[Chinese expert consensus on home management of oral anticoagulants(2024 edition)].

Oral anticoagulants are widely used in the home care of patients who require prevention and treatment of thromboembolic diseases. The irrational use of anticoagulants may cause thrombosis and hemorrhage. Currently, there are no national or international guidelines or consensus providing recommendations for home management of oral anticoagulants. Therefore, the Hospital Pharmacy Professional Committee of the Chinese Pharmaceutical Association organized domestic experts in the fields of clinical pharmacy, cardiovascular surgery, cardiovascular medicine, vascular surgery, respiratory medicine and laboratory science to sort out the relevant issues and compile the expert consensus on the home management of oral anticoagulants. The main contents of this consensus include pharmacological monitoring of oral anticoagulants, the process and precautions of carrying out home management of oral anticoagulants, and treatment of some special conditions during home management, with the aim of enhancing the safety and effectiveness of oral anticoagulants' usage and reducing the adverse events.

Antithrombotic Therapy for Heart Failure in Sinus Rhythm - A Concise Review.

Heart failure (HF) is a common disorder associated with significant morbidity and mortality. It can increase the risk of thromboembolic events, which subsequently lead to increased risk of stroke, ischemic heart disease, thromboembolism, and death. Antithrombotic therapy has been investigated as a potential management strategy for HF patients in sinus rhythm, but its efficacy remains uncertain. Current guidelines do not recommend the routine use of antithrombotics in patients with HF in sinus rhythm without any other indication for their use. Several randomized controlled trials have investigated the efficacy of antithrombotics in HF patients in sinus rhythm. This article provides a concise review of the existing literature to assess the evidence supporting the use of antithrombotics in HF patients in sinus rhythm. The use of warfarin or other anticoagulants has demonstrated a lower risk of stroke but an increased risk of bleeding. The studies demonstrate that anticoagulant therapy in HF patients in sinus rhythm does not provide significant benefits in terms of overall ischemic events or death.

Andexanet alpha versus four-factor prothrombin complex concentrate in DOACs anticoagulation reversal: an updated systematic review and meta-analysis.

BACKGROUND: There is currently a lack of evidence for the comparative effectiveness of Andexanet alpha and four-factor prothrombin complex concentrate (4F-PCC) in anticoagulation reversal of direct oral anticoagulants (DOACs). The primary aim of our systematic review was to verify which drug is more effective in reducing short-term all-cause mortality. The secondary aim was to determine which of the two reverting strategies is less affected by thromboembolic events. METHODS: A systematic review and meta-analysis was performed. RESULTS: Twenty-two studies were analysed in the systematic review and quantitative synthesis. In all-cause short-term mortality, Andexanet alpha showed a risk ratio (RR) of 0.71(95% CI 0.37-1.34) in RCTs and PSMs, compared to 4F-PCC (I2 = 81%). Considering the retrospective studies, the pooled RR resulted in 0.84 (95% CI 0.69-1.01) for the common effects model and 0.82 (95% CI 0.63-1.07) for the random effects model (I2 = 34.2%). Regarding the incidence of thromboembolic events, for RCTs and PSMs, the common and the random effects model exhibited a RR of 1.74 (95% CI 1.09-2.77), and 1.71 (95% CI 1.01-2.89), respectively, for Andexanet alpha compared to 4F-PCC (I2 = 0%). Considering the retrospective studies, the pooled RR resulted in 1.21 (95% CI 0.87-1.69) for the common effects model and 1.18 (95% CI 0.86-1.62) for the random effects model (I2 = 0%). CONCLUSION: Considering a large group of both retrospective and controlled studies, Andexanet alpha did not show a statistically significant advantage over 4F-PCC in terms of mortality. In the analysis of the controlled studies alone, Andexanet alpha is associated with an increased risk of thromboembolic events. CLINICAL TRIAL REGISTRATION: PROSPERO: International prospective register of systematic reviews, 2024, CRD42024548768.

Association Between Aortic Wall Thrombus and Thromboembolic Events After Transfemoral Transcatheter Aortic Valve Replacement.

