Adherence to medications: insights arising from studies on the unreliable link between prescribed and actual drug dosing histories.

Satisfactory adherence to aptly prescribed medications is essential for good outcomes of patient care and reliable evaluation of competing modes of drug treatment. The measure of satisfactory adherence is a dosing history that includes timely initiation of dosing plus punctual and persistent execution of the dosing regimen throughout the specified duration of treatment. Standardized terminology for initiation, execution, and persistence of drug dosing is essential for clarity of communication and scientific progress. Electronic methods for compiling drug dosing histories are now the recognized standard for quantifying adherence, the parameters of which support model-based, continuous projections of drug actions and concentrations in plasma that are confirmable by intermittent, direct measurements at single time points. The frequency of inadequate adherence is usually underestimated by pre-electronic methods and thus is clinically unrecognized as a frequent cause of failed treatment or underestimated effectiveness. Intermittent lapses in dosing are potential sources of toxicity through hazardous rebound effects or recurrent first-dose effects.

[1]  C. Sutton,et al.  Accurate assessment of adherence: self-report and clinician report vs electronic monitoring of nebulizers. , 2011, Chest.

[2]  J Urquhart,et al.  Effects on blood pressure and cardiovascular risk of variations in patients’ adherence to prescribed antihypertensive drugs: role of duration of drug action , 2011, International journal of clinical practice.

[3]  P. Weiden,et al.  Measurement of psychiatric treatment adherence. , 2010, Journal of psychosomatic research.

[4]  I. Wilson Adherence, Placebo Effects, and Mortality , 2010, Journal of general internal medicine.

[5]  J. Urquhart,et al.  Understanding Forgiveness: Minding and Mining the Gaps Between Pharmacokinetics and Therapeutics , 2010, Clinical pharmacology and therapeutics.

[6]  Els Goetghebeur,et al.  A structural mean model to allow for noncompliance in a randomized trial comparing 2 active treatments , 2010, Biostatistics.

[7]  D. Marin,et al.  Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  Steven Pearson,et al.  Relative efficacy of drugs: an emerging issue between regulatory agencies and third-party payers , 2010, Nature Reviews Drug Discovery.

[9]  C. Vogeli,et al.  Primary Medication Non-Adherence: Analysis of 195,930 Electronic Prescriptions , 2010, Journal of General Internal Medicine.

[10]  L. Osterberg,et al.  Electronic monitoring of patient adherence to oral antihypertensive medical treatment: a systematic review , 2009, Journal of hypertension.

[11]  D. Morrow,et al.  Factors Associated With Exacerbation of Heart Failure Include Treatment Adherence and Health Literacy Skills , 2009, Clinical pharmacology and therapeutics.

[12]  J. Trussell Understanding contraceptive failure. , 2009, Best practice & research. Clinical obstetrics & gynaecology.

[13]  T. Nevins,et al.  Quantitative Patterns of Azathioprine Adherence After Renal Transplantation , 2009, Transplantation.

[14]  R. Altman,et al.  Estimation of the warfarin dose with clinical and pharmacogenetic data. , 2009, The New England journal of medicine.

[15]  B. Vrijens,et al.  “White Coat Compliance” Limits the Reliability of Therapeutic Drug Monitoring in HIV-1—Infected Patients , 2008, HIV clinical trials.

[16]  D. Goff,et al.  Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. , 2008, Circulation.

[17]  B. Vrijens,et al.  Decreased adherence to antiretroviral therapy observed prior to transient human immunodeficiency virus type 1 viremia. , 2007, The Journal of infectious diseases.

[18]  J. Cramer,et al.  Methods for integrating medication compliance and persistence in pharmacoeconomic evaluations. , 2007, Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research.

[19]  Wanzhu Tu,et al.  Pharmacist Intervention to Improve Medication Adherence in Heart Failure , 2007, Annals of Internal Medicine.

[20]  J. Urquhart,et al.  Estimation of the comparative therapeutic superiority of QD and BID dosing regimens, based on integrated analysis of dosing history data and pharmacokinetics , 2007, Journal of Pharmacokinetics and Pharmacodynamics.

