© Borgis - New Medicine 3/2003, s. 73-78
Zygmunt Chodorowski
Arterial hypertension in the elderly
1st Department of Internal Medicine, The Medical University of Gdansk, Poland
Head: prof. Zygmunt Chodorowski MD, PhD
Summary
Arterial hypertension, and particularly its isolated systolic type, is a common disease in the the elderly and accounts for 60-70% of the old age population. The present paper includes the latest recommedations of the 7th report of the JNC, the European Society of Hypertension, and the European Society of Cardiology, which highlight the need for combination therapy with two or more antihypertensive drugs.
The choice of single-drug or combination therapy should be individually adjusted and should consider risk factors of atherosclerosis, concomitant diseases, response to treatment and the quality of life.
The most effective treatment of elderly hypertensive patients appears to be the therapy with thiazide diuretics, although any pharmaceutical agents of four main antihypertensive drug groups used in many studies have shown equal benefits. At present, only alpha-adrenolytics seem to have lost their popularity, and are not recommended in single-drug but only in combination therapy.
Angiotensin converting enzyme inhibitors are particularly indicated in left ventricular systolic dysfunction, previous myocardial infarction, diabetic nephropathy, and glomerular nephropathies.
To ensure prevention and nephroprotection in patients with type 2 diabetes and arterial hypertension, angiotensin receptor antagonists are mainly recommended.
Epidemiological studies have shown that the prevalence of arterial hypertension in the elderly population ranges from 60% to 70% (1).
The values of both components of arterial blood pressure change with increasing age. The diastolic pressure increases until the age of 50-60 years; over the subsequent years it remains at a fairly constant level or it even decreases (2). However, the systolic pressure shows an increasingly progressive growth until 80-84 years of age in men, and 75-79 years of age in women. Owing to that, isolated systolic hypertension before the age of 60 years occurs very seldom, but in the elderly, its incidence in the hypertensive population rises up to 50-60%.
Assessment of arterial hypertension in the elderly is particularly specific. A single blood pressure measurement gives no reason for initiating pharmacological treatment since, according to some geriatricians, the´ white coat´ hypertension, or office hypertension, is more frequent in the elderly than in younger age groups. This phenomenon is fairly common and occurs in about 10% of the general population (3). To exclude this, especially with significant fluctuations typical of the elderly, it is recommended to carry out a 24-hour automatic monitoring or 4-6 measurements at home and work, done by the patients themselves, their relatives or friends (4-6). Results of the latter are more compatible with 24-hour automatic blood pressure monitoring than those done at the clinic. The mean result of three or more measurements carried out on three different days, may be the grounds to diagnose arterial hypertension. Blood pressure in the elderly is taken at both arms, since the patient is likely to have a segmental constriction in the diameter of one of the subclavian and/or brachial arteries. It is recommended to do sitting or standing blood pressure measurements in order to recognise a possible orthostatic hypotension (decreased systolic pressure> 20 mmHg, diastolic pressure RR> 10 mmHg) (7, 8). Physical examination should include auscultation of all the accessible large arteries, since the presence of sounds over the blood vessels is crucial for the further management of the patient.
Elderly patients sometimes develop pseudohypertension. It is associated with significant stiffness of the brachial arteries, which does not allow adequate cuff tightening, and this results in high false positive values. Pseudohypertension should be suspected when, inspite of many readings of values typical of severe hypertension, no organ damage can be found. These patients usually show a high discrepancy between high blood pressure values on noninvasive measurements, and normal or slightly increased values found on invasive procedures.
Arterial hypertension in the elderly, including its isolated systolic variant, is a well-documented, independent factor of coronary heart disease, congestive heart failure, cerebral stroke, and sudden death (4, 6). A high pulse pressure (the difference between the systolic and diastolic pressure values), as an index of reduced compliance of large arteries, is a more adequate risk reference of cardiovascular disease than the systolic or diastolic pressure values; it helps identify patients with systolic hypertension who are at a particularly high risk (7). A meta-analysis of almost one million patients showed that at the age> 55 years, the effect of pulse pressure on the risk of cardiovascular events increased (9).
