Vitamin K Antagonist Reversal for Urgent Surgery Using 4-Factor Prothrombin Complex Concentrates: A Randomized Clinical Trial.

Importance: Millions of people take vitamin K antagonists (VKAs). Some people who need urgent surgical procedures require rapid VKA reversal to prevent excessive intraoperative bleeding. Objective: To evaluate the hemostatic noninferiority of an investigational 4-factor prothrombin complex concentrate (4F-PCC) to a control 4F-PCC for rapid VKA reversal before urgent surgery. Design, Setting, and Participants: This phase 3, double-blind, noninferiority randomized clinical trial (LEX-209) was conducted in 24 hospitals in the US, Russia, Georgia, Belarus, Ukraine, and Romania from June 7, 2017, through November 8, 2021; the study was stopped in February 2022. Participants were adult patients taking VKA who had an international normalized ratio (INR) of 2 or higher and needed urgent surgery with a substantial bleeding risk (≥50 mL). Patients were randomized 1:1 to a single infusion of either the investigational 4F-PCC or the control 4F-PCC. Data analysis followed intention-to-treat and per-protocol approaches. Interventions: Single intravenous infusion was dosed by body weight and baseline INR. A dose of 25, 35, or 50 IU/kg of investigational 4F-PCC or control 4F-PCC was administered for baseline INR of 2 to less than 4, 4 to 6, or over 6, respectively. Main Outcome and Measure: The primary end point was hemostatic efficacy at surgery end. An independent adjudication board, blinded to the 4F-PCC treatment allocation, assessed hemostatic efficacy using an objective 4-point scale. Results: A total of 208 patients (median [range] age, 67.5 [31-92] years; 118 males [56.7%]) received the investigational (n = 105) or the control (n = 103) 4F-PCC. The median (range) dose was 25 (16-50) IU/kg in the investigational group and 25 (15-50) IU/kg in the control group, with a median (range) infusion time of 12 (8-50) minutes and 13 (7-30) minutes and a median (range) time from infusion to surgery start of 1.42 (0.25-15.25) hours and 1.50 (0.42-18.50) hours, respectively. Baseline median (range) INR was 3.05 (1.97-21.10) in the investigational group and 3.00 (2.00-11.30) in the control group. In the intention-to-treat analysis, the investigational 4F-PCC was noninferior to the control 4F-PCC, resulting in effective hemostasis in 94.3% of patients vs 94.2% of patients (proportion difference, 0.001; 95% CI, -0.080 to 0.082; P < .001), meeting the prespecified noninferiority margin of 0.15. An INR of 1.5 or lower at 30 minutes after infusion occurred in 78.1% of patients in the investigational group vs 71.8% of patients in the control group (proportion difference, 0.063; 95% CI, -0.056 to 0.181). Thrombotic events (2.9% vs 0%, respectively) and mortality (4.8% vs 1.0%, respectively) were no different than expected for 4F-PCC use. One patient in each treatment group discontinued due to adverse events (cardiac disorders unrelated to 4F-PCC). Conclusions and Relevance: This randomized clinical trial found that the investigational 4F-PCC was hemostatically noninferior to the control 4F-PCC for rapid VKA reversal in patients needing urgent surgery with considerable bleeding risk; the safety profile of these two 4F-PCCs was similar. These results support the investigational 4F-PCC as a therapeutic option for surgical patients requiring rapid VKA reversal. Trial Registration: ClinicalTrials.gov Identifier: NCT02740335.

Factor Xa Inhibitors Versus Vitamin K Antagonists in Atrial Fibrillation Patients with End-Stage Kidney Disease on Dialysis: A Meta-Analysis.

