Janine Tillett, MSLS, AHIP

EVIDENCE SUMMARY

A 28-week RCT compared the effects of placebo, allopurinol (300 mg/d), and febuxostat (80 mg, 120 mg, and 240 mg) on serum uric acid levels (sUA) and gout attacks in 1067 patients with gout and hyperuricemia (94% male, 78% white, 18 to 85 years of age with mean age ranging from 51 to 54 years ± 12 years in each group).¹ Patients also received prophylaxis with either colchicine or naproxen during the first 8 weeks of the study.

During Weeks 1 through 8, investigators found no statistically significant differences in the percentage of patients requiring treatment for gout attacks between the febuxostat 80 mg, allopurinol, and placebo groups (28%, 23%, and 20%, respectively). During Weeks 8 through 28, no statistically significant differences in gout attack rates occurred between the allopurinol and febuxostat groups, although the study didn’t report specific attack rates for this period.

Both allopurinol and all doses of febuxostat reduced sUA to <6 mg/dL more effectively than placebo; more patients treated with febuxostat than allopurinol achieved a uric acid level of less than <6 mg/dL.

Another RCT of 762 mostly white, male patients (mean age 52 years) with gout and sUA >8 mg/dL—35% of whom had renal impairment, defined as creatinine clearance <80 mL/min/1.73m²—also concluded that febuxostat and allopurinol are equally effective in reducing gout attacks (incidence of gout flares during Weeks 9 to 52 was 64% with both febuxostat 80 mg and allopurinol 300 mg).² The percentage of patients with sUA <6 mg/dL at the last 3 monthly visits was 53% in the febuxostat 80 mg group compared with 21% in the allopurinol 300 mg group (P<.001; number needed to treat [NNT]=4]).

One significant limitation of both RCTs was the fixed dose of allopurinol (300 mg/d). US Food and Drug Administration-approved dosing for allopurinol allows for titration to a maximum of 800 mg/d to achieve serum uric acid <6 mg/dL.

Pegloticase is an intravenously administered, recombinant form of uricase, the natural enzyme that converts uric acid to more soluble allantoin. Two RCTs compared pegloticase with placebo in a total of 212 patients with gout (mean age 54 to 59 years; 70% to 90% male) intolerant or refractory to allopurinol (defined as baseline sUA of ≥8 mg/dL and at least one of the following: ≥3 self-reported gout flares during the previous 18 months, ≥1 tophi, or gouty arthropathy.

These trials found that treatment with 8 mg of pegloticase every 2 weeks for 6 months initially increased gout flares during Months 1 to 3 (75% with pegloticase, 53% with placebo; P=.02; number needed to harm [NNH]=5) but then decreased the incidence of acute gout attacks during Months 4 to 6 (41% with pegloticase, 67% with placebo; P=.007; NNT=4).3 In addition, pegloticase resulted in statistically significant improvements in QOL measured at the final visit using the Health Assessment Questionnaire (HAQ) pain scale, the HAQ-Disability Index, and the 36-item Short Form Health Survey.

Colchicine plus probenecid or allopurinol reduces gout attacks

One small, low-quality RCT (N=38) found that colchicine 0.5 mg administered 3 times daily effectively prevented gout attacks when administered concomitantly with probenecid initiated to lower urate (gout attacks per month in colchicine and placebo-treated patients, respectively, were 0.19±0.05 and 0.48±0.12; P<.05).⁴

Another RCT that compared allopurinol with and without colchicine showed that coadministration of colchicine 0.6 mg twice daily reduced gout attacks: 33% of patients treated with colchicine experienced a gout flare compared with 77% of placebo-treated patients (P=.008; NNT=3 over 6 months).⁵

We identified no RCTs that evaluated the uricosuric agent probenecid and no studies that assessed the use of nonsteroidal anti-inflammatory drugs (NSAIDs) to prevent recurrent gout attacks.

RECOMMENDATIONS

Eight weeks of treatment with either allopurinol or febuxostat reduces the frequency of gout attacks equally.The American College of Rheumatology (ACR) guidelines on managing gout recommend allopurinol or febuxostat as first-line pharmacologic urate-lowering therapy, with a goal of reducing sUA to <6 mg/dL. They recommend probenecid as an alternative if contraindications exist or the patient is intolerant to allopurinol and febuxostat.⁶ The guidelines note that allopurinol doses may exceed 300 mg/d, even in patients with chronic kidney disease.

