the implications of noncompliance with antihypertensive medication
TRANSCRIPT
REVIEW ARTICLE Drugs 1996 Aug; 52 (2): 1B6-195 0012-6667/96/000B.()186/S10.00/0
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The Implications of Noncompliance with Antihypertensive Medication Briegeen Girvin1 and G. Dennis Johnston2
1 Drug Utilisation Research Unit, Department of Therapeutics and Pharmacology, The Queen's University of Belfast, Belfast, Northern Ireland
2 Department of Therapeutics and Pharmacology, The Queen's University of Belfast, Belfast, Northern Ireland
Contents Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Methods of Assessing Patient Noncompliance with Antihypertensive Drugs .
1.1 Attendance at a Clinic 1.2 Prescription Refills . 1.3 Patient Interview 1.4 Pill Counts ..... 1.5 Urine Assays . . . . 1.6 Plasma Concentrations 1.7 Electronic Monitoring. .
2. Implications of Noncompliance 2.1 Increased Mortality and Morbidity 2.2 Effects and Risks of Stopping Antihypertensives Other Than Loss of
Blood Pressure Control . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 The Impact of Noncompliance with Different Antihypertensive Agents on
Blood Pressure Control . . . . . 2.3.1 Therapeutic Sufficiency 2.3.2 Trough to Peak Ratio 2.3.3 Thiazide Diuretics 2.3.4 ~-Blockers. . . . . . . 2.3.5 a-Blockers ..... . 2.3.6 Calcium Antagonists 2.3.7 ACE Inhibitors ....
2.4 Excessively High Dose Recommendations in Dose-Ranging Studies . 3. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
186 187 187 187 187 187 188 188 188 189 189
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190 190 190 191 191 191 192 192 193 193
Summary Given the clear evidence that reducing blood pressure decreases the vascular complications of hypertension, loss of efficacy represents the principal complication of noncompliance with antihypertensive therapy. Withdrawal symptoms are also important and occur after abruptly stopping l3-blockers and centrallyacting antihypertensive drugs. Very few studies have been conducted to assess the impact of missing 1 or 2 doses of an antihypertensive agent on short term control of blood pressure. A high trough to peak ratio (>50%) for a once-daily
Noncompliance with Antihypertensives 187
medication suggests a long duration of action. However, methodological problems in the design of the studies to determine trough to peak ratios make comparisons between various medications very difficult. In general, however, stopping a drug with a low trough to peak ratio is more likely to result in loss of antihypertensive effect than a drug with a high ratio. Poor compliance in doseescalating studies with antihypertensive agents may have resulted in excessively high dose recommendations in clinical trials.
Compliance has been defined as 'The extent to which the patient's behaviour (in terms of taking medications, following diets or executing other lifestyle changes) coincides with the clinical prescription' .II]
Few studies have set out to determine the magnitude of reduced blood pressure control when 1 or 2 doses of an antihypertensive medication are omitted. Most investigations that try to link a level of compliance with blood pressure control commonly use overall measures of compliance, e.g. pill counts. When attempts are made to determine a relationship between compliance and blood pressure control it should be remembered that compliance is only one factor that can contribute to a change in blood pressure. Alterations in bodyweight, lifestyle modifications (e.g. exercise, smoking and alcohol intake), recent activity and several other factors can alter a blood pressure measurement. It also depends on the drug(s) and dosage(s) used: a partially compliant patient may have adequate blood pressure control if the doses prescribed are too high.
1. Methods of Assessing Patient Noncompliance with Antihypertensive Drugs
All methods of measuring compliance have drawbacks. A few studies have attempted to link compliance with blood pressure control. However, since the studies involved the use of different medications and dosages and different definitions of compliance and control of blood pressure, the relationship between blood pressure control and compliance has been difficult to determine.
