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Medication adherence research in populations: Measurement issues and other challenges
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Clinical Therapeutics/Volume 29, Number 6, 2007
Editorial Medication Adherence Research in Populations: Measurement Issues and Other Challenges Medication nonadherence is a recognized public health problem in the United States, particularly in patient populations with chronic diseases. Adherence to medications is crucial to the treatment of chronic conditions, which often require that patients be on controller maintenance medications. Rates of nonadherence to treatment with any medication have been reported to vary from 15% to 93%, with an estimated mean adherence rate of 50%.1 The consequences of nonadherence to medications can be profound, ranging from ineffectiveness of treatment and worsening of disease progression to poor outcomes, disease complications, hospitalizations and rehospitalizations, emergency department visits, and even death. Failure to adhere to medication regimens in the United States may cost as much as $300 billion annually.2 The association between increased medication adherence and decreased health care service utilization and costs is well known.3 Among the many factors affecting adherence to therapy are patient demographic characteristics, the costs of medications, the nature of the underlying chronic conditions, and the presence of comorbidities.4,5 Although there have been many studies of adherence rates in populations with chronic disease, problems inherent to medication adherence research remain. This editorial focuses on some of these inherent methodologic issues and challenges. Definitions and applications of the term adherence continue to be inconsistent, despite extensive research directed toward understanding and evaluating the concept. Adherence to medication therapy can be defined as the extent to which a person’s medication-taking behavior coincides with medical advice,6 or the patient’s level of participation once he or she has agreed to the prescribed regimen.7 Adherence is often used interchangeably with the term compliance, which has an authoritative connotation and focuses more on the doctor–patient relationship. Medication adherence is the active and voluntary role played by patients in an ongoing process.7 Intrinsic to its definition is the understanding that it is based on a motivation component. Studies conducted to examine medication adherence should incorporate a theoretical framework that appropriately isolates the construct of adherence. Medication-taking behavior integrates various psychological, interpersonal, and social processes.8 Among psychological and social–cognitive models that provide a framework for understanding the complex phenomenon of adherence, as well as providing tools for reinforcing positive behavior, are the health belief model,9 the theories of reasoned action and planned behavior,10 the health locus of control,11 the self-efficacy theory,12,13 the social cognitive theory,14 and the transtheoretical model.14 Medication adherence is often assessed using cross-sectional study designs that represent a “then–present” scenario rather than capturing actual long-term adherence. Medication adherence reflects ever-changing human behavior, and adherence studies should incorporate theoretical mediators as well as moderators of adherence behavior.7 Using a proper theoretical framework aids in understanding these mediators and moderators of adherence behavior and helps in planning intervention strategies based on the determinants of behavioral change. Lack of a “gold standard” for measuring medication adherence continues to impose challenges. There is an urgent need for more appropriate, accurate, patient-friendly, convenient, and cost-effective measures. There are approximately 10 different ways of measuring medication adherence, among them mean adherence, mean squared rate deviation, daily adherence, daily overdosing and underdosing, adherent dosing, late dosing, adherent timing, delayed timing, and premature timing.15 These methods can be grouped into direct and indirect methods. Each of these categories has its pros and cons. Traditionally, direct methods of medication adherence include assaying drug concentrations in blood or urine. Although this strategy gives an exact account of the drug and is not subject to patients’ response bias, it is highly inconvenient and cost-ineffective for patients as well as investigators. Metabolism, rate of absorption, and excretion differ widely across drug entities, raising the question of the validity of readings of drug concentrations in biologic fluids. Such direct methods rely on the accuracy of the test and the extent to which a patient is adherent before the test, which may lead to erroneous results. 1180