BACKGROUND: Atrial fibrillation (AF) is prevalent among patients with end-stage kidney disease (ESKD) undergoing dialysis, and both conditions are associated with a heightened risk of cardiovascular diseases. Anticoagulation is essential for preventing thromboembolic complications in these patients. This study aimed to evaluate the effects of factor Xa inhibitors compared to vitamin K antagonists (VKAs) for AF patients on dialysis. METHODS: A comprehensive search of PubMed and Embase databases was conducted to identify relevant studies published up to June 2024. Eligible studies compared factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) with VKAs in AF patients on dialysis, with primary outcomes of stroke or systemic embolism(SSE) and major bleeding. RESULTS: A total of 7 studies (3 randomized controlled trials and 4 observational cohorts) were included. For the RCTs, the use of factor Xa inhibitors was associated with a reduced risk of SSE compared to VKAs (odds ratio [OR] = 0.37, 95% confidence interval [CI]:0.15-0.93). There was no significant difference in the risk of major bleeding events between the two groups (OR = 0.65, 95%CI:0.32-1.33). Observational cohort studies yielded similar results with a decreased risk of SSE (hazard ratio [HR] = 0.74, 95%CI:0.57-0.96) and no significant difference in major bleeding (HR = 0.87, 95%CI:0.62-1.22). No differences in treatment effect between apixaban and rivaroxaban were observed for efficacy (p-interaction = 0.44) and safety (p-interaction = 0.21) outcomes. CONCLUSION: Factor Xa inhibitors, particularly apixaban and rivaroxaban, were associated with a lower risk of SEE without an increase in major bleeding, which might be convenient alternatives to VKAs in managing AF in patients with ESKD on dialysis.

Effect of Direct Oral Anticoagulants in Patients with Splanchnic Vein Thrombosis: A Systematic Reviews and Meta-Analysis.

BACKGROUND: Since several studies have examined the use of direct oral anticoagulants (DOACs) in treating patients with splanchnic vein thrombosis (SVT), we conducted a meta-analyses to assess the safety and efficacy of DOACs compared to vitamin K antagonists (VKAs) in this population. METHODS: We conducted a comprehensive search using the PubMed, Embase, and Cochrane Library databases until June 2024. We used odds ratios (ORs) and 95% confidence intervals (CIs) as the effect measures to compare DOACs with VKAs. RESULTS: A total of 9 observational studies were included. The pooled analysis revealed that a trend towards higher complete recanalization rates with DOACs (71.4%) compared to VKAs (55.3%), though not statistically significant (OR 1.95; 95%CI 0.70 to 5.44). For SVT extension, a significant effect was observed favoring DOACs (OR 0.12; 95%CI 0.03 to 0.54). No significant differences were found in other efficacy outcomes or safety outcomes, except for major bleeding, which was significantly lower with DOACs (OR 0.27; 95%CI 0.13 to 0.56). CONCLUSION: DOACs are superior to VKAs in SVT extension and major bleeding, suggesting that DOACs may be a favorable treatment option in the treatment of SVT.

Late-onset vitamin K deficiency presenting as haemorrhagic shock and severe multi-system organ failure.

Vitamin K is an essential dietary cofactor required for the synthesis of active forms of vitamin K-dependent procoagulant proteins. Vitamin K deficiency, particularly late-onset deficiency occurring between 1 week and 6 months of age, can cause a life-threatening bleeding disorder. An exclusively breastfed, full-term, 6-week-old infant male presented with severe haemorrhagic shock and multi-system organ failure related to caregiver refusal of intramuscular vitamin K after birth. Coagulation studies were normalised within 8 hours of intramuscular vitamin K administration. An increasing number of caregivers are refusing intramuscular vitamin K which has led to a rise in the incidence of vitamin K deficiency bleeding. Health policy organisations around the world emphasise the benefits of intramuscular vitamin K and risks of refusal, particularly in exclusively breastfed infants who are at higher risk due to low vitamin K levels in breast milk. This case highlights the multi-system severity of this life-threatening yet preventable disorder.

Antioxidant Properties of Green Plants with Different Vitamin K Contents.

