1458 e-Letters

  • “Re: Letter to the Editor RE: "Restoring mortality data in the FOURIER cardiovascular outcomes trial of evolocumab in patients with cardiovascular disease: a reanalysis based on regulatory data". BMJ Open. 2022;12:3060172.”

    “Re: Letter to the Editor RE: "Restoring mortality data in the FOURIER cardiovascular outcomes trial of evolocumab in patients with cardiovascular disease: a reanalysis based on regulatory data". BMJ Open. 2022;12:3060172.”

    Dear editor,
    In their letter to the editor, Sabatine et al. comment on the restoration study of the FOURIER trial by Erviti et al.1 We agree that some discrepancies in locally established and adjudicated causes of deaths can be expected as part of the adjudication process. However, the trial investigators do not explain why there were so many discrepancies in FOURIER: 41.4% of locally established causes of deaths were not confirmed after central adjudication by the clinical-events committee. The site investigators attributed 358 of 870 deaths (41.1%) to a cardiovascular cause, and the committee 491 (56.4%): a difference of +15.3%. The high rate of discrepancies is surprising because both groups had all detailed clinical information at their disposal as well as the study protocol with definitions for cardiovascular events, and were blinded to the treatment status of the participants. Moreover, several previous studies have shown much lower discrepancy rates in other clinical outcomes trials that tested a drug for the prevention of cardiovascular disease. One recent study concerned the COMPASS trial among 27,395 patients that received rivaroxaban with aspirin, rivaroxaban monotherapy or aspirin monotherapy.2 There were 552 investiga...

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  • Letter to the Editor RE: "Restoring mortality data in the FOURIER cardiovascular outcomes trial of evolocumab in patients with cardiovascular disease: a reanalysis based on regulatory data". BMJ Open. 2022;12:3060172.

    The article by Erviti et al.1 is fundamentally flawed, using incomplete data to reach incorrect conclusions. In FOURIER,2 event adjudication followed a rigorous, pre-specified, blinded process by the TIMI Clinical Events Committee (CEC). The occurrence of potential cardiovascular events of interest triggered collection of a full dossier containing all relevant and available source documents, including hospital notes, laboratory, ECG and imaging data, procedure reports, resuscitation or code summaries, death certificates, and autopsy reports. Each dossier was independently evaluated by 2 experienced, board-certified cardiologists (cardiovascular events) or neurologists (cerebrovascular events), blinded to treatment allocation. The CEC followed well-accepted practices used for 2 decades and supporting multiple peer-reviewed manuscripts and world-wide regulatory filings. Criteria for outcomes were consistent with FDA definitions.3 The adjudication charter was approved by the FDA before the trial commenced. At the end of the trial the FDA audited the adjudication process and results and had no findings of concern.
    In contrast, the authors’ work was post hoc and relied only on one document: the CSR narrative, which was generated predominantly based on limited information provided by the site upon learning of the event and not intended for the purpose of formal event adjudication. It is unclear what training and expertise, if any, those classifying events for this paper ha...

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  • Was it a methodical failure?

    I reviewed Dr. Erviti et all's article and found that the RIAT team likely missed something important related to the trial itself when they analyzed the study data published in the NEJM on February 13, 2019.
    The main point is that the article does not describe the data review process to adjudicate cardiovascular outcomes. The article only mentions the participation of the Data Monitoring Committee for the review of safety events and the adjudication of cases of death related or not to evolocumab. There is no mention of how the Committee was composed and what process was put in place for the adjudications. I can assume that the members of the Committee were physicians trained in cardiology for the review of major cardiovascular events and related deaths. Members of such Committees often request a lot of additional information from sites to review prior to the adjudications. The complete documentation generated for the adjudication of each case is usually not included in the Clinical Study Report (CSR) and is filed in the safety database. The authors also presented in Figures 1 and 2 examples of reports used in their review to determine inconsistent data. Looking at the format of those reports, it appears that they were automatically generated by the study data manager for a high-level description of the cases to include in the CSR. Those reports don’t show all the data that is normally collected in severe events on the CIOMS form for reporting to authorities and...

