**2.1 Terminology: Compliance, adherence and persistence**

The definitions used to describe the concepts of compliance, adherence and persistence are not standardised, which causes many difficulties when comparing or combining results of different studies. The definitions from the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and the WHO are the most widely accepted in the literature.

Medication compliance, as defined by the ISPOR, "refers to the act of conforming to the recommendations made by the provider with respect of timing, dosage and frequency of medication taking" (Carmer et al., 2008). Compliance is expressed as an index number, which is typically given as a percentage and refers to a specified time interval. One of the most commonly used models for calculating medication compliance is the medication possession ratio (MPR). In the model of the MPR, the number of days of medication supplied within the refill interval is divided by the number of days in the refill interval (Peterson et al., 2007). Medication compliance may also be reported as a dichotomous variable, classifying patients into good and poor (or non-) compliance categories (Table 1). The cut-off point of compliance should be determined according to medication and type of disease. However, it is generally set independently at 80%, whether this compliance rate is adequate for disease control or not (Carmer et al., 2008).


**∑ MPR**: ((270+240+210)/3)/360 = 0.66 → 66%\*

\*:Patient is non-compliant (cut-off point: 80%).

│x│: medication supplied,││: medication not supplied

Table 1. Calculation of medication compliance: medication possession ratio (MPR)

According to the definition of ISPOR, medication persistence may be described as "the duration of time from initiation to discontinuation of therapy" (Carmer et al., 2008). Persistence analyses must also define a permissible gap period, which specifies the maximum allowable time period between refills without discontinuation of the therapy. Persistence may be counted in days. However, it can also be given as the percentage of the number of persistent patients at the end of a predefined time period (Patricia et al., 2006) (Table 2). A patient's drug taking behaviour can best be quantified using both parameters: medication compliance and persistence (Carmer et al., 2008).

Although most research in the field has focused on medication compliance and persistence, therapeutic adherence certainly includes other non-drug therapeutic recommendations

There are a number of terms used to describe the extent to which a patient undertakes the recommendations (medication regimens, lifestyle changes, etc.) of health-care providers.

The definitions used to describe the concepts of compliance, adherence and persistence are not standardised, which causes many difficulties when comparing or combining results of different studies. The definitions from the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and the WHO are the most widely accepted in the literature.

Medication compliance, as defined by the ISPOR, "refers to the act of conforming to the recommendations made by the provider with respect of timing, dosage and frequency of medication taking" (Carmer et al., 2008). Compliance is expressed as an index number, which is typically given as a percentage and refers to a specified time interval. One of the most commonly used models for calculating medication compliance is the medication possession ratio (MPR). In the model of the MPR, the number of days of medication supplied within the refill interval is divided by the number of days in the refill interval (Peterson et al., 2007). Medication compliance may also be reported as a dichotomous variable, classifying patients into good and poor (or non-) compliance categories (Table 1). The cut-off point of compliance should be determined according to medication and type of disease. However, it is generally set independently at 80%, whether this compliance rate is

*A* x x x x x x x x x 9x30=270 270/360=0.75 *B* x x x x x x x x 8x30=240 240/360=0.66 *C* x x x x x x x 7x30=210 210/360=0.58

According to the definition of ISPOR, medication persistence may be described as "the duration of time from initiation to discontinuation of therapy" (Carmer et al., 2008). Persistence analyses must also define a permissible gap period, which specifies the maximum allowable time period between refills without discontinuation of the therapy. Persistence may be counted in days. However, it can also be given as the percentage of the number of persistent patients at the end of a predefined time period (Patricia et al., 2006) (Table 2). A patient's drug taking behaviour can best be quantified using both parameters:

Although most research in the field has focused on medication compliance and persistence, therapeutic adherence certainly includes other non-drug therapeutic recommendations

Table 1. Calculation of medication compliance: medication possession ratio (MPR)

**Supply**  (days)

**MPR** 

The most commonly used terms are compliance, adherence and persistence.

**2.1 Terminology: Compliance, adherence and persistence** 

adequate for disease control or not (Carmer et al., 2008).

( 1 month = 30 days)

**Drugs Months** 

**∑ MPR**: ((270+240+210)/3)/360 = 0.66 → 66%\* \*:Patient is non-compliant (cut-off point: 80%).

│x│: medication supplied,││: medication not supplied

medication compliance and persistence (Carmer et al., 2008).

**2. General overview of adherence** 


\*: Patients persisted an average of 120 days ((120+180+60)/3) \*\*: 33% (1/3) of the patients were persistent for 180 days

│x│: medication supplied,││: medication not supplied

Table 2. Calculation of medication persistence

(following diets, executing lifestyle changes, etc.) as well. Explanation of adherence by the WHO also reflects this concept. The WHO definition of adherence is the following: "the extent to which a person's behaviour—taking medication, following a diet, and/or executing lifestyle changes—corresponds with agreed recommendations from a health-care provider" (WHO, 2003). This definition accurately highlights the importance of the patient's active role in their own health-care, which emphasises that the relationship between the patient and the health-care provider should be based on a partnership, instead of a onesided paternal relationship.

Recently, medication adherence has become the preferred term instead of medication compliance. The primary difference between compliance and adherence is that compliance reflects the patient as a passive recipient of medical advice. Furthermore, compliance has also been viewed as a judgmental term when applied to patient behaviour. Thus, medication adherence will be the preferred term from this point forward.

### **2.2 Methods of measuring adherence**

Most studies in adherence research have focused on medication-taking behaviour. Therefore, the following is a brief overview of the methodology of the assessment of medication adherence in COPD. There are a number of ways to assess adherence; nevertheless, there is not a gold standard because each method has strengths and limitations (Table 3).

