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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 -
JAMA Jun 2023In patients with cancer who have venous thromboembolism (VTE) events, long-term anticoagulation with low-molecular-weight heparin (LMWH) is recommended to prevent... (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
In patients with cancer who have venous thromboembolism (VTE) events, long-term anticoagulation with low-molecular-weight heparin (LMWH) is recommended to prevent recurrent VTE. The effectiveness of a direct oral anticoagulant (DOAC) compared with LMWH for preventing recurrent VTE in patients with cancer is uncertain.
OBJECTIVE
To evaluate DOACs, compared with LMWH, for preventing recurrent VTE and for rates of bleeding in patients with cancer following an initial VTE event.
DESIGN, SETTING, AND PARTICIPANTS
Unblinded, comparative effectiveness, noninferiority randomized clinical trial conducted at 67 oncology practices in the US that enrolled 671 patients with cancer (any invasive solid tumor, lymphoma, multiple myeloma, or chronic lymphocytic leukemia) who had a new clinical or radiological diagnosis of VTE. Enrollment occurred from December 2016 to April 2020. Final follow-up was in November 2020.
INTERVENTION
Participants were randomized in a 1:1 ratio to either a DOAC (n = 335) or LMWH (n = 336) and were followed up for 6 months or until death. Physicians and patients selected any DOAC or any LMWH (or fondaparinux) and physicians selected drug doses.
MAIN OUTCOMES AND MEASURES
The primary outcome was the recurrent VTE rate at 6 months. Noninferiority of anticoagulation with a DOAC vs LMWH was defined by the upper limit of the 1-sided 95% CI for the difference of a DOAC relative to LMWH of less than 3% in the randomized cohort that received at least 1 dose of assigned treatment. The 6 prespecified secondary outcomes included major bleeding, which was assessed using a 2.5% noninferiority margin.
RESULTS
Between December 2016 and April 2020, 671 participants were randomized and 638 (95%) completed the trial (median age, 64 years; 353 women [55%]). Among those randomized to a DOAC, 330 received at least 1 dose. Among those randomized to LMWH, 308 received at least 1 dose. Rates of recurrent VTE were 6.1% in the DOAC group and 8.8% in the LMWH group (difference, -2.7%; 1-sided 95% CI, -100% to 0.7%) consistent with the prespecified noninferiority criterion. Of 6 prespecified secondary outcomes, none were statistically significant. Major bleeding occurred in 5.2% of participants in the DOAC group and 5.6% in the LMWH group (difference, -0.4%; 1-sided 95% CI, -100% to 2.5%) and did not meet the noninferiority criterion. Severe adverse events occurred in 33.8% of participants in the DOAC group and 35.1% in the LMWH group. The most common serious adverse events were anemia and death.
CONCLUSIONS AND RELEVANCE
Among adults with cancer and VTE, DOACs were noninferior to LMWH for preventing recurrent VTE over 6-month follow-up. These findings support use of a DOAC to prevent recurrent VTE in patients with cancer.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02744092.
Topics: Female; Humans; Middle Aged; Anticoagulants; Hemorrhage; Heparin, Low-Molecular-Weight; Multiple Myeloma; Neoplasms; Venous Thromboembolism; Factor Xa Inhibitors; Administration, Oral; Recurrence; Comparative Effectiveness Research; Male; Aged
PubMed: 37266947
DOI: 10.1001/jama.2023.7843 -
Circulation Jan 2024There is ambiguity whether frail patients with atrial fibrillation managed with vitamin K antagonists (VKAs) should be switched to a non-vitamin K oral anticoagulant... (Randomized Controlled Trial)
Randomized Controlled Trial
Safety of Switching From a Vitamin K Antagonist to a Non-Vitamin K Antagonist Oral Anticoagulant in Frail Older Patients With Atrial Fibrillation: Results of the FRAIL-AF Randomized Controlled Trial.
BACKGROUND
There is ambiguity whether frail patients with atrial fibrillation managed with vitamin K antagonists (VKAs) should be switched to a non-vitamin K oral anticoagulant (NOAC).
METHODS
We conducted a pragmatic, multicenter, open-label, randomized controlled superiority trial. Older patients with atrial fibrillation living with frailty (≥75 years of age plus a Groningen Frailty Indicator score ≥3) were randomly assigned to switch from international normalized ratio-guided VKA treatment to an NOAC or to continued VKA treatment. Patients with a glomerular filtration rate <30 mL·min·1.73 m or with valvular atrial fibrillation were excluded. Follow-up was 12 months. The cause-specific hazard ratio was calculated for occurrence of the primary outcome that was a major or clinically relevant nonmajor bleeding complication, whichever came first, accounting for death as a competing risk. Analyses followed the intention-to-treat principle. Secondary outcomes included thromboembolic events.
