Explaining evidence-based medicine

The observations by Wiederman et al. [1] on our recently published paper [2] raise some confusion between 'facts' and 'opinions'. In the area of the treatment of sepsis with antithrombin III, the results of our observational study are 'facts' and are therefore a contribution to a better knowledge of this therapeutic problem. While previous evidence was based only on randomised, controlled trials (RCTs), our study has provided some additional evidence using an observational design. Nobody can deny that having data from both RCTs and observational studies is better than having data from only RCTs. The interpretation of our results ('opinions') is another issue. It is well known that the value of observational studies is a matter of debate [3,4,5] and, of course, our study does not make an exception. We think, however, that one cannot always restart from the beginning the debate on the usefulness of observational studies every time one such study is published. The same considerations apply to meta-analysis. Detractors of meta-analysis may argue that there has been a 'spectacular failure ... to predict the outcomes of subsequent large scale RCTs'. Many other researchers have a different and more favourable view. In any case, numerous meta-analyses continue to be published in authoritative journals; in 2001, 152 articles were published in the British Medical Journal, five articles in the New England Journal of Medicine, 60 articles in the Annals of Internal Medicine, 94 articles in the Journal of the American Medical Association, and 10 articles in the Lancet (information based on a PubMed Medline [6] query launched on 11 October 2002 using the syntax: metaanalysis [titl] OR meta-analysis [titl] OR 'systematic review' [titl]; limits: 'only items with abstract'). This shows that the scientific community recognises the 'pros' of this instrument (even though its 'cons' should always be kept in mind). Also in the case of meta-analysis, one cannot restart from the beginning the debate about the usefulness of meta-analysis [7,8] every time an article presents some results of this type. In conclusion, we believe that both observational studies and meta-analytic assessments can be of value in some cases. The scientific community continues to accept them regardless of the occasional strong opinions of individual researchers that dislike these techniques.

Lapses at the New England Journal of Medicine

The purpose of this study is to conduct a systematic review and meta-analysis evaluating the effects of respiratory muscle therapy (ie, oropharyngeal exercises, speech therapy, breathing exercises, wind musical instruments) compared with control therapy or no treatment in improving apnea-hypopnea index ([AHI] primary outcome), sleepiness, and other polysomnographic outcomes for patients diagnosed with obstructive sleep apnea (OSA). Only randomized controlled trials with a placebo therapy or no treatment searched using PubMed, EMBASE, Cochrane, and Web of Science up to November 2018 were included, and assessment of risk of bias was completed using the Cochrane Handbook. Nine studies with 394 adults and children diagnosed with mild to severe OSA were included, all assessed at high risk of bias. Eight of the 9 studies measured AHI and showed a weighted average overall AHI improvement of 39.5% versus baselines after respiratory muscle therapy. Based on our meta-analyses in adult studies, respiratory muscle therapy yielded an improvement in AHI of -7.6 events/h (95% confidence interval [CI] = -11.7 to -3.5; P ≤ .001), apnea index of -4.2 events/h (95% CI = -7.7 to -0.8; P ≤ .016), Epworth Sleepiness Scale of -2.5 of 24 (95% CI= -5.1 to -0.1; P ≤ .066), Pittsburgh Sleep Quality Index of -1.3 of 21 (95% CI= -2.4 to -0.2; P ≤ .026), snoring frequency (P = .044) in intervention groups compared with controls. This systematic review highlights respiratory muscle therapy as an adjunct management for OSA but further studies are needed due to limitations including the nature and small number of studies, heterogeneity of the interventions, and high risk of bias with low quality of evidence.

No rust to judgment

Citation analysis of the ‘big six’ journals in internal medicine

The authors of this editorial belong to the International Committee of Medical Journal Editors (ICMJE). They ask investigators to use the revised ICMJE requirements on publication ethics to guide t...

This review did not find sufficient evidence to support the use of one cycle regimen in preference to another in preparation for FET in subfertile women with regular ovulatory cycles. The most common modalities for FET are natural cycle with or without HCG trigger or endometrial preparation with HT, with or without GnRHa suppression. We identified only four direct comparisons of these two modalities and there was insufficient evidence to support the use of either one in preference to the other.

