Non-vitamin K Antagonist Oral Anticoagulants Research Articles

Optimal adherence threshold to non-vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation to reduce the risk of thromboembolism and death

Abstract Background Poor adherence to non-vitamin K antagonist oral anticoagulants (NOACs) may raise thromboembolic risks in patients with atrial fibrillation (AF). However, the minimal adherence to maintain the protective effects of NOACs is currently unknown. Purpose To investigate thresholds of NOAC adherence in association with thromboembolic and mortality risks. Methods Using two Belgian nationwide healthcare databases, AF patients ≥45 years old with ≥1 NOAC prescription claim between January 1st, 2013 and January 1st, 2019 were identified. Patients were followed from NOAC initiation until the first occurrence of the investigated outcome, treatment discontinuation (>60-day supply gap), switch to VKAs, death, emigration or end of the study period. Adherence was measured using the proportion of days covered (PDC) after one year of treatment. Inverse probability weighted Cox regression (adjusting for 39 confounding covariates) was used to investigate outcomes (identified using International Classification of Diseases-coded hospital discharge diagnoses and medical procedure codes) between NOAC users with a one-year PDC of 100% (reference group) and NOAC users with lower PDCs. Results A total of 92,111 newly-treated AF patients were included during a mean follow-up of 2.7 ± 1.4 years (250,750 person-years of on-treatment follow-up). The proportions of persistent NOAC users with a PDC of 100%, 95-99%, 90-94%, 85-89%, 80-84% and <80% after one year of treatment were 62.7%, 17.4%, 9.5%, 5.1%, 2.8% and 2.5%, respectively. Compared to NOAC users with a one-year PDC of 100%, significantly higher risks of stroke or systemic embolism were observed among NOAC users with PDCs of 85-89% (adjusted hazard ratio (aHR) 1.35, 95% confidence interval (CI) (1.19-1.54)), 80-84% (aHR 1.31, 95%CI (1.08-1.58)) and <80% (aHR 1.64, 95%CI (1.34-2.01)), while no significant differences were observed among NOAC users with one-year PDCs of 95-99% (aHR 1.02, 95%CI (0.94-1.12)) or 90-94% (aHR 1.06, 95%CI (0.95-1.18)) after multivariable adjustment. Significantly higher risks of all-cause mortality (aHR 1.09, 95%CI (1.01-1.17) and major or clinically relevant non-major bleeding (aHR 1.10, 95%CI (1.04-1.16) were observed with decreasing levels of NOAC adherence, starting from NOAC users with a one-year PDC of 90-94% versus 100%. Findings were similar with once-daily and twice-daily dosed NOACs. Conclusion Lower adherence to NOAC treatment is associated with increased risks of thromboembolism, all-cause mortality and bleeding. For adequate stroke prevention in AF, the optimal adherence threshold to NOAC treatment should be at least 90%, irrespective of the dosing regimen of NOACs.Figure 1

Efficacy and safety of under-dose non-vitamin K antagonist oral anticoagulant with atrial fibrillation undergoing PCI: Insights from a nationwide population-based cohort study

Abstract Background The under-dose non-vitamin K antagonist oral anticoagulants (NOACs) are required according to clinical conditions for patients with atrial fibrillation (AF). We aimed to assess the comparative effectiveness and safety of standard-dose and under-dose NOACs undergoing PCI. Methods We studied the retrospective nonrandomized observational cohort of oral anticoagulant native nonvalvular patients with atrial fibrillation treated NOACs (rivaroxaban, dabigatran, apixaban, or edoxaban) from January 2013 to December 2017, based on the Korean Health Insurance Review and Assessment database. We performed head-to-head comparisons of standard-dose and under-dose NOACs. Results We studied standard-dose and under-dose NOACs were 1,095 and 2,136, respectively (Rivaroxaban, 500 vs 782; Dabigatran, 233 vs 709; Apixaban, 244 vs 430; Edoxaban, 118 vs 214). Compared with standard-dose NOACs, low-dose NOACs were associated with lower risk of major bleeding in AF patients with PCI(Rivaroxaban, HR=0.72[0.58∼0.85]; Dabigatran, HR=0.73[0.60-0.86]; Apixaban, HR=0.82[0.69-0.95]; Edoxaban, HR=0.85[0.72-0.98]. Also, the ischemic stroke was significantly different for standard-dose and under-dose NOACs in AF patients with PCI (Rivaroxaban, HR=0.67[0.54-0.80]; Dabigatran, HR=0.68[0.55-0.81]; Apixaban, HR=0.69[0.56-0.82]; Edoxaban, HR=0.70[0.57-0.83]). Conclusions In this nonrandomized Asian cohort study, NOACs(rivaroxaban, dabigatran, apixaban, or edoxaban) were associated with lower risk of major bleeding and ischemic stroke for standard-dose and under-dose NOACs in AF patients with PCI.Table 1.Clinical outcomes

