- Email: [email protected]
Hemolysis, Pump Thrombus, and Neurologic Events in Continuous-Flow Left Ventricular Assist Device Recipients
Hemolysis, Pump Thrombus, and Neurologic Events in Continuous-Flow Left Ventricular Assist Device Recipients Bryan A. Whitson, MD, PhD, Peter Eckman, MD, Forum Kamdar, MD, Alexandra Lacey, BA, Sara J. Shumway, MD, Kenneth K. Liao, MD, PhD, and Ranjit John, MD Department of Surgery, Division of Cardiovascular and Thoracic Surgery, University of Minnesota, Minneapolis, Minnesota; Department of Surgery, Division of Cardiac Surgery, Wexner Medical Center, Ohio State University, Columbus, Ohio; and Department of Medicine, Division of Cardiology, University of Minnesota, Minneapolis, Minnesota
Background. An ongoing challenge in the management of patients with heart failure who receive left ventricular assist devices (LVADs) is achieving optimal anticoagulation. Adverse prothrombotic events include hemolysis or pump thrombus (H/T) and neurologic events (NEs), and all limit the success of LVAD therapy. Our aim was to study the incidence and clinical outcomes associated with these events in a large single-center cohort. Methods. We retrospectively reviewed our prospectively collected database of all patients receiving a HeartMate II (Thoratec Corp, Pleasanton, CA) LVAD from 2005 to 2012. Demographic, clinical, and outcome data were analyzed using standard statistical methods. All adverse events were recorded. Results. Of 193 patients receiving LVADs, we identified 39 H/T events in 26 (13.4%) patients and 22 NEs in 19 (9.8%) patients. Seventy-four percent of events occurred in the last 3 years of the series, during which time 63% of implants were placed. Of patients with H/T, 8 (31% of those having H/T, 4.1% of total) had more than 1 event and 4 (15.4% of those having H/T, 2.1% of total) underwent pump exchanges. Five (23%) patients had NEs after
H/T, and 6 (32%) died as a result of the NE. Of patients with H/T, 27% had preceding episodes of infection, 31% had an international normalized ratio (INR) of less than 1.5, 31% had an INR of 1.5 to 2, 15% had a history of clotting or were hypercoagulable, and 4% had anticoagulation intentionally withheld. Lactate dehydrogenase (LDH), plasma hemoglobin, INR, and platelet determinations were significantly different at the time of H/T compared with baseline values. The survival at 6 months (alive or having undergone transplantation) for those with a prothrombotic event compared with those without was 70% versus 75.2% (p [ 0.5). Conclusions. The incidence of H/T or NEs is significant and results in major morbidity after LVAD placement. Infection and suboptimal anticoagulation are associated with the majority of these events. Identification of patients at higher risk for hemolysis (ie, infection) may allow for modification of anticoagulation regimens to reduce these risks and improve clinical outcomes.
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complications (such as hemolysis or thrombosis) but not excess anticoagulation to contribute to bleeding (eg, gastrointestinal bleeding or NEs). Further complicating the clinical picture is the inherent hematologic effects of continuous-flow LVADs [5] and the need to adjust anticoagulation for patient care. The objectives of this study were to investigate the incidence and clinical outcome associated with anticoagulation and adverse prothrombotic events (hemolysis or pump thrombus [H/T] and neurologic events [NEs]). In addition, we sought to evaluate the effect of these events on long-term survival and determine if antecedent events contributed to these prothrombotic events.
ith more than 200,000 deaths annually in the United States attributed to congestive heart failure [1], the role of durable mechanical circulatory support is rapidly increasing. With increased use of long-term implantable left ventricular assist devices (LVADs) such as the HeartMate II (Thoratec Corp, Pleasanton, CA), which was first implanted in 2004 [2], there has been a varied and wide ranging experience with managing the anticoagulation strategy. This anticoagulation strategy has been nuanced because it requires a delicate balance [3, 4] of adequate anticoagulation to minimize thrombotic
(Ann Thorac Surg 2014;-:-–-) Ó 2014 by The Society of Thoracic Surgeons
Accepted for publication Feb 20, 2014. Presented at the Poster Session of the Forty-ninth Annual Meeting of The Society of Thoracic Surgeons, Los Angeles, CA, Jan 26–30, 2013. Address correspondence to Dr John, Division of Cardiovascular and Thoracic Surgery, University of Minnesota, MMC 207, 420 Delaware St SE Minneapolis, MN 55455; e-mail: [email protected].
Ó 2014 by The Society of Thoracic Surgeons Published by Elsevier Inc
Drs Eckman and John discloses financial relationships with Thoratec and HeartWare.
0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2014.02.041
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WHITSON ET AL CONTINUOUS-FLOW LVAD EVENTS
Patients and Methods We performed a retrospective analysis of our prospectively maintained clinical outcomes database of those patients who underwent operation for placement of a Thoratec HeartMate II LVAD from January 1, 2005 through April 1, 2012. These operations were performed and data were collected at a single-center large academic quaternary care hospital. The patients were evaluated preoperatively and managed postoperatively in a multidisciplinary collaborative manner between the cardiothoracic surgery and heart failure cardiology services. This database and evaluation were approved by our institutional review board with waiver of the need for individual consent.
Clinical Outcomes Definitions We evaluated the demographic and clinical indications of the patients undergoing HeartMate II implantation. In addition, the outcome data were evaluated. Longitudinally, patients were followed for their overall survival, hemolysis or thrombosis events, NEs, preceding inciting events that may predispose to a change in coagulation, their anticoagulation treatment, pump malfunction, and outcome.
Neurologic Events We defined an NE as a transient ischemic attack, a cerebral embolism, an ischemic stroke, or a hemorrhagic stroke. The definition of an NE was the Interagency Registry for Mechanically Assisted Circulatory Support definition of any new, temporary or permanent, focal or global neurologic deficit ascertained by a standard neurologic examination (administered by a neurologist or other qualified physician and documented with appropriate diagnostic tests and consultation note). The examining physician will distinguish between a transient ischemic attack, which is fully reversible within 24 hours (and without evidence of infarction), and a stroke, which lasts longer than 24 hours (or <24 hours if there is evidence of infarction). Each NE must be subcategorized as (1) transient ischemic attack (acute event that resolves completely with 24 hours with no evidence of infarction) or (2) ischemic or hemorrhagic cerebral accident/cerebrovascular accident (event that persists beyond 24 hours or <24 hours associated with infarction on an imaging test).
Hemolysis Hemolysis was defined as clinical evidence of hemolysis (ie, tea-colored urine) along with biochemical evidence (increased level of lactate dehydrogenase ([LDH] greater than twice the baseline value or the upper limit of normal, plasma free hemoglobin value >15 mg/dL) with or without clinical signs of LVAD pump dysfunction.