The ACR recommends anti-inflammatory prophylaxis with colchicine or NSAIDs upon initiation of urate-lowering therapy. Anti-inflammatory prophylaxis should be continued as long as clinical evidence of continuing gout disease exists and until the sUA target has been acheived.7

EVIDENCE SUMMARY

A 28-week RCT compared the effects of placebo, allopurinol (300 mg/d), and febuxostat (80 mg, 120 mg, and 240 mg) on serum uric acid levels (sUA) and gout attacks in 1067 patients with gout and hyperuricemia (94% male, 78% white, 18 to 85 years of age with mean age ranging from 51 to 54 years ± 12 years in each group).¹ Patients also received prophylaxis with either colchicine or naproxen during the first 8 weeks of the study.

During Weeks 1 through 8, investigators found no statistically significant differences in the percentage of patients requiring treatment for gout attacks between the febuxostat 80 mg, allopurinol, and placebo groups (28%, 23%, and 20%, respectively). During Weeks 8 through 28, no statistically significant differences in gout attack rates occurred between the allopurinol and febuxostat groups, although the study didn’t report specific attack rates for this period.

Both allopurinol and all doses of febuxostat reduced sUA to <6 mg/dL more effectively than placebo; more patients treated with febuxostat than allopurinol achieved a uric acid level of less than <6 mg/dL.

Another RCT of 762 mostly white, male patients (mean age 52 years) with gout and sUA >8 mg/dL—35% of whom had renal impairment, defined as creatinine clearance <80 mL/min/1.73m²—also concluded that febuxostat and allopurinol are equally effective in reducing gout attacks (incidence of gout flares during Weeks 9 to 52 was 64% with both febuxostat 80 mg and allopurinol 300 mg).² The percentage of patients with sUA <6 mg/dL at the last 3 monthly visits was 53% in the febuxostat 80 mg group compared with 21% in the allopurinol 300 mg group (P<.001; number needed to treat [NNT]=4]).

One significant limitation of both RCTs was the fixed dose of allopurinol (300 mg/d). US Food and Drug Administration-approved dosing for allopurinol allows for titration to a maximum of 800 mg/d to achieve serum uric acid <6 mg/dL.

Pegloticase is an intravenously administered, recombinant form of uricase, the natural enzyme that converts uric acid to more soluble allantoin. Two RCTs compared pegloticase with placebo in a total of 212 patients with gout (mean age 54 to 59 years; 70% to 90% male) intolerant or refractory to allopurinol (defined as baseline sUA of ≥8 mg/dL and at least one of the following: ≥3 self-reported gout flares during the previous 18 months, ≥1 tophi, or gouty arthropathy.

These trials found that treatment with 8 mg of pegloticase every 2 weeks for 6 months initially increased gout flares during Months 1 to 3 (75% with pegloticase, 53% with placebo; P=.02; number needed to harm [NNH]=5) but then decreased the incidence of acute gout attacks during Months 4 to 6 (41% with pegloticase, 67% with placebo; P=.007; NNT=4).3 In addition, pegloticase resulted in statistically significant improvements in QOL measured at the final visit using the Health Assessment Questionnaire (HAQ) pain scale, the HAQ-Disability Index, and the 36-item Short Form Health Survey.

Colchicine plus probenecid or allopurinol reduces gout attacks

One small, low-quality RCT (N=38) found that colchicine 0.5 mg administered 3 times daily effectively prevented gout attacks when administered concomitantly with probenecid initiated to lower urate (gout attacks per month in colchicine and placebo-treated patients, respectively, were 0.19±0.05 and 0.48±0.12; P<.05).⁴

Another RCT that compared allopurinol with and without colchicine showed that coadministration of colchicine 0.6 mg twice daily reduced gout attacks: 33% of patients treated with colchicine experienced a gout flare compared with 77% of placebo-treated patients (P=.008; NNT=3 over 6 months).⁵

We identified no RCTs that evaluated the uricosuric agent probenecid and no studies that assessed the use of nonsteroidal anti-inflammatory drugs (NSAIDs) to prevent recurrent gout attacks.

