Original Contributions

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).
SHEP Cooperative Research Group

Objective.- To assess the ability of antihypertensive drug treatment to reduce the risk of nonfatal and fatal (total) stroke in isolated systolic hypertension. DESIGN. Multicenter, randomized, double-blind, placebo-controlled. Setting.- Community-based ambulatory population in tertiary care centers. Participants.- 4736 persons (1.06%) from 447,921 screenees aged 60 years and above were randomized (2365 to active treatment, 2371 to placebo). Systolic blood pressure ranged from 160 to 219 mm Hg and diastolic blood pressure was less than 90 mm Hg. Of the participants, 3161 were not receiving antihypertensive medication at initial contact, and 1575 were. The average systolic blood pressure was 170 mm Hg; average diastolic blood pressure, 77 mm Hg. The mean age was 72 years, 57% were women, and 14% were black. Interventions.- Participants were stratified by clinical center and by antihypertensive medication status at initial contact. For step 1 of the trial, dose 1 was chlorthalidone, 12.5 mg/d, or matching placebo; dose 2 was 25 mg/d. For step 2, dose 1 was atenolol, 25 mg/d, or matching placebo; dose 2 was 50 mg/d. Main Outcome Measures.- Primary. - Nonfatal and fatal (total) stroke. Secondary. Cardiovascular and coronary morbidity and mortality, all-cause mortality, and quality of life measures. Results.- Average follow-up was 4.5 years. The 5-year average systolic blood pressure was 155 mm Hg for the placebo group and 143 mm Hg for the active treatment group, and the 5-year average diastolic blood pressure was 72 and 68 mm Hg, respectively. The 5-year incidence of total stroke was 5.2 per 100 participants for active treatment and 8.2 per 100 for placebo. The relative risk by proportional hazards regression analysis was 0.64 (P = .0003). For the secondary end point of clinical nonfatal myocardial infarction plus coronary death, the relative risk was 0.73. Major cardiovascular events were reduced (relative risk, 0.68). For deaths from all causes, the relative risk was 0.87. Conclusion.- In persons aged 60 years and over with isolated systolic hypertension, antihypertensive stepped-care drug treatment with low-dose chlorthalidone as step 1 medication reduced the incidence of total stroke by 36%, with 5-year absolute benefit of 30 events per 1000 participants. Major cardiovascular events were reduced, with 5-year absolute benefit of 55 events per 1000.
(JAMA, 1991;265:3255-3264)

This Article presents the final results of Isolated Systolic Hypertension in the
At the end of this article for a list of the Principal operators of the Systolic Hypertension in the Elderly. requests to Clinical Trials Branch, Division of Dermatology and Clinical Applications, National Lung and Blood Institute, Federal Building, 5C-10B, 7550 Wisconsin Ave, Bethesda, MD (Dr. Jeffrey L. Probstfield)

Elderly Program (SHEP), a double-blind, randomized, placebo-controlled trial of treatment for isolated systolic hypertension (ISH ) in persons 60 years of age and older. The full-scale SHEP study, begun in 1984, set as its primary objective “the determination of whether antihypertensive

drug treatment reduces risk of total stroke (nonfatal and fatal ) in a multi-ethnic cohort of men and women age 60 years and older with ISH.” Previous trials have demonstrated beneficial effects of antihypertensive treatment of diastolic hypertension on major morbidity and mortality, but none has investigated the ability to influence these events for persons 2-21 with ISH. Isolated systolic hypertension is increasingly prevalent with age, especially in those aged 60 years and above. Epidemiologic studies have demonstrated an increase in risk of stroke, other cardiovascular diseases, and death for those with ISH, independent of other risk factors. The SHEP pilot study demonstrated the feasibility of undertaking trials in older people with ISH, including ability to recruit participants. It also established ability of drug therapy to reduce blood pressure among persons with ISH.29 For SHEP, ISH was defined as systolic blood pressure (SBP) greater than 160 mm Hg and diastolic blood pressure (DBP) less than 90 mm Hg, based on the average of four measurements at two baseline visits.1-30 Secondary objectives included assessment of the relationship of antihypertensive treatment to (1) multiple cardiovascular morbidity and mortality end points, including cardiac end points; (2) causespecific and all-cause mortality; (3) multiinfarct dementia, clinical depression, and deterioration of cognitive function; (4) possible adverse effects (5) hospitalizations and intermediate or skilled nursing facility admissions; (6) falls and fractures; and (7) multiple indexes of quality of life.1.30 The SHEP protocol also stipulated two other questions for investigation as subgroup hypotheses 1: (1) Would treatment of ISH reduce the frequency of total stroke (fatal and nonfatal) similarly in those receiving and not receiving
3255

JAMA, June 26, 1991-Vol. 265, No. 24

Prevention of Stroke - SHEP Cooperative Research Group

0.33 (All identified potential participants underwent an initial contact to exclude individuals ineligible by age. No. 12. low serum potassium concentration (<3. or sustained DBP greater than 90 mm Hg. Drug dosage was doubled (including matching placebo) for participants failing to achieve the SBP goal at follow-up visits. eg. At semiannual visits. When the average of four seated blood pressure measurements. consideration was given to resuming drug therapy when it appeared safe. or matching placebo was added as the usual step 2 drug. Potassium supplements were given to all participants who had serum potassium concentrations below 3. For individuals with SBPs greater than 180 mm Hg. If the SBP goal was not reached at the maximal dose of step 1 medication. Blood pressure above a priori escape criteria despite maximal steppedcare therapy was an indication for prescribing known active drug therapy. They were then monitored at multiple drug evaluation visits during a 2. two at each of these visits. (2) Would treatment of ISH reduce the incidence of sudden cardiac death or of coronary death plus nonfatal myocardial infarction similarly in those free of baseline electrocardiographic (ECG) abnormalities and in those with such abnormalities? METHODS The design and methods of SHEP have been reported in detail elsewhere. Baseline SBP (average of four seated blood pressure readings at the first and second baseline visits) was used to establish a goal blood pressure for each participant. All blood pressures during screening and trial follow-up were measured by trained. and when the participant agreed. June 26. or matching placebo (step 1 medication). atenolol. cancer. and had blood drawn. the participant was eligible for the trial.antihypertensive medication at initial control. JAMA. screenees were randomly allocated by the coordinating center to one of two treatment groups.31 They are summarized here. Persons were excluded on the basis of history and/or signs of specified major cardiovascular diseases. certified technicians using standardized techniques with a Hawksley random-zero manometer. the person was eligible for the first baseline visit. were also exclusions. established renal dysfunction. when the participant's blood pressure was above the goal. 1991-Vol.1. blood pressure.2 mmo-l/L).5mg/d. eg. SHEP used primarily mass mailing and community screening techniques. SBP or DBP above the escape criteria (see below). mood.05. Annual visits also included (1) a detailed medical history. or therapy could be discontinued. and a 12-lead ECG was done. When required to reach the blood pressure goal. Eligibility was determined based on study inclusion and exclusion criteria. Escape criteria included SBP greater than 240 mm Hg. When adverse conditions occurred that were considered drug related. Other visits were scheduled when indicated. and other criteria. When atenolol was contraindicated. with no evidence of an underlying nonvascular cause.34 The SBP was defined as the reading at the first Korotkoff sound and DBP as the reading at the last Korotkoff sound. during which they underwent measurement of blood pressure (average of two readings). the dosage of the study medication could be reduced.to 8-week period to determine blood pressure eligibility off medication. heart rate. Sample Size The SHEP design specified a sample size of 4800 participants to test the primary hypothesis. The objective of the stepped-care treatment program was to use the minimal amount of medication to maintain SBP at or below the goal. Other major diseases.30. the goal was a reduction of at least 20 mm Hg. and (4) behavioral assessment. Randomization was stratified by clinical center and by antihypertensive medication status at initial contact. and activities of daily living). with a 2-minute rhythm strip. They were asked to obtain permission from their personal physicians and to sign an informed consent form for drug withdrawal.) sustained SBP greater than 220 mm Hg. The baseline phase consisted of two visits. (3) laboratory tests. Screenees also underwent a physical examination.31) One seated blood pressure reading was taken. All participants were given chlorthalidone. SBP above the goal. All participants had quarterly visits from the date of randomization. after verification of eligibility.5 mmol/L at two consecutive visits.35 signed an additional informed consent form for participation in the trial. Recruitment and Screening For recruitment. Stroke was defined as rapid cause of a new neurologic deficit attributed to obstruction or rupture in the arterial system. Randomization At the completion of the second baseline visit. the goal was a reduction to less than 160 mm Hg.05mg/d. Those remaining eligible at the second baseline visit underwent behavioral assessment (including cognition . with competing risk for the SHEP primary end point or the presence of medical management problems. For persons not receiving anitihypertensive drugs who had a first SBP reading greater than 150 mm Hg. or matching placebo could be substituted. standardized questionnaire were administered to screen for depression and dementia. Follow-up Procedures The SHEP participants were followed up monthly until SBP reached the goal or until the maximum level of stepped-care treatment was reached. 24 was between 160 and 219 mm Hg for SBP and less than 90 mm Hg for DBP. An ECG was also done at the second and final annual visits.SHEP Cooperative Research Group 3256 . (a single visit.37 The defined deficit had to persist for at least 24 hours unless supervened and had to include special localizing findings confirmed by neurologic examination or brain scan. For those with SBPs between 160 and 179 mm Hg. When the mean of the last two readings was between 160 and 219 mm Hg for SBP and less than 100mg Hg for DBP. DBP greater than 115 mm Hg at a single visit. or as requested by the clinician or participant.32 This sample size was used to detect a difference of at least 32% in total stroke incidence with 90% power and a two-sided a of . reserpine. Whenever the dosage was reduced or therapy was discontinued. (2) a complete physical examination. Determination of fatal stroke was Prevention of Stroke . two more readings were taken. Treatment Program Participants were randomozied in a double-blind manner to a once-daily dose of either active drug treatment or matching placebo. 25mg/d. and body weight and a general medical history and detailed review of medication use (prescribed and over the counter) were done. Persons receiving antihypertensive medication at initial contact who had SBPs between 130 and 219 mm Hg and DBPs less than 85 mm Hg and who were free of major illness were eligible for a drug withdrawal procedure. 265. alcoholic liver disease. Ascertainment of End Points Total stroke was the primary end point. the dosage of the step 2 drug could be doubled.

