conduct a systematic review of trials that assessed the effects of nursing interventions to improve medication adherence among discharged, home-dwelling and older adults. Method: we conducted a systematic review according to the methods in the Cochrane Collaboration Handbook and reported results according to the PRISMA statement


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Age and Ageing 2017; 46: 747–754 doi: 10.1093/ageing/afx076 Published electronically 16 May 2017

© The Author 2017. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email:

Nurse interventions to improve medication adherence among discharged older adults: a systematic review


1School of Health sciences, HES-SO Valais — Wallis, University of Applied sciences Western Switzerland, Chémin de l’Agasse 6, Sion, Switzerland 2IUMSP, Lausanne University Hospital, Lausanne, Switzerland 3Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland 4La Source, School of Nursing Sciences, University of Applied Sciences Western Switzerland, Lausanne, Switzerland 5Service of Nephrology and Hypertension, Lausanne University Hospital, Lausanne, Switzerland

Address correspondence to: H. Verloo. Tel: +41 27 606 84 24; Fax +41 27 606 84 01. Email:


Background: discharged older adult inpatients are often prescribed numerous medications. However, they only take about half of their medications and many stop treatments entirely. Nurse interventions could improve medication adherence among this population. Objective: to conduct a systematic review of trials that assessed the effects of nursing interventions to improve medication adherence among discharged, home-dwelling and older adults. Method: we conducted a systematic review according to the methods in the Cochrane Collaboration Handbook and reported results according to the PRISMA statement. We searched for controlled clinical trials (CCTs) and randomised CCTs (RCTs), published up to 8 November 2016 (using electronic databases, grey literature and hand searching), that evalu- ated the effects of nurse interventions conducted alone or in collaboration with other health professionals to improve medi- cation adherence among discharged older adults. Medication adherence was defined as the extent to which a patient takes medication as prescribed. Results: out of 1,546 records identified, 82 full-text papers were evaluated and 14 studies were included—11 RCTs and 2 CCTs. Overall, 2,028 patients were included (995 in intervention groups; 1,033 in usual-care groups). Interventions were nurse-led in seven studies and nurse-collaborative in seven more. In nine studies, adherence was higher in the intervention group than in the usual-care group, with the difference reaching statistical significance in eight studies. There was no sub- stantial difference in increased medication adherence whether interventions were nurse-led or nurse-collaborative. Four of the 14 studies were of relatively high quality. Conclusion: nurse-led and nurse-collaborative interventions moderately improved adherence among discharged older adults. There is a need for large, well-designed studies using highly reliable tools for measuring medication adherence.

Keywords: medication adherence, nurse intervention, nurse-led interventions, nurse-collaborative interventions, systematic review, older people


Medication adherence—defined as the extent to which patients take medication as prescribed by their healthcare professionals—is an important aspect of treatment efficacy, healthcare costs and patient safety [1, 2]. Medication

adherence also implies the notion of concordance, i.e. a process of shared decision-making between patients and healthcare professionals [3]. According to a WHO report, inadequate medication adherence averaged 50% among patients with a chronic disease [4] and represented a signi- ficant problem that led to increased morbidity and



mortality, as well as increased healthcare costs [5, 6]. Many older adults suffer from multiple chronic diseases and are treated with numerous medications. They are, therefore, at a high risk of poor adherence, e.g. missing doses, discontinu- ation, alteration of schedules and doses or overuse [7]. Non- adherence can result in worsening clinical outcomes, including re-hospitalisation, exacerbation of chronic medical conditions and greater healthcare costs [8, 9]. Up to 10% of hospital readmissions have been attributed to non-adherence [6].

Several studies have demonstrated that insufficient medica- tion adherence is common among discharged older adults [9, 10]. Older adults experienced changes in their medication regi- men during hospitalisation [11] and in the 1st week following hospital discharge [8]. Such changes, as well as complex treat- ment plans, tended to decrease medication adherence and could be a reason for a patient’s non-adherence. Older adults may also have restarted taking medications that were discontin- ued during hospitalisation, failed to start new medications initiated during hospitalisation, or taken incorrect dosages [9, 12]. Moreover, medication changes are poorly communicated to the patient at the time of discharge [13]. Older adults are at a particularly high risk of non-adherence in the 1st days or weeks following hospital discharge [9]. Therefore, it is import- ant for healthcare professionals, especially community health- care nurses, to follow-up with older adults early and frequently to keep them adherent to therapy. Nurses are well placed to provide and coordinate adherence-care because they are pre- sent in the majority of healthcare settings, are in close physical proximity to patients, and act as interfaces between patients and physicians [14].

