The National High Blood Pressure Education Program (NHBPEP) was established in 1972 by then Secretary of the Department of Health and Human Welfare, Eliot Richardson, on the recommendation of Theodore E. Cooper, M.D., Assistant Secretary for Health, and Mrs. Mary Lasker. It was in that year that Edward D. Freis, M.D., Senior Medical Investigator of the Veterans Administration, received the Lasker Award for his landmark Veterans Administration Cooperative Studies which first demonstrated the safety and efficacy of antihypertensive therapy. Over the ensuing 27 years, the Joint Coordinating Committee of the NHBPEP has provided the leadership in educating the public and the healthcare professions about the necessity for detecting, evaluating and treating patients with hypertension. The centerpiece of this education program has been the succession of Joint National Committee reports (now in its sixth printing) (1) and many other important working papers concerned with the multitude of aspects of the hypertension problem (from hypertensive diseases in special populations to specific reports related to the unique problems of specific target organ involvement from hypertensive disease, to other related issues dealing with hypertension in the workplace, problems of adherence to antihypertensive therapeutic programs) and others. Moreover, this novel national health education program has served as the template for other important national health education programs by the National Heart, Lung, and Blood Institute (e.g., cholesterol, asthma, smoking).

The result of the NHBPEP has been a greater awareness of the need to initiate treatment of patients with hypertension and the establishment of other national hypertension programs throughout the world. Great gains have been accomplished in society with the recognition of those patients with more severe stages of the disease and, as a result, fewer patients currently present to their physicians or to hospitals with severe hypertensive emergencies. The mortality rates from stroke and coronary heart disease continue to fall (1). Most patients currently have hypertensive disease of lesser severity and most of these people go either unrecognized, untreated or their blood pressures remain uncontrolled until the complications of the disease appear. Formerly, these patients were said to have “mild hypertension” because the severity of their disease was obviously far less than those patients who presented in large numbers with much more severe disease in the earlier years. This review was written with this concern in mind and with the hope that more patients with earlier stages of hypertension would be recognized and would be better treated then they are today (1). It is hoped that the benefits to be reaped will be a break in the ever-increasing curves indicating a progressive rise in cardiac failure and end stage renal disease resulting from hypertension.

Several issues must be addressed before discussing treatment of these patients with less severe stages of hypertension. The first is that detection, evaluation and treatment of patients with hypertension have been less successful in recent years. At the outset of NHBPEP in 1972, only 12% of patients were aware of their hypertension, under treatment and with pressures controlled. Through the efforts of this program, the number of patients with controlled pressures increased significantly. However, recent data indicate an appalling reversal (Table le1)(1- 2). Most patients with hypertension have systolic or diastolic pressures falling between 140 to 159 and 90 to 99 mm Hg, respectively. They may also have target organ involvement, yet they may be included in what heretofore was termed “mild” (presently termed “Stages 1 and 2”) hypertension (Table le2). Many of these patients have isolated borderline systolic pressure elevation (140 to 159 mm Hg), a level that still requires prospective controlled studies to demonstrate efficacy of pressure reduction (3). They should benefit from antihypertensive therapy, and their disease should be deterred from progressing to further target organ involvement or death.

Second, primary prevention of hypertension is feasible (4). Thus, in 1988, approximately 59 million Americans had hypertension (5), but recent reports estimate that this number has diminished to about 43 million (4,6). Explanation for this decrease has been attributed, at least in part, to the active interest of the general public with either “high normal” or Stage I hypertension and who participated in their overall wellness by lifestyle modifications. These interventions have been effective in reducing lesser elevated blood pressure levels to normotensive levels (4).

The third issue is that, until publication of the national recommendations dealing with the prevention, detection, evaluation and treatment of hypertension (JNC-5 and JNC-6), classification of hypertension only considered individuals with diastolic pressures between 89 and 105 mm Hg (i.e., “mild” hypertension). Even in JNC-5, “mild” hypertension included patients whose systolic and diastolic pressures were 140 to 159 or 90 to 99 mm Hg, respectively (5). Because these patients with lower pressure elevations are at risk for increased morbidity and mortality, continued use of the term “mild” conveyed the wrong message to these affected individuals and their physicians. This discussion primarily concerns treatment of patients with Stages 1 and 2 hypertension. We also emphasize attention to those people with “high” normal systolic or diastolic pressures (i.e., 130 through 139 or 85 through 89 mm Hg, respectively) because these individuals are also at increased risk requiring clinical management (Table le2).