For a neurological the coding panel included two cardiologists. 265. and all cases of death. %§ Baseline electrocardiographic abnormalities.9 1.9 71. ‡ Included among the whites were 204 Orientals (5% of whites). participants were referred for expert diagnostic evaluation31 in accordance with American Psychiatric Association criteria38.2) 76.7 (3. (5) left vertricular failure-a symptom. The behavioral assessment included a questionnaire to detect depression and dementia. § P <.7 4. (4) fatal myocardial infarction-autopsy diagnosis or death certificate diagnosis plus preterional hospitalization. %‡ Black men Black Women White men White Women Education.4 (ST depression).6 (6.6 55. y Average† % 60-69 70-79 ³80 Race-sex. (7) Silent ischemic attack-rapid onset neurologic deficit lasting more than 30 seconds and less than 24 hours.5 (4. Cognitive impairment scale score of 4 or greater.4) 76. with a definite or suspected diagnosis within 4 weeks of death.4 70.1 to 8. For combined end results.4 94.1 7.1 (1.1 to 6.9 37. % Smoking.1 (1.5 (5. or an abnormal physical. 7.7 11. this examination and notes by the attending cardiologist and scans or other studies of brain were forwarded to the coordinating center.4 7.31 # One or more of the following Minnesota codes : 1.1 (1. y† Blood pressure. kg/m2† Serum cholesterol.3 12.2 13.5 11. the panel included at least one cardiologist. (6) other cardiovascular death-presumed myocardial infarction that did not meet diagnostic criteria or other cardiovascular causes.30-31 myocardial infarction left ventricular failure.8 60. .4) 170.3 9. For suspected stroke.5) 27.2) 1. % Carotid bruits. mmol/L† Total High-density lipoprotein Depressive symstoms. Death certificates and autopsy reports were obtained for decendents. For Table 1.4 61.25 % normal). unrelated to other known causes.5 (5.8 47.5 10.9 8.2µmol/L.5 9. % History of stroke.3 (9.5 (9. Possible adverse clinical and biological effects of SHEP treatments were evaluated by (1) using a standardized questionnaire that asked participants questions about side effects at annual visits. A diagnosis of dementia had to be confirmed by the SHEP coding panel.3 7.4 (high R waves).4 (9. assumed to be due to cerebral ischaemia with no evidence of an underlying mascular cause.8 21. plus a chest roentroprogam characteristic of congestive heart failure. 31 Depressive symptom scale score of 7 or greater.6) 33.4 47. No.3 (10. 3.1 44. and at visits at which complaints were thought to be due to SHEP medication and by (2) examining serum chemistry data from annual laboratory evaluations.5 44. including two neurologists.0 * SHEP indicates the Systolic Hypertension in the Elderly Program. data requested included ECGs. Statistical Analyses Comparability of baseline characteristics of the two treatment groups was ascertained by x2 tests for categorical variables and JAMA. but not including silent myocardial infarction. Ocurrence of study events listed was confirmed by a coding panel comprising of physicians blind to randomizaion allocation.5 (miscellaneous items).9 14. Definitions of individual secondary end points were (1) sudden cardiac death-death within 1 hour of of severe cardiac symptoms. % History of diabetes.7 (9.6 (6.5) 170.0 6.7) 41.8 4. 4. Information related to study end results was collected by clinic staff.7 (3.4 (0.5 (6.05 for the active treatment group compared with he placebo group. % Evidence of cognititve impairment.1 to 3.4) 11. (2) rapid cardiac death-death within 1 to 24 hours of the onset of severe cardiac symptoms.6 61.6 50.9 1. (3) nonfatal myocardial infarction-typical symptoms consistent with acute myocardial infarction plus either typical SBG changes (including new Q waves) significant enzyme elevation (1. 24 Prevention of Stroke . % Never Formerly Occasionally Daily or nearly daily History of myocardial infarction. For suspected stroke and transient ischemic stroke.7 Total 4736 71. mm Hg† Systolic Diastolic Antihypertensive medication at initial contact. participants with multiple end results were counted only once. unrealized other known causes.7 38. % Current smokers Past smokers Never smokers Alcohol use.3 (Q QS).7 37.1) 6.4 4. discharge or admission sheets were obtained. and other clinical information.6 10. % Pulse rate.8 (AV conduction defects).1 (9.5) 170.9 7.1 0. a standardized neurological action was carried out by a SHEP cardiologist.4 11.3 (10. (8) coronary artery therapeutic procedurescoronary artery bypass graft or coronary angioplasty and (9) renal dysfunctionserum creatinine concentration greater than 265. such as rales or 2+ (moderate) edema. A diagnosis of depression was not reviewed centrally. June 26.7 (3.7 10.8 (10. such as significant dyspnea.2 21.5 9. 84 Hispanics (2% of whites). beats/min† Body-mass index.7 13.4) 11.SHEP Cooperative Research Group 3257 .0 0.Baseline Characteristics of Randomized SHEP Participants by Treatment Group Characteristic No randomized Age. 1991-Vol.5 12.5 93.3 ande 9. 6.0 4.0) 6.6 49. 5.5) 27. chest reports.8) 33.4 53.5 (arthythmias). %5 No limitation of activities of daily living.0 54.6 36. %# Active Treatment Group 2365 71. 8.9) 6.5 13.based on either autopsy or death certificate plus data on preterminal capitalization with a definite diagnosis of stroke.9 14.4 (T wave changes).1 0.3 38.3 Placebo Group 2371 71.1 to 7.8 (ventricular conduction defects).5) 76.3 95.1 to 4. and 9.4) 11.1 to 9.9 38.8 13. For hospitalizations and nursing admissions.6 47.1) 1.0 4. administered at baseline and semiannually.1 50.1 to 5.5) 27.1 to 1.7 4. † Values are mean (SD).9 1.1 70.8 44. at visits after the administration of study drugs was started or stepped up.7) 41.6 21.0 12.4 (0.6 (9. For participants with suspected myocardial infarction or left ventricular failure.3) 1.4 (0. Based on specified questionnaire score38.7) 41. and 41 classified as “Other” (1% of whites). cardiac enzymes.7) 33.

