Individual Non-vitamin K Antagonist Oral Anticoagulants Research Articles

Efficacy and Safety of Oral Anticoagulants in Older Adult Patients With Atrial Fibrillation: Pairwise and Network Meta-Analyses.

To evaluate the efficacy and safety of oral anticoagulants for older adult patients with atrial fibrillation (AF). Pairwise and network meta-analyses. Patients with AF aged ≥75years. PubMed, Embase, and the Cochrane library were searched for published randomized controlled trials and adjusted observational studies evaluating the use of a non-vitamin K antagonist oral anticoagulants (NOACs), vitamin K antagonist, or antiplatelet drug for the prevention of stroke. The primary efficacy and safety outcomes were the composite of stroke and systemic embolism (SSE) and major bleedings. This study included 38 studies enrolling 1,022,908 older adult patients with AF. Results from pairwise meta-analyses showed that NOACs were superior to warfarin for all outcomes, except that dabigatran increased the risk of gastrointestinal (GI) bleedings. Aspirin was associated with a higher risk of SSE and ischemic stroke than warfarin or NOACs. Results of network meta-analyses indicated that apixaban significantly reduced the risk of SSE, major bleedings, and GI bleedings than warfarin, rivaroxaban, and dabigatran. Apixaban, edoxaban, rivaroxaban, and dabigatran reduced the risk of ischemic stroke and intracranial bleeding compared to warfarin. Dabigatran showed lower risk of all-cause mortality than warfarin and of intracranial bleeding than rivaroxaban. NOACs are of at least equal efficacy, or even superior to warfarin. The safety profile of individual NOAC agents was significantly different, as apixaban performs better than the other oral anticoagulants in reducing major bleeding and GI bleeding, whereas dabigatran increased the risk of GI bleeding.

Comparing the risk of dementia in subjects with atrial fibrillation using non-vitamin K antagonist oral anticoagulants versus vitamin K antagonists: a Belgian nationwide cohort study

Atrial fibrillation (AF) is associated with cognitive decline, with anticoagulated subjects potentially having a reduced risk compared with non-anticoagulated subjects. However, whether non-vitamin K antagonist oral anticoagulants (NOACs) may reduce the risk of dementia compared with vitamin K antagonists (VKAs) is unclear yet. Therefore, the risk of dementia was compared between AF subjects on NOACs versus VKAs. AF subjects initiating anticoagulation between 2013 and 2019 were identified in Belgian nationwide data. Inverse probability of treatment weighted Cox regression was used to investigate cognitive outcomes. Among 237,012 AF subjects (310,850 person-years (PYs)), NOAC use was associated with a significantly lower risk of dementia (adjusted hazard ratio (aHR) 0.91, 95% confidence interval (CI) (0.85-0.98)) compared with VKAs. A trend towards a lower risk of vascular dementia (aHR 0.89, 95%CI (0.76-1.04)) and significantly lower risk of other/unspecified dementia (aHR 0.91, 95%CI (0.84-0.99)) were observed with NOACs compared with VKAs, whereas the risk of Alzheimer's disease was similar (aHR 0.99, 95%CI (0.88-1.11)). Apixaban (aHR 0.91, 95%CI (0.83-0.99)) and edoxaban (aHR 0.79, 95%CI (0.63-0.99)) were associated with significantly lower risks of dementia compared with VKAs, while risks were not significantly different with dabigatran (aHR 1.02, 95% CI (0.93-1.12)) and rivaroxaban (aHR 0.97, 95% CI (0.90-1.05)). Comparable risks of dementia were observed between individual NOACs, except for significantly lower risks of dementia (aHR 0.93, 95% CI (0.87-0.98)) and other/unspecified dementia (aHR 0.90 (0.84-0.97)) with apixaban compared with rivaroxaban. NOACs were associated with a significantly lower risk of dementia compared with VKAs, likely driven by apixaban and edoxaban use.

Risk of heart failure in elderly patients with atrial fibrillation and diabetes taking different oral anticoagulants: a nationwide cohort study

