REVIEWS
OF
THERAPEUTICS
Thrombosis in Continuous-Flow Left Ventricular Assist Devices: Pathophysiology, Prevention, and Pharmacologic Management Douglas L. Jennings,1,2,* and Phillip A. Weeks3 1
Nova Southeastern University, Ft. Lauderdale, Florida; 2Jackson Memorial Hospital/Miami Transplant Institute, Miami, Florida; 3Memorial Hermann – Texas Medical Center, Houston, Texas
Continuous-flow left ventricular assist devices reduce short-term mortality and improve quality of life in patients with end-stage heart failure. Unfortunately, device-related complications remain common, with many patients experiencing adverse events within the first year. New literature suggests that rates of device-related thrombosis may be increasing since 2011, which is particularly troublesome given that this pathology can result in a disabling stroke, organ damage, and death. In 2013, a group of practitioners in the field of mechanical circulatory support published a treatment algorithm based on their expert opinion. However, a comprehensive review of the pharmacotherapy of this condition is lacking. A search of the literature revealed 20 separate publications of case reports or case series describing outcomes associated with the use of drug therapy for suspected pump thrombosis. Each of these experiences was limited by small sample size, nonrandomized treatment allocation, and nonstandardized medication dosing. Data describing the outcomes of surgical versus medical management of device thrombosis are also sparse, with only three published reports identified. Based on the review of this limited literature, surgical management appears to be the preferred treatment modality, especially in those with organ hypoperfusion or hemodynamic instability. In patients ineligible for surgery, pharmacotherapy options remain limited. Use of all drug classes described in the literature for the HeartMate II device—fibrinolytics, glycoprotein IIb/IIIa inhibitors, and direct thrombin inhibitors—was hindered by either marginal efficacy or bleeding. Based on historical experience with unfractionated heparin in patients under HeartMate II support, we recommend this agent as a possible option for those with suspected pump thrombosis in lieu of surgical device exchange. For the HeartWare HVAD, limited data suggest that direct intraventricular administration of alteplase may be an acceptable treatment alternative. Additional research is clearly needed to further delineate the role of pharmacotherapy and to identify the optimal agent for managing this potentially life-threatening condition. KEY WORDS thrombosis, left ventricular assist device, thrombolytic, glycoprotein IIb/IIIa inhibitor, direct thrombin inhibitor. (Pharmacotherapy 2015;35(1):79–98) doi: 10.1002/phar.1501
Even with optimal medical therapy, the 1-year mortality rate associated with end-stage heart failure remains greater than 60%.1 Although car*Address for correspondence: Douglas L. Jennings, Nova Southeastern University, Department of Pharmacy Practice, Health Professions Division, 3200 S. University Drive, Ft. Lauderdale, FL 33328; e-mail: [email protected]. Ó 2014 Pharmacotherapy Publications, Inc.
diac transplantation remains the definitive surgical treatment for these patients, fewer than 2500 transplantations are performed in the United States each year.1 Second-generation continuousflow left ventricular assist devices (CF-LVADs) such as the HeartMate II (Thoratec Corp., Pleasanton, CA) and third-generation devices such as the HeartWare HVAD (HeartWare International, Inc., Framingham, MA) currently boast 1-year
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survival rates as high as 90%.2 Both devices are now approved for patients waiting for transplantation (bridge-to-transplantation therapy), and the HeartMate II is approved for those who are ineligible for transplantation (destination therapy). To date, more than 6000 mechanical circulatory support (MCS) pumps have been implanted in patients in the United States alone.2 Given the growing population of patients with heart failure, use of this technology should continue to exponentially increase. Although the reductions in morbidity and mortality are substantial, complications related to device therapy are common, and up to 70% of patients using CF-LVADs will experience a major adverse event during the first year of support.2 Reports from the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) registry initially suggested that the majority of these adverse events were related to infections (8.01 events/100 patient-months) or bleeding complications (9.45 events/100 patientmonths), whereas device-related thrombosis was relatively infrequent (1.66 events/100 patientmonths).2 However, a recently published study suggests that the risk of device-related thrombosis has increased.3 Unfortunately, the exact mechanism for this pathology is multifaceted and remains poorly understood.4 Furthermore, the optimal strategy for managing device-related thrombosis, including the role of pharmacotherapy, has yet to be delineated. In this review, we describe the pathophysiology of device-related thrombosis with the HeartMate II and the HeartWare HVAD and summarize the available evidence related to management of this potentially life-threatening condition with these two devices. Pathophysiology and Preventive Strategies Many variables can contribute to devicerelated thrombosis. Mechanical factors, such as implantation techniques, anatomical derangements (kinking or bending of the inflow or outflow graft), and device settings (reduction in speed) can reduce flow.5 As adequate flow is required to lubricate and cool the device, any anatomical distortions that generate excessive heat could lead to subsequent deposition of fibrin, narrowing of the blood flow pathway, and, ultimately, thrombosis. Although the mechanism for this relationship between heat and thrombosis remains unclear, supporting evidence comes from collective observations in explanted
HeartMate II devices that demonstrated a deposition of material (fibrin and denatured protein) in proximity to the inflow bearing (which is prone to excessive heat during periods of low or turbulent blood flow).3 Updates to the pump itself, particularly the blood-contacting surfaces, can also influence thrombotic risk, as evidenced by early redesigns of the HeartMate II device. Initial versions of this device were prone to thrombus at the inlet and outlet stators, which had relatively narrow channels with high velocities and blood flow disturbances.6 Both of these stators were initially textured, and engineers found that by making them smooth, turbulent blood flow could be reduced, thus improving hemocompatability.6 Finally, patient-specific factors, such as preexisting hypercoagulable conditions, atrial fibrillation, active infection, and uncontrolled hypertension can also increase the possibility of thrombosis.3, 4 Ultimately, the focal point of CFLVAD–related thrombosis is biocompatibility, which includes the interaction of the device with both the coagulation cascade as well as platelet activation. Role of the Coagulation Cascade and Anticoagulation Intensity: HeartMate II Device The hemobiologic relationship between the human body and the first-generation pulsatile LVADs was relatively well understood, and longterm anticoagulation therapy was not required to prevent thrombosis. The HeartMate XVE device, for example, had a unique blood-pumping surface consisting of titanium microspheres and a fibrillar textured inner surface, which promoted the formation of a “pseudointima” that resisted thrombogenesis. On the other hand, the HeartMate II can produce sustained elevations in markers of thrombin generation (thrombin/antithrombin and prothrombin fragments 1,2), as well as demonstrated indicators of endothelial dysfunction (intercellular adhesion molecule, E-selectin, tissue factor).7 This suggests that mechanical support with this device is associated with activation of the extrinsic (tissue factor) pathway of thrombosis and sustained endothelial dysfunction. Additionally, patients under device support display elevations in serum fibrinogen concentrations.8 The coexistence of these two physiologic derangements is particularly problematic, as the combination of excessive thrombin generation and hyperfibrinogenemia can increase the risk of forming faster growing,
PHARMACOTHERAPY OF LEFT VENTRICULAR ASSIST DEVICE THROMBOSIS Jennings and Weeks 81 stronger clots that dissolve more slowly than clots formed with normal concentrations of fibrinogen. Adding to this global state of hypercoagulability, it appears that continuous activation of the contact protein pathway of coagulation may exist at the blood/biomaterial interface, as evidenced by increased concentrations of factor XII and high-molecular-weight kininogen that absorb to the surface of the device.9, 10 The impact of these alterations in both systemic and regional coagulation cascades has been assessed with thromboelastographic assays, which suggest that contact pathway protein-activated coagulation results in a thrombus that develops strength at a significantly faster rate than normal tissue factor-initiated coagulation.11 In addition to having a significantly greater velocity of clot growth compared to tissue factor-initiated coagulation, contact protein-initiated coagulation has been demonstrated to prolong the lifespan of plasma thrombi by more efficient activation of thrombin-activatable fibrinolysis inhibitor and factor XIII (Figure 1).11 Due to the risk of thrombosis seen with the original European experience with the HeartMate II, initial antithrombotic regimens for this
Figure 1. Comparison of tissue factor- and contact proteinmediated activation of coagulation. Although tissue factorinitiated coagulation (black areas) begins more quickly than contact protein activation (factor XII activator, areas with gray hatched lines), contact protein-initiated clot strength increases at a significantly greater velocity. Contact protein activation also prolongs clot life span compared with tissue factor-mediated coagulation. All samples were exposed to tissue plasminogen activator 100 U/ml. Observation time was 1200 sec. Tissue factoractivated coagulation resulted in a clot that began to disintegrate sooner than contact protein-activated plasma coagulation. (Reproduced with permission from reference 11.)
