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Risk reduction associated with lowering systolic blood pressure: Review of clinical trial data
Risk reduction associated with lowering systolic blood pressure: Review of clinical trial data W. Dallas Hall, MD Atlanta, Ga
Hypertension is very common in adults ≥60 years of age. Isolated systolic hypertension (ISH) in particular is a good predictor of events associated with elevated blood pressure such as stroke, coronary heart disease, and congestive heart failure. Two large studies, the Systolic Hypertension in the Elderly Program (SHEP) and the Systolic Hypertension in Europe study (Syst-Eur), have demonstrated that antihypertensive drug therapy for elderly patients with ISH reduces the risk of stroke and other major cardiovascular events. SHEP demonstrated that antihypertensive drug treatment with a diuretic-based regimen in patients ≥60 years of age with ISH reduced the incidence of total stroke by 36%. SHEP also demonstrated a 32% reduction in the incidence of cardiovascular events for patients receiving active treatment. The 5-year average systolic blood pressure (SBP) was 155 mm Hg in the placebo group (n = 2371) compared with 143 mm Hg for the active treatment group (n = 2365). Results from the recently completed Syst-Eur study also support the benefits of antihypertensive treatment in patients ≥60 years of age with ISH. Active treatment in Syst-Eur consisted of the calcium channel blocker nitrendipine, with the addition of enalapril and hydrochlorothiazide as needed to reduce SBP to <150 mm Hg. In the active treatment group, total stroke decreased by 42%, and all cardiovascular events decreased by 31%. At 2 years, sitting SBP had decreased by 13 mm Hg in the placebo group (n = 2297) compared with 23 mm Hg in the active treatment group (n = 2398). (Am Heart J 1999;138:S225-S230.)
High blood pressure is a massive public health problem associated with significant risk for coronary heart disease, stroke, and all other cardiovascular diseases. While the incidence of hypertension increases with age, data indicate that most people ≥35 years of age have systolic blood pressure/diastolic blood pressure (SBP/DBP) above optimal levels (<120/<80 mm Hg) and are therefore at increased risk for cardiovascular disease.1-3 By middle or old age, SBP is more strongly related to cardiovascular complications than DBP and may be used to predict risk for coronary heart disease, cardiovascular disease, heart failure, stroke, and associated deaths.4,5 In the elderly, isolated systolic hypertension (ISH), defined in the United States as SBP ≥140 mm Hg with DBP <90 mm Hg, is a particularly good predictor of subsequent cardiovascular events. ISH is common in people ≥60 years of age, with a prevalence of >25% among those ≥80 years of age.6 Despite the morbidity, mortality, and disability risks associated with elevated blood pressure and the large proportion of older people with hypertension, the relatively fragile physiologic characteristics of the elderly demand a cautious approach to the use of antihypertensive medication because of concerns that antihypertensive medication could be associated with an increased risk for adverse events in this population.7,8 However, data from large clinical trials have documented the ben-
efits of antihypertensive therapy for elderly people with combined systolic and diastolic hypertension.9-12 The benefits of antihypertensive drug therapy for elderly patients with ISH (including those ≥80 years of age) have been demonstrated in two major trials: the Systolic Hypertension in the Elderly Program (SHEP)13 and the Systolic Hypertension in Europe study (SystEur).14 These trials provide data on 1091 patients ≥80 years of age, representing the majority of all patients ≥80 years of age (approximately 1500) ever reported in published randomized clinical trials of antihypertensive treatment. Taken together, the two studies provide convincing data to indicate that antihypertensive drug treatment reduces the risk of stroke and other major cardiovascular events in patients ≥60 years of age with ISH. Following is a summary of each study, highlighting similarities and differences between the two trials.
Systolic Hypertension in the Elderly Program SHEP was a prospective, randomized, placebo-controlled study designed to assess the effect of antihypertensive drug treatment on the risk of fatal and nonfatal (total) stroke in ISH (defined as SBP >160 mm Hg and DBP <90 mm Hg).
Study population From Emory University School of Medicine. Reprint requests: W. Dallas Hall, MD, Emory University School of Medicine, 1100 Parker Place, Atlanta, GA 30324. E-mail: [email protected] Copyright © 1999 by Mosby, Inc. 0002-8703/99/$8.00 + 0 4/0/100200
Of a total of almost 450,000 individuals identified as possible candidates for the study, 4736 subjects ≥60 years of age were randomly assigned into the trial from 16 centers throughout the United States. The high ratio of screened to enrolled participants is almost entirely
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Figure 1
Table I. Baseline characteristics of participants in the Systolic Hypertension in the Elderly Program and Systolic Hypertension in Europe trial SHEP
Figure not available
n Centers Age (range) Women (%) Age 80+ years, n (%) Diabetes, n (%) DBP threshold Entry BP: Range Mean 180+, n (%) Goal systolic BP HBP drugs (mg/d) Initial Add-on
4736 16 71.6 (60-96) 57% 650 (13.7) 583 (12.3) <90 mm Hg 160-219/<90 170/77 710 (15.0) <160 and 21 mm Hg
Chlorthalidone 12.5-25 Atenolol 25-50 Reserpine 0.05-0.10 Entry heart rate (bpm) 70.8 Entry cholesterol (mmol/L) 6.1 Entry HDL cholesterol 1.4 (mmol/L) Current smokers (%) 12.7 History of CVD, n (%) ~1109 (23.4) History of stroke (%) 1.4 History of myocardial 4.9 infarction (%) ECG abnormality (%) 61.0
Syst-Eur 4695 198 70.2 (60-100) 67% 441 (9.4) 492 (10.5) <95 mm Hg 160-219/<95 174/86 1153 (24.6) <150 and 20 mm Hg Nitrendipine 10-40 Enalapril 5-20 HCTZ 12.5-25 73.0 6.0 1.4 7.3 1402 (29.9) 4.1 11.6 43.8*
SHEP, Systolic Hypertension in the Elderly Program; Syst-Eur, Systolic Hypertension in Europe Study; BP, blood pressure; HBP, high blood pressure; HCTZ, hydrochlorothiazide; HDL, high-density lipoprotein; CVD, cardiovascular disease; ECG, electrocardiogram. *Electrocardiographic changes compatible with left-ventricular hypertrophy.
