Interventions to Enhance Adherence to Medications in Patients With Heart Failure
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This report provides an up-to-date review and analysis of those studies that have developed and evaluated medication adherence interventions in CHF. Strategies to enhance adherence provide a potentially valuable strategy for improving survival, reducing hospitalization and managing patient symptoms in CHF.
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Cochrane Central Register of Controlled Trials,MEDLINE, Cumulative Index ofNursing and Allied Health Literature (CINAHL),Embase,and PsychInfo were searched for full published reports to the end of December 2010. All databases were searched from theirstartdate.The search strategy incorporated relevantterms from recentCochrane Reviews on adherence to medication11,12and heartfailure,13and a highly sensitive search strategy developed by the Cochrane group for maximizing the identification of randomized trials wasalso applied in Medline.14The reference listsofall selectedarticlesandrelevantreview articleswerealso searched foradditionalstudies.Only studies/abstractsin English were included because translation services were not available to the authors for this review. Data Extraction Data were extracted from selected studies with the use of a predefined form. Data were extracted by Dr Molloy. Risk of biaswasassessedindependentlybyDrsMolloyand O’Carroll, and discrepancies were resolved by discussing the discrepantjudgments.Details ofinformation extracted are provided in Tables 1 and 2. Study authors were contacted for additional information. Quality Assessment As recommended by theCochrane Reviewers Handbook,14 we assessed study quality according to 4 main sources of potential bias in the identified studies: (1) selection bias, (2) performance bias,(3)attrition bias,and (4)and detection bias. To do this, studies were assessed for adequate sequence generation and allocation concealment(selection bias),the presence ofblinding in outcome assessment(performance and detection bias),and whetherreporting oflossesto follow-up and intention-to-treatanalysis were specified (at- trition bias).Selective reporting bias was notassessed be- cause few studies had published protocols before completing and reporting their studies,making assessing this aspectof bias difficult in most cases. The overall quality assessment for each study was summarized by using a risk-of-bias summary figure,based on Cochrane review recommendations.14 Analysis Pooling of the data was notpossible because of the hetero- geneity ofmeasurementand analysis between studies.We grouped studies according to the main components included in the interventions. This was based on categories specified in a recent systematic review of interventions to enhance adher- ence to lipid-lowering medication.12 Selection of Trials In total,the search strategies identified 1660 records (after removalofduplicate records)ofpotentialrelevance from searches of all 5 electronic databases (Figure 1).An inspec- tion of study titles and the study abstracts revealed that more than 95% of these did not meet the review inclusion criteria. Fifty-three studies were retained forcloserinspection,and only 16 independentstudies derived from these studies met all the review inclusion criteria. The flow of studies through the selection process is summarized in Figure 1. Characteristics of Included Studies Sixteen randomized,controlled trials were identified,con- taining data on 3305 patients with CHF.The median total sample size was 144 patients,with a range of 37–902.The majority ofstudies(9/16)were conducted in the United States. The average age of the study samples ranged from 55 years15to 85 years.16Male participation in trials ranged from 37%17to 99%.18The median follow-up time was 6 months, ranging from 2 weeks to 12 months,with 6 of 16 (38%) of studies having follow-up times of less than 6 months.The mean percentage of patients included at follow-up in the 13 studies thatprovided this data was 79.8%,with a range of 28 –100%.Adherencewasmeasured by self-reportin 5 studies, the medication event monitoring system in 5 studies, tablet counts in 3 studies,and medication refill records in 3 studies.Because ofthe heterogeneity ofmeasurementand limitationsin reporting,itwasnotpossibleto reporta summary ofbaseline rates ofadherence forthe reviewed studies. Table 1 outlines a list of intervention techniques that could be identified from the reviewed studies. Full details of all included studies are provided in Table 2. Risk of Bias in Included Studies All16 studies reported random allocation;however,there was limited information provided on sequence generation and allocation concealmentto evaluate this with confidence for many of the studies in this review. Although double blinding Table 1.List of IndividualIntervention Techniques Specified in the Reviewed Studies Simplification of the medication regimen/consolidation of the medication