Dicloxacillin is an inducer of intestinal P-glycoprotein but neither dicloxacillin nor flucloxacillin increases the risk of stroke/systemic embolism in direct oral anticoagulant users.

AIM: We aimed to assess if dicloxacillin/flucloxacillin reduces the therapeutic efficacy of direct oral anticoagulants (DOACs) and the underlying molecular mechanism. METHODS: In a randomized, crossover study, we assessed whether dicloxacillin reduces oral absorption of drugs through P-glycoprotein (P-gp) during 10 and 28 days of treatment. To study the impact of dicloxacillin/flucloxacillin on intestinal and hepatic expression of P-gp in vitro, we usd LS174T cells and 3D spheroids of primary human hepatocytes. Finally, we used nationwide Danish health registries and the UK's Clinical Practice Research Datalink to estimate hazard ratios (HRs) for the risk of stroke and systemic embolism following dicloxacillin/flucloxacillin exposure among DOAC users, using phenoxymethylpenicillin and amoxicillin as active comparators. RESULTS: Dicloxacillin reduced the area under the curve of dabigatran to a geometric mean ratio 10 days of 0.67 (95% confidence interval [CI]: 0.42-1.1) and geometric mean ratio 28 days of 0.72 (95% CI: 0.39-1.4), suggesting reduced oral absorption via increased P-gp expression. In vitro, dicloxacillin raised P-gp expression in both intestinal and liver cells, while flucloxacillin only affected liver cells. In the pharmacoepidemiologic study, dicloxacillin and flucloxacillin were not associated with increased risk of stroke/systemic embolism (dicloxacillin vs. phenoxymethylpenicillin HR: 0.93, 95% CI: 0.72-1.2; flucloxacillin vs. amoxicillin HR: 0.89, 95% CI: 0.51-1.5). CONCLUSIONS: Dicloxacillin increases expression of intestinal P-gp, leading to reduced oral absorption of dabigatran. However, concomitant use of dicloxacillin/flucloxacillin was not associated with stroke and systemic embolism among DOAC users, suggesting no clinical impact from the drug-drug interaction between dicloxacillin/flucloxacillin and DOACs.

Dual Antithrombotic Therapy versus Anticoagulant Monotherapy for Major Adverse Limb Events in Patients with Concomitant Lower Extremity Arterial Disease and Atrial Fibrillation: A Propensity Score Weighted Analysis.

OBJECTIVE: Patients with symptomatic lower extremity arterial disease (LEAD) are recommended to receive antiplatelet therapy, while direct oral anticoagulants (DOACs) are standard for stroke prevention in patients with atrial fibrillation (AF). For patients with concomitant LEAD and AF, data comparing dual antithrombotic therapy (an antiplatelet agent used in conjunction with a DOAC) vs. DOAC monotherapy are scarce. This retrospective cohort study, based on data from the Taiwan National Health Insurance Research Database, aimed to compare the efficacy and safety of these antithrombotic strategies. METHODS: Patients with AF who underwent revascularisation for LEAD between 2012 - 2020 and received any DOAC within 30 days of discharge were included. Patients were grouped by antiplatelet agent exposure into the dual antithrombotic therapy and DOAC monotherapy groups. Inverse probability of treatment weighting was used to mitigate selection bias. Major adverse limb events (MALEs), ischaemic stroke or systemic embolism, and bleeding outcomes were compared. Patients were followed until the occurrence of any study outcome, death, or up to two years. RESULTS: A total of 1 470 patients were identified, with 736 in the dual antithrombotic therapy group and 734 in the DOAC monotherapy group. Among them, 1 346 patients received endovascular therapy as the index revascularisation procedure and 124 underwent bypass surgery. At two years, dual antithrombotic therapy was associated with a higher risk of MALEs than DOAC monotherapy (subdistribution hazard ratio [SHR] 1.34, 95% confidence interval [CI] 1.15 - 1.56), primarily driven by increased repeat revascularisation. Dual antithrombotic therapy was also associated with a higher risk of major bleeding (SHR 1.43, 95% CI 1.05 - 1.94) and gastrointestinal bleeding (SHR 2.17, 95% CI 1.42 - 3.33) than DOAC monotherapy. CONCLUSION: In patients with concomitant LEAD and AF who underwent peripheral revascularisation, DOAC monotherapy was associated with a lower risk of MALEs and bleeding events than dual antithrombotic therapy.

Temporal trends in anticoagulation use and clinical outcomes among medicare beneficiaries with non-valvular atrial fibrillation.

