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From JNC I to JNC 7—What Have We Learned?
From JNC I to JNC 7—What Have We Learned? Marvin Moser, MD
T he Aim of Science is Not to Open a Door to Endless Wisdom But to Put a Limit to Endless Error. -Bertolt Brecht, The Life of Galileo
T
here are few stories in the history of medicine that are filled with more errors or misconceptions than the story of hypertension and its treatment.1,2 The Joint National Committee Reports on Detection, Evaluation, and Treatment of High Blood Pressure (JNCs) were first published in 1977 and every 4 to 5 years after that to clarify many of these misconceptions and to provide updates of clinical research results for physicians and other individuals involved in the management of hypertension.3-9 For many years until the late 1930s, elevated blood pressure (BP) was considered an essential adaptive phenomenon; prominent US cardiologists and British physicians warned that lowering BP might be harmful. Hay,10 in an editorial, stated that: bThe greatest danger to a man with high BP lies in its discovery, because then some fool is certain to try and reduce itQ. In the 1940s and 1950s, a dramatic change in the approach to hypertension occurred, and although there were still some physicians who continued to have doubts regarding the significance of hypertension, most had accepted that increased BP increased the risk for cardiovascular disease. The literature, however, even as late as 1946, still reflected a common misconception, bMay not the elevation of systemic BP be a natural response to guarantee a more normal circulation to the heart, brain and kidneysQ (bessentialQ hypertension) and that bOverzealous attempts to lower the pressure may do no good and often do harm.Q11 Prominent experts in the 1950s still reported that essential hypertension was a benign disease.12 However, there were pioneers such as Page and Freis13,14 who believed otherwise and began to treat elevated BP. Only patients with severe
hypertension were treated at first because of problems with therapy. The use of a rigid lowsodium Kempner Rice Regimen, consisting mostly of fruit and fruit juice and rice and containing just 20 g of protein, only 5 g of fat, and less than 200 mg of sodium, had resulted in a reversal of malignant hypertension.15 Although the results were temporary, they were exciting for those physicians who used this approach. And although Sir George Pickering, a physicianphilosopher in Great Britain, described the diet as insipid, unappetizing, monotonous, unacceptable, and intolerable,1 the few people who were able to stay on the diet did respond. Kempner15 reported that 322 of 500 patients had improved. Surgical sympathectomies and adrenalectomies had also been performed in patients with severe hypertension with some good results, but adverse reactions were often severe.16 It was clear that better therapies had to be developed if less severe hypertension was to be controlled in large numbers of people. The risk of therapy had to be reduced to justify treatment for patients who were not in danger of an imminent cardiovascular (CV) event. Although epidemiological studies in the 1960s and 1970s confirmed that even minimally elevated systolic BPs (SBPs) or diastolic BPs (DBPs) increased CV risk,17 treatment remained relatively complicated. In the 1950s to 1970s, various other medications were developed— rauwolfia derivatives; vasodilators such as hy-
From the Yale University School of Medicine, New Haven CT 06510, USA. Address reprint requests to Marvin Moser, MD, Clinical Professor of Medicine, Yale University School of Medicine, 13 Murray Hill Rd. Scarsdale, NY 1058. E-mail: [email protected] 0033-0620/$ - see front matter n 2006 Published by Elsevier Inc. doi:10.1016/j.pcad.2006.02.003
Progress in Cardiovascular Diseases, Vol. 48, No. 5 (March/April), 2006: pp 303-315
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304 dralazine, thiazide diuretics, ganglion, and peripheral adrenergic blockers; and the centrally acting a2 agonists, b-adrenergic inhibitors, and a-b–blocker inhibitors.18-23 Many of these medications, especially the ganglion blockers such as hexamethonium or mecamylamine or the peripheral blockers such as guanethedine, effectively decreased BPs and improved signs of target organ involvement, but adverse reactions with these more potent agents were severe and limited patient/physician acceptance. The use of thiazide diuretics and b-blockers greatly simplified care. One of the first clinical outcome trials, the Veterans Administration (VA) Cooperative Study pioneered by Freis,24 demonstrated that lowering BP with the available medications in male patients with severe hypertension dramatically improved their outcome when compared with placebo. The Public Health Study in mild hypertension25 confirmed the results of the VA study in less severe hypertensive patients. None of the 193 patients in the active group, compared with 24 of the 196 patients in the placebo group, progressed to more severe disease with DBPs N110 mm Hg. With sufficient information on hand and a growing scientific base regarding the risk of hypertension and the benefits of treatment, at least in moderately severe or severe hypertensive patients, the National High Blood Pressure Education Program was established in 1973.1 It was apparent from the start that the Federal Government, industry, organized medicine, volunteer groups, physicians, nurses, and other professionals could work together effectively with a Coordinating Committee of the National High Blood Pressure Education Program to control a major disease. In 1977, the First Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure established guidelines for management and introduced the stepped-care approach to hypertension treatment.3 Since then, guidelines have been revised approximately every 4 to 5 years in 1980, 1984, 1988, 1993, 1997, and most recently, in 2003. 4-9 The guideline committees, which originally consisted of 10 individuals chosen from national organizations by the National Heart, Lung and Blood Institute (NHLBI) review and evaluate the available data on diagnostic procedures and
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treatment and publish their conclusions regarding an appropriate approach to management. More recent guideline committees have consisted of 10 to 15 experts chosen by the NHLBI with more than 50 consultants and contributors. More than 30 national organizations approve the report before it is finalized. The guidelines have been disseminated by the NHLBI. From the 6-page report in JAMA in 1977,3 the reports have expanded considerably to a 34-page-long document in 19978 and a 47-page report in 2003.9 Over the years, the guidelines have stressed a scientifically acceptable but relatively simple diagnostic evaluation and encouraged approaches to treatment which, although not suitable for all patients, had been proven effective. These guidelines have been widely accepted by professionals throughout the world. The JNC reports have been criticized by some investigators as being too simple or, on the other hand, too complicated, not workable, or too concerned with cost considerations. In general, however, they have stood the test of time and have evolved as a standard guideline for the management of most hypertensive patients.
What Have We Learned Since the 1970s and How Have the Guidelines Evolved? Criteria for Diagnosis and Treatment of Follow-up In 1977, definitions of what constituted hypertension and the management of various levels of BP were considerably different than those that have evolved over the past 30 years. This was due in part to the fact that, although epidemiological data had established that there was an increasing risk for CV events with SBPs increasing from as low as 115 mm Hg and an arbitrary definition of hypertension as above 140/90 mm Hg in young and middle-aged persons had been established as a definition of hypertension, there were few data on benefit in people with so-called mild hypertension—DBPs below 104. Mild hypertension had been defined as a DBP of 90 to 104 mm Hg in the treatment trials in the 1960s and 1970s. Systolic BP changes had not been considered as primary end points in these studies. The JNC I therefore stated that all adults with DBPs of 120 mm Hg or above, recorded at the
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FROM JNC I TO JNC 7—WHAT HAVE WE LEARNED?
disappearance of sound, should be referred promptly to a source of medical care. All persons with BPs of 160/95 mm Hg or above should have the BP elevation confirmed within 1 month. All persons younger than 50 years with BPs of 140/90 to 160/95 mm Hg should be checked every 2 to 3 months (the implication was that these people did not require specific therapy). All persons older than 50 years with a BP of 140/90 to 160/95 mm Hg should be checked within 6 to 9 months (again, the lack of treatment data greatly influenced this decision). All adults with DBPs b90 mm hg should be advised to have their BP checked yearly. Although recognizing the epidemiological data regarding increased risk from elevated SBP at all ages, the committee chose the DBP as the basis for confirming high BP and recommending disposition because the benefits of treatment of SBP were unclear. It was believed that if both SBPs and DBPs were used as guidelines, the recommendations might be too complex and not consistent with available data at that time. All of these recommendations reflected the lack of treatment data in patients other than those with severe hypertension. Classifications of various levels of BP evolved in JNC III in 1984, JNC VI in 1997, and JNC 7 in 2003 (Table 1), and recommendations for follow-up and treatment changed as more data became available. It had become clear that a persistent BP of higher than 140/90 mm Hg required some treatment regardless of age. The JNCs in 1984 and 1988 still used the terms mild, moderate, and severe hypertension to define various levels of severity, that is, DBPs of 90 to 104 (mild), 105 to 114 (moderately severe), and above 115 mm Hg (severe). Even in the 1980s, SBP was listed separately: 140 to 159, borderline isolated systolic hypertension; above 160 mm Hg, isolated SBP; (Table 1). In contrast, the JNC 7 simplified definitions so there are now only 2 stages of hypertension: stage I, 140 to 159/90 to 99 mm Hg and stage 2, 160/100 mm Hg. This is in recognition of the fact that patients with a persistent BP above 140/90 mm Hg should be treated with specific medication if lifestyle changes do not lower BP to below 140/90 mm Hg and that the management of hypertension is essentially the same in patients with BPs above 160 mm Hg, as it is in
Table 1. Changing Classifications of Levels of BP JNC III (1984)
JNC VI (1997)
DBP (mm Hg)
SBP/DBP (mm Hg) Normal, b120 and b80 Optimal, b120 Prehypertension, and b80 120-139 or 80-89 Normal, b130 Stage I, 140-159 and b85-89 or 90-99
b85, Normal BP 85-89, High-normal BP 90-104, Mild hypertension 105-114, Moderate hypertension N115, Severe hypertension
High-normal, 130-139 or 85-89 Stage I, 140-159 or 90-99
JNC 7 (2003)
Stage II, N160 or z100
Stage II, 160-179 or 100-109 Stage III, N180 or z110
SBP b140, Normal 140-159, Borderline ISH N160, ISH Refs. [5,8,9].
