Parallel-group Randomized Clinical Trials Research Articles

Eligibility Criteria of Randomized Clinical Trials in Critical Care Medicine

Eligibility criteria for randomized clinical trials (RCTs) are designed to select clinically relevant patient populations. However, not all eligibility criteria are strongly justified, potentially excluding marginalized groups, and limiting the generalizability of trial findings. To summarize and evaluate the justification of exclusion criteria in published RCTs in critical care medicine. A systematic sampling review of parallel-group RCTs published in the top 5 general internal medicine journals by impact factor (The Lancet, New England Journal of Medicine, Journal of the American Medical Association, British Medical Journal, and Annals of Internal Medicine) between January 1, 2018, and February 23, 2023, was conducted. RCTs enrolling adults in intensive care units (ICUs) and RCTs enrolling critically ill patients who required life-sustaining interventions typically initiated in the ICU were included. All study exclusion criteria were categorized as either poorly justified, potentially justified, or strongly justified, adapting previously established criteria, independently and in duplicate. In total, 225 studies were identified, 75 of which were included. The median (IQR) number of exclusion criteria per trial was 19 (14-24), with 1455 total exclusion criteria. Common exclusion criteria were related to the risk of adverse reaction to interventions (302 criteria [20.8%]), followed by inability to obtain consent (120 criteria [8.2%]), and treatment limitation decisions (97 criteria [6.7%]). Most exclusion criteria were either strongly justified (1080 criteria [74.2%]) or potentially justified (297 criteria [20.4%]), whereas 5.4% (78 criteria) were poorly justified. Of the 78 poorly justified exclusion criteria, the most common were pregnancy (19 criteria [24.4%]), communication barriers (11 criteria [14.1%]), lactation (10 criteria [12.8%]), and lack of health insurance (10 criteria [12.8%]). Overall, 45 of 75 studies (60.0%) had at least 1 poorly justified exclusion criteria. Most exclusion criteria in critical care medicine RCTs were strongly justifiable. Across poorly justified criteria, the most common exclusions were pregnant or lactating persons, those with communication barriers, and individuals without health insurance. This highlights the need to carefully consider exclusion criteria when designing trials to minimize the inappropriate exclusion of participants and enhance generalizability.

Outcomes in Randomized Clinical Trials Testing Changes in Daily Water Intake

Several public recommendations exist regarding the amount of daily water intake, yet the supporting evidence is not clear, and benefits of increasing water consumption are not well-established. To summarize evidence from randomized clinical trials (RCTs) pertaining to the health-related outcomes associated with increased or decreased daily water consumption. A systematic search of PubMed, Web of Science, and Embase was performed up to April 6, 2023. Studies were included if they aimed to assess the impact of daily water consumption by any defined amount on any health-related outcome. Of 1464 records screened, 18 (1%) eligible studies were included in the review. Among eligible studies, 15 (83%) were parallel group RCTs, and 3 (16%) were crossover studies. Interventions in these studies consisted of a recommendation to alter the daily amount of water intake by a specific amount for a predefined period ranging between 4 days and 5 years, while the control groups were mostly asked to maintain their usual intake habits. The studies assessed various populations. Recurring primary end points included weight loss, fasting blood glucose level, headache, urinary tract infection, and nephrolithiasis. Consuming additional water was associated with greater weight loss (range, 44%-100% more than control conditions) and fewer nephrolithiasis events (15 fewer events per 100 participants over 5 years). Single studies suggested benefits related to migraine prevention, urinary tract infection, diabetes control, and hypotension. Ten studies (55%) reported at least 1 positive result, and 8 studies (44%) reported negative results. This systematic review found that there is a limited number of clinical trials in the literature assessing the benefits of increasing water intake related to a large variety of health outcomes. While the quality and quantity of evidence is limited, a small number of studies suggested benefits of water intake on weight loss and nephrolithiasis, while single studies raised the possibility of benefits for patients with migraine, urinary tract infection, diabetes, and hypotension. Given the low cost and low adverse-effect profile of water, further well-designed studies should assess benefits in these specific conditions.

