Device Therapy for Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome with few options for effective pharmacologic therapies. Numerous device-based approaches to HFpEF therapy have emerged, which aim to treat the clinical and pathophysiologic features common to the varied causes of this syndrome. This review summarizes the current landscape of device therapy in HFpEF with a focus on structural interventions, such as left-to-right atrial shunts; cardiac contractility modulation; autonomic modulation, such as baroreflex activation therapy and splanchnic nerve modulation; and respiratory modulation, such as phrenic nerve stimulation.

Extracorporeal Ultrafiltration for Fluid Overload in Heart Failure: Current Status and Prospects for Further Research.

More than 1 million heart failure hospitalizations occur annually, and congestion is the predominant cause. Rehospitalizations for recurrent congestion portend poor outcomes independently of age and renal function. Persistent congestion trumps serum creatinine increases in predicting adverse heart failure outcomes. No decongestive pharmacological therapy has reduced these harmful consequences. Simplified ultrafiltration devices permit fluid removal in lower-acuity hospital settings, but with conflicting results regarding safety and efficacy. Ultrafiltration performed at fixed rates after onset of therapy-induced increased serum creatinine was not superior to standard care and resulted in more complications. In contrast, compared with diuretic agents, some data suggest that adjustment of ultrafiltration rates to patients' vital signs and renal function may be associated with more effective decongestion and fewer heart failure events. Essential aspects of ultrafiltration remain poorly defined. Further research is urgently needed, given the burden of congestion and data suggesting sustained benefits of early and adjustable ultrafiltration.

Effect of CYP2C9 and VKORC1 Gene Variants on Warfarin Response in Patients with Continuous-Flow Left Ventricular Assist Devices.

Bleeding and thrombotic complications continue to plague continuous-flow left ventricular assist device (CF-LVAD) therapy in patients with end-stage heart failure. Warfarin genotyping information can be incorporated into decision making for initial dosing as recommended by the Food and Drug Administration; however, clinical utility of this data in the CF-LVAD population has not been well studied. Genotypes testing for CYP2C9 and VCORC1 polymorphisms were determined in 90 CF-LVAD patients. Outcomes studied were the association of CYP2C9 (*1, *2, or *3) and VKORC1 (-1639 G>A) gene variants with time-to-target international normalized ratio (INR), total warfarin dose, maintenance warfarin dose. Continuous-flow left ventricular assist device patients carrying a rare variant in the VKORC1 gene had a significantly lower cumulative warfarin dose until target INR achieved (18.9 vs. 35.0 mg, p = 0.002), days spent until INR target achieved (4.9 vs. 7.0 days, p = 0.021), and discharge warfarin dose (3.2 vs. 5.6 mg, p = 0.001) compared with patients with wild-type genotype. Genotype-guided warfarin dosing may lead to safer anticoagulation and potentially improve outcomes in CF-LVAD patients.

Watchful Waiting in Continuous-Flow Left Ventricular Assist Device Patients With Ongoing Hemolysis Is Associated With an Increased Risk for Cerebrovascular Accident or Death.

BACKGROUND: Management of hemolysis in the setting of suspected device thrombosis in continuous-flow left ventricular assist device patients varies widely, ranging from watchful waiting with intensified antithrombotic therapy to early surgical device exchange. The aim of this study was to compare the outcomes of hemolysis events treated with surgical interventions versus medical management alone. METHODS AND RESULTS: A retrospective review of Heartmate II continuous-flow left ventricular assist device patients at 2 centers from January 2009 to September 2014 was completed. Patients were categorized as surgical management if hemolysis refractory to intensification of standard antithrombotic therapy was treated surgically. The primary end point was the first occurrence of cerebrovascular accident (CVA) or death. Sixty-four hemolysis events occurred in 49/367 patients implanted with Heartmate II continuous-flow left ventricular assist devices. Of 49 primary hemolysis events, 24 were treated with surgical interventions. After surgical treatment, 1 patient died and 2 experienced CVAs, as compared with 3 deaths and 9 CVAs in the 25 patients who remained on intensified antithrombotic therapy alone. The 1-year freedom from CVA or death was 87.5% and 49.5% in the surgical and medical cohorts, respectively (P=0.027). Resolution of a primary hemolysis event without CVA or death occurred in 21/24 patients treated with surgical interventions and in 13/25 who remained on medical therapy alone. A similar association between treatment and outcome was noted in the 15 recurrent hemolysis events. CONCLUSIONS: Hemolysis refractory to intensification of antithrombotic therapy identifies continuous-flow left ventricular assist device patients at major risk for CVA and death. Early device exchange should be considered to minimize these risks.