BackgroundHeart failure (HF) is a critical complication in elderly patients with atrial fibrillation (AF) and diabetes mellitus (DM). Recent preclinical studies suggested that non-vitamin K antagonist oral anticoagulants (NOACs) can potentially suppress the progression of cardiac fibrosis and ischemic cardiomyopathy. Whether different oral anticoagulants influence the risk of HF in older adults with AF and DM is unknown. This study aimed to evaluate the risk of HF in elderly patients with AF and DM who were administered NOACs or warfarin.MethodsA nationwide retrospective cohort study was conducted based on claims data from the entire Taiwanese population. Target trial emulation design was applied to strengthen causal inference using observational data. Patients aged ≥ 65 years with AF and DM on NOAC or warfarin treatment between 2012 and 2019 were included and followed up until 2020. The primary outcome was newly diagnosed HF. Propensity score-based fine stratification weightings were used to balance patient characteristics between NOAC and warfarin groups. Hazard ratios (HRs) were estimated using Cox proportional hazard models.ResultsThe study included a total of 24,835 individuals (19,710 NOAC and 5,125 warfarin users). Patients taking NOACs had a significantly lower risk of HF than those taking warfarin (HR = 0.80, 95% CI 0.74–0.86, p < 0.001). Subgroup analyses for individual NOACs suggested that dabigatran (HR = 0.86, 95% CI 0.80–0.93, p < 0.001), rivaroxaban (HR = 0.80, 95% CI 0.74–0.86, p < 0.001), apixaban (HR = 0.78, 95% CI 0.68–0.90, p < 0.001), and edoxaban (HR = 0.72, 95% CI 0.60–0.86, p < 0.001) were associated with lower risks of HF than warfarin. The findings were consistent regardless of age and sex subgroups and were more prominent in those with high medication possession ratios. Several sensitivity analyses further supported the robustness of our findings.ConclusionsThis nationwide cohort study demonstrated that elderly patients with AF and DM taking NOACs had a lower risk of incident HF than those taking warfarin. Our findings suggested that NOACs may be the preferred oral anticoagulant treatment when considering the prevention of heart failure in this vulnerable population. Future research is warranted to elucidate causation and investigate the underlying mechanisms.

Off-label underdosing of four individual NOACs in patients with nonvalvular atrial fibrillation: A systematic review and meta-analysis of observational studies.

Although several meta-analyses have examined the effects of off-label underdosing of nonvitamin K antagonist oral anticoagulants (NOACs) compared with their recommended doses in patients with atrial fibrillation (AF), they combined different kinds of NOACs in their primary analyses. Herein, we first conducted a meta-analysis to separately assess the effects of off-label underdosing versus on-label dosing of four individual NOACs on adverse outcomes in the AF population. The PubMed and Embase database were systemically searched until November 2021 to identify the relevant studies. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled by utilizing a random-effects model. A total of nine studies with 144,797 patients taking NOACs were included in the meta-analysis. In the pooled analysis, off-label underdosing of rivaroxaban was related to an increased risk of stroke or systemic embolism (HR=1.31, 95% CI 1.05-1.63; p=.02), whereas off-label underdosing of apixaban was associated with a higher risk of all-cause death (HR=1.21, 95% CI 1.05-1.40; p=.01). When comparing off-label underdosing versus on-label dosing of dabigatran or edoxaban, no differences were found in the primary and secondary clinical outcomes. Off-label underdosing of rivaroxaban may increase the risk of stroke or systematic embolism, whereas off-label underdosing of apixaban may heighten the incidence of all-cause death.

Non-Vitamin K Antagonist Oral Anticoagulants (NOACs) do not Increase the Risk of Hepatic Impairment in Patients with Non-Valvular Atrial Fibrillation: Insights from Multi-Source Medical Data.

There is controversy over whether non-vitamin K antagonist oral anticoagulants (NOACs) use increase the risk of hepatic impairment in patients with non-valvular atrial fibrillation (NVAF). We conducted a comprehensive assessment using multi-source medical data. We first performed a systematic search of the PubMed, Embase, and Cochrane Library databases (through 11 August 2021) for randomised controlled trials (RCTs) and real-world studies (RWSs) that reported hepatic impairment events in patients with NVAF administered NOACs or vitamin K antagonists (VKAs) therapy. The primary outcomes were hepatic impairment identified by diagnostic liver injury (DLI) or abnormal liver enzyme (ALE). The secondary outcome was hepatic failure. Relative risks (RRs) for RCTs and adjusted hazard ratios (aHRs) for RWSs were calculated separately using random-effects models. We also conducted a disproportionality analysis by extracting reports of hepatic impairment associated with NOACs from the Food and Drug Administration Adverse Event Reporting System (FAERS) database. Reporting odds ratios (RORs) were calculated to identify the statistical associations between NOACs and hepatic impairment. Scenario analyses were further performed to eliminate event- and drug-related competition bias. A total of 559,873 patients from five RCTs and four RWSs were included in the pooled analysis. For RCTs, NOACs use was not associated with an increased risk of DLI (RR: 0.96, 95% confidence intervals (CI): 0.73-1.28) or ALE (RR: 0.91, 95% CI: 0.69-1.19) compared with VKAs. The merged results of RWSs also showed a similar risk of DLI (aHR: 0.88, 95% CI: 0.72-1.09) or ALE (aHR: 0.91, 95% CI: 0.82-1.00) between NOACs and VKAs. The results of hepatic failure were in accordance with the primacy outcomes. Analyses of individual NOACs did not significantly affect the results. Insights from the FAERS database failed to detect hepatic impairment signals for overall NOACs agents (ROR: 0.34, 95% CI: 0.32-0.37). Scenario analyses confirmed the primary results. Insights from multi-source medical data confirmed that NOACs use was not associated with an increased risk of hepatic impairment in patients with NVAF.

