Incidence, Predictors and Outcomes of Major Bleeding in Patients Following Percutaneous Coronary Interventions in Australia.

BACKGROUND: Major bleeding is a serious complication of percutaneous coronary intervention (PCI). We set out to investigate the incidence of major bleeding and its impact on hospitalisation and long-term mortality. METHOD: We examined seven years of registry data encompassing 16,860 PCI procedures. RESULTS: Between 2005 and 2011 major bleeding increased from 1.3% to 3.4%. In patients with ST elevated myocardial infarction (STEMI), the rate increased from 2.3% to 6.4%. The increase remained significant after adjusting for patient and procedural characteristics (OR=1.09/year, p=0.001). Bleeding risk was highest in patients presenting with out-of-hospital cardiac arrest and cardiogenic shock (CS). Women, STEMI patients, those aged over 70yrs or weighing <60kg were at higher risk. Glycoprotein IIb/IIIa-inhibitor use more than doubled the risk of bleeding (OR=2.28, p=<0.001). Mortality rates at one year were 4.18% overall and 7.9% in STEMI. Bleeding was a strong predictor of mortality after adjusting for potential confounders (HR=2.92, 95% CI: 2.08, 4.09). Bleeding significantly increased length of stay (med four days vs seven days) and rehospitalisation at 12 months (OR=1.36, 95% CI: 1.08, 1.70). CONCLUSIONS: Major bleeding rates post-PCI appear to be increasing in Australia. Bleeding increases hospitalisation and is associated with poor clinical outcomes.

Quality of life and healthcare resource use associated with angiographic vasospasm after aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: In this analysis of data from a large clinical trial in aneurysmal subarachnoid hemorrhage, the impact of angiographic vasospasm (aVSP) on specific patient outcomes and inpatient healthcare resource use was assessed. METHODS: This was a post hoc analysis of exploratory end points collected for 409 patients with aneurysmal subarachnoid hemorrhage in the Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage (CONSCIOUS-1) trial. Central reviewers graded severity of aVSP as none, mild, moderate, or severe based on comparison of catheter angiograms obtained at baseline and 7 to 11 days after aneurysmal subarachnoid hemorrhage. Assessments of cognitive status (Mini-Mental State Examination) and patient-relevant outcomes (EuroQol total score and visual analog scale and Functional Status Examination) were administered at Week 12. The relationship between severity of aVSP and these end points as well as inpatient healthcare resource use (intensive care, general ward, and total hospital lengths of stay) was assessed using univariate and multivariate analyses. RESULTS: Cognitive status and all patient-relevant outcome measures varied significantly (P<0.0001) with severity of aVSP (mean for severe aVSP versus no aVSP, respectively: Mini-Mental State Examination, 18.0 versus 27.6; EuroQol total, 0.38 versus 0.74; EuroQol visual analog scale, 50.9 versus 75.5; Functional Status Examination, 20.5 versus 11.7). A significant inverse relationship with severity of aVSP was observed for total hospital days (P=0.008) and days in the intensive care unit (P<0.0001). On average, patients with severe aVSP stayed in the hospital 5 days longer than those with no aVSP. CONCLUSIONS: Severe aVSP is associated with poor cognition, worse patient-relevant outcomes, and greater inpatient healthcare resource use. Future studies assessing new aVSP treatments should include outcome measures that evaluate quality of recovery among survivors.

Funding linked to ongoing research: impact of the bosentan patient registry on pricing in Australia.

OBJECTIVES: Bosentan, a dual endothelin receptor antagonist (ERA), was the first oral drug approved for the treatment of pulmonary arterial hypertension (PAH), a rare disease with poor prognosis. In 2004 the Australian Department of Health agreed to fund bosentan on the pharmaceutical benefits scheme (PBS) on the condition that a registry was established to monitor mortality: if the observed mortality rate was higher than that claimed in the original funding submission then the price of bosentan would be reduced to maintain the original incremental cost-effectiveness ratio (ICER). This article presents the economic implications of the bosentan patient registry (BPR). METHODS: An existing economic model was updated using the results of the BPR. RESULTS: Participation rates were high and the BPR collected 821 patient years of follow-up on 528 patients. Based on the observed raw mortality a 23.7% price reduction would have been needed to maintain the original ICER in idiopathic PAH patients. After allowing for the higher risk patients actually treated in Australia, a 13.5% reduction in bosentan price would have been required. In 2008, however, sitaxentan, a new oral ERA PAH treatment was listed on the PBS at a 15% discount to bosentan. On the basis of cost-minimization, bosentan was forced to reduce its price to that of sitaxentan. After this price reduction the ICER for bosentan was similar to that originally proposed and hence, no additional price reduction was sought by the Pharmaceutical Benefits Advisory Committee (PBAC). CONCLUSIONS: The bosentan PAH registry provided a useful mechanism for monitoring the cost-effectiveness of bosentan after funding approval.

