Emulation of randomized trials of direct oral anticoagulants with claims data and implications for new Factor XI inhibitors.

Direct oral anticoagulants (DOACs) revolutionized the management of thromboembolic disorders. Clinical care may be further improved as Factor XIs undergo large-scale outcome trials. What role can non-randomized database studies play in expediting understanding of these drugs in clinical practice? The RCT-DUPLICATIVE Initiative emulated the design of eight DOAC randomized clinical trials (RCT) using non-randomized claims database studies. RCT study design parameters and measurements were closely emulated by the database studies and produced highly concordant results. The results of the single database study that did not meet all agreement metrics with the specific RCT it was emulating were aligned with a meta-analysis of six trials studying similar questions, suggesting the trial result was an outlier. Well-designed database studies using fit-for-purpose data came to the same conclusions as DOAC trials, illustrating how database studies could complement RCTs for Factor XI inhibitors-by accelerating insights in underrepresented populations, demonstrating effectiveness and safety in clinical practice, and testing broader indications.

Efficacy of human prothrombin complex concentrate in the treatment of warfarin overdose in patients receiving warfarin for mechanical heart valve replacement.

Warfarin, a widely utilized anticoagulant, is paramount for preventing thromboembolic events in patients with mechanical heart valve replacements. However, its narrow therapeutic index can lead to over-anticoagulation and overdose, resulting in serious health risks. This study examines the efficacy of human prothrombin complex concentrate (PCC) in managing warfarin overdose, in comparison with traditional treatments. A retrospective analysis was conducted on 162 adults who presented with warfarin overdose (INR > 5.0) at a tertiary care hospital between 2016 and 2020. Participants were divided into 2 groups-those treated with PCC (n = 57) and those treated with conventional methods (n = 105), including vitamin K and fresh frozen plasma. The primary outcome was the rate of reaching the target (International Normalized Ratio) INR within 24 hours. Secondary outcomes included transfusion requirements, thromboembolic events, adverse reactions, 30-day mortality, and length of hospital stay. PCC demonstrated significant efficacy, with 89.5% of patients achieving the target INR within 24 hours, compared to 64.8% in the control group (P < .05). The PCC group also had reduced transfusion requirements and a shorter average hospital stay. There was no significant difference in thromboembolic events or adverse reactions between the 2 groups, and the reduced 30-day mortality in the PCC group was not statistically significant. Human prothrombin complex concentrate is associated with rapid reaching the target INR, decreased transfusion needs, and shortened hospitalization, making it a promising option for warfarin overdose management. While the results are encouraging, larger, multicenter, randomized controlled trials are necessary to further validate these findings and optimize PCC administration protocols.

Anticoagulation in COVID-19 patients - An updated systematic review and meta-analysis.

BACKGROUND: Thromboembolic events are common complications of COVID-19. Clinical study results on safety and efficacy of anticoagulation in COVID-19 are controversial. MATERIAL AND METHODS: This report is the second update of our systematic review with meta-analysis on randomized controlled trials (RCTs) comparing standard thromboprophylaxis, intermediate or therapeutic dose anticoagulation or no anticoagulation in COVID-19 in- and outpatients. We searched eligible studies up to 5 October 2023. Certainty of evidence was assessed using GRADE. RESULTS: For this update we included fourteen new RCTs and a total of 27 RCTs with 16,789 patients. Certainty of evidence ranged from very low to high depending on outcome and comparison. Standard thromboprophylaxis with low dose anticoagulation may have little or no effect for COVID-19 outpatients compared to no anticoagulation. In inpatients with moderate or severe COVID-19, intermediate dose anticoagulation may decrease any thrombotic events or death, but may increase major bleeding compared to standard thromboprophylaxis. Therapeutic dose anticoagulation decreases thrombotic events or deaths in inpatients with moderate COVID-19, but probably has little or no effect in patients with severe COVID-19 compared to standard thromboprophylaxis with low or intermediate dose anticoagulation. With therapeutic dose anticoagulation, the risk of major bleeding probably increases regardless of COVID-19 severity. We are uncertain on the effect of thromboprophylaxis with low dose anticoagulation compared to no anticoagulation in the post-discharge setting. CONCLUSIONS: Hospitalized, moderately-ill COVID-19 patients may benefit from intermediate or therapeutic dose anticoagulation, while critically ill patients may not. Risk of major bleeding must be considered.

Reports on vascular catheter-associated thromboembolic events in a burn unit - a gap in the literature?

