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Ann Thorac Surg 1996;62:1321-1327
© 1996 The Society of Thoracic Surgeons

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Original Article: Cardiovascular

Low Thromboembolic Risk Without Anticoagulation Using Advanced-Design Left Ventricular Assist Devices

Departments of Surgery, Medicine, and Neurology, College of Physicians and Surgeons, Columbia University, New York, New York, and Texas Heart Institute, Houston, Texas

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Background. A major limitation of cardiac assist devices has been the high incidence of thromboembolic events and their requirement for systemic anticoagulation. The Thermo Cardiosystems HeartMate 1000 IP left ventricular assist device (LVAD) employs a design that may reduce thromboembolic risk and obviate the need for systemic anticoagulation.

Methods. Two hundred twenty-three patients with nonreversible heart failure were supported with the HeartMate LVAD as a bridge to heart transplantation. All patients were monitored prospectively for thromboembolic events. Anticoagulation regimens and occurrence of subclinical thromboembolic events, including those seen by transcranial Doppler examinations in selected patients, were also recorded.

Results. Total time of LVAD support use was 531.2 patient-months. Twenty-three patients (10%) received warfarin postoperatively for 42.4 patient-months (8.2% of total support time). Six patients (2.7%) had thromboembolic events, representing 0.011 events per patient-month of device use.

Conclusions. The thromboembolic complication rate associated with this LVAD is acceptably low despite the minimal anticoagulation employed in this series, allowing consideration of long-term device use for the treatment of heart failure.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
See also page 1328.

Cardiac transplantation has been the mainstay of cardiac replacement therapy for end-stage congestive heart failure since its precipitous rise in popularity in the 1980s. However, the well-documented imbalance between the number of potential transplant recipients and the number of available donor organs [1] is becoming so critical that only status I patients may be eligible for transplants within the next several years [2]. This limitation has generated continued interest in the development of long-term mechanical cardiac support devices. Ventricular assist devices and total artificial hearts have been used to support patients for months and sometimes years [3–7]. Additional preclinical testing has yielded results suggesting that left ventricular assist devices (LVADs) could perform for considerably longer periods [8].

One major limitation to the widespread clinical use of LVADs has been the high rate of associated thromboembolic complications. Left ventricular assist devices, like most other biomechanical devices, activate the coagulation cascade, resulting in device-related thrombus formation. Unstable thrombus exposed to the shearing force of blood flow predisposes to thromboembolic events including stroke and end-organ or extremity ischemia. Attempts to minimize thrombus formation rely heavily on pharmacologic systemic anticoagulation. Despite adequate anticoagulation, thromboembolic complication rates of 30% or higher are commonly reported for patients on LVAD support [9–12]. The adverse event rate is further compounded by the high incidence of bleeding complications related to systemic anticoagulation. The morbidity of these complications has justifiably limited the appraisal of the quality of life that long-term mechanical cardiac assistance could provide.

The Thermo Cardiosystems (Woburn, MA) HeartMate 1000 IP LVAD employs design features to decrease the rate of thromboembolic complications. Textured interior surfaces are used to promote formation of a densely adherent pseudointima. This biologic lining becomes the interface between the device and blood, eliminating direct contact between prosthetic surfaces and blood elements. The absence of a direct blood-device interface makes anticoagulation unnecessary in the majority of cases. Additional device design elements include the use of a short inflow cannula and a "cornerless" pumping chamber with a wandering flow vortex. We have previously reported a low thromboembolic event rate in patients using the HeartMate [13].

To assess the impact of this design on minimizing device morbidity, we report the thromboembolic complications associated with use of the Thermo Cardiosystems HeartMate 1000 IP LVAD in the first 223 patients who received the device as a bridge to transplantation without the use of routine systemic anticoagulation.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
The Device
The HeartMate 1000 pneumatically driven LVAD is a pusher-plate–type blood pump connected via a drive line to a portable external console. The pump consists of a titanium housing (titanium, 90%; vanadium, 4%) that contains a flexible Biomer polyurethane pusher-plate diaphragm. One side of the diaphragm communicates with the blood chamber; the other side is in contact with an air chamber. Programmed pulses of air from the console are delivered to the pump air chamber via a percutaneous driveline. As the gas accumulates within the air chamber, the flexible pusher-plate diaphragm is displaced toward the titanium housing, propelling the blood out of the pump into the arterial system. Food and Drug Administration premarket approval for use of the device as a mechanical bridge to transplantation was granted in October 1994, after 28 years of device development and clinical evaluation.