regimen17,20,25,30 Patient education—individual15–17,19,20,23,25,26,29 Patient education—in groups28 Family education23 Self-monitoring of symptoms17,18,25,28,29 Self-monitoring of adherence17,18,25,28,29 Health care provider monitoring of symptoms directly7,20,25 Health care provider monitoring of symptoms remotely18,20,21,23,24,26 Health care provider monitoring of medication adherence directly16,27 Health care provider monitoring of medication adherence remotely18,21–24,26 Telephone/video telephone prompts to take medication27,29 Enhancing communication and coordination of patient health information between health care providers17,18,22–26 Enhancing motivation to take medications16 –20,23,25,29 Knowledge and skills assessment16,19,22,24 Medication dispensing24 Verbalinstruction16,17,19,20,23–25,27 Environmentalrestructuring18,28 Eliciting socialsupport in the community18,28 Eliciting support from health care providers15,25,26,29 Cognitive restructuring28 Relaxation28 Barrier identification28 Coping planning—planning to overcome barriers28 Molloy et alAdherence to Medication in Heart Failure Review127 by guest on April 8, 2018http://circheartfailure.ahajournals.org/Downloaded from
Table 2.Summary of Studies That Evaluated Intervention Strategies to Enhance Adherence to Medication in Heart Failu in Randomized,Controlled TrialDesigns Sample Size Follow-Up (%) Mean Age, Years (SD) % MaleAdherence Measurement Follow-Up in MonthsKey Study Findings Relating to Adherence Patient education Gwadry-Sridhar19(2005) Canada 136 (99%)C:65 (12) E:67 (14) C:69% E:76% Heart failure medication refillrecords. 1287% intervention group adherent to ACE inhibitor versus 83% control(NS).-Blockers: 87% versus 85% (NS).Digoxin:85% versus 81% (NS).Diuretics:77% versus 77% (NS). Rich20(1996)United States156 (not provided) C:78.4 (6.1) E:80.5 (5.7) C:41% E:26% Pillcounts.1Adherence was 87.9% in patients randomized to the study intervention,compared with 81.1% in the controlgroup. An adherence rate of⬇80% was achieved by 85.0% of the treatment group versus 69.7% of the controlgroup. There was a significant difference in adherence between the groups. Intensified patient care—direct patient contact Bouvy22(2003)The Netherlands 152 (60%)C:70.2 (11.2) E:69.1 (10.2) C:60% E:72% Medication event monitoring system to measure loop diuretic adherence. 6Intervention group had fewer days (2%) without use of loop diuretics compared with the usualcare group (5%).There was a significant difference in adherence between the groups. Goodyer16(1995)United Kingdom 100 (80%)C:85 (5.4) E:84 (4.5) C:24% E:30% Pillcounts.393% of the intervention group was adherent according to pillcount at follow-up versus 51% of the controlgroup.There was a significant difference in adherence between the groups. Laramee23(2003)United States 287 (82%)C:70.8 (12.2) E:70.6 (11.4) C:50% E:58% Self-report measure of medication taking on a 5-point scale:1,never;5, always. 3No difference between groups at 4-wk follow-up.Self-reported adherence was significantly higher at 12-wk follow-up in the intervention group. Murray24(2007)United States 314 (86%)C:62.6 (8.8) E:61.4 (7.7) C:34% E:32% Medication event monitoring system to measure taking and scheduling adherence to allcardiovascular medications. 12Adherence was 67.9% and 78.8% in the controland intervention groups,respectively. These effects dissipated at 3 mo.Medications were taken on schedule 47.2% of the time in the usualcare group and 53.1% of the time in the intervention group but this effect also dissipated at follow-up. Sadik25(2005)United Arab Emirates 221 (94%)C:58.6 E:58.7 C:50% E:50% Self-report binary:Yes/No.1281% of the intervention group was self-reporting to be adherent at 12 mo versus 34% of the controlgroup.There was a significant difference in adherence between the groups. Varma17(1999)Northern Ireland 83 (28–59%)C:76.4 (7) E:75.5 (6) C:37% E:45% Self-report binary and drug use profiles using patient medication records. 12No significant difference between the groups in self-reported data.The intervention group had significantly better adherence,10/13 (77%)versus 3/10 (30%)according to patient medication records;however,only n⫽23 for this analysis. Intensified patient care—telephone or telemonitoring Antonicelli21(2010)Italy57 (not provided) C:79 (6) E:77 (8) C:66% E:57% Self-reported by telephone.No other detail provided. 12The intervention group adherence was significantly higher at 89.7% versus 35.7% in the controlgroup. There was a significant difference in adherence between the groups. (Continued) 128Circ Heart FailJanuary 2012 by guest on April 8, 2018http://circheartfailure.ahajournals.org/Downloaded from
