ORIGINAL ARTICLE

European Journal of Cardio-Thoracic Surgery 45 (2014) 165170

doi:10.1093/ejcts/ezt279 Advance Access publication 4 July 2013

Thienopyridines resistance and recovery of platelet function after

discontinuation of thienopyridines in cardiac surgery patients
Umberto Di Dedda, Marco Ranucci*, Ekaterina Baryshnikova and Serenella Castelvecchio on behalf of the
Surgical and Clinical Outcome Research (SCORE) Group
Department of Cardiothoracic and Vascular Anaesthesia and Intensive Care, IRCCS Policlinico San Donato, Milan, Italy
* Corresponding author. Department of Anaesthesia and Intensive Care, IRCCS Policlinico San Donato, Via Morandi 30, 20097 San Donato Milanese, Milan, Italy.
Tel: +39-02-52774320; fax: +39-02-55602262; e-mail: cardioanestesia@virgilio.it (M. Ranucci).
Received 25 November 2012; received in revised form 5 March 2013; accepted 21 March 2013

Abstract
OBJECTIVES: Patients who undergo cardiac operations under the effects of thienopyridines have a greater risk of major postoperative
bleeding, transfusions and surgical revision due to bleeding. Discontinuation of thienopyridine is suggested but an adequate recovery
period following discontinuation is still under debate, with opinions ranging from 3 to 7 days. The aim of this study was to assess the rate of
recovery of thienopyridine-resistant patients and the time taken for resumption of platelet function after discontinuation of thienopyridine, in the setting of patients scheduled for cardiac operations.

RESULTS: Thienopyridine resistance rate was 28%. Patients receiving clopidogrel had a signicantly higher rate (32%) of resistance, compared with those receiving ticlopidine (14%) and thienopyridine resistance was signicantly associated with platelet count (P = 0.006). The
time taken to recover platelet function after thienopyridine discontinuation was variable between individuals; the only factor associated
with a faster recovery time was the serum bilirubin value (P = 0.002). Platelet aggregation values high enough to avoid major bleeding were
reached 3 days after discontinuation (95% condence interval: 24 days); however, a complete recovery of platelet function was reached
only after 8 days (95% condence interval: 79 days).
CONCLUSIONS: Patient-specic factors determine the effectiveness of thienopyridine treatment and platelet function recovery rate. Among
these, platelet count (for thienopyridine resistance) and serum bilirubin values (for platelet function recovery rate) should be considered.
Keywords: Platelets Bleeding Coronary artery bypass surgery

INTRODUCTION
Anti-platelet agents are nowadays the standard-of-care for coronary patients. Thienopyridines (ticlopidine, clopidogrel and prasugrel) are usually included in the therapeutic regimen, either alone
or in association with other oral anti-platelet agents.
Patients experiencing the therapeutic effects of thienopyridines
and requiring a cardiac surgery operation are at risk for major
postoperative bleeding, surgical re-exploration and allogeneic
blood products transfusions [13].
The existing international guidelines suggest discontinuation of
thienopyridines before cardiac operations whenever feasible.
However, there is no general consensus as to the correct time
frame between the last thienopyridine administration and the day
of the operation. In their previous version [4], the guidelines published by the Society of Thoracic Surgeons and the Society of
Cardiovascular Anaesthesiologists suggested at least 57 days
between discontinuation and surgery; the most recent version [5]
has revised this suggestion, including a statement that in some
patients, even 3 days following discontinuation may be adequate and

that the use of point-of-care platelet function tests may be a reasonable means of indentyng clopidogrel non-responders who do not
need any discontinuation of the drug.
However, a position statement by the Canadian Cardiovascular
Society [6], suggests an interval of at least 5 days between discontinuation and surgery, balancing the risks and benets between
the risk of bleeding and of acute coronary events. Finally, the
Guidelines of the European Society of Cardiology (ESC) and the
European Association for Cardio-Thoracic Surgery (EACTS) [7]
conrm 5 days as the minimum interval after discontinuation of
thienopyridines treatment for elective patients undergoing coronary surgery.
Therefore, the present situation is characterized by a heterogeneity of opinions; moreover, the suggestion of using point-of-care
platelet function tests is currently backed up by little evidence in
terms of reference values, due to the paucity of studies and the use
of different types of point-of-care devices.
At our institution, since 2009, all patients scheduled for heart
operationsand receiving thienopyridines treatment that had not
been discontinued at least one week prior to the operationare

