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Treat-to-Target Works in Gout With No Cardiac Toxicity

  • ACR
Nov 04, 2021 6:30 pm

New research presented this week at ACR Convergence, the American College of Rheumatology’s annual meeting, shows that allopurinol and febuxostat may effectively lower urate levels when used in a treat-to-target approach. Importantly, both urate-lowering therapies were very effective with 90% of patients reaching target urate levels. Additionally, both appeared safe, with no evidence of increased cardiovascular toxicity (Abstract #1900). This abstract will be presented at 11:15am EST on Tuesday, November 9, in a session entitled: Metabolic & Crystal Arthropathies – Basic & Clinical Science (1897–1900).

Gout is a painful and potentially disabling form of arthritis. Gout occurs when excess uric acid, a normal waste product, collects in the body, and needle‐like urate crystals deposit in the joints. The first symptoms usually are intense episodes of excruciatingly painful swelling in single joints, most often in the feet, especially the big toe.

Urate-lowering  therapy  (ULT)  is  a  cornerstone treatment  for  gout  management,  but  there is  a lack  of  data  to  support  the  comparative  efficacy  and  safety  of  the two major  oral  ULTs, allopurinol  and  febuxostat,  when  prescribed in  a  treat-to-target  approach.  There is  also  an urgent  need  to  determine  if  these  ULTs  are safe  and  effective  in  gout  patients  with  chronic kidney  disease  a  common comorbidity.  Researchers  conducted  this  multicenter,  randomized, double-blind,  non-inferiority  trial  to  compare  the  safety  and  efficacy  of  these  two  therapies  for gout  management.

“Gout  affects  4%  of the  U.S.  population  and  is  one  of  the most  painful  chronic  diseases,”  says James  R.  O’Dell,  MD,  Chief,  Division  of  Rheumatology,  at  the  University  of  Nebraska Medical Center  in Omaha and  the  study’s  co-author.  “Our  trial is  the  first  to  compare  allopurinol  to febuxostat  using  the  recommended  treat-to-target,  urate  level  approach.  This  trial  demonstrates that  both  agents  are  highly  effective  and  safe  when  used  in  this  way  and,  importantly,  this  was true in  patients  with  chronic  kidney  disease  as  well.”

For  the  72-week  trial,  940  patients  with  gout  and  a serum  urate  concentration  of  6.8  mg/dl  or higher  were  randomized  to  receive  either  allopurinol  or  febuxostat  between  2017 and  2019. Patients  with  persistent  elevated uric  acid  levels  in  the  blood,  despite  allopurinol  treatment  (300 mg/dl  or  less) were  eligible,  by  design  over  one third of  patients  had  chronic  kidney  disease, Stage  3.  The  trial  had  three  phases:  ULT titration  from  week  0-24,  maintenance therapy  from week  25-48 and  observation  with continued,  stable  ULT from  week  49-72.

Patients  received  initial  doses  of  either  100  mg of  allopurinol  with maximum  titration  to  800  mg, or  40  mg  of  febuxostat  with  maximum  titration to  120  mg  (reduced  to  80 mg  in  2019  at  the request of the  U.S.  Food  and  Drug  Administration).  Patients  also  received  anti-inflammatory treatments  selected  by  the  site  investigator  until  the  start  of  the  third  phase.  The primary outcome  was  the  proportion  of  patients  who  had  one  or  more  gout  flares  during  the  third  phase.

Similarly,  effectiveness  and  tolerability  of  the  two  drugs  in  Stage  3  chronic  kidney  disease patients  were  examined,  as  were  serious  side  effects,  and  the proportion  of  patients  who achieved  a  serum  urate of  less  than  6  mg/dl  by  the  end of  the  second phase  of  the trial.

During the  third  phase,  35%  of  patients  taking  allopurinol  had  one  or  more  gout  flares  compared to 42%  of  patients  taking febuxostat.  Overall,  80%  of  patients  in  the  trial  achieved  a serum  urate level  of  less  than  6.0 mg/dl,  and  92%  achieved  a  level  of  less  than  6.8 mg/dl  during the  second phase,  with  no  difference  between the  two  treatments.  There  were also  no  differences  in  serious side effects  between  the  two  treatment  groups,  including  the  percentage  of  patients  with cardiovascular  events  in  people  with  or  without  chronic  kidney  disease.  That  final  finding  is important,  because  nearly  one  in  every  two gout  patients  suffers  from  renal  insufficiency.   

Allopurinol  was  found to  be  non-inferior  to  febuxostat  when  prescribed  as  part  of  a  treat-totarget  approach in  people with gout,  providing  two  effective,  safe treatment  options  for managing  serum  urate  levels  long term,  the  study’s  findings  show.

“Gout  is  a  common  and  increasing  cause  of  morbidity  in  patients,  as  well  a  major  cause of  work loss,”  says  Dr. O’Dell. “This  trial  shows  that  if  a treat-to-target,  uric  acid-level  approach  with either  allopurinol  or  febuxostat  is  widely  adopted,  chronic  gout  could be essentially  wiped  out.”

The author has no conflicts of interest to disclose related to this subject

Rheumatologists’ Comments

Donald E Thomas Jr

| Nov 06, 2021 3:07 pm

Kudos to Dr. O'Dell, et al. They have shown what many of us already have known but needed to get the word out better in a well-done study. Too many other studies and marketing ploys from newer urate-lowering therapies have said (incorrectly) that most allopurinol patients are unable to reach a therapeutic sUA target. However, many of us in clinical practice have known that they simply do not push the drug dose high enough (up to 800 mg daily). In addition, in the "real world," we also educate our patients on urate-lowering diets (low fructose, etc), and include other therapies, such as losartan, and stop urate-increasing meds (eg HCTZ). Most patients can avoid the more expensive therapies. - Thanks, Dr. O'Dell!

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