A fourth point is that JNC-6 was carefully intended to be “evidence based” (1). However, recommendations in the first five reports were also based on findings of large controlled, multicenter trials, many of which were placebo-controlled. This discussion concerns information published in JNC-6 and thereafter. Finally, for the first time, JNC-6 recommended setting therapeutic goal pressures (usually <140/<90 mm Hg) for most patients, but <130/<85 mm Hg in diabetics.

I believe that one important innovation of JNC-6 having particular pertinence for patients with high normal blood pressure or with Stage 1 hypertension is risk stratification and its value in formulating antihypertensive treatment. These individuals have the greatest likelihood either of developing more severe hypertension or complications from hypertension and other cardiovascular diseases. Inherent in risk stratification is proper measurement of blood pressure, determination of other risk factors (Table le3)and evaluation for target organ damage or other clinical evidence of cardiovascular disease (Table le4). These factors should be assessed carefully by medical history, physical examination and laboratory investigations when the patient is first evaluated and thereafter. From this information patients are categorized into risk groups depending on whether there is target organ involvement or other diseases (Table le5). For the purpose of this discussion, I have added additional risk factors. The JNC-6 acknowledged obesity as a risk factor, but stated that it was “of less significance in the selection of antihypertensive drugs” (1). Treatment with weight reduction measures is of primary importance (7- 8). However, recidivism is prevalent; therefore, emphasizing the need for antihypertensive therapy is highly significant (9- 11), particularly if pharmacologic means for managing obesity become available. Hyperhomocysteinemia has received recent emphasis as a major risk factor (12), requiring folic acid treatment (13). Hyperuricemia is frequently cited as a cardiovascular risk factor (14- 15). Moreover, there is abundant evidence indicating its presence in most untreated hypertensive patients (16), and it also provides an index of early renal involvement in hypertension (17- 19). Because angina pectoris may be present in patients with only hypertensive heart disease, in this discussion I dissociate this manifestation of cardiac involvement (Table le4) from a history of myocardial infarction (MI) (20- 23). Furthermore, patients with a history of renal arterial disease (particularly with atherosclerotic lesions) should also be considered as having significant clinical cardiovascular disease. Each of these factors provides a real basis in selecting treatment.

As indicated in the risk stratification table for selecting treatment, in some patients nonpharmacologic interventions are of proved value (Table le5). This is best exemplified in individuals with high-normal pressures, because primary prevention in essential hypertension has already been demonstrated in them (1,4,9,11). Among the various lifestyle modification strategies effective in controlling elevated arterial pressure are: weight control for those who are 15 percent over ideal body weight, restriction of daily ethanol intake to no more than one ounce per day, reduction of daily sodium intake to 2.4 g and involvement in a regular aerobic exercise program (e.g., 30 to 45 min several days each week). Special mention must be made to emphasize the necessity to discontinue cigarette smoking. This advice not only pertains to overall cardiovascular health, but also for antihypertensive therapy. Experience from the Medical Research Council (Great Britain) and Australian Mild Hypertension Trials have shown that individuals who smoke and take beta-adrenergic blocking agents (beta-blockers)—even if pressure is controlled to the same levels achieved with a diuretic—do not have the same protection from stroke and MI that is conferred by a diuretic (24- 25). Other lifestyle measures recently shown to be of value include maintenance of adequate potassium intake (approximately 90 mmol per day) (26) and, perhaps, of magnesium (27). Rationale for these interventions has been detailed earlier (1,11,28), and will not be detailed herein. Other lifestyle interventions for hypertension treatment have been suggested, but they have not yet been adequately shown to be effective.

In general, JNC-6 recommends that the thiazides and beta-blockers are best indicated for the uncomplicated patient with essential hypertension. These agents should be prescribed initially in less than full doses (e.g., 12.5 or 25 mg for hydrochlorothiazide and 25 mg for atenolol, as examples); they may then be increased to full doses (25 or 50 mg) if pressure is not controlled optimally (i.e., less than 140 or 90 mm Hg, systolic or diastolic, respectively) (1). Since JNC-6 publication, a question has been raised as to recommendation of beta-blockers, suggesting they may not be of value (29). This observation had been considered in JNC-6, and it has eliminated beta-blockers from recommendation in elderly patients with isolated systolic hypertension (1,30). Nevertheless, the beta-blockers had been shown to be of value in studies of younger patients, particularly with diastolic pressure elevation (5,31- 32). Of course, there are some patients whose blood pressures do not respond to either of these agents, and other drugs must be used.

