Aspirin in coronary heart disease

J

Chron Dis

1976, Vol. 29, pp. 625-642. Pergamon

ASPIRIN

Press. Printed in Great Britain

IN CORONARY

HEART

DISEASE

THE CORONARYDRUG PROJECTRESEARCHGROUP (Received

in rruisrdform

8 February

1976)

Abstract-The Coronary Drug Project Aspirin Study (CDPA) was started in late 1972 and terminated in early 1975. The study population was comprised of men selected from three groups originally receiving dextrothyroxine or estrogen therapy in the Coronary Drug Project. All patients had a prior history of myocardial infarction. The length of follow-up ranged from a minimum of 10 months to a maximum of 28 months. A total of 1529 patients were recruited and were randomly assigned on a double-blind basis to aspirin therapy-ne 324 mg tablet t.i.d.dr a corresponding placebo treatment. Data indicate a high level of adherence to the study protocol. No major differences were recorded in use of non-study medications in the two treatment groups. Overall mortality was 5.8% in the aspirin group and 8.3% in the placebo group (an observed difference of 30%). This difference is suggestive of a beneficial effect for aspirin in the treatment of post-MI men but not large enough to be conclusive.

THE HYPOTHESIS that aspirin may have long-term therapeutic value in coronary heart disease has been extant for more than two decades [l-3]. Recent animal studies on the effect of aspirin on platelets and thrombus formation lend support to this hypothesis [4-71. The Coronary Drug Project Aspirin Study (CDPA) was initiated in 1972 to help test this hypothesis. STUDY

PLAN

The CDPA utilized the organizational structure of the Coronary Drug Project (CDP), including 53 clinical centers, a coordinating center, central laboratory, ECG reading center, and drug distribution center [8]. The participating institutions and leading personnel are listed at the end of this paper. Only patients from the three treatment regimens discontinued prior to the scheduled termination of the CDP were eligible for enrollment into the CDPA. These regimens included 5.0 mg estrogen/day [9] (ESG2Fterminated in mid-1970, 6.0 mg dextrothyroxine/day [lo] (DT4bterminated in late 1971, and 2.5 mg estrogen/day [l l] (ESGlkterminated in early 1973. Table 1 gives the numbers of patients enrolled into the CDPA from these three cohorts of patients and the time period of recruitment into the CDPA. The minimum time periods between discontinuation of the CDP medication and entry into the CDPA were 25 months for the ESG2 cohort, eight months for the DT4 cohort, and 6-l/2 months for the ESGl cohort. Reprint requests to CDP Coordinating Center, Division of Clinical Investigation, University of Maryland. 600 Wyndhurst Avenue, Baltimore. Maryland 21210. U.S.A. T.D.29/10--a

625

626

THE CORONARY DRUG PROJECTRESEARCHGROUP TABLE I.PATIENTRECRUITMENTBY FORMERCDP TKEATMENT Time period recruitment

Former CDP treatment Dextrothyroxine, 6 mg/day (DT4) Estrogen, 5.0 mg/day (ESGZ) Estrogen, 2.5 mg/day (ESGl) Total

Number Aspirin

of

assigned to Placebo

Total

I November,

197231 March, 1973 1 November. 197231 March, 1973 18 January, 197415 April. 1974

290

300

590

277

281

558

191 758

190 771

381 1529

The first phase of patient recruitment was undertaken in late 1972 and completed in early 1973 with the simultaneous enrollment of 1148 patients formerly assigned to the ESG2 and DT4 groups. The second phase of patient enrollment was carried out in early 1974 with the enrollment of 381 patients formerly assigned to ESGl treatment. It was recognized from the start that the number of patients who could be recruited under the above plan would only be sufficient to detect gross reductions in morbidity or mortality which might be realized from the treatment. Calculations indicated that even with as much as 3 yr of follow-up, a sample size of 3500 (1750 in each of the aspirin and placebo groups) would be required to assure an 80% power of detecting a true mortality reduction of 25”/d in the aspirin group (assuming an expected 3-yr mortality of 12% in the placebo group [12] and, thus, 9% in the aspirin group); a 5% level of significance for a two-sided test was assumed. Follow-up of CDPA patients for morbidity and mortality was planned from the outset to continue until the termination of data collection in the CDP (February 1975) and perhaps beyond that time depending on the trend of the data. An unsolicited contract proposal was submitted to the National Heart and Lung Institute (NHLI) in mid-1974 requesting support for recruitment of at least 2000 additional patients from the three remaining treatment groups in the CDP after its close and for follow-up of all CDPA patients through February 1978. This proposal was reviewed in accordance with usual NHLI procedures. The proposal was not approved for funding. As a result, data collection in the CDPA ceased with the close of the CDP. PATIENT

ELIGIBILITY

AND

STUDY

METHODS

All patients (only men were studied) in the CDPA were in functional classes I, II, or III of the New York Heart Association [ 131 and by virtue of being previously enrolled in the CDP, had at least one ECG-documented MI prior to entry. Patients were excluded from enrollment in the CDPA because of: Life-limiting diseases other than coronary heart disease such as cancer, chronic renal disease, chronic hepatic disease, and pulmonary insufficiency. Use of aspirin or an aspirin-containing drug on a regular basis and inability to be removed from this regimen. Use of anticoagulant therapy. Hypersensitivity to aspirin.

