Update on the Management of Hypertension: Recent Clinical Trials and the JNC 7

Abstract

The following issues are highlighted: Emphasis is placed on the importance of systolic blood pressure elevations in estimating risk and in determining prognosis. A review of placebo‐controlled clinical trials indicates that cardiovascular events are statistically significantly reduced with diuretic‐ or β blocker‐based treatment regimens. The question of whether blood pressure lowering alone or specific medications make the difference in outcome is discussed. Based on the results of numerous trials, it is apparent that blood pressure lowering itself is probably of greater importance in reducing cardiovascular events than the specific medication used. Meta‐analyses suggest, however, that the use of an agent that blocks the renin‐angiotensin aldosterone system is probably more effective in diabetics and in patients with nephropathy than a regimen based on calcium channel blocker therapy. The Antihypertensive and Lipid‐Lowering treatment to Prevent Heart Attack Trial (ALLHAT) reported no overall difference in coronary heart disease outcome among patients treated with a diuretic‐based compared to a calcium channel blocker‐ or an angiotensin‐converting enzyme inhibitor‐based treatment program. However, patients in the diuretic group experienced fewer episodes of heart failure than in the calcium channel blocker group and fewer episodes of heart failure and strokes than those in the angiotensin‐converting enzyme inhibitor group. Results were similar in diabetics and nondiabetics. Possible reasons for this outcome are discussed. The Australian National Blood Pressure 2 study, which was unblinded, reported a marginally significantly better outcome only in male patients receiving an angiotensin‐converting enzyme inhibitor‐based regimen compared to those receiving a diuretic‐based program. Finally, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) is reviewed. Highlights of this report include the new designation of prehypertension, i.e., blood pressures of 120–139 mm Hg/80–89 mm Hg. The JNC 7 suggested that diuretics should be the first‐step drug of choice in most patients, but listed numerous specific reasons why other agents should be used in special situations. The report stressed that the majority of patients will require two or more medications to achieve goal blood pressure.

Before reviewing results of the recent clinical trials and evaluating the recommendations of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), ¹ it is important to emphasize several issues that have been highlighted in the literature within the past few years.

Figure 1 summarizes an important message. These data are from the Multiple Risk Factor Intervention Trial (MRFIT) ² that followed more than 300,000 men and evaluated their relative risk of a cardiovascular event. While most physicians today are treating diastolic blood pressures (BPs) of 95–100 mm Hg, repeated surveys have demonstrated that many are not treating systolic BPs (SBPs) of 150–159 mm Hg. Yet, as can be seen, the cardiovascular risk of an SBP of 150–159 mm Hg is considerably greater than that of a diastolic BP of 95–100 mm Hg. It has only been in the last few years that the relatively greater importance of an SBP elevation in estimating risk has been emphasized. Data have also shown that an SBP of 140–159 mm Hg confers a greater long‐term risk than an SBP <140 mm Hg. ³

Figure 1.

Relative risk for cardiovascular disease of elevated systolic blood pressure and diastolic blood pressure. Adapted with permission from JAMA. 1990;263:1795–1801. ²

It is important to highlight results of the 17 randomized, placebo‐controlled treatment trials that were completed in the 1960s and 1970s and involved almost 48,000 people. ⁴ , ⁵ , Figure 2 summarizes the findings from these studies. There were significant reductions in congestive heart failure (CHF) (52%), strokes (38%), the occurrence of left ventricular hypertrophy (LVH) (36%), cardiovascular disease (21%), and coronary heart disease events (16%) in diuretic or β blocker‐based treatment programs compared to placebo. It is occasionally forgotten that these agents had a dramatic effect on outcome in hypertensive patients. The decrease in CHF was not a decrease in recurrent heart failure, but a decrease in the occurrence of heart failure in the first place by lowering BP. The prevention of LVH is also of significance and, while it was known that reversal or regression of cardiac hypertrophy in treated hypertensive patients with pretreatment LVH occurred in a high percentage of patients, it is only in recent years that it has been documented that this reduces the occurrence of cardiovascular events and increases survival (Figure 3). ⁶ Thus, the speculation that a decrease in left ventricular muscle mass might lead to an ineffective functioning myocardium has not been confirmed.

