data inconcistency in reporting of cardiovascular events in the FOURIER study

Last edited 01/2023 and last reviewed 01/2023

Data inconcistency in reporting of cardiovascular events in the FOURIER study

The FOURIER trial showed a benefit of the PCSK9 inhibitor evolocumab over placebo with respect to cardiovascular outcomes in patients with cardiovascular disease. However, authors of a study (1) observed some inconsistencies between the information in the Clinical Study Report (CSR) and that in the 2017 primary trial results publication.

• Mortality data in the primary results publication were compared with that in the CSR
  • in cases of discrepancy between the sources, an independent committee blindly readjudicated and restored the cause of death according to the information in the CSR narratives
• Analysis of the FOURIER Clinical Study Report found the clinical events committee and local clinical investigator differed in recorded cause of death in 41.4% of cases.
  • for 360/870 deaths (41.4%), the cause of death adjudicated by the FOURIER clinical events committee differed from that declared by the local clinical investigator
    • when comparing the CSR information with the 2017 primary results publication, the study authors found 11 more deaths from myocardial infarction in the evolocumab group (36 vs 25) and 3 less deaths in the placebo group (27 vs 30, respectively)
    • in the CSR, the number of deaths due to cardiac failure in the evolocumab group was almost double those in the placebo group (31 vs 16)
    • while cardiac and vascular deaths were not assessed as separate outcomes in the original trial analysis, after readjudication, the study authors noted that cardiac deaths were numerically, but non-significantly, higher in the evolocumab group (113) than in the placebo group (88; relative risk (RR) 1.28, 95% CI 0.97 to 1.69, p=0.078), whereas non-cardiac vascular deaths were similar between groups (37 in each; RR 1.00, 95% CI 0.63 to 1.58, p=0.999)
    • the reported HR for cardiovascular mortality in the original trial analysis was 1.05 (95% CI 0.88 to 1.25); after readjudication, we found a greater (although still non-significant) relative increase in cardiovascular mortality in the evolocumab treatment group (RR 1.20, 95% CI 0.95 to 1.51, p=0.13)

The study authors suggest that:

• ".. At the time the trial was terminated early, a non-significantly 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. In the meantime, clinicians should be sceptical about prescribing evolocumab for patients with established atherosclerotic cardiovascular disease.."

Notes:

• The FOURIER trial was planned for 56 months (4.7 years)
  • however, it was terminated early for apparent benefit after a median follow-up of 2.2 years (2)

Reference:

• 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
• Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS, Pedersen TR; FOURIER Steering Committee and Investigators. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017 May 4;376(18):1713-1722.