p3-2 jama_268_10_033
Aspirin Effects on Mortality and Morbidity in Patients With Diabetes Mellitus
Early Treatment Diabetic Retinopathy Study Report14
ETDRS Investigators
Objectives.\p=m-\This report presents information on the effects of aspirin on mor-
tality,the occurrence of cardiovascular events,and the incidence of kidney disease
in the patients enrolled in the Early Treatment Diabetic Retinopathy Study(ETDRS).
Study Design.\p=m-\This multicenter,randomized clinical trial of aspirin vs placebo
was sponsored by the National Eye Institute.
Patients.\p=m-\Patients(N=3711)were enrolled in22clinical centers between April
1980and July1985.Men and women between the ages of18and70years with
a clinical diagnosis of diabetes mellitus were eligible.Approximately30%of all pa-
tients were considered to have type I diabetes mellitus,31%type II,and in39%type
I or II could not be determined definitely.
Intervention.\p=m-\Patients were randomly assigned to aspirin or placebo(two
325-mg tablets once per day).
Main Outcome Measures.\p=m-\Mortality from all causes was specified as the pri-
mary outcome measure for assessing the systemic effects of aspirin.Other
outcome variables included cause-specific mortality and cardiovascular events.
Results.\p=m-\The estimate of relative risk for total mortality for aspirin-treated pa-
tients compared with placebo-treated patients for the entire study period was0.91
(99%confidence interval,0.75to1.11).Larger differences were noted for the oc-
currence of fatal and nonfatal myocardial infarction;the estimate of relative risk was
0.83for the entire follow-up period(99%confidence interval,0.66to1.04).
Conclusions.\p=m-\The effects of aspirin on any of the cardiovascular events con-
sidered in the ETDRS were not substantially different from the effects observed in
other studies that included mainly nondiabetic persons.Furthermore,there was no
evidence of harmful effects of aspirin.Aspirin has been recommended previously
for persons at risk for cardiovascular disease.The ETDRS results support applica-
tion of this recommendation to those persons with diabetes at increased risk of
cardiovascular disease.
(JAMA.1992;268:1292-1300)
THE RATIONALE for including an as?sessment of aspirin in the Early Treat?ment Diabetic Retinopathy Study (ETDRS)was the possibility that
A complete list of the investigators and centers par-ticipating in the Early Treatment Diabetic Retinopathy Study appears at the end of this report.
Reprint requests to the Biometry and Epidemiology Program,National Eye Institute,Room6A-24,9000 Rockville Pike,Bethesda,MD20892(Dr Frederick L. Ferris).aspirin might retard the progression of
diabetic retinopathy.Earlier studies had
demonstrated that persons with diabe?
tes mellitus have altered platelet func?
tion,including platelet aggregation and
disaggregation,14and increased produc?
tion of thromboxane and other metab?
olites of arachidonic acid.5-8Some of these
effects were reversed by aspirin in vitro9
and in vivo.3
Several authors have speculated that
abnormal platelet aggregation and dis-
aggregation and increased thromboxane
production might result in the capillary
closure seen in diabetic retinopathy.2,8"10
In addition,three clinical studies sug?
gested a lower-than-expected preva?
lence of diabetic retinopathy in persons
with diabetes who had been taking sal-
icylates.1113Persons with type I and type
II diabetes mellitus have been observed
to have an increased risk for macrovas-
cular complications,including coronary
heart disease,peripheral vascular dis?
ease,and stroke.1418In view of the ev?
idence for altered platelet function and
increased thromboxane release in dia?
betes,17it was reasonable to expect as?
pirin might reduce the risk of these
events.
The ETDRS was designed to evalu?
ate the effects of photocoagulation and
aspirin on ocular events.1921This mul-
ticenter,randomized clinical trial,spon?
sored by the National Eye Institute,
also provided an opportunity to study
the effects of aspirin on cardiovascular
complications.The study design pro?
vided for the collection of information
on each death and each cardiovascular
hospitalization and on the results of reg?
ular medical examinations.This report
presents information on the effects of
aspirin on mortality,the occurrence of
cardiovascular events,and the incidence
of kidney disease.
PATIENTS AND METHODS
Patient Selection
Patients were enrolled in the ETDRS
between April1980and July1985.Men
and women between the ages of18and
70years at the first screening visit were
eligible.To be considered,patients had to have a clinical diagnosis of diabetes mellitus and one of the following cate?gories of diabetic retinopathy:mild non-proliferative with macular edema,or moderate to severe nonproliferative or early proliferative(less severe than the high-risk proliferative stage,as defined by the Diabetic Retinopathy Study22) with or without macular edema.Visual acuity was required to be better than 20/40in each eye(or20/400if acuity was reduced as a result of diabetic macular edema).Informed consent to participate in this long-term study was obtained from each patient after the goals,ben?efits,and risks of the study were re?viewed and discussed.
The ETDRS exclusion criteria in?cluded systolic blood pressure over210 mm Hg and/or diastolic blood pressure over110mm Hg despite the use of an-tihypertensive medication;history of gastrointestinal hemorrhage or diagno?sis of active gastrointestinal ulcer in the past2years;inability or unwillingness to stop taking anticoagulants or anti-platelet drugs;allergy to aspirin;preg?nancy or lactation;or poor prognosis for 5years of follow-up because of a prior major cardiovascular event,cancer,or another chronic disease.
The procedures for screening and fol?low-up were specified in the ETDRS Manual of Operations.w The study pro?tocol was approved by the committee on human research at each participating institution.
Patient Follow-up
All patients were to be followed up for at least5years,with visits scheduled ev?ery4months to assess visual acuity and drug adherence.During the first3V￡years of the study,a physical examina?tion,medical history,assessment of drug adherence based on pill count and patient interviews,and battery of biochemical and hématologie determinations were performed at annual intervals following entry into the study.During this period, serum thromboxane B2levels and urine salicylate levels were used to assess com?pliance with study treatments at the an?nual visits.For the remainder of the study,physical examinations were per?formed at only the third and fifth annual visits,and thromboxane B2measure?ments were discontinued.