Atrial Fibrillation Ablation in Heart Failure With Reduced vs Preserved Ejection Fraction

Catheter ablation is associated with reduced heart failure (HF) hospitalization and death in select patients with atrial fibrillation (AF) and heart failure with reduced ejection fraction (HFrEF). However, the benefit in patients with HF with preserved ejection fraction (HFpEF) is uncertain. To investigate whether catheter ablation for AF is associated with reduced HF-related outcomes according to HF phenotype. A systematic search of MEDLINE, Embase, and Cochrane Central was conducted among studies published from inception to September 2023. Parallel-group randomized clinical trials (RCTs) comparing catheter ablation with conventional rate or rhythm control therapies in patients with HF, New York Heart Association functional class II or greater, and a history of paroxysmal or persistent AF were included. Pairs of independent reviewers screened 7531 titles and abstracts, of which 12 RCTs and 4 substudies met selection criteria. Data were abstracted in duplicate according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Pooled effect estimates were calculated using random-effects Mantel-Haenszel models. Interaction P values were used to test for subgroup differences. The primary outcome was HF events, defined as HF hospitalization, clinically significant worsening of HF, or unscheduled visits to a clinician for treatment intensification. Secondary outcomes included cardiovascular and all-cause mortality. A total of 12 RCTs with 2465 participants (mean [SD] age, 65.3 [9.7] years; 658 females [26.7%]) were included; there were 1552 participants with HFrEF and 913 participants with HFpEF. Compared with conventional rate or rhythm control, catheter ablation was associated with reduced risk of HF events in HFrEF (risk ratio [RR], 0.59; 95% CI, 0.48-0.72), while there was no benefit in patients with HFpEF (RR, 0.93; 95% CI, 0.65-1.32) (P for interaction = .03). Catheter ablation was associated with reduced risk of cardiovascular death compared with conventional therapies in HFrEF (RR, 0.49; 95% CI, 0.34-0.70) but a differential association was not detected in HFpEF (RR, 0.91; 95% CI, 0.46-1.79) (P for interaction = .12). Similarly, no difference in the association of catheter ablation with all-cause mortality was found between HFrEF (RR vs conventional therapies, 0.63; 95% CI, 0.47-0.86) and HFpEF (RR vs conventional therapies, 0.95; 95% CI, 0.39-2.30) groups (P for interaction = .39). This study found that catheter ablation for AF was associated with reduced risk of HF events in patients with HFrEF but had limited or no benefit in HFpEF. Results from ongoing trials may further elucidate the role of catheter ablation for AF in HFpEF.

Mind games in dentistry: confounded evidence suggests a substantial nocebo response in dental impaction pain model.

A systematic review and metaanalysis of randomized clinical trials (RCTs). Electronic search was conducted in PubMed, Embase, Scopus, Web of Science and the Cochrane Central Register of Controlled Trials (CENTRAL), on 22 May 2021. Eligibility criteria included parallel-group placebo-controlled RCTs assessing analgesics after third molar (M3) surgery in healthy patients, reporting the number of patients with at least one drug-related adverse event (AE), and being published in English. Two reviewers independently screened all identified articles against the eligibility criteria, and performed quality assessment and data extraction. Any disagreements were resolved by discussion involving a third reviewer. The primary outcome was the pooled rate of drug-related AEs in placebo and active arms of RCTs assessing analgesic treatment following M3 surgery. Secondary outcome was the drug-related dropout rates in the same setting. A total of 50 RCTs in 47 articles were included in the analyses. The pooled rates of patients with AE ≥ 1 in the placebo and active arms were 22.8% and 20.6%, respectively. The pooled drug-related dropout rates in the placebo and active arms were 0.24% and 0.08%, respectively. There were no significant risk differences in patients with AE ≥ 1 and drug-related dropouts (p = 0.61 and p = 0.94; respectively). High statistical heterogeneity was found for the proportion of patients with AE ≥ 1 (I2 = 79.7%, p < 0.001), but not for drug-related dropout rates (I2 = 0%, p = 1.00). Patients in the placebo arm reported AEs at a similar frequency as patients receiving active treatment, suggesting that most analgesic-related AEs after M3 surgery may be attributed to the nocebo phenomenon.

