The PARADIGHM (physicians advancing disease knowledge in hypoparathyroidism) registry for patients with chronic hypoparathyroidism: study protocol and interim baseline patient characteristics.

BACKGROUND: The PARADIGHM registry of adult and pediatric patients with chronic hypoparathyroidism evaluates the long-term safety and effectiveness of treatment with recombinant human parathyroid hormone, rhPTH(1-84), and describes the clinical disease course under conditions of routine clinical practice. In this first report, we detail the registry protocol and describe the baseline characteristics of two adult patient cohorts from an interim database analysis. One cohort after study entry were prescribed rhPTH(1-84), and the other cohort received conventional therapy of calcium and active vitamin D. METHODS: An observational study of patients with chronic hypoparathyroidism in North America and Europe, collecting data for ≥10 years per patient. Main outcome measures were baseline patient demographics, clinical characteristics, medications, and disease outcome variables of symptoms, biochemical parameters, and health assessments. Baseline is the enrollment assessment for all variables except biochemical measurements in patients treated with rhPTH(1-84); those measurements were the most recent value before the first rhPTH(1-84) dose. Exclusion criteria applied to the analysis of specified outcomes included pediatric patients, patients who initiated rhPTH(1-84) prior to enrollment, and those who received rhPTH(1-34). Clinically implausible biochemical outlier data were excluded. RESULTS: As of 30 June 2019, data of 737 patients were analyzed from 64 centers; 587 (80%) were women, mean ± SD age 49.1±16.45 years. At enrollment, symptoms reported for patients later prescribed rhPTH(1-84) (n=60) and those who received conventional therapy (n=571), respectively, included fatigue (51.7%, 40.1%), paresthesia (51.7%, 29.6%), muscle twitching (48.3%, 21.9%), and muscle cramping (41.7%, 33.8%). Mean serum total calcium, serum phosphate, creatinine, and estimated glomerular filtration rate were similar between cohorts. Health-related quality of life (HRQoL) 36-item Short Form Health Survey questionnaire scores for those later prescribed rhPTH(1-84) were generally lower than those for patients in the conventional therapy cohort. CONCLUSIONS: At enrollment, based on symptoms and HRQoL, a greater percentage of patients subsequently prescribed rhPTH(1-84) appeared to have an increased burden of disease than those who received conventional therapy despite having normal biochemistry measurements. PARADIGHM will provide valuable real-world insights on the clinical course of hypoparathyroidism in patients treated with rhPTH(1-84) or conventional therapy in routine clinical practice. TRIAL REGISTRATION: EUPAS16927, NCT01922440.

Characterization of patients with adrenal insufficiency and frequent adrenal crises.

OBJECTIVE: This study aimed to characterize the clinical and biochemical features of patients with primary (PAI) and secondary (SAI) adrenal insufficiency who developed adrenal crises (ACs) and estimate the incidence of ACs in these patients. DESIGN: Retrospective case-control analysis of the European Adrenal Insufficiency Registry (EU-AIR; NCT01661387). METHODS: Two thousand six hundred and ninety-four patients with AI (1054 PAI; 1640 SAI) enrolled in EU-AIR. Patients who developed ≥ 1 AC were matchd 1:3 with patients without ACs for age, sex and AI type. Data were collected at baseline and follow-up (mean ± s.d.: PAI 3.2 ± 1.7 years; SAI 2.9 ± 1.7 years). RESULTS: One hundred and forty-eight out of 2694 patients (5.5%; n = 84 PAI; n = 64 SAI) had an AC during the study: 6.53 (PAI) and 3.17 (SAI) ACs/100 patient-years. Of patients who experienced an AC, 16% (PAI) and 9.4% (SAI) experienced ≥ 1 AC/year. The incidence of adverse events, infectious intercurrent illnesses and infectious serious adverse events were higher in patients with ACs than without ACs. No differences were observed in BMI, HbA1c, blood pressure and frequencies of diabetes mellitus or hypertension between subgroups (PAI and SAI, with and without ACs). At baseline, PAI patients with AC had higher serum potassium (4.3 ± 0.5 vs 4.2 ± 0.4 mmol/L; P = 0.03) and lower sodium (138.5 ± 3.4 vs 139.7 ± 2.9 mmol/L; P = 0.004) than patients without AC. At last observation, SAI patients with AC had higher hydrocortisone doses than patients without AC (11.9 ± 5.1 vs 10.1 ± 2.9 mg/m2; P < 0.001). CONCLUSIONS: These results demonstrate that concomitant diseases and cardiovascular risk factors do not feature in the risk profile of AC; however, patients with AC had a higher incidence of infectious events.

