REVIEWARTICLE

Identifying high-risk medication: a systematic literature review

Eva A. Saedder & Birgitte Brock & Lars Peter Nielsen &

Dorthe K. Bonnerup & Marianne Lisby

Received: 14 January 2014 /Accepted: 4 March 2014 /Published online: 27 March 2014# Springer-Verlag Berlin Heidelberg 2014

AbstractPurpose A medication error (ME) is an error that causesdamage or poses a threat of harm to a patient. Several studieshave shown that only a minority of MEs actually causes harm,and this might explain why medication reviews at hospitaladmission reduce the number of MEs without showing aneffect on length of hospital stay, readmissions, or death. Thepurpose of this study was to define drugs that actually causeserious MEs. We conducted a literature search of medicationreviews and other preventive efforts.Methods A systematic search in PubMed, Embase, CochraneReviews, Psycinfo, and SweMed+ was performed. Danishdatabases containing published patient complaints, patientcompensation, and reported medication errors were alsosearched. Articles and case reports were included if theycontained information of an ME causing a serious adversereaction (AR) in a patient. Information concerning AR seri-ousness, causality, and preventability was required forinclusion.

Results This systematic literature review revealed that 47 %of all seriousMEs were caused by seven drugs or drug classes:methotrexate, warfarin, nonsteroidal anti-inflammatory drugs(NSAIDS), digoxin, opioids, acetylic salicylic acid, and beta-blockers; 30 drugs or drug classes caused 82 % of all seriousMEs. The top ten drugs involved in fatal events accounted for73 % of all drugs identified.Conclusion Increasing focus on seven drugs/drug classes canpotentially reduce hospitalizations, extended hospitalizations,disability, life-threatening conditions, and death by almost50 %.

Keywords Adverse reactions .Medication errors .

Medication review . High-risk drugs

Introduction

Throughout recent decades, there has been increasing atten-tion paid to polypharmacy and the risk of harm from medica-tion errors (ME). An ME can cause an adverse reaction (AR),which is defined as a noxious or unintended response toadministration of a medicinal product [1]. An AR, in contrastto an adverse event (AE), is characterized by the fact that acausal relationship between a medicinal product and an oc-currence is suspected [1]. In this study, a serious ME is onecaused by a serious AR. Definitions used in this study areshown in Table 1.

A systematic review from 2007 found that 46.5 % of AEswere judged to be preventable, i.e., they were classified asMEs, of which 16 % were related to prescription [4]. Theseriousness of the ME was not assessed. Another systematicreview from 2009 found 7 % of prescribing errors in hospi-talized patients, but the study was not able to assess theseverity of the errors due to the use of different definitionsof seriousness [5]. The proportion of serious (Table 1) MEs

Electronic supplementary material The online version of this article(doi:10.1007/s00228-014-1668-z) contains supplementary material,which is available to authorized users.

E. A. Saedder (*) : L. P. NielsenDepartment of Clinical Pharmacology, Aarhus University Hospital,Wilhelm Meyers Allé 4, 8000 Aarhus C, Denmarke-mail: ea@farm.au.dk

B. BrockDepartment of Biochemistry and Department of Biomedicine,Aarhus University Hospital, Aarhus, Denmark

D. K. BonnerupHospital Pharmacy, Aarhus University Hospital, Aarhus, Denmark

M. LisbyResearch Centre of Emergency Medicine, Aarhus UniversityHospital, Aarhus, Denmark

Eur J Clin Pharmacol (2014) 70:637–645DOI 10.1007/s00228-014-1668-z

with a known causal relationship to a prescribed drug is, to ourknowledge, not available; however, in general, <1 % of MEscause harm [6]. The low rate of harmful errors might explainwhy no effect has been shown from medication reviews inrelation to hospital admission and mortality. In one systematicreview, no effect of pharmacist-led medication reviews wasfound when assessing all-cause admission andmortality [4]. Arecent Cochrane Review of five randomized controlled trials(1,186 participants), did not find that medication review re-duces mortality or hospital admissions but might reduce emer-gency department (ED) contacts [7].

