Systolic Hypertension: A Guide to Optimal Therapy

Sustained control of hypertension reduces the morbidity and mortality of cardiovascular disease.^1,2 A key message from the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines is that in persons 60 years or older, systolic hypertension is a more important risk factor for cardiovascular disease than diastolic hypertension.² It is the component of blood pressure (BP) most likely to be "uncontrolled" in population studies.³ Systolic hypertension is defined as systolic blood pressure (SBP) of 140 mm Hg or higher and diastolic BP of less than 90 mm Hg.

The latest data from the National Health and Nutrition Examination Survey (NHANES) indicate that more than 50 million Americans have hypertension.⁴ Although awareness and control of hypertension have improved during the past 2 decades, about 30% of hypertensive Americans are unaware that they have hypertension, 40% are not receiving therapy, and 66% or more who are being treated have suboptimal control. Elderly patients are the ones most likely to have inadequately controlled BP (usually SBP).⁵  In this article, we review the pathophysiology of systolic hypertension as well as the most current treatment approaches.

PATHOPHYSIOLOGY
The causes of essential hypertension include genetic factors, increased sympathetic nervous system activity, a variety of circulating humors, and vascular remodeling. Evidence for the role of genetic factors comes from the finding of a clustering of this condition in families.⁶ In addition, there is BP concordance among monozygotic twins and biological siblings compared with adopted siblings raised together.^7,8 A few hypertensive disorders result from single gene mutations (eg, Liddle syndrome), but most cases of essential hypertension probably result from mutations of multiple genes in addition to environmental factors. Notably, persons with hypertension also tend to inherit diabetes and lipid disorders.⁹ Data from studies in families using ambulatory BP monitoring suggest that both systolic and diastolic hypertension patterns are inherited.¹⁰

Hypertension is often characterized by increased sympathetic nervous system activity. Evidence that an elevated heart rate correlates with the development of hypertension corroborates this finding.¹¹  Increased sympathetic tone leads to elevated diastolic pressure, vascular remodeling, and likely end-organ damage, particularly left ventricular hypertrophy (LVH). Humoral factors, such as norepinephrine, angiotensin II, transforming growth factor b, and insulin-like growth factor, are implicated in the enhanced activation of the sympathetic nervous system. There is also evidence of increased sympathetic activity in the kidneys in hypertension.⁹

The vascular remodeling that occurs in hypertension leads to increased peripheral vascular resistance and increased pulse wave velocity. The arterial bed stores substrate-enriched blood and acts as a conduit for its delivery to systemic organs and tissues. Arterial mechanics depend on arterial stiffness, arterial wall thickness, and arterial diameter. Arterial stiffness is a measurable and important cardiovascular risk factor. Arteries stiffen as a consequence of the increased collagen deposition, fragmentation, and loss of elastin that occur with aging. This manifests clinically as elevated pulse wave velocity (PWV), the speed at which the pulse wave travels through the arterial bed.

In young persons, large, healthy arteries such as the aorta have low PWV values. This slower PWV enables the pulse wave to reflect back to the aorta in a timely manner to reduce the pressure load to the smaller peripheral arteries and at the same time reach the central circulation at an appropriate time in the cardiac cycle so as to augment coronary blood flow. Stiff arteries are characterized by increased PWV. Under these conditions, the reflected pulse wave increases the ventricular afterload and the ventricular systolic pressure, and thus puts a greater load on the heart (Figure). This process decreases diastolic pressure and jeopardizes coronary blood flow, which can eventually result in LVH, coronary ischemia, and heart failure. This helps explain why increased SBP heightens cardiovascular risk, particularly in elderly patients.

END-ORGAN MANIFESTATIONS OF UNCONTROLLED SYSTOLIC HYPERTENSION
The goal of therapy for hypertension is to reduce or prevent end-organ damage. The principal targets of hypertension include the heart, the cerebrovascular system, and the kidneys.

