The institutions chosen for the trial were the Minnesota

Transcription

1 Test f Effect f Lipid Lwering by Diet n Cardivascular Risk The Minnesta Crnary Survey Ivan D. Frantz Jr., Emily A. Dawsn, Patricia L. Ashman, Lael C. Gatewd, Glenn E. Bartsch, Kanta Kuba, and Elizabeth R. Brewer The Minnesta Crnary Survey was a.-year, pen enrllment, single end-time, duble-blind, randmized clinical trial that was cnducted In six Minnesta state mental hspitals and ne nursing hme. It Invlved 9 Institutinalized men and 66 Institutinalized wmen. The trial cmpared the effects f a 9% fat cntrl diet (18% saturated fat, % plyunsaturated fat, 16% mnunsaturated fat, 6 mg dietary chlesterl per day) with a 8% fat treatment diet (9% saturated fat, 1% plyunsaturated fat, 1% mnunsaturated fat, 166 mg dietary chlesterl per day) n serum chlesterl levels and the Incidence f mycardlal Infarctins, sudden deaths, and all-cause mrtality. The mean duratin f time n the diets was 8 days, with 168 subjects cnsuming the diet fr ver 2 years. The mean serum chlesterl level In the pre-admissin perid was 27 mg/dl, falling t 17 mg/dl in the treatment grup and 2 mg/dl In the cntrl grup. Fr the entire study ppulatin, n differences between the treatment and cntrl grups were bserved fr cardivascular events, cardivascular deaths, r ttal mrtality. A favrable trend fr all these end-pints ccurred In sme yunger age grups. (Arterisclersis 9:129-1, January/February 1989) The institutins chsen fr the trial were the Minnesta state mental hspitals at Anka, Fergus Falls, Hastings, Mse Lake, St. Peter, and Willmar and the nursing hme at Oak Terrace. Befre initiatin f the experimental phase, the ppulatins were bserved fr a -year perid, during which their suitability fr a lng-term dietary trial was studied. The feeding prgram began in the Willmar State Hspital in Nvember, The prgram was phased in t the ther institutins in successin ver the fllwing 1 mnths. The trial was an utgrwth f the Natinal Diet-Heart Feasibility Study. 1 Methds Ethical Cnsideratins The prject was apprved by the Clinical Research Cmmittee f the University and, after extensive discussin with the relevant institutinal cmmittees, by each f the cllabrating hspitals. N cnsent frms were required n the grunds that the tw diets were bth acceptable as huse diets and the tests all cntributed t better patient care. Befre initiatin f the study in each hspital, all the residents and staff were invited t a meeting at which the investigatrs explained the prject. Samples f the fds were served at these meetings. There was a questin and Frm the Departments f Medicine, Bimetry, and Labratry Medicine and Pathlgy, University f Minnesta, Minneaplis, Minnesta. This wrk was supprted by Grant N. HE 9686 frm the Natinal Heart, Lung, and Bld Institute. Address fr reprints: Ivan D. Frantz Jr., M.D., Divisin f Epidemilgy, Schl f Public Health, University f Minnesta, 611 Beacn Street S.E., Minneaplis, MN. Received March 2,1987; revisin accepted August,1988. answer perid, and the residents were invited t make appintments fr ne-t-ne further explanatins if they wished. They were allwed t decline t participate r t discntinue their participatin at any time. Nnparticipants were served the cntrl diet, which was similar t the pre-study institutinal diets. Bld was nt drawn frm nnparticipants, and electrcardigrams were nt recrded. Participatin was nearly % with fewer than a dzen refusals thrughut the trial. Experimental Plan The riginal ppulatin was initially stratified int 12 cells n the basis f eight variables. These were: age, sex, length f stay in the hspital, weight, bld pressure, diabetes, cigarette smking, and evidence by electrcardigram f a previus mycardial infarctin. When new subjects were admitted later, they were divided amng fur cells, based n nly age and sex. Tw diets were served. The cntrl diet invlved little departure frm the institutinal diet served befre the trial. The treatment diet represented a cmprmise between the B and C diets f the Natinal Diet-Heart Study, with target values f % f calries frm fat, a plyunsaturated/ saturated fat (P/S) rati f 2., and less than 1 mg f chlesterl daily. Bth diets were served in a single line. As a participant entered the line, he r she was handed a label bearing his r her name and a cde number that was incmprehensible t the uninitiated but easily interpreted by the fd servers t determine which diet was t be served. A new set f 21 labels was prepared by cmputer each week fr each participant based n changes in the ppulatin during that week. The label served multiple purpses. 129