The pump is surgically placed in a preperitoneal or intraabdominal pocket created in the abdominal left upper quadrant below the diaphragm. After institution of total cardiopulmonary bypass, the inflow cannula is passed through an opening cored in the apex of the left ventricle. This allows for maximal unloading of the left heart. Blood actively drains from the native heart into the pump chamber, where it is ejected into the aorta via an outflow graft (Fig 1). Porcine bioprosthetic valves, set in Dacron grafts (Dupont, Wilmington, DE), are positioned within the inflow and outflow conduits to ensure unidirectional flow.

View larger version (50K): [in this window] [in a new window]   Fig 1. . Implanted TCI HeartMate 1000 IP left ventricular assist device. Blood drains from left ventricle into pumping chamber and is ejected into ascending aorta via a Dacron graft. Porcine valves maintain unidirectional flow. (Figure courtesy of Thermo Cardiosystems Inc, Woburn, MA.)

No uniform anticoagulation protocol was followed for the LVAD treatment group. Each patient received an anticoagulation regimen based on the judgment of the primary investigator at that center. Use of anticoagulation and antiplatelet agents were recorded for all patients during LVAD support and are reported for the immediate postoperative period and at weeks 1, 2, 4, 8, 16, and 32.

Patients were prospectively monitored for clinically significant thromboembolic events, defined as the development of new transient or persistent focal neurologic deficits on daily neurologic examination or evidence of systemic embolization on physical examination. Thromboembolic events were recorded and are presented in accordance with principles established by Edmunds [14] for the evaluation of cardiac valvular prostheses. Incidence of thromboembolic complication was calculated as a percentage of the total number of patients supported by the device and as an event rate per patient-month of device use. The patient-month rate was chosen because it is more consonant with the time course for which patients were supported than the 100 patient-year rate used to evaluate cardiac valves. In addition, an actuarial curve was calculated to determine the risk of thromboembolic event over time.

Subclinical thromboembolic events were defined as occurrences that have no clinical manifestation, but that were detectable either by diagnostic testing or at autopsy. Autopsies were performed on 69 LVAD patients. Autopsy reports were reviewed specifically for evidence of clinically undetected systemic thromboembolic events. In addition, to determine if subclinical thromboembolic events were occurring during device support, transcranial Doppler studies were done on a small subset of LVAD patients during LVAD support. Twenty-five studies were performed in 8 patients using an EME/Nicolet TC 2020 (Eden Medizinische Elektronik, Uberlingen, Germany) with a 2-MHz pulsed-wave probe. The left or right middle cerebral artery was insonated transtemporally at a depth of 45 to 55 mm and monitored for 30 minutes with the probe held in place using a specially designed headband. High-intensity transient signals (HITS), also known as microembolic signals, were detected using automated counting software and identified using consensus criteria [15].

At the time of explantation all pumps were analyzed immediately in the operating room. The explant protocol required the pump to be disassembled, photographed, and examined. Detailed gross observations were recorded, including the presence of thrombus, fibrin deposits, vegetations, collagen islands, valve appearance, calcification, and pannus formation at either the inflow or outflow tract. In the event of death the same explant protocol was performed.

Statistical Analysis
Data were analyzed using SAS software (SAS Institute, Inc, Cary, NC) and StatXact (Cytel Software Corp, Cambridge, MA). The Kaplan-Meier product limit estimate was used to graphically display the thromboembolic event experience and provide actuarial estimates and 95% confidence intervals. Using graphic techniques (SAS), an exponential distribution was assumed for the freedom from thromboembolic event experience. This allowed calculation of an estimated hazard rate (events/patient-month) and appropriate 95% confidence intervals. Where biomedical proportions were provided (events/persons), exact confidence limits were supplied.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
The average age of the LVAD patient group was 48 ± 12 years (range, 14 to 66 years) with a 6:1 male:female ratio (191/32). Fifty percent of the LVAD group (112 patients) had idiopathic cardiomyopathy, whereas 40% (89 patients) had ischemic cardiomyopathy. The remaining 10% (22 patients) had subacute myocardial infarcts. The mean duration of implantation was 69 ± 68 days (standard deviation) (range, 0 to 344 days). Total time of support on the device was 531.2 patient-months.

