Allopurinol for Secondary Prevention in Patients with Cardiovascular Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Abstract

Background: The effects of allopurinol in patients with cardiovascular disease are not well defined; therefore, the latest evidence is summarized in this study.

Methods: PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases were searched for randomized controlled trials (RCTs) of allopurinol in patients with cardiovascular disease published up to 11 February 2023. The primary outcome was cardiovascular death.

Results: We combined the results of 21 RCTs that included 22,806 patients. Compared to placebo/usual care, allopurinol treatment was not associated with a significant reduction in cardiovascular death (RR 0.60; 95% CI 0.33-1.11) or all-cause death (RR 0.90; 95% CI 0.72-1.12). However, evidence from earlier trials and studies with small sample sizes indicated that allopurinol might confer a protective effect in decreasing cardiovascular death (RR 0.34; 95% CI 0.15-0.76) across patients undergoing coronary artery bypass grafting (CABG) or having acute coronary syndrome (ACS). In comparisons between allopurinol and febuxostat, we observed no difference in cardiovascular death (RR 0.92; 95% CI 0.69-1.24) or all-cause death (RR 1.02; 95% CI 0.75-1.38).

Conclusion: Allopurinol could not reduce cardiovascular (CV) death or major adverse CV outcomes significantly in patients with existing cardiovascular diseases. Given the limitations of the original studies, the potential advantages of allopurinol observed in patients undergoing CABG or presenting with ACS necessitate further confirmation through subsequent RCTs. In the comparisons between allopurinol and febuxostat, our analysis failed to uncover any marked superiority of allopurinol in reducing the risk of adverse cardiovascular incidents.

Keywords: allopurinol; cardiovascular disease; cardiovascular outcomes; febuxostat.

Figure 1

Flowchart of study selection.

Figure 2

Risk of bias: (A) the risk of bias graph and (B) the risk of bias summary.

Figure 3

Outcome: Cardiovascular death. (A) Pooled analysis among all eligible patients with cardiovascular disease; (B) funnel plots using the trim and fill method; (C) pooled analysis among all subgroups with coronary artery disease. Note: Control: Placebo or usual care.

Figure 4

(A) The analysis for all-cause death; (B) the analysis for MACEs; (C) the analysis for MI; (D) the analysis for stroke. Note: Control: Placebo or usual care.

Figure 5

Outcome: (A) The analysis for cardiovascular death; (B) the analysis for all-cause death. Note: Control: Febuxostat.

Figure 6

Outcome: (A) The analysis for MACEs; (B) the analysis for MI; (C) the analysis for stroke. Note: Control: Febuxostat.