Pump Thrombosis Pump thrombus was defined as recurrent, consistent pump controller power spikes, echocardiographic demonstration of thrombus, or pump failure. Furthermore,
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clinical evidence of hemolysis with signs of LVAD pump dysfunction (high power, low pulsatility index) and clinical evidence of heart failure were present and typically confirmed by thrombus within the pump.
HeartMate II LVAD Insertion The LVAD used in this investigation was the HeartMate II LVAD, which is a continuous-flow device consisting of an internal axial-flow blood pump with a percutaneous lead that connects the pump to an external system driver and power source that has been previously described [6]. Details of HeartMate II function and the implantation technique have been described previously [6–8].
Patient and Device Management Following our local practice at the University of Minnesota, we set the speed of the HeartMate II to provide adequate cardiac output and achieve optimal left ventricular decompression while maintaining a pulsatility index greater than 3.5 to 4.0. We optimize the rpm speed, using both hemodynamic and echocardiographic parameters, at the time of LVAD placement in the operating room, during the postoperative period, and if clinical events (new symptoms or suction events) warrant further adjustment. In the operating room, the presence of transesophageal echocardiography and continuous pulmonary artery catheter monitoring helps optimize pump speed to achieve LV decompression without a septal shift toward the left ventricle or evidence of progressive right ventricular dilatation. Goals for central venous pressure are typically 10 to 15 mm Hg, with pulmonary artery systolic pressure less than 45 mm Hg, and cardiac index greater than 2.2 L/min/m2. Pump speed typically is gradually increased by increments of 200 rpm after approximately 48 hours using the pulsatility index as a guide. After transfer out of the intensive care unit and discharge to home, echocardiograms are typically obtained to identify new symptoms of heart failure or suction events [6–8].
Anticoagulation Management Our anticoagulation management consisted of starting coumadin on postoperative day 1 or 2. Our goal INR has evolved from 1.5 to 2.5 to 2.0 to 2.5 in the patient with an LVAD without bleeding diathesis. Once surgical bleeding is no longer a concern, a low-dose heparin drip is initiated. Low-dose enteric-coated aspirin (81 mg daily) is administered as well.
Statistical Analysis Data were analyzed with JMP Pro for Mac, version 9.0.2 (SAS Institute, Cary, NC). For all statistical testing, we used a 2-sided significance level of 0.05. For betweengroup comparisons, we used a 2-sample t test for continuous variables and a c2 test for categorical variables. Unless otherwise stated, results are reported as mean standard deviation. The Kaplan-Meier method was used to compare unadjusted all-cause mortality rates between patients who experienced events and those who did not.
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Table 1. Left Ventricular Assist Device Implantation Indications LVAD Indication
Proportiona (n ¼ 193)
Ischemic cardiomyopathy Dilated cardiomyopathy Other Ischemic, acute myocardial infarction Nonischemic, acute other Cardiogenic shock Nonischemic, acute myocarditis a
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44.6% (86) 33.2% (64) 9.8% (19) 8.8% (17) 2.6% (5) 1.0% (2) 0% (0)
Data may not sum to 100% because of rounding.
Results Demographics During the study period, 193 patients underwent HeartMate II LVAD implantation. The primary indication was ischemic cardiomyopathy (46%) (Table 1) followed by dilated nonischemic cardiomyopathy (34.2%). The mean age at the time implantation was 55.6 13.9 years. Of the 193 LVAD recipients, 78.2% (151 of 193) were men and 21.8% (42 of 193) were women. A preoperative intraaortic balloon pump was used in 84% (175 of 193) of patients. There were 153 patients (79.3%) with no events, 26 (13.5%) patients with H/T, 14 (7.5%) patients with NEs, 40 (20.1%) patients with either H/T or NEs, and 5 patients (2.6%) with H/T and NEs.
Hemolysis or Thrombosis Events In our cohort of 193 LVAD recipients, we identified 39 H/T events in 26 (13.4%) patients. In addition, we identified 22 NEs in 19 (9.8%) patients. Of the total events, 74% occurred in the last 3 years of the series during which 63% of implants were placed. We found that in patients with either hemolysis or thrombosis, 8 patients (31% of patients with H/T, 4.1% of total) had more than 1 event. Those patients with events trended to being older and were significantly more likely to be women (Table 2). Of the 26 patients who had H/T, 4 (15.4% of patients with H/T, 2.1% of total) underwent pump exchanges.
Neurologic Events Five of the 26 patients with H/T had an NE after their H/T event; thus the incidence of NE after H/T was 23%.
Risk Factors/Antecedent Events Of patients with NEs, 6 died as a result of the NE (32%). In patients with H/T, 27% had preceding infection, 31% had an INR of less than 1.5, 31% had an INR of 1.5 to 2, 15% had a history of clotting or were hypercoagulable, and 4% had anticoagulation intentionally withheld. LDH, plasma hemoglobin, INR, and platelet determinations were significantly different at the time of H/T compared with baseline measurements (Table 3). Because of the longitudinal nature of the data collection, the overall incidence, and our registry, we are not able to determine with a high degree of accuracy the incidence of infection in those patients who did not have H/T or NEs. There was no difference in the incidence of any of 16 separately measured comorbid conditions (Table 4). These 16 risk factors are the components of the Charlson comorbidity index. From this analysis, we were not able to predict who would be at a higher risk of having an NE or H/T after HeartMate II LVAD insertion.
Survival The survival rate at 6 months (alive or having undergone transplantation) for patients having an event compared with those who did not was 70% versus 75.2%, (p ¼ 0.5). The overall long-term survival for patients with no events, hemolysis, thrombosis, or NEs was not statistically different (Fig 1). An effect of NEs on overall long-term survival was seen, both when grouped with those with H/T (Fig 2A) and when by itself (Fig 2C) but not when H/T was compared with all other events (Fig 2B).
Comment In our analysis of a single-institution experience with HeartMate II LVADs, we found an overall incidence of hemolysis or thrombotic events of 13.4% and an incidence of NEs (transient ischemic attack, cerebral embolism, ischemic stroke, or hemorrhagic stroke) to be 9.8%. We
Table 2. Demographic Data of Patients With Events and Those Without Hemolysis, Thrombosis or NEsa Variable N Age (y) Sex (% male) Diagnosis Ischemic cardiomyopathy Dilated cardiomyopathy Other Survival after event (d) a
No Event
Hemolysis or Thrombosis Event
Neurologic Event
153 56 13 82%
26 52 16 58%
14 54.7 15 79%
44%
52%
36%
33% 17% 311 (1–2,424)
32% 16% 182.5 (11–2,090)
36% 28% 297 (3–650)
Data may not sum to 100% because of rounding.
