Current evidence of whether proton pump inhibitor (PPI) reduces the risk of gastrointestinal bleeding (GIB) associated with oral anticoagulants (OACs) is limited. Propensity score-weighted cohort and case-crossover studies were conducted separately in England and Hong Kong between 2011.01.01 and 2019.12.31. In the cohort design, we compared the hazards of hospitalised GIB in OAC  +  PPI users with OAC only users in people with atrial fibrillation and found higher hazard of GIB in OAC  +  PPI users in both settings. In the case-crossover design, elevated odds of exposure to PPI only , OAC only and OAC  +  PPI associated with GIB between 30-day hazard and referent periods were similarly found in both settings. Overall, the evidence of an elevated risk of OAC  +  PPI associated with GIB compared with OAC only was modest in the cohort study. Our case-crossover study suggested that residual confounding is likely to explain the association, suggesting that concomitant prescription of PPI with OAC did not modify GIB.

Taking a historical perspective, we review the discovery, pharmacology, and clinical evaluation of the old and new anticoagulants that have been approved for clinical use. The drugs are discussed chronologically, starting in the 1880s, and progressing through to 2024. The innovations in technology used to develop novel anticoagulants came in fits and starts and reflected the advances in science and technology over these decades, whereas the shift from anecdote to evidence-based use of anticoagulants was delayed until the principles of epidemiology and biostatistics were introduced into clinical trial design and to the approval process. Hirudin, heparin, and vitamin K antagonists were discovered by chance, and were used clinically before their mechanism of action was elucidated and before their net clinical benefits were evaluated in randomized clinical trials. Subsequent anticoagulants were designed based on a better understanding of the structure and function of coagulation proteins, including antithrombin, thrombin, and factor Xa, and underwent more rigorous preclinical and clinical evaluation before regulatory approval. By simplifying oral anticoagulation, the direct oral anticoagulants have revolutionized anticoagulation care and have enhanced the uptake of anticoagulation, but bleeding has not been eliminated and there is a need for more effective and convenient anticoagulants for thrombosis triggered by the contact pathway of coagulation. The newly developed factor XIa and XIIa inhibitors have the potential to address these unmet clinical needs and are undergoing clinical evaluation for several indications. SIGNIFICANCE STATEMENT: Anticoagulant therapy is the cornerstone of treatment and prevention of thrombosis, which remains a leading cause of morbidity and mortality worldwide. Elucidation of the structure and function of coagulation enzymes, their cofactors, and inhibitors, coupled with advances in structure-based design led to the discovery of more convenient, safer, and more effective anticoagulants that have revolutionized the management of thrombotic disorders.

Antiphospholipid syndrome (APS), is an autoimmune systemic disorder known to manifest with thrombosis in almost all vessels throughout the body, can also be accompanied by pregnancy morbidity, and is persistent with the presence of antiphospholipid antibodies, including lupus anticoagulant antibodies, or relatively high titers of anticardiolipin, or anti-β2Glycoprotein I antibodies. APS can occur alone or in association with other diseases, more commonly systemic lupus erythematous. In patients with both underlying diseases episodes of arthritis, skin changes in the form of livedo reticularis, thrombocytopenia and leucopenia were more common. Cardiac manifestations have also been reported. Here we present a complicated case of a young female patient with antiphospholipid syndrome and an underlying systemic lupus erythematosus.

Reversal of warfarin-induced anticoagulation using prothrombin complex concentrate (PCC4) is more rapidly achieved than with traditional methods, such as fresh frozen plasma (FFP). In many rural facilities, the availability of both FFP and PCC4 has been limited. A tertiary hospital instituted a program to provide PCC4 to rural sites using an air transport team and pharmacy exchange. We hypothesized that increasing accessibility of PCC4 would shorten time to INR reversal.

This was a retrospective study with the primary outcome being time to INR reversal (INR ≤ 1.6) and time to PCC4 administration from outside hospital admission. Active warfarin prescription, transfer to a tertiary facility, and administration of anticoagulation reversal between January 2013 and December 2020 were required for inclusion. Patients were grouped by dates before and after implementation of the program in August 2016. Linear regressions were performed to determine the effect of the variable and INR reversal methods on the time to INR reversal as well as the time to PCC4 administration. Time-to-event analysis was used to analyze the primary outcome between comparison groups. p values of less than 0.05 were considered significant.

Chart review identified 189 patients: 56 within the pre-implementation group and 133 within the post-implementation group. Statistics were compared between these two groups. The post-implementation group had a shorter time to INR reversal (median 9.97 h) compared with the pre-implementation group (median 14.58 h, p = 0.00004). Time to PCC4 administration was also significantly decreased (p = 0.023). No statistically significant differences were found for hospital survival or 30-day mortality.

In rural hospitals, increasing availability of PCC4 using air medical transport along with a medication exchange program significantly reduces time to PCC4 administration in warfarin anticoagulated patients.

Warfarin (vitamin K antagonist) remains an established anticoagulant for patients at high risk of arterial and venous thromboembolism. The prompt reversal of the anticoagulant effect of warfarin is necessary in the context of major bleeding or emergency surgery because of its extended inhibition of vitamin K-dependent coagulation factors for days. The mainstay of urgent warfarin reversal has been vitamin K administration, and infusion of a three-factor prothrombin complex concentrate (3FPCC) and the option for the addition of fresh frozen plasma as a source of factor VII. With the upcoming introduction in Australia and New Zealand of a four-factor prothrombin complex concentrate (4FPCC), which replaces all the vitamin K-dependent clotting factors, this article updates the previously published warfarin reversal guidelines.