RESULTS
Between January 2018 and June 2022, a total of 2621 patients were screened for eligibility and 1330 patients were randomly assigned (mean age 83 years, median Groningen Frailty Indicator score 4). After randomization, 6 patients in the switch-to-NOAC arm and 1 patient in the continue-with-VKA arm were excluded due to the presence of exclusion criteria, leaving 662 patients switched from a VKA to an NOAC and 661 patients continued VKAs in the intention-to-treat population. After 163 primary outcome events (101 in the switch arm, 62 in the continue arm), the trial was stopped for futility according to a prespecified futility analysis. The hazard ratio for our primary outcome was 1.69 (95% CI, 1.23-2.32). The hazard ratio for thromboembolic events was 1.26 (95% CI, 0.60-2.61).
CONCLUSIONS
Switching international normalized ratio-guided VKA treatment to an NOAC in frail older patients with atrial fibrillation was associated with more bleeding complications compared with continuing VKA treatment, without an associated reduction in thromboembolic complications.
REGISTRATION
URL: https://eudract.ema.europa.eu; Unique identifier: 2017-000393-11. URL: https://eudract.ema.europa.eu; Unique identifier: 6721 (FRAIL-AF study).
Topics: Humans; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Frail Elderly; Frailty; Thromboembolism; Vitamin K; Administration, Oral; Stroke
PubMed: 37634130
DOI: 10.1161/CIRCULATIONAHA.123.066485 -
International Journal of Molecular... Jan 2024Unlike classic APS, CAPS causes multiple microthrombosis due to an increased inflammatory response, known as a "thrombotic storm". CAPS typically develops after... (Review)
Review
Unlike classic APS, CAPS causes multiple microthrombosis due to an increased inflammatory response, known as a "thrombotic storm". CAPS typically develops after infection, trauma, or surgery and begins with the following symptoms: fever, thrombocytopenia, muscle weakness, visual and cognitive disturbances, abdominal pain, renal failure, and disseminated intravascular coagulation. Although the presence of antiphospholipid antibodies in the blood is one of the diagnostic criteria, the level of these antibodies can fluctuate significantly, which complicates the diagnostic process and can lead to erroneous interpretation of rapidly developing symptoms. Triple therapy is often used to treat CAPS, which includes the use of anticoagulants, plasmapheresis, and high doses of glucocorticosteroids and, in some cases, additional intravenous immunoglobulins. The use of LMWH is recommended as the drug of choice due to its anti-inflammatory and anticoagulant properties. CAPS is a multifactorial disease that requires not only an interdisciplinary approach but also highly qualified medical care, adequate and timely diagnosis, and appropriate prevention in the context of relapse or occurrence of the disease. Improved new clinical protocols and education of medical personnel regarding CAPS can significantly improve the therapeutic approach and reduce mortality rates.
Topics: Humans; Antiphospholipid Syndrome; Heparin, Low-Molecular-Weight; Antibodies, Antiphospholipid; Anticoagulants; Cognitive Dysfunction
PubMed: 38203837
DOI: 10.3390/ijms25010668 -
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 -
Chinese Medical Journal Nov 2023Atrial fibrillation (AF), the most common sustained arrhythmia, is associated with a range of symptoms, including palpitations, cognitive impairment, systemic embolism,... (Review)
Review
Atrial fibrillation (AF), the most common sustained arrhythmia, is associated with a range of symptoms, including palpitations, cognitive impairment, systemic embolism, and increased mortality. It places a significant burden on healthcare systems worldwide. Despite decades of research, the precise mechanisms underlying AF remain elusive. Current understanding suggests that factors like stretch-induced fibrosis, epicardial adipose tissue (EAT), chronic inflammation, autonomic nervous system (ANS) imbalances, and genetic mutations all play significant roles in its development. In recent years, the advent of wearable devices has revolutionized AF diagnosis, enabling timely detection and monitoring. However, balancing early diagnosis with efficient resource utilization presents new challenges for healthcare providers. AF management primarily focuses on stroke prevention and symptom alleviation. Patients at high risk of thromboembolism require anticoagulation therapy, and emerging pipeline drugs, particularly factor XI inhibitors, hold promise for achieving effective anticoagulation with reduced bleeding risks. The scope of indications for catheter ablation in AF has expanded significantly. Pulsed field ablation, as a novel energy source, shows potential for improving success rates while ensuring safety. This review integrates existing knowledge and ongoing research on AF pathophysiology and clinical management, with emphasis on diagnostic devices, next-generation anticoagulants, drugs targeting underlying mechanisms, and interventional therapies. It offers a comprehensive mosaic of AF, providing insights into its complexities.
