treatment strategy to control blood pressure optimally in hypertensive patients
TRANSCRIPT
REVIEW ARTICLE
Treatment Strategy to Control Blood Pressure Optimally in HypertensivePatients
BERNARD WAEBER
From the Division of Clinical Pathophysiology and Medical Teaching, University Hospital, PPA BH-19, Lausanne, Switzerland
Waeber B. Treatment strategy to control blood pressure optimally in hypertensive patients. BloodPressure 2001; 10: 62–73.
Pharmacological treatment of hypertension significantly reduces the incidence of cardiovasculardiseases. Unfortunately, only a fraction of hypertensive patients benefit maximally from the protectionafforded by the blood pressure lowering, mainly because the blood pressure control achieved duringantihypertensive therapy remains often insufficient. One way to improve this situation is to individualizethe treatment in determining for each patient the most simple drug regimen, which is at the same timeefficacious and well tolerated. To this end, combining small doses of drugs acting by differentmechanisms is often required. It is also essential that physicians develop skills to motivate their patients tocomply lifelong with the treatment. Key words: antihypertensive treatment, combination therapy,compliance, hypertension, quality of life, side-effects, target blood pressure.
INTRODUCTION
Major efforts have been directed during the last threedecades to diagnose and treat patients with hypertension.This certainly contributed signi� cantly to the decreasedincidence in cardiovascular diseases observed in indus-trialized countries, but much remains to be done, sincehigh blood pressure still represents one of the leadingcauses of morbidity and mortality worldwide [1]. Onemight wonder why a prevailing health problem such ashypertension is only partly solved, despite the availabilityof a large number of medications lowering blood pressureby different mechanisms. The costs associated with thepharmacological treatment might be a limiting factor, butis certainly not the only one, since blood pressure ofhypertensive patients is unsatisfactorily controlled even ifantihypertensive medications are free or can be obtainedfor a small co-payment [2].
It is well established nowadays that drug-induced bloodpressure lowering ef� ciently prevents hypertension-related cardiovascular complications [3, 4]. It is, however,also clear that treated hypertensive patients still exhibit anincreased cardiovascular risk compared with normoten-sive individuals [5]. Several points have to be consideredto explain the incomplete protection afforded by anti-hypertensive therapy in the population. First, hyperten-sion is only one risk factor and, until recently, not enoughattention had been paid to correct all co-existingcardiovascular risk factors [6]. Second, only a fractionof treated hypertensive patients have their blood pressure
truly normalized during antihypertensive treatment [7].Several reasons might account for this unsatisfactoryblood pressure control, including an insuf� cient motiva-tion of physicians who do not try as hard as they should tobring their patients’ blood pressure below a pre-set targetvalue, the availability of medications not effective enoughto normalize blood pressure and, � nally, a poor com-pliance with antihypertensive therapy.
The present review is aimed at addressing the issue ofblood pressure control in hypertensive patients in pointingout several lines of possible action expected to improvethe situation. In particular, an attempt will be made todescribe how to increase antihypertensive ef� cacy withthe blood pressure lowering drugs currently available, andhow to help the patients take them every day for the rest oftheir lives.
THE CONTROL OF BLOOD PRESSURE TODAY
Many nations throughout the world have made tremen-dous progress during recent years in detecting andcontrolling hypertension. A leading role had been playedin this regard in the USA, so the results of large surveysperformed in the adult population of this country(National Health and Nutrition Examination Surveys,abbreviated as NHANES) are particularly relevant [8]. Inthe 1991–1994 survey (NHANES III, phase 2), 68% ofhypertensive Americans were aware that they had hyper-tension (de� ned as a systolic blood pressure ¶140 mmHgand/or a diastolic blood pressure ¶90 mmHg), 53% were
BLOOD PRESSURE 2001; 10: 62–73
Ó 2001 Taylor & F rancis on licence from Blood Pressure. ISSN 0803-7051 BLOOD PRESSURE 2001
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treated but only 27% of all hypertensives had their bloodpressure controlled to <140/90 mmHg [9]. It should bementioned, however, that the conditions of blood pressuremeasurement were not representative of those encoun-tered in everyday practice (a � rst set of blood pressureswas obtained in the patients’ home by a lay interviewer,and a second set by a physician in a mobile examinationcenter).
Using the same de� nition of hypertension (bloodpressure ¶140/90 mmHg), consistently lower rates ofawareness (33%), treatment (26%) and control (6%) wereobserved in England than in the USA [10]. This survey ofthe English adult population was performed in 1994 andwas based on blood pressure measurements obtained by anurse on one occasion in the home of the participants.
A survey re� ecting more closely the reality was carriedout in French adults in 1994 [11]. This survey wasconducted by general practitioners who were asked tocollect data over 1 week of of� ce consultation. No morethan 24% of patients on antihypertensive therapy had theirblood pressure below the cut-off point of 140/90 mmHg.