Figure 2.

Combined results from 17 randomized placebo‐controlled treatment trials (48,000 subjects), diuretic or β‐blocker based. CHF=congestive heart failure; LVH=left ventricular hypertrophy; CVD=coronary vascular disease; CHD=coronary heart disease; *all differences are statistically significant Adapted with permission from Arch Intern Med. 1993;153:578‐581 ⁵ ; Circulation. 1998;97:48–54. ⁶

Figure 3.

Reversal of cardiac hypertrophy in hypertensive patients with initial left ventricular hypertrophy treated by antihypertensive drug therapy. Nonregressors (solid line and bar) (n=52); regressors (hashed line and bar) (n=50). Adapted with permission from N Engl J Med. 1993;329:1912–1917. ³

IS IT BP ALONE OR SPECIFIC MEDICATIONS THAT MAKE THE DIFFERENCE?

Another question to address: Is it BP lowering alone that determines outcome or are specific drugs more effective than others in reducing cardiovascular events? ⁷ There are numerous studies that have demonstrated that BP lowering alone reduced cardiovascular events. For example, in the Verapamil in Hypertension and Atherosclerosis Study (VHAS) ⁸ where verapamil was compared to chlorthalidone in a 2‐year trial, there was no difference in fatal or nonfatal events with an equivalent reduction in BP. This trial emphasized two important points: 1) at the time the study was done, there were suggestions that the use of calcium channel blockers (CCBs) might result in a poor outcome in hypertensive subjects. These were mainly with dihydropyridine CCBs. The results of the VHAS study suggest that the use of a nondihydropyridine CCB plus other medications produce results equivalent to those when a diuretic plus other therapies are used. 2) In this trial, the use of chlorthalidone did not result in any adverse effects on lipid and glucose levels. In the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial, ⁹ there was also no primary end point outcome difference between primarily a diuretic/β blocker regimen and a long‐acting, verapamil‐based treatment program.

Other trials have demonstrated that BP lowering, and not specific medication, accounts for the decrease in cardiovascular events. These include the UK Prospective Diabetes Study (UKPDS) ¹⁰ in hypertensive patients with type 2 diabetes. In this trial, a β blocker‐based treatment program was compared to an angiotensin‐converting enzyme (ACE) inhibitor‐based treatment program. There were two groups achieving different BP goals. In the tight BP group, BPs were reduced to 144/82 mm Hg compared to 154/87 mm Hg in the less tight control group (Table I). The difference of −10/−5 mm Hg in BP outcome resulted in a statistically significant reduction in strokes of 44%, deaths related to diabetes of 32%, heart failure 56%, and microvascular disease, i.e., proteinuria and retinopathy, of 37%. There was no difference in outcome between the captopril‐based and the atenolol‐based treatment programs. Thus, in this trial, it was the BP that made the difference rather than specific medications.

Table I.

Results of Different Levels of Blood Pressure Control in Hypertensive Patients With Type 2 Diabetes ¹⁰

β Blocker Compared to ACEI‐Based Treatment Program
Better control of BP compared to less aggressive treatment in 8.4 year follow‐up of 1148 subjects  End point 144/82 mm Hg compared to 154/87 mm Hg
Reduces risk of:
Stroke	44%
Death related to diabetes	32%
Heart failure	56%
Microvascular disease	37%
MI and sudden death	21% (NS)
No difference in outcome between a captopril‐based and an atenolol‐based treatment program
BP=blood pressure; ACEI=angiotensin‐converting enzyme inhibitor; MI=myocardial infarction; NS=not significant

In the Swedish Trial in Old Patients with Hypertension‐2 (STOP‐2) study, ¹¹ which compared conventional therapies, i.e., diuretics and β blockers to ACE inhibitors and calcium antagonists, BP changes were equivalent among the various medications. The percentages of patients who experienced overall cardiovascular events were similar, although there were some subgroup differences.

