J CUn Epidemiol Vol. 41, No. 12, pp. 1197-1208, 1988 0895-4356/88 $3.00+0.00 Printed in Great Britain Pergamon Press plc

RATIONALE AND DESIGN OF A RANDOMIZED CLINICAL TRIAL ON PREVENTION OF STROKE IN

ISOLATED SYSTOLIC HYPERTENSION

THE SYSTOLIC HYPERTENSION IN THE ELDERLY PROGRAM (SHEP) COOPERATIVE RESEARCH GROUP

(Received in revised form 21 April 1988)

Abstract-Isolated systolic hypertension (1SHki.e. high systolic pressure with nonhypertensive (<90mmHg) diastolic pressure-is a recognized risk factor for cardiovascular disease among individuals in the age group 60 years and above. This observation suggests that antihypertensive treatment might be beneficial. Results of the Systolic Hypertension in the Elderly Program Pilot Study (SHEP-PS) indicated the ‘feasibility of a full-scale clinical trial on the efficacy of drug treatment of ISH.

The Systolic Hypertension in the Elderly Program (SHEP) is a randomized, double-blind, placebo-controlled clinical trial with the primary objective of assessing the effect of drug treatment of ISH-systolic pressure 160-219 mmHg and diastolic pressure <90-on occurrence of fatal and nonfatal stroke. This multicenter clinical trial has a sample size of 4736 participants, with high statistical power to detect a reduction of 32% or more in the study’s primary end point during the 4-6 year period of treatment and follow-up. Low dosage chlorthalidone is the main study drug. Further features of the design of SHEP and the trial’s organization are described.

Systolic hypertension Quality of life

Prevention Stroke Drug treatment Total mortality

1. INTRODUCTION

The Systolic Hypertension in the Elderly Pro- gram (SHEP) is a large-scale long-term multi- center randomized double-blind controlled trial to test efficacy of antihypertensive drug treat- ment in persons age 60 and over with isolated systolic hypertension (ISH), i.e. elevated systolic blood pressure (SBP) (160-219 mmHg) and nonhypertensive diastolic blood pressure (DBP) (~90 mmHg). ISH is an important unresolved clinical therapeutic problem; no large-scale long-term trial data are available on the treat- ment of this condition. Previous randomized controlled trials on efficacy of antihypertensive drug treatment, including the few that involved older people in their samples, have focussed on the problem of elevated diastolic pressure (90 mmHg or higher) and used diastolic hyper-

Reprint requests should be addressed to: Jeffrey L. Probstfield, M.D., Clinical Trials Branch, DECA, NHLBI, Federal Building X10, 7550 Wisconsin Avenue, Bethesda, MD 20892, U.S.A.

tension as the sole or main entry criterion [l-10].

Several population studies have shown that isolated systolic hypertension is associated with increased risk of stroke, coronary heart disease, all cardiovascular and all causes mortality in both middle-aged and older people [l l-181. Prevalence of ISH rises progressively and markedly with age, particularly among persons age 60 and older, in both men and women, black and white [19]. This results in a high prevalence among persons 60 years of age and older. In the SHEP Pilot Study (SHEP-PS), the prevalence of ISH in those screened was 6% in the age group 60-69 years, 11% in the 70-79 age group, and 18% in those 80 years and over [20].

According to data from the U.S. census, in 1980 there were 35.6 million people 60 years and older in the country. A reasonable estimate of the prevalence of ISH (i.e. SBP 2 160 mmHg and DBP ~90 mmHg) in this age group is about 8-l 1% [19]. Thus, there could be at a given time more than 3,000,OOO people with ISH

1197

1198 THE SYSTOLIC HYPERTENSION IN THE ELDERLY PWGRAM COOPERATIVE RESEARCH GROUP

in this country. The magnitude of the problem, coupled with the lack of knowledge on efficacy and safety of drug treatment of ISH, is the main basis for the SHEP trial. The purpose of this manuscript is to describe briefly the design of this placebo-controlled trial.

2. SHEP PILOT STUDY

The stage was set for a definitive trial of efficacy of long-term drug treatment for older persons with ISH by the results of the investigator-initiated SHEP Pilot Study, jointly sponsored by the National Heart, Lung, and Blood Institute (NHLBI), the National Institute of Aging (NIA) and the National Institute of Mental Health (NIMH). The SHEP Pilot Study (SHEP-PS) was a randomized, placebo- controlled trial employing drug therapy of ISH. Step 1 active medication was chlorthalidone; based on a randomized design, beta-blocker (metropolol), reserpine, or hydralazine were evaluated as Step 2 active drugs for patients requiring a second medication. The trial was conducted in five centers to test methods of recruitment, enrollment, adherence and efficacy of antihypertensive medication for lowering blood pressure in older persons with ISH; to assess side effects; and evaluate the potential of the treatment regimen to influence incidence of dementia or depression [20,21].

