Cautionary tales in the interpretation of systematic reviews of therapy trials

This is the second in a series of articles emphasizing the cautions in the interpretation of health-care studies. Systematic reviews are presented as comprehensive, unbiased summaries of evidence and are often referred to by clinicians, guideline developers and health policy-makers. Their strengths and limitations, and how their results can be subject to bias and misinterpretation, are discussed.

Medication management at home: medication risk factor prevalence and inter-relationships

Background and objective: Patients can have medication-related risk factors associated with poor health outcomes that become evident through visiting them in their homes. These medication-related risk factors may not be apparent in pharmacy and general practitioner (GP) records. The aim was to determine the prevalence and inter-relationships of medication-related risk factors for poor patient health outcomes identifiable through 'in-home' observations. Methods: The design was a cross-sectional study of 204 general practice patients living in their own homes and at risk of medication-related poor health outcomes. Medication-related risk factors were identified in the patients' homes by community pharmacists and GPs. Results and discussion: The prevalence of risk factors varied from 8.3% (multiple medication storage locations) to 55.9% (confused by generic and trade names). There were many relationships observed between the medication-related risk factors, with expired medication having the most relationships with other risk factors followed by therapeutic duplication and poor adherence (9, 6 and 6 relationships respectively). Conclusion: Visiting patients' homes may identify medication-related risk factors not otherwise apparent through patient visits to the health practitioner when medications may be brought for review (i.e. 'brown bag' reviews).

An examination of the psychometric properties of the Rosenberg Self-Esteem Scale (RSES) in Chinese acute coronary syndrome (ACS) patients

The psychometric properties of the Rosenberg Self-Esteem Scale (RSES) as a clinical research instrument for acute coronary syndrome (ACS) patients were investigated in a translated Chinese version of the instrument. A confirmatory factor analysis was conducted on the RSES to establish its psychometric properties in 128 ACS patients over two observation points (within 1 week and 6 months post-admission for ACS). Internal and test - retest reliability of the RSES-TOT (all-items) and RSES-POS sub-scale (positively valenced items) were found to be acceptable. The RSES-NEG sub-scale (negatively valenced items) lacked acceptable internal reliability. The underlying factor structure of the RSES comprised two distinct but related factors, though there was inconsistency in best model fit indices at the 1-week observation point. The use of the RSES as two sub-scales (RSES-POS and RSES-NEG) may be clinically useful in evaluating the influence of this important psychological construct on the health outcomes of patients with ACS. Directions for future research are indicated.

A Cochrane review (update 2004): Hylan G-F 20 vs placebo for knee OA

Aim of study: As part of a Cochrane review of viscosupplementation in knee OA, randomised controlled trials (RCT) were reviewed to evaluate evidence for the efficacy of viscosupplementation with Hylan G-F 20 compared to placebo. Methods: Electronic searches were conducted of MEDLINE, EMBASE, Premedline, Current Contents, and CENTRAL. Human, RCT involving Hylan G-F 20 compared to placebo, published prior to 1Q2004, were included. Trials were selected and data extracted by two independent reviewers. Methodological quality was assessed with the Jadad criteria by two reviewers. Data on the OARSI and OMERACT core set clinical outcome measures were extracted where possible. Weighted mean difference (WMD), based on post-test scores, and 95% confidence intervals (CI) were calculated for continuous outcome measures and relative risk (RR) for dichotomous outcome measures. Results: Seven RCT met the inclusion criteria. Median methodological quality was 4 (range 1–5). A further two studies were only reported in abstract form (Jadad score Z 1) and contained insufficient extractable data for inclusion in the analysis. Nine RCT, which compared Hylan G-F 20 to other interventions such as intra-articular corticosteroid, physiotherapy, NSAID, appropriate care, intra-articular gaseous oxygen and other hyaluronan, are not reported here. Twenty-three studies failed to meet inclusion criteria and were excluded. Hylan G-F 20 was more efficacious than placebo at 1–4 weeks post-injection for pain on weight-bearing WMD (random effects [RE]) 13 mm on a 0–100 mm VAS (P Z 0.002) based on 6 RCT. This difference was even greater at 5–13 weeks post-injection, 22 m (RE) (P Z 0.001) based on 5 RCT, and at 14–6 weeks postinjection, 21 m (RE) (P Z 0.006) based on 4 RCT. Hylan G-F 20 was more efficacious than placebo at 1–4 weeks post-injection for pain at night, WMD 7 mm on a 0–100 mm VAS (P Z 0.003) based on 5 RCT. This difference was even greater at 5–13 weeks post-injection, 11 mm (P Z 0.008) based on 4 RCT, and at 14–26 weeks post-injection, 17 mm (P ! 0.00001) based on 3 RCT. There was no significant difference (WMD 8 mm) between Hylan G-F 20 C oral placebo and arthrocentesis C oral placebo at 5–13 weeks post-injection for WOMAC Pain, but Hylan G-F 20 C oral placebo was more efficacious than arthrocentesis C oral placebo for WOMAC Function, WMD 9 mm on a 0–100 mm VAS (P Z 0.01) (Dickson, 2001). Hylan G-F 20 was more effective than placebo at 1–4 weeks postinjection for the variable designed treatment efficacy, WMD 22 mm on a 0–100 mm VAS (P ! 0.00001) based on improvement in 4 RCT. This difference was even greater at 5–13 weeks post injection, 35 mm (P ! 0.00001). Conclusions: Evidence from this updated Cochrane review supports the superior efficacy of Hylan G-F 20 compared to placebo on weight-bearing pain, night pain, function and treatment efficacy in the treatment of knee OA.

