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12
Intensive Hospital-based Cohort Studies
KEITH BEARD
Victoria Infirmary, Glasgow, Scotland
DAVID H. LAWSON
Royal Infirmary, Glasgow, Scotland

INTRODUCTION oping the first major intensive inpatient drug

Until the recognition of chloramphenicol-induced
aplastic anemia1 and thalidomide-associated pho-
comelia,2 adverse drug reaction monitoring was
almost entirely anecdotal. However, the thalido-
mide incident, in particular, led many countries to
set up agencies to collect and evaluate information
on spontaneously reported adverse drug reactions.
These schemes were not without limitations and in
1965 Finney,3 a distinguished Scottish epidemiolo-
gist and statistician, advocated a more rigorous
approach to searching for adverse drug reactions.
He recommended routine recording of all demo-
graphic and clinical information on hospitalized
patients together with all ``events'' occurring in
these patients. This was to be done regardless of
whether any links between drugs and events were
made by their physicians. In his opinion, detailed
analyses of the resulting information, in effect a
series of cohort studies of drug recipients, could lead
to the detection of new and previously unsuspected
adverse drug effects. At about this time, Leighton
Cluff and his colleagues in Baltimore were devel-
monitoring program.4 Their program concentrated
on collecting details of suspected adverse drug
reactions, but in some instances involved formal
hypothesis testing, performed to establish with more
certainty that a suspected reaction was truly an
adverse drug effect.5
These pioneering proposals and studies stimu-
lated interest in this area and several groups began
intensive inpatient monitoring programs to record
suspected adverse drug reactions (ADRs), using as
data collection monitors either medical staff,6
pharmacists,7 or nurses.8 The last named group
has been by far the most successful. It was in 1966
that Hershel Jick and the late Dennis Slone started
a pilot scheme to assess the feasibility of con-
tinuously monitoring large numbers of medical
inpatients. Their goal was to determine the
frequency with which these patients experienced
acute undesired drug effects during hospitaliza-
tion. So successful was this scheme that it was
gradually expanded to medical wards in six
different countries. By 1976, information had been
collected from over 50 000 medical inpatients,

Pharmacoepidemiology, Third Edition. Edited by B. L. Strom.

# 2000 John Wiley & Sons, Ltd.
{Jobs}0688jw/makeup/688ch12.3d
194 PHARMACOEPIDEMIOLOGY
allowing much original research on the association
between short-term drug exposures and acute
ADRs to be carried out. After 1977, the focus of
the program was changed to surgical inpatients.
This new data resource, although smaller, pro-
vided additional information about drug exposure
and events occurring in operating rooms.9 Small
numbers of pediatric10 and psychiatric patients11
were monitored in a similar manner. All these
methods and databases together came to be known
as the Boston Collaborative Drug Surveillance
Program (BCDSP). A review of its published data
gives an impressive idea of the scope of this
approach, which has subsequently been adopted
and applied by other groups.
DESCRIPTION
The aims of intensive hospital-based cohort studies
in pharmacoepidemiology are fourfold: (i) to
provide information on overall patterns of drug
use in hospitals; (ii) to obtain details of acute
adverse events attributable to drugs used in
hospitals, and to determine whether particular
subgroups of hospitalized patients are at greater
risk of experiencing ADRs than others; (iii) to
obtain information on the frequency of certain
major life threatening events occurring during
hospitalization, be they drug related or not; and
(iv) to identify associations between pre-hospital
drug use and diseases or adverse events causing
hospital admissions.
The methods used in this type of study have
been described in detail by Jick and his collea-
gues.12 Briefly, monitors, usually nurses, are
employed to collect routine demographic, social,
and medical information from consecutive admis-
sions to the hospital. Details of drug exposures
before the hospitalization are obtained from
patients by the monitor using a standardized
interview conducted shortly after admission. De-
tails of all drug exposures during the hospitaliza-
tion are also recorded, using standardized self-
coding data collection forms. The monitors attend
ward rounds, where they gather information
concerning undesired or unintended events
thought by the attending physician to be causally
related to drug therapy. The degree of certainty
that any event is indeed drug related is assessed
both by the attending physician and, at a later
date, by an independent clinical pharmacologist.
In addition to ADR data, information on certain
specific events occurring during the hospitalization
is recorded routinely, whether or not these events
are thought to be due to drug therapy. All such
events are major illnesses, and can include sudden
death, jaundice, pulmonary embolism, renal fail-
ure, gastrointestinal bleeding, convulsions, deaf-
ness, and psychosis.
The resulting information is then evaluated for
accuracy and completeness before being entered
into computer files for detailed analysis. During
data entry, several standard tests are applied to the
information to ensure validity and internal con-
sistency. Thereafter the information is available
for detailed analyses. Routine analyses are then
undertaken at regular intervals to search for
associations in the data.
STRENGTHS
The main advantage of the intensive hospital-
based approach to pharmacoepidemiology studies
is the very broad and comprehensive nature of its
primary information sources. This approach has
made many important contributions to our knowl-
edge about the effects of drugs used in hospitals.
