Paying the price of nonadherence: health and financial costs



by N. Maniadakis and
G. Gourzoulidis, Greece

George GOURZOULIDIS, MSc
Research Fellow, Department
of Health Services Management
National School of Public
Health, Athens, GREECE

Nikos MANIADAKIS, BSc, MSc,
PhD, FESC
Director, Department of Health
Services Management
Alternate Dean, National School
of Public Health, Athens
GREECE

Adherence to medication is paramount for optimizing health and economic outcomes, especially in the management of chronic conditions. Unfortunately, there is abundant evidence to show that adherence is often suboptimal and this causes a significant cost in terms of forgone clinical and economic benefit. Nonadherence is associated with increased morbidity, mortality, and health care expenditures. By contrast, better adherence is beneficial for health outcomes and results in lower resource utilization and total health care costs. These findings come from a significant number of studies undertaken across different chronic disease modalities and health care systems, and this reinforces the need to improve performance, for the sake of patients, providers, funding bodies, and tax payers. The latter can be achieved through a comprehensive approach aiming to improve the physician-patient relationship and the patient’s self-management and treatment experience. Recent technological advances in the field of drug discovery and new models of drug delivery, in conjunction with the emerging internet-based revolution in health care may play a pivotal role. The advent and fast growth use of e-devices and e-health systems and all the related innovations in this field generate optimism for improving adherence, even though many developments are still in their infancy and the promise needs to be realized in due course. Apart from the humanistic justification, there is a compelling economic case for improving adherence to pharmaceutical therapy, to reduce wastage of scarce resources, and to eliminate forgone economic benefits in other sectors of health care. Improving adherence to medication must become a top priority for health care systems and health policy, otherwise we will continue to pay a huge price for our inefficiency and tolerance of a significant deficiency of health care systems.

Medicines are often the first and sole choice for intervention in the management of many chronic and acute diseases. Even in cases where they are used in combination with other interventions, medicines remain a significant contributor to the effectiveness and safety of care. Ensuring that patients adhere in full to provider recommendations in respect to the timing, dosing, and frequency of their medication administration, all along the prescribed length of therapy (persistence), is essential in order to optimize health and economic outcomes.1,2 Adherence is of particular importance in the management of chronic diseases such as diabetes, arthritis, hypertension, hypercholesterolemia, and arthritis, where therapy has a continuous, persistent and long-term perspective.3 Evidence indicates that nonadherence is associated with increased morbidity and mortality among patients with chronic diseases.4-6 Moreover, nonadherence has been associated with a high incidence of unwanted side effects, poor quality of life, high rates of hospitalization, poorer health outcomes, and more comorbidities.1,4,6 Apart from the health consequences, the economic burden of nonadherence may be significant, since it may exacerbate chronic conditions, generate adverse health events, and increase health care utilization, and, in turn, total health care costs.7,8 Thus, adherence of patients with chronic disease is of paramount importance for both clinical and economic reasons.

Nonetheless, health care systems are not performing well in this aspect of care. World Health Organization estimates indicate that adherence among people taking long-term therapies for chronic diseases is as low as 50% in developed countries,1 and may be far lower in less developed countries.9 Hence, nonadherence represents a serious challenge in chronic disease management.10 However, tackling this challenge is not straightforward. Adherence is driven by factors associated to the patient (age, sex, marital status, motivation, ethnicity, culture, lifestyle, communication abilities, income, education, health status, quality of life, and comorbidities), the system of care provision (physician access, education and ability for good communication, frequency, quality and time spent on consultations, reimbursement systems and prescription policies, and monitoring mechanisms) and to the medication itself (route, place and frequency of administration, number of concomitant drugs used, safety, efficacy, tolerability, and duration of therapy). All the aforementioned points indicate that adherence represents a complex and multifactorial issue.1,11-13

There are multiple ways to improve adherence. These may focus on improving physician and patient education, the frequency and quality of consultations, the implementation of guidelines, or providing support for drug use at home. Moreover, e-health and m-health devices and new novel technologies and systems offer new and better opportunities for direct and indirect support and monitoring of drug use. Big system data availability and developments in analytics and behavioral research may help us to understand the complex mechanisms of human behavior and the drivers of drug use. Also, improvements in dosage frequency, modes of delivery, fixed-dose combinations, and package infographics are also important. Moreover, as with any problem, it is important for all to understand the magnitude of the costs it imposes and the implications of inactivity and inefficiency. Thus, this article presents evidence from the published literature on the “price” of nonadherence and its economic and medical implications in chronic disease management.

