Antagonists In Patients Research Articles

Cardiovascular and Renal Benefit of Novel Non-steroidal Mineralocorticoid Antagonists in Patients with Diabetes.

Novel non-steroidal mineralocorticoid receptor (MR) antagonists (MRAs) are a new class of drugs blocking adverse MR-mediated effects with an improved benefit-risk profile compared to steroidal MRAs. This review will provide information on the preclinical and clinical pharmacology of this new drug class and will discuss their future clinical applications in patients with cardiorenal disease. Non-steroidal MRAs such as esaxerenone, AZD9977, apararenone, ocedurenone (KBP-5074), and finerenone are newly approved or in clinical development for patients with cardiorenal disease including type 2 diabetes (T2D) and chronic kidney disease (CKD), hypertension -/+ CKD or heart failure. Unlike steroidal MRAs, non-steroidal MRAs do not induce sex hormone-related side effects and appear to mediate a lower risk of hyperkalemia while maintaining compelling clinical efficacy. Recently, new data from several clinical trials with non-steroidal MRAs have been published (e.g., FIDELIO-DKD, FIGARO-DKD, ESAX-DN, and BLOCK-CKD), and additional studies are currently underway (e.g., FINEARTS-HF and CLARION-CKD). These data and the clinical scientific basis for the ongoing studies will be discussed. Non-steroidal MRAs have been extensively explored in diabetic kidney disease. Selected candidates of this drug class reduced UACR in patients with varying degrees of CKD and T2D and have shown convincing cardiorenal protection, in particular finerenone. Furthermore, finerenone is currently tested in patients with heart failure with preserved ejection fraction.

The efficacy and safety of direct oral anticoagulants compared with vitamin K antagonist in patients with hypertrophic cardiomyopathy and atrial fibrillation: a systematic review and meta-analysis

Abstract Background The benefit-risk profile of direct oral anticoagulants (DOAC) therapy in patients with hypertrophic cardiomyopathy (HCM) and atrial fibrillation (AF) have not been well established yet. Purpose This study aimed to evaluate the efficacy and safety of DOAC compared with vitamin K antagonists (VKA) in patients with HCM and AF. Methods PubMed, EMBASE, the Cochrane Library and clinicaltrials.gov were searched to identify studies comparing DOAC with VKA in patients with HCM and AF. Results Five studies involving 8103 patients were included in this meta-analysis. Compared to the VKA group, the DOAC group displayed a significant lower risk of all-cause death [RR (95%CI): 0.44 (0.35-0.55)]. Meanwhile, DOAC therapy group was similar to VKA therapy in reducing ischemic stroke [RR (95%CI): 0.65 (0.33-1.28)] and thromboembolic events [RR (95%CI): 0.95 (0.74-1.22)]. The incidence of major bleeding [RR (95%CI): 0.69 (0.44-1.07)] were comparable between the two groups. Conclusion In patients with HCM and AF, DOAC therapy were superior or non-inferior to VKA therapy in reducing the risk of all-cause death and thromboembolic events, without increasing bleeding risk. Further RCTs are needed to provide more evidence for DOAC therapy in this population.Efficacy and safety endpoints in DOAC th

Direct oral anticoagulants versus vitamin k antagonists in patients with atrial fibrillation and bioprosthesis: a systematic review and meta-analysis

