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Objective A subset of patients with superficial venous thrombosis (SVT) experiences clot propagation towards deep venous thrombosis (DVT) and/or pulmonary embolism (PE). The aim of this systematic review is to identify all clinically relevant cross-sectional and prognostic factors for predicting thrombotic complications in patients with SVT.Design Systematic review.Data sources PubMed/MEDLINE and Embase were systematically searched until 3 March 2023.Eligibility criteria Original research studies with patients with SVT, DVT and/or PE as the outcome and presenting cross-sectional or prognostic predictive factors.Data extraction and synthesis of results The CHecklist for critical Appraisal and data extraction for systematic Reviews of prediction Modelling (CHARMS) checklist for prognostic factor studies was used for systematic extraction of study characteristics. Per identified predictive factor, relevant estimates of univariable and multivariable predictor—outcome associations were extracted, such as ORs and HRs. Estimates of association for the most frequently reported predictors were summarised in forest plots, and meta-analyses with heterogeneity were presented. The Quality in Prognosis Studies (QUIPS) tool was used for risk of bias assessment and Grading of Recommendations, Assessment, Development and Evaluations (GRADE) for assessing the certainty of evidence.Results Twenty-two studies were included (n=10 111 patients). The most reported predictive factors were high age, male sex, history of venous thromboembolism (VTE), absence of varicose veins and cancer. Pooled effect estimates were heterogenous and ranged from OR 3.12 (95% CI 1.75 to 5.59) for the cross-sectional predictor cancer to OR 0.92 (95% CI 0.56 to 1.53) for the prognostic predictor high age. The level of evidence was rated very low to low. Most studies were scored high or moderate risk of bias.Conclusions Although the pooled estimates of the predictors high age, male sex, history of VTE, cancer and absence of varicose veins showed predictive potential in isolation, variability in study designs, lack of multivariable adjustment and high risk of bias prevent firm conclusions. High-quality, multivariable studies are necessary to be able to identify individual SVT risk profiles.PROSPERO registration number CRD42021262819.

Objective To identify and synthesise relevant existing prognostic factors (PF) and prediction models (PM) for hospitalisation and all-cause mortality within 90 days in primary care patients with acute lower respiratory tract infections (LRTI).Design Systematic review.Methods Systematic searches of MEDLINE, Embase and the Cochrane Library were performed. All PF and PM studies on the risk of hospitalisation or all-cause mortality within 90 days in adult primary care LRTI patients were included. The risk of bias was assessed using the Quality in Prognostic Studies tool and Prediction Model Risk Of Bias Assessment Tool tools for PF and PM studies, respectively. The results of included PF and PM studies were descriptively summarised.Results Of 2799 unique records identified, 16 were included: 9 PF studies, 6 PM studies and 1 combination of both. The risk of bias was judged high for all studies, mainly due to limitations in the analysis domain. Based on reported multivariable associations in PF studies, increasing age, sex, current smoking, diabetes, a history of stroke, cancer or heart failure, previous hospitalisation, influenza vaccination (negative association), current use of systemic corticosteroids, recent antibiotic use, respiratory rate ≥25/min and diagnosis of pneumonia were identified as most promising candidate predictors. One newly developed PM was externally validated (c statistic 0.74, 95% CI 0.71 to 0.78) whereas the previously hospital-derived CRB-65 was externally validated in primary care in five studies (c statistic ranging from 0.72 (95% CI 0.63 to 0.81) to 0.79 (95% CI 0.65 to 0.92)). None of the PM studies reported measures of model calibration.Conclusions Implementation of existing models for individualised risk prediction of 90-day hospitalisation or mortality in primary care LRTI patients in everyday practice is hampered by incomplete assessment of model performance. The identified candidate predictors provide useful information for clinicians and warrant consideration when developing or updating PMs using state-of-the-art development and validation techniques.PROSPERO registration number CRD42022341233.

Introduction Meta-analyses show postive effects of telemedicine in heart failure (HF) management on hospitalisation, mortality and costs. However, these effects are heterogeneous due to variation in the included HF population, the telemedicine components and the quality of the comparator usual care. Still, telemedicine is gaining acceptance in HF management. The current nationwide study aims to identify (1) in which subgroup(s) of patients with HF telemedicine is (cost-)effective and (2) which components of telemedicine are most (cost-)effective.Methods and analysis The RELEASE-HF (‘REsponsible roLl-out of E-heAlth through Systematic Evaluation – Heart Failure’) study is a multicentre, observational, registry-based cohort study that plans to enrol 6480 patients with HF using data from the HF registry facilitated by the Netherlands Heart Registration. Collected data include patient characteristics, treatment information and clinical outcomes, and are measured at HF diagnosis and at 6 and 12 months afterwards. The components of telemedicine are described at the hospital level based on closed-ended interviews with clinicians and at the patient level based on additional data extracted from electronic health records and telemedicine-generated data. The costs of telemedicine are calculated using registration data and interviews with clinicians and finance department staff. To overcome missing data, additional national databases will be linked to the HF registry if feasible. Heterogeneity of the effects of offering telemedicine compared with not offering on days alive without unplanned hospitalisations in 1 year is assessed across predefined patient characteristics using exploratory stratified analyses. The effects of telemedicine components are assessed by fitting separate models for component contrasts.Ethics and dissemination The study has been approved by the Medical Ethics Committee 2021 of the University Medical Center Utrecht (the Netherlands). Results will be published in peer-reviewed journals and presented at (inter)national conferences. Effective telemedicine scenarios will be proposed among hospitals throughout the country and abroad, if applicable and feasible.Trial registration number NCT05654961.

