guidelines for treatment of hypertension in the elderly â€” 2002

1

Report

Guidelines for Treatment of Hypertension in the Elderly— 2002 Revised Version —

Toshio OGIHARA＊1, Kunio HIWADA＊2, Shigeto MORIMOTO＊3, Hiroaki MATSUOKA＊4,

Masayuki MATSUMOTO＊3, Shuichi TAKISHITA＊5, Kazuaki SHIMAMOTO＊6, Kazuyuki SHIMADA＊7,

Isao ABE＊8, Yasuyoshi OUCHI＊9, Hisaichiro TSUKIYAMA＊10, Shigehiro KATAYAMA＊11, Yutaka IMAI＊12,

Hiromichi SUZUKI＊11, Katsuhiko KOHARA＊2, Kohya OKAISHI＊3, and Hiroshi MIKAMI＊1

(Hypertens Res 2003; 26: 1–36)

From the Research Group for “Long-Term Prognosis of Hypertension in the Elderly,” Comprehensive Research Projects on Aging and Health, the

Ministry of Health, Labor and Welfare of Japan: ＊1Osaka University Graduate School of Medicine, ＊2Ehime University School of Medicine, ＊3Kanazawa Medical University, ＊4Dokkyo University School of Medicine, ＊5University of the Ryukyus School of Medicine, ＊6Sapporo Medical

University, ＊7Jichi Medical School, ＊8Kyushu University, Graduate School of Medical Sciences, ＊9University of Tokyo Graduate School of

Medicine, ＊ 10International University of Health and Welfare, ＊ 11Saitama Medical University, and ＊ 12Tohoku University Graduate School of

Pharmaceutical Science, Japan.

Address for Reprints: Toshio Ogihara, M.D., Ph.D., Department of Geriatric Medicine, Osaka University Graduate School of Medicine, 2–2

Yamadaoka, Suita, Osaka 565–0871, Japan. E-mail: [email protected]

Received and Accepted September 6, 2002.

novo” types. The former generally develops in middle age asessential hypertension, and becomes systolic hypertension asthe diastolic blood pressure is reduced due to the agingprocess, while the latter develops in old age due to reducedvascular compliance in the large arteries. In addition, thereare some cases with secondary hypertension due to identifiablecauses such as renovascular hypertension.

In the elderly, it has been reported that systolic blood pres-sure is more strongly related with cardiovascular complica-tions—especially stroke, ischemic heart disease, heart fail-ure, end-stage renal disease, and all-cause mortality—than isdiastolic blood pressure (3). Furthermore, it has been demon-strated that increased pulse pressure (the difference betweensystolic blood pressure and diastolic blood pressure) is corre-lated with an increased risk of such complications (4).

The pathophysiology of hypertension in the elderly ischaracterized by increased total peripheral vascular resis-tance, decreased compliance of large and middle arteries, atendency toward decrease in cardiac output and circulatingblood volume, increased lability of blood pressure due toage-related decrease in baroreceptor function, decreasedblood flow, and dysfunction of autoregulation in importanttarget-organs such as the brain, heart, and kidney. Therefore,

Introduction

Hypertension is one of the most significant risk factors forcerebrovascular and heart diseases, which rank as the secondand third most frequent causes of death in Japan, respective-ly. The prevalence of hypertension rises as the populationgrows older, affecting approximately 60% of the Japaneseaged 65 yr or older (1), and there are currently more patientsreceiving treatment for hypertension than for any otherdisease in Japan (2). As the size of the elderly population inour country continues to increase rapidly, hypertension hasbecome one of the most important diseases to control andtreat, and developing an effective strategy for this diseasehas become a matter of great social immediacy. Hyperten-sion in the elderly is composed mostly of essential hyperten-sion, but the pathophysiology of essential hypertension in theelderly differs in many respects from that of essential hyper-tension in the young or middle-aged. In particular, isolatedsystolic hypertension (systolic blood pressure 140 mmHg orgreater, and diastolic blood pressure below 90 mmHg)increases in frequency with age. Isolated systolic hypertensionis divided into two types, the so-called “burned-out” and “de

hypertension in the elderly must be treated with special cau-tion, taking the above-mentioned pathophysiological charac-teristics into consideration. In addition, as with other dis-eases in the elderly, it is necessary for the physician to payclose attention to the activities of daily living (ADL), qualityof life (QOL) and drug compliance of the patient.

Based on the results of numerous clinical intervention tri-als, treatment of hypertension in the elderly—includingtreatment of systolic hypertension—has generally been ofgreat benefit (5–11). However, the efficacy of treatment ofso-called very old hypertensive patients aged 85 yr or olderis still controversial (12). It has already been demonstratedthat the incidence of cerebrovascular disease, ischemic heartdisease and cardiac failure, in addition to all-cause mortality,are decreased by treatment with diuretics or long-actingdihydropyridine Ca antagonists. Although treatment ofhypertension in the elderly with β-blockers significantlydecreases morbidity and mortality of cerebrovasculardisease, it has not been shown to significantly decrease thoseof ischemic heart diseases or all-cause mortality (13). In theUnited States, the therapeutic guidelines of hypertension inthe elderly were published by the National High Blood Pres-sure Education Program Working Group in 1994 (3). In mostcases, however, information on the treatment of hypertensionin the elderly is not released under separate cover, but is pro-vided only as a constituent part of more general guidelines.For example, in the sixth report of the Joint National Com-mittee on Detection, Evaluation, and Treatment of HighBlood Pressure (JNC VI) (14), the issue of hypertension inthe elderly is described in Section 4, “Special Populationsand Situations.”

The treatment guidelines for hypertension published in theUSA and Europe are essentially guidelines for individuals inWestern countries, primarily Caucasians. These guidelinesprovide a detailed summary of the extensive results of hyper-tension studies throughout the world, and they are also ex-pected to be a useful reference for the control and treatmentof hypertension in Japan. However, it is not appropriate toadopt these guidelines indiscriminately to Japanese hyper-tensive patients without consideration of the differences ingenetic and social background. To address this problem, thepresent report constitutes a revised version of the “A Guide-line for Treatment of Hypertension in the Elderly, 1995”(15) prepared by the Comprehensive Research Projects onAging and Health of the Ministry of Health and Welfare, theResearch Group for “Guidelines on Treatment of Hyperten-sion in the Elderly” (Chair: Prof. Toshio Ogihara, OsakaUniversity), and the “Guideline for Hypertension in the El-derly—1999 Revised Version” (16) prepared by the Re-search Group on “Long-Term Prognosis of Hypertension inthe Elderly” (Chair: Prof. Kunio Hiwada, Ehime University)of the above project. Thus, this report is the third edition ofthe guideline. As a first step in developing this revision, aquestionnaire was sent to numerous hypertension specialistsin Japan, asking their opinions on the 1999 version of the

guidelines (17). The fundamental concept of this report isthe same as in the original version: that is, the report presentsguidelines for the control and treatment of the elderly inJapan based not only on the evidences from many recent stud-ies in Western countries and Japan, but also on a considera-tion of the unique lifestyle of Japanese. Based on the re-sponses to the above-mentioned surveys, the opinions andcriticisms of the Japanese hypertension experts were incor-porated into the present revision (17).

This report includes the characteristics of hypertension inthe elderly, diagnosis, necessity of treatment, indications,target levels of blood pressure, choice of first antihyperten-sive drug, treatment and precautions in patients with compli-cations, drug interaction, and consideration of QOL. Howev-er, these guidelines are not intended to present uniform ther-apeutic strategies for hypertension in the elderly, but ratherto show the general concepts. All hypertensive drug recom-mendations presented are considered the best choice current-ly available. However, the effectiveness of individual drugs,particularly angiotensin II receptor blockers (ARBs) and an-giotensin converting enzyme (ACE) inhibitors, for hyper-tension in the elderly should be verified by the results of fur-ther intervention trials in Japanese patients.

1. Blood Pressure Levels and Their CircadianVariation in the Elderly

1-1. Aging and Blood Pressure Levels

Blood pressure changes with age. Systolic blood pressureincreases and diastolic blood pressure decreases withadvancing age, resulting in an increased pulse pressure in theelderly (18). Thus, the prevalence of systolic hypertensionalso increases with advancing age. Pulse pressure, as well assystolic blood pressure, is one of the most important factorsto predict the morbidity and mortality of cardiovasculardisease (19–21). These changes in blood pressure with ageare due mainly to an increased arterial stiffness, and thus todecreased compliance of the large elastic arteries (22).

Hypertension in adults is defined as systolic bloodpressure of 140 mmHg or more or diastolic blood pressure of90 mmHg or more (14). However, since blood pressurechanges with age, the blood pressure level to be treated byantihypertensive drugs and the therapeutic goal pressureshould be established separately for the elderly. Table 1demonstrates the blood pressure values of each age classobtained in 1992 by the Working Group of the Ministry ofHealth and Welfare from healthy elderly Japanese who werenot taking any antihypertensive drugs (23). In the elderlyaged 65 yr or older, systolic blood pressure increased anddiastolic blood pressure decreased slightly with age. On thewhole, the blood pressures of subjects aged 65 to 94 yr were133±19/77±11 mmHg (mean±SD) for men and 134±19/76±10 mmHg for women. According to the Hisayamastudy (24), among those aged 60 yr or older, the cumulative

2 Hypertens Res Vol. 26, No. 1 (2003)

morbidity of cardiovascular disease was significantly higherin those with systolic blood pressure of at least 140 mmHgor diastolic blood pressure of at least 80 mmHg than in thosewith less than 140 mmHg or 80 mmHg, respectively. On theother hand, in the reevaluation of the SHEP study (25), therisk for occurrence of cardiovascular diseases was doubledin those with less than 55 mmHg of diastolic blood pressureunder antihypertensive treatments (25), suggesting thatexcess lowering of diastolic blood pressure may be harmfulin elderly hypertensives.

1-2. Circadian Variation of Blood Pressure in theElderly

1) Circadian Variation of Blood Pressure in the ElderlyNumerous types of blood pressure variation have been rec-ognized, including short-term blood pressure variations suchas cardiac-cycle dependent, respiration-dependent andbaroreceptor reflex-dependent variations, 24-h variation, and

a long-term seasonal variation. Twenty-four-hour variation,i.e., circadian blood pressure variation, is currently the mostextensively studied of these types. Drayer et al. (26) moni-tored blood pressure continuously over a 24-h period in hy-pertensive patients and found nocturnal dipping during sleep;the dipping reached a nadir between 0:00 and 4:00, increasedjust before awaking, remained elevated throughout the day,and gradually decreased in the afternoon to evening.

Physical activity is the most important among the factorsinfluencing circadian blood pressure variation, though men-tal activity also plays an important role. Some reports haveindicated that circadian variation of blood pressure is medi-ated by circadian variations of the endocrine and autonomicnervous systems (27–29). For example, nocturnal decline inblood pressure disappears in the patients with Cushing’s syn-drome or with autoimmune disease treated with glucocorti-coids (30). Lack of nocturnal decline in blood pressure hasbeen seen in patients with autonomic failure, such as in pa-tients with multiple system atrophy, Parkinsonism, spino-

Ogihara et al: Treatment Guideline for Elderly Hypertension 3

Table 1. Blood Pressure (BP) of Healthy Elderly Individuals by Age and Sex

Age (yr) n Systolic BP Diastolic BP

BP (mean±SD) of healthy elderly individuals by age (no antihypertensive drug, obesity, emaciation or ECG abnormality) reported bythe Ministry of Health and Welfare “Study Group on Normal Values of Laboratory Tests in the Elderly,” Subgroup on Blood Pressure(Chairman: Jun Fujii) (23).

Male 63–69 104 127.8±16.3 78.4±7.9070–74 75 130.9±20.8 76.4±9.3075–79 74 136.9±19.2 75.9±11.880–84 49 140.3±17.4 77.7±12.085–89 16 137.1±17.8 74.1±18.3

Female 65–69 101 134.9±17.5 78.3±10.370–74 92 130.8±18.2 74.4±9.1075–79 78 133.6±18.8 74.5±9.8080–84 52 139.8±20.8 75.8±10.185–89 19 135.6±19.8 73.4±9.60

Table 2. Reference Values of 24-h Blood Pressure (BP) in the Elderly

Investigator Subjects Age (yr) Upper limit Sex n 24 h BP Daytime BP Nighttime BP(mmHg) (mmHg) (mmHg)

Imai et al. (32) Japan 60–69 M 054 146/86 153/910 141/82Community Mean＋2SD F 072 150/85 159/910 141/87Normotensives 70–79 M 025 151/84 157/900 148/80

F 026 152/86 162/930 152/80O’Brien et al. (33) Employees 50–79 95 percentile M 054 151/98 155/103 140/90

F 072 160/87 177/970 133/75Kawasaki et al. (34) Japan 60–00 95 percentile M 054 149/84 151/870 147/82

Database F 049 144/82 145/870 141/79Normotensives

Wendelin- Finland 64–87 95 percentile M 099 145/93 154/990 133/82Saarenhovi et al. (35) Community F 112 154/89 158/910 143/85

cerebellar degeneration, or diabetic neuropathy, and some-times nocturnal blood pressure is elevated in such patho-physiological conditions, demonstrating a reversed circadianvariation pattern (28, 29).

The circadian variation of blood pressure in healthy elder-ly is essentially similar to that observed in the elderly withhypertension as described above: i.e., decreases in bloodpressure during sleep, increases in the early morning, de-creases in the afternoon, and temporary increases again inthe evening. The pattern of nocturnal dipping of blood pres-sure changes with age. Particularly in men, the amplitude ofnocturnal dipping decreases with age, and the circadian vari-ation of blood pressure almost disappears in men aged 80 yrand older (31). Reference values of 24-h ambulatory bloodpressure in the elderly have not yet been established, but sev-eral results obtained in cross-sectional studies have been re-ported (Table 2) (32–35).

2) Mean Values of 24-h Blood PressureThe clinical significance of ambulatory blood pressure moni-toring has been widely recognized (36, 37). The 24-h meanis better correlated than casual-clinic pressure values toprevalence of hypertensive target-organ damages such as leftventricular hypertrophy, fundoscopic changes, renal disor-ders, and carotid intima-media thickness, as well as to car-diovascular disease morbidity and mortality. In elderly hy-pertensive patients in Japan, lacunar infarction determined byMRI was observed frequently in the cases with an elevatedmean value of 24-h blood pressure (38). These studies sug-gested that the mean value of 24-h blood pressure is morepredictive than casual-clinic blood pressure values for theprognosis of hypertension (39).

3) Nocturnal Blood PressureRecent studies have emphasized the clinical significance ofnocturnal blood pressure. Those who have ordinary noctur-nal dipping of blood pressure are referred to as dippers, andthose without nocturnal dipping are called non-dippers. Thefrequency of non-dipper status has been reported to increasewith advancing age, and to be associated with high preva-lence of ischemic heart disease and cerebrovascular disor-ders (40). In asymptomatic hypertensive elderly in Japan, theprevalence of lacunar infarction was reported to increase sig-nificantly among non-dippers relative to dippers (41). Anoth-er study reported that extreme dipping of nocturnal bloodpressure was associated with extended periventricular whitematter lesions in elderly women (42). And recent prospectivestudies have revealed that both the morbidity and mortalityof cardiovascular disease were higher among non-dippersthan dippers (42, 43). Extreme dippers who demonstratenocturnal dipping of more than 20% of the daytime bloodpressure have been reported—much like non-dippers—tohave more advanced asymptomatic cerebrovascular lesionsthan dippers, and to run a greater risk of stroke. On the otherhand, another study has reported that the prognosis of

extreme-dippers is similar to that of dippers (44–46).

4) Blood Pressure Elevation in the MorningAmong circadian variations of blood pressure, an increase inblood pressure in the morning is thought to be associatedwith increased incidence of cardiovascular disease, which ispossibly mediated by such mechanisms as increased plateletaggregation due to the rise in sympathetic nerve activity anddecreased fibrinolysis accompanied by activation of therenin-angiotensin system. A rapid increase in blood pressurein the early morning is called a “morning surge.” In fact, it iswell known that acute myocardial infarction, sudden deathand cerebral hemorrhage occur frequently in early morning.Morning surge appears to be due to physical activity afterwake-up, but it has also been demonstrated in some caseseven before wake-up. Morning surge has not been well de-fined, but an early morning pressure elevation of at least 50mmHg (corresponding to the 90th percentile of early morn-ing elevation among normotensive individuals) has generallybeen accepted as a reference, and using this reference, morn-ing surge has been recognized in 52.6% of the elderly withessential hypertension (47). An insufficient duration of ac-tion of antihypertensive drugs is thought to be closely relatedto high blood pressure in the morning (48).

