Multicenter Prospective Cohort Research Articles

The Association Between Perioperative Red Blood Cell Transfusions and 1-Year Mortality After Major Cancer Surgery: An International Multicenter Observational Study.

Packed red blood cell (pRBC) transfusions in patients undergoing surgery for cancer are given to treat anemia or acute hemorrhage. Evidence indicates that pRBC transfusions are associated with poor perioperative and oncological outcomes. The ARCA-1 (Perioperative Care in the Cancer Patient-1) study was designed to test the association between perioperative pRBC transfusions and postoperative morbidity and mortality in patients undergoing cancer surgery. The primary hypothesis of our study was that perioperative pRBC transfusions have a negative impact on postoperative morbidity and 1-year mortality. ARCA-1 was an international multicenter prospective observational cohort study. Participating centers enrolled a minimum of 30 consecutive adult patients with cancer who underwent surgery with curative intent. The primary end point was all-cause mortality 1 year after major cancer surgery. Secondary end points were rates of perioperative blood product use, 1-year cancer-specific mortality, overall survival, and 30-day morbidity and mortality. We performed a propensity score matching analysis to adjust for selection bias. A multivariable logistic regression model was fitted to estimate the effects of significant covariates on 1-year mortality, cancer-related mortality, and overall survival. A total of 1079 patients were included in the study. The rate of perioperative pRBC transfusions was 21.1%. Preoperative comorbidities, including anemia, American Society of Anesthesiologists (ASA) score of III to IV, a history of coronavirus disease 2019 (COVID-19), myocardial infarction, stroke, need for dialysis, history of blood transfusions, and metastatic disease were statistically significantly more frequent in transfused patients compared to nontransfused patients. The 1-year mortality rate was higher in transfused patients before (19.7% vs 6.5%; P < .0001) and after (17.4% vs 13.2%; P = .29) propensity score matching. 1-year mortality was 1.97 times higher in transfused than in no-transfused patients (odd ratio [OR], 1.97; 95% confidence interval [CI], 1.13-3.41). The odds of 1-year cancer mortality for patients who had perioperative pRBCs was 1.82 times higher (OR, 1.82; 95% CI, 0.97-3.43) compared to those who did not receive perioperative pRBC transfusion. The effect of perioperative pRBC transfusion on overall survival was also significant (hazard ratio [HR], 1.85; 95% CI, 1.15-2.99). Transfused patients also had a higher rate of 30-day postoperative mortality before (3.5% vs 0.7%; P = .0009) and after propensity score matching (4.2% vs 1.8%; P = .34). This international, multicenter observational study showed that perioperative pRBC transfusion was associated with an increased mortality risk.

Prevalence and Prognostic Value of Cachexia Diagnosed by New Definition for Asian People in Older Patients With Heart Failure.

The Asian Working Group for Cachexia (AWGC) proposed a new definition of cachexia; however, its impact on cachexia prevalence and overlaps with other conditions, such as sarcopenia and malnutrition, are unclear. We investigated these aspects and the prognostic value of cachexia based on the AWGC on mortality in older patients with heart failure (HF). This study was a secondary analysis of a prospective multicentre cohort, namely, the FRAGILE-HF cohort study. Older (≥ 65 years) patients who had been hospitalized due to decompensated HF were enrolled. We assessed the presence/absence of cachexia based on the AWGC and Evans' criteria. Sarcopenia and malnutrition based on the Asian Working Group for Sarcopenia 2014 and the Global Leadership Initiative on Malnutrition criteria were also assessed to compare their prevalence and the overlaps between them. Patients were stratified in relation to the presence/absence of cachexia based on the AWGC criteria, and their mortality rates were compared. Of the 861 enrolled patients (median [interquartile range] age, 80 years [73-85 years]; male, 58.9%), cachexia, as evaluated based on the AWGC and Evans' criteria, sarcopenia and malnutrition, was present in 74.1%, 36.2%, 20.6% and 55.2% of patients, respectively. AWGC-defined cachexia was most common in the four conditions. All-cause death events occurred in 153 (18.1%) patients in 2 years. AWGC-defined cachexia (adjusted hazard ratio [aHRs], 1.442; 95% confidence interval [95% CI], 0.931-2.233; p = 0.101) was not associated with all-cause mortality in older patients with HF after adjusting for other HF prognosis factors, such as the B-type natriuretic peptide and the Meta-Analysis Global Group in Chronic risk score, whereas cachexia evaluated based on Evans's criteria (aHRs, 1.547; 95% CI, 1.118-2.141; p = 0.009), sarcopenia (aHRs, 1.737; 95% CI, 1.214-2.485; p = 0.003), and malnutrition (aHRs, 1.581; 95% CI, 1.094-2.284; p = 0.015) was associated with all-cause mortality. Three-quarters of older patients with HF had cachexia as evaluated by the AWGC criteria, and this was not associated with a worse prognosis. As the new AWGC cachexia criteria will result in a significantly larger proportion of patients being diagnosed with cachexia, the implementation of the criteria in clinical practice requires further consideration. UMIN-CTR unique identifier: UMIN000023929.

Smoking behavior and the risks of tumor recurrence and progression in patients with non-muscle-invasive bladder cancer.

