435 e-Letters

published between 2020 and 2023

  • Primary Care Physicians Lead the Call to Eliminate COI in Clinical Practice Guidelines

    This research by Mooghali and team provide valuable and disturbing data on the problem of financial conflicts of interest (COI) in clinical practice guidelines.(1) Failure of authors and committee members to accurately disclose potential COI raises concerns about lack of transparency in the process, bias in the resulting guidelines, and ultimately harm to patients.

    The pioneering work in this area was done by the American Academy of Family Physicians, which published in 1994 the first international call for an explicit declaration of conflicts of interest in the development of clinical practice guidelines.(2) This has been followed by policies on COI by other groups of primary care physicians in the US(3,4), the UK(5,6) and Canada(7,8).

    Primary care physicians have been early champions of evidence-based medicine and explicit clinical practice guidelines. They are also the clinicians working at the point of care, partnering with patients to make shared decisions. The best in care requires the best guidance based on the best evidence. Therefore, potential COIs must be fully disclosed and critically managed by all involved in producing, disseminating, and implementing clinical practice guidelines.
    1.Mooghali M, Glick L, Ramachandran R, et al. Financial conflicts of interest among US physician authors of 2020 clinical practice guidelines: a cross- sectional study. BMJ Open 2023;13:e069115. doi:10.1136/ bmjopen-2022-069115
    2. Phillips...

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  • Data of the present study was not able to support the conclusion

    While I agree with the conclusion of this research that it is necessary for the government to communicate uncertainties with the general public about public health and vaccination specifically in the COVID-19 era, I’m afraid that data of the present study was not able to support this conclusion.
    In the emotions part of the result section, the authors reported that no significant between group differences of uncertainty was found in any circumstances, neither after receiving the announcement (p = .091), nor after reading the conflicting information (p = .462), or overall (p = .628). This result indicated that the intervention of the present study failed to manipulate different level of certainty between two intervention groups. All analysis and the corresponding results based on condition as independent variable tended to be invalid because it didn’t pass the manipulation check.
    Under this circumstance, the level of uncertainty before intervention would be a more reasonable choice as the primary independent variable. The similar mediation model in the present study was tested with the level of uncertainty before intervention as independent variable and the vaccination intention after intervention as dependent variable. If trust in government representative and perceived vaccine effectiveness before intervention were tested as mediators in the model, indirect effects of both path were significant, with the trust path β = -0.0898, 95% CI = [-0.1401, -0.0426], and...

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  • Response to Dr. Guijarro

    We thank Dr. Guijarro for his comments (1) and are pleased to respond to his main concerns on our article. He states that “the claim of increased cardiovascular mortality is thus numerically compensated by a reduction in non-cardiovascular mortality”. However, we should bear in mind that both total and cardiovascular mortality were numerically increased in the evolocumab group compared to placebo, which is inconsistent with a significant reduction in cardiovascular events. Additionally, this drug is indicated for patients with previous cardiovascular disease. If potential cardiac harm were confirmed, additional concerns with evolocumab in this population would be reasonably expected.

    We acknowledge that “none of our concerns is supported by any statistically significant difference”. However, since cardiovascular mortality is included in the composite primary endpoint, an exaggerated assessment of cardiovascular mortality could have contributed to inappropriate early termination of the trial ‘for benefit’. If the point estimate we identified of a 20% relative risk increase in cardiovascular mortality were maintained, the non-significant increase from evolocumab might have reached statistical significance before the end of the prespecified 56-month follow-up.

    Dr. Guijarro also mentions that “the FOURIER open label extension study suggests that longer treatment with evolocumab may indeed reduce cardiovascular mortality”(2). However, the results of this study di...

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  • Enhancing nasal antibody responses, mucosal vaccines may prevent SARS COV19 Omicron VOC infection and transmission more effectively, enabling greater control of the pandemic and limiting the emergence of

    Intramuscular (i.m.) ChAdOx1 nCOV19 , trade name "covishield " vaccine of company astrazeneca and sub licensed with Serum Institute of India ( mRNA 1273 vaccine for Spike Protein /RBD) and of Bharat Biotech company's whole virion inactivated Vero cell "co vaccine" which were given to Indian population in two minimum doses( free of cost) , in India ,were remarkably effective in preventing severe COVID-19 pneumonia, ARDS and hospitalisation with all sub variants( VOC) of omicron variants of concern of SARS COV-2 ,those were circulated so far in India since 2021 March and their full dose ( two/ or precautionary 3rd doses in 27% Indians ) use being associated with declining hospitalisation , ARDS, ventilation and COVID 19 related death . However, current vaccines those are given by the Indian government's health department can provide only transient protection against respiratory SARS- COV -2 viral replications , onward transmission and continuing emergence of variants of concern, by contrast, respiratory infection with SARS-CoV-2 could induces more potent serum IGg and IGa antibody mediated ( against spike protein and RBD protein) immunity against breakthrough infections ( re- infection even after vaccination or after clinical or subclinical infection) , mucosal immune defences that could inhibit viral replication and transmission, but did not happened it so in real world . Although covishield/ or co vaccine i.m. vaccinations transi...

