Interventions to promote medication adherence for chronic diseases in India: a systematic review

Introduction Cost-effective interventions that improve medication adherence are urgently needed to address the epidemic of non-communicable diseases (NCDs) in India. However, in low- and middle-income countries like India, there is a lack of analysis evaluating the effectiveness of adherence improving strategies. We conducted the first systematic review evaluating interventions aimed at improving medication adherence for chronic diseases in India. Methods A systematic search on MEDLINE, Web of Science, Scopus, and Google Scholar was conducted. Based on a PRISMA-compliant, pre-defined methodology, randomized control trials were included which: involved subjects with NCDs; were located in India; used any intervention with the aim of improving medication adherence; and measured adherence as a primary or secondary outcome. Results The search strategy yielded 1,552 unique articles of which 22 met inclusion criteria. Interventions assessed by these studies included education-based interventions (n = 12), combinations of education-based interventions with regular follow up (n = 4), and technology-based interventions (n = 2). Non-communicable diseases evaluated commonly were respiratory disease (n = 3), type 2 diabetes (n = 6), cardiovascular disease (n = 8) and depression (n = 2). Conclusions Although the vast majority of primary studies supporting the conclusions were of mixed methodological quality, patient education by CHWs and pharmacists represent promising interventions to improve medication adherence, with further benefits from regular follow-up. There is need for systematic evaluation of these interventions with high quality RCTs and their implementation as part of wider health policy. Systematic review registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022345636, identifier: CRD42022345636.


Introduction
Non-communicable diseases (NCDs) represent leading causes of morbidity and mortality worldwide, with a disproportionate burden in low-and middle-income countries (LMICs) (1). India is currently undergoing a significant epidemiological, demographic, and socioeconomic transition which is driving an epidemic of NCDs-which now accounts for around 4.7 million deaths per year and 226.8 million disability-adjusted life years (2). Treatment of NCDs usually requires long-term medication adherence to maintain optimal health outcomes, prevent the onset and progression of complications, and improve the quality of life (3,4). However, the World Health Organization (WHO) estimates 50% of patients in developed countries do not take their medications as prescribed (5). This figure has been reported to be lower in LMICs like India for a range of NCDs (6)(7)(8)(9). In India, several barriers to adherence have been identified across the WHO's five dimensions of medication adherence (5,10). This includes patient-related factors such as poor understanding of illness and treatment owing to low rates of health literacy (11), healthcarerelated factors such as healthcare accessibility (11), medicationrelated factors such as medication affordability secondary to financial constraints (12), condition-related factors such as the development of complications (13), and socioeconomic factors including socioeconomic status, and existing untreated substance abuse disorder (14). In particular, patient-related factors appear most amenable to interventions that aim to improve medication adherence (15,16).
There is growing evidence showing the benefits of medication adherence improving interventions on NCDs control (17, 18). However, most of the evidence for medication-adherence improving strategies is based on western populations (19); does not distinguish between countries of origin (20), or excludes studies from LMICs due to differences in healthcare systems (21). Existing evidence on adherence promoting interventions in LMICs tends to focus on certain diseases across LMICs without stratifying countrylevel effects (22,23) or is specific for communicable diseases, such as HIV (24,25), where distinct factors such as complex regimens, greater perceived risk, and stigma may influence adherence, compared to NCDs (25, 26).
Given the increasingly aging population in India and the concomitant growing burden of NCDs, low medication adherence imposes a significant healthcare, and financial cost (27, 28). As low medication adherence is partly driven by behavioral factors in India (10-14), there is potential for effective medication-adherence improving interventions to improve health outcomes, which is also one of WHO's key current priorities (5,29). There is need for effective medication adherence-improving interventions based on systematically analyzed evidence. However, to our knowledge, there are no systematic reviews evaluating adherence-promoting interventions in individual LMICs, such as India, which focus on a variety of NCDs. Furthermore, country-specific reviews are important to ensure generalizability of primary studies and tailored large-scale public health interventions to improve realworld outcomes.
This systematic review sought to review the evidence for interventions that promote medication adherence in India for patients with NCDs and provide a qualitative synthesis of results. We aim to allow policy makers and stakeholders to make evidencebased decisions on which adherence promoting interventions are effective, scalable, replicable, generalizable, and cost-effective, disaggregating findings by intervention and NCD. We also aimed to review strategies for measuring medication adherence and provide recommendations to inform design of future studies.

