a Interventions to Enhance Medication Adherence in Chronic Medical Conditions A Systematic Review Sunil Kripalani, MD, MSc; Xiaomei Yao, MD; R. Brian Haynes, MD, PhD Background: Approximately 20% to 50% of patients are not adherent to medical therapy. This review was per- formed to summarize, categorize, and estimate the elfect size (ES) of interventions to improve medication adher- tence in chronic medical conditions, Methods: Randomized controlled tials published from January 1967 to September 2004 were eligible they de- scribed 1 oF more unconfounded interventions intended, toenhance adherence with sel-administered medications inthe treatment of chronic medical conditions, Trials that reported at least 1 measure of medication adherence and 1 clinical outcome, with at least 80% follow-up during 6 months, were inchided, Study characteristics and results foradherence and clinical outcomes were extracted. In ad- dition, ES was calculated for each outcome Results: Among 37 cligible trials (including 12 informa tional, 10 behavioral, and 15 combined informational, be- havioral, and/or social investigations), 20 studies reported ‘significant improvement in atleast 1 adherence measure. “Adherence inereased most consistently with behavioral terventions thatreduced dosing demands 3 of 3 studies, large ES [0.89-1.20}) and those involving monitoring and feed- back G of studies, small to large ES [0.27-0.81]). Adher- ‘ence also improved in 6 multisession informational trials (mall to large ES [0.35-1.13]) and 8 combined interven- tions (small to large ES [absolute value, 0.43-1.20)). Eleven studies 4 informational, 3 behavioral, and combined) dem- ‘onstrated improvement in atleast 1 clinical outcome, but effects were variable (very smallto large ES [0.17-3.41]} and not consistently related to changes in adherence. Conelusion: Several types of interventions are effective in improving medication adherence in chronic medical con- ditions, but few significantly aected clinical outcomes. “Arch Intern Med. 2007;167:540-550 Author Afiiations: Division of General Medicine, Department of Internal Medicine, Emory University School of Medicine, Atlanta, Ga (Dr Kripalani); and Department of Clinical Epidemiology and Biostatistics (Drs Yao and Haynes) and Department of Medicine (Dr Haynes), MeMaster University, Hamilton, Ontario, Downloaded From: https:/jamanetwork.com/ by N ESTIMATED 20% TO 50% of patie their medications as pre- scribed and are said to be nonadhere pliant with therapy." In the setting of chronic medical conditions such as hy= pertension and hypercholesterolemia, medication nonadherence leads to worse medical treatment outcomes, higher hos- pitalization rates, and increased health care costs." Because of this, adherence has been called “the key mediator between medi cal practice and pati s do not take lerventions to improve patient adher- cence, ranging from simple adjustments in the medication regimen to complex mul- Lidisciplinary interventions that address hhealth system barriers and communica lion between patientsand health eare pro- fessionals.""° However, the overall qusl- lty of the literature is poor, with wide variability in study design, including pa- tient population, outcome measure, and duration of follow-up." tis desirable to draw recommendations from a smaller set of high-quality studies, Ina recent review for the Cochrane Da- labase," several simple interventions ap- peared to improve adherence with short- erm regimens, such as a course of antibiotics. However, interventions to im- prove medication use for chronic condi- lions appeared less effective overall and ‘were often mullifaceted, making it more difficult 1o synthesize published evalua tions." In this article, we extend the find- ings of the Cochrane review by providing a more detailed examination of interven- lions to improve adherence in chronic medical conditions, We offer a {rame- work for categorizing these interven- lions and report their relative impact using standardized measure of ellect size (ES) The goal of this review is to help physi- clans better understand the strengths and limitations of tested interventions for improving long: idenuily those that are most successful sm medication use and (©2007 American Medical Association, All rights reserved. Mexico | Access Provided by JAMA. User on 08/23/2021ss} DATA SOURCES Electronic searches f the published lt- erature from January 1997 to Septem ber 2004 were conducted through MEDLINE, CINAHL, PsycINFO, SOCIOFILE,Interational Pharmaceu- teal Abstacis, EMBASE, and The Coch rane Library, without language res thon The exact search strategy varied across databases and generally In- hdd terms for adherence (eg, compl ance, noncompliance, adherence, drop- cuts treatment refua, medcaton we (eg, medication, medicine, dug, treat- ament, regimen, pharmacotherapy), and linia tal desig eg linia rh n= {ervention, outcome, randomized, con- trol) A fll description of the search strategy i provided elsewhere." STUDY SELECTION Reviewers sercened atin tiles, in dex terms andabatacte aval) to \enty potently relevant arcles, tthich were retsteved for fulltext ec Micw. Two reviewer independent as Sessed the ates for poole inclu Sion, Dilferences in sessment were essed by discussion or wih ass tance from third reviewer. ‘rics were selected if they re std randomised consoled tal ht tervention intended erhanceadher- fhce with sleadministcred medica tons used inthe treatnet of chro ted conden Confounding was Judged tobe presents groups were