Abstract Background International guidelines recommend a systematic evaluation of bleeding risk in patients with atrial fibrillation (AF) to guide oral anticoagulation. However, it remains challenging to accurately predict bleeding risk. The biomarker-based ABC-AF-bleeding risk score to predict bleeding in anticoagulated patients with AF has shown promise. Purpose To evaluate the performance of the biomarker-based ABC-AF-bleeding risk score and compare its performance with other bleeding risk scores in 31,605 patients randomized to direct oral anticoagulant or warfarin using individual patient data from three randomized clinical trials. Methods The COMBINE AF biomarker data set contains individual patient data from three pivotal randomized trials (ARISTOTLE, ENGAGE AF-TIMI 48, and RE-LY) comparing apixaban, edoxaban or dabigatran with warfarin, in patients with AF at increased risk of stroke. The ABC-AF-bleeding biomarkers were analyzed in plasma samples collected at baseline (hemoglobin, troponin T high-sensitivity, and GDF-15) using Roche Diagnostics Elecsys assays. The biomarker-based ABC-AF-bleeding risk score (Age, Biomarkers, Clinical history of prior bleeding) was calculated as previously published. The discrimination was assessed by Harrell’s c index and compared with three clinically based bleeding risk scores; HASBLED, ORBIT, and DOAC. Results During a median follow-up time of 2.0 years, a total of 1,572 ISTH major bleeding events occurred (incidence rate per 100 person-years of 2.79) including 593 gastrointestinal (1.04) and 270 intracranial (0.47) bleeding events. The biomarker-based ABC-AF-bleeding score was well calibrated for major bleeding in the total material (Figure). The c indices for major bleeding were 0.68 (95% confidence interval 0.67-0.70), for gastrointestinal bleeding 0.70 (0.68-0.72), and for intracranial bleeding 0.66 (0.63-0.69). The biomarker-based ABC-AF-bleeding risk score provided superior discrimination compared with the clinically based risk scores in the full cohort (Table). The ABC-AF-bleeding risk score also provided superior discrimination for major bleeding in clinically relevant subgroups based on age, sex, body mass index, coronary artery disease, diabetes, heart failure, kidney function, and irrespective of DOAC or VKA use. Conclusions In patients with AF treated with different types of OAC the biomarker-based ABC-AF-bleeding score provide better discrimination of the risk för major bleeding than risk scores based only on clinical factors. The results were consistent for different types of bleeding and across multiple subgroups. There was good calibration when comparing predicted vs observed rate of major bleeding. These findings support the utility of the biomarker-based ABC-AF-bleeding risk score for advancing precision medicine in patients with AF.Calibration of ABC-AF-bleeding scoreTable

Abstract Background/Introduction Patients with atherosclerotic vascular disease are at heightened risk of ischemic events, including adverse limb events. The pathobiology of adverse limb events ranges from events that are predominantly thrombotic such as acute limb ischemia (ALI) to those that are due primarily to progressive atherosclerosis such as worsening functional imitation requiring elective peripheral revascularization and development of critical limb ischemia (CLI). Evolving data suggest that lipoprotein(a) [Lp(a)] may be associated with the risk of adverse limb events; however, which type of events are related to Lp(a) has not been well described. Purpose To evaluate the association between Lp(a) and specific limb outcomes in patients with stable atherosclerotic vascular disease. Methods Data from two randomized clinical trials including patients with stable atherosclerotic vascular disease were combined: TRA2P-TIMI 50 and FOURIER. We measured Lp(a) in baseline samples in the TIMI Clinical Trials Laboratory. Major adverse cardiovascular events (CV death, myocardial infarction (MI), or stroke) were the primary or key secondary outcomes of the trials. Peripheral revascularization procedures occurring during follow up were investigator reported. Adverse limb events, including CLI and ALI, were categorized through the review of safety data by two blinded vascular specialists. MALE was defined as the composite of peripheral revascularization, CLI, or ALI. The association of Lp(a) as a continuous variable and MALE was assessed and adjusted for randomized therapy in each trial, age, sex, race, region, prior MI, prior stroke, peripheral artery disease, hypertension, diabetes mellitus, smoking status, and statin use. Results A total of 28,892 patients were included in the combined analysis population. The median Lp(a) was 36 nmol/L (IQR 12 – 159). A total of 1336 MALE events occurred during follow-up, including 1307 peripheral revascularizations (1237 elective, 173 urgent), 259 CLI events, and 148 ALI events. Lp(a) was associated with an increased risk of MALE (Adj HR 1.07 per SD, 95% CI 1.02 – 1.13, p=0.007, Figure Panel A) with the risk of a similar magnitude for that of MACE (Adj HR 1.05 per SD, 95% CI 1.01 – 1.10, p=0.020). The association of Lp(a) and MALE was driven by peripheral revascularizations including elective revascularization (Adj. HR 1.07, 95% CI 1.02 – 1.13, p=0.010) with a consistent trend for CLI; however, a relationship with ALI was unclear (Figure Panel B). Conclusion In patients with stable atherosclerotic vascular disease, Lp(a) is associated with MALE with the relationship driven by peripheral revascularization and a consistent trend for CLI. Any relationship with ALI, a primarily thrombotic event, is less clear. Overall, these data support the relationship of Lp(a) and progression of lower extremity atherosclerosis.Figure Panel AFigure Panel B