BACKGROUND: Thromboembolic events, particularly strokes, remain a major complication of transcatheter aortic valve replacement (TAVR). Embolic protection devices have failed to show significant clinical benefit in large randomized clinical trials. Aortic wall thrombus (AWT) is often observed on multidetector computed tomography during TAVR work-up, but its prognostic significance is uncertain. OBJECTIVES: This study sought to evaluate the association between the presence of AWT and the incidence of thromboembolic outcomes in patients undergoing transfemoral (TF) TAVR for severe aortic stenosis. METHODS: This was a prospective cohort study of consecutive patients who underwent TF TAVR for severe aortic stenosis between January 2011 and April 2022. A dedicated scale (range: 0-10) was qualitatively used to assess AWT. The primary outcome was a composite of procedural thromboembolic events defined as ischemic stroke, blue toe syndrome, bowel ischemia, or other solid organ infarction. The secondary endpoints were ischemic strokes and procedural death. RESULTS: Of the 641 patients included, severe AWT (score ≥8) was identified in 73 (11.4%). The presence of severe AWT was strongly associated with an increase in the primary outcome (OR: 8.48; 95% CI: 3.36-21.40; P < 0.001). This relationship persisted following multivariable analysis, which adjusted for comorbidities and procedural characteristics. The presence of severe AWT was also found to be associated with an increased incidence of stroke and procedural death (OR: 5.66; 95% CI: 2.00-15.30; P = 0.002 and OR: 4.66; 95% CI: 1.80-11.30; P = 0.002, respectively). CONCLUSIONS: The presence of severe AWT on preprocedural multidetector computed tomography is strongly associated with thromboembolic complications including stroke and mortality after TF TAVR.

Long-term discontinuation of warfarin in a patient with HeartMate 3 left ventricular assist device without thromboembolic events.

The gold standard therapy for end-stage heart failure is cardiac transplantation. However, in the face of a donor shortage, a mechanical assist device such as the left ventricular assist device HeartMate 3 (Abbott Laboratories, Abbott Park, IL, USA) serves as bridging therapy to transplantation and/or destination therapy. Current guidelines recommend anticoagulation with a vitamin K antagonist in combination with low-dose aspirin. We herein report a challenging anticoagulation regimen in a patient with a HeartMate 3 in whom systemic anticoagulation with warfarin was not feasible for 4 years because of low compatibility and a rare X-factor deficiency. This is a rare hematological disorder, estimated to affect approximately 1 in every 500,000 to 1,000,000 people in the general population. The patient finally received a modified anticoagulation regimen involving the combination of rivaroxaban and clopidogrel without warfarin. Under this regimen, the patient remained free of thromboembolic complications for 4 years with in situ placement of the left ventricular assist device. This case illustrates that under specific circumstances, long-term absence of warfarin therapy is feasible in patients with a HeartMate 3.

Effect of drug interactions with non-vitamin-K oral anticoagulants on thromboembolic events in patients with nonvalvular atrial fibrillation.

Introduction: Few real-world studies have investigated drug-drug interactions (DDIs) involving non-vitamin-K antagonist oral anticoagulants (NOACs) in patients with nonvalvular atrial fibrillation (NVAF). The interactions encompass drugs inducing or inhibiting cytochrome P450 3A4 and permeability glycoprotein. These agents potentially modulate the breakdown and elimination of NOACs. This study investigated the impact of DDIs on thromboembolism in this clinical scenario. Method: Patients who had NVAF and were treated with NOACs were selected as the study cohort from the National Health Insurance Research Database of Taiwan. Cases were defined as patients hospitalised for a thromboembolic event and who underwent a relevant imaging study within 7 days before hospitalisa-tion or during hospitalisation. Each case was matched with up to 4 controls by using the incidence density sampling method. The concurrent use of a cytochrome P450 3A4/permeability glycoprotein inducer or inhibitor or both with NOACs was identified. The effects of these interactions on the risk of thromboembolic events were examined with univariate and multivariate conditional logistic regressions. Results: The study cohort comprised 60,726 eligible patients. Among them, 1288 patients with a thromboembolic event and 5144 matched control patients were selected for analysis. The concurrent use of a cytochrome P450 3A4/permeability glycoprotein inducer resulted in a higher risk of thromboembolic events (adjusted odds ratio [AOR] 1.23, 95% confidence interval [CI] 1.004-1.51). Conclusion: For patients with NVAF receiving NOACs, the concurrent use of cytochrome P450 3A4/ permeability glycoprotein inducers increases the risk of thromboembolic events.

