Journal of the American College of Cardiology Vol. 40, No.

2, 2002
© 2002 by the American College of Cardiology Foundation ISSN 0735-1097/02/$22.00
Published by Elsevier Science Inc. PII S0735-1097(02)01954-X

Antiplatelet Therapy

The Effect of Clopidogrel in

Combination With Aspirin When
Given Before Coronary Artery Bypass Grafting
Richard H. Hongo, MD, Jill Ley, RN, MS, CCRN, Stuart E. Dick, MPH, RD,
Rupsa R. Yee, MD, FACC
San Francisco, California
OBJECTIVES This study was designed to evaluate the effect of preoperative clopidogrel on coronary artery
bypass graft surgery (CABG) outcomes.
BACKGROUND Clopidogrel in combination with aspirin, given before percutaneous coronary intervention,
has become the standard for stent thrombosis prevention. Some premedicated patients,
however, are found to have surgical disease on angiography, and irreversible platelet inhibition
becomes a concern for upcoming CABG.
METHODS We prospectively studied 224 consecutive patients undergoing nonemergent first-time
CABG, and compared those with preoperative clopidogrel exposure within seven days (n ⫽
59) to those without exposure (n ⫽ 165).
RESULTS The groups were comparable in age, gender, body surface area, preoperative hematocrit,
preoperative prothrombin time and prior myocardial infarction. The clopidogrel group had
higher 24-h mean chest tube output (1,224 ml vs. 840 ml, p ⫽ 0.001), and more transfusions
of red blood cells (2.51 U vs. 1.74 U, p ⫽ 0.036), platelets (0.86 U vs. 0.24 U, p ⫽ 0.001)
and fresh frozen plasma (0.68 U vs. 0.24 U, p ⫽ 0.015). Moreover, reoperation for bleeding
was 10-fold higher in the clopidogrel group (6.8% vs. 0.6%, p ⫽ 0.018). The clopidogrel
group also had less extubation within 8 h (54.2% vs. 75.8%, p ⫽ 0.002) and a trend towards
less hospital discharge within five days (33.9% vs. 46.7%, p ⫽ 0.094).
CONCLUSIONS Clopidogrel in combination with aspirin before CABG is associated with higher postoper-
ative bleeding and morbidity. These findings raise concern regarding the routine adminis-
tration of clopidogrel before anticipated coronary stent implantation. (J Am Coll Cardiol
2002;40:231–7) © 2002 by the American College of Cardiology Foundation

The early experience of coronary artery stenting was con-
founded by an unacceptably high rate of stent thrombosis
(24%) (1). Today, thrombosis rates are demonstrated to be
⬍2% with elective stent implantation (2– 4). The two
pivotal changes that have had the greatest impact in
decreasing the rate of stent thrombosis have been the
implementation of high-pressure balloon stent expansion
and the use of enhanced antiplatelet therapy.
Combination antiplatelet therapy with aspirin and ticlo-
pidine, a platelet adenosine diphosphate (ADP) receptor
antagonist, emerged as the standard for stent thrombosis
prevention after randomized studies (5,6) demonstrated it to
be more effective than aspirin-antithrombotic regimens.
The use of ticlopidine, however, was not well tolerated
because of gastrointestinal and dermatologic side effects,
and was complicated by rare but serious occurrences of
severe neutropenia and thrombotic thrombocytopenic pur-
pura (7). Clopidogrel, an acetate derivative of ticlopidine,
has demonstrated more potent antiaggregant effect (8),
more rapid onset of action (9), lower rate of serious side
effects (10,11) and better tolerability (11–13). Several ran-
From the Division of Cardiology, California Pacific Medical Center, San Fran-
cisco, California.
Manuscript received November 20, 2001; revised manuscript received April 8,
2002, accepted April 18, 2002.
domized studies (11,14,15) have strongly suggested the
comparable efficacy of clopidogrel and ticlopidine, and have
helped establish the combination of aspirin and clopidogrel
as the current standard for coronary stent thrombosis
prevention.
Clopidogrel and aspirin are usually given to patients
before the diagnostic angiogram whenever there is a possi-
bility of “ad hoc” coronary stent implantation. This practice
has evolved in an attempt to ensure adequate platelet
inhibition at the time of stent implantation. A number of
patients premedicated with this combination, however, are
found to have surgical disease on angiography and do not
undergo stent implantation. In these patients, enhanced and
irreversible platelet inhibition becomes a concern for up-
coming coronary artery bypass graft surgery (CABG). The
purpose of this study was to better define the effects of
preoperative clopidogrel on surgical and clinical outcomes
after CABG.
METHODS
The study population consisted of 409 consecutive patients
that underwent CABG between March 1999 and June
2000. Patients undergoing emergent surgery, and those with
a history of previous cardiac surgery, concomitant valvular
232 Hongo et al. JACC Vol. 40, No. 2, 2002
Preoperative Clopidogrel and Aspirin in CABG July 17, 2002:231–7

