Multivariate Cox Proportional Hazards Regression Research Articles

Impact of donor age ≥65 years on graft survival in large lung transplant cohorts

BackgroundAlthough the demand for allografts continuously surpasses the supply, the majority of lungs offered for transplant are declined based on various factors, including donor age. This in turn sustains the wait-list mortality of patients with end-stage pulmonary disease. MethodsIn this single center, observational cohort study we investigated the impact of donor age on graft survival. We additionally, compared our center’s data to data reported to the International Society for Heart and Lung Transplantation (ISHLT) Thoracic Organ Transplant Registry. Kaplan-Meier method was used to describe overall graft survival. Multivariate Cox proportional hazards regression was used to assess clinical features associated with graft loss. ResultsBetween January 2010 and December 2023, the Alfred performed 1101 single and double lung transplant and the combined ISHLT cohort totaled 32,200 transplants. At the Alfred, grafts originating from donors ≥65 years were used in 13.3% of lung transplant cases and univariate analysis showed no impact of donor age ≥65 on graft survival (HR 0.86, p=0.34). In the combined cohort, North America had a lower proportion of donors aged ≥65 years compared to Europe and the Alfred (2.4% vs 9.8% vs 13.3%, p<0.001). The univariate analysis showed a negative impact of donor age ≥65 on graft survival (HR 1.16, p<0.001). However, this did not hold in a multivariate model (HR 1.06, p=0.298) when adjusted for center experience and recipient characteristics. ConclusionDonor age might impact outcomes to a lesser degree than previously suggested. Therefore, appropriately assessed age-extended lungs should be routinely considered for lung transplantation.

Associations of polycyclic aromatic hydrocarbons exposure with mortality and effect modification by folate biomarkers in a prospective population

The associations of folate biomarkers and polycyclic aromatic hydrocarbons (PAHs) in the general population remain unclear. Therefore, this study aimed to examine whether folate biomarkers are associated with PAHs, and whether folate biomarkers can mitigate adverse health outcome caused by PAHs. This prospective cohort study included 11,246 participants from the National Health and Nutrition Examination Survey (NHANES), which documented 1303 deaths over a mean follow-up of 9.1 years. Multivariable linear regression models were used to examine the relationship between urinary individual PAHs and folate biomarkers. Multivariable Cox proportional hazards regression models were used to calculate hazard ratios and 95 % CIs for the associations of PAHs and folate biomarkers with CVDs mortality and all-cause mortality. We found negative associations between folate in red blood cells (RBC) and urinary 1-Hydroxyphenanthrene (percentage change for a 2·7 fold-increase in folate −4.19 %, 95 % CI -5.80 % to −2.56 %CI), 2-Hydroxyfluorene (−6.66 %, −7.84 % to −5.49 %), 3-Hydroxyfluorene (−5.78 %, −6.77 % to −4.78 %)) and 1-Hydroxynapthalene (−2.75 %, −3.48 % to −2.01 %). The associations between serum folate and PAHs were consistent with those observed for RBC folate, and negative associations were also found between serum folate and 2-Hydroxynapthalene (−4.10 %, −5.26 % to −2.94 %). Within the lowest quartile of folate levels in RBC, there are strong associations of 2-Hydroxyfluorene, 3-Hydroxyfluorene, 1-Hydroxynapthalene, and 2-Hydroxynapthalene with elevated risk of CVDs mortality [HRs (95 % CI) >1]. As folate levels in RBC increase to the third and fourth quartiles, these associations no longer exist [HRs (95 % CI) <1, P-interaction<0.05]. The positive associations between urinary PAHs and CVDs mortality are also eliminated as serum folate levels rise (HRs (95 % CI) <1, P-interaction<0.05). Furthermore, we also found higher levels of folate in both RBC and serum can greatly reduce the adverse impact of 1-Hydroxynapthalene on all-cause mortality. Consistent results were also validated in daily dietary folate and the folic acid supplement intake. Our study highlighted a robust negative relationship between urinary PAHs and folate. Additionally, folate was found to effectively mitigate mortality caused by PAHs, although we did not observe a direct reduction in mortality attributable to folate.

