Febuxostat: Up-to-date advice for treating patients with a history of major cardiovascular disease


This article supersedes the advice issued in the Drug Safety Update published in July 2019.

Advice for healthcare professionals:

  • Febuxostat therapy should be used with caution in patients with pre-existing major cardiovascular disease, especially those with evidence of high urate crystals and tuberculosis load, or those starting urate-lowering therapy. Now be careful.
  • After initiation of febuxostat, prescribers should titrate febuxostat doses to minimize gout flare-ups and inflammation.
  • Clinical guidelines for gout (see, for example, NICE Guideline 219 – Diagnosis and Management of Gout) recommend that allopurinol be offered as first-line treatment for gout patients with severe cardiovascular disease. be careful.
  • Reporting suspected side effects related to febuxostat to the yellow card system

Advice healthcare professionals should give their patients:

  • Febuxostat is used to treat gout by reducing excess uric acid (uric acid salts) in the body, a chemical that prevents gout attacks in the long term. It can also be used to treat and prevent high blood uric acid levels that can occur when starting chemotherapy for blood cancers.
  • New Recommendations for Health Professionals About Use of Febuxostat in Patients With Pre-existing Heart Disease
  • If you currently have or have previously had heart failure, heart disease, or stroke, it is recommended that you consult your doctor before taking febuxostat.
  • Patients already taking febuxostat do not need to do anything, but if you have any concerns, talk to your healthcare professional.

About febuxostat and the treatment of gout

Febuxostat, at doses of 80 milligrams (mg) and 120 mg, is indicated for the treatment of chronic hyperuricemia in conditions where urate deposition has already occurred (including history or presence of nodular or gouty arthritis). Adapted. Febuxostat at a dose of 120 mg is indicated for the prevention and treatment of hyperuricemia in adult patients receiving chemotherapy for hematological malignancies at intermediate to high risk of tumor lysis syndrome. The advice in this article is about treating chronic hyperuricemia (gout).

Gout is a type of inflammatory arthritis caused by monosodium urate crystals that form in and around joints, causing sudden recurrences of severe pain, heat, and swelling. Gout is thought to be associated with an increased risk of cardiovascular disease and cardiovascular death. Gout flare-ups can occur during initiation of urate-lowering treatment due to changes in serum urate levels that result in the mobilization of urate from tissue deposits. Management of gout flares may require the use of nonsteroidal anti-inflammatory drugs, colchicine, or oral corticosteroids.

Cardiovascular disease warning

In July 2019, we advised healthcare professionals to administer febuxo to patients with pre-existing major cardiovascular disease (e.g., myocardial infarction, stroke, unstable angina) unless other treatments are not appropriate. Advised to avoid stat treatment. This is a review of the results of a Phase 4 clinical trial (CARES Study 1) in gout patients with a history of major cardiovascular disease. The CARES study showed that patients assigned to febuxostat had a higher risk of cardiovascular-related and all-cause mortality than those assigned to allopurinol.

The FAST trial, a further study of the cardiovascular safety of febuxostat, has been completed. The FAST trial was conducted in UK, Danish and Swedish patients who had at least one cardiovascular risk factor and had already been treated with allopurinol. The median period is 6 years. In addition, dose-optimized allopurinol was used to control serum uric acid levels prior to randomization. In the FAST study, febuxostat was not inferior to allopurinol therapy for primary cardiovascular endpoints, and unlike the results of the CARES study, long-term use was associated with an increased risk of death or cardiovascular death compared with allopurinol. concluded that it did not.

Following a review of the results of the FAST study and advice from the Human Medicines Committee’s Pharmacovigilance Expert Advisory Group, the product information for febuxostat has been updated to include the results. The product information maintains the cardiovascular warning, but currently advises that patients with pre-existing major cardiovascular disease should be treated with caution with febuxostat.

Treatment should be undertaken with caution, especially in patients with pre-existing major cardiovascular disease with evidence of high urate crystals and tuberculosis tuberculosis burden, or in patients starting urate-lowering therapy. The prescribing clinician should adjust febuxostat appropriately to minimize gouty flare after initiation of febuxostat and to minimize further inflammation.

Also, clinical guidelines for gout (e.g., NICE Guideline 219 – Diagnosis and Management of Gout, updated since the time of FAST study publication) state that allopurinol should be offered as first-line treatment for patients with gout. Also note what is said. People with significant cardiovascular disease (previous myocardial infarction, stroke, unstable angina, etc.).

