historical perspective on the management of hypertension

Historical Perspective on the Management of Hypertension

MARVIN MOSER, M.D. White Plains, New York

Remarkable progress has been made dur!ng the past 20 years in the management of hypertension, a disease that affects approximately one out of every four adults in the United States. In the 199Os, at least half of the Individuals with hypertension were unaware of their disease, and the blood pressures of fewer than 29 percent were controlled at normotensive levels. In contrast, in the 199Os, only a small percentage, perhaps as few as 10 or 15 percent of hypertensive patients, are unaware of their disease and, in many parts of the coun- try, more than 90 percent are being treated to goal blood pressure levels. More effective treatment of hypertension is probably a major reason for the 45 percent decrease In stroke mortality rates in the last 12 years alone and for the dramatic decrease in the number of hypertensive patients in whom renal failure or congestive heart failure develops. In addition, at least a portion of the 25 to 20 percent decrease in coronary mortality rates can probably bs attributed to better management of patients with hypertension. The availability of antihypertensive drugs in the 1950s (rauwola preparations, veratrum derivatives, thiocyanates, hydralaxine, and the ganglion blockers) and the discovery of more effective agents in the period from the 1990s to the present have dramatically improved the prognosis of hypertensive patients. Thiaxide diuretics, centrally acting sympa- tholytic agents, beta-adrengrgic inhibitors, and, more recently, selective alpha-adrenergk inhibitors, converting-enzyme inhibitors, and calcium entry blockers are examples of these medications. All of these agents have some side effects, with varying patient accept- ability. The search continues for newer drugs that are well tolerated, that lower blood pressure by reducing peripheral resistance, and that produce few metabolic changes. A detailed review of the phybi- ologic effects of antihypertensive medications, as well as a critique of the clinical trials and some of the problems noted in the pharma- cologic management of hypertension, is presented.

During the past 30 years, advances in hypertension management have been as dramatic as any in any field of medicine. Although in most cases we still may not understand the exact cause of hypertension, our ability to treat this disease and prevent its complications has progressed steadily from the 1930s and 1940s when there were literally no effective treatments available. Largely as a result of the discovery of antihypertensive drugs and their widespread use, the longevity of hypertensive patients has improved dramatically, with a decrease of about 45 percent in the mortality rate from strokes during the last 12 years and a marked reduction in the number of patients who show a progression from mild to mod-

From Yale University School of Medicine, New Haven, Connecticut. Requests for reprints should be addressed to Dr. Marvin Moser, Davis Avenue Medical Center, 33 Davis Avenue, White Plains, New York 10605.

May 23,1988 The American Journal of Medlclne Volume 80 (suppl 5B) 1

SYMPOSIUM ON TEWOSIN-MOSER

Data from the National Center tar Health Statlslics and the National Heart, Lung and Stood Institute

‘Pmvtslonal Data

Figure 1. Since 1968, and particularly since 1974, there has been a dramatic decline in the mortality rate from coronary heart disease and strokes in the United States. Mortality rates have been ad- justed for age (ages 35 to 74).

erate or severe hypertension [l] (Figure 1). Accelerated or malignant hypertension and acute pulmonary edema secondary to untreated hypertension are rarities. In addition, progression to renal failure has largely been prevented in patients who are treated early and whose blood pressures are kept at normal levels. Although we still be- lieve that patients with less severe hypertension should initially be treated nonpharmacologically and that perhaps as many as 20 to 25 percent will respond with normotensive blood pressure levels, it should be remembered that these were the methods that were used in the 1940s and early 1950% with poor results; progression to more severe disease was common and the longevity of patients, even with mild hypertension, was significantly shortened [2].

No one wishes to use medications that may have side effects if other methods work as well, but even with the newer behavioral modification techniques, nonqharmaco- logic treatment is ineffective in a majority of cases [3]. Al- though it is often difficult to persuade patients who are usually asymptomatic that specific treatment is necessary, a strong case can be made for the treatment of mild hypertension before the onset of target-organ involvement [4]. The blood pressures of most hypertensive patients, even those with severe disease, can be controlled at normotensive levels with the appropriate use of one or more of the effective antihypertensive agents presently available, without significant or therapy-limiting side effects.

HISTORICAL PERSPECTIVE

In the 1,940s as investigators struggled to determine the etiology of hypertension, several groups of antihypertensive drugs were developed [5] (Table I). First, there were the veratrum alkaloids, centrally acting drugs that were effective both orally and parenterally. When administered intravenously, a dramatic decrease in blood pressure resulted, but the range between therapeutic and toxic levels

was narrow; nausea, vomiting, and collapse were not un- common when using these drugs. The veratrum drugs were soon replaced by other more effective and safer agents.