5 -11.3 (12.4 Year Baseline 1 2 3 4 5 Baseline 1 2 3 4 5 Active Treatment Group Placebo Group Systolic Blood Pressure 170.8) 144.SHEP Cooperative Research Group .3mm Hg.4 90. 265. 90% were excluded because of failure to meet blood pressure criteria. All analyses were by treatment assignment at randomization. 1991-Vol.6 8.1 23. and 14% were black (Table 1).0) 68. of those. 70% were eligible for randomization.0 Year 1 2 3 4 5 * The number of participants drops off in year 4 and 5 mainly due to follow-up time. A Data and Safety Monitoring Board met twice per year to review unblinded data on efficacy and safety.8 53. and 5% reported a history of myocardial infarction.8 58.2) 155. As a group. 447921 individuals aged 60 years and above were identified and contacted. Details of recruitment results have been published elsewhere33. About 61% had an ECG abnormality.9) 73.8) 69.7 Treated with Known Active Drug Only Active Treatment Group 3. .4 70. with a body-mass index averaging 27.6) 76. Cumulative event rates were calculated using life table methods.2 (11. The primary hypothesis was assessed with the logrank test39 using time to first stroke as the variable of interest.5kg/m 2 (almost 30% overweight by actuarial criteria). Baseline Characteristics.4 (17. Power analyses for the sub-group hypotheses have been previously described. A total of 4736 participants were randomized into the trial.5 (17.7% completed baseline visit 1.9) 72.7 38. even if there were no benefit from antihypertensive treatment for the rest of the trial. mm Hg* Difference (Active-Placed) +0.9 62. 27%.6 (19.4 Untreated Active Treatment Group 5. About 3% of active treatment group participant were assigned to receive know active therapy because their blood pressure met the escape criteria.6 -11.0) 154.0 -3.6) 71. 11.1 (18.5 Placebo Group 13. of Participants at End of Year* Active Treatment Group 2342 2305 2241 1605 773 Placebo Group 2336 2293 2270 1591 738 Treated (Active Treatment Group) 90..9) Diastolic Blood Pressure 76. 24 Table 3. Of those ineligible.0 (19. the cohort was overweight.3 -3.8 2. Antihypertensive Drug Treatment Status by Year of Follow-up Active Treatment Group. Of those individuals. The distribution of SBP at baseline was 160 to 169 mm Hg. 64% were eligible for baseline visit 2.4 (18.6 -12.7 (9.1 4. Relative risks and percentage differences were calculated by proportional hazards regression analysis40 using the entire duration of followup. 170 to 179 mm Hg.4 8.2 89.5 2.8 (17.2) 142. and 2.5 6. The yield from initial contact to randomization for those not taking antihypertensive medication was 1.6 mm Hg. of those. two thirds of whom were not receiving antihypertensive medication at initial contact.3) 141.7) 142. Only 5% reported limitation in activities of daily living.Mean Systolic and Diastolic Blood Pressure by Treatment Group and Year . standard normal (z) tests for continuous variables.4 Placebo Group 5.4 4. 1575 such participants were randomized.1 -4. 180 to 189 mm Hg.7 (10.5) 170.2 (10. and 41 classified as “other” (1% of whites).of Folow-up Blood Pressure.5 5. 10% and greater than 190 mm Hg. medication was stopped in 13% 3258 Prevention of Stroke . Stratified randomization by antihypertensive drug treatment status at initial contact and by center produced two SHEP groupsassigned to active treatment and placebocomparable at baseline (Table 1). Screenees meeting blood pressure criteria and not receiving antihypertensive medication proceeded directly through two baseline vistis.0 (10.Most participants randomized to the active treatment group received active antihypertensive medication (either according to the SHEP protocol or by prescription) throughout the trial 89% of participants at year 3 and 90% of participants at year 5 (Table2). Included among the whites were 204 Orientals (5% of whites).2) 71.6) 67.5 (9.1 -4.24% and for those taking medication was 0.9 -4.1 +0.8 17.0) 143. Randomization and Baseline Characteristics of SHEP Participants Randomization. No. 84 Hispanics (2% of whites).0 1. pressure criteria underwent drug withdrawal as previously described. The board used stochastic curtailment to evaluate whether the trial should be stopped early. 3161 such participants were randomized. 7% had carotid bruits.1 21.2%]) and meeting blood JAMA..1 (20.82%. 5%.1) 68. Mean SBP was 170.1 (9. Mean age of participants was 72 years. 1985.6) 72. June 26. 57%.6 Unknown Active Treatment Group 4.7 32. and January 15.4 (12. Of all participants 1.3) 67. Two subgroup hypotheses were specified a priori.7) 156. Those taking medication (193 620 persons [43. 88% were randomized.Table 2.0 2.0 -12.3 89.5 (15.7 12.7 7.5 (9. and about 11% manifested symptoms of depression based on standardized questionnaire criteria.0 89. Fewer than 1% had cognitive impairment.4% reported a history of stroke.6% met initial criteria. This was used to calculate the probability that a conclusion based on interim study results would remain unchanged at the trials end.4 (9. 1988.Participants Receiving Antihypertensive Medication by year of Follow-up Medication Status No. Altogether.2 (12.0 8.3) 155. Subgroup hypotheses were tested by the proportional hazards model using the appropriate interaction term.0 (20.1 (12.8) * Values are mean (SD). RESULTS Recruitment Recruitment was done at 16 clinical centers between March 1.1) 154.1 (12. 57% were women. On physical examination.9 Placebo Group 81.1 3.4 -14.5 44. mean DBP was 76.

50 to 0.SHEP Cooperative Research Group 3259 . dose 1 medication only 16% were receiving step 1.2 (0. average systolic blood pressure for the active treatment group. relative risks 0. 2 Table 5. Only the first event (nonfatal) was counted in the total number of events and in calculations of the cumulative stroke rate. x (1 df)=7.. However. the mean SBP active treatment group was substantially lower JAMA. 30% were receiving step 1. 6. of Nonfatal Fatal Participants Stroke Stroke Not Receiving Antihypertensive Medication at Initial Contact 1584 64 5 1577 88 11 0. 1991-Vol. the percentage for whom active antihypertensive drug therapy was prescribed increased progressively. Table 4.2) 2371 3.4 (0. † For the active treatment group compared with the placebo group. solid line with triangles.. x2(1 df)=5.85) Nonfatal Plus Fatal Stroke* 57 96 Active Placebo Relative risk (95% confidence interval)† Active Placebo Relative risk (95% confidence interval)‡ 35 63 SBP and DBP by Treatment and Year of Follow-up Throughout the trial. June 26. and were receiving no antihypertensive.70. No. Prevention of Stroke .0 (0.38-0.64 (95% confidence interval.2 (0. 265. 12% were receiving 2. Unavailable Starting No.01. 3. and broken line with open diastolic blood pressure for the placebo group. a few placebo group participants were deemed to receive active therapy before their blood pressure met the established criteria (mostly due to DBP). 21% were having other active medication. mo *Average systolic and diastic blood pressure during the Systolic Hypertension in the Elderly Program follow-up plotted at 1.0 (0.2 (0.4) 21 0 2264 3 4.57 (0. dose 2 medication.95) Receiving Antihypertensive Medication at Initial Contact 781 32 5 3 61 794 0. of Events Treatment Group No. Thus almost half of the participants were receiving the step 1 drug and more than two thirds of the participants were receiving the step 1 or step 2 drug only. P=.2 (0. broken line with closed circles.5) 613 1 0 6 Placebo Group 1 34 0 1. † There were 103 total events (96 nonfatal and 10 fatal) in the active treatment group and 159 (149 nonfatal and 14 fatal) in the placebo group.5 (0. from 13% at year 1 to 33% at year 3 and 44% at year 5 (Table 2). Events Year Active Treatment Group 1 2365 28 0 1.Storke Events by Treatment Group and Antihypertensive Medication Status at Initial Contact. Follow-up.0 (0.69 (0. 2 ‡ For the active treatment group compared with the placebo group. .51-0. ‡ The last stroke occurred during the 67th month of follow-up.4) 2308 42 0 2 4. average systolic blood pressure for the placebo group. At the 5-year visit.82). due to side effects.2.2 (0. of 100 Participants for Follow-up No. Placebo Group. dose 2 only. mo Fig 2.4) 3 2229 22 2 6.9) 584 3 0 6 * For the active treatment group compared with the placebo group. Only the first event (nonfatal) was counted in the total number of events.7) 1393 24 1 5 9. Throughout the trial. The proportion of participants receiving active antihypertensive medication was consistently higher throughout the study for persons in the active treatment more than for those in the placebo group drugs 89% vs 33% at 3 years and 90% vs 45% at 5 years (Table 2).Cumulative fatal plus nonfatal stroke rate per 100 participants in the active treatment (solid line) and placebo (broken line) groups during the Systolic Hypertension in the Elderly Program).90. The majority of participants randomized to the placebo continued to receive no active antihypertensive medication throughout the trial (Table 2). medication was stopped in 7% due to side effect.40. 11% were receiving step 2. No.4) 2153 18 0 4 5.5) 1438 13 5 5 5.5) 34 2 4 2131 8.1 (0. x (1df)=12. P=0.Total (Nonfatal Plus Fatal) Stroke Rates by Teatment Group and Year of Follow-up* Cumulative Stroke Rate (SE). 1 medication. 24 * Three participants in the active treatment group and four participants in the placebo group had both a nonfatal and a fatal stroke.0003. per No. of all participants in the active treatment group.2 (0.2) 2.3) 2316 22 0 2 3.200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 0 Follow-up. 0. and 12 months and thereafter. P=. Three participants in the active treatment group and four participants in the placebo group had both a nonfatal and a fatal stroke. Solid line with open squares indicates average systolic blood pressure for the active treatment group.