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  • Re: Association of sleep behaviour and pattern with the risk of glaucoma

    Sun et al. conducted a prospective study to evaluate the association between sleep behaviour and subsequent glaucoma (1). The adjusted hazard ratios (95% confidence intervals [CIs]) of individuals with snoring and daytime sleepiness, and insomnia and short/long sleep duration for glaucoma were 1.11 (1.03 to 1.19) and 1.13 (1.06 to 1.20), respectively. Snoring and daytime sleepiness are clinical symptoms of sleep apnea syndrome (SAS), and I present some information on the association between SAS and glaucoma.

    García-Sánchez et al. conducted a meta-analysis to evaluate the relationship between obstructive SAS and eye diseases (2). Although majorities of reports were occupied with low-level evidence, the pooled odds ratios (95% CIs) of obstructive SAS, nonarteritic ischemic optic neuropathy, and diabetic retinopathy for the risk of glaucoma were 1.50 (1.25 to 1.80), 3.62 (1.94 to 6.76), and 1.57 (1.09 to 2.27), respectively. They mainly summarized case-control studies, and additional prospective studies are greatly required for a meta-analysis.

    Regarding the mechanism of the association, Shinmei et al. conducted a prospective study to evaluate the effect of intraocular pressure (IOP) changes during nocturnal sleep in patients with obstructive SAS (3). The mean IOP level during apnea events was significantly lower than that during non-apnea phases. SAS events led to IOP decline during nocturnal sleep, and they considered that episodic hypoxia caused by SAS might...

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  • Sceptical?

    I read your article with great interest, as a physician-scientist trainee who has Familial Hypercholesterolemia and takes Evolocumab as additive therapy. This article demonstrates important discrepancies to address for a very large trial critical to the uptake of PCSK9 inhibitors everywhere. It is disappointing to see such discrepancies.

    My concern with your conclusions, however, is that it seems to vastly overstate the impact of the findings. You suggest that clinicians ought to be sceptical in prescribing this medication. However, the discrepancies you reported did not change any trial conclusions. It does not affect that average change in LDL, which is the primary purpose in prescribing the medication. It also does not offer a plausible explanation why a PCSK9 inhibitor might cause increased cardiac death or vascular event rates. Further, meta-analysis of PCSK9 trials, even with the reported discrepancies, is unlikely to change the overall scientific evidence that PCSK9 inhibitors are safe and effective drugs.

    It is important to be watchful for pharma-biased presentations of RCT results, but likewise is important to avoid sensationalism. I see no reason in these results to discontinue or be sceptical of the power of PCSK9s, and we should be careful as scientists to avoid whiplashing the public towards scepticism of a well-tested drug.

    Statins already have been maligned in the public eye without great cause; let's avoid doing the same to this...

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  • Re: “Restoring mortality data in the FOURIER cardiovascular outcomes trial of evolocumab in patients with cardiovascular disease: a reanalysis based on regulatory data”

    Dear editor,
    Erviti et al. recently restored the causes of death data in the FOURIER trial with the information in the clinical study report (CSR).1 The rationale was that evolocumab had been reported to reduce the risk of myocardial infarction and stroke, but (numerically) increase the risk of cardiovascular death (HR 1.05; 95% CI 0.88 to 1.25).2 Erviti et al. found that the clinical events committee did not confirm the local clinical investigator’s cause of death for 41.4% of cases often without clear supportive clinical evidence.1 As a result, less cardiac and cardiovascular deaths were reported to have occurred in the evolocumab group and more in the placebo group. Re-analysis with the original causes of death data resulted in a higher risk of cardiovascular death (RR 1.20; 95% CI 0.95 to 1.51) and cardiac death (RR 1.28; 95%CI 0.97 to 1.69) than previously reported.1 Erviti et al. concluded that possible cardiac harm due to evolocumab could not be ruled out.1
    Erviti et al could not restore the non-fatal cardiovascular events due to a lack of detailed information for these events in the CSR. We think this is unfortunate, because the reported events raise a number of questions. First, hospitalization for unstable angina (UA) made up 30.0% of the acute coronary syndrome events, which is a considerably higher proportion than that reported for similar populations.2 In the ODYSSEY OUTCOMES trial about alirocumab, it was 5.4%,3 and in the IMPROVE-IT trial about e...