Table 2.Continued Sample Size Follow-Up (%) Mean Age, Years (SD) % MaleAdherence Measurement Follow-Up in MonthsKey Study Findings Relating to Adherence Fulmer27(1999)United States 60 (83%)C:73.7 (5.3) E1:76.2 (8.8) E2:73.1 (6.5) C:? E1:? E2:? Medication event monitoring system to measure up to 4 heart failure–related medications. 2 wkThe controlgroup adherence dropped from 81–57% between baseline and follow-up, whereas the 2 intervention groups remained stable:telephone,76 –74% and video-telephone,82% and 84% at baseline and follow-up,respectively.No significant differences between groups were observed. Jerant26(2003)United States 37 (not provided) C:72.7 (11.4) E1:71.3 (14.1) E2:66.6 (10.9) C:50% E1:42% E2:46% Nurse log of adherence. No other detailprovided. Binary:⬎75% orⱕ75% of doses taken. 6No significant difference in adherence to medication was observed. Ross15(2004)United States107 (76%)C:55 E:57 C:74% E:80% Self-report:General Adherence Scale from the MedicalOutcomes Study. 12No significant difference in self-reported adherence to medication was observed. Wakefield18(2009)United States 148 (74%)C:67.2 (8.5) Telephone E:71.8 (10.2) Videophone E:69.0 (9.6) C:98% Telephone E:100% Videophone E:98% Self-report:The proportion of medications for which the participant’s responses agreed with the directions for use. 6There were no significant differences between the control(91%)and the intervention groups (86%)at 6 mo. Complex behavioral approaches Powell28(2010)United States 902 (70%)C:63.4 (13.3) E:63.8 (13.7) C:52% E:54% Medication event monitoring system to measure ACE inhibitors or (-blockers if the patient was not taking ACE inhibitors). 12No difference between groups at follow-up. Both groups decreased adherence by 7%. Tsuyuki29(2004)Canada276 (100%)C:72 (12) E:71 (12) C:58% E:58% Pharmacy records: Medication possession ratio was calculated based on the No.of days of ACE inhibitor dispensed divided by the No.of days of follow-up. 6No difference between groups at follow-up in adherence to ACE inhibitors. Simplification of the drug regimen Udelson30(2009)United States 269 (91%)C:65.5 (12.8) E:65.1 (11.9) C:71% E:77% Medication event monitoring system to measure carvedilol adherence (5 mo). 5No difference between groups at follow-up. 89.3% of the controlgroup was adherent versus 88% for the experimentalgroup. Note:Although there were 3 arms in this trial, the primary comparison of interest for the adherence measures was the controlled-release carvedilolwith the double-blind twice-daily immediate release formulation;therefore we only focus on this aspect of this study. C indicates controlgroup;E,experimentalgroup;ACE,angiotensin-converting enzyme;NS,nonsignificant;?,not provided. Molloy et alAdherence to Medication in Heart Failure Review129 by guest on April 8, 2018http://circheartfailure.ahajournals.org/Downloaded from
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is not possible in most behavioral trials, the issue of blinding wasaddressed in 31% (5/16)ofstudies.Eleven studies provided information on loss to follow-up, but only 6 studies clearly specified intention-to-treat analyses. Figure 2 provides summary data on risk of bias across the 16 studies. Types of Intervention Interventions could be classified into the 4 main categories identified in a recentreview ofinterventionsto improve adherence to lipid-lowering medication.12Itis importantto note,however,thatseveralmulticomponentinterventions could be included in more than 1 of these 4 categories, and a distinctsetofintervention strategiescategoriesdid not emerge,as can be seen in Tables 1 and 2. (1) Patient Education and Information The educational intervention described by Gwadry-Sridhar et al19found no evidence that this kind of intervention can lead to enhanced adherence.The multidisciplinary intervention described by Rich et al,20which included aspects of education and information provision,found evidence that a multicom- ponent intervention can lead to enhanced medication adher- ence.Itisimportantto notethatthisintervention also incorporated intensified patientcare and simplification or “consolidation” of medication regimens. (2) Intensified Patient Care The 8 studies thatinvolved intensified patientcare can be subdivided into 6 direct patient contact interventions16,17,22–25 and 5 telephone or telemonitoring programs.15,18,21,26,27All 6 ofthe directpatientcontactinterventions led to enhanced medication adherence,whereas only 1 ofthe telephone or telemonitoring programs led to enhanced adherence.Five of the 6 direct patient contact interventions were pharmacist-led. (3) Complex Behavioral Approaches The largest study examining interventions to enhance medi- cation adherence in CHF conducted to date found no evi- dence that that a complex multicomponent intervention that included arangeofbehaviorchangetechniquesled to enhanced medication adherence.28A smaller study that also used a complex intervention that included a range of behavior change strategies also reported null results.29 (4) Simplification of the Drug Regimen The single study that attempted to evaluate this strategy on its own did notfind evidence ofenhanced adherence aftera simplification of the drug regimen.30Simplification of med- ication regimens may have occurred in an unsystematic way in some of the other interventions included in this review.20 Main Findings This review found that 8 of 16 randomized,controlled trials identified provide evidence that adherence to medication can be enhanced in patients with CHF.Intensified patientcare, particularly involving pharmacists,may bebeneficial,as there are at least 5 studies that show intensified care from a pharmacist,16,17,22,24,25in conjunction with other health care professionals, leads to better medication adherence in patients Figure 1.Selection of articles for system- atic review. RCT indicates randomized, controlled trial. Figure 2.Risk of bias summary. 130Circ Heart FailJanuary 2012 by guest on April 8, 2018http://circheartfailure.ahajournals.org/Downloaded from
