FROM ANNALS OF INTERNAL MEDICINE
New gout treatment guidelines support the use of urate-lowering therapy, but find no place for treating patients to achieve any specific serum urate target – a dichotomy that has some rheumatologists scratching their heads.
Created by the American College of Physicians, the gout diagnosis and treatment guideline doesn’t recommend monitoring physiologic response to urate-lowering therapy or treating to specific serum urate target (Ann Int Med. 2016 Nov 1. doi: 10.7326/M16-0570 ). Instead, it says patients should be treated according to their symptomatic response – a recommendation that flies in the face of accepted clinical practice.
But the authors said it’s time to rethink accepted practice, especially when faced with a paucity of randomized data on urate-lowering targets. While the idea of reducing uric acid to the level below which it crystallizes makes “physiologic sense,” the guidelines’ data review found no Grade A evidence to support the practice, said Dr. Robert McLean , a member of the ACP guidelines committee. This recommendation is in conflict with that made by the American College of Rheumatology. That guideline recommends lowering serum urate level to less than 5-6 mg/dL – a range that reliably associated with durable remission of symptoms. This is based largely on Grade C evidence consisting of consensus opinion of experts, case studies, and standard of care, which the ACP did not accept, Dr. McLean said in an interview.
“When we step back and ask the question, ‘Has a randomized, controlled trial looked at this approach?’ The answer is simply no. And we are not willing to take that leap of faith without data.”
Reliance on lower-grade clinical evidence is simply no longer a strong-enough basis for a clinical practice recommendation, Dr. McLean said in an interview. In 2011, the Institute of Medicine raised the bar for guidelines evidence in its report, “ Finding What Works in Health Care : Standards for Systematic Reviews.”
That report explicitly states that a clinical guideline cannot be driven by low-grade evidence, including meta-analysis and expert opinion, Dr. McLean said. The Agency for Healthcare Research and Quality National Guideline Clearinghouse incorporated this into its 2013 revision of guidelines acceptance policy : A review must be based on the highest level of evidence – randomized, controlled studies – and not be driven by expert opinion or review articles. Additionally, the literature reviews upon which guidelines are based must be published in a peer-reviewed journal. Guidelines that don’t meet these criteria will no longer be accepted into the clearinghouse.
“The 2012 ACR guidelines didn’t meet that criteria,” he said. “The authors clearly point out in their methodology section where the evidence is weak and admit that 80% of it is low grade. How can you make a guideline that is 80% based on weak evidence? The ACP doesn’t allow us to do that.”
The argument about whether or not to treat to a specific urate target is not simply philosophical, said Dr. McLean, who authored an accompanying editorial (Ann Int Med. 2016 Nov 1. doi: 10.7326/M16-2401 ). In it, he argued that treating to a prespecified target would certainly help some patients but would probably hurt others.
“Treating to a target necessarily means increasing doses of medication in patients who may be asymptomatic,” he wrote. “Examples exist from other studies using intermediary biomarkers (such as elevated blood pressure or blood glucose level or low hemoglobin level), in which treating to a target resulted in more adverse effects than benefits. Thus, despite the strong biologic appeal of such a strategy and its advocacy by major specialty society guidelines, we judged the strength of evidence for monitoring to be low.”
Tehuni Neogi, MD, of Boston University, also authored an editorial (Ann Int Med. 2016 Nov 1. doi: 10.7326/M16-2401 ) about the document. A proponent of the existing guidelines, Dr. Neogi is strongly opposed to the ACP “treat to symptoms” approach.
“This paradigm also has not been formally tested in a randomized clinical trial, and there’s no scientific evidence to support that strategy and a lot of evidence to show its harm,” she said in an interview. “We have a large clinical experience about the ineffectiveness of that strategy. Patients eventually develop tophi, joint damage, and functional limitations when their physicians only treat their gout flares using anti-inflammatory therapy without addressing their underlying cause of gout – high uric acid. They are often dismayed and upset when they realize their physician had let their gout get to that point by just treating their gout flares.”
In other important ways, the two documents are complementary. Both put NSAIDs, corticosteroids, and colchicine at the heart of treating acute gout attacks.
According to the ACP guideline, these treatment strategies are all supported by high-level evidence, which was drawn from a review of 28 studies.
• Corticosteroids, NSAIDs, and colchicine are effective treatments to reduce pain in patients with acute gout.
• Lower doses of colchicine (1.2 mg, followed by 0.6 mg 1 hour later) are as effective as higher doses (1.2 mg, followed by 0.6 mg/hour for 6 hours) at reducing pain and are associated with fewer gastrointestinal adverse effects.
• Do not initiate long-term uric acid–lowering therapy in most patients after a first gout attack or in patients with infrequent attacks.
• Although evidence supports the benefits of using uric acid–lowering therapy for shorter durations to reduce gout flares, the benefits of long-term use in patients with a single or infrequent gout attacks have not been studied.
• Clinicians should discuss benefits, harms, costs, and individual preferences with patients before initiating uric acid–lowering therapy, including concomitant prophylaxis, in patients with recurrent gout attacks. (Grade: strong recommendation, moderate-quality evidence).
• Febuxostat (40 mg/day) and allopurinol (300 mg/day) are equally effective at decreasing serum urate levels, and prophylactic therapy with low-dose colchicine or low-dose NSAIDs reduces the risk for acute gout attacks in patients initiating urate-lowering therapy.
Allopurinol dosage, however, is one key point upon which the ACP and ACR guidelines are sharply divided. The ACR guideline calls for starting at low doses – 100 mg/day, and even lower in patients with kidney disease – with very slow upward titration, only if necessary, to 300 mg/day or more. Allopurinol is not without risk and should be used with caution, Dr. Neogi wrote in her commentary.
“Continuing a management strategy of starting allopurinol at an inappropriately high dose will perpetuate the problem of unnecessarily increasing flare risk, because this risk in the early treatment phase is directly proportional to the potency of the urate-lowering therapy used.”
However, allopurinol doses of 300 mg/day or less leave more than half of all patients undertreated, she said. This dilemma points up the difficulty with symptomatic treatment. Without checking urate levels, clinicians may be shooting blind when trying to dose appropriately.
She refuted any suggestion that the ACR guidelines were based on a lesser degree of evidence than the ACP document.
“The ACR uses a rigorous evidence-based method to develop treatment guidelines. It is inaccurate to say that ACR relies on lower-class evidence or expert opinion ‘to a large extent.’ In the absence of randomized controlled data, other peer-reviewed, available published data are used to formulate guidance, supported by the known biology.”
Current practices outlined in the ACR document are based on a thorough understanding of the biology of gout and how it progresses. Hard data on uric acid targets would greatly impact current therapeutic thinking. But in the meantime, there are patients to be treated, Dr. Neogi said.
“Of course, it would be ideal if we had randomized trial data to definitively provide insights, but we don’t have that right now. So does that mean that patients should suffer unnecessarily because we can’t use the remaining existing body of scientific knowledge to guide rational treatment decisions? What if funding agencies never fund such a study – should gout patients remain poorly managed? Should we abandon all scientific knowledge that isn’t randomized trial data and just not treat at all while waiting to see if a randomized trial will ever be funded and conducted?”
Dr. McLean sees the flip side of that coin.
“I think the effect of our guideline will be to help push the need for more explicit evidence in treat to target being the right way to go. But right now there is not enough evidence now to endorse that approach.”
Dr. McLean reports personal fees from Takeda Pharmaceuticals speakers’ bureau before 2015. Dr. Neogi had no financial disclosures.