2 ARTERIOSCLEROSIS VOL 9, N 1, JANUARY/FEBRUARY 1989 Table 1. Specificatin and Values fr Experimental Diets Averaged ver Years Diet grup Specified Achieved Ttal fat (% calries) Saturated fat (% calries) Plyunsaturated fat (% calries) Analyses f fds were perfrmed by Wdsn-Tenent Labratries, Memphis, Tennessee. P/S=plyunsaturated/saturated fat rati. Chlesterl (mg/day) P/ S One was t sund a persnal nte with the subject, ne f the many psitive influences which ur study had n the hspitals. The label als enabled the fd service wrker t serve the prper tray withut cmprmising the blind design, and the labels remaining n the sheet prvided the basis fr the daily tally f missed meals. Each mnth the hspital technicians transferred the missing meals data t a "Prt--Punch card." These cards were read by the cmputer and at the end prvided a crrelatin between adherence and chlesterl respnse. Fasting bld was drawn frm every patient n admissin t the hspital, and at 6-mnth intervals thereafter. The serum was frzen and analyzed at a later date t avid ding analyses n patients wh remained in the hspital fr t shrt a time t cntribute significantly t the results. All sera frm all subjects wh remained in the study n either diet fr at least 1 year, frm every subject wh died r had a cardivascular event, and frm a set f additinal subjects matched n age and sex wh did nt have an event were analyzed. When a subject left the hspital and then returned, bld fr the chlesterl determinatin was drawn after he had been back n the diet fr weeks. Dietary Prcedures Traditinal American fds were used fr the cntrl diet, and fds high in plyunsaturated fat and lw in saturated fat and chlesterl were used fr the experimental diet. Baseline dietary data were btained by chemical analysis f cmpsites f a 21-day fd cllectin cnducted at all hspitals during the pre-diet perid. The experimental diet gal was t prvide 18% t 2% f calries frm plyunsaturated fat, t limit saturates t less than 9%, and t maintain the rati f plyunsaturated t saturated fats at mre than 2:1. Chlesterl was t be as lw as culd be achieved withut sacrificing palatability (1 mg per day r less). Specificatins and -year average values are shwn in Table 1. Figures 1 and 2 are plts f seven hspital averages f the P/S rati and the dietary chlesterl cntent, respectively, measured at yearly intervals ver a -year perid. Table 2 shws the cntent f the diets fr sme f the mre imprtant nutrients and minerals. Prcurement f suitable fds fr the treatment diet, (with the desired plyunsaturated fat, which were yet palatable, stable, and indistinguishable frm the crrespnding cmpnents f the cntrl diet) presented a great challenge. It was achieved thrugh cperatin f the study nutritinists, the hspital dietitians, manufactur i.i c * «a..2 ALL HOSPITALS Figure 1. Mean P/S rati f treatment and cntrl diets. The ratis are averages fr all seven hspitals determined by chemical analysis. The pint fr 1968 is the value fr the hspital diets befre the interventin trial. P=piyunsaturated fat and S=saturated fat. 2 ' s ( ( ALL HOSPITALS It J Figure 2. Mean daily chlesterl cntent (mgs/day) f the treatment and cntrl diets. The values are averages fr all seven hspitals determined by chemical analysis. The pint fr 1968 is the value fr the hspital diets befre the interventin trial. ers f fd prducts, and the Fd Inspectin Divisin f the Minnesta Department f Agriculture. Prducts that prved particularly useful were filled milk and ice cream, a whle egg substitute, sft margarine, whipped tpping, filled cheese, lw fat grund beef with added vegetable il, and filled sausage prducts. Labratry Methds Bld was drawn under fasting cnditins. The serum was sealed in glass ampules under nitrgen, and stred at -2 C. Analyses were carried ut fr ttal chlesterl and triglycerides by the standard prtcl f the LJpid Research Clinics. 2 The labratry was standardized and mnitred by the Centers fr Disease in Atlanta.

