Prognostic significance of mitral regurgitation in acute myocardial infarction

The

CORONARY ARTERY DISEASE

American Journal of Cardiology

MAY 15, 1990, VOL. 65, NO. 18

Prognostic Significance of Mitral Regurgitation in Acute Myocardial Infarction Benico Barzilai, MD, Vicki G. Davis, MS, Peter H. Stone, MD, Allan S. Jaffe, MD, and the MILIS Study Group

To define the freqwuy, natural histary and dinical mmmurofmitralregvgiitation correlatesoftbe (MR) deteded after myocardhl infardion, dinkal datafrom649patkntswithdocumentedacute myocardial infarction were w. A rrmrrmr ruggsrthreofMRwaspresentonadmissionin76 patkmts (9%). Patients with MR on a&nissh were olderandmoreapttobefemaleandltmvhRe. Theyalsohadasi@fkntlygreaterfrequaneyof prior infarction and signs and symptoms of congestiveheartfailure.Therewasnodhrenceinthekcation (anterior or infehr) of infarcth. Patients withMRona&nisdonhada36%m&alitycomparedto16%forthosewhodevebpedMRlaterin thahospitakathandlS%forthosewRhoutMR by ausaWtion (p
‘itral regurgitation (MR) occurs frequently in patients with myocardial infarction and is -associated with diminished long-term survival.‘” However, the extent to which MR contributes to or is solely a marker of adverseprognosisis unclear.4 The Multicenter Investigation of the Limitation of Infarct Size (MILIS) was designedto assessthe effectsof hyaluronidase, propranolol, or both, in patients with proven acute myocardial infarction.5 An extensive data set was collected for all patients including an initial history, initial and sequentialphysical examinations, radionuclide testsof ventricular function; frequent enzymatic analysesand assessmentsof short- and long-term mortality. The databasefrom this study thus offers a umque opportunity to further define the natural history of the murmur suggestiveof MR, to investigate the relation of MR to other clinical and laboratory characteristics and to clarify the independent contribution of clinically detected MR to short- and long-term prognosis.

M

METHOD9 A detailed description of the MILIS protocol has been presentedelsewhere.5In brief, patients were eligible for enrollment in MILIS if they were under 76 years of age, had at least 30 minutes of chest discomfort typical of myocardial ischemia and electrocardiographic changessuggestiveof acute ischemia and presented< 18 hours from the onset of chest discomfort. Data eoRa&mr After enrollment, baseline studies were performed before administration of the study drug. The effects of the study drugs on infarct size, ventricular function and mortality have been reported elsewhere.6-8 Baseline measurementsincluded a detailed history and physical examination, 12 electrocardiograms and a resting radionuclide ventriculogram. Serial blood sampleswere collected for measurementof total and creatine k&se-MB on admissionand sampling was From the Cardiovascular Division, Washington University School of continued for the length of the hospital stay. Analysis of Medicine, St. Louis, Missouri, and Cooperating Institutions of the all data was performed at centralized Core LaboratoMulticenter Investigation of the Liitation of Infarct Sii. Thii study ries. Daily physical examinations were performed by inwas supported by contracts NOl-HV-7-2940, 7-2941, 7-2942 and 7vestigators involved in the study. Throughout the hospi2979 from the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services, talization, a MILIS data coordinator recorded the deBethesda,Maryland. Manuscript receivedSeptember 6,1989; revised tails of the daily histories and physical examinations, manuscript receivedand acceptedJanuary 10,199O. recordedall specialproceduresand summarizedthe daiAddress for reprints: Allan S. Jaffe, MD, Washington University School of Medicine, 660 South Euclid, Box 8086, St. Louis, Missouri ly clinical events including the results of all laboratory tests. Follow-up examinations were conducted 3 to 6 63110. THE AMERICAN JOURNAL OF CARDIOLOGY MAY 15, 1990

1169

8

Percentage of 6 Total Population

1

A

2

4

3

6

5

7

8

9

loll

Day tmJREl.pammbgeof~~withmltral

~~tothedsyof~.A=nmbdon.

months after enrollment. Long-term morbidity and mortality were ascertainedat 6-month intervals by telephone. Myocardial infarction was confirmed by measurement of creatine kinase-MB.9 Patients were considered to have had a myocardial infarction if any of the following criteria were met: creatine kinase-MB 113 IU/liter in 12 sequential plasma samplesover a 12-hour period and a pattern of enzyme releasecharacteristic of infarction, creatine k&se-MB 113 III/liter in 1 sample if it represented a 3-fold increase above serial changes or

n n

MR on admission MR(Days l-l 1)

