Intensification patterns and the probability of HbA1c goal attainment in Type 2 diabetes mellitus: real-world evidence for the concept of 'intensification inertia'.

AIMS: To assess the effects of 'clinical' and 'intensification inertia' by evaluating the impact of different intensification interventions on the probability of HbA1c goal attainment using real-world data. METHODS: Electronic health records (Cleveland Clinic, 2005-2016) were used to identify 7389 people with Type 2 diabetes mellitus and HbA1c ≥53 mmol/mol (≥7.0%), despite a stable regimen of two oral antihyperglycaemic drugs for ≥6 months. The participants were stratified by index HbA1c and analysed over a 6-month period for pharmacological intensification, and then for 12 additional months for HbA1c goal attainment (<53 mmol/mol). RESULTS: The probability of HbA1c goal attainment (Kaplan-Meier analysis) in the group with index HbA1c 53-63 mmol/mol (7.0-7.9%) was highest with the addition of oral antidiabetic drugs [57.3% (95% CI 52.1, 62.0)] or glucagon-like peptide-1 receptor agonists [56.7% (95% CI 40.4, 68.6)], in the 64-74 mmol/mol (8.0-8.9%) group with the addition of oral antidiabetic drugs [31.9% (95% CI 25.1, 38.1)] or insulin [30.6% (95% CI 18.3, 41.0)], and in the ≥75 mmol/mol (≥9.0%) group with the addition of glucagon-like peptide-1 receptor agonists [53.0% (95% CI 31.8, 67.6)] or insulin [43.5% (95% CI 36.4, 49.8)]. CONCLUSIONS: Numerical, but not statistically significant, differences in HbA1c goal attainment probability by type of intensification were most marked in people with the highest index HbA1c [≥75 mmol/mol (≥9.0%)]; in this group, injectable therapy showed trends toward greater glycaemic control benefits. Additional research into the phenomenon of intensification inertia is warranted.

[KLF3 regulates the movement, migration and invasion of breast cancer cells through STAT3].

Objective: To observe the effect of KLF3 on the expression of STAT3 in breast cancer cells, and to explore the potential mechanism of KLF3 affecting the movement, migration and invasion of breast cancer cells. Methods: Firstly, the expression of STAT3 was detected by Western blot, real-time fluorescent quantitative PCR, luciferase reporter system and chromatin immunoprecipitation in breast cancer cells. Secondly, the STAT3 promoter mutant was constructed. The plasmid further confirmed the effect of KLF3 on the activity of STAT3 promoter; the cell scratching test and Transwell method were used to detect the ability of cell movement, migration and invasion. Finally, animal experiments were conducted to verify the effect of knockdown of KLF3 on tumor metastasis in animals. Results: In breast cancer cells, knockdown of KLF3 promoted STAT3 protein expression. The mRNA level of STAT3 was increased by (3.58±0.65) fold after knockdown of KLF3 in MDA-MB-231 cells, while the mRNA level of STAT3 was increased by (2.28±0.19) fold after KLF3 knockdown in MCF-7 cells (P<0.001). KLF3 boundto the promoter region of STAT3. The transcriptional activity of STAT3 increased by (2.47±0.87) fold after knockdown of KLF3 in MDA-MB-231 cells, while the transcriptional activity of STAT3 increased by (2.63±0.65) fold after KLF3 knockdown in MCF-7 cells, P<0.01. KLF3 knockdown inhibitedthe movement,migrate and invade of breast cancer cells. Based on this, silence STAT3 partially reversed the function of KLF3. Knockdown of KLF3 promotedtumor metastasis in mice. Conclusions: KLF3 knockdown can promote the transcriptional activity of STAT3, which promotes the protein expression of the latter. KLF3 can affect the movement, migration and invasion of breast cancer cells through STAT3. KLF3 may be a potential target for the treatment of metastatic breast cancer.

Initiation of antihypertensive therapy among new users of cyclooxygenase-2-selective and nonselective NSAIDs.

BACKGROUND: The comparative effects of cyclooxygenase-2- (COX-2) selective inhibitors and nonselective, nonsteroidal anti-inflammatory drugs (NSAIDs) on blood pressure are debated. Clinicians have been concerned about the need for antihypertensive treatment following therapy with these agents. OBJECTIVE: To compare initiation of antihypertensive treatment among new users of the COX-2-selective inhibitor rofecoxib and of nonselective NSAIDs in clinical practice. METHODS: Retrospective cohort study using the MediPlus (UK) database that covers 1.8 million patients throughout the UK. Patients included were at least 50 years of age, had at least 1 prescription for either diclofenac, ibuprofen, naproxen or rofecoxib (drugs of interest, DOIs), and had no prescription for any NSAID, COX-2 inhibitor, or antihypertensive treatment during the 6 months prior to their first/index prescription date. A subset of patients, classified as chronic and persistent new users, had at least 3 prescriptions of the index prescription DOI and did not switch to another DOI during the 6-month follow-up period. Logistic regression analysis, adjusted for potential predictors, was used to assess initiation of new antihypertensive treatment. RESULTS: 18,737 suitable patients were identified (diclofenac 7,861, ibuprofen 8,423, naproxen 1,556 and rofecoxib 897). Those using rofecoxib were older and more likely to be female than those using NSAIDs. During the 6 months following the index prescription, 7.0% of all new users and 11.5% of chronic and persistent new users initiated antihypertensive treatment. After adjusting for potential predictors there were no statistically significant differences in the risk of initiating antihypertensive treatment between new or chronic and persistent new users of rofecoxib, diclofenac, ibuprofen and naproxen (p > 0.05). CONCLUSION: The results of this study did not indicate any significant differences in the initiation of antihypertensive therapy among patients who were prescribed rofecoxib and NSAIDs, even after multiple prescriptions.

