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New approaches to a first-line treatment of hypertension
New Approaches to a First-Line Treatment of Hypertension
Stepped-care treatment of hypertension has been widely adopted, and improvement in control of high blood pressure is probably responsible for the decline in stroke mortality rates in the past 15 years. Yet many trials of the efficacy of the treatment of high blood pressure have failed to demonstrate that lowering blood pressure uging stepped care will prevent coronary heart disease. Recent evidgnce suggests that the benefit of stepped care based on the use of diuretics and beta-blockers may be diminished by simultaneous hgrm from the drugs used. This includes hypokalemia, hypomagngsemia, hyperglycemia, hyperuricemia, elevation of total and iowdgnsity lipoprotein cholesterol levels, elevation of triglyceride levelg, and a decrease in high-density lipoprotein cholesterol levels. Awareness of this has led to the development of alternative choices for first-line treatment of milg high blood pressure. A new approach enlarges the number of options for initial treatment to include calcipm blockers, angiotensin-converting enzyme inhibitors, alphablockers, diuretics, and beta-blockers. Selection of the most appropriate drug is individualized according to the characteristics of the patient. Demographic considerations of age and race are only partially helpful because of frequent exceptions to the rules. Of greater ifnportance are considerations of concurrent disease such as coronary heart disease, diabetes, gout, and hyperlipidemia, for these cqnditions are powerful determinants of the best first-line drug. Substitution, rather than addition, of another drug should be used when the first choice is not successful.
JAMES A. SCHOENBERGER, M.D. Chicago,
Illinois
From the Department of Preventive Medicine, Rush Medical College, Chicago, Illinois. Requests for reprints should be addressed to Dr. James A. Schoenberger, Rush-Presbyterian-St. Luke’s Medical Center, 1725 West Harrison Street, Chicago, Illinois 60612.
28
March
25, 1888
The American
Journal
The number of deaths from coronary heart disease and stroke has been declining steadily in the United States since 1972 [I 1. From 1972 to 1982, coronary heart disease death rates declined 27 percent and stroke death rates 42 percent. The explanation for these declines is complicated by the fact that there are inadequate data on the incidence of nonfatal coronary heart disease and stroke. Hence, it is possible that some of the decline in the number of deaths may be a result of improved treatment or moderation in the severity of the disease process, and the overall incidence of the disease may not have changed. Several studies [2,3], however, do suggest a decline in incidence as well. Therefore, it seems likely that the incidence of both nonfatal and fatal coronary heat-l disease and stroke has been declining significantly in the .lJnited States in the past 15 years. Although coronary heart disease is multifactorial, the identification of elevated blood pressure as an independent risk factor has been widely recognized. In the case of stroke, hypertension is considered to be the major riik factor. It is reasonable to assume that treatment of hypertension might reduce the complications of coronary heart disease and stroke. Based on that assumption, the National Heart, Lung, and Blood Insti-
of Medicine
Volume
84
(suppl 38)
SYMPOSIUM
tute of the National Institutes of Health began an extensive program in 1972, the National High Blood Pressure Education Program. This ambitious program was directed toward increasing the public’s awareness of the importance of treatment of high blood pressure, and increasing the medical profession’s skill in treatment. A series of guidelines to therapy were developed and revised over the years. The most recent statement of these guidelines by the Joint National Committee on the Detection, Evaluation and Treatment of High Blood Pressure, published in 1984 [4], describes the stepped-care approach to treatment. This system has been widely accepted by practicing physicians. About 90 percent of all primary-care physicians use diuretics and about 50 percent use beta-blockers for the treatment of high blood pressure. How much the more aggressive approach to the treatment of high blood pressure and the treatment of milder degrees of elevated blood pressure have contributed to the declining death rates is uncertain. It is known that the amount of undetected hypertension has steadily declined from a high of 50 percent in a survey in Chicago in 1967 to 1972 to a low of 4 percent in a survey in Westchester County, New York, in 1981 to 1982 [5]. At the same time, the percentage of persons with high blood pressure receiving treatment has risen from 25 percent to 87 percent and the percentage of those with high blood pressure under control has risen from 11 percent to 72 percent, respectively. These impressive changes in the management of high blood pressure may well explain some, but not all, of the decline in coronary heart disease mortality rates and most of the decline in the number of deaths caused by stroke. If the widespread adoption of the stepped-care approach to the treatment of hypertension has resulted in pat-t in a striking decline in death rates from coronary heart disease and stroke, one might question the need for or wisdom of a new approach to the treatment of hypertension when the present approach is working very well. Such a course can only be considered if new evidence suggests that, good as it is, the stepped-care approach may not be capable of fully achieving the maximal benefit from lowering elevated blood pressure or may even, in some cases, be harmful. Such evidence has been accumulating and will be reviewed in this study. It will be made clear that how we lower elevated blood pressure may be more important than had been previously appreciated in the past, when greater interest was focused on merely lowering the blood pressure by any means. . METABOLIC CONSEQUENCES OF ANTIHYPERTENSIVE TREATMENT
The adverse effects of the commonly used antihypertensive drugs, the thiazide diuretics and beta-blockers, have been known since their widespread use began. Thus, hypokalemia, hypomagnesemia, hyperglycemia, and hy-
March
25, 1988
ON CALCIUM
ANTAGONISTS-SCHOENBERGER
