Phase 2 study of the efficacy and safety of ponsegromab in patients with cancer cachexia: PROACC-1 study design.

BACKGROUND: Cancer cachexia is a multifactorial metabolic wasting syndrome characterized by anorexia, unintentional loss of weight involving both skeletal muscle and adipose tissues, progressive functional impairment and reduced survival. Therapeutic strategies for this serious condition are very limited. Growth differentiation factor 15 (GDF-15) is a cytokine that is implicated in cancer cachexia and may represent both a biomarker of cancer cachexia and a potential therapeutic target. Ponsegromab is a potent and selective humanized monoclonal antibody that inhibits GDF-15-mediated signalling. Preclinical and preliminary phase 1 data suggest that ponsegromab-mediated inactivation of circulating GDF-15 may lead to improvement in key characteristics of cachexia. The primary objective of this phase 2 study is to assess the effect of ponsegromab on body weight in patients with cancer, cachexia and elevated GDF-15 concentrations. Secondary objectives include assessing physical activity, physical function, actigraphy, appetite, nausea and vomiting, fatigue and safety. Exploratory objectives include evaluating pharmacokinetics, pharmacodynamics, immunogenicity, lumbar skeletal muscle index and Response Evaluation Criteria in Solid Tumors. METHODS: Approximately 168 adults with non-small-cell lung, pancreatic or colorectal cancers who have cachexia and elevated GDF-15 concentrations will be randomized in a double-blind, placebo-controlled study (NCT05546476). Participants meeting eligibility criteria will be randomized 1:1:1:1 to one of three dose groups of ponsegromab (100, 200 or 400 mg) or matching placebo administered subcutaneously every 4 weeks for an initial 12-week treatment period. This is followed by optional open-label treatment with ponsegromab of 400 mg administered every 4 weeks for up to 1 year. The primary endpoint is mean change from baseline in body weight at Week 12. A mixed model for repeated measures followed by a Bayesian Emax model will be used for the primary analysis. Secondary endpoints include physical activity, physical function and actigraphy measured by remote digital sensors; patient-reported appetite-related symptoms assessed by Functional Assessment of Anorexia-Cachexia Therapy subscale scores; anorexia/appetite, nausea and vomiting, and fatigue evaluated according to questions from the Cancer-Related Cachexia Symptom Diary; and incidence of adverse events, safety laboratory tests, vital signs and electrocardiogram abnormalities. PERSPECTIVE: Cancer-related cachexia is an area of significant unmet medical need. This study will support the clinical development of ponsegromab as a novel inhibitor of GDF-15, which may ameliorate key pathologies of cancer cachexia to improve patient symptoms, functionality and quality of life. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT05546476.

Risk of mortality in older adults with loss of appetite: An analysis of Medicare fee-for-service data.

OBJECTIVES: Prior research suggested that loss of appetite (LOA) among adults with Medicare fee-for-service (FFS) insurance in the United States increased the risk of mortality within 1 year; those findings were not adjusted for risk factors and confounders. The objective of this study was to compare the risk of mortality among Medicare FFS beneficiaries with LOA to a control group without LOA while controlling or adjusting for age, comorbidities, body mass index (BMI), and weight loss. DESIGN: Retrospective and observational analysis of Medicare FFS health insurance claims data from October 1, 2015 to December 31, 2021. SETTING: Claims from all settings (e.g., hospital inpatient/outpatient, office, assisted living facility, skilled nursing facility, hospice, rehabilitation facility, home) were included in these analyses. PARTICIPANTS: The LOA group included all individuals aged 65-115 years with continuous Medicare FFS medical coverage (Parts A and/or B) for at least 12 months before a claim with ICD-10 diagnosis code "R63.0 Anorexia". The control group was drawn from individuals aged 65-115 years with continuous Medicare FFS coverage who did not have a diagnosis of R63.0. Individuals with LOA were matched 1:3 to those in the control group based on age, sex, and race/ethnicity. MEASUREMENTS: Mortality in the LOA group was compared to mortality in the control group using Kaplan-Meier and Cox regression analyses and stratified or adjusted in terms of Charlson Comorbidity Index (CCI), claims-based frailty index (CFI), BMI, and weight loss. RESULTS: The study population of 1,707,031 individuals with LOA and 5,121,093 controls without LOA was 61.7% female and 82.2% White. More individuals with LOA compared with the control group had a CCI score 5+ (52.4% vs. 19.4%), CFI score 5+ (31.6% vs. 6.4%), and BMI < 20 kg/m2 (11.2% vs. 2.1%). Median follow-up was 12 months (individuals with LOA) and 49 months (control group). In a matched population, the risk of mortality was significantly higher (unadjusted hazard ratio 4.40, 95% confidence interval 4.39-4.42) for individuals with LOA than the control group. Median survival time was 4 months (individuals with LOA) and 26 months (control group); differences in survival time remained when stratifying by CCI, BMI, and weight loss. CONCLUSION: Individuals with LOA had a substantially increased risk of death even after matching for age, sex, race/ethnicity, and adjusting for comorbidities. These findings highlight the burden of illness in older adults with LOA and the need for therapies.

