Essential hypertension is almost invariably symptomless, and usually detected by routine screening or opportunistic measurement of blood pressure. Key questions to answer in the assessment of a person presenting with an elevated blood pressure are: (1) Do they have hypertension, i.e. is the blood pressure persistently elevated? (2) Are there any associated clinical features that might warrant further evaluation to exclude secondary causes of hypertension? (3) Are there factors that might be contributing to an elevated blood pressure, including lifestyle or dietary factors or concomitant medication? (4) Is there any associated target organ damage or comorbidity that influences the overall cardiovascular disease risk and subsequent treatment of the patient?
It is normal to find large variations in blood pressure measured in a single individual, hence it should be measured as accurately as possible using the British Hypertension Society protocol. All adults should have their blood pressure measured routinely at least every 5 years. Ambulatory blood pressure measurement (ABPM) recordings provide much more information than standard office blood pressure measurements with regard to diagnosis and efficacy of treatment of hypertension.
The appropriate thresholds for diagnosis of hypertension depending on the method of blood pressure measurement are (1) office or clinic—systolic blood pressure (SBP) 140 mmHg, diastolic blood pressure (DBP) 90 mmHg; (2) APPM 24 h—SBP 125 to 130 mmHg, DBP 80 mmHg; daytime—SBP 130 to 135 mmHg, DBP 85 mmHg; night-time—SBP 120 mmHg, DBP 70 mmHg; and (3) home measurements—SBP 130–135 mmHg, DBP 85 mmHg. The European Society of Hypertension classification of hypertension is described in the technical article on this page: enetmd.com/content/hypertension
Isolated office hypertension (‘white coat’ hypertension) should be diagnosed whenever office blood pressure is greater than or equal to 140/90 mmHg on at least three occasions, while 24-h mean and daytime blood pressures are within their normal range.
Fundoscopy is the most convenient method of directly visualizing vascular pathology and provides important prognostic information: three grades are recognized: (1) mild—generalized and focal arteriolar narrowing, arteriolar wall opacification, and arteriovenous nipping; (2) moderate—as (1) plus flame-shaped blot haemorrhages and/or cotton wool spots and/or hard exudates and/or microaneurysms; and (3) severe—as (2) plus swelling of the optic disc.
Aside from measurement of blood pressure and fundal examination as detailed above, particular features to look for on examination are evidence of secondary effects of sustained hypertension on the heart, and features that might suggest the presence of a secondary cause of hypertension (coarctation—absent/delayed femoral pulses, cardiac murmur; and renovascular disease—renal bruit).
Patients with essential hypertension need only a limited number of routine investigations, which must include (1) urine strip test for protein and blood; (2) serum creatinine and electrolytes; (3) blood glucose—ideally fasted; (4) lipid profile—ideally fasted; and (5) electrocardiogram (ECG).
The treatment of hypertension is directed towards reducing risk rather than treating symptoms. There is international consensus that, for office blood pressure, an optimal treatment target should be less than 140/90 mmHg, with a lower target of less than 130/80 mmHg proposed for higher-risk patients, i.e. those with established cardiovascular or renal disease or diabetes. Although early studies focused primarily on diastolic blood pressure as the treatment target, systolic blood pressure is invariably more difficult to control and should be the main focus of treatment.
The most effective lifestyle interventions for reducing blood pressure are (1) modifications to diet to induce weight loss, (2) regular aerobic exercise, and (3) restrictions in alcohol and sodium intake. Many patients will require more than one drug to control blood pressure: monotherapy is rarely sufficient. The blood pressure response to an individual class of blood pressure-lowering medication is heterogeneous, hence there is no ‘perfect drug’ for every patient, but some trials have indicated that certain comorbidities or target organ damage provide compelling indications for inclusion of specific classes of drug therapy in the treatment regimen.
There is wide variation in the international guidelines with regard to the preferred initial therapy for essential hypertension: (1) the (American) Joint National Committee (JNC) VII guideline recommends low-dose thiazide-type diuretic therapy as initial therapy for all patients (unless contraindicated); (2) the recent European guideline suggests that all five main classes of blood pressure-lowering drugs (angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers, β-blockers, calcium channel blockers, and diuretics) are all suitable as initial therapy; (3) the British Hypertension Society/NICE guideline suggests that a calcium channel blocker (C) or alternatively a diuretic (D) are most likely to deliver the most effective initial blood pressure lowering in older people (i.e. ≥55 years), whereas an ACE inhibitor or an angiotensin receptor blocker (A) are preferred initial therapy for younger patients (<55 years), with the caveat that C or D would be the preferred therapy for people of black African origin at any age.
All guidelines recognize that combinations of blood pressure lowering drugs are often required to achieve recommended blood pressure goals, especially in those with high cardiovascular disease risk or comorbidities who are targeted to lower pressures. Only the British guideline provides explicit guidance on preferred combinations of treatment at step 2, i.e. A + C or A + D, and step 3, i.e. A + C + D.
Patients with hypertension and deemed to be at high cardiovascular risk (>20% over 10 years) should receive advice to adjust their lifestyles and be considered for treatment with statin therapy and low-dose aspirin to optimize their risk reduction.
Indications for specialist referral include uncertainty about the decision to treat, investigations to exclude secondary hypertension, severe and complicated hypertension, and resistant hypertension.
Essential hypertension is invariably symptomless and usually detected by routine screening or opportunistic measurement of blood pressure. However, once a patient has been labelled as ‘hypertensive’ it is not uncommon for them to associate preceding symptoms to their elevated blood pressure. Some patients will claim that they can recognize when their blood pressure is elevated, usually on the basis of symptoms such as plethoric features, palpitations, dizziness, or a feeling of tension. Screening surveys have demonstrated that these symptoms occur no more commonly in untreated hypertensive patients than they do in the normotensive population. However, there are two important caveats to the symptomless nature of essential hypertension: (1) symptoms may develop as a consequence of target organ damage, (2) headache may be a feature of severe hypertension.
Most headaches in hypertensive patients are tension headaches, not related to blood pressure at all, although they become more common when patients become aware of the diagnosis. The classic hypertensive headache is present on waking in the morning, situated in the occipital region, radiating to the frontal area, throbbing in quality, and wears off during the course of the day. It is more commonly associated with more severe hypertension. Effective treatment of hypertension reduces the incidence of such headaches. Morning headaches in obese hypertensive patients may be related to sleep apnoea.
Epistaxis is not associated with mild hypertension but is more common in moderate to severe hypertension. However, the associated anxiety can elevate blood pressure when patients present with bleeding, hence it is particularly important that patients are not automatically labelled as hypertensive, with care taken to dissociate hypertension as a cause of epistaxis from a pressor response to the epistaxis itself.
Patients rarely volunteer information about impotence, but there is an increased prevalence of erectile dysfunction in untreated hypertensive men. This is related to two factors: remodelling of small arteries and increased risk of atheroma, both of which vascular changes can reduce penile blood flow despite the elevation in blood pressure. Furthermore, erectile dysfunction can develop or worsen as a consequence of treatment, for the most part related to the reduction in blood pressure before any concomitant change in vascular structure.
This is common in people with untreated hypertension as a consequence of a reduction in urine-concentrating capacity. The symptoms usually improve with treatment.
Symptoms associated with target organ damage
If patients develop cardiac, vascular, cerebrovascular, and/or renal complications as a consequence of long-standing untreated or poorly treated hypertension, then symptoms related to these complications may be present. Target organ damage and associated symptoms are discussed in the technical article on this page: hypertension
Aims of assessment
There are several important issues that must be considered in the assessment of people presenting with an elevated blood pressure:
- ◆ Does the patient have hypertension, i.e. is the blood pressure persistently elevated?
- ◆ Are there any associated clinical features that might warrant further evaluation to exclude secondary causes of hypertension? (see below and the article on secondary hypertension
- ◆ Are there factors that might be contributing to an elevated blood pressure, including lifestyle or dietary factors or concomitant medication?
- ◆ Is there any associated target organ damage or comorbidity that influences the overall cardiovascular disease risk and subsequent treatment of the patient?
These factors, along with the age and ethnicity of the patient, will inform the decision to treat, the urgency of the need to treat, the need for further investigation, and the choice of treatment.
Blood pressure measurement
Large variations in blood pressure measured in a single individual are normal, hence it should be measured as accurately as possible using the British Hypertension Society (BHS) protocol (Bullet list 2). Blood pressure should initially be measured in both arms because there can be large inter-arm difference in blood pressure. The finding of a difference of greater than 10 mmHg may indicate the presence of underlying vascular disease, especially subclavian stenosis. When there is a significant inter-arm difference in blood pressure reading, the arm with the higher pressure should be used for all subsequent measurements.
All adults should have their blood pressure measured routinely at least every 5 years. Those with high-normal blood pressure (systolic blood pressure (SBP) 130–139 mmHg or diastolic blood pressure (DBP) 85–89 mmHg) and those who have had high blood pressure readings at any time previously should have their blood pressure re-measured annually. These measurements can be made in the clinic, in the home setting, or using ambulatory blood pressure monitoring (ABPM) (see below).