Table 1. Baseline Characteristics

Abbreviations and Acronyms Clopidogrel No Clopidogrel
ADP ⫽ adenosine diphosphate (n ⴝ 59) (n ⴝ 165) p Value
CABG ⫽ coronary artery bypass graft surgery
Age (yrs) 66.9 ⫾ 12.4 67.0 ⫾ 10.6 0.732
CLASSICS ⫽ Clopidogrel Aspirin Stent International
Gender (female) 28.8% 26.1% 0.732
Cooperative Study
Body surface area (m2) 1.85 ⫾ 0.27 1.85 ⫾ 0.27 0.650
CURE ⫽ Clopidogrel in Unstable Angina to
Hematocrit (%) 39.1 ⫾ 3.7 38.6 ⫾ 5.2 0.415
Prevent Recurrent Ischemic Events trial
Prothrombin time (s) 11.6 ⫾ 1.2 11.2 ⫾ 1.3 0.091
GP ⫽ glycoprotein
Creatinine (mg/dl) 1.03 ⫾ 0.40 1.35 ⫾ 1.59 0.145
History of MI 52.5% 46.1% 0.448
History of CVA 10.2% 7.3% 0.576
surgery or preoperative exposure to either coumadin or History of CHF 13.6% 24.8% 0.097
platelet glycoprotein (GP) IIb/IIIa inhibitors were excluded Class III to IV angina* 71.1% 47.9% 0.002
(n ⫽ 185). In the remaining 224 patients, those with Aspirin therapy 86.4% 47.3% ⬍0.001
preoperative clopidogrel exposure within seven days of Data are shown as mean ⫾ SD or percentages. *Canadian Cardiovascular Society
surgery (n ⫽ 59) were compared to those without exposure angina class.
CHF ⫽ congestive heart failure; CVA ⫽ cerebral vascular accident; MI ⫽
(n ⫽ 165) for postoperative bleeding and clinical outcomes. myocardial infarction.
Patients with clopidogrel exposure were further grouped
into those with (n ⫽ 51) and without (n ⫽ 8) preoperative hematocrit, prothrombin time and creatinine levels were
aspirin exposure within seven days of surgery, and outcomes also comparable between the groups. There was a signifi-
of these two groups were compared in an effort to isolate the cantly higher prevalence of class III to IV angina (71.1% vs.
effect of clopidogrel. Patients without clopidogrel exposure 47.9%, p ⫽ 0.002) in the clopidogrel group. As expected,
were also grouped into those with (n ⫽ 78) and without there was a high prevalence of concomitant aspirin exposure
(n ⫽ 87) preoperative aspirin exposure, and were compared in the clopidogrel group (86.4%). On the other hand, fewer
in an effort to isolate the effect of aspirin. than half of the patients in the group without clopidogrel
Chest tube outputs assessed at 8 h and 24 h were the exposure had exposure to aspirin (47.3%) (p ⬍ 0.001).
primary measure of postoperative bleeding. Transfusion The postoperative measures of bleeding and blood prod-
quantity was recorded for the four main blood product types uct transfusions are shown in Table 2. The clopidogrel
(red blood cells, platelets, fresh frozen plasma and cryopre- group had a higher mean chest tube output at both 8 h
cipitate). Clinical outcomes specific to CABG recovery (775 ml vs. 516 ml, p ⫽ 0.005) and 24 h (1,224 ml vs.
included reoperation for bleeding, severe low cardiac output, 840 ml, p ⫽ 0.001) after procedure, and a higher mean
mortality, acute myocardial infarction, stroke and postoper- number of transfusions with each blood product type. Only
ative atrial fibrillation. Severe low cardiac output was de- 15% of patients in the clopidogrel group were free of blood