Figure not available
dial infarction by 5%. Approximately 61% of participants had a baseline electrocardiographic abnormality. As a group they were approximately 30% overweight, and 12.7% were smokers. The mean SBP was 170 mm Hg, and mean DBP was 77 mm Hg (Table I). Goal blood pressure was based on baseline SBP. For individuals with a baseline SBP ≥180 mm Hg, the goal was a reduction to <160 mm Hg. For those with a baseline SBP of 160 to 179 mm Hg, the goal was a reduction of ≥20 mm Hg.
Medication
(90%) the result of nonqualifying levels of blood pressure on serial screening visits rather than selection based on other criteria. Of those enrolled, 57% were women. The mean age of participants was 72 years. A history of stroke was reported by 1.4% and a history of myocar-
Of the total study population of 4736 participants, 3161 (67%) were not taking any antihypertensive medication at the screening visits. A stepped-care program was followed, with active treatments consisting of step 1: chlorthalidone 12.5 mg/d (dose 1), 25 mg/d (dose 2); and step 2: atenolol 25 mg/d (dose 1), 50 mg/d (dose 2). All participants were given chlorthalidone (12.5 mg/d) or matching placebo, with the dosage increased to 25 mg/d for those who failed to achieve SBP goal. If neces-
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Table II. Outcomes of the Systolic Hypertension in the Elderly Program and the Systolic Hypertension in Europe trial
Decrease in blood pressure (SBP/DBP) Placebo Drug therapy Difference Final blood pressure (Drug therapy) Risk reduction Stroke* Cardiac end points† All cardiovascular disease end points* All-cause mortality rate
SHEP
Syst-Eur
P (SHEP/Syst-Eur)
15/5 mm Hg 27/9 mm Hg 12/4 mm Hg ~144/68
13/2 mm Hg 23/7 mm Hg 10/5 mm Hg ~151/78
.001/.001 .001/.001
–36% –25% –32% –13%
–42% –26% –31% –14%
.0003/.003 <.05/.03 <.05/.001 NS/.22
SHEP, Systolic Hypertension in the Elderly Program; Syst-Eur, Systolic Hypertension in Europe Study; SBP, systolic blood pressure; DBP, diastolic blood pressure; NS, not significant. *Fatal and nonfatal. †Included fatal and nonfatal cases of heart failure and myocardial infarction and sudden death.
sary to achieve the goal, atenolol (25 mg/d) or matching placebo was added. If contraindicated, atenolol was substituted with reserpine (0.05 to 0.10 mg/d).
Results Medication At 5 years of follow-up, approximately 50% of participants in the active treatment group were receiving step 1 medication only, and more than two thirds were receiving step 1 and/or step 2 medication only. At the end of the 5-year period, 91% of participants who were randomly assigned to active treatment were receiving antihypertensive therapy. Among participants assigned to placebo, the majority continued to receive no active treatment throughout the 5-year trial period. There was, however, a progressive increase in the percentage of placebo recipients who were prescribed active treatment (from 13% at year 1 to 33% at year 3 and 44% at year 5).
Mean SBP and DBP Compared with baseline levels, a substantial reduction in mean SBP (approximately 27 mm Hg) was observed in the active treatment group. The mean DBP was also lower in the active treatment group (a reduction of 9 mm Hg from baseline). In participants assigned to placebo, mean SBP and DBP levels were also consistently lower than at baseline (15 mm Hg and 5 mm Hg, respectively). However, mean SBP levels were substantially and consistently lower for the active treatment group than for placebo, by approximately 12 mm Hg, and mean DBP was reduced by approximately 4 mm Hg in participants randomly assigned to active treatment compared with placebo (Figure 1). The mean 5-year SBP was 155 mm Hg in the placebo group (n = 2371) compared with 143 mm Hg in the active treatment group (n = 2365).
Incidence of stroke The primary end point of the trial—risk of total stroke (fatal and nonfatal)—was reduced by 36% in the active treatment group (Table II). Cumulative stroke rates at 5 years were 5.2 per 100 participants for the active treatment group and 8.2 per 100 for the placebo group, with the absolute reduction in 5-year risk of stroke calculated to be 30 events per 1000 participants. The cumulative difference in total stroke incidence between active treatment and placebo recipients increased throughout the trial, with significant divergence observed between the respective stroke rate curves after approximately 24 months of treatment (Figure 2). This treatment benefit correlated accurately with predicted responses based on blood pressure measurements and was evident for all study age groups, including those ≥80 years of age.
