Ventricular Assist Device Therapy in Advanced Heart Failure

Ventricular Assist Device Therapy in Advanced Heart Failure

47  Ventricular Assist Device Therapy in Advanced Heart Failure Ulrich Jorde, Daniel B. Sims, Dmitri Belov OUTLINE Technology of Left Ventricular Ass...

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47  Ventricular Assist Device Therapy in Advanced Heart Failure Ulrich Jorde, Daniel B. Sims, Dmitri Belov

OUTLINE Technology of Left Ventricular Assist Devices, 493 Bridge to Transplantation, 494 Destination Therapy, 495 Bridge to Recovery, 496

Patient Selection and Evaluation, 496 Adverse Events, 498 Future Directions, 503

The development of reliable left ventricular assist devices (LVADs) has revolutionized heart failure (HF) management. In the cardiac intensive care unit (CICU) context, LVADs are encountered in three situations: first, selection of the appropriate heart failure patients for mechanical circulatory support (MCS) and preoperative evaluation; second, management of these patients perioperatively; and third, treatment of complications and prevention of adverse events. This chapter addresses these issues.

HeartMate II is capable of providing up to 10 L/min of support and is surgically inserted into a preperitoneal pocket (Fig. 47.2A). Blood is pulled out of the LV into the LV inflow cannula, accelerated by a rotor, and then ejected into the outflow graft, which is anastomosed to the ascending aorta. A percutaneous driveline exits in the upper abdomen and connects the device with a portable controller and two batteries for mobile operation, or to a power base unit (PBU) and a wall outlet when a patient is stationary for several hours (e.g., while sleeping). The device provides a constant flow of blood with one back-up speed used in case of a sudden drop of preload. The actual flow is calculated based on the power consumed and is not measured. The typical operating speed range is 8600 to 9600 rpm. Despite antithrombotic coating with titanium microbeads, anticoagulation with a target international normalized ratio (INR) of 2.0 to 3.0 and aspirin are recommended. In distinction to the axial-flow HeartMate II, the HVAD is a miniaturized centrifugal pump (Fig. 47.2B). The smaller size of this device allows implantation into the pericardial space and, often, a shorter operation. The housing contains an impeller suspended by magnets and the device is capable of providing 10 L/min of flow. The usual operating speed range is 2400 to 2800 rpm.1 The Jarvik 2000 (Jarvik Heart, Inc.) is an axial-flow LVAD positioned directly inside the LV and can be implanted through a lateral thoracotomy (Fig. 47.2C). The outflow graft can be anastomosed with the descending aorta, eliminating the need for a more traumatic median sternotomy. Also, the unique feature of this LVAD is that the driveline can be tunneled to a retroauricular area to decrease the risk of infections and allow for submersion in water (i.e., swimming). The Jarvik 2000 is currently in clinical trials in the United States. It is important to appreciate that the presence of a continuousflow device does not necessarily eliminate the presence of a palpable pulse on physical examination. This has an important consequence when measuring a patient’s blood pressure. In the

TECHNOLOGY OF LEFT VENTRICULAR ASSIST DEVICES The initial LVADs were volume displacement pumps known as pulsatile-flow devices. They filled during device diastole and ejected during device systole. As a result, all patients would have a pulse and a measurable systolic and diastolic blood pressure. The HeartMate XVE (Thoratec Corp.) and the Novacor pump, both implantable durable LVADs, could support the systemic circulation. However, both pumps had multiple moving parts, including bearings, valves, and pusher plates that were subject to failure. In addition, the pulsatile pumps were bulky, noisy, and their implantation required a major operation. A paradigm shift in the field of assisted circulation occurred with the introduction of durable, implantable continuous-flow devices. The rationale for continuous flow was the observation that the initial pulsatile flow in the aorta is progressively dampened, transforming into continuous nonpulsatile flow at the level of the capillary (Fig. 47.1). Continuous-flow LVADs have only a single moving part and propel blood forward in a steady, continuous fashion with an axial or centrifugal rotor or an impeller. With this simplified design, the risk of mechanical failure has been greatly reduced. Continuous-flow pumps are also smaller, lighter, and operate in virtual silence. Currently, the HeartMate II (St. Jude Medical) and the HeartWare HVAD (HeartWare) are the only US Food and Drug Administration (FDA)–approved continuous-flow LVADs. The

493

Pressure (mm Hg)

494

PART VI  Advanced Diagnostic and Therapeutic Techniques 120 100 80 60 40 20 0 Lt. Aorta Lg. Sm. Artevent. art. art. rioles

Caps.

Veins

Rt. Pul. vent. art.

Fig. 47.1  Pressure and pulsatility distribution in the systemic circulation. Caps., Capillaries; Lg. art., large artery; Lt. vent., left ventricle; Pulm. art., pulmonary artery; Rt. vent., right ventricle; Sm. art., small artery.

(AVMs). Second, the aortic valve may no longer open, leading to aortic valve fusion and the development of aortic insufficiency. Third, nonpulsatile flow could potentially predispose to pump thrombosis.3 The HeartMate 3 (St. Jude Medical) is a new intrapericardial centrifugal pump with a fully magnetically levitated impeller designed to overcome the shortcomings of older-generation pumps (Fig. 47.2D). A distinctive feature of the HeartMate 3 is an artificial pulsatility created by changing the impeller rotation speed at fixed time intervals (30 times/min). Clinical outcomes with the HeartMate 3 were recently compared with the HeartMate II pump in the MOMENTUM 3 trial.4 There were no significant differences between the groups in the rates of death or disabling stroke; however, a striking difference was observed in suspected or confirmed pump thrombosis (0% vs. 10.1% at 6 months; P < .001) and rate of reoperation for pump malfunction (0.7% vs. 7.7%, P = .002) favoring the newer HeartMate 3.4 It is anticipated that because of these important advantages, the HeartMate 3 has the potential to advance the field of MCS.