Previous studies have shown that interventions such as patient education, the use of medication management tools or electronic monitoring reminders, can help to improve medica- tion adherence and continuity of care among older adults [15, 16]. However, few studies have evaluated the effects of inter- ventions to improve medication adherence after hospital dis- charge. Our systematic review focuses on the effectiveness of nurse-led interventions to improve medication adherence in older home-dwelling patients who are discharged from hos- pital; a previous Cochrane review has looked at a broader range of interventions to enhance medication adherence, in a wide range of patient groups [16]. More specifically, there is lit- tle evidence on the impact of nursing interventions—whether alone or in collaboration with other health professionals—on medication adherence among discharged older adults [9].

This systematic review aimed to determine whether nursing interventions alone, or in collaboration with other health professionals, were effective in improving medication adherence among recently discharged, inpatient, home- dwelling older adults aged 65 years old or more, when com- pared with those receiving usual care.

Methods and materials

This systematic review was conducted according to methods in the Cochrane Collaboration Handbook [17] and results were reported according to the PRISMA statement [18].

Data sources and search criteria

In collaboration with a medical librarian (B.K.), a systematic literature search was conducted for any articles published up to 8 November 2016, using predefined search terms in Medline via PubMed (from 1946), EMBASE (from 1947), CINAHL (from 1937), the Cochrane Central Register of Controlled Trials (from 1992), PsycINFO (from 1806), Web of Science (from 1900), JBI database (from 1998), DARE (from 1996), Tripdatabase (from 1997), the French Public Health Database (from 1878), International Pharmaceutical Abstracts (IPA, from 1970) and clinicaltrial. gov (from 2008).

The syntax consisted of four search themes intersected by the Boolean term ‘AND’. MeSH terms included age-related terms (Aged), medication adherence-related terms (Medication Adherence, Patient Medication Knowledge, Prescription Drug Misuse, Polypharmacy, Drug Therapy, Medication Therapy Management, Pharmaceutical Preparations/Administration and Dosage), nurse-related terms (Nursing, Nursing Care, Nurses, Nurse–Patient Relations, Models of Nursing) and hospital-related terms (Patient Discharge, Continuity of Patient Care, Inpatients, Hospitalisation). The search strategy was then adapted for EMBASE, CINAHL, the Cochrane Central Register of Controlled Trials, PsycINFO, Web of Science, the JBI database, DARE, Tripdatabase, IPA and (see Supplementary data 2, available at Age and Ageing online).

In addition to the electronic database searches, a hand search of the bibliographies of all relevant articles was con- ducted, as was a search of unpublished studies using Google Scholar, Proquest, Mednar and Worldcat, without language restrictions. Finally, a forward citation search of the articles selected was also conducted using Google Scholar.

Study selection

Two authors (H.V. and B.K.) independently screened titles, abstracts and full texts from the literature search to deter- mine their eligibility. Full texts were eligible for review if they were written in English, French or German. Studies included: (i) were either randomised clinical trials (RCTs) or controlled clinical trials (CCTs); (ii) had evaluated the effects of nurse interventions or collaborative interventions with other healthcare professionals on medication adherence compared to a usual-care group and (iii) were conducted among recently discharged (<2 weeks after discharge) older adults (aged ≥65 years old), living at home, and taking at least one prescribed medication for any kind of medical condition. Outcomes were changes in medication adherence during follow-up as measured using different methods [1, 14], i.e. electronic monitors, prescription refills, pill counts, medication adherence tools/questionnaires and patient self-reporting. Disagreements between screeners were resolved by consensus.

Nurse interventions were classified as either nurse-led care and nurse-collaborative care, as provided by Registered

H. Verloo et al.


Nurses (RN). Based on the Cochrane Effective Practice and Organisation of Care taxonomy of health systems inter- ventions [19], we considered patient-level interventions con- ducted by nurses (education, counselling and teaching; reminder interventions using telephone contact, discharge planning or medication adherence aids, e.g. electronic moni- tors or pill dispensers; meetings with a healthcare profes- sional in the patient’s home). These could be alone or in collaboration with pharmacists or physicians. We also con- sidered interventions at the healthcare-professional level (educational meetings and distribution of educational materi- als; educational outreach visits with feedback through medi- cation reviews of medical records; monitoring of medication therapy by assessment, adjustment or change of medication; verbal or oral recommendations to pharmacists or physi- cians; team meetings to discuss care or refer the patient to the physician). Interventions targeting healthcare organisa- tions, legal regulations and financial issues were excluded.

