Oral anticoagulants in patients with atrial fibrillation at low stroke risk: a multicentre observational study.

AIMS: There is currently no consensus on whether atrial fibrillation (AF) patients at low risk for stroke (one non-sex-related CHA2DS2-VASc point) should be treated with an oral anticoagulant. METHODS AND RESULTS: We conducted a multi-country cohort study in Sweden, Denmark, Norway, and Scotland. In total, 59 076 patients diagnosed with AF at low stroke risk were included. We assessed the rates of stroke or major bleeding during treatment with a non-vitamin K antagonist oral anticoagulant (NOAC), a vitamin K antagonist (VKA), or no treatment, using inverse probability of treatment weighted (IPTW) Cox regression. In untreated patients, the rate for ischaemic stroke was 0.70 per 100 person-years and the rate for a bleed was also 0.70 per 100 person-years. Comparing NOAC with no treatment, the stroke rate was lower [hazard ratio (HR) 0.72; 95% confidence interval (CI) 0.56-0.94], and the rate for intracranial haemorrhage (ICH) was not increased (HR 0.84; 95% CI 0.54-1.30). Comparing VKA with no treatment, the rate for stroke tended to be lower (HR 0.81; 95% CI 0.59-1.09), and the rate for ICH tended to be higher during VKA treatment (HR 1.37; 95% CI 0.88-2.14). Comparing NOAC with VKA treatment, the rate for stroke was similar (HR 0.92; 95% CI 0.70-1.22), but the rate for ICH was lower during NOAC treatment (HR 0.63; 95% CI 0.42-0.94). CONCLUSION: These observational data suggest that NOAC treatment may be associated with a positive net clinical benefit compared with no treatment or VKA treatment in patients at low stroke risk, a question that can be tested through a randomized controlled trial.

Non-vitamin K antagonist oral anticoagulants, proton pump inhibitors and gastrointestinal bleeds.

OBJECTIVE: To evaluate if proton pump inhibitor (PPI) treatment reduces the risk of upper gastrointestinal bleeding (UGIB) in patients with atrial fibrillation (AF) treated with non-vitamin K antagonist oral anticoagulants (NOACs). DESIGN: We used a common protocol, common data model approach to conduct a cohort study including patients with AF initiated on a NOAC in Stockholm, Denmark and the Netherlands from April 2011 until July 2018. The outcome of interest was a UGIB diagnosed in a secondary care inpatient setting. We used an inverse probability weighted (IPW) Poisson regression to calculate incidence rate ratios (IRRs), contrasting PPI use to no PPI use periods. RESULTS: In 164 290 NOAC users with AF, providing 272 570 years of follow-up and 39 938 years of PPI exposure, 806 patients suffered a UGIB. After IPW, PPI use was associated with lower UGIB rates (IRR: 0.75; 95% CI: 0.59 to 0.95). On an absolute scale, the protective effect was modest, and was found to be largest in high-risk patients, classified as age 75-84 years (number needed to treat for 1 year (NNTY): 787), age ≥85 years (NNTY: 667), HAS-BLED score ≥3 (NNTY: 378) or on concomitant antiplatelet therapy (NNTY: 373). CONCLUSION: Concomitant treatment with a PPI in NOAC-treated patients with AF is associated with a reduced risk of severe UGIB. This indicates that PPI cotreatment can be considered, in particular among the elderly patients, patients with a HAS-BLED score ≥3, and/or in patients on concomitant antiplatelet therapy.

Persistence and adherence to non-vitamin K antagonist oral anticoagulant treatment in patients with atrial fibrillation across five Western European countries.

AIMS: To assess persistence and adherence to non-vitamin K antagonist oral anticoagulant (NOAC) treatment in patients with atrial fibrillation (AF) in five Western European healthcare settings. METHODS AND RESULTS: We conducted a multi-country observational cohort study, including 559 445 AF patients initiating NOAC therapy from Stockholm (Sweden), Denmark, Scotland, Norway, and Germany between 2011 and 2018. Patients were followed from their first prescription until they switched to a vitamin K antagonist, emigrated, died, or the end of follow-up. We measured persistence and adherence over time and defined adequate adherence as medication possession rate ≥90% among persistent patients only. RESULTS: Overall, persistence declined to 82% after 1 year and to 63% after 5 years. When including restarters of NOAC treatment, 85% of the patients were treated with NOACs after 5 years. The proportion of patients with adequate adherence remained above 80% throughout follow-up. Persistence and adherence were similar between countries and was higher in patients starting treatment in later years. Both first year persistence and adherence were lower with dabigatran (persistence: 77%, adherence: 65%) compared with apixaban (86% and 75%) and rivaroxaban (83% and 75%) and were statistically lower after adjusting for patient characteristics. Adherence and persistence with dabigatran remained lower throughout follow-up. CONCLUSION: Persistence and adherence were high among NOAC users in five Western European healthcare settings and increased in later years. Dabigatran use was associated with slightly lower persistence and adherence compared with apixaban and rivaroxaban.

