Continuous-flow left ventricular assist devices (CF-LVADs) are a standard therapeutic option for patients with end-stage heart failure that restore circulation, preserve organ function, improve functional status, quality of life, and extend survival.1 Continuous-flow left ventricular assist devices can be used as a bridge to transplant, a bridge to recovery, or a destination therapy.2,3
Pump thrombosis is a known major complication of CF-LVADs and is associated with an increased incidence in recent years.4–6 Pump thrombosis can lead to thromboembolic stroke, peripheral thromboembolism, CF-LVAD malfunction with reduced systemic flows, CF-LVAD failure with life-threatening hemodynamic impairment, cardiogenic shock, and death.7 Medical (i.e., direct thrombin inhibitor,8,9 tissue plasminogen activator,10,11 or glycoprotein IIb/IIIa antagonist)12 and surgical (i.e., pump exchange)13–16 treatment options exist. In addition, before the PREVENT (PREVENtion of HeartMate II Pump Thrombosis Through Clinical Management) clinical trial,17 implantation techniques, postoperative anticoagulation, and blood pressure management varied greatly across practitioners and institutions, and consequently, the reported prevalence varies greatly in the literature. Although PREVENT17 has made specific recommendations to avoid pump thrombosis of the HeartMate II, there remains no specific recommendations concerning the management of pump thrombosis, which varies significantly by institution.
In this study, we conducted a systematic review and meta-analysis addressing pump thrombosis in the modern CF-LVAD era to 1) evaluate the comparative effectiveness of surgical versus medical management of pump thrombosis, 2) analyze the temporal change in incidence of pump thrombosis, and 3) examine whether differences exist in the risk of pump thrombosis between CF-LVAD technologies.
Literature Search Strategy
Thorough electronic searches were performed using Ovid Medline, PubMed, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, ACP Journal Club, and Database of Abstracts of Review of Effectiveness from January 2007 to October 2016. To achieve the maximum sensitivity of the search strategy, we combined the terms: “left ventricular assist device,” “assist device,” “assisted circulation,” “thrombosis,” “thrombus,” and “coagulation” as either key words or MeSH terms. The reference lists of all retrieved articles were reviewed for further identification of potentially relevant studies and assessed using the inclusion and exclusion criteria.
Eligible studies for the present systematic review and meta-analysis included those that addressed pump thrombosis with patient cohorts who underwent durable CF-LVAD implantation. Patients with additional devices such as right ventricular assist devices or other temporary mechanical circulatory modalities were excluded from the analysis. When institutions published duplicate studies with accumulating numbers of patients or increased lengths of follow-up, only the most complete reports were included for quantitative assessment with no overlapping time intervals. We excluded studies on patients <18 years of age, studies not published in the English language, and those not involving human subjects. Articles were also excluded if they did not contain information about the thrombotic events and the type of intervention (surgical or medical) and if the thrombus resolved. Pump thrombosis resolution is defined as clinical resolution of pump thrombosis including normalization of power consumption and improvement in biochemical markers of hemolysis. Abstracts, case reports, case series with <10 patients, conference presentations, editorials, reviews, and expert opinions were excluded.
Data were extracted from article texts, tables, and figures (J.L., K.P.). Discrepancies between the two reviewers were resolved by discussion and consensus.
The majority of studies defined pump thrombosis based on the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) Adverse Event definitions (https://www.uab.edu/medicine/intermacs/appendices/app-a-5-0). As the current study spans a wide time interval, the INTERMACS definitions may have changed throughout the study period but were in accordance with the accepted INTERMACS definition at the time of occurrence.
Medical therapy was defined as tissue plasminogen activator, intravenous unfractionated heparin plus a glycoprotein IIb/IIIa inhibitor, or heparin alone not accompanied by device exchange or urgent transplantation for pump thrombus within 72 hours of initiation of treatment. Surgical treatment was defined as device exchange or urgent heart transplantation for pump thrombosis.