Incremental cost-effectiveness analysis comparing rofecoxib with nonselective NSAIDs in osteoarthritis: Ontario Ministry of Health perspective.

BACKGROUND: Clinical trials have shown rofecoxib, a selective inhibitor of cyclo-oxygenase-2, to be associated with fewer gastrointestinal complications than non-selective nonsteroidal anti-inflammatory drugs (NSAIDs). OBJECTIVE: To evaluate the potential clinical and economic consequences of rofecoxib prescription in Ontario, Canada, for patients with osteoarthritis (OA) aged >65 years who did not respond to paracetamol (acetaminophen) therapy. DESIGN: Decision analytic modelling study. METHODS: A model was constructed to compare rofecoxib and nonselective NSAIDs with respect to their gastrointestinal complications in patients with OA. The model had a 1-year horizon and considered direct medical costs from the perspective of the Ontario Ministry of Health. Event rates were estimated from a pooled analysis of 8 phase IIb/Ill clinical trials. The number of perforations, ulcers and bleeds (PUBs) with each strategy was used as the primary measure of effectiveness. RESULTS: In the base-case scenario, the expected total cost per patient-day on nonselective NSAIDs was 1.60 Canadian dollars (Can dollars) versus 1.67 Can dollars on rofecoxib (1999 values). Rofecoxib was associated with 0.0109 fewer PUBs per patient per year. The incremental cost to avoid 1 additional PUB by substituting rofecoxib for nonselective NSAIDs was 2247 Can dollars. The rofecoxib strategy became dominant if a gastroprotective agent was prescribed to more than 27.5% of the patients receiving nonselective NSAIDs. CONCLUSION: For patients with OA aged >65 years in whom paracetamol therapy has failed, rofecoxib may represent a cost-effective alternative to nonselective NSAIDs. Increased costs for drug acquisition are offset, in part. by avoidance of gastrointestinal complications and reduced use of gastroprotective agents. Rofecoxib may offer increased benefit among patients at a higher risk of serious gastrointestinal events.

Cost of prescribed NSAID-related gastrointestinal adverse events in elderly patients.

AIMS: It is well established that nonsteroidal anti-inflammatory drugs (NSAIDs) have gastrointestinal (GI) side-effects. However, the cost of health care resources spent on preventing and managing these side-effects is not clear. The objective of this study was to estimate the direct cost of NSAID-related GI events in an elderly population. METHODS: From the Régie de l'assurance-maladie du Québec (RAMQ) database, we obtained medical, pharmaceutical and demographic records of a 10% random sample (n = 49 033) of seniors who, between January 1, 1993 and December 31, 1997, had a dispensed prescription of a NSAID. Patients who did not have any GI events during the year prior to their first dispensed prescription were included in the cohort. All patients were followed-up for 2 years. The daily direct Canadian dollar costs of GI events that were incurred by these patients while they were on NSAID therapy were compared with those of GI events that were incurred by these same patients while they were not on NSAID therapy. The difference in these daily costs was attributed to NSAIDs. RESULTS: A total of 12 082 new NSAID users were included in the study. Two hundred and seventeen (1.8%) were hospitalized for GI-related problems; of these, 130 (60%) had their GI hospitalization as their first GI event; 3257 (27.0%) used gastroprotective agents (GPAs), and 857 (26.3%) took GPAs without any apparent prior GI symptoms; 801 (6.6%) had GI diagnostic tests; and 661 (5.5%) died. The average direct costs of GI side-effects per patient-day on NSAIDs were 3.5 times higher than those of a patient-day not on NSAIDs. The direct cost of GI side-effects per patient-day on NSAIDs was $1.34, of which more than 70% ($0.94) was attributed to GI events resulting from NSAID treatment. CONCLUSIONS: Approximately one Canadian dollar was added to patient costs for every day he/she was on NSAID therapy. Safer therapies and appropriate patient risk management may potentially reduce NSAID-related health care resource use.

Economic evaluation of rofecoxib versus nonselective nonsteroidal anti-inflammatory drugs for the treatment of osteoarthritis.