Secondary end points Both nonfatal and combined fatal and nonfatal cardiovascular events were lower in the active treatment group than in the placebo group. Over the 5-year period, coronary heart disease (fatal and nonfatal) was reduced by 25% in the active treatment group compared with the placebo group (140 vs 184 events, respectively) (Table II). The corresponding 5-year absolute benefit was estimated to be a reduction of 16 events per 1000 participants. Similarly, a 32% reduction in the incidence of cardiovascular disease (fatal and nonfatal) was observed over the 5-year period in patients receiving active treatment compared with those receiving placebo (289 vs 414, respectively) (Table II). The corresponding 5-year absolute benefit was estimated to be a reduction of 55 events per 1000 participants.
Mortality rates Mortality rates were lower in the active treatment group than in the placebo group for deaths from all causes (213 vs 242 deaths), total cardiovascular causes
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Figure 3
and 55 cases of cardiovascular disease. In an American population of 250 million people, this translates into a potential for 24,000 fewer strokes, 44,000 fewer major cardiovascular events, and 84,000 fewer hospital and nursing home admissions in a 5-year period.
Systolic Hypertension in Europe The benefits of antihypertensive treatment in older patients with ISH (≥60 years of age) have also been demonstrated in the Syst-Eur study.14 This trial was conducted from 1989 to 1997 to investigate whether active treatment based primarily on a long-acting dihydropyridine calcium channel blocker could reduce cardiovascular complications of ISH. As in SHEP, the study followed a prospective, randomized, placebo-controlled design, and the primary end point was reduction in the incidence of fatal and nonfatal stroke.
Study population Mean sitting SBP and DBP during the Syst-Eur trial. Reproduced with permission from Staessen JA, Fagard R, Thijs L, et al. Randomised doubled-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997;350:757-64, copyright 1997 by The Lancet, Ltd.
(90 vs 112 deaths), and total coronary causes (59 vs 73 deaths). Mortality rates for neoplastic diseases were similar in active and placebo groups (75 vs 78 deaths, respectively).
Subgroup analyses When the data were analyzed according to various subgroups, defined by sex, age group, race, baseline electrocardiogram, cholesterol level, prior cardiovascular events, and need for atenolol, the active treatment group continued to show benefit over the placebo group, suggesting that the major benefits observed were associated with antihypertensive diuretic therapy.13,15
The population recruited to Syst-Eur was similar to the SHEP participants in terms of overall patient numbers, patient age, and entry SBP. However, differences existed with regard to the baseline pattern of comorbidity represented in each population; a higher proportion (29.9%) of patients in Syst-Eur had a history of prior cardiovascular disease and considerably more patients in this trial (24.6%) had an SBP level ≥180 mm Hg compared with SHEP (Table I). There were fewer smokers in this trial (7.3%) compared with SHEP (12.7%). The duration of follow-up was also different in the two trials, with SHEP participants being followed for almost twice the duration of those in Syst-Eur. In Syst-Eur, the median follow-up was 24 months, compared with an average follow-up of 4.5 years in SHEP. Each trial included a large number of diabetic patients (11% to 12%), with a combined total of 1075 diabetic patients.
Medication
The efficacy of the active treatment regimen was not compromised by adverse events in this elderly population; the incidences of dementia (1.6% active treatment vs 1.9% placebo) and depression (4.4% active treatment vs 4.7% placebo) were comparable in those randomly assigned to active treatment vs placebo.
Of the total study population of 4695, 2508 (53%) had not received previous antihypertensive medication. Active treatment consisted of the long-acting dihydropyridine calcium channel blocker nitrendipine (10 to 40 mg/d), with the addition of enalapril (5 to 20 mg/d), then hydrochlorothiazide (12.5 to 25.0 mg/d) as required to achieve a goal sitting SBP of <150 mm Hg. After 2 years, nitrendipine was the only treatment given to 60% (597 of 1014) of patients in the active treatment group, and placebo was the only treatment in 40% (343 of 866) of patients in the control arm.
Public health implications
Mean SBP and DBP
Extrapolation of the data to evaluate reduction in number of events per 1000 patients per 5-year period indicated that active treatment could prevent approximately 30 strokes, 16 cases of coronary artery disease,
Blood pressure responses were similar to those in SHEP. At the median 2-year follow-up, sitting SBP decreased by a mean of 13 mm Hg in the placebo group (n = 2297) compared with 23 mm Hg in the active treat-
Adverse events
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ment group (n = 2398). Mean DBP decreased by 2 mm Hg in the placebo group and 7 mm Hg in the active treatment group (Figure 3). Mean between-group differences in sitting SBP and DBP were 10.1 and 4.5 mm Hg, respectively. At the median 2-year follow-up, target blood pressure levels were achieved by 21.4% of placebo recipients compared with 43.5% of the active treatment group (P < .001).
Hall S229
Figure 4
Incidence of stroke Compared with the placebo group, the incidence of fatal and nonfatal stroke combined—the primary end point of the trial—was decreased in the active treatment group by 42% (P = .003). Nonfatal stroke was reduced by 44% (P = .007). Overall, stroke occurred in 77 placebo recipients and 47 active treatment recipients. As in SHEP, the cumulative incidence of total stroke was significantly different between active treatment and placebo groups (Figure 4).
