ACTA FAC

Stevan Ilić, Marina Deljanin Ilić
Institute for prevention, treatment and rehabilitation of rheumatic and cardiovascular diseases, Niška Banja

Hypertension is a chronic disease accounting for the largest number of physician office visits all over the world. With the increasing age of the population, it will become even more common. By the age of ³ 65, more than half of the people will have an elevated blood pressure, in the majority of cases caused by the progressive rise in systolic levels that are an accompaniment of atherosclerotic rigidity of large arteries. Such rises in systolic blood pressure are, not surprisingly, the major predictor of future cardiovascular risk. Fortunately, reductions in high blood pressure protects against stroke and other cardiovascular morbidities, in all groups of patients, even among those around 80 years of age or older (1). The common the hypertension is and more beneficial its treatment is, the overall management of the disease is rather inadequate. The basic problem is the asymptomatic nature of hypertension, making it difficult to maintain a lifelong therapy when no immediate benefits are obvious to the patient (2).
Multiple guidelines for improved management of hypertension have recently been published (3-5). Following the announcement of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) (6) at the end of 2002, the American hypertension guidelines were completely revised and reissued as the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and the Treatment of High Blood Pressure (JNC 7) (4) in the spring of 2003. This was soon followed by guideline updates jointly issued from the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC),(5) which actually updated the 1999 World Health Organization (WHO)/International Society of Hypertension (ISH) guidelines (7).
In this report we would like to review the new blood pressure classification, diagnosing and treatment of arterial hypertension in regard to recent European guidelines (5).

The goal of the new guidelines is to update the 1999 World Health Organization (WHO)/International Society of Hypertension (ISH) guidelines, (7) which the ESH/ESC had previously endorsed but then decided to revise.

The relationship between blood pressure levels and cardiovascular risk is continuous and direct, which makes all numerical definitions and classification of hypertension arbitrary. All numerical definitions must be flexible, resulting from evidence of risk and availability of effective and well-tolerated drugs. Since no new epidemiologic evidence has emerged since 1999, the WHO/ISH classification has been retained (table 1), with the reservation that the threshold for hypertension must be considered as flexible ie, higher or lower based on the total (global) cardiovascular risk profile of each individual. Accordingly, the definition of high-normal blood pressure includes values that may be considered as high (ie, hypertensive) in high-risk individuals or acceptable in lower risk ones.

Blood Pressure Category

Systolic blood pressure (SBP)

mm Hg

Diastolic blood pressure (DBP)

mm Hg

Normal blood pressure

     optimal
     normal
     high-normal

Hypertension

     Grade 1 (mild)
     Grade 2 (moderate)
     Grade 3 (severe)
     Isolated systolic hypertension

< 120
120-129
130-139

140-159
150-179
≥ 180
≥ 140

< 80
80-84
85-89

90-99
100-109
≥110
< 90

According to the guidelines, when a patient's SBP and DBP levels fall into different categories, the higher category should apply. Moreover, in older patients with isolated systolic hypertension, the blood pressure can also be assessed as grades 1, 2, and 3, according to SBP values.

JNC 7 guidelines is American a new blood pressure classification system that includes a category called "prehypertension," ie, people with SBP 120-139 mm Hg or DBP 80-89 mm Hg. However, "normal" in JNC 7 is now defined as SBP < 120 mm Hg and DBP<80 mm Hg, previously called "optimal." JNC 7 has abolished both the "optimal" and "high-normal" categories. Stage 1 hypertension (SBP 140 - 159 or DBP 90 - 99 mm Hg), and Stage 2 (³ 160 mm Hg or DBP ³100 mm Hg) (table 2).

Blood Pressure Category	SBP (mm Hg)		DBP (mm Hg)
Normal	< 120	and	< 80
Prehypertension	120-139	or	80-89
Stage 1 hypertension	140-159	or	90-99
Stage 2 hypertension	≥ 160	or	≥ 100

The main concern about the new category of "prehypertension" is that people who previously considered themselves healthy ("normal") will now believe that they have a disease. This will add to the population of the "worried well," a group that is already putting increasing pressure on healthcare resources in the United States. European guidlines term "prehypertension" has not been accepted.

Global cardiovascular risk makes up an important part of the new guidelines (5). The committee points out that hypertension is often accompanied by other risk factors. Total cardiovascular risk quantification allows more accurate prognostic evaluation of the patient. The timing and type of antihypertensive treatment depend on this profile, and the blood pressure threshold and targets for therapy are modified. Moreover, the need for accompanying antihypertensive treatment is thus modulated.
Therefore, the classification using stratification for total cardiovascular risk has been expanded from the scheme in the 1999 WHO/ISH guidelines to indicate the added risk in some groups of individuals with normal or high blood pressure (table 3).