There is no internationally standardized way of performinga medication review, but many tools have been invented inorder to systematize performing such a review [8]. The firstauthor to suggest a tool to identify problematic medicationadministrationwas Beers in 1991 [9]. Other tools for assessingproblematic medication in elderly patients were created later.Examples are Inappropriate Prescribing in the Elderly Tool(IPET) [10], Medication Appropriateness Index (MAI) [11,12], Screening Tool of Older Persons’ Prescriptions (STOPP)[13], and Screening Tool to Alert Doctors to Right Treatment(START) [14]. The screening tools are primarily created fromthe consensus of experts. Criticism has been brought forwardthat the consensus of experts is not sufficiently evidencebased and that prescribing criteria needs to be based onevidence from the literature [15]. The interesting question iswhether or not medication review according to interven-tions with the different tools would result in a decline inserious ME incidence, rehospitalization, or overall healthcost if investigated prospectively. To our knowledge, thishas not yet been shown [16, 17].

We hypothesized that the reason for a lack of coherencebetween the performance of a medication review and an effecton clinically relevant endpoints is the lack of an evidence-based approach. A literature search is needed in order to definedrugs that have caused serious ARs in patients during theprescription phase because of MEs. We therefore aimed toperform a literature search in order to define problematic orhigh-risk drugs and to compile a list of high-risk drugs.

Materials and methods

Data sources

The literature search was performed in PubMed, Embase,Cochrane Systematic Reviews, and Psycinfo. We alsosearched the Swedish database SweMed+ (Fig. 1). A com-plete list of search terms is shown in Online Resource 1. Theliterature search was limited to full papers on human adults.No other limitations were used. The papers were cross-checked for additional references.

In addition, as a large proportion of MEs are never pub-lished, we searched patient complaints in the publicly availableNational Agency for Patients' Rights and Complaints (NAPRC)database [18]; the home page of The Patient Insurance Associ-ation (PIA) [19], which includes cases of awarded compensa-tion for drug-related injury; and the Danish Patient SafetyDatabase (DPSD) [20], which is a national reporting systemof AEs including MEs. Patients, relatives, and healthcare pro-fessionals are all invited to file a complaint or report an ME tothese three Danish databases. Healthcare professionals are evenrequired by law to do so when relevant. The systems are free tothe public and do not require the assistance of a lawyer. For thepurpose of guiding and teaching, patient reports from thesedatabases are made publicly available in an anonymous form.

Inclusion criteria

Papers or reports containing information about one or moreAR caused by an ME were included if: (1) the AR wasassessed as being serious according to the World HealthOrganization (WHO) criteria (Table 1) or the available infor-mation allowed a direct interpretation of the seriousness of theAR, and (2) the ME occurred during the prescribing or mon-itoring process. In addition, studies or reports from hospitals,emergency departments, nursing homes, and home care wereincluded given that the aforementioned criteria for seriousnessand ME were fulfilled (Table 1).

Exclusion criteria

ARs not caused by MEs were excluded. Additionally, sourcesaddressing ARs in children; those associated with anesthetics

Table 1 Definition of terms used in this analysis

Terminology Definition

Adverse reaction(AR)

An adverse reaction is a response to a medicinalproduct which is noxious and unintended; thisincludes adverse reactions which arise from:

• Use of a medicinal product within the terms of themarketing authorization

• Use outside the terms of the marketing authorization,including overdose, misuse, abuse and medicationerrors

• Occupational exposure [1, 2]

SeriousnessA serious adverse reaction corresponds to any untoward medical occurrence

that at any dose results in death, is life threatening, requires in-patienthospitalization or prolongation of existing hospitalization, results inpersistent or significant disability or incapacity, is a congenital anomaly/birth defect. [1, 2]

Medication error (ME)An error in the stages of the medication process—ordering, dispensing,administering, and monitoring the effect—causing harm or implyinga risk of harming the patient [3]

638 Eur J Clin Pharmacol (2014) 70:637–645

or drugs from outside the European market; and from interac-tions with food, alcohol, and herbal medicine were excluded.Finally, ARs caused by noncompliance and omission of use(e.g., a patient not treated with laxatives when in treatmentwith an opioid) were excluded.

