Time-dependent Cox Regression Research Articles

Device-detected sleep-disordered breathing predicts implantable defibrillator therapy in patients with heart failure

Abstract Funding Acknowledgements Type of funding sources: None. Background Sleep-disordered breathing is highly prevalent in heart failure (HF) and it has been suggested as a risk factor for malignant ventricular arrhythmias. The Respiratory Disturbance Index (RDI) algorithm computed by select implantable cardioverter defibrillators (ICDs) can identify severe sleep apnea (SA). Purpose In the present analysis we evaluated the association between ICD-detected SA and the incidence of appropriate ICD therapy in patients with HF. Methods We enrolled 411 HF patients (age 69±10years, 77% male, ejection fraction 32±8%), implanted with an ICD endowed with an algorithm (ApneaScan, Boston Scientific) that calculates the RDI each night. In this analysis the weekly mean RDI value was considered. The endpoint was the first appropriate ICD shock. The median follow-up was 26 months [25th–75th percentile: 16-35]. Results During follow-up, one or more ICD shocks were documented in 58 (14%) patients. Patients with shocks were younger (66±13years versus 70±10years, p=0.038), and more frequently implanted for secondary prevention (21% versus 10%, p=0.026). The maximum RDI value calculated during the entire follow-up period did not differ between patients with and without shocks (55±15episodes/h versus 54±14episodes/h, p=0.539). However, the ICD-detected RDI showed a considerable variability during follow-up. The overall median of the weekly RDI was 33episodes/h [25th–75th percentile: 24-45]. Using a time-dependent Cox regression model, the continuously measured weekly mean RDI≥45episodes/h was independently associated with shock occurrence (HR:4.63, 95%CI:2.54-8.43, p<0.001), after correction for baseline confounders (age, secondary prevention). Conclusions In HF patients, patients were more likely to receive appropriate ICD shocks during periods of time when they exhibited more sleep-disordered breathing.

Device-Related Complications and Inappropriate Therapies Among Subcutaneous vs. Transvenous Implantable Defibrillator Recipients: Insight Monaldi Rhythm Registry

IntroductionIn the context of randomized clinical trials, subcutaneous implantable cardiac defibrillators (S-ICDs) are non-inferior to transvenous ICDs (T-ICDs) concerning device-related complications or inappropriate shocks in patients with an indication for defibrillator therapy and not in need of pacing. We aimed at describing the clinical features of patients who underwent S-ICD implantation in our clinical practice, as well as the ICD-related complications and the inappropriate therapies among S-ICD vs. T-ICD recipients during a long-term follow-up.Materials and MethodsAll patients undergoing ICD, both S-ICD and TV-ICD, at Monaldi Hospital from January 1, 2015 to January 1, 2019 and followed up at our institution were included in the present analysis. The clinical variables associated with S-ICD implantation were evaluated by logistic regression analyses. We collected the ICD inappropriate therapies, ICD-related complications (including both pulse generator and lead-related complications), ICD-related infections, appropriate ICD therapies, and overall mortality. Kaplan-Meier (KM) analyses were performed to assess the risk of clinical outcome events between the two subgroups. A time-dependent Cox regression analysis was performed to adjust the results.ResultsTotal 607 consecutive patients (mean age 53.8 ± 16.8, male 77.8%) with both TV-ICD (n: 290, 47.8%) and S-ICD (n: 317, 52.2%), implanted and followed at our center for a mean follow-up of 1614 ± 1018 days, were included in the study. At multivariate logistic regression analysis, an independent association between S-ICD implantation and ionic channel disease [OR: 6.01 (2.26–15.87); p < 0.0001] and ischemic cardiomyopathy [OR: 0.20 (0.12–0.35); p < 0.0001] was shown. The KM analysis did not show a significantly different risk of the inappropriate ICD therapies (log rank p = 0.64) between the two subgroups; conversely, a significant increase in the risk of ICD-related complications (log rank p = 0.02) and infections (log rank p = 0.02) in TV-ICD group was shown. The adjusted risk for ICD-related infections [OR: 0.07 (0.009–0.55), p = 0.01] and complications [0.31 (0.12–0.81), p = 0.01] was significantly lower among patients with S-ICD.ConclusionsThe choice to implant S-ICD was mainly driven by younger age and the presence of ionic channel disease; conversely ischemic cardiomyopathy reduces the probability to use this technology. No significant differences in inappropriate ICD therapies were shown among S-ICD vs. TV-ICD group; moreover, S-ICD is characterized by a lower rate of infectious and non-infectious complications leading to surgical revision or extraction.

Definition of the Prognostic Role of MGMT Promoter Methylation Value by Pyrosequencing in Newly Diagnosed IDH Wild-Type Glioblastoma Patients Treated with Radiochemotherapy: A Large Multicenter Study.

