Medizinische Universitäts-Poliklinik, Bonn, Germany
Keywords: drug therapy; compliance
Introduction
Compliance with medical recommendations, especially with drug therapy, has been recognized to represent a complex challenge since its first mentioning by Hippocrates about 2400 years ago [1]. An in-depth scientific approach towards this problem, however, can only be traced over the past three decades with a strong increase in published studies over this period of time (Figure 1). As is generally true in medicine and other scientific subjects, the availability of reliable methods is of crucial importance for scientific progress. Thus, the development of electronic medication event monitoring systems (MEMS) in 1977 has provided the basis for a rapid expansion in understanding the compliance issue [2]. To date, this method represents the gold standard for measuring compliance and its application in many areas of drug research and in clinical practice is rapidly expanding [3,4]. In the following, we will briefly review some of the recent advances in the understanding of medication compliance and will attempt to layout some of the resulting lessons for pharmacotherapy.
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Definitions and methods
In general, the term compliance describes the extent to which a person's behaviour coincides with medical advice. With respect to drug therapy, compliance is defined as the degree of correspondence of the actual dosing history with the prescribed drug regimen [5]. Thus, the measurement of compliance basically represents the comparison of two time-series (as taken versus as prescribed). From this understanding of compliance it becomes obvious that many methods applied in compliance research may be hampered by serious shortcomings (Table 1). Thus, the pill count and the refilling approach (documentation of the dates when the patient refills his prescription allowing to calculate the time-period covered by medication) are easily manipulated by the patient and are not capable to detect even major deviations from the dosing schedule. Drug monitoring of the prescribed agent itself is dependent on the availability of sensitive assays, often requires repeated blood sampling, and is not capable to identify poor long-term compliance in patients whose compliance improves shortly before a doctor's appointment (white-coat-compliance). In addition, low-dose chemical markers as additives to a prescribed therapy such as phenobarbital and digoxin may pose ethical and legal questions and require special formulations of the medication with documented pharmacokinetic qualities. In contrast to the shortcomings of these methods, electronic monitoring fulfils the necessary requirements for analysing compliance as it allows us to document the dosing history.
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Electronic medication event monitoring
A medication event describes a set of actions necessary for taking a dose of medication. Depending on the medication package, electronic monitoring may register a medication event in different ways, such as the joint occurrence of cap removal and dispenser inversion in eyedrop dispensers, aerosol release in inhaler-type applicator systems, as well as blister release or package opening or closing for solid dosage forms (tablets) [3]. An advanced electronic device such as the Aardex Ltd (www.aardex.ch) system is comprised of two components, a plastic vial (pill container) with a closure that contains a micro-electronic circuit capable of registering times when the closure is opened and when it is closed. Electronically stored medication events can be transferred to a computer. These time-series data can subsequently be processed (e.g. chronology plots, calendar display, frequency histograms of interdose intervals) and may be illustrated graphically (Figure 2) [4]. A more detailed description of these systems and a critical review of their use in the clinical setting can be found elsewhere [3,4,6].
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Non-compliance or how much compliance is enough
One of the still ongoing controversies with respect to drug regimen compliance is the question: what degree of deviation of the dosing history from the drug regimen may be defined as non-compliance? The complex background of a suitable definition of non-compliance may be illustrated by comparing a woman taking hormonal contraceptives or a stage IV heart failure patient on loop diuretics on the one hand (A) and a hypertensive or hyperlipidaemic patient on antihypertensive or lipid-lowering therapy on the other hand (B). It seems obvious that a single dose delay or omission may seriously jeopardize the outcome in (A) but is unlikely to do so in (B). Thus, the clinical situation and the therapeutic goal of pharmacotherapy have a strong impact on the definition of non-compliance. In addition, the drugs themselves may make a difference by their different duration of action. Thus, long-acting drugs mayto a certain degreeallow deviations of the dosing history from the drug regimen while short-acting drugs require a close resemblance of the two time-series. This aspect is best described by the drug forgiveness concept. In this context, forgiveness is defined as the drugs post-dose duration of action minus the prescribed dosing interval. Thus, a drug with a recommended once-daily dosing and duration of action of 36 h has a forgiveness of 12 h. From these few points it becomes clear that non-compliance cannot be generally defined and that instead of a definition of non-compliance one has to ask the question: how much compliance is needed to reach the therapeutic goal? Again, the answer to this question may depend on the clinical situation and the forgiveness of the drug (or the drug formulation) under consideration.
Variable compliance: causes and consequences
Numerous factors such as the duration of therapy, the complexity of the prescribed drug regimen and many psychosocial factors, alone or in combination, may contribute to variable compliance with drug therapy [7,8]. In a previous study investigating compliance in treated hypertensive patients using questionnaires, almost half of a variable compliance was due to forgetfulness. The remaining half of the deviations of the dosing history from the prescribed regimen could be attributed to a variety of factors such as side effects of the prescribed medication and irregular lifestyle [9].
