Accepted Article

Received Date : 31-Oct-2014 Accepted Date : 29-Mar-2015 Article type

: Review Article

Antithrombotic Therapy for Left Ventricular Assist Devices in Adults: a Systematic Review Running Head: LVAD antithrombotic therapy

Lisa Baumann Kreuziger, MD, MS. BloodCenter of Wisconsin, Department of Medicine/Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, USA; [email protected]

Benjamin Kim, MD, MPhil, University of California San Francisco, San Francisco, CA; [email protected]

Georg M. Wieselthaler, MD., University of California San Francisco, San Francisco, CA; [email protected]

Corresponding Author: Lisa M. Baumann Kreuziger, MD, MS BloodCenter of Wisconsin 8733 Watertown Plank Road Milwaukee, WI 53226 [email protected] Phone: +1-414-937-6826, Fax: +1-414-937-6580

Abstract Background: Left ventricular assist devices (LVADs) have dramatically increased the survival of adults with endstage systolic heart failure. However, rates of bleeding and thromboembolism remain high. Objectives: We completed a systematic review to evaluate outcomes of adults with LVADs treated with various anticoagulant and antiplatelet strategies. Methods: Databases were searched using the terms “assist device,” “thrombosis,” and “anticoagulant” or “platelet aggregation inhibitor” with appropriate synonyms, device names and manufacturers. Results and Conclusions: Of 977 manuscripts, 24 articles met the inclusion criteria of adults with implanted LVADs where clinical outcomes were defined based on anticoagulant and/or antiplatelet regimen. Most studies

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reported treatment with unfractionated heparin post-operatively which was transitioned to a vitamin K antagonist (VKA). Goal INR varied between 1.5-3.5. Antiplatelet regimens ranged from no treatment to dual therapy. Definition of major bleeding differed between trials and incidence varied between 0% and 58%. The available evidence could not demonstrate a clear benefit of aspirin compared with VKA therapy alone [stroke RR 1.02 (95% CI 0.49-2.1)]. There was a suggestion that treatment with aspirin and dipyridamole decreased the risk of thromboembolism compared to aspirin [RR 0.50 (0.36-0.68)], but the comparison is limited by differences in demographics, devices, and INR goals among studies. Additionally, most studies did not blind to outcomes thus contributing to an increased risk for bias. Clinical equipoise exists as to the most appropriate antithrombotic therapy in LVAD patients. Randomization between regimens within a prospective trial is needed to define the treatment regimen that minimizes both bleeding and thrombotic complications.

Keywords: anticoagulants, hemorrhage, platelet aggregation inhibitors, thrombosis, ventricular assist device

Introduction: Heart failure affects approximately 23 million people globally and is a major burden to the health-care system. [1] In the United States (US) alone, the cost of caring for 5.8 million heart failure patients in 2010 was $39.2 billion.[1] Advanced systolic heart failure carries a dismal average life expectancy of 6 months.[2] For eligible patients, cardiac transplantation can be life-saving; however, due to lack of organ supply, the number of cardiac transplants has reached a plateau of approximately 4200 per year worldwide.[3] The death rate while waiting for a heart transplant in the US is 170/1,000 patient years.[4] Left ventricular assist devices (LVADs) have been developed and can be implanted to bridge patients to heart transplantation or to improve the symptoms of patients ineligible for transplant. Over 1500 LVADs are placed in the US annually, and the number is steadily rising.[5]

LVADs can be categorized based on their mechanism of blood propulsion. In all LVADs, blood flows from the apex of the left ventricle to the LVAD via an inflow cannula and through an outflow graft to the ascending aorta, bypassing the failing natural left ventricle. Currently, all devices have a percutaneous driveline that connects to an external power source and controller. First generation displacement pumps mimic the pulsatility of the natural heart by using a pneumatically or electro-mechanically driven membrane.[6] Due to the oscillating membrane, pulsatile

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devices are not durable long term, and thus, are rarely used in adults anymore.[6] In contrast, second generation continuous flow devices were developed to decrease pump size and improve durability, but generate nonphysiological non-pulsatile flows. Two different types of continuous flow devices are in use today. The HeartMate II® (Thoratec, Pleasanton, CA) is an axial continuous flow device that propels blood via Archimedes’

screw principle of displacing blood from one end of the screw to the other. Due to the small diameter of the rotor of these pumps, very high impeller speeds between 7,000-12,000 rotations per minute (rpm) are required to generate physiologic cardiac flow and create high levels of shear stress (peak stress 2000-4000 dynes/cm2).[7] These high levels of shear can damage blood cells, resulting in a baseline level of hemolysis in patients with the HeartMate II® device.[8] The Jarvik 2000® (Jarvik Heart, Manhattan, NY, USA) is an axial pump that creates partial support of the

left ventricle with up to 7 L of flow per minute.[9] To avoid the wear of mechanical bearings used in axial devices, pumps with magnetic rotor bearings were developed. The HeartWare HVAD® (Heartware Inc., Framingham, MA) and the Terumo DuraHeart® (Terumo Heart, Ann Arbor, MI) contain magnetically levitated rotors that propel blood

by spinning. The VentrAssistTM (Ventracor, Chatswood, Australia) is another centrifugal device utilizing a combined magnetic and hydrodynamic suspension.[10] Centrifugal continuous flow devices have a larger rotor diameter and therefore need a lower rotational speed of 1,800 – 3,000 rpm to generate the same amount of flow. Consequently, baseline hemolysis is less significant with centrifugal devices compared to axial devices.[8] In the US, the HeartMate II® device is approved as a bridge-to-transplant and for destination therapy in patients ineligible

for cardiac transplant, whereas the HVAD® is only approved for bridge-to-transplant at this time. The Jarvik 2000®

is approved for use in Europe and clinical trials are underway in the US for Food and Drug Administration (FDA) approval. The VentriAssistTM is also approved for use in Europe but further regulatory approval was halted due to bankruptcy of the manufacturer. The DuraHeart® is approved for use in Europe and Japan.