Indwelling intravascular catheters are important tools in the care of critically ill patients; however, they have an inherent risk of infection or thromboembolic events. Reports on catheter associated thromboembolic events in burn units are rare, despite being well recognized that burn patients bear an increased baseline risk for thromboembolic events. We describe two catheter-associated thromboembolic complications in burn patients in a burn unit and the morbidity associated with these events. Patients with endovascular catheters in burn units may be at increased risk for severe thromboembolic events associated with intravascular catheters, but specific guidelines for prevention and management of these patients are still missing.

Prophylactic-dose direct oral anticoagulants for non-hospitalised people with COVID-19: A meta-analysis of randomised controlled trials.

Background: Several reviews have been conducted on thromboprophylaxis in non-hospitalised patients with coronavirus disease 2019 (COVID-19). In this systematic review and meta-analysis, we sought to investigate the impact of prophylactic-dose direct oral anticoagulants (DOACs) in this population. Methods: We searched PubMed, Web of Science, EMBASE and Cochrane Library for randomised controlled trials (RCTs) comparing prophylactic-dose DOACs with placebo or no treatment in non-hospitalised patients with COVID-19 until September 2023. The primary efficacy outcome was a composite of all-cause mortality and thromboembolic events, while major bleeding events were the primary safety outcome. We expressed continuous outcome data as mean differences (MDs) with 95% confidence intervals (CIs) and dichotomous outcome data as risk ratios (RRs) with 95% CIs. Results: We included six RCTs involving 4307 patients. Prophylactic-dose DOAC therapy compared with placebo or no treatment was associated with significantly decreased risks of the composite outcome of all-cause mortality and thromboembolic events (1.43% vs 2.67% (RR = 0.53; 95% CI = 0.34-0.82, P = 0.004, I2 = 3%)). Major bleeding events were infrequent, and we detected no significant differences between patients assigned to prophylactic-dose DOACs vs placebo or no treatment (0.19% vs 0.05% (RR = 2.50; 95% CI = 0.49-12.87, P = 0.27, I2 = 0%)). The use of prophylactic-dose DOACs was also associated with a reduction in venous thromboembolism, with no difference in all-cause mortality, arterial thromboembolism, hospitalisations, and clinically relevant nonmajor bleeding between two groups. Sensitivity analyses with the leave-one-out method for the primary efficacy and safety outcome did not change the effect estimate substantially. Conclusions: We found that prophylaxis-dose DOACs could significantly improve clinical outcomes and reduce venous thrombotic events without increasing the risk of major bleeding events compared with placebo or no treatment in non-hospitalised patients with COVID-19. Registration: PROSPERO: CRD42023466889.

Use of apixaban in adults with congenital heart disease and atrial arrhythmias: The PROTECT-AR study.

BACKGROUND: Adults with congenital heart disease (ACHD) and atrial arrhythmias (AA) face an increased risk of thromboembolic events. Limited data exist on the use of non-vitamin K oral anticoagulants for thromboprophylaxis in ACHD. We aimed to assess the effectiveness and safety of apixaban in ACHD patients with AA. METHODS: PROTECT-AR (NCT03854149) was a prospective, multicenter, observational study conducted from 2019 to 2023. ACHD patients with atrial fibrillation, atrial flutter, or intra-atrial re-entrant tachycardia on routine apixaban treatment were included. The historical control group consisted of patients previously on vitamin K antagonist (VKA), who were analyzed prior to their transition to apixaban. The primary effectiveness endpoint was the composite of stroke or thromboembolism. The primary safety endpoint was major bleeding. RESULTS: The study enrolled 218 ACHD patients with AA on apixaban, of which 73 were previous VKA users. The analysis covered 527 patient-years of prospective exposure to apixaban and 169 patient-years of retrospective exposure to VKA. The annualized rate of stroke or thromboembolism was 0.6% in the apixaban group and 1.8% in the VKA group (absolute difference - 1.2%; upper limit of one-sided 95% confidence interval [CI] 0.9%, lower than the predefined non-inferiority margin of +1.8%, Pnon-inferiority < 0.001). The annualized rate of major bleeding was 1.5% in the apixaban group and 2.4% in the VKA group (hazard ratio 0.64; 95% CI 0.19-2.10, P = 0.48). CONCLUSION: In ACHD patients with AA, routine apixaban use exhibited a non-inferior rate of stroke or thromboembolism compared to historical VKA use, alongside a similar rate of major bleeding.

Non-valvular atrial fibrillation in patients on peritoneal dialysis, prevalence, treatment and professionals involved.