Single-session, Preoperative Mindfulness-based Interventions for Total Joint Arthroplasty Patients: Pre- and Postoperative Outcomes from Three Randomized Clinical Trials

These three studies examined whether a brief, preoperative mindfulness-based intervention (MBI) could improve pre- and postoperative TJA outcomes. We conducted three, single-site, three-arm, parallel-group randomized clinical trials at an orthopedic clinic among patients undergoing TJA of the hip or knee. Study 1 (N=285) compared the effects of preoperative mindfulness meditation, hypnotic suggestion, and cognitive-behavioral pain psychoeducation interventions – each delivered in a single, 15-minute group session – on preoperative pain and postoperative physical function. Study 2 (N=118) compared the effects of two different styles of preoperative mindfulness meditation – mindfulness of breath and mindfulness of pain – and cognitive-behavioral pain psychoeducation delivered in a single, 20-minute group session on preoperative pain and postoperative pain and opioid use in the month following surgery. Study 3 (N=127) compared the effects of ultra-brief (i.e., 3-minute), nurse-led, mindfulness of breath and mindfulness of pain interventions on preoperative pain and postoperative physical function relative to a standard nurse consultation. In study 1, the preoperative MBI significantly decreased preoperative pain intensity (p=.006), pain unpleasantness (p=.008), pain medication desire (p=.028) and anxiety (p<.001) while increasing postoperative physical function at 6-week follow-up (p=.010). In study 2, mindfulness of breath was found to most effectively decrease preoperative pain (p=.007), while mindfulness of pain resulted in the least amount of postoperative pain intensity (p=.003) and interference (p=.016). Both mindfulness of breath and mindfulness of pain decreased postoperative opioid use (p<.001). In study 3, mindfulness of breath and mindfulness of pain decreased preoperative pain intensity (p=.022) and unpleasantness (p<.001), and mindfulness of pain also decreased preoperative pain medication desire (p<.001). MBI related changes in preoperative pain unpleasantness predicted better postoperative physical function (p<.001). Embedding brief MBIs in surgical care pathways may be a scalable method of improving patient outcomes.

Misleading Reporting (Spin) in Noninferiority Randomized Clinical Trials in Oncology With Statistically Not Significant Results

Spin, the inaccurate reporting of randomized clinical trials (RCTs) with results that are not statistically significant for the primary end point, distorts interpretation of results and leads to misinterpretation. However, the prevalence of spin and related factors in noninferiority cancer RCTs remains unclear. To examine misleading reporting, or spin, and the associated factors in noninferiority cancer RCTs through a systematic review. A systematic search of the PubMed database was performed for articles published between January 1, 2010, and December 31, 2019, using the Cochrane Highly Sensitive Search Strategy. Two investigators independently selected studies using the inclusion criteria of noninferiority parallel-group RCTs aiming to confirm effects to cancer treatments published between January 1, 2010, and December 31, 2019, reporting results that were not statistically significant for the primary end points. Standardized data abstraction was used to extract information concerning the trial characteristics and spin based on a prespecified definition. The main investigator extracted the trial characteristics while both readers independently evaluated the spin. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. The main outcome was spin prevalence in any section of the report. Spin was defined as use of specific reporting strategies, from whatever motive, to highlight that the experimental treatment is beneficial, despite no statistically significant difference for the primary outcome, or to distract the reader from results that are not statistically significant. The associations (prevalence difference and odds ratios [ORs]) between spin and trial characteristics were also evaluated. The analysis included 52 of 2752 reports identified in the PubMed search. Spin was identified in 39 reports (75.0%; 95% CI, 61.6%-84.9%), including the abstract (34 reports [65.4%; 95% CI, 51.1%-76.9%]) and the main text (38 reports [73.1%; 95% CI, 59.7%-83.3%]). Univariate analysis found that the spin prevalence was higher in reports with data managers (prevalence difference, 27%; 95% CI, 1.1%-50.3%), reports without funding from for-profit sources (prevalence difference, 31.2%; 95% CI, 4.8%-53.8%), and reports of novel experimental treatments (prevalence difference, 37.5%; 95% CI, 5.8%-64.7%). Multivariable analysis found that novel experimental treatment (OR, 4.64; 95% CI, 0.98-22.02) and funding only from nonprofit sources only (OR, 5.20; 95% CI, 1.21-22.29) were associated with spin. In this systematic review, most noninferiority RCTs reporting results that were not statistically significant for the primary end points showed distorted interpretation and inaccurate reporting. The novelty of an experimental treatment and funding only from nonprofit sources were associated with spin.

