Determinants of patient adherence: a review of systematic reviews

Purpose: A number of potential determinants of medication non-adherence have been described so far. However, the heterogenic quality of existing publications poses the need for the use of a rigorous methodology in building a list of such determinants. The purpose of this study was a systematic review of current research on determinants of patient adherence on the basis of a recently agreed European consensus taxonomy and terminology. Methods: MEDLINE, EMBASE, CINAHL, Cochrane Library, IPA, and PsycINFO were systematically searched for systematic reviews published between 2000/01/01 and 2009/12/31 that provided determinants on non-adherence to medication. The searches were limited to reviews having adherence to medication prescribed by health professionals for outpatient as a major topic. Results: Fifty-one reviews were included in this review, covering 19 different disease categories. In these reviews, exclusively assessing non-adherence to chronic therapies, 771 individual factor items were identified, of which most were determinants of implementation, and only 47—determinants of persistence with medication. Factors with an unambiguous effect on adherence were further grouped into 8 clusters of socio-economic-related factors, 6 of healthcare team- and system-related factors, 6 of condition-related factors, 6 of therapy-related factors, and 14 of patient-related factors. The lack of standardized definitions and use of poor measurement methods resulted in many inconsistencies. Conclusions: This study provides clear evidence that medication non-adherence is affected by multiple determinants. Therefore, the prediction of non-adherence of individual patients is difficult, and suitable measurement and multifaceted interventions may be the most effective answer toward unsatisfactory adherence. The limited number of publications assessing determinants of persistence with medication, and lack of those providing determinants of adherence to short-term treatment identify areas for future research.


INTRODUCTION
Enormous progress in the fields of both medicine, and pharmacology has taken place in the last century and led to a completely new paradigm of treatment. Contrary to the past, in which most treatments were only available in hospitals, effective remedies are available now in ambulatory settings. At the same time, the demographic changes that happen to both developed and developing countries, make chronic conditions even more prevalent. All this makes the most modern treatments dependent on patient selfmanagement. Surprisingly often, evidence based treatments fail to succeed because of the human factor known for a few decades as patient non-adherence.
Currently, sound theoretical foundations for adherenceenhancing interventions are lacking (van Dulmen et al., 2007). Therefore, the development of interventions to enhance patient adherence to medication, and maintain long term persistence, requires at least an understanding of the determinants of patient non-adherence to prescribed therapies. This is especially important when the determinants are modifiable risk factors, which, once identified, can then be targeted for beneficial changes.
The published literature identifies hundreds of determinants of non-adherence. Unfortunately, serious drawbacks of the methodology used by numerous studies demand that this list be revised. In particular, many studies do not indicate the relative importance of the 3 identified components of patient adherence: initiation, implementation, and discontinuation. For example, the WHO recommends that determinants be classified in 5 dimensions (Sabate, 2003): socio-economic factors, healthcare team and system-related factors, condition-related factors, therapy-related factors, and patient-related factors, but provides little or no closure in respect to outcome, and in particular, to the stage of adherence process. Moreover, little information exists on the determinants of short-term adherence for acute diseases vs. long-term adherence for chronic diseases.
The objective of this study was to identify and classify the determinants of non-adherence to short-term and long-term treatments for different clinical sectors and population segments. In order to obtain this goal, a retrospective systematic review of the literature was performed, wherein we have adopted the method of reviewing reviews. In order to design a comprehensive, yet evidence-based list of determinants of patient adherence for use in both practical and clinical settings, as well as for theoretical purposes to inform adherence-enhancing interventions, a rigorous taxonomy and terminology of adherence was used, the basis of which was set recently in a form of a European consensus (Vrijens et al., 2012). According to this terminology, adherence to medications is defined as the process by which patients take their medications as prescribed. Adherence has three components: initiation, implementation, and discontinuation, of which initiation is defined as the moment at which the patient takes the first dose of a prescribed medication; the implementation of the dosing regimen, being the extent to which a patient's actual dosing corresponds to the prescribed dosing regimen from initiation until the last dose taken; and discontinuation, being the end of therapy, when the next dose to be taken is omitted and no more doses are taken thereafter (Vrijens et al., 2012).
This study is part of a larger project on patient medication adherence funded by the European Commission called the "ABC (Ascertaining Barriers for Compliance) Project" (http:// www.abcproject.eu). The overall goal of the ABC project was to produce evidence-based policy recommendations for improving patient adherence and by so doing to promote safer, more effective and cost-effective medicines use in Europe.

