Currently, no sensitive, widely available, rapid turnaround assays to measure the effect on coagulation of direct oral anticoagulants exist.The point-of-care ClotChek (Perosphere Technologies Inc.) coagulometer was developed to address this unmet need with high sensitivity and precision. This proof-of-concept study aimed to determine normal clotting time in healthy, non-anticoagulated subjects; summarize clotting times at trough and peak drug concentrations in patients taking apixaban and rivaroxaban; and identify cut-points that maximize both sensitivity and specificity for predicting whether an individual is meaningfully anticoagulated.In 141 normal subjects, the mean clotting time was 244.2 ± 25.8 seconds (median 244.0 seconds; range 183-296 seconds). In 39 patients on apixaban, mean clotting times were 293.9 ± 32.5 seconds at trough and 323.1 ± 27.9 seconds at peak. In 42 patients on rivaroxaban, mean clotting times were 287.8 ± 44.9 seconds at trough and 380.4 ± 41.2 seconds at peak. Strong positive correlations are seen between the anticoagulant drug response determined by the assay and anticoagulant drug levels for apixaban (Spearman's rho = 0.74, p < 0.0001) and for rivaroxaban (Spearman's rho = 0.82, p < 0.0001). ClotChek clotting times showed good sensitivity and specificity to identify meaningful anticoagulation (>75 ng/mL) among patients taking apixaban (AUC = 0.91, 83% sensitivity, 86% specificity) or rivaroxaban (AUC = 0.96, 91% sensitivity, 90% specificity). Similar results were seen using the lower threshold of >30 ng/mL.These results require clinical validation in further studies but suggest that the ClotChek assay could aid physicians at the point of care in making therapeutic decisions in patients with adverse events associated with oral factor Xa inhibitors.

Background Whether frail, elderly patients with atrial fibrillation (AF) on a vitamin K antagonist (VKA) should switch to a direct-acting oral anticoagulant (DOAC) was studied in the FRAIL-AF trial and remains controversial. Objectives The purpose of this study was to evaluate, in the COMBINE-AF data set, the impact on clinical outcomes of switching frail, elderly AF patients from VKA to DOAC. Methods COMBINE-AF consists of individual patient-level data from 71,683 patients with AF in 4 randomized clinical trials comparing DOAC vs warfarin. Frailty was evaluated using a frailty index derived from a modified Rockwood’s Accumulation Model including 18 age-related conditions. Patients with a frailty index score above the median were considered frail. Prespecified outcomes were stroke or systemic embolic events, bleeding events, death, and a net clinical outcome combining these events. Results We identified 5,913 patients who were frail, elderly (age ≥75 years), and VKA-experienced and 52,721 patients who did not meet all 3 of these criteria. Patients were randomized to a standard-dose (SD) DOAC or warfarin. After 27 months median follow-up, there was no heterogeneity in treatment effect with SD-DOAC vs warfarin among those who met all 3 criteria vs those who did not for the endpoints of stroke or systemic embolic events (HR: 0.83 vs 0.81; Pint = 0.75) or for death (HR: 0.95 vs 0.91; Pint = 0.54). Major bleeding was similar with SD-DOAC vs warfarin in frail, elderly, VKA-experienced patients (HR: 1.06 [95% CI: 0.90-1.25]), while it was significantly reduced with SD-DOAC in patients without all 3 criteria (HR: 0.82 [95% CI: 0.76-0.89]; Pint = 0.007). Likewise, the net clinical outcome was similar in the frail, elderly, VKA-experienced patients with SD-DOAC vs warfarin (HR: 1.01 [95% CI: 0.91-1.13]), while significantly reduced with SD-DOAC patients without all 3 criteria (HR: 0.89 [95% CI: 0.85-0.93]; Pint = 0.028). Fatal and intracranial bleeding were significantly reduced with SD-DOAC in both subgroups to a similar degree (both Pint > 0.05), while gastrointestinal bleeding with SD-DOAC was increased to a greater degree in frail, elderly, VKA-experienced patients (HR: 1.83 [95% CI: 1.42-2.36]) compared with those without all 3 criteria (HR: 1.23 [95% CI: 1.09-1.39]; Pint = 0.006). Conclusions Frail, elderly, VKA-experienced patients with AF switched to SD-DOAC experienced significant reductions in stroke or systemic embolism, fatal and intracranial bleeding, and death. Gastrointestinal bleeding was increased with SD-DOAC, while major bleeding and the primary net clinical outcome were similar. Based on these findings, SD-DOAC is a reasonable choice for frail, elderly, VKA-experienced patients to reduce stroke and systemic embolism, death, and the most serious types of bleeding.

