Pump Thrombosis: A Limitation of Contemporary Left Ventricular Assist Devices Navin K. Kapur, MD, Amanda R.Vest, MD, Jennifer Cook, MD, and Michael S. Kiernan, MD Abstract: For the majority of patients with heart failure (HF) the management is non-surgical, but for the most advanced subgroup of patients with heart failure and reduced ejection fraction, mechanical circulatory support (MCS) is becoming a more viable treatment option. Heart transplantation is the ‘gold standard’ for advanced HF therapy, but is limited by donor organ availability. In contrast, MCS utilization has risen exponentially over the past decade. Pump thrombosis is a rare but increasingly recognized cause of morbidity and mortality in this population. In this review, we define the problem of pump thrombosis, discuss diagnostic testing and approaches to the prevention and management of this potentially devastating complication of durable MCS. (Curr Probl Cardiol 2015;40:511–540.)

Left Ventricular Assist Device Pump Thrombosis: A Growing Problem n estimated 5.1 million people are diagnosed with a heart failure (HF) in the United States alone,1 of which approximately half have HF with reduced ejection fraction. For most patients with HF, the management is nonsurgical, but for the most advanced subgroup patients with HF with reduced ejection fraction, mechanical circulatory support (MCS) is an increasingly common treatment option. Heart transplantation is the “gold standard” for advanced HF therapy but is limited by donor organ availability. Heart transplant numbers have remained stable over the

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past decade at approximately 2400 transplants in North America annually.2 In contrast, MCS use has risen exponentially over the past decade, with 3472 continuous-flow left ventricular assist device (CF-LVAD) implants reported to the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) in 2013.3 In 2009, the HeartMate II (HMII) investigators demonstrated superiority of a CF-LVAD over earlier-generation pulsatile devices in a destination therapy (DT) HF cohort who were ineligible for heart transplantation. Pulsatile LVADs were limited by their mechanical integrity, with many pumps failing within 2 years owing to complications such as bearing wear, valve malfunction, or infection (21 pump exchanges among 59 patients).4 Among 133 CF-LVAD recipients, 13 pump exchanges were performed, of which only 2 were owing to pump thrombosis (PT). Subsequent CFLVAD clinical trials demonstrated increasingly encouraging MCS survival rates, but also shed further light on the complications that will need to be overcome if the full potential of LVAD therapy is to be realized. The major complications encountered in the prospective CF-LVAD trials published up until 2012 were bleeding, ventricular arrhythmias, thromboembolic and hemorrhagic strokes, gastrointestinal tract bleeding (GIB), device infections, and right ventricular failure.5,6 Interestingly, PT was a rare complication in this era, affecting only 1%-4% of trial participants, as summarized in Table 1. The HMII bridge-to-transplantation trial (BTT) reported a PT cumulative incidence of 2 of 133 patients at 180 days’ support.7 ADVANCE, the Heartware ventricular assist device (HVAD) BTT trial, recorded a similarly low PT cumulative incidence of 3 of 140 patients at 180 days.6 The PT incidence in the HVAD DT trial is currently awaited, but it should be remembered that as confidence with CF-LVAD therapy has grown, the average age and comorbidity burden of recipients has increased, which may affect the rate of PT occurrence. In contemporary practice, approximately 40% of LVADs are implanted with a DT strategy.3 In addition to the shifts in recipient demographics, anticoagulation regimens have also changed over time. The initially conservative anticoagulation protocol of the HMII BTT trial included postoperative heparin bridging, warfarin with a target international normalized ratio (INR) of 2.03.0, aspirin, and dipyridamole,7 but practice evolved toward less stringent regimens after the publications of 2 key studies. Boyle et al15 studied HMII BTT trial subjects who were discharged at least 1 month before and concluded that that the optimal balance between thromboembolic and bleeding risks lay in the INR range 1.5-2.5. Slaughter et al16 proposed that patients who were not bridged with intravenous heparin in the early 512

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TABLE 1. Reported CF-LVAD pump thrombosis prevalence and incidence rates 2004-2014 References

LVAD Enrollment Number type, strategy years of subjects

Miller et al7 Pagani et al5 Slaughter et al4 Lahpor 201054 Starling 201155

HMII, BTT HMII, BTT

2005-2006 2005-2008

HMII, DT

2005-2007

HMII, BTT and DT HMII, BTT

2004-2008 2008-2010

Aaronson et al6 Park 201256

HVAD, BTT

2008-2010

140

HMII, DT

2007-2009

Starling et al11

HMII, BTT and DT

2004-2013

281 (Midtrial’ group) 837

Kirklin et al12

HMII, BTT and DT

2006-2013

6910

Najjar HVAD, CAP et al13 Uriel et al14 HMII, BTT and DT

2010-2012

Number of PT events

Median or mean duration of support, y

Cumulative patient-years follow-up

Proportion of patients with PT (prevalence)

Events per patient-year (incidence rate)

133 281

2 4

0.35 0.42

61.7 181

1.50 1.42

0.03 0.02

134 (HMII group) 411

5

1.7

211

3.73

0.02

3

0.65

293

0.73

0.01

0.84

142

3

N/A

89.1

19 (in 16 patients)

2.1

498

5.69

0.04

1047

7.9 (confirmed PT, proportion of patients) 4.5 (5.5 including probable PT)

0.07

N/A

7.0

0.08

N/A

10.7

0.12

169 (HMII (2 Pump replacements, group) reason unspecified)

242 (CAP group) 2009-2012 177

72 confirmed PT, in 66 0.65-0.89 (across patients (108 including 3 centers) probable PT) 315 confirmed cases of PT N/A (382 including probable PT) 17 (CAP group only) 0.75 19

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CAP, continued-access protocol; N/A, not available. Note: there is an unknown degree of patient overlap between these cohorts.

N/A

N/A

(1.2% underwent pump replacement) 2.19

(0.01 pump replacement) 0.03

N/A

postoperative phase had a more favorable ratio of thromboembolism to bleeding complications. Hence, many centers began to adopt a less aggressive anticoagulation strategy in their HMII recipients. Gary S. Francis, MD: There is growing recognition that the proper way to anticoagulate patients with nonpulsatile LVADs is still evolving, though guidelines have been developed. This perception has emerged in part owing to the recognition that PT continues to be a persistent problem in patients with nonpulsatile LVADs, although excess bleeding also continues to be an ongoing risk. Acquired von Willebrand factor deficiency can lead to platelet dysfunction in patients with nonpulsatile LVADs. The mechanical pump creates high shear stress, causing consumption of high-molecularweight von Willebrand factor multimers, conferring a predisposition to platelet dysfunction and bleeding (Meyer AL et al, JACC-HF 2014;2:141145). Bleeding from angioectasias may be enhanced by acquired von Willebrand factor deficiency (Brock AS, Cook JL, Ranney N, Rockey DC, “A not-so-obscure cause of gastrointestinal bleeding” N Engl J Med 2015;372:556-561). The risk of bleeding and thrombotic events during LVAD support differs according to sex, age, body mass index, and etiology of HF. Bleeding, in particular GIB, occurs in 20%-25% of patients and is higher with continuous-flow LVADs. PT is typically a more serious event and occurs in approximately 8% of patients. It is clinically characterized by the development of HF symptoms, a palpable pulse in a continuous-flow LVAD, and laboratory evidence of hemolysis (increased lactate dehydrogenase [LDH]). Echocardiography may show left ventricular (LV) dilation, mitral regurgitation, and increased aortic valve opening. These are signs of inability to unload the LV. The Doppler examination may indicate reduced flow through the LVAD. Bleeding and PT continue to plague these patients and have forced us to reassess how these patients should be anticoagulated. To date, this has led to some ongoing debate and uncertainty, especially when PT occurs.