Outcomes after stroke complicating left ventricular assist device.

BACKGROUND: Stroke is one of the leading complications during continuous flow-left ventricular assist device (CF-LVAD) support. Risk factors have been well described, although less is known regarding treatment and outcomes. We present a large single-center experience on stroke outcome and transplant eligibility by stroke sub-type and severity in CF-LVAD patients. METHODS: Between January 1, 2008, and April 1, 2015, 301 patients underwent CF-LVAD (266 HeartMate II [HM I], Thoratec Corp, Pleasanton, CA; 35 HeartWare [HVAD], HeartWare International Inc, Framingham, MA). Stroke was defined as a focal neurologic deficit with abnormal neuroimaging. Intracerebral hemorrhage (ICH) definition excluded sub-dural hematoma and hemorrhagic conversion of an ischemic stroke (IS). Treatment in IS included intra-arterial embolectomy when appropriate; treatment in ICH included reversal of coagulopathy. Stroke severity was measured using the National Institutes of Health Stroke Scale (NIHSS). Outcomes were in-hospital mortality and transplant status. RESULTS: Stroke occurred in 40 patients: 8 ICH (4 HM II, 4 HVAD) and 32 IS (26 HM II, 6 HVAD). Among 8 ICH patients, there were 4 deaths (50%), with NIHSS of 18.8 ± 13.7 vs 1.8 ± 1.7 in survivors (p = 0.049). Among 32 IS patients, 12 had hemorrhagic conversion and 5 were treated with intra-arterial embolectomy. There were 9 deaths (28%), with NIHSS of 16.2 ± 10.8 vs 7.0 ± 7.6 in survivors (p = 0.011). Among the 32 IS patients, 12 underwent transplant, and 1 is awaiting transplant. No ICH patients received a transplant. CONCLUSIONS: In-hospital mortality after stroke is significantly affected by the initial neurologic impairment. Patients with IS appear to benefit the most from in-hospital treatment and often make sufficient recovery to be able to progress to transplant.

Antiplatelet Therapy and Adverse Hematologic Events During Heart Mate II Support.

BACKGROUND: Hematologic adverse events are common during continuous flow left ventricular assist device support; yet, their relation to antiplatelet therapy, including aspirin (ASA) dosing, is uncertain. METHODS AND RESULTS: A single-center retrospective review of all patients supported by a continuous flow left ventricular assist device (Heart Mate II) from June 2006 to November 2014 was conducted. Patients were categorized into 3 groups: (1) ASA 81 mg+dipyridamole 75 mg daily (n = 26) with a target international normalized ratio (INR) of 2 to 3 from June 2006 to August 2009; (2) ASA 81 mg daily (n = 18) from September 2009 to August 2011 with a target INR of 1.5 to 2; and (3) ASA 325 mg daily from September 2011 to November 2014 with a target INR of 2 to 3 (n = 70). Hemorrhagic and thrombotic outcomes were retrieved ≤ 365 days after implantation. Cumulative survival free from adverse events was calculated using Kaplan-Meier curves and Cox proportional hazard ratios were generated. Hemorrhagic events occurred in 6 patients on ASA 81 mg+dipyridamole (26%; 0.42 events per patient year; mean INR at event, 2.2), 4 patients on ASA 81 mg (22%; 0.38 events per patient year; mean INR at event, 2.0), and in 38 patients on ASA 325 mg (54%; 1.4 events per patient year; mean INR at event, 2.2); P = 0.004. Patients on ASA 325 mg had a higher adjusted hazard ratio of 2.9 (95% confidence interval, 1.2-7.0 versus ASA 81 mg+dipyridamole; P = 0.02) and 3.4 (95% confidence interval, 1.2-9.5 versus ASA 81 mg; P = 0.02) for hemorrhagic events. Thrombotic events rates were not different between groups. CONCLUSIONS: High-dose ASA in Heart Mate II patients treated concomitantly with warfarin is associated with an increased hazard of bleeding but does not reduce thrombotic events.

