Download Refill Adherence to Long-Term Drug Treatment with a

Digital Comprehensive Summaries of Uppsala Dissertations
from the Faculty of Pharmacy 60
Refill Adherence to Long-Term
Drug Treatment with a Focus on
Asthma/COPD Medication
KRISTIN KRIGSMAN
ACTA
UNIVERSITATIS
UPSALIENSIS
UPPSALA
2007
ISSN 1651-6192
ISBN 978-91-554-6931-3
urn:nbn:se:uu:diva-8094
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“Drugs don’t work in patients
who don’t take them”
C. Everett Koop, MD.
former US Surgeon General
LIST OF PUBLICATIONS
The thesis is based on the following papers, which will be referred to by
their Roman numerals:
I
Andersson K1, Melander A, Svensson C, Lind O and Nilsson
JLG. Repeat prescriptions: refill adherence in relation to patient
and prescriber characteristics, reimbursement level and type of
medication. Eur J Public Health 2005; 15(6):621-626.
II
Krigsman K, Melander A, Carlsten A, Ekedahl A and Nilsson
JLG. Refill non-adherence to repeat prescriptions leads to treatment gaps or to high extra costs. Pharm World Sci 2007; 29:1924.
III
Krigsman K, Nilsson JLG and Ring L. Refill adherence for patients with asthma and COPD: comparison of a pharmacy record
database with manually collected repeat prescriptions. Pharmacoepidemiol Drug Saf 2007; 16(4):441-448.
IV
Krigsman K, Moen J, Nilsson JLG and Ring L. Refill adherence
by the elderly for asthma/COPD drugs dispensed over a ten-year
period. (submitted)
V
Krigsman K, Nilsson JLG and Ring L. Adherence to multiple
drug therapies: refill adherence to concomitant use of diabetes
and asthma/COPD medication. Pharmacoepidemiol Drug Saf
2007 June 13; [Epub ahead of print].
Reprints were made with the permission of the publishers.
1
Andersson’s surname is now Krigsman
CONTENTS
DEFINITIONS..............................................................................................10
INTRODUCTION ........................................................................................13
BACKGROUND ..........................................................................................15
Definition of adherence ............................................................................15
Factors influencing adherence..................................................................16
Reasons for non-adherence..................................................................17
Consequences of non-adherence..........................................................19
Interventions to improve adherence.....................................................20
Adherence to long-term treatment – asthma/COPD.................................21
Measuring adherence................................................................................22
Pharmacy records ................................................................................26
AIMS OF THE THESIS ...............................................................................28
METHODS ...................................................................................................29
The Swedish pharmacy and drug reimbursement system ........................29
Prescriptions .............................................................................................29
Settings .....................................................................................................30
County of Jönköping............................................................................30
County of Jämtland..............................................................................31
Assessing refill adherence ........................................................................31
Data sources .............................................................................................33
Papers I-II ............................................................................................33
Papers III-V .........................................................................................33
Statistical analysis ....................................................................................35
Ethics........................................................................................................35
RESULTS .....................................................................................................36
Satisfactory refill adherence.....................................................................36
All drugs for long-term medication .....................................................36
Drugs for asthma/COPD......................................................................38
Undersupply .............................................................................................39
All drugs for long-term medication .....................................................39
Drugs for asthma/COPD......................................................................39
Oversupply ...............................................................................................40
All drugs for long-term medication .....................................................40
Drugs for asthma/COPD......................................................................40
Refill adherence to two long-term therapies ............................................40
Costs of oversupply for patients exempt and non-exempt from charges .42
Factors influencing adherence..................................................................43
Gender .................................................................................................43
Age.......................................................................................................43
Treatment time.....................................................................................43
DISCUSSION ...............................................................................................44
Overview of studies included in the thesis ...............................................45
Methodological considerations.................................................................45
Pharmacy records ................................................................................45
Settings ................................................................................................47
Assessing refill adherence ...................................................................47
Asthma/COPD .....................................................................................48
Adherence and non-adherence to chronic drug treatment ........................49
Satisfactory refill adherence ................................................................50
Undersupply.........................................................................................51
Oversupply...........................................................................................52
Refill adherence over a one-year period compared to that over a four-year
period........................................................................................................52
Refill adherence to two long-term therapies ............................................53
Costs of oversupply for patients exempt and non-exempt from charges .54
Factors influencing adherence..................................................................55
Improving patient adherence ....................................................................56
CONCLUSIONS ..........................................................................................58
FUTURE ASPECTS.....................................................................................59
SAMMANFATTNING PÅ SVENSKA .......................................................61
ACKNOWLEDGEMENTS..........................................................................64
REFERENCES .............................................................................................66
ABBREVIATIONS
AIDS
ATC
CI
COPD
DDD
ECHO
ERS
GOLD
HIV
MEMS
OR
OTC
PACT
RCR
SEK
WHO
Acquired Immune Deficiency Syndrome
Anatomical Therapeutic Chemical classification
Confidence Interval
Chronic Obstructive Pulmonary Disease
Defined Daily Dose
Economic, Clinical and Humanistic Outcomes
European Respiratory Society
Global Initiative for Chronic Obstructive Lung Disease
Human Immunodeficiency Virus
Medical Event Monitoring System
Odds Ratio
Over the counter
Prescribing Analysis and Cost Tabulation
Refill Compliance Rate
Swedish Krona (currency), conversion rate
2007-06-01; 100 SEK = € 11 and 100 SEK = US$ 15
World Health Organization
DEFINITIONS
Adherence
“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” [1].
Anatomical Therapeutic
Chemical classification
Classification system for drugs administered
by the WHO Collaborating Centre for Drug
Statistics Methodology, Oslo, Norway [2].
Compliance
“The extent to which a person’s behaviour (in
terms of taking medications, following diets, or
executing life-style changes) coincides with
medical or health advice” [3].
Concordance
Focuses on the consultation process rather than
on a specific patient behaviour, and it has an
underlying ethos of a shared approach to decision-making rather than paternalism [4].
Defined Daily Dose
The (at any given time) assumed average maintenance dose per day for a drug used for its
main indication in adults. Technical unit administered and decided by the WHO Collaborating Centre for Drug Statistics Methodology,
Oslo, Norway [2].
Oversupply
Refilled drugs covering >120% of prescribed
treatment time.
Patient profile
A graph for each individual patient that shows
the date of each dispensation and the time period covered by the dispensed drugs.
Primary non-adherence
Prescriptions issued to patients by their doctor,
but never registered at the pharmacy for dispensing [5].
Repeat prescription
Patients with long-term treatment normally get
several prescriptions in succession. In this thesis the term repeat prescription includes all
prescriptions for the same patient and the same
drug, during the study period. However, in Paper III, the term repeat prescription was referred to as prescribing.
Satisfactory refill adherence Refilled drugs covering 80-120% of prescribed
treatment time.
Undersupply
Refilled drugs covering <80% of prescribed
treatment time.
INTRODUCTION
Many patients do not use their medicines as prescribed. Patient adherence,
i.e. how well patients follow agreed recommendations of medical treatment,
has most likely been an issue for as long as pharmacotherapy has existed,
and it was described by observers as far back as Hippocrates. The problem
of non-adherence has been described worldwide and is seen in all parts of
the population independent of age, gender, race, education or socioeconomic
status [4]. Furthermore, non-adherence is observed in all types of diseases,
i.e. acute and chronic, serious and non-serious and in relation to both symptom-alleviating and other drug treatment [1]. The fact that many patients do
not use their medications as prescribed has been the focus of a vast amount
of research and has given rise to much debate over the last three decades [4].
In the literature, non-adherence to long-term medication therapy has been
reported among approximately half of all patients [1].
Non-adherence is a complex phenomenon that concerns practically every
medical and non-medical treatment. Horne [6] reported that patient adherence to drug therapy is influenced by many factors related to how the patients judge the necessity of their treatment relative to their concerns. These
factors comprise illness perceptions (symptoms), background beliefs (negative orientation to drugs in general) and contextual issues (view of others).
Horne’s conclusion was that there is no typical non-adherent patient; most
patients are non-adherent part of the time [6]. From a patient-centred perspective the meaning of medication in everyday life is more one of selfregulation than of compliance [7].
Non-adherence may involve both under- and oversupply of dispensed prescriptions. The proportion of dispensed prescriptions might be compared
with either the proportion actually prescribed or with the actual drug consumption [1]. It is important to improve adherence in order to achieve improved clinical outcomes as well as reduced health care costs [8-12]. A
meta-analysis [13] showed that good adherence to drugs as well as to placebo was associated with lower mortality. It was concluded that good adherence to drug therapy may be a surrogate marker for an overall healthy behaviour. However, adherence to drug therapy might not always be appropriate.
A requirement for keeping up adherence is that the underlying prescribing is
appropriate and furthermore that the patients have enough information to
13
make their own informed decisions of whether to follow the prescribed
treatment or not.
In this thesis, the focus will be on refill adherence to long-term drug treatment and on different methods for assessing refill adherence. Adherence to
medical treatment will be approached from a general perspective, emphasising long-term treatments, especially adherence to treatment of asthma and
chronic obstructive pulmonary disease (COPD). Asthma/COPD were selected since adherence to these treatments has been found to be particularly
low and improved adherence results in decreased morbidity [12] and mortality [1]. Moreover, the prevalence of these diseases in Sweden is currently
high and increasing [14], which further contributes to the importance of
gaining a greater understanding of adherence to asthma/COPD drugs.
14
BACKGROUND
Definition of adherence
The first and hitherto most common term for describing the phenomenon of
patients not taking their medications as prescribed is “compliance”. In 1976
Sackett and Haynes published one of the first books on compliance [15], and
this was followed by a more comprehensive book in 1979 entitled “Compliance in Health Care” [3], in which the state of the art in compliance research
was summarized. Compliance was defined in a general way as “the extent to
which a person’s behaviour (in terms of taking medications, following diets,
or executing life-style changes) coincides with medical or health advice” [3].
The term compliance is associated with the traditional patient-physician
relationship in which the patient is a passive responder to the physician’s
authoritarian recommendations. Based on this view, non-compliance may be
interpreted as patient incompetence if the patient does not follow the instructions or shows deviant behaviour.
An alternative, more modern term is adherence. The definition of adherence
according to the World Health Organisation (WHO) is [1]; “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”. Consequently, adherence and compliance refer to
the patient’s behaviour in relation to the treatment and are measured in the
same way. However, the term adherence indicates the patient’s behaviour in
relation to the therapy, the provider’s behaviour in relation to the therapy,
the patient/provider relationship as well as the environmental conditions in
which the patient and provider must operate individually and together [1].
Adherence attempts to emphasise that the patient is free to decide whether to
adhere to the doctor’s recommendations or not and that failure to do so
should not be blamed on the patient [3]. The term adherence indicates that
concordance between patient and provider is believed to increase adherence
and is separated from the term compliance through the view of this phenomenon.
15
The term concordance represents an even greater step towards a deeper understanding between patients and physicians, and denotes a process of prescribing and medicine-taking based on partnership between patient and prescriber (including others, such as pharmacists and other carers) [4]. The term
was introduced in 1997 [16]. Concordance is fundamentally different from
both compliance and adherence. It focuses on the consultation process rather
than on a specific patient behaviour, and it has an underlying ethos of a
shared approach in decision-making rather than a paternalistic structure.
Concordance gives the patients the opportunity to be involved in decisionmaking, and the doctor’s task is to ensure that the patients have enough information for making the decisions, and to support them in solving any problems they might have. This decision-making method should have a positive
impact on treatment behaviour, and health outcomes may be improved [4].
In this thesis the term adherence will be used to describe patients’ medication behaviour, since the term has a more positive approach to the treatment
than compliance. The focus will be on assessing refill adherence, which refers to the proportion of dispensed medicines in relation to issued prescriptions.
Factors influencing adherence
Adherence and non-adherence are complex phenomena that probably are
eternal human issues. The average rate of non-adherence to chronic medication has been estimated to be about 50% [1]. Even in clinical trials the average non-adherence rates have been reported to be 22-57% among patients
receiving treatment for chronic diseases [17-20]. Many studies of adherence
and non-adherence have been published, but relatively few Swedish studies
have estimated the proportion of adherence (see below). A Swedish literature
review (ABLA II) focusing on adherence within the Swedish health care
system was published in 2001 [21]. In the conclusion the authors strongly
recommend that the Swedish health care system improve drug adherence,
e.g. through feedback from the pharmacies to the physicians, education efforts for physicians, nurses and pharmacists, research and high-quality
workmanship. Various theses in Sweden have also been presented reporting
results on cardiovascular disease, glaucoma and Human Immunodeficiency
Virus (HIV) patients, and present reflections on medicines, and on adherence
from a general practice perspective [22-29]. There are few assessments of
adherence to chronic lifelong treatment based on longitudinal studies and
none have assessed the degree of adherence to different drug therapies at a
national Swedish level. It is therefore of interest to assess patients’ long-term
adherence in a Swedish setting and to do so, psychometrically sound and
feasible methods are needed.