Taken together, the results of these surveys, as well asthose of other surveys not presented here, show that thereis a considerable room for improvement in the treatmentand the control of hypertension. One should bear in mindthat for many years blood pressure values up to 160/95 mmHg were considered normal. This means thereforethat the observations made in different countries maydepend greatly on the de� nition of hypertension as well asthe recommended intervention thresholds and targets fortreatment accepted locally at the time of the survey.Moreover, there might be a gap between the of� cialrecommendations proposed in a given country and theway a physician is ready to adhere to these recommenda-tions. In this respect it is interesting to look at the controlrate of hypertension in patients (n = 17 359) followed byprimary care physicians (n = 1486) recruited in differentEuropean countries as well as in USA and Canada [12].No more than 20% of the patients reached this targetblood pressure, whatever it was. Thus, the need for moreaggressive treatment of hypertension identi� ed in largepopulation surveys is also obvious when examining thequality of blood pressure control in everyday practice.
Therapeutic management of hypertensive patients in aspecialized center is expected to provide better bloodpressure control than in general practice. This couldindeed be veri� ed, although patients referred to aspecialized clinic probably exhibit a more severe and amore dif� cult form of hypertension to treat [13]. In factthe opposite would have been surprising, since aphysician having a special interest in the � eld ofhypertension is presumably highly motivated to bringblood pressure under control in each of his patients.
When considering the poor blood pressure control
widely observed in hypertensive patients, one mightwonder if the true percentage of patients with a normalblood pressure during antihypertensive treatment is notunderestimated because of the existence of a signi� cant‘white-coat’ blood pressure response to the visit. In manypatients, however, an alert reaction triggered by thepresence of the physician is not responsible for theinadequate blood pressure control seen during antihyper-tensive therapy. This was shown in a large number ofhypertensive patients by non-invasive 24-h ambulatoryblood pressure monitoring [14]. No signi� cant differencewas indeed found between the blood pressure pro� les ofthe treated and the untreated hypertensive patients.
OPTIMAL BLOOD PRESSURE CONTROL: ANIMPOSSIBLE TASK?
Blood pressure control with monotherapies
Essential hypertension is a heterogeneous disease caused
Fig. 1. Percentage of patients (n = 36) with normalized bloodpressure (BP) with the � rst drug administered, or in response toany drug received during the systematic rotation (adapted fromref. [20]).
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by the complex interactions between genetic andenvironmental factors. It is therefore anticipated that noantihypertensive agent allows the normalization of bloodpressure in more than a fraction of hypertensive patients[15]. The response to a medication lowering bloodpressure by a speci� c mechanism can unfortunately notbe predicted with a degree of con� dence in the individualpatient [16]. This unpredictability has been demonstratedin crossover trials in which each patient received severalagents consecutively belonging to different therapeuticclasses [17–19]. Some patients normalized their bloodpressure with all medications, irrespective of their modeof action, but some patients were refractory to allmonotherapies, whereas a few patients responded favor-ably exclusively to one medication. The message istherefore that there is no way to bring blood pressureunder control in each hypertensive patient using mono-therapies. The probability of normalizing blood pressurecan be increased if one is ready to test several therapeuticoptions on a “trial and error” basis. There is nothingwrong with this approach (known as sequential mono-therapy), except that it is tedious and time consumingsince each compound has to be administered for 4–6weeks to gain its maximal antihypertensive ef� cacy [16].This might lead patients to believe that they have a formof hypertension resistant to pharmacological treatmentand to doubt the skills of their physician. Ultimately, thismight discourage some patients to take medications totreat their disease.
What kind of control rate can be expected by applying
the “sequential monotherapy” approach? An answer tothis question was provided recently [20]. In a prospectivetrial, 56 patients with essential hypertension received fourdifferent treatments in monthly cycles (the ACE inhibitorlisinopril 20 mg/day, the beta-blocker bisoprolol 5 mg/day, the long-acting formulation of the calcium-channelblocker nifedipine 30 mg/day, the � xed-dose combinationof hydrochlorothiazide 25 mg/day ‡ triamterene 50 mg/day). Each treatment phase was separated by a 1-monthwash-out period. Only 36 patients completed the cross-over rotation through the four treatment periods. Figure 1shows the percentage of these patients who normalizedtheir blood pressure during the � rst treatment phase,independently of the medication given as the initial drug.It also depicts the percentage of patients who normalizedtheir blood pressure on any drug administered during thefour-way rotation. This analysis was performed usingdifferent criteria to de� ne blood pressure normalcy, either<140/90 or <135/85 mmHg. It appears that the forcedrotation through the four main classes of antihypertensiveagents increased considerably the probability of bloodpressure normalization in each individual. Of note,however, is that as many as 20 patients could not bechallenged by all classes of agents. Actually, this highdiscontinuation rate is of the same order of magnitude asthat observed previously in a large number of hyperten-sive patients who received a diuretic, a beta-blocker, anACE inhibitor or a calcium antagonist as the � rstantihypertensive medication [21]. Thus, after 6 monthsof follow-up, less than half of the patients were still on the
Fig. 2. Percentage of patients with a diastolic blood pressure (BP) <90 mmHg at the end of the titration period (open columns) andpercentage of patients having had a diastolic BP < 90 mmHg at the end of the titration period and having a diastolic BP < 95 mmHg atthe end of 1 year treatment (hatched columns). DILT, diltiazem; CLON, clonidine; ATEN, atenolol; HCTZ, hydrochlorothiazide;PRAZ, prazosine; CAPT, captopril; PLAC, placebo (adapted from ref. [22]).
