Allopurinol

Allopurinol: Extra Caution Urged in High-Risk Groups

Posted by

0


Allopurinol-associated cutaneous adverse reactions severe enough to require hospitalization occurred three to six times as often in Asians, blacks, and Native Hawaiians/Pacific Islanders than in whites or Hispanics, and up to 12 times as often in members of the high-risk groups who were also female and older than 60 years, researchers report in an article published online April 13 in the Annals of the Rheumatic Diseases.

The elevated risk paralleled the frequency of the HLA-B*5801 allele in each ethnic/racial group, and higher risk was also associated with initial allopurinol dosing of more than 100 mg/day. Neither gout nor prior diuretic use was associated with increased risk.

These findings support current recommendations that allopurinol be initiated at a dose of 100 mg/day or lower. The authors also recommend screening of Asian, black, and native Hawaiian/Pacific Islander patients for the presence of HLA-B*5801 before initiating allopurinol, particularly those who also have additional risk factors (female, age >60 years, or chronic kidney disease [CKD]). The risk for allopurinol-associated severe cutaneous reactions (AASCARs) was more than six times higher among Native Hawaiians/Pacific Islanders compared with whites, the first time this racial/ethnic group has been identified as at high risk.

Sarah F. Keller, MD, from the Division of Rheumatology, Allergy, and Immunology, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, and colleagues write, “These findings support the use of extra caution among Native Hawaiians/Pacific Islanders, Asians and blacks when considering allopurinol (including screening for HLA-B*5801), particularly among elderly women with CKD. Importantly, a low initial allopurinol dose (eg, <100 mg/day) was the only modifiable risk factor, which is readily implementable and is also recommended by the latest rheumatology guidelines.”

Researchers Analyzed More Than 400,000 Allopurinol Users

Keller and colleagues used US Medicaid data to identify patients who began using allopurinol between 1999 and 2012. Among these 400,401 allopurinol initiators, they found 203 hospitalized AASCAR cases, with an average 9.6 days of hospitalization. There were also 43 (21%) deaths. They note the analysis included only hospitalized AASCAR cases and likely underestimates the AASCAR risk associated with allopurinol.

The study population was 62% white, 53% male, 52% younger than age 60 years, 5% with CKD, and 61% prescribed allopurinol at an initial dose higher than 100 mg/day.

The primary study objective was to identify high-risk patients, with the goal of finding ways to prevent severe cutaneous adverse events associated with allopurinol. These severe reactions can involve major organs, result in corneal damage and renal insufficiency, and be fatal in up to 32% of cases, the authors write. The researchers defined cutaneous adverse effects using International Classification of Diseases, Ninth Revision, Clinical Modification, codes for dermatitis resulting from drugs and medicines, erythema multiforme, Stevens-Johnson syndrome, Toxic Epidermal Necrolysis, unspecified erythematous conditions, and other unspecified erythematous conditions.

The incident AASCAR cases requiring hospitalization began to appear within 10 days of allopurinol initiation, peaked at about 30 days, and subsided by 90 days. Hospitalization risk was 1 in 3883 whites and Hispanics, 1 in 1227 blacks, 1 in 1429 Asians, and 1 in 571 Native Hawaiians/Pacific Islanders.

AASCAR Risk for Ethnic/racial Groups Linked to HLA-B*5801

Multivariable-adjusted relative risks (RR) for AASCARs compared with those among whites and Hispanics were 3.00 among blacks, 3.03 among Asians, and 6.68 among Native Hawaiians/Pacific Islanders. AASCAR risk roughly paralleled the estimated allele frequency of HLA-B*5801 in these groups in the United States: 1% in whites and Hispanics, 4% in blacks, and 7.4% in Asians. A prior meta-analysis reported the risk of developing AASCARs was up to 97 times higher in patients with the allele than in those without it.

The authors further warn that allele frequency is higher in other Pacific Island countries such as Malaysia, where it is 11% to 22%, so the risk for patients from those areas would be expected to be at least as high as that observed in the current study. The authors explain that the 20% prevalence of HLA-B*5801 in Taiwan is why the Taiwanese Food and Drug Administration adopted an alternate first-line urate-lowering drug for patients with CKD.

