J Thromb Thrombolysis DOI 10.1007/s11239-014-1162-6

Management of anticoagulation and antiplatelet therapy in patients with left ventricular assist devices Lisa M. Baumann Kreuziger

Ó Springer Science+Business Media New York 2014

Abstract Left ventricular assist devices (LVADs) have increased the survival of patients with advanced heart failure fourfold. Despite these advances, significant bleeding and thrombotic complications occur. Hemorrhage requiring surgery has been reported in up to 30 % of adults and 50 % of children after LVAD placement. LVAD thrombosis and embolic stroke lead to significant long-term morbidity. Adults are treated with antithrombotic therapy to prevent thrombotic complications, but the amount and intensity of treatment differs between institutions. The goal international normalized ratio for warfarin therapy varies from 1.5 to 3.0. Some physicians manage adult LVAD patients without antiplatelet medication, whereas other adults are treated with aspirin as a single agent or combined with dipyridamole. In contrast, physicians typically manage children with LVADs using the Edmonton Anticoagulation and Platelet Inhibition Protocol, a detailed algorithm for anticoagulation and antiplatelet treatment modified based on thromboelastography results. LVAD implantation causes consumption of coagulation proteins, activation of fibrinolysis, and loss of high molecular weight von Willebrand protein multimers. How these changes in the coagulation system influence the risk of hemorrhage and initiation of thrombosis is unknown. Prospective, controlled studies are needed to determine the antithrombotic regimen that most effectively balances bleeding and thrombosis in LVAD patients.

Keywords Anticoagulants  Hemorrhage  Platelet aggregation inhibitors  Thrombosis  Ventricular assist device

L. M. Baumann Kreuziger (&) Department of Medicine/Hematology and Oncology, BloodCenter of Wisconsin and Medical College of Wisconsin, 8733 Watertown Plank Road, Milwaukee, WI 53226, USA e-mail: [email protected]

LVAD mechanics and development

Heart failure affects over 5 million people in the United States (US) [1]. Despite the advances in medical therapy, patients with advanced heart failure live for 6 months on average. Heart disease remains the leading cause of death in the US, and 1 in 8 death certificates mention heart failure [1, 2]. Heart failure is a significant economic burden; estimates report that caring for heart failure patients cost the US health care system $39.2 billion in 2010 [1]. Heart failure can be definitively managed with cardiac transplantation, but organ availability limits the number of potential transplants. Between 2,000 and 2,500 heart transplants are performed in the US annually, but over 4,000 patients were listed as candidates for heart transplant in November 2014 [3, 4]. The median time to heart transplantation is between 1.5 months to over a year depending on the patient’s blood type [4]. Left ventricular assist devices (LVADs) were developed to bridge a patient to cardiac transplantation, and approximately 30 % of patients undergoing heart transplant in 2012 were supported with an LVAD [3]. In the US, the HeartMate IIÒ device (Thoratec Corp., Pleasanton, CA) and HeartWare HVADÒ (HeartWare International, Inc., Framingham, MA) are approved for patients awaiting heart transplantation [bridge-to-transplant (BTT)]. In addition, the HeartMate II is approved for patients ineligible for heart transplant as destination therapy.

All LVADs augment or replace the function of the failing left ventricle by extracting blood via an inflow cannula

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inserted into the ventricle and propelling blood into the ascending aorta via an outflow graft. All devices have an external controller and power source that is connected to the LVAD via a percutaneous drive line. First generation LVAD devices contain an oscillating membrane that mimics the pulsatility of the heart, yet is prone to mechanical wear [5]. Due to availability in sizes down to 3 kg body weight, pulsatile devices [ex. Berlin EXCORÒ (Berlin Heart Inc, Woodlands, TX)] continue to be used in pediatrics but are rarely used in adults due to limited durability [5, 6]. Continuous flow devices can be implanted long-term, but create non-pulsatile flow. The HeartMate II is a second-generation axial device that creates flow through spinning of a rotor containing helical blades. Due to the small diameter of the device, the impeller must spin at 7,000–12,000 rotations per minute (rpm) to generate physiologic cardiac flow. To eliminate the need for mechanical bearings, third-generation LVADs containing magnetically levitated rotors were developed. Centrifugal devices (ex. HeartWare HVAD) have larger rotor diameter, thus can create the same amount of flow as axial devices at significantly lower rotational speeds (2,000–3,000 rpm). The amount of shear stress created by the LVAD is directly related to the rotational speed and can cause damage to blood cells; thus, the HeartMate II device is associated with higher levels of baseline hemolysis compared to the HVAD device [7].