Studies on the relationship of cigarette smoking with the risks of recurrence and progression of non-muscle-invasive bladder cancer (NMIBC) are inconsistent and prospective data are scarce. Therefore, we aimed to assess the association of smoking behavior with risks of NMIBC recurrence and progression. We used data of the prospective multi-center cohort study UroLife, including 1495 patients with NMIBC who reported information on smoking at 6 weeks post-diagnosis (baseline; reflecting present and pre-diagnosis). This included smoking status (also based on reporting 3 months post-diagnosis), intensity, duration, pack years, and time since smoking cessation, if applicable. Hazard ratios and 95% confidence intervals (CIs) for risks of first recurrence, multiple recurrences, and progression were computed using multivariable proportional hazards regression models. During a total median follow-up period of 4.6 years, 517 patients developed ≥1 recurrence and 163 had progression. Higher versus lowest categories of smoking intensities and pack years up to baseline were significantly associated with a higher risk of first recurrence. No significant linear associations were found, except for smoking intensity among BCG-treated patients (per 10 cigarettes/day increase: HR 1.23, 95%CI 1.02, 1.48). No associations for smoking status, duration, and time since cessation were observed. Analyses of multiple recurrence risk showed comparable results. Regarding progression risk, no consistent associations were found. In conclusion, heavier smoking was associated with higher recurrence risk, particularly among BCG-treated patients. This may be attributable to persistent damage through its carcinogenic compounds. Given the mixed results across different exposures, the effect of smoking behavior on NMIBC prognosis remains unclear.

Prevalence and aggravation of cervical spine instabilities in rheumatoid arthritis during over 10 years: a prospective multicenter cohort study.

We designed a prospective multicenter cohort study to clarify along-term, > 10-year prevalence and aggravation of cervical spine instabilities in rheumatoid arthritis (RA). In 2001-2002, 634 outpatients were enrolled, and 233 (36.8%) were followed for > 10 years. Cervical spine instability was defined as atlantoaxial subluxation (AAS, > 3-mm atlantodental interval), vertical subluxation (VS, < 13-mm Ranawat value), and subaxial subluxation (SAS, ≥ 2-mm irreducible vertebral translation). The aggravation was determined as ≥ 2mm decrease of the Ranawat value in VS, ≥ 2-mm increase of slippage in SAS, and these new developments. The prevalence of VS and SAS increased during both the initial and last > 5 years (all, p ≤ 0.049). While VS aggravation was associated with pre-existing AAS (p = 0.007) and VS (p = 0.002), SAS aggravation correlated with pre-existing VS (p = 0.002). Multivariable analysis found hand mutilating changes (odds ratio [OR] = 4.048, p = 0.008), RA duration ≥ 5 years (OR = 3.711, p = 0.013), C-reactive protein (CRP) level ≥ 3.8mg/dL (OR = 2.187, p = 0.044), and previous joint surgery (OR = 2.147, p = 0.021) as predictors for VS aggravation. Pre-existing VS (OR = 2.252, p = 0.024) and CRP ≥ 1.0mg/dL (OR = 2.139, p = 0.013) were disclosed as predictors for SAS aggravation. Low disease activity and clinical remission before the development of VS and advanced peripheral joint destruction are essential to prevent progressive cervical spine instability in RA.

A protocol for a Japanese prospective cohort evaluating the features of patients with uncontrolled asthma achieving clinical remission: J-CIRCLE

BackgroundIncreasing expectations that biologics can be used as disease-modifying agents have introduced the concept of clinical remission (CR) in managements of severe asthma. Given the clinical relevance of computed tomography (CT) and blood biomarkers, we hypothesized that further refinement of CR criteria as well as incorporation of CT and blood biomarkers as indicators for structural and biological remission (SR, BR) would enable predicting long-term disease stability in patients with severe asthma treated with biologics. MethodsThis Japanese multicenter prospective observational cohort will enroll patients with severe asthma who will start a new biologic (including a change from another biologic). The enrolled patients will be longitudinally followed up for 3 years. At enrollment, patients will undergo postbronchodilator spirometry, blood tests, fractional exhaled nitric oxide, chest and sinus CT, and patient-reported outcome questionnaires. Follow-up examinations will be performed at 1, 3, 6, 12, 24, and 36 months. The rates of CR resulting from different criteria after 1 year of treatment with biologics will be compared, and factors associated with long-term disease stability after 3 years of biologic treatments will be identified. DiscussionThis multicenter study in Japan will provide data that will help establish more appropriate criteria for CR, structural remission, and biological remission to predict long-term disease stability in patients with severe asthma who receive biologic therapy. Ethics and disseminationThe study was approved by the Ethics Committee of Kyoto University (No. R4419, approval date June 11th, 2024). Trial registrationThe University Hospital Medical Information Network (UMIN000053771).