Twenty-three of 223 patients (10%) received at least one dose of sodium warfarin during LVAD support. Cumulative use of warfarin was 42.4 patient-months (8.2% of total time of device use). Mean duration of sodium warfarin therapy was 1.5 ± 1.2 months (range, 0.25 to 4 months). Forty-nine patients (22%) were treated with intravenous heparin beyond the first postimplantation week. Mean duration of intravenous heparin therapy was 0.77 ± 0.77 months (range, 0.25 to 2.5 months). Table 1 demonstrates all other anticoagulation and antiplatelet regimens used, and the number of patients on each regimen at each time point.

The total thromboembolic event rate per observation month for the LVAD group is 0.011 (95% confidence intervals, 0.0014 to 0.0211). Excluding the 3 patients with predisposing factors for a thromboembolic event decreases the rate to 0.0056 (95% confidence interval, 0.0022 to 0.0135). Table 2 summarizes the thromboembolic events, risk factors, clinical manifestations, and final outcomes. Figure 2 demonstrates the Kaplan-Meier estimate of risk of thromboembolic event over time after LVAD implantation.

View larger version (26K): [in this window] [in a new window]   Fig 2. . (A) Number of patients on device support over time. (B) Kaplan-Meier estimate of risk of thromboembolic (TE) event over time. Squares represent actual thromboembolic events. Vertical bars represent 95% confidence limits. The number of patients on left ventricular assist device (LVAD) support at the time of each event are presented in parentheses. The dotted line illustrates that follow-up occurred up to 13 months with no additional thromboembolic events recorded.

Transcranial Doppler measurements of the middle cerebral arteries detected a mean of 0.52 ± 1.00 HITS per 30-minute session in each of 8 patients tested during LVAD support. No HITS were recorded in 18 of the sessions. None of these patients manifested clinically significant thromboembolic events.

Postexplantation pump analysis revealed appropriately deposited, densely adherent thrombus formation on pump surfaces where it was designed to occur. Typical findings on pump surfaces included nonobstructive pannus formation at the inflow cannula and collagen islands (circular depositions that have been determined to be composed of collagen); no evidence of calcification was found on any of the pumps. Valve and valve graft observations included 7 valves with vegetative growth, 2 valves with small perforations, and densely adherent thrombus associated with 11 valve grafts.

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
In the first 223 patients treated with the Thermo Cardiosystems HeartMate 1000 IP LVAD, only six clinically significant thromboembolic events were documented despite the use of minimal anticoagulation. Further analysis revealed independent risk factors for thromboembolism in 3 of these 6 cases. One patient had fungal sepsis predisposing to valvular vegetation and subsequent thromboembolism. A second patient had loose thrombus on a prosthetic aortic valve that had been placed before LVAD insertion. A previously placed mechanical prosthetic aortic valve is now considered a contraindication to LVAD placement [16]. In a third patient, thrombus developed distal to the aortic valve and in the aortic arch, when an area of stasis was created by anastomosing the outflow graft to the descending aorta. This particular patient had dense adhesions that precluded anastomosis to the ascending aorta. Anastomosis to the ascending aorta, the intended configuration, minimizes potential dead space and subsequent clot formation due to stasis. The remaining three documented thromboembolic events were considered to be directly device related.

Attributing all six thromboembolic events to the device results in a thromboembolic event rate of 3.0%, or an event per patient-month of observation rate of 0.011. If patients with additional risk factors for thromboembolism are excluded, these rates fall to 1.3% and 0.0056, respectively. The Kaplan-Meier estimate of risk for thromboembolic event succinctly illustrates the low risk of thromboembolic event over time. The TCI HeartMate 1000 compares favorably with previously published thromboembolic event rates for similar cardiac assist devices (Table 3). This low thromboembolic rate is even more impressive given the minimal amount of anticoagulation required for this device in contrast to other LVADs. A comparison of reported thromboembolic events rates for implantable LVADs is presented in Table 3.

