Current Cardiology Reviews, 2009, 5, 125-132
1573-403X/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd.
Perioperative Management of Antiplatelet-Drugs in Cardiac Surgery
Raquel Ferrandis*, Juan V. Llau and Ana Mugarra
Department of Anaesthesiology and Critical Care Medicine, Hospital Clínic Universitari, València, Spain
Abstract: The management of coronary patients scheduled for a coronary artery bypass grafting (CABG), who are
receiving one or more antiplatelet drugs, is plenty of controversies. It has been shown that withdrawal of antiplatelet drugs
is associated with an increased risk of a thrombotic event, but surgery under an altered platelet function also means an
increased risk of bleeding in the perioperative period. Because of the conflict recommendations, this review article tries to
evaluate the outcome of different perioperative antiplatelet protocols in patients with coronary artery disease undergoing
and increasing. First treatment of occlusive coronary disease
involves percutaneous revascularization and many times one
or more stents placement. Any percutaneous coronary
intervention causes trauma to the vessel wall, rendering the
endoluminal surface thrombogenic and thus, dual anti-
platelet therapy (mostly aspirin and clopidogrel) is currently
recommended [1, 2].
The incidence of coronary artery disease (CAD) is high
bypass grafting (CABG), the traditional recommendation has
been to stop antiplatelet drugs between 7 to 10 days prior to
surgery . But, withdrawal of aspirin in patients with CAD
has been associated with a 2 to 4-fold increase in the risk of
death and myocardial infarction , being the major
independent predictor of stent occlusion [5, 6]. Thus, the
anaesthesiologist faces the dilemma of stopping the
antiplatelet treatment to avoid bleeding and risking
postoperative stent thrombosis, or to maintain the antiplatelet
therapy perioperatively to avoid the stent thrombosis, so
risking major blood loss and increased transfusion rate.
When these patients are scheduled for coronary artery
therapy in such a situation. Because of the conflict
recommendations, we undertook this systematic review of
the literature to evaluate the outcome of different
perioperative antiplatelet protocols in patients with CAD
We lack scientific evidence on the optimum perioperative
2. MAIN CHARACTERISTICS OF ANTIPLATELET
drugs (APD) are shown in Table 1 [7, 8].
The well established current indications of antiplatelet
particularly activation and subsequent aggregation, although
they make this effect through different ways showing
All of them are capable to inhibit platelet function,
*Address for correspondence to this author at the Raquel Ferrandis Comes,
Servicio de Anestesiología y Reanimación, Hospital Clínic Universitari,
Avda. Blasco Ibáñez, 17, 46010, Valencia, Spain; Tel: 00-34-96-3862653;
Fax: 00-34-96-3987831; E-mail: firstname.lastname@example.org
Recognized Indications of the Antiplatelet Drugs
Indications in Cardiology
• Acute myocardial infarction
• Acute coronary syndrome
- Stable angina
- Unstable angina/acute myocardial infarction without Q wave
• Percutaneous coronary angioplasty with coronary stent
• Atrial fibrillation*
• Patients undergoing CABG surgery
• Some patients with valvulopathies
Indications in Neurology
• Acute phase of stroke
• Secondary prevention of strokes in patients without emboligen
• Patient of valve prosthesis
• Emboligen carotid stenosis
• Carotid endarterectomy
• Patients with Antibodys Antifosfolípidos
• Peripheral artheriopaty with or without intermittent claudication
• Primary prevention in patients with cardiovascular risk
(*) In patients of less than 65 years without another associated risk factor.
different antiaggregant power (Table 2) [9, 10]. APD can be
classified into four groups:
1. Adenosin diphosphate (ADP) receptor antagonists,
such as the thienopyridine drugs ticlopidine and
clopidogrel, which reach their peak of activity after 3-5
days, producing a prolonged antiaggregant effect (7-10
days) due to its long half-life. The inhibitory effects of
126 Current Cardiology Reviews, 2009, Vol. 5, No. 2
Ferrandis et al.
