Restoring mortality data in the FOURIER cardiovascular outcomes trial of evolocumab in patients with cardiovascular disease: a reanalysis based on regulatory data
Bibliographic record
Abstract
OBJECTIVE: The FOURIER trial showed a benefit of the PCSK9 inhibitor evolocumab over placebo with respect to cardiovascular outcomes in patients with cardiovascular disease. However, we observed some inconsistencies between the information in the Clinical Study Report (CSR) and that in the 2017 primary trial results publication. We aimed to restore the mortality data in the FOURIER trial based on the information contained in the death narratives in the CSR. METHODS: 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. RESULTS: 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, we 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, we 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). CONCLUSION: 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. 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. TRIAL REGISTRATION NUMBERS: NCT01764633.
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How this classification was reachedexpand
Direct model labels (unvalidated)
Per-model category and study-design labels from the labeling rounds. They are machine output, unvalidated, and the disagreement between models ships as data. No study design here is MEDLINE-validated yet.
| Model arm | Categories | Study design | Confidence |
|---|---|---|---|
| gemma | Metaresearch Domain: Reproducibility · Genre: Empirical About the Canadian research system: no · About a Canadian topic: no | Observational | high |
| gpt | Metaresearch Domain: Evaluation · Genre: Empirical About the Canadian research system: no · About a Canadian topic: no | Other design | high |
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.036 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.003 | 0.002 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedLabeled directly by 2 models reading the full record.
The models disagree on parts of this classification; every voice is preserved in the section at the end of the page.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".