Included are studies of drug utilization, descriptive
studies of ADRs and their predictors, studies
testing hypotheses about ADRs, and studies
generating hypotheses about ADRs. Additional
information is available about drugs used shortly
before the hospitalization. Examples of each of
these are given in the section on Particular
Applications, below.
Armed with these data, the BCDSP occupied a
unique position in the early 1970s. Validated data
of the highest quality were scarce at this time, as
pharmacoepidemiology was just emerging as a
unique scientific discipline. Various aspects of the
data collection process also broadened its appeal.
The ``collaborative'' nature of the work allowed
international comparisons to be made. The demo-
graphic data available allowed the role of variables
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INTENSIVE HOSPITAL-BASED COHORT STUDIES
such as age and sex to be studied in more detail.
Finally, the inclusion of social habits such as
alcohol and tobacco consumption allowed study of
these potential modifying factors on the incidence
of ADRs. Thus, by the mid-1970s an impressive
and unique body of information had been accu-
mulated using this approach, analyzed in detail
and published in highly reputable, peer reviewed
journals.
WEAKNESSES
Intensive hospital based cohort studies have
provided clinicians and researchers with accurate
reproducible details of acute adverse reactions to
virtually all commonly used drugs available in the
USA and in Europe in the 1960s and 1970s. Since
then, however, there have been some spectacular
examples of ADRs occurring with newly intro-
duced drugs or formulations, including practolol,
benoxaprofen, tienilic acid, zimelidine, Osmosin,
and temafloxacin. More recently, there have been
the major safety issues associated with anorexi-
gens13 and third generation oral contracep-
tives.14, 15 Those concerned with the release of
new drugs, either in the pharmaceutical industry or
in regulatory agencies, are now keen to have
available monitoring systems that will detect such
potentially serious ADRs quickly and efficiently.16
Unfortunately the intensive hospital-based mon-
itoring system, as described above, is not such a
scheme. It is expensive, is applicable only to drugs
used frequently in hospitals, and, most impor-
tantly, the major data set extant of this type is
unlikely to be useful in answering currently
important questions. Other groups, however, have
continued to collect and analyze data and,
although there remains a fundamental problem
with speed, the basic value of the method is
repeatedly demonstrated. Details are given in a
subsequent section.
By definition, intensive hospital based cohort
studies are used to study drugs as they are used in a
restricted (hospitalized) population. Thus, drugs
that are primarily used on a long term basis in the
community will only be studied indirectly when, for
example, patients taking these preparations are
195
admitted to a hospital. The concept of a centralized
collaborative approach is, however, valuable when
dealing with a specific drug that has significant
safety concerns, whether it is used in primary or
secondary care. One such example is clozapine.
Local monitoring centers can link with national
information resources and can also feed back to
prescribers and health care providers, thus improv-
ing the effectiveness of therapy and patient care.17
This is a general application of the target drug
approach as detailed below. In addition, even for
drugs that are used in hospital, a new drug will
usually take some time to penetrate the market
(depending, of course, on advertising and sales
promotion). Thus, a relatively infrequent ADR is
likely to go undetected for long periods of time
within a small, restricted hospital based program,
particularly if the ADR is delayed in onset. Such an
ADR might be occurring at an unacceptably high
rate. For example, aplastic anemia occurring with a
frequency of one case per 5000 courses of treatment
would be considered unacceptable for a new drug,
yet such a frequency could not be detected using
this method. Routine review of the data may yield
an occasional interesting case, but it would certainly
not be possible to establish a large enough body of
evidence to suggest a causal link. This type of
monitoring system is therefore not in direct
competition with the spontaneous reporting
schemes for ADRs operating in the US,18 in
UK,19 and elsewhere (see Chapters 10 and 11),
nor with the well established community based
record linkage cohort studies (see Chapters 15±23).
This type of approach works well in the general
hospital environment, where details of patient
presentation, investigation, treatment, and pre-
scribing are all relatively standardized and well
recorded. In such settings, ward monitors can
document all important and relevant information
on events, prescribing, and possible ADRs without
too much difficulty. For example, drug prescrip-
tion orders tend to be changed no more than once
per day and illnesses tend to follow a predictable
course under these circumstances. This relatively
standardized information can easily be checked,
validated, and entered onto a computer file.
It is also feasible and practical to extract this
information and analyze it.
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196 PHARMACOEPIDEMIOLOGY

However, the system of ward monitoring as
described is not well suited to all types of modern
hospital practice. For example, any attempt to
monitor patients in an intensive care unit by these
techniques is unlikely to yield comprehensible
old and provide us with no information on several
new classes of drugs, such as H2 receptor
antagonists, calcium channel blockers, and angio-
tensin converting enzyme inhibitors. Moreover,
many new individual drugs in previously studied
data. Drug orders may change by the hour and,
unless a monitor is constantly present, may go
unrecorded. Furthermore, the data accumulated in
such cases would be extremely complex and
difficult to analyze. Attempting to attribute events
in such a situation to a particular drug or group of
drugs would be fraught with difficulty and may be
impossible. Therefore, either one would be left to
collect and record all ``events,'' whether drug
attributed or not, or unacceptable errors or biases
could creep into judgments regarding causality.
