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Challenges and Opportunities for Pharmacoepidemiology in Drug-Therapy Decision Making

Mahyar Etminan, Sudeep Gill, Mark FitzGerald and Ali Samii
J. Clin. Pharmacol. 2006; 46; 6
DOI: 10.1177/0091270005283285

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ETMINAN ET AL
10.1177/0091270005283285
PHARMACOEPIDEMIOLOGY
FORUM IN DRUG-THERAPY DECISION MAKING
Challenges and Opportunities
for Pharmacoepidemiology in
Drug-Therapy Decision Making
Mahyar Etminan, PharmD, MSc (Epid), Sudeep Gill, MD, MSc (Epid),
Mark FitzGerald, MB, FRCP(C), and Ali Samii, MD, FRCP(C)
Pharmacoepidemiology is a relatively new and evolving sci-
ence that attempts to quantify mainly adverse drug events
and patterns of drug use in a large population. The strength of
pharmacoepidemiology over randomized trials is the ability
to quantify rare adverse events that may occur over long peri-
ods. Recently, discordance in the results of pharmaco-
epidemiologic studies has made it difficult for clinicians and
policy makers to make informed drug-therapy decisions. This
commentary addresses the strength of pharmacoepide-
P harmacoepidemiology is a relatively new science
that uses principles of epidemiology in quantifying
adverse drug events (ADEs), patterns of drug use, and
drug efficacy in a large population setting. One of the
strengths of pharmacoepidemiology over randomized
controlled trials (RCTs) is quantifying rare ADEs. Al-
though the detection of rare ADEs can arise from RCTs,
From the Division of Clinical Epidemiology, Royal Victoria Hospital and
McGill Health Center, Montreal, Canada (Dr Etminan); the Center for
Clinical Epidemiology and Evaluation, Vancouver Hospital, Vancouver,
Canada (Dr Etminan, Mr FitzGerald); Department of Medicine, Queen’s
University, Kingston, Ontario, Canada (Dr Gill); Faculty of Medicine, Uni-
versity of British Columbia, Vancouver, Canada (Mr FitzGerald); and the
Department of Neurology, University of Washington School of Medicine,
Seattle, Washington, (Dr Samii). Mahyar Etminan initiated the project.
Mahyar Etminan, Sudeep Gill, Mark FitzGerald, and Ali Samii participated
in writing the manuscript. Mahyar Etminan will act as guarantor for the arti-
cle. Mahyar Etminan is funded by Canadian Institutes of Health Research
(CIHR) postdoctoral fellowship awards. Ali Samii is supported by the Na-
tional Institutes of Health and the Department of Veterans Affairs through
the Parkinson Disease Research Education and Clinical Center (PADRECC)
grant. Submitted for publication August 19, 2005; revised version ac-
cepted October 3, 2005. Address for reprints: Dr Mahyar Etminan, Center
for Clinical Epidemiology and Evaluation, Vancouver Hosptial, 7th Floor,
828 West 10th Avenue, Vancouver, B.C., Canada (metminan@shaw.ca).
DOI: 10.1177/0091270005283285
6 • J Clin Pharmacol 2006;46:6-9
FORUM
miology and the advances in the methodology of
pharmacoepidemiologic studies over the years. We also dis-
cuss the potential problem of discordant results and urge
pharmacoepidemiologists to develop good practice guide-
lines for the conduct of pharmacoepidemiologic studies.
Keywords: Pharmacoepidemiology; drug safety; case-
control studies; cohort studies
Journal of Clinical Pharmacology, 2006;46:6-9
©2006 the American College of Clinical Pharmacology
results may be inconclusive, mostly because of lack of
adequate power.
IMPACT OF PHARMACOEPIDEMIOLOGIC
STUDIES ON CLINICAL PRACTICE
In recent years, advances in pharmacoepidemiology
have helped bring to attention serious ADEs secondary
to different drug classes. Perhaps one of the first
pharmacoepidemiologic studies that led to the with-
drawal of a particular drug class was a case-control
study linking appetite-suppressant drugs to cardiac-
valve regurgitation.1 The Food and Drug Administra-
tion recently asked makers of the new atypical
antipsychotic drugs (risperidone, olanzapine, and
quetiapine) to put warning labels on their products as a
result of another case-control study that found an in-
crease in the risk of diabetes in users of olanzapine.2 Fi-
nally, observational studies played an important role in
highlighting the increased risk of cardiac events with
rofecoxib.