BRIDGE TO TRANSPLANTATION

A

B

C

D

Fig. 47.2  Axial (A, C) and centrifugal (B, D) left ventricular assist devices. (A) St. Jude HeartMate II. (B) HeartWare HVAD. (C) Jarvik 2000. (D) St. Jude HeartMate 3.

absence of a palpable pulse, mean arterial pressure (MAP) is measured via Doppler. The blood pressure cuff is inflated above where the Doppler tones are heard, and then the return of sounds auscultated via Doppler is taken as the MAP. MAP measured by Doppler overestimates pressure in the presence of palpable pulse and should not be reported.2 Instead, auscultation of the Korotkoff sounds should be performed. Specific adverse effects related to continuous-flow physiology have emerged. First, nonpulsatile blood flow can lead to gastrointestinal bleeding often owing to arteriovenous malformations

Bridge to transplantation (BTT) refers to the implantation of a durable LVAD in a patient with end-stage HF with the intent of improving the hemodynamics and clinical course until a donor heart is available. Because the demand for donor hearts is always higher than the supply, it is impossible to allocate a donor heart for everyone who needs it in a timely fashion. LVADs are a readily available cardiac replacement while the patient is waiting for a donor heart. As the donor shortage has worsened, the proportion of transplant recipients who required bridging with a durable LVAD increased from 26% in 2004 to more than 50% in 2014.5 In their 2001 landmark study, Frazier et al. summarized the multicenter experience with the pulsatile HeartMate VE LVAD on 280 heart transplant candidates.6 The outcomes were compared with a retrospectively matched cohort of 48 patients. This trial resulted in an impressive improvement of survival from 29% to 67% in the LVAD group at 180 days (Fig. 47.3A). These data indicated that continued management of these mostly desperately ill patients who were failing medical therapy (including an intraaortic balloon pump) without any LVAD support carries a grave prognosis. The outcome is even more impressive considering that the mean waiting time for a donor heart in the control group was only 4 days. Miller et al. evaluated outcomes of 133 patients listed for heart transplantation and bridged with the continuous-flow HeartMate II device.7 The primary outcome was defined as “recovered, transplanted or alive on device by 180 days.” Of the patients, 75% achieved the primary outcome, 19% died while on support, and 4% became ineligible for a transplantation due to irreversible medical complications during LVAD support. Investigators of the ADVANCE trial1 selected the same primary outcome and time point as in Miller et al. and compared the HeartWare HVAD with a cohort from The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) database who received almost exclusively axial-flow devices. An impressive 90.7% of patients receiving an HVAD achieved the

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CHAPTER 47  Ventricular Assist Device Therapy in Advanced Heart Failure

1.00

1.00 VE LVAD Historical Controls

0.90

80

0.70 0.60 0.50

Log-rank analysis: P < .0001

0.40 0.30

74 ± 3%

92 ± 2%

50

30 20 10 0

5

10

15

20

25 30 Weeks

35

40

45

Remaining at Risk 192 247 85 133 0

50

B

58 ± 4%

40

0.10 0

61 ± 3% 68 ± 4% DT Trial (n = 133) P (Log-Rank) = .2081

60

0.20

−0.00

A

DT Post Approval (n = 247)

70 Percent Survival

Percent Survival

0.80

90 ± 2%

90

6

169 82

151 69

12 Months

18

130 62 24

Fig. 47.3  Improvement of probability of survival in advanced heart failure patients treated with a left ventricular assist device. (A) Frazier et al.6 compared outcomes of patients listed for transplantation and bridged with a HeartMate XVE versus historical cohorts. (B) Jorde et al.14 demonstrated a trend toward better survival in the HeartMate II DT post-FDA approval group compared to the initial clinical trial,13 with an absolute difference of 74% vs. 68% at 1 year and 61% vs. 58% at 2 years. DT, Destination therapy; LVAS, left ventricular assist system. (A, From Frazier OH, et al. Multicenter clinical evaluation of the HeartMate vented electric left ventricular assist system in patients awaiting heart transplantation. J Thorac Cardiovasc Surg. 2001;122[6]:1186– 1195. B, From Jorde UP, et al. Results of the destination therapy post-Food and Drug Administration approval study with a continuous flow left ventricular assist device: a prospective study using the INTERMACS registry [Interagency Registry for Mechanically Assisted Circulatory Support]. J Am Coll Cardiol. 2014;63[17]:1751–1757.)

primary endpoint. The patients in the control arm, who almost exclusively received a HeartMate II pump, had a similar success rate of 90.1%. These early studies in a BTT population have proven that prompt implantation of an LVAD is the only meaningful chance for survival available to the sickest patients. These studies also demonstrated a substantial reversibility of organ damage: that is, implantation of LVADs was followed by a significant improvement in biochemical markers of kidney and liver injury.8 Poor durability remained a significant impediment in early LVAD trials.6,9 More recent LVAD models have improved durability and a reduced rate of adverse events. The more favorable adverse effects profile was achieved, at least in part, by miniaturization of LVADs with less dissection and surgical trauma required during the implantation.

DESTINATION THERAPY Destination therapy (DT) refers to the implantation of an LVAD in a patient with end-stage HF who is not a candidate for heart transplant or who is unwilling to undergo a transplant. The most recent INTERMACS report10 indicated that the number of LVADs implanted for BTT (45.7%) was almost equal to the number of LVADs implanted for DT. However, some experts suggest that LVADs still remain underutilized and expect increased use of LVADs for DT.11 It is important to highlight that heart transplantation currently remains the “gold standard” for management of end-stage HF. As a result, patients who receive a DT

LVAD are older and have more comorbidities—important facts to consider when interpreting DT trial results. In the landmark Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial, patients with end-stage HF were randomly assigned to undergo HeartMate I implantation or continued medical management.12 The principal finding of REMATCH was a significantly better survival of patients randomized to the HeartMate I LVAD compared to medically managed patients. Estimates of survival at 1 and 2 years were 52% and 23% in the device group and 25% and 8% in the medical therapy group, respectively. Analysis of mortality revealed that sepsis and LVAD failure were the leading causes of death.12 Of note, all device failure events occurred during the second year as durability was lacking owing to the multiple moving parts in the pulsatile-flow pump. In 2009, Slaughter et al.13 published outcomes of the first randomized trial comparing two LVADs for DT. The patients were assigned to receive either a pulsatile-flow HeartMate I or a continuous-flow HeartMate II. The primary study endpoint, “survival free from disabling stroke and reoperation to repair or replace the LVAD at two years” was achieved by 46% and 11% of patients in HeartMate II and HeartMate I groups, respectively. The survival in the HeartMate II group was better than the survival in the HeartMate I group (58% vs. 24%). Also, the HeartMate II LVAD had a lower hazard of adverse events compared to the HeartMate I LVAD: pump replacement hazard ratio (HR), 0.12 (95% confidence interval [CI], 0.06 to 0.26); right heart failure HR, 0.30 (95% CI, 0.16 to 0.57), sepsis HR, 0.35 (95% CI,

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0.21 to 0.57), and cardiac arrhythmias HR, 0.53 (95% CI, 0.33 to 0.83).13 More recently, Jorde et al.14 presented an analysis of a postapproval “real-world” HeartMate II experience in 247 patients. Several interesting observations were made. First, survival at 12 and 24 months improved to 74% and 61%, respectively; the best survival was achieved in less sick patients (Fig. 47.3B). Second, the risk of some serious adverse events over a 2-year period was even less than in the HeartMate II trial: bleeding 12% (vs. 30%), right heart failure 18% (vs. 23%), sepsis 19% (vs. 41%) and any arrhythmia 37% (vs. 56% in Slaughter et al).13,14 Impressively, with increased familiarity with and management of the pump, the survival rate and adverse-event profile improved outside of the clinical trial setting. In addition to the quantity of life, emphasis should be placed on the quality of life (QOL) post-LVAD and its equal importance to longevity. In this context, two important issues are worth considering. First, QOL does improve post-LVAD implantation. For example, in the HeartMate II DT trial, 80% of patients on a continuous-flow LVAD were in New York Heart Association (NYHA) class I or II 24 months postimplantation with a remarkable improvement of their scores on The Minnesota Living with Heart Failure and The Kansas City Cardiomyopathy Questionnaires.13 Finally, the improvement in exercise capacity, which is one of the components in QOL assessment, is often less than predicted due to limitations related to a suboptimal increase in cardiac output (CO) during exercise and associated comorbidities.15,16