Recruiting and retaining healthcare workers in Scotland to a longitudinal COVID-19 study: a descriptive analysis

BackgroundRapid timescales for the design and delivery of research were common during the COVID-19 pandemic. The recruitment and retention of healthcare workers (HCWs) as participants in research studies are notoriously challenging, but this was exacerbated during the pandemic by the unprecedented demand placed on the workforce. The SARS-CoV-2 Immunity and Reinfection Evaluation (SIREN study) is a prospective multicentre cohort study following HCWs in the UK. This paper discusses the strategies and challenges associated with recruitment and retention of HCW participants in Scotland.MethodsThere were 44,546 HCWs recruited to the SIREN study, of whom 6,285 were recruited by research teams at ten different research sites in Scotland between October 2020 and March 2021. Information on target and actual sample size, availability of resource, recruitment rate, and recruitment and engagement strategies by site was collated from SIREN study documentation and discussions with local key SIREN site staff. Individual-level data from 6,153 HCW participants with ongoing consent for all data usage were also collated, including socio-demographic data and information on withdrawal (in first year) and opt-in to a study extension after one year. Factors associated with these outcomes were explored in logistic regression analyses.ResultsDifferent recruitment strategies were used in each site according to local agreements, protocol and staff capacity, with the recruitment period ranging from 13 to 160 days. The locally-agreed recruitment target was met in four sites. The proportion of participants who withdrew in the first year ranged from 3.1 to 24.8% by site, while subsequent opt-in to a 12-month study extension ranged from 28.6 to 74.8%. The sites with the highest proportions of withdrawals were the same four sites with lowest proportions of opt-in. On an individual level, there was a lower level of retention among younger participants, and those from lower socio-economic backgrounds and minority ethnic groups.ConclusionsSite-specific factors including research-readiness likely had a significant influence on recruitment and retention, more so than the specific recruitment or retention strategies employed. Independent of site factors, individual-level variables influenced recruitment and retention, suggesting targeted strategies may be needed to promote research engagement among particular socio-demographic groups.

Helicobacter pylori prevalence and its spontaneous eradication rate after distal or proximal gastrectomy for gastric cancer: A multicenter prospective cohort study

AbstractBackgroundHelicobacter pylori (H. pylori) eradication is recommended in patients undergoing endoscopic resection for early gastric cancer to reduce recurrence. However, due to the possibility of spontaneous regression secondary to dynamic changes in the remnant stomach, the immediate eradication after gastrectomy for H. pylori carriers remains unclear. This study aimed to investigate the prevalence of H. pylori in Japanese patients with gastric cancer and the spontaneous eradication rate after distal or proximal gastrectomy.MethodsThis multicenter prospective cohort study was conducted at 22 institutions. Eligibility criteria was patients over 20 years planned to undergo R0 gastrectomy for gastric cancer. The primary endpoint was spontaneous eradication rate 1 year after distal or proximal gastrectomy. The prevalence of H. pylori infection before surgery and clinical features related to spontaneous eradication were examined.ResultsA total of 1247 patients were included in this study. The preoperative H. pylori status was positive in 756 patients and negative in 491. Seventy‐nine of the negative patients had an eradication history, totaling 835 (67%) patients preoperatively infected with H. pylori. The infection status of 541 patients was examined 1 year postoperatively; 285 were negative, with a 52.7% spontaneous eradication rate. Spontaneous eradication was significantly higher in male and older patients (&gt;70 years); other factors, such as histological type, gastrectomy method and adjuvant chemotherapy presence, did not affect the rate.ConclusionsAs spontaneous H. pylori eradication occurred in more than half of the analyzed patients, retesting for H. pylori. should be considered before postoperative eradication therapy (UMIN000020280).

Effects of Social Determinants of Health and Social Support on Surgical Outcomes Among Patients Undergoing Hysterectomy.

To describe composite 30-day postoperative complication rates among patients undergoing hysterectomy during the coronavirus disease 2019 (COVID-19) pandemic and to determine baseline and postoperative mental health symptoms, levels of social support, and socioeconomic status and their association with hysterectomy outcomes. This multicenter prospective cohort study at eight centers across the United States enrolled patients who underwent minimally invasive hysterectomy for benign indications during the COVID-19 pandemic. Patients completed preoperative and postoperative surveys assessing mental health (PHQ-9 [Patient Health Questionnaire]), social support (MOS-SS [Medical Outcomes Study Social Support Survey]), and socioeconomic status (Hollingshead Index [Hollingshead Four Factor Index of Socioeconomic Status]). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection rates and 30-day composite complication rates were measured and categorized by Clavien-Dindo Grade. Bivariate associations of survey data on complications were assessed. Logistic regression analyses were used to identify independent predictors of 30-day complications and complication severity. Postoperative complications within 30 days occurred in 67 of 273 (24.5%) patients. Most (88.1%) complications were mild, but eight (11.9%) experienced severe complications. Only three patients (1.1%) tested positive for SARS-CoV-2 infection. There were no differences in complication rates when comparing race and ethnicity, age, or socioeconomic status. Survey responses that indicated more depression and worse support from preoperative to postoperative were seen in patients with severe complications (P=.008 and P=.09, respectively). Multivariate analysis demonstrated that an increase in support scores was protective against severe complications (P=.02). Worsening depression scores were associated with more severe complications (P=.03). This study showed a high rate of complications (24.5%) among patients who underwent hysterectomy during the COVID-19 pandemic. Lower social support and worse mental health status are associated with worse postoperative outcomes after hysterectomy.

Salt Based or BaLanced SolUtion–Trends Existing in Indian Intensive Care Units: A Multicenter Prospective Observational Cohort Study (SOLUTE Study)

Salt Based or BaLanced SolUtion–Trends Existing in Indian Intensive Care Units: A Multicenter Prospective Observational Cohort Study (SOLUTE Study)

Postoperative lymphopaenia as a risk factor for postoperative infections in cancer surgery: A prospective multicentre cohort study (the EVALYMPH study).