16
Many studies consider drug acquisitions covering 80% or more of the prescribed treatment time to indicate satisfactory adherence. However, nonadherence may involve both undersupply/underuse and oversupply/overuse.
Underuse of medication seems to be more common than overuse [1]. It is
less common to define an upper cut-off point of satisfactory refill adherence,
above which there is an oversupply or overuse. This is probably because data
on oversupply are difficult to interpret, since the patient could have had the
drugs dispensed because of exemption from charges or the patient might
want to have drugs available in several locations – at home, at work and at
the vacation home. However some studies define satisfactory adherence as
equal to dispensed refills covering 100±20% [30-32].
Reasons for non-adherence
There is always a reason for reduction or discontinuation of patients’ prescribed medications [33]. Many of the reasons are behavioural and nonadherence is therefore often classified by the patient’s intent, as unintentional or intentional [34].
Unintentional non-adherence occurs when a patient wishes to adhere but is
prevented by forgetfulness or inability, e.g. misunderstanding the regimen,
language barriers in doctor-patient communication or incorrect device technique e.g. the inability to inhale medicines correctly [35-37]. Unintentional
factors are associated primarily with age and clinical variables like depression, anxiety and number of years of condition [34]. Among elderly patients
factors such as concurrent diseases, multimedication (polypharmacy) and
increased liability to adverse drug reactions may increase the tendency of
non-adherence [38]. The most frequently reported reason among younger
persons for taking too little medication is forgetfulness. This is according to
a study examining 195 college students’ adherence, beliefs and attitudes
towards physicians, medicines, illness and health [39].
Intentional non-adherence follows an active decision by the patient. This
means that the decision not to take the medication or to take a lower or
higher dose than prescribed is consciously made [34, 35]. Intentional nonadherence is associated with individuals’ beliefs and cognitions [34]. Effective prescribing must also take into account the patients’ beliefs, expectations and adherence behaviour. The theories of adherence behaviour to drug
treatment have been developed from health behaviour in general and different health behaviour models have been used to study patient adherence, e.g.
the Health Belief Model [40], the Theory of Reasoned Action/the Theory of
Planned Behaviour [41, 42] and the Transtheoretical Model of Behaviour
Change [43]. All of these models describe the medication behaviour as being
17
a result of both internal and external factors like attitude, perceived severity,
perceived barriers, beliefs about outcomes, benefits, costs and motivation;
the models have successfully been implemented in patient adherence studies
[44-46]. One study [46] showed that some variables from the Health Belief
Model and the Theory of Reasoned Action, i.e. barriers, benefits, belief
strength, outcomes evaluation and behavioural intention, had a significant
relationship with adherence [46]. Another study [44] found a correlation
between patients’ overall compliance levels and a composite of patients’
level of health belief motivation (Health Belief Model). The highest levels of
correlations between the areas of compliance and the motivators occurred
with cues to action [44]. Accordingly, health behaviour models contribute to
a greater understanding of patients’ adherence.
Concerning intentional non-adherence Labig et al. [39] found that 25% of
the students studied were likely to stop taking their medicines as soon as
they felt better and 9% were likely to stop early if their medications did not
seem to help. Fear of perceived short- or long-term side-effects may cause
some patients to reduce or discontinue their medication [47-49]. Inadequate
knowledge and negative attitudes towards the treatment, such as lack of trust
in the safety and efficacy of the medication [49, 50], complexity of the regimens, conflict between treatment recommendation and daily life [48] and
lack of readiness before initiating the treatment [51] are considered to be
barriers for adherence. Feeling well without treatment and lack of trust in
health care providers constitute other barriers [48, 49]. Several studies have
also shown that increased user costs decrease drug use [52-55]. Piette et al.
[54] showed that two-thirds of chronically ill older patients never told a clinician in advance that they planned to underuse prescribed medication because of cost, and one third never raised the issue of cost. Their reason for
not talking about their medication cost problems was that nobody had asked
them and most patients reported that they did not think their doctors could
help them with these problems. This background illustrates the importance
of studying the relations between exemption from charges and the economic
consequences of drug oversupply.
Elderly people (65 years and older) in Sweden comprise 17% of the Swedish
population [56]. Age might have an impact on adherence and younger patients tend to have lower adherence than adults and elderly patients [57-62].
In addition, there are also problems specific to old age [63, 64]. Many elderly have multiple chronic diseases and they are the greatest consumers of
prescription drugs. They consume approximately 43% of all prescription
medicines, reflecting 37% of the medication cost [65]. Adherence to treatment is essential for everyone, but might be especially important for the
well-being of elderly patients, and is thus a critically important component
of care [38]. However, the prevalence of cognitive and functional impair18
ments in elderly patients increase their risk of poor adherence [66-68]. Multiple co-morbidities and complex medical regimens further compromise adherence [63, 64, 68, 69]. Age-related changes in pharmacokinetics and
pharmacodynamics make this population even more vulnerable to problems
resulting from non-adherence [38].
Thus non-adherence always has an underlying cause. It is the health care
professional’s responsibility to identify whether a patient is adherent or not
and to identify the cause of any non-adherence [33]. This is important since
the consequences of non-adherence can be quite profound.
Consequences of non-adherence
Health care providers should always consider the possibility of poor adherence as an explanation for therapy failure. However, in many studies the
relationship between inadequate adherence and therapy outcome are poorly
documented. In publications where it has been documented, however, nonadherence is associated with both increased morbidity [12, 70] and mortality
[13, 71].
In turn, non-adherence leads to increased use of health care service [70, 72].
For example, a significantly higher risk of hospitalization was found among
patients with type 2 diabetes who did not obtain at least 80% of their oral
antihyperglycaemic medication across a one-year time frame [73]. In the
USA [74], the total cost of drug-related morbidity and mortality was estimated at $177.4 billion in 2000, a substantial part of which was due to nonadherence. Thus, non-adherence is a serious medical and economic problem
for society [74]. Furthermore, non-adherence can lead to therapy failure and
have negative effects on patients’ health. For example, patients who were
taking >80% of prescribed statins doses were significantly associated with a
lower risk of recurrent myocardial infraction [70]. In conclusion, it is of the
utmost importance to keep adherence as high as possible both from an individual patient’s perspective and from a social perspective.
Sokol et al. [72] conducted a retrospective cohort study and evaluated the
impact of medication adherence on health care utilization and cost for four
chronic conditions (diabetes, hypertension, hypercholesterolaemia and
congestive heart failure), all major drivers of drug spending. For diabetes
and hypercholesterolaemia they conclude that high levels of medication adherence were associated with lower disease-related medical costs. The hospitalization rates were significantly lower for patients with high medication
adherence in all four conditions [72].
19
Only patients with high adherence are included in some clinical trials since
patients with poor adherence reduce the ability to detect treatment effects
[75]. This means that adherence rates in clinical trials may overestimate the
levels of adherence observed in clinical practice. Consequently, any benefit
detected in the trials from a particular treatment can be generalized only to
other patients who are also likely to adhere to the treatment program. Most
patients are non-adherent part of the time and the physicians have therefore
no evidence for a treatment’s effectiveness for these patients [75]. The
treatment may have the greatest potential for reducing disease burden in nonadherent patients [76].
It is important to study the consequences of non-adherence further, especially in order to be able to design effective interventions for the purpose of
improving adherence.
Interventions to improve adherence
It is vital to try to enhance adherence by emphasizing the value of a patient’s
treatment, by focusing on patient motivation and readiness, and by making
the regimen simple and customizing the regimen to the patient’s lifestyle [9].
According to a Cochrane review [77], interventions that were found to have
an impact on adherence in long-term treatment included combinations of
more convenient care (e.g. provision at the worksite), information (e.g. written material), reminders, self-monitoring, reinforcement, counselling, family
therapy and other forms of additional supervision or attention by a health
care provider (physician, nurse, pharmacist and others). However, even the
most extensive interventions promoted only minor improvements in adherence and treatment outcomes. The review [77] showed that only 26 of 58
interventions for long-term treatments reported in 49 randomised controlled
trials were associated with improved adherence, and only 18 of these 58
interventions led to improvements in treatment outcomes. Their conclusion
was that the study design was usually inadequate.
To obtain improvements in adherence and treatment outcomes it is important
to evaluate the interventions in relation to several outcomes. These outcomes
may be both intermediary (e.g. improved adherence) and final outcomes
(e.g. clinical value) [78]. The Economic, Clinical, and Humanistic Outcomes
model (ECHO) depicts the value of a pharmaceutical product or service as a
combination of traditional clinically-based outcomes and more contemporary
measures of economic efficiency and quality of life [78]. Safety and effectiveness are no longer the only salient attributes; the effect on total health
resource utilization, cost, and quality of life must also be evaluated [79].
.
20
Adherence to long-term treatment – asthma/COPD
It has been shown that adherence to treatments of chronic conditions is nonoptimal, and furthermore that adherence to asthma/COPD treatments is particularly low. However, improved adherence results in decreases in both
morbidity [12] and mortality [1]. The refill adherence among patients with
asthma/COPD drugs has not been studied previously in Sweden. Therefore,
it is of interest to assess the long-term adherence to asthma/COPD drugs and
to inform health care professionals about how patients follow their prescribed treatments.
Asthma and COPD are chronic diseases and therefore treatment is likely to
continue over many years. Asthma affects people of all ages whereas COPD
mainly affects older people. The influence of gender on asthma changes with
age; childhood asthma is more common in boys, while women are diagnosed
with asthma more frequently than men [80, 81]. COPD is more common
among men than among women [82], which may be related to differences in
smoking history. However, after adjusting for previous smoking, women
appear to develop more severe airflow obstruction than men [83, 84]. Several environmental factors also contribute to the onset of both asthma and
COPD. The prevalence of asthma and COPD varies from 1 to 13% [85, 86]
and in Sweden the prevalence of physician-diagnosed asthma is about 8%
based on all ages [87]. The prevalence of COPD is 14% in northern Sweden
(20-69 years old) according to the European Respiratory Society (ERS) and
the Global Initiative for Chronic Obstructive Lung Disease (GOLD) [88].
According to WHO, COPD is the fifth leading cause of death in the world
[89].
To differentiate the diagnosis between asthma and COPD, clinical considerations like risk factors, patient age, symptoms and spirometry are used [90].
Indicators of asthma are family history, allergy, a seasonal variability of
symptoms, wheezing, younger age and reversibility [91], while COPD is
more associated with an age of over 45 years [92], current or past smoking,
cough with sputum production and non-reversibility [90].
The treatment goal for asthma is that the patient should be free from symptoms and have no limitation of daily activities, normal lung function, no
emergency visits, satisfactory quality of life and no dangerous side-effects of
the treatment [93]. Swedish and international guidelines recommend daily
use of short-acting bronchodilator agents and anti-inflammatory medicines
or a combination of a long-acting bronchodilator and an inhaled corticosteroid for patients with persistent asthma [93, 94]. The goal for COPD treatment is to reduce symptoms and improve quality of life. The treatment usu-
21
ally consists of anticholinergics, inhaled corticosteroids and long-acting
bronchodilators [93].
Adherence to preventive therapy, like inhaled corticosteroids, is especially
problematic since the patients do not notice an immediate effect of taking the
drug [35]. Many international studies show that adherence to asthma and
COPD medication is generally poor and that only 40-80% of the asthma
medications [10, 57, 59, 95-99] and 45%-60% of the COPD medications
[100-102] are used as prescribed. Poor adherence to regular use of inhaled
corticosteroids is considered to be an important causal factor in the increased
morbidity and mortality of asthma patients [11, 103-107]. Moreover, elderly
patients with asthma and/or COPD who receive inhaled corticosteroids and
also adhere to their treatment plan have lower rates of hospitalization [108].
Among elderly asthma patients, the combination of inhaled corticosteroids
and long-acting beta-adrenoreceptor agonists decreases mortality and hospitalization to a greater extent as compared to either treatment alone [108].
In real life, many patients use multiple drugs for different diseases, especially middle-aged and elderly people. It is a more complex endeavour for
patients with more than one chronic disease to achieve an optimal drug
treatment. The psychological basis for patients’ adherence and nonadherence has interested several researchers [6, 50, 109]. For example, Vég
[109] proposed that the patients’ attitudes to diabetes and its treatment are
associated with adherence behaviour. The study shows that if a patient has
an attitude that will promote or diminish adherence to one chronic drug
treatment this can also be observed for the patient’s treatment for a second
chronic disease. Consequently, a patient with two chronic diseases would be
expected to show the same adherence to the drugs for both diseases. This
hypothesis would imply that a patient with concomitant use of, for example,
asthma/COPD and diabetes drugs would show the same adherence pattern to
both drug treatments. This has, however, not been studied, so it would be of
interest to compare refill adherence patterns for asthma/COPD and diabetes
drugs. This would help to further inform health care providers about patients’ adherence behaviour.
