Beyond Stage C: Considerations in the Management of Patients With Heart Failure Progression and Gaps in Evidence.

Despite treatment with contemporary medical therapies for chronic heart failure (HF), there has been an increase in the prevalence of patients progressing to more advanced disease. Patients progressing to and living at the interface of severe stage C and stage D HF are underrepresented in clinical trials, and there is a lack of high-quality evidence to guide clinical decision making. For patients with severe HF phenotypes, the medical therapies used for patients with less advanced stages of illness are often no longer tolerated or provide inadequate clinical stability. The limited data on these patients highlights the need to increase formal research characterizing this high-risk population. This review summarizes existing clinical trial data and incorporates our considerations for approaches to the medical management of patients advanced "beyond stage C" HF.

Epidemiology of Left Ventricular Assist Device Infections: Findings From a Large Nonregistry Cohort.

BACKGROUND: Infection is a major complication during circulatory support with a left ventricular assist device (VAD). Changes in device characteristics and treatment practices in the last decade can affect the epidemiology of infection. The International Society for Heart and Lung Transplantation (ISHLT) has published recommendations on the prevention and management of VAD infections, but data to support these recommendations remain sparse. METHODS: We performed a retrospective review of 455 patients who underwent VAD placement from 2009 to 2015. Infection episodes were defined using ISHLT criteria and were also grouped as endovascular or local. Analysis included descriptive statistics. RESULTS: There were 174 patients (38.6%) with a VAD infection. Infection incidence was 36.9 cases per 100 person-years of VAD support. The driveline was the most common infection site (67.2%). Systemic inflammatory response syndrome (SIRS) criteria were not satisfied in 29.2% of patients with endovascular infections, and computed tomography (CT) examinations were normal in 37.7% of cases. Gram-positive bacteria caused 65.6% of infections in patients with an available culture. Antimicrobial suppression was used in 72.3% of patients who survived treatment. Median survival after infection was 35 months for patients with VAD-related infections versus 14 months for patients with VAD-specific infections. CONCLUSIONS: VAD infections continue to be a major complication after implantation. Clinical criteria alone were not predictive of serious infections, and many patients with confirmed infection had normal CTs. Patients with VAD-specific infections had lower median survival than patients with VAD-related infections.

Clinical Significance of Early Fluid and Weight Change During Acute Heart Failure Hospitalization.

AIMS: To explore the association of changes in weight and fluid during treatment for acute heart failure (AHF) with clinical endpoints. METHODS AND RESULTS: Weight and net fluid changes recorded at 72-96 hours in 708 AHF patients enrolled in Diuretic Optimization Strategy Evaluation in Acute Decompensated Heart Failure, Cardiorenal Rescue Study in Acute Decompensated Heart Failure, and Renal Optimization Strategies Evaluation in Acute Heart Failure studies were compared with freedom from congestion at 72-96 hours and a composite endpoint of death, rehospitalization, and unplanned hospital visit at 60 days. Weight loss was concordant with net fluid loss in 55%, discordant and less than expected for fluid loss in 34%, and paradoxically discordant or more than expected for fluid loss in 11% of patients. Weight loss, but not fluid loss, was associated with freedom from congestion (odds ratio per 1-kg weight loss = 1.11 [1.03-1.19]) and a nominal reduction in the composite endpoint (hazard ratio per 1-kg weight loss = 0.98 [0.95-1.00]). Outcomes were similar in patients with concordant and discordant weight-fluid loss. CONCLUSION: During treatment for AHF, early changes in weight may be more useful for identifying response to therapy and for predicting outcomes than net fluid output. Nearly one-half of patients receiving decongestive therapies demonstrate discordant changes in weight and fluid; however, discordance was not associated with outcomes.

Internal driveline damage under the costal margin several years after HeartMate II implant: a series of three cases.

