Studies of left ventricular dysfunction (SOLVD) registry: Rationale, design, methods and description of baseline characteristics

CONGESllVE

HEAR-7 FAILURE

Studies of Lefl Ventricular Dysfunction (SOLVD) Registry: Rationale, Design, Methods and Description of Baseline Characteristics Shrikant I. Bangdiwala, PhD, Debra H. Weiner, MPH, Martial G. Bourassa, MD, Gottlieb C. Friesinger II, MD, Jalal K. Ghali, MD, and Salim Yusuf, MD, for the SOLVD Investigators

The Studies of Left Ventricular Dysfunction (SOLVD) comprises 2 double-blind, randomized clinical trials to test improved survival by an angiotensin-converting enzyme inhibitor in patients with lefl ventricular dysfunction, with or without congestive heart failure. Patients entering the trials may be a highly selected subset of the population of such patients; those with the worst and best prognosis are likely to be excluded. To obtain the clinical history of a broader group, a registry of 6,273 patients included a relatively unselected cohort of patients with heart failure or left ventricular dysfunction, or both, from SOLVD hospitals. Registry data were obtained from hospital records. Because data collection from medical records may lead to incomplete data and more investigations in “sicker” patients, 898 randomly chosen subjects from different disease strata were seen in clinic where neurohumoral measures, echocardiograms, x-rays and electrocardiograms were obtained, and a 6-minute walking test was performed. The design and methodologic features, and the baseline characteristics of the participants in this a-tiered registry are described, and its use in complementing the results and interpretation of the SOLVD trials is discussed. (Am1 Cardiol 1992;70:347-353)

From the Collaborative Studies Coordinating Center, University of North Carolina, Chapel Hill, North Carolina; Montreal Heart Institute Research Center, Montreal, Quebec, Canada, Vanderbilt University School of Medicine, Nashville, Temxssee; Louisiana State University Medical Center, Shreveport, Louisiina; and Clinical Trials Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland. This study was supported by contracts from Studies of Left Ventricular Dysfunction, Clinical Trials Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Manuscript received January 21, 1992; revised manuscript received and accepted April 9,1992. Address for reprints: Shrikant I. Bangdiwala, PhD, Department of Biostatistica - Collaborative Studies Coordinating Center, 137 East Franklin Street, Suite 203, Chapel Hill, North Carolina 275 14.

he Studies of Left Ventricular Dysfunction (SOLVD) is a multicenter project comprising 2 double-blind, randomized clinical trials and a patient registry. The trials evaluated the effects of the angiotensin-converting enzyme inhibitor enalapril on mortality, morbidity and quality of life in patients with left ventricular dysfunction, with or without overt congestive heart failure.’ It can be useful to conduct a prospective patient registry in conjunction with a clinical trial. Patients entering most clinical trials are a highly selected subset of the population of patients seen at the participating institutions. In SOLVD, patients with the worst prognoses, such as those who have a clear need for angiotensinconverting enzyme inhibitors2 or a contraindication to their use, were excluded, whereas those with a better prognosis may be less likely to consent to an experimental regimen. Certain subsets, such as those with primarily diastolic dysfunction, are completely excluded by design, because an ejection fraction 535% was the key entry criterion in the trials. Although randomized clinical trials provide an unbiased method of evaluating the effectiveness of a therapy, the clinical course of the participants may not necessarily reflect that of a less selected population. Registries and carefully maintained screening logs can provide information on a more repre sentative patient population and may thus help address the generalizability of results from trials. In cardiovascular research, relatively few trials have been accompanied by registries. 3-5 The best known exception is the Coronary Artery Surgery Study, where the registry was a major emphasis6-* In SOLVD, the registry has the complementary role of addressing questions that the trials may not be able to explore adequately. In addition to its use with the trials, the SOLVD Registry has a useful purpose in its own right. Since the Framingham Heart Study, there has been no broadbased evaluation of patients with clinical congestive heart failure. The spectrum of underlying disease may have changed considerably in the past 3 decades. Furthermore, the Framingham study had only 88 patients with congestive heart failure after 1 year.g Thus, the primary aim of the SOLVD Registry is to study the characteristics and clinical course of a relatively unse lected cohort of patients with left ventricular dysfunction or congestive heart failure presenting in participating hospitals in the United States, Canada and Belgium. Other aims include: (1) to describe the relation of

