Research Article| Volume 31, ISSUE 2, P421-435, February 2009

Download started.


A framework for planning and critiquing medication compliance and persistence research using prospective study designs

      This paper is only available as a PDF. To read, Please Download here.


      Background: Medication compliance and persistence are important determinants of clinical outcomes. With the application of evidence-based therapy, it is increasingly important to ensure that studies that use compliance or persistence as a primary or secondary outcome are designed suitably and employ appropriate analyses to support the inferences made.
      Objective: The aim of this work was to describe the designs of medication compliance/persistence studies and provide guidance on appropriate analyses, with the ultimate goal of helping health providers and payers of health care understand the impact of compliance and persistence on health outcomes.
      Methods: MEDLINE, CINAHL, EMBASE, and all EBM Reviews databases were searched to locate key research articles about prospective medication compliance and persistence studies. Articles published between 1978 and 2008 were included in the search. Inclusion criteria included a focus on medication compliance and persistence, and prospective research designs. Articles that largely focused on retrospective study designs or were based on opinion rather than evidence were excluded.
      Results: A systematic framework was developed that comprised a prospective checklist and a quantitative tool to assess the quality of studies. The key elements of the checklist included the following: title and abstract, introduction or background, objectives, methods and study design, statistical analysis and results, discussion, conclusions, and disclosure of conflicts of interest. For each element, examples are provided to help readers make an informed decision about the design, value, and quality of a particular prospective study.
      Conclusions: The checklist and quantitative tool can be used to provide objective validation of the rigor of prospective research designs. It is anticipated that future research will follow a uniform approach to presentation and evaluation of data, thereby facilitating a clear understanding of the impact of compliance and persistence on health outcomes.

      Key words:

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Clinical Therapeutics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Guyatt GH
        • Haynes RB
        • Jaeschke RZ
        • et al.
        • for the Evidence-Based Medicine Working Group
        Users' Guides to the Medical Literature: XXV. Evidence-based medicine: Principles for applying the Users' Guides to patient care.
        JAMA. 2000; 284: 1290-1296
        • Guyatt G
        • Rennie D
        • Meade M
        • Cook D
        Users' Guides to the Medical Literature: A Manual for Evidence-Based Clinical Practice. 2nd ed. McGraw-Hill, New York, NY2008
        • Friedman LM
        • Furberg CD
        • DeMets DL
        Fundamentals of Clinical Trials. 2nd ed. PSG Publishing, Littleton, MA1985
        • Peterson AM
        • Nau DP
        • Cramer JA
        • et al.
        A checklist for medication compliance and persistence studies using retrospective databases.
        Value Health. 2007; 10: 3-12
      1. National Cancer Institute. Theory at a Glance: A Guide for Health Promotion Practice [National Cancer Institute Web site].

      2. (Accessed)
        • Glanz K
        • Rimer BK
        • Lewis FM
        Health Behavior and Health Education: Theory, Research, and Practice. 3rd ed. Jossey-Bass, San Francisco, CA2002
        • Adams J
        • Scott J
        Predicting medication adherence in severe mental disorders.
        Acta Psychiatr Scand. 2000; 101: 119-124
        • Scott J
        Using Health Belief Models to understand the efficacy-effectiveness gap for mood stabilizer treatments.
        Neuropsychobiology. 2002; 46: 13-15
        • Steele RG
        • Anderson B
        • Rindel B
        • et al.
        Adherence to antiretroviral therapy among HIV-positive children: Examination of the role of caregiver health beliefs.
        AIDS Care. 2001; 13: 617-629
        • Ogden J
        Health Psychology: A Textbook. 2nd ed. Open University Press, Buckingham, UK2000
        • Edwards W
        The theory of decision making.
        Psychol Bull. 1954; 51: 380-417
        • Whitehead D
        A social cognitive model for health education/health promotion practice.
        J Adv Nurs. 2001; 36: 417-425
        • Prochaska JO
        • DiClemente CC
        • Norcross JC
        In search of how people change. Applications to addictive behaviors.
        Am Psychol. 1992; 47: 1102-1114
      3. Family Health International (FHI). Behavior Change—A Summary of Four Major theories.

