The JNC 7 Report: Challenges and Dilemmas in Writing Guidelines

The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) reports have been published at regular intervals for more than 30 years. They have contributed to the National High Blood Pressure Education Program's success in achieving blood pressure control in 34% of Americans with hypertension. ¹ Clearly there is a long way to go, but this result is better than anywhere else in the world.

At first glance the new guidelines may seem only modestly different from their predecessors, but in reality, the seventh JNC report (JNC 7) ¹ departs quite sharply in some key recommendations. The story of JNC 7 though, is not only in the recommendations themselves, but also in the process by which they were achieved. It is the nature of collective statements that they can almost never completely satisfy the persons who write them or read them.

WHY HAVE NEW GUIDELINES?

The main reason for updating or changing a set of guidelines is the appearance of important new data. In this case, a number of major clinical trials in hypertension had been completed within recent years. These formed a basis for reviewing the existing recommendations on the evaluation and management of patients with hypertension. Perhaps the most visible of the new studies was the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), ² but a number of other key trials with major clinical end points, including the second Australian National Blood Pressure Study (ANBP2), ³ the Losartan Intervention For Endpoint Reduction (LIFE) study, ⁴ and others (discussed later) all had major influence. Besides, the existing set of guidelines, JNC VI, ⁵ was published 6 years ago and perhaps was starting to appear dated.

THE GENESIS OF THE GUIDELINES

The JNC (or at least its Executive Committee) is made up of experts in the field of hypertension selected by the sponsor of the guidelines, the National Heart, Lung and Blood Institute (NHLBI). This, of course, is the same government agency that sponsored the ALLHAT study, which itself has become the center of considerable controversy. ⁶ , ⁷ , ⁸ , ⁹ In the conclusion to the ALLHAT study's report—which in the view of many observers could not be validly supported by the results and data of the trial—the ALLHAT officers proclaimed clinical and cost advantages for thiazide‐like diuretics, stating: “They should be preferred for first‐step antihypertensive therapy.” ²

So the members of JNC 7—who should have been independent and able to base their treatment recommendations on objective evaluations of evidence and on their own experience and judgment—faced what appeared to be a fait accompli. But before debating issues of drug selection, we should first consider some of the other major features of a report produced by a group of experts who, at least in some areas, moved boldly from the recommendations of their predecessors.

CLASSIFICATION: A NEW DISEASE IS CREATED

Perhaps the biggest headline of JNC 7—certainly as far as the lay press was concerned—was the creation of a condition called “prehypertension.” This term describes people who have a blood pressure in the range 120/80 mm Hg‐140/90 mm Hg, at which point true hypertension begins. Several million Americans have this newly minted diagnosis of prehypertension. Strictly speaking, JNC 7 is perfectly correct. After all, data from the Framingham cohort have indicated that, if we live long enough, just about all of us will eventually become hypertensive. ¹⁰

But what can physicians, let alone the lay community, do about prehypertension? The JNC recommends such time‐honored strategies as losing weight, reducing dietary sodium, increasing consumption of fresh fruit and vegetables, cutting down alcohol use, and exercising. Good advice, indeed, but what do we recommend to lean patients with prehypertension who are already following a prudent lifestyle? In fact, there is currently no evidence to indicate that lifestyle interventions will improve survival or prevent major cardiovascular events in persons with prehypertension, though these steps might help slow progression to established hypertension.

Also somewhat troubling, many may now be given a label that could not only cause anxiety and other emotional consequences, but have social and economic implications as well. Certainly, some physicians will yearn for the simpler classification of JNC VI, ⁵ in which those in the range now called prehypertension were given less anxiety‐provoking warnings through designations like “normal” and “high normal.” Yet, in raising these semantic questions we should not overlook the Committee's legitimate and well‐intentioned concern: Many patients in this range will eventually be exposed to serious levels of cardiovascular risk unless effective preventive strategies can be devised.

WHATEVER HAPPENED TO RISK STRATIFICATION?

Hypertension is one of several cardiovascular risk factors, including lipid disorders, diabetes or glucose intolerance, left ventricular hypertrophy, microalbuminuria, smoking, and personal or family history of cardiovascular events. It is also known that risk factors tend to cluster together, and that the presence of multiple risk factors amplifies the probability of a major event. For this reason, JNC VI ⁵ created a risk stratification table in which the urgency and the aggressiveness of antihypertensive therapy was a function of both the severity of the hypertension and the number of other risk factors or findings of target organ damage.

Why has JNC 7 abandoned this apparently logical approach? Largely, they have wanted to send the message that hypertensive blood pressure levels are unacceptable under any circumstance and that assertive treatment is required even in the absence of other risk factors. For patients who have concomitant conditions, but whose blood pressures are not sufficiently high to justify antihypertensive therapy, these conditions or risk factors should be treated as appropriate. Quite often (see JNC 7's list of compelling indications), this treatment will in any case require drugs that happen to have antihypertensive properties.

