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The New England Journal of Medicine Jan 2024Subclinical atrial fibrillation is short-lasting and asymptomatic and can usually be detected only by long-term continuous monitoring with pacemakers or defibrillators.... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Subclinical atrial fibrillation is short-lasting and asymptomatic and can usually be detected only by long-term continuous monitoring with pacemakers or defibrillators. Subclinical atrial fibrillation is associated with an increased risk of stroke by a factor of 2.5; however, treatment with oral anticoagulation is of uncertain benefit.
METHODS
We conducted a trial involving patients with subclinical atrial fibrillation lasting 6 minutes to 24 hours. Patients were randomly assigned in a double-blind, double-dummy design to receive apixaban at a dose of 5 mg twice daily (2.5 mg twice daily when indicated) or aspirin at a dose of 81 mg daily. The trial medication was discontinued and anticoagulation started if subclinical atrial fibrillation lasting more than 24 hours or clinical atrial fibrillation developed. The primary efficacy outcome, stroke or systemic embolism, was assessed in the intention-to-treat population (all the patients who had undergone randomization); the primary safety outcome, major bleeding, was assessed in the on-treatment population (all the patients who had undergone randomization and received at least one dose of the assigned trial drug, with follow-up censored 5 days after permanent discontinuation of trial medication for any reason).
RESULTS
We included 4012 patients with a mean (±SD) age of 76.8±7.6 years and a mean CHADS-VASc score of 3.9±1.1 (scores range from 0 to 9, with higher scores indicating a higher risk of stroke); 36.1% of the patients were women. After a mean follow-up of 3.5±1.8 years, stroke or systemic embolism occurred in 55 patients in the apixaban group (0.78% per patient-year) and in 86 patients in the aspirin group (1.24% per patient-year) (hazard ratio, 0.63; 95% confidence interval [CI], 0.45 to 0.88; P = 0.007). In the on-treatment population, the rate of major bleeding was 1.71% per patient-year in the apixaban group and 0.94% per patient-year in the aspirin group (hazard ratio, 1.80; 95% CI, 1.26 to 2.57; P = 0.001). Fatal bleeding occurred in 5 patients in the apixaban group and 8 patients in the aspirin group.
CONCLUSIONS
Among patients with subclinical atrial fibrillation, apixaban resulted in a lower risk of stroke or systemic embolism than aspirin but a higher risk of major bleeding. (Funded by the Canadian Institutes of Health Research and others; ARTESIA ClinicalTrials.gov number, NCT01938248.).
Topics: Aged; Aged, 80 and over; Female; Humans; Male; Anticoagulants; Aspirin; Atrial Fibrillation; Canada; Embolism; Hemorrhage; Pyridones; Stroke; Treatment Outcome; Factor Xa Inhibitors; Double-Blind Method
PubMed: 37952132
DOI: 10.1056/NEJMoa2310234 -
The New England Journal of Medicine Jun 2023The effect of early as compared with later initiation of direct oral anticoagulants (DOACs) in persons with atrial fibrillation who have had an acute ischemic stroke is... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
The effect of early as compared with later initiation of direct oral anticoagulants (DOACs) in persons with atrial fibrillation who have had an acute ischemic stroke is unclear.
METHODS
We performed an investigator-initiated, open-label trial at 103 sites in 15 countries. Participants were randomly assigned in a 1:1 ratio to early anticoagulation (within 48 hours after a minor or moderate stroke or on day 6 or 7 after a major stroke) or later anticoagulation (day 3 or 4 after a minor stroke, day 6 or 7 after a moderate stroke, or day 12, 13, or 14 after a major stroke). Assessors were unaware of the trial-group assignments. The primary outcome was a composite of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death within 30 days after randomization. Secondary outcomes included the components of the composite primary outcome at 30 and 90 days.