PD-L1 (22C3) expression and prognostic implications in esophageal squamous cell carcinoma

Programmed cell death-ligand 1 (PD-L1) clone 22C3 is the only Food and Drug Administration-approved companion diagnostic test for pembrolizumab for the treatment of esophageal squamous cell carcinoma (ESCC). However, prior studies conducted in Asia and Europe have used various PD-L1 antibody clones other than 22C3. We aimed to study the expression profile of PD-L1, specifically of clone 22C3, in ESCC and its significance with regards to histological features, clinical parameters, and overall survival in a case series from two large US hospital systems. PD-L1 (22C3) immunohistochemistry was performed on 82 specimens obtained from 75 patients. Electronic medical records were reviewed to obtain the clinical and follow-up data. Of these specimens, 39 % (32/82) were negative for PD-L1 (22C3) expression (combined positive score (CPS) of 0). The remaining 50 specimens were positive, with CPSs ranging from 1 to 100. Treated specimens showed decreased PD-L1 (22C3) expression compared to untreated specimens. In the multivariate Cox proportional hazards regression model, PD-L1 (22C3) expression was shown to be a favorable prognostic factor for overall survival (p = 0.03, hazard ratio 0.16) only when the CPSs were ≥ 25, independent of surgery, definitive chemotherapy and/or radiotherapy, immunotherapy, and initial clinical stages. We performed a comprehensive study to investigate the expression profile of PD-L1 clone 22C3 in the US patients with ESCC. Our analysis showed that PD-L1 (22C3) expression decreased in treated specimens, and a CPS of ≥25 was associated with a favorable prognosis.

Association between the triglyceride to high density lipoprotein cholesterol ratio and the incidence of metabolic dysfunction-associated fatty liver disease: a retrospective cohort study

BackgroundThe triglyceride to high density lipoprotein cholesterol ratio (TG/HDL-C) is a confirmed predictive factor for insulin resistance and is suggested to be closely related to metabolic dysfunction-associated fatty liver disease (MAFLD), but previous research is inconclusive. The association between TG/HDL-C and MAFLD incidence was further explored in this large-sample, long-term retrospective cohort study.MethodsIndividuals who participated in the Kailuan Group health examination from July 2006 to December 2007 (n = 49,518) were included. Data from anthropometric and biochemical indices, epidemiological surveys, and liver ultrasound examinations were collected and analysed statistically, focusing on the association between TG/HDL-C and the incidence of MAFLD.ResultsDuring a mean follow-up period of 7.62 ± 3.99 years, 24,838 participants developed MAFLD. The cumulative MAFLD incidence rates associated with the first to fourth quartiles of TG/HDL-C were 59.16%, 65.04%, 71.27%, and 79.28%, respectively. The multivariate Cox proportional hazards regression model revealed that the hazard ratios (HRs) (95% CIs) for MAFLD in the second, third, and fourth quartiles were 1.20 (1.16–1.25), 1.50 (1.45–1.56), and 2.02 (1.95–2.10) (P for trend < 0.05), respectively, and the HR (95% CI) corresponding to an increase of one standard deviation in TG/HDL-C was 1.10 (1.09–1.11) (P < 0.05). Subsequent subgroup and sensitivity analyses yielded results similar to those of the main analyses.ConclusionsTG/HDL-C is independently associated with MAFLD risk, with higher TG/HDL-C indicating greater MAFLD risk.

Prognostic nomogram models for elderly patients with differentiated thyroid carcinoma: A population-based study.

This study aimed to develop and validate a prognostic model for elderly patients with differentiated thyroid carcinoma (DTC) based on various demographic and clinical parameters in order to accurately predict patient outcomes. Patients who were diagnosed with DTC and were over 55 years old between 2010 and 2019 were identified from the Surveillance, Epidemiology, and End Results database. The patients were then randomly divided into a training set and a validation set in a 7:3 ratio, and patients from our center were included as an external validation group. Univariate and multivariate Cox proportional hazards regression analyses were performed to identify independent prognostic factors, which were then utilized to develop nomograms for predicting the prognosis. The discriminative ability of the nomograms was evaluated using the concordance index, and the calibration was assessed using calibration plots. The clinical usefulness and benefits of the predictive models were determined through decision curve analysis. The findings of the stepwise Cox regression analysis revealed that several variables, including age, marital status, sex, multifocality, T stage, N stage, and M stage, were significantly associated with overall survival in elderly patients with DTC. Additionally, age, tumor size, multifocality, T stage, N stage, and M stage were identified as the primary determinants of cancer specific survival in elderly patients with DTC. Using these predictors, nomograms were constructed to estimate the probability of overall survival and cancer specific survival. The nomograms demonstrated a high level of predictive accuracy, as evidenced by the concordance index, and the calibration plots indicated that the predicted outcomes were consistent with the actual outcomes. Furthermore, the decision curve analysis demonstrated that the nomograms provided substantial clinical net benefit, indicating their utility in clinical practice.

Changes in physical activity and all-cause mortality among individuals with dementia: a cohort study using the National Health Insurance Service Database in Korea

ObjectiveTo examine associations between the amount and changes in regular physical activity (PA) before and after diagnosis of dementia and all-cause mortality risk, and whether these associations differ by PA...