LVADs have dramatically improved patients’ overall survival and quality of life. A randomized study comparing a pulsatile versus axial continuous flow device in transplant-ineligible patients showed an improvement in 2-year overall survival from 24% to 58% with the continuous flow device.[11] Distance during the 6-minute walk test doubled and heart failure quality of life scores significantly increased with LVAD placement.[11] Current estimates from the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) note further increases in 2-year survival to 61% since US FDAapproval of LVADs for destination therapy.[12]

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Although modern LVADs have quadrupled patients’ average life expectancy, they are associated with both thrombotic and bleeding complications. Stroke, infection, bleeding and heart failure remain the leading causes of death in LVAD patients.[13] There is also significant morbidity associated with LVAD placement. LVAD thrombosis can lead to embolic stroke or pump malfunction. Pump thrombosis is treated by replacement of the LVAD or intensification of antithrombotic therapy, which consequently, increases the risk of hemorrhage.[14] Bleeding is most frequent in the first 3 months after implantation, but long-term, serious gastrointestinal (GI) and intracranial hemorrhage (ICH) can occur.[15] Due to high, nonphysiological shear stress generated by LVADs, all patients have a loss of high molecular weight multimers of von Willebrand protein. Whether the acquired Von Willebrand syndrome is associated with the increased risk of GI bleeding has been the subject of much debate in the literature.[16, 17] Therefore, the intensity of anticoagulant and antiplatelet therapy must balance the bleeding and

thrombotic risk in LVAD patients. Guidelines from the International Society of Heart and Lung Transplantation include recommendations for anticoagulation and antiplatelet therapy for LVAD patients, but these are primarily based on expert opinion.[18] To better understand the thrombotic and bleeding complications associated with various anticoagulant and antiplatelet regimens in adult LVAD patients, we completed a systematic review of the literature.

Methods: Databases including PubMed, OVID, SCOPUS, CINAHL, Cochrane, and Web of Science were searched from database inception through August 4, 2014. Terms including “assist device” and “thrombosis” and “anticoagulant” or “platelet aggregation inhibitor” with exploded headings, associated keywords, medication names, and device manufactures and names were used (Supplemental figure 1). No language, age, study type, publication date, or gender limits were applied. Personal files and references from citation searching of relevant review articles were also evaluated.

Manuscripts were eligible for inclusion if they reported an inception cohort of ≥5 patients with an implanted cardiac device and described thrombotic or bleeding outcomes specific to an anticoagulant and/or antiplatelet regimen.

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Because different devices and anticoagulation strategies are used in pediatrics, only manuscripts reporting devices currently implanted in adults were included. Studies from conference proceedings were eligible for inclusion if sufficient information was included in the abstract. When multiple publications describing the same clinical trial or cohort study were available, only the most recent publication was included.

Two reviewers (LBK and BK) 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 (GW) was used if disagreements about eligibility occurred. The Newcastle-Ottawa scale was used to assess study quality and risk of bias due to the nonrandomized studies included in the systematic review.[19] Despite the lack of control group in most studies, the cohort tool was used as recommended by the Cochrane Collaboration.[20]

Data was independently abstracted by both reviewers. Study type, patient demographics, device name, and type and duration of anticoagulation were abstracted. Outcomes including thromboembolism, stroke, LVAD thrombosis, bleeding and mortality were recorded. Data tables were exchanged and discrepancies were discussed. Descriptive statistics and chi-square tests were used to analyze the data. Relative risk (RR) was calculated with 95% confidence intervals.

Results: Database searches and personal files identified 977 manuscripts of which 873 were excluded after title and abstract screening (Figure 1). The full text of 104 manuscripts was reviewed. The most common reasons for article exclusion were devices not currently in use (31/80, 39 %), lack of original data (15/80, 19%) and undefined anticoagulation regimen (13/80, 16%). Retrospective cohort studies comprised 58% (14/24) of the included studies (Table 1).[21-34] Nine prospective cohort studies [15, 35-42] and a retrospective analysis of a randomized trial [43] were also included. Almost all of the studies did not include a comparison group and thus were deemed of moderate quality.

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The 24 included studies reported outcomes of 2784 LVADs where anticoagulation and antiplatelet therapy was defined (Table 2). The most reported devices included HeartMate II® (1881/2784, 68%) and HVAD® (737/2784, 26%). Average age ranged from 42-62 years. A majority of the LVADs in adults were used long-term, but a range of implantation time between 1 day and 2823 days (i.e. 7.7 years) was reported.

Table 3 outlines the perioperative antithrombotic management of adult patients. Unfractionated heparin was used for post-operative anticoagulation in most adults, with goal activated partial thromboplastin times (aPTTs) generally between 45 and 70 seconds. Bivalirudin was used in one study with a lower aPTT goal of 45-50 seconds.[31] Karimi et al. did not use any anticoagulation in the immediate post-operative period and used aspirin doses between 81-650 mg based on TEG® results (TEG®, Haemoscope Corporation, Niles, IL).[25] Aspirin doses varied between none to

325 mg in the rest of the studies. In axial LVADs, the lowest post-operative bleeding rates were reported in one study that administered 80 mg of aspirin and another report where antiplatelet therapy was adjusted based on platelet function testing results (6% and 9%, respectively).[25, 38] However, another report of patients treated without aspirin had the highest incidence of bleeding (69%).[28] With centrifugal devices, post-operative bleeding occurred in 12% of patients (51/418) treated with aspirin and 43% of patients (22/51) treated with clopidogrel three times weekly.

All adults were transitioned to anticoagulation with vitamin K antagonists (VKAs). Goal INR levels varied but were between 1.5-3.0 in most studies.(Table 4) Four studies decreased their INR goals during the study due to high bleeding rates[15, 27, 32, 37]; whereas, another study increased the INR goal due to thromboembolic events.[34] Definitions of major bleeding varied between transfusion of red blood cells, bleeding in a critical site, or need for surgical intervention. (Table 4) The lack of standardized definition of bleeding between studies limits the ability to compare regimens. Nonetheless, in patients with axial devices, major bleeding was reported in 6%-58% of patients treated with aspirin and 16-40% of patients prescribed aspirin and dipyridamole. Major bleeding was reported in 844% of patients with centrifugal devices. Manuscripts combining outcomes for both types of devices reported major bleeding in 0-49% of patients. Overall, 30% (697/2294) of patients experienced major bleeding.

