Prevalence of drug interactions in elderly patients with multimorbidity in primary care
Abstract
Background Drug interactions (DIs) are a significant cause of medicationrelated problems. The aging population, high chronic diseases prevalence and polypharmacy are closely associated factors. Aim of the review To study the prevalence, types and associated factors of DIs in multimorbidity patients of over 65 years of age in primary care. Methods Relevant studies on DI prevalence in this population were reviewed in PubMed, Cochrane Library and EMBASE (January 2000–December 2015). Independent variables (duration, target population, age, sex, mean of drugs and diseases, geographical localization, DI databases used and study designs) and dependent variables (prevalence, number of DIs per 100 patients and per patient, number of clinicallyrelevant DIs per 100 patients, most common DI and associated factors) were classified for each article. Results The search generated 749 articles and 46 duplicates were discarded. After reviewing, 10 articles were included. Seven studies were observational and 3 were quasiexperimental. Seven out of 10 used interaction databases. Only 2 studies described both actual and potential DIs. The prevalence of multimorbidity patients with DI ranged from 25.1 to 100% and the number of DIs per 100 patients was from 30 to 388.3. All the lower values correspond to the study conducted at the nursing home. This could be due to special care offered in these centres, where the medication is more controlled. The most frequent DIs were reported in five articles. However, these results could not be correlated since they were ranked using different methodologies. ACEIs, diuretics and NSAID were the most common therapeutic groups. Finally, 5 studies identified factors associated with the presence of potential DIs. The number of drugs and age were the most significant factors. Conclusions There is little evidence of prevalence of actual and potential DIs in elderly patients with multimorbidity in outpatient settings, showing widely heterogeneous results.
Full text
Depósito de investigación de la Universidad de Sevilla https://idus.us.es/ Esta es la versión aceptada del artículo publicado en: International Journal of Clinical Pharmacy This is a accepted manuscript of a paper published in: International Journal of Clinical Pharmacy International Journal of Clinical Pharmacy (2017): february 2017 DOI: https://doi.org/10.1007/s11096-017-0439-1 Copyright: El acceso a la versión publicada del artículo puede requerir la suscripción de la revista. Access to the published version may require subscription. “This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: http://dx.doi.org/[10.1007/s11096-017-0439-1]”
23/2/2017 e.Proofing http://eproofing.springer.com/journals/printpage.php?token=IJvv0iW6IfvVYL_jWXk1RsgAHjALBdIU_C6iHIjoOMImQu90bkixrV0XSFKphGdMwRKvo4T1… 1/21 Prevalenceofdruginteractionsin elderlypatientswithmultimorbidityin primarycare SusanaSánchezFidalgo, Phone +34955015466 Email [email protected] MariaIsabelGuzmánRamos, MercedesGalvánBanqueri, MáximoBernabeuWittel, BernardoSantosRamos, PharmacyService, UniversityHospitalValme, AvenidadeBellavista s/n, 41014 Seville, Spain InternalMedicineService, UniversityHospitalVirgendel Rocio, Seville, Spain Abstract Background Drug interactions (DIs) are a significant cause of medication relatedproblems.Theagingpopulation,highchronicdiseasesprevalenceand polypharmacy are closely associated factors. Aim ofthereview To study the prevalence,typesandassociatedfactorsofDIsinmultimorbiditypatientsof