Blood Pressure Goals for Hypertension Guidelines: What Is Wrong With “Optimal”?

Everything should be made as simple as possible, but not simpler.—Albert Einstein

National guidelines for medical practice are proliferating at an impressive rate, and all guidelines have goals. A goal is the purpose toward which an endeavor is directed. Thus, all guidelines share one common goal: to improve the care of patients. In general, guidelines are not absolutely prescriptive in nature, but are intended to assist the practitioner in devising a therapeutic strategy to recommend to an individual patient.

When guidelines are concerned with the management of hypertension, dyslipidemia, or diabetes mellitus, goals are often defined in terms of physiologic parameters (ie, level of blood pressure [BP]) or concentration of blood lipids or fasting or postprandial blood glucose. A goal may then signify the level to which an abnormal physiologic parameter may be corrected to confer benefit as demonstrated by evidence including randomized clinical trials, expert opinion, and basic science.

DEFINING HYPERTENSION BY BP GOALS: HOW WE GOT THERE

Since 1977, when the first report of the Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure (JNC I) was published under the auspices of the National Blood Pressure Education Program of the National Heart, Lung, and Blood Institute, the JNC has provided clinicians with updated clinical guidelines for the diagnosis and treatment of hypertension. ¹ , ² , ³ , ⁴ , ⁵ , ⁶ , ⁷ Unfortunately, the reports do not distinguish between the disease—hypertension—and the measurable, quantified values of the systemic arterial BP. Thus, hypertension and high blood pressure became interchangeable terms in the minds of many. It is not surprising that the history of the management of hypertension is reflected in the classifications of BP levels described by the JNC over the years. ¹ , ² , ³ , ⁴ , ⁵ , ⁶ , ⁷ These classifications became the conceptual basis of the goals for treatment.

In 1977, the first JNC defined hypertension as a diastolic BP (DBP) of 105 mm Hg—but for systolic BP (SBP), it had no recommendations! Although SBP was elevated in the initial clinical trials, data on treatment outcomes were available only for DBP. It was suggested that treatment to lower BP might be considered when DBP was between 90 mm Hg and 105 mm Hg. It seemed to logically follow, then, that the goal of treatment was a DBP of 90 mm Hg.

The salient advances of JNC II were its stratification of patients according to DBP and its recommendation to treat even mild (an unfortunate term) hypertension. The JNC II classification stratum I (mild hypertension) was defined as a DBP between 90 mm Hg and 104 mm Hg; stratum II (moderate hypertension) was DBP between 105 mm Hg and 114 mm Hg; and stratum III was DBP >115 mm Hg. In JNC III, the classifications (and thus, the very definition) of hypertension were broadened downward to include the category of high‐normal BP, defined as DBP between 85 mm Hg and 89 mm Hg. In addition, JNC III recognized the importance of isolated systolic hypertension (SBP ≥160 mm Hg where DBP is <90 mm Hg). The report also created the category of borderline isolated systolic hypertension (SBP between 140 mm Hg and 159 mm Hg where DBP is <90 mm Hg). The major advance in the JNC V report was a staging system of hypertension that replaced the categories of mild, moderate, and severe. ⁵

The JNC VI report made 2 landmark revisions when it was published in 1997. ⁶ First, it changed the committee name to the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, placing unprecedented emphasis on prevention. Second, it set different BP goals for specific populations. For example, the goal BP for patients with diabetes was lower than for nondiabetic patients (130/85 mm Hg vs <140/90 mm Hg), and in patients with macroproteinuria (proteinuria >1 g/d), the goal was even lower: 125/75 mm Hg.

In the most recent report, JNC 7, the levels of BP are defined as: normal (<120/80 mm Hg), prehypertension (120–139/80–89 mm Hg), stage I (140–160/90–110 mm Hg), and stage II (>160/110 mm Hg). ¹ Prehypertension was a term coined by the National High Blood Pressure Education Program to deal with the recognition that risk for cardiovascular disease extends to levels of BP well below those considered hypertensive. Individuals with prehypertension constitute a large population, recently estimated to be as high as 40% among men and 23% among women in the United States. ⁸ Although cardiovascular risk is greater for individuals with the JNC 7 definition of hypertension (>140/90 mm Hg) than for those with prehypertension, the absolute number of cardiovascular events occurring in individuals with prehypertension is actually quite large. ⁸ The evolution of JNC recommendations has recently been reviewed. ⁹

