Atrial fibrillation affects an estimated 33 million individuals worldwide and is a major cause of stroke, heart failure, and death. Anticoagulants substantially reduce the risk of stroke but are also associated with an increased risk of bleeding and especially intracranial hemorrhage which is the most concerning complication. Because of this, many patients are not offered anticoagulants, particularly patients at risk of falls or with a history of falls. It is unclear what anticoagulant treatment these patients should be offered. The Liverpool AF-Falls project aims to investigate this area, and this protocol for a systematic review and meta-analysis aims to define what is the most appropriate anticoagulant treatment option for the management of atrial fibrillation patients at risk of falls or with a history of falls.
This systematic review and meta-analysis will include randomized and non-randomized studies evaluating the safety and efficacy of different anticoagulant treatments (vitamin K antagonist and non-vitamin K antagonist oral anti-coagulant). Bibliographic databases (Cochrane Central Register of Controlled Trials, CINAHL, ClinicalTrials.gov , Embase, MEDLINE, Scopus and Web of Science) will be searched according to a pre-specified search strategy. Titles, abstracts, and full texts will be assessed by two independent reviewers and disagreements resolved with a third independent reviewer. The Cochrane Risk of Bias tool 2 (RoB 2) will be used to assess the risk of bias in randomized trials, and the Risk Of Bias In Non-randomized Studies - of Interventions (ROBINS-I) tool will be used for non-randomized studies. A pairwise meta-analysis based on the fixed and random-effects models will be conducted. Publication bias will be evaluated with a funnel plot and Egger\'s test. Heterogeneity will be assessed with the I2 statistic. If conditions for indirect comparison are met and sufficient data are available, a network meta-analysis will be conducted using frequentist and Bayesian methodologies.
This review will be the first to summarize direct and indirect evidence on the safety and efficacy of anticoagulant treatments in atrial fibrillation patients at risk of falls or with a history of falls. The findings will be important to patients, clinicians, and health policy-makers to inform best practices in the use of these treatments.
PROSPERO registry number: CRD42020201086.

Purpose: There is uncertainty as to which anticoagulant should be used in non-valvular atrial fibrillation (AF) with valvular heart disease. This systematic review and meta-analysis aimed to assess the efficacy and safety of direct-acting oral anticoagulants (DOACs) compared with warfarin in patients with non-valvular AF with valvular heart disease. Methods: We performed a comprehensive literature search using PubMed, Scopus, Embase, and Clinicaltrials.gov from the inception of databases up until August 2, 2021, and the search was updated and finalized on October 17, 2021. The intervention group was DOACs and the control group was warfarin. The primary outcome was systemic embolism and stroke (SSE), and the secondary outcome was major bleeding and intracranial hemorrhage. The pooled effect estimate was reported as the hazard ratio (HR) and odds ratio (OR). Results: There were 21,185 patients from seven studies included in this systematic review and meta-analysis. Stroke and systemic embolism were lower in patients receiving DOACs [HR 0.76 (95% CI 0.67, 0.87), p < 0.001; I2: 5%] compared with warfarin. The subgroup analysis on RCTs showed the significant reduction of SSE in the DOACs group [HR 0.73 (95% CI 0.60, 0.89), p = 0.002; I2: 16%]. There was no significant difference in terms of major bleeding [HR 0.89 (95% CI 0.75, 1.05), p = 0.18; I2: 69%]. Intracranial hemorrhage [HR 0.42 (95% CI 0.22, 0.80), p = 0.008; I2: 73%] were lower in the DOAC group. Conclusion: This meta-analysis indicates that DOACs were associated with a lower risk of SSE and intracranial hemorrhage compared with patients receiving warfarin. There was no significant difference between the two groups in terms of major bleeding.