Thiocyanates were used for a brief period of time for treatment of hypertension and, in some patients, they were effective. Their use was cumbersome, requiring frequent blood analyses. Drugs in this group were not potent or very specific in their role as blood pressure lowering agents. Even injections of typhoid bacilli were used for a short period of time in accelerated or malignant hypertension (61. The only alternative treatments employed during those years were rigid sodium restriction or bilateral sym- pathectomy; these were useful in some cases of severe disease [7,8].

In the early 1950% the rauwolfia compounds were introduced in the United States. These drugs had been used for centuries and were effective catecholamine depletors, both centrally and peripherally. Initial experience suggested that approximately 20 percent of patients would show a response when these agents were used as monotherapy. When used in combination with thiazide diuretics in the late 1950% a hjgh percentage of patients (as many as 80 percent or more in some series) became normotensive [9]. The rauwolfia drugs were relatively inexpensive, effective in a once-a-day dosage, and produced no metabolic changes or deleterious hemodynamic effects. There were reports, however, of serious depressions following the use of these drugs, especially in dosages of more than 0.5 mg per day; depressions often persisted for four to six weeks or more after the drug was stopped. Dosages as high as 1 or 2 mg per day were frequently used and, in cases of hypertensive encephalopathy, as much as 5 to 10 mg was administered intramuscularly. As more was learned about these drugs and lower dosages were used, depression became a less frequent occurrence, although

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this condition is still noted occasionally. It is often subtle and difficult to diagnose early. In my judgement, rauwolfia drugs, in combination with a diuretic agent, still have a place in hypertensive management, although they are not used frequently.

In the early 1950% hydralazine, a vasodilator, was introduced [lo]. This drug also had limited effectiveness as monotherapy because of secondary, reflex sympathetic stimulation (Figure 2). Blood pressure was lowered, but a tachycardia with an increase in cardiac work was almost universally noted. Tachyphylaxis was also common; much of the blood pressure lowering effect would disappear within a relatively short period of time. Hydralazine was used in the treatment of toxemia related to pregnancy and, when combined with a rauwolfia preparation, was also effective in some patients with primary hypertension. It continues to be used as a third-step drug in patients who have not shown a response to a diuretic and an adrenergic inhibiting agent [ll]. In many instances, the alpha- receptor inhibitors or antagonists have replaced the use of hydralazine. Metabolic abnormalities resulting from the use of hydralazine were rare, but a lupus-like syndrome occurred in a small percentage of patients receiving higher dosages (more than 250 mg per day); with suggested dosage ranges of between 100 and 250 mg per day, this finding is rare. A positive antinuclear antibody test result or other evidence of immune reactions may be noted in as many as 40 to 50 percent of cases.

The ganglion blocking agents hexamethonium and, later, pentolinium and mecamylamine were potent antihypertensive agents that were highly effective in treating accelerated or malignant hypertension. In the 1950s they were used with excellent results in patients resistant to other agents [12,13]. Unfortunately, both sympathetic and parasympathetic impulses were blocked, and numerous side effects resulted-bladder atony, a decrease in gas- trointestinal motility, extreme dry mouth, impotence, and, most significantly, postural hypotension. Absorption was often erratic. These drugs are not used today and have been replaced by safer, more reliable medications. In rare instances, a shorter-acting ganglion blocker, such as trimethophan, has proved useful in decreasing the blood pressure if urgent treatment is necessary or during sur- gery, but the newer vasodilators, nitroprusside, calcium entry blockers, or diazoxide, are probably easier to use.

In the 1950s and 1960% other drugs such as guanethi- dine, a peripheral sympathetic inhibiting agent, were introduced. Bethanidine and guanadrel, medications with similar actions, were introduced in the 1970s and 1960s. These agents are also effective and potent and, when used with a diuretic or other adrenergic inhibiting agent, will often produce an excellent response in “resistant” patients. In a high percentage of patients, postural hypotension remains a significant side effect of these medica-

TABLE I Antihypertensive Therapy from 1940 to 1988

1930s 1940s

1950s

1980s

1970s

1980s

Veratrum alkaloids Ganglion blocking agents Catecholamine depletors Vasxtilators Peripheral sympathetic inhibitors Diuretics Central sympathetic inhibitors Beta-adrenergic inhibitors Alpha-adrenergic inhibitors Converting-enzyme inhibitors Calcium antagonists ?Dopamine agonists ?Serotonin inhibitors

Vasodilator

1 IArterial Resistance

I 1 Blood Pressure

1 Stimulation of Sympathetic NS

I lfleninlangiotensin Activity

/ \ IArterial Resistance IAldosterone Levels

\

1 lNa+ Retention/Plasma Volume

1 ICardiac Output

Mood Pressure /

Figure 2. Administration of a vasodilator as monotherapy results in a reflex increase in sympathetic nerve activity, thereby at least partially attenuating the blood pressure lowering effect. NS = nervous system; Na = sodium.

tions, along with the occurrence of ejaculatory impotence. Despite these effects, this group of drugs is still used in selected cases.

