Journal of Thrombosis and Haemostasis, 13 (Suppl. 1): S343–S350

DOI: 10.1111/jth.12928

INVITED REVIEW

Antithrombotic therapy for ventricular assist devices in children: do we really know what to do? M . P . M A S S I C O T T E , * † M . E . B A U M A N , * † J . M U R R A Y ‡ § and C . S . A L M O N D ‡ § *KIDCLOT Pediatric Thrombosis, Stollery Children’s Hospital; †University of Alberta, Edmonton, AB, Canada; ‡Division of Cardiology, Lucile Packard Children’s Hospital Stanford; and §Stanford University, Stanford, CA, USA

To cite this article: Massicotte MP, Bauman ME, Murray J, Almond CS. Antithrombotic therapy for ventricular assist devices in children: do we really know what to do? J Thromb Haemost 2015; 13 (Suppl. 1): S343–S50.

Summary. The use of ventricular assist devices (VADs) in children is increasing. Stroke and device-related thromboembolism remain the most feared complications associated with VAD therapy in children. The presence of a VAD causes dysregulation of hemostasis due to the presence of foreign materials and sheer forces intrinsic to the device resulting in hypercoagulability and potentially lifethreatening thrombosis. The use of antithrombotic therapy in adults with VADs modulates this disruption in hemostasis, decreasing the risk of thrombosis. Yet, differences in hemostasis in children (developmental hemostasis) may result in variances in dysregulation by these devices and preclude the use of adult guidelines. Consequently, pediatric device studies must include safety and efficacy estimates of device-specific antithrombotic therapy guidelines. This review will discuss mechanisms of hemostatic dysregulation as it pertains to VADs, goals of VAD antithrombotic therapy for children and adults, and emerging antithrombotic strategies for VAD use in children. Keywords: drug therapy; heart failure; heart-assist device; pediatrics; thrombosis.

shear forces that impact thrombosis risk. Hemostasis, the reparative process for damaged endothelium, involves the interaction of serine proteases (coagulation proteins) and platelets to form a hemostatic plug. Specific inhibitory mechanisms including protein C and S, AT, TAFI, tPA, plasminogen–plasmin, and thrombomodulin regulate this process. Normal hemostasis is disturbed immediately postVAD implantation due to the introduction of foreign materials and shear forces, which are unique to each device and subsequently activate coagulation proteins, platelets, and vascular endothelium. Consequently, inherent hemostatic inhibitory capacity is overloaded and results in dysregulation of hemostasis and potential thrombosis. Administration of antithrombotic therapy modulates hemostasis and assists the overloaded inhibitory mechanisms in preventing thrombosis. Currently, in children with VADs, the optimal intensity of antithrombotic therapy is unknown and is probably device and individual dependent. In the absence of safety and efficacy studies which are device specific, estimates of the required intensity of antithrombotic therapy often either underestimates or exceeds that which is required, resulting in thrombotic (stroke, pump thrombosis, VTE) or hemorrhagic complications (stroke, chest tube losses, abdominal), respectively. Normal hemostasis

Introduction Evidence-based guidelines for antithrombotic therapy in adults with VADs cannot be directly extrapolated to children due to a number of developmental differences, including pharmacokinetics/pharmacodynamics of therapeutic agents, decreased thrombin generation and fibrinolytic capacity, and increased inhibitory capacity. In addition, VADs have different performance characteristics in children particularly as it pertains to pump flow rates and Correspondence: Mary Patricia Massicotte, 11405 87 Ave, Edmonton, AB T6G 1C9, Canada. Tel.: +1 780 248 5595; fax: +1 800 790 1507. E-mail: [email protected] © 2015 International Society on Thrombosis and Haemostasis

The cell-based model of hemostasis describes the initiation, continuation, and completion of the hemostatic process. Children have unique physiologic differences in hemostasis, which exist across the pediatric age spectrum. These differences, known as ‘developmental hemostasis’ [1–3], influence the incidence, epidemiology, and outcomes of thrombosis in children. The unique coagulation milieu existing during childhood requires the development of age-specific strategies to prevent thrombosis and precludes the use of adult thromboprotective strategies [4]. Compared to adults, children have decreased physiologic levels of proteins involved in coagulation (FXII, XI, X, IX, VII, II), fibrinolysis (plasminogen, PAI, uPA, and tPA), and inhibitors of coagulation (AT, proteins C and S)

