Cardiac radiation dose is associated with inferior survival but not cardiac events in patients with locally advanced non-small cell lung cancer in the era of immune checkpoint inhibitor consolidation.

PURPOSE: We assessed the association of cardiac radiation dose with cardiac events and survival post-chemoradiation therapy (CRT) in patients with locally advanced non-small cell lung cancer (LA-NSCLC) after adoption of modern radiation therapy (RT) techniques, stricter cardiac dose constraints, and immune checkpoint inhibitor (ICI) consolidation. METHODS AND MATERIALS: This single-institution, multi-site retrospective study included 335 patients with LA-NSCLC treated with definitive, concurrent CRT between October 2017 and December 2021. All patients were evaluated for ICI consolidation. Planning dose constraints included heart mean dose < 20 Gy (<10 Gy if feasible) and heart volume receiving ≥ 50 Gy (V50Gy) < 25 %. Twenty-one dosimetric parameters for three different cardiac structures (heart, left anterior descending coronary artery [LAD], and left ventricle) were extracted. Primary endpoint was any major adverse cardiac event (MACE) post-CRT, defined as acute coronary syndrome, heart failure, coronary revascularization, or cardiac-related death. Secondary endpoints were: grade ≥ 3 cardiac events (per CTCAE v5.0), overall survival (OS), lung cancer-specific mortality (LCSM), and other-cause mortality (OCM). RESULTS: Median age was 68 years, 139 (41 %) had baseline coronary heart disease, and 225 (67 %) received ICI consolidation. Proton therapy was used in 117 (35 %) and intensity-modulated RT in 199 (59 %). Median LAD V15Gy was 1.4 % (IQR 0-22) and median heart mean dose was 8.7 Gy (IQR 4.6-14.4). Median follow-up was 3.3 years. Two-year cumulative incidence of MACE was 9.5 % for all patients and 14.3 % for those with baseline coronary heart disease. Two-year cumulative incidence of grade ≥ 3 cardiac events was 20.4 %. No cardiac dosimetric parameter was associated with an increased risk of MACE or grade ≥ 3 cardiac events. On multivariable analysis, cardiac dose (LAD V15Gy and heart mean dose) was associated with worse OS, driven by an association with LCSM but not OCM. CONCLUSIONS: With modern RT techniques, stricter cardiac dose constraints, and ICI consolidation, cardiac dose was associated with LCSM but not OCM or cardiac events in patients with LA-NSCLC.

Impact of Atrial Fibrillation on Heart Failure in Patients Treated With Anthracycline Chemotherapy.

Atrial fibrillation (AF) and anthracyclines are known risk factors for heart failure (HF). The magnitude of the effect of preexisting AF (preanthracycline AF) and newly developed AF (postanthracycline AF) in patients treated with anthracyclines on the occurrence of HF is unknown. The aim of our study was to characterize the impact of preanthracycline and postanthracycline AF on the subsequent occurrence of HF in patients treated with anthracyclines. In 5,598 patients treated with new anthracycline therapy at a tertiary center between 2008 and 2021, propensity score matching was used to match 204 pairs with or without preanthracycline AF and 135 pairs with or without postanthracycline AF. The primary outcome was new-onset symptomatic HF defined by the American Heart Association/American College of Cardiology guidelines. Patients with and without preanthracycline and postanthracycline AF were well matched for age, gender, medications, and cardiovascular risk factors. A total of 45 patients with preanthracycline AF and 23 matched patients developed HF (5-year cumulative incidence: 29% in the preanthracycline AF group and 13% in the matched group, p = 0.003; hazard ratio 2.1, 95% confidence interval 1.3 to 3.4, p = 0.004). A total of 161 patients (2.9%) developed postanthracycline AF. A total of 39 patients (5-year cumulative incidence: 40%) with postanthracycline AF and 9 matched patients (5-year cumulative incidence: 7%) developed HF (hazard ratio 6.1, 95% confidence interval 3.0 to 12.4, p <0.001). Preanthracycline AF and postanthracycline AF are associated with a high incidence of subsequent HF in patients treated with anthracyclines. Prospective studies of therapies are required to decrease HF in these high-risk patients.

