Familial hypercholesterolaemia in UK primary care: a Clinical Practice Research Datalink study of an under-recognised condition.

BACKGROUND: Studies utilising genotyping methods report the prevalence of familial hypercholesterolaemia to be as high as one in 137 of the adult population. AIM: To estimate the prevalence of familial hypercholesterolaemia measured by clinically coded diagnosis, associated treatments, and lipid measurements observed in UK primary care. DESIGN AND SETTING: This was a retrospective analysis using the Clinical Practice Research Datalink (CPRD) GOLD database. METHOD: Patients aged ≥18 years and actively registered on the index date (30 June 2018) formed the study cohort. Point prevalence of familial hypercholesterolaemia for 2018 was estimated overall and for each nation of the UK. Patients with familial hypercholesterolaemia were stratified into primary and secondary prevention groups, defined as those with/without a prior diagnosis of atherosclerotic cardiovascular disease. Prevalence estimates and extrapolations were replicated for these subgroups. Baseline demographic, lipid, and clinical characteristics for the prevalent cohort were presented. RESULTS: In total, 4048 patients with familial hypercholesterolaemia formed the study cohort. The estimated familial hypercholesterolaemia prevalence for the UK was 16.4 per 10 000 (95% confidence interval [CI] = 16.0 to 16.9). Of these, 2646 (65.4%) patients with familial hypercholesterolaemia had a recent prescription for lipid-lowering therapy. Mean lipid levels were lower for those treated with lipid-lowering therapy compared with those untreated: 5.34 mmol/L (SD 1.50) versus 6.25 mmol/L (SD 1.55) for total cholesterol and 3.15 mmol/L (SD 1.34) versus 3.96 mmol/L (SD 1.36) for low-level density lipoprotein cholesterol. CONCLUSION: The estimated prevalence of familial hypercholesterolaemia was one in 608 of the population, less than expected from other studies, which may indicate that familial hypercholesterolaemia is under-recognised in UK primary care. Over one-third of diagnosed patients were undertreated and many did not achieve target goals, placing them at risk of cardiovascular events.

Risk of major adverse cardiovascular events associated with elevated low-density lipoprotein cholesterol in a population with atherosclerotic cardiovascular disease with and without type 2 diabetes: a UK database analysis using the Clinical Practice Research Datalink.

OBJECTIVES: To estimate the 12-month probabilities of major adverse cardiovascular events (MACE) and non-cardiovascular death in patients with atherosclerotic cardiovascular disease (ASCVD) and elevated low-density lipoprotein cholesterol (LDL-C). DESIGN: A retrospective database analysis. SETTING: UK primary care. PARTICIPANTS: Patients were selected from the Clinical Practice Research Datalink (Aurum) linked to Hospital Episode Statistics inpatient and Office of National Statistics mortality datasets. Patients with an ASCVD diagnosis between 01 January 2010 and 31 May 2018 and LDL-C ≥2.6 mmol/L were selected. PRIMARY OUTCOMES: Primary outcomes were 12-month risk of (1) MACE (composite of revascularisation, unstable angina, non-fatal myocardial infarction, non-fatal stroke and cardiovascular death) and (2) non-cardiovascular mortality. Kaplan-Meier survival analysis estimated the probability of each outcome. A Cox proportional hazards model explored covariates associated with MACE. RESULTS: Of 102 245 study patients, 16 501 (16.1%) had a diagnosis of type 2 diabetes (T2DM). 65.5% of those with and 49.9% of those without T2DM had a lipid-lowering therapy (LLT) 6 months prior to index diagnosis. Twelve-month probability of MACE was 7.9% for non-T2DM and 11.8% for T2DM. LDL-C was significantly associated with risk of MACE (HR=1.19 (95% CI 1.16 to 1.22) per 1 mmol/L). History of acute coronary syndrome, other coronary heart disease, stroke and T2DM significantly increased the risk of MACE. Ezetimibe (0.88 (95% CI 0.79 to 0.99)) and low-intensity statins (0.88 (95% CI 0.79 to 0.97)) were associated with reduced 12-month MACE risk.and low-intensity statins 0.88 (95% CI 0.79 to 0.97) CONCLUSION: We confirmed the association between elevated LDL-C and MACE. Many patients with ASCVD and elevated LDL-C were untreated with LLT. With the increasing demands on general practitioners, initiatives aimed at improving identification and treatment of at-risk patients within primary care should be considered.

Incident Comorbidity, Resource Use, and All-Cause Mortality Associated with Prurigo Nodularis: A United Kingdom Retrospective Database Analysis.

