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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 -
Trends in Molecular Medicine Sep 2023Ferroptosis suppressor protein 1 (FSP1) is one of the main regulatory molecules of ferroptosis. FSP1 functions through the FSP1-coenzyme Q10 (CoQ10)-NAD(P)H axis and the... (Review)
Review
Ferroptosis suppressor protein 1 (FSP1) is one of the main regulatory molecules of ferroptosis. FSP1 functions through the FSP1-coenzyme Q10 (CoQ10)-NAD(P)H axis and the vitamin K redox cycle. FSP1 is regulated by upstream factors, including transcription factors and noncoding RNA (ncRNA), and is subject to epigenetic modifications, which affect the progress of FSP1-related diseases. FSP1 is closely associated with the poor prognosis of malignant tumors and plays an important role in disease treatment. This review aims to provide a comprehensive understanding of the role of FSP1 in ferroptosis regulation by summarizing regulatory pathways, possible mechanisms involving FSP1, and the relationship between FSP1 and disease prognosis and treatment.
Topics: Humans; Ferroptosis; Epigenesis, Genetic; NAD; Transcription Factors; Vitamin K
PubMed: 37357101
DOI: 10.1016/j.molmed.2023.05.013 -
Nature Jul 2023Ferroptosis is evolving as a highly promising approach to combat difficult-to-treat tumour entities including therapy-refractory and dedifferentiating cancers. Recently,...
Ferroptosis is evolving as a highly promising approach to combat difficult-to-treat tumour entities including therapy-refractory and dedifferentiating cancers. Recently, ferroptosis suppressor protein-1 (FSP1), along with extramitochondrial ubiquinone or exogenous vitamin K and NAD(P)H/H as an electron donor, has been identified as the second ferroptosis-suppressing system, which efficiently prevents lipid peroxidation independently of the cyst(e)ine-glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis. To develop FSP1 inhibitors as next-generation therapeutic ferroptosis inducers, here we performed a small molecule library screen and identified the compound class of 3-phenylquinazolinones (represented by icFSP1) as potent FSP1 inhibitors. We show that icFSP1, unlike iFSP1, the first described on-target FSP1 inhibitor, does not competitively inhibit FSP1 enzyme activity, but instead triggers subcellular relocalization of FSP1 from the membrane and FSP1 condensation before ferroptosis induction, in synergism with GPX4 inhibition. icFSP1-induced FSP1 condensates show droplet-like properties consistent with phase separation, an emerging and widespread mechanism to modulate biological activity. N-terminal myristoylation, distinct amino acid residues and intrinsically disordered, low-complexity regions in FSP1 were identified to be essential for FSP1-dependent phase separation in cells and in vitro. We further demonstrate that icFSP1 impairs tumour growth and induces FSP1 condensates in tumours in vivo. Hence, our results suggest that icFSP1 exhibits a unique mechanism of action and synergizes with ferroptosis-inducing agents to potentiate the ferroptotic cell death response, thus providing a rationale for targeting FSP1-dependent phase separation as an efficient anti-cancer therapy.
Topics: Humans; Amino Acids; Cysteine; Ferroptosis; Glutathione; NAD; NADP; Neoplasms; Quinazolines; Small Molecule Libraries; Ubiquinone; Vitamin K; Apoptosis Regulatory Proteins; Mitochondrial Proteins
PubMed: 37380771
DOI: 10.1038/s41586-023-06255-6 -
Reproductive Biology and Endocrinology... Aug 2023This study aimed to clarify the effect of antioxidant vitamins supplementation on endometriosis-related pain. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
This study aimed to clarify the effect of antioxidant vitamins supplementation on endometriosis-related pain.
METHODS
A systematic search of PubMed, Web of Science, Cochrane Library, Scopus, and China National Knowledge Infrastructure (CNK) databases was conducted to identify relevant studies published in English and Chinese up to 16 March 2023. The search terms used were "endometriosis" OR "endometrioma" OR "endometrium" AND "antioxidant" OR "Vitamin C" OR "Vitamin E" OR "Vitamin D" OR "25-OHD" OR "25(OH)D" OR "25-hydroxyvitamin D". Eligible studies were randomized controlled trials (RCTs) that assessed pain scores using the Visual Analogue Scale (VAS). Mean differences or odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the effect of antioxidant vitamins supplementation on endometriosis. The quality of the included studies was assessed using the Cochrane Risk of Bias Tool. The study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.