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SOLVD Registry participants with those in the 2 SOLVD trials; (2) to document the relation of selected patient characteristics to morbidity and mortality; and (3) to obtain a detailed characterization of a stratified subsample of such patients, using a wide range of specialized investigations. This report outlines the rationale and design of the SOLVD Registry, as well as baseline characteristics of the participants. MElHoDs OvarviewofRegistrydedgn.Relationa~the

SOLVD m The SOLVD Registry collected data on patients seen in a subset of SOLVD clinical centers during a 14-month period in 1988 to 1989. Data were collected in the following 2 stages: (1) abstracted from medical records of eligible patients (Registry Main Study), and (2) a random sample (stratified by etiolo gy) of Main Study participants was selected to undergo clinical examination and detailed investigations (Registry Substudy). The Registry Main Study examined the relation of previously specified variables routinely collected in clini-

cal practice with mortality and hospitalization overall and in subgroups of participants defined by various patient characteristics. The Registry Substudy investigated the relation of electrocardiographic and echocardiographic measures of left ventricular dysfunction and mass, frequency of arrhythmia, functional and exercise capacity, and neurohumoral levels to subsequent morbidity and mortality. Figure 1 schematically displays the relation of the various SOLVD studies. Men and women aged 21 to 80 years with an ejection fraction 135% are eligible for the SOLVD trials, with exclusions based on clinical history, recent myocardial infarction, current dependence on angiotensin-converting enzyme inhibitors, scheduled cardiovascular surgery, other major life-threatening diseases, women of childbearing potential, use of other investigational medications, and inability to give informed consent or adhere to the prerandomization protocol. Patients with congestive heart failure were eligible for the Treatment Trial, whereas those with left ventricular dysfunction but no history of overt congestive heart failure .were eligible for the Prevention Trial; 18.7% of the

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Main Registry participants and 33% of the Substudy are also in 1 of these trials. Registty study size and power: In all, 6,273 patients were recruited into the Registry from January 1, 1988, to February 28, 1989, a 14month overlap with the trials (Treatment Trial: July 1986 to February 1989; Prevention Trial: July 1986 to May 1990). Power calculations for approximate sample sixes were based on assuming a l-year mortality rate of 12% in the Registry population overall, with estimated death rates ranging from 5 to 36% for various subgroups (primarily those with rare etiologies). These calculations, performed under a variety of scenarios, generally showed excellent (20.98) power to detect between-group relative risks 12 at 3 years and in some cases even at 1 year. Phkipdmg ho@Wsr Eighteen of the 23 SOLVD centers participated in the Registry (15 in the United States, 1 in Belgium, and 2 in Canada). Each center was asked to identify 1 or 2 hospitals for participation. The hospitals represent a variety of institutions, including Veterans Administration hospitals, as well as academic and private institutions (see Appendix). The study was approved by the institutional review boards of all institutions. R-and M scmning: Patients were screened from the following 2 types of sources: (1) echocardiographic, radionuclear and cardiac catheterSOURCES OF PATIENTS

ization laboratories to identify those with an ejection fraction 145%, and (2) hospital discharge records to identify those with a clinical diagnosis of heart failure (Figure 2). Most patients (78.9%) were eligible on the basis of ejection fraction only, 13.8% on the basis of heart failure, and 7.3% on both. Ejection fraction was measured by radionuclide left ventricular angiography (multiplegated activation or tirst pass), left ventricular contrast angiography (right anterior oblique or biplane) or 2dimensional echocardiography (by either arealength method or modiied Simpson’s rule)‘O; no estimated ejection fractions were allowed. Patients recruited from discharge records had to have a primary or secondary diagnosis of congestive heart failure confirmed by radiologic evidence or signs of pulmonary venous congestion (basal or perihilar vascular blurring, Kerley B lines, alveolar or pulmonary edema, or pleural effusion secondary to congestive heart failure). All patients had to be aged 121 years; there was no upper age limit. Patients potentially eligible were listed in chronologic order on screening logs. Clinics varied in sources of screening. Nine of 18 centers recruited primarily from radionuclide laboratories; in all, 46.9% of Registry participants were from this source. Discharge records and catheterization and echocardiographic laboratories were sources of 13.8, 23.8 and 13.8% of participants, respectively. More paEchocardiographii. Radicnuclide

Catheterization Labs

All patients confirmation

with ejection of diagnosis

Hospital discharge diagnosis

CRITERIA

Eligibility

fraction < = 45% or radidogic are entered in Registry log 4

If eiection

fraction

< = 35%.

consider

for trials

FtGURE?.!iOiV9Regkby9ow&Irm.