peruricemia associated with the use of diuretics were accepted as a necessary consequence of lowering the blood pressure. When these metabolic changes occurred, action, often inadequate, was taken to compensate for the changes. Patients in whom hypokalemia developed were given oral potassium supplements or a potassium-sparing diuretic. Patients in whom hyperglycemia developed were given oral antidiabetic agents, dietary instruction, and occasionally insulin. Patients in whom hyperuricemia or gout developed were given uricosuric agents, allopurinol, or anti-inflammatory agents. It was not perceived that these metabolic effects were life threatening or in any way diminished the benefit of lowered blood pressure. Recent evidence, however, suggests that these, plus only recently recognized changes in serum lipid levels associated with diuretic and beta-blocker therapy, may indeed have an adverse effect on survival that diminishes the benefit of lowering blood pressure. Electrolytes. The importance of disturbances in serum electrolytes, particularly potassium and magnesium levels, has now become better appreciated, as a result of the Multiple Risk Factor Intervention Trial [6]. In this study, a subgroup of hypertensive patients with baseline electrocardiographic abnormalities (mainly high precordial R waves, negative T waves, left axis deviation, and ST depression or elevation) was found to experience excess mortality rates associated with the treatment given to the group receiving special intervention compared with the group receiving usual care. The major difference in the treatment was that a higher percentage of men in the group receiving special intervention received 100 mg of hydrochlorothiazide or chlorthalidone than did men in the group receiving usual care. The results of the study are shown in Table I. The trend toward benefit from treatment in the special intervention group was shown for all subgroups except for those hypertensive patients with baseline electrocardiographic abnormalities where there was a 65 percent high death rate [7]. This finding has led to the hypothesis that the mechanism of death in the Multiple Risk Factor Intervention Trial, often sudden, was related to hypokalemia-induced arrhythmia. The depletion of potassium and magnesium with diuretic treatment has been amply documented as have been the increase in ventricular premature beats and serious arrhythmias associated with hypokalemia and hypomagnesemia. These relationships have recently been reviewed [8]. Thus, it appears that myocardial disease may make hypertensive patients especially vulnerable to the effects of electrolyte depletion. This would appear to be so in left ventricular hypertrophy (Multiple Risk Factor Intervention Trial) [7], in myocardial infarction [9], and in congestive heart failure [lo]. In uncomplicated mild hypertension, the signs of early left ventricular hypertrophy were present in about a third of the Multiple Risk Factor Intervention Trial hypertensive patients. These patients
The American
Journal
of Medicine
Volume
84
(suppl 38)
27
SYMPOSIUM
TABLE
ON CALCIUM
I
ANTAGONISTS-SCHOENSERGER
Mortality Rate (per 1,000 persons) According to Hypertensive Abnormalities: Multiple Risk Factor Intervention Trial’
Status and Baseline
Number of Deaths Attributed to Comnaty Heari Disease Special intervention Nonhypertensive, Absent Present Hypertensive, Absent Present ‘Adapted
from
resting
resting
electrocardiographic 13.2 16.6 electrocardiographic 15.6 29.2
II
Special intervention
Usual Care
abnormalities 16.1 25.7
39.1 33.6
33.6 46.0
20.7 17.7
35.9 60.0
43.4 39.7
abnormalities
(71.
Mean Changes (percent) in Plasma Lipid Levels at 72 Months by Antihypertensive Treatment Status: Multiple Risk Factor Intervention Trial* Special intervention
Usual Care
Plasma cholesterol percent change (mg/dl) No treatment Diuretic only Diuretic and propranoiol
-13.1 -9.1 -6.3
-9.1 -2.5 +1.0
Plasma triglyceride percent change (mg/dl) No treatment Diuretic only Diuretic and propranolol
-16.5 16.5 52.2
-11.6 24.9 49.1
“Men not taking antihypertensive Adapted from [7j.
26
Total Number of Deaths
Usual Care
may benefit from reduction of elevated blood pressure at the cost of an increased risk of sudden death. The net result may be a significant lessening in overall benefit. To some extent, the adverse effects of the diuretics on serum electrolytes can be reduced by a reduced dose of diuretic [l l] and it is now current practice to limit the dose of diuretic as much as possible. Lipids. The effect of antihypertensive drug treatment on serum lipid levels was not recognized until the Multiple Risk Factor Intervention Trial study showed that use of thiazide diuretics was associated with a rise in total and low-density lipoprotein cholesterol levels [12,13]. These findings are summarized in Table II, which also includes changes in lipids associated with beta-blocker therapy. These data show that the cholesterol-lowering effect of the diet used in the Multiple Risk Factor Intervention Trial for the men in the group receiving special intervention was reduced by the use of a diuretic or the combination of a diuretic and beta-blocker. Similar findings were noted in the men in the group receiving usual care. The use of a
TABLE
Electrocardiographic
March 25, 1999
agents
at baseline.
The American Journal of Medicine
diuretic alone or in combination with a beta-blocker was associated with a rise in triglyceride levels in both the special intervention and usual care groups. Thus, the benefit of the lowered blood pressure was associated with atherogenic changes in the serum lipids that were only partially blunted by diet. A large number of studies have focused on the effects of antihypertensive therapy on serum lipid levels. Although there is still controversy over the extent and persistence of these effects over time, the bulk of the evidence favors a small, persistent elevation of total and lowdensity lipoprotein cholesterol levels associated with diuretic treatment and a moderate rise in triglyceride levels with a decrease in high-density lipoprotein cholesterol levels following beta-blocker treatment [14]. These changes, a 5 to 8 percent increase in total and low-density lipoprotein cholesterol levels with diuretic treatment, were originally considered by some to be of epidemiologic interest only. However, the results of the Lipid Research Clinics Primary Prevention Trial [15] suggest that these modest changes may, over time, negate the benefit of lowering blood pressure by increasing the atherogenicity of the serum. In the Lipid Research Trial, a decrease in total cholesterol of 25 percent resulted in a decrease in coronary heart disease risk of 40 percent. The regression of risk plotted against the decrease in the total cholesterol level suggested that for every 1 percent decrease in cholesterol level there was a 2 percent decrease in risk. It is reasonable to hypothesize that a 1 percent increase in cholesterol, conversely, increases the risk by 2 percent. In the case of cholesterol, changes induced by antihypertension treatment with diuretics cause a 5 to 8 percent increase in total cholesterol level that would increase the risk of coronary heart disease by 10 to 16 percent. Conventional antihypertensive therapy, using diuretics and/or beta-blockers, in all clinical trials except one [16], has failed to demonstrate protection against the atherosclerotic complications of hypertension. It can be hypothesized that the atherogenic changes accompanying this treatment may explain, in part, this lack of benefit.