Data extraction and risk of bias in the studies included

Two authors (H.V. and B.K.) extracted data independently, using a specially designed and standardised data extraction form. If necessary, any disagreements were resolved through discussion and consultation with the co-authors (V.S. and A.C.). The information extracted from each study included: (i) study author, year of publication and country; (ii) study characteristics (including study setting and design, duration of follow-up and sample size); (iii) participants’ characteristics (including sex, age, medication and medical conditions); (iv) intervention characteristics (including description and fre- quency of nursing interventions, and the healthcare profes- sionals involved); (v) usual-care group’s characteristics; and (vi) types of outcome measures (including medication adherence rates or score, and self-assessment of medication adherence).

Risk of bias in the studies included

Two authors (H.V. and B.K.) independently assessed the risk of bias for all the studies included, using the Cochrane Risk of Bias Tool [20], a validated tool for RCTs [21–24] based on six domains: adequate sequence randomisation, concealment of allocation, blinding of outcome assessors, adequately addressed incomplete outcome data, selective outcome reporting and other risks of bias. Each domain was rated as: (i) low risk of bias, (ii) unclear or (iii) high risk of bias. A study was con- sidered of relatively high quality if it had adequate sequence randomisation and a blinding of outcome assessors (i.e. low risk of bias in both domains). Any disagreement in the quality assessment was resolved by consensus.


Results of the search strategy

In total, 1,546 records were identified using the electronic search strategy, nine using grey literature and references

listed in selected papers, and 825 using the forward citations search. After removal of duplicates, 1,265 records were screened based on title and abstract, and 82 were con- sidered potentially eligible and had their full texts evaluated. A total of 14 studies satisfied the selection criteria and were included (Figure 1).

Characteristics of studies and participants

The 14 studies included were conducted on three conti- nents (Europe, n = 5; Asia, n = 2 and North America, n = 7), in seven countries (Canada, China, Denmark, Italy, Israel, Netherlands and the USA), and were published between 1989 and 2015 (Table 1). Eleven studies were RCTs and three were CCTs. Ten RCTs were randomised at the patient level and one at the hospital level (cluster). Overall, interventions involved nurse-led care in seven stud- ies and nurse-collaborative care in seven more.

The 14 studies involved a total of 2,028 participants (995 in experimental groups; 1,033 in usual-care groups) aged from 63 to 83 years old and followed-up over a mean of 5.3 months (SD = 4.7; range: 1–12 months). All studies included men and women. The patient groups included were older discharged inpatients with cardiovascular dis- eases (n = 8), post-surgical interventions in geriatric and internal medicine units (n = 4), chronic obstructive pulmon- ary disease (n = 1) or stroke with hypertension (n = 1).

Characteristics of nurse interventions

All studies employed discharge planning and patient educa- tion as usual-care activities to improve medication adher- ence. These interventions were carried out in hospital and/ or at the participant’s home (counselling and patient educa- tion/teaching). The interventions exclusively delivered by RNs or implemented in collaboration with other healthcare professionals were multidimensional. Hence, some interven- tions integrated other healthcare professionals and patients through meetings, education sessions or reminders (see Supplementary data 1, available at Age and Ageing online).

The majority of the nurse-led interventions involved comprehensive assessments of medication during home vis- its, verbal advice, medication education and written fact- sheets, care plans and medication schedules, and verbal and written reminders by telephone or using electronic devices, mostly done by nurses and by electronic pill dispensers [21, 22, 24, 25, 28, 32, 33].

The nurse-collaborative interventions were more focused around participants’ clinic visits, integrating coun- selling and comprehensive teaching by a pharmacist or a physician about the importance of medication adherence, and the aid of electronic devices such as weekly tele- monitoring, daily ECG, weighing, medication organisers and electronic patient reminders about medication adher- ence [23, 26, 27, 29–31]. Two collaborative interventions used medication adjustments by the pharmacist, organised

Nurse interventions to improve medication adherence


feedback to other healthcare professionals, and proposed social and personal support [27, 30].