PURPOSE: Oral anticoagulants effectively prevent stroke/systemic embolism among patients with non-valvular atrial fibrillation but remain under-prescribed. This study evaluated temporal trends in oral anticoagulant use, the incidence of stroke/systemic embolism and major bleeding, and economic outcomes among elderly patients with non-valvular atrial fibrillation and CHA2DS2-VASc scores ≥ 2. METHODS: Retrospective analyses were conducted on Medicare claims data from January 1, 2012 through December 31, 2017. Non-valvular atrial fibrillation patients aged ≥ 65 years with CHA2DS2-VASc scores ≥ 2 were stratified by calendar year (2013-2016) of care to create calendar-year cohorts. Patient characteristics were evaluated across all cohorts during the baseline period (12 months before diagnosis). Treatment patterns and clinical and economic outcomes were evaluated during the follow-up period (from diagnosis through 12 months). RESULTS: Baseline patient characteristics remained generally similar between 2013 and 2016. Although lack of oral anticoagulant prescriptions among eligible patients remained relatively high, utilization did increase progressively (53-58%). Among treated patients, there was a progressive decrease in warfarin use (79-52%) and a progressive increase in overall direct oral anticoagulant use (21-48%). There were progressive decreases in the incidence of stroke/systemic embolism 1.9-1.4 events per 100 person years) and major bleeding (4.6-3.3 events per 100 person years) as well as all-cause costs between 2013 and 2016. CONCLUSIONS: The proportions of patients with non-valvular atrial fibrillation who were not prescribed an oral anticoagulant decreased but remained high. We observed an increase in direct oral anticoagulant use that coincided with decreased incidence of clinical outcomes as well as decreasing total healthcare costs.

Effectiveness and safety in non-valvular atrial fibrillation patients switching from warfarin to direct oral anticoagulants in US healthcare claims.

INTRODUCTION: There is a paucity of real-world studies examining the risks of stroke/systemic embolism (SE) and major bleeding (MB) among non-valvular atrial fibrillation (NVAF) patients switching from warfarin to a direct oral anticoagulant (DOAC). This retrospective study was conducted to compare the stroke/SE and MB risks between patients switched from warfarin to apixaban, dabigatran, or rivaroxaban in real-world clinical practice. MATERIALS AND METHODS: This study used data from four United States commercial claims databases from January 1, 2012 to June 30, 2019. The study population included NVAF patients initially treated with warfarin and switched to apixaban, dabigatran, or rivaroxaban within 90 days of their warfarin prescription ending. Patients were matched 1:1 between the DOACs in each database using propensity scores and then pooled for the final analysis. Cox proportional hazards models were used to calculate the risk of stroke/SE and MB. RESULTS AND CONCLUSIONS: The final population consisted of 2,611 apixaban-dabigatran, 12,165 apixaban-rivaroxaban, and 2,672 dabigatran-rivaroxaban pairs. Apixaban vs. dabigatran was associated with a lower risk of stroke/SE (hazard ratio [HR]: 0.61; 95% confidence interval [CI]: 0.39-0.96) and MB (HR: 0.67; 95% CI: 0.50-0.91). Apixaban vs. rivaroxaban was associated with a similar risk of stroke/SE (HR: 0.88; 95% CI: 0.73-1.07) and a lower risk of MB (HR: 0.60; 95% CI: 0.52-0.68). There was no significant difference in either risk between dabigatran and rivaroxaban. These results provide important insights into how the risks of stroke/SE and MB for NVAF patients vary when switching from warfarin to different DOACs.

Residual risk of thromboembolic events despite anticoagulation in Middle Eastern patients with atrial fibrillation. The JoFib study.

OBJECTIVES: To investigate residual risk of thromboembolic events despite anticoagulation in patients with atrial fibrillation form the Middle East. MATERIALS AND METHODS: Using data from the JoFib registry, we described the characteristics of patients treated with anticoagulants (n = 1654) and calculated the incidence rate for thromboembolic events. We constructed multivariable Cox proportional hazard models and calculated the population-attributable fraction to determine clinical factors predictive of residual thromboembolic events. RESULTS: During the one-year follow-up, 57 thromboembolic events occurred (incidence rate 4.1 per 100 person-years). In multivariable time-to-event analysis, prior thromboembolic events (aHR 3.8, 95 %CI 2.2-6.4, p < 0.001) and diabetes (aHR 2.3, 95 %CI 1.3-4.1, p = 0.004) were independently predictive of residual thromboembolism. Percentage of thromboembolic risk attributable to prior thromboembolic events was 30.9 % (95 %CI 13.9-44.6, p = 0.001) and was 37.1 % (95 %CI 8.8-56.6, p = 0.015) for diabetes. Furthermore, the effect of diabetes on thromboembolic events depends on the type of anticoagulant, with diabetes being significantly predictive of thromboembolic events in patients anticoagulated with warfarin (aHR 4.11, 95 %CI 1.81-9.37, p = 0.001), but not non-vitamin K antagonist oral anticoagulants (aHR 1.23, 95 %CI 0.51-2.97, p = 0.643) with a p = 0.045 for interaction. Prior thromboembolism was independently predictive of thromboembolic events in both anticoagulants (aHR 2.67, 95 %CI 1.28-5.58, p = 0.009; aHR 7.33, 95 %CI 3.05-17.65, p < 0.001; respectively; p = 0.084 for interaction). CONCLUSIONS: Middle Eastern patients with atrial fibrillation remain at significant risk of thromboembolism and its recurrence despite anticoagulation, and especially in diabetic patients. Therefore, management should focus on controlling diabetes as well as other modifiable risk factors in addition to antithrombotic therapy.

