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  • 1.
    Blomström Lundqvist, Carina
    et al.
    Department of Cardiology, School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Själander, Sara
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Garcia Rodriguez, Luis A.
    Spanish Centre for Pharmacoepidemiologic Research (CEIFE), Madrid, Spain.
    Åkerborg, Örjan
    Wickenstones Ltd, Carlow, Ireland.
    Jin, Guanyi
    Wickenstones Ltd, Carlow, Ireland.
    Caleyachetty, Amrit
    Wickenstones Ltd, Carlow, Ireland.
    Huelsebeck, Maria
    Bayer AG, Berlin, Germany.
    Bowrin, Kevin
    Bayer Plc, Reading, United Kingdom.
    Schaefer, Bernhard
    Bayer AG, Berlin, Germany.
    Mahdessian, Hovsep
    Bayer AB, Stockholm, Sweden.
    Hofmeister, Lucas
    Bayer AG, Berlin, Germany.
    Levin, Lars-Åke
    Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.
    Impact of non-adherence to direct oral anticoagulants amongst Swedish patients with non-valvular atrial fibrillation: results from a real-world cost-utility analysis2022In: Journal of Medical Economics, ISSN 1369-6998, E-ISSN 1941-837X, Vol. 25, no 1, p. 1085-1091Article in journal (Refereed)
    Abstract [en]

    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.

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  • 2.
    Engdahl, Johan
    et al.
    Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Stockholm, Sweden.
    Straat, Kajsa
    Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Stockholm, Sweden.
    Isaksson, Eva
    Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Stockholm, Sweden.
    Rooth, Elisabeth
    Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Stockholm, Sweden.
    Svennberg, Emma
    Department of Medicine, Huddinge, Karolinska University Hospital, Karolinska Institutet, Stockholm, Stockholm, Sweden.
    Norrving, Bo
    Section of Neurology, Department of Clinical Sciences, Lund University, Lund, Sweden.
    Euler, Mia Von
    School of Medicine, Department of Neurology, Örebro Universitet, Örebro, Örebro, Sweden.
    Hellqvist, Kjersti
    Department of Medicine, Alingsas Lasarett, Alingsas, Sweden.
    Gu, Weigang
    Department of Clinical Sciences, South Hospital, Karolinska Institutet, Stockholm, Stockholm, Sweden.
    Ström, Jakob O
    School of Medicine, Department of Neurology, Örebro Universitet, Örebro, Örebro, Sweden.
    Själander, Sara
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Eriksson, Marie
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Åsberg, Signild
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Wester, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Stockholm, Sweden.
    Multicentre, national, investigator-initiated, randomised, parallel-group, register-based superiority trial to compare extended ECG monitoring versus standard ECG monitoring in elderly patients with ischaemic stroke or transient ischaemic attack and the effect on stroke, death and intracerebral bleeding: the AF SPICE protocol2023In: BMJ Open, E-ISSN 2044-6055, Vol. 13, no 11, article id e073470Article in journal (Refereed)
    Abstract [en]

    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.

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  • 3.
    Grzymala-Lubanski, Bartosz
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Själander, Sara
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Renlund, Henrik
    Svensson, Peter J.
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Computer aided warfarin dosing in the Swedish national quality registry AuriculA: algorithmic suggestions are performing better than manually changed doses2013In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 131, no 2, p. 130-134Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Warfarin treatment with a high time in therapeutic range (TTR) is correlated to fewer complications. The TTR in Sweden is generally high but varies partly depending on local expertise and traditions. A dosing algorithm could minimize variations and increase treatment quality. Here we evaluate the performance of a computerized dosing algorithm.

    MATERIALS AND METHODS: 53.779 warfarin treated patients from 125 centers using the Swedish national quality registry AuriculA. If certain criteria are met, the algorithm gives one of seven possible dose suggestions, which can be unchanged, decreased or increased weekly dose by 5, 10 or 15%. The outcome evaluated by the resulting INR value was compared between dose suggestions arising from the algorithm that were accepted and those that were manually changed. There were no randomization, and outcomes were retrospectively analyzed.