Contribution of Relapse-Independent Progression vs Relapse-Associated Worsening to Overall Confirmed Disability Accumulation in Typical Relapsing Multiple Sclerosis in a Pooled Analysis of 2 Randomized Clinical Trials

Accumulation of disability in multiple sclerosis may occur as relapse-associated worsening (RAW) or steady progression independent of relapse activity (PIRA), with PIRA regarded as a feature of primary and secondary progressive multiple sclerosis. To investigate the contributions of relapse-associated worsening vs relapse-independent progression to overall confirmed disability accumulation (CDA) and assess respective baseline prognostic factors and outcomes of 2 treatments. Analyses occurred from July 2015 to February 2020 on pooled data from the intention-to-treat population of 2 identical, phase 3, multicenter, double-blind, double-dummy, parallel-group randomized clinical trials (OPERA I and II) conducted between August 2011 and April 2015. In the trials, patients with relapsing multiple sclerosis (RMS), diagnosed using the 2010 revised McDonald criteria, were randomized from 307 trial sites in 56 countries; resulting data were analyzed in the pooled data set. Participants were randomized 1:1 to receive 600 mg of ocrelizumab by intravenous infusion every 24 weeks or subcutaneous interferon β-1a 3 times a week at a dose of 44 μg throughout a 96-week treatment period. Confirmed disability accumulation was defined by an increase in 1 or more of 3 measures (Expanded Disability Status Scale, timed 25-ft walk, or 9-hole peg test), confirmed after 3 or 6 months, and classified per temporal association with confirmed clinical relapses (PIRA or RAW). In the pooled OPERA I and II population (1656 of 2096 eligible participants), baseline demographics and disease characteristics were similar for patients randomized to interferon β-1a vs ocrelizumab (mean [SD] age, 37.2 [9.2] vs 37.1 [9.2] years; 552 [66.6%] vs 541 women [65.4%]). After 96 weeks, 12-week composite CDA had occurred in 223 (29.6% by Kaplan-Meier estimate) randomized to interferon β-1a and 167 (21.1%) randomized to ocrelizumab; 24-week composite CDA had occurred in 170 (22.7%) taking interferon β-1a and 129 (16.2%) taking ocrelizumab. The PIRA events were the main contributors to 12-week and 24-week composite CDA after 96 weeks in patients treated with interferon β-1a (174 of 223 [78.0%] and 137 of 170 [80.6%], respectively) and ocrelizumab (147 of 167 [88.0%] and 115 of 129 [89.1%], respectively); a minority had CDA explained by RAW events (69 of 390 [17.7%] and 52 of 299 [17.4%], respectively). Very few patients with composite CDA experienced both RAW and PIRA events (17 of 390 [4.4%] for 12-week and 15 of 299 [5.0%] for 24-week composite CDA). Ocrelizumab (vs interferon β-1a) was associated with reduced risk of composite CDA (hazard ratio [HR], 0.67) and confirmed PIRA (HR, 0.78) and RAW (HR, 0.47) events. Most disability accumulation in RMS is not associated with overt relapses. This indicates an underlying progression in this typical RMS population and challenges the current clinical distinction of relapsing and progressive forms of multiple sclerosis. Ocrelizumab was superior to interferon β-1a in preventing both RAW and PIRA. ClinicalTrials.gov Identifiers: OPERA I (NCT01247324) and OPERA II (NCT01412333).

N-of-1 Trials as a Decision Support Tool in Clinical Practice: A Protocol for a Systematic Literature Review and Narrative Synthesis.

The n-of-1 trial can utilized in clinical practice as a decision support tool, which may improve patient outcomes by providing both the patient and the clinician with objective evidence to inform personalized treatment decisions. As its use broadens, it will be important to study whether the added time and effort of an n-of-1 trial results in measurable improvements in important patient outcomes compared to usual clinical practice. Parallel-group randomized clinical trials testing the n-of-1 approach versus usual care have been undertaken in a number of medical settings. A systematic review will be performed according to PRISMA guidelines, using MEDLINE, Embase, Cochrane, CINAHL, PsycINFO, Scopus, and Web of Science to search for randomized clinical trials in humans, without date or language restriction. Reports from the gray literature and ongoing studies in trial registries will be included. Articles will be screened by two independent reviewers with a third reviewer consulted to adjudicate disagreement. The quality of included studies will be assessed using the Cochrane Collaboration’s tool for assessing risk of bias. A narrative synthesis will explore the differing methodological approaches of the included studies. The protocol will be registered in the PROSPERO registry, and the results of the review will be published in a peer-reviewed journal. To our knowledge, this systematic review will be the first to comprehensively assess the existing research on randomized trials testing the n-of-1 trial approach in clinical practice.

