Platelet Function in Coronary Artery Disease:
Effects of Coronary Surgery and Sulfinpyrazone
JOHN F. CADE, M.D., PH.D., DANIEL J. DOYLE, M.B., B.S., COLIN N. CHESTERMAN, D. PHIL.,
FRANK J. MORGAN, M.D., AND GEORGE C. RENNIE, M.A.
SUMMARY Platelet survival and plasma concentrations of thromboglobulin and platelet factor 4 were
measured in 44 patients before and 6 months after coronary artery bypass grafting. Postoperatively,
patients were randomized to receive sulfinpyrazone, 800 mg/day, or placebo. Preoperatively, platelet
survival was significantly shorter than normal, and plasma concentrations of both platelet-specific proteins
were significantly elevated. Postoperatively, all three indexes of platelet function tended to become normal,
but these changes were statistically significant only in patients treated with sulfinpyrazone. Postoperative
exercise testing correlated significantly with plasma concentrations of B thromboglobulin and platelet
factor 4 measured preoperatively and postoperatively. These results are consistent with reports of the effects
of sulfinpyrazine on platelet involvement in other conditions, and suggest that the drug reduces platelet
activation and inhibits actual destruction. The results also show a relationship between abnormalities of
platelet function and an index of postoperative myocardial ischemia.
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ABNORMALITIES of platelet function have been
well documented in patients with coronary artery disease, 1- supporting the proposition that antiplatelet
drugs might modify the natural history of this condition. This proposition has been tested recently in large,
multicenter trials of antiplatelet drugs in the secondary
prevention of myocardial infarction.5-7 The most positive finding from these trials has been a significant
reduction in sudden death in patients treated with sulfinpyrazone in the first 6 months after acute myocardial infarction.5 8
In patients undergoing coronary artery bypass surgery, Steele et al.9 correlated shortened platelet survival with graft occlusion, raising the possibility that antiplatelet drugs might also be of value after coronary
artery surgery. In the present study, platelet survival
and release were measured in patients with angiographically documented coronary artery disease before
and 6 months after coronary artery bypass surgery, and
the effect of sulfinpyrazone on the postoperative measurements was assessed in a randomized, doubleblind, placebo-controlled trial.
jects of comparable age who were free from clinical
cardiovascular disease.10
Methods
Sulfinpyrazone (Anturane, Ciba-Geigy) was given
in a dose of one 200-mg tablet four times daily. A
placebo tablet of identical appearance was given four
times daily to control patients.
Platelet Function
Platelet survival was determined by standard methods.10 The packed cells were returned to the patient
after the infusion of the 51Cr-labeled, platelet-rich
plasma. Blood samples were then collected twice daily
for 5 days. Criteria for acceptance of platelet survival
data were established before the study and included
platelet label greater than 85%, red cell label less than
10%, plasma label less than 10% and recovery 12
hours after infusion greater than 40%. Radioactivity
was measured in duplicate on heparinized and saponinlysed whole blood samples. Platelet life span was calculated using the multiple-hit model, which gave results that correlated most strongly with plasma
concentrations of platelet-specific proteins.10 Betathromboglobulin (BTG) and platelet factor 4 (PF4)
concentrations in plasma were measured by radioimmunoassay.'l
Sulfinpyrazone
Patients
All patients had disabling angina and were placed on
the waiting list for coronary bypass grafting after angiographic demonstration of operable coronary artery
disease. Selection criteria included freedom from
symptoms of peptic ulcer, absence of the need for
other drugs that might alter platelet function (especially aspirin-containing preparations) and ability to undergo postoperative evaluation. Normal values were
obtained during the course of the study from 15 sub-
Procedure
All preoperative tests were performed during the
week before surgery and at least 1 week after the most
recent cardiac catheterization. Postoperative platelet
function measurements were made approximately 6
months after surgery. Patients were randomized to re-
From the University of Melbourne Departments of Medicine, Royal
Melbourne Hospital, and St. Vincent's Hospital, and St. Vincent's
School of Medical Research, Melbourne, Australia.
Supported in part by grants from the National Nealth and Medical
Research Council of Australia, the National Heart Foundation of Australia, the Herman Trust, the McGuaran Estate and Ciba-Geigy
Treatment was given on a double-blind basis commencing 5 days after surgery and continuing until the
postoperative tests were completed. Compliance was
checked by tablet counts at monthly visits.
(Australia).
Indexes of Myocardial Ischemia
Address for correspondence: Dr. J.F. Cade, Royal Melbourne Hospital, Victoria 3050, Australia.
Received March 31, 1981; revision accepted December 8, 1981.
Circulation 66, No. 1, 1982.
