Diabetes and risk of acute coronary syndrome in callers with chest discomfort: Cross-sectional study in out-of-hours primary care.

AIMS: We investigated the differences in prevalence of acute coronary syndrome (ACS) by presence versus absence of diabetes in males and females with chest discomfort who called out-of-hours primary care (OHS-PC). METHODS: A cross-sectional study performed in the Netherlands. Patients who called the OHS-PC in the Utrecht region, the Netherlands between 2014 and 2017 with acute chest discomfort were included. We compared those with diabetes with those without diabetes. Multivariable logistic regression was used to determine the relation between diabetes and (i) high urgency allocation and (ii) ACS. RESULTS: Of the 2,195 callers with acute chest discomfort, 180 (8.2%) reported having diabetes. ACS was present in 15.3% of males (22.0% in those with diabetes) and 8.4% of females (18.8% in those with diabetes). Callers with diabetes did not receive a high urgency more frequently (74.4% vs. 67.8% (OR: 1.38; 95% CI 0.98-1.96). However, such callers had a higher odds for ACS (OR: 2.17; 95% CI 1.47-3.19). These differences were similar for females and males. CONCLUSIONS: Diabetes holds promise as diagnostic factor in callers to OHS-PC with chest discomfort. It might help triage in this setting given the increased risk of ACS in those with diabetes.

Predictive factors of clot propagation in patients with superficial venous thrombosis towards deep venous thrombosis and pulmonary embolism: a systematic review and meta-analysis.

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.

Accuracy of urgency allocation in patients with shortness of breath calling out-of-hours primary care: a cross-sectional study.

BACKGROUND: In out-of-hours primary care (OHS-PC), semi-automatic decision support tools are often used during telephone triage. In the Netherlands, the Netherlands Triage Standard (NTS) is used. The NTS is mainly expert-based and evidence on the diagnostic accuracy of the NTS' urgency allocation against clinically relevant outcomes for patients calling with shortness of breath (SOB) is lacking. METHODS: We included data from adults (≥18 years) who contacted two large Dutch OHS-PC centres for SOB between 1 September 2020 and 31 August 2021 and whose follow-up data about final diagnosis could be retrieved from their own general practitioner (GP). The diagnostic accuracy (sensitivity and specificity with corresponding 95% confidence intervals (CI)) of the NTS' urgency levels (high (U1/U2) versus low (U3/U4/U5) and 'final' urgency levels (including overruling of the urgency by triage nurses or supervising general practitioners (GPs)) was determined with life-threatening events (LTEs) as the reference. LTEs included, amongst others, acute coronary syndrome, pulmonary embolism, acute heart failure and severe pneumonia. RESULTS: Out of 2012 eligible triage calls, we could include 1833 adults with SOB who called the OHS-PC, mean age 53.3 (SD 21.5) years, 55.5% female, and 16.6% showed to have had a LTE. Most often severe COVID-19 infection (6.0%), acute heart failure (2.6%), severe COPD exacerbation (2.1%) or severe pneumonia (1.9%). The NTS urgency level had a sensitivity of 0.56 (95% CI 0.50-0.61) and specificity of 0.61 (95% CI 0.58-0.63). Overruling of the NTS' urgency allocation by triage nurses and/or supervising GPs did not impact sensitivity (0.56 vs. 0.54, p = 0.458) but slightly improved specificity (0.61 vs. 0.65, p < 0.001). CONCLUSIONS: The semi-automatic decision support tool NTS performs poorly with respect to safety (sensitivity) and efficiency (specificity) of urgency allocation in adults calling Dutch OHS-PC with SOB. There is room for improvement of telephone triage in patients calling OHS-PC with SOB. TRIAL REGISTRATION: The Netherlands Trial Register, number: NL9682 .

[Coumarin or DOAC in frail elderly patients with atrial fibrillation?] / Cumarine of DOAC bij kwetsbare ouderen met atriumfibrilleren?

OBJECTIVE: To investigate whether frail elderly people with atrial fibrillation (AF) who are currently using a vitamin K antagonist (VKA) should be switched to a direct-acting oral anticoagulant (DOAC). DESIGN: Randomized clinical trial. METHODS: 662 frail elderly AF patients were switched to a DOAC, and 661 patients continued their VKA. The primary endpoint was a major or clinically relevant non-major bleeding during 1 year of follow-up. Secondary endpoints included thrombo-embolic events. RESULTS: The mean age of the included patients was 83 years. In the 'switch to DOAC arm', 101 bleeding events (15.3%) occurred and in the 'continue with VKA arm', 62 bleeding events (9.4%); an increase of 69% more bleeding events (P-value 0.001). The number of thrombo-embolic events was not significantly different between both groups. CONCLUSION: Switching from a VKA to a DOAC in frail elderly people with AF leads to 69% more bleeding, without a difference in thrombo-embolic events.