Simple SummaryO6-methylguanine (O6-MeG)-DNA methyltransferase (MGMT) methylation status is a predictive factor for alkylating treatment efficacy and glioblastoma patients, and its prognostic role is still unclear. The quantitative pyrosequencing (PSQ) approach has proven to be feasible for MGMT promoter methylation testing. We report the data of a large study analyzing MGMT promoter methylation status by pyrosequencing and its association with overall survival. We enrolled a large cohort of newly diagnosed Isocitrate Dehydrogenase (IDH) wild-type glioblastoma patients, all with rather homogeneous clinical characteristics, from nine neuro-oncology centers. Our data showed better survival when MGMT > 15% but also suggested a more complex (i.e., non-linear) relationship between survival and MGMT, resulting in an increase in the negative prognostic effect of a decrease in methylation of the MGMT promoter.Background. O6-methylguanine (O6-MeG)-DNA methyltransferase (MGMT) methylation status is a predictive factor for alkylating treatment efficacy in glioblastoma patients, but its prognostic role is still unclear. We performed a large, multicenter study to evaluate the association between MGMT methylation value and survival. Methods. We evaluated glioblastoma patients with an assessment of MGMT methylation status by pyrosequencing from nine Italian centers. The inclusion criteria were histological diagnosis of IDH wild-type glioblastoma, Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ≤2, and radio-chemotherapy treatment with temozolomide. The relationship between OS and MGMT was investigated with a time-dependent Receiver Operating Characteristics (ROC) curve and Cox regression models. Results. In total, 591 newly diagnosed glioblastoma patients were analyzed. The median OS was 16.2 months. The ROC analysis suggested a cut-off of 15% for MGMT methylation. The 2-year Overall Survival (OS) was 18.3% and 51.8% for MGMT methylation <15% and ≥15% (p < 0.0001). In the multivariable analysis, MGMT methylation <15% was associated with impaired survival (p < 0.00001). However, we also found a non-linear association between MGMT methylation and OS (p = 0.002): median OS was 14.8 months for MGMT in 0–4%, 18.9 months for MGMT in 4–40%, and 29.9 months for MGMT in 40–100%. Conclusions. Our findings suggested a non-linear relationship between OS and MGMT promoter methylation, which implies a varying magnitude of prognostic effect across values of MGMT promoter methylation by pyrosequencing in newly diagnosed IDH wild-type glioblastoma patients treated with chemoradiotherapy.

Psychological Impact of Type of Breast Cancer Surgery: A National Cohort Study

BackgroundThe present study assessed the impact of different types of breast surgery on rates of psychological disorders in breast cancer patients.MethodsThis nationwide cohort study, based on Korean Health Insurance Review and Assessment Service claims data, included 26,259 breast patients who underwent surgery from June 1, 2017, to December 31, 2018. Associations between the incidence of psychological disorders and variables were evaluated by time dependent Cox regression analyses.ResultsOf the 26,259 patients, 9394 (35.8%) underwent total mastectomy (TM) and 16,865 (64.2%) underwent partial mastectomy (PM); of the former, 4056 (43.2%) underwent breast reconstruction surgery (RS). A total of 4685 patients (17.84%) were newly diagnosed with psychological disorders after surgery. Multivariable analysis showed that axillary lymph node dissection was significantly associated with increased rates of overall psychological disorders (p < 0.0001), depression (p = 0.0462), anxiety (p < 0.0001) and insomnia (p < 0.0001). The rates of overall psychological disorders (p = 0.0002) and insomnia (p = 0.01) were significantly lower in patients who underwent TM than PM. RS tended to associated with reduced rates of overall psychological disorders in patients who underwent TM. Subgroup analysis showed that, compared with PM, RS after TM significantly associated with a reduced incidence of overall psychological disorders and insomnia in younger patients (< 50 years) and those who underwent sentinel lymph node biopsy.ConclusionIn contrast to general belief, rates of overall psychological disorders and insomnia were lower in patients who underwent TM than PM. Moreover, RS after TM confers psychological benefit in younger patients with early stage breast cancer compared with PM.

A hierarchical approach to combine histological grade and immunohistochemical factors to identify high-risk luminal breast cancers.

BackgroundThe luminal subtype accounts for ~70% of newly diagnosed breast cancer patients. Although it has a better prognosis, approximately 30% of them develop a late relapse. Identifying those patients is of interest to improve treatment decisions.MethodsA retrospective observational, single-centre study based on data from medical records of 572 non-metastatic (I–III) invasive ductal breast carcinoma patients, 448 with luminal tumours and 124 with triple-negative tumours. Kaplan–Meier, Cox regression and time-dependent Cox regression were carried out to obtain the prognosis value of risk factors.ResultsDuring a median observation of 5.5 years, 105 distant metastasis events and 105 all-cause deaths were observed. In addition to known clinicopathological factors (i.e., age, tumour size and lymph node metastasis), the high semi-quantitative expression of both hormone receptors was associated with distant metastasis-free survival (DMFS) (adjusted hazard ratio (HaR): 0.524 (0.316–0.867), p = 0.012) and overall survival (OS) (adjusted HaR: 0.486 (0.286–0.827), p = 0.008). The stratified analysis made it possible to identify risk modification factors. Subsequent stratification by histological grade, Ki-67 and semi-quantitative PR expression or, mainly, the composite semi-quantitative expression of hormone receptors (cHR) enabled the identification of luminal breast cancer patients of adjuvant schema at higher risk for metastasis and death. However, initial analyses including patients of neoadjuvant therapy pointed to a path of subsequent stratification by cHR and histological grade, also enabling grouping of luminal breast cancer patients with similar prognosis for DMFS (cHR ≤ 4+ G2 or G3 versus triple-negative, adjusted HaR: 0.703 (0.415–1.189), p = 0.189) and OS (cHR ≤4+ G2 or G3 versus triple-negative, adjusted HaR: 0.662 (0.403–1.088), p = 0.104).ConclusionThe semi-quantitative expression of both cHR, Ki-67 proliferation index and histological grade can identify luminal breast cancer patients at greater risk of developing metastasis and death when combined in a hierarchical fashion, and could be useful for a better prognosis stratification in services from low- and middle-income countries.