      4. (Accessed)
        • Brassington GS
        • Atienza AA
        • Perczek RE
        • et al.
        Intervention-related cognitive versus social mediators of exercise adherence in the elderly.
        Am J Prev Med. 2002; 23: 80-86
        • Conner M
        • Norman P
        A social cognitive approach.
        in: Conner M Norman P Predicting Health Behaviour. Open University Press, New York, NY2005: 170-222
        • Bandura A
        Self-Efficacy: The Exercise of Control. Freeman, New York, NY1997
        • Cramer JA
        • Roy A
        • Burrell A
        • et al.
        Medication compliance and persistence: Terminology and definitions.
        Value Health. 2008; 11: 44-47
        • Montague T
        Merck Frosst Pharmaceutical Report for the British Pharmaceutical Society on Medication Compliance. Merck Frosst Pharmaceutical, Montreal, Quebec, Canada1997
        • Haynes RB
        A critical review of the “determinants” of patient compliance with therapeutic regimens.
        in: Sackett DL Haynes RB Compliance with Therapeutic Regimens. Johns Hopkins University Press, Baltimore, MD1976: 11-22
      5. Burke LE Ockene IS Compliance in Healthcare and Research. Futura Publishing Co, Inc, Armonk, NY2001
        • 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
        • Lash S
        • Harding J
        “Abandoned prescriptions”: A quantitative assessment of their cause.
        J Managed Care Pharm. 1995; 1: 193-199
        • West JA
        • Miller NH
        • Parker KM
        • et al.
        A comprehensive management system for heart failure improves clinical outcomes and reduces medical resource utilization.
        Am J Cardiol. 1997; 79: 58-63
        • DiMatteo MR
        • Lepper HS
        • Croghan TW
        Depression is a risk factor for noncompliance with medical treat ment: Meta-analysis of the effects of anxiety and depression on patient adherence.
        Arch Intern Med. 2000; 160: 2101-2107
        • McDonald HP
        • Garg AX
        • Haynes RB
        Interventions to enhance patient adherence to medication pre scriptions: Scientific review [published correction appears in JAMA. 2003;289:3242].
        JAMA. 2002; 288: 2868-2879
        • DiMatteo MR
        • Giordani PJ
        • Lepper HS
        • Croghan TW
        Patient adherence and medical treatment out comes: A meta-analysis.
        Med Care. 2002; 40: 794-811
        • McDermott MM
        • Schmitt B
        • Wallner E
        Impact of medication nonadherence on coronary heart disease outcomes. A critical review.
        Arch Intern Med. 1997; 157: 1921-1929
      6. Special Report: Interventions to improve patient adherence with medications for chronic cardiovascular disorders.
        TEC Bull (Online). 2003; 20: 30-32
        • Simpson SH
        • Eurich DT
        • Majumdar SR
        • et al.
        A meta-analysis of the association between adherence to drug therapy and mortality.
        BMJ. 2006; 333: 15
        • Elliott RA
        • Barber N
        • Horne R
        Cost-effectiveness of adherence-enhancing interventions: A quality assessment of the evidence.
        Ann Pharmacother. 2005; 39: 508-515
        • The Evidence-Based Medicine Working Group
        Guyatt G Rennie D Users' Guides to the Medical Literature: A Manual for Evidence-Based Clinical Practice. AMA Press, Chicago, IL2002
        • Volume CI
        • Farris KB
        • Kassam R
        • et al.
        Pharmaceutical care research and education project: Patient outcomes.
        J Am Pharm Assoc (Wash). 2001; 41: 411-420
        • Vrijens B
        • Belmans A
        • Matthys K
        • et al.
        Effect of intervention through a pharmaceutical care program on patient adherence with prescribed once-daily atorvastatin.
        Pharmacoepidemiol Drug Saf. 2006; 15: 115-121
        • Cramer JA
        Consequences of intermittent treatment for hypertension: The case for medication compliance and persistence.
        Am J Manag Care. 1998; 4: 1563-1568
        • Gwadry-Sridhar FH
        • Arnold JM
        • Zhang Y
        • et al.
        Pilot study to determine the impact of a multidisciplinary educational intervention in patients hospitalized with heart failure.
        Am Heart J. 2005; 150: 982
      7. CONSORT Group. The CONSORT Statement.

