Determinants of Non-Adherence to the Medications for Dyslipidemia: A Systematic Review

Figures & data

Figure 1 PRISMA flow diagram for the review.

Notes: PRISMA figure adapted from Liberati A, Altman D, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Journal of Clinical Epidemiology. 2009;62(10). Creative Commons.¹².

Table 1 Quality Assessment of the Articles

Article Identification – Author (Year)	Question 1	Question 2	Question 11	Question 14
Kiortsis et al (2000)^Citation14	Yes	Yes	Yes	No
Mansur et al (2001)^Citation15	Yes	Yes	Yes	No
O’Donnell et al (2001)^Citation16	Yes	Yes	Yes	No
Yang et al (2003)^Citation17	Yes	No	Yes	Yes
Stilley et al (2004)^Citation18	Yes	Yes	Yes	No
Benner et al (2005)^Citation19	Yes	Yes	Yes	Yes
Caspard et al (2005)^Citation20	Yes	Yes	Yes	Yes
Di Martino et al (2005)^Citation21	Yes	Yes	Yes	Yes
Huser et al (2005)^Citation22	Yes	No	No	No
Batal et al (2007)^Citation23	Yes	Yes	Yes	Yes
McGinnis et al (2007)^Citation24	Yes	Yes	Yes	No
Natarajan et al (2007)^Citation25	Yes	Yes	Yes	No
Ye et al (2007)^Citation26	Yes	Yes	Yes	Yes
Chodick et al (2008)^Citation27	Yes	Yes	Yes	Yes
Vinker et al (2008)^Citation28	Yes	Yes	Yes	Yes
Latry et al (2011)^Citation29	Yes	Yes	Yes	No
Wong et al (2011)^Citation30	Yes	Yes	Yes	Yes
Wong et al (2011)^Citation31	Yes	Yes	Yes	Yes
Brogaard et al (2012)^Citation32	Yes	Yes	Yes	No
Cheetham et al (2013)^Citation33	Yes	Yes	Yes	Yes
Christian et al (2013)^Citation34	Yes	Yes	Yes	Yes
Xie et al (2013)^Citation35	Yes	Yes	Yes	Yes
Cicero et al (2014)^Citation36	Yes	Yes	Yes	Yes
Halava et al (2014)^Citation37	Yes	Yes	Yes	Yes
Gaisenok et al (2015)^Citation38	Yes	Yes	No	No
Halava et al (2015)^Citation39	Yes	Yes	Yes	Yes
Korhonen et al (2015)^Citation40	Yes	Yes	Yes	Yes
Warren et al (2015)^Citation41	Yes	Yes	Yes	Yes
Korhonen et al (2016)^Citation42	Yes	Yes	Yes	Yes
Kronish et al (2016)^Citation43	Yes	Yes	Yes	Yes
Tokgözoğlu et al (2016)^Citation44	Yes	Yes	Yes	No
Al-Foraih et al (2017)^Citation45	Yes	Yes	Yes	Yes
Booth et al (2017)^Citation46	Yes	Yes	Yes	No
Devaraj et al (2017)^Citation47	Yes	Yes	Yes	Yes
Hickson et al (2017)^Citation48	Yes	Yes	Yes	Yes
Wawruch et al (2017)^Citation49	Yes	Yes	Yes	No
Chung et al (2018)^Citation50	Yes	Yes	Yes	Yes
do Nascimento et al (2018)^Citation51	Yes	Yes	Yes	Yes
Haddad et al (2018)^Citation52	Yes	Yes	Yes	Yes
Kriegbaum et al (2018)^Citation53	Yes	Yes	Yes	Yes
Ofori-Asenso et al (2018)^Citation54	Yes	Yes	Yes	No
Chen et al (2019)^Citation55	Yes	Yes	Yes	Yes
Phan et al (2019)^Citation56	Yes	Yes	Yes	Yes
Waßmuth et al (2019)^Citation57	Yes	Yes	Yes	No
Bruckert et al (2020)^Citation58	Yes	Yes	Yes	No
Seaman et al (2020)^Citation59	Yes	Yes	Yes	Yes
Shakarneh et al (2020)^Citation60	Yes	Yes	Yes	No

Notes: Question 1. “Was the research question or objective in this paper clearly stated?”, Question 2. “Was the study population clearly specified and defined?”, Question 11. “Were the outcome measures (dependent variables) clearly defined, valid, reliable, and implemented consistently across all study participants?”, Question 14. “Were key potential confounding variables measured and adjusted statistically for their impact on the relationship between exposure(s) and outcome(s)?”.

