Higher allopurinol dosages for gout

A recent New Zealand study assessed the efficacy and safety of higher allopurinol doses in patients with pretty severe gout and comorbidities (see gout allopurinol higher dose annrheum2017 in dropbox, or doi: 10.1136/annrheumdis-2016-210872​).

Details:

--183 patients with gout and taking creatinine clearance (CrCL)-based allopurinol therapy were randomized to continuing routine care vs monthly escalating allopurinol dose to achieve a target serum urate level of <6 mg/dL. Non-blinded study, patients followed 12 months

--mean age 60, 87% male, mean duration of gout 17 years, creatinine 1.58, CrCL 60, BMI 35, 44% palpable tophi, 38% on colchicine/13% NSAIDs/13% on prednisone. 34% diabetic/72% hypertensive/57% hyperlipidemic, 43% cardiovascular disease

--52% had CrCL <60ml/min, 13% CrCL <30 ml/min

--mean baseline serum urate level (SU) was 7.15 mg/dL on mean allopurinol dose of 269 mg/d.

--dose escalation group: increase allopurinol monthly, 50mg if CrCL <60ml/min, otherwise 100mg, to achieve target SU level

Results:

--mean change in SU was -0.34 mg/dL in the control group (?better med adherence by being in the study) vs -1.5 mg/dL in the dose escalation group (p<0.001). This separation was achieved within about 4 months, though took 7 months in those with CrCL <60.

--at month twelve: 32% of controls and 69% in dose escalation group achieve SU <6 mg/dL; this SU level was achieved in each of the last 3 visits in 14% vs 59% (odds ratio, OR=8.0)

--no difference in gout flares or tophus size during the study

--adverse events: 25 in controls, 35 in 22 dose escalation patients . Only one adverse event considered likely to be related to allopurinol, in a patient in the dose escalation group who had high INR after starting warfarin for elective mitral valve replacement.

--mild elevations of LFTs in both groups, and a few had moderate increases in GGT 

--no difference in renal function between the groups (increases from their baselines). Both groups had about 10% of patients getting >20% decrease in CrCL, but similar numbers of patients actually had improvement in CrCL.

--no difference in other lab tests, including CBC (and eosinophilia)

Commentary:

--one presupposition for this study is that it is important to treat SU levels to specific targets. Several groups, including the American College of Rheumatology in 2012 (see gout am coll rheum guidelines2012 in dropbox, or DOI 10.1002/acr.21772 ) and the European League Against Rheumatism (EULAR) in 2016 (http://dx.doi.org/10.1136/annrheumdis-2016-209707​ ), suggest targets of SU levels <6mg/dL in those with recurrent gout and <5 mg/dL in those with severe gout (tophi, chronic arthropathy, frequent attacks). However, there is a counterargument: http://gmodestmedblogs.blogspot.com/2016/12/new-gout-management-guidelines.html questions the validity of treating-to-target for SU levels, noting that there are no studies looking at the clinical outcome of titrating to different targets in an RCT. Observational studies do confirm that those with SU levels <6 have fewer gout flares, but we do not really have the data to make a truly informed decision. These conclusions questioning treating-to-target were similar to the 2016 the AHRQ analysis of the data on the management of gout (see http://gmodestmedblogs.blogspot.com/2016/03/gout-management-ahrq-report.html  )

--allopurinol is FDA-approved to a dose of 800mg, though in the pretty remote past I had a patient with tophaceous gout on even higher levels than that in an attempt to dissolve the extensive tophi (and this was done not uncommonly for those with very high SU levels, probably often due to inborn errors of metabolism), and overall many patients were on higher doses of allopurinol to achieve SU levels <6. However, doses >300mg/d seem to be rarely used more recently, as confirmed in a 2006 study. The concern about higher doses has been adverse effects, including the pretty rare allopurinol hypersensitivity syndrome (fever, rash, eosinophilia, hepatic abnormalities, renal failure, found in <0.1%, so this current study was not powered to detect this), which typically occurs in the first 2 months of therapy and is more common in those with higher starting doses or CKD, and perhaps with concomitant thiazide therapy

--EULAR guidelines comment that it is best to start with allopurinol 100mg/d in those with normal renal function, then increase every 2-4 weeks to achieve the SU target. but, with the most usual prescribed allopurinol dose of 300mg/d, only 50-70% reach the 6 mg/dL target; and those on up to 600-800 mg/d had a 75-80% chance to achieving that target. Starting at a low dose with slow increments seems to reduce the likelihood of gout flares from the allopurinol, and decreases the risk of severe cutaneous reactions. In those with renal impairment, allopurinol should be renal-dosed, starting at 50mg, and  the maximal dose of allopurinol should be adjusted by creatinine clearance in order to decrease the likelihood of severe cutaneous reactions.  If the SU level is not adequately controlled on high-dose allopurinol, consider adding a uricosuric, or consider switch to feboxustat, which seems more effective in patients with CKD. The American College of Rheumatology suggested continued gradual allopurinol dose escalation above the CrCL-based doses to achieve target SU level, with no maximum dose, though they specifically comment that in patients with CKD, it’s okay to exceed 300mg/d.

--not sure how to interpret the lack of clinical improvement in the current study (gout flares, tophi) in those on higher dose allopurinol, though the true separation of SU levels began after 4 months of therapy, so only 8 months of pretty much sustained SU differences between the groups, and only 5 months in those with renal compromise. The lack of benefit from high dose allopurinol is consistent with the observed finding that SU lowering drugs have no clinical effect for 6 -12 months. But why is this? why did a patient of mine with 2+ months of SU level of 4.4 mg/dL on meds have a gout flare?? Not so clear. Part of this may be that patients put on allopurinol can have an increase in gout flares in the first 3-6 months (and, EULAR recommends gout prophylaxis for 6 months after starting urate-lowering therapy), which could counterbalance a protective effect in other patients (no data provided in this study, but perhaps concomitant colchicine prophylaxis could help sort this out). Also, this study did not attempt to achieve SU <5mg/dL, which really is the goal recommended as the target for those with tophaceous or severe gout as in this study (ie, their target was perhaps too high)

-- http://gmodestmedblogs.blogspot.com/2016/12/new-gout-management-guidelines.html​ comments on the role of decreasing fructose intake in lowering uric acid levels (and I have seen some pretty impressive results from stopping sodas), as well as the effect of antihypertensives on SU levels and gout (losartan, especially, but also calcium channel blockers, especially amlodipine, decrease SU levels.)

--also, as a perhaps important side issue, there may also be cardiovascular benefits from  lowering SU levels (see http://gmodestmedblogs.blogspot.com/2019/04/uric-acid-lowering-cardiovasc-benefit.html ​ )

so, CKD does not seem to be a contraindication for using higher doses of allopurinol, especially when slowly titrating up doses to achieve SU in target range, as shown in this population of patients with pretty severe gout and lots of comorbidities. The next step is to have some studies with real clinical outcomes, ideally targeting different levels of SU for patients with different severities of gout, and with concomitant preventive therapy for the first 6 months.​