PUBLIC ATTENTION
is currently focused on adverse drug reactions (ADR) as evidenced by a
recent bill passed by the US Senate requiring pharmaceutical companies to
provide ADR information to consumers.l Heightened interest in ADRs was
stimulated by the thalidomide tragedy in the 1960s.2 To obtain an accurate
estimate of ADR incidence in hospital patients, prospective studies were
done, beginning in the 1960s, in which a defined population could be kept
under close observation by monitors who recorded all ADR occurrences.34
These prospective studies have been done on 2 separate populations of
patients; those admitted to the hospital due to an ADR (ADRAd),6 and those
experiencing an ADR while in the hospital (ADRIn).7 We report here a
meta-analysis of 39 of these prospective studies done in the United States
over a period of 32 years from which we obtained ADR incidences for ADRIn
and for ADRAd and an overall ADR incidence that combines these 2 groups. We
focused mainly on serious and fatal ADRs since they represent the greatest
impact of drug therapy. While recognizing the benefits of drug therapy, we
chose not to compare benefits of drugs to the side effects of drugs.
METHODS Definitions
One step we took
to reduce heterogeneity was to exclude any data that did not use the
following specific definitions:
Adverse Drug
Reaction (ADR).-According to the World Health Organization definition,s this
is any noxious, unintended, and undesired effect of a drug, which occurs at
doses used in humans for prophylaxis, diagnosis, or therapy. This definition
excludes therapeutic failures, intentional and accidental poisoning (ie,
overdose), and drug abuse.8 Also, this does not include adverse events due
to errors in drug administration or noncompliance (taking more or less of a
drug than the prescribed amount).8 Using this conservative definition avoids
overestimating the ADR incidence.
Recently, some
authors prefer the term adverse drug event (ADE), which is an injury
resulting from administration of a drug. In contrast to the World Health
Organization definition of ADR, the definition of ADE includes errors in
administration.9 However, we have chosen the World Health Organization
definition for ADR because of its frequent use in the studies that we
analyzed, and because of our goal to estimate injuries incurred by drugs
that were properly prescribed and administered. In those articles that did
not use the World Health Organization definition (eg, ADE was used), we
examined the raw data and removed adverse events due to errors in
administration. However, this was not always feasible since a few articles
may have included errors in administration but did not report them
separately. Therefore, unfortunately, these latter articles added to the
heterogeneity of our data.
Possible ADR.-This
is an ADR that follows a reasonable temporal sequence and for which the ADR
is a known response to the drug, although the response may also be explained
by the patient's clinical state." Possible ADRs were excluded from our
study.
Serious ADR.-This
is an ADR that requires hospitalization, prolongs hospitalization, is
permanently disabling, or results in death. Serious ADRs include fatal ADRs,
which were also analyzed separately.
Prospective
Studies.-Patients were present during the study, and monitors were able to
interview physicians, nurses, or patients at least once per week. All ADRs
were confirmed prior to patient's discharge from the hospital.
Retrospective
Studies.-Chart reviews were performed after the patient had left the
hospital. These studies were excluded from our analysis.
Literature Search
Electronic
databases were searched using the following key word strategy: adverse drug
or adverse reaction or drug-related or drug-induced and hospital. Three MeSH
(Medical Subject Headings) terms were also used where appropriate (ie,
hospitalization, drugs, drug therapy/adverse effects) in combination with
key words. Databases that we used were MEDLINE (1966-1996), Excerpta Medica
(1980-1996), International Pharmaceutical Abstracts (19701996), and Science
Citation Index (19891996). The reference sections of all retrieved articles
were manually searched for additional studies. In addition, we sent letters
to researchers in the field to request unpublished data in order to reduce
publication bias.
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Selection Criteria
The following
criteria were used:
1. The patients
studied were not selected for particular conditions or specific drug
exposures.
2. Sufficient
information was reported in the published study to calculate the incidence
of ADRs.
3. English
translations of the papers were available.
4. Prospective
monitoring was used to identify ADRs.
5. Definitions
used in the studies coincided with ours (see "Definitions" subsection for
our definitions).
Quality of the Data
Rather than
merely assessing the quality of each study," we chose instead to improve the
quality of our database. First, we used prospective monitoring as an
inclusion criterion to exclude the lowestquality studies (ie, the
retrospective studies). Second, ADRs classified as "possible" were excluded.
Attributing causality is always a problem with ADR detection"2 and, by
excluding possible ADRs, we reduced the number of false positives in the
data.