Causality assessment

A causal relationship between ME and drug should beestablished. The most frequently used method is the Naranjoadverse drug reaction (ADR) probability scale [21] or criteriadeveloped byWulff [22]. For inclusion into our drug database,we required a causal relationship of at least a “possibly” basedon, e.g., Naranjo or categorization A, B, E, or F of Wulffcriteria.

Data extraction

Drugs that met selection criteria were entered into one data-base and the related sources into another database (MicrosoftOffice Access 2010). The drugs were sorted by the Anatom-ical Therapeutic Chemical (ATC) classification system [23].Information registered in the drug database was the genericname, number of patients involved, event, and seriousness.The source was entered into a second database comprisingpapers and reports with their complete citation, the purpose ofthe paper or report, the patient population, country of origin,and type of source information, e.g., case report. The list ofdrugs in the drug database was extracted into a list of high-riskdrugs. When drug classes were representative of an individualdrug, the individual drugs were replaced by drug class.

Results

After removing duplicates, 4,352 references were identified(Fig. 1). Titles/abstracts were screened, and full-text articleswere obtained for 585 references. Of these, only 74 referencesmet inclusion criteria. Another 61 references were obtainedfrom the PIA (three), the NAPRC (32), and the DPSD (26).The 61 patient cases are available from websites [18–20].

Overall characteristics

The 74 papers originated from Europe (34), USA (30),Africa (2), Australia (3), and New Zealand (3): 36 paperswere case reports of one or more cases, and the rest wereepidemiological studies. From the 135 references, 623 MEswere found in 507 patients. Of those 73 were MEs as aresult of methotrexate found in the US Food and DrugAdministration (FDA) Adverse Event Reporting System.Twenty-five of those MEs were fatal, four caused disabilitiesor birth defects, and 44 caused other serious outcomes; 39originated from prescribing [24]. However, it could not bedetermined whether these 39 prescribing errors were fatal orcaused disabilities, birth defects, or other serious outcomes.Therefore, all 73 errors were included, meaning that the 24fatal errors from methotrexate are included, even thoughsome of the fatal errors might have been due to administra-tion or dispensing errors. On the contrary, the number oftheophylline cases may have been much higher; however,problems in interpreting whether or not the errors wererelated to prescribing and interpreting the seriousness ofthe errors led to exclusion of some of these cases. Table 2

Fig. 1 Literature search

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shows the 10 most frequent drugs involved in fatal eventsand the 20 most frequent drugs involved in nonfatal events.

A total of 142/507 (28 %) of patients had a fatal ME. Lackof treatment was seen in 75/623 (12 %) events, lack ofmonitoring in 68 (11 %), and not considering reduced renal

function in 37 (6 %). MEs causing hospitalization constituted45 %. Prolonged hospitalization, disability, and life-threateningconditions represented a minority of the total number of MEs,whereas the noncategorized “serious” events accounted for17 % of the total number. In online resource (ESM) 2, all drugs

Table 2 Top ten fatal and top 20 nonfatal drugs

Fatal and nonfatal MEs

Top 10 of drugs causing fatal MEs

Drug top 10 Number (%) References Consumptiona DDD/1,000/24 h

Methotrexate 37 (26) DPSD annual reports 2008, NAPRC nos. 0127721, 1085807, [24–28] 3.3

Warfarin 13 (9) DPSD annual reports 2010, NAPRC nos. 0128301, 0873420, [29–34] 8.5

