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.

Early anti-coagulation therapy in new-onset atrial fibrillation after coronary artery bypass grafting: a randomized trial pilot study.

BACKGROUND: New-onset postoperative atrial fibrillation (POAF) is a common complication after coronary artery bypass grafting (CABG) surgery, increasing the risk of embolism and stroke. There is a lack of information on the use of anticoagulants in this context. The choice between Warfarin and Direct oral anticoagulants (DOACs) also is not well-established. This randomized study aimed to compare the feasibility and safety of Warfarin and Rivaroxaban in preventing thrombotic events in POAF patients after isolated CABG. METHODS: A total of 66 patients were randomized parallelly with 1:1 allocation to receive either Rivaroxaban (n = 34) or Warfarin (n = 32). Major bleeding events within 30 days after discharge were the primary outcome. Secondary outcomes included minor bleeding events and thrombotic episodes. Clinical characteristics, medication regimens, and left atrial diameter were assessed. Statistical analyses were performed using appropriate tests. RESULTS: No thrombotic episodes were observed in either treatment arm. No major bleeding events occurred in either group. Four minor bleeding events were reported, with no significant difference between the treatment groups (P = 0.6). Patients with atrial fibrillation had significantly larger left atrial diameters compared to those with normal sinus rhythm (40.5 vs. 37.8 mm, P = 0.01). CONCLUSIONS: This pilot study suggests that Warfarin and Rivaroxaban are both safe and effective for preventing thrombotic episodes in POAF patients after isolated CABG. No significant differences in major bleeding events were observed between the two anticoagulants. These findings may support the preference for DOACs like Rivaroxaban due to their convenience and easier maintenance. TRIAL REGISTRATION: Number IRCT20200304046696N1, Date 18/03/2020 https//irct.behdasht.gov.ir/ .

A pilot study of safety and efficacy comparison of low molecular heparin calcium sequential oral anticoagulants in the treatment of cirrhotic portal vein thrombosis.

BACKGROUND: The objective of this study is to compare and assess the efficacy and safety of low-molecular-weight heparin calcium (LMWH-Ca), followed by either warfarin or rivaroxaban, as treatment options for portal vein thrombosis (PVT) in patients with cirrhosis. METHODS: In this pilot study, cirrhotic (with liver function score of Child-Pugh A) patients diagnosed with PVT who were not on anticoagulant therapy received 2 weeks of subcutaneous injections of LMWH-Ca. They were then randomized to either warfarin (a full course of oral warfarin for 6 months) or rivaroxaban (a full course of oral rivaroxaban for 2 months), with 30 cases in each group. After a treatment period of up to 6 months, a comparative analysis was performed to assess the efficacy and safety of both groups. Volumetric changes in PVT were monitored dynamically using enhanced computed tomography scans before treatment at week 2 and month 6. RESULTS: There were no statistically significant differences in the clinical characteristics of the patients between the two groups. Rivaroxaban treatment reduced PVT median volume from 1.83 cm3 at week 2 to 0.0 cm3 at month 6 and prevented the worsening of PVT after 6 months of treatment with LMWH-Ca (P < 0.001). On the other hand, warfarin treatment increased PVT median volume from 1.95 cm3 at week 2 to 3.78 cm3 at month 6 (P = 0.002). None of the 30 patients in the rivaroxaban group had clinically significant gastrointestinal bleeding, while 2 of the 30 patients (7%) in the warfarin group had gastrointestinal bleeding (P = 0.317). CONCLUSION: Rivaroxaban followed by LMWH-Ca is an effective anticoagulant treatment strategy for PVT in cirrhosis.

[Renal failure and drug-drug interactions]. / Bei Niereninsuffizienz auf Arzneimittel-Interaktionen achten!

Renal failure is common and comes with a steep increasing prevalence in older patients. It is a frequent aspect in multimorbidity and associated with polypharmacia. Based on available literature an overview is given concerning important drug-drug interactions and how to avoid or manage them. Among a large variety of possible interactions anticoagulation and diuretic therapy still represent the highest clinical relevance.