OBJECTIVE To evaluate the clinical efficacy of intensive LDL cholesterol (LDL-C) lowering in type 1 diabetes mellitus (T1DM). RESEARCH DESIGN AND METHODS Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) randomized participants with atherosclerotic cardiovascular disease (ASCVD) on statins to evolocumab or placebo (median follow-up 2.2 years). The primary end point (PEP) was cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. RESULTS Of 27,564 participants, 10,834 (39.3%) had type 2 diabetes mellitus (T2DM), and 197 (0.7%) had T1DM. In the placebo arm, there was a stepwise increase in the 2.5-year PEP Kaplan-Meier rate from 11.0% to 15.2% to 20.4% in participants with no diabetes, T2DM, and T1DM, respectively (P < 0.0001). Hazard ratios for PEP with evolocumab were 0.87 (95% CI 0.79-0.96), 0.84 (0.75-0.93), and 0.66 (0.32-1.38) in the no diabetes, T2DM, and T1DM groups, and absolute risk reduction was 1.3%, 2.5%, and 7.3%, respectively. CONCLUSIONS Intensive LDL-C lowering may provide substantial clinical benefit in individuals with T1DM and ASCVD. Additional randomized controlled cardiovascular outcomes trials are needed in this population.

Importance:Chronic kidney disease is common in patients with atrial fibrillation (AF) and is associated with higher rates of bleeding with anticoagulation. In the AZALEA-TIMI 71 randomized clinical trial, abelacimab, a novel factor XI inhibitor, reduced rates of major or clinically relevant nonmajor (CRNM) bleeding compared with rivaroxaban in patients with AF. Objective:To examine the safety of abelacimab vs rivaroxaban across a range of kidney function. Design, Setting, and Participants:The AZALEA-TIMI 71 study randomized patients with AF to 1 of 2 abelacimab doses (150 mg or 90 mg monthly) or to rivaroxaban, with stratification by creatinine clearance (CrCl). Patients with CrCl less than 15 mL/min or receiving dialysis were excluded. This secondary analysis of AZALEA-TIMI 71 examines outcomes by randomized treatment and CrCl at randomization. Intervention:Patients randomized to rivaroxaban with a CrCl greater than 50 mL/min received rivaroxaban, 20 mg, daily, and those with a CrCl of 50 mL/min or less received rivaroxaban, 15 mg, daily. Patients randomized to abelacimab received the assigned dose irrespective of CrCl. Main Outcomes and Measure:The primary outcome was major bleeding or CRNM bleeding. Results:Among 1284 patients, median (IQR) age was 74 (69-78) years and 572 patients (44.5%) were female. Median (IQR) CrCl was 71 (54-90) mL/min, with 264 patients (20.6%) having a CrCl of 50 mL/min or less. In the rivaroxaban group, patients with CrCl of 50 mL/min or less experienced higher rates of major or CRNM bleeding compared with those with CrCl greater than 50 mL/min despite dose reduction (incidence rates, 13.6 vs 7.0 per 100 person-years). Abelacimab reduced major or CRNM bleeding vs rivaroxaban irrespective of CrCl (CrCl ≤50 mL/min: hazard ratio [HR], 0.26; 95% CI, 0.12-0.54; >50 mL/min: HR, 0.40; 95% CI, 0.26-0.62; P value for interaction = .33), with absolute risk reductions of 10.1 vs 4.2 per 100 person-years in those with CrCl of 50 mL/min or less vs greater than 50 mL/min, respectively (P value for interaction = .09). This risk reduction was consistent for major bleeding alone and for a broader composite inclusive of major, CRNM, and minor bleeding. Results were similar when comparing the individual abelacimab doses to rivaroxaban. Conclusions and Relevance:In this secondary analysis of the AZALEA-TIMI 71 randomized clinical trial, abelacimab consistently reduced the risk of bleeding relative to rivaroxaban irrespective of kidney function. These findings suggest that abelacimab may offer a particularly favorable safety profile among those with chronic kidney disease; however, larger studies are necessary to characterize the efficacy of abelacimab for stroke prevention in AF.

