World Health Organization
1999 World Health Organization-International Society of Hypertension Guidelines for the Management of Hypertension
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.
The present Guidelines were prepared by the Guidelines Sub-Committee of the World Health Organization-International Society of Hypertension (WHO-ISH) Mild Hypertension Liaison Committee, the members of which are listed at the end of the text. These guidelines represent the fourth revision of the WHO-ISH Guidelines and were finalised after presentation and discussion at the 7th WHO-ISH Meeting on Hypertension, Fukuoka, Japan, 29th Sept 1st Oct, 1998. Previous versions of the Guidelines were published in Bull WHO 1993,71:503-517 and J Hypertens 1993,11:905-918.
Table of Contents
5.3.1 Smoking cessation
8.1 Blood pressure and cardiovascular disease in
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.
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.
The Guidelines do not deal with the management of more severe hypertension except in the most general terms, nor with the management of patients with secondary forms of hypertension. Furthermore, these Guidelines do not deal with the primary prevention and control of hypertension at the population level. These strategies, which are dealt with elsewhere,6 are complementary to the clinical strategy that is the subject of this Report.
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.
Blood pressure levels, both systolic and diastolic, have been shown to be positively and continuously related to the risk of stroke across a wide range of levels in populations from both Western and Eastern hemispheres.7,8 Among individuals of mostly middle age, a prolonged 5 mmHg lower level of usual diastolic blood pressure (DBP) was shown to be associated with a 35-40% lower risk of stroke, with no lower level identified below which the risks of stroke did not continue to decline. The slope of the association appears to decline somewhat with increasing age;9 however, because the incidence of stroke increases so rapidly with age (see below), the elderly still suffer the large majority of blood pressure-related cerebrovascular disease. Blood pressure levels are positively related to both cerebral haemorrhage and cerebral infarction, but the association appears to be somewhat steeper for haemorrhage than infarction.7
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.
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
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
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.
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.
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.
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.
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
Diabetes whether insulin dependent or non-insulin dependent increases the risks of CHD and ischaemic stroke,37,38 as well as the risk of renal disease. Overall, diabetes typically increases the relative risks of death from CHD and death from stroke about 3 fold. Additionally, among individuals without diabetes, the risks of CHD have been observed to be directly and continuously related to blood insulin39 and blood glucose levels.40
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.
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.
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
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
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.
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
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
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
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.
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
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.
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.
Because of the similarity of the relative risk reductions in different patient groups, the size of the absolute treatment benefits varied in direct proportion to the background level of risk (i.e. patients at highest absolute risk of stroke or CHD experienced the largest absolute reduction in risk). For example,70 there was a 34% reduction in the relative risk of stroke in trials conducted exclusively in older populations and a 43% relative risk reduction in the trials conducted predominantly in individuals of middle age. However, the annual absolute risk reduction was more than two times greater in the trials in older patients: specifically, there were 5 strokes prevented per thousand patients in the trials among older patients, compared with 2 strokes prevented per thousand patients in the trials among younger patients. The outcome was similar for CHD: there was a 19% reduction in relative risk in the trials among older patients and a 14% relative risk reduction in the trials among middle aged patients, but the annual absolute risk reduction was 3 events per thousand older patients and 1 event per thousand younger patients.
There was evidence of reduced stroke risks both in trials of diuretic-based regimens and in trials of beta blocker-based regimens. It has been observed that the evidence for reduced CHD risk was somewhat stronger for diuretic-based therapy than for beta blocker-based therapy, particularly in trials conducted in the elderly.71 However, data from the four trials that directly compared the effects of diuretic- and beta blocker-based regimens on the risks of stroke and CHD in younger and older patients provided no clear evidence of a difference between the regimens in their effects on stroke or CHD.72-75 Nevertheless, even in combination these studies lacked adequate statistical power to determine reliably any modest but potentially important treatment differences (e.g. a 10-15% difference in the relative risk of CHD).
While there are comparatively few data available from these trials about the effects of treatment on heart failure or renal disease, there was evidence of an approximate halving of the risk of heart failure in the trials of diuretic- and beta blocker-based based regimens.76,77 Additional evidence about the effects of beta-blockers on such outcomes is provided by the trials of these agents in patients with heart failure (see 6.4). Similarly, more evidence about the effects of beta blockers on CHD risk is provided by the trials of these agents in patients with prior myocardial infarction (see 6.4).
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.
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.
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
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
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.
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.
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.
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
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.
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.
The clinical and laboratory evaluation of the hypertensive patient should be conducted with four aims in mind:-
A comprehensive clinical history is essential and should include: -
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:-
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.
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:-
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:-
The advantages of home blood pressure measurement are that it may provide numerous values on different days in a setting closer to daily life conditions than the doctor's office. It may also favourably affect patients perceptions of their "hypertension" problems and improve adherence to treatment. It may therefore be a valuable adjunct for checking the effectiveness of treatment.108
Ambulatory blood pressure monitoring also offers the advantages of providing a more realistic setting for blood pressure measurements, and of improving patient perceptions and adherence to treatment. More important however, is the large body of evidence indicating that the target organ damage associated with hypertension is more closely related to 24 hour or day-time average blood pressure than to clinic blood pressure,106,109 particularly if only few office values are obtained.110 There is also evidence that pretreatment ambulatory blood pressure has a prognostic value111-114 and a recent prospective study suggests that regression of target organ damage such as left ventricular hypertrophy is more closely related to changes in 24 hour average than to changes in office blood pressure values.115 While ambulatory blood pressure monitoring is not a substitute for office measurement, it provides an important research tool for investigations of normal and deranged mechanisms of cardiovascular regulation, of the clinical relevance of phenomena such as blood pressure variability and nocturnal hypotension, and of the time-course and homogeneity of the antihypertensive effect of newer drugs or drug combinations.106,116
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.
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.
In contrast to the 1993 Guidelines, the present report does not deal separately with hypertension in the elderly nor with isolated systolic hypertension. Rather, discussion of these two conditions is now part of the main text, since it is widely agreed that the treatment of these conditions is at least as effective in reducing cardiovascular risk as the treatment of classical essential hypertension in middle aged subjects.
Table 1. Definitions and Classification of Blood Pressure Levels
When a patient's systolic and diastolic blood pressures fall into different categories, the higher category should apply.
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.
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.
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.
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%.
Patients with Grade 3 hypertension and one or more risk factors and all patients with clinical cardiovascular disease or renal disease (as defined in Table 2) carry the highest risk of cardiovascular events, of the order of 30% or more over ten years, and thus qualify for the most intensive and rapidly instituted therapeutic regimes.
Risk strata (typical 10 year risk of stroke or myocardial
infarction): Low risk = less than 15%; medium risk = about 15-20% risk;
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.
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:-
In situations where resources are limited it becomes imperative to direct drug treatment to individuals in the high and very high risk groups before considering their use in lower risk patients.
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:-
Lifestyle measures should be instituted wherever appropriate in all patients including those who require drug treatment.
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
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
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.
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.
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.
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.
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.
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.
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.
The six main drug classes used, worldwide, for blood pressure lowering treatment are: diuretics, beta-blockers, calcium antagonists, ACE inhibitors, angiotensin II antagonists and alpha-adrenergic blockers. In some parts of the world, reserpine and methyldopa are also used frequently. There is no reliable or consistent evidence that indicates substantive differences between drug classes in their effects on blood pressure, although there are important differences in the side-effect profiles of each class. There are also important differences between classes in the amount of evidence available from randomised controlled trials on the effects of treatment on morbidity and mortality. While there is a large body of data demonstrating the benefits of the older agents such as diuretics and beta-blockers, there are fewer data available about calcium antagonists and ACE inhibitors, and no reliable data available about alpha-blockers or the most recent classes of agents such as angiotensin II antagonists.
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:-
For patients in the high and very high risk groups drug treatment should be instituted within a few days as soon as repeated measurements have confirmed the patient's blood pressure.
For patients in the medium and low risk groups the initiation of drug therapy will be influenced by:-
For patients in the medium risk group it is desirable to continue with lifestyle measures and to reinforce these if necessary for at least 3 months before considering drug treatment. If however, goal blood pressures are not attained within a maximum of 6 months, drug treatment should be initiated.
For patients in the low risk group having Grade 1 (mild) hypertension, lifestyle measures should be used assiduously for 6 months before considering drug treatment. If however, goal blood pressures are not achieved, drug treatment should be instituted within 1 year.
The exception to this recommendation is for patients in the borderline subgroup with diastolic blood pressures between 90 and 94 mmHg or systolic blood pressure between 140 and 149 mmHg. In this group, the doctor, in consultation with the patient, may choose to persevere with lifestyle measures alone to lower the pressure and reduce cardiovascular risk.
There is one other group of patients that deserves special mention: this is patients with high-normal blood pressure (130-139/85-89 mmHg) who also have diabetes mellitus and/or renal insufficiency. For these patients early and active drug treatment should also be considered, since this has been shown to reduce the rate of loss of renal function (see section 6.5 and 6.6).
All available drug classes are suitable for the initiation and maintenance of antihypertensive therapy, but the choice of drugs will be influenced by many factors illustrated in Table 4 including:-
The physician should tailor the choice of drug to the individual patient, after taking all these factors together with patient preference into account in each case. A practical framework for the management of patients with Grade 1 or Grade 2 hypertension is shown in Figure 1.
Diuretics constitute one of the most valuable classes of antihypertensive drugs. They are inexpensive, effective, generally well tolerated in low doses, and diuretic based treatment regimens have been clearly shown to prevent major cardiovascular events, including stroke and CHD, in a variety of hypertensive patient groups. Many of the unwanted side effects of diuretics such as potassium depletion, reduced glucose tolerance, ventricular ectopic beats and impotence were associated with the use of high doses of diuretics of the order of 50-100 mg daily of hydrochlorothiazide and chorthalidone in the 1970s and 1980s. While there is some evidence from observational studies that the risk of sudden cardiac death in patients treated with non-potassium sparing diuretics can be reduced by their combination with potassium sparing diuretics,149,150 this issue can only be resolved by prospective randomised controlled trials.
Diuretics should be used in low doses equivalent to a maximum of 25 mg daily of hydrochlorothiazide, and often half or less this dose, in order to reduce the adverse effects while still reaping the benefits. Diuretics are particular recommended for the treatment of elderly patients with systolic hypertension78 and of black patients.