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[1–3]. As a result, children generate less thrombin than adults when hemostasis is activated and are generally protected from thrombosis [5]. However, there are high-risk cohorts of children, such as children with VADs, where pathologic thrombosis occurs. Types of VADs in children Although there are a wide variety of VADs that have been used in children over the past two decades, few are in common use today [6]. Devices are classified according to their intended duration of support, that is long-term VADs (used for months to years) and short-term VADs (used for days to a few weeks), and basic pumping mechanism (pulsatile pumps vs. continuous flow pumps). Pulsatile pumps are commonly used in small children, whereas continuous flow pumps are commonly used in larger children and adults [6].

pump head housing, powered electromagnetically by a portable battery. Like the Berlin Heart, the pump is implanted into the left ventricle and aorta on cardiopulmonary bypass. The Heartmate IIÒ cannot be implanted into smaller children and infants (< 1.2 m2), or provide biventricular support reliably. Long-term use has been associated with aortic insufficiency and acquired von Willebrand disease with related gastrointestinal bleeding [8–10]. Heartware HVAD

Use of the HeartwareÒ HVAD, a centrifugal continuous flow pump, has grown rapidly in the last few years among both pediatric and adult heart failure patients. In contrast to the Heartmate II, the HVAD can be used in children as small as 0.8 m2 and can be configured more readily to provide biventricular support [6].

Long-term devices

Short-term devices

Long-term devices are used to support patients with heart failure refractory to medical therapy who require support for several months or years. Most commonly long-term VADs are used for bridge-to-heart transplant and for destination therapy. Three VAD brands account for the vast majority of long-term VADs used in children today. They are (i) the Berlin Heart EXCORÒ Pediatric VAD (Berlin, Germany) (ii) the Thoratec Heartmate IIÒ LVAD (Thoratec Corporation, Pleasanton, CA, USA), and (iii) the HeartwareÒ HVAD (HeartWare Incorporated, Framingham, MA, USA).

Short-term VADs are used to support patients who require support for several days or a few weeks most commonly as a bridge to recovery or decision. The three most common VADs used in children are the LevitronixÒ, CentrimagÒ, and PedimagÒ (Thoratec Corporation, Pleasanton, CA, USA), which are magnetically levitated centrifugal pumps [6,7].

Berlin heart EXCOR pediatric VAD

The Berlin Heart EXCORÒ Pediatric VAD is the most commonly used long-term VAD in children under 18 years of age [7]. The Berlin Heart is a paracorporeal pneumatically driven pulsatile blood pump. The primary advantages of the Berlin Heart are that it is capable of supporting infants and children of all sizes and can be configured easily to support both the left and right heart. The primary disadvantages of the Berlin Heart are a high risk of stroke (29%) and infection [7], the pump is not fully implantable, and requires children to remain hospitalized for the duration of their support on the Berlin Heart in most centers [7]. Heartmate II LVAD

The Heartmate IIÒ is the second most common long-term VAD used in children, and the most common LVAD used in patients above 25–30 kg. The Heartmate IIÒ is a highly reliable continuous flow pump. Blood streams through the pump continuously without flow disruption by valves and is driven by a propeller sitting within the

Hemostatic dysregulation by VADs Endothelium [11–13], hemostatic proteins [11,14], fibrinolysis [11,15], platelets [12], and leukocytes [12] are activated by the presence of a VAD, resulting in increased thrombin production necessitating thromboprophylaxis in patients with VADs. VAD biomaterials and blood activation

Contemporary LVADs use biomaterials such as titanium alloy blood pumps and polyester inflow and outflow grafts that minimize blood activation and have a long history of use in implantable medical devices (IFU Heartmate II). Within seconds of blood material contact, proteins become adsorbed and FXII becomes activated producing minimal thrombin. Platelet activation and adsorption occur within minutes creating the phospholipid surface necessary for further activation of coagulation. Following this process, Xase and IIase result in substantial fibrin formation. Leukocyte activation (CD11b upregulation) occurs within minutes leading to adhesion, while TF expression occurs over hours. Complement activation occurs at all timescales and is linked to platelet and leukocyte activation. Blood exposure to the artificial surface of the VAD results in activation of coagulation and thrombin production, which is demon© 2015 International Society on Thrombosis and Haemostasis