RESULTS
Of 2013 participants (37% with minor stroke, 40% with moderate stroke, and 23% with major stroke), 1006 were assigned to early anticoagulation and 1007 to later anticoagulation. A primary-outcome event occurred in 29 participants (2.9%) in the early-treatment group and 41 participants (4.1%) in the later-treatment group (risk difference, -1.18 percentage points; 95% confidence interval [CI], -2.84 to 0.47) by 30 days. Recurrent ischemic stroke occurred in 14 participants (1.4%) in the early-treatment group and 25 participants (2.5%) in the later-treatment group (odds ratio, 0.57; 95% CI, 0.29 to 1.07) by 30 days and in 18 participants (1.9%) and 30 participants (3.1%), respectively, by 90 days (odds ratio, 0.60; 95% CI, 0.33 to 1.06). Symptomatic intracranial hemorrhage occurred in 2 participants (0.2%) in both groups by 30 days.
CONCLUSIONS
In this trial, the incidence of recurrent ischemic stroke, systemic embolism, major extracranial bleeding, symptomatic intracranial hemorrhage, or vascular death at 30 days was estimated to range from 2.8 percentage points lower to 0.5 percentage points higher (based on the 95% confidence interval) with early than with later use of DOACs. (Funded by the Swiss National Science Foundation and others; ELAN ClinicalTrials.gov number, NCT03148457.).
Topics: Humans; Anticoagulants; Atrial Fibrillation; Embolism; Hemorrhage; Intracranial Hemorrhages; Ischemic Stroke; Stroke; Treatment Outcome; Time Factors; Factor Xa Inhibitors; Recurrence
PubMed: 37222476
DOI: 10.1056/NEJMoa2303048 -
The New England Journal of Medicine May 2024Patients with acute intracerebral hemorrhage who are receiving factor Xa inhibitors have a risk of hematoma expansion. The effect of andexanet alfa, an agent that... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Patients with acute intracerebral hemorrhage who are receiving factor Xa inhibitors have a risk of hematoma expansion. The effect of andexanet alfa, an agent that reverses the effects of factor Xa inhibitors, on hematoma volume expansion has not been well studied.
METHODS
We randomly assigned, in a 1:1 ratio, patients who had taken factor Xa inhibitors within 15 hours before having an acute intracerebral hemorrhage to receive andexanet or usual care. The primary end point was hemostatic efficacy, defined by expansion of the hematoma volume by 35% or less at 12 hours after baseline, an increase in the score on the National Institutes of Health Stroke Scale of less than 7 points (scores range from 0 to 42, with higher scores indicating worse neurologic deficit) at 12 hours, and no receipt of rescue therapy between 3 hours and 12 hours. Safety end points were thrombotic events and death.
RESULTS
A total of 263 patients were assigned to receive andexanet, and 267 to receive usual care. Efficacy was assessed in an interim analysis that included 452 patients, and safety was analyzed in all 530 enrolled patients. Atrial fibrillation was the most common indication for factor Xa inhibitors. Of the patients receiving usual care, 85.5% received prothrombin complex concentrate. Hemostatic efficacy was achieved in 150 of 224 patients (67.0%) receiving andexanet and in 121 of 228 (53.1%) receiving usual care (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 4.6 to 22.2; P = 0.003). The median reduction from baseline to the 1-to-2-hour nadir in anti-factor Xa activity was 94.5% with andexanet and 26.9% with usual care (P<0.001). Thrombotic events occurred in 27 of 263 patients (10.3%) receiving andexanet and in 15 of 267 (5.6%) receiving usual care (difference, 4.6 percentage points; 95% CI, 0.1 to 9.2; P = 0.048); ischemic stroke occurred in 17 patients (6.5%) and 4 patients (1.5%), respectively. There were no appreciable differences between the groups in the score on the modified Rankin scale or in death within 30 days.