What is the effect of constraint-induced movement therapy on children with unilateral cerebral palsy? A Cochrane Review summary with commentary.

e18616 Background: PD-1/PD-L1 targeting monoclonal antibodies (mAbs) improve outcomes in multiple cancer types. Multiple mAbs are in clinical development, and many randomized control trials (RCTs) have been completed or are in progress. These RCTs compete for limited clinical trials infrastructure, human resources and patients. Since the hypothesized benefit of an intervention is a critical determinant of the number of patients required for an RCT, it is crucial that the expected benefit be estimated appropriately. We examined the hypothesized hazard ratio (HHR) and the observed hazard ratio (OHR) in RCTs evaluating PD-1/PD-L1 targeting mAbs. Methods: Publications of RCTs evaluating at least one PD-1/PD-L1 targeting mAbs approved by the US Food and Drug Administration were identified through PubMed searches. The primary publication for each RCT and its associated protocol were retrieved. Two investigators independently extracted HHR, OHR for the primary endpoint among other data elements. The differences (∆HR) in HHR and OHR were analyzed statistically. Updated OHRs (uOHR) were extracted from reports with extended follow-ups. Results: 49 RCTs enrolling 36867 patients were included. 45/49 RCTs were in the palliative setting. HHR was met or exceeded in 22 (45%) RCTs. The mean HHR and OHR were 0.672 and 0.738, respectively. The mean ∆HR was 0.067 (range: -0.300 to 0.895, 95% confidence interval = 0.003 – 0.130). A lower magnitude of effect than hypothesized in 12/29 RCTs in non-small cell lung cancer, melanoma and renal cell carcinoma, but in 15/20 RCTs in other cancer types. OHR was ≥ 1.0 in 6 RCTs (12%). In the palliative setting, ∆HR was larger in more heavily pre-treated patients. PD-L1 expression was not associated with magnitude of effect. However, a higher magnitude of effect was observed for RCTs published in the New England Journal of Medicine. For 18 RCTs with extended follow-ups, uOHR was higher than OHR in 8. Conclusions: The majority of published RCTs evaluating PD-1/PD-L1 targeting mAbs did not achieve their hypothesized magnitude of effect. Investigators’ optimism regarding these agents should be combined with more realistic expectations. The optimism bias requires attention from the cancer clinical research community given the number of these agents in development and the intense interest in evaluating these agents in various disease settings.

PACIFIC: Time for a surgical IIIA uprising

Tubal flushing for subfertility.

Uterine fibroids can cause heavy menstrual bleeding. Medical treatments are considered to preserve fertility. It is unclear whether progestogens or progestogen-releasing intrauterine systems can reduce fibroid-related symptoms. This is the first update of a Cochrane Review published in 2013. To determine the effectiveness of progestogens or progestogen-releasing intrauterine systems in treating premenopausal women with uterine fibroids. We searched the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, and PsycINFO databases to July 2020. We also searched trials registers for ongoing and registered trials, and checked references of relevant trials. All identified published or unpublished randomised controlled trials (RCTs) assessing the effect of progestogens or progestogen-releasing intrauterine systems in treating premenopausal women with uterine fibroids. Two authors independently extracted data, assessed risk of bias, and assessed the quality of the evidence using the GRADE approach. This updated review included four studies with 221 women with uterine fibroids. The evidence was very low quality, downgraded for serious risk of bias, due to poor reporting of study methods, and serious imprecision. Levonorgestrel-releasing intrauterine device (LNG-IUS) versus hysterectomy There was no information on the outcomes of interest, including adverse events. LNG-IUS versus low dose combined oral contraceptive (COC) At 12 months, we are uncertain whether LNG-IUS reduced the percentage of abnormal uterine bleeding, measured with the alkaline hematin test (mean difference (MD) 77.50%, 95% confidence interval (CI) 70.44 to 84.56; 1 RCT, 44 women; very low-quality evidence), or the pictorial blood assessment chart (PBAC; MD 34.50%, 95% CI 11.59 to 57.41; 1 RCT, 44 women; very low-quality evidence); increased haemoglobin levels (MD 1.50 g/dL, 95% CI 0.85 to 2.15; 1 RCT, 44 women; very low-quality evidence), or reduced fibroid size more than COC (MD 1.90%, 95% CI -12.24 to 16.04; 1 RCT, 44 women; very low-quality evidence). The study did not measure adverse events. LNG-IUS versus oral progestogen (norethisterone acetate (NETA)) Compared to NETA, we are uncertain whether LNG-IUS reduced abnormal uterine bleeding more from baseline to six months (visual bleeding score; MD 23.75 points, 95% CI 1.26 to 46.24; 1 RCT, 45 women; very low-quality evidence); increased the percentage of change in haemoglobin from baseline to three months (MD 4.53%, 95% CI 1.46 to 7.60; 1 RCT, 48 women; very low-quality evidence), or from baseline to six months (MD 10.14%, 95% CI 5.57 to 14.71; 1 RCT, 45 women; very low-quality evidence). The study did not measure fibroid size. Spotting (adverse event) was more likely to be reported by women with the LNG-IUS (64.3%) than by those taking NETA (30%; 1 RCT, 45 women; very low-quality evidence). Oral progestogen (dienogest, desogestrel) versus goserelin acetate Compared to goserelin acetate, we are uncertain whether abnormal uterine bleeding was reduced at 12 weeks with dienogest (PBAC; MD 216.00 points, 95% CI 149.35 to 282.65; 1 RCT, 14 women; very low-quality evidence) or desogestrel (PBAC; MD 78.00 points, 95% CI 28.94 to 127.06; 1 RCT, 16 women; very low-quality evidence). Vasomotor symptoms (adverse events, e.g. hot flashes) are only associated with goserelin acetate (55%), not with dienogest (1 RCT, 14 women; very low-quality evidence) or with desogestrel (1 RCT, 16 women; very low-quality evidence). The study did not report fibroid size. Because of very low-quality evidence, we are uncertain whether the LNG-IUS reduces abnormal uterine bleeding or increases haemoglobin levels in premenopausal women with uterine fibroids, compared to COC or norethisterone acetate. There was insufficient evidence to determine whether the LNG-IUS reduces the size of uterine fibroids compared to COC. We are uncertain whether oral progestogens reduce abnormal uterine bleeding as effectively as goserelin acetate, but women reported fewer adverse events, such as hot flashes.