So far, multicentre randomised studies provided indisputable evidence of significant benefits of antihypertensive treatment in the elderly, which resulted in reduced rates of cardiovascular complications and mortality, and increased patient survival (10-12). Pharmacological treatment of hypertension in elderly patients requires considerable deliberation. The therapy should be started in accordance with general recommendations but gradual introduction should be done with particular caution (13, 14). The ´first of all do no harm´ principle (primum non nocere) appears to be unusally meaningful here. Patient management includes those who are highly susceptible to significant age-related blood pressure fluctuations, autonomic neuropathy and multiorgan damage; the patients are particularly prone to orthostatic hypotension (8). The likelihood of easy impairment of the mechanism of the cerebral flow autoregulation and, to a lesser degree, also the coronary flow, makes it mandatory to avoid potent and quick-acting antihypertensive drugs. An excessive and too rapid decrease in the arterial blood pressure in the elderly, may lead to many complications associated with a diminished coronary reserve, impaired renal excretion rate, reduced cerebral blood flow.
In patients with the systolic pressure of 140-160 mmHg and diastolic pressure within the range of 90-100 mmHg, it is recommended to begin the antihypertensive therapy with an initial attempt to offer a non-pharmacological treatment, i.e., a modified lifestyle. This includes a gradual reduction in the body weight in obese patients, regularity and improved quality of night sleep, diminished dietary salt intake (to 5.0 g/d), cessation of smoking, decreased alcohol consumption (to 20 g/d), and regular, isotonic exercise adjusted to individual physical fitness (1, 8, 15-18). The DASH study (Dietary Approaches to Stop Hypertension) showed that a healthy low-sodium diet may have a beneficial effect on other cardiovascular risk factors and may reduce hypertension (19). The JNC 7 report supports the recommendations of the American Society of Public Health, according to which, food manufacturers and restaurant owners are obliged to reduce diatary sodium intake in food by 50% over the next 10 years (8). Occasionally recommended fasting or rigorous dietary restrictions are badly tolerated by elderly persons. They are more susceptible to the hypertensive action of sodium ion, and respond to the dietary salt restriction with a more significant fall in blood pressure. Weight loss, achieved due to a low-calorie diet, and adequate physical exercise, should be gradual and continued. In many patients with a sedentary lifestyle, a beneficial hypotensive effect may be noted following a 30-45 min quick march, consistently trained 5 times/week. However, many patients are not capable of doing such an effort due to multiple organ damage (8). Nevertheless, even a minor physical activity may reduce systolic arterial blood pressure by about 4-8 mmHg (20). Patients with a poorly controlled arterial blood pressure and severe hypertension, should be discouraged from doing more intensive physical exercise (7).
The outcome of a modified lifestyle should not be overestimated, but in well-disciplined patients such a change decreases their requirement for antihypertensives drugs. However, it seldom leads to temporary drug discontinuation. Nevertheless, an altered lifestyle, also in patients with more severe hypertension, is a mandatory measure to complement pharmacological treatment.
On making the decision to initiate pharmacological therapy in an individual patient, it is vital to consider the blood pressure level, resulting organ system complications, concomitant diseases, and risk factors of artherosclerosis. At present, the main treatment objective is not only to reduce the blood pressure to its normal values, but first of all, to maximally diminish the total cardiovascular disease risk, and morbidity and mortality resulting from complications of hypertension (4).
With advancing age, apart from hypertension, other risk factors increase their frequency, e.g., insulin resistance and hyperinsulinaemia, decreased glucose tolerance, diabetes, obesity and overweight, hyperlipidaemia, left ventricular hypertrophy, thickening of the carotid artery wall, increased C-reactive protein concentration (7, 8, 21). Although impaired lipid metabolism becomes milder with age, its atherogenic effect seems to rise. This is accompanied by multiple organ damage, and physiopathological aging processes adversely affect the functions of many organs and systems. First of all, the cardiovascular system shows diminished cardiac output, intravascular volume, organ blood flow, and increased peripheral resistance, venous return, and stiffness of ventricular and arterial walls. In view of the above, antihyper- tensive therapy is usually combined with a complex treatment targeted at regression, if possible, of multiple risk factors of atherosclerosis and accompanying diseases (4, 7, 8).
Wherever possible, the antihypertensive therapy should be aimed at achieving the blood pressure values <140/90 mmHg, provided that these values, as well as drugs themselves, are well tolerated by patients (7, 8). In diabetes, the optimum blood pressure, although usually difficult to obtain, is <130/80 mmHg (8, 22, 23).
