Isolated systolic hypertension (ISH) is currently defined as a systolic blood pressure (SBP) > 140 mm Hg with diastolic blood pressure (DBP) < 90 mm Hg, and not secondary to another disorder. This current definition represents a change from the earlier definition of ISH, utilized in most studies, of SBP > 160-165 mm Hg with DBP < 90-95 mm Hg. It is a disease entity that was once thought to be relatively benign. However, recent data support the view that systolic hypertension, even in the absence of diastolic hypertension, is a significant risk factor which, if left untreated, increases morbidity and mortality across populations.

Current consensus opinion regards a stable blood pressure of < 140/90 mm Hg as a general goal in an unspecified population, with different stages of hypertension corresponding to deviations from this consensus. In 1997, the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure issued guidelines ¹ (JNC VI) for the definition and classification of hypertension (Tables 1 and 2):

This chapter attempts to provide an overview of the data supporting the need for prompt and aggressive treatment of ISH in populations commonly encountered in clinical practice, as well as the experience documented with various treatment regimens.

In spite of trends demonstrating an improvement in both the recognition and the treatment of this disease, hypertension remains a common affliction, with consensus estimates that approximately 50 million patients suffer from hypertension in the United States alone. Although often clinically silent, hypertension is a serious risk factor associated with stroke and cardiovascular morbidity.

The reported prevalence of ISH varies. It increases with advancing age, with recent estimates from the National Health and Nutrition Examination Survey (NHANES III) showing that ISH accounts for 54% of hypertension in patients aged 50 to 59 years and 87% in patients aged 60 years or older.² The reason for this increase may reflect proposed pathophysiologic mechanisms involved in the generation of ISH and discussed below. For many years it was thought that ISH was not strongly associated with the sequelae linked to diastolic or combined hypertension and, as such, specific treatment goals in ISH were less emphasized. As data from landmark studies have demonstrated a link between isolated systolic hypertension and morbidity from multiple causes, the importance of addressing this form of hypertension has emerged.

In older patients with systolic hypertension, systemic arterial compliance is significantly reduced when compared with younger controls; this is thought to be due to an increased rigidity of the arterial walls. Specifically, mechanical changes in arterial walls such as atherosclerosis and gradual loss of aortic distensibility, which decrease overall arterial compliance, are more commonly encountered with advancing age.³ This decrease in compliance results in higher systolic pressures as the large vessels become less able to reduce the pressure generated by the left ventricle by means of distension. However, while increases in peripheral resistance will cause elevations in diastolic blood pressures, the loss of large-vessel elasticity does the opposite. These counteracting forces may keep the diastolic pressure normal in the setting of an increasing systolic pressure.

Because the distensibility of the ascending aorta and other major vessels fails most often due to changes seen with aging, the majority of risks for ISH and the potential benefits of treatment have been demonstrated predominantly in older populations, and the extent to which these data are applicable to younger patients remains to be seen.

Interestingly, some authors have suggested that the same pathophysiologic mechanisms discussed above result, when combined, in a more important elevation in pulse pressure, which is defined as the difference between systolic and diastolic blood pressures. Evidence is beginning to show that elevation in pulse pressure itself may be an important independent risk factor for all-cause and cardiovascular mortality, and analysis of Framington Heart Study data has revealed that neither SBP nor DBP is superior to pulse pressure in predicting coronary heart disease risk.^4,5

Despite its sizable impact on morbidity and mortality, hypertension is often clinically silent, and the most crucial data obtained from the patient may come by way of taking proper sphygmomanometer readings. This is not to say that important information is not available in the history and physical examination; however, in the setting of suspected ISH, these exercises are most helpful in eliminating other causes for the elevated blood pressure and for risk stratification. As such, a detailed discussion is beyond the scope of this chapter.

As noted, the diagnosis of ISH is made by demonstrating a SBP =140 mm Hg with a DBP < 90, following current national recommendations for blood pressure monitoring (Table 3).

The diagnosis of ISH is reserved for situations in which the blood pressure has been measured on several occasions with consistent results, and after exclusion of other causes of widened pulse pressure such as arteriovenous fistulae, thyroid disease, anemia, aortic regurgitation, and intrinsic diseases of the artery such as coarctation.¹ Although the possibility exists for false-positive measurements, to date indirect manometry remains acceptable for both JNC VI and most major trial purposes. If travel to the physician's office is not feasible, or if a patient's anxiety in the office is thought to be distorting results, self-measurement of blood pressure at home is an effective method of identifying patients at higher risk due to ISH.

