The Systolic Hypertension in the Elderly Program (SHEP): An Intervention Trial on Isolated Systolic Hypertension

The Systolic Hypertension in the Elderly Program (SHEP) is a randomized double-blind placebo-controlled trial to determine if antihypertensive treatment of isolated systolic hypertension (ISH) [systolic blood pressure (SBP)≥160 mmHg, diastolic blood pressure (DBP)<90 mmHg] reduces the 5 year incidence of fatal and nonfatal stroke. Between March 1, 1985 and January 15, 1988, 4736 persons (target 4800) with ISH, age 60 years and over, were enrolled. Potential participants met blood pressure (BP) and age criteria. Those on antihypertensive medication prior to enrollment without documented diastolic hypertension had their medication tapered and discontinued, and then met BP criteria (33% of cohort).

Stepped-care therapy with chlorthalidone and atenolol (alternative, reserpine) or matching placebos was initiated as first and second steps. At baseline the trial population was 43.1% male, 56.9% female; 13.9% black, 86.1% non-black. Also, the mean age was 71.6 years; the mean SBP was 170.3 mmHg and the mean DBP was 76.6 mmHg; 59.8% had codeable resting electrocardiographic abnormalities. The trial is now in follow-up phase with scheduled termination in 1991.     

Prevalence of postural hypotension at baseline in the Systolic Hypertension in the Elderly Program (SHEP) cohort.

OBJECTIVE: The objective of this study was to examine the prevalence and correlates of postural hypotension (defined as a drop in systolic blood pressure of greater than or equal to 20 mm Hg) in a cohort of elderly persons with isolated systolic hypertension (ISH). DESIGN: Baseline cross-sectional analysis of the 4,736 persons randomized in the Systolic Hypertension in the Elderly Program (SHEP). SETTING: A randomized multi-center double-blind outpatient clinical trial of the impact of treating ISH. PARTICIPANTS: Men and women age greater than or equal to 60 years with the systolic blood pressure (SBP) greater than or equal to 160 mm Hg and diastolic blood pressure (DBP) less than 90 mm Hg. MEASURES: Medical histories were obtained using interviewer-administered, standardized clinical history forms. At entry into the study, seated and standing BP was measured by certified BP technicians using a random zero sphygmomanometer. Postural hypotension (PH) was assessed at 1 and 3 minutes after the participant arose from a seated position. MAIN RESULTS: PH was found in 10.4% of participants at 1 minute and in 12.0% of participants at 3 minutes. 5.3% of participants demonstrated PH at both time intervals while 17.3% demonstrated PH at either or both of the time intervals. Factors significantly (P less than 0.05) associated with the presence of PH were higher mean SBP and a lower mean body mass index. CONCLUSIONS: Somewhat different persons were defined as having PH based upon the 1 minute and 3 minute standing measures of BP, and prevalence estimates of PH can vary depending on whether one or more intervals of measurement are used. Cross-sectional data analysis indicated that PH, in healthy community-dwelling older persons with ISH, may not be associated with a history of disorders or problems usually thought to be related to PH. However, prospective data are needed to determine the prognostic significance of PH, and whether one or multiple measurements carry more significance.     

Serum uric acid, diuretic treatment and risk of cardiovascular events in the Systolic Hypertension in the Elderly Program (SHEP)

OBJECTIVE: To assess longitudinally the association of serum uric acid and its change due to diuretic treatment with cardiovascular events in hypertensive patients. DESIGN: Cohort study in a randomized trial. SETTING: Cohort of hypertensive patients. PARTICIPANTS: A total of 4327 men and women, aged > or = 60 years, with isolated systolic hypertension, randomized to placebo or chlorthalidone, with the addition of atenolol or reserpine if needed, were observed for 5 years. MAIN OUTCOME MEASURES: Major cardiovascular events, coronary events, stroke and all-cause mortality. RESULTS: Cardiovascular event rates for quartiles of baseline serum uric acid were: I, 32.7 per 1000 person-years; II, 34.5 per 1000 person-years; III, 38.1 per 1000 person-years; and IV, 41.4 per 1000 person-years (P for trend = 0.02). The adjusted hazard ratio (HR), of cardiovascular events for the highest quartile of serum uric acid versus the lowest quartile was 1.32 (95% CI, 1.03-1.69). The benefit of active treatment was not affected by baseline serum uric acid. After randomization, an increase of serum uric acid < 0.06 mmol/l (median change) in the active treatment group was associated with a HR of 0.58 (0.37-0.92) for coronary events compared with those with a serum uric acid increase > or = 0.06 mmol/l. This difference was not explained by blood pressure effects. Those with a serum uric acid increase > or = 0.06 mmol/l in the active treatment group had a similar risk of coronary events as the placebo group. CONCLUSIONS: Serum uric acid independently predicts cardiovascular events in older persons with isolated systolic hypertension. Monitoring serum uric acid change during diuretic treatment may help to identify patients who will most benefit from treatment.     