5) White Coat HypertensionMeasurements of ambulatory blood pressure are useful fordiagnosis of so-called “white-coat hypertension.” White coathypertension is defined as reproducible hypertension demon-strated only at the outpatient clinic (or in a medical setting)and not demonstrated in non-medical settings (as determinedby ambulatory blood pressure monitoring or home bloodpressure measurements) (49), and its prevalence increaseswith advancing age. White coat hypertension (defined as di-astolic blood pressure at the outpatient clinic of 90–104mmHg, and a daytime ambulatory blood pressure mean of134/90 mmHg or less) is reported to occur in 42% of elderlypatients with systolic hypertension aged 65 yr or older (50).Patients with white coat hypertension may have excesshypotension in a non-medical setting due to antihypertensivedrug treatment. Some investigators have claimed that the leftventricular mass in white coat hypertension is intermediatebetween those of sustained hypertension and normotension(51). In many reports on white coat hypertension, bloodpressure in the non-medical setting has been found to be inthe borderline hypertensive range. However, the prognosisand target-organ damage in those with white coat hypertensionare generally thought to be similar to those in individualswith normotension when blood pressure in the non-medicalsetting is in the true normotensive range. This is also generallytrue in elderly white coat hypertension. In this case, “truenormotension” at home is defined as less than 125/80 mmHgaccording to WHO/ISH (1999) (52), while hypertension athome is defined as a blood pressure of 135/85 mmHg andover according to JNC-VI (14).


6) Indication of Monitoring of Ambulatory Blood Pressure inthe ElderlyMeasurements of circadian variation of blood pressure canbe obtained every 15 min to every 1 h with patients in anambulatory state using a portable non-invasive sphygmo-manometer that is widely available. However, it is difficult tomonitor ambulatory blood pressure for all patients with hy-pertension. In practice, therefore, the monitoring should beapplied selectively to only those cases which show: (a) ex-tremely variable casual-clinic blood pressure; (b) no target-organ damage despite the presence of casual-clinic hyperten-sion; (c) a significant difference between home and casual-clinic blood pressure, i.e., suspected white coat hypertension;(d) insufficient control of blood pressure while receiving asufficient dose of antihypertensive treatment (intractable hypertension or resistant hypertension); (e) autonomic dys-function such as diabetic neuropathy; (f) signs suggestive oforthostatic or postprandial hypotension; (g) candidates formeasurement of nocturnal blood pressure; (h) paroxysmalhypertension. Ambulatory blood pressure monitoring hasbeen shown to be useful to predict cardiovascular risk inelderly patients with systolic hypertension (53).

7) Home Blood Pressure MeasurementsBlood pressure information other than casual pressure mea-sured at the outpatient clinic is useful for diagnosis and eval-uation of therapeutic outcomes, particularly in the manage-ment of elderly hypertensive patients with large blood pres-sure fluctuation. In addition, self-measurement enhances thepatient’s motivation for treatment of hypertension. To facili-tate home measurement, a wide range of devices has recentlybeen marketed. Two of these, the wrist-cuff device and fin-ger-cuff device, are reported to be inaccurate and unreliable,and thus are not recommended for practical use (54). Eventhe arm-cuff device for self-measurement of blood pressureshould be regularly calibrated in comparison with the Riva-Rocci-Korotkoff sound method using a mercury sphygmo-manometer. Patients should be instructed to consistentlymeasure their blood pressure at similar times of day and un-der similar conditions. Blood pressure should preferably bemeasured twice daily, once before antihypertensive medica-tion after getting up in the morning (trough effect) and oncein the evening/night at a point when the antihypertensivemedication is still expected to exert a sufficient effect (nearlypeak effect). Although a reference value of home blood pres-sure in the elderly has not yet been established, meta-analy-sis of the international database revealed that the 95th per-centile value of home blood pressure in 2,449 normotensiveswas 135/86 mmHg, and that a home blood pressure of125/79 mmHg corresponded to an ambulatory blood pres-sure of 140/90 mmHg (55). In a community-based popula-tion study, the 95th percentile value of home blood pressuremeasured in the morning in elderly subjects aged 60 yr whowere not taking any antihypertensive drugs was 145/95mmHg (n＝234) (56). In a population-based observational

study in Japan, home blood pressure measurement was re-ported to be more predictive of mortality than casual-screen-ing blood pressure measurement (57). In addition, both sys-tolic hypertension and wide pulse pressure in home bloodpressure measurement have been shown to reflect a poorprognosis (58). Although doctors or nurses may sometimesmeasure blood pressure at the homes of elderly patients,these values differ from those obtained by self-measurementof blood pressure at home. It has been reported that self-measurement of blood pressure at home appears to be usefuleven in the very old (59).

2. Diagnosis of Hypertension in the Elderly

2-1. Diagnostic Criteria and Classifications of Hyperten-sion in the Elderly

One of the characteristics of hypertension in the elderly is ahigh prevalence of systolic hypertension caused by sup-pressed Windkessel function and amplification by reflectedwaves based on arteriosclerosis. No special diagnostic cri-teria for hypertension in the elderly are stated in the WHO-ISH guidelines (52), the JNC VI (14), or the guidelines forthe management of hypertension by the Japanese Society ofHypertension (JSH 2000) (60); systolic blood pressure of140 mmHg and greater and/or diastolic blood pressure of 90mmHg and greater is defined hypertension as in generaladults. In the intervention trial conducted by the Systolic Hy-pertension in the Elderly Program (SHEP) (5), systolic hy-pertension was adopted as a systolic blood pressure of 160mmHg and greater and diastolic blood pressure of below 90mmHg, which inclusion criteria was different from the criteriafor hypertension in general. In many of the epidemiologicalstudies thus far reported, patients with elevated systolic bloodpressure demonstrated a significantly higher prevalence ofcardiovascular diseases. The importance of managing systolichypertension has been also emphasized in the therapeuticguidelines published by JNC VI (14), WHO-ISH (52), andJSH 2000 (60).

2-2. Diagnostic Considerations for Hypertension in theElderly

1) Medical HistoryMedical history is important in the diagnosis of all diseases,and hypertension is no exception. Thus the medical historyshould include the duration and level of elevated blood pres-sure, as well as the subjective symptoms of target organdamage and cardiovascular diseases. To rule out secondaryhypertension, patients should be questioned about the pres-ence of weight change, nocturia, and weakness or protein-uria, all of which are highly important in the differential di-agnosis of secondary hypertension, as will be discussed later.Since essential hypertension might be related to genetic andenvironmental factors, symptoms and past history of cardio-


vascular and renal diseases should be included in addition tofamily history of hypertension.

2) Measurement of Blood PressureBlood pressure should be measured according to JSH 2000(60), taking the mean of two stable pressure values with adifference of no more than 5 mmHg. Hypertension shouldnot be diagnosed by a single measurement of blood pressureat the first visit. If the first blood pressure value is elevated,excluding a systolic blood pressure of 180 mmHg or greateror a diastolic blood pressure of 110 mmHg or greater, orboth, blood pressure is measured at two or more consecutivevisits within the following 4 weeks. A stable systolic bloodpressure mean of 140 mmHg or greater, a stable diastolicblood pressure mean of 90 mmHg or greater, or both may bediagnosed as hypertension (14, 52, 60).

3) Auscultatory GapAfter the first Korotkoff sound is heard on auscultation, itmay disappear for a while and appear again thereafter. In thiscase, the first sound is considered for systolic blood pressure,but it may be underestimated without careful auscultation. Inorder to avoid this underestimation in the elderly, a palpationtechnique should be combined with sufficiently highpressure in the sphygmomanometer cuff.

4) PseudohypertensionPseudohypertension is recognized in those cases of advancedarteriosclerosis in which the arteries are not compressedcompletely by the arm cuff, thereby resulting in a blood pres-sure reading higher than that measured by a direct method.Osler’s procedure (61) is reported to be useful for differenti-ation of pseudohypertension. Upon sufficiently strong com-pression with the arm cuff, Osler’s positive sign is character-

ized by a palpable radial artery without beats, and it tends tobe associated with pseudohypertension. The possibility ofpseudohypertension should be considered for the patientwith marked elevation of blood pressure not accompanied bytarget-organ damage, although pseudohypertension is report-ed to be infrequently recognized in such cases (62).

5) Fluctuation of Blood PressureBlood pressure values fluctuate significantly in all individu-als, healthy or otherwise. They vary much more in the elder-ly than in young individuals, since in the elderly the buffercapacity for controlling blood pressure fluctuation is de-creased due to suppression of baroreceptor sensitivity. Bloodpressure in the elderly tends to be significantly elevated dueto mental stress during conversation with physicians, al-though in some cases it may become almost normal afterseveral patient/physician encounters. In cases in which ele-vated blood pressure is seen without target-organ disorders,the possibility of elevated blood pressure due to mentalstress or white coat hypertension is suggested, and thus theblood pressure may decrease when measured by an automaticsphygmomanometer in an isolated room. Therefore, a singleblood pressure measurement is not sufficient for making anydecision during the management of hypertension in the el-derly, and several visits at 2–4-week intervals for the mea-surement of blood pressure may be necessary. It is also im-portant to measure home blood pressure (63). Orthostatic hy-potension with a decrease in systolic blood pressure of 20mmHg or greater is frequently encountered in the elderly,and particularly in those with myocardial infarction or tran-sient ischemic attack, or in those who have been bedriddenfor a long period of time. In addition, it is important to payattention to such complications as diabetic neuropathy andShy-Drager syndrome, both of which can cause postural orthostatic hypotension. Therefore, blood pressure should bemeasured in sitting and standing positions as well as in asupine position. Postprandial hypotension is also frequently


Table 3. Elderly Patients Suspected of Having RenovascularHypertension

1. Diastolic BP 105 mmHg or greater found after 55 yr of age2. Drug-resistant hypertension controlled by antihypertensive

drugs in the past3. Hypokalemia4. Moderate or severe renal dysfunction5. Abdominal vascular bruits

Table 4. Risk Factors for Cardiovascular Diseases

HypertensionSmokingHypercholesterolemiaDiabetes mellitusAdvanced age (for men aged 60 yr and older and for womenaged 65 yr and older)Family history of juvenile onset cardiovascular disease

Table 5. Organ Damage and Cardiovascular Diseases

HeartLeft ventricular hypertrophyHistory of angina pectoris and myocardial infarctionHeart failure

BrainCerebral hemorrhage, cerebral infarctionTransient ischemic attack

KidneyProteinuriaRenal dysfunction, renal failure

Blood vesselsAtherosclerotic plaquesAortic dissectionOcclusive arterial diseases

BP, blood pressure.

encountered in the elderly. In these cases, the time since thelast meal should be considered at blood pressure monitoring.

6) Diagnosis of Secondary Hypertension in the ElderlyThe frequency of secondary hypertension in the elderly hasbeen reported as approximately 5%, a rate similar to that inyoung and middle-aged individuals (64). However, the con-tent of secondary hypertension is different for the foremostgroup; i.e., endocrinological hypertension due to aldosteron-ism, pheochromocytoma, Cushing syndrome, etc., are infre-quent in the elderly, while renal hypertension is most fre-quently encountered. Renovascular hypertension is a fre-quently occurring type of secondary hypertension in the el-derly (65). Symptoms and findings suggestive of renovascu-lar hypertension are listed in Table 3, and the diagnostic cri-teria for this disease and other types of secondary hyperten-sion in the elderly are discussed below.

a. Renovascular hypertensionMostly due to atherosclerosis in the elderly, and abnormalfindings are recognized usually in bilateral renal arteries.Renovascular hypertension combined with or without essen-tial hypertension should be ruled out when abdominal vascu-lar bruits, rapid elevation of blood pressure during treatmentof hypertension, decreased effect of antihypertensive drugs,or deterioration of renal function caused by angiotensin con-verting enzyme (ACE) inhibitors is recognized. The possibil-ity of the disease should always be considered in new casesof hypertension in the elderly with reference to elevatedplasma renin activity and hypokalemia. Special laboratoryexaminations such as renography, renal scintigraphy andDoppler ultrasonography may also be useful. Angiographyof renal arteries and plasma renin activity measurement onsamples drawn from bilateral renal veins can be used for adefinitive diagnosis.

b. Renal hypertensionIn the elderly, caused more frequently by chronic glomerulonephritis, diabetic nephropathy, chronicpyelonephritis, and amyloidosis than it is by those conditionsin young and middle-aged hypertensives. Measurements ofserum creatinine, endogenous creatinine clearance and uri-nalysis (hematuria, proteinuria, urinary sediments) are usefulfor diagnosis, and onsets of hypertension and proteinuria

should be confirmed especially in the cases with renal dys-function.

c. Primary aldosteronismElderly individuals frequently take herbal medications, and this can occasionally result in pseudo-aldosteronism. Inorder to rule out this condition, patients should be asked todescribe any regularly taken herbal medications, as well asabout the presence of such symptoms as weakness of theextremities, polydypsia and polyuria. Hypokalemia tends tobe attributed to diuretics, but differentiation between thisdisease and primary aldosteronism can often be aided byconfirmation of suppressed plasma renin activity and elevat-ed plasma aldosterone level.

d. PheochromocytomaBecause of the significantly large fluctuation of blood pressure in the elderly, paroxysmal fluctuating hypertensioncharacteristic of pheochromocytoma tends to be overlooked.It should be ruled out when hypertension is complicated withheadache, palpitation, tachycardia, perspiration, weight loss,or hyperglycemia. Pheochromocytoma can be definitivelydiagnosed by assay for increased blood and urinarycatecholamines and catecholamines metabolites, along withabdominal CT and 131I-meta-iodobenzylguanidine (MIBG)scintigraphy to confirm the presence of a tumor mass.

e. Cushing syndromeRarely encountered in the elderly, and suggested by its characteristic physical signs. An ectopic ACTH-producingtumor associated with lung cancer (small cell carcinoma),pancreatic cancer, etc., may be encountered.

7) Classification of Severity of HypertensionPrognosis of hypertensive patients is closely correlated notonly with hypertension itself, but also with other risk factorsfor cardiovascular diseases, with degree of target organ dis-orders, and with cardiovascular complications. In clinicaltreatment for hypertension, the degree of severity of hyper-tension should be evaluated for the prognosis assessment, inaddition to conducting a differential diagnosis of essential orsecondary hypertension. Tables 4 and 5 show risk factors forcardiovascular diseases and organ disorders/cardiovasculardiseases, respectively, in JSH 2000 (60). The severity of car-


Table 6. Stratification of Risk in Patients with Hypertension

BP classification

Risk factors other than BP Mild hypertension Moderate hypertension Severe hypertension(140–159/90–99 mmHg) (160–179/100–109 mmHg) (≥180/≥110 mmHg)

No risk factors Low risk Moderate risk High riskPresence of risk factors beside diabetes Moderate risk Moderate risk High riskPresence of either diabetes, organ damage High risk High risk High riskor cardiovascular disease

BP, blood pressure.


Table 7. Intervention Trials for Hypertension in the Elderly

EWPHE HEP SHEP STOP MRC II STONE

Syst-Eur Syst-China STOP-2 NICS-EH PATE-Hyp SCOPE

＊Statistically significant, ＃myocardial infarction only, HEP, MRC: blood pressure (BP) is an estimated value, ∆fatal cardiovascularaccident vs. β-blockers/diuretics, ☆Ca antagonists vs. diuretics, ● cerebrovascular death, ●● death due to heart diseases, ●●● all cardio-vascular death, angiotensin converting enzyme (ACE) inhibitors vs. Ca antagonists, ▲under treatment, Ca A: Ca antagonist, ACE-I:ACE inhibitors, ARB: angiotensin II receptor blocker, HCTZ: hydrochlorothiazide, ■non-fatal stroke, ■■ primary endpoint (cardiovas-cular death, non-fatal stroke, non-fatal myocardial infarction). STOP, STOP-Hypertension; STOP-2, STOP-Hypertension 2; PATE-Hyp, PATE-Hypertension. †: secondary combined drug

Age (years) ≧60 60–79 ≧60 70–84 65–74 60–79No. of cases 840 884 4,736 1,627 4,396 1,632BP at entry (mmHg)

Systolic BP 160–239 170–280 160–219 180–230 160–209 ≧160& & & & & &/or

Diastolic BP 90–119 105–120 ＜90 ≧90 or ＜115 ≧96105–120

BP before treatment (mmHg) 180/101 197/100 177/77 195/102 185/91 168/98Antihypertensives diuretics β-blockers diuretics (1) β-blockers (1) β-blockers Ca A

methyldopa† diuretics† β-blockers† (2) diuretics (2) diuretics ACE-I†

methyldopa† diuretics†

Study design double blind open double blind double blind single blind single blindFollow-up period (yr) 4.7 4.4 4.5 2.1 5.8 3.0BP after treatment (mmHg)

Active treatment group 150/85 162/77 144/68 167/87 152/77 146/85Placebo group 171/95 180/88 155/71 186/99 166/83 155/90

Treatment effects (relative risk)Cerebrovascular disease 000.64＊ 000.58＊ 000.67＊ 000.53＊ 000.75＊ 000.43＊

Coronary arterial disease 000.82＊ 001.03＊ 000.73＊ 000.87＃ 000.81＊

Cardiac failure 000.78＊ 000.68＊ 000.45＊ 000.49＊ 000.32＊

Cardiovascular diseases, total 000.71＊ 000.76＊ 000.68＊ 000.60＊ 000.83＊ 000.40＊

Age (yr) ≧60 ≧60 70–84 ≧60 ≧60 70–89No. of cases 4,695 2,394 6,614 414 1,748 4,964BP at entry (mmHg)

Systolic BP 160–219 160–219 ≧180 160–220 ≧160 160–179& & ＆/or ＆＆/or ＆/or

Diastolic BP ＜95 ＜95 ≧105 ＜115 ≧90 90–99BP before treatment (mmHg) 174/86 170/86 194/98 172/94 ▲(1) 151/84 166/90

▲(2) 148/82Antihypertensives Ca A Ca A (1) β-blockers/ (1) Ca A (1) ACE-I ARB

diuretics vs. vs. vs.ACE-I† ACE-I† (2) Ca A (2) diuretics (2) CaA HCTZ†

diuretics† diuretics† (3) ACE-IStudy design double blind single blind PROBE double blind open double blindFollow-up period (years) 2.0 4.0 4–6 5 3 5BP after treatment (mmHg)

Active treatment group 151/79 150/81 (1) 159/81 (1) 147/81 (1) 142/80 145/80Placebo or active control group 161/84 159/84 (2) 159/80 (2) 147/79 (2) 141/78 149/82

(3) 159/82Treatment effects (relative risk)

Cerebrovascular disease 000.58＊ 000.62＊ Ca A. ●●●0.787 ■ 0.72＊

Coronary arterial disease 000.70＃ 001.06＃ ∆ 0.97 ●●●0.788Cardiac failure 000.71＊ 000.42＊ ACE-ICardiovascular diseases, total 000.69＊ 000.63＊ ∆ 1.01 ☆0.973 ●●●0.785 ■■0.89＊＊

diovascular diseases may be matched with that of risk factorsand target-organ disorders. The risks for hypertensive pa-tients are classified into three types, low risk, medium riskand high risk, according to whether or not there are majorrisks, hypertensive target-organ disorders or cardiovasculardiseases (Table 6). Advanced age, of course, is a risk factorin itself.