Volume 29 Number 6
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Editorial Indirect methods of assessing medication adherence include patient interviews, self-reports, pill counts, refill records, and measurement of health outcomes. Self-reports and patient interviews are inexpensive, but are subject to social desirability/response bias. Patient interviews, self-report questionnaires, logs, and diaries provide inconsistent data and overestimate adherence.16 Also, the accuracy of the results obtained using such methods depends on patients’ cognitive abilities and the honesty of their replies, as well as on interviewers’ interpretations of patients’ responses. Pill counts can be erroneous because patients may not return bottles that have pills remaining or may throw away remaining pills in order to show adherence. Electronic monitoring methods employ a microprocessor lodged in the cap of the pill bottle that records the time and date that a dose is taken without patients being aware of it. A major assumption underlying this method is that medication is taken whenever the pill bottle is opened. Limitations of this method include the cost of the monitors and the impracticality of their use.17 Most studies in the adherence arena have resorted to use of a more reliable method of adherence assessment: pharmacy prescription refill records.18 Measurement of adherence using pharmacy prescription refill records provides information on the frequency and timeliness of refills of prescribed medication. This is a very inexpensive way of prospectively or retrospectively evaluating adherence without the explicit knowledge of the patient, in that it avoids the Hawthorne effect. This method is considered questionable for assessing dosing adherence, as there is no information on the quantity taken or the timing of intake. Drawbacks include the difficulties of classifying unusual refill patterns, measuring adherence in patients with access to multiple pharmacies, relying on correct coding of the days’ supply of medication (which may become difficult in the case of inhaled and injectable medications), and assuming that “a prescription filled is a prescription taken.” Despite the availability of different methods for measuring adherence, there exist challenges with respect to the measurement of adherence itself. Adherence is inconsistently and inappropriately measured as a dichotomous variable, with yes equaling adherent and no equaling nonadherent. A continuous scale should be employed to ensure that all possible variations and levels of adherence are adequately assessed. The phenomenon of medication adherence is an important link between the process and outcome frameworks of research studies.19 The distinction between the process-oriented and outcomes-oriented approaches often is not clearly stated. It is important to consider whether the outcome of the study is adherence or nonadherence. For example, in the case of a chronic disease such as diabetes, medication adherence rates for maintaining a normal blood glucose level may be different from those that would signal nonadherence leading to unwanted consequences. Researchers recognize the importance and impact of cultural beliefs and the social environment on adherence behavior. However, these factors have not been incorporated into studies measuring adherence, mainly because doing so remains a challenge. An obvious issue that requires attention is how to distinguish the objective study environment from the environment as perceived by the patient. Although randomized clinical trials offer a high amount of control, they fail to capture the real-world scenario in which patients usually undertake their health behavior.7 All of this emphasizes the importance of conducting community-based research studies, which may lend external validity. This calls for collaboration between researchers and the health professionals (eg, physicians, pharmacists, nurses) who are in constant contact with patients. Most interventions are broad based and are applied to all patients.19 To achieve better outcomes with adherence interventions, it would be helpful to tailor the methods to the needs of patients. Each patient has a unique medication-related profile that calls for a combination of strategies. Intervention strategies can be broadly classified into 4 major categories: patient education, improved dosing schedules, increased clinic hours, and improved communication between physicians and patients.20 Education of family members has proven to be effective in improving adherence.21 Methods for improving the dosing schedule include unit-of-use packaging, pill organizers, and patient reminders. The novel calendar blister-pack was reported to have beneficial effects on drug adherence in a geriatric outpatient clinic.22 Blister-pack and unit-of-use packaging have been associated with good adherence.23 Peterson et al24 conducted a meta-analysis of 61 randomized studies of interventions to improve medication adherence and found increases in adherence ranging from 4% to 11%, although no single strategy appeared to be the clear winner. Theory-based interventions should be designed to include multiple assessment time points and to include change variables in the model.7 June 2007