FIGURE 1 | Flow diagram of study selection process.
A range of determinants were extracted based on the source publications. These were further categorized according to their effect on adherence to medication using an adherence determinant matrix. Relevant dimensions included: • Treatment duration: long-vs. short-term treatment; • Components of adherence to medication: implementation of the dosing regimen (defined as the extent to which a patient's actual dosing corresponds to the prescribed dosing regimen) vs. persistence (defined as the length of time between initiation and the last dose which immediately precedes discontinuation) (Vrijens et al., 2012). Determinants were categorized under implementation unless original review wording clearly addressed persistence. • Dimensions of adherence: these were socio-economic factors, healthcare team-and system-related factors, condition-related factors, therapy-related factors, and patient-related factors. In this was original WHO report description followed (Sabate, 2003), with a modification: demographic variables were included under patient-related, instead of socio-economic related factors. • Direction of effect: determinants were classified according to their positive, negative, neutral, or not defined effect on adherence.
Other data extracted from the reviews included scope of the review (medical condition, class of drugs, etc.), studied population, and databases searched by the authors.

RESULTS
In this systematic literature review, 51 systematic reviews were found to contain determinants of adherence to medication. An overview of the review process and reasons for exclusion at various steps within it are detailed in Figure 1. Individual study characteristics are listed in Appendix 2. Great variety was seen in both the start year of the literature searches performed within the source reviews, starting back from as early as 1948, or as late as 2000, as well as the period covered by the search, varying from 5 to over 50 years. Most of the studies accepted broad definitions

FAMILY SUPPORT
Lack of family support Munro et al., 2007;Costello et al., 2008) Irregular supervision by a family member (Munro et al., 2007 P ) Child selfresponsibility for taking medication (Kahana et al., 2008) Family financial support Lanouette et al., 2009) Family support in executing medication Munro et al., 2007;Lanouette et al., 2009) Family emotional support Lanouette et al., 2009) Family involvement during hospitalization or follow-up  FAMILY/CAREGIVERS FACTORS Disorganized biologic families (Kahana et al., 2008;Vreeman et al., 2008) Family in conflict DiMatteo, 2004a;Vreeman et al., 2008;Weiner et al., 2008) Responsibilities in the home (such as providing income and caring for children)  Low parental educational level  Family beliefs about the nature of the patient's illness  More people in household (in children) (DiMatteo, 2004a) Having several adults involved in pill supervision  Two-parent families (Charach and Gajaria, 2008 P ) Family cohesiveness (DiMatteo, 2004a) Having an adult other than the biologic parent as primary caregiver  Higher caregiver education level  Responsibilities in the family  Parental belief that ADHD is a biological condition (Charach and Gajaria, 2008 P ) Mother's perception of the severity of disease  Knowledge of family members regarding disease  Family member with mental illness  Number of people in the household  Parental marital status (Charach and Gajaria, 2008 P )

SOCIAL SUPPORT
Lack of social support Fogarty et al., 2002;DiMatteo, 2004a;Costello et al., 2008;Hirsch-Moverman et al., 2008;Malta et al., 2008;Weiner et al., 2008;Julius et al., 2009;Schmid et al., 2009) Less acculturation  Low social functioning  Low social rank of an illness  Negative publicity regarding HAART or the medical establishment  Emotional support (DiMatteo, 2004a) Good social adjustment Nosé et al., 2003) Including significant others into therapeutic alliance  Supervision of medication administration by others Julius et al., 2009) Patients' support to patients Costello et al., 2008) Social support

