Cochrane Db Syst Rev
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Cochrane Db Syst Rev · Mar 2023
Review Meta AnalysisImpact of active placebo controls on estimated drug effects in randomised trials: a systematic review of trials with both active placebo and standard placebo.
An estimated 60% of pharmacological randomised trials use placebo control interventions to blind (i.e. mask) participants. However, standard placebos do not control for perceptible non-therapeutic effects (i.e. side effects) of the experimental drug, which may unblind participants. Trials rarely use active placebo controls, which contain pharmacological compounds designed to mimic the non-therapeutic experimental drug effects in order to reduce the risk of unblinding. A relevant improvement in the estimated effects of active placebo compared with standard placebo would imply that trials with standard placebo may overestimate experimental drug effects. ⋯ We did not find a statistically significant difference between active and standard placebo control interventions in our primary analysis, but the result was imprecise and the CI compatible with a difference ranging from important to irrelevant. Furthermore, the result was not robust, because two sensitivity analyses produced a more pronounced and statistically significant difference. We suggest that trialists and users of information from trials carefully consider the type of placebo control intervention in trials with high risk of unblinding, such as those with pronounced non-therapeutic effects and participant-reported outcomes.
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Cochrane Db Syst Rev · Mar 2023
ReviewInterventions for improving adherence to iron chelation therapy in people with sickle cell disease or thalassaemia.
Regularly transfused people with sickle cell disease (SCD) and people with thalassaemia are at risk of iron overload. Iron overload can lead to iron toxicity in vulnerable organs such as the heart, liver and endocrine glands, which can be prevented and treated with iron-chelating agents. The intensive demands and uncomfortable side effects of therapy can have a negative impact on daily activities and wellbeing, which may affect adherence. ⋯ The medication comparisons included in this review had higher than average adherence rates not accounted for by differences in medication administration or side effects, though often follow-up was not good (high dropout over longer trials), with adherence based on a per protocol analysis. Participants may have been selected based on higher adherence to trial medications at baseline. Also, within the clinical trial context, there is increased attention and involvement of clinicians, thus high adherence rates may be an artefact of trial participation. Real-world, pragmatic trials in community and clinic settings are needed that examine both confirmed or unconfirmed adherence strategies that may increase adherence to iron chelation therapy. Due to lack of evidence this review cannot comment on intervention strategies for different age groups.
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Cochrane Db Syst Rev · Mar 2023
ReviewUltrasound and shockwave therapy for acute fractures in adults.
The morbidity and socioeconomic costs of fractures are considerable. The length of time to healing is an important factor in determining a person's recovery after a fracture. Ultrasound may have a therapeutic role in reducing the time to union after fracture by stimulating osteoblasts and other bone-forming proteins. This is an update of a review previously published in February 2014. OBJECTIVES: To assess the effects of low-intensity ultrasound (LIPUS), high-intensity focused ultrasound (HIFUS) and extracorporeal shockwave therapies (ECSW) as part of the treatment of acute fractures in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase (1980 to March 2022), Orthopaedic Proceedings, trial registers and reference lists of articles. ⋯ We were uncertain of the effectiveness of ultrasound and shock wave therapy for acute fractures in terms of patient-reported outcome measures (PROMS), for which few studies reported data. It is probable that LIPUS makes little or no difference to delayed union or non-union. Future trials should be double-blind, randomised, placebo-controlled trials recording validated PROMs and following up all trial participants. Whilst time to union is difficult to measure, the proportion of participants achieving clinical and radiographic union at each follow-up point should be ascertained, alongside adherence with the study protocol and cost of treatment in order to better inform clinical practice.
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Cochrane Db Syst Rev · Mar 2023
ReviewUltrasound-guided arterial cannulation in the paediatric population.
In arterial line cannulation in children and adolescents, traditional methods of locating the artery include palpation and Doppler auditory assistance. It is unclear whether ultrasound guidance is superior to these methods. This is an update of a review originally published in 2016. ⋯ We identified moderate-certainty evidence that ultrasound guidance for arterial cannulation compared with palpation or Doppler auditory assistance improves first-attempt success rate, second-attempt success rate and overall success rate. We also found moderate-certainty evidence that ultrasound guidance reduces the incidence of complications, the number of attempts to successful cannulation and the duration of the cannulation procedure.
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Cochrane Db Syst Rev · Mar 2023
ReviewAtaluren and similar compounds (specific therapies for premature termination codon class I mutations) for cystic fibrosis.
Cystic fibrosis (CF) is a common, life-shortening, genetic disorder in populations of Northern European descent caused by the mutation of a single gene that codes for the production of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. This protein coordinates the transport of salt (and bicarbonate) across cell surfaces, and the mutation most notably affects the airways. In the lungs of people with CF, the defective protein compromises mucociliary clearance and makes the airway prone to chronic infection and inflammation, damaging the structure of the airways and eventually leading to respiratory failure. In addition, abnormalities in the truncated CFTR protein lead to other systemic complications, including malnutrition, diabetes and subfertility. Five classes of mutation have been described, depending on the impact of the mutation on the processing of the CFTR protein in the cell. In class I mutations, premature termination codons prevent the production of any functional protein, resulting in severe CF. Therapies targeting class I mutations aim to enable the normal cellular mechanism to read through the mutation, potentially restoring the production of the CFTR protein. This could, in turn, normalise salt transport in the cells and decrease the chronic infection and inflammation that characterises lung disease in people with CF. This is an update of a previously published review. ⋯ Our searches identified 56 references to 20 trials; of these, 18 trials were excluded. Both the included parallel RCTs compared ataluren to placebo for 48 weeks in 517 participants (males and females; age range six to 53 years) with CF who had at least one nonsense mutation (a type of class I mutation). The certainty of evidence and risk of bias assessments for the trials were moderate overall. Random sequence generation, allocation concealment and blinding of trial personnel were well documented; participant blinding was less clear. Some participant data were excluded from the analysis in one trial that also had a high risk of bias for selective outcome reporting. PTC Therapeutics Incorporated sponsored both trials with grant support from the Cystic Fibrosis Foundation, the US Food and Drug Administration's Office of Orphan Products Development and the National Institutes of Health. The trials reported no difference between treatment groups in terms of quality of life, and no improvement in respiratory function measures. Ataluren was associated with a higher rate of episodes of renal impairment (risk ratio 12.81, 95% confidence interval 2.46 to 66.65; P = 0.002; I2 = 0%; 2 trials, 517 participants). The trials reported no treatment effect for ataluren for the review's secondary outcomes of pulmonary exacerbation, computed tomography score, weight, body mass index and sweat chloride. No deaths were reported in the trials. The earlier trial performed a post hoc subgroup analysis of participants not receiving concomitant chronic inhaled tobramycin (n = 146). This analysis demonstrated favourable results for ataluren (n = 72) for the relative change in forced expiratory volume in one second (FEV1) per cent (%) predicted and pulmonary exacerbation rate. The later trial aimed to prospectively assess the efficacy of ataluren in participants not concomitantly receiving inhaled aminoglycosides, and found no difference between ataluren and placebo in FEV1 % predicted and pulmonary exacerbation rate. AUTHORS' CONCLUSIONS: There is currently insufficient evidence to determine the effect of ataluren as a therapy for people with CF with class I mutations. One trial reported favourable results for ataluren in a post hoc subgroup analysis of participants not receiving chronic inhaled aminoglycosides, but these were not reproduced in the later trial, suggesting that the earlier results may have occurred by chance. Future trials should carefully assess for adverse events, notably renal impairment, and consider the possibility of drug interactions. Cross-over trials should be avoided, given the potential for the treatment to change the natural history of CF.