We described comorbidity, resource utilization, and mortality for patients with prurigo nodularis (PN) using data from the Clinical Practice Research Datalink. Patients with incident PN (2008-2018) were selected and matched to controls. Of 2,416 patients with PN, 2,409 (99.7%) were matched to controls. Prevalence of atopic dermatitis (relative risk [RR] = 2.571; 95% confidence interval [CI] = 2.356-2.806), depression (RR = 1.705; 95% CI = 1.566-1.856), anxiety (RR = 1.540; 95% CI = 1.407-1.686), coronary heart disease (RR = 1.575; 95% CI = 1.388-1.787), chronic kidney disease (RR = 1.529; 95% CI = 1.329-1.759), and type 2 diabetes mellitus (RR = 1.836; 95% CI = 1.597-2.111) was significantly higher for patients with PN. Subsequent risk of atopic dermatitis (hazard ratio = 6.58; 95% CI = 5.17- 8.37), depression (hazard ratio = 1.61; 95% CI = 1.30-1.99), and coronary heart disease (hazard ratio = 1.37; 95% CI = 1.09-1.74) were significantly increased. Resource utilization was increased in all settings: incidence rate ratio = 1.48 (95% CI = 1.47-1.49) for primary care, incident rate ratio = 1.80 (95% CI = 1.75-1.85) for inpatients, incident rate ratio = 2.15 (95% CI = 2.13-2.18) for outpatients, and incidence rate ratio = 1.32 (95% CI = 1.27-1.36) for accident and emergency. Respective cost ratios were 1.78 (95% CI = 1.67-1.90), 1.52 (95% CI = 1.20-1.94), 2.34 (95% CI = 2.13-2.58), and 1.55 (95% CI = 1.33-1.80). Total primary and secondary healthcare costs were £2,531 versus £1,333, a cost ratio of 1.62 (95% CI = 1.36-1.94). The adjusted hazard ratio for mortality was 1.37 (95% CI = 1.14-1.66). Patients with PN had significantly increased rates of comorbidity, healthcare resources utilization, and mortality compared with matched controls.

Real-world evidence from the first online healthcare analytics platform-Livingstone. Validation of its descriptive epidemiology module.

Incidence and prevalence are key epidemiological determinants characterizing the quantum of a disease. We compared incidence and prevalence estimates derived automatically from the first ever online, essentially real-time, healthcare analytics platform-Livingstone-against findings from comparable peer-reviewed studies in order to validate the descriptive epidemiology module. The source of routine NHS data for Livingstone was the Clinical Practice Research Datalink (CPRD). After applying a general search strategy looking for any disease or condition, 76 relevant studies were first retrieved, of which 10 met pre-specified inclusion and exclusion criteria. Findings reported in these studies were compared with estimates produced automatically by Livingstone. The published reports described elements of the epidemiology of 14 diseases or conditions. Lin's concordance correlation coefficient (CCC) was used to evaluate the concordance between findings from Livingstone and those detailed in the published studies. The concordance of incidence values in the final year reported by each study versus Livingstone was 0.96 (95% CI: 0.89-0.98), whilst for all annual incidence values the concordance was 0.93 (0.91-0.94). For prevalence, concordance for the final annual prevalence reported in each study versus Livingstone was 1.00 (0.99-1.00) and for all reported annual prevalence values, the concordance was 0.93 (0.90-0.95). The concordance between Livingstone and the latest published findings was near perfect for prevalence and substantial for incidence. For the first time, it is now possible to automatically generate reliable descriptive epidemiology from routine health records, and in near-real time. Livingstone provides the first mechanism to rapidly generate standardised, descriptive epidemiology for all clinical events from real world data.

Epidemiology of prurigo nodularis in England: a retrospective database analysis.

BACKGROUND: Prurigo nodularis is a debilitating skin condition that is classified as rare by the Genetic and Rare Diseases Information Center (GARD) and the National Organization for Rare Diseases (NORD). There are currently no estimates of the prevalence of prurigo nodularis in England. OBJECTIVES: We aimed to address this data gap by describing the epidemiology of prurigo nodularis in a representative dataset derived from the English National Health Service. METHODS: The study utilized data from the Clinical Practice Research Datalink linked to Hospital Episode Statistics inpatient data. Patients with a diagnosis of prurigo nodularis were selected by clinical code in the primary care or inpatient datasets. Case definition was based on a minimum of two distinct diagnoses to maximize specificity. Point prevalence was calculated for the midpoint of 2018 and incidence rates from 2008 to 2018 were presented. For those classified as incident cases, demographic and clinical characteristics were reported. In sensitivity analyses the case definition was modified to relax the multiple diagnosis criteria and to restrict cases to those diagnosed within a maximum of 4 or 10 years of the midpoint prevalence date. RESULTS: Overall, 11 656 patients within the dataset had at least one prurigo nodularis diagnosis. Following application of the relevant inclusion criteria, 2743 patients formed the point prevalent cohort; the estimated prevalence was 3·27 patients per 10 000 population [95% confidence interval (CI) 3·15-3·40]. In sensitivity analyses the estimated prevalence ranged from 2·24 (95% CI 2·14-2·34) to 6·98 (95% CI 6·80-7·16). Incidence over the study period was 2·88 per 100 000 patient-years. Comorbidity was relatively high in this population, notably for atopic dermatitis (52·2%), depression (41·1%) and anxiety (35·4%). CONCLUSIONS: This study supports the NORD/GARD classification of prurigo nodularis as a rare disease with a prevalence of 3·27 patients per 10 000 population, which equates to 18 471 patients living with the disease in England in 2018. The relatively high prevalence of comorbidity observed for these patients may increase the complexity of management.