Aspirin Therapy
Patients were randomly assigned to aspirin or placebo(two325-mg tablets once per day);the randomization was de?signed to provide balance in the number of patients assigned to aspirin or placebo within each clinical center.Both the pla?cebo and aspirin(Bayer)were supplied to the ETDRS Drug Distribution Center
by Glenbrook Laboratories,a division of
Sterling Drug Ine,New York,NY.Nei?
ther the patient nor the clinical center
personnel were informed of the patient's
drug assignment except in the rare event
of a medical emergency.
The daily dose of650mg was selected
because it is sufficient to ensure com?
plete inhibition of platelet aggregation
by blocking cyclooxygenase but not
enough to completely inhibit prostacy-
clin production by endothelial tissue.24
Patients were expected to have good
adherence to a regimen of two325-mg
tablets once per day and to have few
side effects.During the course of the
trial,lower doses of aspirin were con?
sidered because accumulating evidence
suggested that a dose of aspirin as low
as80mg every other day might be suf?
ficient to inhibit platelet aggregation.
After review of all available informa?
tion,including ETDRS data on side ef?
fects,the ETDRS investigators decided
to continue with the dose of650mg/d.
End Points
Mortality from all causes was speci?
fied as the primary end point or out?
come measure for assessing the systemic
effects of aspirin.Other outcome vari?
ables specified at the start of the study
included cause-specific mortality,car?
diovascular events(fatal and nonfatal
myocardial infarction and stroke),am?
putations,and evidence of kidney dis?
ease or failure(dialysis,transplantation,
and/or death due to kidney failure).
The Mortality and Morbidity Classi?
fication Committee(internists and car?
diologists who were not ETDRS clinical
center investigators)19coded the deaths
and hospitalizations for cardiovascular
events.Coding was performed without
knowledge of treatment assignment,ac?
cording to preestablished criteria.Elec?
trocardiogram Reading Center staff
without knowledge of treatment assign?
ment or clinical findings used the Min?
nesota Code25to read the baseline and
5-year follow-up electrocardiograms
(ECGs)(standard supine12-lead ECGs).
At regular intervals the ETDRS Co?
ordinating Center staff prepared data
reports for review by the ETDRS Data
Monitoring Committee.19This group re?
viewed the accumulating data during
the course of the trial for treatment
group differences with respect to visual
function as well as for mortality and
morbidity and for a wide range of pos?
sible adverse effects.
Statistical Considerations
Study Size.—To determine the power
of the study to detect an aspirin effect,the
5-year mortality rate for patients as-
signed to placebo was predicted to be
15%.With1855patients in each group
there was78%power to detect a reduc?
tion in mortality of25%or greater and
99%power to detect a reduction of40%or
greater(ie,from15%to9%or less),with
a=.01for a two-sided test.The effect of
compliance less than100%was also ascer?
tained.If only85%of patients assigned to
aspirin took the study drug or other
platelet-affecting drugs and only75%of
the patients assigned to placebo did not
take aspirin or platelet-affecting drugs,
the expected5-year event rates(assum?
ing a40%treatment effect)would fall to
13.5%for patients assigned to placebo
and increase to9.9%for patients assigned
to aspirin.Under these assumptions,the
study would have a power of78%.
Statistical Methods.—Comparisons
of outcome measures expressed as pro?
portions of events were made with the
two-sample test of equality of propor?
https://www.wendangku.net/doc/c216671573.html,parisons of continuous vari?
ables were based on the two-sample
test of equality of means.26Cumulative
event rates were calculated using the
Cutler-Ederer life table method.27The
Mantel-Cox log-rank statistic28was used
for comparison of life table curves for
the entire period of follow-up.The rel?
ative risk of specified events for patients
assigned to aspirin compared with pa?
tients assigned to placebo was estimated
(along with the99%confidence interval
[CI])using Cox regression with cova-
riates.29A relative risk less than1.0in?
dicates a reduced risk of the outcome
measure for patients assigned to aspirin
compared with patients assigned to pla?
cebo;a relative risk greater than 1.0
indicates an increased risk for patients
assigned to aspirin compared with pa?
tients assigned to placebo.A confidence
interval including1.0indicates that the
observed data are consistent with no
aspirin effect.
To adjust for multiple testing,P<.01
for the two-sided test of the comparison
of mortality from all causes was speci?
fied in advance.For other outcome vari?
ables,.001 provided some evidence of differences between aspirin and placebo,and P<.001 provided stronger evidence of an aspi? rin effect. All patients were counted in the treat? ment groups to which they were ran? domized,regardless of the level of compliance. RESULTS Baseline Characteristics The22participating clinical centers enrolled3711patients,of whom1856 were assigned randomly to aspirin and 1855to placebo.Slightly more than half Table1.—Baseline Characteristics Aspirin, No.(%) (N=1856)Placebo, No.