Predicting thrombus outcome during anticoagulation for left ventricular thrombus

Abstract Background Up to 22% of embolizations have been linked to left ventricular (LV) thrombosis. Oral anticoagulation (OAC) for at least 3 months is recommended for patients with LV thrombus, according to guidelines. The purpose of this study was to predict the resolution of thrombus in patients with LV thrombus who were taking OAC for 3 months. Methods We enrolled patients prospectively from 2020 to 2022 and retrospectively from 2013 to 2019 at a national center of cardiovascular diseases in China. Patients with a history of LV thrombus < 3 months were included. Eligible patients were administered OAC and scheduled for 3 months of follow-up visits. The primary efficacy outcome was the rate of thrombus resolution at 3 months. Safety outcomes and major cardiovascular adverse events were collected. The hazard ratio (HR) and 95% confidence intervals (CIs) were estimated with adjustment for covariates using Cox regression models. Results We identified a total of 380 eligible patients. The median age was 53 (41, 63) years and 310 (81.6%) patients were male. The main underlying etiologies were dilated cardiomyopathy (51.6%). 204 (53.7%) patients received non-vitamin K antagonist oral anticoagulants (NOACs) while the rest were on warfarin within 3 months. In multivariable analysis, patients with NOACs had a higher likelihood of thrombus resolution than those taking warfarin (HR 1.39, 95% CI 1.08 – 1.79, P = 0.011). Lower LV ejection fraction levels and smaller diameter or thickness of thrombi were also the dominant predictors of thrombus resolution followed by a faster heart rate, a higher white blood cell count, therapy of diuretics, beta-blocker, and parental anticoagulation during hospitalization (eight variables, all P < 0.05). At 3 months, 29 patients (7.6%) suffered major cardiovascular adverse events, including 26 emboli and 3 deaths. One patient (0.3%) experienced an ISTH major bleeding. Conclusions Patients with systemic anticoagulation and positive treatment for heart failure achieved a greater rate of thrombus resolution at 3 months. The option of oral anticoagulation might be favorable NOACs, and further randomized controlled studies are warranted to explore.Forest plot of multivariable analysis.

Epidemiology and clinical impact of chronic obstructive pulmonary disease in patients with atrial fibrillation: findings from an european prospective observational registry

Abstract Background The interplay between atrial fibrillation (AF) and chronic obstructive pulmonary disease (COPD) has been poorly investigated and understood, with previous studies reporting unsatisfactory management and poor prognosis of patients with AF and COPD. Purpose To describe the epidemiology, management and natural history of AF patients with COPD using a contemporary European prospective cohort. Methods From a European-wide prospective observational AF registry, we identified patients with COPD as reported by the investigators. We analysed the association between COPD and the odds of receiving oral anticoagulants (OAC) and other pharmacological treatments using multivariable logistic regression models. We also assessed the associations between COPD and risk of major outcomes using multivariable Cox-regression models. Our primary outcome was all-cause mortality; secondary outcome was the risk of major adverse cardiovascular events (MACE). We finally evaluated the interaction between disease-specific treatments for COPD and the risk of major outcomes in AF-COPD patients. Results A total of 10,219 AF patients were included in this analysis (mean age 69.2 ± 11.4 years; 40.3% females); COPD was found in 909 patients (8.9%). Patients with COPD were older, more likely males, and had a higher burden of thromboembolic and bleeding risk factors. No differences were observed in the likelihood of receiving OAC or non-vitamin K antagonist oral anticoagulants (NOAC) in COPD vs. no COPD patients (OR: 1.00, 95%CI: 0.81-1.24, and OR: 0.91, 95%CI: 0.77-1.06, respectively for OAC vs. non OAC and NOAC vs. VKA prescription). Patients with COPD were less likely treated with ACE inhibitors, beta-blockers, amiodarone and class IC antiarrhythmics, while they showed higher odds of receiving diuretic, digoxin, and non-dihydropyridinic calcium channel blockers (Figure 1). Over a median follow-up of 24.3 [IQR: 23.0-25.0] months, the risk of all-cause death was higher among COPD patients (HR: 1.52, 95%CI: 1.28-1.80), as well as the risk of MACE (HR: 1.49, 95%CI: 1.22-1.83) and the composite outcome of ‘all-cause death and MACE’ (HR: 1.50, 95%CI: 1.29-1.74) (Figure 2). No statistically significant interactions were observed between the use of beta-blockers, beta-2 agonists and anticholinergic drugs, and the risk of death in COPD patients. Conclusions COPD was common in AF patients and was associated with higher prescription of rate-control (except for beta-blockers) and lower prescription of rhythm control drugs, with no differences in OAC treatment. COPD was associated with worse prognosis, without significant interaction observed for beta-blockers or other COPD-specific treatment.Figure 1Figure 2

Impact of oral anticoagulants in frail atrial fibrillation patients: a report from an observational registry of european patients

