Short Title: 1999 Guidelines for Management of Hypertension

Reference:  Chalmers J et al.  WHO-ISH Hypertension Guidelines Committee.  1999 World Health Organization - International Society of Hypertension Guidelines for the Management of Hypertension.  J Hypertens, 1999, 17:151-185.

1. Introduction

The present Guidelines come at a critically important time globally for the management of hypertension and the prevention of associated cardiovascular disorders. The second half of the twentieth century has seen a progressive decrease in cardiovascular mortality in North America, Western Europe, Japan and Australasia.1 At the same time, the control of hypertension in these regions has improved considerably. For example, the Health Examination Surveys in the USA have demonstrated that whereas 10% of hypertensive subjects had their blood pressure lowered to below 140/90 mmHg in 1976-80, by 1988-91 the proportion had risen to 27%.2 On the other hand it is important to note that this leaves over 70% of hypertensive subjects with imperfect control (or no treatment at all), as has been reported in many other countries,3 and that there are worrying signs that the rate of improvement has plateaued or even reversed in some cases. In the UK, a recent survey indicated that only 6% of hypertensive patients had their blood pressure lowered to below 140/90 mmHg.4 Additionally, in the USA there is recent evidence that age-adjusted stroke mortality rates have risen slightly and that the rate of decline of coronary heart disease (CHD) mortality has decreased. Moreover, given the ageing population structure of most developed countries, total numbers of strokes and CHD events are typically increasing or remaining static, even in those countries that continue to experience falling age-adjusted event rates.

Even more worrying is the rapid development of the "second wave" epidemic of cardiovascular disease that is now flowing through developing countries and the former socialist republics. It is evident that death and disability from CHD and cerebrovascular disease are increasing so rapidly in these parts of the world that they will rank No. 1 and No. 4 respectively as causes of the global burden of disease by the year 2020.5 Given the central role of elevated blood pressure in the pathogenesis of both CHD and stroke, it is clear that one of the biggest challenges facing public health authorities and medical practitioners is the control of hypertension worldwide, both in individual patients and at the population level.

1.1 Scope and purpose of Guidelines

The present Guidelines are written to guide specialist physicians responsible for the care of patients with high blood pressure. They are complemented by a companion set of "Practice Guidelines" for general practitioners and other clinicians caring for patients with hypertension in various regions around the world. The 1999 Guidelines again concentrate on the management of patients with "mild" hypertension, since there is often uncertainty among clinicians, and policy makers about how to manage this condition. Since the determinants of cardiovascular disease in hypertensive patients are substantially multifactorial, these Guidelines provide recommendations for risk reduction through blood pressure lowering, in a context that recognises the importance of strategies for the management of other risk factors that commonly affect individuals with hypertension.

It is well established that in Western populations, stroke, CHD and other common cardiovascular diseases, such as heart failure, have multiple determinants. The main established predictors of these diseases are described briefly in this section. How well these factors predict cardiovascular disease in non-Western populations is less certain, although recent evidence from Eastern Asian populations suggests that for blood pressure and blood cholesterol there may be similar associations in the East and West.7 There is very little direct evidence about the determinants of common cardiovascular diseases in other large populations such as those of sub-Saharan Africa, India or South America.

2.1 Effects of blood pressure on the risk of cardiovascular disease

2.1.1 Stroke

2.1.2 Coronary heart disease

Blood pressure levels have also been shown to be positively and continuously related to the risks of major CHD events (CHD death or non-fatal myocardial infarction).8 The strength of this association is about two-thirds as steep as that for stroke, and appears to be similar across a broad range of blood pressure levels, that includes both hypertensive and normotensive individuals. Once again, no lower level has been identified below which the risks do not continue to decline.

2.1.3 Heart failure and renal disease

The risks of heart failure and of renal disease have been observed to be related to blood pressure levels, but the sizes of the relationships are less well established than those for stroke and CHD. Nevertheless, there is evidence that patients with a history of hypertension have at least six times greater risk of heart failure than do individuals without such a history,10 and that each 5 mmHg lower level of DBP is associated with at least a one-quarter lower risk of end-stage renal disease.11

2.1.4 Recurrent cardiovascular events

Among individuals with a history of cerebrovascular disease or previous myocardial infarction, there have been reports of both linear12,13,14 and non-linear ("J-shaped")15,16 associations between blood pressure levels and the risks of recurrent events. However, the associations in patients with prior cardiovascular disease are subject to confounding as a consequence of the effects of disease (or its treatment) on blood pressure and, independently, on the risks of recurrence. Studies that have attempted to control for this (either by excluding patients with more severe disease or by excluding early recurrent events) have consistently demonstrated continuous positive associations between blood pressure levels and the longer-term risks of stroke and CHD recurrence. 12,13,14

2.1.5 Pulse pressure and arterial distensibility

There is evidence that pulse pressure (the difference between systolic and diastolic blood pressure) is also positively associated with a variety of cardiovascular diseases.17, 18 However, there remains uncertainty as to whether pulse pressure predicts disease risk independently of either systolic or diastolic blood pressure. Pulse pressure is one index of arterial distensibility. While there are theoretical reasons for expecting arterial distensibility to be independently predictive of cardiovascular disease risk19-22 there are still few data demonstrating such an association.

2.2 Effects of other risk factors on the risk of cardiovascular disease

2.2.1 Age

In most populations, the risks of cardiovascular disease rise steeply with increasing age. For example, among British men, from age 45 to 74, there is a 3-4 fold increase in deaths from stroke and from CHD each decade.23 This powerful effect of age on disease risk has important consequences for the effects of blood pressure and other risk factors on disease occurrence. Specifically, while the relative effects of some risk factors decline as age increases, the absolute effects of these risk factors typically increase with age because of the markedly higher background risk of cardiovascular disease in older people.

2.2.2 Gender

At most ages, the risks of cardiovascular diseases are greater in men than women, although this difference declines with increasing age and is greater for CHD than for stroke. For example, in the United States from age 34 to 74, the risks of death from stroke are 30% higher in men than women, whereas the risks of death from CHD are 2-3 fold greater in men.23 After age 75, the risks of death from stroke and from CHD death are similar in men and women.