BRIDGE TO RECOVERY A different approach for management of HF consists of a combination of MCS with aggressive medical therapy to promote LV recovery. If LV function normalizes, the device could potentially be explanted. Initial enthusiasm with “bridge to recovery” (BTR) dropped off after the realization that only a small proportion (1% to 2%) of patients in large datasets could be weaned from MCS.17 However, when patients were initially classified as BTR at time of implant, they did have higher rates of recovery compared to BTT or DT (11.2% vs. 1.2%). Younger age, nonischemic etiology, and short duration of HF were variables associated with a greater likelihood of recovery. Recently, enthusiasm for a BTR strategy has been renewed by promising short-term results from the Remission from Stage D Heart Failure (RESTAGE-HF) study.18

PATIENT SELECTION AND EVALUATION If a patient is found to be a suitable candidate for an LVAD, particular attention should be paid to the patient’s candidacy for heart transplantation and the timing of implantation. Because most of the indications for MCS evolved from historical indications for heart transplantation, a common clinical dilemma is whether to proceed with an LVAD implant or wait for cardiac transplantation. If the patient is a candidate for heart transplantation and if a prolonged wait time for a donor heart is anticipated, it might be reasonable to proceed with a durable LVAD if no contraindications

exist to ensure hemodynamic and clinical stability while on the waiting list. In addition, patients on LVADs are less likely to become deconditioned and lose muscle mass than those on chronic inotropic therapy.19 Conversely, in a stabilized patient with a favorable blood type and projected short wait time for a donor heart, the best decision might be to wait for a primary transplant without a bridging LVAD. It is important to note that in the United Network of Organ Sharing (UNOS) registry, overall posttransplant survival of patients requiring bridging with an LVAD is the same as patients who are transplanted without having received an LVAD first, with the only exception being patients with increased transplant urgency status due to device infection who possibly have decreased survival.20 For the purpose of prognostication and rapid assessment of patients with severe symptomatic HF, a staging system was developed known as the INTERMACS profiles.21 INTERMACS profile I (“crash and burn”) includes the sickest patients with cardiogenic shock who are hemodynamically unstable despite inotropes and/or counterpulsation. Death is imminent without escalation of support for these patients. A temporary MCS might be a good option in some of these patients while assessing potential reversibility of LV and end-organ damage. If the LV damage is beyond recoverable (or is unlikely to recover without durable LVAD) and the need for assisted circulation persists, evaluation for a durable LVAD should be performed. Currently, the majority (66%) of patients evaluated for LVAD are INTERMACS profile II (“sliding”) and INTERMACS profile III (“stable on inotropes”); the benefit of LVAD is well proven in these patients.10 Long-term therapy with inotropes is associated with poor survival and it is reasonable to proceed with an evaluation for durable LVAD as soon as the patient is declared inotrope dependent. An important observation can be made comparing 1-year survival of INTERMACS II and III patients with the sickest INTERMACS I profile. When an LVAD is implanted for INTERMACS profile I patients, survival to hospital discharge is only 70.4%.When an LVAD is implanted for INTERMACS profile II or III patients, survival to discharge is improved at 93.5% and 95.8%, respectively.22 As a result of this observation, fewer LVADs are now implanted for INTERMACS profile I (only 14.3% in 2014). An appropriate strategy for these very sick patients has evolved to include temporary MCS to allow for reversal of endorgan damage and achievement of clinical stability prior to proceeding with a durable LVAD. One-fifth of LVADs are implanted into patients not receiving inotropes or temporary MCS (INTERMACS profiles IV to VII).10 The recent Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients (ROADMAP) trial addressed suitability of these patients for MCS.23 In this observational trial, outcomes of 200 advanced HF noninotrope-dependent patients with NYHA classes IIIB/IV symptoms were evaluated. In a nonrandomized fashion, patients with 6-minute walk distance less than 300 m and at least one hospitalization for HF in the last year could elect to have an LVAD implanted or elect to continue with optimal medical therapy. While LVAD patients experienced more frequent adverse outcomes (mainly bleeding), NYHA class and health-related QOL were still better with an LVAD23 compared to medically managed



CHAPTER 47  Ventricular Assist Device Therapy in Advanced Heart Failure

497

Ambulatory outpatients

Inpatients with evidence of advanced HF (e.g., inotropes, hypotension)

CPET VO2 <14 mL/kg/min

VO2 >14 mL/kg/min

Candidate for OHT? Yes Patient is expected to get a heart in short time? Yes OHT

No LVAD BTT

Continue to optimize medical therapy No Candidate for LVAD? Yes

DT LVAD

No Palliative care, home inotropes, or clinical trial entry as appropriate

Fig. 47.4  A simplified algorithm of patient selection for left ventricular assist device (LVAD) support. Currently, only patients who are not candidates for OHT should be considered for DT LVAD. BTT, Bridge to transplantation; CPET, cardiopulmonary exercise test; DT, destination therapy; LVAD, left ventricular assist device; OHT, orthotopic heart transplantation.

patients. Findings from the ROADMAP study could yield two interpretations: (1) noninotrope-dependent patients who are severely functionally limited may be appropriate for LVAD therapy and (2) the identical 1-year mortality rates argue for a watchful waiting approach. A proposed algorithm for LVAD evaluation is presented in Fig. 47.4. Absolute contraindications for LVAD implantation are any irreversible end-stage organ damage that can limit survival after LVAD surgery. This includes cirrhosis, permanent hemodialysis, dementia or severe stroke, severe COPD, and malignancy with life expectancy less than 2 years.24 In the CICU setting, important additions to this list include terminal multiorgan failure, ongoing bacteremia, incessant ventricular tachycardia, significant coagulation abnormalities, high bleeding risk, contraindications to anticoagulation with warfarin, severe RV dysfunction, and pregnancy. All contemporary LVADs require the patient’s or caregiver’s ability to comprehend and act upon controller alarms, change batteries, and clean the driveline exit site. Patients and caregivers who are unable to take care of the device due to a medical or psychosocial issue cannot be considered for a durable LVAD. The decision about advanced cardiac therapies in patients with a history of cancer should be made in conjunction with an oncologist. Typically, even patients with recently treated cancer may be candidates for DT if their estimated life expectancy is more than 2 years.24 A number of conditions represent obstacles to achieving optimal life expectancy and QOL. These important relative contraindications for LVAD include severe peripheral vascular disease, poorly controlled diabetes with complications, severe malnutrition, frailty, and lack of a supportive caregiver. Chronic kidney dysfunction traditionally belongs to this group; however, the numeric value for a low glomerular filtration rate (GFR) or an elevated creatinine to set as a contraindication is a subject of ongoing debate. Previous studies demonstrated that renal