Renal complications in patients with chronic hypoparathyroidism on conventional therapy: a systematic literature review : Renal disease in chronic hypoparathyroidism.

A systematic literature review was performed to summarize the frequency and nature of renal complications in patients with chronic hypoparathyroidism managed with conventional therapy. Methodology was consistent with the recommendations outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Peer-reviewed journal articles with specified medical subject heading terms were identified using the PubMed, EMBASE, and Cochrane databases. Data were extracted from eligible articles based on prespecified parameters for clinical outcomes of renal calcifications and disease. Because of the heterogeneity of the data, a meta-analysis could not be conducted. From 1200 potentially relevant articles, data were extracted from 13 manuscripts that reported data for ≥1 of the 19 predefined renal outcomes for ≥10 adult patients (n = 11 manuscripts) or pediatric patients (n = 2 manuscripts). The collective data provide evidence that adult and pediatric patients with chronic hypoparathyroidism and treated with conventional therapy (oral calcium and active vitamin D) had an increased risk of renal complications. The reported rate of nephrolithiasis was up to 36%, with the lowest rates in studies reporting shorter duration of disease. The rate of nephrocalcinosis was up to 38%. Some studies reported a combined nephrolithiasis/nephrocalcinosis outcome of 19% to 31%. Data for renal disease that encompassed a range of renal insufficiency to chronic kidney disease were reported in 10 articles; the reported rates ranged from 2.5% to 41%. In patients who receive long-term treatment with oral calcium and active vitamin D, chronic hypoparathyroidism may be associated with an increased risk of renal complications compared with the general population.

Burden of illness in not adequately controlled chronic hypoparathyroidism: Findings from a 13-country patient and caregiver survey.

OBJECTIVE: To address knowledge gaps regarding burdens associated with not adequately controlled chronic hypoparathyroidism. DESIGN: Global patient and caregiver survey. STUDY POPULATIONS: Patients with chronic hypoparathyroidism not adequately controlled on conventional therapy and their caregivers. MEASUREMENTS: Health-related quality of life (HRQoL) and health status were evaluated using the 36-item Short Form version 2 (SF-36 v2.0) and Five-Level EuroQoL 5 Dimensions (EQ-5D-5L) instruments, respectively. Hypoparathyroidism-associated symptoms were assessed by a disease-specific Hypoparathyroidism Symptom Diary and caregiver burden via the Modified Caregiver Strain Index (MCSI). RESULTS: Data were obtained from 398 patients and 207 caregivers. Patients' self-rated hypoparathyroidism-related symptom severity was none (3%), mild (32%), moderate (53%) or severe (12%). Per the Hypoparathyroidism Symptom Diary, patients reported moderate, severe or very severe symptoms of physical fatigue (73%), muscle cramps (55%), heaviness in limbs (55%) and tingling (51%) over a 7-day recall period. Impacts (rated 'somewhat' or 'very much') were reported by 84% of patients for ability to exercise, 78% for sleep, 75% for ability to work and 63% for family relationships. Inverse relationships were observed between patient self-rated overall symptom severity and HRQoL and health status assessment scores-the greater the symptom severity, the lower the SF-36 and EQ-5D-5L scores. Caregiver burden increased with patient self-rated symptom severity: none, 1.7 MCSI; mild, 5.4 MCSI; moderate, 9.5 MCSI; and severe, 12.5 MCSI. CONCLUSION: Patients with not adequately controlled hypoparathyroidism reported substantial symptoms and impacts. Greater patient symptom severity was associated with decreased patient HRQoL and health status assessments and increased caregiver burden.