Aspirin

in Coronary

Heart

Disease

627

Any other condition contraindicating the use of aspirin (e.g. an active peptic ulcer or a history of upper gastrointestinal bleeding). An orientation session was held with each patient prior to enrollment into the CDPA to familiarize him with its purpose and procedures. It included a review of commonly used compounds containing aspirin and instructions on how to avoid using them. Each patient was given a supply of acetaminophen for use as an analgesic in lieu of aspirin. Propoxyphene hydrochloride was supplied in special cases where acetaminophen was contraindicated. Each patient was examined medically prior to enrollment to assess eligibility and provide baseline information, The initial workup included a resting ECG, chest X-ray, and the following laboratory tests: hematocrit, white blood cell count, absolute neutrophil count, platelet count, partial thromboplastin time, prothrombin activity, and qualitative tests for hematuria, glycosuria and proteinuria (all done at the local clinic research center). Serum samples were collected and sent to the central laboratory for determination of total and direct bilirubin, SGOT, alkaline phosphatase, uric acid, cholesterol, triglyceride, urea-N and PBI. Fasting and 1-hr post-glucose challenge plasma samples were centrally analyzed for glucose. After giving their informed consent. eligible patients were enrolled and randomly assigned to either aspirin or placebo therapy. Separate randomization schedules were used for each of the participating clinical centers and for each of the three cohorts of patients listed in Table 1. Treatments were administered on a double-blind basis. Aspirin and placebo tablets were identical in appearance and were dispensed in bottles of the same size and color. Patients in both treatment groups were instructed to take three tablets of assigned medication per day (i.e. one tablet with a glass of water before the morning, mid-day, and evening meals). Each aspirin tablet contained 324 mg (5 grains) of aspirin. The placebo tablet was comprised primarily of calcium phosphate (198 mg) and microcrystalline cellulose (200 mg). Patients were asked to return to the clinic at four-month intervals. Study forms for the one annual and two non-annual examinations carried out each year were similar to those used in the CDP rg]. Minor modifications were introduced to monitor side effects of aspirin and collect specific information on use of aspirinrelated compounds. The annual examination included an interval medical history, physical examination, resting KG, chest X-ray, and all the laboratory tests (except PBI) done at the initial workup. Non-annual examinations consisted of a short physical examination and laboratory tests carried out at the clinic for hematocrit, white blood cell count, absolute neutrophil count, hematuria, glycosuria, and proteinuria. Urine salicylates and epinephrine-induced platelet serotonin release [ 141 were used as measures of adherence to the prescribed aspirin therapy and of possible aspirin contamination in the placebo group. These analyses were carried out in the central laboratory on urine and specially prepared plasma samples provided as part of the initial workup and each follow-up examination. Results in this paper are based on data obtained by the clinics and received at the Coordinating Center through 1 April, 1975. Deaths occurring after a patient’s closeout visit in February 1975 (or after 14 February, 197.5 if the closeout visit was not completed) were not counted. Efforts were made to ascertain the vital status of patients who did not return to the clinic for the closeout examination.

628

THE CORONARY DRUG PROJECTRFSEARCHGROUP

The vital status for all but three patients (one in the aspirin group and two in the placebo group) was known at the close of this study. These patients were counted as alive for this paper. Differences between the two study treatment groups were evaluated by use of Z values, i.e. the observed difference between the placebo and aspirin groups on a specified characteristic divided by the standard error of the difference [lS]. Life tables were calculated using a procedure described by Littell [16]. Z values for life table results were based on a procedure described by Cox [17]. Adjustments for differences in baseline composition of the aspirin and placebo groups were carried out using multiple linear regression techniques [18]. Conventional tests of significance and the P values derived from such classical procedures are not entirely appropriate for a trial such as the CDPA 1191. While comparisons of total mortality were of prime interest, contrasts of the aspirin and placebo groups on cause-specific mortality, nonfatal events and combinations of fatal and nonfatal events were also used in the evaluation. Furthermore, interim analyses were done on findings for fatal and nonfatal events to monitor the wellbeing of those enrolled. Such interim analyses and the multiple response variables used in monitoring the study complicate the interpretation of conventional tests of significance. The multiplicity of testing increases the probability that one or more comparisons will appear significant. For this reason, conventional statements about attained level of significance will not be given for the Z values presented in this report, although these can be easily obtained by consulting tables for the standard normal distribution. As a reference point, Z values of 1.96 and 2.58 are nominally associated with P values of 0.05 and 0.01, respectively, for two-tailed tests. Clearly, a difference which does not yield a Z value large enough to be regarded as ‘statistically significant’ under such conventional rules of interpretation will be even less ‘significant’ in view of the aforementioned complexities. RESULTS

Characteristics at entry and comparability of the treatment groups The percentages of patients in each of the two treatment groups with various characteristics at entry are given in Table 2. The cutting points selected for continuous variables are the same as those used in a recent publication from the Coronary Drug Project [12]. Slightly more than 60% of the patients were 5.5 yr or older at the time of entry into the CDPA. Approximately one-third were in risk group 2, i.e. they had had two or more MIS or a single MI with serious complications (e.g. sustained arrhythmias, shock, or congestive heart failure) prior TABLE 2. P~RCENTAC~SOF PATIENTSWITH VARIOUSFINDINGSAT ENTRY

Characteristic

at entry

Age at entry, 255 yr Race, nonwhite Risk group 2 Number of previous MIS, >2 Time from last MI to entry, ~5 yr New York Heart Association functional class II or III

% of patients Aspirin Placebo

Z value

62. I 5.4 37.1 24.5 74.4

60.7 6.9 37.7 23.4 76.5

0.58 - 1.19 - 0.00 0.55 - 0.93

51.1

49.0

0.79

Aspirin TABLE 2. PERCENTAGES

in Coronary

Heart

Disease

629

OF PATIENTS WITH VARIOUS FINDINGS AT ENTRY+Conhwd)

Characteristic

% of patients Asp& ’ Placebo

at entry

Z value

Qualifying ECG. class 1 Q waves Physical activity during leisure, light

53.6 62.5

52.4 57.5

0.48 2.03

Definite or suspected history of: Acute coronary insufficiency Angina pectoris Congestive heart failure Intermittent cerebral ischemic attacks Stroke Intermittent claudication Peripheral arterial occlusion

30.3 74.0 24.3 8.8 3.3 20.2 6.2

28.7 73.8 23.2 9.0 2.7 21.8 6.1

0.72 0.09 0.49 - 0.08 0.66 - 0.77 0.09

Cardiomegaly. definite or suspected Q/QS patterns, any T wave findings, any ST segment depression, any ST segment elevation Atrioventricular conduction defects Ventricular conduction defects Frequent premature beats Sinus arrhythmias QRS axis deviation High-amplitude R waves 2 1 codable ECG findings ECG heart rate. 270 beats/min

16.5 48.2 48.5 27.6 3.0 5.5 Il.3 5.4 2. I 9.x x.4 8.4 46.8

17.6 52.2 47.8 23.0 2.9 4.4 9.8 3.8 3.3 11.3 7.8 8.4 46.0

- 0.60 - 1.54 0.2x 2.03 0.20

Relative body weight, L 1.15 Cigarettes/day. 2 1 Systolic blood pressure, > 130 mm Hg Diastolic blood pressure, 285 mm Hg Serum cholesterol. 2250 mg/lOO ml Serum triglyceride. 25 mEq,/l Serum uric acid. 27 mg/lOO ml Plasma fasting glucose, 2 100 mg/lOO ml Plasma one hour glucose, 2180 mg/lOO ml Serum total bilirubin, ~0.50 mg/lOO ml Serum direct bilirubin, 20.25 mg/lOO ml SGOT, 225 Henry units Serum alkaline phosphatase, 2 7.5 King-Armstrong units Plasma urea nitrogen, > 16 mg/lOO ml Protein-bound iodine, ~6 pg/lOO ml

