Discontinuing febuxostat might cause more deaths than continuing febuxostat: the untold story from the CARES trial

Ghang, Byeongzu; Ahn, Soo Min; Kim, Jinseok; Lee, Chang‐Keun; Yoo, Bin

doi:10.1093/rheumatology/kez552

Cited by 13 publications

(11 citation statements)

References 7 publications

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“…A recent national‐wide retrospective cohort study 26 showed that non‐fatal cardiovascular and mortality risk was similar between febuxostat and allopurinol in gout patients. Another study that reanalysed the data from CARES trial, suggest that discontinuation of febuxostat might be a possible risk factor of all‐cause and cardiovascular mortality, showing that a sharp increase in mortality was observed after allopurinol and febuxostat were discontinued 27 . In our study, we did not compare the cardio‐cerebrovascular events between febuxostat and allopurinol.…”

Section: Discussionmentioning

confidence: 69%

Efficacy and tolerability of febuxostat in gout patients on dialysis

Choi

Lee

et al. 2021

Internal Medicine Journal

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Background There are no sufficient data available on the use of febuxostat in patients undergoing dialysis. Aim To investigate the efficacy and tolerability of febuxostat in gout patients on dialysis. Methods We retrospectively reviewed clinical and laboratory data available from a referral centre from January 2012 to December 2018. We included gout patients who initiated febuxostat during dialysis. Data regarding serum uric acid levels before and after the febuxostat treatment and clinical information such as gout attack after febuxostat initiation, as well as adverse events involving febuxostat treatment, were obtained from medical records. Results Among 62 patients who were treated with febuxostat for over 3 months, 45 were undergoing haemodialysis (HD) and 17 were undergoing peritoneal dialysis (PD). The mean serum uric acid level was significantly reduced 3 months after treatment (3.71 ± 1.32 mg/dL) compared with that at the pretreatment level (9.36 ± 2.06 mg/dL) (P < 0.001). The serum uric acid level was observed to be significantly reduced at 3 months in both HD and PD patients and subsequently remained at a significantly reduced level for 12 months. Of the 62 patients, only two stopped febuxostat due to its adverse effects. Initial dose of 80 mg/day was associated with higher adverse events compared to dose of 20–40 mg/day (odds ratio 8.25, 95% confidence interval 1.90–35.97, P = 0.006). Conclusions Febuxostat is efficacious and well tolerated in gout patients on dialysis. Febuxostat taken at dose of 20–40 mg/day might be appropriate initial dose in patients undergoing dialysis.

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Section: Discussionmentioning

confidence: 69%

Efficacy and tolerability of febuxostat in gout patients on dialysis

Choi

Lee

et al. 2021

Internal Medicine Journal

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“…8 Regarding the increased risk of CV mortality associated with febuxostat in the CARES trial, there are previous studies that reanalysed the CARES trial data to calculate the mortality rates on the basis of the median duration of exposure to study drugs (table S12 of the previous work 3 ). 9 In our reanalysis, a 40-fold increase in mortality was observed after allopurinol or febuxostat was discontinued. The sharp increase in mortality was thought to be associated with rapid changes in the serum uric acid levels because of the drug discontinuation (rebound hyperuricaemia), which is a known risk factor for acute gout attacks.…”

Section: How This Study Might Affect Research Practice And/or Policymentioning

confidence: 65%

“…Accordingly, we hypothesised that some CV events may share the same mechanism as those of acute gout attacks (acute inflammation induced by monosodium urate (MSU) crystals in the CV system). 9 We assumed that if fluctuations in uric acid levels triggered CV events, the increase would be rapid in the initial stage after drug discontinuation. Thus, we investigated the incidence of CV events and death in the initial stage after discontinuation of febuxostat or allopurinol using the CARES trial data.…”

Section: How This Study Might Affect Research Practice And/or Policymentioning

confidence: 99%

Increased risk of cardiovascular events and death in the initial phase after discontinuation of febuxostat or allopurinol: another story of the CARES trial

et al. 2022

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ObjectivesThe Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout (CARES) trial suggested a higher risk of cardiovascular (CV) death from febuxostat than from allopurinol. However, a significant number of patients died after discontinuation of febuxostat or allopurinol. We investigated whether major adverse cardiovascular events (MACE) and CV death were increased because of discontinuation of febuxostat or allopurinol using the CARES trial data.MethodsWe compared the MACE that occurred during administration and after discontinuation in the initial phase after discontinuation, and we compared the CV and non-CV mortality rates in the initial phase after discontinuation to determine the impact of discontinuation of febuxostat or allopurinol.ResultsAmong 6190 patients, the incidence rate per 100 person-years for MACE was 3.11 during administration and 6.71 after discontinuation. MACE was significantly increased after discontinuation compared with that during administration within 1 month (HR 7.40; 95% CI 5.38 to 10.17) and 6 months (HR 5.22; 95% CI 4.26 to 6.39). In the analysis excluding death induced by adverse events that occurred up to 1 day after the last medication, the CV mortality rate was higher than the non-CV mortality rate within 6 months (45.7% vs 27.9%, p=0.0001). In addition, changes in serum uric acid levels from baseline to the last measurement before discontinuation were significantly associated with higher MACE risk after drug discontinuation (HR 1.14; 95% CI 1.04 to 1.26).ConclusionsMACE and CV death were increased in the initial stage after discontinuation of febuxostat or allopurinol in patients with gout.

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“…In our opinion febuxostat can even be carefully used in patients with eGFR below 30ml/min/1.73m 2 , in whom it appears to keep its efficacy and safety profiles according to several studies, although these studies were rather small and, for most of them, retrospective [42,43]. The use of febuxostat in patients with a history of severe cardiovascular disease is discouraged by the recent results of the CARES trial, that highlighted an increased mortality rate in such patients treated by febuxostat versus those who received allopurinol [44] and by the risk of cardiovascular events when febuxostat is suddenly stopped in these patients [45]. Severe cardiovascular disease was defined as a history of myocardial infarction or unstable angina, transient ischemic attack, cerebrovascular event, peripheral artery disease, coronary or carotid revascularization or complicated diabetes mellitus.…”

Section: Grade Of Recommendation A-d)mentioning

confidence: 99%