Indirect treatment comparisons including network meta-analysis: Lenvatinib plus everolimus for the second-line treatment of advanced/metastatic renal cell carcinoma.

BACKGROUND: In the absence of clinical trials providing direct efficacy results, this study compares different methods of indirect treatment comparison (ITC), and their respective impacts on efficacy estimates for lenvatinib (LEN) plus everolimus (EVE) combination therapy compared to other second-line treatments for advanced/metastatic renal cell carcinoma (a/mRCC). METHODS: Using EVE alone as the common comparator, the Bucher method for ITC compared LEN + EVE with cabozantinib (CAB), nivolumab (NIV), placebo (PBO) and axitinib (AXI). Hazard ratios (HR) for overall survival (OS) and progression-free survival (PFS) estimated the impact of applying three versions of the LEN+EVE trial data in separate ITCs. Last, to overcome exchangeability bias and potential violations to the proportional hazards assumption, a network meta-analysis using fractional polynomials was performed. RESULTS: Bucher ITCs demonstrated LEN + EVE superiority over EVE for PFS, indirect superiority to NIV, AXI, and PBO, and no difference to CAB. For OS, LEN + EVE was superior to EVE and indirectly superior to PBO, applying original HOPE 205 data. Using European Medicines Agency data, LEN + EVE was directly superior to EVE for OS. Fractional polynomial HRs for PFS and OS substantially overlapped with Bucher estimates, demonstrating LEN+EVE superiority over EVE, alone, NIV, and CAB. However, there were no statistically significant results as the credible intervals for HR crossed 1.0. CONCLUSIONS: Comparing three Bucher ITCs, LEN + EVE demonstrated superior PFS when indirectly compared to NIV, AXI, and PBO, and mixed results for OS. While fractional polynomial modelling for PFS and OS failed to find statistically significant differences in LEN + EVE efficacy, the overall HR trends were comparable.

Risk factors for Pseudomonas aeruginosa infections in Asia-Pacific and consequences of inappropriate initial antimicrobial therapy: A systematic literature review and meta-analysis.

OBJECTIVES: Treating infections of Gram-negative pathogens, in particular Pseudomonas aeruginosa, is a challenge for clinicians in the Asia-Pacific region owing to inherent and acquired antimicrobial resistance. This systematic review and meta-analysis provides updated information on risk factors for P. aeruginosa infection in Asia-Pacific as well as the consequences (e.g. mortality, costs) of initial inappropriate antimicrobial therapy (IIAT). METHODS: Embase and MEDLINE databases were searched for Asia-Pacific studies reporting the consequences of IIAT versus initial appropriate antimicrobial therapy (IAAT) in Gram-negative bacterial infections as well as risk factors for serious P. aeruginosa infection. A meta-analysis of unadjusted mortality was performed using a random-effects model. RESULTS: A total of 22 studies reporting mortality and 13 reporting risk factors were identified. The meta-analysis demonstrated that mortality was significantly lower in patients receiving IAAT versus IIAT, with a 67% reduction observed for 28- or 30-day all-cause mortality (odds ratio=0.33, 95% confidence interval 0.20-0.55; P<0.001). Risk factors for serious P. aeruginosa infection include previous exposure to antimicrobials, mechanical ventilation and previous hospitalisation. CONCLUSION: High rates of antimicrobial resistance in Asia-Pacific as well as the increased mortality associated with IIAT and the presence of risk factors for serious infection highlight the importance of access to newer and appropriate antimicrobials.

Medical resource utilization and costs among Australian patients with genotype 1 chronic hepatitis C: results of a retrospective observational study.