NEs ¼ neurologic events.
p Value 0.092 0.009 0.092
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Table 3. Hematologic Characteristics at the Time of Event Hemolysis or Thrombosis Event Variable
No Event 3
Platelet count (10 /dL) International normalized ratio Total bilirubin (mg/dL) Plasma hemoglobin (mg/dL) Lactate dehydrogenase (U/L)
186 (109–515) 1.3 (1.1–2.2) 1.2 (0.3–4) <15 (<15–19) 630 (303–2,966)
Baseline 220 2.3 0.9 <15 870.5
(100–416) (1.2–3.5) (0.1–3.3) (<15–22) (31–5,824)
At Event 175 1.9 1.8 53.5 3,235.5
(91–502) (1.1–6.4) (0.5–14.5) (<15–385) (627–20,921)
Neurologic Event
p Value
– 2.1 (1.4–7.3) – – –
0.013 0.017 <0.001 <0.001 <0.001
Data are presented as median and range unless otherwise stated.
used a consistent definition for hemolysis and thrombotic complications in our study.
Acquired Coagulation Deficiencies of Continuous-Flow LVADs Continuous-flow LVADs have been shown to have a higher risk of hemolysis and bleeding when compared with pulsatile-pump LVADs. This effect is attributed to the high shear stress conditions of these pumps. The high shear stress contributes to direct hemolysis, thrombocytopenia, increased fibrinolysis [9], and a decrease in the high molecular weight multimers of von Willebrand’s factor [3, 5, 10, 11]. This acquired von Willebrand’s deficiency is similar to Heyde’s syndrome seen in severe aortic stenosis. As a result of these perturbations in the clotting cascade, the use of point-of-care testing for patients with mechanical circulatory support has been Table 4. Comorbidities at the Time of Implantationa
Comorbidity Acquired immunodeficiency syndrome Cerebrovascular accident Chronic obstructive pulmonary disease Congestive heart failure Connective tissue disorder Dementia Hemiplegia History of leukemia History of lymphoma Previous myocardial infarction Peripheral vascular disease Ulcer disease Diabetes Liver disease Kidney disease (Cr >1.5) History of solid malignancy a
No Event (%)
Hemolysis, Thrombosis, or Neurologic Event (%) p Value
1.3
0.0
0.33
4.6 18.3
12.5 20.0
0.09 0.75
88.9 2.6 1.3 0.7 0 5.9 37.9
92.5 7.5 0.0 0.0 0.0 2.5 42.5
0.48 0.18 0.33 0.49 1 0.35 0.62
6.5
5.0
0.71
2.6 38.6 4.1 30.9 10.7
10.0 27.5 2.5 20.0 10.0
0.06 0.18 0.63 0.18 0.88
Data may not sum to 100% because of rounding.
advocated [12]. These tests consist of thromboelastography, platelet function tests (impedance or aggregometry), bleeding time, activated partial thromboplastin time, INR determinations, platelet count, and anti-Xa levels. However, a consistent approach to such testing remains elusive.
Antecedent Events Kato and colleagues [13] evaluated their experience with 307 continuous-flow LVADs (167 HeartMate I and 140 HeartMate II). They found that patients with previous stroke and persistent inflammation or infection had a higher incidence of NEs. Aggarwal and colleagues [14] investigated the association of bloodstream infection and hemorrhagic strokes in 87 patients who underwent HeartMate II implantation. They found that the occurrence of a bloodstream infection after LVAD implantation led to an 8-fold (odds ratio of 7.9) increase in cerebrovascular events after HeartMate II LVAD implantation. In the current study, we did find that 27% of these adverse events were associated with an antecedent infection. This finding in our study is consistent with that of the Columbia group who found that infection or a proinflammatory event can contribute to a systemic hypercoagulable state that could lead to H/T or NE.
Fig 1. Overall survival from time of pump implantation to transplantation, death, or last follow-up for no events (red), neurologic events (NEs) (blue), or hemolysis/thrombosis (green) (p ¼ 0.087).
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WHITSON ET AL CONTINUOUS-FLOW LVAD EVENTS
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Fig 2. Overall survival from time of pump implantation to transplantation, death, or last follow-up for patients with (A) hemolysis/thrombosis or a neurologic event (NE) (blue) versus all others (red) (p ¼ 0.034), (B) those with hemolysis/thrombosis (blue) versus all others (red) (p ¼ 0.41), and (C) Those with NEs (blue) versus all others (red) (p ¼ 0.026).
Anticoagulation After Implantation The practice of postoperative management of anticoagulation in patients with HeartMate II LVADs is varied as well. Some centers routinely bridge patients to oral anticoagulants with intravenous heparin (an enzyme inhibitor of antithrombin III), bivalirudin (a direct thrombin inhibitor), or eptifibatide (a platelet fibrinogen receptor glycoprotein IIb/IIIa inhibitor). Other centers transition patients directly to aspirin and warfarin. The routine use of the direct transition approach, evaluated in a multiinstitutional series of 418 patients, found no difference in incidence of thrombotic or hemorrhagic complications [15]. A goal INR of 2 to 2.5 has been found to be a safe balance to achieve minimal thrombosis events and minimal gastrointestinal bleeding events [16].
systolic amplitude has correlated with pump/outflow graft thrombosis and its resolution [18]. In addition, the use of an echocardiographic ramp study to evaluate for speed optimization and to diagnose pump thrombosis has been proposed [19]. At the University of Minnesota, the routine treatment of thrombosis or hemolysis was increasing the goal INR 2.5 to 3 as well as starting high-intensity intravenous heparin. This approach was routinely used except when heparin-induced thrombocytopenia was suspected or present. Other centers have used eptifibatide routinely with minimal complications [20]. The use of intravenous or intraventricular thrombolytic agents to treat pump thrombus has had mixed efficacy [21, 22]. On a cautionary note, the concomitant use of glycoprotein IIb/IIIa inhibitors and heparin may lead to thrombocytopenia in the treatment of pump thrombosis [23].