Table 2 Articles Assessed in Qualitative Synthesis

Article	Study Design	Setting (Country)	Patient Population	Adherence Measure	Determinants of Non-Adherence
Kiortsis et al (2000)^Citation14	Cross-sectional study, by survey	Clinic (Hôpital Pitié-Salpétrière), Department of Endocrinology and Metabolism, Unit for Prevention of Cardiovascular Diseases (Paris)	193 patients	Compliance was analyzed by the percentage of pills missed during the previous month. Patients were divided into three groups: (i) high compliance (all prescribed pills were taken), (ii) intermediate group (<6% of the prescribed pills were missed) and (iii) low compliance group (patients who missed ≥6% of the prescribed pills)	Increased non-adherence: younger age, smoking habit, perceived high frequency of side effects, higher number of prescription medications, bad doctor–patient relationship, perception that treatment is not effective
Mansur et al (2001)^Citation15	Prospective observational study	Coronariopathy Unit at the Heart Institute, Medical School, University of São Paulo (InCor) (Brazil)	207 patients	Nonadherence was classified as 1) lack of understanding by patients of the physician’s instructions for taking the medication, 2) due to side effects, 3) non-utilization of the medication for other reasons	Increased non-adherence: high cost of the medication, lack of proper instruction on how to use medication
O’Donnell et al (2001)^Citation16	Cross-sectional study, by survey	Multidisciplinary lipid clinic of an integrated health care system	117 patients	Adherence was determined by the number of days (in 30 days) that patients took their lipid-lowering medications exactly as prescribed. 30 days was classified as adherent and ≤29 was classified as nonadherent	Increased non-adherence: perceived burden of the disease Decreased non-adherence: older age, perceived benefits of medication
Yang et al (2003)^Citation17	Retrospective cohort study	UK residents enrolled with selected general practitioners (GPs) (UK)	22.408 patients	Discontinuation of the original LLD was identified when a patient did not receive any further LLD prescription within 3 months after the expected last date of any previous LLD prescription	Increased non-adherence: female sex, smoking habit, less follow-up visits, higher number of non-cardiovascular medications (≥4) Decreased non-adherence: older age, diabetes, taking more classes of cardiovascular medications (≥3), statins or fibrates as initial lipid-lowering drug
Stilley et al (2004)^Citation18	Prospective study	University of Pittsburgh Medical Center (USA)	158 patients	Medication adherence data was tracked with electronic cap monitors, the Medication Event Monitoring System (MEMS). Percentage of days compliant was used to measure adherence in the primary analyses. Adherence to dose and schedule over the entire period was also assessed. Patients were considered adherent if they had a rate of compliance ≥ 80%	Increased non-adherence: anxiety, depression Decreased non-adherence: higher conscientiousness, higher estimated IQ, higher visuospatial/constructional ability
Benner et al (2005)^Citation19	Retrospective cohort study	Enrollees in a Southeastern managed care plan (USA)	9.510 patients	Proportion of days covered (PDC). Subjects were considered adherent if they had a PDC of ≥80%	Increased non-adherence: more months of therapy duration, higher number of prescription medications (9–43) Decreased non-adherence: younger age, cardiovascular intervention, less change in LDL cholesterol concentration at 3 months of therapy, adherence ≥80% during the first 3 months of therapy
Caspard et al (2005)^Citation20	Retrospective observational study	Massachussets health maintenance organization (USA)	4.776 patients	Adherence was measured by Proportion of days covered (PDC). Patients were considered adherent if they had a PDC of ≥80%	Increased non-adherence: younger age (<50 years), female sex, baseline LDL cholesterol ≥190 mg/dL Decreased non-adherence: previous antihyperlipidemia treatment
Di Martino et al (2005)^Citation21	Retrospective observational study	Patients attending general practitioners in the Ravenna area (Italy)	4.764 patients	Poor adherence was defined as a Standardized Mean Daily Dose (SDD) <0.8 tablets/day (less than 80% of the Defined Daily Doses (DDD))	Increased non-adherence: absence of previous atherosclerotic disease, absence of concomitant diseases, smoking habit