BACKGROUND: Results of phase III clinical trials of rofecoxib, a selective inhibitor of cyclooxygenase 2, have shown that osteoarthritis patients treated with rofecoxib had significantly fewer clinically significant gastrointestinal (GI) adverse events than those who received nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). OBJECTIVE: This paper explores the potential economic implications of the use of rofecoxib versus nonselective NSAIDs for the treatment of osteoarthritis via a decision analytic model based on rofecoxib clinical data and the published literature. METHODS: Base-case 1-year analyses were done with data on GI adverse events, specifically perforations, ulcers, and bleeds (PUBs), obtained from a prespecified pooled analysis of the rofecoxib clinical trials. Analyses were also performed using pooled results of two 12-week endoscopic surveillance trials, with adjustments for silent ulcers of 40% and 85%. RESULTS: Under base-case conditions, the expected cost savings in GI problems and comedications averted with rofecoxib versus NSAIDs was 0.81 dollars per day, representing an 85% offset of the difference in drug price. For rofecoxib versus NSAIDs, the expected cost per PUB avoided with rofecoxib was 4738 dollars, and expected cost per year of life saved was 18,614 dollars. In analyses based on endoscopic data, therapy with rofecoxib was less expensive than therapy with NSAIDs, regardless of silent ulcer adjustment. Results were most sensitive to prophylactic GI comedication rates, and were robust over a range of model assumptions and costs. CONCLUSIONS: In this analysis based on differences in clinically significant GI events for osteoarthritis patients, cost differences between rofecoxib and NSAIDs were markedly offset by expected cost savings in GI problems and comedications averted with rofecoxib. Costs per year of life saved with rofecoxib versus NSAIDs were well within accepted benchmarks for cost-effectiveness. When endoscopic data alone were considered, rofecoxib was cost saving across all assumptions about silent ulcer rates.

Effect of rofecoxib therapy on measures of health-related quality of life in patients with osteoarthritis.

BACKGROUND: Bodily pain and physical disability can negatively impact health-related quality of life (HRQL) in patients with osteoarthritis (OA). OBJECTIVE: To assess the effects of treatment with a new agent, rofecoxib, on HRQL in patients with OA. STUDY DESIGN: Randomized, double-blind, 6-week clinical trial comparing treatment with rofecoxib, 5 to 50 mg, with placebo in 672 patients with OA of the hip or knee. MAIN OUTCOME MEASURE: Patient HRQL was assessed at baseline and at the end of treatment using the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). RESULTS: At 6 weeks, mean change from baseline in all SF-36 mental and physical health domain scores demonstrated significant improvement with rofecoxib use (P < .05 for all doses for all SF-36 domains), with evidence of a dose-response relation. Improvements in mental and physical HRQL domains with rofecoxib treatment were significantly greater than those with placebo treatment (P < .05 for each dose of rofecoxib vs placebo for all domains except general health) and highly correlated with improvements observed using disease-specific OA outcome measures such as the Western Ontario and McMaster Universities Osteoarthritis Index-visual Analog 3.0 OA index pain and physical function subscales. The effect of rofecoxib vs placebo treatment on mental health largely disappeared after adjustment for improvement in OA disease-specific measures. CONCLUSIONS: Rofecoxib treatment increased physical and mental HRQL domain scores on the SF-36. Improvements in mental health with rofecoxib use primarily resulted from effective treatment of OA (i.e., reduction in pain and improvement in physical function).

Gastrointestinal-related healthcare resource usage associated with a fixed combination of diclofenac and misoprostol versus other NSAIDs.

OBJECTIVE: To compare gastrointestinal (GI) healthcare resource use (HCRU) and associated costs in patients taking a fixed combination of diclofenac and misoprostol versus other nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: We analysed a sample (49,033 patients) of the Government of Quebec Health Insurance Agency database. Patients were included in the study if they did not have GI events during the year preceding the date of their first NSAID prescription dispensing (the index date). Patients were followed up for 2 years. A 3-stage model was used to determine the factors that influenced the direct medical costs of GI HCRU: (i) a logistic regression model (model 1) to estimate the risk of GI HCRU; (ii) a linear regression model (model 2) to estimate the direct costs of GI HCRU for those who had such events; (iii) multiplying the estimated risks from model 1 by the estimated costs from model 2 gave the estimated direct costs of GI HCRU for all patients. STUDY PERSPECTIVE: Provincial government of Quebec, Canada. RESULTS: 1,533 patients were prescribed diclofenac/misoprostol at the index date and 10,540 another NSAID. Comorbidity markers were not significantly different between the 2 groups. Of the diclofenac/misoprostol patients, 23 (1.5%) were hospitalised for GI problems compared with 194 (1.8%) of the NSAID group; 403 (26.3%) of diclofenac/misoprostol patients used gastroprotective agents compared with 2,849 (27.0%) of the NSAID patients; 118 (7.7%) of diclofenac/misoprostol patients had GI diagnostic tests compared with 682 (6.5%) of the NSAID patients. The average direct medical cost of GI HCRU was 310.52 Canadian dollars ($Can)/patient (1997 values) in the diclofenac/misoprostol group compared with $Can231.19/patient (1997 values) in the NSAID group. When adjusted for baseline factors, the ratio of the total direct medical cost of GI HCRU in the diclofenac/misoprostol group to that of the NSAID group was 1.15 (95% confidence interval: 0.89, 1.48). CONCLUSIONS: Our data showed no significant differences in GI HCRU among patients taking diclofenac/misoprostol compared with those taking NSAIDs.