Measuring adherence

The present article presents the findings of many published research studies on adherence. In daily medical practice and in empirical research, it is somewhat difficult to measure medication adherence. The validity of adherence assessment is based on the method of measurement, which needs to satisfy criteria of validity, reliability, sensitivity to change, and feasibility. Unfortunately, there is currently no single approach satisfying adequately all these properties.

Table I. Methods for measuring adherence.
Abbreviations: EMR, electronic medical records; MPR, medication possession ratio; PDC, proportion
of days covered.
From reference 11: Osterberg and Blaschke. New Engl J Med. 2005;353(5):487-497 and 14: Iuga
and McGuire. Risk Manag Healthc Policy. 2014;7:35-44.

However, adherence is measured in a variety of direct and indirect methods (Table I).11 Direct methods encompass mechanisms such as direct observation of therapy use, measurement of concentrations of a drug or its metabolite in the blood or urine, and detection or measurement in the blood of a biologic marker added to the drug formulation. Although direct methods may be more robust than indirect methods, they have limitations as well.5 First, they are expensive, burdensome to the health care provider, and susceptible to distortion by the patient.11,14 Furthermore, the use of biological markers only reflects short-term adherence, and can overestimate patients’ long-term adherence and can be applied mostly for drugs with long elimination half-lives. Also, interindividual differences in drug absorption and metabolism can also lead to inaccurate conclusions regarding medication adherence.

Indirect methods represent the most common approach to measuring medication adherence. Commonly used indirect measures are based on pharmacy refills, electronic monitoring of prescriptions, and tablet counts. Commonly used methods to quantify adherence include the medication possession ratio (MPR) and the proportion of days covered (PDC). MPR is calculated as the total number of days supplied, divided by the number of days between the first and last refills, while PDC is calculated as the total number of days supplied during an interval, divided by the total number of days during that interval.14,15 An MPR of 80% is often used as the cutoff between adherence and nonadherence, based on its ability to predict hospitalizations across a selection of highly prevalent chronic diseases. Moreover, other indirect methods of adherence assessment are based on questionnaires and diaries completed by patients or electronic medication monitors and other medication use markers from electronic databases and patient records.,11,14 These are easier to use but suffer from many shortcomings as indicated below.

Pharmacy refills provide a convenient, noninvasive, objective and inexpensive method for estimating medication adherence, but such data reflect mainly dispensing rather than actual consumption. Often, electronic monitoring devices may be used to provide more accurate and detailed information on medication- taking behavior, but they come at a cost and may also increase patient awareness and hence they may modify and bias their behavior. Tablet counts are frequently used in clinical trials and adherence research, but are notoriously unreliable and usually provide overestimates. A few self-reported medication adherence questionnaires have been used in the literature, but none of them is without limitations and there is no widely accepted standard. Despite these caveats lots of research using different methods has been undertaken and some useful finding are presented in the following sections.

Adherence and outcomes in the care of chronic disease

Cardiovascular disease
Approximately 50% of patients with cardiovascular disease have poor adherence to their prescribed medications.16 Nonadherent heart disease patients have been estimated to have significantly higher mortality rates than adherent patients.4 This could be attributed to the fact that nonadherent patients fail to achieve their therapeutic targets.17 More specifically, in a retrospective study of 557 patients with heart failure (HF), it was reported that nonadherence was associated with a statistically significant increase in mortality risk.18 Moreover, a systematic review showed that the risk of hospitalization, re-hospitalization, and premature death among nonadherent patients was 5.4 times higher in hypertension, 2.8 times higher in dyslipidemia, and 1.5 times higher in heart disease compared with adherent patients.19 Additionally, a retrospective cohort study20 that evaluated the impact of adherence to statins on nonfatal coronary artery disease (CAD) showed that adherence which exceeds 90% resulted in significant reduction in nonfatal CAD events.