Batal et al (2007)^Citation23	Retrospective cohort study	Denver Health Medical Center (USA)	3.386 patients	Adherence was assessed by an adherence score, calculated as the number of days of drug acquired divided by number of days in the study. High adherence was defined by an adherence score of ≥80% and non-adherent as an adherence score of <80%	Increased non-adherence: female sex, African American ethnicity, Hispanic ethnicity Decreased non-adherence: age (per 10-year increase), 60 versus 30 days supply medication, each additional comorbidity
McGinnis et al (2007)^Citation24	Phase 1: retrospective medical record review Phase 2: cross-sectional telephone survey of patients for whom a medical record review was completed	Kaiser Permanente Colorado, a health maintenance organization that provides integrated health care services to members at 18 medical offices in the Denver-Boulder metropolitan area (USA)	Phase 1: 435 patients Phase 2: 242 patients	Proportion of days covered (PDC). Cohorts were divided into 3 PDC groups: ≥80%, 20–79%, and <20%	Increased non-adherence: less provider follow-up visits, less laboratory visits, bad doctor–patient relationship, reported adverse effects, being unsure of the benefits of statins
Natarajan et al (2007)^Citation25	Cross-sectional study, by survey	Two academic family practice clinics (Halifax, NS)	284 patients	Level of adherence to statin medications was measured by patients’ self-report using the 4-item Morisky scale, a 4-item adherence measure	Decreased non-adherence: older age (>75 years), higher number of other prescribed medications (4–6), healthier lifestyle (exercise and/or healthy diet)
Ye et al (2007)^Citation26	Longitudinal, Retrospective, Cohort Study	Privately insured individuals (USA)	5.548 patients	Adherence was measured by medication possession ratio (MPR). Patients were considered adherent if they had an MPR of ≥80%.	Increased non-adherence: copayment ≥$20, female sex, depression, non-statin lipid lowering drug use Decreased non-adherence: higher age, dyslipidemia
Chodick et al (2008)^Citation27	Retrospective cohort study	Maccabi Healthcare Services (MHS) and from death certificates (Israel)	229.918 patients	Proportion of days covered (PDC). Patients were categorized into 3 groups: adherent (PDC≥80%; partially adherent (PDC≥20% and <80%), or nonadherent (PDC <20%)	Increased non-adherence: female sex, less time of residence in Israel, chronic obstructive pulmonary disease, Alzheimer’s disease, lower LDL cholesterol (<130 mg/dL), moderate statin therapeutic efficacy, lowest socioeconomic level Decreased non-adherence: age (per 10-year increase), more health services utilization (higher number of outpatient visits and hospitalizations), diabetes mellitus, hypertension, taking ACEI, taking β-Blockers, high statin therapeutic efficacy
Vinker et al (2008)^Citation28	Retrospective cohort study	Central District of Clalit Health Services HMO (Israel)	47.680 patients	Adherence was defined as buying at least 80% of the expected number of pills over this a 12 month period.	Increased non-adherence: patients originary from Ethiopia, new immigrants in 1990 Decreased non-adherence: older age, female sex, chronic diseases
Latry et al (2011)^Citation29	Retrospective cohort study	French health insurance system: the Caisse Nationale d’Assurance Maladie des Travailleurs Salariés (Cnam-TS), from Aquitaine region from southwest France (France)	16.397 patients	Adherence was assessed by four criteria: (i) proportion of days covered (PDC) by statins, (ii) regularity of the treatment over time, (iii) persistence of treatment, and (iv) refill delay. The PDC was estimated using the “Continuous Multiple-interval measures of medication Availability” (CMA) definition. A CMA <80% was considered as unsatisfactory	Decreased non-adherence: associated cardiovascular risk factors
Wong et al (2011)^Citation30	Retrospective cohort study	Public, primary care clinics (Hong Kong, China)	11.042 patients	Medication Possession Ratio (MPR). Patients were considered adherent if MPR≥0.8	Decreased non-adherence: older age, provider is a Family Medicine Specialist Clinic, more provider follow-up visits, comorbidities