There are other trials that indicate similar findings. There are, however, comparative trials where different outcomes were noted with different medications. Examples of these include several trials in high‐risk patients (Heart Outcomes Prevention Evaluation [HOPE] trial, ¹² Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria [IRMA 2] trial, ¹³ Irbesartan in Diabetic Nephropathy Trial [IDNT], ¹⁴ Reduction in Endpoints in Noninsulin‐dependent Diabetes Mellitus With the Angiotensin II Antagonist Losartan [RENAAL] study, ¹⁵ African American Study of Kidney Disease and Hypertension [AASK] trial, ¹⁶ and the Losartan Intervention For Endpoint Reduction in Hypertension [LIFE] study ¹⁷ ). These studies indicate that the use of an ACE inhibitor or an angiotensin receptor blocker (ARB), usually with a diuretic, reduces cardiovascular events in high‐risk individuals to a greater degree than a regimen that does not include these medications. This appears to be especially true in diabetic patients with nephropathy.

For example, in the LIFE study, ¹⁷ an ARB (losartan)‐ based treatment program was compared to an atenolol‐based treatment program in high‐risk hypertensive patients with LVH. The losartan group achieved a reduction in the primary end point of 13%, primarily driven by a reduction in strokes of 25% compared to the β blocker‐treated patients (Table II). Achieved BP at the end of the trial was 144/82 mm Hg in the losartan group and 145/82 mm Hg in the atenolol‐treated patients. More than 70% of patients in each group received other medications, primarily thiazide diuretics. In the RENAAL study, ¹⁵ therapy with an ARB plus other medications was compared to a regimen that did not indicate an ARB or an ACE inhibitor. A significant reduction in end‐stage renal disease in type 2 diabetic patients was demonstrated in the arm of the trial that included the use of an ARB. ¹⁵ Although, in the STOP‐2 study, ¹¹ there was no overall difference between conventional therapy and ACE inhibitor plus CCBs when considered together; there were significantly fewer instances of myocardial infarctions (Mis) and heart failure in the ACE inhibitor‐based compared to the CCB‐based treatment patients (Figure 4).

Table II.

Results of an ARB‐Based (Losartan) Compared to a β Blocker‐Based (Atenolol) Treatment Program in Hypertensive Patients With LVH (LIFE Study) ¹⁷

	% Difference Losartan vs. Atenolol	p Value
Primary end point (CV death, MI, stroke)	−13*	0.02
Stroke	−25*	0.001
MI	+7	NS
CV mortality	−11	NS
Total mortality	−10	NS
New‐onset diabetes	−25*	0.001
Achieved blood pressure (BP): losartan 144/82 mm Hg; atenolol 145/82 mm Hg; goal BPs: 45%–50% SBP<140; 89% DBP <90; ARB=angiotensin receptor blocker; LVH=left ventricular hypertrophy; LIFE=Losartan Intervention for Endpoint Reduction in Hypertension; SBP=systolic blood pressure; DBP=diastolic blood pressure; CV=cardiovascular; MI=myocardial infarction; NS=not significant; *statistically significant

Figure 4.

Relative risk of cardiovascular mortality and morbidity for angiotensin‐converting enzyme inhibitors (ACEIs) vs. calcium antagonists (Swedish Trial in Old Patients with Hypertension‐2 study). MI=myocardial infarction; CV=cardiovascular; CHF=congestive heart failure; * significant difference. Adapted with permission from Lancet. 1999;354:1751–1756. ¹¹

Although there is some question about the BP outcome in the HOPE trial, ¹² which included patients with cardiovascular disease, a risk reduction of 22% in MI, stroke, and cardiovascular disease, 25% in cardiovascular deaths, 31% in strokes, and 16% in all‐cause mortality was noted in a group of patients treated with an ACE inhibitor (ramipril) plus other medications compared to a regimen that did not include the ACE inhibitor. Overall, BP differences between the ACE inhibitor‐treated and other patients was only −3/−2 mm Hg. There is, however, still a question of whether or not it was the BP difference or the effects of a specific medication that accounted for the difference in outcome. A small subgroup who received the ACE inhibitor in addition to other medication and was studied with 24‐hour ambulatory monitors showed a greater decrease in BP, especially during the night, than the non‐ACE inhibitor group.