device were aggressive.12 Low-molecular-weight dextran was started early after implantation, usually on postoperative day 3. Intravenous anticoagulation with heparin was then started, followed by warfarin targeted to an international normalized ratio (INR) of 2.5–3.5. However, subsequent analyses suggested that perhaps the risk of the thrombosis was lower than initially perceived. In a study published in 2009, a cohort of 331 patients under HeartMate II support reported only 10 thrombotic events during the first 6 months of device support (compared with 58 bleeding episodes).13 In this population, the risk of thrombotic events was highest when the INR was less than 1.5, whereas the majority of bleeding episodes occurred with an INR greater than 2.5. Based on these data, some centers lowered their target INR range to 1.5–2.5 near the end of 2010 in order to minimize bleeding complications.14 Although the 2009 study was provocative and influenced practice at the time of its publication, the applicability of these findings in the modern era of MCS has been nullified by recent findings.3 In late 2013, alarming data was published suggesting an abrupt increase in the risk of device-related thrombosis in 837 HeartMate II recipients from three different health care systems.3 The results showed that starting in approximately March 2011, the occurrence of confirmed pump thrombosis at 3 months after implantation increased from 2.2% to 8.4% by January 1, 2013. Although the authors cite the aforementioned reduction in anticoagulation intensity as a possible precipitating factor for this increase in risk, they do not provide specific INR values for their cohort at the time of thrombosis, which makes interpretation of their results difficult. Adding further uncertainty to their results is the introduction of sealed vascular grafts in the inflow and outflow conduits of the Heartmate II in early 2011. The purpose of these gelatin-impregnated polyester grafts was to eliminate the need for preclotting prior to implantation, remove the variability in preclotting methods, and reduce postoperative bleeding. However, any change to the blood-contacting surface of the device could potentially alter thrombogenicity, as suggested by the temporal correlation between the rise in thrombosis rates with the deployment of the new grafts. In an analysis published only in abstract form in April 2014, Thoratec presented the thrombosis rates of 2881 pumps implanted in 2011: 1905 with sealed grafts and 976 with unsealed grafts.15 In
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the first 6 months after implantation, there were 120 (6.3%) reports of suspected pump thrombus in 1905 patients with sealed grafts compared with 57 (5.8%) in 976 patients with unsealed grafts (p=NR). Although these data suggest that other factors (e.g., anticoagulation) may be to blame for the increased thrombotic risk reported,3 a final verdict on the impact of the new grafts cannot be reached until the full study is published in a peer-reviewed journal. Additional data supporting these findings3 come from a larger analysis of more than 6,900 patients using the HeartMate II device in the INTERMACS registry, which found that freedom from device exchange or death due to thrombosis had decreased from 99% at 6 months in 2009 to 94% in 2012 (p 3 9 upper limit of normal (usually an abrupt rise) • Low hemoglobin, low hematocrit • High plasma free hemoglobin level (> 40 mg/dl) • Hemoglobinuria, jaundice • Increase in LVEDD • New or worsened mitral valve regurgitation • Frequent opening of the aortic valve • Elevations in power, either persistent or as isolated spikes • Calculated flow increased
LDH = lactate dehydrogenase; LVEDD = left ventricular end-diastolic diameter.
device exchange or urgent heart transplantation represent the most definitive treatment modalities. However, cardiothoracic surgery is not without risks, including the potential for death, stroke, renal failure, and bleeding. The latter complication is particularly troubling in patients on device support for bridge-to-transplantation, as additional exposure to blood products may increase the risk of allosensitization and decreased transplant eligibility. Furthermore, surgery for device exchange may result in temporary downgrading of active listing (status 7) in the United Network for Organ Sharing (UNOS) system (Table 2) while the patient recovers, which means the loss of a potential donor heart that may become available during that time. Finally, an additional surgery for pump exchange will result in formation of scar tissue and adhesions, which will increase the duration and risk of bleeding during subsequent surgery for heart transplantation. In an effort to avoid the complications associated with an emergent repeat cardiac surgery, clinicians managing patients under support with the early CF-LVADs began to explore pharmacotherapy to treat suspected pump thrombosis. One of the earliest published reports described the use of intravenous alteplase 100 mg in eight patients under support with the MicroMed DeBakey (MicroMed Technology, Houston, TX).30 In this series, all 8 patients responded clinically
to therapy and were discharged from the intensive care unit. Only 4 patients experienced bleeding complications (transient epistaxis). In another series, two patients under support from the Jarvik 2000 Flomaker (Jarvik Heart, Inc., New York, NY) with sustained power elevations and suspected thrombosis both responded well to intraventricular alteplase.31 The regimen devised by these authors involved inserting a catheter into the left ventricle through the femoral artery (under standard fluoroscopy) and instilling 1 mg/minute of alteplase until the pump power settings returned to normal. Although these reports established some credence to the potential role of pharmacotherapy in managing device-related thrombosis, they are significantly limited by their small sample sizes, the potential for publication bias, and the use of older devices that are not currently used. At present, the ideal strategy for treating thrombosis in contemporary devices has yet to be defined. A group of practitioners in the field of mechanical circulatory support have published a suggested algorithm based on expert opinion.32 In general, they advocate that patients be admitted to the intensive care unit, and intravenous heparin can be considered if the INR is subtherapeutic. Intravenous inotrope and diuretic therapy can also be used if indicated based on the patient’s hemodynamic presentation. However, agents like glycoprotein IIb/IIIa inhibi-
PHARMACOTHERAPY OF LEFT VENTRICULAR ASSIST DEVICE THROMBOSIS Jennings and Weeks 85 Table 2. United Network for Organ Sharing Stages of Listing for Cardiac Transplantation Listing Stage 1A
Criteria a
b c d
1B 2 7
e aa bb
Location
*
Outpatient or inpatient
Mechanical circulatory support
Total artificial heart Intra-aortic balloon pump Extracorporeal membranous oxygenator Mechanical circulatory support with evidence of device malfunction such as thromboembolism, infection, mechanical failure, or arrhythmias Continuous mechanical ventilation Continuous infusion of a single high-dose intravenous inotrope (e.g., milrinone ≥ 0.5 lg/kg/minute, dobutamine ≥ 7.5 lg/kg/minute) or a combination of agents at any dose in addition to continuous hemodynamic monitoring with a pulmonary artery catheter By exception, granted by more than 50% of the members of the regional review board Mechanical circulatory support that does not qualify for 1Aa or 1Ab status Continuous-infusion inotropes Approved candidate in need of a cardiac transplant who does not meet any 1A or 1B criteria Candidates temporarily unsuitable to receive a transplant due to comorbidity (active infection), recent surgery, social issues (loss of insurance), etc.
Inpatient Outpatient or inpatient Inpatient Inpatient
Inpatient Outpatient Outpatient Outpatient or inpatient
*Stable patients on mechanical circulatory support (i.e., HeartMate II) are limited to 30 days of 1A time, which can be used anytime (e.g., 15 days in month 2 and another 15 days in month 6 of device support).
tors and fibrinolytics are either not discussed or relegated to last-line therapy for nonsurgical candidates. Therefore, further discussion of the evidence reporting the use of these treatment modalities is clearly warranted. Role of Pharmacotherapy in the HeartMate II Device Glycoprotein IIb/IIIa Inhibitors Published reports have described attempted therapy with glycoprotein IIb/IIIa inhibitors, fibrinolytics, and direct thrombin inhibitors in patients with suspected HeartMate II thrombosis (Table 3). The first published report of use of a glycoprotein IIb/IIIa inhibitor was in 2008 and described the use of eptifibatide in a patient with hemolysis and altered device parameters (labile flows and power elevations).33 Intravenous heparin was also started, and, unfortunately, the patient developed heparin-induced thrombocytopenia that required treatment with argatroban. Due to this confounding adverse drug reaction to the heparin, the effect of the eptifibatide could not be assessed. In 2012, the first successful use of eptifibatide was detailed in a pair of published case series describing three patients who presented with hemolysis and power elevations.34, 35 Finally, in 2013, there was a series of two patients who were successfully treated with intraventricular fibrinolytic therapy after failing eptifibatide.36 Additional
details regarding these patients will be discussed in the fibrinolytic therapy section. A larger series of four patients who received eptifibatide was published in early 2014 and, in contrast to previous reports, reported a 75% failure rate (including one death and two device exchanges).37 The largest case series to date was also published in 2014 and included 17 patients using the HeartMate II device who received 22 treatment attempts with eptifibatide for suspected pump thrombosis.38 At this institution, all patients received early intravenous heparin (on postoperative days 1–2) and warfarin with an INR target of 2–3. In this cohort, only three patients responded to eptifibatide therapy; all three were treated during the index hospitalization, with the time from implantation to eptifibatide administration ranging from 6 to 14 days. Combining all of the published case reports and case series yields a cohort of 27 patients who received eptifibatide as attempted therapy for device-related thrombosis in the HeartMate II device. Only seven (26%) of these patients displayed clinical features consistent with treatment success, whereas eight patients died and 13 developed bleeding complications. Given these unfavorable results, along with the small sample size and the inherent limitations of case reports (e.g., publication bias), we cannot advocate for the use of glycoprotein IIb/IIIa inhibitors as a pharmacologic modality for patients with suspected thrombosis of the HeartMate II device.