Furthermore, two studies conducted in HF patients showed that poor medication adherence leads to more frequent hospitalizations, which, in turn, results in higher hospitalization costs.21,22 Notably, a study reported that in Medicare and Medicaid beneficiaries with HF, those with adherence rates of more than 95% had about 15% lower health care costs than those with adherence rates between 80% and 95% ($17 665 vs $20 747).23 Moreover, a retrospective study of 1495 patients with HF (799 patients) or myocardial infarction (696 patients) after acute hospitalization, revealed that adherence and persistence with angiotensin receptor blockers and angiotensin-converting enzyme (ACE) inhibitors resulted in lower risk of re-hospitalization and lower health care costs.24 Similarly, in a retrospective cohort study of 381 422 patients using an integrated pharmacy and medical claims database, higher MPR was associated with reductions in subsequent total health care costs and cardiovascular disease–related hospitalizations.25 Another retrospective cohort study of 137 277 benefit plan patients reported that high levels of adherence were significantly associated with lower overall health care costs for hypertension patients, but not for patients with congestive HF.8 Lastly, a study26 of 2204 beneficiaries with congestive HF reported that a 10% increase in daily pill counts of ACE inhibitors, β-blockers, diuretics, and cardiac glycosides resulted in savings of $390, $510, $13, and $923, respectively, on total health care costs.

Diabetes
Multiple studies have evaluated the relationship between medication adherence and outcomes in diabetes and in general they support a correlation between increased adherence and better health outcomes, which, in turn, results in reduced total cost. More specifically, one study27 reported that the number of disability days was significantly lower in adherent patients than in nonadherent patients.28 Moreover, two studies29,30 reported that a 10% increase in medication adherence leads to a 0.1%30 and 0.12%29 decrease in HbA1c levels, while another study31 indicated that a 25% decrease in medication adherence leads to a 0.35% increase in HbA1c levels. In addition, one study32 found that a 50% increase in medication adherence reduced by 23.3% and 46.2% the hospitalization rates and the emergency department visits, respectively. Similar findings were detected in another study,33 which reported that a 10% increase in medication adherence results in a 1.2% decrease in hospitalization rates and emergency department visits. Furthermore, increased adherence with pharmaceutical therapy has been associated in one study with decreased use of medical care services, due to improved disease control and well-being, though this was not reflected in total therapy costs.34 By contrast, another study found that a 10% increase in adherence of adult patients with type 2 diabetes mellitus was associated with an 8.6% to 28.9% decrease in total annual health care costs.35 Similarly, another study reported that a 10% increase in adherence was associated with a 2% reduction in total medical costs and a 4% reduction in diabetes-related medical costs.36 Finally, a study reported that better medication adherence was associated with decreased hospitalizations and emergency department visits for diabetes or related conditions and that higher total health care costs were observed initially,37 but were lower 5 years after the time of diabetes onset.

Chronic obstructive pulmonary disease
Several studies were carried out to explore the impact of nonadherence on health and economic outcomes in chronic obstructive pulmonary disease (COPD). More specifically, a study conducted in this patient group showed that good adherence was associated with a decreased risk of severe exacerbations and a decreased risk of death,38 even though there are other studies that show no significant difference in mortality between adherent and nonadherent patients.39 Moreover, a 7-year retrospective administrative claims study40 of 55 076 COPD patients showed that a 5% increase in adherence leads to a 2.6% reduction in hospital visits and a 1.8% reduction in emergency department visits. A similar study of 33 816 Medicare beneficiaries diagnosed with COPD found that the annual Medicare spending per patient was $2185 lower in patients with PDC >80% than in patients with PDC <80%.41 Furthermore, a retrospective study compared adherence and outcomes between COPD patients initiating tiotropium (n=1561) or salmeterol/fluticasone (n=2976) therapy using claims data from a large national US health plan. This study showed that pharmacy costs were higher in adherent patients compared with nonadherent patients. In contrast, inpatient stay costs were lower in adherent patients than in nonadherent patients. Finally, another study compared users and nonusers of maintenance medication for COPD and found that the use of maintenance therapy was associated with significantly lower risks of hospitalization and re-hospitalization and reduced health care expenditures.42

Asthma
Studies in asthma patients have shown that better adherence in asthma cohorts was associated with better outcomes across populations and cost savings in those at higher risk. In particular, a retrospective study of 18 456 Medicaid children aged between 2 and 18 years and diagnosed with asthma reported that greater adherence was associated with lower rates of emergency department visits; however, higher medication expenditures outweighed the cost savings related to fewer visits. Moreover, a retrospective study using two years of claims data for 41 234 commercially insured asthmatics indicated that better adherence reduced total therapy costs in high risk patients who had a past history of emergency department visits or hospital admissions43 Both studies suggest that improving medication adherence improves outcomes and is cost-saving in patients with severe disease, while it increases overall cost in patients with mild disease.