Abstract Background The last years showed a substantial increase of interest about the clinical issue of frailty among patients with cardiovascular diseases. Impact of frailty in atrial fibrillation (AF) has been examined in terms of management, quality of life and increased risk of outcomes; nonetheless, the impact of treatment with oral anticoagulants (OAC) remains suboptimally understood. Purpose To analyse the impact of OAC in a cohort of frail AF patients. Methods We used data from a European-wide prospective observational AF registry. Frailty was evaluated with a 40-items frailty index (FI) built according to the cumulative deficit method proposed by Rockwood and Mitnitski. OAC treatment was evaluated at baseline. A net clinical outcome (NCO) of all-cause death, major adverse cardiovascular outcomes, and major bleeding, as well as the single components were the study outcomes. Results Among 10,172 patients available for this analysis, 2,171 (21.3%) were frail. AF frail patients had a mean (SD) age of 71.7 (9.8) years and were 1,073 (49.4%) females. Overall, 1,801 (83.0%) were treated with OAC, of which 1,232 (68.4%) prescribed with vitamin K antagonist (VKA) and 569 (31.6%) prescribed with non-vitamin K antagonist oral anticoagulants (NOACs). Over a mean (SD) follow-up time of 1.56 (0.74) years there were 571 (26.3%) NCO events. Frail patients prescribed with OAC had a lower rate of NCO compared to those not prescribed (27.1% vs. 44.6%, p<0.001). After adjustments, use of OAC was associated with lower risk of NCO and all the other secondary outcomes (Table 1). Regarding the type of OAC, patients prescribed with NOACs reported a lower rate of NCO compared to those prescribed with VKAs (22.7% vs. 29.1%). After adjustments, use of NOACs was associated with a lower risk of NCO and all the other secondary outcomes, except for major bleeding (Table 1). When comparing patients with FI <80th percentile with those with FI ≥80th percentile, adjusted analysis showed that in the FI <80th group the use of OAC was consistently associated with lower risk of all outcomes (except for major bleeding), with a non-statistically significant trend seen in those with FI ≥80th percentile treated with OAC (Table 1). Conclusions In frail AF patients, use of OAC was associated with a lower risk of outcomes, as well as the use of NOACs compared with VKAs. In patients with a very high frailty burden the benefits of OAC may be attenuated.

Risk of incident atrial fibrillation and subsequent use of oral anticoagulants in patients with dementia

Abstract Background Dementia and atrial fibrillation (AF) have many shared risk factors, and the presence of AF is associated with a higher risk of incident dementia. Although patients with dementia have higher risk of adverse cardiovascular events, there are limited data on the risks of incident AF, and the associated AF-related clinical outcomes. Patients with dementia are under-represented in randomised trials, and even if AF is present, oral anticoagulants (OAC) are not prescribed frequently. We aimed to report the incidence of newly-diagnosed AF in dementia patients, and the impact on stroke and bleeding outcomes with vitamin K antagonist (VKA, eg warfarin) and non-VKA OAC (NOACs). Methods Nationwide cohort study of 544,074 patients with dementia, compared to 554,074 age- and sex-matched patients without dementia. Results Rates of newly-diagnosed AF were higher in patients with dementia compared to those without history of dementia (1.89 per 100 person-years vs 1.78 per 100 person-years, respectively); adjusted risk of incident AF was greater in all types of dementia, pre-senile/senile dementia and vascular dementia (Figure 1). When compared to non-OAC users, warfarin use was associated with higher risk of ischaemic stroke (aHR, 1.290; 95% CI, 1.156 - 1.440), intracranial hemorrhage (ICH) risk (aHR, 1.678; 95% CI, 1.346 - 2.09) and major bleeding (aHR, 1.192; 95% CI, 1.073 - 1.323). NOAC use was associated with lower risk of ischaemic stroke (aHR, 0.42; 95% CI, 0.352 - 0.501) and major bleeding (aHR; 0.504, 95% CI, 0.433 - 0.587), when compared to non-OAC use (Figure 2). Conclusions In this large nationwide cohort of dementia patients, the incidence rate of newly-diagnosed or incident AF was higher in patients with dementia compared to patients without dementia. Compared to non-OAC users, NOAC use was associated with a lower risk of ischaemic stroke and major bleeding. Patients with dementia require a holistic approach to their care and management, including the use of NOACs to reduce their risks of clinical events.

Oral anticoagulant use and outcomes in Asian patients with atrial fibrillation in the GLORIA-AF Registry