Coronary vasomotor dysfunction portends worse outcomes in patients with breast cancer.

BACKGROUND: Impaired MFR in the absence of flow-limiting CAD is associated with adverse events. Cardiovascular disease is an important cause of morbidity and mortality in patients with breast cancer. We sought to test the utility of MFR to predict outcomes in a cohort of patients with breast cancer. METHODS: We retrospectively studied consecutive patients with breast cancer or breast cancer survivors who underwent cardiac stress PET imaging from 2006 to 2017 at Brigham and Women's Hospital. Patients with a history of clinically overt CAD, LVEF < 45%, or abnormal myocardial perfusion were excluded. Subjects were followed from time of PET to the occurrence of a first major adverse cardiovascular event (MACE) and all-cause death. RESULTS: The final cohort included 87 patients (median age 69.0 years, 98.9% female, mean MFR 2.05). Over a median follow-up of 7.6 years after PET, the lowest MFR tertile was associated with higher cumulative incidence of MACE (adjusted subdistribution hazard ratio 4.91; 95% CI 1.68-14.38; p = 0.004) when compared with the highest MFR tertile. CONCLUSIONS: In patients with breast cancer, coronary vasomotor dysfunction was associated with incident cardiovascular events. MFR may have potential as a risk stratification biomarker among patients with/survivors of breast cancer.

Usefulness of ventilatory inefficiency in predicting prognosis across the heart failure spectrum.

AIMS: The minute ventilation-carbon dioxide production relationship (VE/VCO2 slope) is widely used for prognostication in heart failure (HF) with reduced left ventricular ejection fraction (LVEF). This study explored the prognostic value of VE/VCO2 slope across the spectrum of HF defined by ranges of LVEF. METHODS AND RESULTS: In this single-centre retrospective observational study of 1347 patients with HF referred for cardiopulmonary exercise testing, patients with HF were categorized into HF with reduced (HFrEF, LVEF < 40%, n = 598), mid-range (HFmrEF, 40% ≤ LVEF < 50%, n = 164), and preserved (HFpEF, LVEF ≥ 50%, n = 585) LVEF. Four ventilatory efficiency categories (VC) were defined: VC-I, VE/VCO2 slope ≤ 29; VC-II, 29 < VE/VCO2 slope < 36; VC-III, 36 ≤ VE/VCO2 slope < 45; and VC-IV, VE/VCO2 slope ≥ 45. The associations of these VE/VCO2 slope categories with a composite outcome of all-cause mortality or HF hospitalization were evaluated for each category of LVEF. Over a median follow-up of 2.0 (interquartile range: 1.9, 2.0) years, 201 patients experienced the composite outcome. Compared with patients in VC-I, those in VC-II, III, and IV demonstrated three-fold, five-fold, and eight-fold increased risk for the composite outcome. This incremental risk was observed across HFrEF, HFmrEF, and HFpEF cohorts. CONCLUSIONS: Higher VE/VCO2 slope is associated with incremental risk of 2 year all-cause mortality and HF hospitalization across the spectrum of HF defined by LVEF. A multilevel categorical approach to the interpretation of VE/VCO2 slope may offer more refined risk stratification than the current binary approach employed in clinical practice.

A-lines and B-lines in patients with acute heart failure.