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1.1 Attendance at a Clinic
Attendance at a blood pressure clinic can give a crude estimate of patient compliance. Early studies showed that the average drop-out rate from keeping appointments at a blood pressure clinic was 50%.[2-5] A more recent estimation of clinic nonattendance was lower at 15.5%.[6]
1.2 Prescription Refills
Monitoring prescriptions can give an overall estimate of drug use in a community. Compliance measured by prescription refills of antihypertensives has been estimated at 66%P] Compliance with hydrochlorothiazide medication has been estimated at 61.2% as determined by monthly prescription refills over a 6-month period.l8] The authors stated that compliance was significantly correlated with mean diastolic blood pressure (r = -0.63, p < 0.05).
1.3 Patient Interview
Some studies have attempted to link compliance assessed by patient interview to blood pressure control and have reported that better compliance results in lower blood pressure. [9, 10] An interesting finding in two other studies was that good diastolic blood pressure control was found in several noncompliant patients, raising the possibility of overtreatment or unnecessary treatment.[1I,12] It is generally accepted that admission of noncompliance is accurate but that denial of noncompliance may be incorrect. Patient report does not coincide with data obtained from electronic monitoring.l13]
1.4 Pill Counts
Pill counts have been the main measure of com-
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pliance in most hyperteRsion studies. In a study by Sackett and colleagues[14] conducted on Canadian hypertensive steelworkers, an arbitrary value of 80% compliance with pill counts was agreed for adequate blood pressure control. This was because only pill counts of 80% or more were associated with a statistically significant reduction in blood pressure. However, the study involved a small sample size and the 80% value was not specific to one drug group since most of the patients were taking various medications.
Since then, many researchers have taken this value of 80% compliance with pill count to represent satisfactory compliance. However, patients may discard any unused pills, and weekly pill counts seem to provide better information than long term average pill counts.[15]
1 .5 Urine Assays
Lowenthal and colleagues[16] tested the urine from 172 hypertensive patients to determine compliance with thiazide diuretics. They found that two-thirds of patients with positive urine tests were 3.2 times as likely to be at goal blood pressure than the one-third with negative urine tests.
The inaccuracies that can be encountered during studies which use urine measurements as a compliance indicator have been discussed by Prinoth et a1.l 17] Many studies have not considered the factors which influence the time interval during which a drug can be detected in the urine following ingestion.
1 .6 Plasma Concentrations
Plasma concentrations of antihypertensive drugs have been used to assess patient compliance,[18] but are not routinely used in clinical practice. Plasma concentrations give no indication of compliance between blood sampling, and the relationship between plasma concentration and effect is poorly defined.
Unfortunately, patients can appear to be compliant by dosing close to the expected blood test, and
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Girvin & Johnston
can temporarily achieve plasma concentrations comparable to those at steady state.
Low-dose phenobarbital (phenobarbitone) has successfully been used as a biological marker to detect noncompliance with certain medications because of its long elimination half-life (tY2~)'p9]
In an outpatient study to monitor the compliance of patients with various conditions, compliance (using plasma phenobarbital concentrations) was related to blood pressure control in 7 hypertensive patients. Five of them had good compliance using phenobarbital concentrations and pill counts, and adequate control of blood pressure. One patient was poorly controlled and found to have no phenobarbital in his blood. It was later found that he had not even collected his prescription although his doctor had rated him as being a 'good complier' .[19]
It has been suggested that greater use should be made of objective drug-induced variables as an assessment of compliance, e.g. lowering of resting heart rate on ~-blockers, and the decrease in potassium and increase in uric acid seen in patients on thiazide diuretics PO] However, it is generally thought that these are too variable to be used as a reliable measure of drug compliance.
1 .7 Electronic Monitoring
The most recent effective development in the measurement of drug compliance has been the use of electronic monitoring. Most of the studies have involved the Medication Event Monitoring System ('MEMS', Aprex Corporation, USA). This consists of a standard pill bottle whose lid is fitted with a microprocessor capable of recording the exact date and time the pill bottle was opened. It cannot confirm whether or not the medication was removed or ingested but it is unlikely that many patients would systematically open and close the bottle without taking the medication.