[21]  Honghu Liu Repeated Measures Longitudinal Analyses of HIV Virologic Response as a Function of Percent Adherence, Dose Timing, Genotypic Sensitivity, and Other Factors , 2006, Journal of acquired immune deficiency syndromes.

[22]  E. Lesaffre,et al.  Effect of intervention through a pharmaceutical care program on patient adherence with prescribed once‐daily atorvastatin , 2006, Pharmacoepidemiology and drug safety.

[23]  Els Goetghebeur,et al.  Modelling the association between adherence and viral load in HIV‐infected patients , 2005, Statistics in medicine.

[24]  L. Osterberg,et al.  Adherence to medication. , 2005, The New England journal of medicine.

[25]  K. Charalabopoulos,et al.  Withdrawal syndrome following cessation of antihypertensive drug therapy , 2005, International journal of clinical practice.

[26]  John Urquhart,et al.  Successful Projection of the Time Course of Drug Concentration in Plasma During a 1‐Year Period From Electronically Compiled Dosing‐Time Data Used as Input to Individually Parameterized Pharmacokinetic Models , 2005, Journal of clinical pharmacology.

[27]  Jingwei Wu,et al.  Association Between Adherence Measurements of Metoprolol and Health Care Utilization in Older Patients with Heart Failure , 2005, Clinical pharmacology and therapeutics.

[28]  E. Goetghebeur,et al.  Structural Mean Effects of Noncompliance , 2004 .

[29]  G. D. Johnston,et al.  Comparison of the effects of a 7-day period of non-compliance on blood pressure control using three different antihypertensive agents , 2004, Journal of hypertension.

[30]  D. Bangsberg,et al.  Modeling the HIV protease inhibitor adherence-resistance curve by use of empirically derived estimates. , 2004, The Journal of infectious diseases.

[31]  A. Struthers,et al.  Furosemide responsiveness, non-adherence and resistance during the chronic treatment of heart failure: a longitudinal study. , 2004, British journal of clinical pharmacology.

[32]  Els Goetghebeur,et al.  Electronic monitoring of variation in drug intakes can reduce bias and improve precision in pharmacokinetic/pharmacodynamic population studies , 2004, Statistics in medicine.

[33]  Richard I. Goldberg,et al.  Acute myocardial infarction as a complication of clonidine withdrawal. , 2003, The Journal of emergency medicine.

[34]  A. Hoes,et al.  Effect of a pharmacist-led intervention on diuretic compliance in heart failure patients: a randomized controlled study. , 2003, Journal of cardiac failure.

[35]  M. Burnier,et al.  Monitoring compliance in resistant hypertension: an important step in patient management. , 2003, Journal of hypertension. Supplement : official journal of the International Society of Hypertension.

[36]  A. Hoes,et al.  Patterns of pharmacotherapy in patients hospitalised for congestive heart failure , 2003, European journal of heart failure.

[37]  Jerry Avorn,et al.  Nonadherence to adjuvant tamoxifen therapy in women with primary breast cancer. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[38]  J. Urquhart History-Informed Perspectives on the Modeling and Simulation of Therapeutic Drug Actions , 2002 .

[39]  Carl Peck,et al.  Postmarketing drug dosage changes of 499 FDA‐approved new molecular entities, 1980–1999 , 2002, Pharmacoepidemiology and drug safety.

[40]  John Urquhart,et al.  Changes in prescribed drug doses after market introduction , 2002, Pharmacoepidemiology and drug safety.

[41]  F. Dobbels,et al.  Profiles of Patients Who Experienced a Late Acute Rejection Due to Nonadherence with Immunosuppressive Therapy , 2001, The Journal of cardiovascular nursing.

[42]  A. Zolopa,et al.  Non-adherence to highly active antiretroviral therapy predicts progression to AIDS. , 2001, AIDS.

[43]  S. Tsutsui A Double-Blind Comparative Study of Zolpidem versus Zopiclone in the Treatment of Chronic Primary Insomnia , 2001, The Journal of international medical research.