Primary treatment success was defined as the patient remaining alive with clinical resolution of pump thrombus, improvement in biochemical markers of hemolysis, and return to normal pump parameters. Furthermore, the patient should be free from 1) stroke, 2) recurrence of pump thrombosis, 3) device exchange, or 4) urgent transplantation (United Network of Organ Sharing Status 1A) within the first 30 days of initial treatment. These definitions of successful and unsuccessful medical therapy follow the classification protocol described by Najjar et al.5
Subgroup Analysis by Trials, Registries, and Individual Cohort Studies
Because of significant overlap of the data, reports based on trials, registries, and individual cohort studies were analyzed separately. Of note, patients in individual cohort studies are also present in registry data and enrolled in trials. In addition, although registries and trials offer a larger number of patients for analysis with greater accuracy than individual cohorts in terms of crude numbers such as pump thrombosis, they lack the granularity in data needed to decipher the outcomes of different management strategies. After ensuring that individual cohort studies were representative of the entire pooled population, as there was significant overlap in patients between trials, registries, and individual cohort reports, we proceeded with further in-depth analysis of the individual cohort reports.
A meta-analysis of proportions was conducted for the available main perioperative and postoperative variables. A weighted Pearson coefficient was used to calculate correlation coefficients for meta-regression analysis of temporal trend of thrombus rates. As we seek to examine the change in thrombus rates over time, it was important to establish an accurate time of occurrence for pump thrombosis. Use of the midpoint of a study period rather than publication year for regression is more reflective of the whole duration of the study period, given there can be a discrepancy between publication date and when the study was performed. The reasons behind this is because midpoint of a study period relies less on year of publication, which may become misleading when a study spans long time periods or if publication of the study is much later than the study period. Both meta-regression analysis using midpoint study period and publication year for temporal trend of pump thrombus are shown to allow interpretation of the results. A meta-analysis of incidence rates was conducted for event rates of pump thrombosis. Annualized incidence rates for pump thrombosis were determined using the metarate function for total events per person years. Heterogeneity was evaluated using Cochran Q and I2 test. A random-effects model was used. All analyses were performed using R software, version 3.3 and Comprehensive Meta-Analysis version 3.2 (R Foundation for Statistical Computing, Vienna, Austria). p Values <0.05 were considered statistically significant.
A total of 1,875 studies were identified that were published between January 2007 and October 2016. After exclusion of duplicate or irrelevant references, 43 articles were retrieved, PRISMA flow diagram shown in Figure 1. Manual search of references did not yield further studies. There was an overlap of reports with 2 trials (1,510 patients), 4 registry reports (20,939 patients), and 37 individual cohorts (6,279 patients). As such, separate analyses for the three categories (trials, registries, and individual cohort studies) were conducted.
The baseline demographics of the entire patient population are summarized in Table 1. A total of 28,728 patients were included in this study, with a median age of 55 (95% confidence interval [CI]: 54–56) and 78.5% being of the male sex. The median body surface area was 1.97 (95% CI: 1.93–2.00), and comorbidities included hypertension (52%), atrial fibrillation (40%), and diabetes (36%). Ischemic etiology accounted for 47% of heart failure resulting in CF-LVAD implantation. The primary indication for CF-LVAD implantation was bridge to transplantation in 53% of patients. The device used for circulatory support was a HeartMate II LVAD (Abbott Laboratories, Lake Bluff, IL) in 78% of patients, a HeartWare HVAD (HeartWare Inc, Framingham, MA) in 19% of patients, and unspecified in the remaining 3% of patients. The mean follow-up period of all studies combined was 12.6 ± 10.4 months.
Occurrence of Pump Thrombosis
Among individual cohorts, there were no significant differences in demographics between patients who developed pump thrombosis compared with those who did not, with respect to age (p = 0.080), sex (p = 0.489), body surface area (p = 0.463), hypertension (p = 0.961), diabetes mellitus (p = 0.948), and ischemic etiology for heart failure (p = 0.106). There was no significant difference in pump thrombosis events for mechanical circulatory support device, with respect to HeartMate II LVAD (p = 0.601) and HeartWare (p = 0.984; Table 2).