NO DEFINED THRESHOLD BP MEANS THAT THE GOAL IS OPTIMAL BP

It is now understood that there is no threshold value for BP that defines the disease of hypertension. ¹⁰ BP is a physical force necessary for accomplishing circulation. Based on normal physiology, the circulatory system is designed to operate at an optimal BP. Although the JNC VI defined an optimal BP as <120/80 mm Hg, this definition was based largely on epidemiologic data indicating increased cardiovascular risk associated with higher Bps. The term optimal, however, means most favorable or desirable. Unfortunately, the term optimal BP was discarded in the JNC 7 in favor of normal BP, with pressures from 120/80 mm Hg to 139/89 mm Hg designated as prehypertension. Normal can mean functioning or occurring in a natural way, free from observable abnormalities or deficiencies; however the first definition of normal is “conforming with, or adhering to, or constituting a norm, standard, pattern, level or type.” From a population point of view, BP may be more correctly described as normal, but since treatment by clinicians involves individuals rather than populations, the concept of an optimal BP is highly relevant. Implicit in this statement is the notion that hypertension is a vascular disorder that produces a chronic increase in BP above that which is optimal for an individual. ¹⁰ Hypertension and increased BP are related, but they are not interchangeable terms. BP is a continuously variable vital sign, and hypertension is a pathologic state of the vasculature.

WHAT IS AN OPTIMAL BP?

Although often viewed simplistically, BP represents a complex interaction of many facets of the circulation. Thus, the measurement of BP provides important information regarding the state of health of the circulation and is truly an important test of cardiovascular health. Moreover, components of the indirectly measured BP (SBP, DBP, and mean [calculated] BP) contain additional information regarding the circulation. Also, BP varies depending on where in the vascular system it is measured, eg, brachial artery pressure vs central aortic BP. Further, BP has circadian, infradian, and ultradian variations, and it varies with exercise, emotional stress, and other conditions. The discussion to follow will deal with the resting BP as recorded in the brachial artery.

The optimal BP must be viewed in the context of the function of the circulation. The function of the circulation is primarily to supply oxygen, nutrients, hormones, and heat to the living cells of the body. Also, the circulation provides a means of disposing of metabolic end products. Importantly, the amount of circulation should be matched to the needs of each cell.

The requirement for oxygen by tissues (mL O₂/g) is a convenient way to begin to look at the requirement for the delivery of blood by the circulation, and forms the basis of the Fick principle for the determination of cardiac output. For a total oxygen consumption at rest of 250 mL/min, the circulatory requirements would be approximately 5 L/min, with the kidney being overperfused and the skeletal muscles underperfused. Interestingly, since each 100 mL of blood carries about 20 mL of oxygen, a cardiac output of 5 L/min delivers a total of 1 L of oxygen, of which only 25% is used. This emphasizes the importance of the other functions of the circulation. For example, because humans are homeotherms, maintaining tissues at the appropriate temperature by the circulation is important for metabolic function, as described by the law of Arrhenius.

At rest, cardiac output will vary depending on the size of the individual. The average man has a body surface area of 1.7 m², with a cardiac output of approximately 5 L/min. The requirement for a cardiac output of 5 L/min is met by a left ventricular stroke volume of approximately 83 mL at a heart rate of 60 bpm. The resulting time course of the arterial BP is determined for practical purposes by the resistance offered by the precapillary arterioles and the systolic impedance to left ventricular ejection provided by the proximal arterial circulation.

Based on these relationships, the mean pressure in the proximal systemic arterial circulation is approximately 100 mm Hg for the average man. This is achieved by a BP of approximately 120/80 mm Hg (mean BP = SBP + (2 · DBP)/3, an estimation of the area under the BP curve). The peak SBP is determined by the impedance to left ventricular ejection offered by the proximal arterial circulation plus the addition of reflected waves. The ejection of a left ventricular stroke volume of 83 mL of blood into an arterial circulation that contains only approximately 500 mL of blood (four fifths of the blood volume is in the veins) without causing an undue increase in SBP depends on the distensibility of the arterial circulation, ie, the Windkessel effect. The volume distensibility is the change in volume/ change in pressure (δV/δP); the pulse pressure (PP) is the stroke volume/distensibility. Thus, based on a cardiac output of 5 L/min and a normal arterial distensibility, the systolic arterial pressure measured in the proximal arterial circulation is approximately 120 mm Hg for the average man (a slightly higher BP would be expected for a larger person and a slightly lower BP for a smaller person).

Therefore, the optimal BP at rest in our average man measured in the brachial artery should be approximately 120/80 mm Hg. This is the pressure that the system is designed to operate with and when the BP is chronically elevated above the optimal value, the pressure damages the blood vessels and overloads the left ventricle. It is equally apparent that alterations in either, or both, systolic and diastolic components of BP signal a disturbance in the circulation. When all components of BP are elevated, it is almost certain that the resistance arterial vessels will be narrowed (the capillary pressures in essential hypertension are usually normal [ie, <25 mm Hg]). The role of the kidney in maintaining such an increase in BP throughout the cardiac cycle is important. On the other hand, since SBP is heavily dependent on the distensibility of the arterial circulation, increases in SBP may be present when constriction of the resistance vessels is not present; hence, the DBP is not elevated and the peripheral vascular resistance is not increased.

