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Introduction: Direct oral anticoagulants (DOACs) used in nonvalvular atrial fibrillation (NVAF) are superior or non-inferior to warfarin in reducing the risk of stroke while at the same time having a similar or lower risk of bleeding. However, reduced doses are prescribed more often than expected from clinical practice and off-label underdosing is a frequent issue. The objective of this study was to compare effectiveness and safety between guideline and off-label dosing of DOACs.

Materials and methods: Auricula, a Swedish anticoagulation registry was used in identifying eligible patients from July 2011 to December 2017. The study cohort consisted of 47,355 patients with newly initiated DOAC (apixaban, dabigatran, or rivaroxaban) after exclusion of 92,316 patients due to concomitant venous thromboembolism, previous mechanical heart valve (MHV) or previous data entry in Auricula. The median durations of follow up were 403, 419, 373 and 209 days in the on-label standard dose cohort, off-label reduced dose cohort, on-label reduced dose cohort and the off-label standard dose cohort respectively. Endpoints (stroke and major bleeding) and baseline characteristics were collected from hospital administrative registers using ICD-10 codes or the Swedish Stroke register. Cohorts were compared using weighted adjusted Cox regression after full optimal matching based on propensity scores.

Results: Off-label underdosing of DOACs (n = 6,187, 9.7 %) was associated with higher risk of major bleeding HR 1.16 (95 % CI 1.05–1.27), other bleeding HR 1.16 (1.04–1.30), myocardial infarction HR 1.47 (1.20–1.80), ischemic stroke HR 1.25 (1.04–1.50) and all-cause mortality HR 1.52 (1.37–1.69) compared to on-label standard dosing (n = 35,065, 55.2 %). Among off-label underdosed DOACs, dabigatran was associated with higher risk of all-cause stroke 1.86 (1.07–3.23), ischemic stroke HR 1.97 (1.10–3.52) and all-cause stroke and systemic embolism HR 1.92 (1.11–3.32) compared to apixaban. Rivaroxaban was associated with major bleeding HR 1.70 (1.41–2.03), gastrointestinal bleeding HR 1.92 (1.33–2.77), and other bleeding HR 1.97 (1.57–2.47) compared to apixaban. The study could not show any differences comparing off-label overdosing of DOACs and on-label reduced dosing, besides lower risk of all-cause mortality HR 0.69 (0.52–0.93) in the overdosed patients.

Conclusions: In this large observational registry-based NVAF cohort, underdosing of DOACs is associated with higher risk of ischemic and all-cause stroke but also major bleeding when compared to on-label dosing. Underlying DOAC therapy may need to be tailored to the specific patient when choosing off-label reduced dosing since underdosed rivaroxaban is associated with higher risk of bleeding complications, and underdosed dabigatran is associated with higher risk of stroke complications, when comparing both with apixaban.

Rationale: The use of direct oral anticoagulants (DOACs) as stroke prophylaxis in patients with non-valvular atrial fibrillation (NVAF) has increased steadily since the introduction in 2011. In Sweden today, more patients are treated with DOACs than with warfarin. However, it is not shown that an increased proportion of DOAC prescriptions correlates to lower event rates of stroke and systemic embolism.

Objectives: This study aims to investigate whether the increased prescription of DOACs in Sweden correlates with lower event rates for all-cause stroke, systemic embolism and bleeding complications, using real-life data for the whole NVAF population.

Design: Nationwide retrospective register study.

Setting: Data were obtained from the Swedish National Patient Registry, covering patients aged 18 years or older with NVAF, between 1 January 2014, and 31 December 2017. Exposure to oral anticoagulants was determined based on pharmaceutical data, calculating treatment duration by the number of pills dispensed and the prescribed daily usage rate. Baseline characteristics and endpoints were collected from hospital administrative registers using International Classification of Diseases, 10th edition (ICD-10) codes.

Participants: All patients with NVAF were identified using ICD-10 codes during the study period. Entry criteria included having a first recorded atrial fibrillation diagnosis after 1 January 2014 or being previously diagnosed with atrial fibrillation before 2014 but still receiving care after this date.

Outcome measures: The outcomes were event rates (per 100 person-years) of ischaemic stroke, systemic embolism, all-cause stroke, major bleeding and intracranial bleeding (including haemorrhagic stroke). Event rates were calculated and compared across the study period using Cox proportional hazard models.