Overall, when different medications are compared, there is little difference in outcome between ACE inhibitor‐based and diuretic‐ or β blocker‐based therapy in hypertensive patients. However, when comparisons are made of ACE inhibitor‐based with CCB‐based therapy in hypertensive patients, there appears, at least in some trials, to be a statistically significantly greater benefit with the ACE inhibitor in coronary heart disease events and heart failure than with CCB‐based therapy. ¹⁸

Thus, although BP lowering probably accounts for the major portion of the benefit in outcome trials, there is some evidence that certain drugs, especially medications that block the renin‐angiotensin‐aldosterone system (usually given in combination with a diuretic), may have specific favorable effects in certain population groups, especially diabetics or patients with renal disease. There may be an advantage to using these drugs earlier in a treatment regimen rather than a CCB. The Outcomes in Hypertensive Patients at High Cardiovascular Risk treated with a regimen based on Valsartan or Amlodipine: the VALUE trial ¹⁹ was reported after this symposium. This study compared the results of a CCB (amlodipine)‐based to an ARB (valsartan)‐based treatment regimen in high‐risk patients for a 4+ year period. ¹⁹ There was no difference in the overall primary composite end point of cardiac morbidity or mortality between the two groups. New‐onset diabetes was less frequent in the ARB‐treated patients, but there were fewer episodes of MI in the amlodipine‐treated patients. Especially during the first year, BPs were lower in this group than in the ARB group. This may have accounted for the difference in outcome.

MONOTHERAPY COMPARED TO THERAPY WITH TWO DRUGS

Antihypertensive monotherapy is effective in only about 40%–50% of hypertensive patients, irrespective of the category of the agent used. There is frequently a need for the use of two medications with different mechanisms of action to reach goal BPs. ²⁰ , ²¹ The advantages of two‐drug therapy have been repeatedly demonstrated, and the advantage of combining two medications in one pill has also been noted. Some of these include the patient's perception of his/her disease. In an era where many hypertensive patients are elderly and are already taking medications for diabetes, lipid abnormalities, arthritis, etc., the addition of one pill rather than two, or two rather than four, is important psychologically. As noted in the JNC 7, many patients will require two medications. Titration to an effective dose will be simplified by using two medications in combination. Any racial differences in response will be eliminated. For example, it is well documented that black patients do not respond as well to β blockers, ACE inhibitors, or ARBs as they do to diuretics or CCBs. However, when an ACE inhibitor, ARB, or a β blocker is combined with a diuretic, racial differences disappear and the degree of response is significantly increased (Figure 5). There are some data to suggest that when combination therapy is used, response rate is greater if one of the components is a diuretic. In comparative studies, a higher percentage of patients responded when a diuretic was part of a treatment regimen than when a diuretic was not used. ²²

Figure 5.

Angiotensin‐converting enzyme inhibitor/diuretic combination therapy: racial differences in response. HCTZ=hydrochlorothiazide; δ=change. Adapted with permission from J Hypertens. 1984;2(suppl 2):81–88. ^l8

A recent study highlights the benefits of combination therapy. In the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) ²³ reported several years ago, patients who had experienced a transient ischemic attack or other cerebrovascular event were treated with an ACE inhibitor, an ACE inhibitor/diuretic combination, or placebo. A statistically significant 28% risk reduction of recurrent strokes was noted in the ACE inhibitor/diuretic group, but not in the ACE inhibitor monotherapy group, compared to placebo.

There is good evidence that combination therapy is a reasonable approach to the management of hypertension and that one of the more effective combinations is a diuretic with an ACE inhibitor, ARB, or a β blocker—agents that block the activity of the renin‐angiotensin‐aldosterone system. Since diuretic use, over time, results in vasodilation with a slight decrease in plasma volume and an increase in the activity of the renin‐angiotensin‐aldosterone system, this combination makes good sense physiologically. The combination of an ACE inhibitor/CCB has also been shown to decrease BP significantly more than either agent alone with less edema than if the CCB was given as monotherapy.