[44]  M. Burnier,et al.  Electronic compliance monitoring in resistant hypertension: the basis for rational therapeutic decisions , 2001, Journal of hypertension.

[45]  B. Prichard,et al.  I1 imidazoline agonists. General clinical pharmacology of imidazoline receptors: implications for the treatment of the elderly. , 2000, Drugs & aging.

[46]  Susan Swindells,et al.  Adherence to Protease Inhibitor Therapy and Outcomes in Patients with HIV Infection , 2000, Annals of Internal Medicine.

[47]  John Urquhart,et al.  Pharmacoeconomic Consequences of Variable Patient Compliance With Prescribed Drug Regimens , 1999, PharmacoEconomics.

[48]  Urquhart Pharmacodynamics of variable patient compliance: implications for pharmaceutical value. , 1998, Advanced drug delivery reviews.

[49]  P. Moons,et al.  Late acute rejection and subclinical noncompliance with cyclosporine therapy in heart transplant recipients. , 1998, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[50]  M. Fava,et al.  Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial , 1998, Biological Psychiatry.

[51]  E. Garland,et al.  Reviews : Pharmacotherapy of adolescent attention deficit hyperactivity disorder: challenges, choices and caveats , 1998, Journal of psychopharmacology.

[52]  J Urquhart,et al.  Contending paradigms for the interpretation of data on patient compliance with therapeutic drug regimens. , 1998, Statistics in medicine.

[53]  B Vrijens,et al.  Comparing compliance patterns between randomized treatments. , 1997, Controlled clinical trials.

[54]  L B Sheiner,et al.  Learning versus confirming in clinical drug development , 1997, Clinical pharmacology and therapeutics.

[55]  T F Blaschke,et al.  Patient compliance and drug failure in protease inhibitor monotherapy. , 1996, JAMA.

[56]  C. Rand,et al.  Noncompliance and treatment failure in children with asthma. , 1996, The Journal of allergy and clinical immunology.

[57]  R. Carney,et al.  A multidisciplinary intervention to prevent the readmission of elderly patients with congestive heart failure. , 1995, The New England journal of medicine.

[58]  C Desforges,et al.  Dose Frequency and Dose Interval Compliance with Multiple Antiepileptic Medications During a Controlled Clinical Trial , 1995, Epilepsia.

[59]  D. Rubin,et al.  Intention‐to‐treat analysis and the goals of clinical trials , 1995, Clinical pharmacology and therapeutics.

[60]  Brian F. Johnson,et al.  A STUDY DESIGN FOR COMPARING THE EFFECTS OF MISSING DAILY DOSES OF ANTIHYPERTENSIVE DRUGS , 1994, American journal of therapeutics.

[61]  S. Weis,et al.  The effect of directly observed therapy on the rates of drug resistance and relapse in tuberculosis. , 1994, The New England journal of medicine.

[62]  K. Calzone,et al.  Adherence to oral tamoxifen: a comparison of patient self-report, pill counts, and microelectronic monitoring. , 1993, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[63]  Christopher J. L. Murray,et al.  Tuberculosis: Commentary on a Reemergent Killer , 1992, Science.

[64]  C. Cox,et al.  Prediction of Diltiazem Plasma Concentration Curves From Limited Measurements Using Compliance Data , 1992, Clinical pharmacokinetics.

[65]  J. Cramer Medication compliance in epilepsy. , 1991, Archives of internal medicine.

[66]  A R Feinstein,et al.  On white-coat effects and the electronic monitoring of compliance. , 1990, Archives of internal medicine.

[67]  J. Cramer,et al.  Compliance declines between clinic visits. , 1990, Archives of internal medicine.

[68]  J. Cramer,et al.  How often is medication taken as prescribed? A novel assessment technique. , 1989, JAMA.

[69]  J. Huttunen,et al.  Lipid alterations and decline in the incidence of coronary heart disease in the Helsinki Heart Study. , 1988, JAMA.

[70]  M. Houston,et al.  Beta-adrenergic blocker withdrawal syndromes in hypertension and other cardiovascular diseases. , 1988, American heart journal.