Hemodynamics in pulmonary arterial hypertension (PAH): do they explain long-term clinical outcomes with PAH-specific therapy?

BACKGROUND: Pulmonary arterial hypertension (PAH) has witnessed dramatic treatment advances over the past decade. However, with the exception of epoprostenol, data from short-term randomized controlled trials (RCTs) have not shown a benefit of these drugs on survival. There remains a need to differentiate between available therapies and current endpoint responses which in turn, could be used to guide treatment selection and provide long-term prognostic information for patients. METHODS: We performed a systematic literature search of MEDLINE and EMBASE databases for RCTs of PAH-specific therapy published between January 1980 and May 2009. Articles were selected if they contained a placebo comparator and described hemodynamic changes from baseline. We applied the weighted mean change in hemodynamic variables to the equation developed by the National Institutes of Health (NIH) Registry to estimate long-term survival with each therapy. RESULTS: Ten RCTs involving 1,635 patients met the inclusion criteria. Suitable hemodynamic data were identified for bosentan, sitaxentan, sildenafil, epoprostenol, beraprost and treprostinil. 77.6% of patients were female and the mean (SD) age was 46.5 +/- 4.9 years. 55.5% of patients had idiopathic PAH (iPAH), 23.9% PAH related to connective tissue disease, and 18.2% PAH related to congenital heart disease. Based on the effects observed in short-term trials and, relative to placebo, all analyzed therapies improved survival. The estimated 1-year survival was 78.4%, 77.8%, 76.1%, 75.8%, 75.2%, and 74.1% for epoprostenol, bosentan, treprostinil, sitaxentan, sildenafil, and beraprost, respectively. These estimates are considerably lower than the 1-year observed survival reported in several open-label and registry studies with PAH-specific therapies: 88% - 97%. CONCLUSION: When applied to the NIH Registry equation, hemodynamic changes from baseline appear to underestimate the survival benefits observed with long-term PAH therapy.

Safety and efficacy of a testosterone metered-dose transdermal spray for treating decreased sexual satisfaction in premenopausal women: a randomized trial.

BACKGROUND: It is not known whether premenopausal women who report low sexual satisfaction and have low circulating testosterone levels will benefit from testosterone therapy. OBJECTIVE: To evaluate the effects of exogenous testosterone in premenopausal women reporting diminished sexual function. DESIGN: Randomized, double-blind, placebo-controlled, dose-ranging trial. SETTING: 6 Australian medical centers. PATIENTS: 261 women age 35 to 46 years who reported a decrease in satisfying sexual activity relative to their younger years and had a morning serum free testosterone level less than 3.8 pmol/L (<1.1 pg/mL). INTERVENTION: 3 different doses of testosterone administered by a metered-dose transdermal spray for 16 weeks or placebo. MEASUREMENTS: The primary outcome was the mean number of self-reported satisfactory sexual events (SSEs) over 28 days at week 16. The frequency of SSEs, total number of sexual events (every 4 weeks), scores from the modified Sabbatsberg Sexual Self-Rating Scale and the Psychological General Well-Being Index, and safety variables were also measured. RESULTS: The number of SSEs increased during the treatment period in the active treatment groups and the placebo group. The mean number of SSEs over 28 days at week 16 was statistically significantly greater for women treated with the intermediate dose of testosterone therapy (one 90-microL spray) than for women treated with placebo. The least-squares mean was 2.48 versus 1.70 SSEs, respectively (event rate ratio, 1.49 [95% CI, 1.01 to 2.18]; P = 0.04). The frequency of SSEs in women treated with low and high doses of testosterone did not differ from that in women who took placebo. The rate ratios based on the least-squares mean rates of SSEs during weeks 4 to 16 for each treatment group showed statistically significant or borderline significant increases in all testosterone groups compared with the placebo group. The rate ratios for the one 56-microL spray, one 90-microL spray, and two 90-microL sprays treatment groups were 1.34 (CI, 0.97 to 1.85; P = 0.081), 1.48 (CI, 1.07 to 2.06; P = 0.018), and 1.38 (CI, 1.00 to 1.92; P = 0.052), respectively. At week 16, 95% of women treated with the one 90-microL dose had a free testosterone level less than the upper limit of the reference range for women. The most frequently reported adverse event was hypertrichosis, which was dose-related and mostly confined to the application site. No clinically relevant changes in blood test values, serum biochemical variables, or vital signs occurred. LIMITATION: The study duration was short, and the placebo effect was strong. CONCLUSION: A daily 90-microL dose of transdermal testosterone improves self-reported sexual satisfaction for premenopausal women with reduced libido and low serum-free testosterone levels by a mean of 0.8 SSE per month. The rate of SSEs with higher and lower testosterone doses did not differ from that with placebo.