Introduction During the COVID-19 pandemic, hospital capacity was strained. Home-based care could relieve the hospital care system and improve patient well-being if safely organised.We designed an intervention embedded in a regional collaborative healthcare network for the home-based management of acutely ill COVID-19 patients requiring oxygen treatment. Here, we describe the design and pilot protocol for the evaluation of the feasibility of this complex intervention.Methods and analysis Following a participatory action research approach, the intervention was designed in four consecutive steps: (1) literature review and establishment of an expert panel; (2) concept design of essential intervention building blocks (acute medical care, acute nursing care, remote monitoring, equipment and technology, organisation and logistics); (3) safety assessments (prospective risk analysis and a simulation patient evaluation) and (4) description of the design of the pilot (feasibility) study aimed at including approximately 15–30 patients, sufficient for fine-tuning for a large-scale randomised intervention.Ethics and dissemination All patients will provide written, informed consent. The study was approved by the Medical Ethics Review Committee of the University Medical Center Utrecht, the Netherlands (protocol NL77421.041.21). The preparatory steps (1–4) needed to perform the pilot are executed and described in this paper. The findings of the pilot will be published in academic journals. If we consider the complex intervention feasible, we aim to continue with a large-scale randomised controlled study evaluating the clinical effectiveness, safety and implementation of the complex intervention.

Objective Literature supports associations between common respiratory tract infections (RTIs) and risk of cardiovascular diseases, yet the importance of RTIs for cardiovascular risk management remains less understood. This systematic review and meta-analysis aimed to estimate the causal effects of RTIs on occurrence of cardiovascular diseases in the general population.Methods MEDLINE and EMBASE were systematically searched up to 4 November 2022. Eligible were all aetiological studies evaluating risk of cardiovascular outcomes after exposure to common RTIs within any follow-up duration. Evidence was pooled using random-effects models if data allowed. The ROBINS-E and GRADE approaches were used to rate risk of bias and certainty of evidence, respectively. All assessments were performed in duplicate.Results We included 34 studies (65 678 650 individuals). Most studies had a high risk of bias. COVID-19 likely increases relative risk (RR (95% CI)) of myocardial infarction (3.3 (1.0 to 11.0)), stroke (3.5 (1.2 to 10)), pulmonary embolism (24.6 (13.5 to 44.9)) and deep venous thrombosis (7.8 (4.3 to 14.4)) within 30 days after infection (GRADE: moderate) and about twofold within 1 year (GRADE: low to moderate). Other RTIs also likely increase the RR of myocardial infarction (2.9 (95% CI 1.8 to 4.9)) and stroke (2.6 (95% CI 1.1 to 6.4)) within 30 days (GRADE: moderate), and to a lesser extent with longer follow-up.Conclusions RTIs likely increase the risk of cardiovascular diseases about 1.5–5 fold within 1 month after infection. RTIs may, therefore, have clinical relevance as target for cardiovascular risk management, especially in high-risk populations.PROSPERO registration number CRD42023416277.

Objective Postmarketing observational studies report that a substantial percentage of patients with atrial fibrillation (AF) receive a reduced non-vitamin K antagonist oral anticoagulant (NOAC) dose without a clear indication. Recently, increasing evidence has become available to explore the clinical consequences of such off-label reduced dosing (OLRD). This study aims to systematically review and meta-analyse observational studies that report clinical outcomes associated with OLRD of NOACs compared with on-label non-reduced dosing (OLNRD) of NOACs in patients with AF.Methods and analysis We performed a systematic literature review and meta-analysis of observational studies reporting clinical outcomes in AF patients with OLRD of an NOAC compared with AF patients with OLNRD of an NOAC. Using random effects meta-analyses, we estimated the risk of stroke/thromboembolism, bleeding and all-cause mortality.Results We included 19 studies with a total of 170 394 NOAC users. In these studies, the percentage of OLRD among patients with an indication for an on-label non-reduced NOAC dose ranged between 9% and 53%. 7 of these 19 studies met the predefined criteria for meta-analysis (n=80 725 patients). The pooled HR associated with OLRD of NOACs was 1.04 (95% CI 0.83 to 1.29; 95% prediction interval (PI) 0.60 to 1.79) for stroke/thromboembolism, 1.10 (95% CI 0.95 to 1.29; 95% PI 0.81 to 1.50) for bleeding and 1.22 (95% CI 0.81 to 1.84; 95% PI 0.55 to 2.70) for all-cause mortality.Conclusion This meta-analysis shows no statistically significant increased risk of stroke/thromboembolism, nor a decreased bleeding risk, nor a difference in risk of all-cause mortality in patients with OLRD of NOACs. Future research may focus on differences between NOACs.