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strated by increased levels of thrombin–antithrombin complexes, prothrombin F1.2, and FPA [11,14,15]. Fibrinolysis is initiated with activation of coagulation. Blood exposure to the artificial surface of the VAD results in activation of coagulation and subsequently fibrinolysis as demonstrated by increased levels of D-dimer [11,15]. The complexity of blood material interactions explains the failure of designing a material that is entirely blood compatible. Hemolysis and VAD shear force activation

Clinical hemolysis produced by sheer forces on red blood cells is an important complication associated with ventricular assist devices [16]. Shear force activates hemostasis by a few mechanisms, including microparticle production from endothelium, leukocytes, and platelets and alteration of von Willebrand multimers [12,17]. Microparticles produced as a result of cellular damage result from phosphatidylserine blebbing and microparticle release. The negative charge of the microparticles due to the phosphatidylserine activates coagulation by interaction with the positively charged serine proteases [12]. The endothelium appears to be activated by shear force. Markers of endothelial dysfunction have been demonstrated in vivo and include vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), E-selectin and endothelial microparticles (E-selectin as a marker, CD62E) [12,13]. Mechanical forces activate platelets [17]; thus, hypotheses exist that VAD shear forces activate platelets. However, the optimal assay to measure platelet function is controversial with measurements in patients with a VAD being inconclusive demonstrating activation in some and no activation in others. [18,19] Studies also used different methods of determining platelet function, thus limiting comparability of results. However, other markers of platelet activation have been demonstrated in vivo. Increased platelet microparticles have been identified using platelet activation markers CD31+/CD61+ [12]. In addition, platelet factor 4 (PF4), beta thromboglobulin (BTG), and thromboxane b2 have been identified in vivo. Activation of leukocytes with production of microparticles has been demonstrated in vivo and identified using leukocyte activation markers CD11b [12]. Microparticles are associated with hypercoagulability with increased quantities demonstrated in adults with VADs [20]. However, although increased adverse events have been demonstrated in the adult VAD population in addition to increased microparticles, thrombosis was only one component of the composite outcome endpoint [21]. Further work is needed to determine the relationship of microparticles and adverse events [16]. Shear force also alters the configuration of von Willebrand multimers exposing platelet-specific binding sites © 2015 International Society on Thrombosis and Haemostasis

which when occupied result in platelet activation [22–25]. In some patients, the alteration and stretching of von Willebrand multimers expose the large molecules to ADAMTS-13 and proteolysis occurs, resulting in possible increased bleeding [17]. Given the challenges with biomaterial and shear force activation of coagulation, antithrombotic therapy is necessary to prevent thrombosis including stroke. Currently, there are device-specific guidelines commonly used to manage adult VAD patients. Conversely and unfortunately, there is limited knowledge and guidance for children with a VAD. Antithrombotic therapy guidelines in adults In adults, Szefner et al. [26] developed the first multitargeted approach to antithrombotic therapy, which included anticoagulation, antiplatelet therapy, and blood viscosity reduction to prevent thrombosis in total artificial hearts [26]. Since that time standardized antithrombotic guidelines have been developed and continue to be refined for adult ventricular assist devices including the LVADs most commonly used in clinical practice today [27–30]. Evolving VAD designs and growth of knowledge on thrombosis prevention make adult recommendations for antithrombotic therapy fluid. Rates of bleeding and stroke reported are 34% (range 15–50%) and 5%, respectively [31,32]. Given the initial high rates of bleeding, the intensity of anticoagulation was decreased, initially without a subsequent increase in thromboembolic events [31,33]. Recent retrospective studies, however, have demonstrated an increase in pump thrombosis (Heartmate II) with undetermined etiology [34,35]. In addition, investigators in the Heartware Bridge to Transplant trial reviewed the database and found that most patients with pump thrombosis had subtherapeutic INRs (< 2.0) on warfarin and were not taking recommended acetylsalicylic acid (ASA) therapy (325 mg) [36,37]. Of those patients who had therapeutic INRs (2–3) and received 325 mg ASA, the rates of bleeding and hemorrhagic strokes were no higher than in those patients who were subtherapeutic [36,37]. Subsequently, recommendations were made for investigators to strictly adhere to INR 2–3 and ASA dose of 325 mg per day. Following this, the time in therapeutic range increased from 35% to 46%, and the annualized rate of pump exchange for suspected thrombosis decreased by 55% [36,37]. Despite continual refinements in antithrombotic therapy in all VADs, bleeding and thrombosis remain the most common adverse events with continuous flow devices most commonly used [31,38,39]. Antithrombotic therapy guidelines in children There are significant limitations in knowledge of antithrombotic therapy in children with VADs including evolving devices, making earlier publications outmoded.