For urgent warfarin reversal, 4FPCC should be used instead of 3FPCC, using the same suggested dose. Vitamin K co-administration is still recommended for more sustained reversal.

The use of 4FPCC for urgent warfarin reversal obviates the need for co-administration of fresh frozen plasma.

 Four-factor prothrombin complex concentrate (4F-PCC) is recommended for vitamin K antagonist reversal in patients with major bleeding or in need of surgery. The most important risk associated with the use of 4F-PCC is the occurrence of thromboembolic events (TEEs). In this review, we aim to evaluate the safety profile of a 4F-PCC (Kcentra®/Beriplex® P/N; CSL Behring, Marburg, Germany) by reviewing pharmacovigilance data.

 A retrospective analysis of postmarketing pharmacovigilance data of Kcentra®/Beriplex® P/N from February 1996 to April 2022 was performed and complemented by a review of clinical studies published between January 2012 and April 2022.

 A total of 2,321,443 standard infusions of Kcentra®/Beriplex® P/N were administered during the evaluation period. Adverse drug reactions (ADRs) were reported in 614 cases (∼1 per 3,781 standard infusions) and 233 of these cases (37.9%) experienced suspected TEEs related to 4F-PCC (∼1 per 9,963 standard infusions); most of these cases had pre-existing or concomitant conditions likely to be significant risk factors for thrombosis. TEE rates were similar when 4F-PCC was used on-label or off-label for direct oral anticoagulant-associated bleeding. Thirty-six cases (5.9%) reported hypersensitivity type reactions (∼1 per 64,485 standard infusions). No confirmed case of viral transmission related to 4F-PCC use was reported. The published literature also revealed a favorable safety profile of 4F-PCC.

 Analysis of postmarketing pharmacovigilance safety reports demonstrated that treatment with 4F-PCC was associated with few ADRs and a low rate of TEEs across multiple indications and settings, thus confirming a positive safety profile of 4F-PCC.

Warfarin is an effective anticoagulant but requires close International Normalized Ratio (INR) monitoring and may occasionally require correction of excessive anticoagulation. Current guidelines provide limited practical guidance on the administration of vitamin K for the management of supratherapeutic INR levels ≥ 5.0 in non-bleeding outpatients.

Based on expert consensus and guidelines, the Atrius Health Anticoagulation Management Services (AMS) has developed internal guidance for oral vitamin K use in highly selected populations. This study will describe the internal guidance for oral vitamin K use and present associated results and clinical outcomes.

Episodes with INR > 5.0 were included, with vitamin K considered for episodes with INR ≥ 6. Moreover, compelling indications and exclusions to select ideal patients for vitamin K intervention were also defined.

Overall, episodes were managed conservatively; of the 246 collected episodes of excessive anticoagulation, in 18 episodes (7%), patients received vitamin K, and in 228 (93%) episodes, patients did not receive vitamin K. The mean index INR was 6.0 (range 5.0 - 10.5, SD 1.07), with nearly 57% of episodes achieving INR correction and 15% of episodes developing INR overcorrection. High thrombotic risk patients, regardless of hemorrhagic risk, were less likely to receive vitamin K. Three episodes (1.2%) resulted in bleeding complications. No thrombotic complications occurred during the 30-day follow-up of the index INR value ≥ 5.0.

Our internal guidance is a novel, standardized approach that serves as a decision support tool for the management of warfarin-associated coagulopathy and vitamin K intervention using patient-specific characteristics and index INR values. This guidance may assist other anticoagulation management services with practical applications and require validation in a prospective clinical trial.

The transition to or from direct oral anticoagulants (DOACs) is common in clinical practice.

A literature search was conducted on PubMed, Google Scholar, and UpToDate up to March 2024 for conditions and approaches for transitioning from one agent to the other. No randomized clinical trials were retrieved except for two studies regarding switching to DOAC in well-conducted vitamin K antagonist (VKA) therapy. A narrative review was conducted addressing the conditions for switching from one agent to the other, such as thromboembolic events and major bleeding during anticoagulation, development or worsening of kidney or liver failure, initiation of interfering drugs, adverse events such as allergic reactions, frailty, patients' preferences, and affordability. During transitions from one anticoagulant to the other, the risk of both thromboembolic and bleeding complications should be minimized. The current approaches for such transitions are derived from those employed in clinical trials evaluating DOAC and from product information.

Many uncertainties remain regarding those circumstances requiring a change in anticoagulant strategies, as they lack evidence-based guidance. It can be envisaged that the problem of switching to and from DOAC will need additional studies especially addressing the conditions and the best approach to such transitions.

Due to their very wide range of indications, anticoagulants are one of the most commonly used drug groups. Although these drugs are characterized by different mechanisms of action, the most common complication of their use is still bleeding episodes, the frequency of which depends largely on the clinical condition of the patient using such therapy. For this reason, to this day, the best method of preventing bleeding complications remains the assessment of bleeding risk using scales such as HAS-BLED. There are many reports in the literature assessing the occurrence of this type of complication after the use of drugs affecting the coagulation process, as well as many reports comparing individual groups of drugs with different mechanisms of action. However, there are still no clear guidelines that would indicate which group of anticoagulants should be preferred in particular groups of patients. The aim of our article is to summarize the data collected so far regarding the safety of using specific groups of anticoagulants and the frequency of bleeding complications after their use.

It is difficult to evaluate adequate dose of heparin for cardiopulmonary bypass (CPB) by activated clotting time (ACT) in a patient receiving both heparin and dabigatran because dabigatran can also prolong ACT. We evaluated the effect of dabigatran by thromboelastography (TEG) to determine adequate heparin dose for CPB.