Wong et al (2011)^Citation31	Retrospective cohort study	Primary care clinic in 1 territory of Hong Kong (China)	12.875 patients	Discontinuation was considered as the absence of a refill prescription in all subsequent clinic visits without issuance of another lipid-lowering agent 180 days from the first prescription date	Decreased non-adherence: older age, male sex, fee payers, provider is a Family Medicine Specialist Clinic, residents in rural districts, more provider follow-up visits, comorbidities, taking fibrates
Brogaard et al (2012)^Citation32	Retrospective cohort study	Department of Cardiology, Odense University Hospital (Denmark)	Two cohorts: 2003: 474 patients 2008: 550 patients	Medication Possession Ratio (MPR). Patients were considered adherent if they had an MPR ≥ 80%	Increased non-adherence: younger age Decreased non-adherence: older age (≥ 80 years)
Cheetham et al (2013)^Citation33	Retrospective cohort study	Kaiser Permanente Southern California (KPSC), a managed care organization (MCO), in Southern California (USA)	19.826 patients	Patients were followed for a period of 90 days after the index date. Patients who did not pick up their new statin prescriptions within this 90-day window were considered primary nonadherent.	Increased non-adherence: African American ethnicity, higher provider age, provider is a high prescriber (>7 statin prescriptions during study) Decreased non-adherence: older age, LDL cholesterol >160 mg/dL, higher health care utilization (ED visits, hospitalizations, clinic visits or any Rx, in a year), higher Charlson Comorbidity Index, provider is male
Christian et al (2013)^Citation34	Retrospective cohort study	US insurance-carrying individuals (USA)	42.685 patients	Adherence was quantified using medication possession ratio (MPR). Patients were categorized into 4 MPR categories (<0.40, 0.40–0.59, 0.60–0.79, and ≥0.80), where 80% or greater is commonly defined as adherent.	Increased non-adherence: female sex, peripheral vascular disease, chronic pulmonary disease, diabetes, liver disease, rheumatic disease Decreased non-adherence: older age, initial treatment drug being niacin + statin, higher prescription drug classes
Xie et al (2013)^Citation35	Cross-sectional study	Twelve cities, and one county, entailing 21 province-level hospitals (equivalent to a teaching hospital in Europe) and six county-level hospitals (equivalent to a district hospital in Europe) (China)	1.890 patients	Medication Possession Ratio (MPR). We defined good compliance has an MPR of ≥80%	Decreased non-adherence: unemployed, cover rate of medicine insurance ≥70%, Province/County hospital, being attended in Cardiology department, very high CVD risk, using statins
Cicero et al (2014)^Citation36	Retrospective cohort study	Lipid clinics of the University of Bologna and the University of Pavia (Italy)	628 patients	Persistence in medication after 2 years	Decreased non-adherence: female sex, family history of early cardiovascular disease, baseline LDL cholesterol, treatment with nutraceuticals versus statins
Halava et al (2014)^Citation37	Prospective cohort study	Data from the Finnish Public Sector Study, a prospective study involving public sector employees in 10 municipalities and 21 hospitals (Finland)	9.285 patients	Proportion of days covered (PDC). Non-adherence was defined as PDC<80%	Increased non-adherence: female sex, younger age (<60 years), single
Gaisenok et al (2015)^Citation38	Retrospective observational study	Preventive Pharmacotherapy Department of the Ministry of Healthcare of the Russian Federation (Russia)	274 patients	Compliance with statin therapy was assessed with information on regularity of statin intake and the responses to four questions: (1) if they knew, according to the results of previous exams, that they had elevated cholesterol levels; (2) what method of hypercholesterolemia correction they used; (3) if they were taking any statins; and (4) if yes, what statin preparation and what dose they were taking.	Increased non-adherence: older age (>70 years) Decreased non-adherence: coronary heart disease, history of myocardial infarction, history of cardiovascular intervention
Halava et al (2015)^Citation39	Prospective cohort study	Retired, insured, swedish patients taking statins (Sweden)	11.718 patients	Adherence was defined as the Proportion of Days Covered (PDC). Non-adherence was defined as (PDC<80%). Adherence was defined as PDC≥80%	Increased non-adherence: retirement