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Fibrinolytic Agents Based on the preliminary success reported with older devices, fibrinolytic therapy has also been attempted in patients under HeartMate II support. The first published report in 2011 describes the successful use of fibrinolytic therapy in a patient with suspected device thrombosis; however, as the focus of the article was on the utility of echocardiography in this clinical setting, specifics regarding the drug and dosage were not provided.39 A subsequent case published in 2013 details a patient admitted with evidence of thrombosis who was unsuccessfully treated with several doses of both intraventricular and intravenous alteplase.40 Also published in 2013, two patients were described who responded to a fibrinolytic after initially failing therapy with intravenous heparin and eptifibatide.36 Survey of the published literature regarding the use of fibrinolytic therapy in the HeartMate II population reveals an extremely limited data set. Only four reported cases have been published, one of which did not include any details about the fibrinolytic agent or dosing regimen. Of the remaining three cases, two reported success with an extended infusion of intraventricular alteplase, whereas one reported clinical failure with a combination of intraventricular and systemic administration. Directly instilling a fibrinolytic agent into the left ventricle requires significant technical expertise in order to avoid potential complications such as local bleeding from the arterial access site or dislodgement of the catheter into the LVAD inflow cannula. Whether direct intraventricular administration of the fibrinolytic mitigates any of the systemic bleeding risk associated with this therapy also remains unknown. Finally, in the event of failure of fibrinolytic therapy, requiring surgery for device exchange, the preoperative drug exposure may result in an increased intraoperative blood loss. In light of these limitations, along with the extremely limited amount of published data, we cannot recommend fibrinolytic therapy for patients with suspected HeartMate II thrombosis. Direct Thrombin Inhibitors In the recently published treatment algorithm for suspected device thrombosis, direct thrombin inhibitors were suggested as an alternative method of anticoagulation.32 Theoretical advantages exist with these agents, particularly argatroban, which is able to effectively inhibit
platelet aggregation and thromboxane generation in the presence of both free and clot-bound thrombin at serum concentrations far less than either heparin or hirudin.41 On the other hand, data from an in vitro thromboelastography study demonstrated that although direct thrombin inhibitors were able to slow thrombin generation, they were inferior to heparin in attenuating clot propagation and strength.42 Unfortunately, in vivo data in CF-LVAD patients with this class of drugs is quite limited. In 2008, a report43 was made of a patient using the HeartMate II device who initially responded to intravenous hirudin; however, this patient’s symptoms returned 3 months after treatment, and he eventually underwent device exchange. A recently published cohort study describes four patients under HeartMate II support with suspected thrombosis who were treated with argatroban therapy.44 Although three patients had resolution of hemolysis, one patient failed therapy and required emergent heart transplantation, and two patients developed bleeding complications. Given the limited response seen in this series, along with significant costs of these agents, additional studies are warranted before direct thrombin inhibitors can be endorsed for use in patients with suspected thrombosis of the HeartMate II. Role of Pharmacotherapy in the HeartWare HVAD While the HeartWare HVAD has been available for use in the United States for a much shorter period of time than the HeartMate II, nearly the same amount of published experiences describing pharmacotherapeutic strategies to manage device thrombosis exists. To date, the available evidence related to management of HeartWare device thrombosis is in the form of case series and case reports (Table 4). The largest experience is taken from the retrospective report of the thrombosis cases encountered in the ADVANCE trial.25 Because the trial protocol did not specify a mandatory management strategy, participants were permitted to manage suspected thrombosis according to their clinical judgment and center-specific practice standards. Of the 34 thrombosis events seen in 30 patients, 4 (11.8%) underwent urgent pump exchange and 30 (88.2%) were initially managed medically. Initial medication therapy ranged from initiation of intravenous heparin to mono-, dual-, and triple- therapy strategies of fibrinolytics,
No. of Patients Drug
2
1
2
Tufts Medical Center (Boston, MA)34
Henry Ford Hospital (Detroit, MI)35
University of Chicago (Chicago, IL)36
Eptifibatide
Eptifibatide
Eptifibatide
Glycoprotein IIb/IIIa Receptor Antagonists Ohio State 1 Eptifibatide University (Columbus, OH)33
Study Center
Not provided
1 lg/kg/min
Patient 2: 180mcg bolus, then 2 lg/kg/ min
Patient 1: 180-lg bolus, then 1 lg/kg/min
2 lg/kg/min
Dosage
Persistent hemolysis, power spikes, and echocardiographic evidence of thrombosis
Resolved hemolysis, power elevations, and acute kidney injury
Resolved hemolysis and power elevations in both patients
Persistent hemolysis and power elevations
Efficacy Outcomes
Table 3. Pharmacotherapy Experience with the HeartMate II Device
None
None
Patient 1: bleeding peptic ulcer treated with epinephrine injection therapy and clip placement Patient 2: bleeding Dieulafoy lesion treated successfully with clip placement
Not reported
Bleeding Outcomes
Transitioned to fibrinolytic therapy (described below)
Patient 2: confirmed laminar thrombosis by CT scan in both the inflow and outflow cannulas; successfully transplanted 65 days later, with no evidence of thrombosis at that time Alive on support
Patient 1: alive on support
Diagnosed with HIT, successfully treated with argatroban
Additional Findings
(continued)
This case adds to reports suggesting that intravenous glycoprotein IIb/IIIa receptor antagonists may be viable options for managing device thromboses that fail to respond to systemic anticoagulation. No comment was provided regarding eptifibatide therapy (comments regarding fibrinolytic therapy are provided below).
Although glycoprotein IIb/IIIa inhibitors may be useful for acute LVAD thrombosis, their use must be monitored closely, as thrombocytopenia and worsening thrombosis may complicate management. Despite the successful outcomes, the role of eptifibatide in the treatment of LVAD thrombosis remains unclear, particularly in light of the associated bleeding risks.
Conclusions
PHARMACOTHERAPY OF LEFT VENTRICULAR ASSIST DEVICE THROMBOSIS Jennings and Weeks 87
1
17 (22 attempts)
Barnes-Jewish Hospital (St. Louis, MO)38
Fibrinolytic Agents Cardiovascular Center RheinRuhr (Essen, Germany)39
4
No. of Patients
Yale School of Medicine (New Haven, CT)37
Study Center
Table 3. (continued)
“Thrombolytic” (drug not specified)
Eptifibatide
Eptifibatide
Drug
Resolution of heart failure symptoms and echocardiographic findings
Three patients had resolution of at least one major indicator* and remained free from continued hemolysis, death, pump exchange, or emergent transplantation
0.1–2 lg/kg/min for a mean duration of 2.64 days (range 0.38– 6.02 days)
Not reported
None
Patient 1: resolved hemolysis Patients 2–4: persistent power elevations, hemolysis, and heart failure symptoms
180-lg bolus, then 1 lg/kg/ min
None
4 patients: hemorrhagic strokes 1 patient: melena 1 patient: nose bleed 1 patient: hematuria requiring urology consultation and intervention
5 patients: gastrointestinal bleeds confirmed by EGD
Bleeding Outcomes
Efficacy Outcomes
Dosage
None
7 patients died: hemorrhagic stroke (2), cardiorespiratory failure (1), VAD malfunction (2), cardiac arrhythmia (1), multisystem organ failure (1) 3 patients underwent pump exchange (presence of thrombosis not reported)
Patient 1: transplant, no thrombus found Patient 2: died (CVA) Patients 3 and 4: device exchange, thrombus found
Additional Findings
(continued)
The measurement of the flow velocity with pulsed wave and continuous-wave Doppler during echocardiography can provide important information about device function and should be performed in every patient with a VAD.
This report suggests that the role for eptifibatide treatment of pump thrombosis may be limited, and, in contrast to a prior report, documents a high failure rate for this therapy, requiring either more aggressive medical therapy (fibrinolysis) or device exchange (as instituted in our experience). Although the overall patient sample size was small, based on this experience, the risk of using eptifibatide to treat suspected LVAD pump thrombosis outweighs the potential benefits of salvaging the existing LVAD in candidates for pump exchange. On the basis of a high occurrence of bleeding events and low rates of clinical resolution at this institution, the use of eptifibatide in the setting of suspected pump thrombosis would not be encouraged
Conclusions
88 PHARMACOTHERAPY Volume 35, Number 1, 2015
1
Tufts Medical Center (Boston, MA)47
Alteplase
Tenecteplase
2
Heart and Diabetes Center North Rhine-Westphalia (Bad Oeynhausen, Germany)46
1
Alteplase or tenecteplase (1 patient also received tirofiban) Tirofiban
Eptifibatide (alone or with heparin)
6 thrombosis events
Drug
Alteplase (eptifibatide, heparin, or both were used in combination in many cases; 8 patients received all 3 agents)
19 thrombosis events
No. of Patients
4
St. Vincent’s Hospital (Sydney, Australia)45
Multicenter (ADVANCE BTT and CAP trial)25
Study Center
1 mg/min intraventricularly for 37 min
10,000 units (50 mg) i.v.
Alteplase 10-50 mg i.v. or tenecteplase 12.525 mg i.v. Not specified
Not specified
15-100 mg
Dosage
Table 4. Pharmacotherapy Experience with the HeartWare HVAD Efficacy Outcomes
Successful, with reductions in left ventricular pressure and cardiac index with improvement in flow reading
Patient 1: unsuccessful, also had significant bleeding event Patient 2: successful (definition not provided)
3/4 patients successfully treated with resolved power elevations and flow reading improvement Successful resolution of power elevations and flow reading improvement
2/4 patients: successful route unknown 3/6 patients: successfully treated
4/7 patients: successfully administered intraventricularly
6/8 patients: successfully administered intravenously
Bleeding Outcomes
None
Patient 1: severe drive-line bleeding requiring surgical repair Patient 2: none
Massive hemothorax requiring surgical drainage; subsequent recurrent epistaxis
Patient 1: recurrent epistaxis Patients 2–4: none
2 patients: hemorrhagic CVAs (1 received tPA, glycoprotein IIb/IIIa inhibitor, and heparin) 2 patients: gastrointestinal bleeds 1 patient: AICD pocket bleed (treatment groups not specified for bleeding outcomes)
Additional Findings
Thrombolysis performed with left ventricular pressure monitoring; fibrinolytic stopped once pressures improved
Patient 2 was treated with fibrinolytic in second episode of pump thrombosis; initial episode was treated with pump exchange
Two patients receiving fibrinolytic therapy died within 48 hours of administration, with multiorgan failure and urosepsis as the attributable causes
5 of the 30 patients managed with drug therapy died (4 after subsequent attempts at device exchange) 3 patients had recurrence of thrombus after medical management
Conclusions
(continued)
Patients were successfully managed medically in 50% of pump thrombus cases with good outcomes. Significant risk factors for pump thrombosis include suboptimal anticoagulation and antiplatelet therapy as well as elevated blood pressure. This suggests that pump thrombus event rates could be reduced through careful adherence to patient management guidelines. Clinically significant pump thrombosis occurs in centrifugal CF-LVADs but can usually be successfully managed with intravenous therapy. Interruption of anticoagulation, inadequate antiplatelet therapy, and sepsis need to be considered as potential underlying etiology in suspected thrombosis. Pump exchange can be avoided with repetitive thrombolysis in some patients. Pump exchange is an effective treatment for HeartWare VAD thrombosis. The associated risk is acceptable. Off-pump surgery may reduce the risks observed with reoperative surgery. Bleeding is a risk of thrombolytic therapy, including intracranial hemorrhage. A potential advantage of intracavitary thrombolysis may be the reduced dose of drug required because of direct application to the LVAD inflow cannula.