CONCLUSIONS
Among patients with intracerebral hemorrhage who were receiving factor Xa inhibitors, andexanet resulted in better control of hematoma expansion than usual care but was associated with thrombotic events, including ischemic stroke. (Funded by Alexion AstraZeneca Rare Disease and others; ANNEXA-I ClinicalTrials.gov number, NCT03661528.).
Topics: Humans; Factor Xa Inhibitors; Aged; Male; Female; Cerebral Hemorrhage; Middle Aged; Recombinant Proteins; Factor Xa; Hematoma; Aged, 80 and over; Atrial Fibrillation; Acute Disease
PubMed: 38749032
DOI: 10.1056/NEJMoa2313040 -
The New England Journal of Medicine Sep 2023Device-detected atrial high-rate episodes (AHREs) are atrial arrhythmias detected by implanted cardiac devices. AHREs resemble atrial fibrillation but are rare and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Device-detected atrial high-rate episodes (AHREs) are atrial arrhythmias detected by implanted cardiac devices. AHREs resemble atrial fibrillation but are rare and brief. Whether the occurrence of AHREs in patients without atrial fibrillation (as documented on a conventional electrocardiogram [ECG]) justifies the initiation of anticoagulants is not known.
METHODS
We conducted an event-driven, double-blind, double-dummy, randomized trial involving patients 65 years of age or older who had AHREs lasting for at least 6 minutes and who had at least one additional risk factor for stroke. Patients were randomly assigned in a 1:1 ratio to receive edoxaban or placebo. The primary efficacy outcome was a composite of cardiovascular death, stroke, or systemic embolism, evaluated in a time-to-event analysis. The safety outcome was a composite of death from any cause or major bleeding.
RESULTS
The analysis population consisted of 2536 patients (1270 in the edoxaban group and 1266 in the placebo group). The mean age was 78 years, 37.4% were women, and the median duration of AHREs was 2.8 hours. The trial was terminated early, at a median follow-up of 21 months, on the basis of safety concerns and the results of an independent, informal assessment of futility for the efficacy of edoxaban; at termination, the planned enrollment had been completed. A primary efficacy outcome event occurred in 83 patients (3.2% per patient-year) in the edoxaban group and in 101 patients (4.0% per patient-year) in the placebo group (hazard ratio, 0.81; 95% confidence interval [CI], 0.60 to 1.08; P = 0.15). The incidence of stroke was approximately 1% per patient-year in both groups. A safety outcome event occurred in 149 patients (5.9% per patient-year) in the edoxaban group and in 114 patients (4.5% per patient-year) in the placebo group (hazard ratio, 1.31; 95% CI, 1.02 to 1.67; P = 0.03). ECG-diagnosed atrial fibrillation developed in 462 of 2536 patients (18.2% total, 8.7% per patient-year).
CONCLUSIONS
Among patients with AHREs detected by implantable devices, anticoagulation with edoxaban did not significantly reduce the incidence of a composite of cardiovascular death, stroke, or systemic embolism as compared with placebo, but it led to a higher incidence of a composite of death or major bleeding. The incidence of stroke was low in both groups. (Funded by the German Center for Cardiovascular Research and others; NOAH-AFNET 6 ClinicalTrials.gov number, NCT02618577; ISRCTN number, ISRCTN17309850.).