47.0 33.9 57.8 35.2 47.6 50.8 23.5 46.8 37.0 62.7 4x.3 53.9

49.7 27.6 56.8 31.1 51.8 52.0 23.7 45.5 38.4 68.0 51.2 56.4

- 1.08 2.66 0.39 I .70 - I.65 - 0.46 - 0.08 0.39 - 0.57 _ 2.09 - 1.1 I - 0.96

47.3 47.1 42.5

46.9 49.5 39.6

0. I 6 - 0.70 I.1 I

Hematocrit, >46”,, WBC. 2 7.500/mm3 Absolute neutrophil

61.4 36.5 40. I

59.5 35.1 37.2

0.75 0.60 1.14

1.7 10.4

1.4 10.0

0.45 0.X

6.3 18.7 9.1 24.8 11.5 35.8

4.8 13.2 6.6 22.4 9.6 37.4

1.31 2.94 1.x1 1.09

Urine glucose, Urine protein.

count,

24.500jmmJ

positive trace or positive

Prescription during period just prior Oral hypoglycemic agents Digitalis Ant&rhythmic agents Diuretics Antihypertensive agents Nitroglycerin

to entry

I .03 0.95 1.44 - I .42 - 0.92 0.47 - 0.0 I 0.29

of:

I.20 - 0.65

THE CORONARY

630

PROJECTRESEARCH

to enrollment into the CDPA. The remaining patients were in risk group 1 (i.e. had had only one uncomplicated MI at the time of enrollment into the CDPA). About half the patients were in New York Heart Association functional class I. All remaining patients were in functional class II, except for 45 in the aspirin group and 21 in the placebo-treated group who were in functional class III. Of the 54 differences observed between the two treatment groups in Table 2, five have Z values equal to or greater than 2.0, ignoring sign. This is close to what would be expected on the basis of chance alone. Dropout and drug

experience

A was defined a patient longer able willing to for scheduled visits and, not maintained his CDPA Only 32 the 1529 enrolled (15 the aspirin and 17 the placebo were so by the of the A record kept for patient of prescriptions of study drug; ence to study prescription assessed as of each visit and assessment was on both pill count the physician’s of the to which prescribed schedule followed. Table gives the age of having various of adherence, as the of medication expressed as percentage of maximum amount-3 lets/day-which could been consumed. levels of were 81.2 82.0% for aspirin and treatment groups, Results in 4 provide further indication the maintenance the integrity the study. major differences recorded in of nonstudy ing medication the two groups. Only and 4.8% those in aspirin and groups, respectively, ever taking outside the of the Less than in both groups reported taking aspirin any of specified list aspirin-containing compounds platelet-affecting during the The great of patients both treatment TABLE 3.

OF PER A~HERENCI TO DOSAGE* OF STUDY MEDICATION OVER THE ENTIKE STUDY PERIOD

Per cent adherence for

entire study

periodt

t&19 2tS-39 4&59 60-79 SO-89 90t Total Mean % adherence Median % adherence

Aspirin (No.) (‘;/,)

Placebo (No.1 C%)

33 23 22 52 98 499 727

26 18 22 70 95 513 744

4.5 3.2 3.0 7.2 13.5 68.6 100.0 81.2 90.0

3.5 2.4 3.0 9.4 12.8 69.0 100.0 82.0

* Three tablets per day. t Highest value possible under method of calculation used. $ ‘Per cent adherence for entire study period’ is the mean of the per cent adherence calculated from information collected at each four month follow-up visit. The per cent adherence for individual follow-up periods was assumed to be zero for dropouts for each four month period they were so classified.

Aspirin

in Coronary

Heart

Disease

631

reported using acetaminophen or propoxyphene hydrochloride in lieu of there was no sizeable difference between the two treatment groups in of these analgesics. Results from the urine salicylate and platelet serotonin tests for patients at entry and by follow-up visit for the two treatment show a substantial separation of the distributions for the two treatment after initiation of study treatment (table available on request). Overall and cause specific

aspirin; the use release groups groups

mortality

Patients were followed for a minimum of 10 months and a maximum of 28 (average-22 months). Patients in the aspirin group experienced a 30% lower percentage of deaths than the placebo group-5.8 and 8.3%, respectively (Table 5). The Z value for this comparison is - 1.90. Adjusting for 54 baseline characteristics using multiple regression techniques yielded virtually the same mortality results-5.7 and 8.4%, respectively. The cumulative mortality rates are plotted in Fig. 1. The Z value for the overall difference in the two mortality curves is - 1.90. The percentage difference in the aspirin group relative to the placebo group for coronary death was 27% (4.6”/;,for aspirin, 6.47: for placebo; Z = - 1.49) and 19% (2.634 for aspirin, 3.2% for placebo; Z = -0.70) for sudden cardiovascular (CV) deaths (i.e. CV deaths occurring within 60 minutes of onset of symptoms). The cumulative life table rates for coronary and sudden CV death are plotted in Figs. 2 and 3, respectively. The Z values for the overall difference in the two mortality curves were - 1.51 and -0.73 for coronary and sudden CV death, respectively. Combined fatal

and nonfatal

CV events

Findings for various combinations of fatal and nonfatal cardiovascular events are summarized in the lower part of Table 5. The largest Z value observed (- 1.49) was for the combination of coronary death or definite nonfatal MI. The percentage for the aspirin group for this combined event was 21% lower than the percentage for the placebo group (8.0% for aspirin, 10.2% for placebo). For the event definite nonfatal MI alone, there was only a slightly lower incidence in the aspirin group than in the placebo group (3.7% for aspirin, 4.2% for placebo; Z = -0.46). Figures TABLE 4. PERCENTAGES OF PATIENTS EVER USING OR PRESCRIBEDVARIOUS TYPES

Type of medication Aspirin Aspirin-containing compounds Platelet-affecting drugs Any of above Acetaminophen Propoxyphene HCl Either acetaminophen propoxyphene HCl