Effectiveness of different debonding techniques and adjunctive methods on pain and discomfort perception during debonding fixed orthodontic appliances: a systematic review.

Pain is an unpleasant side-effect that can be experienced during orthodontic procedures including debonding of fixed appliances. Pain experience can vary depending on the appliance, debonding technique, as well as adjunctive measures used. The primary objective of this systematic review was to assess the effectiveness of different debonding techniques and adjunctive methods on pain/discomfort perception during debonding procedure (PDP) of fixed orthodontic appliances. The secondary objective was to assess the effects of anatomic location and gender on PDP of fixed orthodontic appliances. Multiple electronic databases were searched from inception to August 2018. Reference lists of the included articles were manually screened. Randomized clinical trials (RCTs) and controlled clinical trials were included. Study selection, data extraction, and risk of bias assessment were performed independently by two reviewers according to Cochrane guidelines, with disputes resolved by a third reviewer. Clinical heterogeneity in study design and methodology prevented quantitative synthesis of the data. The search yielded 198 articles after the removal of duplicates. Seven studies were included in the final review with a total of 307 participants aged 12-60 years. Of the four studies comparing different debonding instruments of labial fixed appliances, two studies showed that the lift-off debonding instrument (LODI) produced lower PDP levels than ligature cutting pliers. Three studies compared adjunctive measures to reduce PDP of labial fixed appliances. Finger pressure and bite wafers significantly reduced PDP levels. Analgesics administration (ibuprofen + paracetamol tablets) 1 hour prior to debonding also reduced PDP. PDP was significantly higher in anterior segments and in females. The authors acknowledge that there was clinical heterogeneity among the included studies and that the potential effect of diurnal variation on pain during debonding was not considered in any of the included trials. There is weak evidence indicating that using the LODI may reduce PDP of labial fixed appliances. Adjunctive measures such as an intrusive force with finger pressure, bite wafers, and preoperative analgesia may further aid PDP control. Further well-designed parallel-group RCTs taking into consideration the diurnal variation in pain are required. PROSPERO (CRD42017084474). None. The authors declare that there is no conflict of interest.

Permissive versus restrictive temperature thresholds in critically ill children with fever and infection: a multicentre randomized clinical pilot trial

BackgroundFever improves pathogen control at a significant metabolic cost. No randomized clinical trials (RCT) have compared fever treatment thresholds in critically ill children. We performed a pilot RCT to determine whether a definitive trial of a permissive approach to fever in comparison to current restrictive practice is feasible in critically ill children with suspected infection.MethodsAn open, parallel-group pilot RCT with embedded mixed methods perspectives study in four UK paediatric intensive care units (PICUs) and associated retrieval services.Participants were emergency PICU admissions aged > 28 days to < 16 years receiving respiratory support and supplemental oxygen.Subjects were randomly assigned to permissive (antipyretic interventions only at ≥ 39.5 °C) or restrictive groups (antipyretic interventions at ≥ 37.5 °C) whilst on respiratory support. Parents were invited to complete a questionnaire or take part in an interview. Focus groups were conducted with staff at each unit. Outcomes were measures of feasibility: recruitment rate, protocol adherence and acceptability, between group separation of temperature and safety.ResultsOne hundred thirty-eight children met eligibility criteria of whom 100 (72%) were randomized (11.1 patients per month per site) without prior consent (RWPC). Consent to continue in the trial was obtained in 87 cases (87%). The mean maximum temperature (95% confidence interval) over the first 48 h was 38.4 °C (38.2–38.6) in the restrictive group and 38.8 °C (38.6–39.1) in the permissive group, a mean difference of 0.5 °C (0.2–0.8). Protocol deviations were observed in 6.8% (99/1438) of 6-h time periods and largely related to patient comfort in the recovery phase. Length of stay, duration of organ support and mortality were similar between groups. No pre-specified serious adverse events occurred. Staff (n = 48) and parents (n = 60) were supportive of the trial, including RWPC. Suggestions were made to only include invasively ventilated children for the duration of intubation.ConclusionUncertainty around the optimal fever threshold for antipyretic intervention is relevant to many emergency PICU admissions. A more permissive approach was associated with a modest increase in mean maximum temperature. A definitive trial should focus on the most seriously ill cases in whom antipyretics are rarely used for their analgesic effects alone.Trial registrationISRCTN16022198. Registered on 14 August 2017.