Measuring adherence
Ideally, adherence should be measured at the actual point of consumption,
i.e. ingestion adherence, which is the final assessment goal. However, it is
rarely possible to assess ingestion adherence. Therefore most studies rely on
more easily performed intermediary measurements, or proxies for ingestion
adherence. There are several different methods available (Table 1), but there
is no golden standard despite a vast range of empirical studies about pa22
tients’ adherence. Instead, for high accuracy it is recommended to use a
combination of methods [110]. The methods available to assess adherence
may be grouped into direct and indirect methods.
Examples of direct methods include direct observation of the patient, e.g. in
clinical trials where the patients may be directly observed taking their medications, and monitoring a biological marker or the drug level in blood or
urine. Biological markers are non-toxic, stable, easily detected compounds
(e.g. phenol red) that can be added to medications. Drug levels in serum or
urine are not appropriate to use if the drug has a short half-life, since the
patient may be non-adherent until shortly before a clinic appointment and
return to non-adherent behaviour after the clinic visit [111].
Proxy methods, i.e. indirect methods used to measure adherence, are for
example self-reporting, pill count, electronic monitoring (Medical Event
Monitoring System, MEMS) and use of pharmacy records [110, 112]. Selfreporting via questionnaires, interviews or diaries is the easiest and most
common method. Pill count is the comparison between the amount of medication remaining in the patient’s medication container and the amount that
should have remained if the patient had been fully adherent [110]. Pill count
as well as self-reporting tends to overestimate actual adherence behaviour.
MEMS is a device that contains a microprocessor to record the time and date
of when the patient obtains a dose of medication by registering when an
inhaler is used or a pill box opened [113]. The use of pharmacy records allows the researcher to study early discontinuation of therapy and the dispensation of medication in a manner other than that prescribed, i.e. refill adherence.
23
24
Indirect methods
Self-reporting
Biological markers
Methods of measuring
adherence
Direct methods
Drug level in biologic
fluids
ƒ
ƒ
Easy to use
Patients can provide information about circumstances and
motives affecting nonadherence
Most commonly used method
that allows for comparison between studies
Inexpensive
Objective
Provide objective proof that the
patient ingested a dose of the
drug
ƒ
ƒ
ƒ
ƒ
Objective
Possible to compare with standardized relationship regarding
drug concentration and effect
ƒ
ƒ
Advantages
Table 1. Methods for measuring adherence [1, 9, 110, 112, 113].
ƒ
ƒ
ƒ
ƒ
ƒ
ƒ
ƒ
ƒ
ƒ
ƒ
Accuracy and validity is instrument-dependent, e.g. the
wording of questions might affect patients’ responses
Cognitive or memory limitations might impact the assessment
Overestimation of adherence due to factors like social desirability
For drugs with short half-life, only events shortly before
measuring can be detected
Risk of “white-coat adherence”, i.e. the patient is more
adherent shortly before the visit
Individual variation in metabolism and volume of distribution can over- or underestimate adherence
Expensive
Only yes/no response; no level of adherence
Individual variation in metabolism and volume of distribution can over- or underestimate adherence
Expensive
Disadvantages
Continuous data
Date- and time-specific regarding drug intake
Objective
Feasible in large populations
Longitudinal data
Accurate measure in a comprehensive pharmacy system
Non-invasive
ƒ
ƒ
ƒ
ƒ
ƒ
ƒ
MEMS
Pharmacy records
ƒ
Objective
Easy to use
Inexpensive
Advantages
ƒ
ƒ
ƒ
Methods of measuring
adherence
Pill counts
ƒ
ƒ
ƒ
ƒ
ƒ
ƒ
ƒ
ƒ
ƒ
ƒ
25
Accuracy varies widely, i.e. the patient can discard drugs
before the pill count
No information about medication timing
Overestimation of adherence due to e.g. dumping pills
The drug container may be inconvenient or can be lost
The patient may accidentally or purposefully open the drug
container without taking the drug or take the wrong amount
of the medication
Underestimation of adherence if patients used pill box (e.g.
Dosett) or other storage device
Expensive
Requires a comprehensive system for collecting pharmacy
records information, otherwise the dataset will be incomplete
A dispensed prescription is not equivalent to ingestion of
medication
Overestimation of adherence due to e.g. changes communicated by the physician, but not recorded on the prescription
Disadvantages
Pharmacy records
Pharmacy records are useful for assessing refill adherence for large numbers
of patients with chronic diseases, since patients’ drug use is lifelong and may
thus be measured over a long period of time. The assessments based on
pharmacy record measurements have been shown to correlate positively with
the results based on other measurement techniques like self-reporting, drug
plasma level and clinical outcome data such as diastolic blood pressure [114116], although this approach tends to overestimate adherence [110, 114,
117]. The use of pharmacy records offers an accurate measure of overall
adherence, provided that the refills are measured at several points in time
[30, 114, 118, 119]. This method measures dispensed drugs and therefore an
upper limit for actual drug intake. The use of pharmacy records to assess
medication adherence has increased dramatically with the introduction of
centralized computerized refill records [58, 120-123]. There is a clear distinction between the data provided by databases on prescribed drugs, like the
British Prescribing Analysis and Cost tabulation (PACT) data [124], and
databases on dispensed drugs. Not all prescriptions issued are dispensed at
the pharmacy, and hence pharmacy records do not necessarily equal primary
non-adherence. A British study indicated that 20% of prescriptions never
reach a pharmacy [125]. The patients with the highest rate of prescriptions
not dispensed had low education and socioeconomic levels, and the prescriptions not dispensed were often for psychotropic drugs and antibiotics. In
Sweden, studies show that between 10-14% of repeat prescriptions never
reached a pharmacy [126, 127]. For asthma prescriptions the corresponding
proportion was 20% [126]. If adherence is to be compared to what was prescribed, this primary non-adherence should be considered. The number of
countries with individual pharmacy record databases from which refill adherence could be assessed is increasing [128-130] but the practice is still
rare. Sweden has a few pharmacy record databases, in the county of
Jämtland [131], in Tierp [132] and since July 2005 a national pharmacy record database on dispensed drugs2 [129]. These databases contain data with
patient identities for all dispensed prescriptions in the respective geographic
areas.
The common goal of all refill adherence measures is to reflect the continuity
of medication usage and to capture the timeliness and the frequency of refilling [133]. There are many different ways of assessing adherence using
pharmacy records [114, 134, 135]. In a recent review 11 measures of calculating refill adherence were identified [134]. These are the following: the
Single Interval Measure of Medication Acquisition (CSA); Continuous
2
Swedish Prescribed Drug Register
26
Measure of Medication Acquisition (CMA); Compliance Rate (CR); Dates
Between Fills Adherence Rate (DBR); Continuous Measure of Medication
Gaps (CMG); Continuous Multiple Interval Measure of Oversupply
(CMOS); Medication Possession Ratio (MPR); Refill Compliance Rate
(RCR); Medication Possession Ratio, modified (MPRm); Medication Refill
Adherence (MRA); and Proportion of Days Covered (PDC). These measures
differ substantially, but three parameters characterize all refill adherence
measure, i.e. continuous versus dichotomous distribution, single versus multiple refill intervals, and assessment of medication availability versus gaps in
treatment [114]. As a continuous variable, adherence is assessed repeatedly
during a period, and this makes it possible to identify time intervals during
which drug exposure deviates from the prescribed treatment. When adherence is used as a dichotomous variable, the individual or the dispensing pattern is simply categorized as either adherent or non-adherent. Regardless of
whether adherence is based on a continuous or dichotomous variable, adherence might be calculated based on single refill interval, or based on multiple
refill intervals. A single refill interval means that adherence is assessed between two consecutive refills and a multiple refill interval means that adherence is assessed between more than two refills. The third parameter focuses
on the medication availability (i.e. the prescribed treatment time in relation
to the time between the fills) or treatment gaps (periods of non-adherence)
[114].
Refill adherence can be based on two different types of pharmacy records,
i.e. data from a pharmacy record database and data from manually collected
repeat prescriptions. A database registers and stores all dispensed drugs for
the same individual over time in a well-defined area, e.g. Norway or the
county of Jämtland [130, 131]. Patients’ refill adherence can therefore be
assessed over several years. Manually collected repeat prescriptions contain
information regarding the dispensed drugs for a separate prescription and the
refill adherence can only be assessed for a shorter period, e.g. one year in
Sweden. Countries without a pharmacy record database can only estimate
refill adherence using manually collected repeat prescriptions. The number
of countries with individual pharmacy record databases is still rare. It is
therefore important if a one-year study period based on manually collected
prescriptions might be comparable to estimating refill adherence based on
database registers covering several years, since some countries estimate refill
adherence only from manually collected repeat prescriptions. This will contribute to the establishment of reliable methods for measuring the level of
adherence.
27
AIMS OF THE THESIS
The overall aim of this thesis has been to survey the refill adherence to longterm drug treatment in Sweden, with a special focus on assessing refill adherence for asthma/COPD prescriptions. A further aim has been to compare
methods based on pharmacy records for the assessment of refill adherence.
This thesis has the following specific objectives:
x To survey refill adherence among different patient groups with long-term
medication therapy.
x To assess treatment gaps for dispensed repeat prescriptions with undersupply for long-term medication therapy, and to analyse the relationship
between oversupply, drug cost and exemption from charges.
x To compare refill adherence for asthma/COPD prescriptions based on two
different types of pharmacy records, i.e. data from a pharmacy record database and corresponding data from manually collected repeat prescriptions.
x To survey refill adherence retrospectively over a ten-year period for
asthma/COPD prescriptions dispensed to elderly patients.
x To compare refill adherence patterns regarding concomitant use of diabetes and asthma/COPD medication during a three-year period and to investigate whether patient profiles comprise a feasible and reliable method to
assess refill adherence.
28
METHODS
The Swedish pharmacy and drug reimbursement system
All Swedish pharmacies (about 950 community- and hospital pharmacies
[136]) have been owned by the Swedish Government since 1970 and organized into one pharmacy chain, the National Corporation of Swedish Pharmacies (Apoteket AB) [137].
The drug reimbursement system in Sweden stipulates that all patients pay the
full cost of drugs up to 900 SEK (approximately € 100) during a 12-month
period. The out-of-pocket cost is then gradually reduced and the patients are
exempt from further charges when they have paid a total of 1,800 SEK (approximately € 195) calculated from the time the first prescription was dispensed. This exemption means that patients receive free medications for the
rest of the 12-month period [138, 139]. One criterion for drugs to be reimbursed is that at any dispensation the amount obtained covers a maximum of
three months’ treatment. However, when two/thirds of the time that the
original dispensation was intended to cover has elapsed, a new reimbursed
dispensation is allowed [140].
Prescriptions
A Swedish prescription contains information regarding the patient’s age,
gender, the drug name, the strength, amount and dosage prescribed, date of
dispensed drug, as well as the prescriber’s name and affiliation. From the
drug name the Anatomic, Therapeutic, and Chemical classification code
(ATC) can be determined [2].
In the ATC classification system, the drugs are divided into different groups
according to the organ system on which they act and according to their
chemical, pharmacological and therapeutic properties [2]. In this thesis,
analyses were done based on ATC groups since diagnoses are not available
for all prescriptions.
29
In Sweden, a prescription is valid for one year from the date of issue [141].
A patient with a refill prescription can only fill the medicine for three
months’ use at a time (in order to receive reimbursement), i.e. a maximum of
four times during one year. This means that the prescription has four valid
refills or iterations, i.e. it is a repeat prescription. For long-term treatment,
repeat prescriptions are most commonly issued in Sweden. All drugs sold in
Sweden are prepacked and Swedish pharmacists are not allowed to break the
containers to dispense part of the packages. Further, most packages for longterm use contain medicines to cover a three-month treatment period.
Papers I-IV included repeat prescriptions with fixed dosage (e.g. one dose
two times a day) which had been dispensed at least twice. Prescriptions with
irregular dosage, e.g. two-three doses three times a day, and drugs dosed “as
needed” were excluded. Paper V includes repeat prescriptions both with and
without fixed dosage.
At the time of the studies included in the thesis, the routine at Swedish
pharmacies was to write/print information regarding the date of dispensation
and amount of drug dispensed on the prescription each time it was filled. A
pharmacist can view previous dispensations made at any Swedish pharmacy
for up to one year. A prescription, with the four maximum documented refills, can be seen as a record of a patient’s refill adherence during one year.
