Nonvitamin K Antagonist Oral Anticoagulants Versus Warfarin in Atrial Fibrillation Patients and Risk of Dementia: A Nationwide Propensity-Weighted Cohort Study.

Background It is unclear whether nonvitamin K antagonist oral anticoagulants ( NOAC s) can mitigate dementia development in atrial fibrillation. We compared dementia development among users of NOACs or warfarin in patients with atrial fibrillation with no prior neurological diagnoses. Methods and Results We conducted a Danish nationwide cohort study including 33 617 new oral anticoagulant users with nonvalvular atrial fibrillation, of which 11 052 were aged 60 to 69 years, 13 237 were aged 70 to 79 years, and 9238 were aged 80 years and older. To exclude prevalent non -oral anticoagulants- associated dementia, we considered the at-risk population of patients alive and free of dementia at 180 days following inclusion. We compared rates of new-onset dementia by age and treatment regimen using inverse probability of treatment weighting to account for confounding. Approximately 60% of patients were NOAC users and 40% were warfarin users. Mean follow-up was 3.4 years. Dementia occurred in 41 patients aged 60 to 69 years, 276 patients aged 70 to 79 years, and 441 patients aged 80 years and older. Relative to warfarin users, dementia rates were nonsignificantly lower among NOAC users aged 60 to 69 years (0.11 events/100 person-years versus 0.12 events/100 person-years; weighted hazard ratio, 0.92 [95% CI, 0.48-1.72]) and NOAC users aged 70 to 79 years (0.64 events/100 person-years versus 0.78 events/100 person-years; weighted hazard ratio , 0.86 [95% CI, 0.68-1.09]), whereas NOAC s were associated with significantly higher dementia rates (2.16 events/100 person-years versus 1.70 events/100 person-years; weighted hazard ratio , 1.31 [95% CI, 1.07-1.59]) in patients 80 years and older. Conclusions This nationwide cohort of patients with atrial fibrillation revealed no clinically meaningful difference in dementia development between users of NOACs or warfarin apart from a higher risk in NOAC users 80 years and older, which may relate to residual confounding from selective prescribing and unobserved comorbidities.

Non-Vitamin K Antagonist Oral Anticoagulants Versus Warfarin in Atrial Fibrillation Patients With Intracerebral Hemorrhage.

Background and Purpose- Recurrent bleeding associated with oral anticoagulants (OACs) causes a dilemma in patients with atrial fibrillation (AF) sustaining an intracerebral hemorrhage. Treatment recommendations guiding clinical practice on optimal OAC agent selection in this population are lacking. This study aimed to investigate the comparative effectiveness and safety of non-vitamin K antagonist OAC (NOAC) versus warfarin in patients with AF sustaining an intracerebral hemorrhage. Methods- We conducted a nationwide observational cohort study including patients with AF sustaining an intracerebral hemorrhage and who subsequently claimed an OAC prescription. Contrasts of 1-year risks for ischemic stroke and intracerebral hemorrhage risks were obtained and evaluated by inverse probability treatment weighted absolute risk reduction and risk ratios. Results- Among 622 AF patients with intracerebral hemorrhage, 274 claimed a warfarin prescription and 348 a NOAC prescription. Mean age was 76 years (39% females); 72% had an index nonsevere event and 28% moderate to severe index event according to the Scandinavian Stroke Severity scale. The 1-year ischemic stroke risk was 7.85% for warfarin and 4.01% for NOACs, with a weighted absolute risk reduction of 3.78% (95% CI, -0.15% to 7.71%); the weighted risk ratio was 0.52 (0.27-1.00). For recurrent intracerebral hemorrhage, the risk was 7.00% for warfarin and 5.07% for NOACs. The absolute risk reduction was 1.93% (-2.02% to 5.87%), with an a weighted risk ratio of 0.72 (0.38-1.38). Conclusions- NOACs were associated with a nonsignificant lower risk of ischemic stroke and recurrent intracerebral hemorrhage compared with warfarin. The results add to current recommendations of selecting a NOAC agent for stroke prophylaxis treatment in patients with AF, including those with sustaining an intracerebral hemorrhage.

Risk of recurrence and bleeding in patients with cancer-associated venous thromboembolism treated with rivaroxaban: A nationwide cohort study.

