“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...
“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 investigator-reported (52.2%) and 558 (52.8%) adjudicated cardiovascular deaths among 1057 deaths (difference +0.6%).
A second study investigated the events of the REDUCE-IT trial.3 This trial assessed the effects of icosapent ethyl versus placebo in 8,179 patients with elevated triglycerides that used a statin. The number of investigator-reported and adjudicated cardiovascular deaths was the same: 387 of 592 (65.4%) deaths (difference 0.0%).
A third study analysed the STABILITY trial that compared darapladib to placebo in 15,828 patients with stable coronary disease.4 There were 667 (62.7%) investigator-reported and 638 (60.0%) adjudicated cardiovascular deaths of 1064 deaths (difference -2.7%).
A fourth paper concerned the SOCRATES trial that evaluated the effects of ticagrelor versus aspirin in 13,199 patients after stroke or transient ischemic attack.5 There were 87 (58.8%) investigator-reported and 93 (62.8%) adjudicated cardiovascular deaths among 148 all-cause deaths (difference +4.0%).
The four cited studies demonstrate a high concordance in the number of cardiovascular deaths reported by local investigators and adjudicated by central adjudication committees. Similar results were found for the primary composite outcomes of the investigated trials, which included non-fatal myocardial infarcts and strokes. Hence, the question remains why there was such a large discrepancy in investigator-reported and adjudicated cardiovascular deaths in FOURIER, and whether the non-fatal cardiovascular events show the same discrepancy. If Sabatine et al. have “complete confidence in the adjudicated events”, then why not share the raw data for independent restoration and reanalysis?
F.H. van Bruggen, H. J. Luijendijk
Department of General Practice, UMCG, PO Box 196, 9700 AD Groningen, The Netherlands. E-mail: h.j.luijendijk@umcg.nl
1. Erviti J, Wright J, Bassett K, et al. 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(12):e060172. doi:10.1136/bmjopen-2021-060172
2. Gaba P, Bhatt DL, Dagenais GR et al. Comparison of Investigator-Reported vs Centrally Adjudicated Major Adverse Cardiac Events: A Secondary Analysis of the COMPASS Trial. JAMA Netw Open. 2022;5(11):e224. doi:10.1001/jamanetworkopen.2022.43201
3. Gaba P, Bhatt DL, Giugliano RP, et al. Comparative Reductions in Investigator-Reported and Adjudicated Ischemic Events in REDUCE-IT. J Am Coll Cardiol. 2021. doi:10.1016/j.jacc.2021.08.009
4. Held C, White HD, Stewart RAH, et al. Characterization of cardiovascular clinical events and impact of event adjudication on the treatment effect of darapladib versus placebo in patients with stable coronary heart disease: Insights from the STABILITY trial. Am Heart J. 2019. doi:10.1016/j.ahj.2018.10.010
5. Easton JD, Denison H, Evans SR, et al. Estimated treatment effect of ticagrelor versus aspirin by investigator-assessed events compared with judgement by an independent event adjudication committee in the SOCRATES trial. Int J Stroke. 2019. doi:10.1177/1747493019851282
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...
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 had. The authors claim to have followed the definitions used in FOURIER, but their own commentary calls into question their understanding of the definitions. Most critically, the authors admit their results were overread by an unblinded “Validation Committee” which irreparably taints the process and would not be accepted by regulatory agencies.4
The authors note that in 26% of deaths, the FOURIER CEC final adjudication differed from the investigators’ initial categorization. Curiously, they describe these differences as “inconsistencies.” But the very purpose of the CEC is for trained and qualified experts to apply standardized definitions to properly classify events in a consistent manner using medical source documentation. Such a process will naturally result in reclassification, that is the point.
The authors apply their flawed process to attempt to reassign categories of death. Unsurprisingly, given their reliance on very limited data, primarily they simply increased the number of “undetermined” deaths by more than 50%. The authors describe their 2 best examples of what they felt were “errors” by the FOURIER CEC. In the first case, the authors state the patient “clearly” had an MI, which was “neglected” by the FOURIER CEC. In reality, the source documents show this patient died in his sleep, and thus according to the FDA definitions, the FOURIER CEC properly adjudicated this as sudden cardiac death. In the second case, the authors state the patient died of an MI that was “misadjudicated” by the FOURIER CEC as a non-cardiovascular death. In reality, the source documents show this patient slipped in his kitchen, struck his head, was admitted to the ED with head trauma and died, which would not be considered a CV death.