Atrial fibrillation is the most frequent chronic arrhythmia in patients with chronic kidney disease. Oral anticoagulation with vitamin K antagonists and now direct oral anticoagulants have been and are the fundamental pillars for the prevention of thromboembolic events. However, there are no randomized clinical trials on the risk-benefit profile of oral anticoagulation in patients with chronic kidney disease stage 5 on peritoneal dialysis and there is little evidence in the literature in this population. The objective of our study was to know the prevalence, treatment and professionals involved in the management of atrial fibrillation in peritoneal dialysis patients. For this purpose, we performed a descriptive analysis through a survey sent to different peritoneal dialysis units in Spain. A total of 1,403 patients on peritoneal dialysis were included in the study, of whom 186 (13.2%) had non-valvular atrial fibrillation. In addition, the assessment of the scores of thromboembolic and bleeding risks for the indication of oral anticoagulation was mainly carried out by the cardiologist (60% of the units), as well as its prescription (cardiologist 47% or in consensus with the nephrologist 43%). In summary, patients on peritoneal dialysis have a remarkable prevalence of non-valvular atrial fibrillation. Patients frequently receive oral anticoagulation with vitamin K antagonists, as well as direct oral anticoagulants. The data obtained regarding the scores used for the assessment of thromboembolic and bleeding risk, treatment and involvement by Nephrology indicates that there is a need for training and involvement of the nephrologist in this pathology.

Reversal and resumption of anticoagulants in patients with anticoagulant-associated intracerebral hemorrhage.

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.

Thromboembolic risk of carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for newly diagnosed multiple myeloma: A comparative systematic review and meta-analysis.

Thrombosis represents a frequent and potentially severe complication in individuals diagnosed with multiple myeloma (MM). These events can be driven by both the disease as well as the therapies themselves. Overall, available evidence is inconclusive about the differential thrombogenicity of carfilzomib/lenalidomide/dexamethasone (KRd) and bortezomib/lenalidomide/dexamethasone (VRd). This meta-analysis compares the risk for venous thromboembolism (VTE; including deep venous thrombosis and pulmonary embolism) and arterial thromboembolism (ATE; including myocardial infarction and ischemic stroke) with KRd versus VRd as primary therapy for newly diagnosed MM (NDMM). Out of 510 studies identified after deduplication, one randomized controlled trial and five retrospective cohort studies were included. We analyzed 2304 patients (VRd: 1380; KRd: 924) for VTE events and 2179 patients (VRd: 1316; KRd: 863) for ATE events. Lower rates of VTE were observed in the VRd group when compared with the KRd group (6.16% vs. 8.87%; odds ratio [OR], 0.53; 95% confidence interval [CI], 0.32-0.88; p = .01). Both treatment groups exhibited minimal ATE incidence, with no significant difference between them (0.91% vs. 1.16%; OR, 1.01; 95% CI, 0.24-4.20; p = .99). In view of potential biases from retrospective studies, heterogeneity of baseline population characteristics, and limited access to patient-level data (e.g., VTE risk stratification and type of thromboprophylaxis regimen used) inherent to this meta-analysis, additional research is warranted to further validate our findings and refine strategies for thrombosis prevention in MM.

Left atrial appendage occlusion: On the need of a numerical model to simulate the implant procedure.

Left atrial appendage occlusion (LAAO) is a percutaneous procedure to prevent thromboembolism in patients affected by atrial fibrillation. Despite its demonstrated efficacy, the LAA morphological complexity hinders the procedure, resulting in postprocedural drawbacks (device-related thrombus and peri-device leakage). Local anatomical features may cause difficulties in the device's positioning and affect the effectiveness of the device's implant. The current work proposes a detailed FE model of the LAAO useful to investigate implant scenarios and derive clinical indications. A high-fidelity model of the Watchman FLX device and simplified parametric conduits mimicking the zone of the LAA where the device is deployed were developed. Device-conduit interactions were evaluated by looking at clinical indicators such as device-wall gap, possible cause of leakage, and device protrusion. As expected, the positioning of the crimped device before the deployment was found to significantly affect the implant outcomes: clinician's choices can be improved if FE models are used to optimize the pre-operative planning. Remarkably, also the wall mechanical stiffness plays an important role. However, this parameter value is unknown for a specific LAA, a crucial point that must be correctly defined for developing an accurate FE model. Finally, numerical simulations outlined how the device's configuration on which the clinician relies to assess the implant success (i.e., the deployed configuration with the device still attached to the catheter) may differ from the actual final device's configuration, relevant for achieving a safe intervention.

Prasugrel Single Antiplatelet Therapy versus Aspirin and Clopidogrel Dual Antiplatelet Therapy for Flow Diverter Treatment for Cerebral Aneurysms: A Retrospective Multicenter Study.