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  • Mapping positive health in patients with gastrointestinal disorders

    We would like to add a clinical perspective to the debate on the concept of Positive Health (PH) and its measurement. A decade ago, Huber et al. in 2011 (1) introduced this concept, which provides a broad perspective of people’s health. PH includes six dimensions: bodily functions, mental functions, meaningfulness, quality of life, social participation and daily activities. A dialogue tool was developed to map the dimensions of PH in practice. Meanwhile, the concept is increasingly used in clinical practice and research.

    In 2021, Bock et al. (2) described in this journal how residents experienced the use of the dialogue tool in outpatient consultations. They concluded in this journal that using this tool brings bivalent experiences: on the one hand, it yielded valuable patient information beyond physical health. The dynamic in resident–patient communication was changed. On the other hand, they concluded that the tool was not usable for simple situations, for follow-up consultations and lacked to provide details for super specialised care.

    We agree with Bock et al. that the dialogue tool is helpful but limited in its applicability. Communication is improved via the tool, but there is a need for a more structured approach to obtaining patient data that cover the six PH dimensions. Such more precise data are helpful for following-up of patients, for comparison with other (groups of) patients and for scientific purposes. In practice, gaining a broader insight...

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  • Response to Sudry: Statistical Error

    Thank you for the comment.

    The P values shown in the column in Table 2 are for the ANOVA comparisons between the three intervention groups and, as the correspondent indicates for LDL-Cholesterol, this is shown as P<0.001. The P values described in the text are for the pairwise comparisons for which Table 2 does not show P values but only the 95% CI. Both sets of P values are correct.

    There is no error in our reporting, but in any case, the differences referred to are all conventionally highly statistically significant whether P<0.001 or P<0.0001 and do not alter the interpretation of results.

  • Do green tea flavonoids have an impact on COVID-related respiratory tract infections?

    Dear Editor

    I recently read the article entitled “Flavonoids for viral acute respiratory tract infections: protocol for a systematic review and meta-analysis of randomized controlled trials”

    I'd like to thank the authors for their excellent review and meta-analysis paper, which shows how flavonoids can help with viral acute respiratory tract infections. The article mentioned its role in viral ARTIs such as COVID-19, caused by SARS-CoV-2. Flavonoids have been supported for use in the prevention and treatment of ARTIs because they have antiviral, anti-inflammatory, cytotoxic, antibacterial, antioxidant, and anti-allergic characteristics. However, flavonoids are found in a wide range of phytonutrients. The United States Department of Agriculture (USDA) Database categorizes flavonoid foods as containing flavonols, flavones, flavanones, catechins (flavan-3-ols or flavanols), isoflavones, anthocyanins, and oligomeric or polymeric flavonoids.

    It would have been very helpful if the authors had suggested a specific flavonoid group or chemical structure that might have a positive response to SARS-Covid. For instance, in a Shanghai cohort study, a urine biomarker of tea polyphenol and the risk of colorectal cancer were investigated.[1] The opinion would have been highly appreciated, especially now when COVID is increasing dramatically in various variants and, in China, almost everyone consumes flavonoids in the form of green tea on a daily basis. The suggest...

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  • Author response to Tanisha Johnson, Terry Campbell

    Thank you, Tanisha and Terry for your comment on our recent review of birth pool use. Aware of its inevitable complexity, we are delighted that you find it useful and understandable. Noting your salient point about the majority of the studies having taken place in the Obstetric Unit (OU) setting, we hoped to include studies that were undertaken in midwifery led care birth settings. However, unfortunately we did not find more that matched our eligibility criteria because to enable comparison between land and water-immersed labour/birth, we required research that involved a control group who could have used a birth pool. Despite an increasing usage of birth pools, particularly in midwifery led settings, there is little comparative research available. However, the research which has reported on birth pool use in midwifery led birth settings has not found any safety concerns.
    A key message from this review is that it shows water immersion provides a safe option for women who labour and give birth in the OU setting, resulting in fewer interventions, good outcomes and greater satisfaction with no increased risk to baby other than cord avulsion which clinicians can work to prevent by not taking the whole baby out of the water at speed. This is important because most women labour in the OU setting across multiple countries and securing a birth pool option can modify clinician behaviour and care in a medicalised environment.