Bosentan therapy in patients with pulmonary arterial hypertension: the relationship between improvements in 6 minute walk distance and quality of life.

BACKGROUND AND OBJECTIVE: Bosentan, an oral, dual endothelin receptor antagonist, significantly improves functional status, haemodynamic measures and survival in patients with pulmonary arterial hypertension (PAH). However, there are limited data on the effect of bosentan on quality of life (QOL) and its relationship to changes in functional status, as measured by the 6 minute walk distance (6MWD). METHODS: A retrospective analysis was performed of a large, open-label, multicentre trial (VITAL) of bosentan in patients with PAH. Data for 6MWD were collected at baseline, 3 or 6 months and these results were correlated with QOL measurements collected as part of the assessment of patients enrolled in the trial. RESULTS: Sixty-nine patients with PAH (mean age 52 years) who were enrolled in the trial had valid QOL (SF-36) measurements and 6MWD data that could be retrieved from clinical notes. At 3 and 6 months, bosentan therapy improved 6MWD compared with baseline (49.5 m and 47.2 m, respectively, P < 0.001) as well as QOL domains, with a significant correlation between these two markers on cross-sectional analysis. However, there was a poor relationship when comparing changes in 6MWD with changes in QOL, in response to therapy. CONCLUSION: Bosentan therapy was associated with improvements in QOL and 6MWD for at least 6 months. At all measured time points, there was a close correlation between 6MWD and most QOL domains. QOL is an important parameter and should be considered as part of the standard assessment for any trial investigating therapy in PAH.

Macitentan Improves Health-Related Quality of Life for Patients With Pulmonary Arterial Hypertension: Results From the Randomized Controlled SERAPHIN Trial.

BACKGROUND: Pulmonary arterial hypertension (PAH) leads to reduced health-related quality of life (HRQoL). The objectives of this analysis were to evaluate the effect of macitentan on HRQoL in patients with PAH in the Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN) study. The association between baseline HRQoL and long-term outcomes was also investigated. METHODS: Patients were randomized to placebo, macitentan 3 mg, or macitentan 10 mg once daily. Patients aged 14 years or older completed the 36-Item Short Form Survey (SF-36) at baseline, at month 6 and month 12, and at the end of treatment (EOT). The absolute change from baseline to month 6 in SF-36 scores was calculated. The time to a clinically meaningful deterioration in the SF-36 physical component summary and mental component summary (PCS and MCS) scores and associations between baseline PCS/MCS scores and time to morbidity/mortality events were also assessed. RESULTS: At month 6, macitentan 10 mg significantly improved seven of eight SF-36 domains and the PCS and MCS scores vs placebo. Macitentan 10 mg significantly reduced the risk of a three-point or greater deterioration in PCS (hazard ratio [HR], 0.60; 95% CI, 0.47-0.76; P < .0001) and MCS scores (HR, 0.76; 95% CI, 0.61-0.95; P = .0173) until EOT vs placebo. Patients with a baseline PCS score greater than the median baseline value had a significantly reduced risk of morbidity/mortality compared with patients with a PCS score less than the median; a similar result was observed for the MCS score. CONCLUSIONS: Macitentan significantly improved HRQoL in patients with PAH compared with placebo and significantly reduced the risk of a clinically meaningful HRQoL deterioration. An association between better baseline HRQoL and improved long-term outcomes was shown. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00660179; URL: clinicaltrials.gov.