PHARMACOTHERAPY OF LEFT VENTRICULAR ASSIST DEVICE THROMBOSIS Jennings and Weeks 93
No. of Patients
4
Argatroban
Hirudin
Drug
Not provided
Not provided
Dosage
Patient 1: persistent hemolysis
Patients 2–4: resolved hemolysis
Resolution in power elevations and hemolysis
Efficacy Outcomes
Patient 2: developed subdural hematoma after fall Patient 4: hemorrhagic pericardial effusion
None
Bleeding Outcomes
Patient 1: transplant, with thrombus found Patients 2–4: alive on device support
Symptoms returned 3 months later and patient underwent subsequent transplant with thrombus found
Additional Findings
A large preoperative LV thrombus formation seems to be a risk factor for delayed pump thrombosis. In this case, it is likely that a secondary thrombus formed after cessation of the thrombolytic therapy. Another possibility is that hirudin did not effectively dissolve the primary thrombus. This is the first series showing the use of argatroban to treat hemolysis from suspected device thrombosis in patients with HeartMate II continuous-flow LVADs. The limitations are acknowledged, and further investigation on use of direct thrombin inhibitors with a larger patient dataset and randomized controlled trials will be needed to justify this approach.
Conclusions
HIT = heparin-induced thrombocytopenia; LVAD = left ventricular assist device; CT = computed tomography; CVA = cerebrovascular accident; EGD = esophagogastroduodenoscopy. *Five indicators were assessed, including LDH greater than 2.5 times normal or baseline values, haptoglobin < 10 mg/dl, PFHgb > 40 mg/dl, LVAD dysfunction as evidenced by alarm or echocardiography (ECHO) findings or new persistent high pump powers.
Jackson Memorial Hospital (Miami, FL)44
Direct Thrombin Inhibitors Hannover 1 Medical School (Hannover, Germany)43
Study Center
Table 3. (continued)
90 PHARMACOTHERAPY Volume 35, Number 1, 2015
PHARMACOTHERAPY OF LEFT VENTRICULAR ASSIST DEVICE THROMBOSIS Jennings and Weeks 91 glycoprotein IIb/IIIa inhibitors, and heparin. Medical therapy failed in 15 patients, of whom 12 required pump exchange, 2 went on to emergent transplantation, and 1 died. Outcomes related to specific dual therapy (fibrinolytic + heparin or eptifibatide) regimens are presented in Table 4. Of note, all of the five patients who received heparin monotherapy failed treatment and required either device exchange or transplantation. Results of combination therapy with alteplase, eptifibatide, and heparin were also not promising, as four of the eight patients who received triple therapy failed and required device exchange, whereas one patient died after developing a hemorrhagic cerebrovascular accident. Aside from the experience published from the ADVANCE trial, several single centers have offered their experiences in the form of smaller case series and isolated case reports. The next largest published experience includes five pump thrombosis cases, four of which were managed with peripherally administered fibrinolytics.45 Three of the four patients required repeat administration of fibrinolytics. Two of the four patients survived, but device parameters improved in all four patients. Both patients who died had active infections, and neither death was attributed to pump thrombosis or bleeding. Another case series included six patients, two of whom had been treated with tenecteplase 10,000 units (50 mg) given peripherally as an intravenous bolus dose.46 One of the patients had already undergone pump exchange for a previous episode of device thrombosis, and the treatment with the fibrinolytic was for the recurrent episode of pump thrombosis due to poor compliance and discontinuation of anticoagulation. This patient was treated successfully and without complications. The second patient was managed with fibrinolytic therapy as an initial strategy and was determined by authors to have failed (no details of failure reported) and experienced severe bleeding. Both patients in this series were simultaneously administered heparin to maintain an activated partial thromboplastin time of 50–60 seconds. Four very similar case reports were published that all used similar strategies of intraventricular alteplase administration. All were successful, with similar dosing regimens of 1 mg/minute for varying times (20–37 min) until thrombus resolution, and pump parameter and hemodynamic improvements were directly observed.47–50 The patient from one of the case reports required two consecutive fibrinolytic sessions to achieve
complete resolution of thrombus but was still managed successfully with this technique.49 A recent case report described the use of systemic (assumed to be administered intravenously) alteplase at a dose of 0.1 mg/kg/hr that resolved power elevations and abnormal flow readings of the HeartWare parameters in what was determined by the investigators to be an aspirin nonresponder.51 The final case report involved a patient who presented with a recent history of subtherapeutic INRs who received fibrinolytics to successfully treat the thrombosis but suffered a subarachnoid hemorrhage as a consequence of the fibrinolytic therapy.52 The drug, dosage, and administration route of the fibrinolytic were not specified, and the patient was reported to have recovered from the bleed without neurologic sequelae. As with the HeartMate II device, the HeartWare case reports suffer from publication bias of successful treatment outcomes, along with the nonrandomized use of various pharmacologic agents. Despite these limitations, the analysis taken from the ADVANCE trial is the most reliable of all available data with the HeartWare, and the frequency of success observed within this series seems to indicate that medical therapy can be a successful strategy. Contrary to the HeartMate II literature, more available evidence exists for fibrinolytic therapy than for glycoprotein IIb/IIIa inhibitors in the management of HeartWare device thrombosis, and according to several of the available reports, intraventricular administration of alteplase can be undertaken successfully with acceptable risks of bleeding. Similar to the HeartMate II, intraventricular drug administration with the HeartWare device will require significant caution due to the technical challenges of catheter positioning within the ventricle while avoiding entanglement within the inflow cannula. One commonality identified in the ADVANCE trial analysis and reported consistently in case reports is the association of suboptimal anticoagulation or antiplatelet therapy in the time leading up to the device thrombosis occurrence. This observation emphasizes the importance of strict adherence to anticoagulation and antiplatelet therapy with this device in order to avoid the development of these significant complications. Another limitation of many of the reports of successful medical management is the unknown risk of future thrombosis recurrence. This is a particularly salient issue given that this device is currently only approved as a bridge to trans-
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plant, and therefore many of the patients go on to be transplanted soon after resolution of the thrombosis. This renders the durability of medical therapy in the treatment of HeartWare device thrombosis uncertain, which will be especially relevant once this device is approved for destination therapy. Although the data available at this time indicate that fibrinolytic therapy may be used successfully to treat HeartWare device thrombosis, we were unable to find any data supporting direct thrombin inhibitors in the management of HeartWare device thrombosis, even though this was supported by a recently proposed algorithm for management of LVAD thrombosis.32 In all, there is sufficient evidence to suggest possible efficacy with intravenous or intraventricular fibrinolytics in patients using the HeartWare device who present with early signs of device thrombosis or who may be poor candidates for surgical pump exchange. Although there is some evidence with eptifibatide and a single case report with tirofiban, experience still remains too limited to recommend glycoprotein IIb/IIIa inhibitors as preferred agents for medical management of HeartWare device thrombosis. The currently available evidence regarding combinations including a fibrinolytic agent, a glycoprotein IIb/IIIa inhibitor, and heparin (triple therapy) over single- or dual-therapy strategies suggests an unacceptable potential for serious bleeding complications without any improved efficacy. As with the HeartMate II device, additional randomized studies are warranted to determine the ideal agent and route of administration to medically manage HeartWare device thrombosis. Surgical Management of Device-Related Thrombosis Despite the aforementioned risk and disadvantages of a redo operation, some patients may require surgical management, particularly those with thrombosis associated with device position or graft kinking or those with severe device malfunction and organ hypoperfusion. For patients on the transplantation list, options include either device exchange or escalation of the UNOS listing status (i.e., from 1B to 1A) in order to possibly expedite organ procurement. In nontransplant-eligible patients (i.e., destination therapy), device exchange is the only surgical option. In patients who present with cardiogenic shock or evidence of organ hypoperfusion,
hemodynamic stabilization with either inotrope therapy or a temporary mechanical circulatory support device (intraaortic balloon counterpulsation or extracorporeal membrane oxygenation) is advised prior to device exchange. Surgical device exchange can be accomplished with relatively few complications, particularly if performed by using a subcostal approach as opposed to traditional median sternotomy.53 Short-term outcomes with exchange of the HeartMate II device are acceptable, with an estimated 30-day surgical mortality rate of 6.5%.54 Unfortunately, long-term outcomes appear to be affected, as data from the INTERMACS registry reported that the survival after pump exchange for thrombosis was 56% at 2 years compared with 69% (p
OF
THERAPEUTICS
Thrombosis in Continuous-Flow Left Ventricular Assist Devices: Pathophysiology, Prevention, and Pharmacologic Management Douglas L. Jennings,1,2,* and Phillip A. Weeks3 1
Nova Southeastern University, Ft. Lauderdale, Florida; 2Jackson Memorial Hospital/Miami Transplant Institute, Miami, Florida; 3Memorial Hermann – Texas Medical Center, Houston, Texas
Continuous-flow left ventricular assist devices reduce short-term mortality and improve quality of life in patients with end-stage heart failure. Unfortunately, device-related complications remain common, with many patients experiencing adverse events within the first year. New literature suggests that rates of device-related thrombosis may be increasing since 2011, which is particularly troublesome given that this pathology can result in a disabling stroke, organ damage, and death. In 2013, a group of practitioners in the field of mechanical circulatory support published a treatment algorithm based on their expert opinion. However, a comprehensive review of the pharmacotherapy of this condition is lacking. A search of the literature revealed 20 separate publications of case reports or case series describing outcomes associated with the use of drug therapy for suspected pump thrombosis. Each of these experiences was limited by small sample size, nonrandomized treatment allocation, and nonstandardized medication dosing. Data describing the outcomes of surgical versus medical management of device thrombosis are also sparse, with only three published reports identified. Based on the review of this limited literature, surgical management appears to be the preferred treatment modality, especially in those with organ hypoperfusion or hemodynamic instability. In patients ineligible for surgery, pharmacotherapy options remain limited. Use of all drug classes described in the literature for the HeartMate II device—fibrinolytics, glycoprotein IIb/IIIa inhibitors, and direct thrombin inhibitors—was hindered by either marginal efficacy or bleeding. Based on historical experience with unfractionated heparin in patients under HeartMate II support, we recommend this agent as a possible option for those with suspected pump thrombosis in lieu of surgical device exchange. For the HeartWare HVAD, limited data suggest that direct intraventricular administration of alteplase may be an acceptable treatment alternative. Additional research is clearly needed to further delineate the role of pharmacotherapy and to identify the optimal agent for managing this potentially life-threatening condition. KEY WORDS thrombosis, left ventricular assist device, thrombolytic, glycoprotein IIb/IIIa inhibitor, direct thrombin inhibitor. (Pharmacotherapy 2015;35(1):79–98) doi: 10.1002/phar.1501
Even with optimal medical therapy, the 1-year mortality rate associated with end-stage heart failure remains greater than 60%.1 Although car*Address for correspondence: Douglas L. Jennings, Nova Southeastern University, Department of Pharmacy Practice, Health Professions Division, 3200 S. University Drive, Ft. Lauderdale, FL 33328; e-mail: [email protected]. Ó 2014 Pharmacotherapy Publications, Inc.