IntroductionIntegrated care is effective in reducing all-cause mortality in patients with atrial fibrillation (AF) in primary care, though time and resource intensive. The aim of the current study was to assess whether integrated care should be directed at all AF patients equally.MethodsThe ALL-IN trial (n = 1,240 patients, median age 77 years) was a cluster-randomized trial in which primary care practices were randomized to provide integrated care or usual care to AF patients aged 65 years and older. Integrated care comprised of (i) anticoagulation monitoring, (ii) quarterly checkups and (iii) easy-access consultation with cardiologists. For the current analysis, cox proportional hazard analysis with all clinical variables from the CHA2DS2-VASc score was used to predict all-cause mortality in the ALL-IN trial. Subsequently, the hazard ratio and absolute risk reduction were plotted as a function of this predicted mortality risk to explore treatment heterogeneity.ResultsUnder usual care, after a median of 2 years follow-up the absolute risk of all-cause mortality in the highest-risk quarter was 31.0%, compared to 4.6% in the lowest-risk quarter. On the relative scale, there was no evidence of treatment heterogeneity (p for interaction = 0.90). However, there was substantial treatment heterogeneity on the absolute scale: risk reduction in the lowest risk- quarter of risk 3.3% (95% CI -0.4% - 7.0) compared to 12.0% (95% CI 2.7% - 22.0) in the highest risk quarter.ConclusionWhile the relative degree of benefit from integrated AF care is similar in all patients, patients with a high all-cause mortality risk have a greater benefit on an absolute scale and should therefore be prioritized when implementing integrated care.

BackgroundResearch on the use of home telemonitoring data and adherence to it can provide new insights into telemonitoring for the daily management of patients with heart failure (HF). ObjectiveWe described the use of a telemonitoring platform—including remote patient monitoring of blood pressure, pulse, and weight—and the use of the electronic personal health record. Patient characteristics were assessed in both adherent and nonadherent patients to weight transmissions. MethodsWe used the data of the e-Vita HF study, a 3-arm parallel randomized trial performed in stable patients with HF managed in outpatient clinics in the Netherlands. In this study, data were analyzed from the participants in the intervention arm (ie, e-Vita HF platform). Adherence to weight transmissions was defined as transmitting weight ≥3 times per week for at least 42 weeks during a year. ResultsData from 150 patients (mean age 67, SD 11 years; n=37, 25% female; n=123, 82% self-assessed New York Heart Association class I-II) were analyzed. One-year adherence to weight transmissions was 74% (n=111). Patients adherent to weight transmissions were less often hospitalized for HF in the 6 months before enrollment in the study compared to those who were nonadherent (n=9, 8% vs n=9, 23%; P=.02). The percentage of patients visiting the personal health record dropped steadily over time (n=140, 93% vs n=59, 39% at one year). With univariable analyses, there was no significant correlation between patient characteristics and adherence to weight transmissions. ConclusionsAdherence to remote patient monitoring was high among stable patients with HF and best for weighing; however, adherence decreased over time. Clinical and demographic variables seem not related to adherence to transmitting weight. Trial RegistrationClinicalTrials.gov NCT01755988; https://clinicaltrials.gov/ct2/show/NCT01755988

Objective To develop and validate a symptom-based prediction rule for early recognition of acute coronary syndrome (ACS) in patients with acute chest discomfort who call out-of-hours services for primary care (OHS-PC).Design Cross-sectional study. A diagnostic prediction rule was developed with multivariable regression analyses. All models were validated with internal-external cross validation within seven OHS-PC locations. Both age and sex were analysed as statistical interaction terms, applying for age non-linear effects.Setting Seven OHS-PC in the Netherlands.Participants 2192 patients who called OHS-PC for acute chest discomfort (pain, pressure, tightness or discomfort) between 2014 and 2017. Backed up recordings of telephone triage conversations were analysed.Primary and secondary outcomes measures Diagnosis of ACS retrieved from the patient’s medical records in general practice, including hospital specialists discharge letters. Performance of the prediction rules was calculated with the c-statistic and the final model was chosen based on net benefit analyses.Results Among the 2192 patients who called the OHS-PC with acute chest discomfort, 8.3% females and 15.3% males had an ACS. The final diagnostic model included seven predictors (sex, age, acute onset of chest pain lasting less than 12 hours, a pressing/heavy character of the pain, radiation of the pain, sweating and calling at night). It had an adjusted c-statistic of 0.77 (95% CI 0.74 to 0.79) with good calibration.Conclusion The final prediction model for ACS has good discrimination and calibration and shows promise for replacing the existing telephone triage rules for patients with acute chest discomfort in general practice and OHS-PC.Trial registration number NTR7331.