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Thromboembolic events were significantly lower in patients with axial devices who were treated with aspirin and dipyridamole compared to aspirin alone [10% (103/1076) vs. 19% (46/238), RR 0.50 (95% CI 0.36-0.68)]. Stroke occurred in 6% (60/1076) of patients in studies reporting aspirin and dipyridamole use and 10% (22/230) of patients in the studies reporting aspirin use alone [RR 0.58 (95% CI 0.37-0.93)]. The three studies of patients with axial devices treated without aspirin reported similar rates of thromboembolism (13/96, 14%) and stroke (9/96, 9%) as those reporting aspirin use [thromboembolism RR 1.43 (95% CI 0.81-2.5); stroke RR 1.02 (95% CI 0.49-2.1)].[2628] In total, stroke was reported in 6% of patients (154/2493). LVAD thrombosis occurred in 4% (41/1051) of patients treated with aspirin and dipyridamole, 11% (26/230) with aspirin, and 5% (5/96) without an antiplatelet agent. Manuscripts of centrifugal devices reported a stroke rate of 8% (58/727) and LVAD thrombosis rate of 6% (46/727). In studies that combined outcomes for both types of devices, stroke and pump thrombosis were reported in 4% (5/130) and 3% (4/130), respectively. Among all patients, LVAD thrombosis was noted in 5% (122/2236).

Death was reported in 20% of patients (232/1143: 110/460 axial devices, 106/553 centrifugal devices, and 16/130 in studies of both device types). Five of the 18 studies reporting mortality also noted the severity of heart failure at LVAD implantation.[15, 26, 27, 39, 42] Patients with cardiogenic shock or decompensated heart failure with progressive decline (INTERMACS level 1 or 2) comprised 46% (404/808) of patients with a 19% overall mortality.[15, 26, 27, 39, 42] Cause of death was reported in 11 studies.[15, 26, 27, 31, 35, 37-39, 41, 42] Multiorgan failure was the most frequent cause of death in 31% of patients (56/178). Infection accounted for 15% of deaths (27/178) followed by stroke (13%, 24/178) and right heart failure (11%, 20/178). Bleeding was fatal in 10% of patients (18/178). Mechanical failure of the device was infrequent and caused death in only 5 patients (3%). The incidence of fatal bleeding and thromboembolic complications were similar which further emphasizes the delicate balance between bleeding and clotting in LVAD patients.

Discussion:

The development of second generation continuous flow LVAD devices has dramatically improved the survival and long-term outcome of end-stage heart failure patients, but patients implanted with LVADs still remain at high risk for bleeding, thrombosis, and death. At the time of LVAD insertion, patients are taking maximum medical therapy

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for systolic heart failure, which often includes intravenous inotropic drug support. Many patients are in an urgent state of cardiac failure as classified with the INTERMACSseverity and outcome classification.[44] Due to longstanding heart failure with severe congestion, a large portion of these patients have impaired renal and liver function. Therefore, at LVAD implantation, many patients have a compromised coagulation system due to multi-organ failure on top of which anticoagulation and antiplatelet treatment are required for their advanced heart failure. Postoperative bleeding occurs in up to 69% of patients and often requires reoperation. Beyond the peri-and postoperative periods, 30% of patients on long-term LVAD support suffered bleeding complications. Bleeding often forces physicians to discontinue or deescalate antithrombotic therapy. Reported risk factors for bleeding complications included increase in post-operative total bilirubin, age >65 years [(Hazard Ratio (HR) 1.31], female sex (HR 1.45) and lower pre-operative hematocrit (HR 1.31).[15, 43] Patients with a pre-LVAD history of GI bleeding were more likely to have GI bleeding events after implantation.[29] There is a fine line between bleeding and thrombosis in LVAD patients though, as ischemic stroke was reported in 6% of LVAD patients and accounted for 13% of reported deaths. Bleeding was fatal in 10% of patients when cause of death was noted. Unfortunately not all studies reported cause of death, bleeding, or thromboembolism rates; thus, direct comparisons cannot be made. The INTERMACS registry reported an adverse event rate of 0.09 per patient-year for bleeding requiring surgery and hemorrhagic stroke rate of 0.05 per patient-year in patients implanted after FDA approval of the HeartMate II® device.[12] Ischemic stroke and pump thrombosis both occurred at a rate of 0.03 per patient-year, but case fatality rates were not reported.[12]

The anticoagulant and antiplatelet management strategies varied widely between institutions and different studies. Goal INR was based on institutional experience and changed based on bleeding and thrombosis rates in 5 reports. [15, 27, 32, 34, 37] Based on the available evidence, the role of the antiplatelet therapy during LVAD support is still unclear. Some studies did not use antiplatelet medications whereas others used dual antiplatelet therapy with aspirin and dipyridamole or clopidogrel. Studies involving patients with axial devices treated with aspirin and dipyridamole had lower rates of thromboembolism and stroke compared to studies of patients treated with aspirin alone. This finding is hypothesis-generating only as INR goals, devices, and patient characteristics were not equal between these studies. Additionally, studies that did not include outcomes specified to device type were not included in the comparison, and all studies did not report the same outcomes. A majority of patients in the compared studies,

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however, had HeartMate II® devices implanted. Ultimately, a randomized clinical trial would be needed to adequately compare antithrombotic strategies in LVAD patients.

Whether laboratory testing can assist with optimization of antiplatelet therapy is debated. In children with implanted pulsatile LVADs, TEG® with platelet mapping is routinely used to adjust treatment with aspirin and dipyridamole.[45] One report of HeartMate II® patients used TEG® to adjust antiplatelet treatment to achieve a normal maximum amplitude, a measure of clot strength; thromboembolic and bleeding events were within ranges reported in the literature.[25] The lack of standardized reporting of event rates and definitions seen in this review limits the ability to compare across studies. Another report found aspirin hyporesponsiveness (i.e. preserved platelet aggregation in response to testing with arachidonic acid) in 43% of samples by whole blood aggregometry and 7% of samples tested with TEG® platelet mapping. Intraperson variability using TEG® was very high (567%).[36]

International efforts to standardize thromboelastography via both commercially available methods have unfortunately shown greater-than-acceptable variation for clinical assays.[46] Further study is required before modification of antiplatelet regimens using laboratory assays can be recommended in adults.