Abstract Background Ethnic differences in the management and outcomes of patients with atrial fibrillation (AF) have been shown in previous studies, but available data is still limited, although urgently needed. Purpose to analyse oral anticoagulant (OAC) prescription, OAC discontinuation, and long-term risk of major outcomes in Asian patients with AF, using data from a global prospective cohort study. Methods Using data from the GLORIA-AF Registry Phase II and III, we analysed patients according to their self-reported ethnicity (Asian vs. Non-Asian), and according to Asian ethnic subgroup (i.e. Chinese, Japanese, Korean and other Asian). Odds of OAC prescription were analysed through multivariable logistic regression, while the risk of OAC discontinuation and adverse outcomes were analysed through multivariable Cox-regression model. Primary outcome of this analysis was defined as the composite of all-cause death and major adverse cardiovascular events (MACE). Results 34,421 AF patients were included (70.0±10.5 years, 45.1% females, 6,900 (20.0%) Asian). Compared to Non-Asian subjects, prescription of OAC and non-vitamin K antagonist oral anticoagulant (NOAC) was lower in Asian subjects (Odds Ratio [OR] and 95% Confidence Intervals (CI): 0.23 [0.22-0.25] and 0.66 [0.61-0.71], respectively; Figure 1), but higher in the Japanese subgroup. Asian ethnicity was also associated with OAC discontinuation (Hazard Ratio [HR] and [95%CI]: 1.79 [1.67-1.92]), and lower risk of the primary composite outcome (HR [95%CI]: 0.86 [0.76-0.96]; Figure 2). Among the secondary outcomes, Asian patients had also higher risk of thromboembolism and intracranial haemorrhage, and lower risk of major bleeding events. Conclusions In this large, contemporary cohort of patients with AF, Asian subjects received suboptimal management of thromboembolic risk, and showed a peculiar long-term risk of adverse outcomes. Integrated and appropriate treatment of these patients is crucial to improve their prognosis.Figure 1Figure 2

Abstract 15764: Early versus Late Initiation of Non-Vitamin K Antagonist Anticoagulation After Ischemic Stroke in Patients With Atrial Fibrillation: A Systematic Review and Meta-Analysis

Introduction: Atrial fibrillation (AF) is a common cause of acute ischemic stroke (AIS). Non-vitamin K antagonist oral anticoagulants (NOACs) are recommended for stroke prevention. However, presumed higher risk of hemorrhagic transformation in early (≤ 5 days) start of NOACs delays timing of anticoagulation initiation after AIS. This meta-analysis was conducted to evaluate granularity of data on the timing of initiation of NOACs after AIS in patients with AF. Methods: This meta-analysis followed the PRISMA guidelines and is registered in PROSPERO (CRD42023391198). PubMed, PubMed Central, Embase, and Scopus databases were searched for relevant articles from inception through May 2023. Title and abstract were screened by two independent authors, followed by full text review in Covidence platform. Pertinent data was extracted in Microsoft Excel. Data were analyzed using RevMan v5.4 with odds ratio as effect measure. Results: A total of 6326 studies were identified from database search. Five studies with 7442 patients were included. There was no significant difference between the groups in terms of recurrent stroke (OR 0.86, CI 0.62-1.20;), intracranial hemorrhage (OR 0.71, CI 0.26-1.93), major bleeding (OR 1.22, CI 0.66-2.26) or mortality (OR 0.75, CI 0.44-1.27). However, pooled results from two studies showed a statistically significant lower occurrence of hemorrhagic transformation in early NOAC group as compared to late NOAC group (OR 0.43, CI 0.32-0.60). Conclusions: Based on this meta-analysis, early NOAC initiation after AIS in patients with AF is a safe strategy in terms of efficacy (recurrent stroke) and safety (major bleeding, intracranial hemorrhage, mortality, and hemorrhagic transformation).

Pharmacodynamic Drug-Drug Interactions and Bleeding Outcomes in Patients with Atrial Fibrillation Using Non-Vitamin K Antagonist Oral Anticoagulants: a Nationwide Cohort Study.

Pharmacodynamic drug-drug interactions (PD DDIs) may influence the safety of non-vitamin K antagonist oral anticoagulants (NOACs), but the extent to which PD DDIs increase bleeding risks, remains unclear. Therefore, the impact of PD DDIs on bleeding outcomes in NOAC-treated patients with atrial fibrillation (AF) was investigated. Using Belgian nationwide data, NOAC-treated AF patients were included between 2013-2019. Concomitant use of PD interacting drugs when initiating NOAC treatment was identified. Among 193,072 patients, PD DDIs were identified in 114,122 (59.1%) subjects. After multivariable adjustment, concomitant use of PD interacting drugs was associated with significantly higher risks of major or clinically-relevant non-major bleeding (adjusted hazard ratio (aHR) 1.19, 95% confidence interval (CI) (1.13-1.24)), gastrointestinal (aHR 1.12, 95%CI (1.03-1.22)), urogenital (aHR 1.21, 95%CI (1.09-1.35)) and other bleeding (aHR 1.28, 95%CI (1.20-1.36)), compared to NOAC-treated AF patients without PD interacting drug use. Increased bleeding risks were most pronounced with P2Y12 inhibitors (aHR 1.62, 95%CI (1.48-1.77)) and corticosteroids (aHR 1.53, 95%CI (1.42-1.66)), followed by selective serotonin or serotonin and norepinephrine reuptake inhibitors (SSRI/SNRI, aHR 1.26, 95%CI (1.17-1.35)), low-dose aspirin (aHR 1.14, 95%CI (1.08-1.20)) and non-steroidal anti-inflammatory drugs (NSAID, aHR 1.10, 95%CI (1.01-1.21)). Significantly higher intracranial bleeding risks in NOAC users were observed with SSRI/SNRIs (aHR 1.50, 95%CI (1.25-1.81)) and corticosteroids (aHR 1.49, 95%CI (1.21-1.84)). Concomitant use of PD interacting drugs, especially P2Y12 inhibitors and corticosteroids, was associated with higher major, gastrointestinal, urogenital, and other bleeding risks in NOAC-treated AF patients. Remarkably, higher intracranial bleeding risks were observed with SSRI/SNRIs and corticosteroids.