2.2.3 Pre-existing cardiovascular disease

A history of clinically manifest cardiovascular disease is a particularly important predictor of the future risk of major cardiovascular events. Patients with congestive heart failure, typically experience death rates of 10% or more annually.24 Patients with a history of stroke or TIA, experience stroke risks of 3 to 5% or more annually,25 and the risk of other major cardiovascular events is at least an additional few percent. Among patients with a history of myocardial infarction or unstable angina, the annual incidence of recurrent infarction or CHD death is 4% or more26 and the risk of other major cardiovascular events is an additional one or two percent.

Subclinical manifestations of cardiovascular disease in asymptomatic patients can also be important predictors of future risk. For example, high rates of major clinical events (a few percent per year) occur among patients with significant left ventricular dysfunction,27 ECG evidence of Q waves,28 or ECG evidence of left ventricular hypertrophy.29 Ultrasonographic evidence of left ventricular hypertrophy30 or carotid atherosclerosis31,32 is also associated with increased risks of cardiovascular disease events.

2.2.4 Renal disease and microalbuminuria

Renal disease manifested by raised serum creatinine and proteinuria is an important predictor not only of renal failure but also of major cardiovascular events.33,34 While most types of renal disease are associated with increased risk, diabetic nephropathy appears to confer the greatest risks.35 Typically, the risk of CHD events in patients with end-stage renal disease (irrespective of aetiology) is at least as great as that in patients with a clinical history of CHD. Among diabetics without frank renal disease, microalbuminuria has been observed to be associated with a 2-3 fold increase in the risk of major cardiovascular events.36

2.2.5 Diabetes, hyperinsulinaemia and hyperglycaemia

2.2.6 Smoking

Cigarette smoking increases the risk of CHD and ischaemic stroke at all ages, but is of particular importance in younger people.41 In men under 65 years, smoking has been observed to increase the risk of cardiovascular death 2 fold, while in men aged 85 years or older, the risk was observed to be increased by 20%. In addition to these effects of smoking on cardiovascular diseases, smoking also increases the risks of a wide variety of non-cardiovascular diseases, in particular respiratory and neoplastic diseases.

2.2.7 Lipids and lipoproteins

Increasing levels of both total and LDL cholesterol are associated with increases in the risks of CHD.42 The relative risks appear to decline with increasing age, although the absolute risks typically increase. A 0.6 mmol/l (23.2 mg/dl) lower total cholesterol in men aged 40 years has been observed to be associated with a 54% lower CHD risk, whereas the same difference in cholesterol in men aged 70 years was associated with a 20% lower risk. The effect of HDL cholesterol on CHD risk does not appear to be age-dependent; every 0.03 mmol/l (1.2 mg/dl) increase in HDL cholesterol appears to be associated with at least a 3% reduction in the risk of CHD.43 It is still unclear whether there is any independent effect of triglyceride levels on the risk of cardiovascular disease.

2.2.8 Obesity

Increased body mass index (BMI: kg/m²) is associated with increased risks of CHD. Compared with lean men, men with BMI of 25-29 have been observed to have a 70% greater risk of CHD whereas men with BMI of 29-33 had almost a 3 fold greater risk of CHD.44 The strength of this association appears to decline with age. The risk associated with obesity is likely to be due in part to blood pressure elevation, but reduced HDL cholesterol and increased insulin and glucose may also be involved.45,46

2.2.9 Fibrinogen

Blood levels of fibrinogen are positively associated with the risk of CHD and ischaemic stroke. In several studies, individuals with fibrinogen in the highest tertile had risks of CHD that were about twice as great as those among individuals with fibrinogen in the lowest tertile.47,48

2.2.10 Alcohol

The risk of CHD appears to be reduced among regular consumers of alcohol (e.g. 1-3 standard drinks per day).49 In general, daily consumers of alcohol have a 30-40% lower risk of death from CHD than do non-drinkers.50 However, high levels of alcohol consumption can cause other cardiac disorders and are associated with increased risks of stroke51 (particularly after binge drinking), as well as higher blood pressure levels and higher risks of several non-vascular diseases and injury.

2.2.11 Physical activity

Regular aerobic exercise reduces the risk of CHD. Individuals performing about 20 minutes of light to moderate-intensity exercise daily have been observed to have about a 30% lower risk of death from CHD than do sedentary individuals.52 These benefits may be due in part to the blood pressure lowering effects of exercise, but other metabolic factors that may be activated by exercise, such as increased HDL cholesterol, may also be involved.53

2.2.12 Hormone replacement therapy

In studies of Western populations, the use of hormone replacement therapy (HRT) has been shown to be associated with 30-50% lower risks of CHD among post-menopausal women.54 Whether this association reflects a true protective effects of HRT or of the selection of low risk women for HRT is uncertain. The results of a recent trial of HRT in women with CHD failed to demonstrate any protective effect of HRT for recurrent CHD events.55

2.2.13 Socio-economic status

Socio-economic status – as judged from education, employment or income – is a powerful predictor of the risk of most common cardiovascular diseases. In many studies of a variety of mainly Western populations, lower levels of socio-economic status have been observed to be associated with higher risks of cardiovascular disease. The magnitudes of the associations vary between populations but in the US, individuals with income less than $18,500 in 1980 have been observed to have cardiovascular death rates that are 40% greater than in individuals with income greater than $32,000.56 These associations appear to be mediated, at least in part, by increased levels of most established risk factors, including smoking57 among those in lower socio-economic groups. How widely such associations exist outside Western populations is uncertain; however, there is evidence within some Western populations of heterogeneity of associations among different ethnic groups.58

2.2.14 Ethnicity

Ethnicity is also powerfully related to the risk of most common cardiovascular diseases. In many countries, ethnic minority groups – such as New Zealand Maori59 and United States Native Americans60 – have substantially higher risks of CHD than do the Caucasian majority. Moreover, there is evidence that African Americans are generally at greater risk of stroke,61 and of renal disease62 than are Caucasians from the US, and that South Asians in the UK63 but not Canada64 are at higher risk of these diseases and CHD than are Caucasians from the same countries. There is uncertainty as to how much of these ethnic differences in risk can be ascribed to differences in levels of the established risk factors for cardiovascular diseases.