The Association of Metformin With Heart Failure in Patients With Diabetes Mellitus Receiving Anthracycline Chemotherapy.

Background: The prevention of heart failure (HF) is an important issue in patients treated with anthracyclines. Metformin, widely used to treat diabetes mellitus (DM), protects from anthracycline-induced cardiotoxicity in vitro and in animal models. Objectives: The aim of our study was to test the association of metformin with the occurrence of symptomatic HF in patients with DM receiving anthracyclines. Methods: A total of 561 patients with DM received new anthracycline therapy between 2008 and 2021 in a tertiary care center; propensity score matching was used to compare patients with or without metformin treatment. The primary outcome was new onset symptomatic HF occurring within 1 year of the initiation of anthracyclines. Results: A total of 315 patients (65 ± 11 years of age, 33.7% male) were included. Patients with and without metformin were well matched for age, sex, type of cancer, medications, and cardiovascular risk factors. Six patients treated with metformin and 17 matched patients developed HF within 1 year of anthracycline initiation. The incidence of HF in patients treated with metformin was lower than patients without metformin within 1 year after anthracyclines (cumulative incidence: 3.6% vs 10.5%; P = 0.022; HR: 0.35; 95% CI: 0.14-0.90; P = 0.029). The use of metformin (HR: 0.71; 95% CI: 0.50-1.00; P = 0.049), was also associated with lower mortality. Conclusions: The use of metformin was associated with a lower incidence of HF and overall mortality in patients with DM receiving anthracyclines. Our findings should be further confirmed by randomized control trials.

Early Increases in Blood Pressure and Major Adverse Cardiovascular Events in Patients With Renal Cell Carcinoma and Thyroid Cancer Treated With VEGFR TKIs.

BACKGROUND: Although VEGFR tyrosine kinase inhibitors (TKIs) are a preferred systemic treatment approach for patients with advanced renal cell carcinoma (RCC) and thyroid carcinoma (TC), treatment-related cardiovascular (CV) toxicity is an important contributor to morbidity. However, the clinical risk assessment and impact of CV toxicities, including early significant hypertension, among real-world advanced cancer populations receiving VEGFR TKI therapies remain understudied. METHODS: In a multicenter, retrospective cohort study across 3 large and diverse US health systems, we characterized baseline hypertension and CV comorbidity in patients with RCC and those with TC who are newly initiating VEGFR TKI therapy. We also evaluated baseline patient-, treatment-, and disease-related factors associated with the risk for treatment-related early hypertension (within 6 weeks of TKI initiation) and major adverse CV events (MACE), accounting for the competing risk of death in an advanced cancer population, after VEGFR TKI initiation. RESULTS: Between 2008 and 2020, 987 patients (80.3% with RCC, 19.7% with TC) initiated VEGFR TKI therapy. The baseline prevalence of hypertension was high (61.5% and 53.6% in patients with RCC and TC, respectively). Adverse CV events, including heart failure and cerebrovascular accident, were common (occurring in 14.9% of patients) and frequently occurred early (46.3% occurred within 1 year of VEGFR TKI initiation). Baseline hypertension and Black race were the primary clinical factors associated with increased acute hypertensive risk within 6 weeks of VEGFR TKI initiation. However, early significant "on-treatment" hypertension was not associated with MACE. CONCLUSIONS: These multicenter, real-world findings indicate that hypertensive and CV morbidities are highly prevalent among patients initiating VEGFR TKI therapies, and baseline hypertension and Black race represent the primary clinical factors associated with VEGFR TKI-related early significant hypertension. However, early on-treatment hypertension was not associated with MACE, and cancer-specific CV risk algorithms may be warranted for patients initiating VEGFR TKIs.

