Mortality due to bleeding, myocardial infarction and stroke in dialysis patients.

Essentials Mortality due to bleeding vs. arterial thrombosis in dialysis patients is unknown. We compared death causes of 201 918 dialysis patients with the general population. Dialysis was associated with increased mortality risks of bleeding and arterial thrombosis. Clinicians should be aware of the increased bleeding and thrombosis risks. SUMMARY: Background Dialysis has been associated with both bleeding and thrombotic events. However, there is limited information on bleeding as a cause of death versus arterial thrombosis as a cause of death. Objectives To investigate the occurrence of bleeding, myocardial infarction and stroke as causes of death in the dialysis population as compared with the general population. Methods We included 201 918 patients from 11 countries providing data to the ERA-EDTA Registry who started dialysis treatment between 1994 and 2011, and followed them for 3 years. Age-standardized and sex-standardized mortality rate ratios for bleeding, myocardial infarction and stroke as causes of death were calculated in dialysis patients as compared with the European general population. Associations between potential risk factors and these causes of death in dialysis patients were investigated by calculating hazard ratios (HRs) with 95% confidence intervals (CIs) by the use of Cox proportional-hazards regression. Results As compared with the general population, the age-standardized and sex-standardized mortality rate ratios in dialysis patients were 12.8 (95% CI 11.9-13.7) for bleeding as a cause of death (6.2 per 1000 person-years among dialysis patients versus 0.3 per 1000 person-years in the general population), 13.4 (95% CI 13.0-13.9) for myocardial infarction (22.5 versus 0.9 per 1000 person-years), and 12.4 (95% CI 11.9-12.9) for stroke (14.3 versus 0.7 per 1000 person-years). Conclusion Dialysis patients have highly increased risks of death caused by bleeding and arterial thrombosis as compared with the general population. Clinicians should be aware of the increased mortality risks caused by these conditions.

Guideline-related barriers to optimal prescription of oral anticoagulants in primary care.

Guidelines provide recommendations for antithrombotic treatment to prevent stroke in people with atrial fibrillation, but oral anticoagulant prescriptions in Dutch primary care are often discordant with these recommendations. Suboptimal guideline features (i.e. format and content) have been suggested as a potential explanatory factor for this type of discordance. Therefore, we systematically appraised features of the Dutch general practitioners' (NHG) atrial fibrillation guideline to identify guidelinerelated barriers that may hamper its use in practice. We appraised the guideline's methodological rigour and transparency using the Appraisal of Guidelines, Research and Evaluation (AGREE) II tool. Additionally, we used the Guideline Implementability Appraisal (GLIA) tool to assess the key recommendations on oral anticoagulant prescription. The editorial independence of the guideline group scored highly (88%); scores for other aspects of the guideline's methodological quality were acceptable, ranging from 53% for stakeholder involvement to 67% for clarity of presentation. At the recommendation level, the main implementation obstacles were lack of explicit statements on the quality of underlying evidence, lack of clarity around the strength of recommendations, and the use of ambiguous terms which may hamper operationalisation in electronic systems. Based on our findings we suggest extending stakeholder involvement in the guideline development process, standardising the layout and language of key recommendations, providing monitoring criteria, and preparing electronic implementation parallel with guideline development. We expect this to contribute to optimising the NHG atrial fibrillation guideline, facilitating its implementation in practice, and ultimately to improving antithrombotic treatment and stroke prevention in people with atrial fibrillation.

Gender Disparities in Access to Pediatric Renal Transplantation in Europe: Data From the ESPN/ERA-EDTA Registry.

Inequalities between genders in access to transplantation have been demonstrated. We aimed to validate this gender inequality in a large pediatric population and to investigate its causes. This cohort study included 6454 patients starting renal replacement therapy before 18 years old, in 35 countries participating in the European Society for Paediatric Nephrology/European Renal Association-European Dialysis and Transplant Association Registry. We used cumulative incidence competing risk and proportional hazards frailty models to study the time to receive a transplant and hierarchical logistic regression to investigate access to preemptive transplantation. Girls had a slower access to renal transplantation because of a 23% lower probability of receiving preemptive transplantation. We found a longer follow-up time before renal replacement therapy in boys compared with girls despite a similar estimated glomerular filtration rate at first appointment. Girls tend to progress faster toward end-stage renal disease than boys, which may contribute to a shorter time available for pretransplantation workup. Overall, medical factors explained only 70% of the gender difference. In Europe, girls have less access to preemptive transplantation for reasons that are only partially related to medical factors. Nonmedical factors such as patient motivation and parent and physician attitudes toward transplantation and organ donation may contribute to this inequality. Our study should raise awareness for the management of girls with renal diseases.

