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.

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.

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.

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.

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.

COVID-19 in orthotopic heart transplant recipients and association with donor specific antibodies.

De novo donor-specific antibodies (DSAs) are associated with increased risk of antibody-mediated rejection and worse clinical outcomes after orthotopic heart transplant (OHT). No study has reported the production of DSAs after infection by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in an OHT population. In this retrospective study, we described coronavirus disease 2019 (COVID-19) incidence and clinical course in a large, contemporary OHT cohort. We showed that the case-fatality rate has significantly decreased since the early days of the pandemic, although remains higher than that of the general population. In addition, we found that 10% of OHT recipients developed de novo DSAs or experienced an increase in pre-existing DSAs after COVID-19, with the majority occurring in unvaccinated patients (15% vs 2%). Further studies are necessary to substantiate our findings in an external cohort.

Tolerability of Sacubitril/Valsartan in Patients With Advanced Heart Failure: Analysis of the LIFE Trial Run-In.

BACKGROUND: The LIFE (LCZ696 In Hospitalized Advanced Heart FailurE) trial, which evaluated sacubitril/valsartan in patients with advanced heart failure (HF) with reduced ejection fraction and recent New York Heart Association functional class IV symptomatology, did not require tolerance to a renin angiotensin system antagonist before initiating sacubitril/valsartan, thus affording an opportunity to study the tolerability of sacubitril/valsartan in advanced HF with reduced ejection fraction. OBJECTIVES: The goal of this analysis of the LIFE trial is to characterize the tolerability of initiating sacubitril/valsartan in patients with chronic advanced HF with reduced ejection fraction. METHODS: In the LIFE trial, 445 subjects with advanced HF entered an unblinded run-in period of 3-7 days with sacubitril/valsartan 24/26 mg twice a day. The authors compared characteristics of subjects completing and failing run-in, performed multivariable analysis of clinical parameters associated with run-in failure, and developed a predictive model for short-term intolerance to sacubitril/valsartan. RESULTS: Of 445 subjects entering run-in, 73 (18%) were intolerant of sacubitril/valsartan. Reasons for intolerance included systolic blood pressure <90 mm Hg (59%), symptoms of hypotension/dizziness with systolic blood pressure >90 mm Hg (19%), and renal dysfunction (creatinine >2.0 mg/dL) (12%). Multivariable predictors of intolerance included lower mean arterial pressure, lower serum chloride, presence of an implantable cardioverter-defibrillator and/or cardiac resynchronization device, moderate or greater mitral regurgitation, nonuse of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker at the screening visit, and use of insulin at screening. Subjects with 4 or more predictors had a 48.9% probability of sacubitril/valsartan intolerance. CONCLUSIONS: Intolerance to low doses of sacubitril/valsartan is common in patients with advanced chronic HF with reduced ejection fraction and may be predicted by the presence of certain risk factors. (EntrestoTM [LCZ696] in Advanced Heart Failure [LIFE Study] [HFN-LIFE] NCT02816736).

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.

Effect of Treatment With Sacubitril/Valsartan in Patients With Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial.

Importance: The use of sacubitril/valsartan is not endorsed by practice guidelines for use in patients with New York Heart Association class IV heart failure with a reduced ejection fraction because of limited clinical experience in this population. Objective: To compare treatment with sacubitril/valsartan treatment with valsartan in patients with advanced heart failure and a reduced ejection fraction and recent New York Heart Association class IV symptoms. Design, Setting, and Participants: A double-blind randomized clinical trial was conducted; a total of 335 patients with advanced heart failure were included. The trial began on March 2, 2017, and was stopped early on March 23, 2020, owing to COVID-19 risk. Intervention: Patients were randomized to receive sacubitril/valsartan (target dose, 200 mg twice daily) or valsartan (target dose, 160 mg twice daily) in addition to recommended therapy. Main Outcomes and Measures: The area under the curve (AUC) for the ratio of N-terminal pro-brain natriuretic peptide (NT-proBNP) compared with baseline measured through 24 weeks of therapy. Results: Of the 335 patients included in the analysis, 245 were men (73%); mean (SD) age was 59.4 (13.5) years. Seventy-two eligible patients (18%) were not able to tolerate sacubitril/valsartan, 100 mg/d, during the short run-in period, and 49 patients (29%) discontinued sacubitril/valsartan during the 24 weeks of the trial. The median NT-proBNP AUC for the valsartan treatment arm (n = 168) was 1.19 (IQR, 0.91-1.64), whereas the AUC for the sacubitril/valsartan treatment arm (n = 167) was 1.08 (IQR, 0.75-1.60). The estimated ratio of change in the NT-proBNP AUC was 0.95 (95% CI 0.84-1.08; P = .45). Compared with valsartan, treatment with sacubitril/valsartan did not improve the clinical composite of number of days alive, out of hospital, and free from heart failure events. Aside from a statistically significant increase in non-life-threatening hyperkalemia in the sacubitril/valsartan arm (28 [17%] vs 15 [9%]; P = .04), there were no observed safety concerns. Conclusions and Relevance: The findings of this trial showed that, in patients with chronic advanced heart failure with a reduced ejection fraction, there was no statistically significant difference between sacubitril/valsartan and valsartan with respect to reducing NT-proBNP levels. Trial Registration: ClinicalTrials.gov Identifier: NCT02816736.

