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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.

Objectives: To investigate the prevalence of atrial fibrillation (AF), the proportion of AF patients not receiving oral anticoagulation (OAC) and reasons for abstaining from OAC treatment.

Methods: A retrospective cross-sectional study of patients aged 18 years or older with an AF diagnosis on June 1st 2020 in Västernorrland County, Sweden. AF diagnosis was retrieved using the ICD10 code I.48, and medical records were reviewed for comorbidities and documented reasons to abstain OAC treatment.

Results: Of 197 274 residents in Västernorrland County, 4.7% (9 304/197 274) had a documented AF diagnosis. Of these, 19% (1 768/9 304) had no OAC treatment, including 4.2% (393/9 304) with no indication, 2.5% (233/9 304) with a questionable and 2.5% (231/9 304) with a documented clear contraindication for OAC. In total 9.8% (911/9 304) were not treated with OAC despite indication and no reasonable documented contraindication, thus 90.8% (8 447/9 304) of all AF-patients were eligible for OAC treatment. Common reasons for abstaining treatment without reasonable contraindication were present sinus rhythm in 13.7% (125/911), perceived not an OAC candidate in 10.6% (97/911) and anemia in the past in 4.3% (39/911).

Conclusions: In the population of Västernorrland County, a very high AF prevalence of 4.7% was found, of which just over 90% would theoretically benefit from OAC treatment. This is higher than previously reported and stresses the importance of stroke prevention in this large patient group.

BACKGROUND: Observational studies have shown that women with an early menopause are at higher risk of stroke compared with women with a later menopause. However, associations with stroke subtypes are inconsistent, and the causality is unclear.

METHODS AND RESULTS: We analyzed data of the UK Biobank and EPIC-CVD (European Prospective Investigation Into Cancer and Nutrition-Cardiovascular Diseases) study. A total of 204 244 postmenopausal women without a history of stroke at baseline were included (7883 from EPIC-CVD [5292 from the subcohort], 196 361 from the UK Biobank). Pooled mean baseline age was 58.9 years (SD, 5.8), and pooled mean age at menopause was 47.8 years (SD, 6.2). Over a median follow-up of 12.6 years (interquartile range, 11.8–13.3), 6770 women experienced a stroke (5155 ischemic strokes, 1615 hemorrhagic strokes, 976 intracerebral hemorrhages, and 639 subarachnoid hemorrhages). In multivariable adjusted observational Cox regression analyses, the pooled hazard ratios per 5 years younger age at menopause were 1.09 (95% CI, 1.07–1.12) for stroke, 1.09 (95% CI, 1.06–1.13) for ischemic stroke, 1.10 (95% CI, 1.04–1.16) for hemorrhagic stroke, 1.14 (95% CI, 1.08–1.20) for intracerebral hemorrhage, and 1.00 (95% CI, 0.84–1.20) for subarachnoid hemorrhage. When using 2-sample Mendelian randomization analysis, we found no statistically significant association between genetically proxied age at menopause and risk of any type of stroke.

CONCLUSIONS: In our study, earlier age at menopause was related to a higher risk of stroke. We found no statistically significant association between genetically proxied age at menopause and risk of stroke, suggesting no causal relationship.

Importance: Adverse pregnancy outcomes are recognized risk enhancers for cardiovascular disease, but the prevalence of subclinical coronary atherosclerosis after these conditions is unknown.

Objective: To assess associations between history of adverse pregnancy outcomes and coronary artery disease assessed by coronary computed tomography angiography screening.

Design, Setting, and Participants: Cross-sectional study of a population-based cohort of women in Sweden (n = 10 528) with 1 or more deliveries in 1973 or later, ascertained via the Swedish National Medical Birth Register, who subsequently participated in the Swedish Cardiopulmonary Bioimage Study at age 50 to 65 (median, 57.3) years in 2013-2018. Delivery data were prospectively collected.

Exposures: Adverse pregnancy outcomes, including preeclampsia, gestational hypertension, preterm delivery, small-for-gestational-age infant, and gestational diabetes. The reference category included women with no history of these exposures.

