Atrial fibrillation: trends in prevalence and antithrombotic prescriptions in the community.

INTRODUCTION: In the past decade, the atrial fibrillation (AF) landscape, including the treatment modalities, has drastically changed. This raises the question how AF prevalence and choices in antithrombotic therapy prescription have developed in the community over time. METHODS: Routine care data from the Julius General Practitioners' Network (JGPN) were used to calculate the yearly prevalence of AF and to quantify the percentage of all patients who were prescribed a platelet inhibitor, vitamin K antagonist (VKA), non-VKA oral anticoagulant (NOAC) or no antithrombotic medication. To explore whether certain patient characteristics are associated with selective prescription of oral anticoagulants (OAC), we applied logistic regression analyses. RESULTS: From 2008 through 2017, the JGPN database included 7459 unique AF patients. During this period, the prevalence of AF increased from 0.4% to 1.4%. The percentage of patients prescribed a VKA declined from 47% to 41%, whereas the percentage of patients prescribed a NOAC rose from 0% to 20%. In patients with new-onset AF, older age, heart failure, diabetes mellitus, vascular disease and dementia were independently associated with a higher likelihood of VKA rather than NOAC prescription. In 2017, 25% of all patients with AF and a CHA2DS2-VASc score ≥ 2 were not prescribed OAC therapy (i.e. 8% with platelet inhibitor monotherapy and 17% without any antithrombotic therapy). CONCLUSION: Between 2008 and 2017, AF prevalence in the community more than tripled. Prescription patterns showed possible 'channelling' of VKAs over NOACs in frailer, elderly patients, whereas still about one in every four AF patients with a CHA2DS2-VASc score ≥ 2 was not prescribed any prophylactic OAC therapy.

Clinical profile and contemporary management of patients with heart failure with preserved ejection fraction: results from the CHECK-HF registry.

BACKGROUND: Clinical management of heart failure with preserved ejection fraction (HFpEF) centres on treating comorbidities and is likely to vary between countries. Thus, to provide insight into the current management of HFpEF, studies from multiple countries are required. We evaluated the clinical profiles and current management of patients with HFpEF in the Netherlands. METHODS: We included 2153 patients with HFpEF (defined as a left ventricular ejection fraction ≥ 50%) from the CHECK-HF registry, which included patients from 2013 to 2016. RESULTS: Median age was 77 (IQR 15) years, 55% were women and the most frequent comorbidities were hypertension (51%), renal insufficiency (45%) and atrial fibrillation (AF, 38%). Patients between 65 and 80 years and those over 80 years had on average more comorbidities (up to 64% and 74%, respectively, with two or more comorbidities) than patients younger than 65 years (38% with two or more comorbidities, p-value < 0.001). Although no specific drugs are available for HFpEF, treating comorbidities is advised. Beta-blockers were most frequently prescribed (78%), followed by loop diuretics (74%), renin-angiotensin system (RAS) inhibitors (67%) and mineralocorticoid receptor antagonists (MRAs, 39%). Strongest predictors for loop-diuretic use were older age, higher New York Heart Association class and AF. CONCLUSION: The medical HFpEF profile is determined by the underlying comorbidities, sex and age. Comorbidities are highly prevalent in HFpEF patients, especially in elderly HFpEF patients. Despite the lack of evidence, many HFpEF patients receive regular beta-blockers, RAS inhibitors and MRAs, often for the treatment of comorbidities.

Training general practitioners to improve evidence-based drug treatment of patients with heart failure: a cluster randomised controlled trial.

AIMS: To assess whether a single training session for general practitioners (GPs) improves the evidence-based drug treatment of heart failure (HF) patients, especially of those with HF with reduced ejection fraction (HFrEF). METHODS AND RESULTS: A cluster randomised controlled trial was performed for which patients with established HF were eligible. Primary care practices (PCPs) were randomised to care-as-usual or to the intervention group in which GPs received a half-day training session on HF management. Changes in HF medication, health status, hospitalisation and survival were compared between the two groups. Fifteen PCPs with 200 HF patients were randomised to the intervention group and 15 PCPs with 198 HF patients to the control group. Mean age was 76.9 (SD 10.8) years; 52.5% were female. On average, the patients had been diagnosed with HF 3.0 (SD 3.0) years previously. In total, 204 had HFrEF and 194 HF with preserved ejection fraction (HFpEF). In participants with HFrEF, the use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers decreased in 6 months in both groups [5.2%; (95% confidence interval (CI) 2.0-10.0)] and 5.6% (95% CI 2.8-13.4)], respectively [baseline-corrected odds ratio (OR) 1.07 (95% CI 0.55-2.08)], while beta-blocker use increased in both groups by 5.2% (95% CI 2.0-10.0) and 1.1% (95% CI 0.2-6.3), respectively [baseline-corrected OR 0.82 (95% CI 0.42-1.61)]. For health status, hospitalisations or survival after 12-28 months there were no significant differences between the two groups, also not when separately analysed for HFrEF and HFpEF. CONCLUSION: A half-day training session for GPs does not improve drug treatment of HF in patients with established HF.