2.2.15 Geographic region

There are major differences between geographic regions in the incidence of cardiovascular diseases. Some particularly important trends include the high rates of both CHD and stroke in Eastern Europe, Russia and the Baltic states,65,66 and the high rates of stroke and the low rates of CHD in the People's Republic of China,67 compared to Western Europe and North America. In some parts of Africa, there are high rates of stroke and renal disease, but low rates of CHD.5

2.2.16 Other risk factors

Many other factors – including passive smoking, blood type, LDL particle size, apolipoproteins, plasma renin activity, blood homocysteine levels, blood uric acid levels, several common genetic polymorphisms, several infective agents, and several psychological factors – have been reported to be independently associated with the risks of cardiovascular diseases. For most of these factors, the evidence of an association with cardiovascular disease is less strong than for most of the factors listed above.

3. Interventions to Reduce Cardiovascular Risk in Hypertensive patients

3.1 Effects of blood pressure lowering treatments on mortality and morbidity from cardiovascular disease

3.1.1 Trials of diuretic and beta-blocker based regimens

Previous randomised controlled trials of diuretic- or beta blocker-based regimens, involving a total of about 47,000 patients with hypertension, have collectively demonstrated that, over an average of about 5 years, such treatment produced much of the epidemiologically-expected benefit of the achieved blood pressure reductions.68-70 A net reduction of 5-6 mmHg in usual diastolic blood pressure was associated with a 38% (SD 4) reduction in stroke risk and a 16% (SD 4) reduction in CHD risk, with similar effects on fatal and non-fatal events. The proportional reductions in the risks of stroke and CHD in these trials appeared to be broadly similar in patients with mild, moderate or more severe hypertension, in older or younger patients, and in patients with or without a history of cerebrovascular disease.

3.1.2 Trials of other treatment regimens

There are fewer data available from which to determine the effects on cardiovascular disease risks of blood pressure lowering regimens based on the newer classes of agents in hypertensive patients, although the available evidence is increasing rapidly. Data on the effects of calcium antagonists on cardiovascular disease risks in patients with hypertension are available from one moderate-to-large scale randomised, placebo-controlled trial: in the Syst-Eur trial, nitrendipine-based therapy produced an approximate 10/5 mmHg reduction in blood pressure in patients with systolic hypertension and a 42% reduction in the risk of stroke.79 Similar results were observed in two large, non-randomised, placebo-controlled trials (with alternate treatment assignment): the STONE Study80,81 and the Syst-China trial. 80,81 Collectively, these studies provide evidence that calcium antagonists reduce the risk of stroke, and that the magnitude of this effect appears to be similar to that seen in trials of diuretic- or beta-blocker-based therapy. However, there were few CHD events recorded in these trials and, as a consequence, it is not possible to assess reliably the effects of calcium antagonists on the risk of CHD in these trials. More evidence about the effects of calcium antagonists on CHD events is provided by trials of these agents in patients with a history of myocardial infarction (see 6.4).

To date, only one large-scale trial has provided evidence about the effects of ACE inhibitor-based therapy in patients with uncomplicated hypertension. The Captopril Primary Prevention Project (CAPPP) compared the effects of a captopril-based regimen with other therapy (principally diuretic- or beta-blocker-based regimens) among 10,985 patients with hypertension.82 However, imbalances in the assignment of treatment resulted in a 2 mmHg higher average diastolic blood pressure level at entry in the group assigned captopril-based therapy. This difference in blood pressure alone would be sufficient to confer an increase of 20% in the risk of stroke and an increase in the risk of CHD of 10% among individuals of middle age, such as those included in this study. Hence the imbalance in blood pressure levels could mask real differences that may exist between the regimens in their effects on CHD, and could explain the greater risk of stroke observed among patients assigned the captopril-based therapy. The CAPPP study also reported a reduced risk of diabetes among patients assigned captopril-based therapy, a result that appears less likely to be explained by the observed imbalances at baseline. Additional evidence about the effects of ACE inhibitors on CHD risk is provided by trials in patients with left ventricular dysfunction or heart failure (see 6.4).

Two small studies have reported fewer CHD events among diabetic hypertensive patients randomised to ACE inhibitor-based versus calcium antagonist-based regimens.68,69 However, each of these studies recorded only a small number of CHD events, and, as a consequence, the apparent difference in the effects of these agents requires verification in larger studies. The UK Prospective Diabetes Study (UKPDS 39) involved 1148 hypertensive patients with Type 2 diabetes, and over a median follow-up period of 8 years, there were similar benefits of ACE inhibitor- and beta-blocker-based therapy for a variety of both macrovascular and microvascular disease outcomes83 (see 3.1.3 below). Additional evidence about the effects of ACE inhibitors in patients with diabetes is provided by trials of these agents in patients with renal disease (see 6.5).

At present, no reliable evidence is available from randomised controlled trials about the effects on cardiovascular disease risk of alpha-adrenergic blockers or angiotensin II antagonists. However, large-scale trials involving both these drug types are ongoing.

3.1.3 Trials of different blood pressure targets

The Hypertension Optimal Treatment (HOT) trial used a calcium antagonist (felodipine) -based regimen (with the stepped addition of ACE inhibitors, beta-blockers and diuretics) to investigate the effects of lowering blood pressure to three different targets (£ 80 mmHg, £ 85 mmHg and £ 90 mmHg) in 18,790 hypertensive patients.84 By the end of follow-up, blood pressure had been substantially reduced in all three groups but there were only modest differences in systolic and diastolic blood pressure (about 2 mmHg) between adjacent target groups. These blood pressure differences were less than expected, and the study was not able to determine reliably the most plausible effect of such modest blood pressure differences. There was a non-significant trend towards lower cardiovascular event risk and a marginally significant trend towards fewer CHD events in the group with the lowest target. In the subgroup with diabetes, the trend for total cardiovascular events reached statistical significance. This is consistent with evidence from the UK Prospective Diabetes Study (UKPDS 38), demonstrating that a lower blood pressure target (using either ACE inhibitor- or beta-blocker-based therapy) was associated with reduced risks of major macrovascular events as well as microvascular disease outcomes.85 In that study. the "tight' blood pressure control group achieved average blood pressures of 144/82 mmHg whereas the less tight control group achieved blood pressures of 154/87 mmHg. This 10/5 mmHg reduction in blood pressure was associated with a one-third reduction diabetic deaths, almost a halving of stroke risk, and a one third reduction in microvascular complications.