Greedy caliper propensity score matching can yield variable estimates of the treatment-outcome association-A simulation study.

PURPOSE: Greedy caliper propensity score (PS) matching is dependent on randomness, which can ultimately affect causal estimates. We sought to investigate the variation introduced by this randomness. METHODS: Based on a literature search to define the simulation parameters, we simulated 36 cohorts of different sizes, treatment prevalence, outcome prevalence, treatment-outcome-association. We performed 1:1 caliper and nearest neighbor (NN) caliper PS-matching and repeated this 1000 times in the same cohort, before calculating the treatment-outcome association. RESULTS: Repeating caliper and NN caliper matching in the same cohort yielded large variations in effect estimates, in all 36 scenarios, with both types of matching. The largest variation was found in smaller cohorts, where the odds ratio (OR) ranged from 0.53 to 10.00 (IQR of ORs: 1.11-1.67). The 95% confidence interval was not consistently overlapping a neutral association after repeating the matching with both algorithms. We confirmed these findings in a noninterventional example study. CONCLUSION: Caliper PS-matching can yield highly variable estimates of the treatment-outcome association if the analysis is repeated.

Comparative effectiveness and safety of direct oral anticoagulants versus warfarin in UK patients with atrial fibrillation and type 2 diabetes: A retrospective cohort study.

PURPOSE: To estimate the effectiveness and safety of direct oral anticoagulants (DOACs) compared with warfarin in AF patients with type 2 diabetes (T2DM). METHODS: A retrospective cohort study was designed, using the UK Clinical Practice Research Datalink (August 2011-June 2018). Participants were 1-year naïve users of DOACs or warfarin, followed from the date of first prescription of an oral anticoagulant until the end of the study period, death, discontinuation of treatment, switching to another anticoagulant, or an outcome of interest, whichever came first. Cox regression analysis was performed to estimate the hazard ratio (HR) adjusted for potential confounders. RESULTS: A total of 8555 patients were identified. No significant differences were found between DOACs and warfarin in the risk of stroke (adjusted HR 1.15; 95% CI 0.82-1.60), ischemic and unspecified stroke (adjusted HR 1.23; 95% CI 0.86-1.76) or haemorrhagic stroke (adjusted HR 0.75; 95% CI 0.30-1.85), and myocardial infarction (adjusted HR 1.39;95% CI 0.99-1.97). DOAC and warfarin users were comparable with respect to risk of major bleed (adjusted HR 0.83; 95% CI 0.68-1.03), intracranial bleeding (HR 0.66; 95% CI 0.34-1.30), gastrointestinal bleeding (HR 0.88; 95% CI 0.60-1.30), and bleeding on other clinically relevant sites (HR 0.89; 95% CI 0.60-1.31). In the subgroup analyses stratified by gender and diabetes severity, the risk for stroke and bleeding remained consistent. CONCLUSION: DOACs are effective and safe alternatives to warfarin for the prevention of stroke in AF patients with T2DM.

Association of preceding antithrombotic therapy in atrial fibrillation patients with ischaemic stroke, intracranial haemorrhage, or gastrointestinal bleed and mortality.

AIMS: To analyse 90-day mortality in atrial fibrillation (AF) patients after a stroke or a severe bleed and assess associations with the type of antithrombotic treatment at the event. METHODS AND RESULTS: From the Stockholm Healthcare database, we selected 6017 patients with a known history of AF who were diagnosed with ischaemic stroke, 3006 with intracranial haemorrhage, and 4291 with a severe gastrointestinal bleed (GIB). The 90-day mortality rates were 25.1% after ischaemic stroke, 31.6% after intracranial haemorrhage, and 16.2% after severe GIB. We used Cox regression and propensity score-matched analyses to test the association between antithrombotic treatment at the event and 90-day mortality. After intracranial haemorrhage, there was a significantly higher mortality rate in warfarin compared to non-vitamin K oral anticoagulant (NOAC)-treated patients [adjusted hazard ratio (aHR) 1.36, 95% confidence interval (CI) 1.04-1.78]. After an ischaemic stroke and a severe GIB, patients receiving antiplatelets or no antithrombotic treatment had significantly higher mortality rates compared to patients on NOACs, but there was no difference comparing warfarin to NOACs (aHR 0.84, CI 0.63-1.12 after ischaemic stroke, aHR 0.91, CI 0.66-1.25 after severe GIB). Propensity score-matched analysis yielded similar results. CONCLUSION: Mortality rates were high in AF patients suffering from an ischaemic stroke, an intracranial haemorrhage, or a severe GIB. NOAC treatment was associated with a lower 90-day mortality after intracranial haemorrhage than warfarin.