Cardiovascular disease. Coronary artery disease, heart failure, and LVH are often the result of long-standing hypertension. As discussed above, the vascular remodeling and arterial stiffness that occur with systolic hypertension lead to LVH, diastolic dysfunction and, eventually, diastolic heart failure. Diastolic heart failure is more prevalent than systolic heart failure among the elderly; its morbidity is comparable to that of systolic heart failure.¹²  Patients with diastolic heart failure are often diabetic or obese or have chronic renal disease.

Diastolic heart failure is characterized by increased left ventricular mass, wall thickness, and increased left ventricular end diastolic pressure. Increased myocardial collagen deposition leads to thickening and impaired compliance and relaxation during diastole. Despite a normal ejection fraction on echocardiography, pulmonary edema and decreased exercise tolerance develop in patients with diastolic heart failure as a result of impaired ventricular filling. Uncontrolled hypertension and excessive dietary salt intake exacerbate clinical symptoms.

Cerebrovascular disease. Hypertension is a major modifiable risk factor for stroke, the third leading cause of death in the United States.¹³ The relationship between systolic hypertension and stroke is linear, and stroke risk rises further when other findings of end-organ damage, particularly LVH, are present.¹⁴Kidney disease. Chronic kidney disease (CKD) is both a result and a cause of systolic hypertension. Hypertension is common in CKD and becomes more prevalent with the decrease in glomerular filtration rate.¹⁵ As the number of nephrons declines, the kidney loses its ability to regulate salt excretion and, ultimately, BP. Inappropriate activation of the renin-angiotensin system, impaired nitric oxide synthesis, and an overactive sympathetic nervous system have also been implicated in mediating hypertension in renal disease.^16-18  As renal disease worsens, systolic BP increases, which leads in turn to more severe kidney disease.

TREATMENTLifestyle interventions. Any therapeutic regimen for managing hypertension should include nonpharmacological interventions. The JNC 7 guidelines recommend limitations on dietary sodium (to 2400 mg/d) and alcohol intake, along with weight reduction and aerobic exercise.² Researchers who devised the Dietary Approaches to Stop Hypertension (DASH) diet found that adherence to this diet, which is low in sodium and rich in whole grains, fruits, and vegetables, led to significant reductions in BP compared with a typical American diet.¹⁹ Further reduction of dietary sodium resulted in even larger reductions in SBP for persons with and without hypertension.²⁰

The Prevention of Myocardial Infarction Early Remodeling (PREMIER) trial examined the effects on BP of additional dietary modification, increased physical activity, and limited alcohol intake when combined with the DASH diet. Results demonstrated that the group with the combined interventions had greater reductions in SBP than the groups with less extensive intervention.^21,22  If patients are not sufficiently motivated to strictly follow the DASH approach, we suggest that they avoid adding salt to their food and try as often as possible to eat meals at (or from) home, where salt content can be controlled.

Consumption of more alcohol than what is considered standard (more than 2 drinks at one sitting for women, and more than 3 drinks for men) is associated with elevated BP both acutely and chronically.^23,24  Based on these findings but taking into consideration the evidence of the possible cardioprotective effects of red wine, most experts recommend no more than moderate alcohol intake in patients with hypertension.

Weight loss alone can lead to significant decreases in BP. A study of overweight patients with hypertension demonstrated significant reductions in 24-hour ambulatory BP that correlated with degree of weight loss.²⁵ Patients able to maintain significant weight loss for at least several years also saw modest reductions in BP.²⁶ Unfortunately, many persons find it hard to maintain weight loss, which limits the effectiveness of this therapy.

Increasing physical activity can prevent or reduce hypertension. When compared with persons who remain sedentary, those who engage in aerobic exercise experience significant reductions in BP.²⁷ Effects can be seen with only moderate-intensity exercise, especially with longer duration.²⁸

Pharmacotherapy. Most persons with systolic hypertension require medication along with lifestyle modification to achieve BP goals (Table 1). The goal BP depends on the patient. For patients with isolated systolic hypertension and no other cardiovascular risk factors, the goal is a BP of less than 140/90 mm Hg. Patients with cardiovascular disease risk factors, such as diabetes mellitus, CKD, known coronary artery disease, or previous stroke, benefit from greater BP reduction, with a goal of less than 130/80 mm Hg.