Detailed research results

CARES research

More information about the design and results of the CARES study can be found in the July 2019 Drug Safety Update and published results. In summary, the CARES study was a Phase 4, randomized, double-blind, non-inferiority trial in patients with gout and a history of major cardiovascular disease in the United States, Canada, and Mexico. A total of 6,190 patients were randomized to receive febuxostat or allopurinol and were followed for a median of 32 months.

Major major cardiovascular events (MACE) endpoints occurred in similar proportions in the febuxostat- and allopurinol-treated groups (10.8% vs. 10.4% of patients, respectively; hazard ratio (HR) 1.03, 95% confidence interval (CI) 0.87 to 1.23). . In secondary analysis, the incidence of cardiovascular death was higher in the febuxostat group than in the allopurinol group (4.3% vs. 3.2%, respectively; HR 1.34, 95% CI 1.03 to 1.73). All-cause mortality was also higher in patients assigned to febuxostat than in those assigned to allopurinol (7.8% vs. 6.4%, respectively; HR 1.22, 95% CI 1.01 to 1.47). This was mainly due to the high mortality rate of cardiovascular disease. Death in the febuxostat group.

FAST research

The FAST study was a prospective, randomized, open-label study evaluating the risk of cardiovascular events with febuxostat and allopurinol in 6128 gout patients with at least one cardiovascular disorder in the United Kingdom, Denmark and Sweden , was a blinded endpoint, non-inferiority trial. Risk factor.

Patients had received allopurinol-containing urate-lowering therapy for a median of 6 years. Prior to randomization, they received dose-optimized allopurinol to lower uric acid levels to the European Federation of Rheumatology Association (EULAR) target levels of <0.357 mmol/L (<6 mg/dL). had received

Results from the FAST trial favored febuxostat versus allopurinol therapy for the primary cardiovascular endpoint (composite of non-fatal myocardial infarction or biomarker-positive acute coronary syndrome, non-fatal stroke, or hospitalization for cardiovascular death). showed that it is not inferior to On-treatment incidence was 5.6% for febuxostat and 7.9% for allopurinol (HR 0.85, 95% CI 0.70 to 1.03, p<0.0001, noninferiority). Secondary endpoints for on-treatment febuxostat and allopurinol included cardiovascular death, 2% vs 2.7%, respectively, HR 0.91 (0, 66-1, 27), all-cause mortality, 3.5% vs 5.7%, respectively; HR 0.75 (0 59-0) was included. 95) p<0.0001, non-inferiority.

There are differences between the FAST and CARES study populations and protocols, and the following differences should be considered when comparing and contrasting the results of these trials.

  • Patients treated with febuxostat were older in FAST than in CARES (mean age 71 years (standard deviation) [SD] 6.4) vs median age 64 years (interquartile range) [IQR] 58-71 years old respectively)
  • 33.4% of patients with FAST had a history of cardiovascular disease, compared with 100% of patients with CARES
  • Zero patients started urate-lowering therapy in the FAST compared with 33.7% of patients in the CARES study
  • At baseline immediately prior to randomization, mean serum uric acid levels in FAST study patients were 5 mg/dL (0.297 mmol/L) compared to 8.7 mg/dL (0.517 mmol/L) in CARES.
  • At baseline, fewer patients had tuberculosis tuberculosis in the FAST study compared with CARES (9.8% vs. 21.6% in febuxostat-treated patients, respectively).

Therefore, treatment with febuxostat for chronic hyperuricemia in patients with pre-existing major cardiovascular disease should be performed with caution, in patients with evidence of hyperuric acid crystals and tuberculosis tuberculosis burden, or uric acid Particular caution should be exercised in patients starting descent therapy.

Reporting by yellow card

Healthcare professionals, patients and caregivers are asked to submit reports electronically using the Yellow Card scheme using:

If you suspect any side effects, please report in as much detail as possible, including your medical history, the presence or absence of concomitant medications, the time of onset, and the date of treatment. When reporting on biologics or vaccines, be sure to provide the brand name (or product license number and manufacturer) and specific batch number.

Launch of Yellow Card Biobank

Note that MHRA recently launched the Yellow Card Biobank in a joint venture with Genomics England. The pilot phase begins with allopurinol and rare serious skin reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Additional topics to focus on during the pilot phase will be confirmed in due course.

If you are interested in participating, please visit the Yellow Card Biobank page. Individuals who have previously submitted yellow his card his reports related to the pilot topic may also be asked if they would like to participate. If a medical professional made the report on behalf of the patient, they may be asked to help contact the affected patient to see if they would like to be involved.

Article Citation: Drug Safety Update Vol. 16, Issue 10: May 2023: 3.



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