Systolic Hypertension in the Elderly: Addressing an Unmet Need

REVIEW Systolic Hypertension in the Elderly: Addressing an Unmet Need Daniel A. Duprez, MD, PhD Cardiovascular Division, Medical School, University of Minnesota, Minn. ABSTRACT Systolic hypertension is a major public health issue in the elderly and is often under-recognized and under-treated. The concept that systolic blood pressure increases with age should be considered a pathophysiologic concept. Aging of the cardiovascular system is accompanied by endothelial dysfunction, activation of the renin-angiotensin system and, consequently, vascular remodeling. This process leads to an increase in large artery stiffness and an increase in arterial wave reflections to the heart. These processes in daily clinical practice translate to an increase in systolic blood pressure, which is associated with increased cardiovascular morbidity and mortality. Evidence-based medicine recommendations to treat systolic hypertension in the elderly are based on landmark and recent clinical trials, which clearly demonstrated that treatment of isolated systolic hypertension is associated with significant decreases in cardiovascular morbidity and mortality. However, treatment of systolic hypertension in older adults remains disappointing because therapeutic goals often are not reached. Therefore, emphasis should be placed on the treatment of systolic hypertension in the elderly, and there is need for more effective, individualized antihypertensive therapy. 2008 Elsevier Inc. All rights reserved. The American Journal of Medicine (2008) 121, 179-184 KEYWORDS: Angiotensin II; Arterial stiffness; Elderly; Renin; Systolic hypertension; Vascular remodeling Systolic hypertension, the most frequent type of uncontrolled hypertension in the elderly, is a major public health After the age of 50 or 60 years, increase in blood pressure AGING AND SYSTOLIC HYPERTENSION issue. 1 Increased systolic blood pressure has been acknowledged as a more important risk factor for cardiovascular astolic blood pressure tends to spontaneously decrease with occurs primarily in systolic blood pressure Figure ( 1). Di- disease and appears to play a greater role than elevated increasing age while systolic blood pressure increases, diastolic blood pressure in determining eligibility for antihypertensive therapy. Despite the availability of effective the arterial vasculature. 5 In large arteries, aging results in mainly as a result of the functional and structural changes in antihypertensives, poor control of systolic hypertension appears to be increasing, especially in the older population. mentation of elastin, and an increase in the number and progressive deposition of calcium salts, fraying and frag- 1-4 There is not often consistency in use of the term el-cross-linkinderly. Generally it is considered as an age of 65 years andthe vessel wall. A rigid aorta is less able to buffer the of collagen fibers that increase the rigidity of older, while middle age is considered between 50 and 65pulsatile output from the heart, so increases occur in systolic years of age. Therefore, in all the major studies discussed blood pressure and ventricular afterload, while diastolic here, either age range or mean age of the study populationblood pressure and coronary perfusion decrease. is given. These age-related changes in arterial stiffness and systolic blood pressure are strongly associated with organ damage, cardiac and vascular disease, and an increased risk of morbidity and mortality. 6 Requests for reprints should be addressed to Daniel A. Duprez, MD, Results from large epidemiologic studies have confirmed PhD, Department of Medicine, Cardiovascular Division, VCRC - Room the association between increased systolic blood pressure 270, University of Minnesota, 420 Delaware St. SE, MMC 508, Minneapolis, MN 55455. and the increased risk of morbidity and mortality. A metaanalysis of 61 prospective studies of blood pressure E-mail address: dupre007@umn.edu and 0002-9343/$ -see front matter 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2007.10.027