Through 2011 and 2012, several centers noted increasing frequency of HMII PT events. These observations led to publication of a 3-center analysis combining data from Cleveland Clinic, Washington University Barnes-Jewish Hospital, and Duke University Medical Center.11 Starling et al described 108 cases of confirmed or suspected PT among 895 HMII implants in 837 patients. Confirmed PT was defined as visualized thrombus on the blood-contacting surface of the device or its outflow conduit at the time of pump exchange, transplantation, or autopsy, or occasionally compelling radiographic or echocardiographic evidence accompanied by clinical HF or thromboembolism. Suspected PT was defined as clinical pump malfunction in which PT was suggested by hemolysis (LDH 42.5-fold greater than the laboratory reference upper limit for normal or approximately 600 IU/L), development of unexplained 514

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HF with an echocardiographic finding of poor left ventricular unloading at the patient’s maintenance pump speed, or abnormal pump parameters (power elevations 42 W greater than the baseline value or an absolute of Z10 W). The overall estimated prevalence of PT by Starling et al was 4.7% within the first 6 months of LVAD support, 7.5% during 12 months of support, and 12.3% during 24 months of support. Of particular interest was the apparent threshold date of March 2011, which was consistent among institutions. This date demarcated a steep transition from a 2.2% PT prevalence (95% CI: 1.5-3.4) at 3 months after implantation, to 8.4% (95% CI: 5.0-13.9) by January 2013. Before March 2011, the median time from implantation to thrombosis was 18.6 months, but after this date, PT occurred far earlier at a median of 2.7 months after implantation. Patients with PT incurred excess morbidity and mortality unless they underwent pump exchange or urgent heart transplantation. Concurrently, Kirklin et al described 382 cases of confirmed or suspected PT resulting in pump exchange or death among 6910 HMII INTERMACS registry participants.12 Temporal trends were also apparent in this analysis; freedom from pump exchange or mortality related to thrombosis decreased from 99% at 6 months in 2008-2009 to 95% in 2011 and to 94% in 2012. Multivariable modeling suggested the following risk factors for PT: later implant year, younger age, higher body mass index, white race, higher creatinine level, left ventricular ejection fraction 420%, and higher LDH at 1 month after implantation. Columbia University Medical Center reported a similarly high PT cumulative incidence, occurring in 19 of 177 patients at a mean of 351 ⫾ 311 days after implantation.14 In 5 of the 19 patients, a mechanical proximate cause for PT was identified, including an abnormal inflow cannula position or deformation of the outflow graft. The Food and Drug Administration–operated MAUDE database for postmarket surveillance was investigated for an abstract reporting an “over 400% increase in LVAD thrombosis” among patients with CF-LVAD during the period 2008-2012.17 HVAD-specific contemporary PT data have also been published, with an equivalent incidence rate to the HMII data from Starling et al (Table 1).13 Interestingly, a recent brief report from 3 centers suggested a peak in PT occurrence in 2012, followed by a significant reduction in PT during 2013 toward previously reported postmarketing levels.18 Several mechanisms for CF-LVAD thrombosis have been postulated. Ingestion of cardiac embolus, for example, from the left atrial appendage, Curr Probl Cardiol, December 2015

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FIG 1. Photographs of (A) “red clot” and (B) “white clot” within CF-LVAD after device explantation. (Color version of figure is available online.)

is one possible mechanism for acute thrombus formation. “Red clot” (Fig 1) that is rich in erythrocytes may also form acutely on the bloodcontacting surfaces of the device. This type of thrombus is typically associated with periods of subtherapeutic anticoagulation or stagnant blood flow or both and has a soft consistency. Conversely, “white clot” (Fig 1) comprises platelets and additional amorphous debris within a fibrin mesh. White clot is believed to accumulate more gradually by deposition of fibrin TABLE 2. Factors proposed as contributors to pump thrombosis development Patient factors

Device factors

Atrial fibrillation

Heat generation by pump rotors Left ventricular thrombus or Shear stress– prominent trabeculations induced activation of platelets Left-sided mechanical Regions of stagnant prosthetic valve blood flow Systemic infection Outflow graft kinking or obstruction Hypercoagulable disorder and Thrombogenic bloodheparin-induced contacting device thrombocytopenia (HIT) surfaces Inconsistent medication adherence

Management factors Inadequate anticoagulation in early postoperative phase Subtherapeutic anticoagulation level

Suboptimal antiplatelet agents Inflow cannula malposition or migration Low flow through pump owing to inadequate preload (right ventricular failure and hypovolemia) or excessive afterload (hypertension) Low pump speed settings

Adapted with permission from Goldstein et al.8 516

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and denatured protein near the inflow bearing, potentially owing to shear activation of platelets by turbulence or heat generation around the bearings or both. It is hypothesized that such deposition begins with a subclinical phase that progresses toward hemolysis, abnormal pump function with incomplete left ventricular unloading, and ultimately the possibility of complete occlusion and pump stoppage. Owing to their different pathophysiologies, a red thrombus may be more responsive to anticoagulation or thrombolysis; conversely, the generation of white clot may be responsive to antiplatelet agents, but is unlikely to be pharmacologically reversed once clinically apparent. Both the HMII and HVAD devices have been modified to include sintered titanium surfaces, which promote formation of a pseudointima and reduce thrombogenicity. The pathophysiological elements that may promote PT are commonly categorized as patient, device, and management factors (Table 2), although most are yet to be supported by robust analysis.

Diagnostic Pump Parameters The presentation of PT is often subtle with a subclinical presentation. Abnormalities may be observed from routine laboratories, the patient’s passing observation of tea colored urine, or nonspecific problems related to anemia. The hallmark of PT is hemolysis where acute anemia, elevated LDH, elevated plasma free hemoglobin (pfHgb), hemoglobinuria, and jaundice may be seen. These values should be compared with baseline levels as all supported patients may exhibit a low level of basal hemolysis.11,12 Acute neurologic events or peripheral thromboembolism may result from device thrombosis, and these complications must be addressed expeditiously to prevent permanent disability. The presentation of PT may also include acute congestive symptoms, chest pain, myocardial infarction, or cardiogenic shock. Ultimately, treatment often requires device exchange, which invites morbidity and risk of mortality. Close monitoring of device parameters and laboratory markers is essential for timely diagnosis, and timely investigation in the field now provides insight on the optimal clinical approach. Device parameters are helpful to assess a patient with a suspected PT. To recognize perturbations that suggest thrombosis, the fundamentals of normal pump operation must be understood. Key pump parameters include the speed in revolutions per minute (RPM), power (Watts), flow (liters per minute), and pulsatility. When the device is set at a particular RPM, a certain number of watts are required to maintain pump speed—higher speeds require more watts. Additionally, the power drawn from the pump is proportional to the amount of blood flow through the pump. Curr Probl Cardiol, December 2015

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Put simply: more blood flow = greater power. Blood volume moving through the pump is dependent on the set speed; however, it can be influenced by the native function of the heart. Depending on the contractile function of the heart, patients may have a variable percentage of net cardiac output derived from the left ventricle as opposed to the device alone. For example, if the device provides most cardiac output, the aortic valve may open intermittently, or not at all. In this scenario, aortic pulse pressure and the pulsatility parameter will be low. Alternatively, with more preserved native heart function, left ventricular ejection will occur through the aortic valve with every cardiac cycle and the pulsatility parameter will be high. Consequently, increasing device RPMs should result in higher power utilization and lead to a greater proportion of net cardiac output derived from the device and a lesser proportion from native left ventricular ejection through the aortic valve. In this scenario, elevated power would be associated with decreased device pulsatility and should correlate with clinical evidence of ventricular unloading and improved cardiac output. In the setting of PT, device parameters can become discordant with clinical assessment. A gradual increase in power may be more consistent with layering thrombus on rotor blades or bearings, whereas an abrupt increase in power may suggest thrombus ingestion from the left atrium, aortic root, or left ventricle (Fig 2). As flow is a calculated measure based on power, elevated power may correlate with elevated flows on the pump console; however, patients may exhibit signs of inadequate cardiac output.

FIG 2. Gradually increased power use (rising blue arrow) in a patient with pump thrombosis ultimately treated with thrombolytic therapy (blue arrow directed downward) resulting in resolution of increased power levels. (Color version of figure is available online.)