Prior to the introduction of antihypertensive therapy, assessment should be performrd of the patient´s condition and his biological fitness which frequently does not correspond with his calendar age. In elderly patients, the antihypertensive treatment should be instituted gradually to reach the target values within a few or several weeks (7). With respect to the initial arterial blood pressure and presence or absence of organ damage, the therapy starts with administration of either a low dose of a single drug or a combination of low doses of two drugs (7). If the arterial blood pressure is equal to or greater than 160/100 mmHg, the regimen of two drugs given separately or as a double-component preparation should be considered (8).
To ensure adequate blood pressure control, the majority of patients will need two or more drugs, since in elderly persons it is frequently difficult to reduce the systolic pressure to below 140 mmHg (24-26). The advantage of combination therapy is the possibility to administer lower doses of a few preparations avoiding at the same time, likely side effects produced by higher doses of single drugs. Long-acting drugs are recommended, especially preparations providing 24-hour efficacy with a single daily dose. The drug benefits include better patient compliance in following therapeutic recommendations and minimizing alterations in blood pressure, which protects patients against severe cardiovascular events and development of organ damage. Therefore, preferred are not only effective drugs but mainly those which produce the patient´s good response. Most current antihypertensive drugs may be used in the treatment of the elderly, however, frequently occuring multiorgan damage in this age group restricts administration of some agents.
General malaise, vertigo, impaired body balance, scotomas, confusion and other mental disorders occuring in the course of treatment require reduction in the dosage or change of the type of antihypertensive agents. The higher the blood pressure prior to the therapy the more caution and the longer time required to decrease the dose.
The key benefits of the antihypertensive treatment are due to blood pressure per se. All the major classes of antihypertensive agents may be used in hypertensive treatment, i.e., diuretics, beta-adrenolytics, calcium channel blockers, angiotensin converting enzyme inhibitors and angiotensin receptor antagonists. Preparations of the five basic antihypertensive drug groups decrease blood pressure within the same range. The emphasis on identification of the drug class to be given as the initial preparation in the therapy is not relevant as it is mandatory to use a combination of two or more drugs to achieve the target blood pressure (7). Since many hypertensive patients develop organ system damage, risk factors of atherosclerosis, cardiovascular events and diseases of other systems, the choice of the initial drug should depend on the patients´ present clinical status and also the cost of the therapy.
Our experience shows that the population of hypertensive patients also includes two extreme subgroups. In one subgroup, antihypertensive drug(s) administered at the same dose for a long time help(s) maintain satisfactory BP level(s). In the other subgroup, it is mandatory to increase the drug dose or to add new preparations at a few or several months´ intervals. This occurs more frequently in patients with chronic unstable renal insufficiency, diabetes or arterial hypertension.
It is worth considering the results of the SHEP study showing that in the course of antihypertensive treatment of patients with isolated systolic hypertension, obtained diastolic pressure <70 mmHg, particularly <60 mmHg, helps identify a high risk group with worse therapeutic values (27).
Benefits due to the reduction in arterial hypertension in patients with high normal blood pressure values are confined mainly to the subjects with a previous cerebral stroke (28), coronary heart disease (29), and diabetes (30).
Diuretics
In order to normalize arterial hypertension in the elderly, particularly its isolated systolic variant, thiazides or thiazide derivatives (hydrochlorothiazide, chlorothalidone, indapamide, clopamide are administered. The drugs are also beneficial in the case of concomitant osteoporosis. Many adverse effects of thiazide diuretics may be avoided when they are given at low doses, which does not diminish significantly their efficacy (31). Currently, it is assumed that a daily dose should not exceed 25 mg, and in combination treatment a dose of 12.5 mg is usually sufficient. The risk of post-thiazide hypokalaemia with severe clinical sequaelae in elderly patients, may be prevented with a simultaneous administration of potassium-sparing diuretics or potassium preparations.
