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British Journal of Anaesthesia 111 (S1): i3i17 (2013)



Perioperative management of antiplatelet therapy

A. D. Oprea* and W. M. Popescu

Department of Anesthesiology, Yale University School of Medicine, New Haven, CT, USA
* Corresponding author. E-mail:

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Summary. Worldwide, cardiovascular events represent the major cause of morbidity and
Editors key points mortality. A key role in the pathogenesis of these events is played by platelets.
Antiplatelet medications are Interventional procedures, with placement of coronary and vascular stents, often
commonly used by high-risk represent the preferred therapeutic strategy. Antiplatelet medications are considered
patients presenting for invasive first-line therapy in preventing cardiovascular thrombotic events. A wide array of
procedures. antiplatelet agents is available, each with different pharmacological properties. When
patients on antiplatelet agents present for surgery, the perioperative team must design
Both continuation and
an optimal strategy to manage antiplatelet medications. Each patient is stratified
discontinuation of antiplatelet
according to risk of developing a cardiovascular thrombotic event and inherent risk of
therapy can be associated with
surgical bleeding. After risk stratification analysis, various therapeutic pathways include
significant risks.
continuing or discontinuing all antiplatelet agents or maintaining one antiplatelet
A team-based approach to risk agent and discontinuing the other. This review focuses on the pharmacological and
stratification is critical to pharmacokinetic properties of both older and novel antiplatelet drugs, and reviews
optimizing the perioperative current literature and guidelines addressing options for perioperative antiplatelet
approach to antiplatelet therapy. management.
Keywords: antiplatelet agents; haemorrhage; perioperative period

Antiplatelet agents, used as monotherapy or in combination, atherothrombosis, being implicated in endothelial, thrombot-
have a major role in preventing and managing cardiac and ic, immune, and inflammatory responses.4 Recent evidence
vascular events.1 These medications are of particular rele- suggests that platelets also have a new and previously unsus-
vance, as coronary artery disease and stroke represent the pected role in tissue repair and vascular remodelling.5
top two causes of mortality worldwide, as reported by the In their inactive state, platelets do not adhere to the endo-
World Health Organization in a report updated in 2013.2 thelial wall or to each other. Endothelial activation leads to
Furthermore, the same report shows an increase in mortality exposure of collagen to blood and von Willebrand factor. Plate-
as a result of such events in this decade when compared with let surface glycoprotein receptors [glycoprotein (GP) IbV
the previous one. Physicians are encountering patients who IXa, GP Ia/IIa and IV] interact with these components and
are older and sicker than previously, and anaesthesiologists promote platelet adherence to the vascular subendothelium
frequently encounter patients on medications affecting plate- and subsequent activation. The activated platelet undergoes
let function in the perioperative period. Understanding the conformational changes that result in degranulation of
indications, pharmacokinetics and pharmacodynamics of dense and alpha vesicles with the release of adenosine diphos-
these agents allows physicians to anticipate and address pos- phate (ADP), thromboxane A2 (TxA2), and thrombin. These
sible undesired effects of continuing or discontinuing antipla- platelet-activating substances lead to a conformational
telet agents within this time frame.3 change in the GP IIb/IIIa receptor and its expression on the
platelet membrane. Its surface expression leads to binding of
Role of the activated platelet in coagulation other platelets through fibrinogen bridges. Subsequent to the
Atherothrombosis, a systemic disseminated process affecting release of platelet products (i.e. thrombin, platelet activating
the entire vascular tree, represents the underlying aetiology factor, ADP, TxA2), neighbouring platelet activation and recruit-
for both coronary and cerebral thrombotic events. However, ment occurs, rapidly forming a platelet aggregate. This inter-
the substrate for thrombus formation is atherosclerosis. Plate- acts with fibrin and thrombin and promotes thrombus
let activation represents the key step in the thrombotic pro- formation.6 Moreover, activation of ADP receptors severely
cess. The activated platelet plays not only an important role blunts the antiaggregant and vasodilatory effects of nitric
in the initiation and progression of atherosclerotic disease, oxide and prostaglandin (PG) I2, to which inactive platelets
but also has a quintessential role in the development of are constantly exposed.7

& The Author [2013]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
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BJA Oprea and Popescu