The health care and economic consequences of variable compliance have recently been reviewed [10] and may be illustrated by using data from the Helsinki Heart Study, in which gemfibrozil was used as a lipid lowering agent to prevent coronary events in hyperlipidemic subjects [11]. About one-third of the study population of 4081 subjects was given low-dose digoxin and compliance was assessed by twice yearly measurement of this chemical marker. In addition, compliance was also assessed by pill counts and interviews. These latter methods, however, were shown to clearly overestimate compliance as compared with the chemical marker approach [12]. The absolute risk of a coronary event over the 5-year period studied averaged 4.1% in the placebo and 2.7% in the gemfibrozil group. When analysing the impact of compliance on the protective potential of gemfibrozil it becomes clear that a strong correlation between compliance with the drug regimen and coronary events could be established. Thus, in the lowest quartile of compliance the incidence of coronary events was approximately 3.5-fold higher than in the top quartile. Similarly, the cost to prevent a coronary event is markedly elevated in the poor as compared with the good compliers [10].
Moreover, variable compliance has a significant impact on the outcome of drug treatment in almost every area of medicine that has been looked at. Thus, poor compliance is a significantif not the single most importantcontributing factor in transplant rejection [1317]. Another well-documented example illustrating the ubiquitous significance of the compliance issue is drug therapy of patients with HIV infection. While antiretroviral combination therapy is known to be effective in slowing disease progression, the long-term benefit of these therapies can only be sustained if resistant strains of HIV do not emerge. Among the factors that can result in the emergence of resistance, variable compliance has been shown to play a key role [1820].
The most common clinical situation confronting practising physicians with the issue of compliance may be a patient on antihypertensive drug therapy with an insufficient blood pressure response to treatment. The question to be asked in this everyday situation is whether the patient is in fact a non-responder or a non-complier. Not detecting non-compliance as a contributor to insufficient response is likely to trigger the wrong measures to be taken.
Typical patterns of non-compliance
With the use of electronic medication event monitoring a detailed picture of the patterns of variable compliance is now available. Thus, prolonged intervals between dose administrations are the most common deviation of the dosing history from the prescribed drug regimen [3,5]. Longer lapses of 3 days and more are called drug holidays [21]. Timing of the prescribed dose may vary in other ways, e.g. that a morning dose is taken in the evening and again the next morning. It is obvious that the clinical consequences of a prolonged dosing interval and of dose timing variations in general among others depend on the pharmacological characteristics of a given medication. Another important pattern unknown before MEMS were used to analyse drug regimen compliance is white-coat-compliance [22]. This term is used to describe poor or partial compliers improving their compliance around the time of scheduled follow-up visits [23]. In addition to the aforementioned detrimental health care effects of variable compliance, white-coat-compliance may also induce diagnostic confusion. Thus, blood pressure may be normal during doctor visits in a patient on antihypertensive treatment. However, left ventricular hypertrophy in the same patient may not regress. Another patient may have a sufficient laboratory response to anticoagulant therapy but may nevertheless suffer from recurrent thromboembolism because therapy is insufficient between doctor visits. White-coat-compliance may always be considered when a rapidly drug-responsive surrogate is well controlled at successive office visits but longer-term consequences of treatment are less than expected or absent.
Strategies to cope with variable compliance
Awareness of the problem of variable compliance on the side of the physician is the essential prerequisite for improving compliance. While totally non-compliant behaviour (<10% of a treated population) may easily be traced by failure to achieve both surrogate and therapeutic endpoints partial compliance may only be detected when it is actually measured. In this context, it should be noted that partial compliance is an epidemic in every treated population (3040%). Although our current knowledge of factors associated with non-compliance may help to identify patients at risk [6,24,25] only precise measurements of compliance with electronic systems will allow an exact analysis of the magnitude and the specific pattern of deviation of the dosing schedule from the prescribed drug regimen. Among the underlying circumstances of non-compliance, forgetfulness has to be acknowledged as the single most important factor. In addition to classical behavioural and social strategies, high-tech devices such as interactive pill containers may have a future role in coping with variable compliance due to forgetfulness. Also, forgiving drugs will help to reduce the negative impact of forgetfulness on treatment objectives. With respect to othermore or less contemplatedreasons for variable compliance many if not all of them call for improved and intensified communication of the physician with the patient [6].
Notes
Correspondence and offprint requests to: Prof. Dr Rainer Düsing, Medizinische Universitäts-Poliklinik, Wilhelmstr. 3537, D-53111 Bonn, Germany.
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