Interim Analysis of the Phase II Study: Noninferiority Study of Doxorubicin with Upfront Dexrazoxane plus Olaratumab for Advanced or Metastatic Soft-Tissue Sarcoma.

PURPOSE: To report the interim analysis of the phase II single-arm noninferiority trial, testing the upfront use of dexrazoxane with doxorubicin on progression-free survival (PFS) and cardiac function in soft-tissue sarcoma (STS). PATIENTS AND METHODS: Patients with metastatic or unresectable STS who were candidates for first-line treatment with doxorubicin were deemed eligible. An interim analysis was initiated after 33 of 65 patients were enrolled. Using the historical control of 4.6 months PFS for doxorubicin in the front-line setting, we tested whether the addition of dexrazoxane affected the efficacy of doxorubicin in STS. The study was powered so that a decrease of PFS to 3.7 months would be considered noninferior. Secondary aims included cardiac-related mortality, incidence of heart failure/cardiomyopathy, and expansion of cardiac monitoring parameters including three-dimensional echocardiography. Patients were allowed to continue on doxorubicin beyond 600 mg/m2 if they were deriving benefit and were not demonstrating evidence of symptomatic cardiac dysfunction. RESULTS: At interim analysis, upfront use of dexrazoxane with doxorubicin demonstrated a PFS of 8.4 months (95% confidence interval: 5.1-11.2 months). Only 3 patients were removed from study for cardiotoxicity, all on > 600 mg/m2 doxorubicin. No patients required cardiac hospitalization or had new, persistent cardiac dysfunction with left ventricular ejection fraction remaining below 50%. The median administered doxorubicin dose was 450 mg/m2 (interquartile range, 300-750 mg/m2). CONCLUSIONS: At interim analysis, dexrazoxane did not reduce PFS in patients with STS treated with doxorubicin. Involvement of cardio-oncologists is beneficial for the monitoring and safe use of high-dose anthracyclines in STS.See related commentary by Benjamin and Minotti, p. 3809.

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.

Sacubitril/Valsartan in Advanced Heart Failure With Reduced Ejection Fraction: Rationale and Design of the LIFE Trial.

The PARADIGM-HF (Prospective Comparison of Angiotensin II Receptor Blocker Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial reported that sacubitril/valsartan (S/V), an angiotensin receptor-neprilysin inhibitor, significantly reduced mortality and heart failure (HF) hospitalization in HF patients with a reduced ejection fraction (HFrEF). However, fewer than 1% of patients in the PARADIGM-HF study had New York Heart Association (NYHA) functional class IV symptoms. Accordingly, data that informed the use of S/V among patients with advanced HF were limited. The LIFE (LCZ696 in Hospitalized Advanced Heart Failure) study was a 24-week prospective, multicenter, double-blinded, double-dummy, active comparator trial that compared the safety, efficacy, and tolerability of S/V with those of valsartan in patients with advanced HFrEF. The trial planned to randomize 400 patients ≥18 years of age with advanced HF, defined as an EF ≤35%, New York Heart Association functional class IV symptoms, elevated natriuretic peptide concentration (B-type natriuretic peptide [BNP] ≥250 pg/ml or N-terminal pro-B-type natriuretic peptide [NT-proBNP] ≥800 pg/ml), and ≥1 objective finding of advanced HF. Following a 3- to 7-day open label run-in period with S/V (24 mg/26 mg twice daily), patients were randomized 1:1 to S/V titrated to 97 mg/103 mg twice daily versus 160 mg of V twice daily. The primary endpoint was the proportional change from baseline in the area under the curve for NT-proBNP levels measured through week 24. Secondary and tertiary endpoints included clinical outcomes and safety and tolerability. Because of the COVID-19 pandemic, enrollment in the LIFE trial was stopped prematurely to ensure patient safety and data integrity. The primary analysis consists of the first 335 randomized patients whose clinical follow-up examination results were not severely impacted by COVID-19. (Entresto [LCZ696] in Advanced Heart Failure [LIFE STUDY] [HFN-LIFE]; NCT02816736).