Mechanical issues of different LVADs have a major impact on thrombus formation inside the devices. Suspected pump thrombosis occurred in 6/13 of the first HVAD® patients in Europe, which was attributed to alterations in the

bearing system of the impeller.[41] The inflow cannula of the HVAD® device was originally designed with smooth titanium, but an eccentric growth of tissue around the cannula was found in explanted hearts at transplant. Sintered titanium microspheres were added to the outside of the inflow cannula to facilitate uniform and limited ingrowth of tissue to the sintered surface. However, a recent analysis suggested similar pump thrombosis rates between sintered and non-sintered HVAD® devices, although the duration of follow-up is shorter for patients with sintered

pumps.[47] Four institutions have reported an increase in incidence of thrombosis in the HeartMate II® devices, up

to 12% after 2 years of support.[48] An increase in thrombosis rates was confirmed using the INTERMACS cohort, but suggested a less significant increase. Freedom from LVAD exchange or death due to LVAD thrombosis at 6 months decreased from 99% before 2011 to 94% in 2012.[49] A change in device manufacturing has been investigated but not be found to account for the described changes in HeartMate II® thrombosis rates.[50]

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The delicatebalance between bleeding and thrombosis in LVAD patients is likely influenced by control of VKA therapy. LVAD patients spend less time in the therapeutic range compared to other patients on VKAs. [21, 24] A time in therapeutic range of 31-51% has been reported in LVAD patients compared to 64-81% of atrial fibrillation patients in clinical trials.[21, 24] Of note, it has been shown that a lower percentage of time spent in the therapeutic INR range is associated with increased risks of bleeding and thromboembolic events among patients with atrial fibrillation. [24, 51-53] Bunte et al. did not find a correlation between hemorrhage and the INR prior to a bleeding event in LVAD patients-- mean INR was not different between patients who did and did not bleed—but time-intherapeutic range was not calculated. [15] On the other hand, subtherapeutic INR levels were reported in 31% of patients prior to a hemolytic event or thrombosis.[34] Overall, management of anticoagulation in LVAD patients is challenging, and lack of effective INR control may be associated with bleeding and thrombotic events.

The goal of anticoagulation and antiplatelet therapy is to prevent thromboembolic complications. If a patient experiences LVAD thrombosis despite adequately controlled anticoagulation, there is limited data as to the most effective medical therapy, with only some guidance from consensus panels.[14] The transplant listing can be escalated due to LVAD thrombosis to attempt urgent heart transplant in eligible patients. Obstruction of the inflow cannula due to malposition or kinking of the outflow graft requires surgical correction. A 50% mortality rate has been reported with medical management of patients with a lactate dehydrogenase level >1000 Units/L; thus an LVAD exchange should be considered in these patients.[54] Jennings and Weeks recently summarized the case reports and series of medical therapy for LVAD thrombosis. [55] Treatment with eptifibitide, a glycoprotein IIb/IIIa inhibitor, for HeartMateII® thrombosis was associated with 26% efficacy (7/27) but 48% (13/27) of patients experienced bleeding complications. Resolution of hemolysis associated with LVAD thrombosis was reported in 4 of 5 HeartMate II® patients treated with direct thrombin inhibitors. Use of fibrinolytic therapy has been reported in 4

patients with HeartMate II® thrombosis and 31 patients with HVAD® thrombosis. Fibrinolytic therapy resolved the

LVAD thrombus in 73% of HVAD® patients (11/15 intravenous administration, 8/11 intraventricular administration).[55] Publication bias is likely in case reports and series, though, and larger controlled studies are needed to delineate the most effective therapy for LVAD thrombosis.

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Clinical trials of medical devices differ dramatically from pharmaceutical trials. Almost all reports of adults with LVADs were single-arm studies without a comparison group and numbers of enrolled patients in these trials were low. Nevertheless, randomization between LVAD device implantation and medical therapy is not ethical due to the dramatic improvement in survival associated with LVAD use. However, standardized definitions for bleeding and thrombosis and incidence rates could be utilized to allow for improved comparison across cohort studies. Additionally, adjudication of clinical outcomes by an independent, blinded committee would decrease the possibility for bias. The optimal antithrombotic regimen in LVAD patients remains undetermined. Randomization between well-defined antithrombotic strategies, such as comparing treatment with VKA, aspirin, and dipyridamole to VKAand aspirin therapy, would enable assessment of various regimens to best balance the risks of bleeding and thrombosis in LVAD patients.

Addendum L. Baumann Kreuziger was responsible for design, data abstraction, data analysis, manuscript writing, and final approval; B Kim was responsible for design, data abstraction, data analysis, critical appraisal, and final approval; G. Wieselthaler was responsible for design, critical appraisal, and final approval.

Acknowledgements We appreciate the assistance of the reference librarians at the Medical College of Wisconsin for assistance with the database search and James Anderson with statistical assistance. L Baumann Kreuziger’s time to perform the work was funded by the BloodCenter Research Foundation. Conflict of Interests G. Wieselthaler was a clinical consultant and implant proctor for HeartWare Inc, outside the submitted work. B. Kim reports personal fees from Bayer, outside the submitted work.