3 DIET AND CARDIOVASCULAR RISK Frantz et al. 11 Table 2. Cmparisn f Mean Dally Diet Cmpsitin fr All Hspitals RDA* Mean fr all hspitalsf Diet Cmpsitin Wmen Prtein (g) Calcium (g) Irn (mg) Vitamin A (IU) Thiamine (mg) Ribflavin (mg) Niacin equivalents (mg) Ascrbic acid (mg) 'Recmmended Daily Dietary Allwances frm the Natinal Research Cuncil, 1968 revisin. thandbk analysis values are fr the cntrl diet. All mdified fds (whle egg substitute, filled dairy prducts, and filled prcessed meats) were frmulated t prvide nutrient levels cmparable t the standard prducts. 2 -IO- i? U O Rgure. 1 ISO I r i I I I I I I CONTROL DIET TREATMENT WET I I I I I I I I 2. YEARS ON DIET Awre^eserumcrK)lesterd(X)ncentratins(mg/ml). 1 1 r~ CONTROL DIET TREATMENT DIET O YEARS ON DIET Figure. Average serum triglyceride cncentratins (mg/ ml). Heat-stable lactate dehydrgenase was measured in the labratry f Paul E. Strandjrd. Electrcardigrams were read by Naip Tuna (Chief f Electrcardigraphy at the University f Minnesta Hspitals) and als by technicians in the Labratry f Physilgical Hygiene wh were supervised by Henry Blackburn. Any discrepancies between the tw readings were reslved by cnsultatin between readers. The recrds were classified accrding t the Minnesta Cde.. I I I I I Table. Ttal Participants by Age and Sex Age Wmen Wmen < t t t t t t t t ^ Ttals Ascertainment f Cardivascular Events Three electrcardigrams were recrded n days 1,, and 7 after every suspected event. Bld was drawn at 1, 2,, and days fr measurement f ttal and heat-stable lactic dehydrgenase. Histrical data were recrded by ur technicians after cnsultatin with the attending physician. In additin, an electrcardigram was recrded rutinely n all subjects n admissin t the hspital and at intervals f 6 mnths fr the detectin f silent mycardial infarctins. When subjects returned after an absence frm the hspital, an electrcardigram was recrded if mre than 6 mnths had elapsed since the last tracing. The autpsy percentage was maintained as high as pssible. The verall percentage fr persns in the trial was 7.1%. The reasns fr failure t perfrm autpsies was almst always refusal by relatives r inability t cntact relatives. The arta, heart, and brain were fixed at the institutin and were sent fr study accrding t prtcl by cardiac and neurpathlgists at the University. The principal investigatr visited each f the institutins at frequent intervals and reviewed under masked cnditins the hspital charts, the recrds kept by the trial technicians, the autpsy reprts, and the labratry data (but nt the lipid analyses) n all patients wh had died r wh had had a suspected cardivascular event since his last visit. He cnsulted with the respnsible physician, if

4 12 ARTERIOSCLEROSIS VOL 9, N 1, JANUARY/FEBRUARY 1989 Table. Primary End-pints (Acute and Silent Mycardlal Infarctins and Sudden Deaths) Time in hspital Wmen Ttal (yrs) <1 2=1 22 a Ttal 81.9(2) 1.9(27) 8.8(1). () 1.2 (1) 28.1(69) 88.(7) 1.8(27) 11.(17) 7. (8) 1. (1) 1.(7).6() 1.(27) 11.(16) 8.9() 1. (1) 26.2(62) 27.6(16) 17.(1).(1). (). () 19.9(7) 67. (77) 1.7 (). () 6.6 (1) 1. (2) 27.2(11) 6.6 (6) 16.1 (8) 11. (2).6 (1).6 (1) 2.7(121) These data include peple f all ages. Values are the rates per persn-years with numbers f persns In parentheses. necessary, and then classified the event accrding t the Internatinal Classificatin f Diseases. Data Management Fifteen frms were devised fr recrding the data frm the hspitals and labratries. The data were transferred t magnetic tape t facilitate day-t-day management f the prject and fr later analysis. Results Figure shws the average serum chlesterl cncentratins at 6-mnth intervals ver the duratin f the study. The abscissa represents time n diet, rather than calendar mnths. Mre persns are included, therefre, at the shrter time intervals. The average fall in chlesterl fr the cntrl grup was.7%, and fr the treatment grup, 1.