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Background: Direct oral anticoagulants (DOACs) have been proven to be effective and safe for prevention of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). However, suboptimal adherence, variable dosing and use in patient populations that otherwise would have been excluded from clinical trials may impact the efficacy and safety profile of DOACs in a routine care setting. We compared stroke, bleeding, and mortality rates on and off therapy for standard and low-dose DOACs (apixaban, rivaroxaban, dabigatran) versus warfarin in a Canadian cohort. We also assessed persistence of DOACs compared to warfarin., Methods: We conducted six 1-1 propensity-score matched retrospective cohort analyses using Quebec health administrative databases (2011-2017). NVAF patients (≥18 years) covered by the public medication insurance plan entered the cohort on the first OAC dispensation date. We excluded those with OAC use in the previous year or stroke or bleeding diagnoses in the previous two years. Follow-up ended at death, March 2017 or end of medication coverage by the public plan. Time-dependent Cox regression was applied., Results: We evaluated 10,893 patients initiated on apixaban (7206 standard, 3687 low-dose), 10,190 on rivaroxaban (7396 standard, 2794 low-dose), 5884 on dabigatran (2756 standard, 3128 low-dose), and propensity score-matched warfarin users. Across standard-dose DOACs, compared to warfarin, stroke risks were similar; bleeding risks were lower with apixaban (hazard ratio 0.63; 95% confidence interval 0.52-0.77) and dabigatran (0.47; 0.35-0.64) but not rivaroxaban (0.93; 0.79-1.10); death risks were lower with all DOACs. For low-dose DOACs, rivaroxaban demonstrated higher stroke (1.79; 1.21-2.64) and bleeding risks (1.37; 1.09-1.73); other agents had stroke risks similar to warfarin and bleeding risks lower than warfarin; only low-dose dabigatran had lower death risk (0.59; 0.52-0.68). Treatment discontinuation was lower with DOACs versus warfarin with the exception of low-dose rivaroxaban. The risks of stroke were 2-4 folds higher during time off any OAC versus time on warfarin. The risks of death were higher, while the risks of bleeding were generally lower during times off any OAC., Conclusions: Standard-dose DOACs had similar stroke, better persistence and mortality profiles than warfarin. Only standard dose apixaban and dabigatran had better bleeding profiles than warfarin. Low-dose rivaroxaban had worse persistence, stroke and bleeding profiles than warfarin, while low-dose apixaban and dabigatran had similar stroke and better bleeding profiles. Real-world use of DOACs may explain some of the differences observed in Canadian routine care versus the phase III clinical trials., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: Dabigatran and rivaroxaban are novel oral anticoagulants (NOACs) approved for stroke prevention in atrial fibrillation (AF). Although NOACs are more convenient than warfarin, their lack of monitoring may predispose patients to non-persistence. Limited information is available on NOAC non-persistence rates and related clinical outcomes in clinical practice., Methods: We conducted a retrospective cohort study using administrative data from Ontario, Canada, from January 1998 to March 2014 of patients with AF who were dispensed dabigatran or rivaroxaban. Non-persistence was defined as a gap in dabigatran or rivaroxaban prescriptions ≥14 days. A multivariable Cox proportional hazards model was used to estimate the primary composite outcome of stroke, transient ischaemic attack (TIA) and mortality associated with non-persistence., Results: The cohort consisted of 15 857 dabigatran (age 80.7±6.7 year) and 10 119 rivaroxaban users (age 77.0±7.1 year) with women comprising 52% of each medication group. At 6 months, 36.4% of patients were non-persistent to dabigatran, while 31.9% of patients were non-persistent to rivaroxaban. Stroke/TIA/death was significantly higher for those non-persistent to dabigatran (HR 1.76 (95% CI 1.60 to 1.94); p<0.0001) or rivaroxaban (HR 1.89 (95% CI 1.64 to 2.19); p<0.0001) compared with those who were persistent. Risk of stroke/TIA was markedly higher in non-persistent patients to dabigatran (HR 3.75 (95% CI 2.59 to 5.43); p<0.0001) and rivaroxaban (HR 6.25 (95% CI 3.37 to 11.58); p<0.0001) than those persistent., Conclusions: NOAC non-persistence rates are high in clinical practice, with approximately one in three patients becoming non-persistent to dabigatran or rivaroxaban within 6 months after drug initiation. Non-persistence with either dabigatran or rivaroxaban is significantly associated with worse clinical outcomes of stroke/TIA/death., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