Non-vitamin K antagonist oral anticoagulants (NOACs) are excreted by P-glycoprotein (P-gp) and some are metabolized by CYP450 enzymes such as CYP3A4. Although fewer drug interactions are present with NOACs, it is unclear whether NOACs should also be preferred over vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) using pharmacokinetically interacting drugs. Therefore, the benefit-risk profile of NOACs versus VKAs was investigated in AF patients treated with P-gp and/or CYP450-interacting drugs.
Using PubMed and Embase, randomized controlled trials and observational studies on the effectiveness and safety of NOACs versus VKAs in AF patients using P-gp and/or CYP450-interacting drugs were included. A meta-analysis was performed, calculating relative risks (RR) and 95% confidence intervals (CI) with the Mantel-Haenszel method.
Twelve studies were included, investigating 10,793 NOAC and 10,096 VKA users treated with P-gp/CYP3A4 inhibitors, whereas no studies on P-gp and/or CYP450-inducing drugs were identified. Compared to VKAs, NOACs were associated with a borderline non-significantly lower stroke or systemic embolism (stroke/SE) risk (RR 0.85, 95%CI (0.72-1.01)), significantly lower intracranial bleeding (RR 0.47, 95%CI (0.34-0.65)) and all-cause mortality risks (RR 0.87, 95%CI (0.79-0.95), but significantly higher gastrointestinal bleeding risk (RR 1.74, 95%CI (1.06-2.86)). Among AF patients using amiodarone, NOACs were associated with significantly lower stroke/SE (RR 0.71, 95%CI (0.54-0.93)) and intracranial bleeding risks (RR 0.51, 95%CI (0.29-0.88)), but significantly higher gastrointestinal bleeding risk (RR 2.15, 95%CI (1.24-3.72)) than VKAs.
The benefit-risk profile of NOACs compared to VKAs was preserved in AF patients using P-gp/CYP3A4 inhibitors, including amiodarone.

Atrial fibrillation (AF) represents the most prevalent supraventricular arrhythmia in adults population and up to 15% of AF patients undergo percutaneous coronary intervention (PCI) for coronary artery disease (CAD) during their life. While oral anticoagulants (OACs) exert a protective effect in the setting of stroke prevention and systemic embolization in AF patients, patients undergoing PCI are recommended to receive dual antiplatelet therapy (DAPT) to reduce the risk of cardiovascular death, recurrent myocardial infarction and stent thrombosis. When these two scenarios coexist, as all antithrombotic regimens are burdened by an increase in bleeding risk, antithrombotic regimen and therapy duration must be cautiously tailored on individual patients\' characteristics after attentive assessment of ischemic and bleeding risks. Non-vitamin K oral anticoagulants (NOACs), directly inhibiting either thrombin or factor Xa of the coagulation cascade, have progressively replaced warfarin as first choice OACs in several scenarios; recently, randomized controlled trials have compared antithrombotic regimens including NOAC molecules vs vitamin K antagonists in AF patients undergoing PCI to explore the efficacy and safety of NOACs in this setting. These studies have provided a deeper understanding of antithrombotic therapy after PCI in AF patients and have been promptly implemented by the most recent guidelines on AF and CAD management. The aim of the present review was to summarize the current available literature on the perils and benefits of individual OAC molecules in AF patients with acute and/or chronic coronary syndromes in order to provide guidance on the optimal use of OACs in these complex scenarios.

Left ventricular (LV) thrombus is a potentially serious complication affecting males and females with ischemic and nonischemic cardiomyopathy-specifically, after acute myocardial infarctions of the anterior left ventricular wall and long-standing tachyarrhythmias, respectively. LV thrombi pose significant risks for systemic embolization and devastating stroke events, while also demanding a treatment carrying inherent risks of its own. It is therefore imperative to have accurate detection of these ventricular thrombi and an appropriate understanding of the risks and benefits regarding management. Anticoagulation using warfarin has long been established as the gold-standard level of care in the current guidelines of the American College of Cardiology but the advent of direct oral anticoagulants (DOACs) prompts a re-examination of the literature. The particular question we seek to answer lies in the efficacy of these drugs and the safety and outcomes when used to treat LV thrombi. Recent case reports, meta-analyses, and most recently, the breakthrough of 2 novel randomized controlled trials have shown DOACs to be a promising treatment for LV thrombus. Contrarily, some retrospective cohort reviews suggest less-than-promising outcomes. This meta-analysis hopes to provide a current, curated review of up-to-date safety and efficacy in the documented tales of DOACs and LV thrombi that has been published since early 2020-by selecting these curated case studies, and analyzing the most recent randomized controlled trials, we hope to engage the reader with clearer illustrations of the key components of both the advocacy and warning of this pharmaceutical intervention.

