Adherence to medication in patients with chronic kidney disease: a systematic review of qualitative research

Adherence to medication in patients with chronic kidney disease: a systematic review of... Non-adherence to multipharmacological treatment increases the risk of morbidity, mortality and hospitalization. We know little about the perspective of patients with chronic kidney disease regarding factors influencing medicine taking. This study aimed to synthesize findings from qualitative studies of patients’ experiences of factors that facilitate and hinder adherence to medication. A systematic review of qualitative studies adhering to the Enhancing transparency in reporting the synthesis of qualitative research (ENTREQ) framework. Systematic searches were conducted in several databases. We used thematic synthesis and the Confidence in the Evidence from Reviews of Qualitative Research (CERQual) approach to assess the confidence of the evidence. Nineteen studies involving 381 patients with chronic kidney disease were included. We identified three analytical themes; logistics, benchmarking the need for medication; and the quality of the patient- physician relationship, with seven descriptive sub-themes as factors influencing patients’ adherence to medications. Helping patients to map their everyday activities and motivating them to associate medications with everyday activities may facilitate adherence to medications. Addressing patient beliefs about medications, supporting patients in coping with side effects of medications and eliciting patients’ wishes for involvement in treatment decisions may also facilitate adherence. Barriers to adherence were the costs of buying medications, and lacking understanding of the indications and effects of medications. The findings in this synthesis resonate with previous research and extend the known literature by synthesizing and formally assessing confidence in the evidence. Key words: chronic kidney disease, medication adherence, patient perspective, qualitative review, systematic review Received: June 30, 2017. Editorial decision: November 10, 2017 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfx140/4774630 by Ed 'DeepDyve' Gillespie user on 07 June 2018 2| T.M. Nielsen et al. searching each set of search terms using the Boolean operator Introduction OR and subsequently combining these searches using the Adherence to medication is defined as ‘the extent to which the Boolean operator AND. Along with the electronic searches, we patient’s behaviour matches agreed recommendations from the manually searched reference lists and grey literature. prescriber’ [1]. In chronic kidney disease (CKD), adherence to We uploaded the search into the Covidence software, where medication is a key component of effective disease management two authors (T.M.N., T.T.) independently screened the search [2, 3]. The main goals of medication are to slow progression of the results for eligibility. The search was conducted in January 2016 disease and monitor and correct disease-associated complica- and updated in June 2017. Figure 1 illustrates the literature tions and comorbidities while treating the underlying aetiology search and selection. [3]. Patients with CKD are prescribed a regime of multi- pharmacological treatment often starting with antihypertensives Quality assessment and antidiabetics and subsequently phosphate binders, vitamin We used the Critical Appraisal Skills Programme (CASP) check- D preparations, calcimimetics, erythropoiesis stimulating agents list for qualitative studies to assess individual study quality [8]. and iron supplements [4]. This infers a high burden of pill intake Two authors (T.M.N., M.F.J) independently assessed the studies. with sometimes >20 pills/day [2]. Managing multiple medications and health care appointments, including, for some, dialysis sev- eral times a week, is a challenging task. Not surprisingly, patients Data extraction and analysis may miss medications, intentionally or un-intentionally (1). Included studies were imported into QSR NVivo 10 computer Estimates of non-adherence to medication vary from 17 to 74% data analysis software (QRS International, Melbourne, VIC, among patients with CKD and from 3 to 80% among patients on Australia). Following the method for thematic synthesis haemodialysis, depending on the methods used to assess non- described by Thomas and Harden [9], we extracted data about adherence [2, 3, 5]. This poses a major obstacle to achieving treat- medicine taking from the included studies, for example, all rele- ment goals and increases the risk of morbidity, mortality and vant data presented in the ‘abstract, results and discussion’ sec- hospitalization [3, 4]. Optimizing adherence to medicine is there- tion. To enhance transparency and reproducibility, two authors fore a priority issue for health care providers. (T.M.N., M.F.J.) independently conducted the open line-by-line There is a growing body of research into non-adherence to coding of extracted data. This resulted in a total of 31 initial medication among patients with CKD. Quantitative studies codes that were condensed into 16 preliminary descriptive have focused on the incidence of adherence and identification themes. The descriptive themes were subsequently discussed in of potential risk factors for non-adherence [2]. These studies the author group and a summary of the findings across studies provide valuable insight into the prevalence of non-adherence was drafted. All authors commented on this draft and, through and associated risk factors [2]. They do not, however, uncover further discussion of the preliminary descriptive themes, three life circumstances that may influence adherence from the analytical themes with seven descriptive sub-themes emerged. patient perspective. Qualitative research may contribute to our knowledge by elaborating the patients’ perspectives on non- Assessment of confidence in the review findings adherence. The aim of this qualitative systematic review was to synthesize the available qualitative research on factors that We used the Confidence in the Evidence from Reviews of facilitate and hinder adherence to medication from the perspec- Qualitative Research (CERQual) criteria to assess how much con- tive of patients with CKD. fidence could be placed in our findings [10, 11]. CERQual is based on four key components: methodological limitations, relevance to the review question, coherence and adequacy of the data con- Materials and methods tributing to a review finding [14]. Methodological limitations of A systematic review and thematic synthesis of qualitative stud- the individual studies contributing to each review finding were ies was undertaken. The review was prospectively registered in assessed using the CASP tool. Relevance was assessed by evalu- PROSPERO (CRD42016033070) and conducted according to the ating the applicability of the review findings to the context (per- Enhancing Transparency in Reporting the Synthesis of spective, population, setting) of our review question. Coherence Qualitative Research (ENTREQ) framework [6]. was assessed by the extent to which the pattern that constitutes a review finding was based on evidence that was consistent Inclusion criteria across multiple individual studies. Adequacy was assessed through an overall determination of the degree of richness and We considered English-language studies that explored the the quantity of data supporting a review finding [11]. After experience of medicine taking in adults with CKD. We excluded assessing each of the four components, we judged the confi- studies involving kidney transplant recipients and alternative dence in the themes as high, moderate, low or very low. Our medicine. Due to the anticipated limited evidence base, no starting point was ‘high confidence’, reflecting the assumption search restrictions with regard to year limits were imposed. that each review finding was a reasonable representation of the phenomenon of interest unless there were CERQual components Data source and search that weakened this assumption [11]. See the summary of the We searched MEDLINE, Embase and CINAHL using the system- qualitative findings and CERQual assessments in Table 2. atic search method SPIDER (sample, phenomenon of interest, design, evaluation, research type) [7]. We combined search terms such as ‘chronic kidney failure’, ‘medication adherence’, Results ‘qualitative research’, ‘patient experience’ and ‘qualitative Study characteristics research’ among others (for a full overview of search terms see Table 1). The search strategy was refined in collaboration with Of 1044 potentially relevant articles identified in the search, we an experienced librarian and adapted to each database, first included 19 studies [12–30]. In total, 381 patients with CKD Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfx140/4774630 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Adherence to medication in patients with CKD | 3 Table 1. Search method (SPIDER) and search terms used Search Query MEDLINE Sample Search kidney diseases [Mesh] OR kidney failure, chronic [Mesh] OR renal insufficiency [Mesh] OR renal insufficiency, chronic [Mesh] OR acute kidney injury [Mesh] OR hypertension CKD OR CKD hypertension OR CKD treatment OR haemo- dialysis OR CKD OR peritoneal dialysis OR renal dialysis/pharmacology [Mesh] or kidney failure, chronic* OR renal dialy- sis* OR kidney failure, chronic/drug therapy [Mesh] OR kidney failure, chronic/nursing [Mesh] OR kidney disease* and Phenomenon Search patient compliance/drug effects [Mesh] OR treatment refusal [Mesh] OR self-medication [Mesh] OR self-administra- of interest tion [Mesh] OR patient medication knowledge [Mesh] OR attitude to health/drug effects [Mesh] OR medication adherence [Mesh] OR concordance medication OR patient acceptance of health care/drug effects [Mesh] OR drug therapy OR poly- pharmacy OR treatment refusal* OR medication adherence* OR prescription drug* OR drug* and Design Search grounded theory OR hermeneutic method OR phenomenology OR ethnographic research OR narratives OR discourse analysis OR qualitative research [Mesh] OR nursing evaluation research [Mesh] OR interview [Publication Type] OR inter- views as topic [Mesh] OR nursing methodology research [Mesh] OR observation [Mesh] OR grounded theory [Mesh] OR hermeneutics [Mesh] OR focus groups/methods [Mesh] OR interview* and Evaluation Search patient acceptance OR patient perception OR patient perspective OR patient satisfaction OR patient experience OR patient preference [Mesh] OR patient acceptance of health care [Mesh] OR life change events [Mesh] OR motivation [Mesh] OR patient motivation OR trust [Mesh] OR patient confidence OR health literacy* OR health knowledge, attitude, practice OR quality of life OR patient acceptance and Research type Search qualitative research [Mesh] Embase Sample Search kidney disease* OR kidney failure OR chronic kidney failure OR renal disease* OR renal insufficiency OR chronic renal insufficiency OR renal replacement therapy OR haemodialysis [Mesh] OR peritoneal dialysis [Mesh] OR dialysis patient* OR haemodialysis patient [Mesh] OR kidney disease/drug therapy [Mesh] OR chronic kidney failure/drug therapy [Mesh] OR kidney failure/drug therapy [Mesh] OR renal replacement therapy [Mesh] and Phenomenon Search medication compliance [Mesh] OR patient compliance [Mesh] OR drug therapy [Mesh] OR treatment refusal [Mesh] of interest OR drug refusal OR medication refusal OR health knowledge and behaviour OR self-medication [Mesh] OR drug self- administration [Mesh] OR medication adherence OR patient medication knowledge OR sttitude to health [Mesh] OR poly- pharmacy OR chronic drug therapy OR drug, prescription OR prescription [Mesh] OR drug efficacy [Mesh] and Design Search qualitative research [Mesh] OR qualitative research OR qualitative method OR interview [Mesh] OR qualitative anal- ysis [Mesh] OR research, nursing [Mesh] OR ethnographic research [Mesh] OR ethnography [Mesh] OR observational method [Mesh] OR observation [Mesh] OR focus group interview OR clinical nursing research [Mesh] OR grounded theory [Mesh] OR thematic analysis [Mesh] OR narrative [Mesh] OR phenomenology OR hermeneutics [Mesh] OR phenomenolog- ical research [Mesh] and Evaluation Search patient preference [Mesh] OR patient attitude [Mesh] OR patient satisfaction [Mesh] OR patient experience OR patient perception OR patient motivation OR motivation [Mesh] OR patient perspective OR Personal experience [Mesh] OR patient acceptance and Research type Search qualitative research [Mesh] CINAHL Sample Search kidney disease [Mesh] OR kidney failure, chronic [Mesh] OR renal insufficiency [Mesh] OR renal insufficiency, chronic [Mesh] OR renal replacement therapy [Mesh] OR haemodialysis [Mesh] OR peritoneal dialysis [Mesh] OR dialysis patient [Mesh] and Phenomenon Search patient compliance/drug effects [Mesh] OR treatment refusal/drug effects [Mesh] OR treatment refusal OR pharma- of interest cological and biological treatments [Mesh] OR health behavior/drug effects [Mesh] OR self-medication [Mesh] OR self- administration [Mesh] OR patient medication knowledge [Mesh] OR knowledge medication [Mesh] OR medication history [Mesh] OR drug therapy [Mesh] OR drug therapy OR attitude to health/drug effects [Mesh] OR polypharmacy [Mesh] OR chronic drug therapy [Mesh] OR drug, prescription [Mesh] OR drugs [Mesh] OR medication adherence OR drug adherence and Design Search qualitative research [mesh] OR field study [mesh] or research, nursing [mesh] or ethnographic research [Mesh] or clinical nursing research [Mesh] OR interview [mesh] OR semi structured interview [Mesh] OR observational method [mesh] OR participant observation [Mesh] OR non participant observation [Mesh] OR focus group [mesh] or hermeneutics OR grounded theory [Mesh] OR discourse analysis or thematic analysis or narratives or phenomenological research [Mesh] and (continued) Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfx140/4774630 by Ed 'DeepDyve' Gillespie user on 07 June 2018 4| T.M. Nielsen et al. Table 1. Continued Search Query Evaluation Search patient preference OR patient experience OR patient perception or patient attitude [Mesh] OR patient motivation [Mesh] OR life experience [Mesh] OR patient acceptance or patient perspective OR patient satisfaction OR beliefs or health belief/drug effects [Mesh] or motivation/drug effects [Mesh] OR motivation or patient participation [Mesh] OR patient par- ticipation or health literacy and Research type Search qualitative research [Mesh] Fig. 1. Flow diagram illustrating literature search and selection. participated in the included studies. Of these, 171 patients were motivational interviewing via telephone (2 studies), focus group on haemodialysis and/or peritoneal dialysis and 133 patients interviews (2 studies) and face-to-face interviews and observa- attended renal clinics; for 77 patients, treatments were not tion/focus group interviews in combination (2 studies). Sample clearly described. For a full overview of study characteristics see sizes ranged from 7 to 39 patients and the overall age range was Table 3. The studies originated from nine countries (Australia, 19–90 years. The majority of studies were assessed to have Brazil, Canada, Chile, China, Singapore, Sweden, UK and USA). minor to moderate methodological limitations (8 low, 6 Data were collected using face-to-face interviews (13 studies), medium, 5 high). Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfx140/4774630 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Adherence to medication in patients with CKD | 5 Table 2. Summary of qualitative findings and CERQual assessments CERQual assessment of confidence Relevant in the Review finding articles evidence Explanation of CERQual assessment Logistics Establishing and maintaining routines [16, 17, 18, 19, High In all, 13 studies with minor to significant Establishing and maintaining daily routines in relation to med- 21, 23, 24, confidence methodological limitations, where ications facilitated medicine taking. Across studies, patients 25, 26, 27, most studies had minor to moderate described the difficulty of remembering to take their medica- 28, 29, 30] methodological limitations (6 low, 4 tions, cope with the complexity of a high pill burden with dif- medium, 3 high). Thick data from six ferent dosage times throughout the day and additional countries across five geographical con- instructions about how and when to take certain medica- tinents, but predominantly high tions. They were also challenged by the task of remembering income countries. High coherence to order and renew prescriptions on time, specifically when medicines ran out at different times. Establishing routines promoted maintenance of prescriptions and medicine tak- ing. Changes in established daily routines disrupted medi- cine taking The costs of buying medication [16, 25, 27, 28, Moderate In all, five studies with minor to moderate The costs associated with buying prescribed medications 29] confidence methodological limitations (three low, reduced medicine taking. Patients who were financially bur- two medium). Moderate data from two dened described that they tried to make their supply of med- countries (Singapore and Australia) ications last longer by skipping some doses, taking lower across two geographical continents and doses of medicine than prescribed or, alternatively, asking only high-income countries. High their physician to prescribe double-strength medication to coherence reduce the costs associated with buying medications Benchmarking the need for medication Absence of effect from a lay perspective [14, 16, 17, 18, High In all, 15 studies with minor to significant Absence of any tangible effect of a medication influenced some 19, 20, 21, confidence methodological limitations, where patients’ adherence to medication. A majority of patients 23, 24, 25, most studies had minor to moderate prioritized the medications that they believed to be impor- 26, 27, 28, methodological limitations (7 low, 5 tant and those they felt produced noticeable effects, that is, 29, 30] medium, 3 high). Thick data from eight symptom relief, pain relief or improved clinical parameters. countries across seven geographical Medications benchmarked as ‘less important’ was most pro- continents and predominantly high- nounced in patients with few or no symptoms and/or when income countries. High coherence patients experienced that ‘less important’ medications were hard to swallow or tasted bad. Patients also described reduc- ing dose, timing regime or not taking the medication at all, if the medication imposed side effects and concerns regarding potential interactions Lacking understanding of medication indications and effects [12, 21, 22, 23, Moderate In all, 10 studies with minor to significant Lacking understanding of the indication for medications, pri- 24, 25, 27, confidence methodological limitations, where marily the importance of preventive medications, was a bar- 28, 29, 30] most studies had minor to moderate rier to adherence. Some patients did not know why methodological limitations (5 low, 3 medications were prescribed or how they worked, resulting medium, 2 high). Moderate data from in a lack of understanding of the importance of taking the five countries across four geographical medication. Conversely, knowing why medications were continents and predominantly high- prescribed and how they worked facilitated adherence income. High coherence Spurred by emergent symptoms [13, 18, 25, 26, Moderate In all, five studies with minor to signifi- Emergent symptoms of disease progression made some 27] confidence cant methodological limitations (one patients regret failing to be adherent to their prescribed low, two medium, two high). Moderate medications despite any side effects. Facing dialysis and dis- data from three countries (UK, USA and ease-associated complications, these patients reflected on Australia) across three geographical the importance of medical adherence. Emergent symptoms continents and only high-income coun- changed their benchmarking of the importance of medica- tries. High coherence tions, leading to a higher degree of adherence. The quality of the patient–physician relationship Eliciting patients’ wishes for involvement in decisions concern- [12, 13, 14, 15, High In all, 13 studies with minor to significant ing medication 18, 22, 23, confidence methodological limitations, where Eliciting patients’ wishes for involvement in decisions concern- 24, 25, 26, most studies had minor to moderate ing medication influenced some patients’ adherence to med- 27, 28, 29] methodological limitations (5 low, 5 ication. Across studies patients expressed different wishes medium, 3 high). Thick data from five for being involved in decisions concerning medications. countries across five geographical con- Some patients placed all their trust in the physicians and tinents and predominantly high- readily left them to take control and make decisions on their income. High coherence Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfx140/4774630 by Ed 'DeepDyve' Gillespie user (continued) on 07 June 2018 6| T.M. Nielsen et al. Table 2. Continued CERQual assessment of confidence Relevant in the Review finding articles evidence Explanation of CERQual assessment behalf while others wished to collaborate as equal partners with physicians about treatment-related decisions, including medication. Lack of continuity, time, trust and involvement of patients wishing to partake in treatment led to patients taking matters into their own hands in relation to medicine taking. Lacking information [14, 18, 22, 23, Moderate In all, seven studies with minor to signifi- Feeling insufficiently informed about the indications, effects 24, 25, 28] confidence cant methodological limitations, where and side effects and interactions between prescribed medi- most studies had minor to moderate cations affected adherence negatively. Some patients sus- methodological limitations (three low, pected physicians of withholding information while others three medium, one high). Moderate described getting conflicting information. For example, dif- data from four countries across four ferent information from different physicians or physician geographical continents and only high- information that differed from the drug information sheet. income countries. High coherence This resulted in confusion and apprehension about the med- ication, which in some patients posed a barrier to adherence medications, refilling dosette boxes, ordering and renewing pre- Synthesis scriptions, reminders to take medications). Memory aids and We identified three analytical themes with seven descriptive dosette boxes appeared especially important for patients suffer- subthemes. ing from fatigue, nausea and poor memory. A downside of dos- (1) ‘Logistics’, with the subthemes establishing and main- ette boxes was that patients had to be able to see well enough to taining routines, and the costs of buying medication. read the date and to be able pick up or replace a lost pill with an (2) ‘Benchmarking the need for medication’, with the identical one [16, 18, 25]. subthemes absence of effect from a lay perspective, lacking Participating in activities such as family and social gather- understanding of medication indications and effects and being ings, health care appointments and other meetings tended to spurred by emergent symptoms. disrupt daily routines. Potentially this resulted in patients forget- (3) ‘Quality of the patient–physician relationship’, with the ting to take their medication or deliberately leaving it at home subthemes eliciting patients’ wishes for involvement in deci- and postponing the medication until later. Frequent changes in sions concerning medication and lacking information. the number of medications, type, dosage and timing of medica- A summary of the main analytical and descriptive themes tions also disrupted established routines and reduced adherence. are presented in Table 4. Table 5 presents a selection of patient quotations illustrating each descriptive theme. The costs of buying medication (moderate CERQual confidence) In some studies, patients described the costs of buying pre- Logistics scribed medications as a barrier to adherence. Patients who The logistics surrounding medicine taking were important for were financially burdened tried to make their supply of medica- facilitating or hindering adherence. Logistics involved the prac- tions last longer by skipping doses, taking lower doses of medi- tical challenges of managing complex medication regimes, cine than prescribed or, alternatively, asking their physician to numerous prescriptions and health care appointments, all of prescribe double-strength medication to reduce the costs of which were challenging in the patients’ everyday lives. buying medications. Furthermore, logistics included the costs of buying medication. Benchmarking the need for medication Establishing and maintaining routines (high CERQual confidence) Benchmarking the need for medication was both a facilitator Establishing and maintaining daily routines in relation to medi- and barrier to adherence. Patients used their lay beliefs and cations facilitated adherence. Across studies, patients described experiences of effects and side effects of medications to bench- the difficulty of remembering to take medications and coping mark which medications were important to take and which with the complexity of a high pill burden, different dosage times medications could be omitted, completely or occasionally. throughout the day and specific instructions about how to take certain medications. They were also challenged by the task of Absence of effect from a lay perspective (high CERQual confidence) remembering to renew prescriptions on time, as prescriptions Patients prioritized the medications they felt produced notice- expired at different times. Daily routines promoted the mainte- able effects such as symptom relief, pain relief or improved clin- nance of prescriptions and medicine taking. Facilitating rou- ical parameters. Effective medications from the perspective of tines included memory aids (tally charts, calendars, mobile phone), assisting devices (dosette boxes), taking medicines in patients included antihypertensive medications, diabetes medi- relation to daily activities (meal times or prayers) and reminders cations and analgesics. Medications with less noticeable effects and/or practical support from family or pharmacists (preparing were less important to patients and were more likely to be Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfx140/4774630 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Adherence to medication in patients with CKD | 7 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfx140/4774630 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Table 3. Characteristics of the included studies Total number of Study Country Treatment Stage of disease participants Age (years) Data collection Methodology Analysis Topic Roso et al. [12] Brazil Attending renal CKD Stage 3–5 15 19–85 Face-to-face Qualitative Thematic To explore how patients in clinic interviews exploratory conservative treatment of chronic renal insuffi- ciency care for themselves Clarkson and USA Peritoneal dialy- CKD Stage 5 10 26–85 Face-to-face Qualitative Not stated To explore the lived experi- Robinson sis and interviews exploratory ence of patients with [13] haemodialysis end-stage renal disease Costantini Canada Attending renal CKD Stage 1–3 14 19–69 Face-to-face Qualitative Content To explore the self-manage- [14] clinic interviews exploratory ment experiences of peo- ple with mild to moderate CKD Curtin and USA Haemodialysis CKD Stage 5 18 38–63 Face-to-face Qualitative Content To gain an insight into the Mapes [15] interviews exploratory factors that are associ- ated with some dialysis patients’ ability to live long lives on dialysis Griva [16] Singapore Haemodialysis CKD Stage 5 37 51.3 Face-to-face inter- Qualitative Thematic To explore cultural perspec- (mean views and focus exploratory tives on facilitators and age) group interviews barriers to treatment adherence in HD patients Guerra- Chile Haemodialysis CKD Stage 5 15 22–82 Face-to-face inter- Hermeneutic Thematic To explore the lived experi- Guerrerro views (indirect phenomenological ences of patients on hae- et al. [17] method modialysis regarding observation) adhering to treatment regimens and their per- ception of quality of life Mckillop and UK Attending renal CKD, stage not 10 29–82 Face-to-face Qualitative Thematic To explore attitudes Joy [18] clinic described (but interviews exploratory towards medicines, poly- not Stage 5) pharmacy and adherence in patients with CKD Karamanidou UK Haemodialysis CKD Stage 5 7 32–68 Face-to-face Qualitative Interpretative The experience of renal et al. [19] interviews exploratory phenomenological patients undergoing dial- ysis treatment, focusing on beliefs about their ill- ness, prescribed treat- ment and the challenge of adherence (continued) 8| T.M. Nielsen et al. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfx140/4774630 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Table 3. Continued Total number of Study Country Treatment Stage of disease participants Age (years) Data collection Methodology Analysis Topic Lam et al. [20] China Peritoneal CKD Stage 5 36 35–76 Face-to-face Qualitative Content To explore adherence from dialysis interviews exploratory patients’ perspectives and to describe changes in adherence to a thera- peutic regimen among patients undergoing con- tinuous ambulatory peri- toneal dialysis Lindberg and Sweden Peritoneal dialy- CKD Stage 5 10 39–83 Face-to-face Qualitative Content To explore obstacles to Lindberg sis and interviews exploratory adherence to phosphate- [21] haemodialysis binding medication and to describe the measures taken by dialysis patients to overcome these obstacles Mason et al. UK Treatment not CKD, stage not 9 56–76 Focus group Qualitative Framework To identify and explore [22] described described interviews exploratory approach with knowledge and attitudes tenets of regarding the control of grounded theory blood pressure, patient empowerment and edu- cational needs Rifkin et al. USA Dialysis and CKD Stage 3–5 20 55–84 Face-to-face Qualitative Thematic and To explore the major [23] attending interviews exploratory ethnographic themes surrounding renal clinic medication use and adherence decisions in older kidney disease patients Walker et al. UK Attending renal CKD Stage 4 9 63–83 Face-to-face Qualitative Thematic To explore the experiences [24] clinic interviews exploratory of patients attempting to integrate lifestyle changes into their lives Williams et al. Australia Attending renal CKD Stage 1–5 23 30–77 Face-to-face Qualitative Johnson’s model of To explore factors affecting [25] clinic (but not on interviews exploratory medication adherence to multiple dialysis) adherence prescribed medications for consumers with dia- betic kidney disease from the time of prescription to the time they took their medications (continued) Adherence to medication in patients with CKD | 9 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfx140/4774630 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Table 3. Continued Total number of Study Country Treatment Stage of disease participants Age (years) Data collection Methodology Analysis Topic Williams et al. Australia Attending renal CKD, stage not 23 59.3 Face-to-face Qualitative Framework To examine how irrational [26] clinic described (but (mean interviews exploratory approach accord- thinking affects people’s not on age) ing to Ritchie and adherence to multiple dialysis) Spencer medicines prescribed to manage their diabetic kidney disease Williams and Australia Attending renal CKD Stage 2–4 39 68 (mean Motivational inter- Qualitative Thematic approach To explore the motivation Manias [27] clinic age) viewing via exploratory incorporating the and confidence of people telephone modified Health with coexisting diabetes, Belief Model CKD and hypertension to take their medicines as prescribed Williams et al. Australia Attending renal CKD, stage not 26 73.5 Motivational inter- Qualitative Framework method To examine the perceptions [28] clinic described (but (mean viewing via tele- exploratory according to of a group of culturally not on age) phone with Ritchie and and linguistically diverse dialysis) interpreter Spencer participants with the comorbidities of diabetes, CKD and cardiovascular disease to determine fac- tors that influence their medication self-efficacy through the use of moti- vational interviewing Ghimire et al. Australia Haemodialysis CKD Stage 5 30 44–84 Face-to-face Qualitative Thematic approach To explore factors associ- [29] interviews exploratory incorporating ated with medication WHO medication adherence, and examine adherence model the differential perspec- tives on medication-tak- ing behaviour shown by haemodialysis patients Bowling et al. USA Treatment not CKD Stage 3–5 30 75.1 Focus group Qualitative Grounded theory To identify and describe the [30] described (mean interviews exploratory relationship among fac- age) tors that facilitate or impede CKD self-man- agement for older veter- ans with moderate to severe CKD 10 | T.M. Nielsen et al. Table 4. Summary of the main analytical and descriptive themes Quality of the patient–physician Logistics Benchmarking the need for medication relationship • • • Establishing and maintaining routines Absence of effect from a lay perspective Eliciting patients wishes for involvment (high CERQual confidence) (high CERQual confidence) in decisions concerning medication • • Cost of buying medication (moderate Lacking understanding about medica- (high CERQual confidence) CERQual confidence tion indication and effects (moderate Lacking information (moderate CERQual confidence) CERQual confidence) Spurred by emergent symptoms (mod- erate CERQual confidence) skipped. Skipping ‘less important’ medications was most pro- Eliciting patients’ wishes for involvement in decisions concerning nounced in patients with few or no symptoms and/or when medication (high CERQual confidence) patients experienced that ‘less important’ medications were Patients expressed different wishes for being involved in deci- sions concerning medications. Some placed all their trust in hard to swallow or tasted bad [14, 16, 17, 19, 25, 33]. These medi- physicians and readily let the physician take control and make cations included lipid-lowering agents, histamine H2-receptor decisions on their behalf. Others wished to collaborate as equal antagonists, calcium, phosphate-binding agents, statins, partners with physicians about treatment-related decisions, aspirin, metoclopramide, pantoprazole and vitamins. including medication. They wanted physicians to acknowledge Specifically, calcium and phosphate-binding agents were often their concerns and opinions about medication and wished to missed because of their size, taste and texture [12, 13, 19, 25, 29]. discuss the pros and cons of changes in medications, doses and Patients were also prone to non-adherence when they expe- effects versus side effects. They also wished to discuss how to rienced that side effects outweighed intended therapeutic manage the disease, the prescribed medication and side effects effects. Side effects could range from minor and tolerable to to suit their lifestyle preferences, including what to expect if severe, affecting the patient’s quality of life. Side effects they chose not to follow the prescribed treatment. Some wished included loss of appetite, nausea, stomach pain, hair loss, body to negotiate medicine doses in order to minimize side effects. In aches, muscle pain, weight loss, coated mouth, tremors, dizzi- several studies, patients experienced insufficient time for dis- ness, skin discoloration, low blood sugar, headache, diarrhoea, cussing medications with physicians in the outpatient clinic constipation, loss of sexual function or ‘feeling terrible’. [16, 18, 19, 33], a large turnover in physicians [16, 17], mistrust of Concerns about side effects and long-term adverse effects of the reasons for prescriptions (some suspected that medications polypharmacy also affected adherence, with patients altering were prescribed for research or financial gain) [15, 19, 25, 27] doses or the timing of medications or skipping medications to and non-empathetic communication [14, 15, 17, 19]. Lack of con- prevent side effects. tinuity, time, trust and involvement of patients wishing to par- take in treatment decisions led to patients taking matters into Lacking an understanding of medication indications and effects (moderate their own hands in relation to medicine taking. CERQual confidence) Lacking an understanding of the indication for medications, pri- Lacking information (moderate CERQual confidence) marily the importance of preventive medications, was a barrier Feeling insufficiently informed about the indications, effects, to adherence. Some patients did not know why medications side effects and interactions of prescribed medications affected were prescribed or how they worked, resulting in a lack of adherence negatively. Some patients suspected physicians of understanding of the importance of taking the medication. withholding information, while others described getting con- Conversely, knowing why medications were prescribed and flicting information. For example, different information from how they worked facilitated adherence. different physicians or physician information differed from the drug information sheet. This resulted in apprehension, which Spurred by emergent symptoms (moderate CERQual confidence) in some patients posed a barrier to adherence. Patients suffering from disease-related complications expressed regret about having been non-adherent. Facing dialysis and Discussion disease-associated complications, these patients acknowledged the importance of medical adherence. Emergent symptoms The aim of this review was to synthesize the available qualita- tive evidence on patient experiences of factors that facilitate changed how they benchmarked the importance of medica- and hinder adherence to medication in patients with CKD. We tions, leading to a higher degree of adherence. identified three main themes: logistics, benchmarking the need for medication and the quality of the patient–physician The quality of the patient–physician relationship relationship. The quality of the patient–physician relationship was both a Logistics referred to the complexity of managing and adher- facilitator and barrier to adherence. Some patients highlighted ing to polypharmacy. Patients’ efforts to cope with this com- that they were more likely to adhere to medications when they plexity included daily medication routines, aids and practical felt well-informed and involved in decisions concerning medi- help from family and others. We assessed the confidence of the cation. Others happily delegated medication decisions. Patients evidence for this theme to be high. Similar to our findings, a who lacked information or felt their side effects were not con- cross-sectional study of medication adherence among kidney sidered tended to be less adherent to prescribed medications. transplant recipients’ showed that practical barriers, including Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfx140/4774630 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Adherence to medication in patients with CKD | 11 Table 5. Selection of quotes from patients to illustrate each descriptive theme Contributing Themes Quotations studies Logistics Establishing and ‘When you get into a habit, you’re less likely to forget taking one.’ [26][16, 17, 18, 19, 21, maintaining ‘...once or twice you might forget or if I am somewhere and the medication is at home or you are 23, 24, 25, 26, routines with friends at a particular time you were supposed to have taken the medication when you 27, 28, 29, 30] don’t have the medication with you so at that time...I try not to do that but.. .’[19] ‘I have, as I said, a table system when my tablets are running out to re-order because there are so many of them it’s not just as easy as saying once a month, but they all run out different times and take different levels and what have you. So, I have to keep track of what we’ve got and when we have got it.’ [24] ‘They’ve [the pharmacy] run out of the drug, go to get the prescription and find the prescription has run out, got to go back to the doctor to get another prescription before I get another tablet and that might take a couple of days and then you find you’re back to square one [disease is uncontrolled].’ [25] ‘...I have two pill organizers that I prepare at the same time...put five in the first compartment in the box and the rest in the others. I take the first ones straight away in the morning when I wake up...drink coffee and eat in the morning...and then I take my other morning medications.’ [21] ‘...my medicine is part of my prayers, okay? So that’s a good way to remember it. Like, I gotta say my prayers; I have to take my [medication].’ [23] ‘I’m okay if I’m in the house. It’s when I go out...half the time I’m sitting thinking I forgot my tab- lets.’ [18] ‘Has so many pills I get daughter to refill [medicine prescriptions).’ [28] ‘My wife makes sure I take them...she helps. She gets all medicines ready.’ [29] ‘Been given new tabs (hypoglycaemic agents) to replace other ones. Does not know what they are- chemist fills Dosette box.’ [28] The cost of buy- ‘...and they cost money more every month...I take but I take half...sometimes.. .I make test take [16, 25, 27, 28, 29] ing medication half and if I feel OK then OK...Lasts longer and save money...If I feel bad then I go polyclinic and take all.’ [16] ‘I’m living on my savings...and a bit of pension and a bit of superannuation...so now you only get one month’s supply, so that makes it much more expensive.. .which is a lot of money when you’re just living on the pension. It’s just money I saved when I was working.’ [25] Benchmarking the need for medication Absence of effect ‘It’s to control the blood pressure for your kidneys. Even if I was to miss the other seven, I will take [14, 16, 17, 18, 19, from a lay that one because I know to keep my blood pressure at a good level.’ [18] 20, 21, 23, 24, perspective ‘And I said, yeah, well, no problem I’m gonna take [niacin]. It’s a benefit for my heart...I’m gonna 25, 26, 27, 28, go for it. And I took it for a while...but I didn’t notice any benefit. I mean, nothing direct. I didn’t 29, 30] feel it. If I take niacin, or I don’t take it, no difference. I don’t take metoprolol, I know there’s a difference. I feel different, I feel some fatigue, I feel something missing.’ [23] ‘If my Levomepromazine wasn’t as good and effective for me I wouldn’t take it because of the side effects.’ [18] ‘I spent a good I’d say at least 6 months dancing around with my treatment, just not taking it seri- ous. I wouldn’t say really serious, just it seemed a bit excessive the amount of medication.... There’s no way it could be that bad, you feel good, that’s the worst thing about it in the begin- ning you don’t realize...’[14] ‘Take all the medicines that I need—just not statin and aspirin—and only take half coversyl [peri- ndopril Prefer ramipril...’[28] ‘I think it’s just calcium tablets; it’s not important. I skip it. I dare not do this with other medicines.’ [20] ‘I had to take [antihypertensive medication], whether it was totally necessary or not, never really occurred to me, it was more like “well this is a preventative measure,” so if I ran out of prescrip- tions sometimes I wouldn’t go and get it filled straight away and I’d go for days, sometimes weeks without taking those medications.’ [25] ‘...the tablets are so disgusting, their consistency is so disgusting, so disgusting you don’t want to take... it’s a big enough job taking the pills I’m supposed to take...they (the phosphate binding agent) didn’t taste that great. They’re orange flavoured so that chewing on them is no great joy ...the chewable tablet was much too big. You couldn’t take it with you anywhere.’ [21] ‘Sometimes I wonder if it’s the tablets so I miss them to see and it definitely does affect how I feel, if I’m feeling a bit yucky for a while, feeling a bit nauseous and just want to lie down basically. So I do get side effects that put me off taking them.’ [24] ‘...but then I have other pills against nausea that I add to it.. .my stomach is so weak...nourish- ment first...for me it (the phosphate-binding agent) is absorbed just as well after a meal...nowa- days I go and lie down for a while (after taking the phosphate-binding agent). Ten to fifteen minutes...’[21] (continued) Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfx140/4774630 by Ed 'DeepDyve' Gillespie user on 07 June 2018 12 | T.M. Nielsen et al. Table 5. Continued Contributing Themes Quotations studies Lacking under- ‘I don’t take medicine for my kidneys; there is no medicine for kidneys, only for high blood pres- [12, 21, 22, 23, 24, standing of sure. There is one for the heart, which is metoprolol, and there are two for high blood pressure, 25, 27, 28, 29, medication which are losartan and amlodipine. I only take these three medicines. And at night I take 30] indications simvastatin, but only sometimes; I don’t take it often, because I do the diet and so I sleep well.’ and effects [12] ‘Well I know what some of them are for but I don’t know what they’re all for. Like when you were asking me before, merely because I can’t read what’s on the packet, I just pick which ones I like but I couldn’t tell you which one’s doing what job.’ [25] ‘I’ve managed to get away with it. It’s only the transplant people [who have to take their medi- cines strictly].’ [27] Spurred by emer- ‘...if I had known that not taking my binders would cause my bones to get brittle from the begin- [13, 18, 25, 26, 27] gent ning, I would not care how sick they were making me, and...keep having side effects and symptoms nobody explained why I have this or what caused it.’ [13] ‘I was a lot more spasmodic [taking medications] until my kidney function got to a point where it is now and I’m looking down the barrel of dialysis and that. I’m probably far more regimented than, and more fearful of not taking it, whereas in the past you know I’ve probably gone six months without...sort of (taking my tablets).’ [25] ‘I wasn’t aware of [the dangers of] blood pressure earlier and if I was, it would have been different.’ [27] Quality of the patient–physician relationship Eliciting patients’ ‘Explaining the disease to the fullest, the meds, what’s involved, what can happen, changes that [12, 13, 14, 15, 18, wishes for are going to be happening in your life so that when it happens you’re not wondering what’s 22, 23, 24, 25, involvement going on now.’ [14] 26, 27, 28, 29] in decisions ‘But I...I adjust by myself, cause you can’t listen to the doctor all the time, because I don’t know concerning whether they’re writing a thesis or what, the way they prescribe the medication, every time you medication know more and more medications. But it doesn’t work with me. I refuse to listen, I said no, I don’t want to take. Too much of medication you know... ah. Even the renal tablets...I never touch.’ [15] ‘These [two medicines] are for cholesterol, and I was only taking one pill for cholesterol, and my cholesterol was fine. Sometimes I think these salesmen come around and talk to the doctors and sell them a bill of goods, and the next thing you know, you’re on it.’ [23] ‘If you read what’s on the prescription [insert] you’d be dead...but they should’ve said, “If you have any side effects such as,” and then only two or three of the major ones...Those are not dis- cussed. So, I had to assume that there’s nothing adverse except in rare cases. Well, it turns out that’s not true because everyone I’ve mentioned the [edema] to, they didn’t blink an eye. They sort of smiled, “Oh, we know.” That irritated me a lot...They acted as if they were getting paid to [prescribe it].’ [23] ‘The problem I see is that it’s making me lose my hair...They say it aren’t the medicine. But natu- rally they’re going to say it can’t be the medicine. But what else can it be.. .I’ve tried stopping them all! I go every other night! Then I notice I don’t lose so much hair...He tells me it aren’t got nothing to do with the medication. But I still believe it does.’ [23] ‘I think I’m the boss in this...you’ve got to be the one to do it. So basically I think I’ve played a major role. The doctor can only guide you; you’ve got to be the one to basically do it.’ [14] ‘Does what doctor tells me to do. I really don’t want to take medicines but doctor tells me I have to.’ [28] ‘They usually tell me what they’re giving me and why. And what the result should be and that’s really all I need to know.’ [23] Lacking ‘I think information should be offered in the beginning, it shouldn’t be withheld, and it’s much [14, 18, 22, 23, 24, information harsher to find it out in the end. Hey okay, you’re looking at being on these blood pressure meds 25, 28] the rest of your life, it’s not going to go away. You need to have that realistic expectation from the beginning.’ [14] ‘So see these are things doctors never tell you...Everything I get I go home and check it. Every sin- gle one of my other medicines says the same thing. And you know, you say: “Well, which one is it?’’’ [23] ‘Now I go to somebody senior to him (previous doctor) and when I go to see him...he says...well you shouldn’t have been on this and you shouldn’t have been on that...and you do tend to get confused!’ [22] Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfx140/4774630 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Adherence to medication in patients with CKD | 13 changes in daily routines, were associated with non-adherence treatment, including decisions to not take medications if this is [31]. In another qualitative study, kidney transplant recipients’ what they wish [1, 36]. reported the importance of developing and maintaining rou- Several instruments have been created to elicit patients’ preferences for involvement in decision making, but none tines to facilitate medication adherence [22]. Like other studies, we found that memory aids, assisting of them have been found feasible in routine clinical settings [1, 36]. Chewning et al. [41] stress that we need neutral modes of devices, associated activities, reminders and practical help from assessing patient preferences for involvement in decision family and pharmacists facilitated adherence [23, 24, 35]. Living making in clinical practice so patients do not feel coerced into with a partner or spouse has likewise been shown to increase involvement or non-involvement. Measures for assessing adherence [23, 35]. patient wishes should therefore include explicit response Using tools such as dosette boxes and memory tools may options for both shared decision making and decision delega- affect adherence both positively and negatively [1, 23, 36]. These tion [41]. Furthermore, we need insight into how patients per- tools may constitute a potential barrier to adherence for ceive decisional processes regarding medications and which patients with impaired vision, sensory disturbances or reading decisions they prefer to share with health professionals [41]. difficulties. Clinicians should also be aware that medicine pack- A recent Cochrane review assessing decision aids in people aging, memory tools and multicompartment devices such as facing screening and treatment decisions concluded that deci- dosette boxes do not necessarily increase medication adherence sion aids improved people’s knowledge of risks and benefits [1, 36]. They may, however, be helpful for patients who are for- and their feeling of being informed and clear about their values getful or have practical problems with managing complex medi- [42]. The authors further concluded that more research is cation regimes [1, 36]. The potential benefits of memory tools needed regarding the effect of decision aids on adherence to for adherence in patients with physical and/or cognitive impair- decisions taken [42]. There is evidence that educational and ments warrant further examination. behavioural interventions increase adherence to phosphate Adherence improved when patients associated medications control in adults receiving haemodialysis [43]. Elwyn et al. [44] with daily routines. An approach to supporting medication expand the field by advocating the potential of integrating adherence could be that clinicians systematically help patients shared decision making and motivational interviewing, an inte- map their everyday activities and encourage them to associate gration that would be relevant to examine in the context of medication routines with these activities [1, 35–38]. medication adherence in patients with CKD. Patients used their lay beliefs and experiences of effects ver- The strengths of our study include a comprehensive system- sus side effects of medications to benchmark which medica- atic review method adhering to the ENTREQ framework, the use tions to take and which to potentially omit. The confidence of of investigator triangulation to enhance transparency and the evidence for this theme was high. The Necessity–Concerns reproducibility and the use of the CERQual approach to assess Framework (NCF) suggests that medication adherence is influ- the confidence in our findings. In our review, we report on enced by individual beliefs about the necessity of medications patient-experienced factors influencing adherence to medica- and their potential adverse effects [39]. For patients in the early tion. They correspond to those identified in a World Health stages of kidney disease who did not experience a high symp- Organization (WHO) report on adherence to medication across a tom burden, it appeared harder to acknowledge the need for range of chronic conditions [45]. The focus of our synthesis was medications, particularly if unpleasant side effects overshad- patient-experienced factors. Therefore, we cannot comment on, owed therapeutic effects. Studies have previously found that for example, political or organizational influences mentioned in side effects and the way in which they are addressed by health the WHO report [45]. The sample sizes in the included studies professionals influence adherence to medication [23, 24]. Those could be characterized as relatively small (median 20). patients experiencing side effects that were acknowledged and Nevertheless, all studies reported that data saturation was well-managed became more adherent [23]. A recent systematic achieved. We cannot rule out dissemination bias [46]. In all, 4 of review found that behavioural interventions for coping with 19 studies included were from the same group of authors. We side effects increased adherence in patients with type 2 diabe- cannot rule out that this may have introduced a risk of system- tes [40]. Acknowledging patient experiences of side effects and atic distortion of the phenomenon of interest [11]. We defined exploring patient preferences for managing side effects, reduc- data as all text labelled ‘results’ or ‘findings’, including patient ing doses and switching medications are alternative approaches quotations, as described by Thomas and Harden [9]. This [1]. involved the use of patient quotations gathered in one context The quality of the patient–physician relationship was impor- to answer the review question specified in the current article. tant for adherence. The confidence of the evidence for this To assess the extent to which quotations and other data from theme was also high. Importantly, while some patients were the primary studies supporting our findings were applicable to happy to delegate medication and other treatment decisions to the context (perspective or population, phenomenon of interest, physicians, others desired more information, continuity and setting) specified in our review question, we used the CERQual involvement in decisions concerning treatment and medica- component relevance [11]. We attempted to distinguish varia- tions. These findings are confirmed in a systematic review of tions in factors influencing adherence across treatments and patient preferences for shared decisions in which the majority stages of disease throughout the analysis. However, it was diffi- of patients preferred shared decisions [41]. Similarly, all studies cult to conclude decisively about the influence of, for example, identified a subset of patients who wanted to delegate decisions stages of disease on this basis. Finally, the CERQual approach is [41]. Consequently, the challenge for health professionals is to a developing method for assessing how much confidence to solicit patient preferences for involvement and tailor consulta- place in findings from a qualitative evidence synthesis [11]. As tions accordingly [41]. Furthermore, health professionals need it is still under development, experience with the approach is to be aware that patient preferences may evolve over time [41]. increasing and will contribute to further development. A limita- In line with this, current guidelines urge health professionals to tion of CERQual is that it does not currently address the poten- support patients in making informed decisions about tial risk of dissemination bias. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfx140/4774630 by Ed 'DeepDyve' Gillespie user on 07 June 2018 14 | T.M. Nielsen et al. hemodialysis: a critical review of the literature. 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Adherence to medication in patients with chronic kidney disease: a systematic review of qualitative research

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European Renal Association - European Dialysis and Transplant Association
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© The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA.