The role of the platelet in the coagulation cascade was antiplatelet agent targeting TXA2 formation, newer drugs
defined more recently. Thrombin is generated through activa- protect against thrombosis by interfering with GP IIb/IIIa and
tion of factor VII by phosphate released from the dense gran- ADP receptors10 (Fig. 1). In addition, newer agents targeting
ules. Moreover, the activated platelet provides the necessary pathways responsible for thrombin formation (direct thrombin
surface for activation of other clotting factors and further pro- inhibitors or factor Xa inhibitors) are being investigated as po-
motes thrombus formation. In the inactive state, phosphatidyl- tential adjuncts to antiplatelet drugs.11
serine is present on the inner layer of the platelet membrane. This review focuses on both old and novel antiplatelet drugs,
Subsequent platelet stimulation results in its exposure on the including their pharmacology, indications, and possible peri-
outer layer, thus interacting with the factor VaXa complex operative management strategies.
and ultimately leading to thrombin formation.8

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Additionally, proinflammatory effects of platelets have Specific drugs
received attention lately as critical steps in the initiation of ath-
erosclerosis. Activated platelets release bioactive substances Aspirin
into the local microenvironment, which modify the adhesive Pharmacology
and chemotactic properties of endothelial cells. Increased ASA is an anti-inflammatory and antiplatelet agent whose
chemotaxis enables monocytes and other leucocytes to effect is mediated through irreversible inhibition of cyclooxy-
adhere and transmigrate through the endothelium to inflam- genase 1 and 2 (COX1 and COX2). Its antithrombotic effect is
matory sites.9 primarily due to the inhibition of COX1, which is responsible
Owing to both the key role of platelets in thrombus forma- for inhibiting PGH2 formation from arachidonic acid. PGH2 is
tion and their activation via multiple receptors (ADP, GP IIb/ the precursor for TxA2 formation by platelets (platelet aggre-
IIIa) and pathways (thromboxane formation), a variety of gant and vascular vasoconstrictor), and PGI2 by endothelial
agents targeting different steps in this process have been cells (vascular vasodilator and antithrombotic).12 The doses
developed. While aspirin (ASA) is a well-established required for its anti-inflammatory effects (mediated by COX2

ADP receptor antagonists:

Thrombin Ticlopidine
ADP Prasugrel
TxA Ticagrelor
P2 ADP Cangrelor
abg Y
g b g
a b

Thrombin a ADP

TxA2 b g

signalling ADP
GPIIb/IIIa inhibitors:
Thromboxane abciximab
synthesis inhibitor: eptifibatide
aspirin Platelet tirofiban
GP la/IIa

Fig 1 Therapies targeted at inhibiting various platelet receptors. These include the thromboxane inhibitors, ADP receptor antagonists, and GPIIb/
IIIa inhibitors. Adapted from Meadows and Bhatt,4 with permission. TxA2, thromboxane A2; GP Ia/IIa, glycoprotein Ia/IIa; GP VI, glycoprotein VI; GP
Ib-IX-V, glycoprotein Ib-IX-V; ADP, adenosine diphosphate; GP IIb/IIIa, glycoprotein IIb/IIIa.

Perioperative management of antiplatelet therapy BJA
inhibition) are much higher than the ones required for its anti- primary percutaneous coronary intervention (PCI) or
platelet effect (75 150 mg day21). Doses as low as 2040 mg thrombolysis and continued indefinitely (class I).27 28 This
of ASA a day can inhibit TxA2 formation in healthy volunteers strategy leads to overall reduced mortality. For the PCI
for up to 1 week, with no antithrombotic benefit noted in patient population, ASA significantly reduces early and late
patients receiving doses more than 1500 mg day21.13 stent thrombosis (ST) rates.29 30 As part of a dual antiplatelet
ASA is rapidly absorbed through the enteric mucosa, with therapy (DAPT) regimen, ASA doses of 75 100 mg daily are
peak plasma level attained within 3040 min for regular pre- considered as effective as higher doses in reducing major
parations and a half-life of 20 min14 (Table 1). While antiplatelet adverse cardiac events (MACE) but are associated with less
effects can usually be detected within an hour, enteric-coated bleeding.31 32 After coronary artery bypass grafting (CABG)
preparations slow the rate of absorption that can lead to sub- surgery, ASA decreases saphenous venous graft occlusion and
optimal antiplatelet effects in obese patients.15 19 The irrevers- significantly decreases in-hospital mortality, MI, stroke, and