Secondary end points Nonfatal cardiac end points were decreased by 33% in the active treatment group compared with placebo (P = .03). Fatal and nonfatal cardiac end points combined, including sudden death, were decreased by 26% (P = .03). Similarly, all fatal and nonfatal cardiovascular end points were reduced by 31% (P < .001) in patients assigned to active treatment compared with those assigned to placebo (Table II). In the active treatment group, reductions were also seen in heart failure (nonfatal 36%, P = .06) and in fatal and nonfatal myocardial infarction (30%, P = .12). In view of previous reports of an association between the use of calcium blockers and an increased risk for complications such as gastrointestinal bleeding and cancer in the elderly,7,8 the occurrence of any such events was closely monitored in the trial. The incidence of cancer, benign neoplasm, and bleeding and the rates of non–cardiovascular intercurrent diseases occurred with a similar incidence in active treatment and placebo groups.
Mortality rates There were fewer deaths from cardiovascular causes in the active treatment group compared with placebo (77 placebo vs 59 active treatment; 27%, P = .07). Allcause mortality rates were not significantly different between the two groups (137 deaths in the placebo group vs 123 in the active treatment group, P = .22). Previous case-control and observational studies have questioned the safety of calcium channel blockers as first-line antihypertensive agents in the elderly.7,8,16,17 However, there were no differences in noncardiovascular death rates or the rate of cancer or bleeding between the active treatment and placebo groups in the Syst-Eur study.
Cumulative fatal plus nonfatal stroke rate in active treatment and placebo groups during the Syst-Eur trial. Reproduced with permission from 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;350:757-64, copyright 1997 by The Lancet, Ltd.
Public health implications On the basis of the event rates observed in the placebo group, the data collected in this trial indicate that treatment of 1000 elderly patients with ISH for 5 years could prevent 29 strokes or 53 major cardiovascular events.
Summary The findings of two of the largest clinical trials of treatment for ISH document the clinical benefits of lowering elevated SBP to reduce the risk of cardiovascular events in elderly patients, including those ≥80 years of age. Both SHEP and Syst-Eur provide evidence that ISH should be treated in this population. The trials, which evaluated first-line antihypertensive agents of different classes (diuretics and calcium channel blockers), produced comparable results despite some differences in study design, entry levels of blood pressure, and duration of follow-up. Between-group differences for stroke and myocardial infarction in particular were similar across the two trials (stroke: 36% reduction in SHEP, 42% reduction in Syst-Eur; myocardial infarction: 33% reduction in SHEP, 30% reduction in Syst-Eur). Although there were initial concerns regarding the benefit of antihypertensive therapy in SHEP,18-21 the stepped-care program demonstrated striking efficacy in the elderly population studied, preventing stroke and multiple other end points, including cardiac and cardiovascular events, without major adverse events. Given the high incidence of ISH in the elderly and the significant relations demonstrated between elevated SBP
S230 Hall
and cardiovascular disease in this population,1-3 the findings of SHEP and Syst-Eur are of considerable importance. Antihypertensive therapy with first-line agents of different classes has shown great potential for reducing the significant morbidity and mortality rates associated with stroke and other cardiovascular complications in individuals ≥60 years of age with ISH, without increasing the risk for major adverse events.
References 1. Some risk factors related to the annual incidence of cardiovascular disease and death using pooled repeated biennial measurements. In: Kannel WB, Wolf PA, Garrison RJ, editors. Framingham Heart Study, 30-year follow-up. Bethesda, Md: National Institutes of Health; 1987, publication NIH 87-2703. 2. Wilson PW, Anderson KM, Castelli WP. Twelve-year incidence of coronary heart disease in middle-aged adults during the era of hypertensive therapy: the Framingham Offspring Study. Am J Med 1991;90:11-6. 3. Neaton JD, Wentworth D. Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease: overall findings and differences by age for 316,099 white men: Multiple Risk Factor Intervention Trial (MRFIT). Arch Intern Med 1992;152:56-64. 4. Sagie A, Larson MG, Levy D. The natural history of borderline isolated systolic hypertension. N Engl J Med 1993;329:1912-7. 5. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1997;157:2413-46. 6. Staessen J, Amery A, Fagard R. Isolated systolic hypertension in the elderly. J Hypertens 1990;8:393-405. 7. Pahor M, Guralnik JM, Furberg CD, et al. Risk of gastrointestinal haemorrhage with calcium antagonists in hypertensive persons over 67 years old. Lancet 1996;347:1061-5. 8. Pahor M, Guralnik JM, Ferrucci L, et al. Calcium- channel blockade and incidence of cancer in aged populations. Lancet 1996;348:493-7. 9. Coope J, Warrender TS. Randomised trial of treatment of hypertension in elderly patients in primary care. Br Med J 1986;293:1145-51.
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10. Dahlöf B, Lindholm LH, Hansson L, et al. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lancet 1991;338:1281-5. 11. Lindholm LH, Hansson L, Dahlöf B, et al. The Swedish Trial in Old Patients with Hypertension-2 (STOP-Hypertension-2): a progress report. Blood Press 1996;5:300-4. 12. Ekbom T, Dahlöf B, Hansson L, et al. Antihypertensive efficacy and side effects of three beta-blockers and a diuretic in elderly hypertensives: a report from the STOP-Hypertension study. J Hypertens 1992;10:1525-30. 13. 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;265:3255-64. 14. 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;350:757-64. 15. Kostis JB, Berge KG, Davis BR, et al, for the SHEP Cooperative Research Group. Effect of atenolol and reserpine on selected events in the Systolic Hypertension in the Elderly Program (SHEP). Am J Hypertens 1995;8:1147-53. 16. Furberg CD, Psaty BM, Meyer JV. Nifedipine: dose- related increase in mortality in patients with coronary heart disease. Circulation 1995;92:1326-31. 17. Psaty BM, Heckbert SR, Koepsell TD, et al. The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA 1995;274:620-5. 18. Kaplan NM. Systolic Hypertension in the Elderly Program (SHEP) and Swedish Trial in Old Patients with Hypertension (STOP): the promises and the potential problems. Am J Hypertens 1992;5:331-4. 19. Ménard J, Day M, Chatellier G, et al. Some lessons from Systolic Hypertension in the Elderly Program (SHEP). Am J Hypertens 1992;5:325-30. 20. Staessen J, Fagard R, Amery A. Isolated systolic hypertension in the elderly: implications of SHEP for clinical practice and for the ongoing trials. J Hum Hypertens 1991;5:469-74. 21. Staessen JA, Amery A, Birkenhäger W. Inverse association between baseline pressure and benefit from treatment in isolated systolic hypertension. Hypertension 1994;23:269-70.