Either way, subsequent analyses would be difficult,
if not impossible, to undertake with any degree of
confidence. Having said all that, computerized
hospital systems for recording drug orders and
administration do bring this a step closer. The
ADE Prevention Study Group has monitored
patients in medical and surgical units including
intensive care units.20 Similarly, hospital based
reporting systems have been used to study putative
adverse drug effects, e.g., those related to cardio-
pulmonary bypass.21 Thirteen percent of all
cardiovascular adverse events in these patients
were thought to be related to the administration of
protamine, but only 19% of those were reported.
Intensive hospital based cohort studies require
medical and epidemiologic expertise, trained
monitors at all participating centers, data man-
agers, data entry personnel, computer scientists,
and secretarial help. In addition, many people are
required to collect data. Such a program is
therefore expensive to run. However, this cost
must be viewed in light of the knowledge that can
and has been gained, and in comparison with the
cost of introducing a new chemical entity to the
marketplace. Attempts have been made to quanti-
fy the costs attributed to ADRs.22 This is clearly an
issue of importance to public health and to the
pharmaceutical industry, as evidenced by the
stringent safety requirements imposed by regula-
tory authorities.
Finally, and most importantly, BCDSP hospital
cohort data are now approximately 15± 20 years
classes have appeared, such as antibiotics and -
blockers, which have not been monitored by this
approach. Thus, to be of continuing value, this
approach needs a continuous data collection
program. In recent years a number of smaller
systems have provided useful information and
continue to do so, including local experience with
modern drugs.23, 24
PARTICULAR APPLICATIONS
BCDSP: STUDIES OF THE IN-HOSPITAL
DRUG USE OF MEDICAL INPATIENTS
Drug Utilization Studies
Although studies of prescribing habits and drug
utilization in hospitals were not the primary aims
of the BCDSP, during routine analyses substantial
differences in drug use patterns were noted among
and within the countries participating in the
program. One study was undertaken in which
inpatient drug use in matched Scottish and
American patients was compared and contrasted.25
The American patients received twice as many
drugs as did the Scots, and overall ADR rates were
correspondingly greater. This was despite the fact
that the ADR rate for individual drugs was similar
in the two countries.
Similarly, the use of intravenous fluid therapy
was seen to vary widely among participating
hospitals. Whereas 53% of patients admitted to
one hospital in the US received intravenous fluids,
only 7% of patients admitted to an Israeli hospital
did so. Even within a country with low overall
drug usage such as Scotland, two medical units
within one city with otherwise virtually identical
drug use patterns showed a twofold difference in
intravenous fluid use.26 Studies of this type high-
light the need for careful studies of the reasons for
prescribing expensive drugs if overall drug costs
are to be held in check. A comprehensive data set
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INTENSIVE HOSPITAL-BASED COHORT STUDIES
is essential if meaningful conclusions are to be
made regarding differences in use and expenditure
patterns between institutions, departments, or
prescribers.
Information from hospital based cohort studies
on the most commonly prescribed drugs, their
indications for use, and the most common ADRs
experienced by patients receiving them have been
published in detail elsewhere.27
Descriptive Studies of Adverse Drug Reactions
Drug related deaths are recorded infrequently in
medical inpatients. In a major review of patients
studied during the early years of the program, only
24 drug attributed deaths were found among
24 462 consecutive admissions.28 Most of these
were very ill patients in whom death was the
expected outcome of hospitalization. In only six
cases did it seem possible that the death could have
been prevented. These were five patients who
experienced fluid overload and one who had
hyperkalemia from excessive potassium therapy.
With such large numbers of patients under
study, it is possible to look for uncommon or rare
drug effects that occur after short term drug use.
For example, 119 cases of anaphylaxis, convul-
sions, deafness, or extra-pyramidal symptoms were
found among 38 812 patients who received over
250 000 courses of drug treatment.29 As might be
expected, very few drugs were found to be
responsible, but for those that were, it was possible
to estimate incidence rates, albeit with wide
confidence intervals.
By regularly reviewing the accumulating infor-
mation, it was possible to identify subgroups of the
population who are at a greater than expected risk
of developing ADRs. Thus, for example, in an
early study of heparin, women, especially those
over 60 years old, were found to be at greatest risk
of bleeding.30 The strength of the association was
such that the observation was made after only 97
patients had received the drug, further recipients
serving to confirm the association. More recently
the original observations have been confirmed and
extended, by reviewing data on 2656 patients
receiving heparin therapy. Bleeding was a dose
related phenomenon occurring most often in
197
women, severely ill patients, and patients receiving
aspirin during heparin therapy. The 7 day cumu-
lative risk for bleeding was 9.1%.31
Similarly flurazepam, a commonly used hypno-
tic, was found to have a modest overall ADR rate
of 3.1%, the most common ADR being excessive
drowsiness or ``hangover'' on the morning follow-
ing use.32 However, when the results were reviewed
according to age and dose, it was clearly demon-
strated that this drug had a very high ADR rate in
the elderly, especially when high doses were used.