with CHF. There is emerging evidence that patient education and self-managementtraining alone is noteffective in en- hancing adherence to medication.19,28,29The overallconclu- sion of the methodological quality of the 16 trials included in this review indicate that there is limited high-quality evidence evaluating the effectiveness of specific adherence-enhancing interventions in patients with CHF and thatthe findings of many of the existing randomized, controlled trials should be interpreted with caution.The heterogeneity in intervention techniques and measurement methodology observed between the studies in this review means that a conclusive literature on enhancing adherence to medication in heart failure has yet to emerge.Thismirrorsfindingsfrom otherrelated broader reviews in a range of clinical conditions.11,12 Our assessment of the sample characteristics also revealed thatthe patients enrolled into these studies were notrepre- sentative of the patients with CHF seen in clinical practice in terms ofage and sex profile.This indicates thatselection biases are operating in recruitmentin this area of research, which limitsthegeneralizability ofthesefindings.The relatively shortand variable follow-up timesseen across these 16 studies also show that there are limited data on the sustainability ofboth theintervention strategiesand the intervention effects in those studies thatfound significantly enhancedadherence.Fiveofthereportsincluded23–26,29 incorporated a health economicsevaluation with varying degrees of sophistication;therefore the costimplications of most of the intervention strategies are unknown. However, 2 ofthesestudies26,29reported significanthealth carecost reductions as a consequence of the interventions. This raises the possibility thatmedication-enhancing interventions can reduce health care costs, which may be particularly important in new health carefunding environments,forexample, accountable care organizations in the United States orthe Quality Outcomes Framework in the United Kingdom. Although a number of studies in this review did include interventions thatused information technology,specifically telemonitoring of patients with CHF,13this area of research has yet to evaluate the role or potential of electronic patient records ornew developments in handheld communication devices and social media to enhance adherence to medication in heart failure. Future work should attempt to investigate the potential of these new technologies in motivating,enabling, andpromptingpatientswithheartfailuretotaketheir medications as prescribed. Limitations The most obvious limitation in this review was that quanti- tative meta-analysis was not possible. A recent meta-analysis of 33 studies31testing adherence-enhancing interventions for older adults estimated that effect sizes were likely to be in the small to medium range,with a summary standardized mean difference of 0.33 in medication adherence observed between control and intervention groups. Only 1 of the studies in the published meta-analysis is included in ourreview.20Until there isgreaterconsistency ofmeasurementand analysis across studies, we cannot know whether similar effects can be achieved in CHF populations.Future investigatorsshould therefore assume thatintervention effects willnotbe larger than the small to medium range when conducting sample size calculations for new studies. The limited numberofstudies identified thatdescribe a heterogeneous range of interventions prevent us from draw- ing firm conclusions on many types of adherence promoting strategiesforpatientswith CHF.Forexample,thenull findings forthe one study30in this review thatcompared once-daily dosing with twice-daily dosing should be consid- ered in light of the limitations of that particular study and the considerable evidence in otherconditions thatsimplifying medication regimens is associated with betteradherence.32 There was also limited detailprovided on the contexts in which interventions were delivered. This makes it difficult to know where and when effective interventionsto enhance adherence to medication are best delivered. Implications for Research Adherence to medication and other aspects of self-care for a debilitating symptomatic chronic illness such as CHF is a complex behaviorwith multifactorialdeterminants,6,33in- cluding