The Charles J. and Margaret Roberts professor and chairman, Department of Preventive Medicine, Rush University Medical Center, Chicago, Illinois
The Joint National Committee (JNC) began in 1972 under the auspices of the National High Blood Pressure Education Program, and the first guidelines, known as JNC I, were published in 1977. This report mentioned 28 drugs. The main message was that a diastolic blood pressure (DBP) higher than 105 mm Hg was the appropriate level to begin therapy, and diuretics were recommended as first-line therapy.
JNC II, published in 1980, discussed 34 drugs and again, diuretics were recommended as first-line therapy. JNC III, published in 1984, discussed 42 drugs and reflected two major innovations. First, beta blocking agents were added to diuretics as appropriate first-choice therapy. Second, starting therapy at low doses was recommended.
In the JNC IV guidelines, published in 1988, angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists were added as first-line treatment recommendations. This generated some controversy since no clinical trial that showed a reduction in cardiovascular end points had been done with these drugs. In the JNC V guidelines, issued in 1993, there was a return to support of diuretics and beta blockers as first-line therapy unless there was a reason to use something else. In the JNC VI guidelines, published in 1997, all seven drug classes representing 84 drugs were recommended as potential first-line agents.
One troubling trend at the time JNC VI was published was that both awareness and treatment of hypertension had declined from previous years, reversing a trend that had started in the 1970s. Hypertension awareness had gone from about 50% in the 1970s to 73% in the late 1980s, declining to 68% in the early 1990s. The number of patients receiving treatment for hypertension followed the same pattern, improving from about 30% in the late 1970s to 55% in the late 1980s, then falling slightly to 53% in the 1990s.1 Despite the growing number of drugs available to treat hypertension and the emphasis on the importance of hypertension control, only about one fourth of US citizens were at goal (< 140/< 90 mm Hg) through the mid-1990s, and the treatment-to-goal rates were even lower in older Americans, at 10% to 15%.2
JNC VI included a matrix of five different classifications of blood pressure (BP)—normal, high-normal, and stages 1, 2, and 3. Absolute risk, as well as relative risk, was also taken into account within these classifications. Increasing relative risk was indicated by increasing BP and stages,
and increasing absolute risk by the change from Risk Group A to B to C.
Four points are worth noting regarding the JNC VI guidelines. First, if a patient was in Risk Group C (the highest risk group), defined by the presence of diabetes, renal disease, or heart failure (HF), drug therapy was recommended even if BP was in the high-normal range (130-139/85-89 mm Hg). No prior report recommended treating patients at that low level. Second, the term compelling indications was coined, meaning the use of certain agents for patients with certain complications. Third, in JNC VI, the discussion was no longer about so-called “sequential monotherapy.” Rather, adding drugs from other classes was advocated (“stepped-care”). Finally, hypertension specialists were mentioned for the first time.
In my view, the overriding message of JNC VI was “go for goal and don’t settle for less.” Specifically, the goals of antihypertensive therapy were to achieve a BP of:
• < 140/< 90 mm Hg for patients with uncomplicated hypertension
• < 130/< 85 mm Hg for patients with diabetes, HF, or chronic renal failure
• < 125/< 75 mm Hg for patients with ≥ 1 g proteinuria.
These goals were not dependent on age, sex, or comorbidity.
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) was published in May 2003.3 Many new studies had been reported since the publication of the JNC VI guidelines, and the JNC 7 guidelines [note the change to Arabic numerals] needed to reflect the findings of these new studies. An attempt was also made to simplify JNC VI’s BP classifications and to provide clear, concise guidelines for clinicians.
Studies that highlighted the need for new BP classification
New Framingham data. A 14-year follow-up analysis of data from the Framingham study showed a continuous gradient of increasing cardiovascular (CV) risk across all three BP categories that were classified in JNC VI as high-normal (130 to 139/85 to 89 mm Hg), normal (120 to 129/80 to 84 mm Hg), and optimal (< 120/< 80 mm Hg).4 The JNC VI guidelines did not recommend treatment of patients in these BP categories except for high-normal patients in Risk Group C. In addition, the Framingham cohort study found that the lifetime risk of develop-
ing hypertension (defined as systolic blood pressure [SBP] ≥ 140 or DBP ≥ 90) was greater than 90% in both men and women who were still normotensive at age 55 or 65.5
Prospective Studies Collaboration. This study, which included more than 1 million subjects and 12 million person-years of follow-up in its analysis of data from 61 observational studies, examined the 34,000 deaths from coronary heart disease (CHD) that occurred in patients aged 40 to 89 years with SBP levels of 130 to 180 mm Hg.6 The researchers found a reduction in risk of CHD death for every 20-mm Hg decrement in baseline SBP; this reduction in risk ranged from 51% for patients aged 40 to 49 years to 33% in patients aged 80 to 89 years (figure 1). Similar results were observed for DBP. A significant reduction in CHD death risk was observed for every 10-mm Hg decrement in baseline DBP, with risk reductions ranging from 53% in patients aged 40 to 49 years to 30% in patients aged 80 to 89 years.