Validation of the RIETE, Kuijer, and HAS-BLED Models to Assess 3-Month Bleeding Risk in Anticoagulated Patients Diagnosed with Venous Thromboembolic Disease.

OBJECTIVE: To evaluate the discriminative ability and calibration of the RIETE, Kuijer, and HAS-BLED models for predicting 3-month bleeding risk in patients anticoagulated for venous thromboembolism (VTE). METHODS: External validation study of a prediction model based on a retrospective cohort of patients with VTE seen at the Hospital Universitario San Ignacio, Bogotá (Colombia) between July 2021 and June 2023. The calibration of the scales was evaluated using the Hosmer-Lemeshow test and the ratio of observed to expected events (ROE) within each risk category. Discriminatory ability was assessed using the area under the curve (AUC) of a ROC curve. RESULTS: We analyzed 470 patients (median age 65 years, female sex 59.3%) with a diagnosis of deep vein thrombosis in most cases (57.4%), 5.7% bleeding events were observed. Regarding calibration, adequate calibration cannot be ruled out given the limited number of events. The discriminatory ability was limited with an area under the curve (AUC) of 0.48 (CI 0.37-0.59) for Kuijer Score, 0.58 (CI 0.47-0.70) for HAS-BLED and 0.64 (CI 0.51-0.76) for RIETE. CONCLUSION: The Kuijer, HAS-BLED, and RIETE models in patients with VTE generally do not adequately estimate the risk of bleeding at three months, with a low ability to discriminate high-risk patients. Cautious interpretation is recommended until further evidence is available.

Direct Oral Anticoagulants for Treating Acute Venous Thromboembolism in Children: Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Acute venous thromboembolism (VTE) in children presents unique challenges due to the limitations of standard anticoagulation therapies. Herein, we aimed to systematically review randomized controlled trials (RCTs) evaluating the efficacy and safety of direct oral anticoagulants (DOACs) in pediatric patients with acute VTE. METHODS: PubMed and Embase databases were searched for RCTs comparing DOACs to standard anticoagulation in pediatric VTE patients. Efficacy outcomes included VTE recurrence and all-cause mortality, while safety outcomes comprised major bleeding and other adverse events. RESULTS: Three RCTs with 790 participants were included. When compared with standard anticoagulation, DOACs demonstrated a reduced risk of VTE recurrence (risk difference[RD] = -3%, 95% confidence interval[CI]: -6% to 0%, P = 0.04) and an increased risk of any adverse event (RD = 8%, 95% CI: 1% to 14%, P = 0.02). No significant differences were found in all-cause mortality, major bleeding, clinically relevant non-major bleeding, or total bleeding between the DOAC and control groups. CONCLUSION: DOACs, primarily dabigatran and rivaroxaban, are non-inferior to standard anticoagulants in reducing VTE recurrence in pediatric patients, with comparable safety profiles. Further research is essential to confirm these findings.

Timing of Anticoagulation Resumption and Risk of Ischemic and Hemorrhagic Complications in Patients With ICH and Mechanical Heart Valves.