Tres unequally exept fr the tne wentlon Intended to eubance adher- ce (eg, pallens inthe intervention frou teoted net only tore coco jenn to comply but ase a diferent tMedicaton or dose than these in the Control group Include were quedo repora leat I measure of thedcatlon adherence and cline ou {mes witha est 0% ollow-up fpr tipants during 6 months i te tly rss were ify postive stadles wth negates resulisand less than Inonthstfolloy-up wereincluded be Cause ini fare as unlikely to be felowed by sucess studies of shore term regimens were included in the (Coch rei-butexladed mth estat anlpts to permit a fces on Chronic medical conditions, for which talcrene isa greater concern. Tals tha pertained © poyehise disorders trerceacluded because adherence ger lly lower inpatients with py edondersand unique challenges may (aePnosrep) SRGHINTERN WEDIVOE 167, WARS SOO? also be present, potentially limiting the generalizability of interventions tested in that context.” DATA EXTRACTION For cach eligible study, 1 reviewer ex- tracted feattes ofthe tiem popula tom, study design, interventions and con- trols aswell areas for adherence and dlnial outcomes. When multiple ime Points were provided, data were ex- tracted forthe longest period of follow- tp, provided llow-up remained at east fs. Each extraction was confined by lest other reviewer Other ales on the same tral were retrieved, and au- thore were contacted a needed ford tional deta or vercation of epored analyses DATA SYNTHESIS Theclighle studies difered substantially inpatient population, intervention, ad- tefence measure, and clinial outcome measure, making pooling oresultsin- appropriate Insead studies were groupe byimervention type, usinga taxonomy developed from other sources?" I {Jormational interventions decribed cog- itive strategies designed primarily to dicate and motivate patients situ tonal means, based on the concep that patients who understand their condi- thon and is treatment wll be more in- formed, empowered, and kely to com ply, Informational sessions conducted Individually orinagroup setting aswell as didactic and interactive approaches, wwere included. Examples of inform tional nterventonsare face-to-face oa, telephone, written, or audiovisual edi cation; didactic group class and mailed insructional materia (aot including = tinder or prompts to compl), Beha ioral interventions were stategies de- signed to influence behavior through shaping, reminding (cues), or reward. ingdeatedbehaviog reinforcer). Ex amples include shilling by a eal Cate profesional pilloxes calendars change in packaging, or oer steps in- tended o remind the patient changesin donage schedule to simpy the regimen orallorthe regimen tothe patient sally routine (e reduce ts Behavioral de- tnands), and rewards and reinforce- tment (og. aseesment of adherence with feedback othe patient). Family and Gal interventions involved social sup- port states whether provided by fat ily or another group. Examples are support groups and lamly counseling Group stssions that were primarily d= Cte or informational, rater than sap portve, were ealegorized as informs onal, Combined interventions inched features of 2 or 3 ofthe preceding cat- egores Each included study was class fed by Vauthor using these categories, dlescripors, and examples, This ls Calon was reviewed by atleast 1 other futhor, and disagreements were re- talved by consensts For each outcome, an ES (Cohen 4 with 9596 confidence interval was Calculated from information provided in the article or obtained from the futhors: The ESe compare the differ- ence im effect between study groups, divided by the standard deviation of this diferenc, resulting in standard deviation untis. This measure Is independent of the method of mes. Srement used, thus permiuing com arison of different Interventions cross studies, In this way, ES pro- vides more information than a simple test of significance comparing out- comes in intervention and control groups. The ES can be positive or hegative, depending om the effect of the treatment om the particular out- come measure I the study results are Statistically significant, then the ES is generally sigoficant aswel ‘We calctlated ES according to es tablished methods °" For studies that provided range instead ofa standard de- Fiation, we converted range to stan dard deviation" The abeote value of cach staistclly significant ES was cae gorized as very stall (<0.20), small {6:20 to =0.30), medium (0.50 to 0.80), or large (20.80)." We eile. Inted ESs between each intervention and control group. some studies had more than 2am and provided only an over- all test of significance comparing re- Zulls across experimental groupe, In these cases, the igiicance ofthe ES for intervention-ontrel pars may haved fered fromthe overalsignfieance of r= sults, Aleo, tr study authors did not Specify the number of patients in- ‘volved nthe final analyse we used the Incline sample sizeof exch group to cal- ciate the Es Calculating the Esin this ‘ray, analogous fo an intention teat nalts, may underestimate the ue “ffect of the intervention. EEE The electronic searches returned 15061 citations (including 458 re view articles), 055 of which were judged to merit full-text review. total of 38articles deseribing 37 ran- domized controlled trials met all in- cluston criteria, including 2 articles from the same tial” Among the in- (©2007 American Medical Association, All rights reserved. jamanetvrork.com/ by a Mexico | Access Provided by JAMA. User on 08/23/2021TH ae tea aren” 0 en eid ava Te, de Secon oder ina aes] Tae Rone Pa essa ace en te Da na eed are tfc Sines T—] tid Coruna tstuemet tte dae een {tamer Garon fale Mite tai sre a pau Dering gate Tae dein romonalashenins Sekt ieeons Cintas igure, Study Yow. cluded studies, 13 reported on 12in- usual care (Fable 1). Sample size formational interventions," 10 on ‘behavioral interventions,” and 15 ‘on combined interventions.