I believe that the JNC-6, is a guideline, not to be construed as an absolute recommendation. It provides a straightforward means for selecting therapy in a cost-effective fashion, but there is a wide laterality for flexibility. Since promulgation of JNC-6, several randomized, controlled, multicenter studies have been conducted comparing the efficacy of several agents with diuretics. Thus, verapamil demonstrated efficacy similar to chlorthilidone, but the diuretic produced more hyperuricemia and hyperkalemia than verapamil which was more effective in diminishing carotid wall thickness (33- 34). As indicated, there are certain compelling reasons for using classes of antihypertensive agents other than diuretics and beta-blockers; not every hypertensive patient needs be treated with these two drug classes. Consider the patient with Stage 1 or 2 hypertension with marked bradycardia. That patient may not respond or may have had side effects of a diuretic or an angiotensin converting enzyme (ACE) inhibitor mitigating their use. For the same reason that a beta-blocking agent cannot be administered, certain calcium antagonists (e.g., verapamil, diltiazem) may not be prescribed. Thus, there may be compelling reasons to select a dihydropyridine calcium antagonist. Whereas these compelling indications may not be very common, these and other mitigating clinical situations can occur with sufficient frequency in uncomplicated patients with hypertension to justify their use as well as new classes of agents yet to be developed.

Several “compelling indications” cited in JNC-6 provide exceptions to initial use of diuretics or beta-blockers. These citations suggest other means for treating hypertensive patients with diabetes mellitus, cardiac failure, MI or isolated systolic hypertension, many of whom have Stage 1 or 2 pressure elevation (1). I believe that other compelling reasons exist, some of which were included in JNC-6 as “special indications.” I am not completely sure of this semantic differentiation, although certain comorbid diseases may preferentially merit the use of a diuretic or beta-blocker for both the hypertension and the other disease. The following discussion details the rationale for use of other drug classes for initial therapy of Stage 1 or 2 hypertensive patients. Some concepts are consistent with JNC-6 recommendations; others may either have been published since JNC-6 promulgation or are my point of view, supported by appropriate citations.

Rather than use the terms angina pectoris or MI, I have suggested the broader concept of coronary heart disease (CHD) for several reasons. First, and perhaps most important, we must recognize that the earlier and more recent controlled studies employed the term CHD as a major end point (1,35). Mortality from CHD (in these studies) included not only mortality from MI, but also from unstable or unremitting angina pectoris, sudden cardiac death, lethal cardiac failure, lethal dysrhythmias or unexplained death unsupported by autopsy. This is important to understand because these deaths may result from hypertensive heart disease alone or be associated with occlusive atherosclerotic epicardial coronary arteries (20- 22). Hypertensive heart disease, without significant coexistent coronary arterial atherosclerosis, may be explained hemodynamically by several mechanisms including: increased coronary arterial resistance and minimal resistance, reduced coronary blood flow and flow reserve and increased blood viscosity. These alterations occur experimentally in rats with genetically induced hypertension (36- 37) and in essential hypertensive patients with left ventricular hypertrophy (38- 42). Implicit in the importance of these alterations is increased left ventricular tension and myocardial oxygen demand, ventricular fibrosis (with collagen deposition) and endothelial dysfunction of the coronary vasculature and myocardium (43- 44). The natural history, then, of hypertensive heart disease (even in Stages 1 and 2 patients) may terminate in sudden death, dysrhythmias, impaired systolic or diastolic function and ventricular failure and myocardial microinfarction(s) (45). With coexistent occlusive epicardial atherosclerotic coronary arterial disease, there is exacerbated CHD with its inherent outcomes.