AIMS: Lung ultrasound (LUS) relies on detecting artefacts, including A-lines and B-lines, when assessing dyspnoeic patients. A-lines are horizontal artefacts and characterize normal lung, whereas multiple vertical B-lines are associated with increased lung density. We sought to assess the prevalence of A-lines and B-lines in patients with acute heart failure (AHF) and examine their clinical correlates and their relationship with outcomes. METHODS AND RESULTS: In a prospective cohort study of adults with AHF, eight-zone LUS and echocardiography were performed early during the hospitalization and pre-discharge at an imaging depth of 18 cm. A- and B-lines were analysed separately off-line, blinded to clinical and outcome data. Of 164 patients [median age 71 years, 61% men, mean ejection fraction (EF) 40%], the sum of A-lines at baseline ranged from 0 to 19 and B-line number from 0 to 36. One hundred and fifty-six patients (95%) had co-existing A-lines and B-lines at baseline. Lower body mass index and lower chest wall thickness were associated with a higher number of A-lines (P trend < 0.001 for both). In contrast to B-lines, there was no significant change in the number of A-lines from baseline to discharge (median 6 vs. 5, P = 0.80). While B-lines were associated with 90-day HF readmission or death, A-lines were not [HR 1.67, 95% confidence interval (CI) 1.11-2.51 vs. HR 0.97, 95% CI 0.65-1.43]. CONCLUSIONS: A-lines and B-lines on LUS co-exist in the vast majority of hospitalized patients with AHF. In contrast to B-lines, A-lines were not associated with adverse outcomes.

Sex differences in congestive markers in patients hospitalized for acute heart failure.

AIMS: We sought to examine sex differences in congestion in patients hospitalized for acute heart failure (AHF). Understanding congestive patterns in women and men with AHF may provide insights into sex differences in the presentation and prognosis of AHF patients. METHODS AND RESULTS: In a prospective, two-site study in adults hospitalized for AHF, four-zone lung ultrasound (LUS) was performed at the time of echocardiography at baseline (LUS1) and, in a subset, pre-discharge (LUS2). B-lines on LUS and echocardiographic images were analysed offline, blinded to clinical information and outcomes. Among 349 patients with LUS1 data (median age 74, 59% male, and 87% White), women had higher left ventricular ejection fraction (mean 43% vs. 36%, P < 0.001), higher tricuspid annular plane systolic excursion (mean 17 vs. 15 mm, P = 0.021), and higher measures of filling pressures (median E/e' 20 vs. 16, P < 0.001). B-line number on LUS1 (median 6 vs. 6, P = 0.69) and admission N-terminal pro-B-type natriuretic peptide levels (median 3932 vs. 3483 pg/mL, P = 0.77) were similar in women and men. In 121 patients with both LUS1 and LUS2 data, there was a similar and significant decrease in B-lines from baseline to discharge in both women and men. The risk of the composite 90 day outcome increased with higher B-line number on four-zone LUS2: unadjusted hazard ratio for each B-line tertile was 1.86 (95% confidence interval 1.08-3.20, P = 0.025) in women and 1.65 (95% confidence interval 1.03-2.64, P = 0.037) in men (interaction P = 0.72). CONCLUSIONS: Among patients with AHF, echocardiographic markers differed between women and men at baseline, whereas B-line number on LUS did not. The dynamic changes in B-lines during a hospitalization for AHF were similar in women and men.

Coronary vasomotor dysfunction in cancer survivors treated with thoracic irradiation.

BACKGROUND: We sought to test the hypothesis that thoracic radiation therapy (RT) is associated with impaired myocardial flow reserve (MFR), a measure of coronary vasomotor dysfunction. METHODS: We retrospectively studied thirty-five consecutive patients (71% female, mean ± standard deviation (SD) age: 66 ± 11 years) referred clinically for positron emission tomography/computed tomography (PET/CT) myocardial perfusion imaging at a median (interquartile range, IQR) interval of 4.3 (2.1, 9.7) years following RT for a variety of malignancies. Radiation dose-volume histograms were generated for the heart and coronary arteries for each patient. RESULTS: The median (IQR) of mean cardiac radiation doses was 12.0 (1.2, 24.2) Gray. There were significant inverse correlations between mean radiation dose and global MFR (MFRGlobal) and MFR in the left anterior descending artery territory (MFRLAD): Pearson's correlation coefficient = - .37 (P = .03) and - .38 (P = .03), respectively. For every one Gray increase in mean cardiac radiation dose, there was a mean ± standard error decrease of .02 ± .01 in MFRGlobal (P = .04) and MFRLAD (P = .03) after adjustment. CONCLUSIONS: In patients with a history of RT clinically referred for cardiac stress PET, we found an inverse correlation between mean cardiac radiation dose and coronary vasomotor function.