Differences in guideline-recommended heart failure medication between Dutch heart failure clinics: an analysis of the CHECK-HF registry.

BACKGROUND: Heart failure (HF) is associated with poor prognosis, high morbidity and mortality. The prognosis can be optimised by guideline adherence, which also can be used as a benchmark of quality of care. The purpose of this study was to evaluate differences in use of HF medication between Dutch HF clinics. METHODS: The current analysis was part of a cross-sectional registry of 10,910 chronic HF patients at 34 Dutch outpatient clinics in the period of 2013 until 2016 (CHECK-HF), and focused on the differences in prescription rates between the participating clinics in patients with heart failure with reduced ejection fraction (HFrEF). RESULTS: A total of 8,360 HFrEF patients were included with a mean age of 72.3 ± 11.8 years (ranging between 69.1 ± 11.9 and 76.6 ± 10.0 between the clinics), 63.9% were men (ranging between 54.3 and 78.1%), 27.3% were in New York Heart Association (NYHA) class III/IV (ranging between 8.8 and 62.1%) and the average estimated glomerular filtration rate (eGFR) was 59.6 ± 24.6 ml/min (ranging between 45.7 ± 23.5 and 97.1 ± 16.5). The prescription rates ranged from 58.9-97.4% for beta blockers (p < 0.01), 61.9-97.1% for renin-angiotensin system (RAS) inhibitors (p < 0.01), 29.9-86.8% for mineralocorticoid receptor antagonists (MRAs) (p < 0.01), 0.0-31.3% for ivabradine (p < 0.01) and 64.9-100.0% for diuretics (p < 0.01). Also, the percentage of patients who received the target dose differed significantly, 5.9-29.1% for beta blockers (p < 0.01), 18.4-56.1% for RAS inhibitors (p < 0.01) and 13.2-60.6% for MRAs (p < 0.01). CONCLUSIONS: The prescription rates and prescribed dosages of guideline-recommended medication differed significantly between HF outpatient clinics in the Netherlands, not fully explained by differences in patient profiles.

Use of proton pump inhibitors and risk of iron deficiency: a population-based case-control study.

BACKGROUND: Hypochlorhydric states are an important cause of iron deficiency (ID). Nevertheless, the association between therapy with proton pump inhibitors (PPIs) and ID has long been a subject of debate. This case-control study aimed to investigate the risk of ID associated with the use of PPIs using the UK Clinical Practice Research Datalink (CPRD) database. METHODS: Cases were patients aged 19 years or older with first-time diagnosis of ID between 2005 and 2016 (n = 26 806). The dates of first diagnosis of ID in cases defined the index dates. For each case, one control was matched by age, gender and general practice. A PPI "full" user (PFU) was defined as a subject who had received PPIs for a continuous duration of at least 1 year prior to the index date. A PPI "limited" users (PLU) was a subject who intermittently received PPI therapy. A PPI non-user (PNU) was a subject who received no PPI prescriptions prior to the index date. The odds ratio of ID in PFU and PLU compared to PNU was estimated using conditional logistic regression. RESULTS: Among cases, 2960 were PFU, 6607 PLU and 17 239 PNU. Among controls, 1091 were PFU, 5058 PLU and 20 657 PNU. Adjusted odds ratio of ID in PFU and PLU compared to PNU was 3.60 (95%CI, [3.32-3.91]) and 1.51 (95% CI, [1.44-1.58]). Positive dose-response and time-response relationships were observed. CONCLUSIONS: Chronic PPI use increases the risk of ID. Physicians should consider this when balancing the risks and benefits of chronic PPI prescription.

