Expanding the Scope of Hypertension: Are We Creating New Diseases?

The traditional sources of medical information have been the professional literature or meetings of medical societies. More recently, particularly when dealing with new or controversial ideas, the Internet has become a major provider of information both to health professionals and the lay public. In addition, the lay press prominently features diseases or conditions of interest, with hypertension—which is so common in our population—a frequent target.

So it should not have been surprising, on the last day of the 2006 Annual Meeting of the American Society of Hypertension, Inc. (ASH), to see an article featuring hypertension on the front page of the New York Times. ¹ What was unexpected, though, was the adversarial content of the article. Predominantly, it asserted that scientific and clinical leaders in hypertension, supposedly in concert with forces in the pharmaceutical industry, had created diagnostic recommendations that would dramatically increase the number of people with hypertension or at risk for developing this condition. This, according to selected sources interviewed for the article, would markedly increase the demand for drug products.

Senior representatives of ASH quoted in the article, as well as in a subsequent letter published in the same newspaper, ² strongly refuted this allegation, arguing instead that the goal of new diagnostic initiatives in hypertension is to encourage a strategy of lifestyle changes that would prevent or delay the progression of this widespread condition.

TWO RECENT DEVELOPMENTS AND AN ACCUSATION

The matters that provoked this contentious exchange quite clearly were: first, the recommendations in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) ³ that patients with blood pressure above the normal value of 120/80 mm Hg but below the present diagnostic criterion for hypertension of 140/90 mm Hg be labeled as prehypertensive; and second, the report of the Hypertension Writing Group (HWG) of ASH ⁴ indicating that people in the prehypertension blood pressure range who, in addition, exhibit other major risk factors or evidence of abnormal cardiovascular findings could be regarded as having an early stage (stage 1) of hypertension.

Were the JNC 7 report, which was actually sponsored by the National Institutes of Health (NIH) and not ASH, and the HWG report (entitled “Expanding the Definition”) guilty of what is now sometimes referred to in the press as “disease mongering?” This is by no means the first time this harsh concept has been raised. Indeed, one typical article ⁵ —again in the New York Times—had previously asked, quite independently of hypertension issues, whether contemporary guidelines for diagnosing diabetes, cholesterol abnormalities, and obesity have been motivated by the self‐interest of medical entities—practitioners and major clinical organizations as well as industry—to increase demand for their services and products. Is there any credibility to the claim that leaders in the field of hypertension might be accomplices in disease mongering?

WHAT IS PREHYPERTENSION?

On a population basis, there is a strong link between blood pressure and the risk of fatal and nonfatal cardiovascular and stroke events. ⁶ , ⁷ Starting at a systolic blood pressure of around 115 mm Hg, each increment of 20 mm Hg is associated with approximately a doubling of the probability of major end points. ⁶ Why, then, should we be willing to regard blood pressures above 120/80 mm Hg as acceptable?

JNC 7 and other guidelines committees, however, have recommended that the diagnostic criterion for hypertension, as well as its treatment goal, be 140/90 mm Hg, but for hypertension patients with diabetes or chronic kidney disease, they suggest a goal of 130/80 mm Hg. ³ These recommendations are based on interpretation of evidence garnered from hypertension clinical trials. There is a reasonable presumption that reducing blood pressure to 140/90 mm Hg confers benefits, but we still don't have conclusive information as to whether further reductions would provide additional protection.

Prehypertension represents the uncharted territory between 120/80 and 140/90 mm Hg. It is clear, though, that for almost all Americans there is a progressive increase in blood pressure throughout life, so that almost all people with prehypertension—should they live long enough—will eventually become hypertensive. JNC 7 has argued: Why not encourage people with prehypertension to adopt lifestyle changes that could delay or prevent the inevitable? Since JNC 7 was published, some reports have provided further information on the characteristics of prehypertension, helping us to consider whether it is a clinically valid entity.

SOME RECENTLY DESCRIBED FEATURES OF PREHYPERTENSION

One study that followed a large cohort of subjects in Taiwan confirmed that hypertension status does not remain constant. Over a period of time, individuals classified as prehypertensive can either revert to normal blood pressures or more commonly—particularly at older ages—progress to established hypertension. According to this study, the main predictors of progression from prehypertension to established hypertension were a family history of hypertension, increased waist circumference (suggestive of the metabolic syndrome), and male sex. ⁸ The rate of progression from prehypertension to stage 1 hypertension, in fact, can be rapid. In the Trial of Preventing Hypertension (TROPHY) ⁹ (which is discussed more fully below), more than 60% of prehypertensive patients not receiving active drug therapy progressed to hypertension during a 4‐year period of observation.

Perhaps the most important group of people with prehypertension are the young because they potentially represent the best opportunity to favorably alter the natural history of hypertension. The Bogalusa Heart Study, ¹⁰ which has focused on children, adolescents, and young adults, recently reported clinical comparisons among young people classified as normotensive, prehypertensive, or hypertensive. Young adults with prehypertension, like those with established hypertension, were far more likely than subjects with normal blood pressure to be obese and have evidence of insulin resistance and abnormal lipid profiles.