Continuous-flow left ventricular assist devices and usefulness of a standardized strategy to reduce drive-line infections.

BACKGROUND: Drive-line infection (DLI) is a common complication of left ventricular assist device (LVAD) support, leading to significant morbidity that jeopardizes the benefits of these devices. It has been reported that DLI incidence is related to drive-line dressing strategies. The aim of this study was to determine whether implementation of a standardized drive-line care kit would reduce the incidence of DLIs. METHODS: DLI data were collected prospectively on all LVAD patients implanted between 2009 and 2013 at Columbia University Medical Center. Drive-line care was altered on June 1, 2011, from a dry sterile dressing without a standard anchoring device to a standardized kit, which included silver gauze dressing and a standard anchoring device. The silver dressing was used until the wound incorporated, with a minimum of 1 month. RESULTS: During the study period, 107 patients were implanted with LVADs before implementation of a standardized kit (Group A) and 159 thereafter (Group B). Median follow-up time (censoring at June 2011) for Group A was 8.73 (IQR 3.51 to 17.47) months and 11.65 (IQR 6.66 to 35.20) months for Group B (p = 0.17). DLI event rate improved from 0.18 to 0.07 event per patient-year, corresponding to a relative risk reduction of 62.5%. In addition, the 1-year freedom from infection was significantly increased in Group B (92.46%) compared with Group A (81.94%) (log rank = 0.036). CONCLUSION: The use of a standardized kit, including silver dressing and a standard anchoring device, leads to decrease in DLI with an absolute risk reduction of 11%. Routine use of these dressing techniques is warranted based on our findings, and may lead to reduction of complications related to infections.

Outcomes of contemporary mechanical circulatory support device configurations in patients with severe biventricular failure.

OBJECTIVES: Severe right ventricular failure often is considered a contraindication for left ventricular assist device (LVAD) therapy and necessitates use of biventricular assist devices (BiVADs). Available options for BiVADs are limited, and comparative outcomes are largely unknown. METHODS: Heart transplant candidates who were registered on the United Network for Organ Sharing waitlist and underwent long-term contemporary LVAD (n = 3195) or BiVAD (n = 408) implantation, from January 2010 through June 2014, were retrospectively analyzed. We evaluated clinical characteristics and outcomes of patients requiring a BiVAD, as well as regional differences in utilization of this technology. RESULTS: Patients requiring a BiVAD were younger (48.9 vs 53.3 years), had a higher proportion of nonischemic disease (69.1% vs 58.2%), a higher bilirubin level (0.9 vs 0.7 mg/dL), and a lower 6-month survival rate (68.1% vs 92.7%) after device implantation (all P < .05). Postimplantation and posttransplantation survival was comparable for commonly used BiVAD configurations, including total artificial heart, continuous flow BiVAD, a continuous-flow LVAD coupled with a right-sided device, and pulsatile flow. Significant variation was found in regional utilization of these devices, regardless of differences in transplantation waitlist times. A large body surface area was an independent predictor of mortality on a BiVAD (hazard ratio = 2.12, P = .017). CONCLUSIONS: Outcomes of patients requiring a BiVAD remain poor in the contemporary device era, regardless of the configuration used. Among other clinical factors, body surface area should be incorporated into decision making for device selection in these patients.

Incidence and predictors of myocardial recovery on long-term left ventricular assist device support: Results from the United Network for Organ Sharing database.

BACKGROUND: Mechanical circulatory support (MCS) leads to favorable changes in the failing heart at the molecular, cellular, and structural levels. However, myocardial recovery leading to device explantation is rare. We reasoned that the multicenter United Network for Organ Sharing (UNOS) registry might provide insights into clinical predictors and outcomes of the recovery process. METHODS: The MCS device data set of the UNOS registry was queried for patients with long-term continuous-flow left ventricular assist devices (CF-LVADs) that were explanted for heart transplantation or indication of recovery. Analysis was restricted to adult patients (≥18 years old) who were listed for an initial heart transplantation. Patients with CF-LVADs that were explanted because of recovery were compared with patients with CF-LVADs who underwent transplantation. RESULTS: We identified 594 patients with HeartMate II devices and 92 patients with HeartWare devices. Duration of support was on average 500.4 ± 325.3 days. In 34 (5.0%) patients, devices were explanted secondary to myocardial recovery. Univariate predictors of recovery in patients with long-term LVADs included younger age (40 years vs 53 years), female sex, lower body mass index (25.7 kg/m(2) vs 27.9 kg/m(2)), non-ischemic etiology (91% vs 59%), lack of implantable cardioverter defibrillator at the time of listing (44% vs 79%), and lower serum creatinine (0.97 mg/dl vs 1.28 mg/dl) (all p < 0.05). In the post-explantation period, freedom from death or transplantation was 66% at 1 year. CONCLUSIONS: The incidence of recovery on device support is low in the current MCS era and limited to a select cohort of predominantly young patients with non-ischemic myopathy. Given the high incidence of disease recurrence, patients should be closely followed after device explantation.