Feasibility of Lipid Screening During First Trimester of Pregnancy to Identify Women at Risk of Severe Dyslipidemia.

Background Dyslipidemia is an important risk factor for atherosclerotic cardiovascular disease, especially when disease presents at a young age. Despite national screening guidelines to perform a lipid profile test in children and young adults, many reproductive-age women have not undergone lipid screening. Our objective was to assess the feasibility of lipid screening during the first trimester of pregnancy as a strategy to increase lipid screening rates among women receiving prenatal care. Methods and Results A nonfasting lipid panel was incorporated into routine prenatal care among obstetricians at a single academic clinic. Educational materials and a clinical referral pathway were developed for patients with abnormal results. Over 6 months, 445 patients had a first prenatal care visit. Of the 358 patients who completed laboratory testing, 236 (66%) patients completed lipid testing. Overall, 59 (25%) patients had abnormal results. One patient with previously undiagnosed suspected familial hypercholesterolemia was identified. Barriers to ordering lipid tests included the burden of reviewing additional laboratory results and uncertainty about patient counseling. Conclusions Implementation of nonfasting lipid screening as part of routine prenatal care during the first trimester is feasible and may play a crucial role in timely diagnosis and management of lipid disorders in women of reproductive age. Future work should focus on optimizing health system workflow to minimize burden on clinical staff and facilitate follow-up with appropriate specialists.

Plasma biomarkers associated with adverse outcomes in patients with calcific aortic stenosis.

AIMS: Enhanced risk stratification of patients with aortic stenosis (AS) is necessary to identify patients at high risk for adverse outcomes, and may allow for better management of patient subgroups at high risk of myocardial damage. The objective of this study was to identify plasma biomarkers and multimarker profiles associated with adverse outcomes in AS. METHODS AND RESULTS: We studied 708 patients with calcific AS and measured 49 biomarkers using a Luminex platform. We studied the correlation between biomarkers and the risk of (i) death and (ii) death or heart failure-related hospital admission (DHFA). We also utilized machine-learning methods (a tree-based pipeline optimizer platform) to develop multimarker models associated with the risk of death and DHFA. In this cohort with a median follow-up of 2.8 years, multiple biomarkers were significantly predictive of death in analyses adjusted for clinical confounders, including tumour necrosis factor (TNF)-α [hazard ratio (HR) 1.28, P < 0.0001], TNF receptor 1 (TNFRSF1A; HR 1.38, P < 0.0001), fibroblast growth factor (FGF)-23 (HR 1.22, P < 0.0001), N-terminal pro B-type natriuretic peptide (NT-proBNP) (HR 1.58, P < 0.0001), matrix metalloproteinase-7 (HR 1.24, P = 0.0002), syndecan-1 (HR 1.27, P = 0.0002), suppression of tumorigenicity-2 (ST2) (IL1RL1; HR 1.22, P = 0.0002), interleukin (IL)-8 (CXCL8; HR 1.22, P = 0.0005), pentraxin (PTX)-3 (HR 1.17, P = 0.001), neutrophil gelatinase-associated lipocalin (LCN2; HR 1.18, P < 0.0001), osteoprotegerin (OPG) (TNFRSF11B; HR 1.26, P = 0.0002), and endostatin (COL18A1; HR 1.28, P = 0.0012). Several biomarkers were also significantly predictive of DHFA in adjusted analyses including FGF-23 (HR 1.36, P < 0.0001), TNF-α (HR 1.26, P < 0.0001), TNFR1 (HR 1.34, P < 0.0001), angiopoietin-2 (HR 1.26, P < 0.0001), syndecan-1 (HR 1.23, P = 0.0006), ST2 (HR 1.27, P < 0.0001), IL-8 (HR 1.18, P = 0.0009), PTX-3 (HR 1.18, P = 0.0002), OPG (HR 1.20, P = 0.0013), and NT-proBNP (HR 1.63, P < 0.0001). Machine-learning multimarker models were strongly associated with adverse outcomes (mean 1-year probability of death of 0%, 2%, and 60%; mean 1-year probability of DHFA of 0%, 4%, 97%; P < 0.0001). In these models, IL-6 (a biomarker of inflammation) and FGF-23 (a biomarker of calcification) emerged as the biomarkers of highest importance. CONCLUSIONS: Plasma biomarkers are strongly associated with the risk of adverse outcomes in patients with AS. Biomarkers of inflammation and calcification were most strongly related to prognosis.

