International Task Force for Prevention of
Coronary Heart Disease

CORONARY HEART DISEASE: REDUCING THE RISK

3.5 Management of hypertension

3.5.1 Goal for blood pressure reduction

The aim of blood pressure reduction is to reduce cardiovascular morbidity and mortality with minimal untoward effects. According to WHO/ISH and JNC VI recommendations, systolic blood pressure should be maintained at less than 140 mm/Hg and diastolic blood pressure below 90 mm/Hg. The results of the Hypertension Optimal Treatment (HOT) Study ^48a, a prospective randomized multicentre trial on almost 19,000 patients in twenty-six countries followed for a mean of 3.8 years, have indicated 139 mmHg systolic and 83 mmHg diastolic as the optimal blood pressure levels to be achieved for maximum reduction of cardiovascular risk. Further reduction in diastolic blood pressure below this level was safe. This study has also shown that in high risk patients with a history of CHD, aggressive antihypertensive therapy is safe and effective with no evidence of a U-shaped relationship between attained diastolic blood pressure level and rate of major cardiovascular events. Other modifiable risk factors for cardiovascular disease should be sought for and treated. Those at highest risk need particular care, namely older people, patients with diabetes mellitus and or hyperlipidaemia, patients with left ventricular hypertrophy, decreased renal function, or patients who smoke and can or will not stop. In older people, a reduction in blood pressure to 140/90 mmHg, if tolerated, is advisable; isolated elevated systolic blood pressure should be reduced to below 160 mmHg. Most patients have primary hypertension, as a consequence of the interaction of polygenic susceptibility with unfavorable life styles and adverse dietary habits. The level of risk in the hypertensive patient is heavily influenced by the presence or absence of target organ damage and of other risk factors. It is thus important to assess the patient's global risk by considering all major risk factors. The presence of these risk factors makes careful antihypertensive treatment all the more necessary and urgent. The major risk factors are smoking, plasma lipid abnormalities, diabetes mellitus, left ventricular hypertrophy, male sex, greater age, and a family history of hypertension (with onset earlier than 65 years in women or 55 years in men) and cardiovascular disease. The major organ damage in untreated hypertension involves the heart -in the form of left ventricular hypertrophy, coronary heart disease, and congestive heart failure, the brain - in the form of stroke or transient ischemic attacks-, the kidneys - in the form of nephropathy, the central and peripheral arteries, and the retina.

3.5.2 Non-pharmacological treatment of hypertension

Lifestyle modifications may be very valuable both as initial (or only) treatment of hypertension and as an adjunct to pharmacological therapy (when this proves necessary): in the latter case they may help reduce the number and /or the dosage of antihypertensive drugs needed to control blood pressure. The adoption of healthy lifestyles also bears a potential for primary prevention of hypertension. Moreover, it is helpful in the control of other cardiovascular risk factors often associated to high blood pressure.

• Nonpharmacological measures are appropriate for all hypertensives.
• Weight reduction of as little as 4.5 kg reduces blood pressure in a large proportion of overweight hypertensives.
• Withdrawal of alcohol intake may lower blood pressure in heavy drinkers and improve the response to antihypertensive drug therapy, when this is needed.
• Regular aerobic physical activity - minimum of 30 minutes 5 days per week at moderate intensity - can reduce blood pressure, enhance weight loss, improve general health and reduce the risk of cardiovascular disease and all-cause mortality.
• Reduction of sodium chloride intake to less than 70 mmol (4 g/day) lowers blood pressure in most hypertensive individuals. Its effect may be greater in older persons and those with higher pressures. Several studies have suggested that sodium chloride restriction may bring about other favourable effects, such as reduced diuretic-induced potassium wastage, prevention of urolithiasis by reduction in urinary calcium excretion and regression of left ventricular hypertrophy.
• A high potassium intake should be recommended to everyone, regardless of blood pressure. In particular potassium intakes of 75 mmol/day or above, obtained from natural food sources such as fruits, vegetables and legumes have been shown to reduce the need for antihypertensive medications in hypertensive patients. Attention must be paid to possible fall in serum potassium concentration during prolonged treatment with thiazide diuretics.
• Reduction of saturated fat intake may moderately lower blood pressure: its effect was additive to that of increased fruit and vegetable intake in a recent controlled trial (DASH)^48b.
• Other factors such as calcium, magnesium and protein intakes may also be relevant to blood pressure control.
• Finally, cigarette smoking is a powerful risk factor for cardiovascular disease, and avoidance of tobacco in any form is particularly important for hypertensives.