Do non-vitamin K antagonist oral anticoagulants increase the risk of myocardial infarction?

Non-vitamin K antagonist oral anticoagulants (NOACs), compared with warfarin, have a favorable risk-benefit profile. However, in the RE-LY study in patients with atrial fibrillation (AF), the number of patients with MI was higher in the dabigatran group as compared to the warfarin group. Many meta-analyses showed that dabigatran treatment led to an increased risk of myocardial infarction (MI). Large real-world data (RWD) did not confirm an increase in the risk of MI during dabigatran treatment. In our meta-analysis we excluded RWD, and each of the four drugs was evaluated in two key-phase III randomized controlled trials: in patients with AF and patients with AF and chronic coronary syndrome or acute coronary syndrome treated with percutaneous coronary interventions. In each study, warfarin was the comparator for NOACs. In this homogeneous group of patients, dabigatran, in direct comparison with warfarin, significantly increased the risk of MI by about 30%. Moreover, the risk of MI was also significantly higher than the opposite effect of activated factor (F) X inhibitors (FXa inhibitors) vs. warfarin. In our network meta-analysis, considering individual NOACs in recommended doses, we found an increased risk of MI compared to warfarin only in patients treated with dabigatran 150 mg twice a day and, in particular, 110 mg twice a day. In this review we present evidence supporting our opinion that in patients with AF and coronary stenting, the choice of NOACs (direct FXa vs. thrombin inhibitors) is equally as important as choosing the optimal antiplatelet therapy (single or dual antiplatelet therapy).

Fracture Risks in Patients Treated With Different Oral Anticoagulants: A Systematic Review and Meta-Analysis.

BackgroundEvidence 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 ResultsWe 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 (I 2=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.ConclusionsCompared with warfarin, NOACs are associated with lower risks of bone fracture.

The risk of gastrointestinal hemorrhage with non-vitamin K antagonist oral anticoagulants: A network meta-analysis.

Background:Non-vitamin K antagonist oral anticoagulants (NOACs) have been widely used for stroke prevention in atrial fibrillation (AF) and the treatment and prevention of venous thromboembolism. There is an issue with safety, especially in clinically relevant bleeding. We performed a network meta-analysis to evaluate the risk of major gastrointestinal (GI) bleeding associated with NOACs.Methods:Interventions were warfarin, enoxaparin, apixaban, dabigatran, edoxaban, and rivaroxaban. The primary outcome was the incidence of major GI bleeding. A subgroup analysis was performed according to the following indications: AF, deep venous thrombosis/pulmonary embolism, and postsurgical prophylaxis.Results:A total of 29 randomized controlled trials (RCTs) and 4 large observation population studies were included. Compared with warfarin, apixaban showed a decreased the risk of major GI bleeding (relative risk [RR] 0.54, 95% confidence interval [CI] 0.25–0.76), and rivaroxaban tended to increase this risk (RR 1.40, 95% CI 1.06–1.85). Dabigatran (RR 1.25, 95% CI 0.98–1.60), edoxaban (RR 1.07, 95% CI 0.69–1.65), and enoxaparin (RR 1.24, 95% CI 0.63–2.43) did not significantly increase the risk of GI bleeding than did warfarin. In the subgroup analysis, according to indications, apixaban showed a decreased risk of major GI bleeding (RR 0.50, 95% CI 0.34–0.74) than did warfarin in AF studies. Dabigatran (RR 2.36, 95% CI 1.55–3.60, and rivaroxaban (RR 1.75, 95% CI 1.10–6.41) increased the risk of major GI bleeding than did apixaban. An analysis of studies on venous thromboembolism or pulmonary embolism showed that no individual NOAC or enoxaparin was associated with an increased risk of major GI bleeding compared to warfarin.Conclusion:Individual NOACs had varying profiles of GI bleeding risk. Results of analyses including only RCTs and those including both RCTs and population studies showed similar trends, but also showed several differences.

