In a randomized trial, 1050 patients with cancer who had acute venous thromboembolism were assigned to receive either dalteparin or edoxaban for 6 to 12 months. Edoxaban was noninferior to dalteparin ...with respect to the outcome of recurrent venous thromboembolism or major bleeding.
Abstract Background The use of non-vitamin K antagonist oral anticoagulants (NOACs) instead of vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) and coexisting valvular heart ...disease (VHD) is of substantial interest. Objectives This study explored outcomes in patients with AF with and without VHD in the ENGAGE AF–TIMI 48 (Effective Anticoagulation with factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48) trial, comparing edoxaban with warfarin. Methods Valvular heart disease was defined as history or baseline echocardiography evidence of at least moderate aortic/mitral regurgitation, aortic stenosis, or prior valve surgery (bioprosthesis replacement, valve repair, valvuloplasty). Patients with moderate to severe mitral stenosis or mechanical heart valves were excluded from the trial. Comparisons were made of rates of stroke/systemic embolic event (SSEE), major bleeding, additional efficacy and safety outcomes, as well as net clinical outcomes, in patients with or without VHD treated with edoxaban or warfarin, using adjusted Cox proportional hazards. Results After adjustment for multiple baseline characteristics, compared with no-VHD patients (n = 18,222), VHD patients (n = 2,824) had a similar rate of SSEE but higher rates of death (hazard ratio HR: 1.40; 95% confidence interval CI:1.26 to 1.56; p <0.001), major adverse cardiovascular events (HR: 1.29; 95% CI: 1.16 to 1.43; p <0.001), and major bleeding (HR: 1.21; 95% CI: 1.03 to 1.42; p = 0.02). Higher-dose edoxaban regimen had efficacy similar to warfarin in the presence of VHD (for SSEE, HR: 0.69; 95% CI: 0.44 to 1.07, in patients with VHD, and HR: 0.91; 95% CI: 0.77 to 1.07, in patients without VHD; p interaction pint = 0.26; and for less major bleeding, HR: 0.74; 95% CI: 0.53 to 1.02 in patients with VHD, and HR: 0.82; 95% CI: 0.71 to 0.94, in patients with no VHD; pint = 0.57). Conclusions The presence of VHD increased the risk of death, major adverse cardiovascular events, and major bleeding but did not affect the relative efficacy or safety of higher-dose edoxaban versus warfarin in AF. (Global Study to Assess the Safety and Effectiveness of Edoxaban (DU-176b) vs. Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation ENGAGE AF-TIMI 48; NCT00781391 )
In a phase 1 trial of NI006 for transthyretin amyloid cardiomyopathy, no apparent drug-related serious adverse events occurred. At doses of at least 10 mg per kilogram, amyloid-load surrogates ...appeared to be reduced.
Abstract
In the Hokusai VTE Cancer study, edoxaban was non-inferior to dalteparin for the composite outcome of recurrent venous thromboembolism (VTE) and major bleeding in 1,050 patients with ...cancer-associated VTE. The absolute rate of recurrent VTE was 3.4% lower with edoxaban, whereas the absolute rate of major bleeding was 2.9% higher. The present analysis focuses on the sites, clinical presentation, course and outcome of bleeding events, and the associated tumour types. Major bleeds and their severity (categories 1–4) were blindly adjudicated by a committee using a priori defined criteria, and data were analysed in the safety population. Major bleeding occurred in 32 of 522 patients given edoxaban (median treatment duration, 211 days) and in 16 of 524 patients treated with dalteparin (median treatment duration, 184 days); no patients had more than one major bleed. There were no fatal bleeds with edoxaban, and two with dalteparin. Severe bleeding at presentation (category 3 or 4) occurred in 10 (1.9%) and 11 (2.1%) patients in the edoxaban and dalteparin groups, respectively. The excess of major bleeding with edoxaban was confined to patients with gastrointestinal cancer. However, severe major bleeding at presentation (category 3 or 4) in this sub-group occurred in 5 of 165 (3.0%) and in 3 of 140 (2.1%) patients given edoxaban or dalteparin, respectively.
In conclusion, this analysis suggests that while oral edoxaban is an appropriate alternative to subcutaneous dalteparin for treatment of cancer-associated VTE, the use of edoxaban in patients with gastrointestinal cancer requires careful benefit–risk weighting.