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ible inhibition of COX1 maintains the antithrombotic effects of renal failure rates.33 34
ASA for the lifespan of the platelet (710 days), with slow recov-
eryof overall platelet function of 10% per day due to new platelet Cerebrovascular disease
formation. While it is unclear if there is benefit derived from ASA therapy
for primary prevention of stroke, earlier data showed a 25% re-
Indications and efficacy duction in recurrent cerebrovascular ischaemic events when
used for secondary prevention.35 36 The indications for ASA
Coronary artery disease therapy for secondary prevention of stroke are the same as dis-
Primary prevention. In several trials, ASA therapy in doses of
cussed in detail above. In patients undergoing carotid endarter-
75325 mg daily demonstrated a 3644% reduction in the
ectomy, current guidelines recommend ASA 81325 mg before
rates of subsequent myocardial infarction (MI) with no
the procedure and continued indefinitely if no contraindications
increase in mortality. Newer data are not as convincing for
the use of ASA in primary prevention.20 23 The United States
Preventive Services Task Force recommends ASA 75 mg daily Atrial fibrillation
in patients ,80 yr of age and in whom the cardiovascular Compared with warfarin, ASA is less effective in preventing
benefit is greater than the risk of gastrointestinal (GI) bleeding.24 stroke in patients with non-valvular atrial fibrillation (AF), but
ASA 81 mg daily or 100 mg every other day is recommended can be considered an option in patients who cannot receive
in women at high risk of cardiovascular disease or women anticoagulation.17
65 yr of age with a similar risk/benefit profile.25
Secondary prevention. Patients with stable or unstable angina Risks
receiving ASA 751200 mg daily derive a survival benefit up to In a review including 22 trials, low-dose ASA (75 325 mg daily)
1 yr.26 For patients with acute coronary syndromes (ACS), increased the risk of major GI and intracranial bleeding up
current guidelines recommend ASA 162325 mg given before to two times compared with placebo.38 A meta-analysis of 16

Table 1 Major characteristics of traditional and newer antiplatelet medications

Drug Mechanism of action Loading Maintenance Half-life Time to recover Platelet Administration
dose dose platelet function inhibition route
after drug withdrawal
Aspirin COX-1 inhibition 325 mg 75 325 mg 15 20 30% at 48 h Irreversible Oral
daily min inhibition
Clopidogrel P2Y12 receptor inhibition 300 600 75 mg daily 7 9 h 40% at 3 days Irreversible Oral
mg inhibition
Prasugrel P2Y12 receptor inhibition 60 mg 10 mg daily 7h 2 3 days Irreversible Oral
Ticagrelor P2Y12 and (partly) P2Y1 180 mg 90 mg twice a 7 9 h 57% at 24 h Reversible Oral
receptor inhibition day inhibition
Cangrelor Adenosine triphosphate 30 mg 2 4 mg kg21 3 6 min Rapid (minutes to Reversible I.V.
analogue with a high affinity kg21 min21 hours) inhibition
for the P2Y12 receptor
Abciximab Glycoprotein IIb/IIIa 0.25 mg 0.125 mg kg21 10 15 12 h Reversible I.V.
receptor inhibitor kg21 min21 min inhibition
Eptifibatide Glycoprotein IIb/IIIa 180 mg 2 mg kg21 2.5 h 2 4 h Reversible I.V.
receptor inhibitor kg21 min21 inhibition
Tirofiban Glycoprotein IIb/IIIa 0.4 mg 0.1 mg kg21 2h 2 4 h Reversible I.V.
receptor inhibitor kg21 min21 inhibition

BJA Oprea and Popescu

trials demonstrated that ASA therapy increases the rate of recommended loading dose is 180 mg, with 90 mg twice a
haemorrhagic stroke, despite decreasing ischaemic stroke, day recommended for maintenance.50 51
total stroke, and MI.39 Unlike clopidogrel, ticagrelors effect is independent of
A study including patients undergoing intermediate/high- genetic polymorphism, making it less prone to response vari-
risk non-cardiac procedures found that patients taking ASA ability. It also has a better safety profile than prasugrel.
have no significant difference in bleeding events compared These two considerations, including its efficacy, led to ticagre-
with those in whom ASA was stopped.40 However, cardiac lor virtually replacing clopidogrel as the preferred ADP receptor
surgery patients on ASA have an increased risk for post- antagonist in patients with ACS.52
operative bleeding (as measured by chest tube drainage) Cangrelor is an i.v., direct-acting, reversible ADP antagonist
that does not require reoperation.41 currently in development. It has a fast onset of action, and in-
While ASA is prescribed routinely in doses up to 325 mg fusion rates of 24 mg kg21 min21 result in 80% IPA. Its major

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daily, newer evidence does not support this practice. Doses of advantage is its short half-life (2.6 min). Cangrelor clearance
7581 mg daily have a similar efficacy as higher doses with a is not affected by renal disease. Platelet function recovers
decreased risk of GI bleeding.42 within 5 min of infusion discontinuation.53