** None deseribed purely family or social in- terventions (Figure). Most studies reported a single measure of adherence. However, the choice of measure varied widely, from self-report scales 10 more objective measures obtained by auditing refill rates, performing, pill counts, and assessing the tim- ing of prescription boule opening by Medication Event Monitoring System caps. Approximately half of the studies reported a single clini- cal outcome, which also varied areatly, depending on the patient population, The ES could be calculated in 30 studies for adherence outcomes and in 30 studies for clinical outcomes. Most studies (71% foradherence and 100% for linical outcomes) that did not provide enough information to calculate the ES were not statisti- cally significant, which illustrated a form of reporting bias. INFORMATIONAL, INTERVENTIONS The studies of informational inte ventions each compared intensive education to limited education oF varied from 4610 350. The interven- lions ranged in duration froma single session of less than 1 hour to several hours over many sessions. Counsel- ing was provided by a physician, nurse, health educator, or pharma- cist. Both individual and group ses- sions were described, sometimes in combination, and they were often ac- companied by written materials, Half (6 of 12) ofthese studies re- ported asignificant increase inat least 1 measure of adherence."**2"292 However, 3of these 6 tials had mixed results, Gallefoss etal! reported an improvement among only patients with asthma not those with chronic obstructive pulmonary disease. Levy etal® demonstrated improvement in adherence only for severe, not mild, asthma attacks. In the study by Schaffer and Tian” of 3 educational strategies, 2 were effective Among the 10 studies for which an ES for adherence outcomes could be caleulated,!?" a large ES was observed only in a trial conducted by Pradier et al" of intensive, multisession counseling, for human immunodeficiency virus (HIV) treatment adherence (ES, 1.13 for self-reported adherence) Four other studies! that pro- vided counseling over multiple ses- sions had a small to medium ES (range, 0.35-0.68), and the remain- der Were not significant, Most informational interventions (Bof 12) did notimproveclinical out- comes. Of the 4 studies with atleast 1 positive clinical result, 2 had asmall ES (Pradier etal": ES,-0.39 for HIV RNA level; Levy et al ES, 0.34 for asthma symptom scores). The other 2 tials had medium to large ESs (Gallefossetal"** ES, 0.52 or forced expiratory volume in 1 second in pa- tients with asthma; Cote etal: BS, =0.64 for urgentasthma-related vis lusand3.41 forpeak expiratory low) Eachofthese 4studies provided fairly intensive counseling with reinfore ment over time, Only the interves tions used by Cote etal“and Pradier etal" consistently led tobetterclini- cal outcomes, despite the study by Coteetal having no effect on adher cence owing toa high rate of adhe cence in the control group (97%) Gallefoss etal* again saw improv ment only among the asthma sub- ‘group, and Levy etal"had mixed re sults based on the clinical outcome BEHAVIORAL INTERVENTIONS The sample size of the behavioral studies ranged from 27 to 497 (fable 2). The most common and effective forms of behavioral inte vention were dosage simplifica- tion’#°%* and repeated assessment of medication use with feed- back." Other teals tested spe- -d packaging,” directly ob- served therapy." and cognitive ‘behavior therapy * but none ofthese techniques significantly affected ad- hherence or clinical outcomes. All3 tals of dosage simplification demonstiatedan improvement inad- hherence, whether switeing from 2 doses o I dose per day or from 4 t0 22° The ESsthat could becaleu- lated were large range 089-120)" The mpacton clinical outcomes was mixed. Brown etal found asigoii- cantly higher percentage of pa- tients reached their low-density ix poprotein cholesterol goal when preseribed extended-release niacin ‘compared with the short-acting form (medium £5 0 0.66). However, the study by Baird et ab of once-daily metoprolol demonstrated no (©2007 American Medical Association, All rights reserved. jamanetvrork.com/ by a Mexico | Access Provided by JAMA. User on 08/23/2021Table 1 Informational Interventions ra eT TT sou aS Sins ___aramtoncent! tenets tramernce "aman ina Coane Za Wormslng Tare pest Cand OUEA Ug 58, Pagar I= 000, We ‘rara“emanpten fcrcergonOPhwnh inion ne (Osisdsy) a=0.P 621 m0.21) SoS TRE Sanaa” ie egret, ‘ ee Risener Sete rot dechiwtot (cara elomaion en sn Copal” — Asha =286=31- beeen ino Heeesin tre. 035 (lari (Mom 58 “aH ‘Sorgurancen eestor Tatsmasy “satan eiema ea aic ‘Sect wogan (eet fm ese” olimse Paice re es i ‘aati Shel te, arm ase irony rl Benedtets enact #8 Sovak Linn, P= 8 collation ieeaneed aaagectnan oe Gaieg, Amd .¢-29, LE geg Reid TShe_, (an O81 Ciaran 82, a2 re Scsorseceasesy “iwcridcoses “otha! ‘at ta rend Coca camSif shack, plement 2 saci “eaten Fal secre) (ti rotor” st oombeaps—Q\C =.