In elderly patients (≥ 75 years), evidence of dabigatran efficacy is lacking and increased vigilance is warranted. We aimed to assess dabigatran effectiveness and safety in elderly patients in real-world practice. We conducted a population-based study using administrative databases, in Quebec (1999-2013). Dabigatran users (110/150 mg) were compared with matched warfarin users with regard to stroke and bleeding events. Age was categorised into < 75 or ≥ 75 years. Propensity score adjusted models were used. The cohort consisted of 15,918 dabigatran users and 47,192 matched warfarin users, with 67.3% being elderly patients. The elderly predominantly used the lower dose (80.1%) while younger patients mainly used the higher dose (80.0%). In multivariable analyses adjusted for propensity score, the risk of stroke in elderly patients using dabigatran, was no different than the risk in warfarin users (HR 1.05, 95% CI: 0.93, 1.19) regardless of dabigatran dose. However, dabigatran was associated with lower rates of intracranial haemorrhage (HR 0.60, 95% CI: 0.47-0.76) and higher rates of gastrointestinal bleeding (HR 1.30 95% CI: 1.14-1.50) when compared to warfarin. Based on real-life experience, dabigatran can offer an alternative to warfarin in elderly patients, with fewer intracranial bleeding events. However, caution is warranted for gastrointestinal bleeding.

Background: Sex differences were observed with regard to warfarin treatment in patients with atrial fibrillation, with women having a higher risk of stroke compared with men. We aimed to compare sex differences in use, safety, and effectiveness of dabigatran., Methods and Results: We conducted a population-based cohort study of patients with atrial fibrillation using administrative data in Quebec, Canada, 1999 to 2013. Men and women who filled a prescription for dabigatran (110 and 150 mg bid) were compared with matched warfarin users with respect to their rates of stroke, bleeding, and myocardial infarction events, using propensity score analysis. The cohort comprised 31 786 women (50.4%) and 31 324 men (49.6%). Women had a higher baseline stroke risk and lower baseline bleeding risk compared with men. Women filled more prescriptions for the lower dabigatran dose compared with men (adjusted OR, 1.35; 95% confidence interval, 1.24-1.48). In multivariable analyses adjusted for propensity scores, dabigatran use was associated with a lower risk of bleeding compared with warfarin in men (P for interaction=0.008). Dabigatran was associated with a trend toward lower risk of stroke in women treated with the 150-mg dose (HR, 0.79; 95% confidence interval, 0.56-1.04), but was not associated with a difference in the risk of myocardial infarction compared with warfarin in either sex., Conclusions: In real-life practice, women are more frequently treated with low-dose dabigatran, yet a trend toward lower stroke rates in women taking high-dose dabigatran was observed. Men benefit from lower bleeding rates with dabigatran compared with warfarin., (© 2015 American Heart Association, Inc.)

Background: Warfarin is an effective agent in the prevention of stroke in patients with atrial fibrillation (AF). However, it requires close monitoring with regular visits to health care facilities. To date, it is unknown whether there is a difference in warfarin utilization and outcomes between urban and rural settings., Methods: We used administrative databases to compare warfarin utilization patterns and stroke and major bleeding outcomes in rural and urban settings in a population-based cohort study of patients ≥ 65 years admitted to hospital with a diagnosis of AF in the province of Quebec, Canada, from 1999 to 2007. Patients' postal codes were used to differentiate between rural and urban settings., Results: The cohort comprised 18,198 rural (21.8%) and 65,315 urban (78.2%) patients, with similar mean age of 79 years and a similar burden of comorbidities. Overall, there was marked underutilization of warfarin in both rural and urban settings. Warfarin-filled prescription rates were slightly higher in the rural setting (adjusted OR: 1.16, 95% CI: 1.12-1.20). In multivariable Cox regression analyses, the risk for stroke and major bleeding in rural settings was similar to that in urban settings (stroke: adjusted HR: 1.01, 95% CI: 0.95-1.09; major bleeding: adjusted HR: 1.03, 95% CI: 0.95-1.12)., Conclusions: Patients in rural settings were slightly more likely to fill a prescription for warfarin, but they experienced similar stroke and major bleeding rates to their urban counterparts., (© 2015 National Rural Health Association.)