Considerable variations in growth hormone policy and prescription in paediatric end-stage renal disease across European countries-a report from the ESPN/ERA-EDTA registry.

BACKGROUND: Growth retardation in paediatric end-stage renal disease (ESRD) has a serious impact on adult life. It is potentially treatable with recombinant growth hormone (rGH). In this study, we aimed to quantify the variation in rGH policies and actual provided care in these patients across Europe. METHODS: Renal registry representatives of 38 European countries received a structured questionnaire on rGH policy. Cross-sectional data on height and actual use of rGH on children with ESRD aged <18 years were retrieved from the ESPN/ERA-EDTA Registry. RESULTS: In 21 (75%) of 28 responding countries, rGH is reimbursed for children with ESRD. The specific conditions for reimbursement (minimum age, maximum age and chronic kidney disease stage) vary considerably. Mean height standard deviation scores (SDS) at renal replacement therapy (RRT) [95% confidence interval (CI)] were significantly higher in countries where rGH was reimbursed -1.80 (-2.06; -1.53) compared with countries in which it was not reimbursed [-2.34 (-2.49;-2.18), P < 0.001]. Comparison of the mean height SDS at onset of RRT and final height SDS yielded similar results. Among the 13 countries for which both data on actual rGH use between 2007 and 2011 and data from the questionnaire were available, 30.1% of dialysis and 42.3% of transplanted patients had a short stature, while only 24.1 and 7.6% of those short children used rGH, respectively. CONCLUSION: Reimbursement of rGH associates with a less compromised final stature of ESRD children. In many countries with full rGH reimbursement, the actual rGH prescription in growth-retarded ESRD children is low and obviously more determined by the doctor's and patients' attitude towards rGH therapy than by financial hurdles.

Survival in dialysis patients is different between patients with diabetes as primary renal disease and patients with diabetes as a co-morbid condition.

AIMS/HYPOTHESIS: A previous study in Dutch dialysis patients showed no survival difference between patients with diabetes as primary renal disease and those with diabetes as a co-morbid condition. As this was not in line with our hypothesis, we aimed to verify these results in a larger international cohort of dialysis patients. METHODS: For the present prospective study, we used data from the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry. Incident dialysis patients with data on co-morbidities (n = 15,419) were monitored until kidney transplantation, death or end of the study period (5 years). Cox regression was performed to compare survival for patients with diabetes as primary renal disease, patients with diabetes as a co-morbid condition and non-diabetic patients. RESULTS: Of the study population, 3,624 patients (24%) had diabetes as primary renal disease and 1,193 (11%) had diabetes as a co-morbid condition whereas the majority had no diabetes (n = 10,602). During follow-up, 7,584 (49%) patients died. In both groups of diabetic patients mortality was higher compared with the non-diabetic patients. Mortality was higher in patients with diabetes as primary renal disease than in patients with diabetes as a co-morbid condition, adjusted for age, sex, country and malignancy (HR 1.20, 95% CI 1.10, 1.30). An analysis stratified by dialysis modality yielded similar results. CONCLUSIONS/INTERPRETATION: Overall mortality was significantly higher in patients with diabetes as primary renal disease compared with those with diabetes as a co-morbid condition. This suggests that survival in diabetic dialysis patients is affected by the extent to which diabetes has induced organ damage.

Disparities in policies, practices and rates of pediatric kidney transplantation in Europe.

