Hypertension and Coronary Artery Disease in the Elderly

HYPERTENSION AND CORONARY ARTERY DISEASE IN THE ELDERLY Franz H. Messerli, MD, and Tomasz Grodzicki, MD

VOLUME 1 2 . NUMBER 1 FEBRUARY 1996

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MESSERLI & GRODZICKI

a powerful risk factor for the development of atherosclerosis, CAD, and stroke not only in Western countries but also in Eastern Europe and Asia.", 31,36, 41 Trials performed in different countries demonstrated that the prevalence of hypertension increases parallel with age. According to the most authoritative study for the United States population, the National Health and Nutrition Examination Surveys from 1980 (NHANES-II), the prevalence of hypertension reaches 59.2% in white men 65 to 74 years old and 66.2% in white elderly women.36In the aged black population of the United States, the prevalence of hypertension is even higher: 67.1% in men and 82.9% in women. In a study performed in the Leisure World population at Seal Beach, California, Colandrea et a1 showed an increase of mean systolic blood pressure (SBP) from 133.4 mmHg in the group less than 55 years of age to 165.0 mmHg in the group aged 85 or more." In contrast, the level of diastolic blood pressure (DBP) remained almost constant in spite of increasing age. In a random sample of the population of six Belgian districts, the prevalence of definite hypertension (SBP 2 160 and DBP 2 95 mmHg) rose from 2.7%among men aged 10 to 49 years to 22.2% in the group aged 70 to 79 years." In women the prevalence of hypertension was even higher and reached 37.9% in those aged 70 to 79 years. The differences between the age groups were most apparent when the prevalence of isolated systolic hypertension (ISH) was compared. In the youngest age group (10 to 49 years) ISH occurred with a prevalence of 0.4%, while in the oldest group (280 years) the prevalence was 27.4%.In an epidemioin which blood pressure was mealogic survey performed in Cracow (P0land),4~ sured on one occasion and hypertension was diagnosed when SBP 2160 mmHg and/or DBP 295 mmHg, hypertension was found in 60.3% of participants 70 years old and older. The prevalence of hypertension was slighly lower in younger participants (58.7%in those aged 70 to 74 years) compared with the older participants (64.1%in those 280 years old). The prevalence of isolated systolic hypertension rose from 30.9% among participants aged 70 to 74 years to 37.7%in participants older than 80 years; however, the prevalence of diastolic hypertension decreased from 4.0% to 2.8% in the respective age groups. Two principal approaches exist for determining the cardiovascular risk associated with high blood pressure: long-term follow-up of a hypertensive population and placebo-controlled therapeutic trials. Long-term Follow-up Studies

Thirty-six years of follow-up of the Framingham cohort showed that the risk ratio of coronary heart disease was significantly increased not only in middleaged participants but also in participants older than 65 years.47However, the authors of the Framingham Study found that the risk ratios were slightly lower for the older participants. This observation arises from the fact that in the elderly with normal blood pressure, a biennial rate of cardiovascular events is much higher when compared with that of younger persons. Of note, a linear positive Z-G!

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regardless of the level of diastolic blood pressure.38Similar results were obtained in the Hypertension Detection and Follow-up Program by Curb et al, which involved the screening of 158,906 individuals (30 to 69 years old) for hypertension.16 Among this population each millimeter of mercury increase in SBP was associated with a 1% increase in mortality over 8 years of observation. Moreover, recently published data from the Framingham cohort showed that even borderline ISH (defined as SBP of 140 to 159 mmHg and DBP below 90 mmHg) was associated with a significantly increased risk of cardiovascular events.66In a study from