SOCIAL STIGMA OF A DISEASE
Stigma of a disease at school, at workplace, among the family and friends Vreeman et al., 2008;Reisner et al., 2009) Negative attitude in the patient's social surroundings toward psychiatric treatment  Fear of disclosure and wanting to avoid taking medications in public places  Disclosure of the child's HIV status  Hiding the disease (TB) for fear that employers may discover it  Openly disclosing HIV status to family and friends

DETERMINANTS OF ADHERENCE TO MEDICATION
As many as 771 individual factor items associated with long-term treatment were extracted from the reviewed literature: Despite the broad range of the fields covered with these publications, no publication primarily focusing on short-term therapies was identified, nor were any individual determinants of patient adherence to short-term treatment. The vast majority of individual factor items were determinants of implementation, and only 47 were found to be determinants of persistence with medication. Only three reviews addressed the initiation component of adherence, although no corresponding determinants were provided Vik et al., 2004;Costello et al., 2008).
For 64 individual factor items, no unambiguous information concerning their effect on adherence to medication could be found in the source publication. The remaining factors were

BARRIERS TO HEALTHCARE
Barriers to high-quality care  Lack of providers/caregiver availability (Charach and Gajaria, 2008 P ;Vreeman et al., 2008) Rural settings  Poor access to a health care facility (e.g., long waiting times, queues, lack of privacy, inconvenient appointment times, inconvenient opening hours)  Seeing different language speaking therapist (ie Spanish-speaking therapist in US Latinos)  Difficulty in obtaining sick leave for treatment  Having no time to refill prescriptions, or other pharmacy-related problems  Good access to medication and health service  Good access to a health care facility Munro et al., 2007) Non-emergency referral  Obtaining certification of preventive treatment (for immigrants to US)  Access to care  Greater distance from the clinic Munro et al., 2007) Current inpatient status  Rural settings (vs. urban)  Type of transportation used

DRUG SUPPLY
Poor drug supply (e.g., poor TB medication availability at health care facilities) Munro et al., 2007) Unavailability of medications (e.g., prescription ran out)  Receiving treatment together with methadone from a street nurse (for DOT in TB, in IDU patients)

PRESCRIPTION BY A SPECIALIST
Referral/prescription by a specialist Van Der Wal et al., 2005) Prescription by a psychiatrist (in depression)

INFORMATION ABOUT DRUG ADMINISTRATION
Unclear information about proper drug administration  Greater number of prescribing physicians  Conflicting messages between gps and specialists on medication  Discrepancies between treatment guidelines and common clinical practice (as patients try to ask several specialists)  Use of multiple pharmacies  Doctor's ability to provide appropriate information as to the drug administration Weiner et al., 2008) Being given information about the action of the drugs

HEALTHCARE PROVIDER-PATIENT COMMUNICATION AND RELATIONSHIP
Poor healthcare provider-patient relationship Vermeire et al., 2001;Lacro et al., 2002;Nosé et al., 2003;Vik et al., 2004;Olthoff et al., 2005;Hodari et al., 2006;Munro et al., 2007;Charach and Gajaria, 2008 P ;Costello et al., 2008;Broekmans et al., 2009;Julius et al., 2009) Poor patient-physician communication Gold et al., 2006 P ;Hodari et al., 2006;Munro et al., 2007;Broekmans et al., 2009;Jacobsen et al., 2009;Julius et al., 2009) Lack of trust in doctors and healthcare Broekmans et al., 2009) Lack of patient satisfaction with their healthcare,  Limited caregiver adherence strategies  Quality, duration and frequency of interaction between the patient and doctor  Offering enough time to the patient, leaving space to talk about problems concerning medication or side effects  Patient involvement in decision making (Gold et al., 2006 P ;Ruddy et al., 2009) Encouraging self-management  Doctor responsiveness  Doctor's ability to demonstrate empathy  Doctor's ability to elicit and respect the patient's concerns  Perceived healthcare provider support Costello et al., 2008)
grouped to form 400 individual determinants: 143 with a positive, 155 with negative, and 102 with neutral effect on adherence. In cases where the source publications provided two "mirror" versions of the same factor, e.g., family support and lack of family support" these were recategorized as the factor with a negative effect on adherence, in this case, lack of family support. The determinants were further clustered according to the modified WHO 5 dimension of adherence (see Methods for details). The results are presented in Tables 3-7 as socio-economic-related factors (8 clusters), healthcare team-and system-related factors (6 clusters), condition-related factors (6 clusters), therapy-related factors (6 clusters), and patient-related factors (14 clusters).

