INDIVICUDAL TASK

CRITICAL APPRAISAL SKILLS PROGRAMME

BY
Name : Ni Komang Ayu Cahya Puja Dewi
NIM : 2108551009
Class :A

DEPARTEMENT OF PHARMACY
FACULTY OF MATHEMATICS AND NATURAL SCIENCES
UDAYANA UNIVERSITY
JIMBARAN
2021
A cohort study on the risk of acute liver injury among users of
ketoconazole and other antifungal drugs

L. A. Garcı́a Rodrı́guez,1 A. Duque,2 J. Castellsague,2 S. Pérez-Gutthann2 & B. H. Ch. Stricker3

1 2 3
Centro Español de Investigación Farmacoepidemiológica (CEIFE), Madrid, Spain, Novartis Global Epidemiology, Barcelona, Spain and Department of
Epidemiology and Biostatistics, Erasmus University, Medical School, Rotterdam, The Netherlands

Aims The aim of this cohort study was to estimate the risk of clinical acute liver
injury among users of oral antifungals identified in the general population of the
General Practice Research Database in UK.
Methods The cohort included 69 830 patients, 20–79 years old, free of liver and
systemic disease, who had received at least one prescription for either oral
fluconazole, griseofulvin, itraconazole, ketoconazole, or terbinafine between 1991
and 1996.
Results Sixteen cases of acute liver injury were identified and validated. Ten cases
occurred during nonuse of oral antifungals with a background rate of 0.6 per
100 000 person-months (95% confidence interval 0.3,1.1). Five cases occurred during
current use of oral antifungals. Two were using ketoconazole, another two
itraconazole, and one terbinafine. Incidence rates of acute liver injury were 134.1
per 100 000 person-months (36.8,488.0) for ketoconazole, 10.4 (2.9–38.1) for
itraconazole, and 2.5 (0.4,13.9) for terbinafine. The remaining case was associated
with past use of fluconazole. Ketoconazole was the antifungal associated with the
highest relative risk, 228.0 (95% confidence interval 33.9,933.0), when compared
with the risk among nonusers, followed by itraconazole and terbinafine with relative
risks of 17.7 (2.6,72.6) and 4.2 (0.2,24.9), respectively.
Conclusions Ketoconazole and itraconazole were the two oral antifungal associated
with a marked increase of clinical acute liver injury. The risk associated with
ketoconazole should be taken into account when prescribing it as initial treatment
for uncomplicated fungal infections.
Keywords: acute liver injury, epidemiology, general practice research database,
observational studies, oral antifungals

hepatic injury associated with ketoconazole than with

Introduction
Oral antifungals have been associated with different types
of acute liver injury in a number of case reports and in
several retrospective series. Most of the available data
relate to ketoconazole. Transient asymptomatic changes
in liver function tests can appear in 0.5% to 10% of
patients treated with oral antifungals [1]. Clinical liver
injury appears to be less frequent, although the vast
majority of data come from cases reported to national
pharmacovigilance systems.
Published reviews have reported a higher incidence of
Correspondence: Dr Jordi Castellsague, Novartis Farmacéutica, Global
Epidemiology, Gran Via de les Corts Catalanes 764, 08013 Barcelona, Spain.
Tel.: +3493 306 48 87, Fax: +3493 306 48 94, E-mail: jordi.castellsague@
pharma.novartis.com.
Received 29 January 1999, accepted 1 September 1999.
other systemic antifungals [2, 3]. Some authors have
estimated the incidence to lie between one per 1000 and
3000 patients, after taking into account the effect of
underreporting in spontaneous monitoring systems [4, 5].
In a randomized clinical trial, patients with onychomycosis
treated with ketoconazole had a threefold increased risk
of developing hepatitis compared with patients treated
with griseofulvin [6]. Several cases of liver injury have
been reported in association with griseofulvin [7, 8],
itraconazole [9, 10], and terbinafine [11–14], and most
cases related with fluconazole have occurred in severely
immunodepressed patients [15–20]. In a recent post-
marketing surveillance study with 25 884 patients treated
with terbinafine, two cases of symptomatic cholestatic
hepatic injury considered potentially related to the
treatment were identified [21].