Coagulation system effects from LVADs In addition to hemolysis, LVAD placement leads to significant alterations in coagulation proteins, platelets and von Willebrand protein. Decreased levels of coagulation proteins involved in the contact pathway (factor XI, factor XII, and pre-kallikrein) are found in the first two weeks after LVAD implantation presumably due to consumption [8]. Elevated levels of prothrombin fragment 1.2, D-dimer, thrombinantithrombin and plasmin-antiplasmin complexes suggest thrombus formation and activation of the fibrinolytic system in the presence of an LVAD [8–10]. These changes are most pronounced post-operatively, and levels return to near-normal within 6–12 months [5, 9]. Endothelial cell activation persists as evidenced by increased levels of tissue factor, E-selectin, and intercellular adhesion molecule on circulating endothelial cells of LVAD patients compared to patients undergoing non-LVAD cardiac surgery [10]. Conflicting evidence exists in the literature as to whether circulation of blood through a LVAD causes platelet activation. Plasma markers of platelet activation including soluble P-selectin and CD40 ligand were normal in LVAD patients with various durations of support and doses of aspirin therapy [11]. In contrast, more sensitive assays suggest that platelet activation occurs. One report noted

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elevated P-selectin expression on the platelet surface in LVAD patients [12]. Increased platelet aggregation and thrombin production via a prothrombinase assay have also been reported [12, 13]. The conflicting evidence in the literature is likely due to differences in how platelet activation is measured and the amount of shear stress created by different LVAD devices. Nearly all patients with implanted LVADs develop acquired von Willebrand syndrome with loss of high molecular weight von Willebrand factor multimers [14, 15]. Reports suggest an increased clearance of von Willebrand protein based on an increased ratio of von Willebrand protein to propeptide level. Similar severity of acquired von Willebrand syndrome occurs with HeartMate II and HVAD devices, and these alterations resolve after LVAD removal [15]. A well-known association exists between acquired von Willebrand syndrome due to aortic valve stenosis and GI angiodysplasia (i.e. Heyde syndrome). Approximately 20 % of LVAD patients experience gastrointestinal (GI) bleeding of which 30–40 % occurs due to angiodysplasia [16, 17]. The severity of the acquired von Willebrand syndrome has not been associated with GI bleeding in LVAD patients, however [15, 18]. One case report noted von Willebrand factor concentrate improved angiodysplasia-associated bleeding, but the patient subsequently experienced a LVAD thrombosis [19]. Additional investigation is required to understand the pathophysiology of GI bleeding in LVAD patients and the role that von Willebrand protein might play.

LVAD outcomes In the only randomized study of LVAD devices, the HeartMate II device was compared to the Heartmate XVEÒ, a pulsatile LVAD (Thoratec Corp., Pleasanton, CA), in patients ineligible for heart transplant [20]. Patients implanted with the HeartMate II device had significantly improved actuarial survival compared to the Heartmate XVE [2-years survival 58 vs. 24 % (p \ 0.01), respectively] with less need for LVAD repair or replacement [13/ 134 (10 %) HeartMate II vs. 24/66 (36 %) HeartMate XVE, p \ 0.01]. Bleeding events were frequent with 81 % of patients requiring transfusion and 30 % of patients requiring reoperation in the HeartMate II patients (Table 1). Patients’ quality of life scores and functioning improved from baseline with implantation of both LVADs. The Heartmate II was FDA approved as destination therapy for patients with heart failure in January 2010. In patients awaiting heart transplant, several LVADs are approved for use. Due to competing outcomes of death, transplantation, and LVAD removal due to ventricular recovery, the BTT trials reported combined primary

LVAD antithrombotic therapy Table 1 Clinical trial outcomes for LVADs approved for use in the United States Device

Indication

Patient population

Hemorrhage requiring surgery

Ischemic stroke

Survival

HeartMate II [20]

DT

Adult

40/133 (30 %), 0.23/py

11/133 (8 %), 0.06/py

68 % 1-yeara

HeartMate II [22]

BTT

Adult

41/133 (31 %), 0.78/py

8/133 (6 %), 0.13/py

68 % 1-yeara

HVAD [21]