Real-world clinical outcomes of oral anticoagulants among Japanese patients with atrial fibrillation and concomitant coronary artery disease

BackgroundStroke prevention is complicated in patients with atrial fibrillation (AF) and coronary artery disease (CAD). We compared the risk of major bleeding among Japanese patients with AF and CAD commencing warfarin, dabigatran, or rivaroxaban. MethodsThis study included adults with AF and CAD who were newly prescribed the non-vitamin K antagonist oral anticoagulants (NOACs) dabigatran or rivaroxaban, or warfarin, and registered between 18 April 2011 through 31 December 2020 in the Medical Data Vision hospital-based clinical database. The primary outcome was major bleeding, and the secondary outcome was a composite of stroke, systemic embolism, myocardial infarction, all-cause inpatient mortality, major bleeding, major gastrointestinal bleeding, and intracerebral hemorrhage. Cox proportional hazard models with stabilized inverse probability treatment weighting were used to estimate hazard ratios (HRs) with 95 % CIs via a two-step approach; first between warfarin and each NOAC, then between NOACs if sample size conditions were met. ResultsDabigatran, rivaroxaban, and warfarin groups included 6712, 20,329, and 12,316 patients, respectively. Major bleeding risk was lower in NOACs versus warfarin (dabigatran: HR 0.50, 95 % CI: 0.40–0.62; rivaroxaban: HR 0.78, 95 % CI: 0.69–0.90); this risk was lower with dabigatran compared with rivaroxaban (HR 0.64, 95 % CI: 0.51─0.79). Net clinical benefit was superior to warfarin in both NOACs (dabigatran: HR 0.78, 95 % CI: 0.71–0.85; rivaroxaban: HR 0.83, 95 % CI: 0.78–0.88). ConclusionsAmong real-world Japanese patients with AF and CAD, NOACs were associated with better clinical outcomes than warfarin. Treatment with dabigatran had a lower risk of major bleeding than rivaroxaban.Clinical trial registration: NCT05051904 (ClinicalTrials.gov)

Abstract 072: Risk Factors for Developing Ischemic Strokes While Taking Non‐Vitamin K Antagonist Oral Anticoagulants

Introduction Over the past decade, non‐vitamin K antagonist oral anticoagulants (NOACs) have replaced warfarin as the initial strategy for stroke prevention in non‐valvular atrial fibrillation. However, ischemic strokes occurring in patients taking NOACs are becoming increasingly more frequent. In this study, we aimed to determine the clinical, echocardiographic, and neuroimaging markers associated with developing ischemic strokes in patients taking NOACs for atrial fibrillation. Methods Among atrial fibrillation patients on NOACs with and without ischemic stroke, brain MRIs were reviewed for the presence of neuroimaging markers of small vessel disease. Transthoracic echocardiography reports were reviewed to obtain left atrial volumes, presence of left ventricular hypertrophy, ejection fractions, and presence of wall motion abnormalities. Clinical and radiologic variables with significant differences between groups were entered into a multivariable regression model to determine predictors of ischemic stroke. In the ischemic stroke group, a Cox regression analysis was constructed to determine predictors of ischemic stroke recurrence during follow‐up. Results 112 patients with ischemic stroke and 94 controls (free of ischemic stroke) were included in the study. The mean age (77±9 years vs. 74±11 years, p = 0.13) and proportion of patients with CHA2DS2‐VASc>2 were similar between controls and ischemic stroke patients (82% vs. 83%, p = 0.86). The variables that were significantly different between groups included apixaban use, dabigatran use, prior cerebrovascular events, hemoglobin A1c (HbA1c), left ventricular hypertrophy, left atrial volume index, and severe white matter hyperintensities. After multivariable adjustment, prior cerebrovascular events (aOR 23.86, 95% CI [6.02–94.48]), HbA1c levels (aOR 2.36, 95% CI [1.39–3.99]), left ventricular hypertrophy (aOR 2.73, 95% CI [1.11–6.71]) and left atrial volume index (aOR 1.05, 95% CI [1.01–1.08]) increased the risk of stroke, whereas apixaban use appeared to decrease the risk (aOR 0.38, 95% CI [0.16–0.92]). Among patients with ischemic stroke, there were 103 survivors, 82 (80%) of which had follow‐up data. The median follow‐up duration for these patients was 2.6 (0.5–4.7) years. Of these 82 patients, 11 (13%) experienced an ischemic stroke during the follow‐up period. Malignancy was associated with ischemic stroke recurrence (aHR 4.90, 95% CI [1.35–18.42]) after adjustment for age and chronic renal failure. Conclusion Prior cerebrovascular events, diabetes, left ventricular hypertrophy, and left atrial size are associated with the development of ischemic stroke among NOAC users. Future studies should aim to investigate nonpharmacological stroke prevention strategies in patients with the vascular risk factors and echocardiographic risk markers identified in the present study.