Analysis of the 12,000 deaths
due to stroke in patients aged 50 to 89 years showed a similar trend—each 20-mm Hg decrement in baseline SBP represented a 64% risk reduction in patients 40 to 49 years old and a 33% reduction in patients 80 to 89 years.
Throughout middle and old age, usual SBP was strongly and directly related to vascular (and overall) mortality, without any evidence of a threshold to at least 115/75 mm Hg. An additional and equally important finding was that other risk factors—blood cholesterol level, diabetes, smoking, and weight—did not have any material influence on the proportional differences in vascular mortality associated with a given absolute difference in usual BP.
Implications for JNC 7. These findings led to a new four-tiered BP classification system in JNC 7:
• Normal: SBP < 120 mm Hg and DBP < 80 mm Hg
• Prehypertension: SBP 120 to 139 mm Hg or DBP 80 to 89 mm Hg
• Stage 1 hypertension: SBP 140 to 159 mm Hg or DBP 90 to 99 mm Hg
• Stage 2 hypertension: SBP ≥ 160 mm Hg or DBP ≥ 100 mm Hg.
These changes in BP meant that 22% of Americans who were previously classified as normotensive would now be classified as prehypertensive.7
Studies that helped determine JNC 7 drug therapy recommendations
Several studies published after JNC VI played a critical role in shaping the drug recommendations in JNC 7.
STOP-2. The Swedish Trial in
Old Patients With Hypertension-2 (STOP-2) compared dihydropyridine calcium antagonists to ACE inhibitors and beta blockers/diuretics in more than 6,000 hypertensive persons over 6 years of follow-up. This study showed no clear advantage of one drug class over another.8
NORDIL. The Nordic Diltiazem (NORDIL) study examined the effects of the nondihydropyridine calcium antagonist diltiazem compared with beta blockers/diuretics on CV morbidity and mortality in patients with hypertension. The study found no statistically significant differences between the effect of these drugs on the combined primary end point of fatal and nonfatal stroke, myocardial infarction (MI), and CV death.9
LIFE. The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study enrolled more than 9,000 patients with hypertension and left ventricular hypertrophy and compared two regimens, one that began with a beta blocker (atenolol) and the other with an angiotensin receptor blocker (ARB) (losartan). The losartan-based regimen resulted in lower levels of CV morbidity and death than the atenolol-based regimen. This was the first trial demonstrating the benefits of ARBs in a hypertensive population, although other studies in volunteers with diabetic nephropathy (Irbesartan in Diabetic Nephropathy Trial [IDNT], Reduction in Endpoints in Patients with Non-insulin-dependant diabetes mellitus with the Angiotensin II Antagonist Losartan [RENAAL]) had shown a reduction in end points in those subjects.10
CONVINCE. The Controlled Onset Verapamil Investigation of Cardiovascular Endpoints (CONVINCE) trial compared the standard of care (diuretics or beta blockers) with the nondihydropyridine calcium antagonist verapamil in more than 16,000 patients with hypertension. When the study was stopped, there was no statistically significant difference in the occurrence of the primary end point (stroke, MI, or CV-related death) between the two treatment groups.11
ALLHAT. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was one of the largest trials
(n = 42,418 including doxazosin and n = 33,357 without that arm) and had a great influence on JNC 7 treatment recommendations. One analysis of this trial compared the effect of the calcium antagonist amlodipine with chlorthalidone and the ACE inhibitor lisinopril with chlorthalidone on a combined CV disease (CVD) end point, which included the development of HF, stroke, treatment for angina, and the need for coronary revascularization in patients with hypertension and at least one other CHD risk factor. The group receiving the ACE inhibitor had a 10% greater risk of a CV event and a 15% greater risk of stroke compared with those taking chlorthalidone.12 This difference was seen early in the trial and was maintained throughout the trial.
In a subgroup analysis of patients who experienced stroke, mean follow-up SBP was found to be 2 mm Hg higher in all lisinopril recipients compared with chlorthalidone recipients, and 4 mm Hg higher in the 35% of African Americans in the study. The relative risk of stroke was 40% higher in African Americans than in non—African Americans in the lisinopril versus chlorthalidone comparison.