Efficacy of Atezolizumab in Subsequent Lines of Therapy for NSCLC Patients: Insights from Real-World Data.

This retrospective study involved 147 advanced NSCLC patients treated with atezolizumab following progression on prior platinum-based chemotherapy at two academic centers in Serbia. Data on demographics and clinical, pathological, and molecular characteristics were collected. Median progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and multivariable Cox proportional hazards regression identified outcome predictors. The median PFS was 7.13 months, and median OS was 38.6 months. The overall response rate (ORR) was 15%, with a disease control rate (DCR) of 57.9%. No significant PFS differences were observed between patients treated with atezolizumab in the second line versus later lines. Patients with good performance status (ECOG 0-1) had significantly better PFS compared to those with poorer status (12.03 vs. 1.63 months, p < 0.0001). Atezolizumab is effective in both second-line and later-line settings for advanced NSCLC, particularly in patients with good performance status. This highlights the importance of patient selection based on performance status, as well as the need for wider access to ICIs in resource-limited regions.

Association Between Changes in Skeletal Muscle Quality and Prognosis in Postoperative Patients with Early Gastric Cancer.

Identifying accurate prognostic factors is crucial for postoperative management of early gastric cancer (EGC) patients. Skeletal muscle quality (SMQ), defined by muscle density on computed tomography (CT) images, has been proposed as a novel prognostic factor. This study compared the prognostic significance of SMQ changes with the well-established factor of body weight (BW) loss in the postoperative EGC setting. This single-center retrospective study included 297 postoperative EGC patients (median age 69 years, 68.4% male) who had preoperative and 1-year-postoperative gastrectomy CT images. SMQ was defined as the modified intramuscular adipose tissue content (mIMAC = skeletal muscle density-subcutaneous fat density on CT images) and the change as ΔmIMAC. Log-rank test, Kaplan-Meier survival, and Cox proportional hazards regression analyses were used to assess the associations between prognosis and either ΔmIMAC or BW change (ΔBW). Prognosis prediction by ΔmIMAC and ΔBW was compared by using the area under the curve (AUC) of the receiver operating characteristic curve. ΔmIMAC was significantly associated with prognosis (log-rank test; P = 0.037), but ΔBW was not (P = 0.243). Prognosis was significantly poorer in the severely decreased mIMAC group than in the preserved group (multivariate Cox proportional hazards regression analysis; P = 0.030) but was unaffected by BW changes (P = 0.697). The AUC indicated a higher prognostic value for ΔmIMAC than ΔBW (ΔmIMAC: AUC = 0.697, ΔBW: AUC = 0.542). One-year post-gastrectomy SMQ changes may be better prognostic EGC predictors than BW changes.

Novel scoring system for predicting stone-free rate after flexible ureteroscopy lithotripsy.

This study aims to investigate the factors affecting the stone-free rate (SFR) of flexible ureteroscopy and laser lithotripsy (fURSL) for renal stones and establish predictive models by identifying their prognostic factors. We retrospectively examined 252 patients with renal stones who were treated with fURSL between July 2020 and April 2022. We analyzed the relationship between the patient's clinical data (sex, age, and body mass index), stone status (side, size, location, stone/transverse process pixel ratio [STPR], and the CT value of stone [SCTV]), and SFR to determine the relevant factors and analyze their influence. Additionally, a nomogram was constructed based on these prediction results. A total of 252 patients were enrolled based on the inclusion and exclusion criteria. They were reviewed 7, 30, and 90 days postoperatively, with 46, 23, and 10 patients failing to discharge stones, respectively. Univariate Cox proportional hazard regression results revealed that the SFR was correlated with stone location, diameter (D1, diameter of stone measured by computed tomography [CT]; D2, diameter of stone measured by kidney-ureter-bladder abdominal radiography), SCTV, STPR, and operation time. Multivariate Cox proportional hazard regression was used to develop 2 predictive models for the SFR. The influencing factors of model 1 included D1, location, and SCTV, whereas those of model 2 were D2, location, and STPR. The results are shown in the nomogram. Receiver operating characteristic curves showed no significant difference between models 1 and 2 (P = .498), indicating that the nomogram was highly predictive. After 1000 resamples and internal self-validation, the C-indices of models 1 and 2 were 0.924 and 0.895, respectively, showing that the stone clearance predicted by the nomogram matched the actual situation. Stone location, size, and density (SCTV and STPR) were significant predictors of SFR after fURSL. The scoring system based on these factors may be used to guide optimal treatment strategy selection.