Main Outcomes and Measures: Coronary computed tomography angiography indexes, including any coronary atherosclerosis, significant stenosis, noncalcified plaque, segment involvement score of 4 or greater, and coronary artery calcium score greater than 100. Results: A median 29.6 (IQR, 25.0-34.9) years after first registered delivery, 18.9% of women had a history of adverse pregnancy outcomes, with specific pregnancy histories ranging from 1.4% (gestational diabetes) to 9.5% (preterm delivery). The prevalence of any coronary atherosclerosis in women with a history of any adverse pregnancy outcome was 32.1% (95% CI, 30.0%-34.2%), which was significantly higher (prevalence difference, 3.8% [95% CI, 1.6%-6.1%]; prevalence ratio, 1.14 [95% CI, 1.06-1.22]) compared with reference women. History of gestational hypertension and preeclampsia were both significantly associated with higher and similar prevalence of all outcome indexes. For preeclampsia, the highest prevalence difference was observed for any coronary atherosclerosis (prevalence difference, 8.0% [95% CI, 3.7%-12.3%]; prevalence ratio, 1.28 [95% CI, 1.14-1.45]), and the highest prevalence ratio was observed for significant stenosis (prevalence difference, 3.1% [95% CI, 1.1%-5.1%]; prevalence ratio, 2.46 [95% CI, 1.65-3.67]). In adjusted models, odds ratios for preeclampsia ranged from 1.31 (95% CI, 1.07-1.61) for any coronary atherosclerosis to 2.21 (95% CI, 1.42-3.44) for significant stenosis. Similar associations were observed for history of preeclampsia or gestational hypertension among women with low predicted cardiovascular risk.

Conclusions and Relevance: Among Swedish women undergoing coronary computed tomography angiography screening, there was a statistically significant association between history of adverse pregnancy outcomes and image-identified coronary artery disease, including among women estimated to be at low cardiovascular disease risk. Further research is needed to understand the clinical importance of these associations.

Introduction: Atrial fibrillation (AF) is a major risk factor for ischaemic stroke and transient ischaemic attack (TIA), and AF detection can be challenged by asymptomatic and paroxysmal presentation. Long-term ECG monitoring after ischaemic stroke or TIA is recommended by all major societies in cardiology and cerebrovascular medicine as a secondary prophylactic measure. However, data on stroke reduction are lacking, and the recommendations show significant diversity.

Methods and analysis: AF SPICE is a multicentre, national, investigator-initiated, randomised, parallel-group, register-based trial comparing extended ECG monitoring versus standard ECG monitoring in patients admitted with ischaemic stroke or TIA, with a composite endpoint of stroke, all-cause-mortality and intracerebral bleeding. Patients aged ≥70 years without previous AF will be randomised 1:1 to control (standard ECG monitoring) or intervention (extended ECG monitoring). In the control arm, patients will undergo 48±24 hours (ie, a range of 24-72 hours) of continuous ECG monitoring according to national recommendations. In the intervention arm, patients will undergo 14+14 days of continuous ECG monitoring 3 months apart using an ECG patch device, which will provide an easy-accessed, well-tolerated 14-day continuous ECG recording. All ECG patch recordings will be read in a core facility. In cases of AF detection, oral anticoagulation will be recommended if not contraindicated. A pilot phase has been concluded in 2022, which will transcend into the main trial during 2023-2026, including approximately 30 stroke units. The sample size was calculated to be 3262 patients. The primary outcome will be collected from register data during a 36-month follow-up.

Ethics and dissemination: Ethical approval has been provided by the Swedish Ethical Review Authority, reference 2021-02770. The trial will be conducted according to the ethical principles of the Declaration of Helsinki and national regulatory standards. Positive results from the study have the potential for rapid dissemination in clinical practice.

Trial registration number: NCT05134454.

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.

Aims: A third of non-valvular atrial fibrillation (NVAF) patients are non-adherent to direct oral anticoagulants (DOACs). Estimates of the economic value of full adherence and the cost of two types of adherence improving interventions are important to healthcare planners and decision-makers.

Methods: A cost-utility analysis estimated the impact of non-adherence over a 20-year horizon, for a patient cohort with a mean age of 77 years, based on data from the Stockholm Healthcare database of NVAF patients with incident stroke between 2011 and 2018. Adherence was defined using a medication possession ratio (MPR) cut-off of 90%; primary outcomes were the number of ischemic strokes and associated incremental cost–utility ratio.