    RESULTS: Both the algorithm-based and the manually changed doses had worse outcome if only two instead of three previous INR values were available. The algorithm suggestions were superior to manual dosing regarding percent samples within the target range 2-3 (hit-rate) or deviation from INR 2.5 (mean error). Of the seven possible outcomes from the algorithm, six were significantly superior and one equal to the manually changed doses when three previous INR:s were present.

    CONCLUSIONS: The algorithm-based dosing suggestions show better outcome in most cases. This can make dosing of warfarin easier and more efficient. There are however cases where manual dosing fares better. Here the algorithm will be improved to further enhance its dosing performance in the future.

  • 4.
    Håkansson, Erik
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Brunström, Mattias
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Norberg, Helena
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Själander, Sara
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Lindmark, Krister
    Department of Clinical Sciences Danderyd Hospital, Karolinska Institute, Danderyd, Sweden.
    Prevalence and treatment of diabetes and pre-diabetes in a real-world heart failure population: a single-centre cross-sectional study2022In: Open heart, E-ISSN 2053-3624, Vol. 9, no 2, article id e002133Article in journal (Refereed)
    Abstract [en]

    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.

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  • 5.
    Håkansson, Erik
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Norberg, Helena
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Själander, Sara
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Lindmark, Krister
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Eligibility of Dapagliflozin and Empagliflozin in a Real-World Heart Failure Population2021In: Cardiovascular Therapeutics, ISSN 1755-5914, Vol. 2021, article id 1894155Article in journal (Refereed)
    Abstract [en]

    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.

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  • 6.
    Jansson, Martin
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Cardiology Department, Sundsvall Hospital, Sundsvall, Sweden.
    Själander, Sara
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Sjögren, Vilhelm
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Björck, Fredrik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Renlund, H.
    Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.
    Norrving, B.
    Department of Clinical Sciences Lund, Neurology, Skåne University Hospital, Lund University, Lund, Sweden.
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Reduced dose direct oral anticoagulants compared with warfarin with high time in therapeutic range in nonvalvular atrial fibrillation2023In: Journal of Thrombosis and Thrombolysis, ISSN 0929-5305, E-ISSN 1573-742X, Vol. 55, no 3, p. 415-425Article in journal (Refereed)
    Abstract [en]

    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.

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  • 7.
    Jansson, Martin
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Själander, Sara
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Sjögren, Vilhelm
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Renlund, H.
    Norrving, B.
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Direct comparisons of effectiveness and safety of treatment with Apixaban, Dabigatran and Rivaroxaban in atrial fibrillation2020In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 185, p. 135-141Article in journal (Refereed)
    Abstract [en]

    Introduction: Direct oral anticoagulants (DOACs) have been proven non-inferior or superior to warfarin in preventing stroke and systemic embolism, with a lower risk of major hemorrhage, in patients with non-valvular atrial fibrillation (NVAF). We sought to investigate whether effectiveness and safety differs among apixaban, rivaroxaban and dabigatran. Materials and methods: Patients with newly initiated DOAC treatment were identified from the Swedish anticoagulation quality registry, ranging from January 1, 2013 to December 31, 2015. Patients were assigned to apixaban, dabigatran or rivaroxaban cohorts based on initiated DOAC and dose (standard or reduced). Baseline characteristics and endpoints were retrieved from validated Swedish quality registers and the National Patient Registry. Cohorts were matched using full optimal matching and directly compared. Results: A total of 25,843 NVAF patients were included. Patients treated with standard dose apixaban or dabigatran had lower risk of major bleeding than patients treated with rivaroxaban, HR 0.69 (95% CI 0.54-0.88) and HR 0.64 (95% CI 0.48-0.87). Regarding reduced dose, patients treated with apixaban had lower risk of major bleeding than those treated with dabigatran or rivaroxaban, HR 0.62 (95% CI 0.44-0.88) and HR 0.45 (95% CI 0.33-0.61). In reduced dose, patients treated with dabigatran had the lowest all-cause mortality. No differences in effectiveness were found. Conclusions: In this large real-world NVAF cohort, direct comparisons show a favorable bleeding risk profile for dabigatran and apixaban in standard dose, and for apixaban in reduced dose. No differences in effectiveness were found. This study confirms previous indirect DOAC comparisons. Further studies are needed.