This admittedly simplistic explanation for the concept of an optimal resting BP provides a platform for discussion of the relationship of BP measurements to the disease of hypertension. Perhaps a greater emphasis will be placed on preventing increases in BP rather than just lowering Bps that clearly indicate ongoing target organ damage. The notion of prehypertension as a risk factor does not do justice to the likelihood that in high‐risk individuals, the cardiovascular system is already abnormal when that label is affixed—even though a cardiovascular event has not yet taken place.

DATA SUPPORTING OPTIMAL BP AS A GOAL

There is abundant evidence that decreasing BP to < 140/90 mm Hg in virtually everyone without a contraindication and to <130/80 mm Hg for those with diabetes or chronic kidney disease confers benefit. ⁷ It must be recognized, however, that virtually all of the randomized clinical trials that provided this support used threshold Bps as a requirement for entry. In fact, most used a threshold value of 140/90 mm Hg, a level of BP that was borrowed not from physiologists, but from actuaries working in the insurance industry.

It is now evident that decreasing BP in individuals with Bps higher than the optimal BP—people at increased risk for cardiovascular disease but previously not considered hypertensive because they had not reached an accepted threshold value— results in clinical benefit, at least in patients at high risk. ⁶ , ⁷ , ⁸ In the Heart Outcomes Prevention Evaluation (HOPE) study, ¹¹ the angiotensin‐converting enzyme (ACE) inhibitor ramipril reduced the incidence of cardiovascular events and death from any cause among the more than 9000 high‐risk patients with, or without, Bps >140/90 mm Hg (mean BP at entry, 139/79 mm Hg).

In the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), ¹² treatment with perindopril and indapamide significantly reduced the risk of recurrent stroke by 43% in more than 6105 older patients with a history of stroke. The mean age of the participants was 64 years. Participants were randomly assigned to receive active treatment with an ACE inhibitor‐based BP‐lowering regimen (perindopril with or without the diuretic indapamide), or matched placebo. The mean follow‐up was 4 years. The average BP at entry was 129/78 mm Hg. ¹² Importantly, benefits of treatment were consistent across key patient subgroups on combination therapy, including those with and without hypertension, patients who were Asian and non‐Asian, and for both ischemic and hemor‐rhagic stroke subtypes.

Finally, the recently reported Trial to Prevent Hypertension (TROPHY) ¹³ adds further impetus toward optimal BP as the goal of hypertension treatment—a new definition. The study population had SBPs of 130–139 mm Hg and DBPs of 85–89 mm Hg. A total of 809 subjects were randomized to receive either the angiotensin II type 1 receptor blocker (ARB) candesartan or placebo. The primary end point of the trial was the development of stage 1 hypertension, defined by JNC 7 as a BP of >140/90 mm Hg.

During the first 2 years of the trial, a BP of >140/90 mm Hg occurred in 154 participants in the placebo group and 53 in the candesartan group (relative risk reduction, 66.3%; P<.001). The time course of BP demonstrated a significant reduction in SBP that was approximately 10 mm Hg at 2 years of therapy. After discontinuation of active treatment, an increase in BP occurred in the candesartan group (208 participants developed a BP > 140/90 mm Hg) while 240 increased to stage 1 levels in the placebo group (relative risk reduction, 15.6%; P<.007). Importantly, serious adverse events occurred in 3.5% of the participants assigned to candesartan and 5.9% of those receiving placebo.

Participants in the TROPHY trial had prehypertension as defined by JNC 7, ⁷ but stage 1 hypertension according to the new, expanded definition of hypertension as proposed by the Hypertension Writing Group. ¹⁰ Virtually all participants in TROPHY had cardiovascular risk factors; many had the constellation of abnormalities that constitute the metabolic syndrome.

The Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis (CAMELOT) study included 1991 patients with angiographically documented coronary artery disease and a diastolic BP <100 mm Hg. A substudy of 274 patients ¹⁴ had atherosclerosis progression or regression measured by intravascular ultrasound after 24 months of treatment or placebo. In this substudy, patients whose Bps were <120/80 mm Hg had significant regression of atherosclerosis. Patients with Bps >140/90 mm Hg had the highest rate of progression, and patients with what would now be called prehypertension had no major change in their coronary atherosclerosis. ¹⁴

CONCLUSIONS

I believe that it is not presumptuous to suggest that everyone would like to be in an optimal physiologic state. Determining the risk/benefit of various treatment strategies to maintain optimal BP or to lower BP whenever necessary, however, requires an assessment of the entire patient and the application of clinical judgement. Such evaluations should be performed in the context of global cardiovascular risk. By keeping the goals simple, physiologic, and understandable (eg, optimal BP approximately 120/80 mm Hg, low‐density lipoprotein cholesterol approximately 70 mg/dL, and fasting plasma glucose approximately 80 mg/dL), it will be easier for the treating physician to design a therapeutic strategy for the individual patient.

We are often reminded: primum non nocere. One must consider, however, the results of inaction when the totality of evidence including randomized trials, expert opinion, basic research, and knowledge of physiology all point to a better goal for patients. We must ponder, “How many strokes occurred after the publication of JNC I and II because there was no goal for SBP?” Again, who would not like to be optimal?