Diagnostic accuracy of SPECT and PET myocardial perfusion imaging in patients with left bundle branch block or ventricular-paced rhythm.

BACKGROUND: The difference in diagnostic accuracy of coronary artery disease (CAD) between vasodilator SPECT and PET myocardial perfusion imaging (MPI) in patients with left bundle branch block (LBBB) or ventricular-paced rhythm (VPR) is unknown. METHODS: We identified patients with LBBB or VPR who underwent either vasodilator SPECT or PET MPI and subsequent coronary angiography. LBBB/VPR-related septal and anteroseptal defects were defined as perfusion defects involving those regions in the absence of obstructive CAD in the left anterior descending artery or left main coronary artery. RESULTS: Of the 55 patients who underwent coronary angiography, 38 (69%) underwent SPECT and 17 patients (31%) underwent PET. PET compared to SPECT demonstrated higher sensitivity (88% vs 60%), specificity (56% vs 14%), positive predictive value (64% vs 20%), negative predictive value (83% vs 50%), and overall superior diagnostic accuracy (AUC .72 (95% CI .50-.93) vs .37 (95% CI .20-.54), P = .01) to detect obstructive CAD. LBBB/VPR-related septal and anteroseptal defects were more common with SPECT compared to PET (septal: 72% vs 17%, P = .001; anteroseptal: 47% vs 8%, P = .02). CONCLUSIONS: PET has higher diagnostic accuracy when compared to SPECT for the detection of obstructive CAD in patients with LBBB or VPR.

Cardiology Involvement in Patients with Breast Cancer Treated with Trastuzumab.

BACKGROUND: There is limited evidence regarding the impact of cardiology involvement in the care of cancer patients. OBJECTIVES: We evaluated the impact of cardiology involvement on guideline-adherent cardiovascular monitoring and risk factor management in breast cancer patients treated with trastuzumab. METHODS: In a single-center retrospective cohort study, we evaluated electronic health records from 1,047 breast cancer patients receiving trastuzumab between January 2009 and July 2018. A visit to a cardiology provider beginning from the 3 months prior to cancer therapy initiation until the last contact date defined cardiology involvement. Guideline-adherent monitoring, defined by echocardiography assessment within the 4 months prior to trastuzumab initiation and follow-up echocardiography at least every 4 months during therapy, was compared in patients with and without cardiology involvement prior to treatment initiation. Multivariable associations between cardiology involvement and time-varying risk factors blood pressure (BP) and body mass index (BMI) were assessed using generalized estimating equations. RESULTS: Cardiology involvement occurred in 293 (28%) patients. A higher proportion of patients with cardiology involvement prior to trastuzumab initiation had guideline-adherent monitoring (76.4% versus 60.1%, p=0.007). Cardiology involvement was associated with an average 1.5mmHg (95% CI -2.9,-0.1, p=0.035) lower systolic BP; which was more pronounced in those with hypertension (-2.7mmHg (95% CI -4.6,-0.7, p=0.007)). Cardiology involvement was associated with a lower BMI in patients with baseline BMI≥25 kg/m2 (mean difference; -0.5 (95% CI -1.0,-0.1, p=0.027)). CONCLUSIONS: Cardiology involvement in breast cancer patients treated with trastuzumab is associated with greater adherence to cardiovascular monitoring and modest improvements in risk factor control.

COVID-19 and cardiac arrhythmias.