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same treatment, with no relevant difference foundbetween the four classes of agents.
Another concern regarding the usefulness of mono-therapies in the treatment of essential hypertension is thelong-term ef� cacy. This point is illustrated by the resultsof a large trial in which 1292 hypertensive men wererandomly assigned in a double-blind manner to one of thesix following drugs: the diuretic hydrochlorothiazide(12.5–50 mg/day), the beta-blocker atenolol (25–100 mg/day), the ACE inhibitor captopril (25–100 mg/day), thecalcium antagonist diltiazem (120–360 mg/day, sus-tained-release preparation), the alpha1-blocker prazosin(4–20 mg/day) or the centrally acting sympatholyticclonidine (0.2–0.6 mg/day) [22]. The trial started with a4–8-week titration period and continued for 1 year. Goodresponders were de� ned as patients with a diastolic bloodpressure <90 mmHg at the end of the titration phase and<95 mmHg at completion of the study. Figure 2 showsthe percentage of responders in each study group, both atthe end of the titration phase and at the end of the 1-yearfollow-up. A striking feature was a marked decline inblood pressure control over time with the six types ofantihypertensive agents, even if the criterion to de� ne thesuccess rate was less strict at the end of the trial than at theend of the titration phase. No information is unfortunatelyprovided in this large-scale study on the percentage ofpatients who truly normalized their blood pressure, i.e.that had at the same time their systolic and diastolic bloodpressures controlled.
From a conceptual point of view there is no doubt that“sequential monotherapy” represents an attractive ap-proach to treat hypertensive patients, but this therapeuticapproach is obviously dif� cult to apply in everydaypractice. Most physicians are probably reluctant, for onereason or another, to go through a systematic rotation ofall available classes of antihypertensive agents. One thingto be stressed is that in case of inadequate blood pressurecontrol, substituting an antihypertensive agent for anotherclass is probably wiser than increasing the dose of theineffective medication. This is because antihypertensivemedications exhibit a manifest dose-dependent increasein the incidence of side-effects [23].
Blood pressure control with combination therapy
The principle of polypharmacy in the treatment ofhypertension has gained increasing acceptance duringthe last few years [24–26]. This is especially true for� xed-dose combinations, which are becoming more andmore popular. Historically, this evolution is of interestsince such combinations have been highly appreciated inthe past by general practitioners, while at the same timethey were criticized by pharmacologists and opinionleaders in the � eld of hypertension. The skepticism came
mostly from the fact that dosage adjustments of the agentscontained in � xed-dose combinations were not possible,which was thought to be a limiting factor for the ef� cacyof the drug association.
The rationale for associating medications loweringblood pressure by different mechanisms is mainly theexpectation of an enhanced antihypertensive ef� cacyrelated to the various impacts of the components on thecardiovascular system [24–26]. There might also exist anadditional blood pressure lowering effect due to theattenuation of the counter-regulatory mechanisms that aretriggered whenever pharmacological intervention isinitiated and that tend to blunt the drug-induced bloodpressure fall. For example, the salt depletion mediated bydiuretics activates the renin–angiotensin system, which inturn limits the antihypertensive ef� cacy of the decrease intotal body sodium. The blood pressure effects of thisreactive hyper-reninemia can be prevented by simulta-neous blockade of the renin–angiotensin system, eitherwith an ACE inhibitor or an AT1-receptor antagonist.Likewise, the fall in blood pressure resulting fromcalcium-channel blockade with a dihydropyridine maycause a re� ex increase in sympathetic nerve activity, asre� ected by an acceleration of heart rate, and stimulaterenin secretion. It is therefore appealing to add todihydropyridine a medication that buffers the counter-regulatory responses of the sympathetic nervous systemand the renin–angiotensin system, such as a beta-blocker,an ACE inhibitor or an AT1-receptor antagonist. Finally, amajor advantage linked to the co-administration of drugsacting by different mechanisms is that low doses of one orboth components are usually suf� cient, allowing excel-lent tolerability. For instance, the diuretics have generallyno metabolic side-effects when associated with a blockerof the renin–angiotensin system. The most logical andeffective combinations of antihypertensive agents areshown in Table I.