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In addition, although antithrombotic protocols are described in varying detail, only one guideline for a specific device has been evaluated [40]. Consequently, as new device models emerge, pediatric clinicians have limited resources and must refer to the adult recommendations while simultaneously integrating developmental hemostasis, its influence on antithrombotic therapeutic agents, and past clinical experience to guide antithrombotic therapy in pediatric VAD patients. There are efforts underway to develop evidence-based strategies to guide antithrombotic therapy in this challenging population. Standard definitions of adverse events including bleeding and thrombosis are currently inconsistent, yet are necessary to ensure data reported are comparable. Databases such as the German Heart Database [41] and the US PEDIMacs Registry [42] (NCT 00119834) are affording the opportunity to systematically collect data in children. Copeland et al. [27] retrospectively described (1997-2009) 28 children from 1 month to 16 years of age with a variety of extracorporeal and paracorporeal VADs using unfractionated heparin and antiplatelet therapy including ASA and dipyridamole. TEG was used to monitor anticoagulation and classical platelet aggregation monitored platelet inhibition using the agonists: adenosine diphosphate (ADP), adrenaline, arachadonic acid, and collagen. Adverse events were 29% major bleeding and 25% stroke with 86% surviving to transplant or weaning. Other case series have reported up to 70% major bleeding and up to 70% stroke in children with extracorporeal pulsatile devices [27]. The first prospective study in children consisted of a single arm study, and patients with the EXCOR VAD [7] were compared to a control group consisting of a historical cohort of children on ECMO obtained from the Extracorporeal Life Support Organization (ELSO) database. Antithrombotic guidelines modified from Drews et al. [43] were used in this study [44]. A multitargeted approach was used with agents that were directed against coagulation and platelet activity, as in adult guidelines. This first evaluation of antithrombotic therapy in children with a VAD identified both bleeding (up to 50%) [7] and stroke (29%) rates that were suboptimal yet comparable to previous pediatric studies [7]. The results of this trial using the Edmonton anticoagulation protocol provide a preliminary platform for clinical management of children with VADs and for future studies, including the NIH/ NHLBI-funded study, the PumpKIN study: pumps in kids, infants, and neonates. Anticoagulation therapy in children with a VAD

The goal of anticoagulation therapy is to modulate thrombin production and prevent thrombosis. The type and intensity of the agent used are influenced by developmental hemostasis, device, and patient clinical presentation. The most commonly used pediatric anticoagulant

agents are the same as those used in adults. As of 2011, unfractionated heparin (UFH), the vitamin K antagonist, warfarin, and argatroban have pediatric information within their Federal Drug Administration label in the United States, although optimal dosing is not clear and no randomized clinical trials have been completed in children determining safety and efficacy. Low molecular weight heparin (LMWH) and bivalirudin are both off label agents. In certain circumstances, bivalirudin [45] and argatroban [46] may be used. However, each agent has associated pediatric-specific challenges. Dosing