An 81-year-old woman receiving both heparin and dabigatran was scheduled for an emergency surgical repair of iatrogenic atrial septal perforation. Although ACT was prolonged to 419 s, we performed TEG to distinguish anticoagulation by dabigatran from heparin comparing R in CK and CHK. As the results of TEG indicated residual effect of dabigatran, we reversed dabigatran by idarucizumab and then dosed 200 U/kg of heparin to achieve adequate anticoagulation for CPB by heparin.

TEG could help physicians to determine need for idarucizumab and also an adequate dose of heparin to establish appropriate anticoagulation for CPB.

Regarding adjustments to warfarin dosage, numerous studies have shown that computerized methods are superior to those based on personal experience.

To report the efficacy of a computer-based warfarin management system (WMS) in the Iranian population.

By utilizing the existing dosing algorithms and obtaining expert opinions, we developed a computer-based WMS at a large tertiary cardiovascular center. The time in therapeutic range and the number of international normalized ratio (INR) tests of clinic patients were compared before and after the implementation of WMS.

Overall, 803 patients with 5407 INR tests were included in the before phase and 679 patients with 4189 INR tests in the after phase. The mean time in therapeutic range was 57.3% before and 59% after WMS implementation [mean difference, 1.64; 95% confidence interval (CI), -1.12-4.40]. In the before phase, the mean number of INR tests was 6.7, which dropped to 6.1 tests in the after phase (mean difference, -0.61; 95% CI, -0.97 to -0.24). Only 54.5% of the warfarin dosing prescriptions were consistent with the dosing recommendations of the WMS, and adherence to the WMS was poorest in the highest INR target range.

For the first time in Iran, we demonstrated that a computerized system was as effective as a traditional experience-based method to monitor INR in VKA-anticoagulated patients. Furthermore, it could reduce both the number of INR tests and that of visits.

In the era of direct oral anticoagulants, vitamin K antagonists retain a clinically relevant role in thrombotic disorders. In Italy, approximately 20% of the patients on anticoagulant therapies receives a VKA, in most cases warfarin. The optimal management of this drug is challenging and cannot disregard its intricate and unpredictable pharmacokinetic properties and patient's thrombotic and bleeding risk. Several clinical issues encountered during warfarin treatment are still unanswered and are tentatively addressed by physicians. In this regard, the Italian Federation of Centers for the diagnosis of thrombotic disorders and the Surveillance of the Antithrombotic therapies (FCSA) provides some experience-based good clinical practice's suggestions on the following topics: (1) how to start the anticoagulant treatment with warfarin and warfarin induction regimen; (2) how to manage a subtherapeutic INR value; (3) how to manage a supratherapeutic INR value in asymptomatic patients; and (4) how to manage the association of warfarin with interfering drugs.

Millions of people take vitamin K antagonists (VKAs). Some people who need urgent surgical procedures require rapid VKA reversal to prevent excessive intraoperative bleeding.

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.

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.

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.

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.

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).

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.

ClinicalTrials.gov Identifier: NCT02740335.

Life expectancy of patients with a durable, continuous-flow left ventricular assist device (CF-LVAD) continues to increase. Despite significant improvements in the delivery of care for patients with these devices, hemocompatability-related adverse events (HRAEs) are still a concern and contribute to significant morbility and mortality when they occur. As such, dissemination of current best evidence and practices is of critical importance. This ISHLT Consensus Statement is a summative assessment of the current literature on prevention and management of HRAEs through optimal management of oral anticoagulant and antiplatelet medications, parenteral anticoagulant medications, management of patients at high risk for HRAEs and those experiencing thrombotic or bleeding events, and device management outside of antithrombotic medications. This document is intended to assist clinicians caring for patients with a CF-LVAD provide the best care possible with respect to prevention and management of these events.

Major bleeding occurs annually in 1%-3% of patients on vitamin K antagonists (VKAs), despite close monitoring. Genetic variants in proteins involved in VKA response may affect this risk.

To determine the association of genetic variants (cytochrome P450 enzymes 2C9 [CYP2C9] and 4F2 [CYP4F2], gamma-glutamyl carboxylase [GGCX]) with major bleeding in VKA users, separately and combined, including vitamin K epoxide reductase complex subunit-1 (VKORC1).

A case-cohort study was established within the BLEEDS cohort, which includes 16,570 patients who initiated VKAs between 2012 and 2014. We selected all 326 major bleeding cases that occurred during 17,613 years of follow-up and a random subcohort of 978 patients. We determined variants in CYP2C9, CYP4F2, GGCX, VKORC1 and evaluated the interaction between variant genotypes. Hazard ratios for major bleeding with 95% confidence intervals (95% CI) were estimated by weighted Cox regression.

Genotype was determined in 256 cases and 783 subcohort members. Phenprocoumon was the most prescribed VKA for both cases and the subcohort (78% and 75%, respectively). Patients with major bleeding were slightly older than subcohort patients. CYP4F2-TT carriership was associated with a 1.6-fold (95% CI 0.9-2.8) increased risk of major bleeding compared with CC-alleles, albeit not statistically significant. For the CYP2C9 and GGCX variants instead, the major bleeding risk was around unity. Carrying at least two variant genotypes in CYP2C9 (poor metabolizer), CYP4F2-TT, and VKORC1-AA was associated with a 4.0-fold (95%CI 1.4-11.4) increased risk, while carriers of both CYP4F2-TT and VKORC1-AA had a particularly increased major bleeding risk (hazard ratio 6.7, 95% CI 1.5-29.8) compared with carriers of CC alleles in CYP4F2 and GG in VKORC1. However, the number of major bleeding cases in carriers of multiple variants was few (8 and 5 patients, respectively).

