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Restoring mortality data in the FOURIER cardiovascular outcomes trial of evolocumab in patients with cardiovascular disease: a reanalysis based on regulatory data
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  • Published on: 9 February 2023
    Another independent Analysis of the FOURIER data is required
    • Jochen Schuler, Cardiologist, Research Associate Institute of General Practice, Family Medicine and Preventive Medicine, Paracelsus Private Medical University Salzburg AT

    The question raised by Juan Ervriti and Colleagues (1) whether the obvious benefit of evolocumab is offset by a currently unknown risk is justified and of high clinical relevance. We know active ingredients that effectively lower the atherogenic lipopoproteins, but have an unfavorable benefit-risk ratio under the bottom line (2). Therefore, the raised concerns must be addressed.
    The chosen methodology by Ervriti and Colleagues seems to me feasible, although not perfect. For a comprehensive reanalysis the raw data are required. Unfortunately they never received such data, although they have made many efforts to do so.
    To my opinion, scientific misconduct – as intended by Sabatine et. al. (3) - is not the case with Evriti et al. but rather with the FOURIER authors and the study sponsor, who apparently never answered the questions that were put to them repeatedly and publicly (4).
    The announcement by the FOURIER authors that they will respond to the accusations now promptly (3) is no longer sufficient. They are biased in a number of ways, but primarily because their scientific reputation is at stake. There is no other way to understand their rude reaction.
    From my point of view, it is also highly irritating that neither EMA nor Health Canada seem to have scrutinized the case report forms (CRF) when they approved this new drug. It looks like they've never laid their hands on a FOURIER-CRF. If that is the case, then they trusted the investigators bl...

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    Conflict of Interest:
    None declared.
  • Published on: 30 January 2023
    “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.”
    • Folkert van Bruggen, GP and PhD candidate University Medical Centre Groningen, the Netherlands
    • Other Contributors:
      • Dika Luijendijk, Senior Researcher

    “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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    Conflict of Interest:
    None declared.
  • Published on: 25 January 2023
    Response to Dr. Guijarro
    • Juan Erviti, senior researcher Innovation and Organization Unit, Navarre Health Service, Pamplona, Spain
    • Other Contributors:
      • James M Wright, MD, PhD, Professor
      • Ken Bassett, MD, PhD, Professor
      • Mohamed Ben-Eltriki, PharmD, researcher
      • Ciprian Jauca, Research Associate
      • Luis C Saiz, Pharm D, PhD, researcher
      • Leire Leache, Pharm D, PhD, researcher
      • Marta Gutiérrez-Valencia, PharmD, PhD, researcher
      • Thomas L Perry, MD, PhD, Associate professor

    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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    Conflict of Interest:
    None declared.
  • Published on: 19 January 2023
    Response to Dr. Sabatine et al.
    • Juan Erviti, Pharm D, PhD, senior researcher Innovation and Organization Unit, Navarre Health Service, Pamplona, Spain
    • Other Contributors:
      • James M Wright, MD, PhD, Professor
      • Ken Bassett, MD, PhD, Professor
      • Mohamed Ben-Eltriki, PharmD, researcher
      • Ciprian Jauca, Research Associate
      • Luis C Saiz, Pharm D, PhD, researcher
      • Leire Leache, Pharm D, PhD, researcher
      • Marta Gutiérrez-Valencia, PharmD, PhD, researcher
      • Thomas L Perry, MD, PhD, Associate professor

    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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    Conflict of Interest:
    None declared.
  • Published on: 19 January 2023
    Restoring the credit of PSCK inhibitors for the prevention of cardiovascular events
    • Carlos Guijarro, Internal Medicne. Cardiovascular risk clinic Hospital Universitari Fundacion Alcorcon - Universidad Rey Juan Carlos . Madrid, Spain

    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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    Conflict of Interest:
    I have received fees for lectures and advisory boards from AMGEN and Sanofi
  • Published on: 19 January 2023
    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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    Conflict of Interest:
    None declared.
  • Published on: 13 January 2023
    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.
    • Marc S. Sabatine, MD, MPH, Professor of Medicine; Cardiologist Brigham & Women's Hospital/Harvard Medical School
    • Other Contributors:
      • Stephen D. Wiviott, MD, Professor of Medicine; Cardiologist
      • Anthony C. Keech, MD, Professor of Medicine; Cardiologist
      • Peter S. Sever, PhD, FRCP, Professor of Clinical Pharmacology and Therapeutics
      • Robert P. Giugliano, MD, SM, Professor of Medicine/Cardiologist

    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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    Conflict of Interest:
    MSS reports research grant support 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 grants to the TIMI Study Group through institution from Amgen; AstraZeneca; Daiichi-Sankyo; Eisai; Janssen; Merck; Pfizer, and consulting fees from AstraZeneca; Boston Clinical Research Institute; Icon Clinical; and NovoNordisk. Dr. Wiviott’s wife is a former employee of Merck. RPG reports research grant support through Brigham and Women’s Hospital from: Amgen; Anthos Therapeutics; Ionis; Daiichi-Sankyo; honoraria for lectures or CME programs from Amgen; Centrix; Daiichi-Sankyo; Dr. Reddy’s Laboratories; Medical Education Resources (MER); Medscape; Menarini; Merck; Pfizer; SAJA Pharmaceuticals; Servier; Shanghai Medical Telescope; Voxmedia, and consulting from: Amarin; Amgen; Artivion, Inc.; Bayer; Boston Scientific; Caladrius; CSL Behring; CVS Caremark; Daiichi-Sankyo; Esperion; Gilead; Hengrui; Inari; Janssen; Novartis; Paratek; Pfizer; PhaseBio Pharmaceuticals; Samsung. 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.
  • Published on: 10 January 2023
    Sceptical?
    • John W Davis, Physician-Scientist Trainee University Of Texas Medical Branch At Galveston

    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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    Conflict of Interest:
    I take Evolocumab for Familial Hypercholesterolemia.
  • Published on: 10 January 2023
    Re: “Restoring mortality data in the FOURIER cardiovascular outcomes trial of evolocumab in patients with cardiovascular disease: a reanalysis based on regulatory data”
    • Folkert van Bruggen, GP and pH-D candidate University Medical Centre Groningen, the Netherlands
    • Other Contributors:
      • Dika Luijendijk, Researher

    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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    Conflict of Interest:
    None declared.