Publications

BACKGROUND: Systolic heart failure (HF) is a low-grade systemic inflammatory state. Neutrophil-lymphocyte ratio (NLR) is a nonspecific inflammatory marker with prognostic value in HF. We aimed to determine the relationship between NLR and mortality during left ventricular assist device (LVAD) support.

METHODS AND RESULTS: We retrospectively reviewed LVAD recipients implanted in the years 2010-2018. NLR was recorded before LVAD implantation and at intervals during LVAD support; pre-LVAD and 90-day LVAD NLRs were compared. Cox proportional hazard models were constructed to study the impact of NLR, both before LVAD implantation and at 90 days with LVAD, on mortality during subsequent LVAD support. Among 301 subjects, the median pre-LVAD NLR was 4.7 (interquartile range 3.0-8.0). Higher pre-LVAD NLR was independently associated with increased mortality during a median 324 days of LVAD support (adjusted hazard ratio [HR] 1.03, 95% confidence interval [CI] 1.01-1.06; P = .012, adjusted for pre-LVAD age, HF etiology, white blood count, hemoglobin, blood urea nitrogen, and sodium). After LVAD implantation, the NLR rose initially and then plateaued lower by day 90. Despite the mean decrease, higher 90-day LVAD NLR remained independently associated with increased mortality (adjusted HR 1.06, 95% CI 1.01-1.13; P = .033, stratified by early infection events).

CONCLUSIONS: Higher pre-LVAD NLR is independently associated with mortality during LVAD support. NLR improves during LVAD support, but even accounting for early infections, a higher NLR at day 90 remains associated with subsequent mortality.

INTRODUCTION: Fluoropyrimidines (FPDs) are a fundamental component of many chemotherapy regimens. Cardiotoxic adverse events (AEs) such as angina, ischemia, arrhythmias, and cardiomyopathy associated with 5-fluorouracil (5-FU) and capecitabine (CAPE) have been sparingly described in studies, primarily through case reports. Data from the 1990s revealed an estimated incidence of 0.5% to 19%, with cardiovascular fatalities occurring in ≤28%. The current use of FPDs includes multiple dosing regimens, oral or intravenous delivery, and administration with additional cardiotoxic therapies. As such, it is imperative to better define the cardiotoxicity risk in the modern treatment era. We comprehensively evaluated the incidence, prevalence, and ascertainment of cardiovascular risk factors and disease within ECOG-ACRIN (Eastern Cooperative Group Cancer Research Group - American College of Radiology Imaging Network) Cancer Research Group clinical trials incorporating 5-FU and CAPE.

MATERIALS AND METHODS: Case report forms and clinical study reports from the ECOG-ACRIN Cancer Research Group database of phase II and III clinical trials incorporating 5-FU and CAPE were evaluated. A total of 16 trials from 2002 to 2017 were identified that had used bolus 5-FU (n = 1), continuous infusion 5-FU (n = 10) or CAPE (n = 5).

RESULTS: A history of cardiovascular disease was variably defined and was an exclusion criterion in 13 of the 16 studies (81%). The baseline risk factors and history of cardiac disease were specifically collected in only 3 studies (19%). All studies collected cardiovascular AEs using the Common Terminology Criteria for Adverse Events version available at the time of the study. Fewer than half (7 of 16; 44%) of the study case report forms had also specifically requested information on cardiac ischemia/infarction. In the 12 completed studies with clinical study reports, the following AEs were reported: dyspnea, ≤16%; arrhythmias, ≤6%; and angina, ischemia, and elevated troponin, ≤5%. Some trials only recorded cardiac AEs that were possibly associated with the novel drug being studied and not those attributed to the standard of care in the 5-FU/CAPE arm, further decreasing the numerical incidence.

CONCLUSION: Inconsistent clinical trial reporting of cardiac AEs precluded accurate and precise delineation of the epidemiology of FPD-related cardiovascular AEs. Prospective knowledge of the definition and natural history will lead to the development of risk factor stratification and prechemotherapy interventions to reduce or prevent cardiotoxicity. We propose that the prospective collection of baseline cardiac data and prespecified cardiac endpoints are necessary to fully understand the incidence and cardiac risk of FDPs.

Mucorales organisms are an uncommon cause of invasive fungal infections after solid organ transplantation but are associated with great morbidity and mortality. We report a fatal case of disseminated Cunninghamella infection early after heart transplantation. The patient developed graft dysfunction and elevated markers of myocyte injury and autopsy revealed fulminant fungal myocarditis. This case highlights the need for a high index of suspicion in immunocompromised patients who are not improving with standard antimicrobial therapy.

BACKGROUND: Digoxin has been shown to reduce heart failure hospitalizations with a neutral effect on mortality. It is unknown whether there is heterogeneity of treatment effect for digitalis therapy according to predicted risk of heart failure hospitalization.