DISCUSSION
In this systematic literature review, 51 systematic reviews concerning the determinants of adherence of medication were identified. Remarkably, a vast majority of the reviewed literature provided only determinants of implementation. In fact, many reviews lacked a clear definition of adherence, thus leaving the distinction between implementation and persistence open to interpretation. In the present study, these cases were arbitrarily reclassified under determinants of implementation, assuming that in most cases, authors were interested in the day-to-day execution of drug taking. The recently-agreed European consensus on taxonomy and terminology of adherence has made more precise reporting of research findings in the field of adherence to medication possible (Vrijens et al., 2012). However, in interpreting results of this study, one has to have in mind this limitation. Many reviews reported a positive effect of family and social support on implementation, and a negative effect of the lack of such support ( Table 3). The social stigma of a disease may also be responsible for non-adherence in a number of cases. Finally, economic factors such as unemployment, poverty, lack of, or inadequate medical/prescription coverage, as well as a high out-of-pocket cost of drugs may seriously contribute to non-adherence.
Although non-adherence has often been perceived as the fault of patients, and not of healthcare providers, there is evidence that healthcare system factors have an important impact on adherence ( Table 4). Poor access to healthcare, poor drug supply, unclear information about drug administration, as well as poor follow-up and poor provider-patient communication and relationship may reduce the extent to which patients follow the treatment plan.
Adherence is also related to condition. Asymptomatic nature of the disease, as well as clinical improvement reduce patient motivation to take the drugs as prescribed, whereas disease severity has a positive effect on adherence ( Table 5). Patients are also less happy to take the prescribed medication properly in both chronic and psychiatric conditions.
If treatment is patient unfriendly -e.g., due to frequent dosing, high number of prescribed medications, longer duration of treatment, drug formulation or taste of low acceptance, or the presence of adverse effects, the likelihood of patient adherence drops ( Table 6). Certain drug classes are better adhered to compared with others.
Not surprisingly, many patient-related factors were found to be reported as having an inconsistent impact on adherence in terms of implementation (Table 7). This was particularly true for demographic factors: whereas younger age was reported to have a negative impact on adherence, and older age a positive one, many reviews found no relationship between age and implementation of treatment regimen Vermeire et al., 2001;Lacro et al., 2002;DiMatteo, 2004b;Vik et al., 2004;Olthoff et al., 2005;Hodari et al., 2006;Hirsch-Moverman et al., 2008;Reisner et al., 2009;Ruddy et al., 2009). The male gender was reported to have a negative impact in some reviews Olthoff et al., 2005;Schmid et al., 2009), and the female gender a positive one Pampallona et al., 2002;Chia et al., 2006;Munro et al., 2007;Julius et al., 2009). However, gender was found irrelevant for adherence in many cases Fogarty et al., 2002;Lacro et al., 2002;DiMatteo, 2004b;Vik et al., 2004;Van Der Wal et al., 2005;Charach and Gajaria, 2008;Hirsch-Moverman et al., 2008;Broekmans et al., 2009;Lanouette et al., 2009;Reisner et al., 2009), and male gender was found to have a contrary effect with posttransplant medications (Charach and Gajaria, 2008) and with psychostymulants in children with ADHD . The same was true for marital status, with some reviews indicating that those married tended to have better adherence than those being single or divorced, education level, with better adherence demonstrated by patients with higher levels of education, and ethnicity, with higher adherence in Caucasians. Patient attitudes and believes in favor of diagnosis, health recommendations and www.frontiersin.org July 2013 | Volume 4 | Article 91 | 7 Perception of a clinical improvement  Reduced viral load (in HIV-infected youth)