3. Necessity of Treatment for Hypertensionin the Elderly

In Japan, where the elderly population has been increasingrapidly, it is expected that the incidence of hypertension willcontinue to increase, and thus management of hypertensionin the elderly is an important problem both medically and so-cially. According to the 4th Report of National CardiovascularSurvey published in 1990 by the Ministry of Health andWelfare of Japan, and including of a total of 10,956 indi-viduals aged 30 yr or older, the prevalence of hypertension(140/90 mmHg or greater) among those aged 70 yr or older,irrespective of treatment by antihypertensive medication,was 75.5% in males and 78.9% in females (66). The useful-ness of antihypertensive drugs for treatment of hypertensionin the elderly has been proved through various interventiontrials, although no large-scale intervention trial has been re-ported in Japan. In a small-scale study on hypertension in theelderly, the usefulness of antihypertensive treatment was re-ported in cases of hypertension of 170/90 mmHg or greater(67). Recently, National Intervention Cooperative Study inElderly Hypertensives (NICS-EH) (68) and PATE-Hyperten-sion studies (11) have been reported.

3-1. Necessity of Treatment for Systolic Hypertension

It has been demonstrated through the Framingham andHisayama studies that elevation of either systolic or diastolicblood pressures is an important risk factor of cardiovasculardiseases. The effectiveness of treatment for systolic hyper-tension in the elderly was proved by SHEP trial in the USA(5), in which patients aged 60 yr or older with systolic hy-pertension were divided into an active treatment group(chlorthalidone as step 1 medication) and a placebo group.During the 4.5-yr follow-up, active treatment significantlydecreased the incidence of cerebrovascular disorders, coro-nary arterial diseases and cardiac failure. In addition, fre-quency of cerebrovascular disorders was shown to decreasesignificantly in Systolic Hypertension in Europe (Syst-Eur)trial (9) and Systolic Hypertension in China (Syst-China) tri-al (10), in which patients aged 60 yr or older were treated forsystolic hypertension by administration of the long-acting Caantagonist, nitrendipine (Table 7). Further, the results of apopulation-based observation study demonstrated that sys-tolic blood pressure is a highly important predictive factorfor cardiovascular events (69).

3-2. Usefulness of Treatment for Diastolic Hypertensionand Significance of Pulse Pressure

The European Working Party on High Blood Pressure in theElderly (EWPHE) trial (70) was the first large-scale inter-vention trial consisting solely of elderly hypertensive pa-tients. Intervention trials for hypertension in the elderly, ex-cluding the SHEP trial (5), Syst-Eur trial (9) and Syst-Chinatrial (10), have generally focused on both systolic and dias-tolic hypertension, with only the STOP-Hypertension trialusing an entry criterion of diastolic blood pressure rangingfrom 105–120 mmHg irrespective of systolic blood pressurelevels (6). Table 7 lists the principal intervention trials, inwhich the averaged diastolic blood pressure at entry rangedfrom 91–102 mmHg and the averaged systolic blood pres-sure at entry ranged from 168–197 mmHg (5–10, 68, 70,71). These trials confirm the preventive effect of antihyper-tensive drugs against cardiovascular diseases. Although thepartial influence of systolic blood pressure cannot be exclud-ed, elderly individuals with a diastolic blood pressure of90–95 mmHg or greater would appear to be reasonable can-didates for antihypertensive drug treatment.

A meta-analysis of 9 principal trials on the treatment ofhypertension in individuals aged 60 yr or older found thatoverall deaths decreased 12%, deaths due to stroke decreased36%, deaths due to coronary artery diseases decreased 25%,overall morbidity of cerebrovascular disorders decreased35%, and coronary arterial diseases decreased 15%, thusclearly indicating the efficacy of the treatment (72). On theother hand, there are no clear evidences of the benefit of an-tihypertensive treatment among the hypertensive elderlyaged 80 yr or over. In a subgroup meta-analysis of random-ized controlled trials in individuals aged 80 yr or older, over-all morbidity of stroke and heart failure decreased, but therewas no decrease in either overall morbidity of coronaryartery diseases and cardiovascular diseases or overall deathsdue to these diseases (12).

In the elderly, increases in systolic blood pressure and de-creases in diastolic blood pressure occur as a result of de-creased compliance of the arteries and augmentation of re-flected waves; that is to say, it is thought that increased pulsepressure reflects the advance of atherosclerotic change. It hasbeen reported that systolic blood pressure is correlated tomortality in the elderly, while diastolic blood pressure, incontrast, is negatively correlated to mortality in the elderly(73), and that the risk is not high among diastolic hyperten-sive patients (73, 74) whose systolic blood pressure is withinnormal range. Thus pulse pressure should be taken into con-sideration in the treatment of elderly hypertensives.

3-3. Guidelines of Hypertension Treatment in theElderly in Foreign Countries and Their Problems

Based on various intervention trials and epidemiologicalstudies, several guidelines have been proposed. The JNC


proposed the JNC VI guidelines in 1997, and WHO-ISH alsoreported guidelines for the treatment of hypertension in 1999(14, 52). The 1999 WHO-ISH guidelines proposed that thetherapeutic goal of blood pressure for hypertension in the el-derly should be less than 140/90 mmHg, or slightly higherthan the goal of less than 130/85 mmHg for young patients.According to the results of questionnaires given to Japanesehypertension experts, the goal of blood pressure for the el-derly aged 60 yr or older was most frequently reported to bebelow 150 mmHg, or below 160 mmHg for the elderly aged80 yr and older (75). Hypertension in the elderly constitutesa higher risk for cardiovascular diseases than hypertension inthe young and middle-aged (76), and it has been reportedthat antihypertensive drug treatment in the elderly shouldhave more preventive effects for cardiovascular diseases (77).The New Zealand therapeutic guidelines have recommendedthat antihypertensive drug treatment should be given to thosewho have a 20% or higher prevalence rate of cardiovasculardiseases over the next 10 yr, and risk factors other thanhypertension are emphasized in these guidelines. In addition,the guidelines for management of hypertension of the BritishHypertension Society have recommended that antihyperten-sive drug treatment should be given to those who have a15% or higher prevalence rate of ischemic heart diseases (a20% or higher prevalence rate of cardiovascular diseases)over the next 10 yr (78).

On the other hand, blood pressure may not influence theprognosis for longevity in the very elderly. The STOP-Hy-pertension trial recognized the usefulness of treating hyper-tension in the elderly aged up to 84 yr (6), and no therapeuticeffect was proved for the elderly aged over 80 yr in the EWPHE trial (70). However, because interindividual variationis relatively large in the elderly, the age of each patientshould not be overly emphasized. Even the very elderly agedover 85 yr with marked hypertension (e.g., 180/110 mmHg)may be treated clinically. In the above-mentioned survey ofJapanese hypertension specialists, roughly half the respon-dents reported that they give no special consideration to anupper age-limit for treatment of hypertension (75). Activeantihypertensive treatment is necessary for cases with criticalcomplications. On the other hand, it has been reported thatexcessive blood pressure reduction may cause cardiovascularevents (the so-called “J-curve phenomenon”) (79). There-fore, treatment of hypertension in the elderly should be givencautiously and gradually (80).

4. Patients to Be Treated and Target Levelsof Blood Pressure

Elderly hypertensive patients frequently have multiple organdamage and impaired physiological functions compared toyoung and middle-aged hypertensives, and thus are morelikely to develop various adverse effects and complicationswith antihypertensive drugs. For this reason, it is of primaryimportance to evaluate the necessity of antihypertensive

treatment, and then, if judged necessary, antihypertensivetreatment should be initiated cautiously, in full considerationof the target blood pressure and speed of blood pressure re-duction as well as the physical, mental and social conditionsof each individual.

4-1. Patients to Be Treated

1) AgeElderly hypertensives should be treated like the young andmiddle-aged hypertensives. However, further studies will beneeded to clarify the benefits of antihypertensive treatmentamong the very elderly aged 85 yr or older.

In a Finnish study on the 5-yr survival rate among the veryelderly population, 83% of whom were aged 85 yr or older(81), the survival rate was highest in the group with systolicblood pressure of 160 mmHg or greater and diastolic bloodpressure of 90 mmHg or greater, whereas it was lowest inthe group with lower blood pressure. Thus, hypertensionappears to be unrelated to longevity among the very elderlyaged 85 yr or older; however, half of the individuals in theFinnish study were hospitalized due to illness. The sameinvestigators later performed a similar study among healthy,very elderly individuals, and reported that the lowestmortality rate was observed in the group with systolic bloodpressure of 140–169 mmHg and diastolic blood pressure of70–90 mmHg, and the mortality increased in all othergroups, i.e., those who had either higher or lower bloodpressure than that in the low-mortality group (82). On theother hand, other studies, including the EWPHE (70), STOP-Hypertension (6) and Syst-Eur (83) studies, have providedno clear evidence of the benefit of antihypertensive treatmentin the elderly aged over 80 yr.

According to a meta-analysis of randomized controlled tri-als in individuals aged 80 yr or older, antihypertensive treat-ment did not decrease cardiovascular death, but decreasedmorbidity of stroke and heart failure (12). An ongoing clini-cal trial, the Hypertension in the Very Elderly Trial(HYVET) (84), may clarify whether or not antihypertensivetreatment among the very elderly is beneficial. However,antihypertensive treatment should be continued in patientsalready treated before the age of 80 yr, with care taken toproperly control the doses (85).

2) Blood Pressure Levels for Initiating Antihypertensive DrugTreatmentBoth systolic and diastolic blood pressure levels are impor-tant indices for initiating drug treatment, even in the elderly.In Japan, however, many investigators believe that the initialblood pressure levels for starting antihypertensive drug treat-ment in the elderly might be set differently from those in theyoung and middle-aged, who tend to have less target-organdamage (75), and a number of European and US specialistsagree (85–87). In a survey of hypertension specialists inJapan, the majority of respondents reported that the blood


pressure for initiating drug treatment in the elderly should be a systolic blood pressure of 160 mmHg or greater and adiastolic blood pressure of 90 mmHg or greater (75).

Indeed, the large-scale intervention trials performed ingroups of elderly subjects in Europe and the USA haveshown the beneficial effects of antihypertensive treatment inpatients with systolic blood pressure of 160 mmHg or greaterand diastolic blood pressure of 90–100 mmHg. In addition,because it has been demonstrated in a cohort study byHisayama-cho (24) and Tanno-Sobetsu-cho (88) that a sys-tolic blood pressure of 160 mmHg or greater increased car-diovascular mortality, it is recommended that antihyperten-sive treatment should be initiated when the systolic bloodpressure is 160 mmHg or greater and/or the diastolic bloodpressure 90 mmHg or greater.

It has also been reported in a one-year follow-up studythat a systolic blood pressure of 140–159 mmHg improvedQOL and cardiac hypertrophy (89). If more than onecomplication is present, antihypertensive treatment may beeven more strongly indicated. In cases of severe hypertensionwith a systolic blood pressure of 180 mmHg or greaterand/or a diastolic blood pressure of 110 mmHg or greater,antihypertensive treatment should be started immediately.

4-2. Therapeutic Goal of Blood Pressure

In general, the target blood pressure in the elderly should beset at a higher level than that in the young and middle-aged.This recommendation is based on the facts that the elderlytend to already have target-organ damage and to exhibit altered cerebral autoregulation.

According to a meta-analysis of intervention trials of el-derly hypertensives treated with diuretics and β-blockers, anaverage reduction of 12–19 mmHg in systolic and 4–10mmHg in diastolic blood pressure decreased the morbidity ofstroke by 34%, that of coronary artery disease by 21%, andthat of heart failure by 15% compared with a placebo group(90). In these trials, the reduction of blood pressure from thebaseline value was 19–44 mmHg of systolic and 9–21mmHg of diastolic blood pressure. On the other hand, in re-cent intervention trials for the elderly utilizing Ca blockersand ACE inhibitors (Table 7), the achieved blood pressurewas 144–167 mmHg in systolic and 68–85 mmHg in dia-stolic. Since the possible existence of a J-curve phenome-non—i.e., a tendency, in some cases, for excessive reduction

of blood pressure to increase the incidence of coronary arterydisease and cerebrovascular diseases—has been reported(91–93), one must be cautious when reducing diastolic bloodpressure to below 85 mmHg.

The results of the PATE-Hypertension study in Japan(11), in which the incidences of cardiovascular events werecompared between patients treated with a Ca blocker andthose treated with an ACE inhibitor, indicate that an exces-sive reduction to less than 130 mmHg in systolic bloodpressure may increase the incidences of cardiovascularevents. In addition, a case-control study demonstrated thatblood pressure under the treatment is low level amonghypertensive patients complicated with acute myocardialinfarction or recurrence compared to control groups (94).However, a Hypertension Optimal Treatment (HOT) trial(mean age, 61.5 yr), designed to study the J-curve phenomenon(95) found that the maximum favorable effect was achievedat a systolic blood pressure of 130–140 mmHg and diastolicblood pressure of 80–85 mmHg. In a sub-analysis of elderlysubjects aged 65 yr or older (average age, 70.6 yr), patientswhose target diastolic blood pressure was less than 85mmHg (achieved blood pressure, 145/82 mmHg) had agreater reduction in total cardiovascular events comparedwith those whose diastolic blood pressure was either 90mmHg or less or 80 mmHg or less (96). In addition, theSHEP group showed the relationship of achieved systolicblood pressure to stroke incidence in older patients (averageage, 71.6 yr), demonstrating that patients whose systolicblood pressure was lower than 150 mmHg had the greatestreduction in stroke incidence, while those having a systolicblood pressure lower than 140 mmHg had no significantreduction (97). These results indicate that a target systolicblood pressure of less than 150 mmHg is appropriate forpatients in their 70s. The SHEP study also demonstrated thatpatients with diastolic blood pressure less than 55 mmHghad a 2 times greater risk of cardiovascular events.Therefore, in individuals having a wide pulse pressure, targetdiastolic blood pressure should not be set below 55 mmHg.

In light of these facts, the target blood pressure for indi-viduals in their 60s should be systolic blood pressure ofbelow 140 mmHg and diastolic blood pressure of below 90mmHg, if tolerable, although these values may depend onthe pretreatment blood pressure levels. The target systolicblood pressure for individuals in their 70s and 80s should be,respectively, below 150 mmHg and below 160 mmHg, sincethese patients are more likely to have target-organ damages.Table 8 shows the target blood pressures corresponding to thedifferent age groups. It is possible to improve the prognosisof all age groups by reducing the systolic blood pressure tobelow 140 mmHg and the diastolic blood pressure to below90 mmHg, if tolerable. Although there are pros and cons inregard to various blood pressure targets for the different agegroups, a number of hypertension specialists in Europe agreewith these general targets (86, 87). Recently, based on datafrom the Framingham study, Port et al. demonstrated that


Table 8. Therapeutic Goal of Blood Pressure (BP) forTreatment of Hypertension in the Elderly

Age (yr) 60–69 70–79 80 and older

Biological age is more important than chronological agebecause of the individual difference in elderly subjects.