Results: In the total NVAF population, the proportional decrease in event rates (per 100 treatment years) in 2017 compared with 2014 was ischaemic stroke 24% (1.70-1.30), all-cause mortality 4% (9.40-9.00), all-cause stroke 24% (2.10-1.60) and all-cause stroke and systemic embolism 23% (2.20-1.70). During the same time, the proportion of major bleeding and intracranial bleeding rates, including haemorrhagic stroke, also decreased: 5% (2.00-1.90), 6% (0.68-0.64) and 17% (0.30-0.25), respectively. DOACs use increased from 4.1% to 28.3% in the total population and from 22.7% to 60.9% in newly diagnosed patients.

Conclusions: In the initial years following the introduction when DOAC uptake in the population was high, an increasing proportion of Swedish NVAF patients receiving DOACs was accompanied by lower event rates of all-cause stroke and systemic embolism, ischaemic stroke and all-cause mortality, intracranial bleeding and major bleeding, highlighting the improved risk-benefit balance of DOACs in stroke prophylaxis.

Introduction: Tenecteplase (TNK-tPA) has several benefits over alteplase (tPA) in treatment of acute ischaemic stroke. Randomised controlled trials have shown promising results. In June 2017, the Stroke Unit at Sundsvall County Hospital switched from tPA to TNK-tPA in standard clinical practice. This study examines the effects of that shift.

Methods: All thrombolysis treatments performed during the first twenty-four months with TNK-tPA (168) were compared to the last twenty-four months with tPA (191). Data were collected from patient records. Follow-up time was 30 days. Co-primary outcomes were death and symptomatic intracranial haemorrhage (SICH). Secondary outcomes were types of intracerebral bleeding and cause of death. Tertiary outcome was door-to-needle time (DNT).

Results: Treatment groups were of comparable age (75.7 ± 0.2 years). tPA-treated patients had an NIHSS (National Institutes of Health Stroke Scale) score of 9.2 versus 7.5 for TNK-tPA. Patients older than 80 had more severe strokes (median NIHSS 9 versus 5). SICH occurred in 6 (3.6 %) patients in the TNK-tPA group and in 2 (1.0 %) treated with tPA, odds ratio (OR) 3.41 (0.70–16.7). Numbers for death were 21 (12.5 %) and 31 (15.2 %), OR 0.77 (0.46–1.29), meaning no statistically significant differences in primary outcomes. There were no significant differences in secondary outcomes. Predominant cause of death was cerebral infarction. DNT with tenecteplase was shorter: mean 44 versus 26, and median 35 versus 19 min.

Conclusions: Switching from alteplase to tenecteplase was associated with shorter time to treatment. To draw certain conclusions regarding safety or efficacy would require a larger material.

Direct oral anticoagulants (DOACs) used in nonvalvular atrial fibrillation (NVAF) are dose-reduced in elderly and patients with impaired renal function. Only reduced dose dabigatran is concluded as having similar stroke risk reduction and lower risk of major bleeding than warfarin in the pivotal studies. In clinical practice, reduced dose is prescribed more often than expected making this an important issue. The objective of this study was to compare effectiveness and safety between reduced dose DOACs and high TTR warfarin treatment (TTR ≥ 70%) in NVAF. A Swedish anticoagulation registry was used in identifying eligible patients from July 2011 to December 2017. The study cohort consisted of 40,564 patients with newly initiated DOAC (apixaban, dabigatran, or rivaroxaban) (11,083 patients) or warfarin treatment (29,481 patients) after exclusion of 374,135 patients due to not being warfarin or DOAC naïve, not being prescribed reduced dose, having previous mechanical heart valve (MHV), or being under 18 years old. The median durations of follow up were 365, 419, 432 and 473 days for apixaban, dabigatran, rivaroxaban and warfarin, respectively. Warfarin TTR identified from Auricula was 70.0%. Endpoints (stroke and major bleeding) and baseline characteristics were collected from hospital administrative registers using ICD-10 codes. Cohorts were compared using weighted adjusted Cox regression after full optimal matching based on propensity scores. DOACs are associated with lower risk of major bleeding (HR with 95% CI) 0.85 (0.78–0.93), intracranial bleeding HR 0.64 (0.51–0.80), hemorrhagic stroke HR 0.68 (0.50–0.92), gastrointestinal bleeding HR 0.81 (0.69–0.96) and all-cause stroke HR 0.87 (0.76–0.99), than warfarin. Apixaban and dabigatran are associated with lower risk of major bleeding, HR 0.70 (0.63–0.78) and HR 0.80 (0.69–0.94), and rivaroxaban is associated with lower risk of ischemic stroke, HR 0.73 (0.59–0.96), with higher major bleeding risk, HR 1.31 (1.15–1.48), compared to warfarin. Apixaban is associated with higher all-cause mortality compared to warfarin, HR 1.12 (1.03–1.21). DOACs are associated with lower risk of major bleeding and all-cause stroke, than high quality warfarin treatment, with exception of rivaroxaban that carried higher risk of major bleeding and lower risk of stroke or systemic embolism. In this large observational registry-based NVAF cohort, DOACs are preferred treatment in patients with indication for DOAC dose reduction, even in a high TTR setting.