PSYCHIATRIC CONDITION
Psychiatric disorders Nosé et al., 2003) Negative symptoms/motivational deficits  Lower rates of narcissistic-histrionic personality disorder (in depression)  Severity of psychotic symptoms   self-efficacy were closely related to adherence, as was knowledge of the disease and consequences of poor adherence. On the other hand, many beliefs were found to be possible barriers for strict adherence. Poorer adherence can be expected with either drug or alcohol dependence. Finally, comorbidities and patient history had an inconsistent effect on adherence, with the exception of psychiatric conditions, which was frequently reported to be connected with the lower rates of adherence (Claxton et al., 2001;Jindal et al., 2003;Nosé et al., 2003;Hodari et al., 2006;Munro et al., 2007;Charach and Gajaria, 2008; Frontiers in Pharmacology | Pharmaceutical Medicine and Outcomes Research July 2013 | Volume 4 | Article 91 | 8

WELL ORGANISED TREATMENT
Receiving care in structured settings (e.g., DOT)  Treatment at medical center (Charach and Gajaria, 2008 P ) Well-structured treatment plan  Psychotherapy (along with psychotropic medication)  Medication supervision status  Having a case manager  Being aware of monitoring (Wetzels et al., 2004) Abbreviations: ACEi, angiotensin-converting-enzyme inhibitors; aRB, angiotensin II receptor antagonists; BBs, beta-blockers; CCBs, calcium channel blockers; DOT, directly observed therapy; P , determinant of persistence. Malta et al., 2008;Reisner et al., 2009;Schmid et al., 2009). Only few determinants of persistence were identified. Socioeconomic factors with a negative impact on persistence included high costs of drugs and treatment (Gold et al., 2006;Munro et al., 2007;Costello et al., 2008), poverty , lower socioeconomic status (Charach and Gajaria, 2008), or inadequate medical/prescription coverage (Charach and Gajaria, 2008;Costello et al., 2008). Several healthcare system-related factors also had a negative effect on persistence, such as lack of providers/caregiver availability (Charach and Gajaria, 2008), poor healthcare provider-patient relationship (Charach and Gajaria, 2008), or poor follow-up by providers (Gold et al., 2006). Asymptomatic nature of disease (Gold et al., 2006), as well as clinical improvement, disappearance of symptoms, feeling better/cured Munro et al., 2007), the presence of adverse effects (Gold et al., 2006;Charach and Gajaria, 2008;Costello et al., 2008;Brandes et al., 2009) and complexity of the regimen (Gold et al., 2006;Munro et al., 2007) all decreased patient motivation to persist with treatment, as did high dosing frequency (Charach and Gajaria, 2008), doses during the day (Charach and Gajaria, 2008), and finally, drug ineffectiveness, objective or perceived Charach and Gajaria, 2008;Costello et al., 2008). This findings are of special interest, as longer persistence is a primary goal for adherence-enhancing interventions. On the other hand, it is noteworthy that the vast majority of persistence determinants were also implementation determinants (see Tables 3-7).
Our findings are consistent with those of the other authors DiMatteo, 2004b). However, the strength of this study is the rigorous methodology that we employed to classify literature search findings. A predefined set of criteria, and the use of well-defined terminology to describe the deviation of patients from prescribed treatment allowed a cohesive matrix of factors to be built that were determinants of either adherence or non-adherence. Bearing in mind that at least 200 factors have so far been suggested to play some role in determining adherence , the approach adopted in our study seems to move our understanding of adherence to medication forward. The clear distinction between implementation of the regimen (daily drug-taking) and persistence (continuity of treatment) allows the first, to the best of our knowledge, clear distinction of the determinants of these two components of adherence to medication to be made, thus providing a more detailed insight into the role of some determinants of the adherence process, compared with previous approaches (e.g., the WHO 5 dimensions).
Our analysis provides clear evidence that medication nonadherence is affected by multiple determinants, belonging to several different fields. Many of these factors are not modifiable, and none of them is a sole predictor of adherence. Moreover, some of these factors change with time and can appear at times either to be a cause, or a consequence, of patient non-adherence. Nevertheless, non-adherence should not be perceived as patients' fault only. To the contrary, social factors (such as social support, economic factors, etc.), healthcare-related factors (e.g., barriers to healthcare, and quality of provider-patient communication),