Effectiveness of CHA2DS2-VASc based decision support on stroke prevention in atrial fibrillation: A cluster randomised trial in general practice.

BACKGROUND: Guidelines on atrial fibrillation (AF) recommend the CHA2DS2-VASc rule for anticoagulant decision-making, but underuse exists. We studied the impact of an automated decision support on stroke prevention in patients with AF in a cluster randomised trial in general practice. METHODS: Intervention practices were provided with a CHA2DS2-VASc based anticoagulant treatment recommendation. Reference practices provided care as usual. The primary outcome was incidence of ischaemic stroke, transient ischaemic attack (TIA) and/or thromboembolism (TE). Secondary outcomes were bleeding and the proportion of patients on guideline recommended anticoagulant treatment. RESULTS: In total, 1129 AF patients were included in the 19 intervention practices and 1226 AF patients in the 19 reference practices. The median age was 77 (interquartile range (IQR) 68-75) years, the median CHA2DS2-VASc score was 3.0 (IQR 2.0-5.0). Underuse of anticoagulants in patients with CHA2DS2-VASc score ≥ 2 was 6.6%. After a median follow-up of 2.7 years (IQR 2.3-3.0), the incidence rate per 100 person-years of ischaemic stroke/TIA/TE was 1.96 in the intervention group and 1.42 in the reference group (hazard ratio (HR) 1.3, 95% C.I. 0.8-2.1). No difference was observed in the rate of bleeding (0.79 versus 0.82), or in the underuse (7.2% versus 8.2%) or overuse (8.0% versus 7.9%) of anticoagulation. CONCLUSIONS: In this study in patients with AF in general practice, underuse of anticoagulants was relatively low. Providing practitioners with CHA2DS2-VASc based decision support did not result in a reduction in stroke incidence, affect bleeding risk or anticoagulant over- or underuse.

Real-world heart failure management in 10,910 patients with chronic heart failure in the Netherlands : Design and rationale of the Chronic Heart failure ESC guideline-based Cardiology practice Quality project (CHECK-HF) registry.

AIMS: Data from patient registries give insight into the management of patients with heart failure (HF), but actual data from unselected real-world HF patients are scarce. Therefore, we performed a cross sectional study of current HF care in the period 2013-2016 among more than 10,000 unselected HF patients at HF outpatient clinics in the Netherlands. METHODS: In 34 participating centres, all 10,910 patients with chronic HF treated at cardiology centres were included in the CHECK-HF registry. Of these, most (96%) were managed at a specific HF outpatient clinic. Heart failure was typically diagnosed according to the ESC guidelines 2012, based on signs, symptoms and structural and/or functional cardiac abnormalities. Information on diagnostics, treatment and co-morbidities were recorded, with specific focus on drug therapy and devices. In our cohort, the mean age was 73 years (SD 12) and 60% were male. Frequent co-morbidities reported in the patient records were diabetes mellitus 30%, hypertension 43%, COPD 19%, and renal insufficiency 58%. In 47% of the patients, ischaemia was the origin of HF. In our registry, the prevalence of HF with preserved ejection fraction was 21%. CONCLUSION: The CHECK-HF registry will provide insight into the current, real world management of patient with chronic HF, including HF with reduced ejection fraction, preserved ejection fraction and mid-range ejection fraction, that will help define ways to improve quality of care. Drug and device therapy and guideline adherence as well as interactions with age, gender and co-morbidities will receive specific attention.

Safety of a 1-hour Rule-out High-sensitive Troponin T Protocol in Patients With Chest Pain at the Emergency Department.

BACKGROUND: The 1-hour rule-out high-sensitive cardiac troponin T protocol (hs-cTnT), in which a serial troponin measurement is performed 1 hour after the first to assess the possibility of acute coronary syndrome (ACS), has been implemented in the European guidelines in 2015. Our aim was to assess the safety of this protocol in low-risk patients in the Emergency Department (ED) when implemented in daily practice. METHODS: Patients with acute chest pain presenting to the ED of our hospital and younger than 75 years were included (May 2013 to October 2014, The Netherlands). Hs-cTnT was measured at presentation (T0) and 1-1.5 hours after T0 (T1). Patients with a first troponin (T0) ≥ 0.012 ug/l were excluded. Primary endpoint was the 6-week occurrence of major adverse cardiac events (MACEs), defined as unstable angina, acute myocardial infarction (AMI), percutaneous coronary intervention, significant stenosis managed conservatively, coronary artery bypass grafting, and death. RESULTS: Of the 374 analyzed patients, 16 patients (4.3%) developed 35 MACE. Of these 16 patients with endpoints, 3 were primarily discharged with noncardiac chest pain but returned within 6 weeks with unstable angina. Importantly, no patients experienced an AMI or died during follow-up. CONCLUSION: No AMIs or deaths occurred after introducing the 1-hour hs-cTnT protocol to rule-out ACS in chest pain patients, but other MACE such as unstable angina occurred. Our results suggest the protocol is safe to implement in the ED in The Netherlands.

