Decades of painstaking progress has brought mechanical circulatory support (MCS) with durable implantable left ventricular assist devices (LVADs) to the forefront of therapies for long-term treatment of advanced stage heart failure (HF).1 A significant milestone in the field was the introduction of continuous-flow (CF) LVADs that enabled smaller device designs with markedly improved durability that translated into important clinical benefits, including improved survival, functional status, and quality of life with fewer adverse events when compared with older pulsatile pumps.2–4 The overall attributes of CF technology have resulted in significantly greater adoption of MCS therapy by the medical community. Despite the significant advances with CF technology, the cumulative adverse event burden contributed by stroke, bleeding, device-related infection, and pump thrombosis is high and remains an obstacle to greater adoption of this therapy.5,6
Pump Thrombosis Comes to the Pinnacle of Device Complications
The issue of pump thrombosis in CF LVADs and its recent rise to notoriety is well chronicled in the literature.6–8 In 2013, clinicians at three major ventricular assist device (VAD) centers in the United States8 and investigators from the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS)7 published results of an increase in pump thrombosis in the HeartMate II (HMII) Left Ventricular Assist System (Thoratec, Pleasanton, CA). Starling et al.8 identified 108 cases of pump thrombosis among 895 LVADs implanted in 837 patients (12.2% of recipients). Investigators at INTERMACS7 reported 382 cases of device exchange or death because of pump thrombosis among 6,910 patients (overall rate of 5.5%). Analysis of temporal trends by era identified a sixfold increase in the rates of pump thrombosis from 2011 to 2012. Compared with 2008 through 2009, the freedom from pump exchange or death from thrombosis decreased from 99% at 6 months to 95% in 2011 and 94% in 2012. The rates of pump thrombosis in the reports by Starling et al.8 and Kirklin et al.7 compared with 1.4% of patients or 0.02 events per patient-year reported in the HMII Pivotal Bridge to Transplant Trial (BTT) and continued access protocol (CAP),3 4% of patients or 0.024 events per patient-year in the original cohort reported in the HMII Pivotal Destination Therapy (DT) Trial,4 6% of patients or 0.038 events per patient-year in the CAP phase of the HMII Pivotal DT Trial,9 and 3.6% of patients or 0.027 events per patient-year in the HMII DT Food and Drug Administration (FDA) postapproval study.10
The problem of pump thrombosis has not been limited to CF pumps with axial design and has been observed in durable LVADs with centrifugal technology. Najjar et al.11 reported rates of pump thrombosis within the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial (HeartWare ventricular assist device (HVAD) for the Treatment of Advanced of Advanced Heart Failure; HeartWare HVAD BTT Pivotal Trial; HeartWare, Inc., Miami, FL). Pump thrombus with the HVAD occurred at a rate of 0.08 events per patient-year, and exchange for pump thrombus occurred at a rate of 0.04 events per patient-year.
Not all clinical studies have observed rates of pump thrombosis as high as reported by Starling et al.8 or INTERMACS.7 The Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients (ROADMAP) study was a prospective, multicenter, nonrandomized, controlled, observational study designed to evaluate the effectiveness of initial treatment with LVAD (HMII) versus optimal medical management (OMM) with later transition to LVAD if necessary, in ambulatory patients with New York Heart Association (NYHA) class IIIB or IV limitations who were noninotrope dependent and who met the current FDA approved indications for DT.12 Patients were enrolled into the trial between October 2011 and July 2013 when high rates of pump thrombosis were reported in the studies from Starling et al.8 and INTERMACS.7 Importantly, pump thrombus occurred in only 1.1% at 90 days and in 6.4% at 1 year.
The issue of pump thrombosis has had a significant adverse effect on the field, both from a clinical outcomes perspective and on how current technology is viewed by regulatory agencies and clinicians. Pump thrombosis events are not insignificant and result in substantial morbidity and mortality and likely have additional significant impact on quality of life. In the INTERMACS analysis, pump exchange was associated with higher mortality and a greater incidence of neurologic-related and infection-related morbidity in survivors of pump exchanges.7 After the reports by Starling et al.8 and INTERMACS investigators,7 the National Heart Lung and Blood Institute (NHLBI) placed the Randomized Evaluation of VAD Intervention Before Inotropic Therapy Trial (REVIVE-IT) on hold in November of 2013. REVIVE-IT was an NHLBI-sponsored study investigating LVAD therapy in a population with less advanced HF. After a brief restart, the trial was terminated in March 2015 for futility as a result of changes in clinical equipoise in study investigators caused, in part, from concern for pump thrombosis in the study device. Based on ongoing concerns with the issue of pump thrombosis and other important safety end points such as stroke, FDA recently issued a safety communication (August 5, 2015) highlighting the issue of adverse events with durable LVADs and emphasized the importance of restricting use to currently approved populations to justify the current benefit and risk profile.13
There is general consensus in the MCS field that the rise in incidence of pump thrombosis is because of a multitude of factors related to patient characteristics, limitations in device design, and changes in patient management.6,14 Of the former, examination of patient characteristics has identified younger age, obesity, and noncompliance as contributing causes.7,14 Other factors such as hypercoagulability syndromes and atrial fibrillation are likely important.7 The contribution of device design to risk pump thrombosis is obvious, but how the different technologies influence the proclivity for thrombus remains unknown. In the HeartWare HVAD DT Pivotal Trial, ENDURANCE, sintering of the HVAD inflow cannula was associated with a 48% reduction in any pump thrombus event.15 Of the latter factor, 1) permissiveness to maintain lower international normalized ratio (INR) levels and lower or no antiplatelet therapy in response to frequent bleeding complications, 2) laxity in adhering to principles of good implantation techniques, and 3) desire to maintain pumps at lower speeds to retain aortic valve opening to reduce the incidence of de novo aortic insufficiency are likely important offending factors.6 Clinical trial data from ADVANCE have revealed hypertension (mean arterial pressure > 90 mm Hg), low INR values less than 2, and use of 81 mg or less of aspirin daily as significant risk factors for pump thrombosis in the HVAD, supporting the contention that patient management factors play a significant role in pump thrombosis.11
Data to support these assumptions have often been difficult to obtain because of the lack of standardized clinical practice at VAD centers in the United States. The contribution of patient characteristics and management practices is currently being investigated in the Prevention of REcurrent VENous Thromboembolism (PREVENT) study.16 The PREVENT research is a prospective, multicenter, nonrandomized observational study enrolling 300 subjects undergoing implantation of the HMII. The primary end-point of PREVENT is to investigate the incidence of confirmed pump thrombosis within 3 months of HMII implantation, and investigators will examine risk factors for pump thrombosis including patients characteristics and management practices.