Another study sought to measure changes in inhaled corticosteroid adherence over time and to estimate the effect of this changing pattern on asthma exacerbations44 Adherence to inhaled corticosteroids was estimated from electronic prescription and fill information for 298 participants in the SAPPHIRE study (Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity). The study results showed that adherence was associated with a reduction in exacerbations, but this association reached statistical significance when patients whose adherence was greater than 75% of the prescribed dose (hazard ratio, 0.61; 95% CI, 0.41- 0.90) were compared with patients whose adherence was 25% or less. This pattern was largely confined to patients whose asthma was not well controlled initially. An estimated 24% of asthma exacerbations were attributable to nonadherence to inhaled corticosteroid medications.44

Human immunodeficiency virus
Not many studies have been carried out to explore the impact of adherence on health and economic outcomes in human immunodeficiency virus (HIV) therapy. A retrospective cohort study45 of 325 previously antiretroviral medication-naïve HIV-infected individuals initiating first antiretroviral therapy during the period 1997-2003 was carried out in the USA. The study showed that better adherence to antiretroviral medication resulted in decreased health care utilization and associated costs, but the total medical cost was higher due to a higher cost of antiretroviral therapy. However, the dramatic clinical benefits of antiretroviral therapy suggest that while interventions that promote adherence may not be cost-saving, they can be cost-effective. Similar findings were detected in an observational study46 using administrative data in which highly adherent patients with antiretroviral treatment were found to have higher medication costs but lower acute hospital costs. In contrast, patients with lower adherence to antiretroviral treatment were associated with higher total cost.

Moreover, an observational study of 99 HIV-infected patients in a Veterans Affairs medical center revealed that patients with adherence of 95% or greater had fewer days in the hos- pital (2.6 days per 1000 days of follow-up) than those with less than 95% adherence (12.9 days per 1000 days of follow- up; P=0.001).47

Depression
A retrospective study48 of patients initiating selective serotonin reuptake inhibitor (SSRI) therapy for depression and/or anxiety between July 2001 and June 2002 showed that only approximately 43% of patients were adherent to antidepressant therapy, and those adherent patients were associated with the lowest yearly medical cost. Another study of 65 753 managed care patients found that medical charges due to inpatient treatment, excluding pharmacy charges, were lower for patients remaining on antidepressant drug therapy for at least 90 days, and only when drug costs were added there was no cost difference between adherent and nonadherent patients.49

Moreover, a study of 60 386 adult patients with depression showed that adherent patients had 6-month median unadjusted total health care expenses that were higher compared with nonadherent patients ($5169 vs $2734), and this was also the case for mental health expenditures ($1922 vs $677). After adjustment, adherent patients compared with nonadherent patients incurred an additional cost of $644 in mental health expenditures and $806 in overall health care expenditures in the 6 months following initiation of antidepressant therapy.50

Parkinson disease
Poor compliance has been recognized as an important issue in Parkinson disease (PD).51 In PD, low adherence to therapy may be associated with unsatisfactory control of motor symptoms, more time spent in worse health states, and worse quality of life.51 A study of PD patients from a national database in the USA found that nonadherent patients had significantly higher rates of hospitalizations (2.3 vs 1.8), office visits, and ancillary care visits and higher total medical costs ($15 826 vs $9228) per annum, despite lower prescription drug costs ($2684 vs $3854; P<0.05).52 After adjusting for confounders and comorbidities, nonadherence was associated with a $3451 yearly increase in medical costs.

On the other hand, a study of 7583 beneficiaries examining the association of adherence to anti-parkinson drugs (APDs) with health care utilization and economic outcomes reported that increased adherence is associated with decreased health care utilization and expenditures.53 For example, compared with patients with low adherence, those with high adherence (MPR, 0.90-1.00) had significantly lower rates of hospitalization (RR, 0.86), emergency room visits (RR, 0.91), skilled nursing facility episodes (RR, 0.67), home health agency episodes (RR, 0.83), physician visits (RR, 0.93), as well as lower total health care expenditures (–$2242) over a period of 19 months.