Furthermore, allele frequencies are 7% to 10% among blacks in Kenya and 8% in black South Africans, suggesting a higher AASCAR risk in those populations as well.

The authors write, “The recommendation to screen for HLA-B*5801 or to consider the use of an alternative [urate-lowering drug] would be applicable to Native Hawaiians/Pacific Islanders prior to initiating allopurinol therapy, particularly when additional AASCAR risk factors are present (eg, in the case of being an elderly woman with CKD).”

Furthermore, the various independent risk factors combine to produce even greater risk. Female sex (RR, 1.96) and age 60 years or older (RR, 2.79) were significant independent risk factors for AASCAR. But women older than 60 years from high-risk race/ethnicity groups had a 12-fold higher risk for hospitalized AASCARs than younger men from a low-risk subgroup. Men older than 60 years from one of the high-risk race/ethnicity groups had a more than six-fold higher risk for hospitalized AASCAR than younger men from the same subgroup.

CKD was associated with a multivariable-adjusted RR of 2.33, and initial allopurinol dose more than 100 mg/day was associated with a multivariable-adjusted RR of 1.85. Combining these two independent risk factors in a patient from a high-risk race/ethnicity group produced a relative risk nine times higher than for a patient without CKD with an initial allopurinol dose 100 mg or lower who was from a low-risk race/ethnicity group.

More Cautious Approach to Allopurinol Recommended

The researchers conclude, “[T]hese findings from a large, racially diverse cohort indicate that Native Hawaiians/Pacific Islanders, Asians and blacks all have a substantially higher risk for hospitalized AASCARs compared with whites and Hispanics, calling for heightened vigilance when initiating allopurinol in these racial/ethnic groups. Furthermore, female sex, older age, CKD and an initial allopurinol dose >100 mg/day are all independent risk factors for hospitalised AASCARs and should also be considered when initiating allopurinol to help prevent this severe and potentially fatal adverse reaction.”

Reconsidering Allopurinol for Hypertension

Posted by

0


Of late, we are beginning to look at old drugs that might have new uses. This has been the case with spironolactone, for example, a mineralocorticoid antagonist. It has turned out to be good in heart failure and resistant hypertension.

There are also some ideas that this might be the case with allopurinol, a xanthine oxidase inhibitor widely used in the 1960s, 1970s, and 1980s. A couple of small studies in obese adolescents and adolescent patients with hypertension showed reductions in blood pressure.[1,2]

Is allopurinol a good drug for lowering blood pressure? That is the question that has been posed [in this study by Beattie and colleagues].[3]

It is interesting because there is a plausible mechanism to explain why a xanthine oxidase inhibitor might reduce blood pressure and cardiovascular events. This also is seen with uricosuric agents, so is it just lowering of the uric acid level or is there something special about what allopurinol and similar drugs do?

This is an example of “big data.” Investigators looked at the United Kingdom Clinical Practice Research Datalink to see whether they could tease out which individuals had received allopurinol. They looked at people who were older than 65 years of age, because there were no issues about paying for prescription drugs in that group. The sought to determine how many people were in that group and how the drug influenced their pressure.

Only 3% of the people in that very large database who were over the age of 65 had taken allopurinol. The investigators compared [a subsection of] these people [who had blood pressure readings taken before and after being prescribed allopurinol] with people who had not taken allopurinol, using a propensity analysis that matched people as closely as possible.

The findings were interesting: There was a modest reduction of blood pressure that was not related to the primary uric acid level or to other drugs the patients were taking (80% were on a thiazide diuretic, which can raise uric acid levels), and they saw an issue of physician preference for drugs. They also looked at patients who received no treatment or no change in treatment, with the same results. There was a hint, at least, in certain groups that allopurinol lowered blood pressure.
They recommended giving a high dose (≥ 300 mg daily) of allopurinol. No patient received a higher dose than 300 mg daily. Adolescents received 200 mg twice daily. This is a large assumption—that we ought to be giving people large doses of allopurinol, which can cause Stevens-Johnson syndrome and other side effects.

Before we embark on a good clinical trial, we had better decide whether we are willing to take on the risks associated with this agent. It is very good for the prevention of gout, but should we start giving it to people who don’t have gout and to those in whom it is not indicated?