Heterogeneity
We dealt with
heterogeneity among the studies in numerous ways: (1) we placed considerable
emphasis on the 95% confidence intervals (CIs) to draw attention to the
heterogeneity,l3 (2) we used a random-effects model to do the analysis
because it takes into account the heterogeneity of the various studies,l3,lQ
(3) to reduce heterogeneity, we excluded ADRs caused by errors in
administration, noncompliance, overdose, drug abuse, or therapeutic
failures, (4) for additional ways to reduce heterogeneity, we excluded ADRs
not fitting our strict definitions, possible ADRs, and retrospective data.
Data Extraction
We determined
the incidence of ADRs in the hospital by extracting the total number of
hospital patients in each study experiencing at least 1 ADR and dividing
this value by the total number of hospital patients in each study. The ADR
incidence was expressed as the percent of patients with an ADR. A data
collection form was developed prior to the study for this purpose.
Information on nonserious, serious, and fatal reactions was extracted. Other
data extracted included the year of the study, ward and hospital type in
which the study was performed, mean age, average length of hospital stay,
average number of drug exposures for the patients included in the study, and
the number of men and women in each study. To test for reliability of our
extraction procedures a randomly selected subset of the data was extracted
independently by 2 of us (J.L. and B.H.P.) and was found to be very
consistent for the published ADR incidence for serious, fatal, and all
severities (intraclass correlation coefficient ranging from 0.89 to 0.92).
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Analysis of ADR Incidence
We separately
analyzed the incidence of ADRIn and the incidence of ADRAd and then combined
the 2 groups to obtain an overall ADR incidence. We analyzed ADRs of all
severities (which included nonserious and serious), ADRs that were serious
(which included fatal), and ADRs that were fatal; however, we focused mainly
on the serious and fatal ADRs. For each category, we analyzed the ADR
incidences obtained from the different studies to determine the mean
incidence and the 95% CIs. For this purpose we used a random-effects model
for meta-analysis"5 similar to the method used in the only previous
meta-analysis of ADRAds.16 This is the method of choice because it takes
into account the heterogeneity of the various studies.14
When combining
the incidence of ADRIn and ADRAd to obtain the overall incidence of ADRs, we
avoided double counting patients who were admitted for an ADR and who then
also experienced an ADR while in the hospital by assuming the 2 types of
events to be independent and deriving an adjusted estimate using the
following formula:
Adjusted Overall
Incidence = (Incidence of ADRIn + Incidence of ADRAd) - (Incidence of ADRIn
x Incidence of ADRAd).
This provided a
slightly smaller estimate of the ADR incidence. For example, the mean
estimate for the overall number of serious ADRs per year (see "Results"
section) would change by 33 000 patients, dropping from 2 249 000 (no
adjustment) to 2216000 (our estimate using the adjustment).
When comparing
groups, we used both parametric and nonparametric methods. The results were
always the same for the 2 methods. Hence, for group comparisons, whenever
possible, we reported the results of the more robust nonparametric Wilcoxon
rank sum test.'7 All statistical analyses were performed using the SAS
statistical software package, version 6.11 (Statistical Analysis System,
Cary, NC).
Number of Patients With ADRs
We estimated the
number of hospital patients with ADRs in the United States by using the
incidence of ADRs in US hospitals derived from our data and multiplying this
value by the number of hospital admissions in 1994 in the United States,
obtained from published statistics.ls In 1994, there were 33 125 492
hospital admissions in the United States. We calculated the 1994 fatal
ADRIns as follows:
Number of Fatal
ADRIns in US Hospitals in 1994 (63 000) = Incidence of Fatal ADRIns in
Hospitals in the United States (0.0019) x Number of Hospital Admissions in
the United States (33 125 492).
This estimate is
based on the assumption that our sample is representative of the hospital
population, and, hence, we examined representativeness at some length (see
"Results" section).
RESULTS
Using our 5
selection criteria, 39 of the 153 studies found in the literature were
included in our meta-analysis. Features of these 39 studies are given in
Tables 1 and 2.4-7,9,19-43 Fifty-seven studies were excluded from our
meta-analysis by the 2 blinded investigators because they did not meet our
criteria. In addition 57 of the remaining 96 studies were performed in
countries other than the United States and were excluded from our
meta-analysis because one of our major goals was to determine
representativeness of our sample in order to establish the accuracy of our
summary statistics. Since we only had a sufficient number of studies from
the United States to allow us to perform these tasks, we decided to exclude
the remaining countries from our meta-analysis since a proper analysis for
representativeness for any other country would be impossible to perform.