Comparative safety and effectiveness of non-vitamin K oral anticoagulants versus warfarin in patients with non-valvular atrial fibrillation: A network meta-analysis

The introduction of non-vitamin K antagonist oral anticoagulants (NOACs), with a non-inferior or superior clinical efficacy profile compared to vitamin K antagonists (VKAs), has significantly improved the safety profile and treatment adherence of patients with non-valvular atrial fibrillation (AF). However, few studies have compared the effectiveness and safety of NOACs. Therefore, we conducted this systematic review and network meta-analysis to compare the safety and clinical effectiveness of NOACs and VKAs in patients with non-valvular AF. An online bibliographic search was conducted to retrieve real-world evidence studies published between January 2019 and June 2022. Dabigatran was associated with lower risks of major bleeding, ischemic stroke, and intracranial hemorrhage than warfarin. Among the NOACs, only dabigatran had a lower risk of all-cause mortality than warfarin. Dabigatran was also associated with lower risks of major bleeding and intracranial hemorrhage than rivaroxaban. Our meta-analysis confirms that dabigatran's real-world safety and clinical effectiveness align with the results of pivotal clinical trials.

Heterogeneous distributions in clinical events preceding anticoagulant treatment nonpersistence in patients with venous thromboembolism stratified by active cancer: A nationwide cohort study.

Nonpersistence in anticoagulation therapy is common and associated with undesirable clinical outcomes in patients with venous thromboembolism (VTE). We investigated preceding clinical events of treatment nonpersistence (e.g., switching, discontinuing, or restarting) in VTE patients with and without active cancer using Korean claims database. Clinically significant events including thromboembolic events, hepatic function change and surgery preceded treatment nonpersistence, but heterogeneous distributions of clinical events were observed in the presence of active cancer. Patients with active cancer had a low rate of clinical events preceding treatment nonpersistence, and new active cancer diagnosis in the nonactive cancer group was most common before the switch to parenteral anticoagulants from warfarin or non-vitamin K antagonist oral anticoagulants (NOACs). These findings suggest that clinically significant events can precede treatment nonpersistence and largely paralleled current guidelines for patients with VTE, whereas heterogeneous distributions of clinical events were observed in the presence of active cancer.

Effectiveness and safety of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation at low risk of stroke in japan: a retrospective cohort study.

Contemporary guidelines differ in their recommendations regarding initiating non-vitamin K antagonist oral anticoagulants (NOACs) in patients with atrial fibrillation (AF) at low risk of stroke. This study aimed to examine the effectiveness and safety of NOACs for low-risk AF in a Japanese cohort. In this retrospective cohort study based on the JMDC Claims Database extracted between April 2011 and November 2022, we identified 13 291 patients with AF at low risk of stroke. We performed inverse probability of treatment weighting Cox regression analyses to compare the embolization and bleeding risks between the nontreatment and NOAC groups. Net clinical benefit was defined as the annual incidence of ischaemic stroke events prevented by NOACs after subtracting intracranial haemorrhage (ICH) events attributable to NOACs, multiplied by a weighting factor. The incidences of stroke and ICH in the nontreatment group were 0.47 and 0.15 per 100 person-years, respectively. The NOAC group had higher incidences of ICH (hazard ratio [HR]: 1.73, 95% confidence interval [CI]: 0.75-4.00) and stroke (HR: 1.41, 95% CI: 0.84-2.36). The net clinical benefit of NOAC treatment was -0.35% per year (95% CI: -0.99-0.29%). Non-vitamin K antagonist oral anticoagulants treatment may be associated with a slightly high risk of ICH, and it yielded a neutral clinical benefit in the present Japanese population, which provides reassurance concerning the role of ethnicity in NOAC treatment for patients with AF and suggests a need to assess comprehensive weighting of the respective risk factors.

Impact of P-glycoprotein and CYP3A4-interacting drugs on clinical outcomes in patients with atrial fibrillation using non-vitamin K antagonist oral anticoagulants: a nationwide cohort study.