In chronic congestive heart failure due to arterial hypertension, angiotensin converting enzymes and small doses of spironolactone (25-50 mg/d) are combined with thiazides or loop diuretics, depending on the severity of cardiac insufficiency according to the NYHA class. Among thiazide derivatives, indapamide has the mildest adverse effect on the metabolism of carbohydrates, lipids, potassium, magnesium, and urate. Only loop diuretics, furosemide in particular, are recommended in hypertensive patients with a diminished glomerular filtration rate <30 ml/min and/or serum creatinine concentration> 2.5 mg% (221 mmol/l). Diuretics are usually well tolerated by elderly patients and may be combined with all the remaining antihypertensive drugs.
Results of two research projects conducted over the recent years also implicate advantages of the treatment with thiazide diuretics. The STOP-2 trial (Swedish Trial in Old Patients with Hypertension-2) showed a similar incidence of cardiovascular events in randomized elderly hypertensive patients taking calcium channel blockers, angiotensin converting enzymes or diuretics or beta-adrenolytics (11). The ALLHAT study (The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) reported that a diuretic, calcium channel antagonist, and angiotensin converting enzyme inhibitor exerted similar effects on the incidence of cardiovascular events in patients> 65 years of age (32).
Total results of many randomized research trials helped develop the guidelines of the JNC report which, for most hypertensive patients, recommends the initial treatment with a thiazide diuretic or a thiazide-derivative as single-drug therapy or more frequently, in combination with one antihypertensive agent of other classes (8).
However, Psaty et al. emphasize that thiazide diuretics are still being used inadequately (33).
Beta-adrenergic receptor blockers
Beta-adrenergic receptor blockers are recommended in hypertensive patients with coronary heart disease, particularly those with a history of myocardial infarction, symptomatic supraventricular arrhythmias, migraine, idiopathic tremor, and hyperthyroidism. However, with advancing age, there is a significantly rising number of diseases and metabolic disorders which pose relative or strict contraindications for administering beta-adrenergic receptor blockers (bronchial asthma, chronic bronchitis, diabetes, intermittent claudication, atrioventricular blocks II and III, impaired lipid metabolism).
Certain drugs of this group (carvedilol, bisoprolol, metoprolol) tested in extensive randomized trials proved to be highly effective in concomitant congestive heart failure; they improved the volume of the left ventricular ejection fraction, increased the survival rate, reduced the cardiovascular mortality rate.
In spite of numerous benefits, preparations of this pharmaceutical group are not used widely enough (33).
Angiotensin converting enzyme inhibitors
Angiotensin converting enzyme (ACE) inhibitors reduce angiotensin II levels in the serum and in the arterial smooth muscle cells, inhibit catecholamine secretion and bradykinin degradation. The outcome of the activity is an increased release of nitrogen oxide and vasodilating prostoglandins. By inhibiting the renin-angiotensin-aldosteron axis and adrenergic system, ACE inhibitors improve the function of vascular epithelium damaged by arterial hypertension and aging processes, dilate arteries and veins, diminish the preload and afterload, cease, and occasionally regress the hypertrophy and remodelling of the heart and arterial vessels, improve organ blood supply (34).
Drugs of this group possess metabolic neutrality and do not affect the nervous system; they do not disturb the lipid, carbohydrate and purine metabolism, and may be used in patients with depression, which is frequently present in the elderly.
In comparison with other drugs, ACE inhibitors reduce ventricular hypertrophy more effectively and at a faster rate, produce a nephroprotective effect in patients with diabetic and other nephropathies, are cardioprotective in patients with chronic congestive heart failure and a previous myocardial infarction.
In combination therapy, the drugs may be used with added thiazide and loop diuretics, free calcium-channel antagonists and beta-adrenergic receptor blockers (35). In the elderly, it is recommended to give the first two ACE inhibitor doses before a night´s sleep since it allows avoiding severe complications associated with a fall in blood pressure, i.e., ischaemic cerebral and/or cardiac episodes, and impaired renal function. An initial, gradual increase in ACE inhibitor doses up to individually optimal amounts, should be done without a simultaneous administration of diuretics, and in the case of a diminished glomerular filtration rate, it should be supervised by frequent assessment of the renal function and serum electrolyte concentration. Simultaneously given non-steroidal antiinflammatory drugs and ACE inhibitors may sometimes impair the renal function, probably due to inhibited production of prostaglandins PGE2 and PGI2.