%. The difference between the tw grups was virtually cnstant frm 6 mnths nward. Figure shws the smaller, but definite, difference in plasma triglycerides. CD J uj 96- i 9 c CD O CD Q The mnitring f missed meals was effective, as indicated by the relatinship between adherence and missed meals. Persns assigned t the treatment diet wh missed fewer than % f their meals during the weeks befre their semi-annual bld sample shwed an average decrease in plasma chlesterl f 1.% cmpared with their cntrl measurement. If mre than % f meals were missed, the decrease was 11.% and it deterirated prgressively t 8.9% and 6.2%, respectively, if 2% r % f meals were missed. When persns failed t g thrugh the serving line, they presumably ate elsewhere, althugh sme rutinely skipped breakfast. The ttal number f participants in the study categrized by age and sex is shwn in Table. The ttal number f hspital stays was The average length f each hspital stay was 292 days. The average ttal time in the hspital fr each participant, including multiple admissins, was 8 days. Hspital stays ttaled 6 fr Number f Years Figure. Life-table presentatin f percent f men and wmen f all ages withut cardivascular events. ( ), and cntrl, (- -).

5 DIET AND CARDIOVASCULAR RISK Frantz et al. 1 Table. All Deaths Time in Wmen Ttal (yrs) <1 a1 2=2 19. (99). (9) 1.8 (2) 7.8 (9) 191.(2) 28. (1) 18.2 (27) 8.7 () 89. (6) 1.7 () 2. () 1.2 (17) 89.8(2) 2.2() 18.2(26) 12.1(1) 1.7(1) 1.(11) 19. (8) 11. (26) 18.(1) 26.1 (9) 18.2 (). (2) 2: Ttal 1.2 (1) 6.(18) 1. (1) 6.9(1) 1. (1) 6.9(111) 1.2 (1).(9) 1. (2).8(269) 1. (2) 2.6(28) These data include persns f all ages. Values are the rates per persn-years with numbers f persns in parentheses " a> 92 - ^ Number f Years Figure 6. Life-table presentatin f percent f men and wmen f all ages still living., ( ) and, (- -). the treatment grup and 91 fr the cntrls. Of these, nly 2668 were fr mre than 1 year. The number f persn-years f bservatin was 98, with 9 f these fr persns in the hspital cntinuusly fr mre than 2 years and 29 fr mre than years. Table shws the number f ccurrences f the primary end-pints acute mycardial infarctins, sudden deaths, and silent mycardial infarctins fr men and wmen f all ages, classified accrding t time in hspital. A few mre events ccurred in the treated grup. The data are presented in life table frm in Figure. The similarity f the tw curves is striking. Similar data fr deaths frm all causes are presented in Table and Figure 6. The small difference between the tw life tables is in an unfavrable directin. When the study was initiated, we suspected that any favrable utcme wuld be cnfined t the yunger participants in mst f whm severe athersclersis wuld nt yet be present. It als seemed likely that a fair length f time wuld be required fr the diet t exert an effect. In tw recently reprted drug trials, the LJpid Research Table 6. Trends In 2 Years Ages t 9 grup grup Wmen grup grup Ages t years Man IVIOI 1 grup grup Wmen grup grup Persns n Diets Mre than Events Acute Ml, sudden death, and silent Ml.() 9.8(7).2(2) 6.6().() 16.7(6).8(1) 1.2() All deaths.() 7.() 9.8(6) 6.6() 6.1(2) 11.1().8(1) 1.2() Values are events r deaths per persn-years with numbers f persns in parentheses. Ml=mycardial infarctin.