© 1999 Blackwell Science Ltd Br J Clin Pharmacol, 48, 847–852 847

L. A. Garcı́a Rodrı́guez et al.

In the present cohort study we estimated the risk of Table 1 OXMIS codes in case ascertainment.
clinical acute liver injury among users of either oral
OXMIS code Diagnosis
fluconazole, griseofulvin, itraconazole, ketoconazole, and
terbinafine identified in the general population of UK 070F Fulminant hepatitis
using the General Practice Research Database (GPRD). 570 Hepatitis/liver necrosis
573 Other liver disorders
Methods 5730D Hepatocellular damage
576A Obstructive jaundice
Source population 785CP Pale stools
7851 Enlarged liver
Methodology used in GPRD has been detailed elsewhere 7852 Jaundice
[22]. GPRD contains clinical computerized information 9779PN Drug-induced jaundice
entered by general practitioners (GPs) on their patients. K501 Liver biopsy
Recorded information includes demographics, details of L1151NA Bilirubin serum level abnormal
each general practitioner visit, a summary of specialists’ L3260AB Abnormal liver function test
L3262AB Biochemical liver dysfunction
clinical notes and hospital letters, results of laboratory
L3263AB Abnormal liver enzymes
tests and a free text section. Prescriptions are directly L3263H Liver enzymes raised
generated by the computer system with dosage instruc- L3264AB Abnormal hepatic function
tions included. L109H Alanine aminotransferase raised
A validation study with the GPRD has documented L110H Aspartate aminotransferase raised
the recording of medical data in the general practitioners’ L1002CR Aspartate aminotransferase level raised
computers to be near to complete [23]. Several studies
on drug-induced acute liver injury have been published OXMIS: Oxford Medical Information System.
using the GPRD resource [24]. These studies were able
to quantify the risk of clinical liver injury associated with acute liver injury was defined as a person presenting with
suspected hepatotoxic drugs. symptoms suggestive of liver disorder (nausea, vomiting,
abdominal pain and/or jaundice) referred to a specialist
or admitted to hospital, and who was free of the exclusion
Study cohort criteria. In addition, the following biochemical test results,
The study cohort comprised people aged 20–79 years based on an international consensus meeting, were a
who had received at least one prescription for either oral requisite as part of the case definition of liver injury [25]:
fluconazole, griseofulvin, itraconazole, ketoconazole, or an increase of more than two times the upper limit of
terbinafine between 1 January 1991 and 30 September the normal range in alanine aminotransferase (ALT), or a
1996. We excluded subjects if they had a history of liver combined increase in aspartate aminotransferase (AST),
injury in the preceding 5 years. Subjects with a history alkaline phosphatase (APh) and total bilirubin, provided
of any of the following conditions were also excluded: any was more than twice the upper limit of the respective
cancer, liver disease, gallbladder disease, pancreatic disease, normal range. The liver injury was classified as acute if
heart failure, alcohol abuse, HIV infection, rheumatoid the clinical and laboratory signs had lasted less than 6
arthritis, sarcoidosis, systemic lupus or inflammatory months from the date of onset. The type of liver injury
bowel disease. The final study cohort was constituted by was designated hepatocellular when there was an increase
69 830 individuals. We followed these persons from the more than twice the upper limit of the normal range in
date of first antifungal drug prescription until the earliest ALT alone or R≥5, where R is the ratio of serum
occurrence of a code for liver injury (Table 1), one of activity of ALT over serum activity of APh. Liver injury
the exclusion conditions mentioned above, age greater was designated cholestatic when there was an increase of
than 80 years, death or the end of the study period. more than twice the upper limit of the normal range in
APh alone or R≤2. Liver injury was designated mixed
when 2<R<5.
Case ascertainment
We identified 73 patients with a recorded history
Exposure definition
compatible with acute liver injury. We requested from
the general practitioners all clinical records related to Person time at risk was aggregated in three different time
these events. Case validation was independently performed windows according to use of the study antifungal drugs.
by three of the authors (LAGR, BHChS, and AD) Current use encompassed all the days of prescribed
without knowledge of the exposure status and agreement treatment plus an additional period of 14 days at the end
was reached on all cases after some discussion. A case of of treatment. Past use was defined as the period of

