RUBY-1: a randomized, double-blind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexaban (YM150) following acute coronary syndrome

AIMS: To establish the safety, tolerability and most promising regimen of darexaban (YM150), a novel, oral, direct factor Xa inhibitor, for prevention of ischaemic events in acute coronary syndrome (ACS). METHODS: In a 26-week, multi-centre, double-blind, randomized, parallel-group study, 1279 patients with recent high-risk non-ST-segment or ST-segment elevation ACS received one of six darexaban regimens: 5 mg b.i.d., 10 mg o.d., 15 mg b.i.d., 30 mg o.d., 30 mg b.i.d., or 60 mg o.d. or placebo, on top of dual antiplatelet treatment. Primary outcome was incidence of major or clinically relevant non-major bleeding events. The main efficacy outcome was a composite of death, stroke, myocardial infarction, systemic thromboembolism, and severe recurrent ischaemia. RESULTS: Bleeding rates were numerically higher in all darexaban arms vs. placebo (pooled HR: 2.275; 95% CI: 1.13–4.60, P = 0.022). Using placebo as reference (bleeding rate 3.1%), there was a dose–response relationship (P = 0.009) for increased bleeding with increasing darexaban dose (6.2, 6.5, and 9.3% for 10, 30, and 60 mg daily, respectively), which was statistically significant for 30 mg b.i.d. (P = 0.002). There was no decrease (indeed a numerical increase in the 30 and 60 mg dose arms) in efficacy event rates with darexaban, but the study was underpowered for efficacy. Darexaban showed good tolerability without signs of liver toxicity. CONCLUSIONS: Darexaban when added to dual antiplatelet therapy after ACS produces an expected dose-related two- to four-fold increase in bleeding, with no other safety concerns but no signal of efficacy. Establishing the potential of low-dose darexaban in preventing major cardiac events after ACS requires a large phase III trial. ClinicalTrials.gov Identifier: NCT0099429

Management patterns of non-ST segment elevation acute coronary syndromes in relation to prior coronary revascularization

BACKGROUND: Contemporary guidelines support an early invasive strategy for non-ST elevation acute coronary syndrome (NSTE-ACS) patients who had prior coronary revascularization. However, little is known about the management pattern of these patients in real world. METHODS: We analyzed 3 consecutive Canadian registries (ACS I, ACS II, and Global Registry of Acute Coronary Events [GRACE]/expanded-GRACE) that recruited 12,483 NSTE-ACS patients from June 1999 to December 2007. We stratified the study population according to prior coronary revascularization status into 4 groups and compared their clinical characteristics, in-hospital use of medications, and cardiac procedures. RESULTS: Of the 12,483 NSTE-ACS patients, 71.2% had no prior revascularization, 14.2% had percutaneous coronary intervention (PCI) only, 9.5% had coronary artery bypass graft surgery (CABG) only, and 5% had both PCI and CABG. Compared to their counterparts without prior revascularization, patients with previous PCI and/or CABG were more likely to be male, to have diabetes, myocardial infarction, and heart failure but less likely to have ST-segment deviation or positive cardiac biomarker on presentation. Early use of evidence-based medications was higher among patients with previous PCI only and lower among patients with previous CABG only. After adjusting for possible confounders including GRACE risk score, prior PCI was independently associated with in-hospital use of cardiac catheterization (adjusted odds ratio [OR] 1.18, 95% CI 1.04-1.34, P = .008). In contrast, previous CABG was an independent negative predictor (adjusted OR .77, 95% CI 0.68-0.87, P \u3c .001). There was no significant interaction (P = .93) between previous PCI and CABG. CONCLUSIONS: The NSTE-ACS patients with previous PCI were more likely to be treated invasively. Conversely, patients with prior CABG less frequently received invasive therapy. Future studies should determine the appropriateness of this treatment discrepancy

In-hospital complications after invasive strategy for the management of Non STEMI: women fare as well as men

<p>Abstract</p> <p>Background</p> <p>To analyze the in-hospital complication rate in women suffering from non-ST elevation myocardial infarction treated with percutaneous coronary intervention (PCI) compared to men.</p> <p>Methods</p> <p>The files of 479 consecutive patients (133 women and 346 men) suffering from a Non STEMI (Non ST-segment elevation myocardial infarction) between the January 1^st2006 and March 21^st2009 were retrospectively analyzed with special attention to every single complication occurring during hospital stay. Data were analyzed using nonparametric tests and are reported as median unless otherwise specified. A p value < .05 was considered significant.</p> <p>Results</p> <p>As compared to men, women were significantly older (75.8 <it>vs</it>. 65.2 years; p < .005). All cardiovascular risk factors but tobacco and hypertension were similar between the groups: men were noticeably more often smoker (p < .0001) and women more hypertensive (p < .005). No difference was noticed for pre-hospital cardiovascular drug treatment. However women were slightly more severe at entry (more Killip class IV; p = .0023; higher GRACE score for in-hospital death - p = .008 and CRUSADE score for bleeding - p < .0001). All the patients underwent PCI of the infarct-related artery after 24 or 48 hrs post admission without sex-related difference either for timing of PCI or primary success rate. During hospitalization, 130 complications were recorded. Though the event rate was slightly higher in women (30% <it>vs</it>. 26% - p = NS), no single event was significantly gender related. The logistic regression identified age and CRP concentration as the only predictive variables in the whole group. After splitting for genders, these parameters were still predictive of events in men. In women however, CRP was the only one with a borderline p value.</p> <p>Conclusions</p> <p>Our study does not support any gender difference for in-hospital adverse events in patients treated invasively for an acute coronary syndrome without ST-segment elevation and elevated troponin.</p