Vitamin K, as a natural protector of our blood, bones, kidneys, and brain, is essential for human health. It is also considered an effective anti-aging agent with comprehensive biological effects, including antifungal, antibacterial, anti-inflammatory, analgesic, and even antioxidant properties. Of these, the least is known about the antioxidant properties of natural vitamin K. To fill this gap, this study compared the antioxidant properties of extracts obtained from commonly consumed green plants with different vitamin K contents with the activity of vitamin K standard solutions at concentrations corresponding to the vitamin K contents in the extracts. Various measurement methods were used in the research (i.e., DPPH, FRAP, CUPRAC, and the ß-carotene bleaching test). Among the tested methods, the ß-carotene bleaching test is the most sensitive in the assessment of this unusual compound. In light of the data presented, the antioxidant response of vitamin K alone is dose-dependent. However, in extracts, the activity of this compound is modulated by other constituents present in them. As a result, the activity does not always correlate with vitamin K content. The presented data supplement the knowledge about the antioxidant properties with the contribution resulting from the presence of vitamin K in green plant extracts.

The Importance of Vitamin K and the Combination of Vitamins K and D for Calcium Metabolism and Bone Health: A Review.

The aim of the present review is to discuss the roles of vitamin K (phylloquinone or menaquinones) and vitamin K-dependent proteins, and the combined action of the vitamins K and D, for the maintenance of bone health. The most relevant vitamin K-dependent proteins in this respect are osteocalcin and matrix Gla-protein (MGP). When carboxylated, these proteins appear to have the ability to chelate and import calcium from the blood to the bone, thereby reducing the risk of osteoporosis. Carboxylated osteocalcin appears to contribute directly to bone quality and strength. An adequate vitamin K status is required for the carboxylation of MGP and osteocalcin. In addition, vitamin K acts on bone metabolism by other mechanisms, such as menaquinone 4 acting as a ligand for the nuclear steroid and xenobiotic receptor (SXR). In this narrative review, we examine the evidence for increased bone mineralization through the dietary adequacy of vitamin K. Summarizing the evidence for a synergistic effect of vitamin K and vitamin D3, we find that an adequate supply of vitamin K, on top of an optimal vitamin D status, seems to add to the benefit of maintaining bone health. More research related to synergism and the possible mechanisms of vitamins D3 and K interaction in bone health is needed.

[Biosynthesis of fat-soluble vitamins].

Vitamins are the essential organic substances to ensure the normal life activities of the human body. At present, vitamins are widely used in the pharmaceutical, food, animal farming, beauty and other industries, appearing in increasing application scenarios. Accordingly, the global demand for vitamins has also increased greatly. The current methods of vitamin production mainly include chemical synthesis and biosynthesis, with the latter being greener, more environmentally friendly, safer, and lower in energy consumption. Establishing the method for the biosynthesis of vitamins is of great scientific significance for achieving the goals of low carbon, energy saving, and emission reduction, as well as carbon emission peak and carbon neutrality in China. This paper reviews the research progress in the biosynthesis of vitamins, especially fat-soluble vitamins (vitamins A, D, E, and K), in recent years.

Decreased serum levels of 25-OH vitamin D and vitamin K in patients with type 2 diabetes mellitus.