Beta-adrenoceptor-blocking drugs (beta-blockers) are safe, cheap and effective for use as monotherapy or in combination with diuretics, dihydropyridine calcium antagonists and alpha-blockers. Whereas heart failure used to be a clear contraindication to the use of beta-blockers in standard doses121,123 there is emerging evidence that they may have a beneficial effect when used in very low starting doses in some patients with heart failure.151 Beta-blockers should be avoided in patients with obstructive airways disease and peripheral vascular disease. There have been reports that beta-blockers can aggravate spastic or variant angina in Japanese patients.152 They are often less effective in black patients.
220.127.116.11 ACE inhibitors
All subgroups of calcium antagonists are effective and well tolerated in lowering blood pressure. They are of demonstrated benefit for the prevention of stroke in elderly patients with systolic hypertension. The evidence about the effects of calcium antagonists on cardiovascular disease events is discussed in detail in sections 3 and 6. Long-acting calcium antagonists are preferred and rapid onset short acting calcium antagonists should be avoided. Calcium antagonists are particularly recommended for elderly patients with systolic hypertension79 and for black patients. Adverse effects include tachycardia, flushing, ankle oedema and (with verapamil) constipation.
Angiotensin II - receptor antagonists are the latest major group of antihypertensive drugs to become generally available. They have many features in common with ACE inhibitors including particular value in patients with heart failure. There is still no reliable evidence of their effects on cardiovascular risk in patients with hypertension. However, they have few side effects, which may encourage adherence to therapy and appear to offer one advantage over ACE inhibitors, that is the absence of cough as a side effect.156
Alpha-blockers are safe and effective in lowering blood pressure.157 There is still no evidence about their effects on cardiovascular risk in hypertensive subjects. Their main side effect is postural hypotension which may be a particular problem in elderly patients. Assessment of standing blood pressure is essential. These drugs may have advantages in subjects with dyslipidaemia or glucose intolerance.
A number of centrally acting drugs are also available, some of these are new such as the imidazoline receptor stimulants (agonists), rilmenidine and moxonidine, and others much older such as reserpine, methyldopa and clonidine. Methyldopa has a well documented and continuing place in the treatment of hypertension in pregnancy (see Section 6.2).158 However, the side effects profile of centrally acting agents is generally less favourable than that of the other main classes of available drugs. Where consideration of cost effectiveness favours the use of reserpine in low income populations, the doses used should be much lower than those used in earlier times.
The older vasolidator agents such as hydralazine are also widely used in some regions of the world. However, the side effects of direct vasolilators such as hydralazine and minoxidil - tachycardia, headache and sodium and water retention - make them less suitable for use as first line drugs.
Good communication between the physician and the patient lies at the core of the successful management of hypertension. Since the treatment of hypertension is for life, it is essential that the physician establish a good relationship with the patient, provide the patient with information, both verbal and written, and answer any questions the patient may have. Good information about blood pressure and high blood pressure, about risks and prognosis, about the expected benefits of treatment and about the risks and side effects of treatment will be essential for satisfactory life long control of hypertension.
Failure to establish effective communications and relations will generally lead to poor adherence to antihypertensive therapy and unsatisfactory control of the raised blood pressure. The magnitude of this problem is reflected in population surveys that have demonstrated that hypertension is either untreated or inadequately controlled in around 70-75% of patients worldwide.
One of the best ways to improve adherence to therapy is to involve the patient in making decisions about treatment strategies. Another approach may be to use clinical pharmacists to inform the patient on the use of medications, and on side effects. Well trained clinic nurses will also contribute a great deal to improve compliance with therapy, as will other health professionals such as dieticians and trained counsellors who are experienced in the implementation of lifestyle measures.
Other measures that may help, include the use of home blood pressure measurement, and the involvement of the patient's family in the therapeutic plan.
Hypertension may be termed refractory, when a therapeutic plan that has included attention to lifestyle measures and the prescription of combination drug therapy in adequate doses, has failed to lower blood pressure below 140/90 mmHg in patients with classical essential hypertension, or below 140 mmHg systolic in patients with isolated systolic hypertension. In these situations, referral to a specialist should be considered
There are many causes for resistance to treatment, as illustrated in Box 12 below, including apparent causes such as isolated office ("white coat") hypertension and the failure to use an appropriately large cuff in a patient with a very fat arm. One of the most important causes of refractory hypertension may be poor compliance or adherence to therapy and in this situation, after all else fails, it can be very helpful to suspend all drug therapy while continuing to monitor blood pressure frequently. A fresh start with a new regime may help break a vicious cycle.
Since the aim of treatment is the reduction of the total cardiovascular risk it is at least as important to treat the other risk factors and clinical conditions present in the individual hypertensive patient. This means the physician should either refer the patient to appropriate clinics and specialists, or institute an appropriate regimen of lifestyle factors and drug treatment for associated conditions such as diabetes mellitus, hypercholesterolaemia, CHD, cerebrovascular disease, or renal disease.
The use of aspirin, and of some other antiplatelet agents, has been well documented to reduce the risk of fatal and non-fatal coronary events, of stroke and of cardiovascular death in patients with established coronary or cerebrovascular disease.100 In the light of the results of the HOT Study,84 it is reasonable to recommend the use of low dose aspirin in hypertensive patients whose blood pressure has been rigorously controlled, who are at high risk of CHD, and who are not particularly at risk of bleeding from the gastro-intestinal tract or from other sites.
Cholesterol reduction with a variety of agents has been shown to reduce the risks of initial and recurrent CHD events among patients with a wide range of initial cholesterol levels.26,42,94-97 Trials of HMG CoA reductase inhibitors, conducted primarily among patients with CHD, have also reported reductions in stroke risk. The relative effects of cholesterol lowering therapy appear to be similar in those with or without hypertension. In these circumstances, the use of cholesterol lowering therapy can be recommended for hypertensive patients who have elevated cholesterol or who are for other reasons at high risk of CHD.
During the period of evaluation and stabilisation of treatment, patients need to be seen at frequent intervals to monitor the changes in blood pressure and in the other risk factors and clinical conditions present, and to observe the effects of treatment. Follow-up visits should be used to establish good relations with the patient and to educate the patient on the nature of the condition of hypertension and of the other risk factors or disorders present. The patient should understand why control of hypertension is important, and that treatment should generally continue for a lifetime. The acceptance and implementation of changes in lifestyle in particular, need satisfactory explanation and reinforcement. For successful drug therapy, it is important to explain the possible adverse effects and emphasise the need for regular medication, with early reporting of any side effects.
The frequency of visits will depend on the overall risk category of the patient as well as on the level of blood pressure. Once the goals of therapy have been reached, including the control of other risk factors and the achievement of goal blood pressure, the frequency of visits can be reduced considerably. Patients with a low risk profile and milder degrees of blood pressure elevation (high normal or Grade 1), managed on a single drug could well be seen every six months. It is important that patients not on drug treatment understand the need for monitoring and follow-up and for periodic reconsideration of the need for drug treatment. In more complex cases, patients should be seen at more frequent intervals. If the therapeutic goals, including the control of blood pressure, have not been reached within 6 months, the physician should consider referral to a hypertension specialist.
Antihypertensive therapy is generally "for life". Cessation of therapy by patients who have been correctly diagnosed as hypertensive is usually followed, sooner or later, by the return of blood pressure to pre-treatment levels. Nevertheless, after prolonged blood pressure control it may be possible to attempt a careful progressive reduction in the dose or number of drugs used, particularly among patients strictly observing lifestyle (non-drug) measures. Such attempts to "step down" treatment should be accompanied by careful continued supervision of the blood pressure.
Since a hypertensive patient is typically treated for decades it is likely that the treatment regimen, including the choice of drugs, will undergo multiple changes. It is therefore advisable for all hypertensive patients to keep a record of all treatments used and of their outcomes, and it is the responsibility of doctors and health services to maintain adequate records of treated hypertensive patients and to make them readily available.
The prevalence of hypertension and the incidence of blood pressure-related cardiovascular disease vary considerably between ethnic groups and geographic regions. Ethnic minority groups in many Western populations frequently have higher rates of hypertension,60,159,160 as well as higher rates of major cardiovascular events. The pattern of cardiovascular disease within minority ethnic groups appears to vary by region. For example, in some, but not all, African American populations, renal failure62 and stroke61 are particularly prevalent, In South Asian populations of the UK, CHD, stroke and renal failure rates are all high,63 whereas in Canada, the rates among South Asians are similar to or lower than those in caucasians.64
The pattern of cardiovascular disease in ethnic majority groups also varies considerably between geographic regions. For example, in many Eastern Asian populations, stroke (particularly haemorrhagic stroke) is relatively common whereas CHD is relatively uncommon compared with that seen in Western populations.7 However, the proportional relationships of blood pressure with specific cardiovascular disease risks in Chinese and Japanese populations appears to be very similar to those observed in North American and European populations. The higher incidence of haemorrhagic stroke in Eastern populations appears to reflect, at least in part, a particularly strong association of this type of stroke with blood pressure.7 In other large non-Western populations such as those of sub-Saharan Africa, stroke and renal disease appear to predominate among cardiovascular diseases.5
The available data provide no reason to believe that the relative effects of lowering blood pressure on specific disease risks will vary importantly between ethnic groups or regions, although there may be lesser effects of some specific agents (e.g. ACE inhibitors) in specific ethnic groups (e.g. African Americans). However, because ethnicity and geographic region are such important determinants of absolute risk, it is likely that the absolute effects of treatment will vary markedly between ethnic groups and geographic regions. For example, among individuals with similar levels of blood pressure, the absolute risk of cardiovascular disease will tend to be higher in individuals of South Asian descent in the UK or African Americans in the US compared to Caucasians in the same populations. Therefore, it could be expected that absolute treatment benefits conferred by any given reduction in blood pressure would also be greater in these groups.
The absolute benefits of blood pressure lowering therapy may be particularly great in groups in which there are high risks of events that are very strongly blood pressure-related (e.g. stroke or renal failure). Such populations include many of those in the Eastern Asian region, sub-Saharan Africa as well as African American populations in the US. The rates both of stroke and of CHD are high in Eastern Europe, Russia and the Baltic states,65 suggesting that the absolute effects of treatment in populations from these regions are also likely to be particularly large. Some ongoing randomised controlled trials will provide evidence about the comparative absolute benefits of blood pressure lowering treatments in such diverse populations.161
For regions in which health care resources are particularly scarce, investment in population-based primary prevention strategies may yield the largest dividend. The most cost-effective hypertension treatment programmes will involve the use of the lowest cost drugs (e.g. diuretics, reserpine, beta-blockers, generic formulations of ACE inhibitors, angiotensin II antagonists, calcium antagonists, and other generic agents) in the highest risk groups. The selective treatment of patients with pre-existing cardiovascular or renal disease (irrespective of hypertension severity) or with severe hypertension (systolic >180 mmHg or diastolic >110 mmHg) will result in the greatest ratio of events prevented to numbers of patients treated.
