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CLIN. AND EXPER. HYPERTENSION, 2 1 (5&6), 973-985 ( 1999)
COMPLIANCE WITH ANTIHYPERTENSIVE THERAPY
B. Waeber, M. Burnier*, and H.R. Brunner* Division of Clinical Pathophysiology and Medical Teaching, and *Division of Hypertension and Cardiovascular Medicine
The University Hospital 101 1 Lausanne, Switzerland
Key words: Antihypertensive Therapy, Medication compliance, Compliance measures, Electronic monitoring of compliance, Side-effects
ABSTRACT
Poor compliance with antihypertensive therapy is a major cause of unsatisfactory blood pressure control. The doctor has a key role in all steps that lead the patient to adopt a treatment and to take it as prescribed lifelong. Compliance with therapy is a parameter which is difficult to assess. There is often an important mismatch between the subjective views of physicians and patients regarding long-term drug taking. Electronic monitoring of compliance represents a valuable method to evaluate the "real time" compliance of the patient. Discussing a compliance recording with a patient may help to identify and solve problems linked with everyday adherence to antihypertensive treatment. Improving compliance is an important task not only for the doctors, but also for all healthcare providers.
INTRODUCTION
Unfortunately blood pressure control in hypertensive patients is still far from perfect. As an example, in a large survey performed recently in the U. S., only
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Copyright 0 1999 by Marcel Dekker, Inc. www.dekker.com
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974 WAEBER, BURNER, AND BRUNNER
27% of hypertensive patients had their systolic and diastolic blood pressure below 140 and 90 mmHg, respectively [l]. This was true despite a high level of awareness (68% of the sample population). Several reasons may explain an unsatisfactory blood pressure control: 1) an ineffective therapy; 2) a treatment associated with too many adverse-effects; 3) a poor compliance with the prescribed drug regimen; 4) an overestimation of blood pressure because of the presence of a marked "white-coat'' pressor effect. Interestingly, treatment failure is attributed by 70% of doctors to a problem of adherence to therapy [2]. This contrasts sharply with the view of 8 1 % of patients who claim that they always take their medication. On the patient's perspective, ineffectiveness of antihypertensive therapy is the main cause of inadequate blood pressure control. Obviously, there is a major gap between the patient's and the doctor's perception of compliance with antihypertensive treatment. This illustrates that compliance is a parameter which cannot be easily assessed in everyday practice and which remains often a "black box" for the doctor.
Variable compliance with prescribed medication may contribute substantially to the therapeutic outcomes. Most patients with high blood pressure have to take a life-long treatment. This is not easy for the patient since hypertension is generally an asymptomatic disorder and , unfortunately, any antihypertensive medication might occasionnally cause adverse reactions. Great efforts should therefore be directed towards improving compliance with antihypertensive therapy. This can be done by making the patient better understand the hypertension-related risks and benefits of treatment, as well as by individualising the treatment in order to find for each patient a drug regimen being at the same time efficacious and well tolerated.
METHODS OF COMPLIANCE ASSESSMENT
There is unfortunately no ideal method of measuring compliance [3,4].
1 ) Follow-up The physician may gain some information on his patient's compliance by
looking at his way of keeping appointments. A patient who does not show up
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COMPLIANCE WITH ANTIHYPERTENSIVE THERAPY 975
anymore may however still be on treatment since in many countries the patient is allowed to choose freely his doctor. Based on the experience of a large blood pressure clinic one might expect a drop-out (defined as failure to attend for an appointment and to respond to 2 recall letters sent at an interval of 6 months) of about 25% over a 3 year period [5 ] . Patients included in clinical trials may be particularly well motivated. Thus, in the Medical Research Council trial, no more than 5% of patients allocated to placebo withdrew during the 5 year follow-up [6] . In the U.S., approximately 15% of hypertensives are aware of having an abnormally high blood pressure, but are not on antihypertensive therapy [ 11. The majority of these patients are most likely poor compliers who have decided, for whatever the reason, to interrupt the treatment.
2 ) Outcome of therapy Whether blood pressure is controlled or not during antihypertensive therapy is
a very weak indicator of compliance. Any medication, even if taken regularly, is ineffective in approximately half of hypertensive patients. Even patients with hypertension unresponsive to a multiple drug therapy may be compliant.
3) Direct questioning
patient about his habits of taking the prescribed treatment. This approach is unsuitable as long as a patient claims a good adherence to treatment. It becomes however meaningful if a patient admits spontaneously a noncompliance behaviour. Direct questioning is of little help in the individual patient, although there exists some link, when considering a group of hypertensive patients, between the blood pressure normalization rate and the reported degree of compliance [7] .