Characterization and Associated Costs of Constipation Relating to Exposure to Strong Opioids in England: An Observational Study.

PURPOSE: Opioid use is associated with gastrointestinal adverse events, including nausea and constipation. We used a real-world dataset to characterize the health care burden associated with opioid-induced constipation (OIC) with particular emphasis on strong opioids. METHODS: This retrospective cohort study was conducted using the Clinical Practice Research Datalink, a large UK primary care dataset linked to hospital data. Patients prescribed opioids during 2016 were selected and episodes of opioid therapy constructed. Episodes with ≥84 days of exposure were classified as chronic, with date of first prescription as the index date. The main analysis focused on patients prescribed strong opioids who were laxative naive. Constipation was defined by ≥2 laxative prescriptions during the opioid episode. Patients for whom initial laxative therapy escalated by switch, augmentation, or dose were defined as OIC unstable, and the first 3 lines of OIC escalation were classified. Health care costs accrued in the first 12 months of the opioid episode were aggregated and compared. FINDINGS: A total of 27,629 opioid episodes were identified; 5916 (21.4%) involved a strong opioid for patients who were previously laxative naive. Of these patients, 2886 (48.8%) were defined as the OIC population; 941 (33.26%) were classified as stable. Of the 1945 (67.4%) episodes classified as unstable, 849 (43.7%), 360 (18.5%), and 736 (37.8%) had 1, 2, and ≥3 changes of laxative prescription, respectively. Patients without OIC had lower costs per patient year (£3822 [US$5160/€4242]) compared with OIC (£4786 [US$6461/€5312]). Costs increased as patients had multiple changes in therapy: £4696 (US$6340/€5213), £4749 (US$6411/€5271), and £4981 (US$6724/€5529) for 1, 2, and ≥3 changes, respectively. The adjusted cost ratio relative to non-OIC was 1.14 (95% CI, 1.09-1.32) for those classified as stable and 1.19 (95% CI, 1.09-1.32) for those with ≥3 laxative changes. Similar patterns were observed for patients taking anyopioid, with costs increased for those classified as having OIC (£3727 [US$5031/€4137] vs £2379 [US$3212 /€2641),and for those patients classified as unstable versus stable (£3931 [US$5307/€4363] vs £3432 [US$4633/€3810). Costs increased with each additional line of therapy from £3701 (US$4996/€4108), £3916 (US$5287/€4347), and £4318 (US$5829/€4793). IMPLICATIONS: OIC was a common adverse event of opioid treatment and was poorly controlled for a large number of patients. Poor control was associated with increased health care costs. The impact of OIC should be considered when prescribing opioids. These results should be interpreted with consideration of the caveats associated with the analysis of routine data.

Healthcare utilization and associated costs following initiation of perampanel in patients with epilepsy.

PURPOSE: We compared health service utilization and costs for patients with epilepsy before and after initiation of perampanel and compared with matched controls. METHOD: Patients were selected from the Clinical Practice Research Datalink (CPRD). Patients initiating perampanel were matched to controls initiating an alternate add-on therapy for the same underlying epilepsy subtype. First prescription defined index date. Primary and secondary care contacts and associated costs were aggregated in the 12 months before and after index date. Secondary care contacts were available for a subset (~60%) of patients. RESULTS: Three hundred and forty-three patients treated with perampanel were identified. One hundred and eighty-three (53.4%) were male, mean age was 39.1 (sd: 16.0). Mean epilepsy duration was 21.1 (standard deviation (sd): 13.3) years. Two hundred and eighty-seven (83.7%) were matched to controls. Inpatient admissions with a primary diagnosis of epilepsy (0.5 versus 0.2 per patient-year (ppy), p = 0.002) and neurology specific outpatient appointments (3.2 versus 2.9 ppy, p = 0.041) were significantly reduced following initiation with perampanel. Total costs attributable to epilepsy (£1889 to 1477 ppy) and overall secondary costs (£2593 to £2102) were also significantly reduced. There was no significant difference in primary care, outpatient, or general inpatient admissions. Compared with controls, there was a significant reduction in primary epilepsy admissions (incidence rate ratio (IRR): 0.423; 95% Confidence intervals (CI): 0.198-0.835) but a significant increase in outpatient appointments (1.306; 95% CI: 1.154-1.478) and accident and emergency contacts (1.603; 95% CI: 1.081-2.390) for patients treated with perampanel. CONCLUSION: Treatment with perampanel is associated with reduced epilepsy-related inpatient admissions and accident and emergency contacts.