Drug switching patterns among patients taking non-steroidal anti-inflammatory drugs: a retrospective cohort study of a general practitioners database in the United Kingdom.

OBJECTIVE: To examine the frequency and determinants of switching between different non-steroidal anti-inflammatory drugs (NSAIDs) and the relationship with co-prescription of gastro-protective drugs (GPDs). DESIGN: This was an analysis of 30,654 patients receiving a total of 209,140 NSAID prescriptions in the UK from 1 January 1997 to 31 December 1998 identified through the MediPlus database. Analyses examined switching, repeat, termination and GPD co-prescription rates in new and continuing takers according to age and sex. RESULTS: Each patient received an average of 6.8 prescriptions in the year of study. Of the prescriptions 72.2% were for one of three NSAIDs, ibuprofen, diclofenac, or naproxen, and 7.2% of prescriptions were for fixed combination products of an NSAID plus a gastroprotective drug. At least 16.0% of continuing takers, and 28.5% of new takers switched to another NSAID in the review period. On average, new patients switched more frequently than continuing patients (0.39 switches/patient/year versus 0.23 switches/patient/year, p < 0.001). Switching between NSAIDs decreased with age and was less common in women (p < 0.05). Switching was associated with a 24% and 33% increased probability of GPD prescription in new and continuing takers, respectively. DISCUSSION: The frequency of switching, and of GPD co-prescription at switching, suggest that dissatisfaction with NSAIDs is frequent, and that gastrointestinal intolerance is a common feature of this dissatisfaction.

Use of nonsteroidal anti-inflammatory drugs and gastroprotective agents before the advent of cyclooxygenase-2-selective inhibitors: analysis of a large United States claims database.

BACKGROUND: Previous studies have shown that 20% to 40% of patients requiring nonsteroidal anti-inflammatory drugs (NSAIDs) are concomitantly prescribed gastroprotective agents (GPAs) such as proton pump inhibitors (PPIs) and H2-receptor antagonists. OBJECTIVE: The purpose of this study was to examine NSAID prescription patterns and the concurrent use of GPAs in a large national sample of patients who were prescribed NSAIDs for the first time. METHODS: Patterns of NSAID use, particularly chronic NSAID use, and of concomitant use of GPAs were examined using a large US-based prescription database. Patients with at least 1 NSAID prescription dispensed between May 1 and August 31, 1998, were identified. Persons with any NSAID prescription within 4 months prior to the first (index) prescription were excluded. The remaining patients were defined as new NSAID users and then classified as chronic users (> or = 30 days of supply of NSAIDs during the 120 days of follow-up after the first NSAID prescription) or acute users (<30 days of NSAID supply during the 120 days of follow-up). Concomitant GPA use was defined as receipt of any GPA prescription between the fill date of NSAID prescription and 125% of days of supply. NSAIDs included diclofenac/misoprostol (in a fixed combination), diclofenac, naproxen, nabumetone, ibuprofen, and "other" (comprising several less frequently prescribed agents). Patients were classified as users of a particular NSAID based on the first NSAID prescription they received. GPAs included PPIs, H2-receptor antagonists, and misoprostol. RESULTS: A total of 3,028,808 new NSAID users were identified. Chronic NSAID users (47.8% of the sample) were older than acute users. The percentage of new chronic users aged > or = 65 years for each of the NSAIDs was 41.2% for diclofenac/ misoprostol, 33.0% for nabumetone, 30.8% for diclofenac, 20.4% for naproxen, and 20.3% for ibuprofen. The percentage of women was higher among patients treated with diclofenac/misoprostol than among patients treated with all other NSAIDs (P < 0.001). During the 120 days of follow-up, the percentages of NSAID users with concomitant GPA use were 22.7% for diclofenac/misoprostol, 16.3% for diclofenac, 11.5% for naproxen, 18.0% for nabumetone, 12.3% for ibuprofen, and 14.8% for other NSAIDs. Based on days of supply, the rates of concomitant GPA use were 31.1%, 23.6%, 17.6%, 27.3%, 18.8%, and 22.5% for diclofenac/misoprostol, diclofenac, naproxen, nabumetone, ibuprofen, and other NSAID users, respectively. Among those who were taking GPAs before the NSAID index prescription date, -89% continued GPA therapy. CONCLUSIONS: Approximately 22% of the days of NSAID supply were covered by GPAs. Prior GPA use was the strongest predictor of subsequent concomitant GPA/ NSAID use. Differences in GPA use were observed among patients using different NSAIDs.