Impact of glycated hemoglobin on 2-year clinical outcomes in elderly patients with atrial fibrillation: sub-analysis of ANAFIE Registry, a large observational study.

BACKGROUND: This ANAFIE Registry sub-analysis investigated 2-year outcomes and oral anticoagulant (OAC) use stratified by glycated hemoglobin (HbA1c) levels among Japanese patients aged ≥ 75 years with non-valvular atrial fibrillation (NVAF) with and without clinical diagnosis of diabetes mellitus (DM). METHODS: The ANAFIE Registry was a large-scale multicenter, observational study conducted in Japan; this sub-analysis included patients with baseline HbA1c data at baseline. The main endpoints evaluated (stroke/systemic embolic events [SEE], major bleeding, intracranial hemorrhage, cardiovascular death, all-cause death, and net clinical outcome [a composite of stroke/SEE, major bleeding, and all-cause death]) were stratified by HbA1c levels (< 6.0%; 6.0% to < 7.0%; 7.0% to < 8.0%; and ≥ 8.0%). RESULTS: Of 17,526 patients with baseline HbA1c values, 8725 (49.8%) patients had HbA1c < 6.0%, 6700 (38.2%) had 6.0% to < 7.0%, 1548 (8.8%) had 7.0% to < 8.0%, and 553 (3.2%) had ≥ 8.0%. Compared with other subgroups, patients with HbA1c ≥ 8.0% were more likely to have lower renal function, higher CHA2DS2-VASc and HAS-BLED scores, higher prevalence of non-paroxysmal AF, and lower direct OAC (DOAC) administration, but higher warfarin administration. The HbA1c ≥ 8.0% subgroup had higher event rates for all-cause death (log-rank P = 0.003) and net clinical outcome (log-rank P = 0.007). Similar trends were observed for stroke/SEE. In multivariate analysis, risk of all-cause death (adjusted hazard ratio [aHR]: 1.46 [95% confidence interval 1.11-1.93]) and net clinical outcome (aHR 1.33 [1.05-1.68]) were significantly higher in the HbA1c ≥ 8.0% subgroup. No significant differences were observed in risks of major bleeding or other outcomes in this and other subgroups. No interaction was observed between HbA1c and OACs. Use/non-use of antidiabetic drugs was not associated with risk reduction; event risks did not differ with/without injectable antidiabetic drugs. CONCLUSIONS: Among elderly Japanese patients with NVAF, only HbA1c ≥ 8.0% was associated with increased all-cause death and net clinical outcome risks; risks of the events did not increase in other HbA1c subgroups. Relative event risks between patients treated with DOACs and warfarin were not modified by HbA1c level. TRIAL REGISTRATION: UMIN000024006; date of registration: September 12, 2016.

Geographic variation in clinical outcomes and anticoagulation among medicare beneficiaries with non-valvular atrial fibrillation.

Oral anticoagulants (OACs) have been used to prevent stroke/systemic embolism (SE) among patients with non-valvular atrial fibrillation (NVAF). To evaluate baseline clinical characteristics, incidence rates of stroke/SE and hospitalization for bleeding, and OAC use among elderly patients with NVAF in the US by geographic region. Patients with NVAF were selected from the US Centers for Medicare & Medicaid Services claims database (01JAN2013-31DEC2016). Twelve months of health plan enrollment was required before and after the NVAF diagnosis to evaluate baseline characteristics and outcomes, respectively. Each patient was assigned to a 3-digit zip code based on their primary residence, and geographic variation was visualized using ArcGIS Pro software. Over 2.8 million patients with NVAF were identified. Large geographic variation was observed in clinical characteristics, stroke/SE, hospitalization for bleeding, and OAC use among patients across the US. The zip codes with the highest mean CHA2DS2-VASc scores and frequency of prior bleeding also had the highest incidence of stroke/SE and hospitalization for bleeding. Across 3-digit zip codes, 35-63% of patients were untreated. Overall, the incidence of stroke/SE and hospitalization for bleeding were higher and OAC treatment was less frequent in zip codes located in the Southern US. Baseline clinical characteristics, incidence rates of stroke/SE and hospitalization for bleeding, and OAC usage vary considerably by 3-digit zip code in the US. The additional granularity provided in this study may help clinicians to identify small regions with high-risk of stroke/SE and hospitalization for bleeding and low use of OAC that may benefit from targeted care strategies.

