Antihypertensive Therapy for Prehypertension: Title and subTitle BreakRelationship With Cardiovascular Outcomes

The definition of hypertension has evolved throughout the years. In the past, hypertension was associated with the aging process, and blood pressure levels equal to or higher than 160/100 mm Hg were considered abnormal.¹ Twelve years ago, Frohlich reported that blood pressures higher than 140/90 mm Hg are associated with increased risk of cardiovascular disease (CVD), stroke, and premature death.² In 2003, the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure proposed the term “prehypertension” to designate a systolic blood pressure of 120 to 139 mm Hg and a diastolic blood pressure of 80 to 89 mm Hg.³

This classification was based on data from epidemiologic studies that demonstrated a linear relationship between blood pressure and cardiovascular risk. For each 20–mm Hg increase in systolic blood pressure, 10–mm Hg increase in diastolic blood pressure greater than 115/75 mm Hg, or both, there was a 2-fold increase in mortality associated with stroke and coronary artery disease.⁴ Moreover, individuals with blood pressure levels of 129 to 139 mm Hg systolic and 80 to 89 mm Hg diastolic are at increased risk of developing hypertension and CVD later in life compared with those with levels less than 120/80 mm Hg.^{5 - 6} The identification of patients with prehypertension will allow early intervention such as lifestyle modifications to reduce blood pressure, prevent progression to hypertension, and decrease risk of cardiovascular morbidity and mortality.³

Data from NHANES (National Health and Nutrition Examination Survey) 2005-2006 and other studies have demonstrated that the prevalence of prehypertension varies between 25% to 37% of the US population.^{7 - 8} Approximately 90% of individuals with prehypertension had at least 1 other cardiovascular risk factor above optimal levels, and 68% had at least 1 significant clinical risk factor for heart disease or stroke.⁹ Other studies demonstrated that compared with normotensive individuals, 51% of men and 36% of women with prehypertension had higher levels of blood glucose, total cholesterol, low-density lipoprotein cholesterol, and triglycerides; higher body mass indices; and lower levels of high-density lipoprotein cholesterol.¹⁰

The treatment of hypertension has evolved in the last century.¹ In the early 1900s, there was controversy as to whether lowering blood pressure was beneficial. In 1937, White¹¹ wrote that “the treatment of the hypertension itself is a difficult and almost hopeless task in the present state of our knowledge, and in fact for aught we know, in advanced cases with permanently narrowed coronary and cerebral arteries the hypertension may be an important compensatory mechanism which should not be tampered with.”

Today, multiple clinical trials have demonstrated that among patients with blood pressure levels above 140/90 mm Hg, lowering levels with pharmacological intervention and lifestyle modifications is associated with reductions in cardiovascular morbidity and mortality.² However, pharmacological intervention in persons with prehypertension have yielded disparate results. Some studies have shown benefits, whereas others have not.¹²

In this issue of JAMA, Thompson and colleagues¹³ examine whether treatment with antihypertensive therapy compared to placebo would be associated with decreased cardiovascular morbidity and mortality in patients with blood pressures less than 140/90 mm Hg. The authors performed a meta-analysis of randomized clinical trials that included a variety of patients with a history of CVD or diabetes mellitus but without defined hypertension who received treatment with different antihypertensive agents. The authors demonstrated that in 63 259 participants who received either an angiotensin-converting enzyme inhibitor, an angiotensin receptor blocker, β-blockers, an angiotensin-converting enzyme inhibitor combined with a diuretic, or calcium channel blockers, there was a significant reduction in risk of stroke, congestive heart failure, CVD events, and all-cause mortality compared with those not receiving antihypertensive therapy. However, there was not a statistically significant decrease in the risk of myocardial infarction or CVD mortality with pharmacological intervention, although the point estimates were in the same general direction as those for other cardiovascular outcomes. Patients who had diabetes mellitus without hypertension did not benefit from therapy for the prevention of composite CVD outcomes and all-cause mortality; however, this was a small subset of the total number of trials and therefore the heterogeneity in clinical outcomes could in part be attributable to chance.

The study by Thompson et al adds to understanding of the benefits of treatment with agents designed to lower blood pressure among patients with CVD. The clinical importance of this study is clear: pharmacological intervention in patients with CVD and blood pressure levels less than 140/90 mm Hg is associated with a decreased risk of cardiovascular morbidity and mortality. However, this study does not determine whether lowering blood pressure levels is the reason for improved clinical outcomes. These agents may improve clinical outcomes through multiple other mechanisms, eg, hemodynamic effects unrelated to blood pressure, neurohormonal effects, and tissue-level effects.

The implications of this study for patients without CVD are less clear. Patients with prehypertension who do not have CVD are at increased risk of developing hypertension with associated increases in cardiovascular morbidity and mortality, but the benefits compared with the risks and costs of pharmacological treatments in this group have not been fully assessed. Only 2 studies in the analysis by Thompson et al involving patients with blood pressure levels lower than 140/90 mm Hg and no cardiovascular risk factors demonstrated only a possible benefit, thus leaving unanswered the question of whether to treat patients with prehypertension but without other CVD. Previous studies have demonstrated that the risk of cardiovascular morbidity and mortality increases in a linear fashion with blood pressure levels and that the cardiovascular risk can be lowered proportionate to the amount of blood pressure for all patients with levels above 140/90 mm Hg in a large number of trials.³ Some clinical trials have shown that treatment with antihypertensive agents reduces the rate of progression from prehypertension to hypertension,¹⁴ but the effect on improving cardiovascular outcomes has not been well delineated.

In summary, the meta-analysis by Thompson et al demonstrates that treatment of blood pressures lower than 140/90 mm Hg is associated with benefits for patients with CVD, but more clinical trial data are needed for those without CVD. Because many patients could potentially begin taking medications at young ages and for many years to prevent cardiovascular events, even modest costs and adverse effects need to be considered. Lifestyle modifications that have been shown to reduce blood pressure and decrease cardiovascular morbidity and mortality should be recommended for all patients with blood pressure levels less than 140/90 mm Hg.³ However, to reach firmer conclusions will require more data from randomized trials involving patients with levels less than 140/90 mm Hg to evaluate the effects of various pharmacological therapies on preventing CVD outcomes.