CYP4F2 polymorphism was associated with major bleeding, especially in combination with VKORC1 genetic variants. These variants could be considered to further personalize anticoagulant treatment.

Objectives: To evaluate if there is a difference in International Normalized Ratio (INR) readings taken within the 15 second time frame after lancing the finger vs 30-60 seconds of obtaining a blood drop utilizing a CoaguChek® XS Plus point-of-care (POC) INR machine in patients on warfarin therapy. Methods: All adult patients on anticoagulation therapy with warfarin who were managed in a pharmacist-run anticoagulation clinic were considered for inclusion in the study. The mean difference of INR readings taken less than 15 seconds vs between 30-60 seconds after the blood drop was obtained from the finger was assessed. Results: A total of 62 pairs of INR results were included in the study. There was a mean difference in INR of .076 (95% CI 0.011-.140; P = .0217) when comparing INR readings taken less than 15 seconds and between 30-60 seconds after the blood drop was obtained from the finger. Conclusions: There was a significant difference in INR readings taken less than 15 seconds vs 30-60 seconds after obtaining the blood drop when utilizing a POC INR machine. INR readings taken 30-60 seconds after obtaining a blood drop with the CoaguChek® XS Plus POC INR machine is not acceptable for use to monitor patients on warfarin.

The trauma mortality rate is higher in the elderly compared with younger patients. Ageing is associated with physiological changes in multiple systems and correlated with frailty. Frailty is a risk factor for mortality in elderly trauma patients. We aim to provide evidence-based guidelines for the management of geriatric trauma patients to improve it and reduce futile procedures.

Six working groups of expert acute care and trauma surgeons reviewed extensively the literature according to the topic and the PICO question assigned. Statements and recommendations were assessed according to the GRADE methodology and approved by a consensus of experts in the field at the 10th international congress of the WSES in 2023.

The management of elderly trauma patients requires knowledge of ageing physiology, a focused triage, including drug history, frailty assessment, nutritional status, and early activation of trauma protocol to improve outcomes. Acute trauma pain in the elderly has to be managed in a multimodal analgesic approach, to avoid side effects of opioid use. Antibiotic prophylaxis is recommended in penetrating (abdominal, thoracic) trauma, in severely burned and in open fractures elderly patients to decrease septic complications. Antibiotics are not recommended in blunt trauma in the absence of signs of sepsis and septic shock. Venous thromboembolism prophylaxis with LMWH or UFH should be administrated as soon as possible in high and moderate-risk elderly trauma patients according to the renal function, weight of the patient and bleeding risk. A palliative care team should be involved as soon as possible to discuss the end of life in a multidisciplinary approach considering the patient's directives, family feelings and representatives' desires, and all decisions should be shared.

The management of elderly trauma patients requires knowledge of ageing physiology, a focused triage based on assessing frailty and early activation of trauma protocol to improve outcomes. Geriatric Intensive Care Units are needed to care for elderly and frail trauma patients in a multidisciplinary approach to decrease mortality and improve outcomes.

To evaluate whether a focused, expert medication management intervention is feasible and potentially effective in preventing anticoagulation-related adverse events for patients transitioning from hospital to home.

Randomised, parallel design.

Medical wards at six hospital sites in southern Ontario, Canada.

Adults 18 years of age or older being discharged to home on an oral anticoagulant (OAC) to be taken for at least 4 weeks.

Clinical pharmacologist-led intervention, including a detailed discharge medication management plan, a circle of care handover and early postdischarge virtual check-up visits to 1 month with 3-month follow-up. The control group received the usual care.

Primary outcomes were study feasibility outcomes (recruitment, retention and cost per patient). Secondary outcomes included adverse anticoagulant safety events composite, quality of transitional care, quality of life, anticoagulant knowledge, satisfaction with care, problems with medications and health resource utilisation.

Extensive periods of restriction of recruitment plus difficulties accessing patients at the time of discharge negatively impacted feasibility, especially cost per patient recruited. Of 845 patients screened, 167 were eligible and 56 were randomised. The mean age (±SD) was 71.2±12.5 years, 42.9% females, with two lost to follow-up. Intervention patients were more likely to rate their ability to manage their OAC as improved (17/27 (63.0%) vs 7/22 (31.8%), OR 3.6 (95% CI 1.1 to 12.0)) and their continuity of care as improved (21/27 (77.8%) vs 2/22 (9.1%), OR 35.0 (95% CI 6.3 to 194.2)). Fewer intervention patients were taking one or more inappropriate medications (7 (22.5%) vs 15 (60%), OR 0.19 (95% CI 0.06 to 0.62)).

This pilot randomised controlled trial suggests that a transitional care intervention at hospital discharge for older adults taking OACs was well received and potentially effective for some surrogate outcomes, but overly costly to proceed to a definitive large trial.

NCT02777047.

Four-factor prothrombin complex concentrate (4-PCC) is recommended for rapid reversal of vitamin K antagonists (VKAs) such as warfarin, yet optimal dosing remains uncertain.

A systematic review was conducted of PubMed, Embase, and Ovid MEDLINE (Wolters Kluwer) databases from January 2000 to August 2023 for clinical studies comparing fixed- vs. variable-dose 4-PCC for emergent VKA reversal with at least one reported clinical outcome.

Abstracts and full texts were assessed independently and in duplicate by two reviewers.

Data were extracted independently and in duplicate by two reviewers using predefined extraction forms.

