guidelines for the management hypertension: memorandumfrom

1993 Guidelines for the management of mildhypertension: Memorandum from a WHO/ISHmeeting*

The present guidelines were prepared by the Guidelines Sub-Committee a of the WHO/ISH (Internation-al Society of Hypertension) Mild Hypertension Liaison Committee. They represent the third revision ofthe WHO/ISH guidelines and were finalized after discussions at the Sixth WHO/ISH Meeting on MildHypertension in Chantilly, France, on 28-31 March 1993. The new guidelines discuss the cardiovascularrisk in patients with hypertension, the definition and classification of mild hypertension, drug treatment(including the elderly) and non-drug measures, cost-effectiveness, and further research.

IntroductionPatients with hypertension, even those with mildelevation of blood pressure, are at increased risk ofcardiovascular disease, whether or not symptomsare present. In most countries, as many as 15-25% ofthe adult population are found at screening to haveraised blood pressure; about two-thirds of themhave mild elevation of blood pressure. However, theblood pressure is not persistently raised in all, andnot all need to be treated with antihypertensive drugs.

In preparing these guidelines, the WHO/ISHSub-Committee has been keenly aware that there aremarked differences between individual patients withsimilar levels of hypertension, which have importantimplications for decisions about treatment. Hyperten-sive patients differ with respect to age, blood pres-sure elevation, organ damage and concomitant riskfactors and diseases, and they live in societies wherecardiovascular risk and economic resources also dif-fer widely. Accordingly, the guidelines should not berigid constraints to the practising doctor's decisions.Rather, they provide extensive, critical and well-bal-anced information on the benefits and limitations ofthe various diagnostic and therapeutic interventions,so that the physician may exert the most carefuljudgment in individual cases. Although the most reli-

* The previous WHO/ISH guidelines were published in the Bul-letin of the World Health Organization, 67: 493-498 (1989), and Jour-nal of hypertension, 87: 689-693 (1989). The 1993 guidelineswill be published simultaneously in Clinical and experimentalhypertension. Requests for reprints should be sent to Chief, Car-diovascular Diseases, World Health Organization, 1211 Geneva27, Switzerland. A French translation of this Memorandum willappear in a later issue of the Bulletin.a Guidelines Sub-Committee: A. Zanchetti (Chairman), J. Chalmers(Convenor, K. Arakawa, I. Gyarfas, P. Hamet, L. Hansson,S. Julius, S. MacMahon, G. Mancia, J. Menard, T. Omae, J. Reidand M. Safar.

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able information is that provided by large random-ized trials, these have their own limitations and notall aspects of the management of hypertension havebeen or can be determined by the results of random-ized trials. Scientifically sound interpretation andcautious extrapolation of existing data can also beused to influence clinical decision-making.

Highlights of 1993 guidelines

New sections on:- Systolic hypertension- Hypertension in the elderly- Assessment of cardiovascular risk- Cost-effectiveness- Issues needing further research

Update of sections on:- Blood pressure measurements- Diagnostic evaluation- Goals of treatment- Non-drug measures- First-line drugs- Correction of other major risk factors

Cardiovascular riskAssessment in patients with hypertensionThere is a continuum of cardiovascular risk associa-ted with the level of blood pressure: the higher theblood pressure, the higher the risk of both stroke andcoronary events (1). The dividing line between "nor-motension" and "hypertension" is arbitrary. The cur-rent definition is that this line is the level of bloodpressure above which intervention has been shown toreduce the risk (2). It is well established that the

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lowering of even mildly elevated pressures reducescardiovascular morbidity and mortality. However, adecision to intervene should not depend on bloodpressure alone.

Indeed, among individuals with mild hyperten-sion the risk of serious cardiovascular disease is alsodetermined by a variety of factors other than thelevel of blood pressure. These include (see Table 1)increasing age, male gender, previous cardiovascularevents, target organ damage (such as left ventricularhypertrophy or renal disease), smoking, diabetes,dyslipidaemia (high total and LDL-cholesterol withlow HDL-cholesterol), central obesity, and a seden-tary lifestyle (3). The presence of one or more ofthese factors may be a more important determinantof risk than a mild increase in the level of bloodpressure. Since the absolute benefits of antihyperten-sive treatment will be determined by the absoluterisk of cardiovascular disease (i.e., greater benefitsamong those at higher risk), each of these factorsshould be assessed prior to making decisions abouttreatment.

The absolute risk of serious cardiovascular dis-ease varies greatly among individuals with mildhypertension. At one extreme, in elderly patientswith a history of previous cardiovascular disease, atleast three to five in every hundred will suffer afurther serious event each year (4-7). At the otherextreme, in young individuals with no other risk fac-tors, fewer than one in every thousand will suffer aserious event each year (8, 9). While antihyperten-sive treatment will reduce risks in both these patientpopulations, it may take some decades for clinicalbenefits to become apparent in young patients atlow initial risk.

Table 1: Cardiovascular risk factors favouring treatment

AgeaGenderaFamily history of premature cardiovascular diseaseaRaised systolic blood pressureRaised diastolic blood pressureSmokingRaised total and LDL cholesterolReduced HDL cholesterolLeft ventricular hypertrophyPrevious cardiovascular eventsaPrevious cerebrovascular eventsaDiabetesRenal diseaseMicroalbuminuriaObesitySedentary lifestylea Not modifiable.

The absolute risk of cardiovascular disease inmild hypertension may also vary substantially fromone geographic region to another. Some of theregional variation in the risk of stroke and coronaryevents may be accounted for by regional differencesin the prevalence of the risk factors listed above.However, other evidence indicates that there aresome regional differences that cannot be accountedfor by differences in established risk factors. Ofparticular note are the high rates of stroke in Chinaand Russia. In these populations, stroke incidence isfour times that in the USA and Westem Europe butaverage population blood pressures are only slightlydifferent. For this reason the treatment of mildhypertension in these populations may yield particu-larly large absolute benefits.

Definition and classificationBlood pressure measurementBlood pressure is generally measured by the indirectmethod, using a mercury sphygmomanometer.

Before measurement commences, the patientshould be seated for several minutes in a quiet room;the chair should provide comfortable back support.The arm muscles should be relaxed and the forearmsupported with the cubital fossa at heart level (fourthintercostal space). Blood pressure may also be meas-ured supine and standing, and in each position thearm should be supported at heart level. A cuff ofsuitable size is applied evenly to the exposed upperarm. Care should be taken to avoid tight sleeves. The"standard cuff' available in many countries may betoo small. A cuff for adults must have a bladder13-15 cm wide and 30-35 cm long so as to encirclethe average arm. Larger cuffs are needed for fat armsand smaller ones for children. The cuff is rapidlyinflated until the manometer reading is about30 mmHg above the level at which the pulse disap-pears, and then slowly deflated at approximately2 mmHg/second. During this time the Korotkoffsounds are auscultated through a stethoscope placedover the brachial artery.