The easiest way to assess medication adherence within clinical settings is to collect information from the patient themselves through questionnaires or patient diaries (Agh et al., 2011; Dolce et al., 1991; George et al., 2005, 2006a; Laforest et al., 2010). However, it should be mentioned that self-reporting methods may overestimate a patient's drug-taking behaviour (Dompleing et al., 1992; Rand et al., 1992, 1995). Using postal administration can help to obtain data that are more objective because patients are normally intimidated by their health-care providers and tend to give them the expected answers (Agh et al., 2011). Another commonly used method is the analysis of electronic pharmacy records (Breekveldt-Postma et al., 2007; Cramre et al., 2007; Jung et al., 2009). Retrospective database analysis is rapid and inexpensive. Nevertheless, this approach may also be inaccurate. It evaluates the prescriptions written by physicians or the prescriptions filled by patients, but not the medication intake directly.

Adherence to Therapy in Chronic Obstructive Pulmonary Disease 279

The assessment of therapeutic adherence seems to be more complicated. However, clinical outcomes can be used to evaluate adherence, as these depend largely on the extent to which

Medication non-adherence can take many forms: failure to fill prescriptions (primary nonadherence) or overuse, underuse or alteration of schedule or doses of medication (secondary

Only a limited number of studies have evaluated adherence in patients with COPD. Jung et al. (Jung et al., 2009) examined medication adherence and persistence among a sample of COPD patients during their last year of life. The study reviewed the use of inhaled corticosteroids (ICS), long-acting β2 agonists (LABA), anticholinergics (AC) and methylxanthines (MTX), alone and in combination. The overall MPR to COPD medication was 44%. Approximately 30% of the patients persisted with the therapy, and the overall time to discontinuation was 94.2 days. These rates of cooperation are much lower than the drug-taking rates in other chronic diseases. Adherence in hypertension, dyslipidaemia and diabetes is, on average, 72% (MPR), and persistence is 63% (Cramer et al., 2008). In the previously mentioned study, Jung et al. (Jung et al., 2009) found differences between the mean MPRs of COPD drug classes (MTX: 52%, AC: 38%, ICS: 35%, LABA: 34%). Medication adherence was the highest with MTX. One possible explanation of this finding could be that elderly patients may have more difficulty using inhaled medications; therefore, they prefer

Breekveldt-Postma et al. (Breekveldt-Postma et al., 2007) evaluated medication persistence among COPD patients in the first therapy year; new users of tiotropium, ipratropium, LABA and a fixed combination of LABA and ICS (LABA + ICS) were included in their study. The persistence was the highest, 37%, with tiotropium. The COPD patient's drugtaking behaviour was found to be significantly lower with other inhaled medications (ipratropium: 14%, LABA: 13%, LABA + ICS: 17%). Subgroup analysis of persistence data in patients with prior hospitalisation for COPD indicated that hospitalisation may have an enhancing effect on patient cooperation. The one-year persistence rates were increased by 2– 3 times in the first year after hospitalisation (tiotropium: 61%, ipratropium: 37%, LABA: 41%, LABA + ICS: 33%). A similar study by Cramer et al. (Cramer et al., 2007) examined trends in patient persistence with inhaled COPD medication. They monitored the refill data of ipratropium, ipratropium + salbutamol, formoterol, formoterol + budesonide, salmeterol, salmeterol + fluticason and tiotropium in a cohort of 31,368 COPD patients. The one-year persistence was considerably higher with tiotropium (53%) compared with other treatments (7%–30%). The significant differences in levels of adherence and persistence between

All of the aforementioned studies examined primary adherence, which is based on prescription refill rates. These results represent the maximum possible level of patient cooperation because refill adherence cannot confirm ingestion and does not provide any information on the frequency of medication use. Studies evaluating secondary adherence

inhaled medications could be partially the result of dosing frequency.

can provide data about medication use that is more reliable.

a patient undertakes the recommendations of health-care providers.

non-adherence) (Bourbeau et al., 2007; George et al., 2007; Rand et al., 2005).

**3. Adherence with COPD therapy** 

**3.1 Adherence to medication** 

oral drugs.


\*"Dumping": removing most of the medication at one time.

Table 3. Methods of measuring adherence

Pill count (Dompleing et al., 1992; van Grunsven et al., 2000) and canister weighing (Rand et al., 1995; Simmons et al., 2000) are widely used methods of adherence assessment in clinical trials. Pill counts are limited to oral medications, but canister weighing can also be used to monitor inhaled drugs. These approaches assess only the quantity of the medication removed from the canister without indication of ingestion, dose or dose frequency. Electronic compliance monitoring devices can provide more objective information about medication use than the aforementioned methods (Corden et al., 1997; Simmons et al., 1996, 2000). The cap of the pill bottles can be equipped with a microchip that stores data about each opening. Electronic recording devices (chronologs) can be fitted to metered-dose inhalers and nebulisers as well. Electronic monitors provide an accurate measure of dosing history but also cannot confirm ingestion. The major disadvantage of this method is the price; it is relatively costly.

Medication compliance can also be estimated based on direct assessments, such as direct observation of the medication intake or evaluation of blood levels or urinary excretion of the drug or its metabolite or drug-marker (Clark et al., 1996; Hatton et al., 1996). These methods are unpleasant for the patient and expensive. Interestingly, therapeutic drug monitoring may overestimate the actual adherence rate because patients tend to comply shortly before the drug test but not during the whole observation period. Another limitation is that a biochemical drug test is insensitive to inhaled medication.

The assessment of therapeutic adherence seems to be more complicated. However, clinical outcomes can be used to evaluate adherence, as these depend largely on the extent to which a patient undertakes the recommendations of health-care providers.