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15 Bunte MC, Blackstone EH, Thuita L, Fowler J, Joseph L, Ozaki A, Starling RC, Smedira NG, Mountis MM. Major Bleeding During HeartMate II Support. Journal of the American College of Cardiology. 2013; 62: 2188-96. 10.1016/j.jacc.2013.05.089. 16 Crow S, Chen D, Milano C, Thomas W, Joyce L, Piacentino V, 3rd, Sharma R, Wu J, Arepally G, Bowles D, Rogers J, Villamizar-Ortiz N. Acquired von Willebrand syndrome in continuous-flow ventricular assist device recipients. The Annals of thoracic surgery. 2010; 90: 1263-9; discussion 9. 10.1016/j.athoracsur.2010.04.099. 17 Meyer AL, Malehsa D, Bara C, Budde U, Slaughter MS, Haverich A, Strueber M. Acquired von Willebrand syndrome in patients with an axial flow left ventricular assist device. Circulation Heart failure. 2010; 3: 675-81. 10.1161/CIRCHEARTFAILURE.109.877597. 18 Feldman D, Pamboukian SV, Teuteberg JJ, Birks E, Lietz K, Moore SA, Morgan JA, Arabia F, Bauman ME, Buchholz HW, Deng M, Dickstein ML, El-Banayosy A, Elliot T, Goldstein DJ, Grady KL, Jones K, Hryniewicz K, John R, Kaan A, et al. The 2013 International Society for Heart and Lung Transplantation Guidelines for mechanical circulatory support: executive summary. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2013; 32: 157-87. 10.1016/j.healun.2012.09.013. 19 Wells GA, Shea B, O'Connell D, Peterson J, Welch V, Losos M, Tugwell P. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 20 Cochrane Handbook for Systematic Reviews of Interventions. The Cochrane Collaboration, 2008. 21 Bishop MA, Streiff MB, Ensor CR, Tedford RJ, Russell SD, Ross PA. Pharmacist-Managed International Normalized Ratio Patient Self-Testing Is Associated with Increased Time in Therapeutic Range in Patients with Left Ventricular Assist Devices at an Academic Medical Center. ASAIO Journal. 2014; 60: 193-8. 10.1097/mat.0000000000000047. 22 Demirozu ZT, Radovancevic R, Hochman LF, Gregoric ID, Letsou GV, Kar B, Bogaev RC, Frazier OH. Arteriovenous malformation and gastrointestinal bleeding in patients with the HeartMate II left ventricular assist device. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2011; 30: 849-53. 10.1016/j.healun.2011.03.008. 23 Hayes HM, Dembo LG, Larbalestier R, O'Driscoll G. Management options to treat gastrointestinal bleeding in patients supported on rotary left ventricular assist devices: a single-center experience. Artif Organs. 2010; 34: 703-6. 10.1111/j.1525-1594.2010.01084.x. 24 Jennings D, McDonnell J, Schillig J. Assessment of long-term anticoagulation in patients with a continuous-flow left-ventricular assist device: a pilot study. The Journal of thoracic and cardiovascular surgery. 2011; 142: e1-2. 10.1016/j.jtcvs.2011.03.029. 25 Karimi A, Beaver TM, Hess PJ, Martin TD, Staples ED, Schofield RS, Hill JA, Aranda JM, Klodell CT. Close antiplatelet therapy monitoring and adjustment based upon thrombelastography may reduce lateonset bleeding in HeartMate II ecipients. Interact Cardiovasc Thorac Surg. 2014; 18: 457-65. 10.1093/icvts/ivt546. 26 Litzler PY, Smail H, Barbay V, Nafeh-Bizet C, Bouchart F, Baste JM, Abriou C, Bessou JP. Is antiplatelet therapy needed in continuous flow left ventricular assist device patients? A single-centre experience. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery. 2014; 45: 55-9; discussion 9-60. 10.1093/ejcts/ezt228. 27 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. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery. 2012; 42: 319-23; discussion 23. 10.1093/ejcts/ezr312. 28 Meyer AL, Malehsa D, Budde U, Bara C, Haverich A, Strueber M. Acquired von Willebrand syndrome in patients with a centrifugal or axial continuous flow left ventricular assist device. JACC Heart failure. 2014; 2: 141-5. 10.1016/j.jchf.2013.10.008.

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Accepted Article

29 Morgan JA, Paone G, Nemeh HW, Henry SE, Patel R, Vavra J, Williams CT, Lanfear DE, Tita C, Brewer RJ. Gastrointestinal bleeding with the HeartMate II left ventricular assist device. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2012; 31: 715-8. 10.1016/j.healun.2012.02.015. 30 Muthiah K, Robson D, Macdonald PS, Keogh AM, Kotlyar E, Granger E, Dhital K, Spratt P, Hayward CS. Increased incidence of angiodysplasia of the gastrointestinal tract and bleeding in patients with continuous flow left ventricular assist devices (LVADs). The International journal of artificial organs. 2013; 36: 449-54. 10.5301/ijao.5000224. 31 Pieri M, Agracheva N, Di Prima AL, Nisi T, De Bonis M, Isella F, Zangrillo A, Pappalardo F. Primary anticoagulation with bivalirudin for patients with implantable ventricular assist devices. Artif Organs. 2014; 38: 342-6. 10.1111/aor.12168. 32 Stern DR, Kazam J, Edwards P, Maybaum S, Bello RA, D'Alessandro DA, Goldstein DJ. Increased Incidence of Gastrointestinal Bleeding Following Implantation of the HeartMate II LVAD. Journal of Cardiac Surgery. 2010; 25: 352-6. 10.1111/j.1540-8191.2010.01025.x. 33 von Potapov E, Stepanenko A, Kaufmann F, Henning E, Vierecke J, Lehmkuhl E, Hetzer R, Krabatsch T. Thrombosis and Cable Damage in the HeartWare Pump: Clinical Decisions and Surgical Technique. ASAIO Journal. 2013; 59: 37-40. 10.1097/MAT.0b013e31827c0d79. 34 Whitson BA, Eckman P, Kamdar F, Lacey A, Shumway SJ, Liao KK, John R. Hemolysis, pump thrombus, and neurologic events in continuous-flow left ventricular assist device recipients. The Annals of thoracic surgery. 2014; 97: 2097-103. 10.1016/j.athoracsur.2014.02.041. 35 Frazier OH, Gemmato C, Myers TJ, Gregoric ID, Radovancevic B, Loyalka P, Kar B. Initial clinical experience with the HeartMate II axial-flow left ventricular assist device. Tex Heart Inst J. 2007; 34: 27581. 36 Majeed F, Kop WJ, Poston RS, Kallam S, Mehra MR. Prospective, observational study of antiplatelet and coagulation biomarkers as predictors of thromboembolic events after implantation of ventricular assist devices. Nature clinical practice Cardiovascular medicine. 2009; 6: 147-57. 10.1038/ncpcardio1441. 37 Morshuis M, El-Banayosy A, Arusoglu L, Koerfer R, Hetzer R, Wieselthaler G, Pavie A, Nojiri C. European experience of DuraHeart magnetically levitated centrifugal left ventricular assist system. European journal of cardio-thoracic surgery : official journal of the European Association for Cardiothoracic Surgery. 2009; 35: 1020-7; discussion 7-8. 10.1016/j.ejcts.2008.12.033. 38 Siegenthaler MP, Westaby S, Frazier OH, Martin J, Banning A, Robson D, Pepper J, Poole-Wilson P, Beyersdorf F. Advanced heart failure: feasibility study of long-term continuous axial flow pump support. European heart journal. 2005; 26: 1031-8. 10.1093/eurheartj/ehi163. 39 Slaughter MS, Pagani FD, McGee EC, Birks EJ, Cotts WG, Gregoric I, Howard Frazier O, Icenogle T, Najjar SS, Boyce SW, Acker MA, John R, Hathaway DR, Najarian KB, Aaronson KD. HeartWare ventricular assist system for bridge to transplant: combined results of the bridge to transplant and continued access protocol trial. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2013; 32: 675-83. 10.1016/j.healun.2013.04.004. 40 Moazami N, Steffen RJ, Naka Y, Jorde U, Bailey S, Murali S, Camacho MT, Zucker M, Marascalco PJ, Rao V, Feldman D. Lessons learned from the first fully magnetically levitated centrifugal LVAD trial in the United States: the DuraHeart trial. The Annals of thoracic surgery. 2014; 98: 541-7. 10.1016/j.athoracsur.2014.04.048. 41 Wieselthaler GM, G OD, Jansz P, Khaghani A, Strueber M. Initial clinical experience with a novel left ventricular assist device with a magnetically levitated rotor in a multi-institutional trial. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2010; 29: 1218-25. 10.1016/j.healun.2010.05.016.

