PHARMACOEPIDEMIOLOGYAND PRESCRIPTION

Potentially inappropriate medications and adverse drug reactionsin the elderly: a study in a PharmacoVigilance database

François Montastruc & Cannelle Duguet &Vanessa Rousseau & Haleh Bagheri &Jean-Louis Montastruc

Received: 18 April 2014 /Accepted: 5 June 2014# Springer-Verlag Berlin Heidelberg 2014

AbstractBackground Lists of potentially inappropriate medications(PIM) in the elderly were developed in order to identifypatients and/or drugs at risk of adverse drug reactions(ADRs) or inefficacy. However, the relationship betweenPIMs and ADRs remains discussed. We hypothesized thatPIM use is associated with more ADRs than otherprescriptions.Methods All ADRs registered by the Midi-PyrénéesPharmacoVigilance Center between the 1st January and the30th June 2012 in patients ≥75 years were included. Data onpatients (age, gender, Charlson comorbidity index), drugs(number, ATC classification, Laroche PIM classification)and ADRs (type, seriousness, mechanisms) were analyzed.Results Among the 923 ADRs recorded, 272 (29.5 %)were inpatients ≥75 years. Mean age was 83.5±5.5 years. Mostof them (59 %) were females. Mean Charlson index was5.6±2.0 by ADR report. These 272 prescriptions in-volved 1,775 drugs [mean value, 6.5 (±3.4) drugs byADR report] with 129 (7.3 %) PIM. Main PIM classeswere nervous (n=98, 76.0 %) and cardiovascular(17.8 %) drugs, including 32 atropinics (23.4 %).ADR-associated drugs were mainly antithrombotics, an-tibacterials, and analgesics for non-PIM drugs whereasPIM-associated ADRs were mainly observed withdigoxine, psycholeptics, and psychoanaleptics. ADRswere mainly found with non-PIM drugs (89.3 %).

Associated factors were the number of drugs for PIMsand the number of PIMs for PIM-induced ADRs.Conclusion Out of the ADR reports registered in the Midi-Pyrénées PharmacoVigilance Database for patients ≥75 years,1 drug out of 12 is potentially inappropriate (mainly benzodi-azepines, imipraminic antidepressants, and atropinic drugs).PIM use is not associated with more ADRs’ reports than otherprescriptions.

Keywords Adverse drug reactions . Drugs .

Neuropsychotropics

Introduction

Elderly patients often suffer from several chronic dis-eases and are consequently taking multiple drugs. Ageis associated to important modifications to drug re-sponses leading to susceptibility to drugs [1, 2]. Druginteractions and adverse drugs reactions (ADRs) arefrequent in the elderly [3, 4]. Thus, it was importantto develop tools to optimize quality of drug prescriptionin elderly. Beers proposed in 1991 a first list of poten-tially inappropriate medications (PIM) [5]. Other lists,adapted to different countries and kinds of practices,were developed [6–13]. They defined a PIM as a drug“with an unfavorable benefit-to-risk ratio when safer orequally effective alternatives are available” [10]. One ofthe objectives of PIM lists was to reduce ADRs’ fre-quency, although their interest for this objective remainsdiscussed. The present study investigated such a rela-tionship in a pharmacovigilance database and hypothe-sized that PIM use is associated with more ADRs’reports than other prescriptions.

F. Montastruc : C. Duguet :V. Rousseau :H. Bagheri :J.<L. Montastruc (*)Laboratoire de Pharmacologie Médicale et Clinique, Equipe dePharmacoépidémiologie de l’UMR INSERM 1027, CentreMidi-Pyrénées de Pharmacovigilance, de Pharmacoépidémiologie etd’Informations sur le Médicament, Centre Hospitalier Universitaireet Faculté de Médecine de l’Université de Toulouse, 37 alléesJules-Guesde, 31000 Toulouse, Francee-mail: jean-louis.montastruc@univ-tlse3.fr

Eur J Clin PharmacolDOI 10.1007/s00228-014-1707-9

Methods

The French Pharmacovigilance System was first establishedin 1973. The reporting of “serious” or “unlabelled” ADRs hasbeen compulsory in France since 1984. For each ADR report,informations about patient, ADR and drug exposure are re-corded in the French PharmacoVigilance Database (see [14,15] for more description). All ADRs registered in Midi-Pyrénées area (South Western France, 3 million inhabitants)between the 1st January and the 30th June 2012 in patients≥75 years were included. Charlson comorbidity index [16]and classification of PIM (including atropinic drugs) accord-ing to Laroche [10] were also analyzed. Statistical analysiswas first descriptive and second analytic to investigate asso-ciated factors to PIMs (i.e., reports with at least one PIMversus reports without PIM) and PIM-induced ADRs (yesversus no). Chi-square test was used for comparison of twoqualitative variables and Z test for comparison of quantitativeand qualitative variables.