Prognostic factors and prediction models for hospitalisation and all-cause mortality in adults presenting to primary care with a lower respiratory tract infection: a systematic review.

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.

Heart failure with preserved ejection fraction: everything the clinician needs to know.

Heart failure with preserved ejection fraction (HFpEF) is increasingly recognised and diagnosed in clinical practice, a trend driven by an ageing population and a rise in contributing comorbidities, such as obesity and diabetes. Representing at least half of all heart failure cases, HFpEF is recognised as a complex clinical syndrome. Its diagnosis and management are challenging due to its diverse pathophysiology, varied epidemiological patterns, and evolving diagnostic and treatment approaches. This Seminar synthesises the latest insights on HFpEF, integrating findings from recent clinical trials, epidemiological research, and the latest guideline recommendations. We delve into the definition, pathogenesis, epidemiology, diagnostic criteria, and management strategies (non-pharmacological and pharmacological) for HFpEF. We highlight ongoing clinical trials and future developments in the field. Specifically, this Seminar offers practical guidance tailored for primary care practitioners, generalists, and cardiologists who do not specialise in heart failure, simplifying the complexities in the diagnosis and management of HFpEF. We provide practical, evidence-based recommendations, emphasising the importance of addressing comorbidities and integrating the latest pharmacological treatments, such as SGLT2 inhibitors.

RELEASE-HF study: a protocol for an observational, registry-based study on the effectiveness of telemedicine in heart failure in the Netherlands.

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.

Home-based management of hypoxaemic COVID-19 patients: design of the Therapy@Home pilot study.

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.

Incomplete and possibly selective recording of signs, symptoms, and measurements in free text fields of primary care electronic health records of adults with lower respiratory tract infections.

OBJECTIVES: To assess the completeness of recording of relevant signs, symptoms, and measurements in Dutch free text fields of primary care electronic health records (EHR) of adults with lower respiratory tract infections (LRTI). STUDY DESIGN AND SETTING: Retrospective cohort study embedded in a prediction modeling project using routine health care data of the Julius General Practitioners' Network of adult patients with LRTI. Free text fields of 1,000 primary care consultations of LRTI episodes between 2016 and 2019 were manually annotated to retrieve data on the recording of sixteen relevant signs, symptoms, and measurements. RESULTS: For 12/16 (75%) of the relevant signs, symptoms, and measurements, more than 50% of the values was not recorded. The patterns of recorded values indicated selective recording of positive or abnormal values. Recording rates varied across consultation type (physical consultation vs. home visit), diagnosis (acute bronchitis vs. pneumonia), antibiotic prescription issued (yes vs. no), and between practices. CONCLUSION: In EHR of primary care LRTI patients, recording of signs, symptoms, and measurements in free text fields is incomplete and possibly selective. When using free text data in EHR-based research, careful consideration of its recording patterns and appropriate missing data handling techniques is therefore required.

Safety of Switching From a Vitamin K Antagonist to a Non-Vitamin K Antagonist Oral Anticoagulant in Frail Older Patients With Atrial Fibrillation: Results of the FRAIL-AF Randomized Controlled Trial.

