Cardiovascular Events in Hyperuricemia Population and a Cardiovascular Benefit-Risk Assessment of Urate-Lowering Therapies: A Systematic Review and Meta-Analysis
Hyperuricemia and gout have emerged as significant public health concerns, with numerous guidelines recommending xanthine oxidase inhibitors (XOIs) as the first-line urate-lowering therapies (ULTs) for chronic gout associated with hyperuricemia. However, the impact of treating hyperuricemia and gout with ULTs on cardiovascular (CV) risks remains a contentious issue. This study aims to evaluate the incidence risk of cardiovascular events (CVEs) in the hyperuricemia population, assess the cardiovascular benefit-risk of ULTs in hyperuricemia patients with or without gout across diverse cardiovascular risk subgroups, and specify the safety profiles of different ULTs.
The research methodology involved a comprehensive search of multiple databases, including PubMed, Embase, the Cochrane Library, Wanfang, Chongqing VIP (CQVIP), and the China National Knowledge Infrastructure Database. The search targeted prospective cohort studies and randomized controlled trials (RCTs) published in English and Chinese. The potential medications considered were XOIs and uricosurics. RCTs were categorized into subgroups based on blinding status and patients’ history of CV diseases. Risk ratios (RRs) were calculated and reported with corresponding 95% confidence intervals (CIs) using fixed-effects or random-effects models.
The study included seven prospective cohort studies and 17 RCTs. The analysis revealed that the hyperuricemia population had a higher risk of both major adverse cardiovascular events (MACE) (RR = 1.72, 95% CI 1.28–2.33) and CVEs (RR = 1.35, 95% CI 1.12–1.62) compared to the non-hyperuricemia population. In the subgroup analysis of seven RCTs where XOIs were compared with no-treatment or placebo, five low CV risk studies demonstrated that XOIs reduced the risks of both MACE (RR = 0.35, 95% CI 0.20–0.62) and CVEs (RR = 0.61, 95% CI 0.44–0.85). Conversely, two high CV risk studies indicated that XOIs lowered the risk of CVEs (RR = 0.69, 95% CI 0.54–0.88) but not MACE (RR = 0.62, 95% CI 0.29–1.35). Additionally, in nine RCTs comparing the cardiovascular safety of febuxostat and allopurinol, no significant differences were found in the risk of MACE or CVEs.
The findings suggest that the hyperuricemia population indeed has a higher incidence of CVEs, and XOIs may reduce the incidence of MACE and total CVEs. From a cardiovascular safety perspective, febuxostat was found to be equivalent to allopurinol in this meta-analysis.
Hyperuricemia is a prerequisite for the development of gout, which is characterized by urate crystal deposition in the joints. Maintaining serum uric acid levels below 6 mg/dL is crucial for managing gout. Various guidelines, including those from the British Society for Rheumatology, the Japanese guideline, the American College of Rheumatology, the 3e guidelines, and the European League Against Rheumatism, recommend XOIs as the first-line ULT for chronic gout with hyperuricemia. Beyond gout, hyperuricemia is implicated in vascular endothelial dysfunction, leading to complications such as cerebral, cardiovascular, renal dysfunction, and non-alcoholic fatty liver disease. Despite the widespread attention to uric acid lowering in related studies, the cardiovascular risks associated with treating hyperuricemia and gout with ULTs, including XOIs or uricosurics, remain controversial.
Allopurinol and febuxostat are the most widely used XOIs. Allopurinol, approved since 1965, and febuxostat, first approved in the European Union in April 2008, are both effective in lowering uric acid levels. Febuxostat, a non-purine inhibitor of xanthine oxidase, provides highly selective and potent inhibition of xanthine oxidase and exhibits greater hypouricemic activity than commonly used doses of allopurinol. However, concerns about increased heart-related deaths with febuxostat compared to allopurinol have led to drug safety alerts by Health Canada and the American Food and Drug Administration (FDA). The association between hyperuricemia, gout, and increased cardiovascular disease risk complicates the interpretation of cardiovascular side effects of ULTs in hyperuricemia/gout patients.
This meta-analysis was conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The protocol for this meta-analysis is available in PROSPERO (CRD42018090238). The search strategy involved using keywords such as “hyperuricemia,” “gout,” “cardiovascular,” “uric acid lowering,” “allopurinol,” “febuxostat,” “benzbromarone,” and their corresponding Chinese terms. The inclusion criteria for studies were based on patients, outcomes, and study design, with the primary outcome being MACE and the secondary outcome being all new-onset CVEs.
The study selection process involved three reviewers independently assessing the methodological quality of eligible studies using the Cochrane Risk of Bias tool for RCTs and the Newcastle-Ottawa scale for prospective cohort studies. Data extraction was performed by one reviewer and verified by others, covering general information, design characteristics, baseline characteristics, intervention details, and outcome measures.
The meta-analysis results indicated that hyperuricemia significantly increased the risk of MACE and CVEs compared to non-hyperuricemia. The subgroup analysis of RCTs comparing XOIs with no-treatment or placebo showed that XOIs reduced the risk of MACE and CVEs in low CV risk patients, but the results were less clear in high CV risk patients. The comparison between febuxostat and allopurinol revealed no significant differences in cardiovascular safety.
Sensitivity analysis and publication bias tests were conducted to ensure the robustness of the findings. The sensitivity analysis involved excluding each study in turn and observing the changes in estimated RRs. The Begg rank correlation test and Egger linear regression test were used to assess publication bias, with no significant bias detected.
The discussion highlighted the association between hyperuricemia and CVEs, emphasizing the potential benefits of XOIs in reducing cardiovascular risks. However, the findings also underscored the need for further research, particularly large, long-term RCTs, to confirm these results and address the limitations of the current studies, such as low CVE rates, single-center designs, and variable follow-up durations.
In conclusion, this meta-analysis supports the notion that hyperuricemia is associated with an increased risk of CVEs, and XOIs may reduce the incidence of MACE and total CVEs. The cardiovascular safety profiles of allopurinol and febuxostat were found to be comparable. However, due to the limitations of the included studies, further research is necessary to validate these findings and provide more definitive guidance on the use of ULTs in hyperuricemia and gout patients.
doi.org/10.1097/CM9.0000000000000682
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