(%) (N=1855) Age at entry,y <30324(17.5)302(16.3) 30-49572(30.8)596(32.1) a5096051.7)957(51.6) Sex(M)103155.5)1065(57.4) Race(W)142076.5)1414(76.2) Diabetes Type I55930.1)571(30.8) Type II58731.6)565(30.5) Mixed71038.3)719(38.9) Duration of diabetes,y <1030616.5)304(16.4) 10-19108458.4)1035(55.8) =20466;25.1)516(27.8) Daily use of insulin155283.6)1561(84.2) Use of oral hypoglycémie agents27614.9)257(13.9)￡120%of desirable weight79342.7)748(40.3) ?6cigarettes/day81944.1)822(44.3) Serum cholesterol2:6.20mmol/L*35.2)495(36.0) Low-density llpoprotein cholesterol2:4.15mmol/L*33626.4)328(25.0) Serum creatlnine2:133μ /L* 6.5)139(7.9) Hemoglobin Alc210%*53841.0)584(42.9) Systolic blood pressure,mm Hg a130122866.2)1220(65.8) 2:16038520.7)364(19.6) Dlastollc blood pressure,mm Hg ==8573539.6)716(38.6)￡9055229.7)509(27.5) History of definite or suspected Myocardial infarction111 6.0)99(5.3) Stroke 1.5)38(2.0) Transient ischemie attack26 1.4)29(1.6) Coronary artery disease1417.6)145(7.8) Congestive heart failure 2.6)57(3.1) Intermittent claudication1679.0)180(9.7) Amputation553.0)52(2.8) Elevated blood pressure or prescription for diuretic agents or antihypertensive drugst45.3)806(43.4) Cardiovascular disease history}:91249.1)900(48.5) Proliferative retinopathy in one or both eyes25.7)486(26.2) Clinically significant macular edema in one or both eyes1137|61.3)1126(60.7) *These laboratory values were obtained only for some patients;denominators range from1274to1769. tConsidered present If the patient had systolic blood pressure of160mm Hg or greater or dlastollc blood pressure of95mm Hg or greater or If the patient reported the use of diuretic or antihypertensive agents at the time of entry. ^Cardiovascular disease history was considered present if the patient reported a history of any of the following conditions:coronary artery disease,congestive heart failure,myocardial Infarction,or intermittent claudication. Patients reporting any of the following drug use at the time of entry were also considered to have cardiovascular disease history:long-term antianginal agents,propranolol or other?-blockers,nltroglycerin or other vasodilators, digitalis,antiarrhythmic agents,or diuretic and other antihypertensive agents.Patients who had systolic blood pressure of160mm Hg or greater or diastollc blood pressure of95mm Hg or greater were also considered to have cardiovascular disease history. were male(56%)and the majority were white(76%);30%of the patients were considered to have type I diabetes(Ta?ble1).The National Diabetes Data Group recommendations30concerning the clas?sification of patients with diabetes mel?litus were issued after the ETDRS ini?tiated patient recruitment.Because in?formation on insulin dependence and other data required for that classifica?tion system were not available,an ETDRS classification system was de?veloped.31Patients were classified as having type I diabetes mellitus if the following criteria were met:age at di? agnosis of diabetes30years or less;in? sulin prescribed within1year of diag? nosis,and insulin therapy was never dis? continued;and body weight less than 120%of desirable at the time of screen? ing for the ETDRS.The criteria for type II diabetes mellitus were age at diag? nosis of diabetes greater than30years and insulin never or only intermittently used or age at diagnosis of diabetes greater than40years and body weight 120%or more of desirable weight at the time of screening.Patients not identi- fied as having type I or II diabetes were classified in the category"mixed";the majority of these patients were taking insulin daily. Patients assigned to the treatment groups were comparable with respect to all baseline characteristics listed in Table1.None of the26drug-placebo group comparisons yielded P<.01. Extent of Follow-up Five-year follow-up was specified in the original ETDRS design,and5-year event rates are presented along with 7-year event rates,as in other ETDRS publications.The average follow-up was 5years,with a minimum possible follow- up of approximately4years and a max? imum of9years. All3144surviving patients were asked to return for a final follow-up examina? tion during the closeout period,August 1,1988,through June30,1989.A total of 2807patients completed the closeout visit,164patients were known to be alive but did not complete the visit,706 patients died before the closeout visit could be completed,and34could not be contacted.The vital status of these34 patients(15in the aspirin group and19 in the placebo group)was not known at the time of the data analysis for this report.Each of these patients was in? cluded in the analyses through the date of last contact;the majority had been followed up for at least3years. During the first3years of follow-up, between90%and95%of expected visits were completed.Between80%and90% of patients completed follow-up visits after3years.The proportions of pa? tients missing visits were similar in the aspirin and placebo groups. Adherence to Study Treatment At the end of one year,8.2%of pa? tients assigned to aspirin and7.4%of patients assigned to placebo were not taking their study medication.20The numbers of patients not taking study medication,which increased by about 5%per year for the first5years,were approximately equal in the two groups. Estimates of adherence to assigned med? ication based on urine salicylate levels and thromboxane measurements,when available,yielded similar findings. The ETDRS protocol specified dis? continuation of therapy with the as? signed study medication if any of the following occurred:prescription for a platelet-affecting drug or anticoagulant therapy,pregnancy,hospitalization,or the unmasking of study medication.21The most common reason for stopping ad? ministration of the assigned study med? ication was patient use of known platelet- affecting drugs. Table2.—Deaths by Cause and Nonfatal Events Aspirin,Placebo, No.(%)No.