Seated blood pressure recordings are generally sufficient, with the patient seated and rested for a few minutes beforehand. At least two measurements should be taken, and if the first is >10 mmHg higher than the subsequent measurement, then it should be discarded and further reading taken. Standing blood pressure (after at least 2 min standing) should be measured in elderly or diabetic patients to exclude significant orthostatic hypotension.
The timing of blood pressure measurement should take account of the timing of medication. Treatment decisions should not be based on single blood pressure readings: the average of two readings at each of at least three visits (depending on severity) should be used to guide the decision to treat. The time between visits will vary according to the severity of the hypertension, ranging from days, weeks to months. In patients with severe hypertension, especially when there is unequivocal evidence of target organ damage, the decision to treat may be made at the time of first presentation.
Bullet list 1 British Hypertension Society protocol for blood pressure measurement
- ◆ Use a properly maintained, calibrated, and validated device
- ◆ Measure sitting blood pressure routinely: standing blood pressure should be recorded at the initial estimation in elderly and diabetic patients
- ◆ Remove light clothing, support arm at heart level, ensure hand relaxed and avoid talking during the measurement procedure
- ◆ Use cuff of appropriate size
- ◆ Lower mercury column slowly (2 mm/s)
- ◆ Read blood pressure to the nearest 2 mmHg
- ◆ Measure diastolic as disappearance of sounds (phase V)
- ◆ Take the mean of at least two readings. more recordings are needed if marked differences between initial measurements are found
- ◆ Do not treat on the basis of an isolated reading
Reprinted from Macmillan Publishers Ltd: Journal of Human Hypertension 18, 139–185 (2004).
When measuring blood pressure, the upper arm should be supported at heart level during recordings, and it is important that an appropriate cuff size is used, with the bladder encircling at least 80% of the upper arm. Using too large a cuff results in an underestimation of blood pressure and too small a cuff will lead to overestimation. If the auscultatory method is used to measure blood pressure, then Korotkoff phase I (first appearance of sound) and phase V sounds (disappearance of sound) should be taken for systolic and diastolic pressures, respectively. If phase V goes to zero, then phase IV (muffling of sound) should be recorded.
The beat-to-beat variability associated with atrial fibrillation can make blood pressure measurement difficult and semiautomatic or automated devices can be very inaccurate in such circumstances, in which case multiple readings of auscultatory measurements are recommended.
Blood pressure monitors
The sphygmomanometer has been the mainstay of blood pressure measurement for over 100 years, but its use is likely to decline as a consequence of the decommissioning of mercury-based devices and the emergence of automated and semiautomated devices for routine blood pressure measurement in the office and home and for ABPM.
It is important to note that there are different diagnostic thresholds for the diagnosis of hypertension dependent on the method of measurement, i.e. when using multiple home or ambulatory blood pressure values to measure an average blood pressure, then the average value used to define hypertension is lower than the equivalent office blood pressure threshold of 140/90 mmHg (Table 1 below) and it should be noted—as stated above—that automated devices are inaccurate in patients with atrial fibrillation. Detailed guidance on blood pressure measurement and a wide range of validated monitors is available from http://www.bhsoc.org.
Ambulatory blood pressure measurements (ABPM)
ABPM recordings provide much more information than standard office blood pressure measurements with regard to diagnosis and efficacy of treatment of hypertension. When compared to office blood pressure, there is a much steeper relationship between ABPM averages and target organ damage indices and cardiovascular events, no doubt reflecting that fact that more measurements are obtained and the ‘white coat effect (see below) is eliminated. Generally, ABPM devices are programmed to record blood pressure at 20 min intervals during the day and 30 min intervals at night. A diary is provided to record activity and sleep patterns. In addition to the 24-h blood pressure average, ABPM also provides information on blood pressure profiles, e.g. daytime and night time averages, the ‘dipper status’, i.e. the relationship between night time and day time blood pressure averages, blood pressure variability throughout the day, the morning surge in blood pressure, and—more recently indices—of aortic function via the ambulatory stiffness index. Each of these parameters adds value over and above the assessment of office blood pressure, hence such techniques are increasingly used for the assessment of people with hypertension. Clinical indications for the use of ABPM are shown in Bullet list 2.
|Table 1 Diagnostic thresholds for hypertension according to different methods of measurement|
|SBP (mmHg)||DBP (mmHg)|
|Office or clinic||140||90|
DBP, diastolic blood pressure; SBP, systolic blood pressure.
Home blood pressure measurements
The concept of patients measuring their own blood pressure at home is becoming increasingly popular and may improve adherence to treatment. Validated devices should be used, with an average of duplicate morning and evening home blood pressure measurements recorded daily for 7 days. The measurements should be recorded seated after 5 min rest, with those taken on the first day discarded, leaving at least 24 measurements to be averaged to obtain the home blood pressure average.
‘White coat’ or isolated office hypertension
In some patients office blood pressure is persistently elevated although their 24-h blood pressure or home blood pressure averages are within the normal range. This has been termed ‘white coat’ hypertension or isolated office hypertension. It is important to note that blood pressure will generally fall with repeated readings in all patients, hence it is the chronicity of the office blood pressure elevation that is important to establish the diagnosis.
White coat or isolated office hypertension should be diagnosed whenever office blood pressure is 140/90 mmHg or more on at least three occasions, while 24-h mean and daytime blood pressures are within their normal range. The diagnosis can also be based on home blood pressure values, i.e. average home readings below 135/85 mmHg and office values 140/90 mmHg or more.
Surveys suggest that white coat or isolated office hypertension may be present in as many as 15% of the general population and approximately one-third of all hypertensives. There is considerable debate about its prognostic significance: some studies report association with evidence of hypertensive target organ damage, but others do not. However, overall it appears that white coat hypertension is not benign, with the associated risk probably sitting between those with hypertension confirmed by office readings and ABPM, and those with definitively normal pressures by all methods of measurement. When white coat hypertension is diagnosed, the best advice is to monitor blood pressure and target organ damage via ABPM or home blood pressure averages and not treat unless these pressures are persistently elevated.
Bullet list 2 Possible indications for ambulatory blood pressure monitoring
- ◆ Unusual blood pressure variability
- ◆ Possible ‘white coat’ hypertension
- ◆ Informing equivocal treatment decisions
- ◆ Evaluation of nocturnal hypertension
- ◆ Evaluation of drug-resistant hypertension
- ◆ Determining the efficacy of drug treatment over 24 h
- ◆ Diagnoses and treatment of hypertension in pregnancy
- ◆ Evaluation of symptomatic hypotension
Less attention has been paid to masked hypertension, i.e. patients with a normal office blood pressure but elevated ABPM or home blood pressure averages, than to those with white coat hypertension. Estimates of prevalence range from 10 to 30% of the population, hence a normal office blood pressure does not exclude hypertension. Moreover, as home blood pressure measurement becomes more popular, the detection of masked hypertension will increase. These patients are more likely to have target organ damage and are at increased cardiovascular risk, perhaps more so than those with white coat hypertension. Masked hypertension should be considered in patients who have clinical evidence of hypertensive target organ damage, but in whom office blood pressure appears normal. Treatment should be offered to such patients, aimed at controlling the home blood pressure average.
Fundoscopy is the most convenient method of directly visualizing vascular pathology and provides important prognostic information. Signs of hypertensive retinopathy are frequently seen in adults 40 years and older, and are predictive of incident stroke, congestive heart failure, and cardiovascular mortality—independently of traditional risk factors.
The Keith Wagener classification of fundal appearances has been used for many years, but has serious shortcomings. This classification identified four grades of hypertensive retinopathy. Grade I and II changes, which result from arteriolar thickening, are often difficult to differentiate from each other, and the prognostic significance of the grade I and II subclassification is unclear. A more practical three-grade classification (i.e. mild, moderate, and severe) has been proposed (Table 2 below). The mild changes of generalized retinal–arteriolar narrowing and arteriovenous nipping are related to both the blood pressure at diagnosis and chronic exposure to an elevated blood pressure, hence they appear to be an index of the chronicity of blood pressure elevation. The changes of moderate hypertensive retinopathy are the changes of mild retinopathy plus flame-shaped or blot-shaped haemorrhages, cotton wool spots, hard exudates, microaneurysms, or a combination of all of these factors. Severe retinopathy (malignant or accelerated hypertension) is characterized by all of the aforementioned changes plus swelling of the optic disc. These moderate and severe fundal changes are more closely related to more recent elevation of blood pressure, suggesting they are the consequence of more transient and severe blood pressure elevation.