848 © 1999 Blackwell Science Ltd Br J Clin Pharmacol, 48, 847–852

 Oral antifungals and acute liver injury

90 days following the time window of current use.
Finally, the time period starting after past use was defined
as nonuse. We also assessed exposure to a number of
suspected hepatotoxic drugs among the cases [26].
Analysis
Incidence rates of acute liver injury were calculated using
as denominator both the number of patients exposed to
each individual antifungal drug and the corresponding
person-time at risk. Ninety-five percent confidence
intervals were computed on the basis of a Poisson
distribution of case counts within categories of use. The
Exact program was used to obtain estimates of rate
ratios [27].
Results
The study cohort of 69 830 subjects received a total of
149 384 prescriptions. There were marked age and sex
differences among users of the five antifungal drugs with
a higher proportion of women and young patients among
fluconazole and itraconazole users (Table 2). These
differences were a consequence of varying leading
indications: candidiasis for fluconazole, itraconazole and
ketoconazole, and onychomycosis for griseofulvin and
terbinafine. The average treatment duration was also
variable. Seventy-five percent of fluconazole users and
50% of itraconazole users received one single day
treatment, respectively. Over 90% of ketoconazole users
received less than 1 month of therapy. Close to 80% of
terbinafine users were treated for 1–3 months.
Griseofulvin users were the group with the longest
duration of treatment with one third of patients taking it
for a period longer than 3 months.
We received medical records for 66 patients (90%). In
seven subjects, we did not receive information from the
GPs, or the data received were insufficient to ascertain
case status. Fifty patients did not meet the study case
definition and the reasons for exclusion are presented in
Table 3. Most of the patients presented only with minor
elevations of LFTs, or had their LFTs’ derangement
found through routine monitoring. Thus, 16 individuals
met all case definition criteria. Eleven presented with
jaundice and four were admitted to a hospital. All cases
recovered from the hepatic injury and none of them
resulted in a fatal outcome. Table 4 shows the clinical
and laboratory features of the 16 cases classified according
to their exposure status. Ten cases occurred during
nonuse of oral antifungal drugs corresponding to a
background rate of 0.6 per 100 000 person-months (95%
CI 0.3,1.1). This risk increased considerably with age:
0.4 per 100 000 in persons younger than 60 years and 2.8
per 100 000 in older persons. No material difference was
observed between males and females (0.8 vs 0.5 per
100 000 person-months). Half of the cases among
nonusers were exposed to a hepatotoxic drug (Table 4).
Estimates of incidence rate for current use of individual
antifungal drugs are presented in Table 5. Two cases
occurred during current use of ketoconazole and itracona-
Table 3 Exclusions after review of medical records.
Reasons for exclusion Number excluded
Minor elevation of liver function tests 21
Not referred (routine monitoring) 10
Fatty liver disease 6
Hyperbilirubinemia only 3
Alcoholism 3
Cholelithiasis 3
History of liver disorder 2
Infectious mononucleosis 1
Computer entry error 1
Total 50

Table 2 Age and sex distribution of the study cohort of users of oral antifungals*.

Fluconazole Griseofulvin Itraconazole Ketoconazole Terbinafine

n (%) n (%) n (%) n (%) n (%)

Sex
Women 33 034 (92) 2931 (44) 15 739 (81) 623 (59) 6279 (47)
Men 2799 (8) 3800 (56) 3749 (19) 429 (41) 7151 (53)
Age (years)
20–39 22 267 (62) 2304 (34) 11 575 (59) 525 (50) 4286 (32)
40–59 10 722 (30) 2937 (44) 6155 (32) 371 (35) 5837 (43)
60–69 1748 (5) 982 (15) 1139 (6) 106 (10) 2122 (16)
70–80 1096 (3) 508 (7) 619 (3) 50 (5) 1185 (9)
Total 35 833 6731 19 488 1052 13 430

*Some of the members of the cohort received more than one antifungal drug during the study period.

