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.

Safety and efficacy of degradable vs. permanent polymer drug-eluting stents: a meta-analysis of 18,395 patients from randomized trials.

BACKGROUND: Degradable polymer drug-eluting stents (DP-DES) represent a promising strategy to improve the delayed healing and hypersensitive reaction in the vessel. However, the efficacy and safety of DP-DES vs. permanent polymer drug-eluting stents (PP-DES) are less well defined. The aim of this meta-analysis was to compare the total, short (<30 days), mid (30 days-1 year) and long (>1 year) term outcomes of DP-DES vs. PP-DES METHODS: PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for randomized clinical trials to compare any of approved DP- and PP-DES. Efficacy endpoints were target-lesion revascularization (TLR) and in-stent late loss (ISLL). Safety endpoints were death, myocardial infarction (MI), and composite of definite and probable stent thrombosis (ST). RESULTS: The meta-analysis included 19 RCTs (n=18,395) with interesting results. As compared with DES, there was a significantly reduced very late ST (OR [95% CI]=0.42 [0.24-0.77], p=0.852) and ISLL (OR [95% CI]=-0.07 [-0.12-0.02], p=0.000) in DP-DES patients. However, there were no differences between DP-DES and PP-DES for other safety and efficiency outcomes, except that the stratified analysis showed a significant decreased TLR with DP-DES as compared to paclitaxel-eluting stent (OR [95% CI]=0.41 [0.20-0.81], p=0.457). CONCLUSIONS: DP-DES are more effective in reducing very late ST and ISLL, as well as comparable to PP-DES with regard to death, TLR and MI. Further large RCTs with long-term follow-up are warranted to better define the relative merits of DP-DES.

Safety of medical interventions in children versus adults.

OBJECTIVE: Compare the risk of harm from pharmacologic interventions in pediatric versus adult randomized controlled trials (RCTs). METHODS: We used systematic reviews from the Cochrane Database of Systematic Reviews. We considered separately 7 categories of harms/harm-related end points: severe harms, withdrawals due to harms, any harm, organ system-level harms, specific harms, withdrawals for any reason, and mortality. Systematic reviews with quantitative synthesis from at least 1 adult and 1 pediatric RCT for any of those end points were eligible. We calculated the summary odds ratio (experimental versus control intervention) in adult and pediatric trials/meta-analysis; the relative odds ratio (ROR) in adults versus children per meta-analysis; and the summary ROR (sROR) across all meta-analyses for each end point. ROR <1 means that the experimental intervention fared worse in children than adults. RESULTS: We identified 176 meta-analyses for 52 types of harms/harm-related end points with 669 adult and 184 pediatric RCTs. Of those, 165 had sufficient data for ROR estimation. sRORs showed statistically significant discrepancy between adults and children only for headache (sROR 0.82; 95% confidence interval 0.70-0.96). Nominally significant discrepancies for specific harms were identified in 12 of 165 meta-analyses (RORs <1 in 7, ROR >1 in 5). In 36% of meta-analyses, the ROR estimates suggested twofold or greater differences between children and adults, and the 95% confidence intervals could exclude twofold differences only in 18% of meta-analyses. CONCLUSIONS: Available evidence on harms/harm-related end points from pharmacologic interventions has large uncertainty. Extrapolation of evidence from adults to children may be tenuous. Some clinically important discrepancies were identified.

Quality of reporting in systematic reviews of adverse events: systematic review.