Hospital

12 Month

48 Month

Ft6uw2shoH-dbn5-temllnorWltrhthe~wlth hp8timbwlthMR dtdrrprdbtkn(MR)OUl-, thtkarddaysltollmdthosewithoutMRdulytbne WV. 1170

THE AMERICANJOURNALOF CARDIOLOGY VOLUME65

creatine kinase-MB 113 IU/liter if it was the only blood sample available. Infarct size was estimated from serial values of creatine kinase-MB as previously described. MR was defined as a systolic murmur described as suggestiveof MR by the examining physician. Auscultation was performed in both the supine and left lateral decubitus position. In most cases,the physical examination was performed by one of the MILIS investigators (see Appendix). Systolic murmurs deemednot suggestive of MR by the examining physician were not included in the analysis. Analyses of radionuclide ventriculography ejection fraction was determined by measuring changesin left ventricular activity on a frame-by-frame basis. Ventricular volumes were evaluated by relating the outline of the left ventricle to a series of lead bars of known dimension, which were imaged for calibration.lOJ’ Wall motion was graded as follows for 6 anterior and 4 inferior left ventricular segments:normal = 3, mild hypokinesis = 2, moderate hypokinesis = 1, akinesis = 0 and dyskinesis = -1. Statistical methods: For analysis, patients were divided into 3 groups. Group 1 consistedof patients with MR detected on admission. Group 2 consisted of patients with MR not auscultated on admission but de tected during the hospitalization (days 1 through 11). Group 3 consistedof patients without MR by auscultation at any time. Statistical analyses were done using the Pearsonchi-square test to examine the general asso ciation betweenthe MR groups and the categorizedresponseof interest. No assumptionswere made regarding the different degreesof MR. Similarly, an analysis of variance was usedto test the overall differencesbetween the MR groups with respectto continuous variables. No

tests were done for any difference of an ordered response.12 Unadjusted plots of the estimated cumulative survival were produced by the Kaplan-Meier method. A p value <0.05 was considered significant. Summary statistics for continuous data are presented as mean f standard error. The Cox proportional hazard model was used to test the overall difference in survival in the 3 groups.‘3 The reported p values correspond to the results obtained by the likelihood ratio test. A special risk score was calculated for each patient using 20 variables that have been shown in previous studies to affect survival. This risk score was incorporated into the Cox model to yield the adjusted analysis; no stepwiseselection was performed.

TABLE I Patient Characteristics MR Developing

MRon Admission No. (%) Female Nonwhite Previous MI History of CHF S.3sounds Rales Abnormal neck vein distention Infarct extension ST depression Anterior Ml Transmural Ml Complex VEA

RESULTS Of the 985 patients enrolled in MILIS, 849 were documented to have acute myocardial infarction. A murmur suggestiveof MR was present during the hospitalization in 169 of these 849 patients (20%). On admission, a murmur suggestiveof MR was heard in 76 patients (9%). An additional 93 patients had murmurs first heard on days 1 through 11. Although the murmur fluctuated in many patients, the prevalenceof MR remained constant during hospitalization (Figure 1). Fifty-three percent of the patients with a murmur on day 1 who were evaluated at discharge still had the murmur of MR at the time of discharge.

Daysltoll

NoMR No. (%)

No. (%)

33 (43)

47 (62) 25 (33)

28 (30) 25 (27) 26 (28) ll(12) 25 (27) 48 (52) 20 (22)

171 (25) 124(18) 140 (21) 41(6) 101 (15) 289 (43)

5 (7)

9 (10)

58 (9)

26W 33 (43) 19 (25)

38W’)

23 (32) 5~ (76)

14 (16) 53 (67) 53 (63) 16 (23) 58.2 f 1.1 9.12 f 0.14

34 W) 27(W

Age 66

61.5 f 1.8

Karnofsky Score (admission)

8.00~0.15

CHF = congestive heart failure; VI3 = ventricular ectopic actiwty

84

MI = myocardial

(12)

84 (13) 414(65) 418 (64) 137 (26) 56.2 f 0.4 9.05hO.05

infarcton;

p Value

0.003 0.001

0.034
NS = not signdcant:

Patients with MR at the time of admissionwere older, more commonly female and more likely to be nonwhite (Table I). They compriseda group with a greater incidence of previous myocardial infarction and of congestive heart failure. Accordingly, on initial examination, they more commonly manifested signs of clinical

t

i 0

n 0.6

0.4

4 0

I ‘I 4

1,. 8

s I., 12

, 11.) 16

7,

8, 11 24

20

Months GROUP FlGuRL3.thl4ded-am?es

-

pdhltBWithMRfhthUUd~ltOll;IlO-

Admission

I,, 28

r , 32

I., 36

( . . . . . . . . 40 44 48

in Study

-------.