patients previously listed as stage 3 (N115 mm Hg DBP), except for people with malignant or accelerated hypertension in whom more urgent therapy is necessary. A designation of prehypertension (120-139/80-89 mm Hg) was used in JNC 7 instead of high-normal to highlight the fact that these individuals, although not being labeled as hypertensive, were in need of careful follow-up and changes in lifestyle if appropriate. In addition, over the years from JNC I to JNC 7, an appreciation of the importance of SBP as a risk factor and recognition that lowering isolated elevated SBP (isolated systolic hypertension [ISH]) would reduce morbidity/mortality have led to an emphasis on this entity as a more important guide to risk evaluation and to therapy than the DBP. The definition of ISH has evolved through the years from an SBP of above 160 and a DBP below 90 mm Hg to above 140 and below 90 mm Hg. Recommendations for follow-up evaluations also dramatically changed as more data, especially from the Systolic Hypertension in the Elderly Program (SHEP),26 the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT),27 indicated that early therapy may make a difference in outcome.
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Although, as noted in JNC I, people older than 50 years with BPs as high as 160/95 mm Hg were just advised to have their BP checked within 6 to 9 months, and specific pharmacological were considered optional; JNC 7 recommended specific medical therapy for BPs above 140/90 mm Hg or even lower in patients with renal disease and/or diabetes. The time intervals given for lifestyle modifications to be judged effective have been shortened. In stage II patients (BPs N160/ 100 mm Hg), pharmacological interventions are suggested as initial therapy in addition to lifestyle changes. These recommendations again reflect the results of the numerous clinical trials.
Diagnostic Evaluation Although numerous new technologies and tests for the evaluation of hypertension have evolved over the past 30 years, the recommendations of the JNCs have not changed to a great degree since 1977.28 In 1977, the first JNC suggested that extensive laboratory testing of patients with high BP, such as a routine intravenous pyelogram (IVP), plasma renin, or aldosterone levels, which had been advocated in many medical centers, was not necessary for initial evaluation. They recommended that routine pretreatment workup should be limited to defining the severity of the BP and identifying its complications and associated CV risk factors. bMore complex diagnostic procedures designed to discover specific causes of high BP can be reasonably reserved for those subjects: (1) in whom routine history, physical examination, or the recommended laboratory findings suggest one of the specific recognizable causes; (2) who are under the age of 30, since they have the greatest prevalence of correctable secondary high BP; or (3) in whom drug therapy proves inadequate or unsatisfactory.Q In 1977, the following laboratory tests were suggested before initiating therapy: bhematocrit; urinalysis for protein, blood, and glucose, using the dipstick method; creatinine and/or blood urea nitrogen; serum potassium; and an electrocardiogram.Q bOther tests, which may be helpful, include a chest x-ray, blood sugar, serum cholesterol, serum uric acid, microscopic urinalysis, and blood count. Minimal cost to the patient can sometimes be
achieved by ordering automated blood chemistries. Clinical judgment or abnormal findings obtained during the routine evaluation may suggest other tests, such as an IVP and urinary catecholamines.Q Since 1977, it has been recognized that an echocardiogram may be more predictive of left ventricular hypertrophy, that ambulatory BP monitoring may detect non dippers and more accurately predict target organ involvement, and that impedance studies may quantify the degree of arterial changes and tonometry may help to determine central arterial pressures. However, few of these often expensive techniques have been proven to impact the results of treatment. Despite efforts to convince physicians that 1 or more of these studies are necessary before initiating therapy or to evaluate results of treatment, there is little evidence to suggest that they are necessary for the routine evaluation of hypertensive patients.29,30 The 1977 recommendations have not changed to a great degree over the years. The JNCs have mostly resisted pressures to make expensive testing a routine in the patient’s evaluation. The JNC 7 stated that, broutine laboratory tests recommended before initiating therapy include an electrocardiogram; urinalysis; blood glucose and hematrocrit; serum potassium, creatinine (or the corresponding estimated glomerular filtration rate), and calcium; and a lipid profile (after a 9- to 12-hour fast) that includes high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. Optional tests included measurement of urinary albumin excretion or albumin/creatinine ratio. More extensive testing for identifiable causes is not indicated generally unless BP control is not achievedQ—basically similar recommendations to those in the first 6 JNC reports. The recent JNCs, however, have recognized the importance of evaluating other CV risk factors more carefully than what was done 20 to 25 years ago, as effective therapy for these entities, especially dyslipidemia, became available. None of the committees ignored the potential usefulness of some of the newer tests listed above but appropriately reserved and defined their use for specific patients. For example, some of the uses for these procedures included (1) ABPM in
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FROM JNC I TO JNC 7—WHAT HAVE WE LEARNED?
a patient whose office BPs are consistently above 140/90 m Hg but whose home BPs are consistently below 140/90 mm Hg and (2) an echocardiogram in a patient with BPs of 135/85 to 140/90 mm Hg with dyslipidemia where specific therapy for hypertension might be questioned. If, however, an echocardiogram showed any evidence of left ventricular hypertrophy (LVH), specific medical therapy would clearly be indicated. Although this simple diagnostic evaluation may be questioned by some scientists who are concerned about arterial compliance, especially in older patients, central arterial pressure as a more accurate measure of BP, or specific measures to detect target organ damage, it is quite appropriate and adequate for the intelligent management of most of patients.
Nonpharmacological Approaches All of the JNC reports stressed nonpharmacological or lifestyle management as initial therapy either alone or in combination with medications. Weight reduction and sodium restriction have been demonstrated to be the most effective interventions not only for possible prevention of hypertension but also to lower BP. The effects of these interventions plus a regular, but not necessarily vigorous, exercise program and modification of alcohol intake were summarized in various JNCs as more information became available over the years. The JNC 7 quantified some possible changes with various interventions (Table 2). Benefits of the Dietary Approaches to Stop Hypertension (DASH) diet31 have been highlighted in the recent JNCs. This diet combines the use of an adequate intake of fruits and vegetables with a low-fat dairy intake. Total energy intake must be monitored carefully in obese patients regardless of the diet chosen. The changes in BP noted in Table 2 may be enough in some patients with stage 1 hypertension (BPs 140/90-160/100 mm Hg) to lower BP to a goal level of below 140/90 mm Hg, but in a majority of cases, it was recognized by all of the JNCs that specific medical therapy is usually necessary to achieve goal BPs, especially in patients with other risk factors.32 Because goal BPs have been lowered to 130/80 mm Hg in the recent report in patients
Table 2. Lifestyle Modifications to Manage Hypertension — JNC 7
Modification
Recommendation
Weight reduction
Maintain normal body weight (body mass index 18.5-24.9 kg/m2). Consume a diet rich in fruits, vegetables and low-fat dairy products with a reduced content of saturated and total fat. Reduce dietary sodium intake to no more than 100 mmol/d (2.4 g sodium or 6 g sodium chloride). Engage in regular aerobic physical activity such as brisk walking (at least 30 min/d, most days of the week. Limit consumption to no more than 2 drinks (1 oz or 30 mL ethanol; eg, 24 oz beer, 10 oz wine, or 2 oz 80-proof whiskey) per day in women and lighter-weight persons.
Adopt DASH eating plan
Dietary sodium reduction
Physical activity
Moderation of alcohol consumption
Approximate SBP reduction (range) 5-20 mm Hg/10 kg 8-14 mm Hg
2-8 mm Hg
4-9 mm Hg
2-4 mg
Ref. [9]. The effects of implementing these modifications are dose and time dependent, and could be more or less dramatic for some individuals.
with diabetes or renal disease, the JNC 7 recommended lifestyle changes plus medication as initial therapy in these high-risk patients. In the early JNC reports, a trial of nondrug treatment of 3 to 6 months or longer had been recommended in patients whose DBPs were lower than 104 mm Hg. As noted, these recommendations have gradually evolved because results of the clinical trials demonstrated that early intervention as well as treating to lower levels of BP were effective in reducing both cerebrovascular and CV events.33,34 Although in the 1970s and early 1980s many physicians were reluctant to use medications for patients with
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Fig 1. Some of the landmark clinical trials in hypertension. Asterisk indicates after publication of JNC 7.