Diuretics. Many experts recommend thiazide diuretics as first-line therapy for uncomplicated hypertension, particularly when the goal is SBP reduction. Results of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) found equivalent or superior protection from cardiovascular end points in the thiazide arm.²⁹

Thiazide diuretics are sometimes associated with adverse metabolic effects, such as glucose intolerance, hyperuricemia, and hypokalemia, and they are less effective in controlling BP in patients with impaired kidney function (men with creatinine levels of about 2 mg/dL, women with levels of about 1.8 mg/dL) than in those with normal kidney function. In patients with impaired renal function, a loop diuretic such as bumetanide is often used. We frequently add amiloride or an aldosterone antagonist, such as spironolactone or eplerenone, as a second diuretic with good results; periodic measurement of potassium levels is required. There is renewed interest in aldosterone antagonists because of their apparent ability to improve vascular remodeling.³⁰

ACE inhibitors and ARBs. Most hypertensive patients with persistently elevated SBP require combination therapy. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are often added to thiazide diuretics.³¹ ACE inhibitors and ARBs are relatively safe, infrequently have adverse interactions with other agents, and have beneficial effects on LVH, which are important considerations in elderly patients with systolic hypertension. In some studies, ACE inhibitors and ARBs delayed or prevented the onset of diabetes.³² Moreover, recent trials have demonstrated a lower risk of cardiac end points at equivalent BPs when ACE inhibitors are compared with diuretics.^33,34

Many experts believe that certain classes of antihypertensives, such as ACE inhibitors and ARBs, provide cardiovascular protection beyond their BP-lowering effects. Debate persists about whether ACE inhibitors and ARBs can be considered equivalents. ARBs are indicated in patients who cannot tolerate ACE inhibitors, and evidence suggests that the ARB candesartan may prevent or delay the onset of hypertension.³⁵

Calcium channel blockers. These agents effectively treat systolic hypertension²  and may be favored in patients who require rate control or who have comorbid conditions such as Raynaud phenomenon or migraine. Data also suggest that these agents are particularly effective in treating hypertension in African Americans³⁶ and elderly patients.³⁷ A recent meta-analysis concluded that calcium channel blockers may be superior to other antihypertensives for stroke prevention.³⁸ The long-acting formulations of calcium channel blockers are preferred.

β-Blockers. These agents are indicated following an acute myocardial infarction and are often beneficial for rate control of tachyarrhythmias, particularly atrial fibrillation. However, in the absence of these indications, β-blockers have fallen into disfavor as first-line agents or as monotherapy for hypertension, particularly in older patients with systolic hypertension.

α-Adrenergic agents. These include centrally acting agents such as clonidine and methyldopa. Clonidine effectively lowers BP acutely; however, side effects such as dry mouth and sedation, in addition to the propensity for rebound hypertension after withdrawal of medication or missed doses, limit its usefulness. The transdermal formulation of clonidine has fewer anticholinergic side effects, although some patients experience a skin reaction. An evening dose of guanfacine is effective in some older patients with systolic hypertension, particularly since it may relieve insomnia. a-Adrenergic agents are sometimes used if a comorbid condition (such as prostate hypertrophy) is present.

UNCONTROLLED/RESISTANT SYSTOLIC HYPERTENSION
Resistant systolic hypertension can be defined as continued elevation of BP despite adherence to a regimen of 3 or more antihypertensive drugs (including a diuretic) at appropriate doses. The many factors that contribute to resistant hypertension include inadequate drug therapy, volume expansion, secondary hypertension, ingestion of exogenous substances (including alcohol), nonadherence, and pseudohypertension.39 Many persons with resistant hypertension are elderly; some also have diabetes or CKD. Evaluation. The usual first step is to determine whether patients with resistant hypertension are truly hypertensive (Table 2). Ambulatory BP monitoring or home BP monitoring may be helpful, especially if white-coat hypertension is suspected. One uncommon but quickly eliminated cause is pseudohypertension (which results from calcified arteries that require higher cuff pressures to compress compared with the distending pressure within the artery). Patients with this condition often have no evidence of end-organ damage despite elevated BP, may experience symptoms of orthostasis if treated with antihypertensive therapy, and tend to have calcified vessels on radiography. The following measures are helpful in evaluating patients with resistant hypertension:

