Managing the Increasing Burden of Atrial Fibrillation through Integrated Care in Primary Care: A Cost-Effectiveness Analysis.

Introduction: Integrated care for patients with atrial fibrillation (AF) in primary care reduced mortality compared to usual care. We assessed the cost-effectiveness of this approach. Methods: Dutch primary care practices were randomised to provide integrated care for AF patients or usual care. A cost-effectiveness analysis was performed from a societal perspective with a 2-year time horizon to estimate incremental costs and Quality Adjusted Life Years (QALYs). A sensitivity analysis was performed, imputing missing questionnaires for a large group of usual care patients. Results: 522 patients from 15 intervention practices were compared to 425 patients from 11 usual care practices. No effect on QALYs was seen, while mean costs indicated a cost reduction between €865 (95% percentile interval (PI) -€5730 to €3641) and €1343 (95% PI -€6534 to €3109) per patient per 2 years. The cost-effectiveness probability ranged between 36% and 54%. In the sensitivity analysis, this increased to 95%-99%. Discussion: Results should be interpreted with caution due to missing information for a large proportion of usual care patients. Conclusion: The higher costs from extra primary care consultations were likely outweighed by cost reductions for other resources, yet this study doesn't give sufficient clarity on the cost-effectiveness of integrated AF care.

Capturing Data in Rare Disease Registries to Support Regulatory Decision Making: A Survey Study Among Industry and Other Stakeholders.

INTRODUCTION: In rare diseases, registry-based studies can be used to provide natural history data pre-approval and complement drug efficacy and/or safety knowledge post-approval. OBJECTIVE: The objective of this study was to investigate the opinion of stakeholders about key aspects of rare disease registries that are used to support regulatory decision making and to compare the responses of employees from industry to other stakeholders. METHODS: A web-based survey was used to gauge the importance of (1) common data elements (including safety outcomes), (2) data quality and (3) governance aspects that are generic across different rare diseases. The survey included 47 questions. The data were collected in the period April-October 2019. RESULTS: Seventy-three respondents completed ≥ 80% of the survey. Most of the respondents were from the industry (n = 42, 57%). For safety data, 31 (42%) respondents were in favour of collecting all adverse events. For data quality, the respondents found a level of 30% reasonable for source data verification. For missing data, a level of 20% was considered acceptable. Compared to responders from industry, the other stakeholders found it less relevant to share data with industry and found it less acceptable if the registry is financed by industry. CONCLUSIONS: This study showed that the opinion towards data and governance is well aligned across parties, and issues of data and governance on their own should not pose a barrier to collaboration. This finding is supportive of the European Medicines Agency's efforts to encourage stakeholders to work with existing registries when collecting data to support regulatory decision making.

Limited reliability of experts' assessment of telephone triage in primary care patients with chest discomfort.

OBJECTIVE: Root cause analyses of serious adverse events (SAE) in out-of-hours primary care (OHS-PC) often point to errors in telephone triage. Such analyses are, however, hampered by hindsight bias. We assessed whether experts, blinded to the outcome, recognize (un)safety of triage of patients with chest discomfort, and we quantified inter-rater reliability. STUDY DESIGN AND SETTING: This is a case-control study with triage recordings from 2013-2017 at OHS-PC. Cases were missed acute coronary syndromes (ACSs, considered as SAE). These cases were age- and gender-matched 1:8 with the controls, sampled from the remainder of people calling for chest discomfort. Fifteen experts listened to the recordings and rated the safety of triage. We calculated sensitivity and specificity of recognizing an ACS and the intraclass correlation. RESULTS: In total, 135 calls (15 SAE, 120 matched controls) were relistened. The experts identified ACSs with a sensitivity of 0.86 (95% CI: 0.71-0.95) and a specificity of 0.51 (95% CI: 0.43-0.58). Cases were rated significantly more often as unsafe than the controls (73.3% vs. 22.5%, P < 0.001). The inter-rater reliability for safety was poor: ICC 0.16 (95% CI: 0.00-0.32). CONCLUSIONS: Blinded experts rated calls of missed ACSs more often as unsafe than matched control calls, but with a low level of agreement among the experts.