BACKGROUND AND OBJECTIVES: In patients with mechanical heart valves and recent intracranial hemorrhage (ICH), clinicians need to balance the risk of thromboembolism during the period off anticoagulation and the risk of hematoma expansion on anticoagulation. The optimal timing of anticoagulation resumption is unknown. We aimed to investigate the relationship between reversal therapy and ischemic stroke, between duration off anticoagulation and risk of ischemic strokes or systemic embolism and between timing of anticoagulation resumption and risk of rebleeding and ICH expansion. METHODS: We conducted a retrospective cohort observational study in 3 tertiary hospitals. Consecutive adult patients with mechanical heart valves admitted for ICH between January 1, 2000, and July 13, 2022, were included. The primary end points of our study were thromboembolic events (cerebral, retinal, or systemic) while off anticoagulation and ICH expansion after anticoagulation resumption (defined by the following criteria: increase by one-third in intracerebral hematoma volume, increase by one-third in convexity subdural hemorrhage diameter, or visually unequivocal expansion of other ICH locations to the naked eye). RESULTS: A total of 171 patients with mechanical heart valves who experienced ICH were included in the final analysis. Most of the patients (79.5%) received reversal therapy for anticoagulation. Patients who received anticoagulation reversal therapy did not have increased risk of thromboembolic complications. Time off anticoagulation was not associated with risk of ischemic stroke; only 2 patients had a stroke within 7 days of the ICH, and both had additional major risk factors of thromboembolism. The rate of ischemic stroke/transient ischemic attack while off anticoagulation was lower than the rate of ICH expansion once anticoagulation was resumed (6.4% vs 9.9%). Furthermore, patients who developed ICH expansion had higher mortality compared with patients who had ischemic stroke while being off anticoagulation (41% vs 9%). Use of intravenous heparin bridging upon resumption of warfarin was strongly associated with increased risk of ICH expansion as compared with restarting warfarin without a heparin bridge. DISCUSSION: Withholding anticoagulation for at least 7 days after ICH may be safe in patients with mechanical heart valves. Heparin bridging during anticoagulation resumption may be associated with increased risk of bleeding.

Risks of bleeding and thromboembolic events in patients undergoing colonoscopy on uninterrupted and interrupted anticoagulant therapy in real-world setting.

BACKGROUND: Although anticoagulants may potentially increase the risk of post-colonoscopy bleeding events, temporary discontinuation of medications could elevate the risk of thromboembolism (TE). There is a paucity of data regarding the incidence of bleeding and TE events in patients undergoing colonoscopy while on uninterrupted or interrupted anticoagulant therapy. Therefore, we aimed to ascertain the risks of post-colonoscopy TE and bleeding in patients with continuous or interrupted use of anticoagulant agents. METHODS: The electronic databases of PubMed, Embase, and the Cochrane library were comprehensively searched from inception to March 15, 2024. We identified studies reporting the incidence of bleeding and TE events in patients undergoing colonoscopy with uninterrupted or interrupted anticoagulant therapy. The pooled incidence rate of bleeding and TE events was estimated using a random-effects model. RESULTS: This study included a total of 15 studies involving 63, 017 patients. Overall, the incidence of post-procedural bleeding for uninterrupted and interrupted direct oral anticoagulants (DOACs) was found to be 3.60 % (95 % CI: 1.60 %-5.60 %), and 0.90 % (95 % CI: 0.10 %-10.30 %), respectively. Subgroup analysis revealed that older age patients (≥65 years) had a significantly higher rate of bleeding with uninterrupted DOACs therapy compared to younger age patients (< 65 years) (7.20 % vs. 2.00 %). The highest rate of bleeding was observed in Asia (7.20 %, 95 % CI: 2.20 %-12.10 %). Similarly, the risk of bleeding was significantly increased among patients interrupting DOACs therapy in Asia compared to North America (1.40 % vs. 0.26 %). For patients on uninterrupted and interrupted warfarin, a higher rate of bleeding events was observed in older age patients than younger age patients (4.90 % vs. 0.80 %, and 2.20 % vs. 1.70 %, respectively). Uninterrupted warfarin showed a more significant risk of bleeding in Asia (4.20 %, 95%CI: 1.90 %-6.60 %) compared to North America (1.00 %, 95%CI: 0.50 %-1.50 %). Among those who did not interrupt DOACs therapy, the incidence of TE was the lowest (0.08 %, 95%CI: 0.04 %-0.11 %). CONCLUSION: This study provides a comprehensive assessment of bleeding and TE risks in patients undergoing colonoscopy while receiving uninterrupted or interrupted anticoagulant therapy in the real-world setting. The overall incidence of post-colonoscopy bleeding and TE events is relatively low. However, the uninterrupted DOACs and warfarin are associated with an elevated risk of bleeding, particularly among elderly patients and the Asian population.