180 The American Journal of Medicine, Vol 121, No 3, March 2008 mortality showed that, between the ages of 40 and 69 years, an increase in systolic blood pressure of 20 mm Hg was associated with a more than 2-fold increase in the death rate due to stroke and in the death rates from ischemic heart disease and other vascular causes. 7 Relatively small decreases in mean systolic blood pressure were associated with large absolute reductions in strokes and premature deaths. A 2-mm Hg mean lower systolic blood pressure was equivalent to a 7% lower risk of death from ischemic heart disease and a 10% lower risk of stroke. ROLE OF THE RENIN-ANGIOTENSIN SYSTEM The renin-angiotensin system appears to be one of the most significant contributors to systolic hypertension. It plays an important role in the regulation of blood pressure, water and salt balance, and tissue growth. It functions both as a circulating endocrine system and as a tissue paracrine/ autocrine system, most notably in the heart, brain, kidney, and vasculature. 8 CLINICAL SIGNIFICANCE Systolic blood pressure increases with age, and contributes to increased cardiovascular morbidity and mortality. Aging of the cardiovascular system is accompanied by endothelial dysfunction, activation of the renin-angiotensin system, and vascular remodeling. Treatment of systolic hypertension in older adults remains disappointing. Therapeutic goals often are not reached. Systolic hypertension in the elderly should be aggressively treated to target blood pressure. Angiotensin II is a powerful vasoconstrictor that triggers the release of aldosterone, causing the kidneys to retain sodium and water. This increases blood volume and maintains normal blood pressure in hypotensive situations. Under pathophysiologic conditions, activation of the renin-angiotensin system at the tissue level contributes to the pathogenesis of cardiovascular and renal disease. Angiotensin II triggers vascular inflammation and fibrosis in the heart and kidney, and is associated with the development of atherosclerosis in large vessels. 8 Chronic stimulation of the renin-angiotensin system leads to growth- and fibrosis-promoting processes, which lead to further deleterious effects, including organ damage (Figure 2). Antihypertensive drugs that block the renin-angiotensin system at any one of several points have been shown not only to attenuate organ damage associated with hypertension but also to decrease cardiovascular morbidity and mortality. These include the angiotensinconverting enzyme inhibitors, the angiotensin II receptor blockers, and the aldosterone antagonists. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers have been found to be more effective than beta-blockers and diuretics for regression of left ventricular hypertrophy, a common problem among elderly patients with isolated systolic hypertension that is linked to morbidity and mortality. 9,10 Multiple placebo-controlled trials of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers have shown significant slowing of renal damage in diabetic and nondiabetic nephropathies. 11 A recent substudy analysis of 918 patients with isolated hypertension showed that the angiotensin II receptor blocker telmisartan afforded significantly greater lowering of urinary albumin excretion than hydrochlorothiazide after 6 weeks, regardless of the baseline urinary albumin excretion and despite comparable reductions in systolic blood pressure with both drugs. 12 Figure 1 Effect of aging on systolic and diastolic blood pressure. Systolic and diastolic blood pressure increase in a parallel fashion until the pathophysiologic changes with aging occur. After the age of 50 or 60 years, systolic blood pressure continues to increase, whereas diastolic blood pressure begins to decrease. EVIDENCE-BASED MEDICINE IN THE TREATMENT OF SYSTOLIC HYPERTENSION The evaluation and treatment of hypertension should focus on lowering blood pressure and reducing the risk of cardiovascular and renal morbidity and mortality. Effective therapy should slow or reverse abnormal structural changes in arterial circulation that are associated with systolic hypertension in the elderly. The Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure recommends that systolic blood pressure become the major criterion for diagnosis, staging, and therapeutic management (including lifestyle modification and pharmacotherapy) of hypertension, particularly in middleaged Americans. 13 For most patients, target blood pressure is 140/90 mm Hg. For patients with multiple cardiovascular risk factors, established organ damage, or specific comorbidities (eg, diabetes or renal insufficiency), the target