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In this scenario, inadequate ventricular unloading and persistent aortic valve opening may be seen by echo and the patient may have signs of acute HF or cardiogenic shock. This discordance of elevated pump power and apparent insufficient cardiac output is the hallmark of PT. In this situation, device pulsatility may be increased, decreased, or unchanged. Power elevations that are 42 W greater than the baseline value or are sustained 410 W for more than 24 hours should raise concern for PT.8

Diagnostic Laboratory Assessment In 2014, Cowger et al investigated 2 definitions of device-associated hemolysis in patients supported with CF-LVADs to determine their utility in identifying and predicting device thrombosis. The first INTERMACS hemolysis definition of pfHgb 4 40 with clinical signs and symptoms of hemolysis was compared with a second definition of a serum LDH level 4 600 IU/L (2.5 times value of laboratory normal). Patients were supported for a median of 427 days where the 25th to 75th quartile range was 245793 days. Following INTERMACS criteria, hemolysis occurred in 18% of patients and by LDH criteria 37% of patients. Hemolyzers in the INTERMACS criteria group were shown to have 16% ⫾ 8.3% event-free

FIG 3. The predictive value of lactate dehydrogenase (LDH) levels is superior to serum-free hemoglobin (sfHg) levels as an indicator of CF-LVAD thrombosis. (Adapted with permission from Cowger et al.17) (Color version of figure is available online.)

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survival compared with 85% ⫾ 3.2% event-free survival among nonhemolyzers (P o 0.001, AUC 0.87 ⫾ 0.04). It was shown that following the onset of hemolysis the risk of having an adverse event was 8-fold to 15-fold higher than that in patients without hemolysis. The LDH criterion provided an earlier diagnosis with a more favorable predictive value (LDH sensitivity of 90% and specificity of 85% vs INTERMACS sensitivity of 90% and specificity of 41%)9 (Fig 3). This study was followed closely by Shah et al,10 who evaluated thrombosis events among patients supported by CF-LVADs. Patients with thrombosis were selected following visual inspection of thrombus, and the control group was free of any clinical criteria for suspected device thrombus. LDH levels were elevated in the thrombosis group (LDH 923 ⫾ 560 IU/L vs 361 ⫾ 76 IU/L, P o 0.001). pfHg levels were also elevated in the thrombosis group (pfHg 26.8 ⫾ 18.8 mg/dL vs 10.6 ⫾ 5.3 mg/dL, P o 0.001. Interestingly, among the controls alone, the baseline level of LDH was significantly lower in the continuous-flow devices with centrifugal design as compared with those with axial design (254 ⫾ 46 IU/L vs 361 ⫾ 76 IU/L, P o 0.001). The area under the curve for LDH as marker of device thrombosis was 0.94 þ 0.01, which was significantly higher than pfHg 0.79 þ 0.01 (P o 0.001). Using the criteria of LDH 4 600 IU/L, the sensitivity was 78% and sensitivity 97%, which was superior to the pfHg criteria 440 mg/dL, with a sensitivity of 25% and a specificity of 97%. LDH with the threshold 2.5-fold greater than the normal value allowed for earlier identification of patients who eventually required pump exchange. The cutoff value for pfHg 4 40 which is 6-fold greater than the normal value may be too high a threshold for identifying thrombosis. Gary S. Francis, MD: Elevated LDH is a hallmark of hemolysis. However, clinically evident PT does not develop in all patients with increased LDH levels. Careful clinical evaluation and echocardiographic interrogation of the heart and LVAD are still important in diagnosing PT, as outlined by the authors. Early thrombosis with the HMII is associated with substantial morbidity and mortality with medical management. Device replacement is costly and risky but can be lifesaving. Urgent heart transplantation can sometimes be performed, but device replacement is the more common pathway.

The current INTERMACS adverse event definition for major hemolysis is as follows: pfHgb 4 20 mg/dL or a serum LDH 4 2.5 times the upper limits of reference range, occurring 72 hours after the implantation and associated with one of the following parameters: (1) hemoglobinuria, (2) anemia, (3) hyperbilirubinemia, and (4) pump malfunction or abnormal 520

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pump parameters. This reflects a recent change where the pfHgb cutoff value was decreased from 40 mg/dL, which as reported earlier was not sensitive enough. The evidence suggests that LDH 4 3-fold greater than the reference range is more favorable than pfHgb to assess risk for deviceassociated hemolysis. With a pattern of LDH elevation preceding device thrombosis, all patients have a degree of mild hemolysis. There is utility in routine LDH monitoring to establish a baseline LDH value and to identify early any trends that may indicate thrombus formation.

Diagnostic Imaging Studies In addition to optimizing the pump parameters described earlier, other basic goals of CF-LVAD management include maximizing pump output, reducing cardiac filling pressures, decreasing LV dimensions without overdistending the right ventricle, avoiding suction events, and monitoring for the development of aortic insufficiency. Imaging and hemodynamic studies play a fundamental role in the evaluation and management of CFLVADs. A standard chest radiograph is a simple, first step in the evaluation of CF-LVAD dysfunction. Specifically, the chest radiograph can be used to evaluate inflow cannula positioning, pump position, changes in outflow cannula positioning, and driveline integrity.19 For both the HMII and Heartware LVADs, the inflow cannula should be positioned away from the interventricular septum and pointed posteriorly toward the mitral valve orifice. The pump itself and outflow cannula should be well seated at the

FIG 4. Chest radiography is a critical first step in the evaluation of CF-LVAD dysfunction.(Adapted with permission from Taghavi et al.19) (Color version of figure is available online.)

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FIG 5. The Echocardiographic Ramp Test Algorithm. (Adapted with permission from Uriel et al.24)

LV apex or along the inferior axis of the LV without change compared with previous studies. Shifts in any of these components can lead to low-output conditions, suction alarms, ventricular tachycardia, or hemolysis (Fig 4). Any interruption in LVAD flow can predispose to LVAD thrombosis. The Echocardiographic Ramp Test Algorithm is another imaging approach that has been widely adopted for the evaluation of LVAD thrombosis (Fig 5).21–23 The fundamental principle of the ramp study is that any change in CF-LVAD speed should modulate the magnitude of LV unloading if the CF-LVAD is functioning properly.24 By altering CF-LVAD speed in stepped fashion during echocardiography, one can measure biventricular dimensions, monitor for midline positioning of the interventricular septum, and evaluate aortic valve opening. Each of these measures provides an estimate of the magnitude of LV unloading that the CF-LVAD is capable of achieving. Before initiating a ramp test, patients are required to have an appropriate level of anticoagulation (INR 4 1.8 or partial thromboplastin time [PTT] 4 60) to avoid the development of in situ PT.20 A transthoracic echocardiogram should also be performed at baseline to rule out the presence of an aortic root thrombus, which could become ingested into the CF-LVAD if the aortic valve were to open owing to a reduction in CF-LVAD speeds. 522

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In addition, the presence of moderate to severe aortic regurgitation should preclude a full ramp study owing to the possibility of worsening the regurgitant volume with increased CF-LVAD speeds. Finally, in a patient with ventricular arrhythmias, a full ramp study may trigger a suction event, which can result in worsening ventricular arrhythmias. In 2012, Uriel et al20 reported a series of 17 ramp studies for the evaluation of suspected LVAD thrombosis. Device thrombosis was suspected based on increases in pump power more than 14 days after device implantation, LDH levels more than 1000 or elevated pfHb levels in the absence of other causes of hemolysis, and evidence of left ventricular failure without an obvious source. The authors identified that the negative slope of LV end-diastolic diameter (LVEDD) and pump speed correlates with CF-LVAD function. A more negative slope of LVEDD vs speed suggested normal CF-LVAD function, whereas a less negative slope (LVEDD vs speed 40.16) was diagnostic for CF-LVAD obstruction. Since the publication of this algorithm, numerous reports have explored the potential utility of other echocardiographic measures during the ramp study, including absolute changes in the LVEDD (o0.6 cm), aortic valve opening time (o80 milliseconds), and deceleration time of mitral inflow (o70 milliseconds).25–28 Gary S. Francis, MD: Echocardiographic ramp testing is very useful in the diagnosis of PT as elegantly discussed by the authors. However, one should also be cognizant of the limitations associated with a ramp test when incorporating this test in the diagnostic evaluation of PT. First, the utility of echocardiographic ramp test in the diagnosis of PT in the HVAD is unclear. The diagnostic accuracy of a more negative slope of LVEDD vs speed for PT was studied systematically only in patients with HMII (Uriel N. J Am Coll Cardiol. 2012 Oct 30;60(18):1764-1775). Although the fundamental concept of effective LV unloading with increased pump speed should be true in both HMII and HVAD, it is likely that these results cannot be extrapolated to HVAD, given some unique differences between HMII and HVAD: axial flow vs centrifugal flow and implant position (HMII abdomen and HVAD periocardium). Second, in addition to optimal functioning of the LVAD, loading conditions of the heart could affect the slope of LVEDD vs speed, as the CF-LVADs are afterload sensitive (Adatya S et al. JACC-HF. 2015, in press). For example, the presence of moderately severe aortic regurgitation may lead to a false-positive echocardiographic ramp test result owing to increased ventricular preload and afterload. Therefore, the echocardiographic ramp test can be used as one component in the comprehensive evaluation of a patient with suspected device obstruction. Its results must be interpreted in the context of a patient’s overall clinical status. A normal ramp test finding may not exclude a small thrombus in the assist device, even with an elevated LDH.