Hypertension in pregnancy is usually defined either by an absolute level of blood pressure (e.g. 140/90 mmHg or greater) or by a rise in blood pressure from pre-conception or first trimester levels (e.g. systolic blood pressure rise ³ 25 mmHg and/or diastolic blood pressure rise ³ 15 mmHg).162,163 Hypertension in pregnancy is typically classified as: chronic essential or secondary hypertension; de novo pre-eclampsia or gestational hypertension; or pre-eclampsia superimposed on chronic hypertension. Pre-eclampsia is a multi-system disorder in which raised blood pressure is but one sign. The major maternal abnormalities occur in kidneys, liver, brain and coagulation systems. Impaired uteroplacental blood flow may cause fetal growth retardation or intrauterine death.
It is generally agreed that blood pressures greater than about 170/110 mmHg should be lowered to protect the mother against risk of stroke or eclampsia. However, there is less agreement about the value of treatment for lower levels of blood pressure. The drugs that are most widely used to lower blood pressure acutely in pregnancy include nifedipine, labetolol, and hydralazine.158 Magnesium sulphate may produce some blood pressure lowering effects but is generally inadequate to treat severe hypertension in pregnancy. The drugs most widely used for chronic treatment of raised blood pressure in pregnancy include: beta-blockers; in particular, oxprenolol, pindolol, atenolol (associated with fetal growth retardation when used long-term throughout pregnancy), labetolol, methyldopa, prazosin, hydralazine, nifedipine and isradipine. Antihypertensive agents that are generally avoided during pregnancy include: ACE inhibitors, which are associated with fetal growth retardation, oligohydramnios, neonatal renal failure, and possibly abnormal fetal morphology ("fetal hypotensive syndrome"), and AII receptor antagonists, the effects of which may be similar to those of ACE inhibitors. Diuretics are also used infrequently because of concerns that they may further reduce the already compromised plasma volume, although they have been shown to be effective in randomised controlled trials.164
Lowering blood pressure is only one aspect of the management of pre-eclampsia. Management ideally involves a multidisciplinary team. Maternal and fetal monitoring are essential for the detection of signs of advancing pre-eclampsia or of impending fetal demise, and, thereby, the need for delivery, which remains the definitive management for pre-eclampsia. Aspirin has not been shown to be effective in preventing pre-eclampsia.165 Oral calcium supplementation is not of benefit as prophylaxis against pre-eclampsia in calcium replete populations, but, although evidence is liimted, it is generally agreed that dietary calcium intake should be increased to recommended levels in populations with low calcium diets.
The results of randomised trials provide clear evidence of the benefits and safety of antihypertensive treatment in patients across a wide age range up to about 80 years.166 These trials have not provided any clear evidence of differential proportional effects of therapy in younger and older patients, although the absolute effects are typically greater in older individuals because of their higher risk of cardiovascular events.70 Benefits of treatment have been demonstrated among older patients with classical hypertension (raised systolic and diastolic blood pressures), as well as among older patients with isolated systolic hypertension (raised systolic blood pressure alone).
However, most of the completed studies have included too few patients above this age to provide reliable evidence of benefits or safety. Among the trials reported to date, the oldest average age of patients was in the STOP-Hypertension trial (Swedish Trial in Old Patients with Hypertension).167 In that study, which demonstrated a marked reduction in cardiovascular events among patients assigned active treatment, participants were aged between 70 and 84 years at enrollment (mean 76 years). However, the number of patients in that study above age 80 years was too small for reliable conclusions to be drawn about the effects of treatment on cardiovascular disease risk in this subgroup. In the Syst-Eur trial of treatment for isolated systolic hypertension among patients aged 60 years or older, there was no clear evidence of an association between older age and the size of the treatment effects on combined fatal or non-fatal cardiovascular events, although there was a trend towards a lesser effect on fatal events with increasing age.168
Because of the absence of direct evidence about the effects of blood pressure lowering in the very elderly, and the limited prognostic relevance of blood pressure levels when measured at very old ages, there is uncertainty about the value of antihypertensive treatment for patients over the age of 80 years.161 A large-scale randomised controlled trial has recently been initiated to assess the potential benefits of treatment of hypertension in very old patients. The Hypertension in the Very Old Trial (HYVET) is currently recruiting hypertensive patients aged over 80 years. Patients are randomised to receive either a diuretic-based regimen, a calcium antagonist-based regimen, or no treatment. In addition to this study, several other ongoing trials involving a broader patient group are recruiting some patients older than 80 years. The results of these trials should eventually provide reliable evidence about the effects of blood pressure lowering therapy in this very high risk population.
Individuals with a history of stroke or TIA have very high risks of further cerebrovascular events. Among such patients, the typical stroke rate is 4% or more per year. Individuals with a history of ischaemic stroke or TIA also have high risks of CHD events. The risks of recurrent cerebrovascular events (as well as initial CHD events) appear to be directly related to levels of blood pressure.12-14 Consequently, even modest reduction in blood pressure among such patients could confer worthwhile reductions in the absolute risk of cardiovascular events. In trials among stroke survivors with hypertension, blood pressure lowering therapy produced a 29% (SD 9) reduction in stroke risk and a trend towards a reduction in CHD events.169 The proportional reduction in stroke risk was similar to that observed in patients without stroke; however, the absolute benefits were several times greater). In the three trials of blood pressure lowering agents among patients with a broad range of blood pressures at entry, the effects of treatment were less clear, although there was still a suggestion of benefit.12 The remaining uncertainty about the benefits of treatment for a broad range of patients with cerebrovascular disease should be resolved by PROGRESS (perindopril protection against recurrent stroke study), a trial of ACE inhibitor-based therapy in patients with a history of stroke or TIA.170
Individuals with a history of CHD have very high risks of further CHD events. Among patients with a history of myocardial infarction or unstable angina, the risk of CHD death or non-fatal myocardial infarction is 5% or more per year. Once again, the risk of these recurrent events appears to be directly related to the level of blood pressure.13 There are few data available about the effects of blood pressure lowering in hypertensive patients with CHD. However, many of the more common blood pressure lowering drugs have been assessed in broader groups of patients with CHD, albeit with objectives other than reduction of blood pressure. Beta-blockers have been shown to reduce the risks of both re-infarction and cardiovascular death by about a quarter in patients with myocardial infarction.171 Overall there is no clear evidence from clinical trials that calcium antagonists reduce recurrent CHD events outcomes, but there are suggestive, though not definitive, data demonstrating a reduced risk of myocardial infarction in patients treated with verapamil or diltiazem, and an increased risk in patients treated with immediate release nifedipine.86 Ongoing studies of verapamil, diltiazem and longer-acting dihydropyridine calcium antagonists in hypertensive and non-hypertensive patients with CHD should provide clearer evidence about the effects of these agents on recurrent CHD risk.161 Several large trials of ACE inhibitors in patients with heart failure or left ventricular dysfunction have provided evidence of a reduction of about one-fifth in the risk of myocardial infarction or sudden death.172 In both the trials of beta blockers and the trials of ACE inhibitors, the magnitude of the effects on CHD events appears greater than that which would be expected from the blood pressure lowering alone and seems likely to reflect, at least in part, other cardioprotective effects of these agents. The remaining uncertainty about the effects of ACE inhibitors on CHD events among high risk patients without heart failure or left ventricular dysfunction should be resolved by the HOPE (Heart Outcome Prevention Evaluation) study.173
Patients with congestive heart failure are at particularly high risk of death from cardiovascular disease. There are few data available about the effects of blood pressure lowering specifically among hypertensive patients with heart failure. However, the effects of various blood pressure lowering drugs have been assessed in a broad range of patients with heart failure. Several large trials of ACE inhibitors in patients with heart failure or left ventricular dysfunction have provided evidence of a reduction in mortality of about one-sixth and somewhat larger reductions in heart failure-related morbidity.153 Recent evidence also indicates that beta-blockers reduce the risk of cardiovascular death and the need for hospital admission by about a quarter in patients with heart failure, a group for which beta-blockers were previously thought to be contraindicated. Trials of calcium antagonists in patients with heart failure have produced no evidence of beneficial effects of treatments with these agents.
Hypertension is both a cause and a consequence of renal disease, and irrespective of aetiology, hypertension is a major determinant of renal disease progression.174 Malignant or accelerated hypertension, renal artery stenosis and athero-embolic disease are all important causes of renal disease secondary to hypertension. The role of less severe blood pressure elevations in the genesis of renal failure is less clear, although there is strong evidence of a role for such blood pressure elevations in some populations, e.g. African Americans.62 Primary renal parenchymal disease has been observed to be responsible for 3-4% of hypertension in some populations, and renovascular disease in around 1%.11 Most (80-90%) patients presenting to renal replacement programmes are hypertensive, but patients presenting with the combination of hypertension and renal impairment require definition of macroscopic and/or microscopic renal and/or renovascular anatomy before hypertension can be regarded as the cause of the renal impairment. Diabetic nephropathy, hypertensive nephropathy and primary glomerulonephritis are the three most common causes of end-stage renal failure worldwide. Other important aetiologies include reflux nephropathy, polycystic kidney disease, analgesic nephropathy and secondary glomerulonephritis.
Irrespective of whether hypertension causes renal disease or vice versa, it is clear that hypertension is a major determinant of progression of renal disease and the risk of end-stage failure.11,175 There is also some evidence that any familial tendency to hypertension will increase the prevalence of renal failure in patients with primary renal disorders176 or with diabetes.177 There is little evidence from randomised trials in hypertensive patients to show that treatment modifies the slight risk of developing renal failure, but more compelling evidence that blood pressure control will slow progression in patients with renal failure.178 There has been much interest in the question of whether some classes of antihypertensive agents, in particular ACE-inhibitors, retard progression of renal disease over and above their effects on blood pressure lowering179 but this remains unproven. Evidence from the Modification of Diet in Renal Disease Study suggests that more aggressive blood pressure lowering should be pursued in patients with chronic renal failure and proteinuria. Lower blood pressure targets have been proposed for patients with proteinuria >1G/d (125/75 mmHg) than for patients with lesser proteinuria (130/80 mmHg).