Duprez Systolic Hypertension in the Elderly 181 Figure 2 Effect of aging on arterial stiffness and systolic blood pressure. Endothelial dysfunction and vascular remodeling due to RAS (renin-angiotensin system) activation precedes the development of atherosclerosis, which leads to large-artery stiffness and increases in arterial wave reflections. These pathophysiologic changes contribute to the development of increases in systolic blood pressure in the elderly. is below 130/80 mm Hg. For older hypertensive patients, including those with isolated systolic hypertension (defined as systolic blood pressure 140 mm Hg and diastolic blood pressure 90 mm Hg), treatment recommendations should follow the same principles outlined for the general management of hypertension, although multiple drugs are often necessary to achieve blood pressure targets in the majority of these patients. 13 While blood pressure control can be difficult, it is often achievable through the use of lifestyle modification and combinations of medications. Selection of first-line medication is predicated on a variety of factors, including target organ damage, compelling indications, and other factors such as cost. The value of blood pressure reduction in patients with isolated hypertension has been demonstrated in numerous clinical trials, and studies are ongoing to determine the best interventions. LANDMARK CLINICAL TRIALS A literature search was done in PubMed for isolated systolic hypertension, elderly, clinical trials, and cardiovascular complications from 1980 until now. Only randomized double-blind clinical trials that aimed to study the effect of antihypertensive agents on cardiovascular complications (defined as fatal and nonfatal stroke, fatal and nonfatal coronary heart disease, and other fatal and nonfatal vascular disorders as defined in each trial) in elderly with a mean age above 60 years old with systolic hypertension were withheld for discussion. This literature search gives clinical evidence from several large randomized trials that emerged in the early 1990s, providing convincing support for the routine treatment of systolic hypertension in elderly patients. The Table, available online, summarizes these trials, and absolute and relative outcome results are given. The Systolic Hypertension in the Elderly Program (SHEP) study showed that active blood pressure treatment significantly reduced rates of nonfatal stroke by 36%, total coronary heart disease by 25%, and left ventricular failure by 53% in 4736 elderly patients with systolic hypertension (aged 60 years; mean blood pressure 171/77 mm Hg) who were followed for an average of 4.5 years. 14 A recent follow-up analysis of the SHEP participants showed that treatment improved longterm outcomes, especially among patients who had diabetes. 15 At a mean follow-up of 14.3 years, the cardiovascular mortality rate was significantly lower, 19% in the treatment group versus 22% in the placebo group. Further, patients who developed diabetes during treatment had no significant increase in cardiovascular events and had a better prognosis than those who had preexisting diabetes. In a study of a smaller SHEP cohort (n 268) of patients with isolated systolic hypertension, placebo treatment was associated with a 90% greater risk of death or a cardiovascular event during a 14-year period when compared with active treatment. 16 The Systolic Hypertension in Europe (Syst-Eur) and the Systolic Hypertension in China (Syst-China) trials were 2 other large trials in elderly patients with isolated systolic hypertension, yielding outcomes similar to those of SHEP. 17,18 Each assessed the effect of therapy based on the calcium channel blocker nitrendipine. The European trial included 4695 patients (aged 60 years; mean blood pressure 174/86 mm Hg), and showed that nitrendipine-based therapy significantly reduced stroke by 42% and cardiovascular outcomes by 31%. 17 Likewise, in the Chinese trial, nitrendipine therapy prevented stroke and other cardiovascular complications in 2394 older patients (aged 60 years) with isolated systolic hypertension. 18 Active treatment reduced total stroke by 38%, all-cause mortality by 39%, cardiovascular mortality by 39%, stroke mortality by 58%, and all fatal and nonfatal cardiovascular end points by 37%. A meta-analysis that examined a subset of patients with isolated systolic hypertension from the SHEP, Syst-Eur, and Syst-China trials showed that there was a 23% reduction in cardiovascular events associated with treatment of systolic hypertension compared with no treatment in elderly patients. 19 RECENT CLINICAL TRIALS Following the encouraging findings of the early trials in treating systolic hypertension in older subjects, many new trials have focused on elucidating the effects of angiotensinconverting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, and other blood pressurelowering drugs on mortality and major cardiovascular morbidity (Table, available online). 20-23 The Losartan Intervention For Endpoint reduction (LIFE) trial was a randomized, double-blind study that examined the effects of the angiotensin receptor blocker losartan on cardiovascular