|Table 2 Modern classification of hypertensive retinopathy|
|Mild hypertensive retinopathy||Retinal arteriolar signs, such as generalized and focal arteriolar narrowing, arteriolar wall opacification, and arteriovenous nipping|
|Moderate hypertensive retinopathy||The signs above plus flame-shaped or blot-shaped haemorrhages, cotton-wool spots, hard exudates, microaneurysms, or a combination of all of these factors.|
|Severe hypertensive retinopathy||The signs above plus swelling of the optic disc|
Severe fundal changes are characterized by disc swelling (i.e. papilloedema) resulting from raised pressure in the disc head secondary to severe vascular damage and increased permeability. Venous distension is followed by increased vascularity of the optic disc, which has a pink appearance with blurring of the disc margins and loss of the optic cup. Raising of the optic disc with anterior displacement of the vessels occurs later. The surrounding retina often shows oedema, small radial haemorrhages, and cotton wool exudates. Moderate or severe fundal changes represent malignant or accelerated hypertension and carry the same adverse prognosis and should be treated as a medical emergency. The flame-shaped haemorrhages are superficial and shaped due to constraints imposed by nerve fibres. Dot and blot haemorrhages are deeper than the nerve fibres and thus are not so constrained. Haemorrhages usually disappear after a few weeks of effective blood pressure control. There are two types of exudates: hard or waxy exudates represent the end result of fluid leakage into the fibre layers of the retina from damaged vessels, with fluid reabsorption leaving a protein–lipid residue that is slowly removed by macrophages; soft exudates or cotton wool patches are usually larger than hard exudates and have a woolly, ill-defined edge, but they are not true exudates, rather nerve fibre infarcts caused by hypertensive vascular occlusion. Unlike hard exudates, these lesions disappear within a few weeks of establishing adequate antihypertensive therapy.
Other fundal changes associated with hypertension
Hypertension also predisposes to the development of a number of sight-threatening complications that can be detected by fundoscopy.
This is characterized by dilated and tortuous retinal veins and the presence of retinal haemorrhages, cotton wool spots, and oedema of the macula and optic disc. In the case of central retinal vein occlusion, all four fundal quadrants are involved; only one fundal quadrant is involved if there is a branch vein occlusion. Central retinal vein occlusion can either be ischaemic or nonischaemic, patients with an ischaemic central retinal vein occlusion typically having poor visual acuity and a relative afferent pupillary defect. Ophthalmic follow-up is needed to diagnose and prevent the two main complications of retinal vein occlusion, namely neovascularization and macular oedema.
Due to cholesterol crystals, platelet/fibrin clot, or calcium, this is twice as common in people with hypertension compared to those who are normotensive, with the risk further accentuated in cigarette smokers and those with diabetes.
Also more common in people with hypertension, central retinal artery occlusion typically presents with a sudden, painless, unilateral loss of vision, associated with a cherry red spot. Branch retinal artery occlusion will present with a sudden, painless, visual field defect, and there may be only minimal impairment of central vision.
These can be either fusiform or saccular. They are uncommon, but are usually only seen in patients with hypertension. When they occur, about 20% are bilateral and 10% are multiple. They are usually discovered by routine fundoscopy in asymptomatic hypertensive patients, but can present acutely, with visual loss secondary to haemorrhage or exudation.
This is also more common in people with hypertension, occurring (in one series) with a yearly incidence of 1 in 10 000. It presents with sudden unilateral visual loss and optic disc oedema. There is no effective treatment and prospects for visual recovery are poor.
All patients with hypertension should have a thorough physical examination (Bullet list 3). Aside from measurement of blood pressure and fundal examination as detailed above, particular features to look for are evidence of secondary effects of sustained hypertension on the heart, features that might suggest the presence of a secondary cause of hypertension, and evidence of other vascular pathology (absent pulses, arterial bruits).
Cardiac examination may reveal a sustained apex beat, or features of cardiac failure that might be secondary to hypertension. It is sometimes said that the second component of the aortic sound is loud in moderate or severe hypertension, but this is not a reliable finding.
In coarctation of the aorta the femoral pulses will be absent or diminished and delayed, and there may be various murmurs (usually as systolic murmur at the sternal border and a continuous murmur at the back of the chest), also visible or palpable collateral arteries on the back of the chest or in the axillae. Blood pressure measured in the legs will be lower than that in the arms.
Abdominal bruits are reported in 4 to 20% of normal people, most commonly in those aged less than 40 years, when it is typically systolic and audible only between the xiphisternum and the umbilicus. In patients with severe hypertension that is difficult to control, the finding of an abdominal bruit in both systole and diastole strongly supports the diagnosis of renovascular hypertension, but a bruit confined to systole is much less likely to be of significance.
Patients with essential hypertension need only a limited number of routine investigations, which must include:
- ◆ urine strip test for protein and blood
- ◆ serum creatinine and electrolytes
- ◆ blood glucose—ideally fasted
- ◆ lipid profile—ideally fasted
- ◆ ECG
Bullet list 3 Initial assessment of the patient with hypertension
- ◆ Causes of hypertension
- • Drugs (NSAIDs, oral contraceptive, steroids, liquorice, sympathomimetics, i.e. some cold cures)
- • Renal disease (present, past or family history, proteinuria and/or haematuria: palpable kidney(s)—polycystic, hydronephrosis, or neoplasm)
- • Renovascular disease (abdominal or loin bruit)
- • Phaeochromocytoma (paroxysmal symptoms)
- • Conn’s syndrome (tetany, muscle weakness, polyuria, hypokalemia)
- • Coarctation (radiofemoral delay or weak femoral pulses)
- • Cushings (general appearance)
- ◆ Contributory factors
- • Overweight
- • Excess alcohol (>3 units/day)
- • Excess salt intake
- • Lack of exercise
- • Environmental stress
- ◆ Complications of hypertension/target organ damage
- • Stroke, TIA, dementia, carotid bruits
- • LVH and/or LV strain on ECG, heart failure
- • Myocardial infarction, angina, CABG or angioplasty
- • Peripheral vascular disease
- • Fundal hemorrhages or exudates, papillodema
- • Proteinuria
- • Renal impairment (raised serum creatinine)
- ◆ Cardiovascular disease risk factors
- • Smoking
- • Diabetes
- • Total cholesterol:high-density lipoprotein-cholesterol ratio
- • Family history
- • Age
- • Sex
- ◆ Drug contraindications
CABG, coronary artery bypass graft; LVH, left ventricular hypertrophy; NSAIDs, nonsteroidal anti-inflammatory drugs; TIA, transient ischaemic attack.
These routine investigations help inform the assessment of target organ damage and cardiovascular disease risk. With regard to renal function, many laboratories now report an ‘estimated’ GFR (eGFR) calculated using an algorithm based on the serum creatinine measurement (see Chapters 21.4 and 21.6). If urinary stick testing for protein is positive, this should be followed by quantification on a spot urine sample of the urinary albumin/creatinine ratio (ACR). More sophisticated assessment tools are available, but the list above is sufficient for routine clinical practice. Note that only two of these routine investigations contribute to the detection of underlying causes of hypertension, namely urinalysis (renal causes) and serum creatinine and electrolytes (renal causes and mineralocorticoid excess), although the ECG may rarely show U waves as a clue to one of the hypokalaemic syndromes. Indications for further investigation for causes of secondary hypertension are given in this article: www.enetmd.com/content/secondary-hypertension.
A chest radiograph and urine microscopy are not routinely required. Echocardiography is more sensitive at detecting left ventricular hypertrophy than an ECG, but is not required routinely, although it is valuable to confirm or refute the presence of left ventricular hypertrophy when the ECG shows voltage criteria suggestive of this.
Assessment of cardiovascular disease risk
The cardiovascular risk associated with hypertension is not eliminated by the treatment of blood pressure alone. This is because many patients have established cardiovascular damage which may not necessarily reverse with treatment of blood pressure, also lifestyle habits such as smoking and dietary factors that may not have changed since therapy was initiated. Other factors are also important: patients with high blood pressure often have associated disturbances in their metabolic profile (especially lipids and glucose tolerance) that also contributes to their risk, which has led many international guidelines to recommend that cardiovascular risk should be formally assessed in all patients with hypertension to determine whether they are at low, medium, or high risk.
Risk calculations based on the Framingham cohort have been used in the United States of America and the United Kingdom, and European guidelines have used a risk score based on mortality data from European countries. Pragmatism in risk assessment is important, with the risk factors cited in the guidelines being conventional markers that can easily be documented in a basic clinical setting, i.e. systolic blood pressure, age, gender, low-density lipoprotein (LDL) cholesterol, presence of diabetes, smoking history, and the presence or absence of structural damage, e.g. ECG evidence of left ventricular hypertrophy. Recent surveys suggest that >90% of population attributable risk for cardiovascular disease can be explained by these risk factors. The use of more sophisticated risk assessment by adding any of the recently advocated biomarkers, such as C-reactive protein, adds little to the conventional methods of cardiovascular risk estimation.
Cardiovascular disease risk thresholds for intervention currently define ‘high risk patients’ as having a 10-year Framingham-derived cardiovascular disease risk of 20% or more. The typical hypertensive male aged 55 years or more has this level of cardiovascular disease risk, and it is likely that even lower thresholds would be cost-effective for intervention. Formal cardiovascular disease risk estimation is not necessary for patients with hypertension and established cardiovascular disease, diabetes, or overt end organ damage: they are already at sufficient cardiovascular disease risk to benefit from multifactorial risk factor intervention.