Defining the Characteristics of Chronic Hypoparathyroidism Not Adequately Controlled on Conventional Therapy: Consensus Findings of Three European Delphi Panels.

INTRODUCTION: European Society of Endocrinology (ESE) guidelines provide goals for hypoparathyroidism management but do not define characteristics of chronic hypoparathyroidism that is not adequately controlled. Three European country-specific Delphi panels were conducted to gain consensus on these characteristics. METHODS: Delphi panels were conducted in the UK, Sweden, and Portugal using similar methodology. At each round, panellists considered patients with chronic hypoparathyroidism whose disease is not adequately controlled on conventional therapy according to a matrix of four presentations of patients with chronic hypoparathyroidism: normal biochemical levels/well (group 1), abnormal biochemical levels/well (group 2), normal biochemical levels/unwell (group 3), and abnormal biochemical levels/unwell (group 4), with wellness defined by the patient's persistent symptoms, comorbidities, and complications. For groups 2-4, panellists rated characteristics in five categories (patient characteristics, family history, comorbidities, biochemistry, and symptoms/impact on quality of life [QoL]) with respect to defining a patient as having chronic hypoparathyroidism that was not adequately controlled on conventional therapy. Consensus was achieved when more than 80% of respondents agreed. RESULTS: Among the three countries, panellists agreed that characteristics within four of the five categories (patient characteristics, comorbidities, biochemistry, and symptoms/impact on QoL) were important for defining inadequate control. Characteristics deemed important in groups 2-4 included a history of compliance problems and chronic kidney disease stages 4 and 5. In groups 2 and 4, the biochemical parameters deemed important were serum calcium, urinary calcium, and serum creatinine. In groups 3 and 4, tingling or numbness in the hands/feet and face was the only symptom deemed important in all three countries. CONCLUSION: Delphi panels conducted in three European countries provided national consensus on key parameters of patient characteristics, biochemistry, comorbidities, and symptoms/impact on QoL that define not adequately controlled chronic hypoparathyroidism. These characteristics should be tested more widely for their applicability in clinical practice. FUNDING: Shire International GmbH, Zug, Switzerland, a member of the Takeda group of companies.

Iron parameters in patients with end-stage renal disease receiving lanthanum carbonate or other non-iron-based phosphate binders: Results from a phase 3, randomized open-label study.

OBJECTIVES: The recent availability of iron-based phosphate binders has raised some concerns about iron overload in patients with end-stage renal disease. This study evaluated iron parameters in patients with end-stage renal disease receiving lanthanum carbonate or other non-iron-based phosphate binders. METHODS: This analysis used 2-year follow-up data from an open-label, multicentre, randomized, active-controlled, parallel-group, phase 3 trial of lanthanum carbonate (SPD405-307). After a washout period, if patients' serum phosphate levels exceeded 5.9 mg/dL, they were randomized 1:1 to receive lanthanum carbonate (375-3000 mg/day) or non-iron-based standard therapy during a 6-week dose titration period. Patients achieving control of serum phosphate levels (⩽5.9 mg/dL) received maintenance therapy with lanthanum carbonate or standard therapy for up to 24 months. RESULTS: No clinically relevant changes in mean (standard deviation) iron parameters between the treatment groups (lanthanum carbonate, n = 682; standard therapy, n = 677) from baseline to month 24/final visit were observed: iron (µg/dL), -1.1 (41.8) versus 1.0 (38.7); ferritin (ng/mL), 208.4 (445.1) versus 262.4 (505.5); transferrin saturation (%), 2.8 (18.0) versus 2.8 (17.3); and haemoglobin (g/dL), 0.4 (1.9) versus 0.3 (1.7), respectively (all, p > 0.1). There were no clinically relevant changes in the percentage of patients receiving any anti-anaemic preparation in either treatment group (pre- vs post-randomization: lanthanum carbonate, 94.9% vs 97.8%; standard therapy, 95.1% vs 98.8%, respectively). This is in contrast to the study by Lewis and colleagues, which found significant increases in ferritin and transferrin saturation levels in patients receiving ferric citrate versus active control (calcium acetate and/or sevelamer carbonate) after 52 weeks of therapy. Although serum ferritin and transferrin saturation are the recommended iron indices by the Kidney Disease Outcome Quality Initiative, they are indirect indicators of iron status. Longer-term studies are required to understand fully the potential risks associated with iron overload. CONCLUSION: No evidence of iron accumulation was found in patients with end-stage renal disease receiving lanthanum carbonate or other non-iron-based binders.