3.2 Effects of blood pressure lowering treatments on other major disease outcomes

The trials of diuretic- and beta-blocker-based therapy in patients with hypertension provide evidence of almost identical rates of death from non-cardiovascular causes in patients assigned active treatment or control.68-70 The results of these trials therefore suggest that treatment with these agents is not only effective for cardiovascular disease prevention, but is also safe in terms of the overall risk of death from non-cardiovascular causes during the 5 years of treatment and follow-up in these trials. For the newer agents, there is less evidence from trials in hypertensive patients about the effects of treatment on non-cardiovascular outcomes. However, data from all trials in patients with either hypertension or CHD provide no clear evidence of any excess mortality from non-cardiovascular causes among patients assigned treatment with either ACE inhibitors or calcium antagonists. While there has been debate about possible adverse effects of calcium antagonists on cancer and bleeding risks86 and beneficial effects of ACE inhibitors on cancer risk,87 these observations have been generated primarily by results from a few, potentially biased non-randomised studies. Detailed review of the available evidence from observational studies and randomised trials did not provide clear evidence of an adverse effect of calcium antagonists on the risk of cancer or of bleeding.86 Recent data from the Syst-Eur trial suggest that a calcium antagonist-based blood pressure lowering regimen may reduce the risks of dementia in elderly patients with systolic hypertension.88

3.3 Effectiveness of hypertension management as provided in community practice

3.3.1 Control of blood pressure

A number of studies have investigated the effectiveness of antihypertensive therapy for the control of hypertension in representative population samples.3,4,89 The results of these studies indicate that in most populations studied, a moderate proportion of all hypertensive patients are untreated and a large proportion of treated hypertensive patients still have frankly elevated blood pressure, defined most frequently as SBP>160 mmHg or DBP>95 mmHg. On average, about half of all treated patients in these studies had continuing blood pressure elevation above 160/95 mmHg and three-quarters had blood pressure levels above 140/90 mmHg, although there was wide regional variation. Several studies have reported changes in blood pressure control over time, and these have generally shown trends towards improved control. Male gender and residence in a developing country have been identified as factors associated with poorer blood pressure control.90 The observations in China90 and several other developing countries that only about 10% of treated hypertensive patients reached blood pressures below about 160/95 mmHg are particularly important in this regard. However, very low rates of blood pressure control have also been observed in some studies of Western populations.4

3.3.2 Control of cardiovascular risk

Despite the benefits of blood pressure-lowering treatment established in randomised controlled trials, several population studies have demonstrated that treated hypertensive patients continue to experience substantially higher risks of CHD, stroke and overall mortality than do non-hypertensive individuals some years after beginning antihypertensive drug therapy.34,91 These observations are consistent with other findings indicating more advanced atherosclerosis and more marked left ventricular hypertrophy among treated hypertensive patients compared with non-hypertensive controls.30 The reasons for this persisting risk of cardiovascular complications are uncertain but are likely to involve both modifiable and non-modifiable factors. Non-modifiable factors may include a more frequent history of prior cardiovascular disease, diabetes or a genetic predisposition to cardiovascular complications. Potentially modifiable factors could include blood pressure levels that remain in the upper part of the population distribution and metabolic abnormalities, such as reduced levels of HDL cholesterol and increased levels of LDL cholesterol, insulin and glucose.92 Each of these modifiable factors is associated with obesity, which is also more frequent in treated hypertensive patients than non-hypertensive individuals.

3.4 Effects of modification of other risk factors on mortality and morbidity from cardiovascular disease

3.4.1 Smoking cessation

Smoking cessation confers reduced risks of a large number of diseases including stroke and CHD.41 In particular, there are large reductions in risk among those who quit in middle age or younger. Those who quit before 35 years or middle age typically have a life expectancy that is not different to that of lifelong non-smokers.

3.4.2 Cholesterol lowering

A large body of evidence has demonstrated that cholesterol lowering reduces the risks of CHD events in patients with high cholesterol levels or a history of CHD.42 Dietary restriction of saturated fats can produce modest reductions in cholesterol93 and the newer drug therapies reliably produce large reductions.94 The size of the reduction in CHD risk appears to be proportional to the size of the cholesterol reduction achieved, such that reductions of about 1-1.5 mmol/l (40-60 mg/dl) produced by HMG CoA reductase inhibitors reduce the risk of major CHD events by between a fifth and a third.26,94-97 The effects of these agents on fatal and non-fatal CHD events appear to be of similar magnitude. Reductions in stroke risk have also been observed in the trials of HMG CoA reductase inhibitors, but not in the trials of other cholesterol lowering agents. In the few trials that provided data on cerebral infarction, there was some evidence of reduction in the risk of this stroke subtype.

3.4.3 Treatment of diabetes

There has been uncertainty as to whether blood glucose control in diabetic patients alters the risks of macrovascular disease. The results of the UK Prospective Diabetes Study (UKPDS 33) among 3867 patients with newly diagnosed Type 2 diabetes indicated that therapy with insulin or sulphonylureas over 10 years produced a one-quarter reduction in microvascular disease events, but no clear reduction in macrovascular disease events, although there was a trend towards fewer CHD events in the intensive blood glucose control group.98 Similar results were achieved with metformin therapy in a separate trial by the same group in overweight patients with Type 2 diabetes (UKPDS 34).99 The UKPDS results indicate that blood pressure lowering therapy offers more definite reductions in macrovascular disease for diabetic patients than do interventions for blood glucose control.85

3.4.4 Antiplatelet therapy

For patients with a history of CHD or cerebrovascular disease, there is strong evidence that long-term therapy with aspirin and some other antiplatelet agents reduces the risks of fatal and non-fatal coronary events, stroke and cardiovascular death.100 For patients without a history of cardiovascular disease, there is evidence of reduced risks of CHD but no clear evidence of reduced risks of stroke or of total cardiovascular death.100 The HOT Study investigated the effects of 75 mg aspirin daily on cardiovascular events in patients with hypertension, and demonstrated a one third reduction in the risk of CHD events, but no clear reduction in either ischaemic stroke or cardiovascular death.84 In this study and others, aspirin was shown to increase non-cerebral bleeding risks about two-fold. There was no detectable increase in the risk of cerebral haemorrhage in the HOT Study.