Systolic BP (mmHg) ＜140 ＜150 ＜160Diastolic BP (mmHg) ＜900 ＜900 ＜900

there are no age- or sex-based changes in all-cause mortalityand cardiovascular mortality below the 70th percentile ofsystolic blood pressure, but that such changes increaseremarkably over the 80th percentile of systolic blood pressure(98). Because blood pressure increases with age, the riskthreshold is also expected to increase with age, which wouldsupport the use of different target blood pressures for thedifferent age groups.

During antihypertensive drug treatment in elderly hyper-tensives, postprandial hypotension, orthostatic hypotensionand excessive reduction of nocturnal blood pressure maysometimes occur and aggravate ischemia of important or-gans. Indeed, excessive reductions of blood pressure mightbe associated with an increased risk for cardiovascular dis-eases (79–81). It is thus useful to confirm the adequacy ofdrug treatment by means of 24-h blood pressure monitoringwith a portable automatic sphygmomanometer. Home bloodpressure monitoring is also recommended (99).

4-3. Speed of Blood Pressure Reduction

Doses of antihypertensive drugs must be titrated graduallyand cautiously in the elderly, because metabolism and excre-tion of drugs are delayed in such patients due to age-relateddecreases in the functions of the liver and kidneys (100). Atthe initial stage, antihypertensive treatment should be startedat half of the usual dose given to non-elderly patients, andmay be increased at intervals of more than 4 weeks with atarget blood pressure being achieved in 2–3 months or longer.

5. Lifestyle Modification

Hypertension can be considered a “lifestyle disease.”Lifestyle modification is thus useful in the treatment of hy-pertension in the elderly, although the efficacy of lifestylechange varies among individuals. In the JNC VI (14) andWHO/ISH (52) guidelines, it is recommended that non-med-ication therapy be used as the first step for treatment of hy-pertension, and that it be continued even after antihyperten-sive drug therapy is started. Mild hypertension can becorrected only by lifestyle modification, but moderatehypertension can be normalized by administration of smalldoses of antihypertensive drugs. Non-medication therapy isuseful for the prevention of side effects of antihypertensivedrugs and for the improvement of QOL. However, elderlyindividuals tend to have firmly established lifestyles and tobe resistant to lifestyle modification. For example, familymembers may not cooperate sufficiently with recommendeddietary changes, and other lifestyle modifications may bedifficult for practical reasons.

5-1. Diet

1) Salt RestrictionIn the INTERSALT study (101), a significant correlation be-

tween urinary sodium excretion and elevation of blood pres-sure was recognized with age. In addition, it has been estab-lished that blood pressure tends to remain low even in ad-vancing age in communities where urinary sodium excretionis low, and that the relationship between salt intake andblood pressure elevation is important (102). Based on the re-sponses to abundant salt intake, patients with essential hy-pertension can be divided into two groups, a salt-sensitivegroup showing elevation of blood pressure and a non-saltsensitive group showing no elevation of blood pressure(103). In general, elderly individuals show high sensitivity tosalt, and thus hypertension can be well corrected by restric-tion of salt intake.

Accordingly, mild and moderate hypertension in the elder-ly should be treated first by restriction of salt intake, and byother methods only if salt restriction fails to achieve a favor-able response. The TONE trial (104), the first large-scalerandomized trial, reported that weight reduction and restric-tion of salt intake were effective for treatment of hyperten-sion in the elderly. The JNC VI recommends restricting di-etary salt intake to less than 6 g sodium chloride per day.However, a strict restriction of salt intake from about 13g/day (the mean salt intake in Japan) down to 6 g/day maycause loss of appetite and deteriorate QOL in the elderly.Therefore, it is recommended that salt intake should be ini-tially restricted to below 10 g/day, and then slowly decreasedto below 7 g/day, if possible.

2) Potassium IntakePotassium itself is not significantly effective for hyperten-sion. However, it is thought that increased potassium intakedirectly reduces the risk of cerebral stroke (105), and thatpotassium depletion may induce hypertension and ventricu-lar premature beats. Therefore, increased potassium intakeseems effective for the prevention of cardiovascular diseases.However, increased potassium intake is more effective forlowering blood pressure in patients with high dietary salt in-take than in those with low salt intake. Since it is recognizedthat the dietary sodium/potassium ratio is well correlatedwith blood pressure levels, intake of a diet with a low sodi-um/potassium ratio is recommended. In the elderly, howev-er, careful attention must be paid to cases with renal dys-function, cases with hyporeninemic hypoaldosteronism com-plicated with diabetes mellitus, or cases requiring adminis-tration of aldosterone antagonists.

3) Calcium and Magnesium IntakeA negative correlation has been recognized epidemiological-ly between blood pressure and dietary intake of calcium andmagnesium (106, 107). In Japan, the mean dietary intake ofcalcium is less than the required 600 mg/day, and in fact ishalf of the amount (800–1,300 mg/day) taken in Westerncountries. Therefore, it is recommended that dietary calciumintake be more than 600 mg/day. It has been reported inJapan that magnesium supplements are effective for lowering


blood pressure in hypertensive patients (108).

4) FatSince fish oil (eicosapentaenoic acid) is said to have anti-atherogenic and anti-hypertensive effects, dietary intake ofblue fishes may contribute to the prevention of atherosclerot-ic diseases. Hyperlipidemia is one of the important risk fac-tors for atherosclerosis, and restriction of dietary fat intakeshould be recommended for hyperlipidemic patients.

5-2. Exercise

Studies related to exercise and mortality have generallyagreed that physical activity is inversely correlated withmortality due to circulatory diseases, and thus adequate exer-cise is suggested to prevent atherosclerosis (109). Exercisetreatment is reported to decrease systolic blood pressure by8–18 mmHg and diastolic blood pressure by 5–16 mmHg(110). Exercise treatment is one of the best choices for mildhypertension. However, isometric exercise significantly in-creases both systolic and diastolic blood pressures, and thuscannot be recommended for treating hypertension. Isotonicand aerobic exercises lower diastolic blood pressure andincrease systolic blood pressure during physical activity,and thus can be recommended for treating hypertension.The strength of exercise is recommended to be 40–60% ofthe maximum oxygen intake; an approximately 10 mmHgdepression in systolic blood pressure may be expectedby 30–40 min of exercise 3–5 times per week (111).Exercise helps not only to lower blood pressure, but also toimprove insulin resistance and lower serum triglyceride.While it is not practical to measure the maximum oxygen in-take in all patients, a target of 110 beats per min is used forpatients aged 60 yr or older, as estimated from the relationbetween heart rate and physical activity at 50% maximumoxygen intake at various ages. Therefore, it is recommendedthat exercise treatment consists of isotonic exercise for 30–40min, 3–5 times a week, and that this regimen be continuedindefinitely. However, exercise treatment for hypertension isnot suitable for patients with ischemic heart diseases, heartfailure, renal failure or orthopedic complications.

5-3. Weight Reduction

Obesity is closely associated with blood pressure elevation,most likely due to insulin resistance and sympathetic ner-vous system involvement. It is well known that weight re-duction in obese patients effectively lowers blood pressure.In fact, weight reduction has been shown to lower bloodpressure in 80% of cases, regardless of the extent of obesity,and thus should be widely applied as a useful antihyperten-sive treatment (112, 113). Hypertension is also related to dis-tribution of body fat. Fat distribution mainly in the upperbody, namely a waist/hip ratio of 1.0 or more for males or0.8 or more for females, has been reported to increase mor-

tality due to hypertension, hyperlipidemia, diabetes mellitusor coronary artery diseases.

5-4. Alcohol, Caffeine, and Smoking

1) AlcoholAlcohol intake is positively correlated to blood pressure(14). Moderate and heavy drinkers (30 ml ethanol or moreper day) tend to be significantly more hypertensive than non-drinkers.

2) CaffeineIt has been reported that caffeine can have the acute effectsof increasing blood pressure and decreasing arterial stiffness(114).

3) SmokingSmoking itself may not be directly implicated in raisingblood pressure, but it is one of the major risk factors of car-diovascular diseases. It is, therefore, advised that hyperten-sive patients avoid cigarette smoking, given that treatment ofhypertension is aimed mainly at preventing cardiovasculardiseases.

6. Antihypertensive Drug Therapy

Hypertension in the elderly is a major risk factor for cere-brovascular disease, coronary artery disease, cardiac failure,end-stage renal disease, arteriosclerosis obliterans and all-cause mortality (3), and systolic blood pressure is a betterpredictor of these events than is diastolic blood pressure. Ithas become clear that increased pulse pressure is a good in-dicator for risk of cardiovascular disease (4). Since the late1980s, several large intervention trials have been performedon hypertension in persons aged 60 yr or older, and all havedemonstrated the effectiveness of antihypertensive drug ther-apy. However, antihypertensive drug therapy has not beendefinitely confirmed to be effective in very old hypertensivepatients (85 yr or older), and thus its effectiveness may belimited after a certain age (74). Considering these limita-tions, guidelines for antihypertensive drug therapy are pre-sented as follows.

6-1. Antihypertensive Drugs Used in Large-Scale Intervention Trials for Hypertension in the Elderly

The major antihypertensive drugs conventionally used inlarge-scale intervention trials for hypertension in the elderlyare diuretics and β-blockers. Diuretics are considered stan-dard drugs for use in trials evaluating long-acting Ca antago-nists and ACE inhibitors. In addition, long-acting Ca antago-nists have been used as a first step in several recent large-scale intervention trials for hypertension in the elderly(8–10). ACE inhibitors were used as a first choice in additionto long-acting Ca antagonists in the STOP Hypertension-2


study (115).In the Medical Reserch Council (MRC) trial, the use of β-

blockers resulted in no significant reductions in stroke, coro-nary events or death from all causes compared with theplacebo group (7). Messerli et al. (13) analyzed the results ofthe randomized controlled trials using diuretics and β-block-ers for hypertension in the elderly, and reported that diureticsare effective for reduction of cerebrovascular events, strokemortality, coronary artery disease, cardiovascular mortality,and all-cause mortality in comparison to the placebo group,but β-blockers are not effective for reduction of coronaryartery disease, cardiovascular mortality or all-cause mortali-ty. In the Syst-Eur trial (9) and Syst-China trial (10), a long-acting Ca antagonist significantly reduced the morbidity ofstroke, non-fatal cardiac disease, total cardiac disease, andfatal and non-fatal cardiovascular disease. A long-term treat-ment trial (NICS-EH) of hypertension in Japanese patients(68), although utilizing a relatively small number of partici-pants, reported that a dihydropyridine Ca antagonist was aseffective as a diuretic for the prevention of cardiovasculardiseases. ACE inhibitors showed similar effects on cardio-vascular mortality and morbidity compared with diuretics orβ-blockers in STOP Hypertension-2 (115).

The PATE-Hypertension study indicated that both anACE inhibitor and a dihydropyridine Ca antagonist wereequally beneficial for reducing cardiovascular mortality andmorbidity in elderly hypertensive patients in Japan (11).

6-2. Antihypertensive Drugs for Treating Hypertensionin the Elderly, Selected by Hypertension Specialists inJapan

In 1993, 123 hypertension specialists in Japan (84% re-sponse rate) responded to a questionnaire survey (75), andtwo years later, the results of this survey were used to estab-lish the “A Guideline for Treatment of Hypertension in theElderly, 1995” (15). In 1996, a follow-up questionnaire withitems about the 1995 Guidelines was sent to the previous re-spondents. Among the responding physicians, 65% selectedlong-acting Ca antagonists (Ca antagonists) and ACE in-hibitors as the first choice for hypertension without compli-cations in the elderly, while diuretics and β-blockers wereselected by only 17%.

The 1995 Guidelines indicated that β-blockers and α -blockers were relatively contraindicated for the treatment ofhypertension in the elderly, but in the second questionnaireabout one half of the respondents recognized both blockersas safe for use in the elderly.

Reflecting the changes surrounding antihypertensive drugtherapy in the elderly, a “Guidelines for Hypertension in theElderly—1999 Revised Version” was published (16). A fol-low-up questionnaire survey was carried out to evaluatethese guidelines as well. The guidelines adopted Ca antago-nists, ACE inhibitors, and low-dose diuretics as the first-lineantihypertensive agents for elderly hypertensives withoutcomplications. Out of the 122 respondents, 80 (65%) agreedwith this proposal. However, the proposal met with a nega-tive response from 40 clinical specialists for hypertension(34%). Ten percent of the respondents recommended re-


Fig. 1. Flow chart for treatment of hypertension in the elderly without complications.

ACEI: angiotensin-converting enzyme inhibitors, ARB: angiotensin II receptor blocker＊β-blockers, α-blockers, or αβ-blockers, may be indicated if necessary.

moval of diuretics from the first-line drugs, and 15% recom-mended inclusion of β-blockers in the first-line drugs. Onehundred (82%) of the 122 respondents, an overwhelmingmajority, approved the adoption of angiotensin II receptorblockers (ARBs) as a first-line antihypertensive agent (17).

6-3. Selection of Antihypertensive Drugs

Generally, drugs which meet the following criteria are rec-ommended as first-choice drugs.a. The possibility of administration once or twice a day in or-der to maintain good compliance.b. Long-acting effects (a T/P ratio of at least 50%) of 24 h orlonger, in order to be effective for rapid elevation of bloodpressure in early morning.c. Low price as compared with comparable drugs of thesame efficacy.

1) Patients without ComplicationsFirst-choice drug: Ca antagonists, ACE inhibitors, ARBs ora low dose of diuretics. A therapeutic flow chart is shown inFig. 1. In the event that one of these first-choice drugs isineffective or intolerable, one of the other drugs in the listcan be tried.

a. Ca antagonistsCa antagonists are usually classified into two groups: dihy-dropyridines and benzothiazepine (diltiazem). The antihy-pertensive effect of dihydropyridine Ca antagonists dependson the decrease in peripheral vascular resistance, and thesedrugs achieve an excellent blood pressure reduction, accom-panied by a reflex increase in heart rate and cardiac output.Improved versions of these drugs that act more slowly andfor a longer period of time, and that have little stimulatoryeffect on the sympathetic nerve system and renin-angiotensinsystem, are now on the market.

Based on the results obtained in a randomized-doubleblind trial, the NICS-EH trial (68) in Japan, a dihydropyri-dine Ca antagonist, is as effective as a thiazide diuretic in re-ducing the risks of cardiovascular events, and is superior interms of tolerability. A prospective, randomized, open,blinded endpoint study has proved that diltiazem is effectivein preventing stroke (116). In some patients, diltiazem showsinhibitory effects on the sinus node and atrioventricular con-duction system, resulting in conduction disturbance andbradycardia.

Benefits of Ca antagonists: Summarizing the benefits ofCa antagonists for the treatment of hypertension in the elder-ly, these drugs demonstrate excellent effects in blood pres-sure reduction, and according to the Syst-Eur (9), Syst-Chinatrials (10), and STOP Hypertension-2 study (115), theyclearly reduce the morbidity and mortality of cardiovasculardisease. Ca antagonists are expected to be effective for hyper-tensive patients complicated by such conditions as anginapectoris (dihydropyridines and diltiazem), atrial fibrillation

(diltiazem), and diabetes mellitus with proteinuria (both Caantagonists) (14). Neither type of Ca antagonist has any ef-fects on the metabolism of carbohydrates, lipids, or uric acid.They have few contraindications, and can be used in combi-nation with other classes of antihypertensive drugs.

Disadvantages of Ca antagonists: Dihydropyridine Ca an-tagonists may cause ankle edema, which may be differentiat-ed from congestive heart failure. Care must also be taken also to avoid gingival hypertrophy.

In a meta-analysis of the large available database of ran-domized controlled trials, Ca antagonists were suggested tobe significantly inferior to other types of antihypertensivedrugs, i.e., diuretics, β-blockers and ACE inhibitors, in re-ducing the risks of acute myocardial infarction (117). On theother hand, in another meta-analysis of randomized placebo-controlled trials, it was proposed that Ca antagonists areequal to other types of antihypertensive drugs as diuretics,β-blockers, and ACE inhibitors (118).

b. ACE inhibitorsIn a large, randomized placebo-controlled trial, the STOP-Hypertension 2 trial, ACE inhibitors were shown to be as ef-fective as Ca antagonists and other, older types of antihyper-tensive drugs, such as diuretics and β-blockers (115).

The Heart Outcomes Prevention Evaluation (HOPE) studyindicated that ACE inhibitors reduced the rate of cardiovas-cular events in subjects (55 yr of age or older) who hadevidence of cardiovascular disease or diabetes plus at leastone other cardiovascular risk factor (119). The efficacy ofACE inhibitors in treating elderly patients was proved in theCaptopril Prevention Project (CAPPP) randomized trial(120) and STOP-Hypertension 2 study, which were based onthe results of numerous clinical studies demonstrating theprotective effects of these drugs on target organs. The useful-ness of ACE inhibitors was reported in the PATE-Hyperten-sion study in Japan (11). However, ACE inhibitors also havethe major adverse effects of dry cough and, less frequently,angioedema.