Volume 94 (suppi 38)
SYMPOSIUM
Glucose and Uric Acid. In light of the fact that the effects on electrolytes and lipids probably have an adverse effect on the survival of patients treated with diuretics and beta-blockers, it is no longer safe to assume that the changes in glucose and uric acid metabolism, even in the absence of data, do not share a similar influence. Using this reasoning, drugs that impair glucose or uric acid metabolism or unmask clinical diabetes or gout should be used with caution. In the case of pre-existing abnormalities in glucose or uric acid metabolism, drugs such as the diuretics are contraindicated. SUBJECTIVE EFFECTS OF ANTIHYPERTENSIVE TREATMENT
l
l l
l l
l
HEMODYNAMIC EFFECTS OF ANTIHYPERTENSIVE TREATMENT The hallmark of sustained hypertension is increased peripheral resistance. The ideal antihypertensive drug should lower blood pressure by reducing vascular resistance, especially in the critical beds such as the brain, the coronary circulation, and the kidneys. Drugs that lower blood pressure by reducing cardiac output, such as the beta-blockers, may therefore be less ideal than drugs that act by reduction of peripheral resistance. The relationship of the hypertension and antihypertensive agents on left ventricular function and mass has recently received a great deal of attention. Noninvasive techniques for assessing left ventricular function and
25, 1988
ANTAGONISTS-SCHOENBERGER
The Ideal Antihypertensive Agent
Effective in lowering elevated blood pressure in at least 50 percent of patients as monotherapy Available in a once-a-day formulation to maximize compliance Minimal or no effects on electrolyte levels, serum lipid levels, and glucose metabolism Minimal or no adverse effects on quality of life Lowers blood pressure by decreasing resistance in critical vascular beds Prevents development of left ventricular hypertrophy, or affects its regression if present
TABLE IV
Concern over the subjective side effects of antihypertensive therapy has been increasing in recent years. Although diuretics and beta-blockers are relatively free of serious side effects, they may cause minor changes in the overall sense of well-being of the patient, leading to an unfavorable impact on the quality of life. Recent studies have demonstrated that it is possible to assess the quality of life using validated questionnaires [17]. Drugs differ markedly in their impact on the quality of life. Propranolol and methyldopa were significantly different than converting enzyme inhibitors in having a deleterious effect on the quality of life. The negative impact on quality of life may be increased by the addition of diuretic therapy [18]. These considerations are important because the shortterm benefit of treatment of mild-to-moderate hypertension is low. If the patient perceives that the treatment has an adverse effect on the quality of life, the level of energy, the ability to work, or sexual performance, discontinuation of treatment is highly likely. Studies have shown that 20 to 30 percent of patients in various clinical trials discontinue treatment because of side effects despite vigorous efforts to maintain compliance [19,20]. Even though the benefits of long-sustained treatment on the cardiovascular end points can be demonstrated by clinical trials,-the likelihood of achieving these results in individual patients will be decreased by less than full compliance with the regimen.
March
TABLE Ill
ON CALCIUM
Concurrent Conditions That Influence Selection of First-Line Antihypertensive Treatment
Condition
Drugg;of Choice
Hypokalemia or hypomagnesemia
Elevated
serum
Left ventricular
lipid levels
hypertrophy
lschemic heart diseaseangina or myocardial infarction Diabetes
Heart
failure
Beta-blocker ACE Calcium blockers Alpha-blockers ACE inhibitors Calcium blockers Alpha-blockers ACE inhibitors Alpha-blockers Beta-blockers Beta-blockers ACE inhibitors Calcium blockers Diuretics ACE inhibitors Calcium blockers Alpha-blockers ACE inhibitors
Diuretics
Diuretics Beta-blockers Diuretics Calcium
uric
Diuretics Beta-blockers Diuretics (low potassium) Beta-blockers Calcium blockers Diuretics
ACE inhibitors Calcium blockers Alpha-blockers Beta-blockers Calcium blockers Alpha-blockers ACE inhibitors Diuretics
Asthma and obstructive lung disease
ACE = angiotensin-converting
blockers
None
Diuretics Gout or elevated acid levels
Contraindicated Drugs
Beta-blockers
enzyme.