In their post-hoc, unblinded process, the authors differentially shifted slightly more deaths out of the cardiovascular bin (largely to “undetermined”) in the placebo arm than in the evolocumab arm. That resulted in 25 more cardiovascular deaths in the evolocumab than the placebo arm. However, they deliberately ignore the converse result of their process, which was now 20 fewer undetermined deaths in the evolocumab than the placebo arm.
We have complete confidence in the FOURIER results adjudicated by the TIMI CEC. The paper by Erviti et al. is flawed in design and execution and, in our opinion, a gross disservice to the medical literature, cardiovascular health care providers, and patients.
Disclosures
MSS reports research grant support to the TIMI Study Group through Brigham and Women’s Hospital from: Abbott; Amgen; Anthos Therapeutics; AstraZeneca; Daiichi-Sankyo; Eisai; Intarcia; Ionis; Merck; Novartis; Pfizer; and honoraria for consulting from: Althera; Amgen; Anthos Therapeutics; AstraZeneca; Beren Therapeutics; Boehringer Ingelheim; Fibrogen; Intarcia; Merck; Moderna; Novo Nordisk; Precision BioSciences; Silence Therapeutics.
SDW reports research grant support to the TIMI Study Group through Brigham and Women’s Hospital from: Amgen, AstraZeneca, Daiichi Sankyo, Eisai, Janssen, Merck, and Pfizer. Consulting fees from AstraZeneca, Boston Clinical Research Institute, Icon Clinical, and NovoNordisk. Dr. Wiviott’s wife is a former employee of Merck.
ACK reports grants and personal fees from Abbott and Mylan; personal fees from Amgen, AstraZeneca and Pfizer; grants from Sanofi and Novartis; and personal fees from Bayer.
PSS reports support from the Biomedical Research Centre, Imperial College NHS Trust, grant support from Pfizer, Amgen, and Servier, honoraria and lectures from Amgen, Pfizer and Viatris.
RPG reports research grant support to the TIMI Study Group through Brigham and Women’s Hospital from: Amgen; Anthos Therapeutics; Ionis; Daiichi Sankyo; honoraria for lectures and/or consulting from: Amarin; Amgen; Artivion; Caladrius; Centrix; CSL Behring; Daiichi Sankyo; Dr. Reddy’s Laboratories; Esperion; Gilead; Hengrui; Inari; Janssen; Labcorp; Medical Education Resources; Medscape; Menarini; Merck; Novartis; Paratek; Pfizer; PhaseBio; SAJA; Servier; Shanghai Medical Group; St. Lukes Hospital (Kansas City); Sanofi; Voxmedia.
References
1. Erviti J, Wright J, Bassett K, Ben-Eltriki M, Jauca C, Saiz LC, Leache L, Gutierrez-Valencia M and Perry TL. 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:e060172.
2. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS, Pedersen TR, for the FOURIER Steering Committee and Investigators. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376:1713-1722.
3. Hicks KA, Tcheng JE, Bozkurt B, Chaitman BR, Cutlip DE, Farb A, Fonarow GC, Jacobs JP, Jaff MR, Lichtman JH, Limacher MC, Mahaffey KW, Mehran R, Nissen SE, Smith EE and Targum SL. 2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular Endpoint Events in Clinical Trials: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Cardiovascular Endpoints Data Standards). Circulation. 2015;132:302-61.
4. Sharma A, Mahaffey KW, Gibson CM, Hicks KA, Alexander KP, Ali M, Chaitman BR, Held C, Hlatky M, Jones WS, Mehran R, Menon V, Rockhold FW, Seltzer J, Spitzer E, Wilson M and Lopes RD. Clinical events classification (CEC) in clinical trials: Report on the current landscape and future directions - proceedings from the CEC Summit 2018. Am Heart J. 2022;246:93-104.