BACKGROUND AND PURPOSE: The optimal antiplatelet regimen after flow diverter treatment of cerebral aneurysms is still a matter of debate. A single antiplatelet therapy might be advantageous in determined clinical scenarios. This study evaluated the efficacy and safety of prasugrel single antiplatelet therapy versus aspirin and clopidogrel dual antiplatelet therapy. MATERIALS AND METHODS: We performed a post hoc analysis of 4 retrospective multicenter studies including ruptured and unruptured aneurysms treated with flow diversion using either prasugrel single antiplatelet therapy or dual antiplatelet therapy. Primary end points were the occurrence of any kind of procedure- or device-related thromboembolic complications and complete aneurysm occlusion at the latest radiologic follow-up (mean, 18 months). Dichotomized comparisons of outcomes were performed between single antiplatelet therapy and dual antiplatelet therapy. Additionally, the influence of various patient- and aneurysm-related variables on the occurrence of thromboembolic complications was investigated using multivariable backward logistic regression. RESULTS: A total of 222 patients with 251 aneurysms were included, 90 (40.5%) in the single antiplatelet therapy and 132 (59.5%) in the dual antiplatelet therapy group. The primary outcome-procedure- or device-related thromboembolic complications-occurred in 6 patients (6.6%) of the single antiplatelet therapy and in 12 patients (9.0%) of the dual antiplatelet therapy group (P = .62; OR, 0.712; 95% CI, 0.260-1.930). The primary treatment efficacy end point was reached in 82 patients (80.4%) of the single antiplatelet therapy and in 115 patients (78.2%) of the dual antiplatelet therapy group (P = .752; OR, 1.141; 95% CI, 0.599-2.101). Logistic regression showed that non-surface-modified flow diverters (P = .014) and fusiform aneurysm morphology (P = .004) significantly increased the probability of thromboembolic complications. CONCLUSIONS: Prasugrel single antiplatelet therapy after flow diverter treatment may be as safe and effective as dual antiplatelet therapy and could, therefore, be a valid alternative in selected patients. Further prospective comparative studies are required to validate our findings.

Left atrial appendage occlusion: Percutaneous and surgical approaches in everyday practice.

Prophylactic left atrial appendage occlusion has been suggested as a means of reducing cardioembolism risk in patients with atrial fibrillation. Its clinical benefits have been discussed together with potential endocrine or hemodynamic adverse effects, with conflicting conclusions. We aimed to provide a thorough overview of the current literature and a recommendation for daily clinical decision-making. A comprehensive Medline search through PubMed was conducted to search for relevant articles, which were further filtered using the title and abstract. Sixty-five articles were selected as relevant to the topic. Concomitant left atrial appendage occlusion during cardiac surgery for other reasons is effective in terms of thromboembolism risk reduction in patients with a history of atrial fibrillation and higher CHA2DS2-VASc scores. Surgical occlusion is safe, and epicardial closure techniques are preferred. Thoracoscopic and transcatheter techniques are also feasible, and the individual treatment choice must be tailored to the patient. The concerns about endocrine imbalance or risk of heart failure after occlusion are not supported by evidence. Current evidence is conflicting with regard to hemodynamic consequences of appendage occlusion.

Thromboembolic phenomena in patients with nephrotic syndrome: pathophysiology, risk factors, prophylaxis and treatment.

Thromboembolic events resulting from disturbances in the body's balance of thrombotic and antithrombotic abilities are among the most life-threatening complications of nephrotic syndrome. Certain causes of nephrotic syndrome leave the patient particularly susceptible to thromboembolism. The severity of proteinuria and degree of hypoalbuminaemia are other common predictors of risk. Timely initiation of prophylactic therapy can help prevent morbidity and mortality associated with this complication in patients with nephrotic syndrome. The duration of treatment and choice of therapeutic agent depends on several factors, including the degree of hypoalbuminaemia, risk factors for thrombosis and risk of bleeding. This article reviews current understanding of the pathophysiology and risk factors for thromboembolism associated with nephrotic syndrome, and summarises recommendations and strategies for preventing and treating thromboembolic events in patients with nephrotic syndrome.

Direct oral anticoagulants in trauma patients.