Table 2. Antiaggregant Effect of Some of the Antiplatelet
Adenosin Diphosphate Receptor Antagonists
Ticlopidine 10-14 High
Clopidogrel 7-10 High
GPIIB/IIIA Receptor Antagonists
Eptifibatide 4 hours High
Tirofiban 4 hours High
Abciximab 48-72 hours High
Inhibitors Of Ciclooxygenase 1 Enzyme (COX-1)
ASA 7 High
Piroxicam 7 High
Indometacin 3 High
Ketorolac 2 High
Flurbiprofen 1 High
Ibuprofen 1 Moderate
Naproxen 2 Moderate
Ketoprofen 1 Moderate
Diclofenac 1 Moderate
Salsalate < 1 Weak
Diflunisal < 1 Weak
Paracetamol < 1 Weak
Proparacetamol < 1 Weak
Metamizol < 1 Weak
Rofecoxib 0 No
Celecoxib 0 No
Drugs That Increase The Intraplatelet Levels Of AMPC
Trifusal 7 High
Dipyridamole 1 Moderate
clopidogrel could be attained earlier by using 300 or 600
mg loading dose. Moreover, 600 mg double bolus has
been shown to achieve greater platelet inhibition than
conventional single loading doses .
2. GPIIb/IIIa receptor antagonists, of exclusively
intravenous use, which are more powerful, albeit with a
shorter-lasting action (24 h): eptifibatide, abciximab,
3. Drugs that increase the intraplatelet levels of AMPc.
The best known agent in this group is dipyridamole
(moderate antiaggregant effect lasting about 24 hours).
Other drugs are the I-2 prostaglandin (epoprostenol) and
its analog iloprost, both used by intravenous route with a
brief antiaggregant effect (< 3 h).
4. Inhibitors of ciclooxygenase 1 enzyme (COX-1). The
best known representatives are acetylsalicylic acid
(ASA) and non-esteroidal anti-inflammatory drugs
(NSAIDs). ASA is the most deeply studied one and its
antiaggregant effect takes place with the irreversible
blockade of COX-1, so its action lasts throughout all the
life of the platelet (7-10 days). Nevertheless, from the
third or fourth day usually there is enough number of
platelets to guarantee suitable haemostasis. The NSAIDs
also produce inhibition of platelet aggregation by a
similar mechanism to the ASA, although there are two
important differences: firstly the blocking effect of the
COX-1 is reversible, thus once the drug has been
eliminated from the circulation, the platelet function is
restored; secondly, there is a great difference between
the different NSAIDs in their capacity to inhibit COX-1
and, consequently, in its platelet antiaggregant action.
being continuously updated. In cardiologic patients, some
recent questions of development of the APD deserved to be
Actually the field of the indications of use of the APD is
The role of the aspirin in the primary prevention has
extended its prescription based on related factors of
cardiovascular and/or neurological risk. Moreover the
combination of two APD drugs (mainly ASA and
clopidogrel) in high risk patients is a practice more and
more extended .
Dual antiplatelet therapy has to be maintained at least 12
months after drug eluting stent placement and elective
surgery postponed; if surgery is necessary, at least ASA
should be maintained throughout the periperative period
and the patient operated under its antiaggregant effect
. Probably, in this patient a specific protocol of
antiaggregation in type, combination and duration of
APD need to be applied [13, 14].
The interindividual response to the APD is evident and
it does not seem that a valid universal pattern of
antiaggregation for all the patients exists.