Indications and efficacy

ADP receptor inhibitors
Coronary artery disease
The ADP receptor blockers inhibit platelet aggregation by pre- Patients with ACS. The 2011 European Society of Cardiology
venting the binding of ADP to its specific platelet receptor. Guidelines for the Management of Acute Coronary Syndrome
While the first ADP receptor blocker, ticlopidine, is rarely used recommend ticagrelor as first-line therapy in patients at
now, due to side-effects such as thrombocytopenia, newer moderate-to-high risk of ischaemic events irrespective of
agents (clopidogrel, prasugrel, and ticagrelor) are routinely initial treatment strategy (level of evidence IB). However, in
prescribed as part of a DAPT regimen in patients with ADP-inhibitor-naive patients (especially diabetics) undergoing
ischaemic heart disease. Cangrelor, an investigational ADP re- PCI, prasugrel is the recommended drug of choice (level
ceptor antagonist, is currently in development. of evidence IB). Clopidogrel is reserved only for patients
with contraindications to prasugrel or ticagrelor (level of
evidence IA).54
Clopidogrel is a thienopyridine that requires conversion to an Current American guidelines recommend clopidogrel or
active metabolite that irreversibly binds the ADP receptor. It ticagrelor upon presentation in patients with unstable angina
is usually recommended in doses of 150 600 mg for loading and non-ST-elevation MI (NSTEMI) in whom medical manage-
and 75 mg daily for maintenance. Clopidogrel is eliminated ment is chosen. For patients presenting with ACS and undergo-
both in faeces and urine. The dose does not have to be adjusted ing PCI with stenting, a loading dose of ADP receptor inhibitor
for patients with moderate renal and hepatic disease.43 44 At should be administered, followed by a maintenance daily
regular doses (75 mg daily), clopidogrel achieves a peak dose for at least 1 yr.27 Current evidence strongly suggests
plasma level 2 h after oral ingestion and a plateau of inhibition that the use of ADP receptor inhibitors in the management of
of platelet aggregation (IPA) of 4060% after 37 days.3 ST-elevation MI (STEMI), treated with or without fibrinolytic
Similar to clopidogrel, prasugrel is a newer thienopyridine therapy, improves outcomes.28
prodrug that irreversibly inhibits the ADP receptor for the life-
Patients undergoing PCI not for ACS. The 2011 ACCF/AHA/
span of the platelet (Table 1). Prasugrels active metabolite
Society for Cardiovascular Angiography and Interventions
reaches a peak plasma concentration in 30 min, and has a
Guideline for Percutaneous Coronary Intervention recommend a
7 h elimination half-life.3 As with clopidogrel, dose adjustment
pre-procedure loading dose of an ADP-receptor inhibitor in
is not required for moderate hepatic or renal impairment.45 46
patients undergoing PCI with stenting. In patients receiving
The maximum IPA (7585%) occurs 24 h after a loading
drug-eluting stents (DES) who are not at high risk of bleeding,
dose. Prasugrel is more effective and faster than clopidogrel in
DAPT should be maintained for at least 1 yr. Similarly, in patients
achieving platelet inhibition.47 48 The recommended dose of pra-
receiving bare metal stents (BMS), DAPT should be maintained for
sugrel is 60 mg for loading and 10 mg daily for maintenance.
at least 1 month and ideally up to 12 months. However, newer
Owing to the higher risk of bleeding incurred with prasugrel,
guidelines from the American College of Chest Physicians and
the FDA recommends that smaller doses be used in patients
European Society of Cardiology recommend 4 6 weeks of
75 yr of age, weighing ,60 kg, or with a previous history of
DAPT for patients with BMS and 6 months for patients with
stroke or transient ischaemic attacks (TIAs).47
DES at low risk of ST.55 56 In patients with increased risk of ST,
Ticagrelor is a non-thienopyridine, reversible, non-competitive
a thorough risk benefit analysis of maintaining DAPT for
antagonist of the ADP receptor. Compared with clopidogrel and
more than 12 months should be performed.57
prasugrel, it has a more rapid onset of action and is more
potent, achieving 80% IPA at 2 h after oral ingestion.49 Ticagre- Peripheral arterial disease
lor is eliminated in the faeces. Unlike its predecessors, it needs a Current guidelines recommend clopidogrel as an alternative to
dose adjustment in patients with liver dysfunction, but not with ASA therapy as secondary prevention in patients undergoing
renal disease.50 Ticagrelor has a half-life of 78.5 h. The lower-extremity revascularization or amputation.58