The five centers enrolled and randomized 55 1 participants of 27,199 persons screened, a yield of approx. 2%. Participant adherence to the treatment regimen was excellent, over 90% to both the medication regimen and the visit sched- ule for those who remained on medication. During the first year of the SHEP-PS, only 18.5% of participants stopped taking medi- cation, with a somewhat higher rate in the placebo group (19.4%) than in the active treatment group (15.6%); these rates were con- sidered acceptable [21]. Three months after ran- domization, 75% of the intervention group had reached goal SBP on diuretic therapy alone. The group on active drug therapy had a significant fall in blood pressure, averaging 17 mmHg sys- tolic and 3 mmHg diastolic at 3 months, which was sustained at 12, 24 and 36 months [22]. When asked prior to randomization about symptoms, approximately one-third of all par- ticipants reported troublesome or intolerable symptoms. At 1 year, nearly half of the par- ticipants in the intervention (44%) and placebo (48%) groups reported troublesome or intoler-

able symptoms. Thus, few symptoms could be attributed to drug treatment per se.

Results from the SHEP-PS indicated that a full-scale trial was feasible and worthwhile. Therefore, NHLBI and NIA proceeded with planning for such a trial to determine impact of drug treatment of ISH on rates of stroke, other cardiovascular end points and total mortality.

After obtaining concurrence from their re- spective national advisory councils for commit- ment of funds, in the Fall of 1983 NHLBI and NIA issued Requests for Proposals soliciting candidate organizations to serve as clinical cen- ters and a coordinating center for SHEP. From a large number of proposals, 17 (later reduced to 16) institutions were selected as clinical cen- ters, and a contract was also awarded to a coordinating center to provide data manage- ment, statistical and administrative support including the identification, selection and moni- toring of the central laboratory. Development of the final protocol formally began 1984.

in July

3. SHEP OBJECTIVES, DESIGN AND ORGANIZATION

3. I. Objectives The primary objective of the SHEP is to assess

whether or not the administration of anti- hypertensive drug therapy to persons aged 60 years and over with ISH (SBP > 160 mmHg and DBP c 90 mmHg) reduces the combined inci- dence of fatal and nonfatal stroke over a 5-year period. Incidence of total stroke (i.e. fatal and nonfatal) was selected as the primary end point because it is the major cardiovascular compli- cation most strongly associated with level of SBP, and it is the event most conclusively affected favorably by drug treatment of diastolic hypertension [9, lo].

The secondary objectives of SHEP are to evaluate:

1. The effect of long-term antihypertensive therapy on cardiovascular morbidity and mortality, on cause-specific and all-causes mortality.

2. The effect of long-term antihypertensive therapy on other selected morbidity end points (e.g. multi-infarct dementia, clinical depression, deterioration of cognitive func- tion).

3. Possible adverse effects of chronic use of antihypertensive drug treatment in older people.

Systolic Hypertension in the Elderly 1199

4. Effects of therapy on indices of quality of life, such as all hospital admissions, admis- sions to nursing homes, days of restricted activity, level of functional impairment, incidence of fractures of hip, wrist, and vertebrae.

5. The natural history of ISH in the placebo cohort.

Prior subgroup hypotheses formulated for analysis are:

1. Treatment of ISH will reduce frequency of total stroke (fatal and nonfatal) to a greater degree in those not on anti- hypertensive medication at time of screen- ing than in those on such medication.

2. Treatment of ISH will reduce incidence of sudden cardiac death, or of cardiac death plus nonfatal myocardial infarction, in those with resting ECG abnormalities at baseline to a lesser degree than in those with normal ECGs.

Although other subgroup hypotheses were considered, e.g. regarding presence or absence of prior CVD, and various demographic and personal characteristics, plausible differences as to effects of treatment gave power of less than 50%. Thus, they were not included in the design of SHEP. Considerations underlying power cal- culations for subgroup hypotheses are presented in Appendix I.

3.2. Design

SHEP is a multi-center clinical trial. Men and women aged 60 years and above with ISH- 4736 altogether-have been recruited into this double-blind, placebo-controlled, stepped-care treatment program and are to be followed for an average of 5 years (4-6 years). The primary end point of the trial is total stroke, fatal and nonfatal.

3.2.1. Sample size considerations. A re- cruitment goal of 4800 randomized participants was accepted in the design for SHEP. This number was based on the following consid- erations [23]:

(a) the primary end point is fatal and nonfatal stroke;

(b) the average follow-up period is 5 years; (c) the average annual event rate in the

placebo group is estimated at 1.6%; (d) antihypertensive drug treatment can lower

rate of nonfatal and fatal stroke by 40% [9, lo]; with allowance for dropouts (16%) and cross-overs (19”/0), the observed effect

on this primary end point will be 32%. (This estimate of dropouts and cross-overs is deemed reasonable, based on appli- cation of the lessons from the SHEP Pilot Study. The mean 40% effect observed in previous trials was achieved despite drop- outs and cross-overs);

(e) the competing risk for non-stroke death will be 15.4%; and

(f) a two-tailed test of significance (alpha level) of 0.05 and a power (one minus beta) of 0.90 are employed.

3.2.2. Treatment program. Based on the posi- tive results of the SHEP Pilot Study, par- ticipants were randomized, in equal numbers and in a double-blind manner, at each center to either chlorthalidone (Step 1 drug) or matching placebo. Baseline systolic blood pressure (aver- age of four blood pressure readings at the first and second baseline visits, BV-1 and BV-2) was used to establish a goal blood pressure for each participant. For individuals with a baseline sys- tolic blood pressure above 179 mmHg, the goal is a reduction to no higher than 159 mmHg. For those at 160-179 mmHg, the goal is a reduction by at least 20 mmHg.

