Epidemiology Hypertension JAMES
A. SCHOENBERGER,
and Evaluation: Steps Toward Treatment in the 1990s M.D.,
Chicago, //his
The percentage of persons in the United States over age 65-especially over 85-is increasing more rapidly than other age groups. Two thirds of people over age 65 have blood pressure higher than 140 mm Hg systolic or 90 mm Hg diastolic. Isolated systolic hypertension (systolic blood pressure >160 mm Hg with diastolic blood pressure C90 mm Hg) is also highly prevalent. In a number of clinical trials, treatment of diastolic hypertension in the elderly has been shown to be beneficial, although the value of treatment of isolated systolic hypertension is not yet established. The benefit of antihypertensive therapy on the incidence of stroke and heart failure has been clearly established, but prevention of the atherosclerotic complications of high blood pressure (sudden death or myocardial infarction, for example) has not been convincingly demonstrated. Since clinical trials designed to investigate this atherosclerotic complication of hypertension have relied on stepped-care regimens (diuretics and /? blockers), the question arises whether the use of different drugs might have a better effect on prevention of myocardial infarction. The basis for this supposition includes the known adverse effects of diuretics and p blockers on electrolytes, lipid metabolism, glucose metabolism, insulin resistance, and quality of life. Hypertension treatment in the 1990s will focus on the mechanisms by which blood pressure is lowered by various antihypertensive agents, as well as individualization of drug therapy based on coexisting diseases and conditions. Emphasis will be placed on use of monotherapy whenever possible; diuretics in low doses will probably be used more frequently for second-line therapy. In recognition of their lack of adverse lipid effects and their tolerability, first-line therapy with (Y blockers, angiotensin-converting enzyme inhib-
From the Department of Preventwe Medicine, Rush-PresbyterIan-St. Luke’s Medical Center, ChIcago. Ilknols. Requests for reprints should be addressed to James A. Schoenberger, M.D., 1725 West Harrison Street, ChIcago, Illinois 60612.
itors, and calcium antagonists will become increasingly common. The goal of antihypertensive therapy will be to extend the life expectancy of hypertensive patients to that of subjects without high blood pressure; hopefully, these new treatment approaches will bring us closer to that goal.
T
he median age of the United States population is rising, with the elderly segment increasing relatively more rapidly than any other. It is estimated [l] that 12.7% of the population is age 65 or older, and 1.2% is age 85 or older. These figures translate to approximately 31 million people over age 65, 3 million of whom are over age 85. Further, it is expected that in 20 years nearly 40 million people in this country will be older than 65, and over 6 million of those will be over age 85 [2]. This increasing percentage of elderly persons has an important effect on the health care system because of the heavy use of health care services by older people. Of particular importance is the high prevalence of elevated blood pressure in this age group [3]. If hypertension is defined as a systolic blood pressure of 140 mm Hg or higher or a diastolic blood pressure of 90 mm Hg or higher, 53% of white men and 56.2% of white women aged 65 to 74 years are hypertensive; among blacks at these ages, the comparable figures are 58.5% and 66.5% 131. Management of hypertension in the elderly is, therefore, a major challenge to the U.S. health care system, and improved methods of treatment are urgently needed.
CURRENTGUlDkLlNESFORTHE TREATMENT OF HYPERTENSION Current recommendations for the treatment of hypertension are based on guidelines of the Joint National Committee for the Detection, Evaluation, and Treatment of High Blood Pressure, published in 1988 [4]. For the first time, four alternative classes of drugs were recommended for initial treatment of high blood pressure. As in previous guidelines published by this group, it is recommended that if blood pressure is not successfully controlled by the first choice, a second and possibly
April 25, 1991
The American Journal of Medicine
Volume 90 (suppl 46)
453s
HYPERTENSION
IN AN AGING POPULATION / SCHOENBERGER
TABLE I Coronary Mortality Among Subjects in the MRFIT and HDFP Trials (per 1,000) Electrocardiographic
Abnormalities
Present Special Intervention (Stepped4are) MRFIT HDFP
Absent Usual Care (Referred Care)
29.2 35.1
Special Intervention (SteppedQre)
17.7
15.8
22.0
10.3
Usual Care (Referred Care)
20.7 14.8
iDFP = Hypertension Detection and Follow-up Program; MRFIT = Multiple Risk Factor Intervention Trial. Adapted from Kuller et al [6].
TAB&E II Effects of Antihypertensive
Drugs on Lipid Profile
Drugs
Total Cholesterol
LDL Cholesterol
HDL Cholesterol
Triglyceride
Hypothetical ideal drug Thlazlde diuretics p blockers II blockers Sympatholytics ACE inhibiiors Calcium antagonists
u
c)
9 *
lr* *
T = increase; J= decrease; u = no change.