Predictive performance of the CHA2DS2-VASc rule in atrial fibrillation: a systematic review and meta-analysis.

Essentials The widely recommended CHA2DS2-VASc shows conflicting results in contemporary validation studies. We performed a systematic review and meta-analysis of 19 studies validating CHA2DS2-VASc. There was high heterogeneity in stroke risks for different CHA2DS2-VASc scores. This was not explained by differences between setting of care, or by performing meta-regression. SUMMARY: Background The CHA2DS2-VASc decision rule is widely recommended for estimating stroke risk in patients with atrial fibrillation (AF), although validation studies show ambiguous and conflicting results. Objectives To: (i) review existing studies validating CHA2DS2-VASc in AF patients who are not (yet) anticoagulated; (ii) meta-analyze estimates of stroke risk per score; and (iii) explore sources of heterogeneity across the validation studies. Methods We performed a systematic literature review and random effects meta-analysis of studies externally validating CHA2DS2-VASc in AF patients not receiving anticoagulants. To explore between-study heterogeneity in stroke risk, we stratified studies to the clinical setting in which patient enrollment started, and performed meta-regression. Results In total, 19 studies were evaluated, with over two million person-years of follow-up. In studies recruiting AF patients in hospitals, stroke risks for scores of 0, 1 and 2 were 0.4% (approximate 95% prediction interval [PI] 0.2-3.2%), 1.2% (95% PI 0.1-3.8%), and 2.2% (95% PI 0.03-7.8%), respectively. These were consistently higher than those in studies recruiting patients from the open general population, with risks of 0.2% (95% PI 0.0-0.9%), 0.7% (95% PI 0.3-1.2%) and 1.5% (95% PI 0.4-3.3%) for scores of 0, 1, and 2, respectively. Heterogeneity, as reflected by the wide PIs, could not be fully explained by meta-regression. Conclusions Studies validating CHA2DS2-VASc show high heterogeneity in predicted stroke risks for different scores.

The effects of misclassification in routine healthcare databases on the accuracy of prognostic prediction models: a case study of the CHA2DS2-VASc score in atrial fibrillation.

BACKGROUND: Research on prognostic prediction models frequently uses data from routine healthcare. However, potential misclassification of predictors when using such data may strongly affect the studied associations. There is no doubt that such misclassification could lead to the derivation of suboptimal prediction models. The extent to which misclassification affects the validation of existing prediction models is currently unclear.We aimed to quantify the amount of misclassification in routine care data and its effect on the validation of the existing risk prediction model. As an illustrative example, we validated the CHA2DS2-VASc prediction rule for predicting mortality in patients with atrial fibrillation (AF). METHODS: In a prospective cohort in general practice in the Netherlands, we used computerized retrieved data from the electronic medical records of patients known with AF as index predictors. Additionally, manually collected data after scrutinizing all complete medical files were used as reference predictors. Comparing the index with the reference predictors, we assessed misclassification in individual predictors by calculating Cohen's kappas and other diagnostic test accuracy measures. Predictive performance was quantified by the c-statistic and by determining calibration of multivariable models. RESULTS: In total, 2363 AF patients were included. After a median follow-up of 2.7 (IQR 2.3-3.0) years, 368 patients died (incidence rate 6.2 deaths per 100 person-years). Misclassification in individual predictors ranged from substantial (Cohen's kappa 0.56 for prior history of heart failure) to minor (kappa 0.90 for a history of type 2 diabetes). The overall model performance was not affected when using either index or reference predictors, with a c-statistic of 0.684 and 0.681, respectively, and similar calibration. CONCLUSION: In a case study validating the CHA2DS2-VASc prediction model, we found substantial predictor misclassification in routine healthcare data with only limited effect on overall model performance. Our study should be repeated for other often applied prediction models to further evaluate the usefulness of routinely available healthcare data for validating prognostic models in the presence of predictor misclassification.