DBPs b100 mm Hg or to treat elderly patients unless the SBP was higher than 160 mm Hg, this attitude has changed as clinical trial data have been published and more effective and bettertolerated medications were introduced. We have learned how to use lifestyle interventions more appropriately but also that these may be difficult to implement over long periods. Persistence with these should not defer specific medical therapy if BPs are not lowered.
Treatment Numerous well-designed hypertension treatment trials have been undertaken and reported since the original VA Cooperative trial in the 1960s (Fig 1). The VA trial had reported a significant reduction in CV events in patients with severe hypertension treated with diruetics, reserpine, and hydralazine. Additional studies with these and other medications demonstrated that even patients with less severe or so-called mild hypertension (DBPs 90-104 mm Hg) and elderly subjects with ISH benefit from therapy. Over the years, these trials have clarified these issues: (1) DBPs above 90 mm Hg should be lowered; (2) there is benefit in lowering SBP/ DBP and ISH in elderly patients; (3) most of the reduction in CV events results from lowering BP—but some subsets of patients may respond better to specific medications; and (4) multiple medications (which were used in all of these trials) are necessary to achieve goal BPs in a majority of patients. The JNC recommendations evolved as the results of the trials were reported.
Stepped-Care Based on data from the VA trials and the Hypertension Detection and Follow-up Program,35 which demonstrated a better outcome in patients treated with a diuretic-based regimen compared with a less vigorous treatment program, the JNC I recommended a stepped-care approach with a thiazide diuretic as initial therapy (Fig 2). Investigators and some members of industry criticized the stepped-care approach as being antiacademic and as cookbook therapy and advocated individualized or sequential monotherapy: use one drug, titrate to a maximum dosage, and if this was not effective, try another agent with a different mechanism of action, and so on.... Experience, however, has proven that the stepped-care approach to therapy is physiologically sound and less costly and that patient adherence to treatment is better than with sequential monotherapy. Dr Irvine Page, one of the pioneers in the treatment of hypertension commented (an editorial in Modern Medicine) in 1985: We must not get snarled in nonproblems such as whether stepped-care is good or bad. Stepped-care is merely a way of presenting an orderly scenario in what otherwise threatens to join the New Yorkers Department of Utter Confusion.
Subsequent JNC reports have changed the wording once or twice but basically kept the concept of stepped-care intact and added newer medications for initial therapy as they
FROM JNC I TO JNC 7—WHAT HAVE WE LEARNED?
309
Fig 2. Outline of recommended antihypertensive regimen in JNC I. bExperience with clonidine and prazosin, newly approved, moderately potent antihypertensive agents which may be added or substituted for Step 2 or Step 3 drugs, is limited.Q3
become available. As more trials continued to demonstrate that multiple drug therapy with small doses of 2 or more medications were necessary and more effective than high-dose monotherapy, this approach has become accepted by most physicians. Stepped-care, whatever it is now called, is alive and well.36 As can be noted in the table, diuretics continue to be recommended as initial therapy for most patients and as an integral part of combination therapy if more than 1 medication is used. This recommendation is soundly based on results of many clinical trials including the SHEP and ALLHAT studies. JNC 7 Pharmacological Treatment Extensive clinical trial outcome data have demonstrated that lowering BP with several classes of drugs, including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin-receptor blockers (ARBs), b-blockers, calcium channel blockers (CCBs), and thiazide-type diuretics, will reduce the complications of hypertension. In addition, data also indicate that progression from less severe to more severe hypertension can be dramatically reduced by the use of medication. In the placebo controlled trials, 95 of 13 389 actively treated patients progressed to DBPs above 110 mm Hg, compared with 1493 of
13 342 in placebo patients.33 Thiazide-type diuretics have been an integral part of antihypertensive therapy in most of the outcome trials since the 1960s. In these trials, including ALLHAT,27 diuretics have proven to be as or more effective in preventing the CV complications of hypertension as other medications. In addition, diuretics enhance the antihypertensive efficacy of multidrug regimens, can be useful in achieving BP control, and are more affordable than other antihypertensive agents. Based on these findings, the JNC 7 recommended that thiazide-type diuretics should be used as initial therapy for most, but not all, patients with hypertension, either alone or in combination with one of the other classes (ACEIs, ARBs, b-blockers, and CCBs) (Fig 3). This is consistent with previous JNC recommendations regarding the use of thiazide diuretics (Fig 4) (Table 3). Despite the recommendations of all of the JNCs, diuretics continue to be underused, possibly because they are generic and have not been promoted, as have other agents, for the past 20 to 25 years.37,38 A major reason for poor control of many so-called resistant hypertensives is the lack of use or improper dosing of thiazide diuretics.39 This has been a recurring theme in the JNC reports in the discussions of the causes of treatment resistance.
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Fig 3. Algorithm for treatment of hypertension (JNC 7).9
Treatment in the Elderly As more data become available from studies in the elderly (SHEP,26 Syst Eur,40 and EWPHE (European Working Party on High Blood Pressure in Elderly)41), treatment in this group of patients has been more clearly defined. It became evident that treatment, primarily based on diuretic therapy (or, in the case of Syst Eur,40 the use of a CCB as initial treatment), was highly effective in reducing morbidity/mortality in patients older than 65 years. Results of ALLHAT,27 the Swedish Trial in Older People,42 and other trials clarified the role of therapy in these patients and led to a redefinition of levels of BP that should be treated in this patient population. The JNC III (1984)5 and JNC IV (1988)6 had noted that bthere were no data to confirm the efficacy of antihypertensive treatment in reducing the increased risk of CV disease associated with isolated systolic hypertensionQ (the diagnosis in most elderly patients); bthe decision to
treat must be individualized and physicians should be guided by their clinical judgement.Q Data from the Hypertension Detection and Follow-up Program,35 the Australian National Blood Pressure (Australian),43 and the EWPHE41 trials had reported that elderly patients with DBPs above 90 mm Hg or systolic/diastolic hypertension would benefit from antihypertensive drug therapy—but these patients represented a minority of hypertensive patients in this population. Subsequent trials, such as SHEP,26 demonstrated a dramatic reduction in events in patients with ISH when BP was lowered. Based on results of these trials, the JNC VI in 1998 noted that diuretics or a diuretic plus a b-blocker represented an appropriate initial treatment in elderly patients. A b-blocker was not suggested as preferred initial monotherapy. Both JNC VI and JNC 7 noted that BP lowering was more easily achieved in this population with a CCB or a diuretic rather than a b-blocker or an ACEI. Recent trials appear to confirm this statement.
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FROM JNC I TO JNC 7—WHAT HAVE WE LEARNED?
Fig 4. Hypertension guidelines for initial therapy.
The recommendations of the latest JNC in 2003 are in dramatic contrast to those in the early JNCs: bTreatment recommendations for older individuals, including those with ISH, should follow the same principle outlined for the general care of hypertension. In many individuals, lower initial drug doses may be indicated to avoid symptoms. However, standard doses and multiple drugs are needed in most older individuals to reach appropriate BP goals.Q9 Although definitive data on the management of hypertensive patients older than 80 years are not available, data from a pilot study in this group of subjects and a meta-analysis of data from other studies suggest that therapy be undertaken in these patients, primarily to prevent strokes and heart failure, not necessarily to prolong life (Table 4).44 Other Features of the JNCs The availability of more data on the use and safety of specific and newer medications has led to specific recommendations in JNC VI and JNC
7 for ACEIs, b-blockers, ARBs, and diuretics in hypertensive patients with heart failure; for ACEIs and ARBs, preferentially, usually with a diuretic, in patients with diabetic nephropathy45-47; for the use of ACEI plus a diuretic in poststroke patients to prevent a recurrent stroke48; and others. A major departure from previous recommendations of the first 5 JNCs has been an increasing emphasis on combination therapy, once frowned upon by many physicians in the academic community. For the past 20 years or longer, evidence has accumulated that (1) most patients require more than 1 medication to achieve goal BPs; (2) the use of small doses of 2 different medications, with different mechanisms of action, is more effective in lowering BP and better tolerated than large doses of 1 drug; (3) adherence to therapy is improved, and titration to effective doses of medication is simplified with combination therapy; and (4) cost of care may actually be lower.49,50 Based on these data, JNC VI suggested that combination therapy might be an option for initial therapy, and JNC 7 went even further,
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Table 3. Evolution of the Recommendations for Pharmacological Therapy of the JNC JNC IV (1988) individualized stepped-care
JNC V (1993) modified stepped-care
JNC I (1977) stepped-care
JNC II (1980) stepped-care
JNC III (1988) stepped-care
STEP 1 Diuretics
Diuretics
Less than full Diuretic, b-blocker, Diuretic or b-blocker dose of diuretic calcium antagonist, or b-blocker or ACE inhibitor Alternative therapy: ACEI, CCB, a-b–blocker, or a 1-blocker
Adrenergic inhibiting agents—clonidine, methyldopa, b-blocking drugs, a 1-blocker, rauwolfia.