Proton Pump Inhibitors and Risk of Cardiovascular Disease: A Self-Controlled Case Series Study.

We investigated cardiovascular risk due to proton pump inhibitor (PPI) treatment using a self-controlled case series (SCCS) study design, a type of case-only design and an approach to overcome between-person confounding in which individuals act as their own control. We conducted an SCCS study using the National Health Insurance Service-Health Screening cohort in Korea (2002-2015). The cohort included 303,404 adult participants without prior cardiovascular events, who were followed up until December 2015. The primary outcome was a composite of stroke or myocardial infarction. The SCCS method estimated the age-adjusted incidence rate ratio between periods with and without exposure to PPI among patients with primary outcomes. As sensitivity analysis, conventional multivariable Cox proportional regression analyses were performed, which treated the exposure to PPI and H2 blocker during follow-up as time-dependent variables. In the SCCS design, 10,952 (3.6%) patients with primary outcomes were included. There was no association between PPI exposure and primary outcome (incidence rate ratio 0.98, 95% confidence interval [CI] 0.89-1.09). In the time-dependent Cox regression analyses, both PPI (adjusted hazard ratio 1.36, 95% CI 1.24-1.49) and H2 blocker (adjusted hazard ratio 1.46, 95% CI 1.38-1.55) were associated with an increased risk of the primary outcome. Negative findings in the SCCS design suggest that association between increased cardiovascular risk and PPI, frequently reported in prior observational studies, is likely due to residual confounding related to conditions with PPI treatment, rather than a true relationship.

FC087: Effectiveness of Covid-19 Vaccines in a Large European Haemodialysis Cohort

BACKGROUND AND AIMSTo date, no large-scale study has evaluated the effectiveness of COVID-19 vaccines in hemodialysis patients. We sought to evaluate the effectiveness of vaccines against SARS-CoV-2 infections and death in haemodialysis patients registered in the Fresenius Medical Care (FMC) Nephrocare network.METHODIn this historical, 1:1 matched cohort study, we analysed electronic health records (EHR) of individuals receiving in-center haemodialysis therapy in FMC European dialysis clinics from 1 December 2020, to 31 May 2021 (study period). For each vaccinated patient, an unvaccinated patient was selected among patients registered in the same country and attending a dialysis session within +/–3 days from the vaccination date. Matching without replacement was based on demographics, clinical characteristics, past COVID-19 infections and a risk score representing the local (dialysis centre) background risk of infection at each vaccination date. The infection risk score was calculated from an artificial Intelligence model predicting the risk of COVID-19 outbreak in each clinic over a 2-week prediction horizon. The infection risk score was based on trends in regional COVID-19 epidemic metrics, FMC COVID-19 reporting system and clinical practice patterns. The index date was the date of the first vaccination for the vaccinated and the matching treatment date for the unvaccinated controls. To overcome violation of the proportional hazard assumption, we estimated the effectiveness of the COVID-19 vaccines in preventing infection and mortality rates as 1—hazard ratio estimated from a time-dependent extended Cox regression stratified by country and vaccine type.RESULTSWe included 44 458 patients, 22 229 vaccinated and matched 22 229 unvaccinated. Distribution of covariates was balanced across study arms after matching (Figure 1A). In the effectiveness analysis on mRNA vaccines, we observed 850 SARS-CoV-2 infections and 201 COVID19-related deaths among the 28 110 patients (14 055 vaccinated and 14 055 unvaccinated) during a mean follow up time of 44 ± 40 days. In the effectiveness analysis of viral-vector vaccines, we observed 297 SARS-CoV-2 infections and 64 COVID19-related deaths among 12 888 patients (6444 vaccinated and 6444 unvaccinated) during a mean a follow-up time of 48 ± 32 days (Figure 1B). We observed 18.5/100 patient-year and 8.5/100 patient-year fewer infections and 5.4/100 patient-year and 5.2/100 patient-year fewer COVID-19-related deaths among patients vaccinated with mRNA and viral-vector vaccines respectively, as compared to matched unvaccinated controls. The effectiveness of COVID-19 vaccines concerning both symptomatic infections and COVID-related death along the follow up period is shown in Figure 2.CONCLUSIONIn this matched, historical cohort study, we observed a strong reduction in both SARS-CoV-2 symptomatic infection and COVID-19-related death among dialysis patients receiving an mRNA vaccine. Despite seemingly less protective against symptomatic infections, we observed similar reduction in COVID-19 mortality rate among patients receiving a viral-carrier vaccine.FIGURE 1A:Forest Plot demonstrating covariate distribution balance between exposure groups. Effect Sizes calculated as Cohen's d or Cromer's Negative coefficient indicates that mean or relative frequency was greater among vaccinated patients. Effect Size 0.12 negligible Effect Size-0.1-0.2: small.FIGURE 1B:Absolute frequency and incidence density (95% confidence intervall of events across exposure groups.FIGURE 2:Effectiveness (1-HR) estimates by vaccine type concerning symptomatic, documented infection and COVID-19 related death. Estimates were obtained from extended, cox regression with time-varying covariate.