(%) (N=1856)(N=1855) Death—all causes_340(18.3)_366(19.7)_-1.10 All cardiovascular244(13.1)275(14.8)-1.47 Sudden coronary death47(2.5)67(3.6)-1.91 Cerebrovascular25(1.3)25(1.3)0.00 All noncardiovascular87(4.7)85(4.6)0.15 Cancer16(0.9)14(0.8)0.37 Other noncardiovascular71(3.8)71(3.8)0.00 Cause of death unknown9(0.5)6(0.3)0.78 Fatal or nonfatal myocardial infarction_241(13.0)_283(15.3)_-1.99 Fatal or nonfatal stroke_92(5.0)_78(4.2)_1.10 Amputation_88(4.7)_96(5.2)_-0.61 Hypertension_1393(75.1)_1356(73.1)_1.36 Any of the following239(12.9)227(12.2)0.59 Renal transplantation144(7.8)146(7.9)-0.13 Renal dialysis36(1.9)33(1.8)0.36 Candidate for dialysis101(5.4)100(5.4)0.07 Death from kidney failure_21(1.1)_18(1.0)_0.48 Cardiovascular death,nonfatal myocardial infarction,or stroke_350(18.9)_379(20.4)_-1.21 All deaths,nonfatal myocardial Infarction, or stroke439(23.7)463(25.0)-0.93 At the end of5years of follow-up, 89%of patients assigned to aspirin were taking some aspirin or other platelet-affecting drug(70%were taking the as?signed study aspirin and19%were tak?ing known platelet-affecting agents).In the placebo group,71%were taking only the assigned medication,and18%were taking a known platelet-affecting drug; thus,about82%of patients assigned to placebo were taking neither aspirin nor any other platelet-affecting drug. Total and Cause-Specific Mortality The number and percentage of deaths among patients in each group,shown in Table2,are based on total follow-up. The percentages of patient deaths in the aspirin and placebo groups were nearly equal(18.3%and19.7%,respectively). The majority of deaths in both groups were classified as cardiovascular by the Mortality and Morbidity Classification Committee:244(71.8%)of the340deaths in the aspirin group and275(75.1%)of the366deaths in the placebo group.The patients who died of cardiovascular causes represented13.1%and14.8%of the aspirin and placebo groups,respec?tively.Only a few patients died of cere-brovascular disease,and there was no difference between the treatment groups.About2%of the deaths could not be classified or were attributed to unknown causes. The life table rates for total mortality are plotted in Fig1;those for cardio?vascular mortality in Fig2.The5-year life table rates for total mortality were 12.1%for the aspirin group and14.9% for the placebo group(Table3).The es-tímate of relative risk,based on total mortality for the entire follow-up period (Fig1),was0.91(99%CI,0.75to1.11; P=.24).The5-year cumulative rates for cardiovascular mortality were9.3%and 11.2%for patients assigned to aspirin and placebo,respectively(Table3).The estimate of relative risk for the entire follow-up period(Fig2)was0.87(99% CI,0.70to1.10;P=.12). Morbidity and Combined Mortality/Morbidity End Points The occurrence of definite fatal and nonfatal myocardial infarction and offa- tal and nonfatal stroke as well as the occurrence of other events for the en? tire follow-up period are given in Table 2.More patients assigned to placebo than assigned to aspirin had fatal or nonfatal myocardial infarctions(15.3%vs13.0%). Fatal or nonfatal stroke occurred in5.0% of patients assigned to aspirin and4.2% of patients assigned to placebo.In three fourths of the patient population,hy? pertension was detected at some time during the course of follow-up—75.1% of patients assigned to aspirin and73.1% assigned to placebo.The occurrence of amputation of any limbs or parts of limbs was approximately5%in both groups. Approximately8%in each group had received renal transplants,and about 7.5%in each group were candidates for renal dialysis or had reported renal di? alysis.The occurrence of one or more of these conditions or death attributed to kidney disease occurred in12.9%of pa? tients assigned to aspirin and12.2%of patients assigned to placebo.None of the observed differences was considered Time,y Fig 1.—Life table cumulative event rates tor total mortality for the aspirin(broken line)and placebo (solid line)groups.The relative risk for the entire period of follow-up was0.91(99%confidence interval,0.75to1.11;P=.24). Fig2.—Life table cumulative event rates for cardio? vascular mortality for the aspirin(broken line)and placebo(solid line)groups.The relative risk for the entire period of follow-up was0.87(99%confidence interval,0.70to1.10;P=.12). statistically significant. The5-year event rates for fatal and nonfatal myocardial infarction were9.1% and12.3%for patients assigned to as? pirin and placebo,respectively(Table 3);the estimate of relative risk of my? ocardial infarction for the entire follow- up period was0.83(99%CI,0.66to1.04; P=.04). For fatal and nonfatal stroke,the 5-year event rates were4.5%and3.8% for patients assigned to aspirin and pla? cebo,respectively(Table3).The esti? mate of relative risk for stroke for the entire follow-up period was1.17(99% CI,0.79to1.73;P=.32). The cumulative5-year rates of occur? rence of cardiovascular mortality,non- fatal myocardial infarction,or stroke were14.0%for patients assigned to as? pirin and16.6%for patients assigned to placebo(Table3).The treatment differ? ence for a combined end point that in? cluded total mortality,nonfatal myocar? dial infarction,and stroke was similar to that for the end point that included only Table3.—Five-Year Life Table Rates and Estimates of Relative Risk,Overall and by Sex 5-Year Life Table Rates by Sex 5-Year Life Table Rates Relative Aspirin Placebo Risk Estimate (N=1856)(N=1855)(99%CI*) Adjustedf Relative Males Females Adjusted}Relative Risk Estimate (99%CI) Risk Estimate Aspirin Placebo Aspirin Placebo (99%CI)(N=1031)(N=1065)(N=825)(N=790)Males Females Death—all causes12.114.90.91(0.75to1.11)0.91(0.75to1.11)12.413.811.616.20.94(0.73to1.22)0.88(0.65to1.17) Cardiovascular death9.311.20.87(0.70to1.10)0.87(0.69to1.09)8.610.210.112.50.83(0.61to1.14)0.92(0.66to1.28) Fatal or nonfatal myocardial infarction9.112.30.83(0.66to1.04)0.82(0.65to1.03)8.612.012.60.74(0.54to1.00)0.91(0.65to1.28) Fatal or nonfatal stroke 3.8 1.17(0.79to1.28) 1.17(0.79to1.74) 4.6 3.8 1.07(0.63to1.83) 1.31(0.71to2.39) Cardiovascular death,nonfatal myocardial Infarction,or stroke14.016.60.91(0.75to1.10)0.90(0.74to1.09)13.516.516.80.81(0.63101.05) 1.00(0.75to1.34) All deaths,nonfatal myocardial infarction,or stroke16.520.00.93(0.78to1.10)0.92(0.77to1.09)16.