We will see. This may be a look at big data, but it might also be an abuse of big data before we can make recommendations for clinical practice.

References

  1. Soletsky B, Feig DI. Uric acid reduction rectifies prehypertension in obese adolescents. Hypertension. 2012;60:1148-1156. Abstract
  2. Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial. JAMA. 2008;300:924-930. Abstract
  3. Beattie CJ, Fulton RL, Higgins P, et al. Allopurinol initiation and change in blood pressure in older adults with hypertension. Hypertension. 2014;64:1102-1107. Abstract

Gout Guidelines From ACR Include New Drugs, Diet.

Posted by

0


New gout guidelines from the American College of Rheumatology are meant to improve gout management by providing clinicians with clear, readily implemented guidance on urate-lowering therapy (including diet and lifestyle changes), chronic tophaceous gouty arthropathy (CTGA), analgesic and antiinflammatory management of acute gouty arthritis, and drug prophylaxis of acute attacks.

The guidelines, reported in the October issue of Arthritis Care & Research in two parts, and include guidance on the new drugs febuxostat and pegloticase, recently approved for gout management and not yet addressed in the European League Against Rheumatism or British Society for Rheumatology gout guidelines.

Senior author Robert Terkeltaub, MD, told Medscape Medical News,”This is the first time in the 78-year history of ACR that there have been guidelines for the management of gout. This indicates how seriously people in rheumatology take this and how common the problem has become, with more than 8 million cases in the US, affecting 3.9% of adults. What we have here is a disease that is very well understood but ridiculously poorly managed.” Dr. Terkeltaub is chief of rheumatology at the Veterans Affairs Medical Center in San Diego, California, and professor of medicine and associate division director at the University of California in San Diego.

Old Disease, New Management

Part 1 of the guidelines focuses on hyperuricemia and CTGA. The top recommendation is for more intensive education of patients on diet, lifestyle choices, treatment objectives, and management of concomitant diseases; this includes recommendations on specific dietary items to encourage, limit, and avoid.

“We provide a comorbidity check-list for the clinician that I expect will be very useful in day-to-day practice,” Dr. Terkeltaub said. “We have also provided a cohesive set of diet and lifestyle recommendations. This has been a problem because of the fact and fiction mixed in to diet and lifestyle approaches to gout. The guideline is an advance because it provides a more actionable set of recommendations for physicians to talk about with their patients.”

Table. Comorbidity Checklist for Patients with Gout

Obesity, dietary factors
Excessive alcohol intake
History of urolithiasis
Chronic kidney disease
Potential genetic or acquired causes of uric acid overproduction (inborn error of purine metabolism, psoriasis, myeloproliferative or lymphoproliferative disease)
Lead intoxication

 

Dr. Terkeltaub added, “Many patients feel that diet and moderation alone should be sufficient to manage their gout. Diet is important, but what is really important is getting the serum urate to a target appropriate for that patient. At a bare minimum it should be < 6 mg/dL. In clinical practice the serum uric acid level is no longer part of the routine metabolic panel, but it is inexpensive and should be monitored regularly in gout patients.”

Dr. Terkeltaub noted that dietary or alcohol excess can increase uric acid and trigger acute gout attacks in susceptible individuals, but he said that dietary restrictions alone may not reduce serum urate levels enough to prevent joint damage in gout patients.

“The average age gout patient in our clinical trials has a serum uric acid level between 9.5 and 10 mg/dL. Even ideal diet and alcohol intake will likely lower that by only 10% to 15%, which will not bring the typical gout patient to a serum uric acid of 6 mg/dL. Often people need urate-lowering drugs to get them to the target level and keep them there. People feel that if they have fewer gout attacks, they are better, but the disease will progress unless serum uric acid is reduced to a level where deposits of urate crystals in the joint tissues will disappear,” Dr. Terkeltaub said.

Start Low, Go Slow With Allopurinol

The ACR guidelines recommend treating patients with a xanthine oxidase inhibitor, such as allopurinol, as the first-line pharmacologic urate-lowering therapy approach. The recommended goal is to reduce serum urate to less than 6 mg/dL, and the initial allopurinol dosage should be no greater than 100 mg/d, the guidelines say. This should be followed by gradual increase of the maintenance dose, which can safely exceed 300 mg even in patients with chronic kidney disease.