Protocol registration
The aim of this study was to conduct a systematic review evaluating the efficacy of interventions aimed at improving medication adherence for chronic diseases in India. The study protocol was registered on PROSPERO (Registration ID: CRD42022345636). A preliminary scoping search was performed to refine search criteria and identify outcome measures. This study was undertaken according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework (30). A PRISMA (2020) checklist is shown in the Supplementary material.

Eligibility criteria
The study design was developed using the PICO (participant, interventions, comparisons, outcomes) framework (31).

Participant criteria
Only studies which investigated adherence interventions in India, in outpatient and community populations with at least one eligible non-communicable chronic disease, were considered. NCDs appropriate for inclusion were identified previously in the scoping search and based on those surveyed in the recent SAGE-2 report in India: stroke, angina pectoris, diabetes mellitus, asthma, depression, hypertension, and chronic lung disease (32). We excluded communicable diseases, such as tuberculosis and HIV, as interventions to improve adherence to medications for these diseases are better characterized (24,(33)(34)(35)(36)(37). We also excluded arthritis, as regular medication use is not the mainstay of treatment (38, 39).

Intervention & outcome criteria
Only studies which tested an intervention to improve adherence in patients taking regular medications, either as a primary or secondary outcome, were considered. Examples of eligible interventions were patient education, streamlined medication regimens, and electronic reminders. Studies only investigating interventions targeted at improving medication adherence within a hospital setting were excluded. Adherence outcomes included subjective data based on patient self-reporting and objective measures, such as pill counts. Studies which measured objective clinical parameters and disease outcomes as a proxy for adherence were also included if adherence to treatment was explicitly stated as a study aim.

Search strategy
A comprehensive search strategy, based on the above criteria and the scoping review, was devised. The search strategy was conducted on Ovid Medline, Web of Science, Scopus, and Google Scholar. No restrictions were placed on language, date of publication or geographical region. The full search criteria can be found in Supplementary material. Medical subject headings (MeSH), free-text terms, and Boolean logic were used where available. Searches were run on 20/7/2022. Given the comprehensive search strategy, references of included articles were not checked.

Study selection
The studies retrieved by the search strategy, along with study information and abstract text, were imported into Zotero and then Mendeley for de-duplication (40). A 1,264 unique articles were split amongst reviewers, with each title and abstract screened independently by two reviewers using Rayyan AI (41). Conflicts between the two reviewers were resolved by a third independent reviewer. To ensure the inclusion and exclusion criteria were applied consistently amongst all reviewers, all reviewers screened 50 studies first and any disagreements were discussed by all reviewers until a consensus was reached. Full texts of included studies were screened independently by two reviewers; a third independent reviewer resolved any disagreements between the two original reviewers. For reports where full text was unable to be retrieved, authors were contacted to request their manuscripts-if they failed to respond within 2 months, studies were excluded.

Study criteria
Only randomized control trials were included in qualitative synthesis to ensure conclusions were informed by the best evidence available. Inclusion and exclusion criteria are shown in Table 1.

Data extraction and management
Data extraction was conducted via Google Sheets using a pre-specified template, using a list of features identified during the scoping review. One reviewer performed data extraction for each study, and this was subsequently checked by a second reviewer. The different domains of data extracted are reported in Supplementary material.

Quality assessment
The Cochrane Risk-of-Bias (RoB) 2 tool for randomized control trials and for cluster randomized control trials were used to assess methodological quality (42). RoB assessment was conducted independently by two reviewers for each article, and any disagreements across domains were resolved by a third reviewer. Results were synthesized and formatted using R Studio (43). When multiple papers reported different adherence-related outcomes from the same original study dataset, study weights were adjusted accordingly to prevent double-counting.

Results
A total of 1552 studies were identified from literature searches, of which 288 were removed as duplicates. A further 1,170 were excluded during title and abstract screening. A total of 96 full texts were screened for eligibility, of which 22 were included in this review. A PRISMA flow diagram depicting information flow through different phases of the systematic review is shown in Figure 1.