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More recently, the use of computerized tomography of the chest has emerged as an important aspect of evaluating CF-LVAD dysfunction. Reconstructed computed tomography (CT) images of the chest allow for a 3-dimensional view of inflow cannula and pump positioning, visualization of thrombus within the outflow cannula (Fig 6), and evidence of outflow graft kinking or stenosis (Fig 7). Interpretation of CT images requires an experienced radiologist because defects within the outflow conduits may not always represent intraluminal thrombosis but rather normal postoperative changes. In addition, outflow kinking or stenosis may not be physiologically relevant.

Diagnostic Hemodynamic Studies In select cases, invasive hemodynamic interrogation of CF-LVAD dysfunction may be required when noninvasive laboratory testing does not provide a clear diagnosis.29 Evaluation in the catheterization laboratory begins with an assessment of right heart hemodynamics to cardiac filling pressures, total cardiac output, pulmonary pressures, right ventricular function, and evidence of right-sided valvular disease. To further evaluate pump function, a “ramp” study can be conducted by measuring hemodynamic variables such as pulmonary capillary wedge pressure, pulmonary artery pressures, and cardiac output while monitoring LVAD parameters at incremental levels of flow through the device. In cases where cardiac filling pressures are normal despite significant CF-LVAD dysfunction, a simple

FIG 6. Computerized tomography of the chest in a patient with CF-LVAD can identify intraluminal defects suggestive of thrombus within the outflow graft (arrow). 524

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FIG 7. Computerized tomography of the chest in a patient with CF-LVAD can identify obstruction of the outflow graft at the level of the aortic (Ao) anastomosis (red circle and arrow). (Color version of figure is available online.)

pigtail catheter or a double-lumen Langston catheter to measure LV and aortic pressures may provide a better estimate of CF-LVAD unloading29–31 (Fig 8). Invasive hemodynamics may also be useful when quantifying pressure gradients within the outflow conduit of a CF-LVAD. Careful wiring of the outflow graft with pullback or simultaneous proximal and distal pressure measurements can identify physiologically significant outflow graft obstruction. In select cases, stenting of the outflow graft can resolve the obstruction and avoid the need for CF-LVAD exchange. The same contraindications for cardiac catheterization apply to LVAD as in patients with non-LVAD, with a few noteworthy considerations. First, arterial access under direct visualization may be facilitated by the use of ultrasound and the micropuncture technique given that arterial flow is nonpulsatile in patients with CF-LVADs, who are often chronically anticoagulated. Second, as the LVAD inflow cannula is positioned at the cardiac apex, every attempt to prevent catheter or wire entrapment in the LVAD should be taken. Catheter or wire entrapment could be fatal. Third, nearly 50%-75% of patients with LVAD develop some degree of commissural fusion of the aortic valve. Furthermore, aortic root thrombus can develop owing to stasis, when a CF-LVAD is fully functional. For these reasons, visualization of the aortic root to rule out thrombus and to evaluate aortic valve opening should be performed in advance of left ventricular Curr Probl Cardiol, December 2015

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FIG 8. Hemodynamic tracings of a functional CF-LVAD demonstrating a significant pressure stepup with pullback of a standard pigtail catheter from the left ventricle (LV) to aortic root (Ao).

catheterization or coronary angiography. Finally, before cardiac catheterization, all patients should be evaluated by an interventional cardiologist, HF or transplant specialist, and cardiac surgeon. This multidisciplinary approach is the best way to avoid complications and unnecessary procedures. Gary S. Francis, MD: Recurrent HF observed in a patient with an LVAD is always worrisome, and requires prompt, if not urgent, assessment. PT is the most troubling cause of recurrent HF in these patients, as it can lead to death if not quickly diagnosed and managed. Early studies with HMII (bridge to transplantation) indicated that approximately 2% of patients developed PT, whereas those patients receiving HMII for bridge to destination had an incidence of PT of approximately 4%. More recent data indicate that the incidence of PT is closer to 8% (Starling et al, N Engl J Med 2014;370:33-40). Once PT is identified by methods adequately described by the authors, systemic anticoagulation may need to be adjusted and there should be prompt consultation with the surgeons. Occasionally, mild PT in the hemodynamically stable patient may be resolved with increased anticoagulation. Resolution of PT should be verified by reduced hemolysis, improved HF symptoms, normalized pump parameters, and findings on echocardiography. Our experience has been that most patients with significant PT require pump replacement.

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Prevention of LVAD PT Antithrombotic Protocols Antithrombotic management in the HMII BTT and DT trials included aspirin (81-325 mg daily) for all patients and warfarin with a targeted INR of 2.0-3.0.4,7 Some patients were also prescribed dipyridamole (75 mg 3 times daily). Anticoagulation guidelines also recommended initiation of intravenous unfractionated heparin (UFH) on the first postoperative day (POD) or when chest tube drainage was o50 mL/h. UFH was titrated to achieve a PTT of 45-50 seconds for the first 24 hours, and subsequently over the following 24-hour period (POD 2-3), the target PTT was increased to 50-60 seconds. If stable, the dose was further increased for a PTT goal of 55-65 seconds and was discontinued once the INR was therapeutic. Warfarin was initiated once a patient was able to take oral medications, and antiplatelet therapy was typically initiated on POD 2 or 3. A retrospective analysis of the 418 patients enrolled in the BTT trial subsequently found no difference in the percentage of patients with ischemic or hemorrhagic strokes or PT among the following 3 groups of patients: (1)those who were therapeutically anticoagulated with UFH, (2) those who were anticoagulated with UFH but who did not achieve a therapeutic PTT, or (3) those who were not anticoagulated with UFH.16 From POD 3-30, more patients receiving UFH required transfusion for bleeding events compared with those who did not. Multivariate analysis identified postoperative UFH use as an independent risk factor for bleeding. The authors concluded that HMII patients who were directly transitioned to warfarin and aspirin therapy without UFH did not have an increased short-term risk of thrombotic complications and bleeding was significantly reduced. As related to long-term anticoagulation strategies, a separate analysis of 331 patients enrolled in the HMII BTT trial with at least 1 month of follow-up since initial discharge on support found that 40% of strokes occurred in patients with INRs o 1.5, whereas 33% of hemorrhagic strokes were in patients with INRs 4 3.0.15 The highest incidence of bleeding was at INRs 4 2.5. These post hoc reports led to secular changes in antithrombotic protocols. A consensus statement on the management of patients with continuous-flow devices recommended against routine anticoagulation with UFH in the immediate postoperative period in the absence of other indications.32 A target INR of 1.5-2.5 was also recommended with concomitant aspirin therapy (81-325 mg daily). It is not clear if changes in these preventive strategies contributed to the recently reported increased risk of LVAD thrombosis seen in early postoperative period.11 Given the Curr Probl Cardiol, December 2015