Topics: Humans; Atrial Fibrillation; Stroke; Risk Factors; Anticoagulants; Blood Coagulation; Catheter Ablation; Treatment Outcome
PubMed: 37914663
DOI: 10.1097/CM9.0000000000002906 -
JAMA Network Open Jul 2023Patterns of clinical utilization and comparative effectiveness of anticoagulants for cancer-associated thrombosis (CAT) remain largely unexplored.
IMPORTANCE
Patterns of clinical utilization and comparative effectiveness of anticoagulants for cancer-associated thrombosis (CAT) remain largely unexplored.
OBJECTIVES
To assess patterns of and factors associated with anticoagulant use and to evaluate the comparative effectiveness of contemporary anticoagulants in patients with active cancer in a clinical setting.
DESIGN, SETTING, AND PARTICIPANTS
This retrospective cohort study obtained deidentified OptumLabs electronic health record claims data from January 1, 2012, to September 30, 2019. Adult patients (≥18 years of age) with a primary cancer diagnosis (except skin cancer) during at least 1 inpatient or 2 outpatient visits within 6 months before the venous thromboembolism (VTE) date were included. Data were analyzed from April 2020 to September 2021.
EXPOSURES
The patients were grouped according to the anticoagulant prescribed: (1) direct oral anticoagulants (DOACs), (2) low-molecular-weight heparin (LMWH), and (3) warfarin.
MAIN OUTCOMES AND MEASURES
Odds ratios (ORs) were used to present the association between factors of interest and utilization of anticoagulants. Main efficacy outcomes included risk of VTE recurrence and all-cause mortality. Main safety outcomes included the risk of hospitalization due to major bleeding. Relative treatment effect estimates were expressed as hazard ratios (HRs) with 95% CIs.
RESULTS
This study included 5100 patients (mean [SD] age, 66.3 [12.3] years; 2670 [52.4%] women; 799 [15.7%] Black, 389 [7.6%] Hispanic, and 3559 [69.8%] White individuals). Overall, 2512 (49.3%), 1488 (29.2%), and 1460 (28.6%) filled prescriptions for DOACs, LMWH, and warfarin, respectively. The median (IQR) treatment duration was 3.2 (1.0-6.5) months for DOACs, 3.1 (1.0-6.8) months for warfarin, and 1.8 (0.9-3.8) months for LWMH. Patients with lung (OR, 2.07; 95% CI, 1.12-3.65), urological (OR, 1.94; 95% CI,1.08-3.49), gynecological (OR, 4.25; 95% CI, 2.31-7.82), and colorectal (OR, 2.26; 95% CI, 1.20-4.32) cancer were associated with increased prescriptions for LMWH compared with DOACs. LMWH (HR, 1.47; 95% CI, 1.14-1.90) and warfarin (HR, 1.46; 95% CI, 1.13-1.87) were associated with an increased risk of VTE recurrences compared with DOACs. LMWH was associated with an increased risk of major bleeding (HR, 2.27; 95% CI, 1.62-3.20) and higher all-cause mortality (HR, 1.61; 95% CI, 1.15-2.25) compared with DOACs.
CONCLUSIONS AND RELEVANCE
In this comparative effectiveness study of claims-based data, patients with CAT received anticoagulation for a remarkably short duration in clinical settings. DOACs was associated with a lower risk of VTE recurrence, major bleeding, and mortality. Warfarin may still be considered for patients with contraindications to DOACs and those with poor persistence on LMWH.
Topics: Female; Male; Humans; Anticoagulants; Warfarin; Heparin, Low-Molecular-Weight; Venous Thromboembolism; Retrospective Studies; Hemorrhage; Neoplasms; Thrombosis
PubMed: 37486628
DOI: 10.1001/jamanetworkopen.2023.25283 -
Advances in Therapy Oct 2023Atrial fibrillation (AF) and renal insufficiency often coexist and are increasingly prevalent with advancing age. Both the risk of thromboembolic events and bleeding... (Review)
Review
Atrial fibrillation (AF) and renal insufficiency often coexist and are increasingly prevalent with advancing age. Both the risk of thromboembolic events and bleeding propensity are higher in patients with AF and impaired renal function versus those with good renal health. Direct oral anticoagulants (DOACs) are being increasingly preferred over vitamin K antagonists (VKAs) in the treatment of patients with AF and impaired renal function as VKAs may accelerate progression of chronic kidney disease. DOACs, however, are eliminated by the kidneys to varying degrees, and their dosages must be adapted in accordance with renal function. Since creatinine clearance (CrCl) monitoring is recommended in patients with AF receiving DOAC therapy, CrCl must be routinely monitored in patients at the start and during the course of anticoagulation to avoid deviation from Summary of Product Characteristics dosage specifications. This review article provides an overview of current knowledge on the selection and dose of DOACs including apixaban, dabigatran, edoxaban and rivaroxaban in AF patients at different stages of renal insufficiency, with a special focus on elderly patients with comorbidities and receiving multiple medications. The groups discussed in this review include patients with varying levels of CrCl including hyperfiltration or CrCl > 90 ml/min, CrCl < 90-50 ml/min, CrCl < 50-30 ml/min, CrCl < 30-15 ml/min and end-stage renal disease or on dialysis.