Epidemiology of heart failure.

The heart failure syndrome has first been described as an emerging epidemic about 25 years ago. Today, because of a growing and ageing population, the total number of heart failure patients still continues to rise. However, the case mix of heart failure seems to be evolving. Incidence has stabilized and may even be decreasing in some populations, but alarming opposite trends have been observed in the relatively young, possibly related to an increase in obesity. In addition, a clear transition towards heart failure with a preserved ejection fraction has occurred. Although this transition is partially artificial, due to improved recognition of heart failure as a disorder affecting the entire left ventricular ejection fraction spectrum, links can be made with the growing burden of obesity-related diseases and with the ageing of the population. Similarly, evidence suggests that the number of patients with heart failure may be on the rise in low-income countries struggling under the double burden of communicable diseases and conditions associated with a Western-type lifestyle. These findings, together with the observation that the mortality rate of heart failure is declining less rapidly than previously, indicate we have not reached the end of the epidemic yet. In this review, the evolving epidemiology of heart failure is put into perspective, to discern major trends and project future directions.

Clinical research study implementation of case-finding strategies for heart failure and chronic obstructive pulmonary disease in the elderly with reduced exercise tolerance or dyspnea: A cluster randomized trial.

BACKGROUND: Heart failure (HF) and chronic obstructive pulmonary disease (COPD) often remain undiagnosed in older individuals, although both disorders inhibit functionality and impair health. The aim of the study was to assess the effectiveness of a case-finding strategy of these disorders. METHODS: This is a clustered randomized trial; 18 general practices from the vicinity of Utrecht, the Netherlands, were randomly allocated to a case-finding strategy or usual care. Multimorbid community subjects (≥65 years) with dyspnea or reduced exercise tolerance were eligible for inclusion. The case-finding strategy consisted of history taking, physical examination, blood tests, electrocardiography, spirometry, and echocardiography. Subsequent treatment decisions were at the discretion of the general practitioner. Questionnaires regarding health status and functionality were filled out at baseline and after 6 months of follow-up. Information regarding changes in medication and health care use during the 6 months follow-up was extracted. RESULTS: A total of 829 participants were randomized: 389 in the case-finding strategy group and 440 in the usual care group. More patients in the case-finding group received a new diagnosis of HF or COPD than the usual care group (cumulative incidence 34% vs 2% and 17% vs. 2%, respectively). Scores for health status, functionality, and health care use were similar between the 2 strategies after 6 months of follow-up. CONCLUSIONS: A case-finding strategy applied in primary care to multimorbid older people with dyspnea or reduced exercise tolerance resulted in a number of new diagnoses of HF and COPD but did not result in short-term improvement of health status compared to usual care.

Design of the ZWOT-CASE study: an observational study on the effectiveness of an integrated programme for cardiovascular risk management compared to usual care in general practice.

BACKGROUND: Cardiovascular diseases (CVD) contribute considerably to mortality and morbidity. Prevention of CVD by lifestyle change and medication is important and needs full attention. In the Netherlands an integrated programme for cardiovascular risk management (CVRM), based on the Chronic Care Model (CCM), has been introduced in primary care in many regions in recent years, but its effects are unknown. In the ZWOT-CASE study we will assess the effect of integrated care for CVRM in the region of Zwolle on two major cardiovascular risk factors: systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL-cholesterol) in patients with or at high risk of CVD. METHODS: This study is a pragmatic observational study comparing integrated care for CVRM with usual care among patients aged 40-80 years with CVD (n = 370) or with a high CVD risk (n = 370) within 26 general practices. After 1 yr follow-up, primary outcomes (SBP and LDL-cholesterol level) are measured. Secondary outcomes include lifestyle habits (smoking, dietary habits, alcohol use, physical activity), risk factor awareness, 10-year risk of cardiovascular morbidity or mortality, health care consumption, patient satisfaction and quality of life. CONCLUSION: The ZWOT-CASE study will provide insight in the effects of integrated care for CVRM in general practice in patients with CVD or at high CVD risk. TRIAL REGISTRATION: The ZWOlle Transmural Integrated Care for CArdiovaScular Risk Management Study; ClinicalTrials.gov ; Identifier: NCT03428061; date of registration: 09-02-2018; This study has been retrospectively registered.