BACKGROUND: Rivaroxaban could be an attractive alternative to low molecular weight heparin for the treatment of cancer-associated venous thromboembolism (VTE) but the safety and effectiveness remain unclear. We examined risk of recurrent VTE and major bleeding associated with rivaroxaban treatment of cancer-associated VTE. METHODS: Through linkage of nationwide Danish registries, we identified all adults with cancer-associated VTE initiating treatment with rivaroxaban, 2012-2017. We estimated rates and absolute risk of the primary outcome of recurrent VTE and major bleeding; all-cause mortality was studied as a secondary outcome. RESULTS: We identified 8901 patients with cancer-associated VTE of whom 476 (5.3%) redeemed a prescription for rivaroxaban within 30 days of VTE diagnosis (mean age 71.5 years, 41% females, 57% with pulmonary embolism). Median time from cancer diagnosis to rivaroxaban prescription was 31 days (interquartile range 12-73 days). Most frequent cancers were gastrointestinal (26.1%), genitourinary (23.3%), and hematological cancer (12.6%). Few had distant metastases (7.1%). At 6 months, recurrent VTE occurred in 6.1% (15.1 events per 100 person-years) with the highest absolute risks for genitourinary cancer (8.1%), gastrointestinal cancer (7.3%), and breast cancer (6.5%). Major bleeding occurred in 1.9% (5.3 events per 100 person-years), in particular, in genitourinary cancer (4.5%) and lung cancer (4.2%). Eighty deaths (17.8%) occurred during follow up. CONCLUSION: In this clinical practice setting, rivaroxaban was rarely used for cancer-associated VTE. However, among those who received rivaroxaban, the treatment appeared safe and effective with rates comparable to previous studies of selected populations.

Rivaroxaban Versus Warfarin and Risk of Post-Thrombotic Syndrome Among Patients with Venous Thromboembolism.

BACKGROUND: The effectiveness of rivaroxaban to reduce post-thrombotic syndrome in patients with venous thromboembolism is largely unknown. We compared rates of post-thrombotic syndrome in patients given rivaroxaban versus warfarin in a cohort of patients with incident venous thromboembolism receiving routine clinical care. METHODS: We linked Danish nationwide registries to identify all patients with incident venous thromboembolism who were new users of rivaroxaban or warfarin and compared rates of post-thrombotic syndrome using an inverse probability of treatment-weighting approach to account for baseline confounding. RESULTS: We identified 19,957 oral anticoagulation-naive patients with incident venous thromboembolism treated with warfarin or rivaroxaban (mean age, 64 years; 48% were female, 45.5% had pulmonary embolism). The propensity-weighted rate of post-thrombotic syndrome at 3 years follow-up was 0.53 incidents per 100 person-years with rivaroxaban versus 0.55 per 100 person-years with warfarin, yielding a hazard rate of 0.88 (95% confidence interval, 0.66-1.17). This association remained consistent across types of venous thromboembolism (deep venous thrombosis vs pulmonary embolism, and provoked vs unprovoked venous thromboembolism) and when censoring patients with recurrent venous thromboembolism. CONCLUSIONS: In this clinical practice setting, rivaroxaban was associated with lower but statistically nonsignificant rates of post-thrombotic syndrome, which did not appear to be mediated only by an effect on recurrent venous thromboembolism.

The HAS-BLED, ATRIA, and ORBIT Bleeding Scores in Atrial Fibrillation Patients Using Non-Vitamin K Antagonist Oral Anticoagulants.

BACKGROUND: Various bleeding risk scores have been proposed to assess the risk of bleeding in patients with atrial fibrillation taking oral anticoagulants. Limited data are available with these scores, in users of non-vitamin K antagonist oral anticoagulants. METHODS: Using the Danish registries, we evaluated and compared the risk classification properties of the Hypertension, Age, Stroke, Bleeding tendency/predisposition, Labile international normalized ratios, Elderly age/frailty, Drugs such as concomitant aspirin/nonsteroidal anti-inflammatory drugs or alcohol excess (HAS-BLED), Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA), and Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT) scores for predicting major bleeding in 57,930 atrial fibrillation patients (44.6% female; mean age 73.5 years, standard deviation 11.4 years; mean CHA2DS2-VASc score 3.2, standard deviation 1.8). RESULTS: At 1-year follow-up, C-statistics for ATRIA, HAS-BLED, and ORBIT were approximately 0.59, with only minor differences between scores. Both ATRIA and ORBIT categorized more patients as "low risk" (both >83%, when compared with HAS-BLED, only 53%), and qualitatively, the receiver operating characteristic curves revealed higher sensitivity (62.8%) for HAS-BLED compared with ATRIA (29.7%) and ORBIT (37.1%). The clinical usefulness of scores was evaluated using decision curve analyses at a 1-year perspective. If the intervention threshold is low (<1.7%), the benefit is toward monitoring all patients. If preference is for a major bleeding risk threshold between 1.7% and 2.0%, most benefit was obtained by using HAS-BLED. The ORBIT and ATRIA scores provided better benefit for thresholds between 2.0% and 6.0%. CONCLUSION: This analysis of contemporary bleeding risk score stratification in a "real-world" non-vitamin K antagonist oral anticoagulant users population with atrial fibrillation showed modest predictive values using C-statistics. The scores represent different risk thresholds, with HAS-BLED classifying least patients at low risk and achieving the highest benefit if applying a major bleeding intervention threshold of approximately 2%, whereas benefit from using either ATRIA score or ORBIT score was only evident using higher intervention thresholds.