The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

The ALLHAT trial ²⁴ was a randomized, double‐blind, multicenter, clinical trial to determine whether the occurrence of fatal coronary heart disease or nonfatal MIs was lower for high‐risk, elderly hypertensive patients treated with the newer agents, CCBs, ACE inhibitors, or α blockers, compared to a diuretic‐based regimen. The study originally included 42,418 high‐risk patients. The protocol allowed for an increase in the initial step‐1 agents; chlorthalidone from 12 to 25 mg, amlodipine from 2.5 to 10 mg, lisinopril from 10 to 40 mg, and doxazosin, an α blocker, from 1 to 8 mg. ALLHAT has been criticized because an addon agent could not include one of the study drugs. For example, in the lisinopril group, it would have been logical to add chlorthalidone, or any other thiazide as a second drug. This was not permitted by protocol, although about 20% of patients did receive an ACE inhibitor/diuretic combination. In the amlodipine group, lisinopril could not be added, yet this would have been a logical combination. In the chlorthalidone group, the addition of a β blocker, a logical second choice drug was permitted. The diuretic‐treated patients were able to add a logical second‐step drug while the other groups were not. Some criticism has also centered around the fact that about one third of the subjects were black; a group of individuals who respond better to a diuretic or a CCB than an ACE inhibitor.

An important finding in ALLHAT that has not been emphasized was that >60% of patients were controlled at goal levels compared to the national average of about 35%. The ALLHAT protocol encouraged aggressive titration of medication. Thus, a protocol driven treatment program resulted in better results than less specifically directed treatment regimens. ²⁵

The overall results of ALLHAT showed no difference in the primary end point, MI (fatal and nonfatal), among the diuretic, CCB, and ACE inhibitor groups. This result had not been expected by many investigators. The doxazosin arm of the study was stopped early because of a significantly better outcome in the diuretic group, especially regarding the occurrence of heart failure. An analysis of several secondary end points revealed that patients in the chlorthalidone‐based treatment group had experienced fewer episodes of heart failure and strokes than patients in the lisinopril‐based treatment group and fewer episodes of CHF than patients in the amlodipine‐based treatment group. BPs were lowered to a greater degree in the diuretic group compared to the lisinopril group, especially in black patients where most of the diuretic stroke benefit was noted. Critics note that if a logical second‐step drug had been added to treatment in the ACE inhibitor group, BPs would have been lowered to an equal degree as in the diuretic group, and there would not have been a difference in outcome.

Adverse Effects of Diuretics: Are They of Clinical Importance? An ongoing issue regarding diuretic therapy concerns the question of possible adverse effects of these agents on lipid and glucose metabolism. There is still the perception that these changes may negate the benefits of BP lowering, but are they significant?

In the ALLHAT study, where more than 30% of patients were diabetic with a mean age at baseline of 67 years, the outcome on diuretics was similar in diabetics and nondiabetics. As noted, coronary heart disease primary outcome events were similar in the ACE inhibitor, CCB, and diuretic groups. ALLHAT was a 5–6 year study; over this time there was only a minimal increase in glucose levels in the diuretic‐treated compared to the lisinopril and amlodipine groups. There were, however, 3.5% more people on a diuretic who developed new‐onset diabetes compared to those receiving lisinopril. The question arises: Why use a drug that may increase new‐onset diabetes in a population that is obese and may have signs of the metabolic syndrome?

In the diuretic‐based or diuretic/β blocker‐based clinical trials, which were placebo controlled, there was an increase of about 0.6 of 1% in new‐onset diabetes in treated patients (Table III). ²⁶ In comparative trials, i.e., LIFE, ¹⁷ there was an increase of 4.5/1000 patient years in new‐onset diabetics in the diuretic/β blocker‐treated patients compared to the ARB‐treated patients. In the HOPE study, there were 1% fewer cases of new‐onset diabetes with an ACE inhibitor than with other medications. In the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) trial, ²⁷ there was a trend toward fewer cases in the ARB‐treated group compared to the group not receiving an ARB. In the ALLHAT study, 3.5% more cases were noted with diuretics compared to an ACE inhibitor. In the International Verapamil Trandolapril Study (INVEST), ²⁸ there were 1.1%, in the International Nifedipine Gastrointestinal Therapeutic System study: Intervention as a Goal for Hypertension Therapy (INSIGHT) study, ²⁹ there were 1.3% more new‐onset cases in diuretic or diuretic/β blocker‐based programs compared to other drugs, and, as noted, there were fewer new‐onset diabetics in the ARB‐treated compared to the β blocker‐treated patients in the LIFE study (Table IV). Thus, there is some evidence that the use of a diuretic or β blocker/diuretic‐based treatment regimen may increase new‐onset diabetes compared to other therapies. But, thus far, the data do not suggest that this adversely affects outcome.