Disparities and Impact of Medicaid Expansion on Left Ventricular Assist Device Implantation and Outcomes.

BACKGROUND: Left ventricular assist device (LVAD) therapy is an increasingly viable alternative for patients who are not candidates for heart transplantation or who are waiting for a suitable donor. We aimed to determine whether there is an association between sex, race/ethnicity, insurance coverage, and neighborhood income and access to/outcomes of LVAD implantation. We further analyzed whether access to LVAD improved in states that did versus did not expand Medicaid. METHODS AND RESULTS: Retrospective cohort study using State Inpatient Databases to identify patients 18 to 85 years of age admitted for heart failure, cardiogenic shock, or LVAD implantation from 2012 to 2015. Logistic regression analyses adjusting for age, all the sociodemographic factors above, medical comorbidities, and a hospital random effect were used to quantify odds of receipt of LVADs, as well as outcomes conditional on receiving an LVAD, for the sociodemographic groups of interest. A total of 925 770 patients were included; 3972 (0.43%) received LVADs. After adjusting for age, comorbidities, and hospital effects, women (adjusted odds ratio [aOR], 0.45 [0.41-0.49]), black patients (aOR, 0.83 [0.74-0.92]), and Hispanic patients (aOR, 0.74 [0.64-0.87]) were less likely to receive LVADs than whites. Medicare (aOR, 0.79 [0.72-0.86]), Medicaid (aOR, 0.52 [0.46-0.58]), and uninsured patients (aOR, 0.17 [0.11-0.25]) were less likely to receive LVADs than the privately insured, and patients in low-income ZIP codes were less likely than those in higher income areas (aOR, 0.71 [0.65-0.77]). Among those who received LVADs, women (aOR, 1.78 [1.38-2.30]), patients of unknown race or race other than white, black, or Hispanic (aOR, 1.97 [1.42-2.74]), and uninsured patients (aOR, 4.86 [1.92-12.28]) had higher rates of in-hospital mortality. Medicaid expansion was not associated with an increase in LVAD implantation. CONCLUSIONS: There are meaningful sociodemographic disparities in access and outcomes for LVAD implantation. Medicaid expansion was not associated with an increase in LVAD rates.

Apical Sparing Pattern of Longitudinal Strain and Positive Bone Scintigraphy in Metastatic Myocardial Calcification.

An apical sparing pattern of longitudinal strain and positive radionuclide bone scintigraphy are believed to be specific for the diagnosis of transthyretin cardiac amyloidosis. We report on a young woman with apical sparing of longitudinal strain and positive bone scintigraphy who was found to have metastatic myocardial calcification at autopsy. (Level of Difficulty: Intermediate.).

The Combination of Tricuspid Annular Plane Systolic Excursion and HeartMate Risk Score Predicts Right Ventricular Failure After Left Ventricular Assist Device Implantation.

Right ventricular (RV) failure is difficult to predict and is a major determinant of poor outcomes after left ventricular assist device (LVAD) implantation. We evaluated the associations of the following variables with severe RV failure in LVAD patients: tricuspid annular plane systolic excursion (TAPSE), pulmonary artery pulsatility index (PAPi), simplified RV contraction pressure index (sRVCPI), and HeartMate Risk Score (HMRS). We performed a retrospective case-control study on 216 patients who underwent continuous-flow LVAD implantation between 2008 and 2014. The primary analysis assessed the ability of HMRS, PAPi, sRVCPI, and TAPSE to predict severe RV failure. A secondary analysis evaluated the incremental benefit of combining predictive variables. Seventy-four patients developed severe RV failure (24%). Compared with the control group, the severe RV failure group had lower TAPSE (1.30 vs. 1.55; p < 0.001), lower PAPi (1.77 vs. 2.47; p = 0.001), lower sRVCPI (42.71 vs. 57.82; p < 0.001), and higher HMRS (2.12 vs. 1.65; p < 0.001). All four variables had similar receiver operating characteristic curves with modest area under the receiver operating characteristic curve (0.63-0.67, all p values < 0.001). In the evaluation of combined predictive variables, the combination of TAPSE with HMRS was found to be best for predicting severe RV failure. In summary, patients at risk for severe RV failure after LVAD implantation were successfully identified using TAPSE, PAPi, sRCPI, and HMRS. The combination of TAPSE and HMRS-incidentally, the least invasive and most readily available variables-proved to be superior to RV-centric metrics for predicting severe RV failure. The predictive and clinical use of these two variables should be tested prospectively.