        Date: November 29, 2008
        • Haynes RB
        • Sackett DL
        • Guyatt GH
        • Tugwell P
        Clinical Epidemiology: How to Do Clinical Practice Research. 3rd ed. Lippincott Williams & Wilkins, Philadelphia, PA2006
        • Diggle PJ
        • Liang KY
        • Zeger SL
        Analysis of Longitudinal Data. 2nd ed. Oxford University Press, Oxford, UK2002
        • Moher D
        • Schulz KF
        • Altman DG
        • for the CONSORT GROUP (Consolidated Standards of Reporting Trials)
        The CONSORT statement: Revised recommendations for improving the quality of reports of parallel-group randomized trials.
        Ann Intern Med. 2001; 134: 657-662
        • Altman DG
        • Schulz KF
        • Moher D
        • et al.
        • for the CONSORT GROUP (Consolidated Standards of Reporting Trials)
        The revised CONSORT statement for reporting randomized trials: Explanation and elaboration.
        Ann Intern Med. 2001; 134: 663-694
        • Norman GR
        • Streiner DL
        Biostatistics: The Bare Essentials. 3rd ed. Decker, Hamilton, Ontario, Canada2008
        • Haynes RB
        • Yao X
        • Degani A
        • et al.
        Interventions to enhance medication adherence.
        Cochrane Database Syst Rev. 2005; 4 (CD000011. Update in: Cochrane Database System Rev. 2008;CD000011)
        • Jadad AR
        Randomised Controlled Trials: A User's Guide. BMJ Books, London, UK1998
        • Gehlbach SH
        Interpreting the Medical Literature. McGrawHill, New York, NY2006
        • Qureshi NN
        • Hatcher J
        • Chaturvedi N
        • Jafar TH
        • for the Hypertension Research Group
        Effect of general practitioner education on adherence to antihypertensive drugs: Cluster randomised controlled trial.
        BMJ. 2007; 335: 1030
        • Donner A
        • Klar N
        Design and Analysis of Cluster Randomization Trials in Health Research. Arnold, London, UK2000
        • Mayer D
        Essential Evidence-Based Medicine. Cambridge University Press, New York, NY2004
        • Donner A
        • Klar N
        Pitfalls ofand controversies in cluster randomization trials.
        Am J Public Health. 2004; 94: 416-422
        • Grant RW
        • Devita NG
        • Singer DE
        • Meigs JB
        Polypharmacy and medication adherence in patients with type 2 diabetes.
        Diabetes Care. 2003; 26: 1408-1412
        • Smeeth L
        • Ng ES
        Intraclass correlation coefficients for cluster randomized trials in primary care: Data from the MRC Trial of the Assessment and Management of Older People in the Community.
        Control Clin Trials. 2002; 23: 409-421
        • Hedges LV
        • Hedberg EC
        Intraclass correlation values for planning group randomized trials in education.
        Educ Eval Policy Anal. 2007; 29: 60-87
        • Campbell DT
        • Stanley JC
        Experimental and Quasi-Experimental Designs for Research. R. McNally, Chicago, IL1966
        • Sit JW
        • Yip VY
        • Ko SK
        • et al.
        A quasiexperimental study on a community-based stroke prevention programme for clients with minor stroke.
        J Clin Nurs. 2007; 16: 272-281
        • Gallegos EC
        • Ovalle-Berúmen F
        • Gomez-Meza MV
        Metabolic control of adults with type 2 diabetes mellitus through education and counseling.
        J Nurs Scholarsh. 2006; 38: 344-351
        • Gilbert A
        • Owen N
        • Sansom L
        • Innes JM
        High level of medication compliance and blood pressure control among hypertensive patients attending community pharmacies.
        J Soc Admin Pharm. 1990; 7: 78-83
        • Widmer RB
        • Cadoret RJ
        • Troughton E
        Compliance characteristics of 291 hypertensive patients from a rural midwest area.
        J Fam Pract. 1983; 17: 619-625
        • Mann CJ
        Observational research methods. Research design II: Cohort, cross sectional, and case-control studies.
        Emerg Med J. 2003; 20: 54-60
        • Kottke TE
        • Solbert L
        • Brekke M
        Organizational approaches to improve compliance.
        in: Burke LE Okene IS Compliance in Healthcare and Research. Futura Publishing Co, Armonk, NY2001: 81-90
        • Osterberg L
        • Blaschke T
        Adherence to medication.
        N Engl J Med. 2005; 353: 487-497
        • Streiner DL
        • Norman GR
        Health Measurement Scales: A Practical Guide to Their Development and Use. 2nd ed. Oxford University Press, Oxford, UK1995
        • Haynes RB
        • Ackloo E
        • Sahota N
        • et al.
        Interventions for enhancing medication adherence.
        Cochrane Database Syst Rev. 2008; (CD000011)
        • Kruse W
        Patient compliance with drug treatment—new perspectives on an old problem.
        Clin Investig. 1992; 70: 163-166
        • Steiner JF
        • Prochazka AV
        The assessment of refill compliance using pharmacy records: Methods, validity, and applications.
        J Clin Epidemiol. 1997; 150: 105-116
        • Cramer JA
        Relationship between medication compliance and medical outcomes.
        Am J Health Syst Pharm. 1995; 52: S27-S29
      9. Aardex. The Measurement.