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2048-8505
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Abstract

Non-adherence to multipharmacological treatment increases the risk of morbidity, mortality and hospitalization. We know little about the perspective of patients with chronic kidney disease regarding factors influencing medicine taking. This study aimed to synthesize findings from qualitative studies of patients’ experiences of factors that facilitate and hinder adherence to medication. A systematic review of qualitative studies adhering to the Enhancing transparency in reporting the synthesis of qualitative research (ENTREQ) framework. Systematic searches were conducted in several databases. We used thematic synthesis and the Confidence in the Evidence from Reviews of Qualitative Research (CERQual) approach to assess the confidence of the evidence. Nineteen studies involving 381 patients with chronic kidney disease were included. We identified three analytical themes; logistics, benchmarking the need for medication; and the quality of the patient- physician relationship, with seven descriptive sub-themes as factors influencing patients’ adherence to medications. Helping patients to map their everyday activities and motivating them to associate medications with everyday activities may facilitate adherence to medications. Addressing patient beliefs about medications, supporting patients in coping with side effects of medications and eliciting patients’ wishes for involvement in treatment decisions may also facilitate adherence. Barriers to adherence were the costs of buying medications, and lacking understanding of the indications and effects of medications. The findings in this synthesis resonate with previous research and extend the known literature by synthesizing and formally assessing confidence in the evidence. Key words: chronic kidney disease, medication adherence, patient perspective, qualitative review, systematic review Received: June 30, 2017. Editorial decision: November 10, 2017 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfx140/4774630 by Ed 'DeepDyve' Gillespie user on 07 June 2018 2| T.M. Nielsen et al. searching each set of search terms using the Boolean operator Introduction OR and subsequently combining these searches using the Adherence to medication is defined as ‘the extent to which the Boolean operator AND. Along with the electronic searches, we patient’s behaviour matches agreed recommendations from the manually searched reference lists and grey literature. prescriber’ [1]. In chronic kidney disease (CKD), adherence to We uploaded the search into the Covidence software, where medication is a key component of effective disease management two authors (T.M.N., T.T.) independently screened the search [2, 3]. The main goals of medication are to slow progression of the results for eligibility. The search was conducted in January 2016 disease and monitor and correct disease-associated complica- and updated in June 2017. Figure 1 illustrates the literature tions and comorbidities while treating the underlying aetiology search and selection. [3]. Patients with CKD are prescribed a regime of multi- pharmacological treatment often starting with antihypertensives Quality assessment and antidiabetics and subsequently phosphate binders, vitamin We used the Critical Appraisal Skills Programme (CASP) check- D preparations, calcimimetics, erythropoiesis stimulating agents list for qualitative studies to assess individual study quality [8]. and iron supplements [4]. This infers a high burden of pill intake Two authors (T.M.N., M.F.J) independently assessed the studies. with sometimes >20 pills/day [2]. Managing multiple medications and health care appointments, including, for some, dialysis sev- eral times a week, is a challenging task. Not surprisingly, patients Data extraction and analysis may miss medications, intentionally or un-intentionally (1). Included studies were imported into QSR NVivo 10 computer Estimates of non-adherence to medication vary from 17 to 74% data analysis software (QRS International, Melbourne, VIC, among patients with CKD and from 3 to 80% among patients on Australia). Following the method for thematic synthesis haemodialysis, depending on the methods used to assess non- described by Thomas and Harden [9], we extracted data about adherence [2, 3, 5]. This poses a major obstacle to achieving treat- medicine taking from the included studies, for example, all rele- ment goals and increases the risk of morbidity, mortality and vant data presented in the ‘abstract, results and discussion’ sec- hospitalization [3, 4]. Optimizing adherence to medicine is there- tion. To enhance transparency and reproducibility, two authors fore a priority issue for health care providers. (T.M.N., M.F.J.) independently conducted the open line-by-line There is a growing body of research into non-adherence to coding of extracted data. This resulted in a total of 31 initial medication among patients with CKD. Quantitative studies codes that were condensed into 16 preliminary descriptive have focused on the incidence of adherence and identification themes. The descriptive themes were subsequently discussed in of potential risk factors for non-adherence [2]. These studies the author group and a summary of the findings across studies provide valuable insight into the prevalence of non-adherence was drafted. All authors commented on this draft and, through and associated risk factors [2]. They do not, however, uncover further discussion of the preliminary descriptive themes, three life circumstances that may influence adherence from the analytical themes with seven descriptive sub-themes emerged. patient perspective. Qualitative research may contribute to our knowledge by elaborating the patients’ perspectives on non- Assessment of confidence in the review findings adherence. The aim of this qualitative systematic review was to synthesize the available qualitative research on factors that We used the Confidence in the Evidence from Reviews of facilitate and hinder adherence to medication from the perspec- Qualitative Research (CERQual) criteria to assess how much con- tive of patients with CKD. fidence could be placed in our findings [10, 11]. CERQual is based on four key components: methodological limitations, relevance to the review question, coherence and adequacy of the data con- Materials and methods tributing to a review finding [14]. Methodological limitations of A systematic review and thematic synthesis of qualitative stud- the individual studies contributing to each review finding were ies was undertaken. The review was prospectively registered in assessed using the CASP tool. Relevance was assessed by evalu- PROSPERO (CRD42016033070) and conducted according to the ating the applicability of the review findings to the context (per- Enhancing Transparency in Reporting the Synthesis of spective, population, setting) of our review question. Coherence Qualitative Research (ENTREQ) framework [6]. was assessed by the extent to which the pattern that constitutes a review finding was based on evidence that was consistent Inclusion criteria across multiple individual studies. Adequacy was assessed through an overall determination of the degree of richness and We considered English-language studies that explored the the quantity of data supporting a review finding [11]. After experience of medicine taking in adults with CKD. We excluded assessing each of the four components, we judged the confi- studies involving kidney transplant recipients and alternative dence in the themes as high, moderate, low or very low. Our medicine. Due to the anticipated limited evidence base, no starting point was ‘high confidence’, reflecting the assumption search restrictions with regard to year limits were imposed. that each review finding was a reasonable representation of the phenomenon of interest unless there were CERQual components Data source and search that weakened this assumption [11]. See the summary of the We searched MEDLINE, Embase and CINAHL using the system- qualitative findings and CERQual assessments in Table 2. atic search method SPIDER (sample, phenomenon of interest, design, evaluation, research type) [7]. We combined search terms such as ‘chronic kidney failure’, ‘medication adherence’, Results ‘qualitative research’, ‘patient experience’ and ‘qualitative Study characteristics research’ among others (for a full overview of search terms see Table 1). The search strategy was refined in collaboration with Of 1044 potentially relevant articles identified in the search, we an experienced librarian and adapted to each database, first included 19 studies [12–30]. In total, 381 patients with CKD Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfx140/4774630 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Adherence to medication in patients with CKD | 3 Table 1. Search method (SPIDER) and search terms used Search Query MEDLINE Sample Search kidney diseases [Mesh] OR kidney failure, chronic [Mesh] OR renal insufficiency [Mesh] OR renal insufficiency, chronic [Mesh] OR acute kidney injury [Mesh] OR hypertension CKD OR CKD hypertension OR CKD treatment OR haemo- dialysis OR CKD OR peritoneal dialysis OR renal dialysis/pharmacology [Mesh] or kidney failure, chronic* OR renal dialy- sis* OR kidney failure, chronic/drug therapy [Mesh] OR kidney failure, chronic/nursing [Mesh] OR kidney disease* and Phenomenon Search patient compliance/drug effects [Mesh] OR treatment refusal [Mesh] OR self-medication [Mesh] OR self-administra- of interest tion [Mesh] OR patient medication knowledge [Mesh] OR attitude to health/drug effects [Mesh] OR medication adherence [Mesh] OR concordance medication OR patient acceptance of health care/drug effects [Mesh] OR drug therapy OR poly- pharmacy OR treatment refusal* OR medication adherence* OR prescription drug* OR drug* and Design Search grounded theory OR hermeneutic method OR phenomenology OR ethnographic research OR narratives OR discourse analysis OR qualitative research [Mesh] OR nursing evaluation research [Mesh] OR interview [Publication Type] OR inter- views as topic [Mesh] OR nursing methodology research [Mesh] OR observation [Mesh] OR grounded theory [Mesh] OR hermeneutics [Mesh] OR focus groups/methods [Mesh] OR interview* and Evaluation Search patient acceptance OR patient perception OR patient perspective OR patient satisfaction OR patient experience OR patient preference [Mesh] OR patient acceptance of health care [Mesh] OR life change events [Mesh] OR motivation [Mesh] OR patient motivation OR trust [Mesh] OR patient confidence OR health literacy* OR health knowledge, attitude, practice OR quality of life OR patient acceptance and Research type Search qualitative research [Mesh] Embase Sample Search kidney disease* OR kidney failure OR chronic kidney failure OR renal disease* OR renal insufficiency OR chronic renal insufficiency OR renal replacement therapy OR haemodialysis [Mesh] OR peritoneal dialysis [Mesh] OR dialysis patient* OR haemodialysis patient [Mesh] OR kidney disease/drug therapy [Mesh] OR chronic kidney failure/drug therapy [Mesh] OR kidney failure/drug therapy [Mesh] OR renal replacement therapy [Mesh] and Phenomenon Search medication compliance [Mesh] OR patient compliance [Mesh] OR drug therapy [Mesh] OR treatment refusal [Mesh] of interest OR drug refusal OR medication refusal OR health knowledge and behaviour OR self-medication [Mesh] OR drug self- administration [Mesh] OR medication adherence OR patient medication knowledge OR sttitude to health [Mesh] OR poly- pharmacy OR chronic drug therapy OR drug, prescription OR prescription [Mesh] OR drug efficacy [Mesh] and Design Search qualitative research [Mesh] OR qualitative research OR qualitative method OR interview [Mesh] OR qualitative anal- ysis [Mesh] OR research, nursing [Mesh] OR ethnographic research [Mesh] OR ethnography [Mesh] OR observational method [Mesh] OR observation [Mesh] OR focus group interview OR clinical nursing research [Mesh] OR grounded theory [Mesh] OR thematic analysis [Mesh] OR narrative [Mesh] OR phenomenology OR hermeneutics [Mesh] OR phenomenolog- ical research [Mesh] and Evaluation Search patient preference [Mesh] OR patient attitude [Mesh] OR patient satisfaction [Mesh] OR patient experience OR patient perception OR patient motivation OR motivation [Mesh] OR patient perspective OR Personal experience [Mesh] OR patient acceptance and Research type Search qualitative research [Mesh] CINAHL Sample Search kidney disease [Mesh] OR kidney failure, chronic [Mesh] OR renal insufficiency [Mesh] OR renal insufficiency, chronic [Mesh] OR renal replacement therapy [Mesh] OR haemodialysis [Mesh] OR peritoneal dialysis [Mesh] OR dialysis patient [Mesh] and Phenomenon Search patient compliance/drug effects [Mesh] OR treatment refusal/drug effects [Mesh] OR treatment refusal OR pharma- of interest cological and biological treatments [Mesh] OR health behavior/drug effects [Mesh] OR self-medication [Mesh] OR self- administration [Mesh] OR patient medication knowledge [Mesh] OR knowledge medication [Mesh] OR medication history [Mesh] OR drug therapy [Mesh] OR drug therapy OR attitude to health/drug effects [Mesh] OR polypharmacy [Mesh] OR chronic drug therapy [Mesh] OR drug, prescription [Mesh] OR drugs [Mesh] OR medication adherence OR drug adherence and Design Search qualitative research [mesh] OR field study [mesh] or research, nursing [mesh] or ethnographic research [Mesh] or clinical nursing research [Mesh] OR interview [mesh] OR semi structured interview [Mesh] OR observational method [mesh] OR participant observation [Mesh] OR non participant observation [Mesh] OR focus group [mesh] or hermeneutics OR grounded theory [Mesh] OR discourse analysis or thematic analysis or narratives or phenomenological research [Mesh] and (continued) Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfx140/4774630 by Ed 'DeepDyve' Gillespie user on 07 June 2018 4| T.M. Nielsen et al. Table 1. Continued Search Query Evaluation Search patient preference OR patient experience OR patient perception or patient attitude [Mesh] OR patient motivation [Mesh] OR life experience [Mesh] OR patient acceptance or patient perspective OR patient satisfaction OR beliefs or health belief/drug effects [Mesh] or motivation/drug effects [Mesh] OR motivation or patient participation [Mesh] OR patient par- ticipation or health literacy and Research type Search qualitative research [Mesh] Fig. 1. Flow diagram illustrating literature search and selection. participated in the included studies. Of these, 171 patients were motivational interviewing via telephone (2 studies), focus group on haemodialysis and/or peritoneal dialysis and 133 patients interviews (2 studies) and face-to-face interviews and observa- attended renal clinics; for 77 patients, treatments were not tion/focus group interviews in combination (2 studies). Sample clearly described. For a full overview of study characteristics see sizes ranged from 7 to 39 patients and the overall age range was Table 3. The studies originated from nine countries (Australia, 19–90 years. The majority of studies were assessed to have Brazil, Canada, Chile, China, Singapore, Sweden, UK and USA). minor to moderate methodological limitations (8 low, 6 Data were collected using face-to-face interviews (13 studies), medium, 5 high). Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfx140/4774630 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Adherence to medication in patients with CKD | 5 Table 2. Summary of qualitative findings and CERQual assessments CERQual assessment of confidence Relevant in the Review finding articles evidence Explanation of CERQual assessment Logistics Establishing and maintaining routines [16, 17, 18, 19, High In all, 13 studies with minor to significant Establishing and maintaining daily routines in relation to med- 21, 23, 24, confidence methodological limitations, where ications facilitated medicine taking. Across studies, patients 25, 26, 27, most studies had minor to moderate described the difficulty of remembering to take their medica- 28, 29, 30] methodological limitations (6 low, 4 tions, cope with the complexity of a high pill burden with dif- medium, 3 high). Thick data from six ferent dosage times throughout the day and additional countries across five geographical con- instructions about how and when to take certain medica- tinents, but predominantly high tions. They were also challenged by the task of remembering income countries. High coherence to order and renew prescriptions on time, specifically when medicines ran out at different times. Establishing routines promoted maintenance of prescriptions and medicine tak- ing. Changes in established daily routines disrupted medi- cine taking The costs of buying medication [16, 25, 27, 28, Moderate In all, five studies with minor to moderate The costs associated with buying prescribed medications 29] confidence methodological limitations (three low, reduced medicine taking. Patients who were financially bur- two medium). Moderate data from two dened described that they tried to make their supply of med- countries (Singapore and Australia) ications last longer by skipping some doses, taking lower across two geographical continents and doses of medicine than prescribed or, alternatively, asking only high-income countries. High their physician to prescribe double-strength medication to coherence reduce the costs associated with buying medications Benchmarking the need for medication Absence of effect from a lay perspective [14, 16, 17, 18, High In all, 15 studies with minor to significant Absence of any tangible effect of a medication influenced some 19, 20, 21, confidence methodological limitations, where patients’ adherence to medication. A majority of patients 23, 24, 25, most studies had minor to moderate prioritized the medications that they believed to be impor- 26, 27, 28, methodological limitations (7 low, 5 tant and those they felt produced noticeable effects, that is, 29, 30] medium, 3 high). Thick data from eight symptom relief, pain relief or improved clinical parameters. countries across seven geographical Medications benchmarked as ‘less important’ was most pro- continents and predominantly high- nounced in patients with few or no symptoms and/or when income countries. High coherence patients experienced that ‘less important’ medications were hard to swallow or tasted bad. Patients also described reduc- ing dose, timing regime or not taking the medication at all, if the medication imposed side effects and concerns regarding potential interactions Lacking understanding of medication indications and effects [12, 21, 22, 23, Moderate In all, 10 studies with minor to significant Lacking understanding of the indication for medications, pri- 24, 25, 27, confidence methodological limitations, where marily the importance of preventive medications, was a bar- 28, 29, 30] most studies had minor to moderate rier to adherence. Some patients did not know why methodological limitations (5 low, 3 medications were prescribed or how they worked, resulting medium, 2 high). Moderate data from in a lack of understanding of the importance of taking the five countries across four geographical medication. Conversely, knowing why medications were continents and predominantly high- prescribed and how they worked facilitated adherence income. High coherence Spurred by emergent symptoms [13, 18, 25, 26, Moderate In all, five studies with minor to signifi- Emergent symptoms of disease progression made some 27] confidence cant methodological limitations (one patients regret failing to be adherent to their prescribed low, two medium, two high). Moderate medications despite any side effects. Facing dialysis and dis- data from three countries (UK, USA and ease-associated complications, these patients reflected on Australia) across three geographical the importance of medical adherence. Emergent symptoms continents and only high-income coun- changed their benchmarking of the importance of medica- tries. High coherence tions, leading to a higher degree of adherence. The quality of the patient–physician relationship Eliciting patients’ wishes for involvement in decisions concern- [12, 13, 14, 15, High In all, 13 studies with minor to significant ing medication 18, 22, 23, confidence methodological limitations, where Eliciting patients’ wishes for involvement in decisions concern- 24, 25, 26, most studies had minor to moderate ing medication influenced some patients’ adherence to med- 27, 28, 29] methodological limitations (5 low, 5 ication. Across studies patients expressed different wishes medium, 3 high). Thick data from five for being involved in decisions concerning medications. countries across five geographical con- Some patients placed all their trust in the physicians and tinents and predominantly high- readily left them to take control and make decisions on their income. High coherence Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfx140/4774630 by Ed 'DeepDyve' Gillespie user (continued) on 07 June 2018 6| T.M. Nielsen et al. Table 2. Continued CERQual assessment of confidence Relevant in the Review finding articles evidence Explanation of CERQual assessment behalf while others wished to collaborate as equal partners with physicians about treatment-related decisions, including medication. Lack of continuity, time, trust and involvement of patients wishing to partake in treatment led to patients taking matters into their own hands in relation to medicine taking. Lacking information [14, 18, 22, 23, Moderate In all, seven studies with minor to signifi- Feeling insufficiently informed about the indications, effects 24, 25, 28] confidence cant methodological limitations, where and side effects and interactions between prescribed medi- most studies had minor to moderate cations affected adherence negatively. Some patients sus- methodological limitations (three low, pected physicians of withholding information while others three medium, one high). Moderate described getting conflicting information. For example, dif- data from four countries across four ferent information from different physicians or physician geographical continents and only high- information that differed from the drug information sheet. income countries. High coherence This resulted in confusion and apprehension about the med- ication, which in some patients posed a barrier to adherence medications, refilling dosette boxes, ordering and renewing pre- Synthesis scriptions, reminders to take medications). Memory aids and We identified three analytical themes with seven descriptive dosette boxes appeared especially important for patients suffer- subthemes. ing from fatigue, nausea and poor memory. A downside of dos- (1) ‘Logistics’, with the subthemes establishing and main- ette boxes was that patients had to be able to see well enough to taining routines, and the costs of buying medication. read the date and to be able pick up or replace a lost pill with an (2) ‘Benchmarking the need for medication’, with the identical one [16, 18, 25]. subthemes absence of effect from a lay perspective, lacking Participating in activities such as family and social gather- understanding of medication indications and effects and being ings, health care appointments and other meetings tended to spurred by emergent symptoms. disrupt daily routines. Potentially this resulted in patients forget- (3) ‘Quality of the patient–physician relationship’, with the ting to take their medication or deliberately leaving it at home subthemes eliciting patients’ wishes for involvement in deci- and postponing the medication until later. Frequent changes in sions concerning medication and lacking information. the number of medications, type, dosage and timing of medica- A summary of the main analytical and descriptive themes tions also disrupted established routines and reduced adherence. are presented in Table 4. Table 5 presents a selection of patient quotations illustrating each descriptive theme. The costs of buying medication (moderate CERQual confidence) In some studies, patients described the costs of buying pre- Logistics scribed medications as a barrier to adherence. Patients who The logistics surrounding medicine taking were important for were financially burdened tried to make their supply of medica- facilitating or hindering adherence. Logistics involved the prac- tions last longer by skipping doses, taking lower doses of medi- tical challenges of managing complex medication regimes, cine than prescribed or, alternatively, asking their physician to numerous prescriptions and health care appointments, all of prescribe double-strength medication to reduce the costs of which were challenging in the patients’ everyday lives. buying medications. Furthermore, logistics included the costs of buying medication. Benchmarking the need for medication Establishing and maintaining routines (high CERQual confidence) Benchmarking the need for medication was both a facilitator Establishing and maintaining daily routines in relation to medi- and barrier to adherence. Patients used their lay beliefs and cations facilitated adherence. Across studies, patients described experiences of effects and side effects of medications to bench- the difficulty of remembering to take medications and coping mark which medications were important to take and which with the complexity of a high pill burden, different dosage times medications could be omitted, completely or occasionally. throughout the day and specific instructions about how to take certain medications. They were also challenged by the task of Absence of effect from a lay perspective (high CERQual confidence) remembering to renew prescriptions on time, as prescriptions Patients prioritized the medications they felt produced notice- expired at different times. Daily routines promoted the mainte- able effects such as symptom relief, pain relief or improved clin- nance of prescriptions and medicine taking. Facilitating rou- ical parameters. Effective medications from the perspective of tines included memory aids (tally charts, calendars, mobile phone), assisting devices (dosette boxes), taking medicines in patients included antihypertensive medications, diabetes medi- relation to daily activities (meal times or prayers) and reminders cations and analgesics. Medications with less noticeable effects and/or practical support from family or pharmacists (preparing were less important to patients and were more likely to be Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfx140/4774630 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Adherence to medication in patients with CKD | 7 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfx140/4774630 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Table 3. Characteristics of the included studies Total number of Study Country Treatment Stage of disease participants Age (years) Data collection Methodology Analysis Topic Roso et al. [12] Brazil Attending renal CKD Stage 3–5 15 19–85 Face-to-face Qualitative Thematic To explore how patients in clinic interviews exploratory conservative treatment of chronic renal insuffi- ciency care for themselves Clarkson and USA Peritoneal dialy- CKD Stage 5 10 26–85 Face-to-face Qualitative Not stated To explore the lived experi- Robinson sis and interviews exploratory ence of patients with [13] haemodialysis end-stage renal disease Costantini Canada Attending renal CKD Stage 1–3 14 19–69 Face-to-face Qualitative Content To explore the self-manage- [14] clinic interviews exploratory ment experiences of peo- ple with mild to moderate CKD Curtin and USA Haemodialysis CKD Stage 5 18 38–63 Face-to-face Qualitative Content To gain an insight into the Mapes [15] interviews exploratory factors that are associ- ated with some dialysis patients’ ability to live long lives on dialysis Griva [16] Singapore Haemodialysis CKD Stage 5 37 51.3 Face-to-face inter- Qualitative Thematic To explore cultural perspec- (mean views and focus exploratory tives on facilitators and age) group interviews barriers to treatment adherence in HD patients Guerra- Chile Haemodialysis CKD Stage 5 15 22–82 Face-to-face inter- Hermeneutic Thematic To explore the lived experi- Guerrerro views (indirect phenomenological ences of patients on hae- et al. [17] method modialysis regarding observation) adhering to treatment regimens and their per- ception of quality of life Mckillop and UK Attending renal CKD, stage not 10 29–82 Face-to-face Qualitative Thematic To explore attitudes Joy [18] clinic described (but interviews exploratory towards medicines, poly- not Stage 5) pharmacy and adherence in patients with CKD Karamanidou UK Haemodialysis CKD Stage 5 7 32–68 Face-to-face Qualitative Interpretative The experience of renal et al. [19] interviews exploratory phenomenological patients undergoing dial- ysis treatment, focusing on beliefs about their ill- ness, prescribed treat- ment and the challenge of adherence (continued) 8| T.M. Nielsen et al. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfx140/4774630 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Table 3. Continued Total number of Study Country Treatment Stage of disease participants Age (years) Data collection Methodology Analysis Topic Lam et al. [20] China Peritoneal CKD Stage 5 36 35–76 Face-to-face Qualitative Content To explore adherence from dialysis interviews exploratory patients’ perspectives and to describe changes in adherence to a thera- peutic regimen among patients undergoing con- tinuous ambulatory peri- toneal dialysis Lindberg and Sweden Peritoneal dialy- CKD Stage 5 10 39–83 Face-to-face Qualitative Content To explore obstacles to Lindberg sis and interviews exploratory adherence to phosphate- [21] haemodialysis binding medication and to describe the measures taken by dialysis patients to overcome these obstacles Mason et al. UK Treatment not CKD, stage not 9 56–76 Focus group Qualitative Framework To identify and explore [22] described described interviews exploratory approach with knowledge and attitudes tenets of regarding the control of grounded theory blood pressure, patient empowerment and edu- cational needs Rifkin et al. USA Dialysis and CKD Stage 3–5 20 55–84 Face-to-face Qualitative Thematic and To explore the major [23] attending interviews exploratory ethnographic themes surrounding renal clinic medication use and adherence decisions in older kidney disease patients Walker et al. UK Attending renal CKD Stage 4 9 63–83 Face-to-face Qualitative Thematic To explore the experiences [24] clinic interviews exploratory of patients attempting to integrate lifestyle changes into their lives Williams et al. Australia Attending renal CKD Stage 1–5 23 30–77 Face-to-face Qualitative Johnson’s model of To explore factors affecting [25] clinic (but not on interviews exploratory medication adherence to multiple dialysis) adherence prescribed medications for consumers with dia- betic kidney disease from the time of prescription to the time they took their medications (continued) Adherence to medication in patients with CKD | 9 Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfx140/4774630 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Table 3. Continued Total number of Study Country Treatment Stage of disease participants Age (years) Data collection Methodology Analysis Topic Williams et al. Australia Attending renal CKD, stage not 23 59.3 Face-to-face Qualitative Framework To examine how irrational [26] clinic described (but (mean interviews exploratory approach accord- thinking affects people’s not on age) ing to Ritchie and adherence to multiple dialysis) Spencer medicines prescribed to manage their diabetic kidney disease Williams and Australia Attending renal CKD Stage 2–4 39 68 (mean Motivational inter- Qualitative Thematic approach To explore the motivation Manias [27] clinic age) viewing via exploratory incorporating the and confidence of people telephone modified Health with coexisting diabetes, Belief Model CKD and hypertension to take their medicines as prescribed Williams et al. Australia Attending renal CKD, stage not 26 73.5 Motivational inter- Qualitative Framework method To examine the perceptions [28] clinic described (but (mean viewing via tele- exploratory according to of a group of culturally not on age) phone with Ritchie and and linguistically diverse dialysis) interpreter Spencer participants with the comorbidities of diabetes, CKD and cardiovascular disease to determine fac- tors that influence their medication self-efficacy through the use of moti- vational interviewing Ghimire et al. Australia Haemodialysis CKD Stage 5 30 44–84 Face-to-face Qualitative Thematic approach To explore factors associ- [29] interviews exploratory incorporating ated with medication WHO medication adherence, and examine adherence model the differential perspec- tives on medication-tak- ing behaviour shown by haemodialysis patients Bowling et al. USA Treatment not CKD Stage 3–5 30 75.1 Focus group Qualitative Grounded theory To identify and describe the [30] described (mean interviews exploratory relationship among fac- age) tors that facilitate or impede CKD self-man- agement for older veter- ans with moderate to severe CKD 10 | T.M. Nielsen et al. Table 4. Summary of the main analytical and descriptive themes Quality of the patient–physician Logistics Benchmarking the need for medication relationship • • • Establishing and maintaining routines Absence of effect from a lay perspective Eliciting patients wishes for involvment (high CERQual confidence) (high CERQual confidence) in decisions concerning medication • • Cost of buying medication (moderate Lacking understanding about medica- (high CERQual confidence) CERQual confidence tion indication and effects (moderate Lacking information (moderate CERQual confidence) CERQual confidence) Spurred by emergent symptoms (mod- erate CERQual confidence) skipped. Skipping ‘less important’ medications was most pro- Eliciting patients’ wishes for involvement in decisions concerning nounced in patients with few or no symptoms and/or when medication (high CERQual confidence) patients experienced that ‘less important’ medications were Patients expressed different wishes for being involved in deci- sions concerning medications. Some placed all their trust in hard to swallow or tasted bad [14, 16, 17, 19, 25, 33]. These medi- physicians and readily let the physician take control and make cations included lipid-lowering agents, histamine H2-receptor decisions on their behalf. Others wished to collaborate as equal antagonists, calcium, phosphate-binding agents, statins, partners with physicians about treatment-related decisions, aspirin, metoclopramide, pantoprazole and vitamins. including medication. They wanted physicians to acknowledge Specifically, calcium and phosphate-binding agents were often their concerns and opinions about medication and wished to missed because of their size, taste and texture [12, 13, 19, 25, 29]. discuss the pros and cons of changes in medications, doses and Patients were also prone to non-adherence when they expe- effects versus side effects. They also wished to discuss how to rienced that side effects outweighed intended therapeutic manage the disease, the prescribed medication and side effects effects. Side effects could range from minor and tolerable to to suit their lifestyle preferences, including what to expect if severe, affecting the patient’s quality of life. Side effects they chose not to follow the prescribed treatment. Some wished included loss of appetite, nausea, stomach pain, hair loss, body to negotiate medicine doses in order to minimize side effects. In aches, muscle pain, weight loss, coated mouth, tremors, dizzi- several studies, patients experienced insufficient time for dis- ness, skin discoloration, low blood sugar, headache, diarrhoea, cussing medications with physicians in the outpatient clinic constipation, loss of sexual function or ‘feeling terrible’. [16, 18, 19, 33], a large turnover in physicians [16, 17], mistrust of Concerns about side effects and long-term adverse effects of the reasons for prescriptions (some suspected that medications polypharmacy also affected adherence, with patients altering were prescribed for research or financial gain) [15, 19, 25, 27] doses or the timing of medications or skipping medications to and non-empathetic communication [14, 15, 17, 19]. Lack of con- prevent side effects. tinuity, time, trust and involvement of patients wishing to par- take in treatment decisions led to patients taking matters into Lacking an understanding of medication indications and effects (moderate their own hands in relation to medicine taking. CERQual confidence) Lacking an understanding of the indication for medications, pri- Lacking information (moderate CERQual confidence) marily the importance of preventive medications, was a barrier Feeling insufficiently informed about the indications, effects, to adherence. Some patients did not know why medications side effects and interactions of prescribed medications affected were prescribed or how they worked, resulting in a lack of adherence negatively. Some patients suspected physicians of understanding of the importance of taking the medication. withholding information, while others described getting con- Conversely, knowing why medications were prescribed and flicting information. For example, different information from how they worked facilitated adherence. different physicians or physician information differed from the drug information sheet. This resulted in apprehension, which Spurred by emergent symptoms (moderate CERQual confidence) in some patients posed a barrier to adherence. Patients suffering from disease-related complications expressed regret about having been non-adherent. Facing dialysis and Discussion disease-associated complications, these patients acknowledged the importance of medical adherence. Emergent symptoms The aim of this review was to synthesize the available qualita- tive evidence on patient experiences of factors that facilitate changed how they benchmarked the importance of medica- and hinder adherence to medication in patients with CKD. We tions, leading to a higher degree of adherence. identified three main themes: logistics, benchmarking the need for medication and the quality of the patient–physician The quality of the patient–physician relationship relationship. The quality of the patient–physician relationship was both a Logistics referred to the complexity of managing and adher- facilitator and barrier to adherence. Some patients highlighted ing to polypharmacy. Patients’ efforts to cope with this com- that they were more likely to adhere to medications when they plexity included daily medication routines, aids and practical felt well-informed and involved in decisions concerning medi- help from family and others. We assessed the confidence of the cation. Others happily delegated medication decisions. Patients evidence for this theme to be high. Similar to our findings, a who lacked information or felt their side effects were not con- cross-sectional study of medication adherence among kidney sidered tended to be less adherent to prescribed medications. transplant recipients’ showed that practical barriers, including Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfx140/4774630 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Adherence to medication in patients with CKD | 11 Table 5. Selection of quotes from patients to illustrate each descriptive theme Contributing Themes Quotations studies Logistics Establishing and ‘When you get into a habit, you’re less likely to forget taking one.’ [26][16, 17, 18, 19, 21, maintaining ‘...once or twice you might forget or if I am somewhere and the medication is at home or you are 23, 24, 25, 26, routines with friends at a particular time you were supposed to have taken the medication when you 27, 28, 29, 30] don’t have the medication with you so at that time...I try not to do that but.. .’[19] ‘I have, as I said, a table system when my tablets are running out to re-order because there are so many of them it’s not just as easy as saying once a month, but they all run out different times and take different levels and what have you. So, I have to keep track of what we’ve got and when we have got it.’ [24] ‘They’ve [the pharmacy] run out of the drug, go to get the prescription and find the prescription has run out, got to go back to the doctor to get another prescription before I get another tablet and that might take a couple of days and then you find you’re back to square one [disease is uncontrolled].’ [25] ‘...I have two pill organizers that I prepare at the same time...put five in the first compartment in the box and the rest in the others. I take the first ones straight away in the morning when I wake up...drink coffee and eat in the morning...and then I take my other morning medications.’ [21] ‘...my medicine is part of my prayers, okay? So that’s a good way to remember it. Like, I gotta say my prayers; I have to take my [medication].’ [23] ‘I’m okay if I’m in the house. It’s when I go out...half the time I’m sitting thinking I forgot my tab- lets.’ [18] ‘Has so many pills I get daughter to refill [medicine prescriptions).’ [28] ‘My wife makes sure I take them...she helps. She gets all medicines ready.’ [29] ‘Been given new tabs (hypoglycaemic agents) to replace other ones. Does not know what they are- chemist fills Dosette box.’ [28] The cost of buy- ‘...and they cost money more every month...I take but I take half...sometimes.. .I make test take [16, 25, 27, 28, 29] ing medication half and if I feel OK then OK...Lasts longer and save money...If I feel bad then I go polyclinic and take all.’ [16] ‘I’m living on my savings...and a bit of pension and a bit of superannuation...so now you only get one month’s supply, so that makes it much more expensive.. .which is a lot of money when you’re just living on the pension. It’s just money I saved when I was working.’ [25] Benchmarking the need for medication Absence of effect ‘It’s to control the blood pressure for your kidneys. Even if I was to miss the other seven, I will take [14, 16, 17, 18, 19, from a lay that one because I know to keep my blood pressure at a good level.’ [18] 20, 21, 23, 24, perspective ‘And I said, yeah, well, no problem I’m gonna take [niacin]. It’s a benefit for my heart...I’m gonna 25, 26, 27, 28, go for it. And I took it for a while...but I didn’t notice any benefit. I mean, nothing direct. I didn’t 29, 30] feel it. If I take niacin, or I don’t take it, no difference. I don’t take metoprolol, I know there’s a difference. I feel different, I feel some fatigue, I feel something missing.’ [23] ‘If my Levomepromazine wasn’t as good and effective for me I wouldn’t take it because of the side effects.’ [18] ‘I spent a good I’d say at least 6 months dancing around with my treatment, just not taking it seri- ous. I wouldn’t say really serious, just it seemed a bit excessive the amount of medication.... There’s no way it could be that bad, you feel good, that’s the worst thing about it in the begin- ning you don’t realize...’[14] ‘Take all the medicines that I need—just not statin and aspirin—and only take half coversyl [peri- ndopril Prefer ramipril...’[28] ‘I think it’s just calcium tablets; it’s not important. I skip it. I dare not do this with other medicines.’ [20] ‘I had to take [antihypertensive medication], whether it was totally necessary or not, never really occurred to me, it was more like “well this is a preventative measure,” so if I ran out of prescrip- tions sometimes I wouldn’t go and get it filled straight away and I’d go for days, sometimes weeks without taking those medications.’ [25] ‘...the tablets are so disgusting, their consistency is so disgusting, so disgusting you don’t want to take... it’s a big enough job taking the pills I’m supposed to take...they (the phosphate binding agent) didn’t taste that great. They’re orange flavoured so that chewing on them is no great joy ...the chewable tablet was much too big. You couldn’t take it with you anywhere.’ [21] ‘Sometimes I wonder if it’s the tablets so I miss them to see and it definitely does affect how I feel, if I’m feeling a bit yucky for a while, feeling a bit nauseous and just want to lie down basically. So I do get side effects that put me off taking them.’ [24] ‘...but then I have other pills against nausea that I add to it.. .my stomach is so weak...nourish- ment first...for me it (the phosphate-binding agent) is absorbed just as well after a meal...nowa- days I go and lie down for a while (after taking the phosphate-binding agent). Ten to fifteen minutes...’