a third drug should be added to the regimen. The current guidelines, however, do not include (Yreceptor blocking drugs for initiation of treatment although these agents have been shown to be effective and well tolerated. Further, inadequate emphasis is given to maintaining control with monotherapy by substituting a second drug when blood pressure is not controlled with the first. These objections to the guidelines, as well as increasing awareness of adverse side effects associated with some of the older antihypertensive drugs, suggest that the guidelines may already be outmoded and in need of revision [5]. Adverse Effects of Standard Therapy Among the adverse effects that have recently been the focus of attention are diuretic-induced changes in electrolyte composition in the total body and in the circulation. For example, although it has long been known that hypokalemia and hypomagnesemia result from rigorous diuretic therapy, the fact that hypokalemia could be lethal in the presence of underlying heart disease was only recognized after the Multiple Risk Factor Intervention Trial (MRFIT) [6]. In that study, the patients with nonspecific abnormalities on their baseline electrocardiograms (ECGs) had a higher risk of death associated with the study treatment than the patients randomly assigned to usual care in the medical com48-6
April 25,
1991 The American Journal of Medicine
munity. A retrospective analysis of a similar cohort from the Hypertension Detection and Follow-up Program confirmed this finding (Table I) [6]. Increased mortality was found to be associated with sudden death, and it was subsequently assumed that the high doses of diuretics (50 to 100 mg) used in the MRFIT were associated with hypokalemia and fatal arrhythmia. Current treatment of hypertension has been modified to avoid this complication, and it is now recommended that thiazide diuretics be given in a dose no higher than 50 mglday. Recognizing that the hypokalemia and hypomagnesemia associated with diuretic therapy are dose-related and may precipitate multiple premature ventricular contractions, many physicians have opted for even lower doses. Premature ventricular contractions, which can be innocuous if the heart is healthy, can lead to sudden death in the presence of occult heart disease. Particularly vulnerable to alterations in electrolyte balance associated with antihypertensive treatment are patients with left ventricular hypertrophy (LVH) or coronary artery disease (CAD). Those with heart failure who are receiving digitalis therapy are also at risk. Another recently recognized aspect of antihypertensive therapy is its association with undesirable changes in blood lipids (Table II). Although there is some controversy regarding the persistence of the
Volume 90 (suppl 48)
HYPERTENSION IN AN AGINGPOFlJlATlON/ SCHOENBERGER
changes, the majority of studies [‘7] confirm that there is a consistent lipid effect associated with diuretic therapy that persists as long as the drugs are given. Diuretic therapy induces atherogenic changes in serum, including an increase in total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride levels. The effect on high-density lipoprotein (HDL) cholesterol is reportedly variable. Beta blockers also have been associated with undesirable lipid effects, with less controversy regarding their persistence. In comparison with diuretics, p blockers have been found to cause an even greater increase in triglyceride levels, as well as a definite decrease in HDL cholesterol. As might be expected, when used in combination for treatment of hypertension, diuretic plus p-blocker therapy produces undesirable lipid changes. In contrast, calcium antagonists and angiotensin-converting enzyme (ACE) inhibitors appear to be neutral in their effects on blood lipids. Among antihypertensive treatments, (Yblockers are associated with an improvement in the lipid profile (an increase in HDL cholesterol and a decrease in triglycerides). Although these changes are modest, an average increase of 5% to 8% in total and LDL cholesterol can be anticipated with long-term continued use of diuretics. According to the Coronary Primary Prevention Trial of the Lipid Research Clinics [8] and many other studies [71, the relation between change in LDL cholesterol and incidence of CAD is such that a 1% decrease in total or LDL cholesterol results in a 2% decrease in the risk of CAD [8]. It can thus be argued that a 1% increase in cholesterol would increase CAD risk by 2%, and that the 5% to 8% increase in total and LDL cholesterol observed with long-term use of diuretics would indicate a possible 10% to 16% increase in CAD risk. Of note, drug-induced changes in both lipids and electrolytes may not be entirely dose-dependent and may be seen even at low doses of these antihypertensive agents [9]. Realization that such changes are undesirable has led to an increasing use of alternative methods of treating hypertension. Impact of Coexisting Conditions on Antihypertensive Therapy The problem of LVH is becoming increasingly important in the management of hypertension [lo]. The Framingham Study showed that LVH detected by ECG at least doubled the risk of CAD. Only about 5% of hypertensive patients in that study had LVH as defined by electrocardiographic criteria. More recent studies of hypertensive populations using echocardiography, however, have indicated that as many as 50% of hypertensive subjects may have LVH, and it is now known that risk of CAD is
associated with LVH defined by such echocardiographic criteria [lo]. Recognition of high prevalence of LVH in hypertensive populations is clinically important because not all drugs can affect regression of LVH [ll]. For example, it is generally conceded that diuretics, although they lower blood pressure, do not improve LVH. The benefit of regression of LVH has not yet been demonstrated, but it is generally assumed that reduction of blood pressure without LVH regression is undesirable. The ideal antihypertensive drug should achieve both effects. Presence of LVH thus dictates that the antihypertensive agent prescribed will effectively lower blood pressure and have a positive impact on LVH regression. Recently, there has been growing interest in the interrelations among hypertension, obesity, and diabetes [12]. These conditions are more commonly associated with each other than would be predicted from chance alone, suggesting the possible existence of common underlying etiologic (genetic) factors [13]. A number of studies have shown that some hypertensive subjects are resistant to insulin and, when challenged with a glucose tolerance test, have higher levels of plasma glucose and insulin compared with normotensive subjects. This association with hypertension can also be demonstrated by the fact