Comparison between non-vitamin K antagonist oral anticoagulants versus warfarin for the risk of dementia in Asian patients with non-valvular atrial fibrillation

Abstract Background Atrial fibrillation (AF) is a risk factor for dementia and oral anticoagulant (OAC) use is associated with a decreased risk of dementia in patients with AF. Objective We sought to find whether the risk of dementia would be different between patients treated with non-vitamin K antagonist oral anticoagulants (NOACs) and those treated with warfarin. Methods Using the Korean National Health Insurance database from January 2014 to December 2017, we identified OAC naïve non-valvular AF patients aged 40 years or older. For the comparison, warfarin and NOAC groups were balanced using the inverse probability of treatment weighting method (IPTW). The primary outcome was incident dementia. Patients were censored at the occurrence of dementia, discontinuation of index treatment, or the end of the study period (December 31, 2018). Results Among 72,846 of total study patients, 25,948 were treated with warfarin and 46,898 were treated with NOAC (17,193 with rivaroxaban, 9,882 with dabigatran, 11,992 with apixaban, and 7,831 with edoxaban). Crude incidence of dementia was 4.65 per 100 person-years in warfarin group and 4.98 per 100 person years in NOAC group. Baseline characteristics were well-balanced after IPTW (mean age 72 years, 93% CHA2DS2-VASc ≥2, 58% men). Compared to warfarin, NOAC showed a comparable risk of dementia (hazard ratio [HR] 0.944, 95% confidence interval [CI] 0.934–1.059), vascular dementia (HR 0.921, 95% CI 0.814–1.043) and Alzheimer dementia (HR 1.101, 95% CI 1.019–1.191). When comparing individual NOACs with warfarin, edoxaban was associated with a lower risk of dementia (HR 0.830, 95% CI 0.740–0.931). Rivaroxaban (HR 0.767, 95% CI 0.648–0.907) and edoxaban (HR 0.786, 95% CI 0.620–0.996) were associated with a lower risk of vascular dementia than warfarin. In subgroup analyses, NOAC was associated with a lower incidence of dementia than warfarin particularly in patients with prior stroke (HR 0.891, 95% CI 0.820–0.968) and in patients aged 65–74 years (HR 0.815, 95% CI 0.709–0.936). Conclusion In this large Asian population with AF, NOAC showed a comparable result with warfarin on the risk of dementia. Edoxaban was associated with a lower risk of dementia. NOAC appeared more beneficial especially in those with AF who had a history of prior stroke and aged 65–74 years. Funding Acknowledgement Type of funding source: None

Non-vitamin K oral anticoagulants and risk of fractures: a systematic review and meta-analysis.

Comparative fracture risk for non-vitamin K antagonist oral anticoagulants (NOACs) and vitamin K antagonists (VKAs) among patients with atrial fibrillation (AF) remains unclear. This study aimed to provide summary relative risk (RR) estimates for associations between NOACs vs. VKAs and fracture risk. PubMed, EMBASE, and Cochrane Library were searched from 2010 to 26 May 2020. Observational studies investigating the association between NOACs vs. VKAs and fracture risk in patients with AF were included. The adjusted effect estimates were pooled using the DerSimonian-Laird random effects models. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and the Meta-analysis of Observational Studies in Epidemiological (MOOSE) guidelines were followed. Five observational studies comprising 269 922 patients and 4289 fractures were included. Non-vitamin K antagonist oral anticoagulants use was associated with a lower risk of any fractures compared to VKAs use, with moderate heterogeneity [pooled RR = 0.83, 95% confidence interval (CI): 0.75-0.92, P < 0.001, I2 = 73.0%]. When comparing individual NOAC to VKAs, a statistically significant lower risk of any fractures was found for rivaroxaban (pooled RR = 0.79, 95% CI: 0.71-0.88, P < 0.001, I2 = 55.2%) and apixaban (pooled RR = 0.75, 95% CI: 0.60-0.92, P = 0.007, I2 = 54.5%), but not dabigatran (pooled RR = 0.87, 95% CI: 0.74-1.01, P = 0.061, I2 = 74.6%). No differences were observed in all head-to-head comparisons between NOACs. This large meta-analysis suggests that NOACs use was associated with a lower risk of fractures compared with VKAs. Fracture risks were similar between NOACs. These findings may help inform the optimal anticoagulant choice for patients with AF at high risk of fracture.

Inclusion in the World Health Organization Model List of Essential Medicines of Non-Vitamin K Anticoagulants for Treatment of Non-Valvular Atrial Fibrillation: A Step Towards Reducing the Burden of Cardiovascular Morbidity and Mortality.

