AJH 2004; 17:49S 54S Systolic Blood Pressure Itʼs Time to Take Control Stanley S. Franklin Once considered an inconsequential part of the aging process, an age-associated rise in systolic blood pressure (SBP) occurs as a consequence of increased arterial stiffness and contributes to a high prevalence of systolic hypertension after middle-age. Elevated SBP imparts a predilection toward the onset of vascular events, highlighting the importance of its control. Current philosophy ranks systolic pressure as the most relevant component of blood pressure (BP) for determining risk for cardiovascular and other events in hypertensive patients, particularly those 50 years of age. Despite its prognostic role, SBP remains more difficult to control than diastolic BP (DBP), and most middle-age and older hypertensive patients fail to achieve recommended targets. In part, the lack of strict control of SBP in the more aged population lies in the physiology of hypertension. Younger persons tend toward isolated diastolic hypertension or combined systolic diastolic hypertension, primarily driven by increased peripheral resistance and more effectively treated by antihypertensive medications; whereas older persons develop isolated systolic hypertension (ISH) associated with increased arterial stiffness that appears to be less amenable to current therapies. Thus, diastolic pressure in hypertensive patients often plateaus as patients reach middle-age and subsequently declines, whereas systolic pressure consistently rises through the ensuing decades. Treatment approaches favoring control of DBP frequently result in residual high SBP, putting patients at greater risk for vascular complications. Improving patient outcomes relies on antihypertensive therapy that appropriately addresses control of SBP and pulse pressure, underscoring the importance of therapeutic options that effectively reduce arterial stiffness. Am J Hypertens 2004;17:49S 54S 2004 American Journal of Hypertension, Ltd. Key Words: Blood pressure, hypertension, antihypertensive agents, systolic blood pressure, pulse pressure. Based on epidemiologic studies associating the level of blood pressure (BP) with cardiovascular disease, hypertension has been defined as either an elevation in diastolic BP (DBP) to 90 mm Hg or an elevation in systolic BP (SBP) to 140 mm Hg. Current treatment guidelines advocate classifying and treating patients on the basis of either DBP or SBP elevations, 1,2 but control of SBP in hypertensive patients remains poor because of misperceptions of its prognostic value and the underlying physiology behind systolic pressure elevation and its age-related increase in prevalence. There is much epidemiologic evidence that links age with the development of hypertension. 3,4 The National Health and Nutrition Examination Survey (NHANES), which provides a cross-sectional examination of the adult population in the United States, shows an inexorable increase in SBP with aging, accompanied by the same increase in DBP until about age 50. 3 These trends for DBP and SBP occur in various ethnic groups and in both genders, 3 suggesting that the age-associated changes in BP parameters occur as a physiologic manifestation of the aging process, the result of both environmental factors and genetic predisposition. Because pulse pressure represents the difference between SBP and DBP, the plateau and fall in diastolic pressure seen in aging individuals, together with a continued increase in systolic pressure, leads to increased pulse pressure in both men and women (Fig. 1). 3,5 Until recently, systolic pressure was the underappreciated component of BP. 4 Early treatment guidelines emphasized control of DBP. The reasoning behind this recommendation was due to the unsubstantiated theory that the maintained pressure, reflected by DBP, made a greater contribution to cardiovascular risk than SBP. 6 Additionally, the bias toward control of DBP stemmed from the widespread belief that rising systolic pressure was a normal and inconsequential part of the aging process, obviating the need to treat all but severe isolated systolic hypertension (ISH). 7,8 The leveling off and subsequent decrease in DBP in persons 50 to 60 years old, in the face of rising SBP, suggests that evaluation of therapy based primarily on Received August 18, 2004. Accepted August 23, 2004. From the Department of Medicine, and the Heart Disease Prevention Program, University of California, Irvine, Irvine, California. Address correspondence and reprint requests to Dr. Stanley S. Franklin, 155 Barlock Avenue, Los Angeles, CA 90049. 2004 by the American Journal of Hypertension, Ltd. Downloaded from Published https://academic.oup.com/ajh/article-abstract/17/s3/49s/130351 by Elsevier Inc. 0895-7061/04/$30.00 doi:10.1016/j.amjhyper.2004.08.020