SUB-

STUDY

Refusals

Selected

and

Conduct

echocardiogram

follow-up

via death

consent

FOLLOW-UP Long-term

index

search

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TABLE I Comparison Ventricular Dysfunction

of Categorical, Participants

Demographic at Baseline

and Health-Related

Treatment Trial (n = 2,569)

Age (yr) 21-60 61-70 71-80 >80

Men Women Black Caucasian lschemic heart disease Others etiologies Ejection fraction (%) 125 26-35 36-45 None New York Heart Association class I-II Ill-IV Diabetes mellitus Chronic obstructive pulmonary disease Smoker* Myocardial infarction *Percentages

are adjusted

to account

n

%

1,156

50.0

1,027 385 2,065 504 396 2,061 1,830 262

40.0 15.0 80.4 19.6 15.4 80.2 71.2 10.2

1,311 1,257

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Participants

Registry Main Study (n = 6,273)

n

n

%

2,215 1,521 490

52.4 36.0 11.6

3,747 476 403 3,657 3,518 304

88.6 11.3 9.5 86.5 83.2 7.2

51.0 48.9 -

1,203 3,023

28.5 71.5

1,740 828 663 257

67.7 32.2 25.8 10.0

4,221

568 1,687

48.9 65.7

994 3,382

1

5 647 226

.02

and Studies

of Left

Registry Substudy (n = 898) %

n

%

2,544 2,235 1,177 312 4,630 1,640 696 5,369 4,312 1,960

40.6 35.6 18.8 5.0 73.8 26.1 11.1 85.6 68.7 31.2

450 318 111 17 697 201 102 761 460 438

50.1 35.4 12.4 1.9 77.6 22.4 11.4 84.7 51.2 48.8

1,560 1,991 1,858 864

25.0 31.7 29.6 13.8

268 284 243 103

29.8 31.6 27.1 11.5

-

733 150 170 116

81.6 16.7 18.9 12.9

583 419

72.5 46.7

99.8 0.1 15.3 5.3

1,423 938

22.7 15.0

53.1 80.0

4,076 3,694

73.4 58.9

1

for missing data.

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Registry

Prevention Trial (n = 4,228)

tients (78.9 vs 13.8%) were recruited from laboratories than from discharge records. This difference may bias recruitment toward less ill patients, because it would disproportionately include those undergoing tests on an outpatient basis. Exclusion criteria: Potentially eligible patients fulfilling any 1 of the following conditions were excluded (percentage of total excluded is shown in parentheses): (1) any noncardiac life-threatening disease likely to significantly shorten survival (36.8%); (2) lack of reliable means to contact patient for follow-up, or lack of ade quate medical records (24.6%); (3) inability to give informed consent (patients who died in-hospital during the qualifying visit could be enrolled posthumously, if allowed by the local review board) (20.2%); (4) myocardial infarction, cardiac surgery, percutaneous translumitral coronary angioplasty or balloon valvuloplasty within 7 days (17.1%); and (5) nonvalvular congenital heart disease (1.3%). Data cokction fram me&al recoils: Coordinators completed the baseline form using the patient’s medical records (defined as any accessible data, whether from patient’s chart, laboratory files or computer records). Records were reviewed for the following: (1) demographic and clinical information; (2) evidence of pulmonary congestion on the most recent x-ray if obtained within 6 months and 27 days after myocardial infarction or cardiac surgery or procedure; (3) etiology; (4) clinical history, if obtained within previous 3 months; (5) medications in use at last contact; (6) most recent physical examination within 3 months; (7) most recent 350