Additionally, a multicenter European study conducted to assess the medicine-taking behavior in PD patients found that suboptimal adherence was significantly associated with higher Parkinson motor scores (median, 29; IQR, 20-40) and with greater disability, compared with satisfactory adherence (median, 19; IQR 13–26).54

Osteoporosis
A retrospective study55 of 17 770 women examined the association between adherence with oral bisphosphonate therapy and fracture risk as well as health care resource utilization. The study results showed that during the second-year post–treatment initiation, the risk of osteoporotic fracture was 2.1% in adherent patients and 2.5% in nonadherent patients (P=0.1). Moreover, when analysis was limited to patients aged 75 years or older, nonadherence with bisphosphonates was associated with a probability of osteoporotic fractures that was almost 50% higher than that of adherent patients (OR, 1.49; 95% CI, 1.08-2.04). Nonadherent patients had 13.4% higher medical costs than their adherent counterparts among patients aged 75 years and older (P=0.002).55

Furthermore, in another study,56 which was performed to investigate the impact of adherence to bisphosphonate therapy on the risk of hip fracture, it was reported that for a 1% decrease of the MPR, the risk of hip fracture increased by 0.4% (OR, 0.996; 95% CI, 0.994-0.998; P<0.001). The relative risk reduction for hip fracture was 60% (HR, 0.404; 95% CI, 0.357-0.457; P<0.0001) for persistent patients compared with nonpersistent patients.56 Additionally, a retrospective study57 of 685 505 women with osteoporosis showed that noncompliance was associated with a 20% higher risk of any fracture, a 26% higher risk of inpatient utilization (incidence rate ratio [IRR], 1.26) and a 3% lower rate of outpatient utilization (IRR, 0.97). Noncompliant patients had 13% higher medical costs (cost ratio,1.13) than compliant patients.57

Arthritis
There is also evidence regarding the effects of adherence on outcomes in arthritis management. A multicenter prospective observational cohort study recently investigated self-reported nonadherence to anti-TNF therapy and response to therapy in individuals with rheumatoid arthritis. The study included 392 patients who reported being nonadherent to their treatment at least once within the first 6-month period. Multivariate linear regression analysis showed that nonadherence was significantly associated with a poorer response to therapy.58

Another study assessed adherence to therapy and consumption of care resources (drugs, outpatient services, hospitalizations) using an observational retrospective cohort analysis of administrative databases containing data from 1219 patients with rheumatoid arthritis, psoriasis, and Crohn disease. The mean annual nonpharmacological expenditure for each patient in analysis was €988 for adherent patients and €1255 for nonadherent patients. Higher adherence was thus associated with lower costs.59

A multicenter cohort study of 206 patients with rheumatoid arthritis and 1 year of follow-up found that nonadherence was associated with higher health care costs in the first year of treatment for arthritis. The study results indicated that improving adherence was not only associated with better outcomes, but also with health care cost savings.60

Moreover, a study evaluated adherence to subcutaneous anti-TNFs among rheumatoid arthritis patients who were either new to therapy (naïve) or existing users over 1 year, and it found that adherent patients had fewer ambulatory, emergency department, and inpatient visits compared with nonadherent patients.61

Conclusions

Adherence is a primary determinant of the effectiveness of treatment because poor adherence attenuates optimum clinical benefit. Unfortunately, many studies show that high levels of nonadherence are common across many different chronic disease modalities and health system settings. This should not be acceptable in light of abundant evidence which indicates that, in chronic disease management, better adherence decreases mortality, morbidity, hospitalizations, and emergency department or physician visits and, in most cases, lowers overall total health care costs. Nonadherence is common and contributes significantly to higher morbidity, mortality, and increased health care costs.

Thus, it is paramount to tackle this issue and improving adherence must be a priority for health policy. As it is a phenomenon with multifactorial causes it needs a comprehensive approach. Adherence can be improved through better education, more frequent and qualitative consultations, economic incentives, abolition of barriers in access to medicines and other similar interventions.3,62-64 Nonetheless, the big promise emerges from the technological developments in the medical field and the e-health revolution. Specifically, new innovative drugs and drug delivery approaches improve effectiveness, safety, tolerability, and convenience for patients.

Also, the emerging internet based ecosystem with e-health, m-health, big data, and IT systems and devices, provides an opportunity to aid, monitor, analyze, and improve drug use in an effective way. This endeavor requires the contribution of all stakeholders: patients, clinicians, pharmacists, payers, and pharmaceutical firms.

