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Some economic consequences of noncompliance

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Abstract

The twin problems of poor compliance and poor persistence with prescribed antihypertensive drug regimens appear to be responsible for much of the huge shortfall in the proportion of hypertensives whose treatment brings their blood pressure down to satisfactory levels. A further problem is the confounding of nonresponse and poor compliance in patients with "drug-resistant hypertension," in that about half of such patients are poor compliers, whose response to simple regimens usually proves satisfactory once their compliance with prescribed regimens is corrected. Electronic means for compiling ambulatory patients’ drug dosing histories have now made it both technically and economically feasible to distinguish clearly between noncompliers and nonresponders, which clinical judgment cannot do because it is no better at making this crucial distinction than a coin toss. With the advent of reliable, economical measurements of patient compliance with prescribed drug dosing regimens, we can probably eliminate most of the compliance problems. The problem awaiting us after that is poor persistence with prescribed regimens for antihypertensive and other cardiovascular medicines that are meant for long-term or life-long use. A recent study has shown that median persistence with fully reimbursed drugs of the statin class is only 6 months, which is about one fortieth of the length it should be to realize full benefits of such therapy.

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References and Recommended Reading

  1. Katz R: Regulatory view: use of subgroup data for determination of efficacy. In Compliance in Medical Practice and Clinical Trials. Edited by Cramer JA, Spilker B. New York: Raven Press; 1991:251–264

    Google Scholar 

  2. Cramer JA, Mattson RH, Prevey ML, et al.: How often is medication taken as prescribed? A novel assessment technique. JAMA 1989, 261:3273–3277.

    Article  PubMed  CAS  Google Scholar 

  3. Kruse W, Weber E: Dynamics of drug regimen compliance - its assessment by microprocessor-based monitoring. Eur J Clin Pharmacol 1990, 38:561–565.

    Article  PubMed  CAS  Google Scholar 

  4. Cramer JA: Microelectronic systems for monitoring and enhancing patient compliance with medication regimens. Drugs 1995, 49:321–327.

    PubMed  CAS  Google Scholar 

  5. Kastrissios H, Blaschke TF: Medication compliance as a feature in drug development. Ann Rev Pharmacol Toxicol 1997, 37:451–475.

    Article  CAS  Google Scholar 

  6. Urquhart J: The electronic medication event monitor - lessons for pharmacotherapy. Clin Pharmacokinet 1997, 32:345–356.

    Article  PubMed  CAS  Google Scholar 

  7. Vrijens B, Goetghebeur E: Comparing compliance patterns between randomized treatments. Control Clin Trial 1997, 18:187–203.

    Article  CAS  Google Scholar 

  8. Urquhart J, de Klerk E: Contending paradigms for the interpretation of data on patient compliance with therapeutic drug regimens. Stat Med 1998, 17:251–267. A simple but powerful method for comprehensively summarizing the diversity of temporal patterns of drug intake in ambulatory patients, based on electronic monitoring, which is now widely accepted as the gold standard method for compiling drug dosing histories in ambulatory patients, and the measurement that is the foundation for reliable determination of patient compliance with prescribed drug regimens.

    Article  PubMed  CAS  Google Scholar 

  9. Rubio A, Cox C, Weintraub M: Prediction of diltiazem plasma concentration curves from limited measurements using compliance data. Clin Pharmacokinet 1992, 22:238–246.

    PubMed  CAS  Google Scholar 

  10. Girard P, Sheiner LB, Kastrissios H, Blaschke TF: Do we need full compliance data for population pharmacokinetic analysis? J Pharmacokinet Biopharm 1996, 24:265–282.

    Article  PubMed  CAS  Google Scholar 

  11. Trapnell CB, Donahue SR, Collins JM, et al.: Thalidomide does not alter the pharmacokinetics of ethinyl estradiol and norethindrone. Clin Pharmacol Ther 1998, 64:597–602.

    Article  PubMed  CAS  Google Scholar 

  12. VrijensB, Goetghebeur E: The impact of compliance in pharmacokinetic studies. Stat Meth Med Res 1999, 8:247–262. Illustrates how reliably ascertained drug dosing histories can inform pharmacokinetic studies.