Background:Inflammation plays a central role in the pathophysiology of ST-elevation myocardial infarction (STEMI), being associated with larger infarct size (IS) and worse left ventricular remodeling (LVR). Methotrexate (MTX) is a potent anti-inflammatory drug with potential benefits in the treatment of STEMI. Experimental studies have suggested that a formulation of MTX incorporated into lipid nanoemulsion (LDE-MTX) could be beneficial and safe. Objectives:To evaluate the efficacy and safety of LDE-MTX in patients with STEMI. Methods:Randomized, double-blinded, placebo-controlled, proof-of-concept study. Patients were randomized 4 ± 2 days after first anterior STEMI to receive LDE-MTX (40 mg/m2 intravenous infusion) or LDE-placebo weekly for 6 weeks. The primary efficacy endpoint was left ventricle end-diastolic volume (LVEDV) assessed by cardiac magnetic resonance at 90 ± 7 days post-randomization; the main secondary endpoints were changes in LVEDV, other LVR parameters and IS. Results:Due to the COVID-19 pandemic the study was stopped prematurely, with 32 randomized patients (15 LDE-placebo, 17 LDE-MTX) completing the protocol. At 90 days, there was no difference in LVEDV between groups. Among other secondary endpoints, there appeared to be a greater reduction of IS (%LV) in favor of the LDE-MTX group (-3.9 ± 6.9 vs -9.4 ± 8.4, p = 0.030). LDE-MTX was well tolerated. Conclusions:In patients with STEMI, LDE-MTX appears to be safe but did not influence LVEDV and other LVR parameters, although it possibly reduced infarct size at 90 days. These hypothesis-generating results support further investigation of a novel nanomedicine approach to STEMI in larger trials.

Background: Abdominal aortic aneurysm (AAA) is a common and potentially fatal condition when rupture occurs. Current US guidelines recommend screening by ultrasound in men aged 65–75 with a smoking history. However, AAA remains underdiagnosed using these limited clinical criteria, underscoring the need to explore additional risk factors. We evaluated whether the addition of a polygenic risk score (PRS) for AAA helps identify individuals at higher risk among patients with established cardiometabolic disease. Methods: A genetic analysis was performed by pooling individual patient-level data from 3 TIMI trials (FOURIER, ENGAGE-AF and PEGASUS). AAA events were reported by investigators as adverse events, and blinded study physicians independently reviewed and confirmed all cases. We utilized a recently validated AAA PRS (Nat Genet, 2023) and assessed its association with AAA using Cox proportional hazard models adjusted for age, sex, smoking, history of ASCVD, HTN, hyperlipidemia, DM, trial and ancestry (PC1–5). PRS was analyzed continuously (per 1-SD) and categorically (high [top 20%], intermediate [middle 60%], low [bottom 20%]). Results: A total of 39,960 patients were included (median f/u 2.6 years). Individuals in higher PRS categories had a higher rate of AAA events over time ( Figure 1A ). Even after adjusting for clinical risk factors, a 1-SD higher PRS was independently associated with a 54% higher risk of AAA (HR-adj 1.54 [95% CI 1.35–1.76], p<0.001). Compared with low PRS, an intermediate PRS was associated with a 2-fold risk (HR-adj 2.03 [1.23–3.34], p<0.001), and a high PRS with a 3-fold risk (HR-adj 3.12 [1.82–5.36], p<0.001). The magnitude of risk conferred by a high PRS was comparable to traditional clinical risk factors ( Figure 1B ). Coclusion: In patients with cardiometabolic disease, an AAA PRS was independently associated with risk of AAA events, with a magnitude of risk on par with traditional clinical risk factors.