• Confirm that patients are adhering to the prescribed regimen, are not using excessive dietary salt, are engaging in regular exercise (joints permitting), and are maintaining the appropriate weight.
• Ensure that the dosages of medication are adequate. It may be necessary to titrate the dose of current
diuretics or add another diuretic (such as an aldosterone antagonist or amiloride).
• Review the medication history with special attention to agents that can produce fluid retention and hypertension, such as NSAIDs or cyclooxygenase-2 inhibitors. Inquire about alcohol intake and the use of appetite suppressants, herbals (such as ginseng and yohimbine), and corticosteroids.

About 10% of patients with hypertension have a secondary cause for their condition. Findings from the history (such as cigarette smoking) and physical examination (such as abdominal bruits) may suggest renovascular disease. Other occasional causes of secondary hypertension include aldosteronism, pheochromocytoma, Cushing syndrome, thyroid dysfunction (usually hyperthyroid-ism), CKD, and obstructive sleep apnea.

We recommend performing tests of plasma renin activity and serum aldosterone concentrations in patients with presentations that raise concern about secondary causes of hypertension, such as those who have resistant hypertension, new onset of hypertension before age 20 years or after age 50 years, or an acute rise in previously stable BP. It has been reported that 10% to 20% of patients have suppressed renin activity and a serum aldosterone concentration that exceeds 16 ng/dL.⁴⁰ Debate exists about the incidence of true "primary aldosteronism"; however, our experience of treating patients with potassium-sparing drugs (amiloride or aldosterone antagonists) in response to laboratory evidence of aldosteronism leads us to believe that screening patients with tests of plasma renin activity and serum aldosterone concentration is still useful.

THERAPIES ON THE HORIZON
Newer therapies for hypertension will likely target humoral factors implicated in the pathophysiology of hypertension. Endothelin, an endogenous vasoconstrictor, has recently been implicated in the pathophysiology of hypertension. This peptide is stimulated by decreases in renal blood flow. Animal models of hypertension treated with endothelin receptor antagonists exhibited decreases in blood pressure.⁴¹ A double-blind, randomized, placebo-controlled trial demonstrated BP-lowering effects of the oral formulation of bosentan, an endothelin receptor antagonist.⁴² These effects were also seen when studied in individuals with hypertension and CKD.⁴³ Drug toxicity (ie, teratogenicity, testicular atrophy, and hepatotoxicity) has largely limited the enthusiasm for this drug class, but new agents are in the pipeline.

The renin-angiotensin system plays an important role in mediating hypertension. The ability to block renin directly is another means by which the hypertensive effects of angiotensin II may be inhibited. The recently released renin inhibitor, aliskiren, demonstrates antihypertensive efficacy similar to that of currently available ACE inhibitors and ARBs.⁴⁴ The advantage of aliskiren is that it suppresses renin activity, unlike ACE inhibitors and ARBs, which can lead to a reactive rise in plasma renin activity.

Activation of the sympathetic nervous system is important in the pathophysiology of hypertension. European studies show that selective imidazoline agonists, such as moxonidine and rilmenidine, are reasonably effective and well tolerated.^45-48  These agents improved glucose tolerance and lipid metabolism in some studies.

 

References:

REFERENCES:

1.

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;360:1903-1913.

2.

Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation and Treatment of High Blood Pressure. The JNC 7 Report.

JAMA.

2003;289:2560-2572.

3.

Franklin SS, Jacobs MJ, Wong ND. Predominance of isolated systolic hypertension among middle-aged and elderly US hypertensives: analysis based on National Health and Nutrition Examination Survey (NHANES) III.

Hypertension.

2001;37:869-874.

4.

Burt VL, Whelton P, Roccella EJ, et al. Prevalence of hypertension in the US adult population. Results from the Third National Health and Nutrition Examination Survey, 1988-1991.