Abstract Background/Introduction The large randomized clinical trials published to date have shown that direct oral anticoagulants (DOACs) are as or more effective than vitamin K antagonists (VKAs) in the prevention of thromboembolic events in atrial fibrillation (AF) and generally show a better bleeding risk profile. However, patients with bioprosthetic valves have been underrepresented in RCTs. The aim of this study was to assess the safety and efficacy of DOAC in patients with AF and bioprosthetic valves through a systematic review and meta-analysis including recent evidence from comparative cohort studies and real-world results. Methods A systematic review of the scientific literature and a subsequent meta-analysis were carried out. We included RCTs or comparative observational studies, published from January 2017 to January 2022 comparing DOACs versus vitamin K antagonists in patients with AF or atrial flutter and bioprostheses. We collected data of all-cause mortality, major bleeding, and systemic embolism. The primary outcome of interest was all-cause mortality. Secondary outcomes were systemic embolism or stroke. The primary safety outcome was major bleeding. Results Our analysis included 12 studies, 4 RCTs and 8 observational studies that enrolled a total of 30.283 patients. All-cause mortality 6 observational and 3 RCT were combined. A 9% reduction was found for all-cause mortality in patients treated with DOACs (HR,0.91; P=.0068;95%CI,0.85–0.97;I2=8%). Stroke and systemic embolism 4 RCT and 8 observational studies were combined. No evidence showing a significant effect of DOAC therapy on risk reduction for stroke and embolism was obtained (HR, 0.87; P =.29; 95%CI, 0.67–1.14; I2=45%). Major bleeding The results of the 12 studies were combined. A robustness analysis was performed, and the ENVISAGE RCT was identified as atypical. We therefore proceeded to re-run the meta-analysis without this study’s results. The overall effect size was HR, 0.79 (P = .0001; 95%CI, 0.73-0.85; I2 = 0%), with a 21.1% reduction of major bleeding with DOAC therapy compared with VKA. The present study has several limitations. It has the inherent limitations of the studies included and the combination of findings from comparative observational cohort studies and ad hoc studies from RCTs, which entails a potential source of bias. Second, individual risks for each type of bioprosthesis were not studied. Finally, the four currently marketed DOACs were included in our meta-analysis, but their efficacy and safety were not evaluated separately. Conclusions Our study found that DOAC therapy is associated with a significant reduction of all-cause mortality with no significant increase in the risk of systemic embolism or stroke. This reduction could be attributed to a decrease in major bleeding. Our results therefore suggest that DOACs could be a safer alternative than VKAs in this group of patients.

Direct oral anticoagulants versus vitamin K antagonists in patients with atrial fibrillation on chronic haemodialysis: a systematic review and meta-analysis of randomised controlled trials

Abstract Background Patients with atrial fibrillation (AF) and end-stage renal disease on chronic haemodialysis (HD) are at risk for thromboembolic and bleeding events. The safety and efficacy of direct oral anticoagulants (DOACs) compared with vitamin K antagonists (VKAs) in this population remains unclear. Purpose This systematic review and meta-analysis aimed to compare DOACs with VKAs in patients with AF on chronic HD with regards to cardiovascular mortality, all-cause mortality, ischaemic or uncertain type of stroke, and major or life-threatening bleeding. Methods We systematically searched PubMed, EMBASE, and Cochrane Library for randomised controlled trials (RCTs) comparing DOACs with VKAs in patients with AF on chronic HD from inception to February 2023 in accordance with PRISMA guidelines. Statistical analyses were performed using Review Manager 5.4.1. Heterogeneity was evaluated using I2 statistics. We performed the data extraction following the intention-to-treat principle. Results We selected three RCTs including 341 patients, of whom 176 (51.6%) were randomised to DOACs. Follow-up ranged from 174 days to 3.38 years. There was no significant difference between groups in terms of cardiovascular mortality (RR 1.35; 95% CI 0.71–2.60; p=0.36; I2=0%; Fig. 1A), all-cause mortality (RR 0.99; 95% CI 0.76–1.30; p=0.96; I2=11%; Fig. 1B), ischaemic or uncertain type of stroke (RR 0.52; 95% CI 0.18–1.48; p=0.22; I2=0%; Fig. 2A), or major or life-threatening bleeding (RR 0.69; 95% CI 0.42–1.14; p=0.15; I2=20%; Fig. 2B), with an overall low between-study heterogeneity. Conclusion In this meta-analysis, no significant difference was observed between DOACs and VKAs in cardiovascular mortality, all-cause mortality, ischaemic or uncertain type of stroke, nor major or life-threatening bleeding in patients with AF on chronic HD.Figure 1Figure 2

Clinical safety and narcolepsy-like symptoms of dual orexin receptor antagonists in patients with insomnia: a systematic review and meta-analysis.

Dual orexin receptor antagonists (DORAs) are emerging treatments for insomnia. This meta-analysis study aimed to assess the safety of FDA-approved DORAs (suvorexant, lemborexant, and daridorexant), focusing on narcolepsy-like symptoms associated with these drugs. Five prominent databases were searched to identify randomized controlled trials (RCTs) on this topic. Primary safety outcomes included treatment-emergent adverse events (TEAEs), treatment-related TEAEs, TEAEs leading to discontinuation, and serious TEAEs. Excessive daytime sleepiness (EDS), sleep paralysis, and hallucinations were categorized as adverse events (AEs)-related narcolepsy-like symptoms. Eleven RCTs with 7703 patients were included. DORAs were associated with a higher risk of TEAEs (risk ratio [RR], 1.09; 95% confidence interval [CI], 1.03 to 1.15) and treatment-related TEAEs (RR, 1.69; 95% CI: 1.49 to 1.92) when compared to placebo. The DORA group exhibited a significantly higher risk of EDS (RR, 2.15; 95% CI: 1.02 to 4.52) and sleep paralysis (RR, 3.40; 95% CI: 1.18 to 9.80) compared to the placebo group. This meta-analysis achieved a comparative evaluation of the clinical safety and tolerability of FDA-approved DORAs for primary insomnia, specifically focusing on AEs-related narcolepsy-like symptoms. This study contributes to understanding the safety profile of FDA-approved DORAs for treating insomnia.