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  • Response to Dr. Sabatine et al.

    We thank Dr. Sabatine, Wiviott, Keech, Sever and Giuliano, who have posted Rapid Responses to our article (1), and are pleased that BMJ Open metrics indicate substantial interest.

    We respectfully disagree with Dr. Sabatine et al., with regard to a number of issues they raise.

    1. Dr. Sabatine and colleagues maintain that additional information available in patient dossiers and hospital records would have led us to different results. On the following dates: 13/02/2019, 18/03/2019, and 08/05/2019, we requested assistance to obtain such information from Dr. Sabatine, the corresponding author for the N Engl J Med 2017 report of FOURIER. Additionally, we emailed Dr Sabatine on 11/04/2019 to inform him that a ‘call-to-action’ on the FOURIER trial had been published in the BMJ (2) with the intention to restore the FOURIER trial. Neither Dr. Sabatine nor his colleagues made any reply.

    The problems of event ascertainment, adjudication, and reporting in complex clinical trials will not go away without substantial changes. This is highlighted by the new Lancet inquiry into how the RECORD 4 trial of rivaroxaban was conducted and reported (3). The solution is openness and scientific collaboration, not “data hogging.”

    Patients who volunteer for clinical trials enter an ethical agreement to help discover scientific truth. What would the same patients think if they realized that sponsors and investigators make sure that no one can effectively double check the...

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  • Comparing the Febridx device in accident and emergency and general practice

    It was interesting to read Buntine et al’s (1) experience with the Febridx Point of Care Device in the Accident and Emergency setting. They found a negative predictive value of 80% and a positive predictive value of 78%. The results from our study in general practice demonstrated a negative predictive value of 43%.

    We commenced the use of the Febridx device in an Australian general practice in November 2020, just prior to the outbreak of Covid 19. Our study used clinical follow up, rather than biological markers to determine Febridx effectiveness.

    Our study was designed to compare antibiotic prescribing in those doctors using the device to determine the difference between viral and bacterial illness compared to those doctors relying on their usual clinical skills. Our study was sabotaged by the advent of Covid 19 and the introduction of lockdowns, isolation, and telehealth. Like much of the country, we saw presentations for URTI’s and the subsequent use of all antibiotics, especially those associated with respiratory disease, decrease.

    Our six-doctor general practice used Best Practice clinical software to determine the number of antibiotics prescribed and the number of patients seen each month for each doctor.

    In the 6 months prior to covid epidemic, prescribing of respiratory antibiotics (Amoxycillin, Amoxycillin/Clavulanic acid, Cephalexin, Roxithromycin, Trimethoprim/sulfamethoxazole, Clindamycin, Ciproxin, penicillin) was 7.3 antibiotics...

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  • Restoring the credit of PSCK inhibitors for the prevention of cardiovascular events

    Dear Sir
    The article by Erviti et al. [1] is a provocative reinterpretation of the data from the FOURIER trial [2]. However, their conclusion indicating that clinicians should be ‘sceptical about prescribing evolocumab for patients with established atherosclerotic cardiovascular disease’ is not adequately supported by the data provided.
    First, global mortality did not statistically differ between placebo and evolocumab groups. Therefore, given that total mortality remains unchanged in both groups by Erviti’s analysis, any increase in cardiovascular mortality must be identical numerically to a reduction in non-cardiovascular (+ undetermined) mortality. The claim of increased cardiovascular mortality is thus numerically compensated by a reduction in non cardiovascular mortality. Of note, the FORIER trial was not powered to discriminate the effect of evolocumab on cardiovascular and non cardiovascular mortality; this lack of power remains for Ertivi’s analysis: none of their concerns is supported by any statistically significant difference. Further speculation regarding other individual end point sub group analysis must be interpreted with caution: it is fun to look at, but do not believe them [3]. While it is worth carefully reviewing the adjudication of cardiovascular mortality, FOURIER open label extension study suggest that longer treatment with evolocumab may indeed reduce cardiovascular mortality. [4]
    Even if we remain sceptical about a potential red...

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  • “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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