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Accepted Article

42 Sandner SE, Riebandt J, Haberl T, Mahr S, Rajek A, Schima H, Wieselthaler GM, Laufer G, Zimpfer D. Low-molecular-weight heparin for anti-coagulation after left ventricular assist device implantation. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2014; 33: 88-93. 10.1016/j.healun.2013.10.009. 43 Boyle AJ, Jorde UP, Sun B, Park SJ, Milano CA, Frazier OH, Sundareswaran KS, Farrar DJ, Russell SD, HeartMate IICI. Pre-Operative Risk Factors of Bleeding and Stroke During Left Ventricular Assist Device Support. Journal of the American College of Cardiology. 2014; 63: 880-8. 10.1016/j.jacc.2013.08.1656. 44 Stewart GC, Stevenson LW. Keeping left ventricular assist device acceleration on track. Circulation. 2011; 123: 1559-68; discussion 68. 10.1161/CIRCULATIONAHA.110.982512. 45 Almond CS, Buchholz H, Massicotte P, Ichord R, Rosenthal DN, Uzark K, Jaquiss RD, Kroslowitz R, Kepler MB, Lobbestael A, Bellinger D, Blume ED, Fraser CD, Jr., Bartlett RH, Thiagarajan R, Jenkins K. Berlin Heart EXCOR Pediatric ventricular assist device Investigational Device Exemption study: study design and rationale. American heart journal. 2011; 162: 425-35 e6. 10.1016/j.ahj.2011.05.026. 46 Chitlur M, Sorensen B, Rivard GE, Young G, Ingerslev J, Othman M, Nugent D, Kenet G, Escobar M, Lusher J. Standardization of thromboelastography: a report from the TEG-ROTEM working group. Haemophilia : the official journal of the World Federation of Hemophilia. 2011; 17: 532-7. 10.1111/j.1365-2516.2010.02451.x. 47 Najjar SS, Slaughter MS, Pagani FD, Starling RC, McGee EC, Eckman P, Tatooles AJ, Moazami N, Kormos RL, Hathaway DR, Najarian KB, Bhat G, Aaronson KD, Boyce SW. An analysis of pump thrombus events in patients in the HeartWare ADVANCE bridge to transplant and continued access protocol trial. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2014; 33: 23-34. 10.1016/j.healun.2013.12.001. 48 Starling RC, Moazami N, Silvestry SC, Ewald G, Rogers JG, Milano CA, Rame JE, Acker MA, Blackstone EH, Ehrlinger J, Thuita L, Mountis MM, Soltesz EG, Lytle BW, Smedira NG. Unexpected abrupt increase in left ventricular assist device thrombosis. The New England journal of medicine. 2014; 370: 33-40. 10.1056/NEJMoa1313385. 49 Kirklin JK, Naftel DC, Kormos RL, Pagani FD, Myers SL, Stevenson LW, Acker MA, Goldstein DL, Silvestry SC, Milano CA, Timothy Baldwin J, Pinney S, Eduardo Rame J, Miller MA. Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) analysis of pump thrombosis in the HeartMate II left ventricular assist device. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2014; 33: 12-22. 10.1016/j.healun.2013.11.001. 50 Frazier OH. Increase in left ventricular assist device thrombosis. The New England journal of medicine. 2014; 370: 1464-5. 10.1056/NEJMc1401768#SA3. 51 Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L. Dabigatran versus warfarin in patients with atrial fibrillation. The New England journal of medicine. 2009; 361: 1139-51. 10.1056/NEJMoa0905561. 52 Harper P, Pollock D. Improved anticoagulant control in patients using home international normalized ratio testing and decision support provided through the Internet. Internal medicine journal. 2011; 41: 332-7. 10.1111/j.1445-5994.2010.02282.x. 53 Wallentin L, Yusuf S, Ezekowitz MD, Alings M, Flather M, Franzosi MG, Pais P, Dans A, Eikelboom J, Oldgren J, Pogue J, Reilly PA, Yang S, Connolly SJ. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet. 2010; 376: 975-83. 10.1016/S0140-6736(10)61194-4. 54 Ballew CC, Benton EM, Groves DS, Kennedy JLW, Ailawaid G, Kern JA, Bergin JD. Comparing Survival of HMII Patients with Elevated LDH: Implications for Medical and Surgical Management. The

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Accepted Article

Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 2013; 32: S38. 55 Jennings DL, Weeks PA. Thrombosis in Continuous-Flow Left Ventricular Assist Devices: Pathophysiology, Prevention, and Pharmacologic Management. Pharmacotherapy. 2014. 10.1002/phar.1501.