Add small dose of adrenergic inhibiting agent or thiazide-type diuretic.
STEP 2 Add methyldopa, reserpine, or propranolol.
Add second drug of different class; increase dose of first drug, or substitute a drug of a different class.
Increase dose or substitute another drug, or add a second agent from a different class.
JNC VI (1997)
JNC 7 (2003)
Uncomplicated hypertension:
Thiazide diuretic in most cases; may consider ACEI, ARB, CCB, or b-blocker
Diuretic, b-blocker4 Specific or compelling indications for ARBs, ACEI, a-b–blocker, b-blocker, and CCB Step 2 Substitute another drug or add second agent. Low-dose combination may be appropriate initial therapy.
Specific or compelling Indications for ARBs, ACEI, a-b–blocker, b-blocker, CCB Substitute another drug or add third agent. Low dose combination may be appropriate initial therapy in stage II hypertension (BPs N160/100 mm Hg) or in some high-risk patients with stage I hypertension with diabetes or renal disease.4
4In the elderly, thiazide diuretics or combination thiazide/b-blocker are recommended.
suggesting that this type of approach is recommended as initial treatment in patients with stage II hypertension (BPs N160/110 mm Hg) or even in patients with Stage I hypertension (BPs 140/ 90-160/100 mm Hg) with multiple risk factors— diabetes or renal disease. These updated recommendations are appropriate, based on data from
Table 4. Outcomes of Antihypertensive Treatment in 1566 Subjects Aged 80 Years and Older in Double-blind Trials—3 Year Follow-up No. of events Outcome Stroke4 Coronary events4 Heart failure4 CV deaths All deaths4
Treatment
Control
(n = 824) 51 39
(n = 742) 69 41
Relative risk 0.644 0.85
33 104 208
50 93 180
0.584 1.11 1.144
4Significant difference.
the clinical trials that more than 2 medications are usually necessary to achieve goal BPs in a large majority of patients, especially the elderly and patients with renal disease. Numerous combinations are available and were highlighted in the latest JNCs—diuretics with ACEI, ARBs or b-blocker s, and ACEI/CCBs.51-63 The medical care of hypertensive subjects has progressed steadily since JNC I in 1977. Recommendations are more solidly based on outcome data, adherence and safety problems have been more adequately addressed, and the role of nonpharmacological therapy has been clarified. However, we still have not achieved the level of BP control in the real world of practice that the clinical trials and some studies have achieved. Each JNC has addressed the problems of adherence to therapy. It is increasingly clear that patient adherence is not the only problem to account for the less than 50% control rate in the US. Physician inertia; perhaps lack of apprecia-
FROM JNC I TO JNC 7—WHAT HAVE WE LEARNED?
tion of the benefits of BP lowering, especially in the elderly, and possibly a concern for adverse reactions from medications, may be responsible for many resistant patients. The JNC recommendations have had an impact but are not being followed as carefully as they should be. Results would improve if physicians adhered more closely to the guidelines. The JNC reports are consensus documents; not everyone will agree with their recommendations, but since 1977, they have provided a reasonable, scientifically valid update for treatment practice.
References 1. Moser M: A decade of progress in the management of hypertension. Hypertension 5:808 - 813, 1983 2. Moser M: The treatment of hypertension: a story of myths, misconceptions, controversies and heroics. Darien, CT: LeJacq Communications, Inc, 2002 3. Moser M, Guyther JR, Finnerty F, et al: Report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure. JAMA 237:255 - 261, 1977 4. Krishan I, Moser M, Curry C, et al: Report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure. Arch Intern Med 140:1280 - 1285, 1980 5. Dustan HP, Gifford RW, Frohlich ED, et al: Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. The 1984 Report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure. Arch Intern Med 144:1045 - 1057, 1984 6. Chobanian A, Alderman M, De Quattro V, et al: Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure (JNC IV). Arch Intern Med 148:1023 - 1038, 1988 7. Gifford RW, Alderman MH, Chobanian AV, et al: Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. The Fifth Report of the Joint National Committee on Detection, Evaluation and Treatment of High blood Pressure (JNC V). Arch Intern Med 153:154 - 183, 1993 8. Sheps SG, Black H, Cohen JD, et al: Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 157:2413 - 2446, 1997 9. Chobanian AV, Bakris GL, Black HR, et al: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JAMA 289:2560 - 2572, 2003
313 10. BMJ 1931;2:43-47 11. Scott RW: Clinical blood pressure. in Tice F (ed) Practice of medicine 6:93 - 114, 1946 12. Perrera G: Hypertensive vascular disease: Description and natural history. J Chronic Dis 1:33, 1955 13. Page IH, Taylor RD: Pyrogens in the treatment of malignant hypertension. Mod Concepts Cardiovasc Dis 18:51 - 52, 1949 14. Freis ED, Wilkins RW: Effect of pentaquine in patients with hypertension. Proc Soc Exp Biol Med 64:731 - 736, 1947 15. Kempner W: Treatment of hypertensive vascular disease with rice diet. Am J Med 4:545 - 577, 1948 16. Smithwick R: The effects of sympathectomy upon the mortality and survival rates of patients with hypertension cardiovascular disease. in Bell ET (ed) Hypertension. Minneapolis: Minnesota Press, 1951, pp 429 - 457 17. Kannel WB, Gordon T, Schwartz MJ, et al: Systolic versus diastolic blood pressure and risk of coronary heart disease. The Framingham Study. Am J Cardiol 27:335 - 346, 1971 18. Moser M, Mattingly TW: Critical evaluation of drug therapy of hypertension. Postgrad Med 17:351, 1955 19. Moser M, Macaulay A, Granzen R, et al: Drug therapy of hypertension. II. Experience with reserpine, apresoline, ansolysen, ecolid and mecamylamine. NY State J Med 56:2487, 1956 20. Freis ED, Wanko A, Wilson IM, et al: Treatment of hypertension with chlorothiazide (Diuril). JAMA 166:137, 1958 21. Moser M, Macaulay AK: Chlorothiazide as an adjunct in the treatment of hypertension. Am J Cardiol 3:214, 1959 22. Moser M: Guanethidine and bethanidine in the management of hypertension. Am Heart J 77: 423, 1969 23. Prichard BNC, Gillam PMC: Use of propranolol (Inderal) in treatment of hypertension. Br Med J 2:724 - 727, 1964 24. Freis E, et al, Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressures averaging 90 through 114 mm Hg. JAMA 213:1143, 1970 25. McSmith FW, Edlavitch SC, Krushat WM, et al: Treatment of mild hypertension. Results of a ten-year intervention trial. Circ Res 40:98 - 105, 1977 (suppl 1) 26. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 265: 3255 - 3264, 1991 27. Antihypertensive Therapy and Lipid Lowering Heart Attack Trial (ALLHAT) Collaborative Research Group: Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. JAMA 283:1967 - 1975, 2000
314 28. Moser M: Clinical management of hypertension (ed 7). Caddo, OK: Professional Communications, 2004 29. Moser M: Keep the management of hypertension simple. J Clin Hypertens 6:113, 2004 30. Moser M: Can the cost of care be contained and quality of care maintained in the management of hypertension? Arch Intern Med 154:1665 - 1672, 1994 31. Sacks FM, Svetkey LP, Vollmer WM, et al: Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) Diet. DASH–Sodium Collaborative Research Group. N Engl J Med 344:3 - 10, 2001 32. Moser M: Are lifestyle interventions in the management of hypertension effective? How long should you wait before starting specific medical therapy? An ongoing debate. J Clin Hypertens 7: 324 - 326, 2005 33. Moser M, Hebert P: Prevention of disease progression, left ventricular hypertrophy and congestive heart failure in the hypertension treatment trials. J Am Coll Cardiol 27:1214 - 1218, 1996 34. Hebert PR, Moser M, Mayer J, Hennekens CH, et al: Recent evidence on drug therapy of mild to moderate hypertension and decreased risk of coronary heart disease. Arch Intern Med 153:578 - 581, 1993 35. Five-year findings of the hypertension detection and follow-up program. I. Reduction in mortality of persons with high blood pressure, including mild hypertension. JAMA 242:2562 - 2571, 1979 36. Moser M: Update on the management of hypertension: Recent clinical trials and the JNC 7. J Clin Hypertens 6:4 - 13, 2004 (10 suppl 2) 37. Moser M: Why are physicians not prescribing diuretics more frequently in the management of hypertension? JAMA 279:1813 - 1816, 1996 38. Moser M, Blaufox MD, Freis E, et al: Who really determines your patients’ prescriptions? JAMA 265:498 - 500, 1991 39. Garg JP, Elliott WJ, Folker AC, et al: Resistant hypertension revisited: A comparison of two university-based cohorts. Am J Hypertens 18:619 - 626, 2005 40. Staessen JA, Fagard R, Thijs L, et al, for the Systolic Hypertension–Europe (Syst-Eur) Trial investigators: Morbidity and mortality in the placebo-controlled European Trial on Isolated Systolic Hypertension in the Elderly. Lancet 360:757 - 764, 1997 41. Staessen JA, Bulpitt C, Clement D, et al: Relation between mortality and treated blood pressure in elderly patients with hypertension: Report of the European Working Party on High Blood Pressure in the Elderly. BMJ 298:1552 - 1556, 1989 42. Hansson L, Lindholm LH, Ekbom T, et al: Randomised trial of old and new antihypertensive drugs in elderly patients: Cardiovascular mortality and morbidity in the Swedish Trial in Old Patients with Hypertension-2 (STOP-2) study. Lancet 354: 1751 - 1756, 1999 43. Australian National Blood Pressure Study Management Committee: The Australian Therapeutic Trial in Mild Hypertension. Lancet 1:1261, 1980
