L’Adhésion Thérapeutique, Définition, Mesure, et Gestion Bernard Vrijens, PhD Chief Science O ffi cer, MWV Healthcare Associate Professor of Biostatistics University of Liège, Belgium
Adherence is key to therapeutic success Adherence Effective Effective to Disease Therapies Medications Management “Drugs don’t work in patients who do not take them.” – C. Everett Koop, former US Surgeon General 2
Medication adherence The process by which patients take their medications as prescribed Initiate Implement Persist time Patient does Patient delays, Patient not initiate omits or takes discontinues treament extra doses treatment Binary (yes/no) Dosing history Time to event EU Commission-sponsored research Vrijens et al. Br J Clin Pharmacol 2012;73:691-705. 3
25% of patients do not initiate a new prescription 195,930 e-prescriptions from >75,000 patients M Fischer et al., J Gen Intern. Med, 25(4):284-90, 2010. 4
Daily, 15% of patients do not implement as prescribed Case Study: Dosing History Data over 2 years (2011-2012) N= 16907pts 60 from 95Clin. Trials 50 40 % 30 20 10 0 84% of prescribed doses taken Once Twice Three times daily daily daily How much implementation is enough? DRUGS’ FORGIVENESS Blaschke, Osterberg, Vrijens, Urquhart, Annual Review, 2012. 5
Overall, 40% of patients will have discontinued at month 12 16,907 participants from 95 clinical studies 100 % of patients persisting with the treatment 80 60 % of patients 40 Osteoporosis Hyperlipidemia HIV 20 Diabetes Breast cancer Hypertension Depression 0 0 100 200 300 Time to treatment discontinuation (days) Time (days) Blaschke, Osterberg, Vrijens, Urquhart, Annual Review, 2012. 6
Medication adherence: summary The process by which patients take their medications as prescribed Initiate Implement Persist time During the first Daily, 15% of year, 40% of 25% of patients patients do not do not initiate a patients have implement as new prescription discontinued prescribed treatment Large di ff erences between: Patient attribute Large di ff erences between: • Diseases/drugs • Diseases/drugs Dosing regimen: • Centers • Centers • Once daily: 10% • HC systems • HC systems • Twice daily: 20% • Drug dev/practice • Drug dev/practice Implementation decreases with: • Food requirements • Complexity of treatment 7
Hypertension « Deux Millions de Belges en Souffrent, le soir 28/05/15 » Adherence to prescribed antihypertensive drug treatments: longitudinal study of electronically compiled dosing histories N=4783 patients from 21 clinical studies Vrijens et al., BMJ. 2008 May 17;336(7653):1114-7. 8 Vrijens et al., BMJ. 2008 May 17;336(7653):1114-7.
Does Adherence Really Matter – Even in Serious Conditions? One of the most striking findings of this study is that among children who were adherent to the 6MP regimen, those with high intra-individual variability in TGN levels had a significant risk of relapse (hazard ratio, 4.4; P = .02). … . this study raises the provocative question of whether frequent dose adjustments during maintenance therapy, with resultant variable TGN levels, may be counterproductive in adherent patients. This study clearly demonstrates that even after 63 years of use and study on numerous prospective clinical trials, there is still an opportunity to improve how we use this old but highly effective and important drug. … . we must not lose sight of the fact that precision medicine also applies to optimizing known effective therapy. JAMA Oncol . doi:10.1001/jamaoncol.2015.0245, March 26, 2015 9
Adherence measurement methods Reliable Method Packaging that accurately tracks dosing history Therapeutic drug monitoring Pharmacy refill data Sparse Sampling Rich Sampling Retrospective questionnaire Pill counts Patient diary Biased Method Vrijens & Urquhart, 2005 Journal of Antimicrobial Chemotherapy. 10
“What can be measured can be managed” ‒ Deming, WE Each of the 4 patients took 75% of prescribed doses during a 3-month period Problem with Sporadic Drug Early evening dose dosing holiday discontinuation Vrijens,, Urquhart, White, 2014, Expert Rev Clin Pharmacol; 7(5):633-44. 11 .