Background Evidence on the differences in fracture risk associated with non-vitamin K antagonist oral anticoagulants (NOAC) and warfarin is inconsistent and inconclusive. We conducted a systematic review and meta-analysis to assess the fracture risk associated with NOACs and warfarin. Methods and Results We searched PubMed, Embase, Cochrane Library, Scopus, Web of Science, and ClinicalTrials.gov from inception until May 19, 2020. We included studies presenting measurements (regardless of primary/secondary/tertiary/safety outcomes) for any fracture in both NOAC and warfarin users. Two or more reviewers independently screened relevant articles, extracted data, and performed quality assessments. Data were retrieved to synthesize the pooled relative risk (RR) of fractures associated with NOACs versus warfarin. Random-effects models were used for data synthesis. We included 29 studies (5 cohort studies and 24 randomized controlled trials) with 388 209 patients. Patients treated with NOACs had lower risks of fracture than those treated with warfarin (pooled RR, 0.84; 95% CI, 0.77-0.91; P<0.001) with low heterogeneity (I2=38.9%). NOACs were also associated with significantly lower risks of hip fracture than warfarin (pooled RR, 0.89; 95% CI, 0.81-0.98; P=0.023). A nonsignificant trend of lower vertebral fracture risk in NOAC users was also observed (pooled RR, 0.74; 95% CI, 0.54-1.01; P=0.061). Subgroup analyses for individual NOACs demonstrated that dabigatran, rivaroxaban, and apixaban were significantly associated with lower fracture risks. Furthermore, the data synthesis results from randomized controlled trials and real-world cohort studies were quite consistent, indicating the robustness of our findings. Conclusions Compared with warfarin, NOACs are associated with lower risks of bone fracture.

Cancer-associated thrombosis (CAT) carries significant morbidity and mortality. Low-molecular-weight heparin (LMWH) remains the standard of care, with recent systematic studies suggesting the efficacy and safety of rivaroxaban in the treatment of CAT. Uncertainty, however, remains regarding rivaroxaban efficacy and safety in real-world settings. We performed a systematic review and meta-analysis of studies comparing rivaroxaban to LMWH. We searched PubMed, MEDLINE, and EMBASE. The primary outcome was the net clinical benefit (NCB), while rates of major bleeding (MB), venous thromboembolism (VTE), clinically relevant nonmajor bleeding (CRNMB), and all-cause mortality events were secondary outcomes. Seventeen studies were included in the final analysis. Rivaroxaban had a better NCB (relative risk [RR] = 0.82; 95% CI = 0.75-0.89, Q = 10.51, I 2 = 0%), less VTE events (RR = 0.73, 95% CI = 0.65-0.82, Q = 6.76, I 2 = 0%), and lower all-cause mortality (RR = 0.72, 95% CI = 0.57-0.91, Q = 32.8, I 2 = 79%) compared to LMWH. Additionally, comparable MB events (RR = 1.07, 95% CI = 0.85-1.33, Q = 16.9, I 2 = 11%). However, CRNMB events were higher in the rivaroxaban group (RR = 2.02, 95% CI = 1.46-2.80, Q = 9.9, I 2 = 19%). Additional analyses demonstrated consistency of results. Our review encompassing data from randomized and real-world data suggested rivaroxaban superiority compared to LMWH in terms of a better NCB, fewer VTE events, lower all-cause mortality, and comparable MB risk while carrying a higher risk of CRNMB. These findings support the use of rivaroxaban in the treatment of CAT. Additionally, it warrants a sizable randomized controlled study testing the superiority of rivaroxaban versus LMWH formulation and ascertaining bleeding outcomes according to cancer type and site.