Overview of interventions
We identified 22 RCTs which met the inclusion criteria . Of these 22 studies, 12 investigated the effects of patient education (mean length of follow-up = 6 months); two studies investigated the use of electronic reminder-based systems (mean length of follow-up = 9 months); two studies investigated psychologicalbased approaches (mean length of follow-up = 3.   Table 2 below. Many studies had multiple outcome measures; those most relevant to adherence and corresponding clinical outcomes are reported in Table 2.

Overview of adherence measurements
Adherence can be measured directly, through objective parameters such as pill counts and subjective parameters such as self-rated adherence, or indirectly through reporting on changes in objective clinical parameters which should improve with adherence promoting interventions.
Of the 18 studies that used direct measures of adherence as end-outcomes, three used objective measures of adherence e.g., pill counting (all three studies) (45, 60, 66) and 15 used subjective measures of adherence, such as self-reporting (five studies) (45, 47, 50, 55, 63)or questionnaires (ten studies) (44, 48, 51-54, 56, 57, 59, 64). Questionnaires measuring adherence included the Beliefs about Medicines Questionnaire (BMQ), Morisky Medication Adherence Questionnaire (MMAQ), Medication Adherence Rating Scale (MARS), Medication Adherence Questionnaire (MAQ), and questionnaires specifically designed for the purposes of the relevant study. One study's-outcome was the number of patients advised to adhere to medications rather than medication adherence per se (46). Notably, two studies were deemed "high risk" and eight assessed as "some concerns" for bias in selection of reported results category ( Figure 2). One study was deemed "high risk" and six studies were deemed "some concerns" for bias arising in the randomization process. This was primarily due to lack of reporting of how randomization occurred. One study was assessed as "high risk" while eight were assessed as "some concerns" for bias arising from deviations from intended interventions, mainly due to lack of information surrounding if and how participants and observers were blinded. We also found that only 12 out of 22 studies had registered their study protocol (47, 50, 52, 53, 55-57, 61-64, 66). Overall Risk of Bias is shown in Figure 3. Information on individual study blinding is shown in the Supplementary material.

Education-based interventions delivered by pharmacists
Seven studies examined educational programmes delivered by pharmacists to improve adherence and all showed significant improvements in adherence outcomes assessed (44,45,48,54,57,59,65). The interventions were generally short (10-30 min), personalized sessions which could be delivered repeatedly, and were often combined with provision of written materials and lifestyle advice. Studies found improvement in both objective and subjective metrics of adherence utilizing different regimens of pharmacist led sessions. All identified studies showed some benefits although some studies (44, 45) did not conduct complete statistical tests of significance (44,45) whilst others only followed patients up over 2 months (45, 48). All studies except one (57) were based at single centers and all had relatively low sample sizes.
For example, Sriram et al. found that pharmacist teaching comprising education, medication counseling, and lifestyle advice during baseline and follow-up visits led to an improvement in HbA1c values (p < 0.01) and diabetes-dependent quality of life (p < 0.01) after 8 months compared to usual care across 120 patients with type 2 diabetes (65). Similarly, Simon et al. also found that a verbal counseling session and leaflets from clinical pharmacists focussing on medication adherence and lifestyle advice led to improved HbA1c (p < 0.001) and medication adherence (p < 0.001) scores compared to conventional therapy with basic counseling across 97 patients with type 2 diabetes after 6 months (57).
These benefits were not limited to type 2 diabetes, with Sundararajan et al. utilizing a single 30-min pharmacist counseling session at discharge, addressing subjects such as adherence and lifestyle advice, in patients post-myocardial infarction (54). They found improved medication adherence (p = 0.0001) and cardiovascular clinical parameters such as blood pressure (p < 0.01) after 6 months compared to usual care across 154 patients. Further, Sathvik et al. found improved medication adherence scores across belief and recall domains (p < 0.05) in hypertensive patients given 4 pharmacist education sessions compared to control patients given leaflets alone in a cohort of 150 over 2 months (48). Ponnusankar et al. was the only study to measure adherence using an objective pill-count method and found improved adherence after 2 months in a group of 90 patients with various chronic diseases following pharmacist a counseling session compared to usual care (45). They found an increase in pill-count scores and self-assessed compliance although they did not carry out formal statistical analyses.
Renuga et al. demonstrated potential added value of repeated interventions, showing that verbal counseling and education leaflets provided at baseline and during 3 follow-ups led to further improvements in adherence (p < 0.001) and fasting blood sugar level (p < 0.01) for patients with diabetes after 3 months, compared to the improvements seen with counseling at baseline and follow up alone, across 400 patients with type 2 diabetes (59).
Uniquely, Grover et al. looked at a pediatric asthma cohort and found that a structured programme delivered to both parents and children focussing on themes such as asthma knowledge and medication use improved medication adherence to asthmatic medications and asthma control (p < 0.01) over 6 months compared to control given an information pack and usual care (44). However, their sample size was only 40 parent-child pairs and no statistical analysis on adherence scores were conducted.