Patients with hypertension and deemed to be at high risk should receive strong advice to adjust their lifestyles and be considered for treatment with statin therapy and low dose aspirin to optimize their risk reduction (see below).
Blood pressure is elevated sporadically in everybody. Key objectives in the assessment of essential hypertension are to establish whether blood pressure is persistently elevated; the level to which blood pressure is elevated, i.e. the severity of hypertension; and the presence or absence of hypertension-mediated target organ damage. The initial assessment is usually followed by a period of observation, the duration of which will be dependent on the severity of the hypertension and the associated cardiovascular disease risk and damage. Lifestyle advice should be provided during this observation period, with drug therapy initiated depending on the level of blood pressure and overall cardiovascular disease risk at the end of the observation period.
Establishing the diagnosis
Patients with essential hypertension usually present in one of three ways:
- ◆ As an asymptomatic individual whose blood pressure has been measured at routine examination for employment, insurance, or as a result of screening or preoperatively—the most common presentation
- ◆ As a patient whose blood pressure has been measured opportunistically when presenting with an unrelated disorder; or
- ◆ As a result of symptoms produced by hypertension, or by the acute or chronic complications of hypertension—the least common presentation
Repeated blood pressure measurements over a period of observation are usually necessary to establish the diagnosis. Exceptions to this are patients presenting with severe hypertension in whom fundal examination or other assessment of target organ damage (e.g. left ventricular hypertrophy or renal impairment) clearly reveals the presence of hypertension-mediated damage, indicative of the fact that the blood pressure needs treatment.
The period of observation required before initiating drug therapy is dependent on the severity of the hypertension and the presence or absence of cardiovascular disease, diabetes and/or target organ damage. Those with more severe hypertension and disease require emergency or urgent intervention with drug therapy to lower their blood pressure, whereas those with less severe hypertension and/or the absence of damage or disease can be monitored over a longer period—up to many months—before initiating drug therapy. This period of observation is important because it is used to repeat blood pressure measurements, confirm the presence of sustained hypertension, and get a more accurate appreciation of the associated risk, also to implement lifestyle interventions that may reduce blood pressure.
Diagnostic thresholds for therapeutic intervention and the observation period
The diagnostic thresholds for the levels of hypertension severity are shown in Table 1 above, and the recommended period of observation for different grades of hypertension are shown in Table 3 below. Although there is general consensus about the management of grade II (i.e ≥160/100 mmHg) or more severe hypertension, the British guidelines have traditionally been more cautious than other guidelines with regard to drug therapy for uncomplicated grade I hypertension (140–159/90–99 mmHg) (Table 3). Most other guidelines recommend treating all patients with a blood pressure sustained above 140/90 mmHg, whereas the British guidelines have recommended drug therapy for those with grade I hypertension only when there is associated cardiovascular disease or target organ damage, or a calculated risk of cardiovascular disease at least 20% over 10 years. There is genuine uncertainty about the cost-effectiveness of treating otherwise low risk people with grade I hypertension, but this must be balanced by recognition that the greatest burden of blood pressure attributable disease in populations is in those with grade I hypertension because it is so common. Moreover, blood pressure will invariably continue to rise in patients with grade I hypertension, and there is concern that the subtle vascular damage that is occurring while these patients remain untreated may not be reversible when treatment is eventually initiated at higher levels of pressure. Thus, while a prolonged period of observation and lifestyle intervention for uncomplicated, low risk, grade I hypertension is considered acceptable, it is inevitable that most of these patients will eventually (if not immediately) require drug treatment.
|Table 3 Typical observation periods for different grades of hypertension and associated cardiovascular disease, diabetes, and/or target organ damage|
|Grade of hypertension||Typical observation period|
|Accelerated (malignant) hypertension (papilloedema and/or fundal haemorrhages and exudates or with acute cardiovascular complications e.g. aortic dissection)||Immediate treatment—usually requiring acute hospital admission|
|BP ≥220/120 mmHg||Treat immediately—hospital admission not usually required|
||Confirm by repeated measurements over 1–2 weeks, then treat|
From Williams. B et al. (2004). BMJ, 328, 364–40
The treatment of hypertension is directed towards reducing risk rather than treating symptoms. It is imperative, therefore, to explain the significance of high blood pressure at the earliest opportunity. Many patients find difficulty in grasping the concept of blood pressure variability and are often alarmed by the inevitable occasional high reading. Discussion of the rationale for evaluation and treatment, together with an explanation of the nature of high blood pressure and its very high prevalence, reassures patients and may improve adherence to treatment. Further comprehensive advice for patients may be obtained from http://www.bpassoc.org.uk.
The evidence base identifying the optimal blood pressure treatment targets for hypertension is less substantial than it should be. There is international consensus that for office blood pressure an optimal treatment target should be <140/90 mmHg, and a lower target of <130/80 mmHg has been recommended for higher risk patients, i.e. those with established cardiovascular or renal disease or diabetes. Whether such targets are appropriate for very elderly individuals (i.e. >80 years) has been debated, with a recent study suggesting that at target blood pressure of <150/90 mmHg is appropriate for this age group. It is important to note that as people age, diastolic blood pressure generally falls and systolic blood pressure rises, hence the systolic blood pressure assumes the greatest importance with regard to the treatment target, although it is generally more difficult to control.
Blood pressure is strongly influenced by lifestyle factors such as diet and exercise and their consequences such as weight. Effective lifestyle modification for patients with grade I hypertension may lower blood pressure as much as a single blood pressure lowering drug, and combinations of two or more lifestyle modifications may be even more effective. Lifestyle interventions may reduce the need for drug therapy for people with mild hypertension, can enhance the antihypertensive effects of blood pressure lowering medication, and can favourably influence overall cardiovascular disease risk.
The most effective lifestyle interventions for reducing blood pressure in clinical trials are modifications to diet to induce weight loss, regular aerobic exercise, and restrictions in alcohol and sodium intake. The expected reduction in blood pressure with these lifestyle manoeuvres are shown in Table 4 below, and recommended lifestyle interventions to reduce blood pressure and/or cardiovascular disease risk are shown in Bullet list 4.
Patients are often enthusiastic to try lifestyle changes rather than take drug therapy. This is a reasonable initial option in patients with grade I hypertension who do not have associated target organ damage or high cardiovascular disease risk. In patients with more severe hypertension or those at high risk, lifestyle measures should be recommended alongside drug therapy. This is important because these measures may improve the effectiveness of drug therapy and also contribute to a reduction in overall cardiovascular risk. Note, however, that effective implementation of lifestyle measures requires enthusiasm, knowledge, patience, and considerable time spent with patients and other family members. It is best undertaken by well-trained health professionals, e.g. practice or clinic nurses, and should be supported by clear written information.
|Table 4 Blood pressure reductions associated with lifestyle interventions for patients with hypertension|
|Intervention||Recommendation||Expected SBP reduction (range)|
|Weight reduction||Maintain ideal BMI 20–25 kg/m2)||5–10 mmHg per 10 kg weight loss|
|DASH eating plan||Consume diet rich in fruit, vegetables, low fat dairy products with reduced content of saturated and total fat||8–14 mmHg|
|Dietary sodium restriction||Reduce dietary sodium intake to <100 mmol/day (<2.4 g sodium or <6 g sodium chloride)||2–8 mmHg|
|Physical activity||Engage in regular aerobic physical activity, e.g. brisk walking lor at least 30 min most days||4–9 mmHg|
|Alcohol moderation||Men ≤21 units/week||2–4 mmHg|
|Women ≤14 units/week|
BMI, body mass index; SBP, systolic blood pressure.
- ◆ Weight reduction
- ◆ Reduced salt intake
- ◆ Limitation of alcohol consumption
- ◆ Increased physical activity
- ◆ Increased fruit and vegetable consumption
- ◆ Reduced total fat and saturated fat intake
- ◆ Cessation of smoking
- ◆ Reduced total fat and saturated fat intake
- ◆ Replacement of saturated fats with monounsaturated fats
- ◆ Increased oily fish consumption
Many patients with hypertension are overweight and weight reduction by calorie restriction is an appropriate recommendation. The blood pressure lowering effect of weight reduction may be enhanced by increased regular aerobic physical exercise, by alcohol moderation in heavy drinkers, and by a reduction in sodium intake. On average, blood pressure may fall by as much as 1 mmHg per kg weight loss, although results vary in studies and the maximum overall effect of combined lifestyle interventions is an average of 10 mmHg fall in systolic blood pressure. Body mass index is frequently used as a measure of overweight, but other measures of obesity—particularly central obesity—are better markers of adverse cardiovascular outcomes in people with hypertension. In this regard, weight reduction also has beneficial effects on associated risk factors such as insulin resistance, risk of developing diabetes, and dyslipidaemia.