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...
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 archiving in the security database. The authors based all their investigations and judgments on such reports and repeatedly reproduced that "The narrative contained no evidence to support the cause of death adjudicated by the FOURIER Clinical Events Committee," as shown in Supplement 2.
I agree with the RIAT initiative, however, the lack of information related to the Safety Data Committee, the adjudication process, the detailed safety information, and the generation of the CSR has probably caused a misinterpretation of the data by the authors and draw erroneous conclusions. I also wonder if the journal's reviewers realized these points before accepting the article for publication. I cannot be conclusive about the above, but surely Amgen would further clarify the consistency of the data presented in the NEJM article by providing more robust data from the results of 130 evolocumab clinical trials registered on Clinicaltrial.gov. Finally, the article also mentions that the RIAT team contacted the main author of the article published in NEJM without success. In that sense, a more effective approach might have been to contact Amgen directly and discuss with them the intentions of reviewing the study data. Certainly, this may have helped the authors to gain access to the full safety data and ensure proper review of it.
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...
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 be related to the risk of glaucoma.
Finally, Gracitelli et al. evaluated the function of intrinsically photosensitive retinal ganglion cells (ipRGCs) in patients with glaucoma (4). Sleep polysomnography was applied to subjects for measuring sleep parameters, and retinal nerve fiber layer (RNFL) thickness and the pupillary light reflex were also measured. Patients with glaucoma presented lower total sleep time, sleep efficiency, and minimum oxyhemoglobin saturation compared with the healthy subjects. In addition, patients with glaucoma had significantly higher arousal durations after falling asleep and more periodic limb movements. The RNFL thickness was significantly associated with the peak and sustained responses to the blue flash, but the RNFL thickness was only associated with the mean oxygen desaturation index among sleep parameters. This means that decreased ipRGC function caused by glaucoma is related to poor pupillary response and SAS-related sleep disorder. This is a cross-sectional study, and causal direction should be evaluated by adopting a prospective design.
References
1. Sun C, Yang H, Hu Y, Qu Y, Hu Y, Sun Y, Ying Z, Song H. Association of sleep behaviour and pattern with the risk of glaucoma: a prospective cohort study in the UK Biobank. BMJ Open 2022;12(11):e063676.
2. García-Sánchez A, Villalaín I, Asencio M, et al. Sleep apnea and eye diseases: evidence of association and potential pathogenic mechanisms. J Clin Sleep Med 2022;18(1):265-78.
3. Shinmei Y, Nitta T, Saito H, et al. Continuous intraocular pressure monitoring during nocturnal sleep in patients with obstructive sleep apnea syndrome. Invest Ophthalmol Vis Sci 2016;57(6):2824-30.
4. Gracitelli CP, Duque-Chica GL, Roizenblatt M, et al. Intrinsically photosensitive retinal ganglion cell activity is associated with decreased sleep quality in patients with glaucoma. Ophthalmology 2015;122(6):1139-48.
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...
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 lipid-lowering drug.
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...
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 ezetimibe 12.7%.4 Several cohort studies reported proportions between 7.2% and 18.3%.5–7 No explanation for this high proportion was provided even though hospitalization for UA was a component of the primary composite outcome.
Secondly, evolocumab did not affect the risk of hospitalization for UA (HR 0.99; 95% CI 0.82 to 1.18), but significantly reduced the risk of non-ST-elevation myocardial infarction (NSTEMI; HR 0.77; 95% CI 0.68 to 0.88) and ST-elevation myocardial infarction (STEMI; HR 0.64; 95% CI 0.49 to 0.84).8 UA, NSTEMI and STEMI are all acute coronary syndromes and share common pathophysiological pathways that involve atherosclerosis and thrombosis.9 Therefore, one would expect that lipid lowering therapy would prevent UA, as well as NSTEMI and STEMI. Alirocumab reduced the risk of UA (HR 0.61; 95% CI 0.41-0.92) and NSTEMI (HR 0.82; 95% CI 0.72-0.93) statistically significantly in ODYSSEY OUTCOMES. The risk of STEMI was also (numerically) lower (HR 0.84; 0.64 to 1.11).3,10
Thirdly, as we observed before, the clinical events committee did not confirm a large proportion of the local clinical investigators’ diagnoses of myocardial infarction and stroke either (8% respectively 17%).11 Moreover, the proportion of unconfirmed strokes was higher in the evolocumab group than the placebo group of FOURIER (21% and 14%; p = 0.044).11 The study protocol contained clear definitions for all cardiovascular outcomes that should have ensured appropriate clinical diagnoses for most events.