OF MEDICATION

SINCE

ENTRY

9,, of patients Aspirin Placebo (N = 744) (N = 727)

Z value

5.6

4.8

9.1

9.5

4.0 15.5

4.2 15.3

-0.17 0.12

81.2 10.0

82.4 10.5

-0.61 -0.28

82.1

83.2

-0.55

0.69 -0.31

or

632

THE CORONARY DRUG

PROJECTRESEARCHGROUP

TABLE 5. DEATHS BY CAUSEAND NONFATALEVENTS

Event Death All causes All cardiovascular All noncardiovascular Cause unknown Coronary heart disease Sudden cardiovascular All cancer Other noncardiovascular Definite nonfatal myocardial infarction Coronary death or definite nonfatal myocardial infarction Definite (fatal or nonfatal) pulmonary embolism Definite or suspected fatal or nonfatal pulmonary embolism or thrombophlebitis Definite or suspected fatal or nonfatal stroke or intermittent cerebral ischemic attack Any definite or suspected fatal or nonfatal* cardiovascular event

Aspirin (N = 758) No. with % with event event

Placebo (N = 771) No. with % with event event

2 value

41 2 1 35 20 I 1

5.8 5.4 0.3 0.1 4.6 2.6 0.1 0.1

64 60 4 0 49 25 3 1

8.3 7.8 0.5 0.0 6.4 3.2 0.4 0.1

- 1.90 - 1.87 -0.80 1.01 - 1.49 -0.70 -0.98 0.01

28

3.7

32

4.2

-0.46

61

8.0

79

10.2

2

0.3

3

0.4

9

1.2

9

1.2

0.04

37

4.9

41

5.3

- 0.39

364

48.0

377

48.9

44

- 1.49

-0.43

-0.34

* See Table 6 for list of events.

4 and 5 provide life table plots for definite nonfatal event of coronary death or definite nonfatal MI.

MI and for the combined

Dejnite or suspect nonfatal CV events The percentages of patients ever experiencing various definite or suspect nonfatal CV events during the study are given in Table 6. The largest Z value (ignoring sign) was for the development of hypertension since entry. The incidence of this event was 12.2 and 9.6% in the aspirin and placebo groups. respectively, a 27% higher incidence in the aspirin group (Z = 1.52). Other morbidity and clinical jindings Table 7 gives the percentages of patients with various findings reported by the study physicians on the basis of follow-up medical histories and physical examinations. The comparison with the largest Z value was for macroscopic hematuria (1.2% for aspirin, 0.3% for placebo; Z = 2.16). However, this result might very well be due in part to chance variation since little difference was noted between the two groups in hematuria when measured more precisely using dipsticks (Table 9). Aspirin patients experienced a higher incidence of acute gouty arthritis (2.6%

Aspirin

4

8

in Coronary

12

Heart

16

Disease

20

63.1

24

28

1065

834

MONTHS OF FOLLOW-UP N= 1520

1501

1480

FIG. I. Life table cumulative

1234

1080

rates for death

(,a11 causes).

for aspirin, 0.9% for placebo; Z = 2.10) and podagra (1.3% for aspirin, 0.2% for placebo; Z = 2.15) than placebo patients. All other comparisons listed in Table 7 yielded Z values less than 2.0 (ignoring sign). At every follow-up examination each patient was asked: “Have you had any problems in connection with your study medication since your last visit?’ The

PLACE80

ASPIRIN

z = - 1.51 0 4

8

I I2

I6

20

24

r 28

1065

834

MONTHS OF FOLLOW -UP N = 1520

1501

1480

FIG. 2. Life table cumulative

1234

1080

rates for coronary

death.

THE CORONARYDRUG PROJECTRESEARCH CROUP

634

PLACEBO ASPIRIN

4

B

12

16

20

24

29

MONTHS OF FOLLOW - UP 1501 1480 1234 1080 1065 834 N= 1520 FIG. 3. Life table cumulative rates for sudden cardiovascular

death.

patient’s spontaneous responses were recorded using a checklist on the study form. All problems listed in Table 8 except ‘ringing of ears’ were reported more frequently by the aspirin group than by the placebo group. The comparison yielding the largest difference was for stomach pain. Twice as many aspirin patients complained of such pains as placebo patients (12.504 for aspirin, 6.3% for placebo; Z = 4.08). 12-

PLACEBO ASPIRIN

2 =- 0.48 4

8

I2

I6

20

24

28

831

489

MONTHS OF FOLLOW - UP N =

1471

1404

FIG. 4. Life table cumulative

1303

1040

rates for definite

936 nonfatal

myocardial

infarction.

Aspirin

4

8

in Coronary

12

16

Heart

Disease

20

635

24

28 799

MONTHS OF FOLLOW - UP N= 1514 FIG. 5. Life table

cumulative

1484 rates

1450

1200

1042

1023

for coronary infarction.

death

or definite

nonfatal

myocardial

A total of 26.3% of the aspirin and 26.70/, of the placebo patients had at least one period of hospitalization during the course of the study (table available on request). The majority of the hospital stays were for periods of 14 days or less. Most of the differences observed between the two treatment groups were small; none of the Z values exceeded 2.0 (ignoring sign). Cardiac surgery was done during the study in 1.1 and 2.4% of the patients in the aspirin and placebo groups, respectively. About half of these patients (0.6 and 1.3%, respectively) had saphenous vein bypass surgery. Biomedical, hematologic and clinical measurements Table 9 gives the mean values at entry and after one year for certain biochemical and hematological determinations. Z values recorded in this table are based on the net change observed in the two treatment groups from entry to the first annual follow-up visit. For example, the numerator for the Z value for plasma urea nitrogen is the difference of the two values recorded for the aspirin group (17.2 mg/lOO ml minus 16.4 mg/lOO ml) minus the difference of the two values recorded for the placebo group (16.2 mg/lOO ml minus 16.2 mg/lOO ml); the denominator is the standard error for the difference. The largest Z values recorded were for serum uric acid (Z = 4.68) and plasma urea nitrogen (Z = 3.76). In both cases, the increase in mean level from entry to one year was about 5% in the aspirin group after adjusting for the change in the placebo group. No other Z values were larger than 2.0 (ignoring sign). Table 10 gives the percentages of patients in both the aspirin and placebo groups with certain biochemical or hematological measures ever exceeding specified cutpoints during the follow-up period. The aspirin group had a higher percentage