One particularly elegant study revealed a large
number of factors associated with acute pharma-
cological effects of the hypotensive agent methyl-
dopa.33 In everyday use in the series of university
teaching hospitals covered by the BCDSP, an
average of 10% of 1067 methyldopa recipients
experience clinically significant degrees of hypo-
tension on starting treatment. Detailed analyses of
these subjects showed a strong age relationship:
the younger the patient, the greater the frequency
of hypotension. There were also independent
positive associations between hypotension and
measurements of patient weight, daily drug dose,
degree of hypertension on admission, and kidney
function. The magnitude of these associations was
considerable. Thus, for example, there was a
sixfold greater frequency of drug associated
hypotension in patients with renal impairment
receiving a high initial dose of methyldopa, when
compared with patients without renal impairment
receiving low doses of this drug. These associations
allowed the group to make recommendations for
altering dosing regimens when starting treatment
with methyldopa. There are several important
points that should be noted about this study.
First, the results were biologically and pharmaco-
logically plausible. Second, the effects were pre-
dictable pharmacologic ones. Third, they were
occurring during everyday use of a common
medication. Finally, they were preventable with
careful alteration in dosing.
Other studies of considerable clinical interest
and relevance included those on potassium chlor-
ide,34 furosemide,35 spironolactone,36 and the
interrelationships between diuretic use and elec-
trolyte responses in a large cohort of patients with
congestive cardiac failure.37
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198 PHARMACOEPIDEMIOLOGY
Hypothesis Testing Studies
On routine review of the accumulated data,
certain relationships between ADRs and bio-
chemical data were observed. For example, the
rate of ADRs attributed to phenytoin was noted
to be related to serum albumin concentration,
the rate being 11.4% when serum albumin was
less than 30 g l 1 and 3.8% when serum albumin
was greater than 30 g l 1.38 This relationship was
independent of age, dose of drug, and renal
function, and was likely to be due to phenytoin
being both strongly protein bound and of a
low therapeutic index. Thus, a small decrease
in binding protein may lead to a large increase
in free phenytoin concentrations and toxic
effects.
Although drug interactions are not often a
major clinical issue, they can be found in data of
this type. For example, in 1970 it was suggested
that the hypnotic chloral hydrate might enhance
the anticoagulant activity of warfarin, the pro-
posed mechanism being the displacement of
warfarin from binding sites by the metabolite
trichloroacetic acid. The BCDSP data were ideal
for testing this hypothesis, as they had been
gathered before the hypothesis was put forward
and prescribing doctors were therefore unaware
of a potential interaction, that is there was no
prescribing bias. To test this hypothesis, warfarin
recipients were divided into three groups depend-
ing upon whether they received regular, inter-
mittent, or no chloral hydrate during admission.
The amount of warfarin required to maintain
adequate anticoagulation was found to be in-
versely related to chloral hydrate ingestion, that is
those taking chloral hydrate regularly required
less warfarin. Thus, the original hypothesis was
confirmed.39
Similarly, isolated case reports on the interac-
tion between phenytoin and the antituberculous
drug isoniazid led to concern about their co-
administration. Review of the BCDSP data
revealed that six of 22 patients receiving these
two drugs concurrently experienced central ner-
vous system adverse effects (27%). By contrast,
only 30 of 1093 phenytoin recipients who did not
receive isoniazid experienced these adverse effects
(3%). Thus, these data confirmed the initial
suggestion from the (uncontrolled) spontaneous
reports.40
In an interesting and important study, Duhme
and his colleagues41 compared the adverse reaction
rates attributed to digoxin in two Boston hospitals.
Reactions were reported in 10% of 272 patients at
one hospital and in only 4% of 291 patients at
another. The differences did not appear to be due
to different digoxin dosage, use of other drugs, or
measured patient characteristics. They also did not
appear to be related to reporting bias. In the
hospital with the lower frequency of digoxin
toxicity, serum digoxin levels were monitored
more often (40% of patients) than in the other
hospital (12% of patients). This led the investiga-
tors to conclude that frequent use of serum digoxin
assays in clinical practice could decrease the
frequency with which recipients experience adverse
reactions.
In 1970 it was suggested that hospital patients
with cardiac disease who were treated with tricyclic
antidepressant drugs suffered excess mortality.