Opioids 9 (6) [29, 31, 35–37], NAPRC no 0657122 20.3

Digoxin 8 (6) NAPRC no. 0016212, [31, 38–43] 4.3

Theophylline 9 (6) [31, 34, 44, 45] 0.7

Other anticoagulants 7 (5) [34, 39, 46] 13.8

Acetylic salicylic acid 6 (4) [30, 31, 34, 47] 69.5

NSAID 6 (4) [30, 34, 47] 44.4

Beta-blockers 5 (4) [34, 37, 43, 48] 35.9

Antibiotics 4 (3) [27, 32, 35] 21.5

Total 104/142 (73)

Top 20 of drugs causing hospitalizations, prolonged hospitalizations, life-threatening condition, and disability due to MEs

Drug top 20 Number (%) References Consumptiona DDD/1,000inhabitants/24 h

Methotrexate 51 (11) NAPRC 0343401, DPSD 2009, [24, 27] 3.3

Theophylline 51 (11) [44, 45, 49, 50] 0.7

NSAID 39 (8) NAPRC nos. 0656411, 0553721, 0974223, 0867616. [40, 41, 43, 50–53],DPSD 2010

44.4

Opioids 32 (7) NAPRC nos. 0761608, 0872214, 0231802, 0337703, 0127805. [31, 36, 41,50, 51, 54–57]. DPSD 2007 and 2010.

20.3

Digoxin 28 (6) NAPRC nos. 1083928, 0445228, 0445802, 0658027. [43, 51, 52, 58–63].DPSD 2007 and 2010.

4.3

Acetylic salicylic acid 23 (5) [50, 52, 61, 64], NAPRC 0656411 69.5

Diuretics 22 (5) NAPRC 0867823. [40, 50, 51, 62, 65, 66] 110.7

Antiepileptics 17 (4) NAPRC 0765410. [51, 60, 66–70]. DPSD 2008 and 2010. 16.5

Beta-blockers 17 (4) [40, 50, 51, 64, 66, 71, 72] 35.9

Warfarin 17 (4) [40, 41, 43, 51, 52, 60, 61, 73–75]. DPSD 2005 and 2007. 8.5

Other anticoagulants 15 (3) NAPRC 0763020. [31, 39, 50, 51, 53, 64, 76, 77]. DPSD 2007 13.8

Potassium-sparing diuretics 14 (3) NAPRC 0658027. [30, 51, 59, 66] 7.4

Antibiotics 13 (3) [27, 46, 50, 51, 61, 64, 67, 69, 78]. DPSD 2007 21.5

Sulfonylureas 12 (3) [39, 51] 8.7

ACE inhibitors 11 (2) NAPRC 0658027. [51, 59, 66]. DPSD 2010 111.6

Glucocorticoids 11 (2) [41, 50, 51, 61]. DPSD 2010 13.5

Antipsychotics 10 (2) NAPRC nos. 0445410, 0761609, 0127805. [50, 51, 63, 69, 79].DPSD 2005. PIA 96–0301.

14.7

Calcium-channel blockers 9 (2) NAPRC 0444520. [51, 66, 71] 85.7

Insulin 7 (1) [50, 51, 64, 66, 72]. DPSD 2007 17.5

Antidepressants 7 (1) [42, 50, 51, 79, 80]. PIA 02–1899. 83.2

Total 406/481 (84)

AE adverse event, NSAIDs nonsteroidal anti-inflammatory drugs, DPSD Danish Patient Safety Database, NAPRC National Agency for Patients Rightsand Complaints, PIA Patient Insurance Associationa In 2012, from www.medstat.dk [81]

640 Eur J Clin Pharmacol (2014) 70:637–645

implicated in fatal MEs and their causes are shown. Methotrex-ate and warfarin were most frequently reported in the literatureand were also represented in the top 10 from public databases(data not shown).