Stress due to surgical trauma decreases postoperative lymphocyte counts (LCs), potentially favouring the occurrence of postoperative infections (PIs). We aimed to determine whether postoperative lymphopaenia following thoracic or gastrointestinal cancer surgery is an independent risk factor for PIs and to identify modifiable factors related to anaesthesia and surgical procedures that might affect its occurrence. The EVALYMPH study was a prospective, multicentre cohort study with a 30-day patient follow-up. Multivariate analyses were performed to determine the risk factors for PIs and for postoperative lymphopaenia. Patients were included from January 2016 to September 2017 in 25 French centres. Adult patients admitted for thoracic or gastrointestinal cancer surgery were eligible for inclusion. PIs within 30 days after surgery were defined as urinary tract infections, pneumonia, surgical site infections and other infections (bloodstream infections or pleurisy). Of 1207 patients included, 273 (22.6%) developed at least one infection within 30 days after surgery, with a median [IQR] time to onset of 8 [5 to 11] days. An increased risk of PI was significantly associated with an ASA score of IV: hazard ratio (HR) 4.27 (95% confidence interval (CI), 1.87 to 9.72), surgery > 200 min (HR 1.58 (1.15 to 2.17) and lymphopaenia on postoperative day 1 (POD1) (HR 1.56 (1.08 to 2.25). This risk was associated with changes in postoperative LC over time (P = 0.001) but not with preoperative LC (P = 0.536).POD1 lymphopenia was related to patient characteristics and duration of surgery but not to potentially modifiable other surgical or anaesthetics factors. POD1 lymphopaenia was associated with PIs in patients undergoing thoracic or gastrointestinal cancer surgery. To individualise care, patient characteristics and surgery duration should be taken into account. ClinicalTrials.gov Identifier: NCT02799251.

Baseline inflammatory status affects the prognostic impact of statins in patients with peripheral arterial disease

BackgroundStatins bring favourable effects on the clinical prognosis of patients with atherosclerotic disease partly through their anti-inflammatory properties. However, this effect has not been fully verified in patients with peripheral arterial disease (PAD). We aimed to test whether statins exert different prognostic effects depending on the degrees of inflammation in patients with PAD. MethodsThis study was a sub-analysis of a multicenter prospective cohort of 2321 consecutive patients with PAD who received endovascular therapy (EVT). After excluding patients without information on C-reactive protein (CRP) levels at the time of index EVT, 1974 patients (1021 statin users and 953 non-users) were classified into four groups depending on CRP levels: low CRP (<0.1 mg/dL), intermediate-low CRP (0.1–0.3 mg/dL), intermediate-high CRP (0.3–1.0 mg/dL), and high CRP (>1.0 mg/dL). A composite of death, stroke, myocardial infarction, and major amputation as the primary endpoint was compared between statin users and non-users in each CRP category. ResultsDuring the median observation period of 316 days, the primary composite endpoint occurred in 112 (11.0 %) statin users and 178 (18.7 %) non-users (log-rank test, p < 0.001). However, statin therapy was associated with significantly lower event rates only in the intermediate-high- and high-CRP categories (p = 0.02 and p = 0.008, respectively). Multivariable Cox regression analysis revealed that statin use was independently associated with the primary endpoint only in the high-CRP category (adjusted hazard ratio: 0.64 [95 % confidence interval: 0.41–0.98]). ConclusionStatins may exert favourable prognostic effects in patients with PAD and highly elevated CRP levels.

Prognosis and Risks for Probable Chronic Lung Allograft Dysfunction: A Prospective Multicenter Study.

Chronic lung allograft dysfunction (CLAD) hinders lung transplant success. A 2019 consensus refined CLAD diagnosis, introducing probable or definite CLAD based on persistence of lung function decline. Outcomes and risks for probable CLAD remain uncertain. Determine the prognosis and clinical risks for probable CLAD in a prospective multicenter cohort. Clinical Trials in Organ Transplantation-20 included 745 CLAD-eligible adult lung recipients at 5 centers and applied rigorous methods to prospectively adjudicate probable CLAD. The impact of probable CLAD on graft loss was determined using a Cox model that considered CLAD as a time-dependent covariate. Regularized Cox modeling with LASSO penalty was used to evaluate donor or recipient characteristics and the occurrence and timing of posttransplant events as probable CLAD risks. Similar analyses were performed for definite CLAD. Probable CLAD occurred in 29.7% of patients at 3 years posttransplant and conferred a marked increase in risk for graft loss (unadjusted HR 4.38, p<0.001). Most patients (80%) with probable CLAD progressed to definite CLAD. Cytomegalovirus infection and specifically late presence (>90 days posttransplant) of donor-specific alloantibodies, acute rejection, acute lung injury, or organizing pneumonia contributed the greatest independent information about probable CLAD risk. Definite CLAD risks were similar. Probable CLAD identifies patients at high risk for graft loss, supporting prospective identification of this condition for early initiation of CLAD-directed interventions. More effective strategies to prevent posttransplant cytomegalovirus, inhibit allospecific immunity, and reduce tissue injury are needed to reduce probable CLAD and improve lung recipient survival.

Lung Ultrasound in the Acute Phase of ST-Segment-Elevation Acute Myocardial Infarction: 1-Year Prognosis and Improvement in Risk Prediction.

