Transcript Critical Appraisal of an Article on HARM

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, 1st 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, 1st paragraph, 3rd 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, 2nd paragraph, 1st 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
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, 1st paragraph, 1st
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 0.0000 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+/- 12.4 years old and diagnosed with primary
gout (page 2, results, 1st 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.