50S CONTROLLING SYSTOLIC BLOOD PRESSURE AJH December 2004 VOL. 17, NO. 12, Part 2 FIG. 1. Data from NHANES III reflect the progressive increase of pulse pressure beginning in middle-age. 3 The continuous rise in systolic pressure beginning in the third decade of life combined with the plateau and decline of diastolic pressure in the sixth decade leads to pulse pressure increases after age 50. DBP diastolic blood pressure; NHANES III Third National Health and Nutrition Examination Survey; SBP systolic blood pressure. FIG. 2. Distribution of hypertension subtype in the untreated hypertensive population in NHANES III by age. 10 The prevalence of diastolic hypertension in the untreated hypertensive population declines as patients reach 50 years of age, as ISH becomes more prevalent. Numbers at top of bars represent the overall percentage distribution of untreated hypertension by age US population, NHANES III DBP diastolic blood pressure; NHANES III Third National Health and Nutrition Examination Survey; IDH isolated diastolic hypertension; ISH isolated systolic hypertension; SBP systolic blood pressure; SDH systolic/diastolic hypertension. control of DBP may overlook an increasing prevalence of systolic hypertension. More than 75% of patients with uncontrolled hypertension who receive therapy have DBP of 90 mm Hg. 9 Using the data collected between 1988 and 1991 from the third NHANES study (NHANES III) and the 1991 census, and defining hypertensive patients as those who meet the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) definitions, or those who are already on therapy, reveals that most hypertensive patients are older than age 50 years. Only 27% of these patients fall below this age. 5 The propensity toward age-related hypertension currently three of four hypertensive individuals are 50 years or older 5 will undoubtedly increase over the next few decades, given the aging population of the US. Projecting the estimate to the 2020 census predicts not only an overall increase in the number of hypertensive patients but also an increase in the number four of five of hypertensive patients age 50 years or older. 5 Age-Related Determinants of Hypertension A shift in the type of hypertension mirrors the disproportionate prevalence of hypertensive patients over age 50 years. In the earlier decades of life, more than 75% of untreated hypertensive individuals have a form of diastolic hypertension (systolic diastolic hypertension [SDH] or isolated diastolic hypertension [IDH]); however, a shift toward systolic hypertension occurs when patients reach age 50 (Fig. 2). The number of patients with diastolic hypertension decreases most substantially during 50 to 59 years of age to a little more than 40% and decreases further with each decade. Yet, in the sixth decade of life, systolic hypertension becomes more prevalent, with the greatest increase in ISH in untreated individuals occurring at this time. The percentage of untreated hypertensive patients with ISH continues to increase until the eighth decade. In contrast, the percentage of the untreated population with IDH decreases to less than 2% by the seventh decade. 10 A model involving the physiologic factors that contribute to BP may explain the dichotomy in age-related changes in BP components and the disproportionate distribution of hypertension subtypes. The continued increase in SBP in individuals over age 50 can be largely attributed to increased arterial stiffness, a physiologic factor that increases SBP but reduces the increase in DBP at this age. 11,12 Younger people with hypertension tend toward increased peripheral vascular resistance, which represents the driving force behind IDH and SDH in individuals younger than age 50. 5 Not only do SBP elevations predominate as hypertensive patients age, but also SBP appears to be a more accurate staging criterion on which to base and evaluate treatment. The JNC-7 classification and the World Health Organization (WHO)/International Society of Hypertension (ISH) classification classify stage 1 hypertension as SBP of 140 to 159 mm Hg or DBP of 90 to 99 mm Hg. Stage 2 or greater classifications begin at SBP or DBP that exceed these levels. 1,2 Lloyd-Jones et al 13 analyzed data from patients in the Framingham Heart Study who were not on antihypertensive therapy and found a disparity between SBP and DBP in more than 35% of the 3656 untreated patients. In these discordant patients, 31.6% were classified into a higher stage based on an elevated