Results

PIMs

Description

Among the 923 ADRs recorded during the 6 months, 272(29.5 %) were reported in patients ≥75 years (77 “serious”).Mean age of these 272 patients was 83.5±5.5 years (75–102).Most of them (59 %) were females. Mean Charlson index was5.6±2.0 (3–15) by ADR report. These 272 prescriptions in-volved 1,775 drugs [mean value: 6.5 (±3.4) drugs by ADRreport] with 129 (7.3 %) PIM (Table 1). These PIM included

32 drugs with principal or lateral atropinic properties (24.8 %out of the total of PIMs).

Following drug classification as inappropriate according toLaroche [10] into three subgroups (three main causes), 69were defined as a “benefit-to-risk ratio unfavourable”, 5 witha “questionable efficacy”, and 77 with “both an unfavourablebenefit-to-risk ratio and a questionable efficacy” (total >100%with some PIMs related to several groups). Simultaneous useof drugs with atropinic properties was found in seven cases,simultaneous use of two or more psychotropic drugs from thesame therapeutic class in 34 cases, and association of anticho-linesterase plus atropinic drugs in three reports.

Associated factors

Table 2 describes associated factors in reports with at least onePIM and those without PIM. The unique factor associated toPIM was the number of drugs (Z test, p<0.0003): this meansthat reports with at least one PIM showed more drugs ingeneral than reports without PIM. In contrast, there was noassociation between PIM and age (Z test, p=0.05), gender(Chi-square test, p=0.36) or Charlson index (Z test, p=0.35).

ADRs

Description

Among the 272 notifications, 486 different ADRs were re-ported (mean value 1.8±1.1 ADR, 1–8). Among them, 385(79.2 %) were “serious”, including 310 (64 %) prolongationsof hospitalization and 26 (5.3 %) deaths (at least partly relatedto the ADR). The most frequent ADRs were increased INR(n=27; 9.9 %), anemia (n=22; 8.1 %), hematoma (n=19;7.0 %), acute renal failure (n=11; 4.0 %), cutaneous eruption

Table 1 ATC (Anatomical Therapeutic Chemical) Classification of the 129 PIMs (potentially inappropriate medications) found in the 272 ADRs’reported in the Midi-Pyrénées PharmacoVigilance database between the 1st January and the 30th June 2012 in patients ≥75 years

ATC drug classification of PIM Number of drugs Percentage of total PIM (%) ATC subgroups of PIM n (%)

N Nervous 98 76.0 N03 antiepileptics n=3 (2.3 %)

N02 analgesics n=2 (1.6 %)

N05 psycholeptics n=71 (55.0 %)

N06 psychoanaleptics n=22 (17.0 %)

C Cardiovascular 23 17.8 C01 cardiac therapy (digoxin) n=9 (7.0 %)

C02 antihypertensives n=4 (3.1 %)

C04 peripheral vasodilators n=2 (1.6 %)

C08 calcium channel inhibitors n=8 (6.2 %)

M Musculo skeletal 3 2.3 M04 antigouts 3 (2.3 %)

G Genito urinary 2 1.6 G04 urologicals n=2 (1.6 %)

J Antiinfectious 2 1.6 J01 systemic antibacterials n=2 (1.6 %)

A Alimentary tract and metabolism 1 0.8 A03 drugs for functional gastrointestinal disorders n=1 (0.8 %)

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and hyponatremia (n=9 each; 3.3 %), falls, melena, andvomiting (n=8 each; 2.9 %).

ADRs related to PIMs (i.e., ADRs where PIMs were“suspected”) were found in only 29 reports (10.6 %), includ-ing 18 “serious”ADRs (62.0%). These 29 reports included 55PIMs, i.e., 27 with cardiovascular drugs (49.1 %), 24 withneuropsychotropics [43.6 %, including psycholeptics (24.5 %,i.e., benzodiazepines) and psychoanaleptics (19.1 %, i.e. an-tidepressants)], 2 with musculo-skeletal drugs (3.6 %) and 2with antiinfectious (3.6 %).

ADR-associated drugs were mainly antithrombotics(26.5 % out of the total of ADRs), antibacterials (13.6 %),and analgesics (6.7 %) for non-PIMs, and digoxine (3.0 %),psycholeptics (2.0%), and psychoanaleptics (1.5%) for PIMs.

Associated factors

Table 2 describes the associated factors in ADR reports: first,those induced by PIM and second, those not induced by PIMs.Only one factor was associated to PIM-induced ADRs: thenumber of PIMs (Z test, p<0.0001) [but not age (Z test, p=0.23) or the total number of drugs received (Z test, p=0.40)].