    Article  CAS  Google Scholar 

  13. Urquhart J: Patient compliance with prescribed drug regimens: overview of the past 30 years of research. In Cinquièmes Entretiens du Centre Jacques Cartier. Pharmacoépidémiologie Prescription et Utilisation des Médicaments. Épidémiologie Clinique, vol IV. Lyon: Editions Fondation Marcel Mérieux; 1993:185–217.

    Google Scholar 

  14. Jones JK, Gorkin L, Lian JF, et al.: Discontinuation of and changes in treatment after start of new courses of antihypertensive drugs: a study of a United Kingdom population. BMJ 1995, 311:293–295.

    PubMed  CAS  Google Scholar 

  15. Caro JJ, Salas M, et al.: Persistence with treatment for hypertension in actual practice. Can Med Assoc J 1999, 160:31–38.

    CAS  Google Scholar 

  16. Caro JJ, Speckman JL, et al.: Effect of initial drug choice on persistence with antihypertensive therapy: the importance of actual practice data. Can Med Assoc J 1999, 160:41–47.

    CAS  Google Scholar 

  17. Catalan VS, LeLorier J: Predictors of long-term persistence on statins in a subsidized clinical population. Val Health 2000, 3:417–426. Documents poor persistence with antihypertensive and lipidlowering agents.

    Article  CAS  Google Scholar 

  18. Cramer JA, Rosenheck R: Enhancing medication compliance for people with serious mental disease. J Nervous Mental Dis 1999, 187:53–54.

    Article  CAS  Google Scholar 

  19. Burnier M, Schneider MP, Chiolero A, et al.: Electronic compliance monitoring in resistant hypertension: the basis for rational therapeutic decisions. J Hypertens 2001, 19:335–341. Demonstrates how it is possible, by simple means, to improve patient compliance based on its ongoing, reliable measurement.

    Article  PubMed  CAS  Google Scholar 

  20. WHO: WHO Collaborating Centre for Drug Statistics Methodology. Accessible at http://www.whocc.nmd.no. Accessed September 14, 2001. The site lists changes in defined daily doses since 1980, which reflect changes in generally prescribed dosages since the time of the corresponding product’s market introduction. An analysis of these data is being prepared by Heerdink et al., University of Utrecht.

  21. Cross JT, Lee HK, Nelson JS, et al.: One in five marketed drugs undergoes a dosage change: 1980–1999. Paper presented at Abstracts of the 102nd Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics. Lake Buena Vista, FL. March 6-10, 2001. Documents that one drug in about five (outside the anti-infective category) has undergone a 50% or greater reduction in dose during the past two decades. Increases in dose have also occurred, but are almost altogether confined to the anti-infectious category of drug.

  22. Urquhart J: Pharmaco-economic consequences of variable patient compliance with prescribed drug regimens. Pharmacoeconomics 1999, 15:217–228. Review of the pharmacoeconomic consequences of variable compliance with two of the early lipid lowering agents, cholestyramine and gemfibrozil, based on compliance-stratified analyses carried out in the key trials that demonstrated both the efficacy and the compliancedependent effectiveness of each agent.

    Article  PubMed  CAS  Google Scholar 

  23. Pullar T, Kumar S, Tindall H, Feely M: Time to stop counting the tablets? Clin Pharmacol Ther 1989, 46:163–168.

    Article  PubMed  CAS  Google Scholar 

  24. Rudd P, Byyny RL, Zachary V, et al.: The natural history of medication compliance in a drug trial: limitations of pill counts. Clin Pharmacol Ther 1989, 46:169–176.

    Article  PubMed  CAS  Google Scholar 

  25. Rudd P, Ahmed S, Zachary V, et al.: Improved compliance measures: applications in an ambulatory hypertensive drug trial. Clin Pharmacol Ther 1990, 48:676–685.

    Article  PubMed  CAS  Google Scholar 

  26. 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.

    PubMed  CAS  Google Scholar 

  27. Matsuyama JR, Mason BJ, Jue SG: Pharmacists’ interventions using an electronic medication-event monitoring device’s adherence data versus pill counts. Ann Pharmacother 1993, 27:851–855.

    PubMed  CAS  Google Scholar 

  28. Guerrero D, Rudd P, Bryant-Kosling C, Middleton BF: Antihypertensive medication-taking. Investigation of a simple regimen. Am J Hypertens 1993, 6:586–592.