Risk Stratification:

Once hypertension is established, careful evaluation to identify risk factors, exclusion of hypertension related to a secondary problem, and evaluation of target organ damage should be undertaken as guided by clinical findings. JNC VI guidelines utilize this evaluation (Tables 4 and 5) to risk-stratify patients for treatment considerations.

Outcomes Studies:

Unfortunately, recent studies show that ISH remains a common and undertreated disease in the United States and abroad. A recent review by NHANES III² found that ISH was the most common hypertension subtype in people aged 50 years and older, and that ISH patients composed the largest group of uncontrolled hypertensive patients (65%). Despite evidence that ISH is both the most common form of hypertension in elderly patients as well as evidence that ISH tends to worsen with advancing age, analysis of large populations shows that even among treated patients, blood pressure control is increasingly inadequate among older patients.^1,6

In 1998, the Evaluation and Interventions for Systolic Blood pressure Evaluation: Regional and Global (EISBERG) project⁷ gathered and analyzed data from approximately 17,000 patients in seven countries, including the United States, in an effort to determine the adequacy of blood pressure control in hypertensive disease. The study revealed little improvement in the control of systolic blood pressure, documenting an alarming 90% of control failures. Systolic blood pressure control was achieved in less than 40% of patients who had a goal BP of < 140/90. A review of qualitative data gathered by the project revealed an overall lack of understanding of the disease on the part of patients, coupled with a reluctance on the part of general practitioners to aggressively treat ISH in elderly patients. Taken together, the data from the NHANES III and EISBERG project reveal that current practices are incongruent with the evolving picture of the importance of systolic hypertension and pulse pressure evident from population data.⁸

That ISH is a legitimate, independent risk factor associated with increased end-stage renal disease, cardiac disease, and stroke has been positively demonstrated in the literature.⁹ ISH itself is associated with two to three times the risk of cardiovascular events or mortality across ages and genders; this risk is essentially doubled in diabetic patients or smokers. Other data suggests ISH may independently increase risk for dementia.¹⁰ In fact, elevated systolic blood pressure and elevations in pulse pressures (SBP - DBP) seen in ISH are now believed to have more influence than does diastolic blood pressure on the progression of cardiac disease.

This realization required the design of new studies to directly measure the results of therapeutic interventions in ISH on outcomes. Three major trials^11-13 have investigated the effects on common risk factors of lowering systolic hypertension with pharmacologic agents (Table 6).

SHEP Trial
Briefly, the SHEP trial¹¹ enrolled 4,736 patients aged 60 years or older with ISH (SBP > 160 mm Hg; DBP < 90 mm Hg) in a double-blind, placebo-controlled study using chlorthalidone 12.5mg, which could be doubled to 25 mg (with step-up drugs atenolol 25-50 mg or reserpine 0.05-0.10 mg as needed). Goal SBP reduction was at least 20 mm Hg. The primary end point was nonfatal stroke plus fatal stroke, with other major coronary heart disease (CHD) and cardiovascular disease (CVD) end points secondary. The cohort had a mean age of 72, was 57% female, and had a mean BP of 170/77 mm Hg. The average follow-up was 4.5 years. More than one half of the treatment group received only the step 1 drug. Results showed a reduction in the mean BP to 155/72 for placebo versus 143/68 for the treatment group. Subsequent analysis revealed significant reductions for the treated group in total stroke incidence (-36%; P = .0003), nonfatal myocardial infarction (MI) plus coronary death (-27%), and all cardiovascular events (-32%).

Syst-EUR Trial
Briefly, the Syst-EUR trial¹² enrolled 4,695 patients aged 60 or older with ISH (SBP > 160 mm Hg; DBP < 95 in a double-blind, placebo-controlled study using nitrendipine 10 mg initial, titrated up to 20 mg twice daily (with step-up drugs ± enalapril 5-20 mg, ± hydrochlorothiazide 12.5-25 mg, as needed). Goal SBP reduction was at least 20 mm Hg to less than 150 mm Hg. The primary end point was stroke, with other major CHD and CVD end points secondary. The cohort had a mean age of 70 years, was 27% female, and had a mean BP of 173/85 mm Hg sitting. The average follow-up was 2 years. At 2 years, almost 59% of patients had received only the step 1 drug. Results showed a reduction in the mean BP to 160/83 for placebo versus 150/78 for the treatment group. Subsequent analysis revealed significant reductions for the treated group in all strokes (-42%, P = 0.003); nonfatal strokes (-44%, P = 0.007); nonfatal cardiac end points (-33%, P = 0.03); all fatal and nonfatal cardiac end points (-26%, P = 0.03); all fatal and nonfatal cardiovascular end points (-31%, P = 0.001); and all cerebrovascular events (-34%, P = 0.006).