than at baseline.75 (0.75 (0. 1. The apparent lack of any trend for the small number of black men was based on few events (nine vs eight events). horniclde 5 5 7 3 Other noncardiovascular Indeterminate cause 14 27 Combined End Points Nonfatal myocardial infarction of 104 141 coronary heart disease death Fatal or nonfatal stroke.80 (0.0 events per 100 participants) Table 4). 265. was diagnosed in 103 persons in the active treatment group and 159 persons in the placebo group (Table 4).With a mean followup of 4. 0.95) (Table 5). 3260 0. respiratory disease.47-0.87 (0. With proportional hazards regression using SBP as a continuous variable. by 11 to 14 mm Hg (Table 3 and Fig 1).73-1.00) 0. sudden cardiac death. relative risk for stroke was 0.49-0. rapid cardiac death. the SHEP goal blood pressure was reached by 65% to 72% of persons in the active treatment group but only by 32% to 40% of those in the placebo group. 24 group than for the placebo group.70-1. The cumulative difference in total stroke incidence rates. nonfatal myocardial infarction. By Age.64% (95% confidence interval [CI]. (By life table analysis. angioplasty.38) 0.50 to 0.05) 0.94) 0.0 and 3. suicide.31-1. No.56-1. . By Antihypertensive Drug Treatment Status at Initial Contact.1. The mean DBP of the active treatment group was lower by about 9 mm Hg throughout the trial compared with baseline. one in the active treatment group and five in the placebo group.0003) (Table 4 and Fig 2). For participants receiving antihypertensive medication at initial contact. or 199 289 coronary heart disease death Coronary heart disease§ 140 184 Cardiovascular disease 289 414 Relative Risk (95% Confidence Interval)* 0. 0. coronary artery bypass graft. † Nonfatal myocardial infarction does not include silent myocardial infarction. one in the active treatment group. During the trial. the mean SBP was consistently lower than at baseline. SHEP primary end point data indicates a high degree of consistency in favourable findings for the active treatment group. neoplasm. Sex.05 (0. myocardial infarction.40-1. 1991-Vol.56-0. infectious disease. one in the placebo group.80 (0.13) 1. Mean SBP levels were substantially lower throughout the trial for the active treatment JAMA.80) 0.57 (95% CI.87 (0. one in the placebo group. 1.86 (0. with rates lower in the active treatment group than in the placebo group. aneurysm and endarterectomy. for the placebo group.94) 0. rapid cardiac death.04) 0. transient inschemic attack.82. the favourable trend in stroke incidence for the active treatment compared with the placebo group prevailed irrespective of baseline SBP.85).87 (0.65) 0. Based on proportional hazards regression analysis. Stroke incidence was lower in those randomized to active treatment than in those randomized to placebo for all baseline age groups: 60 to 69 years. Adapted. respective risk of stroke for active treatment compared with placebo was 0. The mean DBP of the placebo group was lower than at baseline by about 4 to 5 mm Hg.57-1.2.46) 1.33-0.48-1. of Events Active Treatment Placebo Group Group (n=2365) (n=2371) Nonfatal Events Stroke 95 149 Transient ischemic attack 62 82 50 74 Myocardial infarction† 30 47 Coronary artery bypass graft 19 22 Angioplasty 48 102 Left ventricular failure 7 11 Renal dysfunction Fatal Events 213 242 Total deaths Total cardiovascular 90 112 Stroke 10 14 Total coronary heart disease 59 73 Sudden death (<1 h) 23 23 Rapid death 21 24 Myocardial infarction 15 26 21 Other Cardiovascular 25 Left ventricular failure 8 7 Other 13 16 Total noncardiovascular 109 103 Neoplastic disease 75 78 Renal disease 2 2 2 Diabetes mellitus 1 Gastrointestinal disease 2 2 Respiratory disease 6 5 10 Infectious disease 7 Accident. and black women. P = .30-1. by about 15 mm Hg. Seventeen of 96 people in the active treatment group and 28 of 149 people in the placebo group who had a nonfatal stroke died during the trial about 20% in each group. seven in the active treatment group and 10 in the placebo group.96) 0. two in the active treatment group and three in the placebo group.79) * Relative risk assessments were done for all types of events except those with fewer than 20 events and indeterminate cause of death. One of the two SHEP subgroup hypotheses was related to the effects of active treatment on participants receiving and not receiving antihypertensive medication at initial contact.96 (0.63 (0. by 26 mm Hg overall (Table 3 and Fig 1). white women. A favourable effect of active treatment was also noted for three of the four major sex-race groups: white men. were as follows stroke. incident stroke.2 per 100 for the placebo group. sudden cardiac death.58-0. and Baseline SBP..Table 6.67 (0. and angioplasty. No. 34 vs 47 events.00 (0.57-0.Morbidity and Mortality by Cause and Treatment Group.49-1.2 per 100 participants Prevention of Stroke .59) 0.54-1. nonfatal or fatal stroke. the primary end point of the trial.71 (0. and unknown or no death certificate.08) 0. 18 vs 66 events.55) 0. 48 vs 74 events and 80 years or older. seven vs 21 events. Race.63 (0.31) for the active treatment group and 8.35-1. relative risk was 0. 2.80-1. Mean DBP was reduced more in the active treatment group than in the placebo group. The cumulative rates for the total period of follow-up (70 months) were 5.2 per 100 for the placebo group).82) 0. 70 to 79 years. increased progressively over the 5 years of the trial (0.2.78) 0.59) 0.60-0. Coronary heart disease includes definite nonfatal or fatal myocardial infarction. Randomization was stratified by whether or not participants were receiving antihypertensive medication at initial contact. Cardiovascular disease includes definite nonfatal or fatal myocardial infarction. For the subgroup not receiving antihypertensive medication at initial contact.67 (0. 21 vs 38 events.05) 0. Thus. 39 vs 64 events.601. one in the active treatment group and four in the placebo group.5 per 100 participants for the active treatment group and 9.5 years.57 (0. one in the placebo group. by about 3 to 4 mm Hg. § Results of death certificate coding for indeterminate causes according to the ninth revision of the International certification of Diseases. 5-year cumulative stroke rates were 5. The absolute reduction in 5year risk of stroke was 30 events per 1000 participants.68 (0.73 (0.56) 0. June 26.51 to 0. coronary artery bypass graft.47-1.SHEP Cooperative Research Group . three in the placebo group.69 (95% CI.38 TO 0. 0. renal disease.46 (0. Total Stroke Incidence All Participants. other noncardiovascular disease. (There were few stroke deaths 10 in the active treatment group and 14 in the placebo group). other cardiovascular disease.71 (0. left ventricular failure. one in the active treatment group.