OBJECTIVES: To examine the quality of reporting of harms in systematic reviews, and to determine the need for a reporting guideline specific for reviews of harms. DESIGN: Systematic review. DATA SOURCES: Cochrane Database of Systematic Reviews (CDSR) and Database of Abstracts of Reviews of Effects (DARE). REVIEW METHODS: Databases were searched for systematic reviews having an adverse event as the main outcome, published from January 2008 to April 2011. Adverse events included an adverse reaction, harms, or complications associated with any healthcare intervention. Articles with a primary aim to investigate the complete safety profile of an intervention were also included. We developed a list of 37 items to measure the quality of reporting on harms in each review; data were collected as dichotomous outcomes ("yes" or "no" for each item). RESULTS: Of 4644 reviews identified, 309 were systematic reviews or meta-analyses primarily assessing harms (13 from CDSR; 296 from DARE). Despite a short time interval, the comparison between the years of 2008 and 2010-11 showed no difference on the quality of reporting over time (P=0.079). Titles in fewer than half the reviews (proportion of reviews 0.46 (95% confidence interval 0.40 to 0.52)) did not mention any harm related terms. Almost one third of DARE reviews (0.26 (0.22 to 0.31)) did not clearly define the adverse events reviewed, nor did they specify the study designs selected for inclusion in their methods section. Almost half of reviews (n=170) did not consider patient risk factors or length of follow-up when reviewing harms of an intervention. Of 67 reviews of complications related to surgery or other procedures, only four (0.05 (0.01 to 0.14)) reported professional qualifications of the individuals involved. The overall, unweighted, proportion of reviews with good reporting was 0.56 (0.55 to 0.57); corresponding proportions were 0.55 (0.53 to 0.57) in 2008, 0.55 (0.54 to 0.57) in 2009, and 0.57 (0.55 to 0.58) in 2010-11. CONCLUSION: Systematic reviews compound the poor reporting of harms data in primary studies by failing to report on harms or doing so inadequately. Improving reporting of adverse events in systematic reviews is an important step towards a balanced assessment of an intervention.

Meta-analysis of randomized controlled trials on the efficacy and safety of intracoronary administration of tirofiban for no-reflow phenomenon.

BACKGROUND: Currently, there is still a lack of an optimal treatment for no-reflow phenomenon (NR). The aim of this simple meta-analysis was to evaluate the efficacy and safety of intracoronary (IC) administration of tirofiban compared with other conventional drugs during percutaneous coronary intervention (PCI) for NR. METHODS: Systematic literature search was done from PubMed, EMBASE, Google Scholar, EBSCO, Springer and CNKI databases without language or time limitation. Randomized controlled trials were enrolled for analyzing if they investigated the treatment of IC administration of tirofiban versus other conventional drugs for NR. RESULTS: Ten studies with 702 patients were included. Significantly, the treatment of tirofiban was more effective in improving the thrombolysis in myocardial infarction (TIMI) flow (OR 0.24, 95% CI 0.15-0.37, P < 0.00001) and reducing major adverse cardiovascular events (MACE) (OR 0.09, 95% CI 0.05-0.18, P < 0.00001). There was a trend to increase the risk of bleeding, but the data of the result did not reach the statistical significance (OR 1.44, 95% CI 0.69-3.00, P = 0.32). CONCLUSIONS: Tirofiban is more effective than conventional drugs for NR during PCI, but the potential risk of bleeding complication induced by tirofiban shouldn't be ignored during clinical practices.

Reporting adverse events in randomized controlled trials in periodontology: a systematic review.

BACKGROUND/AIMS: Reporting of adverse events is of paramount importance in randomized controlled trials (RCTs) to guide the implementation of new therapeutic approaches in clinical practice. The aim of this study was to assess the quality of adverse events reporting in RCTs published in the periodontal literature. MATERIALS AND METHODS: Two authors (CMF and NNG) searched the PubMed and LILACS electronic databases independently and in duplicate to identify RCTs published in periodontology from 2002 to 2003 and from 2011 to 2012. Reporting quality in RCTs was assessed with reference to the 2004 CONSORT Extension for Harms checklist. Differences in adverse events reporting between industry- and non-industry-funded RCTs were also determined. Cohen's kappa statistic was used to determine the extent of inter-reviewer agreement. Fischer's exact test was used to assess differences in reporting between the two samples. RESULTS: The analysis included 246 publications. One hundred twenty-four of 990 (13%) items and 223 of 1460 (15%) items were adequately reported in publications from 2002 to 2003 and from 2011 to 2012 respectively. Three checklist topics were significantly better reported in the 2011-2012 sample; two recommendations were better reported in non-industry-funded trials in publications from both periods. CONCLUSION: Improvement and standardization of adverse events reporting in periodontology are needed.