Table III.

Effects of High‐Dose Diuretic Therapy Compared to Control or Placebo on Glucose Metabolism ²⁶

Study	Years	Serum Glucose (mg/dL)	Hyperglycemia or Diabetes
Oslo	5	No difference D/Pl	No data
EWPHE	3–4	Increase of 6.6 D/Pl	Excess of 6 new cases/1000 patient‐years
MRC	3–4	Increase of 6.6 D/Pl	Excess of 6 new cases/1000 patient‐years
HAPPHY	3–4	Increase of 6.6 D/Pl	Excess of 6 new cases/1000 patient‐years
SHEP	1	Difference of 5 D/Pl	No difference–new onset diabetes Rx/placebo
MRFIT	6		Excess of 5% (SI) diuretics vs. (UC) no diuretics*
Oslo=The Oslo Hypertension Study; D/Pl=diuretics compared with placebo; EWPHE=European Working Party on High Blood Pressure in the Elderly; MRC=Medical Research Council Trial in the Elderly; HAPPHY=Heart Attack Primary Prevention in Hypertension trial; SHEP=Systolic Hypertension in the Elderly Program; MRFIT=Multiple Risk Factor Intervention Trial; SI=special intervention; UC=usual care; *fasting glucose >110 mg/dL 26

Table IV.

Effect of Antihypertensive Therapy on New‐Onset Diabetes

Study	No. of Subjects	Ages	BP	Comment
LIFE	9193	55–85	174/98	Losartan (ARB) compared with atenolol (β blocker) (HCTZ added): 4.5 fewer cases/1000 patient years
HOPE	5720	55+	139/99	ACE inhibitor (ramipril): −1.8% lower incidence compared with other medications
SCOPE	4964	70–89 (76*)	166/90	Candesartan (ARB) based therapy: trend to fewer new onset diabetics compared with other medications
ALLHAT	33,000	67*	146/84	3.5% fewer cases of diabetes with lisinopril than with chlorthalidone
INVEST	>16,000	≥50	—	1.1% fewer new onset diabetes in CCB/ACE compared with β blocker/diuretic
INSIGHT	6321	55–80	>150/95	1.3% higher with diuretics compared with CCB
BP=blood pressure; LIFE=Losartan Intervention for Endpoint Reduction in Hypertension study; ARB=angiotensin receptor blocker; HCTZ= hydrochlorothiazide; HOPE=Heart Outcomes Prevention Evaluation trial; ACE=angiotensin‐converting enzyme; SCOPE=Study on Cognition and Prognosis in the Elderly; ALLHAT=Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial; INVEST=Interventional Verapamil SR/Trandolapril study; CCB=calcium channel blocker; INSIGHT=Intervention as a Goal in Hypertension Treatment; *mean age

Evidence‐based medicine, which is what national guidelines are based on, suggests that the small increase in new‐onset diabetes is not clinically relevant in terms of the benefit from diuretic use, although long‐term trials are necessary to settle this question. There is evidence that in diabetic patients, especially those with proteinuria, a better outcome is noted with an ACE inhibitor‐ or ARB‐based regimen, which usually includes a diuretic, than one based on a CCB. The VALUE trial results also suggest that new‐onset diabetes may be more common with a CCB than an ARB. There is evidence from the UKPDS study that a β blocker‐based regimen will result in the same benefit in type 2 diabetic patients as an ACE inhibitor‐based treatment program if BP is lowered.

The Second Australian National Blood Pressure (ANBP2) Study

The ANBP2 study ³⁰ was a 5‐year study in older people that compared a diuretic to an ACE inhibitor‐based treatment program. In this study, physicians were allowed to use almost any combination of medications. In some ways, it is more practice‐relevant than the ALLHAT trial. The ANBP2 trial was, however, unblinded.

