In the Journals

Allopurinol dose escalation for gout fails to reduce mortality

Ted R. Mikuls

Allopurinol dose escalation for patients with gout did not result in improved survival under the currently common practice of prescribing only limited increases, according to findings published in Arthritis and Rheumatology.

“Gout is the most common form of inflammatory arthritis in the world and impacts about 8 million adults in the United States alone,” Ted R. Mikuls, MD, MSPH, of the Veterans Affairs Nebraska-Western Iowa Health Care System and the University of Nebraska Medical Center, told Healio Rheumatology. “This is particularly noteworthy given the ‘bad company’ that gout likes to keep in terms of higher rates for several comorbid conditions such as diabetes, hypertension, hyperlipidemia, and perhaps not surprisingly, cardiovascular disease.”

According to Mikuls, there have been several previous studies linking uric acid and gout to increased risk for cardiovascular disease.

Allopurinol dose escalation for patients with gout did not result in improved survival under the currently common practice of prescribing only limited increases, according to researchers.
Source: Shutterstock

“Moreover, there have been suggestions that drugs that we use to lower uric acid and treat gout, such as allopurinol — by far the most common urate lowering agent used — may be cardioprotective,” he said. “However, studies looking at this latter issue have largely looked at users vs. nonusers and we believe that approach is prone to substantial bias.

To examine whether allopurinol dose escalation, as is recommended in management guidelines, leads to a reduction in cause-specific mortality, the researchers conducted a 10-year, active-comparator study of patients who received the drug for gout from the U.S. Veterans Health Administration from 1999 to 2010. Propensity score matching with Cox proportional hazards and competing risks regression were used to determine cause-specific mortality differences between dose escalators and nonescalators.

A total of 31,335 patients met the researchers’ eligibility criteria, with 25,378 having the complete data required for propensity score matching. Of those, 6,428 patients were sorted into both propensity-matched cohorts of dose escalators and nonescalators.

According to the researchers, there were 2,867 deaths among both matched cohorts, meaning there were 40.4 deaths per 1,000 person-years. Dose escalators demonstrated a small increase in all-cause mortality (HR = 1.08; 95% CI, 1.01-1.17), with similar effect sizes for CV (HR = 1.08; 95% CI, 0.97-1.21) and cancer mortality (HR = 1.06; 95% CI, 0.88-1.27). In the escalator cohort, dose escalation to achieve a serum urate goal of less than 6 mg/dL was limited, with just 10% receiving daily allopurinol doses of more than 300 mg. Just 31% achieved the serum urate goal after 2 years.

Focusing only on escalators who achieved the serum urate goal, the researchers found a 7% reduction in cardiovascular mortality (HR = 0.93; 95% CI, 0.76-1.14), although this was not statistically significant.

“Based on our results, it’s clear that allopurinol dose escalation, at least as it is currently used in real life practice, does not yield benefit in terms of mortality reductions,” Mikuls said. “This last point is important, because clearly aggressive dose escalation was rarely observed in this study.”

Mikuls noted that, even among patients who received escalated doses, just 10% ever achieved daily doses of more than 300 mg, despite allopurinol being approved for daily doses of up to 800 mg.

“Interesting, there was a trend toward a reduction in CV deaths among the approximate one-third of escalators achieving serum urate goal, suggesting that perhaps a benefit could be seen if more aggressive treat-to-target strategy was more widely adopted,” he said. “Whether gout treatment that better aligns with best practice (particularly one that systematically incorporates dose escalation as part of broader treat-to-target strategy) is still an unknown.” – by Jason Laday

Disclosure: The researchers report funding from the Rheumatology Research Foundation, the University of Nebraska Medical Center and the Nebraska Arthritis Outcomes Research Center.

Ted R. Mikuls

Allopurinol dose escalation for patients with gout did not result in improved survival under the currently common practice of prescribing only limited increases, according to findings published in Arthritis and Rheumatology.

“Gout is the most common form of inflammatory arthritis in the world and impacts about 8 million adults in the United States alone,” Ted R. Mikuls, MD, MSPH, of the Veterans Affairs Nebraska-Western Iowa Health Care System and the University of Nebraska Medical Center, told Healio Rheumatology. “This is particularly noteworthy given the ‘bad company’ that gout likes to keep in terms of higher rates for several comorbid conditions such as diabetes, hypertension, hyperlipidemia, and perhaps not surprisingly, cardiovascular disease.”

According to Mikuls, there have been several previous studies linking uric acid and gout to increased risk for cardiovascular disease.

Allopurinol dose escalation for patients with gout did not result in improved survival under the currently common practice of prescribing only limited increases, according to researchers.
Source: Shutterstock

“Moreover, there have been suggestions that drugs that we use to lower uric acid and treat gout, such as allopurinol — by far the most common urate lowering agent used — may be cardioprotective,” he said. “However, studies looking at this latter issue have largely looked at users vs. nonusers and we believe that approach is prone to substantial bias.

To examine whether allopurinol dose escalation, as is recommended in management guidelines, leads to a reduction in cause-specific mortality, the researchers conducted a 10-year, active-comparator study of patients who received the drug for gout from the U.S. Veterans Health Administration from 1999 to 2010. Propensity score matching with Cox proportional hazards and competing risks regression were used to determine cause-specific mortality differences between dose escalators and nonescalators.

A total of 31,335 patients met the researchers’ eligibility criteria, with 25,378 having the complete data required for propensity score matching. Of those, 6,428 patients were sorted into both propensity-matched cohorts of dose escalators and nonescalators.

According to the researchers, there were 2,867 deaths among both matched cohorts, meaning there were 40.4 deaths per 1,000 person-years. Dose escalators demonstrated a small increase in all-cause mortality (HR = 1.08; 95% CI, 1.01-1.17), with similar effect sizes for CV (HR = 1.08; 95% CI, 0.97-1.21) and cancer mortality (HR = 1.06; 95% CI, 0.88-1.27). In the escalator cohort, dose escalation to achieve a serum urate goal of less than 6 mg/dL was limited, with just 10% receiving daily allopurinol doses of more than 300 mg. Just 31% achieved the serum urate goal after 2 years.

Focusing only on escalators who achieved the serum urate goal, the researchers found a 7% reduction in cardiovascular mortality (HR = 0.93; 95% CI, 0.76-1.14), although this was not statistically significant.

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“Based on our results, it’s clear that allopurinol dose escalation, at least as it is currently used in real life practice, does not yield benefit in terms of mortality reductions,” Mikuls said. “This last point is important, because clearly aggressive dose escalation was rarely observed in this study.”

Mikuls noted that, even among patients who received escalated doses, just 10% ever achieved daily doses of more than 300 mg, despite allopurinol being approved for daily doses of up to 800 mg.

“Interesting, there was a trend toward a reduction in CV deaths among the approximate one-third of escalators achieving serum urate goal, suggesting that perhaps a benefit could be seen if more aggressive treat-to-target strategy was more widely adopted,” he said. “Whether gout treatment that better aligns with best practice (particularly one that systematically incorporates dose escalation as part of broader treat-to-target strategy) is still an unknown.” – by Jason Laday

Disclosure: The researchers report funding from the Rheumatology Research Foundation, the University of Nebraska Medical Center and the Nebraska Arthritis Outcomes Research Center.