Angina was graded preoperatively and postoperatively according to a slightly modified New York Heart
Association classification. 12 Exercise testing was per-
ceive sulfinpyrazone or placebo postoperatively.
29
30
VOL 66, No 1. JULY 1982
CIRCULATION
formed preoperatively and postoperatively on a bicycle ergometer.'3 The development of ST depression
was recorded'3 and the maximal work load was expressed as a percentage of the predicted maximum. 13, 14
Coronary angiography was performed preoperatively
and postoperatively,'5 and vessel patency was graded
as described by Jenkins et al.'6
TABLE 1. Platelet Function Before and After Coronary Surgery
and Sulfinpyrazone
Platelet life
PTG
PF4
span (hours)
(ng/ml)
(ng/ml)
Before After Before After Before After
Group
Placebo
159 180
51
39
11
9
Psychological Testing
Sulfinpyrazone
Total
The Eysenck Personality Questionnaire was administered to 14 patients postoperatively and a score derived on the neuroticism scale.'7
Analyses
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For statistical purposes, the two null hypotheses
were that there were no differences in platelet function
before and 6 months after surgery and that there were
no differences in platelet function between patients
receiving treatment (sulfinpyrazone) or placebo. Three
independent indexes of platelet function were used in
each analysis: platelet survival and plasma concentrations of BTG and PF4. The former hypothesis was
tested in the placebo group by paired t test comparing
preoperative and postoperative values in the same patient. The latter hypothesis was tested by paired t test
comparing, in the treatment group, preoperative and
postoperative values in the same patient, and by unpaired t test comparing, between the treatment and
placebo groups, the changes in platelet function (postoperative minus preoperative value) in each patient.
Comparability of the treatment and placebo groups
preoperatively was assessed by unpaired t test. Preoperatively, the entire group of patients was compared
with normal subjects by unpaired t test.
Results
Forty-four patients entered the study and 39 completed it. There were five withdrawals: three (one sulfinpyrazone and two placebo) because of failure to take
tablets and two (both sulfinpyrazone) because of gastrointestinal side effects.
Platelet Function
Preoperatively, all three indexes of platelet function
were significantly different from normal. Platelet life
span was 143 + 46 hours (mean ± SD) (normal 179 ±
31 hours, p < 0.01), plasma J3TG was 54 ± 20 ng/ml
(normal 32 ± 13 ng/ml, p < 0.01) and plasma PF4
was 12 ± 7 ng/ml (normal 4 ± 3 ng/ml,p < 0.001).'0
For platelet survival, 32% of patients were outside the
normal range (mean + 2 SD), for BTG 32% and for
PF4 53%.
Preoperatively, the treatment and placebo groups
were not significantly different from each other with
respect to plasma BTG and PF4 concentrations, but
platelet life span was significantly shorter in the treatment
group than in the placebo group (p < 0.05) (table 1).
In the placebo group, the preoperative abnormalities
in all three indexes of platelet function tended to become normal postoperatively, but these changes were
not significant (table 1). In the treatment group, the
preoperative abnormalities in all three indexes of plate-
+39 ±44
±20 ±25
122
+39
143
±46
57
±20
54
+20
194
±28
189t
±35
31t
± 11
35t
± 19
±6
+5
16
8*
±5
8*
±5
±10
12
±7
Values are mean ± SD.
*p < 0.05 vs preoperative value.
tp < 0.001 vs preoperative value.
Abbreviations: ITG = beta thromboglobulin; PF4
factor 4.
platelet
let function were significantly improved postoperatively (table 1). The changes in each index of platelet
function were also greater after treatment than after
placebo, but these changes were significant only for
platelet survival (p < 0.05).
We previously showed that plasma concentrations
of BTG and PF4 and indexes of platelet survival were
significantly correlated in patients with coronary artery
disease. "° In the present study, we showed that the
preoperative-to-postoperative changes in these indexes
are also significantly correlated. Thus, for BTG and
PF4, r - 0.52 (p < 0.01); for BTG and platelet life
span, r - 0.27 (NS) for the multiple-hit model, r =
0. 31 (p < 0.05) for the linear model and r = 0.36 (p <
0.05) for the exponential model; for PF4 and platelet
life span, r = 0.54, 0.67 and 0.60 (allp < 0.01) for
the three models, respectively.
Platelet Function and Postoperative Myocardial Ischemia
Postoperative angina did not correlate with any index of platelet function measured either preoperatively
or postoperatively. However, postoperative angina
was significantly related to preoperative angina (F =
3.62, p < 0.05), although not to preoperative exercise
testing or coronary angiography score.