Early post-operative ventricular arrhythmias in patients with continuous-flow left ventricular assist devices.

BACKGROUND: Ventricular arrhythmias (VAs) are common in patients with a continuous-flow left ventricular assist device (CF-LVAD). The causes and clinical significance of early post-operative VAs have not previously been characterized in these patients. The purpose of this study was to assess the incidence, precipitants, and clinical impact of early VAs in patients supported by CF-LVADs. METHODS: Patients with a long-term CF-LVAD receiving care between January 1, 2012, and March 1, 2014, were enrolled and followed prospectively. Implantable cardioverter-defibrillators (ICDs) were interrogated at baseline and throughout the follow-up period. VA was defined as ventricular tachycardia or ventricular fibrillation lasting >30 seconds or effectively terminated by appropriate ICD tachytherapy or external defibrillation. The primary end-point was the occurrence of early VAs (within 30 days of surgery). Secondary end-points were right ventricular (RV) failure and need for VA ablation. RESULTS: There were 162 patients enrolled, and 38 (23.5%) experienced at least 1 early VA. Predictors of early VA were a history of pre-operative VAs, non-ischemic cardiomyopathy, and older age. Several conditions frequently encountered in the early post-operative period were identified as possible precipitants for VA episodes. Early VAs were associated with post-operative RV failure, particularly when patients received shocks instead of anti-tachycardia pacing. CONCLUSIONS: Early VAs are common and are associated with RV failure. ICD shocks, but not anti-tachycardia pacing, for early VAs are associated with acute worsening of RV failure.

Left Ventricular Decompression During Speed Optimization Ramps in Patients Supported by Continuous-Flow Left Ventricular Assist Devices: Device-Specific Performance Characteristics and Impact on Diagnostic Algorithms.

BACKGROUND: Echocardiographic ramp tests have been widely used to help guide speed adjustments and for identification of potential device malfunctions in patients with axial continuous-flow left ventricular assist devices (LVADs) (Heartmate II LVAD [HMII]). Recently, the use of centrifugal-flow LVADs (Heartware LVAD [HVAD]) has been on the rise. The purpose of this study was to evaluate the utility of ramp tests for assessing ventricular decompression in HVAD patients. METHODS AND RESULTS: In this prospective study, ramp tests were performed before index hospitalization discharge or at the time of device malfunction. Vital signs, device parameters (including flow), and echocardiographic parameters (including left ventricular end-diastolic dimension [LVEDD], frequency of aortic valve [AV] opening, and valvular insufficiency) were recorded in increments of 100 rpm, from 2,300 rpm to 3,200 rpm. Twenty-six ramp tests were performed, 19 for speed optimization and 7 for device malfunction assessment. The average speed after the speed optimization ramp tests was 2,534.74 ± 156.32 RPM, and the AV closed at a mean speed of 2,751.77 ± 227.16 rpm, with 1 patient's valve remaining open at the maximum speed. The reduction in LVEDD for each speed increase was significantly different when the AV was open or closed, at -0.09 cm/increment and -0.15 cm/increment, respectively (P = .013), which is significantly different than previously established HMII LVEDD slopes. There were also significant changes in overall device flow (P = .001), upper flow (P = .031), and lower flow (P = .003) after AV closure. The power slope did not change significantly after the AV closed (P = .656). Five of the 19 tests were stopped before completion owing to suction events, but all tests reached ≥3,000 rpm. CONCLUSIONS: The parameter slopes for the HMII cannot be directly applied to ramp studies in HVAD patients. Overall, the LVEDD slope is drastically smaller in magnitude than the previously reported HMII findings, and speed adjustments were not based on the degree of left ventricular unloading. Therefore, the slope of the LVEDD-rpm relationship is not likely to be helpful in evaluating HVAD function.