OBJECTIVE: To evaluate medical resource utilization (MRU) and associated costs among Australian patients with genotype 1 chronic hepatitis C (GT1 CHC), including both untreated patients and those receiving treatment with first-generation protease inhibitor-based regimens (telaprevir, boceprevir with pegylated interferon and ribavirin). METHODS: Medical records were reviewed for a stratified random sample of GT1 CHC patients first attending two liver clinics between 2011-2013 (principal population; PP), supplemented by all GT1 CHC patients attending one transplant clinic in the same period (transplant population; TP). CHC-related MRU and associated costs are reported for the PP by treatment status (treated/not treated) stratified by baseline fibrosis grade; and for the TP for the pre-transplant, year of transplant and post-transplant periods. RESULTS: A total 1636 patients were screened and 590 patients (36.1%) were included. Comprehensive MRU data were collected for 276 PP patients (F0-1 n = 59, F2 n = 58, F3 n = 53, F4 n = 106; mean follow-up = 17.3 months). Thirty-eight (13.8%) were treatment-experienced prior to enrolment; 55 (19.9%) received triple therapy during the study. Data were collected for 112 TP patients (mean follow-up = 29.9 months), 33 (29.5%) received a transplant during the study, and 51 (45.5%) beforehand. The annual direct medical costs, excluding drug costs, were higher among treated PP vs untreated PP (AU$: $1,954 vs $1,202); and year of transplant TP vs pre-/post-transplant TP (AU$: pre-transplant $32,407, transplant $155,138, post-transplant $7,358). LIMITATIONS: To aid interpretation of results, note that only patients with GT1 CHC who are actively managed are included, and MRU data were collected specifically from liver outpatient clinics. That said, movement of patients between hospitals is rare, and any uncaptured MRU is expected to be minimal. CONCLUSIONS: CHC-related MRU increases substantially with disease severity. These real-world MRU data for GT1 CHC will be valuable in assessing the impact of new hepatitis C treatments.

Progression of fibromyalgia: results from a 2-year observational fibromyalgia and chronic pain study in the US.

BACKGROUND: A previous fibromyalgia (FM) research reports that 20%-47% of diagnosed patients may not meet the study definition of FM 1-2 years after diagnosis. The aim of this study was to gain a better understanding of the progression of FM in a geographically diverse cohort over a 2-year time period. METHODS: This cohort study followed 226 subjects recruited online to assess FM and chronic widespread pain (CWP) diagnosis stability over time. At enrollment (baseline), subjects provided informed consent, completed an online questionnaire consisting of the London Fibromyalgia Epidemiology Study Screening Questionnaire to screen for CWP (bilateral pain above/below waist lasting ≥1 week in the past 3 months), visited a site for physician evaluation for FM, and completed a questionnaire with validated patient-reported outcome instruments. Subjects were classified into mutually exclusive groups: FM+CWP+ (screened positive for CWP and received physician diagnosis of FM), FM-CWP+ (screened positive for CWP but did not receive physician diagnosis of FM), and FM-CWP- (screened negative for CWP). Approximately 2 years later (follow-up), subjects were reassessed at the same study site and completed a questionnaire with the same patient-reported outcomes. RESULTS: Seventy-six FM+CWP+ subjects completed assessments at both time points; 56 (73.7%) met the FM study definition at follow-up. Twenty subjects no longer met the FM study definition (eleven became FM-CWP- and nine became FM-CWP+). Ten subjects (two from FM-CWP- and eight from FM-CWP+) transitioned into the FM+CWP+ group at follow-up; they reported more tender points and pain interference with sleep and worse physical function at baseline compared with subjects who did not transition to FM+CWP+. Most (76.7%) of the subjects who transitioned into/out of FM+CWP+ experienced changes in CWP, number of positive tender points, or both. CONCLUSION: The results suggest that some FM+CWP+ patients experience fluctuation in symptoms over time, which may reflect the waxing and waning nature of FM and affect diagnosis and treatment.

Fibromyalgia Outcomes Over Time: Results from a Prospective Observational Study in the United States.