mass using echocardiography are now widely available [21]. The significance of left ventricular hypertrophy defined by electrocardiographic criteria has long been established [22]. Whether similar relationships will be shown to exist for left ventricular hypertrophy defined by echocardiographic criteria is currently under investigation. It is not known if regression of left ventricular hypertrophy will benefit hypertensive patients [23]. Regression can often be achieved in a relatively short period of antihyper-
The Americap
Journal
of Medicine
Volume
84
(suppl 38)
29
SYMPOSIUM
ON CALCIUM
ANTAGONISTS-SCHOENSERGER
tensive treatment. This regression has not been shown to decrease systolic function of the myocardium and there may be improvement in diastolic function [24]. Antihypertensive agents may differ in their ability to effect the regression of left ventricular hypertrophy. Sympatholytic agents including beta-blockers and converting enzyme inhibitors decrease left ventricular hypertrophy. Diuretics and calcium blockers appear to lower blood pressure without affecting regression of left ventricular hypertrophy. Whether this will result in persistence of ventricular ischemia is not known. Additional studies are needed to investigate these issues that may bear importantly on the choice of antihypertensive agents. A NEW APPROACH OF HYPERTENSION
TO THE FIRST-LINE
TREATMENT
The ideal antihypertensive drug would possess the characteristics shown in Table Ill. No single drug now available meets these requirements entirely, but some drugs come closer than others. If we are to use these criteria for selection of alternate approaches to the treatment of high blood pressure rather than the stepped-care approach [4], what guidelines can be established for the selection of a first line drug beyond diuretics or beta-blockers? Among the other drug classes that can be considered for initial treatment are alpha-blockers, converting enzyme inhibi-
tors, calcium blockers, and various modifications of the beta-blockers possessing partial agonist activity or combined alpha- and beta-blockade. Previous clinical experience has suggested that the age and race of the patient may be helpful in selecting initial therapy. In older hypertensive patients, diuretics or calcium blockers appear to elicit the best response. Younger patients are more responsive to beta-blockers. Black patients with hypertension have the best response to diuretics. These demographic characteristics, useful in a general sense, are not invariable and there are numerous individual exceptions to these guidelines that mandate a broader choice of drugs. Selection of which drug to try first should also be influenced by the concurrent conditions present in patients. These considerations are shown in Table IV. The indications and contraindications are relative and not absolute. Wherever possible, treatment with one drug, monotherapy, should be attempted. Substitution, rather than addition, of a second drug seems wiser than the rigid stepwise addition inherent in the stepped-care approach. Only when monotherapy based on trial of at least two drugs has failed to control the blood pressure should two drugs be combined. Careful attention to the impact of the regimen selected on the quality of life of the patient must be maintained to ensure compliance with the treatment for a long period of time.
REFERENCES
4.
5. 6.
7.
8.
30
Feinleib M: The magnitude and nature of the decrease in coronary heart disease mortality rate. Am J Cardiol1984; 54: 2C6C. Pell S, Fayweather WE: Morbidity trends in myocardial infarction in a large employed population, 1957-1979 (abstr). Am Heart Assoc CVD Epidemiol Newsletter 1982; 31: 58. Friedman GD: Decline in hospitalizations of coronary heart disease and stroke: the Kaiser-Permaneute experience in northern California. In: Proceedings of the conference on the decline in coronary heat disease mortality, Bethesda, Maryland, October 24 to 25, 1978. (DHEW report no. NIH 79-1610.) Washington, D.C.: National institutes of Health, 1979; 109114. The 1984 Report of the Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure. (United States Department of Health and Human Services publication no. 84-1008.) Washington, DC.: National Institutes of Health, 1984. Moser M: Historical perspective on the management of hypertension. Am J Med 1988; 80 (suppl 58): l-l 1. Multiple Risk Factor Intervention Trial Research Groups: Baseline resting electrocardiographic abnormalities, antihypertensive treatment, and mortality in the Multiple Risk Factor Intervention Trial. Am J Cardiol 1985; 55: l-5. Grimm RH: The drug treatment of mild hypertension in the Multiple Risk Factor Intervention Trial: a review. Drugs 1986; (suppl 1): 13-21. Potassium/magnesium depletion: Is your patient at risk of sud-
March
25, 1988
The American
Journal
of Medicine
Volume
9.
10.
11.
12.
13.
14.
15.
16.
den death? Hollenberg NK, Hollifield JW, eds. Am J Med 1987; 82 (suppl 3A): l-53. Johansson BW, Dziamski R: Malignant arrhythmias in acute myocardial infarction. Drugs (suppl) 1984; 28: 11-15. Packer M, Gottlieb SS, Blum MA: Immediate and long-term pathophysiologic mechanisms underlying the genesis of sudden cardiac death in patients with congestive heart failure. Am J Med 1987; 82 (suppl 3A): 4-10. Grimm RH, Neaton JD, McDonald M, et al: Beneficial effects from systematic dosage reduction of the diuretic, chlorthelidone: a randomized study within a clinical trial. Am Heart J 1985; 109: 858-884. Grimm RH, Leon A, Hunningheke D: Effects of thiazide diuretics on plasma lipids and lipoproteins in mildly hypertensive men. Ann Intern Med 1987; 94: 7-11. Lasser NL, Grandits G, Caggiule AW, et al: Effects of antihypertensive therapy on plasma lipids and lipoproteins in the Multiple Risk Factor Intervention Trial. Am J Med 1984; 76 (suppl 2A): 52-66. Weidmann P, Uehlinger DE, Gerber A: Antihypertensive treatment and serum lipoproteins. J Hypertens 1985; 54: 3OC34c. Rifkind BM: Lipid Research Clinics Coronary Primary Prevention Trial; results and implications. Am J Cardiol 1984; 54: 3oc-34c. Amery A, Birkenhager W, Brixko P, et al: Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly Trial. Lancet 1985; I: 1349-1354.
64 (suppl
38)
SYMPOSIUM
17.
16.
19.
20.
21.
Croog SH, Levine S, Testa MA, et al: The effects of antihypertensive therapy on the quality of life. N Engl J Med 1986; 314: 1657-1664. Williams GH, Croog SH, Levine S, Testa MA: Impact of antihypertensive therapy on quality of life: effect of hydrochlorothiazide. J Hvoertens 1987; 5 (SUDDI 1): S29-S35. Report of the Medical Research ‘Council Working Party on Mild to Moderate Hypertension: adverse reactions to bendrofluazide and propranolol for the treatment of mild hypertension. Lancet 1981; II: 539-542. Curb JD, Borhani NO, Blaszkowski TP, et al: Long-term surveillance for adverse effects of antihypertensive drugs. JAMA 1985; 253: 3263-3268.
March
25, 1989
22.
23. 24.
The
ON CALCIUM
ANTAGONISTS-SCHOENBERGER
Liebson PR, Savage DD: Echocardiography in hypertension: a review. I. Left ventricular wall mass, standardization and ventricular function. Echocardiography 1986; 3: 181-233, Kannel WB, Gordon T, Offutt D: Left ventricular hypertrophy by electrocardiogram. Prevalence, incidence, and mortality in the Framingham study. Ann Intern Med 1969; 71: 89104. Messerli FH, Devereux RB: Left ventricular hypertrophy-good or evil? Am J Med 1983; 75 (suppl 3A): 1-3. 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. Echocardiography 1987; 4: 215-249.