fined as the need for multiple vasopressors or intra-aortic product exposure.
balloon pump for more than 24 h after surgery. General The clinical outcomes are shown in Table 3. The most
postsurgical outcomes evaluated were duration of intubation striking finding was a 10-fold higher incidence of reopera-
and postoperative length of stay. tion for bleeding in the clopidogrel group (6.8% vs. 0.6%,
Recognized risk factors for perioperative bleeding in p ⫽ 0.018). The clopidogrel group was also less likely to be
cardiac surgery were assessed including advanced age, fe- extubated within 8 h of surgery, and was trending towards
male gender, small body surface area and renal insufficiency being less likely to be discharged from the hospital within
(16,17). Baseline hematocrit and prothrombin time was five postoperative days. There appeared to be less mortality
assessed because of their influence on blood product trans- and fewer postoperative myocardial infarctions and strokes
fusions. Criteria for emergent status and reoperation for
bleeding were in accordance to definitions set out by the Table 2. Chest Tube Outputs and Transfusions
Society of Thoracic Surgeons. The study was approved by Clopidogrel No Clopidogrel
the Institutional Review Board. (n ⴝ 59) (n ⴝ 165) p Value
Statistical analysis. Continuous variables are expressed as Chest tube output (ml)
mean ⫾ SD. Dichotomous variables are shown as percent- 8-h 775 ⫾ 727 516 ⫾ 533 0.005
ages. Mean differences between the groups were analyzed 24-h 1224 ⫾ 1119 840 ⫾ 621 0.001
Transfusions (U)
using the Student t test. Proportional differences were Red blood cells 2.51 ⫾ 2.41 1.74 ⫾ 2.16 0.036
analyzed using the Fisher exact chi-square analysis. A p Platelets 0.86 ⫾ 1.20 0.24 ⫾ 0.60 0.001
value of ⬍0.05 was considered statistically significant. Fresh frozen plasma 0.68 ⫾ 1.69 0.24 ⫾ 0.85 0.015
Cryoprecipitate 0.19 ⫾ 1.31 0.17 ⫾ 1.20 0.774
RESULTS Blood product exposure
Red blood cells 79.7% 58.2% 0.004
The baseline characteristics of those with and without Platelets 50.8% 18.2% ⬍0.001
preoperative clopidogrel exposure were comparable in age, Any blood product 84.7% 61.3% 0.001
gender and body surface area (Table 1). The baseline Data are shown as mean ⫾ SD or percentages.
JACC Vol. 40, No. 2, 2002 Hongo et al. 233
July 17, 2002:231–7 Preoperative Clopidogrel and Aspirin in CABG

Table 3. Clinical Outcomes

Clopidogrel No Clopidogrel
(n ⴝ 59) (n ⴝ 165) p Value
Reoperation for bleeding 6.8% 0.6% 0.018
Severe low cardiac output* 6.8% 3.6% 0.296
Mortality† 1.7% 3.6% 0.678
MI‡ 0% 3.6% 0.344
CVA 3.4% 4.8% 1.000
Atrial fibrillation 44.1% 34.5% 0.211
Deep sternal wound infection 1.7% 1.2% 1.000
Intubation ⱕ8 h 54.2% 75.8% 0.002
Postop length of stay ⱕ5 days 33.9% 46.7% 0.094
Data are shown as percentages. *Defined as multiple vasopressors or intra-aortic balloon pump ⬎24 h. †Defined as all-cause
mortality during hospitalization. ‡Defined as postoperative MI during hospitalization.
CVA ⫽ cerebral vascular accident; MI ⫽ myocardial infarction.