More critical than expected was the assessment of the ACE inhibitor efficacy in a recently conducted meta-analysis of an abundant material of hypertensive patients (36). Staessen and Wang reviewed five randomized clinical trials including a total of 46 553 patients in whom ACE inhibitors were compared with older drugs. Total chance quotients expressing a potential advantage of ACE inhibitors over older drugs were close to 1, and were nonsignificant in terms of the total mortality, cardiovascular mortality and the total incidence of cardiovascular events, myocardial infarctions and cardiac insufficiency (36). Compared with older drugs, ACE inhibitors provided a slightly less efficient protection against cerebral stroke (36).
Free calcium-channel antagonists
In terms of structure and pharmacological effects, free calcium-channel antagonists are a nonhomogenous group; however, they are well tolerated by elderly patients. Long-acting dihydropyridine preparations are given mainly to patients with concomitant coronary disease, diabetes, intermittent claudication, chronic obstructive pulmonary disease, Raynaud´s syndrome. Metabolic neutrality fully supports administration of the drugs in patients with disturbed lipid, carbohydrate and purine metabolism. The benefit of the long-acting drugs, verapamil in particular, offers the possibility to administer them in single daily doses and to maintain reduced BP values in the early and late morning hours, i.e., over the period of increased incidence of cardiovascular complications.
Nitrendipine (10-40 mg/ day) was the basic antihypertensive used in the Syst-Eur trial conducted on patients> 60 years of age. It was significantly effective in the subgroup of diabetic patients with arterial hypertension. The general mortality rate in the group decreased by 55%, cardiovascular mortality fell by 76%, the number of cerebral strokes was diminished by 73%, and the number of cardiovascular events dropped by 63% (37).
Nondihydropyridine preparations (verapamil, diltiazem), long-acting antihypertensive agents, are less frequently administered in elderly patients. Verapamil is recommended in patients with concomitant supraventricular arrhythmias, and due attention is focused on its negative inotropic activity, and prolonged atrioventricular conduction. Both verapamil and, a little less, diltiazem, have properties of reducing microalbuminuria and proteinuria; hence, their combination with ACE inhibitors enhances the nephroprotective effect in patients with hypertension and diabetes.
Angiotensin receptor antagonists
Angiotensin II receptor antagonists (losartan, valsartan, irbesartan, candesartan, telmisartan) display efficacy in decreasing hypertesion, which is comparable to that shown by other basic groups of antihypertensive agents. Like ACE inhibitors, they reduce left ventricular hypertrophy and frequency of organ damage resulting from arterial hypertension, improve heart function and regress many abnormalities in nephropathy, particularly in diabetic nephropathy. The drugs have no effect on bradykinin degradation, so they do not induce cough which is the main adverse effect of the treament with ACE inhibitor.
The LIFE (Losartan Intervention for Endpoint Reduction) study showed that losartan produced a better response and had a significant advantage over atenolol in reducing left ventricular hypertrophy and diminishing the frequency of cardiovascular events, particularly cerebral strokes (38, 39).
In hypertensive patients, candesartan increased release of nitrogen oxide from the vascular endothelium and reduced vasoconstriction of resistance arterioles induced by endothelin 1 (40). Addition of diuretics to angiotensin II receptor antagonists in combination treatment increases the antihypertensive effect of the latter.
Alpha 1-adrenergic receptor blockers
Currently, alpha-adrenolytics are not recommended in single-drug therapy. In the elderly, they may produce hazardous sequelae in orthostatic hypotension which are particularly severe on alcohol consumption (41).
The most extensive randomized clinical trial (ALLHAT) showed that a group of patients treated with doxazocin discontinued their therapy prematurely due to a double increase in the cardiac insufficiency rate, and a 25% increase in the cardiovascular events as compared with a group of patients treated with chlorthalidone (32). At present, alpha-1-adrenergic receptor blockers are recommended only in combination therapy, particularly in patients with mild prostatic hypertrophy and those with impaired lipid metabolism.