=, Teepe aed clase ‘ea —Roptotaris, Fiala er pan O58 (Ain in, (en -012 aor Macc Senn). ewe zat “amigas, setaazng coleaten ite Pert BRS, clam te ‘rman. aes a ‘Sltieamns i hei etnete haa omelette, CCST Stir Peat Lite” Themen Eines tn 5 Caretbte temo) meaeane (ene -09 fa "ied "ma eed” nme lan, aS \osteaas, ae msearyawninn, fours smal gs fbi diyemesne [Sats NN 'eaBei0 8) ts cairn Seer Sar Sir ain ane tpi pie orm roenast po So cae) iat ina ita ne Ani thal teaiy, gel ise (ag 5, ny tise(teescec tn "esas US ta, Urn ott, Nostomacsed (abot mek Chm)” Qhowenatce ak hone 0. Encrara climatacotrer — UStwomy, Crowe: teaucce, "Ba Sirempronin, “nusmd lod, lpaimgsl fea ois Glatt cedankatimgon | Eats eet, “Sean @amimssimane "(uve the Olrecnmecenste ora bis Shr 1- 8/528, lnm 0 olbaien gone foniwoey Eeaiirzoacia SN wags: ee ies ia irre lida iat (oy stenysnts —TBEKog, nie, re rec cera i dae (Gre iisib (Sean st sewn ek Race CET, Alyce Aah |=A0C=41 Eegidaleint Supt cyte agen 020 ‘Wend ‘usin nase (emo) slain a ve UCIT Ey frosbrt sens, Iam Bgardbe Slt stn pti oP oltuion ‘comin (©2007 American Medical Association, All rights reserved. jamanetvrork.com/ by a Mexico | Access Provided by JAMA. User on 08/23/2021Table 4 Informational Interventions (cont) ce "ian neues GGG) Chal oaeame esses 6 Gr sous andSinpleSxs___lvetoncano! sche rameeace maton Cincom Fern Deri 25, Fame sis armas Sepa tos Tihs Ti 229 iam eee ‘nr "ero rocinge ees emma, “Thrzie015 Ine uslegen 45.08 nna, sca ne [03 mmol Po 24 age aera! Sets oe re habe | Ota. Prades HN. =12, Un deed 0 Adhoens Lage 1.18 ChamsinHV NK ton Sa 039 “ans Seer caeden “Bisio tt) “Tsuen eOLt-018) ‘Santa oi sc Erm 02086 ng Silber ‘onan C012 2080 Str aden lSfeopesin a =-030 abe, Iegeopesi Pano ovigs _ HNV.I=05,0=99 Smal goip soos by “eo Pribel s Nom 000 Wh 10am 010 aa Teatheawpasesoml,” en (ieNSeaps, (4371009) coainl (tw Ta2sto0s) feasrg oat Soyo. cag a5 Peat gor AY ands ner sndmeaton argent ety or sit ar tea fe pe ahs pls rsine hese hoa Rowen theo ‘cueing Sep Mae <1, contin, la alle Ai et (os 00, “ite “hotest “eatin ice “aud Ero (8eei0%, “ecemaret Ge): GES 3 Sinipspsbcola . tetieTh Gad, elon 7 Tarksia0 loon 38 claude inde’ (ncasa Pei (aintatson 10, (tri owsredesio ILD AzSH P= te; (hramO77 (I ‘2h 014 Bcesticcat “atte Bice i ‘easton Ge mesa” sata =112 ——bDiusiont Siteponedadroes Now, 030 (FE; epee mons (1) one -005 “at ‘aiomgeneyin nth (peta mans (0073) 6 ra {coariedn Felnwean nail 50.12 mal B (ehor, 038 ‘Steen ne evar eae (430mm essin) oup Sater 880-0 olen pxrcan vey mo). Geraiiaa=08, it i (2) FsF0 (nuns, moj 1=tn0 108, Gein ase Aubrvatns:C, cont cosines COPD, cherie ctu pulmonary disease; DMPA, depot edronprogestroneantate ES, ec si: FE, ove xii vols in acne: VE fred vial capacity; HIV, aman immutedefiancy vs, nsreron INA, natal nara rate Metis, medeaton event montang seem: NA ot alle, ot significant PEE pek expiry do, PRECEDE, Predisposing, Reon, Ertng, Causes ueonal Dagross and Ersuatan. dfn teen eventon a ona groupe “fact ales ot ried inal. ase are titd om fre. fests cine or contmod by parsonal communica wth aaa Court cleus with avalble da {he ES wae eacltd by carer ang mo standard deat, [Tne Sas clube by using modan tad of ean ‘The 5 Clay be nace ving ta ral xml ‘Love cosine ater sehr coo, significant improvement in blood. pressure, whereas Girvin et al ac- tually found a trend toward in- creased blood pressure in the once- daily therapy group. The 4 trials that involved assess- 027-081). The fourth study which simply made home blood pressure values available to the pa- ent and physician, did not im- prove adherence.” Only 1 study in this group produced a clear improve- mentand feedback asked patients to monitor and report their medica- tion use and/or blood pressure.” The 3 studies that then provided pa- tients with tailored feedback, rein- forcement, or rewards demon- strated a significant improvement in adherence (ESs small to large; range, ‘ment in clinical outcomes (Marquez Contreras et al”; ES,0.89 for total cholesterol and 0.78 for low- density lipoprotein cholesterol) Friedman and colleagues” re- ported a decrease in the diastolic blood pressure only after control- ling for baseline blood pressure in adjusted analyses (small ES of 0.29); they found no significant change for systolic blood pressure COMBINED INTERVENTIONS Most (13 of 15) combined interven- lions included informational and behavioral components," and 2 joined socal support strategies with cither informational or behavioral ele- ments (Table 3).°* sample size again varied widely, from 37 to 1113. (Of the 13 studies with informational (©2007 American Medical Association, All rights reserved. jamanetvrork.com/ by a Mexico | Access Provided by JAMA. User on 08/23/2021Table 2. Behavioral Interventions Tease ‘inenaa eer 6) ‘in Odeon Benepe soura ‘Ste Sume_—_—_iaentonconto ‘ence rhea Maura ens, lea Ome sig Hprnion — [Noprloen TP 1 SPAS Ta at! MPEG nasa ‘npc 10 c=18h a Peo file> ypranion Spal mnnd sa) (iO Adbocs (1) Nr, 008 me ‘ms Tea pag 0, (4 nO, pte, rer 22 Fada pais, ont, (2)280% oom iain co at Shown” ype, Como ka ncn Ka Pbdpiy La 08 Mada, 086, ear ‘heeft rm: 680 1A) ‘agora (erom CPt cindy Cot asf st) frndran —-Aypon | Wphoneikadcore Seal.027 | ()Onomsin SBP Gm =115 (ave 016, ta het" Senos there, Totswost) "Toni c=e6rmig 247 (08m by 1% (ase eters ad 2 hana 29 Ste Btwn orSo ak (2lsonen BP ma \eteioasn) ferl=123, giant pet an pecan ra. Cia) Clswexe ram P= Grinsa> pranon,—FEtepl 20mg ay. (hag, 082 0 (or 058 fod” RSST erate mg ey tate 130; men (ante) (eoxre Glopiish” Caleiagnmigica m8 ale 03 a Wate toni tie etamig Saw tan scssmmig P= (2 rae 05% ami Tew a ab, Slee) a1, ye Hpetanon Sentry sar Mat, 078 D8 (nan 0, 1290) Ye 080, var Sl saree ‘orzo 250005) iste odes she, hs Gotha am a3 ‘ty esearch san, te elias Joins Hpetanion Setenonicg ceed al Pscbetdxe, (1) 17 OBP (man Sa, = 859, 02 ca" Eis pesazeathone (mony kn ilu 21 908) {5 ma, e428 tby eae irae as 8 LPS) SocumtomimmrGbes ESTES {38 G28 pasurelthortomi, am Eaeas, Glare it Posconsnpiengien — (Nicoa=7a Pens, “CHAN O50) (Coe ‘ean Bcc asaseste oleate, GEESota bots AMaqut Dlg, Shogo cle t704. Preto Lage OS | (1)Dscecen tal oka (Lag. 080 Citeas SS Yetta aces “Bpeatn “Ebi “naneSiemor eattaas eat t C26) adune pondefodick + 0.6 ol C=fat a3 ration 078 ‘dg ales imasss sas 8agi Pe (cant) ‘eammnson| (aaa RLU rsa 0, clam (rol (263252) ma Go Broil. 