Topics: Aged; Female; Humans; Male; Anticoagulants; Atrial Fibrillation; Embolism; Factor Xa Inhibitors; Hemorrhage; Stroke; Electrodes, Implanted; Double-Blind Method; Arrhythmias, Cardiac; Risk Factors
PubMed: 37622677
DOI: 10.1056/NEJMoa2303062 -
Journal of Thrombosis and Haemostasis :... Jul 2023Oral anticoagulants are a mainstay for the prevention and treatment of arterial and venous thrombosis. Direct oral anticoagulants (DOACs) have replaced vitamin K... (Review)
Review
Oral anticoagulants are a mainstay for the prevention and treatment of arterial and venous thrombosis. Direct oral anticoagulants (DOACs) have replaced vitamin K antagonists for many indications. Currently available DOACs include dabigatran, which inhibits thrombin, and apixaban, edoxaban, and rivaroxaban, which inhibit factor (F) Xa. A new class of DOACs is under development. These new DOACs, which include asundexian and milvexian, inhibit FXIa, which is positioned in the intrinsic pathway of coagulation. Anticoagulants that target FXIa have the potential to be safer than the current DOACs because there is emerging evidence that FXI is essential for thrombosis but mostly dispensable for hemostasis. In addition to the oral inhibitors of FXIa, parenteral inhibitors are also under development. These include fesomersen, an antisense oligonucleotide that reduces the hepatic synthesis of FXI; abelacimab, an antibody that binds to FXI and blocks its activation; and osocimab, an FXIa inhibitory antibody. Focusing on these new agents, this article describes the unmet needs in oral anticoagulation therapy, explains why FXI is a promising target for new oral anticoagulants, reviews phase 2 clinical data on new agents, describes ongoing phase 3 trials, and provides a perspective on the opportunities and challenges for FXI inhibitors.
Topics: Humans; Administration, Oral; Anticoagulants; Dabigatran; Factor Xa Inhibitors; Factor XI; Rivaroxaban
PubMed: 37116752
DOI: 10.1016/j.jtha.2023.04.021 -
Blood Advances Nov 2023Hereditary and acquired thrombophilia are risk factors for venous thromboembolism (VTE). Whether testing helps guide management decisions is controversial. These...
Hereditary and acquired thrombophilia are risk factors for venous thromboembolism (VTE). Whether testing helps guide management decisions is controversial. These evidence-based guidelines from the American Society of Hematology (ASH) intend to support decision making about thrombophilia testing. ASH formed a multidisciplinary guideline panel covering clinical and methodological expertise and minimizing bias from conflicts of interest. The McMaster University GRADE Centre provided logistical support, performed systematic reviews, and created evidence profiles and evidence-to-decision tables. The Grading of Recommendations Assessment, Development, and Evaluation approach (GRADE) was used. Recommendations were subject to public comment. The panel agreed on 23 recommendations regarding thrombophilia testing and associated management. Nearly all recommendations are based on very low certainty in the evidence due to modeling assumptions. The panel issued a strong recommendation against testing the general population before starting combined oral contraceptives (COCs) and conditional recommendations for thrombophilia testing in the following scenarios: (a) patients with VTE associated with nonsurgical major transient or hormonal risk factors; (b) patients with cerebral or splanchnic venous thrombosis, in settings where anticoagulation would otherwise be discontinued; (c) individuals with a family history of antithrombin, protein C, or protein S deficiency when considering thromboprophylaxis for minor provoking risk factors and for guidance to avoid COCs/hormone replacement therapy; (d) pregnant women with a family history of high-risk thrombophilia types; and (e) patients with cancer at low or intermediate risk of thrombosis and with a family history of VTE. For all other questions, the panel provided conditional recommendations against testing for thrombophilia.
Topics: Humans; Female; Pregnancy; United States; Anticoagulants; Venous Thromboembolism; Thrombophilia; Antithrombins; Hematology
PubMed: 37195076
DOI: 10.1182/bloodadvances.2023010177 -
JAMA May 2024Diltiazem, a commonly prescribed ventricular rate-control medication for patients with atrial fibrillation, inhibits apixaban and rivaroxaban elimination, possibly... (Comparative Study)
Comparative Study
IMPORTANCE
Diltiazem, a commonly prescribed ventricular rate-control medication for patients with atrial fibrillation, inhibits apixaban and rivaroxaban elimination, possibly causing overanticoagulation.
OBJECTIVE
To compare serious bleeding risk for new users of apixaban or rivaroxaban with atrial fibrillation treated with diltiazem or metoprolol.
