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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. (9,19,20) One of the goals of ADE 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. (56)
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)
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. (15) For ADRIn,
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 populati!
sis.
Representativeness of Our Sample
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 (59) of 33 million total hospital admissions, (18) 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, 67 000-121 000), 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.
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 (150 108), pulmonary disease (101 077), and accidents (90 523); this would rank ADRs ahead of pneumonia (75 719) and diabetes (53 894). (18) 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 particpated in writing the manuscript.
A complete list of the 104 papers excluded from our meta-analysis is available on request from the authors.
Reprints: Bruce H. Pomeranz, MD, PhD, Departments of Physiology and Zoology, University of Toronto, 25 Harbord St, Toronto, Ontario, Canada M5S 3G5 (e-mail: pomeranz@zoo.utoronto.ca).