Comparison of the GRACE, HEART and TIMI score to predict major adverse cardiac events in chest pain patients at the emergency department.

BACKGROUND: The performance of the GRACE, HEART and TIMI scores were compared in predicting the probability of major adverse cardiac events (MACE) in chest pain patients presenting at the emergency department (ED), in particular their ability to identify patients at low risk. METHODS: Chest pain patients presenting at the ED in nine Dutch hospitals were included. The primary outcome was MACE within 6weeks. The HEART score was determined by the treating physician at the ED. The GRACE and TIMI score were calculated based on prospectively collected data. Performance of the scores was compared by calculating AUC curves. Additionally, the number of low-risk patients identified by each score were compared at a fixed level of safety of at least 95% or 98% sensitivity. RESULTS: In total, 1748 patients were included. The AUC of GRACE, HEART, and TIMI were 0.73 (95% CI: 0.70-0.76%), 0.86 (95% CI: 0.84-0.88%) and 0.80 (95% CI: 0.78-0.83%), respectively (all differences in AUC highly statistically significant). At an absolute level of safety of at least 98% sensitivity, the GRACE score identified 231 patients as "low risk" in which 2.2% a MACE was missed; the HEART score identified 381 patients as "low risk" with 0.8% missed MACE. The TIMI score identified no "low risk" patients at this safety level. CONCLUSIONS: The HEART score outperformed the GRACE and TIMI scores in discriminating between those with and without MACE in chest pain patients, and identified the largest group of low-risk patients at the same level of safety.

Does integrated training in evidence-based medicine (EBM) in the general practice (GP) specialty training improve EBM behaviour in daily clinical practice? A cluster randomised controlled trial.

OBJECTIVES: Evidence-based medicine (EBM) is an important element in the general practice (GP) specialty training. Studies show that integrating EBM training into clinical practice brings larger benefits than stand-alone modules. However, these studies have neither been performed in GP nor assessed EBM behaviour of former trainees in daily clinical practice. SETTING: GP specialty training in the Netherlands. PARTICIPANTS: All 82 third year GP trainees who started their final third year in 2011 were approached for inclusion, of whom 79 (96%) participated: 39 in the intervention group and 40 in the control group. INTERVENTION: Integrated EBM training, in which EBM is embedded closely within the clinical context by joint assignments for the trainee and supervisor in daily practice, and teaching sessions based on dilemmas from actual patient consultations. COMPARISON: Stand-alone EBM training at the institute only. PRIMARY AND SECONDARY OUTCOMES: Our primary outcome was EBM behaviour, assessed by measuring guideline adherence (incorporating rational, motivated deviation) and information-seeking behaviour. Our secondary outcomes were EBM attitude and EBM knowledge. Data were acquired using logbooks and questionnaires, respectively. Analyses were performed using mixed models. RESULTS: Logbook data were available from 76 (96%) of the participating trainees at baseline (7614 consultations), 60 (76%) at the end of the third year (T1, 4973 consultations) and 53 (67%) 1 year after graduation (T2, 3307 consultations). We found no significant differences in outcomes between the 2 groups, with relative risks for guideline adherence varying between 0.96 and 0.99 (95% CI 0.86 to 1.11) at T1, and 0.99 and 1.10 (95% CI 0.92 to 1.25) at T2, and for information-seeking behaviour between 0.97 and 1.16 (95% CI 0.70 to 1.91) and 0.90 and 1.10 (95% CI 0.70 to 1.32), respectively. CONCLUSIONS: Integrated EBM training compared with stand-alone EBM training does not improve EBM behaviour, attitude or knowledge of (future) GPs.

Medical consumption compared for TIMI and HEART score in chest pain patients at the emergency department: a retrospective cost analysis.