Association between aspartate aminotransferase to alanine aminotransferase ratio and mortality in critically ill patients with congestive heart failure

Congestive heart failure (CHF) is a complex clinical syndrome that significantly impacts patient outcomes, especially in critically ill patients admitted to intensive care units (ICUs). The aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio (AST/ALT), has also been reported as a risk factor of cardiovascular diseases. However, few studies investigated the correlations between the AST/ALT ratio and ICU mortality in critically ill patients with CHF. This study investigates the association between the baseline AST/ALT ratio measured within the first 24 h of ICU admission and 28-day ICU all-cause mortality in critically ill patients with CHF. This retrospective cohort study included 4869 critically ill patients with CHF from the eICU Collaborative Research Database. Patients were categorized into tertiles based on their AST/ALT ratio: Tertile 1 (0.13–0.97), Tertile 2 (0.97–1.50), and Tertile 3 (1.50–5.89). Univariate and multivariate Cox proportional hazards regression models were used to evaluate the association between the AST/ALT ratio and 28-day ICU all-cause mortality. Nonlinear threshold effects and subgroup analyses were conducted to assess the robustness of the findings. Kaplan-Meier survival curves were generated to compare survival probabilities across tertiles. Participants with higher AST/ALT ratios were older, had higher illness severity, and experienced worse clinical outcomes. In univariate analysis, the AST/ALT ratio was significantly associated with 28-day ICU mortality (HR: 1.24, 95% CI 1.13–1.37, P < 0.0001). This association remained significant in the fully adjusted multivariate model. The highest tertile of AST/ALT ratio was associated with a significantly higher risk of mortality compared to the lowest tertile across all models (HR: 1.48, 95% CI 1.07–2.03, P = 0.0162 in Model 4). A nonlinear relationship was observed, with a threshold identified at an AST/ALT ratio of 2.08. Below this turning point, the association remained strong (HR: 1.47, 95% CI 1.13–1.91, P = 0.0036), while above it, the association was no longer significant. Subgroup analyses revealed no significant interactions, indicating that the association between AST/ALT ratio and mortality was consistent across various patient characteristics. Survival analysis showed that patients in the highest tertile had the poorest survival outcomes (P < 0.0001). An elevated AST/ALT ratio within the first 24 h of ICU admission is independently associated with increased 28-day ICU all-cause mortality in critically ill patients with CHF.

Disparities in Survival Outcomes Among Patients With Metastatic Melanoma in Texas: Implications for Policy and Interventions in the Era of Immune Checkpoint Inhibitors.

Disparities exist in the length and quality of survival from melanoma. This study evaluated, in a Texas cohort, patient factors associated with melanoma survival and examined if newer immune-oncologic agents extend survival compared with conventional therapies. A retrospective analysis of patients diagnosed with metastatic melanoma from 2011 to 2018 in the Texas Cancer Registry database. Multivariable Cox proportional hazard regression was used to evaluate patient characteristics associated with cancer-specific survival (CSS) and overall survival (OS). The patient cohort was then grouped based on receipt of first-line immunotherapy or other therapies. The association between receipt of immunotherapy and survival was assessed with Kaplan-Meier analysis and inverse probability treatment weighted Cox regression. There were 1372 patients with metastatic melanoma. Factors associated with increased melanoma mortality risk (CSS) included being male (HR: 1.13, 95% CI: 1.02-1.26), non-Hispanic black (HR: 1.28, 95% CI: 1.13-1.45), living in poorer counties (HR: 1.40, 95%CI: 1.20-1.64), and having multimorbidity (HR: 1.35, 95% CI: 1.05-1.74). All minority races and Hispanics had poorer OS compared with non-Hispanic Whites. Patients who received first-line immunotherapy had significantly longer median (interquartile range) survival (CSS: 27.00 [21.00 to 42.00] mo vs. 16.00 [14.00 to 19.00] mo; OS: 22.00 [17.00 to 27.00] mo vs. 12.00 [11.00 to 14.00] mo). They also had reduced mortality risk (HR for CSS: 0.80; 95% CI: 0.73-0.88; P <0.0001; HR for OS: 0.76; 95% CI: 0.69-0.83; P <0.0001) compared with the nonimmunotherapy cohort. This study showed differences in risks from melanoma survival based on patient demographic and clinical characteristics. Low socioeconomic status increased mortality risk, and first-line immunotherapy use favored survival. Health policies and tailored interventions that will promote equity in patient survival and survivorship are essential for managing metastatic melanoma.

Development and validation of nomograms based on the SEER database for the risk factors and prognosis of distant metastasis in gastric signet ring cell carcinoma.