3-218 rl, P= eye LDeetobanatin apy Const wih org (ere. 012_ (Vemma emt: = 64 (None 2 ‘at bya ono fredecers fan (-O08 19038; | a5, ;ai8 02h: drasebenatonofiaimet Faatcane mol awa, O00 (W040 Po Ta cobjame-o1e by tly manber ) (dation) (18) c a2-1 Pe 23 (ase a Ubu antl loge ® cham 8 weed y= 1802) uaa None O08 (apicc 32-3 Po (a2ti a) Webel ogtuettoierteapy al Pusrbatdses ong. (Unda 1=724, (1 on 16 ‘aa (easseconsdung ty, alanis 012 (AT WO88) | 2792 368 Pa, arta cline (mative mal =, (2) eset mean ih agar, -0.26 vais 80,8) iy (aatio 20 ‘brevis BF Hood press Conta confines tara DBP, dasa aod pres ES tlt aw HN human munodticeney vs \itrvenion LDL. vedas Ipopratan chlseak MENS, meeaton vent martonng syst WA, nat sss: NS, not sneant SBP toe ood Dimes, iftnce tween srenton snd con oup- “Cul at be eat ith vale aa, {usted tz age, sx bassin Band baseline acerence, unused arses showed no sigan trance, Tights SBP and Paso showed a wend tong higher akuesin the tarenon gp. ‘Sloodharance was defined a ang to cole! medeatons for 2cansecatve mont [eras alo compare bya 10-pont sal analog seb, [= 093, =0380, 4 =013, P= O12 ‘The ES wa alee yung median stad of masn andy converting range o standard deve, (©2007 American Medical Association, All rights reserved. jamanetvrork.com/ by a Mexico | Access Provided by JAMA. User on 08/23/2021and behavioral elements, 5 demon- strated improvement in all adhe cence measures," and 3 others reported mixed or nearly significant results??? The significant effects ranged in size from small tolarge(ab- solute ES values of 0.43-1.20). No studies in this group were able to demonstrate a signifieant change in all measured clinical parameters, al- though several trials noted a signifi- ceant improvement in at least 1 clini- caloutcome!*"" orastrongtrend. ‘The ESs ranged widely across stud- ies (very small to large ES [0.17- 1.58)). No consistent relationships were observed between interven lion characteristics or disease slate and the success of the interventions. For example, 3 tials implemented relatively similar interventions among patients with asthma, but their reported effects varied sub- stantially." Regarding the 2stud- ies with strong social support ele- ments, both successfully improved adherence (unable to calculate ES), but neither led to beter clinical out See In this systematic review of random ized controlled trials designed to en- hance medication adherence in chronic medical conditions, 16 of 37 trials reported a consistent improve- ment in adherence.” Four other studies noted asignificant change in adherence among a particular pa- tient subgroup, with some but not allofthe adherence measures used, for in a certain arm of a study test ing multiple interventions.” Nine of the 20 trials that had some impact on adherence were able to demonstrate an improvement in some! oral" of the measured clinical outcomes, Of the 17 studies that did not show an im- provement in adherene: proved clinical outcomes; the ap- parent lack of effect on adherence in these studies was probably due to in- sensitive adherence measures oF a ceiling effect. Previous reviews have found 2 im- few if any consistent relationships References 21,25, 28 32, 3437, 39, #2 "4648, 50,51, 36 between the characteristics and effectiveness of interventions to improve adherence.” In the pres- ent study, categorization of the trials by intervention type (infor- ational, behavioral, or combined informational, behavioral, and/or social support) and calculation of ESs permit a few general observa- ions. Behavioral interventions that reduced the dosing demands of individual therapies consis- tently improved adherence with « large ES (0.89-1.20). Apart from this, other successful interven- ons usually contained multiple clements delivered over time. For example, 6 informational inter- ventions that provided educa- onal counseling over a few ses- sions and addressed self-care issues improved adherence with small to large ESs (0.35-1.13) Successful behavioral interven- ions based in monitoring and feedback and the most successful combined interventions also included various elements, such as self-management plans, rein- forcement, and occasionally rewards, Despite the ability of these inter- ventions to improve adherence however, a positive effect on clini cal outcomes was demonstrated in- frequently, and ESs pertaining to clinical outcomes were highly vari- able (very small to large ES [0.17- 3.41). Moreover, results for clini cal outcomes were not consistently related to the magnitude of adher- ence results or the characteristics of the intervention. Unfortunately, many of the studies were relatively small and not sufficiently powered to detect differences in clinieal out- comes, Thus, the results of many of the studies are indeterminate for clinical outcome, rather than clearly negative The adherence