in the clopidogrel group, but the number of events was small
and the results did not reach statistical significance.
Table 4 and Table 5 show the bleeding and transfusion
rates for patients with and without clopidogrel exposure,
respectively. Within the clopidogrel group, patients with
preoperative aspirin exposure appeared to have higher over-
all chest tube outputs and number of transfusions than those
without aspirin exposure. This difference, however, was not
statistically significant, possibly because of the small number
of patients that received clopidogrel alone. Within the
group without clopidogrel exposure, patients with and
without preoperative aspirin exposure had no significant
difference in chest tube output or number of transfusions.
Figure 1 shows the 24-h chest tube output plotted against
time from last clopidogrel dose to surgery in the patients
with clopidogrel exposure. There was poor correlation
between chest tube output and time of delay to surgery
(R2 ⫽ 0.0011). Although all reoperations for bleeding were
in patients with a delay of three days or less, there were very
few patients with a delay of more than three days.
DISCUSSION
In addition to stent thrombosis prevention, the efficacy of
clopidogrel therapy has now been demonstrated in the
setting of acute coronary syndrome and non-ST elevation
myocardial infarction in the recent Clopidogrel in Unstable
Angina to Prevent Recurrent Ischemic Events (CURE) trial
(18). As the indications for clopidogrel expand, the use of
aggressive antiplatelet therapy will be seen in an increasing
number of patients presenting for CABG. A greater under-
standing of the effects of clopidogrel on CABG is therefore
of paramount importance.
In this study, we found that patients exposed to clopi-
dogrel, mostly in combination with aspirin, before non-
emergent first-time CABG had significantly more postop-
erative bleeding and subsequent transfusions. Only 15% of
patients in the clopidogrel group were free of blood product
exposure. The most striking finding was a 10-fold higher
incidence of reoperation for bleeding in the clopidogrel
group (6.8% vs. 0.6%, p ⫽ 0.018). These findings call into
question, in particular, the practice of commencing clopi-
dogrel therapy in addition to aspirin before possible but
undecided coronary stent implantation.
The need for aggressive antiplatelet therapy with a
combination of aspirin and an ADP receptor inhibitor has
been well established for coronary stent thrombosis preven-
tion (5,6,19 –24). Historically, because ticlopidine has a
delayed onset of activity (25,26) and has been shown to have
enhanced efficacy when started several days before coronary
stenting (27), antiplatelet therapy was initiated before the
diagnostic coronary angiography whenever there was a
possibility of subsequent ad hoc stent implantation. This
practice has continued in most centers even as clopidogrel
has effectively replaced ticlopidine.
Clopidogrel, however, has a significantly more rapid
onset of activity when compared with ticlopidine that may
make premedication with clopidogrel unnecessary. After a
300 mg loading dose, clopidogrel displays 30% antiplatelet