CI-524-02 ASSOCIATION BETWEEN DEVICE-DETECTED SLEEP APNEA AND IMPLANTABLE DEFIBRILLATOR THERAPY IN PATIENTS WITH HEART FAILURE

Sleep-disordered breathing is highly prevalent in heart failure (HF) and it has been suggested as a risk factor for malignant ventricular arrhythmias. The Respiratory Disturbance Index (RDI) algorithm computed by select implantable cardioverter defibrillators (ICDs) can identify severe sleep apnea (SA). In the present analysis we evaluated the association between ICD-detected SA and the incidence of appropriate ICD therapy in patients with HF. We enrolled 411 HF patients (age 69±10years, 77% male, ejection fraction 32±8%), implanted with an ICD endowed with an algorithm (ApneaScan, Boston Scientific) that calculates the RDI each night. In this analysis the weekly mean RDI value was considered. The endpoint was the first appropriate ICD shock. The median follow-up was 26 months [25th-75th percentile: 16-35]. During follow-up, one or more ICD shocks were documented in 58 (14%) patients. Patients with shocks were younger (66±13years versus 70±10years, p=0.038), and more frequently implanted for secondary prevention (21% versus 10%, p=0.026). The maximum RDI value calculated during the entire follow-up period did not differ between patients with and without shocks (55±15episodes/h versus 54±14episodes/h, p=0.539). However, the ICD-detected RDI showed a considerable variability during follow-up. The overall median of the weekly RDI was 33episodes/h [25th-75th percentile: 24-45]. Using a time-dependent Cox regression model, the continuously measured weekly mean RDI≥45episodes/h was independently associated with shock occurrence (HR:4.63, 95%CI:2.54-8.43, p<0.001), after correction for baseline confounders (age, secondary prevention). In HF patients, patients were more likely to receive appropriate ICD shocks during periods of time when they exhibited more sleep-disordered breathing.

Long-term exposure to ambient fine particulate matter (PM2.5) and associations with cardiopulmonary diseases and lung cancer in Taiwan: a nationwide longitudinal cohort study

Although a number of studies have reported on the health effects of fine particulate matter (PM2.5) exposure, particularly in North American and European countries as well as China, the evidence about intermediate to high levels of PM2.5 exposures is still limited. We aimed to investigate the associations between long-term exposure to PM2.5 and risk of cardiopulmonary disease incidence in Taiwan with intermediate levels of PM2.5 exposure. A cohort of Taiwanese adults, who participated in the 2001, 2005, 2009 and 2013 National Health Interview Surveys, was followed through 2016 to identify cardiopulmonary disease onset. Exposure to PM2.5 was estimated by incorporating a widespread monitoring network of air quality monitoring stations and microsensors. We used time-dependent Cox regression models to examine the associations between the PM2.5 exposures and health outcomes, adjusting for individual characteristics and ecological covariates. The natural cubic spline functions were used to explore the non-linear effects of the PM2.5 exposure. A total of 62 694 adults from 353 towns were enrolled. Each 10-μg/m3 increase in 5-year average exposure to PM2.5 was associated with a 4.8% increased risk of incident ischaemic heart disease (95% CI: -3.3, 13.6), 3.9% increased risk of incident stroke (95% CI: -2.9, 11.1), 6.7% increased risk of incident diabetes (95% CI: 1.1, 12.7), 15.7% increased risk of incident lung cancer (95% CI: -0.9, 35.1) and 11.5% increased risk of incident chronic obstructive pulmonary disease (95% CI: -0.8, 25.2). The concentration-response curve showed that there was no statistical evidence of non-linearity for most of the disease outcomes except for ischaemic heart disease (P for non-linearity = 0.014). Long-term exposure to intermediate levels of ambient PM2.5 was associated with cardiopulmonary health outcomes. Our study adds value to future application and national burden of disease estimation in evaluating the health co-benefits from ambient air pollution reduction policy in Asian countries.

Lower Urinary Tract Symptoms and Mortality among Finnish Men: The Roles of Symptom Severity and Bother.

The utility of male lower urinary tract symptoms (LUTS) as mortality risk factors remains unclear. We explored LUTS-associated mortality among Finnish men, evaluating the association of symptom severity and bother with risk of death. A questionnaire including the Danish Prostatic Symptom Score was mailed to a population-based cohort of 3,143 men aged 50, 60 and 70 years in 1994, with repeat surveys in 1999, 2004, 2009 and 2015. The men were followed until the end of 2018. Mortality associated with LUTS was analyzed using time-dependent Cox regression adjusted for age and comorbidity, updating symptom data every 5 years, including interaction terms between symptoms and associated bother. Of the 1,167 men in the analysis, 591 (50.6%) died during the 24-year followup. In analyses of moderate and severe symptoms disregarding bother, overall voiding and storage LUTS, daytime frequency and urgency incontinence were associated with increased mortality: the multivariable-adjusted hazard ratios were 1.19 (95% CI 1.00-1.40), 1.35 (1.13-1.62), 1.31 (1.09-1.58) and 2.19 (1.42-3.37), respectively. In analyses disregarding symptom severity and bother, voiding LUTS were associated with decreased mortality, while daytime frequency and nocturia were associated with increased mortality: the HRs were 0.82 (95% CI 0.67-1.00), 1.31 (95% CI 1.09-1.58) and 1.52 (95% CI 1.21-1.91), respectively. Excess mortality associated with bothersome daytime frequency and nocturia tended to be slightly higher: the HRs were 1.86 (95% CI 1.41-2.47) and 1.88 (95% CI 1.38-2.58), respectively. No significant interactions were found between symptoms and associated bother, however. Moderate and severe LUTS are potential risk factors for mortality, independently of their bother.