literatureand pre- sent study had several additional limitations. First, because we in- cluded only published trials, the re- ported findings may overestimate the tue fect of such interventions due to publication bias, Second, out in- clusion eritera were somewhat strin- gent. Many studies with shorter fol- low-up of no measurement of clinical outcomes were exclude and they are listed elsewhere. Third, our ability to categorize the trials into distinct modes of inte vention was limited by the fr quently complex nature of the in terventions, requiring us to make judgments about the predominant components. Fourth, although we calculated ES and can make gen- feral comments about the magni tude of adherence and clinical out- come differences, the included studies were too heterogeneous to warrant pooling in a formal mela analysis. Fifth, the literature re- view was completed in September 2004 and trials published since then may differ in their results, al- though they would be unlikely to substantially change the conclu- sions drawn from the 37 tials in- cluded in this review. Because most of the available literature does not separate out the effects of the individual com- ponents of multifaceted interven- ons, it is not possible to draw definitive conclusions about which features of combined inter ventions are most beneficial Additional research is needed to clarify which features are most responsible for changes in adher- tence and clinical outcomes, with the caveat that individual compo- nents may not prove powerful enough to show important effects Future studies should also examine the effect of varying the intensity of interventions to determine dose- response relationships. Such find- ings would have important im- plications for health systems considering the implementation of patient adherence programs on a large seale. Investigations should be conducted with elinically mean- ingful outcomes as the primary end points and be sufficiently powered to detect a difference in these mea- sures. Most important, future research should seek to understand the determinants of adherence clop and test innovative ways to help people adhere to prescribed medication regimens, rather than persisting ‘with existing approaches. In summary, we found that se ral types of interventions are e fective in improving medication adherence, but few were able 10 demonstrate an impact on clinical behavior and to des (©2007 American Medical Association, All rights reserved. jamanetvrork.com/ by a Mexico | Access Provided by JAMA. User on 08/23/2021Table 3. Combined Interventions patna “inert ESOC) ‘inca oveeme Gece suza___[Sempe sussex tadRacts"s_rArence eaves ones cla uae Ranga etre TR, Fie pees, Oke tewnae Ua OR Stet 2m TH Seah oat Worbod be abr(ssotGtene 2 (0Sw0s5, (isemesrmponinpst7é Germ Otay Satewagenctpin, 89, sal O46 i 0=210,a=-186, (nore 028 Indl cress 302 Pe Ot (aiw0%, Po, (chad 0, Sept op eps Clsalvoptadszwrceto ()masum O88 (2) baredy asteminpst7é 3) eum 288 felon nicer estens, (03208) i cafo.a=-I0L | (Le 20, cc Usud ae auxon Gt, a (nm -02 amphi tare psn 8. GAepossingatime —° (-OsbDi8) furan (pace rae ae a ysl 2m = 78 Cebta.a2213 P= tot (seta hin Sr saeo cont, Beez Pots Sern, HV I-20. EES hanes (Fal pin (Lag) il.) Na aio Cai? duty Seva, Deiat, | (Odeo Sn ebziatt) aa ‘raj ardreovetaries, Pete (eho poids reowes C)siepatadwburnce (0081138) Frivicresteos=ss “(ange om tae, fiksilonngtanng, mans SE, 3) clsuegetmedean = T=aT foumsingatcincesy — C=02e09% 3-25, Simo yonads pons, POT ree end ag, se phone cl 2 ese, home it aren rasta Rumtid —EEGrepparucons hot Pecbed dosaen Nona 15 (1) Die eis. ue ese tate Etmmtgs cut ma, D5) Pi ie ‘erg st rors, emo) (= 8918 (2) Crean prain 12: Fenoemat merino 214-8 PAS Ps $28 ors (3 conc (2m: ‘ues cone or ? sce (6 rg maton (2m Savant pric, eas yea atone Fag skal ora tien Boch ound ene Catecake Atha, N= 168 :Achacdsionpogam 250% oP eas is Mavdscrsstombasig, (1A Sma 048 ‘or (Hiywockangeiten than (gto sd "rans S 12m eens, i Storpn eden pet tow nes, 2 mot P= 08 epi a8 Coupee antery chong Whats 4031.0, “bedet Su) garry ate at Cooisonr Boe" QA rene 25 hers neg lone) earner: "PO TawOst {u t (28) meu, 078, (Usa sn (iiie-oa increas, (ai Cage ‘ret ape (taeieOa ‘Sob a pay ol (a8 ge 5s pla Walston werkorstot: "20h esti, heeseathegsetd. WALCmedum 087 c23sa2 Foe abu th (1-6 038 (aaa nt) Coulata® lchaniceat Montiifomatond o —Sétsmpated ads To tes an, 12:0: ie Sappatistp mectigs (12a Pt Co 034, 4-00 (civ iy ya Usa Fated Atma |=, FEascastmactieion, —Depesingsertsol Las 087. anit rata to 04 ‘horas C=28 tin safmanganeitpn, eoultgradeaios (BH0w14t) eacmbaimn(=4.0=36, (44110070) EA prerotere ta, (cones) an, % Sante andStlorap cals mg) 1=21 C= 08, teranorepan a t2uk S147 Pont Eka ola ob HV.I=68,Eliieounnng dele 90% Prd eee Meum. 051 (1) Unde and (24k (1), 022 fie" C=1al|— bmatonsbat sensaiegt (Othe Dc=sud s=106 | OO 08m) i00 rodeo ae tome tw 1-18 is ae. oder se, ERT Sa P= ine Bstconn vet ran (ia 9 teense, mx jglag7s (lage ‘inte ims iat) Usa apn, (ns nc ca cou 2 Bn, HZ Peary (continued) (©2007 American Medical Association, All rights reserved. jamanetvrork.com/ by a Mexico | Access Provided by JAMA. User on 08/23/2021Table 3. Combined Interventions (cont) Tepiaiee Taxes neaowe e700) ines oo sure ‘SEminseer—_—_inenetegcano ‘nei, teers teases oneal ste aa Teast paras Ge Spits Teg Sateen ral a0) iat ath=t Spt aehue cd mans gray “Thssm039 “leaittcmias 3h Sat, ‘ai ‘Shomer ssmsen ovsengal [2803 (hea (ane 010 jet meager dope C= 07803, (tw Sema menee aren) FAS one Os recanted. 