The analysis comprised three randomized trials and 16 cohort studies comprising a total of 323 participants in randomized trials (161 in fixed dosage and 162 in variable dosage) and 1912 patients in cohort studies (858 in fixed-dose and 1054 in variable dose). Extracranial bleeding was the predominant indication, while intracranial hemorrhage varied. Overall, a fixed-dose regimen may be associated with a lower dose of 4-PCC and results in a reduction in 4-PCC administration time compared with a variable-dose regimen. A fixed-dose regimen also likely results in increased clinical hemostasis. While there is no clear difference between the two regimens in terms of achieving a goal international normalized ratio (INR) less than 2, a fixed-dose regimen is less likely to achieve a goal INR less than 1.5. High certainty evidence indicates that the fixed-dose regimen reduces both mortality and the occurrence of thromboembolic events. Additional subgroup analyses provides exploratory data to guide future studies.

A fixed-dose regimen for 4-PCC administration provides benefits over a variable-dose regimen in terms of dose reduction, faster administration time, improved clinical hemostasis, and reduced mortality and thromboembolic events. Further studies are warranted to better refine the optimal fixed-dose regimen.

The use of anticoagulants has become more frequent due to the progressive aging population and increased thromboembolic events. Consequently, the proportion of anticoagulant-associated intracerebral hemorrhage (AAICH) in stroke patients is gradually increasing. Compared with intracerebral hemorrhage (ICH) patients without coagulopathy, patients with AAICH may have larger hematomas, worse prognoses, and higher mortality. Given the need for anticoagulant reversal and resumption, the management of AAICH differs from that of conventional medical or surgical treatments for ICH, and it is more specific. Understanding the pharmacology of anticoagulants and identifying agents that can reverse their effects in the early stages are crucial for treating life-threatening AAICH. When patients transition beyond the acute phase and their vital signs stabilize, it is important to consider resuming anticoagulants at the right time to prevent the occurrence of further thromboembolism. However, the timing and strategy for reversing and resuming anticoagulants are still in a dilemma. Herein, we summarize the important clinical studies, reviews, and related guidelines published in the past few years that focus on the reversal and resumption of anticoagulants in AAICH patients to help implement decisive diagnosis and treatment strategies in the clinical setting.

Thrombus and cardiovascular diseases pose a significant health threat, and dietary interventions have shown promising potential in reducing the incidence of these diseases. Marine bioactive proteins and peptides have been extensively studied for their antithrombotic properties. They can inhibit platelet activation and aggregation by binding to key receptors on the platelet surface. Additionally, they can competitively anchor to critical enzyme sites, leading to the inhibition of coagulation factors. Marine microorganisms also offer alternative sources for the development of novel fibrinolytic proteins, which can help dissolve blood clots. The advancements in technologies, such as targeted hydrolysis, specific purification, and encapsulation, have provided a solid foundation for the industrialization of bioactive peptides. These techniques enable precise control over the production and delivery of bioactive peptides, enhancing their efficacy and safety. However, it is important to note that further research and clinical studies are needed to fully understand the mechanisms of action and therapeutic potential of marine bioactive proteins and peptides in mitigating thrombotic events. The challenges and future application perspectives of these bioactive peptides also need to be explored.

To analyze the serious medication errors (MEs) on dabigatran, and their related factors, in order to avoid or reduce the occurrence of adverse events.

Serious MEs related to dabigatran were extracted from the WHO global database of reported potential side effects of medicinal products (VigiBase) by using "Medication errors and other product use errors and issues" High Level Group Term (HLGT) of the international Medical Dictionary for Regulatory Activities (MedDRA). Well-documented reports, vigiGrade completeness score ≥ 0.80, or with an informative narrative were analyzed with a focus on the clinical features of the cases. The PCNE Classification for drug-related problems (DRP) was used to classify medication errors in our analysis of cases.

Until January 26, 2020, there were 453 cases with serious MEs related to dabigatran in VigiBase, and 113 were well-documented. Among these, 69 patients (61%) were hospitalized or had prolonged hospitalization, 16 (14%) had life-threatening events, and 12 (11%) died. The MEs occurred in the prescription phase in 77 cases, in administration in 35, and at the dispensing stage in one case. The MEs in prescription were related to a drug selection error in 44 cases (24 concerning contraindications and 20 drug interactions) and to dose error in 33 cases (17 with excessive dose; eight with insufficient frequency; four had an incorrect time; in three, the dose was too low; and in one, too frequent). The MEs in administration were medical-staff-related errors in five cases (three with wrong administration route, one administration omission, and one overdose), patient-related errors in 28 (14 insufficient dose or no administration, seven improper drug storage, four wrong administration method, and three over prescribed dose), and other errors in two (without efficacy monitoring). The dispensing error of a wrong drug strength occurred in a pharmacy. The main adverse events in the 113 patients were haemorrhage in 57 cases (50%) and ischemia in 29 cases (26%).

Based on the analysis of reports in VigiBase, serious MEs related to dabigatran mainly occurred during prescription and administration. Although the incidence of MEs with clinical consequences in the use of dabigatran cannot be determined, attention should be paid to selection of the appropriate dose to a right patient in the prescription, and to patient compliance and storage in drug administration. The patient harm mainly manifested itself as bleeding or ischemia including fatal outcome in rare patients.

Managing gastrointestinal bleeding in patients using antithrombotic agents remains challenging in clinical practice. This review article provides a comprehensive and evidence-based approach to managing acute antithrombotic-related gastrointestinal bleeding, focusing on the triage of patients, appropriate resuscitation, and timely endoscopy. The latest clinical practice guidelines are highlighted to guide decisions concerning the use of reversal agents, temporary interruption, and resumption of antithrombotic drugs. Additionally, preventive measures are discussed to lower the risk of future bleeding and minimize complications among patients prescribed antithrombotic drugs.