The Author 2013. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

ADULT CARDIAC

METHODS: This was a retrospective study, based on 344 patients screened for platelet aggregation before cardiac operations. All the
patients received thienopyridines within 7 days prior to the test. Multiple electrode aggregometry adenosine diphosphate test was used to
assess platelet aggregation before the operation.

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U. Di Dedda et al. / European Journal of Cardio-Thoracic Surgery

routinely screened with a point-of-care platelet function test. The

present study is a retrospective analysis of our data for this patient
population, aimed (i) to assess the rate of non-responsiveness to
thienopyridine in patients and the factors associated with this
condition and (ii) to assess the time required to recover platelet
function after their discontinuation and the factors associated with
the recovery rate.

METHODS
This was a single-centre, retrospective analysis of prospectively
collected data. The study was approved by our local ethics committee (ASL Milano 2 Melegnano) and the need for informed
consent was waived.
Starting in 2009, all patients scheduled for cardiac operations
were evaluated with a pre-operative multiple electrode aggregometry (MEA) test if they were receiving treatment with thienopyridines that had not ceased at least one week prior to the operation.
The MEA test was performed at the point-of-carewithin the operating theatrethe day before the operation or, in the case of
afternoon operations, on the morning of the operation. During
the study period ( January 2009 to March 2012), 344 patients were
tested with MEA before their operations. Prior to 2009, it was our
standard practice to interrupt the thienopyridine therapy at least 5
days before the operation: however, patients may be operated on
even without discontinuation of thienopyridines if considered
urgent cases. Starting in 2011, the patients could be operated on
even when time since discontinuation was less than 5 days, given
acceptable platelet function, indicated by the MEA adenosine diphosphate (ADP) test.
In a previous study [8] we were able to demonstrate that an
MEA ADP test result of <31 U was associated with major postoperative bleeding. Therefore, during the last 12 months, the operation has usually been postponedwhenever feasibleif the
MEA ADP test result was below this cut-off value, and the test was
repeated until the patient reached the desired value of platelet
function. Conversely, the patients were accepted for surgery if the
MEA ADP test result was 31 U.
The use of aspirin was not an exclusion criterion. Due to the
fact that aspirin does not change the MEA ADP test results, no particular measurements were done in patients taking aspirin. At our
institution, aspirin is not discontinued before operation.

Data collection
From our institutional database, we could retrieve the following
data for each patient: demographics; left ventricular ejection fraction (%); recent (30 days) myocardial infarction; unstable angina;
congestive heart failure; active endocarditis; chronic obstructive
pulmonary disease; diabetes on medication; previous cerebrovascular accident; previous heart operation; urgent case; haematocrit
(%); serum creatinine value (mg/dl); serum bilirubin value (mg/dl);
platelet count (cells/l); type of thienopyridine used (ticlopidine,
clopidogrel or prasugrel) and date of last intake; result and date of
the MEA ADP test; postoperative bleeding (ml/12 h) and allogeneic blood transfusions ( packed red cells, fresh frozen plasma and
platelet concentrates). Postoperative bleeding was measured as
the volume of blood collected from the chest drains within the
rst 12 postoperative hours. Packed red cell transfusions were
usually triggered by a haematocrit value <24%; fresh frozen

plasma and platelet concentrates were used in case of bleeding

and under the guidance of postoperative thromboelastography.