Excess costs related to non-steroidal anti-inflammatory drug utilization in general practice.

Data concerning the reasons for consultation and the use of NSAIDs were collected in 4643 patients, seen by 126 GPs over 2 days' consultation. In all, 11.6 per cent took NSAIDs. They were older (49 vs. 46 years, p = 0.02), took more drugs (3 vs. 2.5, p < 0.01), and more had ADRs (8 vs 2 per cent) than non-users, even after correction for age, sex and number of drugs taken. Some 33 per cent of NSAID users also took adjuvant medication for the prevention of gastric injury (including with COX-2 inhibitors meloxicam, nimesulide). Estimated excess costs associated with NSAID use were high, related to excess consultations (GP or specialist, for ADRs, approx. 5-8 million Euros per year in France) and to use of preventive medication (100 million Euros per year at least).

Gastrointestinal symptoms and health related quality of life in patients with arthritis.

OBJECTIVE: To evaluate the relationship between gastrointestinal (GI) symptoms and health related quality of life (QOL) in patients with osteoarthritis (OA) and rheumatoid arthritis (RA). METHODS: A total of 1773 patients with arthritis participating in a longterm outcome study (OA of the hip or knee = 648, RA = 1125) completed mailed surveys that included assessments of GI symptoms and overall GI symptom severity, Short Form-36, the visual analog scale (VAS) for the EuroQol (Health QOL), a VAS global disease severity scale, and measures of disease and psychological status. The overall response rate exceeded 85%. RESULTS: Dyspepsia (heartburn, bloating, or belching) and upper abdominal/epigastric pain were identified as the most important GI contributors to reduction in QOL, and the simultaneous presence of both these symptoms was associated with lower QOL (54.5) compared to those without symptoms (70.9) on the 0-100 Health QOL scale. Similarly, those in the upper tertile of the global GI severity scale had Health QOL scores of 55.7 compared to 76.4 for those in the lower tertile. These differences in GI symptoms and GI severity, however, were reduced substantially when the effects of functional disability, pain, and depression were adjusted for: 62.3 to 68.6 (p = 0.003) and 63.7 to 70.3 (p<0.001) for the GI symptoms and GI severity scales, respectively. CONCLUSION: QOL is significantly impaired among unselected arthritis patients with GI symptoms compared to those without these symptoms. Dyspepsia and upper abdominal/epigastric pain are more strongly related to QOL measures than other GI symptoms, and are common among arthritis patients. It is possible to construct a simple scale of these 2 symptoms or to use the VAS GI severity scale and get a clinically useful idea of the current level of GI distress and alteration of QOL by GI problems. Two components of impairment can be identified, one that is smaller and unrelated to disease or psychological factors, and a second that is larger and includes these factors. Because GI symptoms can alter function, pain, and psychological status, it is likely that the true effect of GI symptoms on QOL is somewhere between the unadjusted and adjusted values cited above.

Gastrointestinal health care resource use and costs associated with nonsteroidal antiinflammatory drugs versus acetaminophen: retrospective cohort study of an elderly population.

OBJECTIVE: To estimate gastrointestinal (GI) health care resource use and direct costs associated with prescription nonsteroidal antiinflammatory drugs (NSAIDs) in an elderly population. METHODS: Using the Government of Quebec's health insurance database, we obtained the medical, pharmaceutical, and demographic records of 73,850 senior citizens who, between 1993 and 1997, had either an NSAID or an acetaminophen prescription dispensed. The date of their first dispensed prescription for an NSAID or acetaminophen was termed their index date. Patients who were not taking oral corticosteroids or anticoagulants at their index date, were not diagnosed with cancer at their index date, and were not hospitalized and did not have any GI events during the year prior to their index date were included in the study. Patients who had a dispensed NSAID prescription at their index date formed the NSAID cohort; the others formed the acetaminophen cohort. All patients were followed up for 2 years. The daily direct costs of GI events incurred during NSAID therapy by the NSAID cohort were compared with those incurred during a similar followup period by the acetaminophen cohort. The difference in these average daily costs was attributed to NSAID use. RESULTS: The NSAID cohort included 5,268 senior citizens and the acetaminophen cohort 2,245. More GI adverse events were observed in the NSAID cohort (odds ratio 2.48, 95% confidence interval 2.06, 3.00). The average daily direct cost of GI events for a day of NSAID therapy attributed to the NSAIDs was $0.84 (Canadian). On average, for each Canadian dollar spent on NSAIDs, an additional $0.66 was spent on their side effects. CONCLUSION: Safer alternatives to NSAIDs would significantly reduce medical care costs for patients in need of NSAID therapy.