We aimed to provide an overview of kidney allocation policies related to children and pediatric kidney transplantation (KTx) practices and rates in Europe, and to study factors associated with KTx rates. A survey was distributed among renal registry representatives in 38 European countries. Additional data were obtained from the ESPN/ERA-EDTA and ERA-EDTA registries. Thirty-two countries (84%) responded. The median incidence rate of pediatric KTx was 5.7 (range 0-13.5) per million children (pmc). A median proportion of 17% (interquartile range 2-29) of KTx was performed preemptively, while the median proportion of living donor KTx was 43% (interquartile range 10-52). The median percentage of children on renal replacement therapy (RRT) with a functioning graft was 62%. The level of pediatric prioritization was associated with a decreased waiting time for deceased donor KTx, an increased pediatric KTx rate, and a lower proportion of living donor KTx. The rates of pediatric KTx, distribution of donor source and time on waiting list vary considerably between European countries. The lack of harmonization in kidney allocation to children raises medical and ethical issues. Harmonization of pediatric allocation policies should be prioritized.

Mortality due to pulmonary embolism, myocardial infarction, and stroke among incident dialysis patients.

BACKGROUND: It is has been suggested that dialysis patients have lower mortality rates for pulmonary embolism than the general population, because of platelet dysfunction and bleeding tendency. However, there is limited information whether dialysis is indeed associated with a decreased mortality risk from pulmonary embolism. OBJECTIVE: The aim of our study was to evaluate whether mortality rate ratios for pulmonary embolism were lower than for myocardial infarction and stroke in dialysis patients compared with the general population. METHODS: Cardiovascular causes of death for 130,439 incident dialysis patients registered in the ERA-EDTA Registry were compared with the cardiovascular causes of death for the European general population. RESULTS: The age- and sex-standardized mortality rate (SMR) from pulmonary embolism was 12.2 (95% CI 10.2-14.6) times higher in dialysis patients than in the general population. The SMRs in dialysis patients compared with the general population were 11.0 (95% CI 10.6-11.4) for myocardial infarction, 8.4 (95% CI 8.0-8.8) for stroke, and 8.3 (95% CI 8.0-8.5) for other cardiovascular diseases. In dialysis patients, primary kidney disease due to diabetes was associated with an increased mortality risk due to pulmonary embolism (HR 1.9; 95% CI 1.0-3.8), myocardial infarction (HR 4.1; 95% CI 3.4-4.9), stroke (HR 3.5; 95% CI 2.8-4.4), and other cardiovascular causes of death (HR 3.4; 95% CI 2.9-3.9) compared with patients with polycystic kidney disease. CONCLUSIONS: Dialysis patients were found to have an unexpected highly increased mortality rate for pulmonary embolism and increased mortality rates for myocardial infarction and stroke.

The EQUAL study: a European study in chronic kidney disease stage 4 patients.

The timing of the start of dialysis in elderly patients is driven by the desire to optimize the quantity and quality of life. Limited data exist on how the level of renal function, and uraemic signs and symptoms can be used to determine when dialysis should be initiated in elderly patients. EQUAL, an international prospective cohort study, aims to address these issues. To this end, it will enroll 3500 patients >65 years of age with CKD of various aetiologies under the care of nephrologists. These patients will be followed until death, discharge from the nephrology clinic to primary care or until the end of the observation period after 4 years of follow-up. At the time of enrollment, patients must have an estimated glomerular filtration rate (eGFR) of 20 mL/min/1.73 m(2) or lower, but should not yet be on dialysis. Standardized data collection will include demographics, lifestyle, comorbidities, uraemic signs and symptoms, nutritional status, medication and routine blood and urine biochemistry. It will also comprise quality of life data, information on decision making including patients preferences and patients satisfaction.

Measuring agreement, more complicated than it seems.

In medicine, before replacing an old device by a new one, we need to know whether the results of the old and new device are similar. This is called determining the agreement between methods. In this paper, we will first discuss various ways to determine the agreement between methods to measure continuous variables, including the t test, the correlation coefficient and the Bland-Altman plot. In the second part, we will discuss methods to determine the agreement between categorical variables, like the χ(2) test and Cohen's ĸ. The latter are often used when studying the agreement between clinicians, definitions, formulas or different data sources.

Control charts in healthcare quality improvement. A systematic review on adherence to methodological criteria.