A major breakthrough in the treatment of hypertension occurred in the mid-l 950s with the ihtroduction of chlorothiazide, an orally effective thiazide diuretic [14,15]. Previ- ous experience with intramuscular mercurial diuretics had demonstrated that diuretics could lower blood pressure when given to patients with congestive heart failure. How- ever, the mercurial diuretics were only effective intramuscularly or intravenously, making their long-term use in hypertension management difficult. The use of thiazide diuretics has greatly simplified management. The combination of a thiazide diuretic with reserpine or a beta

May 23,1986 The American Journal of Mfxllclne Volume 80 (suppl5B) 3


I ‘igure 3. ihe initial response to thiazide diuretic therapy is

a decrease in plasma volume, a decrease in cardiac output, and an increase in total peripheral resistance. However, when therapy is continued, plasma volume and cardiac output return toward normal levels, while total peripheral resistance decreases; the decrease in blood pressure (B.P.) is maintained.

blocker, and, in some cases, hydralazine, has proved effective in large numbers of patients. All of the major clinical trials, the Veterans Administration Study, the United States Public Health Study, the Hypertension Detection and Follow-Up Program Study, the Australian Study, the Oslo Study, and the Swedish Study, used these drugs with good results 116-211.

DIURETICS

Diuretics are long-acting, relatively inexpensive, and highly effective [22]. As monotherapy, they are as effective or more effective than any other antihypertensive drug yet developed. They are particularly effective in black and elderly patients, but they also lower blood pressure in white and younger patients to as great a degree as the beta- or alpha-adrenergic inhibiting agents.

The use of diuretics results in a lower peripheral resistance, a desired physiologic effect. Although initially there is a decrease in plasma volume and a slight decrease in cardiac output with a resultant increase in peripheral resistance, cardiac output returns almost to normal after about six to eight weeks of continuous use, with an increase in plasma volume toward normal levels, a decrease in peripheral resistance, and a continuing lowering of blood pressure (Figure 3) [23]. Subjective side effects are not generally troublesome, especially if lower dosages are used (i.e., 25 to 50 mg per day of hydrochlorotfria- zide), although weakness and impotence can be annoying in some patients. Extreme weakness and, in rare cases, significant hyponatremia may occur, especially in older patients. Metabolic changes do occur, however, and although at present they are mainly of theoretic concern,

there is always the possibility that the changes noted may prove to be of some importance with further long-term use of these medications. For example, an increase in serum cholesterol levels following the use of diuretics has been noted in numerous short-term studies [24]. However, in long-term, two- to five-year studies, this change has not been noted; after one to two years of diuretic use, cholesterol levels usually return to pretreatment levels or below and remain there for at least two to three more years [19,22,25]. There is no evidence at present that the diuretic-induced changes in serum lipid levels are of clinical significance.

A continuing decrease in glucose tolerance has also been described following the long-term use of diuretics [26]. Whether the slight increase in blood glucose (6 to 10 mg/dl) or the change in glucose tolerance is of long-range significance has not yet been determined. In some diabetic patients, the use of diuretics has increased the need for antidiabetic medication or for an increased dosage of insulin.

Elevated serum uric acid is a common finding in diuretic-treated patients, with an average increase of 1.2 to 1.5 mg/dl, and, in some predisposed patients, gout has developed. There are no data, however, to suggest that the increase in uric acid is of significance in terms of cardiovascular risk. It may be advisable for patients with gout to use other medications to achieve blood pressure control and only resort to diuretics if this control is not achieved.