Apixaban Dosing Patterns Versus Warfarin in Patients With Nonvalvular Atrial Fibrillation Receiving Dialysis: A Retrospective Cohort Study.

BACKGROUND & OBJECTIVES: Comparison of clinical outcomes across anticoagulation regimens using different apixaban dosing or warfarin is not well-defined in patients with nonvalvular atrial fibrillation (AF) who are receiving dialysis. This study compared these outcomes in a US national cohort of patients with kidney failure receiving maintenance dialysis. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Patients receiving dialysis represented in the US Renal Data System database 2013-2018 who had AF and were treated with apixaban or warfarin. EXPOSURE: First prescribed treatment with apixaban dosed according to the label, apixaban dosed below the label, or warfarin. OUTCOME: Ischemic stroke/systemic embolism, major bleeding, and all-cause mortality. ANALYTICAL APPROACH: Cox proportional hazards models with inverse probability of treatment weighting. Analyses simulating an intention-to-treat (ITT) approach as well as those incorporating censoring at drug switch or discontinuation (CAS) were also implemented. Inverse probability of censoring weighting was used to account for possible informative censoring. RESULTS: Among 17,156 individuals, there was no difference in risk of stroke/systemic embolism among the label-concordant apixaban, below-label apixaban, and warfarin treatment groups. Both label-concordant (HR, 0.67 [95% CI, 0.55-0.81]) and below-label (HR, 0.68 [95% CI, 0.55-0.84]) apixaban dosing were associated with a lower risk of major bleeding compared with warfarin in ITT analyses. Compared with label-concordant apixaban, below-label apixaban was not associated with a lower bleeding risk (HR, 1.02 [95% CI, 0.78-1.34]). In the ITT analysis of mortality, label-concordant apixaban dosing was associated with a lower risk versus warfarin (HR, 0.85 [95% CI, 0.78-0.92]) while there was no significant difference in mortality between below-label dosing of apixaban and warfarin (HR, 0.97 [95% CI, 0.89-1.05]). Overall, results were similar for the CAS analyses. LIMITATIONS: Study limited to US Medicare beneficiaries; reliance on administrative claims to ascertain outcomes of AF, stroke, and bleeding; likely residual confounding. CONCLUSIONS: Among patients with nonvalvular AF undergoing dialysis, warfarin is associated with an increased risk of bleeding compared with apixaban. The risk of bleeding with below-label apixaban was not detectably less than with label-concordant dosing. Label-concordant apixaban dosing is associated with a mortality benefit compared to warfarin. Label-concordant dosing, rather than reduced-label dosing, may offer the most favorable benefit-risk trade-off for dialysis patients with nonvalvular AF.

Comparing the Clinical Outcomes Observed with Rivaroxaban Versus Warfarin for the Management of Obese Patients with Non-valvular Atrial Fibrillation: a Systematic Review and Meta-analysis.

BACKGROUND: Atrial fibrillation (AF) is an irregular heart rhythm which is becoming more and more common in this new era. Obesity is a risk factor for cardiovascular events, and obese patients are more at risk for stroke. The Framingham Heart Study demonstrated an increase in the developmental risk of AF by 4% for every unit (kg/m2) increase in body mass index (BMI). An anticoagulant is often required for the management of such patients. In this analysis, we aimed to systematically compare the clinical outcomes which were associated with rivaroxaban versus warfarin for the treatment of obese patients with non-valvular AF. METHODS: PubMed, EMBASE, Web of Science, http://www. CLINICALTRIALS: gov , Google Scholar, and Cochrane Central were the searched databases. Clinical outcomes including stroke, systemic embolism, and major bleeding were the endpoints. In this study, dichotomous data were analyzed by the RevMan software version 5.4. Risk ratio (RR) with 95% confidence interval (CI) was used for result interpretation. RESULTS: Ten studies consisting of a total number of 168,081 obese participants were included whereby 81,332 participants were treated with rivaroxaban and 86,749 participants were treated with warfarin. The risks of ischemic (RR: 0.79, 95% CI: 0.74-0.84; P = 0.00001) and hemorrhagic stroke (RR: 0.61, 95% CI: 0.48-0.76; P = 0.0001) as well as systemic embolism (RR: 0.73, 95% CI: 0.62-0.87; P = 0.0004) were significantly lower with rivaroxaban compared to warfarin for the management of these obese patients with non-valvular AF. Rivaroxaban was also associated with a significantly lower risk of major bleeding (RR: 0.75, 95% CI: 0.65-0.87; P = 0.0001). CONCLUSION: Based on this analysis, rivaroxaban seemed to be a better option in comparison to warfarin, due to its association with significantly lower risks of stroke and bleeding outcomes in obese patients with non-valvular AF. However, this hypothesis should further be confirmed in larger clinical trials.