    PubMed  CAS  Google Scholar 

  29. Kruse W, Nikolaus T, Rampmaier J, et al.: Actual versus prescribed timing of lovastatin doses assessed by electronic compliance monitoring. Eur J Clin Pharmacol 1993, 44:211–215.

    Article  Google Scholar 

  30. Matsui M, 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.

    PubMed  CAS  Google Scholar 

  31. Mason BJ, Matsuyama JR, Jue SG: Assessment of sulfonylurea adherence and metabolic control. Diabetes Ed 1995, 21:52–57.

    Article  CAS  Google Scholar 

  32. Lee JY, Kusek JW, Greene PG, et al., for the AASK Pilot Study Investigators: Assessing medication adherence by pill count and electronic monitoring in the African American study of kidney disease and hypertension (AASK) pilot study. Am J Hypertens 1996, 9:719–725.

    Article  PubMed  CAS  Google Scholar 

  33. Schwed A, Fallab CL, Burnier M, et al.: Electronic monitoring of compliance to lipid-lowering therapy in clinical practice. J Clin Pharmacol 1999, 39:402–409.

    Article  PubMed  CAS  Google Scholar 

  34. Choo PW, Rand CS, Inui TS, et al.: Validation of patient reports, automated pharmacy records, and pill counts with electronic monitoring of adherence to antihypertensive therapy. Med Care 1999, 37:846–857.

    Article  PubMed  CAS  Google Scholar 

  35. Liu H, Golin CE, Miller LG, et al.: A comparison study of multiple measures of adherence to HIV protease inhibitors. Ann Intern Med 2001, 134:968–977. Electronic monitoring measurements were compared with returned tablet counts, confirming the conclusions reached by Pullar et al. [23] and Rudd et al. [24].

    PubMed  CAS  Google Scholar 

  36. Meier P: Discussion. J Am Stat Assoc 1991, 86:19–22.

    Article  Google Scholar 

  37. Lee YJ, Ellenberg JH, Hirta DG, Nelson KB: Analysis of clinical trials by treatment actually received: is it really an option. Stat Med 1991, 10:1595–1605.

    Article  PubMed  CAS  Google Scholar 

  38. Efron B, Feldman D: Compliance as an explanatory variable in clinical trials. J Am Stat Assoc 1991, 86:7–17.

    Google Scholar 

  39. Hasford J: Biometric issues in measuring and analyzing partial compliance in clinical trials. In Compliance in Medical Practice and Clinical Trials. Edited by Cramer JA, Spilker B. New York: Raven Press; 1991:265–281.

    Google Scholar 

  40. Hurley FL: Statistical approach to subgroup analyses: patient compliance data and clinical outcomes. In Compliance in Medical Practice and Clinical Trials. Edited by Cramer JA, Spilker B. New York: Raven Press; 1991:243–250.

    Google Scholar 

  41. Sheiner LB, Rubin DB: Intention to treat analysis and the goals of clinical trials. Clin Pharmacol Ther 1995, 57:6–15.

    Article  PubMed  CAS  Google Scholar 

  42. Fischer-Lapp K, Goetghebeur E: Practical properties of some structural mean analyses of the effect of compliance in randomized trials. Controlled Clin Trials 1999, 20:531–546.

    Article  PubMed  CAS  Google Scholar 

  43. Rubin D: Comment: dose-response estimands. J Am Stat Assoc 1991, 86:22–24.

    Article  Google Scholar 

  44. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Institutes of Health, National Heart, Lung, and Blood Institute. Arch Intern Med 1997, 157:2413–2456.

  45. Joffres MR, Ghadirian P, Fodor JG, et al.: Awareness, treatment, and control of hypertension in Canada. Am J Hypertens 1997, 10:1097–1102.

    Article  PubMed  CAS  Google Scholar 

  46. Mancia G, Grassi G: Rationale for the use of a fixed combination in the treatment of hypertension. Eur Heart J 1999, 1(Suppl L):L14-L19. Demonstrates that the shortfall in adequate treatment found in the United States is essentially the same in a number of western European countries.

    Google Scholar 

  47. Urquhart J: Patient compliance as an explanatory variable in four selected cardiovascular trials. In Patient Compliance in Medical Practice and Clinical Trials. Edited by Cramer JA, Spilker B. New York: Raven Press; 1991:301–322.

    Google Scholar 

  48. Johnson BF, Whelton A: A study design for comparing the effects of missing daily doses of antihypertensive drugs. Am J Therapeutics 1994, 1:260–267.