Hypokalemia is a common finding in patients treated with diuretics [27]. In my experience, as well as that of others, a decrease in serum potassium of approximately 0.5 to 0.6 meq/liter has occurred over time in diuretic- treated patients [26]. In most instances, this has not proved to be of clinical significance. The majority of younger patients tolerate this degree of potassium loss without exhibiting symptoms. However, in elderly patients, in patients with ischemic heart disease, ectopy, or diabetes, or in those receiving digitalis, this degree of hypokalemia may be significant; it is important to prevent its occurrence if at all possible. Initial concerns that diuretic- induced hypokalemia resulted in significant ectopy and possibly precipitated sudden death [29,30] have not been confirmed by three recent studies utilizing 24- and 46-hour Holter monitoring in hypertensive patients with and without left ventricular hypertrophy [31-331. In these studies, no correlation has been found between hypokalemia induced by diuretics and arrhythmias or sudden death. Data from the Multiple Risk Factor Intervention Trial Study [25] suggesting that patients with electrocardiographic abnormalities who received high dosages of diuretics were at greater risk of sudden death than were those who received lower dosages have also not been confirmed by subsequent analyses [34]. The subsequent analyses found no correlation between the incidence of death and

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the dosages of diuretic used; no correlations between the incidence of sudden death and potassium levels meas- ured prior to death; and that there were actually fewer deaths among patients treated with high dosages of diuretics who had abnormal pretreatment exercise stress test results (this being the group that would be expected to have the greatest number of patients with ischemic heart disease) than among the patients who received smaller dosages of diuretics. The results of the Multiple Risk Fac- tor Intervention Trial should not be ignored, but there are aberrations in the statistical analysis that suggest the data may have been misinterpreted.

Hypokalemia induced by diuretics should not be ignored and should be prevented if at all possible, but the fear of this metabolic change should not deter physicians from using these medications either as initial therapy or in combination with adrenergic inhibitors in the treatment of hypertension.

BETA-ADRENERGIC INHIBITORS

Beta-adrenergic inhibitors have been used worldwide during the past 20 years and in the United States for the past 10 years. These drugs are effective as antihypertensive agents and, as monotherapy, lower the blood pressure to almost as great a degree in as many patients as diuretics do [22]. They are especially effective in younger patients and should probably be preferentially used in patients with histories of myocardial infarctions or in those hypertensive patients with angina; the decrease in cardiac work and oxygen consumption that results from their use may be especially beneficial in such patients. The use of beta blockers results in a continuing decrease in cardiac output over time with an increase in peripheral resistance- physiologic effects that are not ideal (Figure 4). As monotherapy or in combination with a diuretic, a vasodilator, or an alpha-blocking agent, the beta blockers, however, have proved effective. They produce few metabolic side effects, although a delay in glucose mobilization following hypoglycemia and elevations in triglyceride levels with a reduction in high-density lipoprotein cholesterol levels have been reported. The long-term significance of these changes has not been determined. Patients receiving either a diuretic or a beta-adrenergic inhibiting drug should adhere to a low-fat diet to minimize any possible changes in lipid levels.

Subjective side effects resulting from the use of beta blockers include fatigue, insomnia, nightmares, impotence, and symptoms that result from beta-receptor inhibition in vascular and bronchial smooth muscle tissue. A blockade of beta receptors in peripheral arterioles, for example, leaves alpha stimulation unopposed: vasocon- striction may result and worsen symptoms of peripheral arterial disease or Raynaud’s phenomenon. Inhibition of beta receptors in bronchial smooth muscle may predis-

Peripheral Resistance

cardiac output

DW Week Month

Figure 4. The use of beta-blockers such as propranolol re- duces cardiac output and increases peripheral vascular resistance.

pose to bronchospasm and increase symptoms in asth- matic patients or in patients with chronic bronchitis. Inhibi- tion of beta receptors may decrease the secretion of insulin and may delay recovery from insulin shock in insulin- dependent diabetic patients. Beta-adrenergic inhibitors should be used with care or avoided in patients with asthma, severe peripheral arteriolar disease, or insulin- dependent diabetes. These contraindications are not ab- solute.

Many of the beta-adrenergic inhibitors can be given on a once-a-day basis. They are moderately expensive. The cardio-selective beta blockers metoprolol and atenolol may produce less of an effect on bronchial and vascular smooth muscle when given in small dosages; however, when larger dosages are given, this advantage may no longer be noted. The availability of these drugs has improved blood pressure control in many patients.

CENTRALLY ACTING ANTIHYPERTENSIVES

In the 195Os, alpha methyldopa, a centrally acting antihypertensive drug, was made available. Other central adrenergic inhibiting agents such as clonidine and guana- benz became available within the last 10 years. In my experience, when used as monotherapy, these drugs lower blood pressure in a smaller percentage of patients than do the beta blockers or diuretics. They usually have to be administered twice a day and are moderately expensive. However, when these drugs are used in combination with diuretics, normotensive blood pressure responses result in a majority of cases [35]. A major limitation of these agents are the subjective side effects such as drowsiness, dry mouth, and fatigue, which may occur in about 25 to 30 percent of patients. A positive result on the Coombs’ test and abnormalities in liver chemistry tests also occur with alpha methyldopa, limiting the use of this agent in patients with immune diseases, hematologic problems, or liver disease.