OBJECTIVE: To investigate which risk score (TIMI score or HEART score) identifies the largest population of low-risk patients at the emergency department (ED). Furthermore, we retrospectively calculated the corresponding expected decrease in medical consumption if these patients would have been discharged from the ED. METHODS: We performed analyses in two hospitals of the multicentre prospective validation study of the HEART score, executed in 2008 and 2009. Patients with chest pain presenting to the ED were included and information was collected on major adverse cardiac events (MACEs) and on hospital admissions and diagnostic procedures within 6 weeks. The TIMI and HEART score were calculated for each patient. RESULTS: We analysed 640 patients (59% male, mean age of 60, cumulative incidence of MACE 17%). An estimated total of €763 468 was spent during follow-up on hospital admission and diagnostic procedures. In total, 256 (40%) patients had a HEART score of 0-3 and were considered low risk (miss rate 1.6%), a total of €64 107 was spent on diagnostic procedures and hospital admission after initial presentation in this group. In comparison, 105 (16%) patients with TIMI score of 0 were considered low risk (miss rate 0%), with a total of €14 670 spent on diagnostic procedures and initial hospital admission costs. With different cut-offs for low risk, HEART 0-2 (miss rate 0.7%), would have resulted in a total of €25 365 in savings, compared with €71 905 when an alternative low risk cut-off for TIMI of TIMI≤1 would be used (miss rate 3.0%). CONCLUSIONS: The HEART score identifies more patients as low risk compared with the TIMI score, which may lead to a larger reduction in diagnostic procedures and costs in this low-risk group. Future studies should prospectively investigate whether adhering to the HEART score in clinical practice and early discharge of low-risk patients is safe and leads to a reduction in medical consumption.

Tailoring treatments using treatment effect modification.

BACKGROUND AND OBJECTIVE: Applying results from clinical studies to individual patients can be a difficult process. Using the concept of treatment effect modification (also referred to as interaction), defined as a difference in treatment response between patient groups, we discuss whether and how treatment effects can be tailored to better meet patients' needs. RESULTS: First we argue that contrary to how most studies are designed, treatment effect modification should be expected. Second, given this expected heterogeneity, a small number of clinically relevant subgroups should be a priori selected, depending on the expected magnitude of effect modification, and prevalence of the patient type. Third, by defining generalizability as the absence of treatment effect modification we show that generalizability can be evaluated within the usual statistical framework of equivalence testing. Fourth, when equivalence cannot be confirmed, we address the need for further analyses and studies tailoring treatment towards groups of patients with similar response to treatment. Fifth, we argue that to properly frame, the entire body of evidence on effect modification should be quantified in a prior probability.

Uncovering heart failure with preserved ejection fraction in patients with type 2 diabetes in primary care: time for a change.

Undetected heart failure appears to be an important health problem in patients with type 2 diabetes and aged ≥ 60 years. The prevalence of previously unknown heart failure in these patients is high, steeply rises with age, and is overall higher in women than in men. The majority of the patients with newly detected heart failure have a preserved ejection fraction. A diagnostic algorithm to detect or exclude heart failure in these patients with variables from the medical files combined with items from history taking and physical examination provides a good to excellent accuracy. Annual screening appears to be cost-effective. Both unrecognised heart failure with reduced and with preserved ejection fraction were associated with a clinically relevant lower health status in patients with type 2 diabetes. Also the prognosis of these patients was worse than of those without heart failure. Existing disease-management programs for type 2 diabetes pay insufficient attention to early detection of cardiovascular diseases, including heart failure. We conclude that more attention is needed for detection of heart failure in older patients with type 2 diabetes.

Which dogs with appendicular osteosarcoma benefit most from chemotherapy after surgery? Results from an individual patient data meta-analysis.

Osteosarcoma (OS) is a malignant tumor of mesenchymal origin that produces osteoid. Given that the prognosis can vary considerably between dogs, we aimed to explore whether treatment could be tailored towards patient subgroups, characterized by their predicted risk of mortality. For the current study, a subset of five nonrandomized studies (400 subjects of whom 88 were dead at 5 months follow-up) was used from a previously published 20 study individual patient data meta-analysis. Missing data was dependent on observed variables and was imputed to correct for this dependency. Based on a previously published multivariable prognostic model, the 5-month mortality risk was predicted. Subsequently, in surgically treated dogs, using a logistic regression model with a random intercept for a study indicator, we explored whether chemotherapy effectiveness depended on predicted 5-month mortality risk. After adjustment for potential confounders the main effect of any chemotherapy was 0.48 (odds ratio) (95%CI 0.30; 0.78). Testing for chemotherapy by predicted 5-month mortality risk interaction revealed that the effects of any chemotherapy decreased with increasing predicted risk; interaction OR 3.41 (1.07; 10.84). Results from individually comparing carboplatin, cisplatin, doxorubicin and doxorubicin combination therapy to no chemotherapy, were similar in magnitude and direction. These results indicate that the main treatment effects of chemotherapy do not necessarily apply to all patients.