Benefits of ACE inhibitors: Elderly individuals generallyshow low plasma renin activity; however, the antihyperten-sive effect of ACE inhibitors is almost the same in elderly asin young and middle-aged hypertensives. In elderly patientswith mild or moderate essential hypertension, ACE in-hibitors effectively lower the blood pressure by about 70%.ACE inhibitors have the compelling indication for hyperten-sive patients who are complicated with congestive heartfailure from systolic dysfunction. ACE inhibitors have beenshown to provide beneficial effects in preventing leftventricular remodeling after myocardial infarction, and in re-gressing left ventricular hypertrophy. ACE inhibitors arecompellingly indicated for patients with diabetes mellituswith proteinuria. In addition, they are effective in protectingrenal function in patients with renal failure (serum creatininelevel, below 2 mg/dl) (121). They have few contraindica-tions and can be combined with other classes of antihyper-


tensive drugs. In addition, a recent clinical study has sug-gested that the use of ACE inhibitors was an independentfactor reducing the risk of pneumonia among elderly patients(122).

Disadvantages of ACE inhibitors: The major adverse ef-fects of ACE inhibitors are dry cough, which occurs espe-cially in women, and, less frequently, angioedema. ACE in-hibitors are relatively contraindicated when the serum creati-nine level is 2 mg/dl or greater, and contraindicated for bilat-eral renovascular hypertension.

c. ARBsARBs are now available in Japan, and their antihypertensiveeffect is equivalent to that of ACE inhibitors, but they do notcause the dry cough or angioedema associated with ACE in-hibitors. Based on recent evidence that ARBs show cardiacand renal protective effects, these drugs may be expected toconfer the same degree of protection against organ damageas ACE inhibitors. The randomized large-scale interventiontrials have demonstrated that there are few adverse effects ofARBs in patients with heart failure (123–124).

Benefits of ARBs: Elderly individuals generally show lowplasma renin activity, but the antihypertensive effect ofARBs are almost the same in elderly as in young and mid-dle-aged hypertensives (14). A comparative study found thatthe antihypertensive effects of ARBs are equal to those ofthe standard Ca antagonist, amlodipine (125), and that ARBsare highly effective at reducing blood pressure when used incombination with diuretics or Ca antagonists. Recently, ithas been shown that the ARB losartan is highly effective inreducing cardiovascular mortality and morbidity in hyperten-sive patients (126). ARBs are recommended as a first-linedrug in the JSH 2000 guidelines (60). ARBs have the com-pelling indication for hypertensive patients who are

complicated by diabetes mellitus, chronic heart failure, postmyocardial infarction, renal failure, or cerebrovascular dis-ease. They have few contraindications and few adverse ef-fects. ARBs are useful owing to high tolerance.

Disadvantage of ARBs: The main disadvantage of ARBs isthat their efficacy in elderly hypertensives has not been docu-mented by any large-scale trial, with the exception of theStudy on COgnition and Prognosis in the Elderly (SCOPE)trial. ARBs are relatively contraindicated when the serumcreatinine level is 2 mg/dl or greater, and are contraindicatedfor bilateral renovascular hypertension.

d. DiureticsLarge-scale intervention trials for hypertension in the elderlyin Western countries have established that low doses of di-uretics are useful for prevention of cardiovascular morbidityand mortality (127). In the NICS-EH, a diuretic was shownto be as effective as a Ca antagonist in treating hypertensionin the elderly, but more patients dropped out from the trial ina thiazide group than in group treated with a Ca antagonist(68). Considering the current status of drug prescriptionsin Japan and also the results obtained in the NICS-EH trial,diuretics should be used in combination with Ca antagonistsand/or ACE inhibitors/ARBs, since monotherapy with a lowdose diuretic—e.g., 1 or 2 mg of trichlormethiazide perday—is not successful for reducing blood pressure.

Benefits of diuretics: Diuretics are recommended for treat-ment of hypertensive patients who have a tendency to retainwater. Thiazide diuretics tend to inhibit urinary calcium ex-cretion, and may be useful for the prevention of osteoporo-sis. Diuretics can be used in combination with other classesof antihypertensive drugs, and may even increase their inher-ent effects. They also have the advantage of being inexpen-sive.


○: Preferable choice, △: Careful in use, ×: Contraindicated. ＊1 Caution for dehydration. ＊2 Contraindicated for vasospastic angina pec-toris. ＊3 Start with low dose, and be careful for clinical course. ＊4 Very cautious for patients with 2 mg/dl or greater serum creatinine. ＊5 Loop diuretics. ＊6 Caution for orthostatic hypotension. ＊7 Thiazide diuretics. ACE-I, angiotensin converting enzyme inhibitor;ARBs, angiotensin II receptor blockers.

Table 9. First-Choice Antihypertensive Drugs and Contraindicated Drugs for the Hypertensive Elderly Patients with Complications

Complications Ca antagonists ACE-I /ARBs Diuretics β-Blockers α-Blockers(dihydropyridines)

Cerebrovascular accident, chronic phase ○ ○ ＊1○＊1

Ischemic heart disease ○ ○ ＊2○＊2

Heart failure ○ ○ ＊3△＊3 △Renal insufficiency ○ ＊4○＊4 ＊5○＊5

Diabetes mellitus ○ ○ △ △ ＊6△＊6

Hyperlipidemia ○ ○ △ △ ○Gout (Hyperuricemia) ○ ○ ×Chronic obstructive pulmonary diseases ×Arteriosclerosis obliterans ○ ○ △ ×Osteoporosis ＊7○＊7

Benign prostate hypertrophy ○

Disadvantages of diuretics: Diuretics may cause a varietyof unwanted effects, such as hypokalemia, elevation ofserum LDL-cholesterol levels, decrease of HDL-cholesterollevels, elevation of blood uric acid levels, reduced glucosetolerance, ventricular ectopic beats and impotence. However,these adverse effects are infrequently recognized with lowdoses. Because glucose tolerance and renal function declinewith aging, blood chemistry examinations should be con-ducted periodically.

2) Hypertension with ComplicationsIn hypertensive patients with complications, the first-choicedrug should be selected according to the complications rec-ognized. Table 9 lists the first-choice and contraindicateddrugs for the complications frequently recognized in the el-derly.

6-4. Combination Therapy

Combination therapy should be considered when monothera-py is not successful in reducing blood pressure (Fig. 1).

The following combinations of antihypertensive drugs arerecommended: Ca antagonist＋ACE inhibitor/ARB; Ca an-tagonist＋low dose diuretic (128); ACE inhibitor/ARB＋lowdose diuretic; or a combination of the drugs of first choice.Other antihypertensive drugs, such as β-blockers, α -block-ers, or αβ -blockers, may be used if necessary (Fig. 1).

6-5. Antihypertensive Drugs to Be Prescribed withCaution in the Elderly

Drugs acting on the central nervous system, such as reser-pine, methyldopa, clonidine are relatively contraindicatedfor hypertension in the elderly. In Japan, β-blockers andα -blockers have generally not been used for hypertension inthe elderly, because elderly hypertensive patients frequentlyhave complications for which these drugs are contraindicatedor for which β-blockers are to be used only under specialconditions.(1) Precautions on β-blockers: Because cases of hypertensionin the elderly are often complicated by congestive heart fail-ure, bradycardia, arteriosclerosis obliterans, chronic obstruc-tive pulmonary disease, diabetes mellitus, or impaired glu-cose tolerance, β-blockers are contraindicated or should beprescribed with extreme caution, as indicated above (13).These complications may be present in an occult form in theelderly.(2) Precautions on α -blockers: In elderly hypertensive pa-tients, α -blockers should be prescribed cautiously becausethey frequently induce postural hypotension due to decreasedreflex function of the baroreceptor. Postural hypotensionmay cause dizziness and syncope, occasionally resulting infalls and bone fracture.

The ALLHAT Collaborating Research Group has indicat-ed that, compared with diuretics, α -blockers significantly in-

crease the risk of congestive heart failure (129). According-ly, α -blockers should not be prescribed alone in elderly hy-pertensive patients with latent heart failure.

7. Antihypertensive Treatment of Elderly Hypertensive Patients with Complications

7-1. Cerebrovascular Diseases

Treatment of hypertension complicated by cerebrovasculardiseases is aimed at preventing the progression of brain ischemia and edema, and re-bleeding or expansion ofhematoma in the acute hemorrhagic stroke, and at reducingthe recurrence of stroke in the chronic phase. In this regard,it is important that antihypertensive treatment should be madewith careful consideration given to cerebral hemodynamicsand age.

1) Hypertension and Cerebral CirculationAutoregulation of the brain keeps cerebral blood flow con-stant within a certain range against blood pressure alter-ations. In hypertensive patients, however, the upper and low-er limits of autoregulation are shifted to a higher blood pres-sure level (130). When complicated with cerebrovasculardiseases, cerebral blood flow at rest is reduced not only inthe related lesions but also in other areas of the brain (131).Because of advanced arteriosclerotic changes and reducedvasodilator capacity of the brain, antihypertensive treatmenthas limitations for improving cerebral blood flow and its autoregulation.

2) TreatmentTreatment of elderly hypertensives with cerebrovascular dis-eases differs according to the phase (acute or chronic) andtype of stroke (cerebral hemorrhage, cerebral thrombosis,cerebral embolism, etc.). Before treatment, therefore, it isnecessary to determine the type of stroke by means of med-ical history, clinical findings and brain imagings, includingCT and MRI, as well as by other examinations. It is also im-portant to detect stenosis or occlusion of the major arteriesby means of non-invasive examinations such as carotid ultra-sonography, trans-cranial ultrasonography, or magnetic reso-nance angiography (MRA), followed by conventional an-giography, if necessary. In the case of cerebral embolism,echocardiography is necessary for detecting the embolicsource in the heart.

a. Acute phaseBlood pressure is elevated at the acute phase of stroke, re-gardless of bleeding or infarction, which may be induced byacute stress or reaction to compensate for reduced cerebralperfusion pressure due to increased intracranial pressure. Inaddition, since the elevation of blood pressure in the acutephase may gradually fall with time even in the absence oftreatment, aggressive antihypertensive treatment is not nec-


essary. Cerebral autoregulation is impaired in the acutephase, and then cerebral blood flow becomes dependent onblood pressure, easily resulting in cerebral ischemia due toreduction of blood pressure (132). On the other hand,marked elevation of blood pressure may cause aggravationof cerebral edema. Antihypertensive treatment in patientswith cerebral hemorrhage should be started with carefulmonitoring of neurological signs and symptoms in the fol-lowing cases: when the systolic blood pressure exceeds180–200 mmHg and persists at that level, or when there is aprobability of aggravation of brain edema, expansion ofhematoma or re-bleeding, or worsening of cardiac failure,ischemic heart diseases, or aortic aneurysm.

Blood pressure should be controlled gradually by intra-venous administration of nicardipine, diltiazem or nitroglyc-erin. Special care should be given in the use of these drugs,since they may increase intracranial pressure. Short-actingCa antagonists, such as sublingually administered nifedipine,are not indicated, because of the danger of a rapid, unexpect-ed blood pressure fall. Blood pressure should be lowered toaround 80% of the pretreatment blood pressure, but not tonormotensive levels. On the other hand, antihypertensivetreatment is generally not recommended in the case of cere-bral infarction. However, antihypertensive drug treatmentmay be required when systolic blood pressure is 220 mmHgor greater or the mean pressure exceeds 130 mmHg (133). Inthis case, blood pressure should be lowered gradually toaround 85–90% of the pretreatment blood pressure. In pa-tients who receive thrombolytic therapy and have a bloodpressure of over 180 mmHg systolic and 105 mmHg dias-tolic, especially when these blood pressures rise within thefirst 24 h of thrombolytic therapy, antihypertensive drugsshould be administered intravenously for preventing hemor-rhagic events while carefully monitoring neurological symp-toms (14).

b. Chronic phaseWhen hypertension persists for more than 1 month afteracute strokes, antihypertensive treatment should be initiatedwhile taking account of blood pressure level, age and the ex-tent of brain damage and other organ damages irrespective ofhemorrhage or infarction. However, when hypertension doesnot directly aggravate the circulatory system in the very el-derly aged 85 yr or older, lifestyle modification alone is indi-cated. With regard to the secondary prevention of stroke byantihypertensive drug treatment, we refer to the recentlypublished Perindopril Protection against Recurrent StrokeStudy (PROGRESS) (134). In PROGRESS, over the courseof a 4-yr follow-up period, active treatment based on ACEinhibitors reduced blood pressure 9 mmHg in systolic and 4mmHg in diastolic, and a 28% reduction in the recurrencerate of stroke was observed compared to the placebo group.Moreover, a similar reduction of stroke risk was observed inboth the hypertensive and non-hypertensive subgroup. Thesefindings suggest that antihypertensive treatment may reduce

the risk of stroke recurrence. Since the mean age in thisstudy was 64 yr, a sub-analysis in the elderly would be ofuse, as would a sub-analysis in Japanese.

The initial blood pressure target levels for patients withchronic-phase stroke should be set at below 150–170 mmHgsystolic and below 90–100 mmHg diastolic. Since cerebralhemorrhage is more closely related with hypertension thancerebral infarction, the target levels of blood pressure shouldbe set slightly lower. Since a J-curve phenomenon betweendiastolic blood pressure and the recurrence rate of cerebralinfarction has been reported (93), blood pressure should notbe lowered excessively. Rather, blood pressure should be re-duced gradually, and drug treatment should be started at halfthe usual doses and increased at intervals of 4 weeks orgreater. Thus 2–3 months will be required to achieve the tar-get blood pressure, and monitoring for the possible onset ofcerebrovascular insufficiency should be performed through-out this period. Based on the results of PROGRESS, an ap-propriate final target blood pressure may be less than 140mmHg systolic and less than 90 mmHg diastolic. However,the target blood pressure should be slightly lower in patientswith cerebral hemorrhage or lacunar infarction, and slightlyhigher in those with atherothrombotic infarction.

Atherothrombotic cerebral infarction showing a watershedinfarct commonly occurs in cases with stenosis or occlusionof the internal carotid or other intracranial major arteries,and thus such patients should be treated more cautiously, bymaintaining a slightly higher blood pressure level than inthose with lacunar infarction. Antihypertensive drug therapymay have to be reduced in dosage or discontinued if over-dose is suggested by clinical symptoms such as dizziness,fainting, a sensation of heaviness in the head, or a decreasein memory and vitality suggesting insufficient cerebral perfu-sion, and then surgical treatment (carotid endatherectomy,extra- and intracranial bypass) may be considered. The thera-peutic target blood pressure must be determined for each in-dividual patient through careful monitoring of symptoms,signs, and laboratory test results. In addition to hypertension,other risk factors for cerebral infarction, such as diabetesmellitus, hyperlipidemia, smoking, alcohol intake, etc., mustbe controlled.

c. Selection of antihypertensive drugs at the chronic phaseAntihypertensive drugs must be selected in consideration oftheir direct and indirect pharmacological effects against cere-bral vessels and metabolisms. Antihypertensive drugs withadverse effects against cerebral circulation and metabolism(i.e., reduction of cerebral blood flow) or the brain functionshould be avoided.

Dihydropyridine Ca antagonists have been demonstratedto dilate the cerebral arteries and increase cerebral bloodflow in addition to contributing an antihypertensive effect(135), and certain long-acting Ca antagonists may improveor shift the lower limit of the autoregulation to the left (136).Benzothiazepine Ca antagonists may cause bradycardia,


atrio-ventricular block or reduction of cardiac output due tosuppression of cardiac function, any of which may be harm-ful to the brain. ACE inhibitors shift the lower limit of cere-bral autoregulation to the left with a slight increase in cere-bral blood flow (137). Furthermore, ACE inhibitors improvethickening of vascular walls and have no adverse effects onthe metabolic or central nervous system. In PROGRESS,ACE inhibitors were used as the first-line drugs incombination with diuretics and the recurrence of stroke wasdecreased, so ACE inhibitors can be considered first-linedrugs for the chronic phase of stroke (134).

Acute administration of classical β-blockers reduces cere-bral blood flow; however, chronic administration does notsubstantially change cerebral blood flow (138). β-Blockersshould be avoided in patients with congestive heart failure,atrio-ventricular block or bradycardia. They are, however,suitable for patients with old myocardial infarction or effortangina pectoris. β-Blockers with vasodilatory action may increase cerebral blood flow and improve the lower limit ofautoregulation (139). α -Blockers and αβ -blockers may increase cerebral blood flow by direct effects on cerebralblood vessels richly innervated with sympathetic nerves, andlong-acting α -blockers may be used even in the elderly.However, α -blockers often induce orthostatic hypotensionby blocking the peripheral sympathetic nerves, and thus theyshould be started at small doses and titrated with frequentmonitoring of standing blood pressure. Since diuretics maycause electrolyte imbalance or metabolic disorders in addi-tion to reduced cerebral blood flow by increased hematocrit,they should be prescribed in small doses to minimize theiradverse effects. Sometimes potassium supplementation maybe required. Because, in the PROGRESS report, combina-tion therapy with diuretics and ACE inhibitors resulted in agreater reduction in recurrence of stroke than monotherapy,treatment with both drugs should now be considered as apromising option for patients with a history of stroke.