Evaluation of exacerbations and blood eosinophils in UK and US COPD populations.

BACKGROUND: Blood eosinophil counts and history of exacerbations have been proposed as predictors of patients with chronic obstructive pulmonary disease (COPD) who may benefit from triple therapy (inhaled corticosteroid, long-acting ß2-agonist and long-acting muscarinic antagonist). METHODS: In a retrospective cohort analysis we examined the profiles of COPD patients from the UK Clinical Practice Research Datalink (CPRD) and US Optum Clinformatics™ Data Mart (Optum) databases with reference to exacerbation frequency and blood eosinophil distribution. RESULTS: Of the 31,437 (CPRD) and 383,825 (Optum) patients with COPD, 15,364 (CPRD) and 139,465 (Optum) met the eligibility criteria and were included. Among patients with ≥2 exacerbations and available eosinophil counts in the baseline period (CPRD, n = 3089 and Optum, n = 13414), 17.0 and 13.3% respectively had eosinophil counts ≥400 cells/µL. Patients with ≥2 exacerbations or eosinophil count ≥400 cells/µL during first year, exacerbated at least once (CPRD, 82.8% vs Optum, 80.6%) or continued to have eosinophil count ≥300 cells/µL (76.8% vs 76.5%), respectively in the follow-up year. In both years, a higher variability in the number of exacerbations and eosinophil count was observed in patients with one exacerbation and eosinophil counts between 300 and 400 cells/µL; patients with eosinophil count < 150 cells/µL had the lowest variability. Approximately 10% patients had both ≥2 exacerbations and eosinophil count ≥300 cells/µL across the databases. CONCLUSION: A high variability in blood eosinophil counts over two consecutive years was observed in UK and US patients with COPD and should be considered while making treatment decisions. A small proportion of COPD patients had frequent exacerbations and eosinophil count ≥300 cells/µL.

Outcomes Associated with Treatment of Chronic Pain with Tapentadol Compared with Morphine and Oxycodone: A UK Primary Care Observational Study.

INTRODUCTION: This study compared adverse outcomes and resource use for patients with a diagnosis of pain treated with tapentadol prolonged-release (PR) versus those treated with morphine controlled-release (CR) and oxycodone CR. METHODS: Data were sourced from the Clinical Practice Research Datalink (CPRD), a database derived from UK primary care. Patients prescribed tapentadol PR between May 2011 and December 2016 were selected and matched to two groups of controls treated with either morphine CR or oxycodone CR on gender, age, pain duration, pain site, pain aetiology, Charlson index and prior analgesia. Times to first adverse event (constipation or nausea/vomiting) were compared within a Cox proportional hazards model. Rates of primary care contacts, accident and emergency contacts and, for a subset of patients linked to Hospital Episode Statistics (HES), inpatient admissions and outpatient contacts were compared using incidence rate ratios (IRRs) derived from Poisson regression. RESULTS: A total of 1907 patients prescribed tapentadol PR were identified and 1791 (93.9%) had a pain diagnosis. Of these 1246 (65.3%) were matched to morphine controls and 829 (43.4%) to oxycodone controls. Compared to controls, gastrointestinal adverse events with tapentadol PR treatment were reduced; aHR = 0.532 (0.402-0.703; p < 0.001) versus morphine CR and 0.517 (0.363-0.735; p < 0.001) versus oxycodone CR. Compared with morphine CR, primary care contacts [IRR = 0.831 (0.802-0.861)], accident and emergency attendance [0.739 (0.572-0.951)], outpatient contacts [0.917 (0.851-0.989)] and inpatients contacts [0.789 (0.664-0.938)] were reduced. For oxycodone, the respective figures were 0.735 (0.703-0.768), 0.971 (0.699-1.352), 0.877 (0.799-0.962) and 0.748 (0.601-0.932). CONCLUSION: Tapentadol PR was associated with significantly fewer adverse gastrointestinal events than morphine CR and oxycodone CR in patients with a diagnosis of pain. There was also significantly reduced primary and secondary care resource use. As with all observational studies, potential bias due to residual confounding and confounding by indication should be considered. FUNDING: Grünenthal Ltd.