      10. (Accessed)
        • Myers LB
        • Midence K
        Methodological and conceptual issues in adherence.
        in: Myers LB Midence K Adherence to Treatment in Medical Conditions. Harwood Academic, Amsterdam, The Netherlands1998: 1-24
        • Diaz E
        • Levine HB
        • Sullivan MC
        • et al.
        Use of the Medication Event Monitoring System to estimate medication compliance in patients with schizophrenia.
        J Psychiatry Neurosci. 2001; 26: 325-329
        • Vrijens B
        • Vincze G
        • Kristanto P
        • et al.
        Adherence to prescribed antihypertensive drug treatments: Longitudinal study of electronically compiled dosing histories.
        BMJ. 2008; 336: 1114-1117
        • Cramer JA
        • Ouellette VL
        • Mattson RH
        The effect of microelectronic observation on compliance.
        Epilepsia. 1990; 31 (Abstract): 617-618
        • Waterhouse DM
        • Calzone KA
        • Mele C
        • Brenner DE
        Adherence to oral tamoxifen: A comparison of patient self-report, pill counts, and microelectronic monitoring.
        J Clin Oncol. 1993; 11: 1189-1197
        • Matsui D
        • Hermann C
        • Klein J
        • et al.
        Critical comparison of novel and existing methods of compliance assessment during a clinical trial of an oral iron chelator.
        J Clin Pharmacol. 1994; 34: 944-949
        • Burnier M
        • Schneider MP
        • Chioléro A
        • et al.
        Electronic compliance monitoring in resistant hypertension: The basis for rational therapeutic decisions.
        J Hypertens. 2001; 19: 335-341
        • Urquhart J
        The odds of the three nons when an aptly prescribed medicine isn't working: Non-compliance, non-absorption, non-response.
        Br J Clin Pharmacol. 2002; 54: 212-220
      11. Burke LE Ockene IS Compliance in Healthcare and Research. Futura Publishing Company, Armonk, NY2001
        • Rothman KJ
        • Greenland S
        • Lash TL
        Modern Epidemiology. 3rd ed. Lippincott Williams & Wilkins, Philadelphia, PA2008
        • Cabilio P
        • Masaro J
        Biostatistics Part II Data Analysis and Methods: A Workbook Approach. Dept of Mathematics & Statistics, Acadia University, Wolfville, Nova Scotia, Canada2005
        • Hirsch RP
        • Riegelman RK
        Statistical First Aid: Interpretation of Health Research Data. Blackwell Scientific Publications, Boston, MA1992
        • Silverman BW
        Density Estimation for Statistics and Data Analysis. Chapman & Hall/CRC, Boca Raton, FL1998
        • Grubisic M
        Metric Development for Medication Compliance Using a Distribution Approach [master's thesis]. Acadia University, Wolfville, Nova Scotia, Canada2006
      12. Statistics Department of the University of Auckland. The R Project for Statistical Computing 2007 [R Project Web site].