  • 8.
    Lilja, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Själander, Sara
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Department of Cardiology, Sundsvall Hospital, 856 43, Sundsvall, Sweden.
    Prevalence of atrial fibrillation and reasons for undertreatment with oral anticoagulants2024In: Journal of Thrombosis and Thrombolysis, ISSN 0929-5305, E-ISSN 1573-742X, Vol. 57, p. 101-106Article in journal (Refereed)
    Abstract [en]

    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.

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  • 9.
    Sederholm Lawesson, Sofia
    et al.
    Department of Cardiology, Linköping University Hospital, Department of Health, Medicine, Caring Sciences, Linköping University, Linköping, Sweden.
    Swahn, Eva
    Department of Cardiology, Linköping University Hospital, Department of Health, Medicine, Caring Sciences, Linköping University, Linköping, Sweden.
    Pihlsgård, Mats
    Perinatal and Cardiovascular Epidemiology, Lund University Diabetes Centre, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
    Andersson, Therese
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Angerås, Oskar
    Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Bacsovics Brolin, Elin
    Department of Clinical Science, Technology, Karolinska Institutet, Stockholm, Sweden; Department of Radiology, Capio St Görans Hospital, Stockholm, Sweden.
    Bergdahl, Ellinor
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Blomberg, Marie
    Department of Obstetrics and Gynecology, Linköping University Hospital, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Christersson, Christina
    Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden.
    Gonçalves, Isabel
    Department of Cardiology, Skåne University Hospital, Malmö, Sweden; Cardiovascular Research Translational Studies, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
    Gunnarsson, Omar Sigurvin
    Perinatal and Cardiovascular Epidemiology, Lund University Diabetes Centre, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden; Department of Obstetrics and Gynecology, Skåne University Hospital, Sweden.
    Jernberg, Tomas
    Department of Clinical Sciences, Danderyd University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Johnston, Nina
    Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden.
    Leander, Karin
    Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Lilliecreutz, Caroline
    Department of Obstetrics and Gynecology, Linköping University Hospital, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Pehrson, Moa
    Perinatal and Cardiovascular Epidemiology, Lund University Diabetes Centre, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
    Rosengren, Annika
    Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Medicine, Geriatrics, Emergency Medicine, Sahlgrenska University Hospital, Östra Hospital, Gothenburg, Sweden.
    Sandström, Anette
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Sandström, Anna
    Clinical Epidemiology Division, Department of Medicine, Karolinska Institutet, Stockholm, Solna, Sweden.
    Sarno, Giovanna
    Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden.
    Själander, Sara
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Svanvik, Teresia
    Department of Obstetrics and Gynecology, University of Gothenburg, Institute of Clinical Sciences, Sahlgrenska Academy, Gothenburg, Sweden.
    Thunström, Erik
    Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Medicine, Geriatrics, Emergency Medicine, Sahlgrenska University Hospital, Östra Hospital, Gothenburg, Sweden.
    Wikström, Anna Karin
    Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
    Timpka, Simon
    Perinatal and Cardiovascular Epidemiology, Lund University Diabetes Centre, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden; Department of Obstetrics and Gynecology, Skåne University Hospital, Sweden.
    Association between history of adverse pregnancy outcomes and coronary artery disease assessed by coronary computed tomography angiography2023In: Journal of the American Medical Association (JAMA), ISSN 0098-7484, E-ISSN 1538-3598, Vol. 329, no 5, p. 393-404Article in journal (Refereed)
    Abstract [en]

    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.