Although the incidence of driveline failure has been significantly reduced with the major modification to the driveline connection to the HeartMate II left ventricular assist device (LVAD), internal and external driveline damage continues to be a major reason for pump exchange or driveline repair. We report three cases of internal driveline damage under the costal margin and in the adjacent abdominal wall. All three cases developed occasional electrical disruptions 2-5 years after the original LVAD implant through the median sternotomy. Two patients underwent subcostal LVAD exchange and one had driveline externalization and repair. The driveline velour was well adhered to the costal margin and wire damage was found at the costal margin as well as the subsequent segment in the abdominal wall. Repeated ante-flex bending of the abdominal wall over years appeared to cause the chronic wear and tear of the vertically located driveline under the costal margin. This report will confirm a pitfall of the LVAD driveline location which can potentially cause driveline damage in the mid-to-long term.

Cardiomyopathy in patients after posttransplant cyclophosphamide-based hematopoietic cell transplantation.

BACKGROUND: The use of posttransplant cyclophosphamide (PT-Cy) has contributed significantly to the success of haploidentical hematopoietic cell transplantation (HCT). Furthermore, several studies have shown promising results in the human leukocyte antigen-matched setting. However, the use of high-dose cyclophosphamide has been associated with the development of cardiomyopathy. There is a paucity of data concerning posttransplant cardiac complications in patients undergoing PT-Cy-based HCT. METHODS: A retrospective analysis of 176 patients undergoing HCT with PT-Cy was performed. The overall survival, left ventricular ejection fractions, brain natriuretic peptide levels, and cardiac comorbidities were reviewed. The associations between comorbidities and the onset of heart failure were assessed with a Cox proportional hazards model. RESULTS: Pretransplant cardiomyopathy was found in 16 patients (9.1%) but had no effect on their posttransplant overall survival. Thirty-five patients (21.9%) developed posttransplant cardiomyopathy, which correlated with increased mortality, but this was not statistically different from the frequency-matched non-PT-Cy cohort. The majority of these cardiomyopathies occurred in the setting of an infectious milieu. An age greater than 60 years and an HCT comorbidity index score equal to or greater than 4 were the only risk factors that correlated with posttransplant cardiomyopathy. CONCLUSIONS: The presence of pretransplant cardiomyopathy does not negatively affect overall survival for patients who undergo HCT with PT-Cy. Furthermore, cardiomyopathy in PT-Cy patients is not caused by PT-Cy but is mostly concurrent with infectious complications and is associated with reduced overall survival. Traditional cardiovascular risk factors do not fully predict the occurrence of posttransplant cardiomyopathy. Future research is required to unravel predictive factors for cardiomyopathy after PT-Cy-based HCT. Cancer 2017;123:1800-1809. © 2017 American Cancer Society.

Use of adenosine diphosphate receptor inhibitor prior to left ventricular assist device implantation is not associated with increased bleeding.

Current guidelines recommend adenosine diphosphate receptor inhibitors (ADPRi) be discontinued 5-7 days prior to cardiac surgery due to increased bleeding events, rates of re-exploration, and transfusions. However, the risks of left ventricular assist device (LVAD) implantation in patients taking an ADPRi have not previously been studied. We retrospectively identified 134 eligible patients with ischemic cardiomyopathy that underwent LVAD implantation between July 2009 and August 2013. The cohorts received an ADPRi ≤5 days of surgery (n = 25) versus >5 days prior or not at all (n = 109). Subgroup analyses adjusted for differences in frequency of redo sternotomy between cohorts, excluded patients that received an ADPRi >1 year prior to surgery, and excluded patients with a redo sternotomy. The ADPRi and control groups did not have significant differences in the primary outcomes, intraoperative PRBC units transfused (3.0 vs. 4.0, p = 0.12) or chest tube output within 24 h of surgery (1.66 L vs. 1.80 L, p = 0.61). After adjusting for differences in frequency of redo sternotomy (ADPRi vs. control, 12 vs. 52%, p ≤ 0.001), no significant difference in PRBC units transfused (3.1 vs. 3.5, p = 0.59) or chest tube output (2.04 L vs. 2.04 L, p = 0.98) was seen. No significant difference in 30-day mortality (8.0 vs. 11.0%, p = 0.63), 90-day mortality (16.4 vs. 23.3%, p = 0.42), or length of stay (29.0 vs. 28.0, p = 0.61) was seen. In this single-center experience, use of an ADPRi ≤5 days prior to LVAD implantation was not associated with increased bleeding, length of stay, or mortality.