The results indicate that all cardiovascular events or any death were marginally statistically significantly less with an ACE inhibitor. In contrast to the ALLHAT study, this unblinded trial in an elderly, almost all‐white population with a different protocol, showed a greater benefit with the ACE inhibitor (Figure 6). But, there are some problems with the ANBP2 trial, in addition to the fact that it was not blinded. There was no difference in outcome between an ACE inhibitor and a diuretic in women; almost all of the benefit was noted in men. Thus, men had a better outcome than women, a finding that is difficult to explain. These two, large trials do not contradict one another; they indicate that both ACE inhibitors and diuretics are effective and that different populations may respond differently to different agents.

Figure 6.

Primary result in the Australian Blood Pressure trial. ACEI=angiotensin‐converting enzyme inhibitor; CV=cardiovascular; CI=confidence interval. Adapted with permission from N Engl J Med. 2003;348:583–592. ³⁰

Diagnosis. In a departure from previous recommendations, the JNC 7 ¹ recommended that BPs of 120–139/80–89 mm Hg be classified as prehypertension (Table V). Classification was simplified to only two stages since treatment of BPs 160/100 mm Hg or higher is similar to that of BPs >180/110 mm Hg, which was previously designated as stage 3 hypertension. The major difference was the prehypertension classification. The Committee believed that this designation would encourage physicians and patients to become more active in implementing lifestyle changes to prevent more significant hypertension. But do these levels of BP, i.e., prehypertension (120–139/80–89 mm Hg) imply an increased risk?

Table V.

JNC 7 Blood Pressure (BP) Classification

BP Classification	SBP mm Hg		DBP mm Hg
Normal	<120	and	<80
Prehypertension	120–139	or	80–89
Stage 1 hypertension	140–159	or	90–99
Stage 2 hypertension	≥160	or	≥100
JNC 7=The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; BP=blood pressure; SBP=systolic blood pressure; DBP=diastolic blood pressure. Reproduced with permission from JAMA. 2003;289:2560–2572. 1

Some data suggest that left ventricular mass, which is a major predictor of cardiovascular events, is greater in the prehypertensive patient than in normotensives. On the other hand, the risk for stroke or cardiac mortality is apparently not increased at these levels of BP. Finally, C‐reactive protein levels appear to be higher in people with prehypertension than in individuals with BPs <120/80 mm Hg. This inflammatory marker has recently been identified as a cardiovascular risk factor.

There is some preliminary evidence, therefore, that the designation of prehypertension, which is based on epidemiologic findings that risk increases as systolic BP increases from >110 mm Hg, may also be a marker for the presence of other risk factors or target organ involvement. However, at present, there is no evidence to suggest specific medical therapy in patients with prehypertension, except in some diabetics or patients with renal disease. ³¹

Evaluation. In 1977, the first JNC ³² and all subsequent JNCs, including JNC 7 in 2003, suggested an evaluation of the hypertensive patient that is scientifically valid, relatively simple, and not too costly (Table VI). Echocardiograms were not suggested as part of a routine evaluation. Ambulatory monitoring was not recommended as part of a routine evaluation. Physiologic studies were not suggested as part of a routine evaluation. These procedures may be useful, but they are not necessary as part of the initial workup. Patients can be treated effectively without them in most cases. ³³

Table VI.

Suggested Routine Laboratory Tests in the Evaluation of a Hypertensive Patient: JNC I–JNC 7 ⁵

Electrocardiogram

Urinalysis

Blood glucose and hematocrit

Serum potassium, creatinine, or the corresponding estimated GFR, and calcium

Lipid profile (fasting)

Optional Tests

Measurement of urinary albumin excretion or albumin/creatinine ratio

JNC=The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; GFR=glomerular filtration rate