Assessment of the bioequivalence of a generic cyclosporine A by a randomized controlled trial in stable renal recipients.

BACKGROUND: The aim of this study was to determine the bioequivalence of Cysporin, a generic cyclosporine A, compared with Neoral in stable renal transplant recipients. METHODS: Study design consisted of an open label, two-way crossover, randomized controlled trial of Cysporin versus Neoral in stable renal transplant recipients. In all, 33 patients were enrolled; 31 were randomized and 28 were evaluable. AUCs(0-12) were done on day 14 and 28; C(0) and C(2) were done on days 0, 7, 21 and 35. Dose conversion was 1:1. Outcome measures for serum cyclosporin A concentrations expressed as the mean+/-SD were AUC(0-12) (microg x hr/L), C(max) (microg/L), C(2) (microg/L), T(max) (hr) and T(1/2) (hr). Mean and 90% CI of the ratio Cysporin/Neoral of log-transformed data were calculated using a general linear model. RESULTS: The main pharmacokinetic features were: AUC(0-12): Cysporin 3495+/-1319, Neoral 3853+/-1378 (P<0.05); C(max): Cysporin 755+/-301, Neoral 881+/-368 (P<0.05); C(2): Cysporin 613+/-235, Neoral 672+/-255 (P>0.05); T(max): Cysporin 1.9+/-0.8, Neoral 1.4+/-0.6 (P<0.005); and T1/2: Cysporin 8.8+/-4.3, Neoral 8.7+/-6.2 (P>0.05). Estimated ratios of Cysporin/Neoral were: AUC 0.93 (90% CI 0.88-0.98; P<0.05); C(max) 0.88 (90% CI 0.80-0.97; P<0.05); and T(max) 1.32 (90% CI 1.14-1.53; P<0.005). CONCLUSIONS: Both the extent and rate of absorption of Cysporin are significantly less than those of Neoral. The 90% CI for the ratios of Cysporin/Neoral for AUC and C(max) lie within 0.80-1.25. Hence in this clinical context Cysporin is pharmacologically bioequivalent with Neoral. This study illustrates the importance of testing bioequivalence of generic cyclosporine A products in transplant recipients not healthy volunteers.

Public funding of bosentan for the treatment of pulmonary artery hypertension in Australia: cost effectiveness and risk sharing.

OBJECTIVES: In Australia, no therapeutic agents were subsidised for the treatment of idiopathic pulmonary artery hypertension (iPAH), a rare progressive and severe disease with short life expectancy, until 1 March 2004, when bosentan (a dual endothelin receptor antagonist of high cost) was listed on the Pharmaceutical Benefits Scheme (PBS). Bosentan, in addition to conventional therapy, has been shown to slow iPAH progression and improve clinical and haemodynamic status and symptomatology, compared with placebo and conventional therapy. The objective of this paper is to describe the process of the Australian Pharmaceutical Benefits Scheme listing for bosentan (Tracleer), which included a health economic model assessing the cost effectiveness of bosentan from a healthcare payer perspective, and a risk-sharing arrangement based on the establishment of a patient registry. METHODS: The health economic model predicted the cost, hospitalisation and mortality rates of a population of iPAH patients treated with either the conventional therapy regimen used in Australia or bosentan plus the conventional therapy regimen. The model was implemented as a first-order Monte Carlo simulation with mortality modelled directly as the main clinical outcome. The impacts of proposed continuation criteria, restricting the ongoing use of the drug, were evaluated. Costs and outcomes were discounted at 5% and a sensitivity analysis examined the robustness of the key assumptions. RESULTS: The model predicted that after 5, 10 and 15 years, the difference in average cumulative costs between bosentan plus conventional therapy and conventional therapy alone would be 116,929 Australian dollars (A dollars), A181,808 dollars and A216,331 dollars for each patient, respectively. There would be an associated increase in average life expectancy of 1.39, 2.93 and 3.87 years at 5, 10 and 15 years, respectively, with an incremental cost-effectiveness ratio at 15 years of A55,927 dollars for each life-year gained. Removing the continuation criteria from the model increased the incremental cost-effectiveness ratio to A62,267 dollars (1996-2002 values). CONCLUSIONS: Economic modelling based on improved survival suggests bosentan to be a potentially cost-effective treatment for iPAH. However, the structure of the model and its inputs should be reviewed and updated as more data become available.