that, after normal meals, both plasma insulin and free fatty acids are elevated above the normal level in hypertensive patients. Further, an abnormality in glucose tolerance is aggravated by treatment with drugs such as diuretics and p blockers. These findings have led to the theory that hypertension may be associated, in a condition termed syndrome X, with impaired glucose tolerance, hyperglycemia, insulin resistance, hypertriglyceridemia, hypercholesterolemia, and depressed HDL cholesterol levels [12], all risk factors for increased atherosclerosis of the coronary vessels. This syndrome can occur without frank diabetes mellitus as long as the pancreas compensates for the insulin resistance. When this mechanism fails, overt diabetes also becomes part of the syndrome, underscoring the fact that long-term treatment with diuretics and /? blockers greatly increases the risk of development of diabetes. In contrast, recent data have shown that some antihypertensive drugs improve insulin sensitivity [14]. Because of this factor, such drugs may be attractive alternatives to the standard antihypertensive regimen. Benefits of Antihypertensive Treatment Versus Potential Risks Considering all of the recognized adverse effects of antihypertensive treatment, it is possible that a point could be reached at which the combined risks
April 25, 1991
The American Journal of Medicine
Volume 90 (suppl 48)
4B-5s
HYPERTENSIONIN AN AGINGPOPULATION / SCHOENBERGER
Risk from treatment
Benefit of treatment
Figure 1. Benefit-risk relation of antihypertensive therapy, dependent on side effects of drug and patient’s blood pressure (BP) level.
BP Level
outweigh the advantages of lowering blood pressure. It has been shown in many trials that the benefit of therapy in terms of cardiovascular endpoints is greater in patients with higher blood pressure. In milder hypertension, however, the benefit is difficult to demonstrate in short-term studies. In these cases, adverse effects of drugs such as diuretics and /3 blockers may actually outweigh the benefits achieved from lowering blood pressure. Clearly, the ideal antihypertensive drug should provide the hypertensive patient with the greatest possible benefit and reduce cardiovascular risk to that associated with normotensive persons of the same age and gender (Figure 1). The adverse effects of diuretics and /3 blockers are particularly important in weighing the benefit of treatment of hypertension in relation to prevention of CAD. Meta-analysis of a number of clinical trials carried out by MacMahon et al [15] has shown that no clinically significant benefit for CAD prevention is obtained by treating hypertension with conventional stepped-care drugs such as diuretics and p blockers. In contrast, in terms of the endpoint of fatal or nonfatal stroke, meta-analysis discloses approximately a 40% benefit from treatment. Although one might argue that hypertension is not a recognized risk factor for CAD, and its treatment, therefore, would have no benefit, this view is not supported by extensive epidemiologic data. Today, a widely accepted alternative explanation of the relation between treatment of elevated blood pressure and CAD risk is that antihypertensive treatment with standard regimens has not been effective in preventing CAD, but newer regimens, free of adverse metabolic and electrolyte effects, may produce more favorable results. This hypothesis is being examined in the Treatment of Mild Hypertension Study, now in its pilot phase [16].
4B-a
April 25, 1991
The American Journal of Medicine
TREATMENTOF HYPERTENSIONIN THE 1990s There is a growing consensus that the treatment of hypertension should be individualized. In the past, it was assumed that age and race were important determinants in selecting the ideal antihypertensive drug. Recent studies, however, have shown that older hypertensive patients appear to be responsive not only to diuretics and calcium antagonists, but also to p blockers, ACE inhibitors, and (Y blockers; thus, age is not as critical a factor as was once believed. It should be kept in mind, however, that hypertension in the elderly is accompanied by decreasing cardiac output and increased peripheral resistance. Vasodilators, which do not further reduce cardiac output and thus offer some protection of tissue perfusion, are, therefore, a logical treatment choice. Similarly, race was considered a useful criterion for selection of antihypertensive therapy because it was assumed that black hypertensives responded primarily to diuretics and calcium antagonists. It is now known, however, that black hypertensives also respond to p blockers and ACE inhibitors, although doses may need to be increased [17]. Selection of initial treatment must, therefore, be based on other criteria, such as concurrent conditions in each patient that might influence the response to treatment. Patients with lipid abnormalities, for example, are better treated with lipidneutral drugs such as ACE inhibitors or calcium antagonists, or with drugs such as (Y blockers, which actually have favorable effects on blood lipids. Diuretics and p blockers are relatively contraindicated in these patients. Those with LVH will not benefit from diuretic therapy, and their condition may actually be worsened by direct vasodilators. Patients with diabetes also will be adversely affected by diuretic therapy and often, if their diabetes is insulin-dependent, by p-blocker therapy as
Volume 90 (suppl 46)
TABLE Ill Treatment of Hypertension: Monotherapy, Substitution Therapy, and Combined Therapy Substitution Therapy
Combined Therapy
Diurebc
Calcium blocker
p blocker
ACE inhibltor
ACE inhibitor
/J’ blocker
Calcium antagonist
Dluretlc
a blocker
ACE inhibitor
Calcium blocker & ACE inhibitor ACE inhibitor & diuretic fi blocker & diuretic Diuretic & u blocker ACE inhibitor & p blocker
Monotherapy
well. In contrast, there is growing evidence that ACE inhibitors and calcium antagonists benefit hemodynamic circulation in the glomerulus, thus reducing protein loss, hyperfiltration, and ultimately diabetic glomerulosclerosis. However, clinical data supporting ACE inhibitors as therapy for hypertension in type I diabetics are not yet available in sufficient volume to justify recommending them for this indication. For patients with congestive heart failure, p blockers and certain calcium antagonists may further compromise the condition. Vasodilation, however, has been shown to prolong the life of patients with congestive heart failure, and ACE inhibitors thus appear to be the drugs of choice regardless of whether the congestive heart failure is associated with hypertension. For patients with obstructive lung disease, /3 blockers are contraindicated, although those with partial intrinsic sympathomimetic activity may be tolerated.