American
Journal
of Medicine
Volume
84 (suppl
38)
31
Stepped-care treatment of hypertension has been widely adopted, and improvement in control of high blood pressure is probably responsible for the decline in stroke mortality rates in the past 15 years. Yet many trials of the efficacy of the treatment of high blood pressure have failed to demonstrate that lowering blood pressure uging stepped care will prevent coronary heart disease. Recent evidgnce suggests that the benefit of stepped care based on the use of diuretics and beta-blockers may be diminished by simultaneous hgrm from the drugs used. This includes hypokalemia, hypomagngsemia, hyperglycemia, hyperuricemia, elevation of total and iowdgnsity lipoprotein cholesterol levels, elevation of triglyceride levelg, and a decrease in high-density lipoprotein cholesterol levels. Awareness of this has led to the development of alternative choices for first-line treatment of milg high blood pressure. A new approach enlarges the number of options for initial treatment to include calcipm blockers, angiotensin-converting enzyme inhibitors, alphablockers, diuretics, and beta-blockers. Selection of the most appropriate drug is individualized according to the characteristics of the patient. Demographic considerations of age and race are only partially helpful because of frequent exceptions to the rules. Of greater ifnportance are considerations of concurrent disease such as coronary heart disease, diabetes, gout, and hyperlipidemia, for these cqnditions are powerful determinants of the best first-line drug. Substitution, rather than addition, of another drug should be used when the first choice is not successful.
JAMES A. SCHOENBERGER, M.D. Chicago,
Illinois
From the Department of Preventive Medicine, Rush Medical College, Chicago, Illinois. Requests for reprints should be addressed to Dr. James A. Schoenberger, Rush-Presbyterian-St. Luke’s Medical Center, 1725 West Harrison Street, Chicago, Illinois 60612.
28
March
25, 1888
The American
Journal
The number of deaths from coronary heart disease and stroke has been declining steadily in the United States since 1972 [I 1. From 1972 to 1982, coronary heart disease death rates declined 27 percent and stroke death rates 42 percent. The explanation for these declines is complicated by the fact that there are inadequate data on the incidence of nonfatal coronary heart disease and stroke. Hence, it is possible that some of the decline in the number of deaths may be a result of improved treatment or moderation in the severity of the disease process, and the overall incidence of the disease may not have changed. Several studies [2,3], however, do suggest a decline in incidence as well. Therefore, it seems likely that the incidence of both nonfatal and fatal coronary heat-l disease and stroke has been declining significantly in the .lJnited States in the past 15 years. Although coronary heart disease is multifactorial, the identification of elevated blood pressure as an independent risk factor has been widely recognized. In the case of stroke, hypertension is considered to be the major riik factor. It is reasonable to assume that treatment of hypertension might reduce the complications of coronary heart disease and stroke. Based on that assumption, the National Heart, Lung, and Blood Insti-
of Medicine
Volume
84
(suppl 38)
SYMPOSIUM
tute of the National Institutes of Health began an extensive program in 1972, the National High Blood Pressure Education Program. This ambitious program was directed toward increasing the public’s awareness of the importance of treatment of high blood pressure, and increasing the medical profession’s skill in treatment. A series of guidelines to therapy were developed and revised over the years. The most recent statement of these guidelines by the Joint National Committee on the Detection, Evaluation and Treatment of High Blood Pressure, published in 1984 [4], describes the stepped-care approach to treatment. This system has been widely accepted by practicing physicians. About 90 percent of all primary-care physicians use diuretics and about 50 percent use beta-blockers for the treatment of high blood pressure. How much the more aggressive approach to the treatment of high blood pressure and the treatment of milder degrees of elevated blood pressure have contributed to the declining death rates is uncertain. It is known that the amount of undetected hypertension has steadily declined from a high of 50 percent in a survey in Chicago in 1967 to 1972 to a low of 4 percent in a survey in Westchester County, New York, in 1981 to 1982 [5]. At the same time, the percentage of persons with high blood pressure receiving treatment has risen from 25 percent to 87 percent and the percentage of those with high blood pressure under control has risen from 11 percent to 72 percent, respectively. These impressive changes in the management of high blood pressure may well explain some, but not all, of the decline in coronary heart disease mortality rates and most of the decline in the number of deaths caused by stroke. If the widespread adoption of the stepped-care approach to the treatment of hypertension has resulted in pat-t in a striking decline in death rates from coronary heart disease and stroke, one might question the need for or wisdom of a new approach to the treatment of hypertension when the present approach is working very well. Such a course can only be considered if new evidence suggests that, good as it is, the stepped-care approach may not be capable of fully achieving the maximal benefit from lowering elevated blood pressure or may even, in some cases, be harmful. Such evidence has been accumulating and will be reviewed in this study. It will be made clear that how we lower elevated blood pressure may be more important than had been previously appreciated in the past, when greater interest was focused on merely lowering the blood pressure by any means. . METABOLIC CONSEQUENCES OF ANTIHYPERTENSIVE TREATMENT
The adverse effects of the commonly used antihypertensive drugs, the thiazide diuretics and beta-blockers, have been known since their widespread use began. Thus, hypokalemia, hypomagnesemia, hyperglycemia, and hy-
March
25, 1988
ON CALCIUM
ANTAGONISTS-SCHOENBERGER