Dietary salt reduction
Sodium intake influences blood pressure and all international guidelines recommend dietary sodium restriction. Dietary salt reduction from an average of 10 to 5 g/day (5 g = 1 teaspoon) lowers blood pressure by about 5/2 mmHg, with larger blood pressure falls in elderly people, blacks, and in those with higher initial blood pressure levels. About one-third of people will achieve a reduction of 5/5 mmHg or more. These effects are additive to the blood pressure lowering effect of a healthy diet, e.g. the Dietary Approaches to Stop Hypertension (DASH) diet http://www.nhlbi.nih.gov/health/public/heart/hbp/dash/ (see below).
Many patients will already be aware of the relationship between salt and blood pressure will have discontinued adding salt at the table and even when cooking, but few are aware of the large amount of salt in processed foods, such as bread (one slice contains 0.5 g salt), some breakfast cereals, ready prepared meals, and flavour enhancers such as stock cubes or manufactured sauces. Patients, and those who cook for patients, should be provided with specific written advice, such as that from http://www.bpassoc.org.uk.
Increased fruit and vegetable consumption
Using the DASH diet, which increased vegetable consumption from two to seven portions per day, blood pressure was lowered by around 7/3 mmHg in hypertensive patients. Hypertensive patients should therefore be given clear advice to increase fruit and vegetable intake to at least five portions per day. When this is combined with an increased use of low-fat dairy products and reduction of total and saturated fat, then blood pressure falls averaging 11/6 mmHg are seen. The mechanism whereby fruit and vegetable consumption are thought to lower blood pressure is uncertain, but it may be due to an associated increase in potassium intake, which is compatible with some supplementation studies.
Regular physical activity, especially when combined with dietary measures, can be particularly effective at reducing blood pressure (Table 4). The activity should be regular, aerobic (e.g. brisk walking), and tailored to the individual. For example, three vigorous training sessions per week may be appropriate for fit younger patients, or brisk walking for 20 min/day in older patients. This activity will be expected to reduce systolic blood pressure and diastolic blood pressure by about 2–3 mmHg, with the combination of exercise and diet reducing both by 5–6 mmHg. Heavy physical exercise should be discouraged in people with severe hypertension or those in whom hypertension is poorly controlled. Exercise can be recommenced once drug therapy has been started and blood pressure is better controlled.
In addition to its effects on blood pressure, physical exercise appears to exert a strong protective effect against cardiovascular mortality and is associated with a lower risk of coronary heart disease in men and women. Protection is lost when exercise is discontinued. Any activity appears to be of benefit, but those that are more active appear to gain more protection. A reasonable strategy is regular aerobic exercise (e.g. brisk walking) for at least 30 min, ideally on most days, but at least three days per week.
An alcohol intake of above 21 units per week is associated with blood pressure elevation, and binge drinking is associated with an increased risk of stroke. Hypertensive patients should be advised to limit their alcohol intake to 21 units per week (men) and 14 units per week (women). On average, structured interventions to reduce alcohol consumption have a small effect on blood pressure, reducing systolic blood pressure (and possibly diastolic blood pressure) by about 2–3 mmHg. Consumption of smaller amounts of alcohol, up to the recommended limit, may protect against cardiovascular disease and should not be discouraged.
Sleep and blood pressure
Blood pressure characteristically falls during sleep, and sleep duration impacts on the risk of developing hypertension. The risk of developing hypertension in one survey was increased by about twofold in adults in middle age who sleep 5 h or less each night. This may simply reflect a higher 24-h average blood pressure load and longer duration of sympathetic nervous system activation as a consequence of less time asleep, which in turn would give rise to a higher risk of longer term cardiovascular structural damage, leading to sustained hypertension. Whatever the mechanism, sleep deprivation should be considered in the assessment of people developing hypertension. Consistent with the association between sleep deprivation and hypertension, high blood pressure is more common in patients with obstructive sleep apnoea. Although this could be explained by the fact that both conditions are commoner in males and in obese individuals, a few studies indicate that continuous positive airways pressure can reduce blood pressure, particularly nocturnal pressures, implying a causal relationship.
Lifestyle strategies to reduce cardiovascular risk in hypertensive patients
Patients with hypertension should be encouraged and given support to stop smoking. Nicotine replacement therapy and other strategies are safe and effective in people with hypertension and double the chance of quitting smoking. Those who fail on their first attempt to quit should be encouraged to continue trying: the chance of success increases with the number of quit attempts. Although smoking is not a major contributor to an elevated blood pressure, it does significantly amplify the cardiovascular risk associated with hypertension. Smoking is a major factor related to the persistent increase in coronary and stroke mortality in men with treated hypertension. Those who stop smoking experience a rapid decline in risk, by as much as 50% after 1 year, but up to 10 years may be needed to reach the risk level of those who have never smoked.
Reducing dietary fat intake can reduce serum cholesterol values, which can reduce the risk of cardiovascular disease. All patients should be advised to keep total dietary intake of fat to less than one-third of their total energy intake, to keep the intake of saturated fats to less than one-third of their total fat intake, and to replace saturated fats by an increased intake of monounsaturated fats. These dietary changes can be very effective, but reduce serum cholesterol by only about 6% on average, in part because of difficulty in sustaining such dietary discipline. A regular intake of fish and other sources of ω – 3 fatty acids (at least two servings of fish per week) will further improve lipid profiles and has been shown to reduce blood pressure.
Lifestyle modifications that are ineffective at lowering blood pressure
The best available evidence does not support the use of calcium, magnesium, or potassium supplementation (i.e. tablets), individually or in combination, to achieve a worthwhile reduction in blood pressure. Inadequate information is available from randomized controlled trials to support the recommendation for garlic, herbal, or other complementary medicines.
Psychological stress reduction
Structured interventions to reduce stress e.g. stress management programmes, meditation, yoga, cognitive therapies, breathing exercises, biofeedback, and acupuncture have been shown to modestly reduce blood pressure in some but not all studies. However, many of these interventions are time consuming and have been short term, and it is difficult to know whether they would be an effective intervention for adequate blood pressure control over the longer term.
The treatment of hypertension has been subjected to many large randomized controlled trials that have compared active treatments with placebo, and different treatment strategies with each other. Hypertension has the most impressive evidence base in medicine to guide treatment decisions, and analysis of this has provided important guiding principles with regard to treatment strategies:
- ◆ Effective blood pressure lowering is overwhelmingly important in reducing the risk of major cardiovascular events in people with hypertension, thus the first priority in treatment is to control blood pressure.
- ◆ Many patients will require more than one drug to control blood pressure; monotherapy is rarely sufficient.
- ◆ Although early studies focused primarily on diastolic blood pressure as the treatment target, systolic blood pressure is invariably more difficult to control and should now be the main focus of treatment.
- ◆ The blood pressure response to an individual class of blood pressure lowering medication is heterogeneous, hence there is no ‘perfect drug’ for every patient.
- ◆ Some trials have indicated that certain comorbidities or target organ damage provide compelling indications for inclusion of specific classes of drug therapy in the treatment regimen.
- ◆ There is inadequate clinical outcome data for treatment studies of younger patients as most of the studies, especially the more recent ones, have been conducted in patients over the age of 55 years, and typically with a mean age over 65 years.
Blood pressure lowering therapy is effective at reducing the risk of stroke, myocardial infarction, heart failure, chronic renal disease, peripheral vascular disease, and death. It may also be effective at reducing the risk of vascular dementia. On average, lowering blood pressure by 20/10 mmHg will reduce the risk of major cardiovascular events by one-half, with the reduction in stroke risk appearing to follow the predicted reduction in risk based on the epidemiological association between stroke and blood pressure. There appears to be a shortfall in the reduction in risk of ischaemic heart disease with blood pressure lowering when compared to epidemiological predictions, which is best addressed by attention to concomitant risk factors. Importantly, the risk reduction associated with blood pressure lowering appears to be continuous across a wide range of blood pressures, thus the absolute benefit from treatment is greatest in those with the highest absolute cardiovascular disease risk. This provides the rational for advocating the use of complementary strategies to reduce cardiovascular disease risk, e.g. statins and antiplatelet therapy, in those with established vascular disease, target organ damage, or at high calculated cardiovascular disease risk, i.e. a calculated cardiovascular disease risk of 20% or more over 10 years.