6 1 ARTERIOSCLEROSIS VOL 9, N 1, JANUARY/FEBRUARY 1989 Table 7. Causes f Death Causes Arterisclertic heart disease Vascular lesins f central nervus system Cardiac arrest, heart blck Chrnic brain syndrme, general athersclersis, senility Hypertensive heart and renal disease, ther hypertensive disease, cngestive heart failure Other circulatry disease including rheumatic heart disease Pulmnary emblism and infarctin Malignant neplasm Infectius diseases including influenza and pneumnia Other diseases f central nervus system Pulmnary disease including empyema, lung abscess, and emphysema Gastrintestinal disease Geniturinary disease including pyelnephritis and calculi Diabetes mellitus External causes including fractures, drug reactins, bums, freign bdies, extractin f tth, freezing, heat strke, drwning, and suicide Cngenital malfrmatins Ttals Clinics Primary Preventin Trial 67 and the Helsinki Heart Study, 8 2 years were required befre favrable trends appeared. Therefre, it is f sme interest t lk fr trends in persns n the diets fr at least 2 years wh fell in the age ranges chsen fr thse studies ( t 9 and t years ld, respectively). Such an analysis is presented in Table 6. If ttal time in hspital including multiple admissins is cunted in arriving at the numbers n the diets fr mre than 2 years, nly ne mre death and n mre cardivascular events are identified in the t 9 year age grup. In men yunger than years, there were three events and tw deaths in the treatment grup. In the cntrl grup, there were 11 events and 12 deaths. Table 7 shws the causes f death fr all participants wh died during the study. Discussin The data were viewed in many ther ways. Fr example, persns wh had a pr chlesterl respnse r whse initial electrcardigram shwed evidence f a Wmen previus mycardial infarctin were mitted frm the study. Other cmbinatins f end-pints were examined. Subsequent events after the initial ne in a given subject were disregarded. Nne f these maneuvers changed the cnclusins. Althugh this study did nt shw a statistically significant reductin in cardivascular events r ttal deaths frm the treatment diet, the authrs suspect that it might have shwn such a reductin if the perid f treatment had been lnger in persns in the age range likely t benefit. We included persns f all ages, bth men and wmen, with an average chlesterl cncentratin f 27 mg/dl, cmpared t abut 29 mg/dl fr the participants in the Helsinki and Upid Research Clinics trials. When the study was first prpsed, very lengthy stays in mental hspitals were cmmn. By the end f the initial -year pre-treatment bservatin perid, the practice f vigrus drug treatment and early discharge t the cmmunity was in full swing. Table 6, in which the analysis is cnfined t persns n diet fr at least 2 years and in the age grups chsen

7 DIET AND CARDIOVASCULAR RISK Frantz et al. 1 fr recent drug trials, shws sme favrable trends, but the numbers are far t small t achieve statistical significance. Acknwledgments The authrs thank the medical directrs, hspital administratrs, business managers, dietitians, directrs f nursing, and prject technicians f the seven hspitals. They als thank the University f Minnesta pathlgists, cardilgists, and neurpathlgists wh assisted in the survey. References 1. Natinal Diet Heart Study Research Grup. The Natinal Diet Heart Study Final Reprt. Circulatin 1968;7(suppl I): Llpld Research Clinics Prgram. Manual f labratry peratins, vl 1. LJpid and lipprtein analysis. DHEW publicatin n (NIH) 197: Strandjrd PE, Claysn KJ, Freler EF. Heat stable lactate dehydrgenase in the diagnsis f mycardial infarctin. JAMA1962;182: Blackburn H, Keys A, Slmnsn E, Rautahaiju P, Punsar S. The electrcardigram in ppulatin studies. A classificatin system. Circulatin 196^1: Internatinal classificatin f diseases. Adapted fr indexing hspital recrds by diseases and peratins. DHEW publicatin n (PHS) 1962: Llpld Research Clinics Prgram. The LJpid Research Clinics Crnary Primary Preventin Trial results. I. Reductin in incidence f crnary heart disease. JAMA 198; 21: Llpld Research Clinics Prgram. The Lipid Research Clinics Crnary Primary Preventin Trial results. II. The relatinship f reductin in incidence f crnary heart disease t chlesterl lwering. JAMA 198;21: Frtck MH, El O, Haapa K, et al. Helsinki Heart Study: Primary-preventin trial with gemfibrzil in middle-aged men with dyslipidemia. N Engl J Med 1987;17: Index Terms: cardivascular risk lipid lwering by diet plasma chlesterl