The clinical relevance of common pharmacokinetic interactions with non-vitamin K antagonist oral anticoagulants (NOACs) often remains unclear. Therefore, the impact of P-glycoprotein (P-gp) and CYP3A4 inhibitors and inducers on clinical outcomes in NOAC-treated patients with atrial fibrillation (AF) was investigated. AF patients were included between 2013 and 2019 using Belgian nationwide data. Concomitant use of P-gp/CYP3A4-interacting drugs at the time of NOAC initiation was identified. Among 193 072 NOAC-treated AF patients, 46 194 (23.9%) and 2903 (1.5%) subjects concomitantly used a P-gp/CYP3A4 inhibitor or inducer, respectively. After multivariable adjustment, concomitant use of P-gp/CYP3A4 inhibitors was associated with significantly higher major bleeding [adjusted hazard ratio (aHR) 1.24, 95% confidence interval (CI) (1.18-1.30)] and all-cause mortality risks [aHR 1.07, 95% CI (1.02-1.11)], but not with thromboembolism in NOAC-treated AF patients. A significantly increased risk of major bleeding was observed with amiodarone [aHR 1.27, 95% CI (1.21-1.34)], diltiazem [aHR 1.28, 95% CI (1.13-1.46)], verapamil [aHR 1.36, 95% CI (1.03-1.80)], ticagrelor [aHR 1.50, 95% CI (1.20-1.87)], and clarithromycin [aHR 1.55, 95% CI (1.14-2.11)]; and in edoxaban [aHR 1.24, 95% CI (1.06-1.45)], rivaroxaban [aHR 1.25, 95% CI (1.16-1.34)], and apixaban users [aHR 1.27, 95% CI (1.16-1.39)], but not in dabigatran users [aHR 1.07, 95% CI (0.94-1.23)]. Concomitant use of P-gp/CYP3A4 inducers (e.g. antiepileptic drugs like levetiracetam) was associated with a significantly higher stroke risk [aHR 1.31, 95% CI (1.03-1.68)], but not with bleeding or all-cause mortality. Concomitant use of P-gp/CYP3A4 inhibitors was associated with higher bleeding and all-cause mortality risks in NOAC users, whereas the use of P-gp/CYP3A4 inducers was associated with higher stroke risks.

Disease-Related Knowledge and Need for Revision of Care for Patients with Atrial Fibrillation: A Cross Sectional Study.

To evaluate the disease-related knowledge of outpatients with atrial fibrillation (AF), and the relationship with health literacy and other background variables. In this cross-sectional survey study, conducted in Iceland, patients with AF scheduled for an electrical cardioversion or AF catheter ablation were recruited from a hospital outpatient clinic. They completed the validated Atrial Fibrillation Knowledge Scale (AFKS), a 11-item instrument (with possible score 0-10, 10 being the best knowledge) which evaluates knowledge pertaining to AF in general, AF symptom detection and AF treatment. Health literacy was assessed with the 16 item European Health Literacy Survey Questionnaire (HLS-EU-Q) and patients answered questions about their background. Data was analysed with parametric tests. In total, 185 participants completed the questionnaire (mean age 63 ±10), 77% were male, 74% with previous electrical cardioversion and 76% were on non-vitamin K antagonist oral anticoagulants (NOAC) medication. The mean score on the AFKS was 6.5 (±1.8). The best knowledge was concerning oral anticoagulation therapy (96% answered correctly) and the least knowledge was regarding responses to AF episodes (17% answered correctly). Patients with sufficient health literacy (52%) had better knowledge of AF (M 6.8 ±1.7 vs M 6.3 ±1.9, p = 0.05). Age, educational level, health literacy and AF pattern explained 22% of the variance in AF knowledge. Patients with AF have inadequate knowledge of their condition, potentially as a result of insufficient health literacy. AF knowledge may be improved using integrated management where patients are actively involved in the care and health literacy is considered in the provided patient education.

Real-world data emulating randomized controlled trials of non-vitamin K antagonist oral anticoagulants in patients with venous thromboembolism

BackgroundEmulating randomized controlled trials (RCTs) by real-world evidence (RWE) studies would benefit future clinical and regulatory decision-making by balancing the limitations of RCT. We aimed to evaluate whether the findings from RWE studies can support regulatory decisions derived from RCTs of non-vitamin K antagonist oral anticoagulants (NOACs) in patients with venous thromboembolism (VTE).MethodsFive landmark trials (AMPLIFY, RE-COVER II, Hokusai-VTE, EINSTEIN-DVT, and EINSTEIN-PE) of NOACs were emulated using the South Korean nationwide claims database (January 2012 to August 2020). We applied an active comparator and new-user design to include patients who initiated oral anticoagulants within 28 days from their VTE diagnoses. The prespecified eligibility criteria, exposure (each NOAC, such as apixaban, rivaroxaban, dabigatran, and edoxaban), comparator (conventional therapy, defined as subcutaneous heparin followed by warfarin), and the definition of outcomes from RCTs were emulated as closely as possible in each separate emulation cohort. The primary outcome was identical to each trial, which was defined as recurrent VTE or VTE-related death. The safety outcome was major bleeding. Propensity score matching was conducted to balance 69 covariates between the exposure groups. Effect estimates for outcomes were estimated using the Mantel–Haenszel method and Cox proportional hazards model and subsequently compared with the corresponding RCT estimates.ResultsCompared to trial populations, real-world study populations were older (range: 63–69 years [RWE] vs. 54–59 years [RCT]), with more females (55–60.5% vs. 39–48.3%) and had a higher prevalence of active cancer (4.2–15.4% vs. 2.5–9.5%). The emulated estimates for effectiveness outcomes showed superior effectiveness of NOAC (AMPLIFY: relative risk 0.81, 95% confidence interval 0.70–0.94; RE-COVER II: hazard ratio [HR] 0.60, 0.37–0.96; Hokusai-VTE: 0.49, 0.31–0.78; EINSTEIN-DVT: 0.54, 0.33–0.89; EINSTEIN-PE: 0.50, 0.34–0.74), when contrasted with trials that showed non-inferiority. For safety outcomes, all emulations except for AMPLIFY and EINSTEIN-DVT yielded results consistent with their corresponding RCTs.ConclusionsThis study revealed the feasibility of complementing RCTs with RWE studies by using claims data in patients with VTE. Future studies to consider the different demographic characteristics between RCT and RWE populations are needed.