Decreased Absolute Lymphocyte Count and Increased Neutrophil/Lymphocyte Ratio With Immune Checkpoint Inhibitor-Associated Myocarditis.

Background Myocarditis attributable to immune checkpoint inhibitor (ICI) therapy is a potentially fatal immune-related adverse event. Limited data have suggested an association between baseline and on-treatment absolute lymphocyte count (ALC) and neutrophil/lymphocyte ratio (NLR) and the development of other immune-related adverse events; there are no data characterizing the role of ALC and NLR in ICI-associated myocarditis. Methods and Results This was a case control study of 55 patients with ICI myocarditis and 55 controls without any post-ICI immune-related adverse events. We leveraged clinical testing, where patients underwent routine serial blood counts before and with each ICI cycle to compare the baseline and change in ALC and NLR between cases and controls. The association between the change in these parameters with clinical variables and major adverse cardiac events was also tested. In cases, there was a statistically significant decrease in ALC with myocarditis from baseline (1.6 thousands per cubic milliliter (K/µL); interquartile range, 1.1-1.9 K/µL) to admission (1.1 K/µL; interquartile range, 0.7-1.3 K/µL; P<0.001). Similarly, there was an increase in NLR from baseline (3.5; interquartile range, 2.3-5.4) to admission (6.6; interquartile range, 4.5-14.1; P<0.001). There was no statistically significant change in controls. In follow-up, there were 20 events; larger decreases in ALC (44.6% versus 18.2%; P<0.001) or increases in NLR (156.5% versus 65.1%; P=0.019) were associated with major adverse cardiac events. Conclusions A reduction in ALC and an increase in NLR was seen with ICI myocarditis. A greater decrease in ALC or increase in NLR was associated with subsequent major adverse cardiac events.

Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies: a position statement and new risk assessment tools from the Cardio-Oncology Study Group of the Heart Failure Association of the European Society of Cardiology in collaboration with the International Cardio-Oncology Society.

This position statement from the Heart Failure Association of the European Society of Cardiology Cardio-Oncology Study Group in collaboration with the International Cardio-Oncology Society presents practical, easy-to-use and evidence-based risk stratification tools for oncologists, haemato-oncologists and cardiologists to use in their clinical practice to risk stratify oncology patients prior to receiving cancer therapies known to cause heart failure or other serious cardiovascular toxicities. Baseline risk stratification proformas are presented for oncology patients prior to receiving the following cancer therapies: anthracycline chemotherapy, HER2-targeted therapies such as trastuzumab, vascular endothelial growth factor inhibitors, second and third generation multi-targeted kinase inhibitors for chronic myeloid leukaemia targeting BCR-ABL, multiple myeloma therapies (proteasome inhibitors and immunomodulatory drugs), RAF and MEK inhibitors or androgen deprivation therapies. Applying these risk stratification proformas will allow clinicians to stratify cancer patients into low, medium, high and very high risk of cardiovascular complications prior to starting treatment, with the aim of improving personalised approaches to minimise the risk of cardiovascular toxicity from cancer therapies.

Cardiovascular magnetic resonance in immune checkpoint inhibitor-associated myocarditis.

AIMS: Myocarditis is a potentially fatal complication of immune checkpoint inhibitors (ICI). Sparse data exist on the use of cardiovascular magnetic resonance (CMR) in ICI-associated myocarditis. In this study, the CMR characteristics and the association between CMR features and cardiovascular events among patients with ICI-associated myocarditis are presented. METHODS AND RESULTS: From an international registry of patients with ICI-associated myocarditis, clinical, CMR, and histopathological findings were collected. Major adverse cardiovascular events (MACE) were a composite of cardiovascular death, cardiogenic shock, cardiac arrest, and complete heart block. In 103 patients diagnosed with ICI-associated myocarditis who had a CMR, the mean left ventricular ejection fraction (LVEF) was 50%, and 61% of patients had an LVEF ≥50%. Late gadolinium enhancement (LGE) was present in 48% overall, 55% of the reduced EF, and 43% of the preserved EF cohort. Elevated T2-weighted short tau inversion recovery (STIR) was present in 28% overall, 30% of the reduced EF, and 26% of the preserved EF cohort. The presence of LGE increased from 21.6%, when CMR was performed within 4 days of admission to 72.0% when CMR was performed on Day 4 of admission or later. Fifty-six patients had cardiac pathology. Late gadolinium enhancement was present in 35% of patients with pathological fibrosis and elevated T2-weighted STIR signal was present in 26% with a lymphocytic infiltration. Forty-one patients (40%) had MACE over a follow-up time of 5 months. The presence of LGE, LGE pattern, or elevated T2-weighted STIR were not associated with MACE. CONCLUSION: These data suggest caution in reliance on LGE or a qualitative T2-STIR-only approach for the exclusion of ICI-associated myocarditis.