BACKGROUND: Early studies suggest that coronavirus disease 2019 (COVID-19) is associated with a high incidence of cardiac arrhythmias. Severe acute respiratory syndrome coronavirus 2 infection may cause injury to cardiac myocytes and increase arrhythmia risk. OBJECTIVES: The purpose of this study was to evaluate the risk of cardiac arrest and arrhythmias including incident atrial fibrillation (AF), bradyarrhythmias, and nonsustained ventricular tachycardia (NSVT) in a large urban population hospitalized for COVID-19. We also evaluated correlations between the presence of these arrhythmias and mortality. METHODS: We reviewed the characteristics of all patients with COVID-19 admitted to our center over a 9-week period. Throughout hospitalization, we evaluated the incidence of cardiac arrests, arrhythmias, and inpatient mortality. We also used logistic regression to evaluate age, sex, race, body mass index, prevalent cardiovascular disease, diabetes, hypertension, chronic kidney disease, and intensive care unit (ICU) status as potential risk factors for each arrhythmia. RESULTS: Among 700 patients (mean age 50 ± 18 years; 45% men; 71% African American; 11% received ICU care), there were 9 cardiac arrests, 25 incident AF events, 9 clinically significant bradyarrhythmias, and 10 NSVTs. All cardiac arrests occurred in patients admitted to the ICU. In addition, admission to the ICU was associated with incident AF (odds ratio [OR] 4.68; 95% confidence interval [CI] 1.66-13.18) and NSVT (OR 8.92; 95% CI 1.73-46.06) after multivariable adjustment. Also, age and incident AF (OR 1.05; 95% CI 1.02-1.09) and prevalent heart failure and bradyarrhythmias (OR 9.75; 95% CI 1.95-48.65) were independently associated. Only cardiac arrests were associated with acute in-hospital mortality. CONCLUSION: Cardiac arrests and arrhythmias are likely the consequence of systemic illness and not solely the direct effects of COVID-19 infection.

Clinic nonattendance is associated with increased emergency department visits in adults with congenital heart disease.

OBJECTIVE: To determine the prevalence and predictors of nonattendance in an ACHD outpatient clinic, and to examine the relationship between nonattendance and emergency department (ED) visits, hospitalizations, and death. METHODS: Patients ≥ 18 years who had scheduled appointments at an ACHD outpatient clinic between August 1, 2014 and December 31, 2014 were included. The primary outcome of interest was nonattendance of the first scheduled appointment of the study period, defined as "no-show" or "same-day cancellation." Secondary outcomes of interest were ED visits, hospitalizations, and death until December 2017. RESULTS: Of 527 scheduled visits, 55 (10.4%) were nonattended. Demographic and socioeconomic characteristics such as race, income, and insurance type were associated with non-attendance (all P values < .05), whereas age, gender, and disease complexity were not. On multivariable analysis, predictors of nonattendance were black race (adjusted odds ratio [AOR] 4.95; P < .001), other race (AOR 3.54; P = .003), and history of no-show in the past (AOR 4.95; P < .001). Compared to patients who attended clinic, patients with a nonattended visit had a threefold increased odds of multiple ED visits and a significantly lower rate of ED-free survival over time. There were no significant differences in hospitalizations or death by attendance. CONCLUSIONS: ACHD clinic nonattendance is associated with race and prior history of no-show, and may serve as a marker of higher ED utilization for patients with ACHD.

Symptomatic Heart Failure in Acute Leukemia Patients Treated With Anthracyclines.

