Patient safety in English general practice : the role of routinely collected data in detecting adverse events

The use of routinely collected, or administrative, data for measuring and monitoring patient safety in primary care is a relatively new phenomenon. With increasing availability of data from different sources and care settings, their application for adverse event surveillance needs evaluation. In this thesis, I demonstrated that data routinely collected from primary care and secondary care can be applied for internal monitoring of adverse events at the general practice-level in England, but these data currently have limited use for safety benchmarking in primary care. To support this statement, multiple approaches were adopted. In the first part of the thesis, the nature and scope of patient safety issues in general practice were defined by evidence from a literature review and informal consultations with general practitioners (GPs). Secondly, using these two methods, measures of adverse events based on routinely collected healthcare data were identified. Thirdly, clinical consensus guided the selection of three candidate patient safety indicators for investigation; the safety issues explored in this thesis were recorded incidents with designated adverse event diagnostic codes and complications associated with two common diseases, emergency admissions for diabetic hyperglycaemic emergencies (diabetic ketoacidosis, DKA and hyperglycaemic hyperosmolar state, HHS) and cancer. In the second part of the thesis, the contributions of routinely collected data to new knowledge about potentially preventable adverse events in England were considered. Data from a primary care trust (NHS Brent), national primary care data (from the General Practice Research Database, GPRD) and secondary care data (Hospital Episode Statistics, HES) were used to explore the epidemiology of, and patient characteristics associated with, coded adverse events and emergency admissions for diabetic hyperglycaemic emergencies and cancer. Low rates of adverse events were found, with variation by individual patient factors. Finally, recommendations were made on extending the uses of routinely collected data for patient safety monitoring in general practice

Incidence, Characteristics, and Outcomes of Acute Kidney Injury Treated with Dialysis during Pregnancy and the Postpartum Period

Pregnancy-related acute kidney injury (AKI) may be associated with significant morbidity and mortality in young and often otherwise healthy women. We conducted a retrospective cohort study of all consecutive pregnancies between 1997 and 2011 in Ontario and describe the incidence, characteristics, and outcomes of AKI treated with dialysis (AKI-D) during pregnancy or within 12 weeks postpartum. Of 1,918,789 pregnancies, 188 were complicated by AKI-D (incidence proportion: 1 per 10,000, 95% confidence interval 0.8 to 1.1). Eight women died (4.3% versus 0.01% in the general population) and seven (3.9%) survivors remained dialysis-dependent four months after delivery. The presence of AKI-D was associated with several maternal complications as well as low birth weight, small for gestational age, and preterm birth among infants, although there were no stillbirths and fewer than five neonatal deaths in affected pregnancies. In conclusion, AKI-D in pregnancy is rare. Most affected women and their babies have good short-term outcomes

Quality of care in incident type 2 diabetes and initial presentation of vascular complications: Prospective cohort study using linked electronic health records from CALIBER research platform

Background. Numbers of new cases of type 2 diabetes (T2D) are increasing rapidly. Early and continuing intervention after T2D presentation is crucial for best possible outcomes, ensuring that the existing high burden of T2D will not be aggravated. Identification of patterns of continuous care and predictors for meeting key targets for T2D management can improve quality of care. Glycaemic control is particularly important for primary prevention of vascular complications but its relationship with contemporary cardiovascular diseases (CVDs) has been less explored. More importantly, long-term glycaemic control can be assessed from routine monitoring, potentially providing new insight into T2D management to prevent vascular complications. Linked electronic health records are invaluable data resources for investigating these issues. Objective. To examine the quality of care in an incident T2D cohort through assessment of temporal trends of care, predictors of glycaemic, blood pressure and lipid control, and associations of short-term and long-term glycaemic control with chronic vascular complications. Methods. The data source for studies in this thesis was CALIBER which links electronic health records from primary care, hospitalisation, myocardial infarction and mortality registries. Patients newly diagnosed with T2D between 1998 and 2010 were followed-up until a censoring administrative date or initial occurrence of vascular complications. Trends in receipt of care and attainment of glycaemic, blood pressure and total cholesterol targets were examined. Predictors for meeting the targets were explored using multinomial logistic regressions. Association of early glycaemic control with a range of specific cardiovascular complications were investigated using Cox regressions. A longitudinal metric for glycaemic control was developed by quantifying time spent at target during follow-up and was tested for its association with cardiovascular and microvascular outcomes using mixed logistic regressions. Results. A total of 52,379 incident T2D patients were identified with a median follow-up of over 4 years. Positive trends were observed for blood pressure and total cholesterol control, but not for glycaemic control, whilst attainment of HbA1c and blood pressure targets over time consistently fell short. Older age at diagnosis was an important predictor for meeting the key targets. In 36,149 patients free from prior CVD, early glycaemic and blood pressure control was associated with lower risk for heart failure and peripheral arterial disease, whereas cholesterol control with myocardial infarction and transient ischaemic attack. Shorter duration at glycaemic target was associated with higher risk of major adverse cardiovascular events, cardiovascular death and diabetic retinopathy. Conclusions. This thesis highlights missed opportunities and inequality in T2D care. Both short-term and long-term glycaemic control are important for reducing risk of vascular complications. Limitations and implications of the findings for clinical practice and research were discussed