The top 10 fatal drugs accounted for 73 % of all drugscausing fatal events. Likewise, the top 20 nonfatal drugsaccounted for 84 % of all drugs causing nonfatal eventsreported in the literature. Methotrexate, warfarin, NSAIDS,digoxin, opioids, acetylic salicylic acid, and beta-blockersare represented in the top 10 of both lists and comprise47 % of all serious MEs. In total, the two lists comprise23 different drugs or drug classes and represents 82 % ofall serious MEs.

We identified 144 drugs or drug classes that, in accordancewith the published literature, have caused seriousMEs. Table 3shows the final list of drugs and drug classes after removal ofindividual drugs, which are represented by drug class; themost rarely represented drugs; and drugs due to omission oftreatment (proton-pump inhibitors, levonorgestrel, nitrates,laxatives). Drugs not included in the final list are adenosine,levothyroxine, carbimazole, desmopressin, magnesium, i.v. iron,laxatives, levonorgestrel, naltrexone, natrium aurothiomalate(gold), colchicine, nitrates, proton-pump inhibitors, terbutaline,salbutamol, aminophylline, isocarboxazide, and sumatriptan.The 40 drugs or drug classes caused 572/623 (92 %) of allserious MEs and 131/142 (92 %) of fatal MEs found in theliterature (data not shown). In addition, we compared drugsincluded on our high-risk medication list with drugs foundon the STOPP list, Beers criteria, and IPET. Of the 40drugs or drug classes on our list, 17 can be found on theSTOPP list and 19 on Beers criteria. The overlap betweenour list of high-risk drugs, Beers criteria, and the STOPP listare benzodiazepines, tricyclic antidepressants (TCAs),calcium-channel blockers, and NSAIDs.

Discussion

This literature review revealed that 47 % of all serious MEswere caused by seven drugs or drug classes and that 30 drugsor drug classes caused 82 % of all serious MEs. Being awareof these seven drugs/drug classes—namely, warfarin, digoxin,opioids, methotrexate, beta-blockers, acetylic salicylic acid,and NSAIDs—can potentially reduce hospitalizations/prolonging of hospitalizations, disability, life-threatening con-ditions, and death by almost 50 %. The problems associatedwith these drugs are not unfamiliar to clinicians, and yet, MEsstill occur. Reported problems with methotrexate are stillfairly frequent in recent patient complaints, despite yearsof increased awareness in hospital settings. However, itremains unknown whether these problems have been re-duced over the years or whether the incidence of incorrectprescribing remains the same.

Winterstein et al., using a descriptive analysis of reportsfrom 1994 to 2000 in an AR database reported quite similarfindings to our study of the ten drugs causing 60 % of all MEs[82]. Seriousness criteria in their report were slightly differentfrom ours, as they included two other categories: a reactionthat required a change in drug therapy, and a reaction thatrequired additional therapeutic intervention. Their list com-prised the anticoagulants warfarin and heparin, as well asmorphine, meperidine, insulin, midazolam, digoxin, phenyto-in, cyclosporine, and promethazine. In spite of the differentseriousness criteria, their results align with ours.

A common problem for some drugs on our list as causingfatal events is a narrow therapeutic interval. These are definedas drugs in which a small difference in dose may lead to dose-dependent, serious therapeutic failures or ARs. This applies tomethotrexate, warfarin, digoxin, theophylline, and lithium.Moreover, methotrexate, digoxin, and lithium are excreted100 % though the kidneys and therefore require a stable renalfunction. Characteristics of both of these drugs are likely toincrease the risk of serious MEs.

Theophylline, the methylxanthine most frequently in use,is not recommended if inhaled long-acting bronchodilators areavailable and affordable, according to global chronic obstruc-tive pulmonary disease (COPD) guidelines [83]. In fact, the-ophylline is only recommended as treatment for asthma at-tacks if inhaled β2-agonists are not available, according to theglobal Pocket Guide for Asthma Management and Prevention[84]. Therefore, the clinical use of this drug has declined inrecent years, and cases involving theophylline is rarely seen inrecent patient complaints in Denmark, as opposed to metho-trexate. This indicates that drugs associated with a high risk ofcausing ARs must be abandoned whenever possible, as ac-tions to prevent serious MEs apparently change the frequencyof these ARs very little.

