Prehypertension: To Treat or Not To Treat?

Q: Should patients with prehypertension be treated with antihypertensive drugs?

A: The term "prehypertension" was introduced in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines to describe blood pressures (BPs) of 120/80 mm Hg to 139/89 mm Hg.¹ The authors of the report used this term to alert patients and caregivers to the fact that BPs within this range are associated with increasing cardiovascular risk.

Although there have so far been no clinical outcome trials that demonstrate the benefits of drug treatment in patients with prehypertension, we know that cardiovascular risk increases linearly at levels below those that trigger the use of antihypertensive therapy. This is particularly evident in patients at the higher end of the prehypertension spectrum--persons previously defined as having "high-normal" BP.

The JNC 7 guidelines recommend that prehypertension be managed with aggressive lifestyle modification in an effort to prevent progression to hypertension. However, despite efforts to promote healthy lifestyles, the prevalence of prehypertension in the United States is increasing. Current estimates suggest that as many as 70 million Americans have this condition.

Preliminary evidence for pharmacotherapy. Recently, the Trial of Preventing Hypertension (TROPHY) demonstrated that treatment of prehypertension with candesartan, an angiotensin receptor blocker, reduced the risk of progression to hypertension in some patients.² In this study, 772 participants with high-normal prehypertension were randomized to candesartan, 16 mg/d, or placebo for 2 years. At the end of this period, the candesartan was discontinued and all participants were given placebo for 2 additional years. Throughout the trial, participants were encouraged to undertake lifestyle changes to lower their BP.

At the end of the first 2 years, 40.4% of those in the placebo group had progressed to hypertension, compared with only 13.6% in the candesartan group. However, the efficacy gap closed after 4 years, when 63% of those in the placebo group had progressed to hypertension compared with 53.2% of those in the candesartan group. Although this was only a feasibility study (not a clinical outcome trial), it showed that treatment of prehypertension with candesartan was well tolerated and reduced the risk of incident hypertension during the trial period. Further studies are needed to determine whether strategies that involve early pharmacologic treatment of patients with prehypertension might affect clinical outcomes.

The risks of prehypertension. In addition to its association with increased cardiovascular risk,^3,4 prehypertension often coexists with other cardiovascular risk factors, such as diabetes, chronic renal disease, and the metabolic syndrome. In the TROPHY trial, a significant number of patients met the criteria for the metabolic syndrome and therefore must be considered at increased cardiovascular risk--despite BPs in the prehypertension range.

A recent study of healthy persons with prehypertension or normotension and normal body mass index sought to discover whether levels of adiponectin and resistin, secretory products of adipose tissue, might affect cardiovascular risk.⁵ Adiponectin stimulates fatty acid oxidation and improves glucose metabolism by increasing insulin sensitivity. It also inhibits inflammation and possibly atherogenesis by suppressing the migration of monocytes and macrophages and their transformation into foam cells. Resistin has been implicated in the development of insulin resistance and possibly atherogenesis. The study demonstrated that in the absence of major cardiovascular risk factors, persons with prehypertension have significantly higher resistin plasma levels and lower adiponectin plasma levels than normotensive persons.

The bottom line. Except for patients with diabetes or chronic renal disease, JNC 7 did not propose risk stratification based on other risk factors or target organ damage in prehypertensive patients. It also did not suggest that pharmacologic therapy be considered, because no clinical trial data to support such therapy were available at the time JNC 7 was published. However, for patients with diabetes and chronic renal disease, the JNC 7 guidelines recommend a goal BP below 130/80 mm Hg, regardless of whether these patients have sustained hypertension or a BP at the high end of the prehypertension range.

To add fuel to this discussion, the American Society of Hypertension recently expanded the definition of hypertension, which it describes as a progressive cardiovascular syndrome arising from complex and interrelated causes.⁶ It has become increasingly evident that hypertension rarely occurs in isolation but rather is most commonly observed in association with other risk factors, such as diabetes, chronic kidney disease, dyslipidemia, exogenous obesity, and insulin resistance. The clustering of risk factors in the individual patient determines his or her cardiovascular risk.

Early markers of this cardiovascular syndrome are often present before BP elevation is observed; thus, hypertension cannot be classified solely by discrete BP thresholds. Progressive increases in BP are obviously associated with progressive vascular abnormalities and target organ involvement, which contribute to premature morbidity and mortality. Using the expanded definition of hypertension, it seems appropriate to consider treatment of prehypertension in patients with other risk factors, such as abdominal obesity, hyperglycemia, and dyslipidemia.

Although the number of Americans with prehypertension is increasing, it is evident that we cannot and should not attempt to reduce BP in tens of millions of persons. Prospective clinical outcomes trials in prehypertensive patients will determine future treatment recommendations. In the meantime, we must use a more global approach to evaluation and reduction of major cardiovascular risk factors. We must be more aggressive in treating patients with sustained hypertension by either adding or uptitrating antihypertensive agents to achieve recommended goals. Although lifestyle measures for BP control in prehypertensive and hypertensive patients have had little demonstrable affect on public health, adherence to such measures provides modest reductions in BP, including enhanced benefit when they are used in conjunction with pharmacologic therapy.