The objective of the treatment program is to use the minimal amount of medication that keeps systolic blood pressure at or below goal. All participants are started on 12.5 mg/day of chlorthalidone (or matching placebo). Beta- blocker (atenolol) (25 mg/day) is the usual second-step drug. When atenolol is contra- indicated, reserpine (0.05 mg/day) can be substituted. In an effort to reach goal blood pressure, the drug dose can be doubled (i.e. step-up procedure) unless intolerable side effects or potentially serious changes in blood chem- istry (collectively termed adverse effects) occur. The SHEP clinic visit and treatment schedule is depicted in Fig. 1.

3.2.3. Administrative organization. The par- ticipating units of the trial-16 Clinical Centers, a Coordinating Center, ECG Laboratory, Cen- tral Laboratory, CT Scan Reading Center, Drug Distribution Center and Project Office-are administratively linked through a structure designed to enhance effective commu- nication and collaboration, as well as to moni- tor and maintain operations of the trial. Each participating unit was involved in the planning and development phase of the trial and con- tributed to the writing of the Protocol and Manual of Operations.

1200 THE SYSTOLIC HYPERTENSION 1~ THE ELDERLY PROGRAM COOPERATIVE RESEARCH GROUP

Atenolol,A~,SOmg w_..__.___

Chlorthalldone

Chlorthalldono

t I 1 I I I I I I I I

_______a__

-4 -2 0 8 16 24 TIME IN WEEKS

TAll those first seen while on antl-hypertenslves must have these drugs dlroontinued (see text) through an additional series of visits.

0 Indicates those with BP not reduced to or below goal.

#IIndIcates those with BP reduoed to or below goal.

Fig. 1. SHEP clinic visit and treatment schedule; IC is initial contact, BV, and BV, are baseline visits 1 and 2, respectively; drug dosages are per day.

A Steering Committee, composed of a chair- man, the SHEP Principal Investigators and NHLBI and NIA staff, is the decision-making body for the scientific and technical conduct of the study. SHEP also has a Data and Safety Monitoring Board (DSMB) composed of inde- pendent scientists who are experts in fields relevant to the trial. The Steering Committee Chairman, Director of the SHEP Coordinating Center, and representatives of the Program Office at NHLBI and NIA serve as ex-officio members of the DSMB. This board periodically reviews and evaluates study progress, including data on recruitment, quality control, adherence to clinic visit schedule and to medication, blood pressure control, adverse effects of medication and fatal and nonfatal events. Members of the DSMB make recommendations, as appropriate, regarding the safe conduct and continuation of the study.

4. ENROLLMENT AND FOLLOW-UP PROCEDURE

Recruitment efforts for SHEP, which pro- ceeded from 1 March 1985-15 January 1988, combined mass mailing and community screen- ing techniques. Community screening of age- eligible persons focused on sites where elderly

persons are likely to congregate, such as senior centers, group meal sites, senior housing devel- opments and selected shopping centers and churches. Mass mailings utilized a variety of available lists of age-eligible persons, such as voter registration and drivers license lists. Several centers coupled mass mailings with community screening efforts by conducting mass mailings to targeted zip codes announcing future screenings in that area.

4.1. Recruitment visits

All potential participants thus identified first underwent an initial contact, to exclude individ- uals clearly not eligible by age or blood pressure criteria.

4.2.1. Initial contact. Information collected at the initial contact included: date of birth, whether or not the person was taking anti- hypertensive medications, and one seated blood pressure reading taken with a Hg sphygmo- manometer. For persons not on antihyper- tensive drugs and with a first systolic blood pressure reading > 150 mmHg, two more read- ings were taken. With a mean of these latter two readings in the range 160-219 mmHg SBP and < 100 mmHg DBP, the person was eligible for

Systolic Hypertension in the Elderly 1201

Table 1. SHEP blood pressure eligibility criteria*

Initial contact:

DEV- 1

DEV-2t

BV-1

BV-2

Not on antihypertensive medications

SBP 160-219 mmHg DBP < 100 mmHg Not applicable

Not applicable

SBP I SO-219 mmHg DBP < 95 mmHg SBP IS&219 mmHg DBP < 95 mmHg

On antihypertensive medications

SBP 130-219 mmHg DBP < 85 mmHg SBP 130-219 mmHg DBP < 85 mmHg SBP 160-219 mmHg DBP < 100 mmHg

and average of BV-1 and BV-2: SBP 160-219 mmHg DBP ~90 mmHg

*Mean of second and third readings in the series for DBP and SBP values at initial contact and all drug evaluation visits; mean of two sitting determinations at baseline visits 1 and 2.

tOr subsequent visit in evaluation period, up to 8 wk after withdrawal of anti- hypertensive medications; participants with SBP less than 160 mmHg continue to be followed until SBP is in eligible range, SBP or DBP rise above eligible levels, or the 8wk evaluation period ends.

BV-1 at the clinical research center and every effort was made to schedule him/her for that visit.

Persons on antihypertensive medications at initial contact, with DBP ~85 mmHg, were eligible for a drug withdrawal procedure mon- itored carefully at multiple drug evaluation vis- its (DEV) over short intervals. Participants who qualified to participate in the DEV process were asked to obtain permission of their personal physicians and to sign an informed consent for drug withdrawal. They were followed closely for 8-10 wk of DEV process to determine their blood pressure eligibility. SHEP blood pressure eligibility criteria are described in Table 1.