BACKGROUND:Combining antiplatelet therapy (APT) with conventional anticoagulants increases the risk of bleeding. In the AZALEA-TIMI 71 trial (Safety and Tolerability of Abelacimab [MAA868] vs Rivaroxaban in Patients With Atrial Fibrillation), the novel factor XI inhibitor abelacimab significantly reduced the risk of bleeding compared with rivaroxaban in patients with atrial fibrillation. Whether the safety of combination antithrombotic therapy differs in the context of factor XI inhibition has not been well characterized. METHODS:This prespecified analysis of AZALEA-TIMI 71, which randomized patients between March and December of 2021 to 1 of 2 subcutaneous monthly abelacimab doses (90 or 150 mg) or oral rivaroxaban (20 mg daily, dose reduced to 15 mg in patients with creatinine clearance ≤50 mL/min), stratified patients by planned use of concomitant APT. The primary composite end point of major or clinically relevant nonmajor bleeding and other safety and efficacy outcomes were examined by concomitant APT and randomized treatment. RESULTS:Of 1287 patients (44% female; median age 74 years [interquartile range, 69-78]), 318 (24.7%) were on APT at baseline with planned continuation (15.5% aspirin only, 7.5% P2Y12 inhibitor only, and 1.6% dual APT). In the rivaroxaban arm, the rate of major or clinically relevant nonmajor bleeding was 10.6 per 100 patient-years with concomitant APT versus 7.7 per 100 patient-years without. In the abelacimab arms, the rates were 2.5 and 3.5 per 100 patient-years for the 90-mg and 150-mg doses, respectively, with concomitant APT and 2.7 and 3.1 per 100 patient-years without. Each abelacimab dose significantly reduced major or clinically relevant nonmajor bleeding compared with rivaroxaban, both in those with concomitant APT (adjusted hazard ratio, 0.26 [95% CI, 0.10-0.70] and 0.30 [95% CI, 0.12-0.74] for 90 mg and 150 mg of abelacimab, respectively, versus rivaroxaban) and in those without concomitant APT (adjusted hazard ratio, 0.34 [95% CI, 0.19-0.60] and 0.40 [95% CI, 0.23-0.68] for 90 mg and 150 mg of abelacimab, respectively; Pinteractions=0.56 and 0.60, respectively). Patients with concomitant APT tended to derive greater absolute risk reductions with abelacimab (8.1 and 7.1 for 90 mg and 150 mg of abelacimab, respectively, versus rivaroxaban) than those without concomitant APT (5.0 and 4.6, respectively). CONCLUSIONS:Inhibition of factor XI with abelacimab consistently reduced bleeding compared with rivaroxaban regardless of concomitant APT use, with greater absolute reductions in bleeding in those requiring concomitant APT. These data suggest that factor XI inhibition may be a safe anticoagulant option in patients with atrial fibrillation requiring concomitant APT. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT04755283.

BACKGROUND:Severe hypertriglyceridemia (HTG), defined as a serum triglyceride (TG) concentration ≥500 mg/dl, is present in approximately 1 in every 100 individuals and carries direct clinical consequences, including pancreatitis, which can be life-threatening. Olezarsen is an investigational antisense oligonucleotide targeted to the mRNA for apolipoprotein C-III (apoC-III), a protein known to impair TG clearance by inhibiting lipoprotein lipase and the hepatic uptake of triglyceride-rich remnants. No dedicated trial has tested olezarsen in patients with severe HTG. METHODS:In these 2 pivotal phase 3 trials, CORE-TIMI 72a and CORE2-TIMI 72b, patients with severe HTG were randomized in a 2:1 fashion to either olezarsen (80 mg or 50 mg dose) or matching placebo. Patients will be treated for a total of 12 months and evaluated for the primary endpoint of percent change in TGs from baseline to 6 months compared with placebo. Pooled analyses of CORE and CORE2 will also assess olezarsen's effect on acute pancreatitis events and change in hepatic steatosis. RESULTS:A total of 617 subjects in CORE-TIMI 72a and 446 subjects in CORE2-TIMI 72b were randomized. In these 2 trials, the median age was 54 and 55 years, women made up 24% and 23% of the study population, and the baseline TGs were 836 mg/dl and 749 mg/dl, respectively. A total of 333 subjects, 129 from CORE-TIMI 72a and 204 from CORE2-TIMI 72b, were enrolled in the hepatic MRI substudy. DISCUSSION:Together, CORE-TIMI 72a and CORE2-TIMI 72b are designed to establish the efficacy and safety of olezarsen in patients with severe HTG. TRIAL REGISTRATION:Clinicaltrials.gov: NCT05079919 and NCT05552326.