Hypertension.

1995;25:305-13.

5.

Hyman DJ, Pavlik VN. Characteristics of patients with uncontrolled hypertension in the United States.

N Engl J Med.

2001;345:479-486.

6.

Longini IM, Higgins MW, Hinton PC, et al. Environmental and genetic sources of familial aggregation of blood pressure in Tecumseh, Michigan.

Am J Epidemiol.

1984;120:131-144.

7.

Feinleib M, Garrison RJ, Fabsitz R, et al. The NHLBI twin study of cardiovascular disease risk factors: methodology and summary of results.

Am J Epidemiol.

1977;106:284-285.

8.

Biron P, Mongeau JG, Bertrand D. Familial aggregation of blood pressure in 558 adopted children.

Can Med Assoc J.

1976;1115:773-774.

9.

Oparil S, Zaman A, Calhoun DA. Pathogenesis of hypertension.

Ann Intern Med.

2003;139:761-776.

10.

Fava C, Burri P, Almegren P, et al. Heritability of ambulatory and office blood pressure phenotypes in Swedish families.

J Hypertens.

2004;22:1717-1721.

11.

Palatini P, Julius S. Relevance of heart rate as a risk factor in hypertension.

Curr Hypertens Rep.

1999;3:219-224.

12.

Aurigemma GP, Gaasch WH. Diastolic heart failure.

N Engl J Med.

2004;351:1097-1105.

13.

World Health Organization. WHO World Health Report. Geneva: World Health Organization; 2002.

14.

Lindholm LH, Ibsen H, Dahlšf B, et al; LIFE Study Group. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol.

Lancet.

2002;359:1004-1010.

15.

Shlipak MG, Heidenreich PA, Noguchi H, et al. Association of renal insufficiency with treatment and outcomes after myocardial infarction in elderly patients.

Ann Intern Med.

2002;137:555-562.

16.

Townsend RR. Cardiac mortality in chronic kidney disease: a clearer perspective.

Ann Intern Med.

2002;137:615-616.

17.

Wright RS, Reeder GS, Herzog CA, et al. Acute myocardial infarction and renal dysfunction: a high-risk combination.

Ann Intern Med.

2002;137:563-570.

18.

Williams B, Lacy PS, Thom SM, et al. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study.

Circulation.

2006;113:1213-1225.

19.

Appel LJ, Moore TJ, Obarzanek E, et al. A clinical trial of the effects of dietary patterns on blood pressure.

N Engl J Med.

1997;336:1117-1124.

20.

Sacks FM, Svetkey LP, Vollmer WM, et al. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet.

N Engl J Med.

2001;344:3-10.

21.

Appel LJ, Champagne CM, Harsha DW, et al. Effects of comprehensive lifestyle modification on blood pressure control: main results of the PREMIER clinical trial.

JAMA.

2003;289:2083-2093.

22.

Elmer PJ, Obarzanek E, Vollmer WM, et al. Effects of comprehensive lifestyle modification on diet, weight, physical fitness, and blood pressure control: 18-month results of a randomized trial.

Ann Intern Med.

2006;144:485-495.

23.

Seppa K, Sillanaukee P. Binge drinking and ambulatory blood pressure.

Hypertension.

1999;33:79-82.

24.

Zilkens RR, Burke V, Hodgson JM, et al. Both red wine and beer elevated blood pressure in normotensive men.

Hypertension.

2005;45:874-879.

25.

Schillaci G, Pasqualini L, Vaudo G, et al. Effect of body weight changes on 24-hour blood pressure and left ventricular mass in hypertension: a 4-year follow-up.

Am J Hypertens.

2003;16:634-639.

26.

Aucott L, Pooblan A, Smith WCS, et al. Effects of weight loss in overweight/obese individuals and long-term hypertension outcomes.

Hypertension.

2005;45:1035-1041.

27.

Whelton SP, Chin A, Xin X, et al. Effect of aerobic exercise on blood pressure: a meta-analysis of randomized controlled trials.

Ann Intern Med.

2002;136:493-503.