Consequences of medication non-adherence Initiate Implement Persist time Drugs stop Drugs work Drugs don’t work working in partially or may in patients who do patients who create harm in not initiate them discontinue patients who them implement a dosing regimen sporadically Drug Forgiveness 12
Variable adherence is a major source of variance in drug response Manufacturing and distribution Prescribing Dispensing Adherence PK PD Drug response Harter JJ & Peck CC. Ann N Y Acad Sci 1991;618:563–71. 13
Variable Implementation Creates Drug-Specific Issues of Efficacy and Safety Occasional toxicity Periodic loss of effectiveness Blaschke, Osterberg, Vrijens, Urquhart, 2012, Ann Rev Pharmacol Toxicol, 52:275-301 14
Typical BID advantage: Reduced variability (NOAC) T 1/2 =12 h; T max =3 h Vrijens & Heidbuchel, Europace, 2015
Twice-daily regimen increases forgiveness for similar deviations in adherence (NOACs) Dose X: Once daily Dose X/2: Twice daily Bleeding risk Bleeding risk Concentration Concentration Dosing time Thrombosis risk Thrombosis risk 03:00 03:00 24:00 24:00 21:00 21:00 Dosing time 18:00 18:00 15:00 15:00 12:00 12:00 09:00 09:00 06:00 06:00 03:00 03:00 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 100 Dosing times (day) Dosing times (day) Assuming T 1/2 =12h; T max =3h • 15% missed doses • 15 once-daily missed doses vs. 30 twice-daily missed doses over 100 days Vrijens & Heidbuchel, Europace, 2015
The Struthian Approach is No Longer An Option! Efficacy / Safety Optimal dose Forgiveness Concentration of Drugs 17
Management of adherence: A systems approach Healthcare/Prescribing Policy Community & Institutions Providers & Prescribers Definition Objective Family & “the process of “to achieve the best Carers monitoring and use, by patients, Patient supporting patients’ of appropriately adherence to prescribed medicines medications by in order to maximize the healthcare systems, potential for benefit and providers, patients and minimize the risk of their social networks” harm” Vrijens et al. Br J Clin Pharmacol 2012;73:691-705. 18
“What can be measured can be managed” ‒ Deming, WE Improved medication adherence Example of a successful intervention Focused discussion between healthcare N=392 patients provider and patient based on reliable and detailed adherence data Vrijens, et al., Pharmacoepidemiology and Drug Safety, 2006. 19 .
Patients’ awareness of their adherence patterns changes behavior EU Commission-sponsored study shows this is the biggest factor influencing adherence Showing patients their own dosing errors is the most 20 effective means to % improve adherence EU Commission-sponsored research Demonceau et al, Drugs; April 2013. 20
Elements to change patients’ behavior Training MOTIVATION EDUCATION self-efficacy knowledge MANAGEMENT OF ADHERENCE Package Goals MEASUREMENT awareness Vrijens,, Urquhart, White, 2014, Expert Rev Clin Pharmacol; 7(5):633-44. 21
Appropriate measure of adherence is key to avoid treatment escalation, the driver for costs Poor adherence Initiation-Implementation-Persistence More complex Treatment failure treatments Disease progression 22
Conclusions • Poor adherence to treatments for chronic diseases is a long-neglected worldwide problem of striking magnitude • The advent of uniquely powerful medicines and reliable means to assess adherence have brought patient nonadherence into clear view • Its consequences are: biased clinical study results, poor outcomes of drug treatment, added costs of health-care • Achieving satisfactory adherence may have far greater beneficial impact than any other maneuver to improve medical treatments • Measurement-guided intervention is required to achieve satisfactory adherence to therapeutic drug regimens • Health systems must evolve to meet the challenge of achieving satisfactory adherence to therapeutic drug regimens
Thank You for Your Attention Questions? 19 th ESPACOMP meeting will be held In Prague , Czech Republic , on the 13th and 14th November 2015 24
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