Association of post-diagnosis cardiorespiratory fitness with cause-specific mortality in cancer.

AIMS: The prognostic importance of post-diagnosis assessment of cardiorespiratory fitness (CRF) in cancer patients is not well established. We sought to examine the association between CRF and mortality in cancer patients. METHODS AND RESULTS: This was a single-centre cohort analysis of 1632 patients (58% male; 64 ± 12 years) with adult-onset cancer who were clinically referred for exercise treadmill testing a median of 7 [interquartile range (IQR): 3-12] years after primary diagnosis. Cardiorespiratory fitness was defined as peak metabolic equivalents (METs) achieved during standard Bruce protocol and categorized by tertiles. The association between CRF and all-cause and cause-specific mortality was assessed using multivariable Cox proportional hazard models adjusting for important covariates. Median follow-up was 4.6 (IQR: 2.6-7.0) years; a total of 411 deaths (229, 50, and 132 all-cause, cardiovascular (CV), and cancer related, respectively) occurred during this period. Compared with low CRF (range: 1.9-7.6 METs), the adjusted hazard ratio (HR) for all-cause mortality was 0.38 [95% confidence interval (CI): 0.28-0.52] for intermediate CRF (range: 7.7-10.6 METs) and 0.17 (95% CI: 0.11-0.27) for high CRF (range: 10.7-22.0 METs). The corresponding HRs were 0.40 (95% CI: 0.19-0.86) and 0.41 (95% CI: 0.16-1.05) for CV mortality and 0.40 (95% CI: 0.26-0.60) and 0.16 (95% CI: 0.09-0.28) for cancer mortality, respectively. The adjusted risk of all-cause, CV, and cancer mortality decreased by 26%, 14%, and 25%, respectively with each one MET increment in CRF. CONCLUSION: Cardiorespiratory fitness is a strong, independent predictor of all-cause, CV, and cancer mortality, even after adjustment for important clinical covariates in patients with certain cancers.

Global Longitudinal Strain and Cardiac Events in Patients With Immune Checkpoint Inhibitor-Related Myocarditis.

BACKGROUND: There is a need for improved methods for detection and risk stratification of myocarditis associated with immune checkpoint inhibitors (ICIs). Global longitudinal strain (GLS) is a sensitive marker of cardiac toxicity among patients receiving standard chemotherapy. There are no data on the use of GLS in ICI myocarditis. OBJECTIVES: This study sought to evaluate the role of GLS and assess its association with cardiac events among patients with ICI myocarditis. METHODS: This study retrospectively compared echocardiographic GLS by speckle tracking at presentation with ICI myocarditis (cases, n = 101) to that from patients receiving an ICI who did not develop myocarditis (control subjects, n = 92). Where available, GLS was also measured pre-ICI in both groups. Major adverse cardiac events (MACE) were defined as a composite of cardiogenic shock, arrest, complete heart block, and cardiac death. RESULTS: Cases and control subjects were similar in age, sex, and cancer type. At presentation with myocarditis, 61 cases (60%) had a normal ejection fraction (EF). Pre-ICI, GLS was similar between cases and control subjects (20.3 ± 2.6% vs. 20.6 ± 2.0%; p = 0.60). There was no change in GLS among control subjects on an ICI without myocarditis (pre-ICI vs. on ICI, 20.6 ± 2.0% vs. 20.5 ± 1.9%; p = 0.41); in contrast, among cases, GLS decreased to 14.1 ± 2.8% (p < 0.001). The GLS at presentation with myocarditis was lower among cases presenting with either a reduced (12.3 ± 2.7%) or preserved EF (15.3 ± 2.0%; p < 0.001). Over a median follow-up of 162 days, 51 (51%) experienced MACE. The risk of MACE was higher with a lower GLS among patients with either a reduced or preserved EF. After adjustment for EF, each percent reduction in GLS was associated with a 1.5-fold increase in MACE among patients with a reduced EF (hazard ratio: 1.5; 95% confidence interval: 1.2 to 1.8) and a 4.4-fold increase with a preserved EF (hazard ratio: 4.4; 95% confidence interval: 2.4 to 7.8). CONCLUSIONS: GLS decreases with ICI myocarditis and, compared with control subjects, was lower among cases presenting with either a preserved or reduced EF. Lower GLS was strongly associated with MACE in ICI myocarditis presenting with either a preserved or reduced EF.