Educational-based interventions delivered by community healthcare workers
Four studies examined education-based interventions delivered by community healthcare workers (CHWs), non-physicians who are able to perform certain health-related interventions, especially in more rural areas of India (49,63,64,66). These individuals usually received training on how to deliver educational interventions and then visited patients, providing individualized advice, counseling, and encouragement to take medications. Three studies found improvement in adherence parameters, however in two, objective clinical parameters failed to reflect improvements in subjective adherence metrics (49,66). One study found improved clinical parameters but failed to show improvement in adherence metrics (63). Three of these four studies were large multicentre studies focussing on cardiovascular disease.
Xavier et al. showed the benefits of CHWs in improving both adherence measures and corresponding clinical parameters; in a large multicentre trial they found CHWs were effective at increasing adherence to secondary prevention drugs (p = 0.006) for 806 patients with acute coronary syndrome and improved clinical cardiovascular parameters such as systolic blood pressure (p = 0.002) after 1 year through providing repeated counseling on lifestyle measures and education (64).
Gamage et al. conducted a large cluster trial with 1,734 participants with hypertension and found trained CHWs significantly improved hypertension control compared to usual care (p = 0.001) in 3 socioeconomically distinct regions through their delivery of 6 fortnightly sessions over 3 months to educate patients on their disease, medication, and lifestyle choices (63). However, they did not find significant changes in antihypertensive medication use, indicating this effect may have been primarily due to lifestyle changes.      villages) found CHWs were effective at improving adherence for cardiovascular risk factors (through 6 household visits over 12 months in which they ascertained and reinforced, p = 0.001) and depression (through twice monthly visits in which education and counseling on medication use was provided for 6 months, p < 0.01) compared to usual care respectively, but both did not find significant improvements in corresponding clinical parameters (49,66). Joshi et al. also looked at adherence and BP 6 months after the intervention ended and found a rise in mean blood pressure and a drop in adherence (61).

Educational-based interventions delivered by a multidisciplinary team
Sadeghian et al. (314 patients across two hospitals) utilized a self-management education programme delivered for 2 hours a week over 2 weeks, by a multidisciplinary team to patients with T2DM (58). The intervention team consisted of an endocrinologist, diabetologist, public health expert, dietician, diabetes nurse educator and the investigator. They reported an objective improvement in HbA1c at the 6-months follow-up period (p < 0.001).

Training practitioners
Sylaja et al. conducted a cluster RCT of 243 subjects investigating the effects of improved CHW competency on the secondary prevention of stroke over a period of six months (46). Their intervention consisted of four 45-min training sessions for CHWs focused on the management of acute stroke, drug adherence, care, and physiotherapy. At 6 months follow-up there was an increase in the number of patients advised on medication adherence by CHWs in the intervention group compared to CHWs in the control group (p < 0.001), but this was not associated with significant improvements in blood pressure or fasting blood sugar in the intervention group.

Combining patient education with regular follow-up
Four studies (based on 3 RCTs) focused on multimodal interventions by non-physicians, providing education and counseling in combination with regular follow-up interventions (52,56,60,62). All showed improvements in medication adherence metrics although one did not measure clinical parameters (56)  although two showed no improvement in clinical outcome measures (52,60). Abdulsalim et al. conducted a single-center RCT looking at the benefits pharmacist-led counseling for 260 patients with COPD over a period of 2 years, in combination with monthly telephone calls, to ensure adherence (56). Pharmacist sessions focused on medication adherence and education, as well as lifestyle information, and leaflets were also provided. They found significant improvements in subjectively rated medication adherence (p < 0.001) after 2 years. The study was based on the results of a study by Suhaj et   in combination with weekly reminder boxes and a single telephone follow-up. They reported improved adherence (p < 0.001) but no significant reduction in blood pressure (p = 0.16) for the intervention group compared to controls, which may have been due to unmodified lifestyle factors. Raj et al. looked at tailored advice delivered by a study investigator (such as education if there was poor knowledge) combined with diary and mobile phone reminders in 50 older patients with a range of NCDs (60). They found a significant increase in reported pill counts after 3 months (p = 0.007) and 6 months (p = 0.003) although no significant changes in corresponding clinical parameters. However, they found a decrease in reported pill counts at 6 months relative to 3 months (p = 0.016).