Results: Hypothetical comparisons between cohorts of 1,000 patients with varying non-adherence levels and full adherence (MPR >90%) predicted an additional number of strokes ranging from 117 (MPR = 81–90%) to 866 (MPR <60%), and years of life lost ranging from 177 (MPR = 81– 90%) to 1,318 (MPR < 60%; discounted at 3%). Chronic disease co-management intervention occurring during each DOAC prescription renewal and patient education intervention at DOAC initiation will be cost-saving to the health system if its cost is below SEK 143 and SEK 4,655, and cost-effective if below SEK 858 and SEK 28,665, respectively.

Conclusion: Adherence improving interventions for NVAF patients on DOACs such as chronic disease co-management and patient education can be cost-saving and cost-effective, within a range of costs that appear reasonable to the Swedish healthcare system.

Aims: The aim of this study was to investigate a real-world heart failure (HF) cohort regarding (1) prevalence of known diabetes mellitus (DM), undiagnosed DM and pre-diabetes, (2) if hf treatment differs depending on glycaemic status and (3) if treatment of DM differs depending on HF phenotype.

Methods: All patients who had received a diagnosis of HF at Umeå University Hospital between 2010 and 2019 were identified and data were extracted from patient files according to a prespecified protocol containing parameters for clinical characteristics, including echocardiogram results, comorbidities, fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) values. Patients’ HF phenotype was determined using the latest available echocardiogram. The number of patients with previous DM diagnosis was assessed. Patients without a previous diagnosis of DM were classified as non-DM, pre-diabetes or probable DM according to FPG and HbA1c levels using WHO criteria.

Results: In total, 2326 patients (59% male, mean age 76±13 years) with HF and at least one echocardiogram were assessed. Of these, 617 (27%) patients had a previous diagnosis of DM. Of the 1709 patients without a previous diagnosis of DM, 1092 (67%) patients had either an FPG or HbA1c recorded, of which 441 (41%) met criteria for pre-diabetes and 97 (9%) met criteria for probable diabetes, corresponding to 19% and 4% of the entire cohort, respectively. Patients with HF and diabetes were more often treated with diuretics and beta blockers compared with non-DM patients (64% vs 42%, p<0.001 and 88% vs 83%, p<0.001, respectively). There was no difference in DM treatment between HF phenotypes.

Conclusions: DM and pre-diabetes are common in this HF population with 50% of patients having either known DM, probable DM or pre-diabetes. Patients with HF and DM are more often treated with common HF medications. HF phenotype did not affect choice of DM therapy.

Aims: This study is aimed at investigating the eligibility in a real-world heart failure population for the DAPA-HF (testing dapagliflozin) and EMPEROR-reduced (testing empagliflozin) trials, comparing the eligible real-world patients to trial participants and to characterize the noneligible patients.

Methods: Medical records of all heart failure patients who had a diagnosis of heart failure from the Heart Centre or Department of Internal Medicine at Umea University Hospital were reviewed.

Results: 2433 of the hospital's uptake population of 150 000 had a diagnosis of heart failure. 681 patients had left ventricle ejection fraction <= 40%, and of these 352 (52%) and 268 (39%) patients met eligibility criteria for DAPA-HF and EMPEROR-reduced, respectively. Comparing eligible patients in our population with the DAPA-HF- and EMPEROR-reduced trial populations, we found that eligible real-world patients were older (79.0 vs. 66.2 years and 80.3 vs. 67.2 years, respectively), had worse renal function (eGFR 54.4 vs. 66.0 ml/min/1.73m(2) and 49.5 vs. 61.8 ml/min/1.73m(2), respectively), higher prevalence of atrial fibrillation (56.0% vs. 36.1% and 53.0% vs. 35.6%, respectively), and lower prevalence of diabetes mellitus (21.0% vs. 41.8% and 26.1% vs. 49.8%, respectively). The main reasons for ineligibility were low NT-proBNP or low eGFR. Noneligible patients differed according to reason for ineligibility, where patients with low NT-proBNP were generally younger and healthier, and patients with low eGFR were older and had more comorbidities.

Conclusions: 39-52% of patients with heart failure and reduced ejection fraction in this real-world heart failure population were eligible for SGLT2-inhibitor treatment, corresponding to 11-14% of all heart failure patients. Compared to trial participants, eligible real-world patients were significantly older with worse renal function, more atrial fibrillation, and less diabetes mellitus. Trial entry criteria exclude comparatively young and healthy patients, as well as comparatively old patients with more comorbid conditions.