Eur J Clin Pharmacol (2007) 63:725–731 DOI 10.1007/s00228-007-0324-2

SPECIAL ARTICLE

Potentially inappropriate in the elderly: a French consensus panel list

Marie-Laure Laroche & Jean-Pierre Charmes & Louis Merle

Received: 15 February 2007 /Accepted: 9 May 2007 / Published online: 7 June 2007 # Springer-Verlag 2007

Abstract Results The final list proposed 36 criteria applicable to Objective To evaluate drug-related problems in the elderly, people≥75 years of age. Twenty-nine medications or various lists of potentially inappropriate medications have classes applied to all patients, and five criteria been published in North America. Unfortunately, these lists involved medications that should be avoided in specific are hardly applicable in France. The purpose of this study medical conditions. Twenty-five medications or medication was to establish a list of inappropriate medications for classes were considered with an unfavourable benefit/risk French elderly using the Delphi method. ratio, one with a questionable efficacy and eight with both Method A two-round Delphi method was used to converge unfavourable benefit/risk ratio and questionable efficacy. to an agreement between a pool of 15 experts from various Conclusion This expert consensus should provide prescrib- parts of France and from different backgrounds (five ers with an epidemiological tool, a guideline and a list of geriatricians, five pharmacologists, two pharmacists, two alternative therapies. general practitioners, one pharmacoepidemiologist). In round one, they were sent a questionnaire based on a literature review listing medications and clinical situations. Keywords Inappropriate medications . Elderly . They were asked to comment on the potential inappropri- Delphi method . France ateness of the criteria proposed using a 5-point Likert scale (from strong agreement to strong disagreement) and to Abbreviations suggest therapeutic alternatives and new criteria. In round NSAID nonsteroidal antiinflammatory drug two, the experts confirmed or cancelled their previous SNRI and noradrenaline reuptake inhibitor answers from the synthesis of the responses of round one. SSRI selective serotonin reuptake inhibitor After round two, a final list of potentially inappropriate IMs inappropriate medications drugs was established.

Introduction : M.-L. Laroche L. Merle (*) Drug-related problems are a major public health issue, Department of Pharmacology-Toxicology, especially as many adverse drug reactions are considered Centre of Pharmacovigilance, University Hospital Dupuytren, 87042 Limoges, France preventable. Among these adverse effects, those linked to e-mail: [email protected] unsuitable medications are of particular interest. These M.-L. Laroche drugs named IMs have an unfavourable benefit-to-risk ratio e-mail: [email protected] when safer or equally effective alternatives are available. Therefore, IMs appear as a risk factor for preventable drug- J.-P. Charmes related illnesses. Identifying these medications is of Department of Geriatrics, Hospital Rebeyrol, 87042 Limoges, France paramount importance when treating the elderly, who often e-mail: [email protected] receive many drugs. 726 Eur J Clin Pharmacol (2007) 63:725–731