Effectiveness of endoscopic totally extraperitoneal (TEP) hernia correction for clinically occult inguinal hernia (EFFECT): study protocol for a randomized controlled trial.

BACKGROUND: Groin pain is a frequent complaint in surgical practice with an inguinal hernia being at the top of the differential diagnosis. The majority of inguinal hernias can be diagnosed clinically. However, patients with groin pain without signs of an inguinal hernia on anamnesis or physical examination provide a diagnostic challenge. If ultrasonography shows a hernia that could not be detected clinically, this entity is called a clinically occult hernia. It is debatable if this radiological hernia is the cause of complaints in all patients with inguinal pain. The objective of this study is to assess whether watchful waiting is non-inferior to endoscopic totally extraperitoneal (TEP) inguinal repair in patients with a clinically occult inguinal hernia. METHODS: The EFFECT study is a multicenter non-blinded randomized controlled non-inferiority trial. Adult patients with unilateral groin pain and a clinically occult inguinal hernia are eligible to participate in this study. A total of 160 participants will be included and randomized to TEP inguinal hernia repair or a watchful waiting approach. The primary outcome of this study is pain reduction 3 months after treatment, measured by the Numeric Rating Scale (NRS). Secondary outcomes are quality of life, cost-effectiveness, patient satisfaction and crossover rate. Eight surgical centers will take part in the study. Participants will be followed-up for 1 year. DISCUSSION: This is the first large randomized controlled trial comparing treatments for patients with groin pain and a clinically occult inguinal hernia. To date, there are no interventional studies on the effect of surgery or a watchful waiting approach in terms of pain or quality of life in this subset of patients. A trial comparing the outcomes of the two approaches in patients with a clinically occult inguinal hernia is urgently needed to provide data facilitating the choice between the two treatment options. If watchful waiting is not inferior to surgical repair, costs of surgical repair may be saved. TRIAL REGISTRATION: The study protocol (NL61730.100.17) is approved by the Medical Ethics Committee (MEC-U) of the Diakonessenhuis, Utrecht, The Netherlands. The study was registered at the Netherlands Trial Registry ( NTR6835 ) registered on November 13, 2017.

Prevalence of left ventricular systolic dysfunction and heart failure with reduced ejection fraction in men and women with type 2 diabetes mellitus: a systematic review and meta-analysis.

BACKGROUND: Type 2 diabetes mellitus (T2D) is associated with the development of left ventricular systolic dysfunction (LVSD) and heart failure with reduced ejection fraction (HFrEF). T2D patients with LVSD are at higher risk of mortality and morbidity than patients without LVSD, while progression of LVSD can be delayed or halted by the use of proven therapies. As estimates of the prevalence are scarce and vary considerably, the aim of this study was to retrieve summary estimates of the prevalence of LVSD/HFrEF in T2D and to see if there were any sex differences. METHODS: A systematic search of Medline and Embase was performed to extract the prevalence of LVSD/HFrEF in T2D (17 studies, mean age 50.1 ± 6.3 to 71.5 ± 7.5), which were pooled using random-effects meta-analysis. RESULTS: The pooled prevalence of LVSD was higher in hospital populations (13 studies, n = 5835, 18% [95% CI 17-19%]), than in the general population (4 studies, n = 1707, 2% [95% CI 2-3%]). Seven studies in total reported sex-stratified prevalence estimates (men: 7% [95% CI 5-8%] vs. women: 1.3% [95% CI 0.0.2.2%]). The prevalence of HFrEF was available in one general population study (5.8% [95% CI 3.7.6%], men: 6.8% vs. women: 3.0%). CONCLUSIONS: The summary prevalence of LVSD is higher among T2D patients from a hospital setting compared with from the general population, with a higher prevalence in men than in women in both settings. The prevalence of HFrEF among T2D in the population was only assessed in a single study and again was higher among men than women.