The pressure at which the sounds are first heardis the systolic pressure. The diastolic pressure is thepressure at which the sounds disappear (phase V).Most of the major studies have used the latter point,i.e., disappearance of sounds; the use of muffling ofsounds (phase IV), gives significantly higher diastol-ic pressure values, and is to be avoided. The systolicand diastolic pressures should be measured at leasttwice over a period of no less than 3 minutes; bothshould be recorded and the mean value for bothshould be used. It is also recommended that, on thefirst visit, the blood pressure should be measured onboth arms. Measurement in the standing position

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Guidelines for the management of mild hypertension

should also be performed when postural hypotensionis suspected and in the elderly in whom this condi-tion may be more common.

"White coat hypertension" or "effect" is a condi-tion in which blood pressure is elevated in the pres-ence of a doctor but falls when the subject leaves themedical environment. Measurement by nurses ortrained non-medical staff may reduce but not neces-sarily abolish the "white coat" effect (10). How the"white coat" effect can be precisely defined is con-troversial, however. Calculations on the basis of thedifference between the blood pressure measured inthe doctor's office and home blood pressure or day-time ambulatory blood pressure (see below) arequestionable because this difference may depend onmany more factors than just an alerting reaction. It isnot known whether the "white coat" effect is aninnocent phenomenon. Indeed, it has been suggestedthat subjects showing a marked difference betweenclinic and home blood-pressure measurements maybe at higher cardiovascular risk; at least, they oftenhave other concomitant risk factors (11). It is impor-tant, however, to recognize the condition in order toavoid unnecessary treatment in many subjects.

Semi-automatic and automatic devices for bloodpressure measurement at home and for prolonged(.24 hours) ambulatory blood-pressure monitoringare now available (12). It should be stressed that allthese devices should be tested for accuracy and reli-ability against the standard methods according tostrict protocols (13). Ambulatory devices should betested in ambulatory conditions. Home blood-pres-sure measurement has the advantage of providingmany more readings in a quieter setting than bloodpressure measurement in the doctor's office. Ambu-latory blood pressure monitoring is an interestingresearch technique which is used to investigate bloodpressure variability, behavioural influences on arteri-al pressure, and the time-course of the effects of anti-hypertensive therapy. It is also used, as are homeblood-pressure readings, to provide a supplementarysource of information for diagnostic and therapeuticdecisions (12). Home and ambulatory blood-pressurevalues, however, cannot be equated to readings takenby the conventional method in the clinic by physi-cians or nurses. There is evidence, supported by arecent population survey (14), that both home blood-pressure and ambulatory blood-pressure values, aver-aged over 24 hours, are several mmHg lower thanvalues measured in the clinic. Prognostic standardswith regard to the level of blood pressure to be treat-ed have been based on prospective studies relatingcasual or clinic blood pressure to morbidity and mor-tality. No prospective studies are available providingprognostically valuable standards for home or ambu-

latory blood pressures. Therefore, it is likely thattherapeutic decisions based on clinic blood pressurewill differ from those based on home or ambulatoryblood-pressure measurements (15). For the timebeing, the latter measurements should only be usedin selected cases to complement the blood pressurevalues measured by the physician.

Definition of mild hypertension based ondiastolic blood pressure

Diastolic blood pressure has generally been used todefine mild hypertension. This choice is somewhatarbitrary, but is supported by the fact that diastolicblood pressure has been used as the criterion forinclusion in most randomized therapeutic trials,including those on mild hypertension (16).

Mild hypertension in adults can be defined as apersistent resting level of diastolic blood pressure(phase V) between 90 and 105 mmHg. "Borderline"hypertension (diastolic blood pressure 90-95 mmHg)accounts for about half of mild hypertensive patients.Community screening has shown that up to 20% ofthe population aged 50 years or above have diastolicpressures within the mild hypertensive range at thetime of screening (17). With repeated measurementsover periods of up to 3-6 months, the diastolic pres-sure of almost half of the subjects within the mildhypertension range falls to levels below this range(18, 19).

Persons whose resting values of diastolic bloodpressure remain persistently at or above 90 mmHgafter repeated measurements are at increased risk ofcardiovascular mortality and morbidity, and the riskclearly increases with the height of the diastolicblood pressure. Between 12% and 15% of suchpatients will develop moderate or severe hyperten-sion (diastolic blood pressure >105 mmHg) within3-5 years (19), with a worse prognosis, while theremaining patients stay within the mild range. Therisk of stroke is increased in patients with mildhypertension, and drug treatment has been clearlyshown to reduce the risk by 35-40% (20). In popula-tions with a high level of plasma lipids, the majorcause of cardiovascular mortality and morbidity inpatients with mild hypertension is usually ischaemicheart disease. Lowering of blood pressure with drugsalso reduces the risk of non-fatal myocardial infarc-tion and death from ischaemic heart disease by about15-20%, but the size of the benefit obtained with thetreatments so far tested in controlled clinical trialsappears to be slightly lower than that expected froma long-term decrease in blood pressure of the samemagnitude (20).

In practice when the initial diastolic pressureaverages between 90 and 105 mmHg, measurements

WHO Bulletin OMS. Vol 71 1993 505

Memorandum

Fig. 1. Definition and management of mild hypertension.

DEFINITION:

90-105 mmHg diastolic blood pressure (DBP)and/or

140-180 mmHg systolic blood pressure (SBP)

BP measured at least twice on twodifferent occasions: if mean values are90-105 (DBP) and/or 140-180 (SBP)mmHg

Repeat measurements on at lea,further occasions over a period c

r weeks

BP below 140/90 mmHg:further measurements at 3

After 4 weeks month intervals for a year

3t two)f 4

XDBP 90-l10'140-180 minon-drug tremonitor bloc

=I

DBP 90-95nd/orSBPDBP 95-100 and/or SBPAfter first DBP 90-95 and/or SBP 160-180 mmHg: reinforce non-3 months drug measures and monitor drug measures and consider

blood pressure drug treatment if other riskfactors present

DBP 90-95 and/or SBP DBP 90-95 and/or SBPAfter second 140-160 mmHg, no other risk 140-160 mmHg, with other3 months factors: continue non-drug risk factors: consider drug

treatment and monitor blood treatmentpressure

5 and/or SBPnHg: institute,atment andid pressure

DBP 100 mmHg or above orSBP 160-180 mmHg withDBP 95 mmHg or above:reinforce non-drug measuresand institute drug treatment

DBP 95-100 and/or SBP160-180 mmHg, with or withoutother risk factors: institute drugtreatment

N.B. Institute drug treatment more promptly in patients with evidence of substantial risk of cardiovascular disease or in patients withblood pressure above the mild hypertension range.

should be repeated on at least two further occasionsduring the next 4 weeks. With repeated measure-ments both systolic and diastolic pressures often fallsubstantially. Before labelling a subject as hyperten-sive and deciding to initiate medical treatment, it isnecessary, therefore, to identify those patients with asustained high or increasing blood pressure.