The percentage of patients who developed pump thrombosis in the pooled entire patient population was 10.6% (95% CI: 8.9–12.7), trials was 4.3% (95% CI: 1.2–14.5), registries was 8.8% (95% CI: 5.4–14.1), and individual cohort studies was 11.8% (95% CI: 9.8–14.1; Table 3). The median time to first pump thrombosis for the pooled entire patient population was 7.6 months (95% CI: 5.9–9.3), trials was 11.8 months (95% CI: 7.9–15.6), and individual cohort studies was 7.2 months (95% CI: 5.1–9.4); time to first pump thrombosis was not reported for registries. Of the patients who developed pump thrombosis, the percentage that went on to develop subsequent pump thrombosis for the pooled entire population was 17% (95% CI: 12.8–22.4), trials was 9.7% (95% CI: 3.2–26.1), registries was 12.6% (95% CI: 1.6–15.0), and individual cohort studies was 20.2% (95% CI: 15.2–26.3). The median time to second pump thrombosis after the first pump thrombosis event for the pooled entire patient population was 8.4 months (95% CI: 3.2–13.6), trials was 9.2 months (95% CI: 8.3–10.1), and individual cohort studies was 6.8 months (95% CI: 1.7–12.0); time to second pump thrombosis was not reported for registries.
Pooled annualized event rates for pump thrombosis were pooled using a random-effects meta-analysis. From 12 studies reporting this data, the pooled event rate was 0.136 events per patient year (Table 3).
The treatment groups for patients who developed pump thrombosis were urgent heart transplantation (n = 29), surgical device exchange (n = 634), or medical therapy (n = 266). The number of patients in each treatment arm was too small to allow for comparison between the different monotherapy and combinations of medical therapy (direct thrombin inhibitor, tissue plasminogen activator, or glycoprotein IIb/IIIa antagonist). Outcomes of surgical device exchange and medical management are shown in Table 4. Surgical device exchange for treatment of pump thrombosis resulted in higher success in thrombus resolution compared with medical management for overall pooled population (80.8%; 95% CI: 70.4–88.2 vs. 46.0%; 95% CI: 33.2–59.3; p = 0.001), trials (91.6%; 95% CI: 75.0–97.6 vs. 50.0%; 95% CI: 32.8–67.2; p = 0.002), and individual cohort studies (81.3%; 95% CI: 70.9–88.6 vs. 45.4%; 95% CI: 31.2–60.3; p < 0.001), where registries were not reported. Surgical device exchange for treatment of pump thrombosis had a lower 30 day mortality rate compared with medical management for overall pooled population (8.4%; 95% CI: 4.0–12.9 vs. 25.8%; 95% CI: 17.3–36.5; p = 0.030), trials (8.4%; 95% CI: 2.4–25.0 vs. 16.7%; 95% CI: 7.1–34.3; p = 0.340), and individual cohort studies (16.7%; 95% CI: 9.7–27.3 vs. 34.5%; 95% CI: 25.5–44.9; p = 0.013), where registries were not reported. Recurrence of pump thrombosis after successful therapy was significantly less with surgical device exchange compared with medical therapy for overall pooled population (11.7%; 95% CI: 7.3–18.3 vs. 30.8%; 95% CI: 18.6–46.4; p = 0.001) and individual cohort studies (11.8%; 95% CI: 7.3–18.6 vs. 38.3%; 95% CI: 26.6–51.5; p < 0.001), where trials and registries were not reported.
Complications among those patients treated with medical management include bleeding for the overall pooled population (18.4%; 95% CI: 10.8–29.4) and individual cohort studies (16.6%; 95% CI: 8.2–30.8), where trials and registries were not reported. The other primary complication for patients treated with medical management was hemorrhagic stroke, for the overall pooled population (21.9%; 95% CI: 14.9–30.9) and individual cohort studies (21.9%; 95% CI: 14.9–30.9), where trials and registries were not reported. Urgent device exchange was required significantly less after surgical device exchange compared with medical therapy for overall pooled population (9.4%; 95% CI: 5.4–15.9 vs. 23.4%; 95% CI: 15.5–33.7; p = 0.006) and individual cohort studies (9.4%; 95% CI: 5.4–15.9 vs. 21.2%; 95% CI: 13.4–31.8; p = 0.006) where trials and registries were not reported. Patients with pump thrombosis treated with surgical device exchange were more likely to be discharged home compared with those treated with medical therapy for overall pooled population (85.4%; 95% CI: 77.6–90.8 vs. 62.3%; 95% CI: 52.1–71.6; p = 0.001), trials (91.6%; 95% CI: 75.0–97.6 vs. 83.3%; 95% CI: 65.7–92.9; p = 0.340), and individual cohort studies (84.9%; 95% CI: 73.6–91.9) vs. 60.2%; 95% CI: 49.9–69.6; p = 0.001), where registries were not reported.