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relatively low risk of thrombotic events seen in the clinical trial experience and the lack of prospective data evaluating anticoagulation management strategies, clinical guidelines recommend following the protocols employed in the HMII and HVAD clinical trials targeting an INR of 2.0-3.0 with aspirin therapy.4,6,7,33 In the absence of bleeding, the International Society for Heart and Lung Transplantation Guidelines for MCS recommend heparin bridging in the early postoperative period starting on POD 1-2 with a PTT of 40-60 gradually up-titrated to a goal of 60-80 on POD 2-3.33 Whether antiplatelet therapy adjustment with thromboelastography may reduce the risk of LVAD thrombosis has not yet been explored, although it has been suggested to reduce the risk of GIB events.34 Patients with LVAD have greater time outside the therapeutic INR range than would be anticipated compared with patients treated with warfarin for other indications,35 and subtherapeutic INR has also been identified as a risk factor for the development of LVAD thrombosis.12,13 Patients in the HVAD clinical trial who developed a thrombus had proportion of time in a therapeutic INR range of 40% ⫾ 22.4% compared with 42% ⫾ 26.2% for those without LVAD thrombosis (P = 0.09), and an INR less than 2 was significantly associated with increased risk.13 Likewise, time outside the therapeutic window is reported to be a common cause of LVAD readmissions.36 Recommendations are not available to guide management of subtherapeutic INRs in out-patients supported by LVADs. A recent report documents the feasibility of a pharmacist-driven protocol using half dose of the low-molecular-weight heparin (LMWH) enoxaparin (0.5 mg/ kg subcutaneous injection twice daily) for patients with LVAD with an INR of r 1.7.37 In total, 27 courses of enoxaparin were administered to 18 patients with LVAD in the ambulatory setting with subtherapuetic INRs. Although the authors report a low risk of bleeding events, the efficacy of this approach remains uncertain and protocols vary widely between centers. Sandner et al report on the safety of bridging with LMWH in the early postoperative period within 24 hours of LVAD implantation. The protocol targeted an antifactor Xa level of 0.2-0.4 IU/mL until INR was 2-2.5,38 although antifactor Xa level monitoring is not routinely available at all hospitals. The optimal dose of LMWH to use as a bridge to therapeutic INR remains to be determined. Data are also limited to guide best practices during noncardiac procedures in patients with LVAD. When the risk of surgical bleeding is deemed acceptable, it is generally recommended that patients be bridged with heparin while awaiting the INR to reach a therapeutic range.33 Likewise, GIB may predispose to PT by virtue of interrupting 528

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anticoagulation.39 Clinical experience must guide decision making regarding the handling of anticoagulation during GIB episodes. In the absence of hemodynamic instability or for emergency procedures, we typically avoid acute reversal with administration of fresh frozen plasma. We also typically avoid use of vitamin K in the absence of a strong indication as it will lengthen the postoperative time necessary to achieve a therapeutic INR, although it may reduce the time of procedure. Gary S. Francis, MD: Bleeding in patients with a nonpulsatile LVAD, particularly GIB, is a common complication. Shearing of von Willebrand multimers leads to platelet dysfunction, and bleeding. GIB has been reported to be as high as 40% in these patients. Treatment of bleeding angioectasias can be difficult, and management usually involves supportive care, iron supplementation, blood transfusions when appropriate, and endoscopic therapy. Either the upper or the lower GI tract can be the source of bleeding, but the actual source frequently cannot be identified. There should be a high threshold for transfusion in bridge-to-transplant patients to avoid pre–heart-transplant allosensitization. Endoscopic therapy includes argon plasma coagulation, endoscopic hemoclips, bipolar electrocautery, or some combination of these techniques. Patients with nonpulsatile LVADs are often treated with chronic warfarin and antiplatelet agents to minimize thrombosis, but these agents undoubtedly facilitate GIB of an underlying lesion, such as angioectasias or arteriovenous malformations. Owing to the propensity of von Willebrand factor deficiency and platelet dysfunction that accompanies this deficiency in these patients, discontinuing antiplatelet therapy in patients who develop GIB should be considered.

Surgical Technique Surgical technique has been demonstrated to influence the risk of LVAD thrombosis. An analysis of the Columbia University experience found that 3 of 19 episodes of documented LVAD thrombus could be attributed to inflow cannula malposition.14 In a separate analysis of patients undergoing HMII implantation at 2 institutions, pump pocket depth was lower among patient who developed LVAD thrombosis and the angulation of the inflow cannula was greater compared with those without thrombosis (48.2 ⫾ 6.81 vs 65.4 ⫾ 9.91; P o 0.001). The pump pocket for the HMII needs to be adequately sized and the inflow cannula meticulously positioned to reduce the risk of LVAD thrombosis.

Device Management Lower rotational speeds associated with increased arterial pulsatility and more regular opening of the aortic valve has been associated with increased rates of LVAD thrombosis.40 More regular opening of the aortic valve Curr Probl Cardiol, December 2015

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leads to parallel circulation through the LVAD and the native aortic circulation, as opposed to in series from the heart through the LVAD. When flowing in parallel, reduced blood flow through the LVAD may result in reduced dissipation of heat and increased propensity to develop thrombus.41 Optimal pump speed is achieved when cardiac index and LV size are within reference range and the septum is midline. Although it is considered appropriate to have some residual pulsatility allowing intermittent aortic valve opening, the ideal frequency of aortic valve opening or necessary degree of arterial pulsatility has not yet been determined. The PREVENtion of HMII Pump Thrombosos (PREVENT) trial is ongoing prospective, multicenter study evaluating the incidence of HMII thrombosis when recommended clinical practices are adapted focusing on implantation technique, anticoagulation regimen, pump speed, and blood pressure management. This trial may help in guiding future preventive management strategies to minimize the risk of the development of LVAD thrombus.

Treatment of LVAD PT No uniform algorithm for the management of PT exists (Fig 9). When PT is suspected or confirmed, medical therapeutic interventions include UFH, glycoprotein IIb/IIIa inhibitors, DTIs, and thrombolytic therapy. These therapies may be administered alone or in combination. Clinical presentation may dictate the management strategy, as patients who are hemodynamically unstable with evidence of overt-LVAD malfunction and a low-output state should move rapidly to device exchange. Likewise, patients with evidence of persistent or worsening hemolysis despite medical therapy as well as those with end-organ dysfunction thought to be secondary to device thrombosis likely benefit from an early, invasive strategy. Depending on the clinical syndrome, patients with evidence of LVAD thrombosis complicated by thromboembolic events are also likely best served by LVAD exchange as first-line therapy. Finally, if there is evidence of inflow cannula malposition or outflow graft kinking, assuming surgical candidacy, a surgical approach is likely indicated.8 Urgent listing for transplantation can also be pursued if the estimated waiting time is short and HF symptoms can be managed medically. In the setting of a subacute presentation and in the absence of high-risk features, a stepwise approach may be reasonable, whereby higher risk interventions such as thrombolytic therapy are reserved for patients failing a more conservative strategy.42 Failure rates of medical therapy for LVAD thrombosis are high. The overall response to medical therapies among 530

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FIG 9. Potential management algorithm for suspected VAD thrombosis. VAD, ventricular assist device.

patients who developed LVAD thrombosis in the HVAD BTT clinical trial was 50%.13 It is unclear whether response rates to specific therapeutic interventions are similar between device platforms (axial flow and centrifugal flow). Additionally, adverse bleeding events with medical therapy are common.

Supportive Therapy Patients should be managed in a unit skilled in the monitoring and management of LVAD-related complications. Patients with evidence of a low-output state should be supported with inotropic therapies. Diuretics may be necessary depending on HF symptoms and the presence of congestion.