May 23,1935 The American Journal of Medlclna Volume 50 (ruppl 5B) 5


TABLE II Five Therapeutic Trials of Mild Hypertension: Cumulative Complications in Control and Treated Groups*

Control Treated Percent lmpmvsmenl

Complications Number+ Percent Number+ Percent (Contml - Treated)/Contml

Total momid events 563 9.0 417 6.6 27 Total mortality 342 5.4 252 4.1 24 Cerebrovascular events: fatal and nonfatal 140 2.2 76 1.2 50 Fatal events coronaly 79 1.2 46 0.7 42

*Data from the Veterans Administration Cooperative Study: diastolic blood pressure 90 to 104 mm Hg; United States Public Health Cooperative Study Group; Hypertension Detection and Follow-Up Program: stratum 1; Australian Study; and Oslo Study. ‘rota1 control and treated populations each comprise approximately 6,400 subjects.

ALPHA BLOCKERS

Although phenoxybenzamine has been in use for more than 30 years [36] and pentoiamine has been used as a diagnostic test for pheochromocytoma since the 1940s these drugs are of limited value in the management of hypertension. Both agents will lower blood pressure dramatically in some cases but, because of their lack of alpha-blockade selectivity and their inhibition of both alpha, and alpha2 receptors, the release of norepineph- rine is not decreased following their use; reflex tachycardia and an increase in cardiac work occurs as blood pressure is lowered. These changes may negate the blood pressure response. The first selective alpha, inhibitor, prazosin, was introduced for use in the United States several years ago [371. Several new alpha, blockers such as terazosin [36] and trimazosin are currently being investi- gated and may be released within the near future for use in hypertensive patients. These drugs are effective vasodilators and also function as venodilators. As monotherapy, they are usually not as effective in as great a percentage of hypertensive patients as are either diuretics or beta blockers, but when used in combination with diuretics, normotensive blood pressure levels are achieved in a high percentage of patients. Although the alpha,-receptor inhibitors primarily affect vasoconstrictor tone, my experience indicates that a reflex tachycardia does occur in some cases, suggesting that a degree of alph&-receptor inhibition also occurs. Some of the so-called tachyphylaxis noted with these drugs may be explained by this activity. A weight gain may also be noted when an alpha,- receptor blocker is used without a diuretic. Experience with prazosin indicates that it is an effective antihypertensive agent when used as a second- or third-step drug with a diuretic or with a diuretic and a beta blocker. Initial experience with terazosin suggests a similar degree of useful- ness with the added advantage of once-a-day dosing. These drugs are particularly effective in patients with elevated diastolic blood pressures that are not controlled by other therapy.

Metabolic side effects are minimal. The dosage must be titrated slowly over time, necessitating several visits to a physician or clinic, which may serve as a deterrent to their use as initial monotherapy. A lowering of serum cholesterol levels has been reported when the alpha, inhibitors are used. Subjective side effects, after the first several weeks and after a dosage has been established, have also been minimal in my experience. Impotence, head- ache, asthenia, and light-headedness have been noted. During the titration phase, I have noted episodes of syn- cope or extreme weakness, especially if the drug is added to diuretic therapy. Episodes of dizziness may also occur when dosages are increased, even after the patient has been receiving the therapy for several weeks or months.

CONVERTING-ENZYME INHIBITORS

The converting-enzyme inhibitor captopril has been used in hypertension management for the past several years (391. Enalapril, another converting-enzyme inhibitor, has recently been approved for use in the United States. As monotherapy, these drugs produce normotensive blood pressure levels in approximately 40 to 50 percent of patients and, when used in combination with a diuretic and/ or a beta blocker, are even more effective [40]. Their availability has helped improve the management of many hypertensive patients. Converting-enzyme inhibitors are expensive and require twice-a-day dosing, but they produce few metabolic side effects and are generally well tolerated by patients. Weakness and dizziness have occurred, and I have observed rashes in between 5 and 10 percent of patients receiving captopril. Some rashes are severe and may occur as early as one week after therapy is started or as late as several months after the start of therapy. Rashes are not as common with dosages of 100 to 150 mg per day as they are with higher dosages of 300 to 450 mg per day. Loss of taste, neutropenia, and deteri- oration of renal function are rare except in those patients with bilateral renal artery stenosis or renal insufficiency.