PURPOSE OF REVIEW: Direct oral anticoagulants (DOACs) are increasingly prescribed for prevention of thromboembolic events. Thus, trauma care providers are facing a steadily raising number of injured patients on DOACs. RECENT FINDINGS: Despite a predictable pharmacokinetic profile, the resulting plasma levels of trauma patients upon admission and bleeding risks remain uncertain. Therefore, recent guidelines recommend the measurement of DOAC plasma concentrations in injured patients. Alternatively, DOAC specific visco-elastic tests assays can be applied to identify DOAC patients at bleeding risk.Bleeding complications in trauma patients on DOACs are generally higher compared to nonanticoagulated subjects, but comparable to vitamin K antagonists (VKAs). In particular, a traumatic brain injury does not carry an increased risk of intracranial bleeding due to a DOAK intake compared to VKAs. Current studies demonstrated that up to 14% of patients with a hip fracture are on DOACs prior to surgery. However, the majority can be operated safely within a 24h time window without an increased bleeding rate.Specific antagonists facilitate rapid reversal of patients on DOACs. Idarucizumab for dabigatran, and andexanet alfa for apixaban and rivaroxaban have been approved for life threatening bleeding. Alternatively, prothrombin complex concentrate can be used. Dialysis is a potential treatment option for dabigatran and haemoabsorption with special filters can be applied in patients on FXa-inhibitors. SUMMARY: Current guidelines recommend the measurement of DOAC plasma levels in trauma patients. Compared to VKAs, DOACs do not carry a higher bleeding risk. DOAC specific antagonists facilitate the individual bleeding management.

Fibrillatory wave amplitude and thromboembolic risk in non-anticoagulated patients with atrial fibrillation.

BACKGROUND: The benefit of oral anticoagulation in atrial fibrillation (AF) is well established for patients at elevated stroke risk, but less clear for those at intermediate risk. We investigated whether analysis of electrocardiogram (ECG) derived fibrillatory waves (F-waves) could help identify patients at risk for stroke and systemic embolism (SSE). METHODS: The Finnish Cardioversion (FinCV) study included patients not on permanent anticoagulation therapy who underwent cardioversion for an acute AF episode. We identified 739 individuals with a valid ECG and complete follow-up data. The maximum amplitudes of the F-waves in leads II and V1 were manually measured from the pre-procedure ECG. Patients were categorized into fine and coarse F-wave groups. The optimal lead and amplitude threshold for grouping were found in an events per person-years analysis. SSE were identified from the patient medical records until either anticoagulation was prescribed, AF was deemed chronic, the patient had deceased, or the end of follow-up. RESULTS: Overall 37 (5.0%) patients suffered SSE during the median follow-up time of 5.4 years (1.9-10.8). Measured from lead V1 the SSE rates per 100 person-years were 1.5 and 0.7 in fine and coarse F-wave groups, respectively. Fine F-waves were observed in 112 (15.2%). Baseline characteristics were similar between the groups. Fine F-wave predicted SSE in a competing risk analysis (SHR 2.34, 95%CI 1.12-4.87, p = .023). Analyses from lead II did not provide significant results. CONCLUSION: Electrocardiographic F-wave amplitude may provide additional information on stroke risk in patients with paroxysmal AF and borderline indications or contraindications for anticoagulation.

Current Gaps in the Provision of Safe and Effective Anticoagulation in Atrial Fibrillation and the Potential for Factor XI-Directed Therapeutics.

The global prevalence of atrial fibrillation is rapidly increasing, in large part due to the aging of the population. Atrial fibrillation is known to increase the risk of thromboembolic stroke by 5 times, but it has been evident for decades that well-managed anticoagulation therapy can greatly attenuate this risk. Despite advances in pharmacology (such as the shift from vitamin K antagonists to direct oral anticoagulants) that have increased the safety and convenience of chronic oral anticoagulation in atrial fibrillation, a preponderance of recent observational data indicates that protection from stroke is poorly achieved on a population basis. This outcomes deficit is multifactorial in origin, stemming from a combination of underprescribing of anticoagulants (often as a result of bleeding concerns by prescribers), limitations of the drugs themselves (drug-drug interactions, bioaccumulation in renal insufficiency, short half-lives that result in lapses in therapeutic effect, etc), and suboptimal patient adherence that results from lack of understanding/education, polypharmacy, fear of bleeding, forgetfulness, and socioeconomic barriers, among other obstacles. Often this adherence is not reported to treating clinicians, further subverting efforts to optimize care. A multidisciplinary, interprofessional panel of clinicians met during the 2023 International Society of Thrombosis and Haemostasis Congress to discuss these gaps in therapy, how they can be more readily recognized, and the potential for factor XI-directed anticoagulants to improve the safety and efficacy of stroke prevention. A full appreciation of this potential requires a reevaluation of traditional teaching about the "coagulation cascade" and decoupling the processes that result in (physiologic) hemostasis and (pathologic) thrombosis. The panel discussion is summarized and presented here.