The following is a brief description of some of the hypertension studies involving the 'MEMS' device in relation to antihypertensive efficacy. The interest generated from these studies has been more in terms of assessing drug compliance than at-
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tempting to determine the impact on control of blood pressure.
In a study comparing isradipine and enalapril, both drugs were prescribed twice daily, but less than half of all openings occurred within 12 ± 2 hours.[21] This would have gone undetected using pill counts, which were 92 and 99% for the 2 groups. Over-dispensing also occurred during the 3 days before a scheduled visit.
Electronic monitoring showed that the possible reason for an unexpected rise in blood pressure in I patient taking isradipine was because previous doses had been taken less than 5 hours prior to the clinic assessment, whereas 20 hours had elapsed at the visit when blood pressure control was lost. This suggests that isradipine is relatively short-acting and, for this drug, minor degrees of poor compliance could result in loss of effect.
With hydrochlorothiazide and chlorthalidone, blood pressure reduction related better to the total number of doses taken during a I-month period than to the timing of the dosesp2] This suggests that these drugs may be more 'forgiving' about episodes of noncompliance and that patients should be advised to ingest all prescribed doses, regardless of the time interval between doses. It may also partly account for the long term efficacy of thiazide diuretics compared with ~-blockers in the elderlyP3]
Compliance decreases with time after inclusion into a study and may be related to the frequency of drug administration.[24] Compliance (defined as the percentage of days during which the prescribed number of doses were removed) improved from 59% on a 3 times daily regimen to 84% on a once daily hypertensive regimen. [25] Compliance with amlodipine 5mg once daily, either in the morning or the evening, was found to be higher with morning administration.[26]
In a comparison between 10 and 20mg nifedipine twice daily with a fixed combination of 50mg triamterene plus 25mg hydrochlorothiazide once daily, compliance did not differ between the once daily and twice daily regimensP7] However, days without administration were observed twice as fre-
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quently with the once daily than with the twice daily regimen. More frequent omissions occurred at weekends than during weekdays.
Similar results were obtained in a study comparing twice daily nifedipine and once daily arnlodipine.[28] These studies suggest that once daily administration should only be recommended when the duration of action of the drug extends well beyond the 24-hour interval, thus allowing for inevitable periods of noncompliance.
2. Implications of Noncompliance
2.1 Increased Mortality and Morbidity
The role of antihypertensive therapy in reducing morbidity and mortality has been well documented,[29-31] especially with respect to stroke.[32] Poor compliance with antihypertensive therapy, sufficient to result in loss of antihypertensive control, will clearly cause reversal of the beneficial effects on stroke, cardiovascular disease, hypertensive nephropathy and retinopathy.
The impact of poor drug compliance which has a partial effect on blood pressure control is more difficult to assess but it would be reasonable to assume that the benefits would be less than optimal. Poor compliance is probably the major reason for the low impact of antihypertensive drug therapy in free living populations as compared with those enrolled in drug studies[33] and why the incidence of malignant hypertension has not declined in treated populations.[34] An increased rate of hospitalisation among hypertensive patients who failed to refill their prescriptions has also been demonstrated by Maronde and colleagues)35]
The financial implications of excess morbidity due to noncompliance are potentially enormous. [36,37]
2.2 Effects and Risks of Stopping Antihypertensives Other Than Loss of Blood Pressure Control
A withdrawal syndrome caused by abruptly discontinuing ~-adrenoceptor blocking agents is already a widely described phenomenon. This may
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include tachycardia, malaise, tremor and anxiety.l38] The withdrawal symptoms are associated more with the higher doses of ~-blockers used to treat angina rather than the lower doses used in hypertension. Discontinuation of a ~-blocker in patients with ischaemic heart disease has led to cases of exacerbations of acute angina, myocardial infarction and sudden death. Alderman[39] reported that within several days after stopping propranolol treatment in 6 patients with stable angina, one died and 3 sustained myocardial infarctions.
