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.     

Benefit of Antihypertensive Treatment in the diabetic patients enrolled in the Systolic Hypertension in Europe (Syst-Eur) Trial

In this review we attempt to determine the role of calcium channel blockers in preventing cardiovascular sequelae in patients with both hypertension and diabetes mellitus. The data have been collected from three sources: post-hoc analyses of subgroups of diabetic patients in placebo-controlled hypertension trials (SHEP, Syst-Eur, Syst-China); stepped-care blood pressure-oriented trials (HOT, UKPDS); and comparative trials focusing primarily on metabolic aspects and intermediate endpoints (ABCD, FACET).On balance, the data seem to indicate that long-acting calcium channel blockers score remarkably well in preventing cardiovascular complications in diabetic hypertensive patients.     

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.     

Systolic Hypertension in Europe (Syst-Eur) trial phase 2: objectives, protocol, and initial progress. Systolic Hypertension in Europe Investigators

The Systolic Hypertension in Europe (Syst-Eur) trial proved that blood pressure (BP) lowering therapy starting with nitrendipine reduces the risk of cardiovascular complications in older (> or = 60 years) patients with isolated systolic hypertension (systolic BP > or = 160 mm Hg and diastolic BP < 95 mm Hg). After the completion of the Syst-Eur trial on 14 February 1997, 3506 consenting patients (93.0% of those eligible) were enrolled in phase 2 of the Syst-Eur trial. This open follow-up study aims to confirm the safety of long-term antihypertensive therapy based on a dihydropyridine. To lower the sitting systolic BP below 150 mm Hg (target BP), the first-line agent nitrendipine (10-40 mg/day) may be associated with enalapril (5-20 mg/day), hydrochlorothiazide (12.5-25 mg/day), both add-on study drugs, or if required any other antihypertensive agent. On 1 November 1998, 3248 patients were still being followed, 86 patients had proceeded to non-supervised follow-up, and 43 had died. The median follow-up in Syst-Eur 2 was 14.3 months. At the last available visit, systolic/diastolic BP in the patients formerly randomised to placebo (n = 1682) or active treatment (n = 1824), had decreased by 13.2/5.2 mm Hg and by 4.6/1.6 mm Hg, respectively, so that the between-group BP difference was 1.7 mm Hg systolic (95% Ci: 0.8 to 2.6 mm Hg; P < 0.001) and 0.9 mm Hg diastolic (95% Cl: 0.4 to 1.5 mm mm Hg; P < 0.001). At the beginning of Syst-Eur 2, the goal BP was reached by 25.4% and 50.6% of the former placebo and active-treatment groups; at the last visit these proportions were 55.9% and 63.1%, respectively. At that moment, 45.9% of the patients were on monotherapy with nitrendipine, 29.3% took nitrendipine in combination with other study drugs. Until the end of 2001, BP control of the Syst-Eur 2 patients will be further improved. Cardiovascular complications and adverse events, such as cancer or gastro-intestinal bleeding, will be monitored and validated by blinded experts.     

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.     

Systolic Hypertension in the Elderly Program (SHEP): antihypertensive efficacy of chlorthalidone

The Systolic Hypertension in the Elderly Program (SHEP) is a randomized, blinded test of the efficacy of antihypertensive drug treatment. In a large feasibility trial, 551 men and women who had isolated systolic hypertension and were at least 60 years old received chlorthalidone (25 to 50 mg/day) or matching placebo as the step I drug. After 1 year, 83% of the chlorthalidone group and 80% of the placebo group were still taking SHEP medications. Of those still taking chlorthalidone, 88% had reached goal blood pressure (BP) without requiring a step II drug, and most had responded to the lower dose (25 mg/day). The BP response was similar in all age, sex and race subgroups, with an overall mean difference between randomized groups of 17 mm Hg for systolic BP (p less than 0.001) and 6 mm Hg for diastolic BP (p less than 0.001). The only common adverse effects were asymptomatic changes in the serum levels of potassium (0.5 mEq/liter lower in the chlorthalidone group, p less than 0.001), uric acid (0.9 mg/dl higher, p less than 0.001) and creatinine (0.08 mg/dl higher, p = 0.02). This study indicates that chlorthalidone is effective for lowering BP in elderly patients with systolic hypertension and sets the stage for a larger trial of the effects of such treatment on the incidence of cardiovascular disease.     

Risk and benefit of treatment of isolated systolic hypertension in the elderly: evidence from the Systolic Hypertension in Europe Trial.

The Syst-Eur trial investigated whether active treatment starting with the dihydropyridine calcium channel blocker (CCB) nitrendipine, could reduce the cardiovascular complications of isolated systolic hypertension (ISH) in the elderly. The intention-to-treat analysis showed that active treatment improved outcome. The per-protocol analysis largely confirmed these results. The effect of treatment on total and cardiovascular mortality might be attenuated in very old patients. Further analysis also suggested benefit in those patients who remained on nitrendipine monotherapy. Active treatment was more beneficial in patients with diabetes as compared with those without diabetes at entry and reduced the incidence of dementia by 50%. Analyses of data from the Ambulatory Blood Pressure Monitoring (ABPM) Side Project suggested that most of the benefit of treatment was seen in patients with a daytime systolic BP > or = 160 mm Hg. Finally, a meta-analysis partly based on Syst-Eur data showed that in older hypertensive patients pulse pressure and not mean pressure is the major determinant of cardiovascular risk.     