Detailed review of the BCDSP data on hospita-
lized medical patients showed a high overall rate of
ADRs in tricyclic antidepressant recipients, but
also showed that the rate of sudden death in
tricyclic recipients (0.4%) was similar to that of
nonrecipients (0.3%).42
Smoking might be expected to influence drug
metabolism since substances in cigarette smoke
can induce hepatic microsomal activity. It was also
possible to test this hypothesis in a number of
ways. The effect of the analgesic drug propox-
yphene was found to be inversely related to the
amount of cigarette smoking, regardless of the
condition that required analgesic therapy.43 Simi-
larly, among users of diazepam and chlordiazep-
oxide, drug attributed drowsiness was less
common in smokers than nonsmokers. This effect
was not seen in phenobarbital users. It was
suggested that users of phenobarbital already had
maximally induced enzymes, and that smoking
therefore made no difference.44
Other hypotheses tested included relationships
between tetracycline use and renal impairment
(confirmed),45 increased nephrotoxicity in patients
receiving both aminoglycoside and cephalosporin
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INTENSIVE HOSPITAL-BASED COHORT STUDIES
(not confirmed),46 and amphetamine use and
Hodgkin's disease (not confirmed).47
Hypothesis Generating Studies
Regular review of the BCDSP data often produced
observations which led to hypotheses about pre-
viously unsuspected drug reactions. For example,
after a short period of monitoring, when only 4000
patients had been enrolled, it was observed that
gastrointestinal bleeding was more common in
patients receiving intravenous ethacrynic acid.48
The risk was present both in patients receiving
heparin and in those who did not receive antic-
oagulants. Although other loop diuretics have
gastrointestinal side effects, few, if any, are
associated with gastrointestinal bleeding.
An interesting example of the detection of
increased susceptibility to ADRs was observed
after the BCDSP was expanded to include
monitoring centers in other countries. Skin rashes
were found to be more common in Israeli patients,
especially those receiving the analgesic drug
dipyrone.49 The rates were 2.3% for American
patients, 2.6% for Israeli patients not taking
dipyrone, and 6.6% for Israeli patients taking
dipyrone. This drug was given to a large number of
Israeli patients and the rash often closely followed
the start of drug therapy. The association was
discovered from within the database, since the
absolute frequency was low and the medical
attendants rarely noticed the relationship.
In 1976, the first in a series of new analyses was
undertaken, in which the drug incriminated by the
attending physicians as the cause of a reaction was
ignored. All 507 patients with a drug attributed
skin rash among 22 227 consecutive patients were
systematically reviewed. Having removed all in-
formation on recipients of penicillin and blood-
=blood products from the data set, and having
defined certain rules of causality, 57 separate drugs
were identified as having strong likelihood of
causing skin reactions.50
In a similar way, 57 cases of gastrointestinal
hemorrhage in whom an underlying medical
predisposition to bleed was unlikely and a drug
related cause seemed possible were identified
among 16 646 medical inpatients.51 This review
199
indicated a strong likelihood that steroids, aspirin,
anticoagulants, and ethacrynic acid could cause
gastrointestinal hemorrhage in otherwise healthy
subjects. It must be remembered that, although
this seems a small number of cases, modern
nonsteroidal anti-inflammatory drugs were not in
use at the time.
BCDSP: STUDIES OF THE PREHOSPITAL
DRUG USE OF MEDICAL INPATIENTS
A review of the proportion of patients admitted to
medical wards due to ADRs was published in
1974.52 This emphasized that between 1.8 and
5.6% of admissions to the medical wards of seven
university teaching hospitals were due to such
reactions. Foremost among the drugs associated
with this type of reaction were digoxin, aspirin
containing preparations, insulin, anticoagulants,
and adrenal corticosteroids. However, the period
of interest was initially restricted to the 3 months
preceding hospitalization, as it was felt that patient
recall of drug history for a longer period would be
inaccurate. Regular drug use which stopped for a
period exceeding three months before admission
was not recorded, and any relationship between
this drug use and subsequent morbid events was
undetected. Modern approaches to this method
often have access to computerized prehospital
drug use information (see Chapters 15± 23), thus
eliminating potential recall bias.
This limitation may have been relevant to a
study that sought an association between pre-
hospitalization aspirin use and renal disease.53 No
such association was found. However, the expo-
sure status in some patients with renal disease may
have been distorted by the 3 month rule. Such
patients could have consulted a physician many
months previously because of symptoms from
renal disease and been advised to discontinue
aspirin. If they complied with this request and then
an admission to the hospital occurred later, a
history of exposure to analgesics could have
gone unrecorded. This problem could have been
circumvented by confining analyses to newly
diagnosed cases of the condition under review.
During the study of prehospital aspirin con-
sumption, it was observed that there was a
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200 PHARMACOEPIDEMIOLOGY
significantly lower mortality than expected in this
group of patients. Further analyses revealed that
this was due to a reduction in myocardial
infarction.54 This finding aroused considerable
interest having, as it did, major implications for
prevention. The work was repeated two years later,
using a different group of monitored patients, with
the same negative relationship being demon-
strated.55 Analyses took account of age, sex,
hospital, and reason for drug therapy. Further-
more, the association was found in patients with a
wide range of clinical conditions, such as diabetes,
hypertension, previous myocardial infarction, and
arthritis. Details of potential risk factors such as
diet, exercise habits, and lifestyle were not
recorded. Although these could represent con-
founding factors, none were felt likely to signifi-
cantly alter the result. Similarly, as only
myocardial infarction patients who survived to
reach a hospital could be studied, a theoretical
explanation might be that aspirin takers were more
likely to die in the acute phase of infarction. This
seemed unlikely to explain the findings, however.