BACKGROUND: There is ambiguity whether frail patients with atrial fibrillation managed with vitamin K antagonists (VKAs) should be switched to a non-vitamin K oral anticoagulant (NOAC). METHODS: We conducted a pragmatic, multicenter, open-label, randomized controlled superiority trial. Older patients with atrial fibrillation living with frailty (≥75 years of age plus a Groningen Frailty Indicator score ≥3) were randomly assigned to switch from international normalized ratio-guided VKA treatment to an NOAC or to continued VKA treatment. Patients with a glomerular filtration rate <30 mL·min-1·1.73 m-2 or with valvular atrial fibrillation were excluded. Follow-up was 12 months. The cause-specific hazard ratio was calculated for occurrence of the primary outcome that was a major or clinically relevant nonmajor bleeding complication, whichever came first, accounting for death as a competing risk. Analyses followed the intention-to-treat principle. Secondary outcomes included thromboembolic events. RESULTS: Between January 2018 and June 2022, a total of 2621 patients were screened for eligibility and 1330 patients were randomly assigned (mean age 83 years, median Groningen Frailty Indicator score 4). After randomization, 6 patients in the switch-to-NOAC arm and 1 patient in the continue-with-VKA arm were excluded due to the presence of exclusion criteria, leaving 662 patients switched from a VKA to an NOAC and 661 patients continued VKAs in the intention-to-treat population. After 163 primary outcome events (101 in the switch arm, 62 in the continue arm), the trial was stopped for futility according to a prespecified futility analysis. The hazard ratio for our primary outcome was 1.69 (95% CI, 1.23-2.32). The hazard ratio for thromboembolic events was 1.26 (95% CI, 0.60-2.61). CONCLUSIONS: Switching international normalized ratio-guided VKA treatment to an NOAC in frail older patients with atrial fibrillation was associated with more bleeding complications compared with continuing VKA treatment, without an associated reduction in thromboembolic complications. REGISTRATION: URL: https://eudract.ema.europa.eu; Unique identifier: 2017-000393-11. URL: https://eudract.ema.europa.eu; Unique identifier: 6721 (FRAIL-AF study).

Association of mild kidney dysfunction with diastolic dysfunction and heart failure with preserved ejection fraction.

AIMS: We aim to investigate the association between kidney dysfunction and left ventricular diastolic dysfunction parameters and heart failure with preserved ejection fraction (HFpEF) and whether this is sex-specific. METHODS AND RESULTS: We included participants from the HELPFul observational study. Outpatient clinical care data, including echocardiography, and an expert panel judgement on HFpEF was collected. Estimated glomerular filtration rate (eGFR) was calculated by creatinine and cystatin C without race. The association between eGFR with E/e', left ventricular mass index, relative wall thickness, and stage C/D heart failure was tested by multivariable adjusted regression models, stratified by sex, reporting odds ratios and 95% confidence intervals (95% confidence interval). We analysed 880 participants, mean age 62.9 (standard deviation: 9.3) years, 69% female. Four hundred six participants had mild (37.6%) kidney dysfunction (eGFR: 60-89 mL/min/1.73 m2 ) or moderate (8.5%) kidney dysfunction (eGFR: 30-59 mL/min/1.73 m2 ). HFpEF was significantly more prevalent in participants with mild and moderate kidney dysfunction (10.3% and 16.0%, respectively) than participants with normal kidney function (3.4%). A lower kidney function was associated with higher E/e' and higher relative wall thickness values. Participants with moderate kidney dysfunction had a higher likelihood of American College of Cardiology/American Heart Association stage C/D HF (odds ratio: 2.07, 95% confidence interval: 1.23, 3.49) than participants with normal kidney functions. CONCLUSIONS: Both mild and moderate kidney dysfunction are independently associated with left ventricular diastolic dysfunction parameters and HFpEF. This association is independent of sex and strongest for moderate kidney dysfunction. Considering mild-to-moderate kidney dysfunction as risk factor for HFpEF may help identify high-risk groups benefiting most from early intervention.

Shortness of breath as a diagnostic factor for acute coronary syndrome in male and female callers to out-of-hours primary care.

OBJECTIVE: Chest discomfort and shortness of breath (SOB) are key symptoms in patients with acute coronary syndrome (ACS). It is, however, unknown whether SOB is valuable for recognising ACS during telephone triage in the out-of-hours primary care (OHS-PC) setting. METHODS: A cross-sectional study performed in the Netherlands. Telephone triage conversations were analysed of callers with chest discomfort who contacted the OHS-PC between 2014 and 2017, comparing patients with SOB with those who did not report SOB. We determine the relation between SOB and (1) High urgency allocation, (2) ACS and (3) ACS or other life-threatening diseases. RESULTS: Of the 2195 callers with chest discomfort, 1096 (49.9%) reported SOB (43.7% men, 56.3% women). In total, 15.3% men (13.2% in those with SOB) and 8.4% women (9.2% in those with SOB) appeared to have ACS. SOB compared with no SOB was associated with high urgency allocation (75.9% vs 60.8%, OR: 2.03; 95% CI 1.69 to 2.44, multivariable OR (mOR): 2.03; 95% CI 1.69 to 2.44), but not with ACS (10.9% vs 12.0%; OR: 0.90; 95% CI 0.69 to 1.17, mOR: 0.91; 95% CI 0.70 to 1.19) or 'ACS or other life-threatening diseases' (15.0% vs 14.1%; OR: 1.07; 95% CI 0.85 to 1.36, mOR: 1.09; 95% CI 0.86 to 1.38). For women the relation with ACS was 9.2% vs 7.5%, OR: 1.25; 95% CI 0.83 to 1.88, and for men 13.2% vs 17.4%, OR: 0.72; 95% CI 0.51 to 1.02. For 'ACS or other life-threatening diseases', this was 13.0% vs 8.5%, OR: 1.60; 95% CI 1.10 to 2.32 for women, and 7.5% vs 20.8%, OR: 0.81; 95% CI 0.59 to 1.12 for men. CONCLUSIONS: Men and women with chest discomfort and SOB who contact the OHS-PC more often receive high urgency than those without SOB. This seems to be adequate in women, but not in men when considering the risk of ACS or other life-threatening diseases.

