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Medical Management of Pump-Related Thrombosis in Patients with Continuous-Flow Left Ventricular Assist Devices: A Systematic Review and Meta-Analysis

Dang, Geetanjali*; Epperla, Narendranath; Muppidi, Vijayadershan*; Sahr, Natasha; Pan, Amy§; Simpson, Pippa; Baumann Kreuziger, Lisa‖#

doi: 10.1097/MAT.0000000000000497
Review Article

Pump thrombosis is a dreaded complication of left ventricular assist devices (LVADs). We completed a systematic review to evaluate the efficacy and complications associated with medical management of LVAD thrombosis. Databases were searched using the terms “vad*” or “ventricular assist device” or “heart assist device” and “thrombus” or “thrombosis” or “thromboembolism.” Of 2,383 manuscripts, 49 articles met the inclusion criteria. The risk of partial or no resolution of LVAD thrombosis did not significantly differ between thrombolytic and nonthrombolytic regimens (odds ratio [OR], 0.48; 95% confidence interval [CI], 0.20–1.16). When response to therapy was evaluated based on pump type, there were no significant differences in how patients with a HeartMate II or HeartWare ventricular assist device responded to thrombolytic or nonthrombolytic treatment. Pooled risk of major bleeding in the thrombolytic group was 29% (95% CI, 0.17–0.44) and 12% (95% CI, 0.01–0.57) in the nonthrombolytic group. Odds of death did not differ between thrombolytic and nonthrombolytic regimens (OR, 1.28; 95% CI, 0.42–3.89). Although thrombolytic and nonthrombolytic treatment similarly resolved LVAD thrombosis, major hemorrhage may be increased with the use of thrombolysis. Randomized clinical trials comparing thrombolytic and nonthrombolytic treatment of LVAD thrombosis are needed to establish the most effective and safe option for patients who are not surgical candidates.

From the *Division of Hospital Medicine, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; Division of Biostatistics, Institute of Health and Society, Medical College of Wisconsin, Milwaukee, Wisconsin; §Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Pediatrics and Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin; Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; and #Blood Research Institute, Blood Center of Wisconsin.

Submitted for consideration May 2016; accepted for publication in revised form November 2016.

Disclosure: The authors have no conflicts of interest to report.

Funding was provided by the Blood Center Research Foundation.

Correspondence: Geetanjali Dang, MD, Division of Hospital Medicine, Department of Medicine, Medical College of Wisconsin, 9200 W. Wisconsin Ave., CLCC 5th Fl., Milwaukee, WI 53226. Email: gdang@mcw.edu.

Approximately 5.1 million persons in the United States have heart failure, and the prevalence continues to rise.1 With the increasing number of advanced heart failure patients and a lack of heart transplant donors, mechanical circulatory support devices are increasingly used. Indications for mechanical circulatory support include bridge to transplantation, bridge to recovery, and destination therapy. Left ventricular assist devices (LVADs), one form of mechanical circulatory support, have dramatically improved patients’ overall survival and quality of life.2 With an improvement in overall survival of patients supported with LVADs and an increasing duration of support on LVADs, LVAD-related complications must be minimized. Pump thrombosis is a dreaded complication of both short-term and long-term use of LVADs. Left ventricular assist device thrombosis occurs in 2–13% of adult patients with a continuous-flow LVAD (axial-flow 4–13%, centrifugal-flow 8%)3,4 and 18% of pediatric patients with a paracorporeal device.5 Pump thrombosis denotes the development of clot within the flow path of any component of the pump, including the titanium inflow cannula, the rotor, and the outflow graft. Thrombus can originate in the pump or travel from the left atrium or left ventricle and lodge in the pump components.6 Pump thrombosis can lead to thromboembolic stroke, peripheral thromboembolism, LVAD malfunction with reduced systemic flows, LVAD failure with life-threatening hemodynamic impairment, cardiogenic shock, and death.7

Successful management of LVAD thrombosis has included surgical and pharmacological therapies. Invasive management such as device exchange8,9 and catheter-directed thrombectomy10 have been described. There are no studies in literature comparing the efficacy or adverse outcomes related to pharmacological treatment of LVAD thrombosis. Guidelines have outlined diagnosis and management strategies for LVAD thrombosis,6 but are based on expert or consensus opinion. We completed a systematic review of the literature to evaluate the efficacy and complications associated with medical management strategies for adults with LVAD thrombosis.