BTT

Adult

20/140 (14 %), 0.26/py

10/140 (7 %), 0.11/py

86 % 1-yeara

EXCOR [24]

BTT

Pediatrics

42–50 %b

29 %

88–92 %c

DT destination therapy, BTT bridge-to-transplant, py person-year a

actuarial survival

b

bleeding resulting in death, re-operation, blood transfusion of[4 units packed red blood cells within 7 days of implantation or any transfusion after 7 days

c

survival to transplant or wean from device

outcomes for these events. In the HeartMate II trial published in 2007, 75 % of patients met the primary outcome [16]. The HVAD was evaluated in a prospective cohort study including a control group of patients with contemporaneously implanted LVADs using the Interagency Registry for Mechanical Assisted Circulatory Support (INTERMACS) registry. Although INTERMACS policy does not allow disclosure of device names, 95 % of patients had continuous flow LVADs implanted and the HeartMate II device was the only commercially available continuous flow device available. The trial reported 91 % of HVAD patients met the primary outcome compared to 90 % of the control group (p \ 0.01 for non-inferiority) in 2010 [21]. Improvements in surgical implantation, postoperative care, and medical therapy could account for the steady improvements in survival of patients with LVADs. Despite the improvement in survival, bleeding and thrombotic events occur (Table 1). Hemorrhage requiring reoperation remains common and happens most often in the first 30 days after LVAD placement [21, 22]. Thrombus formation in the LVAD can lead to embolic events including ischemic stroke, transient ischemic attack, arterial thromboembolism, or LVAD dysfunction. Ischemic stroke has been reported in 7–8 % of patients and arterial embolism in 4–7 % of patients. [21, 22] Hemolysis and elevation in the power required to create flow are the clinical markers of LVAD thrombosis. Approximately 2 % of patients were reported in the clinical trials to have confirmed LVAD thrombosis, but recent analysis has suggested that thrombosis in the HeartMate II devices has increased to 12 % at 24 months of support [23]. Neither a change in manufacturing nor patient selection has not been found to account for the differences in LVAD thrombosis rates. Due to size restrictions, continuous flow LVADs cannot be used in children until the teenage years. The Berlin Heart EXCORÒ device was approved by the FDA in December 2012 based upon a prospective study of 48 children awaiting heart transplant [24]. The study was

divided into two cohorts by body surface area and compared to a propensity-score-matched historical control of children treated with extracorporeal membrane oxygenation (ECMO). Median duration of support was 5 days in the ECMO groups compared to 28 and 43 days in the EXCOR cohorts (p \ 0.01). LVAD implantation significantly improved survival to transplant or ventricular recovery at 30 days (96 % for EXCOR cohorts vs. 67–75 % ECMO cohorts). Major bleeding and infection were the most common adverse events; 42–50 % of children experienced major bleeding and 50–63 % had documented infection. Stroke occurred in 29 % of children, and 46 LVAD exchanges were required due to thrombosis, stroke or infection. [24] An update from the Berlin Heart EXCOR database reported a 12 months survival of 75 % in 204 children implanted during the US trial or via compassionate use [6]. Ischemic stroke remained the leading cause of death, followed by respiratory failure and hemorrhagic stroke [6]. Development of the Berlin Heart EXCOR device has profoundly improved the survival of children awaiting heart transplant but the balance between bleeding and thrombosis is tenuous.

Antithrombotic therapy management Due to the thromboembolic complications associated with LVADs, patients are treated with anticoagulation and antiplatelet therapy. The medications used and intensity of antithrombotic therapy varies in adults depending on patient factors, risk of device thrombosis, and institutional preference. Bleeding and thrombotic events are monitored closely during the device trials with adjustments in recommendations for anticoagulation and aspirin treatment [21]. The International Society for Heart and Lung Transplantation has also developed guidelines for mechanical circulatory support that include anticoagulation recommendations [25].