182 The American Journal of Medicine, Vol 121, No 3, March 2008 mortality, stroke, and myocardial infarction. 20 In a subgroup analysis of the LIFE trial, 1326 elderly patients with isolated hypertension (mean age 70 years; mean blood pressure 174/83 mm Hg) and left ventricular hypertrophy received once-daily losartan or atenolol (with hydrochlorothiazide as the second agent in both arms) for a mean of 4.7 years. The composite end point of cardiovascular death, stroke, or myocardial infarction was reduced by 25% with losartan compared with atenolol. Patients receiving losartan also had significant reductions in left ventricular hypertrophy as measured by electrocardiography. The Study of Cognition and Prognosis in the Elderly (SCOPE), a prospective, double-blind, randomized, parallelgroup study, examined the effects of the angiotensin receptor blocker candesartan on cardiovascular events, stroke, and cognition in 4964 elderly patients with mild hypertension (aged 70-89 years; systolic blood pressure 160-179 mm Hg or diastolic blood pressure 90-99 mm Hg). 21 Although this was not a study of isolated systolic hypertension specifically, 30% of the patients had isolated systolic hypertension. After a mean follow-up of 3.7 years, the angiotensin receptor blockerbased treatment reduced nonfatal stroke by 27.8% and stroke by 23.6%. There were no significant differences in myocardial infarction and cardiovascular mortality, and cognitive function was well maintained in both the treatment and placebo groups. Several other studies have lent support to the use of calcium channel blockers as a treatment option for elderly patients with isolated systolic hypertension. The Systolic Hypertension in the Elderly Long-term Lacidipine (SHELL) study compared the effect of lacidipine and chlorthalidone in 1882 elderly patients with isolated systolic hypertension (age 60 years; mean blood pressure 178/87 mm Hg) followed for 32 months. 22 Both drugs markedly reduced systolic blood pressure. The overall incidence of the primary end point, a composite of cardiovascular and cerebrovascular events, was 9.3% in both groups. The International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT) study included 6321 elderly patients (aged 55-80 years) with hypertension and at least 1 additional cardiovascular risk factor. Although not a selective isolated systolic hypertension trial, INSIGHT contained a subgroup of 1498 patients with isolated systolic hypertension (mean blood pressure 173/88 mm Hg) that was analyzed separately. 23 In the subgroup analysis, the calcium channel blocker nifedipine gastrointestinal therapeutic system was compared with the diuretic combination co-amilozide, and it evaluated a composite end point of death due to cardiovascular and cerebrovascular causes and nonfatal stroke, myocardial infarction, and heart failure. Both treatments had similar effects on blood pressure lowering and on the primary outcome (6.0% with nifedipine, 6.6% with co-amilozide). Several short-term studies compared the blood pressurelowering effects and safety of angiotensin receptor blockers and calcium channel blockers in elderly patients with isolated systolic hypertension. Valsartan and Amlodipine for the Treatment of Isolated Systolic Hypertension in the Elderly (Val-Syst), a 24-week randomized, double-blind study, compared the risk/benefit profiles of the angiotensin receptor blocker valsartan with the calcium channel blocker amlodipine in 421 elderly (aged 60-80 years) patients with isolated systolic hypertension. 24 The results showed that valsartan, given alone or in combination with hydrochlorothiazide, showed similar efficacy but better tolerability than amlodipine-based treatment. Overall, adverse events were observed in 31.9% of those receiving amlodipine versus 20.2% of the patients receiving valsartan (P.003), with peripheral edema rates of 26.8% and 4.8%, respectively. Another randomized, double-blind, placebo-controlled 12-week study compared the effects of the diuretic indapamide with the angiotensin receptor blocker candesartan and the calcium channel blocker amlodipine in 1758 patients (aged 40-80 years) with hypertension. 25 In a subgroup of patients with isolated systolic hypertension (n 388, mean age 64 years), the 3 treatments significantly reduced systolic blood pressure; although, indapamide did not change diastolic blood pressure and, thus, reduced pulse pressure significantly. All 3 drugs were well tolerated. The findings from these clinical trials demonstrate that blockade of the renin-angiotensin system at various points in the cascade are effective blood-pressure-lowering medications. Studies listed comparing angiotensin receptor blockers to other regimens showed a lower incidence of stroke, but not of other cardiovascular outcomes, with reninangiotensin-directed regimens, and equivalence of non-renin-angiotensin-treatments in reducing events (calcium channel blockers, diuretics) based on degree of blood pressure lowering. In these randomized clinical trials, the discrepancy in outcome can be due to a difference in reached target blood pressure; for example, in Syst-Eur, 43% of the nitrendipine group reached target blood pressure, but only 21% of the control group did so. Therefore the results of these randomized trials should be interpreted in an appropriate perspective. FUTURE PERSPECTIVES AND DIRECTIONS Potential new markers are being identified to help detect preclinical disease. 