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Accepted Article

Table 1: Characteristics and Quality Assessment of Included Studies

Reference

Bishop [21] Boyle [43] Bunte [15] Demirozu [22] Frazier [35] Hayes [23] Jennings [24] Karimi [25] Litzler [26] Majeed [36] Menon [27] Meyer [28] Moazami [40]

Study Type

Retrospective cohort Retrospective analysis of randomized trial Prospective cohort Retrospective cohort Prospective cohort Retrospective cohort Retrospective cohort Retrospective cohort Retrospective cohort Prospective cohort Retrospective cohort Retrospective cohort Prospective cohort

Funding ASHP Research & Education Foundation

Comparison Group Usual Care Group None, 1◦ study randomized None None None None None None None None None None None

Thoratec NR NR NR NR NR NR NR NR NR NR Terumo Heart, Inc Henry Ford Morgan [29] Retrospective cohort Hospital. None Morshuis [37] Prospective cohort Terumo Heart, Inc None Muthiah [30] Retrospective cohort NR None Pieri [31] Retrospective cohort NR None Sandner [42] Prospective cohort NR None Artificial Heart and National Heart Research Fund None Siegenthaler [38] Prospective cohort Slaughter [39] Prospective cohort Heartware INTERMACS Stern [32] Retrospective cohort NR None von Potapov [33] Retrospective cohort NR None Whitson[34] Retrospective cohort NR None Wieselthaler[41] Prospective cohort NR None INTERMACS=Interagency Registry for Mechanically Assisted Circulatory Support

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Quality Assessment (out of 9)

Blinded Outcome Assessment No

6 Yes 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6

6 9 6 6 6 6

No No No No No No No No No No Yes No Yes No No No No

No No No No No

Accepted Article

Table 2: Patient and Device Characteristics

Bishop [21] Boyle [43] Bunte [15] Demirozu [22] Frazier [35]

Patients n 55 956 139 172 43

Hayes [23] Jennings [24] Karimi [25] Litzler [26] Majeed [36] Menon [27]

36 16 57 27 8 40

Meyer [28] Moazami [40] Morgan [29] Morshuis [37]

102 63 86 33

Reference

Device Type n HMII 51;HVAD 4 HMII HMII HMII HMII VenrAssist 11, Jarvik 2000 13, HVAD 12 HMII HMII HMII Jarvik 2000 6; HMII 2 HMII

Mean Age y 53.2 58.2 54 58 42

Mean implantation time Median (range) 1.5 y 489 d NR 258 d (1-761)

Follow-up Median (range) Mean 562 ± 376 d -

53 57.3 55.7 52.3 58

188 d (7-1516) Mean 479 ± 436 d 316 d (9-833) 245 d (1-1052) HMII: 852 (24-2823) HVAD 664 (73-1422) 267 d (10-952) 176 d (5-456) 197 d (19-1148) Mean, bleed 554 ± 507 d No bleed 364 ± 295 d 5d (5-12) 293 d (1-44 mo)* Mean 167 +/-143 d

245 d (1-1052)

HMII 51; HVAD 51 50.2 DuraHeart 54.8 267 d (10-952) HMII 52.7 176 d (5-456) DuraHeart 55.5 197 d (19-1148) HVAD 33; Muthiah [30] 66 VentrAssist 33 50.3 Pieri [31] 11 HMII 5; HVAD 6 62 1.5 y Sandner [42] 64 HMII 27; HVAD 51 56 at least 106 d Siegenthaler [38] 17 Jarvik 2000 60 Slaughter [39] 332 HVAD 52.8 at least 180 d Stern [32] 20 HMII 54.8 at least 383 d von Potapov [33] 225 HVAD 55.4 152 py Whitson[34] 193 HMII 55.6 at least 2424 d Wieselthaler[41] 23 HVAD 47.9 D=days, mo=months, y=years, py= patient-years, *hospital survivors; DuraHeart, Terumo Heart, Inc., Ann Arbor, Michigan, USA; HM II= HeartMate II, Thoratec Corp., Pleasanton, CA; HVAD, HeartWare, Inc., Miramar, FL, USA); VenrAssist, Ventracor, Chatswood, Australia; Jarvik 2000, Jarvik Heart, Manhattan, NY, USA.

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Accepted Article

Table 3: Perioperative Management and Outcomes of Adult LVAD Patients

Reference

Postoperat ive Anticoagul ation

Perioperative Target

Daily Aspirin Dose

Clopidogrel Dose

Dipyridam ole dose

325 mg 200408, 81-325 mg after 2008

None

None

Postopera tive Bleeding

Axial Device

Bunte [15]

UFH 200408; None from 2008

NR aPTT 45-50 s 50-60 5565 after 24 hours

Frazier [35]

UFH

Karimi [25]

None

Litzler [26]

UFH

N/A aPTT 1.5-2 x control

Menon [27]

UFH

Meyer [28] Siegenthaler [38]

6/43 (14%)

81-100 mg 81 mg to 650 mg^

None

aPTT 50 s

NR, n=4 50-100 mg, n=16 (40%)

None 75 mg, n=2 (5%)

None

UFH

NR

None

None

None

UFH

aPTT 50-70 s

80 mg

None

None

Stern [32] Centrifugal Device

UFH

NR

None

None

None

Meyer [28] Moazami [40]

UFH

NR

None

75 mg three times/week

None

NR

NR

None

None

UFH

aPTT 40-50s 50-60 s

81 mg 80 mg 3/20117/2012; 162325 mg

None

None

UFH

aPTT 50-60 s

80-160 mg

None

None

40/332 (12%) 3/23 (13%)

Bivalirudin

aPTT 45-50 s

NR

None

None

2/11 (18%)

Slaughter [39] Wieselthaler [41] Both Devices Pieri [31]

None

75 mg TID max 1 g/day^

70/139 (50%)*

None

5/57 (9%) 18/27 (67%) 10/40 (25%)* 35/51 (69%) 1/17 (6%) 4/20 (20%)

22/51 (43%) 8/63 (13%)