Health Care Burden in Patients With Adrenal Insufficiency.

OBJECTIVE: This study aimed to estimate the annual health care burden for patients with adrenal insufficiency [AI; primary (PAI), secondary to pituitary disorder (PIT), and congenital adrenal hyperplasia (CAH)] using real-world data. METHODS: Using a US-based payer database comprising >108 million members, strict inclusion criteria with diagnostic codes and pharmacy records were used to identify 10,383 patients with AI. This included 1014 patients with PAI, 8818 with PIT, and 551 with CAH, followed for >12 months. Patients were matched 1:1 to controls, based on age (±5 years), sex, insurance, and region. Multivariable expenditure models were estimated for each AI cohort vs controls as well as subsets by glucocorticoid therapy (hydrocortisone, dexamethasone, prednisone, or multiple therapies). A separate multivariable model was estimated to assess the association between adherence and expenditures. RESULTS: Total annual health care expenditure estimates were significantly higher (P < 0.0001) in all AI cohorts compared with matched controls (PAI $18,624 vs $4320, PIT $32,218 vs $6956, CAH $7677 vs $4203). Patients with AI have more frequent inpatient hospital stays with up to eight to 10 times more days in the hospital per year than their matched controls. In each AI cohort, patients on multiple steroid therapies had higher expenditures in comparison with patients using hydrocortisone therapy alone. In PAI and PIT cohorts taking hydrocortisone only, fewer expenditures were found in higher adherence subsets. CONCLUSION: Patients with AI demonstrate a substantial annual health care burden. Expenditures vary by underlying cause and treatment and are reduced in patients with higher adherence to glucocorticoid replacement.

Long-term safety of once-daily, dual-release hydrocortisone in patients with adrenal insufficiency: a phase 3b, open-label, extension study.

OBJECTIVE: To investigate the long-term safety and tolerability of a once-daily, dual-release hydrocortisone (DR-HC) tablet as oral glucocorticoid replacement therapy in patients with primary adrenal insufficiency (AI). DESIGN: Prospective, open-label, multicenter, 5-year extension study of DR-HC conducted at five university clinics in Sweden. METHODS: Seventy-one adult patients diagnosed with primary AI who were receiving stable glucocorticoid replacement therapy were recruited. Safety and tolerability outcomes included adverse events (AEs), intercurrent illness episodes, laboratory parameters and vital signs. Quality of life (QoL) was evaluated using generic questionnaires. RESULTS: Total DR-HC exposure was 328 patient-treatment years. Seventy patients reported 1060 AEs (323 per 100 patient-years); 85% were considered unrelated to DR-HC by the investigator. The most common AEs were nasopharyngitis (70%), fatigue (52%) and gastroenteritis (48%). Of 65 serious AEs reported by 32 patients (20 per 100 patient-years), four were considered to be possibly related to DR-HC: acute AI (n = 2), gastritis (n = 1) and syncope (n = 1). Two deaths were reported (fall from height and subarachnoid hemorrhage), both considered to be unrelated to DR-HC. From baseline to 5 years, intercurrent illness episodes remained relatively stable (mean 2.6-5.4 episodes per patient per year), fasting plasma glucose (0.7 mmol/L; P < 0.0001) and HDL cholesterol (0.2 mmol/L; P < 0.0001) increased and patient-/investigator-assessed tolerability improved. QoL total scores were unchanged but worsening physical functioning was recorded (P = 0.008). CONCLUSIONS: In the first prospective study evaluating the long-term safety of glucocorticoid replacement therapy in patients with primary AI, DR-HC was well tolerated with no safety concerns observed during 5-year treatment.