Compliance to treatment for hypertension in elderly patients: the SHEP pilot study. Systolic Hypertension in the Elderly Program

Assessing the compliance of people over 60 years of age and older with an antihypertensive treatment regimen was a major objective of the Systolic Hypertension in the Elderly Program (SHEP) pilot study. The study randomized 551 men and women over the age of 60 (mean age = 72 years) to a stepped care treatment that included chlorthalidone or placebo in a double-blind trial. Three measures of compliance to treatment protocol--pill count, self-report, and a urine chlorthalidone assay--all indicated high levels of compliance in 80 to 90% of participants at 3 months and 1 year after randomization. Pill-taking compliance was similar in the active and placebo groups, although the rate of discontinuance from study medications at 1 year was higher in the placebo than in the active group. Compliance was high in all age categories, including those over age 80. These data suggest that elderly patients can achieve high levels of compliance with antihypertensive medications.     

Isolated systolic hypertension in the elderly: implications of Systolic Hypertension in the Elderly Program (SHEP) for clinical practice and for the ongoing trials.

The Systolic Hypertension in the Elderly Program (SHEP) was a double-blind placebo-controlled outcome trial on the treatment of isolated systolic hypertension (systolic pressure: 160-219 mmHg and diastolic pressure less than 90 mmHg). From 447, 921 screenes (age greater than or equal to 60 years) 4,736 patients were randomised. A significant reduction of non-fatal stroke (37%), non-fatal myocardial infarction (33%) and left ventricular failure (54%) was observed in the active treatment group. By contrast, the reduction in transient ischaemic attacks (25%), and in total (13%), cardiovascular (20%), cerebrovascular (29%) and coronary (20%) mortality did not reach a level of statistical significance. SHEP is a landmark trial on the treatment of isolated systolic hypertension (ISH) in the elderly. However, the question to what extent the SHEP results can be extrapolated to clinical practice remains open for debate. Indeed, it is possible that due to selection, the SHEP patients were not entirely representative of the elderly with ISH in the population at large. By contrast with previous intervention studies in elderly patients with combined systolic and diastolic hypertension, the SHEP trail did not demonstrate a significant beneficial effect of antihypertensive treatment on any of the cardiovascular mortality endpoints. Confirmation or rejection of the SHEP results in other trials, including the Syst-Eur study, conducted by the rejection of the SHEP results in other trials, including the Syst-Eur study, conducted by the European Working Party on High Blood Pressure in the Elderly and the Chinese trial in elderly ISH patients, is now awaited.     

Conclusions and Implications of the Systolic Hypertension in the Elderly Program

Isolated systolic hypertension has a higher prevalence with age and an associated excess cardiovascular risk. The Systolic Hypertension in the Elderly Program (SHEP) was a randomized, prospective, double blind clinical trial to assess the efficacy and safety of a antihypertensive regimen based on low dose diuretic therapy in reducing the five year combined incidence of fatal and nonfatal stroke. SHEP demonstrated a significant 36% reduction in stroke incidence. Also, 27% reduction in coronaryheart disease incidence and a 32% reduction in major cardiovascular disease incidencewere achieved. Thebenefits accrued to all subgroups identifiedbased onbaseline age, race, sex, blood pressure, serum cholesterol levels, and ECG abnormalities. A low-dose diuretic regimen should be the initial treatment of choice for most hypertensive patients, based on demonstrated reduction in risk for major cardiovascular events, its safety, acceptanceby patients, and low cost.     