Days l-11

hrthe3gmqmofpdats.A=pntkmtswithoutMR. THE AMERICAN

-----

NoMR

=pdentswlthMRon~hospiW=

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TABLE II Left Ventricular Function and Infarct Size

LVEF (time 0) (%) LVESV index (ml/m*) LVEDVindex (ml/m? MB (ISI) (g Eq/m*)

I

MR on Admission

MR Developing Days 1 to 11

No MR

p Value

41 f 2 65f4 102 f 4 15f2

47 f 2 51 f3 91 f4 19f2

46fl 48f 87fl 17fl

0.047
1

LVEF = left ventricular ejection fraction; LVESV = left ventricular end-systolic volume; LVEDV = left ventricular enddiastokcvolume; MB(ISI) = MB band of creatne kinase normaliied for body surface area.

congestive heart failure (Ss sounds, rales, abnormal neck vein distention). In addition, ST depressionwas more frequently present on their admission electrocardiogram and thus there was a greater incidence of nontransmural myocardial infarction in group 1. The location of infarction was similar among the 3 groups. Inhospital extension was 7% in group 1, 10% in group 2 and 9% in group 3. In-hospital mortality (Figure 2) was slightly greater in group 1 (15 vs 10% in group 2 vs 8% in group 3); however, the difference was not statistically significant and unaffected by treatment group. Group 1, however, did manifest a statistically significant increase in mortality by 12 months. Patients with MR on admission had a 36% mortality by 12 months compared to 16% and 15%for the other 2 groups, respectively.Augmented mortality persistedat 48 months with a mortality of 47% in patients in group 1 compared to a mortality of

26% and 24% in the other 2 groups. Comparison of unadjusted survival curvesdemonstrateda statistically significant difference (p
MR

MR Admision

”

No MR

Dvr t-11

.

MR

MR .4dmisdon

hyr

No MR

1.11

FIGURE 4. Averaga wall motion leore of the mterior ~cgmemts(A)andinfe8Wwgments(B)asassessedbyradbnudda-. 1172

THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 65

Our data confirm that MR detectedby auscultation is common in patients with acute myocardial infarction and that patients with MR at the time of admission have an increasedlong-term mortality. Skilled examiners found evidence of MR in 20% of the patients enrolled in this study. Theseresults are similar to the 17% incidence reported by Maisel et al2 but differ substantially from the data of Heikkilal who described a 55% incidence in 195 consecutive patients. It may be that this discrepancy is related to a difference in classification. Many of the systolic murmurs detected in our patients were classified as ejection murmurs and the difficulty with this distinction is well known.‘T2If all systolic murmurs had been included as suggestiveof MR, our results may have beenmore similar to those of Heikkila. The 20% incidence in our present study is also lower than that of our earlier study using pulsed Doppler to detect MR. This might be expectedsince we and others have documenteda high incidence of undetected MR in

patients with acute infarction.4 In that study, MR was present in 39% of patients within 48 hours of the onset of acute infarction. However, becausethe incidence of MR was still lower than that reported by others who have described an increasing incidence as high as 50% with pulsed Doppler 30 days after myocardial infarction,14 we postulated that patients with MR on admission might differ from those in whom it developedlater. Accordingly, before data analysis, we grouped patients into those with MR on admission and those in whom the murmur was heard later during hospitalization. Survival curves suggestedthat this postulated difference may be of importance becausethere was a substantial increasein mortality for the group with MR on admission compared to those with MR detected later during the hospitalization. However, the patients with MR on admission were older, more frequently female, more frequently nonwhite and more often had a history of congestiveheart failure and previous myocardial infarction. These characteristics are in agreement with those reported previously in patients with Doppler-detected MR.4 Adjustment for the differences in baseline characteristics indicated that MR did not make an independent contribution to the adverse prognosis, MR seems rather to integrate information obtained from history, physical and laboratory findings and thus is a marker of adverseprognosis. We considered MR as a dichotomous variable, that is, we did not include the severity of MR in our analysis becausesuch an estimate from either invasive or noninvasive studies was not available in our database. We

