Thrombolysis in Myocardial Infarction Study Group

Antiphospholipid antibodies (aPL) are directed against phospholipids and phospholipid-binding proteins. Laboratory assays used to detect aPL include serological tests for aPL against β2-glycoprotein 1, cardiolipin and other molecules, as well as functional assays for lupus anticoagulant. The presence of aPL can lead to endothelial dysfunction or a hypercoagulable state through prothrombotic and antifibrinolytic mechanisms. These processes, often in conjunction with a 'second hit', such as trauma, surgery, or other causes of hypercoagulability or stasis, can lead to venous or arterial thrombosis. The thrombotic risk associated with aPL is best recognized in thrombotic antiphospholipid syndrome, characterized by a persistently positive test for lupus anticoagulant or seropositivity for aPL associated with venous, arterial or microvascular thrombosis. However, aPL seropositivity and its clinical effect on thrombotic events have been increasingly recognized in a broader group of individuals who do not meet traditional research criteria for thrombotic antiphospholipid syndrome. In this Review, we provide an overview of the evidence related to aPL seropositivity in individuals with or without previous thrombosis and the clinical relevance of aPL seropositivity in predicting the risk of thrombotic cardiovascular events. We discuss potential management strategies and identify key knowledge gaps that warrant further research.

We performed an individual patient data analysis of COMBINE AF to assess differences in 14 clinically relevant outcomes between patients with paroxysmal (PAF) vs. non-PAF. Cox-proportional-hazards models stratified by trial and adjusted for CHA2DS2-VASc elements were constructed. Sensitivity analyses were performed across subgroups. Among 71,466 patients with AF, 16,609 (23 %) had PAF. The overall follow-up period was 157,225 patient-years (median 2.2 years). Compared with non-PAF patients, PAF patients were more likely to be women (43 % vs 35 %), have prior coronary artery disease (35 % vs 31 %), and use aspirin (41 % vs 32 %), but were less likely to be Asian (12 % vs 15 %) or have CHA₂DS₂-VASc ≥4 (59 % vs 60 %) (all p<0.01). In adjusted analyses, PAF was associated with a lower risk of stroke/systemic embolic event (HR, 0.81; 95 % CI, 0.73-0.90; p<0.001) and all-cause death (HR, 0.81; 95 % CI, 0.75-0.86; p<0.001), but higher risk of major or clinically relevant non-major bleeding (HR, 1.07; 95 % CI, 1.02-1.13; p=0.005). Risk of myocardial infarction was numerically higher in PAF (HR, 1.15; 95 % CI, 1.00-1.32; p=0.057). Major bleeding risk was similar between groups (HR, 1.04; 95 % CI, 0.96-1.12; p=0.36). Findings were consistent across subgroups, trials, anticoagulant types, and sensitivity analyses. Compared to non-PAF, adjusted risks in PAF patients were lower for stroke/systemic embolic event and all-cause death, and higher for major or clinically relevant non-major bleeding and myocardial infarction.These findings highlight clinically important differences in outcomes by AF type that may have clinical applications for AF patients.

Acute coronary syndromes are caused by obstructive coronary thrombosis complicating myocardial ischaemic disease and are dichotomously classified according to their electrocardiographic presentation as ST-segment elevation myocardial infraction or non-ST-segment elevation acute coronary syndrome, either without or with elevated myocardial necrosis markers. Initial diagnosis and risk stratification are reliably guided by symptoms, electrocardiographic changes, and troponin elevation and require exclusion of alternative conditions, such as Type 2 myocardial infarction and myocardial injury due to systemic conditions. Timely coronary angiography is a key component of the initial diagnosis to assess the presence of occlusive coronary artery disease, rather than an myocardial infarction with non-occluded coronary arteries, and the suitability for revascularization. While clinical trials with randomization prior to angiography have shown reduction in recurrent myocardial infarction and urgent revascularization with a neutral effect on mortality from an early invasive approach, increased revascularization rates have been systematically associated with reduced mortality in registries and administrative databases. Complete revascularization in patients with multivessel disease has been shown to reduce mortality compared with culprit-only revascularization. The safety of this approach has been shown even in fragile, elderly, and multimorbid patients. Post-acute treatment should be focused on patient-tailored antithrombotic therapy and disease-modifying secondary prevention approaches. This review describes the complex spectrum of non-ST-segment elevation acute coronary syndrome and the importance of complete clinical and coronary angiographic assessment for optimal patient-centred treatment.