Platelet function testing

Platelet aggregation performance was assessed using Multiplate
(Dynabyte GmbH, Munich, Germany), a point-of-care multiple
electrode platelet aggregation monitoring system based on whole
blood impedance measurement. The method has previously been
described in detail [9]. ADP testing is sensitive towards ADP receptor inhibition induced by direct ADP receptor antagonists, such as
thienopyridines. Increasing electric impedance was electronically
measured for 6 min and expressed as the area under the aggregation curve (AUC), plotted over time (AUC, [U]) by an integrated
software package. Reference ranges indicated by the manufacturer
for ADP testing were AUCs 53122 U.

Platelet function: denitions

Patients were dened as thienopyridine-resistant where:
(i) platelet aggregation value was >60% of the lower limit of the
normal range, in patients who received their last thienopyridine dose within 1 day prior to the test. This corresponds to
an ADP test of 32 U.
(ii) platelet aggregation value >70% of the lower limit of the
normal range, in patients who received their last thienopyridine dose 2 days prior to the test. This corresponds to an ADP
test of 37 U.
(iii) platelet aggregation value >80% of the lower limit of the
normal range, in patients who received their last thienopyridine dose 3 days prior to the test. This corresponds to an ADP
test of 43 U.
(iv) platelet aggregation value within the normal range (>53 U.)
for patients who received their last thienopyridine dose 45
days prior to the test.
The above denitions are arbitrary; however, there is not yet a
consensus for cut-off values dening thienopyridine nonresponsiveness for the various platelet function tests [10]. Studies
using MEA suggested a value of 42 U for patients under full clopidogrel treatment and are therefore compatible with our denitions [11].
The recovery of platelet function after discontinuation of thienopyiridines was assessed in terms of ADP test increase per day
following discontinuation. This was calculated, considering the
lowest and peak values and the number of days between the two
tests, according to the formula:
 
U
Platelet function recovery
day

Peak ADP test U  lowest ADP test U

no: of days between tests

Statistics
Data are expressed as number with percentage, mean and standard deviation for normally distributed variables, and median with

U. Di Dedda et al. / European Journal of Cardio-Thoracic Surgery

interquartile range for non-normally distributed data. Normal distribution was checked with a Kolmogorov-Smirnov test.
Differences between percentages were tested with a two-sided
Fishers exact test. Differences between continuous variables were
tested with a Students t-test for normally distributed variables
and with a Mann-Whitney U-test for non-normally distributed
variables.
Associations between continuous variables were tested with
linear and non-linear univariate or multivariate (stepwise forward)
regression analyses. Associations between continuous variables
and dichotomous variables were tested with univariate or multivariate (stepwise forward) logistic regression analyses, producing
odds ratios with 95% condence intervals (CI).
When non-normally distributed variables were entered into the
regression models, adequate transformations (logarithmic) or
Poisson weighting were applied.
A P value <0.05 was considered signicant for all the tests
applied. For all the statistical analyses, a computerized package
(IBM SPSS Statistics 13.0, Chicago, IL, USA) was used.

167

to avoid a clustering effect. According to this relationship, the

elapsed period for avoiding the risk of major bleeding (>10th
decile of distribution of postoperative bleeding), according to the
previously validated ADP test >31 U, is 2.5 days (95% CI: 1.53.5
days) and the period required for a complete recovery of platelet
function is 8 days (95% CI: 79 days).
The 226 patients identied as thienopyridine responders
received additional tests if the ADP test was <31 U and the operation was postponed. Additionally, some patients screened before
2011 received more than one test, even if the rst ADP test was
31 U. Overall, 67 patients received two MEA tests, 22 received
three and 5 received four or more MEA tests. The individual analysis for the recovery of platelet function was conducted only for
thienopyridine responders who had at least two MEA tests on different days (75 cases).
The mean ADP test increase was 12 U (95% CI: 914) per day
between the lowest and the peak value. Overall, there was a great
individual variability, as shown in Fig. 2.
The main pre-operative patient characteristics collected were
investigated for association with the platelet function recovery
time. The only signicant association was found for serum