Incidence of ADRs
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As shown in
Table 3, the incidence of serious ADRIn was 2.1% (95% CI, 1.9%2.3%) of
hospital patients, while the incidence of serious ADRAd was 4.7% (95% CI,
3.1%-6.2%). The incidence of fatal ADRIn was 0.19% (95% CI, 0.13%-0.26%) of
hospital patients and the incidence of fatal ADRAds was 0.13% (95%
CI,0.04%0.21%). Combining ADRIn and ADRAd, the overall incidence of serious
ADR was 6.7% (95% CI, 5.2%-8.2%) of hospital patients and the overall
incidence of fatal ADRs was 0.32% (95% CI, 0.23%-0.41%). The incidence of
ADRIn of all severities (including nonserious and serious) was 10.9% (95%
CI, 7.9%-13.9%) of hospital patients. The overall incidence of ADRIn plus
ADRAd for ADRs of all severities was 15.1% (95% CI,12.0%-18.1%) of hospital
patients.
Eight ADRIn
articles included the proportion of type A4 (dose-dependent ADRs) and type
B44 (idiosyncratic and/ or allergic ADRs). Of the "all severities" ADRIn,
76.2% (95% CI, 71.0%-81.4%) were type A reactions and 23.8% (95%
CI,18.6%-29.0%) were type B reactions. Unfortunately, none of these studies
reported the proportion of type A and type B reactions for serious and fatal
ADRs.
Number of Hospital Patients With ADRs
As shown in
Table 4, we estimated that 702000 (95% CI, 635000-770000) hospital patients
in the United States experienced a serious ADRIn in 1994. We calculated that
1547000 (95% CI, 1033 000-2 060 000) hospital patients experienced a serious
ADRAd. Combining these values, overall 2 216 000 (95% CI, 1 721000-2 711000)
hospital patients experienced a serious ADR in the United States in 1994. We
calculated that there were 63000 (95% CI, 41000-85000) fatalities due to
ADRIn and another 43 000 (95% CI, 15000-71000) deaths occurred in
association with ADRAd in the United States. Overall in 1994, we estimated
that 106 000 (95% CI, 76 000-137 000) deaths were caused by ADRs in the
United States, which could account for 4.6% (95% CI, 3.3%-6.0%) of the 2 286
000 recorded deaths from all causes during 1994 in the United States.18
Using the mean ADR incidence (106000) or the more conservative lower 95% CI
(76 000), we found that fatal ADRs ranked between the fourth and sixth
leading cause of death in the United States in 1994.
Representativeness of Our Sample Among the many factors possibly influencing
ADR incidence, considerable research has identified average length of
stay,45,46 age,45,47 gender,48,49 and drug exposure.45,46 Therefore, as
shown in Table 5, we checked to see whether the population that we sampled
was representative of the US hospital population"0 vis-a-vis these 4
factors. We determined that the differences were significant for length of
stay and gender but not for age. Unfortunately, we were unable to find
values for the average number of drug exposures from national statistics.
Possible biases in our ADR incidence that may have been caused by the
differences in length of stay or gender are estimated in the "Comment"
section.
Another possible
source of sampling bias might be the year of study, as our meta-analysis
spans 4 decades. Hence, we studied the relationship between ADR incidence
and year of study using a randomeffects linear regression model and found no
significant correlation for ADRIn (r=0.27, P=.14, n=18) or for ADRAd
(r=0.23, P=.34, n=21). The Figure shows these results graphically and
indicates that no change in ADR incidence occurred over the span of our
study. This result seems surprising since great changes have occurred over
the last 4 decades in US hospitals that should have affected the incidence
of ADRs. Perhaps, while length of hospital stay is decreasing,1 the number
of drugs per day may be rising to compensate. Therefore, while the actual
incidence of ADRs has not changed over the last 32 years, the pattern of
their occurrence has, undoubtedly, changed.
|
Table 3.
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Table 4.
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Table 5.
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It should be
noted that additional factors have been proposed to have an effect on ADR
rate: renal function, hepatic function, alcoholism, drug abuse, and severity
of illness.44,52 Unfortunately, these factors were rarely reported in our
sample of studies and, thus, could not be used to determine
representativeness.