Correlation Between Home INR and Core Laboratory INR in Patients Supported with Continuous-Flow Left Ventricular Assist Devices.

It has been well established that patient self-testing (PST) of international normalized ratio (INR) using home monitoring devices increases the average therapeutic time and patient satisfaction. Long-term anticoagulation therapy with warfarin is used in patients with continuous-flow left ventricular assist device (CF-LVAD) to minimize the occurrence of thromboembolic events; however, PST devices have never been tested in patients with CF-LVADs. The purpose of this study was to determine the reliability of the PST device Alere INRatio 2 in patients supported with CF-LVADs. A correlation study was performed in 50 patients with CF-LVAD who were on stable warfarin therapy for a minimum of 3 weeks. Simultaneous INR values were determined from capillary whole blood samples using the Alere PST device and venous blood samples processed in the core laboratory at Columbia University Medical Center. There was a moderate correlation between the venous and the capillary INR values with a correlation coefficient of 0.83. The median difference between the methods was 0.39, with 44 of 50 patients recording higher INRs with Alere. Results remained unchanged after adjusting for use of amiodarone, abnormal hematocrit and liver enzymes, creatinine, and thyroid-stimulating hormone. Point of care testing with Alere correlates moderately well but consistently overestimates INR when compared with conventional laboratory testing in patients with CF-LVAD.

Device exchange in HeartMate II recipients: long-term outcomes and risk of thrombosis recurrence.

Successful long-term use of the HeartMate II (HM II) left ventricular assist device has become commonplace but may be complicated by mechanical failure, infection, or thrombosis necessitating device exchange (DE). A subcostal approach to device exchange with motor exchange only is less traumatic, but long-term outcomes have not been reported. A retrospective chart review of all patients who required HM II to HM II device exchange at our institution was conducted. Of the 232 HM II patients implanted between January 2008 and July 2013, 28 required 36 device exchanges during a follow-up of 33.72 ± 17.25 months. The Kaplan-Meier 1 year survival was 63% for sternotomy exchanges and 100% for subcostal exchanges. Twenty-one exchanges were performed for initial or recurring device thrombosis. Although there was no difference in the risk of subsequent thrombosis after subcostal versus sternotomy exchange, the overall risk of recurring device thrombosis after device exchange for the same was high (31%). HM II device exchange via the subcostal approach has excellent short- and long-term outcomes. Device exchange performed for thrombosis is associated with a high recurrence risk irrespective of surgical approach.

Prior hematologic conditions carry a high morbidity and mortality in patients supported with continuous-flow left ventricular assist devices.

BACKGROUND: Mechanical support leads to an increased risk of both bleeding and thrombotic events, but little is known about the risk of device support in patients with a baseline predisposition to these events. The aim of this study was to examine outcomes among patients with baseline hematologic conditions who underwent continuous-flow LVAD implantation (CF-LVAD). METHODS: We retrospectively reviewed records of 286 patients who underwent CF-LVAD implantation at the Columbia University Medical Center between April 2008 and December 2013. Patients diagnosed with the following hematologic conditions were enrolled: idiopathic thrombocytopenic purpura (ITP); Factor V Leiden; elevated Factor VIII; heparin-induced thrombocytopenia (HIT); or undefined hypercoagulable state. RESULTS: Of the 286 CF-LVAD patients implanted during the study period, 12 were considered to have a significant hematologic condition predisposing them to either bleeding or thrombotic events. The study included 5 patients with ITP, 1 with Factor V Leiden, 1 with elevated Factor VIII, 2 with HIT and 3 patients with undefined hypercoagulable state. Patients were supported for a total of 168.46 months, with a median of 10.76 months (IQR 4.78 to 21.36 months). There was a high frequency of thrombotic (0.57 event per patient-year), neurologic (0.36 event per patient-year) and bleeding (0.64 event per patient-year). Actuarial survival rates at 6 and 12 months were 81.8%, but fell to 49% at 2 years. CONCLUSIONS: Patients with a history of prior hematologic conditions are at high risk for bleeding, thrombotic and neurologic events during device support, leading to early mortality. This case series questions the benefit of CF-LVAD in these patients and the appropriate management with regard to anti-coagulation. Further studies on the outcomes of these patients are warranted.