A Time-Dependent Analysis of Association between Acupuncture Utilization and the Prognosis of Ischemic Stroke.

This study investigated the time-dependent characteristics of acupuncture and analyzed the association between acupuncture utilization and mortality rates, readmission rates, and complications among ischemic stroke patients. Data from the National Health Insurance Service-National Sample Cohort 2.0 from South Korea were used to track patients with subacute and chronic ischemic stroke, who had survived more than one month after onset, between 2010 and 2013. A total of 2299 patients were followed up until 2015. At baseline, the acupuncture group (n = 195) and the control group (n = 2104) had similar ages (acupuncture group: 69.0 ± 11.1 years; control group: 68.5 ± 11.8 years), but the acupuncture group had more comorbidities (Charlson comorbidity index; acupuncture group: 4.7 ± 2.1, control group: 4.3 ± 2.4). According to time-dependent Cox regression survival analysis, acupuncture treatment was associated with low hazard ratios (HR) for death (HR: 0.32; 95% confidence interval (CI): 0.18–0.60), fewer composite complications (HR: 0.34; 95% CI: 0.21–0.53), and reduced urinary tract infection (HR: 0.24; 95% CI: 0.11–0.54). Many acupuncture session sensitivity analyses were performed to assess the robustness using different criteria to define the acupuncture group, and the results were consistent with those of the main analysis. Therefore, acupuncture treatment might be associated with lower mortality rates and the prevention of complications after ischemic stroke.

A Multivariable Approach Using Magnetic Resonance Imaging to Avoid a Protocol-based Prostate Biopsy in Men on Active Surveillance for Prostate Cancer—Data from the International Multicenter Prospective PRIAS Study

BackgroundThere is ongoing discussion whether a multivariable approach including magnetic resonance imaging (MRI) can safely prevent unnecessary protocol-advised repeat biopsy during active surveillance (AS). ObjectiveTo determine predictors for grade group (GG) reclassification in patients undergoing an MRI-informed prostate biopsy (MRI-Bx) during AS and to evaluate whether a confirmatory biopsy can be omitted in patients diagnosed with upfront MRI. Design, setting, and participantsThe Prostate cancer Research International: Active Surveillance (PRIAS) study is a multicenter prospective study of patients on AS (www.prias-project.org). We selected all patients undergoing MRI-Bx (targeted ± systematic biopsy) during AS. Outcome measurements and statistical analysisA time-dependent Cox regression analysis was used to determine the predictors of GG progression/reclassification in patients undergoing MRI-Bx. A sensitivity analysis and a multivariable logistic regression analysis were also performed. Results and limitationsA total of 1185 patients underwent 1488 MRI-Bx sessions. The time-dependent Cox regression analysis showed that age (per 10 yr, hazard ratio [HR] 0.84 [95% confidence interval {CI} 0.71–0.99]), MRI outcome (Prostate Imaging Reporting and Data System [PIRADS] 3 vs negative HR 2.46 [95% CI 1.56–3.88], PIRADS 4 vs negative HR 3.39 [95% CI 2.28–5.05], and PIRADS 5 vs negative HR 4.95 [95% CI 3.25–7.56]), prostate-specific antigen (PSA) density (per 0.1 ng/ml cm3, HR 1.20 [95% CI 1.12–1.30]), and percentage positive cores on the last systematic biopsy (per 10%, HR 1.16 [95% CI 1.10–1.23]) were significant predictors of GG reclassification. Of the patients with negative MRI and a PSA density of <0.15 ng/ml cm3 (n = 315), 3% were reclassified to GG ≥2 and 0.6% to GG ≥3. At the confirmatory biopsy, reclassification to GG ≥2 and ≥3 was observed in 23% and 7% of the patients diagnosed without upfront MRI and in 19% and 6% of the patients diagnosed with upfront MRI, respectively. The multivariable analysis showed no significant difference in upgrading at the confirmatory biopsy between patients diagnosed with or without upfront MRI. ConclusionsAge, MRI outcome, PSA density, and percentage positive cores are significant predictors of reclassification at an MRI-informed biopsy. Patients with negative MRI and a PSA density of <0.15 ng/ml cm3 can safely omit a protocol-based prostate biopsy, whereas in other patients, a multivariable approach is advised. Being diagnosed with upfront MRI appears not to significantly affect reclassification risk; hence, a confirmatory MRI-Bx cannot totally be omitted yet. Patient summaryA protocol-based prostate biopsy while on active surveillance can be omitted in patients with negative magnetic resonance imaging (MRI) and prostate-specific antigen density <0.15 ng/ml cm3. A confirmatory biopsy cannot simply be omitted in all patients diagnosed with upfront MRI.