FORGETFULNESS AND REMINDERS
Forgetting Vik et al., 2004;Schmid et al., 2009;Weiner et al., 2008) Sleeping through a dose  Making use of reminders Munro et al., 2007) Using friends and family as reminders  Having a routine in which taking drugs could be easily incorporated  KNOWLEDGE Lack of comprehension of disease and treatment Olthoff et al., 2005;Gold et al., 2006 P ;Lewiecki, 2007;Charach and Gajaria, 2008 P ;Vreeman et al., 2008) Misunderstanding of the prescription and treatment instructions, and the consequences of non-adherence Munro et al., 2007;Vreeman et al., 2008) Misconceptions reported from the media, lay press, family or friends, about a medication  Obtaining helpful breast cancer information from books or magazines (in breast cancer)  Situational operational knowledge  Understanding the need for strict adherence

HEALTH BELIEFS
Denial of diagnosis Munro et al., 2007) Unrealistic expectations concerning the medication's benefit/risk ratio  Negative patients' beliefs about the efficacy of treatment Munro et al., 2007;Malta et al., 2008;Weiner et al., 2008;Reisner et al., 2009) Negative attitude toward or subjective response to medication  Thinking that the treatment could make the patients ill  Belief that taking medication together with concurrent western or traditional medicines may have negative consequences (in TB)  Belief that pregnancy would increase intolerance to drugs and make TB drugs ineffective  Concerns that the treatment would affect immigration status, and lead to disclosure of illegal immigrant status/incarceration (in TB)  Having doubts, or not being able to accept HIV status  Unresolved concerns about time between taking the drug and its effect  Being suspicious of treatment/medical establishment  Interpreting DOT as distrust  "Being tired" of taking medications (Munro et al., 2007 P ) Feeling that treatment is a reminder of HIV status  Perceived excessive medication use  Feeling persecuted or poisoned  Lack of interest in treatment  Wanting to be free of medications or preferring a natural approach  Belief in the diagnosis  Belief in a particular set of health recommendations  Belief in self-efficacy for taking medication  Self-confidence to maintain health status  Fewer concerns about drugs, belief that medication is safe Charach and Gajaria, 2008 P ) Belief that asthma is not caused by the external factors  Lower belief in natural products and home remedies  Beliefs of control over one's health  Feeling of empowerment (Brandes et al., 2009) Lower control beliefs about cancer-related pain  Perceived benefits of adherence Munro et al., 2007;Costello et al., 2008;Hirsch-Moverman et al., 2008; Desire to avoid burdening family members  More motivation  Belief that they are vulnerable or susceptible to the disease or its consequences  Worrying about the disease  HIV disease attitudes  Feeling invulnerable to the consequences of HIV      Previous psychiatric contacts (in patients with psychosis  Previous use of antidepressants (in depression)  Witnessing the consequences of not following medical advice in relatives with other diseases  Prior history of treatment with stimulants (in ADHD) (Charach and Gajaria, 2008) P Current psychiatric treatment (in depression)  Being less likely to have bartered sex Number of medical conditions  Adherence to other parts of an inpatient treatment program  Presence of mood symptoms (or diagnosis of schizoaffective or bipolar disorder)  Anxiety (   Diabetes, as a comorbidity  Dialysis compliance  (Continued) www.frontiersin.org July 2013 | Volume 4 | Article 91 | 13 Both eye blindness  Impaired motor functioning (Lovejoy and Suhr, 2009) History of infection (in patients after kidney transplantation)  No history of diabetes  Sexual abuse under age of 12 years  Recent incarceration  Receiving standard primary tumour therapy (in tamoxifen use in breast cancer) (Ruddy et al., 2009 P ) during the lifetime (in HIV-infected youth)  Being less likely to have had a sexually transmitted disease since learning their serostatus (in HIV-infected youth)  Type of the dialysis  Patient's transplant history (Kahana et al., 2008; Donor/graft source Kahana et al., 2008) Treated rejection episodes

