**3.1 Adherence to medication**

278 Chronic Obstructive Pulmonary Disease – Current Concepts and Practice

Inexpensive

Inexpensive

the ingestion

*Biological assay* Confirm drug use Expensive

Accurate measure of dosing history

*Therapeutic outcome* Easy to obtain Clinical outcomes can depend

Accurate indication of

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

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

**Indirect methods** 

*Electronic adherence* 

**Direct methods**  *Direct observation of the medication intake* 

*monitoring*

*Patient self-report: adherence questionnaire, patient diary* 

*Pharmacy refill data* Rapid

*Pill count, inhaler weighing* Easy to obtain

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

biochemical drug test is insensitive to inhaled medication.

Table 3. Methods of measuring adherence

price; it is relatively costly.

 **Advantage Disadvantage** 

Easy to obtain Unreliable

Inaccurate:

Inaccurate:

Expensive

incomplete

"Dumping"\*

on other factors

use over time

Pharmacy database can be

No indication of ingestion

No indication of ingestion

No indication of ingestion

Unpleasant for the patient Require large human resources

Unpleasant for the patient Limited information regarding

Insensitive to inhaled drugs

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

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 oral drugs.

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 inhaled medications could be partially the result of dosing frequency.

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 can provide data about medication use that is more reliable.

Adherence to Therapy in Chronic Obstructive Pulmonary Disease 281

Adherence to non-drug therapies, such as respiratory rehabilitation, exercise programs, healthy lifestyle or smoking cessation, is crucial in the management of COPD. Approximately 60% of the patients refuse to take part in rehabilitation programs, and out of those who join, 30% fail to complete the program (Nici et al., 2006). The most important barriers to rehabilitation adherence include exacerbations and progression of COPD (Bourbeau et al., 2007; Brooks et al., 2002). The literature in this field is quite weak; there is a clear need for further research to find out more about the suboptimal adherence to non-drug

Non-adherence in patients with COPD is a multidimensional phenomenon. The factors include the characteristics of the patient, the disease, the therapies and the health-care provider–patient relationship; many of these are potentially modifiable (Baiardini et al.,

COPD is a progressive chronic disease. Adequate cooperation with COPD therapy can improve the patient's quality of life and reduce the frequency of exacerbations but cannot fully control the disease symptoms. A progressive decline in lung function is often interpreted by patients as the medication not helping, so they stop following the recommendations (Chambers et al., 1999). In contrast, a lack of clinical symptoms could also be a reason for suboptimal adherence (DiMatteo, 2004). As implied above, the negative impact of COPD severity or lung function on a patient's adherence is not obvious. Prior studies have shown that disease severity or the post-bronchodilator forced expiratory volume in one second (FEV1) percentage may be either not (Agh et al., 2011) or negatively (Turner et al., 1995) related to adherence. The pathologic characteristics of COPD influence

**Treatment** 

Polypharmacy ↓

Side effects ↓

 Higher dosing frequency ↓ Higher medication cost ↓

**Health-care provider–patient relationship**  Higher quality of communication ↑ Type of caregiver: specialist ↑

Oral administration ↑

 Closer follow-up ↑ Hospitalisation ↑

**4. Factors associated with adherence in patients with COPD** 

**3.2 Adherence to non-drug therapy** 

therapies in patients with COPD.

Poor prognosis ↓

 Disease severity ― Lung function ―

Social support ↑

Gender -

**COPD** 

**Patient** 

2009; Restrepo et al., 2008; WHO, 2003) (Table 4).

Progressive nature of the disease ↓\*

Lack of clinical symptoms ↓

 Demographic factors: old age ↑ Improved quality of life ↓

Psychiatric co-morbidities ↓

\*Influence on adherence: decrease (↓), improve (↑), no effect (―)

**4.1 Factors related to the characteristics of COPD** 

Table 4. Factors associated with adherence in patients with COPD

The Lung Health Study (Rand et al., 1995) was a double-blind, multicentre, randomised, controlled trial on smoking intervention and bronchodilator therapy (ipratropium or placebo) as early interventions of COPD. Satisfactory adherence was reported by 70% of the participants at the first 4-month follow-up visit, but this rate declined to 60% over the next 18 months. The overall adherence estimated by canister weighing was 72% in the first year and 70% in the second year. Nevertheless, in the first year, only 48% of the participants were classified as adherent with both methods. In an ancillary study within the Lung Health Study, medication adherence rates measured by both self-report and canister weighing were compared with data from electronic medication monitoring (Rand et al., 1992). This study found that self-reporting and canister weighing significantly overestimate adherence: only 15% of the participants used their inhaler 2.5 or more times per day (when three puffs per day were prescribed). In addition, 14% of the patients seemed to be "dumping" medication prior to the clinic visit by removing most of the medication at one time (i.e., actuating inhaler more than 100 times in a 3-h interval) to hide non-adherence. The level of adherence with the prescribed medication regimen was best immediately following each follow-up visit and declined during the interval between follow-up visits. The adherence after each visit was lower for each successive follow-up. These trends could be observed only with electronic medication monitors; self-reporting or weighing could not detect these changes (Simmons et al., 1996).

Studies also suggest that while the underuse of medication seems to be one of the largest problems in the management of COPD, overuse is also common. Symptom-relieving drugs, such as short-acting β2 agonists (SABA), are more often overused than maintenance therapies (Dekker et al., 1993). Krigsman et al. (Krigsman et al., 2007a) evaluated the primary adherence in patients with asthma and COPD. The obtained results indicated that 53% of the patients underused and 18% overused their prescribed medication regimens. In another study by Krigsman et al. (Krigsman et al., 2007b), it was found that 59% of COPD patients had an undersupply and 12% had an oversupply of ICS medication.

Eighty-four percent of COPD patients have one or more co-morbidity (Yeo et al., 2006). For this reason, a question arises about whether the level of a patient's adherence is the same with therapies for different chronic diseases. Krigsman et al. (Krigsman et al., 2007c) investigated refill adherence in patients who suffered from diabetes and COPD. Participants showed higher adherence for their diabetes drugs (68%) than their COPD medications (42%).

Long-term oxygen therapy (LTOT) plays an important role in the management of COPD (Würtemberger & Hütter, 2000). The daily duration of oxygen administration is crucial in the effectiveness of LTOT. Pepin et al. (Pepin et al., 1996) found that only 45% of the COPD patients who were prescribed oxygen therapy for an average of 16 hours per day (16±3 h/d) used oxygen for 15 hours or more per day. Another study reported that 23% of the patients who had been prescribed LTOT refused to use liquid oxygen away from home and that 12% underused their oxygen (Würtemberger & Hütter, 2000).

Immunisation with both the influenza and pneumococcal vaccines may produce a number of acute exacerbations, hospitalisation and COPD mortality (Nichol et al., 1999; Varkey et al., 2009). However, the vaccination rates in patients with chronic lung diseases are low (Nichol et al., 1999; Tuppin et al., 2011), and the willingness to vaccinate differs by age group. The influenza vaccination status is significantly higher in patients aged 65 years or older (86.2%) than in the younger population (65.7%) (Mehuys et al., 2010).