  • 10.
    Själander, Sara
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Stroke prevention in atrial fibrillation2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: The Framingham Study from 1991 showed a clear correlation between atrial fibrillation (AF) and ischemic stroke, where patients with AF had an almost fivefold increase in risk of stroke compared with patients without AF. Since then, several trials have evaluated different antithrombotic treatments to reduce the risk of stroke in patients with AF. Other trials have investigated factors that increase the risk of stroke in patients with AF and risk score systems have been developed to categorize patients into low or increased risk of stroke to help clinicians to decide which patients benefit from antithrombotic treatment and in whom it can be abstained, not to expose patients with low stroke risk to an increased risk of bleeding conferred by antithrombotic treatment. The aims of this thesis were: [1] to evaluate if a warfarin dosing algorithm can increase hit rate and decrease mean error compared with manually changed doses; [2] to assess the prevalence and net clinical benefit of aspirin as monotherapy for stroke prevention in AF; [3] to investigate the risk of thromboembolic and haemorrhagic complications within 30 days after electrical cardioversion (ECV) of AF in patients with and without oral anticoagulation (OAC) pre-treatment; and [4] to assess the proportion of patients discontinuing OAC after pulmonary vein isolation (PVI), identify factors predicting stroke after PVI and to investigate risk of complications after PVI with and without OAC.

    Materials and methods: All studies are retrospective and based on data from Swedish national quality registries. In paper I, data from Auricula was used to compare the resulting INR values after algorithmic warfarin dose suggestions and manually changed doses. In paper II data was extracted from the Swedish National Patient Register, the Dispensed Drugs Register and the Cause of Death Register. Patients with aspirin treatment were compared with patients without any antithrombotic treatment regarding risk of thromboembolic and haemorrhagic complications. In paper III data was collected from the Swedish National Patient Register and the Dispensed Drugs Register to examine risk of complications (thromboembolic and haemorrhagic events) within 30 days after cardioversion, comparing patients with and without oral anticoagulation pre-treatment. In paper IV data from six different Swedish national quality registries were used (Swedish Catheter Ablation Register, Auricula, Swedish National Patient Register, Dispensed Drugs Register, Cause of Death Register and Riksstroke). Patients undergoing pulmonary vein isolation (PVI) were investigated for adherence to guidelines regarding oral anticoagulation, predictors for stroke after PVI, as well as risk of ischemic stroke or intracranial haemorrhage after PVI in patients with and without treatment.

    Results: Paper I showed that a computerized dosing algorithm for warfarin in most cases perform as well or better compared with doses that have been changed manually, with a better hit-rate (0.72 vs. 0.67) and a lower mean error (0.44 vs. 0.48). Paper II showed that 32% of 182.678 patients with a diagnosis of AF were on monotherapy with aspirin for stroke prevention. A total of 115.185 patients were included, 58.671 with aspirin treatment and 56.514 without antithrombotic treatment at baseline. After stratification after CHA2DS2-VASc score and after multivariable adjustment, aspirin treatment did not confer a decrease in thromboembolic events. After propensity score mathcing, rate of ischemic stroke was 7.4%/year (95% CI 7.1-7.6) in aspirin treated patients and 6.6%/year (95% CI 6.4-6.9) in patients without antithrombotic treatment. In paper III 22.874 patients undergoing electrical cardioversion were included, 10.722 with and 12.152 without OAC pre-treatment. In patients with low stroke risk (CHA2DS2-VASc 0-1), no thromboembolic complication was seen within 30 days after cardioversion. In patients with CHA2DS2-VASc ≥2, the risk of thromboembolic complications was increased when no oral anticoagulation pre-treatment was used, results that remained after propensity score matching. No difference regarding haemorrhagic complications was seen. Paper IV included a total of 1585 patients undergoing PVI with a mean follow up of 2.6 years. Adherence to current guidelines regarding oral anticoagulation was good in patients with CHA2DS2-VASc ≥2. Previous ischemic stroke was a predictor for a new stroke after PVI. In patients with CHA2DS2-VASc ≥2 stroke risk was increased in patients discontinuing OAC compared to those continuing OAC (1,60%/year vs. 0.34%/year).