1181
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Clinical Therapeutics Medication adherence should be recognized as a multifaceted behavior, requiring the development of better conceptual and analytical frameworks to study adherence in chronic disease populations. Medication adherence research should incorporate all interacting aspects to better capture the true rate of adherence in those with chronic disease conditions and to allow design of adherence-enhancing intervention strategies that focus on the core problem. Better measures of medication adherence are needed that are both cost-effective and take into account unusual refill patterns, use of multiple medications, and unique medication technologies. Medication adherence–improving interventions that take a multidisciplinary strategic approach promise a valuable and efficient tool in this regard. Rajesh Balkrishnan, PhD Sujata S. Jayawant, MS Department of Pharmacy Practice and Administration The Ohio State University Columbus, Ohio
REFERENCES 1. Singh N, Squier C, Sivek C, et al. Determinants of compliance with antiretroviral therapy in patients with human immunodeficiency virus: Prospective assessment with implications for enhancing compliance. AIDS Care. 1996;8:261–269. 2. Bender BG, Rand C. Medication non-adherence and asthma treatment cost. Curr Opin Allergy Clin Immunol. 2004;4:191–195. 3. Aday LA, Begley CE, Lairson DR, et al. Evaluating the Healthcare System: Effectiveness, Efficiency, and Equity. 3rd ed. Ann Arbor, Mich: Health Administration Press; 2004. 4. Balkrishnan R. Predictors of medication adherence in the elderly. Clin Ther. 1998;20:764–771. 5. Ickovics JR, Meisler AW. Adherence in AIDS clinical trials: A framework for research and clinical care. J Clin Epidemiol. 1997; 50:385–391. 6. Haynes RB. Introduction. In: Haynes RB, Taylor DW, Sackett DL, eds. Compliance in Health Care. Baltimore, Md: Johns Hopkins University Press; 1979:1–7. 7. Mihalko SL, Brenes GA, Farmer DF, et al. Challenges and innovations in enhancing adherence. Control Clin Trials. 2004;25: 447–457. 8. Morris LS, Schulz RM. Medication compliance: The patient’s perspective. Clin Ther. 1993;15:593–606. 9. Rosenstock IM. Why people use health services. Milbank Mem Fund Q. 1996;44(Suppl):94–127. 10. Baranowski T, Anderson C, Carmack C. Mediating variable framework in physical activity interventions. How are we doing? How might we do better [published correction appears in Am J Prev Med. 1999;17:98]? Am J Prev Med. 1998;15:266–297. 11. Wallston KA. Hocus-pocus, the focus isn’t strictly on locus: Rotter’s social learning theory modified for health. Cogn Ther Res. 1992;16:183–199. 12. Bandura A. Self-efficacy: Toward a unifying theory of behavioral change. Psychol Rev. 1977;84:191–215. 13. Bandura A. Self-Efficacy: The Exercise of Control. New York, NY: W.H. Freeman and Company; 1997. 14. Prochaska JO, DiClemente CC. Stages of change in the modification of problem behaviors. In: Hersen M, Miller PM, Eisler RM, eds. Progress in Behavior Modification. Vol 28. Sycamore, Ill: Sycamore; 1992:184–218. 15. Feinstein AR. On white-coat effects and the electronic monitoring of compliance. Arch Intern Med. 1990;150:1377–1378. 16. Urquhart J. Role of patient compliance in clinical pharmacokinetics. A review of recent research. Clin Pharmacokinet. 1994;27: 202–215. 17. Farmer KC. Methods for measuring and monitoring medication regimen adherence in clinical trials and clinical practice. Clin Ther. 1999;21:1074–1090. 18. Vermeire E, Hearnshaw H, Van Royen P, Denekens J. Patient adherence to treatment: Three decades of research. A comprehensive review. J Clin Pharm Ther. 2001;26:331–342. 19. Horne R, Clatworthy J, Polmear A, et al, for the Anglo-Scandinavian Cardiac Outcomes Trial. Do hypertensive patients’ beliefs about their illness and treatment influence medication adherence and quality of life. J Hum Hypertens. 2001;15(Suppl 1):S65–S68. 20. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353:487–497. 21. Patton K, Meyers J, Lewis BE. Enhancement of compliance among patients with hypertension. Am J Manag Care. 1997;3: 1693–1698. 22. Wong BS, Norman DC. Evaluation of a novel medication aid, the calendar blister-pack, and its effect on drug compliance in a geriatric outpatient clinic. J Am Geriatr Soc. 1987;35:21–26.