Nonadherence has a significant human cost and is responsible for economic opportunity loss. The worldwide pharmaceutical expenditure is higher than 1 trillion US dollars and to a large extent it concerns chronic drug use. In many chronic diseases nonadherence reaches levels as high as 50%. Put together, these figures make a straightforward and compelling economic case for improving adherence in order to reduce wastage in pharmaceutical expenditure and also forgone economic benefits in other sectors of care. In conclusion, improving adherence to medication must become a top priority for health care systems and health policy. We cannot afford to tolerate this inefficiency. The price is too high. ■

References
1. Sabate Eduardo. Adherence to long-term therapies: evidence for action: World Health Organization. 2003. Available at: http://www.who.int/chp/knowledge/ publications/adherence_full_report.pdf. Accessed April 13, 2017.
2. Cramer JA, Roy A, Burrell A, et al. Medication compliance and persistence: terminology and definitions. Value Health. 2008;11(1):44-47.
3. Mann BS, Barnieh L, Tang K, et al. Association between drug insurance cost sharing strategies and outcomes in patients with chronic diseases: a systematic review. PloS One. 2014;9(3):e89168.
4. Brown MT, Bussell JK. Medication Adherence: WHO Cares? Mayo Clinic Proceedings. 2011;86(4):304-314.
5. Ho PM, Bryson CL, Rumsfeld JS. Medication adherence: its importance in cardiovascular outcomes. Circulation. 2009;119(23):3028-3035.
6. Cohen J, Christensen K, Feldman L. Disease management and medication compliance. Popul Health Manag. 2012;15(1):20-28.
7. Heisler M, Choi H, Rosen AB, et al. Hospitalizations and deaths among adults with cardiovascular disease who underuse medications because of cost: a longitudinal analysis. Med Care. 2010;48(2):87-94.
8. Sokol MC, McGuigan KA, Verbrugge RR, Epstein RS. Impact of medication adherence on hospitalization risk and healthcare cost. Med care. 2005;43(6): 521-530.
9. De Geest S, Sabate E. Adherence to long-term therapies: evidence for action. Eur J Cardiovasc Nurs. 2003;2(4):323.
10. Burkhart PV, Sabate E. Adherence to long-term therapies: evidence for action. J Nurs Scholarsh. 2003;35(3):207.
11. Osterberg L, Blaschke T. Adherence to medication. New Engl J Med. 2005; 353(5):487-497.
12. Piette JD, Heisler M, Wagner TH. Cost-related medication underuse: do patients with chronic illnesses tell their doctors? Arch Intern Med. 2004;164(16): 1749-1755.
13. Soumerai SB, Pierre-Jacques M, Zhang F, et al. Cost-related medication nonadherence among elderly and disabled medicare beneficiaries: a national survey 1 year before the medicare drug benefit. Arch Intern Med. 2006;166(17): 1829-1835.
14. Iuga AO, McGuire MJ. Adherence and health care costs. Risk Manag Healthc Policy. 2014;7:35-44.
15. Lam WY, Fresco P. Medication adherence measures: an overview. BioMed research Int. 2015;2015:217047.
16. Kronish IM, Ye S. Adherence to cardiovascular medications: lessons learned and future directions. Progr Cardiovasc Dis. 2013;55(6):590-600.
17. Bermingham M, Hayden J, Dawkins I, et al. Prospective analysis of LDL-C goal achievement and self-reported medication adherence among statin users in primary care. Clin Ther. 2011;33(9):1180-1189.
18. Fitzgerald AA, Powers JD, Ho PM, et al. Impact of medication nonadherence on hospitalizations and mortality in heart failure. J Card Fail. 2011;17(8):664-669.
19. Gwadry-Sridhar FH, Manias E, Zhang Y, et al. A framework for planning and critiquing medication compliance and persistence research using prospective study designs. Clin Ther. 2009;31(2):421-435.
20. Bouchard MH, Dragomir A, Blais L, Berard A, Pilon D, Perreault S. Impact of adherence to statins on coronary artery disease in primary prevention. Br J Clin Pharmacol. 2007;63(6):698-708.
21. Chui MA, Deer M, Bennett SJ, et al. Association between adherence to diuretic therapy and health care utilization in patients with heart failure. Pharmacotherapy. 2003;23(3):326-332.
22. Mockler M, O’Loughlin C, Murphy N, et al. Causes and consequences of nonpersistence with heart failure medication. Am J Cardiol. 2009;103(6):834-838.