26 There is evidence that high-sensitivity C-reactive protein, for example, a marker for acute and low-grade inflammation, may indicate reductions in largeartery elasticity, which subsequently leads to elevated systolic blood pressure. 27 This information may be useful when performing primary prevention cardiovascular screening in asymptomatic individuals. Central aortic blood pressure measurement, which interprets the shape of pulse waves measured at the wrist, may also be a better predictor of stroke or myocardial infarction than peripheral blood pressure measurement and may be more indicative of how well a drug is performing. Regardless of reductions in cuff blood pressure, beneficial effects on central arterial pressure may still occur, which may

Duprez Systolic Hypertension in the Elderly 183 explain the apparent pressure-independent effects of drugs such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. In the Conduit Artery Function Evaluation study, different blood pressure-lowering treatment regimens had different effects on central aortic pressures, despite similar effects on brachial pressure. 28 The use of both peripheral and central aortic assessments may be more sensitive for detecting cardiovascular disease than cuff blood pressure alone and is increasingly more common in office practice. Future pharmacological treatments are most likely to affect the early mechanisms of vascular disease and focus on reducing arterial stiffness. Clearly, renin-angiotensin system blockade protects against cardiovascular events and reduces mortality, as demonstrated by the success of the angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in clinical trials. However, pharmacological renin-angiotensin blockade is possible at other reninangiotensin sites as well. 29 A promising new strategy is the direct inhibition of renin, which catalyzes the first, ratelimiting step in the renin-angiotensin system pathway. Although a number of renin inhibitors were developed in the past 2 decades, they were not clinically useful drugs because of poor pharmacokinetics and potency. Encouraging results have recently been reported with aliskiren, the first representative of a new class of nonpeptide, orally active renin inhibitors that was recently approved by the United States Food and Drug Administration as monotherapy or in combination with other antihypertensive agents. 29 Clinical data have demonstrated that once-daily aliskiren achieves dosedependent reductions in plasma renin activity and systolic blood pressure over 4-week 30 and 8-week study periods with no rebound effects on blood pressure after treatment withdrawal. 31 Additionally, aliskiren is safe and well tolerated in the patient populations assessed. 30,31 Recently, the first large-scale study designed to assess the effects of dual renin system blockade with the direct renin inhibitor aliskiren and the angiotensin receptor blocker valsartan versus each drug alone in 1797 patients with mild-to-moderate (stage 1-2) diastolic hypertension was published. 32 Aliskiren in combination with valsartan significantly lowered mean sitting systolic and diastolic blood pressure compared with either agent alone in this patient population. Currently, there is an ongoing clinical trial, the AGELESS trial, assessing the efficacy of aliskiren compared with ramipril in systolic hypertension in patients aged 65 years. Additional studies are ongoing and continue to explore the safety and efficacy of aliskiren, as well as other renin inhibitors, and also the possibility of inhibiting multiple steps in the renin-angiotensin system with combination therapies. CONCLUSION Systolic hypertension is the most frequent type of hypertension in the elderly. Age-related changes in arterial stiffness and systolic hypertension are strongly associated with organ damage, cardiac and vascular disease, and an increased risk of morbidity and mortality. Although treatment of systolic hypertension in older adults has resulted in substantial reductions in mortality and cardiovascular events, current hypertension control rates remain disappointing. The renin-angiotensin system plays a significant role in the pathogenesis and progression of systolic hypertension. Currently, there