Perioperative management of antiplatelet therapy BJA
Carotid and vertebral artery disease intracranial bleeding compared with clopidogrel.66 Compared
The most recent guidelines recommend clopidogrel for a with ticagrelor, clopidogrel is safer with regard to GI-related
period of 36 months in patients with carotid or vertebral risks, including fewer overall and spontaneous GI bleeding
artery dissection associated with TIA or stroke.37 Patients events, but data regarding prasugrel are inconclusive.79
with a history of an ischaemic cerebrovascular accident and Cangrelor was not associated with increased risk of serious
presenting with extracranial carotid or vertebral atheroscler- bleeding.80
osis should receive either clopidogrel monotherapy or ASA
and extended-release dipyridamole.59 Glycoprotein IIb/IIIa receptor inhibitors
Patients who have undergone carotid endarterectomy
Glycoprotein IIb/IIIa inhibitors antagonize platelet function by
should receive therapy with ASA (75 325 mg daily) or clopido-
inhibiting cross-linking of platelets and subsequent aggrega-
grel for long-term prophylaxis against ischaemic stroke. In

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tion. Abxicimab, eptifibatide, and tirofiban have been approved
patients undergoing carotid stenting, DAPT is recommended
by the US FDA to be used as adjuncts for patients with ACS or
for 30 days before and after the procedure.37
undergoing PCI.81
Atrial fibrillation
The 2011 ACCF/AHA/Heart Rhythm Society Focused Update on Pharmacology
the Management of Patients with Atrial Fibrillation recom- Abxicimab rapidly binds to platelets, achieving almost immedi-
mends the use of ADP receptor inhibitors in situations where ate 80% IPAwhen given as a bolus dose of 0.25 mg kg21 or as an
warfarin therapy is contraindicated (class IIb).60 infusion of 0.125 mg kg21 min21. Most of the drug binds to pla-
telets and is not excreted in the urine. Its metabolism appears
The CURE trial established that combination therapy with ASA to correlate with platelet degradation.82 Consequently, throm-
and clopidogrel is superior to ASA alone by significantly redu- bocytosis requires increased dosing of the drug. Since very little
cing the rate of MACE in patients with ACS.61 Similar results drug is available in the blood, its effects can be rapidly reversed
were demonstrated in patients undergoing PCI.62 64 The by platelet transfusion.83 Abciximab has a plasma half-life of
newly developed oral antiplatelet agents, prasugrel and tica- 10 min and platelet function recovers over 48 h, although inhib-
grelor, were identified to be superior to clopidogrel when ition of platelet GP IIb/IIIa receptors can be documented up to
used in combination with ASA in reducing the risk of MACE in 15 days after drug discontinuation.84
patients with ACS undergoing PCI.65 69 The efficacy of cangre- Eptifibatide given as a single 180 mg kg21 min21 bolus and
lor is still a subject of debate and thus this drug has not yet 2 mg kg21 min21 infusion produces rapid and sustained high-
received FDA approval. Initially, cangrelor was not found to grade IPA (80% within 15 min). It is renally excreted (75%)
be superior to clopidogrel when treating patients with ACS and, unlike abciximab, there is unbound drug available in the
undergoing PCI.70 71 However, more recent studies show that plasma.82 Therefore, platelet transfusions are unlikely to
cangrelor significantly reduces the rate of ischaemic events, in- reverse its antiplatelet effects since circulating drug would
cluding ST, in patients undergoing PCI, with no significant in- most likely rapidly inhibit newly transfused platelets. Thus
crease in severe bleeding.72 73 reversal relies primarily on stopping the medication, requiring
4 h to achieve 50% of normal platelet aggregation.85
Risks Tirofiban has an onset of action within 5 min after the initi-
Bleeding is the most significant side-effect associated with ation of infusion. The ACS dosage of tirofiban includes a 30 min
ADP receptor-blocker therapy. When compared with patients loading dose of 0.4 mg kg21 min21 followed by an infusion of
receiving ASA therapy alone for ACS, patients receiving DAPT 0.10.15 mg kg21 min21. Return of platelet aggregation to
with clopidogrel and ASA had an increase in major, minor, .80% of pre-treatment value occurs at 4 h after stopping
and GI bleeding. However, no increase in the incidence of drug infusion. Tirofiban has a plasma half-life of 1.5 2 h. It is
fatal bleeding was noted.61 A high loading dose of clopidogrel removed by both renal and biliary excretion. Patients with
(600 mg) leads to increased rates of major bleeding events renal insufficiency require dose adjustment of tirofiban86
when compared with doses of 300 mg.74 (Table 1).
A large meta-analysis concluded that patients receiving clo- The main difference between abciximab and the smaller
pidogrel within 7 days before CABG had a higher risk of major molecules tirofiban and eptifibatide is the rate at which they
bleeding and related complications (reoperation and transfu- dissociate from GP IIb/IIIa receptors (hours for abciximab vs
sions).75 In patients with ACS, prasugrel was found to have a seconds for tirofiban and eptifibatate). In addition, the lower
higher incidence of major, life-threatening, and fatal bleeding affinity of eptifibatide for GP IIb/IIIa receptors compared
when compared with clopidogrel.76 Despite increased chest with tirofiban means that a greater concentration of the
tube drainage after CABG, patients on prasugrel did not former is required to achieve the same degree of IPA.87
require more red blood cell transfusions compared with clopi-
dogrel.77 Maintenance with prasugrel is frequently associated Indications and efficacy
with minor or minimal bleeding, but major bleeding is rare.78 The 2012 ACCF/AHA Focused Update of the Guideline for
Ticagrelor was associated with a higher rate of major bleed- the Management of Patients with Unstable Angina/Non-ST-
ing unrelated to CABG surgery including higher rates of fatal Elevation Myocardial Infarction recommend the use of i.v. GP