diac transplantation remains the definitive surgical treatment for these patients, fewer than 2500 transplantations are performed in the United States each year.1 Second-generation continuousflow left ventricular assist devices (CF-LVADs) such as the HeartMate II (Thoratec Corp., Pleasanton, CA) and third-generation devices such as the HeartWare HVAD (HeartWare International, Inc., Framingham, MA) currently boast 1-year
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survival rates as high as 90%.2 Both devices are now approved for patients waiting for transplantation (bridge-to-transplantation therapy), and the HeartMate II is approved for those who are ineligible for transplantation (destination therapy). To date, more than 6000 mechanical circulatory support (MCS) pumps have been implanted in patients in the United States alone.2 Given the growing population of patients with heart failure, use of this technology should continue to exponentially increase. Although the reductions in morbidity and mortality are substantial, complications related to device therapy are common, and up to 70% of patients using CF-LVADs will experience a major adverse event during the first year of support.2 Reports from the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) registry initially suggested that the majority of these adverse events were related to infections (8.01 events/100 patient-months) or bleeding complications (9.45 events/100 patientmonths), whereas device-related thrombosis was relatively infrequent (1.66 events/100 patientmonths).2 However, a recently published study suggests that the risk of device-related thrombosis has increased.3 Unfortunately, the exact mechanism for this pathology is multifaceted and remains poorly understood.4 Furthermore, the optimal strategy for managing device-related thrombosis, including the role of pharmacotherapy, has yet to be delineated. In this review, we describe the pathophysiology of device-related thrombosis with the HeartMate II and the HeartWare HVAD and summarize the available evidence related to management of this potentially life-threatening condition with these two devices. Pathophysiology and Preventive Strategies Many variables can contribute to devicerelated thrombosis. Mechanical factors, such as implantation techniques, anatomical derangements (kinking or bending of the inflow or outflow graft), and device settings (reduction in speed) can reduce flow.5 As adequate flow is required to lubricate and cool the device, any anatomical distortions that generate excessive heat could lead to subsequent deposition of fibrin, narrowing of the blood flow pathway, and, ultimately, thrombosis. Although the mechanism for this relationship between heat and thrombosis remains unclear, supporting evidence comes from collective observations in explanted
HeartMate II devices that demonstrated a deposition of material (fibrin and denatured protein) in proximity to the inflow bearing (which is prone to excessive heat during periods of low or turbulent blood flow).3 Updates to the pump itself, particularly the blood-contacting surfaces, can also influence thrombotic risk, as evidenced by early redesigns of the HeartMate II device. Initial versions of this device were prone to thrombus at the inlet and outlet stators, which had relatively narrow channels with high velocities and blood flow disturbances.6 Both of these stators were initially textured, and engineers found that by making them smooth, turbulent blood flow could be reduced, thus improving hemocompatability.6 Finally, patient-specific factors, such as preexisting hypercoagulable conditions, atrial fibrillation, active infection, and uncontrolled hypertension can also increase the possibility of thrombosis.3, 4 Ultimately, the focal point of CFLVAD–related thrombosis is biocompatibility, which includes the interaction of the device with both the coagulation cascade as well as platelet activation. Role of the Coagulation Cascade and Anticoagulation Intensity: HeartMate II Device The hemobiologic relationship between the human body and the first-generation pulsatile LVADs was relatively well understood, and longterm anticoagulation therapy was not required to prevent thrombosis. The HeartMate XVE device, for example, had a unique blood-pumping surface consisting of titanium microspheres and a fibrillar textured inner surface, which promoted the formation of a “pseudointima” that resisted thrombogenesis. On the other hand, the HeartMate II can produce sustained elevations in markers of thrombin generation (thrombin/antithrombin and prothrombin fragments 1,2), as well as demonstrated indicators of endothelial dysfunction (intercellular adhesion molecule, E-selectin, tissue factor).7 This suggests that mechanical support with this device is associated with activation of the extrinsic (tissue factor) pathway of thrombosis and sustained endothelial dysfunction. Additionally, patients under device support display elevations in serum fibrinogen concentrations.8 The coexistence of these two physiologic derangements is particularly problematic, as the combination of excessive thrombin generation and hyperfibrinogenemia can increase the risk of forming faster growing,
PHARMACOTHERAPY OF LEFT VENTRICULAR ASSIST DEVICE THROMBOSIS Jennings and Weeks 81 stronger clots that dissolve more slowly than clots formed with normal concentrations of fibrinogen. Adding to this global state of hypercoagulability, it appears that continuous activation of the contact protein pathway of coagulation may exist at the blood/biomaterial interface, as evidenced by increased concentrations of factor XII and high-molecular-weight kininogen that absorb to the surface of the device.9, 10 The impact of these alterations in both systemic and regional coagulation cascades has been assessed with thromboelastographic assays, which suggest that contact pathway protein-activated coagulation results in a thrombus that develops strength at a significantly faster rate than normal tissue factor-initiated coagulation.11 In addition to having a significantly greater velocity of clot growth compared to tissue factor-initiated coagulation, contact protein-initiated coagulation has been demonstrated to prolong the lifespan of plasma thrombi by more efficient activation of thrombin-activatable fibrinolysis inhibitor and factor XIII (Figure 1).11 Due to the risk of thrombosis seen with the original European experience with the HeartMate II, initial antithrombotic regimens for this
Figure 1. Comparison of tissue factor- and contact proteinmediated activation of coagulation. Although tissue factorinitiated coagulation (black areas) begins more quickly than contact protein activation (factor XII activator, areas with gray hatched lines), contact protein-initiated clot strength increases at a significantly greater velocity. Contact protein activation also prolongs clot life span compared with tissue factor-mediated coagulation. All samples were exposed to tissue plasminogen activator 100 U/ml. Observation time was 1200 sec. Tissue factoractivated coagulation resulted in a clot that began to disintegrate sooner than contact protein-activated plasma coagulation. (Reproduced with permission from reference 11.)