is a good scientific rationale for using agents that act on the renin-angiotensin system in the treatment of systolic hypertension, and ongoing studies are investigating the best use of these agents alone and in combination. New definitions for hypertension may serve to better identify elderly patients who are at higher cardiovascular risk and may be candidates for early intervention. Better tools, such as ambulatory blood pressure monitoring, are becoming more readily available to accurately assess and monitor hypertension. Ongoing large-scale studies are assessing the effects of various classes of antihypertensive agents on the vascular tree beyond just lowering blood pressure and may lead to improved treatment algorithms for isolated systolic hypertension in the elderly. References 1. Franklin SS, Jacobs MJ, Wong ND, et al. 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184 The American Journal of Medicine, Vol 121, No 3, March 2008 12. Vogt L, Navis G, Koster J, et al. The angiotensin II receptor antagonist telmisartan reduces urinary albumin excretion in patients with isolated systolic hypertension: results of a randomized, double-blind, placebocontrolled trial. J Hypertens. 2005;23:2055-2061. 13. Chobanian AV, Bakris GL, Black HR, et al. 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. 14. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA. 1991;265:3255-3264. 15. Kostis JB, Wilson AC, Freudenberger RS, et al. Long-term effect of diuretic-based therapy on fatal outcomes in subjects with isolated systolic hypertension with and without diabetes. Am J Cardiol. 2005; 95:29-35. 16. Sutton-Tyrrell K, Wildman R, Newman A, Kuller LH. Extent of cardiovascular risk reduction associated with treatment of isolated systolic hypertension. Arch Intern Med. 2003;163:2728-2731. 17. Staessen JA, Fagard R, Thijs L, et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet. 1997;350:757-764. 18. Liu L, Wang JG, Gong L, et al, for the Systolic Hypertension in China (Syst-China) Collaborative Group. Comparison of active treatment and placebo in older Chinese patients with isolated systolic hypertension. J Hypertens. 1998;16:1823-1829. 19. Staessen JA, Gasowski J, Wang JG, et al. Risks of untreated and treated isolated systolic hypertension in the elderly: meta-analysis of outcome trials. Lancet. 2000;355:865-872. 20. Kjeldsen SE, Dahlof B, Devereux RB, et al. Effects of losartan on cardiovascular morbidity and mortality in patients with isolated systolic hypertension and left ventricular hypertrophy: a Losartan Intervention for Endpoint Reduction (LIFE) substudy. JAMA. 2002;288: 1491-1498. 21. Lithell H, Hansson L, Skoog I, et al. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens. 2003;21:875-886. 22. Malacco E, Mancia G, Rappelli A, et al. Treatment of isolated systolic hypertension: the SHELL study results. Blood Press. 2003; 12:160-167. 23. Mancia G, Ruilope LM, Palmer CR, et al. Effects of nifedipine GITS and diuretics in isolated systolic hypertension a subanalysis of the INSIGHT study. Blood Press. 2004;13:310-315. 24. Malacco E, Vari N, Capuano V, et al. A randomized, double-blind, active-controlled, parallel-group comparison of valsartan and amlodipine in the treatment of isolated systolic hypertension in elderly patients: the Val-Syst study. Clin Ther. 2003;25:2765-2780. 25. London G, Schmieder R, Calvo C, Asmar R. Indapamide SR versus candesartan and amlodipine in hypertension: the X-CELLENT Study. Am J Hypertens. 2006;19:113-121. 26. Duprez DA, Cohn JN. Monitoring vascular health beyond blood pressure. Curr Hypertens Rep. 2006;8:287-291. 27. Duprez DA, Somasundaram PE, Sigurdsson G, et al. Relationship between C-reactive protein and arterial stiffness in an asymptomatic population. J Hum Hypertens. 2005;19:515-519. 28. Williams B, Lacy PS, Thom SM, et al. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation. 2006;113:1213-1225. 29. Azizi M, Webb R, Nussberger J, Hollenberg NK. Renin inhibition with aliskiren: where are we now, and where are we going? J Hypertens. 2006;24:243-256. 30. Stanton A, Jensen C, Nussberger J, O Brien E. Blood pressure lowering in essential hypertension with an oral renin inhibitor, aliskiren. Hypertension. 2003;42:1137-1143. 31. Oh B-H, Mitchell J, Herron JR, et al. Aliskiren, an oral renin inhibitor, provides dose-dependent efficacy and sustained 24-hour blood pressure control in patients with hypertension. J Am Coll Cardiol. 2007; 49:1157-1163. 32. Oparil S, Yarows SA, Patel S, et al. Antihypertensive efficacy and safety of dual renin system intervention with aliskiren, an oral direct renin inhibitor, and valsartan: a randomized, double-blind comparison versus monotherapy. Lancet. 2007;370:221-229.