III

Variables

Used in Cox Proportional

Model

Propranolol acceptable Anterior ischemia/infarction Previous myocardial infarction Angrna History of arrhythmia Antiarrhythmic therapy (prevrous 3 weeks) Rales at admission Congestive heart failure (previous 3 weeks) STelevation (admission) Cigarette smoking p blockers Diabetes Transmural ischemia/infarction Gender Hypotension (admission) Race Heart rate (admission) Left ventricular ejection fraction (admission) Age Karnofsky score (3 weeks before myocardial

infarction)

dependedon the clinical assessmentof the presenceor absenceof MR for our study. Despite the well-known inaccuracy of auscultation, patients with MR on admission still exhibited poorer survival. Finally, our data do not allow us to separate new from previously present MR. The lack of an independent contribution of MR to prognosisdiffers somewhatfrom previous studies. Maise1et al2 reported that the presenceof a systolic murmur suggestive of MR at discharge was the tenthranked variable in their multivariate analysis of sur-

-

P Is ;

Hazards

__ ___ __.

; 0.8

1 TABLE

-v-----L 0.7

-

t

i

0

n 0.6 : 0.5

i

0.4

-I 0

4

8

I 12

1

I 16

3 / I 20 Months

GROUP FIGURE 5. Adbsted

survival

Admission

-------.

curves of the 3 groups efemmed

I 1 24

’ / / ” 28

/ ’ ” 32

’ ” 36

1 40

”

” 44

1 48

in Study Days

l-1,

-----

No MR

in Figure 3. THE AMERICAN

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MAY 15. 1990

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vival. However, in their study, only patients with holosystolic murmurs detectedany time during hospitalization were included. Thus, they selectedthose patients with more severeMR on admission or those who developed more severe MR thereafter. We included all patients with murmurs suggestiveof MR and therefore have probably studied a more heterogenousspectrum of regurgitant lesionsmasking a prognostic effect of severe regurgitation. This interpretation is consistent with the data of Hickey et all5 who, in a study of angiographically defined MR in over 11,000patients with documented coronary artery disease,reported that mitral insufficiency score was an independent predictor of survival only in patients with moderate or severe MR (3% or onesixth of the patients with MR). The mechanismsof MR in this setting are unclear. Izumi et alI6 in a study using color flow Doppler suggested2 major causative factors: asynergy of the papillary muscle or contiguous ventricular segment or enlargement of the mitral anulus. In our study, there was a significantly decreasedwall motion scorein the anterior segmentsof patients with MR on admission.In addition, both systolic and diastolic volumes were significantly enlarged. These findings support the notion that asynergy contiguous to the papillary muscle or anular dysfunction may contribute to MR in these patients. REFERENCES

1. Heikkila .I. Mitral incompetencecomplicating acute myocardial infarction, i?r

Heart J 1967,.29:162-l 69.

2. Maisel AS, Gilpin EA, Klein L, LeWinter M, Henning H, Collins D. The murmur of papillary muscledysfunction in acute myocardial infarction. Clinical features and prognostic implications. Am Heart J 19%6;112:705-711, 3. LehmannKG, Francis CK, DodgeHT. Mitral regurgitation in early myocardial infarction is the strongest predictor of mortality (abstr). Circulation 19%6:74(suppII):&304. 4. Barailai B, GesslerC, Perez JE, SchaabC, Jaffe AS. Significance of Doppler detected mitral regurgitation in acute myocardial infarction. Am J Cardiol 19%%51:220-223. 5. The MILIS Study Group. National Heart, Lung and Blood Institute Multicenter investigationof the Limitation of Infarct Size (MILIS): designand methodsof the clinical trial: an investigation of beta-blockadeand hyaluronidase for treatment of acute myocardial infarction. In: Muller JE, ed.American Heart Association monograph no. 100. Dallas: American Heart Association, 19%4:1-134. 6. MILIS Study Group. Hyaluronidase therapy for acute myocardial infarction: resultsof a randomized,blinded, multicenter trial. Am J Cardio/19%6;57:12361243.