Transdermal Buprenorphine Relieves Neuropathic Pain: A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Trial in Diabetic Peripheral Neuropathic Pain.

OBJECTIVE: To evaluate the efficacy and safety of transdermal buprenorphine in patients with diabetic peripheral neuropathic pain (DPNP). RESEARCH DESIGN AND METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel-group trial enrolled patients with type 1 or type 2 diabetes and stable glycemic control who had been experiencing moderate to severe DPNP for at least 6 months on maximal tolerated conventional therapy. Patients were randomly assigned to receive buprenorphine (5 µg/h) or placebo patches. The dose was titrated to effect to a maximum of 40 µg/h. Paracetamol was available as rescue analgesia. The severity of pain and other symptoms of DPNP were assessed daily in a patient diary and at clinic visits. RESULTS: One hundred eight-six patients were enrolled, with 93 randomized to either buprenorphine or placebo. A high proportion of patients did not complete the study (buprenorphine 37 of 93, placebo 24 of 93). The main reason for premature withdrawal in the buprenorphine group was adverse events commonly due to untreated nausea and/or vomiting. Among the per-protocol population, more patients in the buprenorphine group (86.3%) experienced a 30% reduction in average versus baseline pain at week 12 than those in the placebo group (56.6%, P < 0.001). A nonsignificant trend favored the buprenorphine group within the intention-to-treat analysis of the same end point (51.7% vs. 41.3%, P = 0.175). CONCLUSIONS: Transdermal buprenorphine, when tolerated, is an effective therapy for DPNP and provides another option to manage this challenging painful condition. Nausea and constipation need to be managed proactively to optimize treatment outcomes.

The relationship between quality of life, Mini-Mental State Examination, and the Instrumental Activities of Daily Living in patients with Alzheimer's disease.

Alzheimer's disease (AD) affects the cognitive function and capacity for independent living of the elderly, however little is known about the measurement of patient's overall health-related quality of life (HRQoL) and its relationship to these effects. We examined the relationship between patient/caregiver-rated HRQoL and cognition (using the Mini-Mental State Examination (MMSE)) or Instrumental Activities of Daily Living (IADL). One hundred AD patients participating in an open-label trial of donepezil were followed for 6 months. Cognition and function were assessed using the MMSE (clinician-rated) and IADL scale (caregiver-rated). Patient QoL, as assessed by the Assessment of Quality of Life (AQoL) scale, was rated separately by patients and their primary caregivers. Mean patient-rated AQoL was 0.60, whilst caregiver-rated AQoL was 0.50. Patient and caregiver AQoL assessments correlated (r = 0.37, P = 0.0038) for all levels of disease severity. Patient-rated AQoL scores ranged from 0.52 for patients with severe AD, to 0.71 for patients with mild AD. Caregiver-rated AQoL scores ranged from 0.40 to 0.59. There were approximately linear relationships between the AQoL and MMSE scores (patient-rated r = 0.30, P < 0.0001; caregiver-rated r = 0.28, P < 0.0001), and AQoL and IADL scores (patient-rated r = 0.36, P < 0.0001; caregiver-rated r = 0.43, P < 0.0001). Patient self-assessment of AQoL is a useful instrument for measuring HRQoL in AD that displays an approximately linear relationship with MMSE, IADL, and caregiver-rated AQoL.

An intragastric balloon in the treatment of obese individuals with metabolic syndrome: a randomized controlled study.

OBJECTIVE: There are limited controlled data for intragastric balloons (IGB) in obesity treatment. This randomized, controlled study evaluated the efficacy and safety of an IGB in obese individuals with metabolic syndrome (MS). DESIGN AND METHODS: Sixty-six adults (BMI: 30-40 kg/m(2)) were randomized to IGB for 6 months, with a 12 month behavioral modification (IGB Group; "IGBG"), or 12 month behavioral modification alone (Control Group; "CG"). The primary outcome was percentage change in body weight. RESULTS: Thirty-one subjects (female: 68%; mean age: 43; mean BMI: 36.0) were randomized to IGBG and 35 (66%; 48; 36.7) to CG. At 6 months, there was a significantly greater weight loss in the IGBG: -14.2 vs. -4.8; P < 0.0001. This was associated with a significantly greater reduction in waist circumference, and an improvement in quality of life, with a trend for a larger %MS remission (50% vs. 30%; n.s.). At month 12, the differences in weight loss were enduring: -9.2 vs. -5.2; P = 0.007. Gastrointestinal-related adverse events were common in the IGBG, resolving predominantly within two weeks. The IGB was removed prematurely in three subjects (one for refractory gastrointestinal symptoms). CONCLUSIONS: Statistically significant and clinically relevant improvements in weight loss and health outcomes were observed with the IGBG at 6 months versus behavioral modification alone. The differential weight loss was still evident 6 months after IGB removal.