28.

Ishikawa-Takata K, Ohta T, Tanaka H. How much exercise is required to reduce blood pressure in essential hypertensives: a dose-response study.

Am J Hypertens.

2003;16:629-633.

29.

The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. 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; 288:2981-2987.

30.

Kuster GM, Kotlvar E, Rude MK, et al. Mineralocorticoid receptor inhibition ameliorates the transition of myocardial failure and decreases oxidative stress and inflammation in mice with chronic pressure overload.

Circulation.

2005;111:420-427.

31.

Townsend RR, Holland OB. Combination of converting enzyme inhibitor with diuretic for the treatment of hypertension.

Arch Intern Med.

1990;150:1175-1183.

32.

Yusuf S, Gerstein H, Hoogwerf B, et al. Ramipril and the development of diabetes.

JAMA.

2001;286:1882-1885.

33.

Wing LM, Reid CM, Ryan P, et al. A comparison of outcomes with angiotensin-converting-enzyme inhibitors and diuretics for hypertension in the elderly.

N Engl J Med.

2003;348:583-592.

34.

Dahlöf B, Sever PS, Poulter NR, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial.

Lancet.

2005;366:895-906.

35.

Julius S, Nesbitt SD, Egan BM, et al; Trial of Preventing Hypertension (TROPHY) Study Investigators. Feasibility of treating prehypertension with an angiotensin-receptor blocker.

N Engl J Med.

2006;354:1685-1697.

36.

Materson BJ, Reda DJ, Cushman WC, et al. Single-drug therapy for hypertension in men. A comparison of six antihypertensive agents with placebo.

N Engl J Med.

1993;328:914-921.

37.

Tuomilehto J, Rastenyte D, Birkenhager WH, et al. Effects of calcium channel blockade in older patients with diabetes and systolic hypertension.

N Engl J Med.

1999;340:677-684,

38.

Wang JG, Li Y, Franklin SS, Safar M. Prevention of stroke and myocardial infarction by amlodipine and angiotensin receptor blockers. A quantitative review.

Hypertension.

2007;50:181-188.

39.

Moser M, Setaro JF. Resistant or difficult-to-control hypertension.

N Engl J Med.

2006;355:385-392.

40.

Kaplan NM. The current epidemic of primary aldosteronism: causes and consequences.

J Hypertens.

2004;22:863-869.

41.

Clozel M, Breu V, Burri K, et al. Pathophysiologic role of endothelin revealed by the first orally active endothelin receptor antagonist.

Nature.

1993;365:759-761.

42.

Krum H, Viskoper RJ, Lacourciere Y, et al. The effect of an endothelin receptor antagonist, bosentan, on blood pressure in patients with essential hypertension.

N Engl J Med.

1998;338:784-791.

43.

Goddard J, Johnston NR, Hand MF, et al. Endothelin-A receptor antagonism reduces blood pressure and increases renal blood flow in hypertensive patients with chronic renal failure: a comparison of selective and combined endothelin receptor blockade.

Circulation.

2004;109:1186-1193.

44.

Muller DN, Luft DC. Direct renin inhibitions with aliskiren in hypertension and target organ damage.

Clin J Am Soc Nephrol.

2006;1:221-228.

45.

Benedict CR. Centrally acting antihypertensive drugs: re-emergence of sympathetic inhibition in the treatment of hypertension.

Current Hypertension Reports.

1999;1:305-312.

46.

Sanjuliani AF, de Abreu VG, Francischetti EA. Selective imidazoline agonist moxonidine in obese hypertensive patients.

International J Clin Practice.

2006;60:621-629.

47.

Abellán J, Leal M, Hernández-Menárguez F, et al. Efficacy of moxonidine in the treatment of hypertension in obese, noncontrolled hypertensive patients.

Kidney Int Suppl.

2005;93:S20-S24.

48.

Meredith PA, Reid JL. Efficacy and tolerability of long-term rilmenidine treatment in hypertensive diabetic patients. A retrospective analysis of a general practice study.

Am J Cardiovasc Drugs.

2004;4:195-200.