Diuretic therapy without adequate protection from secondary hypokalemia increases the likelihood of dysrhythmias and sudden death (46). Much of this enhanced risk may be attenuated by administration of supplemental potassium, potassium-sparing agents or low-dose diuretics (47). Thus, when low-dose thiazides were used in multicenter studies, the 26% reduction in CHD deaths, initially predicted by the earliest meta-analysis (in which a significant 14% was achieved) (35), was confirmed (48), and this was achieved in elderly patients.

Without adequate control of pressure and left ventricular afterload, increased myocardial oxygen demand results. Beta-blockers have been shown to be safe and effective in patients with angina pectoris (with or without atherosclerosis) as a result of their ability to reduce pressure, heart rate, left ventricular mass and myocardial metabolic oxygen demand (49- 51). If these agents prove inadequate, calcium antagonists may be used if the agent selected does not adversely compromise chronotropic and inotropic myocardial function. These provisions are included in JNC-6 but, in addition, ACE inhibitors alone or with angiotensin II (type 1) receptor blockers (ARBs) may be of value. Experimental and clinical studies have reported that these two classes of antihypertensive agents are capable of increasing coronary blood flow and flow reserve, thereby improving the altered coronary hemodynamics associated with hypertensive heart disease (36,52). Experimental (and early clinical) studies have indicated that these compounds improve endothelial dysfunction explainable by reduced ACE- and chymase-generated angiotensin II, increased bradykinin (by ACE inhibitors), increased nitric oxide generation and other effects of ACE inhibition (e.g., PAI-1 inhibition of intravascular thrombosis, anti-inflammatory factors) (53- 55). Additionally, the literature is replete with data from many studies in which ACE inhibitors were given to patients following MI demonstrating reduction in deaths, prevention of subsequent MI and preventing or ameliorating cardiac failure (54- 58). Hence, abundant data exist to support the use not only of beta-blockers and calcium antagonists for patients with hypertension with CHD, but also for ACE inhibitors and ARB’s. If the ACE-inhibitor (or ARB) is not effective in controlling pressure, it still may be used with other antihypertensive drugs for its vascular, myocardial and renal protective actions.

One important and well-accepted indication for use of beta-blockers (specifically those without intrinsic sympathomimetic activity) is prevention of a second MI (49- 51). Much has been written recently about the insufficient use of these agents for this purpose (59). This is particularly important in hypertensive patients following MI and does not preclude administration with ACE inhibitors because of drug interaction (1). The JNC-6 suggests that the use of ACE inhibitors after MI should be restricted to those patients with only systolic dysfunction. However, their value after MI was assessed in patients with fairly normal systolic dysfunction, and they prevented death, second infarction and subsequent cardiac failure (56- 58). Diastolic dysfunction in hypertension has become more common, particularly in the elderly or in patients with ischemic heart disease (60); both situations are associated with increased ventricular collagen (61). Angiotensin converting enzyme inhibitors provide particular promise in those patients because of their potential to reduce fibrosis (62- 64).

JNC-6 specifically advocates ACE inhibitors, alone or with diuretics, in cardiac failure, but two points were not discussed. First, we reiterate the observation that ACE-inhibitors are not administered often enough and in inadequate doses (65). Establishing optimal dosing is more difficult for normotensive individuals in whom the end point of pressure reduction is not utilized. Second, when ACE inhibitors are prescribed for hypertensive patients, maximally effective doses of the ACE inhibitor (or ARB) may not be sufficient to control pressure. In that event, they may be used with another drug class, provided the additional agent does not adversely effect ventricular function.

Specific concerns have been raised about the so-called J-curve, particularly in patients with ischemic heart disease. Discussion of this is useful in the context of isolated systolic hypertension and patients with lesser elevated diastolic pressure. Inherent in this hypothesis is potential risk of coronary events when arterial pressure is reduced excessively in patients with CHD because the diastolic pressure is responsible for myocardial perfusion (66). Earlier support of this phenomenon was provided by retrospective studies (67- 68). However, recent data from prospectively controlled trials, involving patients with and without hypertension, have failed to support these concerns. One group of studies, conducted in patients with isolated systolic hypertension in the elderly, used diuretics, beta-blockers, and a calcium antagonist (24,69- 71). None demonstrated increased coronary events. Diastolic pressure, originally less than 90 to 95 mm Hg, was reduced further without provoking coronary events. Furthermore, even in those studies that involved primarily normotensive individuals following MI, the ACE inhibitors reduced diastolic pressure and decreased coronary events (56- 58). More recently, a dihydropyridine calcium antagonist (nitrendipine) was employed for elderly patients with isolated systolic hypertension and demonstrated significant protection from fatal and nonfatal strokes; there was no increase in coronary events even though diastolic pressure was reduced (71).