Settings
County of Jönköping (Papers I-II)
The studies reported in Papers I and II were performed using data from
manually collected repeat prescriptions in the county of Jönköping. The
county of Jönköping has 332,000 inhabitants, corresponding to 3.6% of the
Swedish population [56]. It is located in the middle of the southern part of
Sweden, and contains 2% of the Swedish land area [56] (Figure 1). There are
13 municipalities with 35 health centres, three hospitals and 33 pharmacies
in the county [142]. The drug utilization in the county of Jönköping approximately equals the Swedish average (628 and 620 DDD per inhabitant,
respectively, in the year 2000) [65].
30
Jämtland
Jönköping
Figure 1. Map of Europe and the geographic locations of the county of
Jönköping (Papers I-II) and the county of Jämtland in Sweden (Papers IIIV).
County of Jämtland (Papers III-V)
The studies reported in Papers III, IV and V were performed using data from
manually collected repeat prescriptions as well as repeat prescriptions from a
pharmacy record database in the county of Jämtland. The county has a population of approximately 127,000 inhabitants [56] and is located in the middle
of Sweden (Figure 1). Jämtland includes 8% of the Swedish land area, but
only 1.4% of the population [56]. The county hospital in Östersund dominates the health care service, but there are also 30 health centres and 23
pharmacies [143]. The drug utilization in the county of Jämtland was 579
DDD per inhabitant in the year 2000 [65].
Assessing refill adherence (Papers I-V)
Satisfactory refill adherence for each repeat prescription, assessed either
from manually collected repeat prescription or from a pharmacy record database, was defined as dispensed refills covering 100±20% (Papers I-IV) of
the prescribed treatment time, calculated as shown in the formula:
31
satisfactory refill adherence
number of prescribed treatment days
* 100
number of days between the fills
80 120 %
This approach is called the Refill Compliance Rate (RCR) [134] and the cutoff point (100±20%) used is based on previous studies [30-32].
In Paper V, satisfactory refill adherence was defined as >80% of prescribed
treatment time [58, 73, 144]. In all other papers, undersupply means that the
patient had drug dispensed to cover <80% of the prescribed treatment time
and oversupply >120% of prescribed treatment time.
A patient with 100% refill adherence would be dispensed a drug for a treatment period of 100 days and then get back to the pharmacy to pick up a refill
after 100 days (indicating no gaps between the fills). A divergence from
prescribed treatment time of more than 20% would either lead to a treatment
gap, i.e. undersupply, or drug stockpiling, i.e. oversupply. To evaluate the
extent to which each patient had their prescriptions refilled over time, the
supply for each prescribing was analysed over the entire year as shown in
Figure 2.
77%
Fill 1
77%
130 days
143%
143%
Fill 2
Fill 2
70 days
Fill 1
130 days
70 days
Drug
available
Drug
available
100
200 Days
Time between refills
(days and refill adherence %)
100
200 Days
Time when medicine was available
for the patient.
Figure 2. Evaluation of refill adherence of a repeat prescription with 100
days’ prescribed treatment time. In the left graph the patient has satisfactory
refill adherence, i.e. has medicine available during the whole period,
whereas the patient in the right graph has undersupply because of a gap of 30
days in the middle of the period.
A new approach was introduced to assess refill adherence, i.e. “patient profiles” (Paper V). These profiles consist of a graph per patient with the date of
each dispensation and the time period covered by the dispensed drugs along
the x-axis and the different drugs along the y-axis. Patients’ dispensation
32
patterns and treatment persistency over time were assessed based on the
graphs using visual inspection or “eyeballing”, which is a more direct
method of analysis. All patient graph assessments were carried out by two
independent raters and an inter-rater agreement was calculated. The final
classification of refill adherence was determined by consensus.
Data sources
Papers I-II
The studies (Papers I-II) were performed using data from repeat prescriptions collected during one week of November 2002 at the 16 largest pharmacies in the county of Jönköping. All types of dispensed drugs were covered.
No pharmacy record database was available in the county of Jönköping.
The pharmacy staffs were instructed to make photocopies of all repeat prescriptions (both sides) which had at least two dispensations and fixed dosing.
The copies were de-identified at the pharmacies and sent to the research
group. The refill adherence per dispensation was determined from each prescription.
In Paper II the treatment gaps were analysed as the number of days that the
patients had no drug available for their treatment (refill adherence <80%).
For patients with refill adherence >120% the cost of oversupply of each drug
package dispensed was determined from the official Swedish drug price list
of November 2002. To calculate the cost of oversupply, the number of days
beyond 120% coverage for each prescription was multiplied by the cost per
day. The costs were measured in Swedish Krona (100 SEK = € 11 (November 2002)).
Papers III-V
The studies (Papers III-V) were performed using data from the local pharmacy record database in the county of Jämtland. This database has been
available since 1970 [131, 145]. Prescriptions dispensed to individuals born
on the same four dates of each month are included, yielding a representative
sample of 13% of the population (17 000 persons) [131]. The participation is
voluntary and only prescriptions dispensed at a pharmacy in the county are
registered. Tourists and other non-residents of the county are excluded from
the database. The database contains information regarding medicine dispensations per individual, including prescribed drugs, doses, and date dispensed,
amount of supplied drug and category of prescribing physician (or
33
nurse/dentist) [131]. The identities of the individuals and the doctors are
confidential. Diagnoses are not included in the database.
Paper III includes prescriptions issued to residents of Jämtland for
asthma/COPD drugs, adrenergics and steroids in combination for inhalation
(ATC code R03AK) and glucocorticosteroids and anticholinergics for inhalation (ATC code R03B) dispensed in 2002 to individuals 10 years and
older. Younger patients were excluded since these drugs can be dispensed
for other indications. In this paper, both manually collected repeat prescriptions and prescriptions from the pharmacy record database with at least two
dispensations and fixed dosage were included for the same year for comparative analyses in refill adherence. The manually collected repeat prescriptions
were collected from filed prescriptions for 2002 at a large pharmacy in
Östersund, the largest city in the county of Jämtland. Refill adherence for a
four-year period 1999-2002 from the pharmacy record database was also
determined.
Paper IV includes dispensed asthma/COPD drugs, adrenergics and steroids
in combination for inhalation (ATC code R03AK), glucocorticosteroids
(ATC code R03BA) and anticholinergics for inhalation (ATC code R03BB)
from the Jämtland pharmacy record database for the period 1994-2003 to
individuals 60 years and older. The refill adherence was analysed separately
for the three drug types and in relation to repeat prescription characteristics
like patient gender, age and treatment time.
Paper V includes patients 50 years and older who had both diabetes and
asthma/COPD drugs dispensed during 2001-2003. Patients younger than 50
years were excluded since few of these patients used drugs for type 2 diabetes. Drugs included were insulin (ATC code A10A), oral antihyperglycaemic
drugs (ATC code A10B), long-acting adrenergics (ATC code R03AC), combination products for inhalation, (ATC code R03AK), glucocorticosteroids
(ATC code R03BA) and anticholinergics (ATC code R03BB). Drugs like
insulin without fixed dosages were also included and the refill adherence
was based on the assumption that the patients used one defined daily dose
(DDD) per day. Short-acting selective beta-2-adrenoreceptor agonists (ATC
code R03AC) were excluded since they are prescribed for use “as needed”
and the refill adherence for these drugs could therefore not be determined.
Refill adherence was determined from calculated refill adherence and from
patient profiles.
34
Statistical analysis
Data were analysed using the Microsoft® Office Excel 2003 software and
SPSS for Windows, version 12.0 [146]. A value of p<0.05 was considered
significant in this thesis.
ƒ z-test was used to determine the differences in refill adherence related to patient characteristics, type of drug and reimbursement level
(Paper I).
ƒ Median and interquartile deviation was used to illustrate under- and
oversupply among repeat prescriptions with 90-100 days dispensation intervals (Paper II).
ƒ Independent t-test was used when comparing differences in cost between exempt and non-exempt patients (Paper II)
ƒ A 95% confidence interval (CI) was used to compare proportions in
refill adherence (Papers III -V).
ƒ Mann-Whitney test and a crude regression (univariate analysis) were
used to compare differences in refill adherence between age, gender
and treatment time (Papers IV-V).
ƒ Logistic regression was used to determine which explanatory variables influence the refill adherence, while adjusting for covariates
(Papers IV-V). Variables in the univariate analysis with p-values
less than 0.1 were included in the logistic regression model (Paper
V) [147].
ƒ Cohen’s kappa was used to measure inter-rater reliability between
the two raters (Paper V).
ƒ Correlation coefficient was used to compare refill adherence to patients with diabetes and asthma/COPD drugs (Paper V).
ƒ The Bland and Altman limits of agreement method was used to
compare patients’ refill adherence to diabetes and asthma/COPD
drugs (Paper V).
Ethics
According to Swedish regulations, no permission was needed from the Research Ethics Committee in relation to the studies included in Papers I and II
because no personal identification was used on the prescriptions, only gender
and age. The Regional Research Ethics Committee at Lund University (Dnr.
318/2004) approved the studies included in Papers III-V.
35
RESULTS
An overview of the results is presented in Table 2. Refill adherence was
assessed as satisfactory, under- and oversupply, respectively. In general, for
all long-term medication, satisfactory refill adherence was 57% and for
asthma/COPD it varied between 28 and 42%. Undersupply was more common than oversupply for dispensed asthma/COPD drugs, whereas no difference was found between under- and oversupply for all drugs used in longterm medication. More details are presented below.
Table 2. Overview of the results from the included papers.
Paper
Period
Included drugs
I & II Nov 2001- All drugs for
Nov 2002 long-term
medication
Included
repeat prescriptions (rp)
/ patients (p)
Satisfactory
refill adherence
(%)
Undersupply
(%)
Oversupply
(%)
3636 (rp)
57
21
22
III
2002,
Asthma/COPD
1999-2002
2851, 4902 (rp)
858 (rp)
351, 282
29
421, 432
53
231, 292
18
IV
1994-2003 Asthma/COPD
819 (rp)
28
59
12
68
42
32
58
---
V
2001-2003 Diabetes
56 (p)
Asthma/COPD
1
Manually collected repeat prescriptions in 2002
2
Pharmacy record database in 2002
Satisfactory refill adherence (Papers I-V)
All drugs for long-term medication (Papers I-II)
Among 3,636 copies of repeat prescriptions for long-term treatment, 57%
were dispensed with satisfactory refill adherence. The differences were large
between different drug groups and the most important drug groups are
shown in Table 3 (Paper I).
36
Table 3. The refill adherence for different types of medicines.
ATC
code
G03A
C01A
H03AA
N06AA
C07AB
B01AC
M04A
C10AA
A10B
C09A
G03C
N06AB
C03C
C03A
N03
N05A
A06
C09C
R03A
N02A
A02BC
M01A
R03B
M01AH
N06D
Type of drugs
Hormonal contraceptives
for systemic use
Cardiac glycosides
Thyroid hormones
Non-selective monoamine reuptake inhibitors
Beta blocking agents,
selective
Platelet aggregation inhibitors excl. heparin
Antigout preparations
HMG CoA reductase
inhibitors
Oral blood glucose lowering drugs
ACE Inhibitors
Estrogens
Selective serotonin reuptake inhibitors
Loop diuretics
Thiazides
Antiepileptics
Antipsychotics
Laxatives
Angiotensin II-blockers
Adrenergic antiasthmatics for inhalation
Opioids
Proton pump inhibitors
Anti-inflammatory and
antirheumatic products,
non-steroids
Other anti-asthmatics for
inhalation
Coxibs
Anti-dementia drugs
Number of Satisfactory refill Undersupply/
prescriptions
adherence
oversupply
%
%
42
81
12 / 7
44
100
75
71
30
67
9 / 16
13 / 16
20 / 13
307
66
14 / 21
285
63
14 / 22
40
63
20 / 18
212
62
11 / 27
87
59
16 / 25
136
161
59
58
12 / 29
25 / 17
101
58
22 / 20
144
56
51
31
45
67
57
55
55
52
51
49
22 / 22
27 / 18
25 / 20
32 / 16
31 / 18
19 / 31
40
43
23 / 35
31
93
42
39
29 / 29
37 / 25
67
39
37 / 24
47
34
40 / 26
22
5
23
20
41 / 36
20 / 60
37
The highest satisfactory refill adherence was 81% for hormonal contraceptives for systemic use and the lowest was 20% for anti-dementia drugs. Antiasthmatics for inhalation (34%), proton pump inhibitors (39%) and antiinflammatory and anti-rheumatic drugs (39%) all had low satisfactory refill
adherence.
Repeat prescriptions dispensed to patients with full exemption from charges
showed lower satisfactory refill adherence than prescriptions dispensed to
patient without exemption from charges (51% and 58%, respectively;
p<0.05).
Drugs for asthma/COPD (Papers I, III-V)
The satisfactory refill adherence for asthma/COPD drugs varied between 21
and 42%. Figure 3 presents the distribution of repeat prescriptions for inhaled corticosteroids in relation to refill adherence (Paper IV).