Impact of treatment with pioglitazone on stroke outcomes: A real-world database analysis.

AIMS: Randomized controlled trials have reported an association between pioglitazone and reduced incidence of stroke in type 2 diabetic (T2DM) and insulin-resistant populations. We investigated this association within a real-world database. MATERIALS AND METHODS: T2DM patients who initiated pioglitazone between 2000 and 2012 were extracted from the Clinical Practice Research Datalink (CPRD), a UK routine data source. Two non-exposed control cohorts were matched according to age, gender, HbA1c, diabetes duration, stroke history, co-morbidities and prior T2DM regimen. Control cohort-1 comprised patients initiating a new T2DM therapy as their respective case initiated pioglitazone. Control cohort-2 maintained the same T2DM regimen as their respective case prior to the case initiating pioglitazone. Primary outcome was incident stroke; other outcomes included mortality, length of hospital stay and stroke recurrence. RESULTS: A total of 4234 patients initiating pioglitazone were matched to controls in cohort-1 and 3604 in cohort-2. For the primary outcome there were significantly reduced hazard ratios (HRs) for cases: controls. For cohort 1, the HR was 0.666 (95% CI, 0.466-0.952) during the therapy period and was 0.750 (0.612-0.919) over the entire observation period; for cohort 2, respective HRs were 0.516 (0.336-0.794) and 0.773 (0.611-0.978). There was no significant difference in 30-day mortality rate or rate of recurrent stroke. For stroke events that required hospitalization, there was a significant difference in length of stay for patients discharged to usual residence (median, 3.0 days vs 7.0 days; P = .008) for control cohort-2 while undergoing treatment. CONCLUSIONS: In support of evidence from 2 large randomized trials, these observational data show that pioglitazone has a potent effect in reducing stroke events in patients with type 2 diabetes.

Glucose Control and Weight Change Associated with Treatment with Exenatide Compared with Basal Insulin: A Retrospective Study.

INTRODUCTION: The aim of the study was to compare glycemic and weight change outcomes for type 2 diabetes patients treated with either exenatide once-weekly (EQW) or exenatide twice-daily (EBID) with those patients treated with basal insulin (BI). METHODS: Retrospective data (2010-2014) were extracted from the Clinical Practice Research Datalink, a UK primary care database. Patients previously naïve to injectable therapy initiating EQW, EBID, or BI were extracted and matched by propensity score within two analyses (EQW vs BI and EBID vs BI). Absolute and relative change in HbA1c and weight from baseline and the proportion of patients achieving HbA1c ≤ 7.0% (53 mmol/mol) combined with weight reduction targets of (1) any weight loss or (2) ≥ 5.0% from baseline were compared at 6 and 12-24 months. RESULTS: A total of 485 patients initiated EQW, 3573 EBID, and 13,503 BI. In the propensity matched EQW versus BI analysis, mean HbA1c decreased with changes of - 1.33% (- 14.5 mmol/mol) and - 1.24% (- 13.5 mmol/mol) at 6 months and - 1.19% (- 13.0 mmol/mol) and - 1.17% (- 12.8 mmol/mol) at 12-24 months, respectively. Respective weight change was - 3.7 kg versus + 1.2 kg (p < 0.001) and - 3.2 kg versus + 2.5 kg (p < 0.001). Significantly more EQW patients achieved the combined HbA1c ≤ 7.0% (53 mmol/mol) and weight loss target (22.4% versus 9.9% at 6 months and 18.2% versus 8.0% at 12-24 months, respectively) and HbA1c ≤ 7.0% (53 mmol/mol) and minimum 5% weight loss (11.8% versus 3.7% at 6 months, and 8.0% versus 0.0% at 12-24 months). For EBID versus BI, similar results were found. CONCLUSION: In this real-world data analysis, exenatide QW and exenatide BID were associated with similar glycemic control and greater weight reduction compared with basal insulin.

Impact of differing glucose-lowering regimens on the pattern of association between glucose control and survival.