Effect of immunosuppression for primary renal disease on the risk of cancer in subsequent renal transplantation: a population-based retrospective cohort study.

BACKGROUND: To measure the risk of cancer in renal transplantation for recipients who had previously been treated with immunosuppressive agents for primary renal disease. METHODS: A retrospective population-based cohort study of 5970 renal transplant recipients in Australia registered on the Australia and New Zealand Dialysis and Transplant Registry between 1982 and 1997 and followed until 2007. Data about the incidence of a range of cancer types from this Registry were compared with cancer incidence data for the general population matched for cancer type, year of incidence, age, and gender derived from national cancer records. Outcome measures for each cancer group with or without pretransplantation immunosuppression were cancer-specific standardized incidence ratios and a multivariate hazard ratio (HR) standardized to 1. RESULTS: For those treated with pretransplantation immunosuppression, the risks for four cancer groups during renal transplantation were significantly increased: anogenital cancer (HR, 3.13; confidence interval [CI], 1.92-5.11; P<0.0001), non-Hodgkin's lymphoma (HR, 2.37; CI, 1.53-3.68; P=0.0001), breast cancer (HR, 2.52; CI, 1.13-5.61; P=0.024), and urinary tract cancer (excluding kidney) (HR, 1.84; CI, 1.13-3.01; P=0.015). However, the risks of cancer in the oral cavity and pharynx, kidney, thyroid, colon, leukemia, lung, melanoma, prostate, and stomach were not significantly increased. CONCLUSIONS: Pretransplantation immunosuppression for primary renal disease increases the risks of four cancer types in renal transplantation while sparing the others. Patients in whom this treatment is being considered should be informed of these risks.

A software program designed to educate patients on age-related skin changes of facial and exposed extrafacial regions: the results of a validation study.

BACKGROUND: A software program called "HOYS" has been developed to depict various aspects and degrees of aging at 35 constituent subregions of seven distinct facial or exposed extrafacial regions. This program is underpinned by five-point photonumeric Likert scales characterizing skin surface and volume changes across five decades for each of the 35 subregions, and features an interactive skin-age assessment with a treatment-prioritization tool. In this study, the reliability and reproducibility of these scales was evaluated. METHODS: Eleven physicians and 19 non-physicians participated in this study. The five images from each of the 35 Likert scales in the HOYS program were shown on a total of 43 display boards, with selected subregions presented at rest or with movement, consistent with this program. Each image was randomly labeled between "A-E," corresponding to a range of skin ages by decade from 20-69 years. Each rater was asked to rank these images from youngest to oldest (or least to most severe deficit) for each scale and to repeat this exercise 2 hours later, with the intra- and inter-rater reliability evaluated. The raters were also asked to estimate the age of a single randomly allocated image on each scale for the purposes of internal validation. RESULTS: The overall inter-rater reliability of the raters was high at the first ranking session (weighted kappa: 0.78; 95% confidence intervals [95% CI]: 0.77-0.79) and this was confirmed when repeated 2 hours later (0.82; 95% CI: 0.81-0.83), with an intra-rater reliability of 0.76 (95% CI: 0.75-0.77). There was no significant difference in the physicians' and non-physicians' rankings. The raters also accurately estimated the actual age of the single randomly allocated image from each of the 43 stations (0.72; 95% CI: 0.70-0.74). A very similar pattern was observed when the ratings of a constituent of one of the seven regions, the perioral/lower face, were analyzed for expounding purposes. CONCLUSION: The high reliability and reproducibility of the ranking in this validation study suggests that the five-point photonumeric Likert scales used in the HOYS program are an accurate depiction of age-related changes over five decades in the seven facial and extrafacial regions represented in this program, from the ages of 20-69 years.

United States cost-effectiveness study of two dry eye ophthalmic lubricants.