Results

Thienopyridine resistance
The screening for thienopyridine resistance was conducted in 332
out of the overall population of 344 patients. The remaining
twelve patients received the rst MEA ADP test more than 5 days
after discontinuation of the drug and presented normal values of
aggregometry: for those patients, it was not possible to analyse
their data for possible thienopyridine resistance. According to our
denitions, 94 patients (28%) were thienopyridine-resistant.
Various factors were investigated for association with thienopyridine resistance. Due to the low number of patients who received
prasugrel, the type of drug used was analysed as clopidogrel
(264 patients) vs ticlopidine (59 patients). The only signicant
differences between responders and non-responders were found
in the type of thienopyridine used and patients platelet counts
(Table 2).
Platelet count and use of clopidogrel were found to be independently associated with thienopyridine resistance in a multivariate model of logistic regression. Due to the non-normal
distribution of platelet count, a logarithmic transformation was
applied.

Platelet function recovery

Within the population of thienopyridine responders (226 patients)
the ADP test results signicantly increased (P = 0.001) with increasing numbers of elapsed days following discontinuation of thienopyridine (Fig. 1). This analysis includes only one value per patient,

Table 1: Demographics, clinical details and laboratory data

of the patient population (n = 344)
Variable

Age (years)
Weight (kg)
Height (cm)
Gender male
Platelet count ( 1000/l)
Serum creatinine value (mg/dl)
Serum bilirubin value (mg/dl)
Haematocrit (%)
Left ventricular ejection fraction (%)
Recent myocardial infarction
Unstable angina
Congestive heart failure
Previous cardiac surgery
Diabetes on medication
Chronic obstructive pulmonary disease
Previous cerebrovascular accident
Active endocarditis
Urgent procedure
Isolated coronary operation
Isolated valve operation
Combined coronary + valve operation
Others
Ticlopidine treatment
Clopidogrel treatment
Prasugrel treatment
Days after discontinuation
Ongoing
One
Two
Three
Four
Five
Six or more
Postoperative bleeding (ml/12 h)
Packed red cells transfusions
Fresh frozen plasma transfusions
Platelet concentrates transfusions

Number (%) or mean standard

deviation or median
(interquartile range)
67.6 10.6
75.0 (6782)
170 (162174)
278 (81)
195 (158239)
1.0 (0.81.2)
0.5 (0.40.7)
39 (3541)
50 (4560)
75 (17.7)
22 (6.4)
18 (5.1)
12 (3.5)
74 (21)
24 (7.0)
7 (2.0)
2 (0.6)
32 (9.3)
220 (64)
17 (5)
68 (20)
39 (11)
59 (17)
275 (80)
10 (3)
41 (12)
58 (17)
49 (14)
37 (11)
40 (12)
30 (9)
89 (25)
412 (256600)
189 (55)
31 (9)
55 (16)

ADULT CARDIAC

Demographics, clinical details and laboratory data relating to our

patient population are depicted in Table 1. The most commonly
used thienopyridine was clopidogrel (255 patients; 80%), followed
by ticlopidine (59 patients; 17%) and prasugrel (10 patients; 3%).
All patients were under full dose of anti-platelet agents at the time
of discontinuation (daily dose of 75 mg of clopidogrel or 250500
mg of ticlopidine or 10 mg of prasugrel), with or without additional salycilates (100 mg daily dose).

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Table 2: Factors associated with thienopyridine resistance

Factor

Thienopyridine resistant (n = 92)

Thienopyridine responsive (n = 231)

P-value

180 (68)
51 (86)
184 (155229)

0.004
0.005

Odds ratio (95% CI)

P-value

2.1 (1.044.1)
3.1 (1.387.2)

0.038
0.006

number (%) or median (interquartile range)

Clopidogrel treatment
84 (32)
Ticlopidine treatment
8 (14)
Platelet count ( 1000/l)
213 (170256)
Logistic regression analysis for thienopyridine resistance
Factor
Regression coefficient
Constant
7.7
Clopidogrel treatment
0.73
Platelet count (ln)
1.14
CI: confidence interval; ln: logarithmic

Figure 1: Linear regression analysis of the association between the number of

days following discontinuation of thienopyridine and recovery of platelet function. Dashed lines represent the 95% condence interval. MEA: multiple electrode aggregometry.