3.4.5 Other factors

The effects of modifying other factors that are known to determine cardiovascular disease risk are less certain. The evidence cited above (see 2.0) suggests the potential for modification of weight, exercise, alcohol intake, plasma fibrinogen to alter cardiovascular disease risks, but this has not yet been demonstrated in intervention studies. There has also been much recent interest in the possible effects of antioxidant vitamins such as vitamins E and C on the risks of CHD and stroke. While there is a rationale for believing that increased dietary intakes of these vitamins may confer worthwhile benefits and little risk, there is presently little direct evidence to support this.101 Several ongoing trials of vitamin supplements should provide reliable evidence about the effects of such interventions on a range of outcomes within the next few years.

4. Clinical Evaluation

The clinical and laboratory evaluation of the hypertensive patient should be conducted with four aims in mind:-

to confirm a chronic elevation of blood pressure and determine its level.

to exclude or identify secondary causes of hypertension.

to determine the presence of target organ damage and to quantify its extent.

to search for other cardiovascular risk factors and clinical conditions that may influence prognosis and treatment.

4.1 Clinical history

A comprehensive clinical history is essential and should include: -

family history of hypertension, diabetes, dyslipidaemia, CHD, stroke, or renal disease.

duration and previous levels of high blood pressure, and results and side effects of previous antihypertensive therapy.

past history or current symptoms of CHD and heart failure, cerebrovascular disease, peripheral vascular disease, diabetes, gout, dyslipidaemia, bronchospasm, sexual dysfunction, renal disease, other significant illnesses, and information on the drugs used to treat those conditions.

symptoms suggestive of secondary causes of hypertension.

careful assessment of lifestyle factors including dietary intake of fat, sodium and alcohol, quantitation of smoking and physical activity, and enquiry of weight gain since early adult life as a useful index of excess body fat.

detailed enquiry of intake of drugs or substances that can raise blood pressure, including oral contraceptives, non-steroidal anti-flammatory drugs, liquorice, cocaine and amphetamines. Attention should be paid to the use of erythropoietin, cyclosporins or steroids for concomitant disorders.

• personal, psychosocial and environmental factors that could influence the course and outcome of antihypertensive care including family situation, work environment, and educational background.

4.2 Physical examination

A full physical examination is essential and will include careful measurement of blood pressure as described below. Other important elements of the physical examination include:-

measurement of height and weight, and calculation of Body Mass Index (weight in kilograms divided by height in meters, squared).

examination of the cardiovascular system particularly for heart size, for evidence of heart failure, for evidence of arterial disease in the carotid, renal and peripheral arteries, and for coarctations of the aorta.

examination of the lungs for rales and bronchospasm and of the abdomen for bruits, enlarged kidneys, and other masses.

examination of the optic fundi and of the nervous system for evidence of cerebrovascular damage.

4.3 Blood pressure measurement

Because blood pressure is characterised by large spontaneous variations,102 the diagnosis of hypertension should be based on multiple blood pressure measurements, taken on several separate occasions.

4.3.1 Office or clinic blood pressure measurement

Blood pressure should be measured as described in standard textbooks,103,104 with the patient in a sitting position using a mercury sphygmomanometer or other non-invasive device. The accuracy of non-mercury devices should be ensured by comparison with values simultaneously obtained from a mercury sphygmomanometer. Since the medical use of mercury is likely to be progressively restricted around the world, the calibration and accuracy of non-mercury devices will become increasingly important.

When measuring blood pressure, particular care should be taken to:-

allow the patient to sit for several minutes in a quiet room before beginning blood pressure measurement.

use a standard cuff with a bladder that is 12-13 cm x 35 cm, with a larger bladder for fat arms and a smaller bladder for children.

use phase 5 Korotkoff sounds (disappearance) to measure the diastolic pressure.

measure the blood pressure in both arms first visit if there is evidence of peripheral vascular disease.

measure the blood pressure in standing position in elderly subjects, diabetic patients and in other conditions in which orthostatic hypotension is common.

place the sphygmomanometer cuff at heart level, whatever the position of the patient.

4.3.2 Home and ambulatory blood pressure measurement

Non-invasive semi-automatic and automatic devices are now available for blood pressure measurement at home and for ambulatory blood pressure monitoring over periods of 24 hours or more. Both of these approaches provide useful additional clinical information and have a place in the management of the hypertensive patient, but in both cases there are three important limitations:-

first, there is limited data available about the prognostic value of both home105 and ambulatory blood pressure measurements.106 Further prospective studies are required to determine whether such measurements offer material advantages over conventional blood pressure measurements for the prediction of morbidity and mortality. Therefore information obtained from these methods must be regarded as supplementary to conventional measurements, not as a substitute;

second, studies conducted in general populations and in hypertensive individuals have demonstrated that blood pressure values obtained by home measurements or by ambulatory monitoring are several mmHg lower than those obtained by office measurements with 24 hour average or home blood pressure values of around 125/80 mHg corresponding to clinic pressures of 140/90 mmHg; 107

third, the devices used should be checked for accuracy and performance over time against other well-validated blood pressure measurement devices using standardised protocols. Currently available home devices that measure the pressure in the fingers or the arm below the elbow should be avoided.

4.4 Laboratory investigations

In all regions of the world, routine investigations should include urinalysis for blood, protein and glucose, and microscopic examination of urine. Blood chemistry should include measurements of potassium, creatinine, fasting glucose, and total cholesterol. An electrocardiogram should also be performed. In some regions of the world this list of routine investigations is frequently expanded to include some of the optional investigations listed below.

Optional investigations will be guided by the findings from the history, examination and routine investigations. Such investigations should be conducted if the results are likely to have important implications for the management of the individual patient in question. These tests may include measurement of high density lipoprotein cholesterol, low density lipoprotein cholesterol and triglycerides, of uric acid, and of hormone assays such as plasma renin activity, plasma aldosterone and urinary catecholamines. Echocardiography should be performed whenever the clinical assessment reveals the presence of target organ damage or suggests the possibility of left ventricular hypertrophy or of other cardiac disease, since increased left ventricular mass is associated with increased cardiovascular risk and this information should be helpful in deciding whether to institute drug treatment. Similarly, vascular ultrasonography should be performed whenever the presence of arterial disease is suspected in the aorta, carotid or peripheral arteries. Assessment of arterial distensibility might also be considered in some patients although the complexity of the techniques involved, the lack of standardisation of procedures, and uncertainty about its place in management, makes it largely a research tool. Renal ultrasonography should be performed if renal disease is suspected. The cost of investigations should be considered in the context of the needs of the individual patient and the availability of resources in the particular health system or region.