Poor prognosis in patients with distant metastasis of gastric signet ring cell carcinoma (GSRC), and there are few studies on the development and validation of the diagnosis and prognosis of distant metastasis of GSRC. The Surveillance, Epidemiology, and End Results database was used to identify patients with GSRC from 2004 to 2019. Univariate and multivariate logistic regression analysis were used to identify independent risk factors for distant metastasis of GSRC, while univariate and multivariate Cox proportional hazard regression analysis were used to determine independent prognostic factors for patients with distant metastasis of GSRC. Two nomograms were established, and model performance was evaluated using receiver operating characteristic curves, calibration plots, and decision curve analysis. A total of 9703 cases with GSRC were enrolled, among which 2307 cases (23.78%) were diagnosed with distant metastasis at the time of diagnosis. Independent risk factors for distant metastasis included age, race, and T stage. Independent prognostic factors included T stage, chemotherapy, and surgery. The receiver operating characteristic curve, calibration curve, decision curve analysis curve, and Kaplan-Meier survival curve of the training set and validation set confirmed that the 2 nomograms could accurately predict the occurrence and prognosis of distant metastasis in GSRC. Two nomograms can serve as effective prediction tools for predicting distant metastasis in GSRC patients and the prognosis of patients with distant metastasis. They have a certain clinical reference value.

All-cause and cause-specific mortality risks in individuals with diabetes living alone: A large-scale population-based cohort study

AimsThe rise in one-person households is a global trend. We aimed to investigate mortality risk in individuals with diabetes living alone (IDLA) using a large-scale population-based database. MethodsA total of 2,447,557 adults with type 2 diabetes were identified from the Korean National Health Information Database. One-person households were defined based on the number of registered family members. The risks of all-cause and cause-specific mortalities were estimated using a multivariable Cox proportional hazards regression model. ResultsDuring a median follow-up period of 6.0 years, 191,084 deaths (7.8 %) occurred. IDLA had a higher risk of mortality compared to those not living alone after adjusting for potential confounders (HR 1.20, 95 % CI: 1.18–1.22). This association was more prominent in younger individuals, men, and those with low income, and it was dependent on the duration of living alone. The risks of cause-specific mortality were all significantly higher in the IDLA group compared with the non-IDLA group. Adherence to favorable lifestyle behaviors was associated with a significant reduction in all-cause mortality, particularly in IDLA. ConclusionsThe elevated risk of mortality in IDLA highlights the need for tailored medical interventions and social assistance, particularly for those with unhealthy lifestyles or low income.

Variation in the detection of lymphovascular invasion in T1 colorectal cancer and its impact on treatment: A nationwide Dutch study.

Lymphovascular invasion (LVI) plays an important role in determining the risk of lymph node metastasis (LNM) in T1 colorectal cancer (CRC) patients and influencing treatment decisions and patient outcomes. This study evaluated how the detection of LVI varies between Dutch laboratories and investigated its impact on the treatment and oncological outcomes of T1 CRC patients. Pathology reports and clinical data of T1 CRC patients who underwent local resection between 2015 and 2019 were obtained from the Dutch nationwide pathology databank (Palga cohort, n=5513). Data on the standard of LVI diagnosis (H&E/Immunohistochemistry) were not available. We categorized laboratories as low, average, or high detectors and evaluated the impact of LVI detection practice on the surgical resection rate and the proportion of LNM-negative (LNM-) surgeries. In the second part of the study, we used the Dutch T1 CRC Working Group cohort (n=1268) to evaluate the impact of LVI detection practice on cancer recurrences during follow-up. Multivariable logistic regression analyses and Cox proportional hazard regression were used to study the association between LVI detection practice and the outcomes. In the PALGA cohort, the proportion of surgical resections after local resection of a T1 CRC was significantly higher among patients diagnosed by laboratories with a high LVI detection rate (high vs. low: adjusted OR [aOR] 1.87; 95% confidence interval [CI] 1.52-2.31) as was the proportion of LNM-surgeries (aOR 1.73; 95% CI 1.39-2.15). In the second cohort, no significant difference was observed in cancer recurrences among patients diagnosed in laboratories with high detection rates compared with low detection rates (aHR 2.23; 95% CI 0.94-5.23). These findings suggest that a high detection rate of LVI does not improve oncological outcomes and may expose more patients to unnecessary oncological surgery, emphasizing the need for standardization of LVI diagnosis.

Outcomes of patients treated with chemotherapy for breast cancer during pregnancy compared with nonpregnant breast cancer patients treated with systemic therapy.