Antithrombotic management after aortic valve replacement with biological prosthesis: a meta-analysis.

BACKGROUND: We aimed to summarise the existing knowledge regarding antithrombotic medications following surgical aortic valve replacement (SAVR) using a biological valve prosthesis. METHODS: We performed a meta-analysis of studies that reported the results of using antithrombotic medication to prevent thromboembolic events after SAVR using a biological aortic valve prosthesis and recorded the outcomes 12 months after surgery. Since no randomised controlled trials were identified, observational studies were included. The analyses were conducted separately for periods of 0-12 months and 3-12 months after surgery. A random effects model was used to calculate pooled outcome event rates and 95% confidence intervals (CIs). RESULTS: The search yielded eight eligible observational studies covering 6727 patients overall. The lowest 0- to 12-month mortality was observed in patients with anticoagulation (2.0%, 95% CI 0.4-9.7%) and anticoagulation combined with antiplatelet therapy (2.2%, 95% CI 0.9-5.5%), and the highest was in patients without antithrombotic medication (7.3%, 95% CI 3.6-14.2%). Three months after surgery, mortality was lower in anticoagulant patients (0.5%, 95% CI 0.1-2.6%) than in antiplatelet patients (3.0%, 95% CI 1.2-7.4%) and those without antithrombotics (3.5%, 95% CI 1.3-9.3%). There was no eligible evidence of differences in stroke rates observed among medication strategies. At 0- to 12-month follow-up, all antithrombotic treatment regimens resulted in an increased bleeding rate (antiplatelet 4.2%, 95% CI 2.9-6.1%; anticoagulation 7.5%, 95% CI 3.8-14.4%; anticoagulation combined with antiplatelet therapy 8.3%, 95% CI 5.7-11.8%) compared to no antithrombotic medication (1.1%, 95% CI 0.4-3.4%). At 3- to 12-month follow-up, there was up to an eight-fold increase in the bleeding rate in patients with anticoagulation combined with antiplatelet therapy when compared to those with no antithrombotic medication. Overall, the evidence certainty was ranked as very low. CONCLUSION: Although this meta-analysis reveals that anticoagulation therapy has a beneficial tendency in terms of mortality at 1 year after biological SAVR and suggests potential advantages in continuing anticoagulation beyond 3 months, it is limited by very low evidence certainty. The imperative for cautious interpretation and the urgent need for more robust randomised research underscore the complexity of determining optimal antithrombotic strategies in this patient population.

Efficacy and safety of antithrombotic therapy for preventing and treating pediatric thromboembolic disease: a systematic review.

This review used traditional and network meta-analyses (NMA) to conduct a comprehensive study of antithrombotic therapies in children with thromboembolic disease. We searched the PubMed, Embase, Cochrane Library, Web of Science and ClinicalTrials.gov databases from their inception to 26 February, 2023. And we finally included 16 randomized controlled trials. In the prevention of thromboembolic events (TEs), the use of anticoagulants had a low risk of TEs (relative risk (RR) 0.73, 95% CI 0.56 to 0.94) and a high risk of minor bleeding (RR 1.43, 95% CI 1.09 to 1.86) compared with no anticoagulants. In the treatment of TEs, direct oral anticoagulants (DOACs) were not inferior to standard anticoagulation in terms of efficacy and safety outcomes. In NMA, rivaroxaban and apixaban showed the lowest risk for TEs and major or clinically relevant nonmajor bleeding. According to the overall assessment of efficacy and safety, dabigatran may be the best choice for children with thromboembolic disease. The results of our study will provide references and suggestions for clinical drug selection.