HYPERTENSION AND CORONARY ARTERY DISEASE IN THE ELDERLY

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Finland, the prevalence of CAD and associated risk factors was studied in 413 men aged 70 to 89, and the results showed that manifestations of CAD were correlated inversely with high-density lipoprotein cholesterol (HDL-C)and positively with the total cholesterol/HDL-C ratio, triglycerides (TG), and hypertenion.^^ In another Finnish the relationship between different risk factors and CAD events was studied during a 3.5-year follow-up in a randomly selected population sample 65 to 74 years of age at baseline. Of 1298subjects participating in the study at baseline, 1069 were nondiabetic and 229 had non-insulin-dependent diabetes mellitus (NIDDM). In multiple logistic regression analyses including all study participants, NIDDM (P <0.01), male sex ( P <0.05), previous myocardial infarction (MI) (P <0.05), current smoking ( P <0.001), systolic blood pressure (P <0.001), and low HDL-C (P <0.01) predicted all CAD events (CAD death or nonfatal MI). Similarly, in a study of 707 men born in 1913whose medical histories were followed by Welin et a1 for 8 years, the incidence of CAD increased 1.6-fold from the lowest to the highest quintile of total cholesterol levels, 2.7-fold from the lowest to the highest quintile of TG, and 2.2-fold among those with diabete~.'~ On the other hand, blood pressure, smoking habits, and two measurements of obesity were not significantly related to incidence of CAD. Benfante et a16studied risk factors for the 12-year incidence of definite CAD among 3440 men who were middle-aged (51 to 59 years old) and 1419 men who were elderly (65 to 74 years old). In multivariate models, total cholesterol, cigarette smoking, systolic blood pressure, and diabetes mellitus were significant predictors of incident CAD for both age groups. While the relative risks for the variables studied were similar between the two age groups, the excess risk was typically between 1.5 to 2.0 times higher for the older compared with the middle-aged men. Though the risk ratio for some hazards in the elderly is sometimes questioned, it is offset by a greater incidence of cardiovascular events in advanced age so that the attributable risk and the potential benefit of treatment rise with age. Thus, preventive efforts in the elderly may have substantial potential benefit. Placebo-controlled Therapeutic Trials

The above epidemiologic observations have been confirmed by trials such as the European Working Party on High Blood Pressure in the Elderly (EWPHE), the Systolic Hypertension in the Elderly Program (SHEP)," a Swedish Trial in Old Patients with Hypertension (STOP-Hypertension)? and the Medical Research Council trial of treatment of hypertension in older adults (MRC).52All these trials demonstrated that reduction in blood pressure with active treatment was associated with a significant decrease in occurrence of most of the cardiovascular endpoints when compared with placebo. The relative risks of event (treated versus control) for coronary disease were as follows: EWPHE, 0.80; SHEP, 0.73; STOP, 0.87; MRC, 0.81. In an overview published by MacMahon and Rodgers, the authors analyzed results obtained from five randomized trials in patients over the age of 60 years.49These trials involved a total of 12,483 patients with a mean entry blood pressure of 181/88 mmHg. The difference in blood pressure between study and control groups over a follow-up period of 4.7 years reached 15/6 mmHg and was associated with a 34% reduction in stroke and a 19%reduction in coronary heart disease incidence. Similar conclusions were reached by Insua et a135in their metaanalysis involving nine major trials with 15,559 patients older than 59 years. Death rates in the control group varied between 2.7%and 77.2%.Overall, treated patients had an approximately 12% reduction in all-cause mortality (odds ratio, 0.88; 95% confidence interval [CI], 0.80 to 0.97; 953 events compared with 1069 events,

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MESSERLI & GRODZICKI

P = 0.009). A 36% red-uction in stroke mortality and a 25% reduction in coronary heart disease mortality (odds ratio, 0.75; CI, 0.64 to 0.88; 263 events compared with 350 events, P <0.001) were observed. Coronary morbidity was reduced 15% (odds ratio, 0.85; CI, 0.73 to 0.99; 325 events compared with 379 events, P = 0.036) and stroke morbidity was reduced 35%. These results are (partially) in accordance with trends in fatal and nonfatal events of coronary artery disease. Improvements in the mortality rates of ischemic heart disease have been observed over the last two decades in most developed countries including Australia, the United States, Canada, and Belgium. At the same time, however, in some countries (Switzerland, Romania, Poland) mortality In the United States a downward trend in fatal rates of CAD have in~reased.~' MI was observed in the last decade. In 1984 the acute MI fatality rate was 7.5% for those aged less than 65 years and 22.4% for those older than 65 years; in 1990 the respective numbers were 5.0% and 17.6%.24Simultaneously, data from the National Hospital Discharge Survey for 1980, 1985, and 1990 showed a marked increase in the rate of cardiac catheterization and coronary bypass graft procedures at ages 45 to 64 and above 64 years. This increase is much more distinct in the elderly and in the last survey (1988 to 1990) the number of procedures in older men was higher than that in younger men.24An analysis of trends in nonfatal CAD in the United States between 1980 and 1989 revealed that the prevalence of nonfatal CAD decreased among both men and women 45 to 54 years of age.2' These trends may result from efforts to decrease risk factors for CAD in the younger group, such as smoking, hypercholesterolemia, and hypertension. On the other hand, the prevalence of nonfatal CAD increased steeply in the elderly, from 100 per 1000 to 179 per 1000 among men 75 to 84 years of age (P <0.001). In women 75 to 84 years of age it increased from 5 per 1000 per year to 15 per 1000 per year (P <0.01).28This increase in the elderly may be related to: 1. Better prophylactic care in younger subjects that postpones occurrence of CAD 2. Easier access for elderly patients to diagnostic procedures 3. Increased prevalence of aging-dependent risk factors such as hypertension, glucose intolerance, or NIDDM