    Conclusion: Oral anticoagulation is still underutilized for prevention of stroke and systemic embolism in patients with atrial fibrillation. Patients with risk factors for stroke (CHA2DS2-VASc ≥2p) benefit from continuous oral anticoagulation treatment to prevent stroke, also in conjunction with electrical cardioversion and after pulmonary vein isolation. If warfarin is chosen, a computerised dosing algorithm can facilitate and standardize warfarin dosing and lead to better resulting INR values than manually changed doses. Aspirin should not be used for stroke prevention in patients with atrial fibrillation.

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  • 11.
    Själander, Sara
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Holmqvist, Fredrik
    Smith, J Gustav
    Platonov, Pyotr G
    Kesek, Milos
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Svensson, Peter J
    Blomström-Lundqvist, Carina
    Tabrizi, Fariborz
    Tapanainen, Jari
    Poci, Dritan
    Jönsson, Anders
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Assessment of use vs discontinuation of oral anticoagulation after pulmonary vein isolation in patients with atrial fibrillation2017In: JAMA cardiology, ISSN 2380-6583, E-ISSN 2380-6591, Vol. 2, no 2, p. 146-152Article in journal (Refereed)
    Abstract [en]

    Importance: Pulmonary vein isolation (PVI) is a recommended treatment for patients with atrial fibrillation, but it is unclear whether it results in a lower risk of stroke.

    Objectives: To investigate the proportion of patients discontinuing anticoagulation treatment after PVI in association with the CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years [doubled], diabetes, stroke [doubled], vascular disease, age 65-74 years, sex category [female]) score, identify factors predicting stroke after PVI, and explore the risk of cardiovascular events after PVI in patients with and without guideline-recommended anticoagulation treatment.

    Design, Setting, and Participants: A retrospective cohort study was conducted using Swedish national health registries from January 1, 2006, to December 31, 2012, with a mean-follow up of 2.6 years. A total of 1585 patients with atrial fibrillation undergoing PVI from the Swedish Catheter Ablation Register were included, with information about exposure to warfarin in the national quality register Auricula. Data analysis was performed from January 1, 2015, to April 30, 2016.

    Exposures: Warfarin treatment.

    Main Outcomes and Measures: Ischemic stroke, intracranial hemorrhage, and death.

    Results: In this cohort of 1585 patients, 73.0% were male, the mean (SD) age was 59.0 (9.4) years, and the mean (SD) CHA2DS2-VASc score was 1.5 (1.4). Of the 1585 patients, 1175 were followed up for more than 1 year after PVI. Of these, 360 (30.6%) discontinued warfarin treatment during the first year. In patients with a CHA2DS2-VASc score of 2 or more, patients discontinuing warfarin treatment had a higher rate of ischemic stroke (5 events in 312 years at risk [1.6% per year]) compared with those continuing warfarin treatment (4 events in 1192 years at risk [0.3% per year]) (P = .046). Patients with a CHA2DS2-VASc score of 2 or more or those who had previously experienced an ischemic stroke displayed a higher risk of stroke if warfarin treatment was discontinued (hazard ratio, 4.6; 95% CI, 1.2-17.2; P = .02 and hazard ratio, 13.7; 95% CI, 2.0-91.9; P = .007, respectively).

    Conclusions and Relevance: These findings indicate that discontinuation of warfarin treatment after PVI is not safe in high-risk patients, especially those who have previously experienced an ischemic stroke.

  • 12.
    Själander, Sara
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Holmqvist, Fredrik
    Smith, J. Gustav
    Platonov, Pyotr G.
    Kesek, Milos
    Svensson, Peter J.
    Blomström-Lundqvist, Carina
    Tabrizi, Fariborz
    Tapanainen, Jari
    Poci, Dritan
    Jönsson, Anders
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Oral anticoagulation after pulmonary vein isolation: a nationwide register studyManuscript (preprint) (Other academic)
  • 13.
    Själander, Sara
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Svensson, Peter J.
    Friberg, Leif
    Atrial fibrillation patients do not benefit from acetylsalicylic acid2014In: Europace, ISSN 1099-5129, E-ISSN 1532-2092, Vol. 16, no 5, p. 631-638Article in journal (Refereed)
    Abstract [en]