OBJECTIVE: Oral anticoagulants are crucial for preventing systemic thromboembolism in atrial fibrillation (AF), with guidelines preferring non-vitamin K antagonist oral anticoagulants (NOACs) over vitamin K antagonists (VKAs) in the general AF population. However, as NOACs are administered in fixed doses, concerns of unintentional underdosing in morbidly obese patients and unintentional overdosing in underweight patients have emerged. Therefore, a critical appraisal of the benefit-risk profile of NOACs in AF patients across the body weight spectrum is needed.
RESULTS: After searching Medline, this systematic review discusses the impact of body weight on the risk-benefit profile of NOACs versus VKAs. The meta-analysis demonstrated that NOAC use in obese and class III obese AF patients (body mass index (BMI) ≥ 30 and ≥ 40 kg/m2, respectively) was associated with significantly lower stroke/systemic embolism (stroke/SE) risks (RR 0.82, 95%CI [0.71-0.96] and RR 0.75, 95%CI [0.64-0.87], respectively), similar to lower major bleeding risks (RR 0.83, 95%CI [0.69-1.00] and RR 0.74, 95%CI [0.57-0.95], respectively) and similar mortality risks (RR 0.92, 95%CI [0.73-1.15] and RR 1.17, 95%CI [0.83-1.64], respectively) compared to VKAs. In AF patients ≤ 60 kg, significantly lower stroke/SE (RR 0.63, 95%CI [0.56-0.71]) and major bleeding risks (RR 0.71, 95%CI [0.62-0.80]), but similar mortality risks (RR 0.68, 95%CI [0.42-1.10]), were observed for NOAC- versus VKA-treated patients.
CONCLUSIONS: The benefit-risk profile of NOACs seems preserved in (morbidly) obese AF patients and patients with low body weight. However, more data are needed on underweight AF patients (BMI < 18.5 kg/m2) and on differences between NOACs in these patients.

BACKGROUND: Early surgery has been consistently demonstrated to reduce complications and mortality in hip fracture patients. There remains no general consensus, however, regarding the optimal time to surgery for hip fracture patients who are on novel oral anticoagulants (NOAC) on admission and its effect on clinical outcomes after surgery. The objective of this review was to assess the effect of preoperative NOAC therapy on time to surgery and postoperative complications in hip fracture patients.
METHODS: We performed a systematic review of the literature using the PubMed, Embase, and Cochrane Library electronic databases. Relevant articles were identified and included if they: (i) included patients on NOAC therapy on admission who did not undergo reversal; (ii) included a control group of patients not on any anticoagulation; (iii) included time from admission to surgery; and (iv) included one of the following outcomes: blood transfusion, venous thromboembolism (VTE), stroke, readmission, and mortality.
RESULTS: Nine studies were included with a total of 4,419 patients. There were 414 NOAC patients and 4,005 non-anticoagulated patients. Six of the nine studies found a significant increase in time to surgery for patients on NOAC therapy. Three of the seven studies that reported rates of blood transfusion found a significantly higher incidence of transfusion in patients on NOACs. None of the studies found a significant difference in VTE and stroke. One of the two studies that reported readmissions showed a higher risk of readmission for patients on NOACs. Eight of the nine included studies found no significant difference in postoperative mortality rates between the NOAC and control groups, with the remaining study finding a higher mortality rate only in patients on NOAC therapy who underwent fixation and not those who underwent arthroplasty.
CONCLUSIONS: These mixed findings suggest that delay to surgery may not be warranted in the urgent surgical setting of patients on NOAC therapy who sustain hip fractures.

BACKGROUND: The use of anticoagulant medications leads to a higher risk of developing traumatic intracranial hemorrhage (tICH) after a mild traumatic brain injury (mTBI). The management of anticoagulated patients can be difficult to determine when the initial head computed tomography is negative for tICH. There has been limited research on the risk of delayed tICH in patients taking direct oral anticoagulant (DOAC) medications.
OBJECTIVE: Our aim was to determine the risk of delayed tICH for patients anticoagulated with DOACs after mTBI.
METHODS: We conducted a systematic review using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and searched several medical databases to examine the risk of delayed tICH in patients on DOACs.
RESULTS: There were 1252 nonduplicate studies that were identified through an initial database search, 15 of which met our inclusion and exclusion criteria and were included in our analysis after full-text review. A total of 1375 subjects were combined among the 15 studies, with 20 instances of delayed tICH after mTBI. Nineteen of the 20 patients with a delayed tICH were discharged without any neurosurgical intervention, and 1 patient on apixaban died due to a delayed tICH.
CONCLUSIONS: This systematic review confirms that delayed tICH after mTBI in patients on DOACs is uncommon. However, large, multicenter, prospective studies are needed to confirm the true incidence of clinically significant delayed tICH after DOAC use. Due to the limited data, we recommend using shared decision-making for patients who are candidates for discharge.