antiplatelet therapy (Table 3) [15, 16]. From our point of
view, we could distinguish two groups: patients with chronic
treatment who are scheduled for cardiac surgery and patients
who require urgent surgery, most of them with double
Then, we face different type of patients who benefit from
3. CARDIOVASCULAR RISK AFTER ANTIPLATE-
LET DRUGS WITHDRAWAL
occlusive vascular events reduce the combined outcome of
any serious vascular event by about one quarter, non-fatal
myocardial infarction by one third, non-fatal stroke by one
quarter, and vascular mortality by one sixth (with no
apparent adverse effect on other death) . Aspirin has
been the most widely studied APD, with doses of 75-150 mg
daily at least as effective as higher daily doses. Keeping
patients on aspirin prior to surgery may help to attenuate the
inflammatory response during the operative period and may
also reduce cardiovascular events while awaiting surgery
The antiplatelet therapy in patients at high risk of
achieved with aspirin, although irreversible for target
platelets, lasts until a significant pool of new platelets is
produced. Nevertheless, a complete recovery of platelet
aggregation has been observed by day 3 (in 50% healthy
As we have previously described, the platelet inhibition
Perioperative Management of Antiplatelet-Drugs in Cardiac Surgery Current Cardiology Reviews, 2009, Vol. 5, No. 2 127
young men)  which seems due in part of a biological
platelet aggregation “rebound phenomenon”. In fact, after
aspirin discontinuation, the recovery of cyclooxigenase
activity may occur rapidly, with a heterogeneous synthesis of
thromboxane A2 by fresh platelets , which may have
possible hazardous effects in patients with cardiovascular
disease . Nevertheless, none of the guidelines support the
assessment of platelet reactivity by using point-of-care
cardiovascular risk of perioperative APD withdrawal, most
of them in non-cardiac surgery, but we did not find any study
comparing the cardiovascular risks of preprocedural APD
withdrawal directly against APD continuation. Instead of it,
we collect some studies that report the frequency of APD
(aspirin) withdrawal preceding
syndrome (Table 4) [4, 22-24].
Many studies have been recently published describing the
recommend cessation for 5-7 days before surgery. The
CURE study  and its sub-analyses show that cessation of
clopidogrel in these patients and for this time period is
associated with a 1% increase in the risk of myocardial
infarction. In non-surgical patients, with acute coronary
artery syndrome, the first 90-day interval after stopping
treatment with clopidogrel was associated with a
significantly higher risk of adverse events (incidence rate
ratio of 1.98) .
Talking about clopidogrel, most guidelines would
4. BLEEEDING RISK WITH PERIOPERATIVE
TREATMENT OF ANTIPLATELET DRUGS
procedural-bleeding risks with and without aspirin. Ex-
cluding studies on cardiac surgery, aspirin multiplied
baseline-bleeding rate by a factor of 1.5 , although
mortalities possibly caused by bleeding occurred only after
transurethral prostatectomy  and intracranial neuro-
There are many clinical studies comparing peri-
but there seems to have an increase of bleeding with a
tendency to need more transfusion requirements in patients
under the effect of aspirin [29-35]. Thus, in a recent
systematic review of randomized and observational studies
, pre-operative aspirin maintenance was associated with
a significant increase in the volume of post-operative
bleeding (mean difference 114 ml) and transfusion
requirements (mean difference 0.34 units), with not
significantly difference in the rates of reoperation; with the
subgroup analysis, the authors conclude that this bleeding
could be minimized by the use of aspirin doses less than 325
mg/day. Another metanalysis  shows similar results,
highlighting that the rate of platelet transfusion was similar
in both groups.
Focus on cardiac surgery, the results are heterogeneous
could be lower if the CABG surgery is performed off-pump,
and patients under the effect of aspirin seems to be at less
Bleeding complications and transfusion requirements
Recommendations on the Use of Antiplatelet Agents
Clinical Setting Recommendation Grade
Ischaemic heart disease
Chronic stable angina
Acute coronary syndrome without ST-segment elevation with PCI
Acute myocardial infarction with ST elevation
Acute myocardial infarction with ST elevation and with primary PCI
Aspirin or clopidogrel (as alternative)
Aspirin or clopidogrel + aspirin (more effective)
Aspirin or clopidogrel + aspirin (more effective)
i.v. GPIIb/IIIa inhibitors
i.v. GPIIb/IIIa inhibitors
Prior myocardial infarction Aspirin or clopidogrel (as alternative) 1A
Elective PCI + stent application
Clopidogrel or ticlopidine
PCI: Percutaneous coronary intervention. Grades of recommendation as defined by Guyatt et al. .
Table 4. Aspirin Withdrawal Preceding Acute Cardiovascular Syndrome
Number of Patients
Admitted for ACS
% Patients with Recent
Withdrawal of APD
% Withdrawal for Surgery
Time between Withdrawal
Aspirin and ACS
Collet, 2004 1358 73(5.4%) 74.38% 11.9±0.8
Collet, 2000 475 11(2.3%) 81% 10
Ferrari, 2005 1236 51(4.1%) 13.72% 10±1.9
ACS: acute cardiovascular syndrome
128 Current Cardiology Reviews, 2009, Vol. 5, No. 2
Ferrandis et al.
risk for bleeding or for reoperation due to postoperative
haemorrhage , even if aspirin is associated with
clopidogrel and not discontinued within 2 days of surgery
(no differences with the discontinuation more than 6 days
before surgery or between 2 and 5 days before surgery) .