All patients should be given advice to modifytheir lifestyle, as appropriate, by stopping smoking,reducing obesity, limiting alcohol and dietary satu-rated fat, and engaging in regular, mild dynamicexercise. This advice should form a very importantpart of the strategies to reduce blood pressure and toimprove cardiovascular health. Salt restriction mayassist in lowering the blood pressure. Management

decisions should be made after discussing with thepatient and his/her family and outlining the risks andbenefits of various intervention strategies (21).

Practical guidelines are illustrated in Fig. 1.

* At 4 weeks from initial measurements(1) Patients whose diastolic blood pressures fallbelow 90 mmHg within 4 weeks should have furthermeasurements at 3-month intervals for a year.

(2) If the diastolic blood pressure remains between90 and 105 mmHg, appropriate non-drug treatmentfor all patients (see below) should be instituted andthe blood pressure monitored on several occasionsduring the following 3 months.

WHO Bulletin OMS. Vol 711993506


* After the first 3-month period

(3) If the diastolic blood pressure is 100 mmHg orabove, drug treatment should be instituted.(4) If the diastolic blood pressure is 95-100 mmHg,non-drug measures should be reinforced, and drugtreatment considered especially when other cardio-vascular risk factors are present.(5) If the diastolic blood pressure remains between90 and 95 mmHg, non-drug measures should be re-inforced and long-term observation of the patientcontinued.

* After a second 3-month period(6) If the diastolic blood pressure is 95 mmHg orabove at the end of the second 3-month period, drugtreatment should be instituted even when other cardio-vascular risk factors are absent.(7) Patients whose diastolic pressure remainsbetween 90 and 95 mmHg after prolonged observa-tion also have an increased risk of cardiovasculardisease. This is more marked when the systolic bloodpressure is also elevated, as well as in elderly people,smokers, diabetics, individuals with raised plasmalipids or left ventricular hypertrophy, and those witha family history of cardiovascular disease. Drugtreatment should be considered for such patients whoare at higher risk. Lower-risk subjects, if not treatedwith drugs, should be further assessed at about 3-month intervals and appropriate non-drug measuresshould be maintained or reinforced.

Definition of mild hypertension based onsystolic blood pressure

Although most of the randomized therapeutic trialson mild hypertension have defined and treatedpatients on the basis of diastolic blood pressuresonly, there is mounting evidence that systolic valuesshould also be taken into account in defining andmanaging mild hypertension. Indeed cardiovascularrisk is as strongly associated with systolic as withdiastolic values, with no evidence of a threshold be-low which a decrease in systolic pressure does not re-duce the risk (22). Furthermore, some of the interven-tion studies on mild hypertension indicate that car-diovascular events more closely correlate with achievedsystolic than diastolic blood pressure values (9).

From epidemiological data on incidence ofstrokes and coronary events, the range of systolicblood pressures corresponding to diastolic bloodpressures of 90-105 mmHg, i.e., the range definingmild diastolic hypertension, is approximately140-180 mmHg (22), and intervention trials haveshown treatment benefits when systolic values of160 mmHg and above are lowered (5, 7).

When mild hypertension is defined according tosystolic blood pressure, management should followthe same practical guidelines previously outlined forhypertension defined according to diastolic values.Fig. 1 summarizes a flow-chart of decision-makingbased on systolic as well as diastolic pressures. Insummary, a diagnosis of mild hypertension based onsystolic blood pressure can be made when systolicvalues of 140-180 mmHg (associated or not withdiastolic blood pressures of 90-105 mmHg) arerepeatedly measured during at least 4 weeks, atwhich time only non-pharmacological intervention isto be recommended. After three additional months ofobservation, drug treatment should be institutedwhen the systolic blood pressure is 160-180 mmHgand diastolic values are at least 95 mmHg, or withdiastolic values below 95 mmHg if other cardiovas-cular risk factors are present. After a second 3-monthperiod, persistent systolic values of 160-180 mmHgmay justify drug treatment even when the diastolicblood pressure is below 95 mmHg and there are noother risk factors; at this time even systolic valuesbetween 140 and 160 mmHg with substantial riskfactors may deserve drug treament.

In most cases both systolic and diastolic valueswill be in the respective mild hypertensive ranges,but in other cases either isolated mild diastolichypertension or isolated mild systolic hypertensionmay occur. Isolated systolic hypertension can befound in adolescents and young people but is partic-ularly common in the elderly (6-10% of individualsaged 65-74 years in a recent population study (23)).Isolated systolic hypertension in adolescents andyoung people has different mechanisms comparedwith that of the elderly, and there is no evidence thatisolated mild systolic hypertension in young peopleshould be treated, apart from lifestyle counselling.On the other hand, isolated systolic hypertension inthe elderly (often beyond the mild range) not onlycarries additional risk (22), but has recently beenshown to benefit significantly from pharmacologicalreduction of elevated systolic blood pressure (seebelow). In adults below 60 years of age, althoughthere is little direct evidence of benefit from treatingisolated systolic hypertension (which is also infre-quent at this age), it seems reasonable to considerdrug therapy in subjects with systolic blood pressurevalues persistently equal to or above 160 mmHgeven if diastolic values are below 90 mmHg, andparticularly when other risk factors are present.

Classification of hypertensionAs mentioned at the beginning of this Memorandum,the risk associated with raised blood pressureincreases progressively throughout the entire rangeof blood pressure values (1) and the dividing line


Memorandum

between "normotension" and "hypertension" is arbi-trary. However, the considerations made in the sec-tions above allow an operational classification ofhypertension to be made. This classification is illus-trated in Table 2 as a practical guide to management.As previously mentioned, the term "mild" hyperten-sion refers to individuals with either diastolic bloodpressures in the range 90-105 mmHg or systolicblood pressures in the range 140-180 mmHg. Theterm "borderline hypertension" is used in the sub-group of mild hypertensive subjects with diastolicblood pressure between 90 and 95 mmHg or systolicblood pressure between 140 and 160 mmHg. Theterm "mild" is used to convey the information thatthe blood pressure is mildly elevated, but it does notimply that the absolute risk of cardiovascular diseaseis always mildly elevated. For instance, in an indi-vidual at high risk of stroke or myocardial infarc-tion mild hypertension may considerably aggravatethis risk, and the reduction of even mildly elevatedblood pressure is likely to confer large benefits. Thesame considerations apply to patients with diabeticnephropathy. Furthermore, mild hypertension ishighly prevalent and places a heavy burden on manypopulations.