Thromboembolic and bleeding complications after elective cardioversion of atrial fibrillation: a nationwide cohort study.

AIMS: Elective cardioversion (ECV) is routinely used in atrial fibrillation (AF) to restore sinus rhythm. However, it includes a risk of thromboembolism even during adequate oral anticoagulation treatment. The aim of this study was to evaluate the risk of thromboembolic and bleeding complications after ECV in a real-life setting utilizing data from a large AF population. METHODS AND RESULTS: This nationwide register-based study included all (n = 9625) Finnish AF patients undergoing their first-ever ECV between 2012 and 2018. The thromboembolic and bleeding complications within 30 days after ECV were analysed. The mean age of the patients was 67.7 ± 9.9 years, 61.2% were men, and the mean CHA2DS2-VASc score was 2.6 ± 1.6. Warfarin was used in 6245 (64.9%) and non-vitamin K oral anticoagulants (NOACs) in 3380 (35.1%) cardioversions. Fifty-two (0.5%) thromboembolic complications occurred, of which 62% were ischaemic strokes, 25% transient ischaemic attacks, and 13% other systemic embolisms. Thromboembolic events occurred in 14 (0.4%) NOAC-treated patients and in 38 (0.6%) warfarin-treated patients (odds ratio 0.77; confidence interval: 0.42-1.39). The median time from ECV to the thromboembolic event was 2 days, and 78% of the events occurred within 10 days. Age and alcohol abuse were significant predictors of thromboembolic events. Among warfarin users, thromboembolic complications were more common with international normalized ratio (INR) <2.5 than INR ≥2.5 (0.9% vs. 0.4%, P = 0.026). Overall, 27 (0.3%) bleeding events occurred. CONCLUSION: The rate of thromboembolic and bleeding complications related to ECV was low without significant difference between NOAC- and warfarin-treated patients. With warfarin, INR ≥2.5 at the time of cardioversion reduced the risk of thromboembolic complications.

Feline Aortic Thromboembolism: Recent advances and future prospects.

PRACTICAL RELEVANCE: Feline aortic thromboembolism (FATE) is commonly encountered in clinical medicine, especially in emergency situations. This often devastating syndrome usually develops secondarily to severe heart disease, and has short- and long-term consequences. CLINICAL FEATURES: The clinical presentation of FATE is consistent with peripheral ischemic neuropathy, usually in both pelvic limbs. Diagnosis is relatively straightforward, but can be assisted with Doppler ultrasound, point-of-care ultrasound or infrared thermal imaging. RECENT ADVANCES AND FUTURE PROSPECTS: Interpretation of survival rates in cats with FATE has been hampered by historically high admission euthanasia, but recent studies suggest a survival rate with supportive care of 30-40%. Moreover, with advances in post-FATE thromboprophylaxis, median survival times of over 1 year are being achieved. Future directions include use of thrombolytic agents and treatment of common FATE sequelae such as acute kidney injury and reperfusion injury. OUTLINE: This article, aimed at small animal veterinarians, including emergency practitioners, reviews key aspects of the clinical presentation, diagnosis and treatment options for FATE, with a view to guiding client and veterinarian decision-making. Three case studies are included to illustrate the practical application of information presented in the review. EVIDENCE BASE: There are limited prospective studies on FATE, although the recent literature reflects a resurgence in clinical research interest in the past few years. Advances in FATE treatment will benefit many cats and it is important that research efforts continue to identify appropriate treatment modalities.

Factor XI inhibition in hemodialysis patients: the safer anticoagulation?

Chronic hemodialysis patients exhibit an excessive cardiovascular risk and a marked increase in both thromboembolism and bleeding episodes. Factor XI inhibition may provide anticoagulation, with a low risk of bleeding, and several factor XI inhibitors, including fesomersen, an antisense oligonucleotide, are under development. Recently, a phase 2 study of fesomersen showed a good safety profile in chronic hemodialysis patients and suggested that clotting rates of the arteriovenous fistula and the dialysis circuit are lower.