Is there a real need for combination antihypertensivetherapy? A positive answer is strongly supported by theexperience accumulated in the Hypertension Optimal
Table I. Most logical and effective combinations ofantihypertensive agents
Diuretic ‡ Beta-blocker‡ ACE inhibitor or AT1-receptor
antagonistBeta-blocker ‡ Calcium antagonist
(dihydropyridine)‡ Alpha1-blocker
ACE inhibitor ‡ Calcium antagonistor AT1-receptor
antagonist‡ Alpha1-blocker
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Treatment (HOT) study, a trial in which the antihyper-tensive treatment was initiated and/or intensi� ed in alarge number of patients (n = 18790) to reach a targetdiastolic blood pressure (either µ90, µ85 or µ80 mmHg)[27]. After a 3.8-year follow-up, the proportion of patientshaving achieved the assigned goal blood pressure wasexceptionally high, at 86, 73 and 55%, respectively, but toobtain these impressive results the administration of twoor more drugs was required in the majority of patients (63,68 and 74%, respectively). Another piece of evidencecomes from the UK Prospective Diabetes Study (UKPDS)involving 1148 type 2 diabetics with hypertension. Theassociation of at least two drugs was necessary in 60% ofpatients when trying to achieve a tight blood pressurecontrol (<150/85 mmHg) [28].
Many clinical trials have demonstrated that � xed-low-dose combinations of two different drug classes produceblood pressure reductions that are greater than thoseproduced by the same agents used alone [24–26]. One ofthem is of particular interest since it led the Food andDrug Administration (FDA) in the USA to approve for the� rst time a low-dose � xed combination as � rst linetherapy [29]. In this multifactorial drug trial, low doses ofa cardioselective beta-blocker (bisoprolol 2.5 mg) and adiuretic (hydrochlorothiazide 6.25 mg) in combination for12 weeks were indeed shown to control diastolic bloodpressure (µ90 mmHg) in a large fraction of patients(59%) while preserving a placebo-like tolerability [30].
Another trial is noteworthy because it con� rms, usingan original analysis, that a � xed-low-dose combination ofan ACE inhibitor (perindopril 2 mg) and a diuretic(indapamide 0.625 mg) makes it possible effectively tocontrol blood pressure over a prolonged period [31]. Thisstudy included elderly patients (65–85 years old) withdiastolic or systolo-diastolic hypertension, or isolated
systolic hypertension. They were randomized to receivefor an initial 3-month period either one tablet/day of the� xed-dose combination (n = 193) or placebo (n = 190).The patients on active treatment were then maintained onthe previous drug regimen for 12 additional months, withthe possibility of doubling the dose of the combination inthe absence of blood pressure normalization (de� ned as adiastolic blood pressure µ90 mmHg in patients withdiastolic or systolo-diastolic hypertension at inclusion anda systolic blood pressure <160 mmHg in patients withisolated systolic hypertension at inclusion). Twenty-eightper cent of patients needed the dosage adjustment. Sixtypatients having not normalized their blood pressureduring the initial 3-month placebo period were alsotreated for 12 months with the perindopril/indapamidecombination. Figure 3 shows the percentage of all patientshaving received the active treatment (n = 253) whonormalized their blood pressure at one or more visitsduring the study period. Another analysis was thenperformed to assess if patients exhibiting a normal bloodpressure at initiation of treatment maintained a normalblood pressure during long-term follow-up. This turnedout to be the case, as illustrated in Figure 3, since 80% ofpatients who initially normalized their blood pressure inresponse to the very low-dose perindopril–indapamidecombination remained normotensive throughout theobservation period.
Monotherapy vs combination therapy
In terms of overall therapeutic ef� cacy, � xed-dosecombinations of two low doses of drugs acting bydifferent mechanisms undoubtedly represent an adventsince they allow the control of blood pressure in morepatients than individual drugs, while keeping dose-dependent side-effects to a minimum [24–26, 32]. Thisexplains the increasing number of such preparationsavailable on the market, and why some of thesepreparations have even been approved as � rst-line therapy[9]. It is important in this context to look at the positiontaken by experts in widely accepted guidelines withrespect to the clinical indication of � xed-low-dosecombinations. For example, the Sixth Report of the JointNational Committee on Prevention, Detection, Evalua-tion, and Treatment of High Blood Pressure (JNC-VI)considers low-dose combinations as possibly appropriatefor initiating antihypertensive therapy, but the associationof two agents from different classes used in a normaldosage is regarded mainly as an option for patientsunresponsive to single-drug therapy [9]. Taking intoaccount these guidelines, � xed-low-dose combinations ofantihypertensive agents are regarded today as a keystonefor the pharmacological management of patients withhigh blood pressure.