PATHOPHYSIOLOGY

In an elderly patient with established essential hypertension, two distinctly different pathogenic processes should be considered. Firstly, progressive aging per se affects the cardiovascular system resulting in age-specific changes; secondly, the cardiovascular system of an elderly patient with hypertension is exposed to the long-standing high blood pressure which accelerates some of the pathologic change^.^^,^^ Similarities between these two conditions-age and hypertensionmake a proper diagnosis of the severity of hypertension more difficult (Table 1).

Decreased Arterial Compliance-Pathophysiologic Hallmark of Hypertension in the Elderly

Arterial compliance decreases with age because of progressive atheromatosis and medial hypertrophy, and therefore systolic hypertension becomes a common and hazardous entity in the elderly population. Dart et alZ0studied aortic mechanical properties and left ventricular function and structure in 10 elderly subjects

HYPERTENSION AND CORONARY ARTERY DISEASE IN THE ELDERLY

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Table 1. COMMON FEATURES OF AGING AND HYPERTENSION -

- -

Arteries Heart

Kidneys Hormonal system Brain

Aging and Hypertension-Similarities Arterial stiffening, decreased baroreceptor function, atherosclerosis Slower early diastolic filling Left ventricular hypertrophy Decreased coronary reserve Lower sensitivity to beta-adrenergic stimulation Decline in renal blood flow and number of nephrons Low renin, high catecholamines, hyperinsulinemia-glucose intolerance, diabetes mellitus, dysliproproteinemia Dementia

with untreated ISH and 16 normotensive subjects of similar age. Aortic distensibility was significantly reduced among subjects with ISH. The thickness of the interventricular septum was approximately 20% greater in the hypertensive subjects (P <0.01), and the average wall thickness to radius ratio was increased by 30%. Deceleration time was significantly greater (P <0.01), and the ratio of early to late transmitral diastolic peak flow velocities was significantly less in the hypertensive (P <0.05) than in the normotensive group. Left ventricular systolic function was well preserved. Another study demonstrated that even borderline isolated systolic hypertension is associated with cardiovascular damage. According to the results of Sagie et al,65the sum of left ventricular wall thicknesses (septum + posterior wall) was significantly higher in participants with borderline ISH than in normotensive participants (20.5 versus 19.7 mm; P = 0.002).After adjustment for age and other clinical variables, comparisons between the groups revealed that peak velocity of early filling and the ratio of early-to-late peak velocities were lower in the hypertensive group (40 versus 44 cm/s [P = 0.031 and 0.69 versus 0.76 [P = 0.011, respectively). Extremely increased arterial stiffness may lead to increased systolic blood pressure as determined by the indirect method and is commonly called pseudohyp e r t e n ~ i o nThis . ~ ~ entity should be kept in mind when high blood pressure values are present without any target organ damage. The careless treatment of such patients may result in hypotension and lead to syncope. The Osler's maneuver has been recommended for proper evaluation of these patients. Furthermore, aged hypertensive patients show a distinctly increased total peripheral resistance when compared with younger subjects with similar blood pressure levels.55 Besides increased arterial stiffness and higher peripheral resistance, elderly patients are characterized by decreased intravascular volume and significantly diminished reactivity of the baroreceptor reflex, making them particularly vulnera~ ~ ,the ~ ~other hand, decreased ble for postural and postprandial h y p o t e n ~ i o n .On baroreceptor reflex may lead to the occurrence of a white coat hypertension that cannot be considered innocent. Kuwajima et a145studied 67 elderly individuals older than 60 years: 17 patients with white coat hypertension, 34 patients with true hypertension, and 16 normotensive control subjects. White coat hypertension was defined as a mean 24-hour ambulatory systolic blood pressure of less than 140 mmHg associated with office hypertension. Left atrial dimension and left ventricular mass index were significantly greater in the white coat hypertension group than in the normotensive group (P <0.05) but were similar to values in the true hypertensive group. Left ventricular diastolic function, expressed by lateto-early filling ratio of diastolic mitral flow, showed increasing impairment in the