function usually improves post-LVAD in the majority of patients; however, it starts to decline again after 1 year of support.25 We consider presence of a primary renal disease with creatinine 2.5 mg/dL or greater despite optimization of hemodynamics with inotropes and/or temporary MCS as a relative contraindication for DT LVAD. However, in exceptional cases, an option of LVAD bridging followed by a combined heart-kidney transplantation may be considered. Although transplantation remains the gold standard for management of end-stage HF patients, some important advantages of LVADs over heart transplantation exist. Individuals with pulmonary vascular resistance greater than 5 Wood units can be supported by an LVAD in the absence of concomitant RV failure.11,26 Several publications indicate that so-called “fixed” pulmonary hypertension (pulmonary hypertension that does not improve despite medical therapy) does, in fact, improve post-LVAD implantation.26,27 Second, obesity with a body mass index greater than 35 kg/m2 is only a relative contraindication for MCS. In addition, improvement of hemodynamics and clinical state with an LVAD may allow a morbidly obese patient to undergo bariatric surgery and thus lose weight to become a heart transplant candidate. Third, on rare occasions in patients who would be unable to tolerate immunosuppressive therapy owing to drug interactions or are otherwise unwilling to undergo a transplant for personal reasons, DT LVAD offers better survival than optimal medical therapy.14 Because of the complexity of the decisions in advanced HF patients, LVAD centers have specialized protocols and teams dedicated to selecting appropriate candidates for MCS. A standard minimal workup should include evaluation by a heart failure specialist, social worker, psychiatrist, palliative care team, and a cardiothoracic surgeon. We found that palliative care consultants are particularly helpful coordinating decision making; such consultation is now mandated by the Center for Medicare Services

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for DT implants. Because all contemporary FDA-approved LVADs require antithrombotic therapy, a history of bleeding diathesis must be investigated and documented. Individuals with a prior unprovoked deep venous thrombosis or pulmonary embolism should have a full hypercoagulable workup performed and be evaluated by a hematologist. Infectious diseases, nephrology, and hepatology consultants should see the patients as appropriate. For hospitalized decompensated patients, placement of a pulmonary artery catheter is required for optimization of right-sided pressures prior to the surgery (right atrial pressure below 15 mm Hg is a reasonable goal). For patients with a history of coronary artery bypass graft surgery, a chest computed tomographic (CT) scan is indicated to map bypass grafts and prevent trauma to them during the surgery. Cardiac anatomy and the presence of concomitant structural heart disease, including intracardiac thrombi, should be evaluated with an echocardiogram. Atrial septal defects, including patent foramen ovales, should be closed during cardiopulmonary bypass. Their absence should be confirmed by a bubble study in all patients, as their presence in the setting of an LVAD would turn a left-to-right shunt into a right-to-left shunt and lead to hypoxia. Because aortic regurgitation is likely to progress on a continuousflow LVAD, in every patient with more than mild aortic insufficiency, the valve should be repaired or replaced with a bioprosthesis. Presence of a mechanical aortic valve is not a contraindication for an LVAD; however, the valve should be patch-closed or exchanged with a bioprosthesis to prevent left ventricular outflow tract and valve thrombosis. Patients with a bioprosthetic aortic valve or any prosthetic valve in the mitral position do not require any additional procedures. Moderate and severe mitral valve stenosis is extremely rare in LVAD candidates, but if present (Fig. 47.5), it should prompt correction

A

during the surgery. On the other hand, even severe mitral insufficiency does not necessarily require additional mitral valve procedures, as it is prone to improve after LVAD implantation owing to normalization of LV filling pressures and reverse LV remodeling. Tricuspid valve insufficiency is extremely common in this population, but the approach to its management is a subject of controversy. Recent analysis of six studies addressing this issue showed that tricuspid valve repair was associated with longer cardiopulmonary bypass time without any early mortality or morbidity benefits.28 Other small studies suggest that tricuspid valve repair does not decrease the rate of late right heart failure.29

Adverse Events Table 47.1 lists some of the adverse events post-LVAD placement. Of note, despite frequent hospitalizations for an adverse event, the majority of patients spend greater than 90% of their time out of the hospital.30 The two major perioperative complications are surgical bleeding and right ventricular (RV) failure. Early reports noticed an elevated risk of mediastinal bleeding post-LVAD compared to other open-heart procedures.31 Importantly, bleeding requiring reoperation and the number of units transfused correlated with 1-year mortality in some studies.32 Significant delayed bleeding requires interruption of anticoagulation and may predispose to pump thrombosis. Conversely, before and during initiation of unfractionated heparin, chest tube output should be meticulously monitored. Cardiac tamponade is suggested by a combination of elevated central venous pressure (CVP) and hypotension and mandates an emergent echocardiogram to look for pericardial effusion or pericardial hematoma in order to differentiate tamponade from RV failure. Although respiratory variation of the pulsatility index has been described to diagnosis cardiac

B Fig. 47.5  Transthoracic apical four-chamber view of a 47-year-old woman with mitral stenosis, mitral regurgitation, and nonischemic cardiomyopathy. (A) End diastole. The mitral valve leaflets are thickened and have a “hockey-stick” appearance (arrow); the left atrium is enlarged. Color flow mapping shows characteristic aliasing proximal to the stenotic mitral valve (arrowheads) and “candle-flame” diastolic left ventricular (LV) inflow. Mitral valve area by pressure half-time was 1.3 cm2 on transesophageal echocardiography. (B) Systolic frames demonstrate lack of LV contraction and severe mitral regurgitation. The patient underwent left ventricular assist device placement and mitral valve replacement (see Video 47.1).