ANBP-2. The Second Australian National Blood Pressure Study (ANBP-2) compared ACE inhibitors with diuretics and found that outcomes were slightly better in the ACE inhibitor group, but only in men and if all events were counted (HF, stroke, CVD, CHD), not simply the first event as is customary.13
Other studies. Taking the results of these individual trials a step further, Staessen and colleagues compared the results of older and newer clinical BP trials.14 Both the older and newer trials showed that lowering SBP, even by modest amounts, can have a significant impact on CV
outcomes. For instance, the Heart Outcomes Prevention Evaluation (HOPE) showed that as little as a
3-mm Hg difference in SBP between groups (ramipril versus placebo)
can result in about a 25% decrease in CV event risk.
The analysis by Staessen and colleagues revealed no consistent advantage with the use of any particular agent in terms of MI risk, a possible advantage for ARBs over other agents in terms of stroke risk, inferiority of calcium antagonists,
a slight advantage for ACE inhibitors in terms of HF risk, and a clear disadvantage for alpha blockers for all CV events.
The more recent Blood Pressure Lowering Treatment Trialists’ Collaboration found similar results15:
• For CHD: no differences were observed in comparisons of ACE inhibitors or calcium antagonists versus diuretics and beta blockers,
or ACE inhibitors versus calcium antagonists.
• For stroke: ACE inhibitors were slightly inferior to diuretics/beta blockers and calcium antagonists; in turn, calcium agonists were slightly superior to diuretics/beta blockers.
• For HF: diuretics/beta blockers were marginally superior to ACE inhibitors and clearly superior to calcium antagonists. ACE inhibitors were superior to calcium antagonists.
• For all major CV events there were no marked differences between different drug classes.
The effect of ARBs on
• ARBs appear to be superior for reducing the risks of HF and stroke and not inferior with respect to other CV outcomes (CHD, major CV events, CV death, total mortality) compared with other agents.
The impact of BP reductions
• Small reductions in SBP reduce
the incidence of stroke, CHD, major CV events, and CV death, but not HF; there is a trend toward a reduction in all-cause mortality with SBP reduction.
The results of clinical trials shed light on a key piece of the puzzle—namely, the utility of monotherapy in treating hypertension. Materson and colleagues showed that even with a modest DBP goal of less than 95 mm Hg, only about half of the study participants were able to achieve this goal after 1 year of monotherapy with any of the five classes of drugs studied (figure 2).16 In the Hypertension Optimal Treatment (HOT) study, 75% of subjects randomized to a DBP goal of less than 80 mm Hg needed more than one drug. Still, average BP in that subset was 140/86 mm Hg.17 Bakris and colleagues examined the number of antihypertensive drugs needed to reach target in several recent studies.18 The five major trials they examined showed that patients usually required three or four drugs to reach target BP. The percentage of patients requiring more than one drug was 63% in ALLHAT, 58% in the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), and 70% in the CONVINCE study. In spite of this ag-gressive therapy, DBP goal (< 90 mm Hg) was reached in 90% of subjects but only 60% achieved the SBP goal of less than 140 mm Hg. In a study conducted at our clinic, the average number of antihypertensive drugs taken per day by patients was four.19 Implications of recent studies Based on the findings from the individual drug trials published since JNC VI, as well as several meta-analyses, the following points can be made. First, the importance of decreasing BP to improve an individual’s CV health is clearly evident. Second, small decreases in BP can result in a large reduction in CV risk. Third, many different drugs are effective in reducing CVD risk. Finally, two or more drugs are typically needed to reduce elevated BP to target ranges. These new insights were incorporated into the JNC 7 guidelines (figure 3).3 Overall, the initial drug choices in JNC 7 are simpler than they were in JNC VI. Table 1 lists the classification and management strategy for BP in adults in the JNC 7 guidelines. Individuals with a BP less than 120/80 mm Hg are classified as normal. For patients with prehypertension (SBP 120-139 mm Hg or DBP 80-89 mm Hg), the recommendation is lifestyle modification to reduce BP and prevent the development of hypertension. Drug treatment is recommended only if a compelling indication, such as diabetes or chronic kidney disease, is present in patients in the prehypertension category. Drug recommendations for the compelling indications were based on results from clinical trials (table 2), usually not trials in hypertension but in those with typical complications of hypertension (HF) or with conditions seen often in hypertensives (diabetes). The drugs used in these trials, however, are drugs that are also used to treat hypertension.
For patients with stage 1 hypertension (without a compelling indication), thiazide-type diuretics are the drugs of choice for most patients. For patients with stage 2 hypertension (without a compelling indication), the recommendation is to begin therapy with two drugs. For patients with compelling indications, the recommendation is to first treat the compelling indication, and if not at goal, add other drugs and consider consultation with a specialist.