3.5.3 Drug treatment of hypertension

When starting drug treatment, the doctor takes into account: the degree of blood pressure elevation, the presence of target organ damage, and the presence of clinical cardiovascular disease and other risk factors. A low initial dose of the drug of choice is used; the dose is then titrated upward, at a rate dependent on the patientīs age, blood pressure level and response. Once the full dosage is achieved, if response is inadequate a second drug from another class should be added. However, if the patient is experiencing significant untoward effects or no response, the first drug should be replaced with another one from a different class. Optimal therapy should provide 24 h control with a once-daily dose. Long-acting formulations are preferred for many reasons. Adherence is better with once-daily dosing; for some agents, fewer tablets incur lower costs; control of blood pressure is persistent and smooth; and protection is provided against the risk of sudden death, heart attack, and stroke due to the abrupt increase in blood pressure after arising from overnight sleep. Furthermore, the duration of action is generally such that missing a dose does not result in a dangerous increase in blood pressure.

Five classes of drugs are acceptable for first-line treatment of hypertension. Since in a number of randomized controlled trials reductions in cardiovascular morbidity and mortality has been obtained with the use of thiazide diuretics and b-blockers, it is suggested that treatment be initiated using one of these agents unless there is indication for the use of another type of drug.

An attempt to decrease the dosage and for the number of antihypertensive drugs should be considered after hypertension has been controlled effectively for at least one year (step-down therapy). The reduction should be made in a deliberate, slow, and progressive manner. Step-down therapy is particularly successful in patients who have been able to make sustained lifestyle modifications.

Scheme for pharmacological management of hypertension:

I. Begin or continue diet and other lifestyle modifications

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II. If target systolic and diastolic pressures are not reached (140/90 mmHg and possibly lower, in patients with diabetes mellitus or renal disease), proceed to administration of

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Initial drugs of choice e.g. low-dosage thiazide diuretics, or ß-blockers (unless contraindicated)

Alternative initial drugs, as based on randomized trials:

III. If blood pressure is reduced but target not achieved:

Add second agent (e.g. diuretic if not yet used).

Continue adding from other classes if necessary.

In resistant cases consider referral to specialist.

If response is persistently inadequate check drug and diet compliance; if the patient develops significant adverse effects substitute drug with one from a different class.

3.5.3.1 Thiazide diuretics

• Thiazide diuretic use is supported by clinical trial evidence of reduced and all-cause cardiovascular morbidity and mortality.
• Low doses of thiazide diuretics potentiate the effect of other agents with modest, if any, adverse effects.
• Low-dose thiazide diuretics ( e.g. hydrochlorothiazide 6.25-12.5 mg/day) are highly effective in older hypertensive patients and in older patients with isolated systolic hypertension. Side-effects include potassium depletion and arrhythmias, hyperuricaemia and gout, impaired glucose tolerance, and hyperlipidaemia, but these are seen almost exclusively with dosage higher than 25 mg/day.
• The risk of hypokalaemia can be reduced by reducing sodium and enhancing potassium intake and, if at all necessary, using thiazides in conjunction with potassium-sparing agents (amiloride, spironolactone or triamterene) and by using no more than 25 mg/day of hydrochlorothiazide or chlorthalidone.
• Thiazide diuretics are not effective in patients with advanced renal failure (creatinine > 2.5 mg/dl), in which case they may be replaced with loop diuretics.

3.5.3.2 Beta-blockers

• ß-blockers have been extensively tested in clinical trials of mortality and morbidity.
• ß-blockers may be the drugs of choice for hypertensive patients with coronary artery disease or prior myocardial infarction.
• ß-blockers decrease peri-operative cardiovascular risk in older patients undergoing major operations for any reasons and decrease the risk of atrial fibrillation in patients undergoing bypass surgery.
• Although ß-blockers may cause diabetic patients to be less aware of hypoglycaemia and although both thiazides and ß-blockers may unfavorably alter lipid profiles, randomized controlled trials suggest that these agents remain effective in hypertensive patients with diabetes.
• Side effects of ß-blockers include severe asthma in predisposed patients, worsening intermittent claudication, aching of the legs, precipitation of latent heart failure and an increasing degree of heart block.
• Side effects may be less frequent with cardio-selective and vasodilator ß-blockers. Although side-effects of ß-blockers with intrinsic sympathomimetic activity are less common, this class of ß-blockers has failed to reduce morbidity and mortality.

