Critical Appraisal of an Article on HARM

Clinical Question Is there potential harm after administering allopurinol in patients with gout and azotemia? PUBMED Mesh Terms: – Allopurinol – Gout – Adverse Events – Kidney Function

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Critical Appraisal: Relation Between Adverse Events Associated with Allopurinol and Renal Function in Patients with Gout Vasquez-Mellado et al.

Relevance Is the objective of the article on harm similar to your clinical dilemma? Yes. Our patient is a 50 year old male with gout & azotemia and we proposed to treat him with Allopurinol 200 mg. We are concerned of the safety of using allopurinol in our patient and this study addresses our clinical dilemma because its objective is to determine the prevalence of adverse reactions attributable to allopurinol in patients with primary gout according to dose and creatinine clearance rate (page 1, objective). The article attempts to elaborate and explain the harm of administering high dose of allopurinol even when the creatinine clearance level of the patient is low (which is manifested in azotemic conditions).

Validity Guidelines Were there clearly identified comparison group? Yes. Employing a retrospective cohort study design, the study was designed to divide the patients into two groups, A and B. Group A (those without exposure to high dose allopurinol) composed of patients whose allopurinol maintenance dose according to their creatinine clearance rate (recommended by Hande et al). On the other hand, Group B (those with exposure to high dose allopurinol) composed of patients whose maintenance dose exceeded the dose recommended for their creatinine clearance rate (page 2, methods, last paragraph).

Validity Guidelines Were the exposures and outcomes measured in the same way in the groups compared? Yes. Diligent and fair observation for the outcome was done in both groups with the exposure as well as the groups without the exposure. The study is a retrospective cohort which thoroughly reviewed the clinical records of patients. (page 1, methods, 1 st sentence).

Validity Guidelines Was follow-up sufficiently long and complete? Yes. Drug administration lasted for a mean duration of 3.3 years (page 2, results, 1 st paragraph, 3 rd sentence). This should have given ample time for patients following up and physicians taking note of any adverse effects brought forth by allopurinol in both groups. Although not explicitly mentioned, follow-up was complete because the journal reported that “only five patients (4% all men) from the WHOLE group [both groups A and B] developed allopurinol related adverse reactions” (Results, 2 nd paragraph, 1 st sentence).

Validity Guidelines Is the temporal relationship between the exposure and outcome correct and dose-response gradient present? The study showed temporal relationship between the exposure (administration of high dose allopurinol) and outcome (development of adverse reaction); although there were very minimal occurrences. Only five patients out of all 120 patients experienced adverse effects to allopurinol. The adverse events noted after drug intake were rash (3 out of 120; 2 from group A, 1 from group B), allopurinol hypersensitivity syndrome (1 out of 120; 1 from group A), fixed pigmented drug eruption (1 out of 120; 1 from group B) and leukocytoclastic vasculitis (1 out of 120; 1 from group B). The study was not able to present a dose-response gradient. The study had no intention of measuring a temporal response between the exposure and outcome and determining a dose-response gradient.

Validity Guidelines OVERALL, IS THE STUDY VALID? Yes, the study can be considered valid. The retrospective cohort study had a relatively good sample size (n=120), compared well two groups that had different exposures to allopurinol (group A – low dose, group B – high dose) and were able to determine the presence of very low prevalence of adverse reactions to the drug. Thus, pointing out that it is not harmful; although increasing allopurinol dose and administering it to the patient should be cautioned properly.

Results

What is the magnitude of the association between exposure and outcome? The study showed that the frequency of adverse events was very low in both groups (page 3, discussion, 1 st paragraph, 1 st sentence).

RR of 0.51 stresses that exposure does not cause significant or potential harm to the population.

Results Was the estimate of the risk precise? More or less, yes. P value for serum creatinine for both groups is 0.003; serum BUN 0.000, creatinine clearance is and allupurinol maintenance doses NS (page 2, table 1). No confidence intervals were used in the study.

Patient Care Are the study patients similar to my own? Yes, although not entirely. Our patient, a 50 year old obese male, diagnosed with primary gout and azotemia is similar to the patients in the study which were mostly male (118 out of 120, 98.3%), aged 52.7+/ years old and diagnosed with primary gout (page 2, results, 1 st paragraph). Sixty eight (group B) out of 120 patients had a creatinine clearance of 54.6 ml/min (table 1), a low creatinine clearance indicative of azotemia – similar to the profile of the patient involved in the case.

Patient Care Should I attempt to stop the exposure? No. Since the risk of harm from high-dose allopurinol is low, there is no need to stop administering the medication. The study shows that allopurinol does not increase prevalence of significant potential harm to patients diagnosed with gout (page 1, conclusions). However, it is important to monitor the dose increase and administration of higher than usual dose of allopurinol in patients with gout to prevent adverse events, no matter how rare they may be. If the medication is withdrawn, the hyperuricemia in the patient may persist which can lead not only to renal problems but also musculoskeletal abnormalities as well, which are very lethal to the patient. The usual complications of gout would be joint pains, inflamed tophi and kidney damage. Alternative drugs that can be used as a substitute for allopurinol include febuxostat (another type of xanthine oxidase inhibitor), pegloticase (urate oxidase) and ethylenediaminetetraacetic acid (EDTA, chelator).

Resolution of the Problem What will I do to my patient? Since this journal claims that there is no increase in prevalence of adverse reactions to allopurinol in patients who received higher allopurinol maintenance doses than those recommended according to creatinine clearance rate and that the occurrence of adverse reactions to the drug is very minimal, I will continue administering allopurinol to my patient. However, I will be cautious in management whenever I increase the drug dosage to be administered.