device were aggressive.12 Low-molecular-weight dextran was started early after implantation, usually on postoperative day 3. Intravenous anticoagulation with heparin was then started, followed by warfarin targeted to an international normalized ratio (INR) of 2.5–3.5. However, subsequent analyses suggested that perhaps the risk of the thrombosis was lower than initially perceived. In a study published in 2009, a cohort of 331 patients under HeartMate II support reported only 10 thrombotic events during the first 6 months of device support (compared with 58 bleeding episodes).13 In this population, the risk of thrombotic events was highest when the INR was less than 1.5, whereas the majority of bleeding episodes occurred with an INR greater than 2.5. Based on these data, some centers lowered their target INR range to 1.5–2.5 near the end of 2010 in order to minimize bleeding complications.14 Although the 2009 study was provocative and influenced practice at the time of its publication, the applicability of these findings in the modern era of MCS has been nullified by recent findings.3 In late 2013, alarming data was published suggesting an abrupt increase in the risk of device-related thrombosis in 837 HeartMate II recipients from three different health care systems.3 The results showed that starting in approximately March 2011, the occurrence of confirmed pump thrombosis at 3 months after implantation increased from 2.2% to 8.4% by January 1, 2013. Although the authors cite the aforementioned reduction in anticoagulation intensity as a possible precipitating factor for this increase in risk, they do not provide specific INR values for their cohort at the time of thrombosis, which makes interpretation of their results difficult. Adding further uncertainty to their results is the introduction of sealed vascular grafts in the inflow and outflow conduits of the Heartmate II in early 2011. The purpose of these gelatin-impregnated polyester grafts was to eliminate the need for preclotting prior to implantation, remove the variability in preclotting methods, and reduce postoperative bleeding. However, any change to the blood-contacting surface of the device could potentially alter thrombogenicity, as suggested by the temporal correlation between the rise in thrombosis rates with the deployment of the new grafts. In an analysis published only in abstract form in April 2014, Thoratec presented the thrombosis rates of 2881 pumps implanted in 2011: 1905 with sealed grafts and 976 with unsealed grafts.15 In
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the first 6 months after implantation, there were 120 (6.3%) reports of suspected pump thrombus in 1905 patients with sealed grafts compared with 57 (5.8%) in 976 patients with unsealed grafts (p=NR). Although these data suggest that other factors (e.g., anticoagulation) may be to blame for the increased thrombotic risk reported,3 a final verdict on the impact of the new grafts cannot be reached until the full study is published in a peer-reviewed journal. Additional data supporting these findings3 come from a larger analysis of more than 6,900 patients using the HeartMate II device in the INTERMACS registry, which found that freedom from device exchange or death due to thrombosis had decreased from 99% at 6 months in 2009 to 94% in 2012 (p 3 9 upper limit of normal (usually an abrupt rise) • Low hemoglobin, low hematocrit • High plasma free hemoglobin level (> 40 mg/dl) • Hemoglobinuria, jaundice • Increase in LVEDD • New or worsened mitral valve regurgitation • Frequent opening of the aortic valve • Elevations in power, either persistent or as isolated spikes • Calculated flow increased
LDH = lactate dehydrogenase; LVEDD = left ventricular end-diastolic diameter.
device exchange or urgent heart transplantation represent the most definitive treatment modalities. However, cardiothoracic surgery is not without risks, including the potential for death, stroke, renal failure, and bleeding. The latter complication is particularly troubling in patients on device support for bridge-to-transplantation, as additional exposure to blood products may increase the risk of allosensitization and decreased transplant eligibility. Furthermore, surgery for device exchange may result in temporary downgrading of active listing (status 7) in the United Network for Organ Sharing (UNOS) system (Table 2) while the patient recovers, which means the loss of a potential donor heart that may become available during that time. Finally, an additional surgery for pump exchange will result in formation of scar tissue and adhesions, which will increase the duration and risk of bleeding during subsequent surgery for heart transplantation. In an effort to avoid the complications associated with an emergent repeat cardiac surgery, clinicians managing patients under support with the early CF-LVADs began to explore pharmacotherapy to treat suspected pump thrombosis. One of the earliest published reports described the use of intravenous alteplase 100 mg in eight patients under support with the MicroMed DeBakey (MicroMed Technology, Houston, TX).30 In this series, all 8 patients responded clinically
to therapy and were discharged from the intensive care unit. Only 4 patients experienced bleeding complications (transient epistaxis). In another series, two patients under support from the Jarvik 2000 Flomaker (Jarvik Heart, Inc., New York, NY) with sustained power elevations and suspected thrombosis both responded well to intraventricular alteplase.31 The regimen devised by these authors involved inserting a catheter into the left ventricle through the femoral artery (under standard fluoroscopy) and instilling 1 mg/minute of alteplase until the pump power settings returned to normal. Although these reports established some credence to the potential role of pharmacotherapy in managing device-related thrombosis, they are significantly limited by their small sample sizes, the potential for publication bias, and the use of older devices that are not currently used. At present, the ideal strategy for treating thrombosis in contemporary devices has yet to be defined. A group of practitioners in the field of mechanical circulatory support have published a suggested algorithm based on expert opinion.32 In general, they advocate that patients be admitted to the intensive care unit, and intravenous heparin can be considered if the INR is subtherapeutic. Intravenous inotrope and diuretic therapy can also be used if indicated based on the patient’s hemodynamic presentation. However, agents like glycoprotein IIb/IIIa inhibi-
PHARMACOTHERAPY OF LEFT VENTRICULAR ASSIST DEVICE THROMBOSIS Jennings and Weeks 85 Table 2. United Network for Organ Sharing Stages of Listing for Cardiac Transplantation Listing Stage 1A
Criteria a
b c d
1B 2 7
e aa bb
Location
*
Outpatient or inpatient
Mechanical circulatory support
Total artificial heart Intra-aortic balloon pump Extracorporeal membranous oxygenator Mechanical circulatory support with evidence of device malfunction such as thromboembolism, infection, mechanical failure, or arrhythmias Continuous mechanical ventilation Continuous infusion of a single high-dose intravenous inotrope (e.g., milrinone ≥ 0.5 lg/kg/minute, dobutamine ≥ 7.5 lg/kg/minute) or a combination of agents at any dose in addition to continuous hemodynamic monitoring with a pulmonary artery catheter By exception, granted by more than 50% of the members of the regional review board Mechanical circulatory support that does not qualify for 1Aa or 1Ab status Continuous-infusion inotropes Approved candidate in need of a cardiac transplant who does not meet any 1A or 1B criteria Candidates temporarily unsuitable to receive a transplant due to comorbidity (active infection), recent surgery, social issues (loss of insurance), etc.
Inpatient Outpatient or inpatient Inpatient Inpatient
Inpatient Outpatient Outpatient Outpatient or inpatient
*Stable patients on mechanical circulatory support (i.e., HeartMate II) are limited to 30 days of 1A time, which can be used anytime (e.g., 15 days in month 2 and another 15 days in month 6 of device support).
tors and fibrinolytics are either not discussed or relegated to last-line therapy for nonsurgical candidates. Therefore, further discussion of the evidence reporting the use of these treatment modalities is clearly warranted. Role of Pharmacotherapy in the HeartMate II Device Glycoprotein IIb/IIIa Inhibitors Published reports have described attempted therapy with glycoprotein IIb/IIIa inhibitors, fibrinolytics, and direct thrombin inhibitors in patients with suspected HeartMate II thrombosis (Table 3). The first published report of use of a glycoprotein IIb/IIIa inhibitor was in 2008 and described the use of eptifibatide in a patient with hemolysis and altered device parameters (labile flows and power elevations).33 Intravenous heparin was also started, and, unfortunately, the patient developed heparin-induced thrombocytopenia that required treatment with argatroban. Due to this confounding adverse drug reaction to the heparin, the effect of the eptifibatide could not be assessed. In 2012, the first successful use of eptifibatide was detailed in a pair of published case series describing three patients who presented with hemolysis and power elevations.34, 35 Finally, in 2013, there was a series of two patients who were successfully treated with intraventricular fibrinolytic therapy after failing eptifibatide.36 Additional
details regarding these patients will be discussed in the fibrinolytic therapy section. A larger series of four patients who received eptifibatide was published in early 2014 and, in contrast to previous reports, reported a 75% failure rate (including one death and two device exchanges).37 The largest case series to date was also published in 2014 and included 17 patients using the HeartMate II device who received 22 treatment attempts with eptifibatide for suspected pump thrombosis.38 At this institution, all patients received early intravenous heparin (on postoperative days 1–2) and warfarin with an INR target of 2–3. In this cohort, only three patients responded to eptifibatide therapy; all three were treated during the index hospitalization, with the time from implantation to eptifibatide administration ranging from 6 to 14 days. Combining all of the published case reports and case series yields a cohort of 27 patients who received eptifibatide as attempted therapy for device-related thrombosis in the HeartMate II device. Only seven (26%) of these patients displayed clinical features consistent with treatment success, whereas eight patients died and 13 developed bleeding complications. Given these unfavorable results, along with the small sample size and the inherent limitations of case reports (e.g., publication bias), we cannot advocate for the use of glycoprotein IIb/IIIa inhibitors as a pharmacologic modality for patients with suspected thrombosis of the HeartMate II device.
