Of the nine cohort studies, four had data for only one treatment (thrombolytic or nonthrombolytic) available. Therefore, we performed a sensitivity analysis of the five studies with comparative results. Hypergeometric-Normal model showed that thrombolytic regimens were 3.57 times more likely to have major bleed than nonthrombolytic regimes (95% CI, 1.07–11.88; p < 0.05) although NN model (OR, 2.71; 95% CI, 0.83–8.86; p < 0.1) and BN model (OR, 2.40; 95% CI, 0.96–6.03; p < 0.1) were only marginally significant.
Data from the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial indicate that LVAD implantation increase survival and quality of life compared with optimal medical management alone.65 The survival of patients with continuous-flow LVADs continues to improve, but these patients still remain at a high risk for fatal complications such as pump thrombosis. The incidence of pump thrombosis reported in the initial and extended clinical trials of continuous-flow devices ranged from 0.014 to 0.03 events per patient-year, but increased incidence of pump thrombosis has been noted.2,66–68 In the setting of suspected thrombosis, surgical device exchange or urgent heart transplantation represent the most definitive treatment modalities. However, cardiothoracic surgery is not without risks. An additional surgery for pump exchange can result in formation of scar tissue and adhesions, which can increase the duration and risk of bleeding during subsequent surgery for heart transplantation.69 Therefore, it is important to explore medical management strategies to treat pump thrombosis for transplant candidates or patients who cannot withstand surgery. Several studies have compared surgical with medical management for pump thrombosis.4,12,70 However, no previous reported studies have compared medical treatment of pump thrombosis.
Our systematic review and meta-analysis show that data regarding the efficacy and safety of medical management of LVAD thrombosis are limited to case reports, case series, or small single institute cohort studies. Jennings and Weeks69 recently summarized the case reports and series of medical and surgical treatment of LVAD thrombosis and highlighted that management strategies varied widely between institutions. However, comparison between the different treatment regimens was not reported. Complete thrombus resolution occurred in 65% of patients receiving a thrombolytic regimen and in 43% of patients who received a nonthrombolytic regimen. The ineffective nature of heparin monotherapy to resolve LVAD thrombosis likely affected the estimate of the nonthrombolytic regimens. The cohort studies showed that no or partial resolution of LVAD thrombosis did not significantly differ between thrombolytic and nonthrombolytic regimens (OR, 0.48; 95% CI, 0.20–1.16). Case reports and series showed that the pooled risk of major bleeding in the thrombolytic regimens was 29% and 12% in the nonthrombolytic regimens. A 3.57 times increased odds of major bleeding was found for thrombolytic regimens in the sensitivity analysis using HN model. However, the NN model and BN model were only marginally significant, indicating the instability of the model. There were no differences in risk of death in the two groups. Because of the uncontrolled nature of the comparison, it is possible that severity of illness, severity of the thrombosis, or duration of symptoms were worse in patients who received thrombolytics, which could have influenced patients’ mortality outside bleeding and resolution of the pump thrombosis. Randomized or controlled prospective studies would be needed to control for these confounding factors. The limited number of patients at each site and institutional preferences may make completion of a randomized trial difficult. On the basis of the available evidence, providers should understand that the use of thrombolytic therapy, either intraventricular or systemic, is likely associated with an increased risk of major hemorrhage.
Combining outcomes of patients with LVAD thrombosis allows a summary of the published knowledge base for treatment of these patients and is hypothesis-generating for future studies. This approach has limitations, however. The strength of the conclusions depends on the quality of the available literature, which is limited by the inherent biases associated with case reports and series. No randomized controlled trials have been conducted to date. Publication bias is likely in case reports and case series as researchers and journals are more likely to publish effective therapies. Almost all the reports did not have a comparison group and numbers of reported patients were low. The definitions used for the diagnosis and the resolution of pump thrombosis varied between different studies. Ramp studies were not often performed. Moreover, the dosages, route of administration, and the durations of use of the antithrombotic regimens also varied widely between institutions. Patient characteristics among the studies differed, and the studies ranged over 10 years which could have also biased the results. It is also possible that the outcomes and adverse events may have been misclassified between treatment regimens based on the reviewers’ interpretation of the data. However, the data were meticulously reviewed by two different reviewers and compared to minimize this possibility. Moreover, in most studies, medical management was used in patients that were hemodynamically stable at the time of presentation. Thus, it is difficult to extrapolate the results of this analysis to high-risk group of patients. Further studies are needed to determine the role of medical management in such patient population in comparison with surgical management. Despite these limitations, this study systematically assessed the efficacy and safety of the various medical regimens for the management of pump thrombosis, provides data to clarify the role of nonsurgical management of pump thrombosis, and a basis for future prospective or randomized studies.
In conclusion, our systematic review of 49 studies consisting of 238 continuous-flow LVAD patients discusses existing therapeutic options and provides estimate of resolution of pump thrombosis and major hemorrhage associated with thrombolytic and nonthrombolytic regimens. Additional prospective studies evaluating the dosing and route of administration of thrombolysis and controlled comparison to anticoagulant or antiplatelet therapies are needed to define optimal management strategies for this vexing condition.
The authors appreciate the assistance of the reference librarians at the Medical College of Wisconsin with the database search.
Geetanjali Dang was responsible for design, data abstraction, data analysis, manuscript writing, critical appraisal, and final approval; Narendranath Epperla was responsible for design, data abstraction, critical appraisal, and final approval; Vijayadershan Mupiddi was responsible for data abstraction, critical appraisal, and final approval. Natasha Sahr, Amy Pan, and Pippa Simpson were responsible for data analysis, critical appraisal, and final approval. Lisa Baumann Kreuziger was responsible for design, manuscript writing, critical appraisal, and final approval.
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pump thrombosis; ventricular assist device; thrombolysis; direct thrombin inhibition; platelet GP IIb/IIIa receptor inhibition