Finally, the J-shape curve was not detected in the Hypertension Optimal Treatment (HOT) trial, in which another dihydropyridine calcium antagonist (felodipine) was used (72). This study was designed specifically to lower diastolic pressure progressively in three groups of patients. An additional finding of this study was the safety of aspirin therapy in cardiovascular protection, and there were no bleeding episodes. Hence, in considering treatment of patients with either isolated systolic hypertension in the elderly or to reduce diastolic pressures below 80 mm Hg, no increased coronary events or J-shape curve were demonstrated. Therefore, the JNC-6 recommendation for diuretics or long-acting dihydropyridine calcium antagonists seems appropriate in elderly patients with isolated systolic hypertension.

As presented in JNC-6, hypertensive patients with type-1 diabetes should be considered for special treatment. The most important therapeutic recommendation in these patients is that a goal pressure (<130/<85 or lower, 125/75 mm Hg) based on several large prospective studies (73- 77) must be established. This pressure goal is safe with respect to CHD as noted previously. Furthermore, there were recommendations to use diuretics in low dosages and beta-blockers with particular care because these latter agents may mask symptoms of hyperinsulinism. Finally, the ACE inhibitors were recommended for this compelling reason, but I believe that, in some instances, ARBs and certain calcium antagonists should also be considered. Before discussing the rationale for these comments, brief discussion is necessary to explain the intrarenal hemodynamic alterations in diabetes that mandate reconsideration of therapy.

First, we must appreciate that, whereas antihypertensive therapy with diuretics and beta-blockers had been associated with reduced morbidity and mortality from stroke and CHD, during these years the numbers of hypertensive patients progressing into end stage renal disease (ESRD) continued to increase unabatedly (78). Nephrologists have not explained adequately why this occurs, but several reasons have been offered. First, antihypertensive therapy had not lowered pressure sufficiently to stop, reverse and prevent ESRD. Second, the antihypertensive therapy that was available did not prevent ESRD or, according to therapeutic nihilists, drug therapy (in general) will not prevent ESRD. Third, and perhaps most important, other classes of antihypertensive drugs yet to be developed may possess different modes of action that will prevent ESRD. To be sure, certain lines of evidence have strongly suggested that goal pressures were not low enough to prevent ESRD (73- 77). Furthermore, it is also probably true that the earlier classes were not specific enough in action to reverse the intrarenal hemodynamic alterations. Indeed, in experimental studies with diuretics alone, nephrosclerosis progressed pathophysiologically (53,79).

At this point, it is appropriate to describe the intrarenal hemodynamic derangements associated with progression to ESRD. These alterations are manifested by renal ischemia and increased glomerular hydrostatic pressure that promotes protein ultrafiltration and ultimate development of glomerular sclerosis (53,80). It is now clear that the ACE inhibitors (and probably ARBs) increase renal blood flow while reducing glomerular hydrostatic pressure through dilation of both afferent and efferent glomerular arterioles (74,81- 84). Unfortunately, general thinking has suggested that the calcium antagonists, which also increase renal flow and produce afferent glomerular arteriolar dilation, are inappropriate for this therapeutic mission because they do not dilate efferent arterioles. Although this may be so for some calcium antagonists, it is not so for all (85). This class of drugs is highly heterogeneous and some agents are appropriate for treating hypertensive patients with renal involvement.

Angiotensin converting enzyme inhibitors have now been tested for prevention of ESRD. Because hypertensive patients with diabetes mellitus, or who are black, are the most susceptible to progression to ESRD, the first controlled multicenter studies involved these patients with type 1 diabetes. These studies demonstrated that ACE inhibitors reduced proteinuria, prevented further impairment of renal function and prevented (or retarded) development of ESRD (86- 88). Other studies in hypertensive diabetics (type 2) have demonstrated similar findings (77). Still other reports have demonstrated improvement in nondiabetic hypertensive patients (86- 88). Finally, several studies are in progress concerned with black essential hypertensive patients and others with type 2 diabetes (89- 90).