Figure 3: Linear regression analysis of association between serum bilirubin

values and recovery of platelet function. Dashed lines represent the 95% condence interval.

Platelet function, postoperative bleeding and

transfusions
Thienopyridine-resistant patients demonstrated a non-signicant
(P = 0.116) lower incidence of postoperative bleeding (385 ml/12
h; interquartile range 250600 ml/12 h) vs non-resistant patients
(450 ml/12 h; interquartile range 275606 ml/12 h).
No differences were observed for packed red cells and fresh
frozen plasma transfusions; conversely, platelet concentrates were
transfused at a signicantly (P = 0.05) higher rate in non-resistant
patients (19.2%) vs resistant patients (9.9%).
The last ADP test result before the operation was signicantly
associated (P = 0.002) with postoperative bleeding, according to a
logarithmic regression analysis with Poisson weighting (Fig. 4) and
with the need for postoperative platelet concentrate transfusions,
according to a binary logistic regression analysis (P = 0.001).
Figure 2: Individual changes in platelet function according to the number of
days following discontinuation of thienopyridine. MEA: multiple electrode
aggregometry.

bilirubin levels, with a greater rate of recovery for higher values of

bilirubin. Due to the non-normal distribution of these values, a
logarithmic transformation was applied. Figure 3 shows the platelet function recovery time according to the serum bilirubin values
(data presented without logarithmic transformation).

Comment
The main results of our study are:
(i) Thienopyridine resistance occured in about 28% of the
patients; at a signicantly higher rate in patients treated with
clopidogrel, compared with ticlopidine, and in patients with
high values of platelet count.

Figure 4: Logarithmic regression analysis of association between the last ADP

test before the operation and the postoperative bleeding. MEA: multiple electrode aggregometry.

(ii) The recovery time for platelet function in thienopyridine

responders is highly variable between individuals, but signicantly faster in patients with elevated serum bilirubin levels.
(iii) Platelet function immediately before a cardiac surgery operation is a determinant of postoperative bleeding and requirement for platelet concentrates transfusions.
It is well known that patients treated with ticlopidine or clopidogrel may react with different levels of platelet dysfunction, due to
individual genomic patterns and the fact that, being pro-drugs,
thienopyridines need absorption and subsequent liver activation
to become active compounds [12, 13]. Different denitions of clopidogrel resistance have been proposed [1416]. From the clinical
point of view, anti-platelet drug resistance is a high on treatment
platelet reactivity, based on pre-dened cut-off values. In two
recent works [1116], arbitrary cut-off values with different assays
have been proposed for the denition of resistance: among
others, platelet aggregation >46.8 U/min in response to ADP by
MEA has been set as a threshold for identication of resistant
patients, both to clopidogrel and prasugrel. Another study using
MEA suggested a value of 42 U for patients under full clopidogrel
treatment [11].
In our study, the incidence of thienopyridine resistance (28%) is
consistent with that reported in many other previous studies,
reporting rates between 2040% [17, 18].
There are several mechanisms potentially responsible for hypoor non-responsiveness to thienopyridines. Among these, poor
compliance or under-dosing, increased platelet turnover, genetic
factors (i.e. polymorphisms of CYP 450 system or P2Y12 receptor)
affecting both pharmacokinetics and pharmacodynamics of the
agent, drug-drug interactions or comorbidities [19]. Prasugrel,
because of a different bio-transformation pathway, results in
faster, more consistent platelet inhibition and, at the same time,
lower susceptibility to metabolic phenotypes when compared
with clopidogrel [17].
Thienopyridine resistance has been investigated mainly in relation to clopidogrel and little information exists as to the incidence of this phenomenon in ticlopidine-treated patients. Our
data demonstrate that ticlopidine treatment carries a lower rate
of resistance than clopidogrel; however, we lack specic data to
interpret this observation. Conversely, the second factor identied as independently associated with thienopyridine resistance,
platelet count, deserves some speculation. First of all, it cannot
be completely ruled out that the evidence of a greater platelet