No. Prevention of Stroke . The data regarding this subgroup hypothesis suggest benefit from active treatment for both those with and without baseline ECG abnormalities.0 5. For participants with baseline ECG abnormalities.7 3. 1991-Vol.4 10. second only to cardiovascular disease as a main cause of mortality for SHEP participants.Hospitalizations due to any reason were recorded for 1027 treatment group participants (admissions) and 1086 placebo participants (2204 admissions). Prevaience.3 11.1 1.86 for angioplasty (Table 6). % Active Treatment Group 12. By proportional hazards regression analysis.5 1.3 1.0 2. and coronary causes (59 vs 73 deaths) (death of relative risks..6 2.1 2.5 2.53 to 1.4 10.8 33.4 2.8 Symptom Mucopulmonary breathlessness on standing Feelings of unsteadiness or imbalance Loss of consciousness / passing out Heart beating fast or skipping beats Heart beating unusually slowly Chest pain or heaviness Unusual shortness of breath Unusual tiredness Numb hands Muscle swelling Unsocial unsual worry or anxiety Trouble with memory/concentration Depression that interfered with activities Problems in sleeping Nightmares Problems in sexual function Loss of appetite Fractures Muscle weakness or cramping Unusual indigestion Change in bowel habits Excessive thirst Nausea or vomiting Passing black stools or red blood in stools Rash or bruising Actual joint pain Headaches Waking frequently at night to urinate Unspecified problem Unspecified problem characterized as intolerable z 2.Table 7. Deaths by Cause. the mean serum uric acid. The hypothesis dealt with the relationship of treatment assignment to risk of these events in persons with and without baseline ECG abnormalities. For more than 90% of these people a referral was completed.0 3.8 28.4 0.4 7.9 Baseline ECG Abnormalities.0 23.4 6. with the 5-year absolute benefit estimated at 55 events per 1000 participants.4 91. 14% of persons in the active treatment group and 15% in the placebo group met the questionnaire 3261 Morbidity and Mortality From Cardiovascular and Noncardiovascular Causes Nonfatal Cardiovascular Events.80 to 0.3 15. During follow-up the mean serum potassium concentration was lower in the active treatment group than in the placebo group.8 13. All nonfatal and fatal cardiovascular events numbered 289 in the active treatment group and 414 in the placebo group. glucose.9 0. 265.7 2.7 0.9 25. there were 25% fewer events in the active treatment group.4 3.6 24. was similar (75 and 78 deaths) for the active treatment and placebo groups.1 4.SHEP Cooperative Research Group .2 12. 0.1 Placebo Group 10. About 4% of person in the active treatment and placebo groups met questionnaire referral criteria for expert evaluation of possible dementia (Table 9).5 36.1 1.8 28.5 26.94).4 7.8 6.8 1.8 15. the main reason for failure to achieve referral was participant refusal. 0.9 11. The difference observed in total deaths from coronary heart disease JAMA.1 21.2 3. Adverse Effects At baseline.9 8. numbered 140 for the active treatment group and 184 for the placebo group (Table 6).29).3 2. uricacid. Hospitalizations and Nursing Home admission. For the end point of sudden and rapid death.0 1.Prevalence of Symptoms Ever Characterized as Troublesome or intolerable by Treatment Group.3 8.46 for left ventricular failure to 0. and the mean serum sodium concentration was similar in the two groups (Table 8).2 4.8 9.7 2.6%) receiving active treatment and 44 (1.6 -1.9 1.87) (Table 6).5 0.6 4. serum potassium.2 7.1 10.The end points for the second SHEP a priori subgroup hypothesis were the incidence of nonfatal myocardial infarction plus coronary death and the incidence of sudden and rapid death. the relative risk of nonfatal myocardial infarction plus coronary death was 0. During the trial.. For the subgroup of people free of baseline ECG abnormalities.9%) receiving placebo had a diagnosis of dementia made and confirmed by the coding panel During the trial. and sodium levels out of the specified ranges were reported more frequently in the active treatment group than in the placebo group (Table 8). with relation risks ranging from 0.Nonfatal and fatal major cardiovascular events were consistently lower for active treatment than placebo.6 -1.3 0. This represented 32% fewer events in the active treatment group. There were few events for the end point of sudden and rapid death 15 in the active treatment group and 10 in the placebo group. During follow-up. Thirty-seven participants (1.50 to 0.5 25.6 5.7 12.7 26.4 86.4 8.. June 26.The number of was lower for active treatment for placebo for mortality from all deaths (213 vs 242 deaths). The number of deaths from neoplastic diseases.4 8. the relative risk of nonfatal myocardial infarction plus coronary death for active treatment compared with placebo was 0.4 20.9 1.6 31.83 (95%CI. and cholesterol concentrations were higher in the active treatment group. total cardiovascular causes (90 vs 112 deaths).0 25. Intermediate care nursing admissions were recorded for 52 treatment group participants (58 admission) and 58 placebo group participants (65 admissions).2 5.4 10.4 4.9 1. glucose.3 2. with the 5-year absolute benefit estimated at 16 events per 1000 participants. nonfatal plus fatal.4 28. 0. 24 was largely due to the difference in the number of fatal myocardial infarctions. All coronary heart disease events.0 6.6 4. cholesterol. Combined Nonfatal and Fatal Cardiovascular Events.1 3.8 2. The number of nonfatal cardiovascular was consistently lower for active assignment than for placebo.6 19.9 9.6 32.5 3.6 24. there were 29 events in the active treatment group and 36 events in the placebo group..0 11.69 (95% CI.1 20.8 14.2 2. reported rates of certain problems were greater in the active treatment group than in the placebo group (Table 7). the number of clinical complaints was comparable in the active treatment and placebo groups.