Prior studies of patients treated for breast cancer during pregnancy (PrBC) report mixed outcomes and are limited by substandard treatment, small cohorts, and short follow-up. This study compared survival outcomes of PrBC patients treated with chemotherapy during pregnancy with nonpregnant patients matched by age, year of diagnosis, stage, and subtype. PrBC patients treated from 1989 to 2022 on prospective institutional protocols were eligible. Disease-free survival (DFS), overall survival (OS), and progression-free survival (PFS) were estimated using the Kaplan-Meier method and multivariable Cox proportional hazards regression. Among 143 PrBC and 285 nonpregnant patients, median follow-up was 11.4 years. Survival differences were statistically significant, with median DFS and OS not attained for PrBC patients versus 5.6 years (95% confidence interval [CI], 3.6-15.4; p=.0001) and 19.3 years (95% CI, 14.1-not estimated; p=.0262) for nonpregnant patients, respectively. Median PFS was 24.1 years (95% CI, 15.8-not estimated) for PrBC patients versus 8.4 years (95% CI, 6.4-10.9) for the nonpregnant cohort (p=.0008). Study cohort was associated with DFS, PFS, and OS in multivariable analyses, with the nonpregnant cohort having increased risks of disease recurrence (hazard ratio [HR], 1.91; 95% CI, 1.33-2.76; p=.0005) and disease progression or death (HR, 1.68; 95% CI, 1.19-2.39; p=.0035), and shorter OS (HR, 1.52; 95% CI, 1.01-2.29; p=.0442). These data suggest that PrBC patients treated with chemotherapy during pregnancy have at least comparable, if not superior, outcomes than nonpregnant patients with similar age, cancer stage, and subtype. Analyses excluding patients with postpartum breast cancer were unable to be performed and are a priority for future confirmatory studies.

Serum Pyridoxal 5'-Phosphate and Pyridoxic Acid Ratio Index with Prognosis of Colorectal Cancer: A Prospective Cohort Study.

Studies on the association between serum vitamin B6 status and colorectal cancer prognosis are limited and have yielded inconsistent results. This study investigated the association of pyridoxal 5'-phosphate (PLP) and pyridoxic acid ratio (PAr) index with colorectal cancer survival. A total of 1286 colorectal cancer patients diagnosed since 2010 were selected from the Guangdong Colorectal Cancer Cohort study. Serum levels of PLP, pyridoxal, and 4-pyridoxic acid were measured using ultra-high-performance liquid chromatography-tandem mass spectrometry. The study followed overall mortality and colorectal cancer-specific mortality until December 2023. Multivariable Cox proportional hazards regression models were applied to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs). Restricted cubic spline and stratified analysis were performed. During a median follow-up of 77.36 months, 331 deaths were recorded, with 293 specifically attributed to colorectal cancer. Higher PLP levels were associated with a longer overall survival (HRQ4 vs. Q1, 0.63; 95% CI: 0.46, 0.87; p for trend = 0.008) and colorectal cancer-specific survival (HRQ4 vs. Q1, 0.62; 95% CI: 0.44, 0.87; p for trend = 0.006). Non-linear associations were observed between serum PLP and overall and colorectal cancer-specific survival (p for non-linear < 0.05). However, PAr was not significantly associated with either overall survival (HRQ4 vs. Q1, 1.03; 95% CI: 0.75, 1.41) or colorectal cancer-specific survival (HRQ4 vs. Q1, 1.01; 95% CI: 0.72, 1.42). The association between serum PLP and both overall survival and colorectal cancer-specific survival (p for interaction < 0.05) varied by alcohol drinking status. Higher serum PLP levels, but not PAr, may be associated with improved overall and colorectal cancer-specific survival.

Haemorrhagic risk in elderly patients with atrial fibrillation that develop low platelet count during direct oral anticoagulant treatment: insights from the ATHERO-AF study

Abstract Background Bleeding risk in atrial fibrillation (AF) patients is complex and dynamic. Among others, thrombocytopenia has been suggested as a bleeding risk factors. No data on thrombocytopenia occurring during direct oral anticoagulants (DOACs) therapy are available. Purpose We investigated the incidence rate of thrombocytopenia and major bleeding (MB) in AF patients on DOACs. We also investigated whether the addition of incident thrombocytopenia to the HAS-BLED score might increase its predictive value compared to baseline HAS-BLED calculation. Methods 955 AF patients from the prospective ongoing ATHERO-AF study followed for a mean of 38.4±26.6 months. All patients were on DOACs. Thrombocytopenia was defined by a platelet count &amp;lt;150 x109/L registered during follow-up visits. MB events were defined according to ISTH definition and were recorded at each follow-up visit. Patients with thrombocytopenia at baseline were excluded. Multivariable Cox proportional hazards regression analysis was used to calculate the hazard ratio (HR) with 95% Confidence interval (95%CI) for each factor in relation to bleeding risk. Results Mean age was 77.3±9.0 years and 40.1% were women. During a follow-up, 139 patients developed thrombocytopenia with an incidence rate of 0.8% per year. We recorded no difference between thrombin and factor Xa inhibitors. During follow-up, 179 bleedings occurred, of which 80 were major. Patients experiencing bleedings were more likely to suffer from arterial hypertension, heart failure, anaemia and had higher CHA2DS2-VASc and HAS-BLED scores. At multivariable Cox proportional hazards regression analysis, factors associated with MB were incident thrombocytopenia (HR 1.995, 95%CI 1.211-3.288), antiplatelet use (HR 2.716 95%CI 1.269-5.816) and age (HR 1.033, 95%CI 1.003-1.064). The addition of incident thrombocytopenia to the HAS-BLED score increased the predictive value of baseline HAS-BLED in patients without thrombocytopenia for MB events (AUC from 0.54 to 0.61, p=0.016). Conclusion Incident thrombocytopenia is associated with an increased risk of MB. The addition of incident thrombocytopenia to the baseline HAS-BLED score increased its predictive value, suggesting that continuous bleeding risk evaluation of AF patients may provide additional prognostic information compared to the baseline only.