MARVIN MOSER 44. Moser M: Treatment of hypertension in the very elderly: A clinician’s point of view. J Clin Hypertens 5:310 - 315, 2003 45. Brenner BM, Cooper ME, de Zeeuw D, et al: Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy (RENAAL). N Engl J Med 345:861 - 869, 2001 46. Lewis EJ, Hunsicker LG, Clarke WR, et al: Renoprotective effect of the Angiotensin-Receptor Antagonist Irbesartan in patients with Nephropathy Due to Type 2 Diabetes (IDNT). N Engl J Med 345: 851 - 860, 2001 47. Parving HH, Lennert H, Brochner-Mortensen J, et al: The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. Irbesartan Microalbuminuria Type II Diabetes in Hypertensive Patients (IRMA II). N Engl J Med 345:870 - 878, 2001 48. PROGRESS Collaborative Group: Randomised trial of a perindopril-based blood-pressure–lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet 358: 1033 - 1041, 2001 49. Moser M, Black HR: The role of combination therapy in the management of hypertension. Am J Hypertens 11:73S - 78S, 1998 50. Moser M, Prisant LM: Low-dose combination therapy. Am Fam Physician 56:1275 - 1282, 1997 51. MRC Working Party: Medical Research Council trial of treatment of mild hypertension: Principal results. Br Med J 291:97 - 104, 1985 52. MRC Working Party: Medical Research Council trial of treatment of hypertension in older adults: Principal results. BMJ 304:405 - 412, 1992 53. Dahlof B, Lindholm LH, Hansson L, et al: Morbidity and mortality in the Swedish trial in old patients with hypertenison (STOP-Hypertension). Lancet 338:1281 - 1285, 1991 54. Neaton JD, Grimm Jr RJH, Prineas RJ, et al, for the Treatment of Mild Hypertension Study Research Group: Treatment of Mild Hypertension Study: Final results. JAMA 270:713 - 724, 1993 55. The Heart Outcomes Prevention Evaluation Study Investigators: Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 342:145 - 153, 2000 56. United Kingdom Prospective Diabetes Study Group: Efficacy of atenolol and captopril in reducing risk of macrovasuclar and microvascular complications in type 2 diabetes: UKPDS 39. BMJ 317:713 - 720, 1998 57. Brown MJ, Palmer CR, Cataigne A, et al, for the INSIGHT Study Group: Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium channel blocker or diuretic in the International Nifedipine GITS Study: Intervention as a Goal for Hypertension Treatment (INSIGHT). Lancet 356:366 - 372, 2000 58. Hansson L, Hedner T, Lund-Johansen P, et al, for the NORDIL Study Group: Randomised trial of effects of calcium antagonists compared with diuretics and B-blockers on cardiovascular morbidity and mortality
FROM JNC I TO JNC 7—WHAT HAVE WE LEARNED? in hypertension: The Nordic Diltiazem (NORDIL) study. Lancet 356:359 - 365, 2000 59. Heart Outcome Prevention Evaluation (HOPE) Study Investigators: Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: Results of the HOPE study and the MICRO HOPE Substudy. Lancet 255:253 - 259, 2000 60. Wing LM, Reid CM, Ryan P, et al, for the Second Australian National Blood Pressure Study Group: A comparison of outcomes with angiotensin-converting-enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med 348:583 - 592, 2003 61. Dahlof B, Devereux RB, Kjedlsen SE, et al: Cardiovascular morbidity and mortality in the Losartan Intervention for Endpoint Reduction in Hypertension Study (LIFE). Lancet 359:995 - 1003, 2002
315 62. Julius S, Kjeldsen SE, Weber M, et al, for the VALUE trial group: Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: The Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) Trial. Lancet 363:2002 - 2031, 2004 63. Dahlof B, Sever PS, Poulter NR, et al, for the ASCOT investigators: Prevalence of cardiovascular events with an antihypertensive regimen of amlodipine adding penndopril as required versus atenolol adding bendroflumethiazide as required in the Anglo-Scandinavian Cardiac Outcome Trial– Blood Pressure Lowering Arm (ASCOT-BPLA): A multicentre randomised controlled trial. Lancet 366:895 - 906, 2005
T he Aim of Science is Not to Open a Door to Endless Wisdom But to Put a Limit to Endless Error. -Bertolt Brecht, The Life of Galileo
T
here are few stories in the history of medicine that are filled with more errors or misconceptions than the story of hypertension and its treatment.1,2 The Joint National Committee Reports on Detection, Evaluation, and Treatment of High Blood Pressure (JNCs) were first published in 1977 and every 4 to 5 years after that to clarify many of these misconceptions and to provide updates of clinical research results for physicians and other individuals involved in the management of hypertension.3-9 For many years until the late 1930s, elevated blood pressure (BP) was considered an essential adaptive phenomenon; prominent US cardiologists and British physicians warned that lowering BP might be harmful. Hay,10 in an editorial, stated that: bThe greatest danger to a man with high BP lies in its discovery, because then some fool is certain to try and reduce itQ. In the 1940s and 1950s, a dramatic change in the approach to hypertension occurred, and although there were still some physicians who continued to have doubts regarding the significance of hypertension, most had accepted that increased BP increased the risk for cardiovascular disease. The literature, however, even as late as 1946, still reflected a common misconception, bMay not the elevation of systemic BP be a natural response to guarantee a more normal circulation to the heart, brain and kidneysQ (bessentialQ hypertension) and that bOverzealous attempts to lower the pressure may do no good and often do harm.Q11 Prominent experts in the 1950s still reported that essential hypertension was a benign disease.12 However, there were pioneers such as Page and Freis13,14 who believed otherwise and began to treat elevated BP. Only patients with severe
hypertension were treated at first because of problems with therapy. The use of a rigid lowsodium Kempner Rice Regimen, consisting mostly of fruit and fruit juice and rice and containing just 20 g of protein, only 5 g of fat, and less than 200 mg of sodium, had resulted in a reversal of malignant hypertension.15 Although the results were temporary, they were exciting for those physicians who used this approach. And although Sir George Pickering, a physicianphilosopher in Great Britain, described the diet as insipid, unappetizing, monotonous, unacceptable, and intolerable,1 the few people who were able to stay on the diet did respond. Kempner15 reported that 322 of 500 patients had improved. Surgical sympathectomies and adrenalectomies had also been performed in patients with severe hypertension with some good results, but adverse reactions were often severe.16 It was clear that better therapies had to be developed if less severe hypertension was to be controlled in large numbers of people. The risk of therapy had to be reduced to justify treatment for patients who were not in danger of an imminent cardiovascular (CV) event. Although epidemiological studies in the 1960s and 1970s confirmed that even minimally elevated systolic BPs (SBPs) or diastolic BPs (DBPs) increased CV risk,17 treatment remained relatively complicated. In the 1950s to 1970s, various other medications were developed— rauwolfia derivatives; vasodilators such as hy-
From the Yale University School of Medicine, New Haven CT 06510, USA. Address reprint requests to Marvin Moser, MD, Clinical Professor of Medicine, Yale University School of Medicine, 13 Murray Hill Rd. Scarsdale, NY 1058. E-mail: [email protected] 0033-0620/$ - see front matter n 2006 Published by Elsevier Inc. doi:10.1016/j.pcad.2006.02.003