It was to be over ten years before this finding was
confirmed in a subsequent randomized clinical
trial, and of course, aspirin is now a very
important therapeutic tool in prevention and
treatment of cardiovascular disease.
There exists within the framework of such an
elaborate system for data collection the possibility
of gathering information on substances which,
although not drugs or medications in the accepted
sense, may nevertheless have pharmacological
actions or interactions with other drugs. Informa-
tion on tea, coffee, and alcohol consumption was
collected by the group. From the regular review of
this information came the observation that regular
coffee drinking was associated with nonfatal
myocardial infarction.56 Risk was found to be
increased twofold and was found to be indepen-
dent of age, sex, previous myocardial infarction,
other cardiac conditions, obesity, diabetes, smok-
ing, and occupation. Further corroborative evi-
dence was obtained in a separate cross-sectional
study carried out in 1972 (see below), where risks
of the same magnitude were found.57 Various
explanations for the finding are theoretically
possible.
Using a similar (case ± control) approach, an
association was sought between alcohol consump-
tion and myocardial infarction, but neither an
increase nor a decrease in risk due to alcohol
consumption was demonstrated.58
Starting at a time when quantitative information
about ADRs was poor or nonexistent, the BCDSP
has been the most successful group to study
hospital based cohorts of drug recipients and to
quantify the adverse effects of established drugs. A
summary of the studies reported by these workers
was published in 1986.59 By 1974, its Director,
Hershel Jick, was able to review his work at
BCDSP and conclude that, although ADRs are
common and may affect many millions of Amer-
icans annually, their severity and the rates with
individual drugs are remarkably low.60 After that
time, the emphasis of research work at BCDSP
shifted to different information sources (see
Chapters 15 and 23), although ad hoc studies are
still conducted from time to time using their
original methodology.
Other Intensive Hospital Based Cohort
Studies
Although the largest proportion of analyses from
the BCDSP involved medical inpatients, detailed
studies have been undertaken on smaller numbers
of patients in pediatric wards10 and psychiatric
wards.11 Further analyses of the psychiatric
resource revealed a strong negative association
between chlorpromazine associated drowsiness
and cigarette smoking habits.61 Thereafter, a
modest monitoring program was undertaken on
5232 surgical patients.9 This study emphasized the
higher number of drugs used in surgical patients
when compared to medical patients and also
indicated a measurable proportion of ADRs
occurring in these patients. Further detailed re-
views of this surgical data resource defined the
prevalence of acute respiratory events occurring
after general anesthesia in the recovery room.62
In addition, although the BCDSP has accumu-
lated the largest database using short term in-
hospital cohort studies, it is by no means the
only group that has been using this approach.
The initial pediatric drug monitoring studies
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INTENSIVE HOSPITAL-BASED COHORT STUDIES
undertaken by Jick and his colleagues10 were soon
discontinued, in large part because the information
suggested that the rates of reactions were low in all
but seriously ill young children. It was therefore
concluded that the cost-effectiveness of this type of
monitoring in pediatric wards was relatively low.
Mitchell and his colleagues undertook a monitor-
ing project in a large pediatric ward based on
techniques similar to the original BCDSP study.63
Several important findings emerged in addition to
essential basic quantitation of drug utilization
problems. In 1985, they published an important
study showing a significant inverse relationship
between body weight and risks of hyperglycemia
following infusion with 10% dextrose solutions.64
This emphasized the importance of careful dosage
adjustment of treatments in the neonatal period
and the necessity of continued vigilance even with
apparently simple treatment regimens to avoid
serious adverse effects. More recently, a review of
the risks of heparin therapy used to monitor
patency of venous access demonstrated a positive
association with intraventricular hemorrhage in
low birth weight infants.65 In view of their
findings, it is perhaps a cause for concern that
these workers showed a significant increase in drug
use in low birth weight infants when comparing
data from 1978± 79 with 1985± 86, especially in the
first week of treatment in the intensive care unit. In
the latter phase, some 71% of admissions to the
neonatal intensive care unit had received gentami-
cin during their stay, and approximately 60% each
received sodium chloride, potassium chloride, and
heparin. Such reports emphasize the need for
continued careful monitoring of this vulnerable
age group of patients. Recognizing the limitations
of inpatient monitoring, the group has recently
stressed the importance of the randomized con-
trolled trial in monitoring for drug safety in
children (see Chapter 33). In a large study, no
increase in risk of hospitalization for gastrointest-
inal bleeding, renal failure, or anaphylaxis was
found in short term users of ibuprofen.67
In the field of general medical inpatient mon-