The inconsistencies in the reported non-fatal cardiovascular events in FOURIER question how these events were adjudicated. Erviti et al’s findings did not reassure us. Therefore, it is necessary to investigate how many non-fatal events were reclassified by the clinical events committee, and what the original clinical diagnoses were. To enable such a restoration of the non-fatal cardiovascular events in FOURIER, we ask the medication authorization agencies to request a CSR that includes the related case report forms and make it publicly available.
F.H. van Bruggen, H. J. Luijendijk
Department of General Practice, UMCG, PO Box 196, 9700 AD Groningen, The Netherlands. E-mail: h.j.luijendijk@umcg.nl
References
1. Erviti J, Wright J, Bassett K et al. 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:e060172. doi:10.1136/bmjopen-2021-060172
2. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376(18):1713-1722. doi:10.1056/nejmoa1615664
3. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 2018;379(22):2097-2107. doi:10.1056/nejmoa1801174
4. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015;372(25):2387-2397. doi:10.1056/nejmoa1410489
5. Eggers KM, Jernberg T, Lindahl B. Unstable Angina in the Era of Cardiac Troponin Assays with Improved Sensitivity—A Clinical Dilemma. Am J Med. 2017. doi:10.1016/j.amjmed.2017.05.037
6. D’Souza M, Sarkisian L, Saaby L, et al. Diagnosis of Unstable Angina Pectoris Has Declined Markedly with the Advent of More Sensitive Troponin Assays. Am J Med. 2015. doi:10.1016/j.amjmed.2015.01.044
7. Toušek P, Bauer D, Neuberg M, Nováčková M, Mašek P, Tu Ma P, Kočka V, Moťovská Z WP. Patient characteristics, treatment strategy, outcomes, and hospital costs of acute coronary syndrome: 3 years of data from a large high-volume centre in Central Europe. Eur Hear J. 2022;Mar 30;24. doi:10.1093/eurheartjsupp/suac001
8. Wiviott SD, Giugliano RP, Morrow DA, et al. Effect of Evolocumab on Type and Size of Subsequent Myocardial Infarction: A Prespecified Analysis of the FOURIER Randomized Clinical Trial. JAMA Cardiol. 2020;5(7):787-793. doi:10.1001/jamacardio.2020.0764
9. Falk E, Nakano M, Bentzon JF, Finn A V., Virmani R. Update on acute coronary syndromes: The pathologists’ view. Eur Heart J. 2013. doi:10.1093/eurheartj/ehs411
10. White HD, Gabriel Steg P, Szarek M, et al. Effects of alirocumab on types of myocardial infarction: Insights from the ODYSSEY OUTCOMES trial. Eur Heart J. 2019;40(33):2801-2809. doi:10.1093/eurheartj/ehz299
11. van Bruggen FH, Nijhuis GBJ, Zuidema SU, Luijendijk HJ. Response to letter to the editor re: ‘serious adverse events and deaths in PCSK9 inhibitor trials reported on ClinicalTrials.gov: a systematic review.’ Expert Rev Clin Pharmacol. 2021. doi:10.1080/17512433.2021.1874350
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...
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 in the patient’s health and its developments are key for optimal patient care and good clinical practice.
