrophic, problem in the LVAD patient. With the initiation of left ventricular assistance, left ventricular decompression may "unmask" right ventricular failure. Right heart contractility may be further impaired by perioperative blood transfusions, with the associated rise in pulmonary vascular resistance, or right coronary artery air embolism. In the current study all patients were weaned from CPB on inotropic agents, whereas more than one-third of patients received nitric oxide, a potent pulmonary vasodilator [11]. Four (6%) patients were separated from CPB on some form of right atrial to pulmonary artery or left atrial shunt. These shunts were created for temporary support of the patient’s right heart after the initiation of left ventricular assistance. Recognizing that even mild right ventricular dysfunction can impair LVAD filling, a number of reports have described extracorporeal membrane oxygenation-type shunts that can be used to bypass the right heart immediately after CPB [12, 13]. These shunts work in parallel with the patient’s right heart and are designed to reduce right ventricular work while providing adequate left ventricular preload. When right ventricular contractility improves, usually within a few minutes to an hour, the patient is decannulated.
In the current study, 9 (13%) patients ultimately fulfilled the criteria for right ventricular failure. Three (4%) patients left the operating room supported with either extracorporeal membrane oxygenation or an RVAD. These numbers compare favorably to previously reported series. In the HeartMate VE LVAD bridge trial right heart failure, defined as the need for an RVAD, occurred in 31 (11%) of 280 patients [6]. In a series of 245 patients supported with either the HeartMate or Novacor device reported by Ochiai and colleagues [14], 23 (9%) patients required RVAD support after LVAD implantation. Kavarana and colleagues [15] recently described 69 patients who received HeartMate VE LVAD support. The definition of right heart failure in their series was the same as that used in the REMATCH trial. Twenty-one (30%) of 69 patients met the criteria for right ventricular dysfunction; 1 patient required RVAD support.
Although right heart failure has been shown to result in an increased ICU and hospital LOS [15], this conclusion was not supported by the current study. Despite a higher adverse event rate in the LVAD patients when compared with the patients who were managed medically, both patient groups had a similar 30-day survival rate [3].
Patients with end-stage heart failure who require blood pump support are predisposed to infectious complications. These patients are at risk for nosocomial infection as a result of a prolonged preoperative hospital stay, during which time the patient is frequently monitored with invasive tubes and catheters. The chronically ill, frequently malnourished patient must undergo long operation. The percutaneous drive line is a potential portal of entry for infection, and it is thought that the blood-contacting surface of the VAD may alter the LVAD recipient’s immune response [16]. In the HeartMate VE LVAD bridge trial, infection was defined as a positive culture in association with leukocytosis [6]. In that trial an infection developed in 125 of 280 (45%) patients. Device-related infection occurred in 113 (40%) patients. The most common device-related infection, the drive line exit site, occurred in 90 (32%) patients.
Infection rates reported in Food and Drug Administration (FDA) PreMarket Approval safety and effectiveness summaries vary from 44% (HeartMate VE LVAD) to 66% (Novacor) [17]. The Novacor VAD is the only other implantable blood pump approved by the FDA for use as a bridge to transplant. In the bridge to transplant trial of this device, sepsis was a causative factor for both early and late mortality [18]. Although a device-related infection in the bridge patient is best managed by device explantation and transplant [19], this end point is not feasible in the patient in whom the VAD is permanently implanted. The morbidity of infection in the LVAD recipient was reflected in the current study in that sepsis was found to be highly predictive of a longer LOS for the implant hospitalization. The device-related infection rate is not expected to decrease until device design modifications eliminate the percutaneous drive line.
Patients supported with the HeartMate VE LVAS in the REMATCH trial experienced improved hemodynamics and functional class. These data establish a benchmark for the frequency of adverse events in destination therapy. The information provided herein also suggests opportunities for improvements in patient management that might ultimately translate into better outcomes and reduced LOS.
Acknowledgments
The authors gratefully acknowledge the assistance with data analysis provided by the International Center for Health Outcomes and Innovation Research (InCHOIR) at Columbia University.
References
This article has been cited by other articles:
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 J. M. Schaffer, G. J. Arnaoutakis, J. G. Allen, E. S. Weiss, N. D. Patel, S. D. Russell, A. S. Shah, and J. V. Conte Bleeding Complications and Blood Product Utilization With Left Ventricular Assist Device Implantation Ann. Thorac. Surg., March 1, 2011; 91(3): 740 - 749. [Abstract] [Full Text] [PDF]
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 J. W. Long, A. H. Healy, B. Y. Rasmusson, C. G. Cowley, K. E. Nelson, A. G. Kfoury, S. E. Clayson, B. B. Reid, S. A. Moore, D. U. Blank, et al. Improving outcomes with long-term "destination" therapy using left ventricular assist devices. J. Thorac. Cardiovasc. Surg., June 1, 2008; 135(6): 1353 - 1361. [Abstract] [Full Text] [PDF]
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E. D. Feller, E. N. Sorensen, M. Haddad, R. N. Pierson, F. L. Johnson, J. M. Brown, and B. P. Griffith Clinical Outcomes Are Similar in Pulsatile and Nonpulsatile Left Ventricular Assist Device Recipients Ann. Thorac. Surg., March 1, 2007; 83(3): 1082 - 1088. [Abstract] [Full Text] [PDF]
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