Korhonen et al (2015)^Citation40	Prospective cohort study	Finnish Public Sector (10 towns and 6 hospital districts) (Finland)	1.916 patients	Proportion of days covered (PDC). Non-adherence was defined as PDC<80%	Increased non-adherence: higher number of childhood adversities (only in men), experiencing severe conflicts in the family
Warren et al (2015)^Citation41	Linked data from a prospective study	Data from a prospective study of 267,091 Australians with age ≥45 years to national data sets on prescription reimbursements, general practice claims, hospitalizations and deaths (Australia)	36.144 patients	Medication possession ratio (MPR). Patients were considered adherent if MPR≥80%	Increased non-adherence: highest education qualification, language spoken at home is other than English, single, widowed or separated, employed, annual income ≥ $70.000, smoking habit, new statin user, very high psychological distress Decreased non-adherence: older age, private health insurance, obesity, past smoker, self-reported heart disease, higher number of comorbidities, living in more remote areas
Korhonen et al (2016)^Citation42	Prospective cohort study	Employees of ten towns and six hospital districts who were targeted by questionnaire surveys in 2/4-year intervals since 2000 (Finland)	1.924 individuals	Adherence was measured using the Proportion of Days Covered (PDC). Non-adherence was defined as PDC<80%	Increased non-adherence: depression, anxiety
Kronish et al (2016)^Citation43	Retrospective cohort study	Centers for Medicare and Medicaid Services Chronic Condition Data Warehouse (USA)	6.618 patients	Proportion of days covered (PDC). Patients were categorized as nonadherent (PDC <80%) or adherent (PDC ≥80%)	Increased non-adherence: older age (>75 years), diabetes mellitus, depression, dementia Decreased non-adherence: being eligible for low-income subsidy
Tokgözoğlu et al (2016)^Citation44	National cross-sectional non-interventional observational study	14 centers of family medicine/general practice and cardiology clinics (Turkey)	532 patients	Discontinuation of statin therapy is defined as failure to renew a statin prescription with a ≥30-day gap between the end of a prescription and the start of the next prescription	Increased non-adherence: higher educational status, negative coverage of information about statin treatment and side effects (hepatic, renal and muscular) on television, patients’ lack of sufficient knowledge regarding high cholesterol and related risks
Al-Foraih et al (2017)^Citation45	Cross-sectional study study	Twelve polyclinic/general practice clinics across 4 of the 6 governorates in Kuwait (Kuwait)	200 patients	Adherence was assessed using the 8-item self-report Morisky Medication Adherence Scale (MMAS-8)	Increased non-adherence: diabetes Decreased non-adherence: older age
Booth et al (2017)^Citation46	Retrospective cohort study	Medicare beneficiaries with a hospitalization for myocardial infarction (USA)	158.795 patients	Proportion of Days Covered (PDC) High persistence was defined as PDC ≥80%	Increased non-adherence: not having a history of statin use, others than non-Hispanic white, cardiologist care prior to myocardial infarction hospitalization, diabetes mellitus, history of chronic kidney disease, heart failure, coronary heart disease, statin intolerance Decreased non-adherence: male sex, low-income subsidy, higher area-level median income, region of residence, statin use prior to myocardial infarction event, coronary stent insertion, being hospitalized for ≥5 days, using moderate-intensity and high-intensity statins
Devaraj et al (2017)^Citation47	Cross-sectional study, by survey	Urban primary care clinic (Malaysia)	398 patients	8-item Morisky Medication Adherence Scale. A patient was considered adherent if had a score≥6	Increased non-adherence: male sex, duration of lipid lowering therapy (>10 years), taking medication(s) at night or at no specific time, more follow-up visits, single follow-up clinic