Transcranial direct current stimulation (tDCS) effects on traumatic brain injury (TBI) recovery: A systematic review.

ABSTRACT.Traumatic brain injury (TBI) is a major cause of chronic disability. Less than a quarter of moderate and severe TBI patients improved in their cognition within 5 years. Non-invasive brain stimulation, including transcranial direct current stimulation (tDCS), may help neurorehabilitation by boosting adaptive neuroplasticity and reducing pathological sequelae following TBI.Methods:we searched MEDLINE/PubMed and Web of Science databases. We used Jadad scale to assess methodological assumptions.Results:the 14 papers included reported different study designs; 2 studies were open-label, 9 were crossover randomized clinical trials (RCTs), and 3 were parallel group RCTs. Most studies used anodal tDCS of the left dorsolateral prefrontal cortex, but montages and stimulation parameters varied. Multiple studies showed improved coma recovery scales in disorders of consciousness, and improved cognition on neuropsychological assessments. Some studies showed changes in neurophysiologic measures (electroencephalography (EEG) and transcranial magnetic stimulation (TMS), correlating with clinical findings. The main methodological biases were lack of blinding and randomization reports.Conclusion:tDCS is a safe, non-invasive neuromodulatory technique that can be given as monotherapy but may be best combined with other therapeutic strategies (such as cognitive rehabilitation and physical therapy) to further improve clinical cognitive and motor outcomes. EEG and TMS may help guide research due to their roles as biomarkers for neuroplasticity.

Systematic review and meta-analysis of sutures coated with triclosan for the prevention of surgical site infection after elective colorectal surgery according to the PRISMA statement.

Background:Several randomized clinical trials (RCTs) conducted to evaluate the effect of triclosan-coated suture on surgical site infection (SSI) yield to controversial results. The primary purpose of this systematic review and meta-analysis was to analyze the available RCTs, comparing the effect of triclosan-coated suture with uncoated suture on the incidence of SSI after elective colorectal operations. As secondary endpoint of the analysis, we considered length of hospital stay after surgery.Methods:We performed a systematic literature review through Medline, Embase, Pubmed, Scopus, Ovid, ISI Web of Science, and the Cochrane Controlled Trials Register searching for RCTs published from 1990 to 2015. To conduct these meta-analyses, we followed the guidelines and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Study inclusion criteria were as follows: parallel-group RCTs in adult populations reporting the closure of the abdominal wall after elective colorectal operation with triclosan-coated suture or noncoated suture, and reporting the outcomes considered in the meta-analysis.Results:Six trials including 2168 patients (1102 treated and 1066 controls) provided data on SSIs. The overall rate was 11.7% (129/1102) in the triclosan group and 13.4% (143/1066) in the control group (odds ratio 0.81, 95% confidence interval [CI] 0.58–1.13, P = 0.220). Heterogeneity among studies was moderate (I2 = 44.9%). No evidence of publication bias was detectable. Five RCTs (1783 patients; 914 treated and 689 controls) described hospital length of stay with no significant effect (mean difference: −0.02, 95% CI −0.11 to −0.07, P = 0.668). The I2 test for heterogeneity was 0% (P = 0.836). Moderator analyses showed no significant differences were detected in analyses comparing the suture materials (polydioxanone vs polyglactin). In open-label trials, the odds ratio for SSI risk was 0.62 (95% CI 0.20–1.93, P = 0.413), 0.77 in single-blind (95% CI 0.31–1.95, P = 0.583) and 0.85 in double-blind trials (95% CI 0.46–1.54, P = 0.582).Conclusions:Our findings failed to demonstrate a significant protective effect of triclosan-coated sutures on the occurrence of SSI after elective colorectal resections. Further large RCTs are needed before introducing this technology into clinical practice.