BJA Oprea and Popescu

IIb/IIIa inhibitors in combination with ASA and heparin, both in is the inherent bleeding risk of certain procedures and the
patients treated medically and interventionally.27 88 The 2013 impact of bleeding on overall patient outcome (Table 2).
ACCF/AHA Guideline for the Management of ST-Elevation Based on the role of platelets in the coagulation cascade,
Myocardial Infarction recommends, as a reasonable approach, various point-of-care testing devices have been developed.
initiation of therapy with heparin and an i.v. GP IIb/IIIa receptor However, there are differences in the sensitivity of these tests
antagonist such as abciximab (Level of Evidence: A), high-bolus- in assessing recovery of platelet function after discontinuation
dose tirofiban (Level of Evidence: B), or double-bolus eptifibatide of ADP receptor inhibitors and significant interindividual variabil-
(Level of Evidence: B) at the time of PCI.28 ity in results. Therefore, the role of these tests in strategies for
Many studies have evaluated the efficacy of i.v. GP IIb/IIIa perioperative management of antiplatelet agents is evolving.94
inhibitors in ACS. A meta-analysis involving 21 trials concluded
that GP IIb/IIIa inhibitors significantly reduce the combined Aspirin

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endpoint of death, non-fatal MI, or urgent revascularization In patients on ASA for AF or for primary prevention of MI and
at 30 days in patients undergoing PCI. Similar outcomes were stroke, the drug can be stopped 710 days before operation
identified in patients with medically treated NSTEMI and in without major consequences. In patients on ASA for secondary
patients with STEMI treated with angioplasty.89 prevention, discontinuation is associated with increased risk of
cardiovascular complications [odds ratio (OR) 3.1], peaking
at 810 days for coronary thrombosis and 14 days for cerebro-
The rates of bleeding encountered with GP IIb/IIIa inhibitor vascular events.95 For patients who have undergone PCI with
therapy have been higher than those seen with placebo.90 stenting, the likelihood of ST is much higher (OR 90) when
A pooled analysis of 14 randomized studies including a total ASA is discontinued.95 97
of 28 000 patients treated with heparin and a GP IIb/IIIa inhibi- Bleeding risk has been assessed in a meta-analysis involving
tor or placebo found that the incidence of intracerebral haem- 49 590 patients on low-dose ASA, with results ranging from
orrhage was similar between the two groups. Moreover, no very little bleeding for dermatological, ophthalmological, vis-
difference was identified when treatment with a GP IIb/IIIa in- ceral, minor abdominal, endoscopic, dialysis catheter insertions,
hibitor alone was compared with heparin alone.91 and minor dental procedures to 75% in patients undergoing
transurethral prostate biopsy. A large trial on patients undergo-
Perioperative management of antiplatelet agents ing orthopaedic surgery (hip replacement) reported an increase
Perioperative management of antiplatelet agents is complex, in GI bleeding and a decrease in postoperative haemoglobin
so the team of perioperative clinicians (anaesthesiologist, (average of 2 g litre21), and also an increased need for blood
surgeon, and prescribing physicianeither neurologist or transfusions (53 ml on average). Despite that, there was no in-
cardiologist) should participate in decision-making. Several crease in mortality.98 Orthopaedic patients undergoing spinal
factors need to be considered before a decision to continue fusion or femoral neck fractures had no increase in bleed-
or stop antiplatelet agents perioperatively. An important ing.99 101 Patients undergoing tonsillectomy have a 7.2-fold in-
factor is the initial indication for antiplatelet therapy and, crease in rates of reoperation for haematomata compared with
most importantly, the consequences of stopping the drug those not on ASA.102 Vascular surgery patients have a small in-
before the operation. Premature discontinuation of antiplate- crease in bleeding complications.103 Newer studies, in high-risk
let agents including GP IIb/IIIa inhibitors is associated with patients on low-dose ASA undergoing non-cardiac surgery,
an increase in thrombotic events due to a rebound effect on show a decrease in MACE, but no overall increase in bleeding
platelet activation.92 93 The other important factor to consider complications.40 104 105