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CALCIUM ENTRY BLOCKERS

Although as yet unapproved for antihypertensive .treatment in the United States, calcium entry blockers have proved useful in the management of hypertension. My experience with diltiazem, nifedipine, and nitrendipine suggests that these drugs, as monotherapy, are almost as effective as diuretic agents in lowering blood pressure [41,42]. They appear to be equally effective in blackS and whites and are effective in the elderly. They are expensive, require at least twice-a-day dosing (except for nitrendipine, which can be taken one to two times per day) and titration may require several visits. Few, if any, significant metabolic effects have been reported. With some of the calcium entry blockers, conduction disturbances have been noted on the electrocardiogram. Flushes, head- aches, palpitations, edema, and weakness are the most common side effects. These agents will probably enjoy wide acceptance in the future as antihypertensive drugs.

Today, some of these early drugs are of historic interest only-hexamethonium, phenoxybenzamine, the veratrum alkaloids, or pentolinium-but these were the tools with which we treated hypertension in the 1950s when numerous individual reports indicated that hypertension could be controlled and lives prolonged even with these “primitive” drugs. As more effective medications became available, it became necessary to document these initial experiences with long-term trials, and that is what has been done.

WHAT HAS BEEN ACCOMPLISHED

Since the 1950% several major clinical studies have established the fact that early treatment of hypertension will prevent complications and prolong life [16-161. These studies have been extensively discussed elsewhere, but a brief review is appropriate. The Veterans Administration Study examined a group of male patients and demonstrated in moderately and severe hypertensive patients that the lowering of blood pressure dramatically improved the prognosis. Acute pulmonary edema and heart failure were virtually eliminated; the number of strokes, both hemorrhagic and thrombotic, was markedly decreased; left ventricular hypertrophy was reversed; and the progression of renal disease was halted in many patients whose blood pressure was lowered. A statistically significant decrease in the incidence of myocardial infarction or death from coronary artery disease was not, however, documented in treated patients over a short period of time, although there was a trend in that direction, and the benefits of treatment in less severely ill patients was not clearly established.

The U.S. Public Health Study on Mild Hypertension confirmed the findings of the Veterans Administration Study-” hypertensive” complications were reduced and progression to more severe disease prevented-but no

definite proof was forthcoming that the mortality from myocardial infarction or sudden death was reduced by therapy, although again a trend in that direction was noted. It was not unexpected that there was no statistical difference achieved in a study dealing with a small number of men with mild hypertension who were relatively young, a group in which the incidence of coronary disease would be expected to be low. Table II summarizes the results of these as well as several other clinical trials with regard to morbidity and mortality in treated patients.

The Hypertension Detection and Follow-Up Program attempted to clarify the effects of blood pressure lowering on less severe degrees of hypertension and on the incidence of myocardial infarction and deaths from coronary disease. This was a multicenter study involving approximately 11,000 men and women that, although its design has been faulted, has answered several questions. In this study, more than 5,000 patients underwent rigorous treatment to achieve goal blood pressure levels, utilizing the stepped-care method of therapy originally elaborated in the 1977 Joint National Committee Report on Detection, Evaluation, and Treatment of High Blood Pressure [43] (diuretics as first-step therapy, reserpine or, later in the study, propranolol, as second-step therapy, and hydrala- zinc as third-step therapy). Another group of 5,000 patients were returned to their communities for usual and customary care. At the end of five years, systolic and diastolic blood pressures had been reduced in both groups but to a lower level in a greater percentage of patients in the specially treated group. Overall mortality was reduced to a greater degree in this group, with a 45 percent reduction in stroke mortality rates and, importantly, a reduction of 20 percent in deaths from myocardial infarction, when compared with the less vigorously treated patients. A benefit was noted even in the so-called mild hypertensive patients with diastolic pressures of 90 to 104 mm Hg (Table Ill). Therapeutic benefits were noted in patients with several levels of less severe hypertension (90 to 94,94 to 99, or 100 to 104 mm Hg). Of great importance was the fact that, although mortality and morbidity were reduced even in those patients who were treated after the onset of target-organ involvement, the level from which risk was reduced was considerably higher, an argument for early treatment before evidence of complications (Table IV). Additional data from the Hypertension Detection and Follow-Up Program suggest that the incidence of angina and initial as well as recurrent myocardial infarctions was also decreased [16].

The Hypertension Detection and Follow-Up Program has been criticized because of its failure to include a placebo group. Some critics have stated that it was not a trial of antihypertensive therapy but one that tested the effects of better overall medical care. It is most probable, based upon our experience with other studies, that if there had

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SYMFOSIUM ON TERAZOSIN-MOSER

TABLE Iii Hypertension Detection and Follow-Up Program: Percentage Reduction in Mortality In Stratum-l Subjects According to Entry Characteristics [la]

Entry Characteristics

Stepped Care Referred Care

Rate per 1,000 Rate per 1,000 Number of Deaths Patient-Years Number of Deaths Patlent-Years

Reductien In Mortality (p-t)

Not receiving antihypertensive treatment and without target-organ damage:’

Entry diastolic blood pressure: 90-94 mm Hg 36 7.0 54 10.6 34.0 95-99 mm Hg 39 6.4 53 11.6 27.6 100-104 mm Hg 31 9.3 44 11.6 19.6

‘Target-organ damage included left ventricular hypertrophy on the electrocardiogram, history of myocardial infarction, stroke, and intermittent claudication, and serum creatinine greater than 1.7 mg/dl.