1 25 (250029, ae laine econ, Wericemnacoapens (azi025) ann lig! -27. Camis mimi) Mae 72 Sd er rr ‘Shekel tsp ng) 1-88 138) Ta25.0=85, ‘att Mascot crane settreg yeallnghgC=11 ip 0 iresear at iseeve, (asta) ales renbars opps ‘Raman othe akel ed 5 Gre, oon 238 Pot eta, Alo ge senna See mtn (os 021 ar TR), “iaddeorthnn. naa te) at, iam i eran ae lwp ve hoa 040 tnd Poke ¢ (aie, ‘ie Glenda (deta ean spt wu: (01719088) |eanessaa rots Boot Sat Hpsraion, 2 2h ices 1) 80K Psibed YO PIS tue ay edt, wristny organs dee ol ar, i Bhi ogame So) P= Elston estes mies (lyme reba bak res Pet obit (olamcrae carga ‘semen Pete. 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P= soci Dib, ‘Baal stems tmpy Serene (ge AY ‘Ha nga, Tema “ie “YS “Titi meri “tombe ons “Gone ami 0, edcatmandsrsat(iDgeip $20 = 33 ()iegaz-a2 iY earl ol scl ager G3 =-A6 oma P= ns cclan ecy ‘sop Smusgenet ‘neg ‘breve Ceol confines rena COPD cane csv pulmonary dae DBP, date Hood press Stet sl Hb, amogibin Ihara immunedetcngy vis; HROOL, healed quality of if | erenon, nt aval NS ro seat PE peak epratory Te ‘5.35 d-ta Sharefom Hel Survey, ene sven renin and anol ups cul at be cated with avaiable ata, 4 Pale recaltd tom resus in arc. Lover care ineates ete adorn. Sierenton group hal re urgent ists han conta groups [Rests bt or coxtmed by ptsandlcommunzaton wth authors. ‘Higher soreness ote adherence, (©2007 American Medical Association, All rights reserved. ijjamanetwork.com’ by a Mexico | Access Provided by JAMA. User on 08/23/2021 Downloaded From: https:/‘outcomes. Based on this review of the literature, the most elfective in- lerventions appear to be those that simplify dosing demands. Inter- ventions that invelve monitoring and feedback, as well as informa- ional interventions delivered over multiple sessions, are probably also effective Accepted for Publication: August 23, 2006. Correspondence: Sunil Kripalani, MD, MSe, Diviston of General Medi- cine, Department of Internal Medi cine, Emory University School of Medicine, 49 Jesse Hill Jr Dr SE, Ailanta, GA 30303 (skripal@emory edu). ‘Author Contributions: Dr Kripalani Ihad full access to all of the data in. the study and takes responsibility for the integrity of the data and the ac- curacy of the data analysis, Study ‘concept and design: Keipalani and. Haynes. Acquisition of data Kripalani, Yao, and Haynes. Analy- sis and interpretation of data: Kripalant, Yao, and Haynes. Drajt- ing of the manuscript: Kripalani, Yao, and Haynes. Critical revision of the ‘manuscript for important intellec- ‘wal content: Kripalani and Yao. Sta tistical analysis: Kripalani and Yao. ‘Obtained funding: Haynes. Adminis ‘trative, technical, and material sup- port: Yao and Haynes, Study super vision: Kripalani and Haynes Financial Disclosure: None re- ported Punding/Support: Dr Kripalan was supported by a Mentored Patient ‘Oriented Research Career Develop- ment Award (grant K23 HLO77507) and formerly by the Emory Men- tored Clinical Research Scholars Pro- ‘gram (National Institutes of Healthy National Center for Research Resources grant K12 RROI7643). Dr Haynes is supported by the Michael Gent Professorship. Role of the Sponsors: The funders hhad no role in the design and con- duct of the study; collection, man- agement, analysis, and interpreta tion of the data; or the preparation, review, or approval of the manu- seripl. Acknowledgment: We thank Stephen Walter, PhD, McMaster University, for his assistance with ES calculations and comments on an (aePnosrep) SRGHINTERN WEDIVOE 167, WAR SE SOO? carly draft of the manuscript. We also thank Heather McDonald, MSc, Ageel Degani, MSc, and Amit Garg, Mb, PhD, for their contributions 10 previous Cochrane reviews, Se 1. isteotR vasasnsinpati aereoe to medial commanders a quae ein 1 50 yuars of aseneh Med Care. 2006:2 0-208. OswbagL Busca Adbencetomezaton Eg Med 205 358487 97 ays, alr, ace DL. es. Cam nen Hel Care Batt, Ma Los Hop- ins Unis Press 170 4 Diaea i, ordaniP, Lepper HS, Croghan TW Pst sien nade nent oes: a matanais Med Cav. 20020: nse Sokol, Mesuian KA, errugge BR, sin S.Imactt mada athranc on hospi ion rind alae ae. Mad Cre. 205 e920, rit, Meiko J Maal dbase re Search tmeforachangein econ? Med Cae oot2-07-1, Donald HF, arg AX Hays RB nan tons to enkanes patent aheence to mas tones: screen JANA 202 ve2ase-207, Parson Taj, Fey Meta ot traf itrverions 1 improve medication dere. AJ Heath ys Par 200380: tsr-s, or DL Hal, Maric, Nrdstom 8, Cr tn. Srl 8 Efecnees of aantans ‘wimpron pain compte: a mateanais Meg Cre 1008361138111 10. Kruger, Fala 5, Berge BA. Inpovingas. race ad parse: evi dase. etfieretn anédesrigton ot tp 1- rds adherens, Pm Asso 20848668578 col, Vemuri F, Sng Acta a inf mthoeay tte tone ato cmpanes. Ate Pharmacare. 1980; resi, ayes, YaoX Dear, KepaaniS xg Netlonsd i. Inventions oannance mide tan adhatece octane Untabce St Re 2o0s4;coon0| 12, Haynes RB, Orernans tomlin ee ‘sean rhe cfatmtfHays 7B alr DW Sake DL ee. Compliance eat ar Baines, Meh opin Un ory Pes 10794042 1. Kruse Mond, Hye A Mursner, Moy etodstoimptovemedcatonadhrncen p= tenth hypertension: cure status and ture directions. Cur Opia Caco. 200520, 26-00. 15, Water Ny SM, Dovies TO. Deoping ata sry ofimerenions usd inane it act of esac, psu stands ck ‘bearTaxonomy's20éelopmens20papet ‘2007008 pat cased Neer 29, 205. 