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Fibrinolytic Agents Based on the preliminary success reported with older devices, fibrinolytic therapy has also been attempted in patients under HeartMate II support. The first published report in 2011 describes the successful use of fibrinolytic therapy in a patient with suspected device thrombosis; however, as the focus of the article was on the utility of echocardiography in this clinical setting, specifics regarding the drug and dosage were not provided.39 A subsequent case published in 2013 details a patient admitted with evidence of thrombosis who was unsuccessfully treated with several doses of both intraventricular and intravenous alteplase.40 Also published in 2013, two patients were described who responded to a fibrinolytic after initially failing therapy with intravenous heparin and eptifibatide.36 Survey of the published literature regarding the use of fibrinolytic therapy in the HeartMate II population reveals an extremely limited data set. Only four reported cases have been published, one of which did not include any details about the fibrinolytic agent or dosing regimen. Of the remaining three cases, two reported success with an extended infusion of intraventricular alteplase, whereas one reported clinical failure with a combination of intraventricular and systemic administration. Directly instilling a fibrinolytic agent into the left ventricle requires significant technical expertise in order to avoid potential complications such as local bleeding from the arterial access site or dislodgement of the catheter into the LVAD inflow cannula. Whether direct intraventricular administration of the fibrinolytic mitigates any of the systemic bleeding risk associated with this therapy also remains unknown. Finally, in the event of failure of fibrinolytic therapy, requiring surgery for device exchange, the preoperative drug exposure may result in an increased intraoperative blood loss. In light of these limitations, along with the extremely limited amount of published data, we cannot recommend fibrinolytic therapy for patients with suspected HeartMate II thrombosis. Direct Thrombin Inhibitors In the recently published treatment algorithm for suspected device thrombosis, direct thrombin inhibitors were suggested as an alternative method of anticoagulation.32 Theoretical advantages exist with these agents, particularly argatroban, which is able to effectively inhibit
platelet aggregation and thromboxane generation in the presence of both free and clot-bound thrombin at serum concentrations far less than either heparin or hirudin.41 On the other hand, data from an in vitro thromboelastography study demonstrated that although direct thrombin inhibitors were able to slow thrombin generation, they were inferior to heparin in attenuating clot propagation and strength.42 Unfortunately, in vivo data in CF-LVAD patients with this class of drugs is quite limited. In 2008, a report43 was made of a patient using the HeartMate II device who initially responded to intravenous hirudin; however, this patient’s symptoms returned 3 months after treatment, and he eventually underwent device exchange. A recently published cohort study describes four patients under HeartMate II support with suspected thrombosis who were treated with argatroban therapy.44 Although three patients had resolution of hemolysis, one patient failed therapy and required emergent heart transplantation, and two patients developed bleeding complications. Given the limited response seen in this series, along with significant costs of these agents, additional studies are warranted before direct thrombin inhibitors can be endorsed for use in patients with suspected thrombosis of the HeartMate II. Role of Pharmacotherapy in the HeartWare HVAD While the HeartWare HVAD has been available for use in the United States for a much shorter period of time than the HeartMate II, nearly the same amount of published experiences describing pharmacotherapeutic strategies to manage device thrombosis exists. To date, the available evidence related to management of HeartWare device thrombosis is in the form of case series and case reports (Table 4). The largest experience is taken from the retrospective report of the thrombosis cases encountered in the ADVANCE trial.25 Because the trial protocol did not specify a mandatory management strategy, participants were permitted to manage suspected thrombosis according to their clinical judgment and center-specific practice standards. Of the 34 thrombosis events seen in 30 patients, 4 (11.8%) underwent urgent pump exchange and 30 (88.2%) were initially managed medically. Initial medication therapy ranged from initiation of intravenous heparin to mono-, dual-, and triple- therapy strategies of fibrinolytics,
No. of Patients Drug
2
1
2
Tufts Medical Center (Boston, MA)34
Henry Ford Hospital (Detroit, MI)35
University of Chicago (Chicago, IL)36
Eptifibatide
Eptifibatide
Eptifibatide
Glycoprotein IIb/IIIa Receptor Antagonists Ohio State 1 Eptifibatide University (Columbus, OH)33
Study Center
Not provided
1 lg/kg/min
Patient 2: 180mcg bolus, then 2 lg/kg/ min
Patient 1: 180-lg bolus, then 1 lg/kg/min
2 lg/kg/min
Dosage
Persistent hemolysis, power spikes, and echocardiographic evidence of thrombosis
Resolved hemolysis, power elevations, and acute kidney injury
Resolved hemolysis and power elevations in both patients
Persistent hemolysis and power elevations
Efficacy Outcomes
Table 3. Pharmacotherapy Experience with the HeartMate II Device
None
None
Patient 1: bleeding peptic ulcer treated with epinephrine injection therapy and clip placement Patient 2: bleeding Dieulafoy lesion treated successfully with clip placement
Not reported
Bleeding Outcomes
Transitioned to fibrinolytic therapy (described below)
Patient 2: confirmed laminar thrombosis by CT scan in both the inflow and outflow cannulas; successfully transplanted 65 days later, with no evidence of thrombosis at that time Alive on support
Patient 1: alive on support
Diagnosed with HIT, successfully treated with argatroban
Additional Findings
(continued)
This case adds to reports suggesting that intravenous glycoprotein IIb/IIIa receptor antagonists may be viable options for managing device thromboses that fail to respond to systemic anticoagulation. No comment was provided regarding eptifibatide therapy (comments regarding fibrinolytic therapy are provided below).
Although glycoprotein IIb/IIIa inhibitors may be useful for acute LVAD thrombosis, their use must be monitored closely, as thrombocytopenia and worsening thrombosis may complicate management. Despite the successful outcomes, the role of eptifibatide in the treatment of LVAD thrombosis remains unclear, particularly in light of the associated bleeding risks.
Conclusions
PHARMACOTHERAPY OF LEFT VENTRICULAR ASSIST DEVICE THROMBOSIS Jennings and Weeks 87
1
17 (22 attempts)
Barnes-Jewish Hospital (St. Louis, MO)38
Fibrinolytic Agents Cardiovascular Center RheinRuhr (Essen, Germany)39
4
No. of Patients
Yale School of Medicine (New Haven, CT)37
Study Center
Table 3. (continued)
“Thrombolytic” (drug not specified)
Eptifibatide
Eptifibatide
Drug
Resolution of heart failure symptoms and echocardiographic findings
Three patients had resolution of at least one major indicator* and remained free from continued hemolysis, death, pump exchange, or emergent transplantation
0.1–2 lg/kg/min for a mean duration of 2.64 days (range 0.38– 6.02 days)
Not reported
None
Patient 1: resolved hemolysis Patients 2–4: persistent power elevations, hemolysis, and heart failure symptoms
180-lg bolus, then 1 lg/kg/ min
None
4 patients: hemorrhagic strokes 1 patient: melena 1 patient: nose bleed 1 patient: hematuria requiring urology consultation and intervention
5 patients: gastrointestinal bleeds confirmed by EGD
Bleeding Outcomes
Efficacy Outcomes
Dosage
None
7 patients died: hemorrhagic stroke (2), cardiorespiratory failure (1), VAD malfunction (2), cardiac arrhythmia (1), multisystem organ failure (1) 3 patients underwent pump exchange (presence of thrombosis not reported)
Patient 1: transplant, no thrombus found Patient 2: died (CVA) Patients 3 and 4: device exchange, thrombus found
Additional Findings
(continued)
The measurement of the flow velocity with pulsed wave and continuous-wave Doppler during echocardiography can provide important information about device function and should be performed in every patient with a VAD.
This report suggests that the role for eptifibatide treatment of pump thrombosis may be limited, and, in contrast to a prior report, documents a high failure rate for this therapy, requiring either more aggressive medical therapy (fibrinolysis) or device exchange (as instituted in our experience). Although the overall patient sample size was small, based on this experience, the risk of using eptifibatide to treat suspected LVAD pump thrombosis outweighs the potential benefits of salvaging the existing LVAD in candidates for pump exchange. On the basis of a high occurrence of bleeding events and low rates of clinical resolution at this institution, the use of eptifibatide in the setting of suspected pump thrombosis would not be encouraged
Conclusions
88 PHARMACOTHERAPY Volume 35, Number 1, 2015
1
Tufts Medical Center (Boston, MA)47
Alteplase
Tenecteplase
2
Heart and Diabetes Center North Rhine-Westphalia (Bad Oeynhausen, Germany)46
1
Alteplase or tenecteplase (1 patient also received tirofiban) Tirofiban
Eptifibatide (alone or with heparin)
6 thrombosis events
Drug
Alteplase (eptifibatide, heparin, or both were used in combination in many cases; 8 patients received all 3 agents)
19 thrombosis events
No. of Patients
4
St. Vincent’s Hospital (Sydney, Australia)45
Multicenter (ADVANCE BTT and CAP trial)25
Study Center
1 mg/min intraventricularly for 37 min
10,000 units (50 mg) i.v.
Alteplase 10-50 mg i.v. or tenecteplase 12.525 mg i.v. Not specified
Not specified
15-100 mg
Dosage
Table 4. Pharmacotherapy Experience with the HeartWare HVAD Efficacy Outcomes
Successful, with reductions in left ventricular pressure and cardiac index with improvement in flow reading
Patient 1: unsuccessful, also had significant bleeding event Patient 2: successful (definition not provided)
3/4 patients successfully treated with resolved power elevations and flow reading improvement Successful resolution of power elevations and flow reading improvement
2/4 patients: successful route unknown 3/6 patients: successfully treated
4/7 patients: successfully administered intraventricularly
6/8 patients: successfully administered intravenously
Bleeding Outcomes
None
Patient 1: severe drive-line bleeding requiring surgical repair Patient 2: none
Massive hemothorax requiring surgical drainage; subsequent recurrent epistaxis
Patient 1: recurrent epistaxis Patients 2–4: none
2 patients: hemorrhagic CVAs (1 received tPA, glycoprotein IIb/IIIa inhibitor, and heparin) 2 patients: gastrointestinal bleeds 1 patient: AICD pocket bleed (treatment groups not specified for bleeding outcomes)
Additional Findings
Thrombolysis performed with left ventricular pressure monitoring; fibrinolytic stopped once pressures improved
Patient 2 was treated with fibrinolytic in second episode of pump thrombosis; initial episode was treated with pump exchange
Two patients receiving fibrinolytic therapy died within 48 hours of administration, with multiorgan failure and urosepsis as the attributable causes
5 of the 30 patients managed with drug therapy died (4 after subsequent attempts at device exchange) 3 patients had recurrence of thrombus after medical management
Conclusions
(continued)
Patients were successfully managed medically in 50% of pump thrombus cases with good outcomes. Significant risk factors for pump thrombosis include suboptimal anticoagulation and antiplatelet therapy as well as elevated blood pressure. This suggests that pump thrombus event rates could be reduced through careful adherence to patient management guidelines. Clinically significant pump thrombosis occurs in centrifugal CF-LVADs but can usually be successfully managed with intravenous therapy. Interruption of anticoagulation, inadequate antiplatelet therapy, and sepsis need to be considered as potential underlying etiology in suspected thrombosis. Pump exchange can be avoided with repetitive thrombolysis in some patients. Pump exchange is an effective treatment for HeartWare VAD thrombosis. The associated risk is acceptable. Off-pump surgery may reduce the risks observed with reoperative surgery. Bleeding is a risk of thrombolytic therapy, including intracranial hemorrhage. A potential advantage of intracavitary thrombolysis may be the reduced dose of drug required because of direct application to the LVAD inflow cannula.