Atrial fibrillation in patients with severe mental disorders and the risk of stroke, fatal thromboembolic events and bleeding: a nationwide cohort study.

OBJECTIVES: Outcomes of atrial fibrillation (AF) in patients with severe mental disorders are largely unknown. We compared rates of stroke, fatal thromboembolic events and bleeding in patients with AF with and without mental disorders. DESIGN: Nationwide registry-based cohort study. SETTING: Denmark (population 5.6 million), 2000-2015. PARTICIPANTS: Patients with AF with schizophrenia (n=534), severe depression (n=400) or bipolar disease (n=569) matched 1:5 on age, sex and calendar time to patients with AF without mental disorders. EXPOSURE: Inpatient or hospital-based outpatient diagnosis of schizophrenia, severe depression or bipolar disease. PRIMARY AND SECONDARY OUTCOME MEASURES: HRs for stroke, fatal thromboembolic events and major bleeding comparing patients with and without mental disorders estimated by Cox regression with sequential adjustment for risk factors for stroke and bleeding, comorbidity and initiation of oral anticoagulant therapy (OAT). RESULTS: Compared with matched comparisons, crude 5-year HRs of ischaemic stroke were 1.37 (95% CI 0.88 to 2.14) for schizophrenia, 1.36 (95% CI 0.89 to 2.08) for depression and 1.04 (95% CI 0.69 to 1.56) for bipolar disease. After adjusting for risk factors, comorbidity and OAT, these HRs declined towards the null. Crude HRs of fatal thromboembolic events were 3.16 (95% CI 1.78 to 5.61) for schizophrenia, 1.31 (95% CI 0.67 to 2.56) for depression and 1.53 (95% CI 0.93 to 2.53) for bipolar disease. Rates of major bleeding were increased in patients with schizophrenia (crude HR 1.37, 95% CI 0.99 to 1.90) and severe depression (HR 1.25, 95% CI 0.87 to 1.78) but not bipolar disease (HR 0.82, 95% CI 0.58 to 1.15). CONCLUSION: Patients with AF with schizophrenia or severe depression experienced increased rates of stroke and major bleeding compared with matched comparisons. This increase was largely explained by differences in the prevalence of risk factors for stroke and bleeding, comorbidity and initiation of OAT during follow-up. Patients with AF with schizophrenia further experienced higher mortality following thromboembolic events than matched comparisons without mental disorders.

Bleeding Complications in Anticoagulated Patients With Atrial Fibrillation and Sepsis: A Propensity-Weighted Cohort Study.

BACKGROUND: Sepsis may adversely affect bleeding risk in anticoagulated patients with atrial fibrillation (AF), but the impact of warfarin treatment in such patients is poorly described. This registry-based nationwide cohort study examined safety of oral anticoagulant treatment (OAC) in patients with preexisting AF who were hospitalized because of incident sepsis in the period 2000-2015. METHODS AND RESULTS: We identified 3030 AF patients who were warfarin users at the time of sepsis diagnosis, and we used inverse probability of treatment weighting to compare the rates of bleeding, thromboembolic events, and death within 90 days after sepsis diagnosis with a comparable cohort of 55721 patients without warfarin treatment and known AF. Weighted 90-day bleeding rates were slightly higher among warfarin users compared with nonusers (0.14 versus 0.12 per 100 person-years), yielding a weighted hazard ratio of 1.19 (95% confidence interval, 1.00-1.41). Thromboembolic event rates during the 90-days after sepsis were marginally higher among warfarin users versus nonusers (0.04 versus 0.03; hazard ratio: 1.25, 95% confidence interval, 0.89-1.76), while the 90-day all-cause mortality was substantially lower among warfarin users (hazard ratio: 0.64, 95% confidence interval, 0.58-0.69). Various sensitivity analyses conducted to challenge the robustness these findings yielded results that were consistent with the main findings. CONCLUSIONS: AF patients who are on warfarin therapy at sepsis diagnosis experienced an increase in bleeding rates within the 3 months following sepsis. Warfarin use was associated with lower mortality, despite virtually comparable thromboembolic event rates.