peruricemia associated with the use of diuretics were accepted as a necessary consequence of lowering the blood pressure. When these metabolic changes occurred, action, often inadequate, was taken to compensate for the changes. Patients in whom hypokalemia developed were given oral potassium supplements or a potassium-sparing diuretic. Patients in whom hyperglycemia developed were given oral antidiabetic agents, dietary instruction, and occasionally insulin. Patients in whom hyperuricemia or gout developed were given uricosuric agents, allopurinol, or anti-inflammatory agents. It was not perceived that these metabolic effects were life threatening or in any way diminished the benefit of lowered blood pressure. Recent evidence, however, suggests that these, plus only recently recognized changes in serum lipid levels associated with diuretic and beta-blocker therapy, may indeed have an adverse effect on survival that diminishes the benefit of lowering blood pressure. Electrolytes. The importance of disturbances in serum electrolytes, particularly potassium and magnesium levels, has now become better appreciated, as a result of the Multiple Risk Factor Intervention Trial [6]. In this study, a subgroup of hypertensive patients with baseline electrocardiographic abnormalities (mainly high precordial R waves, negative T waves, left axis deviation, and ST depression or elevation) was found to experience excess mortality rates associated with the treatment given to the group receiving special intervention compared with the group receiving usual care. The major difference in the treatment was that a higher percentage of men in the group receiving special intervention received 100 mg of hydrochlorothiazide or chlorthalidone than did men in the group receiving usual care. The results of the study are shown in Table I. The trend toward benefit from treatment in the special intervention group was shown for all subgroups except for those hypertensive patients with baseline electrocardiographic abnormalities where there was a 65 percent high death rate [7]. This finding has led to the hypothesis that the mechanism of death in the Multiple Risk Factor Intervention Trial, often sudden, was related to hypokalemia-induced arrhythmia. The depletion of potassium and magnesium with diuretic treatment has been amply documented as have been the increase in ventricular premature beats and serious arrhythmias associated with hypokalemia and hypomagnesemia. These relationships have recently been reviewed [8]. Thus, it appears that myocardial disease may make hypertensive patients especially vulnerable to the effects of electrolyte depletion. This would appear to be so in left ventricular hypertrophy (Multiple Risk Factor Intervention Trial) [7], in myocardial infarction [9], and in congestive heart failure [lo]. In uncomplicated mild hypertension, the signs of early left ventricular hypertrophy were present in about a third of the Multiple Risk Factor Intervention Trial hypertensive patients. These patients
The American
Journal
of Medicine
Volume
84
(suppl 38)
27
SYMPOSIUM
TABLE
ON CALCIUM
I
ANTAGONISTS-SCHOENSERGER
Mortality Rate (per 1,000 persons) According to Hypertensive Abnormalities: Multiple Risk Factor Intervention Trial’
Status and Baseline
Number of Deaths Attributed to Comnaty Heari Disease Special intervention Nonhypertensive, Absent Present Hypertensive, Absent Present ‘Adapted
from
resting
resting
electrocardiographic 13.2 16.6 electrocardiographic 15.6 29.2
II
Special intervention
Usual Care
abnormalities 16.1 25.7
39.1 33.6
33.6 46.0
20.7 17.7
35.9 60.0
43.4 39.7
abnormalities
(71.
Mean Changes (percent) in Plasma Lipid Levels at 72 Months by Antihypertensive Treatment Status: Multiple Risk Factor Intervention Trial* Special intervention
Usual Care
Plasma cholesterol percent change (mg/dl) No treatment Diuretic only Diuretic and propranoiol
-13.1 -9.1 -6.3
-9.1 -2.5 +1.0
Plasma triglyceride percent change (mg/dl) No treatment Diuretic only Diuretic and propranolol
-16.5 16.5 52.2
-11.6 24.9 49.1
“Men not taking antihypertensive Adapted from [7j.
26
Total Number of Deaths
Usual Care
may benefit from reduction of elevated blood pressure at the cost of an increased risk of sudden death. The net result may be a significant lessening in overall benefit. To some extent, the adverse effects of the diuretics on serum electrolytes can be reduced by a reduced dose of diuretic [l l] and it is now current practice to limit the dose of diuretic as much as possible. Lipids. The effect of antihypertensive drug treatment on serum lipid levels was not recognized until the Multiple Risk Factor Intervention Trial study showed that use of thiazide diuretics was associated with a rise in total and low-density lipoprotein cholesterol levels [12,13]. These findings are summarized in Table II, which also includes changes in lipids associated with beta-blocker therapy. These data show that the cholesterol-lowering effect of the diet used in the Multiple Risk Factor Intervention Trial for the men in the group receiving special intervention was reduced by the use of a diuretic or the combination of a diuretic and beta-blocker. Similar findings were noted in the men in the group receiving usual care. The use of a
TABLE
Electrocardiographic
March 25, 1999
agents
at baseline.
The American Journal of Medicine
diuretic alone or in combination with a beta-blocker was associated with a rise in triglyceride levels in both the special intervention and usual care groups. Thus, the benefit of the lowered blood pressure was associated with atherogenic changes in the serum lipids that were only partially blunted by diet. A large number of studies have focused on the effects of antihypertensive therapy on serum lipid levels. Although there is still controversy over the extent and persistence of these effects over time, the bulk of the evidence favors a small, persistent elevation of total and lowdensity lipoprotein cholesterol levels associated with diuretic treatment and a moderate rise in triglyceride levels with a decrease in high-density lipoprotein cholesterol levels following beta-blocker treatment [14]. These changes, a 5 to 8 percent increase in total and low-density lipoprotein cholesterol levels with diuretic treatment, were originally considered by some to be of epidemiologic interest only. However, the results of the Lipid Research Clinics Primary Prevention Trial [15] suggest that these modest changes may, over time, negate the benefit of lowering blood pressure by increasing the atherogenicity of the serum. In the Lipid Research Trial, a decrease in total cholesterol of 25 percent resulted in a decrease in coronary heart disease risk of 40 percent. The regression of risk plotted against the decrease in the total cholesterol level suggested that for every 1 percent decrease in cholesterol level there was a 2 percent decrease in risk. It is reasonable to hypothesize that a 1 percent increase in cholesterol, conversely, increases the risk by 2 percent. In the case of cholesterol, changes induced by antihypertension treatment with diuretics cause a 5 to 8 percent increase in total cholesterol level that would increase the risk of coronary heart disease by 10 to 16 percent. Conventional antihypertensive therapy, using diuretics and/or beta-blockers, in all clinical trials except one [16], has failed to demonstrate protection against the atherosclerotic complications of hypertension. It can be hypothesized that the atherogenic changes accompanying this treatment may explain, in part, this lack of benefit.