Introduction Callers with acute shortness of breath (SOB) are a challenge for telephone triage at out-of-hours primary care (OHS-PC) as SOB could be the sign of a potentially life-threatening disease, yet mostly is a symptom of a broad range of self-limiting disorders. Current telephone triage practice is mainly expert based and clear evidence on accuracy, safety and efficiency of the use of the Netherlands Triage Standard (NTS) by triage nurses based on the eventual clinical outcome is lacking for this domain.Methods and data analysis Multiple methods study in five OHS-PC services in the Utrecht region, the Netherlands. Data will be collected from OHS-PC electronic health records (EHR) and backed up tapes of telephone triage conversations, which will be linked to routine primary care EHR data. In cross-sectional studies, we will (1) validate the NTS urgency classification for adults with SOB against final diagnoses and (2) develop diagnostic prediction models for urgent diagnoses (eg, composite endpoint of urgent diagnoses, pulmonary embolism, acute coronary syndrome, acute heart failure and pneumonia). We will develop improvement measures for the use of the NTS by triage nurses through practice observations and semistructured interviews with patients, triage nurses and general practitioners (GPs). In an action research approach, we will, in collaboration with these stakeholders, implement and evaluate our findings in both GP and triage nurse educational programmes as well as in OHS-PC services.Ethics and dissemination The Medical Ethics Review Committee Utrecht, the Netherlands, approved the study protocol (protocol 21/361). We will take into account the ‘code of conduct for responsible research’ of the WHO, the EU General Data Protection Regulation and the ‘Dutch Medical Treatment Contracts Act’. Results will be disseminated in peer-reviewed publications and at (inter)national meetings.Trial registration number NL9682.

Objective To estimate the incidence of ischaemic heart disease, atrial fibrillation and heart failure in community patients with or without chronic obstructive pulmonary disease (COPD).Methods For this population-based study, we used primary care data of the Julius General Practitioners’ Network. Eligible participants were aged 40–80 years old and contributed data between January 2014 and February 2019. Participants were divided into groups according to COPD status and were followed up for new ischaemic heart disease, atrial fibrillation and/or heart failure. Age-specific and sex-specific incidence and incidence rate ratios were calculated for patients with and without COPD.Results Mean follow-up was 3.9 years, 6223 patients were included in the COPD group, and 137 028 individuals in the background group without COPD. Incidence rates of all three heart diseases increased with age and were higher in males, independent of presence of COPD. Incidence rate ratios for patients with COPD, adjusted for age and sex, were 1.69 (95% CI 1.49 to 1.92) for ischaemic heart disease, 1.56 (95% CI 1.38 to 1.77) for atrial fibrillation and 2.96 (95% CI 2.58 to 3.40) for heart failure.Conclusion The incidence of all major cardiovascular diseases is higher in patients with COPD, with the highest incidence rate ratio observed for heart failure.

ObjectivesCardiovascular 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.DesignAnalysis of anonymised routine care data extracted from electronic medical records from three large Dutch primary care registries.SettingPrimary care.ParticipantsConsecutive 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 measuresA 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).ResultsThe full model performed better than the simple model (likelihood ratio test pConclusionsFor 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.

Introduction The early stages of chronic progressive cardiovascular disease (CVD) generally cause non-specific symptoms that patients often do not spontaneously mention to their general practitioner, and are therefore easily missed. A proactive diagnostic strategy has the potential to uncover these frequently missed early stages, creating an opportunity for earlier intervention. This is of particular importance for chronic progressive CVDs with evidence-based therapies known to improve prognosis, such as ischaemic heart disease, atrial fibrillation and heart failure.Patients with type 2 diabetes or chronic obstructive pulmonary disease (COPD) are at particularly high risk of developing CVD. In the current study, we will demonstrate the feasibility and effectiveness of screening these high-risk patients with our early diagnosis strategy, using tools that are readily available in primary care, such as symptom questionnaires (to be filled out by the patients themselves), natriuretic peptide measurement and electrocardiography.Methods and analysis The Reviving the Early Diagnosis-CVD trial is a multicentre, cluster randomised diagnostic trial performed in primary care practices across the Netherlands. We aim to include 1300 (2×650) patients who participate in a primary care disease management programme for COPD or type 2 diabetes. Practices will be randomised to the intervention arm (performing the early diagnosis strategy during the routine visits that are part of the disease management programmes) or the control arm (care as usual). The main outcome is the number of newly detected cases with CVDs in both arms, and the subsequent therapies they received. Secondary endpoints include quality of life, cost-effectiveness and the added diagnostic value of family and reproductive history questionnaires and three (novel) biomarkers (high-sensitive troponin-I, growth differentiation factor-15 and suppressor of tumourigenicity 2). Finally newly initiated treatments will be compared in both groups.Ethics and dissemination The protocol was approved by the Medical Ethical Committee of the University Medical Center Utrecht, the Netherlands. Results are expected in 2022 and will be disseminated through international peer-reviewed publications.Trial registration number NTR7360.