Effect of Dietary Phenolic Compounds on Incidence of Cardiovascular Disease in the SUN Project; 10 Years of Follow-Up.

The health benefits of plant-based diets have been reported. Plant-based diets found in Spain and other Mediterranean countries differ from typical diets in other countries. In the Mediterranean diet, a high intake of phenolic compounds through olives, olive oil, and red wine may play an important role in cardiovascular prevention. Prospective studies carried out in Mediterranean countries may provide interesting insights. A relatively young Mediterranean cohort of 16,147 Spanish participants free of cardiovascular disease (CVD) was followed (61% women, mean (SD) age 37(12) years at baseline) for a median of 12.2 years. Dietary intake was repeatedly assessed using a 136-item validated food frequency questionnaire, and (poly)phenol intake was obtained using the Phenol-Explorer database. Participants were classified as incident cases of CVD if a medical diagnosis of myocardial infarction, stroke, or cardiovascular death was medically confirmed. Time-dependent Cox regression models were used to assess the relationship between (poly)phenol intake and the incidence of major CVD. A suboptimal intake of phenolic compounds was independently associated with a higher risk of CVD, multivariable-adjusted hazard ratio for the lowest versus top 4 quintiles: 1.85 (95% CI: 1.09–3.16). A moderate-to-high dietary intake of phenolic compounds, especially flavonoids, is likely to reduce CVD incidence in the context of a Mediterranean dietary pattern.

Association Between Preoperative Fibrinogen-to-Albumin Ratio and All-Cause Mortality After Off-Pump Coronary Artery Bypass Grafting: A Retrospective Observational Study.

The fibrinogen-to-albumin ratio (FAR) is a recently introduced prognostic marker for patients with coronary artery disease. The present study investigated whether the FAR is associated with clinical outcome after off-pump coronary artery bypass grafting (OPCAB). We retrospectively reviewed 1759 patients who underwent OPCAB (median duration of follow-up, 46 months). To evaluate the association between FAR and mortality in OPCAB patients, time-dependent coefficient Cox regression analyses were used to assess the association between FAR and all-cause mortality. In multivariable time-dependent coefficient Cox regression analyses, preoperative FAR was an independent risk factor for all-cause mortality after OPCAB (adjusted hazard ratio, 1.051; 95% confidence interval, 1.021-1.082). In the restricted cubic spline function curve of the multivariable-adjusted relationship between the preoperative FARs, a linear increase in the relative hazard for all-cause mortality was observed as the FAR increased (P = .001). A higher FAR is associated with increased all-cause mortality after OPCAB. The preoperative FAR could be a prognostic factor for predicting higher mortality after OPCAB.

Abstract EP43: Obesity And Incident Cardiovascular Disease (CVD): The Jackson Heart Study

Background: Although obesity is a well-established risk factor for the development of cardiovascular disease (CVD), it is unclear which anthropometric measure(s) of obesity are the best predictors of CVD. Methods: Using data from 3491 African Americans (mean age: 58.3±12.1; 65.2% women) in the Jackson Heart Study, we examined the associations of incident CVD and its individual components (Coronary heart disease (CHD), heart failure, and stroke) with time-dependent obesity measures (body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR) and waist-to-hip ratio (WHR)). Time-to-event analyses were conducted using time-dependent Cox regression models. Obesity measures were analyzed both as dichotomous (obese vs. non-obese) and standardized continuous predictors. Covariates included age, sex, systolic blood pressure, diastolic blood pressure, and smoking status. Results: There were 331 incident CVD events, including 122 CHD, 192 heart failure, and 95 stroke events. The median follow-up time is 9.04 (Quartile Range: 1.83) years. Comparing obese to non-obese participants, adjusted hazard ratios (aHR) (95% CI) for CVD were 1.38 (1.10, 1.72), 1.36 (1.05, 1.76), 1.23 (0.80, 1.89), and 1.38 (1.04, 1.82) for BMI, WC, WHtR and WHR, respectively. The corresponding aHRs (95% CI) using standardized continuous BMI, WC, WHtR and WHR measures were 1.27 (1.14, 1.43), 1.32 (1.18, 1.47), 1.31 (1.18, 1.46), and 1.24 (1.12 1.39). The significant associations between CVD and obesity measures were largely driven by heart failure. The associations in younger age group (&lt; 60 yrs) were more significant than those in older age group (&gt;= 60 yrs). Conclusions: Dichotomous and standardized continuous BMI, WC and WHR measures were all associated with incident CVD. For WHtR, only the standardized continuous measure was significantly associated with incident CVD. The risk of CVD associated with obesity is not evident in the elderly.