Diagnostic yield of a proactive strategy for early detection of cardiovascular disease versus usual care in adults with type 2 diabetes or chronic obstructive pulmonary disease in primary care in the Netherlands (RED-CVD): a multicentre, pragmatic, cluster-randomised, controlled trial.

BACKGROUND: Progressive cardiovascular diseases (eg, heart failure, atrial fibrillation, and coronary artery disease) are often diagnosed late in high-risk individuals with common comorbidities that might mimic or mask symptoms, such as chronic obstructive pulmonary disease (COPD) and type 2 diabetes. We aimed to assess whether a proactive diagnostic strategy consisting of a symptom and risk factor questionnaire and low-cost and accessible tests could increase diagnosis of progressive cardiovascular diseases in patients with COPD or type 2 diabetes in primary care. METHODS: In this multicentre, pragmatic, cluster-randomised, controlled trial (RED-CVD), 25 primary care practices in the Netherlands were randomly assigned to usual care or a proactive diagnostic strategy conducted during routine consultations and consisting of a validated symptom questionnaire, followed by physical examination, N-terminal-pro-B-type natriuretic peptide measurement, and electrocardiography. We included adults (≥18 years) with type 2 diabetes, COPD, or both, who participated in a disease management programme. Patients with an established triple diagnosis of heart failure, atrial fibrillation, and coronary artery disease were excluded. In the case of abnormal findings, further work-up or treatment was done at the discretion of the general practitioner. The primary endpoint was the number of newly diagnosed cases of heart failure, atrial fibrillation, and coronary artery disease, adjudicated by an expert clinical outcome committee using international guidelines, at 1-year follow-up, in the intention-to-treat population. FINDINGS: Between Jan 31, 2019, and Oct 7, 2021, we randomly assigned 25 primary care centres: 11 to usual care and 14 to the intervention. We included patients between June 21, 2019, and Jan 31, 2022. Following exclusion of ineligible patients and those who did not give informed consent, 1216 participants were included: 624 (51%) in the intervention group and 592 (49%) in the usual care group. The mean age of participants was 68·4 years (SD 9·4), 482 (40%) participants were female, and 734 (60%) were male. During 1 year of follow-up, 50 (8%) of 624 participants in the intervention group and 18 (3%) of 592 in the control group were newly diagnosed with heart failure, atrial fibrillation, or coronary artery disease (adjusted odds ratio 2·97 [95% CI 1·66-5·33]). This trial is registered with the Netherlands Trial Registry, NTR7360, and was completed on Jan 31, 2023. INTERPRETATION: An easy-to-use, proactive, diagnostic strategy more than doubled the number of new diagnoses of heart failure, atrial fibrillation, and coronary artery disease in patients with type 2 diabetes or COPD in primary care compared with usual care. Although the effect on patient outcomes remains to be studied, our diagnostic strategy might contribute to improved early detection and timely initiation of treatment in individuals with cardiovascular disease. FUNDING: Dutch Heart Foundation.

Predicting adverse outcomes in adults with a community-acquired lower respiratory tract infection: a protocol for the development and validation of two prediction models for (i) all-cause hospitalisation and mortality and (ii) cardiovascular outcomes.