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Editorial 23. Murray MD, Birt JA, Manatunga AK, Darnell JC. Medication compliance in elderly outpatients using twice-daily dosing and unit-of-use packaging. Ann Pharmacother. 1993;27:616–621. 24. Peterson AM, Takiya L, Finley R. Meta-analysis of trials of interventions to improve medication adherence. Am J Health Syst Pharm. 2003;60:657–665.
doi:10.1016/j.clinthera.2007.06.008
June 2007
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6/29/07
10:00 AM
Page 1180
Clinical Therapeutics/Volume 29, Number 6, 2007
Editorial Medication Adherence Research in Populations: Measurement Issues and Other Challenges Medication nonadherence is a recognized public health problem in the United States, particularly in patient populations with chronic diseases. Adherence to medications is crucial to the treatment of chronic conditions, which often require that patients be on controller maintenance medications. Rates of nonadherence to treatment with any medication have been reported to vary from 15% to 93%, with an estimated mean adherence rate of 50%.1 The consequences of nonadherence to medications can be profound, ranging from ineffectiveness of treatment and worsening of disease progression to poor outcomes, disease complications, hospitalizations and rehospitalizations, emergency department visits, and even death. Failure to adhere to medication regimens in the United States may cost as much as $300 billion annually.2 The association between increased medication adherence and decreased health care service utilization and costs is well known.3 Among the many factors affecting adherence to therapy are patient demographic characteristics, the costs of medications, the nature of the underlying chronic conditions, and the presence of comorbidities.4,5 Although there have been many studies of adherence rates in populations with chronic disease, problems inherent to medication adherence research remain. This editorial focuses on some of these inherent methodologic issues and challenges. Definitions and applications of the term adherence continue to be inconsistent, despite extensive research directed toward understanding and evaluating the concept. Adherence to medication therapy can be defined as the extent to which a person’s medication-taking behavior coincides with medical advice,6 or the patient’s level of participation once he or she has agreed to the prescribed regimen.7 Adherence is often used interchangeably with the term compliance, which has an authoritative connotation and focuses more on the doctor–patient relationship. Medication adherence is the active and voluntary role played by patients in an ongoing process.7 Intrinsic to its definition is the understanding that it is based on a motivation component. Studies conducted to examine medication adherence should incorporate a theoretical framework that appropriately isolates the construct of adherence. Medication-taking behavior integrates various psychological, interpersonal, and social processes.8 Among psychological and social–cognitive models that provide a framework for understanding the complex phenomenon of adherence, as well as providing tools for reinforcing positive behavior, are the health belief model,9 the theories of reasoned action and planned behavior,10 the health locus of control,11 the self-efficacy theory,12,13 the social cognitive theory,14 and the transtheoretical model.14 Medication adherence is often assessed using cross-sectional study designs that represent a “then–present” scenario rather than capturing actual long-term adherence. Medication adherence reflects ever-changing human behavior, and adherence studies should incorporate theoretical mediators as well as moderators of adherence behavior.7 Using a proper theoretical framework aids in understanding these mediators and moderators of adherence behavior and helps in planning intervention strategies based on the determinants of behavioral change. Lack of a “gold standard” for measuring medication adherence continues to impose challenges. There is an urgent need for more appropriate, accurate, patient-friendly, convenient, and cost-effective measures. There are approximately 10 different ways of measuring medication adherence, among them mean adherence, mean squared rate deviation, daily adherence, daily overdosing and underdosing, adherent dosing, late dosing, adherent timing, delayed timing, and premature timing.15 These methods can be grouped into direct and indirect methods. Each of these categories has its pros and cons. Traditionally, direct methods of medication adherence include assaying drug concentrations in blood or urine. Although this strategy gives an exact account of the drug and is not subject to patients’ response bias, it is highly inconvenient and cost-ineffective for patients as well as investigators. Metabolism, rate of absorption, and excretion differ widely across drug entities, raising the question of the validity of readings of drug concentrations in biologic fluids. Such direct methods rely on the accuracy of the test and the extent to which a patient is adherent before the test, which may lead to erroneous results. 1180