Heparin Heparin as monotherapy has rarely been reported as successful. In an analysis of the HVAD BTT trial, 5 patients were treated with heparin alone, none of whom had successful resolution.13 Furthermore, the medical interventions were reported hierarchically—individuals were listed only at Curr Probl Cardiol, December 2015

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the highest level therapy received and heparin was listed as the lowest level medical therapy. Of the 26 episodes treated initially with nonheparin medical therapy, it was not reported how many first failed heparin before transitioning to an alternative intervention. Gary S. Francis, MD: The practice at our center regarding PT is to admit the patient to the hospital, discontinue the warfarin, continue aspirin, and obtain a baseline anti-Xa level. Intravenous high-intensity UFH is started. We and others (McIlvennan CK, Page RL, Ambardekar AV, Breike A, Lindenfeld J. Activated partial thromboplastin time overestimates anti-coagulation in LVAD patients. J Heart Lung Transplant. 2014:12;1312-1314) have found that monitoring activated PTT (aPTT) overestimates the degree of anticoagulation in patients with LVADs. The aPTT may be falsely elevated in patients with continuous-flow LVADs leading to insufficient anticoagulation when infusing UFH. This may be partly owing to a defect in von Willebrand factor, which occurs in virtually all patients with nonpulsatile flow LVADs. There is speculation that the von Willebrand deficiency may allow for increased proteolysis of factor VIII leading to an increase in aPTT, but this mechanism has not been verified. Moreover, very recent data (Adatya et al. JACC-HF, 2015 in press) fail to support this hypothesis. We prefer to follow anti-Xa levels when using UFH in patients with suspected PT. A therapeutic anti-Xa level is 0.3-0.7 U/mL. I recognize that not all centers employ this approach, and the strategy of how patients with LVAD PT should be anticoagulated remains empirical and rests on local center experience.

Glycoprotein 2b3a Inhibitors Glyoprotein (GP) 2b3a inhibitors are a class of intravenous antiplatelet agents that prevent platelet aggregation and thrombus formation. Although successful case reports are available of GP2b3a,43,44 this reflects a publishing bias to report treatment success. Tellor et al45 report the largest single-center series of eptifibatide for the treatment of LVAD thrombus in 17 patients (16 HMII) with 22 separate episodes. Overall, 60% of patients received concomitant UFH. Of the 22 attempts, only 3 (18%) had resolution of 1 or more patient-specific indicators of LVAD thrombosis while also remaining free from continued hemolysis, death, pump exchange, or emergent heart transplant. Bleeding events occurred in 65% of patients during the infusion and 7 patients died. Intracranial hemorrhage was the cause of death in 2 of these cases. Similar to these findings, success with GP2b3a inhibitors was achieved in only 3 of 6 cases reported from the HVAD BTT clinical trial.13 Given their experience, Tellor et al45 conclude that the risk of eptifibatide outweighs potential therapeutic benefit. Of note, in this series, 41% of patients had evidence of LVAD dysfunction at the time of GP2b3a administration, suggesting a 532

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potentially late presentation of disease. It is unclear whether aggressive intervention before the onset of LVAD dysfunction would increase the probability of success.

Direct Thrombin Inhibitors A working group on LVAD thrombosis proposed an algorithm for the management of suspected LVAD thrombosis.8 A stepwise approach is recommended beginning with the administration of intravenous heparin. If resolution of hemolysis is not achieved, the authors recommend consideration of DTIs. DTIs can bind to both free as well as clot-bound fibrin. Although the safety of bivalirudin in patients with LVAD has not been reported, compared with UFH, it is associated with less bleeding when administered to patients undergoing percutaneous coronary intervention.46 A single-center experience in 6 patients with 10 episodes of suspected LVAD thrombosis reported a clinical response to bivalirudin in 9 of the 10 admissions.47 Response was defined as resolution of hemolysis allowing transition to warfarin and discharge to home. No major bleeding events were reported; however, 3 of the 6 responders developed recurrent thrombosis requiring LVAD exchange at later time points: 111-259 days after completion of bivalirudin therapy. A case series of 4 patients with LVAD thrombus also reported success with argatroban.48

Thrombolytics Successful reports of thrombolytic therapy administered centrally in the left ventricular cavity as well as systemically via peripheral venous cannulation are available.30,49,50 The largest experience from Duke University Medical Center reports a series of 8 patients who failed firstand second-line therapy with heparin and eptifibatide administered in a stepwise fashion.42 The tissue plasminogen activator (tPA) alteplase was infused via a pigtail catheter advanced across the aortic at a rate of 1 mg/ min over 30-50 minutes with concomitant UFH to achieve an activated clotting time 4200 seconds. Successful resolution of hemolysis was achieved in 3 patients, 3 patients died, and 1 underwent emergent LVAD exchange and another cardiac transplantation. In a separate multicenter experience, tPA led to successful resolution in 12 of 19 (63%) cases of LVAD thrombosis in the HVAD BTT trial.13 Success was similar whether it was administered peripherally (6 of 8 patients) or centrally (4 of 7 patients), whereas 4 patients (2 successful) did not have the site of administration recorded. As with other medical treatment options, it is unclear whether axial- or centrifugal-flow devices are more likely to Curr Probl Cardiol, December 2015

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respond differently to tPA. We consider tPA as a last-line therapy reserved for patients who have failed other medical therapies and are not a candidate for or decline LVAD exchange. Although treatment failure to medical therapy is high, survival among patients who successfully respond to medical therapy is high. In the HVAD trial, among patients who had medically treated thrombus, 180-day survival was 92%. Bleeding events and recurrence following early resolution are common. Among 6 patients successfully treated with bivalirudin, recurrence occurred in 3 patients at time points greater than 100 days after thrombus resolution.47 This allows a potential window of opportunity for cardiac transplantation among BTT recipients. Thus, assuming that greater safety data are generated, despite a high risk of recurrence, an early medical therapy approach may be reasonable among appropriately selective patients.

Surgical Exchange The high rate of medical treatment failure as well as the high risk of recurrence following early “success” leads to frequent device exchange among patients presenting with LVAD thrombosis. Thrombus recurrence, however, is also possible following LVAD exchange. There are patient characteristics that may predispose individuals to a prothrombotic state. Although failure to respond to medical therapy is common, freedom from recurrence is not guaranteed following exchange, and risk of recurrence should be discussed during the shared-decision-making process. Additionally, although alternative approaches are available, device exchange may require repeat sternotomy, which can increase the difficulty of subsequent sternotomy necessary at the time of transplantation in BTT recipients. Bleeding requiring transfusion at the time of exchange may also increase risk of allosensitization. Although survival following LVAD exchange has improved, exchange remains associated with increased mortality. Among patients enrolled in the INTERMACS registry, 12-month survival following initial implant as well as first and second exchanges were 80%, 65%, and 50%, respectively (P o 0.0001).3 A total of 77 replacement procedures were recorded among the 1128 patients enrolled in the HMII BTT and DT clinical trials.51 The etiology of LVAD malfunction leading to replacement included LVAD thrombosis in addition to other causes. There were 5 deaths (6.5%) within 30 days, and although long-term survival is reduced compared with the primary-implant procedure, device exchange can be performed safely. Survival among those who received an exchange for thrombus in the HVAD BTT trial was 69% at 180 days. Survival for the 4 patients going 534

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directly to exchange without an initial trial of medical therapy was 100%. Although this suggests an early surgical approach may be preferable to a delayed, stepwise strategy, an analysis of exchange events in the INTERMACS registry did not find a difference in survival for emergent vs elective device exchange.12 In contrast, the combined experience of 3 large academic medical centers led to the finding that survival following HMII exchange or urgent transplantation for device thrombosis was similar to HMII survival without thrombosis. Mortality at 180 days, however, among patients who were managed with neither transplantation nor replacement was 48.2%. Patients who were treated with medical therapy alone and did poorly were presumably not surgical candidates.11 This may account for the differences in survival seen among patients treated medically in the HVAD BTT trial reported earlier compared with the Starling et al11 experience.13 The Starling et al report highlights the significant mortality associated with LVAD thrombosis among patients who fail to respond with medical therapy alone. Causes of death following LVAD exchange include bleeding, right ventricular failure, multiorgan system failure, and device thrombosis.51 CT angiography of the LVAD is necessary to evaluate patency of the outflow graft. Evidence of outflow graft thrombosis may alter the surgical approach requiring a full sternotomy for outflow graft and pump exchange vs selective exchange of the pump alone. Presence of thrombus in the outflow graft may also dictate an early need for surgical intervention as opposed to an initial trial of medical therapy. Ota et al52 report the preferred technique via a subcostal approach for HMII exchange at Colombia University. In this series of 30 patients with LVAD thrombus undergoing HMII exchange, 16 patients underwent a subcostal approach whereas 14 had devices exchanged through a full sternotomy. Retrospective analysis of outcomes found that postoperative bleeding within 24 hours of surgery was less in the subcostal compared with the sternotomy group. Similarly, cardiopulmonary bypass times were significantly shorter in the subcostal group as was the risk of prolonged intubation. Subcostal exchange was also associated with reduced length of intensive care unit stay. There were no differences in other complications, including risk of death, between surgical groups. Avoidance of full median sternotomy is also possible for exchange of the HVAD via a lateral thoracotomy.53 The overall small number of events and heterogeneity of reported therapies do not allow strong inferences to be made about preferred strategies for the management of LVAVD thrombosis. Overall, findings seem to support a trial of medical therapy among patients who are Curr Probl Cardiol, December 2015