Warfarin management is associated with severe complications, highlighting the critical need to evaluate the quality of its administration.

To evaluate the quality of warfarin management for patients managed in primary healthcare centers by measuring the percentage of Time in Therapeutic Range (TTR) and the proportion of extreme out-of-range international normalized ratio (INR) values.

This is a cross-sectional study. Data was extracted from a national dataset retrieved from the largest primary healthcare provider in Qatar. TTR was calculated using the traditional method. Inferential and descriptive analyses were performed as appropriate.

Four hundred ninety-four patients met the inclusion criteria. The mean (SD) TTR was 45.3 % (17.5). This was significantly lower than the recommended cutoff value (P<0.001). Extreme out-of-range INR accounted for 24.7 % of total INR readings.

The management of patients taking warfarin in Qatar is inadequate. More effective strategies are warranted to ensure safe and effective therapy.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, significantly impacting patients' quality of life and increasing the risk of death, stroke, heart failure, and dementia. Over the past two decades, there have been significant breakthroughs in AF risk prediction and screening, stroke prevention, rhythm control, catheter ablation, and integrated management. During this period, the scale, quality, and experience of AF management in China have greatly improved, providing a solid foundation for the development of guidelines for the diagnosis and management of AF. To further promote standardized AF management, and apply new technologies and concepts to clinical practice in a timely and comprehensive manner, the Chinese Society of Cardiology of the Chinese Medical Association and the Heart Rhythm Committee of the Chinese Society of Biomedical Engineering have jointly developed the Chinese Guidelines for the Diagnosis and Management of Atrial Fibrillation. The guidelines have comprehensively elaborated on various aspects of AF management and proposed the CHA2DS2-VASc-60 stroke risk score based on the characteristics of AF in the Asian population. The guidelines have also reevaluated the clinical application of AF screening, emphasized the significance of early rhythm control, and highlighted the central role of catheter ablation in rhythm control.

Although direct oral anticoagulants (DOACs) are generally safe and TDM is not required, blood levels of the drug are important information for response decisions in emergency care. In this study, an attempt was made to develop a disposable sensor chip for the rapid detection of edoxaban in blood, a type of DOAC. Molecularly imprinted polymers with edoxaban tosilate as a template and sodium p-styrene sulfonate as a functional monomer were grafted onto the surface of graphite particles, mixed with silicon oil dissolved in ferrocene to form a paste, and filled onto a substrate made of plastic film. Sensor chips were fabricated. The current obtained from this sensor by voltammetry within 150 s depended on the edoxaban concentration. Sensitivity to edoxaban was also confirmed in bovine whole blood. The potential of disposable sensors to rapidly detect edoxaban in whole blood was demonstrated in this study, although selectivity, reproducibility, and sensitivity need to be improved for practical use.

Guidelines for anticoagulation management services recommend personnel be specially trained in warfarin management and suggest using tools such as decision-support software. To date, there have been no Canadian studies documenting the quality of warfarin management using a similar guideline recommended approach.

A cross-sectional, retrospective observational study was conducted to measure the quality of pharmacist-led warfarin management using point-of-care international normalized ratio (INR) testing and decision-support software in various ambulatory settings in Canada. Settings included 4 family health teams in Ontario and 40 community pharmacies across Nova Scotia. Quality was measured using time in therapeutic range (TTR) and was reported in 3 manners: mean TTR, median TTR and time-weighted mean TTR.

The primary outcome included 963 patients. The combined mean and median TTR for the 2019 Ontario family health teams and Nova Scotia pharmacies was 74.2% and 77.3% (interquartile range 64%-87.9%), respectively. The time-weighted mean TTR was 76.3%.

To the best of our knowledge, the TTR achieved by this model of care is the highest reported in Canadian general practice. Since Thrombosis Canada defines good-quality warfarin management as a TTR of 60% or greater, and many studies have reported an association between higher TTR values and lower rates of thrombosis and hemorrhage, this model of care may have significant benefits for patients.

This study demonstrates the high quality of anticoagulation management provided by specially trained pharmacists using point-of-care INR testing and decision-support software. These results support expanded access to this service for all Canadians. Can Pharm J (Ott) 2024;157:xx-xx.

Sex, age, medical history, treatment, tobacco use, and race (SAMe-TT2R2) score helps detect patients at risk of suboptimal anticoagulation control. A score above two suggests poor control; however, non-Caucasian status being assigned two points might hinder the recognition of poor control in patients of other races.

To evaluate the SAMe-TT2R2 score's ability to predict poor anticoagulation control [defined as time in therapeutic range (TTR) < 60-70%] in Asian and non-Asian populations on vitamin K antagonists (VKAs).

We searched PubMed, Cochrane Library, Scopus, SpringerLink, and Web of Science using the keyword "SAMe-TT2R2." Articles published before April 2022 were screened. We gathered mean TTR and diagnostic accuracy data for different SAMe-TT2R2 thresholds and conducted meta-analyses using random-effects models.

A total of 30 studies were included (N = 36,690). The overall mean TTR differences were - 4.88 and - 6.41 for the cutoffs of ≥ 3 and ≥ 4, respectively. For non-Asian patients, the mean TTR differences were - 3.86, - 5.12, and - 8.09 for the cutoffs ≥ 2, ≥ 3, and ≥ 4, respectively. For Asian patients, the mean TTR differences were - 3.99 and - 4.07 for the cut-offs ≥ 3 and ≥ 4, respectively. The highest positive likelihood ratio (LR+) for the Asian subgroup was 1.17 [95% confidence interval (CI): 1.06-1.28; I2 = 0%, p heterogeneity = 0.500] at cutoff ≥ 4 and for the non-Asian subgroup, at cut-off ≥ 3, the LR+ was 1.24 (95% CI 1.14-1.34; I2 = 0% p heterogeneity = 0.455). The lowest LR- was found at a lower cutoff for both races (at cutoff ≥ 3 and ≥ 2 for Asian and non-Asian subgroups, respectively). The pooled results of other accuracy parameters were modest at all cutoffs, except for the sensitivity at cutoff ≥ 3 in the Asian subgroup (83.05%).

