Association of Febuxostat to Cardiovascular Mortality in Gout: A Systematic Review
Notice bibliographique
Résumé
Introduction: Gout, a systemic metabolic disorder characterized by hyperuricemia, is an independent risk factor for cardiovascular (CV) disease. Febuxostat, a potent xanthine oxidase inhibitor, has demonstrated superior urate-lowering efficacy compared to allopurinol. However, its CV safety profile has been the subject of significant controversy following conflicting results from two major randomized controlled trials (RCTs), the CARES and FAST trials, and a subsequent FDA black box warning regarding increased mortality risk. This systematic review aims to synthesize the current evidence on the association between febuxostat and CV mortality in patients with gout. Methods: A systematic search was conducted in PubMed/MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials for RCTs and observational cohort studies comparing the CV safety of febuxostat with allopurinol or other controls in patients with gout or hyperuricemia. Data on primary outcomes (CV mortality, all-cause mortality) and numerous secondary CV outcomes were extracted. The quality of RCTs was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool, and observational studies were assessed with the Newcastle-Ottawa Scale. Results: Seventeen studies, including five major RCTs and twelve observational studies and meta-analyses, were included. A significant signal for increased mortality was identified. The pivotal CARES trial, involving 6,190 high-risk CV patients, found that febuxostat was associated with a statistically significant increase in CV mortality (Hazard Ratio 1.34, 95% Confidence Interval [CI] 1.03–1.73) and all-cause mortality (HR 1.22, 95% CI 1.01–1.47) compared to allopurinol. This finding was supported by a meta-analysis by Cuenca et al. (2019) (Relative Risk for CV death 1.29, 95% CI 1.01–1.66) and an Austrian cohort study. However, a substantial body of conflicting evidence exists. The FAST trial (n=6,128) found febuxostat to be non-inferior to allopurinol, with no increased risk of CV or all-cause mortality. Multiple large-scale cohort studies and meta-analyses corroborated the findings of the FAST trial, reporting no significant difference in mortality or major adverse cardiovascular events (MACE). Discussion: The discrepancy in findings is largely attributable to critical differences in study populations and methodologies between the CARES and FAST trials. CARES enrolled patients with established, severe CV disease who were often initiating urate-lowering therapy, whereas FAST studied a lower-risk population already stable on allopurinol. The high rate of participant discontinuation in the CARES trial represents a significant risk of bias. Emerging evidence suggests the increased risk may be concentrated in the treatment initiation phase or may be linked to sUA fluctuations following treatment discontinuation, rather than a direct pharmacological effect of the drug itself. Conclusion: A significant association between febuxostat and increased cardiovascular mortality has been demonstrated, primarily driven by the CARES trial in a specific high-risk population. While this signal warrants significant clinical caution, it is contradicted by other high-quality evidence. The risk appears conditional rather than universal. Clinical decisions should involve careful patient selection and shared decision-making, reserving febuxostat for patients intolerant to allopurinol, particularly those with a high CV burden.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,091 | 0,024 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; les deux têtes enseignantes s’accordent sur ce qui est montré ici.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».