í19.816.220.20.88(0.70to1.11)0.97(0.75to1.26) *AII relative risk estimates are based on the entire follow-up.CI indicates confidence interval. tWith0indicating"no"and1indicating"yes,"relative risk estimates were adjusted for the following:age greater than30years,age greater than50years,male,nonwhlte, type I diabetes mellitus,type II diabetes mellitus,and clinical center. tWith0indicating"no"and1indicating"yes,"relative risk estimates were adjusted for the following:age greater than30years,age greater than50years,nonwhite,type I diabetes mellitus,type II diabetes mellitus,and clinical center. e50 o o >40 Time,y Fig3.—Life table cumulative event rates for fatal or nonfatal myocardial infarction for the aspirin(bro?ken line)and placebo(solid line)groups.The rela?tive risk for the entire period of follow-up was0.83 (99%confidence interval,0.66to1.04;P=.04). cardiovascular deaths(Table3). Cox regression was used to estimate relative risk adjusted for age,gender, race,type of diabetes,and clinical cen?ter.These estimates of relative risk and 99%CIs were very similar to the un?adjusted estimates(Table3). Findings by Gender Among the3711patients enrolled in the ETDRS,1615(44%)were women.A larger proportion of women than men were nonwhite(29%vs19%),had type II diabetes(36%vs28%),and weighed more than120%of desirable body weight (51%vs34%). Cox regression with covariates was used to estimate relative risk for males and females.The estimates of relative risk for each of the specified end points were quite comparable for males and females.A slightly greater reduction in the occurrence of fatal and nonfatal my? ocardial infarction was noted for males (relative risk,0.74)than for females(rel? ative risk,0.91),and a slightly higher relative risk for stroke was noted for females(1.31)than for males(1.07,Ta? ble3). Patients by Type of Diabetes The baseline characteristics of pa? tients classified by type of diabetes are given in Table4.The patients assigned to aspirin were comparable to those as? signed to placebo within each of these three groups. The numbers of deaths from all causes and from specific causes as well as the other clinical events observed during follow-up are given in Table5for pa? tients in each of the three groups de? fined by diabetes type.No statistically significant treatment differences were observed. Life table rates at5years and esti? mates of relative risk based on all follow- up for specified events in patients clas? sified by type of diabetes are given in Table6.All of the estimates of relative risk were less than1.0except for the occurrence of fatal or nonfatal stroke. The99%CIs for all estimates of relative risk included1.0,indicating no statisti? cally significant treatment differences. Other Clinical Findings and Side Effects At scheduled visits,local laboratory tests were performed when there was an indication of possible toxicity or sus? picion of toxicity.The percentage of pa? tients who had one or more laboratory tests scheduled for this reason at any time during follow-up was10.9%for pa? tients assigned to aspirin and9.6%for patients assigned to placebo.About53% of these tests yielded abnormalities.No significant treatment differences were observed for any of these abnormalities. Only a few patients(2%)in both groups had some indication of bleeding;that is, hemoglobin less than100g/L or hema- tocrit less than0.30,hematuria,or blood in the stool. Electrocardiograms Central reading of the baseline ECGs identified major abnormalities in180 (10%)of1856patients assigned to as? pirin and in156(8%)of1855patients assigned to placebo.These abnormali? ties included Q-wave changes,ST de? pression or elevation,T-wave changes, atrioventricular block,right or left bun? dle branch block,atrial fibrillation,ta? chycardia,and arrhythmias.The major? ity of the ECGs were classified as nor? mal(74%and76%for patients assigned to aspirin and placebo,respectively).The remainder were classified as having other abnormalities. Of1376patients assigned to aspirin who had normal baseline ECGs,942 (68%)had follow-up ECGs at the fifth annual follow-up visit or a subsequent visit.Among1406patients who had nor? mal baseline ECGs and were assigned to placebo,916(65%)had follow-up ECGs.Many of the patients who did not have follow-up ECGs had died before Table4.—Baseline Characteristics of Patients Classified by Diabetes Type Type I Mixed Aspirin, No.(%) (N=559)Placebo, No.(%) (N=571) "l Aspirin, No.(%) (N=710) Placebo, No.(%) (N=719) Type II Aspirin, No.(%) (N=587) Placebo, No.(%) (N=565) Age at entry,y <30284(50.8)262(45.9)40(5.í40(5.6) 30-49258(46.2)288(50.4)259(36.5)268(37.3)55(9.4)40(7.1) 2:5017(3.0)21(3.7)411(57.9)411(57.2)532(90.6)525(92.9) Sex(M)337(60.3)365(63.9)391(55.1)425(59.1)303(51.6)275(48.7) Race(W)529(94.6)539(94.4)514(72.4)504(70.1)377(64.2)371(65.7) Duration of diabetes,y <1017(3.0)23(4.0)79(11.1)80(11.1)210(35.8)201(35.6) 10-19347(62.1)331(58.0)415(58.5)405(56.3)322(54.9)299(52.9) 2:20195(34.9)217(38.0)216(30.4)234(32.5)55(9.4)65(11.5) Daily use of insulin558(99.8)571(100.0)689(97.0)696(96.8)305(52.0)294(52.0) Use of oral hypoglycémie agents1(0.2)1(0.2)25(3.5)24(3.3)250(42.6)232(41.1) :120%of desirable weight331(46.6)311(43.3)462(78.7)437(77.3) 2:6cigarettes/day273(48.8)268(47.0)315(44.4)352(49.0)231(39.4)202(35.8) Serum cholesterol2:6.20mmol/L85(21.3)111(25.2)207(41.0)195(37.3)178(41.4)189(46.1) Low-density llpoprotein cholesterol 2:4.15mmol/L80(20.