Main messages for primary care from the 2016 European Guidelines on cardiovascular disease prevention in clinical practice.

In 2016, a new version of the European Guidelines on Cardiovascular Prevention was released, representing a partnership between the European Association for Cardiovascular Prevention and Rehabilitation of the European Society of Cardiology (ESC) and nine European societies, including Wonca-Europe. The ESC guidelines underscore the importance of a lifetime approach to cardiovascular (CV) risk since both CV risk and prevention are dynamic and continuous as patients' age and/or accumulate co-morbidities. Healthy people of all ages should be encouraged to adopt a healthy lifestyle, as well as improved lifestyle and reduced risk factor levels are paramount in patients at increased risk of developing cardiovascular disease (CVD) and in those with established CVD. Healthcare professionals, and especially general practitioners, play an important role in helping patients achieve this and should set a personal example of healthy lifestyle behaviour. The ESC guidelines are based on 'to do' and 'not to do' messages. Of note, what remains uncertain is stated at the end of each dedicated chapter, confirming that guidelines are not absolute rules, and should be interpreted in the light of the healthcare worker's knowledge and experience, patient preferences and the local social, cultural and economic situation.

Integrated management of atrial fibrillation including tailoring of anticoagulation in primary care: study design of the ALL-IN cluster randomised trial.

INTRODUCTION: In our ageing society, we are at the merge of an expected epidemic of atrial fibrillation (AF). AF management requires an integrated approach, including rate or rhythm control, stroke prevention with anticoagulation and treatment of comorbidities such as heart failure or type 2 diabetes. As such, primary care seems to be the logical healthcare setting for the chronic management of patients with AF. However, primary care has not yet played a dominant role in AF management, which has been in fact more fragmented between different healthcare providers. This fragmentation might have contributed to high healthcare costs. To demonstrate the feasibility of managing AF in primary care, studies are needed that evaluate the safety and (cost-)effectiveness of integrated AF management in primary care. METHODS AND ANALYSIS: The ALL-IN trial is a multicentre, pragmatic, cluster randomised, non-inferiority trial performed in primary care practices in a suburban region in the Netherlands. We aim to include a minimum of 1000 patients with AF aged 65 years or more from around 18 to 30 practices. Duration of the study is 2 years. Practices will be randomised to either the intervention arm (providing integrated AF management, involving a trained practice nurse and collaboration with secondary care) or the control arm (care as usual). The primary endpoint is all-cause mortality. Secondary endpoints are cardiovascular mortality, (non)-cardiovascular hospitalisation, major adverse cardiac events, stroke, major bleeding, clinically relevant non-major bleeding, quality of life and cost-effectiveness. ETHICS AND DISSEMINATION: The protocol was approved by the Medical Ethical Committee of the Isala Hospital Zwolle, the Netherlands. Patients in the intervention arm will be asked informed consent for participating in the intervention. Results are expected in 2019 and will be disseminated through both national and international journals and conferences. TRIAL REGISTRATION NUMBER: This trial is registered at the Netherlands Trial Register (NTR5532).

Effect of Using the HEART Score in Patients With Chest Pain in the Emergency Department: A Stepped-Wedge, Cluster Randomized Trial.