Isolated systolic hypertension is a comprehen-sive term indicating all patients with systolic bloodpressures equal to or greater than 140 mmHg anddiastolic blood pressures lower than 90 mmHg. Thisgroup with systolic pressures of .160 mmHg have sofar been shown to benefit from treatment; subjectswith systolic blood pressure values between 140 and160 mmHg and diastolic pressures below 90 mmHgcan be classified as having "borderline" isolated sys-tolic hypertension. Classifying subjects with diastolicblood pressures between 85 and 89 mmHg or systol-ic blood pressures between 130 and 139 mmHg as

Table 2: Classification of hypertension by blood pres-sure level

Systolic Diastolicblood pressure blood pressure

(mmHg) (mmHg)

Normotension <140 and <90

Mild hypertension 140-180 and/or 90-105

Subgroup: Borderline 140-160 and/or 90-95hypertension

Moderate and severe >180 and/or >105hypertensiona

Isolated systolic hyper- >140 and <90tension (ISH)

Subgroup: Borderline 140-160 and <90ISH

a Risk to be indicated by reporting the actual values of systolicand diastolic pressures.

"high normal" individuals (24) cannot be justified atthe moment, and carries the risk of labelling a verylarge number of subjects.

As cardiovascular risk is associated with bloodpressure levels in a continuous way, it appears rea-sonable that, beyond the range of mild hypertension,the risk of hypertension is indicated by reporting theactual values of systolic and diastolic blood pressure.As suggested in the 1978 WHO Expert CommitteeReport (25), the term "stage" is better used to indi-cate the absence, presence or severity of complica-tions, rather than to classify different blood pressurelevels (Table 3).

EvaluationA complete history and physical examination areessential. Factors of significance include a familyhistory of hypertension, diabetes, hyperlipidaemia,ischaemic heart disease or stroke; a personal historyof symptoms suggestive of ischaemic heart disease,cardiac failure, or transient cerebral ischaemic epi-sodes; a history of kidney disease, diabetes or bron-chospasm; previous measurements of blood pressure;and details of lifestyle, educational level, and socio-logical factors. There should be careful quantitation

Table 3: Classification of hypertension by extent oforgan damage

Stage I: No objective signs of organic changes

Stage Il: At least one of the following signs oforgan involvement:

- Left ventricular hypertrophy (X-ray,electrocardiography, echocardiography)

- Generalized and focal narrowing of theretinal arteries

- Proteinuria and/or slight elevation ofplasma creatinine concentration(1.2-2.0 mg/dl)

- Ultrasound or radiological evidence ofatherosclerotic plaque (carotid arteries,aorta, iliac and femoral arteries)

Stage IlIl: Both symptoms and signs have appeared as aresult of organ damage. These include:- Heart: angina pectoris, myocardial infarction,

heart failure- Brain: transient ischaemic attack, stroke,

hypertensive encephalopathy- Optic fundi: retinal haemorrhages and exu-

dates with or without papilloedema- Kidney: plasma creatinine concentration

above 2.0 mg/dl, renal failure- Vessels: dissecting aneurysm, symptomatic

arterial occlusive disease



of smoking and alcohol consumption. Weight gainsince early adult life can provide a useful index ofexcess body fat. Patients should be questioned on theingestion of prohypertensive substances or drugs,notably oral contraceptives, nonsteroidal anti-inflam-matory drugs, liquorice, cocaine, etc. Attentionshould be paid to the possible use of erythropoietin,ciclosporin, or steroids for concomitant diseases.Physical examination should include measurement ofweight and height, evaluation of heart size, examina-tion of optic fundi, and evidence of arterial disease inthe carotid, renal and peripheral arteries. Certainminimum investigations should be performed in allpatients. These are analysis for blood, protein, andglucose in the urine, microscopic examination of theurine, estimations of plasma potassium, creatinine,total and HDL-cholesterol, uric acid and blood glu-cose, and an electrocardiogram. Echocardiography iswidely used in assessing left ventricular mass; thequality of the results depends on the patient's mor-phology and the operator's training, but its cost-effectiveness in the evaluation of mild hypertensivesubjects has not been investigated. None the less, theimportant prognostic role of left ventricular hypertro-phy has made echocardiography a frequent compo-nent of the diagnostic work-up of the hypertensivepatient, particularly in those cases in which evalua-tion of left ventricular mass and geometry may helpto decide about initiation of treatment. Ultrasound isalso useful in evaluating the carotid and abdominalaorta walls, and renal morphology. In selected cases,further investigations should be carried out to ex-clude curable causes of hypertension. The cost of in-vestigations should be considered when a decisionis made for a given patient.

Treatment: general conceptsEffects of antihypertensive treatment on therisks of cardiovascular events

Randomized controlled trials have shown that inpatients with mild hypertension the lowering ofblood pressure with antihypertensive drugs decreasesmorbidity and mortality from cardiovascular disease.On average, a 5-6 mmHg reduction in diastolicblood pressure (and 10 mmHg reduction in systolicblood pressure) reduced stroke risk by about a thirdand the risk of coronary events by about a sixth (20).It is likely, however, that the benefits of antihyper-tensive therapy have been underestimated by most ofthe randomized controlled trials for at least threereasons: (1) in many trials of active vs placebo treat-ment there has been extensive cross-over of patientsfrom placebo to active treatment; (2) in several trialslow-risk patients were preferentially included; and

(3) most trials have been relatively short term (3 to 5years' duration), and the full effects of blood pres-sure reduction, on coronary events in particular, maytake a decade or more to become manifest. Since theabsolute risk of coronary events in young patients islow, the initial goal of treatment is to prevent theprogression of disease processes such as left ventri-cular hypertrophy and, possibly, atherosclerosisrather than discrete events (26).

Factors influencing initiation of treatment

Diastolic and systolic blood pressure values areimportant for initiation of treatment, and it should bestressed that, whenever blood pressure values abovethe mild hypertension range (i.e., systolic 180 anddiastolic 105 mmHg or above; see Table 2) are meas-ured, a decision to treat with drugs should be takenafter a shorter observation period than the one sug-gested in Fig. 1 for mild hypertension.

However, several factors other than diastolic andsystolic blood pressures and age may influence thedecision to begin drug treatment.