4.1.2. Baseline evaluation visits. This phase, which consisted of two visits, represented the beginning of data transmission to the SHEP central data base. Eligibility was established based on the study inclusion and exclusion critera listed in Table 2. Since SHEP is a placebo-controlled trial, patients were excluded on the basis of a history and/or signs of major cardiovascular disease likely to require pharma-

cologic and other treatment, e.g. previous myo- cardial infarction (MI), coronary artery surgery, major arrhythmias, conduction defect, recent stroke, carotid artery disease, history of tran- sient ischemic attack (TIA) with a bruit matched with TIA localization, two or more TIAs and signs or symptoms in a single neurological distribution. Major disease with resultant com- peting risk in regard to the SHEP primary end point was also a basis for exclusion, e.g. renal insufficiency. Persons with possible major prob- lems of medical management*.g. those with insulin dependent diabetes, history of dementia, evidence of alcohol abuse-were also excluded. Also, incidence of dementia is an important secondary end point of the trial, and this too was a reason for excluding persons with this condition at baseline. Since a beta blocker is the Step 2 medication for the SHEP active treat- ment group, persons with bradycardia were also excluded, as were people maintained on beta- blockers, diuretics, other antihypertensive drugs, anticoagulants, or experimental drugs on recommendation of their physicians.

Table 2. Major SHEP inclusion and exclusion criteria

1. Inclusion Age: 260 years BP: SBP 16CL219 mmHg

DBP < 90 mmHg 2. Exclusion

(a) Atria1 fibrillation or flutter, A-V block, multifocal VPB, bradycardia less than 50 beats per min, or permanent pacemaker

(bl Recent MI, recent stroke with residua, coronary bypass surgery during past 6 months, insulin dependent diabetes, dementia, history of renal insufficiency, dementia, or alcohol abuse

1202 THE SYSTOLIC HYPERTENSION IN rns ELDERLY PROGRAM CWPERATIVE RESEARCH GROUP

At the baseline visits, participants received a physical examination including a 1Zlead ECG. Blood pressure was measured with a Hawksley random-zero manometer, and this device is be- ing used throughout the trial to reduce observer bias. Systolic pressure is defined as the pressure at the first recognized Korotkoff sound. Di- astolic pressure is defined as the last Korotkoff sound. Since so-called pseudo-hypertension was deemed to be a low prevalence condition in persons eligible for SHEP, and randomization would assign people with this condition to the two groups with comparative probability, the SHEP design did not provide for procedures to assess this condition [24].

If the participant was eligible at BV-2, he/she received a behavioral assessment and was re- quested to sign an informed consent for par- ticipation in the trial. Randomization took place at BV-2 after informed consent was reviewed and signed.

4.2. Randomization

Immediately after completion of BV-2, el- igible participants were randomly allocated to either active treatment or placebo regimen. Randomization was stratified by clinic center and by antihypertensive medication status (on or off) at initial contact. The random assign- ment to one of the two study groups was made by the coordinating center and transmitted to the clinical center by telephone after verification of eligibility was completed. Each participant was assigned a drug bottle number for the Frst step and dose of the treatment program. A randomization report was then mailed to each clinical center.

Restricted randomization was used to ensure

that sample sizes were about equal in the active and placebo treatment groups during the course of recruitment. All analyses are to be based on participants’ original treatment group assign- ment (i.e. the “intention to treat” principle).

4.3. Follow-up procedures

SHEP participants are followed monthly until their SBP reaches goal or until the maximum level of stepped care is reached. All participants also have quarterly visits from date of random- ization. Components of the behavioral evalu- ation, which allow for rapid assessment of de- pression, dementia and impairment of activities of daily living, are administered at most quar- terly visits, in addition to measurement of blood pressure, heart rate, body weight, a general medical history of symptoms and complaints and a detailed review of prescribed and over- the-counter medications being taken (including aspirin-containing preparations). SHEP labora- tory tests and their frequency of administration are shown in Table 3.

In addition to the required visits described above, other visits may be scheduled in the SHEP clinic for various reasons. These include the following:

1. The participant is above goal SBP. 2. The participant is at “escape” SBP or DBP

levels (see Section 4.4 below). 3. The serum potassium is less than

3.2 mEq/l. 4. The clinician or patient feel that a clinic

visit is necessary.

The SHEP Manual of Operations specifies approaches for dealing with these and other medical needs of the participants.

Table 3. Laboratory and ECG procedures and their frequency

Procedures

Serum chemistries: Alkaline phosphatase Blood urea nitrogen Calcium Creatinine Glucose SGOT Sodium Uric acid

Serum potassium

Frequency

Baseline and annual

Basline, 1 month, annual plus visit after Step 1 dose is increased

Total serum cholesterol, HDL cholesterol and triglycerides Baseline, year 1, year 3 and final annual Hb/Hct, WBC (local) Baseline and annual Qualitative test for urine chlorthalidone Year 1 Dipstick urinalysis (local) Baseline and annual ECG and 2-min rhythm strip Baseline, year 2 and tinal annual

Situation

Systolic Hypertension in the Elderly

Table 4. SHEP systolic blood pressure escape criteria

SBP level Action

1203

I. Anytime > 240 mmHg Individual “open-label”* therapy should be initiated 2. Participant not on maximum dosage 220-239 mmHg Return in 2 wk; if SBP remains above 220 mmHg, move to

of study drugs next drug dose or step 3. Participant on maximum dosage of 220-239mmHg Return in 2 wk; if SBP remains above 220 mmHg, individual

study drugs open-label therapy should be initiated

*Open label means double blind is broken and participant is treated with a stepped care regimen of active antihypertensive medication; this may include one or more drugs different than the SHEP active medications.