Effectiveness and Safety of Standard-Dose Nonvitamin K Antagonist Oral Anticoagulants and Warfarin Among Patients With Atrial Fibrillation With a Single Stroke Risk Factor: A Nationwide Cohort Study.

Importance: The randomized clinical trials comparing nonvitamin K antagonist oral anticoagulants (NOACs) vs warfarin largely focused on recruiting high-risk patients with atrial fibrillation with more than 2 stroke risk factors, with only the trials testing dabigatran or apixaban including few patients with 1 stroke risk factor. Despite this, regulatory approvals of all NOACs have been based on stroke prevention for patients with atrial fibrillation with 1 or more stroke risk factors. Objective: To compare the effectiveness and safety study of standard-dose NOACs (dabigatran at 150 mg twice daily, rivaroxaban at 20 mg once daily, and apixaban at 5 mg twice daily) and warfarin in patients with atrial fibrillation with 1 low-risk, nonsex-related stroke risk factor. Design, Setting, and Participants: This nationwide observational cohort study used data from Danish registries to determine the inverse probability of treatment-weighted comparative effectiveness and safety of standard-dose NOACs (dabigatran at 150 mg twice daily, rivaroxaban at 20 mg once daily, and apixaban at 5 mg twice daily) compared with treatment with warfarin among 14 020 patients with atrial fibrillation with 1 low-risk, nonsex- related stroke risk factor. Main Outcomes and Measures: Rates of ischemic stroke/systemic embolism, death, and bleeding. Results: Of 14 020 participants, 5151 (36.7%) were women, and the median age for participants was 66.5 years. For the principal effectiveness end point of ischemic stroke/systemic embolism, no significant differences of the NOACs compared with treatment with warfarin across strata were evident. For the end point of "any bleeding," this was significantly lower for treatment with apixaban (hazard ratio [HR], 0.35; 95% CI, 0.17-0.72) and dabigatran (HR, 0.48; 95% CI, 0.30-0.77) compared with warfarin in the main analysis, and was not significantly different for treatment with rivaroxaban vs warfarin (HR, 0.84; 95% CI, 0.49-1.44). There was broad consistency across most subgroups in the sensitivity analyses and whether 1- or 2.5-year follow-up periods were analyzed. However, falsification end points generally did not falsify, indicating the possible presence of residual confounding across these comparisons, presumably related to selective prescribing and unobserved covariates. Conclusions and Relevance: In this Danish cohort study of patients with atrial fibrillation and a single stroke risk factor, there was no difference between NOACs compared with treatment with warfarin in terms of the risk of having an ischemic stroke/systemic embolism. For "any bleeding," this was lower for treatment with apixaban and dabigatran compared with warfarin. These data do not allow for a definitive statement of the comparative effectiveness or safety of NOACs because of the possible residual confounding that was unmasked with falsification outcomes.

Effectiveness and safety of reduced dose non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study.