When comparing our list of high-risk drugs with theSTOPP list and Beers criteria, one must keep in mind thatthe two latter were developed with a focus on the agingpopulation, in contrast to our list, which includes events foundin the adult population. Considering the list compiled in ourstudy is based on the reporting of events and the two othertools were developed from expert statements, a major differ-ence could be that serious MEs in the aging population mightbe reported less frequently because they are misinterpreted ascomorbidities, which are more frequent in the elderly. In fact,the lists only have four drugs in common: benzodiazepines,TCA, calcium-channel blockers, and NSAIDs (Table 3).Drugs found on the STOPP list are antimuscarines,diphenoxylate, loperamide, prochlorperazine, proton-pumpinhibitors, anticholinergic drugs, estrogens, and first-generation antihistamines. Removing some of these drugs willmost likely improve overall patient well-being.

The fact that existing lists are not developed to catch ARs[85] may in part explain why several attempts to show that

Eur J Clin Pharmacol (2014) 70:637–645 641

medication review performed according to either list do notimpact clinical endpoints, such as hospitalization/prolongedhospitalization, persistent or significant disability, life-threatening condition, death, and overall health costs [7].Another likely explanation is the importance of monitoringpatients during treatment and using a rational choice of drugand dose. Each day, patients are hospitalized due to drugproblems, even though the drug prescribed was the right

drug and dose at the time of prescription. For example, apatient may be successfully treated with antihypertensivesand present normal blood pressures until the day the patientis dehydrated or febrile. Eleven percent of the serious MEsin this literature search were reported as being caused by alack of monitoring. The problem with monitoring has beenthoroughly discussed by Steinman et al. [86]. They con-clude that most efforts to reduce ARs and MEs have

Table 3 Drug classes or singledrugs most frequently causingserious medication errors (MEs)in the literature and comparisonwith drugs included in the STOPPcriteria, Beers criteria, and IPET

STOPP Screening Tool of OlderPerson’s Prescriptions, IPET In-appropriate Prescribing in theElderly Tool, NSAIDs nonsteroi-dal anti-inflammatory drugs,SSRI selective serotonin reup-take inhibitors, TCA tricyclicantidepressants, SNRI serotonin–norepinephrine reuptakeinhibitors

Drug/drug class STOPP [13](> 65 years)

Beers[9](> 65 years)

IPET [10](> 70 years)

Methotrexate

Warfarin X

Opioids X

Digoxin X X

Theophylline X

Low-molecular-weight heparins

Antithrombotics X X

NSAID X X X

Beta blockers X X

Other oral anticoagulants X

Thiazides X X

Antiepileptics X

Antimycotics

Potassium-sparing diuretics X

Oral antidiabetics Glibenclamide (X)

Drugs with effect on renin-angiotensin system

Glucocorticoids X X

Calcium-channel blockers X X X

Antipsychotics X X

Insulin X

SSRI X X

TCA X X X

Protease inhibitors

Nitrofurantoin X

Loop diuretics X

Antineoplastic agents X

Allopurinol

Amiodaron X

Metoclopramide X

Lithium

Benzodiazepines X X X

Potassium

Azathioprine

Alpha blockers X X

Statins

Paracetamol

SNRI

Sympathomimetics

Trimethoprim

642 Eur J Clin Pharmacol (2014) 70:637–645

focused on preventing errors at the time of prescribing,even though most ARs and MEs do not result from choos-ing improper drugs or drug doses but represent known drugside effects that occur during treatment.