BACKGROUND: The HEART (History, Electrocardiogram, Age, Risk factors, and initial Troponin) score is an easy-to-apply instrument to stratify patients with chest pain according to their short-term risk for major adverse cardiac events (MACEs), but its effect on daily practice is unknown. OBJECTIVE: To measure the effect of use of the HEART score on patient outcomes and use of health care resources. DESIGN: Stepped-wedge, cluster randomized trial. (ClinicalTrials.gov: NCT01756846). SETTING: Emergency departments in 9 Dutch hospitals. PATIENTS: Unselected patients with chest pain presenting at emergency departments in 2013 and 2014. INTERVENTION: All hospitals started with usual care. Every 6 weeks, 1 hospital was randomly assigned to switch to "HEART care," during which physicians calculated the HEART score to guide patient management. MEASUREMENTS: For safety, a noninferiority margin of a 3.0% absolute increase in MACEs within 6 weeks was set. Other outcomes included use of health care resources, quality of life, and cost-effectiveness. RESULTS: A total of 3648 patients were included (1827 receiving usual care and 1821 receiving HEART care). Six-week incidence of MACEs during HEART care was 1.3% lower than during usual care (upper limit of the 1-sided 95% CI, 2.1% [within the noninferiority margin of 3.0%]). In low-risk patients, incidence of MACEs was 2.0% (95% CI, 1.2% to 3.3%). No statistically significant differences in early discharge, readmissions, recurrent emergency department visits, outpatient visits, or visits to general practitioners were observed. LIMITATION: Physicians were hesitant to refrain from admission and diagnostic tests in patients classified as low risk by the HEART score. CONCLUSION: Using the HEART score during initial assessment of patients with chest pain is safe, but the effect on health care resources is limited, possibly due to nonadherence to management recommendations. PRIMARY FUNDING SOURCE: Netherlands Organisation for Health Research and Development.

Prognostic burden of heart failure recorded in primary care, acute hospital admissions, or both: a population-based linked electronic health record cohort study in 2.1 million people.

AIMS: The prognosis of patients hospitalized for worsening heart failure (HF) is well described, but not that of patients managed solely in non-acute settings such as primary care or secondary outpatient care. We assessed the distribution of HF across levels of healthcare, and assessed the prognostic differences for patients with HF either recorded in primary care (including secondary outpatient care) (PC), hospital admissions alone, or known in both contexts. METHODS AND RESULTS: This study was part of the CALIBER programme, which comprises linked data from primary care, hospital admissions, and death certificates for 2.1 million inhabitants of England. We identified 89 554 patients with newly recorded HF, of whom 23 547 (26%) were recorded in PC but never hospitalized, 30 629 (34%) in hospital admissions but not known in PC, 23 681 (27%) in both, and 11 697 (13%) in death certificates only. The highest prescription rates of ACE inhibitors, beta-blockers, and mineralocorticoid receptor antagonists was found in patients known in both contexts. The respective 5-year survival in the first three groups was 43.9% [95% confidence interval (CI) 43.2-44.6%], 21.7% (95% CI 21.1-22.2%), and 39.8% (95% CI 39.2-40.5%), compared with 88.1% (95% CI 87.9-88.3%) in the age- and sex-matched general population. CONCLUSION: In the general population, one in four patients with HF will not be hospitalized for worsening HF within a median follow-up of 1.7 years, yet they still have a poor 5-year prognosis. Patients admitted to hospital with worsening HF but not known with HF in primary care have the worst prognosis and management. Mitigating the prognostic burden of HF requires greater consistency across primary and secondary care in the identification, profiling, and treatment of patients. TRIAL REGISTRATION: NCT02551016.

Overdiagnosis of heart failure in primary care: a cross-sectional study.