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Glucose and Uric Acid. In light of the fact that the effects on electrolytes and lipids probably have an adverse effect on the survival of patients treated with diuretics and beta-blockers, it is no longer safe to assume that the changes in glucose and uric acid metabolism, even in the absence of data, do not share a similar influence. Using this reasoning, drugs that impair glucose or uric acid metabolism or unmask clinical diabetes or gout should be used with caution. In the case of pre-existing abnormalities in glucose or uric acid metabolism, drugs such as the diuretics are contraindicated. SUBJECTIVE EFFECTS OF ANTIHYPERTENSIVE TREATMENT
l
l l
l l
l
HEMODYNAMIC EFFECTS OF ANTIHYPERTENSIVE TREATMENT The hallmark of sustained hypertension is increased peripheral resistance. The ideal antihypertensive drug should lower blood pressure by reducing vascular resistance, especially in the critical beds such as the brain, the coronary circulation, and the kidneys. Drugs that lower blood pressure by reducing cardiac output, such as the beta-blockers, may therefore be less ideal than drugs that act by reduction of peripheral resistance. The relationship of the hypertension and antihypertensive agents on left ventricular function and mass has recently received a great deal of attention. Noninvasive techniques for assessing left ventricular function and
25, 1988
ANTAGONISTS-SCHOENBERGER
The Ideal Antihypertensive Agent
Effective in lowering elevated blood pressure in at least 50 percent of patients as monotherapy Available in a once-a-day formulation to maximize compliance Minimal or no effects on electrolyte levels, serum lipid levels, and glucose metabolism Minimal or no adverse effects on quality of life Lowers blood pressure by decreasing resistance in critical vascular beds Prevents development of left ventricular hypertrophy, or affects its regression if present
TABLE IV
Concern over the subjective side effects of antihypertensive therapy has been increasing in recent years. Although diuretics and beta-blockers are relatively free of serious side effects, they may cause minor changes in the overall sense of well-being of the patient, leading to an unfavorable impact on the quality of life. Recent studies have demonstrated that it is possible to assess the quality of life using validated questionnaires [17]. Drugs differ markedly in their impact on the quality of life. Propranolol and methyldopa were significantly different than converting enzyme inhibitors in having a deleterious effect on the quality of life. The negative impact on quality of life may be increased by the addition of diuretic therapy [18]. These considerations are important because the shortterm benefit of treatment of mild-to-moderate hypertension is low. If the patient perceives that the treatment has an adverse effect on the quality of life, the level of energy, the ability to work, or sexual performance, discontinuation of treatment is highly likely. Studies have shown that 20 to 30 percent of patients in various clinical trials discontinue treatment because of side effects despite vigorous efforts to maintain compliance [19,20]. Even though the benefits of long-sustained treatment on the cardiovascular end points can be demonstrated by clinical trials,-the likelihood of achieving these results in individual patients will be decreased by less than full compliance with the regimen.
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TABLE Ill
ON CALCIUM
Concurrent Conditions That Influence Selection of First-Line Antihypertensive Treatment
Condition
Drugg;of Choice
Hypokalemia or hypomagnesemia
Elevated
serum
Left ventricular
lipid levels
hypertrophy
lschemic heart diseaseangina or myocardial infarction Diabetes
Heart
failure
Beta-blocker ACE Calcium blockers Alpha-blockers ACE inhibitors Calcium blockers Alpha-blockers ACE inhibitors Alpha-blockers Beta-blockers Beta-blockers ACE inhibitors Calcium blockers Diuretics ACE inhibitors Calcium blockers Alpha-blockers ACE inhibitors
Diuretics
Diuretics Beta-blockers Diuretics Calcium
uric
Diuretics Beta-blockers Diuretics (low potassium) Beta-blockers Calcium blockers Diuretics
ACE inhibitors Calcium blockers Alpha-blockers Beta-blockers Calcium blockers Alpha-blockers ACE inhibitors Diuretics
Asthma and obstructive lung disease
ACE = angiotensin-converting
blockers
None
Diuretics Gout or elevated acid levels
Contraindicated Drugs
Beta-blockers
enzyme.
