An open-label, 6-month study of allopurinol safety in gout: the lasso study

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SCIENCE
An open-label, 6-month study of allopurinol safety in gout: the lasso study
Key Take-Away: 
  • Dose-titration strategy may generally be well tolerated at allopurinol doses >300 mg daily. However, no new safety signals for dose >300 mg were indicated in this study.
  • The incidence of treatment emergent adverse events possibly related to allopurinol was highest in <300-mg (15.2%) and lowest in the 300-mg category (9.5%).

The incidence and prevalence of gout is increasing worldwide. This chronic arthritic disease is characterized by hyperuricemia [i.e., serum uric acid concentrations (sUA) exceeding 6.8 mg/dL, the limit of urate solubility] and by symptoms and signs

ABSTRACT: 
Background: 

The incidence and prevalence of gout is increasing worldwide. This chronic arthritic disease is characterized by hyperuricemia [i.e., serum uric acid concentrations (sUA) exceeding 6.8 mg/dL, the limit of urate solubility] and by symptoms and signs resulting from inflammatory responses to monosodium urate crystals deposited in joints and associated connective tissues from extracellular fluids saturated for uric acid. Allopurinol is most widely prescribed first-line sUA-lowering agent in gout with limited data on dose-titrated allopurinol.

 

Rationale behind research

  • Despite the use of allopurinol for nearly 50 years, there is limited data on the safety and efficacy of dose-titrated allopurinol, particularly for doses exceeding 300 mg/d
  • This open label study was conducted to assess safety and sUA-lowering efficacy of allopurinol in adults with gout by titrating allopurinol to effect—that is, a dose achieving sUA < 6 mg/dL
  • Objective

To investigate the safety and efficacy of allopurinol under conditions where investigators were encouraged to titrate to optimal, medically appropriate doses

Methods: 

 

Study outcomes

  • Primary outcome: Incidence of treatment emergent adverse events (TEAEs) reported during titrated doses of allopurinol
  • Secondary outcome: Measurements of sUA lowering efficacy and frequency of gout flares requiring treatment

Time-points

  • Efficacy
  • Primary outcome: Baseline and up to 6 months
  • Secondary outcome: Baseline and up to 6 months
Results: 

 

Baseline: Most of the patients included were male and white. Baseline co-morbidities included were hypertension, hypercholesterolemia, obesity, hypertriglyceridemia and diabetes mellitus. More than half of the patients had mild or moderately impaired renal function. The mean (SD) daily allopurinol dose during study was 269.5 (111.7) mg over SD duration of 148.3 (50.0) days

Allopurinol Dose Titration

  • Out of 986 patients who received an initial allopurinol dose <200 mg/d, 722 (73%) were receiving at least 200 mg allopurinol daily at the last sUA determination, but only 152 (15%) were receiving allopurinol at >300 mg daily
  • Out of 746 patients who started the study at allopurinol doses of 200 mg or greater, only 125 (17%) were receiving a higher dose at final sUA determination. Overall, of 1732 patients initiating the study, 937 (54.1%) completed the study on a higher allopurinol daily dose than at baseline. The maximum daily allopurinol dose at any time during study was <300 mg in 250 patients (14.4%), 300 mg in 1132 patients (65.4%), and >300 mg in 350 patients (20.2%)
  • Patients who received a maximum dose >300 mg/d during study had more severe disease at baseline (i.e., longer gout duration, greater incidence of tophi, and more gout flares in the prior year). The proportion of patients with baseline CrCl < 60 mL/min was greater in <300-mg category (29.2%) than 300-mg (13.8%) and >300-mg categories (9.7%). Other baseline characteristics and rates of co morbidities were similar across dosing categories
  • Primary outcome
    • In total, 955 patients (55.1%) experienced TEAE, including 185 patients (10.7%) with TEAE reported possibly related to allopurinol and 183 (10.6%) with a TEAE possibly related to flare prophylaxis. The most common TEAEs in total population were upper respiratory tract infection, diarrhea and arthralgia
    • The incidence of TEAEs possibly related to allopurinol was highest in <300-mg (15.2%) and lowest in 300-mg category (9.5%). The most common TEAEs possibly related to allopurinol (in <300-, 300-, and >300-mg categories, respectively) were alanine aminotransferase increase (2.0%, 1.1%, and 2.0%), diarrhea (1.2%, 1.1%, and 2.0%) and rash (2.0%, 0.8%, and 0.3%)

Figure 1: TEAE Possibly Related to Allopurinol

  • Secondary outcome
    • sUA-lowering efficacy of allopurinol

At 6 month, 35.9% of patients had sUA < 6.0 mg/dL. A greater proportion of patients met this target in >300-mg category (48.3%) than 300-mg (35.0%) and <300-mg categories (22.4%). Mean decreases in sUA from baseline to month 6 were 1.5 (1.84), 2.4 (1.97) and 2.7 (2.04) mg/dL in <300-, 300-, and >300-mg categories, respectively, representing decreases of 16.6%, 25.1% and 28.7%.

  • Incidences of gout flares requiring treatment

Approximately one-third of patients (33.4%) experienced one or more gout flares requiring treatment, with a greater proportion in >300-mg (44.3%) than 300-mg (33.7%) or <300-mg (16.4%) categories. 

 

 

 

 

 

 

 

 

 

Figure 2: Incidences of Gout Flares Requiring Treatment

 

Conclusion: 

The result indicates no new safety signals for allopurinol at doses >300 mg daily. There were minor differences in the incidence of TEAEs possibly related to allopurinol among all dosing categories while rate of adherence were high for all doses. Despite encouragement to treat to target, 300 mg daily was the most commonly used dose, and significant proportions of patients did not achieve target sUA.

The results of this study are consistent with the results from another study which has shown that achievement of the target sUA range is associated with gout control and also the studies of allopurinol at higher doses have reported greater rates of achievement of target sUA. The results of this study may prove valuable for future trials of allopurinol as monotherapy and in combination with current and emerging therapies in the treatment of gout.

Seminars in Arthritis and Rheumatism 2015
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