Efficacy and Safety of Long-Term Anticoagulation Therapy with Direct Oral Anticoagulants versus Vitamin K Antagonist in Patients with Cerebral Venous Thrombosis

Efficacy and Safety of Long-Term Anticoagulation Therapy with Direct Oral Anticoagulants versus Vitamin K Antagonist in Patients with Cerebral Venous Thrombosis

Administration of luteal GnRH antagonist in patients with high serum progesterone levels on the day of egg retrieval

Administration of luteal GnRH antagonist in patients with high serum progesterone levels on the day of egg retrieval

Non-steroidal mineralocorticoid receptor antagonists in patients with chronic kidney disease and type 2 diabetes.

Chronic kidney disease (CKD) in patients with type 2 diabetes (T2D) is a major health challenge associated with a disproportionately high burden of end-stage renal disease, cardiovascular disease and death. This review summarizes the rationale, clinical evidence and practical implementation for non-steroidal mineralocorticoid receptor antagonists (nsMRAs), a drug class now approved and recommended for patients with T2D and CKD at risk of cardiorenal disease progression. Three nsMRAs (finerenone, esaxerenone and apararenone) have been evaluated but finerenone is currently the only approved nsMRA for this indication. Two large-scale, placebo-controlled, Phase 3 studies evaluated finerenone added to a maximally tolerated dose of an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker. Over >2 years of treatment, finerenone was associated with a significant reduction in composite endpoints of renal and cardiovascular outcomes versus placebo. Esaxerenone or apararenone have both shown significant improvements in albuminuria versus placebo. In general, nsMRAs were well tolerated. Hyperkalaemia was the most notable treatment-related adverse event and could generally be managed through serum potassium monitoring and dose adjustments. The nsMRAs are now an important component of recommended treatment for CKD associated with T2D, providing a significant reduction in the risk of cardiorenal progression beyond what can be achieved with glucose and blood pressure control.

Meta-Analysis Comparing Direct Oral Anticoagulants Versus Vitamin K Antagonists in Patients With Chronic Thromboembolic Pulmonary Hypertension

Meta-Analysis Comparing Direct Oral Anticoagulants Versus Vitamin K Antagonists in Patients With Chronic Thromboembolic Pulmonary Hypertension

An Evidence-Based Approach to Anticoagulation Therapy Comparing Direct Oral Anticoagulants and Vitamin K Antagonists in Patients With Atrial Fibrillation and Bioprosthetic Valves: A Systematic Review, Meta-Analysis, and Network Meta-Analysis

Direct oral anticoagulants (DOACs) are a newer class of anticoagulants that inhibit factor Xa or factor IIa and include drugs such as rivaroxaban, apixaban, edoxaban, betrixaban, and dabigatran. Although vitamin K antagonists (VKAs) have been traditionally used to prevent thromboembolic events, DOACs have gained popularity because of their faster onset and offset of action and reduced need for monitoring. This study aimed to provide more data for anticoagulants in patients with atrial fibrillation with bioprosthetic heart valves by incorporating all available trials to date. A search was performed across 5 electronic databases to identify relevant studies. We analyzed the data using a pooled risk ratio for categorical outcomes and used the I2 test to determine heterogeneity. The quality of randomized controlled trials was assessed using the Cochrane risk of bias assessment tool, and the National Institutes of Health tool was used for observational studies. Our study included a frequentist network meta-analysis (MA) of the aggregate data to obtain the network estimates for the outcomes of interest. We retrieved 28 studies with a total of 74,660 patients with bioprosthetic heart valves. Our MA significantly showed that DOACs decrease the risk of all-cause bleeding (risk ratio [RR] 0.80, 95% confidence interval [CI] 0.75 to 0.85, p >0.00001), stroke and systemic embolization (RR 0.89, 95% CI 0.80 to 0.99, p=0.03), and intracranial bleeding outcomes (RR 0.62, 95% CI 0.45 to 0.86, p=0.004) compared with VKA. In contrast, there was no significant difference between the compared groups in major bleeding (RR=0.92, 95% CI 0.84 to 1.02, p=0.10) and all-cause mortality outcomes (RR=0.96, 95% CI 0.85 to 1.07, p=0.43), respectively. In addition, the network MA results did not favor any of the studied interventions over each other (p <0.05) regarding all-cause bleeding, mortality, stroke and systemic embolization, and major bleeding outcomes. In conclusion, our study found that DOACs are more effective in reducing the risk of bleeding, stroke, systemic embolism, and intracranial bleeding than VKAs. However, no significant difference was observed in the incidence of gastrointestinal bleeding, major bleeding, thromboembolic events, and all-cause mortality. In addition, our network MA did not identify any specific DOAC treatment as more favorable than others.