Table 2 Bleeding risk in non-cardiac surgery

Surgical haemorrhagic risk Blood transfusion requirement Type of surgery

Low Usually not required Peripheral, plastic, and general surgery biopsies
Minor orthopaedic, otolaryngology, and general surgery
Eye anterior chamber
Dental extraction and surgery
Intermediate Frequently required Visceral surgery
Cardiovascular surgery
Major orthopaedic surgery
Urological surgery
Reconstructive surgery
High Possible bleeding in a closed space Intracranial neurosurgery
Spinal canal surgery
Eye posterior chamber surgery

Perioperative management of antiplatelet therapy BJA
In patients undergoing cardiac surgery, preoperative ASA or cerebrovascular events, these agents can be stopped before
administration increases postoperative bleeding and red blood operation without major consequences.47 On the other hand,
cell requirements with no effect on mortality, re-exploration ADP receptor inhibitors are a major component of the DAPT
rate, and perioperative MI.106 A new meta-analysis concluded recommended pre- and post-PCI with stenting. Several aspects
that ASA was associated with increased chest tube drainage in need to be considered in patients with stents undergoing
this patient population and might be associated with a greater re- surgery: the appropriate time frame after stent placement
quirement for blood products.41 Patients on ASA have a 2.7-fold before surgery can be safely performed, the potential conse-
increase in blood transfusion rates during transurethral prostatec- quences of stopping DAPT, the urgency of the intervention, and
tomy compared with placebo.107 In neurosurgical procedures, the bleeding risk associated with the intervention.110
ASA use has led to increased mortality.102 108
In conclusion, with the exception of high-risk bleeding proce- Recommended duration of DAPT after PCI

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dures (intracranial and medullary canal surgery, posterior Many studies have revealed that premature discontinuation of
chamber of the eye surgery, and transurethral prostate resec- DAPT before the recommended interval necessary for com-
tion), ASA continuation perioperatively is not associated with plete endothelialization of the stent can lead to fatal conse-
significant bleeding events or with increased mortality.47 99 109 quences.111 Studies in DES patients demonstrated that
Therefore, the 2012 ACCP guidelines on Perioperative Manage- premature discontinuation of clopidogrel was the most import-
ment of Antithrombotic Therapy recommend continuing ASA ant factor leading to early ST (hazard ratio of 57) and fatal out-
in the perioperative period for patients at high cardiovascular comes (mortality 45% for patients developing ST).112 Late ST
risk55 (Fig. 2). has also been linked to discontinuation of clopidogrel after
1 yr of DAPT.113
ADP receptor inhibitors The perioperative period is marked by a prothrombotic
As with ASA, when the ADP receptor inhibitors are recom- state due to increased levels of circulating fibrinogen and
mended for treatment of AF or primary prevention of cardiac C-reactive protein.114 115 This hypercoagulable state leads to

ASA ASA+ADP inhibitors

High-risk situations
<2 weeks PTCA Low-risk situations
Primary Secondary
<6 weeks MI
prevention prevention
<6 weeks BMS
<6 months DES
<12 months DES
with increased risk
High risk of bleeding All other surgeries of ST

Emergency Urgent Elective

Delay surgery
surgery surgery surgery

Low risk of High risk of Intermediate risk of

bleeding bleeding bleeding

Stop ADP
Stop ADP inhibitors
Stop ASA for inhibitors and
Continue treatment continue ASA
710 days ASA


Fig 2 Algorithm for perioperative management of antiplatelet therapy. Adapted from Di Minno and colleagues,99 with permission. ADP, adenosine
diphosphate; ASA, aspirin; PTCA, percutaneous transluminal coronary angioplasty; BMS, bare metal stent; DES, drug-eluting stent; MI, myocardial
infarction; ST, stent thrombosis.