BACKGROUND: Community-acquired lower respiratory tract infections (LRTI) are common in primary care and patients at particular risk of adverse outcomes, e.g., hospitalisation and mortality, are challenging to identify. LRTIs are also linked to an increased incidence of cardiovascular diseases (CVD) following the initial infection, whereas concurrent CVD might negatively impact overall prognosis in LRTI patients. Accurate risk prediction of adverse outcomes in LRTI patients, while considering the interplay with CVD, can aid general practitioners (GP) in the clinical decision-making process, and may allow for early detection of deterioration. This paper therefore presents the design of the development and external validation of two models for predicting individual risk of all-cause hospitalisation or mortality (model 1) and short-term incidence of CVD (model 2) in adults presenting to primary care with LRTI. METHODS: Both models will be developed using linked routine electronic health records (EHR) data from Dutch primary and secondary care, and the mortality registry. Adults aged ≥ 40 years with a GP-diagnosis of LRTI between 2016 and 2019 are eligible for inclusion. Relevant patient demographics, medical history, medication use, presenting signs and symptoms, and vital and laboratory measurements will be considered as candidate predictors. Outcomes of interest include 30-day all-cause hospitalisation or mortality (model 1) and 90-day CVD (model 2). Multivariable elastic net regression techniques will be used for model development. During the modelling process, the incremental predictive value of CVD for hospitalisation or all-cause mortality (model 1) will also be assessed. The models will be validated through internal-external cross-validation and external validation in an equivalent cohort of primary care LRTI patients. DISCUSSION: Implementation of currently available prediction models for primary care LRTI patients is hampered by limited assessment of model performance. While considering the role of CVD in LRTI prognosis, we aim to develop and externally validate two models that predict clinically relevant outcomes to aid GPs in clinical decision-making. Challenges that we anticipate include the possibility of low event rates and common problems related to the use of EHR data, such as candidate predictor measurement and missingness, how best to retrieve information from free text fields, and potential misclassification of outcome events.

Incidence and individual risk prediction of post-COVID-19 cardiovascular disease in the general population: a multivariable prediction model development and validation study.

Aims: Previous studies suggest relatively increased cardiovascular risk after COVID-19 infection. This study assessed incidence and explored individual risk and timing of cardiovascular disease occurring post-COVID-19 in a large primary care database. Methods and results: Data were extracted from the UK's Clinical Practice Research Datalink. Incidence rates within 180 days post-infection were estimated for arterial or venous events, inflammatory heart disease, and new-onset atrial fibrillation or heart failure. Next, multivariable logistic regression models were developed on 220 751 adults with COVID-19 infection before 1 December 2020 using age, sex and traditional cardiovascular risk factors. All models were externally validated in (i) 138 034 vaccinated and (ii) 503 404 unvaccinated adults with a first COVID-19 infection after 1 December 2020. Discriminative performance and calibration were evaluated with internal and external validation. Increased incidence rates were observed up to 60 days after COVID-19 infection for venous and arterial cardiovascular events and new-onset atrial fibrillation, but not for inflammatory heart disease or heart failure, with the highest rate for venous events (13 per 1000 person-years). The best prediction models had c-statistics of 0.90 or higher. However, <5% of adults had a predicted 180-day outcome-specific risk larger than 1%. These rare outcomes complicated calibration. Conclusion: Risks of arterial and venous cardiovascular events and new-onset atrial fibrillation are increased within the first 60 days after COVID-19 infection in the general population. Models' c-statistics suggest high discrimination, but because of the very low absolute risks, they are insufficient to inform individual risk management.

Developing a personalized remote patient monitoring algorithm: a proof-of-concept in heart failure.

Aims: Non-invasive remote patient monitoring is an increasingly popular technique to aid clinicians in the early detection of worsening heart failure (HF) alongside regular follow-ups. However, previous studies have shown mixed results in the performance of such systems. Therefore, we developed and evaluated a personalized monitoring algorithm aimed at increasing positive-predictive-value (PPV) (i.e. alarm quality) and compared performance with simple rule-of-thumb and moving average convergence-divergence algorithms (MACD). Methods and results: In this proof-of-concept study, the developed algorithm was applied to retrospective data of daily bodyweight, heart rate, and systolic blood pressure of 74 HF-patients with a median observation period of 327 days (IQR: 183 days), during which 31 patients experienced 64 clinical worsening HF episodes. The algorithm combined information on both the monitored patients and a group of stable HF patients, and is increasingly personalized over time, using linear mixed-effect modelling and statistical process control charts. Optimized on alarm quality, heart rate showed the highest PPV (Personalized: 92%, MACD: 2%, Rule-of-thumb: 7%) with an F1 score of (Personalized: 28%, MACD: 6%, Rule-of-thumb: 8%). Bodyweight demonstrated the lowest PPV (Personalized: 16%, MACD: 0%, Rule-of-thumb: 6%) and F1 score (Personalized: 10%, MACD: 3%, Rule-of-thumb: 7%) overall compared methods. Conclusion: The personalized algorithm with flexible patient-tailored thresholds led to higher PPV, and performance was more sensitive compared to common simple monitoring methods (rule-of-thumb and MACD). However, many episodes of worsening HF remained undetected. Heart rate and systolic blood pressure monitoring outperformed bodyweight in predicting worsening HF. The algorithm source code is publicly available for future validation and improvement.