4) Pill count
In a clinical setting the easiest way to evaluate compliance is to interview the
Pill count has been traditionally used to monitor compliance in antihypertensive drug trials. It tends to overestimate compliance, mainly because patients may deliberately discard tablets before returning the container to his doctor [3]. There is some evidence that compliance assessed by pill count must be 80% or more in order to obtain significant blood pressure reductions [8].
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WAEBER, BURNER, AND BRUNNER 976
5 ) Drug assays and chemical markers The measurement of plasma or urine concentrations of antihypertensive drugs
or their metabolites as an indicator of compliance is attractive. This is also true for the determination of chemical markers [3]. The major drawback of this approach is the possible existence of a "toothbrush effect", which relates to the fact that a noncomplier may resume a perfect compliance a few days before the next visit
P I . 6 ) Prescription refills
Monitoring prescriptions of antihypertensive drugs may be useful to evaluate compliance. This can hardly be done in the individual patient if the doctor is not at the same time prescriber and dispenser of the medications. This technique is especially useful to assess compliance in a community of hypertensive patients, for example those belonging to a given medical care system [ 10-121.
7 ) Electronic medication monitoring
dispensers that record each time at which the container is opened. Most of the experience accumulated so far with'lreal time" compliance has been gained using the Medication Event Monitoring System (MEMS) [13]. It is assumed that the patient ingests the tablet@) as prescribed each time he is removing the cap with a microcircuitry incorporated.
It is now possible to monitor compliance using electronic medication
T d p I E
Underutilization of antihypertensive drugs is expected to be associatd with an unsatisfactory blood pressure control and, thereby, with a suboptimal prevention of cardiovascular complications. Admittedly, theE has been until now only little support for such a view. Two studies should be quoted here. In the first one the association of underutilization of antihypertensive drugs and acutecare readmissions was evaluated in 113 patients [ 141. All patients had been hospitalized with a primary or secondary diagnosis of hypertension. They were
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COMPLIANCE WITH ANTIHYPERTENSIVE THERAPY 977
then observed for readmission for the next 18 months. During this period the noncompliance rate of each patient was calculated as the ratio of the number of days when the patient had no antihypertensive drugs (based on pharmacy records) divided by the number of days of observation. The noncompliance rate averaged 39% in the 28 patients who had to be readmitted, which was significantly higher than the corresponding rate (1 1 %) seen in patients who were not rehospitalized.
A second study deals with the impact of noncompliance with antihypertensive therapy on health care costs [lo]. Paid claims data from the California Medicaid program were used for the analysis. The primary outcome variable was the total cost of health care during the first year after initiation of antihypertensive therapy in patients aged 40 and over (n=6'419). Approximately 86% of the patients (n=5'504) interrupted or discontinued purchasing any blood pressure lowering drug during this period. Each of these patients consumed on the average $873 more than patients who filled the prescriptions regularly during the study period (n=9 15). The increased costs were essentially related to hospital expendatures ($637), indicating that withdrawal of therapy led to serious complications. These observations are of great interest: they clearly show that noncompliance represents for hypertensive patients a high risk situation and that hospitalization is frequently required if antihypertensive treatment is discontinued.
THE DIFFERENT PROCESSES OF COMPLIANCE WITH ANTIHYPERTENSIVE THERAPY
In considering long-term pharmacological treatment of hypertension, three different steps can be identified, i.e. the adoption, the execution and the discontinuation process [ 151. This is exemplified in Figure 1.
1) The adoption process
therapeutic implication, that is to initiate a lifelong treatment. At that time the patient has generally no symptoms and no clinically apparent cardiovascular complication. The doctor plays a key role in the adoption process: he has to make
A difficult step for the patient is to accept the diagnosis of hypertension and its
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978 WAEBER, BURNIER, AND BRUNNER
Good communication
Understanding
Satisfaction
+ + + Adoption Execution Continuation process process
FIG. 1 : A good communication between the doctor and his patient reinforces the adoption and the execution processes. It also helps the patient to continue the treatment.
the patient understand the hypertension-related risk, the benefits expected from lowering blood pressure and the need for a continual blood pressure control even if there is no obvious immediate advantage of therapy. An excellent patient-doctor relationship is a priority at this stage to promote adoption of the prescribed treatment [ 161.