Warfarin is well studied in patients with non-valvular atrial fibrillation (AF). It has low complication rates for patients achieving individual Time in Therapeutic Range (iTTR)>70%. The risk scores SAMe-TT2R2 and PROSPER are designed to predict future TTR, but are derived from a heterogeneous population with generally low iTTR. The aim of this study was to evaluate predictors for high and low iTTR in an AF population in Sweden, where there is a generally good anticoagulation control. A retrospective register study based on Swedish warfarin dosing system AuriculA, including 28,011 AF patients starting treatment during 1 January 2006 to 31 December 2011. Complications and risk factors were analysed and related to iTTR. Mean age was 73.7 (SD +/- 9.5) years, with 42.0% women. Mean CHA(2)DS(2)-VASc score (SD) was 3.6 (+/- 1.7). For patients with iTTR<60% there were over three times higher prevalence of excessive alcohol consumption than for patients with iTTR>70% (3.7% vs. 1.1%). Previous stroke were more prevalent for patients with high than low iTTR (17.1% vs. 20.3%). Concomitant comorbidities were associated with increased risk of poor iTTR. In Swedish AF patients, excessive alcohol use is clearly associated with iTTR below 60%. Patients with previous stroke are more likely to get iTTR above 70%, unlike those with concomitant disorders who more often have poor anticoagulation control. The SAMe-TT2R2-score cannot be applied in Sweden.

IMPORTANCE: Vitamin K antagonist (eg, warfarin) use is nowadays challenged by the non-vitamin K antagonist oral anticoagulants (NOACs) for stroke prevention in atrial fibrillation (AF). NOAC studies were based on comparisons with warfarin arms with times in therapeutic range (TTRs) of 55.2% to 64.9%, making the results less credible in health care systems with higher TTRs.

OBJECTIVES: To evaluate the efficacy and safety of well-managed warfarin therapy in patients with nonvalvular AF, the risk of complications, especially intracranial bleeding, in patients with concomitant use of aspirin, and the impact of international normalized ratio (INR) control.

DESIGN, SETTING, AND PARTICIPANTS: A retrospective, multicenter cohort study based on Swedish registries, especially AuriculA, a quality register for AF and oral anticoagulation, was conducted. The register contains nationwide data, including that from specialized anticoagulation clinics and primary health care centers. A total of 40 449 patients starting warfarin therapy owing to nonvalvular AF during the study period were monitored until treatment cessation, death, or the end of the study. The study was conducted from January 1, 2006, to December 31, 2011, and data were analyzed between February 1 and November 15, 2015. Associating complications with risk factors and individual INR control, we evaluated the efficacy and safety of warfarin treatment in patients with concomitant aspirin therapy and those with no additional antiplatelet medications.

EXPOSURES: Use of warfarin with and without concomitant therapy with aspirin.

MAIN OUTCOMES AND MEASURES: Annual incidence of complications in association with individual TTR (iTTR), INR variability, and aspirin use and identification of factors indicating the probability of intracranial bleeding.

RESULTS: Of the 40 449 patients included in the study, 16 201 (40.0%) were women; mean (SD) age of the cohort was 72.5 (10.1) years, and the mean CHA2DS2-VASc (cardiac failure or dysfunction, hypertension, age ≥75 years [doubled], diabetes mellitus, stroke [doubled]-vascular disease, age 65-74 years, and sex category [female]) score was 3.3 at baseline. The annual incidence, reported as percentage (95% CI) of all-cause mortality was 2.19% (2.07-2.31) and, for intracranial bleeding, 0.44% (0.39-0.49). Patients receiving concomitant aspirin had annual rates of any major bleeding of 3.07% (2.70-3.44) and thromboembolism of 4.90% (4.43-5.37), and those with renal failure were at higher risk of intracranial bleeding (hazard ratio, 2.25; 95% CI, 1.32-3.82). Annual rates of any major bleeding and any thromboembolism in iTTR less than 70% were 3.81% (3.51-4.11) and 4.41% (4.09-4.73), respectively, and, in high INR variability, were 3.04% (2.85-3.24) and 3.48% (3.27-3.69), respectively. For patients with iTTR 70% or greater, the level of INR variability did not alter event rates.

