Compliance The hidden cause of treatment failure

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Compliance The hidden cause of treatment failure

• Dr Leonie Rynn

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The best medication in the world is completely
useless unless people take it
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The need to develop strategies to improve
adherence is an essential element in reducing
the global burden of disease WHO 2003
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Consistent Pill Taking

• We try hard
• But were not very good at it!

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Non-Compliance

• Not an accusation.
• Its human nature

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Compliance Asthma

• 266 Randomly selected adolescents 13 17yrs of
  age
• Compliance assessed by written questionnaire

Kyngas HA Nurse Health Sci. 1999 1195-202
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Compliance Rheumatoid Arthritis (RA)

• 556 pts with RA followed for 3 years
• Compliance assessed annually by interview

Viller F et al. J Rheumatol. 1999262114-2122.
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Compliance Hypertension
Mallion et al, J Hypertension, 1998
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Compliance Diabetes

• Adherence rate for two drugs for diabetes
• 54 refill rate
• Long-term compliance
• 72.5 by pill count
• 50.7 by electronic cap

Melikan et al, Clin. Ther., 2002. Paes et al,
Pharm. World Sci, 1998
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The problem of poor compliance
Patients not adhering by disease area ()
Whitney HAK et al. Annals of Pharmacotherapy 1993.
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Compliance

• Full compliance
• Taking all medication as prescribed
• Partial compliance
• Occasionally missing or questioning the need for
  medication
• Non- compliance
• Complete cessation of medication

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Schizophrenia

• Taking medication over an extended period of time
  is hard for any condition
• Schizophrenia is no exception

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With Schizophrenia

• Single largest amount of outcome variance is
  accounted for by medication response
• Current treatment philosophy emphasizes the
  concept of using the lowest effective dose of
  medication

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Partial Compliance

• Problems with compliance have an immediate impact
• Becomes an issue when the threshold of lowest
  effective dose is not reached

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Compliance

• Problems with compliance affects
• some patients all of the time?
• all patients some of the time?
• Great uncertainty in identifying which ones at
  which times

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Evidence to date

• 50 will stop medication within 1 year
• 75 will stop medication within 2 years
• Prescription refill rates show less than 10 are
  filled fully
• Average no of days that a patient with
  schizophrenia is without medication because of
  failure to refill prescription is 110 125 days

Gray et al (2002)
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How can it be identified?

• Ask the patient
• Different inquirers get different answers
• Patients may truly believe they are compliant
• Veligan Study - 60 stated they took every dose
• 8 actually did
• Ask the clinician
• Overly optimistic when predicting medication
  compliance
• Prediction 95
• Actual was 38

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How can it be identified?

• Rx refills
• Refill is only part of the pill taking process
• Microchips
• Opening the bottle is one step closer
• Serum level
• A gold standard? or recent activity?

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Impact

• Partial compliance or interruptions in
  medication are ultimately damaging and costly to
  the patient
• Lack of full recovery
• Reappearance of symptoms
• Relapse
• Rehospitalisation

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Poor Compliance Affects Rehospitalisation Rates
Percent
Medication Possession Ratio
Valenstein M, et al. Medical Care.
200240630-639.
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Impact
Gilmer et al. Am J Psych 2004
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Impact

• A 10 day gap in medication doubles the odds of
  being hospitalised
• A 30 day gap in medication (after 3 months of
  medication) quadruples the suicide attempt rate

Keith S. Unpublished data. 2003, R.M.C.
Herings, and J.A. Erkens, Submitted to BMJ
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Impact

• We cannot simply reverse the onset of clinical
  deterioration in patients not on medication with
  vigorous pharmacological interventions
• Relapse rate doubles compared to those maintained
  on continuous medication

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Impact of Partial Adherence Asthma
Impact on Illness
Impact on Patient
Weeks
Days
Months
Hours
Missed Doses
Courtesy of Robert Lasser and Sam Keith
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Impact of Partial Compliance Schizophrenia
Impact on Patient
Impact on Illness
Duration of Missed Doses
Courtesy of Samuel Keith
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Psychotic RelapseWhat is the impact on the
person?
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Psychotic RelapseWhat is the impact on the
person?

• Is it biological degeneration?
• Is it treatment resistance?
• Is it demoralization?