OBJECTIVES: Use of Shewhart control charts in quality improvement (QI) initiatives is increasing. These charts are typically used in one or more phases of the Plan Do Study Act (PDSA) cycle to monitor summaries of process and outcome data, abstracted from clinical information systems, over time. We summarize methodological criteria of Shewhart control charts and investigate adherence of published QI studies to these criteria. METHODS: We searched Medline, Embase and CINAHL for studies using Shewhart control charts in QI processes in direct patient care. We extracted methodological criteria for Shewhart control charts, and for the use of these charts in PDSA cycles, from textbooks and methodological literature. RESULTS: We included 34 studies, presenting 64 control charts of which 40 control charts plotted two phases of the PDSA cycle. The criterion to use 10-35 data points in a control chart was least adhered to (48.4% non-adherence). Other criteria were: transformation of the data in case of a skewed distribution (43.7% non adherence), when comparing data from two phases of the PDSA cycle the Plan phase (the first phase) needs to be stable (40.0% non-adherence), using a maximum of four different rules to detect special cause variation (14.1% non-adherence), and setting control limits at three standard deviations from the mean (all control charts adhered). CONCLUSION: There is room for improvement with regard to the methodological construction of Shewhart control charts used in QI processes. Higher adherence to all methodological criteria will decrease the risk of incorrect conclusions about the process being monitored.

Ethnic differences in stillbirth and early neonatal mortality in The Netherlands.

BACKGROUND: Ethnic disparities in perinatal mortality are well known. This study aimed to explore the contribution of demographic, socioeconomic, health behavioural and pre-existent medical risk factors among different ethnic groups on fetal and early neonatal mortality. METHODS: We assessed perinatal mortality from 24.0 weeks' gestation onwards in 554 234 singleton pregnancies of nulliparous women in the linked Netherlands Perinatal Registry over the period 2000-2006. Logistic regression modelling was used. RESULTS: Considerable ethnic differences in perinatal mortality exist especially in fetal mortality. Maternal age, socioeconomic status and pre-existent diseases could not explain these ethnic differences. Late booking visit could explain some differences. Compared with the Dutch, African women had an increased fetal mortality risk of OR 1.7 (95% CI 1.4 to 2.1); South Asian women, 1.8 (1.4 to 2.3); other non-Western women, 1.3 (1.1 to 1.6) and Turkish/Moroccan women, 1.3 (1.1 to 1.4). The risk on early neonatal mortality was only increased in other non-Western women, OR 1.3 (1.0 to 1.8). Ethnic differences were even present in the women without risk factors including preterm births. Mortality risk for East Asian and other Western women was lower or comparable with the Dutch. CONCLUSION: Important ethnic differences in fetal mortality exist, especially among women of African and South Asian origin. Ethnic minorities should be more acquainted with the significance of early start of prenatal care. Tailored prenatal care for women with African and South Asian origin seems necessary. More research on underlying cause of deaths is needed by ethnic group.

Travel time from home to hospital and adverse perinatal outcomes in women at term in the Netherlands.

OBJECTIVE: To study the effect of travel time, at the start or during labour, from home to hospital on mortality and adverse outcomes in pregnant women at term in primary and secondary care. DESIGN: Population-based cohort study from 2000 up to and including 2006. SETTING: The Netherlands Perinatal Registry. POPULATION: A total of 751,926 singleton term hospital births. METHODS: We assessed the impact of travel time by car, calculated from the postal code of the woman's residence to the 99 maternity units, on neonatal outcome. Logistic regression modelling with adjustments for gestational age, maternal age, parity, ethnicity, socio-economic status, urbanisation, tertiary care centres and volume of the hospital was used. MAIN OUTCOME MEASURES: Mortality (intrapartum, and early and late neonatal mortality) and adverse neonatal outcomes (mortality, Apgar <4 and/or admission to a neonatal intensive care unit). RESULTS: The mortality was 1.5 per 1000 births, and adverse outcomes occurred in 6.0 per 1000 births. There was a positive relationship between longer travel time (≥20 minutes) and total mortality (OR 1.17, 95% CI 1.002-1.36), neonatal mortality within 24 hours (OR 1.51, 95% CI 1.13-2.02) and with adverse outcomes (OR 1.27, 95% CI 1.17-1.38). In addition to travel time, both delivery at 37 weeks of gestation (OR 2.23, 95% CI 1.81-2.73) or 41 weeks of gestation (OR 1.52, 95% CI 1.29-1.80) increased the risk of mortality. CONCLUSIONS: A travel time from home to hospital of 20 minutes or more by car is associated with an increased risk of mortality and adverse outcomes in women at term in the Netherlands. These findings should be considered in plans for the centralisation of obstetric care.