169

aggregability at the MEA ADP test, that is directly proportional to

platelet count, may be somehow biased by a laboratory artefact.
MEA has been validated in a wide range of platelet concentrations and is independent from platelet count, at least in the
range 80 000400 000 cells/l [18]. However, we must not fail to
consider that a certain degree of impedance change at the MEA
test may be ascribed to a larger platelet count, rather than to
improved platelet function. Given this possible bias, our results
introduce the hypothesis that anti-platelet therapy should be
titrated, considering the central role of platelet count and that
higher doses may be needed to adequately inactivate platelets in
case of thrombocytosis.
The second main topic addressed by our study deals with the
time period before cardiac surgery, following discontinuation of
thienopyridines. Actually, this point deals with two different and
opposite risks: that of acute coronary events in cases of premature
drug cessation and that of postoperative bleeding in cases of
excessive residual anti-platelet effect.
A recent meta-analysis conrms that recent exposure to clopidogrel is associated with increased risk of postoperative death,
re-operations for bleeding, blood loss and need for transfusions
[20]. Another systematic review demonstrates that patients
exposed to thienopyridines, who undergo surgical operations
(both cardiac and non-cardiac), experienced higher rates of
stroke, surgical revisions due to bleeding and mortality [21].
According to a recent meta-analysis, in acute coronary syndrome
patients undergoing coronary artery bypass graft, rates of mortality, myocardial infarction and major adverse cardiovascular events
were no different with or without recent clopidogrel exposure
[22]. However, patients recently exposed to clopidogrel had a
higher surgical revision rate, greater postoperative bleeding and
required more allogeneic blood product transfusions [22]. Other
studies could not conrm these results [23, 24].
It is reasonable to hypothesize that one of the factors introducing a bias in these studies may be the inclusion of a variable
number of thienopyridine-resistant patients, who could actually
be operated on, even under full anti-platelet treatment, without
additional bleeding risks. In this respect, our study conrms the
potentially important role of a point-of-care test to identify
thienopyridine-resistant patients and avoid unnecessary delay of
the operation. Overall, the existing evidence is in favour of associating patients recently exposed to thienopyridines with a greater
risk of bleeding following surgery, whereas there is greater debate
over the possible benecial effects of continuing thienopyridine
therapy, in terms of reduction of major cardiovascular events.
Within the group of thienopyridine responders, the time
required for recovery of platelet function suffers from a certain
degree of individual variation: however, what is still unclear from a
clinical point of view is what level of platelet function we should
accept, to be able to safely operate on our patients. If we consider
our previously validated cut-off value of 31 U at the MEA ADP test
as the lowest acceptable value to exclude major postoperative
bleeding, then a discontinuation time of three days seems reasonable, based on the present analysis.
Periods of between 4 and 8 days following discontinuation
(moderate anti-platelet effect zone in Fig. 1) correspond to a moderate platelet dysfunction and probably represent the optimal
timing for the operation. If the target is a complete recovery of
platelet function, then at least 8 days are required, with 95% CI
extending to 9 days. The variability between individuals in the
time for recovery of platelet function is probably dependent on a
number of factors that are outside the variables measured in the