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order of the normotension, white coat hypertension, and true hypertension groups. The relation between fractional shortening and end-systolic stress did not shift downward after hand grip exercise in the white coat hypertension group, indicating that functional reserve in the left ventricle was maintained. In summary, related to high blood pressure, cardiovascular risk in the elderly is caused primarily b y vascular abnormalities such as increased arteriolar resistance and large-artery stiffness and the effect of increased early pulse-wave reflection. All of these arterial consequences carry a meaningful hazard for the heart.

Aging and Hypertension: Cardiac Sequelae, Heart Consequences

Left ventricular mass progressively increases throughout life, reaching its greatest magnitude in sene~cence.~~ Left ventricular hypertrophy (LVH) remains a feature representative both for arterial hypertension and aging. In the normotensive elderly, LVH is a consequence of a degenerative process in connective tiss~e.4~ In spite of age, in hypertensive patients LVH is an answer for increased endsystolic wall stress (ESWS) and by thickening the walls leads to normalization of ESWS. LVH by echocardiographic criteria can be found in up to 50% of elderly patients with hypertension. Although LVH is certainly associated with aging, it cannot be recognized as a harmless phenomenon; it is associated with a higher rate of fatal events. The development of LVH, even in the absence of coronary stenosis, is associated with reduction in coronary reserve, an increased number of arrhythmias, progressing deterioration of left ventricular function, and a higher m ~ r t a l i t y . ' ~ , Degeneration ' ~ , ~ ~ , ~ ~ of collagen that can be observed in advanced age Higher left impairs left ventricular filling and leads to diastolic dysf~nction.'~ ventricular end-diastolic pressure may, in some cases, lead to pulmonary edema in spite of well-preserved systolic function as it was described by Topol et aLal Though the number of studies comparing left ventricular function in aged patients with and without LVH is limited, the appearance of LVH in the elderly appears associated first with further deterioration in diastolic function and consequently with decline of contractile left ventricular parameters. The prognostic significance of left ventricular hypertrophy has been demonstrated in studies from Framingham or the Cornell Hospital, showing significantly increased cardiovascular morbidity and mortality even in the absence of other risk factor^!^,^^

DIAGNOSIS

Coronary artery disease (CAD) in the elderly presents a diagnostic puzzle. The proper diagnosis of CAD in the elderly involves multiple difficulties such as: Lower pain perception related to autonomic dysfunction Lower actixrjtIy I ~ ~ 7 e l - e ~,r ~ ~,ractix~iti~s T l a ~ r do nnt trigger -- mvncardial . ischemia Frequent concomitant diseases-pulmonary, gastrointestinal, or musculoskeletal disorders that may mimic or mask CAD symptoms, or may cause angina without coronary stenosis (anemia, thyrotoxicosis) Frequently used drugs that can further lower pain perception (nonsteroidal anti-inflammatory drugs) or imitate CAD-related electrocardiographic (ECG) abnormalities (digoxin) Frequent ECG abnormalities without CAD symptoms and inability to perform exercise tests because of musculoskeletal or high blood pressure limitations