Treatment of isolated systolic hypertension in the elderly: the Syst-Eur trial. Systolic Hypertension in Europe (Syst-Eur) Trial Investigators.

The Syst-Eur study investigated whether active antihypertensive treatment could reduce cardiovascular complications in elderly patients with isolated systolic hypertension. Patients (> or = 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 between-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.     

Hypertension, changes in high-density lipoproteins and antihypertensive therapy

The risk for development of coronary heart disease (CHD) is related to a number of factors. Among these, both hypertension and various lipid abnormalities have been shown to play an important role. A clear inverse relation between high-density lipoprotein (HDL) cholesterol and CHD has been observed in numerous observational and short studies. Pharmacologic treatment of hypertension has been shown to reduce dramatically some of the sequelae of high blood pressure--renal failure, cerebrovascular accidents and congestive heart failure. However, a consistent reduction in associated CHD has not been demonstrated, and the dissociation between reducing blood pressure and reduction in CHD has not been definitively explained. One of the suggested explanations relates to alterations in blood lipid levels that may be induced by certain antihypertensive agents. Changes in HDL cholesterol levels or other lipid alterations due to antihypertensive therapy could modify the beneficial effects achieved by the direct reduction of blood pressure. If so, antihypertensive agents could be subclassified as atherogenic or antiatherogenic depending on the associated changes in lipid levels. Therefore, the antihypertensive agents of choice for patients whose cholesterol levels are a concern would be those that reduce the CHD risk factor of hypertension without compromising the risk factor associated with a patient's lipid profile.     

Comparison of mortality benefit of immediate thrombolytic therapy versus delayed primary angioplasty for acute myocardial infarction

Primary percutaneous coronary intervention (PPCI) yields superior mortality outcomes compared with thrombolysis in ST-elevation acute myocardial infarction (STEMI) but takes longer to administer. Previous meta-regressions have estimated that a procedure-related delay of 60 minutes would nullify the benefits of PPCI on mortality. Using a combined database from randomized clinical trials and registries (n = 2,781) and an independently developed model of mortality risk in STEMI, we developed logistic regression models predicting 30-day mortality for PPCI and thrombolysis by examining the influence of baseline risk on the treatment effect of PPCI and on the hazard of treatment delay. We used these models to solve mathematically for "time interval to mortality equivalence," defined as the PPCI-related delay that would nullify its expected mortality benefit over thrombolysis, and to explore the influence of baseline risk on this value. As baseline risk increases, the relative benefit of PPCI compared with thrombolytic therapy significantly increases (p = 0.002); patients with STEMI at relatively low risk of mortality accrue little or no incremental mortality benefit from PPCI, but high-risk patients benefit greatly. However, as baseline risk increases, the hazard associated with longer treatment-related delay also increases (p = 0.007). These 2 effects are compensatory and yield a roughly uniform time interval to mortality equivalence of approximately 100 minutes in patients who have at least a moderate degree of mortality risk (> approximately 4%). In conclusion, the mortality benefits of PPCI and the hazard of PPCI-related delay depend on baseline risk. Previous meta-regressions appear to have underestimated the PPCI-related delay that would nullify the incremental benefits of PPCI.     

Effects of Isolated Systolic Hypertension and Essential Hypertension on Large and Middle-sized Artery Compliance

Background: Systolic hypertension of the elderly is characterized by a reduction in arterial compliance. Whether and to what extent this involves arteries of various structure and size is not well known. Objective: To study carotid and radial artery compliance in systolic hypertension of the elderly, compared to essential hypertension and normotension. Methods     

Follow-up of renal function in treated and untreated older patients with isolated systolic hypertension. Systolic Hypertension in Europe (Syst-Eur) Trial Investigators