Long-term persistence and adherence with non-vitamin K oral anticoagulants in patients with atrial fibrillation and their associations with stroke risk.

AIMS: Studies on adherence and persistence with non-vitamin K oral anticoagulant (NOAC) treatment have relied on data from the early years of NOAC availability. We aimed to study long-term adherence and persistence with NOACs and their association with stroke risk. METHODS AND RESULTS: From the Stockholm Healthcare database, we included 21 028 atrial fibrillation patients claiming a first NOAC prescription from July 2011 until October 2018, with more than 1000 patients having more than 5 years of follow-up (median: 2.0, interquartile range: 1.0-3.2). Persistence rates, defined as continuing to claim NOAC prescriptions within a 90-day gap, decreased to 70% at the end of follow-up. However, 85% of the patients were treated at the end of the study due to reinitiations. Adherence, calculated as medication possession rate (MPR) in 3 and 6-month intervals among persistent users, remained stable at 90%, with 75% of patients having an MPR >95% throughout the study period. Using a case-control design, we calculated associations of persistence and adherence with stroke risk, adjusting for potential confounders. The outcome was a composite of ischaemic or unspecified stroke and transient ischaemic attack. Non-persistence and poor adherence were both associated with increased stroke risk [non-persistence adjusted odds ratio (aOR): 2.05; 95% confidence interval (CI): 1.49-2.82, 1% reduction MPR aOR: 1.03; CI: 1.01-1.05]. There was no association between non-persistence or poor adherence and the falsification endpoints; fractions and respiratory infections, indicating no 'healthy-adherer' effect. CONCLUSION: Persistence rates decreased slowly over time, but persistent patients had high adherence rates. Both non-persistence and poor adherence were associated with an increased stroke risk.

Concomitant Anticoagulant and Antidepressant Therapy in Atrial Fibrillation Patients and Risk of Stroke and Bleeding.

We aimed to quantify the effects of antidepressant (AD) use in oral anticoagulant (OAC)-treated patients with atrial fibrillation (AF). Using the Stockholm Healthcare database, we analyzed AF patients initiated with an OAC. Outcomes were severe bleeds and strokes and were analyzed using Cox models. We included 17,210 patients claiming warfarin and 13,385 claiming a non-vitamin K OAC. The number of patients that claimed an AD during follow-up was 4,303. Concomitant OAC and AD use was associated with increased rates of severe bleeds (4.7 vs. 2.7 per 100 person-years) compared with OAC treatment alone (adjusted hazard ratio (aHR) 1.42, confidence interval (CI): 1.12-1.80), but not significantly associated with increased stroke rates (3.5 vs. 2.1 per 100 person-years, aHR 1.23, CI: 0.93-1.62). No significant differences in risks were observed between different OAC classes or different AD classes. In conclusion, concomitant use of an OAC and an AD is associated with an increased bleeding risk.

Eliminated patient fee and changes in dispensing patterns of asthma medication in children-An interrupted time series analysis.