Table 1 Landmark and Recent Clinical Trials in Elderly Patients with Systolic Hypertension Trial Name and Design Patients n SHEP 14 (1991) Randomized, doubleblind, placebo-controlled Mean Age Median Follow-up Mean Initial SBP/DBP (mm Hg) Regimens and End Points 4736 71.6 4.5 170/77 Chlorthalidone with atenolol or reserpine if necessary Primary end point: nonfatal and fatal (total) stroke Secondary end points: cardiovascular morbidity and mortality, dementia, clinical depression and cognitive function, falls and fractures SHEP 15 Extension (2005) 4732 71.6 14.3 170/77 Chlorthalidone with atenolol or reserpine if necessary Primary end point: long-term mortality Syst-Eur 17 (1997) Randomized, doubleblind, placebo-controlled 4695 70.3 2.0 174/86 Nitrendipine combined with or replaced by enalapril, hydrochlorothiazide, or both if necessary Primary end point: Nonfatal and fatal (total) stroke Outcomes Absolute Total stroke: 5.2% (123/2365), treatment group 8.2% (194/ 2371), placebo group All coronary heart disease events: 5.9% (140/2365), treatment group: 7.7% (184/2371), placebo group All fatal and nonfatal cardiovascular events: 12.2% (289/2365), treatment group 17.5% (414/2371), placebo group Depression: 4.4% (104/2365), treatment group 4.7% (112/2371), placebo group No significant difference between groups Cardiovascular mortality: 19% (450/2363), treatment group 22% (515/2369), placebo group Subjects who developed diabetes during treatment had no significant increase in cardiovascular events and had a better prognosis than those who had pre-existing diabetes All stroke: 7.9 events per 1000 patient-years, treatment group 13.7 events per 1000 patientyears, placebo group Nonfatal stroke: 5.7 events per 1000 patient-years, treatment group 10.1 events per 1000 patient-years, placebo group All fatal and nonfatal cardiovascular events: 23.3 events per 1000 patient-years, treatment group 33.9 events per 1000 patientyears, placebo group Relative Total stroke: 36% reduction in the placebo group RR 0.64, 95% CI, 0.50-0.82 P.0003 All coronary heart disease events: 25% reduction in the treatment group compared with the placebo group RR 0.75, 95% CI, 0.60-0.94 All fatal and nonfatal cardiovascular events: 32% reduction in the placebo group RR 0.68, 95% CI, 0.58-0.79 HR 0.854, 95% CI, 0.751-0.972 P.05 All stroke: 42% reduction in the placebo group 95% CI,.17-.60 P.003 Nonfatal stroke: 44% reduction in the placebo group 95% CI,.14-.63 P.007 All fatal and nonfatal cardiovascular events: 31% reduction in the placebo group 95% CI,.14-.45 P.001 Duprez Systolic Hypertension in the Elderly 184.e1

Table 1 Continued Trial Name and Design Syst-China 18 (1998) Randomized, single-blind, placebo-controlled LIFE 20 substudy (2002) Randomized, doubleblind, parallel-group Patients n Mean Age Median Follow-up Mean Initial SBP/DBP (mm Hg) Regimens and End Points 2394 66.4 3.0 171/86 Nitrendipine with captopril, hydrochlorothiazide, or both if necessary Primary end point: Nonfatal and fatal (total) stroke 1326 70 4.7 (mean) 174/83 Losartan or atenolol with hydrochlorothiazide if necessary Primary end point: Composite of cardiovascular death, stroke, or myocardial infarction Outcomes Absolute All stroke: 13.0 events per 1000 patient-years, treatment group 20.8 events per 1000 patientyears, placebo group All fatal and nonfatal cardiovascular events: 21.4 events per 1000 patient-years, treatment group 33.3 events per 1000 patient-years, placebo group Total mortality: 17.4 events per 1000 patient-years, treatment group 28.4 events per 1000 patient-years, placebo group Cardiovascular mortality: 9.4 events per 1000 patient-years, treatment group 5.2 events per 1000 patient-years, placebo group Stroke mortality: 2.9 events per 1000 patient-years, treatment group 6.9 events per 1000 patient-years, placebo group Cardiovascular death, stroke, or myocardial infarction: 25.1 events per 1000 patientyears, losartan group 35.4 events per 1000 patient-years, atenolol group Relative All stroke: 38% reduction in treatment group compared with placebo group 95% CI,.09-.58 