636

THE

CORONARY

DRUG PROJECTRESEARCHGROUP

TABLE6. PERCENTAGES OF PATIMTSHAVINGDEFINITE OR SUSPECTED NONFATAL CARDIOVASCULAR EVENTS SINCE

Event

ENTRY

No. of men

Aspirin ‘A with event

Placebo No. of % with men event

Z value

Myocardial infarction Acute coronary insufficiency New angina pectoris*

727 727 187

5.1 5.4 12.8

744 744 195

5.4 7.0 16.4

-0.25 - 1.29 - 0.99

Congestive heart failure Increase in heart size New hypertension

727 656 656

11.4 6.6 12.2

744 667 667

10.1 7.6 9.6

0.83 - 0.77 1.52

Peripheral arterial occlusion Peripheral arterial embolism Arterial aneurysm New intermittent claudication*

727 656 656 582

2.6 0.0 0.2 5.0

744 667 667 585

2.3 0.0 0.0 5.6

0.41 1.01 - 0.50

Stroke Intermittent attacks

727

1.7

744

1.6

0.06

727

3.6

744

4.0

-0.46

Pulmonary embolism Thrombophlebitis

727 727

0.1 1.0

744 744

0.5 0.8

- 1.32 0.32

Atria1 fibrillation Ventricular premature beatsmultifocal or in runs Ventricular premature beatsother Other arrhythmias

727

2.3

744

1.9

0.61

727

0.0

744

0.0

727 727

4.3 19.0

744 744

3.5 17.6

0.76 0.68

Any of above

727

47.0

744

46.5

0.21

cerebral ischemic

* Patients with a history of the event at entry excluded.

TABLE

7.

PERCENTAGES OF PATIENTS WITH NEW CLINICAL FINDINGS DURING THE FOLLOW-UP PERIOD

Clinical finding

No. of patients

Aspirin % with event

Placebo No. of % with patients event

Z value

Peptic ulcer Gastritis Hematemesis

727 727 727

2.8 5.4 0.4

744 744 744

2.2 3.9 0.3

0.75 1.34 0.47

Bloody stools Black tarry stools Blood in urine (macroscopic)

727 727

3.0 2.8

744 744

2.8 1.5

0.23 1.70

722

1.2

741

0.3

2.16

Acute gouty arthritis Podagra Tophi Uric acid stones

540 542 546 545

2.6 1.3 0.0 0.6

544 550 553 551

0.9 0.2 0.2 0.9

2.10 2.15 - 0.99 -0.69

Aspirin TABLE 8. PERCENTAGES

Problem Nausea without Vomiting Heartburn Stomach pain Diarrhea

in Coronary

Heart

Disease

637

OF PATIENTS REPORTING PROBLEMS AT ONE OR MORE FOLLOW-UP VISITS

% of patients Aspirin Placebo (N = 727) (N = 744)

reported vomiting

Itching of the skin Urticaria Other types of rash Ringing of ears

Z value

5.1 0.8 5.6 12.5 1.2

3.2 0.7 3.9 6.3 0.3

1.79 0.34 1.57 4.08 2.16

1.1 0.6 1.2 0.1

0.5 0.1 0.9 0.3

1.20 1.37 0.55 -0.56

with urine protein 2 2 + , urea nitrogen 2 20 mg/lOO ml, and systolic blood pressure 2 160 mm Hg than the placebo group. The Z values were 3.66, 2.30, and 2.18, respectively. Aspirin trials now underway will provide information to help indicate whether these differences are expressions of a real effect or simply due to chance variation. Total mortality

in subgroups

of patients

The mortality results for the three cohorts of patients defined in Table 1 are given in Table 11. The overall mortality in the DT4 cohort was only about half that observed in the ESG2 cohort. The overall mortality in the ESGl cohort was considerably lower than in the other two cohorts (3.1% for ESGl as compared to 10.99:; for ESG2 and 5.9% for DT4). This is due to the substantially shorter follow-up period for this cohort (mean, 11.5 months) than for the ESG2 and DT4 cohorts (mean, 25.5 months). The mortality for the aspirin group was 31% lower than for placebo in the DT4 cohort (4.8% for aspirin, 7.0% for placebo; Z = -1.12) 43% lower in the ESG2 cohort (7.9% for aspirin, 13.9% for placebo; Z = -2.25), and 100% higher in the ESGl cohort (4.2% for aspirin, 2.1% for placebo; Z = 1.16). None of the percentages in Table 11 were substantially altered after adjusting for 54 baseline characteristics. DISCUSSION

Mortality in the aspirin group was 5.8% as compared with 8.3% in the placebo group, a 30% lower mortality for the aspirin group. These percentages remained virtually unchanged with adjustment for 54 baseline characteristics using multiple linear regression. The observed difference in mortality is suggestive of a beneficial therapeutic effect for aspirin in the secondary prevention of coronary heart disease. However, the numbers of patients studied and the length of follow-up for individual patients were not sufficient to draw a definitive conclusion in this regard. Moreover, the fact that only men with a prior history of estrogen or dextrothyroxine therapy in the CDP were studied raises questions as to the generalizability of these findings to larger populations of post-MI patients.

638

THE CORONARY DRUG PROJECTRESEARCH GROUP TABLE9. MEAN LEVELSOF SPECIFIEDVARIABLES AT ENTRYAND FOLLOW-UPEXAMINATION*

Variable

AT

THE FIRSTANNUAL

Mean levels Aspirin Placebo

Z value

Plasma urea nitrogen (mg/lOO ml) At entry First annual follow-up No. of patients

16.4 17.2 529

16.2 16.2 534

3.16

Serum uric acid (mg/lOO ml) At entry First annual follow-up No. of patients

6.12 6.54 530

6.13 6.21 535

4.68

Hematocrit (%) At entry First annual follow -up No. of patients

46.4 46.2 526

46.5 46.3 530

0.06

Blood pressure (mm Hg) Systolic At entry First annual follow-up No. of patients

133.2 134.6 525

131.4 132.7 531

0.14

Diastolic At entry First annual follow-up No. of patients

81.8 82.0 525

80.9 90.9 531

0.40

Urine glucose (per cent positive on dipstick) At entry First annual follow-up No. of patients

2.10 2.29 525

1.33 1.33 528

0.17

Urine protein (per cent on dipstick) At entry First annual follow-up No. of patients

1.90 3.62 525

1.14 2.21 528

0.55

Blood in urine (per cent positive on dipstick) At entry First annual follow-up No. of patients

0.38 1.53 523

0.95 2.08 528

0.01

* For cohort of patients with observations both at entry and at one year.