In 2016, all prescription drugs included in the reimbursement system in Sweden were made available for children (age 0-17 years) without any patient fees. Our aim was to estimate the association between this intervention and the dispensing patterns of asthma medications among children. Dispensing data on asthma medications for all children living in Stockholm County during 2014-2017 were selected to include two years before (January 2014-December 2015) and after (January 2016-December 2017) the intervention. In an uncontrolled before and after study, the measures of utilization were as follows: the proportion of children with at least one dispensed asthma medication (prevalence); the number of children initiated on treatment after an 18-month drug-free period (incidence); the number of defined daily doses (DDDs) dispensed per child; and the number of children with at least two prescriptions with controller medication (inhaled corticosteroid or leukotriene receptor antagonist) dispensed during 18 months (persistence). In an interrupted time series (ITS) analysis, all measures were included except for persistence. Socio-economic status was defined using Mosaic data. The prevalence increased after the intervention (from 11.9% to 13.0%). However, the ITS analysis showed a positive trend already before the intervention, and consequently, the increase was not attributable to the intervention. For incidence, similar patterns were observed. There was an increase in dispensed volumes related to the intervention, 46.3 DDDs/child/month before and 51.1 after the intervention (P-value 0.01). The proportion of children with persistent asthma medication increased from 46.0% to 51.9% in children with low socio-economic status. In conclusion, the intervention was only modestly associated with changes in the dispensing patterns of asthma medication, with the volume dispensed per child increasing slightly, particularly in children with low socio-economic status.

Improved Stroke Prevention in Atrial Fibrillation After the Introduction of Non-Vitamin K Antagonist Oral Anticoagulants.

Background and Purpose- The purpose of this study was to investigate the impact of improved antithrombotic treatment in atrial fibrillation after the introduction of non-vitamin K antagonist oral anticoagulants on the incidence of stroke and bleeding in a real-life total population, including both primary and secondary care. Methods- All resident and alive patients with a recorded diagnosis for atrial fibrillation during the preceding 5 years in the Stockholm County Healthcare database (Vårdanalysdatabasen) were followed for clinical outcomes during 2012 (n=41 008) and 2017 (n=49 510). Results- Pharmacy claims for oral anticoagulants increased from 51.6% to 73.8% (78.7% among those with CHA2DS2-VASc ≥2). Non-vitamin K antagonist oral anticoagulant claims increased from 0.4% to 34.4%. Ischemic stroke incidence rates decreased from 2.01 per 100 person-years in 2012 to 1.17 in 2017 (incidence rate ratio, 0.58; 95% CI, 0.52-0.65). The largest increases in oral anticoagulants use and decreases in ischemic strokes were seen in patients aged ≥80 years who had the highest risk of stroke and bleeding. The incidence rates for major bleeding (2.59) remained unchanged (incidence rate ratio, 1.00; 95% CI, 0.92-1.09) even in those with a high bleeding risk. Poisson regression showed that 10% of the absolute ischemic stroke reduction was associated with increased oral anticoagulants treatment, whereas 27% was related to a generally decreased risk for all stroke. Conclusions- Increased oral anticoagulants use contributed to a marked reduction of ischemic strokes without increasing bleeding rates between 2012 and 2017. The largest stroke reduction was seen in elderly patients with the highest risks for stroke and bleeding. These findings strongly support the adoption of current guideline recommendations for stroke prevention in atrial fibrillation in both primary and secondary care.

Valproic acid utilization among girls and women in Stockholm: Impact of regulatory restrictions.

OBJECTIVE: In November 2014, the European Medicines Agency (EMA) strengthened restrictions on the use of valproic acid in girls and women of childbearing potential. The objective of this study was to determine whether there has been a change in initiations of valproic acid treatment to females after the regulatory restrictions and to assess if such changes differed between indications (epilepsy and psychiatric disorder). METHODS: An interrupted time-series analysis was conducted using all initiations of valproic acid in Stockholm, Sweden. from January 2011 to June 2017. Female and male patients aged 0-45 years with a recorded diagnosis of epilepsy and/or a psychiatric disorder were compared. RESULTS: Before the EMA warning, a decline in trend of valproic acid initiations was seen in patients with epilepsy. After the warning, a significant decrease of valproic acid initiations was seen in women with a psychiatric disorder, but not in women with epilepsy. SIGNIFICANCE: The regulatory warning appeared to have significantly influenced valproic acid initiations in women of childbearing age with a psychiatric disorder. No effect was seen in women with epilepsy, probably because the decline had started long before.

The changing multiple sclerosis treatment landscape: impact of new drugs and treatment recommendations.