30
25
20
15
10
5
0
04
10
-1
4
20
-2
4
30
-3
4
40
-4
4
50
-5
4
60
-6
4
70
-7
4
80
-8
4
90
10 -94
011 1 04
01
12 14
01
13 24
01
14 34
014
15 4
01
16 54
01
17 64
01
18 74
018
19 4
019
4
>2
00
Number of repeat prescriptions
35
% refill adherence
Undersupply
Satisfactory refill
adherence
Oversupply
Figure 3. Distribution of repeat prescriptions for inhaled corticosteroids
(n=569) in relation to refill adherence during the ten-year period of 19942003. Black bars represent prescriptions with satisfactory refill adherence,
i.e. 100±20% of prescribed treatment time.
The comparison between manually collected repeat prescriptions and the
pharmacy record database resulted in a tendency for a lower satisfactory
refill adherence for manually collected repeat prescriptions (Paper III). A
38
longer study period does not seem to influence the level of satisfactory refill
adherence (Table 4).
Table 4. Refill adherence for asthma/COPD medicines (ATC codes R03AK
and R03B) estimated from manually collected repeat prescriptions and the
pharmacy record database in the county of Jämtland, Sweden.
Refill
adherence
Data capturing methods
Manually collected
Pharmacy record
Pharmacy record
repeat prescriptions %
database %
database %
(year 2002; n=285)
(year 2002; n=490)
(1999-2002; n=858)
Satisfactory
35
28
29
Undersupply
42
43*
53*
Oversupply
23
29*
18*
Total non65
72
71
adherence
* Significant difference in refill adherence between pharmacy record database 2002
and pharmacy record database 1999-2002 in undersupply and oversupply, p<0.05.
Undersupply (Papers I-V)
All drugs for long-term medication (Papers I-II)
The proportion of repeat prescriptions showing an undersupply in relation to
long-term treatment was 21% (n=762) of all repeat prescriptions. In Paper I,
the variation between different drug groups was approximately 11-40% (Table 3); HMG CoA reductase inhibitors had 11% undersupply and steroids for
inhalation had 40% undersupply. For the repeat prescriptions with 90-100
days dispensation intervals, the median treatment gap per interval was 53±23
(interquartile deviation) days (Paper II). Accordingly, this implies that nonadherent patients were without drugs more than half of the prescribed treatment time. Undersupplies for repeat prescriptions dispensed to patients with
exemption from charges were lower than for those without exemption (16%
and 22%, respectively; p<0.05).
Drugs for asthma/COPD (Papers I, III-V)
The variation in undersupply for included asthma/COPD drugs was 40-59%.
The distribution of undersupply of inhaled corticosteroids is illustrated in
Figure 3, where the level of undersupply is fairly constant down to the 5%
refill adherence level. In Paper III, the comparison of undersupply during
39
one year between manually collected repeat prescriptions and repeat prescriptions from a pharmacy record database indicated no differences, but the
comparison of one-year data to data for the four-year period showed an increased undersupply with longer treatment time (Table 4).
Oversupply (Papers I-IV)
All drugs for long-term medication (Papers I-II)
In total, 22% (n=816) of the repeat prescriptions were dispensed with oversupply and the variation between different drug groups was approximately
16-35% (Table 3). Cardiac glycosides and thyroid hormones were dispensed
with 16% oversupply whereas adrenergic anti-asthmatics for inhalation were
dispensed with 35% oversupply (Paper I). For the repeat prescriptions for all
drugs used in long-term medication with 90-100 days dispensation intervals,
the median oversupply per interval was 28±6 (interquartile deviation) days
(Paper II). There was a significantly higher oversupply for repeat prescriptions dispensed to patients exempt from charges than for repeat prescriptions
dispensed to patients without exemption (33% and 19%, respectively;
p<0.05).
Drugs for asthma/COPD (Papers I, III-IV)
The oversupply among repeat prescriptions for included asthma/COPD
drugs was 12-26%. The repeat prescription data from the pharmacy record
database for one year indicate a higher oversupply than the manually collected repeat prescriptions (29% and 23%, respectively; p>0.05) in Paper III
(Table 4). Comparing one-year to the four-year data from the pharmacy record database showed a higher oversupply to one-year (29%) than to fouryear (18%). In Paper IV, the differences in oversupply between combination
drugs for inhalation, inhaled corticosteroids and anticholinergics for inhalation showed that there was a greater oversupply of combination drugs and
anticholinergics for inhalation than for inhaled corticosteroids.
Refill adherence to two long-term therapies (Paper V)
The pharmacy record database included 5,563 patients 50 years and older in
2001. Among these patients, 93 individuals had dispensed drugs for both
diabetes and asthma/COPD during 2001-2003 and 56 individuals fulfilled
the inclusion criteria. For each of these an individual patient profile graph
was produced. In Figure 4, three representative patient profiles illustrate the
40
variation between the patients’ drug supply when using diabetes and
asthma/COPD drugs.
Undersupply
Drugs
Patient 1
Male 75 years, 12 dispensations
in
rm
tfo .
e
.
M
.
.
de
i
am .
ncl
.
be
i
l
.
G
e
ni d
so .
e
d
.
Bu
2001
2002
2004
Satisfactory refill adherence to all drugs
Drugs
de
mi ..
cl a ...
n
be
...
G li
..
ol
ter ...
e
..
lm
Sa
...
..
e..
d
i
n .
so ..
de
...
Bu
.
2001
Drugs
2003
Patient 2
Male 74 years, 32 dispensations
2002
2003
2004
Satisfactory refill adherence to diabetes drugs
Patient 3
Male 75 years, 29 dispensations
in
rm ..
tfo ..
e
..
M
.
...
..
i d..e
l am ..
c
n
..
ib e
.
Gl
...
..
i de..
n
so 2001
de
Bu
2002
2003
2004
Figure 4. Patient profiles for three individuals. Patient 1: Undersupply of all
drugs. Patient 2: Satisfactory refill adherence to all three drugs, in contrast to
the calculated refill adherence when this patient showed satisfactory refill
adherence to glibenclamide and salmeterol but not to budesonide. Patient 3:
Satisfactory refill adherence to diabetes drugs and undersupply of
asthma/COPD drugs.
41
From the patient profiles it was concluded that 29 individuals had the same
dispensation patterns (same dispensation interval) for both diabetes and
asthma/COPD drugs. Most of these patients (86%) had satisfactory refill
adherence and 14% showed an undersupply. Among the 27 patients with
different dispensing patterns for both drugs, 93% showed a satisfactory refill
adherence to the diabetes drugs and an undersupply of asthma/COPD drugs.
The rest of the patients (7%) showed an undersupply of the diabetes drugs
and a satisfactory refill adherence to asthma/COPD drugs. The inter-rater
reliability for assessing refill adherence based on patient profile graphs was
=0.80, which is consider to be excellent [148].
Refill adherence based on patient profiles showed that 89% (CI=81-97) of
the patients were classified as having satisfactory refill adherence to diabetes
drugs and 48% (CI=35-61) to asthma/COPD drugs. For calculated refill adherence the corresponding level was 68% (CI=59-77) to diabetes drugs and
42% (CI=32-52) to asthma/COPD drugs. There is a significant difference in
refill adherence between diabetes and asthma/COPD drugs based on both
methods. This is also the case for undersupply. The correlation coefficient
and the limit of agreement method showed the same results; there is a difference between dispensation patterns for patients with concomitant use of diabetes and asthma/COPD drugs.
Costs of oversupply for patients exempt and nonexempt from charges (Paper II)
The included 3,636 repeat prescriptions had a total sales value of 5.1 million
SEK (€ 0.55 million). The extra cost of oversupply for the 517 non-exempt
patients was 99,000 SEK (191 SEK per prescription) and for the 299 exempt
patients the cost was 131,000 SEK (438 SEK per prescription). Accordingly,
the difference in cost of oversupply between exempt and non-exempt patients amounts to 32,000 SEK or 247 SEK (€ 27) per prescription.
An extrapolation to all of Sweden from our sample means that the additional
cost of oversupply for exempt patients compared to non-exempt patients
amounts to 142 million SEK (€ 15 million) per year. This corresponds to
0.6% of the total cost of all prescribed drugs in Sweden 2002 [149].
42
Factors influencing adherence (Papers I, IV-V)
Gender
When all drugs for long-term medication were considered, more repeat prescriptions were dispensed to women (60%) than to men (40%) (Paper I).
There was no significant difference in satisfactory refill adherence between
repeat prescriptions dispensed to men and women (p>0.05). Men had more
repeat prescriptions dispensed with oversupply than women (p<0.05) and
fewer repeat prescriptions with undersupply (p<0.05). These differences
were not seen for asthma/COPD or diabetes drugs in Papers IV and V
(p>0.05). Prescriptions dispensed to women were to a greater extent exempt
from charges than prescriptions dispensed to men (Paper I).
Age
Younger people (30-39 years) seem to have lower satisfactory refill adherence and higher undersupply than older people (Paper I). In Papers IV and
V, there were no differences in refill adherence between ages for diabetes
and asthma/COPD drugs (p>0.05).
Treatment time
Paper IV determined that repeat prescriptions dispensed over a period of
two-four years had higher satisfactory refill adherence (p<0.05), whereas
treatment time for five-ten years showed no differences in refill adherence
(p>0.05) as compared to zero-one years of treatment. In Paper V, there was
no difference in refill adherence between different years of treatment times
for patients with dispensed diabetes and asthma/COPD drugs (p>0.05).
43
DISCUSSION
No previous Swedish study has focused on adherence to different long-term
drug therapies. Similarly, no Swedish study has assessed refill adherence to
asthma/COPD drugs. Researchers and doctors have expressed a need for
Swedish data since data from other countries cannot be directly applied to
the Swedish situation [21]. This thesis is the first large study of adherence to
long-term medication focusing on some of the most common drug therapies
in Sweden. The results establish that the adherence pattern to long-term
drugs in Sweden is similar to those reported from other countries. Furthermore, this thesis has contributed to methods development regarding assessment of refill adherence based on pharmacy records. Repeat prescriptions
from a pharmacy record database have been compared with manually collected repeat prescriptions. In addition, this thesis introduced a patient profile approach as a new method to illustrate and assess patients’ refill adherence. Based on the pharmacy record database, it was possible to determine
refill adherence pattern for concomitant use of two different chronic drug
treatments.
The most important conclusion from this thesis is that satisfactory refill adherence to asthma/COPD medication in Sweden is low, on average 30%.
The same pattern is displayed for repeat prescriptions dispensed to the elderly. These results are in agreement with results from international studies
even if large variations have been reported (40-78%) [10, 95, 96]. Furthermore, it was shown that undersupply to asthma/COPD drugs is more common than oversupply. Refill adherence measurement during a one-year period gave the same results independently of whether the repeat prescriptions
are from a pharmacy record database or are manually collected. When patients had concomitant use of diabetes and asthma/COPD drugs, the dispensation patterns differed for these drugs, i.e. they did not have the same adherence pattern to both therapies. For example, diabetes drugs were more
associated with satisfactory refill adherence and the asthma/COPD drugs
more with undersupply.
44
Overview of studies included in the thesis
Based on the aims of this thesis (presented on page 28), the studies included
to assess refill adherence are illustrated in Figure 5. The results of the large
study (Paper I) on refill adherence to all drugs used in long-term medication
were the bases for all the subsequent studies in Papers II-V.
Refill adherence to all drugs used in long-term drug therapies (Paper I)
Consequences
of under- and
oversupply
(Paper II)
Comparison of data
sources, manually
collected repeat
prescriptions vs. a
pharmacy record
database (Paper III)
Refill adherence to inhaled steroids in
asthma/COPD, 10-year
follow up (Paper IV)
Refill adherence to
multiple long-term
therapies, diabetes
and asthma/COPD
(Paper V)
Figure 5. Overview of the studies presented in the thesis.
The focus on assessing refill adherence to asthma/COPD drugs was decided
based on the results in Paper I that showed that refill adherence to asthma
and/or COPD was low. To verify the results in Paper I, a larger number of
repeat prescriptions for asthma/COPD drugs were studied in Papers III-V.
Improving adherence to asthma/COPD drugs is likely to improve therapy
outcome in these diseases. This thesis contributes new information regarding
adherence and non-adherence to asthma/COPD treatments.
Methodological considerations
Pharmacy records
A number of limitations must be considered when pharmacy records are
used to measure refill adherence. First, the level of refill adherence is influenced by previous prescriptions’ refills, i.e. before the first registered dispen45
sation included in the study. This could have involved both undersupply and
oversupply. However, there was no possibility to verify patients’ earlier dispensations, but if this had been possible it might have shown that some patients would have been considered adherent instead of non-adherent and vice
versa.
Second, only filed repeat prescriptions were manually collected at the pharmacy in Östersund. The prescription is filed when all refills are dispensed or
the expiry date has passed. This means that repeat prescriptions which were
dispensed only twice, and for which the patient did not return to the pharmacy to obtain the rest of the refills, are not included in the study. These
patients could be more non-adherent due to fewer dispensations or they
might have had a seasonal asthma.