Medical wards
are overrepresented in our database, and some articles in the literature
suggest that ward type might have an effect on ADR incidence.9,40,53,54
Unfortunately, there is insufficient power in the 39 studies to calculate
the incidence of ADRs for each ward type individually. Without these data,
we cannot determine the possible effect that ward-type distribution might
have on our ADR incidence. Nevertheless, in the "Comment" section, we
estimate the possible bias due to ward type.
Similar to ward
type, hospital type may also introduce bias into our results. It is thought
that teaching hospitals contain more seriously ill patients than nonteaching
hospitals, which may lead to a higher incidence of ADRs in teaching
hospitals, but this has never been proven.35,55 Teaching hospitals are
overrepresented in our sample. However, when we compared ADR incidences for
teaching and nonteaching hospitals in our study, we found no significant
differences. Thus, despite an overrepresentation of teaching hospitals in
our sample, there may not be a major bias.
Finally, our
letters to researchers in the field produced no evidence of publication
bias.
COMMENT
We have found
that serious ADRs are frequent and more so than generally recognized. Fatal
ADRs appear to be between the fourth and sixth leading cause of death. Their
incidence has remained stable over the last 30 years.
There has been
only one previous meta-analysis of ADR hospital studies,16 and it focused
only on ADRAd. Our article differs from this report in many respects: (1) we
studied incidence of ADRIn as well as ADRAd, (2) we combined ADRAd and ADRIn
to obtain the overall incidence of ADRs, (3) we gave special emphasis to
serious and fatal ADRs, (4) we improved the quality of the data by excluding
retrospective studies and by excluding ADRs that were classified as
"possible," (5) we examined the representativeness of our sample, and (6) we
estimated the total number of patients in US hospitals experiencing ADRs.
Recent studies
have focused on ADEs, which include errors in administration.920 One of the
goals of ADF, research is to alert physicians about the preventability of
many ADEs.20 In contrast, our study on ADRs, which excludes medication
errors, had a different objective: to show that there are a large number of
serious ADRs even when the drugs are properly prescribed and administered.
We found that a
high proportion of ADRs (76.2%) were type A reactions. This may suggest that
many ADRs are due to the use of drugs with unavoidably high toxicity. For
example, warfarin often results in bleeding. It has been shown that careful
drug monitoring in hospitals leads to a reduction of many of these ADRs,
suggesting that some type A and type B ADRs may be due to inadequate
monitoring of therapies and doses.5
Recent studies
have shown that the costs associated with ADRs may be very high. Research to
determine the hospital costs directly attributable to an ADR estimated that
ADRs may lead to an additional $1.56 to $4 billion in direct hospital costs
per year in the United States.57,58
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Heterogeneity
As outlined in
the "Methods" section, we dealt with heterogeneity in numerous ways. After
taking these measures, we examined the remaining heterogeneity. We
determined whether 4 factors thought to affect ADR incidence (age, gender,
drug exposure, and length of stay) contributed to the remaining
heterogeneity in our data using a linear regression version of the
random-effects model.l5 For ADR In, we found that number of drug exposures
and length of hospital stay jointly accounted for 43% of the variance
(r=0.65, P=.009, n=18). For the rate of ADRAd, when age was included in the
model, the variance was reduced by 27% (r=0.52, P=.04, n=14). Gender did not
contribute to the variance. Thus, a great deal of the heterogeneity could be
attributed to factors well known to affect ADR rates: number of drug
exposures per patient, length of hospital stay, and the age of patients.
This result indicates that much of the heterogeneity is due to variation in
the populations examined in the various articles and, hence, only a portion
of the variation could merely be attributed to inconsistent methods among
the individual studies. For example, if the different investigators use
different methods of ascertainment regarding what represents an ADR, they
will find different rates. Another example of inconsistent methodology is
the problem that some articles did not separate out administration errors.
Methodological variation such as this is a limitation of meta-analysis.
|
 |
|
|
Incidence of adverse drug reactions (ADRs) in 39 studies distributed
over 32 years. All 39 points are not visible as several are
superimposed on each other. Linear regression, using a
random-effects model, showed no significant correlation for either
those experiencing an ADR while in the hospital (ADRln) (r=0.27,
P=.14) or those admitted to the hospital due to an ADR (ADRAd)
(r=0.23, P=.34). |
Representativeness of Our Sample
In the "Results"
section, we found that for the 5 factors examined 3 were possible sources of
bias: length of stay, gender, and ward type. Thus, we have attempted to
estimate the size of the sampling bias due to these 3 factors as follows. As
seen in Table 5, we had a higher average length of hospital stay than the US
national average (10.6 days vs 7.6 days).Is While the literature
qualitatively reports a relationship between the incidence of ADR In and
length of stay,245,4 there are no quantitative estimates. Therefore, we
performed a linear regression analysis on our own data using a
random-effects model'5 regressing the incidence of ADRIn of all severities
on average length of stay to obtain a slope of 0.007 (P=.008) and deduced
that increasing the length of hospital stay from 7.6 to 10.6 days would
possibly cause the incidence of ADRIn of all severities to rise from the
adjusted value of 8.7% to our value of 10.9%.