Fig. 3. Proportion of patients (%) who normalized their diastolicblood pressure (DBP) at least on one occasion during a 12-month treatment with the perindopril/indapamide combinationor sustained a normalized diastolic blood pressure during thisperiod (adapted from ref. [31]).
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BARRIERS TO BLOOD PRESSURE CONTROL
Socioeconomic factors
A number of barriers to hypertension control have beenreported in the literature, including socioeconomic factorssuch as racial and ethnic factors, poor educational statusand unemployment, not having a health insurance,dif� cult accessibility to healthcare providers and exces-sive cost of management and medications [33, 34].Obviously the condition “sine qua non” for a hypertensivepatient to normalize his blood pressure is not only theawareness of the risk linked with hypertension, but alsothe real possibility to choose if he wants to be treated ornot. One might expect therefore to control optimal bloodpressure in hypertensive patients having easy access tofree care. In fact, this is not the case. For example, the careof 800 hypertensive men, all regular users of healthcareprovided at � ve Departments of Veterans Affairshospitals in New England, has been recently examined[2]. Fewer than 25% of the surveyed patients had theirblood pressure <140/90 mmHg, although medications forpatients treated at Veterans Affairs sites are either free oravailable for a small co-payment. Thus, despite favorablecircumstances, the treatment of hypertension in thecommunity remains a dif� cult task. This is true even ifantihypertensive treatment is recognized to be cost-effective in developed countries [35].
Factors related to the physician
Blood pressure measurement has become a routineprocedure at almost each medical visit. Having a normalblood pressure is for most patients a synonym of goodhealth, which explains why it is not easy for many patientsto accept the diagnosis of hypertension, particularlybecause they are most of the time symptomless. Whatthe role of physicians in this context? They have � rst tomake their patient understand what is meant by anabnormally high blood pressure, the cardiovascular riskassociated with the elevation of blood pressure and theprotection afforded by blood pressure lowering measures[36]. In order to ful� ll this task, the physicians have to beconvinced about the necessity to diagnose and treathypertension, and should be ready to invest time toeducate and encourage their patients. A strong motivation
of physicians implies that they try to comply with of� cialrecommendations when taking care of their patients andthat they are familiarized with the rational approaches tohygienic and pharmacological treatment of hypertension.A lot has been done during the last few years toimplement the new guidelines in clinical practice, but alot still needs to be done to compel every physician toapply more rigorous strategies than previously.
One possible problem is related to the diversity ofguidelines proposed by different organizations. This maybe regarded by physicians as disturbing and represents asource of irritation. With regard to the target bloodpressure during antihypertensive treatment, a close look atthe JNC VI, 1999 WHO/ISH and British HypertensionSociety guidelines, however, reveals a large consensus(Table II) [9, 37, 38].
Physicians are often reluctant to intensify the treatmentwhen the target blood pressure is not achieved, asindicated by the results of a survey conducted in clinicalpractice: physicians did not change anything in thetreatment in as much as 84% of patients when theymeasured persistently high blood pressures at the visit[39]. Unfortunately, it is not easy to modify the clinicalbehavior of physicians in a primary care setting. Thiscan be exempli� ed by a study in which 25 generalpractitioners followed a special educational program inthe � eld of hypertension and were asked to lower bloodpressure of their hypertensive patients (n = 740) to µ160/90 mmHg [40]. A peer review of medical case recordswas performed at inclusion in the trial as well as againafter a 12-month follow-up. The proportion of patientswith initially a blood pressure >160/90 mmHg was 69%.This proportion was slightly reduced to 64% despite theeducational intervention. Thus, there is something wrongwith the management of hypertension in the community.Physicians, for whatever the reason, still seem unwillingto intensify medical therapy when needed to bring bloodpressure below a preset value. One reason could be thefear of increasing the risk of myocardial infarction andstroke by lowering blood pressure too excessively [41].This should, however, no longer be a concern since, in theHOT study, there was no J-curve phenomenon apparent,the smallest incidence of major cardiovascular eventshaving been observed at a systolic and diastolic blood
Table II. Target blood pressures (mmHg) to achieve during antihypertensive treatment (adapted from refs [9, 37, 38])
Young and middle-aged patients Older patients Diabetic patients Patients with renal patients
JNC VI <140/90 and lower if tolerated <140/90 <130/85 <130/85<125/75 if proteinuria >1 g/24 h
1999 WHO/ISH <130/85 <140/90 <130/85 <130/851999 BHS <140/85 <140/85 <140/80 Not speci� ed
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pressure of 139 and 83 mmHg, respectively [27]. More-over, in elderly patients with isolated systolic hyperten-sion, antihypertensive treatment had a protective effectdespite further reduction of diastolic blood pressure [42,43].