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Perioperative anticoagulation management Prior to LVAD placement, patients are often treated with anticoagulation or antiplatelet therapy due to history of thrombosis, atrial fibrillation, or ischemic heart disease. In the BTT trials, 50–60 % of patients were anticoagulated with heparin prior to LVAD placement and 30 % were taking aspirin [21, 22]. Additionally, heart failure causes renal and liver impairment, which can further compromise the coagulation system. At LVAD implantation, 30 % of patients are stable but inotrope-dependent, 36 % are progressively declining, and 14 % are in cardiac shock [26]. Placement of the LVAD requires a median sternotomy or thoracotomy, use of cardiopulmonary bypass, and an intraperitoneal pump pocket for the HeartMate II device. Due to the extent of surgery and baseline coagulopathy, bleeding is most common in the post-operative period and use of anticoagulation must be adjusted accordingly. Heparin is reversed using protamine after completion of cardiopulmonary bypass. Anesthesiologists target protamine dose to normalize the activated clotting time (ACT). The ACT has been shown to be insensitive to residual heparin, and alternate measurement strategies including thromboelastography [TEGÒ (Haemoscope Corporation, Niles, IL)] have been evaluated [27]. Aspirin is typically started in the first 24–72 h post-operatively. Anticoagulation with heparin is recommended to begin once hemostasis is achieved on post-operative day 1, and the goal prolongation of the activated partial thromboplastin time is gradually increased over the subsequent days [25]. Typically, warfarin is started once the chest tubes have been removed and the patient can take oral medication. Despite the recommendations for heparin bridging to warfarin, 29 % of patients in the HeartMate II trials did not receive heparin [28]. These patients were treated at high volume centers in the later years of the trial. Thrombotic and bleeding outcomes were the same in the first 3 post-operative days. Significantly fewer patients required transfusion for bleeding in the group of patients not treated with heparin compared to patients treated with therapeutic heparin (16 % no heparin vs. 32 % therapeutic heparin), but bleeding events requiring surgery were similar [28]. No significant differences in baseline characteristics were found to allow prospective identification of which patients might benefit from less intensive post-operative anticoagulation. Long-term anticoagulation management Vitamin K antagonists (VKA) are the standard of care for long-term anticoagulation in adult LVAD patients [25]. Alternative anticoagulation strategies have been evaluated, however. A case series of seven patients who were switched from acenocoumarol to dabigatran 110 mg twice daily showed similar thromboembolic rates during

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treatment but less major bleeding (0.128 bleeds/personyear on dabigatran vs. 0.547 bleeds/person-year on acenocoumarol, p = 0.001). Major bleeding was defined as a decline in hemoglobin by 2–5 g/dl or transfusion of 2–4 units of packed red blood cells [29]. A randomized, openlabel study comparing dabigatran and VKA therapy is ongoing in Austria (EudraCT number 2010-024534-38). The trial of patients with mechanical heart valves treated with dabigatran was terminated early due to increased thromboembolic and bleeding complications [30]. Therefore, outside of a clinical trial, LVAD patients should be anticoagulated with VKA therapy. Anticoagulation goals for VKA treatment vary between reported studies, but expert guidelines suggest targeting international normalized ratio (INR) of 2.0–3.0 [25]. Institutional experience and complication rates impact the INR target. Two single institution studies decreased their INR goals to less than 2.0 due to high bleeding rates [31, 32], while another increased the INR goal from 1.5–2.5 to 2.0–2.5 due to thromboembolic events [33]. The clinical trials allow for variation in anticoagulation based on institutional practice, but this variation limits the ability to determine the most effective anticoagulation target. VKA therapy is challenging to manage in LVAD patients. One study found that 54 % of patients on longterm warfarin treatment required a change in warfarin dosing after LVAD placement without additional interacting medications. The median difference in weekly dose was 22 % (range 8–44 %) and most patients (5/7) required a decrease in dose [34]. Inter-individual variation is also noted in long-term management of VKA treatment. LVAD patients only spend 31–51 % of time-in-therapeutic range (TTR), which is significantly less than the general population at anticoagulation clinics [35, 36]. Similar to studies in atrial fibrillation, patient self-testing improves TTR, but it is unknown whether TTR influences clinical outcomes in LVAD patients [36]. Bishop et al. did not note a difference in bleeding or thromboembolic events between the usual care and patient self-testing cohorts despite a 14 % difference in TTR [36]. Another report showed similar mean INR values between patients with and without bleeding, but TTR was not calculated [31]. Thrombotic events are likely multifactorial and control of anticoagulation remains a factor. One study found subtherapeutic INR levels in 31 % of patients prior to a hemolytic event or confirmed thrombosis [33]. LVAD patients require anticoagulation with VKAs but remain a difficult population to manage. Antiplatelet therapy Institutional preference plays a large role in the dose and which antiplatelet medications are used in adult LVAD patients. One institution in France reported managing