7. Roberts R, Croft C, Gold HK, Tyler DH, Jaffe AS, Muller JE, Mullin SM. Parker C, PassamaniER, Poole WK, Raabe DS, Rude RE, Stone PH. Turi G, Sobel BE, Willerson JT, Braunwald E, and the MILIS Study Group. Effect of propranolol on myocardial infarct sizein a randomized,blinded,multicenter trial. N Engl J Med 19%4;311:21%-225. 6. Roberta R, Braunwald E, Muller JE, Croft C, Gold HK, Hartwell TD, Jaffe AS, Mullin SM. Parker C, PassamaniER, Poole K, Robertson T, Raabe DS, Rude RE, Stone PH. Turi ZG, Sobel BE, Willerson JT, and the MILIS Study Group. The effect of hyaluronidaseon mortality and morbidity in patients with early peaking of plasma MB CK and nontransmural ischemia: retrospective analysis of MILIS data. Er Heart J 19%%,60;290-29%. 9. Henry PD. Roberts R, Sobel BE. Rapid separationof plasmacreatine kinase &enzyme by batch absorption with glass beads.Clin Chem 1975;21:844-849. 10. Burow RD, StraussHW, Singleton R, PondM, Rehn T, Bailey JR, Griffith LC, Nickolf E, Pitt B. Analysis of left ventricular function from multigated acquisition cardiac blood pool imaging. Comparison to contrast angiography. Circulation

1977;56:1024-102%.

11. Biello DR. Sampathkumaran KS, Geltman EM, Britson WD, Scott DJ, Grbac TR. Determination of left ventricular ejection fraction; a new methodthat requires minimal operator training. J Nucl Med Tech& 19%1,9:77-80. 12. Kaplan EL, Meier P. Nonparametric estimation from incompleteobservations. J Am Stat Assoc 195%;53:457-481. 13. Cox DR. Regressionmodelsand life-tables. JR Stat Sot (B) 1972;34:1%7202. 14. Loperfido F, Biasucci LM, PennestriF, Laurenzi F, Gimigliano F, Vigna C,

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Rossi E, Favuzzi A, Santarelli P, Manzoli U. PulsedDoppler echocardiographic analysis of mitral regurgitation after myocardial infarction. Am J Cardiol 19%6;5%:692-697.

15. Hickey MSJ, Smith LR, Muhlbaier LH, Harrell FE, RevesJG, Hinohara T, Califf RM, Pryor DB, Rankin JS. Current prognosisof ischemicmitral regurgitation: implications for future management.Circulation (suppl I) 19%%;7%:I-51-I59. 16. Izumi S, Miyatake K, BeppuS, Park YD, Nagata S, Kinoshita N, Sakakibara H, Nimura Y. Mechanismsof mitral regurgitation in patientswith myocardial infarction: a study usingreal-time two-dimensionalDoppler flow imaging and echocardiography.Circulation 1986: 76:77-785.

APPENDIX Mu&enter Investigation of the Limitation Infarct Size Study Personnel

of

Clinical Centers: Barnes Hospital, Washington University School of Medicine, St. Louis, Missouri: Allan S. Jaffe, MD,

Principal Investigator; Robert Roberts, MD, Principal Investigator; Edward Geltman, MD, Co-Investigator; Dan Biello, MD, Nuclear Medicine Coordinator; RosanneWettach, RN, MNP, Research Nurse Coordinator; Ava Ysaguire, Susan Payne and Linda Wilson, Data Coordinators. Massachusetts General Hospital, Boston, Massachusetts:

Herman K. Gold, MD, Principal Investigator; Robert C. Leinbath, MD, Principal Investigator; Tsunehiro Yasuda, MD; Wendy Werner, RN, and Mary McHugh, RN, Research Nurse Coordinators; Harry Garabedian, Data Coordinator. Medical Center Hospital of Vermont, University of Vermont College of Medicine, Burlington, Vermont: Daniel S. Raabe, Jr, MD, Principal Investigator; Walter Gundel, MD; Marian Domell, RN, Maureen Hawley, RN, Patricia Beecher, RN, Kathleen Cornell, RN, and Karen Helminger, RN, Re search Nurse Coordinators; Raina Maynard, Data Coordinator. Brigham and Women’s Hospital, Harvard Medical School, Boston: EugeneBraunwald, MD, Principal Investigator; Peter

H. Stone, MD, JosephS. Alpert, MD, and Robert Rude, MD, Clinical Unit Directors; Nancy E. Taplin, RN, Kathryn Shea, RN, Debbie Shiner, RN, ResearchNurse Coordinators. Parkland Memorial Hospital, University of Texas Health Science Center at Dallas, Texas: James T. Willerson, MD, Principal Investigator; Robert E. Rude, MD, Clinical Unit Director; Charles Croft, MD; Robert Dillon, MD, Kevin Whee Ian, MD, Christopher Wolfe, MD; Barbara Moses, RN, Sandra Cochran, RN, Marvin Akers, RN, Joan Reinert Corey, RN, Vickie Gillespie, RN, and Barbara Fitzpatrick, RN, Research Nurse Coordinators; Kris Kraft, Unit Clerk. Creatine Kinase Core Laboratory, Washington University School of Medicine, St. Louis: Burton E. Sobel, MD, Principal