Utility of Cardiac Magnetic Resonance to assess association between admission hyperglycemia and myocardial damage in patients with reperfused ST-Segment Elevation Myocardial Infarction

International audienceAbstract: Aims: to investigate the association between admission hyperglycemia and myocardial damage in patients with ST-segment elevation myocardial infarction (STEMI) using Cardiac Magnetic Resonance (CMR). Methods: We analyzed 113 patients with STEMI treated with successful primary percutaneous coronary intervention. Admission hyperglycemia was defined as a glucose level >= 7.8 mmol/l. Contrast-enhanced CMR was performed between 3 and 7 days after reperfusion to evaluate left ventricular function and perfusion data after injection of gadolinium-DTPA. First-pass images (FP), providing assessment of microvascular obstruction and Late Gadolinium Enhanced images (DE), reflecting the extent of infarction, were investigated and the extent of transmural tissue damage was determined by visual scores. Results: Patients with a supramedian FP and DE scores more frequently had left anterior descending culprit artery (p = 0.02 and < 0.001), multivessel disease (p = 0.02 for both) and hyperglycemia (p < 0.001). Moreover, they were characterized by higher levels of HbA(1c) (p = 0.01 and 0.04), peak plasma Creatine Kinase (p < 0.001), left ventricular end-systolic volume (p = 0.005 and < 0.001), and lower left ventricular ejection fraction (p = 0.001 and < 0.001). In a multivariate model, admission hyperglycemia remains independently associated with increased FP and DE scores. Conclusion: Our results show the existence of a strong relationship between glucose metabolism impairment and myocardial damage in patients with STEMI. Further studies are needed to show if aggressive glucose control improves myocardial perfusion, which could be assessed using CMR

Performance of non-invasive tests and histology for the prediction of clinical outcomes in patients with non-alcoholic fatty liver disease: an individual participant data meta-analysis

BACKGROUND: Histologically assessed liver fibrosis stage has prognostic significance in patients with non-alcoholic fatty liver disease (NAFLD) and is accepted as a surrogate endpoint in clinical trials for non-cirrhotic NAFLD. Our aim was to compare the prognostic performance of non-invasive tests with liver histology in patients with NAFLD. METHODS: This was an individual participant data meta-analysis of the prognostic performance of histologically assessed fibrosis stage (F0-4), liver stiffness measured by vibration-controlled transient elastography (LSM-VCTE), fibrosis-4 index (FIB-4), and NAFLD fibrosis score (NFS) in patients with NAFLD. The literature was searched for a previously published systematic review on the diagnostic accuracy of imaging and simple non-invasive tests and updated to Jan 12, 2022 for this study. Studies were identified through PubMed/MEDLINE, EMBASE, and CENTRAL, and authors were contacted for individual participant data, including outcome data, with a minimum of 12 months of follow-up. The primary outcome was a composite endpoint of all-cause mortality, hepatocellular carcinoma, liver transplantation, or cirrhosis complications (ie, ascites, variceal bleeding, hepatic encephalopathy, or progression to a MELD score ≥15). We calculated aggregated survival curves for trichotomised groups and compared them using stratified log-rank tests (histology: F0-2 vs F3 vs F4; LSM: 2·67; NFS: 0·676), calculated areas under the time-dependent receiver operating characteristic curves (tAUC), and performed Cox proportional-hazards regression to adjust for confounding. This study was registered with PROSPERO, CRD42022312226. FINDINGS: Of 65 eligible studies, we included data on 2518 patients with biopsy-proven NAFLD from 25 studies (1126 [44·7%] were female, median age was 54 years [IQR 44-63), and 1161 [46·1%] had type 2 diabetes). After a median follow-up of 57 months [IQR 33-91], the composite endpoint was observed in 145 (5·8%) patients. Stratified log-rank tests showed significant differences between the trichotomised patient groups (p<0·0001 for all comparisons). The tAUC at 5 years were 0·72 (95% CI 0·62-0·81) for histology, 0·76 (0·70-0·83) for LSM-VCTE, 0·74 (0·64-0·82) for FIB-4, and 0·70 (0·63-0·80) for NFS. All index tests were significant predictors of the primary outcome after adjustment for confounders in the Cox regression. INTERPRETATION: Simple non-invasive tests performed as well as histologically assessed fibrosis in predicting clinical outcomes in patients with NAFLD and could be considered as alternatives to liver biopsy in some cases. FUNDING: Innovative Medicines Initiative 2

Performance of non-invasive tests and histology for the prediction of clinical outcomes in patients with non-alcoholic fatty liver disease: an individual participant data meta-analysis.