A way to establish a list of IMs in the elderly is the use of Methods an expert consensus to develop explicit criteria when clinical information is lacking. Explicit criteria have already been The Delphi method, developed by the Rand Corporation in proposed in the United States and Canada. In 1991, Beers the 1950s, is a research method allowing a consensus et al. developed the first list of criteria for determining IM use opinion to be reached among experts, using questionnaires, in nursing home residents [1]. In 1997, this criteria list was through an iterative process known as rounds [10]. We used expanded so as to include drugs whose risk may outweigh two rounds in our study. The responses from the first round their benefit in all patients older than 65 years, whatever were collected and analysed; a revised questionnaire based their dwelling place [2]. A last updating of the Beers criteria on the results of this analysis was then submitted to the was published by Fick et al. in 2003 [3]. In Canada, McLeod same experts to converge to an agreement from the average et al. proposed another IM list because of a disagreement responses. with some medications identified by Beers [4]. The Canadian The study was organised in six phases: (a) creation of the explicit criteria identified medications in the context of preliminary questionnaire of IMs from a literature review, drug–drug and drug–disease interactions. In these various (b) recruitment of the experts, (c) mailing of the round-one cases, the explicit criteria were obtained through a literature questionnaire, (d) analysis of the answers and creation of the review and a questionnaire evaluated by national experts new questionnaire, (e) mailing of this round-two question- involved in geriatric care, clinical pharmacology, psycho- naire based on round-one synthesis and (f) final analysis. pharmacology, clinical pharmacy and ambulatory care. A preliminary questionnaire about IM in the elderly was These North American criteria are not adapted to the constructed from the Beers lists (1991, 1997, 2003), the European situation. Availability of drugs, clinical practice, Canadian criteria (1997), the criteria adapted to French socioeconomic levels and health system regulations are practice (2001), and the guidelines of the French Medicine different from those prevailing in the United States and Agency (Agence Française de Sécurité Sanitaire des Canada and are even different between European countries Produits de Santé, AFFSaPS) on medication prescribing in [5, 6]. Nevertheless, we think the discrepancies between the elderly (June 2005) [1–3, 4, 7, 11]. The questionnaire European countries are smaller than those that can be was composed of criteria that covered two categories: (a) identified when comparing North American and European medications or medication classes that should generally be practices. To our knowledge, up to now, no criteria for IMs avoided in the elderly as being either ineffective or prone to have been developed for European countries. induce a risk when a safer alternative is available and (b) In France, an IM list derived from the 1997 Beers criteria medications that should be avoided in specific medical was elaborated in 2001 by nine French experts (five geri- conditions. atricians, four pharmacologists) and used in three studies Fifteen experts were invited to participate. The panel was [7–9]. Most of the Beers criteria were included in this list, composed of five pharmacologists, one pharmacoepidemi- except drugs not available in France, drugs necessitating ologist, five geriatricians, two pharmacists (one from dose information and drugs that should not be used in the hospital and one from community practice) and two general elderly under specific medical conditions. Three criteria practitioners with clinical geriatric qualification (one from were added: concomitant use of two (or more) nonsteroidal urban and one from rural areas). They were all selected anti-inflammatory drugs, concomitant use of two (or more) from different geographic parts of France. All the experts psychotropic drugs from the same therapeutic class and use accepted and participated in all the rounds of the study. of any medications with properties other In April 2006, the round-one questionnaire was sent to than those listed by Beers. This list has some limits: lack the panel of experts together with information on how to fill of a consensus method, exclusion of some criteria (dose, in the forms. This preliminary questionnaire included 37 drugs in specific medical conditions), obsolescence of the criteria: 30 drugs or drug therapeutic classes independently list as a consequence of marketing and removal of drugs from the diagnoses and seven criteria linked to specific from the pharmaceutical market since 2001. Therefore, this medical conditions. Each criterion was to be evaluated by list is hardly usable in other pharmacoepidemiological the experts using a 5-point Likert scale [12]; a score of 1 studies or in public health intervention for minimising meant a strong agreement on the inappropriateness, 3 meant drug-related problems. Besides, none of these lists (neither an equivocal opinion and 5 meant a strong disagreement North American nor that presently used in France) about inappropriateness. Experts were also invited to suggest suggested any alternative drugs to replace inappropriate safer alternative therapeutics and to add other criteria. medications. The responses were used to create the second question- The aim of this study was to establish a list of IMs for naire. Items with a median score of 1 or 2 were retained in the French elderly population using the Delphi method and the IM list; items with