Abstract Background In hemodynamically stabilized patients with acute decompensated heart failure (ADHF) enrolled in the PIONEER-HF trial, compared with enalapril, sacubitril/valsartan started in-hospital and continued for 8 weeks was well tolerated, achieved a greater reduction in NT-proBNP, and reduced cardiovascular death or rehospitalization for HF. Nearly 1/2 of patients achieved the target dose of blinded study drug. We performed an exploratory analysis of the safety and efficacy of sacubitril/valsartan according to the dose level dispensed at 4 weeks in PIONEER-HF Methods PIONEER-HF was a randomized, double-blind, active-controlled trial of sacubitril/valsartan vs. enalapril in 881 hospitalized ADHF pts following hemodynamic stabilization. Blinded study medication was administered for 8-weeks, with initial dosing selected based on the systolic blood pressure (SBP) at randomization (starting dose 24/26 or 49/51 mg twice daily vs 2.5 or 5 mg twice daily) and titrated toward a target of sacubitril/valsartan 97 mg/103 mg twice daily, or enalapril 10 mg twice daily with an algorithm using SBP along w/ the investigator's assessment of tolerability. Results At the week 4 visit, 199 patients (45.2%) in the sacubitril/valsartan group and 210 (47.6%) in the enalapril group were dispensed the target dose. Baseline characteristics were similar in the 2 treatment groups within each dose level. The prespecified adverse events of special interest were similar between sacubitril/valsartan and enalapril irrespective of dose level (Table) with no significant heterogeneity. In addition, there was no heterogeneity across dose levels in the favorable effect of sacubitril/valsartan on the change in NTproBNP by week 8 (Table, p-interaction=0.54) or the serious composite endpoint (p-interaction=0.71). Efficacy and Safety by Dose-Tier Conclusion In hemodynamically stabilized patients with ADHF, the safety and efficacy of sacubitril/valsartan appears generally consistent among patients at various dose levels. Acknowledgement/Funding Novartis Pharmaceuticals

In stable patients with a history of atherosclerosis, the investigational protease-activated receptor (PAR)-1 antagonist vorapaxar was effective at reducing further atherothrombotic events. This article presents data from the Thrombin Receptor Antagonist in Secondary Prevention-TIMI 50 Trial [TRA 2P; NCT00526474] which showed that vorapaxar significantly reduced the risk of deaths from cardiovascular disease, myocardial infarction, or stroke compared with placebo.

Objective. We sought to validate 3 methods for automated safety monitoring by evaluating clinical trials with elevated adverse events. Methods. An automated outcomes surveillance system was used to retrospectively analyze data from 2 randomized, TIMI multicenter trials. Trial A was stopped early due to elevated 30-day mortality rates in the intervention arm. Trial B was not stopped early, but there was transient concern regarding 30-day intracranial hemorrhage rates. We compared statistical process control (SPC), logistic regression risk adjusted SPC (LR-SPC), and Bayesian updating statistic (BUS) methods with a standard prospective 2-arm event rate analysis. Each method compares observed event rates to alerting boundaries established with previously collected data. In this evaluation, the control arms approximated prior data, and the intervention arms approximated the observed data. Results. Trial A experienced elevated 30-day mortality rates beginning 7 months after the start of the trial and continuing until termination at month 14. Trial B did not experience elevated major bleeding rates. Combining the alerting performance of each method across both trials resulted in sensitivities and specificities of 100% and 85% for SPC, 0% and 100% for BUS, and 100% and 93% for both LR-SPC models, respectively. Conclusion. Both SPC and LR-SPC methods correctly identified the majority of months during which the cumulative event rates were elevated in trial A but were susceptible to false positive alerts in trial B. The BUS method did not result in any alerts in either trial and requires revision.