Rasch analysis of the Western Ontario MacMaster questionnaire (WOMAC) in 2205 patients with osteoarthritis, rheumatoid arthritis, and fibromyalgia.

OBJECTIVE: Advances in health measurement have led to the application of Rasch Item Response Theory (IRT) analysis (Rasch analysis) to evaluate instruments measuring health status and quality of life of patients, including the Health Assessment Questionnaire and SF-36. This study investigated the extent to which the Western Ontario MacMaster osteoarthritis questionnaire (WOMAC) satisfies the Rasch model, particularly in respect to unidimensionality, item separation, and linearity. METHODS: The study included a total of 2205 patients, 1013 with rheumatoid arthritis (RA), 655 with osteoarthritis of the knee or hip (OA), and 537 with fibromyalgia. All patients completed the WOMAC as part of a longitudinal study of rheumatic disease outcomes. To examine whether the WOMAC pain and function scales each fits the Rasch model, the Winsteps program was used to assess item difficulty, scale unidimensionality, item separation, and linearity. RESULTS: Although the WOMAC worked best in OA, regardless of disorder, both the pain and function scales were unidimensional, had adequate item separation, and had a long range (25-150) of linearity in the function scale. Several functional items, however, had a high information weight fit (INFIT) statistic, indicating poor fit to the model. These items included "getting in and out of the bath" and "going down stairs." CONCLUSION: The WOMAC generally satisfies the requirements of Rasch item response theory across all disorders studied, and is an appropriate measure of lower body function in OA, RA and fibromyalgia. Although some individual items do not fit well, it is not likely that removing such items would result in more than overall minimal differences, and it will be difficult to remove traces of multidimensionality while keeping the central constructs of progressive lower body musculoskeletal abnormality intact. In addition, it is possible that a "purer", still more unidimensional instrument would be less useful in clinical trials and epidemiological studies by restricting the range of the scale.

The SF-36 Health Survey as a generic outcome measure in clinical trials of patients with osteoarthritis and rheumatoid arthritis: tests of data quality, scaling assumptions and score reliability.

OBJECTIVE: To evaluate the psychometric assumptions underlying the construction and scoring of SF-36 scales and summary measures among clinical trial participants with arthritis. METHODS: Cross-sectional SF-36 data from the baseline assessment of adult patients (n = 1,016) participating in four placebo-controlled clinical trials of treatment for arthritis were analyzed with blinding as to treatment. Tests of the completeness of data, scaling assumptions, internal-consistency reliability, and factor structure of SF-36 scales were performed for the combined sample. Eligible participants had at least a 6-month history of moderate to severe osteoarthritis or rheumatoid arthritis of the knee or hip. Participants meeting inclusion criteria had undergone a washout period of 3-14 days before baseline assessment to bring about a flare state in osteoarthritis or rheumatoid arthritis symptoms. Baseline sample sizes for the three osteoarthritis trials were n = 121, n = 341, and n = 187. The baseline sample size for the rheumatoid arthritis trial was n = 367. The average age of participants was 60 years, and the majority were females (72%). Measured were functional health and well-being scales and physical and mental health summary measures from the SF-36 Health Survey acute form. RESULTS: Missing responses ranged from 0.0% to 1.5% across SF-36 items, and scale scores could be computed for 96.8% to 100% of participants across trials. In all four trials, item internal consistency tests were passed (91.4%-97.1%) and item discriminant validity tests were passed (96.9%-100.0%). Across the four trials, internal-consistency reliability coefficients ranged from a low of 0.75 to a high of 0.91 for the eight scales (median = 0.84), exceeding the minimum standards for group comparisons. Ceiling effects were minimal for most scales, and floor effects were noteworthy for the role physical and role emotional scales. Physical and mental health factors identified in previous studies were replicated. CONCLUSION: The SF-36 Health Survey proved to be a psychometrically sound tool for the assessment of the health status of adult participants in clinical trials of arthritis.

The SF-36 Health Survey as a generic outcome measure in clinical trials of patients with osteoarthritis and rheumatoid arthritis: relative validity of scales in relation to clinical measures of arthritis severity.