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Confusion or dementia Family or doctor inclination to depreciate the complaints of elderly patients Because of the topical limitations of this article, we are focusing only on the most important of the previously mentioned problems. The perception of angina in the elderly and its relationship to autonomic function has been recently studied by Ambepitiya et a1 in a prospective study of patients with exertional myocardial ischemia.' Anginal perceptual threshold (APT) was defined as the time between onset of 1-mm ST depression to the onset of angina during treadmill stress testing. Autonomic function was studied using responses to the valsalva maneuver, to deep breathing, and to standing. APT in the older patients was delayed by a median of 49 seconds versus 30 seconds in the young patients (P <0.001). In the high APT subgroup (APT >30 seconds) significant correlation existed between APT prolongation and impaired valsalva response. These results suggest that warning signs of critical MI are delayed and that autonomic dysfunction may be one of the underlying mechanisms. The clinical consequence of an increased angina threshold may be a higher incidence of silent ischemia, which was detected by Aronow2in 34% of elderly patients with stable CAD. Also atypical manifestation of MI with dyspnea as a major sign and a high prevalence of unrecognized Q-wave MI (21% to 43%) in the elderly may be related to lower pain perception. Lusiani et a14$retrospectively studied a group of 94 patients (mean age 68.5 years) with acute MI and evaluated the prevalence, clinical features, and short-term course of the atypical forms (symptoms other than chest pain). An atypical MI was found in 30 patients. Abdominal pain, paroxysmal dyspnea, and pulmonary edema were the most frequent symptoms (33%, 17%, 13%, respectively). Significantly fewer patients with atypical MI had a history of angina pectoris (P <0.05). Also, in a Chinese study by Teng et a175the octogenarian patients had more frequent atypical presentation and postinfarctional congestive heart failure; whereas infarct size, location, and development of Q-wave, major arrhythmias, and cardiac wall rupture were not different among the age subsets. Also, the octogenarians were less likely than the younger patients to have received thrombolytic therapy, mostly because of delayed diagnosis and arrival at the hospital. The high prevalence of resting ECG abnormalitie~~~ makes this simple method less valuable in the diagnosis of CAD in the elderly compared with younger subjects. Fortunately, promising newer methods such as seism~cardiography,'~ dobutamine echocardiography,5 dipyridamole thallium-201 69 dipyridamole echocardiography? and transesophageal echocardiography" have been introduced for cardiac evaluation in the elderly, which should considerably increase the accuracy of diagnosing CAD in this patient group. Unfortunately, the age-related bias in the management of elderly patients with coronary artery disease is still observed. Cave et all0 examined the usage pattern of coronary angiography in 535 patients initially referred for adenosine single photon emission computed tomography (SPECT) thallium imaging. Coronary angiography was carried out more often in patients under 70 years of age than in those over 70 years of age (33% versus 23%, P <0.01). Even in patients with abnormal adenosine SPECT thallium results, coronary angiography was less frequently performed in the elderly (31% versus 46%, P <0.01). Stepwise discriminant analysis of clinical and scintigraphic variables identified four independent predictors of the need for coronary angiography: the abnormal thallium image results, the size of the perfusion abnormality, sex, and age. The authors concluded that coronary angiography is less often performed in women and elderly patients even when initial screening results are abnormal.

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MESSERLI & GRODZICKI

THERAPY

Antihypertensive Treatment: Benefit or Hazard?

Though most studies reveal a significant cardiovascular risk reduction with antihypertensive treatment, questions still remain that cannot be clearly answered. Will Very Old Patients (>80 Years) Benefit from Antihypertensive Treatment?

The beneficial effects of blood pressure lowering in very old patients have not been conclusively demonstrated. Most of the published studies did not include patients older than 80 years (MRC in the Elderly), included a group that was too small (EWPHE), or did not demonstrate any significant benefit in this age group (STOP Hypertension). Only the SHEP trial investigators were able to show a decrease in the number of nonfatal strokes in very old patients with isolated systolic hypertension. The recently initiated Hypertension in the Very Elderly Trial (HWET) in Europe will attempt to answer this question? The trial was started in 1994 and patients were randomly assigned either to control, diuretic (bendroflumethiazide), or angiotensin converting enzyme (ACE)-inhibitor (lisinopril) treatment. Until the results of the HWET are published, other cardiovascular risks factors, patient history, and target organ damage must be considered before deciding on drug therapy. How Far Should Blood Pressure Be Lowered?

In a retrospective analysis of the effect of lowering blood pressure on the mortality from MI in 902 patients with hypertension, Cruickshank et a1 found that diastolic blood pressure below 85 mmHg was associated with an increase in MI rate.15They suggested that low diastolic blood pressure may lead to a hazardous decrease of coronary perfusion pressure, especially in patients with concomitant coronary artery stenosis or left ventricular hypertrophy. Though this theory seems reasonable and was confirmed by a retrospective meta-analysis of numerous trials such as the Goteborg Primary Prevention Trial, the New York Employee Cohort study, and the Hypertension Detection and Follow-up Program, prospective data are still lacking." In contrast, the results of the SHEP study did not confirm the previously described relationship, and even in subjects with very low diastolic blood pressure a decrease in risk throughout follow-up was observed.70On the other hand, remember that patients included in this trial had low baseline diastolic blood pressure, and therefore the SHEP population may not be relevant for such analysis. A similar J-shaped curve has been demonstrated in epidemiologic studies. In the previously mentioned study from Cracow, the medical histories of 512 participants (70 to 93 years old) have been followed since 1985.*'In an intermediate