CHAPTER 47  Ventricular Assist Device Therapy in Advanced Heart Failure



499

TABLE 47.1  Adverse Events Presented per

Patient-Year in Individuals With HeartMate II (HM II) LVAD and HVAD Adverse Events Bleeding requiring reoperation Gastrointestinal bleeding Drive-line infection Sepsis Right hear failure Stroke Ischemic stroke Hemorrhagic stroke Pump thrombosis De novo aortic insufficiency

Hm II Event Rate

HVAD Event Rate

0.09–0.23

0.19–0.26

0.17–0.38 0.12–0.37 0.18–0.35 0.16–0.36 0.083–0.13 0.031–0.06 0.052–0.07 0.024–0.027 0.22–0.32

0.23–0.27 0.08–0.25 0.04–0.24 0.04–0.33 0.12–0.2 0.09–0.11 0.08–0.09 0.07–0.08 NRa

LVAD, Left ventricular assist device; NR, not recorded. a One report73 suggests low incidence of de novo aortic insufficiency in HVADs equipped with Lavare cycle not available in the United States. Modified from Slaughter MS, et al. Advanced heart failure treated with continuous-flow left ventricular assist device. N Engl J Med. 2009;361(23):2241–2251; Jorde UP, et al. Results of the destination therapy post-Food and Drug Administration approval study with a continuous flow left ventricular assist device: a prospective study using the INTERMACS registry (Interagency Registry for Mechanically Assisted Circulatory Support). J Am Coll Cardiol. 2014;63(17):1751– 1757; Jorde UP, et al. Prevalence, significance, and management of aortic insufficiency in continuous flow left ventricular assist device recipients. Circ Heart Fail. 2014;7(2):310–319; and Soleimani B, et al. Development of aortic insufficiency in patients supported with continuous flow left ventricular assist devices. ASAIO J. 2012;58(4):326–329.

tamponade,33 it and other physical examinations findings, such as pulsus paradoxus, are not reliable and an echocardiogram is always needed (Fig. 47.6). Emergent drainage or hematoma evacuation is the only definitive treatment of cardiac tamponade. Approximately 1 out of 5 patients develop some form of RV failure after LVAD surgery. Unfortunately, it is difficult to predict this prior to LVAD implantation.34 INTERMACS defines early RV failure as a need for a prolonged (>14 days) course of inotropes or placement of a right ventricular assist device (RVAD). With a functioning LVAD in place, cardiac output is dependent on the ability of the RV to provide sufficient preload to the left side of the heart; however, increased RV preload may unmask preexisting RV failure. Changes in RV geometry are also important. Although multiple algorithms were suggested to predict the development of RV failure, they performed poorly when applied to individual patients.35 The presence of elevated CVP and significant RV dilation raises concerns that additional RV support may be required perioperatively. Patients with low pulmonary artery pressure in the setting of high CVP have, in fact, already developed RV failure. Patients with significant RV failure despite initial treatment, including inhaled nitric oxide, should not leave the operating room without an RVAD. In a study by Takeda et al., the development of RV failure requiring an RVAD identifies patients with a poor prognosis.36 Those with an unplanned RVAD had only a 49% chance to be weaned from

Fig. 47.6  A transthoracic echocardiogram from a patient with refractory hypotension shortly post–left ventricular assist device implantation. Parasternal long-axis view shows a large anterior hematoma (arrow) and posterior pericardial effusion causing compression of the right ventricle free wall (arrowheads) and small LV cavity (see Video 47.2).

RVAD support and 6-month survival in the unweaned subgroup was dismal (13%). The availability of the percutaneously placed Impella RP (Abiomed, Inc.) offers a new and enticing temporary mechanical support option for the failing RV. This platform has the ability to be removed at the bedside without requiring a repeat trip to the operating room to reopen the chest.37 Pharmacologic treatment of early and late RV failure consists of optimization of preload, augmentation of RV contractility, and reduction of pulmonary vascular resistance. If the patient is hypotensive and vasoplegic, a preferential vasoconstrictor is vasopressin, which does not increase pulmonary vascular resistance as all other vasopressors do.38 LVAD speed must be optimized to avoid any left heart contribution to elevated pulmonary pressure. Care must be taken to optimize the speed to keep the interventricular septum midline and allow the RV to have a geometric shape conducive to contraction. Nitric oxide followed by sildenafil39 in combination with milrinone are used as pharmacologic agents to lower pulmonary artery pressures. Macitentan is currently being evaluated for treatment of pulmonary hypertension in post-LVAD patients.40 Occasionally, late refractory RV failure dictates placement of an RVAD and heart transplantation listing if pulmonary vascular resistance is permissive. The importance of the RV in the management of LVAD patients cannot be overstated. With intermediate and long-term use, common LVAD complications are infection and gastrointestinal bleeding. The relative immunosuppression of critical illness and the presence of large amounts of foreign material leave LVAD patients particularly susceptible to infectious complications. Infections in LVAD patients can be classified into VAD-specific, VAD-related, and non-VAD infections.41 LVAD-specific infections can occur in the device pocket or surrounding surgical area, along the percutaneous drive lines, and inside the device itself. Goldstein et al. found that 19% of patients with a continuous-flow device had a percutaneous site infection (PSI) at 1 year.42 Trauma of the driveline exit site is important in the pathogenesis of PSI.

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In the same study, young age was the only risk factor identified in the development of a PSI. This is likely due to a more active lifestyle in younger patients, predisposing to driveline trauma. Mean time to the first PSI was 6.6 months.42 This highlights the importance of ongoing driveline care in the prevention of infection postdischarge. The majority of the PSIs were bacterial (87.5%), with Staphylococcus and Pseudomonas emerging as the most common organisms.34 No pathogen is isolated in 11.5% of patients.43 Evaluation of LVAD patients with a suspected infection should include a complete blood count, blood cultures, and chest radiograph. All patients with purulent drainage from a surgical site or driveline should have samples sent for Gram stain, KOH, and routine bacterial and fungal cultures. When physical examination is equivocal for the extent of the infection or a surgical collection is suspected, imaging with a CT or ultrasound scan may be helpful. For patients with positive blood cultures with a pathogen known to cause endocarditis, an echocardiogram should be obtained. A consensus statement recommends diagnosis of VAD-related endocarditis according to several major and minor criteria similar to the modified Duke criteria.41 Management of device-related infections is challenging owing to the formation of an antibiotic-resistant biofilm on the surface of the device that is virtually resistant to penetration with antimicrobial agents. A prolonged course of culture-guided antibiotics is usually required. The risk of superinfection and morbidity is high. In one study of 40 superficial PSIs, 13 (32.5%) progressed to deep infections.43 When the infection spreads deep along the driveline or to the pocket, surgical drainage with removal of infected tissue and obtaining a deep culture is necessary. The use of sustained-release antibiotic beads has been reported by some groups.44 The most severe form of infection, VAD-related endocarditis, is rare. Urgent listing for transplantation or pump exchange once the blood cultures are sterile is required and suppressive antibiotics are necessary as long as the LVAD is still in place. Because prevention of LVAD-related infections is extremely important, methicillin-resistant Staphylococcus aureus (MRSA) decontamination, in addition to meticulous care of the driveline exit site, is strongly emphasized.45 Gastrointestinal (GI) bleeding in LVAD patients is common. The observed higher GI bleeding rate in continuous-flow LVADs does not obviate the importance of antithrombotic management in thrombosis prevention (discussed later). The rate of GI bleeding following continuous-flow LVAD implantation ranges from 23 to 63 events per 100 patient-years46,47 and is disproportionately high compared to patients receiving warfarin for other indications (i.e., anticoagulation for mechanical valves, which carries a major bleeding risk of 1.2–2.6 events per 100 patient-years).48,49 Formation of GI tract AVMs and acquired von Willebrand deficiency syndrome have been proposed as mechanisms responsible for this discrepancy. The latter condition is caused by destruction of large biologically active multimers of von Willebrand factor by the pump and resolves after cardiac transplantation.50 In the Study of Reduced Anti-Coagulation/Anti-Platelet Therapy in Patients with the HeartMate II LVAS (US-TRACE) trial, deescalation of double antithrombotic therapy to a single or even no agent still resulted in a subsequent major bleeding event in 43%