Poor compliance with antihypertensive therapy
A prerequisite to an attempt to normalize blood pressureof a patient needing antihypertensive therapy is that thepatient regularly takes the prescribed drug regimen. Thisis obvious, but the problem of compliance withantihypertensive therapy is still dif� cult to solve.Discussing compliance might be felt as a potential sourceof con� ict by both the patient and his physician, so thatthis issue is not systematically addressed. In fact, it ismore convenient for the physician to “trust” his patientthan to give him the feeling that he has some doubt abouthis willingness to adhere to the treatment. When facinghis patient, the physician should therefore bear in mindthat the way his patient complies with therapy remainsmost often a “black box”, with no true desire to open itfrom one side or another. This is well illustrated by thegap existing between the physicians’ and the patients’perception of poor compliance as a cause of inadequateblood pressure control. Thus, in a large European survey,81% of hypertensive patients stated that they used to taketheir medication(s) every day, while 70% of physiciansadvanced poor patients’ compliance as a cause oftreatment failure [39].
The assessment of compliance with antihypertensivetherapy
There is unfortunately no ideal method of assessingcompliance with antihypertensive therapy in everydaypractice [44, 45]. How the patient keeps the appointmentsgiven by the physician and re� lls drug prescriptions canbe taken as an indicator of compliance. The outcome oftherapy does, however, not provide valuable information,as even a perfect complier might be unresponsive to agiven drug regimen. Direct questioning may be helpful ifthe patient admits spontaneously to a non-compliantbehavior. No valuable conclusion can be drawn, however,if the patient is claiming that he/she takes the medica-tion(s) as prescribed. Other approaches have been used inclinical trials, such as pill count, the detection of drugs orchemical markers in the blood or the urine. Pill counttends to overestimate compliance since some patientsmight deliberately discard tablets before returning thecontainer to the physician. It seems that complianceassessed by this method has to be 80% or greater to obtaina signi� cant blood pressure lowering effect [46]. Withregard to drug and chemical marker assays, the majordrawback is the possible existence of a “toothbrush
effect”, which resumes to the fact that a non-compliermay decide to take again his medication(s) a few daysbefore the next visit [47].
An appealing way to monitor compliance is the use anelectronic medication dispenser with a microcircuitincorporated in the cap that allows a record to be madeeach time the container is opened [48]. Such a deviceenables one to evaluate “real time” compliance and,consequently, to gain information on dosing intervals.The only assumption to be made is that the patient ingeststhe tablet(s) after opening of the vial.
Impact of poor compliance on the outcome ofhypertensive patients
The fact that a patient forgets sporadically to take hisantihypertensive medication(s) for 1 or 2 days (drug“holidays”) leads to a progressive loss of the drug’saction, as shown from short-term studies [49], but thislack of therapeutic coverage probably does not representsa major risk of developing a sudden cardiovascularcomplication, except if the medication consists of acentrally acting sympatholytic agent able to cause arebound hypertension [50] or a beta-blocker if the patienthas an underlying coronary heart disease [51]. Duringchronic treatment of hypertension, even complete dis-continuation of treatment is not generally associated witha prompt return of blood pressure to high levels, possiblybecause of the reversal of functional and/or structuralabnormalities at the level of the vascular wall owing to theprolonged blood pressure lowering [52]. In the long term,however, non-compliance is expected to increase thecardiovascular risk known to be linked with untreatedhypertension.
The existence of a causal relationship betweentherapeutic compliance and the occurrence of cardiovas-cular events is suggested by the results of two recentstudies. In the � rst, the impact of under-utilization ofantihypertensive drugs and acute-care readmissions wereevaluated in 113 patients [53]. All patients had beenpreviously hospitalized with a primary or secondarydiagnosis of hypertension. They were then observed forreadmission for the next 18 months. During this period thenon-compliance rate of each patient was calculated as theratio of the number of days when the patient had noantihypertensive drugs (based on pharmacy records)divided by the number of days of observation. The non-compliance rate averaged 39% in the 28 patients who hadto be readmitted, which was signi� cantly higher than thecorresponding rate (11%) seen in patients who were notrehospitalized.
The second study evaluated the in� uence of non-compliance with antihypertensive therapy on healthcarecosts [54]. Paid claims data from the California Medicaid
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program were used for the analysis. The primary outcomevariable was the total cost of healthcare during the � rstyear after initiation of antihypertensive treatment in 6419patients aged 40 and over. A total of 5504 patients (86%)interrupted purchasing any blood pressure lowering drugduring this period. It ended up that each of these patientsconsumed on the average 873 US$ more than the 915patients who � lled the prescriptions regularly during thestudy. The increased costs were essentially related tohospital expenditures (637 US$), indicating that with-drawal of therapy led to serious complications evenduring a rather short follow-up. Thus, these � ndingsstrongly support the view that treatment of hypertensionhas a bene� cial cost–effectiveness ratio.