The main classes of blood pressure lowering therapies are summarized below. The over-riding treatment priority is to control blood pressure, but there is general consensus amongst international guidelines about indications and contraindications for the use of specific classes of blood pressure lowering therapy in specific clinical situations, and these are detailed in Tables 5 and 6 below. It is important to note that these lists are not comprehensive and are subject to change as new evidence emerges, and the reader is directed towards the information sheets for each specific drug for more detailed prescribing information.
|Table 5 Indications favouring the use of specific classes of blood pressure lowering drugs|
|Angiotensin receptor blockers||
|Calcium antagonists (dihydropyridines)||
|Calcium antagonist (verapamil/diltiazem||
Thiazide-type diuretics were the first major class of drug used to treat hypertension on a large scale and they remain one of the main therapeutic options for the treatment of essential hypertension. Commonly used examples include chlorthalidone, hydrochlorthiazide, and bendroflumethiazide. Thiazide-type diuretics lower blood pressure by a complex series of mechanisms. Urinary loss of sodium resulting from a blockade of renal tubular reabsorption of sodium is integral to the antihypertensive effect. The early changes in salt and water balance are often accompanied by counter-activation of several vasoconstrictor mechanisms including the renin–angiotensin–aldosterone system, which may transiently raise peripheral vascular resistance and attenuate blood pressure lowering. There is subsequently a gradual reduction in peripheral vascular resistance and a new steady state of reduced total body sodium and blood pressure.
|Table 6 Compelling and possible contraindications to specific classes of blood pressure lowering therapies|
|Calcium antagonists (dihydropiridines)||
|Calcium antagonists (verapamil, diltiazem)||
|Angiotensin receptor antagonists||
ACE, angiotensin converting enzyme; AV, atrioventricular.
Data from Williams et al. BHS Guidelines 2004. Guidelines for management of hypertension: report of the fourth working party of the British Hypertension Society, 2004—BHS IV
The sustained actions of thiazide/thiazide-like diuretics on the kidney make them preferable to loop diuretics for the control of blood pressure. This is because loop diuretics are shorter acting, and the short-term sodium and water loss is usually compensated for by sodium retention during the latter part of the dosing interval and reduced blood pressure lowering efficacy. There is really no place for loop diuretics in the routine management of essential hypertension, but thiazide-type diuretics become ineffective in patients with a glomerular filtration rate below 30 ml/min and in such patients loop diuretics are often required for effective blood pressure lowering, especially when there is clinical evidence of sodium and water retention.
The main adverse effects of thiazide-type diuretics are hypokalaemia, hyponatraemia (less commonly), impaired glucose tolerance, and small increments in blood levels of LDL cholesterol and triglycerides. Thiazide-type diuretics also elevate serum uric acid levels and should be avoided in patients predisposed to gout, also avoided in those receiving lithium because of a high risk of lithium toxicity. An incidental advantage of thiazides may be reduction in osteoporosis as a result of calcium retention.
To minimize the adverse effects of thiazide-type diuretics, low doses of these drugs have been recommended by guidelines for the treatment of essential hypertension, and these are well tolerated. On the basis of some small studies it has been assumed that the dose response to thiazide-type diuretics is generally flat (unlike the adverse affect profile), and this has been used to further justify the low dose strategy for thiazide-type diuretics, but it should be emphasized that some patients do respond to and tolerate higher doses. Moreover, when thiazides are combined with drugs that block the renin–angiotensin system, e.g. ACE inhibition, then the dose response is steeper and higher doses may be used in patients with more resistant hypertension (see below).
Potassium-retaining diuretics, e.g. spironolactone or amiloride, are effective blood pressure lowering agents that are much less commonly used for the routine treatment of hypertension. They can be very effective in combination with thiazide-type diuretics, and are increasingly used as part of a multidrug strategy for the treatment of resistant hypertension (see below). They are used and effective in large doses in the treatment of primary aldosteronism. They have the advantage over thiazide-type diuretics in not causing hypokalemia or hyperuricaemia and do not impair glucose tolerance, but spironolactone causes nipple tenderness and gynaecomastia in some patients, which is dose dependent and can limit its use. Moreover, if potassium-sparing diuretics are used in combination with drugs that block the activity of the renin–angiotensin system or in patients with renal impairment, then monitoring of serum potassium is required because of the increased risk of hyperkalaemia.
β-Adrenoceptor blocking drugs (β-blockers)
β-Blockers reduce blood pressure and cardiovascular events in patients with hypertension. Most β-blockers, with the exception of those with strong intrinsic sympathomimetic activity, reduce cardiac output due to their negative chronotropic and inotropic effects. As with diuretics, short-term haemodynamic responses can be offset by counter-activation of vasoconstrictor mechanisms, which may limit initial blood pressure lowering. Longer term reduction in arterial pressure, which occurs over days, is due to restoration of vascular resistance to pretreatment levels. Partial blockade of renin release from the kidney may contribute to the later haemodynamic response.
β-Blockers differ in their duration of action, their selectivity for β1 receptors, lipophilicity, and partial agonist activity. Side effects include lethargy, aches in the limbs on exercise, impaired concentration and memory, erectile dysfunction, vivid dreams, and exacerbation of symptoms of peripheral vascular disease and Raynaud’s syndrome. They are contraindicated in asthma and can cause adverse metabolic effects, including impaired glucose tolerance and worsening of dyslipidaemia—notably reduced HDL-cholesterol and raised triglycerides. There is accumulating evidence that β-blockers increase the likelihood of new-onset diabetes, particularly when combined with thiazide-type diuretics. Moreover, recent meta-analyses suggest that there is a shortfall in cardiovascular protection with β-blocker-based treatment for hypertension (especially in stroke reduction) when compared to treatment with other main drug classes. As a consequence, recent British guidelines suggest that β-blockers are no longer preferred as an initial therapy for routine hypertension and should only be used when there is a compelling indication other than blood pressure control, e.g. in patients with hypertension and angina or chronic heart failure. One caveat is in younger women of childbearing potential, in whom β-blockers are often very effective at lowering blood pressure, perhaps due to higher renin levels of younger people, and are safer than ACE inhibition or angiotensin receptor blockers in those anticipating pregnancy.
Calcium channel blockers
This class of drug has been extensively used in treating hypertension since the 1970s: they are very effective at reducing blood pressure and have an extensive evidence base supporting their use. In addition to their blood pressure-lowering properties, they are also effective antianginal agents.
There are two main groups of calcium channel blocker (CCB), the dihydropyridines (e.g. amlodidpine, nifedipine) and the nondihydropyridines (e.g. diltiazem, verapamil). The dihydropyridine CCBs act mainly by inducing relaxation of arterial smooth muscle by blocking L-type calcium channels, thereby inducing peripheral vascular relaxation with a fall in vascular resistance and arterial pressure. Nondihydropyridine CCBs also block calcium channels in cardiac muscle and reduce cardiac output. Verapamil has an additional antiarrhythmic action through its effects on the atrioventricular node.
The earlier formulations of some dihydropyridines, such as capsular nifedipine, had a rapid onset of action, unpredictable effects on blood pressure, and were accompanied by reflex sympathetic stimulation and tachycardia. With the availability of longer-acting formulations of dihydropyridine CCBs, these shorter-acting CCBs have no place in the management of hypertension, even (and especially) in the emergency setting.
Side effects of dihydropyridine CCBs include dose-dependent peripheral oedema, which is not due to fluid retention but results from transudation of fluid from the vascular compartments into the dependent tissues due to precapillary arteriolar dilatation. This oedema does not respond to diuretic therapy but is alleviated by limb elevation, and there is emerging evidence that it may be also reduced by coadministration of an ACE inhibitor or angiotensin receptor blocker because of their effects on venous capacitance. Gum hypertrophy can occur with dihydropyridine CCBs, but is rarely seen with nondihydropyridine CCBs. Nondihydropyridine CCBs cause less peripheral oedema but are negatively inotropic and negatively chronotropic and should therefore be avoided in patients with compromised left ventricular function, and used with caution in combination with β-blockers. Verapamil use is commonly accompanied by constipation.
Blockade of the renin–angiotensin system
The renin–angiotensin system (RAS) has become a very popular target for drug development to treat hypertension. Inhibition of the renin–angiotensin system is predictably effective at lowering blood pressure by inhibiting the various central and peripheral pressor effects of angiotensin II, and blockade may also lower blood pressure by other mechanisms involving improvements in endothelial function, vagal tone and baroreceptor function, and via inhibition of the renal tubular reabsorption of sodium. In addition, inhibition of the renin–angiotensin system has been promoted by clinical trial evidence showing reduced morbidity and mortality with these treatments in patients with heart failure, delay the progression of renal disease, and reduction in cardiovascular events in patients at high cardiovascular risk.
The ACE inhibitors, which block the conversion of angiotensin I to angiotensin II, were the first effective strategy to inhibit the renin–angiotensin system and have been used to treat hypertension since the late 1970s. The resulting reduction in levels of angiotensin II leads to vasodilatation and a fall in blood pressure. Angiotensin II has many additional actions that are potentially harmful to the cardiovascular system and have been implicated in the pathogenesis of structural changes in the heart, blood vessels, and kidneys in hypertension.
Sharp falls in blood pressure following the introduction of ACE inhibitors may occur when the renin–angiotensin system is activated, e.g. in patients who are dehydrated, in heart failure, or have accelerated hypertension. This is rarely a problem when therapy is initiated in uncomplicated hypertensive patients. Side effects of ACE inhibitors include the development of a persistent dry cough in about 20% of users. This is more common in women and in people from Asia, and only disappears after discontinuation of the drug. Another rare but important complication is angio-oedema, which occurs in around 1% but is much more common in the black population (c.4%). ACE inhibitors should be avoided in women of childbearing potential because of the danger of fetal renal malformation. They should not be used in patients with bilateral renal artery disease because they may precipitate deterioration in renal function and renal failure. Careful monitoring of renal function and serum potassium is also required in patients with more advanced renal impairment of any cause because of the risk of hyperkalaemia.