PrevAleNce and Associated factors of inappropriaTe dosing of direct Oral anticoaguLants In pAtients with Atrial Fibrillation: the ANATOLIA-AF Study.

PURPOSE: Inappropriate dosing of direct oral anticoagulants is associated with an increased risk of stroke, systemic embolism, major bleeding, cardiovascular hospitalization, and death in patients with atrial fibrillation. The main goal of the study was to determine the prevalence and associated factors of inappropriate dosing of direct oral anticoagulants in real-life settings. METHODS: This study was a multicenter, cross-sectional, observational study that included 2004 patients with atrial fibrillation. The study population was recruited from 41 cardiology outpatient clinics between January and May 2021. The main criteria for inappropriate direct oral anticoagulant dosing were defined according to the recommendations of the European Heart Rhythm Association. RESULTS: The median age of the study population was 72 years and 58% were women. Nine-hundred and eighty-seven patients were prescribed rivaroxaban, 658 apixaban, 239 edoxaban, and 120 dabigatran. A total of 498 patients (24.9%) did not receive the appropriate dose of direct oral anticoagulants. In a logistic regression model, advanced age, presence of chronic kidney disease and permanent atrial fibrillation, prescription of reduced doses of direct oral anticoagulants or edoxaban treatment, concomitant use of amiodarone treatment, and non-use of statin treatment were significantly associated with potentially inappropriate dosing of direct oral anticoagulants. CONCLUSION: The study demonstrated that the prevalence of inappropriate direct oral anticoagulant dosing according to the European Heart Rhythm Association recommendations was 24.9% in patients with atrial fibrillation. Several demographic and clinical factors were associated with the inappropriate prescription of direct oral anticoagulants.

What to do with device-detected atrial high-rate episodes: Summary of the evidences.

Cardiac implanted electronic devices (CIEDs), that perform atrial sensing via an atrial electrode, commonly detect self-terminating atrial arrhythmias. Nomenclature of these arrhythmias is defined as atrial high-rate episodes (AHREs) and subclinical atrial fibrillation (SCAF). We have provided a comprehensive summation of the trials regarding the incidence and adverse outcomes of AHREs. The reported incidence of AHRE varies considerably (approximately 10%-70%) between studies depending on the definition of AHRE, duration of follow-up and the clinical profile of the population. There is increasing evidence related with the association between AHREs' and stroke and/or systemic embolism. However, risk of stroke and/or systemic embolism seems to be less than the risk associated with clinical AF. There is still lack of sufficient evidence related with oral anticoagulation (OAC) in patients with AHRE to reduce thromboembolic risk. Although, the strongest association of OAC treatment with reduction in stroke has been reported to be observed among patients with device detected SCAF episodes of >24 h; it is still questionable whether AHRE is a direct cause of thromboembolic event or just a marker of increased risk. Results of ongoing randomized clinical trials (NOAH-AFNET 6 and ARTESIA) will provide robust evidence on effect of OAC therapy on AHREs.

Association between lipoprotein(a) and thromboembolism in patients with non-valvular atrial fibrillation: a cross-sectional study.

BACKGROUND: Lipoprotein(a) [Lp(a)] is a recognized risk factor for ischemic stroke (IS); however, its role in thromboembolism in patients with non-valvular atrial fibrillation (NVAF) remains controversial. We aimed to assess the association of Lp(a) and IS and systemic embolism (SEE) in NVAF patients. METHODS: In total, 16,357 patients with NVAF were recruited from the First Affiliated Hospital of Xinjiang Medical University from January 1, 2009, to December 31, 2021, and were divided into groups based on Lp(a) quartiles. Logistic regression models analyzed the association between Lp(a), IS, and SEE. The restriction cubic spline was used to assess the potential nonlinear relationship between Lp(a), IS, and SEE. We conducted subgroup analyses and estimated the multiplicative interaction between the stratified variables and Lp(a) to investigate whether the association between Lp(a) and IS and SEE was affected by age, sex, anticoagulants, and CHA2DS2-VASc score. RESULTS: We identified 1319 IS and 133 SEE events. After correcting for CHA2DS2-VASc score and other potential confounders, each 1-standard deviation (SD) increase in log-Lp(a) was related to a 23% increased risk of IS (odds ratios [OR], 1.23; 95% confidence intervals [CI], 1.07-1.41). NVAF patients in the highest Lp(a) quartile were 1.23-fold more likely to have IS than those in the lowest quartile (OR, 1.23; 95% CI, 1.04-1.45). A positive linear relationship between Lp(a) and IS risk was observed (P for nonlinear = 0.341). In the fully adjusted model, subjects had a 1.78-fold increased risk of SEE for each 1-SD increase in log-Lp(a) (OR, 2.78; 95% CI, 1.78-4.36). Subjects in the highest Lp(a) quartile had a 2.38-fold elevated risk of SEE (OR, 3.38; 95% CI, 1.85-6.19) compared with the lowest quartile. Furthermore, Lp(a) had a nonlinear relationship with the risk of SEE (P for nonlinear = 0.005). CONCLUSIONS: Elevated Lp(a) concentration was significantly associated with IS and SEE, suggesting that Lp(a) may be an emerging biomarker that can help clinicians identify patients at high risk of thromboembolism in this population.