Why caution is recommended with post‐hoc individual patient matching for estimation of treatment effect in parallel‐group randomized controlled trials: The case of acute stroke trials

A post-hoc individual patient matching procedure was recently proposed within the context of parallel group randomized clinical trials (RCTs) as a method for estimating treatment effect. In this paper, we consider a post-hoc individual patient matching problem within a parallel group RCT as a multi-objective decision-making problem focussing on the trade-off between the quality of individual matches and the overall percentage of matching. Using acute stroke trials as a context, we utilize exact optimization and simulation techniques to investigate a complex relationship between the overall percentage of individual post-hoc matching, the size of the respective RCT, and the quality of matching on variables highly prognostic for a good functional outcome after stroke, as well as the dispersion in these variables. It is empirically confirmed that a high percentage of individual post-hoc matching can only be achieved when the differences in prognostic baseline variables between individually matched subjects within the same pair are sufficiently large and that the unmatched subjects are qualitatively different to the matched ones. It is concluded that the post-hoc individual matching as a technique for treatment effect estimation in parallel-group RCTs should be exercised with caution because of its propensity to introduce significant bias and reduce validity. If used with appropriate caution and thorough evaluation, this approach can complement other viable alternative approaches for estimating the treatment effect.

Inhaled Nitric Oxide for Acute Respiratory Distress Syndrome and Acute Lung Injury in Adults and Children

Acute hypoxemic respiratory failure, defined as acute lung injury and acute respiratory distress syndrome, are critical conditions associated with frequent mortality and morbidity in all ages. Inhaled nitric oxide (iNO) has been used to improve oxygenation, but its role remains controversial. We performed a systematic review with meta-analysis and trial sequential analysis of randomized clinical trials (RCTs). We searched CENTRAL, Medline, Embase, International Web of Science, LILACS, the Chinese Biomedical Literature Database, and CINHAL (up to January 31, 2010). Additionally, we hand-searched reference lists, contacted authors and experts, and searched registers of ongoing trials. Two reviewers independently selected all parallel group RCTs comparing iNO with placebo or no intervention and extracted data related to study methods, interventions, outcomes, bias risk, and adverse events. All trials, irrespective of blinding or language status were included. Retrieved trials were evaluated with Cochrane methodology. Disagreements were resolved by discussion. Our primary outcome measure was all-cause mortality. We performed subgroup and sensitivity analyses to assess the effect of iNO in adults and children and on various clinical and physiological outcomes. We assessed the risk of bias through assessment of trial methodological components. We assessed the risk of random error by applying trial sequential analysis. We included 14 RCTs with a total of 1303 participants; 10 of these trials had a high risk of bias. iNO showed no statistically significant effect on overall mortality (40.2%versus 38.6%) (relative risks [RR] 1.06, 95% confidence interval [CI] 0.93 to 1.22; I² = 0) and in several subgroup and sensitivity analyses, indicating robust results. Limited data demonstrated a statistically insignificant effect of iNO on duration of ventilation, ventilator-free days, and length of stay in the intensive care unit and hospital. We found a statistically significant but transient improvement in oxygenation in the first 24 hours, expressed as the ratio of Po₂ to fraction of inspired oxygen (mean difference [MD] 15.91, 95% CI 8.25 to 23.56; I² = 25%). However, iNO appears to increase the risk of renal impairment among adults (RR 1.59, 95% CI 1.17 to 2.16; I² = 0) but not the risk of bleeding or methemoglobin or nitrogen dioxide formation. iNO cannot be recommended for patients with acute hypoxemic respiratory failure. iNO results in a transient improvement in oxygenation but does not reduce mortality and may be harmful.