Anticoagulation Alone vs Anticoagulation Plus Aspirin or DAPT Following Left Atrial Appendage Occlusion.

BACKGROUND: The prevalence of and outcomes associated with different antithrombotic strategies after left atrial appendage occlusion (LAAO) are not well described. OBJECTIVES: This study sought to evaluate patterns of antithrombotic medication strategies at discharge following LAAO with the Watchman FLX device in real-world practice and to compare the risk of adverse events among the different antithrombotic regimens. METHODS: The authors evaluated patients in the NCDR (National Cardiovascular Data Registry) LAAO Registry who underwent LAAO with the second-generation LAA closure device between 2020 and 2022. They grouped patients by mutually exclusive discharge antithrombotic strategies and compared the rates of adverse events at 45 days and 6 months using multivariable Cox proportional hazards regression. RESULTS: Among 53,878 patients undergoing successful LAAO with the second-generation LAA closure device, the most common antithrombotic discharge regimens were direct oral anticoagulant (DOAC) plus aspirin (48.3%), DOAC alone (22.6%), dual antiplatelet therapy (8.1%), warfarin plus aspirin (7.7%), and DOAC plus P2Y12 inhibitor (4.9%). In multivariate analysis, DOAC alone had a lower rate of major adverse events and major bleeding at 45 days of follow-up compared with DOAC plus aspirin (major adverse events: HR: 0.78; 95% CI: 0.68-0.91; major bleeding: HR: 0.69; 95% CI: 0.60-0.80). These differences persisted at 6 months. Warfarin without aspirin also showed lower rates of major bleeding at both time points. No differences were seen in stroke/transient ischemic attack or device-related thrombus. CONCLUSIONS: In real-world U.S. practice, discharge on DOAC alone or warfarin alone was associated with a lower rate of adverse events compared with DOAC plus aspirin.

Perioperative Management of Antiplatelet and Anticoagulant Therapy in Patients Undergoing Interventional Techniques: 2024 Updated Guidelines from the American Society of Interventional Pain Physicians (ASIPP).