Background: Current observational studies on warfarin use and the risk for stroke and bleeding in patients with atrial fibrillation (AF) undergoing dialysis found conflicting results., Methods and Results: We conducted a population-based retrospective cohort study of patients aged ≥65 years admitted to a hospital with a primary or secondary diagnosis of AF, in Quebec and Ontario, Canada from 1998 to 2007. The AF cohort was grouped into dialysis (hemodialysis and peritoneal dialysis) and nondialysis patients and into warfarin and no-warfarin users according to the first prescription filled for warfarin within 30 days after AF hospital discharge. We determined the association between warfarin use and the risk for stroke and bleeding in dialysis and nondialysis patients. The cohort comprised 1626 dialysis patients and 204 210 nondialysis patients. Among dialysis patients, 46% (756/1626) patients were prescribed warfarin. Among dialysis patients, warfarin users had more congestive heart failure and diabetes mellitus, but fewer prior bleeding events in comparison with the no-warfarin users. Among dialysis patients, warfarin use, in comparison with no-warfarin use, was not associated with a lower risk for stroke (adjusted hazard ratio, 1.14; 95% confidence interval, 0.78-1.67) but was associated with a 44% higher risk for bleeding (adjusted hazard ratio, 1.44; 95% confidence interval, 1.13-1.85) after adjusting for potential confounders. Propensity score-adjusted analyses yielded similar results., Conclusions: Our results suggest that warfarin use is not beneficial in reducing stroke risk, but it is associated with a higher bleeding risk in patients with AF undergoing dialysis.

Background: Stroke is a debilitating condition with an increased risk in patients with atrial fibrillation. Although data from clinical trials suggest that both rate and rhythm control are acceptable approaches with comparable rates of mortality in the short term, it is unclear whether stroke rates differ between patients who filled prescriptions for rhythm or rate control therapy., Methods and Results: We conducted a population-based observational study of Quebec patients ≥65 years with a diagnosis of atrial fibrillation during the period 1999 to 2007 with the use of linked administrative data from hospital discharge and prescription drug claims databases. We compared rates of stroke or transient ischemic attack (TIA) among patients using rhythm (class Ia, Ic, and III antiarrhythmics), versus rate control (β-blockers, calcium channel blockers, and digoxin) treatment strategies (either current or new users). The cohort consisted of 16 325 patients who filled a prescription for rhythm control therapy (with or without rate control therapy) and 41 193 patients who filled a prescription for rate control therapy, with a mean follow-up of 2.8 years (maximum 8.2 years). A lower proportion of patients on rhythm control therapy than on rate control therapy had a CHADS(2) (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and previous stroke or TIA) score of ≥2 (58.1% versus 67.0%, P<0.001). Treatment with any antithrombotic drug was comparable in the 2 groups (76.8% in rhythm control versus 77.8% in rate control group). Crude stroke/TIA incidence rate was lower in patients treated with rhythm control in comparison with rate control therapy (1.74 versus 2.49, per 100 person-years, P<0.001). This association was more marked in patients in the moderate- and high-risk groups for stroke according to the CHADS(2) risk score. In multivariable Cox regression analysis, rhythm control therapy was associated with a lower risk of stroke/TIA in comparison with rate control therapy (adjusted hazard ratio, 0.80; 95% confidence interval, 0.74, 0.87). The lower stroke/TIA rate was confirmed in a propensity score-matched cohort., Conclusions: In comparison with rate control therapy, the use of rhythm control therapy was associated with lower rates of stroke/TIA among patients with atrial fibrillation, in particular, among those with moderate and high risk of stroke.