The prevalence of hypertension is 1.5 to 2 times greater in patients with diabetes mellitus compared with matched non-diabetic individuals.181 Type 1 diabetes mellitus is associated with hypertension only when albuminuria and early nephropathy develop, but Type 2 diabetes mellitus may be associated with hypertension at or even preceding diagnosis.182 Type 2 diabetes and hypertension are associated with an insulin resistant state (Syndrome X) characterised by hyperinsulinaemia, dyslipidaemia and obesity,183 but a causal relationship between insulin resistance and hypertension has not yet been established.184 The co-existence of diabetes mellitus and hypertension is important, as they are multiplicative risk factors for macrovascular and microvascular disease, resulting in increased risks of cardiac death, CHD, congestive heart failure, cerebrovascular disease and peripheral vascular disease.182,185 Macrovascular complications account for the majority of deaths in the diabetic population and the absence of hypertension is associated with long-term survival.186 Microvascular disease resulting in diabetic nephropathy and retinopathy leads to significant morbidity and mortality. The progressive decline in glomerular function that is seen in diabetic patients with hypertension, especially those with albuminuria, can be slowed with antihypertensive treatment187 ACE inhibitors have been shown to slow the rate of decline in renal function and reduce the risk of dialysis in normotensive Type 1 diabetic subjects with proteinuria.154 Hypertension is also associated with an increased incidence of diabetic retinopathy188 and treatment with ACE-inhibitors has been shown to reduce the progression of retinopathy in normotensive Type 1 diabetic subjects.189
Non-pharmacological interventions such as weight loss have been shown to improve insulin resistance and blood pressure in hypertensive diabetic patients190 and similar lifestyle modifications are recommended for the initial treatment of hypertension and diabetes mellitus individually or when these diseases co-exist. Pharmacological treatment of hypertension in diabetic patients can potentially differ from the non-diabetic because of differing effects on lipid profiles, insulin sensitivity and glucose metabolism.191 Diuretics and beta-blockers are reported to reduce insulin sensitivity and increase triglyceride levels. However, diuretic-based regimens have been shown to reduce cardiovascular events in diabetic patients with hypertension.182 Beta-blockers potentially mask hypoglycaemic awareness, but in practice this is not a major contraindication considering the clear evidence of benefits of beta-blockers in diabetic patients after myocardial infarction.192 ACE-inhibitors and calcium antagonists are thought not to alter insulin sensitivity or lipid profiles, but the CAPPP study has recently reported that hypertensive patients assigned captopril-based therapy had a lower risk of developing diabetes than did patients assigned diuretic- or betablocker-based therapy.82,191 Recently, the UK Prospective Diabetes Study (UKPDS 38 and 39) has demonstrated that there were similar benefits of ACE inhibitor- and beta-blocker-based therapy for a variety of both macrovascular and microvascular disease outcomes in patients with Type 2 diabetes.83,85 Two small randomised controlled trials have reported that ACE-inhibitors have a more favourable effect on CHD events compared with calcium antagonists in diabetic patients.193,194 These results are consistent with either a more favourable effect of ACE-inhibitors or, alternatively, an adverse effect of calcium antagonists, on vascular events in hypertensive diabetic patients. However, since these studies were small and their results less than definitive, further evidence is required to determine whether there are true differences between these drug classes in their effects on macrovascular events.
In the HOT Study of calcium-antagonist based therapy,84 there was evidence that lowering blood pressure to the lowest target level (diastolic <80 mmHg) in diabetic hypertensive patients resulted in lower risks of cardiovascular events. This finding is consistent with evidence from the UK Prospective Diabetes Study (UKPDS 38), demonstrating that a lower achieved blood pressure (144/82 mmHg vs 154/87 mmHg) was associated with significantly reduced risks of major macrovascular disease events as well as microvascular disease outcomes.85 The likelihood that diabetic hypertensive patients will benefit from low target blood pressures is consistent with the evidence from trials of blood pressure lowering in normotensive diabetic patients with or without renal disease.195
Translating the recommendations of clinical guidelines and the findings from research studies into daily clinical practice remains a daunting challenge, no less in the treatment of hypertension than in other fields. The rule of halves (only half of all hypertensive patients are aware that they have hypertension, only half of those aware are actually on treatment, and only half of those on treatment have their blood pressure well controlled) still applies in many countries around the world, and even the most affluent countries have only doubled the proportion of well controlled hypertensive patients to approximately one quarter (see 3.1.1). This only serves to emphasise the validity of Alexander Lomas' statement "Words without action: the production, dissemination and impact of consensus recommendations".196 It is now plain that as a stand-alone tool, practice guidelines neither change clinical practice nor affect health outcomes.196-199 The evidence from many analyses has established that in order to improve physician performance or other health outcomes, it is necessary to put in place a range of measures reaching locally into the practice site and involving local medical practitioners in an active way. 196-199 This is plainly beyond the direct capacity or resources of the WHO-ISH Guidelines Committee, but it is hoped to achieve far greater penetration to medical practitioners through alliances and partnerships with national and regional hypertension societies, leagues against hypertension and hypertension research councils.
These guidelines, which are being published in specialist medical journals will be accompanied by a much briefer companion set of "Practice Guidelines" intended for translation into many languages and distribution to local medical practitioners in many countries. The presidents of the leagues and societies affiliated with the International Society of Hypertension and the World Hypertension League have agreed to assist in forming national alliances with government agencies, with professional medical associations and colleges and with public education groups in order to develop action programs for the implementation of the recommendations in these guidelines. The WHO-ISH Guidelines can serve as a model and a stimulus for the development of custom-built national recommendations, adapted to suit the local cultural, economic and social realities. It is hoped that such modified recommendations could be embedded in an implementation plan that reaches local medical practitioners and local communities alike. Such programs could embrace both the clinical strategies set out in these pages, and the mass strategies necessary for hypertension control at the population level.
There is a pressing need for observational epidemiological studies as well as randomised controlled trials in populations from Asia, Africa and Latin America, so as to provide direct evidence about the risks associated with blood pressure and other risk factors, and to determine the effects of blood pressure lowering treatments in patients from these large populations. The detection and quantification of any regional differences that may have relevance for decisions about the strategies adopted for both prevention and treatment of cardiovascular diseases.7 Importantly, such research would obviate the need to extrapolate from research conducted in other geographically and ethnically distinct populations..
Reliable data are urgently needed on the prognostic significance of blood pressure values obtained by ambulatory blood pressure monitoring or by self-measurement, particularly at home. In this regard, the prognostic significance of isolated clinic ("white coat") hypertension also needs clarification. Further trials of ambulatory blood pressure measurement-guided treatment versus standard therapy would also be of value. More research is also required to determine the independent prognostic relevance of the various other indices of blood pressure and arterial distensibility that have been developed. This includes further investigation of pulse pressure in comparison with mean arterial pressure, diastolic pressure and systolic pressure. It should also include investigation of the prognostic relevance of other indices of arterial distensibility and stiffness.
It is essential to continue to extend trials of blood pressure lowering to include high risk groups with or without hypertension but with other major risk factors for cardiovascular events such as diabetes, renal insufficiency, cerebrovascular disease, CHD, peripheral vascular disease or atrial fibrillation. There is a strong rationale for expecting a wide range of patients both hypertensive and normotensive with these conditions to benefit from blood pressure lowering.
The results of the UKPDS together with the subgroup results for patients with diabetes in the HOT study provide strong evidence that lower blood pressure targets among diabetic patients are associated with important reductions in cardiovascular risk. More research is required to determine whether there are similar advantages of a lower blood pressure target in other high risk groups. Studies investigating the effects of combination therapy versus monotherapy in patients at high risk of cardiovascular events would be helpful in this regard.
While there is reasonably good evidence about the independent prognostic significance of left ventricular hypertrophy (assessed by electrocardiogram or echocardiogram), there is a need for better evidence about the prognostic significance of other surrogate endpoints including carotid atherosclerosis, endothelial dysfunction and microalbuminuria (particularly among non-diabetic patients), for the separate risks of stroke and CHD events. Further trials evaluating the effects of blood pressure lowering treatments on the risks of cardiovascular events among individuals with these conditions would also be valuable. Furthermore, it would be of particular interest to determine whether different agents producing the same blood pressure reduction are differentially effective in reversing or retarding the progression of these conditions; and, if so, whether this has implications for cardiovascular disease.
The causes of cardiovascular disease in hypertensive patients are clearly multifactorial, and there is a strong case for the conduct of factorial randomised trials investigating the separate and joint effects of blood pressure lowering treatments and other intervention modalities. For example, in active- or placebo-controlled trials of new blood pressure lowering agents, it would be of value to include factorial assignment to such interventions as cholesterol lowering, folic acid (for homocysteine lowering), and/or antioxidant vitamins
There are many ongoing trials of the new classes of blood pressure lowering agents, and more will be required as new drugs are developed. Most of the ongoing studies are head-to-head comparisons of older and newer agents in which the advantages and disadvantages of one or other treatment may be modest and difficult to detect. Another approach that is likely to evidence of clearer benefits is to randomise patients to new treatments or to placebo against a background of treatment with standard therapy. In this way the full effects of any new treatment will be demonstrated (i.e. the combined effects of blood pressure lowering plus any independent protective effects).
Despite the limited success of efforts to date, research is still required to identify both genetic factors that may be predictive of cardiovascular disease events, particularly in younger individuals, and genetic factors that may predict response to blood pressure lowering treatment.
Members of the Guidelines Committee were appointed by the Liaison Committee of the World Health Organization and the International Society of Hypertension. They were chosen to represent a range of experience, viewpoints and geographic regions. In order for readers of these Guidelines to take account of any potential conflicts of interest among members of the subcommittee, each member was asked to declare relevant financial interests including research supported by pharmaceutical companies, current consultancies for such companies and shares in any such companies. Details of all such interests have been provided to the Liaison Committee of the World Health Organization and International Society of Hypertension. One committee member held shares in a pharmaceutical company, a few held consultancies, and most received support for research from a variety of companies.