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clinically stable without evidence of device malfunction or a low-output state. If patients do not respond to early medical interventions, consideration should be given to moving expeditiously to LVAD exchange before the onset of clinical instability. Data supporting UFH as monotherapy are limited, and GP2b3a inhibitors have been associated with increased risk of bleeding. Although the safety profile of DTIs administered in other patient populations is reassuring, they are expensive and similarly lack data regarding therapeutic efficacy.

LVAD PT: Future Directions With an aging population, improved device engineering, improved management algorithms, and limited donor heart availability of orthotopic transplantation, the threshold for CF-LVAD implantation may begin to extend beyond patients with New York Heart Association IV HF. PT, however, remains a major cause of morbidity and mortality for patients with CF-LVAD . Future devices will require improved components to reduce the propensity for thrombosis, including bearingless, magnetically levitated pump systems; improved outflow graft designs; novel software algorithms that promote native aortic valve opening by modulating pump speeds; and specialized coatings to reduce platelet heat activation and aggregation. In addition, novel approaches to adjunct pharmacology will be required. Studies are needed to further characterize which patients are most likely to respond to medical interventions vs immediate device exchange. The preferred agent, dosage, and treatment duration are also not yet known. A biomarker that could help distinguish clot composition (platelet rich vs fibrin laden) would be anticipated to be useful to guide therapeutic decision making. It could be anticipated that depending on the clot composition, some patients may be less likely to respond to antithrombotic therapies and more likely to require LVAD exchange. Data are not available regarding the use of novel oral anticoagulants such as apixaban for thrombus prophylaxis in LVAD recipients, and these agents are not recommended for the prevention or treatment of LVAD thrombosis at the present time. In many ways, CF-LVAD thrombosis will mirror the natural history of coronary stent thrombosis, which underwent many years of basic, translational, engineering, and clinical investigation to limit this potentially life-threatening and debilitating complication. Gary S. Francis, MD: The authors are to be congratulated for this very up-todate and comprehensive review of this important and complex topic. PT in patients with nonpulsatile LVADs came on the scene approximately 2 years ago with the surprising publication by Starling et al. (Starling RC et al, 536

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Unexpected abrupt increase in LVAD thrombosis. N Engl J Med. 2014;370:3340). Several large transplant centers reported a substantial increase in PT during the rapidly growing use of nonpulsatile LVADs. PT and GIB continue to be important adverse effects in these patients, and have challenged HF specialists to better understand their causes and treatment. PT is the more serious of these 2 complications, is not rare, can be difficult to diagnose, and is sometimes fatal if unrecognized or mismanaged. The authors have provided us with a superb overview of how to anticipate, diagnose, and manage these problems. The lead author is an interventional cardiologist with advanced training in HF, and is especially well trained to deal with the complex problems of PT. Although guidelines have emerged regarding diagnosis and treatment of PT, this problem will continue to plague us for now, as the use of nonpulsatile LVADs continues to expand even beyond heart transplant centers. This is a complication that all cardiologists should at least be aware of, and should have knowledge of how suspected PT should be promptly triaged, diagnosed, and managed.

REFERENCES 1. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics—2014 update: a report from the American Heart Association. Circulation 2014;129(3):e28. 2. Lund LH, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung Transplantation: Thirty-first Official Adult Heart Transplant Report—2014; Focus Theme: Retransplantation. J Heart Lung Transplant 2014;33(10):996-1008. 3. Kirklin JK, Naftel DC, Pagani FD, et al. Sixth INTERMACS annual report: a 10,000patient database. J Heart Lung Transplant 2014;33(6):555-64. 4. Slaughter MS, Rogers JG, Milano CA, et al. Advanced heart failure treated with continuous-flow left ventricular assist device. N Engl J Med 2009;361(23):2241-51. 5. Pagani FD, Miller LW, Russell SD, et al. Extended mechanical circulatory support with a continuous-flow rotary left ventricular assist device. J Am Coll Cardiol 2009;54 (4):312-21. 6. Aaronson KD, Slaughter MS, Miller LW, et al. Use of an intrapericardial, continuousflow, centrifugal pump in patients awaiting heart transplantation. Circulation 2012;125 (25):3191-200. 7. Miller LW, Pagani FD, Russell SD, et al. Use of a continuous-flow device in patients awaiting heart transplantation. N Engl J Med 2007;357(9):885-96. 8. Goldstein DJ, John R, Salerno C, et al. Algorithm for the diagnosis and management of suspected pump thrombus. J Heart Lung Transplant 2013;32(7):667-70. 9. Cowger JA, Romano MA, Shah P, et al. Hemolysis: a harbinger of adverse outcome after left ventricular assist device implant. J Heart Lung Transplant 2014;33(1):35-43. 10. Shah P, Mehta VM, Cowger JA, Aaronson KD, Pagani FD. Diagnosis of hemolysis and device thrombosis with lactate dehydrogenase during left ventricular assist device support. J Heart Lung Transplant 2014;33(1):102-4. 11. Starling RC, Moazami N, Silvestry SC, et al. Unexpected abrupt increase in left ventricular assist device thrombosis. N Engl J Med 2014;370:33-40. Curr Probl Cardiol, December 2015

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12. Kirklin JK, Naftel DC, Kormos RL, et al. Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) analysis of pump thrombosis in the HeartMate II left ventricular assist device. J Heart Lung Transplant 2014;33(1):12-22. 13. Najjar SS, Slaughter MS, Pagani FD, et al. An analysis of pump thrombus events in patients in the HeartWare ADVANCE bridge to transplant and continued access protocol trial. J Heart Lung Transplant 2014;33(1):23-34. 14. Uriel N, Han J, Morrison KA, et al. Device thrombosis in HeartMate II continuousflow left ventricular assist devices: a multifactorial phenomenon. J Heart Lung Transplant 2014;33(1):51-9. 15. Boyle AJ, Russell SD, Teuteberg JJ, et al. Low thromboembolism and pump thrombosis with the HeartMate II left ventricular assist device: analysis of outpatient anti-coagulation. J Heart Lung Transplant 2009;28(9):881-7. 16. Slaughter MS, Naka Y, John R, et al. Post-operative heparin may not be required for transitioning patients with a HeartMate II left ventricular assist system to long-term warfarin therapy. J Heart Lung Transplant 2010;29(6):616-24. 17. Wang JX, Lee EH, Bonde P. Over 400% increase in LVAD thrombosis reported to the FDA’s manufacturer and user facility device experience (MAUDE) database from 2010 to 2012. J Heart Lung Transplant 2014;33(4):S9-10. 18. Stulak JM, Maltais S. A different perspective on thrombosis and the HeartMate II. N Engl J Med 2014;370(15):1467-8. 19. Taghavi S, Ward C, Jayarajan SN, Gaughan J, Wilson LM, Mangi AA. Surgical technique influences HeartMate II left ventricular assist device thrombosis. Ann Thorac Surg 2013;96(4):1259-65. 20. Uriel N, Morrison KA, Garan AR, et al. Development of a novel echocardiography ramp test for speed optimization and diagnosis of device thrombosis in continuousflow left ventricular assist devices: the Columbia ramp study. J Am Coll Cardiol 2012;60(18):1764-75. 21. Topilsky Y, Hasin T, Oh JK, et al. Echocardiographic variables after left ventricular assist device implantation associated with adverse outcome. Circ Cardiovasc Imaging 2011;4(6):648-61. 22. Fine NM, Topilsky Y, Oh JK, et al. Role of echocardiography in patients with intravascular hemolysis due to suspected continuous-flow LVAD thrombosis. JACC Cardiovasc Imaging 2013;6(11):1129-40. 23. Ammar KA, Umland MM, Kramer C, et al. The ABCs of left ventricular assist device echocardiography: a systematic approach. Eur Heart J Cardiovasc Imaging 2012;13 (11):885-99. 24. Jung MH, Hassager C, Balling L, Russell SD, Boesgaard S, Gustafsson F. Relation between pressure and volume unloading during ramp testing in patients supported with a continuous-flow left ventricular assist device. ASAIO J 2015;61(3):307-12. 25. Kato TS, Colombo PC, Nahumi N, et al. Value of serial echo-guided ramp studies in a patient with suspicion of device thrombosis after left ventricular assist device implantation. Echocardiography 2014;31(1):E5-9. 26. Nahumi N, Jorde U, Uriel N. Slope calculation for the LVAD ramp test. J Am Coll Cardiol 2013;62(22):2149-50. 538