a range ofindividualand social-environmentfac- tors.34,35Although earlier studies have reviewed the broader issues of adherence to health professionals’ self-care recom- mendation in CHF,5this review focused on those interven- tions that specifically address medication adherence for 3 key reasons. First, the association between medication adherence and health outcomes is more precisely described,2,4whereas the benefits of other aspects of adherence to CHF self-care cannotbeestimated with thesamedegreeofprecision because of measurement and study design limitations that are inherent in studying these phenomena, for example, weighing oneself daily and limiting sodium intake. Second, adherence to medication is a very different behavioral phenomenon36 than other aspects of adherence to self-care in heart failure thatislikelytohavedifferentdeterminants.Finally, intervention strategies to enhance adherence to medication are likely to be of a different form than many other aspects ofadherence to self-care,given the unique barriersand facilitatorsto thisbehavior.5,33Therefore,there isclearly scopeto develop afocusforfurtherinvestigation into adherence to medication in heart failure as opposed to more generalized management of self-care in heart failure.5 Four of the studies included in this review18,21,28,30have been published since the Cochrane review of interventions for enhancing medication adherence,11and only 1 of the studies25 included in the present review was included in that Cochrane review.Another more recentrelevantreview on improving adherence to cardiovascularmedication10included only 4 studies from the present review.16,24,27,30 Many of the reviewed studies provided limited information on the contentof the study interventions.This prevents the development of a cumulative body of research or even simple replication of individual studies. The increasing emphasis on publishing detailed protocol reports in advance of the study commencementhasreduced thisproblem in more recent studies.This area ofresearch would,however,be greatly strengthened by the development of a taxonomy of behavior change techniques for medication adherence– enhancing in- terventionsto standardizethecontent,classification,and Molloy et alAdherence to Medication in Heart Failure Review131 by guest on April 8, 2018http://circheartfailure.ahajournals.org/Downloaded from
description ofintervention strategies.Thevalueofsuch taxonomies is gaining increasing recognition in other areas of behavioral science that focus on the role self-care in promot- ing health.37Becausethecontentand contextofmany adherence-enhancing interventions is not clearly specified in standardized terminology and theory from behavioral science is often absent, the approaches to intervention development in thisareacan belikened to developing antihypertensive medications without any understanding of the pharmacology of the medication, the physiology of systemic blood pressure control,or the pathophysiology of hypertension.38 Implications for Practice There is clearly scope to significantly improve outcomes in heart failure by enhancing adherence to those existing med- ications thatare known to reduce morbidity and mortality from heartfailure.CHF medication regimens have become increasingly complex asnew treatmentshaveemerged,6 which provides a challenge for patients with CHF to manage. Practitioners should consider that developing effective meth- ods to increase patient adherence to existing medications with known efficacy could have far greater health benefits than providing new treatments thatmay notbe followed.11The reviewed studies do provide evidence thatenhanced adher- ence to medications can be achieved in heart failure patients and thatthe role of pharmacists may be particularly impor- tant,in particular,directcommunication between patient, pharmacists,and otherhealth careproviders.22,24,25This review also suggests thatpatienteducation aboutCHF or self-management training alone may not be effective. Overall it is clear, however, that formal recommendations on the best approachesto enhanceadherenceto medication in CHF cannot be derived from the existing studies. New studies with more clearly justified and specified methodology are required to generate a cumulative body of findings that could be used to inform clinical practice. In particular, more explicit use of behavioral sciences in developing adherence interventions in CHF is clearly warranted. Conclusions Itmay be possible to improve adherence to medication in patients with CHF by using a range of strategies;however, thespecification ofeffectivetechniquesrequiresgreater clarity in thisliterature.There iscurrently limited high- quality evidence on the effectiveness of interventions that aim to enhance adherence to medication in typicalheartfailure patients,and furtherresearch isneeded to identify the optimum strategies for implementation in clinical practice. Disclosures None. 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