If necessary, elderly patients should receive a low dose of a diuretic combined with an ACE inhibitor or a long-acting dihydropyridine-derivative. Patients with concomitant coronary heart disease require intensive antihypertensive therapy since they have already developed organ damage. In such patients, their response to a rapidly decreased blood pressure is manifested by a sudden release of catecholamines, which may result in arrhythmias, ischaemia or myocardial infarction. Owing to that, they should be recommended only long-acting antihypertensive drugs, effective also in the morning hours when cardiovascular events are most frequent. Combination treatment of beta-blockers and calcium dihydropyridine antagonists is recommended (4). In elderly patients with arterial hypertension following myocardial infarction and/or chronic cardiac insufficiency, it is generally recommended to combine ACE inhibitors with certain beta-adrenergic receptor blockers (carvedilol, bisoprolol, metoprolol) and aldosterone receptor antagonists (42, 43).
It is, however, potentialy harmful to combine ACE inhibitors with potassium-sparing diuretics (hyperkaliaemia), verapamil or dilithiazem with beta-blockers (congestive heart failure, bradycardia, bradyarrhythmia), alpha-1-adrenergic receptor blockers with calcium dihydropyridine antagonists (orthostatic hypotension).
It is recommended to include patients´ family members in the educational process to supervise their drug intake and compliance with doctors´ orders. Taking blood pressure by the patients at home, using available semi-automatic devices, encourages the patient to closely cooperate and share the responsibility for optimum drug dosage. Patients have a chance to make their own observations on the effiicacy of the therapy and recurrence of hypertension when drugs are discontinued. Such observations motivate patients and mobilize them to continue the cooperation with their physicians.
Certain hope arises for more objectivity in the drug self-administration by patients. It is associated with the idea of introducing drug packagings with a built-in microprocessor to register precisely the time of each episode of opening the packaging (44). However, the process of implementation of the new monitoring system is definitely not very dynamic. In view of that, on everyday basis, the physician can only use empathy, which almost always raises patients´ confidence and mobilizes them to act in a positive manner (45).
Piśmiennictwo
1. Wolz M. et al.: Statement from the National High Blood Pressure Education Program: prevalence of hypertension. Am. J. Hypertens. 2000; 13:103-4. 2. Izzo J.L. Jr et al.: Clinical Advisory Statement. Importance of systolic blood pressure in older Americans. Hypertension 2000; 35:1021-4. 3. Pickering T.G. et al.: Blood Pressure Monitoring. Task force V: White-coat hypertension. Blood Press Monit. 1999; 4:333-41. 4. Carretero O.A., Oparil S.: Essential hypertension: part II: treatment. Circulation 2000; 101:446-53. 5. Verdecchia P.: Prognostic value of ambulatory blood pressure: current evidence and clinical implications. Hypertension 2000; 35:844-51. 6. Frohlich E.D.: Recognition of systolic hypertension for hypertension. Hypertension 2000; 35:1019-20. 7. Guidelines Committee. 2003 European Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension. J. Hypertens. 2003; 21:1011-53. 8. Chobanian A.V. et al.: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289:2560-72. 9. Lewington S. et al.: Prospective Studies Collaboration: Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360:1903-13. 10. Wang J.G. et al.: Chinese trial on isolated systolic hypertension in the elderly. Systolic Hypertension in China (Syst-China) Collaborative Group. Arch. Intern. Med. 2000; 160:211-20. 11. Hansson L. et al.: Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study. Lancet 1999; 354:1751-6. 12. Staessen J.A. et al.: Risks of untreated and treated isolated systolic hypertension in the elderly: meta-analysis of outcome trials. Lancet 2000; 355:865-72. 13. Mancia G., Grassi G.: Systolic and diastolic blood pressure control in antihypertensive drug trials. J. Hypertens. 2002; 20:1461-4. 14. Fagard R.H. et al.: Survey on treatment of hypertension and implementation of World Health Organization/International Society of Hypertension risk stratification in primary care in Belgium. J. Hypertens. 2002; 20:1297-302. 15. Ben-Dov I. et al.: Marked weight reduction lowers resting and exercise blood pressure in morbidly obese subjects. Am. J. Hypertens. 2000; 13:251-5. 