AJH December 2004 VOL. 17, NO. 12, Part 2 CONTROLLING SYSTOLIC BLOOD PRESSURE 51S FIG. 3. Staging by JNC based on SBP and DBP. 10 The vast majority of hypertensive patients over the age of 50 years may be accurately staged using SBP as the sole criterion. DBP diastolic blood pressure; JNC Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; SBP systolic blood pressure. SBP versus 3.8% on the basis of DBP alone. When added to the proportion of patients with congruent stages of SBP and DBP (64.6%), SBP as the sole criterion provided correct classification in approximately 96% of cases. We extended those findings using the larger NHANES survey population and found that SBP accurately staged 94% of hypertensive patients aged 50 years or more. Of these correctly staged patients, approximately 85% were upstaged on the basis of SBP alone, with the other 9% upstaged because of congruent SBP and DBP. In contrast, using the DBP alone as the staging parameter accurately classified only about 7% of these patients (Fig. 3). 10 These observations support the role of SBP in determining BP staging and eligibility for therapy. As suggested by their age-dependent divergent patterns of onset, diastolic hypertension (IDH and SDH) and ISH may be two distinct disorders with significant overlap. The conversion from diastolic hypertension to ISH in middleage has been attributed to weakened diastolic hypertension. 5 Although some individuals who have had untreated or poorly treated diastolic hypertension at a younger age develop ISH as they age, data from the Framingham Study suggest that only a minority of patients acquire ISH in this manner. Decreases in DBP in patients after age 60 years were observed in both normotensive and untreated hypertensive individuals, suggesting a pathway of acquisition of ISH unrelated to previous diastolic hypertension. 14 These data imply the physiologic consequences of the aging process largely drive ISH. Aging, accelerated by accumulation of advanced glycation end products (AGE), leads to increased arterial stiffness and contributes to the development of ISH. 14,15 Cardiovascular Risks Despite the preponderance of evidence otherwise, some clinicians base SBP control on the outdated rule of thumb that the SBP target is the patient s age plus 100 mm Hg. Numerous studies negate this supposition that rising SBP is an inconsequential part of the aging process that is not worthy of treatment. 16,17 The Multiple Risk Factor Intervention Trial (MRFIT) of 316,099 men demonstrated that, although SBP and DBP were among the most significant predictors of death due to coronary heart disease (CHD) in all age groups, the risk of CHD death increased more substantially with increasing SBP compared with the risk of CHD death associated with increasing DBP in middleaged men. The age-adjusted CHD death rate was associated with increasing DBP to 70 mm Hg and increasing SBP to 110 mm Hg, with the greatest increases associated with rises in SBP. 16 Thus, SBP was a stronger predictor of CHD death than DBP, 16 and patients with the highest pulse pressures in this study had the highest overall risk. 18 Using the Framingham data, we extended this observation to identify the relative roles of SBP, DBP, and pulse pressure in determining the risk of fatal and nonfatal CHD. After adjusting for age, sex, and other risk factors, increased SBP was associated with greater risk of CHD. The correlation between SBP and increased risk of CHD occurred at any DBP. When patients were analyzed in groups according to their SBP (mean SBP of 110, 130, 150, and 170 mm Hg), the opposite trend occurred. Within each SBP group, a lower DBP was associated with a greater risk of CHD, suggesting that pulse pressure was the more predictive factor. Because pulse pressure represents the difference between SBP and DBP, holding the SBP constant as the DBP lowers increases the pulse pressure. Similar findings, in which systolic and pulse pressure provided the greatest prognostic value for the development of congestive heart failure, have been reported in subsequent analyses of the Framingham data set. 19 Pulse pressure represents an easily calculated surrogate marker for arterial stiffness, 5,14 which has been demonstrated to be an independent predictor of coronary events in hypertensive patients. 20 When considering the components of blood pressure, SBP, DBP, and pulse pressure can individually predict the risk of coronary events. 16,18 In our study, we demonstrated that when SBP and DBP are considered in tandem, the former was positively associated with risk but the latter was inversely related to risk. These data suggest the magnitude of the difference between SBP and DBP, or the pulse pressure, is the best BP predictor of the risk of coronary events in middle-age and beyond. There are important caveats to consider when equating pulse pressure with cardiovascular risk. Clinical application of pulse pressure may be limited in some patients because determinants of brachial artery pulse pressure are quite complex. Factors other than arterial stiffness, including heart rate, cardiac contractility, and venous pressure, functionally influence pulse pressure. 20 Pulse pressure is only an indirect marker of arterial stiffness; the true risk factor for future cardiovascular events is the arterial stiff-