(1) Gender. Premenopausal women are at a 50%lower risk of cardiovascular disease than men of thesame age (3), and the absolute benefit of treatment isless conspicuous in this group of women than inmen, unless other risk factors are present. Further-more, in males hypertension appears to be frequentlyunderdiagnosed and undertreated (23).

(2) Cardiovascular complications. Clinical, echocar-diographic or radiological evidence of left ventricu-lar hypertrophy is a predictor of a substantially high-er incidence of morbid events (27, 28) and istherefore a clear indication to begin treatment. Clini-cal, electrocardiographic or angiographic evidence ofischaemic heart disease in hypertensive patientsrequires lowering of blood pressure in addition totreatment of the underlying disorder. A history ofcerebrovascular disease (e.g., transient cerebralischaemia or stroke, especially cerebral or subarach-noid haemorrhage) is also a clear indicator for theinitiation of treatment. It has not been fully proven,however, that antihypertensive therapy can preventthe recurrence of strokes. The presence and nature ofcardiovascular complications may also influence thechoice of treatment.

(3) Renal disease. Raised serum creatinine and pro-teinuria are predictors not only of renal impairmentbut also of a higher incidence of cardiovascularevents (29). If either is present, drug treatmentshould be started. In patients with chronic renal fail-ure, particularly those with diabetic nephropathy,even blood pressure values in the borderline range


Memorandum

represent a considerable risk and must be lowered bydrugs.

(4) Diabetes. Diabetes and hypertension are frequentconcomitant diseases and hypertension is a potentadditional risk factor in diabetes and vice versa. Thepresence of microalbuminuria is an early indicator ofthis increase in risk (30). There is good evidence thattreatment of high blood pressure or even a loweringof normal blood pressure in diabetic patients reducesmicroalbuminuria, slows the decline in renal func-tion, and delays the development of diabetic neph-ropathy (31). Therefore, the presence of diabetes(both insulin- and non-insulin dependent forms) inpatients with mild hypertension is a clear indicationto begin antihypertensive treatment. In these patientsparticular attention should also be paid to accompa-nying disorders of lipid metabolism.

(5) Other cardiovascular risk factors. Continuedcigarette smoking, elevated fasting glucose, elevatedserum total cholesterol, and low HDL-cholesterol allmarkedly increase the cardiovascular risk associatedwith high blood pressure (3) and increase the abso-lute benefit of lowering the blood pressure. There-fore, the presence of one or more of these risksshould influence the decision towards early drugtreatment and the intensive use of appropriate non-drug measures, and may also influence the choice ofthe antihypertensive drugs.

(6) Family history. A family history of hypertensionor of premature stroke, heart disease, or sudden car-diac death should influence the decision towardsearly drug treatment.

(7) Low-income populations. A decision to initiatedrug treatment and, more broadly, the range ofactions desirable for hypertension control will varywith a population's resources, constraints, mortalitystructure, and the resulting health care priorities. Indeveloping countries costs may make it difficult toextend all choices of diagnostic procedures and drugtherapies to all individuals with mild hypertension.Advice on modification of lifestyle should be of par-ticular benefit in such circumstances before resortingto drug therapy. Although individualized counsellingand structured programmes (see below) will be diffi-cult to provide in most developing countries, popula-tion-based initiatives to reduce average blood pres-sure levels would be worthwhile. In low-incomesocieties it is a realistic approach to train auxiliariesfor measuring blood pressure, and for simple urinetesting, and to follow a less rigorous evaluationschedule. Although higher-risk individuals should betreated pharmacologically, careful choice of drugswith increased emphasis on cost-effectiveness

becomes particularly important with growing eco-nomic constraints. Increasing the public's awarenessof the hazards of hypertension, measuring of bloodpressure at every opportunity, regular surveillance ofhypertensive individuals, and educating the popula-tion about factors that may raise blood pressure oraggravate existing hypertension are measures asimportant in low income as in affluent populations.Political and public education is particularly impor-tant in reducing tobacco dependency, and promotingthe production and marketing of healthy foods.Indeed, it is the responsibility of the medical practi-tioner to participate in educating the public and inpersuading govemments.

Hypertension in the elderlyIn absolute terms, hypertension is a much greaterrisk of cardiovascular events in the elderly than inyounger people. In Westem populations, amongthose with mild hypertension the 10-year risk of amajor cardiovascular event ranges from less than 1%in individuals aged 25-34 years to more that 30% inthose aged 65-74 years (3). Correspondingly, numer-ous intervention trials have shown that the absolutebenefit of antihypertensive therapy is particularlyhigh in the elderly.

In addition to the results of the European Work-ing Party on High Blood Pressure in the Elderly(EWPHE) trial published in 1985 (4), which clearlydemonstrated the beneficial effect of antihyperten-sive medication in the elderly, the results of threeprospective placebo-controlled therapeutic trials inelderly hypertensives have been reported in 1991 and1992. All demonstrated significant reduction of car-diovascular morbidity or mortality. The SystolicHypertension in the Elderly Program (SHEP) (5)specifically examined the value of antihypertensivetreatment in elderly men and women (.60 years)with isolated systolic hypertension (systolic bloodpressure 160-219 mmHg and diastolic blood pres-sure <90 mmHg): highly significant reductions infatal and non-fatal cardiovascular events wereobserved. The Swedish Trial in Old Patients withHypertension (STOP-Hypertension) (6) evaluatedactive antihypertensive therapy versus placebo in"old elderly" patients (aged 70-84 years) with sys-tolic blood pressure 180-230 mmHg. Fatal and non-fatal strokes were reduced by 47%, all "primary end-points" (i.e., fatal and non-fatal stroke, fatal andnon-fatal myocardial infarction and other cardiovas-cular death) by 40% and total mortality by 43%, allchanges being statistically highly significant. TheMedical Research Council trial in older adults (aged65-74 years) (7) with systolic blood pressure of160-209 mmHg and a diastolic blood pressure<115 mmHg showed a 25% reduction in stroke mor-



tality and morbidity and a 17% reduction in all cardio-vascular events, both of which were significant.From the results of all these trials it is obvious thatantihypertensive therapy in elderly patients withhypertension, be it isolated systolic or combined sys-tolic and diastolic, provides relative benefits, interms of percent reduction in cardiovascular morbid-ity and mortality, that are of at least the same magni-tude (about 20-50%) as the benefits of treatment inyoung and middle-aged hypertensive patients.Furthermore, since the cardiovascular event inci-dence is high in the elderly, the same relative reduc-tion in risk as in younger patients provides a greaterabsolute benefit in this age group.