Subcommittee Members: Michael Alderman (Albert Einstein College of Medicine, New York); Kikuo Arakawa (Fukuoka University, Fukuoka); Lawrie Beilin (University of Western Australia, Perth); John Chalmers (chairman) (University of Sydney, Sydney); Serap Erdine (Turkish Society of Hypertension and Atherosclerosis, Istanbul); Masatoshi Fujishima (Kyushu University, Fukuoka); Pavel Hamet (Hotel Dieu de Montreal, Montreal); Lennart Hansson (University of Uppsala, Uppsala); Lewis Landsberg (Northwestern University Medical School, Chicago); Frans Leenen (University of Ottawa Heart Institute, Ottawa); Lars Lindholm (Lund University, Lund); Liu Lisheng (Chinese Academy of Medical Sciences, Beijing); AFB Mabadeje (University of Lagos, Lagos); Stephen MacMahon (University of Auckland, Auckland); Giuseppe Mancia (Ospedale San Gerardo, Monza); Ingrid Martin (World Health Organization, Geneva); Albert Mimran (Hopital Lapeyronie, Montpellier); Karl-Heinz Rahn (University of Munster, Munster); Arturo Ribeiro (UNIFESP EPM, Sao Paulo); Peter Sleight (University of Oxford, Oxford); Judith Whitworth (Commonwealth Department of Health and Family Services, Canberra); Alberto Zanchetti (University of Milan, Milan).
Writing Committee: John Chalmers (chairman), Stephen MacMahon, Giuseppe Mancia and Judith Whitworth, with assistance from Laurie Beilen, Lennart Hansson, Bruce Neal, Anthony Rodgers, Cliona Ni Mhurchu and Taane Clark (University of Auckland, Auckland).
1. Uemura K, Pisa Z. Trends in cardiovascular disease mortality in industrialised countries since 1950. Wld Hlth Statist Quart 1988;41:155-168.
2. Burt VL, Cutler JA, Higgins M, Horan MJ, Labarthe D, Whelton P, Brown C, Roccella EJ. Trends in the prevalence, awareness, treatment, and control of hypertension in the adult US population. Data from the Health Examination Surveys, 1960 to 1991. Hypertension 1995;26:60-69.
3. Marques-Vidal P, Tuomilehto J. Hypertension awareness, treatment and control in the community: is the "rule of halves" still valid? J Human Hyperten 1997; 11:213-220.
4. Colhoun HM, Dong W, Poulter NR. Blood pressure screening, management and control in England: results from the health survey for England 1994. J Hypertens 1998;16:747-752.
5. Murray CJL, Lopez AD, eds. The Global Burden of Disease. A comprehensive assessment of mortality and disability from diseases, injuries, and risk factors in 1990 and projected to 2020. World Health Organization. Harvard University Press, 1996.
6. WHO Expert Committee. Hypertension Control. WHO Technical Report Series no 862. Geneva: World Health Organization 1996:
7. Eastern Stroke and Coronary Heart Disease Collaborative Research Group. Blood pressure, cholesterol and stroke in Eastern Asia. Lancet 1998; In press
8. MacMahon S, Peto R, Cutler J, Collins R, Sorlie P, Neaton J, Abbott R, Godwin J, Dyer A, Stamler J. Blood pressure, stroke, and coronary heart disease. Part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990;335:765-774.
9. Prospective Studies Collaboration. Cholesterol diastolic blood pressure, and stroke: 13,000 strokes in 45,000 people in 45 prospective cohorts. Lancet 1995;346:1647-1653.
10. Kannel WB, Casteili WP, McNamara PM, McKee PA, Feinleib M. Role of blood pressure in the development of congestive heart failure. The Framingham Study. N Engl J Med 1972;287:781787.
11. Klag MJ, Whelton PK, Randall BL, Neaton JD, Brancati FL, Ford CE, Shulman NB, Stamler J. Blood pressure and end-stage renal disease in men. N Engl J Med 1996;334: 13-18.
12. Rodgers A, Neal B, MacMahon S. The effects of blood pressure lowering in individuals with cerebrovascular disease: an overview of randomised controlled trials. Neurol Rev Int 1997;2: 12-15.
13. Flack J, Neaton J, Grimm R, Shih J, Cutler J, Ensrud K, MacMahon S, for the Multiple Risk Factor Intervention Trial Research Group. Blood pressure and mortality among men with prior myocardial infarction. Circulation 1995;92:2437-2445.
14. Neal B, Clark T, MacMahon S, Rodgers A, Baigent C, Collins R. Blood pressure and the risk of recurrent vascular disease. Am J Hypertens 1998; 11 (4 (part 2)):25A.
15. Irie K, Yamaguchi T, Minematsu K, Omae T. The J-curve phenomenon in stroke recurrence. Stroke 1993;24:1844-1849.
16. Cruickshank JM, Thorp JM, Zacharias FJ. Benefits and potential harm of lowering high blood pressure. Lancet 1987;:581-583.
17. Benetos A, Safar M, Rudnichi A, Smulyan H, Richard JL, Ducimetieere P, Guize L. Pulse pressure: a predictor of long-term cardiovascular mortality in a French male population. Hypertension 1997;30: 1410-1415.
18. Madhavan S, Ooi WL, Cohen H, Alderman MH. Relation of pulse pressure and blood pressure reduction to the incidence of myocardial infarction. Hypertension 1994;23:395-401.
19. Safar ME, London GM, Asmar R, Frohlich ED. Recent advances on large arteries in hypertension. Hypertension 1998;32:156-161.
20. Blacher J, Pannier B, Guerin AP, Marchais SJ, Safar ME, London GM. Carotid arterial stiffness as a predictor of cardiovascular and all-cause mortality in end-stage renal disease. Hypertension 1998;32:570-574.
21. Safar ME, Girerd X, Laurent S. Structural changes of large conduit arteries. J Hypertens 1996;14:545-555.
22. Giannattasio C, Failla M, Mangoni M, Scandola L, Fraschnin N, G. M. Evaluation of arterial compliance in humans. Clin Exp Hypertens 1996;18:347-362.
23. World Health Organization. World Health Statistics Annual. Geneva: World Health Organization, 1995.
24. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991 ;325:293-302.
25. UK-TIA Study Group. The United Kingdom transient ischemic attack (UK-TM) aspirin trial: final results. J Neurol Neurosurgery, Psychiatry 1991 ;54: 1044-1054.
26. The LIPID Study Group. Prevention of mortality and cardiovascular events with pravastatin in 9,014 patients with coronary heart disease and broad range of cholesterol levels. N Engl J Med 1998;1n press
27. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992;327:685-691.
28. Wong ND, Levy D, Kannel WB. Prognostic significance of the electrocardiogram after Q wave myocardial infarction. The Framingham Study. Circulation 1990;81:780-789.
29. MacMahon S, Collins G, Rautaharju P, Cutler J, Neaton J, Prineas R, Crow R, Stamler J, for the Multipie Risk Factor Intervention Trial Research Group. Electrocardiographic left ventricular hypertrophy and effects of antihypertensive drug therapy in hypertensive participants in the Multiple Risk Factor Intervention Trial. Am J Cardiol 1989;63:202-210.
30. Levy D, Garrison R, Savage D, Kannel W, Castelli W. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl JMed 1990;322:1561-1566.
31. Salonen JT, Salonen R. Ultrasonographically assessed carotid morphology and the risk of coronary heart disease. Arterioscler & Throm 1991;11:1245-1249.
32. Zanchetti A, Agatiti RE, Dal PC, Lernetti G, Magnami B, Pessina A, for the VHAS Investigators. The Verapamil in Hypertension and Atherosclerosis Study (VHAS): results of long-term randomised treatment with either verapamil or chlorthalidone on carotid intima-media thickness. J Hypertens 1998;16 (Nov):ln press.
33. Shulman NB, Ford CE, Hall WD, Blaufox MD, Simon D, Longford HG, Schneider KA, on behalf of the Hypertension Detection and Follow-up Program Group. Prognostic value of serum creatinine and effect of treatment of hypertension on renal function. Hypertension 1989;13(Suppl 1):90-93.
34. Samuelsson O, Wilhelmsen L, Elmfeldt D, Pennert K, Wedel H, Wikstrand J, Berglund G. Predictors of cardiovascular morbidity in treated hypertension: Results from the Primary Preventive Trial in Goteborg, Sweden. J Hypertens 1985;3:167-176.
35. US Renal Data System. USRDS 1997 Annual Report. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases 1997:
36. Gall M-A, Borch-Johnsen B, Hougaard P, Nielsen FS, Parving H-H. Albuminuria and poor glycemia control predict mortality in NIDDM. Diabetes 1995;44:1303-1309.
37. Stamler J, Vaccaro O, Neaton JD, Wentworth D, for the Multiple Risk Factor Intervention Trial Research Group. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993;16:434-444.
38. Abbott RD, Donahue RP, MacMahon SW, Reed DM, Yano K. Diabetes and the risk of stroke: The Honolulu Heart Project. JAMA 1987;257:949-952.
39. Despres J-P, Lamarche B, Mauriege P, Cantin B, Dagenais GR, Moorjani S, P-J. L. Hyperinsulinemia is an independent risk factor for ischemic heart disease. N Engl J Med 1996;334:952-957.
40. Gerstein HC, Yusuf S. Dysglycaemia and risk of cardiovascular disease. Lancet 1996;347:949-950.
41. Doll R, Peto R, Wheatley K, Gray R, Sutherland I. Mortality in relation to smoking: 40 years' observations on male British doctors. Br Med J 1994;309:901 -111.
42. Law MR, Wald NJ, Thompson SG. By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease? Br Med J 1994;308:367-373.
43. Gordon DJ , Probstfield J L, Garrison RJ , Neaton J D, Castelli WP, Knoke J D, Jacobs DR, Bangdiwala S, Tyroler HA. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation 1989;79:8-15.
44. Rimm EB, Stampfer MJ, Ciovannucci E, Ascherio A, Spiegelman D, Colditz GA, Willett WC. Body size and fat distribution as predictors of coronary heart disease among middle-aged and older US men. Am JEpidemiol 1995;141:1117-1127.
45. Stampfer MJ, Sacks FM, Salvini S, Willett WC, Hennekens CH. A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction. N Engl J Med 1991;325:373-381.
46. Stern MP, Haffner SM. Body fat distribution and hyperinsulinemia as risk factors for diabetes and cardiovascular disease. Arteriosclerosis 1986;6:123-130.