52S CONTROLLING SYSTOLIC BLOOD PRESSURE AJH December 2004 VOL. 17, NO. 12, Part 2 ness itself. 20 Thus, assessing pulse pressure from brachial arteries can lead to many pitfalls, and valid studies comparing the use of pulse pressure versus SBP for assessment of cardiovascular risk and therapeutic benefits are lacking. However, pulse pressure assessment may be useful in identifying patients with high-risk systolic hypertension, such as older persons with ISH; treating these patients aggressively will reduce both systolic and pulse pressure. Because the majority of individuals with systolic hypertension are over age 50 years and have ISH, the focus should be on treating systolic hypertension. 11 Therapeutic Benefits During the past few decades, the treatment approach for older hypertensive patients has steadily evolved. In the early 1970s, prevailing wisdom questioned the benefit of antihypertensive agents in patients over age 65. 21 Beginning in the early 1990s, the publication of three major placebo-controlled studies that specifically addressed the treatment of ISH in older patients changed the perception of the significance of SBP control. In 1991, the landmark Systolic Hypertension in the Elderly Program (SHEP) study first established that ISH increased the risk of adverse cardiovascular and other events and that older patients benefited from treatment. The European Syst-Eur and the Asian Syst-China trials corroborated these findings. 17 Staessen et al 22 conducted a meta-analysis of the 11,825 patients who participated in these major trials and an additional 3868 patients with ISH aged 60 years or more who participated in other trials. This examination found that antihypertensive treatment significantly reduced fatal and nonfatal coronary events by 23% (P.001), fatal and nonfatal strokes by 30% (P.0001), cardiovascular events by 26% (P.0001), cardiovascular mortality by 18% (P.01), and total mortality by 13% (P.02) (Fig. 4). Additionally, a highly significant 49% reduction in fatal and nonfatal heart failure was reported using data from the SHEP study (P.001). 23 These results clearly demonstrate that antihypertensive treatment in patients over age 60 reduces morbidity and mortality. Furthermore, these studies negate the assumptions that age-related changes in BP are safe, and they reinforce the emerging paradigm that treatment will benefit patients with elevated systolic pressure even when these patients have normal diastolic pressure. Currently, life expectancy in the United States is 77 years, 24 which merits questioning the benefit of antihypertensive agents in patients over this age. A meta-analysis of several trials that included 1670 patients age 80 years or more, suggests even very old patients may benefit from antihypertensive treatment. In these patients, active treatment produced a 34% reduction in stroke (P.014), a 39% reduction in heart failure (P.01), and a 22% reduction in major cardiovascular events (P.01) (Fig. 4). The reduction in coronary events was not statistically significant, and no reduction in mortality was observed. 25 FIG. 4. Treatment effect on relative risk of mortality and major vascular events in middle-aged and older patients in the metaanalyses by Staessen et al 22 and Gueyffier et al. 25 Antihypertensive treatment significantly improves cardiovascular and other outcomes in hypertensive patients over the age of 60 years, as well as in those over the age of 80. CHF congestive heart failure; CV cardiovascular. These results imply that although antihypertensive treatment may not extend the lives of octogenarians, treatment may enhance the quality of their lives through prevention of strokes, heart failure, and major cardiovascular complications. Achieving Therapeutic Goals Because antihypertensive treatment of patients age 60 years and older improves outcomes, awareness of hypertension and access to treatment are both important factors in achieving therapeutic goals. During the past decades, awareness of hypertension has steadily increased; however, in the most recent NHANES survey (1999 to 2000), awareness was approximately 70%, the same as in the previous NHANES survey, conducted approximately 5 years prior. Thus, a substantial proportion (31%) of hypertensive persons in the US continue to be unaware of having hypertension, with nearly one-half of these being persons over the age of 65 years. 9 Furthermore, of the patients treated, many remain above recommended BP goals. Nearly 60% of hypertensive patients receive antihypertensive therapy, but only about one-fourth achieve the recommended SBP of 140 mm Hg. 9,26 Not unexpectedly, the vast majority of treatment failures occur in patients over age 50. Only 14% of failures occurred in patients under this age, whereas 86% of treatment failures occurred in older individuals, with most failures occurring in those with ISH. 10 Given that diastolic hypertension is more predominant in younger