The in� uence of antihypertensive drug regimen oncompliance
The tolerability. Hypertension is an asymptomaticcondition in most patients with high blood pressurewhile antihypertensive therapy may cause adverseeffects [55]. This explains why it is dif� cult for manypatients to adhere to a lifelong antihypertensivetreatment. Labeling subjects as hypertensive might beenough to impair the patients’ quality of life, asre� ected for instance by an increased absenteeism fromwork [56]. Moreover, an excessive absenteeism forhealth-related disorders has also been shown in patientson antihypertensive therapy in comparison with theremainder of the population [57]. Actually, theoccurrence of adverse events is one of the main reasonswhy hypertensive patients withdraw from drug therapy.For example, the prevalence of patient-initiatedmodi� cations of drug instructions (use of lower dosageand/or fewer drugs than prescribed) increases inproportion of the occurrence of problems duringtreatment, as illustrated by the results of a study inwhich 632 patients on antihypertensive therapy weresurveyed for 1 year [58]. The percentage of patientswho modi� ed drug instructions was 17 in the absenceof problems, but this percentage increased to 29, 41 and58 in patients who reported one, two or three or moreproblems, respectively. In another survey performed inthe UK, 322 out of 948 (34%) treated hypertensive
patients felt that they had experienced unacceptableside-effects [59]. The majority of these patients (78%)advised their doctor of the side-effects, but a fewpatients (9%) spontaneously stopped taking theirmedication.
The drug chosen to initiate antihypertensive therapymight in� uence long-term compliance, possibly becauseof more or less favorable side-effects pro� les. Thisquestion has been addressed in several managed-careorganizations by analyzing the re� ll failure. For example,22 918 patients aged 40 and over living in Saskatchewan(Canada) received a diuretic (40%), an ACE inhibitor(30%), a calcium antagonist (13%) or a beta-blocker(10%) [60] as initial antihypertensive medication. Thepercentage of patients persistent on the same medicationafter 1 year was greatest on the class of ACE inhibitors(83%), followed by that on the calcium antagonists(81%), beta-blockers (78%) and diuretics (74%). A retro-spective analysis of prescriptions was also performed in8643 elderly hypertensive patients belonging to the NewJersey Medicaid and Medicare program in USA [61].Compliance was de� ned as the number of days in whichantihypertensive therapy was available to the patient
Table III. Adverse experiences and medication non-compliance in hypertensive patients (adapted from ref. [65])
Well-controlled blood pressure(n = 4266)
Poorly controlled blood pressure(n = 1587)
% of patients with side-effects 49 61a
% of intentional non-compliers 18 25a
% of unintentional non-compliers 23 32a
a p < 0.001, poorly vs well-controlled blood pressure (<160/95 mmHg).
Fig. 4. Adherence rate to once-a-day and twice-a-day anti-hypertensive treatment during an average of 4.6 months. Thepatients were considered adherent if 80% of the time intervalsbetween the drug container openings were within 24 § 6 and12 § 3 h for the once-a-day and the twice-a-day treatment,respectively (adapted from ref. [66]).
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during the 12 months following the start of the treatment.Patients were considered good compliers when compli-ance was 80% or higher. The compliance observed duringdiuretic therapy was taken as a reference value. Allmedications given as monotherapy were associated with asigni� cantly better compliance compared with diuretics,the ACE inhibitors having proven to be the best in thisrespect. ACE inhibitors are known to be well toleratedand generally do not compromise the patients’ quality oflife [62]. This might facilitate long-term compliance withtreatment and explain why patients continue to take ACEinhibitors more often than other classes of antihyperten-sive agents. This is also true for newer medications suchas AT1-antagonists, which have a placebo-like tolerabilityand a high persistence rate during chronic treatment [63].The same advantages most likely apply to � xed-low-dosecombinations, since small dosages of the individualcomponents are generally enough to control bloodpressure, allowing the incidence of adverse drug reactionsto remain close to that of placebo.
In order to reach the target blood pressures recom-mended nowadays, intensive antihypertensive therapy isoften required. It is important to point out that thepatients’ wellbeing does not deteriorate in hypertensivepatients whose blood pressure is low as a result ofantihypertensive therapy. Indeed, during the � rst 6months of the HOT study, the lower the diastolic bloodpressure achieved, the greater the improvement in well-being (p < 0.05) [64].