Lung ultrasound (LUS) has emerged as a useful tool in the acute phase of patients admitted for ST-segment-elevation myocardial infarction. However, its long-term significance remains uncertain, and risk scores do not include LUS findings as a predictor. This study aims to assess the 1-year prognostic value of LUS and its ability to enhance existing risk scores. This is a multicenter prospective cohort study involving 373 patients with ST-segment-elevation myocardial infarction. LUS was performed during the first 24 hours after angiography. LUS results were assessed both as a categorical (wet/dry lung) and continuous variable (LUS score). The primary end point comprised the following major adverse cardiovascular events: all-cause mortality or hospitalization for heart failure, acute coronary syndrome, or stroke within 1 year. We also evaluated whether LUS could enhance the predictive value of the GRACE (Global Registry of Acute Coronary Events) score. Major adverse cardiovascular events occurred in 51 (13.7%) patients over a median follow-up of 368 days. After multivariate analysis, the LUS score was an independent predictor (hazard ratio [HR], 1.06 [95% CI, 1.01-1.10]; P=0.009] for each additional B-line), whereas the categorical classification was an independent predictor in patients with ST-segment-elevation myocardial infarction Killip I (HR, 3.12 [95% CI, 1.34-7.31]; P=0.009). Incorporating LUS into GRACE resulted in a net reclassification index of 31.6% and a significant increase in the area under the curve; GRACE alone scored 0.705 compared with GRACE+LUS 0.791 (P=0.002). Detecting B-lines on LUS at the acute phase predicts major adverse cardiovascular events at 1 year in patients with ST-segment-elevation myocardial infarction and enhances the predictive value of the GRACE score. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04526535.

Proenkephalin improves risk prediction in acute coronary syndromes: derivation and external validation of the KID-ACS risk score

Abstract Background Early assessment of renal and mortality risk in patients with acute coronary syndromes (ACS) is essential to guide treatment decisions according to international guidelines. Circulating proenkephalin (PENK) is a stable opioid metabolite with fast response to changes in kidney function. Purpose This study examined the predictive value of PENK for acute kidney injury (AKI) and mortality in patients presenting with acute coronary syndromes (ACS). Methods Plasma PENK levels were measured using a validated sandwich immunoassay in a prospective multicentre ACS cohort from Switzerland (n = 4 787) and in validation cohorts from the UK (n = 1 141) and Czechia (n = 920). A biomarker-enhanced risk score for simultaneous prediction of both in-hospital acute kidney injury (AKI) and 30-day death (KID-ACS score) with model coefficients adjusted to the outcome was derived and externally validated. In the development of the in-hospital AKI model, patients from one participating study centre were reserved for external validation (Swiss validation cohort). Results Circulating PENK ranked among the top predictors of renal outcomes and mortality in patients with ACS. Accounting for established risk factors and risk models, circulating PENK levels at presentation were independently associated with in-hospital AKI (per log2 increase: adjusted odds ratio [OR] 1.56, 95% CI 1.14 – 2.12, P = 0.005) and with 30-day mortality (per log2 increase: adjusted OR 2.69, 95% CI 1.89 – 3.84, P &amp;lt; 0.001). Dynamic changes in PENK levels within the first 12-24 hours after presentation were strongly and independently associated with in-hospital AKI (increase vs. decrease: adjusted OR 2.83, 95% CI 1.98 – 4.05, P &amp;lt; 0.001). The simple 6-item KID-ACS risk score for in-hospital AKI and 30-day mortality integrates PENK levels at presentation and showed an AUC of 0.72 (95% CI 0.68 – 0.76) for in-hospital AKI, and of 0.91 (95% CI 0.87 – 0.95) for 30-day mortality in the derivation cohort. Upon external validation, KID-ACS had similarly high performance for in-hospital AKI (Swiss validation cohort: AUC 0.73, 95% CI 0.70 – 0.77; Czech validation cohort: 0.74, 95% CI 0.68 – 0.80) and 30-day mortality (UK validation cohort: AUC of 0.87, 95% CI 0.82 – 0.91; Czech validation cohort: 0.91, 95% CI 0.87 – 0.94). The simple 6-item KID-ACS score was non-inferior to established risk models and significantly outperformed the CA-AKI risk score in predicting in-hospital AKI (Zurich cohort: delta AUC 0.11, 95% CI 0.07 – 0.15, P = 0.001) and the GRACE 2.0 in predicting 30-day mortality (UK cohort: delta AUC 0.05, 95% CI 0.01 – 0.09, P = 0.027). Conclusions Circulating PENK was identified as independent predictor of in-hospital AKI and 30-day mortality in patients with ACS. The simple 6-item KID-ACS risk score integrates circulating PENK levels and provides a novel tool for simultaneous assessment of renal and mortality risk in patients presenting with ACS.Independent Predictive Value PENKPerformance and validation of KID-ACS

Prediction of 10-year risk for recurrent atherosclerotic cardiovascular events in a secondary prevention population: Insights from CHART-2 and Suita studies in the Japanese population