Moreover, some articles have associated preoperative aspirin
maintenance with a decreased risk of mortality in CABG
patients without significant increase in haemorrhage, blood
product requirements, or related morbidities , even with
aspirin usage within the 5 days preceding surgery .
age, smaller body mass index, non-elective cases, 5 or more
distal anastomosis are more important risk factors for re-
exploration for bleeding after CABG than aspirin ingestion,
which is consistent with other previous studies [42, 43].
Thus, some surgical and patients characteristics as older
thienopyridines that antagonist irreversibly the platelet
adenosine diphosphate. It has showed to increase bleeding
after CABG in many articles [44-48], although there is
another report in which the maintenance of clopidogrel does
not increase bleeding or transfusion requirements . The
optimal waiting period after last clopidogrel administration
is not known but appears to be at least 5 days before CABG
; if the patient need to be antiaggregated near before
cardiac surgery, probably the best option is to use low-dose
aspirin perioperatively, once clopidogrel has been discon-
tinued . Finally, it has been published that a combined
preoperative treatment with heparin infusion could prevent
the increased blood loss associated to the administration of
clopidogrel, which may have been attributable to a conser-
vation of coagulation factors, as evidenced by the increased
plasma fibrinogen concentrations with combined prophy-
lactic treatment .
The other common drugs used as antiplatalet agent are
the intravenous GP IIb/IIIa platelet receptor antagonist
(tirofiban, eptifibate and abciximab). While eptifibatide and
tirofiban have a competitive binding and are rapidly cleared,
with an almost recovered platelet function in about 4 hours
, abciximab causes prolonged and irreversible effect,
with inhibition of platelet function and aggregation lasting
24-48 hours . Transfusion of platelets rapidly reverses
the inhibitory effects of abciximab , but it is of very little
utility during infusion or suddenly after eptifibatide or
tirofiban. No data are available in the literature on the impact
of tirofiban or eptifibatide treatment on emergency CABG;
however their short half-life and short-lasting action after
stopping the infusion is a potential advantage for the
performance of CABG with reduced risk of bleeding [55-
58], so no delay in surgery has been recommended . In
patients treated with abciximab, delaying emergency or
urgent CABG for 12 hours has been recommend [59, 60],
but other authors suggest rapid discontinuation of abciximab
infusion and undelayed intervention [61, 62]. In any case,
platelet transfusion should be considered only when
increased bleeding is encountered (not prophylactically), and
only after cessation of cardiopulmonary bypass .
Other drugs that have become increasingly common are
4.1. Methods to Avoid Bleeding
of methods intended to minimize perioperative transfusion:
In cardiac surgery, we should also take care of a variety
preoperative autologous donation, intra- and postoperative
cell salvage, and the use of drugs, such as aprotinin (a
protease inhibitor), desmopressin (that induces the release of
factor VIIIvW) and tranexamic acid (TXA) and epsilon-
aminocarproic acid (EACA) (that mainly inhibit plasmin
binding to fibrin).
number of allogenic transfusions after cardiac surgery and
the proportion of patients requiring reoperation because of
bleeding . Recent publications, however, have
questioned the safety of this agent, reporting not only an
increase in renal impairment but an increased risk of long-
term mortality following CABG surgery [65-67]. The FDA
and the EMEA have recently suspended its use, pending of a
complete analysis of a randomized prospective trial in
Canada (BART trial), which has shown similar results in
terms of mortality.
Many studies have shown that aprotinin decreased the
effect on reducing the proportion of patients receiving
transfusion after CABG , but its efficacy seemed to vary
depending on the use of aspirin. While some authors have
shown that desmopressin reduced the postoperative blood
loss and the transfusion requirements in patients treated with
aspirin within 7 to 5 days before surgery compared to
placebo [68-70], no effect was found in patients treated
within 2 days before CABG .