AJH December 2004 VOL. 17, NO. 12, Part 2 CONTROLLING SYSTOLIC BLOOD PRESSURE 53S patients, these data suggest that current antihypertensive therapy more effectively controls diastolic pressure than systolic pressure. Analyzing treatment failures by age reveals the agerelated discrepancy in the successful control of both facets of BP. Approximately 50% of younger patients who failed treatment had both SBP and DBP that were not at target goals, representing a concordant failure in this younger population. In stark contrast, older patients who failed to achieve treatment goals had discordant failure. Only 17% of patients age 50 years or older were above their DBP goal, but 82% were well above their SBP target goal. 10 The tendency toward discordant failure amplifies with increasing age. Using data from the Framingham study, Lloyd-Jones et al 27 demonstrated age-related changes in the ability to reach the target DBP and SBP goals. More patients over the age of 75 years than under the age of 60 achieved their DBP goal (92% v 85%, respectively); however, the SBP target became progressively more difficult to obtain. In patients age 60 years or less, 69% reached their SBP goal, compared with 48% of patients 61 to 75 years old, and 34% of patients over age 34. That the target SBP apparently becomes more difficult to achieve with age might be explained by a failure in treatment approach. In the past, treatment guidelines focused on DBP, relegating SBP control to minimal importance. Some clinicians feared reaching excessively low DBP and therefore were fearful of lowering SBP even at pressures 150 or 140 mm Hg as long as the DBP remained at its target. Failure to use optimal polypharmacy and, in particular, failure to incorporate diuretics as part of polypharmacy, may have also hampered the ability to control ISH. In addition, not treating to the lower target goals in high-risk patients with diabetes and kidney disease likely further contributed to the disappointingly high incidence of treatment failures. Although several aspects involving treatment approaches may explain the failure to optimally control ISH overall, the bottom line may be that there is a substantial number of patients in whom systolic hypertension is recalcitrant to correction. This category of patients includes those with stage 2 ISH whose SBP is well above 160 mm Hg; those with left ventricular hypertrophy (LVH) and diastolic dysfunction; those with complicated hypertension in terms of diabetes, coronary heart disease, prior stroke, renal disease, and peripheral vascular disease; and those who are truly resistant to failure for three drug therapy. Many older patients with ISH fall into this category. Treatment approaches that minimize arterial stiffness include a variety of approved and investigational agents; however, most conventional antihypertensive drugs fall short of optimally reducing age-related increases in pulse pressure. 28 Many BP medications have general antihypertensive properties that influence arterial stiffness. For example, most antihypertensive agents will reduce arterial stiffness on a functional basis, simply by reducing peripheral vascular resistance. 29 The ability of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARB) to promote regression of LVH and arterial remodeling have an important long-term effect on arterial stiffness. In addition, nitrates in doses that do not affect peripheral vascular resistance can decrease early wave reflection and change the significant central pulse pressure component to lower the left ventricular load on the heart, even without a significant change in arterial stiffness. 11,30 Some agents appear to possess properties that specifically influence arterial stiffness. Although poorly understood, reduced-sodium diets that are used to achieve negative salt balance, with or without the use of diuretics, can influence arterial stiffness. 11 The aldosterone-inhibiting effects of spironolactone may reduce collagen accumulation in arteries. 11 In animal models, AGE crosslinking breakers have been shown to prevent arterial stiffening. In the future, these agents may be very important treatment options for patients who do not reach SBP targets. Conclusions The new systolic paradigm emphasizes the importance of controlling SBP to improve patient outcomes. In middleaged and older patients, SBP repeatedly has been found to be superior to DBP for correctly classifying BP stages, indicating patients who have increased arterial stiffness and determining the risk for cardiovascular disease. Achieving benefit from antihypertensive treatment appears to rely on optimal control of SBP. Reaching target systolic pressure levels may require the use of polypharmacy, perhaps with new agents that specifically and effectively target arterial stiffness. References 1. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, Jones DW, Materson BJ, Oparil S, Wright, JL, Roccella EJ: The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560 2572. 2. World Health Organization: 2003 World Health Organization (WHO)/International Society of Hypertension statement on the management of hypertension. J Hypertens 2003;21:1983 1992. 3. 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