BACKGROUND: Patients with prior ischemic stroke are at high risk for recurrent stroke and other major adverse cardiovascular events (MACE). The incremental benefit of achieving very low LDL-C in such patients remains undefined. HYPOTHESIS: In stable ASCVD patients with prior ischemic stroke, achieving very low LDL-C is associated with a lower risk of MACE without an excess in hemorrhagic stroke. METHODS: Participants with history of ischemic stroke were selected for the current analysis from the FOURIER trial, a randomized placebo-controlled trial studying evolocumab in patients with stable ASCVD (median follow-up 2.2 years) and the open-label extension study (median follow-up extended by 5 years) at participating sites. Using a modified-Poisson regression models, we examined the relationship between achieved LDL-C with the incidences of the composite primary endpoint (CV death, myocardial infarction, stroke, and hospitalization for unstable angina or coronary revascularization) and stroke-related endpoints (all type, ischemic, and hemorrhagic) adjusted for clinical covariates. RESULTS: A total of 5,291 patients with history of ischemic stroke, occurring at a median of 3.3 years prior to enrollment, were followed for a total of 14,418 patient years (max follow-up 8.6 years). Median achieved LDL-C with evolocumab was 31.5 mg/dl (IQR 21.5-47.0 mg/dL). Patients with lower achieved LDL-C (modeled continuously) exhibited significantly lower annualized incidence rates (IR) of the primary composite endpoint (P trend <0.001, panel A). When LDL-C was modeled categorically, the lowest IRs for the primary endpoint and for stroke were observed in patients whose achieved LDL-C was below 40 mg/dl, whereas there was no difference in hemorrhagic stroke (panel B). CONCLUSION: In patients with prior ischemic stroke, achieving very low LDL-C (<40 mg/dl) was associated with a lower long-term risk of MACE, including recurrent stroke, without an increase in hemorrhagic stroke. These findings suggest to lower LDL-C target in patients with prior ischemic stroke further than current guidelines.

AIMS:We studied the efficacy and safety of icosapent ethyl (IPE) 4g daily in reducing the risk of myocardial infarction (MI) across different MI subtypes and sizes, among REDUCE-IT high-risk patients with hypertriglyceridemia. METHODS:REDUCE-IT was a phase 3b, double-blind multicenter trial. Patients with established CVD or diabetes who were treated with statins and had moderate hypertriglyceridemia were randomized to receive IPE 4g daily or placebo. The current analysis focused on MI subtypes (fatal MI, nonfatal MI, ST-segment elevation MI (STEMI), non-STEMI (NSTEMI)), as well as MI size (measured by multiples of troponin upper limit of normal) and MI-related complications. Safety outcomes included treatment emergent adverse events (TEAEs), bleeding, atrial fibrillation, and flutter. RESULTS:At 5.7 years follow-up, MI incidence was lower with IPE compared with placebo (8.6% vs 12.0%), hazard ratio (HR) 0.69 (95% CI 0.58-0.81, P<0.0001). STEMI incidence was lower with IPE (2.7% vs 3.9%, HR 0.60, 95% CI 0.44-0.81, P=0.0008), as was NSTEMI incidence (5.9% vs 7.8%, HR 0.73, 95% CI 0.60-0.89, P=0.001). Fatal and nonfatal MIs were reduced with IPE (HR 0.55, 95% CI 0.30-1.01, P=0.05 and HR 0.70, 95% CI 0.59-0.82, P<0.0001, respectively). Stratification by size revealed IPE reduced most MIs, but the protective effect was higher for larger MIs (P<0.0001). Further analyses showed benefits in MI-related outcomes, including reductions in spontaneous MI and MI-related complications. Among patients who developed MI, safety outcomes showed no significant increase in serious bleeding, atrial fibrillation or flutter, or adverse events with IPE. CONCLUSION:IPE significantly reduced MI across most subtypes and sizes in statin-treated patients with elevated triglycerides at increased cardiovascular risk. TRIAL REGISTRATION:ClinicalTrials.gov Identifier NCT01492361.