a median score of 4 or 5 were ex- to propose safer, effective alternatives. cluded from the list. Items with a median score of 3 were Eur J Clin Pharmacol (2007) 63:725–731 727 resubmitted. A synthesis was elaborated, based on the ourable benefit-to-risk ratio and a questionable efficacy experts’ arguments and on the criteria suggested and then (Table 1). sent to the experts as round-two questionnaire. In August 2006, the round-two questionnaire was sent to the panel of experts. This second questionnaire also Discussion included a synthetic table grouping the results of round- one scores, enabling the experts to compare their answers to We propose a list of explicit criteria for identifying the those of the members of their expert panel. The new criteria potentially IM use in the population 75 years of age and older and the criteria necessitating a consensus were evaluated in France. These criteria were identified from conditions with the same 5-point Likert scale. Experts confirmed the with, (a) an unfavourable benefit to risk ratio, (b) a ques- proposed therapeutic alternatives and indicated the reasons tionable efficacy or (c) an unfavourable benefit-to-risk ratio of criteria inappropriateness: (a) unfavourable benefit-to- together with a questionable efficacy. Safer therapeutic risk ratio, (b) questionable efficacy and (c) unfavourable alternatives were also indicated for each criterion. benefit-to-risk ratio and questionable efficacy. At the end of This first French list of potentially IMs, based on a the last round, a final list of inappropriate drugs was consensus of experts, regrouped the opinion of practitioners retained. In this second round, experts also indicated from commonly involved in the management of drugs given to what age this list of IMs could be applied. elderly people. The geographical dispersion and the various practice modes give a large overview of medical and pharmaceutical practices in France. The French experts Results considered that the list could be applicable in the the population aged 75 years and older, as from this age on, The expert panel considered this list was applicable to pharmacokinetic and pharmacodynamic changes are signif- people 75 years of age and older. Younger elderly patients icant enough to markedly alter the response to medications were considered as quite similar to middle-aged adults. [13]. The French list of potential IMs proposed here retains In the first round, 37 criteria were submitted to the panel some of the Beers criteria. Several drugs or therapeutic drug of experts. Thirty criteria were considered by these experts classes were not selected, as they are not available on the as inappropriate in the elderly (median score: 1 or 2). One French market (pentazocine, , fluraze- criterion was not selected: (median score: 4). pam, meperidine, oorphenadrine, guanadrel, , For six criteria, no consensus was obtained, so they were to , , , ethacrynic acid, be submitted again during the second round of evaluation desiccated thyroid) or are no longer available, as they are (dextropropoxyphene-paracetamol, , long-term judged harmful and ineffective, such as (except prescription of NSAIDs, long-term prescription of NSAIDs ). Several criteria were not considered for the for patients with a history of hypertension, long-term consensus, as they differed from common medical practi- prescription of NSAIDs for patients with a history of renal ces: unopposed estrogens, for instance, are not prescribed in failure and antispasmodic drugs with anticholinergic prop- France without association with in the erties). Three criteria were proposed by the experts treatment of menopause. Phenylbutazone, dropped from (association of drugs with anticholinergic properties, con- the 2003 Beers list, was integrated in the French list comitant use of drugs with anticholinergic properties because of the serious haematological effects it could together with anticholinesterase drugs and myorelaxants induce. Among the criteria added in the 2003 Beers list, with anticholinergic properties). two drugs were not judged as inappropriate by French After the issue of the second round of evaluation, among experts: fluoxetine, which was not considered as more 39 criteria, five were definitely eliminated by the French prone to induce problems than any other selective serotonin experts (dextropropoxyphene-paracetamol, fluoxetine, reuptake inhibitor, and amiodarone, which was judged as long-term prescription of NSAIDs, long-term prescription effective and as susceptible to inducing adverse effects as of NSAIDs for patients with a history of hypertension and do the other available antiarrhythmics [14]. Conversely, the long-term prescription of NSAIDs for patients with a French experts, like their North American counterparts, history of renal failure). The final list contained 34 criteria: considered nitrofurantoin, short-acting and stim- 29 medications or medication classes to be used in all older ulant laxatives as inappropriate in the elderly. Lastly, the people and five criteria related to medications that should obtained consensus allowed confirmation of criteria added be avoided in specific medical conditions (Table 1). Among in the previous list and adapted to French practice: these 34 criteria, 25 were considered inappropriate as their concomitant use of two (or more) nonsteroidal anti- benefit-to-risk ratio was unfavourable, 1 was considered inflammatory drugs, concomitant use of two (or more) with questionable efficacy and eight with both an unfav- psychotropic drugs from the same therapeutic class and use 728 Table 1 Final list of potentially inappropriate medications (IMs) for the French population 75 years of age and older