Contemporary clinical and economic outcomes among oral anticoagulant treated and untreated elderly patients with atrial fibrillation: Insights from the United States Medicare database

BackgroundOral anticoagulants (OACs) mitigate the risk of stroke in atrial fibrillation (AF) patients.ObjectiveElderly AF patients who were treated with OACs (apixaban, dabigatran, edoxaban, rivaroxaban, or warfarin) were compared against AF patients who were not treated with OACs with respect to their clinical and economic outcomes.MethodsNewly diagnosed AF patients were identified between January 2013 and December 2017 in the Medicare database. Evidence of an OAC treatment claim on or after the first AF diagnosis was used to classify patients into treatment-defined cohorts, and these cohorts were further stratified based on the initial OAC prescribed. The risks of stroke/systemic embolism (SE), major bleeding (MB), and death were analyzed using inverse probability treatment weighted time-dependent Cox regression models, and costs were compared with marginal structural models.ResultsThe two treatment groups were composed of 1,421,187 AF patients: OAC treated (N = 583,350, 41.0% [36.4% apixaban, 4.9% dabigatran, 0.1% edoxaban, 26.7% rivaroxaban, and 31.9% warfarin patients]) and untreated (N = 837,837, 59.0%). OAC-treated patients had a lower adjusted risk of stroke/SE compared to untreated patients (hazard ratio [HR]: 0.70; 95% confidence interval [CI]: 0.68–0.72). Additionally patients receiving OACs had a lower adjusted risk of death (HR: 0.56; 95% CI: 0.55–0.56) and a higher risk of MB (HR: 1.57; 95% CI: 1.54–1.59) and this trend was consistent across each OAC sub-group. The OAC-treated cohort had lower adjusted total healthcare costs per patient per month ($4,381 vs $7,172; p < .0001).ConclusionFor the OAC-treated cohort in this elderly US population, stroke/SE and all-cause death were lower, while risk of MB was higher. Among OAC treated patients, total healthcare costs were lower than those of the untreated cohort.

Abstract P4-09-07: Psychological impact of type of breast cancer surgery: A national cohort study

Abstract Background Type of breast surgery and breast reconstruction after mastectomy may affect the psychological well-being of breast cancer patients. The present study assessed the impact of different types of breast surgery on rates of psychological disorders in breast cancer patients. Patients &amp; Methods This nationwide cohort study, based on Korean Health Insurance Review and Assessment Service (HIRA) claims data, included 26,259 patients who were diagnosed with invasive breast cancer and underwent surgery from June 1, 2017, to December 31, 2018. Associations between the incidence of psychological disorders and variables such as type of breast cancer surgery, patient age, and insurance type were evaluated by univariable and multivariable time dependent Cox regression analyses. Results Of the 26,259 patients, 9,394 (35.8%) underwent total mastectomy (TM) and 16,865 (64.2%) underwent partial mastectomy (PM); of the former, 4,056 (43.2%) underwent breast reconstruction surgery (RS). The median follow-up time for all patients was 194 days (interquartile range 74-334 days). A total of 4685 patients (17.84%) were newly diagnosed with psychological disorders after breast cancer surgery. Multivariable analysis showed that axillary lymph node dissection (ALND) was significantly associated with increased rates of overall psychological disorders (hazard ratio [HR] 1.337 p&amp;lt;0.0001), depression (HR 1.124 p=0.0462), anxiety (HR 1.459, p&amp;lt;0.0001) and insomnia (HR 1.238, p&amp;lt;0.0001). The rates of overall psychological disorders (HR 0.889, p=0.0002) and insomnia (HR 0.897, p=0.01) were significantly lower in patients who underwent TM than PM. The rates of overall psychological disorders (HR 0.837, p=0.0001) and insomnia (HR 0.831, p=0.0021) were also significantly lower in patients who underwent TM followed by RS than in patients who underwent PM. RS tended to reduce the rate of overall psychological disorders in patients who underwent TM. Subgroup analysis showed that, compared with PM, RS after TM significantly reduced the incidence of insomnia in younger patients (&amp;lt;50 years) and those who underwent sentinel lymph node biopsy (SLNBx). Conclusion In contrast to general belief, rates of overall psychological disorders and insomnia were higher in patients who underwent PM than TM. Compared with PM, RS after TM resulted in significantly lower rates of psychological disorders and insomnia in younger patients (age &amp;lt;50 years) and those who underwent SLNBx at a median &amp;lt; 1 year postoperatively. ALND was associated with increased rates of overall psychological disorders, depression, anxiety and insomnia. Citation Format: Soo Kyung Ahn, Sohee Oh, Jongjin Kim, Jung-Seok Choi, Ki-Tae Hwang. Psychological impact of type of breast cancer surgery: A national cohort study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-09-07.

Lifetime Cardiovascular Disease Risk by Coronary Artery Calcium Score in Individuals With and Without Diabetes: An Analysis From the Multi-Ethnic Study of Atherosclerosis.