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subjects with an SBP greater than 200 mmHg (54.8%)when compared with those with an SBP of 120 to 139 mmHg (34.8%).However, this highest mortality (81.2%) was observed among subjects with very low initial SBP (less than 120 mmHg). The relationship between total mortality and diastolic blood pressure was also Jshaped. Corresponding results were derived from other prospective trials conducted in Hong Kong,3' and Denmark." Though we cannot neglect the supposition that increased mortality in participants with very low blood pressure may be related to initially worse health status, and even if all the data concerning

HYPERTENSION AND CORONARY ARTERY DISEASE IN THE ELDERLY

49

the J-shaped curve are not fully validated, one should keep them in mind together with the previously mentioned features of hypertension in the elderly: 1. Decreased baroreceptor function concomitant with high prevalence of atherosclerosis, and left ventricular hypertrophy-risk of hypotension and target organ hypoperfusion 2. Decreased renal function-diminished drug clearance 3. Higher rate of metabolic disorders (glucose intolerance, diabetes, gout) 4. Multidrug treatment (po1ypragmasia)-interaction of drugs

Consequently, very aggressive and rapid blood pressure lowering should be avoided in elderly patients especially when they show coronary artery disease or left ventricular hypertrophy. What Drug Should Be Preferred?

Recent meetings of the American Heart Association, the European Society of Hypertension, and the International Society of Hypertension were dominated by discussions of whether diuretics and beta-blockers should be preferred in the therapy of hypertension as suggested by the Fifth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC V).36Contrary to the JNC V recommendation, the World Health Organization/International Society of Hypertension committee suggested that therapy should be based on the individual profile of the patient and that calcium channel blockers and ACE inhibitors may be used as first-line agents.27The antihypertensive effect of most of the modern agents is similar as shown in the final results of the Treatment of Mild Hypertension Study (TOMHS)57which compared 5 different agents (acebutolol, amlodipine, chlorthalidone, doxazosin, and enalapril maleate) with placebo. Unfortunately, the results of this unique study do not pertain to the elderly populations because the upper limit of age was 69 years. Moreover, patients with a history or clinical evidence of cardiovascular disease were excluded from the study. Contrary to the TOMHS trial, a comparison of six antihypertensive agents (diltiazem, clonidine, atenolol, hydrochlorothiazide, prazosine, and captopril) with placebo performed by Materson et a15' showed that the efficacy of the antihypertensive drug highly depends on demographic characteristics such as age and race. Searching the literature published in 1994, one can find numerous studies on use of different antihypertensive agents (ACEinhibitors-enalapril, perindopril, quinapril; calcium antagonists-nifedipine, nitrendipine, manidipine, diltiazem, isradipine, amlodipine, felodipine; betablockers-atenolol, metoprolol; hydrochlorothiazide; and ketanserin) in elderly patients that demonstrate their efficacy in the therapy of hypertension in the elderly,4,23'28'34, 40,51,58, hl,86-88 The authors of this review agree that the optimal choice of antihypertensive strategy should be based on the results of long-term studies (according to JNC V), but it should be stressed that all of these trials included patients free of major complications such as dementia, recent stroke, MI, diabetes mellitus requiring insulin, or overt heart failure. Therefore, the results pertain to rather healthy subjects, in contrast to most of the patients treated in everyday practice. So far the results of large long-term studies including patients with complications are not available, and therefore we suggest considering the results of smaller studies evaluating not only hard but also soft or surrogate end-points in tailoring optimal antihypertensive drug therapy for particular patients. -

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MESSERLI & GRODZICKI

Antihypertensive Therapy in Primary and Secondary Prevention Beta-Blockers

Beta-blockers are extremely useful in CAD because they decrease myocardial oxygen demand. Therefore, they exert strong antianginal, antiarrhythmic, and cardioprotective effects.@,78, 85 Unfortunately, because of the high prevalence of heart failure, sick-sinus syndrome, peripheral artery disease, glucose intolerance and diabetes, and chronic obstructive pulmonary disease, beta-blockers are a poor choice for long-term treatment of elderly patients. On the other hand, multiple studies have shown that beta-blockers reduce the reinfarction rate and mortality after MI in elderly patient^.^,^^,^^ Therefore they remain a good choice in secondary prevention of CAD. The newer agents such as labetalol, carvedilol, bopindolol, and celiprolol are partially free of the deleterious effects and, especially in combination with dihydropyridine calcium antagonists, seem to be the treatment of choice for elderly patients with CAD.59 Diuretics