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27. Estep JD, Vivo RP, Cordero-Reyes AM, et al. A simplified echocardiographic technique for detecting continuous-flow left ventricular assist device malfunction due to pump thrombosis. J Heart Lung Transplant 2014;33(6):575-86. 28. Estep JD, Vivo RP, Krim SR, et al. Echocardiographic evaluation of hemodynamics in patients with systolic heart failure supported by a continuous-flow LVAD. J Am Coll Cardiol 2014;64(12):1231-41. 29. http://www.cathlabdigest.com/articles/Management-Continuous-Flow-Left-Ventricu lar-Assist-Device-Patients-Cardiac-Catheterization-. 30. Kiernan MS, Pham DT, DeNofrio D, Kapur NK. Management of HeartWare left ventricular assist device thrombosis using intracavitary thrombolytics. J Thorac Cardiovasc Surg 2011;142(3):712-4. 31. Kapur NK, Upshaw J, Kiernan MS, Pham DT. Left ventricular assist device thrombosis presenting as an acute coronary syndrome. J Thorac Cardiovasc Surg 2014;147(6):e72-3. 32. Slaughter MS, Pagani FD, Rogers JG, et al. Clinical management of continuous-flow left ventricular assist devices in advanced heart failure. J Heart Lung Transplant 2010;29(4 Suppl):S1-39. 33. Feldman D, Pamboukian SV, Teuteberg JJ, et al. The 2013 international society for heart and lung transplantation guidelines for mechanical circulatory support: executive summary. J Heart Lung Transplant 2013;32(2):157-87. 34. Karimi A, Beaver TM, Hess PJ, et al. Close antiplatelet therapy monitoring and adjustment based upon thrombelastography may reduce late-onset bleeding in heartmate ii recipients. Interact Cardiovasc Thorac Surg 2014;18(4):457-65. 35. Jennings D, McDonnell J, Schillig J. Assessment of long-term anticoagulation in patients with a continuous-flow left-ventricular assist device: a pilot study. J Thorac Cardiovasc Surg 2011;142(1):e1-2. 36. Drews T, Dandel M, Krabatsch T, et al. Long-term mechanical circulatory support in 198 patients: largest single-center experience worldwide. ASAIO J 2011;57(1):9-16. 37. Borden M, Kiernan MS, Pham DT, DeNofrio D, Sylvia L. Bridging with halftherapeutic dose enoxaparin in outpatients with left ventricular assist devices and subtherapeutic international normalized ratios. J Heart Lung Transplant 2015. pii: S10532498(15)01029-3. 38. Sandner SE, Riebandt J, Haberl T, et al. Low-molecular-weight heparin for anticoagulation after left ventricular assist device implantation. J Heart Lung Transplant 2014;33(1):88-93. 39. Stulak JM, Lee D, Haft JW, et al. Gastrointestinal bleeding and subsequent risk of thromboembolic events during support with a left ventricular assist device. J Heart Lung Transplant 2014;33(1):60-4. 40. Saeed O, Maybaum S, Alessandro DD, Goldstein DJ, Patel SR. Aortic valve opening and thrombotic events with continuous-flow left ventricular assist devices. J Heart Lung Transplant 2014;33(1):109-12. 41. Mehra MR, Stewart GC, Uber PA. The vexing problem of thrombosis in long-term mechanical circulatory support. J Heart Lung Transplant 2014;33(1):1-11. 42. Schlendorf K, Patel CB, Gehrig T, et al. Thrombolytic therapy for thrombosis of continuous flow ventricular assist devices. J Card Fail 2014;20(2):91-7. Curr Probl Cardiol, December 2015

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43. Thomas MD, Wood C, Lovett M, Dembo L, O’Driscoll G. Successful treatment of rotary pump thrombus with the glycoprotein iib/iiia inhibitor tirofiban. J Heart Lung Transplant 2008;27(8):925-7. 44. Al-Quthami AH, Jumean M, Kociol R, et al. Eptifibatide for the treatment of heartmate ii left ventricular assist device thrombosis. Circ Heart Fail 2012;5(4):e68-70. 45. Tellor BR, Smith JR, Prasad SM, Joseph SM, Silvestry SC. The use of eptifibatide for suspected pump thrombus or thrombosis in patients with left ventricular assist devices. J Heart Lung Transplant 2014;33(1):94-101. 46. Bertrand OF, Jolly SS, Rao SV, et al. Meta-analysis comparing bivalirudin versus heparin monotherapy on ischemic and bleeding outcomes after percutaneous coronary intervention. Am J Cardiol 2012;110(4):599-606. 47. Sylvia LM, Ordway L, Pham DT, DeNofrio D, Kiernan M. Bivalirudin for treatment of lvad thrombosis: a case series. ASAIO J 2014;60(6):744-7. 48. Badiye A, Hernandez GA, Chaparro S. Argatroban as novel therapy for suspected thrombosis in patients with continuous-flow left ventricle assist device and hemolysis. ASAIO J 2014;60(3):361-5. 49. Jahanyar J, Noon GP, Koerner MM, et al. Recurrent device thrombi during mechanical circulatory support with an axial-flow pump is a treatable condition and does not preclude successful long-term support. J Heart Lung Transplant 2007;26(2):200-3. 50. Rothenburger M, Wilhelm MJ, Hammel D, et al. Treatment of thrombus formation associated with the micromed debakey vad using recombinant tissue plasminogen activator. Circulation 2002;106(12 Suppl 1):I189-92. 51. Moazami N, Milano CA, John R, et al. Pump replacement for left ventricular assist device failure can be done safely and is associated with low mortality. Ann Thorac Surg 2013;95(2):500-5. 52. Ota T, Yerebakan H, Akashi H, et al. Continuous-flow left ventricular assist device exchange: clinical outcomes. J Heart Lung Transplant 2014;33(1):65-70. 53. Deuse T, Reichenspurner H. Do not touch the sternum—thoracotomy incisions for hvad implantation. ASAIO J 2014;60(2):234-6. 54. Lahpor J, Khaghani A, Hetzer R, et al. European results with a continuous-flow ventricular assist device for advanced heart-failure patients. Eur J Cardiothorac Surg 2010;37(2):357-61. 55. Starling RC, Naka Y, Boyle AJ, et al. Results of the post-U.S. Food and Drug Administration-approval study with a continuous flow left ventricular assist device as a bridge to heart transplantation: a prospective study using the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support). J Am Coll Cardiol 2011;57(19):1890-8. 56. Park SJ, Milano CA, Tatooles AJ, et al. Outcomes in advanced heart failure patients with left ventricular assist devices for destination therapy. Circ Heart Fail 2012;5(2): 241-8.

540

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