of patients within 1 year. This illustrates the intrinsic predisposition of continuous-flow LVAD recipients to bleeding complications even with minimal or no antithrombotic therapy.51 Aspirin dose is an important factor that can potentially contribute to bleeding. Saeed et al. retrospectively compared different regimens of aspirin therapy.52 While the rate of thrombotic events was similar in patients with a HeartMate II LVAD, bleeding episodes were three times more likely for the group taking aspirin 325 mg compared to 81 mg. However, in the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial, low-dose aspirin was found to be associated with HVAD thrombosis and strokes.53,54 This is an example of a device-specific thrombotic and bleeding profile requiring a device-specific therapy. Most LVAD bleeding events are managed therapeutically with blood transfusion and proton pump inhibitors. Initial evaluation of overt bleeding should include endoscopy in an attempt to locate and manage the source of blood loss. The upper GI tract is responsible for 40% to 50% of bleeding events from gastric erosions, ulcers, or AVMs. In one meta-analysis,55 obscure bleeding was present in 19% of patients; it was speculated that most of these cases originated from angiodysplasias in the duodenum or jejunum. Endoscopic maneuvers to stop bleeding are usually successful in the short term; however, in up to 50% of patients, rebleeding occurs.56 Capsule endoscopy has limited diagnostic accuracy but should be considered for recurrent and obscure bleeding events. Similarly, octreotide should be considered for all patients with GI bleeding and angiodysplasias, although experience with this agent is primarily reported in case reports and case series.57,58 Pump thrombosis is a potentially fatal complication of continuous-flow LVADs. According to the INTERMACS registry, the peak of pump thrombosis occurs within the first 3 months after LVAD insertion. An abrupt increase of pump thrombosis in 2010 to 2012 still remains poorly understood but was possibly related to a loosening of anticoagulation requirements, changing thrombosis definition, changes in thrombosis screening, or device design changes. All potential causes of thrombosis could be classified as related to the patient, pump, or management.59 Pump-related factors are unique for each device and stem from abnormal flow and interactions between the blood components and LVAD surface. For example, in the HeartMate II pump, globular clots were reported on the inflow bearings and in regions of sharp angulation.60 In contrast, laminar fibrin deposits develop on the impeller of HVAD pumps when a thrombotic event occurs.61 Outflow graft kinking or impingement of the inflow cannula by the interventricular septum (Fig. 47.7) or LV free wall can also result in altered flow patterns and thrombosis.62 Patient-related factors include a preexisting or acquired hypercoagulable state, infection, sepsis, or dehydration.59 Subtherapeutic INR is the most commonly encountered management-related factor. Similarly, erythropoietin use is associated with LVAD thrombosis and should be avoided.63 Hypertension with a MAP greater than 90 mm Hg with the potential to decrease pump flow is another risk factor identified in the ADVANCE study.53 Pump thrombosis has a diverse spectrum of clinical presentations. Asymptomatic device alarms or hemolysis with darkening

CHAPTER 47  Ventricular Assist Device Therapy in Advanced Heart Failure



A

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B Fig. 47.7  In this patient with HeartMate II left ventricular assist device the inflow cannula (arrowheads) was malpositioned and the tip was occasionally impinged by interventricular septum (arrows), causing symptoms (see Video 47.3). (A) Apical four-chamber view showing the circularappearing left ventricular device inflow cannula abutting the interventricular septum. (B) Parasternal long-axis view showing the inflow cannula abutting the interventricular septum.

B

A

Fig. 47.8  M-mode echocardiograms from the same patient in Fig. 47.7 with a (A) normally functioning HeartMate II left ventricular assist device and (B) pump thrombosis. In A, the aortic valve is closed on each beat. In B, the left ventricle is now distended and the aortic valve opens on every beat (arrow). Pump thrombosis was confirmed during a device exchange (see Video 47.4).

of the urine might be the only sign of pump thrombus.64 On the other side of this spectrum are patients with thromboembolic events, new HF, and cardiogenic shock. Understanding that elevation of plasma lactate dehydrogenase (LDH) level is related to pump thrombosis allows early diagnosis of this condition by routine measurement of LDH levels.59 Release of LDH is likely caused by blood cell destruction secondary to deposition of thrombotic material on different pump components. In addition to LDH level, all patients with a suspected pump thrombus should be admitted to the hospital, started on unfractionated heparin or bivalirudin, and should have a chest radiograph and echocardiogram. Findings suspicious for pump thrombus include poor LV uploading, worsening of mitral regurgitation (MR) and one-to-one opening of a previously closed aortic valve (Fig. 47.8). CT angiogram may be useful to evaluate the position of the inflow cannula and the outflow graft.

An echocardiographic ramp study has proven valuable in HeartMate II patients with an LV end-diastolic dimension slope absolute value of less than 0.16, which is highly suggestive of obstructive thrombus.59 The same benefit of an echocardiographic ramp study was not demonstrated for HeartWare patients. Instead, the log files should be reviewed for presence of power spikes (Fig. 47.9).65 If the peak power is elevated less than 200% and growth rate of the power curve is less than 1.25, then thrombolysis might be helpful. On the other hand, outcomes of thrombolysis for HeartMate II thrombosis were unsatisfactory. This highlights the importance of pump- and patient-specific treatment decisions. Emergent pump exchange or cardiac transplantation is the recommended treatment for HeartMate II and HVAD thrombosis with red alarms, pump stoppage, or shock.65 While controversial, emerging data indicate that it may be useful to exchange a HeartMate II pump even in the absence of pump malfunction or hemodynamic compromise. In a study by Levin et al.,66

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1st treatment Sept. 29

10000

Pump exchange Oct. 6

Power (mWatts)

9000 8000 7000 6000 5000 4000 3000

2nd treatment Oct. 2

2000 1000 0 00:03:47 09/21/10

00:00:00 09/23/10

00:00:00 09/25/10

00:00:00 09/27/10

00:00:00 09/29/10

00:00:00 10/01/10

00:00:00 10/03/10

00:00:00 10/05/10

00:00:00 10/07/10

Fig. 47.9  HVAD power consumption during pump thrombus and after multiple treatments. A device thrombus in which the patient received two unsuccessful doses of tissue plasminogen activator (on September 29 and October 2) before eventually requiring a pump exchange on October 6. (Modified from Jorde UP, et al. Identification and management of pump thrombus in the HeartWare left ventricular assist device system: a novel approach using log file analysis. JACC Heart Fail. 2015:3[11]:849–856.)