Reduced Cardiorespiratory Fitness and Increased Cardiovascular Mortality After Prolonged Androgen Deprivation Therapy for Prostate Cancer.

BACKGROUND: Prolonged androgen deprivation therapy (ADT) is favored over short-term use in patients with localized high-risk prostate cancer (PC). OBJECTIVES: This study sought to compare cardiorespiratory fitness (CRF) and cardiovascular (CV) mortality among patients with PC with and without ADT exposure and to explore how duration of ADT exposure influences CRF and CV mortality. METHODS: Retrospective cohort study of patients referred for exercise treadmill testing (ETT) after a PC diagnosis. PC risk classification was based on Gleason score (GS): high risk if GS ≥8; intermediate risk if GS = 7; and low risk if GS <7. CRF was categorized by metabolic equivalents (METs): METs >8 defined as good CRF and METs ≤8 as reduced CRF. ADT exposure was categorized as short term (≤6 months) versus prolonged (>6 months). RESULTS: A total of 616 patients underwent an ETT a median of 4.8 years (interquartile range: 2.0, 7.9 years) after PC diagnosis. Of those, 150 patients (24.3%) received ADT prior to the ETT; 99 with short-term and 51 with prolonged exposure. 504 patients (81.8%) had ≥2 CV risk factors. Prolonged ADT was associated with reduced CRF (odds ratio [OR]: 2.71; 95% confidence interval [CI]: 1.31 to 5.61; p = 0.007) and increased CV mortality (hazard ratio [HR]: 3.87; 95% CI: 1.16 to 12.96; p = 0.028) in adjusted analyses. Although the association between short-term ADT exposure and reduced CRF was of borderline significance (OR: 1.71; 95% CI: 1.00 to 2.94; p = 0.052), there was no association with CV mortality (HR: 1.60; 95% CI: 0.51 to 5.01; p = 0.420) in adjusted Cox regression models. CONCLUSIONS: Among patients with PC and high baseline CV risk, prolonged ADT exposure was associated with reduced CRF and increased CV mortality.

Lung Ultrasound in Acute Heart Failure: Prevalence of Pulmonary Congestion and Short- and Long-Term Outcomes.

OBJECTIVES: This study sought to assess the prevalence, changes in, and prognostic importance of B-lines, a pulmonary congestion measure by using a simplified lung ultrasonography (LUS) method in acute heart failure (AHF). BACKGROUND: Pulmonary congestion is an important finding in AHF, but conventional methods for its detection are insensitive. METHODS: In a 2-site, prospective, observational study, 4-zone LUS was performed early during hospitalization for AHF (LUS1) and at discharge (LUS2). B-lines were quantified off-line, blinded to clinical findings and outcomes, by a core laboratory. RESULTS: Among 349 patients (median, 75 years of age; 59% men; mean ejection fraction 39%), the sum of B-lines in 4 zones ranged from 0 to 18 (LUS1). The risk of an adverse in-hospital event increased with rising number of B-lines on LUS1: the odds ratio for each B-line tertile was 1.82 (95% confidence interval [CI]: 1.14 to 2.88; p = 0.011). B-line count decreased from a median of 6 (LUS1) to 4 (LUS2; p < 0.001) over 6 days (median). In 132 patients with LUS2 images, the risk of HF hospitalization or all-cause death was greater in patients with a higher number of B-lines at discharge. This relationship was stronger closer to discharge: unadjusted hazard ratio (HR) at 60 days was 3.30 (95% CI: 1.52 to 7.17; p = 0.002); 2.94 at 90 days (95% CI: 1.46 to 5.93; p = 0.003); and 2.01 at 180 days (95% CI: 1.11 to 3.64; p = 0.021). The association between number of B-lines and short- and long-term outcomes persisted after adjusting for important clinical variables, including N-terminal pro-B-type natriuretic peptide. CONCLUSIONS: Pulmonary congestion using a simplified 4-zone LUS method was common in patients with AHF and improved with therapy. A higher number of B-lines at baseline and discharge identified patients at increased risk for adverse events.