Other risk factors and disease history	Blood Pressure
	Optimal and normal	High-normal	Grade 1	Grade 2	Grade 3
No other risk factors	Average risk	Average risk	Low added risk	Moderately added risk	High added risk
1-2 risk factors	Low added risk	Low added risk	Moderate added risk	Moderate added risk	Very high added risk
≥ 3 risk factors, TOD, or diabetes	Moderate added risk	High added risk	High added risk	High added risk	Very high added risk
ACC	High added risk	Very high added risk	Very high added risk	Very high added risk	Very high added risk
ACC = associated clinical conditions; TOD = target organ damage

The total level of risk is the main indication for intervention, but lower or higher pressure values are also more or less stringent indicators for blood pressure-lowering intervention. The terms "low added", "moderate added", "high added", and "very high added" risk are calibrated to indicate an approximate absolute 10-year risk of cardiovascular disease of < 15%, 15% to 20%, 20% to 30%, and > 30% added risk, respectively, according to Framingham criteria (8), or an absolute risk of fatal cardiovascular disease of < 4%, 4% to 5%, 5% to 8%, and > 8%, respectively, according to the SCORE (Systemic Coronary Risk Evaluation) chart (9). The word "added" is used because it accounts for an increase in relative risk and, for example, could negate the misleading impression that patients at "low risk" are below average risk (they are actually at low added risk). The total cardiovascular risk is depedend from other risk factors, presence of target organ damage, presence of diabetes and associated clinical conditions.

The most common risk factors for cardiovascular disease used for stratification are:

• Levels of systolic and diastolic blood pressure
• Men aged > 55 years
• Women aged > 65 years
• Smoking
• Dyslipidemia: total cholesterol > 6.5 mmol/L (> 250 mg/dL) or LDL-cholesterol > 4.0 mmol/L (> 155 mg/dL) or HDL-cholesterol:
men: < 1.0 mmol/L (< 40 mg/dL);
women: < 1.2 mmol/L (< 48 mg/dL)
• Family history of premature cardiovascular disease (men < 55 years, women < 65 years)
• Abdominal obesity (abdominal circumference ≥102 cm in men, ≥88 cm in women)
• C-reactive protein ≥1 mg/dL

The importance of target organ damage (TOD) for determining overall cardiovascular risk is also emphasized. The practicing physician should seek evidence for organ involvement including:

• Left ventricular hypertrophy
ECG: Sokolow-Lyons > 38 mm; Cornell >2440mm*ms
Echocardiogram: LVMI for men >125, for woman >110 g/m²
• Ultrasound evidence of arterial wall thickening (carotid IMT ≥0.9 mm) or atherosclerotic plaque
• Slight increase in serum creatinine men 115 - 133, women 107 - 124 µmol/l
• Microalbuminuria (30-300 mg/24h; albumen-creatinine ratio: men ≥22, women ≥31 mg/gr; men ≥2.5, women ≥3.5 mg/mmol)

Other factors the guidelines points to as influencing prognosis are the presence/absence of diabetes mellitus and of associated clinical conditions:

• Cerbovascular disease: iscahemic stroke, cerebral haemorrage or transient iscaemic attack• Heart disease: Myocardial infarction, angina, coronary revascularization or congestive heart failure• Renal disease: diabetic nephropathy, renal impairement (serum creatinine - men > 133, woman > 124 µmol/l; proteinuria (>300 mg/24h)• Peripheral vascular disease• Advanced retinopathy: hemorrhagies or exudates papilloedema

Diagnostic procedures are aimed at: establishing blood pressure levels, identifying secondary causes of hypertension and evaluating the overall cardiovascular risk. The diagnostic procedures comprise: medical history, phasical examination, repeated blood pressure measuremenst and laboratory and instrumental investigations. Laboratory investigations are directed at providing evidence of additional risk factors, searching for seconday hypertension and assessing absence and presence of target organ damage. Laboratory investigations may be routine tests, recommended tests and expanded evaluation (domain of the specialist):

Routine tests
• Fasting plasma glucose
• Serum total cholesterol
• HDL cholesterol
• Fasting serum trigliceride
• Serum creatinine
• Serum potassium
• Haemoglobin and haematocrit
• Urinanalysis dipstick test and urinary sediment examination
• Electrocardiogram

Recomended tests
• Echocardiogram
• Carotid (and femoral) ultrasound
• C-reactive protein
• Microalbuminuria (essential test in diabetics patients)
• Quantitative proteinuria (if dipstick test positive)
• Fundoscopy (in severe hypertension)

Extended evaluation (domain of the specialist)
• Complicated hypertension: test of cerebral, cardiac and renal function
• Search for secondary hypertension: measure- ment of renin, aldosterone, corticosteroids, catecholamines, arteriography, renal and adrenal ultrasound, compjuter-assisted tomography, brain magnetic resonance imaging

    The primary goal of treatment is to achieve the maximum reduction in the long-term total risk of cardiovascular morbidity and mortality. On the basis of current evidence from trials, blood pressures should be lowered to < 140/90 mm Hg at least, and, if tolerated, to levels < 130/80 mm Hg in diabetic patients. The guidelines for initiating antihypertensive treatment are based on 2 criteria: the total level of cardiovascular risk (table 3), and SBP and DBP levels (table 1). The total level of cardiovascular risk is the main indication for intervention, but lower or higher blood pressure values are also less or more stringent indicators for blood pressure lowering intervention.
    Decision for initiation of antihypertensive treatment based on initial blood pressure levels and total risk level.