RESULTS
A total of 13 RCTs involving 589 patients were included in this meta-analysis. We identified 11 studies that evaluated the effect of antioxidant vitamins supplementation on endometriosis-related pain. The results indicated that the supplementation of antioxidant vitamins can effectively alleviate endometriosis-related pain. Subgroup analysis showed that the supplementation of vitamin E (with or without vitamin C) had a positive effect on improving clinical pelvic pain in patients with chronic pelvic pain. Conversely, supplementation of vitamin D was associated with a reduction in pelvic pain in endometriosis patients, but the difference was not statistically significant compared to the placebo. Additionally, we observed changes in oxidative stress markers following vitamin supplementation. Plasma malondialdehyde (MDA) concentration decreased in patients with endometriosis after antioxidant vitamin supplementation, and the plasma MDA level was inversely correlated with the time and dose of vitamin E and C supplementation. Furthermore, the inflammatory markers in peritoneal fluid, including RANTES, interleukin-6, and monocyte chemoattractant protein-1, significantly decreased after antioxidant therapy. These findings suggest that antioxidant vitamins may alleviate pain in endometriosis patients by reducing inflammation.
CONCLUSIONS
The included studies support the potential role of antioxidant vitamins in the management of endometriosis. Supplementation with antioxidant vitamins effectively reduced the severity of dysmenorrhea, improved dyspareunia and pelvic pain, and enhanced quality of life in these patients. Therefore, antioxidant vitamin therapy could be considered as an alternative treatment method, either alone or in combination with other approaches, for endometriosis-related pain.
TRIAL REGISTRATION
PROSPERO registration number: CRD42023415198.
Topics: Female; Humans; Antioxidants; Pelvic Pain; Vitamins; Endometriosis; Vitamin A; Ascorbic Acid; Vitamin K; Dietary Supplements
PubMed: 37644533
DOI: 10.1186/s12958-023-01126-1 -
American Journal of Nephrology 2024Both atrial fibrillation and venous thromboembolism (VTE) are highly prevalent among patients with chronic kidney disease (CKD). Until recently, warfarin was the most... (Review)
Review
BACKGROUND
Both atrial fibrillation and venous thromboembolism (VTE) are highly prevalent among patients with chronic kidney disease (CKD). Until recently, warfarin was the most commonly prescribed oral anticoagulant. Direct oral anticoagulants (DOACs) have important advantages and have been shown to be noninferior to warfarin with respect to stroke prevention or recurrent VTE in the general population, with lower bleeding rates. This review article will provide available evidence on the use of DOACs in patients with CKD.
SUMMARY
In post hoc analyses of major randomized studies with DOACs for stroke prevention in atrial fibrillation, in the subgroup of participants with moderate CKD, defined as a creatinine clearance (CrCl) of 30-50 mL/min, dabigatran 150 mg and apixaban were associated with lower rates of stroke and systemic embolism, whereas apixaban and edoxaban were associated with lower bleeding and mortality rates, compared with warfarin. In retrospective observational studies in patients with advanced CKD (defined as a CrCl <30 mL/min) and atrial fibrillation, DOACs had similar efficacy with warfarin with numerically lower bleeding rates. All agents warrant dose adjustment in moderate-to-severe CKD. In patients on maintenance dialysis, the VALKYRIE trial, which was designed initially to study the effect of vitamin K on vascular calcification progression, established superiority for rivaroxaban compared with a vitamin K antagonist (VKA) in the extension phase. Two other clinical trials using apixaban (AXADIA and RENAL-AF) in this population were inconclusive due to recruitment challenges and low event rates. In post hoc analyses of randomized studies with DOACs in patients with VTE, in the subgroup of participants with moderate CKD at baseline, edoxaban was associated with lower rates of recurrent VTE, whereas rivaroxaban and dabigatran were associated with lower and higher bleeding rates, respectively, as compared to warfarin.
KEY MESSAGES
DOACs have revolutionized the management of atrial fibrillation and VTE, and they should be preferred over warfarin in patients with moderate-to-severe CKD with appropriate dose adjustment. Therapeutic drug monitoring with a valid technique may be considered to guide clinical management in individualized cases. Current evidence questions the need for oral anticoagulation in patients on maintenance dialysis with atrial fibrillation as both DOACs and VKAs are associated with high rates of major bleeding.