The results of a study conducted by Psaty et al.l40] suggest that even patients with no prior history of ischaemic heart disease are at risk of developing ischaemic heart disease if they stop taking their ~-blockers. Patients on ~-blockers with a compliance value of less than 80% (determined from prescription refills) had a 4-fold increase in the relative risk of developing coronary artery disease. The ischaemic event occurred between 2 and 23 days after their prescriptions ran out. Partial compliance with diuretic therapy was not associated with any increased risk.
Withdrawal syndromes may occur after abruptly discontinuing high doses of centrally-acting antihypertensives such as methyldopa and clonidine, involving symptoms of sympathetic overactivity.l41] Withdrawal of clonidine can lead to a dangerous, sometimes fatal increase in blood pressure[42,43] which is exaggerated in patients also taking ~-blockers.l44]
2.3 The Impact of Noncompliance with Different Antihypertensive Agents on Blood Pressure Control
The concept of therapeutic sufficiency and trough to peak ratios may be important in assessing the implications of noncompliance with antihypertensives.
2.3. 1 Therapeutic Sufficiency Therapeutic sufficiency has been defined as the
achievement of 'defined goals of disease control and prevention despite patients' imperfect behaviour and clinicians' imperfect prescriptions' .[45]
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Girvin & Johnston
This does not necessarily mean that the drug must have a long t'l1P, but instead it attempts to relate the drug's pharmacokinetics to its pharmacodynamics.
Medications with a long duration of action are said to be 'forgiving' in that omission of 1 or 2 doses will not interfere with the overall therapeutic effect.l46] Recently, there has been an interest in developing medications which allow for partial compliance.
Levy[47] has recently drawn attention to a pharmacokinetic parameter, Km, which was originally described in the 1960s. 'K' is the terminal elimination rate constant and om' is the slope of a plot of drug effect versus log drug concentration. 'Forgiving' drugs have low Km values, which may be due to a long tyzP with subsequent low K value or a small m value irrespective of V/2p.
2.3.2 Trough fo Peak Ilotio The rationale behind the US Food and Drug Ad
ministration (FDA) guidelines on trough to peak ratios has been recently discussed.[48] It is recommended that for whatever chosen dosage interval of an antihypertensive agent, the trough to peak ratio should exceed 50%. This was in an attempt to prevent the licensing of unnecessarily high doses of drugs to extend their duration of action.
It is considered that a high trough to peak ratio suggests a long duration of action, which might in theory allow for periods of partial compliance. However, the data from studies assessing trough to peak ratios are very conflicting because of various methodological problems in assessing the ratio. Some of the problems include: (i) failure to include placebo responses; (ii) non-uniformity in the definition of when the trough and peak effects occur; (iii) different methods of measuring ambulatory blood pressure and the possible inaccuracies in these methods.
It has also been proposed that the nature of the concentration-effect relationship will affect the trough to peak ratio.l49] Meredith and Elliott[49] propose that the trough to peak ratio of drugs with a linear concentration-effect relationship is relatively insensitive to the dose. Examples of drugs
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with this linear relationship include prazosin, doxazosin, nifedipine, verapamil and amlodipine.
However, drugs with a sigmoid concentrationeffect relationship (e.g. enalapril and cilazapril) have a trough to peak ratio which changes with changing dose.l491 Relatively few studies have been designed to assess how quickly the antihypertensive action of a drug is lost after discontinuation or during periods of partial compliance such as one or two missed doses. The following is a summary of the available information.
2.3.3 Thiazide Diuretics In a study to estimate the duration of action of
hydrochlorothiazide, 7 patients took placebo for at least 8 weeks, followed by hydrochlorothiazide 100 mg/day for 12 weeks, followed by placebo for another 12 weeks.l501 Mean arterial pressures taken at noon during the latter placebo phase were lower than during the placebo run-in phase (p < 0.05). This suggests that the antihypertensive effect of hydrochlorothiazide was carried over into the placebo phase.