Discussion

The present study was performed in order to, first, describeADRs related to PIM in a Pharmacovigilance database and,secondly, to investigate if PIM use was associated with moreADRs’ reports than other prescriptions. We found a relativelylow percentage of PIMs (7.3 %), the most frequently beingbenzodiazepines, imipraminics, and antidepressants.Moreover, 23.4 % of PIM were atropinics. PIM-associatedADRs were mainly observed with digoxine, psycholeptics,and psychoanaleptics. PIM were not associated with moreADRs’ reports than other drugs.

Several points need to be discussed. First, PIM use waslargely studied in several conditions, including Alzheimer’sdisease [7, 9, 12, 17] or prescriptions delivered in a

community pharmacy [18]. None study studied PIM prescrip-tion in a pharmacovigilance database, built to record sponta-neous ADRs’ notifications. ADRs differed between PIM andother drugs. ADRs associated to PIM were mainly observedwith digoxine, benzodiazepines, and imipraminic antidepres-sants. In contrast, antithrombotics, antibacterials, and analge-sics were involved in ADRs for other drugs. This is in accor-dance with large pharmacoepidemiological studies performedin France where anticoagulants and nonsteroidal anti-inflammatory drugs were the main drugs involved in hospi-talizations for ADRs [19, 20].

The second interesting point is the investigation of PIM-associated factors. Few studies have investigated this point.PIM use was not associated with age, gender, or severity of thedisease (Charlson index). The sole factor related to PIM was thenumber of drugs. This finding agrees with the classical notionthatmore the number of drugs prescribed is high,more importantis the risk of inadequate prescriptions [21, 22]. Age and the totalnumber of drugs received were not associated to ADRs.

In contrast, the number of PIM was associated to PIM-induced ADRs, suggesting that more elevated is the numberof PIM, more marked is the risk of ADRs. This association isdiscussed in the literature. Lindley [23] found that out ofadmissions in a teaching hospital attributed to ADRs, 50 %were due to PIMs, and concluded that much drug-relatedmorbidity in the elderly population may be avoidable.Among 236 patients ≥65 years, Lund [24] described an inap-propriate prescribing in 98.7 %, using the medication appro-priateness index, a predictor of ADRs. In contrast, Laroche[25], in patients ≥70 years admitted to an acute medicalgeriatric unit, found that the number of drugs was higher inpatients suffering from ADRs but was unable to describe anassociation between PIM and ADRs. Budnitz [26], investigat-ing the National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project(2007–2009) concluded that only 1.2 % of hospitalizationswere related to high-risk medications. More recently, anassociation between PIM (according to Beers) and therisk of unplanned hospitalization was described in el-derly patients [27].

Table 2 Description of the associated factors

Total (N=272) PIM PIM-induced ADRs

Reports with at least one(N=96)

Reports without(N=176)

Yes(N=29)

No(N=243)

Age, mean (SD) 83.5 (5.5) 84.3 (5.6) 83.0 (5.4) 84.6 (5.6) 83.3 (5.5)

Gender, female, n (%) 160 (58.8) 60 (62.5) 100 (56.8) 17 (58.6) 143 (58.8)

Charlson comorbidity index adjusted on age,mean (SD)

5.6 (2.0) 5.5 (1.9) 5.7 (2.0) 5.3 (1.4) 5.7 (2.0)

Number of drugs by ADR report, mean (SD) 6.5 (3.4) 7.5 (3.4) 5.9 (3.2) 7.0 (3.5) 6.5 (3.4)

Number of PMIs by ADR report, mean (SD) 1.5 (0.9) – – 1.6 (0.7) 0.4 (0.7)

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Finally, the main result of our work is that most of theADRs reported are not related to PIM, suggesting that PIMlists can be only one of the means to reduce ADR occurrencein elderly people.

Our work suffers from somemethodological drawbacks, asmost pharmacovigilance studies dealing with spontaneousnotifications. This work included data coming from sponta-neous notifications. It did not describe exhaustively all PIMoccurred Midi-Pyrénées area, but only those reported.Underreporting is well known in pharmacovigilance surveys[28]. Estimation could be also biased according to severalfactors, one of the most important being the “seriousness” ofADR. Moreover, it is known that a “serious” and/or“unlabelled” ADR occurring with a new drug is more likelyto be reported than another kind of ADR [14]. However, thegoal of our study was not to record exhaustively all PIM-related ADRs, but to describe the characteristics of thoseincluding PIM and declared to a PharmacoVigilance Center.

In conclusion, out of the ADR reports registered in theMidi-Pyrénées PharmacoVigilance Database for patients≥75 years, around 1 drug out of 12 is potentially inappropriate(mainly benzodiazepines, imipraminic antidepressants, andatropinic drugs). Most of ADRs reported in the database arerelated to non-PIM drugs, since PIMs are associated with only1 ADR out of 10. PIM use is not associated with more ADRs’reports than other prescriptions.

Conflict of interest None

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