CONCLUSIONS AND RELEVANCE: Well-managed warfarin therapy is associated with a low risk of complications and is still a valid alternative for prophylaxis of AF-associated stroke. Therapy should be closely monitored for patients with renal failure, concomitant aspirin use, and poor INR control.

Background and Aim

Warfarin treatment discontinuation is significant among patients with atrial fibrillation (AF). Studies mainly focused on whether the proportion of warfarin persistence and discontinuationare clinically appropriate are absent. This study evaluates warfarin persistence with focus on predictors for, and reasons to, warfarin discontinuation in AF patients.

Methods

From the national quality register AuriculA, all AF patients in Sundsvall, Sweden, on warfarin treatment on January first, 2010 were included. These 478 patients were followed until discontinuation or study-stop December 31, 2013. By going through each patient’s medical record risk factors for thromboembolism, bleeding and causes of discontinuation were obtained.

Results

Proportion of warfarin persistence was 0.91 (95% confidence interval (CI) 0.89 to 0.93) after one year and 0.73 (95% CI 0.69 to 0.77) after four years. Previous intracranial bleeding, excessive alcohol use, anemia and pulmonary or peripheral emboli were each associated with over two times higher risk of discontinuation (hazard ratio (HR) 5.66, CI 2.23-14.36, HR 2.54, CI 1.48-4.37, HR 2.40, CI 1.38-4.17, and HR 2.13, CI 1.02-4.46). Among patients discontinuing, 50.5% were due to questionable causes, such as sinus rhythm (33.9%), patients demand (10.1%) and falls (8.2%). The majority (43.1%) of treatment discontinuers were changed to aspirin, while 40.4% of them were left without medical stroke prophylaxis.

Conclusions

Although persistence to warfarin among AF patients proves higher than previously reported, there is room for improvement since half of the discontinuers have questionable reasons for treatment stop and the majority of them receive no other efficient stroke prophylaxis.

Background

Ischemic stroke is a serious condition often associated to presence of atrial fibrillation (AF). Use of anticoagulants for AF patients greatly reduces the risk of stroke. Warfarin is the most commonly used anticoagulant in Sweden. The aim of this thesis was to study the impact of warfarin treatment quality in Swedish stroke prevention.

Methods

Study I, II and IV were relatively large multicentre, retrospective, cohort studies based on Swedish registries, especially AuriculA, a quality register for AF and anticoagulation. Background data as well as bleeding and thromboembolic complications were retrieved from the National Patient Register. The Cause of Death Register was used in study II and IV. The Swedish Prescribed Drug Register was used in study IV, for data on concomitant acetylsalicylic acid (ASA) use. Study period was January 1, 2006, to December 31, 2011. Study III enrolled all warfarin treated AF patients in Sundsvall, registered in AuriculA on January 1, 2010. This smaller cohort was followed until discontinuation or study-stop December 31, 2013. All used data were collected from each patient’s medical record.

Results

The annual risk of major bleedings and thromboembolic events for warfarin treated patients, including all different indications for warfarin, was relatively low (2.24% and 2.66%), with incidence of intracranial bleeding of 0.37% per treatment year. The overall mean time in therapeutic range (TTR) was 76.5%. Patients started on warfarin due to AF had a mean TTR of 68.6%, with an annual risk of major bleeding and thromboembolic events of 2.23% and 2.95%, and with 0.44% annual risk of intracranial bleeding. No significant differences in overall complications were found when comparing treatment monitored in anticoagulation clinics (ACC) with treatment monitored in primary health care centers (PHCC). There were significantly increased risk of both overall major bleedings and thromboembolic events for those warfarin treated AF patients receiving additional ASA treatment, having individual TTR (iTTR) below 70%, or having high international normalized ratio (INR) variability. AF patients with low INR variability had generally lower complication rates, compared with patients with high INR variability. There were however no alteration on cumulative incidence of complications due to INR variability, for AF patients with iTTR ≥70%. The overall proportion of persistence to warfarin treatment for stroke patients with AF was found to be 0.69 after 2 years treatment and 0.47 after 5 years. Stroke patients with diagnosed dementia at baseline were more than two-times likely of discontinuing warfarin than others. Excessive alcohol use, chronic obstructive pulmonary disease, cancer and chronic heart failure were baseline diagnoses each associated with over 20% increased risk of treatment discontinuation. Lower persistence to treatment was linked to increasing start-age and CHA2DS2-VASc scores. As documented reasons for warfarin treatment discontinuation in AF patients, we found regained sinus rhythm as the most common addressed cause (31.2%), followed by problematic monitoring and bleedings. We estimated that only half (49.5%) of the treatment discontinuations were clinically well motivated.