After discontinuation of chlorothiazide 500 mg/day and chlorthalidone 100 mg/day, blood pressure was measured for 1, 2, 3 and 7 days after withdrawal.l511 The full antihypertensive effect of chlorothiazide was present after 24 hours and of chlorthalidone after 3 days. This suggests that chlorthalidone could be given every 3 days although the dosage used was higher than the currently recommended dosage for hypertension of 12.5 to 25 mg/day.
2.3.413-Blockers 144 hypertensive patients were given either
betaxolol 10 mg/day or atenolol 50 mg/day for 5 weeks.l521 Patients were then given placebo tablets for 2 days. Ambulatory blood pressure monitoring showed that the magnitude and duration of blood pressure response 24 to 48 hours after a dose of betaxolol was statistically superior to that of aten-0101.
In a study designed to investigate the length of antihypertensive action of atenolol, 12 hypertensive patients were given atenolol100 mg/day for 2
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weeks.l531 The drug was then withdrawn and blood pressure measurements made during the 3 days after withdrawal. A significant resting blood pressure reduction was found 34 and 48 hours after administration of the last 100mg tablet, suggesting that blood pressure would still be controlled for 1 or 2 days after a dose omission.
In another study, 35 hypertensive patients were given 600mg atenolol for 3 weeks.l541 After stopping the medication, their blood pressure showed a slow return to baseline over 3 weeks. However, the dosage in this study was much higher than the dosage of 50 to 100 mg/day currently used to treat hypertension.
The trough to peak ratios of atenolol (50 to 100mg; n = 20) and acebutolol (400 to 500mg, n = 19) were determined and compared in a placebocontrolled double-blind randomised study.[551 The diastolic trough to peak ratio was 46% for atenolol and 71 % for acebutolol. The reduction in diastolic blood pressure during the final 6-hour period for atenolol was significantly less than during the first 18 hours of the dosage interval. However, for acebutolol this difference was not found to be significant.
The fact that the longer duration of action of one drug over another is not necessarily linked to the drug's tY2~ is illustrated by the observation that bopindolol (tY2~ 4 to 5 hours) lowers blood pressure when given at weekly intervals.[561
2.3.5 a-Blockers Doxazosin was given once daily to 6 hyperten
sive men for 4 weeks.l571 24-hour monitoring showed that the reduction in blood pressure was no longer detected on days 2 and 7 after drug withdrawal. Withdrawal of doxazosin did not result in any rebound hypertension/cardiovascular complications, or any symptoms related to sympathetic overactivity. Doxazosin treatment produced a significant reduction in daytime but not night-time systolic and diastolic blood pressure. In another study, doxazosin produced a significant reduction in blood pressure during the early morning hours when administered at night.l581
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2.3.6 Calcium Antagonists The antihypertensive effect of amlodipine has
been demonstrated during the 48-hour period after drug withdrawal in 18 hypertensive patients.[59) Ambulatory monitoring showed no statistical difference between the first and second 24-hour postdose blood pressure reading. This would suggest that one dose on alternate days would not significantly impair blood pressure control.
Nifedipine, verapamil and diltiazem all have a short t1/2~ and a relatively short duration of action. However, nifedipine has recently been reformulated as nifedipine gastrointestinal therapeutic system (GITS) for once-daily administration which, during steady-state administration, has been shown to maintain a statistically significant reduction in blood pressure for up to 36 hours)60) The trough to peak: ratio for nifedipine GITS has been reported to be 81 % for the 30mg dose and 107% for the 60mg dose)61)
Lacidipine is thought to have a relatively long duration of action, with a placebo-corrected trough to peak ratio of 62.5% (4 mg/day) and 71.1 % (6 mg/day»)62)
2.3.7 ACE Inhibitors Most of the trough to peak ratio data so far have
been performed on the ACE inhibitors. Zannad[63) has reviewed 136 studies concerning this group of drugs and collated the trough to peak: ratio information on only 19 well designed studies. These are summarised in table I.