WOMAC 20, 50, 70 response levels in patients treated with Rofecoxib for osteoarthritis

Aim of study: The goal of this post-hoc analysis was to examine the difference between treatment groups when varying the target response level from at least a 20% improvement from baseline, to at least 50% and 70% improvements in Phase III studies of rofecoxib in patients with osteoarthritis. Methods: The analysis focused on results from two 6-week, placebo-controlled, ibuprofen-comparator, Phase III osteoarthritis studies. These studies employed a flare design requiring a minimum level of symptoms at entry following discontinuation of prior analgesics. Two definitions of ‘‘patient improved’’ from baseline were used: (1) WOMAC-P: a reduction in the WOMAC pain score and (2) WOMAC-PFS: a reduction in the WOMAC pain score and either a reduction in the WOMAC stiffness or function score. The improvement target was increased from 20% to 50% to 70%, relative to baseline, to investigate how the increase affects the ability to detect the differences between treatment groups. Analyses were conducted on the average and last of all measurements collected during a 6-week treatment period. Results: In the ibuprofen-comparator studies, 1545 patients were randomized to placebo, rofecoxib 12.5 mg once daily, rofecoxib 25 mg once daily, and ibuprofen 800 mg three times daily in a 1:3:3:3 ratio. The percentages of patients who met the improvement targets decrease as the target increases from 20% to 50% to 70%. There were meaningful differences between the active treatment and placebo that were inversely related to the improvement target. For example, there was a 31 (P ! 0.001), 21 (P ! 0.001), and 12 (P ! 0.001) percentage-point difference between rofecoxib 25 mg and placebo for the 20%, 50%, and 70% targets for WOMAC-P. For WOMAC-PFS, the differences between rofecoxib 25 mg and placebo were 33 (P ! 0.001), 18 (P ! 0.001), and 9 (P ! 0.01) percentage points for the 20%, 50%, and 70% improvement targets. Conclusions: Meaningful differences between active treatments and placebo were detected at all three response levels associated with the WOMAC-P and WOMAC-PFS endpoints. The differences between groups were more dramatic at the 20% and 50% response levels. The WOMAC (20,50,70)-P and WOMAC (20,50,70)-PFS endpoints further confirm, at an individual patient level, the clinical benefit of rofecoxib in the treatment of osteoarthritis that was previously reported as a difference in means.

Predictors of osteoarthritis(OA) improvement in patients treated with Hylan G-F for knee OA.