Medication adherence

Five studies assessed medication adherence as the primary outcome [23, 26, 29, 32, 34] and nine studied it as a sec- ondary outcome [21, 22, 24, 25, 27, 28, 30, 31, 33]. Pill counts [29] were used to measure medication adherence, as were the following standardised, validated instruments: the Brief Medication Questionnaire (BMQ) [25, 27], the Medication Adherence Scale [28], the Medication Error Rating [21], the Medication Possession Rating [26, 31] and the Modified Centre for Adherence Support Evaluation (CASE) adherence index [39]. Self-reported measures [22, 30, 32–34] and the medication pharmacy prescription refill [23] were used in almost half of the studies retrieved (see Supplementary data 3, available at Age and Ageing online).

A 1-month study using pill counts was conducted by a pharmacist visiting patients at home or during patients’ pharmacy visits [29]. Tsuyuki et al. [31] employed pharmacy records over 6 months to calculate the Medication Possession Ratio, documented as one of the most accurate and reliable methods of measuring medication adherence [35]. Barnason et al. and Eggink et al. measured medication adherence over three and one-and-a-half months, respect- ively, using the BMQ [36]; Garcia-Aymerich et al. employed the Medication Adherence Scale [37] over 12 months; and Kennedy used the Medication Error Rating Tool [38] over 1 month to discriminate between medication adherence and non-adherence. Tsuyuki et al. [31] and Wolfe and Schirm [32] measured medication adherence using the Medication Possession Ratio and the Medication Rating Scale, respect- ively. Weller employed a weekly/monthly pill dispenser and measured medication adherence over 3 weeks using the CASE adherence index [39]. Self-reporting was based on

Figure 1. PRISMA flow diagram summarising the results of the search strategy.

H. Verloo et al.


telephone calls, interviews during home visits or the analysis of participants’ logbooks (see Supplementary data 3, available at Age and Ageing online). Home visits varied between daily [29], weekly [24, 30, 33], and monthly follow-up visits [22, 32], mostly made by a nurse or a pharmacist. Telephone call follow-up and adherence reminders varied from weekly [21, 24, 25, 28, 31, 33, 34], monthly, to three-monthly contacts [26, 27]. One study assessed participants’ weight weekly using an electronic device [31] and Antonelli et al. assessed weekly electrocardiograms (ECG) by tele monitoring [34]. Only four of the 14 studies reported the duration of the interventions [22, 23, 28, 30]. Table 1 presents the nurse-led, nurse-collaborative interventions and the details of the fre- quency and the durations of the interventions.

Effects of nurse interventions

The diversity of measurement instruments, medical condi- tions and the complexity of the intervention designs made it difficult to summarise the effects of those interventions on the improvement of medication adherence. In nine

studies, medication adherence was higher in the interven- tion group than in the usual-care group, and the difference reached statistical significance in eight of them. Three out of seven nurse-led interventions [21, 28, 33] and five out of seven collaborative-care interventions [23, 26, 29, 30, 34] significantly improved medication adherence.

Nurse-led interventions among cardiac patients by Zhao et al. [33], COPD patients by Garcia-Aymerich et al. [28], and post-surgical patients by Kennedy et al. [21] were all associated with improvements in medication adherence. No improvements were observed in the studies conducted among stroke patients by Hornnes et al. [22], geriatric patients by Weller [24], or post-surgical patients by Wolf and Schirm [32].

Nurse-collaborative interventions conducted among cardiac patients by Antonicelli et al. [34], Bisharat et al. [26], Rich et al. [29] and Rinfret et al. [23] were all associated with improve- ments in medication adherence. However, nurse-collaborative interventions among cardiac patients conducted by Eggink et al. [27] and Tsuyuki et al. [31] were not associated with improvements in medication adherence. In the study by

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Table 1. Characteristics of the studies included

References, country

Design Setting Medical condition Study duration (months)

Type of intervention

Usual care

Antonicelli et al. [34], Italy

RCT Outpatient clinic Congestive heart failure

12 Nurse- collaborative intervention

Routinely planed care visits in the outpatient clinic with a nurse

Barnason et al. [25], USA

RCT Hospital care with follow-up

Heart failure 3 Nurse-led intervention

Routine discharge procedure for patients with heart failure carried out by a nurse