Adenosine A2A receptor is a tumor suppressor of NASH-associated hepatocellular carcinoma

Inhibition of adenosine A2A receptor (A2AR) is a promising approach for cancer immunotherapy currently evaluated in several clinical trials. We here report that anti-obesogenic and anti-inflammatory functions of A2AR, however, significantly restrain hepatocellular carcinoma (HCC) development. Adora2a deletion in mice triggers obesity, non-alcoholic steatohepatitis (NASH), and systemic inflammation, leading to spontaneous HCC and promoting dimethylbenzyl-anthracene (DMBA)- or diethylnitrosamine (DEN)-induced HCC. Conditional Adora2a deletion reveals critical roles of myeloid and hepatocyte-derived A2AR signaling in restraining HCC by limiting hepatic inflammation and steatosis. Remarkably, the impact of A2AR pharmacological blockade on HCC development is dependent on pre-existing NASH. In support of our animal studies, low ADORA2A gene expression in human HCC is associated with cirrhosis, hepatic inflammation, and poor survival. Together, our study uncovers a previously unappreciated tumor-suppressive function for A2AR in the liver and suggests caution in the use of A2AR antagonists in patients with NASH and NASH-associated HCC.

The Risk of Neuropsychiatric Adverse Events With Use of Leukotriene Receptor Antagonists in Patients With Asthma: Analysis of Korea’s National Health Insurance Sharing Service Database

Montelukast, a selective leukotriene receptor antagonist, is a commonly prescribed allergy medication but its potential association with neuropsychiatric adverse events is concerning. To analyze Korea's National Health Insurance System claims records to identify the risk of neuropsychiatric adverse events in patients with asthma treated with montelukast. This retrospective population-based study analyzed the National Health Insurance claims records of the entire Korean population between 2008 and 2015. We compared the risk of neuropsychiatric adverse events among patients with asthma using inhaled corticosteroids and/or long-acting β2-agonists with montelukast or pranlukast and those not using leukotriene receptor antagonists (control group). There was no increased risk of the composite outcome of all measured neuropsychiatric adverse events in patients with asthma who were prescribed montelukast or pranlukast compared with those who were not. However, montelukast use was associated with an increased risk of hallucinations (inverse probability treatment weighting hazard ratio, 1.45; 95% CI, 1.07-1.96) and attention problems (inverse probability treatment weighting hazard ratio, 1.24; 95% CI, 1.01-1.52). Significant negative hazards for disorientation, anxiety, stress reactions, and somatic symptoms were observed in the montelukast group. When grouped by sex, the risk of hallucinations and attention problems was higher in men prescribed montelukast compared with the controls. We did not observe an increase in all neuropsychiatric adverse events in the leukotriene receptor antagonist-treated group; however, an increased risk of hallucinations and attention problems was observed in those taking montelukast, regardless of the medication administration period.

Efficacy and safety of direct oral anticoagulants vs vitamin K antagonists in patients with atrial fibrillation and end-stage renal disease on hemodialysis: A systematic review and meta-analysis