    Oral anticoagulation is the recommended treatment for stroke prevention in patients with atrial fibrillation. Notwithstanding, many patients are treated with acetylsalicylic acid (ASA) as monotherapy. Our objective was to investigate if atrial fibrillation patients benefit from ASA as monotherapy for stroke prevention. Retrospective study of patients with a clinical diagnosis of atrial fibrillation between 1 July 2005 and 1 January 2009 in the National Swedish Patient register, matched with data from the National Prescribed Drugs register. Endpoints were ischaemic stroke, thrombo-embolic event, intracranial haemorrhage, and major bleeding. The study population consisted of 115 185 patients with atrial fibrillation, of whom 58 671 were treated with ASA as monotherapy and 56 514 were without any antithrombotic treatment at baseline. Mean follow-up was 1.5 years. Treatment with ASA was associated with higher risk of ischaemic stroke and thrombo-embolic events compared with no antithrombotic treatment. Acetylsalicylic acid as monotherapy in stroke prevention of atrial fibrillation has no discernable protective effect against stroke, and may even increase the risk of ischaemic stroke in elderly patients. Thus, our data support the new European guidelines recommendation that ASA as monotherapy should not be used as stroke prevention in atrial fibrillation.

  • 14.
    Själander, Sara
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Sjögren, Vilhelm
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Renlund, Henrik
    Norrving, Bo
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Dabigatran, rivaroxaban and apixaban vs. high TTR warfarin in atrial fibrillationManuscript (preprint) (Other academic)
    Abstract [en]

    Objective: New oral anticoagulants are non-inferior compared with warfarin regarding stroke prevention in atrial fibrillation, with similar or decreased risk of bleeding. However, it is unclear whether high TTR warfarin is as effective and safe as NOACs. Our objective was to investigate efficacy and safety of apixaban, dabigatran or rivaroxaban compared with warfarin in clinical practice.

    Methods: Nationwide retrospective cohort study based on Swedish quality registries. Atrial fibrillation patients initiated on apixaban, dabigatran, rivaroxaban or warfarin between 2013-01-01 and 2015-12-31 were included. Main outcomes measures were all-cause stroke and systemic embolism, all-cause stroke, ischemic stroke, hemorrhagic stroke; major bleeding, intracranial bleeding, gastrointestinal bleeding, other bleeding (fatal or requiring hospital care); all-cause mortality; myocardial infarction.

    Results: The study included 64382 patients corresponding to 81176 treatment years. Of these, 37174 patients were instituted on warfarin, 6574 on dabigatran, 8323 on rivaroxaban and 12311 on apixaban. In warfarin treated patients, the time in therapeutic range was 71.4 %. After propensity score matching, there was no significant difference in risk of stroke or systemic embolism between NOAC and warfarin treated patients. Hazard ratios for major bleeding events were 0.63(95%CI 0.52-0.75) for apixaban, 0.74(0.62-0.87) for dabigatran and 1.06(0.92-1.23) for rivaroxaban, compared with warfarin.

    Conclusions: This study showed no difference between apixaban, dabigatran, or rivaroxaban compared to high TTR warfarin treatment regarding stroke prevention. However, fewer bleeding events were seen for apixaban and dabigatran, but not for rivaroxaban. Further studies are needed on the comparability of individual NOACs with respect to bleeding risks. 

  • 15.
    Själander, Sara
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Sjögren, Vilhelm
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Renlund, Henrik
    Norrving, Bo
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Dabigatran, rivaroxaban and apixaban vs. high TTR warfarin in atrial fibrillation2018In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 167, p. 113-118Article in journal (Refereed)
    Abstract [en]

    Introduction: New oral anticoagulants are non-inferior compared with warfarin regarding stroke prevention in atrial fibrillation, with similar or decreased risk of bleeding. However, it is unclear whether high TTR warfarin is as effective and safe as NOACs. Our objective was to investigate efficacy and safety of apixaban, dabigatran or rivaroxaban compared with warfarin in clinical practice.