4.4. Monitoring for escape blood pressure levels repeated to study any impact related to elevated and adverse efects SBP and its treatment.

An escape blood pressure indicates a special action. SBP and DBP escape criteria, listed in Tables 4 and 5, are predefined, and the required actions are specified in the SHEP Manual of Operations. If conditions occur that may be harmful and are considered drug-related ad- verse effects (e.g. symptomatic postural hypo- tension, depression, asthma or bronchospasm, Raynaud’s phenomena, serious lethargy), the medication (or placebo) thought to be associ- ated with that adverse effect may be stepped down to progressively lower levels (or immedi- ately discontinued, if warranted by severity of adverse effects). Whenever medication is reduced or discontinued, consideration is given on a regular basis to carefully resuming study drug if the blood pressure goes above goal, provided the participant is willing to cooperate.

The behavioral assessment consists of two parts. Part 1 is designed to assess the most critical behavioral functions and is administered in all SHEP centers. It includes a modified version of the Shortcare, a series of questions which screen for the presence of depression or dementia [25], the Center for Epidemiologic Studies Depression Scale [26], an activities of daily living scale [27] and a social network questionnaire [28]. In addition to these func- tions, an expanded behavioral battery called Behavioral Part 2 is administered annually in six of the 16 clinics. The purpose of this expanded battery is to provide tests of cognitive function more sensitive to subtle changes over time.

5. MORTALITY AND MORBIDITY END POINTS

4.5. Behavioral evaluation

Lowering SBP in older persons could have either an adverse or a beneficial effect on overall quality of life or on specific areas of physical, cognitive, affective, or social function. There- fore, a comprehensive behavioral assessment was developed to study each of these dimensions as well as the participant’s global self- assessment of his or her quality of life. As mentioned previously, the behavioral assessment was administered at baseline and is periodically

Mortality and morbidity end points are listed in Table 6, with a brief definition of each. For possible strokes, a neurological evaluation is carried out by a SHEP neurologist. This evalu- ation plus all notes by other neurologists, a CT or MRI scan, X-rays, or other studies of the head, and any other pertinent information are sent to the coordinating center. Based on all available pertinent information, each end point diagnosis is confirmed by the unanimous vote of a team consisting of three physician in- vestigators who are blinded to the random-

Table 5. SHEP diastolic blood pressure escape criteria

Situation DBP level Action

I. Anytime 3115mmHg Individual open-label therapy should be initiated 2. Participant not on maximum dosage 95-114 mmHg Return in 1-2 wk; if DBP remains 95114, move to next drug

of study drugs dose or step; return in l-2 wk and repeat step-up until DBP is less than 95 or maximum dose of study drugs reached

3. Participant not on maximum dosage 9(r94 mmHg On two consecutive monthly visits; move to next drug dose of study drugs or step; repeat until DBP 190 or maximum dose of study

drugs reached 4. Participant on maximum dosage of 9S-114mmHg Return in 1-2 wk; if DBP still 9>114, initiate individual

study drugs open-label therapy 5. Participant on maximum dosage of 90-94 mmHg On three consecutive monthly visits; initiate open-label drug

study drugs or nonpharmacologic therapy

C.E 11,12--E

1204 THE SYSTOLIC HYPERTENSION IN THE ELDERLY PRCIGRAM COOPERATIVE RESEARCH GROUP

Table 6. Definitions of major cardiovascular events

Type of event

Stroke

Left ventricular failure

Transient ischemic attack

Myocardial infarction

Sudden death

Angina pectoris Multiinfarct-dementia

Criteria for event

Abrupt onset of new neurologic deficit lasting at least 24 hr, with specific localizing finding confirmed by unequivocal physical examination or laboratory data and without evidence for an underlying nonvascular cause Dyspnea or fatigue associated with a third heart sound or increased jugular venous pressure and basilar rales or increased markings on X-ray Rapid onset of a focal neurologic deficit lasting less than 24 hr, assessed to be due to ischemia, without evidence for an underlying nonvascular cause Definite ECG evidence for an acute myocardial infarction, or probable ECG evidence plus transient abnormal enzymes, or prolonged cardiac pain plus transient abnormal enzymes, or definite autopsy evidence Death within 1 hr of first evidence of acute cardiovascular symptoms or signs and unrelated to other known disease Positive Rose questionnaire at annual visit SHORT-CARE, score of 4 or greater on two consecutive visits and neurological evaluation including CT-scan and Haschinski score

ization allocation. If these three fail to reach a unanimous decision, the entire membership of the SHEP Morbidity and Mortality Committee, also blinded to the randomization allocation, arbitrates by a majority vote.