LVAD antithrombotic therapy

HeartMate II patients without antiplatelet therapy. Ischemic stroke occurred in 2 of 23 patients (0.059/patient year) and no LVAD thrombotic events were reported [37]. An ongoing cohort study in Europe, to be completed in April 2015, is evaluating the outcomes of HeartMate II patients treated with reduced anticoagulant or antiplatelet regimens (NCT01477528). A majority of trials and institutions report using aspirin 81–325 mg; consensus guidelines also recommend aspirin therapy [25]. A review of the continuous access protocol for the HVAD found a stroke incidence of 0.089/ person-year. The investigators recommended increasing the aspirin dose from 81 to 325 mg, which lead to a 55 % decline in the rate of LVAD exchange for thrombosis and a decrease in stroke incidence to 0.047/person-year [38]. In addition to aspirin, other centers prescribe dipyridamole, an antiplatelet medication that inhibits platelet activation through increased cyclic AMP. In a systematic review of HeartMate II patients treated with aspirin as a single agent or in combination with dipyridamole, a stroke rate of 0.17 events/person-year was reported [39]. The aspirin dosing in the six combined studies varied between 81 and 325 mg and dipyridamole between 75 mg once daily to three times daily [39]. In adults, only one study has reported using laboratory testing to modify antiplatelet therapy. Karimi et al. adjusted antiplatelet treatment for HeartMate II patients to achieve normal maximum amplitude (MA), a measure of clot strength and platelet function, on TEG. The thromboembolic and bleeding events in this series were within ranges reported in the literature, but lack of standardized definitions in the literature limit the comparison [40]. Overall, antiplatelet therapy varies significantly in the literature and comparisons across studies are difficult. Management of children In contrast to adult patients, TEG is used extensively to modify antithrombotic therapy for children with LVADs. Researchers in Edmonton, Alberta, Canada spearheaded development of a pediatric LVAD anticoagulation and platelet inhibition protocol (Table 2) [41]. Similar to adults, protamine is used to reverse the effect of heparin after cardiopulmonary bypass. Unfractionated heparin is started 24–28 h post-operatively and the dose is titrated to an antiXa level is 0.35–0.5 units/ml. Antithrombin is supplemented using antithrombin concentrate or plasma if antithrombin activity is\70 %. TEG is obtained during surgery, immediately in the post-operative period, and then at least every 24 h. The anti-Xa target is adjusted to maintain a TEG Kaolin R-time between 8 and 15 min. At 48 h, dipyridamole is started at 4 mg/kg/day if the patient is stable and meets appropriate laboratory parameters (Table 2). Once the chest tubes have been removed, aspirin is given if the MA remains [72 mm, G [ 8, and arachidonic acid inhibition is\70 %.

In contrast to adults, aspirin is given twice daily in children (1 mg/kg/day in divided doses). Once stable, anticoagulation is switched from unfractionated heparin to enoxaparin (1.5 mg/kg every 12 h if B3 months old, 1 mg/kg every 12 h if [3 months) with a goal anti-Xa level of 0.6–1.0 units/ml. In children over a year old, oral anticoagulation with VKA is used long term. Children are started on VKA at 0.2 mg/kg/day and the dose is adjusted to maintain an INR of 2.7–3.5 [41]. TTR reported from studies of children range from 71 to 82 %, but have limited number of LVAD patients included [42].

Management of LVAD complications Hemorrhage The need to withhold or reverse anticoagulation in LVAD patients depends on the location and severity of hemorrhage. Treatment of LVAD patients with vitamin K due to bleeding has not been associated with an increased risk of thrombotic events [43]. A four-factor prothrombin complex concentrate (KCentraÒ, CSL Behring Gmbh, Marburg, Germany) is FDA approved to reverse the anticoagulant effect of VKA treatment and normalizes the INR faster than plasma transfusion [44]. Red blood cell transfusion should be considered in patients with anemia due to hemorrhage, but weighed against the risk of alloimmunization in heart transplant candidates. For significant GI bleeding, endoscopic evaluation and management is recommended to assist with local control of hemorrhage [45]. In patients refractory to endoscopy treatment, octreotide can be considered; a case series of seven LVAD patients with chronic GI bleeding suggested a trend towards decreased hospital admissions and transfusions using octreotide therapy [46]. Other treatment options for refractory GI bleeding include surgical management, change in LVAD speed, von Willebrand concentrate administration or upgrading the transplant status [19, 45]. Anticoagulation and antiplatelet therapy should be restarted when the patient has stabilized to balance risk of re-bleeding and LVAD function. A retrospective review of patients with intracerebral hemorrhages reported no thromboembolic complications after restarting warfarin after a median of 10.5 days and aspirin after 6 days. The report did not mention when unfractionated heparin therapy was initiated, however [47]. Overall, a multimodal approach is required to manage hemorrhage in LVAD patients. Thrombosis LVAD thrombosis can cause stroke, systemic embolism, or LVAD failure. LVAD thrombosis is diagnosed through a combination of laboratory markers of hemolysis and