In all trials, with the single exception of theMedical Research Council trial, benefit rangesbetween one event prevented each year for every 35treated patients and one event prevented for every 90treated patients. Old age, therefore, renders antihy-pertensive therapy particularly beneficial. Accordingto the STOP-Hypertension study (6), significant ben-efits are also seen in the "old elderly" without anyclear upper limit of age. In the oldest patients, how-ever, caution is needed in the use of drugs, especiallyif other medications are also prescribed for associat-ed diseases. It should also be remembered that inelderly patients the blood pressure elevation canoften be controlled by low-dose medication. Bearingin mind these precautions, antihypertensive therapycan be instituted in the elderly along the same gener-al guidelines as in young and middle-aged patients.

Goal of treatment

Since the relationship between blood pressure andcardiovascular risk is continuous, it seems appropri-ate for the goal of treatment to be the maximum tol-erated blood pressure reduction. There is very goodevidence from epidemiological studies that, withinthe "normal" range of both systolic and diastolicpressures, the lower the blood pressure, the lower therisks of both stroke and coronary events (1). Theclaim that lowering the diastolic pressure below85 mmHg, at least in particular groups of patients(such as those with ischaemic heart disease), raisesthe risk above that associated with a more moderateblood pressure reduction (32) is unproven, but is cur-rently being tested by a randomized trial (33). Untilsuch evidence becomes available, it may be worthrecalling that the safety of blood pressure reductioneven at very low initial blood pressure levels hasbeen indicated by the results of trials in patients withcongestive heart failure or after myocardial infarctionwho have been treated with angiotensin-convertingenzyme (ACE) inhibitors or beta-blockers. Further-more, patients in the SHEP study (5), with an aver-

age initial diastolic blood pressure of 77 mmHg,exhibited substantial benefits with further loweringof diastolic blood pressure.

On the basis of available evidence, it wouldseem desirable to achieve blood pressures of theorder of at least 120-130/80 mmHg in youngpatients with mild hypertension. In elderly patientswith elevation of both systolic and diastolic bloodpressure it would seem desirable to lower bloodpressure to below 140/90 mmHg, while in patientswith isolated systolic hypertension the goal of treat-ment should be to achieve a systolic blood pressureof at least 140 mmHg if this is tolerated. When homeblood pressure or ambulatory blood pressure meas-urements are used to help in the evaluation of bloodpressure achieved by treatment, it should be remem-bered that the values provided by these methods are,on average, several mmHg lower than the clinicblood pressures (14); therefore, the blood pressure tobe attained by treatment, when assessed by thesetechniques, should be set at a lower level to avoidundertreatment.

Modes of treatmentNon-pharmacological interventions

Several non-pharmacological interventions are recom-mended in the primary prevention of hypertensionand other cardiovascular diseases and have been theobject of a recent joint WHO/ISH statement (21).These interventions have also been shown to lowerblood pressure in patients with mild hypertension. Asdiscussed in this statement (21), weight reduction inoverweight subjects, reduction of alcohol consump-tion to no more than 20-30 g of ethanol per day,regular mild (not strenuous) exercise in seden-tary subjects (such as walking, jogging, cycling orswimming), and sodium chloride restriction to nomore than 5 g/day (at least in some patients) areeffective in lowering the blood pressure. It is known,however, that these lifestyle modifications are diffi-cult to apply on a large scale, that compliance tosuch recommendations is poor in the long-term, andthat the ability of non-pharmacological interventionsto reduce mortality and morbidity in hypertensionhas not been proved directly. Nevertheless, it appearsreasonable to advise that efforts to lower blood pres-sure by lifestyle modifications should normally pre-cede any decision about the necessity for drug treat-ment of mild hypertension. It should be rememberedthat some of these measures may take severalmonths to become fully effective. If a decision ismade to begin drug treatment, a structured program-me of non-pharmacological intervention remains animportant component of the overall therapeutic pro-


Memorandum

gramme, even in patients with an initial blood pres-sure above the mild hypertension range, for whomdrug requirements may consequently be reduced.

Control of associated risksTobacco. All the large-scale trials of treatment ofmild hypertension have confirmed that treated hyper-tensive patients who smoke tobacco have a greaterincidence of both stroke and coronary heart diseasethan equally treated hypertensive patients who do notsmoke (19, 34). It is likely that the pressor effect ofsmoking (35) has been underestimated by the usualrecommendation of avoiding smoking before meas-uring blood pressure. Repeated advice as to how todiscontinue smoking is therefore of major impor-tance, and will need to be coupled with particularefforts to prevent consequent weight gain. Intensiveadvice programmes, supported when necessary bypharmacological treatment of nicotine addiction,are more effective than haphazard admonitions.

Lipids. Since high serum cholesterol levels and dia-betes also unfavourably influence the long-termprognosis of hypertensive persons, nutritional coun-selling and, when appropriate, drug treatment areindicated to control these risk factors. If dietarymeasures are to be successful, a careful follow-upshould be instituted. Since increased physical activ-ity is also likely to reduce the risk of cardiovasculardisease, it is appropriate in mildly hypertensivepatients.

Oral contraceptive pills and hormonal replacementtherapy. Altemative methods of contraception shouldbe considered for hypertensive women in place ofestrogen-progesterone-containing oral contraceptivesas these substances may raise the blood pressure aswell as carry other cardiovascular risks (36).

Hormone replacement therapy is being increas-ingly used to prevent osteoporosis in postmenopausalwomen. There is evidence that replacement with es-trogen alone reduces coronary risk (37), but the evi-dence is less for combined estrogen/progesteronetherapy. Such combinations are generally recom-mended for women with an intact uterus to protectagainst uterine malignancy. There is no contraindica-tion to the use of hormone replacement therapy inhypertension but blood pressure should be monitoredmore frequently, as it is not yet clear whether hyper-tensive responses may occur in some women.

It should be emphasized that the above-men-tioned non-pharmacological interventions, whetheror not they lower the blood pressure, can reduce theoverall risk of cardiovascular disease and significant-ly contribute to global health care.

Antihypertensive drugsRandomized trials of antihypertensive treatment haveshown the benefits of lowering the blood pressureand although most of these trials have used diuretics,centrally acting drugs, vasodilators and/or beta-block-ers, often in combination, there is no evidence so farto show that the benefits are due to any particularclass of antihypertensive agents rather than to thelowering of blood pressure per se. Also in several ofthe recent trials of antihypertensive treatment in theelderly, as many as 60-70% of the patients on activetreatment received a combination of two or moredrugs, and the real evidence provided by these trialsis about the benefit of lowering blood pressure.

Several classes of drugs can be recommended asfirst-line treatment of mild sustained hypertension.They may be listed, in order of proven benefit basedon mortality-morbidity studies: (1) diuretics, (2)beta-blocking drugs, and (3) ACE inibitors, calciumantagonists, alpha-adrenoceptor blocking drugs.