(82(19.3)135(28.2)121(24.2)121(29.8)125(32.3) Serum creatlnine2:133μ /L12(2.3)24(4.3)53(7.9)63(9.2)49(8.8)52(9.7) Hemoglobin A,c2:10%175(45.1)228(51.9)222(44.3)220(42.9)141(33.3)136(33.3) Systolic blood pressure,mm Hg 2:130214(38.3)237(41.6)523(73.7)505(70.2)491(83.6)478(84.6) =16026(4.7)32(5.6)155(21.8)153(21.3)204(34.8)179(31.7) Dlastollc blood pressure,mm Hg 2:85159(28.4)147(25.8)278(39.2)288(40.1)298(50.8)281(49.7) 2:90104(18.6)94(16.5)213(30.0)205(28.5)235(40.0)210(37.2) History of definite or suspected Myocardial infarction4(0.7))(1.6)61(8.6)50(7.0)46(7.8)40(7.1) Stroke3(0.5)2(0.4)1(1.1)20(2.8)16(2.7)16(2.8) Transient ischemie attack2(0.4)13(1.8)16(2.2)11(1.9)13(2.3) Coronan/artery disease4(0.7)1(1.4)70(9.9)70(9.7)67(11.4)67(11.9) Congestive heart failure1(0.2)22(3.1)25(3.5)25(4.3)32(5.7) Intermittent claudication25(4.5)35(6.1)79(11.1)89(12.4)63(10.7)56(9.9) Amputation4(0.7)5(0.9)30(4.2)28(3.9)21(3.6)19(3.4) Elevated blood pressure or prescription for diuretic agents or antihypertensive drugs111(19.9)98(17.2)332(46.8)341(47.4)397(67.6)367(65.0) Cardiovascular disease history119(21.3)112(19.6)372(52.4)395(54.9)421(71.7)393(69.6) Proliferative retinopathy in one or both eyes224(40.1)240(42.0)159(22.4)153(21.3)94(16.0)93(16.5) Clinically significant macular edema in one or both eyes222(39.7)213(37.3)448(63.1)472(65.6)467(79.6)441(78.1) the fifth annual follow-up visit(108in the aspirin group and135in the placebo group);other patients were not expected to complete the fifth annual visit be?cause of their dates of entry. Among patients who had follow-up ECGs,60(6%)of942assigned to aspirin and63(7%)of916assigned to placebo had one or more major abnormalities identified on central reading.Only six (10%)of60aspirin-treated patients and eight(13%)of63placebo-treated pa?tients with major abnormalities on a fol?low-up ECG had reported nonfatal my?ocardial infarctions before the follow-up ECG was obtained. Patients who had major abnormali?ties identified on the follow-up ECG but who had not reported a myocardial in?farction were considered to have had a "silent"myocardial infarction.The num?bers of patients who had"silent"myo?cardial infarctions were54and55in the aspirin and placebo groups,respectively, for a total of109.Six patients assigned to aspirin and two assigned to placebo were reported to have a myocardial in? farction after the follow-up ECG.These eight were counted in the number of fatal and nonfatal infarctions(Table2). The other"silent"myocardial infarctions were not included in the number of fatal and nonfatal infarctions in Table2.Add? ing these"silent"myocardial infarctions increases the number of fatal and non- fatal myocardial infarctions to289(16%) in the aspirin group and336(18%)in the placebo group(P=.038). COMMENT The ETDRS is the largest multicenter, placebo-controlled clinical trial of aspi? rin in patients with diabetes mellitus. Total mortality in this study(the pri? mary end point for evaluating systemic effects of aspirin)was slightly lower in patients assigned to aspirin during the first6years of follow-up(Fig1).The estimate of relative risk for the entire period was0.91;the small reduction in the aspirin group was not statistically significant by study criteria.A small but not statistically significant reduc? tion in cardiovascular mortality in the aspirin group was also https://www.wendangku.net/doc/c216671573.html,rger differences between the aspirin and pla? cebo groups were observed for the oc? currence of fatal and nonfatal myocar? dial infarction;the estimate of relative risk for the aspirin group was0.83for the entire follow-up period(99%CI,0.66 to1.04).If"silent"infarctions were in? cluded,the estimate of relative risk did not change substantially. The observed reduction in the occur? rence of fatal and nonfatal myocardial infarction for the aspirin group,based on only the first5years of follow-up (estimate of relative risk,0.72;99%CI, Table5.—Deaths by Cause and Nonfatal Events by Diabetes Type Type I Mixed Aspirin, No.(%) (N=559)Placebo, No.(%) (N=571) Aspirin, No.(%) (N=710) Placebo, No.(%) (N=719) Type II Aspirin, No.(%) (N=587) Placebo, No.(%) (N=565) Death—all causes29(5.2)39(6.8)150(21.1)165(22.9)161(27.4)162(28.7) All cardiovascular17(3.0)26(4.6)110(15.5)125(17.4)117(19.9)124(21.9) Sudden coronary death2(0.4)2(0.4)22(3.1)30(4.2)23(3.9)35(6.2) Cerebrovascular1(0.2)5(0.9)10(1.4)8(1.1)14(2.4)12(2.1) All noncardiovascular10(1.8)13(2.3)35(4.9)36(5.0)42(7.2)36(6.4) Cancer0(0.0)1(0.2)10(1.4)4(0.6)6(1.0)9(1.6) Other noncardiovascular10(1.8)12(2.1)25(3.5)32(4.5)36(6.1)27(4.8) Cause unknown2(0.4)0(0.0)5(0.7)4(0.6)2(0.3)2(0.4) Fatal or nonfatal myocardial Infarction25(4.5)31(5.4)109(15.4)134(18.6)107(18.2)118(20.9) Fatal or nonfatal stroke7(1.3)12(2.1)36(5.1)32(4.5)49(8.3)34(6.0) Amputation11(2.0)14(2.5)48(6.8)45(6.3)29(4.9)37(6.5) Hypertension331(59.2)318(55.7)555(78.2)555(77.2)507(86.4)483(85.5) Any of the following78(14.0)76(13.3)94(13.2)99(13.8)67(11.4)52(9.2) Renal transplantation41(7.3)52(9.1)69(9.7)66(9.2)34(5.8)28(5.0) Renal dialysis24(4.3)21(3.7)11(1.5)10(1.4)1(0.2)2(0.4) Candidate for dialysis24(4.3)29(5.1)50(7.0)46(6.4)27(4.6)25(4.4) Death from kidney failure1(0.2)1(0.2)7(1.0)9(1.3)13(2.2)8(1.4) Cardiovascular death,nonfatal myocardial infarction,or stroke34(6.1)42(7.4)150(21.1)174(24.2)166(28.3)163(28.8) All deaths,nonfatal myocardial infarction,or stroke45(8.1)52(9.1)187(26.3)213(29.6)207(35.3)198(35.0) Table6.—Five-Year Life Table Rates and Estimates of Relative Risk by Diabetes Type Type I Mixed Aspirin, No.