itoring studies, those from the University of Berne,
Switzerland, deserve special mention. In 1974,
Hoigne and colleagues began routine systematic
followup of all patients hospitalized in several
201
Berne medical units.68 This program, known as the
Comprehensive Hospital Drug Monitoring Berne
(CHDMB), has published many interesting and
valuable papers on ADRs.69 Because of its size,
this program is one of the few data resources
whose work can be compared with that of the
BCDSP. Their initial reports on drug related
deaths in 17 285 medical patients in two teaching
hospitals indicated an incidence of 0.4 per 1000
patients, a figure similar in magnitude to the 0.9
per 1000 patients recorded in a BCDSP study of
26 462 subjects.28
CHDMB has published reports on drug induced
blood dyscrasias70 and on allergic reactions to
drugs.71 CHDMB published two reports on skin
reactions attributed to penicillins and their rela-
tionship to allopurinol use.72, 73 These were of great
methodologic interest because, although they
confirmed the high frequency of exanthemata
associated with penicillins reported by BCDSP,74
they did not reveal an excess in patients con-
comitantly receiving penicillins and allopurinol, a
finding initially coming from BCDSP.75 The
CHDMB reviewed all the published information
and concluded that the most likely explanation for
the discrepancy was variations in the length of
exposure to penicillins in the two studies. An
alternative explanation, however, could be that the
CHDMB data set was a record of all penicillin or
allopurinol attributed rashes, whereas the BCDSP
data set was collected and analyzed to look at
virtually all rashes occurring in the monitored
wards. The judgments inherent in deciding
whether to include a patient in the Berne data
could have introduced unwanted bias into an
otherwise excellent system. These findings high-
light the need both for extreme care in the analyses
of this type of information and clarity in the
documentation of the final results.
Data collection continues in two centers in Berne
and St Gallen. By 1993, the database contained
information on 48 005 consecutive admissions of
34 840 patients. By recording prescription informa-
tion from the 21 day prehospitalization period, the
Swiss workers have contributed to the growing
body of published information on the association
between upper gastrointestinal bleeding and non-
steroidal anti-inflammatory drugs.76 Twenty years
{Jobs}0688jw/makeup/688ch12.3d
202 PHARMACOEPIDEMIOLOGY
of experience have been reviewed in recent reports
of drug induced asthma and skin reactions.77, 78
Older information from these databases has re-
cently revealed further information on heparin
induced thrombocytopenia, antibiotics=colitis, and
diuretics=hypokalemia.79, 80, 81
The general methodology found recent applica-
tion in an Italian project running under the
acronym ARIES (Adverse Reaction Identification
Evaluation System). The project was developed as
a collaborative effort between ICI ±Pharma and
several hospital departments that comprise the
Gruppo di Ricerca sulla Epidemiologia del Farm-
aco. Physicians worked with external monitors in
the collection of data of three forms: (i) demo-
graphic and administrative information together
with ICD coded diagnoses, (ii) prescription in-
formation including drug name, route, dose, and
starting and stopping dates, and (iii) adverse event
information obtained using a simple algorithm.
Data collected between 1988 and 1991 yielded
information on 9000 patients and 60 000 prescrip-
tions. Much of this early effort was directed
towards drug utilization studies,82 but there existed
within the framework the possibility of conducting
hypothesis generating and testing studies similar to
those conducted using the Boston and Swiss data.
THE FUTURE
Having highlighted some of the strengths and
drawbacks of this approach, and provided some
examples, it is relevant to conclude this review by
looking ahead and attempting to assess how this
technique of intensive hospital based monitoring
might continue to contribute to our knowledge
about ADRs.
First, patterns of drug use change as our
understanding of pathophysiology advances, new
indications for old drugs emerge, often after many
years of research, and established drugs are used in
new formulations. Furthermore, patterns of hos-
pitalization change as economic and political
developments proceed. Populations change as
birth rates change and longevity increases. For
all of these reasons, it is predictable that patterns
of ADRs will change with time. It might therefore
be both reasonable and justifiable to conduct this
type of intensive monitoring exercise every ten
years or so, in order to keep abreast of current
drug therapy and modes of clinical practice. The
period over which monitoring might be done
would not be crucially important. Indeed if a large
number of centers were recruited and enough staff
employed to cope with data handling, the required
number of patients, say 50 000, could be processed
quite quickly. Such a development would be both
useful and justified. It would offer information of
considerable value to prescribers, manufacturers,
and regulators alike. However, the main advantage
of periodically repeating the BCDSP exercise
would be that all recently marketed drugs that
have reached significant usage levels in hospitals
could be monitored, their acute toxicity profile
determined, and their interaction with other drugs
and with smoking and alcohol habits assessed.