23. Esposito D, Bagchi AD, Verdier JM, Bencio DS, Kim MS. Medicaid beneficiaries with congestive heart failure: association of medication adherence with healthcare use and costs. Am J Manag Care. 2009;15(7):437-445.
24. Sun SX, Ye X, Lee KY, Dupclay L, Jr., Plauschinat C. Retrospective claims database analysis to determine relationship between renin-angiotensin system agents, rehospitalization, and health care costs in patients with heart failure or myocardial infarction. Clin Ther. 2008;30 Pt 2:2217-2227.
25. Pittman DG, Chen W, Bowlin SJ, Foody JM. Adherence to statins, subsequent healthcare costs, and cardiovascular hospitalizations. Am J Cardiol. 2011;107 (11):1662-1666.
26. Lopert R, Shoemaker JS, Davidoff A et al. Medication Adherence and Medicare Expenditure Among Beneficiaries With Heart Failure. Am J Manag Care. 2012; 18(9):556-563.
27. Gibson TB, Song X, Alemayehu B et al. Cost sharing, adherence, and health outcomes in patients with diabetes. Am J Manag Care. 2010;16(8):589-600.
28. Martinez YV, Prado-Aguilar CA, Rascon-Pacheco RA, Valdivia-Martinez JJ. Quality of life associated with treatment adherence in patients with type 2 diabetes: a cross-sectional study. BMC Health Serv Res. 2008;8:164.
29. Barron J, Wahl P, Fisher M, Plauschinat C. Effect of prescription copayments on adherence and treatment failure with oral antidiabetic medications. PT. 2008; 33(9):532-553.
30. Rozenfeld Y, Hunt JS, Plauschinat C, Wong KS. Oral antidiabetic medication adherence and glycemic control in managed care. Am J Manag Care. 2008; 14(2):71-75.
31. Rhee MK, Slocum W, Ziemer DC et al. Patient adherence improves glycemic control. Diabetes Educ. 2005;31(2):240-250.
32. Encinosa WE, Bernard D, Dor A. Does prescription drug adherence reduce hospitalizations and costs? The case of diabetes. Adv Health Econ Health Serv Res. 2010;22:151-73.
33. Jha AK, Aubert RE, Yao J, Teagarden JR, Epstein RS. Greater adherence to diabetes drugs is linked to less hospital use and could save nearly $5 billion annually. Health Aff (Millwood). 2012;31(8):1836-1846.
34. Hepke KL, Martus MT, Share DA. Costs and utilization associated with pharmaceutical adherence in a diabetic population. Am J Manag Care. 2004;10(2 Pt 2):144-151.
35. Balkrishnan R, Rajagopalan R, Camacho FT, Huston SA, Murray FT, Anderson RT. Predictors of medication adherence and associated health care costs in an older population with type 2 diabetes mellitus: a longitudinal cohort study. Clinical Ther. 2003;25(11):2958-2971.
36. Shenolikar RA, Balkrishnan R, Camacho FT, Whitmire JT, Anderson RT. Comparison of medication adherence and associated health care costs after introduction of pioglitazone treatment in African Americans versus all other races in patients with type 2 diabetes mellitus: a retrospective data analysis. Clin Ther. 2006;28(8):1199-1207.
37. Cheng SH, Chen CC, Tseng CH. Does medication adherence lead to lower healthcare expenses for patients with diabetes? Am J Manag Care. 2013;19(8): 662-670.
38. Vestbo J, Anderson JA, Calverley PM et al. Adherence to inhaled therapy, mortality and hospital admission in COPD. Thorax. 2009;64(11):939-943.
39. Turner J, Wright E, Mendella L, Anthonisen N. Predictors of Patient Adherence to Long-term Home Nebulizer Therapy for COPD. Chest. 1995;108(2):394-400.
40. Toy EL, Beaulieu NU, McHale JM et al. Treatment of COPD: relationships between daily dosing frequency, adherence, resource use, and costs. Respir Med. 2011;105(3):435-441.
41. Simoni-Wastila L, Wei YJ, Qian J et al. Association of chronic obstructive pulmonary disease maintenance medication adherence with all-cause hospitalization and spending in a Medicare population. American J Geriatr Pharmacother. 2012;10(3):201-210.
42. Stuart BC, Simoni-Wastila L, Zuckerman IH et al. Impact of maintenance therapy on hospitalization and expenditures for Medicare beneficiaries with chronic obstructive pulmonary disease. American J Geriatr Pharmacother. 2010;8(5): 441-453.
43. Mattke S, Martorell F, Hong SY, Sharma P, Cuellar A, Lurie N. Anti-inflammatory medication adherence and cost and utilization of asthma care in a commercially insured population. J Asthma. 2010;47(3):323-329.