Abstract Background Despite the European Society of Cardiology (ESC) guidelines advocating risk prediction models for secondary prevention in established atherosclerotic cardiovascular disease (ASCVD) patients, such models for Japanese individuals remain limited, owing to their comparatively lower ASCVD risk than Western populations. Given this gap, there is a need to develop tailored risk assessment tools for Japanese ASCVD patients to optimize secondary prevention strategies. Purpose Leveraging data from two large-scale, long-term cardiovascular cohorts in Japan, our aim was to develop and externally validate a 10-year risk model predicting recurrent cardiovascular events among patients with established ASCVD. Methods The CHART-2 and Suita studies, large-scale prospective observational multicenter cohort studies in Japan, served as the primary data sources for this investigation. From the CHART-2 study, which comprised 3,560 patients with a history of coronary artery disease or ischemic stroke, we derived our risk model. External validation was conducted using data from the Suita study, which included 445 patients with similar ASCVD backgrounds. The primary outcome of interest was a composite endpoint encompassing cardiovascular death, myocardial infarction, or stroke. Variable selection was performed based on clinically relevant factors previously employed in established risk scores (SMART, REACH, and TRS 2°P risk scores). Logistic regression was utilized for model development, and the predictive performance was assessed using the C-index. Results Over a median follow-up of 10.1 years, the derivation cohort experienced 756 cardiovascular events. Patients in the derivation cohort had an average age of 68.9 ± 10.6 years, with 91% and 24% having a history of coronary artery disease and ischemic stroke, respectively. Using logistic regression, the multivariate model revealed a higher recurrent risk associated with several factors including age, smoking status, systolic blood pressure, diabetes, renal function, number of ASCVD events, atrial fibrillation, lipid levels, left ventricular systolic dysfunction, and statin use. A simple risk score based on these predictors demonstrated a &amp;gt;5-fold gradient of 10-year recurrent risk with a C-index of 0.65 (95% CI 0.63-0.68, Figure). The prediction model was externally validated in the Suita study wit 245 cardiovascular events and a median follow-up of 10.4 years, showing good discriminative ability with a C-index of 0.64 (95% CI 0.60–0.68). Conclusion Our newly developed prediction model offers a valuable tool for identifying individuals at heightened risk of recurrent cardiovascular events over a 10-year period, thereby facilitating more targeted and effective secondary prevention strategies tailored to the unique characteristics of Japanese ASCVD patients.

The gut-microbiome derived phenylacetylglutamine predicts adverse events in patients with acute coronary syndromes

Abstract Background and Introduction The gut microbiota-derived metabolite phenylacetylglutamine (PAG) is associated with incident cardiovascular events(1). Acute coronary syndromes (ACS) present a major health challenge, especially as population ages(2). Data from our group show increased PAG levels during aging in humans. However, the predictive potential of PAG for mortality and major adverse cardiovascular events (MACE) in patients (pts) with ACS is unknown. Purpose Here, we investigated the potential of PAG to predict ischemic and fatal events in pts with acute coronary syndromes (ACS). We also compared the predictive potential of PAG to another relevant gut-microbiota derived metabolite involved in CVD, namely Trimethylaminoxyde, (TMAO), and we evaluated their cumulative risk potential. Methods A total of 1’848 patients were enrolled in Cohort I of the SPUM-ACS study – a multi-center prospective ACS cohort study from Switzerland. Overall survival and incident MACE after 1 year follow-up were analyzed using Kaplan-Meier (KM) estimates and compared by log-rank test after patient stratification into PAG tertiles. Uni- and multivariable Cox-regression models were fit to calculate the hazard ratios for 1-year MACE in a crude model and adjusted model (adjusted for established confounders). Healthy controls served as additional controls. PAG plasma levels were quantified using LC-HRMS. Results The median PAG plasma level in the healthy control group was 1.76µM, whereas for the whole ACS patient population it was 1.92µM (Table 1). Pts in the third PAG tertile had a two times higher MACE rate and a four times higher mortality rate compared to pts in the first PAG tertile (p&amp;lt;0.001). (Table 2). PAG levels were significantly higher in pts who presented with MACE (2.63µM) or died (3.1µM) within the 1-year follow-up compared to the healthy control subjects (p&amp;lt;0.0001) (Figure 1A). Spearman correlation analysis revealed that plasma PAG levels were positively associated with age (r=0.43, p&amp;lt;0.0001), while a negative association with eGFR was observed (r=-0.51, p&amp;lt;0.0001) (Figure 1B). KM estimates indicated that pts in the highest PAG tertile had significantly higher 1-year MACE risk relative to those with low levels (Figure 1C; p&amp;lt;0.001 log rank). Following multivariable adjustment, PAG remained an independent predictor for MACE at 1-year follow-up with a hazard ratio (HR) of 1.8 (95% CI, 1.1–3.2, p=0.048) (Figure 1D). KM estimates of both, high levels of PAG and high levels of TMAO together, indicate that the combination of these two detrimental metabolites leads to an even higher risk of 1-year MACE relative to lower levels (Figure 1E). Conclusion PAG is a novel and independent predictor of adverse outcomes in patients with ACS. This study indicates the role of the gut-microbiome and its metabolites in predicting ischemic and fatal outcomes of pts with established CVD.