BACKGROUND: The frequency of performance of interventional techniques in chronic pain patients receiving anticoagulant and antiplatelet therapy continues to increase. Understanding the importance of continuing chronic anticoagulant therapy, the need for interventional techniques, and determining the duration and discontinuation or temporary suspension of anticoagulation is crucial to avoiding devastating complications, primarily when neuraxial procedures are performed. Anticoagulants and antiplatelets target the clotting system, increasing the bleeding risk. However, discontinuation of anticoagulant or antiplatelet drugs exposes patients to thrombosis risk, which can lead to significant morbidity and mortality, especially in those with coronary artery or cerebrovascular disease. These guidelines summarize the current peer reviewed literature and develop consensus-based guidelines based on the best evidence synthesis for patients receiving anticoagulant and antiplatelet therapy during interventional procedures. STUDY DESIGN: Review of the literature and development of guidelines based on best evidence synthesis. OBJECTIVES: To provide a current and concise appraisal of the literature regarding the assessment of bleeding and thrombosis risk during interventional techniques for patients taking anticoagulant and/or antiplatelet medications. METHODS: Development of consensus guidelines based on best evidence synthesis included review of the literature on bleeding risks during interventional pain procedures, practice patterns, and perioperative management of anticoagulant and antiplatelet therapy. A multidisciplinary panel of experts developed methodology, risk stratification based on best evidence synthesis, and management of anticoagulant and antiplatelet therapy. It also included risk of cessation of anticoagulant and antiplatelet therapy based on a multitude of factors. Multiple data sources on bleeding risk, practice patterns, risk of thrombosis, and perioperative management of anticoagulant and antiplatelet therapy were identified. The relevant literature was identified through searches of multiple databases from 1966 through 2023. In the development of consensus statements and guidelines, we used a modified Delphi technique, which has been described to minimize bias related to group interactions. Panelists without a primary conflict of interest voted on approving specific guideline statements. Each panelist could suggest edits to the guideline statement wording and could suggest additional qualifying remarks or comments as to the implementation of the guideline in clinical practice to achieve consensus and for inclusion in the final guidelines, each guideline statement required at least 80% agreement among eligible panel members without primary conflict of interest. RESULTS: A total of 34 authors participated in the development of these guidelines. Of these, 29 participated in the voting process. A total of 20 recommendations were developed. Overall, 100% acceptance was obtained for 16 of 20 items. Total items were reduced to 18 with second and third round voting. The final results were 100% acceptance for 16 items (89%). There was disagreement for 2 statements (statements 6 and 7) and recommendations by 3 authors. These remaining 2 items had an acceptance of 94% and 89%. The disagreement and dissent were by Byron J. Schneider, MD, with recommendation that all transforaminals be classified into low risk, whereas Sanjeeva Gupta, MD, desired all transforaminals to be in intermediate risk. The second disagreement was related to Vivekanand A. Manocha, MD, recommending that cervical and thoracic transforaminal to be high risk procedures.Thus, with appropriate literature review, consensus-based statements were developed for the perioperative management of patients receiving anticoagulants and antiplatelets These included the following: estimation of the thromboembolic risk, estimation of bleeding risk, and determination of the timing of restarting of anticoagulant or antiplatelet therapy.Risk stratification was provided classifying the interventional techniques into three categories of low risk, moderate or intermediate risk, and high risk. Further, on multiple occasions in low risk and moderate or intermediate risk categories, recommendations were provided against cessation of anticoagulant or antiplatelet therapy. LIMITATIONS: The continued paucity of literature with discordant recommendations. CONCLUSION: Based on the review of available literature, published clinical guidelines, and recommendations, a multidisciplinary panel of experts presented guidelines in managing interventional techniques in patients on anticoagulant or antiplatelet therapy in the perioperative period. These guidelines provide a comprehensive assessment of classification of risk, appropriate recommendations, and recommendations based on the best available evidence.

Geriatric Pharmacotherapy Case Series: Clotting and Gender-Affirming Care.

Background A transfeminine patient is a 79-year-old with past medical history significant for type 2 diabetes mellitus, hypertension, gender dysphoria, chronic kidney disease, dyslipidemia, total left hip replacement, and recent provoked deep venous thromboembolism (DVT). She was seen by a pharmacist in a primary care clinic after her discharge from a skilled nursing facility. The patient was experiencing symptoms of gender dysphoria after discontinuation of her estradiol in setting of her DVT. Assessment Her renal function was calculated to ensure she was on appropriate dosing of her medications. Because her DVT was provoked, providers determined she would require only 3 months of anticoagulation. Her laboratory test results showed a subtherapeutic estradiol level and her estradiol was restarted. Additionally, aspirin was being prescribed for primary prevention of atherosclerotic cardiovascular disease and was discontinued. Outcome She has significant improvement in her gender dysphoria symptoms with resuming her estradiol and now has a therapeutic estradiol level. She is tolerating her direct oral coagulant well and reports good quality of life. Conclusion When reviewing medications for patients it is important to take several factors into account, including dose, appropriate indication, and patient preference. Pharmacists play a key role, through collaboration with providers, in assessing these medication-specific factors. Estradiol was stopped in this patient because of her DVT, but given her DVT was provoked after a recent surgery, it was unlikely that estradiol was the cause of her clot. Weighing the risks and benefits for any patient is important when determining what medications are appropriate to continue. Additionally, calculating renal function appropriately in a gender-non-conforming patients ensures appropriate and safe dosing.

Trajectories of Frailty and Clinical Outcomes in Older Adults With Atrial Fibrillation: Insights From the Shizuoka Kokuho Database.