[71]  M. Kass,et al.  A miniature compliance monitor for eyedrop medication. , 1984, Archives of ophthalmology.

[72]  S. Langlois,et al.  Comparison of withdrawal phenomena after propranolol, metoprolol and pindolol. , 1982, British journal of clinical pharmacology.

[73]  J. Stewart,et al.  Cardiac hyper‐ and hyporesponsiveness after pindolol withdrawal , 1982, Clinical pharmacology and therapeutics.

[74]  S. Langlois,et al.  Metoprolol withdrawal phenomena: Mechanism and prevention , 1982, Clinical pharmacology and therapeutics.

[75]  M. Houston Abrupt Discontinuation of Antihypertensive Therapy , 1981, Southern medical journal.

[76]  D. Sackett,et al.  Can Simple Clinical Measurements Detect Patient Noncompliance? , 1980, Hypertension.

[77]  T. Blaschke,et al.  Studies on the clinical pharmacology of prazosin. I: Cardiovascular, catecholamine and endocrine changes following a single dose. , 1980, British journal of clinical pharmacology.

[78]  H. F. Wood,et al.  RHEUMATIC FEVER IN CHILDREN AND ADOLESCENTS. A LONG-TERM EPIDEMIOLOGIC STUDY OF SUBSEQUENT PROPHYLAXIS, STREPTOCOCCAL INFECTIONS, AND CLINICAL SEQUELAE. I. DESCRIPTION OF THE INVESTIGATIVE TECHNIQUES AND OF THE POPULATION STUDIED. , 1964, Annals of internal medicine.

[79]  M Christopher Roebuck,et al.  Medication adherence leads to lower health care use and costs despite increased drug spending. , 2011, Health affairs.

[80]  S. Cosgrove,et al.  Antimicrobial stewardship. , 2011, Infectious disease clinics of North America.

[81]  T. Gilmer,et al.  Evaluation of the First Year of a Pilot Program in Community Pharmacy: HIV/AIDS Medication Therapy Management for Medi-Cal Beneficiaries , 2009, Journal of managed care pharmacy : JMCP.

[82]  W. J. Elliott,et al.  Adherence to prescribed antihypertensive drug treatments: longitudinal study of electronically compiled dosing histories , 2009 .

[83]  R B Haynes,et al.  Interventions for enhancing medication adherence. , 2008, The Cochrane database of systematic reviews.

[84]  Haynes Rb,et al.  Interventions for enhancing medication adherence (Review) , 2008 .

[85]  Yingying Ma,et al.  How well do clinicians estimate patients’ adherence to combination antiretroviral therapy? , 2007, Journal of General Internal Medicine.

[86]  G. Chouinard,et al.  Persistent tardive rebound panic disorder, rebound anxiety and insomnia following paroxetine withdrawal: a review of rebound-withdrawal phenomena. , 2006, The Canadian journal of clinical pharmacology = Journal canadien de pharmacologie clinique.

[87]  J. Urquhart How Much Compliance Is Enough? , 2004, Pharmaceutical Research.

[88]  Jeffrey S. Barrett,et al.  Pharmacokinetic/Pharmacodynamic Modeling in Drug Development , 2004 .

[89]  T F Blaschke,et al.  Medication compliance as a feature in drug development. , 1997, Annual review of pharmacology and toxicology.

[90]  S T Cole,et al.  Mechanisms of drug resistance in Mycobacterium tuberculosis. , 1996, Current topics in microbiology and immunology.

[91]  P. Meredith,et al.  Concentration-effect analysis of antihypertensive drug response. Focus on calcium antagonists. , 1994, Clinical pharmacokinetics.

[92]  C. Peck,et al.  Chronobiology. Suggestions for integrating it into drug development. , 1991, Annals of the New York Academy of Sciences.

[93]  Ling-Fu Meng,et al.  Patient Compliance in Medical Practice and Clinical Trials , 1991 .

[94]  J. Guillebaud The forgotten pill--and the paramount importance of the pill-free week. , 1987 .

[95]  Malcolm Rowland,et al.  Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications , 1980 .