© 1999 Blackwell Science Ltd Br J Clin Pharmacol, 48, 847–852 849

L. A. Garcı́a Rodrı́guez et al.

Table 4 Clinical and laboratory findings

Exposure to Exposure to other and drug exposure of cases of acute liver
Age oral potentially injury.
(years) Sex* ALT † AP† Pattern‡ antifungals§ hepatotoxic drugs

30 M 3.2 1.0 M Itraconazole No

51 F 4.3 1.7 M Itraconazole Amitriptyline
51 F 7.8 1.2 H Ketoconazole No
63 M 2.6 3.0 C Ketoconazole No
25 F 6.0 11.5 C Terbinafine Chlorpromazine
36 F 30.0 2.0 H Past use No
28 F 17.2 1.4 H Nonuse No
35 F 15.5 1.9 H Nonuse NSAIDs, nifedipine
39 F 3.3 1.0 H Nonuse No
42 F 6.8 1.2 H Nonuse No
48 F 7.2 1.8 M Nonuse Minocycline
50 M 2.1 0.7 M Nonuse No
63 M 10.2 4.0 M Nonuse Phenytoin
65 F 1.8 3.1 C Nonuse Clavulanic acid
67 F 5.7 3.1 C Nonuse Sulfasalazine
69 M 24.3 1.9 H Nonuse No

F=female; M=male; C=cholestatic; H=hepatocellular; M=mixed. †Multiplier of upper

limit of normal value of alanine aminotransferase (ALT) and alkaline phosphatase (AP). ‡Pattern
of liver injury. §Itraconazole, ketoconazole and terbinafine indicate current exposure to these
antifungals. Case with past use had been exposed to fluconazole.

Table 5 Crude incidence rates of acute liver injury among current users of oral antifungals.

Incidence rate
(95% confidence interval)
Per 10 000 Per 100 000 Relative risk*
Antifungal Patients Person-months Cases patients person-months (95% CI )

Fluconazole 35 833 29 701 0 0.0 (0.0, 1.0) 0.0 (0.0, 12.9) 0.0 (0.0, 20.0)
Griseofulvin 6731 35 841 0 0.0 (0.0, 5.5) 0.0 (0.0, 10.7) 0.0 (0.0, 16.5)
Itraconazole 19 488 19 168 2 1.0 (0.1, 3.7) 10.4 (2.9, 38.1) 17.7 (2.6, 72.6)
Ketoconazole 1052 1492 2 19.0 (2.3, 68.7) 134.1 (36.8, 488.0) 228.0 (33.9, 933.0)
Terbinafine 13 430 40 638 1 0.7 (0.02, 4.2) 2.5 (0.4, 13.9) 4.2 (0.2, 24.9)

*Non use person time was used as reference group.

zole, respectively, one case with terbinafine, and no cases
were found with current use of fluconazole and griseoful-
vin. All five cases developed during the first month of
starting antifungal treatment. Ketoconazole presented the
greatest absolute risk with an incidence rate of 134 per
100 000 person-months followed by itraconazole (10.4
per 100 000 person-months) and terbinafine (2.5 per
100 000 person-months). Ketoconazole was the antifungal
drug associated with the greatest relative risk compared
to the background risk among nonusers (Table 5),
followed by itraconazole and terbinafine.
Discussion
In this retrospective cohort study, we assessed the risk of
acute liver injury to antimycotics in a large population
under everyday circumstances. Because of the low number
of detected cases, effect modification by gender or age
could not be assessed. Therefore, only crude rates are
presented. When compared to the risk in nonusers, the
risk of acute liver injury was markedly increased in users
of ketoconazole and itraconazole, and slightly increased
in users of terbinafine. The risk of acute liver injury
among ketoconazole users was the greatest with a relative
risk exceeding 200 compared with nonuse. In view of
the low background risk of idiopathic symptomatic
hepatic injury in the general population, almost 134 extra
cases occurred per 100 000 person-months of treatment
with ketoconazole. Thus almost 1 in every 500 users of
ketoconazole developed acute liver injury. This is higher
than has been estimated in earlier studies with the
exception of one clinical trial [6]. In a recent review of