A third factor that may distort the refill adherence measured from repeat
prescriptions in Papers I-III is the possibility that the patients have used
more than one prescription for the same drug at the same time. In such a
case, a patient with satisfactory refill adherence would be classified as nonadherent with undersupply. Paper III shows that 11% of the individuals had
used more than one repeat prescription of the same medicine during the
same year. The majority of these patients showed an oversupply. Oversupply
might be a problem and is likely to differ for different diseases. Among
those with undersupply only 3% used more than one repeat prescription. For
the determination of undersupply, this was therefore not seen as a problem.
In Papers III-V, a reliable pharmacy record database was used where all
dispensations are registered and this potential error is therefore eliminated.
Further, in Papers I and II, 16 pharmacies in the county of Jönköping collected the repeat prescriptions. We were informed that, due to lack of time,
some of these pharmacies did not copy all repeat prescriptions. It could be
estimated that approximately 33% of all repeat prescriptions dispensed at the
participating pharmacies were collected. However, there is no reason to believe that this sample would omit prescriptions for any particular type of
drug and we consider that 33% is a large representative sample of the bulk of
prescriptions. The assessed refill adherence (Table 3) should therefore be
valid.
Finally, some of the prescriptions in our studies (Papers I-V) may have been
intended for temporary medication only. However, such information was not
apparent from the prescription or from the Jämtland database. It could be
assumed that the number of such prescriptions is small and should not influence the results.
46
Settings
The county of Jönköping was selected for collecting prescriptions for the
studies in Papers I and II since the level of drug utilization in this county is
close to Sweden’s average [65]. The month of November was selected because the drug sales in this month are close to one-twelfth of the sales for the
whole year [65]. In Paper I it was therefore concluded that the sample of
repeat prescriptions from the county of Jönköping would be representative of
that of all of Sweden.
Some limitations should be considered in the comparison of refill adherence
determined using a pharmacy record database with those from manually
collected repeat prescriptions during the same time and in the same area. The
aim of the study in Paper III was to compare data collection methods and not
to compare different populations. Since the patients’ identities in the database are confidential, it was not possible to compare the drug dispensations
registered in the database with those from the manually collected repeat prescriptions for the same individuals. To minimize a potential error the two
data sets should be as similar as possible. The manually collected repeat
prescriptions were obtained from the largest community pharmacy in the
town of Östersund, the major city in the county of Jämtland. This pharmacy
dispensed 21% of the total prescriptions of the county [65]. Since commuting to Östersund is common, the prescriptions dispensed by the participating
pharmacy represent inhabitants from all over the county. Therefore, the
manually collected repeat prescriptions were considered to be representative
for the whole county and therefore comparable with corresponding data from
the pharmacy record database.
The pharmacy record database in Jämtland contains only prescriptions dispensed in the county. Therefore, if patients had their drugs refilled outside
the county, these dispensed drugs are not registered in the database. Since
there is no major city in the vicinity of Jämtland, it was assumed that only
few prescriptions were filled outside the county.
Assessing refill adherence
The level of refill adherence is influenced by numerous factors and therefore
drug supply may diverge from medication use and under- and oversupply
from under- and overuse. The dispensation pattern may also fluctuate over
time for an individual patient.
In Papers I-IV satisfactory refill adherence was defined as a drug supply
covering 80-120% of prescribed treatment time. Patients in Sweden may
refill the prescription with reimbursement when two/thirds of the prescribed
47
treatment time has elapsed [140]. Hence, the definition of satisfactory refill
adherence might perhaps more correctly have been defined as 67-133% of
prescribed treatment time. But this would have hampered international data
comparisons. The definition or cut-off points should instead be based on
clinical relevance. Many of the studies about adherence in the literature have
used the definition 80-120% of prescribed treatment time [30-32]. So far this
definition is not based on clinical data. The level of acceptable divergence
from the prescribed dose is likely to vary for different therapies. For most
therapies the acceptable level of adherence has not been described in the
literature. HIV therapy is an exception. Here the patients need to take a
minimum of 95% of prescribed antiretroviral doses in order to avoid resistance development [150], even if this cut-off point could possibly be decreased today due to better medications. For diseases like asthma and COPD,
lower levels of adherence than HIV are probably acceptable, but this has not
been studied. The changes in recommended minimal intake of HIV therapy
indicated that the level of satisfactory adherence should be evaluated at regular intervals, according to treatment changes. If we do not take into account
different therapies’ cut-off points and also continuously revise them, how
can we then properly assess adherence? Today’s assessments favour comparability at the expense of relevance. On the other hand, however, today’s
assessments may not really be comparable since they may be based on irrelevant cut-off points for most treatments. At this time, the definitions of
satisfactory adherence for most diseases are lacking and therefore 80-120%
is the most reliable definition today.
The assessed refill adherence may be influenced by whether a patient is hospitalised and hence supplied with medication by the hospital. Such a patient
could be considered non-adherent although the patient had satisfactory drug
supply. Today in Sweden, most patients are normally hospitalised for less
than one week, and then referred to other types of care with medication obtained from prescriptions. Therefore hospitalization should not be a major
problem in the thesis.
Asthma/COPD
There are certain problems associated with the determination of refill adherence to asthma/COPD drugs since the diseases often have irregular dosage
schedules. Therefore, many of the dispensations, both among the manually
collected repeat prescriptions and those recorded in the database, were excluded since they were prescribed to be taken “as needed” or with irregular
dosage (e.g. two-three doses two times a day). Therefore it was sometimes
difficult to determine the refill adherence over a long period, as seen in Paper IV, where the aim was to analyse repeat prescriptions during a ten-year
period although most of the repeat prescriptions were only analysed for a
48
period shorter than three years. In Paper V, where the refill adherence to
drug therapies for patients with two chronic diseases was investigated, the
use of insulin and long-acting adrenergics without fixed dosing were assumed to be one DDD per day. For most asthma/COPD drugs, except shortacting selective beta-2-adrenoreceptor agonists, there is a close agreement
between prescribed daily doses and DDD [151] but for diabetes this has not
been investigated. The doctors may also orally adjust the doses up or down
without documenting this on the prescription. This may occur, for example,
when the patient becomes ill and the patient can therefore deviate from the
prescribed dose but still be adherent to the doctors’ oral advice. Patients can
also change the dose on their own initiatives. No such information was
available in these studies.
In the pharmacy record databases in Sweden and in most of the manually
collected repeat prescription, information about diagnoses is not reported.
Asthma and COPD share some characteristics but are in many aspects two
separate conditions. Ideally, these conditions should be analysed separately,
but this was not possible due to lack of diagnostic information in the database. However, the assumption is that the included drugs are prescribed for
preventive treatment to patients with diagnosed asthma and/or COPD, since
these drugs only have these indications approved in Sweden. Short-acting
selective beta-2-adrenoreceptor agonists may be prescribed for other respiratory disorders than asthma/COPD, but they were excluded here.
Adherence and non-adherence to chronic drug treatment
Patients with chronic diseases can have different drug refill strategies and
therefore also different adherence. A majority of the prescriptions were refilled close to the time when the last dose was estimated to be used (<68% of
the repeat prescriptions in this thesis); others were undersupplied (21-59% of
the repeat prescriptions) or oversupplied (12-29% of the repeat prescriptions).
For the patient, adherence to drug therapy is of interest if the prescribing is
proven to be beneficial. The right medication should be prescribed for the
right person, in the right dose, at the right time, for the right condition and
for the right reason. A meta-analysis concluded that good adherence to
proven beneficial drug therapy is associated with lower mortality (Odds Ratio (OR) 0.55; 95% CI 0.49-0.62) than good adherence to harmful drug therapy (OR 2.90; 95% CI 1.04-8.11) [13]. Non-adherence to prescribed medication can sometimes be justified, e.g. if the patient gets side-effects and makes
an intentional and rational decision not to follow through on the prescribed
medication. In this connection, the concept of “intelligent non-compliance”
49
has been discussed [23]. The aim of all drug therapy is benefit for the patient, not adherence in itself.
Adherence to asthma/COPD drugs not only depends on when the drugs are
taken, but also on how. Even if a patient has satisfactory adherence, the inhalation technique could be incorrect and inadequate amounts of the drug are
delivered. In one study of inhaled drugs [37], the two most common errors
made by patients were device-independent errors and included not breathing
out before actuation of the device (29%) and failure to hold the breath for a
few seconds after inhalation (28%). These errors were observed in 40-47%
of the patients and some patients made more than one error. Accordingly,
adherence may be improved by educating both patients and physicians in the
correct use of inhaler devices.
Patients’ attitudes to drug treatment seem to influence adherence more than
clinical and socio-demographic characteristics [4]. Lack of motivation and
readiness before initiating the treatment are other factors that influence adherence [4, 51]. An important key to improving patients’ adherence behaviour is a patient-centred and open discussion at the start of the therapy including its complexity and the potential side effects, and other factors which
may modify patients’ perception of the likelihood of adherence [46]. In this
thesis, variables that could influence patients’ attitudes have not been studied
since this was not the aim of the investigations.
Satisfactory refill adherence
The variation in satisfactory refill adherence between different types of longterm medications was large, ranging from 81% for contraceptives to 20% for
anti-dementia drugs (Table 3). Women using contraceptives are probably
highly motivated to have constant access to the drugs. Some drugs (serotonin
reuptake inhibitors, AII blockers) had lower satisfactory refill adherence
than related older drugs (tricyclic antidepressants, selective beta-blockers)
despite allegedly fewer side effects, which should favour higher adherence
[152, 153]. Anti-asthmatics for inhalation had low satisfactory refill adherence and this is in agreement with previous studies [10, 57, 95-98, 100-102].
In the literature, satisfactory refill adherence varies depending on drug
treatment. A review analysed the level of satisfactory refill adherence to oral
hypoglycaemic drugs and found a variation from 36% to 93% [154]. In another large drug group, antihypertensive drugs, 53% of the patients had satisfactory refill adherence [32]. In Paper IV, inhaled corticosteroids, anticholinergics and combinations of adrenergics and steroids all had low satisfactory refill adherence. The exceptionally low adherence rate for
asthma/COPD treatment including steroids initiated detailed studies.
50
In Paper III, satisfactory refill adherence was compared for manually collected repeat prescriptions with repeat prescriptions from the pharmacy record database for 2002. The expectation was that repeat prescriptions from
the database should have higher satisfactory refill adherence than for the
manually collected ones, since the database registered and linked all dispensations for the individuals during the study period. The results in the study
indicated the opposite, but the difference was not significant. One explanation could be that all manually collected repeat prescriptions were filed at the
pharmacy in Östersund and therefore all refills were often dispensed on the
prescription. Probably, if the repeat prescriptions were collected continuously as in Papers I and II, lower satisfactory refill adherence might be observed for manually collected repeat prescriptions than from the database.
Undersupply
Over 40% of the asthma/COPD drugs were undersupplied and therefore the
patients could not medicate as intended by the prescribers. This is in agreement with several reports in the literature [59, 99]. In an international cohort
study [99] with 8,829 subjects from 14 countries, only 17% had used inhaled
corticosteroids on a daily basis at follow-up. Another study [59] showed that
only 36% of the patients had used inhaled corticosteroids on a regular basis.
Factors associated with underuse of inhaled corticosteroids were young age,
non-white race, lower symptom severity, lower use of inhaled -agonist and
not possessing a peak flow meter [59]. Other explanations for undersupply
include the possibility that some patients may be afraid to use steroids over
long periods and may thus reduce or discontinue the treatment. Secondly,
inhaled corticosteroids do not have an immediate effect and it is therefore
more difficult to motivate the patients to be adherent. Some patients relieved
from symptoms may believe that they have been cured of their asthma and
therefore decide that they no longer need to take their medicine. Finally,
non-adherence for elderly patients may increase with concurrent diseases,
polypharmacy and sensitivity to adverse drug reactions [38].
Patients with undersupply of a drug most likely underuse their drugs. Patients with a refill adherence of 80% lack drugs for 18 days of a normal 90day treatment period. This implies that the range defined as satisfactory refill
adherence might inflict considerable gaps in the treatment. A treatment gap
of 18 consecutive days could lead to therapeutic failure depending on the
disease and treatment. For patients with HIV this is especially unsatisfactory
[150]. For asthma/COPD, the therapeutic consequences of undersupply may
be that the patients have more symptoms or adjust to unnecessary breathing
problems or acquire more respiratory infections. The median medication gap
for patients with undersupply reported in Paper II was 53 days of a 90-100
days’ treatment period. Many studies have shown that non-adherence is
51
strongly associated with increased morbidity [12, 70] and mortality [13, 71,
103], but in this study there was no possibility to explore the health consequences of low adherence. More attention should be directed toward developing solutions that reduce preventable morbidity, mortality and costs association with drug-related problems.