Potential Expanded Indications for Neprilysin Inhibitors.

PURPOSE OF REVIEW: The goal of this article is to review potential expanded indications for neprilysin inhibitors. This article reviews the rationale and design for ongoing and future trials of sacubitril/valsartan in cardiovascular and non-cardiovascular disease. RECENT FINDINGS: Randomized trial data are lacking for use of sacubitril/valsartan in acute heart failure and advanced heart failure. Mechanistic data from animal studies suggest a role for neprilysin inhibition in the treatment of post-myocardial infarction systolic dysfunction and heart failure with preserved ejection fraction. Beyond the cardiovascular system, renal and neurological function may be impacted by neprilysin inhibition. Forthcoming randomized trials will address the clinical impact of sacubitril/valsartan on these conditions. Neprilysin inhibition with sacubitril/valsartan offers a new therapeutic strategy with a broad range of potential therapeutic actions. In PARADIGM-HF, the combination of neprilysin and RAAS inhibition was proven to be superior to enalapril for patients with stable NYHA class II-III heart failure and reduced left ventricular ejection fraction. Preliminary data suggests it may also have a role in other cardiovascular and non-cardiovascular disease. Several ongoing and planned studies will determine the extent of its benefit for these other indications.

Clinical Implications of Serum Albumin Levels in Acute Heart Failure: Insights From DOSE-AHF and ROSE-AHF.

BACKGROUND: Hypoalbuminemia is common in patients with chronic heart failure and, as a marker of disease severity, is associated with an adverse prognosis. Whether hypoalbuminemia contributes to (or is associated with) worse outcomes in acute heart failure (AHF) is unclear. We sought to determine the implications of low serum albumin in patients receiving decongestive therapies for AHF. METHODS AND RESULTS: Baseline serum albumin levels were measured in 456 AHF subjects randomized in the DOSE-AHF and ROSE-AHF trials. We assessed the relationship between admission albumin levels (both as a continuous variable and stratified by median albumin [≥3.5 g/dL]) and worsening renal function (WRF), worsening heart failure (WHF), and clinical decongestion by 72 hours; 7-day cardiorenal biomarkers; and post-discharge outcomes. The mean baseline albumin level was 3.5 ± 0.5 g/dL. Albumin was not associated with WRF, WHF, or clinical decongestion by 72 hours. Furthermore, there was no association between continuous albumin levels and symptom change according to visual analog scale or weight change by 72 hours. Albumin was not associated with 60-day mortality, rehospitalization, or unscheduled emergency room visits. CONCLUSIONS: Baseline serum albumin levels were not associated with short-term clinical outcomes for AHF patients undergoing decongestive therapies. These data suggest that serum albumin may not be a helpful tool to guide decongestion strategies.

Timing and Causes of Readmission After Acute Heart Failure Hospitalization-Insights From the Heart Failure Network Trials.

BACKGROUND: Readmission or death after heart failure (HF) hospitalization is a consequential and closely scrutinized outcome, but risk factors may vary by population. We characterized the risk factors for post-discharge readmission/death in subjects treated for acute heart failure (AHF). METHODS AND RESULTS: A post hoc analysis was performed on data from 744 subjects enrolled in 3 AHF trials conducted within the Heart Failure Network (HFN): Diuretic Optimization Strategies Evaluation in Acute Heart Failure (DOSE-AHF), Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF), and Renal Optimization Strategies Evaluation in Acute Heart Failure (ROSE-AHF). All-cause readmission/death occurred in 26% and 38% of subjects within 30 and 60 days of discharge, respectively. Non-HF cardiovascular causes of readmission were more common in the ≤30-day timeframe than in the 31-60-day timeframe (23% vs 10%, P = .016). In a Cox proportional hazards model adjusting a priori for left ventricular ejection fraction <50% and trial, the risk factors for all-cause readmission/death included: elevated baseline blood urea nitrogen, angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) non-use, lower baseline sodium, non-white race, elevated baseline bicarbonate, lower systolic blood pressure at discharge or day 7, depression, increased length of stay, and male sex. CONCLUSIONS: In an AHF population with prominent congestion and prevalent renal dysfunction, early readmissions were more likely to be due to non-HF cardiovascular causes compared with later readmissions. The association between use of ACEI/ARB and lower all-cause readmission/death in Cox proportional hazards model suggests a role for these drugs to improve post-discharge outcomes in AHF.