COMMENTS All five classes of antihypertensive agents (diuretics, p blockers, ACE inhibitors, calcium antagonists, and (Yblockers) may be appropriate for initiating antihypertensive treatment, depending on the individual patient profile. If the initial therapeutic choice is ineffective, any number of possible substitutions may be made (Table III). If blood pressure is not controlled with monotherapy after several attempts, a patient will probably require a combination of two or more drugs. Diuretics, which have been rapidly losing favor as antihypertensive agents, are perhaps appropriate as second-step drugs if given in small doses. Addition of a diuretic
often effectively lowers blood pressure with minimal side effects. It can be anticipated that the blood pressure of as many as 40% to 50% of hypertensive patients will be controlled with single-drug therapy, and the rest will require a combination of two drugs. Overall, it can be realistically expected that hypertension can be controlled in as many as 90% to 95% of patients [X3].
REFERENCES 1. Hollmann MI: US Population Estimates by Age, Sex, Race, and Hispanic Origin, Current Population Reports, Population Estimates and Projections, Series P-25, No. 1057, March 1990. 2. Wetrogran S: ProJections of the Populabon of States by Age, Sex, and Race: 1989 to 2010. Current Populabon Reports, Population Estimates and Projections, Series P-25, No. 1053, January 1990. 3. Drrzd T, Dannenberg AL, Engel A: Blood Pressure Levels in Persons 18-74 Years of Age in 1976-80 and Trends in Blood Pressure From 1960 to 1980 in the United States. Data from the National Health Survey, Series 11, No. 234, Hyattsville, Mary land, July 1986. 4. The Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure: The 1988 report of the Joint National Committee on Detection, Evaluatron, and Treatment of High Blood Pressure. Arch Intern Med 1988; 148: 1023-1038. 5. Schoenberger JA: Mild hypertension. The rationale for treatment. Am Heart J 1986; 112: 872-876. 6. Kuller LH, Hulley SB, Cohen JD. et al: Unexpected effects of treating hypertension in men with electrocardiographic abnormalities: A critical review. Circulabon 1986; 73: 114-123. 7. Landinoss CK, Neuman SL: The effects of anbhypertensive agents on serum lrpids and lipoproteins. Arch Intern Med 1988; 148: 1280-1288. 8. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial Results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA 1984; 251: 356-366. 9. Weinberger MH: Anbhypertensive therapy and lipids: Evidence, mechanisms, and impkcations. Arch Intern Med 1985; 145: 1102-1105. 10. Messerli FH: Clinical determinants and consequences of left ventricular hypertrophy. Am J Med 1983; 75(3A): 51-56. 11. Liebson PR, Savage DD: Echocardiography in hypertension: A review. II. Echocardiographic studies of the effects of antihypertensive agents on left ventricular wall mass and function. Echocardrography 1987; 4: 215-249. 12. Reaven GM: Role of insulin resistance in human disease. Diabetes 1988; 37: 1595-1607. 13. Ferranrni E, Buzzigoni G, Bonadonna R, et al: Insulin resistance in essential hypertensron. N Engl J Med 1987; 317: 350-357. 14. Pollare T, Lithell H, Berne C: A comparison of the effects of hydrochlorothiazide and captopril on glucose and lipid metabolrsm in patients with hypertension, N Engl J Med 1989; 321: 868-873. 15. MacMahon SW, Cutler JA, Furburg CD, et at The effects of drug treatment for hypertension on morbiddy and mortality from cardiovascular d&ease: A review of randomized, controlled trials. Prog Cardiovasc DIS 1986; 24 (suppl 1): 99-118. 16. Stamler J, Prineas RJ, Neaton JD, et al: Background and design of the new U.S. trial on diet and drug treatment of “mild” hypertension (TOMHS). Am J Cardiol 1987; 59(14): 51G-60G. 17. Schoenberger JA: Individualized hypertensive therapy: An alternative to stepped-care treatment. Postgrad Med 1987; 81: 92-95, 99-100. 18. Chobanian AV: Introduction to a symposrum: Beta-blockade, cardio-selectivity, and intnnstc sympathomrmetrc actrvity. Am J Cardrol 1987; 59: lF-2F.