To gain this additional information and insight, we propose to use already existing and validated questionnaires to measure the six dimensions of PH. The achievement of Huber et al. is that they combined already defined manifestations of health in a new conceptualisation of health. The use of already available and validated questionnaires is advantageous in several ways. First, no additional time is required for developing and validating new measures. Second, the available norm values of validated questionnaires allow for comparison between patient groups. Third, this approach will enable researchers to specify PH in disease-specific patient populations, which offers essential information for clinical practice. Validated disease- or organ-specific instruments for bodily functions are available for most disorders or organ systems. For example, the validated Gastrointestinal Symptom Rating Scale (GSRS) (3) is used to quantify bodily symptoms in patients with gastrointestinal disorders.
That the items in the existing questionnaires partially overlap, as Prinsen et al. (4) argue, is, in our opinion, not a problem. The dimensions should not be considered separately but integrally. For our research population of patients with gastrointestinal disorders, we use the GI diseases specific symptom score GSRS (3) and the score for malnutrition SNAQ (5) for bodily symptoms and functions. Furthermore, we use the general questionnaires PHQ-9 (6), GAD-7 (7), SF-36 (8), DEQ (subscale meaningful) (9), EQ-5D (10) and WPAI-GH (11), thus covering all dimensions of PH.
Critics may argue that we deviate from the original conceptualisation of PH as an individual experience. The validated measures we propose are self-report questionnaires and thus both helpful for research purposes but also to understand how the patients experiences his or her health.
1. Huber M, Knottnerus JA, Green L, Horst Hvd, Jadad AR, Kromhout D, et al. How should we define health? BMJ. 2011; 343:d4163.
2. Bock LA, Noben CYG, Yaron G, George ELJ, Masclee AAM, Essers BAB, et al. Positive Health dialogue tool and value-based healthcare: a qualitative exploratory study during residents' outpatient consultations. BMJ Open. 2021; 11:e052688.
3. Kulich KR, Madisch A, Pacini F, Piqué JM, Regula J, Van Rensburg CJ, et al. Reliability and validity of the Gastrointestinal Symptom Rating Scale (GSRS) and Quality of Life in Reflux and Dyspepsia (QOLRAD) questionnaire in dyspepsia: a six-country study. Health Qual Life Outcomes. 2008; 6:12.
4. Prinsen CAC, Terwee CB. Measuring positive health: for now, a bridge too far. Public Health. 2019; 170:70-7.
5. Kruizenga HM, Seidell JC, de Vet HC, Wierdsma NJ, van Bokhorst-de van der Schueren MA. Development and validation of a hospital screening tool for malnutrition: the short nutritional assessment questionnaire (SNAQ). Clin Nutr. 2005; 24:75-82.
6. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001; 16:606-13.
7. Löwe B, Decker O, Müller S, Brähler E, Schellberg D, Herzog W, et al. Validation and standardization of the Generalized Anxiety Disorder Screener (GAD-7) in the general population. Med Care. 2008; 46:266-74.
8. Jenkinson C, Wright L, Coulter A. Criterion validity and reliability of the SF-36 in a population sample. Qual Life Res. 1994; 3:7-12.
9. Galardi M. Validation of the disease experience questionnaire for working age adults with chronic conditions. 2020.
10. Payakachat N, Ali MM, Tilford JM. Can The EQ-5D Detect Meaningful Change? A Systematic Review. Pharmacoeconomics. 2015; 33:1137-54.
11. Yarlas A, Maher SM, Bayliss MS, Lovley A, Cappelleri JC, DiBonaventura MD. Psychometric validation of the work productivity and activity impairment questionnaire in ulcerative colitis: results from a systematic literature review. J Patient Rep Outcomes. 2018; 2:62.
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.
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...
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 suggestion on specific flavonoids might be very helpful for researchers specifically who are looking at green tea consumption and its impact on the current respiratory COVID infection, which might be protective for those who consume green tea regularly.
1. Yuan, J.M., et al., Urinary biomarkers of tea polyphenols and risk of colorectal cancer in the Shanghai Cohort Study. Int J Cancer, 2007. 120(6): p. 1344-50.
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.
“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,
Show MoreIn 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...
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.
Show MoreIn 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...
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.
Show MoreThe 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...
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...
Show MoreI 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...
Show MoreDear editor,
Show MoreErviti 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...
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...
Show MoreThank 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.
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...
Show MoreThank 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.
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