Association between the cumulative excessive systolic blood pressure and left ventricular mass index

Abstract Background Ambulatory blood pressure (ABP) has been increasingly adopted in day-to-day clinical practices. Although clinicians can access an enormous amount of information regarding an individual’s blood pressures (BPs) through the ABP monitoring (ABPM), to date, only the mean BP is utilized as the diagnostic threshold of hypertension and the therapeutic target for BP control and no other indices were widely used to assess the burdens of high BP in the ABPM. Because elevated systolic BPs (SBPs) cumulatively damage the myocardium and induce hypertrophy and fibrosis, we hypothesized that the summated value of BP readings beyond a target level may be the better indicator of the overall BP loads than the mean BP value. Methods The Korean ABP registry is a multicenter prospective longitudinal cohort study performed in outpatients with hypertension. Among 5,965 patients enrolled in the registry, 951 patients with valid ABPM records and appropriate echocardiography measurements included in the study. The left ventricular mass (LVM) was normalized using the height2.7(m) (LVM index [LVMIH2.7] = LVM/Height2.7). The cumulative excessive SBP CE-SBP) was defined as the summation of the products of excessive SBPs (≥135 mmHg during wake, ≥10 mmHg during sleep) and the durations of the excessive SBP (Figure 1). Results The CE-SBP was non-linearly associated with both the office SBP and the mean SBP, but the association strength was much greater with the mean SBP than with the office SBP (R2=0.902 vs. R2=0.430). In linear regression models, the association of the CE-SBP with the LVMIH2.7 (R2=0.112 [0.074-0.149]) was greater than that of the office SBP (R2=0.072 [0.040-0.103]), the mean SBP (R2=0.082 [0.049-0.116]) or the mean SBP during sleep (R2=0.99 [0.063-0.134]). Non-linear regression models using restrictive cubic spline fits also showed that the association strength was greater with the CE-SBP (R2=0.117 [0.078-0.155]) than with the office SBP, mean SBP or mean SBP during sleep (Figure 2). Left ventricular hypertrophy (LVH) defined as the LVMIH27 ≥54 g/m2.7 was better predicted with the CE-SBP than with the other SBPs. The association between the CE-SBP and LVMIH27 was stronger in the patients not taking antihypertensive medications (R2=0.121) and strongest in those with the non-dipper pattern (R2=0.125). Combination with the variability indices (successive variation and average real variability) during sleep or the maximum SBP during sleep significantly improved the association strength of CE-SBP with LMMIH27, whereas the combination with the mean SBP or the variability indices during the entire period did not, in the linear models. Conclusion The CE-SBP was more strongly associated with the LVMIH27 than the office SBP and the mean SBP in the ABPM. This result suggests that the CE-SBP may be the better indicator of overall BP loads than the office SBP or the mean SBP in the ABPM, in patients with hypertension.Figure 1Figure 2

Differential impact of clinic BP target on the prevalence and predictors of the masked uncontrolled hypertension and white-coat uncontrolled hypertension

Abstract Background Although intensive blood pressure (BP) control have been advocated, major clinical practices guidelines still recommend clinic BP (cBP) &amp;lt; 149/90 mmHg as the target for antihypertensive therapy. But, cBP targets could influence the prevalence and predictors of any hypertension phenotype. We investigated how different cBP targets impacted on the prevalence and predictors of masked uncontrolled hypertension (MUCH) and white-coat uncontrolled hypertension (WUCH) using the Korean Ambulatory Blood Pressure (KorABP) registry. Methods A multicenter prospective longitudinal cohort study was performed in outpatients with hypertension. Among 5,965 patients enrolled in the KorABP registry, 1,601 patients on antihypertensive medications with a valid ambulatory BP monitoring record were included in this study. Two different cBP targets, &amp;lt;130/80mmHg (intensive) and &amp;lt;140/90 mmHg (conventional) were investigated. Results Controlled ambulatory BP (aBP; &amp;lt;130/80 mmHg) was observed in 472 patients (29.5%). Controlled cBP was shown in 348 patients (21.7%) with the intensive cBP target and in 697 patients (43.5%) with the conventional cBP target. Controlled hypertension, WUCH, MUCH and uncontrolled hypertension were found in 294, 174, 54, and 1,075 patients with the intensive target and in 378, 94, 319 and 810 patients with the conventional target, respectively. Among the patients with controlled cBP, the prevalence of MUCH markedly decreased with the intensive target (15.5%), compared to the conventional target (45.8%). In contrast, among the patients with uncontrolled cBP, the prevalence of WUCH had only 3.8% increase with the intensive target (10.4%), compared to the conventional target (14.2%) (Figure 1). With the conventional target, 75.9% of patients with MUCH had cBP between 130/80 mmHg and 139/89 mmHg. The concordance between the controlled aBP and controlled cBP was higher with the intensive target than with the conventional target (Cohen’s κ 0.62 [0.58-0.67] vs. 0.46 [0.41-0.50]). The logistic models for MUCH included the left ventricular mass index and underuse of antihypertensive drugs (&amp;lt;2 types of drugs) as the common predictors of the both targets. With the conventional target, clinic systolic BP and diastolic BP were the strongest predictors of MUCH, but the cBP was not a predictor of MUCH with the intensive target. The logistic models for WUCH included beta-blocker use, increased heart rate and lower waist circumference and clinic systolic BP as the common predictors of WUCH with the both target. The logistic model for MUCH performed better with the conventional target, whereas the logistic model for WUCH performed better with the intensive target (Figure 2). Conclusion The use of the intensive cBP target (&amp;lt;130/80 mmHg) could reduce the prevalence of MUCH with minimal increase in the prevalence of WUCH and would provide the better assessment for the BP control status than the use of the conventional cBP target (&amp;lt;140/90 mmHg).Figure 1Figure 2

Clinical characteristics and predictors of recurrence from the Australia-New Zealand Spontaneous Coronary Artery Dissection (ANZ-SCAD) registry