Studies have demonstrated age-dependent increases in dose per kg of UFH, LMWH, and VKA in children related to increased metabolism and clearance of the agents [4]. There are few small studies describing the doses of bivalirudin and argatroban in children with a VAD with confirmed heparin-induced thrombocytopenia (HIT) [47] or inordinate challenges with heparin [45]. Despite safety and efficacy data, antithrombin concentrate administration in children with a VAD is increasing [48]. As an adjunct to UFH therapy, the rationale for increasing antithrombin levels is to achieve a target antiFactor Xa level with a lower dose of UFH [49,50], thus potentially minimizing the pharmacologic effects of uncomplexed UFH [51,52]. Retrospective studies published in children receiving extracorporeal membrane oxygenation (ECMO) have used various dosing regimens, including bolus doses up to 100 IU kg 1 [53], continuous infusion with mean dose of 73 IU kg 1 over 24 h [54], or a 4-h infusion with the calculated dose using the following formula: 100 (target antithrombin value) (antithrombin value on laboratory test) 9 weight [55]. In addition, use of large bolus dose averaging 241 IU kg 1 (< 3 months of age 341 IU kg 1; ≥ 3 months of age 141 IU kg 1) has also been described [50]. In the EXCOR study, administration of antithrombin was recommended if the level was < 70% [7], but no specific dosing guidance was given. If administering antithrombin, the UFH infusion should be decreased to avoid a large increase in the anticoagulant effect and potential bleeding. The PTT and/or anti-Factor Xa and antithrombin level should be measured after antithrombin administration. Monitoring

An anti-Factor Xa level is accepted to be a better measure of heparin effect than the PTT [56,57]. This is thought to be especially true in pediatrics given the effect of age on the PTT although recent studies have suggested that challenges exist with both methods in children [58– 60]. Thromboelastography is hypothesized to provide an accurate assessment of in vivo hemostasis with the R-value reflecting UFH anticoagulant effect [61,62]. © 2015 International Society on Thrombosis and Haemostasis

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Lack of venous access in children is problematic, resulting in blood samples being drawn from central lines protected by UFH flushes or infusion. As a result, samples are contaminated with heparin from the central line [63]. As an attempt to correct this issue, blood samples obtained from a central line ought to be drawn after a generous normal saline flush and blood discard in attempt to remove any contaminating heparin [63]. With LMWH, an elevated PTT will alert the clinician to sample contamination with UFH [63]. Currently, bivalirudin and argatroban are monitored using the PTT. More frequent INR monitoring of VKA in children is necessary due to changes in dietary intake, frequency of childhood illnesses, multiple medications with congenital anomalies, and dosing errors (DIME). The use of a home INR meter is demonstrated to improve time in therapeutic range and address challenges with venous access [64]; however, the accuracy of the meter INR in children with a VAD is suboptimal [65]. Antiplatelet therapy in children with a VAD

The goal of antiplatelet therapy is to modulate platelet activation. Antiplatelet agents most commonly used are essentially the same as those used in adults, however are all off label. ASA, dipyridamole, and clopidogrel are the agents currently used. Weight-based dosing is used; however, there are no pharmacokinetic/pharmacodynamic or dosing studies in children to guide management [66]. Monitoring

There is no ideal method for measuring platelet function in children despite the established methods used to manage adults. Thromboelastography using the TEGÒ with Platelet Mapping PMÒ (Braintree, MA, USA) was the method used in the EXCOR study [40] to measure function and guide antiplatelet dosing. The principle advantages of the TEG©/PMTM include a whole-blood sample, which more closely represents the in vivo hemostatic system, and the relatively small volume of blood (3–5 mL) required for testing compared to other platelet function assays (e.g. platelet aggregometry). While these advantages have helped make TEG©/PMTM the most widely used test for global hemostasis and platelet function in the field of pediatric VADs, several limitations exist. These include the lack of validated target ranges, proven dose–response relationship to common platelet inhibitors, and potential technical challenges including lack of reproducibility and interpretability of test results. Classic platelet aggregometry often used has limitations as it requires large blood samples, which is suboptimal for chronic management of children on VAD support. Other methods of platelet function testing have not been consistently demonstrated to be accurate and precise [67]. © 2015 International Society on Thrombosis and Haemostasis

Future potential targets for therapeutic agents Current antithrombotic agents broadly target hemostatic components, resulting in bleeding side effects. Recent data have emerged that suggest the use of alternative therapeutic strategies aimed at modulating specific hemostatic targets involved in thrombosis may alleviate agentspecific adverse events. These new potential targets include microparticles, neutrophil extracellular traps (NETs), Factor XII, and histones known as poly P. Inhibiting these specific targets in children with a VAD might optimize thromboprophylaxis while minimizing bleeding. Microparticles