Topics: Humans; Warfarin; Rivaroxaban; Dabigatran; Atrial Fibrillation; Venous Thromboembolism; Retrospective Studies; Treatment Outcome; Anticoagulants; Hemorrhage; Stroke; Renal Insufficiency, Chronic; Vitamin K; Administration, Oral; Pyridines; Thiazoles
PubMed: 38035566
DOI: 10.1159/000535546 -
Journal of Thrombosis and Haemostasis :... Dec 2023Fibrinolysis is the system primarily responsible for removal of fibrin deposits and blood clots in the vasculature. The terminal enzyme in the pathway, plasmin, is... (Review)
Review
Fibrinolysis is the system primarily responsible for removal of fibrin deposits and blood clots in the vasculature. The terminal enzyme in the pathway, plasmin, is formed from its circulating precursor, plasminogen. Fibrin is by far the most legendary substrate, but plasmin is notoriously prolific and is known to cleave many other proteins and participate in the activation of other proteolytic systems. Fibrinolysis is often overshadowed by the coagulation system and viewed as a simplistic poorer relation. However, the primordial plasminogen activators evolved alongside the complement system, approximately 70 million years before coagulation saw the light of day. It is highly likely that the plasminogen activation system evolved with its roots in primordial immunity. Almost all immune cells harbor at least one of a dozen plasminogen receptors that allow plasmin formation on the cell surface that in turn modulates immune cell behavior. Similarly, numerous pathogens express their own plasminogen activators or contain surface proteins that provide binding sites for host plasminogen. The fibrinolytic system has been harnessed for clinical medicine for many decades with the development of thrombolytic drugs and antifibrinolytic agents. Our refined understanding and appreciation of the fibrinolytic system and its alliance with infection and immunity and beyond are paving the way for new developments and interest in novel therapeutics and applications. One must ponder as to whether the nomenclature of the system hampered our understanding, by focusing on fibrin, rather than the complex myriad of interactions and substrates of the plasminogen activation system.
Topics: Humans; Fibrinolysis; Fibrinolysin; Plasminogen Activators; Plasminogen; Fibrin; Serine Proteases
PubMed: 38000850
DOI: 10.1016/j.jtha.2023.09.012 -
Nutrients Dec 2023Cognitive impairment and dementia are burgeoning public health concerns, especially given the increasing longevity of the global population. These conditions not only... (Meta-Analysis)
Meta-Analysis Review
Improving Cognitive Function with Nutritional Supplements in Aging: A Comprehensive Narrative Review of Clinical Studies Investigating the Effects of Vitamins, Minerals, Antioxidants, and Other Dietary Supplements.
Cognitive impairment and dementia are burgeoning public health concerns, especially given the increasing longevity of the global population. These conditions not only affect the quality of life of individuals and their families, but also pose significant economic burdens on healthcare systems. In this context, our comprehensive narrative review critically examines the role of nutritional supplements in mitigating cognitive decline. Amidst growing interest in non-pharmacological interventions for cognitive enhancement, this review delves into the efficacy of vitamins, minerals, antioxidants, and other dietary supplements. Through a systematic evaluation of randomized controlled trials, observational studies, and meta-analysis, this review focuses on outcomes such as memory enhancement, attention improvement, executive function support, and neuroprotection. The findings suggest a complex interplay between nutritional supplementation and cognitive health, with some supplements showing promising results and others displaying limited or context-dependent effectiveness. The review highlights the importance of dosage, bioavailability, and individual differences in response to supplementation. Additionally, it addresses safety concerns and potential interactions with conventional treatments. By providing a clear overview of current scientific knowledge, this review aims to guide healthcare professionals and researchers in making informed decisions about the use of nutritional supplements for cognitive health.
Topics: Humans; Vitamins; Antioxidants; Quality of Life; Dietary Supplements; Minerals; Vitamin A; Cognition; Vitamin K; Aging; Observational Studies as Topic
PubMed: 38140375
DOI: 10.3390/nu15245116 -
American Journal of Obstetrics &... Aug 2023Tranexamic acid is a cost-effective intervention for the prevention of postpartum hemorrhage among women who undergo cesarean delivery, but the evidence to support its... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
Tranexamic acid is a cost-effective intervention for the prevention of postpartum hemorrhage among women who undergo cesarean delivery, but the evidence to support its use is conflicting. We conducted this meta-analysis to evaluate the efficacy and safety of tranexamic acid in low- and high-risk cesarean deliveries.