RECOMMENDATIONS

Eight weeks of treatment with either allopurinol or febuxostat reduces the frequency of gout attacks equally.The American College of Rheumatology (ACR) guidelines on managing gout recommend allopurinol or febuxostat as first-line pharmacologic urate-lowering therapy, with a goal of reducing sUA to <6 mg/dL. They recommend probenecid as an alternative if contraindications exist or the patient is intolerant to allopurinol and febuxostat.⁶ The guidelines note that allopurinol doses may exceed 300 mg/d, even in patients with chronic kidney disease.

The ACR recommends anti-inflammatory prophylaxis with colchicine or NSAIDs upon initiation of urate-lowering therapy. Anti-inflammatory prophylaxis should be continued as long as clinical evidence of continuing gout disease exists and until the sUA target has been acheived.7

EVIDENCE SUMMARY

A 28-week RCT compared the effects of placebo, allopurinol (300 mg/d), and febuxostat (80 mg, 120 mg, and 240 mg) on serum uric acid levels (sUA) and gout attacks in 1067 patients with gout and hyperuricemia (94% male, 78% white, 18 to 85 years of age with mean age ranging from 51 to 54 years ± 12 years in each group).¹ Patients also received prophylaxis with either colchicine or naproxen during the first 8 weeks of the study.

During Weeks 1 through 8, investigators found no statistically significant differences in the percentage of patients requiring treatment for gout attacks between the febuxostat 80 mg, allopurinol, and placebo groups (28%, 23%, and 20%, respectively). During Weeks 8 through 28, no statistically significant differences in gout attack rates occurred between the allopurinol and febuxostat groups, although the study didn’t report specific attack rates for this period.

Both allopurinol and all doses of febuxostat reduced sUA to <6 mg/dL more effectively than placebo; more patients treated with febuxostat than allopurinol achieved a uric acid level of less than <6 mg/dL.

Another RCT of 762 mostly white, male patients (mean age 52 years) with gout and sUA >8 mg/dL—35% of whom had renal impairment, defined as creatinine clearance <80 mL/min/1.73m²—also concluded that febuxostat and allopurinol are equally effective in reducing gout attacks (incidence of gout flares during Weeks 9 to 52 was 64% with both febuxostat 80 mg and allopurinol 300 mg).² The percentage of patients with sUA <6 mg/dL at the last 3 monthly visits was 53% in the febuxostat 80 mg group compared with 21% in the allopurinol 300 mg group (P<.001; number needed to treat [NNT]=4]).

One significant limitation of both RCTs was the fixed dose of allopurinol (300 mg/d). US Food and Drug Administration-approved dosing for allopurinol allows for titration to a maximum of 800 mg/d to achieve serum uric acid <6 mg/dL.

Pegloticase is an intravenously administered, recombinant form of uricase, the natural enzyme that converts uric acid to more soluble allantoin. Two RCTs compared pegloticase with placebo in a total of 212 patients with gout (mean age 54 to 59 years; 70% to 90% male) intolerant or refractory to allopurinol (defined as baseline sUA of ≥8 mg/dL and at least one of the following: ≥3 self-reported gout flares during the previous 18 months, ≥1 tophi, or gouty arthropathy.

These trials found that treatment with 8 mg of pegloticase every 2 weeks for 6 months initially increased gout flares during Months 1 to 3 (75% with pegloticase, 53% with placebo; P=.02; number needed to harm [NNH]=5) but then decreased the incidence of acute gout attacks during Months 4 to 6 (41% with pegloticase, 67% with placebo; P=.007; NNT=4).3 In addition, pegloticase resulted in statistically significant improvements in QOL measured at the final visit using the Health Assessment Questionnaire (HAQ) pain scale, the HAQ-Disability Index, and the 36-item Short Form Health Survey.