BackgroundThe prevalence of atrial fibrillation (AF) in individuals with end-stage renal disease (ESRD) on chronic hemodialysis is increasing. The optimal anticoagulant choice in this population is unclear since these patients were excluded from the pivotal randomized controlled trials (RCTs) of direct oral anticoagulants (DOACs) vs. vitamin K antagonists (VKAs) in the general AF population. We aimed to assess the efficacy and safety of DOACs vs. VKAs in patients with AF and ESRD on chronic hemodialysis through a systematic review and meta-analysis of all available evidence. Patients/MethodsWe performed a systematic search in MEDLINE and Scopus for RCTs or observational studies of patients with AF and ESRD on chronic hemodialysis who were treated with DOACs or VKAs. The outcomes of interest included ischemic stroke, the composite of ischemic stroke or systemic embolism, major bleeding, gastrointestinal bleeding, minor bleeding events and all-cause mortality. ResultsAmong 397 studies identified from the literature search, six studies (three RCTs and three observational studies) were included in the meta-analysis. Compared with VKA-treated patients, those treated with DOACs had similar risk of ischemic stroke (RR:0.76, 95% CI:0.41–1.41), ischemic stroke or systemic embolism (RR:0.65, 95% CI:0.38–1.10), major bleeding (RR:0.79, 95% CI:0.49–1.28) and all-cause death (RR:0.79, 95% CI:0.56–1.12). The risk of gastrointestinal bleeding was lower in DOAC- vs VKA-treated patients in three eligible observational studies (RR:0.73, 95% CI: 0.54–0.99, I2 = 79%) but this was not confirmed in two eligible RCTs (RR:0.69, 95% CI: 0.33–1.43, I2 = 0%). ConclusionsAmong AF patients with ESRD on chronic hemodialysis, the risk of ischemic stroke, ischemic stroke or systemic embolism, minor bleeding, major bleeding, and all-cause mortality is similar in patients treated with DOACs compared to VKAs. Given that the meta-analysis of RCTs on gastrointestinal bleeding did not confirm the results of the meta-analysis of the observational studies, it cannot be concluded that gastrointestinal bleeding is lower among DOAC-treated patients. Protocol registrationPROSPERO CRD42023391966

Frequent vascular access thrombosis in a patient with end stage kidney disease on hemodialysis.

Vascular access thrombosis (VAT) is common among patients receiving hemodialysis and leads to missed dialysis treatments, hospitalizations, catheter placement, and graft/fistula abandonment. This article reviews the association between hypercoagulability and VAT and the high prevalence of hypercoagulable states in end-stage kidney disease (ESKD). This article reviews the role of antithrombotic and anticoagulant medications in preventing VAT. The article concludes by reviewing the unique challenges of using vitamin K antagonists in patients with ESKD.

Targeting MDM2 in Soft-Tissue Sarcomas (and Other Solid Tumors): The Revival?

Summary:Murine double minute 2 (MDM2) inhibitors represent an opportunity to target p53 in solid tumors with wild-type TP53 and particularly in some sarcomas characterized by a consistent amplification of the MDM2 gene. In this issue of Cancer Discovery, LoRusso and colleagues and Koyama and colleagues report the results of two early-phase studies investigating two different TP53–MDM2 antagonists in patients with soft-tissue sarcomas and other solid tumors.See related article by LoRusso et al., p. 1802 (5) .See related article by Koyama et al., p. 1814 (8) .

How to Use Interleukin-1 Antagonists in Pericarditis.

Recurrent pericarditis (RP) is one of the most common complications of pericarditis, affecting 15-30% of patients after an initial episode and >40% after a first recurrence.[1, 2] Up to 5-10% of RP patients develop multiple recurrences that are difficult to treat and refractory to conventional anti-inflammatory therapy, suggestive of refractory corticosteroid-dependent, colchicine-resistant RP.[2, 3] Several treatment options are suggested for such patients, including interleukin-1 (IL-1) antagonists, which are currently off-label for treating pericarditis in Canada.[1, 3] This paper aims to provide a focused guide to using anti-IL-1 agents (specifically anakinra and rilonacept), including practical tips from our experience.

Direct oral anticoagulants vs. vitamin K antagonists in patients with antiphospholipid syndrome: a systematic review and meta-analysis.

MEDLINE, Embase, and Cochrane Central databases were searched for randomized controlled trials comparing efficacy and safety of VKAs and DOACs inhibitors in patients with APS. Recurrent thrombosis, all-cause mortality, stroke, adverse reactions, and bleeding were among outcomes of interest. Mantel-Haenszel weighted random-effects model was used to calculate relative risks (RRs) with 95% CIs. The analysis included 625 patients from four randomized controlled trials and one post hoc analysis. Meta-analysis showed statistically non-significant difference between DOACs inhibitors and VKAs in the recurrent thrombosis risk (arterial or venous) [RR 2.77 (95%, CI 0.79, 9.65); P=0.11, I2=50%]. Consistent results were revealed among patients with the previous history of arterial thrombosis [RR 2.76 (95% CI 0.93, 8.16); P=0.75, I2=0%], venous thrombosis [RR 1.71 (95% CI 0.60, 4.84); P=0.31, I2=15%] and patients who were triple antiphospholipid positive [RR 4.12 (95% CI 0.46, 37.10); P=0.21, I2=58%]. DOACs inhibitors were significantly associated with increased risk of stroke [RR 8.51 (95% CI 2.35, 3.82); P=0.47, I2=0%]. DOACs exhibited increased risk of stroke among patients with APS. In addition, although not significant, the higher RRs among patients on DOACs may indicate higher risk of thrombotic events associated with DOACs.