Pump Thrombosis In evaluating patients for pump thrombosis, echocardiography may be a useful adjunct to aid diagnosis [17–19]. The use of Doppler echocardiography to evaluate the diastolic flow velocity and difference in diastolic and
Hemolysis or Thrombosis Management Algorithm The clinical algorithm to hemolysis and suspected pump thrombosis currently used at the University of Minnesota is presented in Fig 3. In this management algorithm, a
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Fig 3. University of Minnesota algorithm for management of left ventricular assist device (LVAD) hemolysis or pumpassociated thrombus. (1A ¼ organ transplant status 1A; AV ¼ aortic valve; CT ¼ computed tomography; Echo ¼ echocardiography; Hb ¼ hemoglobin; ICU ¼ intensive care unit; INR ¼ international normalized ratio; LDH ¼ lactate dehydrogenase; LV ¼ left ventricle; PWP ¼ pulmonary wedge pressure; RHC ¼ right heart catheterization.)
high index of suspicion of H/T is needed. This suspicion index is wedded with the clinical scenario. When there are clinical, physiologic, and echocardiographic data that support the diagnosis, an aggressive approach to modulating anticoagulation therapy is undertaken. This is most efficiently and accurately undertaken in the inpatient setting. Patients with hemolysis or pump thrombosis, or both, are usually upgraded to status IA on the heart transplant waiting list if they are bridge-to-transplantation patients receiving LVADs. We reserve the option of pump exchange for patients with pump thrombosis with worsening heart failure despite aggressive anticoagulation therapy. Patients may be considered for thrombolytic therapy if they are not candidates for surgical pump exchange (only 1 patient in our experience received intraventricular thrombolytic therapy and had a successful outcome). In our series, we considered an elevated LDH value of greater than twice the upper limit of normal to be a concern for hemolysis. At the University of Minnesota, the range is 325 to 750 U/L; therefore, our cutoff was 1500 U/L.
Limitations Our study is affected by several limitations that can introduce bias, including the fact that this is a retrospective study. The decision to perform the placement of the HeartMate II LVAD was dependent on the clinical condition of the patient and the judgment of the surgeon and heart failure cardiology teams. Although there were no differences in the proportion of comorbid illnesses between cohorts, the patient population is overall small and heterogeneous. This study is limited by its singleinstitution observational nature. This study is strengthened by careful prospective data collection. All procedures were carried out by an
experienced surgeon/heart failure cardiology team to reduce variability in patient management. The approach to the patient who had an event was standardized, and we believe that this approach contributed to the satisfactory outcomes of those patients with H/T or NEs.
Clinical Relevance The incidence of H/T or NEs is significant and results in major morbidity after LVAD placement. Infection and suboptimal anticoagulation are associated with the majority of events. Identification of patients at higher risk for hemolysis (ie, infection) may allow for modification of anticoagulation regimens to reduce these risks and improve clinical outcomes. The need for a balanced anticoagulation profile is needed to maintain optimum outcomes after LVAD.
References 1. O’Connell JB, Bristow MR. Economic impact of heart failure in the United States: time for a different approach. J Heart Lung Transplant 1994;13:S107–12. 2. Frazier OH, Delgado RM 3rd, Kar B, Patel V, Gregoric ID, Myers TJ. First clinical use of the redesigned HeartMate II left ventricular assist system in the United States: a case report. Tex Heart Inst J 2004;31:157–9. 3. Eckman PM, John R. Bleeding and thrombosis in patients with continuous-flow ventricular assist devices. Circulation 2012;125:3038–47. 4. Kurien S, Hughes KA. Anticoagulation and bleeding in patients with ventricular assist devices: walking the tightrope. AACN Adv Crit Care 2012;23:91–8. 5. Slaughter MS. Hematologic effects of continuous flow left ventricular assist devices. J Cardiovasc Transl Res 2010;3: 618–24. 6. John R, Kamdar F, Eckman P, et al. Lessons learned from experience with over 100 consecutive HeartMate II left
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7. 8.
9.
10.
11. 12. 13.
14.
15.
ventricular assist devices. Ann Thorac Surg 2011;92:1593–9; discussion 1599–600. Griffith BP, Kormos RL, Borovetz HS, et al. HeartMate II left ventricular assist system: from concept to first clinical use. Ann Thorac Surg 2001;71:S116–20; discussion S114–6. John R, Kamdar F, Liao K, Colvin-Adams M, Boyle A, Joyce L. Improved survival and decreasing incidence of adverse events with the HeartMate II left ventricular assist device as bridge-to-transplant therapy. Ann Thorac Surg 2008;86:1227–34; discussion 1234–5. Slaughter MS, Sobieski MA, Gallagher C, Graham J, Brandise J, Stein R. Fibrinolytic activation during long-term support with the HeartMate II left ventricular assist device. ASAIO J 2008;54:115–9. Suarez J, Patel CB, Felker GM, Becker R, Hernandez AF, Rogers JG. Mechanisms of bleeding and approach to patients with axial-flow left ventricular assist devices. Circ Heart Fail 2011;4:779–84. Yuan N, Arnaoutakis GJ, George TJ, et al. The spectrum of complications following left ventricular assist device placement. J Card Surg 2012;27:630–8. Gorlinger K, Bergmann L, Dirkmann D. Coagulation management in patients undergoing mechanical circulatory support. Best Pract Res Clin Anaesthesiol 2012;26:179–98. Kato TS, Schulze PC, Yang J, et al. Pre-operative and postoperative risk factors associated with neurologic complications in patients with advanced heart failure supported by a left ventricular assist device. J Heart Lung Transplant 2012;31:1–8. Aggarwal A, Gupta A, Kumar S, et al. Are blood stream infections associated with an increased risk of hemorrhagic stroke in patients with a left ventricular assist device? ASAIO J 2012;58:509–13. Slaughter MS, Naka Y, John R, et al. Post-operative heparin may not be required for transitioning patients with a
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16.
17.
18.
19.
20. 21.
22. 23.
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HeartMate II left ventricular assist system to long-term warfarin therapy. J Heart Lung Transplant 2010;29:616–24. Menon AK, Gotzenich A, Sassmannshausen H, Haushofer M, Autschbach R, Spillner JW. Low stroke rate and few thrombo-embolic events after HeartMate II implantation under mild anticoagulation. Eur J Cardiothorac Surg 2012;42:319–23; discussion 323. Aissaoui N, Paluszkiewicz L, Koertke HH, Morshuis M, Gummert J. Echocardiography can be more sensitive than thoracic computed tomography in detecting a thrombus in the inflow cannula of a continuous left ventricular assist device. Echocardiography 2011;28:E215–6. Paluszkiewicz L, Gursoy D, Spiliopoulos S, et al. HeartMate II ventricular assist device thrombosis—an echocardiographic approach to diagnosis: can Doppler evaluation of flow be useful? J Am Soc Echocardiogr 2011;24:350.e1–e4. Uriel N, Morrison KA, Garan AR, et al. Development of a novel echocardiography ramp test for speed optimization and diagnosis of device thrombosis in continuous-flow left ventricular assist devices: the Columbia ramp study. J Am Coll Cardiol 2012;60:1764–75. Jennings DL, Cabrera R, Wang DD, Tita C. Successful treatment of a continuous flow left ventricular assist device thrombosis with eptifibatide. ASAIO J 2012;58:633–5. Kamouh A, John R, Eckman P. Successful treatment of early thrombosis of HeartWare left ventricular assist device with intraventricular thrombolytics. Ann Thorac Surg 2012;94: 281–3. Tang GH, Kim MC, Pinney SP, Anyanwu AC. Failed repeated thrombolysis requiring left ventricular assist device pump exchange. Catheter Cardiovasc Interv 2013;81:1072–4. Blais DM, Sun B, Vesco P, Louis LB, Sai-Sudhakar C, Firstenberg MS. Profound thrombocytopenia with glycoprotein IIb/IIIa inhibitors plus heparin for pump thrombus. J Heart Lung Transplant 2008;27:1361–2.