Table I suggests that lisinopril, enalapril and trandolapril have a sufficient trough to peak ratio to justify once daily administration.[63) In a recent placebo-controlled double-blind randornised study, 88 hypertensive patients were given either trandolapril 2mg or enalapril 20mg as a single dose in the morning.[64) Ambulatory blood pressure data were analysed for a 48-hour period after the last dose to assess the effects of a day with no dose. Trandolapril sustained a more favourable antihypertensive effect during the 'missed dose' day. On active treatment, the trough to peak: ratios for trandolapril were 90% (systolic) and 54% (diastolic), the corresponding values for enalapril both
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Girvin & Johnston
Table I. Trough to peak ratios for various ACE inhibitors
ACE inhibitor Trough to peak ratio' (%)
Captopril 0-40b ,c
Enalapril 40-80
Lisinopril 40-80
Perindopril 30d
Quinapril 30-40d
Ramipril 40-50d
Trandolapril 50-100
a The trough to peak ratio represents the ratio of the reduction in diastolic blood pressure (DBP) achieved immediately pre-dose compared with the peak reduction in DBP post-dose.
b Trough to peak ratios calculated for morning dose.
c Trough to peak ratios calculated for evening dose.
d Values ?50 have been reported in other sources or studies not included in this analysis.
being 49%. After the missed dose, the ratios for trandolapril were 58% (systolic) and 36% (diastolic) and for enalapril they were 10% (systolic) and 19% (diastolic). This study suggests that trandolapril sustains its antihypertensive effect better than enalapril following a missed dose.
Correlations between mean plasma concentrations of antihypertensives and changes in blood pressure have been made with conflicting results in groups of patients. Recently Meredith and Elliott[65) have shown that for various agents, kineticdynamic relationships can be more clearly defined when study participants are considered individually.
Such a concentration-effect relationship has been defined for blood pressure response in individual patients with controlled release nifedipine,l66) verapamil,l67) doxazosin,[68) prazosin[69) and enalapril. [70) Meredith and Elliott[65) have predicted (using data derived from concentration-effect modelling studies) the implications of noncompliance of a missed dose in terms of blood pressure control with controlled release nifedipine, enalapril and amlodipine. They predicted blood pressure control would be lost after a missed dose of enalapril and controlled release nifedipine but not with amlodipine.
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2.4 Excessively High Dose Recommendations in Dose-Ranging Studies
There are several problems associated with the dose-escalating design in assessing dose-response relationshipsPl] In this type of study, the dose is increased at regular intervals and analysis of the results usually includes responders and nonresponders.
Noncompliant patients will constitute a large percentage of the nonresponders and, in this type of design, will receive the highest dose. This results in higher doses being recommended in early drug development with an increased risk of adverse effects. In]
3. ConclUSions
There is a need for more studies to investigate the duration of action of antihypertensive agents, in particular the effects of partial compliance, e.g. missing 1 or 2 doses and then resuming therapy. Physicians should be aware of the fact that many of their patients are noncompliant or partially compliant. Attempts should be made to improve compliance by emphasising the importance of taking antihypertensive medications regularly and the fact that treatment will probably be indefinite. Where possible, the dosage regimen should be simplified. However, only drugs with a duration of action exceeding 24 hours should be recommended for once-daily administration.
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Correspondence and reprints: Dr CD. Johnston, Department of Therapeutics and Pharmacology, The Queen's University of Belfast, The Whitla Medical Building, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland.
Fourth International Congress on
Essential Fatty Acids and Eicosanoids Date: 20-24 July 1997
Venue: Edinburgh, Scotland
For further information, please contact: Vicki GrantlWendy Adesegun
clo Meeting Makers 50 George Skeet Glasgow Gl1QA
SCOTLAND
Tel.: +44 (0) 141 553 1930 Fax: +44 (0) 141 552 0511 e-mail: [email protected]
© Adis International Limited. All rights reserved. Drugs 1996 Aug: 52 (2)