PURPOSE: Dry eye is thought to be the most common ocular problem in the United States. However, it is only recently that it has been recognized as a disease with significant economic burden and impact on quality of life. This article presents an economic model of cost-effectiveness of two ophthalmic lubricants commonly used in the treatment of dry eye-Systane and Refresh Tears. METHOD: We conducted a meta-analysis, pooling the results of two clinical trials of patients with dry eye treated with Systane and Refresh Tears which presented response rates for improvements in ocular dryness, the key symptom of dry eye. An economic model was used to estimate the incremental cost-effectiveness ratio (ICER) for Systane versus Refresh Tears over a 12 month treatment period. RESULTS: Systane is significantly more effective than Refresh Tears at improving symptoms of "dryness" (75% vs 41%). Systane costs on average $57.79 per year more than Refresh Tears. Assigning a quality-adjusted life year (QALY) gain of 0.03 to responders results in an incremental cost per QALY gain of $5,837. CONCLUSION: Both Refresh Tears and Systane are effective and cost-effective interventions. Systane costs more than Refresh Tears, however clinical trial evidence shows it to be more effective. The ICER for Systane versus Refresh Tears is well below the generally accepted $50,000 per QALY threshold.

Impact of inhaled corticosteroids on cortisol suppression in adults with asthma: a quantitative review.

BACKGROUND: Studies examining the effects of inhaled corticosteroids (ICSs) on cortisol suppression show inconsistent results, and there is uncertainty regarding the dose-response relationship between ICSs and cortisol suppression. OBJECTIVE: To determine, using meta-analysis, the extent of cortisol suppression after administration of clinically relevant ICS doses in adults with asthma. METHODS: Database searches (MEDLINE, EMBASE, and The Cochrane Library) using appropriate indexed terms were performed to identify eligible articles for review. Articles reporting the effects of ICSs on cortisol levels in asthmatic adults, measured using the cumulative serum or plasma cortisol, morning serum or plasma cortisol, or cumulative overnight urinary free cortisol method, were identified. All available cortisol measurements were extracted. Cortisol suppression was estimated, and treatment arms were grouped into low-, medium-, and high-dose ranges according to the Global Initiative for Asthma guidelines. A multivariate model was used to determine relationships between ICS dose and cortisol suppression and to explore sources of heterogeneity among trials. RESULTS: Thirty-one studies providing information on 216 measures of cortisol suppression were included in this meta-analysis. Cortisol suppression in the low-, medium-, and high-dose groups were estimated to be 17.92% (95% confidence interval [CI], 11.08%-24.77%), 26.55% (95% CI, 17.29%-35.80%), and 36.31% (95% CI, 26.48%-46.13%), respectively. CONCLUSIONS: Statistically significant cortisol suppression was evident at low doses of ICSs and increased with dose. These results support an impact of all ICSs on endogenous cortisol levels and underscore the importance of titrating ICS doses to the minimum required to maintain symptom control.

Comparison of benefits and risks of rosuvastatin versus atorvastatin from a meta-analysis of head-to-head randomized controlled trials.

The benefit from statin therapy is proportional to the low-density lipoprotein (LDL) cholesterol reduction. However, adverse events appear to be related to dose rather than LDL cholesterol reduction. Although serious side effects are rare, any comparison of statins requires scrutiny of the relation between therapeutic effect and risk of side effects. This report sought to determine whether the additional LDL cholesterol lowering with rosuvastatin over atorvastatin could be obtained without increased risk of short-term adverse events. Twenty-five studies (approximately 20,000 patients) were identified that provided 28 comparisons of 1:1 dose ratios, 20 comparisons of 1:2 dose ratios, and 6 comparisons of 1:4 dose ratios. Treatment difference in benefit (percentage of LDL cholesterol reduction) and risk (odds ratios for myalgia, increased alanine aminotransferase >3 times the upper limit of normal, creatine kinase >10 times the upper limit of normal, and percentage of change in glomerular filtration rate, as well as deaths, serious adverse events, and withdrawals caused by adverse events) were estimated using meta-analysis and presented in benefit-risk planes. Rosuvastatin was more efficacious than the same dose of atorvastatin (1:1 dose ratio) or a 2 times higher dose (1:2 dose ratio) of atorvastatin. There was no significant difference between rosuvastatin and a 4 times higher dose of atorvastatin (1:4 dose ratio). There were no significant differences between rosuvastatin and atorvastatin at any dose ratio for adverse events. Percentages of change in GFR improved significantly with both treatments. In conclusion, at 1:1 and 1:2 dose ratios, significant additional decreases in LDL cholesterol were obtained using rosuvastatin compared with atorvastatin at a similar risk of the adverse events presented.