Background. An ongoing challenge in the management of patients with heart failure who receive left ventricular assist devices (LVADs) is achieving optimal anticoagulation. Adverse prothrombotic events include hemolysis or pump thrombus (H/T) and neurologic events (NEs), and all limit the success of LVAD therapy. Our aim was to study the incidence and clinical outcomes associated with these events in a large single-center cohort. Methods. We retrospectively reviewed our prospectively collected database of all patients receiving a HeartMate II (Thoratec Corp, Pleasanton, CA) LVAD from 2005 to 2012. Demographic, clinical, and outcome data were analyzed using standard statistical methods. All adverse events were recorded. Results. Of 193 patients receiving LVADs, we identified 39 H/T events in 26 (13.4%) patients and 22 NEs in 19 (9.8%) patients. Seventy-four percent of events occurred in the last 3 years of the series, during which time 63% of implants were placed. Of patients with H/T, 8 (31% of those having H/T, 4.1% of total) had more than 1 event and 4 (15.4% of those having H/T, 2.1% of total) underwent pump exchanges. Five (23%) patients had NEs after
H/T, and 6 (32%) died as a result of the NE. Of patients with H/T, 27% had preceding episodes of infection, 31% had an international normalized ratio (INR) of less than 1.5, 31% had an INR of 1.5 to 2, 15% had a history of clotting or were hypercoagulable, and 4% had anticoagulation intentionally withheld. Lactate dehydrogenase (LDH), plasma hemoglobin, INR, and platelet determinations were significantly different at the time of H/T compared with baseline values. The survival at 6 months (alive or having undergone transplantation) for those with a prothrombotic event compared with those without was 70% versus 75.2% (p [ 0.5). Conclusions. The incidence of H/T or NEs is significant and results in major morbidity after LVAD placement. Infection and suboptimal anticoagulation are associated with the majority of these events. Identification of patients at higher risk for hemolysis (ie, infection) may allow for modification of anticoagulation regimens to reduce these risks and improve clinical outcomes.
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complications (such as hemolysis or thrombosis) but not excess anticoagulation to contribute to bleeding (eg, gastrointestinal bleeding or NEs). Further complicating the clinical picture is the inherent hematologic effects of continuous-flow LVADs [5] and the need to adjust anticoagulation for patient care. The objectives of this study were to investigate the incidence and clinical outcome associated with anticoagulation and adverse prothrombotic events (hemolysis or pump thrombus [H/T] and neurologic events [NEs]). In addition, we sought to evaluate the effect of these events on long-term survival and determine if antecedent events contributed to these prothrombotic events.
ith more than 200,000 deaths annually in the United States attributed to congestive heart failure [1], the role of durable mechanical circulatory support is rapidly increasing. With increased use of long-term implantable left ventricular assist devices (LVADs) such as the HeartMate II (Thoratec Corp, Pleasanton, CA), which was first implanted in 2004 [2], there has been a varied and wide ranging experience with managing the anticoagulation strategy. This anticoagulation strategy has been nuanced because it requires a delicate balance [3, 4] of adequate anticoagulation to minimize thrombotic
(Ann Thorac Surg 2014;-:-–-) Ó 2014 by The Society of Thoracic Surgeons
Accepted for publication Feb 20, 2014. Presented at the Poster Session of the Forty-ninth Annual Meeting of The Society of Thoracic Surgeons, Los Angeles, CA, Jan 26–30, 2013. Address correspondence to Dr John, Division of Cardiovascular and Thoracic Surgery, University of Minnesota, MMC 207, 420 Delaware St SE Minneapolis, MN 55455; e-mail: [email protected].
Ó 2014 by The Society of Thoracic Surgeons Published by Elsevier Inc
Drs Eckman and John discloses financial relationships with Thoratec and HeartWare.
0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2014.02.041
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WHITSON ET AL CONTINUOUS-FLOW LVAD EVENTS
Patients and Methods We performed a retrospective analysis of our prospectively maintained clinical outcomes database of those patients who underwent operation for placement of a Thoratec HeartMate II LVAD from January 1, 2005 through April 1, 2012. These operations were performed and data were collected at a single-center large academic quaternary care hospital. The patients were evaluated preoperatively and managed postoperatively in a multidisciplinary collaborative manner between the cardiothoracic surgery and heart failure cardiology services. This database and evaluation were approved by our institutional review board with waiver of the need for individual consent.
Clinical Outcomes Definitions We evaluated the demographic and clinical indications of the patients undergoing HeartMate II implantation. In addition, the outcome data were evaluated. Longitudinally, patients were followed for their overall survival, hemolysis or thrombosis events, NEs, preceding inciting events that may predispose to a change in coagulation, their anticoagulation treatment, pump malfunction, and outcome.
Neurologic Events We defined an NE as a transient ischemic attack, a cerebral embolism, an ischemic stroke, or a hemorrhagic stroke. The definition of an NE was the Interagency Registry for Mechanically Assisted Circulatory Support definition of any new, temporary or permanent, focal or global neurologic deficit ascertained by a standard neurologic examination (administered by a neurologist or other qualified physician and documented with appropriate diagnostic tests and consultation note). The examining physician will distinguish between a transient ischemic attack, which is fully reversible within 24 hours (and without evidence of infarction), and a stroke, which lasts longer than 24 hours (or <24 hours if there is evidence of infarction). Each NE must be subcategorized as (1) transient ischemic attack (acute event that resolves completely with 24 hours with no evidence of infarction) or (2) ischemic or hemorrhagic cerebral accident/cerebrovascular accident (event that persists beyond 24 hours or <24 hours associated with infarction on an imaging test).
Hemolysis Hemolysis was defined as clinical evidence of hemolysis (ie, tea-colored urine) along with biochemical evidence (increased level of lactate dehydrogenase ([LDH] greater than twice the baseline value or the upper limit of normal, plasma free hemoglobin value >15 mg/dL) with or without clinical signs of LVAD pump dysfunction.
Pump Thrombosis Pump thrombus was defined as recurrent, consistent pump controller power spikes, echocardiographic demonstration of thrombus, or pump failure. Furthermore,
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clinical evidence of hemolysis with signs of LVAD pump dysfunction (high power, low pulsatility index) and clinical evidence of heart failure were present and typically confirmed by thrombus within the pump.