Table 4. Patients With Clopidogrel Exposure Table 5. Patients Without Clopidogrel Exposure
Aspirin No Aspirin Aspirin No Aspirin
(n ⴝ 51) (n ⴝ 8) p Value (n ⴝ 78) (n ⴝ 87) p Value
Chest tube output (ml) Chest tube output (ml)
8-h 817 ⫾ 761 509 ⫾ 395 0.320 8-h 501 ⫾ 427 530 ⫾ 616 1.000
24-h 1274 ⫾ 1165 800 ⫾ 480 0.270 24-h 809 ⫾ 545 869 ⫾ 687 1.000
Transfusions (U) Transfusions (U)
Red blood cells 2.59 ⫾ 2.53 2.00 ⫾ 1.41 1.000 Red blood cells 1.84 ⫾ 2.15 1.64 ⫾ 2.17 1.000
Platelets 0.94 ⫾ 1.26 0.38 ⫾ 0.52 0.360 Platelets 0.25 ⫾ 0.54 0.23 ⫾ 0.65 1.000
Fresh frozen plasma 0.78 ⫾ 1.79 0 0.355 Fresh frozen plasma 0.22 ⫾ 0.84 0.26 ⫾ 0.86 1.000
Cryoprecipitate 0.22 ⫾ 1.40 0 1.000 Cryoprecipitate 0.14 ⫾ 1.14 0.19 ⫾ 1.25 1.000
Data are shown as mean ⫾ SD. Data are shown as mean ⫾ SD.
234 Hongo et al.
Preoperative Clopidogrel and Aspirin in CABG
Figure 1. Relationship between 24-h postoperative chest tube output and time to surgery after last clopidogrel dose in patients with clopidogrel exposure
(n ⫽ 59). The broken line is the regression line. Open circles ⫽ reoperation for bleeding.
activity in 5 h, nearly approximating the 40% steady-state
antiplatelet activity achieved with a 75 mg daily dose (9).
The main circulating metabolite, an inactive carboxylic acid
derivative, has a peak plasma concentration in 1 h (28). In
the CURE study, survival benefit was seen in 2 h (18).
Clopidogrel loading has been administered after stent
implantation in two randomized studies. The Clopidogrel
Aspirin Stent International Cooperative Study (CLASSICS)
demonstrated superior safety of clopidogrel over ticlopidine
with an overall low incidence of cardiac events when given
after intracoronary stenting (14). The trial, however, was
designed as a safety study and had insufficient power to
assess the efficacy of therapy. The trial also excluded patients
with increased risk for stent thrombosis, a group thought to
benefit most from combination aspirin and ADP inhibitor
therapy (29). Taniuchi et al. (11) studied a population that
included higher risk patients and found a similar 30-day
stent thrombosis rate between patients receiving clopidogrel
and patients receiving ticlopidine, both administered after
stent implantation (2.02% vs. 1.92%, p ⫽ 0.901).
Managing patients with clopidogrel exposure. In this
new era of aggressive platelet inhibition in coronary disease,
the optimal management of patients presenting for CABG
receiving clopidogrel is still evolving. The findings from this
study suggest that these patients should have surgery de-
layed, when possible, to allow platelet function to recover.
The optimal duration of this delay, however, is still unclear
and further evaluation is needed. In the CURE study (18),
patients that stopped taking clopidogrel within five days of
CABG had a trend towards more major bleeding than those
on placebo (9.6% vs. 6.3%, p ⫽ 0.06). There was no excess
JACC Vol. 40, No. 2, 2002
July 17, 2002:231–7
of major bleeding reported, however, in patients that had
CABG more than five days after the last clopidogrel dose
(4.4% vs. 5.3%). In this study, there was poor correlation
between 24-h chest tube output and duration of delay to
surgery. Although all reoperations occurred in patients with
a delay of three days or less, there were very few patients
with more than a three-day delay.
If CABG cannot be safely delayed, platelet transfusions
can be considered when rapid reversal of clopidogrel is
needed. In the setting of abciximab exposure before CABG,
however, prophylactic platelet transfusions have been cau-
tioned against because of the possibility of acute reversal of
the clinical benefits of platelet inhibition (30,31). With
abciximab exposure, it has been recommended to reserve
platelet transfusions for patients that display clinical bleed-
ing after discontinuation of extracorporeal circulation and
neutralization of heparin with protamine (32,33). Whether
the same recommendations are applicable to clopidogrel is
still to be seen.
Aprotinin, an antifibrinolytic agent, has been successfully
used in cardiac surgery to reduce overall bleeding and
transfusion requirements in patients exposed to aspirin
(34 –36). Aprotinin is appealing because whereas it reduces
overall bleeding, it appears to preserve platelet function
during cardiopulmonary bypass (37,38). Its use has been
shown to reduce bleeding time prolongation from clopi-
dogrel in animals (39). The efficacy of aprotinin in patients
receiving clopidogrel, however, has not yet been evaluated.
Preoperative antiplatelet therapy and CABG. Aorto-