ADULT CARDIAC

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U. Di Dedda et al. / European Journal of Cardio-Thoracic Surgery

present study. However, we can identify serum bilirubin level as a

new and clinically relevant factor associated with a faster platelet
function recovery time.
Patients with serum bilirubin levels exceeding 1.5 mg/dl demonstrated a platelet function recovery time in the range of 2040
U/day. This means that, even in the presence of a total blunting of
platelet function, these patients may recover an acceptable value
(>31 U) of platelet function after only 2448 h.
The effects of bilirubin on platelet function and in terms of
aggregability have been recognized for more than 30 years.
Unconjugated bilirubin increases the negative electrophoretic mobility of platelets. This mechanism leads to platelet aggregation,
even at a bilirubin concentration of 1.5 mg/dl [25].
Altogether, the evidence that the platelet function recovery
time is highly individualizedand dependent on factors that are
only partially measurablestrengthens the role of point-of-care
tests in following the time course of platelet function recovery
after discontinuation of anti-platelet agents.
As a nal conrmation of the importance of MEA ADP testing
and possibly other point-of-care tests, we can conrm in our
series that there is a signicant and clinically relevant association
between the peak value of the ADP test result immediately before
the operation and the postoperative bleeding rate and need for
platelet concentrates transfusions.
There are some limitations in our study. The rst is its retrospective
nature; the second is that, due to the changing policy on deciding to
postpone the operation during the study period, not all the patients
received more than one ADP test or the same number of tests.
This limited the number of patients analysed for platelet function
recovery time. The changes in platelet function were not assessed
daily, but indirectly calculated from the elapsed time between two
tests. Additionally, perceptions of major bleeding and acceptable
levels of platelet function to avoid it are institutionally-based, albeit
already published [10]. Finally, the denition for thienopyridine
resistance in this study (as in the previous ones) is arbitrary.
Thienopyridine treatment and its discontinuation before
cardiac and other major surgical operations still remains a
complex topic that involves a number of factors, the majority of
which are not measurable in clinical terms. In our study we were
able to conrm that platelet function point-of-care tests have a
valuable role to play in assessing individuals responses to antiplatelet agents and the recovery of their platelet function following discontinuation of anti-platelet drugs.

[4]

[5]

[6]

[7]
[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]
[18]

[19]

Funding
[20]

This work was supported by local research funds of the IRCCS

Policlinico San Donato.
[21]

Conict of interest: none declared.

REFERENCES

[22]
[23]

[1] Hongo RH, Ley J, Dick SE, Yee RR. The effect of clopidogrel in combination
with aspirin when given before coronary artery bypass grafting. J Am Coll
Cardiol 2002;40:23137.
[2] Yende S, Wunderink RG. Effect of clopidogrel on bleeding after coronary
artery bypass surgery. Crit Care Med 2001;29:227175.
[3] Berger JS, Frye CB, Harshaw Q, Edwards FH, Steinhubl SR, Becker RC.
Impact of clopidogrel in patients with acute coronary syndromes requiring

[24]
[25]