(%) (N=559)Placebo, No.(%) (N=571) Relative Risk (99%CI*) Aspirin, No.(%) (N=710) Placebo, No.(%) (N=719) Type II Relative Risk (99%CI) Aspirin,Placebo, No.(%)No.(%)Relative Risk (N=587)(N=565)_(99%CI) Death—all causes17(3.2)27(5.0)0.77(0.41to1.45)89(13.1)120(17.6)0.90(0.67to1.20)108(19.2)115(21.6)0.92(0.69to1.23) Cardiovascular death Fatal or nonfatal myocardial Infarction 10(1.9)18(3.4)0.68(0.30to1.51)69(10.3)90(13.3)0.87(0.62to1.22)83(15.1)87(16.8)0.88(0.63to1.22) 13(2.5)21(3.9)0.83(0.42to1.66)73(10.9)102(15.2)0.80(0.57to1.11)72(13.4)90(17.3)0.83(0.59to1.17) Fatal or nonfatal stroke4(0.8)10(1.8)0.60(0.18to2.04)29(4.6)25(3.9) 1.11(0.59to2.07)42(8.1)29(6.0) 1.37(0.77to2.43) Cardiovascular death, nonfatal myocardial Infarction,or stroke18(3.4)30(5.5)0.83(0.46to1.51)104(15.4)134(19.6)0.85(0.63to1.13)123(22.4)128(24.4)0.95(0.71to1.26) All deaths,nonfatal myocardial Infarction, or stroke25(4.7)38(6.9)0.89(0.53to1.50)122(17.8t)163(23.6)0.86(0.66to1.11)146(26.0)154(28.7)0.97(0.75to1.26) *AII relative risk estimates are based on the entire follow-up.CI indicates confidence Interval. tP<.01(ztest of cumulative rate by Greenwood's formula). 0.55to0.95),was larger than the esti?mate based on all follow-up(estimate of relative risk,0.83;99%CI,0.66to1.04). A time-dependent analysis suggests that the ratio of the hazard rate for the as^ pirin group to the rate for the placebo group decreases with longer follow-up (data not shown).This apparent change in relative risk between the beginning and the end of the study may be due to decreased adherence to study medica?tion during the later years of follow-up, to aspirin delaying rather than prevent?ing myocardial events,to random vari?ability,or to other reasons. Of3711patients enrolled,approxi?mately30%were classified by ETDRS criteria as having type I and30%type II diabetes;the remaining40%were classi?fied as not definitely type I or II(the mixed group).For most of the events con?sidered in this report,the aspirin vs pia-cebo treatment effects on patients in each of the three diabetes classification groups differed little from those for the entire ETDRS patient population.Aspirin- placebo differences for these events were also similar for men and women.Al? though slightly larger reductions in the occurrence of myocardial infarction were noted for patients who reported a history of cardiovascular disease,these differ? ences were not significant. Table7summarizes the results from four large studies of the effect of aspirin on cardiovascular disease.Although each study evaluated the effect of aspirin on cardiovascular disease,there are impor? tant differences among these studies.The ETDRS is the largest single study of per? sons with diabetes and includes persons with and without a history of cardiovas? cular disease.The US Physicians'Health Study32and the trial of British male doc- tors33studied low doses of aspirin in male physicians without significant cardiovas? cular disease at study entry.Only a small percentage of these physicians had diabe? tes mellitus.The first report of the Anti- platelet Trialists'Collaboration included the findings from25randomized trials of antiplatelet therapy(aspirin,dipyrida- mole,or sulfinpyrazone alone or in com? bination)in patients with a history of car? diovascular disease.34A recent report from the Antiplatelet Trialists'Collabo? ration group expanded the previous study to include data from31trials and in? cluded some information on the4643pa? tients with a history of diabetes at the time of entry into these trials.35 Although the populations studied dif? fered in each of these four studies,there are some similarities in their results. The reductions in the relative risk of total mortality and increases in the rei- Table7.—Relative Risk of Cardiovascular Events by Study Total Mortality Myocardial Infarction Stroke Important Vascular Events Study No.Enrolled No.of Events Relative Risk No.of Events Relative Risk No.of Events Relative Risk No.of Events Relative Risk Early Treatment Diabetic Retinopathy Study All follow-up37117060.915240.83*170 1.177290.91 First5years37114760.80*3710.72t139 1.165370.82* Physicians'Health Study32 All enrolled220714440.963780.56t217 1.220.82t Diabetics533NR*370.39NR NR Trial of British male doctors3351390.90§ Antiplatelet Trialists' Collaboration35 Nondiabetics63762NR NR NR62610.77II Diabetics NR NR NR8850.8111 *Ps.05. tPs.01. JNR indicates not reported. §Ratio of events to person-years. llOdds ratio. ative risk of stroke in each of these stud?ies(if they reported on either end point) were all in the same direction but were all small and statistically nonsignificant. The reductions in the relative risk for myocardial infarction alone or in com?bination with other important vascular events were also all in the same direc?tion but varied somewhat in the size of the relative risk.Some of these reduc?tions in relative risk associated with as?pirin use were statistically significant. The reduced risk of myocardial in?farction in the aspirin group compared with that for the placebo group in the ETDRS did not achieve statistical sig-nificance by study criteria,except when the results for only the first5years of follow-up were considered.The effects of aspirin on any of the cardiovascular events considered in the ETDRS were not substantially different from the ef? fects observed in other studies that in? cluded diabetic and nondiabetic patients, although the evidence of beneficial ef? fects of aspirin were not as large as in some of the studies.There was no evi? dence that the results for women were different than for men. Aspirin neither prevented the devel? opment of high-risk proliferative retin? opathy nor increased the risk of vitre- ous hemorrhage,as reported else? where.20Although aspirin had neither beneficial nor harmful effects in the eye, the small reduction of cardiovascular events seen in this study of persons with diabetes is concordant with results of other studies of aspirin and cardiovas? cular disease.Aspirin has been recom? mended previously for persons at risk for cardiovascular disease.The ETDRS results support application of this rec? ommendation to those persons with di? abetes at increased risk of cardiovascu? lar disease. This report was supported under contracts from the National Eye Institute. 