One of the limitations of RCTs is their failure to ad-
dress adherence to drug therapy, mostly because of the
controlled environment inherent in the nature of the
design of such studies. Availability of large administra-
 PHARMACOEPIDEMIOLOGY IN DRUG-THERAPY DECISION MAKING
tive databases has allowed clinicians to explore adher-
ence to drug therapy in a real clinical setting. One ex-
ample was the degree of adherence to statin therapy in
older adults. Despite numerous RCTs showing the effi-
cacy of these drugs in preventing cardiac events and
their relatively safe adverse events profile, data on ad-
herence of these drugs were lacking. A recent cohort
study using the Ontario linked databases showed that
adherence to statins among older adults is relatively
low.4
ADVANCES IN
PHARMACOEPIDEMIOLOGY
Pharmacoepidemiology has come a long way since the
early 1980s when reserpine was linked to an increased
risk of breast cancer based on a poorly conducted
hospital-based case-control study in which inappro-
priate selection of controls gave rise to a spuriously
high odds ratio.5 In the past 20 years, advances in both
epidemiology and biostatistics have allowed for novel
methods of controlling for confounding and bias as
well as addressing methods of quantifying ADEs with
an irregular risk pattern. For example, optimal meth-
ods of control selection have allowed for conducting
more valid case-control studies.6 Sophisticated com-
puter software has allowed for complex statistical anal-
yses that control for the time-dependent nature of pre-
scription drugs that may have otherwise biased the
results of cohort studies.7 Use of propensity scores, a
method of predicting the probability of a subject’s re-
ceiving a drug based on the baseline covariate informa-
tion for that subject, has to some extent mimicked the
process of randomization in retrospective cohort stud-
ies.8 Finally, the case-crossover design, a relatively
novel study design, has allowed for exploring the asso-
ciation between transient drug exposures with acute
events.9
DISCORDANCE AMONG
PHARMACOEPIDEMIOLOGIC STUDIES
What has probably undermined the validity of
pharmacoepidemiologic studies the most has been dis-
cordance in drug efficacy among studies addressing
the same question. Although the first study that hinted
at the potential increase in the risk of myocardial in-
farction (MI) associated with the use of rofecoxib, other
pharmacoepidemiologic studies failed to find this as-
sociation. Ray et al conducted a retrospective cohort
study using the Tennessee Medicaid Programme.3 The
authors found an increase in the risk of MI with high-
dose rofecoxib use (25 mg or greater) but not with low-
FORUM
dose rofecoxib use (less than 25 mg). Mamdani et al
used the Ontario linked databases to answer the same
questions.10 The authors did not find any increase in
the risk of MI with regular rofecoxib use. The discrep-
ancy may lie in the method of defining exposure in the
2 studies. Ray et al stratified exposure by dose (low vs
high), whereas Mamdani et al looked at only current
use. This discrepancy may also be the reason a pooled
analysis of data from RCTs of rofecoxib failed to find an
association.11 Given that ADEs may be dose dependent,
Mamdani et al may have missed this association. This
is a classic example in pharmacoepidemiology,
whereby inadequate assessment of drug dose and dura-
tion may compromise validity of a drug safety study.