PHARMACOTHERAPY OF LEFT VENTRICULAR ASSIST DEVICE THROMBOSIS Jennings and Weeks 93
No. of Patients
4
Argatroban
Hirudin
Drug
Not provided
Not provided
Dosage
Patient 1: persistent hemolysis
Patients 2–4: resolved hemolysis
Resolution in power elevations and hemolysis
Efficacy Outcomes
Patient 2: developed subdural hematoma after fall Patient 4: hemorrhagic pericardial effusion
None
Bleeding Outcomes
Patient 1: transplant, with thrombus found Patients 2–4: alive on device support
Symptoms returned 3 months later and patient underwent subsequent transplant with thrombus found
Additional Findings
A large preoperative LV thrombus formation seems to be a risk factor for delayed pump thrombosis. In this case, it is likely that a secondary thrombus formed after cessation of the thrombolytic therapy. Another possibility is that hirudin did not effectively dissolve the primary thrombus. This is the first series showing the use of argatroban to treat hemolysis from suspected device thrombosis in patients with HeartMate II continuous-flow LVADs. The limitations are acknowledged, and further investigation on use of direct thrombin inhibitors with a larger patient dataset and randomized controlled trials will be needed to justify this approach.
Conclusions
HIT = heparin-induced thrombocytopenia; LVAD = left ventricular assist device; CT = computed tomography; CVA = cerebrovascular accident; EGD = esophagogastroduodenoscopy. *Five indicators were assessed, including LDH greater than 2.5 times normal or baseline values, haptoglobin < 10 mg/dl, PFHgb > 40 mg/dl, LVAD dysfunction as evidenced by alarm or echocardiography (ECHO) findings or new persistent high pump powers.
Jackson Memorial Hospital (Miami, FL)44
Direct Thrombin Inhibitors Hannover 1 Medical School (Hannover, Germany)43
Study Center
Table 3. (continued)
90 PHARMACOTHERAPY Volume 35, Number 1, 2015
PHARMACOTHERAPY OF LEFT VENTRICULAR ASSIST DEVICE THROMBOSIS Jennings and Weeks 91 glycoprotein IIb/IIIa inhibitors, and heparin. Medical therapy failed in 15 patients, of whom 12 required pump exchange, 2 went on to emergent transplantation, and 1 died. Outcomes related to specific dual therapy (fibrinolytic + heparin or eptifibatide) regimens are presented in Table 4. Of note, all of the five patients who received heparin monotherapy failed treatment and required either device exchange or transplantation. Results of combination therapy with alteplase, eptifibatide, and heparin were also not promising, as four of the eight patients who received triple therapy failed and required device exchange, whereas one patient died after developing a hemorrhagic cerebrovascular accident. Aside from the experience published from the ADVANCE trial, several single centers have offered their experiences in the form of smaller case series and isolated case reports. The next largest published experience includes five pump thrombosis cases, four of which were managed with peripherally administered fibrinolytics.45 Three of the four patients required repeat administration of fibrinolytics. Two of the four patients survived, but device parameters improved in all four patients. Both patients who died had active infections, and neither death was attributed to pump thrombosis or bleeding. Another case series included six patients, two of whom had been treated with tenecteplase 10,000 units (50 mg) given peripherally as an intravenous bolus dose.46 One of the patients had already undergone pump exchange for a previous episode of device thrombosis, and the treatment with the fibrinolytic was for the recurrent episode of pump thrombosis due to poor compliance and discontinuation of anticoagulation. This patient was treated successfully and without complications. The second patient was managed with fibrinolytic therapy as an initial strategy and was determined by authors to have failed (no details of failure reported) and experienced severe bleeding. Both patients in this series were simultaneously administered heparin to maintain an activated partial thromboplastin time of 50–60 seconds. Four very similar case reports were published that all used similar strategies of intraventricular alteplase administration. All were successful, with similar dosing regimens of 1 mg/minute for varying times (20–37 min) until thrombus resolution, and pump parameter and hemodynamic improvements were directly observed.47–50 The patient from one of the case reports required two consecutive fibrinolytic sessions to achieve
complete resolution of thrombus but was still managed successfully with this technique.49 A recent case report described the use of systemic (assumed to be administered intravenously) alteplase at a dose of 0.1 mg/kg/hr that resolved power elevations and abnormal flow readings of the HeartWare parameters in what was determined by the investigators to be an aspirin nonresponder.51 The final case report involved a patient who presented with a recent history of subtherapeutic INRs who received fibrinolytics to successfully treat the thrombosis but suffered a subarachnoid hemorrhage as a consequence of the fibrinolytic therapy.52 The drug, dosage, and administration route of the fibrinolytic were not specified, and the patient was reported to have recovered from the bleed without neurologic sequelae. As with the HeartMate II device, the HeartWare case reports suffer from publication bias of successful treatment outcomes, along with the nonrandomized use of various pharmacologic agents. Despite these limitations, the analysis taken from the ADVANCE trial is the most reliable of all available data with the HeartWare, and the frequency of success observed within this series seems to indicate that medical therapy can be a successful strategy. Contrary to the HeartMate II literature, more available evidence exists for fibrinolytic therapy than for glycoprotein IIb/IIIa inhibitors in the management of HeartWare device thrombosis, and according to several of the available reports, intraventricular administration of alteplase can be undertaken successfully with acceptable risks of bleeding. Similar to the HeartMate II, intraventricular drug administration with the HeartWare device will require significant caution due to the technical challenges of catheter positioning within the ventricle while avoiding entanglement within the inflow cannula. One commonality identified in the ADVANCE trial analysis and reported consistently in case reports is the association of suboptimal anticoagulation or antiplatelet therapy in the time leading up to the device thrombosis occurrence. This observation emphasizes the importance of strict adherence to anticoagulation and antiplatelet therapy with this device in order to avoid the development of these significant complications. Another limitation of many of the reports of successful medical management is the unknown risk of future thrombosis recurrence. This is a particularly salient issue given that this device is currently only approved as a bridge to trans-
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plant, and therefore many of the patients go on to be transplanted soon after resolution of the thrombosis. This renders the durability of medical therapy in the treatment of HeartWare device thrombosis uncertain, which will be especially relevant once this device is approved for destination therapy. Although the data available at this time indicate that fibrinolytic therapy may be used successfully to treat HeartWare device thrombosis, we were unable to find any data supporting direct thrombin inhibitors in the management of HeartWare device thrombosis, even though this was supported by a recently proposed algorithm for management of LVAD thrombosis.32 In all, there is sufficient evidence to suggest possible efficacy with intravenous or intraventricular fibrinolytics in patients using the HeartWare device who present with early signs of device thrombosis or who may be poor candidates for surgical pump exchange. Although there is some evidence with eptifibatide and a single case report with tirofiban, experience still remains too limited to recommend glycoprotein IIb/IIIa inhibitors as preferred agents for medical management of HeartWare device thrombosis. The currently available evidence regarding combinations including a fibrinolytic agent, a glycoprotein IIb/IIIa inhibitor, and heparin (triple therapy) over single- or dual-therapy strategies suggests an unacceptable potential for serious bleeding complications without any improved efficacy. As with the HeartMate II device, additional randomized studies are warranted to determine the ideal agent and route of administration to medically manage HeartWare device thrombosis. Surgical Management of Device-Related Thrombosis Despite the aforementioned risk and disadvantages of a redo operation, some patients may require surgical management, particularly those with thrombosis associated with device position or graft kinking or those with severe device malfunction and organ hypoperfusion. For patients on the transplantation list, options include either device exchange or escalation of the UNOS listing status (i.e., from 1B to 1A) in order to possibly expedite organ procurement. In nontransplant-eligible patients (i.e., destination therapy), device exchange is the only surgical option. In patients who present with cardiogenic shock or evidence of organ hypoperfusion,
hemodynamic stabilization with either inotrope therapy or a temporary mechanical circulatory support device (intraaortic balloon counterpulsation or extracorporeal membrane oxygenation) is advised prior to device exchange. Surgical device exchange can be accomplished with relatively few complications, particularly if performed by using a subcostal approach as opposed to traditional median sternotomy.53 Short-term outcomes with exchange of the HeartMate II device are acceptable, with an estimated 30-day surgical mortality rate of 6.5%.54 Unfortunately, long-term outcomes appear to be affected, as data from the INTERMACS registry reported that the survival after pump exchange for thrombosis was 56% at 2 years compared with 69% (p