Syst-China Trial
Briefly, the Syst-China trial¹³ enrolled 1,253 patients aged 60 years or older with ISH (SBP > 160 mm Hg; DBP < 95 mm Hg) in a single-blind, placebo-controlled study using nitrendipine 10 mg initial, titrated up to 20 mg twice daily (with step-up drugs ± captopril 12.5-50 mg, ± hydrochlorothiazide 12.5-50 mg, as needed). The goal SBP reduction was at least 20 mm Hg to less than 150 mm Hg. The primary end point was fatal and nonfatal stroke, with other major CHD and CVD end points secondary. The cohort had a mean age of 66.5 years, was 35.6% female, and had a mean BP of 170/86 sitting. The average follow-up was 2 years. Results showed a reduction in the mean BP to 159/84 for placebo versus 150/81 for the treatment group. Subsequent analysis revealed significant reductions for the treated group in all strokes (-38%, P = 0.01); all-cause mortality (-39%, P = 0.003); cardiovascular mortality (-39%, P = 0.03), stroke mortality (-58%, P = 0.02), and all cardiovascular end points (-37%, P = 0.004).

The results of these trials were pooled into a meta-analysis,¹⁴ which concluded that active treatment did reduce risk factors associated with ISH; specifically, active treatment reduced all-cause mortality by 17%, cardiovascular mortality by 25%, all cardiovascular end points by 32%, all strokes by 37%, and all myocardial infarction by 25%.

A further demonstration of the risk reduction associated with treatment of elderly patients with ISH is apparent in another meta-analysis by Staessen et al,¹⁵ in which the data from the above three trials were pooled with data from five additional trials featuring subgroups of elderly ISH patients (patients aged 60 years or older and using SBP > 160 and DBP < 90-95 mm Hg to define ISH). The results of this meta-analysis revealed untreated ISH to be related to total and cardiovascular mortality, with a 10 mm Hg increase in SBP correlating with a nearly 10% increased risk of all measured complications except for coronary events. Conversely, active treatment of systolic hypertension to reduce a pretreatment mean of 174/83 mm Hg by -5.96% systolic and -4.91% diastolic reduced total mortality by 13% (P = 0.02), cardiovascular death by 18% (P = 0.01), all cardiovascular fatal and nonfatal events by 26% (P < 0.0001), stroke by 30% (P < 0.0001), and coronary events by 23% (P = 0.001).

The data supporting an aggressive approach toward controlling ISH in the elderly is evident; however, some reports have suggested that the practice of reducing blood pressure in elderly patients may itself lead to complications. The three landmark trials above^11-13 did not generally achieve reductions in blood pressure below 140/72 mm Hg, nor did they generally segregate elderly patients into subgroups. At least one study¹⁶ has shown a statistically significant increase in elderly patients' risk of stroke when DBP falls below 65 mm Hg in patients treated for hypertension (compared with controls). Additionally, an analysis of the SHEP cohort revealed that, in treated patients, a DBP of < 70 mm Hg was associated with increased stroke, CHD, and CVD,¹⁷ although treated patients never performed worse than placebo patients in terms of CVD events. Finally, there are reports that in the very elderly patient population (eg, ages > 80-85), higher levels of blood pressure may correlate with improved mortality. However, a meta-analysis of several antihypertensive drug therapy trials in patients age > 80 years did not support withholding treatment of hypertension in this population.¹⁸ Clearly, these studies demonstrate the need for further work to clarify the goal of blood pressure reduction efforts in selected scenarios.

An approach to individual patients can incorporate the data discussed above with the current JNC VI guidelines (Table 7) in order to select an approach to therapy that maximizes benefits of blood pressure reduction in patients with ISH. What follows are broad recommendations for specific interventions that can be used in the clinical setting of patient care:

Lifestyle Modification:

As noted previously, the risks of ISH are higher in patients with diabetes and in smokers; thus, tight control of the former and cessation of the latter are important in reducing morbidity and mortality. Interestingly, the diabetic subsegment of the SHEP trial showed almost twice the reduction in absolute risk from all major cardiovascular events compared with nondiabetic patients, although the population in this instance was limited to relatively well-controlled non-insulin-dependent patients.¹⁹ This further underscores the need to address both diseases concomitantly in order to maximize patient benefits.