Realistically, cost is likely to be the main
limiting factor. As hospital information systems
improve, so does the extent and quality of
information on drug prescribing and administra-
tion. Additional linkage to demographic, labora-
tory, procedures, and morbidity information raises
the possibility of comprehensive multipurpose in-
hospital information that would allow ongoing
safety monitoring of the intensive in-hospital type,
and indeed go a long way towards achieving the
proposals for a scientifically rigorous system
proposed by Finney in 1965.3
Were a general monitoring program to be
instituted on a regular basis every decade or so,
even then information on newly marketed drugs
would remain scarce. However, this could be
circumvented by selected (targeted) drug monitor-
ing studies. Such studies have been undertaken
many times in the past, and clozapine has already
been cited as a more recent example.17 Target drug
surveillance is a modification of the basic system
whereby, rather than selecting a hospital service
and scrutinizing all patients and all drugs in that
service, a drug of interest is selected and all users of
that drug, regardless of location within the
hospital, are studied. For example, Koch-Weser
and his colleagues at the Massachusetts General
Hospital performed a classic study of this type,
reviewing information on 317 patients receiving
{Jobs}0688jw/makeup/688ch12.3d
INTENSIVE HOSPITAL-BASED COHORT STUDIES
colistin treatment. Detailed analyses showed that
altering the method of dose adjustment in patients
with renal impairment would be likely to reduce
the ADR rate significantly.83 This system has been
used by the Boston group to study various drugs,
including intravenous cimetidine84 and atracur-
ium, a neuromuscular blocking agent for use in
anesthesia.85, 86 The work of the monitor in such a
system is clearly different, for there must be close
liaison with the hospital pharmacy if all drug users
are to be identified and located. In this situation
the monitor works throughout the hospital and
interacts with many more people than his or her
counterpart in the previously described system, so
such a monitor must be both highly efficient and a
good communicator.
The target drug system is certainly a more
efficient way of answering specific questions about
new drugs, and is therefore a more efficient
approach for this defined purpose than the general
inpatient monitoring system. It also lends itself to
the multicenter approach. The Drug Surveillance
Network is a nationwide network of clinical
pharmacists in the USA and Canada. Clinical
pharmacists in over 300 hospitals record relevant
information and monitor progress and outcomes
in consecutive eligible patients. Studies on anti-
biotic use have highlighted potential problems
with renal and hematological ADRs, and metho-
dological issues related to misclassification have
also been addressed.87, 88
Another way of focusing resources in an
intensive hospital based monitoring program is
by selecting specific patient groups who, for
various reasons, may be worthy of particularly
detailed study. The pediatric monitoring program
conducted by Mitchell was referred to earlier.63± 66
An additional example of such a group would be
elderly persons, who are at considerable risk of
developing ADRs by virtue of high drug usage, if
for no other reason. Subjects over the age of 65
years comprise about 15% of the UK population
and consume about 35% of prescribed drugs. They
also comprise over half the total hospitalized
population. ADRs in the elderly are common.
Hurwitz89 provided documentation of this in her
study of medical inpatients in Belfast. Williamson
and Chopin90 studied a group of admissions to
203
geriatric assessment units and predictably found a
high rate of ADRs. They documented the drugs
most frequently responsible and demonstrated a
link between prehospitalization polypharmacy and
ADRs. A significant proportion of hospital
admissions is thought, at least in part, to be due
to ADRs.91 There remains overall concern that
elderly patients are at considerable risk from
ADR,92, 93 although the complex relationship
between age, altered physiology, multiple drug
exposures, and multiple disease states needs careful
interpretation.
Monitoring systems for assessing ADRs in
elderly subjects have largely been confined to acute
medical wards, although community based record
linkage gives exciting opportunities to investigate
drug exposure and outcomes in a very different
group. Few studies have investigated elderly sub-
jects in chronic care institutions, a group at high
risk from serious reactions.94 A program gathering
such data on a routine basis would be desirable, and
the intensive hospital based system could be
adapted for use in this environment.
In a detailed review of the ``state of the art'' of
the discovery of drug induced illness, the Director
of the BCDSP defined the contribution of various
different research strategies to this end.95 He
emphasized that the cohort approach was most
useful in situations where a drug causes a
significant increase in an already high baseline
risk of an event or illness. Such situations are
relatively unusual, albeit still of major importance.
This view was upheld by Venning96± 100 who
undertook a detailed study of identification of
adverse reactions to new drugs.
Finally, in the US the Joint Commission for
Accreditation of Hospitals now requires all hospi-
tals to develop the capability to document and
evaluate ADRs that occur in their patients. This
could simply involve the passive collection of
spontaneous reports of adverse reactions occurring
in the hospitals. Alternatively, it could result in
systems as thorough as the existing systems for
monitoring for nosocomial infections or even as
thorough as the intensive hospital based cohort
studies described here.
It seems likely therefore that intensive hospital
based cohort studies of suspected adverse drug
{Jobs}0688jw/makeup/688ch12.3d
204 PHARMACOEPIDEMIOLOGY
reactions and of events in drug recipients will
remain a relevant technique for studying selected
drugs in specific circumstances for some time.
General monitoring of medical inpatients by this
approach would be useful if undertaken periodi-
cally by a trained research team, and may be a
useful by-product of rapidly developing informa-
tion systems.
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