BACKGROUND: Access to echocardiography in primary care is limited, but is necessary to accurately diagnose heart failure (HF). AIM: To determine the proportion of patients with a GP's diagnosis of HF who really have HF. DESIGN AND SETTING: A cross-sectional study of patients in 30 general practices with a GP's diagnosis of heart failure, based on the International Classification of Primary Care (ICPC) code K77, between June and November 2011. METHOD: Electronic medical records of the patients' GPs were scrutinised for information on the diagnosis. An expert panel consisting of two cardiologists and an experienced GP used all available diagnostic information, and established the presence or absence of HF according to the criteria of the European Society of Cardiology (ESC) HF guidelines. RESULTS: In total, 683 individuals had a GP's diagnosis of HF. The mean age was 77.9 (SD 11.4) years, and 42.2% were male. Of these 683, 79.6% received cooperative care from a cardiologist. In 73.5% of cases, echocardiography was available for panel re-evaluation. Based on consensus opinion of the panel, 434 patients (63.5%, 95% confidence interval [CI] = 59.9 to 67.1) had definite HF, of which 222 (32.5%, 95% CI = 30.9 to 34.1) had HF with a reduced ejection fraction (HFrEF), 207 (30.3%, 95% CI = 29.0 to 31.6) had HF with a preserved ejection fraction (HFpEF), and five (0.7%, 95% CI = 1.2 to 2.6) had isolated right-sided HF. In 17.3% of cases (95% CI = 14.4 to 20.0), the panel considered HF absent, and in 19.2% (95% CI = 16.3 to 22.2) the diagnosis remained uncertain. CONCLUSION: More than one-third of primary care patients labelled with HF may not have HF, and such overdiagnosis may result in inadequate patient management.

Cost-effectiveness of screening strategies to detect heart failure in patients with type 2 diabetes.

BACKGROUND: Heart failure (HF), especially with preserved ejection fraction (HFpEF) is common in older patients with type 2 diabetes (T2DM), but often not recognized. Early HF detection in older T2DM patients may be worthwhile because treatment may be initiated in an early stage, with clear beneficial treatment in those with reduced ejection fraction (HFrEF), but without clear prognostic beneficial treatment in those with HFpEF. Because both types of HF may be uncovered in older T2DM, screening may improve health outcomes at acceptable costs. We assessed the cost-effectiveness of five screening strategies in patients with T2DM aged 60 years or over. METHODS: We built a Markov model with a lifetime horizon based on the prognostic results from our screening study of 581 patients with T2DM, extended with evidence from literature. Cost-effectiveness was calculated from a Dutch healthcare perspective as additional costs (Euros) per additional quality-adjusted life-year (QALY) gained. We performed probabilistic sensitivity analysis to assess robustness of these outcomes. Scenario analyses were performed to assess the influence of the availability of effective treatment of heart failure with preserved ejection fraction. RESULTS: For willingness to pay values in the range of €6050/QALY-€31,000/QALY for men and €6300/QALY-€42,000/QALY for women, screening-based checking the electronic medical record for patient characteristics and medical history plus the assessment of symptoms had the highest probability of being cost-effective. For higher willingness-to-pay values, direct echocardiography was the preferred screening strategy. Cost-effectiveness of all screening strategies improved with the increase in effectiveness of treatment for HFpEF. CONCLUSIONS: Screening for HF in older community-dwelling patients with T2DM is cost-effective at the commonly used willingness-to-pay threshold of €20.000/QALY by checking the electronic medical record for patient characteristics and medical history plus the assessment of symptoms. The simplicity of such a strategy makes it feasible for implementation in existing primary care diabetes management programs.

Effectiveness of an interactive platform, and the ESC/HFA heartfailurematters.org website in patients with heart failure: design of the multicentre randomized e-Vita heart failure trial.