Prednisolone is associated with a worse lipid profile than hydrocortisone in patients with adrenal insufficiency.

OBJECTIVE: Prednisolone is used as glucocorticoid replacement therapy for adrenal insufficiency (AI). Recent data indicate that its use in AI is associated with low bone mineral density. Data on risk factors for cardiovascular disease in patients with AI treated with prednisolone are scarce, despite this condition being the predominant cause of excess mortality. We aimed to address this question using real-world data from the European Adrenal Insufficiency Registry (EU-AIR). DESIGN/METHODS: EU-AIR, comprising of 19 centres across Germany, the Netherlands, Sweden and the UK, commenced enrolling patients with AI in August 2012. Patients receiving prednisolone (3-6 mg/day, n = 50) or hydrocortisone (15-30 mg/day, n = 909) were identified and grouped at a ratio of 1:3 (prednisolone:hydrocortisone) by matching for gender, age, duration and type of disease. Data from baseline and follow-up visits were analysed. Data from patients with congenital adrenal hyperplasia were excluded. RESULTS: Significantly higher mean ± s.d. total (6.3 ± 1.6 vs 5.4 ± 1.1 mmol/L; P = 0.003) and low-density lipoprotein (LDL) cholesterol levels (3.9 ± 1.4 vs 3.2 ± 1.0 mmol/L; P = 0.013) were identified in 47 patients on prednisolone vs 141 receiving hydrocortisone at baseline and at follow-up (P = 0.005 and P = 0.006, respectively). HbA1c, high-density lipoprotein and triglyceride levels, body mass index, systolic and diastolic blood pressure and waist circumference were not significantly different. CONCLUSIONS: This is the first matched analysis of its kind. Significantly higher LDL levels in patients receiving prednisolone relative to hydrocortisone could predict a higher relative risk of cardiovascular disease in the former group.

Management of glucocorticoid replacement in adrenal insufficiency shows notable heterogeneity - data from the EU-AIR.

CONTEXT AND OBJECTIVE: Treatment for adrenal insufficiency (AI) remains suboptimal. Despite glucocorticoid replacement, patients with AI have reduced life expectancy and quality of life. This study aimed to describe the spectrum of management of glucocorticoid replacement in patients with AI enrolled in the European Adrenal Insufficiency Registry (EU-AIR). DESIGN, SETTING AND PATIENTS: EU-AIR is a prospective, multinational, multicentre, observational study initiated in August 2012 to monitor the long-term safety of glucocorticoid replacement in routine clinical practice in Germany, the Netherlands, Sweden and the UK (ClinicalTrials.gov identifier: NCT01661387). This analysis included 1166 patients with primary and secondary AI (mean disease duration 16·1 ± 11·6 years) receiving long-term glucocorticoid replacement therapy. MAIN OUTCOME MEASURE: Glucocorticoid type, dose, frequency and treatment regimen were examined. RESULTS: Most patients (87·4%) were receiving hydrocortisone. The most common dose range, taken by 42·2% of patients, was 20 to <25 mg/day; however, 12·6% were receiving doses of ≥30 mg/day. Hydrocortisone was being taken once daily by 5·5%, twice daily by 48·7%, three times daily by 43·6% and four times daily by 2·1%. Patients with primary AI received higher replacement doses than those with secondary AI (23·4 ± 8·9 and 19·6 ± 5·9 mg/day, respectively). Twenty-five different regimens were being used to deliver a daily hydrocortisone dose of 20 mg. CONCLUSIONS: We have shown significant heterogeneity in the type, dose, frequency and timing of glucocorticoid replacement in real-world clinical practice. This reflects dose individualization based on patient symptoms and lifestyle in the absence of data supporting the optimal regimen.