Desmopressin has not shown a statistically significant
allogenic blood, but has not statistically significant effect on
reoperations because of bleeding , both in on- and in off-
pump surgery . This effect is no consistent in all the
studies, excluding patients with APD, prophylactic use of
TXA did not result in any significant decrease in
postoperative bleeding in one study , but reduced
postoperative bleeding and fibrinolysis in another . In
patients treated with aspirin, the administration of a single
dose of TXA (30 mg/kg) immediately before cardio-
pulmonary bypass significantly reduced postoperative
bleeding and inhibited fibrinolysis .
The TXA decreases the portion of patients receiving
shown any statistically significant effect .
There are very few studies with EACA that have not
4.2. Monitors of Platelet Function Perioperatively
monitoring consists of a platelet count and prothrombin (PT)
and activated partial thromboplastin (aPTT) times, omitting
platelet function. However, these routine tests are insensitive
predictors of bleeding and perioperative changes in platelet
count shows poor correlation with changes in platelet
function . It would be helpful in the perioperative
management of APD to have a haemostatic test to identify
the patients at bleeding risk because of platelet dysfunction
related with the administration of any APD.
The current standard of care for perioperative coagulation
Optical platelet aggregometry is considered at present the
reference assay for diagnosis of platelet disorders ,
although it is not completely standardized, the laboratory
work up is complex and it is not possible to be performed
immediately before the surgery. The Platelet Function
Analyser (PFA-100) explores the platelet adhesive capacity,
Several tests could be used to assess the platelet function.
Perioperative Management of Antiplatelet-Drugs in Cardiac Surgery Current Cardiology Reviews, 2009, Vol. 5, No. 2 129
measuring the closure time taken for a platelet plug to
occlude an aperture in a membrane impregnated with
collagen and epinephrine or ADP ; ASA and clopidogrel
have been shown to prolong this closure time, but without
evident correlation with a perioperative bleeding. The
PlateletworksTM analyser measures the percentage of
aggregation of whole blood before and after the exposure to
ADP; its results are contradictory when compared with
optical aggregometry: good correlation for clopidogrel 
but of limited use for ASA . Thromboelastogrphy (TEG)
is a whole blood coagulation monitor, which can
demonstrate the alteration of platelet aggregation, but is
unable to detect the defects that occur with ASA or
demonstrate the ADP blockade caused by clopidogrel.
with perioperative bleeding and further clinical inves-
tigations are necessary in this field, although they can help
us to reduce the rate of reoperation for bleeding (TEG), in
part by helping to differentiate surgical from nonsurgical
bleeding , or to improve appropriate platelet transfusion
Unfortunately any of these tests has good correlation
5. GUIDELINES AND RECOMMENDATIONS
antiaggregant agents scheduled for cardiac surgery is a major
topic of interest and concern for all perioperative caregivers.
Many recommendations could be found in the available
published papers [8, 13, 14, 36, 37, 51, 82-85] and they
could be summarized as follows:
The management of patients under the effect of
1. Patient Treated with Aspirin
Aspirin should be maintained in patients at high risk for
arterial thrombotic complications. The optimal dose of
aspirin ranges between 75 and 325 mg and in the
perioperative period, in the majority of patients, it would
be enough the maintenance of low-dose of aspirin.
In the case of high risk of bleeding, some drugs that
decrease postoperative bleeding, as TXA or EACA
(with limited evidence to support the use of one agent
over the other) could be used; desmopresine might be
considered preoperatively only in patients with acquired
or inherited defects in primary haemostasis detected by
abnormal point-of-care test, as PFA-100.
2. Patient Treated with Clopidogrel
If the patient is on treatment with clopidogrel and needs
to be antiaggregated near before cardiac surgery,
probably the best option is to discontinue clopidogrel (at
least 5 days before surgery) and use low-dose aspirin
perioperatively (75-125 mg daily).
Dual antiplatelet therapy is associated with too high
bleeding risk. If it is mandatory to maintain this protocol
before surgery (probably only in patients with a drug-
eluting stent implanted less than 12 months ago), and
because of the concerns about premature discontinuation
of clopidogrel in these very high thrombotic risk
patients, several algorhythms have been proposed,
including the administration of an intravenous
glycoprotein IIb/IIIa inhibitor or unfractionated heparin
as “bridging therapy”. At present, there is no enough
evidence-based date to support this strategy.