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laboratory tests (sodium, potassium, blood urea nitrogen and creatinine) within 6 months; (8) most recent electrocardiogram within 3 months, but not within 72 hours of myocardial infarction; and (9) most recent coronary arteriography if within 12 months. Enrollment was defined as the date of the qualifying measurement (ejection fraction or x-,ray). Selection for Registry Substudy: Registry participants were selected for the Substudy using a randomization scheme stratified by primary etiology. All patients with rare etiologies (active myocarditis, aortic or mitral valvular heart disease, or idiopathic or specific cardiomyopathy) were selected. Patients with ischemic or hypertensive heart disease were sampled at the same rate; this varied during the recruitment period, but averaged 36% over the study. A high-quality echocardiogram, based on criteria specified in the protocol, was required at the visit before the patient was entered into the Substudy. Of 3,229 patients selected, 1,026 (32%) attended the visit, and 898 (88%) had echocardiograms of adequate quality to be included in the Substudy. Substudy evaluation procedures: The Substudy visit consisted of the following: (1) clinical history, (2) physical examination, (3) chest x-ray if not obtained within 7 days of myocardial infarction or cardiac surgery or procedure, (4) electrocardiogram if 172 hours after myocardial infarction, (5) self-administered “Ladder of Life” questionnaire” to assess global life satisfaction, (6) 7Ominute ambulatory electrocardiographic monitoring, (7) blood samples for neurohumoral determinations (plasma renin activity, norepinephrine, arginine Al JGUST 1. 1992

TABLE II Comparison of Continuous Studies of Left Ventricular Dysfunction Variable

Demographic Participants

and Selected at Baseline

Treatment

Weight (kg) Height (cm) Heart rate Systolic blood pressure Diastolic blood pressure Cardiothoracic ratio Plasma norepinephrine (pg/ml)t Plasma renin activity (ng/ml/hr)t Arginine vasopressin (pg/ml) Atrial natriuretic peptide (pg/ml)

Clinical

Trial

e + ir f f r f 5

81.4 f 74.9 f 125.4 f 77.9 f 0.50 2 435.5 +1.2 f 2.4 2 108.0 f

13.3 17.7 10.3 0.07 331.8 6.0 1.7 83.5

tPlasma renin activity values are reported only for registry participants not receiving baseline for trials) may increase plasma renin activity. If all registry substudy participants

RESULTS in conjmdh

with a clinical

Registry

14.5 12.5 16.5 9.6 0.06 209.6 2.0 1.4 68.7

Participants

trial:

Tables I and II compare demographic and selected clinical factors of Registry participants with baseline data from SOLVD trial participants. The age distribution of the SOLVD Registry participants 180 years is similar to that of the Treatment Trial participants and slightly older than that of the Prevention Trial participants. The Registry Main Study and Substudy have a slightly higher proportion of women than do the trials; there are no substantial racial differences. Differences in distribution of etiology and ejection fraction between the Registry and the 2 trials reflect design differences. Other characteristics were similarly distributed among all 3 studies. Of the Registry participants considered for but

and Randomized

Registry Main Study 79.0 170.7 81.5 127.5 77.0

‘‘2 f f f * * * * *

Registry Substudy

18.0 10.1 16.8 21.6 12.7

angiotensin-converting enzyme inhibitors, because are included, mean value is 4.8 k 10.1 nglmllhr.

vasopressin and atria1 natriuretic peptide),12 and (8) 6minute walking test. l3 The ambulatory electrocardiogram and blood for neurohumoral analysis were obtained as specified by the central laboratories.10 Fdkwup: All participants not known to have died during the initial qualifying hospital visit were contacted 1 year after enrolhnent to determine vital status and inquire about interim hospitalizations. Standard forms regarding these events were completed from hospital charts, death certificates and interviews with relatives. In all, vital status was ascertained for 98.7% of the participants, and hospitalization was ascertained for 95.8%. Subsequent follow-up will be conducted by searches of national death indexes. Training and quality controk A manual of operations providing details for all procedures for the Registry Main Study and Substudy was distributed to all coordinators. Before beginning the study, coordinators attended a 2-day training session. Coordinating center personnel disseminated protocol clarifications throughout the study. Extensive data quality checks were conducted during and at the end of the study. The central laboratories responsible for neurohumoral, echocardiographic and ambulatory electrocardiographic analyses conducted their own quality control procedures. Neurohumoral samples with known values were regularly sent with study samples and analyzed for deterioration. Use of a registry