Incretin treatment and risk of pancreatitis in patients with type 2 diabetes mellitus : systematic review and meta-analysis of randomised and non-randomised studies

Objective To investigate the risk of pancreatitis associated with the use of incretin-based treatments in patients with type 2 diabetes mellitus. Design Systematic review and meta-analysis. Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov. Eligibility criteria Randomised and non-randomised controlled clinical trials, prospective or retrospective cohort studies, and case-control studies of treatment with glucagon-like peptide-1 (GLP-1) receptor agonists or dipeptidyl peptidase-4 (DPP-4) inhibitors in adults with type 2 diabetes mellitus compared with placebo, lifestyle modification, or active anti-diabetic drugs. Data collection and analysis Pairs of trained reviewers independently screened for eligible studies, assessed risk of bias, and extracted data. A modified Cochrane tool for randomised controlled trials and a modified version of the Newcastle-Ottawa scale for observational studies were used to assess bias. We pooled data from randomised controlled trials using Peto odds ratios, and conducted four prespecified subgroup analyses and a post hoc subgroup analysis. Because of variation in outcome measures and forms of data, we describe the results of observational studies without a pooled analysis. Results 60 studies (n=353 639), consisting of 55 randomised controlled trials (n=33 350) and five observational studies (three retrospective cohort studies, and two case-control studies; n=320 289) were included. Pooled estimates of 55 randomised controlled trials (at low or moderate risk of bias involving 37 pancreatitis events, raw event rate 0.11%) did not suggest an increased risk of pancreatitis with incretins versus control (odds ratio 1.11, 95% confidence interval 0.57 to 2.17). Estimates by type of incretin suggested similar results (1.05 (0.37 to 2.94) for GLP-1 agonists v control; 1.06 (0.46 to 2.45) for DPP-4 inhibitors v control). Analyses according to the type of control, mode, duration of treatment, and individual incretin agents suggested no differential effect by subgroups, and sensitivity analyses by alternative statistical modelling and effect measures did not show important differences in effect estimates. Three retrospective cohort studies (moderate to high risk of bias, involving 1466 pancreatitis events, raw event rate 0.47%) also did not suggest an increased risk of pancreatitis associated with either exenatide (adjusted odds ratios 0.93 (0.63 to 1.36) in one study and 0.9 (0.6 to 1.5) in another) or sitagliptin (adjusted hazard ratio 1.0, 0.7 to 1.3); a case-control study at moderate risk of bias (1003 cases, 4012 controls) also suggested no significant association (adjusted odds ratio 0.98, 0.69 to 1.38). Another case-control study (1269 cases, 1269 controls) at moderate risk of bias, however, suggested that the use of either exenatide or sitagliptin was associated with significantly increased odds of acute pancreatitis (use within two years v no use, adjusted odds ratio 2.07, 1.36 to 3.13). Conclusions The available evidence suggests that the incidence of pancreatitis among patients using incretins is low and that the drugs do not increase the risk of pancreatitis. Current evidence, however, is not definitive, and more carefully designed and conducted observational studies are warranted to definitively establish the extent, if any, of increased risk

Generating Reliable and Responsive Observational Evidence: Reducing Pre-analysis Bias

A growing body of evidence generated from observational data has demonstrated the potential to influence decision-making and improve patient outcomes. For observational evidence to be actionable, however, it must be generated reliably and in a timely manner. Large distributed observational data networks enable research on diverse patient populations at scale and develop new sound methods to improve reproducibility and robustness of real-world evidence. Nevertheless, the problems of generalizability, portability and scalability persist and compound. As analytical methods only partially address bias, reliable observational research (especially in networks) must address the bias at the design stage (i.e., pre-analysis bias) including the strategies for identifying patients of interest and defining comparators. This thesis synthesizes and enumerates a set of challenges to addressing pre-analysis bias in observational studies and presents mixed-methods approaches and informatics solutions for overcoming a number of those obstacles. We develop frameworks, methods and tools for scalable and reliable phenotyping including data source granularity estimation, comprehensive concept set selection, index date specification, and structured data-based patient review for phenotype evaluation. We cover the research on potential bias in the unexposed comparator definition including systematic background rates estimation and interpretation, and definition and evaluation of the unexposed comparator. We propose that the use of standardized approaches and methods as described in this thesis not only improves reliability but also increases responsiveness of observational evidence. To test this hypothesis, we designed and piloted a Data Consult Service - a service that generates new on-demand evidence at the bedside. We demonstrate that it is feasible to generate reliable evidence to address clinicians’ information needs in a robust and timely fashion and provide our analysis of the current limitations and future steps needed to scale such a service