Two relatively recent examples hypothesized that
statins can lower the risk of fractures in older adults.12,13
Both studies were published in JAMA, used a case-
control design, and also used the General Practice Re-
search Databases as their primary source of data. Sur-
prisingly, one study found a protective association,12
whereas the other found no association.13 Finally, a re-
cent cohort study showed a protective association with
the use of inhaled corticosteroids in preventing mor-
bidity and mortality in patients with chronic obstruc-
tive pulmonary disease.14 The results of this study were
soon contradicted and accredited to a bias that may
have arisen in the study design.15
An important issue is whether the discordance in
pharmacoepidemiologic studies is attributable mainly
to the limitations of the science or to the poor quality in
conducting and reporting pharmacoepidemiologic
studies. It is now evident that even RCTs are not im-
mune to potentially biased results when robust meth-
odology is not incorporated in either the study design
or the reporting of the results. The Woman’s Health Ini-
tiative, the largest RCT that looked at the effect of estro-
gen on cardiovascular disease and cancer in
postmenopausal women, has been recently criticized
for possible bias. This bias is thought to have been in-
troduced as a result of the unblinding of approximately
40.5% of hormone replacement users and 7% of pla-
cebo users.16 At least part of the inconsistency in
pharmacoepidemiologic literature may be attributed to
the lack of standards in the conducting and the
reporting of pharmacoepidemiologic studies.
We agree that for drug-related questions that can be
addressed by RCTs, clinicians must use results of
pharmacoepidemiologic studies only for hypothesis
generating. However, RCTs cannot answer all impor-
tant drug-related questions including rare ADEs or the
effect of prescription drugs on the risk of motor vehicle
crashes.17 In such circumstances, clinicians may have
no choice but to incorporate results of pharmaco-
7
 ETMINAN ET AL
epidemiologic studies into their clinical decision
making.
IMPROVING METHODS
OF REPORTING FOR
PHARMACOEPIDEMIOLOGIC STUDIES
We believe that methods of reporting for pharmaco-
epidemiologic studies must be improved, and this
initiative must be taken by medical journals that fre-
quently publish these studies. A group of epidemiolo-
gists based in the United Kingdom is developing guide-
lines for methods reporting observational studies. The
Standards for the Reporting of Observational Studies in
Epidemiology (STROBE)18 is meant to set standards for
the reporting of observational studies (cohort studies,
case-control studies, cross-sectional studies) in the
hopes that STROBE like Consolidated Standards of Re-
porting Trials (CONSORT) may improve the quality of
the reporting of observational studies.
We believe that standards for the reporting of
pharmacoepidemiologic studies are necessary. But
these standards must be specific to pharmacoepidemi-
ology as opposed to observational studies as a whole.
For example, STROBE does not address reporting of
the more complex epidemiologic study designs such as
the case-crossover9 and case-time-control19 studies,
both of which have played an integral role in exploring
ADEs. A case-crossover study is essentially a case-
control study in which the cases act as their own con-
trols. Because the cases act as their own controls, the
degree of between-person confounding that may be
present in a classic case-control study (in which con-
trols are simply those who do not have the disease) is
minimized. This design is most suitable for situations
in which a certain drug is used transiently (for exam-
ple, a benzodiazepine that is used on an as-needed ba-
sis) and in which the risk of an adverse event associ-
ated with that drug is not constant but rises sharply and
then falls over time. An example of this design is a rela-
tively recent study that explored the use of short-acting
benzodiazepines and risk of car accidents.20 The case-
time-control study is similar to a case-crossover study
in which a set of controls are used to adjust for any tem-
poral changes that may affect prescription drug use.21
Both these designs are relatively new and require
methodological and analytical considerations that may
be different from those in classic cohort and case-
control studies.
Pharmacoepidemiology is emerging as a
subspecialty within epidemiology, mostly because of
the need for monitoring prescription drug exposures in
large populations over time. Differences in prescribing
8 • J Clin Pharmacol 2006;46:6-9
behavior, comorbidity, and limitations of large admin-
istrative databases have identified biases that are either
unique to pharmacoepidemiologic studies or may
present themselves more frequently in these studies.
One example is confounding by indication, which may
occur if the outcome thought to be associated with a
specific drug may actually be the result of the disease or
condition in question. Another example is a relatively
new bias referred to as immortal time bias in cohort
studies, which arises when the time dependency of
prescription drug use in a large cohort is not adequately
controlled for.7
Pharmacoepidemiology will continue to play a ma-
jor role in drug-therapy decision making. We urge
pharmacoepidemiologists to develop stricter stan-
dards in conducting and reporting pharmaco-
epidemiologic studies so that results of these studies
may help clinicians make more informed drug-therapy
decisions.
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9