Between

Prevention Trial

79.9 * 17.3 80.0 124.9 76.8 0.53 531.8 2.6 3.1 151.5

Variables

79.9 172.0 80.4 126.7 77.3 0.53 498.3 2.2 2.6 96.4

such treatment

t f r 2 2 f r -tf e

16.9 9.6 16.3 19.4 11.9 0.07 305.4 5.2$ 1.8 72.6

(which was not allowed

at

not randomized into either trial, 833 were receiving angiotensin-converting enzyme inhibitors and 384 refused to participate. In Table II, no substantial differences between the Registry and trial participants are seen, with the exception of certain neurohormones that were measured only in Registry Substudy participants and in a subset of the trials’ participants. In summary, patients in the Registry were approximately comparable to those in the trials, except for differences implicit by design. sdection biases: To understand the effect of the recruitment source, the distributions of selected patient characteristics were compared between patients enrolled on the basis of congestive heart failure diagnosis and left ventricular dysfunction. Table III presents the distribution of age, etiology and ejection fraction in Registry patients separately for those with and without congestive heart failure. Patients with radiologic confiiation of congestive heart failure were considerably older, and had a lower prevalence of TABLE Ill Percent Distribution in Registry Patients Age and Ejection Fraction by Status of Radiologically Congestive Heart Failure at Baseline

Without Known CHF

With CHF

Etiology lschemic heart disease Hypertensive heart disease Aortic or valvular heart disease Specific cardiomyopathy Idiopathic cardiomyopathy Myocarditis Age I 60 years Ejection fraction -< 25%*

of Etiology, Confirmed

Men (n = 766)

Women (n = 5561

Men (n = 3,864)

Women (n = 1,084)

52.9

42.3

78.0

60.5

14.8

22.3

3.4

7.1

7.4

14.4

5.3

10.7

6.3

4.3

3.3

3.2

18.4

16.6

9.8

18.1

0.3 29.8 46.3

0.2 20.1 38.4

0.2 46.8 27.7

0.4 36.7 26.8

*Patients recruited through discharge diagnosis need not have measured ejection (thus. denominators for first 2 columns are 294 and 164, respectively). Three patients had missing gender data.

fraction

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91 TABLE

Iv

Comparison

of Participants

Age I 60 years Men/women Black/white lschemic heart disease Ejection fraction I 25% Diabetes mellitus Chronic obstructive pulmonary disease Cigarette smoker Myocardial infarction Pulmonary edema Pulmonary congestion on x-ray

and Nonparticipants

38.8 68.3131.7 12.4184.8 48.0 26.5 21.8 16.9 73.4 44.7 38.4 33.8

in

50.1 77.6122.4 11.4184.7 51.2 29.8 18.9 12.9 72.5 46.7 29.6 23.7

ischemic heart disease and a lower ejection fraction than those recruited without radiologically confirmed heart failure (and thus were eligible owing to low ejection fraction). Reasons for nonparticipation in the Registry Substudy varied by clinic. Because of the greater burden on participants compared with that for the Main Study, the refusal rate was higher. Hospitals that offer tertiary care or serve a geographically dispersed population had a high nonparticipation rate because of problems of distance, which accounted for 11% of nonparticipation across all clinics. Furthermore, 14% of nonparticipants did not participate because of severe illness or physical handicap, and 28% died between the time of selection and the Substudy visit. These reasons for nonparticipation (especially the latter 2) suggest that participants in the Substudy are relatively less ill than those in the Main Study. The requirement for a good-quality echocardiogram excluded many patients after selection and consent. To examine nonparticipation biases, demographic variables and measures of severity of illness were compared between patients in the Substudy and those selected for the Substudy who did not participate (Table IV). Nonparticipants tended to be older and female, whereas participants had a higher proportion of history of smoking and myocardial infarction. Nonparticipants more frequently had history of pulmonary edema (38.4 vs 29.6%) and congestion on x-ray (33.8 vs 23.7%) than did participants. DISCUSSION

The cohort of patients in the SOLVD Registry (n = 6,273) and trials (n = 6,797) probably represents the largest group of patients with left ventricular dysfunction ever characterized. The Registry has been SUD cessful in including a broad, more representative and relatively unselected cohort compared with the trials. The large number of participants with clinically rare etiologies is a unique and statistically powerful resource for the study of morbidity and mortality in these subgroups. The Registry is also the first such cohort selected from 18 different clinical centers across 3 countries. 352