Context: Stroke is a serious complication associated with atrial fibrillation (AF). Women with AF are at higher risk of stroke compared with men. Reasons for this higher stroke risk in women remain unclear, although some studies suggest that undertreatment with warfarin may be a cause., Objective: To compare utilization patterns of warfarin and the risk of subsequent stroke between older men and women with AF at the population level., Design, Setting, and Patients: Population-based cohort study of patients 65 years or older admitted to the hospital with recently diagnosed AF in the province of Quebec, Canada, 1998-2007, using administrative data with linkage between hospital discharge, physicians, and prescription drug claims databases., Main Outcome Measures: Risk of stroke., Results: The cohort comprised 39,398 men (47.2%) and 44,115 women (52.8%). At admission, women were older and had a higher CHADS(2) (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient ischemic attack) score than men (1.99 [SD, 1.10] vs 1.74 [SD, 1.13], P < .001). At 30 days postdischarge, 58.2% of men and 60.6% of women had filled a warfarin prescription. In adjusted analysis, women appeared to fill more warfarin prescriptions compared with men (odds ratio, 1.07 [95% CI, 1.04-1.11]; P < .001). Adherence to warfarin treatment was good in both sexes. Crude stroke incidence was 2.02 per 100 person-years (95% CI, 1.95-2.10) in women vs 1.61 per 100 person-years (95% CI, 1.54-1.69) in men (P < .001). The sex difference was mainly driven by the population of patients 75 years or older. In multivariable Cox regression analysis, women had a higher risk of stroke than men (adjusted hazard ratio, 1.14 [95% CI, 1.07-1.22]; P < .001), even after adjusting for baseline comorbid conditions, individual components of the CHADS(2) score, and warfarin treatment., Conclusion: Among older patients admitted with recently diagnosed AF, the risk of stroke was greater in women than in men, regardless of warfarin use.

Background: Amiodarone is associated with dysfunction of the thyroid. Concerns have arisen regarding the potential for adverse effects with generic formulations of amiodarone. We evaluated and compared the risk of thyroid dysfunction between patients using brand-name versus generic formulations of amiodarone and identified risk factors for thyroid dysfunction., Methods: We conducted a retrospective cohort study of patients with atrial fibrillation aged 66 years and older. We used administrative databases that linked information on demographics and clinical characteristics, claims for prescription drugs and discharges from hospital. We estimated thyroid dysfunction using person-year incidence., Results: Of the 60,220 patients in the cohort, 2804 (4.7%) used the brand-name formulation of amiodarone and 6278 (10.4%) used the generic formulation. Baseline characteristics between these two groups were comparable. The median maintenance dose of amiodarone was 200 mg/d for both groups. The total incidence rate for thyroid dysfunction was 14.1 per 100 person-years for both formulations. The mean time to clinical dysfunction of the thyroid was 4.32 years for the brand-name formulation and 4.09 years for the generic formulation. In a multivariate analysis, there was no significant difference in the incidence rates of thyroid dysfunction between the generic and brand formulations (hazard ratio 0.97, 95% confidence interval 0.87-1.08). Factors associated with an increased risk of thyroid dysfunction were being a woman, increasing age and having chronic obstructive pulmonary disease., Interpretation: In this population-based study, we saw no difference between brand-name and generic formulations of amiodarone in terms of incidence of thyroid dysfunction.

Estimates from clinical trials and small observational studies of the incidence of pulmonary toxicity (PT) associated with amiodarone range from 1% to 10%. We report a unique study of the population-based incidence and potential predictors of PT in a real-world atrial fibrillation (AF) population. We conducted a retrospective cohort study of patients ≥65 years old discharged with AF using linked administrative databases from Quebec, Canada from 1999 to 2007. "Users" and "nonusers" of amiodarone were identified by prescriptions dispensed within 7 days after hospital discharge. PT was defined through International Classification of Diseases, Ninth Revision and Tenth Revision codes for pulmonary fibrosis, alveolar/interstitial lung disease, and adult respiratory distress syndrome. Potential risk factors for PT were identified using multivariable Cox regression. PT occurred in 250 of 6,460 amiodarone users (3.87%) and 676 of 50,993 nonusers (1.33%). Age-standardized PT incidences were 28.30 and 16.02 per 1,000 person-years in men and women users, respectively, and 14.05 and 8.82 per 1,000 person-years in nonusers, respectively. It was associated with amiodarone exposure at all doses (≤200 mg/day, hazard ratio 1.62, 1.35 to 1.96; >200 mg/day, 1.46, 1.22 to 1.75). Other predictors of PT included increasing age (1.01 per year, 1.00 to 1.02), male gender (1.37, 1.19 to 1.57), chronic obstructive pulmonary disease (2.53, 2.21 to 2.89), and renal disease (1.26, 1.06 to 1.50). In conclusion, the population-based incidence of amiodarone PT is in the lower range of what has been previously reported. However, patients with AF who use amiodarone have an approximately 50% higher risk of PT than nonusers. Clinicians may be able to use the present results to identify patients at higher risk for PT and implement strategies to increase monitoring or select alternative therapy., (Copyright © 2011 Elsevier Inc. All rights reserved.)