Anti-platelet drugs (aspirin or ticlopidine) or anti-coagu-lants (warfarin) are also recommended in order to preventthe recurrence of artery-to-artery embolism in atherothrom-botic infarction, or cardiogenic embolism with atrial fibrilla-tion.

7-2. Ischemic Heart Diseases

Hypertension is well known as one of the important risk fac-tors for ischemic heart diseases, as demonstrated by theFramingham and many other studies (140). Hypertension notonly causes acceleration of coronary atherosclerosis, but alsofrequently causes cardiac hypertrophy due to continuous me-chanical overload. In the hypertrophied heart, myocardialoxygen consumption is increased due to an afterload in-crease, and coronary flow reserve is decreased due to insuffi-cient proliferation of the coronary capillaries and a decreasein reflex vasodilatation of the coronary arteries (141–143).Thus, both coronary atherosclerosis and cardiac hypertrophy

strongly influence the pathogenesis of ischemic heart dis-ease.

1) DiagnosisThe clinical symptoms of ischemic heart disease in the elder-ly are often atypical. In addition, the frequency of asympto-matic myocardial ischemia is high in the elderly. Nearly one-half of patients with myocardial infarction do not experiencechest pain, and many cases begin with cognitive disorders,disturbance of consciousness or other symptoms suggestiveof heart failure. Non-invasive diagnostic procedures foracute myocardial infarction include electrocardiography,echocardiography, blood CPK-MB and troponin-T. Ischemicevidence in cases of effort angina pectoris, unstable anginapectoris and old myocardial infarction can be confirmed bystress electrocardiography, Holter electrocardiography, myo-cardial scintigraphy, or echocardiographic evaluation of ventricular wall motion, and these laboratory tests are alsouseful in follow-up studies.

2) TreatmentTreatment of hypertension complicated with ischemic heartdiseases is aimed at prevention of angina attacks, develop-ment of myocardial infarction, and recurrence of myocardialinfarction, and at maintenance of cardiac functions by theprevention of left ventricular remodeling. Therefore, selec-tion of antihypertensive drugs must be based not only ontheir ability to lower blood pressure, but also on other effectsagainst coronary atherosclerosis, coronary blood flow, car-diac load and myocardial protection.

a. Therapeutic target blood pressureAntihypertensive drug therapy is given to patients with asystolic blood pressure of 160 mmHg or greater and adiastolic blood pressure of 90 mmHg or greater. The targetblood pressures are a systolic blood pressure of below 140mmHg and a diastolic blood pressure of below 90 mmHg.However, excessive reduction of blood pressure may result indevelopment of ischemic heart diseases, and thus bloodpressure must be carefully controlled. Even the PATE-Hypertension report (11), in which the incidence ofcardiovascular events was compared between patients treatedwith a Ca blocker and those treated with an ACE inhibitor,suggested that an excessive reduction to less than 130 mmHgin systolic blood pressure may increase the incidence ofcardiovascular events. In addition, the occurrence of ischemiacould be influenced by a low nocturnal blood pressure valueof below 110/70 mmHg in hypertensive patients (144).

b. Selection of antihypertensive drugsβ-Blockers and long-acting Ca antagonists are recommend-ed for hypertension complicated with effort angina becausethese drugs decrease cardiac afterload of the left ventricleand reduce myocardial oxygen consumption. ACE in-hibitors/ARBs are the first choice in cases with myocardial


infarction because of their inhibitory action against leftventricular remodeling (145).(1) Ca antagonists: Dihydropyridine Ca antagonists lowerblood pressure remarkably and increase coronary blood flowwith little effects on glucose or lipid metabolisms, and thusthey are suitable for cases of hypertension complicated byangina pectoris. Long-acting Ca antagonists are suitable forpatients with rest angina and unstable angina, because theyinhibit coronary spasms. Benzothiazepine Ca antagoniststend to inhibit cardiac functions and induce bradycardia, andthus should be used cautiously in elderly patients. Caantagonists usually do not improve the prognosis ofhypertension after myocardial infarction (146), but may beeffective in combination with ACE inhibitors. Amlodipineshowed no demonstrable effect on angiographic progressionof coronary atherosclerosis but was significantly associatedwith fewer ischemic events for unstable angina andrevascularization compared with the placebo group in thePREVENT study, which was designed to test whetheramlodipine would slow the progression of early coronaryatherosclerosis in patients with angiographically documentedcoronary artery disease (147).(2) β-Blockers: β-Blockers have both negative chronotropicand negative inotropic effects, decrease myocardial oxygenconsumption caused by decreased heart rate and myocardialcontractility, and are effective for angina with improvedmyocardial ischemia. β-Blockers are especially effective forhypertension complicated with unstable angina and effortangina associated with severe coronary stenosis, becausethey effectively decrease increased heart rate and elevatedblood pressure on physical exercise and increase exertionaltolerance. However, they are contraindicated for coronaryspasm, because they worsen the clinical symptoms of thisdisease. β-Blockers without intrinsic sympathomimeticactivity (ISA) have superior cardiac protective effects, and areknown to effectively prevent the recurrence of myocardialinfarction (148). They are contraindicated, however, forpatients with bronchial asthma or chronic obstructivepulmonary diseases, and should be used cautiously for thoseelderly patients whose cases are frequently complicated byconduction disorders, bradycardia or cardiac failure.(3) ACE inhibitors: ACE inhibitors not only decrease cardiacafterload by decreasing total peripheral vascular resistance,but also protect the myocardium, inhibit left ventricularremodeling (145), and improve the prognosis of cardiacfailure (149). Therefore, ACE inhibitors are the first choicefor patients with cardiac failure complicated by hypertensionafter myocardial infarction. ACE inhibitors significantlyreduced the rates of heart failure, myocardial infarction, andangina pectoris in a broad range of high-risk patients whodid not have a low ejection fraction but showed evidence ofvascular diseases in the HOPE trial (119). They have alsobeen suggested to exert antiatherosclerotic and vascularprotective effects. However, they should be used with specialcaution for cases with moderate or severe renal failure

(serum creatinine over 2.0 mg/dl), and a small initial doseshould be prescribed in elderly patients who commonly ex-hibit latent renal insufficiency.(4) Diuretics: Diuretics show excellent antihypertensiveeffects in the elderly, and are expected to inhibit cardiachypertrophy and dilatation. Interventional megatrialsperformed in Western countries have also confirmed theefficacy of diuretics for treatment of hypertension in theelderly (6, 7). However, care must be taken with regard totheir various side effects, such as hyperlipidemia, glucosemetabolic disorders, dehydration and, in cases with cardiachypertrophy, arrhythmia due to hypokalemia.(5) α -Blockers: α -Blockers exert vasodilative effects onboth arteries and veins, and thus reduce cardiac load; theyhave no adverse effects on glucose or lipid metabolisms.However, elderly patients administered α -blockers are likelyto develop orthostatic hypotension, and thus these drugsshould be prescribed cautiously with a small initial dose.(6) Nitrites: Oral nitrites are effective for preventing anginalattacks. Continuous intravenous infusion of nitrites is mostsuitable in the acute stage of myocardial infarction associatedwith hypertension.

7-3. Heart Failure

Hypertension causes cardiac hypertrophy and ischemic heartdiseases due to acceleration of coronary atherosclerosis anddecreased coronary reserve, and both cardiac hypertrophyand ischemic heart diseases play an important role in the de-velopment of heart failure. In elderly patients, distensibilityof the left ventricle is decreased in spite of its normal con-tractility (150, 151), and heart failure will develop as a resultof either atrial fibrillation or flutter in the absence of any un-derlying disease, arrhythmia due to conduction defects or leftventricular diastolic disorder due to cardiac amyloidosis.

1) DiagnosisOccasionally, heart failure in the elderly may be accompa-nied by cerebral symptoms such as disturbance of conscious-ness, disorientation, or delirium. Chest X-ray films can beused to detect cardiac enlargement, increased pulmonaryvascularity, changes in pulmonary interstitial tissue or pleur-al effusion. Cardiac function can be easily evaluated andmonitored by means of echocardiography and the determina-tion of peripheral venous pressure (normally 5–10 cmH2O).Electrocardiography is useful for diagnosing ischemic heartdiseases, cardiac hypertrophy, arrhythmia and conductiondefects.

2) TreatmentTreatment of heart failure is aimed at reducing cardiac work,correcting over-hydration, and increasing myocardial con-tractility. Any diseases underlying heart failure should becarefully evaluated.


a. Hypertension associated with acute left-ventricular failureAcute left-ventricular failure constitutes a hypertensiveemergency, and should be corrected with antihypertensivetreatment by reducing cardiac afterload and myocardial oxy-gen consumption and thereby increasing cardiac output. Itcan be treated effectively by oral administration of ACE in-hibitors or continuous intravenous infusion of nitrites or Caantagonists (nicardipine) in combination with intravenous in-jection of furosemide. In elderly patients, however, specialprecautions must be taken to avoid development of reducedblood flow of the coronary arteries, brain and kidneys due toacute reduction of blood pressure. Blood pressure reductionof more than 20% should not be planned at first. Antihyper-tensive treatment with a target reduction to 160/100 mmHgafter 2–6 h is recommended. Treatment with heparin forthrombosis prevention should also be considered (14, 152).

b. Hypertension associated with chronic heart failureLeft ventricular distensibility is decreased even in thehealthy elderly, and the elderly with cardiac diseases fre-quently develop heart failure even though left ventricularcontractility remains normal. Cardiac hypertrophy evenwithout coronary stenosis is prone to develop into myocar-dial ischemia due to decreased coronary flow reserve that isdue, in turn, to insufficient coronary vasodilatation and rela-tively reduced coronary capillary proliferation (141–143).Therefore, treatment of hypertension is aimed at first regress-ing cardiac hypertrophy and then protecting the myocardi-um, in order to maintain and improve cardiac functions andcoronary blood flow. In principle, the therapeutic targetblood pressures will be the normal levels (below 140/90mmHg).

c. Selection of antihypertensive drugs(1) Diuretics: Hypertension complicated with pulmonaryedema, pleural effusion or peripheral edema is treated mainlywith loop diuretics, because they decrease venous bloodflow and venous blood pressure, resulting in improvement ofedema. In addition, they improve pulmonary congestion bydecreasing pulmonary capillary wedge pressure. Decrease inend-diastolic volume due to diuresis causes a decrease inpreload and hence decreases in cardiac work and myocardialoxygen consumption, enabling the improvement of heartfailure. Special care should be given in cases of elderlypatients with dehydration, decreased cerebral or renal bloodflows due to diuresis, or arrhythmia due to hypokalemia,the latter of which may necessitate administration of analdosterone antagonist. It has been proved that spironolactonesubstantially reduces the risk of both morbidity and mortalityamong patients with severe heart failure (153). Diuresisshould be attempted gradually, as rapid dehydration maytrigger formation of thrombosis.(2) ACE Inhibitors: ACE inhibitors are effective forvasodilatation in both arteries and veins, resulting in reducedcardiac loading, myocardial protection, and then improvement

of the prognosis of heart failure (149). Thus, ACE inhibitorsare extremely useful antihypertensive drugs, and should bethe first-choice drugs in cases with heart failure. In thoseelderly patients who frequently experience renal dysfunction,a small initial dose is recommended.(3) ARBs: The ELITE II study showed that ARBs are aseffective as ACE inhibitors for improving the prognosis ofheart failure (123). Furthermore, ARBs have now been madeavailable because they have a lower incidence of adverseeffects than ACE inhibitors. The efficacy of combinationtherapy with both drugs is currently under investigation.(4) β-Blockers: Carvedilol has been shown to improve theprognosis of chronic heart failure due to left ventricularsystolic dysfunction (154). Usually, a small initial dose ofβ-blockers (metoprolol, bisoprolol) is recommended,followed by gradually increased doses, and this regimencould be utilized by many cardiologists. However, theindication of β-blockers in the elderly should be limited,especially for the patients whose cases are complicated with obstructive pulmonary diseases, arteriosclerosis obliterans,diabetes mellitus or bradycardia.(5) Ca antagonists: Ca antagonists are arterial vasodilators.Their marked peripheral vasodilatation decreases themyocardial oxygen consumption due to decrease in cardiacafterload, and increases coronary blood flow due to coronaryvasodilatation. Long-acting Ca antagonists (amilodipine orfelodipine) do not aggravate the prognosis of non-ischemicheart failure (155).(6) α -Blockers: Based on the primary outcomes of theALLHAT, prescription of α -blocker alone should be avoidedfor the treatment of heart failure (129).

7-4. Diabetes Mellitus

Hypertension is commonly complicated with diabetes mellitusor vice versa (156). In addition, the morbidity of hyperten-sion and glucose metabolic abnormality increase with aging(157, 158), and thus hypertension in the elderly is frequentlyassociated with glucose metabolic abnormality. It has beensuggested that essential hypertension and glucose/lipidsmetabolic disorders belong to so-called insulin-resistant syn-drome in cases where there is a background of insulin resis-tance (159), and elderly patients are known to have de-creased insulin sensitivity (156). Cases of diabetes mellitusassociated with essential hypertension are mostly type 2(non-insulin dependent) diabetes mellitus (NIDDM) both inelderly and non-elderly patients. The pathogenesis of type 2diabetes mellitus is known to be related to both decreased in-sulin secretion and increased insulin resistance based on ag-ing and heredity. The etiology and pathogenesis of essentialhypertension are likely to be related also to decreased insulinsensitivity and hyperinsulinemia, and the complications ofdiabetes mellitus and/or obesity decrease insulin sensitivity.The complications of diabetes mellitus in cases of hyper-tension increase the incidence of atherosclerotic diseases,


and thus hypertension must be more strictly controlled insuch cases (14). Essential hypertension complicated with di-abetes mellitus is pathophysiologically characterized by in-creased body fluid and decreased renin-angiotensin systemand sympathetic nerve activity (160). When complicatedwith diabetic nephropathy, hypertension is more influencedby renal involvement, causing marked increases in body flu-id and sodium (160). Furthermore, hypertension itself causesaggravation of diabetic nephropathy, prevention of which in-volves adequate management of hypertension and glomeru-lar hyperfiltration.

1) DiagnosisGlucose tolerance reduces with aging, but usually remainsrelatively mild. Therefore, the diagnostic criteria of diabetesmellitus in the elderly may be the same as in the young andmiddle-aged, i.e., fasting plasma glucose levels of 126 mg/dlor greater, postprandial glucose levels of 200 mg/dl orgreater or 200 mg/dl or greater at 2 h after the glucose toler-ance test, which levels should be confirmed twice on otherdays, according to the Japanese Diabetes Association guide-lines. However, plasma glucose levels after oral glucose in-take will definitely increase with aging, and the diagnosis ofdiabetes mellitus should be made carefully if diagnosed onlyby an oral glucose tolerance test.

2) TreatmentThe therapeutic target levels of blood pressure are a systolicblood pressure of below 140 mmHg and diastolic blood pres-sure of below 90 mmHg. In the absence of any urgency,lifestyle modifications are considered first, followed by addi-tion of antihypertensive drug therapy if improvement isinsufficient. In the JNC VI, WHO/ISH and JSH 2000, it isrecommended that the therapeutic target blood pressure levelshould be lower than 130/85 mmHg in hypertension com-plicated with diabetes mellitus, and this target has recentlyobtained wide acceptance. Accordingly, diabetes mellitus inelderly hypertensives should be treated similarly as in theyoung and middle-aged (161).

a. Lifestyle modificationObesity is prevalent among hypertensive cases complicatedwith type 2 diabetes mellitus (162). Weight reduction by re-striction of dietary calories is indispensable for obese pa-tients, and it is useful not only for improvement of glucosemetabolism but also for lowering blood pressure. Inpractice, patients are advised to reduce their weight by di-etary and exercise treatments, and by avoiding foods withhigh cholesterol and saturated fatty acids. Salt restriction isexpected to lower blood pressure, but it should be made cau-tiously in patients with orthostatic hypotension due to diabet-ic neuropathy in elderly patients, who are generally prone toblood volume depletion.

b. Antihypertensive drug therapyBecause ACE inhibitors/ARBs or Ca blockers increase in-sulin sensitivity, these drugs should be used as the firstchoice in cases of elderly hypertensive patients complicatedwith diabetes mellitus. In fact, in the Intervention as a Goalin Hypertension Treatment (INSIGHT) trial, which used di-uretics or a Ca blocker with a mean follow-up period of fouryears, the frequency of new diabetic cases among patientstreated with Ca blockers was 23% lower than that in the di-uretic-treated group (163). Both the HOPE (119) and CAPPP(120) trials have shown that the frequency of new diabeticcases in the ACE inhibitors group was lower than that in theplacebo or diuretic/β-blockers group. Diuretics and β-block-ers decrease insulin sensitivity and may cause deleterious ef-fects on glucose/lipids metabolism (164). Although, α -blockers increase insulin sensitivity and improve lipids me-tabolism, α -blockers should be used cautiously because theyfrequently induce postural hypotension.