Senescence rates in patients with end-stage renal disease: a critical appraisal of the Gompertz model.

The most frequently used model to describe the exponential increase in mortality rate over age is the Gompertz equation. Logarithmically transformed, the equation conforms to a straight line, of which the slope has been interpreted as the rate of senescence. Earlier, we proposed the derivative function of the Gompertz equation as a superior descriptor of senescence rate. Here, we tested both measures of the rate of senescence in a population of patients with end-stage renal disease. It is clinical dogma that patients on dialysis experience accelerated senescence, whereas those with a functional kidney transplant have mortality rates comparable to the general population. Therefore, we calculated the age-specific mortality rates for European patients on dialysis (n=274 221; follow-up=594 767 person-years), for European patients with a functioning kidney transplant (n=61 286; follow-up=345 024 person-years), and for the general European population. We found higher mortality rates, but a smaller slope of logarithmic mortality curve for patients on dialysis compared with both patients with a functioning kidney transplant and the general population (P<0.001). A classical interpretation of the Gompertz model would imply that the rate of senescence in patients on dialysis is lower than in patients with a functioning transplant and lower than in the general population. In contrast, the derivative function of the Gompertz equation yielded the highest senescence rates for patients on dialysis, whereas the rate was similar in patients with a functioning transplant and the general population. We conclude that the rate of senescence is better described by the derivative function of the Gompertz equation.

Racial minority groups on dialysis in Europe: a literature review.

AIMS: To provide an overview of the existing data on non-Caucasian dialysis patients within Europe, and to explore whether these data confirm differences between non-Caucasian and Caucasian dialysis patients that were found in other parts of the world. METHOD: A query consisting of the combination "dialysis", "ethnicity", and "Europe" was applied in PubMed, EMBASE, Web of Science, CINAHL, and the Cochrane Library. RESULTS: Ten papers were included in this study. Studies from the United Kingdom (UK) and the Netherlands confirm the higher incidence of end-stage renal disease (ESRD) in non-Caucasians. In other European countries these findings were not confirmed. In studies from the UK, the Netherlands, and Spain a younger age at initiation of dialysis treatment for non-Caucasians compared to Caucasians was reported, this is also found in non-European studies. Regarding comorbid conditions at the start of renal replacement therapy (RRT), vascular disease was less common, while diabetes was more common among non-Caucasians compared to Caucasians. Large non-European studies also demonstrated less vascular disease among non-Caucasians initiating RRT than among Caucasians. The survival advantage for non-Caucasian compared to Caucasian RRT patients is confirmed in one large study from the UK and in a Dutch study. Reasons for the better survival of non-Caucasians are not understood completely. CONCLUSIONS: Only a few studies are available on non-Caucasian dialysis patients in Europe. The available data confirm findings of other studies throughout the world on racial differences on dialysis. More research is needed to understand the higher incidence and better survival in non-Caucasian patients, and also in countries where there are currently no relevant data.

Confounding.

In confounding, the effect of the exposure of interest is mixed with the effect of another variable. It is important to identify relevant confounders and remove the confounding effect as much as possible. There are three criteria that need to be fulfilled to determine whether a variable could be considered a potential confounder. The first criterion is that the variable needs to be associated with the exposure. The second criterion is that the variable needs to be associated with the outcome or disease. The third criterion is that the variable should not be an intermediate variable in the causal pathway between exposure and outcome. Only if all the criteria are fulfilled is the variable under question a confounder. If one incorrectly adjusts for a variable that is not a confounder, one risks overadjustment or adjustment for spurious associations. Confounders can be prevented from entering the study, during the design of a study, or if this is not possible, one can try to remove it during the analysis phase.

Patients' representations of their end-stage renal disease: relation with mortality.