Objective To examine clinical effectiveness and safety of apixaban 2.5 mg, dabigatran 110 mg, and rivaroxaban 15 mg compared with warfarin among patients with atrial fibrillation who had not previously taken an oral anticoagulant.Design Propensity weighted (inverse probability of treatment weighted) nationwide cohort study.Setting Individual linked data from three nationwide registries in Denmark.Participants Patients with non-valvular atrial fibrillation filling a first prescription for an oral anticoagulant from August 2011 to February 2016. Patients who filled a prescription for a standard dose non-vitamin K antagonist oral anticoagulant (novel oral anticoagulants, NOACs) were excluded. To control for baseline differences in the population, a propensity score for receipt of either of the four treatment alternatives was calculated to apply an inverse probability treatment weight.Intervention Initiated anticoagulant treatment (dabigatran 110 mg, rivaroxaban 15 mg, apixaban 2.5 mg, and warfarin).Main outcome measures Patients were followed in the registries from onset of treatment for the primary effectiveness outcome of ischaemic stroke/systemic embolism and for the principal safety outcome of any bleeding events.Results Among 55 644 patients with atrial fibrillation who met inclusion criteria, the cohort was distributed according to treatment: apixaban n=4400; dabigatran n=8875; rivaroxaban n=3476; warfarin n=38 893. The overall mean age was 73.9 (SD 12.7), ranging from a mean of 71.0 (warfarin) to 83.9 (apixaban). During one year of follow-up, apixaban was associated with higher (weighted) event rate of ischaemic stroke/systemic embolism (4.8%), while dabigatran, rivaroxaban, and warfarin had event rates of 3.3%, 3.5%, and 3.7%, respectively. In the comparison between a non-vitamin K antagonist oral anticoagulant and warfarin in the inverse probability of treatment weighted analyses and investigation of the effectiveness outcome, the hazard ratios were 1.19 (95% confidence interval 0.95 to 1.49) for apixaban, 0.89 (0.77 to 1.03) for dabigatran, and 0.89 (0.69 to 1.16) for rivaroxaban. For the principal safety outcome versus warfarin, the hazard ratios were 0.96 (0.73 to 1.27) for apixaban, 0.80 (0.70 to 0.92) for dabigatran, and 1.06 (0.87 to 1.29) for rivaroxaban.Conclusion In this propensity weighted nationwide study of reduced dose non-vitamin K antagonist oral anticoagulant regimens, apixaban 2.5 mg twice a day was associated with a trend towards higher rates of ischaemic stroke/systemic embolism compared with warfarin, while rivaroxaban 15 mg once a day and dabigatran 110 mg twice a day showed a trend towards lower thromboembolic rates. The results were not significantly different. Rates of bleeding (the principal safety outcome) were significantly lower for dabigatran, but not significantly different for apixaban and rivaroxaban compared with warfarin.

Comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study.

OBJECTIVE:  To study the effectiveness and safety of the non-vitamin K antagonist oral anticoagulants (novel oral anticoagulants, NOACs) dabigatran, rivaroxaban, and apixaban compared with warfarin in anticoagulant naïve patients with atrial fibrillation. DESIGN:  Observational nationwide cohort study. SETTING:  Three Danish nationwide databases, August 2011 to October 2015. PARTICIPANTS:  61 678 patients with non-valvular atrial fibrillation who were naïve to oral anticoagulants and had no previous indication for valvular atrial fibrillation or venous thromboembolism. The study population was distributed according to treatment type: warfarin (n=35 436, 57%), dabigatran 150 mg (n=12 701, 21%), rivaroxaban 20 mg (n=7192, 12%), and apixaban 5 mg (n=6349, 10%). MAIN OUTCOME MEASURES:  Effectiveness outcomes defined a priori were ischaemic stroke; a composite of ischaemic stroke or systemic embolism; death; and a composite of ischaemic stroke, systemic embolism, or death. Safety outcomes were any bleeding, intracranial bleeding, and major bleeding. RESULTS:  When the analysis was restricted to ischaemic stroke, NOACs were not significantly different from warfarin. During one year follow-up, rivaroxaban was associated with lower annual rates of ischaemic stroke or systemic embolism (3.0% v 3.3%, respectively) compared with warfarin: hazard ratio 0.83 (95% confidence interval 0.69 to 0.99). The hazard ratios for dabigatran and apixaban (2.8% and 4.9% annually, respectively) were non-significant compared with warfarin. The annual risk of death was significantly lower with apixaban (5.2%) and dabigatran (2.7%) (0.65, 0.56 to 0.75 and 0.63, 0.48 to 0.82, respectively) compared with warfarin (8.5%), but not with rivaroxaban (7.7%). For the combined endpoint of any bleeding, annual rates for apixaban (3.3%) and dabigatran (2.4%) were significantly lower than for warfarin (5.0%) (0.62, 0.51 to 0.74). Warfarin and rivaroxaban had comparable annual bleeding rates (5.3%). CONCLUSION:  All NOACs seem to be safe and effective alternatives to warfarin in a routine care setting. No significant difference was found between NOACs and warfarin for ischaemic stroke. The risks of death, any bleeding, or major bleeding were significantly lower for apixaban and dabigatran compared with warfarin.