AIMS: To characterize survival in relation to achieved glycated haemoglobin (HbA1c) level within alternative glucose-lowering regimens with differing risks of hypoglycaemia. METHODS: Data were extracted from the UK Clinical Practice Research Datalink and the corresponding Hospital Episode Statistics. Patients with type 2 diabetes prescribed glucose-lowering therapy in monotherapy or dual therapy with metformin between 2004 and 2013 were identified. Risk of all-cause mortality within treatment cohorts was evaluated using the Cox proportional hazards model, introducing mean HbA1c as a quarterly updated, time-dependent covariable. RESULTS: There were 6646 deaths in a total follow-up period of 374 591 years. Survival for lower (<7%) vs moderate HbA1c levels (≥7%, <8.5%) differed by cohort: metformin, adjusted hazard ratio (aHR) 1.03 (95% confidence interval [CI] 0.95-1.12); sulphonylurea, aHR 1.11 (95% CI 0.99-1.25); insulin, aHR 1.47 (95% CI 1.25-1.72); combined regimens with low hypoglycaemia risk, aHR 1.02 (95% CI 0.94-1.10); and combined regimens with higher hypoglycaemia risk excluding insulin, aHR 1.24 (95% CI 1.13-1.35) and including insulin, aHR 1.28 (95% CI 1.18-1.37). Higher HbA1c levels were associated with increased mortality in regimens with low hypoglycaemia risk. Post hoc analysis by HbA1c deciles revealed an elevated risk of all-cause mortality for the lowest deciles across all cohorts, but particularly in those regimens associated with hypoglycaemia. High HbA1c was associated with no difference, or a small increase in mortality risk in regimens with increased risk of hypoglycaemia. CONCLUSIONS: The pattern of mortality risk across the range of HbA1c differed by glucose-lowering regimen. Lower HbA1c was associated with increased mortality risk compared with moderate control, especially in those regimens associated with hypoglycaemia. High levels of HbA1c were associated with the expected elevated mortality risk in regimens with low hypoglycaemia risk.

Healthcare resource utilization and related financial costs associated with glucose lowering with either exenatide or basal insulin: A retrospective cohort study.

AIMS: Type 2 diabetes is a major health problem placing increasing demands on healthcare systems. Our objective was to estimate healthcare resource use and related financial costs following treatment with exenatide-based regimens prescribed as once-weekly (EQW) or twice-daily (EBID) formulations, compared with regimens based on basal insulin (BI). MATERIALS AND METHODS: This retrospective cohort study used data from the UK Clinical Practice Research Datalink (CPRD) linked to Hospital Episode Statistics (HES). Patients with type 2 diabetes who received exenatide or BI between 2009 and 2014 as their first recorded exposure to injectable therapy were selected. Costs were attributed to primary care contacts, diabetes-related prescriptions and inpatient admissions using standard UK healthcare costing methods (2014 prices). Frequency and costs were compared between cohorts before and after matching by propensity score using Poisson regression. RESULTS: Groups of 8723, 218 and 2180 patients receiving BI, EQW and EBID, respectively, were identified; 188 and 1486 patients receiving EQW and EBID, respectively, were matched 1:1 to patients receiving BI by propensity score. Among unmatched cohorts, total crude mean costs per patient-year were £2765 for EQW, £2549 for EBID and £4080 for BI. Compared with BI, the adjusted annual cost ratio (aACR) was 0.92 (95% CI, 0.91-0.92) for EQW and 0.82 (95% CI, 0.82-0.82) for EBID. Corresponding costs for the propensity-matched subgroups were £2646 vs £3283 (aACR, 0.80, 0.80-0.81) for EQW vs BI and £2532 vs £3070 (aACR, 0.84, 0.84-0.84) for EBID vs BI. CONCLUSION: Overall, exenatide once-weekly and twice-daily-based regimens were associated with reduced healthcare resource use and costs compared with basal-insulin-based regimens.

Non-Response to Antibiotic Treatment in Adolescents for Four Common Infections in UK Primary Care 1991-2012: A Retrospective, Longitudinal Study.

We studied non-response rates to antibiotics in the under-reported subgroup of adolescents aged 12 to 17 years old, using standardised criteria representing antibiotic treatment failure. Routine, primary care data from the UK Clinical Practice Research Datalink (CPRD) were used. Annual, non-response rates by antibiotics and by indication were determined. We identified 824,651 monotherapies in 415,468 adolescents: 368,900 (45%) episodes for upper respiratory tract infections (URTIs), 89,558 (11%) for lower respiratory tract infections (LRTIs), 286,969 (35%) for skin/soft tissue infections (SSTIs) and 79,224 (10%) for acute otitis media (AOM). The most frequently prescribed antibiotics were amoxicillin (27%), penicillin-V (24%), erythromycin (11%), flucloxacillin (11%) and oxytetracycline (6%). In 1991, the overall non-response rate was 9.3%: 11.9% for LRTIs, 9.5% for URTIs, 7.1% for SSTIs, 9.7% for AOM. In 2012, the overall non-response rate was 9.2%. Highest non-response rates were for AOM in 1991-1999 and for LRTIs in 2000-2012. Physicians generally prescribed antibiotics to adolescents according to recommendations. Evidence of antibiotic non-response was less common among adolescents during this 22-year study period compared with an all-age population, where the overall non-response rate was 12%.