Volume 29 Number 6
1180_ED_balkrishnan
6/29/07
10:00 AM
Page 1181
Editorial Indirect methods of assessing medication adherence include patient interviews, self-reports, pill counts, refill records, and measurement of health outcomes. Self-reports and patient interviews are inexpensive, but are subject to social desirability/response bias. Patient interviews, self-report questionnaires, logs, and diaries provide inconsistent data and overestimate adherence.16 Also, the accuracy of the results obtained using such methods depends on patients’ cognitive abilities and the honesty of their replies, as well as on interviewers’ interpretations of patients’ responses. Pill counts can be erroneous because patients may not return bottles that have pills remaining or may throw away remaining pills in order to show adherence. Electronic monitoring methods employ a microprocessor lodged in the cap of the pill bottle that records the time and date that a dose is taken without patients being aware of it. A major assumption underlying this method is that medication is taken whenever the pill bottle is opened. Limitations of this method include the cost of the monitors and the impracticality of their use.17 Most studies in the adherence arena have resorted to use of a more reliable method of adherence assessment: pharmacy prescription refill records.18 Measurement of adherence using pharmacy prescription refill records provides information on the frequency and timeliness of refills of prescribed medication. This is a very inexpensive way of prospectively or retrospectively evaluating adherence without the explicit knowledge of the patient, in that it avoids the Hawthorne effect. This method is considered questionable for assessing dosing adherence, as there is no information on the quantity taken or the timing of intake. Drawbacks include the difficulties of classifying unusual refill patterns, measuring adherence in patients with access to multiple pharmacies, relying on correct coding of the days’ supply of medication (which may become difficult in the case of inhaled and injectable medications), and assuming that “a prescription filled is a prescription taken.” Despite the availability of different methods for measuring adherence, there exist challenges with respect to the measurement of adherence itself. Adherence is inconsistently and inappropriately measured as a dichotomous variable, with yes equaling adherent and no equaling nonadherent. A continuous scale should be employed to ensure that all possible variations and levels of adherence are adequately assessed. The phenomenon of medication adherence is an important link between the process and outcome frameworks of research studies.19 The distinction between the process-oriented and outcomes-oriented approaches often is not clearly stated. It is important to consider whether the outcome of the study is adherence or nonadherence. For example, in the case of a chronic disease such as diabetes, medication adherence rates for maintaining a normal blood glucose level may be different from those that would signal nonadherence leading to unwanted consequences. Researchers recognize the importance and impact of cultural beliefs and the social environment on adherence behavior. However, these factors have not been incorporated into studies measuring adherence, mainly because doing so remains a challenge. An obvious issue that requires attention is how to distinguish the objective study environment from the environment as perceived by the patient. Although randomized clinical trials offer a high amount of control, they fail to capture the real-world scenario in which patients usually undertake their health behavior.7 All of this emphasizes the importance of conducting community-based research studies, which may lend external validity. This calls for collaboration between researchers and the health professionals (eg, physicians, pharmacists, nurses) who are in constant contact with patients. Most interventions are broad based and are applied to all patients.19 To achieve better outcomes with adherence interventions, it would be helpful to tailor the methods to the needs of patients. Each patient has a unique medication-related profile that calls for a combination of strategies. Intervention strategies can be broadly classified into 4 major categories: patient education, improved dosing schedules, increased clinic hours, and improved communication between physicians and patients.20 Education of family members has proven to be effective in improving adherence.21 Methods for improving the dosing schedule include unit-of-use packaging, pill organizers, and patient reminders. The novel calendar blister-pack was reported to have beneficial effects on drug adherence in a geriatric outpatient clinic.22 Blister-pack and unit-of-use packaging have been associated with good adherence.23 Peterson et al24 conducted a meta-analysis of 61 randomized studies of interventions to improve medication adherence and found increases in adherence ranging from 4% to 11%, although no single strategy appeared to be the clear winner. Theory-based interventions should be designed to include multiple assessment time points and to include change variables in the model.7 June 2007