850 © 1999 Blackwell Science Ltd Br J Clin Pharmacol, 48, 847–852


eight studies that estimated the risk of acute liver injury
associated with several drugs using GPRD, only two
drugs, chlorpromazine and isoniazid, presented a compar-
able level of increased risk of liver injury, (incidence
greater than one per 1000 users) [24].
In the current study, it is highly unlikely that the
results are explained by bias or confounding. Because the
complete patient population attended by about 1500
general practitioners served as the source population for
identifying our study cohort, selection bias is rather
unlikely. Patients with a history of liver disease were
excluded. This means that our estimates of absolute risk
for all oral antifungal drugs are conservative as a
consequence of depletion of susceptible persons.
Information bias might result from the awareness of
doctors and patients that ketoconazole and itraconazole
might cause liver injury. If this leads to more frequent
visits and laboratory assessments, the ascertainment of
liver injury might differ between antimycotics. Our study,
however, was restricted to symptomatic cases which
makes such information bias an improbable explanation
for our results. Also confounding by indication is unlikely
as uncomplicated candidiasis (1 case), tinea pedis (1 case)
and mycotic skin infections (3 cases) are not known as
risk factors for acute liver injury.
The risk of hepatic injury was highest with ketocona-
zole and itraconazole. Both agents are azole derivatives
which have been associated with several cases of
symptomatic hepatic injury but most reports concern
ketoconazole [3–5, 9, 10]. Among the cases with
ketoconazole reported in the literature, the onset was
mostly within 6 months after starting therapy with 200–
400 mg daily [25]. Biochemically, the pattern was mostly
hepatocellular but several cases of mixed cholestatic-
hepatocellular or cholestatic injury have also been
reported. Most patients recovered after discontinuation
but several cases of fatal hepatic necrosis have been
reported. Histology confirmed the hepatocellular pattern
in most patients, varying from cellular unrest to confluent
centrolobular or even massive necrosis. In high doses,
ketoconazole induced significant hepatic injury in several
animal species after 2–4 weeks administration. Although
the precise mechanism is unknown, it has been speculated
that hepatotoxicity of ketoconazole could result from
its interference with membrane sterol synthesis or by
inhibiting hydrogen peroxidase degrading enzymes, e.g.
catalase and cytochrome c peroxidase [28].
In conclusion, ketoconazole and itraconazole were the
two oral antifungal drugs associated with a marked
increased risk of clinical acute liver injury in our study.
Specially the high risk observed with ketoconazole may
be an argument for reevaluating its role as initial treatment
for uncomplicated fungal infections and restricting its use
to deep mycoses.
© 1999 Blackwell Science Ltd Br J Clin Pharmacol, 48, 847–852
Oral antifungals and acute liver injury
We thank to Dr Felix Arellano for his early contribution in the
design of the study, and to the staff at EPIC and the participating
general practitioners for their excellent collaboration.
CEIFE received a research grant from Novartis. Dr Stricker has
no financial relationships with Novartis nor with CEIFE.
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© 1999 Blackwell Science Ltd Br J Clin Pharmacol, 48, 847–852
CASP Checklist: 12 questions to help you make sense of a Cohort Study

How to use this appraisal tool: Three broad issues need to be considered when appraising a
cohort study:

Are the results of the study valid? (Section A)

What are the results? (Section B)
Will the results help locally? (Section C)

The 12 questions on the following pages are designed to help you think about these issues
systematically. The first two questions are screening questions and can be answered quickly.
If the answer to both is “yes”, it is worth proceeding with the remaining questions. There is
some degree of overlap between the questions, you are asked to record a “yes”, “no” or
“can’t tell” to most of the questions. A number of italicised prompts are given after each
question. These are designed to remind you why the question is important. Record your
reasons for your answers in the spaces provided.

About: These checklists were designed to be used as educational pedagogic tools, as part of a
workshop setting, therefore we do not suggest a scoring system. The core CASP checklists
(randomised controlled trial & systematic review) were based on JAMA 'Users’ guides to the
medical literature 1994 (adapted from Guyatt GH, Sackett DL, and Cook DJ), and piloted with
health care practitioners.
For each new checklist, a group of experts were assembled to develop and pilot the checklist
and the workshop format with which it would be used. Over the years overall adjustments
have been made to the format, but a recent survey of checklist users reiterated that the basic
format continues to be useful and appropriate.
Referencing: we recommend using the Harvard style citation, i.e.: Critical Appraisal Skills
Programme (2018). CASP (insert name of checklist i.e. Cohort Study) Checklist. [online]
Available at: URL. Accessed: Date Accessed.