Bisharat et al. [26], Israel

CCT Hospital with transition care programme

Chronic heart failure 9 Nurse- collaborative intervention

Discharge counselling by a nurse

Eggink et al. [27], Netherlands

RCT Hospital patients at discharge

Heart failure 1.5 Nurse- collaborative intervention

Routine discharge planning, including information about drug therapy delivered by a nurse

Garcia-Aymerich et al. [28], Spain

RCT Hospital and home healthcare setting

Chronic obstructive pulmonary disease

12 Nurse-led intervention

Standard discharge procedure for COPD patients

Hornnes et al. [22], Denmark

RCT Hospital and home healthcare setting

Stroke with hypertension

12 Nurse-led intervention

Stroke unit’s standardised discharge routine care

Kennedy [21], USA

RCT Hospital and home healthcare setting

Geriatric inpatients 1 Nurse-led intervention

Usual discharge care and information sheet

Rich et al. [29], USA

RCT Hospital and home healthcare setting

Congestive heart failure

1 Nurse- collaborative intervention

Conventional medical care and hospital’s standardised discharge protocol and pre- discharge medication instructions

Rinfret et al. [23], Canada

RCT Hospital inpatient follow-up at home

Drug-eluding stent with anti-platelets

12 Nurse- collaborative intervention

Usual counselling before discharge

Rytter et al. [30], Denmark

RCT Hospital and municipality care centres

Geriatric inpatients 3 Nurse- collaborative intervention

Usual care made up of a short patient education session by a nurse prior to hospital discharge

Tsuyuki et al. [31], Canada

RCT Hospital discharge follow-up programme

Heart failure 6 Nurse- collaborative intervention

Usual discharge planning

Weller [24], USA CCT Hospital care with follow-up

Geriatric inpatients 3 Nurse-led intervention

Usual discharge medication education

Wolfe and Schirm [32], USA

CCT Hospital and home healthcare setting

Geriatric inpatients 1.5 Nurse-led intervention

Usual discharge planning procedure

Zhao and Wong [33], China

RCT Hospital transitional care programme

Coronary heart disease

3 Nurse-led intervention

Routine usual-care protocol

Nurse interventions to improve medication adherence


Rytter et al. [30] a nurse-collaborative intervention among post-surgical patients was associated with improvements in medication adherence (P = 0.03).

Risk of bias and methodological quality of the studies

Figure 2 shows the risk of bias graph in included studies. In most domains, few studies had a low risk of bias. Only 4 of 14 studies displayed adequate sequence randomisation and a blinding of outcome assessors and were thus considered of relatively high quality.


To the best of our knowledge, this was the first systematic review to evaluate nurse interventions aimed at improving medication adherence among discharged older patients, based on RCTs and CCTs. In total, 14 studies were included, incorporating 2,028 participants. Interventions were nurse-led in seven studies and nurse-collaborative in seven more. In nine studies, medication adherence was higher in the intervention group than in the usual-care group, and this difference reached statistical significance in eight studies. The five remaining studies showed no differ- ence in medication adherence. However, very few studies were of relatively high quality. We concluded that nurse-led and nurse-collaborative interventions can improve medica- tion adherence among discharged older adults.

This review has several limitations. One limitation was that many of the studies failed to provide sufficient detail to allow a precise assessment of the risk of bias, or the exact nature, frequency and duration of the intervention tested itself. Additionally, intervention and usual-care groups were not always described in sufficient detail. For example, although a study might clearly state that patients received reminders, the means of administering them was not always described, or was only partly described. This also raised the issue, in many of the studies, of an adequate description of the usual-care group. Some studies merely reported that the participants in the usual-care group received usual care, but did not describe what this entailed. If usual care was already

performing relatively well, then it would be harder to show any improvement due to the intervention. Since we used the term ‘ageing’ as a Mesh term or keyword in the search strategy, we may have missed some relevant studies.