1181
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10:00 AM
Page 1182
Clinical Therapeutics Medication adherence should be recognized as a multifaceted behavior, requiring the development of better conceptual and analytical frameworks to study adherence in chronic disease populations. Medication adherence research should incorporate all interacting aspects to better capture the true rate of adherence in those with chronic disease conditions and to allow design of adherence-enhancing intervention strategies that focus on the core problem. Better measures of medication adherence are needed that are both cost-effective and take into account unusual refill patterns, use of multiple medications, and unique medication technologies. Medication adherence–improving interventions that take a multidisciplinary strategic approach promise a valuable and efficient tool in this regard. Rajesh Balkrishnan, PhD Sujata S. Jayawant, MS Department of Pharmacy Practice and Administration The Ohio State University Columbus, Ohio
REFERENCES 1. Singh N, Squier C, Sivek C, et al. Determinants of compliance with antiretroviral therapy in patients with human immunodeficiency virus: Prospective assessment with implications for enhancing compliance. AIDS Care. 1996;8:261–269. 2. Bender BG, Rand C. Medication non-adherence and asthma treatment cost. Curr Opin Allergy Clin Immunol. 2004;4:191–195. 3. Aday LA, Begley CE, Lairson DR, et al. Evaluating the Healthcare System: Effectiveness, Efficiency, and Equity. 3rd ed. Ann Arbor, Mich: Health Administration Press; 2004. 4. Balkrishnan R. Predictors of medication adherence in the elderly. Clin Ther. 1998;20:764–771. 5. Ickovics JR, Meisler AW. Adherence in AIDS clinical trials: A framework for research and clinical care. J Clin Epidemiol. 1997; 50:385–391. 6. Haynes RB. Introduction. In: Haynes RB, Taylor DW, Sackett DL, eds. Compliance in Health Care. Baltimore, Md: Johns Hopkins University Press; 1979:1–7. 7. Mihalko SL, Brenes GA, Farmer DF, et al. Challenges and innovations in enhancing adherence. Control Clin Trials. 2004;25: 447–457. 8. Morris LS, Schulz RM. Medication compliance: The patient’s perspective. Clin Ther. 1993;15:593–606. 9. Rosenstock IM. Why people use health services. Milbank Mem Fund Q. 1996;44(Suppl):94–127. 10. Baranowski T, Anderson C, Carmack C. Mediating variable framework in physical activity interventions. How are we doing? How might we do better [published correction appears in Am J Prev Med. 1999;17:98]? Am J Prev Med. 1998;15:266–297. 11. Wallston KA. Hocus-pocus, the focus isn’t strictly on locus: Rotter’s social learning theory modified for health. Cogn Ther Res. 1992;16:183–199. 12. Bandura A. Self-efficacy: Toward a unifying theory of behavioral change. Psychol Rev. 1977;84:191–215. 13. Bandura A. Self-Efficacy: The Exercise of Control. New York, NY: W.H. Freeman and Company; 1997. 14. Prochaska JO, DiClemente CC. Stages of change in the modification of problem behaviors. In: Hersen M, Miller PM, Eisler RM, eds. Progress in Behavior Modification. Vol 28. Sycamore, Ill: Sycamore; 1992:184–218. 15. Feinstein AR. On white-coat effects and the electronic monitoring of compliance. Arch Intern Med. 1990;150:1377–1378. 16. Urquhart J. Role of patient compliance in clinical pharmacokinetics. A review of recent research. Clin Pharmacokinet. 1994;27: 202–215. 17. Farmer KC. Methods for measuring and monitoring medication regimen adherence in clinical trials and clinical practice. Clin Ther. 1999;21:1074–1090. 18. Vermeire E, Hearnshaw H, Van Royen P, Denekens J. Patient adherence to treatment: Three decades of research. A comprehensive review. J Clin Pharm Ther. 2001;26:331–342. 19. Horne R, Clatworthy J, Polmear A, et al, for the Anglo-Scandinavian Cardiac Outcomes Trial. Do hypertensive patients’ beliefs about their illness and treatment influence medication adherence and quality of life. J Hum Hypertens. 2001;15(Suppl 1):S65–S68. 20. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353:487–497. 21. Patton K, Meyers J, Lewis BE. Enhancement of compliance among patients with hypertension. Am J Manag Care. 1997;3: 1693–1698. 22. Wong BS, Norman DC. Evaluation of a novel medication aid, the calendar blister-pack, and its effect on drug compliance in a geriatric outpatient clinic. J Am Geriatr Soc. 1987;35:21–26.
1182
Volume 29 Number 6
1180_ED_balkrishnan
6/29/07
10:00 AM
Page 1183
Editorial 23. Murray MD, Birt JA, Manatunga AK, Darnell JC. Medication compliance in elderly outpatients using twice-daily dosing and unit-of-use packaging. Ann Pharmacother. 1993;27:616–621. 24. Peterson AM, Takiya L, Finley R. Meta-analysis of trials of interventions to improve medication adherence. Am J Health Syst Pharm. 2003;60:657–665.
doi:10.1016/j.clinthera.2007.06.008
June 2007
1183