Thus, the JNC-6 recommendations are appropriate:

However, I believe these recommendations do not go far enough. Thus, patients with type 2 diabetes and proteinuria, with or without impaired renal function, should be treated similarly. Furthermore, meaningful studies must be designed to demonstrate efficacy of ACE inhibitors and ARBs in nondiabetic hypertensives (with essential hypertension) having proteinuria and impaired renal function. These patients include a very important segment of the hypertensive population with proteinuria who are at great risk for progression to ESRD.

But what about the calcium antagonists? Several calcium antagonists have been shown to experimentally and clinically reduce glomerular hydrostatic pressure and to dilate both efferent as well as afferent glomerular arterioles (e.g., diltiazem, nitrendipine, felodipine) (85,91- 94). But the clinical information has been clouded by findings that have shown that the ACE inhibitors may be preferable to calcium antagonists. In one study, diabetic hypertensives had less progressive renal disease with enalapril than with nisoldipine, and patients treated with nisoldipine had more nonfatal cardiovascular complications (95). Many inferred from this study that calcium antagonists should not be used in ESRD. In truth, because cardiac involvement from hypertension is already present, once renal involvement from hypertension occurs (19), it may be wise to use both an ACE inhibitor and a specific calcium antagonist. The issue may not simply be either one class of drugs versus the other. Furthermore, and most important, if there is evidence of bilateral occlusive renal arterial disease (in which ACE inhibitors are contraindicated), certain calcium antagonists may be preferable. Thus, we conclude that there is ample evidence to suggest that, in addition to patients with hypertension and type I diabetes mellitus, other patients at risk for ESRD should also be treated with additional classes of agents.

Considerable discussion has been generated about ideal antihypertensive drugs for patients with hyperlipidemia. All classes may be considered “lipid neutral” although short-term treatment with thiazides may elevate LDL cholesterol and beta-blockers may reduce HDL cholesterol. The alpha-adrenergic receptor blockers have been recommended for reducing cholesterol (but this has not been demonstrated for FDA approval). However, this latter class of agents is of value in men with benign prostatic hyperplasia and hypertension, distinctly for possible treatment of both diseases. The thiazides may also be useful in osteoporosis and in certain renal calculi. Calcium antagonists are of value in some patients with supraventricular tachycardia (i.e., verapamil, diltiazem), cyclosporin-associated hypertension and migraine headaches. Adrenergic inhibitors (including beta-blockers) are of value in patients with hyperthyroidism, hyperdynamic beta-adrenergic circulatory state and intention tremor.

Treatment of hypertension over the past four decades has been a remarkable story of evolution: evolution in our understanding of the pathophysiology of the disease that is associated with an inextricable evolution in the development of newer drugs. These two areas of medical progress have dramatically altered the management of patients with hypertensive diseases as well as other diseases previously unsuccessfully treated. Thus, prevalence of hypertensive emergencies has dramatically diminished; deaths from stroke and CHD have remarkably improved, and means to prevent the emergence of hypertension primarily are now established. Nevertheless, numbers of hypertensive patients with cardiac failure and with ESRD are progressively increasing. Thus, in the early 1970s, hypertension was the most common cause of cardiac failure (96); it remains so today (97). In those earlier years, patients with ESRD and hypertension were less numerous, probably because patients succumbed to earlier occurring complications of hypertension. More specific therapeutic means to deal with, and perhaps prevent, these target organ complications are now available. However, the most effective means of preventing these unwanted outcomes of hypertension have been available for some time: early recognition of hypertension, immediate treatment of the earliest manifestations of the slightest elevations of systolic as well as diastolic pressure and prompt recognition of the earliest clinical manifestations of target organ involvement.

To say that we have been doing a good job with early recognition and treatment of Stages 1 and 2 hypertension is contrary to the facts. The truth is that we are witnessing a reversal of our earlier gains. This can be changed; this must be changed. Thus, the best means of achieving and sustaining new gains is prompt recognition of the earliest stages of hypertension and our immediate and continued intervention to control what heretofore has been termed “mild” hypertension. If we continue to perceive these evidences of early hypertensive disease as “mild,” the most common diagnoses of hospitalizations and morbidity (e.g., cardiac failure and ESRD) will continue to adversely affect our population and our economy.