The antihypertensive ef� cacy. Poor compliance withantihypertensive therapy is one possible cause ofinadequate blood pressure control. During long-termfollow-up of hypertensive patients, the degree of com-pliance should be regarded as a matter of more or lessrather than yes and no. This is exempli� ed by theresults of a survey performed in Japan [65]. A total of5853 hypertensive patients treated for hypertensionreturned completed questionnaires about their currentblood pressure, the way they tolerate the prescribedtreatment and the extent to which they comply withphysicians’ instructions. Well-controlled blood pressurewas de� ned as a systolic blood pressure <160 mmHgand a diastolic blood pressure <95 mmHg. Thefrequency with which the patients deliberately modi� edthe physician’s instructions for taking antihypertensivemedication(s) constituted an index of intentional non-compliance. Similarly, the frequency with which thepatients forgot to take their medication(s) was used asan indicator of unintentional non-compliance. Therelationship between blood pressure control andcompliance is shown in Table III. It appears that theproportion of patients with side-effects was signi� cantlygreater when blood pressure was poorly controlled thanwhen it is well controlled. Interestingly, the percentage
of both intentional and unintentional non-compliers wasalso signi� cantly greater in the poor blood pressurecontrol group. This observation therefore con� rms thatthe presence of side-effects has a negative impact oncompliance and, consequently, on the quality of bloodpressure control.
One should bear in mind that some patients may beperfect compliers and still exhibit high blood pressures.This might discourage several of them and lead towithdrawal from follow-up. The early use of combinationtherapy, in particular of � xed-low-dose combinations, canbe helpful in avoiding repeated unsuccessful attempts tonormalize blood pressure and, for this reason, mayreinforce the motivation of the patient to adhere to theprescribed treatment.
The simplicity of drug regimen. When consideringlong-term treatment of hypertension it appears highlydesirable to simplify maximally the drug regimen inorder to help the patients to take the medication(s)every day as prescribed. In this respect the once-a-daydosing is expected to be ideal provided it has a durationof action long enough to control blood pressurethroughout the day. There is indeed evidence that once-a-day dosing is associated with a better compliance thanmultiple dosings. One recent study has con� rmed thisview using electronic compliance monitoring [66]. Inthis trial, 313 black hypertensive patients were followedfor an average of 4.6 months. Adherence to the once-a-day and the twice-a-day drug dosing schedules wasconsidered acceptable if 80% of the time intervalsbetween the drug container openings were within24 § 6 or 12 § 3 h, respectively (Fig. 4). With the once-a-day regimen (n = 227) the adherence rate was 49%, ascompared to only 5% with the twice-a-day regimen(n = 86). The observed difference is very impressive andshould urge physicians to prescribe as often as possiblemedications which can be administered once a day. It isnoteworthy that target blood pressure was achieved in31% of participants who were adherent, as comparedwith 16% only in non-adherent patients. In this context,� xed-low-dose combinations seem especially attractivesince they allow two different medications to be givenwithout having to double the number of tablets.
The need for an integrated approach to improvecompliance with antihypertensive therapy
Low compliance with antihypertensive drug regimens isstill a common cause of unsatisfactory blood pressurecontrol. What can be done to improve this situation? A� rst step is to ameliorate the patient–physician commu-nication [36]. The task of the physician is not only todiagnose hypertension and to prescribe antihypertensivemedications. It is also to make the patients understand
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what hypertension is, the cardiovascular risk linked withhigh blood pressure and the bene� ts to expect fromlifestyle and pharmacological interventions. To this end,it is vital that physicians and their patients act as partnershaving a common interest, i.e. the control of high bloodpressure. The physicians should certainly not restrict theirrole to that of a prescriber if they hope that their patientswill follow their advice.
The physicians should try to individualize antihyper-tensive therapy and to � nd for each patient the mostsimple drug regimen that is at the same time ef� caciousand well tolerated. They have also to take advantage ofthe various possibilities available to support the motiva-tion of the patients, including the intervention of otherhealthcare professionals, in particular nurses and phar-macists [67]. The multidisciplinary approach helps torecognize the patients’ barriers, and therefore directsefforts to facilitate compliance by taking into accountsocial, cultural, psychological and economic factors. Anumber of strategies may be used to improve compliance,including educational tools, the planning of hypertension-related visits at regular intervals, self-monitoring of bloodpressure [67–69], as well as more sophisticated methodssuch as telephone follow-up and electronic monitoring ofcompliance [70–72].
CONCLUSIONS
There is today a large variety of medications acting byvarious mechanisms to treat hypertension. One has toadmit, however, that blood pressure of the majority ofhypertensive patients is inadequately controlled, partlybecause the treatment is not conducted intensivelyenough, but partly also because the medication(s) arenot taken as prescribed. Lowering blood pressure inhypertensive patients requires therefore not only a broadchoice of effective and well-tolerated medications, butalso skills to motivate them to comply lifelong with thetreatment. Fixed-dose combination therapy appears veryappealing in this context because of a broad ef� cacy dueto the different impacts on the cardiovascular system, anexcellent tolerability related to the low dosages of itscomponents and a simplicity of use which is expected tofacilitate the long-term adherence to the treatment.
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Submitted March 5, 2001; accepted March 9, 2001
Address for correspondence:
Professor B. Waeber, MDDivision of PathophysiologyUniversity HospitalPPA BH-19CH-1011 LausanneSwitzerlandTel: (‡41 21) 314 07 60Fax: (‡41 21) 314 14 32E-mail: [email protected]
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