A trial of free-living individuals involving the use of a drug as commonly available as aspirin poses special problems. As a matter of fact, it has been suggested that such trials are futile because of difficulties in maintaining integrity of design [20,21]. The experience in the CDPA indicates this is not the case. There was little evidence of contamination of either treatment group with unauthorized aspirin usage. Less than 6% of the patients in either treatment group reported using aspirin outside the study context. Aspirin usage can produce a variety of side effects. As already noted, twice as many patients on aspirin complained of stomach pain (Z = 4.08) as compared

Aspirin

in Coronary

Heart

639

Disease

TABLE 10. PERCENTAGESOF PATIENTSWITH MEASUREMENTSEVER OUTSIDE SPECIFIEDLIMITS*

Measurement Plasma urea nitrogen, mg/lOO ml 220 230 Serum uric acid, mg/lOO ml 28 210 Hematocrit. ?< 538 <36 Blood pressure, mm Hg Systolic 2160 2180 Diastolic 290 2110 Urine glucose, positive Urine protein >I+ z2+ * Excludes

patients

with abnormal

Aspirin No. of patients

Y”

CDP

Dextrothyroxine, 6 mg/day (DT4) Estrogen, 5.0 mg/day (ESGZ) Estrogen, 2.5 mg,/day (ESGl) Total

treatment

‘I0

Z value

440 535

11.1 1.5

450 544

12.2 1.3

2.30 0.29

496 540

12.9 2.2

507 541

Il.6 1.7

0.61 0.67

713 123

4.3 2.2

132 739

5.3 2.3

647 112

21.3 6.3

679 733

16.6 7.0

2.18 - 0.49

533 714 711

42.2 6.0 4.4

587 733 732

40.2 4.0 3.7

0.68 1.81 0.65

707 717

6.6 5.3

733 736

5.6 I.8

0.84 3.66

-0.87 -0.11

values at entry.

TABLE 11. PERCENTAGESOF DEATHS BY FORMERCDP

Former

Placebo No. of patients

Aspirin No. of “b patients deaths

TREATMENT

Placebo No. of I!,, patients deaths

Z value

290

4.8

300

7.0

- 1.12

277

7.9

281

13.9

- 2.25

191 758

4.2 5.8

190 771

2.1 8.3

-

1.16 I .9O

to those on placebo. However, there was no marked excess incidence of development of worsening of peptic ulcer in the aspirin group (2 = 0.75). Plasma urea nitrogen and urine protein levels were higher in the aspirin than in the placebo group-a finding consistent with previous reports in the medical literature [22]. A marked increase in the urinary excretion of uric acid in man following the administration of large doses of salicylates has been repeatedly noted virtually since the introduction of aspirin [22]. Paradoxically, low dosage levels of aspirin -1-2 g/day-have been shown to diminish urinary excretion of uric acid and to elevate serum uric acid levels [23]. The findings in the CDPA are consistent with this observation. A mean 5% elevation in serum uric acid level occurred in the aspirin group. Furthermore, 14 patients in the aspirin group and five in the placebo group (Z = 2.10) were reported to have developed gouty arthritis during the study. Podagra was also more common in the aspirin group than in the placebo group (Z = 2.15).

640

THE CORONARY DRUG PROJECTRESEARCHGROUP

Since 1971, there have been four other studies reported in which the relationship of aspirin use and coronary heart disease was investigated [24-271. The study reported by Heikinheimo and Jarvinen [24] was a controlled trial with an allocation of patients to aspirin (1.0 g/day) or placebo on the basis of birthdate. The study involved both men and women residing in a nursing home for the aged. A total of 430 patients were studied and followed for a I-yr period. The controlled trial carried out by Elwood et al. [25] involved only men with a prior history of MI. A total of 1239 patients were enrolled and randomly assigned to aspirin (300 mg per day) or to placebo. The study started in February 1971 and data collection terminated in September 1973. Random allocation to treatment was not possible under the design employed by the Boston Collaborative Drug Surveillance Group [26] or by Hammond and Garfinkel [27]. The former study was carried out on hospitalized patients and findings were based on the observed relationship between recent aspirin usage and discharge diagnosis in those studied. The study by Hammond and Garfinkel was based on the prospective follow-up of a large population for mortality after collection of information on the frequency of aspirin usage. The studies by Elwood et al. and the Boston Collaborative Drug Surveillance Group yielded suggestive but not conclusive evidence that aspirin is beneficial in the treatment of coronary heart disease. The other two studies cited above failed to yield any evidence of benefit or harm for aspirin in the treatment of this disease. Clearly, more information is needed on the therapeutic value of aspirin in the treatment of coronary heart disease. Studies now being planned or already under way [28] may help resolve present uncertainties. In the interim, results available to date may lead to a further increase in the already massive use of aspirin, both via physician prescription and self-medication. The availability of aspirin as a non-prescription drug and the general belief that aspirin usage poses little or no risk to the user make this a potentially serious problem since aspirin is, in fact, a powerful drug that can have serious side effects. Certainly, long-term use of any medication-including aspirin-should be undertaken only with provision for monitoring for long-term ill-effects. Acknowledgements-The Principal Investigators of the Coronary Drug Project Aspirin Study are indebted to Dr. Hershel Jick for making available preliminary findings of the Boston Collaborative Drug Surveillance Program Aspirin Study during the planning phase of this project. The preparers of this manuscript also wish to express their appreciation to: Mary M. Dorn. Frances M. Fazio, Barbara L. Fisher, Nancy E. Garner, Richard D. Gross, Dorothy T. Harris, Robert K. Harris, Cheryl L. Kelly, Robert C. Reynolds, and Jane L. Schmansky of the CDPA Coordinating Center for their assistance in preparing this manuscript. Study Funding acknowledgement-The Coronary Drug Project was carried out was a Collaborative Study supported by research grants and other funds from the National Heart and Lung Institute.