ALCOHOL OR SUBSTANCE ABUSE
Substance abuse Lacro et al., 2002;Nosé et al., 2003;Munro et al., 2007;Malta et al., 2008;Lanouette et al., 2009) Injection drugs use (vs. non-injection ones)  Younger age of first marijuana use  Alcohol abuse  Smoking Schmid et al., 2009) Less recent drug use in the previous 3 months (in HIV-infected youth)  Medication taking priority over substance use  Drug addiction treatment, especially substitution therapy (for HIV treatment in drug users)  Drinking less, or non-drinking Reisner et al., 2009) Injective drug using
condition characteristics, as well as therapy-related factors (such as patient friendliness of the therapy) play an important role in defining adherence. Consequently, multifaceted interventions may be the most effective answer toward unsatisfactory adherence, and its consequences. In their review of reviews of effectiveness of adherence-enhancing interventions, van Dulmen et al. found effective interventions in each of four groups: technical, behavioral, educational and multi-faceted or complex interventions (van Dulmen et al., 2007). In their Cochrane review, Haynes et al. (Haynes et al., 2008) observed that most of the interventions that were effective for long-term care were complex, targeting multiple adherence determinants. We believe that evidence accumulated in this study may help in designing such effective interventions, and thus, be applied in both clinical practice and public health.
Bearing in mind the number of identified determinants and their inconsistent effect on adherence, prediction of non-adherence of individual patients is difficult if not impossible. In particular, the inconsistent effect of demographic variables on patient adherence explains partly why healthcare providers are ineffective in predicting adherence in their patients (Okeke et al., 2008). In fact, their prediction rate is no better than a coin toss (Mushlin and Appel, 1977). Neither age, gender, marital status, nor education proved to fully explain the variance in patient adherence across conditions and settings. Therefore, in order to reveal cases of non-adherence, validated tools (e.g., Morisky, or MARS questionnaires), and objective assessment methods (electronic monitoring widely accepted as a gold standard) are strongly advisable (Osterberg and Blaschke, 2005). In daily practice, relevant databases, such as electronic health records, and pharmacy fill records, may be effectively used for screening for non-adherence (Carroll et al., 2011;Grimes et al., 2013). On the other hand, adherence-enhancing interventions are worth considering to implement in daily clinical practice, to be used on a regular basis for every individual patients.
Finally, another strength of this systematic literature review is the identification of existing gaps in our understanding of adherence. Of note is that despite the broad inclusion criteria adopted for this search, no systematic review was identified which provides determinants of adherence with short-term treatments. Considering the high prevalence of non-adherence to short-term therapies, and especially, to antibiotics (Kardas et al., 2005;Vrijens et al., 2005), our findings identify this field as an important area for future research.
The major limitation of this study was connected with the data available within the source publications that were used for this review. Most did not provide any precise definition of adherence, nor any numeric values to describe the effect of the particular determinants on adherence (e.g., the effect size), thus making secondary analysis not manageable. The poor designs of many original studies on determinants of non-adherence could affect the conclusions of identified reviews, and indirectly, the results of this review.
The "review of reviews" methodology we employed in the present study proved to be a valuable tool for gathering relevant studies. However, despite the fact that the source reviews adopted different focuses, the certain level of overlap in primary studies they reviewed cannot be ruled out. Nevertheless, as the aim of the study was to build a comprehensive list of determinants, and not to perform a meta-analysis, this possible overlap was not a source of additional bias.
Finally, although our selection of the databases searched was only arbitral, it did correspond with the major goal, i.e., identification of publications describing determinants of adherence to medication. According to our experience, and knowledge of similar publications, broadening the scope of the databases included would not add much to the findings.