BACKGROUND: Longitudinal research on outcomes of patients with fibromyalgia is limited. OBJECTIVE: To assess clinician and patient-reported outcomes over time among fibromyalgia patients. METHODS: At enrollment (Baseline) and follow-up (approximately 2 years later), consented patients were screened for chronic widespread pain (CWP), attended a physician site visit to determine fibromyalgia status, and completed an online questionnaire assessing pain, sleep, function, health status, productivity, medications, and healthcare resource use. RESULTS: Seventy-six fibromyalgia patients participated at both time points (at Baseline: 86.8% white, 89.5% female, mean age 50.9 years, and mean duration of fibromyalgia 4.1 years). Mean number of tender points at each physician visit was 14.1 and 13.5, respectively; 11 patients no longer screened positive for CWP at follow-up. A majority reported medication use for pain (59.2% at Baseline, 62.0% at Follow-up). The most common medication classes were opioids (32.4%), SSRIs (16.9%), and tramadol (14.1%) at Follow-up. Significant mean changes over time were observed for fibromyalgia symptoms (modified American College of Rheumatology 2010 criteria: 18.4 to 16.9; P=0.004), pain interference with function (Brief Pain Inventory-Short Form: 5.9 to 5.3; P=0.013), and sleep (Medical Outcomes Study-Sleep Scale: 58.3 to 52.7; P=0.004). Patients achieving ≥2 point improvement in pain (14.5%) experienced greater changes in pain interference with function (6.8 to 3.4; P=0.001) and sleep (62.4 to 51.0; P=0.061). CONCLUSION: Fibromyalgia patients reported high levels of burden at both time points, with few significant changes observed over time. Outcomes were variable among patients over time and were better among those with greater pain improvement.

The Comparative Burden of Chronic Widespread Pain and Fibromyalgia in the United States.

BACKGROUND/PURPOSE: Little information exists on the comparative patient and economic burden of chronic widespread pain (CWP) and fibromyalgia (FM) in the United States. METHODS: This multistage, observational study included an online screening survey of a large geographically diverse US sample to assess CWP status, a physician/site visit to determine FM diagnosis, and an online subject questionnaire to capture clinical characteristics, pain, health status, functioning, sleep, healthcare resource use (HRU), productivity, and costs. Based on the screener and physician evaluation, mutually exclusive groups of subjects without CWP (CWP-), with CWP but without FM (CWP+), and with confirmed FM were identified. RESULTS: Disease burden was examined in 472 subjects (125 CWP-, 176 CWP+, 171 FM). Age, race, and ethnicity were similar across groups. Mean body mass index and number of comorbidities increased from CWP- to CWP+ to FM (P = 0.0044, P < 0.0001, respectively). From CWP- to CWP+ to FM, there were reductions in health status (EQ-5D, SF-12) and sleep outcomes (MOS-SS, SSQ) (all P < 0.05). Pain severity, interference with function (BPI-SF), and overall work impairment (WPAI:SHP) increased from CWP- to CWP+ to FM (all P < 0.0001). Higher proportions of CWP+ (52.8%) and FM subjects (62.6%) were taking pain-related prescription medications relative to CWP- subjects (32.8%; P < 0.0001). Significant differences in total direct and indirect costs across the three groups (both P < 0.0001) were observed, with highest costs among FM subjects. CONCLUSION: Fibromyalgia subjects were characterized by the greatest disease burden with more comorbidities and pain-related medications, poorer health status, function, sleep, lower productivity, and higher costs.

Adenocarcinoma of the oesophagus: incidence and survival rates in New South Wales, 1972-2005.