Hickson et al (2017)^Citation48	Retrospective cohort study	Medicare beneficiaries taking statins, with age ≥ 66 years and with an acute myocardial infarction hospitalization in 2008–2010 (USA)	113.296 patients	Proportion of days covered (PDC). Patients were categorized into 3 categories: severely nonadherent (PDC <40%), moderately nonadherent (PDC 40–79.9%), and adherent (PDC ≥80%)	Increased non-adherence: African American ethnicity, Hispanic ethnicity, higher baseline Charlson Comorbidity Index, dementia/Alzheimer’s disease, depression, revascularization/cardiac intervention, ischemic heart disease, rhabdomyolysis/myopathy, higher length of stay in hospital post cardiovascular event Decreased non-adherence: dual insurance eligibility (Medicare and Medicaid), follow-up care by Cardiologist only
Wawruch et al (2017)^Citation49	Retrospective cohort study	The sample for this study was assembled from the database of the General Health Insurance Company (Slovak Republic).	797 patients	Treatment gap was defined as the presence of an at least 6-month period without any statin prescription. Patients with a treatment gap period were designated as ‘non-persistent’, whereas those without such a gap were designated as ‘persistent’ patients	Increased non-adherence: female sex Decreased non-adherence: older age (≥65 years), hypertension, diabetes mellitus, hypercholesterolemia, higher number of medications
Chung et al (2018)^Citation50	Prospective, non-interventional, observational study	Hospital Departments of Neurology (Korea)	991 patients	Patient self-reported adherence to statin therapy was assessed using the Morisky Medication Adherence Scale (MMAS-8)	Increased non-adherence: taking high statin dose, higher daily number of medication pills Decreased non-adherence: patients’ awareness of hyperlipidemia, current drinker
do Nascimento et al (2018)^Citation51	Cross-sectional study, by survey	1305 primary healthcare services located in 272 Brazilian cities (Brazil)	8.803 patients	Adherence was assessed by asking patients whether they missed any dose in the 7 days prior to the interview. Patients who reported missing at least one dose in the past 7 days were classified as having poor adherence	Decreased non-adherence: older age, higher education, dyslipidemia and diabetes mellitus, heart diseases, polypharmacy (≥5), alcohol use, not using emergency care
Haddad et al (2018)^Citation52	Cross-sectional study	20 community pharmacies from all 5 districts of Lebanon (list provided by the Lebanese Order of Pharmacists) (Lebanon)	247 patients	Adherence was assessed using a 3 questions questionnaire, asking patients about the frequency, percentage, and rating response of their statin use during previous month. Possible responses were divided in 6 categories: 0%, 20%, 40%, 60%, 80% and 100%. A total score was calculated by summing all 3 answers and presented in a percentage.	Increased non-adherence: divorced, widowed, primary and university level of education, smoking 15 cigarettes per day, not alcohol drinkers, duration of dyslipidemia Decreased non-adherence: married, single, secondary educational level, non-smokers, occasional alcohol drinking, better illness perception, better treatment satisfaction, better quality of life perception
Kriegbaum et al (2018)^Citation53	Cross-sectional study, by survey	Danish population participating in “LIFESTAT – Living with Statins Project” (Denmark)	3.050 patients	Discontinuation was based on self-reporting of current statin use in the interview, with 3 possible predefined answers. Discontinuation was defined as those who answered: “I have previously used cholesterol lowering drugs”	Increased non-adherence: experience of side effects, fear of side effects, feelings of uncertainty and confusion regarding information on statins (from both mass media and from general practitioners)
Ofori-Asenso et al (2018)^Citation54	Retrospective cohort study	A 10% random sample of the Australian population from data from the Pharmaceutical Benefits Scheme (Australia)	49.380 patients	The number of days on statin were calculated, assuming a dosage of 1 tablet daily. Discontinuation was defined as the first ≥90 days without statin coverage	Increased non-adherence: older age (>75 years), female sex, therapeutic initiated by general practitioner, diabetes Decreased non-adherence: taking atorvastatin or rosuvastatin (VS simvastatin), use of cardiovascular pharmacotherapies (antiplatelet, β-blockers, ACE inhibitors or ARBs)
