Investigators writing in BMJ Open called for “a complete restoration of FOURIER trial data.” Amgen, the maker of evolocumab, said it stood by the data.
This article was updated January 5 with statements from Amgen.
A strong warning has been issued for evolocumab (Repatha) by researchers from Spain and Canada on use of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor among adult patients who have established atherosclerotic cardiovascular disease following their analysis of purported inconsistencies between the FOURIER trial’s Clinical Study Report (CSR) and publication of primary trial results in 2017.
Publishing their findings just last week in BMJ Open, the international team from Navarre Health Service, Navarre Institute for Health Research, and The University of British Columbia, wrote how they wanted to restore the trial’s mortality data “based on the information contained in the death narratives in the CSR.”
Amgen, the maker of evolocumab, pushed back strongly against the findings in an emailed statement. "We stand behind the integrity and validity of the FOURIER trial and results. As mentioned in the BMJ Open manuscript, there are a number of limitations to the Erviti et al. analysis resulting in an incomplete assessment of the FOURIER data and a flawed conclusion," the statement read.
First approved in August 2015 for patients needing additional lowering of their low-density lipoprotein cholesterol, evolocumab received an additional indication in 2017, via the FDA’s priority review process, as a preventive treatment for heart attack, stroke, and coronary revascularizations. This followed results from FOURIER, presented at the American College of Cardiology Scientific Sessions in 2017. Evolocumab also has indications to treat adult and pediatric patients who have forms of familial hypercholesterolemia.
With that approval in 2015, the PCSK9 inhibitor ran into barriers to coverage from payers, who made it difficult for patients to access both evolocumab and its chief competitor, alirocumab (Praluent), due to concerns about cost, which was initially more than $14,000 a year.
Then, there was a protracted patent dispute between Amgen and Sanofi/Regeneron, which saw judgement handed down against Amgen for its intellectual property claims against Praluent.
Now, these new findings raise another round of questions.
After independent review, the investigators for the present study found a 41.4% inconsistency rate between FOURIER clinical events and those noted by the local clinical investigator for the CSR. This equates to a different cause of death in 360 of 870 instances.
Eleven of these deaths were due to myocardial infarction (MI) in the evolocumab group, bringing the death total from MI to 36 compared with the previous total of 25 from the primary analysis. Deaths from MI also dropped from 30 to 27 in the placebo group. Further, the evolocumab group was found to have twice the amount of cardiac failure–related deaths vs the placebo group: 31 vs 16.
In addition, although deemed nonsignificant, there was a higher total of cardiac deaths seen in the evolocumab group—113 vs 88—representing a 28% higher risk of that outcome following use of evolocumab (relative risk [RR], 1.28; 95% CI, 0.97-1.69; P = .078). Noncardiac vascular-related deaths, however, were shown to be similar, coming in at 37 each following data readjudication (RR, 1.00; 95% CI, 0.63-1.58; P = .999).
Overall, the risk of cardiovascular mortality was 5% according to the primary data analysis (HR, 1.05; 95% CI, 0.88-1.25) published in The New England Journal of Medicine, and the re-review found a risk of 20% (RR, 1.20; 95% CI, 0.95-1.51; P = .13).
A team of Restoring Invisible and Abandoned Trials (RIAT) investigators was formed for the new review of the FOURIER data in 2018. This team then applied to the European Medicines Agency (EMA), Health Canada, and the FDA for the FOURIER trial’s CSR. Access was granted only by the first 2 agencies, with the FDA noting in October 2019 that it could take up to 7 years for release of the CSR, according to the BMJ Open article.
All death narratives from the CSR were assessed by the RIAT secretary in the new analysis, and a cause of death was reassigned following the readjudication whenever the narrative information did not match the adjudication reporting.
“After readjudication, deaths of cardiac origin were numerically higher in the evolocumab group than in the placebo group in the FOURIER trial, suggesting possible cardiac harm,” the study investigators concluded. “At the time the trial was terminated early, a nonsignificantly higher risk of cardiovascular mortality was observed with evolocumab, which was numerically greater in our readjudication. A complete restoration of the FOURIER trial data is required.”
Top lessons learned from the readjudication are the great need for independent scrutiny of medical data and that CSRs, while valuable overall at indicating trial findings, may still contain gaps. Because of these, the authors indicate “all narratives for events should be included in the CSR.”
The Amgen statement disputed these conclusions. First, it outlined the FOURIER clinical trial event adjudication process in detail, saying it followed standards set by the FDA, other regulatory agencies, and other cardiovascular outcomes trials, which arose after 2008 due to controversy that some drugs for type 2 diabetes were actually causing cardiovascular harm.
Amgen's statement said, "The TIMI Study Group (which conducted FOURIER) had access to all information within each adjudication package that would not have been contained in a clinical study report narrative, enabling them to make a more accurate determination of the cause of death."
Additional reporting by Mary Caffrey.
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. Published online December 30, 2022. doi:10.1136/bmjopen-2021-060172