Jason Lazarou, MSc; Bruce H. Pomeranz, MD, PhD; Paul N. Corey, PhD
Objective: To estimate the incidence of serious and fatal adverse drug reactions (ADR) in hospital patients.
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 2216000 (1721000-2711000) hospitalized patients had serious ADRs and 106000 (76000-137000) 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.
From the Full-Text Article:
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,  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.  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. 
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 ]
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.  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 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.
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).18 While the literature qualitatively reports a relationship between the incidence of ADRIn and length of stay, [21, 45-46] there are no quantitative estimates. Therefore, we performed a linear regression analysis on our own data using a random-effects model  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 States59 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 106000 (95% CI, 76000-137000) to 93000 (95% CI, 67000-121000), 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.
Perhaps, our most surprising result was the large number of fatal ADRs. We estimated that in 1994 in the United States 106000 (95% CI, 76000-137000) 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 76000 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 (743460), cancer (529904), stroke (150108), pulmonary disease (101077), and accidents (90523); this would rank ADRs ahead of pneumonia (75719) and diabetes (53894).18 Moreover, when we used the mean value of 106000 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.