4.5 Definition and classification of hypertension

The continuous relationship between the level of blood pressure and the risk of cardiovascular events, and the arbitrary nature of the definition of hypertension have contributed to the variation in the definitions issued by various national and international authorities and particularly by the Joint National Committee in the USA121,122 and the WHO-ISH Guidelines Committee.123 Accordingly, in order to reduce confusion and provide more consistent advice to clinicians around the world, the WHO-ISH Guidelines Committee has agreed to adopt in principle the definition and classification provided in JNC VI. This new definition defines the lower limits of hypertension as 140 mmHg systolic and 90 mmHg diastolic, the same as the lower limits for the "borderline sub group" of mild hypertension in the 1993 WHO-ISH Guidelines.123 The new Guidelines emphasise that the decision to lower the elevated pressure in a particular patient is not based on the level of blood pressure alone but on assessment of the total cardiovascular risk in that individual.

Hypertension is therefore defined as a systolic blood pressure of 140 mmHg or greater and/or a diastolic blood pressure of 90 mmHg or greater in subjects who are not taking antihypertensive medication. A classification of blood pressure levels in adults over the age of 18 is provided in Table 3. The terms "Grade" 1, 2 and 3 have been chosen rather than the terms "Stage" 1, 2 and 3 used by JNC VI, since the word "stage" implies progression over time in a way that does not necessarily apply here.124 Otherwise, the values chosen and the terms used are those used in JNC VI. The terms "mild", "moderate" and "severe" used in previous versions of the WHO-ISH Guidelines, would correspond to Grades 1, 2 and 3, respectively. The widely used term "borderline hypertension", becomes a subgroup within Grade 1 hypertension. It must be emphasised that the term "mild hypertension" does not imply a uniformly benign prognosis, but is used simply to contrast with more severe elevations of blood pressure.

4.6 Stratification of patients by absolute level of cardiovascular risk

Decisions about the management of patients with hypertension should not be based on the level of blood pressure alone, but also on the presence of other risk factors, concomitant diseases such as diabetes, target organ damage, and cardiovascular or renal disease, as well as other aspects of the patient's personal, medical and social situation. To assist with this, these guidelines provide a simple method by which to estimate the combined effect of several risk factors and conditions on the future absolute risk of major cardiovascular events. The estimates are based on age, gender, smoking, diabetes, cholesterol, history of premature cardiovascular disease, the presence of target organ damage, and history of cardiovascular or renal disease. They were calculated from data on the average 10 year risk of cardiovascular death, non-fatal stroke or non-fatal myocardial infarction among participants (average initial age of 60 years; range 45-80 years) in the Framingham Study.

Four categories of absolute cardiovascular disease risk are defined (low, medium, high and very high risk). Each category represents a range of absolute disease risks. Within each range, the risk of any one individual will be determined by the severity and number of risk factors present. So, for example, individuals with very high levels of cholesterol or a family history of premature cardiovascular disease in several first-degree relatives will typically have absolute risk levels that are at the higher end of the range provided. Similarly, individuals with other risk factors listed in Table 2 may also have absolute risk levels that are towards the higher end of the range for the category.

How well these estimates predict the absolute risk of cardiovascular disease in Asian, African or other non-Western populations is uncertain. In those countries in which CHD incidence is relatively low and heart failure or renal disease is more common, the risk factors used to stratify risk in Table 3 should also be useful in stratifying the risk of these diseases.

4.6.1 Low risk group

The low risk group includes men below 55 and women below 65 years of age with Grade 1 hypertension and no other risk factors. Among individuals in this category, the risk of a major cardiovascular event in the next ten years is typically less than 15%. The risk will be particularly low in patients with borderline hypertension.

4.6.2 Medium risk group

This group includes patients with a wide range of blood pressures and risk factors for cardiovascular disease. Some have lower blood pressures and multiple risk factors, whereas others have higher blood pressures and no or few other risk factors. This is the patient group for which the clinical judgement of the responsible doctor will be paramount in determining the need for drug treatment and the time interval before it should be instituted. Among subjects in this group, the risk of a major cardiovascular event over the next ten years is typically about 15-20%. The risk will be closer to 15% in those patients with Grade 1 (mild) hypertension and only one additional risk factor.

4.6.3 High risk group

This group includes patients with Grade 1 or Grade 2 hypertension who have three or more risk factors listed in Table 2, diabetes or target organ damage and patients with Grade 3 ("severe") hypertension without other risk factors. Among these patients the risk of a major cardiovascular event in the following ten years is typically about 20-30%.

4.6.4 Very high risk group

 

Risk Factors For Cardiovascular Diseases I. Used for risk stratification   Levels of systolic and diastolic blood pressure (Grades 1-3)  Men >55 years  Women >65 years  Smoking  Total cholesterol >6.5 mmo/l (250 mg/dl)  Diabetes  Family history of premature cardiovascular disease  II. Other factors adversely influencing prognosis   Reduced HDL cholesterol  Raised LDL cholesterol  Microalbuminuria in diabetes  Impaired glucose tolerance  Obesity  Sedentary lifestyle  Raised fibrinogen  High risk socioeconomic group  High risk ethnic group  High risk geographic region

Target Organ Damage1 Left ventricular hypertrophy (electrocardiogram, echocardiogram or radiogram)  Proteinuria and/or slight elevation of plasma creatinine concentration (1.2 - 2.0 mg/dl)  Ultrasound or radiological evidence of atherosclerotic plaque (carotid, iliac and femoral arteries, aorta)  Generalised or focal narrowing of the retinal arteries

Associated Clinical Conditions2 Cerebrovascular disease   ischaemic stroke  cerebral haemorrhage  transient ischaemic attack  Heart disease   myocardial infarction  angina  coronary revascularisation  congestive heart failure  Renal disease   diabetic nephropathy  renal failure (plasma creatinine concentration >2.0 mg/dl)  Vascular disease   dissecting aneurysm  symptomatic arterial disease  Advanced hypertensive retinopathy   haemorrhages or exudates  papilloedema