©CASP this work is licensed under the Creative Commons Attribution – Non-Commercial-
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Critical Appraisal Skills Programme (CASP) part of Oxford Centre for Triple Value Healthcare Ltd www.casp-uk.net
 "A Cohort study on the risk of acute liver injury among users of ketoc
Paper for appraisal and reference:.........................................................................................................
Section A: Are the results of the study valid?

1. Did the study address a clearly Yes HINT: A question can be ‘focused’
focused issue?
✔ in terms of
Can’t Tell • the population studied
• the risk factors studied
No
• is it clear whether the study tried to
detect a beneficial or harmful effect
• the outcomes considered

Comments: The population studied were users of ketoconazole and other oral
antifungal drugs. In addition, the population studied was the general
population of UK using the GPRD. This artocle examines the risk factors for
the use of ketoconazole and other oral antifungal drugs namely injury. The
results of the study are also clear because they have describe the risks of
each antifungal drug based on previous research data.

2. Was the cohort recruited in Yes HINT: Look for selection bias which might
an acceptable way? ✔ compromise the generalisability of the
Can’t Tell findings:
• was the cohort representative of a
No
defined population
• was there something special about the
cohort
• was everybody included who should
have been

Comments: Source of the population is clear from the general population in the UK using the GPRD. However, the population
is not clear because there is no information about the dose of antifungal drugs that can be risk factor for liver
injury. The population consisted of people aged 20-79 tyears eho had received at least one prescription of the
antifungal drug under study. Other than that, I also haven't found anything special about the cohort. Then the
article explains that not all of these people can be subject of this research. The subjects excluded from this study
were people with a history of liver injury in the past 5 years, cancer, liver disease, gallbladder disease, pancreatic
disease, heart failure, alcohol abuse, HIV infection, rheumatoid arthritis, sarcoidosis, lupus, systemic of
inflammantory bowel disease. From the statement above, it is known that the cohort was recruited in an
acceptable manner.

Is it worth continuing?

2
 3. Was the exposure accurately
measured to minimise bias?
Can’t Tell • did they use subjective or objective
Yes HINT: Look for measurement or
✔ classification bias:
measurements
No • do the measurements truly reflect what
you want them to (have they been
validated)
• were all the subjects classified
into exposure groups using the
same procedure

Comments: The authors of this article use objective measurements because the authors consider data and facts and do not
use their opinions at all in making the article. The measurements made already reflect what the readers want and
have been validated by GPRD. Validation studies with GPRD have documented recorded medical data on
general practitioner's computers. In addition, several studies on drug-incluced acute liver injury have been
published using the GPRD sourse so that these studies are able to measure the risk of clinical liver injury
associated with suspected hepatotoxic drugs. However, the amount of subject data is uncertain in this study and
there are some cases where data is not available.

4. Was the outcome accurately Yes HINT: Look for measurement or

measured to minimise bias? ✔ classification bias:
Can’t Tell • did they use subjective or objective
measurements
No • do the measurements truly reflect what
you want them to (have they been
validated)
• has a reliable system been
established for detecting all the cases (for
measuring disease occurrence)
• were the measurement
methods similar in the different groups
• were the subjects and/or
the outcome assessor blinded to
exposure (does this matter)

Comments: The Authors of this article use objective measurements because the aouthors consider data and facts and do not
use their opinions at all in making yhis article. The measurements reflect what the reader wants and have been
independently validated by three authors (LAGR, BHChS, and AD) without knowing the exposure status and
agreement was reached in all cases after some discussion. The article also has a reliable system to detect all
cases, namely OXMIS (Oxford Medical Information System). The methods used in the GPRD have been from the
measurement result obtained later, namely acute liver injury (if clinical and laboratory signs have lasted less than
6 monts from the date of onset more than equal to 5), cholestatic liver injury (when there is an increase in more
than twice the upper limit of the normal range on APh alone or R less than 2), and mixed liver injury (2<R<5).
Subjects or outcome assessors were not blinded.

3
5. (a) Have the authors identified Yes HINT:
all important confounding ✔ • list the ones you think might be
factors? Can’t Tell important, and ones the author missed

No

Comments: In my opinion, the list presented by the author is is complete and nothing
has been missed, such as the author has carefully considered the subject
to be used by giving exceptions to the subject.