Hypertension is very common in adults ≥60 years of age. Isolated systolic hypertension (ISH) in particular is a good predictor of events associated with elevated blood pressure such as stroke, coronary heart disease, and congestive heart failure. Two large studies, the Systolic Hypertension in the Elderly Program (SHEP) and the Systolic Hypertension in Europe study (Syst-Eur), have demonstrated that antihypertensive drug therapy for elderly patients with ISH reduces the risk of stroke and other major cardiovascular events. SHEP demonstrated that antihypertensive drug treatment with a diuretic-based regimen in patients ≥60 years of age with ISH reduced the incidence of total stroke by 36%. SHEP also demonstrated a 32% reduction in the incidence of cardiovascular events for patients receiving active treatment. The 5-year average systolic blood pressure (SBP) was 155 mm Hg in the placebo group (n = 2371) compared with 143 mm Hg for the active treatment group (n = 2365). Results from the recently completed Syst-Eur study also support the benefits of antihypertensive treatment in patients ≥60 years of age with ISH. Active treatment in Syst-Eur consisted of the calcium channel blocker nitrendipine, with the addition of enalapril and hydrochlorothiazide as needed to reduce SBP to <150 mm Hg. In the active treatment group, total stroke decreased by 42%, and all cardiovascular events decreased by 31%. At 2 years, sitting SBP had decreased by 13 mm Hg in the placebo group (n = 2297) compared with 23 mm Hg in the active treatment group (n = 2398). (Am Heart J 1999;138:S225-S230.)
High blood pressure is a massive public health problem associated with significant risk for coronary heart disease, stroke, and all other cardiovascular diseases. While the incidence of hypertension increases with age, data indicate that most people ≥35 years of age have systolic blood pressure/diastolic blood pressure (SBP/DBP) above optimal levels (<120/<80 mm Hg) and are therefore at increased risk for cardiovascular disease.1-3 By middle or old age, SBP is more strongly related to cardiovascular complications than DBP and may be used to predict risk for coronary heart disease, cardiovascular disease, heart failure, stroke, and associated deaths.4,5 In the elderly, isolated systolic hypertension (ISH), defined in the United States as SBP ≥140 mm Hg with DBP <90 mm Hg, is a particularly good predictor of subsequent cardiovascular events. ISH is common in people ≥60 years of age, with a prevalence of >25% among those ≥80 years of age.6 Despite the morbidity, mortality, and disability risks associated with elevated blood pressure and the large proportion of older people with hypertension, the relatively fragile physiologic characteristics of the elderly demand a cautious approach to the use of antihypertensive medication because of concerns that antihypertensive medication could be associated with an increased risk for adverse events in this population.7,8 However, data from large clinical trials have documented the ben-
efits of antihypertensive therapy for elderly people with combined systolic and diastolic hypertension.9-12 The benefits of antihypertensive drug therapy for elderly patients with ISH (including those ≥80 years of age) have been demonstrated in two major trials: the Systolic Hypertension in the Elderly Program (SHEP)13 and the Systolic Hypertension in Europe study (SystEur).14 These trials provide data on 1091 patients ≥80 years of age, representing the majority of all patients ≥80 years of age (approximately 1500) ever reported in published randomized clinical trials of antihypertensive treatment. Taken together, the two studies provide convincing data to indicate that antihypertensive drug treatment reduces the risk of stroke and other major cardiovascular events in patients ≥60 years of age with ISH. Following is a summary of each study, highlighting similarities and differences between the two trials.
Systolic Hypertension in the Elderly Program SHEP was a prospective, randomized, placebo-controlled study designed to assess the effect of antihypertensive drug treatment on the risk of fatal and nonfatal (total) stroke in ISH (defined as SBP >160 mm Hg and DBP <90 mm Hg).
