Definitions
One step we took to reduce heterogeneity was to exclude any data that did not use the following specific definitions:
Data Sources.- Four electronic databases were searched from 1966 to 1996.
Study Selection.- Of 153, we selected 39 prospective studies from US hospitals.
Data Extraction.- Data extracted independently by 2 investigators were analyzed by a random-effects model. To obtain the overall incidence of ADRs in hospitalized patients, we combined the incidence of ADRs occurring while in the hospital plus the incidence of ADRs causing admission to hospital. We excluded errors in drug administration, noncompliance, overdose, drug abuse, therapeutic failures, and possible ADRs. Serious ADRs were defined as those that required hospitalization, were permanently disabling, or resulted in death.
Data Synthesis.- The overall incidence of serious ADRs was 6.7% (95% confidence interval [CI], 5.2%-8.2%) and of fatal ADRs was 0.32% (95% CI, 0.23%-0.41%) of hospitalized patients. We estimated that in 1994 overall 2 216 000 (1 721 000-2 711 000) hospitalized patients had serious ADRs and 106 000 (76 000-137 000) had fatal ADRs, making these reactions between the fourth and sixth leading cause of death.
Conclusions.- The incidence of serious and fatal ADRs in US hospitals was found to be extremely high. While our results must be viewed with circumspection because of heterogeneity among studies and small biases in the samples, these data nevertheless suggest that ADRs represent an important clinical issue.
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. (1) 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. (3-5) 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, (8) 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. (10) 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 (1970-1996), and Science Citation Index (1989-1996). 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.
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, (11) we chose instead to improve the quality of our database. First, we used prospective monitoring as an inclusion criterion to exclude the lowest-quality studies (ie, the retrospective studies). Second, ADRs classified as "possible" were excluded. Attributing causality is always a problem with ADR detection (12) 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, (13) (2) we used a random-effects model to do the analysis because it takes into account the heterogeneity of the various studies, (13,14) (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 correla!
tion coefficient ranging from 0.89 to 0.92).
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 (15) 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 xIncidence 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 2 216 000 (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. (17) 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. (18) 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)xNumber 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 (* Table 1*) and(* Table 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.
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Number of Hospital Patients With ADRs
As shown in (* Table 4*), we estimated that 702 000 (95% CI, 635 000-770 000) hospital patients in the United States experienced a serious ADRIn in 1994. We calculated that 1 547 000 (95% CI, 1 033 000-2 060 000) hospital patients experienced a serious ADRAd. Combining these values, overall 2 216 000 (95% CI, 1 721 000-2 711 000) hospital patients experienced a serious ADR in the United States in 1994. We calculated that there were 63 000 (95% CI, 41 000-85 000) fatalities due to ADRIn and another 43 000 (95% CI, 15 000-71 000) 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 (106 000) 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.
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