Objectives To identify clinical variables that are associated with the diagnosis acute coronary syndrome (ACS) in women and men with chest discomfort who contact out-of-hours primary care (OHS-PC) by telephone, and to explore whether there are indications whether these variables differ among women and men.Design Cross-sectional study in which we compared patient and call characteristics of triage call recordings between women with and without ACS, and men with and without ACS.Setting Nine OHS-PC in the Netherlands.Participants 993 women and 802 men who called OHS-PC for acute chest discomfort (pain, pressure, tightness or discomfort) between 2014 and 2016.Primary outcome measure Diagnosis of ACS retrieved from the patient’s medical record in general practice, including hospital specialists’ discharge letters.Results Among 1795 patients (mean age 58.8 (SD 19.5) years, 55.3% women), 15.0% of men and 8.6% of women had an ACS. In both sexes, retrosternal chest pain was associated with ACS (women with ACS vs without 62.3% vs 40.3%, p=0.002; men with ACS vs without 52.5% vs 39.7%, p=0.032; gender interaction, p=0.323), as was pressing/heavy/tightening pain (women 78.6% vs 61.5%, p=0.011; men 82.1% vs 57.4%, p=

Objectives Telephone triage of patients suspected of transient ischaemic attack (TIA) or stroke is challenging. Both TIA and stroke more likely occur during daytime, with a peak in the morning hours. Thus, the time of calling might be a helpful determinant during telephone triage. We assessed the time of calling in patients with stroke-like symptoms who called the out-of-hours services in primary care (OHS-PC), and evaluated whether the time of calling differed between patients with TIA or stroke compared with those with mimics.Design Cross-sectional study.Setting Six OHS-PC locations in the Netherlands.Participants 1269 telephone triage recordings of patients calling the OHS-PC because of stroke-like symptoms. We collected information on patient characteristics, symptoms, time of calling and urgency allocation. The final diagnosis related to each triage call was based on letters from the neurologist (retrieved from the patient’s general practitioner).Primary and secondary outcome measures The primary outcome measures were the time of calling hourly and 4 hourly, and the risk of TIA or stroke/hour. The secondary outcome measure was the risk ratio of TIA or stroke in the morning (08:00—12:00h) versus other hours.Results Mean age was 68.6 (SD±18.5) years, 56.9% were women and 50.0% had a TIA or stroke. The risk ratio of TIA or stroke among people calling with stroke-like symptoms between 08:00—12:00h versus other hours was 1.13 (95% CI 1.00 to 1.28, p=0.070). After correction for age and sex, the adjusted risk ratio was 0.94 (95% CI 0.80 to 1.10, p=0.434).Conclusion In patients who called the OHS-PC because of stroke-like symptoms, the time of calling did not differ between patients with TIA or stroke and patients with mimics.Trial registration number The Netherlands National Trial Registry (NTR7331).

Objective Clinical prediction rules (CPRs) followed by D-dimer testing were shown to safely rule out venous thromboembolism (VTE) in about half of all suspected patients in controlled and experienced study settings. Yet, its real-life impact in primary care is unknown. The aim of this study was to determine the real-life impact of CPRs for suspected VTE in primary care.Design Cross-sectional cohort study.Setting Primary care in the Netherlands.Participants Patients with suspected deep venous thrombosis (n=993) and suspected pulmonary embolism (n=484).Interventions General practitioners received an educational instruction on how to use CPRs in suspected VTE. We did not rectify incorrect application of the CPR in order to mimic daily clinical care.Main outcome measures Primary outcomes were the diagnostic failure rate, defined as the 3-month incidence of VTE in the non-referred group, and the efficiency, defined as the proportion of non-referred patients in the total study population. Secondary outcomes were determinants for and consequences of incorrect application of the CPRs.Results In 267 of the included 1477 patients, VTE was confirmed. When CPRs were correctly applied, the failure rate was 1.51% (95% CI 0.77 to 2.86), and the efficiency was 58.1% (95% CI 55.2 to 61.0). However, the CPRs were incorrectly applied in 339 patients, which resulted in an increased failure rate of 3.31% (95% CI 1.07 to 8.76) and a decreased efficiency of 35.7% (95% CI 30.6 to 41.1). The presence of concurrent heart failure increased the likelihood of incorrect application (adjusted OR 3.26; 95% CI 1.47 to 7.21).Conclusions Correct application of CPRs for VTE in primary care is associated with an acceptable low failure rate at a high efficiency. Importantly, in nearly a quarter of patients, the CPRs were incorrectly applied that resulted in a higher failure rate and a considerably lower efficiency.