1.3 0. the SHEP decrease of 27% in incidence of nonfatal myocardial infarction plus coronary heart disease death for the active treatment group is similar to results of the Hypertension detection and Follow-up program and greater than those in other trials..44.9 2. and baseline SBP.3 0. the total stroke incidence was reduced by 36% in the active treatment group (P=.3 2..0003).2±83.5 0. (As anticipated by the SHEP design. Combined results of all diastolic hypertension trials indicate that sustained decrease in blood pressure recorded for active intervention produced an overall reduction in incidence of major coronary events of 14% (95% CI.2 6.. Favorable findings are consistent for the active treatment group compared with the placebo group irrespective of age.8 Placebo Group (n = 1821) 4. The SHEP medication regimen showed no evidence of adverse effect on coronary risk for people with baseline ECG abnormalities8. This result was observed even though about 35% of those assigned to placebo took known antihypertensive medications during the trial.. June 26. there was a favorable trend for total mortality.0 3..6 0.3 Placebo Group (n = 2202) 4. Findings from SHEP and other trials suggest that antihypertensive drug treatment is broadly effective.3 0..1 2..1±1.2 . 7.9 3.0) 82 (3.6) Positive diagnosis Depression 329 (13. 1. the reduction in incidence was 32% for the active treatment group.8% 6.1±1.8 16.5±0.4 z . the primary end point in people aged 60 years and older with ISH.4±0. For the coronary heart disease end point..5 .6 . with similar reductions in the stroke rate for people with either diastolic hypertension or ISH. The positive SHEP outcome was achieved with minimum effective doses of antihypertensive drugs in a stopped care regimen structured to achieve and maintain a goal blood pressure at least 20 mm Hg below baseline and 160 mm Hg.Table 8. In fact. and absolute benefit estimated at 5 years was 30 events per 1000 participants.2 3.3 . this difference was not statistically significant. 30% to 54%).2 z -25.9) 357 (15. we conclude that the SHEP drug regimen for reduction of blood pressure significantly reduced the incidence of stroke in persons aged 60 years and above with ISH.76 Serum sodium mm0l/L Mean ± SD % with values £ 130 1y Active Treatment Group (n = 1882) 4.1 3.7 5.. 5. 24 Prevention of Stroke . The incidence of nonfatal myocardial infarction (not including silent myocardial infarction) plus coronary death was 27% lower in the active treatment group than in the placebo group.5 1. sex-race.0% 6.. 7.1±2.) Favorable outcome for the active treatment group occurred for participants receiving and not receiving antihypertensive medication at initial contact.. We used the minumum number of participants Table 9... the Medical Research Council trial..0 6..47. No.3 .2 2.0 .7) referral criteria the for expert evaluation of possible depression (Table 9).. SHEP recorded a favorable trend for participants with and without baseline ECG abnormalities.6 4. and 12 smaller trials combined45. including the Hypertension Detection and follow-up program trial.1±83. ...5±0.6 139.7 139.2±83.1) 272 (11.0 .6 4.1 321. 13. for SHEP participants with baseline ECG abnormalities (61% of those randomized). 104 (4.0 315.0 139..6 6.5) 112 (4.0 374. For all cardiovascular events (289 in the active treatment and 414 in the placebo group). 9. 4% to 24%).0 1.Serum Biochemical Values by Treatment Group Baseline Active Treatment Group (n = 2218) Serum potassium mm0l/L Mean ± SD % with values < 3.4 138. We recognize that persons not receiving antihypertensive drugs at initial contact might be more accurately characterized as individuals with ISH than those receiving such treatment.8 6.8 Serum glucose mm0l/L Mean ± SD % with values ³ 11. 2.4%) randomized to active treatment and 112(4. The 36% reduction in stroke incidence is similar to that found in trials of drug therapy for diastolic hypertension.5) 44 (1. 3. It JAMA.7 .6 4.2 .. randomized 2365 Dementia Qualified for referral 98 (4.. This is an absolute benefit at 5 years of 55 events per 1000 participants.2 10.6±2.. However..1) 83 (3. During the entire 70 months of study follow-up.6 6. and cardiovascular disease.1 7.6±2. regardless of medication status at initial contact.3 6.5 0.. 1991-Vol.1 327. The significant positive outcome on its primary end point of stroke is consistent with the trend found in the SHEP pilot study.2 Serum uric acid micromol/L Mean ± SD % with values ³ 594.9 .3±1. these previous trials recorded a 42% reduction in stroke incidence (95% CI. The SHEP is the first trial to test the efficacy of antihypertensive drug treatment on clinical end points for persons with ISH. 4.4) Positive diagnosis Placebo Group 2371 94 (4. the incidence rate of nonfatal myocardial infarction plus coronary heart disease death was 31% lower for active treatment..Dementia and Depression by Treatment Group No. the main reason for failure to achieve referral was participant refusal.5 0. 5.1 Serum cholesterol mm0l/L Mean ± SD % with values ³ 7..3 . 6.8±2.2 8.4 0. Overall.4±2.8 .46. Of participants in the two groups.9±3.1±0.7±101.1 Ever Placebo Group (n = 2189) ..4 0. In addition to positive findings for the incidence of stroke. 2.1±1.4 Active Treatment Group (n = 2255) .0±1..7) Referred 104 (4. coronary heart disease.. The death rate from all causes was 13% lower in the active treatment group than in the placebo group. % Active Treatment Group No.8 -7.5) Referred 37 (1.4 5. 265. For more than 75% of these people a referral was completed...1 7.9) Qualified for referral 254 (10. 0.SHEP Cooperative Research Group 3262 . This differences was maintained when the combined coronary heart disease end point also included coronary angioplasty and coronary artery bypass grafting. COMMENT The SHEP antihypertensive drug treatment regimen significantly reduced the risk of total stroke.3 * The number of participants in each treatment group and time period varied because of invalid values. 11. given the sample size of the trial. Moreover.0±1.7%) randomized to placebo had a diagnosis of depression.