Our study results suggest that a higher SAMe-TT2R2 score resulted in a greater reduction of TTR among Asian and all races. The accuracy parameters showed the highest sensitivity for poor TTR at the SAMe-TT2R2 cutoff of ≥ 3 for Asian patients. However, the ability to identify patients likely to have poor TTR was limited. Further research is needed to enhance the risk assessment for poor anticoagulation control with VKAs.

The protocol of this systematic review was registered in the International Prospective Register of Scientific Reviews: PROSPERO, registration number CRD42021291865.

Deaths from high-risk pulmonary embolism (PE) appear to have increased in the US over the last decade. Modifiable risks contributing to this worrisome trend present opportunities for physicians, researchers, and healthcare policymakers to improve care.

We sought to contextualize contemporary, high-risk PE epidemiology and examine clinical trials, quality improvement opportunities, and healthcare policy initiatives directed at reducing mortality.

We observed significant and modifiable excess mortality due to high-risk PE. We identified several opportunities to improve care including: (1) rapid translation of forthcoming data on reperfusion strategies into clinical practice; (2) improved risk stratification tools; (3) quality improvement initiatives to address presumptive anticoagulation practice gaps; and (3) adoption of health policy initiatives to establish pulmonary embolism response teams and address the social determinants of health.

Addressing knowledge and practice gaps in intermediate and high-risk PE management must be prioritized and informed by forthcoming high-quality data. Implementation efforts are needed to improve acute PE management and resolve treatment disparities.

Plasma is overused as a blood product worldwide; however, data supporting appropriate use of plasma is scant. Its most common utilization is for treatment of coagulopathy in actively bleeding patients; it is also used for coagulation optimization prior to procedures with specific coagulation profile targets. A baseline literature review in PUBMED and Google Scholar was done (1 January 2000 to 1 June 2023), utilizing the following search terms: plasma, fresh frozen plasma, lyophilized plasma, indications, massive transfusion protocol, liver disease, warfarin reversal, cardiothoracic surgery, INR < 2. An initial review of the titles and abstracts excluded all articles that were not focused on transfusional medicine. Additional references were obtained from citations within the retrieved articles. This narrative review discusses the main indications for appropriate plasma use, mainly coagulation factor replacement, major hemorrhage protocol, coagulopathy in liver disease, bleeding in the setting of vitamin K antagonists, among others. The correlation between concentration of coagulation factors and INR, as well as the proper plasma dosing with its volume being weight-based, is also discussed. A high value approach to plasma utilization is supported with a review of the clinical situations where plasma is overutilized or unnecessary. Finally, a discussion of novel plasma products is presented for enhanced awareness.

Pulmonary embolism (PE) is a life-threatening disease where preemptive anticoagulation is recommended by guidelines for patients with intermediate to high pretest risk of PE.

The primary objective of our study was to describe the use of preemptive anticoagulation from the emergency department (ED) or inpatient wards stratified by risk assessment score.

We performed a retrospective observational cohort study of consecutive patients undergoing computed tomography pulmonary angiography (CTPA) for investigation of PE. Patients were classified as either ED patients or hospital ward patients based on where the CTPA was requested. The pretest risk of PE was calculated using the Revised Geneva Score (RGS) and patients were divided into low and intermediate to high risk.

A total of 392 consecutive patients who underwent CTPA at Monash Health were reviewed. There were 108 (27.6%) patients who were categorised as low risk (RGS 0-3) and 284 (72.4%) categorised as intermediate to high risk (RGS >3). There were 29 (7.4%) patients overall who received preemptive anticoagulation. Diagnostic yield of CTPA in the ED was low, with only four of 144 (2.8%) CTPA scans positive for PE. The yield of CTPA was higher in ward patients, with 63 of 248 (25.4%) being diagnostic of PE.

The use of preemptive anticoagulation for suspected PE was uncommon and was not influenced by the pretest probability of PE as determined by a validated clinical prediction tool. This may reflect concerns regarding haemorrhagic complications without any clear evidence of benefit. Diagnostic yield of CTPA performed in the ED was low.

Plastic surgery trainees are often called to render care in the emergency department (eg, for established patients, trauma, burns). Broad-based knowledge in pharmacotherapeutics during these encounters is critical. This includes an understanding of pain medications, anxiolytics, local anesthetics, antibiotics, anticoagulants, antidotes, and more to ensure optimal patient care. The purpose of this report is to describe 25 frequently used and other important medications that plastic surgery trainees should know for an adult emergency department encounter.

Anticoagulation management can effectively prevent complications in patients undergoing cardiac valve replacement (CVR). The emergence of eHealth tools provides new prospects for the management of long-term anticoagulants. However, there is no comprehensive summary of the application of eHealth tools in anticoagulation management after CVR.

Our objective is to clarify the current state, trends, benefits, and challenges of using eHealth tools in the anticoagulation management of patients after CVR and provide future directions and recommendations for development in this field.