Natural History of Patients Taking Rifaximin-α for Recurrent Hepatic Encephalopathy and Risk of Future Overt Episodes and Mortality: A Post-hoc Analysis of Clinical Trials Data.

PURPOSE: Hepatic encephalopathy (HE) is a complication of cirrhosis signaling decompensation and is associated with mortality. There has been little characterization of HE once an incident episode has occurred and of what effect the transition to overt HE might have on outcomes. We characterized the relationships between the number of previous HE episodes and risk of subsequent episodes and mortality to better understand the natural history of HE. METHODS: Data on 321 patients from a 24-month, open-label, nonrandomized trial evaluating the long-term safety profile and tolerability of twice-daily rifaximin-α 550 mg were analyzed. Patients were followed for a mean of 1.5 years (total follow-up of 467 years). FINDINGS: There were a total of 334 HE episodes and 75 deaths, corresponding to unadjusted event rates of 715 HE episodes and 161 deaths per 1000 years. There was a direct association between rate of subsequent HE episodes and number of prior HE episodes; the risk of subsequent HE episodes was elevated for each additional HE episode (hazard ratio = 1.23; 95% CI, 1.19-1.29). There was a nonlinear, nonmonotonic relationship between risk of death and number of prior HE episodes; risk initially increased, then decreased, and finally plateaued as the number of prior HE episodes increased. IMPLICATIONS: Patients with a larger number of previous, overt HE episodes had a greater risk for subsequent episodes. However, mortality risk decreased after the third episode of HE. A plausible hypothesis to explain this finding is that risk of mortality may be reduced in patients receiving long-term rifaximin-α therapy.

Comparative estimated effectiveness of antibiotic classes as initial and secondary treatments of respiratory tract infections: longitudinal analysis of routine data from UK primary care 1991-2012.

Purpose To compare the estimated effectiveness of seven frequently prescribed antibiotic classes as initial and secondary treatments of upper respiratory tract infections (URTIs) and lower respiratory tract infections (LRTIs) 1991-2012. The main outcome measure was a surrogate for estimated antibiotic effectiveness. Methods Routine, primary care data from the UK Clinical Practice Research Datalink (CPRD) were used. Having established standardized criteria representing antibiotic treatment failure, estimated treatment effectiveness rates were calculated as one minus the treatment failure rate. For each year from 1991 to 2012, estimated effectiveness rates by treatment line, indication, and sub-indication were calculated. These were presented by antibiotic class, with a sub-analysis for the macrolide clarithromycin. Findings From approximately 58 million antibiotic prescriptions in CPRD, we analyzed 8,654,734 courses of antibiotic monotherapy: 4,825,422 courses (56%) were associated with URTI; 3,829,312 (44%) were associated with LRTI. Amino-penicillins (4,148,729 [56%]), penicillins (1,304,561 [18%]), and macrolides (944,622 [13%]) predominated as initial treatments; macrolides (375,903 [32%]), aminopenicillins (275,866 [23%]), and cephalosporins (159,954 [14%]) as secondary treatments. Macrolides and aminopenicillins had estimated effectiveness rates ≥80% across the study period as initial treatments of URTI and LRTI. In secondary use, only macrolides maintained these rates: 80.7% vs. 79.8% in LRTI, 85.1% vs. 84.5% in throat infections, 80.7% vs. 82.3% in nasal infections, 83.5% vs. 83.8% in unspecified URTI in 1991 and 2012, respectively. Implications After more than two decades, macrolides remained amongst the most effective antibiotic classes for both URTI and LRTI in initial and secondary antibiotic treatment when a further antibiotic course was prescribed. Limitations Antibiotic treatments were classified as intention to treat. It is unknown whether the prescription was redeemed or taken correctly. We do not know the etiology of these infections, therefore evidence of antibiotic non-response may relate to sub-optimal diagnosis and inappropriate treatment rather than antibiotic effectiveness for true bacterial infections.

Antibiotic treatment failure in four common infections in UK primary care 1991-2012: longitudinal analysis.

