1. Defining Adherence and Persistence
Sapna N. Patel
UCSF Pharm. D. Candidate 2008
Preceptor Dr. Craig S. Stern
March 21, 2008

2. Pictures

3. Relevance
Evaluating adherence & persistence is necessary for accurate assessment of:
Cost-effectiveness of therapy
Quantifying drug exposure in a population over time
Drug Utilization Patterns for Formulary Development
Identifying appropriate therapy for patients
Assessing clinical outcomes of treatment
Prior Authorization Criteria
Define cost-effectiveness

4. Impact of A&P Low adherence & persistence
Increased morbidity & mortality
Increased health-care costs
“Forgiveness”: therapeutic effects of drug therapy despite noncompliance

5. Proposed Definitions
International Society for Pharmacoeconomics and Outcomes Research (ISPOR)
Adherence (compliance): the extent to which a patient acts in accordance with the prescribed interval & dose of a dosing regimen
Persistence refers to the act of continuing treatment for the prescribed duration
Treatment adherence & persistence together contributes to overall drug effectiveness
Conceptually, compliance and persistence represent two constructs that are based on one’s belief in the efficacy of the medication, the severity of their illness, and their ability to control it with medication.
Compliance follows the initial appraisal of the health threat and behavioral changes to develop the habit of taking medication in accordance with the physician’s prescription (time, quantity, and frequency).
Medication compliance. Medication compliance (synonym: adherence) refers to the act of conforming to the recommendations made by the provider with respect to timing, dosage, and frequency of medication taking.
Therefore medication compliance may be defined as “the extent to which a patient acts in accordance with the prescribed interval and dose of a dosing regimen.”
Compliance is measured over a period of time and reported as a percentage.
This definition is operationalized in prospective assessments as dose taking in relation to what was prescribed. Table 1 shows compliance patterns for a patient prescribed a once-daily medication. Electronic monitoring provides sufficient details to calculate the number of doses taken daily as well as whether the doses were taken at appropriate intervals (e.g., approximately 12 hours apart for a twice-daily dosing). Additional details can be obtained as number of days with extra doses or without any doses.
The definition is operationalized in retrospective assessments as the number of doses dispensed in relation to the dispensing period, often called the “medication possession ratio (MPR)” [28]. Compliance with the prescription is assumed when the medication is dispensed.
Retrospective prescription claims database analyses lack the details of daily dosing that are available with prospective electronic monitoring; however, as these tools are often the only sources available for assessing compliance, it is suggested that this caveat is noted when describing compliance in these instances.

6. CMS Definitions

7. Current Issues Multiple definitions and measurement models
Hinder health outcomes & cost-effectiveness analysis
Prevent comparisons of different studies
Standardized definition would:
Help develop more effective strategies to enhance medication related A&P and decrease health-care costs

8. Measures of Adherence Direct Indirect
Desired observation or study evaluation period
“Between fills” periods
Treatment Gaps

9. Direct Methods Method Pros Cons Directly Observed Therapy
Most accurate
Time consuming
Impractical
Hiding pills
Medicine or Metabolite Blood Levels
Objective
Expensive
Metabolism variation
White coat
adherence
Biologic Markers in blood

10. Indirect Methods Method Pros Cons Questionnaires, self-reporting
Cost-effective
Time consuming
Useful in clinical setting
Subjective
Infrequent visits =
increased error
Prescription rate refills
Objective
Expensive
Metabolism variation
White coat Adherence
Pill Counts
Easy-to-do
Quantitative results
Easily altered by
patient

11. Measuring Adherence: Medication Possession Ratio (MPR)
total days’ supply
MPR =
X 100
total # days evaluated
353/365 X = fill in%
Equals overall percent adherence value (medication availability)
Adherence over observation period

12. MPR (cont) Pros: Easy to calculate Widely used adherence measure Cons:
Participants get >1 fill in one day (ex: vacation supply)
Change in prescribing directions
Refills occur close to study termination

13. “Between Fills” Measures
Days Between Fills Adherence Rate (DBR)
DBR =
(last claim date – 1st claim date) – total days’ supply
last claim date – 1st claim date
X 100
1 -
Compliance Rate (CR)
total days’ supply – last days’ supply
CR =
X 100
last claim date – 1st claim date
Refill Compliance Rate (RCR)
total days’ supply
last claim date – 1st claim date
RCR =
X 100
Medication Possession Ratio, Modified (MPRm)
total days’ supply
MPRm =
X 100
(last claim date – 1st claim date) + last days’ supply

14. “Between Fills” Measures
Pros:
Helps accounts for cutoff examination date period
Consistent results seen with denominator of total study evaluation period
Cons:
In cases of single refills
Smaller denominator 
Cannot assess/overestimation of adherence

15. Treatment Gaps CMG = Ex: (362-365)/362 = 0.00 or -0.01
total gap days
CMG =
total days’ study participation – total days’ supply
total days’ study participation
Continuous Measure of Medication Gaps (CMG) :Provides time patient does not have medication available (%)
Ex: ( )/362 = or -0.01
Range:
0.0 = complete adherence
1.0 = complete non-adherence
(-) values = surplus days (due to early refill or overfill)