Two Approaches to Triple Antithrombotic Therapy in Patients with Acute Coronary Syndrome and Non-Valvular Atrial Fibrillation Treated with Percutaneous Coronary Intervention: Which Is More Efficient and Safer?

Patients with acute coronary syndrome (ACS) and atrial fibrillation (AF) treated with percutaneous coronary intervention (PCI) are at high risk of bleeding and thromboembolic events. Thus, optimal treatment strategies in this challenging subset have been controversial. Herein, we aim to investigate different triple antithrombotic treatment (TAT) strategies in patients with ACS and AF after PCI. This was a retrospective, single-center study based on all consecutive patients with the diagnosis of ACS and AF treated with vitamin K antagonists (VKA) or non-vitamin K antagonist oral anticoagulants (NOAC) plus dual antiplatelet therapy using a P2Y12 inhibitor (clopidogrel) and aspirin (for 1 to 3 months) and observed for 12 months for major adverse cardiac events (MACE) and major or clinically relevant non-major bleeding incidents. MACE occurred in 26.6% of patients treated with the VKA and 30.9% with NOAC (p = 0.659). Bleeding occurred in 7.8% of patients treated with VKA and 7.4% with NOAC (ns). Among patients with ACS and AF who had undergone PCI, there was no significant difference in the risk of bleeding and ischemic events among those who received TAT with NOAC and VKA.

Minimal Adherence Threshold to Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation to Reduce the Risk of Thromboembolism and Death: A Nationwide Cohort Study.

Poor adherence to non-vitamin K antagonist oral anticoagulants (NOACs) may raise thromboembolic risks in patients with atrial fibrillation (AF). However, the minimal adherence to maintain the protective effect of NOACs is currently unknown. Therefore, we investigated thresholds of NOAC adherence in association with thromboembolic and mortality risks. Patients with AF initiating NOACs between 2013 and 2019 were identified in Belgian nationwide data. Adherence was measured using the proportion of days covered (PDC) after one year of treatment. Inverse probability of treatment weighted Cox regression was used to investigate outcomes. 92,111 persons were included (250,750 person-years). Compared to NOAC users with a one-year PDC of 100%, significantly higher risks of stroke or systemic embolism were observed among NOAC users with PDCs of 85-89% (adjusted hazard ratio (aHR) 1.35, 95% confidence interval (CI) (1.19-1.54)), 80-84% (aHR 1.31, 95%CI (1.08-1.58)) and < 80% (aHR 1.64, 95%CI (1.34-2.01)), while no significant differences were observed among NOAC users with one-year PDCs of 95-99% (aHR 1.02, 95%CI (0.94-1.12)) or 90-94% (aHR 1.06, 95%CI (0.95-1.18)). Significantly higher risks of all-cause mortality were observed with decreasing levels of NOAC adherence, which were already higher among NOAC users with a one-year PDC of 90-94% versus 100% (aHR 1.09, 95%CI (1.01-1.17)). Findings were similar with once-daily and twice-daily dosed NOACs. Poor adherence to NOACs is associated with increased risks of thromboembolism and all-cause mortality. The minimal adherence threshold should be ≥ 90%, preferably even ≥ 95%.

Effectiveness and safety of non-vitamin K antagonist oral anticoagulant in the treatment of patients with morbid obesity or high body weight with venous thromboembolism: A meta-analysis.

Venous thromboembolism (VTE) poses a significant health risk to patients with morbid obesity or high body weight. Non-vitamin K antagonist oral anticoagulants (NOACs) are emerging treatments, but their effectiveness and safety compared with vitamin K antagonists (VKAs) in this population are yet to be thoroughly studied. We conducted a systematic review and meta-analysis, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Four electronic databases were searched for relevant studies comparing the efficacy and safety of NOACs and VKAs in treating patients with VTE with a body mass index > 40 kg/m2 or body weight > 120 kg. Eligible studies were scored for quality using the Newcastle-Ottawa Scale. Thirteen studies were included. The meta-analysis results showed that compared to VKAs, NOACs significantly decreased the risk of VTE occurrence (odds ratio = 0.72, 95% CI: 0.57-0.91, I2 = 0%, P < .001) and were associated with a lower risk of bleeding (odds ratio = 0.74, 95% CI: 0.58-0.95, I2 = 0%, P < .05). Subgroup analysis showed that in the cancer patient subgroup, both risks of VTE occurrence and bleeding were lower in the NOAC group than in the VKA group. In patients without cancer, the risk of VTE was significantly lower in the NOAC group. NOACs appear to be more effective and safer than VKAs in patients with morbid obesity or a high body weight with VTE. However, further large-scale randomized controlled trials are required to confirm these findings.