From these perspectives, it was perfectly reasonable for the Committee to put the previous risk stratification approach in abeyance. If JNC 7 overreached in some of its other recommendations, it certainly was pragmatic in this one. It might be assumed that in the more complete version of JNC 7 yet to come some efforts will be made to use risk estimates in determining specific therapies.

NO CHANGE IN THE TARGETS

Two de facto risk groups remain: patients with diabetes or renal insufficiency, and the rest. For the latter group, target blood pressure, as in JNC VI, ⁵ is below 140/90 mm Hg.

Setting therapeutic blood pressure goals for patients with diabetes and for those with renal insufficiency who are unquestionably at an exaggerated risk of cardiovascular events was a challenging judgment. Some studies have suggested that blood pressure targets more stringent than 140/90 mm Hg provide additional protection for these patients, but clinical trials aimed at confirming and defining this benefit have not yet concluded. On balance, though, the Committee saw this as a situation where, in the absence of firm data, a more aggressive strategy rather than a conservative one may actually be the more prudent approach. Right now, it would be hard to disagree with the recommendations of the JNC 7 authors that a target below 130/80 mm Hg is appropriate for these high‐risk patients.

GETTING STARTED: COMBINATION THERAPY COMES OF AGE

JNC 7 asserts that it is important to get off to a good start in treating hypertension. Reducing blood pressure quickly can raise patients' confidence in their treatment and have the added benefit of reducing doctor visits and other costs and inconveniences. The Committee supports a 20/10 mm Hg rule: If blood pressure exceeds the targets of 140/90 mm Hg or 130/80 mm Hg by at least 20/10 mm Hg (in other words, 160/100 mm Hg or 150/90 mm Hg), then treatment can be initiated with combination therapy (either a fixed combination or two drugs prescribed separately).

The idea of starting with two‐drug treatment has been considered previously ⁵ but the decision of JNC 7 to endorse the recently published suggestion of linking this strategy to the Stage 2 blood pressure threshold of 160/100 mm Hg ¹¹ adds helpful further authority. Many experienced clinicians already follow this strategy and so will be pleased with the recommendation. Not surprisingly, the Committee suggests that a diuretic usually be part of the combination. Good advice, because combining diuretics with agents such as angiotensin‐converting enzyme (ACE) inhibitors, angiotensin receptor blockers, and β blockers certainly adds to antihypertensive efficacy. But, adding calcium channel blockers to these other drugs is just as efficacious; and like the diuretics, they provide useful clinical outcomes benefits.

There are some minor objections to starting with a combination. For example, if side effects occur it may not be clear which drug is responsible and how best to adjust the treatment; and another concern is that those patients with Stage 2 hypertension whose blood pressure could be controlled with a single agent, albeit a low probability, will not get the opportunity to receive that more simple therapy. Still, this recommendation by JNC 7 will be very popular and reinforce the message that control of blood pressure is the most important initial priority in managing hypertension.

WHERE ANGELS FEAR TO TREAD: RECOMMENDING THE FIRST DRUG

From the beginning, Committee members faced a situation in which they had limited room to maneuver. To emphasize its own relevance as a Federal agency capable of influencing health policy and economics, the NHLBI had already used its interpretation of ALLFLAT to widely publicize the supposed superiority and cost benefits of diuretics to the public and to Congress. ALLFLAT demonstrated that there was no difference in the primary end point of coronary events with diuretics, a calcium channel blocker, or an ACE inhibitor, but claimed that there were fewer events with the diuretic in some subsets of patients.

Even those members of the JNC 7 Committee who had not themselves been ALLHAT authors, and who were aware of serious flaws in the study, were not empowered to substantially alter the NHLBFs position. To be fair, though, voices on the Committee worked energetically to modify the recommendation for universal use of diuretics as first‐line hypertension therapy. It is worth examining the ways in which this effort was pursued.

Read the Fine Print: An Overarching Caveat

It is reasonable to assume that in considering drug selection, those members of JNC 7 with clinical and scientific backgrounds must have quickly recognized an obvious point: To recommend a single drug class for across‐the‐board, first‐line use would be to promote the absurdity that all hypertension, in all patients, is the same.

From pivotal work of their own and of others, they knew that diverse factors like age, ethnicity, gender, and body weight not only affect blood pressure responses to differing drugs, ¹² but also major clinical outcomes. ² , ³ , ⁴ , ¹³ Indeed, this understanding becomes clearly apparent in JNC 7's treatment algorithm for patients without compelling indications. So, along with suggesting a thiazide‐type diuretic for starting treatment in Stage 1 hypertension, the Committee goes on to add this remarkable sentence: “May consider ACE inhibitor, ARB [angiotensin receptor blocker], beta‐blocker, CCB [calcium channel blocker] or combination.” ¹ In effect, they have opened the door for practitioners to initiate therapy with whichever type of drug they believe most suitable for each patient.