Recently, several sub-analyses of large-scale interventiontrials of diabetic patients with isolated systolic hypertensionhave been reported—i.e., analyses of the SHEP, Syst-Eurand STOP-Hypertension 2 trials—and have shown that treat-ment of elderly hypertensive diabetic patients with conven-tional antihypertensive drugs (low doses of diuretics, β-blockers, or both) is as effective as treatment with newerdrugs such as Ca blockers or ACE inhibitors in terms ofachieving reductions in cardiovascular events (165–167).ACE inhibitors may act to protect the kidneys in diabeticnephropathy, but may deteriorate renal function in the caseswith serum creatinine of over 2.0 mg/dl. Special care shouldbe taken when prescribing α -blockers in cases of hyperten-sion with diabetic neuropathy, since they may cause ortho-static hypotension. Diuretics should be prescribed at lowdose with careful monitoring of their serum potassium anduric acid levels.

In hypertensive patients with ischemic heart disease, β-blockers may be used if necessary. However, among hyper-tensive patients treated with oral hypoglycemic agents or es-pecially insulin, β-blockers should be prescribed cautiouslybecause they may mask or prolong hypoglycemic symptoms.

Summarizing the confirmed outcomes of trials and stud-ies, the recommended first-choice antihypertensive agentsare ACE inhibitors and Ca antagonists, which may improveglucose metabolism and protect against cardiovascularevents. Very recently, ARBs have been reported to be effec-tive in delaying the progression of diabetic nephropathy andreducing cardiovascular events, especially strokes, suggest-ing the possibility that this class of drug will be one of thefirst-line antihypertensive drugs (168). α-Blockers, β-block-ers or diuretics may be used based on the individual diabeticcomplications/organ damages and added as the second- orthird-line hypotensive drugs.


7-5. Renal Diseases

Hypertension associated with renal diseases is classified into those cases with chronic glomerulonephritis, those withdiabetic nephropathy and those with nephrosclerosis (so-called hypertensive renal diseases). Renovascular hyperten-sion may be encountered in association with renal arte-riosclerosis in the elderly, especially in bilateral renal arterialstenosis resulting in decreased renal function (ischemicnephropathy). The terminal stage of renal diseases is knownas uremia, and the most common reason for hemodialysis inJapan is now diabetic nephropathy. For the past 10 or moreyears, the number of cases of diabetic nephropathy andnephrosclerosis has nearly doubled (169). Cases of mild ormoderate hypertension are frequently associated with cere-brovascular diseases and cardiac diseases, but only rarelywith renal diseases. However, renal insufficiency may pro-ceed even in cases of mild hypertension (170). Hypertensionis definitely a risk factor for development of renal insuffi-ciency, regardless of the type of renal insufficiency, andshould be treated sufficiently to lower blood pressure.

1) DiagnosisIt is well known that renal function decreases with age evenin healthy individuals, and in the very elderly it is thought todecrease to roughly 50% of the level in young individuals(171). In hypertension in the elderly, associated renal dis-eases are closely related to both hypertension and renal arte-riosclerosis. Renal function tests necessary at the initial visitinclude urinalysis and blood chemistry tests (serum creati-nine, urea nitrogen, electrolytes and uric acid). In addition,routine examinations, such as chest X-ray, electrocardiogra-phy and, if possible, echocardiography and abdominal ultra-sonography, should be performed in order to detect any car-diovascular diseases. If necessary, creatinine clearance mayalso be assessed to evaluate glomerular filtration rate (GFR),since serum creatinine levels, particularly in the elderly, maybe within a normal range even though renal insufficiency ex-ists. Renovascular hypertension should be ruled out in hyper-tensives showing rapid onset, resistance to treatment or pro-gressive renal insufficiency.

2) TreatmentIn hypertension with renal diseases, non-pharmacologicaltreatment, particularly dietary treatment, is required. It ismost important to reduce salt intake. However, it is risky toreduce salt intake rapidly. Accordingly, the target value forsalt intake should be set at about 7 g/day, and reduced gradu-ally, based on monitoring of the serum creatinine value.

Restriction of protein intake (30–60 g/day, 0.5–0.8g/kg/day) may be required depending on the severity of renalinsufficiency and salt intake (3–6 g/day) based on bloodpressure levels and edema. Frequency of hypertensive renaldiseases in hypertensives is not as high as that of cerebrovas-cular and cardiac diseases. However, it has been reported

that cases with blood pressure higher than 140/90 mmHgpromote renal insufficiency faster than those with normal oradequately controlled blood pressure (172), and thus evenmild hypertension may promote renal diseases. Elevation ofintraglomerular pressure might exist from the early stages ofdiabetic nephropathy, and in such cases relates the progres-sion of renal diseases. Therefore, the therapeutic target bloodpressure should be set a little lower, to below 140–150/90mmHg, in hypertension complicated with renal diseases. TheJNC VI guidelines recommend a therapeutic goal of below130/85 mmHg in the cases with proteinuria below 1 g/day,and of below 125/75 mmHg in those with proteinuria of 1g/day or more (172). The so-called “J-curve phenomenon”has not been recognized between lowering of blood pressureand progression of renal insufficiency, but renal functionshould be monitored carefully in elderly hypertensives, sinceelevation of serum creatinine is commonly experienced inassociation with rapid lowering of blood pressure. A morethan 50% decline of renal function may be expected in caseswith serum creatinine of over 1.3 mg/dl, and such patientsshould be monitored by measuring the serum creatinine andelectrolytes every 1–6 months.

a. Selection of antihypertensive drugsDiuretics, ARBs, ACE inhibitors and Ca antagonists aremainly prescribed in cases of hypertension associated withrenal insufficiency. A small dose of diuretics is recommend-ed for the cases with body fluid retention, and at a serum cre-atinine level of over 1.5–2.0 mg/dl, loop diuretics are usedinstead of thiazide diuretics. ACE inhibitors are used for el-derly hypertensives with mild renal dysfunction, and are ex-pected to demonstrate long-term protection of the kidneys bydecreasing systematic and intraglomerular blood pressure.Their effectiveness has also been proved clinically in diabet-ic nephropathy (173). However, ACE inhibitors should becarefully used for cases with moderate renal dysfunction(serum creatinine over 2.0 mg/dl), which they may furtheraggravate, and in such cases should be monitored at mostcautiously serum creatinine and potassium levels.

Bilateral renovascular hypertension should be ruled out ifa rapid decline of renal function is recognized in an elderlypatient. Ca antagonists have a mild diuretic action, and maybe widely applicable, regardless of the severity of renal dys-function, so they could be used in combination with ACE in-hibitors or ARBs. Most β-blockers do not significantly influ-ence renal function, although some are reported to decreaserenal blood flow (RBF) and GFR; those with trans-hepaticexcretion are preferred. Vasodilators and sympatholyticdrugs may result in body fluid retention, and may be effec-tive in combination with a small dose of diuretics. α-Block-ers are well indicated for elderly patients with prostatic hy-pertrophy, but should be followed up for orthostatic hypoten-sion in cases with renal insufficiency due to diabeticnephropathy.


7-6. Hyperlipidemia

Hyperlipidemia and hypertension, as well as diabetes melli-tus, obesity and smoking, are important risk factors for de-velopment of arteriosclerosis, and because the combinationof hypertension and hyperlipidemia may aggravate arte-riosclerosis, these conditions should be adequately con-trolled. In the elderly, aging itself is one of the important riskfactors for atherosclerosis, and in elderly subjects, hyperlipi-demia has been considered less important in arteriosclerosisthan in middle-aged or younger subjects. However, manystudies have demonstrated that hyperlipidemia in the elderlyalso synergistically increases the morbidity of ischemic heartdiseases (174).

Hypo-HDL-cholesterolemia is also considered to be oneof the important risk factors for atherosclerosis (175). Noconclusive report has yet been made as to whether hyper-triglyceridemia is an independent risk factor for atheroscle-rosis. At present, it is reasonable to suppose that hyper-triglyceridemia in the elderly would be a risk factor whenhypercholesterolemia, hypo-HDL-cholesterolemia, impairedglucose tolerance and obesity are present at the same time.

1) DiagnosisAccording to the Practice Guidelines for Hyperlipidemia re-ported in 1997 (176), the diagnostic criteria for hyperlipi-demia include a serum total cholesterol of 220 mg/dl orgreater, triglyceride of 150 mg/dl or greater, and HDL-cho-lesterol of below 40 mg/dl. These diagnostic reference val-ues may be applied also for the elderly. Hyperlipidemiashould be differentiated into primary and secondary (diabetesmellitus, hypothyroidism, drug-induced, etc.) types.

2) TreatmentBecause elderly subjects often have multiple pathologicaldisorders, antihypertensive drugs should be used carefullywith consideration to each patient’s condition. Ca antag-onists or ACE inhibitors are recommended for treating hy-pertensives who also manifest hyperlipidemia, because thesedrugs are more beneficial for lipid metabolism than other an-tihypertensive drugs. α-Blockers, which also favor lipid me-tabolism, should be cautiously used for elderly patients,since they often manifest orthostatic hypotension. Becausethe ALLHAT trial showed that more heart failure occurredin patients treated with α-blockers than diuretics, α-blockersare better not used for elderly who potentially have de-creased cardiac function. ARBs are considered as effectiveas ACE inhibitors for treating hypertension complicated withhyperlipidemia in the elderly, though the evidence of thisparity is still limited.

Target blood pressure for patients with hyperlipidemiashould be less than 140/90 mmHg if possible.

In cases in which hypertension has been treated and hy-perlipidemia still cannot be corrected by lifestyle modifica-tions such as diet and exercise, antihyperlipidemic drugs are

better prescribed. The following drugs should be used care-fully for elderly: constipation with cholestyramine, lowHDL-cholesterol with probucol, elevated creatine phosphok-inase (CPK) and rhabdomyolysis with HMG-CoA reductaseinhibitors, and facial hot flush with nicotinates.

7-7. Vascular Complications

1) Arteriosclerosis Obliterans (ASO)Patients with intermittent claudication, the most characteris-tic symptom of ASO, complain of weakness and pain in theunilateral or bilateral extremities on walking, and eventuallyare unable to walk due to painful twitching of the lower ex-tremities. Hypertensive patients complicated with ASOshould be treated with antihypertensive drugs which improveblood circulation.

a. DiagnosisMorbidity of ASO increases with aging, but many elderlypatients may not complain of typical intermittent claudica-tion or ischemic symptoms because of their low physical ac-tivity (177). Therefore, physical examination of elderly hy-pertensive patients at the first visit should include carefulpalpation of the upper and lower extremities, especially thefemoral, popliteal and dorsal arteries, to rule out ASO. IfASO is suspected, blood flow in the corresponding areasshould be measured using a Doppler flowmeter. Togetherwith a careful analysis of the patient’s medical history, anankle brachial systolic blood pressure index (ABI) of lessthan 0.9 confirms the diagnosis (178).

During the follow-up encounters, patients are carefullymonitored for any change in subjective complaints, and bypalpation of the extremities and non-invasive perfusion pres-sure measurement. ASO is usually classified by Fontaine’sclassification as follows: stage I, no symptoms or mild coldflush and numbness; stage II, intermittent claudication; andstage III, cases in which the walking distance is decreased tobelow 30 m with pains or in which there is pain at rest due tochronic ischemia, and which require surgical treatment.

b. TreatmentAll patients should be advised to quit smoking and take reg-ular exercise if possible (179). The principal treatment forASO consists of surgical operation, such as percutaneoustransluminal angioplasty (PTA) for patients complaining ofadvanced intermittent claudication or for Fontaine stage IIIpatients. Drug therapy is supplementary only. Antihyperten-sive drugs must be selected not to decrease blood circulation,including collateral circulation. In general, diuretics (177)and β-blockers (180) tend to cause aggravation of ischemicsymptoms due to reduction of blood flow of the injured andcollateral blood vessels. ACE inhibitors are effective atmaintaining or increasing blood flow of the lower extremi-ties and thus improving exercise tolerance capacity(177–181). Furthermore, the results of the HOPE study indi-


cate that ACE inhibitor can reduce the risk of cardiovascularcomplication in patients with ASO (119). α-Blockers are al-so expected to be effective for patients with ASO (177), al-though no clinical evidence has yet been obtained. Dihy-dropyridine Ca antagonists have strong vasodilatation ef-fects, and are recognized to be effective for patients withASO (182). It has been reported that nicardipine adminis-tered to ASO patients with normal blood pressure resulted inworsening of clinical symptoms, probably due to stealing ofblood from the injured blood vessels (181). Therefore, caremust be taken in the administration of short acting drugs thatcause rapid vasodilatation. It has been reported that vera-pamil improves physical movement (183). β-Blockers withcardiac selectivity or vasodilatatory action are reported notto aggravate peripheral blood circulation (184, 185), butshould be administered cautiously to patients with ASO (14).

Blood pressure should be lowered to a level that will notdecrease the perfusion pressure of the diseased extremity. Itmay be necessary to determine this level individually foreach patient, depending on the extent of vascular stenosisand development of collateral circulation, but in general thetarget blood pressure should stay at around 150–160/90mmHg, slightly higher than that for the elderly non-compli-cated hypertensives. After the initiation of treatment, patientsare monitored by measuring blood pressure routinely at theupper arms and the diseased extremity by Doppler hemodro-mometer, and also followed-up by subjective complaints andperiodically by thermography to determine any clinical ag-gravation of ischemic symptoms.

For the management of ASO it is important not to over-look any complication, particularly the risk factors for ather-osclerosis other than hypertension, such as hyperlipidemiaand diabetes mellitus. Patients with ASO frequently haverenovascular hypertension (186), for which ACE inhibitorsshould be prescribed very cautiously. Patients with claudica-tion have a three times higher rate of mortality comparedwith age-matched controls. They also have higher risk fordevelopment of myocardial infarction and stroke (178). It isimportant to bear in mind that the prognosis of ASO patientswhose cases are complicated by ischemic heart diseases isvery poor (187), and that antihypertensive drugs must be se-lected with extreme caution.

2) Aortic AneurysmIt has been demonstrated that rupture is much more likely tooccur when a thoracic aneurysm exceeds 6 cm in diameterand an abdominal aneurysm exceeds 4–5 cm in diameter. Ac-cordingly, surgical treatment is the first choice in such cases.

a. DiagnosisPresence of aneurysm is confirmed by radiographic examina-tion, such as by CT. In the case of either thoracic or abdomi-nal aneurysms, the prognosis becomes very poor once theaneurysms have ruptured.

The risk of rupture increases with the size of the aneu-

rysm. Surgical intervention is indicated for a thoracicaneurysm more than 6 cm in diameter [5.5 cm in the ascend-ing aorta and 6.5 cm in the descending aorta (187)] or for anabdominal aneurysm more than 5 cm in diameter (189). Thepresence of symptoms such as pain and rapid increase in size(10 mm/yr) also indicate surgical intervention. On the otherhand, early surgical repair of asymptomatic abdominalaneurysms 4.0–5.5 cm in diameter has been shown not toresult in any benefit (187–190).

b. TreatmentHypertension contributes to the degeneration of the aorticwall, and is one of the risk factors for aneurysmal enlarge-ment. The protective effect of β-blockers on rupture is notconclusive (191). There is no evidence that other antihyper-tensive drugs have any effect on the expansion of aorticaneurysm or on postoperative blood pressure control. How-ever, it is generally recommended that blood pressure shouldbe controlled at 140/85 mmHg or below with careful check-ing for symptoms of other atherosclerotic disease (60). Anti-hypertensive drugs need to be selected based on other con-comitant complications. Dissecting aneurysm of Stanfordtype B is usually managed medically. β-Blockers have beenshown to be effective in such cases (192). When using otherclasses of antihypertensive drugs, it is recommended that aβ-blocker be added to reduce reflex tachycardia and increasein contractility. The target systolic blood pressure should bemaintained at 120 mmHg or below at the chronic stage ofrupture or the postoperative period (60).

8. Drug Interactions with AntihypertensiveTreatment

Elderly hypertensive patients frequently have other diseases,and thus are likely to receive many drugs from other physi-cians. Accordingly, they tend to encounter various drug in-teractions with antihypertensive drugs. The age-related de-crease in the function of multiple organs, and particularly ofthe kidneys, may promote accumulation of drugs, resultingin the development of adverse effects, the exaggeration ofdrug interactions, and the further deterioration of organ func-tions. The drugs prescribed by other physicians must there-fore be confirmed, and patients must be carefully monitoredfor possible drug interactions. The following are some of thepossible drug interactions (Table 10). It should be noted,however, that few interactions with ARBs have yet been re-ported. And central sympatholytic drugs and peripheral neu-ronal blockers have been excluded from the following list,because they are rarely prescribed for elderly hypertensivepatients.