Assess other risk factors, target organ damage (particularly renal), diabetes, associated clinical conditions

↓

Initiate lifestile modification and correction of other risk factors or disease

↓

State absolute risk (see Table 3)

↓ ↓ ↓ ↓

very high high moderate low

Begin drug Begin drug Monitor BP No BP
treatment treatment frequently intervention

Recommendations for individuals with grades 1 and 2 hypertension (SBP 140-179 mm Hg or DBP 90-109 mm Hg on several occasions) include:

Assess other risk factors, target organ damage, diabetes, associated clinical conditions

↓

Initiate lifestile modification and correction of other risk factors or disease

↓

Stratify absolute risk (see table 3)

↓ ↓

very high high

Begin drug        Begin drug
treatment          treatment
promptly          promptly

↓

moderate

     Monitor BP
    and other
     risk factors
     for at least 3 months

↓

low

Monitor BP
and other risk
risk factors for
3-12 months

↓ ↓

SBP ≥ 140        SBP < 140
or DBP ≥ 90     and DBP <90
mmHg              mmHg

Begin               Continue
drug                 to
treatment         monitor

↓ ↓

SBP≥140-159 SBP< 140
or DBP≥90-99 and DBP<90 mmHg mmHg

Consider           Continue
drug                   to
treatment           monitor
and elict
patients
preference

Recommendations for individuals with grades 3 hypertension (SBP ≥180 mm Hg or DBP≥ 110 mm Hg on repeated measurements within a few day) include:

Lifestyle changes. Lifestyle measures should be instituted whenever appropriate in all pateints, including subjects with normal blood presure and patients who require drug treatment. The purpose is to lower blood pressure and to control other risk factors and present clinical condition. Lifestile measures include:

Principles of drug treatment: monotherapy or combination therapy. It is recommended that monotherapy should be started gradually, and target blood pressure values achieved progressively through several weeks, in most patients. The proportion of patients requiring combination therapy will depend on baseline blood pressure values. In grade 1 hypertensives, monotherapy is more frequently likely to be succesful. According to the baseline blood pressure and the presence or absence of complications, it appears resonable to initiate therapy either with a low dose of a single drug or with a low dose combination of two drugs (figure 1).

Combination Therapy. Drug combinations found to be effective and well tolerated include:

• Diuretic and beta-blocker
• Diuretic and ACE inhibitor or angiotensin receptor antagonist
• Calcium antagonist (dihydropyridine) and beta-blocker
• Calcium antagonist and ACE inhibitor or angiotensin receptor antagonist
• Calcium antagonist and diuretic
• Alpha-blocker and beta-blocker
• Other combinations (eg, with centrally acting agents, including alpha2-adrenoceptor agonists and imidazoline-I2 receptor modulators, or ACE inhibitors or angiotensin receptor antagonist) can be used, if necessary.
• In many cases, 3 or 4 drugs may be necessary.

A disadvantage of combination therapy is the potential exposure of patients to unnecessary drugs, but control of blood pressure and its complications is more likely. The application of low-dose combinations are more likely to be free of side effects, and fixed-dose combinations available in Europe are likely to have the practical advantage of optimizing compliance. The approach in which patients will likely depend on the initial blood pressure, risk factors, and the presence or possibility of target organ damage should be ascribed to this decision.
Choice of antihypertensive agents. The guidelines stress that the main benefits of antihypertensive therapy are due to the lowering of blood pressure per se. They list the standard major classes of antihypertensive agents suitable for the initiation and maintenance of therapy:

• Diuretics
• Beta-blockers
• Calcium channel blockers
• ACE inhibitors
• Angiotensin-receptor blockers
• Regarding a final class, alpha-adrenergic receptor blockers, the arm of the only trial testing an alpha-blocker (the doxazosin arm of ALLHAT) was terminated early, for an excess of cardiovascular events. Alpha-blockers should be considered as a therapeutic option, particularly for combination therapy.

The European guidelines refrain from recommending specific classes of drugs as initial treatment. Nevertheless, the guidelines recognize that there is evidence to support variable effects of specific drug classes on special subsets of patients. These include the elderly, pregnant women, diabetic patients, patients with concomitant cerebrovascular disease, coronary heart disease, or congestive heart failure, deranged renal function, or resistant hypertension. Specific indications are given for the major classes of antihypertensive drugs (table 4).