Topics: Aged; Humans; Atrial Fibrillation; Renal Insufficiency; Kidney; Renal Insufficiency, Chronic; Prescriptions; Anticoagulants; Fibrinolytic Agents
PubMed: 37594666
DOI: 10.1007/s12325-023-02544-8 -
Medical Sciences (Basel, Switzerland) Aug 2023Venous thromboembolism (VTE), comprising pulmonary embolism (PE) and deep vein thrombosis (DVT), poses a significant risk during and after hospitalization, particularly... (Review)
Review
Venous thromboembolism (VTE), comprising pulmonary embolism (PE) and deep vein thrombosis (DVT), poses a significant risk during and after hospitalization, particularly for surgical patients. Among various patient groups, those undergoing major orthopedic surgeries are considered to have a higher susceptibility to PE and DVT. Major lower-extremity orthopedic procedures carry a higher risk of symptomatic VTE compared to most other surgeries, with an estimated incidence of ~4%. The greatest risk period occurs within the first 7-14 days following surgery. Major bleeding is also more prevalent in these surgeries compared to others, with rates estimated between 2% and 4%. For patients undergoing major lower-extremity orthopedic surgery who have a low bleeding risk, it is recommended to use pharmacological thromboprophylaxis with or without mechanical devices. The choice of the initial agent depends on the specific surgery and patient comorbidities. First-line options include low-molecular-weight heparins (LMWHs), direct oral anticoagulants, and aspirin. Second-line options consist of unfractionated heparin (UFH), fondaparinux, and warfarin. For most patients undergoing knee or hip arthroplasty, the initial agents recommended for the early perioperative period are LMWHs (enoxaparin or dalteparin) or direct oral anticoagulants (rivaroxaban or apixaban). In the case of hip fracture surgery, LMWH is recommended as the preferred agent for the entire duration of prophylaxis. However, emerging factor XI(a) inhibitors, as revealed by a recent meta-analysis, have shown a substantial decrease in the occurrence of VTE and bleeding events among patients undergoing major orthopedic surgery. This discovery poses a challenge to the existing paradigm of anticoagulant therapy in this specific patient population and indicates that factor XI(a) inhibitors hold great promise as a potential strategy to be taken into serious consideration.
Topics: Humans; Factor XIa; Anticoagulants; Venous Thromboembolism; Heparin, Low-Molecular-Weight; Heparin; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Pulmonary Embolism
PubMed: 37606428
DOI: 10.3390/medsci11030049 -
Europace : European Pacing,... Aug 2023Stroke prevention in patients with atrial fibrillation (AF) is one pillar of the management of this common arrhythmia. Substantial advances in the epidemiology and... (Review)
Review
Stroke prevention in patients with atrial fibrillation (AF) is one pillar of the management of this common arrhythmia. Substantial advances in the epidemiology and associated pathophysiology underlying AF-related stroke and thrombo-embolism are evident. Furthermore, the introduction of the non-vitamin K antagonist oral anticoagulants (also called direct oral anticoagulants) has clearly changed our approach to stroke prevention in AF, such that the default should be to offer oral anticoagulation for stroke prevention, unless the patient is at low risk. A strategy of early rhythm control is also beneficial in reducing strokes in selected patients with recent onset AF, when compared to rate control. Cardiovascular risk factor management, with optimization of comorbidities and attention to lifestyle factors, and the patient's psychological morbidity are also essential. Finally, in selected patients with absolute contraindications to long-term oral anticoagulation, left atrial appendage occlusion or exclusion may be considered. The aim of this state-of-the-art review article is to provide an overview of the current status of AF-related stroke and prevention strategies. A holistic or integrated care approach to AF management is recommended to minimize the risk of stroke in patients with AF, based on the evidence-based Atrial fibrillation Better Care (ABC) pathway, as follows: A: Avoid stroke with Anticoagulation; B: Better patient-centred, symptom-directed decisions on rate or rhythm control; C: Cardiovascular risk factor and comorbidity optimization, including lifestyle changes.
Topics: Humans; Atrial Fibrillation; Stroke; Heart; Anticoagulants; Contraindications
PubMed: 37622590
DOI: 10.1093/europace/euad226