HeartMate II LVAD Insertion The LVAD used in this investigation was the HeartMate II LVAD, which is a continuous-flow device consisting of an internal axial-flow blood pump with a percutaneous lead that connects the pump to an external system driver and power source that has been previously described [6]. Details of HeartMate II function and the implantation technique have been described previously [6–8].
Patient and Device Management Following our local practice at the University of Minnesota, we set the speed of the HeartMate II to provide adequate cardiac output and achieve optimal left ventricular decompression while maintaining a pulsatility index greater than 3.5 to 4.0. We optimize the rpm speed, using both hemodynamic and echocardiographic parameters, at the time of LVAD placement in the operating room, during the postoperative period, and if clinical events (new symptoms or suction events) warrant further adjustment. In the operating room, the presence of transesophageal echocardiography and continuous pulmonary artery catheter monitoring helps optimize pump speed to achieve LV decompression without a septal shift toward the left ventricle or evidence of progressive right ventricular dilatation. Goals for central venous pressure are typically 10 to 15 mm Hg, with pulmonary artery systolic pressure less than 45 mm Hg, and cardiac index greater than 2.2 L/min/m2. Pump speed typically is gradually increased by increments of 200 rpm after approximately 48 hours using the pulsatility index as a guide. After transfer out of the intensive care unit and discharge to home, echocardiograms are typically obtained to identify new symptoms of heart failure or suction events [6–8].
Anticoagulation Management Our anticoagulation management consisted of starting coumadin on postoperative day 1 or 2. Our goal INR has evolved from 1.5 to 2.5 to 2.0 to 2.5 in the patient with an LVAD without bleeding diathesis. Once surgical bleeding is no longer a concern, a low-dose heparin drip is initiated. Low-dose enteric-coated aspirin (81 mg daily) is administered as well.
Statistical Analysis Data were analyzed with JMP Pro for Mac, version 9.0.2 (SAS Institute, Cary, NC). For all statistical testing, we used a 2-sided significance level of 0.05. For betweengroup comparisons, we used a 2-sample t test for continuous variables and a c2 test for categorical variables. Unless otherwise stated, results are reported as mean standard deviation. The Kaplan-Meier method was used to compare unadjusted all-cause mortality rates between patients who experienced events and those who did not.
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Table 1. Left Ventricular Assist Device Implantation Indications LVAD Indication
Proportiona (n ¼ 193)
Ischemic cardiomyopathy Dilated cardiomyopathy Other Ischemic, acute myocardial infarction Nonischemic, acute other Cardiogenic shock Nonischemic, acute myocarditis a
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44.6% (86) 33.2% (64) 9.8% (19) 8.8% (17) 2.6% (5) 1.0% (2) 0% (0)
Data may not sum to 100% because of rounding.
Results Demographics During the study period, 193 patients underwent HeartMate II LVAD implantation. The primary indication was ischemic cardiomyopathy (46%) (Table 1) followed by dilated nonischemic cardiomyopathy (34.2%). The mean age at the time implantation was 55.6 13.9 years. Of the 193 LVAD recipients, 78.2% (151 of 193) were men and 21.8% (42 of 193) were women. A preoperative intraaortic balloon pump was used in 84% (175 of 193) of patients. There were 153 patients (79.3%) with no events, 26 (13.5%) patients with H/T, 14 (7.5%) patients with NEs, 40 (20.1%) patients with either H/T or NEs, and 5 patients (2.6%) with H/T and NEs.
Hemolysis or Thrombosis Events In our cohort of 193 LVAD recipients, we identified 39 H/T events in 26 (13.4%) patients. In addition, we identified 22 NEs in 19 (9.8%) patients. Of the total events, 74% occurred in the last 3 years of the series during which 63% of implants were placed. We found that in patients with either hemolysis or thrombosis, 8 patients (31% of patients with H/T, 4.1% of total) had more than 1 event. Those patients with events trended to being older and were significantly more likely to be women (Table 2). Of the 26 patients who had H/T, 4 (15.4% of patients with H/T, 2.1% of total) underwent pump exchanges.
Neurologic Events Five of the 26 patients with H/T had an NE after their H/T event; thus the incidence of NE after H/T was 23%.
Risk Factors/Antecedent Events Of patients with NEs, 6 died as a result of the NE (32%). In patients with H/T, 27% had preceding infection, 31% had an INR of less than 1.5, 31% had an INR of 1.5 to 2, 15% had a history of clotting or were hypercoagulable, and 4% had anticoagulation intentionally withheld. LDH, plasma hemoglobin, INR, and platelet determinations were significantly different at the time of H/T compared with baseline measurements (Table 3). Because of the longitudinal nature of the data collection, the overall incidence, and our registry, we are not able to determine with a high degree of accuracy the incidence of infection in those patients who did not have H/T or NEs. There was no difference in the incidence of any of 16 separately measured comorbid conditions (Table 4). These 16 risk factors are the components of the Charlson comorbidity index. From this analysis, we were not able to predict who would be at a higher risk of having an NE or H/T after HeartMate II LVAD insertion.
Survival The survival rate at 6 months (alive or having undergone transplantation) for patients having an event compared with those who did not was 70% versus 75.2%, (p ¼ 0.5). The overall long-term survival for patients with no events, hemolysis, thrombosis, or NEs was not statistically different (Fig 1). An effect of NEs on overall long-term survival was seen, both when grouped with those with H/T (Fig 2A) and when by itself (Fig 2C) but not when H/T was compared with all other events (Fig 2B).
Comment In our analysis of a single-institution experience with HeartMate II LVADs, we found an overall incidence of hemolysis or thrombotic events of 13.4% and an incidence of NEs (transient ischemic attack, cerebral embolism, ischemic stroke, or hemorrhagic stroke) to be 9.8%. We
Table 2. Demographic Data of Patients With Events and Those Without Hemolysis, Thrombosis or NEsa Variable N Age (y) Sex (% male) Diagnosis Ischemic cardiomyopathy Dilated cardiomyopathy Other Survival after event (d) a
No Event
Hemolysis or Thrombosis Event
Neurologic Event
153 56 13 82%
26 52 16 58%
14 54.7 15 79%
44%
52%
36%
33% 17% 311 (1–2,424)
32% 16% 182.5 (11–2,090)
36% 28% 297 (3–650)
Data may not sum to 100% because of rounding.