6. CONCLUSION

Isolated systolic hypertension is a frequently encountered problem in the older population. It is associated with a significantly increased risk of mortality and morbidity. Whether pharma- cological treatment confers benefit or not in terms of reduced incidence of cardiovascular diseases, particularly incidence of stroke, is un- known. There is also a need to determine whether or not such treatment has an effect (favorable or unfavorable) on multi-infarct de- mentia, psycho-social status and general quality of life. Other completed or ongoing clinical trials in the U.S. and elsewhere, which dealt with the issue of efficacy of drug treatment of hypertension in older population groups with

high diastolic pressure, did not address the important questions posed in the SHEP design. This is the case in regard to the European Working Party on High Blood Pressure in the Elderly Trial [5,6], the randomized trial of treatment of hypertension in elderly patients in primary care [7], the Swedish Trial in Old Patients with Hypertension, STOP-Hyper- tension [8] and the HDFP in its subgroup aged 60-69 years at entry [3].

The results of SHEP are expected to be available in the early 199Os, and may help resolve these issues of major importance to medical practice and public health in our ever- increasing older population.

Acknowledgements-SHEP is a national cooperative random- ized controlled trial funded by the National Heart, Lung, and Blood Insitute and the National Institute of Aging. The project is supported by the HHS Contracts, numbers: NO-HC-48052, NO-HC-48053, NO-HC-48054, NO-HC- 48055, NO-HC-48056, NO-HC-48057, NO-HC-48058, NO- HC-48060, NO-HC-48061, NO-HC-48062, NO-HC-48063, NO-HC-48064, NO-HC-48065, NO-HC-48066, NO-HC- 48067, NO-HC-48068, NO-HC-48069.

The following is a listing of key professional personnel of the trial at its clinical and support centers: Albert Einstein College of Medicine

Principal investigator: M Donald Blaufox, MD, PhD Co-principal investigator: Sylvia Wassertheil-Smaller, PhD Key personnel: William Frishman, MD

Zirel Sweezy Gail Miller, RN Judy F Dillon, RN

Emory University S&ml of Medicine Principal investigator: Key personnel:

W Dallas Hall, MD Deanne Unger, RNC Cori Hamilton, MPA Gail McGray

Kaiser Pemanente Center for Health Research Principal investigator: Co-principal investigator: Key personnel:

Thomas Vogt, MD, MPH Merwyn R Greenlick, PhD Kathy Reavis, RN Stephanie Hertert Vicki Wegener, RN, FNP

Systolic Hypertension in the Elderly 1205

Medical Research Institute of San Frracisco Principal investigator: Co-principal investigator: Co-investigator: Key personnel:

McFate Smith, MD, MPH S Leonard Syme, PhD Philip Frost, MD Jacqueline Smith, RN Geri Bailey, RN Ann Slaby, MS

Miami Heart Institute Principal investigator: Co-investigator Key personnel:

Northwestern University Medical Schaol Principal investigator: Co-principal investigator: Co-investigator: Key personnel:

Pacific Health Research Institute Principal investigator: Former principal investigator: Co-principal investigator: Key personnel:

Robert Wood Johnson Medical School Principal investigator: Co-investigator: Key personnel:

University of Alabama, Birmingham Principal investigator: Co-principal investigator: Key personnel:

University of California, Davis Principal investigator: Co-investigator: Key personnel:

University of Kentucky Medical Center Principal investigator: Co-principal investigator: Former principal investigator: Co-investigator: Key personnel:

University of Minnesota Principal investigator: Co-principal investigator: Key personnel:

Jeffrey Raines, PhD, FACC Frank L Canosa. MD Melissa Jones Avril Sampson, MD Maria Terris, MD Garcia Garrison-Thomas, RN, MSN

David Berkson, MD Jeremiah Stamler, MD Rose Stamler, MA Hemantha Surath, MD Flora Gosch, MD Gina Civinelli Patricia Hershinow, RN Joseph Harrington Edna Pardo

Helen Petrovich, MD J David Curb, MD, MPH Fred I Gilbert. Jr. MD Mary Hoffmeikr, RN Lei Honda-Sigall, RN Sandra Bon Akina, RN Frances Wakashige

John B Kostis, MD Clifton R Lacy, MD Nora Cosgrove, RN Susan Krieger, RN

Harold W Schnaper, MD Glenn Hughes, PhD Phillip Johnson Pat Pierce Lisa Carlisle Julia Hall

Nemat 0. Borhani, MD, MPH Philip G Weiler, MD Marshall Lee, MD Alfred0 Burlando. MD Francis LaBaw, RN Susan Pace, RN Patty Borhani

Gordon Guthrie, MD John Wright, MD Theodore Kotchen, MD William Markesbery, MD Jane Kotchen, MD Arlene Johnson, PhD Rita Schrodt, BSN Ellen Y. Christian. PA-C Shelley Felder

Richard H Grimm, Jr, MD, PhD Marvin S Segal, MD Stephen Mascioli, MD Julie Levin Mary Perron, RN Mary McDonald, RN, ANP

1206 THE SYSTOLIC HYPERTENSION IN THE ELDERLY PROGRAM COOPERATIVE SEARCH GROUP

University of Pittsburgh Principal investigator: Co-principal investigator: Key personnel:

