previous reviews used more narrow criteria, considering exclu- sively inappropriate drug selection or dose [47] and unnecessary therapy [51] preventable. Thus, preventability due to other reasons, such as lack of monitoring or prescribing a prophylactic medication for an expected ADR, may have been overlooked in previous studies resulting in lower preventability estimates. In addition, 12 out of 16 articles on outpatients in our meta-analysis were published in the 21st century while all articles in the previous reviews on PADRs were published in the 20th century. Even though it may not be concluded from our results that the preventability of ADRs among outpatients would have increased over time, the increasing interest in and discussion on patient safety since the late 1990s’ [52] may have fostered acknowledging preventability in newer studies. The lack of other review studies on the percentage of outpatients with PADRs or the preventability of ADRs among inpatients hinders comparison to previous evidence. In one review on all drug-related adverse events, at median 4.3% of all admissions among outpatients were considered drug-related and preventable [11]. Their higher estimate compared to ours on PADRs exclusively (2%) was expected, as they included events beyond ADRs, such as therapeutic failures, drug intoxications and misuse. Among inpatients, previous reviews have found that the median preventability of all drug-related adverse events is 35% and 46% [6,12], ranging between 19% and 90% in individual studies. These are comparable to our estimate that 45% of ADRs are preventable among inpatients experiencing ADRs during hospital stay. Compared to previous reviews, our meta-analysis provides more consistent estimates on the preventability of ADRs and the proportion of patients with PADRs as our outcome measure is more standardised. Study implications This meta-analysis demonstrates that PADRs are a significant cause of morbidity among outpatients and that roughly half of all ADRs among adult outpatients and inpatients may be prevented. In the included articles resulting in these preventability estimates, a common criteria for preventability was ‘‘the drug event was due to a drug treatment procedure inconsistent with present-day knowledge of good medical practice or was clearly unrealistic, taking the known circumstances into account’’ [39]. Others considered ADRs preventable when they occurred due to contraindications, inappropriate dose or moni- toring, interactions, ignoring toxic serum drug concentrations or previous allergic reactions, or noncompliance [40]. ADRs occurring for these reasons need to be diminished to reduce the burden of ADRs, related costs [31,44], and unnecessary patient harm. Thus, effective intervention strategies and safety measures References 1. de Vries EN, Ramrattan MA, Smorenburg SM, Gouma DJ, Boermeester MA (2008) The incidence and nature of in-hospital adverse events: A systematic review. Qual Saf Health Care 17(3): 216–223. 10.1136/qshc. 2007.023622. 2. Lazarou J, Pomeranz BH, Corey PN (1998) Incidence of adverse drug reactions in hospitalized patients: A meta-analysis of prospective studies. JAMA 279(15): 1200–1205. 3. Muehlberger N, Schneeweiss S, Hasford J (1997) Adverse drug reaction monitoring--cost and benefit considerations. part I: Frequency of adverse drug reactions causing hospital admissions. Pharmacoepidemiol Drug Saf 6 Suppl 3: S71-7. 2-I. 4. Beijer HJ, de Blaey CJ (2002) Hospitalisations caused by adverse drug reactions (ADR): A meta-analysis of observational studies. Pharm World Sci 24(2): 46–54. 5. Kongkaew C, Noyce PR, Ashcroft DM (2008) Hospital admissions associated with adverse drug reactions: A systematic review of prospective observational studies. Ann Pharmacother 42(7): 1017–1025. 10.1345/aph.1L037. 6. Krahenbuhl-Melcher A, Schlienger R, Lampert M, Haschke M, Drewe J, et al. (2007) Drug-related problems in hospitals: A review of the recent literature. Drug Saf 30(5): 379–407. Preventable Adverse Drug Reactions – Meta-Analysis for preventing ADRs need to be incorporated into healthcare in system-level. As support for prevention strategies, such as medication reviews, to reduce medication-related harm is limited [53], further evidence on interventions to prevent ADRs and their implementation in healthcare is required. However, errors related to use of medications will to some extent always occur mainly due to the human imperfection in mental functioning and due to the complex nature of medical practice [54]. Our meta-analysis also highlights the lack of evidence on PADRs. Despite our thorough search strategy, we did not identify studies on PADRs occurring in primary care. Thus, our findings are likely to represent only the most serious PADRs among outpatients. Further, only two studies allowed estimating the percentage of inpatients with PADR, and the generated overall estimate was imprecise. Therefore, future research should investigate PADRs in the general population, especially among people without emergency visits or hospitalisation and among inpatients during hospital stay. As identified in previously [55,56], better consensus on defining and assessing preventability should also be reached to decrease heterogeneity between studies and enable more precise estimates in future meta-analyses. This meta-analysis corroborates that PADRs are a significant burden to healthcare among adult outpatients. Among both outpatients and inpatients, approximately half of all ADRs are preventable. Although preventability estimates vary across studies, our results demonstrate that further evidence on prevention strategies is required. The percentage of patients with PADRs among inpatients and in primary care is largely unknown and should be investigated in future research. Supporting Information Checklist S1 (DOC) Protocol S1 (DOC) Acknowledgments We thank the librarian of the Nordic School of Public Health, Susanne Tidblom-Kjellberger, for her advice in conducting the database searches. Author Contributions Conceived and designed the experiments: KH KMH MP SH. Performed the experiments: KH KMH MP SH. Analyzed the data: KMH MP. Contributed reagents/materials/analysis tools: KH KMH MP SH. Wrote the paper: KH KMH MP SH. 7. Leendertse AJ, Visser D, Egberts AC, van den Bemt PM (2010) The relationship between study characteristics and the prevalence of medication-related hospitalizations: A literature review and novel analysis. Drug Saf 33(3): 233–244. 10.2165/11319030-000000000-00000. 8. World Health Organization (2008) Fact sheet No293. Medicines: Safety of medicines – adverse drug reactions. Geneva: World Health Organization. 9. Rodriguez-Monguio R, Otero MJ, Rovira J (2003) Assessing the economic impact of adverse drug effects. Pharmacoeconomics 21(9): 623–650. 10. Goettler M, Schneeweiss S, Hasford J (1997) Adverse drug reaction monitoring-- cost and benefit considerations. part II: Cost and preventability of adverse drug reactions leading to hospital admission. Pharmacoepidemiol Drug Saf 6 Suppl 3: S79-90. pp 2-O. 11. Winterstein AG, Hatton RC, Gonzalez-Rothi R, Johns TE, Segal R (2002) Identifying clinically significant preventable adverse drug events through a hospital’s database of adverse drug reaction reports. Am J Health Syst Pharm 59(18): 1742–1749. 12. Kanjanarat P, Winterstein AG, Johns TE, Hatton RC, Gonzalez-Rothi R, et al. (2003) Nature of preventable adverse drug events in hospitals: A literature review. Am J Health Syst Pharm 60(17): 1750–1759. PLoS ONE | www.plosone.org 8 March 2012 | Volume 7 | Issue 3 | e33236