B

A

Fig. 47.10  A patient with a left ventricular assist device (LVAD) had recalcitrant ventricular tachycardia. (A) Parasternal long-axis view demonstrates almost complete obliteration of LV cavity (arrow). A large pleural effusion was an incidental finding (arrowhead). (B) The study was repeated after administration of intravenous fluids and LVAD speed decrease. LV cavity size has increased to 4 cm (arrow). The patient was no longer in ventricular tachycardia after improvement in the LV chamber size (see Video 47.5).

HeartMate II patients with an LDH level greater than 700 U/L refractory to medical therapy who underwent device exchange through a subcostal approach had a lower 1-year risk of stroke and death compared to those who were managed with continued medical therapy (87.5 vs. 49.5%). LVAD patients with sustained ventricular tachycardia (VT) may tolerate the arrhythmia without hemodynamic collapse. However, VT should be managed urgently to avoid deterioration of RV function. The majority of patients will have some symptoms at presentation, although they may not be specific. The correct diagnosis relies entirely on obtaining an electrocardiogram. The majority of VT occurs within the first 30 days of device

implantation67 and might be caused by electrolyte abnormalities, β-blocker withdrawal, and the proarrhythmic effect of inotropes. A history of preoperative VT68 and the absence of β-blockade67 were identified as predisposing factors for VT in the early postoperative setting. Possible mechanisms of monomorphic VT include creation of a reentrant loop around the inflow cannula or preexistent scars. An LVAD-specific cause of VT is a suction event.69 This occurs when the LV wall comes in contact with the inflow cannula in the setting of volume depletion or too high a pump speed. Rapid identification by echocardiogram is essential so that the speed can be decreased or volume given to correct this mechanical cause of VT (Fig. 47.10).



CHAPTER 47  Ventricular Assist Device Therapy in Advanced Heart Failure

Management of VT consists of discontinuing proarrhythmic drugs, correction of electrolyte abnormalities, appropriate use of β-blockers and antiarrhythmic drugs, and timely echocardiogram to rule out suction. LVAD speed might need to be adjusted in the presence of suction events. In situations in which VT cannot be controlled, VT ablation can be attempted. Late aortic insufficiency (AI) has emerged as a complication of long-term therapy with continuous-flow devices. The pathogenesis of AI relates to the loss of aortic valve opening followed by fusion of the leaflets. At least moderate AI is expected to develop in 38% of patients after 3 years if an aortic valve opening strategy is not prospectively used.70 Persistent recirculation of blood from the LVAD to the LV and back to the LVAD creates a closed loop. Although patients may present with symptoms of HF, the clinical significance of less than severe AI post-LVAD is unknown. An increase in LVAD flow might be the first clue to the development of this condition. Diagnostic evaluation is complicated by the fact that traditional echocardiographic methods of AI assessment underestimate its severity.71 The best management

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approach is unknown. However, in severe symptomatic cases, use of transcatheter or surgical aortic valve replacement has been described.72

FUTURE DIRECTIONS The field of MCS has advanced considerably in the previous two decades. An entirely new paradigm related to continuous-flow devices has emerged. Careful patient selection and prompt recognition and management of complications have been shown to improve outcomes.10,14 Research on smaller, minimally invasive pumps, hemocompatible pumps, and fully implantable pumps without a driveline are ongoing. The ultimate goal of therapy with an LVAD is to provide uncomplicated long-term hemodynamic support appropriate to circulatory demands. The full reference list for this chapter is available at ExpertConsult.com.



CHAPTER 47  Ventricular Assist Device Therapy in Advanced Heart Failure

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19. McCarthy PM. Implantable left ventricular assist device bridge-to-transplantation: natural selection, or is this the natural selection? J Am Coll Cardiol. 2002;39(8):1255–1257. 20. Healy AH, et al. Impact of ventricular assist device complications on posttransplant survival: an analysis of the United network of organ sharing database. Ann Thorac Surg. 2013;95(3):870–875. 21. Stevenson LW, et al. INTERMACS profiles of advanced heart failure: the current picture. J Heart Lung Transplant. 2009;28(6):535–541. 22. Boyle AJ, et al. Clinical outcomes for continuous-flow left ventricular assist device patients stratified by pre-operative INTERMACS classification. J Heart Lung Transplant. 2011;30(4):402–407. 23. Estep JD, et al. Risk assessment and comparative effectiveness of left ventricular assist device and medical management in ambulatory heart failure patients: results from the ROADMAP study. J Am Coll Cardiol. 2015;66(16):1747–1761. 24. Feldman D, 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):157–187. 25. Tromp TR, de Jonge N, Joles JA. Left ventricular assist devices: a kidney’s perspective. Heart Fail Rev. 2015;20(4):519–532. 26. Martin J, et al. Implantable left ventricular assist device for treatment of pulmonary hypertension in candidates for orthotopic heart transplantation-a preliminary study. Eur J Cardiothorac Surg. 2004;25(6):971–977. 27. Mikus E, et al. Reversibility of fixed pulmonary hypertension in left ventricular assist device support recipients. Eur J Cardiothorac Surg. 2011;40(4):971–977. 28. Dunlay SM, Deo SV, Park SJ. Impact of tricuspid valve surgery at the time of left ventricular assist device insertion on postoperative outcomes. ASAIO J. 2015;61(1):15–20. 29. Oezpeker C, et al. Tricuspid valve repair in patients with left-ventricular assist device implants and tricuspid valve regurgitation: propensity score-adjusted analysis of clinical outcome. Interact Cardiovasc Thorac Surg. 2015;21(6): 741–747. 30. Forest SJ, et al. Readmissions after ventricular assist device: etiologies, patterns, and days out of hospital. Ann Thorac Surg. 2013;95(4):1276–1281. 31. Goldstein DJ, Beauford RB. Left ventricular assist devices and bleeding: adding insult to injury. Ann Thorac Surg. 2003;75(suppl 6):S42–S47. 32. Schaffer JM, et al. Bleeding complications and blood product utilization with left ventricular assist device implantation. Ann Thorac Surg. 2011;91(3):740–747, discussion 747–749. 33. Zalawadiya SK, Lindenfeld J, DiSalvo T. Rapid diagnosis of cardiac tamponade using pulsatility index variability in a patient with a HeartWare ventricular assist device. Circulation. 2015;131(13):e387–e388. 34. Kormos RL, et al. Right ventricular failure in patients with the HeartMate II continuous-flow left ventricular assist device: incidence, risk factors, and effect on outcomes. J Thorac Cardiovasc Surg. 2010;139(5):1316–1324. 35. Loghmanpour NA, et al. A bayesian model to predict right ventricular failure following left ventricular assist device therapy. JACC Heart Fail. 2016;4(9):711–721. 36. Takeda K, et al. Outcome of unplanned right ventricular assist device support for severe right heart failure after implantable left ventricular assist device insertion. J Heart Lung Transplant. 2014;33(2):141–148.