To assess lifetime cardiovascular disease (CVD) risk by coronary artery calcium (CAC) score in individuals with diabetes from the Multi-Ethnic Study of Atherosclerosis (MESA) and compare risk with that in individuals without diabetes. We developed a microsimulation model with well, diabetes, post-CVD, and death health states using multivariable time-dependent Cox regression with age as time scale. We initially used 10-year follow-up data of 6,769 MESA participants, including coronary heart disease (CHD) (n = 272), heart failure (n = 201), stroke (n = 186), and competing death (n = 619) and assessed predictive validity at 15 years. We externally validated the model in matched National Health and Nutrition Examination Survey (NHANES) participants. Subsequently, we predicted CVD risk until age 100 years by diabetes, 10-year pooled cohort equations risk, and CAC score category (0, 1-100, or 100+). The model showed good calibration and discriminative performance at 15 years, with discrimination indices 0.71-0.78 across outcomes. In the NHANES cohort, predicted 15-year mortality risk corresponded well with Kaplan-Meier risk, especially for those with diabetes: 29.6% (95% CI 24.9-34.8) vs. 32.4% (95% CI 27.2-37.2), respectively. Diabetes increased lifetime CVD risk, similar to shifting one CAC category upward (from 0 to 1-100 or from 1-100 to 100+). Patients with diabetes and CAC score of 0 had a lifetime CVD risk that overlapped with that of individuals without diabetes who were at low 10-year pooled cohort equations risk (<7.5%). Patients with diabetes carry a spectrum of CVD risk. CAC scoring may improve decisions for preventive interventions for patients with diabetes by better delineating lifetime CVD risk.

Incidence of Depression after Traumatic Brain Injury: A Nationwide Longitudinal Study of 2.2 Million Adults.

Although improvements in acute care for traumatic brain injury (TBI) have increased the patient survival rate, many survivors often suffer from neuropsychiatric sequelae such as depression. This study investigated the influence of TBI on the risk of depression using South Korean nationwide data. Data were extracted from the National Health Insurance Service database for patients who experienced TBI from 2010 to 2017 (n = 1,141,593) and for 1:1 matched controls without TBI (n = 1,141,593). Patients under 18 years old or with a history of depression were excluded. TBI was used as a time-varying exposure and a time-dependent Cox regression model was adopted. Age, sex, insurance premium and type, region of residence, past psychiatric diseases, and Charlson Comorbidity Index were adjusted. The incidence of depression in the patients with TBI and matched controls was 34.60 and 21.42 per 1000 person-years, respectively. The risk of depression was higher in the patients with TBI (hazard ratio [HR] 1.19, 95% confidence interval [CI] = 1.18-1.20) than in the matched control group. After stratification by sex and age, the risk was higher in men and the younger age group. In subgroup analyses, patients with skull fracture showed the highest risk of depression. Notably, during the first year after TBI, the depression risk was almost 11 times higher than that in the matched control group (HR 11.71, 95% CI = 11.54-11.87). Our findings highlight a significant association of TBI with an increased risk of subsequent depression. Therefore, continuous awareness with regard to patients' mental health is needed.

Clinical outcomes of concomitant use of proton pump inhibitors and regorafenib in patients with metastatic colorectal cancer: A multicenter study.

130 Background: Tyrosine kinase inhibitors (TKI) are the most common oral drugs in cancer patients. Similarly, proton pump inhibitors (PPI) are commonly used to relieve dyspeptic symptoms in patients with cancer. However, gastric pH levels may affect the absorption of TKI through the gastrointestinal system. However, all TKIs do not have the same chemical structure, and the absorption rate of each TKI depends on their solubility in different gastric pH levels. Limited data is available about the clinical outcomes of concomitant use of PPI and regorafenib in patients with metastatic colorectal cancer (mCRC). We present here the results of the multicenter study following the initial results of our single-center experience. Methods: Patients with mCRC treated with regorafenib were included in this multicenter and retrospective study. Patients prescribed PPI after initiation of regorafenib were assigned to the PPI user group, and the remaining patients were assigned to the PPI non-user group. To exclude immortal time bias, the log-rank test was performed between PPI non-user and all patients. The primary outcome was overall survival (OS), and secondary outcomes were time to treatment failure (TTF) and adverse events (AEs) profile. Results: Two hundred and seventy-two patients from eight cancer centers were included in this study. Most patients were male (59.9%), had liver metastasis (62.1%), and received regorafenib in the third line (52.2%). The median age at the initiation of regorafenib was 60 years (interquartile range (IQR): 51-66)). Eastern Cooperative Oncology Group performance score was 0 or 1 in approximately three out of four patients. The rate of patients with K-RAS mutation was 46.7%. There were 131 (48.2%) and 141 (51.8%) in the PPI user and non-user groups, respectively. The most prescribed PPI was pantoprazole (40.4%). At a median 34.2 months follow-up, the median OS was 6.9 months (95% Confidence Interval (CI): 5.3-8.5) and 7.7 months (95% CI:6.6-8.8) in the PPI non-user and all patients, respectively. No statistical significance was observed between the groups (p = 0.913). The median TTF was 3.3 months (95% CI: 2.6-3.9) and 3.4 months (95% CI:2.9-4.0) in the PPI non-user and all patients, respectively. No statistical significance was observed between the groups (p = 0.651). In the time-dependent covariate Cox regression model, there was no difference between PPI user and non-user groups in OS and TTF (adjusted Hazard Ratio (aHR):0.96, 95% CI:0.74-1.24, p = 0.735 for OS; aHR:0.88, 0.68-1.14, p = 0.354 for TTF). The rates of all AEs were also similar in the PPI user and non-user groups (p = 0.628). Conclusions: To our knowledge, this was the first study evaluating the effect of concomitant use of PPI and regorafenib in patients with mCRC, and no adverse survival and safety outcome was observed with the concomitant use of PPI and regorafenib in those patients.