ObjectiveTo systematically review evidence comparing the effect of low-dose versus high-dose ACE inhibitors (ACEIs) on all-cause and cardiovascular mortality and hospitalisation, functional capacity and side effects in patients with heart...

Simple SummaryIn this manuscript, we investigate the reporting rate of health-related quality of life (HRQoL) in phase III RCTs evaluating therapies in advanced genitourinary cancers published between 2010 and 2022. Results showed underreporting of HRQoL and the need to dedicate more attention to its assessment.Background: As recommended in the European Society for Medical Oncology (ESMO) guidelines, assessment of health-related quality of life (HRQoL) should be a relevant endpoint in randomized controlled trials (RCTs) testing new anticancer therapies. However, previous publications by our group and others revealed a frequent underestimation and underreporting of HRQoL results in publication of RCTs in oncology. Herein, we systematically reviewed HRQoL reporting in RCTs testing new treatments in advanced prostate, kidney and urothelial cancers and published between 2010 and 2022. Methods: We searched PubMed RCTs testing novel therapies in genitourinary (GU) cancers and published in fifteen selected journals (Annals of Oncology, BMC Cancer, British Journal of Cancer, Cancer Discovery, Clinical Cancer Research, Clinical Genitourinary cancer, European Journal of Cancer, European Urology, European Urology Oncology, JAMA, JAMA Oncology, Journal of clinical Oncology, Lancet, Lancet Oncology and The New England Journal of Medicine). We excluded trials investigating exclusively best supportive care or behavioral intervention, as well as subgroup or post hoc analyses of previously published trials. For each RCT, we investigated whether HRQoL assessment was performed by protocol and if results were reported in the primary manuscript or in a secondary publication. Results: We found 85 eligible trials published between 2010 and 2022. Only 1/85 RCTs (1.2%) included HRQoL among primary endpoints. Of note, 25/85 (29.4%) RCTs did not include HRQoL among study endpoints. HRQoL results were non-disclosed in 56/85 (65.9%) primary publications. Only 18/85 (21.2%) publications fulfilled at least one item of the CONSORT-PRO checklist. Furthermore, 14/46 (30.4%) RCTs in prostate cancer, 12/25 (48%) in kidney cancer and 3/14 (21.4%) in urothelial cancer reported HRQoL data in primary publications. Next, HRQoL data were disclosed in primary manuscripts of 12/32 (37.5%), 5/13 (38.5%), 5/16 (31.3%) and 5/15 (33.3%) trials evaluating target therapies, chemotherapy, immunotherapy and new hormonal agents, respectively. Next, we found that HRQoL data were reported in 16/42 (38%) and in 13/43 (30.2%) positive and negative trials, respectively. Finally, the rate of RCTs reporting HRQoL results in primary or secondary publications was 55.3% (n = 47/85). Conclusions: Our analysis revealed a relevant underreporting of HRQoL in RCTs in advanced GU cancers. These results highlight the need to dedicate more attention to HRQoL in RCTs to fully assess the value of new anticancer treatments.

ObjectivesAdherence to pharmacological intervention in clinical trials is crucial for the correct estimation of medication effect and side effects. The Template for Intervention Description and Replication (TIDieR) - a 12-item...