While the average blood pressure fall induced ingroups of patients by each of the different categoriesof drugs is similar, there are large variations in thereduction induced in the individual patient. Theappropriate choice of a particular class of antihyper-tensive drugs for a patient may also be determinedby the individual's other characteristics, since thereare such extensive differences in the risk profile andin side-effects in different patients.

The choice of the initial drug therapy of an indi-vidual hypertensive patient is a challenge for thephysician and should not be restricted, on theoreticalor economic grounds, to any one or two of the vari-ous classes of drugs which have been tested so far,although it is also the physician's responsibility togive due consideration to the cost of drugs.

Finally, we should bear in mind that the real evi-dence of benefit (risk ratios for mortality, stroke, andcoronary events) has been obtained largely over arelatively short time (of about 2.5 years to the termi-nating event). Such end-points may not be relevantfor younger patients with hypertension, who mayhave decades of treatment ahead of them. For suchpatients a reduction in progression of cardiovascularlesions may be of greater relevance (26, 38).

(a) DiureticsDiuretics have been widely used as first-line antihy-pertensive therapy and diuretic-based therapy hasbeen shown to be clearly effective in the preventionof cardiovascular morbidity and mortality, especiallyfatal and non-fatal stroke (20). Particularly in largedoses, diuretics may cause a variety of unwantedmetabolic effects (principally potassium depletionand reduced glucose tolerance (39), ventricular



ectopic beats, and impotence (19)), which can bereduced if the dose is kept as low as possible. Low-dose diuretics remain effective, not only in loweringelevated blood pressure, but in reducing cardiovascu-lar morbidity and mortality, as shown in recent trialsof antihypertensive therapy in the elderly (4-7).Diuretics are inexpensive. They are also particularlyvaluable as ancillary treatment to enhance the effec-tiveness of many other antihypertensive drugs. Com-bination of diuretics with potassium-sparing drugs orwith ACE inhibitors may prevent potassium deple-tion.

(b) Beta-adrenoceptor-blocking drugsBeta-blocking drugs are widely and effectively usedto initiate treatment for mild hypertension. Beta-blocker-based antihypertensive therapy has beenshown to reduce cardiovascular morbidity and mor-tality (20). Numerous beta-blocking drugs are avail-able, some with cardioselective properties, otherswith partial agonist activity or with alpha-blockingor vasodilator properties. Although beta-blockershave been shown to prevent fatal and non-fatal coro-nary events in patients with a previous myocardialinfarction (40), they have not been shown to haveany consistent advantage over diuretics for theprimary prevention of myocardial infarction.

Beta-blocking drugs are particularly useful inhypertensive patients with effort angina, tachy-arrhythmias, or a past myocardial infarction. Theyshould be avoided in patients with obstructive air-ways disease, heart failure, and peripheral vasculardisease. They have limitations in patients with dys-lipidaemia or reduced glucose tolerance (39), as wellas in athletes or physically active subjects.

(c) ACE inhibitorsACE inhibitors are effective in lowering blood pres-sure. They are generally well tolerated and have beenshown not to exert untoward effects on serum lipidsand on glucose homoeostasis (39). Possible adverseeffects include persistent cough and, rarely, angio-oedema. In patients with renovascular disease,deterioration in renal function has been reported.ACE inhibitors should be avoided in women consid-ering child-bearing and are definitely contraindicatedin the second half of pregnancy, since they mayincrease fetal and neonatal death (41). Their safetyprofile is otherwise good.

ACE inhibitors have been shown to reduce car-diovascular mortality and morbidity, including coro-nary events (42-45), in patients with congestiveheart failure and after a myocardial infarction inpatients with a reduced ejection fraction. In thesepatients a reduction of left ventricular dilatation hasalso been reported (44). The ability of the ACE

inhibitors to reduce cardiovascular events in hyper-tension has not yet been proven in controlled clinicaltrials.

(d) Calcium antagonistsThere are three major classes of calcium antagonistswith different characteristics (phenylalkylamine,dihydropyridine and benzothiazepine derivatives),but all are effective in lowering blood pressure.

Troublesome side-effects may include initialtachycardia, headache, flushing (especially with fast-acting dihydropyridines), ankle oedema and (withphenylalkylamine derivatives), and constipation.With few exceptions, they do not have undesirablemetabolic effects (39) and their safety profile inhypertension appears good. However, the safety ofdihydropyridines in early pregnancy has not beenfully established. In patients with atheroscleroticarterial disease the calcium antagonists may reducethe development of new plaques (46), but studieswith fast-acting short-duration dihydropyridines havebeen discouraging in providing evidence of secon-dary prevention of ischaemic heart disease (47, 48).On the other hand, verapamil and diltiazem havebeen reported to reduce morbidity and mortality inpost-myocardial infarction patients, provided thatheart failure or left ventricular dysfunction are absent(47). As with all recent classes of antihypertensiveagents, the calcium antagonists' ability to reduce car-diovascular events in hypertension has not yet beenproven in controlled clinical trials.

(e) Alpha-adrenoceptor-blocking drugsAlpha-adrenoceptor-blocking drugs effectivelyreduce blood pressure and have limited side-effects.Their dose should be carefully titrated, however, inorder to avoid postural hypotension, a complicationparticularly undesirable in the elderly. A favourableaspect of this class of drugs is a potential beneficialeffect on lipid and glucose homoeostasis (39). Aswith all newer classes of antihypertensive agents, thealpha-blockers' ability to reduce morbidity and mor-tality has not been proven in controlled clinicaltrials.

(f) Other classesCentrally acting drugs are also effective antihyper-tensive agents and have been used for many years,mostly in association with diuretics. Several con-trolled clinical trials have proved their ability in anti-hypertensive therapy to reduce cardiovascular events(20). In particular, methyldopa remains an important,well-validated agent to treat effectively hypertensionin pregnancy (49). The side-effect profile of central-ly acting drugs, however, is less favourable than thatfor the antihypertensive agents previously men-


Memorandum

tioned. If consideration of cost-effectiveness shouldfavour the use of centrally acting drugs, such asreserpine, in low-income populations, it is recom-mended that they be used in much lower doses thancommonly prescribed in earlier years.

Direct vasodilators, such as hydralazine andminoxidil, are also quite effective in lowering bloodpressure, but some of their side-effects (tachycardia,headache, and sodium and water retention) make itdifficult to use them as monotherapy.