BACKGROUND Histologically assessed liver fibrosis stage has prognostic significance in patients with non-alcoholic fatty liver disease (NAFLD) and is accepted as a surrogate endpoint in clinical trials for non-cirrhotic NAFLD. Our aim was to compare the prognostic performance of non-invasive tests with liver histology in patients with NAFLD. METHODS This was an individual participant data meta-analysis of the prognostic performance of histologically assessed fibrosis stage (F0-4), liver stiffness measured by vibration-controlled transient elastography (LSM-VCTE), fibrosis-4 index (FIB-4), and NAFLD fibrosis score (NFS) in patients with NAFLD. The literature was searched for a previously published systematic review on the diagnostic accuracy of imaging and simple non-invasive tests and updated to Jan 12, 2022 for this study. Studies were identified through PubMed/MEDLINE, EMBASE, and CENTRAL, and authors were contacted for individual participant data, including outcome data, with a minimum of 12 months of follow-up. The primary outcome was a composite endpoint of all-cause mortality, hepatocellular carcinoma, liver transplantation, or cirrhosis complications (ie, ascites, variceal bleeding, hepatic encephalopathy, or progression to a MELD score ≥15). We calculated aggregated survival curves for trichotomised groups and compared them using stratified log-rank tests (histology: F0-2 vs F3 vs F4; LSM: 2·67; NFS: 0·676), calculated areas under the time-dependent receiver operating characteristic curves (tAUC), and performed Cox proportional-hazards regression to adjust for confounding. This study was registered with PROSPERO, CRD42022312226. FINDINGS Of 65 eligible studies, we included data on 2518 patients with biopsy-proven NAFLD from 25 studies (1126 [44·7%] were female, median age was 54 years [IQR 44-63), and 1161 [46·1%] had type 2 diabetes). After a median follow-up of 57 months [IQR 33-91], the composite endpoint was observed in 145 (5·8%) patients. Stratified log-rank tests showed significant differences between the trichotomised patient groups (p<0·0001 for all comparisons). The tAUC at 5 years were 0·72 (95% CI 0·62-0·81) for histology, 0·76 (0·70-0·83) for LSM-VCTE, 0·74 (0·64-0·82) for FIB-4, and 0·70 (0·63-0·80) for NFS. All index tests were significant predictors of the primary outcome after adjustment for confounders in the Cox regression. INTERPRETATION Simple non-invasive tests performed as well as histologically assessed fibrosis in predicting clinical outcomes in patients with NAFLD and could be considered as alternatives to liver biopsy in some cases. FUNDING Innovative Medicines Initiative 2

Rationale and design of the GRACE (Global Registry of Acute Coronary Events) Project: a multinational registry of patients hospitalized with acute coronary syndromes

BACKGROUND: Acute coronary syndromes (ACS), including the spectrum of conditions from unstable angina to ST segment elevation myocardial infarction, represent a major cause of morbidity and mortality throughout the world. GRACE (the Global Registry of Acute Coronary Events) is a large, prospective, multinational observational study of patients hospitalized with ACS. The aim of GRACE is to improve the quality of care for patients with ACS by describing differences in, and relationships between, patient characteristics, treatment practices, and in-hospital and postdischarge outcomes at hospitals around the world. A goal of this study is to study approximately 10,000 patients with ACS on an annual basis. METHODS: A total of 18 cluster sites in 14 countries in North America, South America, Europe, Australia, and New Zealand are currently collaborating in GRACE. Clusters were chosen on the basis of local demographic characteristics and hospital facilities to ensure a representative sample of patients with ACS from each country. Patients are identified by use of either active or passive surveillance approaches. A standardized core case report form is completed for all patients. Information on patient demographics, medical history, acute symptoms, clinical characteristics, electrocardiographic findings, treatment approaches, and in-hospital outcomes is collected. Patients are followed up at 6 months after hospital discharge to identify recurrent coronary events, use of various medications, and mortality. CONCLUSIONS: The information collected from the GRACE project will provide important and extensive insights into patient demographic and clinical characteristics, current practice patterns, and outcomes for patients with ACS from a number of countries throughout the world. Given the pressures of practicing evidence-based medicine, the results of GRACE should provide a multinational perspective into these important outcomes and identify practice variations that will allow new opportunities to improve patient care