Atrial fibrillation burden: an update-the need for a CHA2DS2-VASc-AFBurden score.

Atrial fibrillation (AF) is an established independent risk factor for stroke. Current guidelines regard AF as binary; either present or absent, with the decision for anti-coagulation driven by clinical variables alone. However, there are increasing data to support a biological gradient of AF burden and stroke risk, both in clinical and non-clinical AF phenotypes. As such, this raises the concept of combining AF burden assessment with a clinical risk score to refine and individualize the assessment of stroke risk in AF-the CHA2DS2VASc-AFBurden score. We review the published data supporting a biological gradient to try and construct a putative schema of risk attributable to AF burden.

Efficacy and Safety of Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation Undergoing Elective Surgical Procedures: A Meta-analysis.

Objective: The study objective was to determine if peri-operative bridging anticoagulation in patients with atrial fibrillation is beneficial or harmful.Design: Systematic review and meta-analysis.Setting: Inpatient or in-hospital setting.Participants: Adults with atrial fibrillation having a CHADS2 score >1 undergoing elective surgical procedure on anticoagulation.Methods: A systemic search of multiple databases (Cochrane, Medline, PubMed) was performed regarding studies conducted on efficacy and safety of perioperative bridging anticoagulation in patients with atrial fibrillation. Studies identified were reviewed by two authors individually before inclusion. The results were then pooled using Review Manager to determine the combined effect. Stroke/systemic embolism was considered as the primary efficacy outcome. Major bleeding was the primary safety outcome.Results: The systematic search revealed 108 potential articles. The full texts of 28 articles were retrieved for assessment of eligibility. After full text review, 25 articles were excluded. Three articles met inclusion criteria. No significant difference in stroke/systemic embolism with bridging anticoagulation was noted (risk ratio, 1.25-95% confidence interval [CI], 0.55-2.85). Bridging was associated with significantly higher risk of major bleeding (risk ratio, 3.29-95% CI, 2.25-4.81).Conclusion: An individualized approach is required when initiating peri-operative bridging anticoagulation. There is certainly a higher risk of bleeding with bridging anticoagulation and no difference in stroke/systemic embolism. However, the results cannot be extrapolated to patients who have valvular atrial fibrillation or CHADS2 score of 5 or greater.

Cardiovascular outcomes, bleeding risk, and achieved blood pressure in patients on long-term anticoagulation with the thrombin antagonist dabigatran or warfarin: data from the RE-LY trial.

AIMS: A J-shaped association of cardiovascular events to achieved systolic (SBP) and diastolic (DBP) blood pressure was shown in high-risk patients. This association on oral anticoagulation is unknown. This analysis from RELY assessed the risks of death, stroke or systemic emboli, and bleeding according to mean achieved SBP and DBP in atrial fibrillation on oral anticoagulation. METHODS AND RESULTS: RE-LY patients were followed for 2 years and recruited between 22 December 2005 until 15 December 2007. 18.113 patients were randomized in 951 centres in 54 countries and 18,107 patients with complete blood pressure (BP) data were analysed with a median follow-up of 2.0 years and a complete follow-up in 99.9%. The association between achieved mean SBP and DBP on all-cause death, stroke and systemic embolic events (SSE), major, and any bleeding were explored. On treatment, SBP >140 mmHg and <120 mmHg was associated with all-cause death compared with SBP 120-130 mmHg (reference). For SSE, risk was unchanged at SBP <110 mmHg but increased at 140-160 mmHg (adjusted hazard ratio (HR) 1.81; 1.40-2.33) and SBP ≥160 mmHg (HR 3.35; 2.09-5.36). Major bleeding events were also increased at <110 mmHg and at 110 to <120 mmHg. Interestingly, there was no increased risk of major bleeding at SBP >130 mmHg. Similar patterns were observed for DBP with an increased risk at <70 mmHg (HR 1.55; 1.35-1.78) and >90 mmHg (HR 1.88; 1.43-2.46) for all-cause death compared to 70 to <80 mmHg (reference). Risk for any bleeding was increased at low DBP <70 mmHg (HR 1.46; 1.37-1.56) at DBP 80 to <90 mmHg (HR 1.13; 1.06-1.31) without increased risk at higher achieved DBP. Dabigatran 150 mg twice daily showed an advantage in all patients for all-cause death and SSE and there was an advantage for 110 mg dabigatran twice daily for major bleeding and any bleeding irrespective of SBP or DBP achieved. Similar results were obtained for baseline BP, time-updated BP, and BP as time-varying covariate. CONCLUSION: Low achieved SBP associates with increased risk of death, SSE, and bleeding in patients with atrial fibrillation on oral anticoagulation. Major bleeding events did not occur at higher BP. Low BP might identify high-risk patients not only for death but also for high bleeding risks. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov-Identifier: NCT00262600.