Technology-based interventions
Two studies investigated the effects of reminder-based systems on medication adherence (47, 51).
Kleinman et al. assessed the impact of a Gather Health, a mobile-Health diabetes management platform on medication adherence and frequency of blood glucose self-testing at three centers across 91 patients with type 2 diabetes (47). After 6 months follow-up, they found that the intervention group had significantly improved self-reported medication (p = 0.03), increased frequency of blood glucose self-testing (p = 0.01) and improvement in HbA1c compared to control (p = 0.02). Similarly, Shetty et al. conducted a single-center pilot study to investigate the effectiveness of mobile short message services on adherence in 215 diabetic patients (51). Messages were sent once every 3 days, and both content and frequency varied based on subjects" preferences. At 1 year followup they reported no significant difference in mean HbA1c values between both groups (p value not stated) but found a significant increase in the percentage of subjects with HbA1c < 8% in the intervention group compared to controls (p < 0.007). They stated that drug prescriptions were followed satisfactorily by both groups although which specific questionnaire was used was not stated.

Fixed dose combinations
Thom et al. conducted a large multi-center trial across 1,000 patients investigating the effects of fixed-dose-combination based strategies (polypills) on self-reported adherence and changes in blood pressure in those with cardiovascular disease or high risk of cardiovascular disease (the UMPIRE trial) (50). At follow-up (median = 15 months) those in the intervention group taking a polypill with their CVD medications were found to have improved self-reported medication adherence compared to usual care (p < 0.001). Improvements in adherence were associated with improvements in clinical parameters such as reductions in systolic blood pressure (p < 0.001) and LDL-C (p < 0.001).

Psychological therapies
Valsaraj et al. found that weekly 50-min cognitive behavioral therapy (CBT) sessions for 80 patients with chronic kidney disease undergoing dialysis, were associated with increases in dialysis adherence (p = 0.001) and drug adherence (p < 0.001) compared to non-directive counseling (53). These changes in adherence were associated with concomitant changes in objective parameters such as systolic blood pressure (p = 0.001), diastolic blood pressure (p = 0.001), Hb (p =0.001), and inter-dialysis weight gain (p = 0.001).
Pillai et al. reported on a collaborative stepped care intervention to improve adherence to anti-depressants across 2,796 patients with depression (55). The intervention involved psychoeducation, antidepressants prescribing, and interpersonal psychotherapy delivered according to illness severity and patient response. Compared to normal care (which included increased access antidepressant prescribing), they found improved self-reported adherence over a course of a month (OR = 6.10, 95% CI 3.67-10.14) and a significantly higher proportion completed at least 90 days of antidepressants, compared to usual care (although exact p values are not stated). Table 3 shows a summary of the evidence for adherence promoting measures broken down by disease. Of the studies retrieved, three studies examined respiratory disease, six focussed on type 2 diabetes, eight on cardiovascular disease, two on depression, one on renal disease and 2 looked across NCDs (not included in Table 3).

Pharmacist patient education
Three trials showed evidence for increased adherence and improved HbA1c and fasting blood glucose after 3-8 months.
Improvements in corresponding subjective adherence and objective clinical parameters. Benefits from both one-off and follow-up interventions seen.
Reminder-based systems Two trials that found improvements in medication adherence and HbA1c after 6 month-1 year.
Versatile, cheap programmes based on apps and text messages. Improvements in corresponding subjective adherence and objective clinical parameters.
Limited sample sizes (mean = 153). Moderate follow-up (mean 9 months). Low-mixed methodological quality. Results may not be applicable to those without smartphones or less familiar with technology.
MDT-led group self-management educational programme One trial showing improvements in HbA1c after 6 months.
MDT-approach can provide guidance on adherence as well as lifestyle advice (across exercise, medication use, diet etc.