47. Woodward M, Lowe GDO, Rumley A, Tunstall-Pedoe H. Fibrinogen as a risk factor for coronary heart disease and mortality in middle-aged men and women. The Scottish Heart Health Study. Eur Heart J 1998;19:55-62.
48. Ernst E, Resch KL. Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature. Ann Intern Med 1993; 118:956-963.
49. Rimm ER, Klatsky A, Grobbee D, Stampher MJ. Review of moderate alcohol consumption and reduced risk of coronary heart disease: is the effect due to beer, wine or spirits? Br Med J 1996;312:731-716.
50. Thun MJ, Peto R, Lopez AD, Monaco JH, Henley SJ, C.W. H, Doll R. Alcohol consumption and mortality among middle-aged and elderly US adults. N Engl J Med 1997;337:1705-1714.
51. Wannamethee SG, Shaper AG. Patterns of alcohol intake and risk of stroke in middle-aged British men. Stroke 1996;27: 1033-1039.
52. Leon AS, Myers MJ, Connett J, for the MRFIT Research Group. Leisure time physical activity and the 16-year risks of mortality from coronary heart disease and all-causes in the Multiple Risk Factor Intervention Trial (MRFIT). Int J Sports Med 1997;18(Suppl 3):S208-S215.
53. Arakawa K. Effect of exercise on hypertension and associated complications. Hypertens Res 1996; 19(Suppl): S87-S91.
54. Grodstein F, Stampfer JJ, Colditz GA, Willett WC, Manson JE, Joffe M, Rosner B, Fuchs C, Hankinson SE, Hunter DJ, Hennekens CH, Speizer FE. Postmenopausal hormone therapy and mortality. N Engl J Med 1997;336:1769-1775.
55. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS). JAMA 1998;280:605-613.
56. Davey-Smith G, Neaton JD, Wentworth D, Stamler R, Stamler J. Socioeconomic differentials in mortality risk among men screened for the Multiple Risk Factor Intervention Trial: I. White men. Am J Pub Health 1996;86:486-496.
57. Whitlock G, MacMahon S, Vander Hoorn S, Davis P, Jackson R, Norton R. Socioeconomic distribution of smoking in a population of 10,529 New Zealanders. NZ Med J 1997;110:327-330.
58. Sheth T, Bosch J, Chen J, Anand S, Nargundkar M, Nair C, Yusuf S. Ethnic differences in socioeconomic status and mortality. 50th annual meeting of the Canadian Cardiovascular Society. Can J Cardiol 1997;13(Suppl C):89C.
59. Tipene-Leach D, Stewart A, Beaglehole R. Coronary heart disease mortality in Auckland Maori and Europeans. NZMedJ 1991;104:55-57.
60. Lee EJ, Cowan LD, Welty TK, Sievers M, Howard WJ, Oopik A, Wang W, Yeh J, Devereux RB, Rhoades ER, Fabsitz RR, Go O, Howard BV. All-cause mortality and cardiovascular disease mortality in three American Indian populations, aged 45-74 years, 1984-1988. The Strong Heart Study. Am J Epidemiol 1998;147:995-1008.
61. Broderick J, Brott T, Kothari R, Miller R, Khoury J, Pancioli A, Gebel J, Mills D, Minneci L, Shukla R. The Greater Cincinnati/Northern Kentucky Stroke Study. Preliminary first-ever and total incidence rates of stroke among blacks. Stroke 1998;29:415421.
62. Klag MJ, Whelton PK, Randall BL, Neaton JD, Brancati FL, Stamler J. End-stage renal disease in African-American and white men. JAMA 1997;277:1293-1298.
63. Cappuccio FP. Ethnicity and cardiovascular risk: variations in people of African ancestry and South Asian origin. J Human Hyperten 1997; 11:571 -576.
64. Sheth T, Nair C, Nargundkar M, Anand S, Yusuf S. Cardiovascular and cancer mortality among Whites, South Asians, and Chinese in Canada from 1979 to 1993: An analysis of 2.6 million deaths. Can MedAssoc J 1998;1n press
65. WHO-MONICA Project, Tunstall-Pedoe H, Kuulasmaa K, Amouyel P, Arveiler D, Rajakangas AM, Pajak A. Myocardial infarction and coronary deaths in the World Health Organization MONICA Project. Registration procedures, event rates, and case-fatality rates in 38 populations from 21 countries in four continents. Circulation 1994;90:583-612.
66. WHO-MONICA Project, Stegmayr B, Asplund K, Kuulasmaa K, Rajakangas A-M, Thorvaldsen P, Tuomilehto J. Stroke incidence and mortality correlated to stroke risk factors in the WHO MONICA Project. An ecological study of 18 populations. Stroke 1997;28:1367-1374.
67. Yao C, Wu Z, Wu Y. The changing pattern of cardiovascular diseases in China. Wld Hlth Statist Quart 1993 ;46: 113-118.
68. Collins R, Peto R, MacMahon S, Herbert P, Fiebach NH, Eberiein KA, Godwin J, Qizibash N, Taylor JO, Hennekens CH. Blood pressure, stroke, and coronary heart disease. Part 2, short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet 1990;335:827-839.
69. Collins R, MacMahon S. Blood pressure, antihypertensive drug treatment and the risks of stroke and of coronary heart disease. Br Med Bull 1994;50:272-298.
70. MacMahon S, Rodgers A. The effects of antihypertensive treatment on vascular disease: reappraisal of the evidence in 1994. Joumal of Vascular Medicine and Biology 1993;4:265-271.
71. Messerli FH, Grossman E, Goldbourt U. Are beta-blockers efficacious as first-line therapy for hypertension in the elderly? A systematic review. JAMA 1998;279: 1903-1907.
72. Medical Research Council Working Party. MRC trial of treatment of mild hypertension: principal results. Br Med J 1985;291 :97-104.
73. Medical Research Council Working Party. Medical Research Council trial of treatment of hypertension in order adults: principal results. Br Med J 1992;304:405-412.
74. The IPPPSH Collaborative Group. Cardiovascular risk and risk factors in a randomised trial of treatment based on the beta-blocker oxprenolol: the international prospective primary prevention study in hypertension (IPPPSH). J Hypertens 1985;3:379-392.
75. Wilhelmsen L, Berglund G, Elmfeld D, Fitzsimons T, Holzgreve H, Hosie J, Hornkvist P-E, Pennert K, Tuomilehto J, Wedel H, on behalf of the Heart Attack Primary Prevention in Hypertension Trial Research Group. Beta-blockers versus diuretics in hypertensive men. Main results from the HAPPHY trial. J Hypertens 1987;5:561-572.
76. Kostis JB, Davis BR, Cutler J, R.H. G, Berge KG, Cohen JD, Lacy CR, Perry HM, Blaufox MD, Wassertheil-Smoller S, Black HR, Schron E, Berkson DM, Curb JD, McFate Smith W, McDonald R, Applegate WB, for the SHEP Cooperative Research Group. Prevention of heart failure by antihypertensive drug treatment in older persons with isolated systolic hypertension. JAMA 1997;278(212-216)
77. Yusuf S, Thomas T, Abbott RD. Changes in hypertension treatment and in congestive heart failure mortality in the United States. Hypertension 1989;13(Suppl 1):1-74-1-79.
78. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991;265:3255-3264.
79. Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhager WH, Bulpitt CJ, De Leeuw PW, Dollery CT, Fletcher AK, Forette F, Leonetti G, Nachev C, O'Brien ET, Rosenfeld J, Rodicio JL, Tuomilehto J, Zanchetti A, for the Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997;350:757-764.
80. Gong L, Zhang W, Zhu Y, Zhu J, 11 collaborating centres in the Shanghai area, Kong D, Page V, Ghadirian P, LeLorier J, Hamet P. Shanghai trial of nifedipine in the elderly (STONE). J Hypertens 1996;14:1237-1245.
81. Liu L, Wang JG, Gong L, Liu G, Staessen JA, for the Systolic Hypertension in China (SystChina) Collaborative Group. Comparison of active treatment and placebo for older Chinese patients with isolated systolic hypertension. J Hypertens 1998; I n press
82. Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Nikiason A, Luomannmaki K, Dahlof B, de Faire U, Morlin C, Karlberg BE, Wester PO, Bjorck J-E, for the CAPPP Study Group. Principal results of the Captopril Prevention Project (CAPPP). Lancet 1998; in press.
83. UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. Br Med J 1998;317:713-720.
84. Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Menard J, Julius S, Rahn KH, Wedel H, Westerling S, for the HOT Study Group. Effects of intensive blood pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998;351:1755-1762.
85. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. Br Med J 1998;317:703-713.
86. Ad Hoc Subcommittee of the Liaison Committee of the World Health Organisation and the International Society of Hypertension. Effects of calcium antagonists on the risks of coronary heart disease, cancer end bleeding. JHypertens 1997;15:105-115.
87. Lever AF, Hole DJ, Gillis CR, McCallum IR, McInnes GT, MacKinnon PL, Meredith PA, Murray LS, Reid JL, Robertson JWK. Do inhibitors of angiotensin-l-converting enzyme protect against risk of cancer? Lancet 1998;352: 179-184.
88. Forette F, Seux MC, Thijs L, Staessen JA. Antihypertensive treatment and prevention of dementia in older patients with isolated systolic hypertension: the Syst-Eur results. J Hypertens 1998;16(Suppl2):S22 (abstract 29Z21).
89. Mancia G, Sega R, Miiesi C, Cesana G, Zanchetti A. Blood pressure control in the hypertensive population. Lancet 1997;349:454-457.
90. Tao S, Wu X, Duan X, Fang W, Hao J, Fan D, Wang W, Li Y. Hypertension prevalence and status of awareness, treatment and control in China. Chin Med J 1995; 108:483-489.
91. Isles CG, Walker LM, Beevers GD, Brown I, Cameron HL, Clarke J, Hawthorne V, Hole D, Lever AF, Robertson JWK, Wapshaw JA. Mortality in patients of the Glasgow Blood Pressure Clinic. J Hypertens 1986;4:141-156.
92. Gamble G, MacMahon S, Culpan A, Ciobo C, Whalley G, Sharpe N. Atherosclerosis and left ventricular hypertrophy: persisting problems in treated hypertensive patients. J Hypertens 1998; 16:1389-1395.
93. Tang JL, Armitage JM, Lancaster T, Silagy CA, Fowler GH, Neil HAW. Systematic review of dietary intervention trials to lower blood total cholesterol in free-living subjects. Br Med J 1998;316:1213-1220.
94. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344 1383-1389.
95. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ, for the West of Scotland Coronary Prevention Study group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333(20):13011307.
96. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JMO, Wun CC, Davis BR, Braunwald E, for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996; 335: 1001 -1009.
97. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM, for the AFCAPSITexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998;279:1615-1622.
98. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-853.
99. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with mefformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854-865.
100. Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy - I: Prevention of death, myocardial infarction and stroke by prolonged antiplatelet therapy in various categories of patients. BrMedJ 1994;308:81-106.
101. Hennekens CH, Buring JE, Peto R. Antioxidant vitamins - benefits no yet proved. N Engl J Med 1994;330: 1080-1081.
102. Mancia G, Parati G, Di Rienzo M, Zanchetti A. Blood pressure variability. In: Zanchetti A, Mancia G, (eds). Handbook of Hypertension. Pathophysiology of hypertension. Elsevier Science, 1997:117-169. vol 17.
103. Laragh JH, Brenner BM, eds. Hypertension: Pathophysiology, Diagnosis and Management. 2nd ed. New York: Raven Press, 1995. vol 2, chapters 112-115, p 1897-1952.
104. Swales JD, ed. Textbook of Hypertension. London: Blackwell, 1994. Chapter 55, p 989-1008
105. Ohkubo T, Imai Y, Tsuji I, Nagai K, Kato J, Kikuchi N, Nishiyama A, Aihara A, Sekino M, Kikuya M, Ito S, Satoh H, Hisamichi S. Home blood pressure measurement has a stronger predictive power for mortality than dose screening blood pressure measurement: a population-based observation in Ohasama, Japan. J Hypertens 1998;16:971-975.
106. Mancia G, Di Rienzo M, Parati G. Ambulatory blood pressure monitoring use in hypertension research and clinical practice. Hypertension 1993;21:510-524.
107. Mancia G, Sega R, Bravi D, De Vito G, Valagussa F, Cesana G, Zanchetti A. Ambulatory blood pressure normality: results from the PAMELA Study. J Hypertens 1995; 13:1377-1390.
108. Pyorala K, Graham I, Mancia G, Poole-Wilson P, Wood D, on behalf of the Task Force,. Prevention of coronary heart disease in clinical practice. Recommendations of the Task Force of the European Society of Cardiology, European Atherosclerosis Society and European Society of Hypertension. Eur Heart J 1998;1n press
109. Zanchetti A, Bond MG, Henning M, Neiss A, Mancia G, Dai Palu C, Hansson L, Magnani B, Rahn K-H, Reid J, Rodicio J, Safar M, Eckes L, Ravinetto R, on behalf of the ELSA Investigators. Risk factors associated with alterations in carotid intima-media thickness in hypertension: baseline data from the European Lacidipine Study on Atherosclerosis. J 16/11/98 Hypertens 1998;16:949-961.
110. Fagard RH, Staessen JA, Thijs L. Prediction of cardiac structure and function by repeated clinic and ambulatory blood pressure. Hypertension 1997;29:22-29.
111. Perloff D, Sokolow M, Cowan R, Juster R. Prognostic value of ambulatory blood pressure measurement. J Hypertens 1989;7(Suppl 3):S3-S10.
112. Verdecchia P, Porcellati C, Shillaci G, Borgioni C, Ciucci A, Battistelli M. Ambulatory blood pressure: an independent predictor of prognosis in essential hypertension. Hypertension 1994;24:793-801.
113. Redon J, Campos C, Narciso ML, J.L. R, Pasquale JM, Ruilope LM. Prognostic value of ambulatory blood pressure monitoring in refractory hypertension: a prospective study. Hypertension 1998;31:712-718.
114. Ohkubo T, Imai Y, Tsuji I, Nagai K, Ito S, Satoh H, Hisamichi S. Reference values for 24-hour ambulatory blood pressure monitoring based on a prognostic criterion: Ohasama study. Hypertension 1998;32:255-259.
115. Mancia G, Zanchetti A, Agebiti-Rosei E, Benemio G, De Cesaris R, Fogari R, Pessino A, Porcellati C, Salvetti A, Trimarco B, for the SAMPLE Study Group. Ambulatory blood pressure is superior to clinic blood pressure in predicting treatment-induced regression of left ventricular hypertrophy. Circulation 1997;95: 1464-1470.
116. Mancia G, Omboni S, Parati G. Assessment of antihypertensive treatment by ambulatory blood pressure. J Hypertens 1997; 15(Suppl 2): S43-S50.
117. Pickering TG, James GD, Boddie C, Harshfield GA, Blank S. How common is white coat hypertension? JAMA 1988;259:225-228.
118. Mancia G, Zanchetti A. Editors' corner: white-coat hypertension: misnomers, misconceptions and misunderstandings. What should we do next? J Hypertens 1996;14:1049-1052.
119. Parati G, Ulian L, Santicciu C, Omboni S, Mancia G. Difference between clinic and daytime blood pressure is not a measure of the white coat effect. Hypertension 1998;31 :1185-1189.
120. Mancia G, Parati G, Pomidossi G, Grassi G, Casadei R, Zanchetti A. Alerting reaction and rise in blood pressure during measurement by physician and nurse. Hypertension 1987;9:209-215.
121. Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. The fifth report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC V). Arch Intern Med 1993;153:154-183.
122. Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. The sixth report of the Joint National Committee on Prevention, Detection, and Treatment of High Blood Pressure (JNC VI). Arch Intern Med 1997;157:2413-2446.
123. The Guidelines Subcommittee of the WHO-ISH Mild Hypertension Liaison Committee. 1993 Guidelines for the Management of Mild Hypertension. Memorandum from a World Health Organization-International Society of Hypertension Meeting. J Hypertens 1993;11:905-918.
124. Chalmers J, Zanchetti A. Reply to a critique of the 1996 World Health Organisation expert committee report on hypertension. J Hypertens 1997; 15:684-685.
125. Lindholm L, Ejlertsson G, Schersten B. High risk of cerebrovascular morbidity in well treated male hypertensives: a retrospective study of 40-59 year old hypertensives in a Swedish primary care district. Acta Med Scand 1984;216:251-259.
126. Silagy C, Mant D, Fowler G, Lodge M. Meta-analysis on effficacy of nicotine replacement therapies in smoking cessation. Lancet 1994;343:139-142.
127. Stamler J. Epidemiologic findings on body mass and blood pressure in adults. Ann Epidemiol 1991; 1: 347-362.
128. Reid CM, Dart AM, Dwar EM, Jennings GL. Interactions between the effects of exercise and weight loss on risk factors, cardiovascular haemodynamics and left ventricular structure in overweight subjects. J Hypertens 1994;12:291-301.
129. Puddey IB, Parker M, Beiling LJ, Vandongen R, Masarei JRL. Effects of alcohol and caloric restrictions on blood pressure and serum lipids in overweight men. Hypertension 1992;20:533541.
130. Whelton PK, Appel LJ, Espeland MA, Applegate WB, Ettinger WH, Kostis JB, Kumanylaka S, Lacy CR, Johnson KC, Folmar S, Cutler JA, for TONE Collaborative Research Group. Sodium reduction and weight loss in the treatment of hypertension in older persons. A randomized controlled trial of nonpharmacologic interventions in the elderly (TONE). JAMA 1998;279:839846.
131. Puddey IB, Beilin LJ, Rakic V. Alcohol, hypertension and the cardiovascular system: A critical appraisal. Addiction Biol 1997;2:159-170.
132. Puddey IB, Beilin LJ, Vandongen R. Regular alcohol use raises blood pressure in treated hypertensive subjects. A randomized controlled trial. Lancet 1987;i:647-651.
133. Law MR. Epidemiological evidence on salt and blood pressure. Am J Hypertens 1997;10:42S45S.
134. Cutler JA, Follman D, Alexander PS. Randomised controlled trials of sodium reduction: An overview. Am J Clin Nutr 1997;65 (Suppl):643S-651S.
135. Rouse IL, Armstrong BK, Beilin LJ. The relationship of blood pressure to diet and lifestyle in two religious populations. J Hypertens 1983;1 :65-71.
136. Margetts BM, Beilin LJ, Vandongen R, Armstrong BK. Vegetarian diet in mild hypertension: A randomized controlled trial. Br Med J 1986;293:1468-1471.
137. Appel LJ, Moore TJ, Obarzanek E, Vollmer WM, Svetkey LP, Sacks FM, Bray GA, Vogt TM, Cutler JA, Whindhauser MM, Lin PH, Karanja N. A clinical trial of the effects of dietary patterns on blood pressure. N Engl J Med 1997; 336:1117-1124.
138. Bao DG, Mori TA, Burke V, Puddey IB, Beilin LJ.
Effects of dietary fish and weight reduction on ambulatory blood pressure
in overweight hypertensives. Hypertension 1998;32:710-717.
140. Arakawa K. Antihypertensive mechanism of exercise. J Hypertens 1993; 11 :223-229.
141. Fagard RH. The role of exercise in blood pressure control: supportive evidence. J Hypertens 1995; 13:1223-1227.
142. Puddey IB, Cox K. Exercise lowers blood pressure - sometimes? Or did Pheidippides have hypertension? J Hypertens 1995; 13:1229-1233.
143. Beilin LJ. Stress coping, lifestyle and hypertension: A paradigm for research prevention and non-pharmacological management of hypertension. Clin Exp Hypertens 1997;19:739-752.
144. Lindquist TL, Beilin LJ, Knuiman MW. Influence of lifestyle, coping and job stress on blood pressure in men and women. Hypertension 1997;29:1-7.
145. Nyklicek I, Vingerhoets JJM, Van Heck GL. Hypertension and objective and self-reported stressor exposure: A review. J Psychosom Res 1996;40:585-601.
146. Pickering TG, Devereux RB, James GD, Gerin W, Landsbergis P, Schnall PL, Schwartz JE. Environmental influences on blood pressure and the role of job strain. J Hypertens 1996;14(Suppl 5):S179-S185.
147. Parati G, Pomidossi G, Albini F, Malaspina D, Mancia G. Relationship of 24 hour blood pressure mean and variability to severity of target organ damage in hypertension. Hypertension 1987;5:93-98.
148. Frattola A, Parati G, Cuspidi G, Albini F, Mancia G. Prognostic value of 24 hour blood pressure variability. J Hypertens 1993; 11:1133-1137.