A change from a sedentary lifestyle to a more active lifestyle with a formal exercise program is often recommended in patients suffering from chronic illness, and in fact may be beneficial in patients with ISH. However, one study²⁰ of the effects of an exercise program targeting an intensity of 65% maximum predicted heart rate in elderly patients (age 64 ± 7 years old) with ISH failed to demonstrate improvements in large-artery mechanics or blood pressure over an 8-week period, suggesting that exercise alone is insufficient to treat ISH in this group. The authors suggest that longer programs, or introduction of the program at a younger age, are as-yet unproved alternatives worth exploring.

Dietary modification is important in subgroups of patients with diabetes and hyperlipidemia, and additionally there are data to support a significant mean reduction in SBP of 11.8 mm Hg in a group of patients with stage 1 ISH (SBP 140-159 mm Hg pretreatment) treated with the use of the DASH diet.²¹ This is an inexpensive, attractive alternative for compliant patients with mild ISH, and the magnitude of reduction in SBP is comparable with many low-dose drug regimens.

Pharmacotherapy:

Ideal agents would target those pathophysiologic derangements that are thought to be present in ISH, and without causing serious side effects. In particular, the emergence of widened pulse pressure as a significant independent risk factor for mortality highlights the importance of avoiding agents whose actions might increase the pulse pressure—for example, agents that cause profound decreases in diastolic blood pressure. For ISH, then, a theoretic advantage would be seen in agents having a direct vasodilatory effect on the aorta and large vessels, improving arterial compliance and reversing the changes that are seen with aging and ISH.

Diuretics
Diuretics remain first-line agents in the treatment of ISH in the elderly since the impressive results of the SHEP trial,¹¹ with good control often seen at relatively low doses of agent. A review of a series of smaller studies suggests that thiazide diuretics may be superior to beta blockers in patients with ISH.²²

Calcium Channel Blockers
Calcium channel blockers are thought to improve arterial compliance, thus reversing the mechanisms seen in ISH. In addition, they are relatively well tolerated in a number of comorbid conditions. Both the Syst-EUR¹² and the Syst-China¹³ studies utilized low-dose, slow-release calcium channel blockers in the treatment of ISH, with significant reductions in key end points.^12,13 Interestingly, one benefit seen in the Syst-Eur and Syst-China trials that was not seen with diuretics was a preservation of Mini-Mental State Examination scores and a reduced rate of dementia (by 50%) in treated patients.¹⁰

Beta Blockers
Beta blockers have proven cardioprotective effects, which make their use appealing especially in patients with known tachycardia, coronary disease, or previous myocardial infarction. Although studies have shown that propranolol may be less effective in older patients with ISH in whom reduced distensibility of the aorta is thought to be a causative mechanism,³ beta blockers with intrinsic sympathomimetic activity or combined alpha-beta blockers may be more effective in this population.

Nitrates
Nitrates have vasodilatory action on conduit vessels and may alter the timing of reflected pressure waves within the arterial system in a manner advantageous to treatment of ISH. The oral forms have been shown to reduce SBP without serious changes in DBP, and have been tolerated in elderly patients.

Angiotensin-converting Enzyme Inhibitors/
Angiotensin Receptor Blockers
Angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce proteinuria and to slow renal disease, improve systolic dysfunction, and lower SBP in patients with ISH. It is likely that angiotensin receptor blockers (ARBs) will show similar efficacy, although they remain less studied. That ACE inhibitors have shown multiple beneficial effects in patients with coronary heart disease and nephropathy make them an especially attractive therapy for patients with ISH and these comorbid conditions. Several recent studies have also confirmed the benefit of ARBs for the nephropathy of type 2 diabetes mellitus.

Other Agents
There are a variety of alternate possible selections available that can be tailored to an individual patient's comorbidities and tolerance. One cautionary note: we do not recommend using alpha-adrenergic blockers as first-line agents at this time, as they may be associated with increased cardiovascular events and congestive heart failure compared with other agents.

Summary
ISH has been conclusively shown to be an important risk factor for cardiovascular morbidity and mortality in affected patients. It is thought that the pathophysiologic mechanisms leading to ISH put the elderly population at higher risk for this disease. This is a disease in which the diagnosis can be easily made, and effective follow-up documented, at routine clinic appointments without the need for invasive studies. Effective and proven first-line agents include diuretics and calcium channel blockers, although many other agents are available as well. Treatment should be individualized to the patient and congruent with comorbid conditions.

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