April 25, 1991
The American Journal of Medicine
Volume 90 (suppl 48)
40-7s
A. SCHOENBERGER,
and Evaluation: Steps Toward Treatment in the 1990s M.D.,
Chicago, //his
The percentage of persons in the United States over age 65-especially over 85-is increasing more rapidly than other age groups. Two thirds of people over age 65 have blood pressure higher than 140 mm Hg systolic or 90 mm Hg diastolic. Isolated systolic hypertension (systolic blood pressure >160 mm Hg with diastolic blood pressure C90 mm Hg) is also highly prevalent. In a number of clinical trials, treatment of diastolic hypertension in the elderly has been shown to be beneficial, although the value of treatment of isolated systolic hypertension is not yet established. The benefit of antihypertensive therapy on the incidence of stroke and heart failure has been clearly established, but prevention of the atherosclerotic complications of high blood pressure (sudden death or myocardial infarction, for example) has not been convincingly demonstrated. Since clinical trials designed to investigate this atherosclerotic complication of hypertension have relied on stepped-care regimens (diuretics and /? blockers), the question arises whether the use of different drugs might have a better effect on prevention of myocardial infarction. The basis for this supposition includes the known adverse effects of diuretics and p blockers on electrolytes, lipid metabolism, glucose metabolism, insulin resistance, and quality of life. Hypertension treatment in the 1990s will focus on the mechanisms by which blood pressure is lowered by various antihypertensive agents, as well as individualization of drug therapy based on coexisting diseases and conditions. Emphasis will be placed on use of monotherapy whenever possible; diuretics in low doses will probably be used more frequently for second-line therapy. In recognition of their lack of adverse lipid effects and their tolerability, first-line therapy with (Y blockers, angiotensin-converting enzyme inhib-
From the Department of Preventwe Medicine, Rush-PresbyterIan-St. Luke’s Medical Center, ChIcago. Ilknols. Requests for reprints should be addressed to James A. Schoenberger, M.D., 1725 West Harrison Street, ChIcago, Illinois 60612.
itors, and calcium antagonists will become increasingly common. The goal of antihypertensive therapy will be to extend the life expectancy of hypertensive patients to that of subjects without high blood pressure; hopefully, these new treatment approaches will bring us closer to that goal.
T
he median age of the United States population is rising, with the elderly segment increasing relatively more rapidly than any other. It is estimated [l] that 12.7% of the population is age 65 or older, and 1.2% is age 85 or older. These figures translate to approximately 31 million people over age 65, 3 million of whom are over age 85. Further, it is expected that in 20 years nearly 40 million people in this country will be older than 65, and over 6 million of those will be over age 85 [2]. This increasing percentage of elderly persons has an important effect on the health care system because of the heavy use of health care services by older people. Of particular importance is the high prevalence of elevated blood pressure in this age group [3]. If hypertension is defined as a systolic blood pressure of 140 mm Hg or higher or a diastolic blood pressure of 90 mm Hg or higher, 53% of white men and 56.2% of white women aged 65 to 74 years are hypertensive; among blacks at these ages, the comparable figures are 58.5% and 66.5% 131. Management of hypertension in the elderly is, therefore, a major challenge to the U.S. health care system, and improved methods of treatment are urgently needed.
CURRENTGUlDkLlNESFORTHE TREATMENT OF HYPERTENSION Current recommendations for the treatment of hypertension are based on guidelines of the Joint National Committee for the Detection, Evaluation, and Treatment of High Blood Pressure, published in 1988 [4]. For the first time, four alternative classes of drugs were recommended for initial treatment of high blood pressure. As in previous guidelines published by this group, it is recommended that if blood pressure is not successfully controlled by the first choice, a second and possibly
April 25, 1991
The American Journal of Medicine
Volume 90 (suppl 46)
453s
HYPERTENSION
IN AN AGING POPULATION / SCHOENBERGER
TABLE I Coronary Mortality Among Subjects in the MRFIT and HDFP Trials (per 1,000) Electrocardiographic
Abnormalities
Present Special Intervention (Stepped4are) MRFIT HDFP
Absent Usual Care (Referred Care)
29.2 35.1
Special Intervention (SteppedQre)
17.7
15.8
22.0
10.3
Usual Care (Referred Care)
20.7 14.8
iDFP = Hypertension Detection and Follow-up Program; MRFIT = Multiple Risk Factor Intervention Trial. Adapted from Kuller et al [6].