16. He J. et al.: Long-term effects of weight loss and dietary sodium reduction on incidence of hypertension. Hypertension 2000; 35:544-9. 17. Kelley G.A., Kelley K.S.: Progressive resistance exercise and resting blood pressure: A meta-analysis of randomized controlled trials. Hypertension 2000; 35:838-43. 18. Taylor-Tolbert N.S. et al.: Ambulatory blood pressure after acute extercise in older men with essential hypertension. Am. J. Hypertens. 2000; 13:44-51. 19. Sacks F.M. et al.: DASH-Sodium Collaborative Research Group: Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group. N. Engl. J. Med. 2001; 344:3-10. 20. Fagard R.H.: Exercise characteristics and the blood pressure response to dynamic physical training. Med. Sci. Sports Exerc. 2001; 33, suppl. 6:S484-92. 21. Ridker P.M.: Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 2003; 107:363-9. 22. American Diabetes Association: Treatment of hypertension in adults with diabetes. Diabetes Care 2003; 26, suppl.: 1:S80-82. 23. National Kidney Foundation Guideline. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Kidney Disease Outcome Quality Initiative. Am. J. Kidney Dis. 2002; 39, suppl. 2:S1-246. 24. Cushman W.C. et al.: ALLHAT Collaborative Research Group: Success and predictors of blood pressure control in diverse North American settings: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). J. Clin. Hypertens. 2002; 4:393-404. 25. Black H.R. et al.: Baseline Characteristics and Early Blood Pressure Control in the CONVINCE Trial. Hypertension 2001; 37:12-18. 26. Hyman D.J., Pavik V.N.: Characteristics of patients with uncontrolled hypertension in the United States. N. Engl. J. Med. 2001; 345:479-86. 27. Somes G.W. et al.: The role of diastolic blood pressure when treating idolated systolic hypertension. Arch. Intern. Med. 1999; 159:2004-9. 28. PROGRESS Collaborative Group: Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet 2001; 358:1033-41. 29. Yusuf S. et al.: Effects of an angiotension-converting-enzyme inhibitor, rahibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N. Engl. J. Med. 2000; 342:145-53. 30. Schrier R.W. et al.: Effects of aggressive blood pressure control in normotensive type 2 diabetic ppatients on albuminuria, retinopathy and strokes. Kidney Int. 2002; 61:1086-97. 31. Weir M.R., Moser M.: Diuretics and beta-blockers: is there a risk for dyslipidemia? Am. Heart J. 2000; 139:174-83. 32. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288:2981-97. 33. Psaty B.M. et al.: Cardiovascular Health Study. Time trends in high blood pressure control and the use of antihypertensive medications in older adults: the Cardiovascular Health Study. Arch. Intern. Med. 2002; 162:2325-32. 34. White W.B.: Benefits of antihypertensive therapy in older patients with hypertension. Arch. Intern. Med. 2000; 160:149-50. 35. MacMahon S.: Blood pressure and the risk of cardiovascular disease. N. Engl. J. Med. 2000; 342:50-2. 36. Staessen J.A. et al.: Cardiovascular prevention and blood pressure reduction: a quantitative overview updated until 1 March 2003. J. Hypertens. 2003; 21:1055-76. 37. Tuomilehto J. et al.: Effect of calcium-channel blockade in older patients with diabetes abd systolic hypertension. Systolic Hypertension in Europe Trial Investigators. N. Engl. J. Med. 1999; 340:677-84. 38. Dahlof B. et al.: LIFE Study Group: Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet 2002; 359:995-1003. 39. Kjeldsen S.E. et al.: LIFE (Losartan Intervention for Endpoint reduction) Study Group. Effects of losartan on cardiovascular and left ventricular hypertrophy: a Losartan Intervention for Endpoint Reduction (LIFE) substudy. JAMA 2002; 288:1491-8. 40. Ghiadoni L. et al.: Effects of the angiotensin II type 1 receptor blocked candesartan on endothelial function in patients with essential hypertension. Hypertension 2000; 35:501-6. 41. Kawano Y. et al.: Interaction of alcohol and an alpha1-blocker on ambulatory blood pressure in patients with essential hypertension. Am. J. Hypertens. 2000; 13:307-12. 42. Dargie H.J.: Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomized trial. Lancet 2001; 357:1385-90. 43. Pitt B. et al.: Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N. Engl. J. Med. 2003; 348:1309-21. 44. Andrejak M. et al.: Electronic pill-boxes in the evaluation of antihypertensive treatment compliance: comparison of once daily versus twice daily regimen. Am. J. Hypertens. 2000; 13:184-90. 45. Barrier P.A. et al.: Two words to improve physician-patient communication: what else? Mayo Clin. Proc. 2003; 78:211-4.