mass using echocardiography are now widely available [21]. The significance of left ventricular hypertrophy defined by electrocardiographic criteria has long been established [22]. Whether similar relationships will be shown to exist for left ventricular hypertrophy defined by echocardiographic criteria is currently under investigation. It is not known if regression of left ventricular hypertrophy will benefit hypertensive patients [23]. Regression can often be achieved in a relatively short period of antihyper-
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tensive treatment. This regression has not been shown to decrease systolic function of the myocardium and there may be improvement in diastolic function [24]. Antihypertensive agents may differ in their ability to effect the regression of left ventricular hypertrophy. Sympatholytic agents including beta-blockers and converting enzyme inhibitors decrease left ventricular hypertrophy. Diuretics and calcium blockers appear to lower blood pressure without affecting regression of left ventricular hypertrophy. Whether this will result in persistence of ventricular ischemia is not known. Additional studies are needed to investigate these issues that may bear importantly on the choice of antihypertensive agents. A NEW APPROACH OF HYPERTENSION
TO THE FIRST-LINE
TREATMENT
The ideal antihypertensive drug would possess the characteristics shown in Table Ill. No single drug now available meets these requirements entirely, but some drugs come closer than others. If we are to use these criteria for selection of alternate approaches to the treatment of high blood pressure rather than the stepped-care approach [4], what guidelines can be established for the selection of a first line drug beyond diuretics or beta-blockers? Among the other drug classes that can be considered for initial treatment are alpha-blockers, converting enzyme inhibi-
tors, calcium blockers, and various modifications of the beta-blockers possessing partial agonist activity or combined alpha- and beta-blockade. Previous clinical experience has suggested that the age and race of the patient may be helpful in selecting initial therapy. In older hypertensive patients, diuretics or calcium blockers appear to elicit the best response. Younger patients are more responsive to beta-blockers. Black patients with hypertension have the best response to diuretics. These demographic characteristics, useful in a general sense, are not invariable and there are numerous individual exceptions to these guidelines that mandate a broader choice of drugs. Selection of which drug to try first should also be influenced by the concurrent conditions present in patients. These considerations are shown in Table IV. The indications and contraindications are relative and not absolute. Wherever possible, treatment with one drug, monotherapy, should be attempted. Substitution, rather than addition, of a second drug seems wiser than the rigid stepwise addition inherent in the stepped-care approach. Only when monotherapy based on trial of at least two drugs has failed to control the blood pressure should two drugs be combined. Careful attention to the impact of the regimen selected on the quality of life of the patient must be maintained to ensure compliance with the treatment for a long period of time.
REFERENCES
4.
5. 6.
7.
8.
30
Feinleib M: The magnitude and nature of the decrease in coronary heart disease mortality rate. Am J Cardiol1984; 54: 2C6C. Pell S, Fayweather WE: Morbidity trends in myocardial infarction in a large employed population, 1957-1979 (abstr). Am Heart Assoc CVD Epidemiol Newsletter 1982; 31: 58. Friedman GD: Decline in hospitalizations of coronary heart disease and stroke: the Kaiser-Permaneute experience in northern California. In: Proceedings of the conference on the decline in coronary heat disease mortality, Bethesda, Maryland, October 24 to 25, 1978. (DHEW report no. NIH 79-1610.) Washington, D.C.: National institutes of Health, 1979; 109114. The 1984 Report of the Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure. (United States Department of Health and Human Services publication no. 84-1008.) Washington, DC.: National Institutes of Health, 1984. Moser M: Historical perspective on the management of hypertension. Am J Med 1988; 80 (suppl 58): l-l 1. Multiple Risk Factor Intervention Trial Research Groups: Baseline resting electrocardiographic abnormalities, antihypertensive treatment, and mortality in the Multiple Risk Factor Intervention Trial. Am J Cardiol 1985; 55: l-5. Grimm RH: The drug treatment of mild hypertension in the Multiple Risk Factor Intervention Trial: a review. Drugs 1986; (suppl 1): 13-21. Potassium/magnesium depletion: Is your patient at risk of sud-
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25, 1988
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den death? Hollenberg NK, Hollifield JW, eds. Am J Med 1987; 82 (suppl 3A): l-53. Johansson BW, Dziamski R: Malignant arrhythmias in acute myocardial infarction. Drugs (suppl) 1984; 28: 11-15. Packer M, Gottlieb SS, Blum MA: Immediate and long-term pathophysiologic mechanisms underlying the genesis of sudden cardiac death in patients with congestive heart failure. Am J Med 1987; 82 (suppl 3A): 4-10. Grimm RH, Neaton JD, McDonald M, et al: Beneficial effects from systematic dosage reduction of the diuretic, chlorthelidone: a randomized study within a clinical trial. Am Heart J 1985; 109: 858-884. Grimm RH, Leon A, Hunningheke D: Effects of thiazide diuretics on plasma lipids and lipoproteins in mildly hypertensive men. Ann Intern Med 1987; 94: 7-11. Lasser NL, Grandits G, Caggiule AW, et al: Effects of antihypertensive therapy on plasma lipids and lipoproteins in the Multiple Risk Factor Intervention Trial. Am J Med 1984; 76 (suppl 2A): 52-66. Weidmann P, Uehlinger DE, Gerber A: Antihypertensive treatment and serum lipoproteins. J Hypertens 1985; 54: 3OC34c. Rifkind BM: Lipid Research Clinics Coronary Primary Prevention Trial; results and implications. Am J Cardiol 1984; 54: 3oc-34c. Amery A, Birkenhager W, Brixko P, et al: Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly Trial. Lancet 1985; I: 1349-1354.
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17.
16.
19.
20.
21.
Croog SH, Levine S, Testa MA, et al: The effects of antihypertensive therapy on the quality of life. N Engl J Med 1986; 314: 1657-1664. Williams GH, Croog SH, Levine S, Testa MA: Impact of antihypertensive therapy on quality of life: effect of hydrochlorothiazide. J Hvoertens 1987; 5 (SUDDI 1): S29-S35. Report of the Medical Research ‘Council Working Party on Mild to Moderate Hypertension: adverse reactions to bendrofluazide and propranolol for the treatment of mild hypertension. Lancet 1981; II: 539-542. Curb JD, Borhani NO, Blaszkowski TP, et al: Long-term surveillance for adverse effects of antihypertensive drugs. JAMA 1985; 253: 3263-3268.
March
25, 1989
22.
23. 24.
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Liebson PR, Savage DD: Echocardiography in hypertension: a review. I. Left ventricular wall mass, standardization and ventricular function. Echocardiography 1986; 3: 181-233, Kannel WB, Gordon T, Offutt D: Left ventricular hypertrophy by electrocardiogram. Prevalence, incidence, and mortality in the Framingham study. Ann Intern Med 1969; 71: 89104. Messerli FH, Devereux RB: Left ventricular hypertrophy-good or evil? Am J Med 1983; 75 (suppl 3A): 1-3. 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. Echocardiography 1987; 4: 215-249.
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