over 65 years of age in primary care. Methods Relevant studies on DI prevalence in this population were reviewed in PubMed, Cochrane Library and EMBASE (January 2000–December 2015). Independent variables (duration, target population, age, sex, mean of drugs and diseases, geographicallocalization,DIdatabasesusedandstudydesigns)anddependent variables(prevalence,numberofDIsper100patientsandperpatient,number ofclinicallyrelevant DIs per 100patients, most common DIand associated factors) were classified for each article. Results The search generated 749 articles and 46 duplicates were discarded. After reviewing, 10 articles were included. Seven studies were observational and 3 were quasiexperimental. Seven out of 10 used interaction databases. Only 2 studies described both actualand potential DIs. Theprevalence of multimorbidity patientswith DI 1,* 1 1 2 1 1 2
23/2/2017 e.Proofing http://eproofing.springer.com/journals/printpage.php?token=IJvv0iW6IfvVYL_jWXk1RsgAHjALBdIU_C6iHIjoOMImQu90bkixrV0XSFKphGdMwRKvo4T1… 2/21 rangedfrom25.1to100%andthenumberofDIsper100patientswasfrom 30 to 388.3. All the lower values correspond to the study conducted at the nursing home. This could be due to special care offered in these centres, wherethemedicationismorecontrolled.ThemostfrequentDIswerereported infivearticles.However,theseresultscouldnotbecorrelatedsincetheywere rankedusingdifferentmethodologies.ACEIs,diureticsandNSAIDwerethe most common therapeutic groups. Finally, 5 studies identified factors associatedwiththepresenceofpotentialDIs.Thenumberofdrugsandage were the most significant factors. Conclusions There is little evidence of prevalenceofactualandpotentialDIsinelderlypatientswithmultimorbidity inoutpatientsettings,showingwidelyheterogeneousresults. Keywords Aged Druginteraction Outpatients Patientswithmultimorbidity Prevalence Impactonpractice • Thereviewhighlightstheneedtocheckinteractionsinelderlypatientswith multimorbidity,asthiscanbeeffectiveinreducingdrugrelatedproblem. • Databasesofinteractionsshouldbeintegratedintoelectronicprescription systemsasastandardpracticeinhealthsystems. Introduction Inrecentyears,healthsystemshavebeenawareoftheimportanceofpatient safetyasapriorityobjective.Medicationerrorsand,withinthese,drug interactions(DIs)areoneofthemostimportantcausesofpotentially inappropriatemedication[1].Preventivecareisbecomingapriorityinhealth systemsallovertheworld. DIsaredefinedas2ormoredrugsthatinteractinsuchawaythatthe effectivenessortoxicityofoneormoredrugsismodified.Thesearepreventable medicationerrorsassociatedwithseriousadverseeventsanddeath[2].The agingpopulation,thehighprevalenceofchronicdiseasesandpolypharmacyare amongthefactorscloselyassociatedwithpotentialDIs.Moreover,theelderly
23/2/2017 e.Proofing http://eproofing.springer.com/journals/printpage.php?token=IJvv0iW6IfvVYL_jWXk1RsgAHjALBdIU_C6iHIjoOMImQu90bkixrV0XSFKphGdMwRKvo4T1… 3/21 populationisgrowing,resultinginaconcomitantincreaseinchronicdiseases andfunctionalimpairment[3]whichrequiremultiplemedicationsor polypharmacy[4, 5].Thisgroupofpatientspresentsdifficultiesintheprimary caresettingsincethehandlingofdifferenthealthproblemsisparticularly complex,asitisahigherriskpopulation.Patientswithmultimorbidityare potentiallymorelikelytoexperiencesafetyincidents,suchasDIs,duetothe complexityoftheirneedsandthefrequencyoftheirinteractionswiththehealth services.Arecentreviewconcludedthattheassociationbetweenmultimorbidity andpatientsafetyiscomplexandvarieswiththetypeofmultimorbidityand safetyincident[6 ]. Understandingoftheinteractionsandtheassessmentofitsclinicalrelevancein patientswithmultimorbidityaswellasthestratificationofitsseveritycanhelp optimizethequalityofprescribinginthesepatients,thusimprovingtheirsafety. Areviewoftheliteraturehasrevealednopapersthatsummarisealltheavailable evidenceaboutthisgroupofpatientswhoarethemostsusceptibletosuffering DIs. Aimofthereview Theaimofthisreviewwastosummarizethepublicationsthatfocusonthe prevalence,typesandassociatedfactorsofDIsinover65yearoldpatientswith multimorbidityinprimarycare. Methods Searchstrategy MeSHtermsandkeywordswereusedtosearchtheMEDLINE,Cochrane LibraryandEMBASEdatabases(June2000toDecember2015)(Table1). Publicationspriorto2000werenotincludedinthesearchinordernottodistort theprevalencedataas,duringthisperiod,therewasagreaterincreaseinthe numberofdrugsusedforchronicpathologies.Databasesearcheswere supplementedbyhandsearchesofreferenceslistsofthepapersincluded.We excludedstudiesinlanguagesotherthanSpanishorEnglish. Table1 FullsearchstrategyusedinmedlineMEDLINEandembaseEMBASE #1.(druginteraction[MeSHTerms])ANDprevalence[MeSHTerms] #2.(druginteractionANDprevalence) #3.(((((ambulatorycare[MeSHTerms])ORprimarycare[MeSHTerms])OR outpatient[MeSHTerms])ORnursinghome[MeSHTerms])ORambulatory) #4.(ambulatorycareORprimarycareORoutpatientORnursinghome) #5.(((((chronic)ORelderly[MeSHTerms])ORold*)ORaged[MeSHTerms])OR pluripathological)ORmultimorbid*)ORcomorbid*[MeSHTerms]) #6.(chronicORelderlyORold*ORagedORpluripathologicalOR
23/2/2017 e.Proofing http://eproofing.springer.com/journals/printpage.php?token=IJvv0iW6IfvVYL_jWXk1RsgAHjALBdIU_C6iHIjoOMImQu90bkixrV0XSFKphGdMwRKvo4T1… 4/21 #6.(chronicORelderlyORold*ORagedORpluripathologicalOR multimorbidit*ORcomorbidit*) #7.#1AND#3AND#5 #8.#2AND#4AND#6 #9.#7OR#8 #10.limit10fromJan2000toDec2015 #1.‘druginteraction’/expOR’druginteraction’AND(‘prevalence’/expOR prevalence)AND[2000–2015]/py #2.‘ambulatorycare’/expOR‘ambulatorycare’OR‘primarycare’/expOR ‘primarycare’OR‘outpatient’/expOR‘outpatient’OR‘nursinghome’/expOR ‘nursinghome’ #3.‘chronicallyill’OR‘elderly’OR‘aged’ORpluripathologicalOR ‘multimorbidity’OR‘comorbidity’ #4.1#AND#2AND#3 Inclusionandexclusioncriteria WeidentifiedallthepublishedarticlesthatcontemplateDIsinelderlychronic patientswithmultimorbidityinanoutpatientsetting.Elderlywasdefinedas beingover65yearsofage[7, 8]andpatientswithmultimorbidityasthosewith twoormorechronicdiseases.Studiesprovidingprevalenceofinteractionsor datatobecalculatedwereincluded.TheactualDIsweredefinedonthebasisof clinicalevidenceofanadverseeffectonthepatient,andpotentialDIswere definedasthosedescribedinaninteractiondatabase. Exclusioncriteriawere:reviews,articlesfocusedonhospitalsettings,articles notincludingpatientswithchronicconditions,thosefocusedonspecific diseasesorinteractions,articlesincludingonlyDIsbyplantsorarticles includingonlyinteractionsbetweendrugsanddiseasesornutrients.Papers whosefulltextcouldnotbefoundwerealsoexcluded. Reviewprocedureanddataextraction Tworeviewers(SSFandMIGR)independentlyassessedpublicationsfor eligibility.Thedecisiontoincludestudieswasinitiallymadebasedonthestudy titleandabstract;whenastudycouldnotbedefinitelyexcluded,thefulltext wasobtainedforevaluation.Whenmorethanonepublicationwasfoundabout thesamestudy,thatwhichincludedthemostinterestingspecificinformation wasselected.Discrepanciesbetweentheassessorswereresolvedbyanother researcher(BSR). Independentvariablesweretabulated:studyduration,targetpopulation, geographicallocation,DIdatabasesusedandstudydesigns.Theaverageage, drugsanddiseaseswerealsocollected. Themainoutcomesrecordedinthisstudywere:
23/2/2017 e.Proofing http://eproofing.springer.com/journals/printpage.php?token=IJvv0iW6IfvVYL_jWXk1RsgAHjALBdIU_C6iHIjoOMImQu90bkixrV0XSFKphGdMwRKvo4T1… 5/21 (I) PrevalenceofpatientswithDIs:definedasthenumberofpatientshaving atleastoneDIdividedbythetotalnumberofpatientsstudied. (II) NumberofDIsper100patients:definedasthenumberofDIsinthetotal studypopulation. (III) NumberofDIsperpatient:definedasthenumberofDIsdividedbythe numberofpatientssufferingatleastoneDI. (IV) NumberofclinicallyrelevantDIsper100patients:definedasthe numberofclinicallyrelevantDIsinaccordancewiththeauthors’and databasecriteria(Table2). Table2 DIdefinitioninaccordingtodatabase References Interaction database ClassificationofDI Clinically relevant [ 10 ] Thompson micromedex program A:theyarenotofclinical importance C D B:theeffectoftheinteraction hasnotyetbeenestablished C:DIcausespossiblechanges inthetherapeuticeffects,or caneffects,ormaycause adverseeffects,butcanbe avoidedadjustingthe individualdrugdoses D:DIisapotentialforsevere adverseeffects;individualdose adjustmentisdifficultinthese cases [ 11 ] DDIsDatabase Information System Majorseverity:nodefinedand noaccesstodatabase Major Moderate Moderateseverity:nodefined andnoaccesstodatabase Minor:nodefinedandno accesstodatabase [ 14 ] DrugReax systemBot database Majorseverity:DIcancause hospitalizationordeath Major Moderate Moderateseverity:DIcan produceaclinicaldeterioration oflesserentitywithout requiringhospitalizationor death
23/2/2017 e.Proofing http://eproofing.springer.com/journals/printpage.php?token=IJvv0iW6IfvVYL_jWXk1RsgAHjALBdIU_C6iHIjoOMImQu90bkixrV0XSFKphGdMwRKvo4T1… 6/21 References Interaction database ClassificationofDI Clinically relevant Minorseverity:DIwithout detectableclinical consequences [ 15, 16 ] ABDAdatabase http://www.wuv gmbh.de Seriousrelevance:DIislife threatening,permanent physicaldisabilitiesare probable Serious Moderate Moderaterelevance:Dosage adaptationisnecessaryand/or concomitanttreatmentrequires continuousmonitoring Minorrelevance:DIisbarely affectingpatient’shealth.DDI appliesforspecialpatients groups Insignificantrelevance Notevidence [ 17 ] LexiInteract database A:noknowninteraction C D X B:specifiedagentsmay interact,butthereislittleorno evidenceforclinicalconcern C:specifiedagentsmay interactinaclinically significantmannerand monitoringoftherapyis suggested D:twomedicationsmay interactinaclinically significantmannerand modificationoftherapyis suggested X:contraindicatedcombination (V) MostcommonDI. (VI) FactorsassociatedwithpotentialDIs.Studyofpossiblefactors associatedwithpotentialDIsincludingpatientcharacteristicsanddrug therapycharacteristics. Alldependentvariablesweremeasured,wheneverpossible,forbothclinicaland potentialinteractions. Qualityassessmentofthestudies ®
23/2/2017 e.Proofing http://eproofing.springer.com/journals/printpage.php?token=IJvv0iW6IfvVYL_jWXk1RsgAHjALBdIU_C6iHIjoOMImQu90bkixrV0XSFKphGdMwRKvo4T1… 7/21 Atwelveitemqualityassessmenttoolwasused,basedonthecriteriafor assessingthequalityofmedicationerrorstudies,whichwasdescribedby Nabovatietal.[9 ].Overallqualityscoresrangedfrom0to12(0–6 points=poor;7–9points=moderate;10–12points=high). Qualitativeaggregatedresultsweremainlyreportedduetovariationsinthe methodsusedwhenreportingDIsstatistics. Results Searchesidentified749articles,ofwhich46duplicateswerediscarded.After theinitialscreeningoftitlesandabstracts,100fulltextstudieswereassessedfor eligibility.Subsequently,10articlesmettheinclusioncriteria [10, 11, 12, 13, 14, 15, 16, 17, 18, 19].Figure1 showsaflowdiagram. Fig.1 .