Abstract Background Spontaneous coronary artery dissection (SCAD) is an increasingly recognised cause of acute coronary syndrome (ACS), particularly in young women. Our understanding of SCAD remains incomplete with limited prospective data on determinants of SCAD recurrence. Purpose We aimed to describe the clinical characteristics, incidence and predictors of SCAD recurrence and major adverse cardiovascular events (MACE) in patients with SCAD from a large, multicentre registry. Methods Observational, multi-centre prospective and retrospective cohort study recruiting patients with SCAD from 23 hospitals in Australia and New Zealand. Patients aged=&amp;gt;18 years with SCAD and an ACS were eligible for inclusion. Prospectively recruited patients gave their informed consent while a waiver of consent was granted for retrospectively recruited patients. An independent core laboratory adjudicated invasive coronary angiography images to confirm the diagnosis of SCAD. The primary outcome was SCAD recurrence, defined as de novo spontaneous dissection with new ACS symptoms and cardiac enzyme elevation, not due to extension of the index lesion. Cox proportional hazard models were used to evaluate the association between SCAD recurrence and predefined clinical variables. Results From a total 487 patients recruited, 423 (132 prospective and 291 retrospective) patients with SCAD confirmed on core laboratory review were included for analysis. Mean age was 52.4±10.7 years, 89.7% were female and 73.1% were Caucasian. At discharge, 75.2% were on beta-blockers, 27.9% single antiplatelet and 61.9% dual antiplatelet (DAPT). At 15 (interquartile range 5-36) months median follow-up, SCAD recurrence occurred in 3.3%, with an overall MACE of 6.6%. On multivariate analysis, the presence of fibromuscular dysplasia (FMD) or other extra-cardiac vascular abnormalities [adjusted hazard ratio (HR) 5.63, 95% confidence interval (CI), 2.09-15.3, p&amp;lt;0.001], and past history of stroke (adjusted HR 7.99, 95% CI, 1.51-42.4, p=0.015) were associated with higher SCAD recurrence. Discharge beta-blockers was not independently associated with SCAD recurrence, while dual antiplatelet therapy that combined ticagrelor with aspirin was associated with a higher risk of recurrence (adjusted HR 2.47, 95% CI, 1.9-15.6, p=0.048). Conclusion SCAD recurrence comprised half of overall MACE in people with SCAD. The risk of SCAD recurrence was more than 5-fold higher in patients with FMD or other extra-cardiac vascular abnormalities. Dual-antiplatelet therapy that comprised ticagrelor and aspirin was associated with a higher risk of SCAD recurrence.

Clinical characteristics and predictors of adverse cardiovascular events from the australia-new zealand spontaneous coronary artery dissection (ANZ-SCAD) registry

Abstract Background Spontaneous coronary artery dissection (SCAD) is an increasingly recognised cause of acute coronary syndrome (ACS), predominantly affecting women. Our understanding of SCAD remains incomplete with limited prospective data on determinants of major adverse cardiovascular events (MACE). Purpose We aimed to describe the clinical characteristics of patients with SCAD from a large, multicentre SCAD registry. We aimed to identify the predictors of MACE (defined as the composite of all-cause death, non-fatal myocardial infarction, stroke, heart failure, and revascularisation). Methods Observational, multi-centre prospective and retrospective cohort study recruiting patients with SCAD from 23 hospitals in Australia and New Zealand. Patients aged=&amp;gt;18 years with SCAD and an ACS were eligible for inclusion. Prospectively recruited patients gave their informed consent with a waiver of consent for retrospectively recruited patients. All invasive coronary angiography imaging was adjudicated by an independent core laboratory to confirm the diagnosis of SCAD. Cox proportional hazard analysis was used to evaluate the association between MACE and SCAD recurrence with predefined clinical variables. Results From a total 487 patients recruited, 423 (132 prospective and 291 retrospective) patients with SCAD confirmed on core laboratory review were included for analysis. Mean age was 52.4±10.7 years, 89.7% were female and 73.1% were Caucasian. Percutaneous coronary intervention (PCI) was performed in 10.6% of patients. On discharge, 64% of conservatively managed patients were on dual antiplatelet therapy (DAPT). At 15 (interquartile range 5-36) months median follow-up, the accumulated MACE rate was 6.6%. On multivariate analysis, percutaneous coronary intervention (PCI) was associated with a higher risk of MACE [hazard ratio (HR) 3.50, 95% confidence interval (CI) 1.56-7.89, p=0.002], while discharge on at least one antiplatelet medication was associated with a lower risk of MACE (HR 0.13, 95% CI, 0.05-0.36, p&amp;lt;0.001). In patients managed conservatively (n=353), discharge on at least one antiplatelet medication (n=337) was associated with lower MACE (HR 0.27, 95% CI 0.1-0.73, p=0.01), with no difference between single and dual antiplatelet therapy (DAPT) (p=0.74). In patients managed conservatively and on DAPT (n=226), aspirin and clopidogrel was associated with a lower risk of MACE (HR 0.31, 95% CI 0.10-0.93, p=0.038) compared with DAPT consisting of aspirin and ticagrelor (HR 3.25, 95%CI 1.07-9.85 p=0.038) on multivariate analysis. Conclusion Patients with SCAD are at significant risk of MACE. In conservatively managed patients treated with DAPT, aspirin and clopidogrel was independently associated with a lower risk of MACE than aspirin and ticagrelor