Dapagliflozin versus empagliflozin and major adverse cardiovascular events in type 2 diabetes: a nationwide cohort study

Abstract Background Large randomized clinical trials have shown that sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of adverse kidney and cardiovascular outcomes in patients with heart failure, chronic kidney disease, or type 2 diabetes mellitus (T2DM) at high risk of atherosclerotic cardiovascular disease. Whether these effects might differ between individual SGLT2-inhbitors remain unclear given the lack of head-to-head comparisons. Purpose To examine the association between treatment with dapagliflozin versus empagliflozin and the long-term rate of major adverse cardiovascular events (MACE) in patients with T2DM. Methods Using nationwide registries, all Danish residents with T2DM, who initiated treatment with dapagliflozin or empagliflozin from 2015 to 2020, were identified. Only treatment with dapagliflozin or empagliflozin was considered in the present analysis, since approximately 3% initiated treatment with other SGLT2-inhibitors (i.e., canagliflozin and ertugliflozin). Patients were followed from date of the first claimed prescription of dapagliflozin or empagliflozin until the outcome of interest, emigration, death, or end of study (December 31, 2021). The primary outcome was a composite endpoint of major adverse cardiovascular events (i.e., time to first heart failure hospitalisation, acute myocardial infarction (AMI), stroke, or all-cause mortality). The primary outcome was compared between the dapagliflozin and empagliflozin group, overall and in prespecified subgroups of interest, with multivariable Cox proportional hazards regression models. Results In total, 61,031 patients with T2DM initiated treatment with dapagliflozin (N=21,028; 34.5%) or empagliflozin (N=40,003; 65.5%). The median age of study population was 62.6 years (25th-75th percentile, 54.2-70.8 years), and 62.6% were men. There were no clinically significant differences between the dapagliflozin and empagliflozin group with respect to age, sex, and clinical characteristics. The median follow-up was 3.1 years (25th-75th percentile, 1.9-4.5 years). The adjusted long-term hazard ratios of the primary outcome, overall and in prespecified subgroups of interest, are displayed in the Figure. Compared with empagliflozin, treatment with dapagliflozin was not associated with a significantly different rate of the primary outcome (HR 1.02 [95% CI, 0.97-1.07]). The observed association was consistent across clinically relevant subgroups, including in patients with and without heart failure, chronic kidney disease, and atherosclerotic cardiovascular disease. Conclusion In a large, nationwide cohort of patients with T2DM, treatment with dapagliflozin was associated with a similar rate of major adverse cardiovascular outcomes compared with empagliflozin, and this association was consistent across clinically relevant subgroups. These findings suggest that the benefits of SGLT2-inhibitors can be characterized as a class-effect.

Combined evaluation of liver and kidney function improves prediction of clinical outcome in patients with chronic heart failure and reduced ejection fraction