Non-vitamin K antagonist oral anticoagulants (NOACs) represent a paradigm shift in the treatment of non-valvular atrial fibrillation (AF) with major practice guidelines around the world recommending NOACs over vitamin K antagonist oral anticoagulants for initial treatment of AF for stroke prevention. Here we describe the evidence collated and the process followed for the successful inclusion of NOACs into the 21st WHO Model List of Essential Medicines (EML).Individual NOACs have been reported to be non-inferior or superior to warfarin in preventing stroke and systemic embolism in eligible AF patients with a reduction in the risk of stroke and systemic embolism and a lower risk of major bleeding in patients with non-valvular AF compared with warfarin in both RCTs and real-world data.The successful inclusion of NOACs in the WHO EML is an important step forward in the global fight against cardiovascular morbidity and mortality, especially in low- and middle-income countries, where the burden of disease is high and limited access to diagnosis and treatment translates into a higher burden of morbidity, mortality, and economic costs.

Association Between Nonvitamin K Antagonist Oral Anticoagulants or Warfarin and Liver Injury: A Cohort Study.

The risk of liver injury in patients with atrial fibrillation (AF) using nonvitamin K antagonist oral anticoagulants (NOACs) has not been previously examined using liver function tests as the primary outcome in the real-world setting. This study assessed the association between NOACs (dabigatran, rivaroxaban, and apixaban) and warfarin and the risk of liver injury, as defined by laboratory tests. Patients newly diagnosed with AF and prescribed NOACs or warfarin between 2010 and 2016, identified using the Hong Kong Clinical Database and Reporting System, were matched on age, sex, health status scores, comorbidities, and medications by propensity score on a 1:1 ratio. Risk of liver injury, defined as laboratory test values >3 times the upper limit of normal of alanine aminotransferase or aspartate aminotransferase and >2 times the upper limit of normal of total bilirubin, was compared between NOAC and warfarin users using Cox proportional hazards regression. After propensity score matching, 13,698 patients were included, of which 141 (2.1%) NOAC users and 232 (3.4%) warfarin users developed liver injury. The hazard ratio (HR) for NOAC vs warfarin users was 0.71 (95% confidence interval: 0.58-0.89). When comparing individual NOACs, only dabigatran (hazard ratio: 0.63; 95% confidence interval: 0.48-0.82) was associated with a lower risk of liver injury. Among patients with AF, NOACs as a group, and dabigatran alone were associated with a significantly lower risk of laboratory-based liver injury when compared with warfarin. However, liver injury occurs more frequently in real-world practice than in NOAC randomized controlled trials.

Comparison of dabigatran, rivaroxaban, and apixaban for effectiveness and safety in atrial fibrillation: a nationwide cohort study

AimsThe aim of this study was to compare the risk of stroke or systemic embolism (SE) and major bleeding in patients with atrial fibrillation (AF) using dabigatran, rivaroxaban, and apixaban in routine clinical practice.Methods and resultsUsing nationwide registries in Norway from January 2013 to December 2017, we established a cohort of 52 476 new users of non-vitamin K antagonist oral anticoagulants (NOACs) with AF. Users of individual NOACs were matched 1:1 on the propensity score to create three pairwise-matched cohorts: dabigatran vs. rivaroxaban (20 504 patients), dabigatran vs. apixaban (20 826 patients), and rivaroxaban vs. apixaban (27 398 patients). Hazard ratios (HRs) for the risk of stroke or SE and major bleeding were estimated. In the propensity-matched comparisons of the risk of stroke or SE, the HRs were 0.88 [95% confidence interval (CI) 0.76–1.02] for dabigatran vs. rivaroxaban, 0.88 (95% CI 0.75–1.02) for dabigatran vs. apixaban, and 1.00 (95% CI 0.89–1.14) for apixaban vs. rivaroxaban. For the risk of major bleeding, the HRs were 0.75 (95% CI 0.64–0.88) for dabigatran vs. rivaroxaban, 1.03 (95% CI 0.85–1.24) for dabigatran vs. apixaban, and 0.79 (95% CI 0.68–0.91) for apixaban vs. rivaroxaban.ConclusionIn this nationwide study of patients with AF in Norway, we found no statistically significant differences in risk of stroke or SE in propensity-matched comparisons between dabigatran, rivaroxaban, and apixaban. However, dabigatran and apixaban were both associated with significantly lower risk of major bleeding compared with rivaroxaban.

P4759Factors associated with inappropriate under-dosing of non-vitamin k antagonist oral anticoagulants (NOACs) by labelling criterion in patients with non-valvular atrial fibrillation in the UK