Cardiovascular Toxicities Associated With Ibrutinib.

BACKGROUND: Ibrutinib has revolutionized treatment for several B-cell malignancies. However, a recent clinical trial where ibrutinib was used in a front-line setting showed increased mortality during treatment compared with conventional chemotherapy. Cardiovascular toxicities were suspected as the culprit but not directly assessed in the study. OBJECTIVES: The purpose of this study was to identify and characterize cardiovascular adverse drug reactions (CV-ADR) associated with ibrutinib. METHODS: This study utilized VigiBase (International pharmacovigilance database) and performed a disproportionality analysis using reporting odds ratios (ROR) and information component (IC) to determine whether CV-ADR and CV-ADR deaths were associated with ibrutinib. IC compares observed and expected values to find associations between drugs and adverse drug reactions using disproportionate Bayesian-reporting; IC025 (lower end of the IC 95% credibility interval) >0 is significant. RESULTS: This study identified 303 ibrutinib-associated cardiovascular deaths. Ibrutinib was associated with higher reporting of supraventricular arrhythmias (SVAs) (ROR: 23.1; 95% confidence interval: 21.6 to 24.7; p < 0.0001; IC025: 3.97), central nervous system (CNS) hemorrhagic events (ROR: 3.7; 95% confidence interval: 3.4 to 4.1; p < 0.0001; IC025: 1.63), heart failure (ROR: 3.5; 95% confidence interval: 3.1 to 3.8; p < 0.0001; IC025: 1.46), ventricular arrhythmias (ROR: 4.7; 95% confidence interval: 3.7 to 5.9; p < 0.0001; IC025: 0.96), conduction disorders (ROR: 3.5; 95% confidence interval: 2.7 to 4.6; p < 0.0001; IC025: 0.76), CNS ischemic events (ROR: 2.2; 95% confidence interval: 2.0 to 2.5; p < 0.0001; IC025: 0.73), and hypertension (ROR: 1.7; 95% confidence interval: 1.5 to 1.9; p < 0.0001; IC025: 0.4). CV-ADR often occurred early after ibrutinib administration. Importantly, CV-ADR were associated with fatalities that ranged from ∼10% (SVAs and ventricular arrhythmias) to ∼20% (CNS events, heart failure, and conduction disorders). Ibrutinib-associated SVA portends poor prognosis when CNS events occur concomitantly, with 28.8% deaths (15 of 52 cases). CONCLUSIONS: Severe and occasionally fatal cardiac events occur in patients exposed to ibrutinib. These events should be considered in patient care and in clinical trial designs. (Evaluation of Reporting of Cardio-vascular Adverse Events With Antineoplastic and Immunomodulating Agents [EROCA]; NCT03530215).

Carvedilol Among Patients With Heart Failure With a Cocaine-Use Disorder.

OBJECTIVES: This study sought to assess the safety of carvedilol therapy among heart failure (HF) patients with a cocaine-use disorder (CUD). BACKGROUND: Although carvedilol therapy is recommended among certain patients with HF, the safety and efficacy of carvedilol among HF patients with a CUD is unknown. METHODS: This was a single-center study of hospitalized patients with HF. Cocaine use was self-reported or defined as having a positive urine toxicology. Patients were divided by carvedilol prescription. Subgroup analyses were performed by strata of ejection fraction (EF) ≤40%, 41% to 49%, or ≥50%. Major adverse cardiovascular events (MACE) were defined as cardiovascular mortality and 30-day HF readmission. RESULTS: From a cohort of 2,578 patients hospitalized with HF in 2011, 503 patients with a CUD were identified, among whom 404 (80%) were prescribed carvedilol, and 99 (20%) were not. Both groups had similar characteristics; however, those prescribed carvedilol had a lower LVEF, heart rate, and N-terminal pro-B-type natriuretic peptide concentrations at admission and on discharge, and more coronary artery disease. Over a median follow-up of 19 months, there were 169 MACEs. The MACE rates were similar between the carvedilol and the non-carvedilol groups (32% vs. 38%, respectively; p = 0.16) and between those with a preserved EF (30% vs. 33%, respectively; p = 0.48) and were lower in patients with a reduced EF taking carvedilol (34% vs. 58%, respectively; p = 0.02). In a multivariate model, carvedilol therapy was associated with lower MACE among patients with HF with a CUD (hazard ratio: 0.67; 95% confidence interval; 0.481 to 0.863). CONCLUSIONS: Our findings suggest that carvedilol therapy is safe for patients with HF with a CUD and may be effective among those with a reduced EF.