Gabapentin Versus Tricyclics for Neuropathic Pain

To the Editor: Chou and colleagues are to be commended for tackling a challenging and important subject with their detailed meta-analysis comparing gabapentin with tricyclic antidepressants for the treatment of neuropathic pain.1 The authors argue that prior analysts have over-emphasized the strength of the evidence derived from indirect meta-analysis. I believe that Chou and colleagues have over-emphasized the strength of evidence derived from direct meta-analysis in this case. The authors’ direct meta-analysis relies on three head-to-head randomized clinical trials (RCTs) comparing gabapentin to tricyclic antidepressants. However, one of these trials,2 clearly identified as “an open-label pilot study,” should not be included simply because it lacks any attempt at blinding. Blinding is considered to be a critical component of good RCT design because trials in which patients or investigators are aware of their treatment allocation are more likely to produce biased results than blinded studies, especially in trials with subjective outcomes like pain.3,4 Bias for gabapentin would be especially likely within an open-label trial that occurred during a remarkably intense and elaborate marketing campaign.5 This might explain the extraordinary response to gabapentin in this trial (85%), which was the only head-to-head trial showing a better response to gabapentin than to tricyclics. Without the open-label trial, there are two small head-to-head trials comparing gabapentin with two different tricyclic antidepressants in two different neuropathic pain conditions. One of these trials, using a crossover design with only 21 patients, found a higher response rate for amitriptyline (67% vs. 52%), though the difference was not statistically significant.6 The other trial, using a parallel group design, found similar outcomes for gabapentin and for nortriptyline.7 Neither trial was adequately powered to detect differences between active treatment arms. Neither trial included a placebo comparison to ensure assay sensitivity (i.e., that the trials had the ability to distinguish between active and inactive treatments), which is “essential to the interpretation of” trials comparing active treatments.8 The authors’ analysis does not include unpublished trials. The promotion of gabapentin was subsequently shown to be extraordinarily comprehensive, and included deliberate suppression of negative clinical trials results.5 At least one large (325 patients), multi-center double-blind RCT studying gabapentin in patients with painful diabetic neuropathy is known to have remained unpublished, almost certainly because the highest dosage studied (2400 mg/d) failed to show a better analgesic response for gabapentin (30%) than for placebo (25%, P > 0.05).9 It is certainly possible that additional negative trials for gabapentin, some possibly comparing gabapentin to tricyclics, also remained unpublished. The authors also did not include an unpublished double-blind parallel group RCT comparing amitriptyline to pregabalin and to placebo in 254 patients with painful diabetic neuropathy (extensive detail is provided about this trial by the US FDA).10 This trial showed a higher response rate for amitriptyline (47%) than for pregabalin (40%) or placebo (30%, P 0.05 for placebo comparison with pregabalin; no comparison between amitriptyline and gabapentin is provided). Chou and colleagues have also over-represented the response rate to gabapentin in one of the trials. They report that 17 of 19 patients treated with gabapentin achieved a good analgesic response, but the published report of this trial indicates that there were 19 gabapentin-treated patients in the first crossover period.11 There were a total of 40 gabapentin-treated patients, so the true response rate to gabapentin in the trial was 17/40 (43% rather than 90%). If one does not include the open-label trial then the head-to-head trials tend to favor tricyclics, but there does not seem to be enough data to conduct a meaningful meta-analysis. As the authors report, indirect meta-analysis favors tricyclics through a broad range of sensitivity analyses, and inclusion of the unpublished trial data and reduction of the response rate in the gabapentin trial described above may tilt the balance further in favor of tricyclics. The authors argue that more head-to-head trials are needed, which is certainly true.12 Until there are adequately powered and designed head-to-head double-blind RCTs, the best relative ranking of efficacy seems to come from the indirect meta-analyses, despite the limitations the authors describe in their manuscript.

Sources and handling of losses to follow-up in parallel-group randomized clinical trials in dogs and cats: 63 trials (2000–2005)

To determine the sources and handlingof losses to follow-up (LTF) in parallel-group randomized clinical trials (RCTs). 63 parallel-group RCTs of > 24 hours' duration published from January 2000 through December 2005. Journals were hand searched for eligible reports. Details concerning the presence, cause, and amount of LTF; statistical handlingof data missingbecause of LTF; type of analyses performed; number of animals randomly allocated and analyzed; and the acknowledgement of the potential impact of LTF were recorded. RESULTS In 81% (51/63) of trials, LTF were reported. In 80% (41/51) of those studies, losses in the analysis were ignored, and in only 18% (9/51) was the potential impact of LTF on study results acknowledged. Of the 47 studies in which sources of LTF were reported, 72% had loss of subjects because of investigator withdrawals, 30% because of deaths, and 26% because of owner withdrawals. Median loss of subjects for those studies was 12% because of investigator withdrawal (range, 2% to 52%), 8% because of death (1% to 28%), and 4% because of owner withdrawal (2% to 33%). Most RCTs had LTF, most of which were attributable to investigators removing randomly allocated animals from the study. In most studies, data from animal LTF were ignored and, therefore, only a subgroup of randomly allocated subjects was included in the data analysis. Most reports did not address the potential for a postrandomization selection bias associated with ignoring LTF and did not acknowledge the potential impact of the missingdata on their results.