This finding has two important implications. The first is that identifying young people with metabolic changes can serve to predict those at risk for prehypertension and hypertension, and the second is that the close association of metabolic changes with prehypertension indicates that this condition may be far from benign and is deserving of focused lifestyle interventions. Several years ago we observed in a cohort of apparently normotensive individuals (those with normal blood pressures or prehypertension) that the presence of a family history of hypertension, independent of body weight, was predictive of adverse metabolic findings as well as early evidence of changes in arterial and cardiac function. ¹¹

A study of Israeli adolescents (aged 16–19 years) demonstrated that by JNC 7 criteria, almost 57% of boys and 36% of girls from a cross‐sectional population‐based analysis had prehypertension. ¹² Somewhat alarmingly, while the presence of obesity or overweight were strong predictors of this condition, the mean body mass index for the cohort as a whole was <22 kg/m². In fact, only 11% were overweight and 3.2% were obese. The authors of this report emphasized, appropriately, that lifestyle changes would be a critical strategy for young people with excess weight, yet at the same time it would appear that other factors must also contribute to the development of prehypertension. We have previously drawn attention to the fact that lean hypertensive people, like the obese, are at high cardiovascular risk. ¹³

THE NEW DEFINITION OF HYPERTENSION

In its simplest sense, the new definition of hypertension provided by the ASH HWG recognizes that findings other than blood pressure, including additional risk factors or evidence of abnormal cardiovascular findings, should influence how we classify affected individuals. ⁴ Of note, stage 1 hypertension under this new definition includes patients with blood pressure below 140/90 mm Hg (the JNC 7 criterion) provided that there is evidence of other cardiovascular risk or disease factors. Largely, stage 1 hypertension by this definition is very similar to what recent reports have described as being typical for prehypertensive patients, and clearly there is an overlap with the metabolic syndrome and its link to increased events.

The chief goal of the new definition and classification of hypertension is to stimulate further research, either by longitudinal observations or by therapeutic interventions. The goal is to eventually provide guidance for managing the large number of people who fit this profile. ¹⁴ Claims in the New York Times report ¹ that the new definition is a device for increasing drug use are totally unfounded. No such recommendations have yet been made and, until more research is done, they cannot be made.

A FIRST LOOK AT EARLY INTERVENTION

Well before the term prehypertension was created, some clinicians were expressing editorial concern about patients described as having “very mild hypertension.” ¹⁴ Based on published clinical observations in such patients, as well as data from animal models, we argued that increased activity of the renin—angiotensin system or the sympathetic system could possibly explain the genesis of hypertension in susceptible patients. Subsequently, TROPHY was undertaken. ⁹

Since this work has been published and critiqued elsewhere, let it simply be said that this was a blinded study in prehypertensive patients randomized to 2 years of treatment with either an angiotensin receptor blocker or placebo. Then, for a further 2 years, all patients received placebo. The primary end point of the study was the appearance of clinical hypertension. By the end of the initial 2‐year period, the incidence of new hypertension was reduced by 66% in the actively treated group and, by the end of the following 2 years, by 16%.

Since these findings were significant, attention has started to focus on the possibility of early therapeutic intervention in prehypertension. The active treatment in TROPHY was well tolerated and, compared with placebo, did not impair quality of life, adding to the argument that therapeutic strategies should be studied further. A key characteristic of the prehypertensive patients recruited for TROPHY was that their mean age at study baseline was almost 50 years. In considering opportunities to delay or prevent progression of prehypertension, the findings discussed earlier would suggest that a younger cohort might be more appropriate for future studies of hypertension prevention.

WHAT COMES NEXT? TWO RESEARCH MANDATES

The growing literature on prehypertension has drawn attention to the fact that there are many such individuals—tens of millions in the United States—who fit this definition. A sizable fraction of this large group have concomitant risk factors that, in all probability, will amplify the adverse effects of their blood pressure elevations on cardiovascular outcomes. No one denies that the thoughtful use of lifestyle modifications should be the initial response to such individuals.

At least two directions of research are called for. One must be TROPHY‐like, examining further whether it is possible to prevent new‐onset hypertension by active early intervention. This strategy to change the natural history of hypertension would best be tested in young adults and might require an intervention even more prolonged than in the recent study. ⁹

The second research direction should be aimed at middle‐aged or older people with prehypertension who also have concomitant clinical evidence of increased cardiovascular risk. These patients, who would actually be classified as having stage 1 hypertension by the HWG, should be studied in randomized clinical trials (if possible, placebo‐controlled) comparing the effects of differing therapeutic strategies on major end points.

Until results are known, there cannot be broad recommendations for prehypertension strategies other than lifestyle changes. But surely credit must be given to the NIH for recognizing the concept of prehypertension and to the HWG of ASH for proposing the new definition, particularly if they are responsible for stimulating important new directions of research. Is this disease mongering? I don't think so. Potentially, the term lifesaving would be more apt.

Disclosure: Dr. Weber was an author of the Trial of Preventing Hypertension (TROPHY) and the Report of the American Society of Hypertension, Inc. Hypertension Working Group.