Colchicine plus probenecid or allopurinol reduces gout attacks

One small, low-quality RCT (N=38) found that colchicine 0.5 mg administered 3 times daily effectively prevented gout attacks when administered concomitantly with probenecid initiated to lower urate (gout attacks per month in colchicine and placebo-treated patients, respectively, were 0.19±0.05 and 0.48±0.12; P<.05).⁴

Another RCT that compared allopurinol with and without colchicine showed that coadministration of colchicine 0.6 mg twice daily reduced gout attacks: 33% of patients treated with colchicine experienced a gout flare compared with 77% of placebo-treated patients (P=.008; NNT=3 over 6 months).⁵

We identified no RCTs that evaluated the uricosuric agent probenecid and no studies that assessed the use of nonsteroidal anti-inflammatory drugs (NSAIDs) to prevent recurrent gout attacks.

RECOMMENDATIONS

Eight weeks of treatment with either allopurinol or febuxostat reduces the frequency of gout attacks equally.The American College of Rheumatology (ACR) guidelines on managing gout recommend allopurinol or febuxostat as first-line pharmacologic urate-lowering therapy, with a goal of reducing sUA to <6 mg/dL. They recommend probenecid as an alternative if contraindications exist or the patient is intolerant to allopurinol and febuxostat.⁶ The guidelines note that allopurinol doses may exceed 300 mg/d, even in patients with chronic kidney disease.

The ACR recommends anti-inflammatory prophylaxis with colchicine or NSAIDs upon initiation of urate-lowering therapy. Anti-inflammatory prophylaxis should be continued as long as clinical evidence of continuing gout disease exists and until the sUA target has been acheived.7

Evidence summary

AAAs occur in 5% to 10% of men and 0.5% to 1.5% of women between 65 and 79 years of age.^1,2 Risk factors include age, smoking, male sex, and family history.² AAAs are 3 to 5 times more likely in patients with a smoking history.² Approximately 9000 deaths annually are linked to AAAs in the United States, mostly in men older than 65 years.² Mortality after rupture approaches 80% for patients who reach a hospital and 50% for patients who undergo emergent surgery.²

Screening reduces AAA deaths in men, but not all-cause mortality

A Cochrane review assessing the use of ultrasound to screen for AAA analyzed 4 population-based RCTs involving 127,891 men and 9342 women.¹ Participants in each trial were randomly assigned to screening with ultrasound or no intervention.

The reviewers reported that screening significantly reduced mortality from AAA in men 65 to 79 years of age (odds ratio [OR]=0.60; 95% confidence interval [CI], 0.47-0.78). They found no support for decreased mortality in women (OR=1.99; 95% CI, 0.36-10.88).

The study also found no significant reduction in all-cause mortality 3 to 5 years after screening in men 65 to 79 years of age (OR=0.95; 95% CI, 0.85-1.07) or women (OR=1.06; 95% CI, 0.93-1.21), probably because of the low overall incidence of AAA.¹ For men 65 to 79 years of age, the NNS is 769 over 3 years to prevent one death.¹

Limitations of the study include disproportionate male representation because only 1 of the 4 trials in the Cochrane review enrolled women. Moreover, the analysis didn’t include smoking, although smoking increases the risk of AAA 3- to 5-fold. The NNS may be significantly different for smokers than nonsmokers.^1,2

Recommendations

The US Preventive Services Task Force (USPSTF) recommends a one-time ultrasound screening for AAA in men between 65 and 74 years of age who have ever smoked.² The USPSTF advises against routine screening in women and concludes that insufficient evidence exists to advocate for or against routine screening in men 65 to 74 years who have never smoked.²

The Canadian Society for Vascular Surgery recommends a population-based screening program for men 65 to 75 years of age who are candidates for surgery and are willing to participate.³

Acknowledgements

The opinions and assertions contained herein are the private views of the authors and not to be construed as official nor as reflecting the views of the United States Air Force Medical Service or the US Air Force at large.

Evidence summary

AAAs occur in 5% to 10% of men and 0.5% to 1.5% of women between 65 and 79 years of age.^1,2 Risk factors include age, smoking, male sex, and family history.² AAAs are 3 to 5 times more likely in patients with a smoking history.² Approximately 9000 deaths annually are linked to AAAs in the United States, mostly in men older than 65 years.² Mortality after rupture approaches 80% for patients who reach a hospital and 50% for patients who undergo emergent surgery.²

Screening reduces AAA deaths in men, but not all-cause mortality

A Cochrane review assessing the use of ultrasound to screen for AAA analyzed 4 population-based RCTs involving 127,891 men and 9342 women.¹ Participants in each trial were randomly assigned to screening with ultrasound or no intervention.

