Allopurinol tied to less mortality compared to febuxostat among patients with CVD

China: A study published in the Frontiers in Pharmacology mentioning a comparison between Allopurinol and Febuxostat has concluded that allopurinol treatment causes less cardiovascular mortality. At the same time, febuxostat still needs cautious use in patients with gout and cardiovascular diseases.

Gout is characterized by elevated serum urate levels, ranging from 0.68% to 3.90%. This metabolic disease is a risk factor for cardiovascular disease, and such patients suffer from hypertension (74 %), stroke (10%), and myocardial infarction (14 %). As per guidelines from many countries, Febuxostat and Allopurinol are recommended first-line drugs for the management of gout.

Allopurinol (xanthine oxidase inhibitor) is most effective in treating chronic gout, while Febuxostat selectively inhibits two forms of xanthine oxidase.

Trials suggest febuxostat is more effective than Allopurinol. However, the U.S. FDA issued two warnings in 2017 and 2019, according to which febuxostat increases cardiovascular mortality and all-cause mortality more than Allopurinol in gout patients. The results of many trials display inconsistent conclusions in this aspect.

According to the previous meta-analysis, Allopurinol prevents cardiovascular disease in gout patients, and there is a need to interpret the difference in cardiovascular safety between febuxostat and Allopurinol. Considering this, a meta-analysis was conducted by a team of researchers led by Xudong Guan from the Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China, to evaluate the cardiovascular safety of febuxostat and Allopurinol based on reconstructed individual-patient data.

The key points of the study are:

• The database searched were PubMed, Embase, CBM, CNKI, WanFang, Central, and VIP (inception to 30 January 2022).

• RCTs evaluating the cardiovascular safety of febuxostat or Allopurinol for the management of gout patients were included.

• Individual patient data (IPD) were extracted and reconstructed based on Kaplan–Meier curves.

• Risk ratios (RRs), cardiovascular mortality, and all-cause mortality were calculated by a multi-level flexible hazard regression model in 1-stage meta-analyses.

• Log-rank test calculated p values.

• Two RCTs were included, with 12,318 participants; the two inclusion trials were FAST and CARES.

• In CARES, allopurinol and Febuxostat dose was 200–600 mg/day and 40–80 mg/day, respectively.

• In FAST, the dose of Allopurinol and febuxostat was 100–900 mg/day and 80–120 mg/day.

• The patients had a history of gout with cardiovascular comorbidities.

• There was no significant difference in the two groups' incidence of major cardiovascular events. [RR, 0.99]. The calculated p-value was 0.87.

• There was no significant difference in cardiovascular mortality [RR 1.17]. The p-value was 0.08.

• The all-cause mortality had an RR, of 1.03, with a p-value of 0.62.

• In 2-stage meta-analyses, there was no significant difference in any outcomes at any time, and the evidence was moderate-to-low-certainty.

Isla S Mackenzie from MEMO Research of the Division of Molecular and Clinical Medicine at the University of Dundee, UK  has previously interpreted that Febuxostat is non-inferior to allopurinol therapy and long-term use does not lead to death and serious adverse events as compared to Allopurinol.

The researchers wrote the risk of adverse drug events increases with increasing drug dose. In CARES, the lower dose of Febuxostat increased all-cause mortality and cardiovascular mortality more than FAST. Therefore, we believe that the result of FAST is consistent with our conclusion and is more reliable.

Febuxostat does not increase the incidence of MACE, cardiovascular death, or all-cause death in treating patients with gout, compared to Allopurinol, they said.

In CARES, the percentage of myocardial infarction, stroke, and peripheral artery disease was 40%, 14%, and 12%, while in FAST, these percentages were lower and recorded as 10%, 5%, and 5%, respectively.

The co-researcher, Shengzhao Zhang, from the Department of Pharmacy, Karamay Central Hospital, Xinjiang, China, wrote, "As a method which evaluates the robustness of 1-stage meta-analysis, our results of 2-stage meta-analysis showed consistent results." They wrote, "Our research results are still reliable and can provide specific reference significance for clinical practice and certain basis for selecting XOI drugs for clinical treatment of gout.

The study had limitations. The inclusion criteria were not strict and included patients of various diseases, the language is limited to Chinese and English which may have omitted many studies, and Only two studies were included.

Febuxostat has a similar cardiovascular profile, based on the reconstructed IPD, to Allopurinol in patients without the atherosclerotic disease. Still, in cardiovascular disease patients, Allopurinol causes less cardiovascular mortality than febuxostat.

Febuxostat use still needs caution due to the inconsistent results. As mentioned in funding, NS was supported under the Health Commission Program grants.

Further reading:

Guan, X., Zhang, S., Liu, J., Wu, F., Zhou, L., Liu, Y., & Su, N. (2022). Cardiovascular safety of febuxostat and Allopurinol in patients with gout: A meta-analysis. Frontiers in Pharmacology.https://doi.org/10.3389/fphar.2022.998441