1. Coben J Sttti!Pover Aah fr the Bs oo Scie nde Hee Lance Eth eros 108 17, Hodges LV, On. Staistc! Methods for 0 a a 2 (©2007 American Medical Association, All rights reserved. Downloaded From: https:/fjamanetwork.com/ by a Mexico | Access Provided by JAMA. User on 08/23/2021 Mr anassOvdFeadaiPres: 1085 Waters a0 Elect ses can clltsor suds reprig ange fo outa varies ‘in Een. nr. GalfoaeF, aka PS How done patie ss ‘nar se-narageent among anata pent von tute ulnar de (Seat mado? Amd asp it ‘a9;602000-205. Gafss alka PS, RsgnrdPK. Cay fie sus ar pat auction inaranom ad conoled stuty on astina and cone ob Sout plana disease Ar Jap Cr ae ed on. 15087287 ano Ctins TE, Cat P, Orne Lane M fet of cousin ta improve camplance in Meccan women reeaing dept metonpo (sero surate, Contraception 200% iene Cot Bow DM, Richa P, aren, st ‘i Bout. Euston two tern ‘tna ntreton for au stints canst. lag wth an aut asthma eaerbaton. Am J esi Gt Cre ed. 20011531815 140. Hi Br otnson Ett att eds ‘anon aderercete dug eset hau tod aes andoniee coal rl. an teu 200 0 36075, Laporte, Oust 5, uchmulr-Crar ta Conglanze and tay NR oo rar caagulans with ferent halt-ives: aan lomsad tril. Thromb Haemost. 200888; sea, Lay ML, Robb, Alen J, ober, nd, Winer RL. Arandomzd corre eiuronct ‘pcan edvaon loving ie and mrgenc deparmeat attendee fr acte Stns Resid 200 90008. Nace A Wren. Theol ote aebanse ‘vemertcrplanes al se- marae lawing hoe! amieson. spr Med 200 pasi-ase Patron Gf, Flare KO, aun M, Vit 1H, Sar, Krum act pharmacist anced ome vats onthe atome of pe lowering du ey. in Par Tr 2004 27090, Frade rz, Spi 8, et al. cary ofan educatonal and courslg navn o rence to ight active anretonral harap: French prospec conoled study, HY Cin Tals 200892118 ving MK, Tompson MA, Farting Ft: [ZTAO6 Hap EnancsAhaenceo titetrvita Therapy (HEART) Study Team Inpactatan deat progam anefiescyand aidhorenc wit 2 twee-aly lamivudi $idovuine/bacavie regimen in undarepe Seed Hinder Agu imute De fe Synde 2003S TT. Schafer $0, Tan . Ponting aherenes ‘ec ttn sd asta education Cs Fee 2004136080, ‘ans SM agar AF, Colin VT, Sehaten i sere Anitennton pregame ung ‘he ASE made aimed at esncigasene a ‘dlscerts wth tina att Ede Cone uoraean 20, Barc Bote oor Carher, tal As ticay,toetance and compancs of once-aly verev wen daly metaprall Ee ae in hypertension. Clio Ines Med 1984 T5102, Becker LA, GK, Sobel E. Mose ZanPy 0 4 oot A radi lf pil pack ‘ngofansyperensivemadatons. Fam Pc ‘e227 26, Srown 86, Barly Poulin Ot al Moderate osetia hry wih nic, lest, ed oes ede lo-esty ipopetn holst = 10 mga pate wth hype Spdania and coronary artery disease. Ar J Cait ton7 a0 ts, Fodman RY, Kaz LE, Jet Ata Atco musiesos syste for matringand cour hy pens wth prensa. npaton aon adherence ade presureconta. Art “yp 195 9285202 ‘Ginn 8, MeDemietB, Jonson GD. com pason of nlp 20 gence daly versus 10 ‘ng ice intr food rss ve nad patie camplanc. J Hypertens. 1986, 73627-1631 Haya 8, Sse OL, GREOnES, ta. Inproe- ‘net of mdzaoncamplane i uncooled persion. Lanet 107 11255-1288. Jonson AL Tar OW, Sack DL, Due CW, ‘Shimzu AS Satecring af lod presen ‘he manager of perro. CHAL 1978 ‘onuae 09, Marquez Contreras E, Casate Martine J Cortada tal Efe of anita. tion fo improve Weatmant compliance in hyperipigeras. Ato Prima 200438, aea50 Waly JO, Khan MA, Nell JW, Khan MH ects of ha ect bern campo un of DOTS fr tubers ranomieed anole alia Pisa, Lancet 200757 utces Weber, hen Crist Sea. tt ot (aePnosreD) SRGHINTERN WEDIVOE 167, WAR SE SOO? 2 a « a. a inci copitve behaouranenion ona ernceta aren cap prospec femae Anbi Ter 20048506, aly WC, Ricard JM i, rks CM, Soong 1 Windzor Ak Maral Aranda ‘wimpro sa-nanaenert paces of ats vith ats Ach Ino led 190 50688. 16. Bran VM, Saar JO, Ryn, Mey K HELV Meson Adres trenton Group. Aaherance to anata therapy in HIV= insted pda pans improves th hans ase inensive nung irenion AIDS Pe te Gar STDS 200418355362 rH vane Lair, Tal, str, Wg ian 0 Efecto at educatan on camp ca wth asta ment einen and eatin acetone active auto ats, An hou Di 180857 4616. Cte Carier A Roichaud Petal ene an hia mority of asthma education gro- (yams baad an st-rangument plans fon ingteatentopinzaton Ae. Respi Crit Cae Me. 1671536001514 Cau AL. Toor, Eon Murdoch PS, Ha (yeas 0, randomised contol il ots Nor Lz Heath Meaning in oer pple wh Ischaemic ar ce The reba Pre Age Agang, 204 3848-258 Fata Oli Tra ata ue an program nan inet pati ere tency deparmant. Ped Asthma Alergy Soman 200871071, nobel Camons A Lona etal. Adbernce to er ace areal xtra mpl of inci aeeeean Enferm nic io tin T0776 4 61 2 fs (©2007 American Medical Association, All rights reserved. Downloaded From: https:/fjamanetwork.com/ by a Mexico | Access Provided by JAMA. User on 08/23/2021 ‘are Baton A, Sula Sith es ‘A Timbul HA pharma charg orhos- ale elder patna randomized con ‘ole i. ge Aging, 2030-0 Patarson GM, MeLeun S Migen KS. Aran- aise ie sepa improw pec lance with antianvlat hetay, Eilepsia fnsezstr2t7 Peto JD, Weber M, MePhe J, Mah CA ‘aumer 8, Capa Ao aoa cls ith rus flo-upngrovsel.crand ghee onl among wineable patent with abs? ‘rnd 2000-18202 Suet OL, Heyes RE, Gitson 5, ar aise inca al a states for inprirg ‘meeaton compan prima hyperensi, ne 1875:1208-1207, Tea A, Fumar OF, Fore AU, ta. rsp tiene eam canal study td tara eiay o spsctic nenaren a impos long tm acaenes high ata ‘eo harap. Acar inne Det Sd 0025221228 ‘ol Faris ME, Kseam Cox, Cae 8, Pharmaceutical cae research and edvston oer pati euzomes. J Am Pharm Assoc fas) ont 20, WenbetgerM,Maray MO, Mara 06, ea. Etetiees of parmaist are for aera wth rene seas dense: a randomize ca trol il AN 2002268154602 Wyse, Greco P, Haris MA, Bub J White 1 Behavior thay foams of adlscas wth ates mamcane orator ti, Datiws Cre 2001264416,