“Clinicians often start allopurinol at doses that are too high but maintain allopurinol at doses that are too low,” Dr. Terkeltaub said. “We give specific guidance on start low, go slow dose escalation.”

To avoid allopurinol toxicity, the guidelines recommend considering HLA-B*5801 prescreening of patients at particularly high risk for severe adverse reaction to allopurinol (eg, Koreans with stage 3 or worse kidney disease and all patients of Han Chinese and Thai descent).

For CTGA, the guidelines recommend combination therapy, with 1 xanthine oxidase inhibitor (allopurinol or febuxostat) and 1 uricosuric agent, when target urate levels are not achieved. They advise using probenecid as an alternative first-line urate-lowering drug in the setting of contraindication or intolerance to at least 1 xanthine oxidase inhibitor (except in patients with creatinine clearance below 50 mL/min). They also recommend pegloticase in patients with severe gout disease who do not respond to standard, appropriately dosed urate-lowering therapy.

“We provide guidance for dose-escalation of urate-lowering therapy for specific case scenarios of mild, moderate, and severe disease including for patients with destructive joint disease that is chronic to their gout. These provide ways to assess the patient in an office setting on clinical findings alone, with serum uric acid. Pictorial representation of most severe patients should help identify who needs more intensive uric acid-lowering therapy,” Dr. Terkeltaub said.

Acute Gout Requires Prompt Treatment

Part 2 of the guidelines covers therapy and prophylactic antiinflammatory treatment for acute gouty arthritis. These guidelines recommend initiating pharmacologic therapy within 24 hours of onset of acute gouty arthritis attack while continuing urate-lower therapy without interruption.

Nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids, or oral colchicine are the recommended first-line treatment for acute gout, and combinations of these medications can be used for severe or unresponsive cases.

To prevent the acute gout flares that may accompany the early stages of urate-lowering therapy, the guidelines recommend oral colchicine or low-dose NSAIDs as long as there is no medical contraindication or lack of tolerance.

Dr. Terkeltaub advised caution with colchicine dosing. “One of the major problems in quality of care is that people were getting drowned in colchicine for acute gout. We assessed the evidence and decided to go with the FDA [Food and Drug Administration]-approved regimen of low-dose colchicine for early acute gout flare. That is a major recommendation. When people get drowned in high doses of colchicine for a long time for acute gout, the rate of adverse events is quite high.”

The recommendations were prepared during a 2-year project by an ACR task force panel that included 7 rheumatologists, 2 primary care physicians, a nephrologist, and a patient representative. The draft guidelines then went through 3 rounds of peer review, Dr. Terkeltaub said.

“I’d like to see better education of physicians and other primary caregivers, including nurse practitioners and physician assistants, and then better education of gout patients. If we only accomplish that, we’ll have accomplished a lot. There has been a systematic failure of both quality of care and patient education in gout,” Dr. Terkeltaub said.

Doug Campos-Outcalt, MD, scientific analyst for the American Academy of Family Physicians, reviewed the new guidelines for Medscape Medical News. Dr. Capos-Outcalt is chair of the Department of Family Medicine at the University of Arizona College of Medicine in Phoenix.

Dr. Campos-Outcalt said, “This is a reasonable, limited number of guidelines that are implementable. You don’t like to see guidelines that have 50 recommendations. The ACR guidelines also present, from a family physician perspective, no major changes in standard-of-care.” However, Dr. Campos-Outcalt suggested that a broader effort to disseminate the guidelines to primary care physicians will be needed because few of them regularly read the journal in which the guidelines appear.

Dr. Campos-Outcalt told Medscape Medical News that the guidelines seem reasonable but that before being influenced by them, he would like to take a closer look at the level of evidence each recommendation is based on. “We don’t like to see recommendations based on low-level evidence,” he said. Only about 20% of the ACR recommendations were based on top-quality “level A” evidence (supported by more than 1 randomized clinical trial or meta-analysis). About half of the recommendations were based on level C evidence (consensus opinion of experts, case studies, or standard of care).

Source: Mescape.com