Subtypes of atrial fibrillation with concomitant valvular heart disease derived from electronic health records: phenotypes, population prevalence, trends and prognosis.

AIMS: To evaluate population-based electronic health record (EHR) definitions of atrial fibrillation (AF) and valvular heart disease (VHD) subtypes, time trends in prevalence and prognosis. METHODS AND RESULTS: A total of 76 019 individuals with AF were identified in England in 1998-2010 in the CALIBER resource, linking primary and secondary care EHR. An algorithm was created, implemented, and refined to identify 18 VHD subtypes using 406 diagnosis, procedure, and prescription codes. Cox models were used to investigate associations with a composite endpoint of incident stroke (ischaemic, haemorrhagic, and unspecified), systemic embolism (SSE), and all-cause mortality. Among individuals with AF, the prevalence of AF with concomitant VHD increased from 11.4% (527/4613) in 1998 to 17.6% (7014/39 868) in 2010 and also in individuals aged over 65 years. Those with mechanical valves, mitral stenosis (MS), or aortic stenosis had highest risk of clinical events compared to AF patients with no VHD, in relative [hazard ratio (95% confidence interval): 1.13 (1.02-1.24), 1.20 (1.05-1.36), and 1.27 (1.19-1.37), respectively] and absolute (excess risk: 2.04, 4.20, and 6.37 per 100 person-years, respectively) terms. Of the 95.2% of individuals with indication for warfarin (men and women with CHA2DS2-VASc ≥1 and ≥2, respectively), only 21.8% had a prescription 90 days prior to the study. CONCLUSION: Prevalence of VHD among individuals with AF increased from 1998 to 2010. Atrial fibrillation associated with aortic stenosis, MS, or mechanical valves (compared to AF without VHD) was associated with an excess absolute risk of stroke, SSE, and mortality, but anticoagulation was underused in the pre-direct oral anticoagulant (DOAC) era, highlighting need for urgent clarity regarding DOACs in AF and concomitant VHD.

Effectiveness and safety of direct oral anticoagulants compared to warfarin in treatment naïve non-valvular atrial fibrillation patients in the US Department of defense population.

BACKGROUND: Clinical trials have demonstrated that direct oral anticoagulants (DOACs) are at least non-inferior to warfarin in reducing the risk of stroke/systemic embolism (SE) among patients with non-valvular atrial fibrillation (NVAF), but the comparative risk of major bleeding varies between DOACs and warfarin. Using US Department of Defense (DOD) data, this study compared the risk of stroke/SE and major bleeding for DOACs relative to warfarin. METHODS: Adult patients with ≥1 pharmacy claim for apixaban, dabigatran, rivaroxaban, or warfarin from 01 Jan 2013-30 Sep 2015 were selected. Patients were required to have ≥1 medical claim for atrial fibrillation during the 12-month baseline period. Patients with a warfarin or DOAC claim during the 12-month baseline period were excluded. Each DOAC cohort was matched to the warfarin cohort using propensity score matching (PSM). Cox proportional hazards models were conducted to evaluate the risk of stroke/SE and major bleeding of each DOAC vs warfarin. RESULTS: Of 41,001 identified patients, there were 3691 dabigatran-warfarin, 8226 rivaroxaban-warfarin, and 7607 apixaban-warfarin matched patient pairs. Apixaban was the only DOAC found to be associated with a significantly lower risk of stroke/SE (hazard ratio [HR]: 0.55; 95% confidence interval [CI]: 0.39, 0.77; p < 0.001) and major bleeding (HR: 0.65; 95% CI: 0.53, 0.80; p < 0.001) compared to warfarin. Dabigatran and rivaroxaban initiation were associated with similar risk of stroke/SE (dabigatran: HR: 0.68; 95% CI: 0.43, 1.07; p = 0.096; rivaroxaban: HR: 0.83; 95% CI: 0.64, 1.09; p = 0.187) and major bleeding (dabigatran: HR: 1.05; 95% CI: 0.79, 1.40; p = 0.730; rivaroxaban: HR: 1.07; 95% CI: 0.91, 1.27; p = 0.423) compared to warfarin. CONCLUSION: Among NVAF patients in the US DOD population, apixaban was associated with significantly lower risk of stroke/SE and major bleeding compared to warfarin. Dabigatran and rivaroxaban were associated with similar risk of stroke/SE and major bleeding compared to warfarin.