Temporal Change in Incidence of Pump Thrombosis
A meta-regression of all studies (Figure 2) was consistent with a temporal increase of the thrombosis rate with respect to midpoint study period (p = 0.040) and a possible temporal increase in thrombosis rate with respect to publication year (p = 0.050). A meta-regression stratified by trials, registries, and individual cohort studies was also performed (Figure 3). Although trials (Figure 3, A and B) and registry reports (Figure 3, C and D) do not provide enough granularity, individual cohort studies reflect the trend of temporal increase in thrombosis rate, both with respect to midpoint study period (Figure 3, E) and publication year (Figure 3, F), corresponding to the meta-regression of all studies (Figure 2, A and B).
In this systematic review and meta-analysis, the overall rate of pump thrombosis for the pooled patient population was 10.6%, which is closer to the registry and individual cohort studies than it was to the rate of pump thrombosis reported in clinical trials. The reasons behind this finding include 1) a lack of standard surgical and medical management, 2) extended follow-up period for registry and individual cohort studies, and 3) differing time period during which CF-LVAD implantation took place across the studies.
Despite significant heterogeneity in the results presented, our study reveals several important findings. There does not appear to be a significant difference in pump thrombosis events between the HeartMate II and HeartWare CF-LVAD technologies. Overall, surgical pump exchange was superior to medical therapy resulting in a higher success rate for resolution of pump thrombosis, lower mortality rate, and a significantly lower recurrence rate. A meta-regression of all studies suggests a temporal increase of pump thrombosis rate with respect to midpoint study period (p = 0.040) and a possible temporal increase in thrombosis rate with respect to publication year (p = 0.050). However, as the aggregation of all studies may introduce the bias of overlapping patient populations, a meta-regression stratified by trials, registries, and individual cohort studies was also performed. Despite being nonsignificant when stratified in this manner, the overall trend continues to suggest a temporal increase in thrombosis rate.
Continuous-flow left ventricular assist device support is an accepted therapy for end-stage heart failure with improved survival and quality of life and near-equivalent survival as heart transplantation.18 Pump thrombosis is an widely recognized adverse event of CF-LVAD support with various risk factors identified including later implant year, younger age, elevated baseline creatinine, higher body mass index, white race, and left ventricular ejection fraction >20%.19–21 Causes for pump thrombosis can be divided into patient issues (i.e., comorbidities and patient compliance with anticoagulation), mechanical issues (i.e., the pump and its components, surgical implantation techniques including inflow cannula angle/position, bend relief disconnect, or deformed outflow graft), and nonmechanical issues.20 These nonmechanical issues can be further subdivided into prepump factors (e.g., atrial fibrillation and right ventricular failure), postpump factors (e.g., reduced flow within the aortic root), and systemic factors (e.g., inflammation, infection, withholding of anticoagulation therapy in the setting of bleeding, and preexisting/de novo hypercoagulable states).20
Pump thrombosis has garnered increased attention in light of recent literature observing a steep increase in the incidence of CF-LVAD thrombosis beginning in 2011.4,13,22,23 To address this, we performed a meta-regression using both the midpoint of the study period and publication year. Use of the midpoint of the study period for regression is considered to be more accurate, whereas publication year becomes misleading when the study spans longer time periods or when the study is published much later than the study period. Meta-regression of all studies in the present systematic review with respect to both the midpoint study period and publication year are consistent with the temporal increase in thrombosis rate described. The precise reasons for this change in pump thrombosis rates remains obscure but may include heightened awareness, diagnosis, and reporting of pump thrombosis; possible subtle changes in pump manufacturing; and changes in practice.13 Although it is possible that duration on support may contribute to the increased thrombosis risk over time, the format of this study does not allow for assessment of that. As well, there may have been varying anticoagulation bridging strategies and suboptimal target international normalized ratio levels due to recognized concerns for bleeding complications associated with mechanical circulatory support device therapy.24,25 In addition, patient selection has changed since Food and Drug Administration approval for destination therapy in January 2010, allowing more implants in patients potentially at higher risk of thrombosis.26