Microparticles (MP) [12,68,69] are produced by activated or damaged cells including platelets, leukocytes, and endothelial cells. The majority of MP have negatively charged phosphatidylserine exposed on their surface [70] and contain cell surface proteins including TF [71] both factors rendering them to be procoagulant [72]. Neutrophil extracellular traps (NETs)

Infection is one of the more common adverse events in patients with a VAD. Microorganisms activate neutrophils by a cell death program to release nucleic acids lined with granular components (such as myeloperoxidase, neutrophil elastase, and cathepsin G) creating fibrous nets with antimicrobial properties capable of destroying bacteria, fungi, and viruses. In addition, NETs activate coagulation and platelets by providing a negatively charged surface for the activation of FXII [73] and histones [74], respectively. Factor XII

FXII appears to play a role in thrombosis when activated without being essential to normal hemostasis. Studies have demonstrated that FXII-deficient mice have decreased thrombosis in experimental thrombosis models without increased bleeding [75]. In addition, FXII-deficient patients do not exhibit increased bleeding. However, activation of FXII by negatively charged surfaces (e.g. biomaterials of a VAD), extracellular RNA [76], NETs, and poly P [77] results in activation of FXIa and ultimately thrombin production. A study in dogs receiving extracorporeal membranous oxygenation (ECMO) and FXII antibody as the thromboprotective agent instead of unfractionated heparin was successful and did not cause bleeding [78]. Poly P

Poly P is released from activated platelets or microorganisms with long-chain polymers contained in microorgan-

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isms being strong activators of FXII and affecting fibrin clot structure [79], and short-chain polymers contained in platelets increase FV activation and inhibit TFPI [80]. In addition, poly P enhances fibrin clot structure stability. Conclusions The best way to prevent thrombosis in children with a VAD is dependent on a number of factors including type of VAD (biomaterials and shear force), clinical condition of the patient, and limitations of agents used. Further studies are urgently needed in this population testing new VADs and thromboprotective agents, both existing and novel. Risk factors for bleeding and thrombosis should be identified to provide patient-tailored antithrombotic therapy. Finally, monitoring methods for antithrombotic therapy must be improved and validated to provide optimal therapy that is both safe and effective. By proceeding with this plan, the unknown will become the known in managing these challenging pediatric patients. Disclosure of Conflict of Interests The authors state that they have no conflict of interest. References 1 Andrew M, Paes B, Milner R. Development of the human coagulation system in the full-term infant. Blood 1987; 70: 165–72. 2 Andrew M, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L. Maturation of the hemostatic system during childhood. Blood 1992; 80: 1998–2005. 3 Monagle P, Barnes C, Ignjatovic V, Furmedge J, Newall F, Chan A, De Rosa L, Hamilton S, Ragg P, Robinson S, Auldist A, Crock C, Roy N, Rowlands S. Developmental haemostasis. Impact for clinical haemostasis laboratories. Thromb Haemost 2006; 95: 362–72. 4 Monagle P, Chan AKC, Goldenberg NA, Ichord RN, Journeycake JM, Nowak-G€ ottl U, Vesely SK. Antithrombotic therapy in neonates and children: antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest 2012; 141: e737S– 801S. 5 Massicotte P, Leaker M, Marzinotto V, Adams M, Freedom R, Williams W, Vegh P, Berry L, Shah B, Andrew M. Enhanced thrombin regulation during warfarin therapy in children compared to adults. Thromb Haemost 1998; 80: 570–4. 6 Vanderpluym CJ, Fynn-Thompson F, Blume ED. Ventricular assist devices in children: progress with an orphan device application. Circulation 2014; 129: 1530–7. 7 Fraser CD Jr, Jaquiss RD, Rosenthal DN, Humpl T, Canter CE, Blackstone EH, Naftel DC, Ichord RN, Bomgaars L, Tweddell JS, Massicotte MP, Turrentine MW, Cohen GA, Devaney EJ, Pearce FB, Carberry KE, Kroslowitz R, Almond CS. Berlin Heart Study I. Prospective trial of a pediatric ventricular assist device. N Engl J Med 2012; 367: 532–41. 8 Cowger J, Pagani FD, Haft JW, Romano MA, Aaronson KD, Kolias TJ. The development of aortic insufficiency in left ventricular assist device-supported patients. Circ Heart Fail 2010; 3: 668–74.

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