TABLE IV Hypertension Detection and Follow-Up Program: Percentage Reduction in Mortality in Stratum-l Subjects (diastolic blood pressure 88 to 184 mm Hg) According to Presence or Absence of Pretreatment Target-Organ Damage [18]

EntrY Characteristics Sample

Size

Stopped Can Refsrnd Care

Number of MOrtallty Sample Number of MOMlty Reduction In Deaths Rate Size Deaths Rate Mortality

Target-organ damage present’ 501 76 15.6 460 92 20 22.0 Target-organ damage absent 3,402 153 4.5 3,462 199 5.6 22.4

‘Target-organ damage included left ventricular hypertrophy on the electrocardiogram, history of myocardial infarction, stroke, and intermittent claudication, and serum creatinine greater than 1.7 mg/dl.

TABLE V Estimates of Benefit from Treating Mild, Uncomplicated Hypertension- Hypertension Detectlon and Follow-Up Program Data [18]

Treatment Gmup

Deaths lmm All Cardlovasculsr Disease Causes

(per 1,tlOtf patient years)

Usual care 6.7 Special treatment 6.4 Difference 2.3 (or 46,000 per year*)

*Assuming 20 million patients with mild hypertension in the United States.

been a placebo control group, the differences in outcome would actually have been more definite. There are other arguments against the theory of “better overall care” making the difference. There were no differences in weight, smoking cessation rates, or lipid levels between the routinely treated and specially treated groups, all factors that might have accounted for the reduced mortality. importantly, in patients in the specially treated group, there was a reduction in the incidence of left ventricular hypertrophy and stroke, complications that are clearly linked to hypertension and are not usually related to the type of medical

care followed. The Hypertension Detection and Follow-Up Program, in my opinion, has answered the question: is there a benefit from treating mild hypertension? It would also appear that effective treatment will decrease the occurrence of myocardial infarction, as well as the number of deaths. Potential benefits suggested by the Hypertension Detection and Follow-Up Program data, in terms of reducing mortality in the United States, indicate that approximately 46,000 fewer deaths might occur per year if the 20 million individuals with mild hypertension were effectively treated. This is based upon a reduction from 6.7 to 6.4 per 1,000 patient years in the specially treated group compared with the routinely treated group (Table V).

The Australian Therapeutic Trial in Mild Hypertension [19] has also demonstrated a reduction in cardiovascular mortality in treated patients, compared with those given placebo (Table VI). The Oslo Study [20] was the only trial that appeared to demonstrate no benefit of treatment. However, the artifact created by the Oslo Study was the result of a small number of patients.

Two recently completed clinical trials, the European Working Party Study on Hypertension in the Elderly [44] and the Medical Research Council Study [45], have also demonstrated an overall decrease in cerebrovascular and cardiovascular mortality in hypertensive patients when blood pressure has been lowered. It appears that the

0 May 23,1986 lfw Ame&an Journal of Medfclns Vofumo SD (suppl5B)


major clinical trials have established the fact that the treatment of hypertension, even mild hypertension, is beneficial. In the clinical trials in which the control group either received no medication or a placebo, about 12 percent (1,318 of 11,129) had a progression to more severe disease. In the groups of actively treated patients in the same trials, only 82 of 11,208 patients had such a progression. This low rate of disease progression is another argument for early treatment (Table VII). It should be remembered that much of the benefit reported in these studies resulted from the use of only a limited number of antihypertensive medications. It remains to be seen whether better results will be reported in trials using beta- or alpha-adrenergic inhibiting agents, converting-enzyme inhibitors, or calcium ehtry blockers.