Should patients prescribed long-term low-dose aspirin receive proton pump inhibitors? A systematic review and meta-analysis.

BACKGROUND: Several clinical guidelines recommend the use of proton pump inhibitors (PPIs) in patients taking low-dose aspirin but report no or limited supporting data. We conducted a systematic review and meta-analysis to examine the effects of co-administration of PPIs in patients taking low-dose aspirin on the risks of adverse gastrointestinal (GI) and cardiovascular (CV) events, and on patient adherence to aspirin. METHODS: We searched PUBMED, EMBASE and Cochrane Central Register of Controlled Trials databases for relevant articles published through November 2013. We included randomised controlled trials (RCTs) and observational studies in patients taking low-dose aspirin with and without PPIs. Risk of bias was assessed using the Cochrane Collaboration's tool (for RCTs) and the Newcastle-Ottawa Scale (for observational studies). Pooled risk ratios (RRs) were computed using a random-effects model. RESULTS: We included 13 studies, of which 12 (2 RCTs and 10 observational studies) reported on GI events, and one (cohort study) on both GI bleeding and CV events. No study reported on adherence to aspirin. Co-administration of PPIs in patients receiving low-dose aspirin was associated with risk reductions of 73% (RR 0.27, 95% CI 0.17-0.42) and 50% (RR 0.50, 95% CI 0.32-0.80) in the occurrence of peptic ulcer and GI bleeding respectively. There was evidence of bias in publications reporting on the GI events. CONCLUSIONS: The practice of co-prescribing PPIs in patients taking low-dose aspirin is supported by some data, but the evidence is rather weak. It currently remains unclear whether the benefits of co-administration of PPIs in users of low-dose aspirin outweigh their potential harms.

Ankle injuries in the Netherlands: Trends over 10-25 years.

Ankle injuries are a common health problem; data on ankle injury rates and time trends in the population at large are scarce. Our aim was to investigate the incidence of and time trends in population-based and emergency department-treated ankle injuries related to sports activities and other activities related to daily living. Data were obtained from one national survey on accidents and injuries (2000-2010) and one based on emergency department data (1986-2010). Linear regression was used to determine linear trends in ankle injuries per 1000 person-years. The number of ankle injuries related to sports activities and other activities of daily living increased from 19.0 to 26.6 per 1000 person-years (P = 0.002). The number of sports-related ankle injuries treated in emergency departments decreased from 4.2 to 1.5 per 1000 person-years (P < 0.001), and from 3.2 to 2.1 per 1000 person-years (P < 0.001) for other activities of daily living. According to our data, the incidence rates of all ankle injuries are around 5.5 times higher than those registered at emergency departments. The high incidence rates of ankle injuries highlight the need for proper ankle injury treatment and prevention.

Breast-feeding and health consequences in early childhood: is there an impact of time-dependent confounding?

BACKGROUND: Estimated effects of breast-feeding on childhood health vary between studies, possibly due to confounding by baseline maternal and child characteristics. Possible time-dependent confounding has received little consideration. Our aim was to evaluate the impact of such confounding. METHODS: We estimated the relationship between cumulative exclusive breast-feeding up to 6 months and wheezing, rash and body mass index (BMI) at 12 months [in the Whistler cohort (n = 494) and PROBIT (n = 11,463)], and wheezing, rash, asthma, hay fever, eczema, allergy and BMI at age 6.5 years (PROBIT). We adjusted for time-dependent confounding by weight, length, rash, respiratory illness and day care attendance using marginal structural models (MSMs). RESULTS: Weight and day care attendance appeared potential time-dependent confounders, since these predicted breast-feeding status and were influenced by previous breast-feeding. However, adjustment for time-dependent confounders did not markedly change the estimated associations. For example, in PROBIT the adjusted increase in BMI at 12 months per 1-month increase in exclusive breast-feeding was 0.04 (95% CI -0.09 to 0.01) using logistic regression and -0.06 (95% CI -0.11 to -0.01) using MSM. In Whistler, these estimates were each -0.05 (95% CI -0.10 to 0.00). CONCLUSIONS: In two cohort studies, there was little evidence of time-dependent confounding by weight, length, rash, respiratory illness or day care attendance of the effects of breast-feeding on early childhood health.