3.5.3.3 Angiotensin converting enzyme (ACE)-inhibitors

• ACE-inhibitors are indicated for the treatment of patients with reduced left ventricular function (ejection fraction of less than 40%) and/or heart failure or previous myocardial infarction.
• Randomized trials suggest that ACE-inhibitors retard the development of diabetic nephropathy (microalbuminuria or substantial proteinuria).
• Hypertensive patients with reduced renal function may benefit from ACE-inhibitors, particularly if they have heavy proteinuria.
• ACE-inhibitors should be avoided in patients with bilateral renal artery stenosis, which should be suspected in patients with such conditions as advanced peripheral vascular disease and/or aneurysm of the abdominal aorta.
• The side-effects of ACE-inhibitors include chronic dry cough and, more rarely, angioneurotic oedema.

3.5.3.4 Calcium channel blockers

• Calcium channel blockers are generally well tolerated when long acting formulations are used.
• In a recently completed randomized trial of systolic hypertension in elderly patients, a long-acting dihydropyridine calcium channel blocker was the initial therapy. The trial showed a reduction in stroke and cardiovascular mortality in the treated group^48c.
• Calcium channel blockers exert no adverse metabolic effects.
• Short-acting formulations such as immediate-release nifedipine have precipitated ischaemic events and, in large doses, may increase coronary mortality in patients who have had a myocardial infarction. Short-acting calcium channel blockers should therefore be used with great caution, if at all.
• Although calcium channel blockers may reduce symptoms in patients with angina pectoris, they have not been shown to reduce the death rate in this group; therefore beta-blockers are preferred in such patients.
• After myocardial infarction with preserved left ventricular function, the calcium channel blockers verapamil and diltiazem have been shown to reduce cardiac events and mortality to some extent.
• The side effects of calcium channel blockers include headache and ankle oedema.

3.5.3.5 Alpha blockers

• a-blockers are effective, generally well tolerated (apart from occasional postural hypotension after the first dose).
• They have favourable effects on plasma lipoproteins and do not adversely influence glucose metabolism. Some studies have shown that they may improve insulin sensitivity.
• Patients with benign prostatic hypertrophy may experience symptomatic relief.

3.5.3.6 Angiotensin II (AT1) receptor antagonists

These drugs have been introduced recently, and so far no morbidity or mortality trials have been published. The AT1 receptor blockers are effective in lowering blood pressure and are well tolerated. They have no effects on glucose or lipid metabolism and unlike ACE-inhibitors do not seem to cause bradykinin-associated adverse effects such as cough or angioneurotic oedema. Several smaller studies suggest that AT1 receptor blockers decrease left ventricular hypertrophy and improve cardiac function in patients with congestive heart failure. AT1 receptor blockers should be considered when an ACE-inhibitor is indicated but cannot be used because of side-effects.

3.5.4 Hypertension in patients with metabolic abnormalities

Metabolic abnormalities - including obesity, dyslipidemia, impaired glucose tolerance or frank diabetes mellitus - often coexist with hypertension, insulin resistance being a common background in many patients. Lifestyle modifications are the first approach to both conditions, and the physician's first approach is to control overweight, reduce intake of saturated fat, cholesterol, salt, and alcohol and to advise increased physical activity.

In high doses, thiazide diuretics may increase plasma total cholesterol, LDL-cholesterol, and triglyceride levels. These effects appear not to occur with low dosages. b-blockers may increase triglyceride and cholesterol, and reduce HDL-cholesterol. Nevertheless, in the SHEP study ⁴⁹, the combination of these agents reduced the risk of stroke and coronary events equally in elderly patients with normal or elevated lipid levels. a-blockers decrease plasma cholesterol and increase HDL-cholesterol. ACE-inhibitors, calcium channel blockers and centrally acting agents do not influence plasma lipid values.

3.5.5 Hypertension in older persons

Although advancing age is a risk factor for heart disease that cannot be modified, the treatment of hypertension in older persons (including those with only systolic hypertension) is most gratifying. Four randomized, prospective, double-blind trials have shown that blood pressure reduction in hypertensive persons aged 60 years or above decreases the incidence of stroke by more than 30% and the incidence of myocardial infarction by more than 20%. A decrease in total mortality has also been reported. Thiazide diuretics and beta blockers were used in 3 trials; nitrendipine was the initial medication in another study. Analysis of the SHEP study showed that thiazides alone or in combination with beta blockers benefited diabetic as well as nondiabetic hypertensives. Furthermore, non pharmacological approaches (particularly dietary salt restriction and weight loss if necessary) are also effective in the elderly. The goal of treatment in older hypertensives is similar to that in the young (i.e. <140 <90 mmHg if at all possible). An intermediate goal of 160 mmHg systolic may be set for those patients with marked systolic hypertension.