Discussion
This review summarizes the evidence from 22 RCTs collectively evaluating adherence strategies in over 10,000 patients with NCDs across India and finds moderate evidence for adherence-improving strategies for patients that improve health outcomes. To our knowledge, it is the first review that systematically evaluates the evidence for adherence promoting interventions in India, focussing on patients with NCDs. There is the most consistent evidence for patient education from CHWs and pharmacists, with further benefits from reminder-based systems. Available evidence is primarily focussed on patients diagnosed with CVD and T2DM.
Eleven studies found that CHWs and pharmacist education was effective at improving adherence, across direct and indirect metrics, which is consistent with lack of knowledge, negative attitudes, and low health literacy as key barriers to adherence in LMICs such as India (14, 67, 68). The efficacy of such interventions is in keeping with the "Information-Motivation-Strategy" model in which it is vital patients have the correct information and believe in their treatment to improve adherence (69). Educational interventions are among the most common strategies evaluated to improve adherence in existing literature, tending also to focus on nonphysician health workers such as nurses or pharmacists, and there is moderate evidence of their efficacy from systematic reviews primarily based on MEDCs (20,21,70).
CHWs can be trained in large numbers relatively cheaply. They therefore represent potentially cost-effective strategies to improve, adherence, treatment capacity and health-related lifestyle choices and consequently improve health-outcomes (64, 71). This is in keeping with existing literature, where similar "lay health workers" have been found to be effective and scalable interventions in the context of communicable diseases globally with the potential to reduce costs of healthcare through task-shifting (72). Both a recent WHO review of reviews focussing predominantly on LMICs, and other LMIC specific systematic reviews, have also found that CHWs can improve outcomes and reduce healthcare costs through a variety of health-related tasks such as screening and counseling as well as adherence-promotion, although common limitations cited also include mixed methodological quality and study heterogeneity (66,71,73,74). Furthermore, health-systems level changes such as allowing CHWs to provide medications directly to patients, can help overcome access and cost barriers and thus provide further benefits (66,75). CHWs can reach individuals who are less likely to access services such as pharmacists or inpatient facilities and provide a personalized approach to address heterogenous health barriers that exist for such individuals (63, 66). Therefore, a combination of health-education providers, involving doctors, pharmacists and CHWs, may be necessary in India to reach individuals in rural and remote settings, balancing efficacy with increased costs of more time-consuming individual based interventions.
Four studies found that reminder-based systems, in the form of either telephone calls or text messages, increased adherence when combined with education strategies (52,56,60,62). Their findings are in concordance with available literature; a review focussing on CVD across LMICs also found benefits when education was combined with reminders (22); reviews from LMICs focussing on antiretroviral therapy found additive benefits from multimodal interventions involving electronic reminders combined measures such as counseling (24,76); and a large review, predominantly including MEDC-based studies, also found an additional benefit of reminder-based systems when combined with educational initiatives (20). However, the effects of reminder-based systems when used alone were ambiguous (47, 51), perhaps reflecting the need to first address underlying barriers to adherence attributable to lack of patient education or suboptimal patient provider communication prior to addressing patient forgetfulness (14). Several meta-analyses conducted in MEDCs have found mobilebased reminders to be effective at increasing medication adherence for T2DM and cardiovascular disease through overcoming practical barriers of adherence and supporting disease self-management (77,78). Reminder-based interventions when used in isolation may be less effective in India compared to MEDCs due to lower rates of health literacy and smartphone usage, both of which are rapidly increasing (79)(80)(81).
More resource intensive interventions such as MDT-mediated patient education and psychological based therapies e.g., CBT and psychoeducation were found to be effective at increasing  55,58). The benefits of psychosocial interventions in improving adherence have also been shown in a systematic review for patients with bipolar disorder in LMICs (23). Given the difficulty in providing large-scale initiatives through MDT-and psychological-based approaches, given their relative time and resource demands such interventions may best be used selectively with those with poor adherence refractory to other interventions. One study found that use of a FDCs increased medication adherence for CVD (50). This was in keeping with a large review from LMICs focussing on CVD which found FDCs to be the most effective strategy for improving medication adherence (22) and a large systematic review of 67 studies, mostly conducted in MEDCs, which also found FDCs to improve adherence compared to multiple pill regimens (82). Whilst FDCs reduces choice of medications and doses, risking suboptimal control of CVD clinical parameters, the authors found this was offset by improved adherence through reducing medication-regimen complexity (12,50). As FDCs represent promising adherence promoting strategies, further studies are needed to assess their use for treating a larger variety of NCDs that typically require polypharmacy, such as diabetes and CVD, along with public health measures to address accessibility and affordability barriers (83).