OBJECTIVE: To evaluate the validity of SF-36 Health Survey (SF-36) scale scores and summary measure scores to describe the health burden of arthritis and to be responsive to clinical indicators of arthritis severity used in four clinical trials. METHODS: Adults participating in four double-blinded, placebo-controlled clinical trials of therapy for osteoarthritis or rheumatoid arthritis were administered the SF-36 concurrent with clinical measures of disease severity (n = 1,016). Data were collected before treatment and 2 weeks after treatment. Mean SF-36 scores for all patients with arthritis at baseline were compared to a sociodemographically equivalent national norm to test the ability of the SF-36 to describe the burden of arthritis. To test the responsiveness of SF-36 scores to clinical measures of arthritis severity, mean SF-36 scale scores were compared across patients differing in arthritis severity before treatment. Two-week mean SF-36 change scores were compared across patients who improved in arthritis severity (responders) versus patients who did not improve (nonresponders). F-statistics and relative validity coefficients were computed to determine how well each SF-36 scale and summary measure discriminated among arthritis severity levels and distinguished treatment responders from nonresponders, relative to the best scale. RESULTS: Large and statistically significant differences in mean SF-36 scale scores and summary measures were found such that trial participants scored in worse health than a sociodemographically equivalent US general population norm. In addition, the largest SF-36 scale scores were found to significantly differ across clinically defined levels of arthritis severity. Finally, it was found that the SF-36 scales that best discriminate among arthritis severity groups cross-sectionally were also best at discriminating treatment responders from nonresponders. CONCLUSION: Results of this study support the validity of the SF-36 to document the health burden of arthritis and as a measure of generic health outcome for clinical trials of alternative treatments for osteoarthritis and rheumatoid arthritis patients.

The SF-36 Arthritis-Specific Health Index (ASHI): I. Development and cross-validation of scoring algorithms.

An arthritis-specific health index (ASHI) for the SF-36 Health Survey was developed by studying its responsiveness to changes in clinical indicators of arthritis severity. Longitudinal data from 1,076 patients participating in four placebo-controlled trials were analyzed. All had at least a 6-month history of moderate to severe osteoarthritis or rheumatoid arthritis of the knee or hip. All had undergone a washout period of 3 to 14 days before baseline assessment to bring about a flare state in osteoarthritis or rheumatoid arthritis symptoms. Their average age was 60 years and 72% were female. Change scores for the eight-scale SF-36 health profile (acute version) and five arthritis-specific measures of disease severity (knee pain on weight bearing, time to walk 50 feet, physician global evaluation of symptom severity and impact, patient global evaluation of symptom severity and impact, and pain intensity visual analogue scale) were computed by subtracting scores before treatment from scores at two-week follow-up. Canonical correlation methods were used to derive weights for changes in SF-36 scales to score a single index (ASHI) that maximized its correlation with changes in the set of five clinical measures of arthritis severity. The weights used to score the ASHI were cross-validated in a 25% holdout group (N = 144) from the first two osteoarthritis trials and in two additional osteoarthritis and rheumatoid arthritis trials (N = 530). Only one SF-36 canonical variate (ASHI) correlated significantly (F = 4.69, P < 0.0001) with the clinical canonical variate that served as the "criterion" measure of change in the severity of arthritis. Changes in the ASHI and clinical canonical variate were substantially correlated in the developmental sample (r = 0.628, P < 0.0001) and on cross-validation (r = 0.629, P < 0.0001). The clinical canonical variate correlated highly (r = 0.75-0.88) with changes in all but one of the five clinical measures (50-foot walk; r = 0.41). The pattern of correlations between changes in SF-36 scales and the ASHI indicated that ASHI is primarily a measure of bodily pain (r = 0.92) and other aspects of physical and role functioning and well-being (r = 0.69 for Role-Physical, r = 0.68 for Physical Functioning, r = 0.52 for Social Functioning, and r = 0.51 Vitality). The patterns of correlations between SF-36 scales and the ASHI were very similar across developmental and cross-validation samples. This research demonstrates the feasibility and generalizability of a single ASHI scored from changes in responses to the SF-36 Health Survey. The generic SF-36 health profile, which has already been shown to be useful in comparing arthritis with other diseases and treatments, can also be scored specifically to make it more useful in studies of osteoarthritis and rheumatoid arthritis.

The SF-36 Arthritis-Specific Health Index (ASHI): II. Tests of validity in four clinical trials.

