Nonspecific adverse events in knee osteoarthritis clinical trials: a systematic review.

BACKGROUND: Adverse events (AEs) derived from nonspecific activity of treatments can impair the validity of trials, and even make it difficult to identify specific AEs associated with treatments. To better understand these nonspecific AEs, we investigated the AEs in placebo groups by using knee osteoarthritis clinical trials. METHODS: Randomized, placebo-controlled, knee osteoarthritis trials were identified by searching electronic databases. We determined the rate of patients with AEs and the rate of dropouts caused by AEs in the active and placebo groups. Furthermore, we calculated the rate of patients for individual AEs in the placebo groups. Finally, we performed secondary analyses to identify the factors associated with these rates. RESULTS: Overall, 272 papers reporting 281 trials were included in the analysis. The rates of patients with AEs were 31.8% in the active groups and 27.4% in the placebo groups. The rate of the placebo groups accounted for 86.2% of the rate of the active groups. The rates of dropouts caused by AEs were 5.2% in the active groups and 4.8% in the placebo groups. The rate of the placebo groups accounted for 92.3% of the rate of the active groups. AEs in the placebo groups included a number of clinical conditions, with elevated alanine aminotransferase (0.59%; 95% CI: 0.46 to 0.77) being the most common objective outcome and headache (4.48%; 95% CI: 4.20 to 4.79) being the most frequent subjective outcome. The rate of patients with AEs and the rate of dropouts caused by AEs were associated with the treatment type, delivery route, and study design. CONCLUSIONS: The nonspecific AEs substantially accounted for the development of AEs in the active groups and included conditions involving the entire body.

Clinically meaningful nocebo effect occurs in acupuncture treatment: a systematic review.

OBJECTIVE: To investigate the nocebo effect using randomized acupuncture trials that include sham and no-treatment groups. STUDY DESIGN AND SETTING: Electronic databases were searched to retrieve eligible trials from their inception until June 2013. Risk differences were then calculated using the acupuncture and sham groups to determine the treatment effect and the sham and no-treatment groups to determine the nocebo effect. RESULTS: In total, 58 eligible trials were analyzed. On the basis of the rate of patients with any adverse event in 31 trials reporting available data, the treatment effect was 0.012 (95% confidence interval [CI]: 0.003, 0.021), with a number needed to harm (NNH) of 83 (95% CI: 48, 333). The nocebo effect was 0.049 (95% CI: 0.012, 0.086), with an NNH of 20 (95% CI: 12, 83). By contrast, the rate of dropouts due to adverse events in 39 trials reporting available data showed no differences for both effects. In addition, nearly 70% of the trials reported zero dropouts in the sham and no-treatment groups. CONCLUSION: Our findings suggest that (1) the nocebo effect of acupuncture is clinically meaningful and (2) the rate of patients with any adverse event may be a more appropriate indicator of the nocebo effect.

Eligibility criteria in knee osteoarthritis clinical trials: systematic review.

There is an increasing concern over generalizability of trial results. We investigated eligibility criteria of knee osteoarthritis clinical trials. Eligible trials were randomized, placebo-controlled trials that were identified by searches in MEDLINE, SCOPUS, and the Cochrane Central Register of Controlled Trials. We then attempted to extract data on the eligibility criteria by employing predetermined criteria. From 355 randomized knee osteoarthritis trials, we reviewed data categorized by non-osteoarthritis-related and osteoarthritis-related factors. A variety of items were used in the eligibility criteria. Regarding the non-osteoarthritis-related factors, ethical considerations, such as inability to give an informed consent (79.4 %) or medical conditions potential for risks by test treatments (56.0 %) or by participation in a trial (57.2 %), were the common reasons for excluding patients from a trial. Concerning the osteoarthritis-related factors, most of the trials did not specify age and symptom severity. When trials specifying these items were investigated, patients with 40 to 80 years in age and grade 2 in the Kellgren-Lawrence scale were mostly included into a trial. For the pain intensity, patients with ≥20-40 in the 100-mm visual analog scale and ≥6-8 in the WOMAC pain subscale were commonly enrolled into a trial. These findings warrant further investigation on the generalizability of trial results.

Barriers to participant retention in knee osteoarthritis clinical trials: a systematic review.

OBJECTIVE: We investigated the reasons and rates of attrition in knee osteoarthritis trials through a systematic review of randomized, placebo-controlled, clinical trials. METHODS: Randomized trials were identified by searches conducted in MEDLINE, SCOPUS, and the Cochrane Central Register of Controlled Trials. We then attempted to identify and describe the reasons for attrition and their associated themes. For each theme, we calculated the rate of patients who discontinued a trial from the total number of dropouts in each trial. The rates obtained with different trials were combined using a random effects model. We also performed a random effects meta-regression analysis to identify sources associated with the rates. RESULTS: Overall, 259 studies consisting of 266 trials and 13,593 patients were included in the analysis. From these, we short-listed 54 attrition reasons and identified 21 key themes. "Ineffectiveness" and "adverse event" were the reasons frequently reported by >5% of the dropouts. On further investigation of the theme ineffectiveness, the attrition rate was associated with delivery routes of treatment, trial duration, flare design, prohibition of usual analgesics, and allowing the use of escape medication. In cases of adverse events, we found that the treatment type and delivery route affected the attrition rate. CONCLUSIONS: Our findings not only support the importance of the intention-to-treat analysis, but also suggest the possibility of controlling the attrition at the study level.

Effects of pulsed electromagnetic field on knee osteoarthritis: a systematic review.

OBJECTIVE: Many reviews have been previously published on the efficacy of pulsed electromagnetic field (PEMF) in the management of knee OA. However, their results regarding pain and function yielded conflicting conclusions. Therefore this study was conducted to determine the efficacy of PEMF as compared with a placebo. METHODS: We reviewed randomized, placebo-controlled trials using electronic databases. We also manually reviewed sources to identify additional relevant studies. RESULTS: Fourteen trials were analysed, comprising 482 patients in the treatment group and 448 patients in the placebo group. When the efficacy of PEMF in treating pain was investigated, no significant effects were observed at any of the time points considered. However, when trials employing high-quality methodology were analysed, PEMF was significantly more effective at 4 and 8 weeks than the placebo. When the efficacy of PEMF was evaluated for function, a significant improvement was observed 8 weeks after the treatment initiation, with a standardized mean difference of 0.30 (95% CI 0.07, 0.53). No significant association was found between the use of PEMF and the occurrence of adverse events, as indicated by a relative risk of 1.47 (95% CI 0.67, 3.20). However, three (21.4%) trials applied electromagnetic field intensity over the levels recommended by the International Commission on Non-Ionizing Radiation Protection. CONCLUSION: The present study provided suggestive evidence supporting PEMF efficacy in the management of knee OA. Our results further raise the need for more well-controlled trials, employing adequate methodology, to conclusively evaluate the efficacy of PEMF.