The reviewers reported that screening significantly reduced mortality from AAA in men 65 to 79 years of age (odds ratio [OR]=0.60; 95% confidence interval [CI], 0.47-0.78). They found no support for decreased mortality in women (OR=1.99; 95% CI, 0.36-10.88).

The study also found no significant reduction in all-cause mortality 3 to 5 years after screening in men 65 to 79 years of age (OR=0.95; 95% CI, 0.85-1.07) or women (OR=1.06; 95% CI, 0.93-1.21), probably because of the low overall incidence of AAA.¹ For men 65 to 79 years of age, the NNS is 769 over 3 years to prevent one death.¹

Limitations of the study include disproportionate male representation because only 1 of the 4 trials in the Cochrane review enrolled women. Moreover, the analysis didn’t include smoking, although smoking increases the risk of AAA 3- to 5-fold. The NNS may be significantly different for smokers than nonsmokers.^1,2

Recommendations

The US Preventive Services Task Force (USPSTF) recommends a one-time ultrasound screening for AAA in men between 65 and 74 years of age who have ever smoked.² The USPSTF advises against routine screening in women and concludes that insufficient evidence exists to advocate for or against routine screening in men 65 to 74 years who have never smoked.²

The Canadian Society for Vascular Surgery recommends a population-based screening program for men 65 to 75 years of age who are candidates for surgery and are willing to participate.³

Acknowledgements

The opinions and assertions contained herein are the private views of the authors and not to be construed as official nor as reflecting the views of the United States Air Force Medical Service or the US Air Force at large.

Evidence summary

AAAs occur in 5% to 10% of men and 0.5% to 1.5% of women between 65 and 79 years of age.^1,2 Risk factors include age, smoking, male sex, and family history.² AAAs are 3 to 5 times more likely in patients with a smoking history.² Approximately 9000 deaths annually are linked to AAAs in the United States, mostly in men older than 65 years.² Mortality after rupture approaches 80% for patients who reach a hospital and 50% for patients who undergo emergent surgery.²

Screening reduces AAA deaths in men, but not all-cause mortality

A Cochrane review assessing the use of ultrasound to screen for AAA analyzed 4 population-based RCTs involving 127,891 men and 9342 women.¹ Participants in each trial were randomly assigned to screening with ultrasound or no intervention.

The reviewers reported that screening significantly reduced mortality from AAA in men 65 to 79 years of age (odds ratio [OR]=0.60; 95% confidence interval [CI], 0.47-0.78). They found no support for decreased mortality in women (OR=1.99; 95% CI, 0.36-10.88).

The study also found no significant reduction in all-cause mortality 3 to 5 years after screening in men 65 to 79 years of age (OR=0.95; 95% CI, 0.85-1.07) or women (OR=1.06; 95% CI, 0.93-1.21), probably because of the low overall incidence of AAA.¹ For men 65 to 79 years of age, the NNS is 769 over 3 years to prevent one death.¹

Limitations of the study include disproportionate male representation because only 1 of the 4 trials in the Cochrane review enrolled women. Moreover, the analysis didn’t include smoking, although smoking increases the risk of AAA 3- to 5-fold. The NNS may be significantly different for smokers than nonsmokers.^1,2

Recommendations

The US Preventive Services Task Force (USPSTF) recommends a one-time ultrasound screening for AAA in men between 65 and 74 years of age who have ever smoked.² The USPSTF advises against routine screening in women and concludes that insufficient evidence exists to advocate for or against routine screening in men 65 to 74 years who have never smoked.²

The Canadian Society for Vascular Surgery recommends a population-based screening program for men 65 to 75 years of age who are candidates for surgery and are willing to participate.³

Acknowledgements

The opinions and assertions contained herein are the private views of the authors and not to be construed as official nor as reflecting the views of the United States Air Force Medical Service or the US Air Force at large.