Conclusions

Quality of Swedish warfarin treatment in initiated stroke prevention is high, with generally low rates of complications and high TTRs, no matter treatment in ACC or PHCC, including high long time persistence to warfarin in secondary stroke prevention. For better outcome in future warfarin stroke prophylactic treatment clinicians should aim for iTTRs above 70%, avoid additional ASA therapy, support fragile patients like those with excessive alcohol use and dementia, and base decisions on treatment discontinuations on solid medical arguments.

INTRODUCTION: Warfarin treatment discontinuation is significant among patients with atrial fibrillation (AF). For AF patients with stroke a warfarin persistence rate of 0.45 after 2years has previously been reported. No consistent predictors for discontinuation have been established.

AIMS: Evaluation of warfarin persistence and variables associated with discontinuation, in a large Swedish cohort with unselected stroke/TIA patients with AF treated with warfarin.

MATERIALS AND METHODS: 4 583 patients with stroke/TIA and AF in the Swedish National Patient Register (NPR), from 1. Jan 2006 to 31. Dec 2011, were matched with the Swedish national quality register AuriculA. They were followed until treatment cessation, death or end of study. Baseline characteristics and CHA2DS2VASc score were retrieved from NPR. Treatment-time was retrieved from AuriculA.

RESULTS: Overall proportion of warfarin persistence was 0.78 (95% confidence interval (CI) 0.76 to 0.80) after one year, 0.69 (95% CI 0.67 to 0.71) after 2years and 0.47 (95% CI 0.43 to 0.51) after 5years. Variables clearly associated with higher discontinuation were dementia (hazard ratio (HR) 2.22, CI 1.51-3.27) and alcohol abuse (HR 1.66, CI 1.19-2.33). Chronic obstructive pulmonary disease (COPD), cancer and chronic heart failure (CHF) were each associated with over 20% increased risk of treatment discontinuation. Higher CHA2DS2VASc score and start-age lead to lower persistence (p<0.001).

CONCLUSIONS: Persistence to warfarin in unselected stroke/TIA patients with AF is in Sweden greater than previously reported. Lower persistence is found among patients with high treatment start-age, incidence of dementia, alcohol abuse, cancer, CHF, COPD and/or high CHA2DS2VASc score.

BACKGROUND: Warfarin treatment in Sweden holds a high standard with time in therapeutic range (TTR) over 75%. Internationally, specialized anticoagulation clinics (ACC) have shown higher TTR compared to primary health care centres (PHCC).

OBJECTIVES: To compare warfarin treatment quality in Sweden for ACC versus PHCC, thereby clarifying whether centralization is for the better.

PATIENTS/METHODS: In total 77.058 patients corresponding to 217.058 treatment years with warfarin in the Swedish national quality register AuriculA from 1. Jan 2006 to 31. Dec 2011. Information regarding TTR was calculated from AuriculA, while patient characteristics and complications were retrieved from the Swedish National Patient Register.

RESULTS: Of the 100.554 treatment periods examined, 78.7% were monitored at ACC. Mean TTR for INR 2-3 for all patients irrespective of intended target range was 76.5% with an annual risk of bleeding or thrombotic events of 2.24% and 2.66%, respectively. TTR was significantly higher in PHCC compared to ACC (79.6% vs. 75.7%, p<0.001), with no significant difference in overall risk of complications. Treatment periods for atrial fibrillation, except intended direct current conversion, showed similar results between ACC and PHCC without significant difference in annual risk of bleeding (2.50% vs. 2.51%) or thrombosis (3.09% vs. 3.16%). After propensity score matching there was still no significant difference in complication risk found.

CONCLUSIONS: Warfarin treatment quality is consistently high in both ACC and PHCC when monitored through AuriculA in Sweden, both measured as TTR and as risk of complications. In this setting, centralized warfarin monitoring is not likely to improve the results.