In the 1990s, the angiotensin receptor blockers (ARBs), which are highly selective inhibitors of the angiotensin II type 1 receptor (AT-1), emerged as an alternative to ACE inhibition. In general they are as effective as ACE inhibitors at reducing blood pressure, but appear to have a longer duration of action, and in common with ACE inhibitors they inhibit the actions of angiotensin II on the cardiovascular system and kidney. They are very well tolerated by patients, with a placebo-like adverse effect profile. Cough and angio-oedema are much less likely to occur than with ACE inhibitors and most guidelines recommend switching patients to an ARB when an ACE-induced cough occurs. Cautions and contraindications are similar to those outlined for ACE inhibitors.
A third strategy to inhibit the renin–angiotensin system for the treatment of hypertension is direct renin inhibition, the first nonpeptide, orally active, direct renin inhibitor being aliskiren. This has high specificity for renin and is a potent renin inhibitor with a long half life (c.24 h). It inhibits the rate-limiting step in angiotensin production, notably the renin-dependent conversion of angiotensinogen to angiotensin I, and appears to have similar blood pressure lowering efficacy to other means of inhibiting the renin system, i.e. ACE inhibition or ARBs, but with less side effects than ACE inhibition. The contraindications to use of direct renin inhibitors are similar to those for ACE inhibition or ARBs. The results of ongoing clinical trials will ultimately define their role in the hierarchy of treatment.
α-Adrenergic blocking drugs
The original members of this class (e.g. prazosin) were short acting drugs that blocked the activation of α1 adrenoceptors in the vasculature, leading to vasodilatation. The dosages that were initially recommended were too high, and postural hypotension and syncope proved serious problems that retarded the acceptance of this class of drugs, although the use of lower doses and the development of longer-acting agents (e.g. doxazosin) has largely overcome this problem. Blockade of sphincteric receptors improves symptoms in patients with benign prostatic hypertrophy, and occasionally these same sphincteric effects can worsen symptoms of stress incontinence in women. Uniquely amongst antihypertensive drugs, the α1-antagonists produce modest favourable changes in plasma lipids, with a reduction in total and LDL cholesterol and triglycerides, and an increase in high-density lipoprotein (HDL) cholesterol.
Centrally acting sympatholytic drugs
Some of the earliest drugs developed to treat hypertension targeted the activation of the sympathetic nervous system at various levels, including the cardiovascular regulatory nuclei in the brainstem, the peripheral autonomic ganglia, and the post ganglionic sympathetic neuron. With one or two exceptions, few of these agents have any residual role to play in the modern treatment of hypertension because side effects are common, often unpleasant, and potentially harmful.
Methyldopa reduces sympathetic outflow from the brainstem. It was originally developed in the late 1950s and for many years it was one of the mainstays of antihypertensive therapy. However, it frequently causes sedation, impaired psychomotor performance, dry mouth, and erectile dysfunction. This unfavourable impact upon quality of life led to it being replaced by more effective drugs, although it is still used extensively in the management of hypertension of pregnancy, which is now its main indication.
Clonidine is now rarely used because of its short duration of action and risk of a withdrawal syndrome after discontinuing the drug; sudden discontinuation results in a rebound rise in catecholamines with features that may resemble phaeochromocytoma, such as severe hypertension, tachycardia, and sweating. This is exacerbated when patients are also receiving nonselective β-blockers such as propranolol. The syndrome is treated by readministering the drug and then gradually discontinuing it, or the intravenous infusion of labetalol in an emergency.
Moxonidine is a newer centrally acting agent that is an imidazoline receptor agonist, acting to reduce sympathetic outflow and blood pressure. It has a lower incidence of side effects and is better tolerated than other centrally acting agents.
Hydralazine was previously extensively used as part of a stepped care regimen. However, its main disadvantages were sympathetic activation and the development of a lupus-like syndrome, particularly in patients with the slow acetylator genotype, which together with the need for multiple daily dosage have resulted in its replacement by other agents, except for occasional use in severe hypertension and hypertension associated with pregnancy. No endpoint trials have been carried out.
Minoxidil is a very potent vasodilator. Its used is confined to specialist centres for the treatment of severe and resistant hypertension because of its side effects, which include stimulation of body hair growth, tachycardia, and severe fluid retention. For this reason, combination with a potent loop diuretic and a β-blocker is almost always necessary.
Pharmacological treatment strategies
Initial drug therapy
After a suitable period of observation and after assessment of concomitant risk factors, comorbid disease and overall cardiovascular disease risk, a decision may be reached to treat the patient with drug therapy. However, even when this is contemplated it is important to continue to emphasize the importance of lifestyle changes to reduce cardiovascular risk and enhance the efficiency of blood pressure lowering medications, and it is also important to view the patient’s blood pressure in the context of their overall cardiovascular risk burden and decide whether other therapies such as statins and antiplatelet therapy might also be appropriate.
Once a decision has been made to initiate drug therapy, it is usual to commence treatment with a single drug. Monotherapy will on average reduce systolic pressure by 7 to 13 mmHg and diastolic pressure by 4 to 8 mmHg. This will give some indication as to whether monotherapy is likely to be effective at achieving the recommended blood pressure goal, but there is marked heterogeneity in response among individuals to particular drugs. Treatment should normally commence with a low dose of the drug selected. If an adequate response is not obtained, the dose of the initial drug can be increased. However, if there has not been much response to the starting dose and the patient’s blood pressure remains well short of the target blood pressure, then a more appropriate action would be to add a second drug, either separately or as a combination tablet, mindful of the fact that most people with hypertension require two or more drugs to adequately control their blood pressure. Alternatively, if the initial drug produced a weak response, or none at all, and the patient could conceivably get to their blood pressure goal on monotherapy, then the first drug could be discontinued and replaced with another class of antihypertensive agent.
The heterogeneity of blood pressure responses to different classes of BP-lowering drugs and the likelihood that most people will be uncontrolled by monotherapy, has led to the suggestion that more people should be initiated on treatment with low-dose combination therapy. Low-dose two-drug combination therapy has been recommended in European and American hypertension guidelines for the treatment of patients whose blood pressure is greater than 20/10 mmHg above their goal blood pressure and therefore unlikely to achieve their goal blood pressure with monotherapy. The United States guideline has been explicit in stating that this combination would usually involve a diuretic. The concept of initial therapy with a two-drug combination has in part been driven by concern that the up-titration of treatment in people at high risk may be too slow and leave them at risk for too long.
There is wide variation in the international guidelines with regard to the preferred initial therapy for essential hypertension. In the United States of America, the Joint National Committee (JNC) VII guideline recommended low dose thiazide-type diuretic therapy as initial therapy for all patients (unless contraindicated), reflecting a view that the most important driver of benefit was blood pressure control and that the low dose diuretic was the most cost-effective way to deliver that.
The recent European guideline suggested that all five main classes of blood pressure lowering drugs (ACE inhibitors, angiotensin receptor blockers, β-blockers, calcium channel blockers, and diuretics) were all suitable as initial therapy and that choice would in part reflect physician preference and the concomitant conditions and specific indications and contraindications for different drug classes in an individual patient (Table 6).
The British Hypertension Society/NICE guideline adopted a different approach. Their analysis of the data suggested that a calcium channel blocker (C) or alternatively a diuretic (D) would be most likely to deliver the most effective initial blood pressure lowering in older people (i.e. ≥55 years), whereas an ACE inhibitor or an angiotensin receptor blocker (A) would be the preferred initial therapy for younger patients (<55 years), with the caveat that C or D would be the preferred therapy for people of black African origin at any age. The rationale for this recommendation was founded on the observation that plasma renin levels fall as people age and are lower in blacks at any age. Therefore drugs that target the renin system are more likely to be more effective initial therapy in higher renin younger patients, whereas the converse in true with ageing. These guidelines also recommended against the use of β-blockers as a preferred initial therapy (especially for older patients), unless there were compelling indications, because (1) they appear less effective at reducing the risk of stroke than the alternatives, (2) they are associated with an increased risk of developing diabetes, and (3) they are the least cost-effective treatment option for essential hypertension.
Combination therapy for controlling blood pressure
All guidelines recognize that combinations of blood pressure lowering drugs are often required to achieve recommended blood pressure goals, especially in those with high cardiovascular disease risk or comorbidities who are targeted to lower pressures. The European guidelines provide a diagram to illustrate suitable combinations of treatment. The American JNC VII guidelines suggest that whatever combination is used, it should usually include a diuretic, consistent with the fact that they have recommended that initial therapy would usually be with a diuretic. Only the British guideline provides explicit guidance on preferred combinations of treatment at step 2, i.e. A + C or A + D, and step 3, i.e. A + C + D. The recent ACCOMPLISH study suggested that A+C may be more effective than A+D at preventing cardiovascular events, despite similarities in BP control.