Abstract Background Current labelling for NOACs considers dose adjustments based on renal function and for some also patients' age, weight, comorbidities, and concomitant treatments. There is limited data on factors associated with inappropriately underdosing of NOACs according to the label in routine care. Purpose To assess factors associated with inappropriate underdosing among patients initiating treatment with NOACs for NVAF in the United Kingdom (UK) general practice by applying respective EU labelling criterion. Methods This retrospective cohort study utilized data from The Health Improvement Network and Clinical Practice Research Datalink in the UK. New users of NOACs aged ≥18 years with ≥1-year enrolment in the databases from Jan 2011 - Dec 2016 were included. Three mutually exclusive cohorts of new users of apixaban, dabigatran and rivaroxaban with NVAF were identified with the date of prescription being the index date. Patients with any recent record (within 3 months) of other indications (DVT, PE or hip/knee surgery) were excluded. Appropriate and inappropriate underdosing were defined based on the criterion in the EU label of individual NOACs. Results There were 30,467 new users of NOACs with NVAF during the study period. Of these, 23,444 new users of NOACs received an appropriate dose based on label recommendations. They were 4,953 new users who were inappropriately under-dosed (29.4% in apixaban, 8.7% in dabigatran and 9.1% in rivaroxaban. Older age (70+) was a strong predictor of inappropriate underdosing among apixaban (odds ratio (OR) 7.3; 95% CI: 5.6–9.6) and rivaroxaban (OR 2.8; 95% CI: 2.1–5.4) but not for dabigatran users (OR 0.4; 95% CI: 0.3–0.6). Female apixaban and rivaroxaban users were at greater risk of inappropriate underdosing. For all three NOACs, inappropriate underdosing was less frequent in recent years. Inappropriate underdosing was more frequent among new users with antecedents of intracranial bleed. Inappropriate underdosing was more frequent in apixaban users with a history of ischaemic stroke and rivaroxaban users with history of Ischaemic heart disease. There was no inappropriate underdosing among all new users of NOACs with eGFR under 30. 25.5% of apixaban users and less than 0.5% of rivaroxaban new users with eGFR between 30 and 50 were inappropriately under-dosed. Frailty was a predictor of inappropriate underdosing among apixaban and rivaroxaban new users and the risk increased with greater level of frailty. CHA2DS2VASc score of ≥4 in apixaban users and increasing HAS-BLED scores in apixaban and dabigatran users were significantly associated with inappropriate underdosing but not in rivaroxaban. Conclusions Apixaban had the highest proportion of patients who were inappropriately under-dosed compared to other NOACs. Different factors associated with inappropriate dosing from this study would inform about the factors that are taken into consideration before prescribing different doses of NOACs. Acknowledgement/Funding The study is funded by Bayer AG

Novel Oral Anticoagulants for Primary Stroke Prevention in Hypertrophic Cardiomyopathy Patients With Atrial Fibrillation.

Background and Purpose- Hypertrophic cardiomyopathy patients with atrial fibrillation are at increased risk of stroke, and anticoagulation is strongly recommended. However, limited data are available regarding the safety and effectiveness of non-vitamin K antagonist oral anticoagulants (NOACs) for primary prevention of stroke. Methods- Using the Korean Health Insurance Review and Assessment Service database, we identified 2397 patients with hypertrophic cardiomyopathy and nonvalvular atrial fibrillation on oral anticoagulation from 2013 to 2016 without history of ischemic stroke, intracranial hemorrhage (ICH), or gastrointestinal bleeding (992 on warfarin and 1405 on NOACs). Inverse probability of treatment weighting with propensity scores was used to balance covariates between treatment groups. Risk for ischemic stroke, ICH, gastrointestinal bleeding, death, and their composite outcome associated with NOAC use was assessed with warfarin use as the reference. Results- During a mean follow-up of 1.6 years, the incidence rates of ischemic stroke, ICH, gastrointestinal bleeding, death, and composite outcome were all significantly lower in the NOAC than in the warfarin group (stroke, 2.8 versus 5.0; ICH, 0.5 versus 1.3; gastrointestinal bleeding, 2.3 versus 3.0; death, 3.0 versus 5.1; composite, 7.5 versus 12.5 events per 100 person-years). NOACs were associated with significantly lower risks of ischemic stroke (hazard ratio [HR], 0.47; 95% CI, 0.32-0.68), ICH (HR, 0.31; 95% CI, 0.14-0.69), gastrointestinal bleeding (HR, 0.62; 95% CI, 0.40-0.96), death (HR, 0.45; 95% CI, 0.31-0.65), and the composite outcome (HR, 0.48; 95% CI, 0.38-0.61) than warfarin. The same trend was observed regardless of the NOAC dose and across various high-risk subgroups. In analysis of individual NOACs, all NOACs were associated with lower risks of ischemic stroke and composite outcome. Conclusions- NOACs showed superior effectiveness and safety versus warfarin in the primary prevention of stroke versus warfarin in real-world Asian hypertrophic cardiomyopathy with atrial fibrillation.

Non-vitamin K Antagonist Oral Anticoagulants and Cognitive Impairment in Atrial Fibrillation: Insights From the Meta-Analysis of Over 90,000 Patients of Randomized Controlled Trials and Real-World Studies.