5. (b) Have they taken account of Yes HINT:

the confounding factors in the
design and/or analysis?
• look for restriction in design, and
Can’t Tell techniques e.g. modelling, stratified-,
regression-, or sensitivity analysis to
No correct, control or adjust for confounding
✔ factors

Comments: After I read the article, I didn't find any restriction in design and tecniques
like modeling, stratification and others. In addition, the dosage of drugs that
can be a confounding factor is not included.

HINT: Consider
6. (a) Was the follow up of
subjects complete enough?
Yes
✔ • the good or bad effects should have
had long enough to reveal
Can’t Tell themselves
• the persons that are lost to follow-up
No may have different outcomes than
those available for assessment
• in an open or dynamic cohort, was
there anything special about the
outcome of the people leaving, or the
exposure of the people entering the
cohort
6. (b) Was the follow up of Yes
subjects long enough? ✔
Can’t Tell

No

4




Comments: This study uses data from past cases, that of the records from the hospital. The authors
have studied the data well so that, there is no possibility of patients being dischagred in
the middle of treatment or study period. In addition, researchers also follow cases or make
observations to the end and don't get left behind the middle of the road. However, there is
no statement in the cohort explaining it.


Section B: What are the results?



7. What are the results of this study? HINT: Consider
• what are the bottom line
results
• have they reported the rate or
the proportion between the
exposed/unexposed, the
ratio/rate difference
• how strong is the association
between exposure and
outcome (RR)
• what is the absolute risk
reduction (ARR)

Comments: The bottom line result is ketoconazole was the antifungal associated with the highest
relative risk, when compared with the risk among non users, followed ny itraconazole and
terbinafine with relative risk of 17.7 (2.6,72.6) and 4.2 (0.2,24.9), respectively. I didn't finf
the ratio of exposed and unexposed patient in this article. The relationship between
exposure and outcome is very strong because exposure has an attachment to the results
obtained because the exposure is divided into 3 time as described in the method of
exposure definition section.

8. How precise are the results? HINT:
• look for the range of the confidence
intervals, if given

Comments: The In the article, there are differences in the results of each drug and
some results have a weaker level of confidence because the confidence
interval too wide. Itraconacole was 10.4 (2.9 - 38.1) and terbinafine was 2.5
(0.4, 13.9).

5


9. Do you believe the results? Yes HINT: Consider
• big effect is hard to ignore
Can’t Tell • can it be due to bias, chance or
✔
confounding
No • are the design and methods of this
study sufficiently flawed to make the
results unreliable
• Bradford Hills criteria (e.g. time
sequence, dose-response gradient,
biological plausibility, consistency)

Comments: As for the results, I can't fully believe because there still biases or cofounding factors that
are lacking, namely the number of the dose of antifungal drugs that can cause acute liver
injury. However, the consistency of the author has been good in the process of compiling
and also looking for the appropriate data and analyzing it to get result.

Section C: Will the results help locally?

10. Can the results be applied to Yes HINT: Consider whether
the local population? • a cohort study was the appropriate
Can’t Tell method to answer this question
✔
• the subjects covered in this study could
No be sufficiently different from your
population to cause concern
• your local setting is likely to differ
much from that of the study
• you can quantify the local benefits and
harms

Comments: Judging from the instruments used to determine the percentage of risk from the use of
antifungal drugs, the population, and the research objectives were correct. However, I think
this research needs to be specified again, so that it can be applied to the local population.



11. Do the results of this study fit Yes
with other available ✔
evidence? Can’t Tell

No


Comments: The results of the study are in accordance with the available evidence from the supporting
data that has been provided through the tables. As in table 5, it has been shown that the
ketoconazole is the antifungal associated with the highest relative risk, when compared
with the risk among non users, followed by itraconazole and terbinafine.

6


12. What are the implications of Yes HINT: Consider
this study for practice? • one observational study rarely
provides sufficiently robust
Can’t Tell
evidence to recommend changes

to clinical practice or within health
No policy decision making
✔ • for certain questions,
observational studies provide the
only evidence
• recommendations from
observational studies are always
stronger when supported by other
evidence

Comments: I think this cohort has insufficient evidence. This because it is only proven by data
without direct research. The number of patient data is also still lacking, so other
supporting data are needed. Evidence from other studies does not show the same type
of drug that can cause liver injury. So, this study has not been able to change clinical

practice or change health policy.