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Materials and Methods

The current analysis conforms to standard guidelines and was written according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.11 PubMed, SCOPUS, Ovid Medline, Cochrane, and the Web of Science were searched through July 15, 2016. Studies were identified using the following medical subject headings and keywords including “vad*” or “ventricular assist device” or “heart assist device” and “thrombus” or “thrombosis” or “thromboembolism.” Studies were included if they reported patients >18 years of age with confirmed or suspected LVAD thrombosis of continuous-flow devices. Confirmed pump thrombosis was defined as a thrombus on the blood-contacting surfaces of the LVAD, its inflow cannula, or its outflow conduit at pump replacement, urgent transplantation, or autopsy. Suspected pump thrombosis was defined as a clinical diagnosis of pump-related malfunction and hemolysis as reported by the individual publications.12 Exclusion criteria included studies describing pulsatile LVADs, thrombosis resulting due to heparin-induced thrombocytopenia, studies not published in the English language, and abstracts without published full text articles. Articles were also excluded if they did not contain information about the thrombotic events, the type of medical intervention, and if the thrombus resolved. Two reviewers (G.D. and N.E.) independently evaluated the titles and abstracts to determine eligibility for inclusion. If either reviewer believed the article was eligible, the full manuscript was reviewed. Eligibility was agreed upon through discussion between the reviewers. A third reviewer (L.B.K.) was used if disagreements about eligibility occurred. If additional information pertaining to the published articles was needed, the authors of the respective article were contacted. The Newcastle-Ottawa scale was used to assess study quality and risk of bias because of the nonrandomized studies included in the systematic review.13 Despite the lack of a control group in most studies, the cohort tool was used as recommended by the Cochrane Collaboration.

Data were independently abstracted by both reviewers. Study type, patient demographics, device name, and type and duration of anticoagulation were abstracted. Outcomes including resolution of thrombus, major or minor bleeding, need for escalation of care, and mortality were recorded. Complete thrombus resolution was defined as clinical improvement, along with improvement in VAD parameters, as well as laboratory parameters for hemolysis. Interagency Registry for Mechanical Assisted Circulatory Support (INTERMACS) adverse event definitions were used for major and minor bleeding. Data tables were exchanged, and discrepancies were discussed.

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Statistical Analysis

Percentages and odds ratios (ORs) with 95% confidence limits were used to describe the data. For the nine cohort studies, the study was assumed to be random to estimate the overall log of odds ratio for thrombolytic versus nonthrombolytic treatments. A half was added to all four numbers in the two-by-two table if there were a zero so that this could be calculated. Different assumptions can be made about the variation. Because of the sparse data, in addition to a Normal-Normal (NN) model, we also explored Hypergeometric-Normal (HN) model and Binomial-Normal (BN) model.14 We performed an NN model on the nine cohort studies. Hypergeometric-Normal and BN models could not be fit. A sensitivity analysis was also performed by excluding four cohort studies: Oezpeker et al. (2016),15 Scandroglio et al. (2016),16 Tellor et al. (2014),17 and Rothenburger et al. (2002)18 because these studies only had one group of treatment. A BN model was performed on the cases reports and case series. The pooled risk was compared with 0.5. The OR or pooled risk and 95% confidence interval (CI) were estimated and forest plot was shown. Funnel plots were employed to check publication bias. Study weights were calculated as 1 over the sum of variance and estimated amount of total heterogeneity. p ≤ 0.05 was considered significant. Statistical analysis and graphs were performed using SAS 9.4 (SAS Institute, Cary, NC) and R metafor package.19

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Results

Database searches identified 2,383 manuscripts, of which 2,274 were excluded after title and abstract screening (Figure 1). The full text of 109 manuscripts was reviewed. The most common reasons for article exclusion were no medical intervention (28/60, 47%), device not currently in use (9/60, 15%), lack of information on thrombosis (8/60, 13%), lack of information on medical intervention or patient outcomes (7/60, 12%), and unknown device type (5/60, 8%). Fourteen recurrent events were excluded from the analysis. The 49 included studies (40 case reports and case series and nine retrospective cohort studies) reported 238 patients with thrombotic events (Tables 1 and 2). Retrospective cohort studies composed of 18% (9/49) of the included studies (Table 2).4,15–18,60–63 None of the these studies were controlled trials and thus were deemed of moderate quality. The most reported devices included HeartWare ventricular assist device (HVAD; 120/216, 56%), HeartMate II (HMII; 76/216, 35%), and MicroMed DeBakey (14/216, 6%). A majority of the LVADs in adults were used long-term, but a range of implantation time between 1 day and 1,713 days was reported. Median time since implantation for thrombolytic and nonthrombolytic regimens was 186 and 146 days, respectively. Median follow-up period of all studies combined was 180 days (range 1–1107 days).