8-1. Adverse Interactions between AntihypertensiveDrugs

The combination of β-blockers and diltiazem may cause



Tab

le 1

0.D

rug

Inte

ract

ions

bet

wee

n A

ntih

yper

tens

ive

and

Non

-Ant

ihyp

erte

nsiv

e D

rugs

Incr

easi

ng a

ntih

yper

tens

ive

effe

ctD

ecre

asin

g an

tihyp

erte

nsiv

e ef

fect

Poss

ible

eff

ects

on

non-

antih

yper

tens

ive

drug

s, r

esul

ts o

f in

tera

ctio

ns

Atte

ntio

n sh

ould

be

paid

to

pote

ntia

l in

tera

ctio

ns o

ther

tha

n th

ose

liste

d in

the

tab

le. A

ngio

tens

in I

I an

tago

nist

s ar

e no

t lis

ted

beca

use

of p

auci

ty o

f in

form

atio

n, b

ut t

he i

nter

actio

nsre

late

d to

blo

ckad

e of

the

reni

n-an

giot

ensi

n sy

stem

may

dev

elop

as

thos

e w

ith A

CE

inhi

bito

rs (

indi

cate

d by＊

). C

entr

al s

ympa

thol

itics

and

per

iphe

ral n

euro

nal b

lock

ers

are

excl

uded

.N

SAID

s: n

on-s

tero

idal

ant

i-in

flam

mat

ory

drug

s, A

CE

: ang

iote

nsin

con

vert

ing

enzy

me.

Ca

anta

goni

sits

AC

E in

hibi

tors

β-B

lock

ers

Diu

retic

s

α-B

lock

ers

Cim

etid

ine

Mac

rolid

e an

tibio

tics,

an

tifun

gal

azol

e:fe

lodi

pine

, nif

edip

ine

Gra

pefr

uit j

uice

: som

e di

hydr

opyr

idin

es

Diu

retic

s (v

olum

e de

plet

ion)＊

Chl

orpr

omaz

ine

Cim

etid

ine,

qui

nidi

ne:

β-bl

ocke

rs m

etab

-ol

ized

in th

e liv

er

Rif

ampi

cin

Phen

obar

bita

l

NSA

IDs＊

Ant

acid

s(R

ifam

pici

n: lo

sart

an)

NSA

IDs

Rif

ampi

cin,

phe

noba

rbita

l, sm

okin

g:β-

bloc

kers

m

eabo

lized

in

th

e liv

erA

ntac

ids

NSA

IDs

Ster

oids

Cho

lest

yram

ine,

col

estim

ide:

thi

azid

edi

uret

ics

NSA

IDs

Dig

oxin

, car

bam

azep

ine,

tria

zola

m, m

idaz

olam

: a r

ise

in b

lood

leve

lsw

ith d

iltia

zem

Am

ioda

rone

: si

nus

arre

st,

AV

blo

ck,

card

iac

arre

st w

ith d

iltia

zem

,ni

fedi

pine

, rep

orte

dT

heop

hylli

ne: a

ris

e in

blo

od le

vels

with

dilt

iaze

mSi

mva

stat

in, l

ovas

tatin

: a r

ise

in b

lood

leve

ls w

ith d

iltia

zem

Cis

apri

de: Q

T p

rolo

ngat

ion,

ven

tric

ular

arr

hyth

mia

Cyc

losp

orin

e, ta

crol

imus

: a r

ise

in b

lood

leve

ls w

ith C

a an

tago

nist

sL

ithiu

m: n

euro

toxi

c ef

fect

s w

ith d

iltia

zem

, rep

orte

d

Potta

sium

＊: h

yper

kale

mia

NSA

IDs＊

: a d

eter

iora

tion

of r

enal

fun

ctio

n, h

yper

kale

mia

Dig

oxin＊

: a r

ise

in b

lood

leve

ls in

sev

ere

hear

t fai

lure

Allo

puri

nol:

seru

m s

ickn

ess-

like

synd

rom

e an

d St

even

s-Jo

hnso

n sy

n-dr

ome

with

cap

topr

il, r

epor

ted

Ant

ihyp

ergl

ycem

ic d

rugs

: hyp

ogly

cem

iaL

ithiu

m: a

ris

e in

blo

od le

vels

Ant

ihyp

ergl

ycem

ic d

rugs

: mas

king

and

pro

long

atio

n of

hyp

ogly

cem

iaD

igox

in: m

arke

d br

adyc

ardi

a w

ith p

ropr

anol

ol, r

epor

ted

Ant

iarr

hyth

mic

dru

gs: c

ondu

ctio

n de

fect

s, a

rrhy

thm

ia, d

ecre

ased

car

-di

ac f

unct

ion

Dru

gs f

or c

old

and

nasa

l con

gest

ion

cont

aini

ng s

ympa

thom

imet

ics:

an

incr

ease

in b

lood

pre

ssur

eSi

lden

afil:

exce

ssiv

e fa

ll of

blo

od p

ress

ure

with

nip

radi

lol

Dig

oxin

: dig

italis

into

xica

tion

by h

ypok

alem

iaO

ral a

ntih

yper

glyc

emic

dru

gs: a

n in

crea

se in

req

uire

men

t dos

es w

ithpo

tass

ium

-los

ing

diur

etic

sA

min

ogly

cosi

des:

an

incr

ese

in to

xici

ty to

kid

neys

and

aco

ustic

ner

ves

with

loop

-diu

retic

sN

SAID

s: r

enal

fai

lure

with

tria

mte

rene

, rep

orte

dG

lycy

rrhi

zine

: hyp

okal

emia

with

pot

assi

um-l

osin

g di

uret

ics

Am

anta

dine

: a r

ise

in b

lood

leve

ls, r

epor

ted

Lith

ium

: a r

ise

in b

lood

leve

ls

Alc

ohol

: aug

men

ted

fall

in b

lood

pre

ssur

e

marked bradycardia, atrioventricular conduction distur-bances or heart failure. The combination of potassium-spar-ing diuretics and either ACE inhibitors or ARBs may causehyperkalemia, and such combinations are therefore con-traindicated for patients with renal insufficiency. In cases inwhich the renin-angiotensin system is activated by diuretics,additional administration of ACE inhibitors or ARBs maycause excessive reduction of blood pressure. The combina-tion of α-blockers and either diuretics or β-blockers may belikely to cause orthostatic hypotension. (193)

8-2. Cardiovascular Drugs

1) DigitalisElevation of blood concentrations of digoxin due to dilti-azem seems to be mild (194), but the possibility of such ele-vation should be kept in mind when the two drugs are com-bined for treatment of an elderly patient. Elevation of digox-in concentrations due to captopril has been reported in casesof severe heart failure (195). ACE inhibitors are apt to in-duce renal dysfunction in cases of heart failure, renal arterialstenosis and hypovolemia, and they should be used carefullyin combination with digitalis. The combination of digitalisand potassium-losing diuretics may cause digitalis intoxica-tion, and the combination of digitalis with β-blockers or dil-tiazem may cause severe bradycardia.

2) NitratesNitrates exert vasodilatory effects, and may exert an additivevasodilatory action in combination with various antihyper-tensive drugs. In cases complicated by coronary artery dis-eases and treated by nitrates, antihypertensive drugs shouldbe carefully administered to avoid an excessive fall in bloodpressure, since the J-curve phenomenon on coronary arterydiseases has been reported (196). Patients should be in-formed of the possibility of an excessive reduction of bloodpressure and the possible occurrence of orthostatic hypoten-sion upon urgent use of nitrates.

3) Antiarrhythmic DrugsThe combination of β-blockers and diltiazem may cause se-vere bradycardia, arrhythmia and decreased cardiac function.The combination of antiarrhythmic drugs and potassium-los-ing diuretics may cause aggravation of proarrhythmic re-sponses due to hypokalemia and hypomagnesemia.

8-3. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

NSAIDs inhibit the synthesis of prostaglandins, and may al-so inhibit the antihypertensive effects of ACE inhibitors, di-uretics, β-blockers, α-blockers and ARBs (197, 198). Whencombined with triamterene, indomethacin has been reportedto induce acute renal failure (199). In cases with a decreasedrenal blood flow, the combination of NSAIDs and ACE in-hibitors is apt to induce decreased renal function and hyper-

kalemia. Among NSAIDs, indomethacin and piroxicam havethe strongest adverse effects, and sulindac and aspirin havemild ones. Ca antagonists are little affected by NSAIDs.

8-4. Drugs for Metabolic Disorders

1) Antihyperlipidemic DrugsDiltiazem has been reported to enhance the serum choles-terol-lowering effects of simvastatin (200) and to raise theserum levels of lovastatin. The antihypertensive effects ofACE inhibitors may increase in combination with either lo-vastatin or pravastatin (201). Cholestyramine (202) andcolestimide, anion-exchange resins, inhibit the intestinal ab-sorption of thiazide diuretics. Therefore, diuretics should beadministered 1 h before or 4 h after intake of these drugs.

2) Antihyperuricemic DrugsThere has been a single case report of an elderly patientcomplicated with heart failure and chronic renal failure whodied due to hypersensitivity (fever, arthralgia, erythema mul-tiforme, etc.) following administration of allopurinol com-bined with captopril (203). Diuretics diminish the effects ofuricosuric agents.

3) Antihyperglycemic DrugsIn combination with ACE inhibitors, antihyperglycemicdrugs have been reported to induce hypoglycemic attack(204). β-Blockers may mask the symptoms consistent withhypoglycemia, which could be prolonged. Potassium-losingdiuretics may increase the required doses of oral antihyper-glycemic drugs.

4) PotassiumThe combination of potassium-sparing diuretics and ACE in-hibitors or ARBs may cause hyperkalemia, and this combi-nation is contraindicated in cases of renal insufficiency.

8-5. Drugs Acting on Digestive Organs

1) H2-blockersCimetidine inhibits cytochrome P-450 enzyme in the liverand may cause an increase in serum concentrations of Ca an-tagonists and β-blockers (propranolol, metoprolol, labetalol,etc.) which are metabolized in the liver (205, 206). Raniti-dine has a mild affinity with the enzyme, but this affinity isdose-dependent.

2) AntacidsAntacids inhibit gastrointestinal absorption of ACE in-hibitors and β-blockers (14, 207).

3) CisaprideWhen combined with diltiazem, cisapride, a promotilityagent, has a risk of inducing prolongation of QT interval andventricular arrhythmia (208).


4) GlycyrrhizinGlycyrrhizic acid enhances hypokalemia in combinationwith potassium-losing diuretics.

8-6. Drugs for Respiratory Disorder

1) Drugs for Common ColdDuring treatment with β-blockers, the administration ofdrugs for common cold/nasal congestion (many over-the-counter drugs, Dan Rich®) which contain phenyl-propanolamine or other sympathomimetic drugs may in-crease blood pressure due to unopposed α-adrenergic stimu-lation (14).

2) TheophyllineThe blood concentration of theophylline rises in combinationwith diltiazem (205).

8-7. Antibiotics and Antifungal Drugs

Rifampicin induces cytochrome P-450 enzyme, and inhibitsthe antihypertensive effects of Ca antagonists and β-blockerswhich are metabolized in the liver (14). Rifampicin increasesoral clearance of losartan and decreases the half-life valuesof losartan and its active metabolite E3174 (209). Macrolideantibiotics such as erythromycin, clarithromycin, etc. and an-tifungal drugs such as itraconazole may increase the bloodconcentrations of felodipine and nifedipine due to inhibitionof the enzymes (205, 210). Fluconazole interacts with losar-tan by inhibiting its conversion to the active metaboliteE3174 (211). Combinations of aminoglycosides and loop di-uretics increase renal toxicity and acoustic nerve defects(212).

8-8. Centrally Acting Drugs

Diltiazem may raise blood concentrations of triazolam (213)and midazolam (214) and increase their sedative actions.Thiazide diuretics have been reported to increase the anti-Parkinsonism effects of amantadine (215). Diltiazem is apt toraise the blood concentrations of carbamazepine, resulting inthe development of neurotoxicity. ACE inhibitors, diureticsand losartan may raise the blood concentrations of lithium,an anti-manic drug. Phenobarbital and phenytoin decreasethe blood concentrations of Ca antagonists.

8-9. Glucocorticoids

In combination with potassium-losing diuretics, glucocorti-coids may enhance hypokalemia. Diltiazem has been report-ed to increase the blood concentration of oral methylpred-nisolone and to greatly enhance its adrenal suppressant ef-fects (216).

8-10. Immunosuppressants

Diltiazem and nicardipine increase the blood concentrationsof cyclosporine (205). However, felodipine and nifedipinedo not demonstrate such an effect. Carvedilol, a β-blocker,also increases cyclosporine concentrations (217). It has beenreported that the combination of cyclosporine and enalaprilleads to development of renal failure (218). Diltiazem,nifedipine (219) and nilvadipine increase the blood concen-trations of tacrolimus.

8-11. Urogenital Drugs

Sildenafil (Viagra®) is contraindicated for patients with is-chemic heart diseases, particularly for those taking nitrates(220). It has been reported that, in patients treated with am-lodipine, sildenafil decreased blood pressure by 8/7 mmHg,which was similar to the changes in normotensive subjects(221). However, patients receiving multiple antihypertensivedrugs may experience an excessive reduction of blood pres-sure with sildenafil (220). The combination of sildenafil andnipradilol (Hypadil®), a β-blocker having an NO radical, iscontraindicated.

In patients treated with antihypertensive drugs, the α-blocker tamsulosin, which is prescribed for dysuria due toprostate hypertrophy, may induce orthostatic hypotension.

8-12. Beverages

A bitter constituent in grapefruit juice inhibits the metabo-lism of Ca antagonists such as felodipine, nifedipine, ni-trendipine, etc., and thus increases antihypertensive effects(222). It has been reported that after a 7-day intake of grape-fruit juice the maximum blood concentrations of nisoldipinesignificantly increased for at least three days (223). Prazosinaccentuates alcohol-induced hypotension at 2–4 h after in-gestion (224).

9. QOL Considerations

9-1. Characteristics of QOL in the Elderly

The QOL of patients has been regarded as an important issuein various fields of medical practice．Because uncomplicat-ed hypertension is associated with fewer subjective symp-toms than other diseases, QOL in hypertension has been de-fined in a much broader sense (225); i.e., in the managementof hypertension, QOL is considered to consist of such compo-nents as physical symptoms, psychological state, and func-tional capacity to perform social activities, which in turn in-fluence such perceptions as life outlook, life satisfaction andsense of well-being (226).

Elderly patients have much more complex QOL problemsthan young or middle-aged patients because of their specificsocial and psychological circumstances, as well as their mul-


tiple organ disorders whether in the presence or absence ofhypertension. The problems pertinent to the QOL evaluationof elderly hypertensive patients, which should be taken intoconsideration prior to antihypertensive treatment, are 1)depressive tendencies; 2) complication by dementia; and 3)the influence of other diseases.

The psychological state of the elderly is well characterizedby a sense of loss in several areas. 1) Physical and mental ac-tivities invariably decrease with aging, and losses in social oreconomic status, as well as the death of a spouse or otherfamily members, are common and highly conducive to de-pression. 2) In the assessment of QOL in the elderly, demen-tia is as important as depression. In this regard, it is impor-tant that cognitive function in the elderly be evaluated sepa-rately from QOL. 3) Finally, elderly patients frequently suf-fer from chronic diseases that have an undeniable impact ontheir QOL, particularly in the case of diseases that signifi-cantly affect ADL, such as stroke.

9-2. Assessment of QOL in the Elderly

Assessment tools for the QOL of elderly patients, whichhave been described above, should be able to evaluate notonly the direct influence of physical diseases, but also vari-ous specific problems pertinent to this age group. For thispurpose, a simple and easily understood questionnaire(227) is available, which adopts the concept of the five di-mensions for QOL assessment developed by Levine andCroog (226). This questionnaire is also designed to evaluategeneral symptoms, willingness to work or daily routines,physical symptoms, quality of sleep, emotional states, sexualactivity or interest, life satisfaction, self-control, daily activi-ties, etc. A more detailed questionnaire for the assessment ofQOL in elderly hypertensives (228) was developed in Japanand includes such important subjective and social compo-nents as 1) subjectively perceived inconveniences in dailylife due to illness; 2) life satisfaction; 3) emotional stability;4) the sense of life vitality and fulfillment; and 5) the senseof personal independence.

9-3. Antihypertensive Drug Choices Based on QOL Ef-fects

Among the important factors that potentially affect the QOLof elderly hypertensive patients, it is important to considersubjective symptoms or laboratory abnormalities due to theadverse effects of drugs, as well as the expected adverse ef-fects particular to each antihypertensive drug based on itspharmacological properties. ACE inhibitors, long-acting Caantagonists, small doses of diuretics and some β-blockersare reported to have little or no adverse effect on the QOL ofelderly hypertensive patients (227, 229–231). In a HOTstudy, in which elderly patients were treated with the long-acting Ca antagonist felodipine, it was reported that the QOLwas improved in direct proportion to the antihypertensive ef-

fects of the drug (232). Though the number of reports is stilllimited, ARBs have been shown to have favorable QOLeffects comparable to those of ACE inhibitors in elderlyhypertensive patients (233), and long-term treatment ofelderly patients with an ARB has been shown to result inbetter reduction of hypertension and better improvement ofcognitive function than the use of a diuretic (234). In orderto maintain or improve the QOL of elderly hypertensivepatients, the appropriate antihypertensive drugs should beindividually selected for each patient, taking the presence ofany complications into account. In terms of QOL, ACEinhibitors, ARBs, and long-acting Ca antagonists are thedrugs of choice for the treatment of hypertension in theelderly.

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