Though diuretics are efficacious antihypertensive agents in elderly patients with essential hypertension, metabolic disturbances such as hypokalemia, hypomagnesemia, altered metabolism of glucose and lipids, hyperreninemia, and increased adrenergic stimulation partially override the beneficial blood pressurelowering effect on cardiac mortality. In patients with hypertension and diabetes, diuretics are associated with an accelerated decline in renal function and high m~rtality.~' On the other hand, a meaningful antiosteoporotic effect of thiazides has been recently confirmed in a large community-based sample of 1696 patients. Morton et alS6demonstrated that thiazides users had significantly higher bone mineral density of the ultradistal radius, hip, and lumbar spine. This beneficial effect of thiazides clearly becomes an important consideration, especially in elderly women, in view of the fact that hip fractures are still one of the most deadly complicationsin elderly women. In subjectswith hypertension and CAD, thiazides should be used in combination with potassium-sparing agents, and they may be used as first-line agents in patients with left ventricular failure with edema. Calcium Antagonists

Calcium antagonists lower arterial pressure by reducing total peripheral resistance and improving arterial compliance. Therefore they seem to be agents of choice for elderly patients. The recent laboratory and clinical findings make calcium channel blockers an attractive choice for elderly patients with hypertension who are at risk of or are suffering from atheromatosis, but further confirmatory clinical studies are needed.'jODihydropyridine calcium antagonists decrease left ----L-Z---l-.,- .. . . ., . . . - . -2cc +.-. + h ~ %.A.43?+?72++77~~ ." !=cc=?. -- +!?s -fi-.4;h~7,4?fi-?7?<.4;-s -.--.---. Nondihydropyridine calcium antagonists, particularly verapamil, are excellent agents in patients with congestive heart failure secondary to impaired left ventricul& filling or diastolic dysYfunction that is a common*sequefa of long-standing hypertension, LVH, and CAD.67Verapamil is also highly superior to beta-blockers in reduction of LVH without depression of left ventricular function in elderly subjects.'j8In a recently published study, Arrighi et a13 revealed that verapamil enhances left ventricular diastolic filling in normotensive middle-aged and elderly subjects without affecting systolic function. In the elderly, peak filling rate (ex"-AL.A.L-A-A

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HYPERTENSION AND CORONARY ARTERY DISEASE IN THE ELDERLY

51

pressed in fractional stroke volume per second) increased with verapamil from 4.3 2 1.0 to 5.7 2 1.0 (P < 0.01) and time to peak filling rate decreased from 185 2 31 to 147 2 15 milliseconds (P < 0.01). Calcium antagonists in slow-release formulation are excellent agents in elderly patients with hypertension and concomitant angina. Acute-release formulations of dihydropyridine calcium antagonists should be strictly avoided, because they precipitate an inappropriate reduction in arterial pressure with profound cardioacceleration leading to MI and even acute MI.64,83 Contrary to observations with nifedipine and nitrendipine, a Danish Verapamil Infarction Trial (DAVIT)-I1 study has documented that verapamil given 1 week after acute MI diminishes reinfarction rate and increases survival.77The decrease in reinfarction rate induced by verapamil was in excess of 20%,similar to that documented with beta-blockers. In patients with non-Q-wave infarction with left ventricular failure, diltiazem reduces reinfarction rates.79Nondihydropyridine calcium antagonists have negative chronotropic and inotropic effects and should therefore be avoided in patients with heart blocks or congestive failure from systolic dysfunction. Though betablockers remain the agents of choice in the management of patients after MI, verapamil or diltiazem should be considered when beta-blockers are contraindicated. Angiotensin-Converting Enzyme Inhibitors