UFH=unfractionated heparin, NR=not reported, aPTT=activated partial thromboplastin time, s=seconds, mg=milligrams, TID=three times daily, g=gram ^Adjusted using TEG® (Haemoscope Corporation, Niles, IL) for a goal MA 60-70 mmHg; *Outcomes at 30 days post-operative

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Accepted Article

Table 4: Long-term Management and Outcomes in Adult LVAD Patients

Reference

Antiplat elet

VKA INR Goal

Minor Bleed

Major Bleed

Major Bleed Definition

TE events

Stroke

TIA

Pump Thromb osis

Death

2-2.5

8/51 (16%)

8/23 (35%) 20/51 (39%)

GI, epistasis GI, ICH

2/23 (9%) 10/51 (20%)

2/23(9% ) 6/51 (12%)

4/51 (8%)

0/23 (9%) 4/51 (8%)

7/23 (9%) 20/51 (39%)

81/139 (58%) 2/4 (50%)

INTERMA CS GI, epistasis

-

-

-

-

0/4 (0%)

GI + transfusion

-

-

-

-

19/86 (22%) 1/17 (6%)

0/4 (0%) 1/8 (13%) 4/17 (24%)

2/17 (12%)

2/17(1 2%)

0/17 (0%)

3/86 (3%) 8/17 (47%)

-

-

40/193 (20%)

19/193 (10%)^

-

26/193 (13%)+

-

2/40 (5%)† 96/956 (10%)

2/40 (5%)† 58/956 (6%)

2/43 (4%) 5/57 (9%)

Axial Device None

Litzler [26] None

Meyer [28] ASA

Bunte [15]

ASA ASA ASA

ASA(n =16) C (n=2)

Menon [27]

Demirozu [22] Frazier [35] Karimi [25]

Stern [32] Jennings [24] Centrifugal Device Moazami [40] Morshuis [37] Morshuis [37] Slaughter [39]

2-2.5

-

NR 1.52.5 2.53.5 1.52.5 22.5

-

ASA

Whitson[34 ]

Boyle [43]

-

ASA

Litzler [26] Majeed [36] Morgan [29] Siegenthaler [38]

2-3 2-3  1.72.5

ASA + D ASA + D ASA + D ASA + D^ ASA + D

-

2.5 2.02.5

-

2-3

-

1.52.5

-

2-3 1.52.5 2-3 1.52.0

NR 2-3

2/57 (4%)

32/172 (19%) 1/43 (16%) 10/57 (18%)

0/16 (0%)

8/20 (40%) 0/16 (0%)

ASA ASA ASA ASA

2-3 2.53.5 2.02.5 2.03.0

3/40 (8%) 361/956 (38%)

1/11 (9%) 3/22 (14%) -

28/63 (44%) 1/11 (9%) 3/22 (14%) 68/332 (20%)

ICH

GI, surgery, ≥2 units PRBC ≥2 units PRBC GI, ≥2 units PRBC

0/4 (0%)

-

1/40 (3%)† 38/956 (4%)

-

1/43 (2%) 1/57 (2%)

1/43 (2%) 2/57 (4%)

0/18 (0%) 3/57 (5%)

9/43 (21%) 8/57 (14%)

0/20 (0%) 0/16 (0%)

0/20 (0%) 1/16 (6%)

0/20 (0%)

-

TIMI

0/20 (0%) 1/16 (6%)

-

-

NR

8/63 (13%)

Surgery

-

Surgery INTERMA CS

44/332 (13%)

8/63 (13%) 5/11 (45%) 0/22 (0%) 25/332 (8%)

6/63 (10%) 2/11 (18%) 3/22 (14%) 16/332 (5%)

0/63 (0%) 0/11 (0%) 0/22 (0%) 14/332 (4%)

9/63 (14%) 6/11 (55%) 1/22 (5%) 55/332 (17%)

GI INTERMA CS

GI

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0/40 (0%)

44/139 (32%) 1/4 (25%)

10/40 (25%)

Accepted Article

ASA Wieselthale r[41] Meyer [28] von Potapov [33] Muthiah [30] Both Devices Pieri [31] Sandner [42]

2.53.0 2-3 2.53.0 2.03.0

0/23 (0%) 4/51 (8%)

4/23 (17%) 10/51 (20%)

-

5/66 (8%)

2-3

-

0/11 (0%)

2-2.5 Varie d 1.23.5

-

-

C ASA+D * NR

ASA ASA ASA, C (n=1)

Surgery, GI, ≥2 units PRBC GI, ICH

8/23 (35%) 20/51 (39%)

-

-

2/23 (9%) 6/51 (12%) 12/225 (5%)

GI

-

-

-

-

-

Transfusio n

-

0/11 (0%) 3/64 (5%)

0/11(0 %) 0/64 (0%)

0/11(0% ) 0/64 (0%)

1/11 (9%) 1/64 (2%)

-

6/23 (26%) 14/51 (27%) 12/225 (5%)

-

INTERMA 11/55 2/55 4/55 CS (20%) (4%) (7%) ASA+ GI + ≥2 C 1.85/36 units Hayes [23] 2.5 (8%) PRBC VKA=Vitamin K antagonist, INR=international normalized ratio, TE=thromboembolic events, TIA=transient ischemic attack; ASA=aspirin, C=clopidogrel, D=dipyridamole,GI=gastrointestinal bleeding, ICH=Intracranial hemorrhage, PRBC=packed red blood cells, NR=Not Reported; INTERMACS=Interagency Registry for Mechanically Assisted Circulatory Support, TIMI=Thrombolysis In Myocardial Infarction; ^Adjusted using TEG for a goal Maximum amplitude of 60-70 mmHg; *Adjusted based on light transmission aggregometry, platelet function analyzer-100, and multiplate without goal reported; ^ includes hemorrhagic stroke and TIA; + includes hemolysis events; † stroke in one patient taking aspirin, stroke and pump thrombosis in one patient who discontinued antiplatelet therapy; INTERMACs bleeding definition (suspected internal or external bleeding that resulted in death, reoperation, hospitalization, or any transfusion of pRBC. Bishop [21]

-

27/55 (49%)

-

1/23 (4%) 4/51 (8%)

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3/23 (13%) 32/102 (31%)

14/55 (25%)

-

Accepted Article This article is protected by copyright. All rights reserved.