METHODS AND RESULTS: We conducted a post hoc analysis of the Digitalis Investigator Group (DIG) studies, randomized controlled trials of digoxin vs placebo in participants with heart failure and left ventricular ejection fraction ≤45% (main DIG study, n = 6800) or >45% (ancillary DIG study, n = 988). Using a previously derived multistate model to risk-stratify DIG study participants, we determined the differential treatment effect on hospitalization and mortality outcomes. There was a 13% absolute reduction in the risk of any heart failure hospitalizations (39% vs 52%; odds ratio 0.58; 95% confidence interval 0.47-0.71) in the digoxin vs placebo arms in the highest-risk quartile, compared with a 3% absolute risk reduction for any heart failure hospitalization (17% vs 20%; odds ratio 0.84; 95% confidence interval, 0.66-1.08) in the lowest-risk quartile. There were 12 fewer total all-cause hospitalizations per 100 person-years in the highest-risk quartile compared with an increase of 8 hospitalizations per 100 person-years in the lowest-risk quartile. There was neutral effect of digoxin on mortality in all risk quartiles and no interaction between baseline risk and the effect of digoxin on mortality (P = .94).

CONCLUSIONS: Participants in the DIG study at higher risk of hospitalization as identified by a multistate model were considerably more likely to benefit from digoxin therapy to reduce heart failure hospitalization.

Patients with breast cancer have higher rates of cardiovascular disease than age-matched controls. Anthracyclines and trastuzumab increase the risk of heart failure (HF) and radiation increases the risk of ischemic heart disease, valvular disease and HF. Older age, low normal ejection fraction, history of coronary artery disease (CAD), cardiac risk factors, higher cumulative anthracycline exposure, combination anthracycline and trastuzumab and/or radiation all increase the risk of cardiac events post treatment. Clinical prediction models (CPMs) and/or genetic testing may be useful in guiding treatment decisions but further external validation is necessary. Screening for asymptomatic cardiotoxicity using echocardiography after completion of therapy is reasonable in patients receiving anthracyclines and/or radiation, especially in those with traditional cardiac risk factors such as hypertension, diabetes, hyperlipidemia, and obesity or with low normal baseline left ventricular ejection fraction (LVEF). Elevated cardiac troponins during anthracycline therapy and early reductions in myocardial deformation may predict subsequent reductions in LVEF but further research is needed to demonstrate clinical benefit to routine screening and early treatment. Neurohormonal antagonist therapy with ACEi/ARBs and beta-blockers are indicated in patients with reduced ejection fraction and ongoing research will clarify the role for neurohormonal antagonists and statins for the prevention of breast cancer therapy cardiotoxicity. Patients treated for breast cancer should be educated on the evidence for optimal lifestyle behaviors such as not smoking, regular exercise, healthy diet and maintaining a healthy weight in reducing the risk of cardiovascular disease. Traditional cardiac risk factors such as hypertension, diabetes and hyperlipidemia should be optimally managed to reduce the risk of cardiovascular events in patients treated for breast cancer.

BACKGROUND: Outpatients with heart failure (HF) who are at high risk for HF hospitalization and death may benefit from early identification. We sought to develop and externally validate a model to predict both HF hospitalization and mortality that accounts for the semicompeting nature of the 2 outcomes and captures the risk associated with the transition from the stable outpatient state to the post-HF hospitalization state.

METHODS AND RESULTS: A multistate model to predict HF hospitalization and all-cause mortality was derived using data (n=3834) from the HEAAL study (Heart Failure Endpoint evaluation of Angiotensin II Antagonist Losartan), a multinational randomized trial in symptomatic patients with reduced left ventricular ejection fraction. Twelve easily and reliably obtainable demographic and clinical predictors were prespecified for model inclusion. Model performance was assessed in the SCD-HeFT cohort (Sudden Cardiac Death in Heart Failure Trial; n=2521). At 1 year, the probability of being alive without HF hospitalization was 94% for a typical patient in the lowest risk quintile and 77% for a typical patient in the highest risk quintile and this variability in risk continued through 7 years of follow-up. The model c-index was 0.72 in the derivation cohort, 0.66 in the validation cohort, and 0.69 in the implantable cardiac defibrillator arm of the validation cohort. There was excellent calibration across quintiles of predicted risk.

CONCLUSIONS: Our findings illustrate the advantages of a multistate modeling approach, providing estimates of HF hospitalization and death in the same model, comparison of predictors for the different outcomes and demonstrating the different trajectories of patients based on baseline characteristics and intermediary events.

CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00000609 and NCT00090259.

Left ventricular assist device (LVAD) thrombosis is associated with high morbidity and mortality because of device malfunction, embolic events, and hemolysis. There remains uncertainty as to whether immediate device exchange versus an initial trial of anticoagulant and antiplatelet therapy is most appropriate in hemodynamically stable patients. We conducted a retrospective analysis of all LVAD implantations at a single center between January 2009 and June 2013 with follow-up through December 2013. Suspected LVAD thrombosis occurred in 20% of patients (N = 25) over a median follow-up of 275 days. Medical therapy led to resolution of hemolysis, and discharge to home, in 15 of 25 (60%) cases; however, this strategy was associated with intracranial hemorrhage in 4 patients and readmission with recurrent thrombosis in 10 patients. The 30 day, 6 month, and 1 year freedom from suspected LVAD thrombosis was 96.5, 85.9, and 80.3% in HeartMate II devices and 100, 92.9, and 87.1% in HeartWare ventricular assist devices, respectively (p = 0.11). Although medical treatment with intravenous heparin, antiplatelet agents, antithrombotic agents, or thrombolytic therapy can lead to initial resolution of hemolysis, the risks of recurrence after transition to warfarin and adverse events are high.