    Article  Google Scholar 

  49. Levy G: A pharmacokinetic perspective on medicament noncompliance. Clin Pharmacol Ther 1993, 54:242–244.

    Article  PubMed  CAS  Google Scholar 

  50. Kruse W, Rampmaier J, Ullrich G, Weber E: Patterns of drug compliance with medication to be taken once and twice daily assessed by continuous electronic monitoring in primary care. Int J Clin Pharmacol Ther 1994, 32:453–457.

    Google Scholar 

  51. Brun J: Patient compliance with once-daily and twice-daily oral formulations of 5-isosorbide mononitrate: a comparative study. J Int Med Res 1994, 22:266–272.

    PubMed  CAS  Google Scholar 

  52. Mounier-Vehier C, Bernaud C, Carré A, et al.: Compliance and antihypertensive efficacy of amlodipine compared with nifedipine slow-release. Am J Hypertens 1998, 11:478–486.

    Article  PubMed  CAS  Google Scholar 

  53. Girvin B, McDermott BJ, Johnston GD: A comparison of enalapril 20 mg once-daily versus 10 mg twice-daily in terms of blood pressure lowering and patient compliance. J Hypertens 1999, 17:1627–1631. Demonstrates with reliable data that the differences between once and twice daily drug regimens are marginal.

    Article  PubMed  CAS  Google Scholar 

  54. Veterans Administration Cooperative Study Group on Hypertensive Agents: Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressure averaging 115 through 129 mm Hg. JAMA 1967, 202:1028–1034.

    Article  Google Scholar 

  55. Veterans Administration Cooperative Study Group on Hypertensive Agents: Effects of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA 1970, 213:1143–1152.

    Article  Google Scholar 

  56. Urquhart J: Controlled drug delivery: pharmacologic and therapeutic aspects. J Intern Med 2000, 248:357–376. Implants may turn out to be a major approach to solving the compliance and persistence problems. This review article provides an overview of the present state of drug delivery systems.

    Article  PubMed  CAS  Google Scholar 

  57. International Conference on Harmonisation. Choice of control group in clinical trials. FDA Docket No. 99D-3082. Fed Reg 1999, 64:51767–51780.

    Google Scholar 

  58. Urquhart J: Demonstrating effectiveness in a post-placebo era. Clin Pharmacol Ther 2001, 70:115–120. Describes the importance of assay sensitivity in active-control trials, and the importance of satisfactory patient compliance in trials whose credibility depends on adequate assay sensitivity.

    Article  PubMed  CAS  Google Scholar 

  59. Coronary Drug Project Research Group: Influence of adherence to treatment and response of cholesterol on mortality in the coronary drug project. N Engl J Med 1980, 303:1038–1041.

    Article  Google Scholar 

  60. Cramer J, Vachon L, Desforges C, Sussman NM: Dose frequency and dose interval compliance with multiple antiepileptic medications during a controlled clinical trial. Epilepsia 1995, 36:1111–1117.

    Article  PubMed  CAS  Google Scholar 

  61. Nuesch R, Schroeder K, Dieterle T, et al.: Relation between insufficient response to antihypertensive treatment and poor compliance with treatment: a prospective case-control study. BMJ 2001, 323:142–146.

    Article  PubMed  CAS  Google Scholar 

  62. Haynes RB: Improving patient adherence: state of the art, with a special focus on medication taking for cardiovascular disorders. In Compliance in Healthcare and Research (American Heart Association Monograph Series). Edited by Burke LE, Ockene IS. Armonk, NY: Futura Publishing Co., 2001:3–21. Nice overview on the current state of the field by one its pioneers.

    Google Scholar 

  63. Efron B: Foreword to the Limburg Compliance Symposium. Stat Med 1998, 17:249–250.

    Article  Google Scholar 

  64. Cox D: Discussion of the Limburg Compliance Symposium. Stat Med 1998, 17:387–389. Cox has played a seminal role in the development of modern biostatistics. His words about the compliance problem, as it was discussed at the Limburg Compliance Symposium in 1995, are apt.

    Article  Google Scholar 

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Urquhart, J. Some economic consequences of noncompliance. Current Science Inc 3, 473–480 (2001). https://doi.org/10.1007/s11906-001-0009-7

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