Tables 1 and 3 outline the antithrombotic management of adult patients admitted with LVAD-related pump thrombosis. Sacher et al.20 reported a single patient who had complete resolution of symptoms without bleeding when the international normalized ratio goal was increased from 2.0–2.5 to 2.5–3.5 and aspirin was increased to 325 mg daily. Of the other reports, unfractionated heparin (UFH) was the most commonly used agent. It was used either alone or in combination with thrombolytic and GPIIb/IIIa inhibitor or direct thrombin inhibitor agents in most adults, with goal-activated partial thromboplastin times (aPTTs) between 60 and 90s. Thirty-one patients were treated with intravenous (IV) UFH alone with complete thrombus resolution in only 23% (7/31) of patients. Escalation of care to pump exchange or heart transplant occurred in 48% (15/31) of these patients. No minor bleeding events occurred, while major bleeding events were reported in 10% (3/31) of patients.4,60–63,21–27 Intravenous UFH was used in combination with a GPIIb/IIIa inhibitor and a direct thrombin inhibitor in the management of 51 events resulting in complete resolution in 49% (25/51) of the cases and no or partial resolution in 51% (26/51) cases. Major bleeding events were noted in 35% (18/51) cases.4,17,26,30–37,60–63 GPIIb/IIIa inhibitor or direct thrombin inhibitor therapy alone (goal PTT of 50–75 sec) was used in 39 patients with pump thrombosis resulting in complete thrombus resolution in 49% (19/39) of patients. Major bleeding events were noted in 10% (4/39) of patients, and there was one reported death (Table 4).17,18,28–30,48,63

Thrombolytic therapies were used either alone (IV or intraventricular) or as a dual therapy (along with UFH or GPIIb/IIIa inhibitor or direct thrombin inhibitor) in 98 patients resulting in a complete resolution in 66% (65/98) of patients. Major bleeding was reported in 19% (19/98) patients. Likewise, minor bleeding occurred in 19% (19/98) patients. There were 20 reported deaths in this group of patients.4,15,25,26,38–46,48,50–64 Thrombolytics were used as a triple or a quadruple drug therapy (i.e., in combination with IV UFH and either GPIIb/IIIa inhibitor or direct thrombin inhibitor) in 18 patients resulting in a complete resolution in 56% (10/18) of patients. There were six major bleeding events and one minor bleeding event.4,46–49,61,63 Overall, 16% (37/238) of reported patients died among all the medical regimens.

Because individual patient information was presented in the case report and case series, outcomes were aggregated to assess thrombus resolution, risk of bleeding, and death. Overall, treatment with a thrombolytic regimen failed to completely resolve the thrombus in 31% of patients (pooled risk for partial or no thrombus resolution was 0.22 [95% CI, 0.06–0.55]; Figure 2A), whereas nonthrombolytic regimens reported 40% of patients with partial or no response to therapy (pooled risk 0.43 [95% CI, 0.23–0.65]; Figure 2B). Funnel plot analysis did not show significant publication bias. Pooled risk of major bleeding in the thrombolytic group was 29% (95% CI, 0.17–0.44), p < 0.01 (Figure 3A) and nonthrombolytic group was 12% (95% CI, 0.01–0.57), p < 0.1 (Figure 3B). The pooled risk of death was 20% for thrombolytic regimens (95% CI, 0.06–0.47, p < 0.05) and 6% (95% CI, 0.003–0.58, p < 0.1) for nonthrombolytic regimens.

When response to therapy was evaluated based on pump type, there were no significant differences in how patients with an HMII or HVAD responded to thrombolytic or nonthrombolytic treatment in resolution (nonthrombolytic regimen [no or partial resolution] OR 0.94 [95% CI, 0.30–2.97]; thrombolytic regimen OR 1.18 [95% CI, 0.35–3.99]). Risk of major hemorrhage, minor hemorrhage, intracranial hemorrhage, or death did not significantly differ likely because of the limited number of events within the groups. The number of patients in each treatment arm was too small to allow for comparison between the different treatments (i.e., heparin monotherapy versus direct thrombin inhibitors) within the thrombolytic and nonthrombolytic regimen groups.

Because the cohort studies reported patients treated with thrombolytic and nonthrombolytic regimens, the treatment regimens could be compared. There was no statistically significant difference between thrombolytic and nonthrombolytic regimen for resolving the pump thrombotic events (OR, 0.48; 95% CI, 0.20–1.16; Figure 4). No statistically significant difference in major bleeding was found between patients treated with thrombolytic and nonthrombolytic regimens (OR, 1.95; 95% CI, 0.69–5.53; Figure 5). Mortality was similar in thrombolytic and nonthrombolytic regimens (14% [12/87] vs. 16% [12/74]; OR, 1.28 [95% CI, 0.42–3.89]).

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.

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Discussion

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.

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Acknowledgment

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

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