The key bodies of the CDP and CDPA and associated of February 1975:

senior personnel

as

Policy Board: Robert W. Wilkens, M.D. (Chairman); Jacob E. Bearman, Ph.D.; Edwin Boyle, M.D.; W. McFate Smith, M.D., M.P.H.; Christian R. Klimt, M.D., Dr. P. H. (ex &icio); Jeremiah Stamlcr, M.D. (ex ofJicio); Max Halperin, Ph.D. (ex o&k); William J. Zukel, M.D. (ex oficio). Steering Conmittee: Jeremiah Stamler, M.D. (Chairman); Kenneth G. Berge, M.D. (Vice-Chairman); David M. Berkson, M.D.; William H. Bernstein, M.D.; Henry Blackburn, M.D.; Joseph H. Boutwell, M.D.; Jerome Cornfield: William T. Friedewald, M.D.; Lawrence M. Friedman, M.D.; Nicholas J.

Aspirin in Coronary Heart Disease

641

Galluzzi. M.D.; Max Halperin, Ph.D.; Kenneth Hyatt, M.D.; Christian R. Klimt, M.D., Dr. P.H.; Charles A. Laubach, Jr., M.D.; Jessie Marmorston, M.D.; Nanette Wenger, M.D. Coordinating Center (University of Maryland, Baltimore): Christian R. Klimt, M.D., Dr. P. H. (Director); Curtis L. Meinert, Ph.D. (Deputy Director); Gene11 L. Knatterud, Ph.D. (Deputy Director); Paul L. Canner, Ph.D.; Sandra A. Forman, MS.; Elizabeth C. Heinz; Yih-Min Bill Huang, Ph.D.; William F. Krol, Ph.D. Centrul Laboratory: (Center for Disease Control, Atlanta, GA): Joseph Boutwell, M.D. (Medical Director); Dayton Miller, Ph.D. (Chief); John Donahue, M.S.; James Gill, Jr., M.S.; Sara Gill. ECG Center (University of Minnesota, Minneapolis): Henry Blackburn, M.D. (Director of the Laboratory of Physiological Hygiene); Ronald J. Prineas. M.D. (Director of the ECG Center); David R. Jacobs, Ph.D.; Gretchen Newman. Nutional Heart and Lung Institute StafS (Bethesda, MD): Eleanor M. K. Darby, Ph.D.; William T. Friedewald, M.D.; Lawrence M. Friedman, M.D.; Max Halperin, Ph.D.; Robert I. Levy, M.D.; Robert L. Ringler, Ph.D.; William J. Zukel, M.D. Drug Procurement and Distribution Center (lJ.S. Public Health Service. Perry Point, MD): Salvatore D. Gasdia (Officer in Charge). Editorial Review Board: Jeremiah Stamler, M.D. (Chairman); Kenneth G. Berge, M.D.; Henry Blackburn, M.D.; Jerome Cornfield; William T. Friedewald, M.D.; Lawrence M. Friedman, M.D.; Max Halperin, Ph.D.; Christian R. Klimt, M.D., Dr. P.H.; Bernard Tabatznik. M.D.; Robert W. Wilkins. M.D.; Nanette Wenger, M.D. Datu and Safety Monitoring Committee: Curtis L. Meinert, Ph.D. and Jeremiah Stamler, M.D. (CoChairman); E. Cowles Andrus, M.D.; Kenneth G. Berge, M.D.; Paul L. Canner, Ph.D.; Thomas C. Chalmers. M.D.; Jerome Cornfield; William T. Friedewald, M.D.; Lawrence M. Friedman, M.D.; James Gillette, M.D.; Max Halperin, Ph.D.; Christian R. Klimt, M.D.. Dr. P.H.; Robert I. Levy. M.D.; Dayton T. Miller, Ph.D.; Ronald J. Prineas, M.D. Principal Investigators, Clinic Research Centers: Samuel Baer, M.D. (Albert Einstein Medical Center, Philadelphia. PA); Allan H. Barker, M.D. (Salt Lake Clinic Research Foundation, Salt Lake City, UT); Kenneth G. Berge, M.D. (Mayo Clinic, Rochester, MN): Nathaniel Berk, M.D. (Sidney Hillman Medical Center, Philadelphia, PA); David M. Berkson, M.D. (St. Joseph Hospital, Chicago, IL); William H. Bernstein, M.D. (Mount Sinai Medical Center, Miami Beach, FL); Frank L. Canosa, M.D. (Miami Heart Institute, Miami Beach, FL); Ralph E. Cole, M.D. (Medical Associates Research Foundation, Chelmsford. MA); Elmer E. Cooper, M.D. (Santa Rosa Medical Center, San Antonio, TX); Ephraim Donoso, M.D. (The Mount Sinai Hospital, NY); Dean A. Emanuel, M.D. (Marshfield Clinic, Marshfield. WI); Irving Ershler, M.D. (University of Utah, Salt Lake City, UT); Nicholas J. Galluzzi, M.D. (USPHS Hospital, Staten Island, NY); Mario Garcia-Palmieri, M.D. (University of Puerto Rico, San Juan); Peter C. Gazes, M.D. (Medical University of South Carolina, Charleston); Fred I. Gilbert, Jr., M.D. (Pacific Health Research Institute, Honolulu, HI); Ernst Greif, M.D. (Maimonides Medical Center, Brooklyn. NY); Robert L. Grissom, M.D. (University of Nebraska, Omaha); Jacob I. Haft. M.D. (Veterans Administration Hospital, Bronx, NY); Olga M. Haring, M.D. (Northwestern University, Chicago, IL): R. G. Hutchinson, M.D. (University and Veterans Administration Hospitals, Jackson, MS); Kenneth Hyatt. M.D. (USPHS Hospital, San Francisco, CA): Richard J. Jones, M.D. (University of Chicago. IL); Robert M. Kohn, M.D. (Buffalo General Hospital, Buffalo, NY); Ward Laramore, i&D. (Veterans Administration Hosuital.. Indiananohs. IN): Charles A. Laubach. Jr.. M.D. (Geisineer Medical Foundation, Danville, PA); Rglph Lazzara,‘M.D. (Vk;erans Administration Hospital: Mia$, FL); Sidney A. Levine. M.D. (Melrose-Wakefield Hospital, Melrose, MA): Bernard I. Lewis, M.D. (Palo Alto Medical Clinic and Research Foundation, CA); Irving M. Liebow, M.D. (Case Western Reserve University, Cleveland, OH); Donald McCaughan, M.D. (Veterans Administration Hospital, West Roxbury, MA); Jessie Marmorston, M.D. (University of Southern California, Los Angeles); Louis B. Mathews, Jr., M.D. (Hitchcock Clinic, Hanover, NH); Gordon L. Maurice, M.D. (Providence Hospital, Portland, OR); Edward L. Michals, M.D. (USPHS Hospital, New Orleans. LA); Charles B. Moore. M.D. (Ochsner Clinic, New Orleans, LA); David Z. Morgan, M.D. (West Virginia University, Morgantown); John H. Morledge, M.D. (Jackson Clinic and Foundation, Madison, WI); Robert W. Oblath. M.D. (University of Nebraska, Omaha); Thaddeus E. Prout, M.D. (Greater Baltimore Medical Center, Baltimore. MD); Richard R. Pyle, M.D. (Lovelace Foundation, Albuquerque, NM); Bernard A. Sachs, M.D. (Montefiore Hospital and Medical Center, Bronx. NY); Paul Samuel. M.D. (Long Island Jewish Hospital, Jamaica, NY); Robert C. Schlant. M.D. (Emory University/Grady Memorial Hospital, Atlanta. GA); Henry K. Schoch, M.D. (Ann Arbor Hospital Group, Ann Arbor, MI): James A. Schoenberger, M.D. (Rush-Presbyterian-St. Lukes Medical Center, Chicago, IL); Ralph C. Scott, M.D. (University of Cincinnati Medical Center, Cincinnati, OH); Marvin S. Segal, M.D. (Mount Sinai Hospital, Minneapolis, MN); Bernard Tabatznik, M.D. (North Charles General Hospital, Baltimore, MD); Ernest 0. Theiien. M.D. (University of Iowa Hospital, Iowa City); Joseph A. Wagner. M.D. (The Bryn Mawr Hospital. Bryn Mawr, PA); J. Richard Warbasse, M.D. (USPHS Hospital. Baltimore. MD): C. Basil Williams. M.D. (Ogden Research Foundation, Ogden, UT).