        Date: November 29, 2008
        • Gibbons JD
        • Chakraborti S
        Nonparametric Statistical Inference. 3rd ed. M Dekker, New York, NY1992
        • Yu AP
        • Yu YF
        • Nichol MB
        • Gwadry-Sridhar F
        Delay in filling the initial prescription for a statin: A potential early indicator of medication nonpersistence.
        Clin Ther. 2008; 30: 761-774
        • Zeger SL
        • Liang KY
        • Albert PS
        Models for longitudinal data: A generalized estimating equation approach [published correction appears in Biometrics. 1989;45:347].
        Biometrics. 1988; 44: 1049-1060
        • Smith DM
        • Diggle PJ
        Compliance in an anti-hypertension trial: A latent process model for binary lon gitudinal data.
        Stat Med. 1998; 17: 357-370
        • Girard P
        • Blaschke TF
        • Kastrissios H
        • Sheiner LB
        A Markov mixed effect regression model for drug compliance.
        Stat Med. 1998; 17: 2313-2333
        • Collett D
        Modelling Survival Data in Medical Research. 1st ed. Chapman & Hall, London, UK; New York, NY1994
        • Mielke Jr, PW
        • Berry KJ
        Permutation Methods: A Distance Function Approach. Springer, New York, NY2001
        • Hughes D
        When drugs don't work: Economic assessment of enhancing compliance with interventions supported by electronic monitoring devices.
        PharmacoEconomics. 2007; 25: 621-635
        • Ramsey S
        • Willke R
        • Briggs A
        • et al.
        Good research practices for cost-effectiveness analysis alongside clinical trials: The ISPOR RCT-CEA Task Force report.
        Value Health. 2005; 8: 521-533
        • Hughes D
        • Cowell W
        • Koncz T
        • Cramer J
        • for the International Society for Pharmacoeconomics & Out comes Research Economics of Medication Compliance Working Group
        Methods for integrating medication compliance and persistence in pharmacoeconomic evaluations.
        Value Health. 2007; 10: 498-509
        • Rabin R
        • de Charro F
        EQ-5D: A measure of health status from the EuroQol Group.
        Ann Med. 2001; 33: 337-343
      14. The EuroQol Group. What is EQ5D? EQ-5D is standardised instrument for use as a measure of health outcome [EuroQol Group Web site].

        Date: November 29, 2008
      16. Kind P Brooks R Rabin R EQ-5D Concepts and Methods: A Developmental History. Springer, Dordecht, The Netherlands2005
        • Horsman J
        • Furlong W
        • Feeny D
        • Torrance G
        The Health Utilities Index (HUI®): Concepts, measurement properties and applications.
        Health Qual Life Outcomes. 2008; 1 (Accessed): 1-54
        Date: November 29, 2008
        • Sokol MC
        • McGuigan KA
        • Verbrugge RR
        • Epstein RS
        Impact of medication adherence on hospitalization risk and healthcare cost.
        Med Care. 2005; 43: 521-530