Thinking Three-Dimensionally: A Self- and Externally-Controlled Approach to Screening for Drug-Drug-Drug Interactions Among High-Risk Populations.

The global rise in polypharmacy has increased both the necessity and complexity of drug-drug interaction (DDI) assessments, given the growing potential for interactions involving more than two drugs. Leveraging large-scale healthcare claims data, we piloted a semi-automated, high-throughput case-crossover-based approach for drug-drug-drug interaction (3DI) screening. Cases were direct-acting oral anticoagulant (DOAC) users with either a major bleeding event during ongoing dispensings for potentially interacting, enzyme-inhibiting antihypertensive drugs (AHDs) (Study 1), or a thromboembolic event during ongoing dispensings for potentially interacting, enzyme-inducing antiseizure medications (ASMs) (Study 2). 3DI detection was based on screening for additional drug exposures that served as acute outcome triggers. To mitigate direct effects and confounding by concomitant drugs, self-controlled estimates were adjusted using negative cases (external "control" DOAC users with the same outcomes but co-dispensings for non-interacting AHDs or ASMs). Signal thresholds were set based on P-values and false discovery rate q-values to address multiple comparisons. Study 1: 285 drugs were examined among 3,306 episodes. Self-controlled assessments with q-value thresholds yielded 9 3DI signals (cases) and 40 DDI signals (negative cases). External adjustment generated 10 3DI signals from the P-value threshold and no signals from the q-value threshold. Study 2: 126 drugs were examined among 604 episodes. Assessments with P-value thresholds yielded 3 3DI and 26 DDI signals following self-control, as well as 4 3DI signals following adjustment. No 3DI signals met the q-value threshold. The presented self- and externally-controlled approach aimed to advance paradigms for real-world higher order drug interaction screening among high-susceptibility populations with pre-existent DDI risk.

Savings associated with surgical aortic valve replacement with a RESILIA tissue valve based on seven-year COMMENCE trial results.

BACKGROUND: Bioprostheses with RESILIA tissue demonstrate a reduction in calcification and improve health outcomes in pre-clinical and clinical studies. Prior economic analyses which relied on 5 years of evidence from the COMMENCE trial demonstrate financial savings for RESILIA tissue valves relative to mechanical valves after surgical aortic valve replacement (SAVR). Given the recent release of 7-year COMMENCE data, this economic evaluation updates the estimate for long-run savings of bioprosthetic valves with RESILIA. METHODS: Simulation models estimated disease progression across two hypothetical SAVR cohorts (tissue vs. mechanical) of 10,000 patients each in the US. The primary comparison calculated the SAVR-related expenditures associated with each valve type ($US, 2023). Health outcome probabilities were based on the COMMENCE trial though year 7 and projected for an additional 8 years based on prior studies of tissue and mechanical SAVR. Costs for key outcomes (mortality, reoperation, bleeding, thromboembolism, endocarditis) and anticoagulant monitoring were sourced from the literature. Incidence rates of health outcomes associated with mechanical valves relied on relative risks of tissue valve versus mechanical valve patients. RESULTS: Seven-year savings are $13,415 (95% CI = $10,472-$17,321) per patient when comparing RESILIA versus mechanical SAVR. Projected 15-year savings were $23,001 ($US, 2023; 95% CI = $17,802-$30,421). Most of the 15-year savings are primarily attributed to lower anti-coagulation monitoring costs ($21,073 in ACM savings over 15 years), but lower bleeding cost (savings: $2,294) and thromboembolism-related expenditures (savings: $852) also contribute. Reoperation and endocarditis expenditures were slightly larger in the RESILIA cohort. If reoperation relative risk reverts from 1.1 to 2.2 (the level in legacy tissue valves) after year 7, savings are $18,064. RESILIA SAVR also reduce costs relative to legacy tissue valves. CONCLUSION: Patients receiving RESILIA tissue valves are projected to have lower SAVR-related health expenditures relative to mechanical and legacy tissue valves.

Left Atrial Appendage Closure: Therapy Overview and Future Perspective.