Criteria Reasons Alternative drugs

Unfavourable benefit/risk ratio Analgesics 1 Indomethacin Severe CNS adverse effects. Second-choice drug NSAIDs except phenylbutazone 2 Phenylbutazone Severe haematological adverse effects. To be avoided NSAIDs except indomethacin 3 Concomitant use 2 or more NSAIDs No enhancement of efficacy, albeit increase of adverse effect risk Use only one NSAID Drugs with anticholinergic properties 4 Anticholinergic : , , Muscarinic-blocking agents with cardiotoxicity when overdosed. SSRIs, SNRIs , , , , , at times more active than SSRIs, but their benefit/risk ratio is less favourable in the elderly. Second-choice drugs 5 drugs: , , propericiazine, Muscarinic-blocking drugs. Second choice drugs Atypical with less , , , anticholinergic activity (, , , , ), meprobamate 6 Anticholinergic drugs: , , Muscarinic-blocking drugs. Cognition impairment Dose of short- or intermediate half-life hypnotic ≤ half the dose given to young subjects 7 Anticholinergic : , , Muscarinic-blocking drugs. Sedation, drowsiness , , ... alimemazine, , , , , dexchlorpheniramine-betamethasone, 8 Anticholinergic muscle relaxants and antispasmodic drugs: Muscarinic-blocking drugs. To be avoided when possible Trospium or other drugs with less , , anticholinergic activity 9 Concomitant use of drugs with anticholinergic properties Enhanced adverse effects No association Sedative or hypnotic drugs 10 Long-acting (half-life≥20 h : bromazepam, Protracted activity, increased likelihood of adverse effects Dose of short- or intermediate-life diazepam, chlordiazepoxide, prazepam, clobazam, nordazepam, occurrence (drowsiness, fall...) benzodiazepine≤half the dose given in young loflazepate, nitrazepam, flunitrazepam, clorazepate, clorazepate- subjects , aceprometazine, estazolam Antihypertensives 63:725 (2007) Pharmacol Clin J Eur 11 Centrally acting antihypertensives: , , The aged are more sensitive to sedation, hypotension, , Other antihypertensive drugs, except moxonidine, , syncope short-acting calcium-channel blockers and 12 Short-acting calcium-channel blockers: nifedipine, Postural hypotension, or stroke Other antihypertensive drugs, except centrally acting antihypertensives and reserpine 13 Reserpine Drowsiness, depression, GI disturbance Other antihypertensive drugs, except short- acting calcium-channel blockers and centrally acting antihypertensives Antiarrhythmics − 14 Digoxin>0.125 mg/day or digoxin serum concentration>1.2 ng.ml 1 Increased sensitivity of the elderly. The dose should remain≤0.125 Digoxin≤0.125 mg/day or serum concentration −1 mg/day or preferably should be adapted to maintain serum between 0.5 and 1.2 ng.ml – − 731 concentration < 1.2 ng.ml 1 Table 1 (continued)

Criteria Reasons Alternative drugs u lnPamcl(07 63:725 (2007) Pharmacol Clin J Eur 15 Disopyramide Heart failure, anticholinergic effect Amiodarone, other antiarrhythmics Antiplatelet drugs 16 Ticlopidine Blood and adverse effects Clopidogrel, aspirin Gastrointestinal drugs 17 Confusion. More interactions than with other H2-blocking drugs Proton-pump inhibitors and other H2 antagonists: , , , 18 Stimulant laxatives: bisacodyl, , castor oil, sodium Worsening of irritable bowel syndrome Osmotic laxatives picosulfate, cascara, sennosides, aloe... Hypoglycaemic 19 Long-acting sulfonylureas: carbutamide, glipizide Protracted hypoglycaemia Short- or intermediate-acting sulfonylureas, insulin, metformin, alpha-glucosidase –