There is currently is no consensus on the appropriate use of surgical or medical interventions for the treatment of pump thrombosis in CF-LVADs. The choice of initial treatment should be directed by patient-specific factors such as clinical stability, patient preference, suitability for pump exchange surgery or thrombolytic therapy, and potential for allosensitization in bridge to transplant patients.27 As per the INTERMACS report, the 1 year survival after primary CF-LVAD implantation is approximately 80%, 65% after a second implant, and 50% after a third implant.13 Furthermore, there was a greater incidence of neurologic-related and infection-related morbidity in survivors of pump exchanges.6 To avoid the associated morbidity and mortality associated with surgical pump exchange, different conservative approaches have been adopted for treating patients with pump thrombosis using heparin, direct thrombin inhibitors, platelet glycoprotein IIb/IIIa inhibitor or thrombolysis (local or systemic), or combinations of different approaches.12,28–30
There may be a role in the intensification of standard anticoagulation and antiplatelet therapy in hemolysis of unknown significance without pump or end-organ dysfunction to avoid the need for definitive treatment.6 However, medical therapy carries the inherent inability to assess whether the thrombus is fully resolved or simply reduced enough for symptoms to regress.27 In this study, compared with surgical therapy, medical therapy has a lower success rate (45.4% vs. 81.3%; p < 0.001) and higher mortality rate compared with initial surgical therapy alone (34.5% vs. 16.7%; p = 0.013). Successful medical therapy was also accompanied with high rates of morbidity from bleeding and hemorrhage stroke,31 wherein the risk of these complications is even greater because of continuous baseline anticoagulation medication.5,7 Furthermore, despite successful resolution of pump thrombosis in patients who received medical therapy alone, the recurrence rate is more than three times greater than in those with initial surgical therapy alone (38.3% vs. 11.8%; p < 0.001), in which 21.2% ultimately require urgent device exchange or heart transplantation. Given the various medical therapy regimens, it is possible that the optimal medical therapy was not applied nor has it been identified and standardized. Our findings are consistent with prior retrospective cohort reports.4,5,10,15,32–34 Should medical therapy be undertaken first and prove to be unsuccessful given the high rate of unresolved thrombus,5,7,35 urgent surgical therapy should be undertaken without delay with the preparation for the need for massive blood transfusions due to the hyperanticoagulated state.36 A noninvasive technique to washout occlusive thrombus in the inflow cannula by stopping and restarting the pump while having carotid artery filters to capture thrombus to minimize risk of cerebral thromboembolism has been introduced.37 Larger studies and longer follow-up are currently lacking with this method.
When the diagnosis of pump thrombosis is clear, consideration should be given for a definitive surgical option if the patient is deemed a surgical candidate.38 Device exchange is generally successful with a low recurrence rate after successful resolution of pump thrombosis; however, it is a costly procedure, highly invasive, exposes patients on antithrombotic therapy to the risk of major bleeding complications, infections, and can affect heart transplant graft survival outcome due to allosensitization.39,40 Early device exchange potentially removes the root cause of future pump dysfunction and embolic events, such as cerebrovascular accidents.15,34 In the minority of patients who experience pump thrombosis recurrence despite device exchange, reasons of recurrent pump thrombosis may be secondary to patient related risk factors such as undetected hypercoagulability disorders that remain unchanged after device exchange or to issues with the inflow conduit and outflow graft which are generally left in situ.41 With the evolution of alternate surgical approaches such as the off-pump anterolateral thoracotomy and minithoracotomy15,42,43 and subcostal44 and subxiphoid45–47 approaches, the mortality rate of patients who underwent device exchange was similar to those patients without thrombosis in the series reported by Starling et al.,4 with most of the excess mortality in the pump thrombosis group treated with medical therapy.4 The majority of patients who undergo CF-LVAD device exchange survive and return to an acceptable quality of life.48 As such, surgical therapy demonstrates favorable safety profiles and should be considered first line once pump thrombosis is established and in situations of hemolysis refractory to medical therapy.44