Background: The relationship between the use of non-vitamin K antagonist oral anticoagulants (NOACs) and the impairment of cognition in atrial fibrillation (AF) remains unknown.Methods: A comprehensive database search of Medline, Embase, Cochrane Library databases, and ClinicalTrials.gov Website was performed for randomized controlled trials (RCTs) reporting cognitive impairment events and observational nationwide database studies reporting adjusted hazard ratio (HR) in AF patients with NOACs. The primacy outcome was a composite of any cognitive impairment. Summary of HRs and 95% confidence intervals (95%CI) were calculated using the fixed- and random-effects models. Subgroup analyses were undertaken according to the individual NOACs, study types, and duration of follow-up.Results: Finally, eight studies including 97,595 patients (77,643 patients in 6 RCTs and 19,952 patients in 2 observational database studies) met the inclusion criteria, among which 55,337 (56.7%) patients were receiving NOACs and 42,258 (43.3%) patients were receiving vitamin K Antagonists (VKAs) or acetylsalicylic acid. The results showed a borderline significant association between the use of NOACs and the lower risk of cognitive impairment when compared with VKAs/ acetylsalicylic acid (HR: 0.80, 95%CI: 0.63–0.98 for fixed-effects model; HR: 0.77; 95%CI: 0.53–1.01 for random-effects model), with no significant heterogeneity between the studies (I2 = 39.4%, P = 0.12). The results were consistent across the key subgroups (Pinteraction > 0.05 for each).Conclusions: The results indicated that the use of NOACs might lower the tendency on the risk of cognitive impairment in comparison to VKAs/acetylsalicylic acid, and further RCTs and real-world studies are required on an urgent basis to obtain a robust result.

Association of Intracranial Hemorrhage Risk With Non–Vitamin K Antagonist Oral Anticoagulant Use vs Aspirin Use

Non-vitamin K antagonist oral anticoagulants (NOACs) might be an attractive choice for stroke prevention in people without atrial fibrillation who may harbor a potential source of cardiac emboli, but not if certain individual NOACs carry risks of intracranial hemorrhage that are heightened relative to aspirin. To conduct a systematic review and meta-analysis of randomized clinical trials to assess the risk of intracranial hemorrhage with individual NOACs vs aspirin across all indications. We searched PubMed, Embase, CENTRAL, and ClinicalTrials.gov from inception to May 28, 2018, with the terms novel oral anticoagulants, non-vitamin K antagonist oral anticoagulants, direct oral anticoagulants, dabigatran, rivaroxaban, apixaban, edoxaban, warfarin, Coumadin, vitamin K antagonist, aspirin, acetylsalicylic acid, or ASA, and major bleeding, fatal bleeding, or intracranial hemorrhage. We restricted our search to clinical trials on humans. There were no language restrictions. Randomized clinical trials of 3 months or longer that included a comparison of the outcomes of NOAC use vs use of aspirin. Two investigators independently abstracted data from eligible studies. We computed a fixed-effect estimate based on the Mantel-Haenszel method. Odds ratios (ORs) with 95% CI were used as a measure of the association of individual NOAC vs aspirin with the risk of intracranial hemorrhage. The hypothesis that intracranial hemorrhage risk would be higher with NOACs than aspirin was formulated during data collection. Our principal analysis included 5 randomized clinical trials comparing 1 or more NOACs with aspirin, with 39 398 individuals enrolled. Pooling the results from the fixed-effects model showed that a dose of 15 to 20 mg of rivaroxaban once daily was associated with an increased risk of intracranial hemorrhage (2 trials; OR, 3.31 [95% CI, 1.42 to 7.72]) compared with aspirin, while a 10-mg dose of rivaroxaban once daily or a 5-mg dose twice daily (3 trials; OR, 1.43 [95% CI, 0.93 to 2.21]) and a 5-mg dose of apixaban twice daily (1 trial; OR, 0.84 [95% CI, 0.38 to 1.88]) were not. A 15-mg to 20-mg dose of rivaroxaban once daily is associated with substantially increased risks of intracranial hemorrhage, while smaller daily doses of rivaroxaban and apixaban were not, implying that risk increase is dose dependent. It may be worthwhile to conduct randomized clinical trials comparing specific NOACs in specific doses (eg, apixaban, 5 mg twice daily) and aspirin in patients without atrial fibrillation, but with potential sources of cardiac emboli that could cause stroke.

Risk of cognitive impairment with non-vitamin K antagonist oral anticoagulants in atrial fibrillation: Protocol for a systemic review of randomized controlled trials and real-world studies.

