Pharmacoepidemiology
Ø Pharmacoepidemiology
applies the methods of epidemiology to the content area of clinical
pharmacology.
EPIDEMIOLOGIC STUDY DESIGNS:
CASE REPORTS
Case reports are simply
reports of events observed in single patients. As used in Pharmacoepidemiology,
a case report describes a single patient who was exposed to a drug and
experiences a particular, usually adverse, outcome.
For example, one
might see a published case report about a young woman who was taking oral
contraceptives and who suffered a pulmonary embolism.
Case reports are
useful for raising hypotheses about drug effects, to be tested with more
rigorous study designs. However, in a case report one cannot know if the
patient reported is either typical of those with the exposure or typical of
those with the disease.
Certainly, one cannot usually determine
whether the adverse outcome was due to the drug exposure or would have happened
anyway. As such, it is very rare that a case report can be used to make a
statement about causation.
One exception to this would be when the outcome
is so rare and so characteristic of the exposure that one knows that it was
likely to be due to the exposure, even if the history of exposure were unclear.
An example of this is clear cell vaginal
adenocarcinoma occurring in young women exposed inutero to
diethylstilbestrol. Another exception would be when the disease course is very
predictable and the treatment causes a clearly apparent change in this disease
course.An example would be the ability of penicillin to cure
streptococcal endocarditis, a disease that is nearly uniformly fatal in the
absence of treatment. Case reports can be particularly useful to document
causation when the treatment causes a change in disease course which is
reversible, such that the patient returns to his or her untreated state when the
exposure is withdrawn, can be treated again, and when the change returns upon
repeat treatment. Consider a patient who is suffering from an overdose of
methadone (a long-acting narcotic) and is comatose. If this patient is then
treated with naloxone (a narcotic antagonist) and immediately awakens,this would
be very suggestive that the drug indeed is efficacious as a narcotic antagonist.
As the naloxone wears off the patient would become comatose again, and then if
he or she were given another dose of naloxone the patient would awaken again.
This, especially if repeated a few times,would represent strong evidence that
the drug is indeed
effective as a
narcotic antagonist. This type of challenge–re challenge situation is relatively
uncommon, however, as physicians generally will avoid exposing a patient to
a drug if the patient experienced an adverse reaction to it in the past.
CASE SERIES
Case
series are collections of patients, all of whom have a
single exposure, whose clinical outcomes are then evaluated and described.
Often they are
from a single hospital or medical practice. Alternatively, case series can be
collections of patients with a single outcome, looking at their antecedent
exposures. For example, one might observe 100 consecutive women under the age of
50 who suffer from a pulmonary embolism, and note that 30 of them had been taking
oral contraceptives.
After drug
marketing, case series are most useful for two related purposes.
They
can be useful for quantifying the incidence of an adverse reaction.
They can be useful for being certain that any
particular adverse effect of concern does not occur when observed in a
population which is larger than that studied prior to drug marketing.The
so-called “Phase IV” post marketing surveillance study of prazosin was conducted
for the former reason, to quantitate the incidence of first-dose syncope from
prazosin. The“Phase IV” post marketing surveillance study of cimetidine was
conducted for the latter reason.
Metiamide was an
H-2 blocker, which was withdrawn after marketing outside the US because it
caused agranulocytosis. Since cimetidineis chemically related to metiamide
there was a concern that cimetidine might also cause agranulocytosis. In both examples,
the manufacturer asked its sales representatives to recruit physicians to
participate in the study. Each participating physician then enrolled the next
series of patients for whom the drug was prescribed.
In this type of
study, one can be more certain that the patients are probably typical of those
with the exposure or with the disease, depending on the focus of the study.
However, in the
absence of a control group, one cannot be certain which features in the
description of the patients are unique to the exposure, or outcome. As an
example,one might have a case series from a particular hospital of 100
individuals with a certain disease, and note that all were men over the age of
60. This might lead one to conclude that this disease seems to be associated
with being a man over the age of 60.
However, it would be clear that this would be
an incorrect conclusion once one noted that the hospital this case series was
drawn from was a Veterans Administration hospital, where most patients are
men over the age of 60.
In the previous example of pulmonary embolism
and oral contraceptives, 30% of the women with pulmonary embolism had been using
oral contraceptives.However, this information is not sufficient to
determine whether this is higher, the same as, or even lower than would have been
expected. For this reason, case series are also not very useful in determining
causation, but provide clinical descriptions of a disease or of patients who
receive an exposure.
CASE–CONTROL STUDIES
Case–control
studies are studies that compare cases with a disease to
controls without the disease, looking
for differences in antecedent exposures.
As an example,
one could select cases of young women with venous thromboembolism and compare
them to controls without venous thromboembolism, looking for differences in
antecedent oral contraceptive use. Several such studies have been
performed,generally demonstrating a strong association between the use of oral
contraceptives and venous thromboembolism.
Case–control
studies can be particularly useful when one wants to study multiple possible
causes of a single disease,as one can use the same cases and controls to
examine any number of exposures as potential risk factors.
This design is
also particularly useful when one is studying a relatively rare disease, as it
guarantees a sufficient number of cases with the disease.
Using case–control studies, one can study rare
diseases with markedly smaller sample sizes than those needed for cohort studies.
For example, the classic study of
diethylstilbestrol and clear cell vaginal adenocarcinoma required only 8 cases
and 40 controls, rather than the many thousands of exposed subjects that would
have been required for a cohort study of this question. Case–control studies
generally obtain their information on exposures retrospectively, i.e., by
recreating events that happened in the past. Information on past exposure to
potential risk factors is generally obtained by abstracting medical records or by
administering questionnaires or interviews.
As such,
case–control studies are subject to limitations in the validity of
retrospectively collected exposure information.In addition, the proper
selection of controls can be a challenging task, and inappropriate control
selection can lead to a selection bias, which may lead to incorrect
conclusions.Nevertheless, when case–control studies are done well, subsequent
well-done cohort studies or randomized clinical trials, if any, will generally
confirm their results. As such, the case–control design is a very useful
approach for pharmacoepidemiology studies.
A cross sectional study measures the prevalence of health
outcomes or determinants of health, or both, in a population at a point in time
or over a short period.
They are usually done through surveys, chart reviews, or
database analyses.
They provide a view of the state of affairs at that time,
and provide an estimate of the prevalence of utilization and of outcomes.
Such information can be used to explore aetiology - for
example, the relation between cataract and vitamin status has been examined in
cross sectional surveys.
These types of studies have been used to compare drug
use between countries or regions within a country. Very large differences
suggest that reasons for those differences should be investigated and policies
examined to determine whether outcomes and costs also differ and whether
changes should be made.
However, associations must be interpreted with caution. Bias
may arise because of selection into or out of the study population.
A cross sectional
survey of asthma in an occupational group of animal handlers would
underestimate risk if the development of respiratory symptoms led people to
seek alternative employment and therefore to be excluded from the study. A
cross sectional design may also make it difficult to establish what is cause and
what is effect.