Also, as shown
in Table 5, the proportion of female patients in our sample was lower than
the national average (50% vs 60%). Using several studies reporting an
increased incidence of ADRs among females, we were able to determine that,
at most, the risk ratio for women vs men could be as high as 1.5 for both
ADRIn and ADRAd. Assuming the worst-case scenario, the adjusted value for
the overall incidence of ADRs of all severities in the United States becomes
15.7% (95% CI, 12.7%-18.8%) compared with our value of 15.1% (95% CI,
12.0%-18.1%).
Finally, with
regard to ward type, there was insufficient power in 39 studies to determine
precisely the effect of ward-type discrepancies. Instead, we made a crude
determination of the worst-case scenario of ward bias. If we assumed (1)
that obstetrical wards have zero ADRs and (2) that we sampled zero
obstetrical patients, and, since there are about 4 million obstetrical ward
patients each year in the United States"9 of 33 million total hospital
admissions,ls then the total number of ADRs occurring in the United States
would be 4/33 lower than our estimates. Thus the overall number of fatal
ADRs in the United States would drop from 106 000 (95% CI, 76 000-137 000)
to 93 000 (95% CI, 67 000121000), which would make ADRs between the fourth
and seventh leading cause of death in the United States rather than between
the fourth and sixth leading cause as reported above. Regarding other ward
types, psychiatric wards tend to have a higher ADR incidence and pediatric
wards a lower ADR incidence than medical wards,53,54 so these 2 biases might
cancel out. Thus, altogether, there probably is a small net upward bias in
our ADR incidence due to our overrepresentation of medical wards.
It is important
to note that we have taken a conservative approach, and this keeps the ADR
estimates low by excluding errors in administration, overdose, drug abuse,
therapeutic failures, and possible ADRs. Hence, we are probably not
overestimating the incidence of ADRs despite the 3 small sampling biases
discussed earlier.
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CONCLUSIONS
Perhaps, our
most surprising result was the large number of fatal ADRs. We estimated that
in 1994 in the United States 106 000 (95% CI, 76 000-137 000) hospital
patients died from an ADR. Thus, we deduced that ADRs may rank from the
fourth to sixth leading cause of death. Even if the lower confidence limit
of 76 000 fatalities was used to be conservative, we estimated that ADRs
could still constitute the sixth leading cause of death in the United
States, after heart disease (743 460), cancer (529 904), stroke (150108),
pulmonary disease (101077), and accidents (90523); this would rank ADRs
ahead of pneumonia (75 719) and diabetes (53 894).ls Moreover, when we used
the mean value of 106 000 fatalities, we estimated that ADRs could rank
fourth, after heart disease, cancer, and stroke as a leading cause of death.
While our results must be viewed with some circumspection because of the
heterogeneity among the studies and small biases in the sample, these data
suggest that ADRs represent an important clinical issue.
This work was
supported by a grant (Dr Pomeranz) and a scholarship (Mr Lazarou) from the
National Science Engineering Research Council, Ottawa, Ontario.
J. L. Lazarou
did this work in partial fulfillment of his MSc degree at the University of
Toronto, Ontario; B. H. Pomeranz, MD, PhD, was the principal investigator;
and P. N. Corey, PhD, was the statistician who contributed to the
conception, design, analysis and interpretation of the data, and also
participated in writing the manuscript.
A complete
list of the 104 papers excluded from our meta-analysis is available on
request from the authors.
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From the Departments of
Zoology (Mr Lazarou and Dr Pomeranz), Physiology (Dr Pomeranz), and Public
Health Sciences (Dr Corey), University of Toronto, Toronto, Ontario
Reprints: Bruce H. Pomeranz, MD, PhD, Departments of Physiology and Zoology,
University of Toronto, 25 Harbord St, Toronto, Ontario, Canada MSS 3G5
(e-mail: pomeranz@zoo.utoronto.ca)
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Alexander DeLuca, M.D. 