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304 dralazine, thiazide diuretics, ganglion, and peripheral adrenergic blockers; and the centrally acting a2 agonists, b-adrenergic inhibitors, and a-b–blocker inhibitors.18-23 Many of these medications, especially the ganglion blockers such as hexamethonium or mecamylamine or the peripheral blockers such as guanethedine, effectively decreased BPs and improved signs of target organ involvement, but adverse reactions with these more potent agents were severe and limited patient/physician acceptance. The use of thiazide diuretics and b-blockers greatly simplified care. One of the first clinical outcome trials, the Veterans Administration (VA) Cooperative Study pioneered by Freis,24 demonstrated that lowering BP with the available medications in male patients with severe hypertension dramatically improved their outcome when compared with placebo. The Public Health Study in mild hypertension25 confirmed the results of the VA study in less severe hypertensive patients. None of the 193 patients in the active group, compared with 24 of the 196 patients in the placebo group, progressed to more severe disease with DBPs N110 mm Hg. With sufficient information on hand and a growing scientific base regarding the risk of hypertension and the benefits of treatment, at least in moderately severe or severe hypertensive patients, the National High Blood Pressure Education Program was established in 1973.1 It was apparent from the start that the Federal Government, industry, organized medicine, volunteer groups, physicians, nurses, and other professionals could work together effectively with a Coordinating Committee of the National High Blood Pressure Education Program to control a major disease. In 1977, the First Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure established guidelines for management and introduced the stepped-care approach to hypertension treatment.3 Since then, guidelines have been revised approximately every 4 to 5 years in 1980, 1984, 1988, 1993, 1997, and most recently, in 2003. 4-9 The guideline committees, which originally consisted of 10 individuals chosen from national organizations by the National Heart, Lung and Blood Institute (NHLBI) review and evaluate the available data on diagnostic procedures and
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treatment and publish their conclusions regarding an appropriate approach to management. More recent guideline committees have consisted of 10 to 15 experts chosen by the NHLBI with more than 50 consultants and contributors. More than 30 national organizations approve the report before it is finalized. The guidelines have been disseminated by the NHLBI. From the 6-page report in JAMA in 1977,3 the reports have expanded considerably to a 34-page-long document in 19978 and a 47-page report in 2003.9 Over the years, the guidelines have stressed a scientifically acceptable but relatively simple diagnostic evaluation and encouraged approaches to treatment which, although not suitable for all patients, had been proven effective. These guidelines have been widely accepted by professionals throughout the world. The JNC reports have been criticized by some investigators as being too simple or, on the other hand, too complicated, not workable, or too concerned with cost considerations. In general, however, they have stood the test of time and have evolved as a standard guideline for the management of most hypertensive patients.
What Have We Learned Since the 1970s and How Have the Guidelines Evolved? Criteria for Diagnosis and Treatment of Follow-up In 1977, definitions of what constituted hypertension and the management of various levels of BP were considerably different than those that have evolved over the past 30 years. This was due in part to the fact that, although epidemiological data had established that there was an increasing risk for CV events with SBPs increasing from as low as 115 mm Hg and an arbitrary definition of hypertension as above 140/90 mm Hg in young and middle-aged persons had been established as a definition of hypertension, there were few data on benefit in people with so-called mild hypertension—DBPs below 104. Mild hypertension had been defined as a DBP of 90 to 104 mm Hg in the treatment trials in the 1960s and 1970s. Systolic BP changes had not been considered as primary end points in these studies. The JNC I therefore stated that all adults with DBPs of 120 mm Hg or above, recorded at the
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disappearance of sound, should be referred promptly to a source of medical care. All persons with BPs of 160/95 mm Hg or above should have the BP elevation confirmed within 1 month. All persons younger than 50 years with BPs of 140/90 to 160/95 mm Hg should be checked every 2 to 3 months (the implication was that these people did not require specific therapy). All persons older than 50 years with a BP of 140/90 to 160/95 mm Hg should be checked within 6 to 9 months (again, the lack of treatment data greatly influenced this decision). All adults with DBPs b90 mm hg should be advised to have their BP checked yearly. Although recognizing the epidemiological data regarding increased risk from elevated SBP at all ages, the committee chose the DBP as the basis for confirming high BP and recommending disposition because the benefits of treatment of SBP were unclear. It was believed that if both SBPs and DBPs were used as guidelines, the recommendations might be too complex and not consistent with available data at that time. All of these recommendations reflected the lack of treatment data in patients other than those with severe hypertension. Classifications of various levels of BP evolved in JNC III in 1984, JNC VI in 1997, and JNC 7 in 2003 (Table 1), and recommendations for follow-up and treatment changed as more data became available. It had become clear that a persistent BP of higher than 140/90 mm Hg required some treatment regardless of age. The JNCs in 1984 and 1988 still used the terms mild, moderate, and severe hypertension to define various levels of severity, that is, DBPs of 90 to 104 (mild), 105 to 114 (moderately severe), and above 115 mm Hg (severe). Even in the 1980s, SBP was listed separately: 140 to 159, borderline isolated systolic hypertension; above 160 mm Hg, isolated SBP; (Table 1). In contrast, the JNC 7 simplified definitions so there are now only 2 stages of hypertension: stage I, 140 to 159/90 to 99 mm Hg and stage 2, 160/100 mm Hg. This is in recognition of the fact that patients with a persistent BP above 140/90 mm Hg should be treated with specific medication if lifestyle changes do not lower BP to below 140/90 mm Hg and that the management of hypertension is essentially the same in patients with BPs above 160 mm Hg, as it is in
Table 1. Changing Classifications of Levels of BP JNC III (1984)
JNC VI (1997)
DBP (mm Hg)
SBP/DBP (mm Hg) Normal, b120 and b80 Optimal, b120 Prehypertension, and b80 120-139 or 80-89 Normal, b130 Stage I, 140-159 and b85-89 or 90-99
b85, Normal BP 85-89, High-normal BP 90-104, Mild hypertension 105-114, Moderate hypertension N115, Severe hypertension
High-normal, 130-139 or 85-89 Stage I, 140-159 or 90-99
JNC 7 (2003)
Stage II, N160 or z100
Stage II, 160-179 or 100-109 Stage III, N180 or z110
SBP b140, Normal 140-159, Borderline ISH N160, ISH Refs. [5,8,9].
patients previously listed as stage 3 (N115 mm Hg DBP), except for people with malignant or accelerated hypertension in whom more urgent therapy is necessary. A designation of prehypertension (120-139/80-89 mm Hg) was used in JNC 7 instead of high-normal to highlight the fact that these individuals, although not being labeled as hypertensive, were in need of careful follow-up and changes in lifestyle if appropriate. In addition, over the years from JNC I to JNC 7, an appreciation of the importance of SBP as a risk factor and recognition that lowering isolated elevated SBP (isolated systolic hypertension [ISH]) would reduce morbidity/mortality have led to an emphasis on this entity as a more important guide to risk evaluation and to therapy than the DBP. The definition of ISH has evolved through the years from an SBP of above 160 and a DBP below 90 mm Hg to above 140 and below 90 mm Hg. Recommendations for follow-up evaluations also dramatically changed as more data, especially from the Systolic Hypertension in the Elderly Program (SHEP),26 the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT),27 indicated that early therapy may make a difference in outcome.
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Although, as noted in JNC I, people older than 50 years with BPs as high as 160/95 mm Hg were just advised to have their BP checked within 6 to 9 months, and specific pharmacological were considered optional; JNC 7 recommended specific medical therapy for BPs above 140/90 mm Hg or even lower in patients with renal disease and/or diabetes. The time intervals given for lifestyle modifications to be judged effective have been shortened. In stage II patients (BPs N160/ 100 mm Hg), pharmacological interventions are suggested as initial therapy in addition to lifestyle changes. These recommendations again reflect the results of the numerous clinical trials.