NEs ¼ neurologic events.
p Value 0.092 0.009 0.092
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Table 3. Hematologic Characteristics at the Time of Event Hemolysis or Thrombosis Event Variable
No Event 3
Platelet count (10 /dL) International normalized ratio Total bilirubin (mg/dL) Plasma hemoglobin (mg/dL) Lactate dehydrogenase (U/L)
186 (109–515) 1.3 (1.1–2.2) 1.2 (0.3–4) <15 (<15–19) 630 (303–2,966)
Baseline 220 2.3 0.9 <15 870.5
(100–416) (1.2–3.5) (0.1–3.3) (<15–22) (31–5,824)
At Event 175 1.9 1.8 53.5 3,235.5
(91–502) (1.1–6.4) (0.5–14.5) (<15–385) (627–20,921)
Neurologic Event
p Value
– 2.1 (1.4–7.3) – – –
0.013 0.017 <0.001 <0.001 <0.001
Data are presented as median and range unless otherwise stated.
used a consistent definition for hemolysis and thrombotic complications in our study.
Acquired Coagulation Deficiencies of Continuous-Flow LVADs Continuous-flow LVADs have been shown to have a higher risk of hemolysis and bleeding when compared with pulsatile-pump LVADs. This effect is attributed to the high shear stress conditions of these pumps. The high shear stress contributes to direct hemolysis, thrombocytopenia, increased fibrinolysis [9], and a decrease in the high molecular weight multimers of von Willebrand’s factor [3, 5, 10, 11]. This acquired von Willebrand’s deficiency is similar to Heyde’s syndrome seen in severe aortic stenosis. As a result of these perturbations in the clotting cascade, the use of point-of-care testing for patients with mechanical circulatory support has been Table 4. Comorbidities at the Time of Implantationa
Comorbidity Acquired immunodeficiency syndrome Cerebrovascular accident Chronic obstructive pulmonary disease Congestive heart failure Connective tissue disorder Dementia Hemiplegia History of leukemia History of lymphoma Previous myocardial infarction Peripheral vascular disease Ulcer disease Diabetes Liver disease Kidney disease (Cr >1.5) History of solid malignancy a
No Event (%)
Hemolysis, Thrombosis, or Neurologic Event (%) p Value
1.3
0.0
0.33
4.6 18.3
12.5 20.0
0.09 0.75
88.9 2.6 1.3 0.7 0 5.9 37.9
92.5 7.5 0.0 0.0 0.0 2.5 42.5
0.48 0.18 0.33 0.49 1 0.35 0.62
6.5
5.0
0.71
2.6 38.6 4.1 30.9 10.7
10.0 27.5 2.5 20.0 10.0
0.06 0.18 0.63 0.18 0.88
Data may not sum to 100% because of rounding.
advocated [12]. These tests consist of thromboelastography, platelet function tests (impedance or aggregometry), bleeding time, activated partial thromboplastin time, INR determinations, platelet count, and anti-Xa levels. However, a consistent approach to such testing remains elusive.
Antecedent Events Kato and colleagues [13] evaluated their experience with 307 continuous-flow LVADs (167 HeartMate I and 140 HeartMate II). They found that patients with previous stroke and persistent inflammation or infection had a higher incidence of NEs. Aggarwal and colleagues [14] investigated the association of bloodstream infection and hemorrhagic strokes in 87 patients who underwent HeartMate II implantation. They found that the occurrence of a bloodstream infection after LVAD implantation led to an 8-fold (odds ratio of 7.9) increase in cerebrovascular events after HeartMate II LVAD implantation. In the current study, we did find that 27% of these adverse events were associated with an antecedent infection. This finding in our study is consistent with that of the Columbia group who found that infection or a proinflammatory event can contribute to a systemic hypercoagulable state that could lead to H/T or NE.
Fig 1. Overall survival from time of pump implantation to transplantation, death, or last follow-up for no events (red), neurologic events (NEs) (blue), or hemolysis/thrombosis (green) (p ¼ 0.087).
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Fig 2. Overall survival from time of pump implantation to transplantation, death, or last follow-up for patients with (A) hemolysis/thrombosis or a neurologic event (NE) (blue) versus all others (red) (p ¼ 0.034), (B) those with hemolysis/thrombosis (blue) versus all others (red) (p ¼ 0.41), and (C) Those with NEs (blue) versus all others (red) (p ¼ 0.026).
Anticoagulation After Implantation The practice of postoperative management of anticoagulation in patients with HeartMate II LVADs is varied as well. Some centers routinely bridge patients to oral anticoagulants with intravenous heparin (an enzyme inhibitor of antithrombin III), bivalirudin (a direct thrombin inhibitor), or eptifibatide (a platelet fibrinogen receptor glycoprotein IIb/IIIa inhibitor). Other centers transition patients directly to aspirin and warfarin. The routine use of the direct transition approach, evaluated in a multiinstitutional series of 418 patients, found no difference in incidence of thrombotic or hemorrhagic complications [15]. A goal INR of 2 to 2.5 has been found to be a safe balance to achieve minimal thrombosis events and minimal gastrointestinal bleeding events [16].
systolic amplitude has correlated with pump/outflow graft thrombosis and its resolution [18]. In addition, the use of an echocardiographic ramp study to evaluate for speed optimization and to diagnose pump thrombosis has been proposed [19]. At the University of Minnesota, the routine treatment of thrombosis or hemolysis was increasing the goal INR 2.5 to 3 as well as starting high-intensity intravenous heparin. This approach was routinely used except when heparin-induced thrombocytopenia was suspected or present. Other centers have used eptifibatide routinely with minimal complications [20]. The use of intravenous or intraventricular thrombolytic agents to treat pump thrombus has had mixed efficacy [21, 22]. On a cautionary note, the concomitant use of glycoprotein IIb/IIIa inhibitors and heparin may lead to thrombocytopenia in the treatment of pump thrombosis [23].
Pump Thrombosis In evaluating patients for pump thrombosis, echocardiography may be a useful adjunct to aid diagnosis [17–19]. The use of Doppler echocardiography to evaluate the diastolic flow velocity and difference in diastolic and
Hemolysis or Thrombosis Management Algorithm The clinical algorithm to hemolysis and suspected pump thrombosis currently used at the University of Minnesota is presented in Fig 3. In this management algorithm, a
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Fig 3. University of Minnesota algorithm for management of left ventricular assist device (LVAD) hemolysis or pumpassociated thrombus. (1A ¼ organ transplant status 1A; AV ¼ aortic valve; CT ¼ computed tomography; Echo ¼ echocardiography; Hb ¼ hemoglobin; ICU ¼ intensive care unit; INR ¼ international normalized ratio; LDH ¼ lactate dehydrogenase; LV ¼ left ventricle; PWP ¼ pulmonary wedge pressure; RHC ¼ right heart catheterization.)
high index of suspicion of H/T is needed. This suspicion index is wedded with the clinical scenario. When there are clinical, physiologic, and echocardiographic data that support the diagnosis, an aggressive approach to modulating anticoagulation therapy is undertaken. This is most efficiently and accurately undertaken in the inpatient setting. Patients with hemolysis or pump thrombosis, or both, are usually upgraded to status IA on the heart transplant waiting list if they are bridge-to-transplantation patients receiving LVADs. We reserve the option of pump exchange for patients with pump thrombosis with worsening heart failure despite aggressive anticoagulation therapy. Patients may be considered for thrombolytic therapy if they are not candidates for surgical pump exchange (only 1 patient in our experience received intraventricular thrombolytic therapy and had a successful outcome). In our series, we considered an elevated LDH value of greater than twice the upper limit of normal to be a concern for hemolysis. At the University of Minnesota, the range is 325 to 750 U/L; therefore, our cutoff was 1500 U/L.