Quality of life in pulmonary arterial hypertension: improvement and maintenance with bosentan.

BACKGROUND: Bosentan (an oral dual endothelin receptor antagonist) improves symptoms and cardiac hemodynamics and reduces clinical worsening in patients with pulmonary arterial hypertension (PAH). The VITAL study assessed the effect of bosentan on quality of life in patients with WHO Functional Class III or IV PAH (idiopathic or associated with connective tissue diseases). METHODS: Quality of life was assessed prospectively using the MOS SF-36 and AQOL questionnaires. Baseline readings and scores at 3 and 6 months were collected, in addition to other efficacy and safety data. RESULTS: Among the 177 study patients, SF-36 scores were significantly improved at 3 months in the domains of physical functioning (27.3 to 34.8; p < 0.0001), role-physical (16.6 to 30.9; p < 0.0001), vitality (35.2 to 41.1; p = 0.0003), social functioning (48.0 to 58.6; p < 0.0001), mental health (64.2 to 72.0; p = 0.005) and role-emotional (44.8 to 58.1; p = 0.001). Improvements were seen in all etiologic sub-groups and were maintained in patients who remained on bosentan. An improvement in AQOL measures at 3 months was also noted for patients with baseline WHO Functional Class III. CONCLUSIONS: Bosentan significantly improves quality of life in patients with idiopathic PAH or PAH associated with connective tissue diseases.

Idiopathic- and scleroderma-related pulmonary arterial hypertension: outcomes and QOL on bosentan.

Idiopathic pulmonary arterial hypertension (previously known as primary pulmonary hypertension) is a devastating disease of insidious onset, late diagnosis, progressive functional disability and poor prognosis. However, treatment with pulmonary arterial hypertension-specific agents has already changed the outlook wherever these agents are accessible. The process of economic evaluation of treatment for idiopathic pulmonary arterial hypertension is challenging due to limitations common to clinical studies in rare diseases, such as small patient numbers limiting survival information, lack of directly comparable trials for the efficacy of different drugs and a paucity of quality of life measurements. Bosentan (Tracleer), Actelion), has proven effective in clinical trials, and is the most frequently used pulmonary arterial hypertension-specific agent worldwide. It has additionally undergone a comprehensive quality of life trial and economic evaluation as therapy for idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension associated with scleroderma. This review explores the role of bosentan in providing cost-effective therapy compared with alternative treatments, and addresses the future considerations required to ensure accessible patient care for idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension associated with scleroderma.

CHART: congestive cardiac failure in hospitals, an Australian review of treatment.

Despite strong evidence supporting the use of angiotensin-converting enzyme inhibitors (ACED, beta-blockers, and spironolactone in heart failure, evidence suggests these drugs are under-used and under-dosed. The aim of the present study was to determine the impact of hospitalisation on heart failure pharmacotherapy in patients with congestive heart failure (CHF). A retrospective study was conducted, based on 300 consecutive admissions with the medical record diagnosis of heart failure, in each of seven grade one teaching hospitals. At admission, 49.5% of patients were treated with ACEI, 19.2% with beta-blockers and 8.1% with spironolactone. Twenty-six per cent of untreated patients started ACEI treatment during their hospital stay, and 9.4% started beta-blockers The main determinants of treatment with ACEI at discharge were a primary diagnosis of heart failure (odds ratio (OR) = 1.886) and the presence of a potential contraindication (high creatinine OR = 0.458, cough OR = 0.187, renal artery stenosis OR = 0.309). Patients were less likely to be discharged on beta-blockers if greater than 85 years of age (OR = 0.545), or there was mention of airways disease (OR = 0.347), asthma (OR = 0.238) or type 2 diabetes (OR = 0.721) on the medical record. Patients admitted by a cardiologist were more likely to be discharged on beta-blockers (OR = 3.207). Spironolactone was more likely used in patients with primary diagnosis of heart failure (OR = 1.549), aged less than 85 years (OR = 0.319), and/or admitted by a cardiologist (OR = 1.827). The substantial number of patients admitted to hospital with a secondary diagnosis of heart failure should be targeted for therapeutic optimisation.