642

THE CORONARY DRUG PROJECTRESEARCH GROUP REFERENCES

1. Craven LL: Acetylsalicylic acid, possible preventive coronary thrombosis. Ann West Med & Surg 4: 95-99, 1950 2. Craven LL: Experiences with aspirin (acetylsalicylic acid) in the nonspecific prophylaxis of coronary thrombosis. Miss Valley Med J 75: 38+ 1953 3. Craven LL: Prevention of coronary and cerebral thrombosis. Miss Valley Med J 78: 213-215, 1956 4. Jorgensen L, Rowsell HC, Hovig T et al.: Resolution and organization of platelet-rich mural thrombi in carotid arteries of swine. Am J Path 51: 681-693, 1567 5. Evans G. Packham MA. Nishizawa EE et al.: The effect of acetvlsalicvlic < , acid on olatelet function. J Exp tied 128: 877-894, 1968 6. Weiss HJ. Danese CA, Voleti CD: Prevention of experimentally induced arterial thrombosis by aspirin. Fed Proc 29: 381, 1970 7. Field HW, Hass WK (Eds): Aspirin, Platelets, and Stroke. St. Louis: WH Green, 1971 8. The Coronary Drug Project Research Group: The Coronary Drug Project. Design, methods and baseline results (AHA Monograph No. 38). Circulation 47 (suppl I), 1973 9. The Coronary Drug Project Research Group: The Coronary Drug Project. Initial findings leading to modifications of its research nrotocol. JAMA 214: 1303-1313. 1970 10. The Coronary Drug Project Research Group: The Coronary Drug Project. Findings leading to further modifications of its protocol with respect to dextrothyroxine. JAMA 220: 996-1008, 1972 11. The Coronary Drug Project Research Group: The Coronary Drug Project. Findings leading to discontinuation of 2.5 mg/day estrogen group. JAMA 226: 652-657, 1973 12. The Coronary Drug Project Research Group: The Coronary Drug Project. Clofibrate and niacin in coronary heart disease. JAMA 231: 36c-381, 1975 13. Criteria Committee of New York Heart Association: Diseases of the Heart and Blood Vessels: Nomenclature and Criteria for Diagnosis. 6th Edn. Boston: Little-Brown, 1964 14. Valdorf-Hansen JF, Zucker MB: Effect of temperature and inhibitors on serotonin-‘%I release from human platelets. Am J Physiol 220: 105-l 11, 1971 15. Armitage P: Statistical Methods in Medical Research. New York: John Wiley, 1971 16. Littell AS: Estimation of the T-year survival rate from follow-up studies over a limited period of time. Human Biol 24: 87-l 16, 1952 17. Cox DR: Regression models and life-tables. J Roy Stat Sot B 34: 187-202, 1972 18. Draper NR, Smith H: Applied Regression Analysis. New York: John Wiley, 1966 19. Armitage P: Sequential Medical Trials. Springfield, Illinois: Charles C. Thomas, 1960 20. Wood L: Treatment of atherosclerosis and thrombosis with aspirin. Lancet 2: 532-533, 1972 21. Wood L: Will controls in trials of aspirin really avoid aspirin? New Eng Med J 292: 538, 1975 22. Gross M, Greenberg LA: The Salicylates: A Critical Bibliographic Review. New Haven: Hillhouse Press, 1948 23. Yu TF, Gutman AB: Study of the paradoxical effects of salicylate in low, intermediate and high dosage on the renal mechanisms for excretion of urate in man. J Clin Invest 38: 1298-1315, 1959 diseases in 24. Heikinheimo R, Jarvinen K: Acetylsalicylic acid and arteriosclerotic-thromboembolic the aged. J Am Geriat Sot 19: 403405., 1971 25. Elwood PC, Cochrane AL, Burr ML et al.: A randomized controlled trial of acetyl salicylic acid in the secondary prevention of mortality from myocardial infarction. Brit Med J 1: 436440, 1974 26. Boston Collaborative Drug Surveillance Group: Regular aspirin intake and acute myocardial infarction. Brit Med J 1: 44&443, 1974 27. Hammond EC, Garfinkel L: Aspirin and coronary heart disease: Finding of a prospective study. Brit Med J 2: 269-271. 1975 28. Klimt C: Clinical trials in thrombosis, 5th Cong Int. Sot Thrombosis and Hemostasis. Paris, France, July 22, 1975