Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies.Lazarou J; Pomeranz BH; Corey PN Department of Zoology, University of Toronto, Ontario, Canada. From the Departments of Zoology (Mr Lazarou and Dr Pomeranz), Physiology (Dr Pomeranz), and Public Health Sciences (Dr Corey), University of Toronto, Toronto, Ontario. ---------------------------------------------------------------------------------------------------------------------- JAMA. 1998;279:1200-1205 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. METHODSDefinitions 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 Selection Criteria 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 Heterogeneity Data Extraction Analysis of ADR Incidence 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 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). RESULTSUsing 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. Incidence of ADRs Eight ADRIn articles included the proportion of type A (44) (dose-dependent ADRs) and type B (44) (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 Representativeness of Our Sample 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 random-effects 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). (* Figure 1*) 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, (51) 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.
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. COMMENTWe 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 Representativeness of Our Sample 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. CONCLUSIONSPerhaps, 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. ---------------------------------------------------------------------------------------------------------------------- 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). REFERENCES1. Gray J. Bill would force drug makers to give customers data on risks.
New York Times. July 25, 1996:A11. |
Page Tools:
What's New:
- Don’t allow yourself to be fooled by the agents of disinformation and confusion
- Stop Codex!
- Facts and Fiction About 2009 Swine Flu Pandemic
- Say NO to the Lisbon Treaty!
- Wiki-Rath
- Exposing the Agents of Disinformation
- The Ghosts of Auschwitz Have Arrived in Latin America
- Big Media: Not an Ally in the Campaign for Vitamin Freedom
- Interview with Paul Anthony Taylor
- The dam of the “business with the AIDS epidemic” is breaking
- Genocide Then and Now
- Swine Flu and Human Influenza – Questions and Answers