149. Siscovick D, Raghunathan T, Psaty B, Keopsell T, Wicklund K, Xiphong Lin M, Cobb L, Rantaharju P, Copass M, Wagner E. Diuretic therapy for hypertension and the risk of primary cardiac arrest. N Engl J Med 1994;330: 1852-1857.
150. Hoes A, Grobbee D, Lubsen J, Man in't Veld A, Van der Does E, Hofman A. Diuretics, betablockers, and the risk of sudden cardiac death in hypertensive patients. Ann Intem Med 1995; 123:481 -187.
151. Doughty R, Rodgers A, Sharpe N, MacMahon S. Effects of beta-blocker therapy on mortality in patients with heart failure. Eur Heart J 1997; 18:560-565.
152. Yasue H, Kugiyama K. Coronary spasm: Japanese View. Coronary Artery Dis 1990;1 :668-673.
153. Garg R, Yusuf S, for the Collaborative Group on ACE Inhibitor Trials. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA 1995;273: 1450-1456.
154. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD, for the Collaborative Study Group. The effect of angiotensin converting enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 1993; 329: 1456-1462.
155. Israili Z, Hall W. Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy. A review of the literature and pathophysiology. Ann Intern Med 1992; 117:234-242.
156. Johnston C. Angiotensin receptor antagonists: focus on losartan. Lancet 1995;346:1403-1407.
157. Neaton JD, Grimm RH, Prineas RJ, Stamler J, Grandits GA, Elmer PJ, Cutler JA, Flack JM, Schoenberger JA, McDonald R, Lewis CE, Liebson PR, for the Treatment of Mild Hypertension Study Research Group. Treatment of Mild Hypertension Study. Final results. JAMA 1993;270:713-724.
158. Brown MA, Whitworth JA. Pregnancy. In: Bennett WM, McCarron DA, (eds). Contemporary Issues in Nephrology: Pharmacology and Management of Hypertension. New York: Churchill Livingstone, 1994: 89-116. vol 28.
159. Cooper RS, Liao Y, Rotimi C. Is hypertension more severe among US Blacks, or is severe hypertension more common? Ann Epidemiol 1996;6: 173-180.
160. Bullen C, Tipene-Leach D, Vander Hoorn S, Jackson R, Norton R, MacMahon S. Ethnic differences in blood pressure: findings from the Fletcher Challenge-University of Auckland University Heart and Health Study. NZMedJ 1996;109:395-397.
161. World Health Organization-International Society of Hypertension Blood Pressure Lowering Treatment Trialists' Collaboration. Protocol for prospective collaborative overviews of major randomized trials of blood pressure lowering treatments. J Hypertens 1998;16:127-137.
162. National High Blood Pressure Education Program Working Group. National High Blood Pressure Education Program Working Group Report on High Blood Pressure in Pregnancy. American Journal of Obstetrics and Gynecology. 1990:1689-1712. vol 163).
163. Australasian Society for the Study of Hypertension in Pregnancy. Management of hypertension in pregnancy: executive summary. Med J Aust 1993; 158:700-702.
164. Collins R, Yusuf S, Peto R. Overview of randomised trials of diuretics in pregnancy. Br Med J Clin Res Ed 1985;290:17-23.
165. CLASP Collaborative Group. CLASP: a randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. Lancet 1994;343:619-629.
166. MacMahon S, Rodgers A. The effects of blood pressure reduction in older patients: an overview of five randomized controlled trials in elderly hypertensives. J Clin Exp Hypert 1993; 15:967-978.
167. Dahlof B, Lindeholm LH, Hansson L, Schersten B, Ekbom T, Wester PO. Morbidity and mortality in the Swedish trial in old patients with hypertension (STOP-Hypertension). Lancet 1991 ;338:1281-1285.
168. Staessen JA, Fagard R, Thijs L, Celis H, Birkenhager WH, C.J. B, de Leeuw PW, Fletcher AK, Babarskiene M-R, Forette F, Kocemba J, Laks T, Leonetti G, Nachev G, Petrie JC, Tuomilehto J, Vanhanen H, Webster J, Yodfat Y, Zanchett A, for the Systolic Hypertension in Europe Trial Investigators. Subgroup and per-protocol analysis of the randomized European Trial on Isolated Systolic Hypertension in the Elderly. Arch Intern Med 1998;158:1681-1691.
169. The INDANA (INdividual Data ANalysis of Antihypertensive interventional trials) Project Collaborators, Gueyfffier F, Boissel J-P, Boutitie F, Pocock S, Coope J, Cutler J, Ekbom T, Fagard R, Friedman L, Kerlikowske K, Perry M, Prineas R, Schron E. Effect of antihypertensive treatment in patients having already suffered from stroke. Gathering the evidence. Stroke 1997;28:2557-2562.
170. PROGRESS Management Committee. Blood pressure lowering for the secondary prevention of stroke: rationale and design for PROGRESS. J Hypertens 1996;14(suppl 2):S41-S46.
171. Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 1985;27:335-371.
172. Lonn EM, Yusuf S, Jha P, Montague TJ, Teo KK, Benedict CR, Pitt B. Emerging role of angiotensin-converting enzyme inhibitors in cardiac and vascular protection. Circulation 1994;90:2056-2069.
173. The HOPE Study Investigators. The HOPE (Heart Outcome Prevention Evaluation) Study: the design of a large, simple randomised trial of an angiotensin converting enzyme inhibitor (ramipril) and vitamin E in patients at high risk of cardiovascular events. Can J Cardiol 1996;12:127-137.
174. Brown MA, Whitworth JA. Hypertension in human renal disease. J Hypertens 1992; 10:701 -712.
175. Iseki K, Ikemiya Y, Fukiyama K. Blood pressure and risk of end-stage renal disease in a screened cohort. Kidney Int 1996;49(S55):S69-71.
176. Ritz E, Rambausek M, Hasslacher C, Mann J. Pathogenesis of hypertension in renal. Am J Nephrol 1989;9:85-90.
177. Krolewski AS, Canessa M, Warran JH, Laffel LMB, Christlich AR, Knowler WC, Rand Ll. Predisposition to hypertension and susceptibility to renal disease in insulin dependent diabetes mellitus. N Engl J Med 1988;318: 140-145.
178. Bergstrom J, Alvestrand A, Bucht H, Gutlerrez A. Progression of chronic renal failure in man is retarded with more frequent clinical follow-ups and better blood pressure control. Clin Nephrol 1986;25: 1 -6.
179. Ihle BU, Whitworth JA, Shahinfar S, Cnaan A, Kincaid-Smith PS, Becker GJ. Angiotensin converting enzyme inhibition in non-diabetic progressive renal insufficiency: a controlled double-blind trial. Am J Kidney Dis 1996;27:489-495.
180. Peterson JC, Adler S, Bukart JM, Greene T, Hebert LA, Hunsicker LG, King AJ, Klahr S, Massry SG, Seifter JL, for the Modification of Diet in Renal Disease (MDRD) Study Group. Blood pressure control, proteinuria and the progression of renal disease. Ann Intem Med 1995; 123:754-762.
181. Simonson DC. Etiology and prevalence of hypertension in diabetic patients. Diabetes Care 1988; 11:821 -827.
182. Epstein M, Sowers JR. Diabetes mellitus and hypertension. Hypertension 1992;19:403-418.
183. Reaven GM, Lithell H, Lansberg L. Hypertension and associated metabolic abnormalities. The role of insulin resistance and the sympathoadrenal system. N Engl J Med 1996;334:374-381.
184. Haffner SM. Insulin and blood pressure: fact or fantasy? J Clin Endocrinol Metab 1993;76:541542.
185. Grossman E, Messerli FH. Diabetic and hypertensive heart disease. Ann Intern Med 1996; 125:304-310.
186. Borch-Johnson K, Nissen R, Nerup J. Blood pressure after 40 years of insulin-dependent diabetes. Nephron 1985;4: 11 -12.
187. Mogensen CE. Long-term antihypertensive treatment inhibiting progression of diabetic nephropathy. Br Med J 1982;285:685-688.
188. Knowler WC, Bennett PH, Ballintine EJ. Increased incidence of retinopathy in diabetics with elevated blood pressure. N Engl J Med 1980;302:645-650.
189. Chaturvedi N, Sjolie A-K, Stephenson JM, Abrahamian H, Keipes M, Castellarin A, Rogulja-Pepenok Z, Fuller JH, and the EUCLID Study Group. Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. Lancet 1998;351:28-31.
190. Su HY, Sheu WH, Chin HM, Jeng CY, Chen YD, Reaven GM. Effect of weight loss on blood pressure and insulin resistance in normotensive and hypertensive obese individuals. Am J Hypertens 1995;8:1067-1071.
191. Lithell HO. Hyperinsulinemia, insulin resistance, and the treatment of hypertension. Am J Hypertens 1996;9:150S-154S.
192. Kjekshus J, Gilpin E, Cali G, Blackey AR, Henning H, Ross J. Diabetic patients and betablockers after acute myocardial infarction. Eur Heart J 1990;11 :43-50.
193. Tatti P, Pahor M, Byington RP, Di Mauro P, Guarisco R, Strollo G, Strollo F. Outcome results of the Fosinopril versus Amlodipine cardiovascular events randomized trial (FACET) in patients with hypertension and NIDDM. Diabetes Care 1998;21:597-603.
194. Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW. The effect of nisoldipine as compared to enalapril on cardiovascular outcomes in patients with non-insulin dependent diabetes and hypertension. N Engl J Med 1998;338:645-652.
195. Ruilope LM, Garcia-Robles R. How far should blood pressure be reduced in diabetic hypertensive patients? J Hypertens 1997;15(suppl 2):S63-S65.
196. Lomas J. Words without action? The production, dissemination and impact of consensus recommendations. Ann Rev Public Health 1991 ;12:41-65.
197. Davis DA, Thomson MA, Oxman AD, Haynes RB. Evidence for the effectiveness of CME. A review of 50 randomised controlled trials. JAMA 1992;268: 1111 -1117.
198. Oxman AD, Thomson MA, Davis DA, Haynes RB. No magic bullets: a systematic review of 102 trials of interventions to improve professional practice. Can Med Assoc J 1995;153:1423-1431.
199. Grol R, Dalhuijsen J, Thomas S, in 't Veld C, Rutten G, Mokkink H. Atrributes of clinical guidelines that influence use of guidelines in general practice: observational study. Br Med J 1998;317:858-861.