Serum Bicarbonate in Acute Heart Failure: Relationship to Treatment Strategies and Clinical Outcomes.

BACKGROUND: Though commonly noted in clinical practice, it is unknown if decongestion in acute heart failure (AHF) results in increased serum bicarbonate. METHODS AND RESULTS: For 678 AHF patients in the DOSE-AHF, CARRESS-HF, and ROSE-AHF trials, we assessed change in bicarbonate (baseline to 72-96 hours) according to decongestion strategy, and the relationship between bicarbonate change and protocol-defined decongestion. Median baseline bicarbonate was 28 mEq/L. Patients with baseline bicarbonate ≥28 mEq/L had lower ejection fraction, worse renal function and higher N-terminal pro-B-type natriuretic peptide than those with baseline bicarbonate <28 mEq/L. There were no differences in bicarbonate change between treatment groups in DOSE-AHF or ROSE-AHF (all P > .1). In CARRESS-HF, bicarbonate increased with pharmacologic care but decreased with ultrafiltration (median +3.3 vs -0.9 mEq/L, respectively; P < .001). Bicarbonate change was not associated with successful decongestion (P > .2 for all trials). CONCLUSIONS: In AHF, serum bicarbonate is most commonly elevated in patients with more severe heart failure. Despite being used in clinical practice as an indicator for decongestion, change in serum bicarbonate was not associated with significant decongestion.

Team-Based Care for Managing Noncardiac Conditions in Patients with Heart Failure.

HF is a condition in which the prognosis and treatment are often defined by comorbidities, many of which are noncardiac. Knowledge of the interactions between HF and specific comorbidities is essential, yet to date the clinical trial evidence base for managing comorbidity in patients with HF is limited; further investigations are clearly needed. Perhaps the most pressing need is a focus on the overall multimorbidity state and its relationship to HF-a need that should be addressed in forthcoming trials. Successful navigation between HF and common interacting comorbidities requires coordination of care and team-based approaches that continually evolve to meet patient needs.

Giant Left Ventricular Aneurysm With Dynamic Right Ventricular Compression and Subsequent End-Stage Heart Failure.

We report a case of a patient with a missed anterior myocardial infarction and associated ischemic cardiomyopathy. The patient had a massive true left ventricular aneurysm causing dynamic right ventricular compression, with associated cardiogenic shock, for which a heart transplantation was ultimately performed.

Escalating Surgical Treatment for Left Ventricular Assist Device Infection and Expected Mortality: Clinical Risk Prediction Score.