inhibitors 731 Other muscle relaxants 20 Methocarbamol, baclofen, tetrazepam Drowsiness, amnesia, fall Thiocolchicoside, mephenesine With clinical conditions 21 Prostate adenoma, chronic urinary retention: drugs with Urinary retention risk increased anticholinergic properties (criteria 4–9, 15, 29, 30, 34) 22 Closed-angle glaucoma : drugs with anticholinergic properties Acute-angle glaucoma risk increased (criteria 4–9, 15, 29, 30, 34) 23 Urinary incontinence: , Aggravation of urinary incontinence, postural hypotension 24 : drugs with anticholinergic properties (criteria 4–9, 15, 29, Aggravation of cognitive impairment 30, 34), , , , neuroleptics except olanzapine and risperidone, benzodiazepines 25 Chronic constipation: drugs with anticholinergic properties (criteria Bowel-occlusion risk, postural hypotension 4 –9, 15, 29, 30, 34) , centrally acting antihypertensives (criteria 11) Questionable efficacy 26 Cerebral vasodilators: , , No really proven efficacy while postural hypotension and fall risks Therapeutic abstention dihydroergotoxine, ginkgo-biloba, , , are increased with most vasodilators , , piracetam, , raubasine- dihydroergocristine, troxerutin-, , vincamine, vincamine-rutoside Unfavourable benefit/risk ratio and questionable efficacy Sedative or hypnotic drugs 27 Dose of short- or intermediate- half-life benzodiazepines > half the No proven improvement of efficacy when the daily dose is above Dose of short- or intermediate- half-life dose given in young subjects: lorazepam>3 mg/j, oxazepam>60 half that prescribed to young adults and increase of adverse effects benzodiazepine≤ half the dose given in mg/j, alprazolam>2 mg/j, triazolam>0,25 mg/j, temazepam>15 young subjects mg/j, clotiazepam>5 mg/j, loprazolam>0,5 mg/j, lormetazepam> 0,5 mg/j, >5 mg/j, > 3,75 mg/j Gastrointestinal drugs 28 Meprobamate for gastro-intestinal dysfunction Drowsiness, confusion 29 Gastrointestinal antispasmodic drugs with anticholinergic properties: No proven efficacy. Muscarinic-blocking agents , phloroglucinol association with belladonna, clidinium bromure-chlordiazepoxide,