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L. M. Baumann Kreuziger Table 2 Summary of Edmonton Anticoagulation and Platelet Inhibition Protocol for management of children with the Berlin Heart EXCORÒ pediatric VAD [41] Medication

Initiation parameters

Goal

Antithrombin concentrate or plasma

Antithrombin activity \70 %

Antithrombin activity [70 %

Protamine

Completion of cardiopulmonary bypass

Complete heparin reversal (institution dependant parameters)

24 h post-implantation, platelets [20,000/ll, normal TEG Platelet MappingTM, TEG MA [46 mm and G [ 6

Anti-Xa 0.35–0.5 units/ml, TEG R 8.0–15.0

48 h post-implantation, platelets [40,000/ll, TEG MAKH [ 56 mm

ADP G 6–10

4 days post-implantation, TEG MAKH [ 72 mm, G [ 8

ADP G 6–10

Enoxaparin

Age \ 1 year, [48 h post-implantation, normal creatinine

Anti-Xa 0.6–1.0 units/ml

Warfain

Age C 1 year, full oral diet

INR 2.7–3.5

Perioperative

Postoperative Unfractionated heparin

Antiplatelet Dipyridamole

Aspirin

Platelet MappingTM AA inhibition [70 % Platelet MappingTM AA inhibition [70 %

Long-term anticoagulant

Ò

TEG (Haemoscope Corporation, Niles, IL) MA maximum amplitude, MAKH maximum amplitude Kaolin Heparinase, INR international normalized ratio, AA arachidonic acid inhibition, ADP adenosine diphosphate

changes in LVAD flow or power. Expert guidance has been published on diagnosis and management of suspected LVAD thrombosis [48]. Surgical correction is required for malposition or obstruction of the inflow cannula or outflow graft. Additionally, LVAD exchange should be considered in patients with a lactate dehydrogenase level [1000, as medical therapy alone is associated with a 50 % mortality in this population [49]. Surgical exchange can lead to additional exposure to blood products and downgrading on the transplant list while the patient recovers. Options for medical therapy of LVAD thrombosis range from thrombolysis to use of IV anticoagulants (i.e. unfractionated heparin or direct thrombin inhibitors) or IV antiplatelet therapy (i.e. eptifibatide). Case reports and series note limited efficacy of thrombolysis, direct thrombin inhibitor, and eptifibatide treatment with major bleeding event rates up to 50 % [50]. Additional study is needed to understand the mechanism and most appropriate therapy for LVAD thrombosis.

Many questions about the pathophysiology of GI bleeding and initiation of thrombosis remain. Antithrombotic therapy is required to prevent stroke and LVAD thrombosis. LVAD patients have more variability in VKA management than other patient populations which likely increases their risk of thrombosis and hemorrhage. Children with LVADs are typically managed using the Edmonton Anticoagulation and Platelet Inhibition Protocol, whereas anticoagulation and antiplatelet therapies in adults are based on institutional preference that varies widely. Prospective, controlled studies are needed to determine the antithrombotic regimen that most effectively balances bleeding and thrombosis in LVAD patients. Acknowledgments I would like to thank Rachel Bercovitz for editorial assistance. Conflict of interest interest.

The author declares that she has no conflict of

References Conclusions Development of LVADs has quadrupled the survival of patients with heart failure, yet LVAD implantation is associated with bleeding and thrombotic complications.

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Management of anticoagulation and antiplatelet therapy in patients with left ventricular assist devices.

Left ventricular assist devices (LVADs) have increased the survival of patients with advanced heart failure fourfold. Despite these advances, signific...
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