University of Tennessee Principal investigator: Co-principal investigator: Key personnel:

Robert McDonald, MD Lewis H Kuller. MD Mary Beth Al&an, RN Shirley Arch (deceased) Betsy Gahagan, RN Jerry Noviello, PhD

William A Applegate, MD, MPH Stephen T Miller, MD Laietha Goodwin, RN Alice Wallace. RN Janet Elam, SS

Washington University Principal investigator: Co-principal investigator: Key personnel:

H Mitchell Perry, Jr, MD Greta Camel, MD Jerome Cohen, MD Sharon Carmody Judy Jensen, RN Elizabeth Perry Diana Tessereau, RN

Yale University Principal investigator: Co-principal investigator: Key personnel:

Henry Black, MD Charles K Francis, MD Janice A Davey, MSN Lynn Lanoue Linda Loesch Diane Christianson, RN

Coordinating Center, The University of Texas Health Science Center at Houston, School of Public Health Principal investigator: C Morton Hawkins, ScD Co-principal investigator: Barry R Davis, MD, PhD Key personnel: Sara Pressel, MS

Robert Byington, PhD Lemuel A Moye, MD, PhD Richard B Shekelle, PhD Darwin R Labarthe, MD, PhD Robert J Hardy, PhD William Fields, MD

Program Office, National Heart, Lung, and Blood Institute Project officer: Jeffrey L Probstfield, MD Deputy project officer: Eleanor Schron, RN, MS Former project officers: Jeffrey A Cutler, MD, MPH

Curt Furberg, MD, PhD Biostatistics branch: Janet Wittes, PhD

Edward Lakatos, PhD Contracting officer: C Eugene Harris Contract specialist: Linda Gardner

National Institute on Aging Lot B Page, MD J David Curb, MD, MPH

Steering Committee Chairman Kenneth G Berge, MD

Data and Safety Monitoring Board Chairperson: Members:

James C Hunt, MD CE Davis. PhD

Central Chemical Laboratory

Raymond’ W Gifford, MD Millicent W Higgins, MD Adrian M Ostfeld, MD John W Rowe, MD K. Warner Schaie, MD Herman A. Tyroler, MD Jack P Whisnant, MD Joseph A Wilbur, MD

S Raymond Gambino, MD

Systolic Hypertension in the Elderly 1207

Drug Distribution Center Richard Moss

CT Reading CVG Krishna Rao, MD R Nick Bryan, MD, PhD

ECG Laboratory Ronald J Prineas, MB, MS, PhD Denise Hesselroth

Consultants to SHEP Marilyn Albert, PhD, Assistant Professor, Psychiatry and Neurology, Harvard Medical School and Massachusetts General Hospital

Lisa F Berkman, PhD, Associate Professor, Epidemiology, Yale University School of Medicine

Judy Luhr, PhD, Department of Neuropsychology, Long Island Jewish Medical Center

Thomas R Price, MD, Department of Neurology, University of Maryland Hospital

Kenneth Schneider, MD, Director of Hospital Laboratories, Department of Pathology, Duke University Medical Center

Drugs are being supplied by the Lemmon Company, AH Robins and Stuart Pharmaceuticals.

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REFERENCES

Veterans Administration Cooperative Study Group on Antihypertensive Agents. Effects of treatment on mor- bidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114mmHg. JAMA 1970; 213: 114331152. Management Committee of the Australian Therapeutic Trial in Mild Hypertension. The Australian theraoeutic trial in mild hypertension-Report by the Management Committee. Lancet 1980: 1: 1261-1267. Blaufox MD (Guest Ed.); Hypertension Detection and Follow-up Program Cooperative Group Editorial Board. Results and implications of the Hypertension Detection and Follow-up Program. Prog Cardiov Dis 1986; 29 (Suppl 1): I-124. Medical Research Council Working Party. MRC trial of treatment of mild hypertension: principal results. Br Med J 1985; 291: 97-104. Amery A, Birkenhlger W, Brixko P, Bulpitt C, Cle- ment B, Deruyttere M, DeSchaepdryver A, Dollery C, Fagard R, Forette F, Forte J, Hamdy R, Henry JF. Joossens JV, Leonetti G, Lund-Johansen P, O’Malley K, Petrie J, Strasser T. Tuomilehto J. Williams B. Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly Trial. Lnncet 1985; 1: 1349-1354. Amery A, Birkenhlger W, Brixko P, Bulpitt C, Cle- ment D, Deruyttere M, DeSchaepdryver A, Dollery C, Fagard R, Forette F, Forte J, Hamdy R, Henry JF, Joossens JV, Leonetti G, Lund-Johansen P, O’Malley K, Petrie JC, Strasser T, Tuomilehto J, Williams B. Efficacy and antihypertensive drug treatment accord- ing to age, sex, blood pressure and previous cardio- vascular disease in patients over the age of 60. Lancet 1986; 2: 589-592. Coope J, Warrender TS: Randomized trial of treat- ment of hypertension in elderly patients in primary care. Br Med J 1986; 293: 1145-1151.