B cell elimination in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disorder with a worldwide distribution, potentially life-threatening with considerable morbidity. The elimination of pathogenic B cells has emerged as a rational therapeutic option. Many open label studies have reported encouraging results in which clinical and serological remission have invariably been described, often enabling the reduction of steroid and immunosuppressive treatment. However, the results from randomized controlled studies have been disappointing and several questions remain to be answered. In this review we will focus on results of B cell direct depletion in the treatment of patients with systemic lupus erythematosus.

Testing a noninferiority hypothesis: what to anticipate when the adverse event is rare.

While randomized controlled trials may not be considered efficient for investigating rare adverse events based on their size, biases associated with other epidemiological designs may justify the additional resources. In certain contexts it may be appropriate, for example, to inflate the noninferiority (NI) margin to decrease the sample size, provided the excess risk that will be ruled out remains clinically relevant. The implication of a reduced sample size on the number of events anticipated from the trial is often not considered at the study design phase but may have important ramifications. To assess the implications of modifying study design parameters, approximations are presented for (a) how likely it is that no events will be observed, (b) how many events should be anticipated, and (c) how likely it is that v or more events will be observed. The approximations presented are intended to serve as tangible a priori expectations from the study. This work is motivated from an FDA Advisory Committee meeting regarding a discussion at the association between long-acting beta-agonists and asthma-related deaths.

Medical records-based postmarketing safety evaluation of rare events with uncertain status.

We develop a simple statistic for comparing rates of rare adverse events between treatment groups in postmarketing safety studies where the events have uncertain status. In this setting, the statistic is asymptotically equivalent to the logrank statistic, but the limiting distribution has Poisson and binomial components instead of being Gaussian. We develop two new procedures for computing critical values, a Gaussian approximation and a parametric bootstrap. Both numerical and asymptotic properties of the procedures are studied. The test procedures are demonstrated on a postmarketing safety study of the RotaTeq vaccine. This vaccine was developed to reduce the incidence of severe diarrhea in infants.

A Bayesian group sequential approach to safety signal detection.

Clinical safety data, usually reported as clinically manifested adverse events (AEs) according to the Medical Dictionary for Regulatory Activities (MedDRA), are routinely collected during the course of a clinical trial involving comparative groups, and periodical monitoring of the safety events is often required to determine whether excessive occurrence of a set of AEs is associated with treatment. To accommodate the structure of reported AEs with the MedDRA system, a Bayesian hierarchical model has been proposed for the analysis of clinical safety data. However, the characteristics of sequential use of the Bayesian method has not been studied. In this paper the Bayesian hierarchical model is applied in a group sequential manner for multiple interim analyses of safety events. A decision-theoretic approach is employed to determine threshold values in the safety signaling process. The proposed approach is illustrated through simulations and a real example.

Efficacy and safety of zotarolimus-eluting stents compared with sirolimus-eluting stents in patients undergoing percutaneous coronary interventions--a meta-analysis of randomized controlled trials.

BACKGROUND: Whether ZES can further improve angiographic and clinical outcomes compared to SES still remains uncertain. OBJECTIVES: The aim of this study was to assess the efficacy and safety of zotarolimus-eluting stents (ZES) compared with sirolimus-eluting stents (SES) in patients undergoing percutaneous coronary interventions (PCI). METHODS: Major electronic information sources were explored for randomized controlled trials comparing ZES with SES among patients undergoing PCI during at least 9 months follow-up. The primary efficacy outcomes were target lesion revascularization (TLR), target vessel revascularization (TVR), and major adverse cardiac events (MACE); safety outcomes were stent thrombosis (ST), myocardial infarction (MI), and cardiac death. RESULTS: Seven comparative studies were identified (a total of 5983 patients). When compared with ZES at 12-month follow-up, SES significantly reduced risk of MACE (relative risk [RR]: 0.74, 95% confidence interval [CI]: 0.61 to 0.89, p=0.002), and TLR (RR:0.39; 95% CI: 0.29 to 0.52; p<0.00001), without significant differences in terms of TVR (RR:0.68, 95% CI: 0.38 to 1.20; p=0.18), ST (RR:0.71; 95% CI: 0.39 to 1.31; p=0.28), cardiac death (RR:0.83; 95% CI: 0.49-1.42, p=0.50) or MI (RR:1.08; 95%CI: 0.80 to 1.45; p=0.62). CONCLUSIONS: At 12-month follow-up, SES are superior to ZES in reducing the incidences of TLR and MACE in patients undergoing PCI, without significant differences in terms of TVR, ST, cardiac death, and MI.