2 ) The execution process The execution process is by far the most difficult for the patient since it deals
with his daily life for years. Each day the patient has to take the prescribed treatment as recommended by his doctor. During this phase the doctor has still to motivate his patient, but multiple interventions may be useful to improve compliance, for example by other healthcare professionals, in particular nurses and pharmacists [16]. The multidisciplinary approach helps to recognize the patient's barriers, and therefore to direct efforts to facilitate compliance in taking into account social, cultural, psychological and economic factors. During this phase a number of strategies may improve compliance, including educational tools, self-monitoring of blood pressure, telephone follow-up and electronic monitoring of compliance [17-191. The main sequential factors that oppose long-
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COMPLIANCE WITH ANTIHYPERTENSIVE THERAPY 979
term adherence to antihypertensive therapy are a poor communication between the patient and his doctor, a low motivation (from either the patient, his doctor or both), logistical barriers (excessive costs,...), the Occurence of side-effects, complex and/or ineffective drug regimens and unsufficient periodical reinforcement of compliance [4].
3 ) The discontinuation process A substantial fraction of patients treated for hypertension decide, for various
reasons, to discontinue therapy. Most of these patients are lost to follow-up. The responsability of such treatment failure has to be shared by the patients and the health providers, especially the doctors. Not enough time was probably reserved for educating and counsiling activities [ 161.
THE INFLUENCE OF ANTIHYPERTENSIVE DRUG REGIMEN ON COMPLIANCE
1 ) The tolerability Any antihypertensive drug may occasionally cause adverse effects and
therefore have a negative impact on compliance. This can be illustrated by the results of a study in which 632 patients on antihypertensive therapy were surveyed for 1 year [20]. The aim was to assess using a questionnaire the prevalence of patient-initiated modifications of drug instructions (use of lower dosage and/or fewer drugs than prescribed) in relation to the occurence of problems (symptoms of high blood pressure, adverse drug effects, perceived memory problems with drug taking, perceived negative patient role and/or barriers to drug taking in everyday life). Figure 2 shows that the prevalence of modifications increased linearly as a function of the number of problems experienced.
In another study, the reasons for stopping or altering antihypertensive therapy were investigated by surveying in the U.K. a total of 178 family doctors and 948 hypertensive patients [21]. The doctors felt that 18% of their hypertensive patients did not comply with the antihypertensive therapy and that, of these non-compliant patients, 22% were not adhering to treatment because of side-effects. Among the
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980 WAEBER, BURNER, AND BRUNNER
loo 1
60
40
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%
No problems 1 problem 2 problems 3 or more (n=131) (n=191) (n= 158) problems
(n= 137)
Fig. 2 : Percentage of patients modifying drug instructions according to the number of reported problems (from ref. 20)
patients, 34% reported that they had experienced unacceptable side-effects. The majority of these patients (78%) advised their doctor of the side-effects while a few patients (9%) spontaneously stopped taking their medication.
These obsevations highlight the necessity of tailoring the drug regimen to the individual patient, the goal being to normalize blood pressure of each patient without interfering adversely with his quality of life.
2) The type of antihypertensive agent The class of agents used to initiate antihypertensive therapy might influence
long-term compliance, possibly because of more or less favourable side-effect profiles. Several studies have adressed this question by analysing the refill failure in managed-care organizations. In a cohort of hypertensive patients who were enrollees of Tennessee's Medicaid managed-care program, refill failure (if a refill was not obtained within 36 days of the last prescription for that medication) occurred in 33% of 7'413 refill opportunities [22]. The frequency of refill failure was 30% for beta-blockers, 29% for calcium channel blockers, 35% for ACE inhibitors and 34% for thiazide diuretics. The refill opportunities for these 4 major classes of antihypertensive agents were 199,2806,602 and 3'272, respectively.
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COMPLIANCE WITH ANTIHYPERTENSIVE THERAPY 98 1
Manifestly, this large disparity in refill opportunities between the different treatments renders the interpretation of the results difficult.
More meaningful are the observations made in 27'364 hypertensive patients aged 40 and over and living in Saskatchewan [ 121. All these patients received for the first time an antihypertensive treatment which consisted mainly of diuretics (40%), beta-blockers (lo%), ACE inhibitors (30%) or calcium antagonists (13%). Overall, 78% of patients were still on the same treatment after one year. Patients who had an ACE inhibitor as initial drug were however significantly more often on the same medication after one year in comparision with patients having started the treatment with the other types of antihypertensive agents.