DATA SOURCES
We searched MEDLINE (via PubMed), Embase, the Cochrane Library, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform portal from inception to April 2022 (updated October 2022 and February 2023) with no language restrictions. In addition, grey literature sources were also explored.
STUDY ELIGIBILITY CRITERIA
All randomized controlled trials that investigated the prophylactic use of intravenous tranexamic acid in addition to standard uterotonic agents among women who underwent cesarean deliveries in comparison with a placebo, standard treatment, or prostaglandins were included in this meta-analysis.
METHODS
We used the revised Cochrane Risk of Bias tool (RoB 2.0) to assess the quality of the included randomized controlled trials. RevMan 5.4 was used to conduct all statistical analyses using a random-effects model.
RESULTS
We included 50 randomized controlled trials (6 in only high-risk patients and 2 with prostaglandins as the comparator) that evaluated tranexamic acid in our meta-analysis. Tranexamic acid reduced the risk for blood loss >1000 mL, the mean total blood loss, and the need for blood transfusion in both low- and high-risk patients. Tranexamic acid was associated with a beneficial effect in the secondary outcomes, including a decline in hemoglobin levels and the need for additional uterotonic agents. Tranexamic acid increased the risk for nonthromboembolic adverse events but, based on limited data, did not increase the incidence of thromboembolic events. The administration of tranexamic acid before skin incision, but not after cord clamping, was associated with a large benefit. The quality of evidence was rated as low to very low for outcomes in the low-risk population and moderate for most outcomes in the high-risk subgroup.
CONCLUSION
Tranexamic acid may reduce the risk for blood loss in cesarean deliveries with a higher benefit observed in high-risk patients, but the lack of high-quality evidence precludes any strong conclusions. The administration of tranexamic acid before skin incision, but not after cord clamping, was associated with a large benefit. Additional studies, especially in the high-risk population and focused on evaluating the timing of tranexamic acid administration, are needed to confirm or refute these findings.
Topics: Humans; Female; Pregnancy; Tranexamic Acid; Blood Loss, Surgical; Cesarean Section; Randomized Controlled Trials as Topic; Postpartum Hemorrhage; Antifibrinolytic Agents; Prostaglandins
PubMed: 37311484
DOI: 10.1016/j.ajogmf.2023.101049 -
International Journal of Molecular... Jan 2024The objective of the present review was to summarize the molecular mechanisms associated with the effects of the vitamins A, C, E and K, and group B vitamins on bone and... (Review)
Review
The objective of the present review was to summarize the molecular mechanisms associated with the effects of the vitamins A, C, E and K, and group B vitamins on bone and their potential roles in the development of osteoporosis. Epidemiological findings have demonstrated an association between vitamin deficiency and a higher risk of developing osteoporosis; vitamins are positively related to bone health upon their intake at the physiological range. Excessive vitamin intake can also adversely affect bone formation, as clearly demonstrated for vitamin A. Vitamins E (tocopherols and tocotrienols), K2 (menaquinones 4 and 7) and C have also been shown to promote osteoblast development through bone morphogenetic protein (BMP)/Smad and Wnt/β‑catenin signaling, as well as the TGFβ/Smad pathway (α‑tocopherol). Vitamin A metabolite (all‑trans retinoic acid) exerts both inhibitory and stimulatory effects on BMP‑ and Wnt/β‑catenin‑mediated osteogenesis at the nanomolar and micromolar range, respectively. Certain vitamins significantly reduce receptor activator of nuclear factor kappa‑B ligand (RANKL) production and RANKL/RANK signaling, while increasing the level of osteoprotegerin (OPG), thus reducing the RANKL/OPG ratio and exerting anti‑osteoclastogenic effects. Ascorbic acid can both promote and inhibit RANKL signaling, being essential for osteoclastogenesis. Vitamin K2 has also been shown to prevent vascular calcification by activating matrix Gla protein through its carboxylation. Therefore, the maintenance of a physiological intake of vitamins should be considered as a nutritional strategy for the prevention of osteoporosis.
Topics: Humans; Vitamins; Cholecalciferol; beta Catenin; Vitamin A; Bone Density; Osteoporosis; Vitamin K; Bone Morphogenetic Proteins; Wnt Signaling Pathway
PubMed: 38063255
DOI: 10.3892/ijmm.2023.5333