Diagnostic Evaluation Although numerous new technologies and tests for the evaluation of hypertension have evolved over the past 30 years, the recommendations of the JNCs have not changed to a great degree since 1977.28 In 1977, the first JNC suggested that extensive laboratory testing of patients with high BP, such as a routine intravenous pyelogram (IVP), plasma renin, or aldosterone levels, which had been advocated in many medical centers, was not necessary for initial evaluation. They recommended that routine pretreatment workup should be limited to defining the severity of the BP and identifying its complications and associated CV risk factors. bMore complex diagnostic procedures designed to discover specific causes of high BP can be reasonably reserved for those subjects: (1) in whom routine history, physical examination, or the recommended laboratory findings suggest one of the specific recognizable causes; (2) who are under the age of 30, since they have the greatest prevalence of correctable secondary high BP; or (3) in whom drug therapy proves inadequate or unsatisfactory.Q In 1977, the following laboratory tests were suggested before initiating therapy: bhematocrit; urinalysis for protein, blood, and glucose, using the dipstick method; creatinine and/or blood urea nitrogen; serum potassium; and an electrocardiogram.Q bOther tests, which may be helpful, include a chest x-ray, blood sugar, serum cholesterol, serum uric acid, microscopic urinalysis, and blood count. Minimal cost to the patient can sometimes be
achieved by ordering automated blood chemistries. Clinical judgment or abnormal findings obtained during the routine evaluation may suggest other tests, such as an IVP and urinary catecholamines.Q Since 1977, it has been recognized that an echocardiogram may be more predictive of left ventricular hypertrophy, that ambulatory BP monitoring may detect non dippers and more accurately predict target organ involvement, and that impedance studies may quantify the degree of arterial changes and tonometry may help to determine central arterial pressures. However, few of these often expensive techniques have been proven to impact the results of treatment. Despite efforts to convince physicians that 1 or more of these studies are necessary before initiating therapy or to evaluate results of treatment, there is little evidence to suggest that they are necessary for the routine evaluation of hypertensive patients.29,30 The 1977 recommendations have not changed to a great degree over the years. The JNCs have mostly resisted pressures to make expensive testing a routine in the patient’s evaluation. The JNC 7 stated that, broutine laboratory tests recommended before initiating therapy include an electrocardiogram; urinalysis; blood glucose and hematrocrit; serum potassium, creatinine (or the corresponding estimated glomerular filtration rate), and calcium; and a lipid profile (after a 9- to 12-hour fast) that includes high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. Optional tests included measurement of urinary albumin excretion or albumin/creatinine ratio. More extensive testing for identifiable causes is not indicated generally unless BP control is not achievedQ—basically similar recommendations to those in the first 6 JNC reports. The recent JNCs, however, have recognized the importance of evaluating other CV risk factors more carefully than what was done 20 to 25 years ago, as effective therapy for these entities, especially dyslipidemia, became available. None of the committees ignored the potential usefulness of some of the newer tests listed above but appropriately reserved and defined their use for specific patients. For example, some of the uses for these procedures included (1) ABPM in
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a patient whose office BPs are consistently above 140/90 m Hg but whose home BPs are consistently below 140/90 mm Hg and (2) an echocardiogram in a patient with BPs of 135/85 to 140/90 mm Hg with dyslipidemia where specific therapy for hypertension might be questioned. If, however, an echocardiogram showed any evidence of left ventricular hypertrophy (LVH), specific medical therapy would clearly be indicated. Although this simple diagnostic evaluation may be questioned by some scientists who are concerned about arterial compliance, especially in older patients, central arterial pressure as a more accurate measure of BP, or specific measures to detect target organ damage, it is quite appropriate and adequate for the intelligent management of most of patients.
Nonpharmacological Approaches All of the JNC reports stressed nonpharmacological or lifestyle management as initial therapy either alone or in combination with medications. Weight reduction and sodium restriction have been demonstrated to be the most effective interventions not only for possible prevention of hypertension but also to lower BP. The effects of these interventions plus a regular, but not necessarily vigorous, exercise program and modification of alcohol intake were summarized in various JNCs as more information became available over the years. The JNC 7 quantified some possible changes with various interventions (Table 2). Benefits of the Dietary Approaches to Stop Hypertension (DASH) diet31 have been highlighted in the recent JNCs. This diet combines the use of an adequate intake of fruits and vegetables with a low-fat dairy intake. Total energy intake must be monitored carefully in obese patients regardless of the diet chosen. The changes in BP noted in Table 2 may be enough in some patients with stage 1 hypertension (BPs 140/90-160/100 mm Hg) to lower BP to a goal level of below 140/90 mm Hg, but in a majority of cases, it was recognized by all of the JNCs that specific medical therapy is usually necessary to achieve goal BPs, especially in patients with other risk factors.32 Because goal BPs have been lowered to 130/80 mm Hg in the recent report in patients
Table 2. Lifestyle Modifications to Manage Hypertension — JNC 7
Modification
Recommendation
Weight reduction
Maintain normal body weight (body mass index 18.5-24.9 kg/m2). Consume a diet rich in fruits, vegetables and low-fat dairy products with a reduced content of saturated and total fat. Reduce dietary sodium intake to no more than 100 mmol/d (2.4 g sodium or 6 g sodium chloride). Engage in regular aerobic physical activity such as brisk walking (at least 30 min/d, most days of the week. Limit consumption to no more than 2 drinks (1 oz or 30 mL ethanol; eg, 24 oz beer, 10 oz wine, or 2 oz 80-proof whiskey) per day in women and lighter-weight persons.
Adopt DASH eating plan
Dietary sodium reduction
Physical activity
Moderation of alcohol consumption
Approximate SBP reduction (range) 5-20 mm Hg/10 kg 8-14 mm Hg
2-8 mm Hg
4-9 mm Hg
2-4 mg
Ref. [9]. The effects of implementing these modifications are dose and time dependent, and could be more or less dramatic for some individuals.
with diabetes or renal disease, the JNC 7 recommended lifestyle changes plus medication as initial therapy in these high-risk patients. In the early JNC reports, a trial of nondrug treatment of 3 to 6 months or longer had been recommended in patients whose DBPs were lower than 104 mm Hg. As noted, these recommendations have gradually evolved because results of the clinical trials demonstrated that early intervention as well as treating to lower levels of BP were effective in reducing both cerebrovascular and CV events.33,34 Although in the 1970s and early 1980s many physicians were reluctant to use medications for patients with
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Fig 1. Some of the landmark clinical trials in hypertension. Asterisk indicates after publication of JNC 7.
DBPs b100 mm Hg or to treat elderly patients unless the SBP was higher than 160 mm Hg, this attitude has changed as clinical trial data have been published and more effective and bettertolerated medications were introduced. We have learned how to use lifestyle interventions more appropriately but also that these may be difficult to implement over long periods. Persistence with these should not defer specific medical therapy if BPs are not lowered.
Treatment Numerous well-designed hypertension treatment trials have been undertaken and reported since the original VA Cooperative trial in the 1960s (Fig 1). The VA trial had reported a significant reduction in CV events in patients with severe hypertension treated with diruetics, reserpine, and hydralazine. Additional studies with these and other medications demonstrated that even patients with less severe or so-called mild hypertension (DBPs 90-104 mm Hg) and elderly subjects with ISH benefit from therapy. Over the years, these trials have clarified these issues: (1) DBPs above 90 mm Hg should be lowered; (2) there is benefit in lowering SBP/ DBP and ISH in elderly patients; (3) most of the reduction in CV events results from lowering BP—but some subsets of patients may respond better to specific medications; and (4) multiple medications (which were used in all of these trials) are necessary to achieve goal BPs in a majority of patients. The JNC recommendations evolved as the results of the trials were reported.
Stepped-Care Based on data from the VA trials and the Hypertension Detection and Follow-up Program,35 which demonstrated a better outcome in patients treated with a diuretic-based regimen compared with a less vigorous treatment program, the JNC I recommended a stepped-care approach with a thiazide diuretic as initial therapy (Fig 2). Investigators and some members of industry criticized the stepped-care approach as being antiacademic and as cookbook therapy and advocated individualized or sequential monotherapy: use one drug, titrate to a maximum dosage, and if this was not effective, try another agent with a different mechanism of action, and so on.... Experience, however, has proven that the stepped-care approach to therapy is physiologically sound and less costly and that patient adherence to treatment is better than with sequential monotherapy. Dr Irvine Page, one of the pioneers in the treatment of hypertension commented (an editorial in Modern Medicine) in 1985: We must not get snarled in nonproblems such as whether stepped-care is good or bad. Stepped-care is merely a way of presenting an orderly scenario in what otherwise threatens to join the New Yorkers Department of Utter Confusion.