Abstract Background/Introduction The liver and the kidneys are important organs for body homeostasis and are both affected by heart failure (HF) either by systemic venous congestion or hypoperfusion. Purpose We aimed to verify whether the Model for End-stage Liver Disease eXcluding International normalized ratio (MELD-XI), as well as a combination of cholestatic liver and kidney function tests carry prognostic value in patients with chronic HF with reduced ejection fraction (HFrEF). The liver parameters included alkaline phosphatase (ALP), gamma glutamyl-transpeptidase (GGT), and total bilirubin, while kidney parameters consisted of eGFR and the tubular damage markers urinary N-acetyl-beta-D-glucosaminidase (NAG) and kidney injury molecule (KIM)-1. Methods We categorized 250 patients with HFrEF on the basis of baseline biomarker levels. We assumed elevated NT-proBNP indicates hemodynamic congestion necessary to induce congestive liver or kidney dysfunction. Thus, in every organ damage category, NT-proBNP level above median was incorporated, next to any 2 out of 3: ALP, GGT or total bilirubin above median for liver dysfunction; any 2 out of 3 NAG or KIM-1 above median or eGFR below median for kidney dysfunction; or coexistence of liver and kidney dysfunction as defined above. Additionally, a subgroup of patients with both NT-proBNP and MELD-XI above the median was analyzed. The primary endpoint was a composite of cardiovascular death, heart transplantation, LVAD implantation, and hospitalization for acute or worsened HF, whichever occurred first. Univariable and multivariable Cox proportional hazard regression models were used. Results Median (Q1-Q3) age of the study population was 68 (58-76) years; 184 (74%) were men, 62 (25%) in NYHA class III or IV, and mean left ventricular ejection fraction (LVEF) was 31±9%. During a median (Q1-Q3) follow-up of 2.2 (1.4-2.5) years, 66 (26%) patients reached the primary endpoint. We observed that liver dysfunction, kidney dysfunction or their coexistence was associated with significantly higher risk of reaching the primary endpoint (HR 3.54, 95% CI 1.75–7.16; HR 1.85, 95% CI 1.00–3.41; HR 2.52, 95% CI 1.03–6.11 respectively) in the clinically adjusted model (Table 1). Higher MELD-XI was associated with higher risk of reaching the primary endpoint in an unadjusted model but not in a clinically adjusted model. Figure 1 presents event-free survival probability of patients falling into organ dysfunction categories. Conclusions Our results show that markers of cholestatic liver function and kidney function predict unfavorable clinical outcome and provide better prognostic value in chronic HFrEF patients than the MELD-XI alone. Thus, screening for liver and kidney damage may help identify high-risk patients in whom more careful observation and individualized therapy is warranted.Fig 1.Event-free survival probability

Associations between neutrophil-percentage-to-albumin ratio level and all-cause mortality and cardiovascular disease-cause mortality in general population: evidence from nhanes 1999-2010

Abstract Introduction Chronic inflammation is a recognized independent risk factor for cardiovascular disease (CVD), highlighting the need for reliable inflammatory indicators to predict CVD(1). As an inflammatory indicator which has been proved to have predictive value for the prognosis of CVDs, neutrophil percentage-to-albumin ratio (NPAR) has obtained increasing attention(2,3), but further research is needed to confirm the relationship with mortality in general population. Purpose To explore whether NPAR can serve as a predictive inflammatory indicator for CVD-cause and all-cause mortality in general population. Methods This prospective cohort study included 21317 individuals who participated in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2010. The baseline NPAR level was calculated as Neutrophil percentage (%) * 100/Albumin (g/dl). Data for CVD and all-cause mortality were acquired by linking the cohort database with the National Death Index through December 31, 2019.Weighted Kaplan–Meier curves with log-rank tests were conducted to access cumulative survival differences across different NPAR results. Restricted cubic spline analyses were employed to examine the nonlinear association. Multivariable Cox proportional hazards regression models were used to compute hazard ratios and 95% CIs. Receiver Operating Characteristic (ROC) curves were used to compare predictive value of NPAR with systemic immune inflammation index (SII) and neutrophils percent. Results In this cohort study, during 270014 person-years of follow-up, 4074 all-cause deaths and 1116 CVD-cause deaths were documented. We found significant associations between elevated NPAR and both CVD-cause and all-cause mortality in Kaplan–Meier curves (both P for log-rank test&amp;lt;0.001). Restricted cubic splines revealed non-linear associations between NPAR level and both CVD-cause (P=0.018 for nonlinearity) and all-cause mortality (P&amp;lt;0.001 for nonlinearity) (Figure 1A and 1B). After adjusting for confounding factors, participants in the highest NPAR tertile had a significantly increased risk of all-cause mortality (HR: 1.46, 95% CI: 1.33-1.61) and CVD-cause mortality (HR: 1.54, 95% CI: 1.32-1.80) compared to those in the lowest tertile, while no association was detected for individuals in the middle tertile (Figure 2). The effect of NPAR was consistent across most subgroups, with no significant interaction with most covariates except for high cholesterol (CVD-cause mortality: P=0.014, all-cause mortality: P=0.022). Further ROC analysis confirmed that NPAR had higher predictive value than neutrophil percent and SII. Conclusions Elevated NPAR level was significantly associated with an increased risk of all-cause and CVD-cause mortality in general population.Given its easy-to-calculate nature and high predictive value, NPAR index, with implications in public health, deserves greater attention in inflammatory assessment and cardiovascular prevention.Figure 1 Nonlinear associationFigure 2 Cox regression table