Limitations Our study is affected by several limitations that can introduce bias, including the fact that this is a retrospective study. The decision to perform the placement of the HeartMate II LVAD was dependent on the clinical condition of the patient and the judgment of the surgeon and heart failure cardiology teams. Although there were no differences in the proportion of comorbid illnesses between cohorts, the patient population is overall small and heterogeneous. This study is limited by its singleinstitution observational nature. This study is strengthened by careful prospective data collection. All procedures were carried out by an
experienced surgeon/heart failure cardiology team to reduce variability in patient management. The approach to the patient who had an event was standardized, and we believe that this approach contributed to the satisfactory outcomes of those patients with H/T or NEs.
Clinical Relevance The incidence of H/T or NEs is significant and results in major morbidity after LVAD placement. Infection and suboptimal anticoagulation are associated with the majority of events. Identification of patients at higher risk for hemolysis (ie, infection) may allow for modification of anticoagulation regimens to reduce these risks and improve clinical outcomes. The need for a balanced anticoagulation profile is needed to maintain optimum outcomes after LVAD.
References 1. O’Connell JB, Bristow MR. Economic impact of heart failure in the United States: time for a different approach. J Heart Lung Transplant 1994;13:S107–12. 2. Frazier OH, Delgado RM 3rd, Kar B, Patel V, Gregoric ID, Myers TJ. First clinical use of the redesigned HeartMate II left ventricular assist system in the United States: a case report. Tex Heart Inst J 2004;31:157–9. 3. Eckman PM, John R. Bleeding and thrombosis in patients with continuous-flow ventricular assist devices. Circulation 2012;125:3038–47. 4. Kurien S, Hughes KA. Anticoagulation and bleeding in patients with ventricular assist devices: walking the tightrope. AACN Adv Crit Care 2012;23:91–8. 5. Slaughter MS. Hematologic effects of continuous flow left ventricular assist devices. J Cardiovasc Transl Res 2010;3: 618–24. 6. John R, Kamdar F, Eckman P, et al. Lessons learned from experience with over 100 consecutive HeartMate II left
Ann Thorac Surg 2014;-:-–-
7. 8.
9.
10.
11. 12. 13.
14.
15.
ventricular assist devices. Ann Thorac Surg 2011;92:1593–9; discussion 1599–600. Griffith BP, Kormos RL, Borovetz HS, et al. HeartMate II left ventricular assist system: from concept to first clinical use. Ann Thorac Surg 2001;71:S116–20; discussion S114–6. John R, Kamdar F, Liao K, Colvin-Adams M, Boyle A, Joyce L. Improved survival and decreasing incidence of adverse events with the HeartMate II left ventricular assist device as bridge-to-transplant therapy. Ann Thorac Surg 2008;86:1227–34; discussion 1234–5. Slaughter MS, Sobieski MA, Gallagher C, Graham J, Brandise J, Stein R. Fibrinolytic activation during long-term support with the HeartMate II left ventricular assist device. ASAIO J 2008;54:115–9. Suarez J, Patel CB, Felker GM, Becker R, Hernandez AF, Rogers JG. Mechanisms of bleeding and approach to patients with axial-flow left ventricular assist devices. Circ Heart Fail 2011;4:779–84. Yuan N, Arnaoutakis GJ, George TJ, et al. The spectrum of complications following left ventricular assist device placement. J Card Surg 2012;27:630–8. Gorlinger K, Bergmann L, Dirkmann D. Coagulation management in patients undergoing mechanical circulatory support. Best Pract Res Clin Anaesthesiol 2012;26:179–98. Kato TS, Schulze PC, Yang J, et al. Pre-operative and postoperative risk factors associated with neurologic complications in patients with advanced heart failure supported by a left ventricular assist device. J Heart Lung Transplant 2012;31:1–8. Aggarwal A, Gupta A, Kumar S, et al. Are blood stream infections associated with an increased risk of hemorrhagic stroke in patients with a left ventricular assist device? ASAIO J 2012;58:509–13. Slaughter MS, Naka Y, John R, et al. Post-operative heparin may not be required for transitioning patients with a
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16.
17.
18.
19.
20. 21.
22. 23.
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HeartMate II left ventricular assist system to long-term warfarin therapy. J Heart Lung Transplant 2010;29:616–24. Menon AK, Gotzenich A, Sassmannshausen H, Haushofer M, Autschbach R, Spillner JW. Low stroke rate and few thrombo-embolic events after HeartMate II implantation under mild anticoagulation. Eur J Cardiothorac Surg 2012;42:319–23; discussion 323. Aissaoui N, Paluszkiewicz L, Koertke HH, Morshuis M, Gummert J. Echocardiography can be more sensitive than thoracic computed tomography in detecting a thrombus in the inflow cannula of a continuous left ventricular assist device. Echocardiography 2011;28:E215–6. Paluszkiewicz L, Gursoy D, Spiliopoulos S, et al. HeartMate II ventricular assist device thrombosis—an echocardiographic approach to diagnosis: can Doppler evaluation of flow be useful? J Am Soc Echocardiogr 2011;24:350.e1–e4. Uriel N, Morrison KA, Garan AR, et al. Development of a novel echocardiography ramp test for speed optimization and diagnosis of device thrombosis in continuous-flow left ventricular assist devices: the Columbia ramp study. J Am Coll Cardiol 2012;60:1764–75. Jennings DL, Cabrera R, Wang DD, Tita C. Successful treatment of a continuous flow left ventricular assist device thrombosis with eptifibatide. ASAIO J 2012;58:633–5. Kamouh A, John R, Eckman P. Successful treatment of early thrombosis of HeartWare left ventricular assist device with intraventricular thrombolytics. Ann Thorac Surg 2012;94: 281–3. Tang GH, Kim MC, Pinney SP, Anyanwu AC. Failed repeated thrombolysis requiring left ventricular assist device pump exchange. Catheter Cardiovasc Interv 2013;81:1072–4. Blais DM, Sun B, Vesco P, Louis LB, Sai-Sudhakar C, Firstenberg MS. Profound thrombocytopenia with glycoprotein IIb/IIIa inhibitors plus heparin for pump thrombus. J Heart Lung Transplant 2008;27:1361–2.