Hypokalemia associated with diuretic use and cardiovascular events in the Systolic Hypertension in the Elderly Program

The treatment of hypertension with high-dose thiazide diuretics results in potassium depletion and a limited benefit for preventing coronary events. The clinical relevance of hypokalemia associated with low-dose diuretics has not been assessed. To determine whether hypokalemia that occurs with low-dose diuretics is associated with a reduced benefit on cardiovascular events, we analyzed data of 4126 participants in the Systolic Hypertension in the Elderly Program (SHEP), a 5-year randomized, placebo-controlled clinical trial of chlorthalidone-based treatment of isolated systolic hypertension in older persons. After 1 year of treatment, 7.2% of the participants randomized to active treatment had a serum potassium <3.5 mmol/L compared with 1% of the participants randomized to placebo (P<0.001). During the 4 years after the first annual visit, 451 participants experienced a cardiovascular event, 215 experienced a coronary event, 177 experienced stroke, and 323 died. After adjustment for known risk factors and study drug dose, the participants who received active treatment and who experienced hypokalemia had a similar risk of cardiovascular events, coronary events, and stroke as those randomized to placebo. Within the active treatment group, the risk of these events was 51%, 55%, and 72% lower, respectively, among those who had normal serum potassium levels compared with those who experienced hypokalemia (P<0.05). The participants who had hypokalemia after 1 year of treatment with a low-dose diuretic did not experience the reduction in cardiovascular events achieved among those who did not have hypokalemia.     

老年单纯收缩期高血压患者左心收缩功能的评价

目的 研究探讨老年单纯收缩期高血压（EISH）血流动力学改变。方法 应用彩色超声多普勒检测30例EISH患者及28例老年健康对照组左心收缩功能及相关血流动力学参。结果 EISH组左心收缩功能指标：SV、CO、EF、CI明显高于对照组,直线相关分析显示EISH组脉压差水平与上述各参数呈显著正相关,r值分别为0．43,0．56,0．46,0．45,同时研究组心率水平明显高于对照组（P＜0．05）。结论 EISH存在显著的血流动力学异常,主要表现在左室收缩功能亢进,长期处于高心排血量及高负荷状态。     

老年单纯收缩期高血压患者左心收缩功能的评价

目的研究探讨老年单纯收缩期高血压(EISH)血流动力学改变。方法应用彩色超声多普勒检测30例EISH患者及28例老年健康对照组左心收缩功能及相关血流动力学参数。结果EISH组左心收缩功能指标SV、CO、EF、CI明显高于对照组,直线相关分析显示EISH组脉压差水平与上述各参数呈显著正相关,r值分别为0.43,0.56,0.46,0.45,同时研究组心率水平明显高于对照组(P<0.05)。结论EISH存在显著的血流动力学异常,主要表现在左室收缩功能亢进,长期处于高心排血量及高负荷状态。     

老年单纯收缩期高血压研究进展

高血压是一个十分严重的公众健康问题,导致心、脑、肾靶器官的损害,最终导致死亡。单纯收缩期高血压是老年高血压最常见的一种类型,随着我国人口的日益老龄化,单纯收缩期高血压日渐增多,其临床治疗中如何平衡降低过高的收缩压而使原本就偏低的舒张压不至于过低,一直是困扰心血管学术界的一大难题。现就老年单纯收缩期高血压近年的流行病学状况、发病机制及治疗进展做一简要概述。     

老年收缩期高血压与无症状性腔隙脑梗塞发病的研究

对老年单纯收缩期高血压腔隙性脑梗塞发病情况进行研究，61例老年收缩期高血压（ISH组）和59例老年对照组（NT组）进行脑CT扫描。两组年龄分别为67.85±5．55和66.85±6.03岁。两组病例均无有相关临床症状和神经定位体征。结果表明腔隙性脑梗塞（LCI）者ISH组占31．11％，NT组占15．25％，两组对比有显著性差异（P＜0.05）。LCI部位两组均以基底节为多见，说明无症状LCI多见于高血压。     

老年单纯收缩期高血压的治疗进展

单纯收缩期高血压是心血管疾病的重要危险因素。大量研究显示,积极控制单纯收缩期高血压可以显著降低不良心血管事件危险性。我国高血压防治指南建议将老年单纯收缩期高血压患者收缩压降低至150 mm Hg以下。生活方式干预是治疗老年单纯收缩期高血压的基石,但多数患者需要降压药物治疗才能使血压达标。对于没有明确并发症的老年单纯收缩期高血压患者,可首选利尿剂、长效钙通道阻滞剂或血管紧张素受体拮抗剂,但对于已经发生靶器官损害者则应根据药物的强制性适应证确定治疗方案。     

The prevention of dementia with antihypertensive treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur) study