Background: Insulin resistance and/or insulin secretion dysfunction are crucial causes of type 2 diabetes mellitus (T2DM). Although some studies have suggested potential roles for vitamins D and K in glucose metabolism and insulin sensitivity, there is limited and inconclusive research on their levels in T2DM patients and their relationship with blood glucose levels and insulin resistance. Additionally, there is a lack of large-scale clinical trials and comprehensive studies investigating the combined effects of vitamins D and K on T2DM. Methods: A total of 195 participants with newly diagnosed T2DM were included in the research group, while 180 volunteers undergoing physical examinations in our hospital served as the control group. Fasting plasma glucose (FPG) was estimated using the glucose-oxidase technique, and fasting serum insulin (FINS) was evaluated by radioimmunoassay. FPG and FINS were used to calculate the homeostasis model assessment-insulin resistance (HOMA-IR). Serum vitamin D levels were measured using 25-hydroxyvitamin D, and vitamin K levels were evaluated using phylloquinone (VK1) and menaquinone (VK2) via ultra-high performance liquid chromatography and tandem mass spectrometry. Receiver operating characteristic (ROC) analysis was performed to assess the predictive value of these vitamins for T2DM. Results: Circulating levels of 25-hydroxyvitamin D (25.95 ± 10.42 ng/mL), VK1 (1.24 ± 0.89 ng/mL), and VK2 (0.2 ± 0.21 ng/mL) in T2DM patients were significantly lower than in the control group (37.46 ± 13.95 ng/mL for 25-hydroxyvitamin D, 1.99 ± 1.39 ng/mL for VK1, and 0.33 ± 0.22 ng/mL for VK2; p<0.001 for all comparisons). ROC analysis indicated that 25-hydroxyvitamin D, VK1, and VK2 could predict the occurrence of T2DM, with AUC values of 0.75, 0.69, and 0.71, respectively. In T2DM patients, 25-hydroxyvitamin D levels were positively correlated with VK1 (r=0.43, p<0.001) and VK2 (r=0.40, p<0.001) levels. FPG and HOMA-IR in T2DM patients were negatively correlated with circulating levels of 25-hydroxyvitamin D (r=-0.57, p<0.001), VK1 (r=-0.44, p<0.001), and VK2 (r=-0.36, p<0.001). Conclusion: Circulating levels of vitamins D and K are lower in T2DM patients and show significant correlations with blood glucose levels and insulin resistance. These findings suggest that measurements of 25-hydroxyvitamin D, VK1, and VK2 could have predictive value for T2DM, highlighting the potential roles of these vitamins in T2DM management.

Direct Oral Anticoagulants versus Vitamin K Antagonists for Left Ventricular Thrombus: A Meta-Analysis with Trial Sequential Analysis. / Anticoagulantes Orais Diretos versus Antagonistas da Vitamina K para Trombo Ventricular Esquerdo: Uma Metanálise com Análise Sequencial de Ensaios.

BACKGROUND: Vitamin K antagonists (VKAs) are the recommended first-line treatment for left ventricular thrombus (LVT); however, direct oral anticoagulants (DOACs) have been considered an alternative therapy. OBJECTIVES: To evaluate the efficacy and safety of DOACs compared with VKAs therapy in patients with LVT. METHODS: PubMed, Embase, and Cochrane were systematically searched for randomized clinical trials or cohort studies that compared DOACs versus VKAs for LVT. Risk ratios (RRs) were computed for binary endpoints, with 95% confidence intervals (95% CIs). Statistical significance was defined as p value < 0.05. RESULTS: A total of 4 randomized clinical trials and 29 cohort studies were included, with 4,450 patients assigned to either DOACs or VKAs. There was no significant difference between groups for stroke or systemic embolic (SSE) events (RR 0.84; 95% CI 0.65 to 1.07; p = 0.157), stroke (RR 0.73; 95% CI 0.48 to 1.11; p = 0.140), systemic embolic (SE) events (RR 0.69; 95% CI 0.40 to 1.17; p = 0.166), thrombus resolution (RR 1.05; 95% CI 0.99 to 1.11; p = 0.077), any bleeding (RR 0.78; 95% CI 0.60 to 1.00; p = 0.054), clinically relevant bleeding (RR 0.69; 95% CI 0.46 to 1.03; p = 0.066), minor bleeding (RR 0.73; 95% CI 0.43 to 1.23; p = 0.234), major bleeding (RR 0.87; 95% CI 0.42 to 1.80; p = 0.705), and all-cause mortality (RR 1.05; 95% CI 0.79 to 1.39; p = 0.752). Compared with VKAs, rivaroxaban significantly reduced SSE events (RR 0.35; 95% CI 0.16 to 0.91; p = 0.029) and SE events (RR 0.39; 95% CI 0.16 to 0.95; p = 0.037). CONCLUSIONS: DOACs had a similar rate of thromboembolic and hemorrhagic events, as well as thrombus resolution, compared to VKAs in the treatment of LVTs. Rivaroxaban therapy had a significant reduction in thromboembolic events, compared to VKAs.