Efficacy and safety assessment of mineralocorticoid receptor antagonists in patients with chronic kidney disease

BackgroundThe objective of our study is to evaluate the efficacy and safety of mineralocorticoid receptor antagonists (MRAs) and determine the optimal MRA treatment regimen in patients with chronic kidney disease (CKD). MethodsWe searched PubMed, Embase, Web of Science, and the Cochrane Library from their inception to June 20, 2022. The composite kidney outcome, cardiovascular events, urinary albumin to creatinine ratio (UACR), estimated glomerular filtration rate (EGFR), serum potassium, systolic blood pressure (SBP), diastolic blood pressure (DBP), creatine and creatine clearance were included for analysis. We conducted pairwise meta-analyses and Bayesian network meta-analyses (NMA) and calculated the surface under the cumulative ranking curve (SUCRA). ResultsWe included 26 studies with 15,531 participants. By pairwise meta-analyses, we found that MRA treatment could significantly reduce UACR in CKD patients with or without diabetes. Notably, compared to placebo, Finerenone was associated with a lower risk of composite kidney outcome and cardiovascular events. Data from NMA demonstrated an overt UACR reduction without increasing serum potassium by Apararenone, Esaxerenone, and Finerenone in CKD patients. Spironolactone decreased SBP and DBP but elevated CKD patients' serum potassium. ConclusionsCompared to placebo, Apararenone, Esaxerenone, and Finerenone might ameliorate albuminuria in CKD patients without causing elevated serum potassium levels. Remarkably, Finerenone conferred a cardiovascular benefit, and Spironolactone lowered blood pressure in CKD patients.

Comparing the efficacy and safety of direct oral anticoagulants with vitamin K antagonist in patients with atrial fibrillation and chronic kidney disease stages IV and V: systematic review and meta-analysis

Aim. This study aims to compare efficacy and safety of direct oral anticoagulants (DOAC) with vitamin K antagonist (VKA) in patients with atrial fibrillation (AF) and chronic kidney disease (CKD) stages IV and V.Material and methods. We systematically searched the PubMed, Google Scholar, Web of Science databases from 1990 to 2022 and included all published studies that compared DOACs with VKA in patients with atrial fibrillation and chronic kidney disease stages IV and V. To search the articles, we used the PICO strategy: Patient, Intervention, Comparison, Outcome of Interest. Data extraction was undertaken by five independent researches, and then a meta-analysis was performed.Results. Out of all, 6 studies were included in the meta-analysis: 3 randomized controlled trials (n=353) and 3 retrospective analyses (n=37470). The efficacy of DOACs was comparable with VKA. In terms of safety, DOACs and VKA also showed no statistical differences: hemorrhagic stroke, major/minor/gastrointestinal bleeding, general mortality.Conclusion. In terms of efficacy and safety, the indicators of DOACs and VKA were generally comparable.

Management of bleeding in patients on direct oral anticoagulants in emergency department: where we are and where we are going.

Many patients who access in the emergency department for acute bleeding are on anticoagulants; before specific reversal agents were developed, bleeding on anticoagulants was burdened with a substantial increase in morbidity and mortality. Clinical trials demonstrated favourable risk-benefit profiles of direct-acting oral anticoagulants compared with vitamin K antagonists in patients with atrial fibrillation and compared with low molecular weight heparin in patients treated and prevented from venous thromboembolism. Even if they drastically reduced some types of bleeding, particularly intracranial haemorrhage, they have not completely eliminated this risk. The arrival of a patient with active bleeding in the emergency department is always a critical scenario that involves resources and costs. In critical setting, the diagnosis and treatment of bleeding should occurred simultaneously. Understanding the pathophysiological mechanisms that occur during bleeding is essential for establish the most appropriate therapies and improve the standard of care of the haemorrhagic patients.