(g) Combination of drugsIf monotherapy with a compound of any of the fivemajor pharmacological classes mentioned above hasbeen found ineffective in lowering blood pressure ina given patient, it is reasonable to substitute the firstdrug with a compound belonging to a different class.If a single drug has been partly effective it may bepreferable to add a small dose of a second drugrather than to increase the dose of the first. Effectivecombinations utilize compounds from differentdrug groups. This permits the addition of differentprimary actions while minimizing the homoeostaticcompensations that limit the fall in pressure. Com-bination therapy also minimizes side-effects byencouraging the use of drugs in low doses.

An additive effect has been shown when com-bining:- a diuretic with a beta-blocker or an ACE inhibi-

tor or an alpha-blocker;- a beta-blocker with an alpha-blocker or a dihy-

dropyridine calcium antagonist; and- an ACE inhibitor with a calcium antagonist.

In order to achieve the full goal of antihyperten-sive treatment in all hypertensive patients (i.e., themaximum tolerated reduction in blood pressure),two-drug and sometimes three-drug combinationsmay frequently be required.

For reasons of convenience, cost and increasedpatient compliance, preparations that combine twodrugs in a single tablet or capsule may be appropri-ate for many hypertensive patients, once the needand dose for the constituent drugs have been estab-lished.

Follow-up

During the stabilization period of treatment, patientsneed to be seen at regular intervals until the bloodpressure levels are satisfactorily controlled. Themain task of doctors during follow-up is to ensurethat the target systolic and diastolic blood pressure isreached and maintained and that other risk factorsare controlled. Gradual and careful lowering of bloodpressure will minimize the side-effects and compli-

cations, and will improve compliance. Sometimestelling a patient that he or she has hypertension("labelling") may be followed by anxiety or moodchanges. Additional support (e.g., reassurance aboutthe prognosis, stress on the ability to lead normalactive lives, and explanation of any new symptomsthat may appear) is therefore particularly important.Self-measurement of blood pressure may be helpfulto ensure compliance. After stabilization of bloodpressure, follow-up visits at 3-6 month intervals maybe adequate.

During each visit the blood pressure should bemeasured and side-effects monitored, including acareful assessment of the patient's quality of life.Whenever possible, close contact with the patient'sfamily is helpful. During follow-up visits, non-pharmacological measures (particularly cessationof smoking, control of serum cholesterol and weight,moderation of alcohol intake, and institution of physi-cal exercise) should be reinforced. Pharmacologicaltherapy should be reconfirmed or readjusted. In casesresistant to therapy further etiological investigationshould be performed. Depending on the drugs used,appropriate laboratory investigations should be per-formed at regular intervals.

As a rule, antihypertensive therapy should bemaintained indefinitely. Cessation of therapy inpatients who had been correctly diagnosed as hyper-tensives (see criteria above and flow-chart) is usuallyfollowed-sooner or later-by return of blood pres-sure to pretreatment levels. Nevertheless, after pro-longed blood pressure control it may be possible toattempt a careful progressive reduction in the dose ornumber of drugs used, especially in patients strictlyobserving non-drug treatment. Attempts to stepdown the treatment should be accompanied, how-ever, by careful, continued supervision of bloodpressure.

A hypertensive patient is typically treated forseveral decades, and during that period majorchanges in the available drugs occur and newpractical issues arise. It is likely that under the influ-ence of pharmacological progress, as well as habits,advertisements or economical considerations, apatient's treatment will undergo multiple changes. Itis in the interest of every patient to carefully documentall the drugs taken over many years, in conjunctionwith a careful analysis of their efficacy, clinical toler-ability and biochemical effects. It is also the respon-sibility of both doctors and health services to makethe history of a treated hypertensive patient easilyavailable.

Cost-effectivenessThe cost-effectiveness of treating hypertension variesmarkedly with the degree of cardiovascular risk in



various subgroups of patients with hypertension.Cost-effectiveness is more apparent in elderly sub-jects and in patients with previous cardiovasculardisease, in whom the benefit is realized within ashorter time span, than it is in younger patients, inwhom the benefit is delayed for many years duringwhich the costs of management accumulate. On theother hand, the costs of treating cardiovascular com-plications of hypertension such as stroke make thetreatment of hypertension a very cost-effective pro-cess in high-risk groups, in whom the incidence ofstroke is reduced by over 40%.

While the costs of relatively expensive diagnos-tic procedures and drugs are readily justified in high-risk groups, the practising physician should givecareful consideration to the costs associated with theinvestigation and treatment of patients with mildhypertension without associated risk factors. Primaryprevention of hypertension and strategies based onchanging the lifestyle of the whole population mayoffer the most cost-effective means of reducing themorbidity and mortality associated with mild hyper-tension. The effectiveness of these approaches inprimary prevention requires further validation.

Further researchMany issues require resolution and some are beingaddressed by major studies already in progress. Thequestion of goal blood pressures and the "J curve" isbeing addressed by the HOT study (33). Evidencefor reduction of morbidity and mortality by thenewer classes of antihypertensive drugs is clearlyneeded. This question is currently being addressedby the STOP-II (50) and the Syst-Eur (51) studies inthe elderly. A major study in middle-aged subjectscomparing the benefits of the newer agents withthose provided by diuretics and beta-blockers mayalso be desirable.

In young and middle-aged subjects with mildhypertension, in whom the short-term incidence ofcardiovascular events is rather low, trials monitoringprogression/regression of organ damage (such as leftventricular hypertrophy, carotid artery wall media-intima thickness and plaques, proteinuria and micro-albuminuria) may also provide relevant informationon the comparative effectiveness of various classesof antihypertensive agents. A related issue is whetherthe reversal of organ damage, in particular left ven-tricular hypertrophy, is accompanied by commensu-rate reduction in cardiovascular risk. It would also beimportant to investigate whether combining antihy-pertensive and antiplatelet therapies can furtherreduce cardiovascular events in hypertensive patients(as is being studied in the HOT trial (33)), andwhether combining antihypertensive and lipid-lower-

ing treatments can help to reduce the progression ofatherosclerosis. Another important issue concerns thepotential benefit of lowering blood pressure in sub-jects with blood pressures lower than 140/90 mmHgbut with other factors that markedly increase the risk(diabetes, previous transient ischaemic attack, neph-ropathies, etc.). Methods for optimizing the choice ofantihypertensive drugs for each individual patientneed to be improved, and research on the effective-ness of different methods of hypertensive manage-ment should be promoted in different countries andpopulations.

More data are clearly needed on the prognosticsignificance of blood pressure values obtained byambulatory blood-pressure monitoring or by self-measurements taken at home or at work. The quan-tification and the prognostic significance of "whitecoat" hypertension should be addressed.

Finally, developments in genetic research mayhelp to clarify further which hypertensive patientsare at particular risk of developing cardiovasculardisease and events, and indicate the subjects in great-est need of preventive therapy.

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guidelines for the management hypertension: memorandumfrom

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