Study population From Emory University School of Medicine. Reprint requests: W. Dallas Hall, MD, Emory University School of Medicine, 1100 Parker Place, Atlanta, GA 30324. E-mail: [email protected] Copyright © 1999 by Mosby, Inc. 0002-8703/99/$8.00 + 0 4/0/100200
Of a total of almost 450,000 individuals identified as possible candidates for the study, 4736 subjects ≥60 years of age were randomly assigned into the trial from 16 centers throughout the United States. The high ratio of screened to enrolled participants is almost entirely
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Figure 1
Table I. Baseline characteristics of participants in the Systolic Hypertension in the Elderly Program and Systolic Hypertension in Europe trial SHEP
Figure not available
n Centers Age (range) Women (%) Age 80+ years, n (%) Diabetes, n (%) DBP threshold Entry BP: Range Mean 180+, n (%) Goal systolic BP HBP drugs (mg/d) Initial Add-on
4736 16 71.6 (60-96) 57% 650 (13.7) 583 (12.3) <90 mm Hg 160-219/<90 170/77 710 (15.0) <160 and 21 mm Hg
Chlorthalidone 12.5-25 Atenolol 25-50 Reserpine 0.05-0.10 Entry heart rate (bpm) 70.8 Entry cholesterol (mmol/L) 6.1 Entry HDL cholesterol 1.4 (mmol/L) Current smokers (%) 12.7 History of CVD, n (%) ~1109 (23.4) History of stroke (%) 1.4 History of myocardial 4.9 infarction (%) ECG abnormality (%) 61.0
Syst-Eur 4695 198 70.2 (60-100) 67% 441 (9.4) 492 (10.5) <95 mm Hg 160-219/<95 174/86 1153 (24.6) <150 and 20 mm Hg Nitrendipine 10-40 Enalapril 5-20 HCTZ 12.5-25 73.0 6.0 1.4 7.3 1402 (29.9) 4.1 11.6 43.8*
SHEP, Systolic Hypertension in the Elderly Program; Syst-Eur, Systolic Hypertension in Europe Study; BP, blood pressure; HBP, high blood pressure; HCTZ, hydrochlorothiazide; HDL, high-density lipoprotein; CVD, cardiovascular disease; ECG, electrocardiogram. *Electrocardiographic changes compatible with left-ventricular hypertrophy.
Figure not available
dial infarction by 5%. Approximately 61% of participants had a baseline electrocardiographic abnormality. As a group they were approximately 30% overweight, and 12.7% were smokers. The mean SBP was 170 mm Hg, and mean DBP was 77 mm Hg (Table I). Goal blood pressure was based on baseline SBP. For individuals with a baseline SBP ≥180 mm Hg, the goal was a reduction to <160 mm Hg. For those with a baseline SBP of 160 to 179 mm Hg, the goal was a reduction of ≥20 mm Hg.
Medication
(90%) the result of nonqualifying levels of blood pressure on serial screening visits rather than selection based on other criteria. Of those enrolled, 57% were women. The mean age of participants was 72 years. A history of stroke was reported by 1.4% and a history of myocar-
Of the total study population of 4736 participants, 3161 (67%) were not taking any antihypertensive medication at the screening visits. A stepped-care program was followed, with active treatments consisting of step 1: chlorthalidone 12.5 mg/d (dose 1), 25 mg/d (dose 2); and step 2: atenolol 25 mg/d (dose 1), 50 mg/d (dose 2). All participants were given chlorthalidone (12.5 mg/d) or matching placebo, with the dosage increased to 25 mg/d for those who failed to achieve SBP goal. If neces-
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Table II. Outcomes of the Systolic Hypertension in the Elderly Program and the Systolic Hypertension in Europe trial
Decrease in blood pressure (SBP/DBP) Placebo Drug therapy Difference Final blood pressure (Drug therapy) Risk reduction Stroke* Cardiac end points† All cardiovascular disease end points* All-cause mortality rate
SHEP
Syst-Eur
P (SHEP/Syst-Eur)
15/5 mm Hg 27/9 mm Hg 12/4 mm Hg ~144/68
13/2 mm Hg 23/7 mm Hg 10/5 mm Hg ~151/78
.001/.001 .001/.001
–36% –25% –32% –13%
–42% –26% –31% –14%
.0003/.003 <.05/.03 <.05/.001 NS/.22
SHEP, Systolic Hypertension in the Elderly Program; Syst-Eur, Systolic Hypertension in Europe Study; SBP, systolic blood pressure; DBP, diastolic blood pressure; NS, not significant. *Fatal and nonfatal. †Included fatal and nonfatal cases of heart failure and myocardial infarction and sudden death.
sary to achieve the goal, atenolol (25 mg/d) or matching placebo was added. If contraindicated, atenolol was substituted with reserpine (0.05 to 0.10 mg/d).
Results Medication At 5 years of follow-up, approximately 50% of participants in the active treatment group were receiving step 1 medication only, and more than two thirds were receiving step 1 and/or step 2 medication only. At the end of the 5-year period, 91% of participants who were randomly assigned to active treatment were receiving antihypertensive therapy. Among participants assigned to placebo, the majority continued to receive no active treatment throughout the 5-year trial period. There was, however, a progressive increase in the percentage of placebo recipients who were prescribed active treatment (from 13% at year 1 to 33% at year 3 and 44% at year 5).
Mean SBP and DBP Compared with baseline levels, a substantial reduction in mean SBP (approximately 27 mm Hg) was observed in the active treatment group. The mean DBP was also lower in the active treatment group (a reduction of 9 mm Hg from baseline). In participants assigned to placebo, mean SBP and DBP levels were also consistently lower than at baseline (15 mm Hg and 5 mm Hg, respectively). However, mean SBP levels were substantially and consistently lower for the active treatment group than for placebo, by approximately 12 mm Hg, and mean DBP was reduced by approximately 4 mm Hg in participants randomly assigned to active treatment compared with placebo (Figure 1). The mean 5-year SBP was 155 mm Hg in the placebo group (n = 2371) compared with 143 mm Hg in the active treatment group (n = 2365).