Summary
Of the new direct oral anticoagulants, direct factor Xa inhibitors are limited by the absence of a proven reversal agent. We assessed the safety, tolerability and impact on anticoagulation ...reversal of ciraparantag (PER977) alone and following a 60 mg dose of the FXa inhibitor edoxaban. Escalating, single IV doses of ciraparantag were administered alone and following a 60 mg oral dose of edoxaban in a double-blind, placebo-controlled fashion to healthy subjects. Serial assessments of the pharmacokinetics and pharmacodynamic effects of ciraparantag were performed. Eighty male subjects completed the study. Following edoxaban (60 mg), a single IV dose of ciraparantag (100 to 300 mg) demonstrated full reversal of anticoagulation within 10 minutes and sustained for 24 hours. Fibrin diameter within clots was restored to normal 30 minutes after a single dose of 100 to 300 mg ciraparantag as determined by scanning electron microscopy and change in fibrin diameter quantified by automated image analysis. Potentially related adverse events were periorbital and facial flushing and cool sensation following IV injection of ciraparantag. Renal excretion of ciraparantag metabolite was the main elimination route. There was no evidence of procoagulant activity following ciraparantag as assessed by D-dimer, prothrombin fragments 1.2, and tissue factor pathway inhibitor levels. In conclusion, ciraparantag in healthy subjects is safe and well tolerated with minor, non-dose limiting adverse events. Baseline haemostasis was restored from the anticoagulated state with doses of 100 to 300 mg ciraparantag within 10–30 minutes of administration and sustained for at least 24 hours.
Institution where the work was performed: Duke University Clinical Research Unit, Duke University Medical Center, Durham, NC USA
Summary Background Warfarin is the most widely used oral anticoagulant worldwide, but serious bleeding complications are common. We tested whether genetic variants can identify patients who are at ...increased risk of bleeding with warfarin and, consequently, those who would derive a greater safety benefit with a direct oral anticoagulant rather than warfarin. Methods ENGAGE AF-TIMI 48 was a randomised, double-blind trial in which patients with atrial fibrillation were assigned to warfarin to achieve a target international normalised ratio of 2·0–3·0, or to higher-dose (60 mg) or lower-dose (30 mg) edoxaban once daily. A subgroup of patients was included in a prespecified genetic analysis and genotyped for variants in CYP2C9 and VKORC1 . The results were used to create three genotype functional bins (normal, sensitive, and highly sensitive responders to warfarin). This trial is registered with ClinicalTrials.gov , number NCT00781391. Findings 14 348 patients were included in the genetic analysis. Of 4833 taking warfarin, 2982 (61·7%) were classified as normal responders, 1711 (35·4%) as sensitive responders, and 140 (2·9%) as highly sensitive responders. Compared with normal responders, sensitive and highly sensitive responders spent greater proportions of time over-anticoagulated in the first 90 days of treatment (median 2·2%, IQR 0–20·2; 8·4%, 0–25·8; and 18·3%, 0–32·6; ptrend <0·0001) and had increased risks of bleeding with warfarin (sensitive responders hazard ratio 1·31, 95% CI 1·05–1·64, p=0·0179; highly sensitive responders 2·66, 1·69–4·19, p<0·0001). Genotype added independent information beyond clinical risk scoring. During the first 90 days, when compared with warfarin, treatment with edoxaban reduced bleeding more so in sensitive and highly sensitive responders than in normal responders (higher-dose edoxaban pinteraction =0·0066; lower-dose edoxaban pinteraction =0·0036). After 90 days, the reduction in bleeding risk with edoxaban versus warfarin was similarly beneficial across genotypes. Interpretation CYP2C9 and VKORC1 genotypes identify patients who are more likely to experience early bleeding with warfarin and who derive a greater early safety benefit from edoxaban compared with warfarin. Funding Daiichi Sankyo.
Abstract
Aims
To investigate the relationship between body mass index (BMI) and outcomes in patients with atrial fibrillation (AF).