Safety and effectiveness of oral factor Xa inhibitors versus warfarin in nonvalvular atrial fibrillation patients at high-risk for falls.

Prescribers' concern regarding falls resulting in intracranial hemorrhage is often cited as a justification for under-utilization of oral anticoagulation. We evaluated the safety and effectiveness of oral factor Xa inhibitors versus warfarin in nonvalvular atrial fibrillation patients at high-risk for falls. Using MarketScan claims from 11/2012-3/2017, we identified adult, oral anticoagulation-naïve, new-initiators of oral factor Xa inhibitors or warfarin with nonvalvular atrial fibrillation, ≥ 12 months of insurance coverage prior to starting oral anticoagulation and a predicted 2-year risk of falls ≥ 15%. Differences in baseline covariates between cohorts were balanced using inverse probability-of-treatment weights based on propensity scores. Hazard ratios (HRs) and 95% confidence intervals (CIs) for intracranial hemorrhage and stroke or systemic embolism were estimated. Among 25,144 nonvalvular atrial fibrillation patients at high-risk for falls (observed fall rate = 11.8%/person-year), oral factor Xa inhibitor use was associated with a 43% (95% CI = 5-65%) reduced hazard of intracranial hemorrhage compared to warfarin. Oral factor Xa inhibitors did not significantly reduce the hazard of stroke or systemic embolism versus warfarin (HR = 0.86, 95% CI = 0.66-1.11). Findings for the intracranial hemorrhage and stroke or systemic embolism endpoints were similar when apixaban and rivaroxaban were evaluated separately versus warfarin (p-interaction ≥ 0.64 for all). Oral factor Xa inhibitors reduced patients' risk of intracranial hemorrhage and were at least as effective in preventing stroke or systemic embolism as warfarin in nonvalvular atrial fibrillation patients at high-risk for falls.

Anticoagulation combined with antiplatelet therapy in patients with left ventricular thrombus after first acute myocardial infarction.

Aims: There are limited data about the optimal anti-thrombotic therapy for preventing embolism while minimizing bleeding events in patients with first acute myocardial infarction (AMI) complicated by left ventricular thrombus (LVT). Methods and results: Among 2301 consecutive patients with AMI hospitalized between 2001 and 2014, we studied 1850 patients with first AMI who discharged alive to investigate clinical characteristics, incidence of systemic embolism (SE), and association between anticoagulation and embolic or bleeding events. Left ventricular thrombus was diagnosed by echocardiography, left ventriculography, or cardiac magnetic resonance imaging in 92 (5.0%) patients (62 ± 12 years). During a median follow-up period of 5.4 years (interquartile range 2.1-9.1 years), SE occurred in 15 of 92 patients with LVT (16.3%) and 51 of 1758 patients without LVT (2.9%), respectively. Kaplan-Meier analysis showed a significantly higher incidence of SE in the LVT group (log-rank test, P < 0.001). Multivariate analysis showed that LVT was an independent predictor of SE. Among the LVT patients treated with vitamin K antagonists (n = 84), we compared the patients with therapeutic range (TTR) ≥50% (n = 34) and those with TTR <50% (n = 50). Only one embolic event developed in the TTR ≥50% group and nine embolic events developed in the TTR <50% group (2.9% vs. 19%, P = 0.036). There was no difference in major bleeding events (TTR ≥50%; 9% vs. TTR <50%; 8%, P = 0.89). Conclusion: Appropriate anticoagulation therapy may decrease the incidence of embolic events without increasing the incidence of bleeding events in patients with first AMI complicated by LV thrombus.

Non-Vitamin K-Dependent Oral Anticoagulants for Nonvalvular Atrial Fibrillation in Patients With CKD: Pragmatic Considerations for the Clinician.

Management of atrial fibrillation (AF) in patients with advanced chronic kidney disease (CKD) poses a complex conundrum because of higher risks for both thromboembolic and bleeding complications compared to the general population. This makes it particularly important for clinicians to carefully weigh the risks versus benefits of anticoagulation therapy to determine the individualized net clinical benefit for every patient. During the past few years, 4 non-vitamin K-dependent oral anticoagulant (NOAC) agents have supplemented warfarin in the therapeutic armamentarium for the prevention of systemic thromboembolism in nonvalvular AF. However, the use of NOACs in CKD specifically mandates a nuanced understanding due to their varying dependence on renal clearance, with resultant safety implications related to either underdosing (thromboembolism) or excessive drug exposure (bleeding). This pragmatic review highlights unique considerations pertaining to accurate estimation and temporal monitoring of kidney function in the context of NOAC use with specific clinical deliberations and variables when determining whether an NOAC is appropriate for a patient with CKD. The dependence of NOACs on renal clearance and several troubling safety signals in the published literature suggest that it is vital for nephrologists to be active members of a multidisciplinary team caring for these high-risk patients with CKD and AF.