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:e060172
Marc S. Sabatine, MD, MPH,1 Stephen D. Wiviott, MD,1 Anthony C. Keech, MD,2 Peter S. Sever, PhD, FRCP,3 Robert P. Giugliano, MD, SM1
1TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital and Harvard Medical School
2Sydney Medical School, National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney
3National Heart and Lung Institute, Imperial College, London
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.
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.
PDF – Response to FOURIER reanalysis in BMJ Open by Sabatine, Wiviott, Keech, Sever and Giugliano