Measures of adherence
Several studies found significant improvements in subjective adherence metrics without corresponding changes in objective clinical parameters (46,49,52,60,66). This may have reflected inadequate pharmacological therapy, emphasizing the importance of optimizing medical management, such as dose titration or additions of second line medications, in combination with adherence-promoting interventions (66,(84)(85)(86). It may also reflect trials that did not assess concomitant lifestyle changes alongside improving medication adherence; the potential for CHWs and pharmacists to counsel on weight loss, exercise and smoking cessation represent effective additional methods of improving health outcomes (52). Finally, small study sizes, limited time frames and controls which encouraged patients to seek additional care may also be responsible for a proportion of this effect (49,60). We recommend future interventions aiming to improve medication utilize regular reviews to optimize a patients' pharmacological management and involve simultaneous counseling and assessment of lifestyle measures.

Limitations
This review's conclusions are limited by mixed methodological quality in included studies. Moderate and high risk of bias across studies was primarily due to bias in selection of reporting results, lack of information on how randomization occurred, and if and how participants and observers were blinded. To mitigate reporting bias, we recommended that future RCTs pre-register their study protocol online. Additionally, more information is required on randomization and blinding processes used to ensure high methodological quality.
Additional limitations relate to the nature of the included studies. Firstly, there is volunteer bias to which all RCTs are subject, meaning it is unclear how generalizable these findings are to those who are more vulnerable or with lower health literacy. Secondly, most included studies primarily used subjective measures of adherence such as validated questionnaires or selfreporting, while only three employed objective measures of adherence. Subjective measures are liable to recall bias and social desirability bias, generally resulting in over-reporting and may limit the generalizability of our results, although a range of these questionnaires have been found to be valid across NCDs (87)(88)(89)(90). Thirdly, of the available studies, there were few large multicentre RCTs and in general follow-up periods were short (median follow-up was 6 months). As medication adherence rates tend to decline with time from intervention possibly due to participant fatigue and waning novelty, followup mechanisms and evaluating for sustained effects are crucial to determining the efficacy of adherence promoting measures (24,60,66). Fourthly, given the relatively small number of included studies (22) across a large number of states and regions within India it was not possible to give a breakdown by state, where different healthcare systems and socioeconomic factors may influence adherence barriers and interventions. Finally, the COVID-19 pandemic has driven a shift that has rapidly changed the field of medication adherence, so previous studies (15/22 were published before 2020) may lack current day validity, especially for interventions dependent on technology such as mHealth (91).
Future large RCTs with long follow-up periods to test for sustained improvements in adherence, utilizing methods that attenuate volunteer bias (for example methods that increase recruitment rates), are required to further evaluate adherence-improving measures (92,93). We recommend future studies evaluate adherence-improving measures using a variety of corresponding adherence and clinical metrics, utilizing objective measures of adherence where possible alongside simpler subjective measures.

Conclusion
We identified 22 RCTs evaluating interventions to improve medication adherence for community-based patients with NCDs in India. Most RCTs used subjective measures of adherence, many of which also measured objective corresponding clinical parameters. The lack of widespread use of and improvements in objective measures of adherence limits the internal validity and generalizability of findings. Furthermore, scalability of these interventions and their incorporation in wider health programmes requires systematic evaluation of real-world efficacy. This is especially relevant for patients from lower socioeconomic backgrounds and for those living in remote regions with limited access to weaker public health systems. Although the majority of primary studies supporting the conclusions were of mixed methodological quality, patient education by CHWs .
/fpubh. . and pharmacists represent promising interventions to improve medication adherence, with further benefits from regular followup. Given the rising burden of NCDs and concomitant poor medication adherence, such programmes merit further evaluation as potentially cost-effective and scalable ways to improve health outcomes and quality of life across patients with NCDs in India.

Data availability statement
The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding authors.