Introduction Anticoagulation therapy is pivotal in the management of stroke prevention in atrial fibrillation (AF). Prospective registries, containing longitudinal data are lacking with detailed information on anticoagulant therapy, treatment adherence and AF-related adverse events in practice-based patient cohorts, in particular for non-vitamin K oral anticoagulants (NOAC). With the creation of DUTCH-AF, a nationwide longitudinal AF registry, we aim to provide clinical data and answer questions on the (anticoagulant) management over time and of the clinical course of patients with newly diagnosed AF in routine clinical care. Within DUTCH-AF, our current aim is to assess the effect of non-adherence and non-persistence of anticoagulation therapy on clinical adverse events (eg, bleeding and stroke), to determine predictors for such inadequate anticoagulant treatment, and to validate and refine bleeding prediction models. With DUTCH-AF, we provide the basis for a continuing nationwide AF registry, which will facilitate subsequent research, including future registry-based clinical trials.Methods and analysis The DUTCH-AF registry is a nationwide, prospective registry of patients with newly diagnosed ‘non-valvular’ AF. Patients will be enrolled from primary, secondary and tertiary care practices across the Netherlands. A target of 6000 patients for this initial cohort will be followed for at least 2 years. Data on thromboembolic and bleeding events, changes in antithrombotic therapy and hospital admissions will be registered. Pharmacy-dispensing data will be obtained to calculate parameters of adherence and persistence to anticoagulant treatment, which will be linked to AF-related outcomes such as ischaemic stroke and major bleeding. In a subset of patients, anticoagulation adherence and beliefs about drugs will be assessed by questionnaire.Ethics and dissemination This study protocol was approved as exempt for formal review according to Dutch law by the Medical Ethics Committee of the Leiden University Medical Centre, Leiden, the Netherlands. Results will be disseminated by publications in peer-reviewed journals and presentations at scientific congresses.Trial registration number Trial NL7467, NTR7706 (https://www.trialregister.nl/trial/7464).

Background: Diagnosing heart failure (HF) is difficult, relying on medical history, symptoms, and signs only. Clinical guidelines recommend natriuretic peptides (NPs) as an additional diagnostic test, notably to exclude HF in suspected patients. NP testing has been available since 2003 for primary care in the Netherlands, but little is known about its uptake. Aim: To evaluate the trend in ordering and appropriateness of NP testing in primary care. Design & setting: An observational study was performed between January 2005 and December 2013. Nine Dutch general practices participated, with 21 000 registered people (approximately 4300 aged ≥65 years). Method: The total number of patients undergoing NP testing each year was calculated per 1000 patient years (PY) based on the total practice population. NP levels were used to assess whether NP testing was applied to exclude or confirm HF. Results: The number of NP testing increased from 2.5 per 1000 PY in 2005 to 14.0 per 1000 PY in 2013, with a peak in 2009 of 15.6 per 1000 PY. The proportion of participants with N-terminal B-type natriuretic peptide (NTproBNP) below 125 pg/ml (the exclusionary threshold recommended by the European Society of Cardiology [ESC] guidelines on HF) was on average 30%, and highest in the first year (47%). Conclusion: After a rapid uptake of NP testing in primary care from 2005 onwards, the use of it seemed to stabilise after 2009, thus leaving patients who are prone to HF without an optimal diagnostic work-up.

Introduction Clinical 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 analysis The 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

Introduction Combined with patient history and physical examination, a negative D-dimer can safely rule-out pulmonary embolism (PE). However, the D-dimer test is frequently false positive, leading to many (with hindsight) ‘unneeded’ referrals to secondary care. Recently, the novel YEARS algorithm, incorporating flexible D-dimer thresholds depending on pretest risk, was developed and validated, showing its ability to safely exclude PE in the hospital environment. Importantly, this was accompanied with 14% fewer computed tomographic pulmonary angiography than the standard, fixed D-dimer threshold. Although promising, in primary care this algorithm has not been validated yet.Methods and analysis The PECAN (Diagnosing Pulmonary Embolism in the context of Common Alternative diagNoses in primary care) study is a prospective diagnostic study performed in Dutch primary care. Included patients with suspected acute PE will be managed by their general practitioner according to the YEARS diagnostic algorithm and followed up in primary care for 3 months to establish the final diagnosis. To study the impact of the use of the YEARS algorithm, the primary endpoints are the safety and efficiency of the YEARS algorithm in primary care. Safety is defined as the proportion of false-negative test results in those not referred. Efficiency denotes the proportion of patients classified in this non-referred category. Additionally, we quantify whether C reactive protein measurement has added diagnostic value to the YEARS algorithm, using multivariable logistic and polytomous regression modelling. Furthermore, we will investigate which factors contribute to the subjective YEARS item ‘PE most likely diagnosis’.Ethics and dissemination The study protocol was approved by the Medical Ethical Committee Utrecht, the Netherlands. Patients eligible for inclusion will be asked for their consent. Results will be disseminated by publication in peer-reviewed journals and presented at (inter)national meetings and congresses.Trial registration NTR 7431.