TAB&E II Effects of Antihypertensive
Drugs on Lipid Profile
Drugs
Total Cholesterol
LDL Cholesterol
HDL Cholesterol
Triglyceride
Hypothetical ideal drug Thlazlde diuretics p blockers II blockers Sympatholytics ACE inhibiiors Calcium antagonists
u
c)
9 *
lr* *
T = increase; J= decrease; u = no change.
a third drug should be added to the regimen. The current guidelines, however, do not include (Yreceptor blocking drugs for initiation of treatment although these agents have been shown to be effective and well tolerated. Further, inadequate emphasis is given to maintaining control with monotherapy by substituting a second drug when blood pressure is not controlled with the first. These objections to the guidelines, as well as increasing awareness of adverse side effects associated with some of the older antihypertensive drugs, suggest that the guidelines may already be outmoded and in need of revision [5]. Adverse Effects of Standard Therapy Among the adverse effects that have recently been the focus of attention are diuretic-induced changes in electrolyte composition in the total body and in the circulation. For example, although it has long been known that hypokalemia and hypomagnesemia result from rigorous diuretic therapy, the fact that hypokalemia could be lethal in the presence of underlying heart disease was only recognized after the Multiple Risk Factor Intervention Trial (MRFIT) [6]. In that study, the patients with nonspecific abnormalities on their baseline electrocardiograms (ECGs) had a higher risk of death associated with the study treatment than the patients randomly assigned to usual care in the medical com48-6
April 25,
1991 The American Journal of Medicine
munity. A retrospective analysis of a similar cohort from the Hypertension Detection and Follow-up Program confirmed this finding (Table I) [6]. Increased mortality was found to be associated with sudden death, and it was subsequently assumed that the high doses of diuretics (50 to 100 mg) used in the MRFIT were associated with hypokalemia and fatal arrhythmia. Current treatment of hypertension has been modified to avoid this complication, and it is now recommended that thiazide diuretics be given in a dose no higher than 50 mglday. Recognizing that the hypokalemia and hypomagnesemia associated with diuretic therapy are dose-related and may precipitate multiple premature ventricular contractions, many physicians have opted for even lower doses. Premature ventricular contractions, which can be innocuous if the heart is healthy, can lead to sudden death in the presence of occult heart disease. Particularly vulnerable to alterations in electrolyte balance associated with antihypertensive treatment are patients with left ventricular hypertrophy (LVH) or coronary artery disease (CAD). Those with heart failure who are receiving digitalis therapy are also at risk. Another recently recognized aspect of antihypertensive therapy is its association with undesirable changes in blood lipids (Table II). Although there is some controversy regarding the persistence of the
Volume 90 (suppl 48)
HYPERTENSION IN AN AGINGPOFlJlATlON/ SCHOENBERGER
changes, the majority of studies [‘7] confirm that there is a consistent lipid effect associated with diuretic therapy that persists as long as the drugs are given. Diuretic therapy induces atherogenic changes in serum, including an increase in total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride levels. The effect on high-density lipoprotein (HDL) cholesterol is reportedly variable. Beta blockers also have been associated with undesirable lipid effects, with less controversy regarding their persistence. In comparison with diuretics, p blockers have been found to cause an even greater increase in triglyceride levels, as well as a definite decrease in HDL cholesterol. As might be expected, when used in combination for treatment of hypertension, diuretic plus p-blocker therapy produces undesirable lipid changes. In contrast, calcium antagonists and angiotensin-converting enzyme (ACE) inhibitors appear to be neutral in their effects on blood lipids. Among antihypertensive treatments, (Yblockers are associated with an improvement in the lipid profile (an increase in HDL cholesterol and a decrease in triglycerides). Although these changes are modest, an average increase of 5% to 8% in total and LDL cholesterol can be anticipated with long-term continued use of diuretics. According to the Coronary Primary Prevention Trial of the Lipid Research Clinics [8] and many other studies [71, the relation between change in LDL cholesterol and incidence of CAD is such that a 1% decrease in total or LDL cholesterol results in a 2% decrease in the risk of CAD [8]. It can thus be argued that a 1% increase in cholesterol would increase CAD risk by 2%, and that the 5% to 8% increase in total and LDL cholesterol observed with long-term use of diuretics would indicate a possible 10% to 16% increase in CAD risk. Of note, drug-induced changes in both lipids and electrolytes may not be entirely dose-dependent and may be seen even at low doses of these antihypertensive agents [9]. Realization that such changes are undesirable has led to an increasing use of alternative methods of treating hypertension. Impact of Coexisting Conditions on Antihypertensive Therapy The problem of LVH is becoming increasingly important in the management of hypertension [lo]. The Framingham Study showed that LVH detected by ECG at least doubled the risk of CAD. Only about 5% of hypertensive patients in that study had LVH as defined by electrocardiographic criteria. More recent studies of hypertensive populations using echocardiography, however, have indicated that as many as 50% of hypertensive subjects may have LVH, and it is now known that risk of CAD is
associated with LVH defined by such echocardiographic criteria [lo]. Recognition of high prevalence of LVH in hypertensive populations is clinically important because not all drugs can affect regression of LVH [ll]. For example, it is generally conceded that diuretics, although they lower blood pressure, do not improve LVH. The benefit of regression of LVH has not yet been demonstrated, but it is generally assumed that reduction of blood pressure without LVH regression is undesirable. The ideal antihypertensive drug should achieve both effects. Presence of LVH thus dictates that the antihypertensive agent prescribed will effectively lower blood pressure and have a positive impact on LVH regression. Recently, there has been growing interest in the interrelations among hypertension, obesity, and diabetes [12]. These conditions are more commonly associated with each other than would be predicted from chance alone, suggesting the possible existence of common underlying etiologic (genetic) factors [13]. A number of studies have shown that some hypertensive subjects are resistant to insulin and, when challenged with a glucose tolerance test, have higher levels of