Oversupply
Oversupply is more difficult to interpret than undersupply. Therefore many
studies do not indicate an upper level of refill adherence [58, 73, 144]. Oversupply can involve drug overuse and drug dependence that might lead to
medical problems, but it can also involve patients giving their drugs to others. Another possible cause of oversupply is drug stockpiling, particularly
for patients exempt from charges. Therefore, it is of interest to have an upper
cut-off point for refill adherence, for instance to analyse the economic consequences of oversupply in relation to the reimbursement system. In Paper I,
significantly higher oversupply was found for patients exempt from charges
than for those who were non-exempt, 33% and 19% respectively. For some
patients, the doctor might recommend increasing the dosage at some stage,
e.g. during a cold when the patients has asthma. This would result in more
frequent refills and be registered as oversupply. Moreover, for practical reasons patients with asthma/COPD might want to have several inhalers, at
home, at work, at the vacation home and/or in the car. Such stockpiling is
probably the most common reason for oversupply in this thesis.
Much of the dispensed medication is never used because of oversupply, side
effects, changed treatment, low patient adherence or the patient’s death
[155]. Therefore, some packages are returned to the Swedish pharmacies for
destruction. The amount of returned drugs has been estimated to be about
4.6% of concomitant sales in volume with a value of 600 million SEK (€ 65
million) per year [156]. The stockpiling may thus be considerably larger than
estimated here from the refill adherence of repeat prescriptions.
Refill adherence over a one-year period compared to
that over a four-year period
A comparison of refill adherence in the pharmacy record database for a oneyear and a four-year period might indicate if a one-year study period is acceptable for estimating refill adherence. As shown in Paper III the satisfactory refill adherence level for the four-year period does not differ from that
of the one-year period. The one-year study period seems to underestimate
52
the proportion of undersupply and overestimate oversupply. Hence, over
shorter time periods there is a risk of underestimating non-adherence.
Factors which contribute to the differences in under- and oversupply could
be that some repeat prescriptions were dispensed outside the county of
Jämtland and were therefore not registered in the database (no information).
This is estimated as undersupply and might be more common during a
longer time period. Oversupply can also even out over four years, since a
one-year oversupply can be compensated by a one-year undersupply. Depending on the cut-off point when refill adherence is determined, the patient
might either be adherent or non-adherent. Therefore, this study concludes
that longer study periods represent a more reliable pattern of refill adherence
than one year and give a better overview of patients’ refill adherence. We
have been unable to find studies comparing refill adherence for two different
time periods, but longitudinal studies of adherence showed an adherence
level of 50-95% depending on drug type [58, 120, 121, 123], and the adherence decreased with increased number of treatment years [120, 121, 123].
In Sweden, for studies assessing refill adherence before the new national
pharmacy record database was set up and in areas where a previous local
pharmacy record database is not available, refill adherence information may
be obtained from copies of the patients’ repeat prescriptions as in Papers I-II.
This means that when estimating refill adherence before the year 2005, the
vast majority of all estimations of refill adherence must be based either on
manually collected repeat prescriptions, or on data from one of two local
pharmacy record databases in the county of Jämtland [131] and in Tierp
[132]. Some years in the future, when more data has been included in the
national database, this will be a comprehensive data source for refill adherence studies.
Refill adherence to two long-term therapies
The patient profiles (Figure 4) for patients with concomitant use of diabetes
and asthma/COPD drugs were used as a new approach introduced to complement the calculated refill adherence. These drugs, diabetes and
asthma/COPD, were chosen since the drugs are specific for these two diagnoses and they are used in chronic lifelong diseases. It could be argued that
the comparison is not justified since the two diseases are very different, as
are the types of treatment. However, the aim was to evaluate whether the
refill adherence related to one chronic disease differs from refill adherence
for another chronic disease.
53
The patient profiles seem to increase the accuracy in the determination of
each patient’s refill adherence over time (Figure 4, patient 2). In Paper V, the
inter-rater reliability score (=0.80) indicated that the raters interpreted the
graphs consistently and thus indicated a feasible and reliable method for
estimating patients’ overall adherence. The refill adherence determined
based on the patient profiles was in the same direction as the calculated refill
adherence but showed a somewhat higher satisfactory refill adherence for
diabetes drugs than for asthma/COPD. The reason could be that the patients
consider diabetes to be a more serious disease than their asthma/COPD,
since severity of the illness is one factor that influences adherence [40] and
therefore patients follow the prescribed therapy more rigorously.
The initial hypothesis that patients with satisfactory refill adherence to diabetes drugs would also have satisfactory refill adherence to asthma/COPD
drugs was not supported. But it must be taken into consideration that the
sample size was small. However, the same pattern was also found in a study
with concomitant use of antihypertensive and lipid-lowering medication
where half of the patients did not have the same adherence to both therapies
[157]. A patient who uses two different drug treatments may have different
reasons to be adherent to the different drug therapies. Therefore, in addition
to patients’ attitudes other factors like disease characteristics and type of
treatment may contribute as well. This was supported by Bardel et al. [60].
Costs of oversupply for patients exempt and nonexempt from charges
Oversupply leads to additional costs and in the sample of patients in Paper II
the extra cost of oversupply among exempt compared to non-exempt patients
was 32,000 SEK or 247 SEK (€ 27) per prescription (Paper II). The extrapolation of this cost from the county of Jönköping to the whole of Sweden may
be justified knowing that the level of drug utilization in relation to the population (628 and 620 DDD per inhabitant, respectively, in the year 2000) and
the level of cost per inhabitant (2,428 and 2,508 SEK per inhabitant, respectively, in the year 2000) is approximately equal for these areas [65]. Such an
extrapolation showed that in 2002 patients with exemption from charges and
oversupply generated 142 million SEK (€ 15 million) higher drug cost than
patients without exemption. We have been unable to find any similar studies.
Oversupply of drugs, both for exempt and non-exempt patients, will lead to
increasing cost of destruction, since patients change medication, get side
effects, have low patient adherence or die [155, 156]. Therefore, health care
54
professionals should advise the patients to fill their prescription as intended,
and to avoid oversupply.
A drug reimbursement system has an effect on adherence, and the drug consumption decreases with increased co-payment [52, 53, 55, 139]. Papers I
and II also showed that undersupply was more common for non-exempt
patients compared to exempt patients (p<0.05). People with low incomes
also have lower adherence due to drug cost [55, 158, 159]. However, when
the pharmacy reimbursement system pays part of the total cost of the drugs
consumed, both the quantity consumed and the price of the products dispensed increase [139]. The reimbursement system will thus restrict overconsumption and oversupply. An effective measure for decreasing pharmaceutical oversupply could be a small co-payment for all prescriptions, but it
would have the disadvantage of leading to health problems for patients with
low incomes. In conclusion, Papers I-II indicated that the reimbursement
system in Sweden means better drug supply and hopefully better adherence
at a low cost (142 million SEK = € 15 million). It is also important that clinicians take an active role in discussing patients’ medication cost problems to
minimize non-adherence.
Factors influencing adherence
The gender ratio of collected repeat prescriptions (60% women) in Papers III was similar to the gender ratio of prescription customers at Swedish pharmacies [65]. In Paper I there was no difference in satisfactory refill adherence between prescriptions dispensed to men and women, but repeat prescriptions to women showed higher undersupply and lower oversupply than
repeat prescriptions to men. In Papers IV and V these differences were not
seen for diabetes and asthma/COPD drugs; in other words there was no difference between gender and refill adherence. Gender differences in refill
adherence may therefore depend on the type of therapy, but a quantitative
review of patients’ adherence research concludes that there is no relationship
between gender and adherence among adults [57]. However, a relationship
exists among paediatric patients; in paediatric samples, women are more
adherent than men [57].
Satisfactory refill adherence to all drugs used in long-term treatment tended
to be lower among younger patients than among adults and older patients, as
shown in previous studies [57-62]. This may explain why there were no differences in refill adherence between ages in Papers IV and V, in which only
patients 50 years and older were included. The results were expected, since
younger patients have more irregular schedules than adults and thus it is
more difficult for them to remember to take the drugs.
55
In Paper V there was no difference in refill adherence between different
years of treatment times for dispensed diabetes and asthma/COPD drugs,
whereas in Paper IV there was a difference for repeat prescriptions dispensed
for two-four years but not for five-ten years as compared to zero-one years
of treatment. Repeat prescriptions dispensed for two-four years of treatment
time indicated higher satisfactory refill adherence than zero-one years. This
means that no general trend in lower satisfactory refill adherence with longer
treatment time was seen as could be expected [120, 121, 123, 157]. An explanation could be that the patients forget to use the drug or decide to take a
lower dose than prescribed as time goes by (more than four years) and the
refill adherence therefore decreases again.
Improving patient adherence
Improving adherence is a continuous and dynamic process [1]. This thesis
has indicated that the level of refill adherence is low. There is no single activity that will improve adherence of all patients. For patients with asthma
and COPD, simplification of therapy like reducing dosing frequency, combined inhalers, type of inhaler or memory aids might be sufficient for motivated and informed patients, while education or psychological counselling
will be more appropriate for others [6, 35, 38, 160, 161]. Adrenergics plus
steroids in a single inhaler is also cost-effective [162, 163]. One study [64]
concludes that elderly patients need better information on medication and
various aids to improve adherence. Individuals receiving three or more
drugs, or drugs from several doctors, living alone, and with predementia
symptoms should have special attention because of higher risk of nonadherence [64]. Adherence and satisfaction are expected to be optimized
when the prescriber arranges many short visits instead of few and longer
visits [164, 165].
The health care professionals may also contribute to better adherence. Studies show that health care professionals need to enhance their education and
their co-operation in training asthma/COPD patients to monitor their disease,
for example by adjusting the treatment according to symptoms [166]. Better
listening and communication skills of the health care professionals can also
improve the way in which they present information, motivate patients and
reinforce progress [9, 167, 168]. Quality indicators are probably helpful for
health care professionals to improve therapies [169]. Open-ended questions
and providing reassuring messages helps patients feel that they are part of a
partnership that is aimed at controlling their condition [168].
56
Other important factors are respect for patients’ health beliefs and involving
them in the treatment decision [170]. This can foster an atmosphere of mutual responsibility and concordance over prescribed medicine taking [160].
This can all be included in the term “concordance” which is promoted as a
tool to improve adherence [4]. An underlying expectation based on this thesis is that health professionals want to construct programs for improved drug
adherence. The programs could for example contain a more open-ended
discussion between provider and patient about the patient’s attitude and
readiness for treatment. The lack of a match between patient readiness and
the prescriber’s attempts at intervention means that treatments are frequently
prescribed to patients who are not ready to follow the prescriber’s treatment.
Health care professionals should be able to assess the patient’s readiness to
adhere, and provide information and advice on how to do it. It is also important to follow up the patient’s progress at every contact and identify any
misunderstandings that may arise.
A stronger commitment to a multidisciplinary approach is needed to make
progress towards adherence. It comprises coordination of a range of actions
from physicians, nurses and pharmacists but also from researchers, health
planners and policy-makers.
57
CONCLUSIONS
x
x
x
x
x
58
Among repeat prescriptions (n=3636) to patients with different longterm medications, 57% were dispensed with satisfactory refill adherence whereas 21% were undersupplied (<80%) and 22% oversupplied
(>120%). The variation in satisfactory refill adherence between different types of medicines was large (20-81%).
When repeat prescriptions for long-term medication were dispensed
with undersupply, patients had drugs available half of the prescribed
treatment time. Patients who were exempt from charges had a higher
oversupply (33%) than non-exempt patients (19%), leading to unnecessary costs for society.
The proportion of satisfactory refill adherence, under- and oversupply
for repeat prescriptions from a pharmacy record database (n=490) as
compared to manually collected repeat prescriptions (n=285), did not
differ over a one-year period. However, refill adherence based on a
one-year period seems to underestimate undersupply and overestimate
oversupply, as compared to a four-year period.
More than 50% of the repeat prescriptions for preventive
asthma/COPD drugs dispensed to elderly patients showed an undersupply.
Patients with concomitant use of diabetes and asthma/COPD drugs
showed disparate dispensation patterns for their two drugs. The use of
patient profiles seems to be a feasible and reliable (=0.80) method to
complement the calculated refill adherence method, but it needs to be
further studied in larger and more divergent populations.
FUTURE ASPECTS
New and exciting potentials for pharmacoepidemiological research were
made possible with the new national pharmacy record database that was set
up in July 2005 in Sweden [129]. This new register contains linked patient
data for all dispensed prescriptions from the whole Swedish population, but
does not include data on over-the-counter (OTC) drugs, herbal remedies or
medications used in hospital. Furthermore, it does not include information
on diagnoses [129]. This register represents one of the largest populationbased pharmacoepidemiological databases in the world [129]. The new register has opened the door for studies on a national level and will be very
valuable when studying patterns of drug utilization. The information from
the register is possible to link to other epidemiological registers in Sweden
such as the Hospital Discharge Register and the Cause of Death Register.