Investigating the Effects and Mechanisms of Combined Vitamin D and K Supplementation in Postmenopausal Women: An Up-to-Date Comprehensive Review of Clinical Studies.

Aging is a complex process and a significant risk factor for chronic diseases. Menopause, a component of aging in women, is associated with several important cardiometabolic conditions including metabolic syndrome, osteoporosis, and cardiovascular diseases. Menopausal women could benefit from preventative strategies that may decrease morbidity and mortality and improve their quality of life. Vitamins D and K are essential nutrients required for bone health, immune function, and reducing cardiovascular risks, yet their synergistic effect is less understood in aging women. This is the first comprehensive review to summarize the evidence found in randomized clinical trials of the beneficial effects of vitamin D and K co-treatment in postmenopausal women. In our literature search across key electronic databases such as Cochrane, PubMed, and Ovid, we identified 31 pertinent studies. Overall, significant findings indicate that the combined intake of vitamins D and K may positively affect cardiovascular and bone health in postmenopausal women, emphasizing the importance of maintaining a healthy diet rich in vegetables and fermented dairy products. Given the challenges in obtaining all necessary nutrients solely through the diet, vitamin D and K supplements are recommended for postmenopausal women to promote healthy aging and well-being.

Impact of patient selection in clinical trials: application of ROCKET AF and ARISTOTLE criteria in GARFIELD-AF.

BACKGROUND: The extent to which differences in results from Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) and Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial (ROCKET) atrial fibrillation (AF)-the landmark trials for the approval of apixaban and rivaroxaban, respectively, for non-valvular AF-were influenced by differences in their protocols is debated. The potential influence of selection criteria on trial results was assessed by emulating these trials in data from the Global Anticoagulant Registry in the Field (GARFIELD)-AF registry. METHODS: Vitamin K antagonist (VKA) and non-vitamin K oral antagonist (NOAC) users from GARFIELD-AF were selected according to eligibility for the original ARISTOTLE or ROCKET AF trials. A propensity score overlap weighted Cox model was used to emulate trial randomisation between treatment groups. Adjusted HRs for stroke or systemic embolism (SE) within 2 years of enrolment were calculated for each NOAC versus VKA. RESULTS: Among patients on apixaban, rivaroxaban and VKA, 2570, 3560 and 8005 were eligible for ARISTOTLE, respectively, and 1612, 2005 and 4368, respectively, for ROCKET AF. When selecting for ARISTOTLE criteria, apixaban users had significantly lower stroke/SE risk versus VKA (HR 0.57; 95% CI 0.34 to 0.94) while no reduction was observed with rivaroxaban (HR 0.98; 95% CI 0.68 to 1.40). When selecting for ROCKET AF criteria, safety and efficacy versus VKA were similar across the NOACs. CONCLUSION: Apixaban and rivaroxaban showed similar results versus VKA in high-risk patients selected according to ROCKET AF criteria, whereas differences emerged when selecting for the more inclusive ARISTOTLE criteria. Our results highlight the importance of trial selection criteria in interpreting trial results and underline the problems faced in comparing treatments across rather than within clinical trials.

Vitamin K: a potential missing link in critical illness-a scoping review.