PURPOSE: The purpose of this study is to describe the utilization of disease-modifying treatments (DMTs) in relapsing-remitting multiple sclerosis (MS) and assess the impact of both the introduction of new drugs and treatment recommendations (local recommendation on rituximab use issued at the largest MS clinic in Stockholm and regional Drug and Therapeutics Committee (DTC) recommendation on how dimethyl fumarate should be used). METHODS: Interrupted time series analyses using monthly data on all MS patients treated with DMTs in the Stockholm County, Sweden, from January 2011 to December 2017. RESULTS: There were 4765 individuals diagnosed with MS residing in the Stockholm County from 2011 to 2017. Of these, 2934 (62%) were treated with an MS DMT. Since 2011, fingolimod, alemtuzumab, teriflunomide, dimethyl fumarate, peginterferon beta-1a, and daclizumab were introduced. Only fingolimod and dimethyl fumarate significantly impacted MS DMT utilization. In parallel, the use of rituximab off-label increased steadily, reaching 58% of all DMT-treated MS patients by the end of the study period. The local recommendation on rituximab was associated with an increase in rituximab use. The regional DTC recommendation on dimethyl fumarate was associated with a decrease in dimethyl fumarate use. CONCLUSIONS: Three MS DMTs-fingolimod, dimethyl fumarate, and rituximab off-label-impacted MS DMT utilization in the Stockholm County. The associations between the treatment recommendations and the subsequent changes in MS DMT utilization indicate that such interventions can influence the uptake and utilization of new drugs used in the specialized care setting.

Factors associated with antithrombotic treatment decisions for stroke prevention in atrial fibrillation in the Stockholm region after the introduction of NOACs.

PURPOSE: The purpose of this study was to investigate the influence of patient characteristics such as age and stroke and bleeding risks on decisions for antithrombotic treatment in patients with atrial fibrillation (AF). METHODS: This was a retrospective, population-based study including AF patients initiated with either warfarin, dabigatran, rivaroxaban, apixaban, or low-dose aspirin (ASA) between March 2015 and February 2016. Multivariate models were used to calculate adjusted odds ratios (aOR) for factors associated with treatment decisions. RESULTS: A total of 6765 newly initiated patients were included, most with apixaban (46.4%) and least with ASA (6.7%). There were more comorbidities in patients initiated with ASA or warfarin compared to the cohort average. Patients with high stroke risks had higher chances of receiving ASA (CHA2DS2-VASc ≥5 vs 0; aOR 2.01; 95% confidence interval (CI) 1.12-3.33). Among patients receiving oral anticoagulants, patients with high bleeding risks more often received warfarin (ATRIA score 5-10 vs 0-3; aOR 1.40; CI 1.20-1.64). Among NOACs, apixaban was preferred for patients with higher stroke risks (aOR 1.78; CI 1.31-2.41), high bleeding risks (aOR 1.54; CI 1.26-1.88) and high age (age group ≥85 vs 0-65; aOR 1.84; CI 1.44-2.35). Conversely, dabigatran treatment was associated with lower ages and lower risks. CONCLUSIONS: High stroke and bleeding risks favored choices of warfarin or ASA. Among patients receiving NOACs, apixaban was favored for elderly and high-risk patients whereas dabigatran was used in lower risk patients. The inadvertent use of ASA, especially among those with high stroke risks, should be further discouraged.

Effects of policy interventions on the introduction of novel oral anticoagulants in Stockholm: an interrupted time series analysis.

AIMS: The aim of the present study was to assess the effect of policy interventions - i.e. reimbursement decisions, guidelines and regional recommendations - on the prescribing of oral anticoagulant treatment in patients with atrial fibrillation (AF). METHODS: Interrupted time series analyses were carried out using monthly data on all patients with a recorded diagnosis of AF newly initiated (switchers and anticoagulant-naïve patients alike) on warfarin, dabigatran, rivaroxaban or apixaban in the Stockholm region from April 2011 until February 2016. RESULTS: A total of 34 165 initiations in 27 942 patients were included. The publication of the European Guidelines was associated with an increase in novel oral anticoagulant (NOAC) initiations of 12.5% [95% confidence interval (CI) 7.3, 17.7] after 5 months. The choice between the different NOACs was mainly associated with changes in the regional recommendations, with apixaban initiations increasing by 19.5% (95% CI 16.3, 22.7) 5 months after the drug was recommended as a first-line alternative to warfarin. Dabigatran received a second-line recommendation but initiations decreased by -9.5% (95% CI -12.6, -6.4), and initiations of rivaroxaban, which had no specific recommendation, decreased by -9.2% (95% CI -12.7, -5.7). A steady decrease in warfarin and increase in NOAC initiations was seen throughout the study period and from November 2015, AF patients were more likely to receive apixaban than any other anticoagulant, while less than 20% of the initiations were with warfarin. CONCLUSIONS: After reimbursement and inclusion in the European guidelines, the NOACs started gaining in popularity, while changes in regional recommendations were associated with the biggest change in prescribers' choice between the different NOACs.