Adherence In Renal Transplant: What Difference Does it Make

1. Adherence In Renal Transplant: What Difference Does it Make? Janice Bissonnette RN, MScN, ACNP, PhD (c) The Ottawa Hospital: Renal Transplant Program CAT 2006

2. 2 Learning Objectives Define Non-Adherence (NA) Present past and present research on adherence trends and link to graft failure Review current tools for measuring patient adherence Discuss predictive value of certain adherence indicators

3. 3 Defining Non-Adherence“Tip of the Iceberg Phenomena” What do you think it means? Not taking meds, missing meds, taking too much, not taking enough, wrong time, wrong dose, wrong pill ! Missing appointments, not booking appointments, not doing blood work, not returning calls, refusing treatment regimen! Over or under use, wrong time Taking the wrong medicine Not finishing medication Administration errors Using another persons medication Using old, possibly expired medicationOver or under use, wrong time Taking the wrong medicine Not finishing medication Administration errors Using another persons medication Using old, possibly expired medication

4. 4 What does the literature say? Compliance (the “C” word): infers conformity to medical or health recommendations. Concordance: consensual agreement about treatment taking established between patient and practitioner. Adherence: non-judgmental, statement of fact rather than blame of the patient, prescriber, or treatment. Adherence ? Concordance

5. 5 Dimensions of Adherence: some things we think we know…. Initial non-adherence or defaulting 2% - 20%, possibly as high as 50% average 8.7% Refill adherence or persistence Decreases over time Not all non-adherence is improper medication use rational non-adherence Considered a major cause of late renal allograft failure A potential modifiable risk factor for poor outcomes Rationale non-adherence, pts make a “rationale” choice to not take meds, change regimen etc Rationale non-adherence, pts make a “rationale” choice to not take meds, change regimen etc

6. 6 Health Effects increased morbidity treatment failures exacerbation of disease more frequent physician visits increased hospitalizations Death Economic impact: lost wages, sick time Costs of Non-adherence, estimates…… > 100 billion dollars annually 125,000 unnecessary deaths 10% (more than 1,000,000) of all hospitalizations may be due to noncompliance 50% of all medication use Costs of Non-adherence, estimates…… > 100 billion dollars annually 125,000 unnecessary deaths 10% (more than 1,000,000) of all hospitalizations may be due to noncompliance 50% of all medication use

7. 7 Patient Considerations Factors believed to be associated with NA in Renal tx patient knowledge prior adherence behavior ability to integrate into daily life / complexity of the particular drug regimen health beliefs (low self efficacy) social support (including practitioner relationships)

8. 8 Patient Considerations Factors which are NOT believed to be associated with compliance race, gender, income or education patient intelligence actual seriousness of the disease or the efficacy of the treatment

9. 9 Patients at higher risk: Multiple daily dosing qd < bid < tid, < qid Patient perceptions effectiveness, side effects, cost Poor communication patient practitioner rapport Psychiatric illness less likely to comply

10. 10 Benchmark Adherence Rates Disease Epilepsy Arthritis Hypertension Diabetes Oral contraceptives HRT Asthma Cochrane Review, Oct, 2005 Rates of Non-Adherence (NA) 30% to 50% 50% to 71% 40% (average) 40% to 50% 8% 57% 20%

11. 11 Persistence Persistency curves after 1 year as much as a 50 percent decline after 5 years, adherence as low as 29% to 33% greatest declines in first six months Cochrane Review, 2005 Persistence refers to adherence to prescription refillsPersistence refers to adherence to prescription refills

12. 12 Cochrane Review Oct 2005 Interventions for Medication Adherence Background: People typically take < 50% of prescribed medications. Efforts to assist pts with adherence might improve the benefits & efficiency of health care, but also might increase its adverse effects. Objectives: To summarize results of RCT’s of interventions to help pts follow prescriptions for meds, focusing on trials that measured both adherence and clinical outcomes. Search strategy was only up until Aug 2001, Medline, Cinahl, Cochrane library, international pharmaceutical abstracts, psychinof, & sociol file, bibliographies in articles on pt adherence, contact with authors or original & review articles on topics. Search strategy was only up until Aug 2001, Medline, Cinahl, Cochrane library, international pharmaceutical abstracts, psychinof, & sociol file, bibliographies in articles on pt adherence, contact with authors or original & review articles on topics.

13. 13 Cochrane Review Oct 2005 Interventions for Medication Adherence Selection Criteria: Unconfounded RCT Intervention to improve adherence with prescribed medications Measuring both med adherence and treatment outcome At least 80% f/u in each group For long-term studies, at least 6 month f/u for studies with positive initial findings Selection criteria selected if reported an unconfounded RCT of an intervention to improve adherence with prescribed medications, measuring both medication adherence & tx outcome, with at least 80% follow-up of each group studied & for long-term txs, at least 6 months f/u for studies with positive initial findings. Confounding – ie 2 groups received the same prescription for penicillin but different instructions, providing an unconfounded comparision for the instrustions, bu the the 3rd group in the same trial received a different drug, by a different route, with a diff dose & schedule, making it impossible to separate out independent effects. Selection criteria selected if reported an unconfounded RCT of an intervention to improve adherence with prescribed medications, measuring both medication adherence & tx outcome, with at least 80% follow-up of each group studied & for long-term txs, at least 6 months f/u for studies with positive initial findings. Confounding – ie 2 groups received the same prescription for penicillin but different instructions, providing an unconfounded comparision for the instrustions, bu the the 3rd group in the same trial received a different drug, by a different route, with a diff dose & schedule, making it impossible to separate out independent effects.