Lifestyle modifications were, again, appropriately suggested as initial therapy. Table VII estimates the BP lowering to be expected with various interventions. If a patient loses 22 lb, he/she would probably experience a lowering of SBP by about 10 mm Hg. The Dietary Approaches to Stop Hypertension (DASH) eating plan is recommended. This is a balanced diet containing fruit, vegetables, and low‐fat dairy products. Dietary sodium restriction might result in an SBP decrease of about 4–5 mm Hg. Physical activity, not necessarily running, but walking briskly 3–4 times a week, bicycle riding, walking up stairs, etc., and moderation of alcohol, if indicated, will also help to lower BP. But, if lifestyle changes are not effective, the recommendations suggest that in stage 1 hypertension (140–159/90–99 mm Hg), thiazide diuretics should represent initial drug therapy for most patients (Table IX). Other drugs can be used or a combination might be given if diabetes or renal disease is present. The duration of lifestyle changes depends on the presence or absence of other risk factors. In a 65‐year‐old man with diabetes, it is appropriate to start drug therapy at the same time as lifestyle modifications. In a 45‐year‐old stage 1 hypertensive woman without other risk factors, a 3–6 month trial is justified. In stage 2 hypertension, in a departure from previous recommendations, two medications are recommended for many patients to achieve goal BPs. One of the components should be a diuretic. Combination therapy is, therefore, considered appropriate in stage 1 hypertension in high‐risk patients with diabetes and renal disease and in patients with stage 2 hypertension (BPs >160/100 mm Hg).

Table VII.

Lifestyle Modification ¹

Modification	Approximate SBP Reduction (Range)
Weight reduction	5–20 mm Hg/10 kg weight loss
Adopt DASH eating plan	8–14 mm Hg
Dietary sodium reduction	2–8 mm Hg
Physical activity	4–9 mm Hg
Moderation of alcohol consumption	2–4 mm Hg
SBP=systolic blood pressure; DASH=Dietary Approaches to Stop Hypertension

Table IX.

Initial Drug Choices Without Specific Indications (JNC 7 Algorithm for Drug Treatment of Hypertension)

Stage 1 Hypertension (SBP 140–159 mm Hg or DBP 90–99 mm Hg)	Stage 2 Hypertension* (SBP ≥160 MM HG OR DBP ≥100 MM Hg)
Thiazide‐type diuretics for most May consider ACEI, ARB, BB, CCB, or combination	Two‐drug combination for most (usually thiazide‐type diuretic and ACEI, or ARB, or BB, or CCB)
JNC 7=The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; SBP=systolic blood pressure; DBP=diastolic blood pressure; ACEI=angiotensin‐converting enzyme inhibitor; ARB=angiotensin receptor blocker; BB=β blocker; CCB=calcium channel blocker; *combination therapy may also be appropriate initial therapy in stage 1 hypertensive patients with diabetes or renal disease. Adapted with permission from JAMA. 2003;289:2560‐2572. 1

There are different indications for different medications. These are listed in Table VIII. Lowering the BP to goal levels of <140/90 mm Hg, or even lower to 130/80–85 mm Hg in patients with diabetes or renal disease, should be the objective of treatment, regardless of the medication chosen. The key messages of the JNC recommendations for therapy are: 1) thiazides as initial therapy for most patients; and 2) if BPs are >160/100 mm Hg, combination therapy is appropriate.

Table VIII.

Specific or Compelling Indications for Different Medications

Indication	Initial Therapy
Diabetes	Thiazide diuretic, BB, ACEI, ARB, CCB
Chronic kidney disease	ACEI, ARB
Recurrent stroke prevention	Thiazide diuretic, ACEI
Heart failure	Thiazide diuretic, BB, ACEI, ARB, aldosterone antagonist
Post‐myocardial infarction	BB, ACE‐I, aldosterone antagonist
High CAD risk	Thiazide diuretic, BB, ACEI, CCB
BB=β blocker; ACEI=angiotensin‐converting enzyme inhibitor; ARB=angiotensin receptor blocker; CCB=calcium channel blocker; CAD=coronary artery disease

There are many available medications, if used appropriately, that can control BP in most hypertensive patients. There are also many medications under investigation; perhaps one of these will prove to be more effective than those available at present. However, a major problem may not be the lack of available effective antihypertensive therapies but the fact that some physicians are not titrating medication to appropriate dosages or using appropriate combinations of drugs. ³⁴