Upshaw et al.17 from Tufts Medical Center have presented a single center, retrospective observational study of 118 patients undergoing implantation of 125 durable CF axial or centrifugal LVADs. Of the 125 LVADs, there were 24 patients with 25 devices treated for suspected pump thrombosis for an event rate of 0.17 events per patient-year. Freedom from pump thrombosis was 97.5% at 30 days, 87.8% at 6 months, and 82.2% at 1 year. Comparison of pump thrombosis rates was made between the HMII and HVAD, and although the HVAD demonstrated a clinically important lower rate of thrombosis, the differences observed by the Tufts group were not significant, likely because of a small number of events. A number of medical treatments were applied to the patients who presented with pump thrombosis including initial heparin (60%) or bivalirudin (33%) followed by additional medical therapies with eptifibatide, alteplase, or surgical intervention with pump exchange. Medical therapies were associated with a high rate of recurrence.
The study by Upshaw et al.17 raises a number of important issues regarding the state of investigation of pump thrombosis in CF LVADs. First, although a standard definition of both “suspected” and “confirmed” pump thrombosis exists in INTERMACS, there has not been uniform application of this definition in the literature and rates of “suspected” pump thrombosis have been generally underreported. In the study by Upshaw et al.,17 a rise in lactate dehydrogenase (LDH) three times the upper limits of normal in the absence of clinical findings, symptoms, or pump abnormalities that precipitated a hospital admission or cardioembolic event in the absence of an identifiable source were considered cases of “suspected” thrombosis. There is no uniform consensus in the field that an isolated elevation in LDH, in the absence of clinical signs or symptoms or evidence of pump dysfunction, warrants hospital admission with intensification of anticoagulation therapies or thrombolytic therapies. However, available evidence does support that isolated LDH elevations, particularly early after pump implantation, portend a high risk of pump exchange and other adverse events such as stroke.8,18,19 Thus, close LDH monitoring should be investigated as part of an overall strategy to detect and intervene early in the process of pump thrombus formation. Additionally, treatment protocols for device thrombosis varied and evolved over time and seemed not to be specific to device type in this study. Response to treatment likely varies by device type, as the nature of the thrombus problem is different between the HVAD and HMII. For the HVAD, the onset of the thrombus event is generally more acute (i.e., days) with clinical signs and symptoms and abnormalities in pump parameters present at the time of diagnosis.11,20 The source of the thrombus is likely embolic in nature because of the formation of thrombus at the interface of the left ventricle and inflow cannula.11 The HMII generally has a more insidious onset (i.e., weeks to months) with less clinical signs and symptoms and less obvious abnormalities in pump parameters.19 Pannus and thrombus formation at the inflow or outflow bearing is the major site of thrombus formation.14 It is becomingly increasingly clear that strategies to treat thrombosis are device specific. Device specific diagnosis and treatment strategies have been recently reported by Jorde et al.20 who demonstrated that the use of log file analysis of the HVAD, independent of biochemical data, at the time of pump thrombosis presentation provided prognostic information on the probability of success with thrombolytic therapy for the HVAD.
Moving the Field Forward
How is the problem of pump thrombosis best approached? First, a more thorough collection of patient variables and consensus on uniform patient management strategies are needed to more thoroughly investigate the relationship to pump thrombosis. Device specific approaches to understanding the inciting factors for pump thrombosis and its diagnosis and treatment should be incorporated into future studies. Finally, new technology has contributed to the largest gains in survival and reduction in adverse event burden over the past 2 decades. Emphasis on device designs that address the important issue of device–blood interface and compatibility are needed to address thromboembolism. The HeartMate 3 (HM3; Thoratec, Pleasanton, CA) is a new CF LVAD with centrifugal design with complete magnetic levitation of the internal impeller. The results of 50 patients undergoing implantation of the HM3 as part of the Conformité Européene (CE) Mark clinical study demonstrated a 0% incidence of pump thrombosis, hemolysis and need for pump exchange at 6 month follow-up.21 These data provide early encouraging results that pump thrombosis may be effectively addressed with enhancements in pump designs. These findings will require further validation in the larger pivotal trial of the HM3 in the United States with the MOMENTUM 3 U.S. IDE Clinical Trial.22
The issue of pump thrombosis is complex, and solutions to the problem have been elusive. However, recent studies have provided important insights into the issues and have provided a framework to move the field forward. New technology brings further hope that the issue of pump thrombosis may be manageable or even solvable.
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