A review of autopsy reports revealed a potentially device-related thromboembolic event in 1 additional patient. This patient died of a refractory arrhthymia, but at autopsy was found to have thrombus in the carotid artery without evidence of cerebral ischemia. Two patients were noted to have thrombus in the distal aorta consistent with intraaortic balloon pump origin. An additional patient, who died during implantation, was noted to have a renal artery embolus thought not related to the device. The remaining 4 patients with evidence of end-organ infarct at autopsy all suffered from disseminated intravascular coagulation related to sepsis and had multisystem organ failure at the time of death. An analysis of 152 autopsies of patients with a diagnosis of dilated cardiomyopathy demonstrated that 16% of patients had evidence of systemic emboli and 33% of patients had evidence of both systemic and pulmonary emboli [22]. Similarly, in an autopsy series of cardiac transplant patients, cerebral infarcts were present in 20% of cases [23].

Transcranial Doppler studies revealed low levels of detectable microembolic activity during device support. Microembolic signals or HITS have been correlated with cerebrovascular symptoms predominantly in carotid artery disease [24, 25] and in patients undergoing carotid endarterectomy [26] and coronary artery bypass grafting [27]. Studies attempting to define a correlation between HITS and cardiac sources of emboli have had mixed results [28, 29].

At present there are three reports on Doppler-detected microembolic events in LVAD patients [30–32]. We previously reported preliminary studies in 4 LVAD patients in which we detected three to five HITS during 3-minute insonation periods [33]. No neurologic symptoms developed in any of these patients. Nabavi and associates [34] detected three to 40 HITS per 30-minute session in 4 serially examined patients on Novacor LVAD support. In this study, frequency of HITS was thought to be predictive of embolic complications. Knepper and colleagues [35] reported on 3 patients during Novacor LVAD support with Doppler-detected HITS related to neurologic events. All 3 studies were done before publication of standard criteria for HITS and may overestimate the actual number of microembolic events.

A number of questions regarding HITS in LVAD patients remain unanswered, including the composition of microemboli, source, clinical significance, and potential treatments. Animal models have shown that emboli consisting of platelet aggregates, thrombus, atheroma, fat, and air result in HITS on TCD monitoring [36]. The native left ventricle has been identified as a potential source of thrombus during left ventricular assistance [37], but it is unclear if the left ventricle or the device is the source of the microemboli in these cases. In addition, the clinical significance of HITS in LVAD patients and the correlation between HITS and thromboembolic risk is not known. It is also not apparent at this time whether these microemboli are causing subtle neurologic deficits that require more sensitive psychomotor testing to detect. Finally, the effects of anticoagulation on the frequency of HITS had not been delineated.

The Thermo Cardiosystems HeartMate 1000 IP LVAD uses an unusual strategy in an effort to achieve compatibility with the human coagulation system. In place of a smooth surface to minimize thrombogenicity, this device has highly textured surfaces designed to promote thrombogenicity. This surface encourages formation and adherence of a pseudoneointimal lining [33]. Figure 3 shows the textured surfaces of the pump interior and the diaphragm at explantation. Upon contact with a textured surface, a blood-derived biological lining is formed, which serves as the long-term blood-contacting interface, obviating the need for systemic anticoagulants. The initial step is for a fibrin-cellular coagulum to form over the surface of the device. Thrombus then forms and is anchored by fibrin deposition within the textured surface interstices. Figure 4 demonstrates the electron microscopic appearance of the pseudoneointimal lining over time. The pseudoneointimal lining has been shown in previous studies to be composed primarily of compact fibrin, collagen (types I, III, and IV), endothelial cells, and mononucleated cells [34, 35, 38, 39]. Recent flow cytometry and immunohistochemical staining studies have demonstrated that pluripotent hematopoietic stem cells colonize the textured surfaces of the TCI LVAD [40].

View larger version (91K): [in this window] [in a new window]   Fig 3. . Blood-contacting surfaces of the TCI HeartMate 1000 IP left ventricular assist device at explantation.

View larger version (97K): [in this window] [in a new window]   Fig 4. . Pseudointimal lining of explanted pump at (A) 5, (B) 19, and (C) 41 days. (x1,000 before 24% reduction.)

View larger version (143K): [in this window] [in a new window]   Fig 5. . Radiolabeled albumin demonstrates "wandering vortex" in ex-vivo studies.

In conclusion, the observed thromboembolic rate of 2.7% or 0.011 events per patient-month of device use is extremely low. In addition, the textured lining used in this device precludes the need for systemic anticoagulation in most patients. Although LVADs clearly do not represent a panacea for treating end-stage heart disease, their anticipated thromboembolic complication rate and functional performance justify consideration of their evaluation as a "destination" therapy for these patients.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Presented at the Thirty-second Annual Meeting of The Society of Thoracic Surgeons, Orlando, FL, Jan 29–31, 1996.