 

	BLOOD PRESSURE (mmHg)
Other Risk Factors & Disease History	Grade 1 (mild hypertension) SBP 140-159 or  DBP 90-99	Grade 2 (moderate hypertension) SBP 160-179 or  DBP 100-109	Grade 3 (severe hypertension) SBP ³ 180 or  DBP ³ 110
I.. no other risk factors	LOW RISK	MED RISK	HIGH RISK
II. 1-2 risk factors	MED RISK	MED RISK	V HIGH RISK
III. 3 or more risk factors or TOD1 or diabetes	HIGH RISK	HIGH RISK	V HIGH RISK
IV. ACC2	V HIGH RISK	V HIGH RISK	V HIGH RISK

Risk strata (typical 10 year risk of stroke or myocardial infarction): Low risk = less than 15%; medium risk = about 15-20% risk;
high risk = about 20-30%; very high risk = 30% or more
1. TOD – Target Organ Damage (Table 2)
2. ACC – Associated Clinical Conditions, including clinical cardiovascular disease or renal disease (Table 2)

5. Treatment

5.1 Goals of treatment

The primary goal of treatment of the patient with high blood pressure is to achieve the maximum reduction in the total risk of cardiovascular morbidity and mortality. This requires treatment of all the reversible risk factors identified, such as smoking, raised cholesterol or diabetes and the appropriate management of associated clinical conditions, as well as treatment of the raised blood pressure per se. The intensity with which the clinician treats these risk factors will plainly increase with the number and severity of risk factors, with the existence of associated clinical conditions, and with increasing absolute risks of major cardiovascular events, as indicated in Table 3.

Since the relationship between cardiovascular risk and blood pressure is continuous, without a lower threshold, the goal of antihypertensive therapy should be to restore blood pressure to levels defined as "normal;" or optimal" (Table 1). Indeed there is evidence that a major determinant of the risk reduction conferred by antihypertensive therapy is the level of blood pressure achieved.91,125 Comparison of outcomes between the three randomised blood pressure target groups in the HOT Study (diastolic pressure <90, 85, or 80 mmHg) were unable to detect significant differences in the risk of cardiovascular disease between adjacent target groups.84 However, the results of that study confirm that there is no increase in cardiovascular risk in the patients randomised to the lowest target group (diastolic pressure <80 mmHg). Among diabetic patients in the HOT Study, there were significantly lower risks of cardiovascular disease in those patients assigned to the lowest blood pressure target. Similarly, the results of the UK Prospective Diabetes Study85 demonstrated that tight blood pressure control (with an average achieved blood pressure of 144/82 mmHg) conferred a substantial reduction in the risk of major cardiovascular events compared to less tight blood pressure control (with an average achieved blood pressure of 154/87 mmHg). It would seem desirable to achieve optimal or normal blood pressures in young, middle aged or diabetic subjects (below 130/85 mmHg; Table 1) and at least high normal blood pressures in elderly patients (below 140/90 mmHg; Table 1).

Stratification of patients in terms of their total cardiovascular risk (Table 3) is not only useful for determining the threshold for initiating antihypertensive drug treatment, it is also useful for setting the goal blood pressure that should be achieved and the intensity with which this goal should be pursued. Plainly, the higher the risk, the more important it becomes to reach the goal blood pressure that is set, and to treat the other risk factors that have been identified.

When home or ambulatory blood pressure measurements are used to evaluate the efficacy of treatment, it must be remembered that day time values provided by these methods (compared with office measurements) are on average around 10-15 mmHg lower for systolic blood pressure and 5-10 mmHg lower for diastolic blood pressure. Treatment goals should therefore be modified appropriately when these methods are used.

5.2 Management strategy

Having assessed the patient and determined the overall risk profile, including the level of blood pressure elevation, the responsible physician should determine whether the patient is at low, medium, high or very high risk of cardiovascular disease events, as shown in Table 3. This will help the physician, in consultation with the patient, to determine whether to:-

institute immediate drug treatment for the hypertension and the other risk factors or conditions present (high and very high risk groups).

monitor blood pressure and other risk factors for several weeks and obtain further information before deciding whether to institute drug treatment (medium risk group).

observe the patient over a significant period of time before deciding whether to institute drug treatment (low risk).

Having decided on the broad strategy for management, the physician should then determine the specific therapeutic goals for the individual patient, and draw up a comprehensive therapeutic plan to lower the blood pressure and reduce the overall cardiovascular risk in order to attain these goals. This plan will include consideration of:-

monitoring - of blood pressure and other risk factors.

lifestyle measures - to lower the blood pressure and control the other risk factors.

drug treatment - to lower blood pressure and to control the other risk factors and clinical conditions present.

5.3 Lifestyle measures

While there is no direct randomised evidence demonstrating that reducing blood pressure through lifestyle measures reduces the risk of cardiovascular disease, this seems likely given all the other evidence suggesting that the benefits of antihypertensive treatment are determined primarily by the blood pressure reduction per se rather than by any other independent effect of particular treatment modalities.

Lifestyle measures (or non-pharmacological treatments) are used for a number of complementary reasons as outlined in the WHO Technical Report on Hypertension Control:6

to lower the blood pressure in the individual patient.

to reduce the need for antihypertensive drugs and maximise their efficacy.

to address the other risk factors present.

for primary prevention of hypertension and associated cardiovascular disorders in populations.

5.3.1 Smoking cessation

Smoking cessation is perhaps the single most powerful lifestyle measure for the prevention of both cardiovascular and non-cardiovascular diseases in hypertensive patients. All hypertensive patients who smoke should receive appropriate counselling for smoking cessation. Nicotine replacement therapy should also be considered, since it appears to augment other interventions for smoking cessation.126

5.3.2 Weight reduction

Excess body fat contributes to blood pressure levels from infancy and is the most important factor predisposing to hypertension.127 Weight reduction of as little as 5 kg reduces blood pressure in a large proportion of hypertensive individuals who are more than 10% overweight and also has a beneficial effect on associated risk factors such as insulin resistance, diabetes, hyperlipidaemia and left ventricular hypertrophy. The blood pressure lowering effects of weight reduction may be enhanced by simultaneous increase in physical exercise,128 by alcohol moderation in overweight drinkers,129 and by reduction of sodium intake in older hypertensive subjects (TONE Study).130 Weight loss of at least 5 kg should be recommended in the first instance, with further increments of 5 kg depending upon the response and the patients' weight.