DESIGN, SETTING, AND PARTICIPANTS
This retrospective cohort study included Medicare beneficiaries aged 65 years or older with atrial fibrillation who initiated apixaban or rivaroxaban use and also began treatment with diltiazem or metoprolol between January 1, 2012, and November 29, 2020. Patients were followed up to 365 days through November 30, 2020. Data were analyzed from August 2023 to February 2024.
EXPOSURES
Diltiazem and metoprolol.
MAIN OUTCOMES AND MEASURES
The primary outcome was a composite of bleeding-related hospitalization and death with recent evidence of bleeding. Secondary outcomes were ischemic stroke or systemic embolism, major ischemic or hemorrhagic events (ischemic stroke, systemic embolism, intracranial or fatal extracranial bleeding, or death with recent evidence of bleeding), and death without recent evidence of bleeding. Hazard ratios (HRs) and rate differences (RDs) were adjusted for covariate differences with overlap weighting.
RESULTS
The study included 204 155 US Medicare beneficiaries, of whom 53 275 received diltiazem and 150 880 received metoprolol. Study patients (mean [SD] age, 76.9 [7.0] years; 52.7% female) had 90 927 person-years (PY) of follow-up (median, 120 [IQR, 59-281] days). Patients receiving diltiazem treatment had increased risk for the primary outcome (RD, 10.6 [95% CI, 7.0-14.2] per 1000 PY; HR, 1.21 [95% CI, 1.13-1.29]) and its components of bleeding-related hospitalization (RD, 8.2 [95% CI, 5.1-11.4] per 1000 PY; HR, 1.22 [95% CI, 1.13-1.31]) and death with recent evidence of bleeding (RD, 2.4 [95% CI, 0.6-4.2] per 1000 PY; HR, 1.19 [95% CI, 1.05-1.34]) compared with patients receiving metoprolol. Risk for the primary outcome with initial diltiazem doses exceeding 120 mg/d (RD, 15.1 [95% CI, 10.2-20.1] per 1000 PY; HR, 1.29 [95% CI, 1.19-1.39]) was greater than that for lower doses (RD, 6.7 [95% CI, 2.0-11.4] per 1000 PY; HR, 1.13 [95% CI, 1.04-1.24]). For doses exceeding 120 mg/d, the risk of major ischemic or hemorrhagic events was increased (HR, 1.14 [95% CI, 1.02-1.27]). Neither dose group had significant changes in the risk for ischemic stroke or systemic embolism or death without recent evidence of bleeding. When patients receiving high- and low-dose diltiazem treatment were directly compared, the HR for the primary outcome was 1.14 (95% CI, 1.02-1.26).
CONCLUSIONS AND RELEVANCE
In Medicare patients with atrial fibrillation receiving apixaban or rivaroxaban, diltiazem was associated with greater risk of serious bleeding than metoprolol, particularly for diltiazem doses exceeding 120 mg/d.
Topics: Aged; Aged, 80 and over; Female; Humans; Male; Atrial Fibrillation; Diltiazem; Drug Therapy, Combination; Embolism; Factor Xa Inhibitors; Hemorrhage; Hospitalization; Medicare; Metoprolol; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; United States
PubMed: 38619832
DOI: 10.1001/jama.2024.3867 -
Circulation Sep 2023Current clinical decision tools for assessing bleeding risk in individuals with atrial fibrillation (AF) have limited performance and were developed for individuals...
BACKGROUND
Current clinical decision tools for assessing bleeding risk in individuals with atrial fibrillation (AF) have limited performance and were developed for individuals treated with warfarin. This study develops and validates a clinical risk score to personalize estimates of bleeding risk for individuals with atrial fibrillation taking direct-acting oral anticoagulants (DOACs).