Exploring the relationship between age and health conditions using electronic health records: from single diseases to multimorbidities

Background Two enormous challenges facing healthcare systems are ageing and multimorbidity. Clinicians, policymakers, healthcare providers and researchers need to know “who gets which diseases when” in order to effectively prevent, detect and manage multiple conditions. Identification of ageing-related diseases (ARDs) is a starting point for research into common biological pathways in ageing. Examining multimorbidity clusters can facilitate a shift from the single-disease paradigm that pervades medical research and practice to models which reflect the reality of the patient population. Aim To examine how age influences an individual’s likelihood of developing single and multiple health conditions over the lifecourse. Methods and Outputs I used primary care and hospital admission electronic health records (EHRs) of 3,872,451 individuals from the Clinical Practice Research Datalink (CPRD) linked to the Hospital Episode Statistics admitted patient care (HES-APC) dataset in England from 1 April 2010 to 31 March 2015. In collaboration with Professor Aroon Hingorani, Dr Osman Bhatti, Dr Shanaz Husain, Dr Shailen Sutaria, Professor Dorothea Nitsch, Mrs Melanie Hingorani, Dr Constantinos Parisinos, Dr Tom Lumbers and Dr Reecha Sofat, I derived the case definitions for 308 clinically important health conditions, by harmonising Read, ICD-10 and OPCS-4 codes across primary and secondary care records in England. I calculated the age-specific incidence rate, period prevalence and median age at first recorded diagnosis for these conditions and described the 50 most common diseases in each decade of life. I developed a protocol for identifying ARDs using machine-learning and actuarial techniques. Finally, I identified highly correlated multimorbidity clusters and created a tool to visualise comorbidity clusters using a network approach. Conclusions I have developed case definitions (with a panel of clinicians) and calculated disease frequency estimates for 308 clinically important health conditions in the NHS in England. I have described patterns of ageing and multimorbidity using these case definitions, and produced an online app for interrogating comorbidities for an index condition. This work facilitates future research into ageing pathways and multimorbidity

The Association between Depression, Anxiety and Clinical Outcomes for Type 2 Diabetes Mellitus

Objective: To evaluate the impact of depression and/or anxiety on clinical outcomes of diabetes, including glycosylated hemoglobin (HgA1c), blood glucose, blood pressure, total cholesterol, weight and LDL among patients with incident type 2 diabetes mellitus (T2DM). Method: A retrospective cohort study utilizing electronic medical record (EMR) data from a primary care physician (PCP) group practice was conducted to identify patients newly diagnosed with T2DM with at least 6 months pre-diagnosis and 12 months post-diagnosis of EMR data using International Classification of Disease 9th edition Clinical Modification (ICD-9-CM) coding. The presence of comorbid depression and anxiety was identified to identify four cohorts: (1) patients with T2DM only, (2) patients with T2DM and depression, (3) patients with T2DM and anxiety, and (4) patients with T2DM and depression and anxiety. Data regarding patients’ demographic, clinical characteristics, lab results and medication utilization during the first year following diagnosis of T2DM (the index date) were gathered. Analyses included comparison of patients’ demographics and clinical characteristics (using matching), evaluation of clinical outcomes of diabetes with regard to mental illness diagnosis, and examination of mental illness treatment and mental illness severity. Finally, factors predicting HgA1c goal attainment were assessed via the use of a logistic regression model. Result: The inclusion/exclusion criteria led to a study sample of 1822 T2DM patients amongst whom 1410 had T2DM only, 148 had T2DM and concomitant depression, 215 had T2DM and concomitant anxiety, 49 had T2DM and both depression and anxiety. Significant reductions in HgA1c occurred across all four groups from baseline to follow-up (p Conclusion: The findings suggest that comorbid depression and/or anxiety have limited singular influence upon clinical outcomes of diabetes among patients with T2DM. Further work should examine additional clinical outcomes for diabetes and model the influence of demographic and clinical contributors to these outcomes. Limitations of the study include generalizability, degree of missing data, lack of information on other potentially influential predictors, misclassification bias and reliability of coding utilized to isolate study sample