23/2/2017 e.Proofing http://eproofing.springer.com/journals/printpage.php?token=IJvv0iW6IfvVYL_jWXk1RsgAHjALBdIU_C6iHIjoOMImQu90bkixrV0XSFKphGdMwRKvo4T1… 8/21 AQ1 Table3showstheirgeneralcharacteristics.Sevenstudieswereobservational andthreewerequasiexperimental.Eightoutof10usedinteractiondatabases, whiletheremainingtwousedalistdevelopedbyMaloneetal.[20]andthe MedicationAppropriatenessIndex(MAI)[21].Sevenofthemwereperformed indifferentregionsinEuropeandtheremainingthreewerecarriedoutin America,TaiwanandMexico. Table3 Descriptiveanalysisoftheincludedstudies References Duration Target population Age Meanof drugs Meanof diseases Location [ 19 ] No specified African Americanwho sufferfrom chronichealth conditions 65–94 7.68±4.02 5.23±3.01 0–17illness SouthLos Angeles [ 18 ] Jun2006 toDec 2008 baseline Elderly,mostly multimorbidity patientswith limitedmobility 78.3 6.3±3.7 7.8±3.3 German ruralareas [ 17 ] OctDec 2011 Elderlypatients with2omore prescriptions dischargedfrom theInternal MedicineClinic 72(65–91) 4(range1– 8) 6(range2– 14) Croatia [ 16 ] Jun2006 toDec 2008 Elderly, multimorbid population 78.82±8.2 6.8±3.3 6.3±3.7 German ruralarea [ 15 ] AGnES1 NovDec 2005 Elderly, multimorbid populationwith reducedmobility 74.8±10.7 6.7±3.1 Nospecified German ruralarea AGnES2 March– May 2006 70.8±9.7 7.5±3.8 AGnES3 Oct 2006 March 2007 75.5±7.5 7±3.5 [ 14 ] March 2003to March 2005 Pluripathological and polymedicated patients 74.5±9.8 8.46±2.49 2.5±2.6 3Health Centreof Seville
23/2/2017 e.Proofing http://eproofing.springer.com/journals/printpage.php?token=IJvv0iW6IfvVYL_jWXk1RsgAHjALBdIU_C6iHIjoOMImQu90bkixrV0XSFKphGdMwRKvo4T… 15/21 interpretationoftheresultsdifficult.Severalconsiderationsmustbebornein mindwheninterpretingthem.Firstly,thereisvariabilityintermsof methodology.Inmoststudies,themedicationwasobtainedfrommedicalrecords and/orelectronicprescriptionandanalysedusingdifferentdatabases,DIlistsor MAI[10, 11, 12, 13, 17 ].However,otherstudiescollecteddatafromhome medicationreviews[ 15, 16, 18 ]andtwostudiesusedaninterviewtoexamine medication.Reviewofmedicalrecordsispossiblythemethodthatdetectedthe highestnumberofDIswhencomparedwithothermethods[26].Moreover, regardingdatabases,thereisvariabilityinhowtodefinetheirclinical importance.Thedatabases,theclassificationofclinicalrelevanceandcriteria usedcanhaveasignificanteffectonthenumberofDIsidentified,andasa result,ontheirprevalence,leadingtomisunderstandingsifinteractionsarenot carefullyevaluated[ 28 ].RodriguezTeroletal.[29 ],highlightedthegreat differencesinthenumberofDIsincluded,thecriteriaforclinicalsignificance andothercharacteristicsofdifferentwidelyuseddatabases.Inthisway,wemust takeintoaccountthatdatabasesarenotspecifictoelderlychronicpatientswith multimorbidity.Moreover,thereisnouniversallistofmedicationsandcriteria forassessingtheoverallmedicationusedbyolderpatientswithmultimorbidity [5]. Secondly,theresultsdifferdependingonthetypeofpathologiesofthetarget population[25].Finally,differentsamplesizesandgeographiclocationscan alsoaffectprevalencedata.Countriesusedifferentsetsofmedicationsdueto registrationissuesand/orlocaldrugprocurementpoliciesandastructurefor financingmedicationthatmaycontributetodifferencesinprescriptionpatterns [5].Furthermore,differencesinthequalityofprescribingacrossgeographical regionshavealsobeenhighlightedrecently[30]. ACEIs,diureticsandNSAIDarethemostfrequentlytherapeuticgroups involved.Agerelatedchangesinrenalfunctionmakeelderlypatients susceptibletotherenaleffectofACEIs,especiallyifadministered concomitantlywithotherdrugsthatcaninfluencerenalfunctionsuchas diuretics[31].Alteredrenalfunctionalsoputselderlypatientsatgreatriskof medicationinducedalterationsinpotassiumhomeostasis[ 32].Otherauthors haveshownthattheinteractionbetweenACEIsandotherpotassium concentrationincreasingdrugsisoneofthemostfrequentDIsinhospitalized andnonhospitalizedpatients[33, 34]. Withrespecttoassociatedfactors,theresultsshowthatDIprevalenceinpatients withmultimorbidityisassociatedwithpolypharmacy,ageandthenumberof illnesses,inconcordancewithpreviousknowledgeaboutchronicpatients [25, 35, 36, 37, 38, 39].DIsfrequentlyoccurinolderadultsduetoshared
23/2/2017 e.Proofing http://eproofing.springer.com/journals/printpage.php?token=IJvv0iW6IfvVYL_jWXk1RsgAHjALBdIU_C6iHIjoOMImQu90bkixrV0XSFKphGdMwRKvo4T… 16/21 metabolicpathwaysbetweenthedrugsthemselves[19, 40],aswellastheuseof multiplemedications.Moreover,polytherapyincreasesthecomplexityof therapeuticmanagementandtherebytheriskofclinicallyimportantDIs,which canbothinducethedevelopmentofADRorreduceclinicalefficacy. Furthermore,ageishighlyassociatedwiththealteredmetabolismofsome drugs. Thisreviewhasseverallimitations.Itisbasedonaliteraturesearchofthree databases,althoughthesearchcarriedoutforarticlesinthereferencesof previouslyselectedstudiesmayhavecompensatedthislimitation.Numerous articlescouldnotbeincludedsincethenumberofdiseaseswasnotspecified, andwehavethusnotbeenabletodeterminetheconditionofpatientswith multimorbiditywithcertainty. Thisarticleemphasizestheneedforphysicianstobevigilantregardingpotential DIsinapopulationwithcomorbidconditions.Furthermore,thenumberofdrugs usedtotreatelderlychronicpatientsshouldbeminimizedtoreducethe incidenceofDIrelatedADRs.Nevertheless,itissometimesdifficulttoreduce thenumberofdrugsprescribedforpatientswithmultiplechronicconditions. Therefore,othertherapeuticalternativesaswellasthemonitoringofchronic treatmentbyamultidisciplinaryteamcouldgreatlyreduceexposuretoDIs[41]. Inthefuture,itwouldbedesirabletohaveimprovedtechnologyandthe existenceofapreventivetoolagainstpatients’exposuretoDIs.Databasesof interactionsshouldbesimpleandmoreintegratedintoelectronicprescription systems,ashasbeencommonpracticeinsomeEuropeancountriesforover 20years.Thedatabasesshouldbemoreaccurateandsuccessfulinguiding physicianstoprescribesafelyandappropriately.Anyactionthatreduces morbidityinthispatientgroupcanhaveahighimpactontheconsumptionof resources,bothinhospitalsandinprimarycare. FuturestudiesshouldfocusonDIcriteriathathavesufficientclinical significanceandarerelevanttoelderlypatientswithmultimorbidity. Conclusions InspiteofscantevidenceoftheprevalenceofactualandpotentialDIsinelderly patientswithmultimorbidityinoutpatientsettingsandtheheterogeneousresults, wecanconcludetheprevalenceinthispopulationishigh,withACEIs,diuretics andNSAIDbeingthemostcommontherapeuticgroups.Moreover,thenumber ofdrugsandagearetheassociatedfactorsthataremostsignificantlyinvolved.
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