plasma glucose and insulin compared with normotensive subjects. This association with hypertension can also be demonstrated by the fact that, after normal meals, both plasma insulin and free fatty acids are elevated above the normal level in hypertensive patients. Further, an abnormality in glucose tolerance is aggravated by treatment with drugs such as diuretics and p blockers. These findings have led to the theory that hypertension may be associated, in a condition termed syndrome X, with impaired glucose tolerance, hyperglycemia, insulin resistance, hypertriglyceridemia, hypercholesterolemia, and depressed HDL cholesterol levels [12], all risk factors for increased atherosclerosis of the coronary vessels. This syndrome can occur without frank diabetes mellitus as long as the pancreas compensates for the insulin resistance. When this mechanism fails, overt diabetes also becomes part of the syndrome, underscoring the fact that long-term treatment with diuretics and /? blockers greatly increases the risk of development of diabetes. In contrast, recent data have shown that some antihypertensive drugs improve insulin sensitivity [14]. Because of this factor, such drugs may be attractive alternatives to the standard antihypertensive regimen. Benefits of Antihypertensive Treatment Versus Potential Risks Considering all of the recognized adverse effects of antihypertensive treatment, it is possible that a point could be reached at which the combined risks
April 25, 1991
The American Journal of Medicine
Volume 90 (suppl 48)
4B-5s
HYPERTENSIONIN AN AGINGPOPULATION / SCHOENBERGER
Risk from treatment
Benefit of treatment
Figure 1. Benefit-risk relation of antihypertensive therapy, dependent on side effects of drug and patient’s blood pressure (BP) level.
BP Level
outweigh the advantages of lowering blood pressure. It has been shown in many trials that the benefit of therapy in terms of cardiovascular endpoints is greater in patients with higher blood pressure. In milder hypertension, however, the benefit is difficult to demonstrate in short-term studies. In these cases, adverse effects of drugs such as diuretics and /3 blockers may actually outweigh the benefits achieved from lowering blood pressure. Clearly, the ideal antihypertensive drug should provide the hypertensive patient with the greatest possible benefit and reduce cardiovascular risk to that associated with normotensive persons of the same age and gender (Figure 1). The adverse effects of diuretics and /3 blockers are particularly important in weighing the benefit of treatment of hypertension in relation to prevention of CAD. Meta-analysis of a number of clinical trials carried out by MacMahon et al [15] has shown that no clinically significant benefit for CAD prevention is obtained by treating hypertension with conventional stepped-care drugs such as diuretics and p blockers. In contrast, in terms of the endpoint of fatal or nonfatal stroke, meta-analysis discloses approximately a 40% benefit from treatment. Although one might argue that hypertension is not a recognized risk factor for CAD, and its treatment, therefore, would have no benefit, this view is not supported by extensive epidemiologic data. Today, a widely accepted alternative explanation of the relation between treatment of elevated blood pressure and CAD risk is that antihypertensive treatment with standard regimens has not been effective in preventing CAD, but newer regimens, free of adverse metabolic and electrolyte effects, may produce more favorable results. This hypothesis is being examined in the Treatment of Mild Hypertension Study, now in its pilot phase [16].
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The American Journal of Medicine
TREATMENTOF HYPERTENSIONIN THE 1990s There is a growing consensus that the treatment of hypertension should be individualized. In the past, it was assumed that age and race were important determinants in selecting the ideal antihypertensive drug. Recent studies, however, have shown that older hypertensive patients appear to be responsive not only to diuretics and calcium antagonists, but also to p blockers, ACE inhibitors, and (Y blockers; thus, age is not as critical a factor as was once believed. It should be kept in mind, however, that hypertension in the elderly is accompanied by decreasing cardiac output and increased peripheral resistance. Vasodilators, which do not further reduce cardiac output and thus offer some protection of tissue perfusion, are, therefore, a logical treatment choice. Similarly, race was considered a useful criterion for selection of antihypertensive therapy because it was assumed that black hypertensives responded primarily to diuretics and calcium antagonists. It is now known, however, that black hypertensives also respond to p blockers and ACE inhibitors, although doses may need to be increased [17]. Selection of initial treatment must, therefore, be based on other criteria, such as concurrent conditions in each patient that might influence the response to treatment. Patients with lipid abnormalities, for example, are better treated with lipidneutral drugs such as ACE inhibitors or calcium antagonists, or with drugs such as (Y blockers, which actually have favorable effects on blood lipids. Diuretics and p blockers are relatively contraindicated in these patients. Those with LVH will not benefit from diuretic therapy, and their condition may actually be worsened by direct vasodilators. Patients with diabetes also will be adversely affected by diuretic therapy and often, if their diabetes is insulin-dependent, by p-blocker therapy as
Volume 90 (suppl 46)
TABLE Ill Treatment of Hypertension: Monotherapy, Substitution Therapy, and Combined Therapy Substitution Therapy
Combined Therapy
Diurebc
Calcium blocker
p blocker
ACE inhibltor
ACE inhibitor
/J’ blocker
Calcium antagonist
Dluretlc
a blocker
ACE inhibitor
Calcium blocker & ACE inhibitor ACE inhibitor & diuretic fi blocker & diuretic Diuretic & u blocker ACE inhibitor & p blocker
Monotherapy
well. In contrast, there is growing evidence that ACE inhibitors and calcium antagonists benefit hemodynamic circulation in the glomerulus, thus reducing protein loss, hyperfiltration, and ultimately diabetic glomerulosclerosis. However, clinical data supporting ACE inhibitors as therapy for hypertension in type I diabetics are not yet available in sufficient volume to justify recommending them for this indication. For patients with congestive heart failure, p blockers and certain calcium antagonists may further compromise the condition. Vasodilation, however, has been shown to prolong the life of patients with congestive heart failure, and ACE inhibitors thus appear to be the drugs of choice regardless of whether the congestive heart failure is associated with hypertension. For patients with obstructive lung disease, /3 blockers are contraindicated, although those with partial intrinsic sympathomimetic activity may be tolerated.