Finally, the goals of antihypertensive therapy in JNC 7 compared with JNC VI remained the same except for a 5-mm Hg lowering of the DBP in the second group listed below:
• < 140/< 90 mm Hg for patients with uncomplicated hypertension • < 130/< 80 mm Hg for patients with diabetes, HF, or chronic renal failure, and the elimination of “< 125/< 75 mm Hg for those with proteinuria.” The African American Study of Kidney Disease did not confirm the benefit of the lower goal. These goals are not dependent on age, sex, or comorbidity.
In summary, the key messages of the JNC 7 guidelines are as follows: SBP/DBP. For individuals older than 50 years, elevated SBP is a more important CVD risk factor than is elevated DBP. CV risk. CVD risk doubles with each 20/10-mm Hg increment greater than 115/75 mm Hg. Individuals who are normotensive at age 55 or 65 have a more than
90% lifetime risk of developing hypertension.
Prehypertensive classification. Individuals with an SBP of 120 to 139 mm Hg or a DBP of 80 to 89 mm Hg are classified as prehypertensive. These individuals face an increased risk of future hypertension and should adopt health-promoting lifestyle modifications to prevent CVD.
Drug therapy recommendations. Thiazide-type diuretics should be used as initial drug therapy for most patients with uncomplicated hypertension, either alone or in combination with agents from other drug classes.
Compelling indications. Certain high-risk conditions, including MI, HF, diabetes, and chronic kidney disease are compelling indications for the use of other types of antihypertensive agents (ie, ACE inhibitors, ARBs, calcium antagonists, beta blockers).
Combination drug therapy. Most patients with hypertension will require two or more drugs to reach goal BP (< 140/90 mm Hg; < 130/80 mm Hg for patients with diabetes and/or renal disease). If BP is more than 20/10 mm Hg above goal, initiate drug therapy with agents from two classes, one drug choice usually being a thiazide-type diuretic.
Cardiology Review: What’s the rate of progression to hypertension in the group of individuals classified as prehypertensive?
Dr. Black: From the Framingham data, we’ve learned that the rate of progression without intervention is about a 10/5-mm Hg increase over about 14 years. This is the group we’re trying to turn around…trying to get people thinner, to consume less salt, and to be more active to try to slow the progression. I don’t think we can prevent it entirely.
The Trial for Preventing Hypertension study is an interesting ongoing study in prehypertensive subjects which is now almost finished. In this study, half the participants are being given the ARB candesartan and half are given placebo for 2 years. Then the patients on the ARB will be taken off of it for the last 2 years of the study to determine if we can change the natural history of hypertension.
Cardiology Review: How would you manage an elderly patient with a BP of 160/60 mm Hg?
Dr. Black: I’d be very careful, but I would still treat them. The initial DBP in the Systolic Hypertension in the Elderly Program was 77 mm Hg. It was reduced to 69 mm Hg on average, and strokes were reduced about 40%. So in totality, that group is going to benefit. If there was a group in which treatment could be particularly troublesome, it was those few with DBP less than 60 mm Hg.
Getting SBP down is difficult with our current medicines, and all we’ve been able to do, both in CONVINCE and ALLHAT, is get about 60% of patients to goal.
Cardiology Review: What do you think of the idea of taking a more aggressive approach in prehypertensive patients, namely, putting them on an inexpensive drug like hydrochlorothiazide, if there are no contraindications, to keep BP from getting to 140 mm Hg?
Dr. Black: It’s hard to get the risk-benefit in your favor in people with very low risk unless you use a drug that’s very safe. When it comes to antihypertensives, I think only two classes of drugs would, in fact, meet that criterion, and diuretics are not necessarily one of them. There are some problems with diuretics and certainly with ACE inhibitors. I think ARBs and calcium antagonists meet the criteria. ARBs are extremely well tolerated, and calcium antagonists have nuisance side effects. You don’t see potentially serious problems, such as angioedema, asthma, or gout from these agents, and that’s something that we need to think about if we’re going to take an approach to reduce BP in low-risk people.
Cardiology Review: Do you have any insights into how insurance companies are going to address the prehypertensive category?
Dr. Black: As many of us suspected, we found that the industry does not care what we label somebody. The insurance industry has their own actuaries, and they calculate risk the way they want, regardless of our label.
Cardiology Review: Is the meta-bolic syndrome addressed in the guidelines?
Dr. Black: It is. We discuss it but don’t recommend treating the prehypertensive subject with signs of the metabolic syndrome unless a compelling indication is present. I don’t think we have evidence yet that treating metabolic syndrome per se, if it hasn’t led to diabetes, is going to be beneficial.