BACKGROUND: Left ventricular assist devices (LVAD) improve survival for patients with cardiac failure, but LVAD specific infections (VSI) remain a challenge with poorly understood predictive risk factors. Furthermore, the indications and utility of escalating medical treatment to surgical debridement and potential flap reconstruction are not well-characterized. STUDY DESIGN: A retrospective review of consecutive patients undergoing primary LVAD implantation at a tertiary academic center was performed. The primary outcomes measures were 90-day and overall mortality after VSI. Cox proportional hazards regression was used to generate a risk-prediction score for mortality. RESULTS: Of the 760 patients undergoing primary LVAD implantation, 255 (34%) developed VSI; of these 91 (36%) were managed medically, 134 (52%) with surgical debridement, and 30 (12%) with surgical debridement and flap reconstruction. One-year survival after infection was 85% with median survival of 2.40 years. Factors independently associated with increased mortality were diabetes (hazard ratio (HR) 1.44, p=0.04), methicillin-resistant Staphylococcus aureus infection (HR 1.64, p=0.03), deep space (pump pocket/outflow cannula) involvement (HR 2.26, p<0.001) and extra-corporeal membrane oxygenation after LVAD (HR 2.52, p<0.01. Factors independently associated with decreased mortality were flap reconstruction (HR 0.49, p=0.02) and methicillin-sensitive Staphylococcus aureus infection (HR 0.63, p=0.03). A clinical risk prediction score was developed using these factors and showed significant differences in median survival, which was 5.67 years for low-risk (score 0-1), 3.62 years for intermediate-risk (score 2), and 1.48 years for high-risk (score >3) (p<0.001) patients. CONCLUSIONS: We developed a clinical risk prediction score to stratify VSI patients. In selected cases, escalating surgical treatment was associated with increased survival. Future work is needed to determine if early surgical debridement and flap reconstruction can alter outcomes in select cases of VSI.

Established Clinical Prediction Rules for Bleeding Had Mediocre Discrimination in Left Ventricular Assist Device Recipients.

Left ventricular assist devices (LVAD) reduce mortality in patients with end-stage heart failure, but LVAD management is frequently complicated by bleeding. Bleeding prediction post-LVAD implantation is challenging as prediction rules for hemorrhage have not been rigorously studied in this population. We aimed to validate clinical prediction rules for bleeding, derived in the atrial fibrillation and venous thromboembolism populations, in an LVAD cohort. This was a retrospective cohort study of LVAD recipients at an academic center. The primary end-point was time to gastrointestinal bleed or intracranial hemorrhage after implant; the secondary end-point was time to any major hemorrhage after hospital discharge. Four hundred and eighteen patients received an LVAD (135 HeartMate II, 125 HeartMate 3, 158 HVAD) between November 2009 and January 2019. The primary end-point occurred in 169 (40.4%) patients with C -statistics ranging 0.55-0.58 (standard deviation [SD] 0.02 for all models). The secondary end-point occurred in 167 (40.0%) patients with C -statistics ranging 0.53-0.58 (SD 0.02 for all models). Modifying the age and liver function thresholds increased the C -statistic range to 0.56-0.60 for the primary and secondary end-points. In a sensitivity analysis of HeartMate 3 patients, prediction rules performed similarly. Existing prediction rules for major bleeding had mediocre discrimination in an LVAD cohort.

The Association of the UNOS Heart Allocation Policy Change With Transplant and Left Ventricular Assist Device Access and Outcomes.

In October 2018, the allocation policy for adult orthotopic heart transplant (OHTx) in the United States was changed, with the goal of reducing waitlist mortality and providing broader sharing of donor organs within the United States. This study aimed to assess the association of this policy change with changes in access to OHTx versus left ventricular assist devices (LVADs), overall and in key sociodemographic subgroups, in the United States from 2016 to 2019. We identified all patients receiving OHTx or LVAD between 2016 and 2019 using the National Inpatient Sample. Controlling for medical co-morbidities, prepolicy trends, and within-hospital-year effects, we fit a dynamic logistic regression model to evaluate patient and hospital factors associated with receiving OHTx versus LVAD before versus after policy change. We also examined the frequency of temporary mechanical circulatory support in the same fashion. We identified 2,264 patients who received OHTx and 3,157 who received LVADs during the study period. In its first year of implementation, the United Network for Organ Sharing policy change of 2018 was associated with no overall change utilization of OHTx versus LVAD. In OHTx recipients, the frequency of use of temporary mechanical circulatory support changed from 15.6% in the before period to 42.6% in the after period (p <0.001). Although the policy change was associated with differences in the odds of receiving an OHTx versus LVAD between different regions of the country, there were no significant changes based on age, gender, race/ethnicity, insurance status, or rurality. In conclusion, the United Network for Organ Sharing policy change on access to OHTx was associated with no overall change in OHTx versus LVAD use in its first year of implementation although we observed small changes in relative odds of transplant based on rurality. Shifts in regional allocation were not significant overall, although certain regions appeared to have a relative increase in their use of OHTx.