Introduction In the Netherlands, the ‘Netherlands Triage Standard’ (NTS) is frequently used as digital decision support system for telephone triage at out-of-hours services in primary care (OHS-PC). The aim of the NTS is to guarantee accessible, efficient and safe care. However, there are indications that current triage is inefficient, with overestimation of urgency, notably in suspected acute cardiovascular disease. In addition, in primary care settings the NTS has only been validated against surrogate markers, and diagnostic accuracy with clinical outcomes as the reference is unknown. In the Safety First study, we address this gap in knowledge by describing, understanding and improving the diagnostic process and urgency allocation in callers with symptoms suggestive of acute cardiovascular disease, in order to improve both efficiency and safety of telephone triage in this domain.Methods and analysis An observational study in which 3000 telephone triage recordings (period 2014–2016) will be analysed. Information is collected from the recordings including caller and symptom characteristics and urgency allocation. The callers’ own general practitioners are contacted for the final diagnosis of each contact. We included recordings of callers with symptoms suggestive of acute coronary syndrome (ACS) or transient ischaemic attack (TIA)/stroke. With univariable and multivariable logistic regression analyses the diagnostic accuracy of caller and symptom characteristics will be analysed in terms of predictive values with urgency level, and ACS and TIA/stroke as outcomes, respectively. To further improve our understanding of the triage process at OHS-PC, we will carry out additional studies applying both quantitative and qualitative methods: (i) case-control study on serious adverse events (SAE), (ii) conversation analysis study and (iii) interview study with triage nurses.Ethics and dissemination The Medical Ethics Committee Utrecht, the Netherlands endorsed this study (National Trial Register identification: NTR7331). Results will be disseminated at scientific conferences, regional educational sessions and publication in peer-reviewed journals.

BACKGROUND: Although it is known that patients with chronic obstructive pulmonary disease (COPD) generally do have an increased heart rate, the effects on both mortality and non-fatal pulmonary complications are unclear. We assessed whether heart rate is associated with all-cause mortality, and non-fatal pulmonary endpoints. METHODS: A prospective cohort study of 405 elderly patients with COPD was performed. All patients underwent extensive investigations, including electrocardiography. Follow-up data on mortality were obtained by linking the cohort to the Dutch National Cause of Death Register and information on complications (exacerbation of COPD or pneumonia) by scrutinizing patient files of general practitioners. Multivariable cox regression analysis was performed. RESULTS: During the follow-up 132 (33%) patients died. The overall mortality rate was 50/1000 py (42-59). The major causes of death were cardiovascular and respiratory. The relative risk of all-cause mortality increased with 21% for every 10 beats/minute increase in heart rate (adjusted HR: 1.21 [1.07-1.36], p = 0.002). The incidence of major non-fatal pulmonary events was 145/1000 py (120-168). The risk of a non-fatal pulmonary complication increased non-significantly with 7% for every 10 beats/minute increase in resting heart rate (adjusted HR: 1.07 [0.96-1.18], p = 0.208). CONCLUSIONS: Increased resting heart rate is a strong and independent risk factor for all-cause mortality in elderly patients with COPD. An increased resting heart rate did not result in an increased risk of exacerbations or pneumonia. This may indicate that the increased mortality risk of COPD is related to non-pulmonary causes. Future randomized controlled trials are needed to investigate whether heart-rate lowering agents are worthwhile for COPD patients.

BACKGROUND: In diagnostic studies, a single and error-free test that can be used as the reference (gold) standard often does not exist. One solution is the use of panel diagnosis, i.e., a group of experts who assess the results from multiple tests to reach a final diagnosis in each patient. Although panel diagnosis, also known as consensus or expert diagnosis, is frequently used as the reference standard, guidance on preferred methodology is lacking. The aim of this study is to provide an overview of methods used in panel diagnoses and to provide initial guidance on the use and reporting of panel diagnosis as reference standard. METHODS AND FINDINGS: PubMed was systematically searched for diagnostic studies applying a panel diagnosis as reference standard published up to May 31, 2012. We included diagnostic studies in which the final diagnosis was made by two or more persons based on results from multiple tests. General study characteristics and details of panel methodology were extracted. Eighty-one studies were included, of which most reported on psychiatry (37%) and cardiovascular (21%) diseases. Data extraction was hampered by incomplete reporting; one or more pieces of critical information about panel reference standard methodology was missing in 83% of studies. In most studies (75%), the panel consisted of three or fewer members. Panel members were blinded to the results of the index test results in 31% of studies. Reproducibility of the decision process was assessed in 17 (21%) studies. Reported details on panel constitution, information for diagnosis and methods of decision making varied considerably between studies. CONCLUSIONS: Methods of panel diagnosis varied substantially across studies and many aspects of the procedure were either unclear or not reported. On the basis of our review, we identified areas for improvement and developed a checklist and flow chart for initial guidance for researchers conducting and reporting of studies involving panel diagnosis. Please see later in the article for the Editors' Summary.