The question is: What can the list of high-risk drugs beused for? It could be built into an algorithm in which eachdrug is assigned a score according to the level of risk to thepatient. The scores of the different drugs could then be addedinto a total score of risk to the patient. Furthermore, scorescould be integrated into an electronic system in order togenerate a computerized, automated total score for eachpatient based on the list of drugs that patient is taking,with a total score reflecting the degree of increased risk.Thus, a patient with a score above a certain limit could beoffered a clinically relevant intervention.

Strengths and weaknesses

There are some limitations to this work. We revealed thatthe number of fatal MEs constituted a large part of thetotal number of MEs (28 %). This is not surprising whenconsidering an expected publication bias. Fatal cases arereported more frequently than other cases and are mostlyfound in case reports. Further, cases with an expectedcausality between drug and AR are more likely to bereported than if the causality is less obvious. Because ofpublication bias, it is not possible to estimate frequenciesof MEs caused by different drugs, and there may be moredrugs that cause serious MEs than found by a literaturesearch. In other words, there is no numerator. Table 2shows the drug consumption in Denmark in 2012; thefrequency of serious MEs caused by some drugs is veryhigh compared to the frequency of use of those drugs, e.g.,methotrexate. Another limitation is that drugs that have beenon the market for many years will turn up a greater number oftimes despite a decline in clinical use compared with newerdrugs. This might falsely lead to the conclusion that old drugsare less safe than new drugs. An example is a second-generation antipsychotic, which might be as risky as compa-rable first-generation drugs, but serious MEs have not yetoccurred or been published. In our list of high-risk drugs, weattempted to take this into account by including drug classesrather than single drugs when relevant.

The search through patient complaints, awarded compen-sations for drug-related injury, and the National Reporting andLearning system has not, to our knowledge, been done before.However, as it is mainly severe cases that are available to thepublic, data cannot be considered complete. Further, it mustbe assumed that not all cases are reported, including lesssevere MEs. Additionally, some cases might have beenreported and published in more than one database. In mostinstances, however, the information was sufficient to con-clude that this was not the case.

The list of high-risk drugs developed from the literaturesearch depends on the original author’s interpretation of aserious ME. Assessments will presumably differ betweenevaluators, and in most cases, the original author’s interpreta-tion must be trusted, as the amount of information available inthe papers is too sparse to assess the evaluation. Anotherlimitation might be that cases reported as severe ARs andcaused by MEs but not classified as such were not includedin this study. However, when comparing our study to thereview by Salvi et al. [87], which included both ARs andMEs that specifically caused hospitalization, our list of drugsis in line with theirs. Those authors found that drugs respon-sible for hospitalizations due to all ARs, including MEs, werehematological agents, primarily warfarin and antiplateletagents; antidiabetic drugs, primarily insulin; cardiovasculardrugs, primarily diuretics; analgesic drugs, including primar-ily NSAIDS, but also opioids and paracetamol; and centralnervous system drugs, including benzodiazepines, antidepres-sants, antipsychotics, antiepileptics, and mood-stabilizingdrugs. Despite the fact that the study by Salvi et al. was limitedto hospitalizations and included ARs not caused byMEs, theirresults are surprisingly similar to ours, emphasizing that a fewdrugs appears to be responsible for the majority of ARs andMEs.

Conclusion

Ten drugs or drug classes caused two thirds (72 %) of all fatalevents, and seven of those drugs or drug classes caused half(47 %) of all serious MEs. The serious problems caused bythese drugs have apparently not changed over the years whencomparing older and newer references, despite of numerousefforts to improve the quality and safety of prescribing inrecent years (e.g., daily use of methotrexate instead of weekly).Applying our list of 40 drugs or drug classes to an algorithmthat allow determination of patients need for medicationreview, it could potentially predict nine of ten serious MEsand nine of ten fatal MEs. However, predicting problems is notnecessarily the same as avoiding them, and we are left with thisgreat challenge.

Conflict of interest and funding None.

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