Chen et al (2019)^Citation55	Population-based retrospective cohort study	Taiwan National Health Insurance claims (Taiwan)	169.624 patients	Medication possession ratio (MPR) and Proportion of days covered (PDC). Good adherence was considered if PDC≥0.80%	Increased non-adherence: older age (>75 years), renal disease, liver disease, depression, chronic obstructive pulmonary disease, taking insulin, digitalis, OADs, ACEIs or diuretics Decreased non-adherence: female sex, previous statin user, revascularization/cardiovascular procedures, hyperlipidemia, taking β-blockers, ARBs or antiplatelet agents, healthcare provider is a Medical Center, statin prescribed by Cardiovascular Medicine or Cardiovascular Surgery
Phan et al (2019)^Citation56	Retrospective population-based cohort study	Integrated healthcare system in Southern California (USA)	5.629 patients	Proportion of Days Covered (PDC). Adherence levels were categorized as: high (≥80%), partial (≥40% and <80%), and low (<40%)	Increased non-adherence: heart failure Decreased non-adherence: male sex, Caucasian, hyperlipidemia, higher adherence to β-blocker
Waßmuth et al (2019)^Citation57	Monocentric, prospective cohort study	Department of Cardiology and Department of Cardiac Surgery of the University Clinic Halle (Saale) (Germany)	542 patients	Adherence was defined has unchanged if statins and/or ezetimibe were unchanged, newly prescribed, or increased. Non-adherence was considered if statins and/or ezetimibe were stopped or dosage was decreased	Increased non-adherence: peripheral artery disease, atrial fibrillation, coronary artery bypass surgery Decreased non-adherence: taking aspirin, P2Y12 inhibitors or β-blockers (at discharge from cardiovascular event)
Bruckert et al (2020)^Citation58	Retrospective observational cohort study	The Pharmacoepidemiologic General Research eXtension (PGRx)-acute coronary syndrome (ACS) registry, from cardiology centres (France)	2.695 patients	Adherence was measured using the Proportion of Days Covered (PDC). Patients were considered adherent if they had a PDC ≥80%	Decreased non-adherence: previous cardiovascular disease event
Seaman et al (2020)^Citation59	Retrospective observational study	Western Australian Population (Australia)	205.924 patients	Medication possession ratio (MPR), with the threshold of adherence defined as 80%	Increased non-adherence: younger age, living in more remote areas, not having previous ischemic heart disease, not having previous coronary artery revascularization procedure, not having previous statin use, beneficiary status, not taking cardiovascular medication, higher number of other medications Decreased non-adherence: older age
Shakarneh et al (2020)^Citation60	Cross-sectional study, by survey	Two middle governmental primary healthcare clinics in the cities of Ramallah and Bethlehem (Palestine)	185 patients	Adherence was determined using the 4-item Morisky medication adherence scale (MMAS-4). Total scores were summed (range 0–4), with scores of 0–1 denoting high adherence and 2–4 denoting low adherence	Increased non-adherence: low education (illiterate), polypharmacy (> 4), comorbidities, concerns about side effects

Table 3 Main Determinants Associated with Non-Adherence

Main Identified Determinants Associated with Non-Adherence
	Associated with Higher Non-Adherence	Associated with Lower Non-Adherence
Age	Younger age (≤ 50 years)	Older age
Sex	Female sex	Male sex
Ethnicity	African American Hispanic	Caucasian
Marital Status	Divorced Separated Widowed Single	Married
Habits	Smoking habits	Alcohol drinking habits
Comorbidities	Chronic obstructive pulmonary disease Alzheimer disease/dementia Depression Diabetes Anxiety Hepatic disease Chronic kidney disease Peripheral vascular disease Heart failure	Higher number of comorbidities Higher number of cardiovascular risk factors Present heart disease Hypertension
Medications	New users of lipid-lowering medications Patients presenting side effects or concerns about them Higher duration of lipid-lowering treatment	Patients taking β-blockers Patients taking antiplatelets
Cardiovascular diseases and interventions		History of cardiovascular disease events History of cardiac intervention or revascularization procedure
Healthcare services utilization		Higher healthcare services utilization Patients treated in cardiology Patients treated in family medicine Having health insurance Higher number of follow-up visits
Other determinants	Unemployment Bad doctor–patient relationship

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