Subsequent JNC reports have changed the wording once or twice but basically kept the concept of stepped-care intact and added newer medications for initial therapy as they
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309
Fig 2. Outline of recommended antihypertensive regimen in JNC I. bExperience with clonidine and prazosin, newly approved, moderately potent antihypertensive agents which may be added or substituted for Step 2 or Step 3 drugs, is limited.Q3
become available. As more trials continued to demonstrate that multiple drug therapy with small doses of 2 or more medications were necessary and more effective than high-dose monotherapy, this approach has become accepted by most physicians. Stepped-care, whatever it is now called, is alive and well.36 As can be noted in the table, diuretics continue to be recommended as initial therapy for most patients and as an integral part of combination therapy if more than 1 medication is used. This recommendation is soundly based on results of many clinical trials including the SHEP and ALLHAT studies. JNC 7 Pharmacological Treatment Extensive clinical trial outcome data have demonstrated that lowering BP with several classes of drugs, including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin-receptor blockers (ARBs), b-blockers, calcium channel blockers (CCBs), and thiazide-type diuretics, will reduce the complications of hypertension. In addition, data also indicate that progression from less severe to more severe hypertension can be dramatically reduced by the use of medication. In the placebo controlled trials, 95 of 13 389 actively treated patients progressed to DBPs above 110 mm Hg, compared with 1493 of
13 342 in placebo patients.33 Thiazide-type diuretics have been an integral part of antihypertensive therapy in most of the outcome trials since the 1960s. In these trials, including ALLHAT,27 diuretics have proven to be as or more effective in preventing the CV complications of hypertension as other medications. In addition, diuretics enhance the antihypertensive efficacy of multidrug regimens, can be useful in achieving BP control, and are more affordable than other antihypertensive agents. Based on these findings, the JNC 7 recommended that thiazide-type diuretics should be used as initial therapy for most, but not all, patients with hypertension, either alone or in combination with one of the other classes (ACEIs, ARBs, b-blockers, and CCBs) (Fig 3). This is consistent with previous JNC recommendations regarding the use of thiazide diuretics (Fig 4) (Table 3). Despite the recommendations of all of the JNCs, diuretics continue to be underused, possibly because they are generic and have not been promoted, as have other agents, for the past 20 to 25 years.37,38 A major reason for poor control of many so-called resistant hypertensives is the lack of use or improper dosing of thiazide diuretics.39 This has been a recurring theme in the JNC reports in the discussions of the causes of treatment resistance.
310
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Fig 3. Algorithm for treatment of hypertension (JNC 7).9
Treatment in the Elderly As more data become available from studies in the elderly (SHEP,26 Syst Eur,40 and EWPHE (European Working Party on High Blood Pressure in Elderly)41), treatment in this group of patients has been more clearly defined. It became evident that treatment, primarily based on diuretic therapy (or, in the case of Syst Eur,40 the use of a CCB as initial treatment), was highly effective in reducing morbidity/mortality in patients older than 65 years. Results of ALLHAT,27 the Swedish Trial in Older People,42 and other trials clarified the role of therapy in these patients and led to a redefinition of levels of BP that should be treated in this patient population. The JNC III (1984)5 and JNC IV (1988)6 had noted that bthere were no data to confirm the efficacy of antihypertensive treatment in reducing the increased risk of CV disease associated with isolated systolic hypertensionQ (the diagnosis in most elderly patients); bthe decision to
treat must be individualized and physicians should be guided by their clinical judgement.Q Data from the Hypertension Detection and Follow-up Program,35 the Australian National Blood Pressure (Australian),43 and the EWPHE41 trials had reported that elderly patients with DBPs above 90 mm Hg or systolic/diastolic hypertension would benefit from antihypertensive drug therapy—but these patients represented a minority of hypertensive patients in this population. Subsequent trials, such as SHEP,26 demonstrated a dramatic reduction in events in patients with ISH when BP was lowered. Based on results of these trials, the JNC VI in 1998 noted that diuretics or a diuretic plus a b-blocker represented an appropriate initial treatment in elderly patients. A b-blocker was not suggested as preferred initial monotherapy. Both JNC VI and JNC 7 noted that BP lowering was more easily achieved in this population with a CCB or a diuretic rather than a b-blocker or an ACEI. Recent trials appear to confirm this statement.
311
FROM JNC I TO JNC 7—WHAT HAVE WE LEARNED?
Fig 4. Hypertension guidelines for initial therapy.
The recommendations of the latest JNC in 2003 are in dramatic contrast to those in the early JNCs: bTreatment recommendations for older individuals, including those with ISH, should follow the same principle outlined for the general care of hypertension. In many individuals, lower initial drug doses may be indicated to avoid symptoms. However, standard doses and multiple drugs are needed in most older individuals to reach appropriate BP goals.Q9 Although definitive data on the management of hypertensive patients older than 80 years are not available, data from a pilot study in this group of subjects and a meta-analysis of data from other studies suggest that therapy be undertaken in these patients, primarily to prevent strokes and heart failure, not necessarily to prolong life (Table 4).44 Other Features of the JNCs The availability of more data on the use and safety of specific and newer medications has led to specific recommendations in JNC VI and JNC
7 for ACEIs, b-blockers, ARBs, and diuretics in hypertensive patients with heart failure; for ACEIs and ARBs, preferentially, usually with a diuretic, in patients with diabetic nephropathy45-47; for the use of ACEI plus a diuretic in poststroke patients to prevent a recurrent stroke48; and others. A major departure from previous recommendations of the first 5 JNCs has been an increasing emphasis on combination therapy, once frowned upon by many physicians in the academic community. For the past 20 years or longer, evidence has accumulated that (1) most patients require more than 1 medication to achieve goal BPs; (2) the use of small doses of 2 different medications, with different mechanisms of action, is more effective in lowering BP and better tolerated than large doses of 1 drug; (3) adherence to therapy is improved, and titration to effective doses of medication is simplified with combination therapy; and (4) cost of care may actually be lower.49,50 Based on these data, JNC VI suggested that combination therapy might be an option for initial therapy, and JNC 7 went even further,
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Table 3. Evolution of the Recommendations for Pharmacological Therapy of the JNC JNC IV (1988) individualized stepped-care
JNC V (1993) modified stepped-care
JNC I (1977) stepped-care
JNC II (1980) stepped-care
JNC III (1988) stepped-care
STEP 1 Diuretics
Diuretics
Less than full Diuretic, b-blocker, Diuretic or b-blocker dose of diuretic calcium antagonist, or b-blocker or ACE inhibitor Alternative therapy: ACEI, CCB, a-b–blocker, or a 1-blocker
Adrenergic inhibiting agents—clonidine, methyldopa, b-blocking drugs, a 1-blocker, rauwolfia.
Add small dose of adrenergic inhibiting agent or thiazide-type diuretic.
STEP 2 Add methyldopa, reserpine, or propranolol.
Add second drug of different class; increase dose of first drug, or substitute a drug of a different class.
Increase dose or substitute another drug, or add a second agent from a different class.
JNC VI (1997)
JNC 7 (2003)
Uncomplicated hypertension:
Thiazide diuretic in most cases; may consider ACEI, ARB, CCB, or b-blocker
Diuretic, b-blocker4 Specific or compelling indications for ARBs, ACEI, a-b–blocker, b-blocker, and CCB Step 2 Substitute another drug or add second agent. Low-dose combination may be appropriate initial therapy.
Specific or compelling Indications for ARBs, ACEI, a-b–blocker, b-blocker, CCB Substitute another drug or add third agent. Low dose combination may be appropriate initial therapy in stage II hypertension (BPs N160/100 mm Hg) or in some high-risk patients with stage I hypertension with diabetes or renal disease.4
4In the elderly, thiazide diuretics or combination thiazide/b-blocker are recommended.
suggesting that this type of approach is recommended as initial treatment in patients with stage II hypertension (BPs N160/110 mm Hg) or even in patients with Stage I hypertension (BPs 140/ 90-160/100 mm Hg) with multiple risk factors— diabetes or renal disease. These updated recommendations are appropriate, based on data from
Table 4. Outcomes of Antihypertensive Treatment in 1566 Subjects Aged 80 Years and Older in Double-blind Trials—3 Year Follow-up No. of events Outcome Stroke4 Coronary events4 Heart failure4 CV deaths All deaths4
Treatment
Control
(n = 824) 51 39
(n = 742) 69 41
Relative risk 0.644 0.85
33 104 208
50 93 180
0.584 1.11 1.144
4Significant difference.
the clinical trials that more than 2 medications are usually necessary to achieve goal BPs in a large majority of patients, especially the elderly and patients with renal disease. Numerous combinations are available and were highlighted in the latest JNCs—diuretics with ACEI, ARBs or b-blocker s, and ACEI/CCBs.51-63 The medical care of hypertensive subjects has progressed steadily since JNC I in 1977. Recommendations are more solidly based on outcome data, adherence and safety problems have been more adequately addressed, and the role of nonpharmacological therapy has been clarified. However, we still have not achieved the level of BP control in the real world of practice that the clinical trials and some studies have achieved. Each JNC has addressed the problems of adherence to therapy. It is increasingly clear that patient adherence is not the only problem to account for the less than 50% control rate in the US. Physician inertia; perhaps lack of apprecia-
FROM JNC I TO JNC 7—WHAT HAVE WE LEARNED?
tion of the benefits of BP lowering, especially in the elderly, and possibly a concern for adverse reactions from medications, may be responsible for many resistant patients. The JNC recommendations have had an impact but are not being followed as carefully as they should be. Results would improve if physicians adhered more closely to the guidelines. The JNC reports are consensus documents; not everyone will agree with their recommendations, but since 1977, they have provided a reasonable, scientifically valid update for treatment practice.
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