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Multiple Relapses May Lead to Continuing
Neurodegeneration

• Deterioration in schizophrenia is probably the
  result of neurodegeneration
• Many patients who stop treatment and then relapse
  fail to regain prior level of function
• Early intervention is key
• Antipsychotics may improve long-term outcome by
  counteracting neurodegeneration

Lieberman JA, et al. J Clin Psychiatry
199657(suppl 9) 5-9. Sheitman BA, et al.
Psychiatric Res. 199832143-150.
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Impact of Multiple Relapses
Average time to remission in three successive
episodes (N10)
Adapted from Lieberman J et al., J Clin
Psychiatry 1996.
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Is continuous therapy the answer?
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Long-term Studies of Continuous vs Targeted
Maintenance

• 5 studies with at least 1 year of follow-up
• Compared continuous antipsychotic treatment with
  targeted treatment given only when patients
  showed early signs of clinical worsening

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Continuous vs Targeted Maintenance
Rates of Relapse After 1 Year
Kane JM. N Engl J Med. 199633434-41.
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Clinical Solutions
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Psychosocial Solutions

• Education of physicians, families and persons
  suffering from schizophrenia
• Need long-term model of schizophrenia
• Must recognize increasing penalty of each relapse
• Families, friends and patients should not have to
  be pill police
• Development of effective compliance therapies

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Long-Acting Medication

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Advantages

• Confidence in medication availability
• Predictable and stable plasma levels
• No first pass metabolism - Lower dose possible
• A missed injection does not lead to abrupt
  withdrawal
• A missed injection (non-compliance) is
  immediately known
• Advantages for patients
• Freedom from daily pill taking
• Consistent contact with treatment team

Kane JM et al. Eur Neuropsychopharmacol
1998855-66.
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Potential to Improve Relapse Rates With Depot vs
Oral Antipsychotics
Relapsed ()
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48
2
-16
24
9


Mantel-Haenszel P lt 0.0002. Davis JM et al.
Drugs. 199447741-773.
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These Were All Conventional DepotsWould the
Same Be True of atypicals?

• One year, open label study
• Stable patients
• Switched from
• Oral Atypical to long-acting atypical (same drug)

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1-year Trial Prior Antipsychotic (AP)
Medication
None
HAL oral
OLZ
Other oral
Other-D
HAL
FLP
PER
RIS 4 mg/d or less
Typical Depots n 188 (25.9)
n 208 (28.7)
FLX
RIS over 4 mg/d
n 128 (17.7)
ZUC
Multiple antipsychotics
n 120 (16.6)
Fleischhacker et al. J Clin Psych. Oct 2003
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Conventional Depot to Long-acting Atypical
measure of efficacy
Mean PANSS Total Score
P lt 0.001 vs prior AP





12 24 36 50
EP (weeks)
Fleischhacker et al. J Clin Psych. Oct 2003
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Oral Atypical to Long-acting Atypical (same
drug) A measure of compliance
Mean PANSS Total Score
P lt 0.05 P lt 0.001 vs prior AP










12 24 36 50
EP
Fleischhacker et al. J Clin Psych. Oct 2003
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Efficacy AnalysisOral Atypical to Long-acting
Atypical Categorical Improvement
(n78) (n118)
Patients
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60
20
Improvement in PANSS from Baseline to Endpoint
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Why not use a long-acting injectable?Beliefs vs
Reality
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Patients Often Prefer Long-acting Antipsychotics
Wistedt, 1997
Jacobsson, 1980
Eastwood, 1997
Pereira, 1997
Hoencamp, 1995
Desai, 1999
50
0
100
Percentage
Compared oral atypical with conventional
long-acting. Walburn J et al. Br J Psychiatry.
2001179300-307.
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Compliance

• Clinical Decision-Making

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The Decisions Facing EVERY Clinician
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Why clinically consider a long-acting atypical
antipsychotic for early episode?

• They have the most to lose
• 80 will have a second episode and with each
  episode recovery is less complete
• Adherence problems
• Greater after first episode because model of
  chronic illness not established
• 75 off medication by 2 years

Robinson DG, et al. Arch Gen Psychiatry
1999562417 Lieberman J, et al. J Clin
Psychiatry 199657(Suppl. 9)6871 Weiden PJ,
Zygmunt A. J Pract Psychiatry Behav Health
199710610
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Why clinically consider a long-acting atypical
antipsychotic for early episode?

• Remission
• 5 times longer with medication than without
• A cognitive impairment that affects
• attention, persistence, attitude

Robinson DG, et al. Arch Gen Psychiatry
1999562417 Lieberman J, et al. J Clin
Psychiatry 199657(Suppl. 9)6871 Weiden PJ,
Zygmunt A. J Pract Psychiatry Behav Health
199710610
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Non-Compliance

• Not reasonable to expect in schizophrenia
• All data point to this
• The illness itself makes it difficult
• A critically important aspect of recovery

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Compliance

• If we really believe that medication works
• We need to be sure that it is delivered
• Not necessarily to those who refuse
  medicationpeople have the right to decline
• To those who really want to take it, but because
  of the illness they have, they are unable to do
  so.