BackgroundZalunfiban is a glycoprotein IIb/IIIa (integrin αIIbβ3) inhibitor designed for subcutaneous administration on first medical contact with patients with suspected ST-segment elevation myocardial infarction (STEMI).MethodsAn international, double-blind, placebo-controlled trial randomly assigned patients with STEMI in a 1:1:1 ratio to receive a single subcutaneous injection of zalunfiban (0.11 mg/kg or 0.13 mg/kg) or placebo. The primary efficacy end point was a hierarchical proportional odds model ranking seven end points from worst to best: all-cause death, stroke, recurrent myocardial infarction, acute stent thrombosis, new-onset or rehospitalization for heart failure, larger infarct size, or no end point through 30 days. The primary safety end point was the occurrence of severe or life-threatening bleeding as per the global use of strategies to open occluded coronary arteries (GUSTO) criteria.ResultsThe trial randomly assigned 2467 patients (853 to zalunfiban 0.11 mg/kg, 818 to zalunfiban 0.13 mg/kg, and 796 to placebo). The primary efficacy end point was significantly improved by zalunfiban (adjusted odds ratio 0.79; 95% confidence interval, 0.65 to 0.98; P=0.028). GUSTO severe bleeding was similar between those who received zalunfiban versus placebo (1.2% vs. 0.8%; P=0.40), but GUSTO mild to moderate bleeding was increased (6.4% vs. 2.5%; P<0.001). Angiography showed faster coronary blood flow with zalunfiban versus placebo (corrected frame count of the infarct-related artery 109 [interquartile range 35 to 176] vs. 176 [interquartile range 40 to 176]; P=0.012).ConclusionsIn patients with STEMI, zalunfiban administered at first medical contact significantly improved preintervention infarct-related patency and reduced the likelihood of a worse 30-day multicomponent hierarchical clinical end point. Zalunfiban was not associated with increased severe or life-threatening bleeding but was associated with increased mild to moderate bleeding. (Funded by CeleCor Therapeutics; CELEBRATE ClinicalTrials.gov number, NCT04825743.)

Bolus thermodilution is the most commonly used invasive assessment for coronary microvascular dysfunction (CMD). However, variability in thermodilution transit time measurements (TTM) affects calculated Coronary Flow Reserve (CFR) and Index of Microvascular Resistance (IMR) values. This study determined variables associated with transit time variability and quantified confidence intervals for the range of measured CFR and IMR values. The CoroFlow Cardiovascular System (Coroventis, Sweden) and PressureWire™ X Guidewire (Abbott) were used to collect 2541 TTM from 259 vessels at 14 US sites included in the FlowLab Study. Correlations with baseline patient and procedural variables were determined by both linear and mixed linear models. Mixed linear models with the physician or vessel as the random effect were computed. Monte Carlo simulations of CFR and IMR were performed to determine 95% confidence intervals for thresholds of 2.5 for CFR and 25 for IMR. Mixed linear analysis with vessel as the random effect provided the best model fit (R2 = 0.948). In this model, RCA vessel location (p < 0.001) and pressure sensor distance < 5 cm (p < 0.005) were significantly associated with transit time. Monte Carlo simulations identified a "gray zone" range of 2.1-3.1 for CFR and 19-31 for IMR. Minimizing variability in invasive CMD assessment is essential for improving diagnostic accuracy and guiding clinical decision-making as testing becomes more widespread. In this study, target vessel choice (RCA) and pressure sensor placement were identified as key modifiable sources of transit time variability. Clinically applicable confidence intervals around CFR and IMR values were defined.

Combining multiple studies for evidence synthesis can improve the precision of effect estimates and enable investigation of more granular clinical research questions. However, individual participant data (IPD) meta-analyses are often limited by the presence of systematically missing covariates that are only available in a subset of studies. Common solutions include removing missing covariates from the analyses or excluding studies that have not collected the missing covariates. Both approaches risk losing valuable information and introducing bias. Two additional approaches have been proposed: bivariate meta-analysis and multiple imputation of systematically missing data. The potential advantages and performances of these approaches, however, have only been discussed using simulation studies. In this analysis, we used data from five large cardiovascular clinical trials and illustrate the advantages and applicability of these two approaches in retaining missing covariates across various scenarios of increased complexity as compared to the more common approaches of excluding the covariates or the studies. Our results showed that both bivariate meta-analysis and multiple imputation of systematically missing data preserve information and improve the precision of the combined estimates. The findings underscore the importance of retaining information that is otherwise lost due to systematically missing values.

Optimizing second-line therapy for type 2 diabetes is challenging due to interindividual variability in response. We conducted a pharmacogenomic genome-wide association study (GWAS) in the Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness (GRADE) Study to identify genetic predictors of glycemic response to insulin glargine, glimepiride, liraglutide, and sitagliptin, when added to metformin in a diverse population. We identified 21 genome-wide significant loci associated with treatment response. rs1905505, a non-coding variant near SLC2A2, the gene encoding the glucose transporter GLUT2, was enriched in Africans/African Americans and conferred a 36% increased risk of treatment failure on glimepiride (p=4.83×10). Carriers had impaired β-cell function, evidenced by a lower C-peptide index during OGTT, and diminished glucose-lowering response to an acute sulfonylurea challenge. Genetic manipulation in zebrafish confirmed that slc2a2 disruption attenuates the glucose-lowering effect of glimepiride. In conclusion, genetic variation influences glycemic response to medications, with SLC2A2 emerging as a key determinant of sulfonylurea response.Clinical Trial registration number:NCT01794143