Comparison of the safety between first- and second-generation drug eluting stents: meta-analysis from 19 randomized trials and 16,924 patients.

BACKGROUND/OBJECTIVE: Despite the effectiveness of first generation drug eluting stent, DES-1 (Taxus and Cypher) in avoiding restenosis and the need for new revascularizations, a slightly increase in stent thrombosis, ST have been published. Second generation drug eluting stent, DES-2 has been developed to optimize the results of percutaneous coronary intervention in terms of efficacy and safety, for avoiding early and late ST. Our objective was to compare the risk of ST between DES-1 and DES-2. METHODS: We performed a meta-analysis of 19 randomized trials. Overall 16,924 patients; 7294 were allocated to DES-1 and 9630 were allocated to DES-2. The primary endpoint was to compare the risk of overall ST during the first year. Other clinical outcomes of interest were to compare the incidence of early (<1 month) and late ST (>1 month-<1 year). RESULTS: The incidence of overall ST was not increased in patients receiving DES-1 (1.13% DES-1 vs 0.75% DES-2, OR 0.79, 95% CI:0.45-1.40, p 0.43). There were no significant differences in the incidence of; early ST (0.85% DES-1 vs 0.53% DES-2, OR 0.68, 95% CI:0.31-1.51, p 0.35) and late ST (0.40% DES-1 vs 0.25% DES-2, OR 0.69, 95% CI:0.39-1.24, p 0.22). CONCLUSIONS: During the first year after stent implantation, we didn't found differences in ST between DES-1 and DES-2. Most of ST was produced under appropriate anti-platelet therapy so it is possible that many other factors such as; clopidogrel resistance, procedural complications or stent malapposition were implicated. Safety after longer follow-up (>1 year) remains unclear.

Managing the underestimated risk of statin-associated myopathy.

In clinical practice 5-10% of patients receiving statins develop myopathy, a side effect that had been systematically underestimated in the randomized controlled trials with statins. The most common manifestation of myopathy is muscle pain (usually symmetrical, involving proximal muscles) without creatinine kinase (CK) elevation or less frequently with mild CK elevation. Clinically significant rhabdomyolysis (muscle symptoms with CK elevation >10 times the upper limit of normal and with creatinine elevation) is extremely rare. Myopathy complicates the use of all statins (class effect) and is dose-dependent. The pathophysiologic mechanism of statin-associated myopathy is unknown and probably multifactorial. The risk of statin-associated myopathy can be minimized by identifying vulnerable patients (i.e. patients with impaired renal or liver function, advanced age, hypothyroidism, etc.) and/or by eliminating-avoiding statin interactions with specific drugs (cytochrome P-450 3A4 inhibitors, gemfibrozil, etc.). In symptomatic patients, the severity of symptoms, the magnitude of CK elevation and the risk/benefit ratio of statin continuation should be considered before statin treatment is discontinued. Potential strategies are the use of the same statin at a lower dose and if symptoms recur the initiation of fluvastatin XL 80 mg daily or rosuvastatin intermittently in low dose (5-10mg), combined usually with ezetimibe 10mg daily. Failure of these approaches necessitates the use of non-statin lipid lowering drugs (ezetimibe, colesevelam). In order to provide evidence based recommendations for the appropriate management of statin-intolerant patients we need randomized clinical trials directly comparing the myopathic potential of different lipid-lowering medications at comparable doses.