OBJECTIVE: The SF-36 Arthritis-Specific Health Index (ASHI) was constructed to improve the responsiveness of the SF-36 Health Survey to changes in the severity of arthritis through the use of arthritis-specific scoring algorithms. This study compared the responsiveness of the ASHI and other generic scales and summary measures scored from the SF-36 in clinical trials of health outcomes for patients with arthritis. METHODS: Longitudinal data for patients (n = 835) participating in four placebo-controlled trials were analyzed. Study participants had at least a 6-month history of moderate to severe osteoarthritis or rheumatoid arthritis of the knee or hip. All had undergone a washout period of 3 to 14 days before baseline assessment to bring about a flare state in osteoarthritis or rheumatoid arthritis symptoms. Their average age was 60 years, and 72% were female. Responders and nonresponders were classified on the basis of physician assessments of changes in arthritis severity, with blinding as to treatment group; treated and untreated (placebo) groups were also compared. For the SF-36 ASHI, generic physical (PCS) and mental (MCS) component summary measures and each of eight subscales scored from the SF-36 (acute version) change scores were computed by subtracting scores before treatment from scores at 2-week follow-up. To evaluate empirical validity, analyses of variance were performed. For each measure, an F-ratio was computed for the comparison between clinically defined groups of responders and nonresponders and between groups of patients assigned to placebo versus drug therapy. Relative validity (RV) coefficients were computed for the ASHI in comparison with PCS, MCS, and the best SF-36 scale to determine which was more responsive. RESULTS: In analyses of each of the four trials and all trials combined, RV coefficients for the ASHI were higher than those for both of the generic SF-36 summary measures and for the most valid SF-36 scale (Bodily Pain), with only one exception. Across 40 tests of validity in distinguishing treated from untreated patients, the ASHI was 5% to 19% more valid than the best SF-36 scale (RV = 1.05-1.19; RV = 1.10 in all trials combined). The generic summary measures (PCS and MCS) were much less valid in these tests (RV = 0.67 and 0.27, respectively). In analyses of responders and nonresponders, RV coefficients for the ASHI ranged from 0.70 to 1.22 (RV = 1.04 in all trials combined), in comparison with the best SF-36 subscale, which was always Bodily Pain. RV coefficients were lower for PCS (RV = 0.75) and much lower than the MCS (RV = 0.18) in comparisons of treatment outcomes based on all trials combined. CONCLUSION: The ASHI appears to be more valid than the eight SF-36 scales and PCS and MCS summary measures for purposes of distinguishing between treated and untreated patients and between clinical responders and nonresponders. This study demonstrates the feasibility of improving the validity of the SF-36 through the use of arthritis-specific scoring while retaining the option of generic scoring, which makes it possible to also compare results across diseases and treatments.

Characteristics associated with ability to prevent adverse drug reactions in hospitalized patients.

We conducted a retrospective analysis to identify characteristics of preventable adverse drug reactions (ADRs). We reviewed reports on 612 ADRs occurring in hospitalized patients over 4 years, identified by the hospital's spontaneous ADR reporting program, and classified the events as potentially preventable or not preventable. Characteristics related to ADR preventability in the univariate analysis were the patient's clinical service, organ system involved in the ADR, class of drug causing the ADR, relationship to dosage, type of ADR, and probability that the reaction was due to the drug. Among these, relationship to dosage (p<0.001) and type of ADR (p<0.001) appeared to be most strongly related to preventability. In a multivariate analysis, preventable ADRs were associated with dosing (OR 3.82, 95% CI 2.42-6.03) and previous allergy to the drug (OR 3.46, 95% CI 1.01-11.88). An ADR that was classified as an allergic (OR 0.50, 95% CI 0.27-0.94) or idiosyncratic reaction (OR 0.44, 95% CI 0.28-0.71) was unlikely to be considered preventable. Preventable ADRs in hospitalized patients are likely to be dosage related or to occur among patients allergic to the specific agent.

Prevalence and cost of hospitalization for gastrointestinal complications related to peptic ulcers with bleeding or perforation: comparison of two national databases.

The purpose of this study was to determine the prevalence and cost of hospitalization for upper gastrointestinal complications, including peptic ulcers with hemorrhage or perforation. Upper gastrointestinal complications and corresponding economic data were obtained from two sources. The first was a 20% sample of all community hospital discharges (about 6 million per year) from 11 states for 1991 and 1992 Hospital Cost Utilization Project; HCUP-3). The second source of data was a claims database for employees of large US corporations and their dependents for 1992, 1993, and 1994 (about 3.5 million covered lives per year; MarketScan). A group of ICD-9 codes for the diagnosis of peptic and gastroduodenal ulcers with bleeding or perforation were used to identify hospital admissions because of upper gastrointestinal complications. Similar patterns were observed across the MarketScan and HCUP-3 databases regarding hospitalization with diagnoses related to gastrointestinal complications identified according to the ICD-9 codes. The average age of patients with upper gastrointestinal complications was 66 years in the HCUP-3 database and 52 years in the MarketScan database. The average annual rates of upper gastrointestinal complications as a primary or secondary diagnosis were 6.4 and 6.7 per 1000 discharges for 1991 and 1992, respectively (HCUP-3), and 4.3, 4.2, and 4.9 per 1000 admissions for 1992, 1993, and 1994, respectively (MarketScan). The average length of stay for upper gastrointestinal complications as a primary diagnosis was 7.8 days in 1991 and 7.5 days in 1992 (HCUP-3) and 6.1, 5.1, and 5.1 days in 1992, 1993, and 1994, respectively (MarketScan). The national average total charge for hospitalization for gastrointestinal problems as a primary diagnosis was $12,970 in 1991 and $14,294 in 1992 (HCUP-3). The average total reimbursement for hospitalizations related to upper gastrointestinal problems was $15,309 in 1992, $12,987 in 1993, and $13,150 in 1994 (MarketScan). Hospital admissions for upper gastrointestinal complications are expensive. The rate and cost per admission are higher for the older population. The results on the elements covered by both databases are consistent. Therefore the databases complement each other on the type of information abstracted.