1991. Coope J. Curb JD. 13. Ann NY Acad Sci. Borhani NO. 1970. Medical Research Council Working party. given its prevalence and the high rates of cardiovascular diseases in those aged 60 years and older. 3:434-436.40(suppl 1 ):98-105. Systolic Hypertension in the Elderly Program (SHEP): baseline characteristics of the randomized sample. et al. Blood pressure (systolic and diastolic)and risk of fatal coronary hart disease. and Blood institute of Study Group for Evaluating Treatment in Mild hypertension. 35. Hypertnsion and risk of stroke in an elderly population. Based on the effects of this regimen (plus regression to the mean adaptation to clinic assessment). JAMA. JAMA. Klawans HL. The SHEP findings are congruent with the combined results of previous trials of drug treatment for diastolic hypertension in efficacy of preventing not only stroke but also coronary heart disease and all cardiovascular disease43. Smith WM. AH Robins Co. Birkenhager W. III. JAMA. 304:267-288. BMJ. Wyeth Laboratories/Ayerst Laboratories. Petrovitch H. Med Clin North Am. JAMA. JAMA. This result was achieved with use of stepped-care treatment with low-dose chlorthalidone as step 1 medication. 7. Aplegate WB. 1991. Treatment of mild hypertension: results of a 10 year intervention trial. 11. et al.17(suppl II)2:15. 16. BMJ. Rutan GH.56:913-920. Effects of treatment on morbidity in hypertension. average SBP of the active treatment group was lower during the trial by at 26 mm Hg. dementia and disability. The step 2 medication was usually low-dose atenolol or low-dose reserpine. Treatment of mild hypertension: a 5-year controlled drug trial: the Oslo study. This study was supported by contracts with the National Heart. Richmond. 37. Hypertension in the elderly. Shekelle RB. Lancet. 27. Mortality associated with diastolic hpertension and isolated systolic hypertension among men screened for the Multiple Risk Factor Intervention Trial. including the incidence of major cardiac and cardiovascular events.41:239245. J Chronic Dis. Carter AB. Systolic hypertension in the elderly. In: Frohlich ED. Systolic Hypertenion in the Elderly Program (SHEP): antihypertensive efficacy of cholorthalidone. Berge K. The Australian therapeutic trial in mild hypertension.05 mg/d added as needed. Pa. Davis B. 34. 33. Diagnostic and Statistical Manual of Mental Disorders. Reduction in stroke incidence among persons with high blood pressure.17(suppl II):152-161. Lancet. 23. 1984:39:166-169. Schoenberger JA. 1986:31(suppl 1):41-45. et al.0 mg/d if needed. The SHEP was unique in two it used low-dose chlorthalidone. Mantel N Evaluation of survival data and two new rank order statistics arising in its consideration. et al. Am J Med. Hulley SB. II: results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. 24. Sellersville. Systolic Hypertension in the Elderly Program (SHEP): baseline characteristics of the randomized sample. 1985. Lynd CN. Cochrane AL. Hypertension. 17. eds. 20. 9. Amery A. 1985. Camel GH. 1977. 1977-:40(suppl 1):180-187. as the step 1 medicine. BMJ. 14.291:97-104. Helgeland A. Neaton JD. Australian National Blood Pressure Management Committee. 39. Dyer AR. 2. Veterans Administration Cooperative Study group on Antihypertensive Agents. 1977. 15. 22. Hypertension 1991. participants were older people ISH. stepped drug regimen. 1990. DC: Aamerical Psychiatric Association: 1987. Lung. suarez L. Black HR. Veterans Administration/ National Heart. Rationale and design of a randomized clinical trial on prevention of stroke in isolated systolic hypertension. Hypertension.17(suppl II):162-167. and (4) with no incidence of depression or favorable findings were demonstrated for multiple secondary end of the trial. Veterans Administration Cooperative Study Group Antihypertensive Agents. 1988. Furberg Cd. This regimen was associated with only an infrequent experience of adverse effects and no evidence increase in dementia depression. may be as for step 1 drug treatment of blood pressure as any other drug. These findings indicate a considerable potential for decreasing morbidity and disability by effective sustained drug treatment of ISH. In conclusion. 229:409-418. The SHEP results may have implications for current uncertainties for optimal drug treatment regimens for diastolic hypertension. Va. 1:1349-1354. 25. 1983. 18. Hypertension-stroke Cooperative Study Group. 265. Effect of stepped care on the incidence of myocardial infarction and angina pectoris. Hypotensive therapy in stroke survivors. Systolic Hypertension in the Elderly Program (SHEP): baseline characteristics of the randomized sample. Bailey G. Effect of antihypertension treatment on stroke recurrence.17(suppl II):62-76. 1974. Smith WM. 38. The importance of this question is underscored on the comparative costs of oral and newer drugs49. Amercial Psychiatirc Association. 1970. Neaton JD. Circulation 1988. The average DBP of the active group was about 3 to 4 mm lower than the placebo group DBP data demonstrate an ability to and sustain control of ISH in persons with a low-dose. Weiler PG. Effects of treatment on morbidity in hypertension: results in patients with diastolic blood pressure averaging 115 through 129 mm Hg. Tex: University of Texas School of Public Health: 1990. (3) with a low-order adverse effects. 1: reduction in mortality in persons with high blood pressure. 1966. 293:1145-1151. (2)with the of participants assigned to active therapy being at or below the goal pressure. 1978. Effects of treatment in hypertension: results of a controlled study. and Blood Institute Study Group for Cooperative studies on Antihypertensive Therapy: Mild Hypertension. 247:633-638. 1973. Mortality and morbidity results from the European Working Party on High Blood Pressure In the Elderly trial. 6. 8. The favorable SHEP results reflect that a low-dose oral diuretic. 24 Prevention of Stroke . Stamler J. 3. Circ Res. 1:485-489. IX:: behavioural characteristics. Drugs were supplied by the Lemmon Co. 1967. Llindeman RD. High level adherence to this regimen was maintained throughout the 5 years of the trial. Barrettconnor E. 5. Lung. 1980. Helgeland A. JAMA. et al.6(suppl 1): 198-206. Wentworth DN. McDonald RH. Isolated systolic hypertension and Mortality after age 60 years Am J epidemiol.17(suppl II):16-23. Cutler JA. Five year findings of the Hypertension Detection and Follow-up Program. Hypertenion. 1974. 30. an epidemiologic assessment. Systolic Hypertension in the Elderly Program (SHEP): baseline characteristics of the randomized sample. 19. Lancet. Criqui MH. Systolic hypertension in the elderly: controlled or uncontrolled. Nilchaman Mz. Am J Cardiol. Drugs. ed preventive Aspects of Coronary Heart Disease. Washington. References 1. II.13(suppl 1):2-12. Oslo hypertension study. MRC trial of treatment of mild hypertensi-on principal results. 1991. Hypertension Detection and Follow-up Program Cooperative Croup.77:504-514. 1985.65-84. 26. The Systolic Hypertension in the Elderly program (SHEP) Cooperative Research Group. Gurland B. Randomized trial of treatment of hypertension in the elderly in primary care. 1991-Vol. et al. Chiappini M.Houston.19:227-240. This was increased to a maximum 15. 202:1028-1034. 7:976-980. Garland C.used low-dose chlorthalidone. 12 Hypertension Detection and Follow-up Program Cooperative Group. Hypertention 1989. 1970. Systolic Hypertension in the Elderly Program (SHEP): baseline characteristics of the randomized sample. 29. especially hypertension. 242:25722576.5:71-75. 213:1143-1152 4. J Clin Epidemiol.61:513-529. Colandrea MA. Warrender TS. Stamler J. 31. SHEP Manual of Operation revised ed. Hypertenion 1991. 118:365-376. June 26. X: analysis. Golden RR. 1: 1261-1267. Gurland B.41:1197-1208. Revised Third Edition. Circulation. Farinaro E. Challop J: The SHORT-CARE : an efficient instrument for the assessment of depression. Blaufox MD. Furberg CD. Committee on Nomenclature and Statistics. and Stuart Pharmaceuticals. Veterans Administration/ National Heart. US Public Health Service Hospitals Cooperative Study Group.SHEP Cooperative Research Group 3263 . Wittes J. In all these trials efficacy diuretic was the step 1 treatment. et al. 242:2562-2571. V: baseline blood pressure and pulse rate measurements.5 mg/d. 32. 1979. Systolic Hypertersion in the Elderly Program (SHEP): baseline characteristics of the randomized sample. No. 1979. Hypertensio-n 1984. Pressel S. Probstfiled JL. 36. Lung.et al. Kuller Lh. 69:725-732. Hypertension Detection and Follow-up Program Cooperative Group. Hypertention. Probstfield JL. 10. Evaluateion of drug treatment in mild hypertension: VA-NHLBI feasibility trial. II: screening and recruitment. 1982. Hypertension Detection and Follow-up Program Cooperative Group. Data from large-scale. including mild hypertension.1980. 1991. Stamler J. 1: rationale and design. N Engl J Med. Five-year findings of the Hypertension Detection and follow-up program. Stroke. The effect of treatment on mortality in 'mild' hypertension. particularly chlorthalidone. Bainton O. 1982. Shekelle RB. JAMA. and the Blood Institute and the National Institute on Aging. Wilmington. 1986. Wolff FW. Wentworth D. SHEP demonstrated efficacy of active antihypertensive drug treatment in preventing persons aged 60 years and old ISH. Treatment of mild hyper-tension: preliminary results 2-year feasibility trial. Ostfeld AM. 0. J Gerontol. Hypertension Deduction and follow-up Program Cooperative Group. Teresi JA. Circ Res. Five-Year Findings of the Hypertension Detection and Follow-up Program. Fridman Gd. Brixko P. Control of moderately raised blood pressure: report of a cooperative randomized controlled trial. long randomized trials are not available such data are needed48. Barraclough M. Labarthe DR. 28. Philadelphia. mortality by race-sex and age. Leren P. Byington R. Del. Pa: Fa Davis Co Publishers. 21.12.17(suppl II):1-171.