44. Williams LK, Peterson EL, Wells K, et al. Quantifying the proportion of severe asthma exacerbations attributable to inhaled corticosteroid nonadherence. J Allergy Clin Immunol. 2011;128(6):1185-91.e2.
45. Gardner EM, Maravi ME, Rietmeijer C, Davidson AJ, Burman WJ. The association of adherence to antiretroviral therapy with healthcare utilization and costs for medical care. Applied Health Econ Health Policy. 2008;6(2-3):145-155.
46. Barnett PG, Chow A, Joyce VR et al. Determinants of the cost of health services used by veterans with HIV. Med Care. 2011;49(9):848-856.
47. Paterson DL, Swindells S, Mohr J et al. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med. 2000;133 (1):21-30.
48. Cantrell CR, Eaddy MT, Shah MB, Regan TS, Sokol MC. Methods for evaluating patient adherence to antidepressant therapy: a real-world comparison of adherence and economic outcomes. Med Care. 2006;44(4):300-303.
49. Eaddy MT, Druss BG, Sarnes MW, Regan TS, Frankum LE. Relationship of total health care charges to selective serotonin reuptake inhibitor utilization patterns including the length of antidepressant therapy—results from a managed care administrative claims database. J Manag Care Pharm. 2005;11(2): 145-150.
50. Robinson RL, Long SR, Chang S et al. Higher costs and therapeutic factors associated with adherence to NCQA HEDIS antidepressant medication management measures: analysis of administrative claims. J Manag Care Pharm. 2006;12(1):43-54.
51. Grosset D. Therapy adherence issues in Parkinson’s disease. J Neurol Sci. 2010;289(1-2):115-118.
52. Davis KL, Edin HM, Allen JK. Prevalence and cost of medication nonadherence in Parkinson’s disease: evidence from administrative claims data. Mov Dis. 2010;25(4):474-480.
53. Wei Y-J, Palumbo FB, Simoni-Wastila L et al. Antiparkinson Drug Adherence and Its Association with Health Care Utilization and Economic Outcomes in a Medicare Part D Population. Value Health. 2014;17(2):196-204.
54. Grosset D, Antonini A, Canesi M et al. Adherence to antiparkinson medication in a multicenter European study. Mov Dis. 2009;24(6):826-832.
55. Sharman Moser S, Yu J, Goldshtein I, et al. Cost and Consequences of Nonadherence With Oral Bisphosphonate Therapy: Findings From a Real-World Data Analysis. Ann Pharmacother. 2016;50(4):262-269.
56. Rabenda V, Mertens R, Fabri V et al. Adherence to bisphosphonates therapy and hip fracture risk in osteoporotic women. Osteoporos Int. 2008;19(6):811-818.
57. Modi A, Siris ES, Tang J, Sen S. Cost and consequences of noncompliance with osteoporosis treatment among women initiating therapy. Curr Med Res Opin. 2015;31(4):757-765.
58. Bluett J, Morgan C, Thurston L, et al. Impact of inadequate adherence on response to subcutaneously administered anti-tumour necrosis factor drugs: results from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate cohort. Rheumatology (Oxford). 2015;54(3):494-499.
59. Degli Esposti L, Sangiorgi D, Perrone V, et al. Adherence and resource use among patients treated with biologic drugs: findings from BEETLE study. Clinicoecon Outcomes Res. 2014;6:401-407.
60. Pasma A, Schenk C, Timman R, et al. Does non-adherence to DMARDs influence hospital-related healthcare costs for early arthritis in the first year of treatment? PloS One. 2017;12(2):e0171070.
61. Borah BJ, Huang X, Zarotsky V, Globe D. Trends in RA patients’ adherence to subcutaneous anti-TNF therapies and costs. Current medical research and opinion. 2009;25(6):1365-1377.
62. Gourzoulidis G, Kourlaba G, Stafylas P, Giamouzis G, Parissis J, Maniadakis N. Association between copayment, medication adherence and outcomes in the management of patients with diabetes and heart failure. Health Policy. 2017;121 (4):363-377.
63. Eaddy MT, Cook CL, O’Day K, Burch SP, Cantrell CR. How patient cost-sharing trends affect adherence and outcomes: a literature review. PT. 2012;37(1): 45-55.
64. Goldman DP, Joyce GF, Zheng Y. Prescription drug cost sharing: associations with medication and medical utilization and spending and health. JAMA. 2007; 298(1):61-69.

Keywords: adherence; compliance; drug; medicine; persistence; pharmaceutical