16. Measuring Persistence
Minimum-Refills Model
Proportion of Days Covered Model
Refill Sequence Model
Anniversary Model

17. Minimum-Refills Model
Persistence: Pt being dispensed a minimum # of Rx’s per year

18. Minimum-Refills Model
Pros:
Might be useful for describing “as needed” medication use
Cons:
Does not account for length of time between refills
Does not account for amount of time each refill should last

19. Proportion-of-Days-Covered Model
Persistence: Enough medication dispensed to cover a specified proportion of days within a fixed interval (ex: 1 year)
Example: 210 days’ supply/365 day interval = 58% PDC during the 1st year

20. Proportion-of-Days-Covered Model
Pros:
Relies on uniform evaluation period for all patients
Shorter follow-up times create bias in PDC (higher numbers)
Fewer opportunities for noncompliance/nonpersistence
Cons:
Cut-off arbitrary
No info about timeliness of refilling or persistence

21. Refill-Sequence Model
PG: Permissible gap
Persistence: total duration of a continuous sequence of refills
Unacceptable gap: Interval between the date of the 1st Rx and refill considered to be nonpersistence
Defined persistence as the total duration of a continuous sequence of refills, although the operational definition of a continuous sequence varied from study to study.
Refill-sequence models of persistence focus on quantifying the length of the total interval. Such models calculate the time between the date of the first prescription and the point at which an unacceptable gap between refills occurs. Thus, if a patient has not refilled a prescription within a predetermined number of days, the patient is considered to have discontinued therapy and is thereafter considered nonpersistent. Refill-sequence models of persistence generally permit switches among drugs with shared indications.
The grace period allowed for the gap in medication differed across studies. Grace period should NOT be arbitrary.
From Ref 3 (p.455) The length of the GP can reflect issues related to medication half-life, clinical efficacy, dosage titration, or source of refilling. It can also be a function fo the # of days in the previous Rx’s supply. However, this may be problematic with mail-order. Using ½ the previous Rx’s days’ supply (for mail-order, it would be a 90 day supply) would give us a 45 day grace period, which may be too generous.
The figure illustrates the sensitivity of refill-sequence models of persistence to the length used for the permissible gap. This sensitivity may offset the slight advantage conferred by not requiring an accurate measure of days supplied per prescription. When maximum days supplied is regulated (ie, by insurers or local health authorities), reasonable estimates of persistence may be achieved using those limits in conjunction with refill-sequence models.
Sensitivity of model dependent on the grace period used
“Continuous” sequence defined differently from study to study
Con: Does NOT incorporate info about med-taking behavior w/in interval of interest

22. Refill-Sequence Model
Pros:
Permit switches between Rxs with same indication
Increased accuracy of measuring persistence when
Information can be used to assess effect of an intervention aimed at improving persistency
Cons:
May not consider all refilling behavior across the observation period.
Once an individual is classified as nonpersistent, future refilling behavior is no longer considered
Patient could have discontinued or switched medications
PG not well defined

23. Anniversary Model Patient 1: more consistent
4 Fills
Monthly Fill
Persistence: Rx refilled within a specified interval (e.g., +/- 30 days) surrounding the anniversary of 1st Rx
Both patients are persistent at 1 year
Patient 1: more consistent

24. Anniversary Model Pros: Cons:
Simple to use
Accurate method for timeliness of medication refilling IF small refill gaps are small
Cons:
No consideration given to refills within the 1-year interval
Patient is persistent, but not necessarily adherent
This is a HYPOTHETICAL patient. According to this definition, he IS persistent!
The simplest method of measuring persistence with treatment is the anniversary model, in which a patient is deemed persistent for 1 year if she/he refills a prescription within a specific interval surrounding the anniversary of her/his first prescription (eg, -+30 days).
This method uses a simple, dichotomous measure of persistence (persistent vs not persistent), with no consideration of prescription refills within the 1-year interval.
Applying the anniversary model, the hypothetical patient would be considered persistent at 1 year.
This method is limited by the fact that it doesn’t take any fills w/in the 1-year interval into account. Thus, an Rx can be filled a year apart and the patient can still be considered persistent (though not adherent).

25. Summary

26. References
Osterberg L, Blaschke T. Adherence to Medication. N Engl J Med 2005;353;5:
Caetano PA, Lam JMC, Morgan SG. Toward a standard definition and measurement of persistence with drug therapy: Examples from research on statin and antihypertensive utilization. Clin Therapeutics 2006;28:
Cramer JA, Roy A, Burrell A, et al. Medication compliance and persistence: Terminology and definitions. Value Health 2008;11. [Epub June 25, 2007]
Sikka R, Xia F, Aubert RE. Estimating medication persistency using administrative claims data. Am J Managed Care 2005;11:
Hess LM, Raebel MA, Conner DA, Malone DC. Measurement of adherence in pharmacy administrative databases: A proposal for standard definitions and preferred measures. Ann Pharmacother 2006;40:
Hughes D, Cowell W, Koncz T, Cramer JA. Methods for integrating medication compliance and persistence in pharmacoeconomic evaluations. Value Health 2007;10(6):
assessed March 20, 2008.