    Materials and methods: Nationwide retrospective cohort study based on Swedish quality registries. Atrial fibrillation patients initiated on apixaban, dabigatran, rivaroxaban or warfarin between 2013-01-01 and 2015-1231 were included. Main outcome measures were all-cause stroke and systemic embolism, all-cause stroke, ischemic stroke, hemorrhagic stroke; major bleeding, intracranial bleeding, gastrointestinal bleeding, other bleeding (fatal or requiring hospital care); all-cause mortality; myocardial infarction.

    Results: The study included 64,382 patients corresponding to 81,176 treatment years. Of these, 37,174 patients were instituted on warfarin, 6574 on dabigatran, 8323 on rivaroxaban and 12,311 on apixaban. In warfarin treated patients, the time in therapeutic range was 71.4%. After propensity score matching, there was no significant difference in risk of stroke or systemic embolism between NOAC and warfarin treated patients. Hazard ratios for major bleeding events were 0.63(95% CI 0.52-0.75) for apixaban, 0.74(0.62-0.87) for dabigatran and 1.06(0.92-1.23) for rivaroxaban, compared with warfarin.

    Conclusions: This study showed no difference between apixaban, dabigatran, or rivaroxaban compared to high TTR warfarin treatment regarding stroke prevention. However, fewer bleeding events were seen for apixaban and dabigatran, but not for rivaroxaban. Further studies are needed on the comparability of individual NOACs with respect to bleeding risks.

  • 16.
    Själander, Sara
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Svensson, Peter J.
    Friberg, Leif
    Atrial fibrillation patients with CHA2DS2-VASc > 1 benefit from oral anticoagulation prior to cardioversion2016In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 215, p. 360-363Article in journal (Refereed)
    Abstract [en]

    Background: Electrical cardioversion of atrial fibrillation is associated with an increased risk of embolic stroke, but is generally considered safe if performed within 48 h after onset. Our objective was to investigate if thromboembolism and bleeding in association with cardioversion of atrial fibrillation differed between patients with and without oral anticoagulation.

    Methods: Retrospective study of patients with atrial fibrillation undergoing electrical cardioversion from national Swedish health registries from January 1st 2006 until December 1st 2010. Main outcome measures were thromboembolism and bleeding.

    Results: In total 22,874 atrial fibrillation patients underwent electrical cardioversion, 10,722 with and 12,152 without oral anticoagulation pre-treatment. Patients with low stroke risk (CHA(2)DS(2)-VASc 0-1) did not suffer from any thromboembolic complications within 30 days after cardioversion. After adjustment for factors included in CHA(2)DS(2)-VASc and after propensity score matching, patients without oral anticoagulation had higher risk for thromboembolic complications, odds ratio 2.54 (95% confidence interval 1.70-3.79) and odds ratio 2.51 (95% confidence interval 1.69-3.75). There were no significant differences regarding bleeding complications between patients with or without anticoagulation after adjustment for factors included in HAS-BLED, odds ratio 1.08 (95% confidence interval 0.51-2.25), nor after propensity score matching, odds ratio 1.00 (95% confidence interval 0.48-2.10).

    Conclusion: The results suggest that electrical cardioversion without prior anticoagulation may not be safe for patients with risk factors for thromboembolism (CHA(2)DS(2)-VASc score >1 point).