COMMENTS All five classes of antihypertensive agents (diuretics, p blockers, ACE inhibitors, calcium antagonists, and (Yblockers) may be appropriate for initiating antihypertensive treatment, depending on the individual patient profile. If the initial therapeutic choice is ineffective, any number of possible substitutions may be made (Table III). If blood pressure is not controlled with monotherapy after several attempts, a patient will probably require a combination of two or more drugs. Diuretics, which have been rapidly losing favor as antihypertensive agents, are perhaps appropriate as second-step drugs if given in small doses. Addition of a diuretic
often effectively lowers blood pressure with minimal side effects. It can be anticipated that the blood pressure of as many as 40% to 50% of hypertensive patients will be controlled with single-drug therapy, and the rest will require a combination of two drugs. Overall, it can be realistically expected that hypertension can be controlled in as many as 90% to 95% of patients [X3].
REFERENCES 1. Hollmann MI: US Population Estimates by Age, Sex, Race, and Hispanic Origin, Current Population Reports, Population Estimates and Projections, Series P-25, No. 1057, March 1990. 2. Wetrogran S: ProJections of the Populabon of States by Age, Sex, and Race: 1989 to 2010. Current Populabon Reports, Population Estimates and Projections, Series P-25, No. 1053, January 1990. 3. Drrzd T, Dannenberg AL, Engel A: Blood Pressure Levels in Persons 18-74 Years of Age in 1976-80 and Trends in Blood Pressure From 1960 to 1980 in the United States. Data from the National Health Survey, Series 11, No. 234, Hyattsville, Mary land, July 1986. 4. The Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure: The 1988 report of the Joint National Committee on Detection, Evaluatron, and Treatment of High Blood Pressure. Arch Intern Med 1988; 148: 1023-1038. 5. Schoenberger JA: Mild hypertension. The rationale for treatment. Am Heart J 1986; 112: 872-876. 6. Kuller LH, Hulley SB, Cohen JD. et al: Unexpected effects of treating hypertension in men with electrocardiographic abnormalities: A critical review. Circulabon 1986; 73: 114-123. 7. Landinoss CK, Neuman SL: The effects of anbhypertensive agents on serum lrpids and lipoproteins. Arch Intern Med 1988; 148: 1280-1288. 8. Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial Results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA 1984; 251: 356-366. 9. Weinberger MH: Anbhypertensive therapy and lipids: Evidence, mechanisms, and impkcations. Arch Intern Med 1985; 145: 1102-1105. 10. Messerli FH: Clinical determinants and consequences of left ventricular hypertrophy. Am J Med 1983; 75(3A): 51-56. 11. Liebson PR, Savage DD: Echocardiography in hypertension: A review. II. Echocardiographic studies of the effects of antihypertensive agents on left ventricular wall mass and function. Echocardrography 1987; 4: 215-249. 12. Reaven GM: Role of insulin resistance in human disease. Diabetes 1988; 37: 1595-1607. 13. Ferranrni E, Buzzigoni G, Bonadonna R, et al: Insulin resistance in essential hypertensron. N Engl J Med 1987; 317: 350-357. 14. Pollare T, Lithell H, Berne C: A comparison of the effects of hydrochlorothiazide and captopril on glucose and lipid metabolrsm in patients with hypertension, N Engl J Med 1989; 321: 868-873. 15. MacMahon SW, Cutler JA, Furburg CD, et at The effects of drug treatment for hypertension on morbiddy and mortality from cardiovascular d&ease: A review of randomized, controlled trials. Prog Cardiovasc DIS 1986; 24 (suppl 1): 99-118. 16. Stamler J, Prineas RJ, Neaton JD, et al: Background and design of the new U.S. trial on diet and drug treatment of “mild” hypertension (TOMHS). Am J Cardiol 1987; 59(14): 51G-60G. 17. Schoenberger JA: Individualized hypertensive therapy: An alternative to stepped-care treatment. Postgrad Med 1987; 81: 92-95, 99-100. 18. Chobanian AV: Introduction to a symposrum: Beta-blockade, cardio-selectivity, and intnnstc sympathomrmetrc actrvity. Am J Cardrol 1987; 59: lF-2F.
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The American Journal of Medicine
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