BACKGROUND: After the double-blind, placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial ended in February 1997, randomized patients were offered active study medication for a further period of observation. OBJECTIVE: To refine the estimates of the long-term effects of antihypertensive therapy on the incidence of dementia. METHODS: Eligible patients had no dementia and were at least 60 years old. Their systolic blood pressure at entry was 160 to 219 mm Hg, with diastolic blood pressure below 95 mm Hg. Antihypertensive therapy was started immediately after randomization in the active treatment group, but only after termination of the double-blind trial in the control patients. Treatment consisted of nitrendipine (10-40 mg/d), with the possible addition of enalapril maleate (5-20 mg/d), hydrochlorothiazide (12.5-25 mg/d), or both add-on drugs. RESULTS: Median follow-up increased from 2.0 years in the double-blind trial to 3.9 years overall. The incidence of dementia doubled from 32 to 64 cases, 41 of whom had Alzheimer disease. Throughout follow-up, systolic/diastolic blood pressure was 7.0/3.2 mm Hg higher in the 1417 control patients than in the 1485 subjects randomized to active treatment. At the last examination, the blood pressure difference was still 4.2/2.9 mm Hg; 48.1%, 26.4%, and 11.4% of the control patients were taking nitrendipine, enalapril, and/or hydrochlorothiazide, whereas in the active treatment group these proportions were 70.2%, 35.4%, and 18.4%, respectively. Compared with the controls, long-term antihypertensive therapy reduced the risk of dementia by 55%, from 7.4 to 3.3 cases per 1000 patient-years (43 vs 21 cases, P<.001). After adjustment for sex, age, education, and entry blood pressure, the relative hazard rate associated with the use of nitrendipine was 0.38 (95% confidence interval, 0.23-0.64; P<.001). Treatment of 1000 patients for 5 years can prevent 20 cases of dementia (95% confidence interval, 7-33). CONCLUSION: The extended follow-up of Syst-Eur patients reinforces the evidence that blood pressure-lowering therapy initiated with a long-acting dihydropyridine protects against dementia in older patients with systolic hypertension.     

Treatment of Isolated Systolic Hypertension in the Elderly: The Syst-Eur Trial

The Syst-Eur study investigated whether active antihypertensive treatment could reduce cardiovascular complications in elderly patients with isolated systolic hypertension. Patients ≥ 60 years) were randomly assigned to active treatment (n = 2398), i.e. nitrendipine, with the possible addition of enalapril and hydrochlorothiazide, or matching placebos (n = 2297). In the intention-to-treat analysis, the beween-group difference in blood pressure amounted to 10.1/4.5 mm Hg (P < 0.001). Active treatment reduced the total incidence of stroke (primary endpoint) by 42% (P = 0.003), of all cardiac endpoints by 26% (P = 0.03), and of all cardiovascular endpoints combined by 31% (P < 0.001). Cardiovascular mortality was slightly lower on active treatment (-27%; P = 0.07), but all-cause mortality was not influenced (-14%; P = 0.22). For total (P = 0.009) and cardiovascular mortality (P = 0.09), the benefit of antihypertensive treatment weakened with advancing age and for total mortality it decreased with higher systolic blood pressure at entry (P = 0.05). The benefits of active treatment were not independently related to gender or to the presence of cardiovascular complications at entry. Further analyses also suggested benefit in patients who were taking nitrendipine as the sole therapy. The per-protocol analysis largely confirmed the intention-to-treat results. It can be concluded that stepwise antihypertensive drug treatment, starting with the dihydropyridine calcium channel blocker nitrendipine, improves prognosis in elderly patients with isolated systolic hypertension.     

硝酸酯类药物对老年单纯收缩期高血压的有益作用

目的观察硝酸酯类药物对老年单纯收缩期高血压(ISH)患者降压治疗的有益作用.方法87例ISH患者随机分为对照组46例和治疗组41例,对照组给予非洛地平缓释片5 mg,每日一次口服,治疗组在上述治疗的基础上给予加用单硝酸异山梨酯(ISMN)20 mg,每日二次口服,疗程8周.结果(1)治疗组从第2周开始收缩压(SBP)下降幅度即大于对照组,且先于对照组于第4周降至正常,差别有显著性(P＜0.05);(2)从第2周开始治疗组舒张压(DBP)下降幅度即小于对照组(P＜0.05),第6周开始差距进一步加大,差别有显著性(P＜0.01),整个观察期内治疗组DBP下降幅度始终小于对照组,且从第4周开始处于相对稳定状态;(3)第2周开始治疗组PP下降幅度即大于对照组(P＜0.05),第4周开始差距进一步加大,差别有显著性(P＜0.01).结论硝酸酯类药物能降低ISH患者的SBP,而对DBP影响不大,使PP减小,对ISH患者降压治疗的有益.