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Dahlof B, Hansson L, Lindholm L, Rastam L, Scher- sten B, Wester PO. STOP Hypertension: Swedish trial in old patients with hypertension. J Hypertension 1986; 4: 51 l-513. MacMahon SW, Cutler JA, Furberg CD, Payne GH. The effects of drug treatment for hypertension on morbidity and mortality from cardiovascular disease: a review of randomized controlled trials. Prog Cardiov Dii 1986; 29 (Suppl 1): 99-118. Hebert PR, Fiebach NH, Eberlein KA, Taylor JO, Hennekens CH. The community-based randomized trials of pharmacologic treatment of mild-to-moderate hypertension. Am J Epidemiol 1988; 127: 581-590. Build and Blood Pressure Study. Society of Actuaries Vol. I. Chicago; 1959. Shekelle R, Ostfeld A, Klawans HL Jr. Hypertension and risk of stroke in an elderly population. Stroke 1974; 5: 71-75. Kannel WB, Dawber TR, Sorlie P, Wolf B. Com- ponents of blood pressure and risk of athero- thrombotic brain infarction: the Framingham study. Stroke 1976; I: 327-331. Dyer AR, Stamler J, Shekelle RB, Schoenberger JA, Farinaro E. Hypertension in the elderly. Med Clin North Am 1977; 61: 513-529. Colandrea MA, Friedman GD, Nichaman MZ, Lynd CN. Systolic hypertension in the elderly. An epi- demiologic assessment. Circulation 1970; 4 1: 239-245. Garland C, Barrett-Connor E, Suarez L, Criqui MH. Isolated systolic hypertension and mortality after age 60 years. A prospective population-based study. Am J Epidemiol 1983; 118: 365-376. Curb JD, Borhani NO, Entwisle G, Tung B, Kass E, Schnaper H, Williams W. Berman R. Isolated svstolic hypertension in 14 communities. Am J Epidemioi 19851 121: 362-370. Stamler J. Blood pressure (systolic and diastolic) and risk of fatal coronary heart disease. Hypertension, in press. Blood Pressure of Adults by Race and Area: United States, 1976-80. National Center for Health Statistics: 1986; Series I I, No 234. Smith WM (for the SHEP-PH Group). Isolated sys- tolic hypertension in the elderly program. Curr Med Res Opinion 1982; 8: 19-29. Hulley SB, Furberg CD, Gurland B, McDonald R,

1208 THE SYSTOLIC HYPERTENSION IN m ELDERLY PROGRAM COOPEUTIVE RESEARCH GROUP

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Perry M, Schnaper HW, Schoenberger JA, Smith WM. Vogt TM (for the SHEP Research Group). Systolic Hypertension in the Elderly Program (SHEP): anti- hypertensive efficacy of chlorthalidone. ‘Am J Car&l 1985; 56: 913-920. Black DM, Brand RJ, Greenlick M, Hughes G, Smith J (for the SHEP Pilot Research Group). Compliance to treatment for hypertension in elderly patients: the SHEP pilot study. J Ceront 1987; 42: 552-557. Lakatos E. Sample size determination in clinical trials with time-dependent rates of losses and non- compliance. Controlled Clin Trials 1986; 7: 189-199. O’Callaghan WG, Fitzgerald DJ, G’Malley K, O’Brien E. Accuracy of indirect blood pressure measurement in the elderly. Br Med J 1983; 286: 1545-1546. Garland B, Golden RR, Teresi JA, Challop J. The short-care: an efficient instrument for the assessment of depression, dementia and disability. J Cerontol 1984; 39: 166169. Radloff LS. The CES-D scale: a self-report depression scale for research in the general population. Appl Psycho1 Meas 1977; 1: 385401. Branch LG, Katz S, Kniepmann K. A prospective study of functional status among community elders. Am J Public Health 1984; 74: 266268. Branch LG, Berkman LF, Brock DB, Cosmatos D, Keough ME, Lemke JH, McGloin J, Morris MC. Social functioning. In Cornoni-Huntley J, Brock DB, Ostfeld AM, Taylor DO, Wallace RB, Eds. Established Populations for Epidemiologic Studies of the Elderly. Resource Data Book, NIH Publication No 864443. Bethesda MD: National Institutes of Health; 1986: 33-55.

APPENDIX I

Considerations for Power Calculation for Subgroup Hypotheses

Those who are taking antihypertensive agents at first screening and qualify for the trial after medication with- drawal may represent, in part, individuals with diastolic hypertension whose blood pressure has not risen to the pretreatment level during the drug evaluation visits to the SHEP clinics. They may also represent individuals who may be sicker than those not on antihypertensives at screening visits. If the net reduction in primary end points for those not on medication when initially screened is 40% while the net reduction for those initially on medication is only IO%, then the power to detect the difference in treatment effect is 80%. This power will be similar for detecting the 3040% effect among those participants not on antihypertensive medications (“pure ISH”), i.e. 80%.

The assumption for the subgroup hypothesis in par- ticipants with certain baseline ECG abnormalities is that they may be at increased risk for sudden death when treated with antihypertensive agents. If we assume that the 5-year sudden death rate is 1.3% among all participants random- ized to the control group, that 35% of the participants have ECG abnormalities, that among those with normal ECGs the reduction in the rate of sudden death is 20%, and that among the participants with ECG abnormalities, the sudden death rate in the treated group is 20% higher than among the controls, then the power to detect a difference in the treatment effects between the two groups would be 60%. It should be noted that doses of chlorthalidone used in SHEP are lower than what was used in other trials.