LAdhsion Thrapeutique, Dfinition, Mesure, et Gestion Bernard Vrijens, - - PowerPoint PPT Presentation

L’Adhésion Thérapeutique, Définition, Mesure, et Gestion

Bernard Vrijens, PhD


Chief Science Officer, MWV Healthcare
 Associate Professor of Biostatistics 
 University of Liège, Belgium

Adherence is key to therapeutic success

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Effective Disease Management

Effective Therapies

Adherence to Medications

“Drugs don’t work in patients who do not take them.”

– C. Everett Koop, former US Surgeon General

Medication adherence

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The process by which patients take their medications as prescribed

time Œ Initiate  Implement Ž Persist

Patient does not initiate treament Binary (yes/no) Patient delays,

• mits or takes

extra doses Dosing history Patient discontinues treatment Time to event

Vrijens et al. Br J Clin Pharmacol 2012;73:691-705. EU Commission-sponsored research

25% of patients do not initiate a new prescription

4 M Fischer et al., J Gen Intern. Med, 25(4):284-90, 2010.

195,930 e-prescriptions from >75,000 patients

Daily, 15% of patients do not implement as prescribed

5 Blaschke, Osterberg, Vrijens, Urquhart, Annual Review, 2012.

How much implementation is enough? DRUGS’ FORGIVENESS 84% of prescribed doses taken

Case Study: Dosing History Data over 2 years (2011-2012)

10 20 30 40 50 60 Once daily Twice daily Three times daily

N= 16907pts from 95Clin. Trials

%

Overall, 40% of patients will have discontinued at month 12

6 Blaschke, Osterberg, Vrijens, Urquhart, Annual Review, 2012.

Time to treatment discontinuation (days) % of patients persisting with the treatment

100 200 300 20 40 60 80 100

Osteoporosis Hyperlipidemia HIV Diabetes Breast cancer Hypertension Depression

% of patients Time (days)

16,907 participants from 95 clinical studies

Medication adherence: summary

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The process by which patients take their medications as prescribed

time Œ Initiate

25% of patients do not initiate a new prescription

Large differences between:

• Diseases/drugs
• Centers
• HC systems
• Drug dev/practice

Ž Persist

During the first year, 40% of patients have discontinued treatment

Large differences between:

• Diseases/drugs
• Centers
• HC systems
• Drug dev/practice

 Implement

Daily, 15% of patients do not implement as prescribed

Patient attribute Dosing regimen:

• Once daily: 10%
• Twice daily: 20%

Implementation decreases with:

• Food requirements
• Complexity of treatment

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

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N=4783 patients from 21 clinical studies

Vrijens et al., BMJ. 2008 May 17;336(7653):1114-7.

Vrijens et al., BMJ. 2008 May 17;336(7653):1114-7.

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Does Adherence Really Matter – Even in Serious Conditions?

JAMA Oncol. doi:10.1001/jamaoncol.2015.0245, March 26, 2015 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

• pportunity 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.

Adherence measurement methods

10 Vrijens & Urquhart, 2005 Journal of Antimicrobial Chemotherapy.

Reliable Method Sparse Sampling Biased Method Rich Sampling

Patient diary Therapeutic drug monitoring Pharmacy refill data Packaging that accurately tracks dosing history Pill counts Retrospective questionnaire

“What can be measured can be managed”

‒Deming, WE

11 Vrijens,, Urquhart, White, 2014, Expert Rev Clin Pharmacol; 7(5):633-44. .

Early discontinuation Drug holiday Problem with evening dose Sporadic dosing

Each of the 4 patients took 75% of prescribed doses 
 during a 3-month period

Consequences of medication non-adherence

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time Œ Initiate

Drugs don’t work in patients who do not initiate them

Ž Persist

Drugs stop working in patients who discontinue them

 Implement

Drugs work partially or may create harm in patients who implement a dosing regimen sporadically

Drug Forgiveness

Variable adherence is a major source

• f variance in drug response

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Manufacturing and distribution Prescribing Dispensing Adherence PK PD Drug response

Harter JJ & Peck CC. Ann N Y Acad Sci 1991;618:563–71.

Variable Implementation Creates Drug-Specific Issues of Efficacy and Safety

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Periodic loss of effectiveness

Occasional toxicity

Blaschke, Osterberg, Vrijens, Urquhart, 2012, Ann Rev Pharmacol Toxicol, 52:275-301

Typical BID advantage: Reduced variability (NOAC)

Vrijens & Heidbuchel, Europace, 2015

T1/2=12 h; Tmax=3 h

Twice-daily regimen increases forgiveness for similar deviations in adherence (NOACs)

Assuming T1/2=12h; Tmax=3h

Dose X: Once daily Dose X/2: Twice daily

Dosing times (day) Dosing time

03:00 06:00 09:00 12:00 15:00 18:00 21:00 24:00 03:00 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95

Dosing times (day)

03:00 06:00 09:00 12:00 15:00 18:00 21:00 24:00 03:00 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 100

Bleeding risk Thrombosis risk Bleeding risk Thrombosis risk

Dosing time Concentration Concentration

• 15% missed doses
• 15 once-daily missed doses vs. 30 twice-daily missed doses over 100 days

Vrijens & Heidbuchel, Europace, 2015

Optimal dose

The Struthian Approach is No Longer An Option!

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Concentration of Drugs Efficacy / Safety Forgiveness

Management of adherence: A systems approach

18 Vrijens et al. Br J Clin Pharmacol 2012;73:691-705.

Patient Family & Carers Providers & Prescribers Community & Institutions Healthcare/Prescribing Policy

Definition “the process of monitoring and supporting patients’ adherence to medications by healthcare systems, providers, patients and their social networks” Objective “to achieve the best use, by patients,

• f appropriately

prescribed medicines in order to maximize the potential for benefit and minimize the risk of harm”

“What can be measured can be managed”

‒Deming, WE

19 Vrijens, et al., Pharmacoepidemiology and Drug Safety, 2006. .

Focused discussion between healthcare provider and patient based on reliable and detailed adherence data Improved medication adherence

Example of a successful intervention

N=392 patients

Patients’ awareness of their adherence patterns changes behavior

20 Demonceau et al, Drugs; April 2013. EU Commission-sponsored research

EU Commission-sponsored study shows this 
 is the biggest factor influencing adherence

20 %

Showing patients their own dosing errors is the most effective means to improve adherence

21 Vrijens,, Urquhart, White, 2014, Expert Rev Clin Pharmacol; 7(5):633-44.

Elements to change patients’ behavior

Training Package Goals

MANAGEMENT OF ADHERENCE

EDUCATION knowledge MEASUREMENT awareness MOTIVATION self-efficacy

Appropriate measure of adherence is key to avoid treatment escalation, the driver for costs

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Poor adherence

Initiation-Implementation-Persistence

Disease progression More complex treatments Treatment failure

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
• ther 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?

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19th ESPACOMP meeting will be held In Prague, Czech Republic,

• n the 13th and 14th November

2015