OBJECTIVE: To investigate trends in the incidence of adenocarcinoma (AC) of the oesophagus in New South Wales, factors associated with a diagnosis of AC, and factors associated with survival of patients with AC. DESIGN AND SETTING: We examined all cases of invasive oesophageal cancer recorded in the NSW Central Cancer Registry from 1972 to 2005. The Accessibility/Remoteness Index of Australia was used to assess geographical remoteness and the Index of Relative Socio-Economic Disadvantage to assess socioeconomic status. MAIN OUTCOME MEASURES: Incidence of AC; factors associated with diagnosis of AC and survival of patients with AC. RESULTS: The overall incidence of oesophageal AC in NSW increased in both males and females (annual percentage change, 4.2% [95% CL, 2.7%, 5.8%] in males [1988-2005] and 4.3% [95% CL, 1.8%, 7.0%] in females [1983-2005]). A diagnosis of AC was significantly associated with being male (adjusted odds ratio [AOR], 4.37 [95% CL, 3.84, 4.98]; P < 0.001); a younger age at diagnosis (P trend < 0.001); having distant rather than localised disease spread (AOR, 2.12 [95% CL, 1.82, 2.48]; P < 0.001); higher socioeconomic status (P trend < 0.001); and living in an inner regional area (AOR, 1.26 [95% CL, 1.11, 1.43]; P < 0.001) or outer regional area (AOR, 1.19 [95% CL, 1.00, 1.41]; P = 0.05) compared with a major city. Early diagnosis of AC was associated with substantial improvement in survival outcomes: patients with metastatic disease at diagnosis had a three times greater risk of dying than those with localised AC at diagnosis. CONCLUSION: The incidence of AC is increasing in NSW. Possible contributing factors include increasing obesity, which is associated with increased incidence of gastro-oesophageal reflux disease. Survival may be improved by diagnosis at an earlier stage and changes in modifiable risk factors (eg, smoking, diet, exercise).

Degree-of-spread artefact in the New South Wales Central Cancer Registry.

OBJECTIVE: To describe a data artefact in degree-of-spread at first presentation in the New South Wales Central Cancer Registry (NSW CCR), the only Australian cancer registry that records degree-of-spread data for all solid tumours. METHOD: Trends in the proportions of cancer cases diagnosed annually over 1972-2004 by degree-of-spread categories of localised, regional, distant and unknown were calculated for each major cancer type. RESULTS: Excepting breast cancer and melanoma, the proportion of localised cancer cases reported from 1993-1998 was approximately 5% lower than expected, and was mirrored by an artefactual increase in unknown degree-of-spread cases. CONCLUSION: This artefact was caused by the introduction of the Electronic Notification System and cannot easily be remedied retrospectively. However, regional and distant categories of degree-of-spread in the NSW CCR data are reliably recorded for the 1972-2004 period. IMPLICATIONS: It is important that past and present cancer data users are notified and understand the quality issues with NSW CCR degree-of-spread data, and use it as recommended to avoid anomalous results or conclusions.

Empiric validation of the rural Australian Medical Undergraduate Scholarship 'rural background' criterion.

OBJECTIVE: Rural Australian Medical Undergraduate Scholarships (RAMUS) provide 10,000 dollars per annum to selected medical students with a rural background. Eligibility criteria include having lived in a rural community for five consecutive or eight cumulative years. We sought to validate the above-specified criterion using data from the Australian National Rural Background Study. DESIGN: National case control study stratified by jurisdiction. PARTICIPANTS: Two thousand four hundred and fourteen Australian-trained rural and urban general practitioners (GPs). MAIN OUTCOME MEASURE: Whether the RAMUS rural background criterion was met or not. RESULTS: Doctors who met the RAMUS rural background criterion were more likely to be in rural practice (odds ratio = 2.50; 95% confidence interval, 1.97-3.18) than those who did not. This was true for all jurisdictions (except for the Northern Territory) and ranged from 1.95 for South Australia to 3.57 for Victoria. CONCLUSION: Rural GPs are more likely to fulfil the RAMUS rural background criterion, supporting the existence of the RAMUS scheme.

Trial of nurse-run asthma clinics based in general practice versus usual medical care.