BACKGROUND: The increasing prevalence of frailty has gained considerable attention due to its profound influence on clinical outcomes. However, our understanding of the progression of frailty and long-term clinical outcomes in older individuals with atrial fibrillation remains scarce. METHODS: Using data from 2012 to 2018 from a comprehensive claims database incorporating primary and hospital care records in Shizuoka, Japan, we selected patients aged ≥65 years with atrial fibrillation who initiated oral anticoagulant therapy. The trajectory of frailty was plotted using Sankey plots, illustrating the annual changes in their frailty according to the electronic frailty index during a 3-year follow-up after oral anticoagulant initiation, along with the incidence of clinical adverse outcomes. For deceased patients, we assessed their frailty status in the year preceding their death. RESULTS: Of 6247 eligible patients (45.1% women; mean age, 79.3±8.0 years) at oral anticoagulant initiation, 7.7% were categorized as fit (electronic frailty index, 0-0.12), 30.1% as mildly frail (>0.12-0.24), 35.4% as moderately frail (>0.24-0.36), and 25.9% as severely frail (>0.36). Over the 3-year follow-up, 10.4% of initially fit patients transitioned to moderately frail or severely frail. Conversely, 12.5% of severely frail patients improved to fit or mildly frail. Death, stroke, and major bleeding occurred in 23.4%, 4.1%, and 2.2% of patients, respectively. Among the mortality cases, 74.8% (N=1183) and 3.5% (N=55) had experienced moderately or severely frail and either a stroke or major bleeding in the year preceding their death, respectively. CONCLUSIONS: In a contemporary era of atrial fibrillation management, a minor fraction of older patients on oral anticoagulants died following a stroke or major bleeding. However, their frailty demonstrated a dynamic trajectory, and a substantial proportion of death was observed after transitioning to a moderately or severely frail state.

Anticoagulation in Pediatric Patients.

The use of antithrombotic agents is increasing in infants, children and adolescents. The more recent routine inclusion of children in FDA-monitored clinical trials has propelled the rapid accumulation of safety and efficacy data on these agents in pediatric patients. Antithrombotic agents in current use include indirect or antithrombin-dependent anticoagulants, intravenous direct thrombin inhibitors, direct oral anticoagulants (DOACs) targeting thrombin or factor Xa, antiplatelet agents and thrombolytic therapies. Each class of antithrombotic agent has distinct mechanisms of action, clearance routes, half-lives, safety and dosing. Anticoagulant efficacy is dependent upon the specific clinical indication and stability of the pediatric patient. Duration of anticoagulant course is also dependent upon the clinical indication as well as rate of thrombus resolution. This manuscript reviews the mechanism of action, route of administration, route of clearance and plasma half-life for the antithrombotic agents in current use in children. Use of anticoagulation in the context of thrombolytic therapy is discussed.

Regional citrate anticoagulation with continuous renal replacement therapy as a cause of hypercalcemia.

CLINICAL RELEVANCE: Awareness of the causes of hypercalcemia is essential for timely diagnosis of calcium disorders and optimal treatment. Citrate is commonly used as an anticoagulant during continuous renal replacement therapy (CRRT). Accumulation of citrate in the systemic circulation during CRRT may induce several metabolic disturbances, including total hypercalcemia and ionized hypocalcemia. The aim of the present study is to increase awareness of citrate accumulation and toxicity as a cause of hypercalcemia by relating three cases and reviewing the pathophysiology and clinical implications. OBSERVATIONS: We utilized electronic health records to examine the clinical cases and outlined key studies to review the consequences of citrate toxicity and general approaches to management. CONCLUSIONS: Citrate toxicity is associated with high mortality. A safe threshold for tolerating hypercalcemia during citrate anticoagulation is not clearly defined, and whether citrate toxicity independently increases mortality has not been resolved. Greater attention to citrate toxicity as a cause of hypercalcemia may lead to earlier detection, help to optimize the management of systemic calcium levels, and foster interest in future clinical studies.