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N Engl J Med.1989;321:129-135.33.Peto R,Gray R,Collins R.Randomized trial of prophylactic daily aspirin in British male doctors. BMJ.1988;296:313-316. 34.Antiplatelet Trialists'Collaboration.Second- ary prevention of vascular disease by prolonged antiplatelet treatment.BMJ.1988;296:320-331. 35.Antiplatelet Trialists'Collaboration.Overall ef- fects on major vascular events:subgroup issues and comparison of agents.Read before the40th Annual Scientific Session of the American College of Cardiology;March6,1991;Atlanta,Ga. EARLY TREATMENT DIABETIC RETINOPATHY STUDY INVESTIGATORS Albany(NY)Medical College.—Aaron Kassoff,MD. Eye Research Institute of Retina Foundation/Retina Associates,Boston, Mass.—Sheldon M.Buzney,MD;J.Wallace McMeel,MD;John J.Welter,MD, PhD;Gerald J.Doyle,MD;Rodney L.Immerman,OD;Gerald R.Friedman,OD. Good Samaritan Hospital and Medical Center,Portland,Ore.—Michael L. Klein,MD;Richard Dreyer,MD;Richard Chenoweth,MD;Irvin Handelman, MD;Richard Hohl,MD;Robert Blesbroeck,MD;Jack Sipperley,MD. Hermann Eye Center,University of Texas,Houston.—Charles A.Garcia, MD;Michael A.Bloome,MD;Richard S.Ruiz,MD. Holy Cross Hospital,Salt Lake City,Utah—F.Tempel Riekhof,MD;William A.Bohart,MD;Roy A.Goodart,MD;Dana H.Clarke,MD. Ingalls Memorial Hospital,Harvey,III.—David H.Orth,MD;Timothy P. Flood,MD;Kirk H.Packo,MD;Jayant Malhotra,MD;Akbar Rahmanl,MD; Edward J.Winter,MD;Harish Bhatla,MD. Johns Hopkins Hospital(Wilmer Institute),Baltimore,Md.—Robert P. Murphy,MD;Stuart L.Fine,MD;Michael J.Elman,MD;Frederick L.Ferris III, MD;Thaddeus E.Prout,MD;Arnall Patz,MD;Thomas A.Rice,MD;David Newsome,MD. Joslin Diabetes Center(Beetham Eye Institute),Boston,Mass.—Lloyd M. Aiello,MD;Lawrence I.Rand,MD;Sabera T.Shah,MD;Ramachandiran Cooppan,MD;Jerry Cavallerano,OD,PhD;Robert Poole,OD;Philip Silver, OD;Jose Briones,Jr,MD;Mohammed Z.Wafai,MD;Abdul C.Asmal,MD, PhD. Louisiana State University Eye Center,New Orleans.—Rudolph M.Fran?klin,MD;Laurence Arend,MD;Donald Bergsma,MD;Lance Turkish,MD; Paul Beer,MD;Denis Carroll,MD;Edgar Thomas,MD. Medical College of Wisconsin,Milwaukee.—Thomas C.Burton,MD;Gary W.Abrams,MD;Hak-Joong Kim,MD;George A.Williams,MD;Trexler M. Topping,MD;Frederick H.Reeser,MD;Thomas M.Aaberg,MD;Gregory S. Brinton,MD;James K.Kingham,MD;Travis A.Meredith,MD. Michigan State University(Associated Retinal Consultants),East Lansing.—Raymond R.Margherio,MD;Patrick L.Murphy,MD;Morton S. Cox,MD;Michael Trese,MD;Steven Winokur,MD. Pacific Presbyterian Medical Center,San Francisco,Calif.—Everett Ai,MD; Robert Sorenson,MD;Gary Arsham,MD;John Cavender,MD. UCLA Center for Health Sciences(Jules Stein Eye Institute),Los Angeles, Calif.—Stanley M.Kopelow,MD;Alan L.Shabo,MD;Jose C.Briones,Jr,MD; Richard D.Hornichter,MD.University of Illinois,Chicago.—Norman P.Blair,MD;Morton F.Goldberg, MD;C.Ronald Lindberg,MD;Neil L.Ross,MD;Lynn E.Hauser,MD;Jose Cunha-Vaz,MD,PhD;J.Terry Ernest,MD,PhD;James C.Liang,MD;Steven .Cohen,MD;Charles Vygantas,MD;Gerald Williams,MD. University of Miami,Fla(Bascom Palmer Eye Institute).—Harry W.Flynn, Jr,MD;George W.Blankenship,MD. University of Minnesota,Minneapolis.—William H.Knobloch,MD;Robert C. Ramsay,MD;Herbert L.Cantrill,MD;Frederick C.Goetz,MD;Byron Hoogw-erf,MD. University of Puerto Rico,Rio Piedras.—JoséBerrocal,MD;Raúl Pérez, MD;A.Ramos Umpierre,MD. University of Washington,Seattle.—James L.Kinyoun,MD;Robert E.Kai?ina,MD;Craig G.Wells,MD;Steven V.Guzak,MD;Jerry Palmer,MD. University of Wisconsin,Madison.—Frank L.Myers,MD;George H. Bresnick,MD;Suresh R.Chandra,MD;Matthew D.Davis,MD;Ronald Klein, MD;Thomas S.Stevens,MD;Ingolf H.Wallow,MD;Russell Dixon,MD;Ed?ward Ehrlich,MD;Robin Ewart,MD. Wayne State University(Kresge Eye Institute),Detroit,Mich.—Robert N. Frank,MD;Stephenie Lucas,MD;Fred Whitehouse,MD;Harold Weiss,MD; Ann E.Ballen,MD;Michael Teske,MD;Maria Warth,MD. Wills Eye Hospital,Philadelphia,Pa—William E.Benson,MD;William S. Tasman,MD;Gary C.Brown,MD;J.Archibald McNamara,MD. Zweng Memorial Retinal Research Foundation,Menlo Park,Calif.—Hunter L.Little,MD;Robert L.Jack,MD;Lawrence Basso,MD. Central Laboratory(Centers for Disease Control,Atlanta,Ga).—Dayton T. Miller,PhD;Elaine Gunter;David D.Bayse,PhD;W.Harry Hannon,PhD; James E.Myrick,PhD. Coordinating Center(Maryland Medical Research Institute,Baltimore).—Genell L.Knatterud,PhD;Marian R.Fisher,PhD;Mary Jane Prior,PhD; Franca Barton,MS;Joseph Kufera,MA. Drug Distribution Center(US Public Health Service,Perry Point,Md).—Thomas https://www.wendangku.net/doc/c216671573.html,ler,MS;CDR James K.Hooper,MS. ECG Coding Center(University of Minnesota,Minneapolis).—Richard S. Crow,MD;Richard R.Baker,MD;Ronald Prineas,MBBS,PhD. Fundus Photograph Reading Center(University of Wisconsin,Madison) .—Matthew D.Davis,MD;Larry D.Hubbard,MAT;Yvonne L.Magli;Paul Segal,MD. National Eye Institute,National Institutes of Health,Bethesda,Md.—Frederick L.Ferris III,MD;Richard L.Mowery,PhD;Emily Y.Chew,MD; Daniel G.Seigel,ScD;Gary Cassel,MD.