coronary grafts have a significant rate of acute thrombotic
occlusion. Within the first few months after CABG, the
JACC Vol. 40, No. 2, 2002
July 17, 2002:231–7
cumulative vein graft patency rate is between 77% and 90%
(40). Aspirin therapy started immediately after CABG not
only improves early graft patency but also improves survival
(41– 44). Although preoperative aspirin was initially found
to increase rates of reoperation for bleeding, transfusions
and hospital stay with CABG (45– 49), subsequent studies
have not found the same increase in bleeding (50 –52). In
fact, preoperative aspirin is now suggested to decrease
mortality in CABG patients (53).
Even though excessive bleeding with preoperative clopi-
dogrel was found in this study, the safety of aggressive
platelet inhibition in the setting of cardiac surgery has been
reported in patients with preoperative abciximab (32). In
fact, it has been suggested that platelet inhibition with GP
IIb/IIIa inhibitors, or “platelet anesthesia,” may allow plate-
lets to escape the hemostatic effects of cardiopulmonary
bypass and may improve postoperative hemostasis (54).
Decreased platelet loss has been seen with GP IIb/IIIa
inhibition during simulated cardiopulmonary bypass (55),
and animal studies have shown a reduction in postoperative
bleeding (56,57).
The potential benefit of preoperative antiplatelet therapy
in CABG, beyond aspirin, is still poorly defined, however.
Even so, the use of clopidogrel before CABG is intriguing.
Clopidogrel may be uniquely effective in preventing acute
thrombotic graft closure, not simply because of its potency
in comparison to aspirin, but also because of its mechanism
of action. The shear-induced platelet activation seen with
cardiopulmonary bypass is inhibited by clopidogrel within
hours (58,59). Clopidogrel has also been found to be
superior to aspirin for secondary prevention of ischemic
events after CABG (60). If the bleeding with preoperative
clopidogrel can be minimized while preserving its antiplate-
let effect, a role for preoperative clopidogrel in CABG may
emerge in the future.
Study limitations. The imbalance of class III to IV angina
(71.1% vs. 47.9%, p ⫽ 0.002) raises concern that there may
be differences in the use of antithrombotic and other
antiplatelet agents between the groups that may be influ-
encing outcomes. Patients receiving either GP IIb/IIIa
inhibitors or coumadin were excluded from the study. Any
difference in preoperative heparin exposure is felt unlikely to
affect postoperative bleeding because of the extensive use of
heparin during CABG and its reversal with protamine.
Nonetheless, because patients were not randomized to
clopidogrel exposure, unrecognized confounding factors
may exist. In addition, the nurses measuring and recording
chest tube drainage were not actively blinded to clopidogrel
or aspirin exposure, thus allowing possible bias.
We were unable to fully evaluate the effect of aspirin in
this study. There was no increase in bleeding or transfusions
when aspirin alone was compared with no antiplatelet
therapy. Within the clopidogrel group, more bleeding and
transfusions were seen in patients that also received aspirin,
but these increases were not found to be statistically signif-
icant. Although synergy of clopidogrel and aspirin has been
Hongo et al. 235
Preoperative Clopidogrel and Aspirin in CABG
described (61,62), this could not be adequately assessed in
this study because the number of patients that received only
clopidogrel was limited. The results of this study essentially
reflect the effects of the combination of clopidogrel and
aspirin and cannot be generalized to patients that are
receiving clopidogrel alone.
Clinical implications. In this study, the use of clopidogrel
in combination with aspirin before nonemergent first-time
CABG was associated with higher postoperative bleeding
and morbidity. These findings raise concern regarding the
routine administration of clopidogrel before anticipated but
undecided coronary stent implantation. Further studies will
be needed, however, to better define the role of clopidogrel
before CABG. For now, it may be sensible to delay surgery,
when possible, in patients recently exposed to the combi-
nation of clopidogrel and aspirin.
Acknowledgment
We thank Lynne Day for her secretarial assistance.
Reprint requests and correspondence: Dr. Rupsa R. Yee, Divi-
sion of Cardiology, California Pacific Medical Center, 2333
Buchanan Street, San Francisco, California 94115. E-mail:
phillimx@sutterhealth.org.
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