Exploring Inpatient Hospitalizations and Morbidity in Patients With Adrenal Insufficiency.

CONTEXT: Patients with adrenal insufficiency (AI) (primary AI [PAI], secondary AI due to a pituitary disorder [PIT] and congenital adrenal hyperplasia [CAH]) have reduced life expectancy; however, the underlying explanation remains unknown. OBJECTIVE: To evaluate characteristics, comorbidities, and hospitalizations in AI patients. DESIGN: Retrospective observational. SETTING AND POPULATION: Using a United States-based national payer database comprising of more than 108 million members, strict inclusion criteria including diagnostic codes and steroid prescription records were used to identify 10 383 adults with AI; 1014 with PAI, 8818 with PIT, and 551 with CAH. Patients were matched 1:1 to controls, based on age (±5 y), gender, insurance, and region and followed for more than 12 months. INTERVENTION: None. MAIN OUTCOME MEASURES: Demographic variables, comorbidities (diabetes mellitus [DM] types 1 and 2, depression, anxiety, hyperlipidemia, hypertension) and hospitalization incidence. RESULTS: Compared with controls, patients with AI had higher odds of DM, hypertension, hyperlipidaemia, depression, and anxiety, ranging from an odds ratio (OR) of 1.51 for hyperlipidaemia in PAI to 3.85 for DM in CAH. Odds of having DM (OR, 3.85; 95% confidence interval, 2.52-5.90) or anxiety (OR, 2.99; 95% confidence interval, 2.02-4.42) compared with controls were highest in CAH, whereas depression was highest in PAI and PIT (OR, 2.40 and 2.55). ORs of hyperlipidaemia and hypertension (OR, 1.98 and 2.24) were highest in the PIT cohort. Inpatient admissions were more frequent in PAI (4.64:1; P < .0001) and PIT (4.00:1; P < .0001) than controls; infection was the most common cause for admission. CONCLUSION: Patients with AI carry a significant metabolic and psychiatric burden, with higher risk of comorbidities and hospital admissions than matched controls.

Achieving a physiological cortisol profile with once-daily dual-release hydrocortisone: a pharmacokinetic study.

OBJECTIVE: Oral once-daily dual-release hydrocortisone (DR-HC) replacement therapy was developed to provide a cortisol exposure-time profile that closely resembles the physiological cortisol profile. This study aimed to characterize single-dose pharmacokinetics (PK) of DR-HC 5-20mg and assess intrasubject variability. METHODS: Thirty-one healthy Japanese or non-Hispanic Caucasian volunteers aged 20-55 years participated in this randomized, open-label, PK study. Single doses of DR-HC 5, 15 (3×5), and 20mg were administered orally after an overnight fast and suppression of endogenous cortisol secretion. After estimating the endogenous cortisol profile, PK of DR-HC over 24h were evaluated to assess dose proportionality and impact of ethnicity. Plasma cortisol concentrations were analyzed using liquid chromatography-tandem mass spectrometry. PK parameters were calculated from individual cortisol concentration-time profiles. RESULTS: DR-HC 20mg provided higher than endogenous cortisol plasma concentrations 0-4h post-dose but similar concentrations later in the profile. Cortisol concentrations and PK exposure parameters increased with increasing doses. Mean maximal serum concentration (Cmax) was 82.0 and 178.1ng/mL, while mean area under the concentration-time curve (AUC)0-∞ was 562.8 and 1180.8h×ng/mL with DR-HC 5 and 20mg respectively. Within-subject PK variability was low (<15%) for DR-HC 20mg. All exposure PK parameters were less than dose proportional (slope <1). PK differences between ethnicities were explained by body weight differences. CONCLUSIONS: DR-HC replacement resembles the daily normal cortisol profile. Within-subject day-to-day PK variability was low, underpinning the safety of DR-HC for replacement therapy. DR-HC PK were less than dose proportional - an important consideration when managing intercurrent illness in patients with adrenal insufficiency.