Postoperative exercise testing was significantly correlated with plasma concentrations of BTG and PF4
measured both preoperatively and postoperatively
(table 2), but not with platelet survival. Postoperative
exercise testing (percent predicted) was also related to
preoperative angina (F = 4.42, p < 0.01), although
not to preoperative exercise testing or coronary
angiography score.
Postoperative coronary angiography (graft patency)
was not correlated with any of the indexes of platelet
function, measured either preoperatively or postoperatively. However, graft patency was significantly related to preoperative coronary angiography score (F =
8.57, p < 0.05), although not to preoperative angina
or exercise testing.
Platelet Function and Psychological Testing
Abnormal platelet function tended to be associated
with lower neuroticism scores, but these changes were
not statistically significant.
PLATELET FUNCTION AFTER CORONARY SURGERY/Cade et al.
TABLE 2. Relation of Platelet Release and Exercise Testing
Exercise testing
Platelet
release
JTG
Preop
Change
PF4
Preop
ST depression
Postop
Change
% predicted
Postop
Change
0.46*
NS
NS
NS
0.48t
-0.38*
0.46*
NS
NS
NS
0.51t
NS
NS
NS
NS
Change
NS
Values are correlation coefficient (r).
*p < 0.05.
tp < 0.001.
Abbreviations: See table 1.
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Discussion
In this study, patients with coronary artery disease
had significant abnormalities in platelet survival and
plasma concentrations of BTG and PF4. Between onethird and one-half of the patients had values outside the
normal range. After coronary artery surgery, all three
indexes of platelet function returned toward normal.
These changes were statistically significant only in
patients treated with sulfinpyrazone.
Preoperatively, platelet survival was fortuitously
shorter in patients randomized to the treatment group,
so that the postoperative effects of sulfinpyrazone on
platelet survival are difficult to assess. Since the lack
of preoperative comparability of the treatment and
control groups did not apply to the plasma concentrations of 13TG and PF4, the significant decrease in these
levels postoperatively in the treatment group, but not
in the placebo group, suggests that sulfinpyrazine did,
in fact, tend to normalize the platelet changes in patients with coronary artery disease undergoing coronary artery bypass grafting.
The effect of sulfinpyrazone in normalizing platelet
function after coronary artery surgery is consistent
with reports in which the shortened platelet survival in
patients with gout,"8 prosthetic heart valves,'9 20 recurrent venous thromboembolism2' and coronary artery
disease3 has been prolonged after treatment with sulfinpyrazone. In the present study, release of plateletspecific proteins, as well as platelet survival, were
normalized after drug treatment, which indicates that
sulfinpyrazone reduced platelet activation as well as
inhibited destruction.
Coronary artery bypass grafting reduces angina
postoperatively, but improvement in objective indexes
has been harder to document.4 22 All three indexes of
platelet function showed a trend toward normalization
postoperatively, even in the placebo group (NS). This
finding could have interesting implications for determining the site of production in the circulation of the
platelet changes in patients with coronary artery disease.4 The usual presumption is that such platelet
changes are generated diffusely and are associated with
the generalized arterial disease that such patients are
prone to have. If these changes resolve after coronary
artery surgery alone, it would imply that even small
31
segments of diseased arteries can give rise to platelet
activation detectable systemically. However, other
possible explanations for platelet activation preoperatively are circulating catecholamines generated by
pain, fear, or stress, although in a limited survey we
could not show any relation between psychological
testing and platelet function.
The clinical effects, if any, of the normalization of
platelet function after coronary artery surgery and sulfinpyrazone cannot be determined from the present
study. Preliminary reports indicate that other antiplatelet agents, aspirin with and without dipyridamole, for
example, do not increase graft patency.23' 24 However,
it is possible that an improved clinical outcome could
accompany the normalization of platelet function in
such patients, because abnormalities of platelet function are postulated to be associated with clinical thromboembolic disease. This therapeutically encouraging
postulate is supported by the present study, in which
one index of postoperative myocardial ischemia (exercise testing) was significantly correlated with plasma
concentrations of BTG and PF4 measured both postoperatively and preoperatively. The correlation with
postoperative BTG levels supports a pathogenetic relationship between platelet activation and myocardial
ischemia. The correlation with preoperative 3TG and
PF4 levels suggests that these tests might have predictive clinical value.
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CIRCULATION
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Platelet function in coronary artery disease: effects of coronary surgery and
sulfinpyrazone.
J F Cade, D J Doyle, C N Chesterman, F J Morgan and G C Rennie
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Circulation. 1982;66:29-32
doi: 10.1161/01.CIR.66.1.29
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1982 American Heart Association, Inc. All rights reserved.
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