Another limitation was the difficulty in accurately asses- sing medication adherence. It is well documented that stud- ies using self-reporting by patients overestimate medication adherence [40]. These studies are at a high risk of bias when the participant is not blinded to the intervention. The lack of blinding is a limitation; it is especially problematic when adherence was estimated using questionnaires. Indeed, patients in the intervention group may have overes- timated their self-reported adherence. Although validated questionnaires are available, their accuracy and reliability are often limited and they depend on the context in which they are used [41]. Pill count is a more objective measure, used in some studies, and it is less exposed to bias than methods based on self-reporting. However, most pill counts are done using pill containers that the participant manages alone or brings along to visits to healthcare professionals, and in these circumstances counts can clearly be altered by the participant [42]. Intervention components that could be explored further include newer information and communi- cation technologies used in addition to regular care, and the specific or coordinated roles of allied health professionals. The duration of intervention varies largely from one study to the other. The association between the duration of inter- vention and the effect on the outcome was not clear.

All the studies included were relatively small, with sample sizes ranging from 40 to 303 participants. Relatively small studies are more likely to miss significant differences in medi- cation adherence, even when the intervention substantially improves medication adherence [43]. If clinical trial studies need hundreds or thousands of participants to show that interventions improve medication adherence over usual care, then it is unlikely that improving medication adherence among older patients will have a substantial effect on major health outcomes [43]. Innovative ideas to improve medication adherence should be tested in much larger trials in order to document their effects on clinically important outcomes (including adverse effects), their feasibility in everyday practice settings, and their sustainability.

0% 20% 40% 60% 80% 100%

No other risk of bias?

Selective outcome reporting?

Incomplete outcome data adressed?

Blinding of outcome assessors?

Allocation concealment?

Adequate sequence generation randomization?

Yes (low risk of bias) Unclear No (high risk of bias)

Figure 2. Risk-of-bias graph in included studies based on review authors’ judgments about each domain of the risk-of-bias tools.

H. Verloo et al.


Finally, the lack of substantial evidence could be explained by the fact that we do not understand exactly what medication adherence problems consist of in sufficient detail. Frameworks to assist the development of complex interven- tions, therefore, advise preparatory assessments involving patients and other stakeholders, in order to better understand the problems and the context. More objective measures of medication adherence are needed to determine intervention effects accurately, and investigators should make use of best- in-class adherence measures, such as prescription monitoring. Researchers should invariably design studies to minimise the risk of bias and should report their procedures clearly.

Despite an extensive search, we may have missed some trials that met all of the present study’s criteria. We identi- fied 14 studies evaluating the effect of nurse interventions on medication adherence among discharged older patients. Overall, this systematic review was conducted using high methodological standards, and it is, therefore, highly cred- ible. However, due to the important heterogeneity between studies (design, type of intervention) and their relatively low quality, the level of confidence in the true effect of the nurse interventions on medication adherence is low. Therefore, there is still a need for large, well-designed RCTs using highly reliable tools. Of note, non-adherence is also of concern among younger patients, notably those with chronic psychiatric diseases such as schizophrenia and major depression. To the best of our knowledge, there has been no systematic review evaluating the effects of nurse interventions to improve medication adherence at the time of discharge among this type of patients.


This systematic review examined the effects of nurse-led and nurse-collaborative interventions to improve medica- tion adherence among discharged home-dwelling older adults. The complex nurse-led and nurse-collaborative inter- ventions retained for this study tended to improve the medication adherence to long-term medication prescrip- tions among home-dwelling older adults. However, very few studies were of a relatively high quality, thus limiting our confidence in the true effect of these interventions. There is, therefore, a need for further well-designed studies involving large samples and using highly reliable tools, for example, innovative e-health technologies (telephone appli- cations) combined with pill counts to measure medication adherence among home-dwelling older adults.

Key points

• Nurse interventions to improve medication adherence. • Insufficient medication adherence is common among dis- charged older adults.

• Improving medication adherence among recently dis- charged inpatient.

Supplementary data

Supplementary data are available at Age and Ageing online.

Authors’ contributions

Study design and concept: H.V. and V.S. Writing of study protocol: all authors. Data acquisition: H.V., B.K. and T.K. Data analysis and interpretation: H.V., A.C., T.K. and V.S. Article drafting: H.V. Critical revision of the article for important intellectual content: H.V., V.S., A.C., B.K. and T.K. Statistical analysis: A.C. and T.K. All authors revised the article for important intellectual content and gave their final approval for the submitted version.

Conflicts of interest

The authors declared no conflicts of interest.


No external funding was implicated in this systematic review.


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Received 25 July 2016; editorial decision 1 March 2017

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