, diphenoxylate-, , 729 tiemonium 730 Eur J Clin Pharmacol (2007) 63:725–731

of any medications with anticholinergic properties other than those listed by Beers. The Delphi method is a consensus technique used and validated in various health domains such as nursing, clinical practice or education [15, 16]. This technique has some limitations. The reliance on intuitive judgements is obviously not an accurate method and depends mostly on the panel of experts chosen. Every expert would summarise their experience in a single answer. However, a complex situation such as the study of the appropriateness of drugs given to elderly patients with multiple adverse-effect- facilitating factors can hardly be solved. Participants could olexadine Drowsiness: acetyl-leucine, beta- histine, Rhinitis: saline the antibiogram : Cough: clobutinol, Antibiotics with renal elimination according to change opinions between rounds, which may introduce some biased responses, as the results of the first round were made available to all participants who could thus compare their opinions to that expressed by their group. Experts were consulted separately and were not able to debate; this would allow for more clear-cut opinions but would complicate the path towards a consensus. Nevertheless, the Delphi method allows experts to express their opinions independently and confidentially without the pressures that may occur during a face-to-face meeting [17]. Finally, the consensus obtained is the average of the experts’ responses due to the convergence of opinions throughout the successive rounds. The Delphi method allowed the proposal of explicit criteria for assessing prescribing quality to older people. However, explicit criteria tools are stringent and do not take into account the clinical context of prescribing [18]. For instance, the NSAIDs criterion was much debated between experts with respect to dose, administration duration, neuropathy, allergic reaction. Bacterial resistanceprotracted in use case of No proven efficacy. Muscarinic-blocking agents.sedation Confusion, No improved efficacy but increase of adverse effects No association Illogical association of two antagonistic mechanismscontinuity No association or not of treatment, co-prescriptions, age and renal and cardiovascular functions. Finally, NSAIDs were not classified as inappropriate, but the use of these drugs with neither adaptation to the clinical condition nor surveillance was considered harmful and inappropriate. Therefore, for several criteria, the French list encom- passes some clinical conditions, especially those most frequently encountered in geriatric practice. However, their number is limited, as considering the clinical condition of the patient together with the drugs given adds complexity and hampers the epidemiological analysis. As Beers emphasised, these criteria do not allow the identification of all cases of the use of potentially IMs [2]. Only the main ones are mentioned in this study. They are based on expert opinions and are not drawn from an evidence-based methodology [19, 20]. This list of criteria is a general guide for assessing the potential inappropriateness of medications. Nevertheless, for a given patient, a benefit-to-risk ratio has also to be (continued) antidrowsiness drugs with anticholinergicbuclizine, properties: , , , meclozine, , , , pimethixene, promethazine, association , ... therapeutic class anticholinergic properties drug associations assessed due to evaluation of the clinical condition, co- – morbidities, functional status, drugs received and progno- 30 Antiemetics, cough suppressants, nasal decongestants, or 31 Dipyridamole32 Nitrofurantoin Less efficient than aspirin. and postural hypotension Can induce renal insufficiency, pneumopathy, Antiplatelet peripheral drugs except ticlopidine 33 Concomitant use of two or more psychotropic drugs from the same 34 Concomitant use of anticholinesterase drugs and drugs with Other drugs with anticholinergic properties Antiplatelet drugs Antimicrobial Drug Table 1 Criteriasis. Reasons This set of criteria should not be used as a substitute Alternative drugs for Eur J Clin Pharmacol (2007) 63:725–731 731 the clinical evaluation, which could lead reasonably, at 4. McLeod PJ, Huang AR, Tamblyn RM, Gayton DC (1997) times, to the appropriate prescription of supposedly Defining inappropriate practices in prescribing for elderly people: a national consensus panel. Can Med Assoc J 156:385–391 inappropriate and second-choice drugs such as indometha- 5. Fialova D, Topinkova E, Gambassi G, Finne-Soveri H, Jonsson PV, cin, antidepressants, or antipsychotics with anti- Carpenter I, Schroll M, Onder G, Sorbye LW, Wagner C, cholinergic properties (Table 1). Reissigova J, Bernabei R, AdHOC Project Research Group This list should not be seen by people without adequate (2005) Potentially inappropriate medication use among elderly home care patients in Europe. JAMA 293:1348–1358 clinical expertise as an absolute prohibition against pre- 6. Gallagher P, Barry P, O’Mahony D (2007) Inappropriate prescrib- scribing certain medications [19]. Care should also be taken ing in the elderly. J Clin Pharm Ther 32: 113–121 to prevent this list from being considered solely as an 7. Lechevallier-Michel N, Gautier-Bertrand M, Alperovitch A, Berr C, opposable reference for economic purposes, for instance, by Belmin J, Legrain S, Saint-Jean O, Tavernier B, Dartigues JF, Fourrier-Reglat A, The 3C Study Group (2005) Frequency and risk the social security system: its first aim is epidemiological; factors of potentially inappropriate medication use in a community- its second aim is the supply of clinical guidelines. It is not dwelling elderly population: results from the 3C study. Eur J Clin devised for the economic regulation of care but can, Pharmacol 60:813–819 however, help reduce the cost of drug misuse. 8. Laroche ML, Charmes JP, Nouaille Y, Fourrier A, Merle L (2006) Impact of hospitalisation on inappropriate medication use in the elderly. Drugs Aging 23:49–59 9. Laroche ML, Charmes JP, Nouaille Y, Picard N, Merle L (2007) Is Conclusion inappropriate medication use a major cause of adverse drug reactions in the elderly? Br J Clin Pharmacol 63:177–186 10. Dalkey NC (1969) The Delphi method: an experimental study of a This French list of potentially IMs should be seen as a group opinion. Rand Corporation, Santa Monica reference because it is derived from an expert consensus. Its 11. http://agmed.sante.gouv.fr/htm/10/iatro/iatro.pdf use may help to reduce the occurrence of adverse drug- 12. Matell MS, Jacoby J (1971) Is there an optimal number of related problems in the elderly. It could also be used as a alternatives for Likert scale items? I: reliability and validity. Educ Psychol Measure 31:657–674 teaching tool for training medical students and doctors in 13. Merle L, Laroche ML, Dantoine T, Charmes JP (2005) Predicting the use of appropriate drugs in the elderly. This is a public and preventing adverse drug reactions in the very old. Drugs health tool, the impact of which could be measured by Aging 22:375–392 epidemiological studies provided it is reviewed periodically 14. Lafuente-Lafuente C, Mouly S, Longas-Tejero MA, Mahe I, Bergmann JF (2006) Antiarrhythmic drugs for maintaining sinus to ensure that it remains up to date and suited to the rhythm after cardioversion of atrial fibrillation : a systematic evolution of drug use. In addition, it could serve as a basis review of randomized controlled trials. Arch Intern Med 166: for initiating a European list based on a consensus between 719–728 experts from different countries. 15. 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