Methods and results
In the ENGAGE AF-TIMI 48 trial, patients with ...AF were randomized to warfarin (international normalized ratio 2.0–3.0) or edoxaban. The cohort (N = 21 028) included patients across BMI categories (kg/m2): underweight (<18.5) in 0.8%, normal (18.5 to <25) in 21.4%, overweight (25 to <30) in 37.6%, moderately obese (30 to <35) in 24.8%, severely obese (35 to <40) in 10.0%, and very severely obese (≥40) in 5.5%. In an adjusted analysis, higher BMI (continuous, per 5 kg/m2 increase) was significantly and independently associated with lower risks of stroke/systemic embolic event (SEE) hazard ratio (HR) 0.88, P = 0.0001, ischaemic stroke/SEE (HR 0.87, P < 0.0001), and death (HR 0.91, P < 0.0001), but with increased risks of major (HR 1.06, P = 0.025) and major or clinically relevant non-major bleeding (HR 1.05, P = 0.0007). There was a significant interaction between sex and increasing BMI category, with lower risk of ischaemic stroke/SEE in males and increased risk of bleeding in women. Trough edoxaban concentration and anti-Factor Xa activity were similar across BMI groups >18.5 kg/m2, while time in therapeutic range for warfarin improved significantly as BMI increased (P < 0.0001). The effects of edoxaban vs. warfarin on stroke/SEE, major bleeding, and net clinical outcome were similar across BMI groups.
Conclusion
An increased BMI was independently associated with a lower risk of stroke/SEE, better survival, but increased risk of bleeding. The efficacy and safety profiles of edoxaban were similar across BMI categories ranging from 18.5 to >40.
BACKGROUND:The ABC (age, biomarker, clinical history)-stroke and ABC-bleeding risk scores incorporate clinical variables and cardiovascular biomarkers to estimate risk of stroke or systemic embolic ...events and bleeding, respectively, in patients with atrial fibrillation. These scores have been proposed for routine clinical use, but their performance in external cohorts remains uncertain.
METHODS:ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation—Thrombolysis in Myocardial Infarction 48) was a multinational randomized trial of the oral factor Xa inhibitor edoxaban in patients with atrial fibrillation and a CHADS2 score ≥2. We performed a nested prospective biomarker study in 8705 patients, analyzing baseline high-sensitivity troponin T (hsTnT), NT-proBNP (N-terminal B-type natriuretic peptide), and growth differentiation factor-15 (GDF-15), as well as in serial samples after 12 months. The ABC-stroke (age, prior stroke/transient ischemic attack, hsTnT, NT-proBNP) and ABC-bleeding (age, prior bleeding, hemoglobin, hsTnT, and GDF-15) scores were tested. Hazard ratios were adjusted for estimated glomerular filtration rate and the components of the CHA2DS2-VASc and HAS-BLED scores, respectively. Discrimination and reclassification were compared with these established scores.
RESULTS:Median baseline hsTnT, NT-proBNP, and GDF-15 levels were 13.7 ng/L (25th–75th percentiles, 9.6–20.4 ng/L), 811 pg/mL (386–1436 pg/mL), and 1661 pg/mL (1179–2427 pg/mL), respectively. Elevated hsTnT, NT-proBNP, and GDF-15 were independently associated with higher rates of stroke or systemic embolic events, and elevated hsTnT and GDF-15 were independently associated with higher rates of major bleeding (P<0.001 for each). The ABC-stroke and ABC-bleeding scores were well calibrated and yielded higher c indexes than the CHA2DS2-VASc score for stroke or systemic embolic events (0.67 95% CI, 0.65–0.70 versus 0.59 95% CI, 0.57–0.62; P<0.001) and HAS-BLED score for major bleeding (0.69 95% CI, 0.66–0.71 versus 0.62 95% CI, 0.60–0.64; P<0.001), respectively. The ABC-stroke and ABC-bleeding scores stratified patients within CHA2DS2-VASc and HAS-BLED risk categories (P<0.001 for both). Patients with ABC-bleeding scores predicting a high 1-year risk of bleeding (>2%) derived greater benefit from treatment with edoxaban compared with warfarin.
CONCLUSIONS:The ABC-stroke and ABC-bleeding scores evaluated in this anticoagulated clinical trial cohort were well calibrated and outperformed the CHA2DS2-VASc and HAS-BLED scores, respectively. These scores may help identify patients most likely to derive a benefit from treatment with non–vitamin K antagonist oral anticoagulants.
CLINICAL TRIAL REGISTRATION:URLhttps://www.clinicaltrials.gov. Unique identifierNCT00781391.
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