Hughes. Mary Hoffmeier. Prineas. 1966. Allman. Donna M. Ronald J Prineas. Cori Hamilton. Alice Wallace. DC. Camel. ScD. Recruitment and Adherence Subcommittee. Bethesda. Jenny Brown. MD (deceased).Flora Gosch.-John B. MD. Former Project Officers. RN. RN. MD. Contract Specialist: Linda Gardner. Davis.Judith Jensen. MD. MBBS. PhD. Drug Topics Red Book. 46. Jane Kotchen. Miami (Fla) Heart Institute.Patricia Hershinow. Durham. MD. Washington. Sharon Carmody.SHEP Cooperative Research Group 3264 .. Vogt. Laverne Parr. Wittes J. Maria Canosa-Terris.Richard H. MD. ScD (Principal Investigator). MD. Bethesda. Harold W. RN. Mass.44:579-585. PhD. Maureen Magnani.James Hunt.Elizabeth Perry. Joseph E. Ray W. Contracting Officer: C. Md. Gale Rutan. and Treatment of High Blood Pressure. Sylvin Smoller. RN. Debra Egan. Davis. DrPH (Co-Principal Investigator). Conn. RN. Lot Page. C.. Gail Miller. MD (chair). Md. MD. MD.Cancer Chemother Rep. 1990. NC. Melissa Jones. et al. 48. MD. Memphis. MD. Yale University. June 26.-Helen Petrovitch. Comman Stat. J R Stat Soc B. The 1988 report on the Joint National Committee on Detection.William Merashoff. Charles K. MD. Bearden. MPH (Principal Investigator). Littleton. RN. Margaret Chiappini. Adrian M. Ostfeld. PhD. Calif. Birmingham. Publications and Presentations Subcommittee.. MD (Principal Investigator).335:827-838. Prineas RJ. Smith WM. Wright. MS. 1985.. 1990. Pacific Health Research Institute. Vogt. Deputy Project Officer:Eleanor Schron. Clevale (Ohio) Clinic Foundation. MD. Arlene Gilligan.Keneeth G. FNP. M D . DC.BSN. MSW. Relationship among baseline resting ECG abnormalities. MPH (Principal Investigator). PA-C. BSN. Stanley Slater. Jack P. RN. Endpoints and Toxicity subcommittee.55:1-15. MD Margaret Bodellan. Conn.Josephine Jones. Memphis. et al.H. PhD (Principal Investigator). Rocheter. Janet Wittes. Kostis JB. MD. Betsy Gahagan. MS. NC. MD. III. Schnaper MD. MS. Krishna Rao. Brons. Davey. Durham. Mt Sinai Medical Center. The B-value: a tool for monitoring data. Daivis. Applegate. 51. Julia Hall. 1990. Hypertension Detection and Follow-up Program Cooperative Research Group. NJ). Guthrie.Thomas M. Elanna Sommers. Higg MD. Perry Hm Jr. Other Key Personnel: Thomas P. Miller. RN. John C. Vanessa P. Chapel Hill. Marlene McKenzie.Nemat O. MacMahon S. Emory University School of Medicine.. Ga. Ellen Christian. Davis. DC. MD. MD (chair). M P H . National Heart. Susan Krieger. PA-C. RN.-thomas M. RN.Marilyn Albert. Susan Surette. MD: Darwin R. Piscataway. University of California. State College. Blaszkowski. John W.Gordon P.-M. RN. C u t l e r. 1990.Kathy Reavis. MD (Principal Investigator ). MPH. RN. PhD. No.. MD. Berge. Borhani. RN. Donald Blaufox. RN. Black. Baltimore). MD. MD (Principal Investigator). Stratified by other risk factors.14::312335. Lan KKG. MD. Lisa Carlisle. PhD. Data and Safety Monitoring Board. Lynn Hanna. Hypertension. Dallas Hall. Lung. 1985. MD. Shirey Arch (deceased).-Evan Hadley. Deanne J Unger. Multiple Risk Factor Intervention Trial Research Group. Laretha Goodwin. Margaret Huber. Arlene Johnson. Lexington. PhD. RN. MPH (chair). University of Tennessee. 45. MD. Teresa Radebaugh.-Richard M. PhD. Electrocardiographic Laboratory (University Minnesota. MD (chair). Chicago. Promed. Atlanta. One. Susan Pace. Shekelle. PhD. 1991-Vol. Yale University School of Medicine. Mo. RN. Angleline Merlo. Alice Stafford. Marshall Lee. RN. MD:Joseph Harrington. 40. Minneapolis. Geri Bailey. University. Regression models and life tables.Hawaii. Am J Cardiol. Whisnant. MPH (chair). BSN. Univesity of Minnesota. Morbidity and mortality in the Systolic Hypertension in the Elderly Program (SHEP) Pilot Study. Rowe. NJ: Medical Economics Books. PhD. Diane Christianson. University of Pittsburgh. Berge. MD.Mitchell Perry. MD. 1991:17(suppl II):123-151.31 Albert Einstein College of Medicine. Pennsyivam State University. Mary Perron. Linda Loesche. Chapel Hill. Jerry Noviello. National Institute on Aging. PhD. findings: standards and Procedures for Measurement and Classification. MD. University of Medicine and Dentistry of New Jersey. Theodore Kotchen. Oradell. Mitchell Perry. O'Brien. Laura Farley. MD.G. Labarthe. Collins R. Drug Selection Working Group Robert McDonald. RN.Fred I.. PhD. Mortality findings for stepped-care and referred-care participants in the Hypertenion Detection and follow-up Program. Raymond Gambr MD. Kostis. Biometrics. Sandy Biggio. Cox DR. June Gregonis. RN (chair).. Fields. Kaiser Permanente Center for Health Research. University of Medical Fla. Crow RS. PhD (Principal Investigator). David Curb. 41. MD. RN.148:1023-1038. RN. MD. Floral Park. Jr. Sara Pressel.V. Robert Wood Johnson Medical School. Yale University. Grimm. PhD. MD (Principal Investigator). Judith Jensen. Sandra Akina. Applegate. Alfredo Burlando. Barry R. MBA. PhD. Operations and Medical Care Subcommittee. Phillip Johnson. NY: K. 50. MD. MD.William B.. Circulation . University of Kentucky Medical Center.. Philip Frost MD. Duke University Medical Center. Anne Hayman. Louis. Jean Maler. Lisa F. 43. Md. Ann Slaby. New York. MD. Evaluation. Executive Committee.34::187-220. MD. Janet Wittes Washington. New Haven. School of Public Health. 42. Linda Jones.Jeremiah Stamler.Biostatistics Officers: Edward Lakatos. Computed Tomogram Reading (Univesity. Borhani. 1988.19:3571-3584. Richard Suzman. 1982. Arckiontern Med. MD. BSN. Jeffrey L. Millicent W. Ga. CRNP. Mayo Clinic. Drug Distribution Center. Herman A. University of Texas Health Science Center at Houston (Coordinationg Center). Stephen T. Nicholas Scalfratto. Jimmie Brumagen. and Blood Institute.L. PhD. Peto R.20:4-13. Berkman. Thomas R. Stroke. RN. NY. RN. MPH (Principal Investigator). Moye.Ziral Sweezy. PhD. MPH (Principal Investigator). Gilbert. Minneapolis). MN: Marcia Nielsen. Schneider. MD. Central Chemical Laboratory (Met Path Laboratories. Kenneth A. RN. MD (Co-Principal Investigator). Richard Moss... RN.-William B. PA-C. Gary L. Clifton R. Glenn H. Blood pressure. MD (chair). Joseph A Wilber. Julie Levin. Sheila Lame. Allen. and Blood Institute. Mayo clinic. Lancet. Jr. MD.. Harvand Medical School and Massachusetts General Hospital. Warner Schaie. MD (Chair).W. Blackburn H. RN.Kenneth G.-Henry R. Clarissa Wittenberg. MD.. RN. Willam Markesbery. Probstfield. National Heart.J. Duke University Medical Center. M D . Behavioural Assessment Subcommittee. PhD. Hardy RJ. RN.Gail McCray.Lewis H. PhD (Principal Investigator). MD. MD. Teterboro. MD.-Nemat O.C. David Curb. Jr. 1988. MSN. Nora Cosgrove. Minn. PhD. JAMA. PhD. MPH Washington. Portland. MD (Principal Investigator). Frances LaBaw. Systolic Hypertensive in the elderly program (SHEP) baseline characteristics of the randomized sample VIII: electrocardiographic characteristics. University of North Carena. William S. Jeffrey A. RN. Janice A..William McFate Smith.Ralph E. SHEP COOPERATIVE GROUP INVESTIGATORS Investigators at the 16 clinical centers and coordination and service centers of the SHEP Coopetative Group are listed below. antihypertensive treatment and mortality in the Multiple Risk Factor Intervention Trial. St. Clinic Coordinators Subcommittee. MD (chair). et al. McDonald RH. For full membership in all SHEP subcommittees see Black et al. Rochester. RN. Eugene Harris. 44. MD (Principal Investigator). Judith Challop-Lubt. MPH. MD. 265. 1972.MD. New Haven. Gareia Carrison. II: short- term reductions in blood pressure: overview of randomized drug trials in their epidemiological context. MD (Principal Investigator). Davis BR. Atlanta. C u r t F u r b e r g .-David Berkson. The Multiple Risk Factor Intervention Trial Research Group. MD. New Haven. Richard B. Curb JD. Recruitment Coordinators Working Gronp JosephHarrington (chair) Scientific Review and Ancillary Studies Subcommittee. Greenlick.50:163-170. MD. Univesity of North Carolina.. Md. Kuller. E. MD. University of Alabama. 1989. Cottingham. Vicky Wegener. Frishman. Patty Karlen. Boston. Dallas Hall. stroke and coronary heart disease. RN. MD.Richard Crow. Bethesda. MD. Lung. MD. Minn (Chair). Northwestern University Medical School. MD. Jack Guralnik. Francis. Jeremiah Stamler. John Wright-PSG Inc. MD C. Pa. Patty Borhani. Price University of Maryland Hospital. Jacqueline Smith. Rita Schrodt. Jr. Pat Pierce. Consultants.. Philip Weile University of California. MD.Fred Walburn. RNC. William H.S. MD. Lei Honda-Sigall. Steering Committee. Gifford. the Minesota Code Manual of Electrocardiographic. RN. 49. PhD: Stephanie Hertert. Perry Point. Lemuel A. 47.W. Joint National Committee. Greta H. MD. Washington. Tyholer. Robert McDonald. Wollam. Medical Research Institute of San Francisco. University of Tennessee. Lacy.. Prineas R. Merwyn R. Honolulu.Project Officer. NY. 24 Prevention of Stroke . MBBS. Maryland. Upper Bound for type I error and type II error rates in conditional power calculations. Elisa Serantes. Baltimore Donald J. PhD. MPH (chair). Amelia Rose. Program Office. Morton Hawkins. Jereome Cohen. MD.. PhD.82:1616-1628. RN. Health Care Financing Administration. Jeff Raines. Mortality after 10 years for hypertensive participants in the Multiple Risk Factor Intevention Trial. J. MN. RN. Naldi Ritch: Avril Sampson. MD (Principal Investigator).