OBJECTIVE: To characterise failure of antibiotic treatment in primary care in the United Kingdom in four common infection classes from 1991 to 2012. DESIGN: Longitudinal analysis of failure rates for first line antibiotic monotherapies associated with diagnoses for upper and lower respiratory tract infections, skin and soft tissue infections, and acute otitis media. SETTING: Routine primary care data from the UK Clinical Practice Research Datalink (CPRD). MAIN OUTCOME MEASURES: Adjusted rates of treatment failure defined by standardised criteria and indexed to year 1 (1991=100). RESULTS: From 58 million antibiotic prescriptions in CPRD, we analysed 10,967,607 monotherapy episodes for the four indications: 4,236,574 (38.6%) for upper respiratory tract infections; 3,148,947 (28.7%) for lower respiratory tract infections; 2,568,230 (23.4%) for skin and soft tissue infections; and 1,013,856 (9.2%) for acute otitis media. In 1991, the overall failure rate was 13.9% (12.0% for upper respiratory tract infections; 16.9% for lower respiratory tract infections; 12.8% for skin and soft tissue infections; and 13.9% for acute otitis media). By 2012, the overall failure rate was 15.4%, representing an increase of 12% compared with 1991 (adjusted value indexed to first year (1991) 112, 95% confidence interval 112 to 113). The highest rate was seen in lower respiratory tract infections (135, 134 to 136). While failure rates were below 20% for most commonly prescribed antibiotics (amoxicillin, phenoxymethylpenicillin (penicillin-V), and flucloxacillin), notable increases were seen for trimethoprim in the treatment of upper respiratory tract infections (from 29.2% in 1991-95 to 70.1% in 2008-12) and for ciprofloxacin (from 22.3% in 1991-95 to 30.8% in 2008-12) and cefalexin (from 22.0% in 1991-95 to 30.8% in 2008-12) in the treatment of lower respiratory tract infections. Failure rates for broad spectrum penicillins, macrolides, and flucloxacillin remained largely stable. CONCLUSIONS: From 1991 to 2012, more than one in 10 first line antibiotic monotherapies for the selected infections were associated with treatment failure. Overall failure rates increased by 12% over this period, with most of the increase occurring in more recent years, when antibiotic prescribing in primary care plateaued and then increased.

The effect of withdrawal of rosiglitazone on treatment pathways, diabetes control and patient outcomes: a retrospective cohort study.

AIMS: To describe the withdrawal of rosiglitazone and the impact upon glycaemic control; intensification of therapy; and progression to major adverse cardiovascular events (MACE), cancer and mortality. METHODS: Data were from the Clinical Practice Research Datalink (CPRD), a longitudinal U.K. database. Rosiglitazone use was profiled from launch (2000) until withdrawal (2010). Patients discontinuing from July 2010 were included in the analysis to ascertain the impact on glycaemic control; therapy intensification; and progression to MACE, death and cancer. For comparison, patients were matched to those maintained on pioglitazone as a control group. RESULTS: Rosiglitazone use peaked in May 2007. Of patients prescribed rosiglitazone at discontinuation 54.1% patients used a dual-therapy regimen; most commonly with metformin (46.7%). 65.1% patients remained at the same stage of the diabetes pathway following discontinuation. 51.7% of patients replaced rosiglitazone with pioglitazone. Patients discontinuing were more likely (HR=2.29), to subsequently intensify therapy than controls. After discontinuation of rosiglitazone there was a significant increase in HbA1c, from a median of 6.9% to 7.3%. In matched analysis, there was a significantly greater increase in HbA1c for rosiglitazone patients (0.33% versus 0.10%). Following discontinuation, crude rates for MACE, cancer and mortality were 8.4, 17.9 and 15.8 pkpy, respectively. None was significantly different in the matched analysis. CONCLUSION: Withdrawal of rosiglitazone was associated with worsening glucose control and subsequent intensification of treatment regimen.

External validation of the UKPDS risk engine in incident type 2 diabetes: a need for new type 2 diabetes-specific risk equations.

OBJECTIVE: To evaluate the performance of the UK Prospective Diabetes Study Risk Engine (UKPDS-RE) for predicting the 10-year risk of cardiovascular disease end points in an independent cohort of U.K. patients newly diagnosed with type 2 diabetes. RESEARCH DESIGN AND METHODS: This was a retrospective cohort study using routine health care data collected between April 1998 and October 2011 from ∼350 U.K. primary care practices contributing to the Clinical Practice Research Datalink (CPRD). Participants comprised 79,966 patients aged between 35 and 85 years (388,269 person-years) with 4,984 cardiovascular events. Four outcomes were evaluated: first diagnosis of coronary heart disease (CHD), stroke, fatal CHD, and fatal stroke. RESULTS: Accounting for censoring, the observed versus predicted 10-year event rates were as follows: CHD 6.1 vs. 16.5%, fatal CHD 1.9 vs. 10.1%, stroke 7.0 vs. 10.1%, and fatal stroke 1.7 vs. 1.6%, respectively. The UKPDS-RE showed moderate discrimination for all four outcomes, with the concordance index values ranging from 0.65 to 0.78. CONCLUSIONS: The UKPDS stroke equations showed calibration ranging from poor to moderate; however, the CHD equations showed poor calibration and considerably overestimated CHD risk. There is a need for revised risk equations in type 2 diabetes.