Left Atrial Appendage Closure Compared With Oral Anticoagulants for Patients With Atrial Fibrillation: A Systematic Review and Network Meta-Analysis.

BACKGROUND: Percutaneous left atrial appendage closure (LAAC) has been suggested as an alternative to long-term oral anticoagulation for nonvalvular atrial fibrillation, but comparative data remain scarce. We aimed to assess ischemic and bleeding outcomes of LAAC compared with vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) for the prevention of cardioembolic events in patients with atrial fibrillation. METHODS AND RESULTS: Embase and MEDLINE were searched for randomized trials comparing LAAC, VKAs, and DOACs. The primary efficacy end point was any stroke or systemic embolism. Treatment effects were calculated from a network meta-analysis and ranked according to the surface under the cumulative ranking curve. Seven trials and 73 199 patients were included. The risk of the primary end point was not statistically different between LAAC versus VKAs (odds ratio [OR], 0.92 [95% CI, 0.62-1.50]) and LAAC versus DOACs (OR, 1.11 [95% CI, 0.71-1.73]). LAAC and DOACs resulted in similar risk of major or minor (OR, 0.93 [95% CI, 0.61-1.42]) and major bleeding (OR, 0.92 [95% CI, 0.58-1.46]); however, after exclusion of procedural bleeding, bleeding risk was significantly lower in those undergoing LAAC. Both LAAC and DOACs reduced the risk of all-cause death  compared with VKAs (LAAC versus VKAs: OR, 0.70 [95% CI, 0.53-0.91]; DOACs versus VKAs: OR, 0.90 [95% CI, 0.85-0.95], respectively). DOACs ranked as the best treatment for stroke or systemic embolism prevention (66.9%) and LAAC for reducing major bleeding (63.9%) and death (96.4%). CONCLUSIONS: As a nonpharmacological alternative to oral anticoagulation for atrial fibrillation, LAAC showed similar efficacy and safety compared with VKAs or DOACs. Prospective confirmation from larger studies is warranted.

Anticoagulant therapy in renal insufficiency theme: Anticoagulation in complex situations.

Many patients with impaired renal function have concurrent indications for anticoagulant therapy, including atrial fibrillation and venous thromboembolism. For mild chronic kidney disease, data from clinical trials and existing guidelines can be applied to clinical management. The benefits and harms of anticoagulation therapy in patients with more advanced renal impairment are nuanced, as both thrombotic and bleeding risk are increased. Until recently, data regarding anticoagulants in severe renal impairment were primarily observational, but emerging evidence includes a few small clinical trials and the emergence of novel agents hypothesized to have improved efficacy and safety in this population. In this review, we summarize existing data on anticoagulation in patients with chronic kidney disease. We suggest a framework for anticoagulation decision-making in the burgeoning worldwide population of patients with chronic kidney disease.

Management of apixaban anticoagulation in a patient requiring therapeutic plasma exchange: a case report and a literature review.

Therapeutic plasma exchange (TPE) is used as an effective treatment modality for a variety of autoimmune disorders. Apart from its desired effect of removing pathological blood components, it also can remove coagulation factors and drugs. Currently, there is an insufficient amount of information regarding the use of direct oral anticoagulants in this setting. In this article, we present a case report of a patient with myasthenia gravis and chronic anticoagulation with apixaban who underwent a series of TPE while continuing apixaban treatment. We observed that only 10% of daily dose was removed by the procedure and plasma levels of apixaban corresponded with expected range. TPE was not associated with shortened drug plasma half-life. We did not observe any significant alteration of apixaban pharmacokinetics during the period of TPE therapy, as well as no thrombotic or bleeding events. This case report supports the use of apixaban in patients treated by TPE, nevertheless, to firmly establish apixaban efficacy and safety profile in this clinical setting further research is needed.