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The study of the clinical course of this cohort has the potential to provide useful insights into the hospitalbased management of congestive heart failure. In general, registries are limited by lack of standardization of inclusion and exclusion criteria, variation in screening methods, incomplete data, lack of uniformity of definitions, and referral biases. The SOLVD Registry standardized definitions, methods and procedures across clinical centers and collected data prospectively. As a hospital-based (rather than population-based) study, the Registry is limited to the referring population and is prone to biases resulting from socioeconomic and clinical differences in the types of patients seeking medical attention, differences among medical communities in decisions to measure ejection fraction or to use quantitative or estimated values, differences in the criteria for diagnosis of congestive heart failure and other uncontrolled factors. However, because the SOLVD Registry was conducted in a subset of the same hospitals where the SOLVD trials were conducted, similar biases would be found in both cohorts. Because of the absence of substantial differences in demographic and clinical variables between the Registry and the trials (other than those by design), the Registry cohort can be viewed as the population from which SOLVD trial participants would be selected, and with the aforementioned considerations, as representative of the population of patients with left ventricular dysfunction at these institutions. As expected, the participants in the SOLVD Registry are different from those in the trials. The Registry has more participants with higher ejection fractions, more older patients, fewer patients with ischemic heart disease as the etiology, more patients with hypertensive heart disease, more women, and more patients with pulmonary edema than have the trials. By design, there were proportionately more patients with very low ejec tion fractions (125%) in the SOLVD trials than in the Registry. Whereas 30% of patients in the Registry have ejection fractions >35%, by design there are no such patients in the SOLVD trials. Hence, by some criteria patients in the Registry have less illness, and by other criteria they are sicker. The purpose of the Registry appears to have been achieved, it includes patients at both ends of the spectrum of left ventricular dysfunction who were excluded from the SOLVD trials, and additional rare etiologies and pathophysiologies are also present. Acknowledgment: We wish to thank Ningling Jiang, Mark Park, Gregory Brusseau, and George Williams for statistical computing, and Linda Clark and Darla Szilvay for typing the manuscript.

APPENDIX Parliipating hospitals and central agencies: University of Michigan Hospital, Ann Arbor, Michiganz

John Nicklas,* Bertram Pitt, Jan Vasbinder, Greg Henry, Penny Papadopoulos, Laura Quain, and Susan Schreiber; University of Alabama at Birmingham, Birmingham, Alabama: William Rogers,* Vera A. *Principal AUGUST

1, 1992

Investigator

Bittner,* and Glenda H. Blackburn; We& Roxbury I4 West Roxbury, Massachusetts: Kevin M. McIntyre,* Joseph Loscalzo, G.V.R.K. Sharma, Daniel Pietro, and Patricia Woods; Mont Godinne University Hospital, Brussels, Belgium: B. Marchandise,* E. Schroeder, R. Kremer, and C. Libois-Kesch; Buffalo General Hospital, Buffalo, New York: Robert M. Kahn,* Lois D. Banks, and Nancy A. Roberts; Cook County Hospital, Chicago, Illinois: Jalal K. Ghali (until August 1990),* James Mathew (since September 1990),* Krishnan Nambudiri, Sandra Davidson, Susan Standford, Bashar Al-Aswad, and Corless Taylor; Shands Hospital, and VA Medical Center, Gainesville, Florida: Carl J. Pepine,* J. Russell Green, Eileen Handberg, Cindy Kohuth, and Lithia Wright; Victoria General Hospital, Halifax, Nova Scotia, Canada: David E. Johnstone,* Monica Francis, and Beryl Carew; Baylor College of Medicine, Houston, Texas: James B. Young,* Claudette Foreman, and Linda Miller; Michigan State University, Lansing, Michigan Philip C. Kirlin* (satellite center: Butter-worth Hospital, Grand Rapids, Michigan: Kristin McKay and Mary VanDerHospital,

Puy); Montreal Canada: Martial

Heart

Institute,

Montreal,

Quebec,

G. Bourassa (Registry Chairman),* Claude Goulet, Gilbert Gosselin, Michel Joyal, Diane Leclerc, and Suzanne Morin, Vanderbilt University School of Medicine, Nashville, Tennessee: Gottlieb C. Friesinger II (Registry Vice Chairman),* Louise A. Brown, and Yvonne D. Bernard; University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey: John B. Kostis,* Daniel M. Shindler, Sophia

Karstensen, Nora Cosgrove, Susan Krieger, and Laurie Casazza (satellite center: University of Medicine and Dentistry

of New Jersey, Browns

Mills,

New Jersey:

Barbara Hill and Lee Wood); Oregon Health Sciences University and VA Medical Center, Portland, Oregon Barry Greenberg,* Maureen Guiollotte, and Cass Lang; Rhode

Island

Hospital,

Providence,

Rhode Island:

Robert J. Capone,* Concetta F. Lamore, and Kathy Handshaw; University of Rochester School of Medicine and Dentistry, Rochester, New York: William B. Hood,* Chang-seng Liang, and Kathleen D. Miller; Overlook Hospital, Summit, New Jersey: John J. Gregory* and Trudy Kimball, Westchester Medical Center, Hawthorne, New York: Michael V. Herman,* Richard H. Kay, Melvin B. Weiss, Steven R. Ripa, and Nancy Treulieb. *Principal

Investigator

Coordinating center: Collaborative Studies Coordinating Center, Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina: Shri-

kant Bangdiwala,* Debra Weiner, Lars Ekelund, and Kirkwood Adams. Neurohumoral central laborateries: University of Texas Medical Center, Galveston, and University of Texas Health Science Center, Houston, Texas: Claude

Benedict* and David Cappohno. Echocardiography central laboratory: Methodist Hospital, Houston, Texas: Miguel Quinones.* Hdtet central laboratory: Baylor College of Medicine, Houston, Texas: Craig Pratt* and Marilyn Fran&.

Project office: Clinical Trials Branch, National Heart, Lung, and Blood Institute, National Institutes for Health, Bethesda, Maryland: Salim Yusuf (Project

Officer)* and Jeffrey Probstfield.

1. SOLVD Investigators. Studies of Left Ventricular Dysfunction (SOLVD) rationale, design, and methods. Two trials that evaluate the effect of enalapril in patients with reduced ejection fraction. Am J Cardiol 1990;6:315-322. 2. CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study. N Engl J Med 1987;16:1429-1435. 3. Lipid Research Clinics Program. The Coronary Primary Prevention Trial. Design and implementation. J Chron Dis 1979;2:609-631. 4. Aspirin in Myocardial Infarction Research Group. A randomized controlled trial of aspirin in persons recovered from myocardial infarction. JAMA 1980;43: 661-669. 5. The Systolic Hypertension in the Elderly Program (SHEP) Cooperative Research Grotto. Rationale and de&n of a randomized clinical trial on orevention of stroke in isoiated systolic hypert&sion. J Clin Epidemiol 1988;1:i197-1208. 6. Principal Investigators of CASS and Their Associates. The National Heart, Lung, and Blood Institute Coronary Artery Surgery Study (CASS). Circulation 198i;3(suppl I):l-81. 7. Chaitman BR, Ryan TJ, Kronmal RA, Foster ED, Frommer PL, Killip T, and the CASS investigators. Coronary Artery Surgery Study (CASS). Comparability of 10 year survival in randomized and randomizable patients. J Am C&Z Cardiol 1990;16:1071-1078. 8. Judge KW, Paw&an Y, Caldwell J, Gersh BJ, Kennedy JW. Congestive heart failure symptoms in patients with preserved left ventricular systolic function. Analysis of the CASS registry. J Am CON Cardiol 1991;18:377-382. 9. Margolis JR, Giium RF, Feinleib M, Brasch RC, Fabsitz RR. Community surveillance for coronary heart disease. The Framingham Cardiovascular Disease Survey: methods and preliminary results. Am J Epidemiol 1974;100:425-436. 10. SOLVD Manual of Ooerations. Collaborative Studies Coordinatine Center. Department of Biostatist&, University of North Carolina. August 1986. Il. Andrew FM, Withey SB. Developing measures of Perceived lie quality. Results from several national surveys. Social Indicator Research 1974;1:1-26. 12. Francis GS, Benedict C, Johnstone DE, Kirlin PC, Nicklas J, Liang C, Kubo SH, Rudin-Tore&y E, Yusuf S. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A suhstudy of the Studies of Left Ventricular Dysfunction (SOLVD). Circulation 1990;82:17241729. 13. Guyatt GH, Sullivan MJ, Thompson PJ, Fallen EL, Pugsley SO, Taylor DW, Berman LB. The 6-minute walk. A new measure of exercise capacity in patients with chronic heart failure. Can Med Assoc J 1985;132:919-923.

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