BACKGROUND:Patients with an autoimmune or inflammatory disease (AIID) are at increased cardiovascular risk and may benefit more from statin therapy. In the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), the PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor evolocumab lowered low-density lipoprotein cholesterol levels, but not hsCRP (high-sensitivity C-reactive protein) levels, and reduced the risk of cardiovascular events. METHODS:FOURIER was a randomized trial of evolocumab versus placebo in 27 564 patients with stable atherosclerosis who were taking statins. This analysis focused on the effect of evolocumab in patients with or without an AIID, defined as any autoimmune or chronic inflammatory condition. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, unstable angina, or coronary revascularization. RESULTS:At baseline, 889 patients (3.2%) had an AIID, most commonly rheumatoid arthritis (33.7%) or psoriasis (15.6%). Median (interquartile range) low-density lipoprotein cholesterol levels were 90.0 mg/dL (79.5-105.5) and 91.5 mg/dL (79.5-108.5) in patients with or without an AIID, respectively (P=0.025), and the placebo-adjusted percent reduction with evolocumab was consistent (60.2% versus 59.0%; P=0.57). Baseline hsCRP was higher in patients with an AIID (median 2.1 versus 1.7 mg/L; P<0.001) and did not significantly change with evolocumab in either group. Compared with placebo, evolocumab reduced the rate of the primary end point by 14% in patients without an AIID (hazard ratio, 0.86 [95% CI, 0.80-0.93]) and by 42% in patients with an AIID (hazard ratio, 0.58 [95% CI, 0.38-0.89]; Pinteraction=0.066). Likewise, evolocumab reduced the key secondary end point of cardiovascular death, myocardial infarction, or stroke by 19% in patients without an AIID (hazard ratio, 0.81 [95% CI, 0.74-0.89]) and 58% in those with an AIID (hazard ratio, 0.42 [95% CI, 0.24-0.74]; Pinteraction=0.022). CONCLUSIONS:Intensive lowering of low-density lipoprotein cholesterol levels with evolocumab may lead to greater relative reduction in cardiovascular events in patients with an AIID. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT01764633.

Heart failure (HF) and chronic kidney disease (CKD) are closely interconnected conditions. Congestion, a central element in HF and CKD pathophysiology, progresses from haemodynamic changes to pulmonary oedema, with asymptomatic pulmonary congestion and an isolated increase in brain natriuretic peptide (BNP) as an intermediate step. Management strategies include sodium restriction, diuretics and emerging technologies for fluid monitoring. Diuretics, while essential, present challenges such as resistance and side effects, necessitating combination therapies and alternatives, like SGLT-2 inhibitors and, in special cases, ultrafiltration. Personalized approaches are critical to improving clinical outcomes in HF and CKD.

Background: Chronic kidney disease (CKD) is associated with significant morbidity and mortality, especially in patients with concurrent heart disease who share many similar risk factors. Recent studies support a polygenic contribution to CKD, suggesting that a polygenic risk score (PRS) may have utility in predicting clinically significant progression of kidney disease. Methods: All patients who consented for genetic testing in 3 large TIMI clinical trials (SAVOR, FOURIER, DECLARE) were included in the study. Pts were binned as high (top 20%), intermediate, or low (bottom 20%) genetic risk using a genome-wide PRS developed to predict CKD in a diverse population (Mandla et al., 2024, Wuttke et al., 2019). A Cox model was used to calculate adjusted hazard ratios (aHR) across genetic risk groups for a 3-point renal composite outcome (eGFR decrease ≥40%, end-stage renal disease, or renal death). HRs were adjusted for age, sex, genetic ancestry, HTN, DM, CAD, PAD, smoking, and hyperlipidemia. Results: Of 35,182 pts across the 3 trials, 514 (1.46%) had a composite renal outcome over 2.5-yrs median follow-up with Kaplan-Meier event rates for those in low, intermediate, and high genetic risk groups of 0.83% (n=76), 1.05% (n=283), 1.59% (n=147), respectively ( p-trend <0.001). After adjustment for clinical risk factors, the PRS was independently associated with an aHR (per 1-SD) for the composite renal outcome of 1.17 (95% CI, 1.10-1.26, p<0.001). The PRS predicts risk of the composite renal outcome across the range of baseline eGFRs (Fig. 1). Notably, the PRS was associated with an enhanced ability to predict for the renal composite outcome in patients with eGFR <60 (aHR per 1-SD of 1.23 [1.10-1.38], p <0.001) compared to 1.11 [1.02-1.22, p =0.0196] in patients with eGFR≥60 ( p-heterogeneity =0.03). Indeed, in patients with at least CKD stage 3B (eGFR <45), the absolute excess risk of the renal composite outcome in patients with high vs. low genetic risk over 2.5 yrs was 4.36% compared to 0.30% in high vs. low genetic risk patients with CKD stage 2B or better (eGFR ≥60). Conclusions: A kidney disease PRS, when added to clinical risk factors, improves the prediction of developing clinically significant renal disease. The absolute risk excess was largest in patients with pre-existing CKD and therefore may be a useful risk marker for disease progression.