5.3.3 Moderation of alcohol consumption

Notwithstanding the evidence that an alcohol intake of up to 3 "standard" drinks a day may lower the risk of CHD,131 there is a linear relationship between alcohol consumption, blood pressure levels, and the prevalence of hypertension in populations. Alcohol attenuates the effects of antihypertensive drug therapy but its pressor effect is, at least partially, reversible within 1-2 weeks by moderation of drinking by around 80%.132 Heavier drinkers (5 or more standard drinks a day) may experience a rise in blood pressure after acute alcohol withdrawal and be more likely to be diagnosed as hypertensive at the beginning of the week if they have a weekend drinking pattern. Accordingly, hypertensive patients who drink alcohol should be advised to limit their consumption to no more than 20-30 gm of ethanol per day for men, and no more than 10-20 gm of ethanol per day for women. They should be warned against the heightened risks of stroke associated with binge drinking.

5.3.4 Reduction in salt intake

Epidemiologic studies suggest that dietary salt intake is a contributor to blood pressure elevation and to the prevalence of hypertension.133 The effect appears to be enhanced by a low dietary intake of potassium containing foods. Randomised controlled trials in hypertensive patients indicate that reducing sodium intake by 80-100 mmol (4.7-5.8 gm) per day from an initial intake of around 180 mmol (10.5 gm) per day will reduce blood pressure by an average of around 4-6 mmHg systolic.134 However, individuals vary considerably in their responses to changes in dietary salt, with black, obese and elderly subjects the most sensitive. A recent study in older hypertensive patients showed no adverse effects of a reduction in sodium of 40 mmol (2.3 gm) per day and after 18 months there was a significant reduction in the need for antihypertensive drug therapy.130 The aim of dietary sodium reduction should be to achieve an intake of less than 100 mmol (5.8 gm) per day of sodium or less than 6 gm per day of sodium chloride. Patients should be advised to avoid added salt, to avoid obviously salted foods, particularly processed foods, and to eat more meals cooked directly from natural ingredients. Counselling by trained dieticians and monitoring of urinary sodium are necessary in most cases. The high sodium – low potassium content of many preserved foods is drawn to the attention of the food industry.

5.3.5 Complex dietary changes

Vegetarians have lower blood pressure than meat eaters135 and vegetarian dietary patterns can lower blood pressure in hypertensive patients.136 A series of controlled dietary trials indicate that these effects depend on a combination of effects of fruit, vegetables, fibre and low saturated fat intake rather than the presence or absence of meat protein. This conclusion has been confirmed in a recent study in which older subjects with mild or borderline hypertension were randomised for eight week periods to continue their normal diet, to increase fruit and vegetable consumption alone, or to also reduce their consumption of total and saturated fat.137 Increasing fruit and vegetable consumption alone caused blood pressures to fall by 3/1 mmHg while the added measure of reducing fat intake led to a fall of 6/3 mmHg. In the patients with higher initial blood pressures, there was a fall of 11/6 mmHg with the combined dietary regime. The presence of higher intakes of calcium, magnesium or potassium may have contributed to the beneficial effects of some of these diets. Regular fish consumption as part of a weight reducing diet may enhance blood pressure reduction in obese hypertensive patients and yield additional benefits on lipid profiles.138 Hypertensive patients should be advised to eat more fruit and vegetables, to eat more fish and to reduce their fat intake.

5.3.6 Increased physical activity

Sedentary patients should be advised to take up modest levels of aerobic exercise on a regular basis, such as a brisk walk or a swim for 30-45 minutes, 3-4 times a week.139 Such mild exercise may be more effective in lowering the blood pressure than more strenuous forms of exercise such as running or jogging, and may lower the systolic pressure by about 4-8 mmHg.140-142 Isometric exercise e.g. heavy weight lifting can have a pressor effect and should be avoided.

5.3.7 Psychological factors and stress

Psychological factors, personality factors and stress are associated with the adoption of many less healthy lifestyle patterns associated with hypertension and increased risk of cardiovascular disease.143,144 In this sense, helping individuals to cope with stress may have an important impact on their blood pressure and on compliance with antihypertensive medications.145,146 Whether there are more direct effects of sustained stress on long-term blood pressure levels is a subject requiring ongoing research. To date, trials of various stress management procedures for blood pressure control have been unconvincing.

5.3.8 Other measures

Lifestyle measures are fundamental for the management of diabetes and the treatment of hyperlipidaemia, and appropriate measures should be instituted when these disorders are present in the hypertensive patient. These will generally include a diet low in saturated fat and rich in vegetables and fruit.

Interventions with limited or unproven efficacy in lowering blood pressure include bio-feedback, micronutrient alterations and dietary supplementation with calcium, magnesium, and fibre.

5.4 Drug treatment for lowering blood pressure

5.4.1 Principles of drug treatment

There is general agreement on the principles governing the use of antihypertensive drugs to lower blood pressure, independent of the choice of particular drugs. These principles include:-

the use of low doses of drugs to initiate therapy, beginning with the lowest available dose of the particular agent, in an effort to reduce adverse effects. If there is a good response to a low dose of a single drug but the pressure is still short of adequate control, it is reasonable to increase the dose of the same drug, provided that it has been well tolerated.

the use of appropriate drug combinations (see Box 11) to maximise hypotensive efficacy while minimising side effects. It is often preferable to add a small dose of a second drug rather than increasing the dose of the original drug. This allows both the first and second drugs to be used in the low dose range that is more likely to be free of side effects. In this context, the use of the fixed low dose combinations that are increasingly available in the USA and Europe, may be advantageous.122

changing to a different drug class altogether if there is very little response or poor tolerability to the first drug used, before increasing the dose of the first drug or adding a second drug.

the use of long-acting drugs providing 24-hour efficacy on a once daily basis. The advantages of such drugs include improvement in adherence to therapy and minimisation of blood pressure variability, as a consequence of smoother, more consistent blood pressure control. This may provide greater protection against the risk of major cardiovascular events and the development of target organ damage.147,148