This gives good opportunities to explore drug use and disease associations
and also the risks, benefits, effectiveness and health economical aspects of
drug use. For example, it would be possible to use the register to verify the
results in this thesis at a national level. One option would be to further study
the refill adherence to concomitant drug use. To validate refill adherence
assessments, it is important to study how often prescribers have orally adjusted a patients’ dose due to disease fluctuation over time without this being
recorded on the prescription. Knowledge about this improves the reliability
of the calculated refill adherence. Future studies may also utilise the national
register to study patient profile patterns in larger and more divergent patient
populations.
The necessary levels of adherence to different treatments for achieving positive treatment outcomes are not well studied. In the area of Acquired Immune Deficiency Syndrome (AIDS)/HIV some studies have been conducted,
and it has been shown that patients with HIV need to take a minimum of
95% of prescribed antiretroviral doses in order to avoid resistance development [150]. The corresponding percentages for optimal treatment outcome
for asthma/COPD drugs or other chronic diseases are not reported in the
literature. Further research is therefore needed to establish these necessary
adherence levels to optimize treatment outcome without having to aim for a
100% adherence level. Another important aspect is to further evaluate the
use of new technologies such as electronic reminders using cell phones and
personal digital assistants to help patients improve adherence. In addition,
59
more complex and well-designed interventions to improve adherence need to
be performed.
In Sweden, all persons get all their drugs refunded over a certain limit. The
maximum annual out-of-pocket amount is 1,800 SEK (€ 195). There is a
need for further studies to evaluate whether the current refunding system
impacts drug use and its variation in different age groups, in different income levels and for different drugs. Moreover, the Swedish pharmacy monopoly is presently under discussion. The government has initiated a commission of inquiry to investigate how the monopoly can be abolished. If that
happens both prescription drugs and OTC drugs may become more available
and hopefully also at a lower price (the reimbursement system will probably
remain in place). Furthermore the accessibility might change and there might
also be potential consequences regarding pharmaceutical competence of
drug distribution and patient safety issues. This could have an impact on
adherence, making it important to evaluate the consequences of a deregulation.
Accomplishing concordance between patients and health care personnel such
as doctors, nurses and pharmacists is the best approach to achieving good
adherence. Therefore, it is important to feed back the results of welldesigned interventions to stimulate health care professionals to create concordance at each patient encounter and how to use concordance as a tool to
improve patient adherence. Further, patient adherence needs to be monitored
and patients’ motivation and readiness to adhere must be addressed continuously. This thesis shows a complex adherence picture, i.e. a wide variation in
dispensed prescriptions and hence in patients’ medication behaviour. Further
analysis of this complex pattern needs to be considered in future studies.
.
60
SAMMANFATTNING PÅ SVENSKA
Följsamhet har beskrivits som den ultimata absorptionsbarriären och det
illustreras i följande citat av C. Everett Koop: ”Läkemedel verkar inte hos
patienter som inte tar dem”. Bristande följsamhet till läkemedelsordinationer
är ett välkänt problem och internationella studier visar att följsamheten är
högst 50% vid långtidsmedicinering. I Sverige finns en del övergripande
studier som fokuserar på kvaliteten på förskrivningen men inga svenska studier har hittills studerat uttagsföljsamheten på en nationell nivå.
Patienterna följer inte alltid läkemedelsordinationerna utan använder sina
läkemedel utifrån den egna synen på behandlingen. Detta kan medföra både
under- och överanvändning och leda till misslyckad terapi med onödigt lidande och sjukdom som följd. Oföljsamhet leder också till onödiga kostnader i form av förlorad arbetsinkomst, vårdbesök, inläggningar på sjukhus och
att dyr medicin blir felanvänd eller oanvänd (kassation). Oföljsamhet kan
ibland vara bra t.ex. om behandlingen inte är ändamålsenlig.
Detta är den första svenska studien av uttagsföljsamhet som studerar alla
läkemedel för långtidsmedicinering och speciellt astma och kroniskt obstruktiv lungsjukdom (KOL). Det övergripande syftet med avhandlingen var att
kartlägga följsamheten till läkemedel för långtidsmedicinering i Sverige med
speciellt fokus på hur patienter hämtar ut läkemedel (uttagsföljsamhet) mot
astma/KOL. Syftet var också att bidra med metodutveckling inom området
läkemedelsutköp. Specifika syften var att uppskatta uttagsföljsamheten för
olika patientgrupper med långtidsbehandling, undersöka under- och överutköp, om läkemedelskostnader påverkas av frikort, jämföra två olika datainsamlingsmetoder, äldres uttagsföljsamhet till astma/KOL läkemedel, se om
patienter med två olika kroniska sjukdomar har samma utköpsmönster till
båda läkemedlen och även undersöka om patient profiler är en bra metod för
att uppskatta uttagsföljsamhet.
De första två studierna bygger på insamlade avidentifierade kopior av flergångsrecept från 16 apotek i Jönköpings läns landsting. Genom bestämning
av uttagsintervall fastställdes om patienterna hade läkemedel tillgängliga, så
att de över huvud taget har kunnat vara följsamma till läkarens ordination.
Uttagsföljsamhet beräknades genom att antalet dagar som ordinationen räckte dividerades med antal dagar mellan utköpen. Analyser genomfördes med
61
avseende på både under- och överutköp. Tillfredsställande uttagsföljsamhet
definierades som att patienten hämtat ut läkemedel så att det täckte 80-120%
av den ordinerade behandlingstiden.
Resultaten visar att den genomsnittliga tillfredställande uttagsföljsamheten
för all långtidsmedicinering i Jönköpings läns landsting, var 57% (n=3 636).
Vidare var underutköpet 21% och överutköpet 22%. Patienter som underutköpte läkemedel hade bara läkemedel tillgängligt under halva behandlingstiden. Kartläggningen visar också att de som hade frikort överutköpte läkemedel i högre utsträckning (33%) än de som inte hade frikort (19%) och detta
leder till onödiga kostnader för samhället. Skillnaden i uttagsföljsamhet mellan olika läkemedelsgrupper var stor, högst uttagsföljsamhet uppmättes för
medel för antikonception (81%) och lägst för demensmedel (20%). Astmaläkemedel för inhalation hade en låg uttagsföljsamhet (<40%).
De övriga studierna i avhandlingen baserades på läkemedelsutköp hos ett
representativt urval av 17 000 jämtlänningar registrerade i den s.k. Jämtlandsstudien, en receptdatabas med individuppgifter. Läkemedel mot astma/KOL var i fokus för dessa studier. Uttagsföljsamheten bestämdes både
genom att beräkna uttagsföljsamheten som i de två första studierna och genom introduktionen av s.k. patientprofiler. Dessa profiler illustrerar grafiskt
hur varje patient hämtar ut sina läkemedel. Grafen visade datumen för varje
utköp och hur länge respektive utköp räckte tidsmässigt.
Endast en tredjedel av patienterna med läkemedel mot astma/KOL hade en
tillfredställande uttagsföljsamhet i enlighet med läkarnas ordinationer. Detta
gällde även för de äldre patienterna. Man kan därför anta att många patienter
är underbehandlade. Vid jämförelse av registerdata med manuellt insamlade
recept visar den manuella metoden på god validitet, åtminstone vid astma/KOL. Detta är av vikt för att kunna studera uttagsföljsamhet när registerdata inte är tillgängligt.
I Jämtlandsdatabasen var det 56 patienter som använde läkemedel mot både
diabetes typ 2 och astma/KOL. Av dessa patienter hade 52% samma utköpsmönster för både läkemedelsgrupperna och de flesta av patienterna hade
en tillfredsställande uttagsföljsamhet. Resterande 48% hade därmed olika
utköpsmönster och det fanns ingen korrelation när det gäller utköpsmönster
för dessa läkemedel. Hypotesen att patienter med tillfredsställande uttagsföljsamhet till diabetesläkemedel också skulle ha tillfredsställande uttagsföljsamhet till astma/KOL-läkemedel kunde därför inte fastställas.
Sammanfattningsvis visade avhandlingen på att hälften av alla recept som
hämtades ut för långtidsmedicinering hade en tillfredsställande uttagsföljsamhet medan motsvarande siffra för astma/KOL läkemedel var 30%. Resul62
taten uppvisade också att underutköp av astma/KOL läkemedel var vanligare
än överutköp. Patienter med frikort överutköpte läkemedel i större utsträckning än de patienter utan frikort. Manuellt insamlade recept antydde ha en
god validitet vid jämförelse med registerdata för att uppskatta uttagsföljsamhet. Patienter som använde läkemedel mot två kroniska sjukdomar hade olika utköpsmönster för de både läkemedlen. Patient profiler visade sig vara en
användbar metod med en hög överrensstämmelse mellan två oberoende bedömare. Profilerna användes för att komplettera den beräknade uttagsföljsamheten, men fler studier behövs med större och fler populationsgrupper.
Det nya nationella läkemedelsregistret i Sverige ger stora möjligheter i framtiden att undersöka läkemedelsanvändningen och därmed uttagsföljsamheten
i ett vidare perspektiv.
63
ACKNOWLEDGEMENTS
This work was performed at NEPI Foundation (The Swedish Network for
Pharmacoepidemiology) in collaboration with the Department of Pharmacy,
The Pharmaceutical Outcomes Research Group, Uppsala University, Uppsala, Sweden.
The financial support of the National Corporation of Swedish Pharmacies
(Apoteket AB) and the Swedish Association for Senior Citizens (SPF) is
gratefully acknowledged.
I would like to express my sincere gratitude to all who have contributed to
this thesis, and especially to:
My supervisor Lena Ring; your competence, enthusiasm, quick thinking and
constructive criticism have all given me tremendous support during these
years. When I had statistical problems, you were always there to help.
Thanks also for all your positive e-mails!
My co-supervisor Lars G Nilsson; thank you for opening the door to research and introducing me to the field of adherence. You are a wonderful
person with extensive scientific knowledge; thank you for always being
there and being positive about my work. You made it possible to start and
also to finalise this thesis!
My co-supervisor Arne Melander; thanks for valuable comments on manuscripts, for sharing your large professional network and for all of your support.
My co-authors and co-workers:
Carin Svensson and Owe Lind for collaboration and carrying out the study in
the county of Jönköping.
Anders Carlsten for friendly collaboration and for your thoughtfulness.
Anders Ekedahl for all your help and good comments on the manuscript.
Janne Moen, for excellent collaboration, for your friendship and your endless inspiration, and for all our more or less constructive discussions….
Hans Johansson at Apoteket AB, for your statistical support and for all extracted data from the pharmacy record database in the county of Jämtland.
64
Carina Werner at Apoteket Hjorten in Östersund, for providing space, help
and the possibility for me to copy the prescriptions in Jämtland.
Karolina Antonov and Per Lindberg, for new good ideas and very fruitful
discussions during my half-time seminar. Also Karolina for excellent commentaries on my manuscript.
Sofia Kälvemark-Sporrong, thanks for really helpful commentaries on my
manuscript.
My first room-mates, Inger Nordström-Torpenberg and Sune Petersson for
scientific and non-scientific discussions about everything and nothing and
for your inspiration and care. Also, Anna-Malin Nilsson for the year you
joined us.
To all my former and present colleagues at the Pharmaceutical Outcomes
Research Group for all nice discussions about science and life and for all
your inspiration and support in different ways; Ida Bergström, Hanna Fagerlind, Åsa Kettis Lindblad, Christina Ljungberg, Janne Moen, Anna Montgomery, Annika Nordén-Hägg, Ola Nordqvist, Tobias Renberg, Lena Ring,
Birgitta Rylén, Björn Södergård, Mary Tully and Andy Wallman.
Eva Nises Ahlgren, Harriet Pettersson and Ulla Wästberg-Galik for always
being very helpful with practical matters at the department.
To all my friends for supporting me, for giving me a pleasant leisure time
and for always being there!
My warmest thanks to:
My parents, Britt and Göran, for everything…. For your endless support,
time and love.
My sisters, Maria and Sara, and my brother Markus, for all inspiration, love
and sharing of thoughts.
Words can not express what you all mean to me!
And above all:
To Kristian, my husband, for your unlimited love and support, and for being
who you are!!
65
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Acta Universitatis Upsaliensis
Digital Comprehensive Summaries of Uppsala Dissertations
from the Faculty of Pharmacy 60
Editor: The Dean of the Faculty of Pharmacy
A doctoral dissertation from the Faculty of Pharmacy, Uppsala
University, is usually a summary of a number of papers. A few
copies of the complete dissertation are kept at major Swedish
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Pharmacy. (Prior to January, 2005, the series was published
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