14. 14 Intervention Categories Studied More instruction of patients Counseling about target disease, compliance with therapy, side-effects Automated telephone, computer-assisted patient monitoring and counseling Manual telephone f/u Family interventions Increasing convenience of care Simplified dosing Different formulations Self-monitoring strategies Reminders Dose-dispensing units/charts Appt & refill reminders Reinforcement or rewards for improved adherence ie reduced frequency of visits Crisis intervention Direct observation Lay health mentoring Comprehensive pharmaceutical care Psychological therapy Almost all interventions for long-term conditions were considered complex, making generalizations problematic about which works & which doesn’t. Most measures of adherence were imprecise, often relying on self-report (which is known to over estimate adherence (Haynes 1980) For research to advance need objective measures As general guide need studies with a single intervention grp & control grp with at least 60 participants per grp to have 80% power to detect an absolute difference of 25% in the proportion of patients judged to have adequate adherence Adherence is a process measure, a means to an end…interventions to increase adherence consume resources & attempts to increase adherence can have adverse effects (loss of privacy & autonomy, increase adverse effects of treatments if taken in higher doses etc)Almost all interventions for long-term conditions were considered complex, making generalizations problematic about which works & which doesn’t. Most measures of adherence were imprecise, often relying on self-report (which is known to over estimate adherence (Haynes 1980) For research to advance need objective measures As general guide need studies with a single intervention grp & control grp with at least 60 participants per grp to have 80% power to detect an absolute difference of 25% in the proportion of patients judged to have adequate adherence Adherence is a process measure, a means to an end…interventions to increase adherence consume resources & attempts to increase adherence can have adverse effects (loss of privacy & autonomy, increase adverse effects of treatments if taken in higher doses etc)

15. 15 Main Results: 57 RCTs Differences across studies, in venues, clinical disorders, interventions, adherence measures, & reporting, outcome measures…so there was insufficient common ground for quantifying differences between groups or calculating effect sizes that would permit quantitative summarization of findings across studies. Some of negative results, unconvincing because of the sm numbers of participants studied (low statistical power) Outcomes…should be noted that clinical improvements in studies were seldom in major clinical outcomes such as death or stroke, rather, usually evaluated intermediate outcomes such as serum cholesterol, triglycerides or lung function.Differences across studies, in venues, clinical disorders, interventions, adherence measures, & reporting, outcome measures…so there was insufficient common ground for quantifying differences between groups or calculating effect sizes that would permit quantitative summarization of findings across studies. Some of negative results, unconvincing because of the sm numbers of participants studied (low statistical power) Outcomes…should be noted that clinical improvements in studies were seldom in major clinical outcomes such as death or stroke, rather, usually evaluated intermediate outcomes such as serum cholesterol, triglycerides or lung function.

16. 16 Study Examples

17. 17 Adherence Studies in Renal TransplantLiterature ReviewDenhaerynck et al, Transplant Intern, 2005. 38 articles, 17 studies reported on prevalence of Adh with IST Methods: Self-report, collateral reports, assay, refill Rx, or EM Results: Prevalence of NA range 2-67% Weighted mean prev = 27.7% Conclusions: Non-adherence contributed to 20% (n=3) of LAR, & 15% (n=8) graft losses Consistent determinants of nonadherence were younger age, social isolation and certain cognitions (low SE, health beliefs). Evidence based on older IST regimens. Percentages underestimate the contribution of NA in poor clinical outcome Socioeconomic factors alone (except age & social isolation) show limited association with NA Prevalence – calculated over all studies that measured adherence by self-report was 27.7% One study, only on measuring non-adh by chart review found low adh of 2%...appears to lack sensitivity. Non-adherence is not assessed as a std clinical parameter in most tx programs…..therefore chart review would likely result in low % rates.Prevalence – calculated over all studies that measured adherence by self-report was 27.7% One study, only on measuring non-adh by chart review found low adh of 2%...appears to lack sensitivity. Non-adherence is not assessed as a std clinical parameter in most tx programs…..therefore chart review would likely result in low % rates.

18. 18 Adherence Studies in Renal Transplant……Prospective Cohort testing clinical consequences of NonAdh with IST Prevalence – calculated over all studies that measured adherence by self-report was 27.7% One study, only on measuring non-adh by chart review found low adh of 2%...appears to lack sensitivity. Non-adherence is not assessed as a std clinical parameter in most tx programs…..therefore chart review would likely result in low % rates.Prevalence – calculated over all studies that measured adherence by self-report was 27.7% One study, only on measuring non-adh by chart review found low adh of 2%...appears to lack sensitivity. Non-adherence is not assessed as a std clinical parameter in most tx programs…..therefore chart review would likely result in low % rates.