The left atrial appendage (LAA) has gained increasing attention in the field of cardiology as a potential site for intervention in patients with atrial fibrillation (AF) and an elevated risk of thromboembolic events. Left atrial appendage occlusion (LAAO) has emerged as a promising therapeutic strategy to mitigate the risk of stroke and systemic embolism, especially in individuals who are unsuitable candidates for long-term anticoagulation therapy. This review aims to provide a comprehensive analysis of the current state of LAAO, encompassing its anatomic considerations, procedural techniques, clinical outcomes, and future directions.

Educational status and the risk of adverse outcomes in Asian patients with atrial fibrillation: a report from the prospective APHRS-AF Registry.

BACKGROUND: The aim of this study was to evaluate the impact of educational status (ES) on the clinical course of Asian patients with atrial fibrillation (AF). METHODS: We used data from the prospective APHRS-AF Registry. ES was classified as follows: low (primary school), medium (secondary), and high (University). The primary outcome was a composite of all-cause death, thromboembolic events, acute coronary syndrome, and heart failure. Secondary outcomes were each component of the primary outcome, cardiovascular death, and major bleeding. The one-year risk of primary and secondary outcomes was assessed through Cox-regressions. Adherence to the Atrial fibrillation Better Care (ABC) pathway was assessed. RESULTS: Among 2697 AF patients (69±12 years, 34.8% females), 34.6% had low ES; 37.3% had medium ES; and 28.1% had high ES. Compared to patients with medium-high ES, patients with low ES were older, more often females, with a higher prevalence of cardiovascular risk factors, and a lower ABC pathway adherence (30.4% vs. 40.2%, P<0.001). On multivariable analysis, low ES was associated with a higher risk for the primary outcome (HR 1.52,95%CI 1.11-2.06) and all-cause death (HR 1.76,95%CI 1.10-2.83) than medium-high ES. A significant interaction was found for the risk of composite outcome among the different age strata, with the higher risk in the elderly (P for int=0.008), whereas the beneficial effect of the ABC pathway was irrespective of ES (P for int=0.691). CONCLUSIONS: In Asian AF patients, low ES is associated with high mortality. Efforts to improve education and include ES evaluation in the integrated care approach for AF are necessary to reduce the cardiovascular burden in these patients.

The left atrial appendage: An enigmatic friend or foe and implications of closure.

The left atrial appendage (LAA) is often thought of as a vestigial organ serving as a nidus for clot formation in those with atrial fibrillation (A-fib). The LAA, however, has unique anatomy which allows it to serve special functions in the human body. Closing the LAA has been shown to decrease the risk of thromboembolic events in patients who cannot tolerate anticoagulation. Several methods of closure exist including percutaneous endocardial closure, epicardial closure, and surgical clipping. In addition to decreasing stroke risk, there appears to be physiologic changes that occur after LAA closure. This comprehensive review aims to describe the functions of the LAA, compare the different methods of closure, and propose a new method for identifying which patients may benefit from LAA closure versus anticoagulation based on each patients' individual comorbidities rather than their contraindications.

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.

Perils of reduced dose apixaban in atrial fibrillation/flutter - A case report with a brief literature review.

Patients with atrial fibrillation/atrial flutter (AF) are notoriously predisposed to thromboembolic events secondary to the development of thrombi within the left atrium of the heart. AF accompanied by a fairly decent CHA2DS2-VASc score is a known indication for full anticoagulation, frequently with direct oral anticoagulants (DOACs), such as apixaban. Following extensive studies weighing the benefits of anticoagulation versus risks of major bleeding, patients meeting two or more of the dose-reduction criteria (age ≥80 years, weight ≤60 kg, and/or creatinine ≥ 1.5 mg/dL) require appropriate step-down to a reduced dose of apixaban. However, with rising concern for bleeding complications, many physicians are found to have been reducing the dose of apixaban despite the patient not completely meeting the defined criteria. Our study particularly emphasizes the risk of significantly increased thromboembolic complications in the setting of sub-therapeutic anticoagulation, in patients with both appropriately and inappropriately reduced doses of apixaban.