Contemporary axial-flow and centrifugal-flow CF-LVADs pump blood through narrow flow pathways, which may contribute to hemolysis, platelet activation, and damage to von Willebrand factor.24,49–51 The HeartMate II is an axial-flow pump, whereas the HeartWare device is a centrifugal pump.52 When compared with HeartMate II, the HeartWare LVAD is associated with lower stable phase lactate dehydrogenase levels but higher fibrin degradation products.20 Furthermore, the HeartWare LVAD can be placed intrapericardially rather than requiring creation of an anchoring pocket and may be less prone to cannula malapposition over time because of ventricular decompression.20 Whether these differences between CF-LVAD platforms lead to different risk of development of pump thrombosis remains unknown. In the current study, there was no significant difference in pump thrombosis events for mechanical circulatory support device, with respect to HeartMate II and HeartWare CF-LVADs. The HeartMate 3 (Abbott) is a new, miniaturized centrifugal-flow device designed to enhance hemocompatibility by minimizing shear force effects on blood components by integrating a fully magnetically levitated rotor for frictionless movement, wide blood flow gaps, and a texturized blood–biomaterial interface.53 Additionally, the device pumps asynchronous to the patient’s cardiac cycle to help avoid blood stasis and thrombotic complications.54 A multi-institutional prospective trial evaluating the HeartMate 3 initiated in 2014 demonstrates promising 1 year outcomes in 27 patients with no cases of hemolysis, pump thrombosis, or pump failure.55
This meta-analysis has several key limitations and must be interpreted with care. Regional differences exist in patient selection, center experience, pump implantation techniques, anticoagulation maintenance, and clinical management of pump thrombosis (e.g., use of different surgical techniques and anticoagulation protocols) contributing to heterogeneity. Data on patient severity of illness, severity of thrombosis, duration of symptoms, presence of end-organ dysfunction, or other conditions that may have influenced their suitability for specific therapeutic strategies were not available. Although patients in the medical therapy arm were grouped together, the actual medical regimens, doses, route of administration, and durations of use were heterogeneous, thus the efficacy of specific antithrombotic regimen in comparison to surgical therapy remains uncertain. Because of the lack of granularity reported in the studies, it was not possible to analyze differences between various medical regimens. The definitions used for the diagnosis and the resolution of pump thrombosis varied between different studies with heterogeneity of patients from both a clinical trial and a postapproval setting. Given the inherent limitations in detecting subclinical thrombus formation with diverse presentations and etiology, it is also possible that there may be an underestimation of pump thrombosis events.56 We acknowledge that this heterogeneity in study population is a fundamental limitation that cannot be addressed because of the inability to extract sufficient detail from the pooled data.
Despite these limitations, this study systematically assessed the efficacy and safety of surgical and medical management of pump thrombosis, confirms the temporal increase in pump thrombosis, and forms a basis for future studies. Larger, prospective studies are needed to 1) better characterize the patients with pump thrombus who would benefit from a trial of medical therapy first versus those who should undergo primary pump exchange; 2) elicit whether device-specific differences in pump thrombosis rate and severity exists, especially with the emergence of newer technology such as the HeartMate 3; and 3) identify the optimal regimen, dosage, route of administration, and duration of medications that provide the optimal balance between efficacy and safety. Given that it has been suggested that use of activated partial thromboplastin time assay to monitor the intensity of heparin therapy may not be accurate in the CF-LVAD population,57 further studies are needed to identify the ideal method to monitor anticoagulation therapy and thrombus resolution.
The results of our systematic review of 43 studies consisting of 28,728 CF-LVAD patients suggest that surgical device exchange is superior to medical therapy resulting in a higher success rate for resolution of pump thrombosis and a lower mortality and recurrence rate. Randomized controlled prospective studies and large multicenter collaborations are needed to compare these clinical approaches and their resultant outcomes to guide decision-making for the management of CF-LVAD thrombosis.
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Keywords:Copyright © 2019 by the American Society for Artificial Internal Organs
ventricular assist device; pump thrombosis; pump exchange; thrombolysis; systematic review