Drug-resistant hypertension can be defined as blood pressure that is not controlled despite treatment with an appropriate combination of three drug therapies (e.g. A + C + D) prescribed at their maximum recommended and tolerated doses. In the absence of evidence of target organ damage, white coat hypertension should be excluded by 24-h ambulatory monitoring. Other causes for resistant hypertension include (1) secondary hypertension (e.g. renovascular or endocrine); (2) ingestion of drugs that may raise blood pressure (e.g. nonsteroidal anti-inflammatory agents); (3) heavy alcohol intake; (4) sodium and fluid retention as a result of inadequate diuretic therapy; and (5) poor patient adherence to treatment.
Most patients with drug-resistant hypertension are likely to be retaining sodium and will respond to further diuretic therapy. A suppressed plasma renin despite treatment with A + C + D would be indicative of sodium retention because these treatments would be expected to elevate plasma renin, hence the preferred initial approach to treatment in this situation is further diuretic therapy, either with increased dosage of the thiazide diuretic, or using low dose spironolactone (e.g. 25 mg/day), or amiloride (10–20 mg/day), with careful monitoring of electrolytes. For some patients with very severe drug resistant hypertension it may be necessary use a combination of monoxidil, loop diuretic, and β-blocker to improve blood pressure control.
Poor adherence to therapy is often difficult to detect in hypertensive patients and can lead to expensive investigations for secondary causes. One way of detecting effectiveness of treatment is to use ABPM to monitor blood pressure after directly observed consumption of medication. Although this may not resolve the problem of adherence with treatment, it will identify whether the treatment is effective if adhered to, thus avoiding the need for further investigations. Where adherence is obviously poor, a number of manoeuvres can help to improve it. The treatment should be made as simple as possible, using once-daily drugs and combination tablets, and a carer needs to be involved in administering medication to those who are confused. Whenever possible, effective communication with full information and involvement of the patient in his or her treatment is essential. Nurses, pharmacists, and other health professionals can play a vital role in this process.
It is essential that patients are monitored regularly and it is important that this message is conveyed to the patient. In the early stages of treatment the frequency of monitoring will be determined by the response to therapy, comorbidities, and the complexity of the treatment regimen required to control the blood pressure. Once blood pressure is controlled, patients should be reviewed at least annually, and most will be reviewed every 6 months. Patients are increasingly monitoring their own blood pressure in the intervening period.
Withdrawal of therapy
The vast majority of patients with hypertension require lifelong therapy. Some with grade 1 hypertension who make substantial adjustments to their lifestyle may obtain sufficient fall in their blood pressure to warrant withdrawal of monotherapy. However, patients with target organ damage or those at high cardiovascular disease risk should not usually have their therapy withdrawn, unless there is a compelling clinical reason to do so. It is also important to note that in patients with previously severe hypertension that has subsequently been well controlled, treatment withdrawal may not always result in an immediate increase in blood pressure. This can sometimes convey the false impression that treatment may no longer be required because blood pressure can sometimes take many months to progressively rise back to dangerously high pretreatment values. Thus, any patient who discontinues therapy must remain under review with regular monitoring of their blood pressure, and all but a very few will require treatment again.
Indications for specialist referral
There are circumstances when referral to a specialist centre is indicated for the management of hypertension. These include uncertainty about the decision to treat, investigations to exclude secondary hypertension, severe and complicated hypertension, and resistant hypertension, among others as detailed in Bullet list 5.
Medication to reduce cardiovascular risk
Blood pressure should not be treated in isolation and should be considered as part of a comprehensive strategy to reduce cardiovascular disease risk. In this regard, patients at high risk, i.e. those with established cardiovascular disease, target organ damage, and/or diabetes, or those with a calculated cardiovascular disease risk which is elevated (e.g. ≥20% over 10 years), should be considered for additional interventions to reduce risk. These include reinforcement of lifestyle advice, especially smoking cessation, and treatment with statin therapy to further reduce their risk of stroke and coronary disease. In recent studies the routine use of statins to reduce total cholesterol values by 1 mmol/litre has been associated with a reduction in the risk of ischaemic heart disease events by about one-third and stroke by about one-fifth, over and above the benefit already accrued from blood pressure lowering. Moreover, the relative risk reduction associated with statin therapy in higher risk hypertensive patients was not dependent on a high baseline cholesterol value.
Bullet list 5 Recommended and possible indications for specialist referral for patients with hypertension
- ◆ Accelerated hypertension (severe hypertension with grade III—IV retinopathy)
- ◆ Particularly severe hypertension (>220/120 mmHg)
- ◆ Impending complications (e.g. transient ischaemic attack, left ventricular failure)
- ◆ Any clue in history or examination of a secondary cause, e.g. hypokalemia with increased or high normal plasma sodium (Conn’s syndrome)
- ◆ Elevated serum creatinine
- ◆ Proteinuria or haematuria
- ◆ Sudden-onset or worsening of hypertension
- ◆ Resistance to multidrug regimen, i.e. ≥3 drugs
- ◆ Young age (any hypertension <20 years; needing treatment <30 years)
- ◆ Multiple drug intolerance
- ◆ Multiple drug contraindications
- ◆ Persistent nonadherence or noncompliance
- ◆ Unusual blood pressure variability
- ◆ Possible white coat hypertension
- ◆ Hypertension in pregnancy
Once blood pressure has been controlled, higher risk hypertensive patients should also be considered for treatment with low dose aspirin (75 mg/day). This has been shown to reduce the incidence of myocardial infarction in higher-risk patients over 50 years old and should be offered routinely to patients who fall in this category and who do not have contraindications. In view of the increased incidence of haemorrhage, it is not indicated in lower-risk hypertensive patients.
Hypertension in specific groups of patients
Hypertension is more prevalent in blacks, is associated with more target organ damage and consequently carries a worse prognosis, with a particularly high risk of stroke. Black patients as a group tend to respond better to diuretics, calcium channel blockers, and dietary salt restriction than white patients. ACE inhibitors, angiotensin receptor blockers, and β-blockers are generally less effective as initial therapy, but become more effective when combined with diuretics and/or calcium channel blockers.
Most people with hypertension are elderly. If a blood pressure of 140/90 mmHg or more is used to define hypertension, then over 70% of people over the age of 60 years will be hypertensive, with most of these having isolated systolic hypertension. Surveys suggest that doctors consistently underestimate the risks and undertreat hypertension in older people, which is somewhat paradoxical in that elderly people have much higher absolute risk than younger people with hypertension and therefore much to gain from blood pressure lowering. There are, however, some important considerations when treating older people:
- ◆ The arterial wall stiffening that gives rise to systolic hypertension and increased pulse pressure (isolated systolic hypertension) is also associated with impaired baroreflex sensitivity, with increased risk of orthostatic hypotension, hence it is important to record lying and standing blood pressure in elderly patients.
- ◆ eGFR declines with age and renal conservation of sodium and fluid in the face of depletion is impaired, thus elderly patients are more prone to dehydration as a result of diuretic therapy.
- ◆ Clearance of drugs and their active metabolites is decreased as a result of declining hepatic and renal function.
- ◆ Cardiac function and reserve are often reduced, such that patients are much more likely to develop cardiac failure. This explains why endpoint trials of hypertension treatment have consistently shown reductions in morbidity and mortality from cardiac failure.
- ◆ Comorbidity is much more common.
- ◆ Communication and adherence with therapy may be more difficult with decline in cognitive function. Some evidence from clinical trials suggests that this decline may be retarded by antihypertensive treatment.
Despite these considerations, elderly people tolerate blood pressure lowering medications well, and the benefits of blood pressure reduction are impressive with regard to reductions in morbidity and mortality due to stroke, ischaemic heart disease, and heart failure. As a general rule, drug regimens should be as simple as possible and dosages increased more gradually, the greatest danger resulting from lowering pressure too much and too rapidly. Until recently there was uncertainty about the risks and benefits of treating hypertension in very elderly people, i.e. those over the age of 80 years, but a recent study in this age group confirmed that treatment was well tolerated and associated with impressive reductions in the risk of stroke, heart failure, and mortality. Thus, there is no reason to manage very elderly patients any differently from those who are not as old. Biological rather than chronological age should be the deciding factor in initiating antihypertensive treatment, but there is never any substitute for clinical common sense—the elderly man with mild cognitive impairment, prone to falls, and with occasional dizziness on standing up, is not likely to be well served by the doctor who advocates medication to reduce marginally elevated blood pressure.
Although secondary hypertension is more common in children than in adults, no specific cause is found for hypertension in most adolescents. The criteria for drug treatment, however, have to be modified because of the lower normal blood pressure range. The JNC guidelines recommend that blood pressures above the 95th percentile—taking into account age, height, and sex—should be considered elevated. In principle, treatment regimens are the same as those recommended for adults, with appropriate dose adjustment.