A retrospective analysis of prescriptions was also performed in 8'643 elderly hypertensives (aged 65 to 99) belonging to the New Jersey Medicaid and Medicare programs [ 1 13. Compliance was defined as the number of days in which antihypertensive therapy was available to the patient during the 12 months following the initiation of treatment. Patients were considered good compliers when compliance was 80% or higher. Diuretics were the most frequently prescribed drugs (50%), followed by beta-blockers (1 2%), calcium antagonists (12%) and ACE inhibitors (5%). Other medications accounted for 17% and 4% of patients had multiple drugs as initial therapy. Figure 3 shows the odds ratio for good compliance (adjusted for age, race and gender). The compliance observed during diuretic therapy was taken as reference value. All medications given as monotherapy were associated with a significantly better compliance as compared with diuretics, ACE inhibitors being the best in this respect. Interesting findings were also that good compliance was inversely related to comorbid cardiac disease as well as to the need of multiple drug therapy.
Taken together, the choice of the drug to initiate antihypertensive therapy might have important implications for the subsequent adherence to treatment. The use of of newer drugs appear in this regard particularly appealing.
3) The mode of administration
once-daily dosing appears in this respect optimal. There are now available numerous antihypertensive drugs with prolonged duration of action allowing to
Simplification of treatment is expected to facilitate long-term compliance. The
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* 280% of days coverered
Fig. 3 : Initial drug choice as a factor related to antihypertensive therapy compliance. The y axis depicts the odds ratio for good compliance for patients beginning antihypertensive therapy. For each variable, the odds ratio is indicated by the horizontal line and the 95% confidence interval by the vertical line (from ref. 14).
control blood pressure throughout the day when given once a day. So far there was however no definitive proof that once-a-day dosing is associated with a better compliance as compared with more frequent dosings. Whether there exists a difference in compliance between a once-a-day and a twice-a-day drug regimen has been tested recently using the MEMS device [23]. In this study 313 black hypertensive patients were followed for an average of 4.6 months. Adherence by MEMS to the once-a-day and the twice-a-day drug dosing shedules was considered acceptable if 80% of the time intervals between MEMS openings were within 24+6 h or 12+3 h, respectively. The following table compares the frequency of adherence and nonadherence with once-and twice-a-day dosing:
Adherent Nonadherent
Once-a-day (n=227) 1 12 (49) % 115 (51%) Twice-a-day (n=86) 5 (5) % 81 (95%)
Pill counts were also performed in this study to assess compliance. Acceptable adherence by pill count (if 80% to 100% of the prescribed pills were not returned)
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COMPLIANCE WITH ANTIHYPERTENSIVE THERAPY 983
was observed in 68% of cases. In 47% of those cases, compliance assessed by electronic monitoring showed however a nonadherence pattern. Blood pressure control was better in good than in poor compliers.
USEFULNESS OF ELECTRONIC MONITORING OF COMPLIANCE
"Real time" monitoring of compliance makes it possible not only to evaluate the percentage of precribed doses taken, but allows also to measure the intervals between doses as well as to assess the extent to which some intervals may be longer than the drug's duration of action, in which case drug action is interrupted. It also enables to detect errors in dosings such as skipping one or more sequential doses (drug hollidays). Electronic monitoring of compliance is particularly useful in clinical trials [3]. Noncompliers go generally undetected and are often misjudged as ''non responders". The identification of such patients can therefore be very helpful to interpret the observations. This approach should not be regarded as an intrusion in the privacy of the patient's life, but as a privileged occasion of discussion between the patient and his physician. The objective record of drug intake can reinforce the patient's motivation and improve his compliance with medication regimens. In a recent trial carried-out by practicing physicians, patients remaining hypertensive for several weeks despite the once-a-day administration of an antihypertensive drug were asked to continue the same treatment for 3 additional months (Waeber et al, manuscript in preparation). The patients were explained to take the medication using a MEMS, which obliged the doctors in charge of the patients to raise the potential problem of noncompliance. A significant fall in blood pressure was seen during the 3 month observation period, even though the patients appeared previously resistant to the used medication.
CONCLUSIONS
The treatment of hyprtension remains a difficult task: there are still too many patients who have their blood pressure unsatisfactorily controlled. A frequent
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WAEBER, BURNIER, AND BRUNNER 984
reason is a poor adherence to the drug regimen. The doctor should imperatively keep in mind the problem of compliance when he prescribes antihypertensive agents. This will urge him to inquire regularly about baniers to optimal compliance and help the patient to seek solutions for improving its adherence to the prescribed treatment.
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