BACKGROUND: In the outcome trials that provided information on renal function in older hypertensive patients, diuretics and beta-blockers were mostly used as first-line drugs. The long-term renal effects of calcium-channel blockers remain unclear. OBJECTIVE: To compare the changes in renal function in 2,258 treated and 2,148 untreated patients with isolated systolic hypertension, of whom 455 had diabetes mellitus and 390 had proteinuria. METHODS: We performed a post-hoc analysis of the double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) Trial. Active treatment was initiated with nitrendipine (10-40 mg/day) with the possible addition of enalapril (5-20 mg/day), hydrochlorothiazide (12.5-25 mg/day), or both, titrated or combined to reduce the sitting systolic blood pressure by at least 20 mmHg, to less than 150 mmHg. The main outcome measures were serum creatinine concentration and creatinine clearance calculated by the formula of Cockroft and Gault. RESULTS: Serum creatinine concentration at the time when participants were randomly allocated to study groups was less than 176.8 micromol/l (2.0 mg/dl), averaging 88 micromol/l. At the time of the last serum creatinine measurement, the blood pressure difference (P< 0.001) between the two groups was 11.6/4.1 mmHg. In the intention-to-treat analysis (11,427 patient-years), serum creatinine and the calculated creatinine clearance were not influenced by active treatment. However, in the patients assigned randomly to receive active treatment, the incidence of mild renal dysfunction (serum creatinine at least 176.8 mmol/l) decreased by 64% (P= 0.04) and that of proteinuria by 33% (P= 0.03). Active treatment reduced the risk of proteinuria more in diabetic than in non-diabetic patients: by 71%, compared with 20% (P= 0.04). In non-proteinuric patients, active treatment did not influence serum creatinine, whereas in patients with proteinuria at entry to the study, serum creatinine decreased on active treatment (P< 0.001). Furthermore, in on-randomized treatment comparison stratified for risk at baseline, serum creatinine concentration did not change (P= 0.98) in patients continuing to receive monotherapy with nitrendipine, whereas it increased by 6.73 mmol/l (P < 0.001) in patients who received hydrochlorothiazide alone or in combination with other study medication (P < 0.001 for difference in trends). CONCLUSIONS: In older patients with isolated systolic hypertension, antihypertensive treatment starting with the dihydropyridine calcium-channel blocker, nitrendipine, did not decrease blood pressure at the expense of renal function and prevented the development of proteinuria, especially in diabetic patients.     

Effects of antihypertensive therapy on hypertensive vascular disease

Hypertension is associated with alterations in the structure, function, and mechanical properties of large and small arteries. Changes in the endothelium, smooth muscle cell, extracellular matrix, and possibly the adventitia, contribute to complications of hypertension. In large arteries, vascular hypertrophy is found, often with increased stiffness of media components. In small arteries, particularly in mild hypertension, rearrangement of smooth muscle cells around a smaller lumen without changes in media volume (eutrophic remodeling) occurs; in more severe hypertension, hypertrophic remodeling with increased vascular stiffness can be found. Vascular remodeling is accompanied by an increase in the extracellular matrix, particularly collagen deposition. Recent studies have demonstrated that vascular remodeling and endothelial dysfunction of small and large vessels may be normalized by treatment with some antihypertensive agents (angiotensin converting enzyme inhibitors, angiotensin AT1 receptor antagonists, and long-acting calcium channel blockers). Angiotensin converting enzyme inhibitors have now been shown to improve outcomes in hypertensive patients, an effect that may in part be related to the vascular protective effects reviewed here.     

Antihypertensive Therapy in Elderly Patients with Isolated Systolic Hypertension: Third Progress Report of the Syst-Eur Trial

The Syst-Eur trial is a randomised, double-blind, placebo-controlled trial that examines the hypothesis that antihyper-tensive treatment can prevent or delay cardiovascular complications in elderly patients (> 60 years) with isolated systolic hypertension. On March, 1st 1993 a total of 1395 patients with a sitting systolic blood pressure on placebo averaging 160–219 mmHg and a diastolic blood pressure < 95 mmHg were randomised into this trial. The placebo and active treatment groups were similar at randomisation with respect to age (7 2 ±7 years, mean ± SD), percentage of women (68%), percentage of patients with cardiovascular complications (30%) and sitting blood pressures (175±12/85±6 mmHg). The fall in sitting systolic and diastolic blood pressures from baseline to 2 years was significantly more pronounced (p<0.001) in the actively treated (-22±18/-6±9 mmHg) as compared with the placebo treated Syst-Eur patients (-10±20/- 1±9 mmHg). Active treatment consists of nitrendipine if necessary associated with a converting-enzyme inhibitor and a thiazide. Whether treatment with these antihypertensive agents results in a clinically meaningful reduction of cardiovascular morbidity and mortality is the subject of investigation in this trial.     

Effects of antihypertensive therapy on sexual activity in hypertensive men

Sexual dysfunction has a high prevalence among hypertensive men, and hypertension per se, regardless of drugs, has been suggested to affect sexual function. The available studies have not clarified which factors play a major role in the pathogenesis of sexual dysfunction in hypertensive men. Neurovascular factors, however, seem to be especially important, (in particular defective nitric oxide activity), although hormonal and psychogenic factors cannot be excluded. Further studies are needed to answer the important question of whether erectile dysfunction seen in hypertension may be one expression of vascular disease and target organ damage. The incidence of sexual dysfunction is exacerbated by antihypertensive drug treatment. There is evidence that some classes of drugs, such as diuretics, centrally acting sympatholitic drugs, and a-blockers have a greater impact on sexual function than other classes, such as calcium antagonists and angiotensin converting enzyme inhibitors. Present evidence on the effects of angiotensin II antagonists is limited, but some data suggest that sexual function in men receiving these drugs not only is not altered, but even improves. Since sexual function is an important aspect of quality of life for the individual, it is important in treating hypertension to ensure that the drugs used have the lowest possible potential for causing sexual problems. This ensures the best balance between therapeutic efficacy and quality of life, which is essential for compliance.