Background:The association between use of non-vitamin K antagonist oral anticoagulants (NOACs) with cognitive impairment in atrial fibrillation (AF) remains unknown.Methods:An electronic search of Medline, Embase, Cochrane Library databases and ClinicalTrials.gov Website will be performed for randomized controlled trials (RCTs) that reported cognitive impairment events and observational nationwide database studies that reported adjusted hazard ratio (HR) in AF patients with NOACs. The primacy outcome will be a composite of any forms of cognitive impairment. HRs and their 95% confidence intervals (95% CI) will be calculated by using fixed- and random-effects models. Subgroup analyses will be undertaken based on individual NOACs, study types and follow-up duration.Results:This study will provide evidence of the association between use of NOACs and risk of cognitive impairment in patients with AF by pooling the results of RCTs and real-world studies.Conclusions:The results will bring about vigorous evidence in this topic and provide optimal anticoagulation strategy in AF patients at high risk of cognitive disorder.Ethics and dissemination:Ethical approval is not applicable for this study.PROSPERO registration number:CRD42018103849.

Non-vitamin K Antagonist Oral Anticoagulants vs. Warfarin at Risk of Fractures: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Warfarin is a traditional oral anticoagulant for preventing thrombotic events in patients with atrial fibrillation (AF) and venous thromboembolism. Along with the widespread clinical use, the potential association between warfarin use and fracture risk have been addressed gradually. Non-vitamin K antagonist oral anticoagulants (NOACs), targeting thrombin or Xa factor, have been recommended as an optimal alternative due to their favorable property of thromboembolism prophylaxis and reduced bleeding risk. However, evidence of the fracture risk with NOACs use is limited. Therefore, the present study investigated this issue by a meta-analysis. Medline, Embase, Cochrane Library and the ClinicalTrials.gov Website were searched for randomized controlled trials (RCTs) that reported the fracture data of NOACs and warfarin. The primacy outcome was a composite of any fracture. Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated using random- or fixed-effects models according to between-study heterogeneity. Heterogeneity was assessed through I2 test and Q statistic, and the number of patients needed to treat (NNT) was calculated based on fracture incidence. Subgroup analyses were conducted according to individual NOACs, indications, and duration of follow up. Finally, 12 RCTs involving 89,549 patients were included, among which 44,816 (50%) receiving NOACs and 44,733 (50%) receiving warfarin. Overall, 1,139 (1.3%) patients including 515 NOACs users (1.1%) and 624 warfarin users (1.4%) developed fracture. Risk of fracture was significantly lower in NOACs compared to warfarin (RR: 0.82, 95%CI: 0.73–0.93, P = 0.001), with a NNT of 333. No significantly decreased risk was detected according to fracture sites. Subgroup analysis confirmed that the estimate of decreased fracture risk was derived mainly from AF patients receiving long-term anticoagulation treatment. The meta-regression did not detect any potential confounding on fracture risk. No heterogeneity between the studies (I2 = 15.0%) and no publication bias was identified. In conclusion, the use of NOACs was associated with a lower risk of fracture compared to warfarin, but with a relatively low absolute risk reduction. Therefore, screening for the fracture risk should be considered before initiating anticoagulation treatment. For patients who are at high risk of fracture or expected long-term treatment of anticoagulation, NOACs may represent a preferable alternative to warfarin.

Severity of renal impairment in patients with heart failure and atrial fibrillation: implications for non-vitamin K antagonist oral anticoagulant dose adjustment.

The non-vitamin K antagonist oral anticoagulants (NOACs) have varying degrees of renal elimination which may be challenging in patients with heart failure (HF) and atrial fibrillation (AF). We examined the severity and variation in renal impairment, and the proportion of patients requiring NOAC cessation or dose reduction. A retrospective analysis of patients with HF and AF in the Candesartan in Heart failure Assessment of Reduction in Mortality and Morbidity programme was carried out. Trends in renal impairment over 26 months were defined using Cockcroft-Gault (CG), simplified Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations. Mean estimated glomerular filtration rate (eGFR) was worse at every time point in patients with AF compared with those without AF, the difference being ∼11 mL/min (CG), 9 mL/min (CKD-EPI), and 7 mL/min (MDRD). As renal function declined, CG classified a greater proportion of patients as having moderate or severe CKD and agreement with MDRD/CKD-EPI declined. At least moderate renal impairment was present in a quarter of patients with AF at baseline, a third by study completion, and approaching a half at least once during follow-up. The projected need for NOAC dose reduction was accordingly high, though it varied between individual NOACs due to different criteria for adjustment. Renal impairment in patients with HF and AF is common, fluctuates, progresses, and frequently mandates NOAC dose reduction, though the need for cessation is rare. Baseline renal function, the method of estimating GFR, and intensity of monitoring should be considered when commencing oral anticoagulation.