Hypoglycaemia in older people with dementia and diabetes

Objective To explore the effect of hypoglycaemia on adverse events in older people with diabetes and dementia and determine the feasibility of using continuous glucose monitoring in this patient group. Methods Systematic review on continuous glucose monitoring in older people with diabetes: Hypothesis-generating systematic review to inform my feasibility study and to identify gaps in the evidence. Feasibility study: I conducted a feasibility study of continuous blood glucose monitoring to explore continuous glucose monitoring in older people with diabetes and memory problems. Pharmacoepidemiological study: Retrospective cohort study using the Clinical Research Practice Datalink database to test the effect of exposure to hypoglycaemia in older patients with dementia. Systematic review and meta-analysis on the associations between hypoglycaemia and adverse events in older people treated with glucose-lowering agents: Updated systematic review and meta-analysis of serious adverse events associated with hypoglycaemia in older patients treated with glucose-lowering agents. Findings Systematic review on continuous glucose monitoring in older people with diabetes: 9 studies were included with a total of nearly 1000 patients. Hypoglycaemic episodes occurred in a sizeable proportion and most of these episodes were asymptomatic. Some patients spent nearly 2 hours per day in the hypoglycaemic range. CGM is acceptable to patients and improved health-related well-being. Feasibility study: 12 participants completed the study and found using CGM device acceptable. Data capture with this device varied considerably (3%-92%). The device captured hypoglycaemic episodes in 6 participants, two of which lasted for over 300 minutes. Pharmacoepidemiological study: Older people with dementia and diabetes who have had a hypoglycaemic event are at substantially higher risk of death, cardiovascular events, falls, fractures and emergency department attendances, than those who have not had a hypoglycaemic event. Systematic review and meta-analysis on the associations between hypoglycaemia and adverse events in older people treated with glucose-lowering agents: 42 included studies with over 2 million patients. Hypoglycaemia is associated with an 80% increased risk in vascular complications, a doubling in risk of all-cause mortality, a 55% increased risk in dementia, and a 78% and 68% increased risk in falls and fractures respectively. Conclusions My research has highlighted the complications associated with hypoglycaemia in older people with diabetes and dementia and set the ground work for future studies using continuous glucose monitoring in this patient group

Enhancing drug safety through active surveillance of observational healthcare data

Drug safety continues to be a major public health concern in the United States, with adverse drug reactions ranking as the 4th to 6th leading cause of death, and resulting in health care costs of $3.6 billion annually. Recent media attention and public scrutiny of high-profile drug safety issues have increased visibility and skepticism of the effectiveness of the current post-approval safety surveillance processes. Current proposals suggest establishing a national active drug safety surveillance system that leverages observational data, including administrative claims and electronic health records, to monitor and evaluate potential safety issues of medicines. However, the development and evaluation of appropriate strategies for systematic analysis of observational data have not yet been studied. This study introduces a novel exploratory analysis approach (Comparator-Adjusted Safety Surveillance or COMPASS) to identify drug-related adverse events in automated healthcare data. The aims of the study were: 1) to characterize the performance of COMPASS in identifying known safety issues associated with ACE inhibitor exposure within an administrative claims database; 2) to evaluate consistency of COMPASS estimates across a network of disparate databases; and 3) to explore differential effects across ingredients within ACE inhibitor class. COMPASS was observed to have improved accuracy to three other methods under consideration for an active surveillance system: observational screening, disproportionality analysis, and self-controlled case series. COMPASS performance was consistently strong within 5 different databases, though important differences in outcome estimates across the sources highlighted the substantial heterogeneity which makes pooling estimates challenging. The comparative safety analysis of products within the ACE inhibitor class provided evidence of similar risk profiles across an array of different outcomes, and raised questions about the product labeling differences and how observational studies should complement existing evidence as part of a broader safety assessment strategy. The results of this study should inform decisions about the appropriateness and utility of analyzing observational data as part of an active drug safety surveillance process. An improved surveillance system would enable a more comprehensive and timelier understanding of the safety of medicines. Such information supports patients and providers in therapeutic decision-making to minimize risks and improve the quality of care

Environmental heat and acute kidney injury in older adults: A matched case-control study

This matched case-control study examined the association between environmental heat exposure and hospital encounters with acute kidney injury (AKI) among adults, 66 years and older, in the province of Ontario, Canada. We matched 52,913 cases who had an AKI event during the warm seasons (April to September) of 2005 to 2012 with 174,222 controls who did not have an AKI event. We matched cases to controls on date, age, sex, residential status, income, and history of chronic kidney disease using a variable one to four matching ratio. We classified heat periods as three consecutive days where the 95th percentile of area-specific daily maximum temperature was reached or exceeded. We determined associations using conditional logistic regression. Compared to non-heat periods, high heat periods were significantly associated with greater risk of AKI (adjusted odds ratio 1.11, 95% confidence interval 1.00 to 1.23)