  • 17.
    Tschiderer, Lena
    et al.
    Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands; Institute of Health Economics, Medical University of Innsbruck, Innsbruck, Austria.
    Peters, Sanne A. E.
    Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands; The George Institute for Global Health, School of Public Health, Imperial College London, London, United Kingdom; The George Institute for Global Health, University of New South Wales, NSW, Sydney, Australia.
    van der Schouw, Yvonne T.
    Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands.
    van Westing, Anniek C.
    Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands; Division of Human Nutrition and Health, Wageningen University, Wageningen, Netherlands.
    Tong, Tammy Y. N.
    Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
    Willeit, Peter
    Institute of Health Economics, Medical University of Innsbruck, Innsbruck, Austria; Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
    Seekircher, Lisa
    Institute of Health Economics, Medical University of Innsbruck, Innsbruck, Austria.
    Moreno-Iribas, Conchi
    Instituto de Salud Pública y Laboral de Navarra, Pamplona, Spain; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.
    Huerta, José María
    Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Department of Epidemiology, Murcia Regional Health Council-IMIB, Murcia, Spain.
    Crous-Bou, Marta
    Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO)– Bellvitge Biomedical Research Institute, (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain; Department of Epidemiology, Harvard T.H. Chan School of Public Health, MA, Boston, United States.
    Söderholm, Martin
    Department of Neurology, Skåne University Hospital, Malmö, Lund and Malmö, Sweden; Department of Clinical Sciences, Malmö, Lund University, Malmö, Sweden.
    Schulze, Matthias B.
    Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany.
    Johansson, Cecilia
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Själander, Sara
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Heath, Alicia K.
    SwedenDepartment of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
    Macciotta, Alessandra
    Centre for Biostatistics, Epidemiology, and Public Health (C-BEPH), Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
    Dahm, Christina C.
    Department of Public Health, Aarhus University, Aarhus, Denmark.
    Ibsen, Daniel B.
    Department of Public Health, Aarhus University, Aarhus, Denmark; Steno Diabetes Center Aarhus, Aarhus, Denmark; MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom; Department of Nutrition, Exercise and Sports, University of Copenhagen, Frederiksberg, Denmark.
    Pala, Valeria
    Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
    Mellemkjær, Lene
    Danish Cancer Society Research Center, Copenhagen, Denmark.
    Burgess, Stephen
    Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; Heart and Lung Research Institute, University of Cambridge, Cambridge, United Kingdom; MRC Biostatistics Unit, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom.
    Wood, Angela
    Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
    Kaaks, Rudolf
    Division of Cancer Epidemiology, German Cancer Research Center, DKFZ, Heidelberg, Germany.
    Katzke, Verena
    Division of Cancer Epidemiology, German Cancer Research Center, DKFZ, Heidelberg, Germany.
    Amiano, Pilar
    Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Ministry of Health of the Basque Government, Sub Directorate for Public Health and Addictions of Gipuzkoa, San Sebastian, Spain; Biodonostia Health Research Institute, Epidemiology of Chronic and Communicable Diseases Group, San Sebastian, Spain.
    Rodriguez-Barranco, Miguel
    Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Escuela Andaluza de Salud Pública (EASP), Granada, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain.
    Engström, Gunnar
    Department of Clinical Sciences, Malmö, Lund University, Malmö, Sweden.
    Weiderpass, Elisabete
    International Agency for Research on Cancer, World Health Organization, Lyon, France.
    Tjønneland, Anne
    Danish Cancer Society Research Center, Copenhagen, Denmark; Department of Public Health, Section of Environmental Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
    Halkjær, Jytte
    Danish Cancer Society Research Center, Copenhagen, Denmark.
    Panico, Salvatore
    School of Medicine, Federico II University, Naples, Italy.
    Danesh, John
    BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; National Institute for Health and Care Research Cambridge Biomedical Research Centre, Cambridge University Hospitals, Cambridge, United Kingdom; The National Institute for Health and Care Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics, University of Cambridge, Cambridge, United Kingdom; Human Genetics, Wellcome Sanger Institute, Saffron Walden, United Kingdom; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, United Kingdom; British Heart Foundation Centre of Research Excellence, Division of Cardiovascular Medicine, Addenbrooke’s Hospital, Cambridge, United Kingdom.
    Butterworth, Adam
    Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom; Heart and Lung Research Institute, University of Cambridge, Cambridge, United Kingdom; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, United Kingdom; NIHR Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge, Cambridge, United Kingdom; BHF Centre of Research Excellence, School of Clinical Medicine, Addenbrooke’s Hospital, Cambridge, United Kingdom.
    Onland-Moret, N. Charlotte
    Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands.
    Age at menopause and the risk of stroke: observational and mendelian randomization analysis in 204 244 postmenopausal women2023In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, E-ISSN 2047-9980, Vol. 12, no 18, article id e030280Article in journal (Refereed)
    Abstract [en]

    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.

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