3. Patient Treated with GP IIb/IIIa Inhibitor
In emergency surgery, if the patient is under the effect
of a glycoprotein IIb/IIIa inhibitor, it might be
considered the platelet transfusion (mainly if it is
abciximab) if there is too much bleeding; due to the
short-acting time of eptifibatide or tirofiban, the delay of
surgery is not recommended in the case of previous
administration of them.
4. Postoperative Treatment
If aspirin therapy has been interrupted before surgery, it
should be administered early after surgery, always
within 48 hours after CABG, and preferably within 6
hours after surgery. Dose ranges between 150-325
mg/day; optimal benefit could be reach with 325
mg/day, at least the first year.
There is no specific recommendation for resuming
clopidogrel after surgery, and it seems to have no
superiority over aspirin; if it is indicated instead of
aspirin, the timing for its administration could be the
same as for aspirin, but it is not recommended a loading
dose (300-600 mg) if first administration is close after
Blood salvage techniques use must be encouraged, as
the devices that conserve blood (intraoperative blood
salvage) or the use of autologous blood predonation or
Platelet transfusion is not indicated as prophylaxis to
avoid bleeding, even if the patient is under the effect of
aspirin or clopidogrel, and its administration must be
reserved if necessary to control excessive bleeding.
It is necessary an optimal preparation of the patient,
avoiding anaemia stimulating the administration of
drugs that increase preoperative blood volume, as
erythro-poietin in combination with iron.
Several guidelines recommend a multimodality app-
roach to blood conservation with the setting-up of
consensus algorhythms and point-of-care testing.
perioperative period of cardiac surgery requires close colla-
boration between cardiologists, surgeons and anaesthesio-
logists. It is necessary to avoid thrombotic complications
maintaining the antiaggregation, but balancing bleeding
The handicap of management of antiplatelet agents in the
increased bleeding if it is maintained until surgery, mainly if
Patients treated with long-term APD could be at risk for
130 Current Cardiology Reviews, 2009, Vol. 5, No. 2
Ferrandis et al.
there are any other outstanding variable as indicator of risk:
advanced age, preoperative anaemia, reoperative o complex
procedures, emergency operations or non-cardiac patient co-
morbidities. If the patient is under the effect of one or more
of these drugs the associated bleeding risk might be carefully
balanced and an alternative antiaggregation protocol could
be considered. Moreover, the drugs to minimize bleeding
could play an important role and might be in consideration.
faces up to the decision to maintain the treatment up to
surgery. The choice for one or the other option should be
based on the individual balance between the risk to develop
any cardiovascular event if the APD has been withdrawn and
the complications associated as result of the major bleeding
if the APD has been maintained until the day of the surgery.
The decision to stop the APD some days before surgery
above, we know that clopidogrel maintenance prior to
cardiac surgery is associated with a more blood product
usage, a 2-5 fold increase in the risk of re-exploration and
30-100% increase in the chest drain blood loss. The
withdrawal of clopidogrel prior to surgery, between 5 and 7
days, could be associated with a little increase of the risk of
myocardial infarction, estimated around 1% while the patient
is waiting for surgery . Between patients under aspirin,
its withdrawal 2-3 days before surgery could reduce
perioperative blood loss, risk for transfusion and reoperation
for bleeding. This practice seems safe for patients without
acute coronary syndromes, but for urgent cardiac surgery,
the risk of perioperative infarction is higher and the balance
is favourable to the maintenance of aspirin up to the day of
Summarising both possibilities and the comments stated
dation is to stop clopidogrel at least 5 days and, preferably,
10 days prior to surgery to minimize blood loss. In the case
of aspirin, the recommendation is to maintain it up to surgery
and beyond the time of surgery. But in the case of patients,
who are not at high risk for cardiac events, the routine
recommendation is to stop aspirin or clopidogrel prior to
surgery because of risk of bleeding and morbi-mortality
associated in these patients .
So, for patients scheduled for CABG, the recommen-
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Received: 09 May, 2008 Revised: 11 August, 2008 Accepted: 11 August, 2008