METHODS
Among individuals taking dabigatran 150 mg twice per day from 44 countries and 951 centers in this secondary analysis of the RE-LY trial (Randomized Evaluation of Long-Term Anticoagulation Therapy), a risk score was developed to determine the comparative risk for bleeding on the basis of covariates derived in a Cox proportional hazards model. The risk prediction model was internally validated with bootstrapping. The model was then further developed in the GARFIELD-AF registry (Global Anticoagulant Registry in the Field-Atrial Fibrillation), with individuals taking dabigatran, edoxaban, rivaroxaban, and apixaban. To determine generalizability in external cohorts and among individuals on different DOACs, the risk prediction model was validated in the COMBINE-AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) pooled clinical trial cohort and the Quebec Régie de l'Assurance Maladie du Québec and Med-Echo Administrative Databases (RAMQ) administrative database. The primary outcome was major bleeding. The risk score, termed the DOAC Score, was compared with the HAS-BLED score.
RESULTS
Of the 5684 patients in RE-LY, 386 (6.8%) experienced a major bleeding event, within a median follow-up of 1.74 years. The prediction model had an optimism-corrected C statistic of 0.73 after internal validation with bootstrapping and was well-calibrated based on visual inspection of calibration plots (goodness-of-fit =0.57). The DOAC Score assigned points for age, creatinine clearance/glomerular filtration rate, underweight status, stroke/transient ischemic attack/embolism history, diabetes, hypertension, antiplatelet use, nonsteroidal anti-inflammatory use, liver disease, and bleeding history, with each additional point scored associated with a 48.7% (95% CI, 38.9%-59.3%; <0.001) increase in major bleeding in RE-LY. The score had superior performance to the HAS-BLED score in RE-LY (C statistic, 0.73 versus 0.60; for difference <0.001) and among 12 296 individuals in GARFIELD-AF (C statistic, 0.71 versus 0.66; for difference = 0.025). The DOAC Score had stronger predictive performance than the HAS-BLED score in both validation cohorts, including 25 586 individuals in COMBINE-AF (C statistic, 0.67 versus 0.63; for difference <0.001) and 11 945 individuals in RAMQ (C statistic, 0.65 versus 0.58; for difference <0.001).
CONCLUSIONS
In individuals with atrial fibrillation potentially eligible for DOAC therapy, the DOAC Score can help stratify patients on the basis of expected bleeding risk.
Topics: Humans; Atrial Fibrillation; Factor Xa Inhibitors; Dabigatran; Rivaroxaban; Anticoagulants
PubMed: 37621213
DOI: 10.1161/CIRCULATIONAHA.123.064556 -
International Journal of Molecular... Jul 2023Preeclampsia (PE) is a pregnancy-specific disorder affecting 4-10% of all expectant women. It greatly increases the risk of maternal and foetal death. Although the main... (Review)
Review
Preeclampsia (PE) is a pregnancy-specific disorder affecting 4-10% of all expectant women. It greatly increases the risk of maternal and foetal death. Although the main symptoms generally appear after week 20 of gestation, scientific studies indicate that the mechanism underpinning PE is initiated at the beginning of gestation. It is known that the pathomechanism of preeclampsia is strongly related to inflammation and oxidative stress, which influence placentation and provoke endothelial dysfunction in the mother. However, as of yet, no "key players" regulating all these processes have been discovered. This might be why current therapeutic strategies intended for prevention or treatment are not fully effective, and the only effective method to stop the disease is the premature induction of delivery, mostly by caesarean section. Therefore, there is a need for further research into new pharmacological strategies for the treatment and prevention of preeclampsia. This review presents new preventive methods and therapies for PE not yet recommended by obstetrical and gynaecological societies. As many of these therapies are in preclinical studies or under evaluation in clinical trials, this paper reports the molecular targets of the tested agents or methods.
Topics: Pregnancy; Female; Humans; Pre-Eclampsia; Cesarean Section; Placentation; Oxidative Stress; Vascular Endothelial Growth Factor Receptor-1
PubMed: 37569476
DOI: 10.3390/ijms241512100