OBJECTIVE: The aim of this study was to assess the ability of nurse-run asthma clinics based in general practice compared with usual medical care to produce at least a moderate improvement in the quality of life of adults with asthma. METHODOLOGY: A randomized controlled trial involving 80 asthma clinic and 90 usual medical care asthma participants, aged 18 years and older was conducted in 11 general practices in Adelaide. The main outcome measure was the St George's respiratory questionnaire (SGRQ), from which quality-of-life scores were used to assess therapeutic benefit. Lung function measurements and health services utilization data were also collected. RESULTS: One hundred and fifty-three participants (90%) were reviewed at follow up after 6-9 months. There was little difference between groups in baseline measures or for the 6-month follow-up outcomes, including the mean difference in total SGRQ scores (-0.5, 95% confidence interval (CI) -4.0, 2.9) and the mean difference in percentage predicted FEV(1) (2.3%, 95% CI -0.7, 5.3 pre-bronchodilator; 0.4%, 95% CI -5.1, 5.9 post-bronchodilator). Trends in health services utilization were noted. CONCLUSIONS: Nurse-run asthma clinics based in general practice and usual medical care were similar in their effects on quality of life and lung function in adults. These findings cannot be generalized to hospital outpatients and other clinics that manage more severe asthmatic patients.

Randomized controlled trial of unflued gas heater replacement on respiratory health of asthmatic schoolchildren.

BACKGROUND: Previous studies do not provide a clear picture of the relationship between nitrogen dioxide (NO(2)) exposure and asthma. METHODS: Eighteen schools using unflued gas heating in winter were randomly allocated to either retain their heaters (10 control schools) or to have replacement flued gas or electric heaters installed at the beginning of winter (8 intervention schools). Fortnightly telephone interviews were used to record daily individual asthma symptoms that occurred over 12 weeks (including winter). Lung function and histamine challenge tests were performed at baseline and the end of the study. NO(2) was measured in each school classroom on 9 days and in each household on 3 days spread over the study period. RESULTS: From 199 primary school children that met the eligibility criteria, 45 intervention and 73 control children agreed to participate. Baseline characteristics were similar between groups. Difficulty breathing during the day (Relative Risk [RR] = 0.41; 95% CI: 0.07, 0.98) and night (RR = 0.32; 95% CI: 0.14, 0.69), chest tightness during the day (RR = 0.45; 95% CI: 0.25, 0.81), and daytime asthma attacks (RR = 0.39; 95% CI: 0.17, 0.93) were significantly reduced in the intervention group. Percentage predicted forced expiratory volume in one second (FEV(1)), the concentration of histamine inducing a 20% fall in FEV(1) (PD(20)), and the dose-response slope (DRS) were similar between groups at follow-up. Mean (standard deviation) NO(2) levels were 15.5 (6.6) parts per billion (ppb) and 47.0 (26.8) ppb in the intervention and control schools respectively (P < 0.001). CONCLUSIONS: Asthma symptoms were reduced following a replacement intervention that removed high exposure to NO(2). Such replacement should be considered a public health priority for schools using unflued gas heating during winter.

The Australian Orthopaedic Association National Joint Replacement Registry.

In the financial year ending June 2002, 26 689 hip replacements and 26089 knee replacements (total, 52778) were performed in Australia. Hip and knee replacement procedures have increased between 5%-10% each year for the past 10 years, with a combined increase in hip and knee replacement of 13.4% in the past year. The revision rate for hip replacement surgery in Australia is unknown but is estimated to be 20%-24%; the revision rate for hip replacement surgery in Sweden is 7%. Although data collection for the Registry is voluntary, it has 100% compliance from hospitals undertaking joint-replacement surgery.

Factors associated with rural practice among Australian-trained general practitioners.