AIMS: Electronic health support (e-health) may improve self-care of patients with heart failure (HF). We aim to assess whether an adjusted care pathway with replacement of routine consultations by e-health improves self-care as compared with usual care. In addition, we will determine whether the ESC/HFA (European Society of Cardiology/Heart Failure Association) website heartfailurematters.org (HFM website) improves self-care when added to usual care. Finally, we aim to evaluate the cost-effectiveness of these interventions. METHODS: A three-arm parallel randomized trial will be conducted. Arm 1 consists of usual care; arm 2 consists of usual care plus the HFM website; and arm 3 is the adjusted care pathway with an interactive platform for disease management (e-Vita platform), with a link to the HFM website, which replaces routine consultations with HF nurses at the outpatient clinic. In total, 414 patients managed in 10 Dutch HF outpatient clinics or in general practice will be included and followed for 12 months. Participants are included if they have had an established diagnosis of HF for at least 3 months. The primary outcome is self-care as measured by the European Heart Failure Self-care Behaviour scale (EHFScB scale). Secondary outcomes are quality of life, cardiovascular- and HF-related mortality, hospitalization, and its duration as captured by hospital and general practitioner registries, use of and user satisfaction with the HFM website, and cost-effectiveness. PERSPECTIVE: This study will provide important prospective data on the impact and cost-effectiveness of an interactive platform for disease management and the HFM website. CLINICAL TRIAL REGISTRATION: unique identifier: NCT01755988.

No Added Value of Novel Biomarkers in the Diagnostic Assessment of Patients Suspected of Acute Coronary Syndrome.

BACKGROUND: Despite the availability of high-sensitive troponin (hs-cTnT), there is still room for improvement in the diagnostic assessment of patients suspected of acute coronary syndrome (ACS). Apart from serial biomarker testing, which is time-consuming, novel biomarkers like copeptin have been proposed to expedite the early diagnosis of suspected ACS in addition to hs-cTnT. We determined whether placenta derived growth factor (PlGF), soluble Fms-like tyrosine kinase 1 (sFlt-1), myoglobin, N-terminal prohormone B-type Natriuretic Peptide (NT-proBNP), growth-differentiation factor 15 (GDF-15) and copeptin improved early assessment of chest pain patients. METHODS: This prospective, single centre diagnostic FAME-ER study included patients presenting to the ED with symptoms suggestive of ACS. Blood was collected to measure biomarkers, notably, hs-cTnT was retrospectively assessed. Added value of markers was judged by increase in AUC using multivariable logistic regression. RESULTS: Of 453 patients enrolled, 149 (33%) received a final diagnosis of ACS. Hs-cTnT had the highest diagnostic value in both univariable and multivariable analysis. PPVs of the biomarkers ranged from 23.5% (PlGF) to 77.9% (hs-cTnT), NPVs from 67.0% (PlGF) to 86.4% (hs-cTnT). Only myoglobin yielded diagnostic value in addition to clinical symptoms and electrocardiography (ECG) (AUC of clinical model 0.80) with AUC of 0.84 (p<0.001). However, addition of hs-cTnT was superior (AUC 0.89, p<0.001). Addition of the biomarkers to our clinical model and hs-cTnT did not or only marginally (GDF-15) improved diagnostic performance. CONCLUSION: When assessing patients suspected of ACS, only myoglobin had added diagnostic value beyond clinical symptoms and ECG. However, when combined with hs-cTnT, it yields no additional diagnostic value. PlGF, sFlt-1, NT-proBNP, GDF-15 and copeptin had no added value to the clinical model or hs-cTnT.

The impending epidemic of chronic cardiopulmonary disease and multimorbidity: the need for new research approaches to guide daily practice.