Angiotensin-converting enzyme (ACE) inhibitors lower arterial blood pressure by decreasing total peripheral resistance while maintaining or enhancing systemic and regional blood Despite the fact that plasma renin activity is often low in elderly hypertensive patients, all ACE inhibitors lower blood pressure in the geriatric p ~ p u l a t i o n . ~This ~ , ~clearly ~ , ~ ~demonstrates ,~~ that the antihypertensive and antiproliferative effect of ACE inhibition is not solely dependent on circulating plasma renin activity. ACE inhibitors reduce LVH to a much greater extent than do any other antihypertensive agent and do not cause deterioration of left ventricular fun~tion.'~ ACE inhibitors in secondary prevention, when given after acute MI, prevent progressive dilation of the left chamber (remodeling).The multicenter Survival and Ventricular Enlargement Trial (SAVE) that evaluated the effect of captopril on morbidity and mortality after MI in patients with left ventricular dysfunction (ejection fraction < 40%) showed a significant reduction in both total (19%) and cardiovascular mortality (21%),a lower risk of reinfarction (25%),and beneficial effects on a variety of other cardiovascular endpoint^.^^ The lower incidence of new MIS may be attributable to the modulation of hormonal factors that increase coronary tone, to improved subendocardial perfusion, or to slower thickening of the vascular wall. Because ACE inhibitors lower both preload and afterload of the left ventricle, they are the agents of choice in patients with hypertension and congestive heart failure or systolic d y s f u n ~ t i o n .On ~ ~the , ~ ~other hand, according to the results of the Consensus-2 trial, giving ACE inhibitors in the early phase of MI seems hazardous, especially in patients with low blood pressure.74A favorable effect of lisinopril given alone or with transdermal glyceryl trinitrate (GTN) was demonstrated for elderly patients.25Lisinopril, started within 24 hours after the onset of acute MI, produced significant reductions in overall mortality and in the combined outcome measure of mortality and severe ventricular dysfunction. No excess of unfavorable clinically relevant events in the treated groups was reported. In patients with renal failure, high doses of ACE inhibitors deteriorate renal function and can lead to life-threatening hyperkalemia. Milder degrees of hyperka-

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MESSERLI & GRODZICKI

lemia are not uncommon with ACE inhibition, because in elderly patients the mechanism of potassium excretion is often disturbed due to hyporenimic hypoaldosteronism, renal failure, or both. In patients showing hyperreninemia (caused by pretreatment with a diuretic, renal failure, congestive heart failure, or atherosclerotic stenosis of renal artery), a severe decrease in blood pressure can be observed. Peripherally Acting Antiadrenergic Drugs

The postsynaptic alpha-blockers favorably affect dyslipoproteinemia; they lower total cholesterol and increase high-density lipoprotein cholesterol. Though the long-term benefits of these beneficial lipid effects still remain to be determined (particularly in the elderly), postsynaptic alpha-blockers should be considered first-line agents for hypertensive patients with dyslipoproteinemias. In addition, alpha-blockade in smooth muscles partially diminishes the symptoms of dysuria such as frequency, urgency, nocturia, and sensation of incomplete emptying that On the other are associated with benign prostate hyperplasia in elderly hand, they dilate capacitance vessels; orthostatic hypotension may occur, particularly with the first dose, inappropriate increase of the dose, or pretreatment with a diuretic. Elderly patients with rigid arteries and reduced baroreceptor activity are at increased risk of this potentially hazardous side effect. Other Interventions

Postmenopausal estrogen replacement has been associated with favorable levels of cardiovascular risk factor modification. Manolio et a1,5O who studied

Decreased Arterial

Compliance

Arrhythmias

SECONDARY

Ca Antagonist

Atherosclerosis

LVH

Dysfunctional Endothelium

4iV Diastolic*Dysfunction \ &:~i2k dihydropyridine Ca Antagonist Beta Blocker

*ACE Inhibitor Diuretic

Figure 1. Pathophysiologic relationships between hypertension and coronary artery disease

HYPERTENSION AND CORONARY ARTERY DISEASE IN THE ELDERLY

53

present and past estrogen use in 2955 women (265years old) in the Cardiovascular Health Study, found that estrogen use (past or present) was strongly associated with lower levels of low-density lipoprotein cholesterol, fibrinogen, glucose, insulin, and obesity and higher high-density lipoprotein cholesterol levels. Estrogen users also had lower levels of subclinical disease as measured by carotid intimalmedial thickness, carotid stenosis grade, and Doppler mitral peak flow velocities. These findings suggest that postmenopausal estrogen use may be associated with a lower risk of cardiovascular disease in women well into the eighth decade of life. In summary, we would like to propose the following diagram (Fig. 1)of the pathophysiologic relationships between hypertension and coronary artery disease that may be kept in mind when considering antihypertensive therapy.

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