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37. Anderson MB, et al. Benefits of a novel percutaneous ventricular assist device for right heart failure: the prospective RECOVER RIGHT study of the Impella RP device. J Heart Lung Transplant. 2015;34(12):1549–1560. 38. Tsuneyoshi I, et al. Hemodynamic and metabolic effects of low-dose vasopressin infusions in vasodilatory septic shock. Crit Care Med. 2001;29(3):487–493. 39. Hamdan R, et al. Prevention of right heart failure after left ventricular assist device implantation by phosphodiesterase 5 inhibitor. Artif Organs. 2014;38(11):963–967. 40. https://clinicaltrials.gov/ct2/show/NCT02554903. U.S. National Institutes of Health, 2016. 41. Hannan MM, et al. Working formulation for the standardization of definitions of infections in patients using ventricular assist devices. J Heart Lung Transplant. 2011;30(4):375–384. 42. Goldstein DJ, et al. Continuous-flow devices and percutaneous site infections: clinical outcomes. J Heart Lung Transplant. 2012;31(11):1151–1157. 43. Koval CE, et al. Evolution and impact of drive-line infection in a large cohort of continuous-flow ventricular assist device recipients. J Heart Lung Transplant. 2014;33(11):1164–1172. 44. McKellar SH, et al. Treatment of infected left ventricular assist device using antibiotic-impregnated beads. Ann Thorac Surg. 1999;67(2):554–555. 45. Sinha P, et al. Infections during left ventricular assist device support do not affect posttransplant outcomes. Circulation. 2000;102(19 suppl 3):III194–III199. 46. Crow S, et al. Gastrointestinal bleeding rates in recipients of nonpulsatile and pulsatile left ventricular assist devices. J Thorac Cardiovasc Surg. 2009;137(1):208–215. 47. Boyle AJ, 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):881–887. 48. Cannegieter SC, et al. Optimal oral anticoagulant therapy in patients with mechanical heart valves. N Engl J Med. 1995;333(1):11–17. 49. Cannegieter SC, Rosendaal FR, Briet E. Thromboembolic and bleeding complications in patients with mechanical heart valve prostheses. Circulation. 1994;89(2):635–641. 50. Uriel N, et al. Acquired von Willebrand syndrome after continuous-flow mechanical device support contributes to a high prevalence of bleeding during long-term support and at the time of transplantation. J Am Coll Cardiol. 2010;56(15):1207–1213. 51. Katz JN, et al. Safety of reduced anti-thrombotic strategies in HeartMate II patients: a one-year analysis of the US-TRACE Study. J Heart Lung Transplant. 2015;34(12):1542–1548. 52. Saeed O, et al. High dose antiplatelet therapy increases early bleeding risk but does not reduce thrombotic events in patients with CF-LVADs. J Heart Lung Transplant. 34(4): S209-S210. 53. Najjar SS, 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. 54. Teuteberg JJ, et al. The HVAD left ventricular assist devicerisk factors for neurological events and risk mitigation strategies. JACC Heart Fail. 2015;3(10):818–828. 55. Draper KV, Huang RJ, Gerson LB. GI bleeding in patients with continuous-flow left ventricular assist devices: a systematic

review and meta-analysis. Gastrointest Endosc. 2014;80(3): 435–446 e1. 56. Cushing K, Kushnir V. Gastrointestinal bleeding following LVAD placement from top to Bottom. Dig Dis Sci. 2016;61(6):1440–1447. 57. Uriel N. Alternative Approaches to Reccurent Bleeding Octreotide, Hormonal Therapy, etc; 2016. ISHLT 2016: 36th Annual Meeting and Scientific Sessions. Oral presentation. 58. Juricek C, et al. Use of long acting octreotide in an outpatient clinic reduces the rate of gastro-intestinal bleeding in continuous flow LVAD patients. J Heart Transplant. 35(4):S82–S83. 59. Uriel N, et al. Device thrombosis in HeartMate II continuousflow left ventricular assist devices: a multifactorial phenomenon. J Heart Lung Transplant. 2014;33(1):51–59. 60. Kirklin JK, 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. 61. Aissaoui N, et al. HeartWare continuous-flow ventricular assist device thrombosis: the Bad Oeynhausen experience. J Thorac Cardiovasc Surg. 2012;143(4):e37–e39. 62. Taghavi S, et al. Surgical technique influences HeartMate II left ventricular assist device thrombosis. Ann Thorac Surg. 2013;96(4):1259–1265. 63. Nassif ME, et al. Clinical outcomes with use of erythropoiesis stimulating agents in patients with the HeartMate II left ventricular assist device. JACC Heart Fail. 2015;3(2):146–153. 64. Birati EY, et al. Ventricular assist device thrombosis: a wide spectrum of clinical presentation. J Heart Lung Transplant. 2015;34(4):613–615. 65. Jorde UP, et al. Identification and management of pump thrombus in the HeartWare left ventricular assist device system: a novel approach using log file analysis. JACC Heart Fail. 2015;3(11):849–856. 66. Levin AP, et al. Watchful waiting in continuous-flow left ventricular assist device patients with ongoing hemolysis is associated with an increased risk for cerebrovascular accident or death. Circ Heart Fail. 2016;9(5). 67. Refaat M, et al. Ventricular arrhythmias after left ventricular assist device implantation. Pacing Clin Electrophysiol. 2008;31(10):1246–1252. 68. Garan AR, et al. Ventricular arrhythmias and implantable cardioverter-defibrillator therapy in patients with continuousflow left ventricular assist devices: need for primary prevention? J Am Coll Cardiol. 2013;61(25):2542–2550. 69. Vollkron M, et al. Suction events during left ventricular support and ventricular arrhythmias. J Heart Lung Transplant. 2007;26(8):819–825. 70. Jorde UP, et al. Prevalence, significance, and management of aortic insufficiency in continuous flow left ventricular assist device recipients. Circ Heart Fail. 2014;7(2):310–319. 71. Grinstein J, et al. Accurate quantification methods for aortic insufficiency severity in patients with LVAD: role of diastolic flow acceleration and systolic-to-diastolic peak velocity ratio of outflow cannula. JACC Cardiovasc Imaging. 2016;9(6): 641–651. 72. Parikh KS, et al. Percutaneous transcatheter aortic valve closure successfully treats left ventricular assist device-associated aortic insufficiency and improves cardiac hemodynamics. JACC Cardiovasc Interv. 2013;6(1):84–89.



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73. Bhagra S, et al. Development of de novo aortic valve incompetence in patients with the continuous-flow HeartWare ventricular assist device. J Heart Lung Transplant. 2016;35(3):312–319.

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