COMMENTS

There has been a marked improv&ent in blood pressure control rates in the 1970s and 1980s compared with the number of patients under effective treatinent in the 1960s (Table VIII). Blood pressure control has been achieved through treatment in approximately 6Q to 70 percent of hypertensive patients at many ceriiers. Stroke mortality rates have decreased by more than 45 percent in the past 15 years (Figure 1). The downward slope qf stroke dea?hs that had begun in the 1960s and progressed at ihe rate of 1 .O or 1.5 percent a year has clearly accelerated to a rate of 5 to 6 percent a year since the initiation of the National High Blood Pressure Education Program and the con- certed efforts of many groups in this countj to control the epidemic of cardiovascular disease. Control of high blood pressure has been an important factor in reducing the iil-

TABLE VI Australian Therapeutic Trldl: Incidence of Fatal and Nonfatal Trial End Points In Patlents with Mild Hypertension [19]

Trial End Points

Active Treatment (n = 1,721)

Number of End Poinls Rate’

Placebo (n = 1,706)

Number oi End Poinir Rate*

Fatal Cardiovascular Noncardiovascular Total

Nonfatal All trial endpoints

4 0.8 13 2.5+ 5 0.9 6 1.2 9 1.J 19 3.7*

82 15.5 108 20.8+ 91 17.2 127 24.5*

‘Rates per 1,000 person-years exposure to risk. +p co.05. *p cO.025. “p <O.Ol.

cidence of cardiovascular disease and the resulting deaths. The statement that the cardiovascular epidemic of the 1950s and 1960s would continue indefinitely because our population was aging has been proven false.

It is obvious that with the improvement in therapeutic modalities, a great& number of hypertensive patients are Ljeing treated to goal levels wiih fewer side effects than was possible 15 to 20 years ago. The search for new ther- apies continues, and the number of patients with uncon- trolled blood pressure or who are unable to continue with a medication because of troublesome side effects must be reduced still further. Although there are no definitive data demonstrating that the metabolic changes occurring after the use of some antihypertensive drugs adversely affect

TABLE VII Effect of Treatment on Preventing krogression from Mild to More Severe kypertenslon (diastolic blood pressure greater than 110 mm Hg): Findings from Major Clinical Trials

Number of Patlsnts

Placebo Active Tmalment

SW Mild Progrewed to Mild Pr&ressed to (rengs for mild hypertension) Hypettenrion Mom Severe Olseare Hypartemion Mom Severs Disease

U.S. Public Health Cooperative study (90-114 mm Hg) 196 24’ 193 0

Veterans Administration Cooperative study (90-l 14 mm Hg) 194 20 186 0

Australian study (95-109 mm Hg) 1,706 202 1,721 5

Oslo “dy (90-l 10 mm Hg)+ 379 65 406 1

Medical Research Council study (90-109 mm Hg) 8,654 1.011 8,700 76

Total 11,129 1,318 11,206 82

*Diastolic blood pressure greater than 130 mm Hg. +12.5 percent of patients had systolic hypertension only.

Mey 22,1986 The Amrkan Journal Of Madkine Volume 80 (suppi 56) 9


TABLE VIII Status of Hypertension Control

National Westchester Westchester Heart Hypertension Detection County, County,

Survey Chlcago Atlanta and Follow-Up Program New York Chicago Minneapolis Chlcago Now Yorlr (1960-1962) (1967-1971) (1970) (1973-1974) (1975) (1977) (1980-1981) (1982) (Ml-1962)

Number examined 6,672 22,929 6,012 156,906 11,534 117,954 1,656 56,078’ 35,560 Percent with diastolic

blood pressure exceeding 95 mm Hg 15 20 23 13.2 23 13.2 14 ? ?’

Percent unaware of high blood pressure 43 59 19 25 21 11.9 13 6 4

Percent with high blood pressure being treated 36 25 57 54 60 76.1 76.1 69 67

Percent with high blood pressure under control 16 11 36 36 43 59.3 59.3 61 72

*Includes unknown number of repeat examinations.

outcome, it would represent a major advance if blood pressure lowering over time could be achieved in a large number of patients without such effects. Hence, research- ers continue to search for effective medications that will decrease peripheral resistance without producing specific metabolic changes.

The use of newer, specific alpha,-blocking agents, calcium entry blockers, and converting-enzyme inhibitors, and the potential use of dopamine agonists or serotonin inhibitors should be carefuliy evaluated over long periods of time. At the same time, research into behavioral and environmental changes is necessary to help define as- pects of hypertension that can be prevented, while more must be learned about how to apply techniques for behav-

ioral changes. Although the U.S. public has responded by reducing tobacco consumption by more than 22 percent and reducing saturated fat intake by almost 30 percent, more must be done to decrease risk factors other than hypertension if the number of deaths from coronary heart disease are to be reduced still further. Above all, management of hypertension must be kept at a simple and afford- able level. The last 20 years have been decades of progress, but even better results should be expected as medications from the 1950s and 1980s are combined with medications from the 1980s and 1990s. Hypertension should be an easily controllable disease in the next decade and its complications should be even more rare than they are in 1988.

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historical perspective on the management of hypertension

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