Incidence of stroke The primary end point of the trial—risk of total stroke (fatal and nonfatal)—was reduced by 36% in the active treatment group (Table II). Cumulative stroke rates at 5 years were 5.2 per 100 participants for the active treatment group and 8.2 per 100 for the placebo group, with the absolute reduction in 5-year risk of stroke calculated to be 30 events per 1000 participants. The cumulative difference in total stroke incidence between active treatment and placebo recipients increased throughout the trial, with significant divergence observed between the respective stroke rate curves after approximately 24 months of treatment (Figure 2). This treatment benefit correlated accurately with predicted responses based on blood pressure measurements and was evident for all study age groups, including those ≥80 years of age.
Secondary end points Both nonfatal and combined fatal and nonfatal cardiovascular events were lower in the active treatment group than in the placebo group. Over the 5-year period, coronary heart disease (fatal and nonfatal) was reduced by 25% in the active treatment group compared with the placebo group (140 vs 184 events, respectively) (Table II). The corresponding 5-year absolute benefit was estimated to be a reduction of 16 events per 1000 participants. Similarly, a 32% reduction in the incidence of cardiovascular disease (fatal and nonfatal) was observed over the 5-year period in patients receiving active treatment compared with those receiving placebo (289 vs 414, respectively) (Table II). The corresponding 5-year absolute benefit was estimated to be a reduction of 55 events per 1000 participants.
Mortality rates Mortality rates were lower in the active treatment group than in the placebo group for deaths from all causes (213 vs 242 deaths), total cardiovascular causes
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Figure 3
and 55 cases of cardiovascular disease. In an American population of 250 million people, this translates into a potential for 24,000 fewer strokes, 44,000 fewer major cardiovascular events, and 84,000 fewer hospital and nursing home admissions in a 5-year period.
Systolic Hypertension in Europe The benefits of antihypertensive treatment in older patients with ISH (≥60 years of age) have also been demonstrated in the Syst-Eur study.14 This trial was conducted from 1989 to 1997 to investigate whether active treatment based primarily on a long-acting dihydropyridine calcium channel blocker could reduce cardiovascular complications of ISH. As in SHEP, the study followed a prospective, randomized, placebo-controlled design, and the primary end point was reduction in the incidence of fatal and nonfatal stroke.
Study population Mean sitting SBP and DBP during the Syst-Eur trial. Reproduced with permission from Staessen JA, Fagard R, Thijs L, et al. Randomised doubled-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997;350:757-64, copyright 1997 by The Lancet, Ltd.
(90 vs 112 deaths), and total coronary causes (59 vs 73 deaths). Mortality rates for neoplastic diseases were similar in active and placebo groups (75 vs 78 deaths, respectively).
Subgroup analyses When the data were analyzed according to various subgroups, defined by sex, age group, race, baseline electrocardiogram, cholesterol level, prior cardiovascular events, and need for atenolol, the active treatment group continued to show benefit over the placebo group, suggesting that the major benefits observed were associated with antihypertensive diuretic therapy.13,15
The population recruited to Syst-Eur was similar to the SHEP participants in terms of overall patient numbers, patient age, and entry SBP. However, differences existed with regard to the baseline pattern of comorbidity represented in each population; a higher proportion (29.9%) of patients in Syst-Eur had a history of prior cardiovascular disease and considerably more patients in this trial (24.6%) had an SBP level ≥180 mm Hg compared with SHEP (Table I). There were fewer smokers in this trial (7.3%) compared with SHEP (12.7%). The duration of follow-up was also different in the two trials, with SHEP participants being followed for almost twice the duration of those in Syst-Eur. In Syst-Eur, the median follow-up was 24 months, compared with an average follow-up of 4.5 years in SHEP. Each trial included a large number of diabetic patients (11% to 12%), with a combined total of 1075 diabetic patients.
Medication
The efficacy of the active treatment regimen was not compromised by adverse events in this elderly population; the incidences of dementia (1.6% active treatment vs 1.9% placebo) and depression (4.4% active treatment vs 4.7% placebo) were comparable in those randomly assigned to active treatment vs placebo.
Of the total study population of 4695, 2508 (53%) had not received previous antihypertensive medication. Active treatment consisted of the long-acting dihydropyridine calcium channel blocker nitrendipine (10 to 40 mg/d), with the addition of enalapril (5 to 20 mg/d), then hydrochlorothiazide (12.5 to 25.0 mg/d) as required to achieve a goal sitting SBP of <150 mm Hg. After 2 years, nitrendipine was the only treatment given to 60% (597 of 1014) of patients in the active treatment group, and placebo was the only treatment in 40% (343 of 866) of patients in the control arm.
Public health implications
Mean SBP and DBP
Extrapolation of the data to evaluate reduction in number of events per 1000 patients per 5-year period indicated that active treatment could prevent approximately 30 strokes, 16 cases of coronary artery disease,
Blood pressure responses were similar to those in SHEP. At the median 2-year follow-up, sitting SBP decreased by a mean of 13 mm Hg in the placebo group (n = 2297) compared with 23 mm Hg in the active treat-
Adverse events
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ment group (n = 2398). Mean DBP decreased by 2 mm Hg in the placebo group and 7 mm Hg in the active treatment group (Figure 3). Mean between-group differences in sitting SBP and DBP were 10.1 and 4.5 mm Hg, respectively. At the median 2-year follow-up, target blood pressure levels were achieved by 21.4% of placebo recipients compared with 43.5% of the active treatment group (P < .001).