[21] (continued) Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfx140/4774630 by Ed 'DeepDyve' Gillespie user on 07 June 2018 12 | T.M. Nielsen et al. Table 5. Continued Contributing Themes Quotations studies Lacking under- ‘I don’t take medicine for my kidneys; there is no medicine for kidneys, only for high blood pres- [12, 21, 22, 23, 24, standing of sure. There is one for the heart, which is metoprolol, and there are two for high blood pressure, 25, 27, 28, 29, medication which are losartan and amlodipine. I only take these three medicines. And at night I take 30] indications simvastatin, but only sometimes; I don’t take it often, because I do the diet and so I sleep well.’ and effects [12] ‘Well I know what some of them are for but I don’t know what they’re all for. Like when you were asking me before, merely because I can’t read what’s on the packet, I just pick which ones I like but I couldn’t tell you which one’s doing what job.’ [25] ‘I’ve managed to get away with it. It’s only the transplant people [who have to take their medi- cines strictly].’ [27] Spurred by emer- ‘...if I had known that not taking my binders would cause my bones to get brittle from the begin- [13, 18, 25, 26, 27] gent ning, I would not care how sick they were making me, and...keep having side effects and symptoms nobody explained why I have this or what caused it.’ [13] ‘I was a lot more spasmodic [taking medications] until my kidney function got to a point where it is now and I’m looking down the barrel of dialysis and that. I’m probably far more regimented than, and more fearful of not taking it, whereas in the past you know I’ve probably gone six months without...sort of (taking my tablets).’ [25] ‘I wasn’t aware of [the dangers of] blood pressure earlier and if I was, it would have been different.’ [27] Quality of the patient–physician relationship Eliciting patients’ ‘Explaining the disease to the fullest, the meds, what’s involved, what can happen, changes that [12, 13, 14, 15, 18, wishes for are going to be happening in your life so that when it happens you’re not wondering what’s 22, 23, 24, 25, involvement going on now.’ [14] 26, 27, 28, 29] in decisions ‘But I...I adjust by myself, cause you can’t listen to the doctor all the time, because I don’t know concerning whether they’re writing a thesis or what, the way they prescribe the medication, every time you medication know more and more medications. But it doesn’t work with me. I refuse to listen, I said no, I don’t want to take. Too much of medication you know... ah. Even the renal tablets...I never touch.’ [15] ‘These [two medicines] are for cholesterol, and I was only taking one pill for cholesterol, and my cholesterol was fine. Sometimes I think these salesmen come around and talk to the doctors and sell them a bill of goods, and the next thing you know, you’re on it.’ [23] ‘If you read what’s on the prescription [insert] you’d be dead...but they should’ve said, “If you have any side effects such as,” and then only two or three of the major ones...Those are not dis- cussed. So, I had to assume that there’s nothing adverse except in rare cases. Well, it turns out that’s not true because everyone I’ve mentioned the [edema] to, they didn’t blink an eye. They sort of smiled, “Oh, we know.” That irritated me a lot...They acted as if they were getting paid to [prescribe it].’ [23] ‘The problem I see is that it’s making me lose my hair...They say it aren’t the medicine. But natu- rally they’re going to say it can’t be the medicine. But what else can it be.. .I’ve tried stopping them all! I go every other night! Then I notice I don’t lose so much hair...He tells me it aren’t got nothing to do with the medication. But I still believe it does.’ [23] ‘I think I’m the boss in this...you’ve got to be the one to do it. So basically I think I’ve played a major role. The doctor can only guide you; you’ve got to be the one to basically do it.’ [14] ‘Does what doctor tells me to do. I really don’t want to take medicines but doctor tells me I have to.’ [28] ‘They usually tell me what they’re giving me and why. And what the result should be and that’s really all I need to know.’ [23] Lacking ‘I think information should be offered in the beginning, it shouldn’t be withheld, and it’s much [14, 18, 22, 23, 24, information harsher to find it out in the end. Hey okay, you’re looking at being on these blood pressure meds 25, 28] the rest of your life, it’s not going to go away. You need to have that realistic expectation from the beginning.’ [14] ‘So see these are things doctors never tell you...Everything I get I go home and check it. Every sin- gle one of my other medicines says the same thing. And you know, you say: “Well, which one is it?’’’ [23] ‘Now I go to somebody senior to him (previous doctor) and when I go to see him...he says...well you shouldn’t have been on this and you shouldn’t have been on that...and you do tend to get confused!’ [22] Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfx140/4774630 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Adherence to medication in patients with CKD | 13 changes in daily routines, were associated with non-adherence treatment, including decisions to not take medications if this is [31]. In another qualitative study, kidney transplant recipients’ what they wish [1, 36]. reported the importance of developing and maintaining rou- Several instruments have been created to elicit patients’ preferences for involvement in decision making, but none tines to facilitate medication adherence [22]. Like other studies, we found that memory aids, assisting of them have been found feasible in routine clinical settings [1, 36]. Chewning et al. [41] stress that we need neutral modes of devices, associated activities, reminders and practical help from assessing patient preferences for involvement in decision family and pharmacists facilitated adherence [23, 24, 35]. Living making in clinical practice so patients do not feel coerced into with a partner or spouse has likewise been shown to increase involvement or non-involvement. Measures for assessing adherence [23, 35]. patient wishes should therefore include explicit response Using tools such as dosette boxes and memory tools may options for both shared decision making and decision delega- affect adherence both positively and negatively [1, 23, 36]. These tion [41]. Furthermore, we need insight into how patients per- tools may constitute a potential barrier to adherence for ceive decisional processes regarding medications and which patients with impaired vision, sensory disturbances or reading decisions they prefer to share with health professionals [41]. difficulties. Clinicians should also be aware that medicine pack- A recent Cochrane review assessing decision aids in people aging, memory tools and multicompartment devices such as facing screening and treatment decisions concluded that deci- dosette boxes do not necessarily increase medication adherence sion aids improved people’s knowledge of risks and benefits [1, 36]. They may, however, be helpful for patients who are for- and their feeling of being informed and clear about their values getful or have practical problems with managing complex medi- [42]. The authors further concluded that more research is cation regimes [1, 36]. The potential benefits of memory tools needed regarding the effect of decision aids on adherence to for adherence in patients with physical and/or cognitive impair- decisions taken [42]. There is evidence that educational and ments warrant further examination. behavioural interventions increase adherence to phosphate Adherence improved when patients associated medications control in adults receiving haemodialysis [43]. Elwyn et al. [44] with daily routines. An approach to supporting medication expand the field by advocating the potential of integrating adherence could be that clinicians systematically help patients shared decision making and motivational interviewing, an inte- map their everyday activities and encourage them to associate gration that would be relevant to examine in the context of medication routines with these activities [1, 35–38]. medication adherence in patients with CKD. Patients used their lay beliefs and experiences of effects ver- The strengths of our study include a comprehensive system- sus side effects of medications to benchmark which medica- atic review method adhering to the ENTREQ framework, the use tions to take and which to potentially omit. The confidence of of investigator triangulation to enhance transparency and the evidence for this theme was high. The Necessity–Concerns reproducibility and the use of the CERQual approach to assess Framework (NCF) suggests that medication adherence is influ- the confidence in our findings. In our review, we report on enced by individual beliefs about the necessity of medications patient-experienced factors influencing adherence to medica- and their potential adverse effects [39]. For patients in the early tion. They correspond to those identified in a World Health stages of kidney disease who did not experience a high symp- Organization (WHO) report on adherence to medication across a tom burden, it appeared harder to acknowledge the need for range of chronic conditions [45]. The focus of our synthesis was medications, particularly if unpleasant side effects overshad- patient-experienced factors. Therefore, we cannot comment on, owed therapeutic effects. Studies have previously found that for example, political or organizational influences mentioned in side effects and the way in which they are addressed by health the WHO report [45]. The sample sizes in the included studies professionals influence adherence to medication [23, 24]. Those could be characterized as relatively small (median 20). patients experiencing side effects that were acknowledged and Nevertheless, all studies reported that data saturation was well-managed became more adherent [23]. A recent systematic achieved. We cannot rule out dissemination bias [46]. In all, 4 of review found that behavioural interventions for coping with 19 studies included were from the same group of authors. We side effects increased adherence in patients with type 2 diabe- cannot rule out that this may have introduced a risk of system- tes [40]. Acknowledging patient experiences of side effects and atic distortion of the phenomenon of interest [11]. We defined exploring patient preferences for managing side effects, reduc- data as all text labelled ‘results’ or ‘findings’, including patient ing doses and switching medications are alternative approaches quotations, as described by Thomas and Harden [9]. This [1]. involved the use of patient quotations gathered in one context The quality of the patient–physician relationship was impor- to answer the review question specified in the current article. tant for adherence. The confidence of the evidence for this To assess the extent to which quotations and other data from theme was also high. Importantly, while some patients were the primary studies supporting our findings were applicable to happy to delegate medication and other treatment decisions to the context (perspective or population, phenomenon of interest, physicians, others desired more information, continuity and setting) specified in our review question, we used the CERQual involvement in decisions concerning treatment and medica- component relevance [11]. We attempted to distinguish varia- tions. These findings are confirmed in a systematic review of tions in factors influencing adherence across treatments and patient preferences for shared decisions in which the majority stages of disease throughout the analysis. However, it was diffi- of patients preferred shared decisions [41]. Similarly, all studies cult to conclude decisively about the influence of, for example, identified a subset of patients who wanted to delegate decisions stages of disease on this basis. Finally, the CERQual approach is [41]. Consequently, the challenge for health professionals is to a developing method for assessing how much confidence to solicit patient preferences for involvement and tailor consulta- place in findings from a qualitative evidence synthesis [11]. As tions accordingly [41]. Furthermore, health professionals need it is still under development, experience with the approach is to be aware that patient preferences may evolve over time [41]. increasing and will contribute to further development. A limita- In line with this, current guidelines urge health professionals to tion of CERQual is that it does not currently address the poten- support patients in making informed decisions about tial risk of dissemination bias. Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfx140/4774630 by Ed 'DeepDyve' Gillespie user on 07 June 2018 14 | T.M. Nielsen et al. hemodialysis: a critical review of the literature. Eur J Med Res Implications for research and clinical practice 2009; 14: 185–190 We need more evidence on the effect of memory tools, includ- 6. Tong A, Flemming K, McInnes E et al. Enhancing transpar- ing digital solutions, in patients with CKD, including those with ency in reporting the synthesis of qualitative research: cognitive and/or physical impairments. Studies examining the ENTREQ. BMC Med Res Methodol 2012; 12: 181 effect of behavioural interventions for coping with side effects 7. Cooke A, Smith D, Booth A. Beyond PICO: the SPIDER tool for are also relevant. Furthermore, research into the effect of mod- qualitative evidence synthesis. Qual Health Res 2012; 22: els for shared decision making on adherence in patients with 1435–1443 CKD is needed. Finally, additional qualitative studies involving 8. Critical Appraisal Skills Programme (CASP) Qualitative Checklist. subgroups of patients with CKD and different treatment regi- http://docs.wixstatic.com/ugd/dded87_7e983a320087439e94 mens and stages of disease are needed to further contextualize 533f4697aa109c.pdf (22 November 2017, date last accessed) adherence. 9. Thomas J, Harden A. Methods for the thematic synthesis of Our review suggests that health professionals play an impor- qualitative research in systematic reviews. BMC Med Res tant role in influencing patients’ medication adherence. Helping Methodol 2008; 8: 1–10 patients to map daily routines and associate medicine taking 10. Noyes J, Lewin S. Supplemental guidance on selecting a method of qualitative evidence synthesis, and integrating with daily routines may facilitate adherence. Likewise, our find- qualitative evidence with Cochrane intervention reviews. In: ings indicate that health professionals should acknowledge Noyes J (ed). 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Clinical Kidney JournalOxford University Press

Published: Dec 25, 2017

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