European Adrenal Insufficiency Registry (EU-AIR): a comparative observational study of glucocorticoid replacement therapy.

BACKGROUND: Increased morbidity and mortality associated with conventional glucocorticoid replacement therapy for primary adrenal insufficiency (primary AI; estimated prevalence 93-140/million), secondary AI (estimated prevalence, 150-280/million, respectively) or congenital adrenal hyperplasia (estimated prevalence, approximately 65/million) may be due to the inability of typical glucocorticoid treatment regimens to reproduce the normal circadian profile of plasma cortisol. A once-daily modified-release formulation of hydrocortisone has been developed to provide a plasma cortisol profile that better mimics the daytime endogenous profile of cortisol. Here, we describe the protocol for the European Adrenal Insufficiency Registry (EU-AIR), an observational study to assess the long-term safety of modified-release hydrocortisone compared with conventional glucocorticoid replacement therapies in routine clinical practice (ClinicalTrials.gov identifier: NCT01661387). METHODS: Patients enrolled in EU-AIR have primary or secondary AI and are receiving either modified-release or conventional glucocorticoid replacement therapy. The primary endpoints of EU-AIR are the incidence of intercurrent illness, adrenal crisis and serious adverse events (SAEs), as well as the duration of SAEs and dose changes related to SAEs. Data relating to morbidity, mortality, adverse drug reactions, dosing and concomitant therapies will be collected. Patient diaries will record illness-related dose changes between visits. All decisions concerning medical care are made by the registry physician and patient. Enrolment is targeted at achieving 3600 patient-years of treatment (1800 patient-years per group) for the primary analysis, which is focused on determining the non-inferiority of once-daily modified-release replacement therapy compared with conventional glucocorticoid therapy. RESULTS: Recruitment began in August 2012 and, as of March 2014, 801 patients have been enrolled. Fifteen centres are participating in Germany, the UK and Sweden, with recruitment soon to be initiated in the Netherlands. CONCLUSIONS: EU-AIR will provide a unique opportunity not only to collect long-term safety data on a modified-release preparation of glucocorticoid but also to evaluate baseline data on conventional glucocorticoid replacement. Such data should help to improve the treatment of AI.

Statins and risk of cancer: a retrospective cohort analysis of 45,857 matched pairs from an electronic medical records database of 11 million adult Americans.

OBJECTIVES: The purpose of this study was to determine whether cancer can be attributed to statin use among a general population of older adults in the United States with at least 3 years of follow-up. BACKGROUND: Statins are widely prescribed drugs in the United States for the management of dyslipidemia, atherosclerosis, and cardiovascular event risk reduction. Unsettled scientific debate about the association of statins with cancer continues, with high-profile studies showing conflicting results. METHODS: A retrospective cohort analysis of the incidence of cancer in older adults who have and who have not used statins was performed. More than 11 million analyzable patient records from January 1990 through February 2009 were drawn from the General Electric Centricity electronic medical records database. Propensity matching found pairs of patients receiving and not receiving statin therapy who shared similar propensities for statin use. RESULTS: Propensity score methods matched 45,857 comparison pairs of patients taking a statin and patients not taking a statin. The average time in the database was 8 years, with pairs being followed for an average of 4.6 and 4.7 years. After matching, the incidence of cancer in patients taking a statin was 11.37% compared with 11.11% in matched patients not taking a statin. Multivariate-matched Cox regression analysis showed a nonsignificant hazard ratio of 1.04 (95% confidence interval: 0.99 to 1.09). Kaplan-Meier curves for diagnosis of any cancer up to 10 years also showed no difference for patients taking a statin and those not taking a statin. CONCLUSIONS: This retrospective analysis of nearly 46,000 propensity-matched pairs demonstrated no statistically significant increased risk of cancer associated with statins.