Investigator; Robert Roberts, MD, Principal Investigator; Allan S. Jaffe, MD; Cynthia Ritter, Laboratory Coordinator; Steven Mumm, Laboratory Technician. Cardiovascular Pathology Core Laboratory, Duke University Medical Center, Durham, North Carolina: Donal B.

Hackel, MD, Principal Investigator; Raymond E. Ideker, MD, PhD; Keith A. Reimer, MD, PhD; Eileen Mikat, PhD. Technetium-99m Pyrophosphate Myocardial Scintigram Core Laboratory, University of Texas Health Science Center at Dallas: JamesT. Willerson, MD, Principal Investigator; Samu-

el E. Lewis, MD, Laboratory Director; Robert W. Parkey, MD, Laboratory &Director; Irma Dobbins, Laboratory Ccordinator. Holter Recording Core Laboratory, Washington University School of Medicine: Lewis J. Thomas,Jr., MD, Principal Inves-

tigator; Robert Roberts, MD, Co-Principal Investigator; Kenneth A. McKusick, MD, Clinical Director, Nuclear Medicine Division; Tsunehiro Yasudo, MD; Karen Kelly, Laboratory

Coordinator; Annali Kiers, Laboratory Coordinator and Nuclear Medicine Technician; Leander Blakeman,Laboratory Coordinator and Nuclear Medicine Technician; Merrill Griff, Laboratory Coordinator and Nuclear Medicine Technician. Electrocardiogram Core Laboratory, Harvard Medical School/Brigham and Women’s Hospital: Eugene Baunwald,

MD, Principal Investigator; John D. Rutherford, MD, Laboratory Director; Zoltan G. Turi, MD, Laboratory Director; James E. Muller, MD, Laboratory Co-Director; Peter H. Stone, MD, Laboratory Co-Director for ETT Analysis; Gail Z. Alymer, Susan G. Albert, PA. Jennifer Forage, and Michael Miller, Laboratory Coordinators; Neil Rhodes,Matthew Levine, Jeremy Pool and John Rees,Programmer/Analysis; Jane So&up and David Mayberry, Computer Operators.

Susan K. Settergren, MS, B.J.G. York, MS, James H. Crowder, MPH, Carolyn Stuart, MSPH, and Vi&i Davis, MS, Statisticians; Lee Larsen, Statistical Clerk. Clinical Coordinating Center, Harvard Medical School/ Brigham and Women’s Hospital: Eugene Baunwald, MD,

Principal Investigator; JamesE. Muller, MD; Zoltan G. Turi, MD; Ellenjane Scheiner, Project Coordinator; Norman R. Stein, Financial Administrator. Program Office, Cardiac Diseases Branch, Division of Heart and Vascular Diseases, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland:

Thomas Robertson, MD, Project Officer; Eugene R. Passamani, MD, Project Officer; Michael B. Mock, MD, Project Officer; SuzanneM. Mullin, RN, MPH, Clinical Trials Nurse Data Coordinating Center, Research Triangle Institute, Administrator; J. Roland Castle, Contract Officer; Patrick M. Research Triangle Park, North Carolina: W. Kenneth Poole, Sullivan, Contract Officer; K. Gordon Lan, PhD, David DePhD, Principal Investigator; Tyler D. Hartwell, PhD, Co-Prin- Mets, PhD, JamesWare, PhD, Biostatisticians. cipal Investigator; Corette Parker, MSPH, Project CoordinaMZLIS Policy Advisory Board: William L. Ashburn, MD; tor, Biostatistician; Connie Hobbs, Norma Fox, MPH, and Eugene Braunwald, MD; Paul Canner, PhD; Robert L. Frye, Susan Warwick, RN, Data Coordinators: Priscilla Rigby, RN, MD (Chairman); Lawrence E. Hinkle, Jr, MD; Andrew Z. Data Management Coordinator; Thomas S. Farrell and Debra Keller, DMD; Paul Meier, PhD; Leroy Walters, PhD; Nanette Fleischman, Computer Programmers;Nancy Gustafson, MS, Wenger, MD.

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