Despite the JNC 7 Committee's loyal claim that “diuretics have been virtually unsurpassed in preventing the cardiovascular complications of hypertension,” they had clearly realized that there is also an impressive array of highly credible clinical outcomes evidence to support the broad use of other major drug classes as baseline therapy. ² , ³ , ⁴ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸

Compelling Indications: Guided by Evidence

Common heart and kidney conditions, as well as major risk factors like diabetes mellitus, are often associated with hypertension. When these conditions are known to benefit from specific therapies, such as ACE inhibitors or angiotensin receptor blockers in diabetes or heart failure, or β blockers following myocardial infarction, they are known as compelling indications.

However, in ALLHAT, ² patients were randomized to treatment with a diuretic, a calcium channel blocker, or an ACE inhibitor without regard for these special situations. For this reason, the claimed success of the diuretic in ALLHAT seemed to suggest that the concept of compelling indications was not so compelling after all. In other words, ALLHAT aficionados could have argued: Why not start all hypertensives on a diuretic and consider condition‐appropriate drugs as second‐line therapy?

To its credit, the Committee rejected such an approach and instead created a detailed listing of clinical trials to identify relevant must‐use drugs across a broad range of key conditions that frequently coexist with hypertension. For the relatively large number of patients who have compelling indications, it was possible for the members of JNC 7 to side‐step the NHLBF's diuretics‐first dictum (though, of course, in many cases the addition of a low‐dose diuretic will eventually be considered to help optimize blood pressure control).

THE HIGH COST OF SAVING MONEY

The money to be saved by prescribing generic diuretics as first‐line therapy may turn out to be illusory. Diuretics, particularly when used in the relatively full therapeutic doses that were tested in ALLHAT—corresponding by some estimates to hydrochlorothiazide doses of up to 50 mg daily—often cause metabolic changes. Potassium, glucose, and uric acid are all affected, and this means that patients on such therapy incur the costs of being monitored regularly with blood tests.

Then, when abnormalities are detected, the result is additional expense of further doctor visits and the prescription of appropriate remedies to compensate for these changes. If diabetes mellitus is produced—remember that in ALLHAT the patients receiving a diuretic were 43% more likely than those on an ACE inhibitor to incur new‐onset diabetes ² diagnosed as a fasting glucose >126 mg/dL (11.6% compared to 8.1% with an ACE inhibitor, an important absolute difference of 3.5%)—the cost of monitoring for diabetes must also be factored in. When these items are considered, bearing in mind that the highly competitive nature of the hypertension drug marketplace has tended to keep costs fairly well contained, clinical need rather than acquisition cost should be the preferred basis for drug selection.

WHEN THE FIRST DRUG DOESN'T WORK

Sometimes the first drug tried with a patient does not work. Previous guidelines suggested that if there was a partial response, it would be appropriate to either increase the dose or add a second drug. If there was virtually no response at all, it was recommended that the drug be discontinued and an agent from a completely different class be tried. This understanding that different mechanisms operate to sustain hypertension in different patients is very much part of the physiologic approach conceived by Laragh ¹⁹ about 30 years ago.

In a departure from previous guidelines, JNC 7 appears to have discarded this important knowledge about hypertension and even in patients with Stage 1 hypertension focuses on rapid progression to combination therapy before fully exploring single agents. Although not a major issue for patients with Stage 2 hypertension, in whom even the best‐chosen drug will usually require a complementary agent, the addition rather than substitution approach to poor responses in patients with less severe hypertension could result in unnecessary and excessive use of noncontributory drugs. Hopefully, practicing clinicians will continue to search for the simplest ways to control blood pressure in their patients.

For resistant hypertension, JNC 7 provides a most‐helpful troubleshooting list to guide clinicians, and when a patient has truly difficult‐to‐manage hypertension, they offer the excellent suggestion to get help from one of the growing number of hypertension specialists accredited by The American Society of Hypertension Specialists Program.

COMMENT

There is plenty about JNC 7 to engender lively discussion, including creation of the prehypertension category, the simpler approach to risk stratification, starting with combination therapy in patients who are 20/10 mm Hg above their goal blood pressure, rapid addition of a second drug rather than substitution when the first drug doesn't work, and how the Committee dealt with the predetermined issue of the diuretic as the default drug to start therapy.

Even so, when considering treatment recommendations we should not overstate the controversy. Let it be said that diuretics are very useful in many patients with hypertension as first‐line treatment as well as contributing effectively to combinations. Unquestionably, diuretics have a critical role to play in the management of hypertension, but exactly the same can be said for the other major antihypertensive drug classes. Guidelines that prescriptively favor one class over others clearly ignore the diverse nature of hypertension. Instead, it is far more important to provide advice on how to best use all the available tools for achieving optimal results in each patient. In the final analysis this is the major message of JNC 7, and it is a good one.

Disclosure:

The author provides speaking or consulting services for Boehringer‐Ingelheim, Bristol‐Myers Squibb, Merck, Novartis, Sanofi‐Synthelabo, and Sankyo.