19. 19 Adherence Studies in Renal Transplant……Studies estimating contribution of NonAdh with IST on LAR or Graft Loss Michelon, drug regimens axa/pred, axa/pred/cya, mmf/cya/pred, fk/aza/pred: Brazil Matas: drug regimens aza/mmf/pred USA Gaston: Kidney & KP tx, with graft loss because of chronic rejection beyond 6 mos, USA Garcia: Brazil, received impt of med adh ed after 1991Michelon, drug regimens axa/pred, axa/pred/cya, mmf/cya/pred, fk/aza/pred: Brazil Matas: drug regimens aza/mmf/pred USA Gaston: Kidney & KP tx, with graft loss because of chronic rejection beyond 6 mos, USA Garcia: Brazil, received impt of med adh ed after 1991

20. 20 Adherence Studies in Renal Transplant Baines, Joseph, & Jindal; Clin Transplant, 2002 Background: Relationship between LAR after DD & medical compliance. Methods: N= 26, Retrospective analysis, all pts who received tx in CyA era (6 year period). Rejections divided into early & late based on time from tx. Biopsy confirmed. LAR after 90 day. Administered Long-term Medication Behaviour Self-Efficacy Scale (LTMBS). Sub scales max score 3. Results: 24 questionnaires, 22 returned Mean score = 2.17 Low SE 1/3, when experiencing physical & psy side-effects LAR, hypothesis tested is that LAR, a major cause of graft loss & chronic rejection are caused by medical non-compliance as more likely to be related to inadequate drug levels because of non-compliance versus early rejection which may be more likely related to immunological reasons ie DGF, HLA mismatch, PRA level & type of immunosuppressive. LTMBS – to determine confidence & SE with taking meds in certain situations, , analyzed in relationship to compliance behaviour LTMBS initially used in conjunction with electronic tagging in a longitudinal study of 150 tx to evaluate subclinical non-compliance with CyA over a 3 mos period. 27 item instrument, scores range 1-3, 3 being most confidentLAR, hypothesis tested is that LAR, a major cause of graft loss & chronic rejection are caused by medical non-compliance as more likely to be related to inadequate drug levels because of non-compliance versus early rejection which may be more likely related to immunological reasons ie DGF, HLA mismatch, PRA level & type of immunosuppressive. LTMBS – to determine confidence & SE with taking meds in certain situations, , analyzed in relationship to compliance behaviour LTMBS initially used in conjunction with electronic tagging in a longitudinal study of 150 tx to evaluate subclinical non-compliance with CyA over a 3 mos period. 27 item instrument, scores range 1-3, 3 being most confident

21. 21 Measuring Non-Adherence in theTransplant Population What is a robust, clinically useful definition of medication non-adherence? How much adherence is enough? Is there a true threshold-effect? Does adherence play an important role in late acute rejections or chronic allograft dysfunction? Do some drugs or drug schedules lend themselves to better adhere, and if so, does it make a significant (or clinically significant) difference? Nevins & Matas, Transplantation, 77(5),2004

22. 22 Measuring Adherence patient self-reports clinical outcomes pill counts refill records biological & chemical markers “White coat adherence” electronic monitors (EM) MAS Medication Adherence Scale BMQ Brief Medical Questionnaire ITAS & ITBS Immunosuppressant Therapy Adherence Scale IST Barrier scale LTMBS Long-term Medication Behaviour Self-Efficacy scale Self report scales Range from complicated to simple, such as: How often have you taken your prescribed medication in the past four weeks? MAS, BMQ, ITAS 4 items, LTMBS 27 items Self-reports – often results in under estimation of adherence Biological/chemical assay – despite being a direct method, only allows determining med intake over a ltd time period, depending on the half-life of the drug. White coat adherence – patients correct intake in the light of a pending clinic visit, may distort interpretation of therapeutic blood levels EM- pill bottle that contains a microprocessor fitted cap to save the date & time of each opening Registration of a pillbox opening does not prove ingestion…. EM- shows superior sensitivity compared with other methods (cross-validation studies), allows assessing of nonadh as a continuous variable in a multidimensional manner (ie the taking & timing dimension of medication administration) Self report scales Range from complicated to simple, such as: How often have you taken your prescribed medication in the past four weeks? MAS, BMQ, ITAS 4 items, LTMBS 27 items Self-reports – often results in under estimation of adherence Biological/chemical assay – despite being a direct method, only allows determining med intake over a ltd time period, depending on the half-life of the drug. White coat adherence – patients correct intake in the light of a pending clinic visit, may distort interpretation of therapeutic blood levels EM- pill bottle that contains a microprocessor fitted cap to save the date & time of each opening Registration of a pillbox opening does not prove ingestion…. EM- shows superior sensitivity compared with other methods (cross-validation studies), allows assessing of nonadh as a continuous variable in a multidimensional manner (ie the taking & timing dimension of medication administration)