BACKGROUND: Vitamin K is essential for numerous physiological processes, including coagulation, bone metabolism, tissue calcification, and antioxidant activity. Deficiency, prevalent in critically ill ICU patients, impacts coagulation and increases the risk of bleeding and other complications. This review aims to elucidate the metabolism of vitamin K in the context of critical illness and identify a potential therapeutic approach. METHODS: In December 2023, a scoping review was conducted using the PRISMA Extension for Scoping Reviews. Literature was searched in PubMed, Embase, and Cochrane databases without restrictions. Inclusion criteria were studies on adult ICU patients discussing vitamin K deficiency and/or supplementation. RESULTS: A total of 1712 articles were screened, and 13 met the inclusion criteria. Vitamin K deficiency in ICU patients is linked to malnutrition, impaired absorption, antibiotic use, increased turnover, and genetic factors. Observational studies show higher PIVKA-II levels in ICU patients, indicating reduced vitamin K status. Risk factors include inadequate intake, disrupted absorption, and increased physiological demands. Supplementation studies suggest vitamin K can improve status but not normalize it completely. Vitamin K deficiency may correlate with prolonged ICU stays, mechanical ventilation, and increased mortality. Factors such as genetic polymorphisms and disrupted microbiomes also contribute to deficiency, underscoring the need for individualized nutritional strategies and further research on optimal supplementation dosages and administration routes. CONCLUSIONS: Addressing vitamin K deficiency in ICU patients is crucial for mitigating risks associated with critical illness, yet optimal management strategies require further investigation. IMPACT RESEARCH: To the best of our knowledge, this review is the first to address the prevalence and progression of vitamin K deficiency in critically ill patients. It guides clinicians in diagnosing and managing vitamin K deficiency in intensive care and suggests practical strategies for supplementing vitamin K in critically ill patients. This review provides a comprehensive overview of the existing literature, and serves as a valuable resource for clinicians, researchers, and policymakers in critical care medicine.

Building evidence on safety of endovascular thrombectomy for patients under anticoagulation with vitamin K antagonists.

A recent study by Brian Mac Grory and colleagues investigated the safety of endovascular thrombectomy (EVT) among patients under vitamin K antagonists (VKAs) use within 7 days prior to hospital admission. Through this retrospective, observational cohort study, they found prior VKA use did not increase the risk of symptomatic intracranial hemorrhage (sICH) overall. However, recent VKA use with a presenting international normalized ratio (INR) > 1.7 was associated with a significantly increased risk of sICH. Future large-scale randomized controlled trials should be conducted to further clarify the effects and feasibility of EVT therapy in ischemic stroke patients under anticoagulation.

Rivaroxaban versus vitamin K antagonist treatment on the progression of coronary calcification: the IRIVASC-trial.

Vitamin K antagonists (VKA) remain the only option of anticoagulation for people with mechanical valve replacement and due to their wider availability and lower acquisition costs, VKA's remain widely used in low- and middle-income countries. It has been suggested that prolonged use of VKAs can increase the development of vascular and valvular calcification, though this effect has not been examined in larger randomized prospective trials. This investigator-initiated multicenter, prospective, randomized, open-label interventional trial randomized patients with baseline coronary or valvular calcification and an indication for prolonged oral anticoagulation therapy to Marcumar or Rivaroxaban. Patients were followed-up through repeat coronary computed tomographies to measure the progression of coronary and valvular calcification for up to 24 months. 192 patients were randomized between 2013 and 2018 to receive either Rivaroxaban or Marcumar and followed for up to 24 months. Coronary calcification significantly increased over time although there was no significant difference in progression between the groups after 12 and 24 months as measured by the Agatston score [360.7 (90.2; 1075.3) vs 380.4 (136.4; 1546.9) p = 0.69], the volume score [295.8 (93.0; 995.3) vs 335.5 (128.7; 1316.9) p = 0.95] and the mass score [58.5 (15.9; 172.0) vs 71.1 (24.8; 257.3) p = 0.5]. Dephosphorylated, uncarboxylated matrix Gla Protein (Dp-ucMGP) significantly decreased in the VKA group [Δ dp-uc MGP - 95.2 (- 554.1; 156.0) vs 231.3 (- 59.7; 388.1) p < 0.001]. There does not appear to be a relevant effect of vitamin K inhibition by the vitamin K antagonist marcumar upon coronary calcification.