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Figure 4
Incidence of stroke Compared with the placebo group, the incidence of fatal and nonfatal stroke combined—the primary end point of the trial—was decreased in the active treatment group by 42% (P = .003). Nonfatal stroke was reduced by 44% (P = .007). Overall, stroke occurred in 77 placebo recipients and 47 active treatment recipients. As in SHEP, the cumulative incidence of total stroke was significantly different between active treatment and placebo groups (Figure 4).
Secondary end points Nonfatal cardiac end points were decreased by 33% in the active treatment group compared with placebo (P = .03). Fatal and nonfatal cardiac end points combined, including sudden death, were decreased by 26% (P = .03). Similarly, all fatal and nonfatal cardiovascular end points were reduced by 31% (P < .001) in patients assigned to active treatment compared with those assigned to placebo (Table II). In the active treatment group, reductions were also seen in heart failure (nonfatal 36%, P = .06) and in fatal and nonfatal myocardial infarction (30%, P = .12). In view of previous reports of an association between the use of calcium blockers and an increased risk for complications such as gastrointestinal bleeding and cancer in the elderly,7,8 the occurrence of any such events was closely monitored in the trial. The incidence of cancer, benign neoplasm, and bleeding and the rates of non–cardiovascular intercurrent diseases occurred with a similar incidence in active treatment and placebo groups.
Mortality rates There were fewer deaths from cardiovascular causes in the active treatment group compared with placebo (77 placebo vs 59 active treatment; 27%, P = .07). Allcause mortality rates were not significantly different between the two groups (137 deaths in the placebo group vs 123 in the active treatment group, P = .22). Previous case-control and observational studies have questioned the safety of calcium channel blockers as first-line antihypertensive agents in the elderly.7,8,16,17 However, there were no differences in noncardiovascular death rates or the rate of cancer or bleeding between the active treatment and placebo groups in the Syst-Eur study.
Cumulative fatal plus nonfatal stroke rate in active treatment and placebo groups during the Syst-Eur trial. Reproduced with permission from 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;350:757-64, copyright 1997 by The Lancet, Ltd.
Public health implications On the basis of the event rates observed in the placebo group, the data collected in this trial indicate that treatment of 1000 elderly patients with ISH for 5 years could prevent 29 strokes or 53 major cardiovascular events.
Summary The findings of two of the largest clinical trials of treatment for ISH document the clinical benefits of lowering elevated SBP to reduce the risk of cardiovascular events in elderly patients, including those ≥80 years of age. Both SHEP and Syst-Eur provide evidence that ISH should be treated in this population. The trials, which evaluated first-line antihypertensive agents of different classes (diuretics and calcium channel blockers), produced comparable results despite some differences in study design, entry levels of blood pressure, and duration of follow-up. Between-group differences for stroke and myocardial infarction in particular were similar across the two trials (stroke: 36% reduction in SHEP, 42% reduction in Syst-Eur; myocardial infarction: 33% reduction in SHEP, 30% reduction in Syst-Eur). Although there were initial concerns regarding the benefit of antihypertensive therapy in SHEP,18-21 the stepped-care program demonstrated striking efficacy in the elderly population studied, preventing stroke and multiple other end points, including cardiac and cardiovascular events, without major adverse events. Given the high incidence of ISH in the elderly and the significant relations demonstrated between elevated SBP
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and cardiovascular disease in this population,1-3 the findings of SHEP and Syst-Eur are of considerable importance. Antihypertensive therapy with first-line agents of different classes has shown great potential for reducing the significant morbidity and mortality rates associated with stroke and other cardiovascular complications in individuals ≥60 years of age with ISH, without increasing the risk for major adverse events.
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10. Dahlöf B, Lindholm LH, Hansson L, et al. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lancet 1991;338:1281-5. 11. Lindholm LH, Hansson L, Dahlöf B, et al. The Swedish Trial in Old Patients with Hypertension-2 (STOP-Hypertension-2): a progress report. Blood Press 1996;5:300-4. 12. Ekbom T, Dahlöf B, Hansson L, et al. Antihypertensive efficacy and side effects of three beta-blockers and a diuretic in elderly hypertensives: a report from the STOP-Hypertension study. J Hypertens 1992;10:1525-30. 13. 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;265:3255-64. 14. 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;350:757-64. 15. Kostis JB, Berge KG, Davis BR, et al, for the SHEP Cooperative Research Group. Effect of atenolol and reserpine on selected events in the Systolic Hypertension in the Elderly Program (SHEP). Am J Hypertens 1995;8:1147-53. 16. Furberg CD, Psaty BM, Meyer JV. Nifedipine: dose- related increase in mortality in patients with coronary heart disease. Circulation 1995;92:1326-31. 17. Psaty BM, Heckbert SR, Koepsell TD, et al. The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA 1995;274:620-5. 18. Kaplan NM. Systolic Hypertension in the Elderly Program (SHEP) and Swedish Trial in Old Patients with Hypertension (STOP): the promises and the potential problems. Am J Hypertens 1992;5:331-4. 19. Ménard J, Day M, Chatellier G, et al. Some lessons from Systolic Hypertension in the Elderly Program (SHEP). Am J Hypertens 1992;5:325-30. 20. Staessen J, Fagard R, Amery A. Isolated systolic hypertension in the elderly: implications of SHEP for clinical practice and for the ongoing trials. J Hum Hypertens 1991;5:469-74. 21. Staessen JA, Amery A, Birkenhäger W. Inverse association between baseline pressure and benefit from treatment in isolated systolic hypertension. Hypertension 1994;23:269-70.