Angiotensin II Type 1 Receptor Antibody-mediated Rejection Following Orthotopic Heart Transplant: A Single-center Experience.

BACKGROUND: Antibody-mediated rejection (AMR) following orthotopic heart transplant (OHT) causes significant morbidity and mortality. There are limited data on antibodies to the angiotensin II type 1 receptor antibody (AT1R-Ab) causing rejection following OHT. METHODS: This is a retrospective, single-center study that presents our 2-y experience with a series of 11 patients with evidence of nonspecific graft dysfunction and pathologic levels of AT1R-Ab. The clinical outcomes and treatments were compared to a group of 10 patients, also with evidence of nonspecific graft dysfunction, but who had nonsignificant AT1R-Ab titers. RESULTS: The mean age of the AT1R-Ab cohort was 52% and 73% were bridged to transplant with an left ventricular assist device. The average left ventricular ejection fraction at presentation was 45%, and most were not on an angiotensin receptor blocker (ARB). Endomyocardial biopsies in those with elevated AT1R-Ab levels frequently showed reactive endothelium/endocardium without C4d or intravascular CD68 staining. Ten patients (91%) were started on an ARB. Other therapies included plasmapheresis and IVIg (64%), with 4 patients also receiving rituximab. Most patients had symptom improvement, but minimal change in graft function at an average 6 mo of follow-up. CONCLUSIONS: The role of AT1R-Ab-mediated rejection in OHT recipients remains poorly understood. More than half of patients at our center who presented with graft dysfunction in the absence of acute cellular rejection or AMR were found to have elevated AT1R-Ab titers. Empiric AMR treatment in conjunction with ARB therapy may improve patient outcomes. Future studies are needed to better define the optimal treatment modalities for ATR1-Ab-mediated AMR.

Association of bleeding with serotonergic antidepressants in patients receiving left ventricular assist device support.

STUDY OBJECTIVE: This study sought to determine whether SA use is associated with bleeding in patients receiving CF-LVAD support. DESIGN: A retrospective cohort analysis was conducted of all adult patients who received CF-LVAD implantation at our institution. SETTING: Barnes-Jewish Hospital between July 1, 2009, and October 1, 2018. PATIENTS: Patients at least 18 years of age who received a HVAD™ (HeartWare Corp.), HeartMate II™ (St. Jude Medical), or HeartMate 3™ (St. Jude Medical) CF-LVAD and survived for at least 30 days postoperatively were included. INTERVENTION: Patients who received SAs (n = 203) were compared to those who did not (n = 391) from 30 days to 18 months following implantation. The primary outcome was the incidence of first bleeding events including gastrointestinal bleed (GIB), epistaxis, or intracerebral hemorrhage (ICH). MEASUREMENTS AND MAIN RESULTS: During follow-up, 219 patients had bleeding events: 93 of 203 (45.8%) in the SA group versus 126 of 391 (32.2%) in the control group (p = 0.001). After adjustment for age, angiotensin-converting enzyme (ACE) inhibitor and angiotensin receptor blocker (ARB) use, history of bleeding events, history of smoking, and CF-LVAD type, SA use remained associated with bleeding (adjusted odds ratio: 1.75, 95% confidence interval: 1.22-2.51, p = 0.002). HeartMate 3™ patients experienced less bleeding than HeartMate II™ patients (adjusted odds ratio 0.46, 95% confidence interval: 0.23-0.90, p = 0.024). CONCLUSIONS: In this single-center, retrospective cohort of patients supported with CF-LVADs, SA use was associated with the incidence of first bleeding events, primarily driven by GIB. Further studies are needed to assess any differential risk of bleeding among SA agents and to assess the utility of altering antithrombotic strategies.