coronary artery bypass surgery: A multicenter analysis. J Am Coll Cardiol

2008;52:16931701.
Ferraris VA, Ferraris SP, Saha SP, Hessel EA 2nd, Haan CK, Royston BD et al.
Perioperative blood transfusion and blood conservation in cardiac
surgery: the Society of Thoracic Surgeons and The Society of
Cardiovascular Anaesthesiologists clinical practice guideline. Ann Thorac
Surg 2007;83 (5 Suppl):S2786.
Ferraris VA, Brown JR, Despotis GJ, Hammon JW, Reece TB, Saha SP et al.
2011 Update to The Society of Thoracic Surgeons and the Society of
Cardiovascular Anaesthesiologists Blood Conservation Clinical Practice
Guidelines. Ann Thorac Surg 2011;91:94482.
Fitchett D, Eikelboom J, Fremes S, Mazer D, Singh S, Bittira B et al. Dual
anti-platelet therapy in patients requiring urgent coronary artery bypass
grafting surgery: A position statement of the Canadian Cardiovascular
Society. Can J Cardiol 2009;25:68389.
Wijns W, Kolh P, Danchin N, Di Mario C, Volkmar Falk V, Folliguet T et al.
Guidelines on myocardial revascularization. Eur Heart J 2010;31:250155.
Ranucci M, Baryshnikova E, Soro G, Ballotta A, De Benedetti D, Conti D.
Surgical and Clinical Outcome Research (SCORE) Group. Multiple electrode whole-blood aggregometry and bleeding in cardiac surgery patients
receiving thienopyridines. Ann Thorac Surg 2011;91:12329.
Tth O, Calatzis A, Penz S, Losonczy H, Siess W. Multiple electrode aggregometry: a new device to measure platelet aggregation in whole blood.
Thromb Haemost 2006;96:78188.
Bonello L, Tantry US, Marcucci R, Blindt R, Angiolillo DJ, Becker R et al.
Working Group on High On-Treatment Platelet Reactivity. Consensus and
future directions on the denition of high on-treatment platelet reactivity
to adenosine diphosphate. J Am Coll Cardiol 2010;56:91933.
Sibbing D, Braun S, Morath T, Mehilli J, Vogt W, Schmig A et al. Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and
early drug-eluting stent thrombosis. J Am Coll Cardiol 2009;53:84956.
Sibbing D, Morath T, Braun S, Stegherr J, Mehilli J, Vogt W et al.
Clopidogrel response status assessed with Multiplate point-of-care analysis and the incidence and timing of stent thrombosis over six months following coronary stenting. Thromb Haemost 2010;103:15159.
Serebruany V, Cherala G, Williams C, Surigin S, Booze C, Kuliczkowski W
et al. Association of platelet responsiveness with clopidogrel metabolism:
role of compliance in the assessment of resistance. Am Heart J 2009;158:
92532.
Gurbel PA, Bliden KP, Hiatt BL, OConnor CM. Clopidogrel for coronary
stenting: response variability, drug resistance and the effect of pretreatment platelet reactivity. Circulation 2003;107:2098113.
Gurbel PA, Becker RC, Mann KG, Steinhubl SR, Michelson AD. Platelet
function monitoring in patients with coronary artery disease. J Am Coll
Cardiol 2007;50:182234.
Mueller I, Besta F, Schulz C, Massberg S, Shoenig A, Gawaz M. Prevalence
of clopidogrel non-responders among patients with stable angina pectoris
scheduled for elective coronary stent placement. Thromb Haemost 2003;
89:78387.
Alexopoulos D. Prasugrel resistance: Fact or ction. Platelets 2012;23:
8390.
Toth O, Clatzis A, Penz S, Losonczy H, Siess W. Multiple electrode aggregometry: a new device to measure platelet aggregation in whole blood.
Thromb Haemost 2006;96:78188.
Uchiyama S. Clopidogrel resistance: identifying and overcoming a barrier
to effective anti-platelet treatment. Cardiovascular Therapeutics 2011;29:
e100e111.
Biancari F, Airaksinen KE, Lip GY. Benets and risks of using clopidogrel
before coronary artery bypass surgery: systematic review and
meta-analysis of randomized trials and observational studies. J Thorac
Cardiovasc Surg 2012;143:66575.
Nijjer SS, Watson G, Athanasiou T, Malik IS. Safety of clopidogrel being
continued until the time of coronary artery bypass grafting in patients
with acute coronary syndrome: a meta-analysis of 34 studies. Eur Heart J
2011;32:297088.
Au AG, Majumdar SR, McAlister FA. Pre-operative thienopyridine use and
outcomes after surgery: a systematic review. Am J Med 2012;125:8799.
Kim JH, Newby LK, Clare RM, Shaw LK, Lodge AJ, Smith PK et al.
Clopidogrel use and bleeding after coronary artery bypass graft surgery.
Am Heart J 2008;156:88692.
Grujic D, Martin D. Pre-operative clopidogrel: is seven days enough? Am
Surg 2009;75:90913.
Kosztolnyi G, Jobst K. The effect of bilirubin on the surface charge and
aggregation tendency of platelets in cord blood. Eur J Pediatr 1979;131:
11318.