P.01 All fatal and nonfatal cardiovascular events: 37% reduction in treatment group compared with placebo group 95% CI,.14-.53 P.004 Total mortality: 39% reduction in treatment group compared with placebo group 95% CI,.16-.57 P.003 Cardiovascular mortality: 39% reduction in treatment group compared with placebo group 95% CI,.04-.61 P.03 Stroke mortality: 58% reduction in treatment group compared with placebo group 95% CI,.14-.80 P.02 Cardiovascular death, stroke, or myocardial infarction: 25% reduction with losartan compared with atenolol RR 0.75, 95% CI, 0.56-1.01 P.06 Losartan decreased ECG-LVH more than atenolol (P.001) 184.e2 The American Journal of Medicine, Vol 121, No 3, March 2008

Table 1 Continued Trial Name and Design Patients n SCOPE 21 (2003) Prospective, 4964 double-blind, (30% were randomized, parallelgroup ISH) SHELL 22 (2003) Prospective, open design INSIGHT 23 subanalysis (2004) Prospective, randomized, double-blind Mean Age Median Follow-up Mean Initial SBP/DBP (mm Hg) Regimens and End Points 76.4 3.7 166/90 Candesartan with open-label active antihypertensive therapy added as needed. Primary end points: Major cardiovascular events, a composite of cardiovascular death, nonfatal stroke, and nonfatal myocardial infarction Secondary end points: Cardiovascular death, nonfatal and fatal stroke, and myocardial infarction, cognitive function measured by the MMSE and dementia 1882 72 2.6 178/87 Chlorthalidone or lacidipine Primary end point: composite of cardiovascular and cerebrovascular events 6321 55-80 3.0 173/88 Nifedipine or co-amilozide (with 1498 ISH) (range) (hydrochlorothiazide plus amiloride) with addition of atenolol or enalapril Primary end points: Cardiovascular death, myocardial infarction, heart failure, or stroke Outcomes Absolute First major cardiovascular event: 26.7 events per 1000 patientyears, candesartan group 30.0 events per 1000 patient-years, control group Nonfatal stroke: 7.4 events per 1000 patient-years, candesartan group 10.3 events per 1000 patient-years, control group All stroke: 9.7 events per 1000 patient-years, candesartan group 12.8 events per 1000 patientyears, control group Composite of cardiovascular and cerebrovascular events: 9.4% (88/940), chlorthalidone group 9.6% (90/942), lacidipine group All-cause mortality: 13.0% (122/ 940), chlorthalidone group 15.4% (145/942), lacidipine group Cardiovascular death, myocardial infarction, heart failure, or stroke: Patients with ISH: 6.0% (44/738) nifedipine 6.6% (50/760) co-amilozide Patients without ISH: 6.4% (156/ 2419) nifedipine 5.5% (132/ 2404) co-amilozide Relative First major cardiovascular event: 10.9% reduction with candesartan compared with control 95% CI, 6.0-25.1 P.19 Nonfatal stroke: 27.8% reduction with candesartan compared with control 95% CI, 1.3-47.2 P.04 All stroke: 23.6% reduction with candesartan compared with control 95% CI, 0.7-42.1 P.056 No significant differences were seen in myocardial infarction and cardiovascular mortality. No between-group differences were seen in the proportion of patients who had a significant cognitive decline or who developed dementia Composite of cardiovascular and cerebrovascular events: HR 1.01, 95% CI, 0.75-1.36 P.94 All-cause mortality: HR 1.23, 95% CI, 0.97-1.57 P.09 Cardiovascular death, myocardial infarction, heart failure, or stroke: OR 0.90, 95% CI, 0.59-1.37 P.67 OR 1.19, 95% CI, 0.93-1.51 P.16 SBP systolic blood pressure; DBP diastolic blood pressure; SHEP Systolic Hypertension in the Elderly Program; RR relative risk; CI confidence interval; HR hazards ratio; Syst-Eur Systolic Hypertension in Europe; Syst-China Systolic Hypertension in China; LIFE Losartan Intervention for Endpoint; ECG-LVH electrocardiographic-left ventricular hypertrophy; SCOPE Study on Cognition and Prognosis in the Elderly; ISH isolated systolic hypertension; MMSE Mini Mental State Examination; SHELL Systolic Hypertension in the Elderly Long-term Lacidipine; INSIGHT International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment; OR odds ratio. Duprez Systolic Hypertension in the Elderly 184.e3