This scoping review follows the 5-step framework developed by Arksey and O'Malley. We searched 5 databases such as PubMed, MEDLINE, Web of Science, CINAHL, and Embase using keywords such as "eHealth," "anticoagulation," and "valve replacement." We included papers on the practical application of eHealth tools and excluded papers describing the underlying mechanisms for developing eHealth tools. The search time ranged from the database inception to March 1, 2023. The study findings were reported according to the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews). Additionally, VOSviewer (version 1.6.18) was used to construct visualization maps of countries, institutions, authors, and keywords to investigate the internal relations of included literature and to explore research hotspots and frontiers.

This study included 25 studies that fulfilled the criteria. There were 27,050 participants in total, with the sample size of the included studies ranging from 49 to 13,219. The eHealth tools mainly include computer-based support systems, electronic health records, telemedicine platforms, and mobile apps. Compared to traditional anticoagulation management, eHealth tools can improve time in therapeutic range and life satisfaction. However, there is no significant impact observed in terms of economic benefits and anticoagulation-related complications. Bibliometric analysis suggests the potential for increased collaboration and opportunities among countries and academic institutions. Italy had the widest cooperative relationships. Machine learning and artificial intelligence are the popular research directions in anticoagulation management.

eHealth tools exhibit promise for clinical applications in anticoagulation management after CVR, with the potential to enhance postoperative rehabilitation. Further high-quality research is needed to explore the economic benefits of eHealth tools in long-term anticoagulant therapy and the potential to reduce the occurrence of adverse events.

The number of patients treated with coagulation disorders, and more specifically with anticoagulant therapy, has increased worldwide in recent years due to increased life expectancy in developed countries. The protocols for managing this type of patient in oral surgery has varied over recent years, especially after the appearance of new direct-acting oral anticoagulants (DOACs). The assessment of risk of bleeding in this type of patient when undergoing a surgical procedure continues to be a controversial issue for patients, dentists and general practitioners. The objective of this document is to offer recommendations, based on evidence, for decision making for patients with coagulopathies who require dental surgical intervention.

Based on the indications of the "Preparation of Clinical Practice guidelines in the National Health System. Methodological manual", we gathered a group of experts who agreed on 15 PICO questions based on managing patients with coagulation disorders in dental surgical procedures, such as fitting of implants or dental extractions.

The 15 PICO questions were answered based on the available evidence, being limited in most cases due to the lack of a control group. Two of the PICO questions were answered by the experts with a grade C recommendation, while the rest were answered with grade D.

The results of this review highlight the need to undertake well designed clinical trials with control groups and with a representative sample size.

Venous thromboembolism (VTE) is a common cardiovascular disease that seriously threatens human lives. Anticoagulant therapy is considered to be the cornerstone of VTE treatment. An increasing number of studies has been updated in the VTE anticoagulation field. However, no bibliometric analyses have assessed these publications comprehensively. Therefore, our study aimed to analyze the global status, hotspots, and trends of anticoagulant therapy for VTE.

The relevant literature on VTE anticoagulation published between 2012 and 2021 was retrieved and collected from the Web of Science Core Collection database. VOSviewer, Cooccurrence Matrix Builder, gCLUTO, and some online visualization tools were adopted for bibliometric analysis.

A total of 15,152 related articles were retrieved. In recent years, the research output of VTE anticoagulation gradually increased. The United States was the most productive country. International cooperation is concentrated in North America and Europe; the most influential documents, journals, authors, and organizations were also from these two continents. Research hotspots mainly focus on clinical guidelines, VTE in special populations, non-vitamin K oral anticoagulants (NOACs), and parenteral anticoagulation. The research frontiers and trends include the assessment of NOACs and the antithrombotic management of VTE complicated with coronavirus disease 2019 (COVID-19).

This bibliometric analysis provides a systematic overview of the VTE anticoagulation research, which will facilitate researchers to better understand the situation of VTE anticoagulation. Future studies should be dedicated to NOACs application and VTE-combined COVID-19 patients.

Hospital overload is a persistent occurrence in daily practice. Interventions such as point-of-care testing (POCT) are needed to alleviate the pressure faced by healthcare providers and administrators.

An invited panel of experts from Saudi Arabia was formed under the auspices of the Saudi Heart Association in order to discuss local treatment gaps in the management of patients receiving anticoagulation therapy. This was done in a series of meetings, which resulted in the development of official recommendations for the implementation of POCT for anticoagulation monitoring in the country. Recommendations were based on a comprehensive literature review and international guidelines taking into consideration local clinical practice, clinical gaps, and treatment/testing availabilities.

Vitamin K antagonist (VKA)-based anticoagulation therapy requires routine monitoring. POCT is a promising model of care for the monitoring of International Normalized Ratio (INR) in patients receiving oral anticoagulation in terms efficacy, safety and convenience. The availability of POC INR testing should not replace the use of standard laboratory anticoagulation monitoring. However, there are several indications for implementing POCTINR monitoring that was agreed upon by the expert panel. POCT for anticoagulation monitoring should primarily be used in the warfarin (or other VKA) monitoring clinic in order to ensure treatment efficiency, cost-effectiveness of care, patient satisfaction, and quality of life improvement. The expert panel detailed the requirements for the establishment of a warfarin (or other VKA) monitoring clinic in terms of organization, safety, quality control, and other logistic and technical considerations. The limitations of POCT should be recognized and recommendations on best practices should be strictly followed. Core laboratory confirmation should be sought for patients with higher INR results (>4.7) on POCT. Proper training, quality control, and regulatory oversight are also critical for preserving the accuracy and reliability of POCT results.

POCT enables more rapid clinical decision-making in the process of diagnosis (rule-in or rule-out), treatment choice and monitoring, and prognosis, as well as operational decision-making and resource utilization. POCT thus can fulfill an important role in clinical practice, particularly for patients receiving VKAs.