Background The clinical utility of a heart failure (HF) polygenic risk score (PRS) is uncertain. Objectives The purpose of this study was to investigate the ability of an HF PRS to predict new-onset HF in individuals across the spectrum of cardiovascular risk. Methods An HF PRS (>1 million single nucleotide variations) was used to stratify individuals from 7 clinical studies to low (quintile [Q] 1), intermediate (Q2-Q4), or high (Q5) genetic risk. In 6 trials of patients at elevated cardiovascular risk, HRs adjusted for clinical factors were derived for the risk of hospitalization for HF using Cox-PH models, and discrimination and calibration was explored. Analyses were conducted in a separate data set of individuals at low cardiovascular risk. Results We studied 74,897 patients without HF, of which 51,627 were at elevated cardiovascular risk (median age 65 years; 71% men; median follow-up 2.5 years). After adjusting for clinical factors, individuals with intermediate and high HF PRS carried a 2- and 5-fold increased rate of new-onset HF, respectively (intermediate risk: HRadj: 2.01 [95% CI: 1.62-2.49]; P < 0.001; high-risk: HRadj: 5.00 [95% CI: 3.99-6.27]; P < 0.001). Addition of the HF PRS to a clinical model improved the AUC (0.787 [95% CI: 0.775-0.798] to 0.822 [95% CI: 0.811-0.832]). Results were consistent in 23,270 individuals at low cardiovascular risk over 20-year follow-up. Conclusions An HF PRS is a strong and independent predictor for new-onset HF in individuals across the spectrum of cardiovascular risk. The polygenic contribution to HF is complementary to established clinical risk assessment.

Background Epistaxis is common with antithrombotic therapy and is often troublesome to patients, yet its frequency, severity, and outcomes are poorly characterized. Methods and Results Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 (ENGAGE AF‐TIMI 48) randomized 21 105 patients with atrial fibrillation and CHADS2 risk score ≥2 to higher‐dose edoxaban regimen (60 mg daily, dose‐reduced to 30 mg), lower‐dose edoxaban regimen (30 mg, dose reduced to 15 mg, daily), or warfarin. Bleeds were adjudicated using International Society on Thrombosis and Haemostasis criteria. Patients with intracranial hemorrhage during follow‐up were excluded; those with >1 bleeding event were categorized according to their most severe event. The safety cohort with interval censoring during drug interruption was analyzed. Proportions were compared using Pearson's chi‐square test and treatment arms were compared using a Cox proportional hazards model. Among 5247 patients with a bleeding event, 1008 (19.2%) had epistaxis and 4239 (80.8%) had nonepistaxis bleeding. Epistaxis events were less severe than nonepistaxis bleeds (International Society on Thrombosis and Haemostasis major: 3.2% versus 20.7%; clinically relevant nonmajor: 64.7% versus 60.1%; minor: 32.1% versus 19.2%; P <0.001). Permanent drug discontinuation was similar following epistaxis versus nonepistaxis bleeding in patients with major (59.4% versus 53.6%; P =0.52) or clinically relevant nonmajor (32.5% versus 33.3%; P =0.70) bleeding but was significantly higher in patients with minor epistaxis versus other minor bleeds (33.3% versus 23.9%; P =0.001). Compared with warfarin, higher‐dose edoxaban regimen had similar risk of epistaxis (hazard ratio [HR], 1.09 [95% CI, 0.95–1.26]), whereas lower‐dose edoxaban regimen conferred reduced risk (HR, 0.73 [95% CI, 0.62–0.86]). Conclusions Epistaxis was frequent, and despite being overall less severe than nonepistaxis bleeding, was associated with similar rates of anticoagulant discontinuation. Compared with warfarin, lower‐dose edoxaban regimen reduced the risk of epistaxis by 27% whereas higher‐dose edoxaban regimen had no effect. Registration URL: https://clinicaltrials.gov ; Unique Identifier: NCT00781391 .