Optimizing CAD diagnosis in China with CT angiography.

BACKGROUND: Diagnosis of coronary artery disease (CAD) in China with coronary angiography (CA) can be challenging because of high disease prevalence and limited resources. Coronary computed tomography angiography (CTA) may provide an opportunity to minimize invasive diagnostic procedures among intermediate-risk patients indicated for CA and increase patient access to diagnosis of CAD in a cost-effective manner. OBJECTIVE: This study was conducted to evaluate the potential costs and efficiency of using CTA in combination with CA to optimize diagnosis and care of patients with suspected CAD in China. METHODS: We conducted a cost-consequences analysis from the perspective of Fuwai Hospital in Beijing. We developed a decision-analytic model that compared a diagnostic strategy of CA only with a strategy of CTA in combination with CA for patients with intermediate pretest probability of significant CAD and indicated for CA. RESULTS: In the base-case analysis, use of CTA in combination with CA led to a cost-savings of US $597 per patient evaluated compared with the CA-only diagnostic strategy. The hospital cost per angiography-confirmed diagnosis of CAD was US $8,103 for CTA followed by CA compared with US $9,148 for CA only. The unit cost of CA, and CTA sensitivity were the most influential parameters on the results. The range of cost savings associated with use of CTA followed by CA was US $768 - US $461 per patient over a CAD prevalence range of 14% - 59%. CONCLUSION: The results of our study suggest that CTA implementation in China for intermediate-risk patients indicated for CA may optimize the patient population that undergoes invasive CA procedures and may provide cost savings for Chinese hospitals.

Resource utilisation, charges and mortality following hospital inpatient admission for congestive heart failure among the elderly in the US.

OBJECTIVES: This study examined resource utilisation, charges and mortality among congestive heart failure (CHF) patients over the course of the first year following initial hospital discharge for CHF in the US. METHODS: The Medicare Standard Analytic Files for the years 1998 through to 2001 were used for the analysis. The study sample included patients with an inpatient hospitalisation between the 1st January 1999 and the 31st December 2000 with a primary ICD-9 diagnosis code of CHF. Statistical analysis including univariate and multivariate regression analysis were conducted. RESULTS: Within 1 year following initial CHF discharge, 50% of patients had at least one all-cause readmission and 20% had at least one CHF-related readmission. The mean total charges among all patients was $36,230 (SD $55,086). Of the patients 20% incurred more than $55,000 in medical charges during the year after discharge; 10% incurred charges exceeding $90,000. More than one-half of the CHF patients visited the emergency department within 3 months of hospital discharge, and within 1 year almost one-third of the CHF patients (31.4%) died. CONCLUSIONS: The charges, morbidity and mortality associated with CHF patients are significant. Reducing these risks through more effective disease management offers the potential for substantial cost savings.

Modern imaging of the hand, wrist, and forearm.

A review of the current state of the relevant diagnostic imaging technologies and methods and their clinical application in imaging common conditions of the hand, wrist, and forearm is presented. Evolving and future imaging technologies are also considered.

Role of angiotensin receptor blockers in the prevention and treatment of arrhythmias.

The renin-angiotensin system is a key regulatory system that is activated in many forms of cardiovascular disease. It is well established that angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are important therapeutic agents in the treatment of hypertension, myocardial infarction, and congestive heart failure. More recent research has suggested that renin-angiotensin system activation may also play a critical role in the genesis of atrial and ventricular arrhythmias. The possible role of renin-angiotensin system activation in arrhythmogenesis suggests that ACE inhibitors and ARBs may be important therapeutic agents in the prevention and treatment of arrhythmias. This review summarizes the current evidence for the use of ARBs in the treatment of atrial and ventricular arrhythmias.