Mortality caused by acute cardiopulmonary disease is decreasing, and in many countries the population is aging rapidly. Yet, the life-years gained are often spent with multiple chronic and slowly progressive conditions, and this particularly applies to patients with cardiopulmonary disease. Affected individuals often have multiple diagnoses related to the cardiopulmonary-metabolic axis with accelerated aging and gradually progressive failure of organs that provide the body with oxygen and nutrients. This more or less reflects an "engine running out of fuel." This, for instance, is the case with the concurrent presence of COPD and heart failure in one patient that is often combined with other comorbidities such as atrial fibrillation, renal failure, or diabetes. This asks for a paradigm shift: away from single-disease-oriented patient management and toward patient-tailored multimorbidity medicine. Daily clinical practice is already recognizing this on a daily basis, yet clinical research and guidelines are still lagging behind. Thus, novel research approaches are needed to better guide evidence-based clinical practice. These approaches include the construction of diagnostic models to predict the presence of multiple diseases simultaneously, individual patient data meta-analysis as a method to examine variation in the effects of treatments or diagnostic tests depending on comorbidity, and the construction of therapeutic prediction models that predict the therapeutic effect of drugs based on the presence (or absence) of relevant comorbidity. We argue that multimorbidity should be regarded as a "friend" and not as a "foe" in clinical research addressing the current clinical problems in daily practice.

Performance of prior event rate ratio adjustment method in pharmacoepidemiology: a simulation study.

PURPOSE: Prior event rate ratio (PERR) adjustment method has been proposed to control for unmeasured confounding. We aimed to assess the performance of the PERR method in realistic pharmacoepidemiological settings. METHODS: Simulation studies were performed with varying effects of prior events on the probability of subsequent exposure and post-events, incidence rates, effects of confounders, and rate of mortality/dropout. Exposure effects were estimated using conventional rate ratio (RR) and PERR adjustment method (i.e. ratio of RR post-exposure initiation and RR prior to initiation of exposure). RESULTS: In the presence of unmeasured confounding, both conventional and the PERR method may yield biased estimates, but PERR estimates appear generally less biased estimates than the conventional method. However, when prior events strongly influence the probability of subsequent exposure, the exposure effect from the PERR method was more biased than the conventional method. For instance, when the effect of prior events on the exposure was RR = 1.60, the effect estimate from the PERR method was RR = 1.13 and from the conventional method was RR = 2.48 (true exposure effect, RR = 2). In all settings, the variation of the estimates was larger for the PERR method than for the conventional method. CONCLUSION: The PERR adjustment method can be applied to reduce bias as a result of unmeasured confounding. However, only in particular situations, it can completely remove the bias as a result of unmeasured confounding. When applying this method, theoretical justification using available clinical knowledge for assumptions of the PERR method should be provided.

Fast assessment and management of chest pain without ST-elevation in the pre-hospital gateway: rationale and design.

BACKGROUND: For chest pain patients without ST-segment elevation in the pre-hospital setting, current clinical guidelines merely offer in-hospital risk stratification and management, as opposed to chest pain patients with ST-segment elevation for whom there is a straightforward pre-hospital strategy for diagnosis, medication regimen and logistics. The FAMOUS TRIAGE study will assess the effects of introducing a pre-hospital triage system that reliably stratifies chest pain patients without ST-segment elevation into 1) patients at high risk for NSTEMI requiring a direct transfer to a PCI-hospital; 2) patients at intermediate risk for a major adverse cardiac event (MACE) who could be evaluated at the nearest non-PCI hospital; and 3) patients at low risk for MACE (benign non-cardiac chest pain) who could have further evaluation at home or in a primary care setting. METHODS: The FAMOUS TRIAGE study will be performed in three phases. In the first phase an appropriate pre-hospital risk stratification tool will be designed for chest pain patients without ST-segment elevation by means of a retrospective and a prospective study. The second phase of the project represents the external validation of the risk stratification models, and in the third and final phase an optimal risk stratification tool will be implemented into clinical practice. Clinical and economical endpoints before and after implementation of the pre-hospital risk stratification tool will be compared to assess clinical benefit and cost-effectiveness. CONCLUSION: The FAMOUS TRIAGE project is a triple phase study that aims to optimize the pre-hospital management of chest pain patients without ST-segment elevation by providing tools for pre-hospital identification of NSTEMI or exclusion of acute coronary syndrome at home. TRIAL ID: NTR4205. Dutch Trial Register [http://www.trialregister.nl]: trial number 4205.