OBJECTIVE: To determine the factors associated with general practitioners' current practice location, with particular emphasis on rural location. DESIGN: Observational, retrospective, case-control study using a self-administered questionnaire. SETTING: Australian general practices in December 2000. PARTICIPANTS: 2414 Australian-trained rural and urban GPs. MAIN OUTCOME MEASURE: Current urban or rural practice location. RESULTS: For Australia as a whole, rural GPs were more likely to be male (odds ratio [OR], 1.42; 95% CI, 1.17-1.73), Australian-born (OR, 1.95; 95% CI, 1.55-2.45), and to report attending a rural primary school for "some" (OR, 2.21; 95% CI, 1.69-2.89) or "all" (OR, 2.79; 95% CI, 1.94-4.00) of their primary schooling. Rural GPs' partners or spouses were also more likely to report "some" (OR, 2.75; 95% CI, 2.07-3.66) or "all" (OR, 2.86; 95% CI, 2.02-4.05) rural primary schooling. A rural background in both GP and partner produced the highest likelihood of rural practice (OR, 6.28; 95% CI, 4.26-9.25). For individual jurisdictions, a trend towards more rural GPs being men was only significant in Tasmania. In all jurisdictions except Tasmania and the Northern Territory, rural GPs were more likely to be Australian-born. CONCLUSIONS: GPs' and their partners' rural background (residence and primary and secondary schooling) influences choice of practice location, with partners' background appearing to exert more influence.

Hospital attendance prediction tool also identifies impaired quality of life in adults with asthma in general practice.

STUDY OBJECTIVE: To assess the ability of an adult risk screening questionnaire (RSQ), previously shown to predict attendance at hospital emergency departments, to identify impaired quality of life in adult patients with asthma in general practice. DESIGN: Baseline data from an RCT of asthma clinics in general practice, using the St. George Respiratory Questionnaire (SGRQ) to measure quality of life. SETTING: Twelve general practices in Adelaide, Australia. RESULTS: A total of 184 adult asthmatics were recruited, with a mean (standard deviation) age of 50.3 years (16.6 years). Age, gender, weight, number of comorbidities, smoking status, FEV1 and percent predicted FEV1 (pre-and post-bronchodilator), peak flow (pre and post), and RSQ were independently related to SGRQ scores. After adjusting for potential confounders, an RSQ score predictive of hospital attendance was also associated with an average increase (worsening) in SGRQ total score of 11.9 (95% CI: 7.6, 16.3), an average increase in activity score of 9.0 (2.5, 15.5), symptom score of 14.8 (8.6, 21.0), and impact score of 13.1 (8.6, 17.6). These represent clinically significant differences. CONCLUSION: An RSQ score predictive of hospital attendance should alert the general practitioner to explore and address symptom, activity, and impact domains associated with impaired quality of life in adult asthma.

The effectiveness of coordinated care for people with chronic respiratory disease.

OBJECTIVES: To evaluate the effectiveness of coordinated care for chronic respiratory disease. DESIGN AND SETTING: Community-based geographical control study, in western (intervention) and northern (comparison) metropolitan Adelaide (SA). PARTICIPANTS: 377 adults (223 intervention; 154 comparison) with chronic obstructive pulmonary disease, asthma or other chronic respiratory condition, July 1997 to December 1999. INTERVENTION: Coordinated care (includes care coordinator, care guidelines, service coordinator and care mentor). MAIN OUTCOME MEASURES: Hospital admissions (any, unplanned and respiratory), functionality (activities of daily living) and quality of life (SF-36 and Dartmouth COOP). RESULTS: At entry to the study, intervention and comparison subjects were dissimilar. The intervention group was 10 years older (P < 0.001), less likely to smoke (P = 0.014), had higher rates of hospitalisation in the previous 12 months (P < 0.001) and had worse self-reported quality of life (SF-36 physical component summary score [P < 0.001] and four of nine COOP domains [P = 0.002-0.013]). After adjustment for relevant baseline characteristics, coordinated care was not associated with any difference in hospitalisation, but was associated with some improvements in quality of life (SF-36 mental component summary score [P = 0.023] and three of nine COOP domains [P = 0.008-0.031]) compared with the comparison group. CONCLUSIONS: Coordinated care given to patients with chronic respiratory disease did not affect hospitalisation, but it was associated with an improvement in some quality-of-life measures.