Patients' and GPs' views and expectations of home monitoring with a pulse oximeter: a mixed-methods process evaluation of a pilot randomised controlled trial.

BACKGROUND: Research on how home monitoring with a pulse oximeter is executed and experienced by patients with an acute illness such as COVID-19 and their GPs is scarce. AIM: To examine the process of structured home monitoring with a pulse oximeter for patients with COVID-19, their caregivers, and their GPs. DESIGN AND SETTING: This was a mixed-method process evaluation alongside a pilot feasibility randomised controlled trial. Patients drawn from a general practice setting, with COVID-19, and aged ≥40 years with cardiovascular comorbidities were included. METHOD: Quantitative trial data from 21 intervention group participants (age 63.2 years) were used, plus qualitative data from semi-structured interviews with 15 patients (age 62.9 years), eight informal caregivers, and 10 GPs. RESULTS: Adherence to the intervention was very high; 97.6% of protocolised peripheral oxygen saturation (SpO2) measurements in the first 14 days until admission to hospital were recorded (677/694, median daily per patient 2.7). Three identified themes from the interviews were: (a) user-friendliness of home monitoring: easy use of the pulse oximeter and patient preference of a three times daily measurement scheme; (b) patient empowerment: pulse oximeter use enhanced patient self-assurance and empowered patients and informal caregivers in disease management; and (c) added value to current clinical decision making. GPs perceived the pulse oximeter as a useful diagnostic tool and did not experience any additional workload. They felt more secure with remote monitoring with a pulse oximeter than only phone-based monitoring, but emphasised the need to keep an overall view on the patient's condition. CONCLUSION: Structured home monitoring by pulse oximetry supports patients and their informal caregivers in managing, and GPs in monitoring, acute COVID-19 disease. It appears suitable for use in acutely ill patients in general practice.

Estimated causal effects of common respiratory infections on cardiovascular risk: a meta-analysis.

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.

Home-based initiatives for acute management of COVID-19 patients needing oxygen: differences across The Netherlands.

OBJECTIVE: During the COVID-19 pandemic new collaborative-care initiatives were developed for treating and monitoring COVID-19 patients with oxygen at home. Aim was to provide a structured overview focused on differences and similarities of initiatives of acute home-based management in the Netherlands. METHODS: Initiatives were eligible for evaluation if (i) COVID-19 patients received oxygen treatment at home; (ii) patients received structured remote monitoring; (iii) it was not an 'early hospital discharge' program; (iv) at least one patient was included. Protocols were screened, and additional information was obtained from involved physicians. Design choices were categorised into: eligible patient group, organization medical care, remote monitoring, nursing care, and devices used. RESULTS: Nine initiatives were screened for eligibility; five were included. Three initiatives included low-risk patients and two were designed specifically for frail patients. Emergency department (ED) visit for an initial diagnostic work-up and evaluation was mandatory in three initiatives before starting home management. Medical responsibility was either assigned to the general practitioner or hospital specialist, most often pulmonologist or internist. Pulse-oximetry was used in all initiatives, with additional monitoring of heart rate and respiratory rate in three initiatives. Remote monitoring staff's qualification and authority varied, and organization and logistics were covered by persons with various backgrounds. All initiatives offered remote monitoring via an application, two also offered a paper diary option. CONCLUSIONS: We observed differences in the organization of interprofessional collaboration for acute home management of hypoxemic COVID-19 patients. All initiatives used pulse-oximetry and an app for remote monitoring. Our overview may be of help to healthcare providers and organizations to set up and implement similar acute home management initiatives for critical episodes of COVID-19 (or other acute disorders) that would otherwise require hospital care.

Integrated care in patients with atrial fibrillation- a predictive heterogeneous treatment effect analysis of the ALL-IN trial.

INTRODUCTION: Integrated 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. METHODS: The 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. RESULTS: Under 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. CONCLUSION: While 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.