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IntroductionClinical guidelines recommend non-vitamin K antagonist oral anticoagulants (NOACs) over vitamin K antagonists (VKAs) for stroke prevention in most patients with atrial fibrillation (AF). Frail elderly were under-represented in the landmark NOAC-trials, leaving a knowledge gap on the optimal anticoagulant management (VKA or NOAC) in this increasing population. The aim of the Frail-AF (FRAIL-AF) study is to assess whether switching from international normalised ratio (INR)-guided VKA-management to a NOAC-based treatment strategy compared with continuing VKA-management is safe in frail elderly patients with AF.Methods and analysisThe FRAIL-AF study is a pragmatic, multicentre, open-label, randomised controlled clinical trial. Frail elderly (age ≥75 years plus a Groningen Frailty Indicator score ≥3) who receive VKA-treatment for AF in the absence of a mechanical heart valve or severe mitral valve stenosis will be randomised to switch to a NOAC-based treatment strategy or to continue INR-guided VKA-management. Patients with severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m2) will be excluded from randomisation. Based on existing trial evidence in non-frail patients, we will aim to explore whether NOAC-treatment is superior to VKA-therapy in reducing major or clinically relevant non-major bleeding events. Secondary outcomes include minor bleeding, the composite of ischaemic and haemorrhagic stroke, health-related quality of life and cost-effectiveness. The follow-up period for all subjects is 12 months.Ethics and disseminationThe protocol was approved by the Medical Research Ethics Committee of the University Medical Center Utrecht, the Netherlands and by the Central Committee on Research Involving Human Subjects, the Netherlands. All patients are asked written informed consent. Results are expected in 2022 and will be disseminated through peer-reviewed journals as well as presentations at national and international conferences.Trial registration numberEudraCT: 2017-000393-11; The Netherlands Trial Registry: 6721 (FRAIL-AF study).

Objectives Cardiovascular conditions were shown to be predictive of clinical deterioration in hospitalised patients with coronavirus disease 2019 (COVID-19). Whether this also holds for outpatients managed in primary care is yet unknown. The aim of this study was to determine the incremental value of cardiovascular vulnerability in predicting the risk of hospital referral in primary care COVID-19 outpatients. Design Analysis of anonymised routine care data extracted from electronic medical records from three large Dutch primary care registries. Setting Primary care. Participants Consecutive adult patients seen in primary care for COVID-19 symptoms in the ‘first wave’ of COVID-19 infections (March 1 2020 to June 1 2020) and in the ‘second wave’ (June 1 2020 to April 15 2021) in the Netherlands. Outcome measures A multivariable logistic regression model was fitted to predict hospital referral within 90 days after first COVID-19 consultation in primary care. Data from the ‘first wave’ was used for derivation (n = 5,475 patients). Age, sex, the interaction between age and sex, and the number of cardiovascular conditions and/or diabetes (0, 1, or ≥2) were pre-specified as candidate predictors. This full model was (i) compared to a simple model including only age and sex and its interaction, and (ii) externally validated in COVID-19 patients during the ‘second wave’ (n = 16,693). Results The full model performed better than the simple model (likelihood ratio test p<0.001). Older male patients with multiple cardiovascular conditions and/or diabetes had the highest predicted risk of hospital referral, reaching risks above 15–20%, whereas on average this risk was 5.1%. The temporally validated c-statistic was 0.747 (95%CI 0.729–0.764) and the model showed good calibration upon validation. Conclusions For patients with COVID-19 symptoms managed in primary care, the risk of hospital referral was on average 5.1%. Older, male and cardiovascular vulnerable COVID-19 patients are more at risk for hospital referral.