Address reprint requests to Dr Oz, Department of Surgery, Columbia-Presbyterian Medical Center, 177 Fort Washington Ave, New York, NY 10032.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 

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				V. Rao, J. P. Slater, N. M. Edwards, Y. Naka, and M. C. Oz Surgical management of valvular disease in patients requiring left ventricular assist device support Ann. Thorac. Surg., May 1, 2001; 71(5): 1448 - 1453. [Abstract] [Full Text] [PDF]

				P. M. Portner, P. G. M. Jansen, P. E. Oyer, D. R. Wheeldon, and N. Ramasamy Improved outcomes with an implantable left ventricular assist system: a multicenter study Ann. Thorac. Surg., January 1, 2001; 71(1): 205 - 209. [Abstract] [Full Text] [PDF]

				A. G. Rose, S. J. Park, A. J. Bank, and L. W. Miller Partial aortic valve fusion induced by left ventricular assist device Ann. Thorac. Surg., October 1, 2000; 70(4): 1270 - 1274. [Abstract] [Full Text] [PDF]

				D.W. Quinn, T.J.J. Jones, and T.R. Graham Mechanical Circulatory Support Sources of Emboli and Neurological Outcome Seminars in Cardiothoracic and Vascular Anesthesia, July 1, 2000; 4(2): 115 - 120. [Abstract] [PDF]

				T. B. Spanier, J. M. Chen, M. C. Oz, D. M. Stern, E. A. Rose, and A. M. Schmidt TIME-DEPENDENT CELLULAR POPULATION OF TEXTURED-SURFACE LEFT VENTRICULAR ASSIST DEVICES CONTRIBUTES TO THE DEVELOPMENT OF A BIPHASIC SYSTEMIC PROCOAGULANT RESPONSE J. Thorac. Cardiovasc. Surg., September 1, 1999; 118(3): 404 - 413. [Abstract] [Full Text] [PDF]

				D. G. Pennington, T. E. Oaks, and D. P. Lohmann Permanent ventricular assist device support versus cardiac transplantation Ann. Thorac. Surg., August 1, 1999; 68(2): 729 - 733. [Abstract] [Full Text] [PDF]

				R. T.V. Kung and M. Rosenberg Heart Booster: a pericardial support device Ann. Thorac. Surg., August 1, 1999; 68(2): 764 - 767. [Abstract] [Full Text] [PDF]

				D. R. Gross Concerning thromboembolism associated with left ventricular assist devices Cardiovasc Res, April 1, 1999; 42(1): 45 - 47. [Full Text] [PDF]

				D. J. Goldstein, M. C. Oz, and E. A. Rose Implantable Left Ventricular Assist Devices N. Engl. J. Med., November 19, 1998; 339(21): 1522 - 1533. [Full Text] [PDF]

				S. A. Hunt and O.H. Frazier Mechanical Circulatory Support and Cardiac Transplantation Circulation, May 26, 1998; 97(20): 2079 - 2090. [Full Text] [PDF]

				J. J. DeRose Jr, J. P. Umana, M. Argenziano, K. A. Catanese, H. R. Levin, B. C. Sun, E. A. Rose, and M. C. Oz Improved Results for Postcardiotomy Cardiogenic Shock With the Use of Implantable Left Ventricular Assist Devices Ann. Thorac. Surg., December 1, 1997; 64(6): 1757 - 1762. [Abstract] [Full Text]

				A. C. Gelijns, A. F. Richards, D. L. Williams, M. C. Oz, J. Oliveira, and A. J. Moskowitz Evolving Costs of Long-Term Left Ventricular Assist Device Implantation Ann. Thorac. Surg., November 1, 1997; 64(5): 1312 - 1319. [Abstract] [Full Text]

				E. A. Rose, A. C. Gelijns, A. J. Moskowitz, D. F. Heitjan, L. W. Stevenson, W. Dembitsky, J. W. Long, D. D. Ascheim, A. R. Tierney, R. G. Levitan, et al. Long-Term Use of a Left Ventricular Assist Device for End-Stage Heart Failure N. Engl. J. Med., November 15, 2001; 345(20): 1435 - 1443. [Abstract] [Full Text] [PDF]

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