Recent observational studies suggest that β-blockers may improve long-term prognosis in patients with chronic obstructive pulmonary disease (COPD). We assessed whether β-blocker use improves all-cause mortality in patients with episodes of acute bronchitis.An observational cohort study using data from the electronic medical records of 23 general practices in the Netherlands. The data included standardized information about daily patient contacts, diagnoses, and drug prescriptions. Cox regression was applied with time-varying treatment and covariates.The study included 4,493 patients aged 45 years and older, with at least one episode of acute bronchitis between 1996 and 2006. The mean (SD) age of the patients was 66.9 (11.7) years, and 41.9% were male. During a mean (SD) follow up period of 7.7 (2.5) years, 20.4% developed COPD. In total, 22.7% had cardiovascular comorbidities, resulting in significant higher mortality rates than those without (51.7% vs. 12.0%, p

Background: Coronavirus disease 2019 (COVID-19) is a systemic disease with cardiovascular involvement, including cardiac arrhythmias. Notably, new-onset atrial fibrillation (AF) and atrial flutter (AFL) during hospitalisation in COVID-19 patients has been associated with increased mortality. However, how this risk is impacted by age and sex is still poorly understood. Methods: For this multicentre cohort study, we extracted demographics, medical history, occurrence of electrical disorders and in-hospital mortality from the large international patient registry CAPACITY-COVID. For each electrical disorder, prevalence during hospitalisation was calculated. Subsequently, we analysed the incremental prognostic effect of developing AF/AFL on in-hospital mortality, using multivariable logistic regression analyses, stratified for sex and age. Results: In total, 5782 patients (64% male; median age 67) were included. Of all patients 11.0% (95% CI 10.2–11.8) experienced AF and 1.6% (95% CI 1.3–1.9) experienced AFL during hospitalisation. Ventricular arrhythmias were rare (

Background Timely recognition of patients with acute coronary syndromes (ACS) is important for successful treatment. Previous research has suggested that women with ACS present with different symptoms compared with men. This review assessed the extent of sex differences in symptom presentation in patients with confirmed ACS. Methods and Results A systematic literature search was conducted in PubMed, Embase, and Cochrane up to June 2019. Two reviewers independently screened title‐abstracts and full‐texts according to predefined inclusion and exclusion criteria. Methodological quality was assessed using the Newcastle‐Ottawa Scale. Pooled odds ratios (OR) with 95% CI of a symptom being present were calculated using aggregated and cumulative meta‐analyses as well as sex‐specific pooled prevalences for each symptom. Twenty‐seven studies were included. Compared with men, women with ACS had higher odds of presenting with pain between the shoulder blades (OR 2.15; 95% CI, 1.95–2.37), nausea or vomiting (OR 1.64; 95% CI, 1.48–1.82) and shortness of breath (OR 1.34; 95% CI, 1.21–1.48). Women had lower odds of presenting with chest pain (OR 0.70; 95% CI, 0.63–0.78) and diaphoresis (OR 0.84; 95% CI, 0.76–0.94). Both sexes presented most often with chest pain (pooled prevalences, men 79%; 95% CI, 72–85, pooled prevalences, women 74%; 95% CI, 72–85). Other symptoms also showed substantial overlap in prevalence. The presence of sex differences has been established since the early 2000s. Newer studies did not materially change cumulative findings. Conclusions Women with ACS do have different symptoms at presentation than men with ACS, but there is also considerable overlap. Since these differences have been shown for years, symptoms should no longer be labeled as “atypical” or “typical.”

Abstract Background General Practitioners (GPs) in the Netherlands routinely register all patient contacts electronically. These records include longitudinally gathered clinical information of the patient contacts in coded data and free text. Methods Diagnoses are coded according to the International Coding of Primary Care (ICPC). Drug prescriptions are labelled with the Anatomical Therapeutic Chemical Classification (ATC), and letters of hospital specialists and paramedic health care professionals are linked or directly incorporated in the electronic medical files. A network of a large group of GPs collecting routine care data on an ongoing basis can be used for answering various research questions. Results The Julius General Practitioners’ Network (JGPN) database consists of routine care data from over ten years of a dynamic cohort of around 370,000 individuals registered with the participating GPs from the city of Utrecht and its vicinity. Health care data are extracted anonymously every quartile of a year and these data are used by researchers. Conclusion We describe the content and usability of our JGPN database, and how a wide variety of research questions could be answered, as illustrated with examples of published articles.

2016 ESC GUIDELINES FOR THE DIAGNOSIS AND TREATMENT OF ACUTE AND CHRONIC HEART FAILURE.The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC).Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.