BACKGROUND: Self-regulation theory explains how patients' illness perceptions influence self-management behaviour (e.g. via adherence to treatment). Following these assumptions, we explored whether illness perceptions of ESRD-patients are related to mortality rates. METHODS: Illness perceptions of 182 patients participating in the NECOSAD-2 study in the period between December 2004 and June 2005 were assessed. Cox proportional hazard models were used to estimate whether subsequent all-cause mortality could be attributed to illness perception dimensions. RESULTS: One-third of the participants had died at the end of the follow-up. Mortality rates were higher among patients who believed that their treatment was less effective in controlling their disease (perceived treatment control; RR = 0.71, P = 0.028). This effect remained stable after adjusting for sociodemographic and clinical variables (RR = 0.65, P = 0.015). CONCLUSIONS: If we consider risk factors for mortality, we tend to rely on clinical parameters rather than on patients' representations of their illness. Nevertheless, results from the current exploration may suggest that addressing patients' personal beliefs regarding the effectiveness of treatment can provide a powerful tool for predicting and perhaps even enhancing survival.

Linear and logistic regression analysis.

In previous articles of this series, we focused on relative risks and odds ratios as measures of effect to assess the relationship between exposure to risk factors and clinical outcomes and on control for confounding. In randomized clinical trials, the random allocation of patients is hoped to produce groups similar with respect to risk factors. In observational studies, exposed and unexposed individuals may differ not only for the presence of the risk factor being tested but also for a series of other factors that are potentially related to the study outcome, thus making 'confounding' very likely. One of the most important uses of multivariate modeling is precisely that 'of controlling for confounding' to let emerge the effect of the risk factor of interest on the study outcome. In this paper, we will discuss linear regression analysis for the examination of continuous outcome data and logistic regression analysis for the study of categorical outcome data. Furthermore, we focus on the most important application of multiple linear and logistic regression analyses.

Confounding: what it is and how to deal with it.

As confounding obscures the 'real' effect of an exposure on outcome, investigators performing etiological studies do their utmost best to prevent or control confounding. Unfortunately, in this process, errors are frequently made. This paper explains that to be a potential confounder, a variable needs to satisfy all three of the following criteria: (1) it must have an association with the disease, that is, it should be a risk factor for the disease; (2) it must be associated with the exposure, that is, it must be unequally distributed between exposure groups; and (3) it must not be an effect of the exposure; this also means that it may not be part of the causal pathway. In addition, a number of different techniques are described that may be applied to prevent or control for confounding: randomization, restriction, matching, and stratification. Finally, a number of examples outline commonly made errors, most of which result from 'overadjustment' for variables that do not satisfy the criteria for potential confounders. Such an example of an error frequently occurring in the literature is the incorrect adjustment for blood pressure while studying the relationship between body mass index and the development of end-stage renal disease. Such errors will introduce new bias instead of preventing it.

Bias in clinical research.

The quality of a clinical study depends on internal and external factors. Studies have internal validity when, random error apart, reported differences between exposed and unexposed individuals can be attributed only to the exposure under investigation. Internal validity may be affected by bias, that is, by any systematic error that occurs in the design or in the conduction of a clinical research. Here we focus on two major categories of bias: selection bias and information bias. We describe three types of selection biases (incidence-prevalence bias, loss-to-follow-up bias, and publication bias) and a series of information biases (i.e. misclassification bias--recall bias, interviewer bias, observer bias, and regression dilution bias--and lead-time bias).

Measures of effect: relative risks, odds ratios, risk difference, and 'number needed to treat'.

Epidemiological studies aim at assessing the relationship between exposures and outcomes. Clinicians are interested in knowing not only whether a link between a given exposure (e.g. smoking) and a certain outcome (e.g. myocardial infarction) is statistically significant, but also the magnitude of this relationship. The 'measures of effect' are indexes that summarize the strength of the link between exposures and outcomes and can help the clinician in taking decisions in every day clinical practice. In epidemiological studies, the effect of exposure can be measured both in relative and absolute terms. The risk ratio, the incidence rate ratio, and the odds ratio are relative measures of effect. Risk difference is an absolute measure of effect and it is calculated by subtracting the risk of the outcome in exposed individuals from that of unexposed.