Aim of study: Different criteria for treatment response were explored to identify predictors of OA improvement. Analyses were based on data from a previously reported 1-year randomized controlled trial of appropriate care with or without hylan G-F 20 in patients with knee OA. Methods: Five definitions of ‘‘patient responder’’ from baseline to month 12 were examined: at least 20% reduction in WOMAC pain score; at least 20% reduction in WOMAC pain score and at least 20% reduction in either the WOMAC stiffness or function score; OARSI responder criteria (Propositions A and B) for intra-articular drugs; and OMERACT-OARSI responder criteria (Proposition D). As an a posteriori analysis, multivariable logistic regression models for each definition of patient responder were developed using a forward selection method. The following variables were defined prior to modeling and considered in the model along with two-way interactions: age (O65 years), BMI, gender, X-ray grade (0, I, II vs III, IV), co-morbidity (1 or 2 conditions vs 3 or more), duration of OA in study knee (years), previous surgery of study knee, hylan G-F 20 injection technique, WOMAC pain, stiffness and function, and treatment group. Results: Hylan G-F 20 was a predictor of improvement for all patient responder definitions P ! 0.001; odds of improvement were 2.7 or higher for patients in the hylan G-F 20 group compared to appropriate care without hylan G-F 20. For three of the five patient responder definitions, X-ray grade was a predictor of improvement (P ! 0.10; lower X-ray grade increased the odds of improvement). For four of the five patient responder definitions, duration of OA was a predictor of improvement (P ! 0.10; shorter duration of OA increased the odds of improvement). Conclusion: Analyses showed that appropriate care with hylan G-F 20 is the dominant predictor of patient improvement. While high grade structural damage does not preclude a response, patients who are targeted early in the disease process when less structural damage has occurred, may have a greater chance of improvement.

Prevalence of patient with low intensity pain symptom severity states during treatment with Rofecoxib and Ibuprofen for osteoarthritis

Aim of study: To examine the prevalence of low intensity symptom severity states in patients taking placebo, rofecoxib 12.5 mg once daily, rofecoxib 25 mg once daily, or ibuprofen 800 mg three times daily using a post-hoc definition of low pain intensity states (BLISS Index) based on the WOMAC Index. Methods: Two 6-week, double-blind, parallel-group, placebocontrolled, ibuprofen-comparator studies were conducted to measure the efficacy of rofecoxib in patients with knee or hip osteoarthritis. These studies employed a flare design requiring a minimum level of symptoms at entry following discontinuation of prior analgesics. The WOMAC Pain subscale (100 mm visual analog scale) was used as the pain measure. In separate analyses, WOMAC pain subscale scores from each patient were compared to five thresholds of pain:%5 mm, %10 mm, %15 mm, %20 mm, and %25 mm. The percent of patients with BLISS states (1) on average over 6 weeks, (2) at any time during the study, and (3) at week 6 was computed for each treatment group and threshold. The treatment group percentages were compared using Fisher’s exact test. Results: During the study, patients received placebo (N Z 143), rofecoxib 12.5 mg (N Z 461), rofecoxib 25 mg (N Z 459), or ibuprofen (N Z 465). For each pain threshold and treatment group, the percent of patients with BLISS states at any time (e.g., 50% for rofecoxib 25 mg) exceeded the percentage at week 6 (e.g., 40% for rofecoxib 25 mg) which, in turn, exceeded the percentage with BLISS states on average (e.g., 32% for rofecoxib 25 mg). The percentages of patients in the active treatment groups with BLISS states on average were significantly different than observed in the placebo group at the%15 mm threshold (8–11% points vs placebo, P ! 0.01), %20 mm level (10–15% points, P ! 0.01), and %25 mm level (14–17% points, P ! 0.001). Significant differences between the active treatments and placebo were also observed at the %10 mm threshold (8–9% points, P ! 0.05) for measurements at week 6 and at the%10 (12–14% points, P !0.001) and%5 mm thresholds (5–7% points, P ! 0.05) for patients with BLISS states at any time. Conclusion: These measures of BLISS states differentiate all three active treatment groups from placebo and further confirm, at an individual patient level, the clinical benefit of rofecoxib in the treatment of osteoarthritis. Furthermore, they provide information on the prevalence of patients achieving low (%15 mm, %20 mm, %25 mm), and very low (%5 mm, %10 mm) pain severity states.