OBJECTIVES: The purpose of this study was to investigate the occurrence and develop a risk score for heart failure (HF) in acute leukemia. BACKGROUND: Knowledge is scarce regarding the incidence and risk factors of symptomatic HF in patients with acute leukemia. METHODS: Baseline clinical and echocardiographic parameters, including indices of cardiac function (left ventricular ejection fraction and myocardial strain [global longitudinal strain; GLS]), were obtained in 450 patients with acute leukemia treated with anthracyclines, before chemotherapy initiation. Potential risk factors for HF were evaluated using Fine and Gray's regression analysis, and from this, a 21-point risk score was generated. RESULTS: Forty patients (8.9%) developed HF. The HF risk score included a baseline GLS >-15% (indicative of greater impairment) (6 points), baseline left ventricular ejection fraction <50%, pre-existing cardiovascular disease, acute myeloid leukemia (4 points each), cumulative anthracycline dose ≥250 mg/m2 (2 points), and age >60 years (1 point). Patients were stratified into low (score 0 to 6), moderate (score 7 to 13), and high risk (score 14 to 21). The estimated 1-year cumulative incidence of HF for low-, moderate-, and high-risk groups was 1.0%, 13.6%, and 35.0%, respectively (p < 0.001). The HF risk score was also predictive of all-cause mortality (p < 0.001). After adjustment for age and leukemia type, however, only GLS was significantly associated with all-cause mortality (hazard ratio: 1.73; 95% confidence interval: 1.30 to 2.31; p < 0.001). CONCLUSIONS: We developed a baseline risk score to determine risk of HF in patients with acute leukemia. Additional studies are needed to determine the external validity of these findings.

Effect of comedication of bupropion and other antidepressants on body mass index.

BACKGROUND: Weight gain as an adverse effect of monotherapy of antidepressant has been well-studied. The effects of augmentation therapy involving multiple antidepressants, on weight changes needs to be adequately addressed. OBJECTIVE: To study the co-medication effects of bupropion in combination with six individual antidepressants on body mass index (BMI) using EMR based data analysis. METHODS: Allscripts data warehouse was used to identify patients on monotherapy of five selective serotonin reuptake inhibitor (SSRI) drugs, escitalopram, sertraline, citalopram, paroxetine, fluoxetine, one selective norepinephrine reuptake inhibitor (SNRI) duloxetine and the aminoketone, bupropion for at least 180 days. We also identified patients on co-medication of SSRI/SNRI drugs with bupropion. Six ANCOVA models were built to compare the short term effects on BMI, among monotherapy and co-medication groups. The patients' clinical conditions and demographics were included to account for confounding effects. RESULTS: Monotherapy of all the SSRI/SNRI drugs showed significant weight increase, consistent with that of previous studies. The co-medication of bupropion and escitalopram showed a significantly higher increase in BMI than monotherapy (P = 0.0102). The increase in BMI in the other five co-medication groups was not significantly different from their respective monotherapy groups. CONCLUSION: Our study reports an adverse weight gain on co-medication of escitalopram and bupropion, which warrants further validation studies. Considering co-medication effects of antidepressants on weight is important to design robust depression treatment plans.

Co-medication of pravastatin and paroxetine-a categorical study.

Electronic Medical Records (EMRs) are wealthy storehouses of patient information, to which data mining techniques can be prudently applied to reveal clinically significant patterns. Detecting patterns in drug-drug interactions, leading to adverse drug reactions is a powerful application of EMR data mining. Adverse effects of drug treatments can be investigated by mining clinical laboratory tests data which are reliable indicators of abnormal physiological functions. We report here the co-medication effects of pravastatin (HMG-CoA reductase inhibitor) and paroxetine (selective serotonin reuptake inhibitor (SSRI) anti-depressant) on significant clinical parameters, identified through a data mining analysis conducted on the Allscripts data warehouse. We found that the concomitant drug treatments of pravastatin and paroxetine increased the mean values of glucose serum from 113.2 to 132.1 mg/dL and international normalized ratio (INR) from 2.18 to 2.52, respectively. It also decreased the mean values of estimated glomerular filtration rate (eGFR) from 43 to 37 mL/min/1.73 m(3) and blood CO2 levels from 24.8 to 23.9 mEq/L respectively. Our findings indicate that co-medication of pravastatin and paroxetine might have significant impact on blood anti-coagulation, kidney function, and glucose homeostasis. Our methodology can be applied to any EMR data set to reveal co-medication effects of any drug pairs.