Cardiotoxicity of Immune Checkpoint Inhibitors.

PURPOSE OF REVIEW: Immunotherapies, particularly immune checkpoint inhibitors (ICI), are revolutionary cancer therapies being increasingly applied to a broader range of cancers. Our understanding of the mechanism, epidemiology, diagnosis, and treatment of cardiotoxicity related to immunotherapies remains limited. We aim to synthesize the limited current literature on cardiotoxicity of ICIs and to share our opinions on the diagnosis and treatment of this condition. RECENT FINDINGS: The incidence of ICI-associated myocarditis ranges from 0.1 to 1%. Patients with ICI-associated myocarditis often have a fulminant course with a case fatality rate of 25-50%. The diagnosis of this condition poses many challenges because independently a normal electrocardiogram, biomarkers, or a preserved left ventricular function do not rule out ICI-associated myocarditis. Endomyocardial biopsy should be pursued when clinical suspicion remains despite normal non-invasive tests. Data on optimal screening and surveillance tools are lacking. Cessation of ICIs, combined with high dose corticosteroids and other immunosuppressant approaches are the cornerstones of the treatment of ICI-associated myocarditis. This condition may recur when patients are re-challenged with these agents and the decision to resume ICIs should be made through a multidisciplinary discussion. Immunotherapies have changed the landscape of cancer treatment. Recognizing and managing cardiotoxicity related to ICIs is of critical importance. Our understanding of ICI-cardiotoxicity has improved, but large information gaps remain for further research. Due to the high case fatality rate, any type of cardiac symptoms or signs in a patient who has recently started an ICI should prompt consideration of ICI-cardiotoxicity.

Influenza vaccination and myocarditis among patients receiving immune checkpoint inhibitors.

BACKGROUND: Influenza vaccination (FV) is recommended for patients with cancer. Recent data suggested that the administration of the FV was associated with an increase in immune-related adverse events (irAEs) among patients on immune checkpoint inhibitors (ICIs). Myocarditis is an uncommon but serious complication of ICIs and may also result from infection with influenza. There are no data testing the relationship between FV and the development of myocarditis on ICIs. METHODS: Patients on ICIs who developed myocarditis (n = 101) (cases) were compared to ICI-treated patients (n = 201) without myocarditis (controls). A patient was defined as having the FV if they were administered the FV from 6 months prior to start of ICI to anytime during ICI therapy. Alternate thresholds for FV status were also tested. The primary comparison of interest was the rate of FV between cases and controls. Patients with myocarditis were followed for major adverse cardiac events (MACE), defined as the composite of cardiogenic shock, cardiac arrest, hemodynamically significant complete heart block and cardiovascular death. RESULTS: The FV was administered to 25% of the myocarditis cases compared to 40% of the non-myocarditis ICI-treated controls (p = 0.01). Similar findings of lower rates of FV administration were noted among myocarditis cases when alternate thresholds were tested. Among the myocarditis cases, those who were vaccinated had 3-fold lower troponin levels when compared to unvaccinated cases (FV vs. No FV: 0.12 [0.02, 0.47] vs. 0.40 [0.11, 1.26] ng/ml, p = 0.02). Within myocarditis cases, those administered the FV also had a lower rate of other irAEs when compared to unvaccinated cases (36 vs. 55% p = 0.10) including lower rates of pneumonitis (12 vs. 36%, p = 0.03). During follow-up (175 [IQR 89, 363] days), 47% of myocarditis cases experienced a MACE. Myocarditis cases who received the FV were at a lower risk of cumulative MACE when compared to unvaccinated cases (24 vs. 59%, p = 0.002). CONCLUSION: The rate of FV among ICI-related myocarditis cases was lower than controls on ICIs who did not develop myocarditis. In those who developed myocarditis related to an ICI, there was less myocardial injury and a lower risk of MACE among those who were administered the FV.