BJA Oprea and Popescu

increased atheromatous plaque instability, which, in associ- diabetes mellitus.119 129 Newer data suggest that for low-risk
ation with premature discontinuation of the ADP receptor in- patients undergoing low- to intermediate-risk procedures, a
hibitor, can have dire consequences (mortality varying from delay of surgery for 6 months after DES placement might be
30% to 86%).116 117 These effects are augmented by an ADP re- sufficient. However, in high-risk patients, it might be prudent
ceptor inhibitor discontinuation rebound phenomenon, clearly to wait 12 months after DES implantation before proceeding
demonstrated for clopidogrel and also well described with with elective procedures.129
ASA cessation, which is responsible for a cluster of thrombotic
The recommended duration for continuing DAPT in patients Management of DAPT in relation to the surgical
receiving PCI varies with different guidelines. While there is no bleeding risk
controversy regarding the minimum duration of DAPT after In patients with coronary stents, in addition to the risk of

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balloon angioplasty only (2 weeks) and after BMS placement MACE, the clinician needs to take into account the bleeding
(46 weeks), the optimal duration after DES placement is risk incurred in the perioperative period.102 Patients undergo-
uncertian.30 119 The 2007 ACC/AHA Guidelines on Perioperative ing low bleeding risk procedures (endoscopy, dental extraction,
Cardiovascular Evaluation and Care for Noncardiac surgery rec- plastics procedures, minor orthopaedic, vitroretinal, and minor
ommend a minimum of 12 months of uninterrupted DAPTafter general surgeries) can proceed without DAPT discontinu-
DES placement, whereas the 2010 ESC guidelines on myocar- ation.47 130 135
dial revascularization and the 2012 ACCP guidelines on peri- The complication rate varies in intermediate bleeding risk pro-
operative management of antithrombotic therapy endorse a cedures in patients on DAPT with ASA and clopidogrel. Severe
minimum of 6 months.55 56 119 Initial data showed that discon- complications are eight times more likely after Mohs procedures
tinuation of clopidogrel 6 months after placement of a DES is in patients on DAPT than in control subjects taking ASA mono-
associated with a 23 times higher incidence of late ST com- therapy.136 A study of 647 patients undergoing vascular
pared with patients receiving BMS.120 121 However, more recent surgery and receiving DAPT with clopidogrel and ASA up to the
literature suggests that prolonging DAPT for a period longer day of surgery concluded that maintenance of DAPT is not asso-
than 12 months in DES patients is not significantly more effective ciated with increased bleeding complications or transfusion
than ASA monotherapy in reducing the rate of MACE.122 requirements. Prior data had reported increased hematomata
The question of 6 or 12 months of DAPTafter DES placement associated with carotid endarterectomy.137 138 Another registry
was recently addressed in several trials. A prospective trial of 10 406 patients undergoing vascular procedures (carotid end-
involving 1443 DES patients receiving either 6 or 12 months arterectomy, lower extremity bypass, endovascular aneurysm
of DAPT showed that the risk of target vessel failure at repair, or open abdominal aortic aneurysm repair) found that
12 months is similar.123 Another randomized trial including bleeding, transfusion requirements, and reoperation rates for
2013 patients with BMS and DES demonstrated that a bleeding were similar among the four patient groups based on
regimen of 24 months compared with 6 months of clopidogrel an antiplatelet regimen (ASA vs ASA plus clopidogrel vs clopido-
therapy was not more effective in reducing the composite end- grel vs no antiplatelet therapy). The average transfusion require-
point of death due to any cause, MI, or stroke.124 Newer data ment was 500700 ml in all groups.139
evaluate the safety of discontinuing DAPT after 3 months Patients undergoing thoracic surgery do not seem to experi-
after placement of a zotarolimus-eluting stent (second- ence increased bleeding while on clopidogrel, but the incidence
generation DES). In a randomized study of 2117 patients, 3 of perioperative MI is significantly higher among patients with
months of DAPT were non-inferior compared with the standard stents discontinuing DAPT in the perioperative period.140 142
12 months therapy in the occurrence of the primary endpoint Retrospective data from patients undergoing major lung resec-
at 1 yr (cardiovascular death, MI, ST, target vessel revasculari- tion while on clopidogrel showed no differences in transfusion
zation, or bleeding).125 This was confirmed in a smaller study of requirements, reoperations for bleeding, or MACE compared with
128 patients.126 patients who stopped clopidogrel.143 Similarly, more recent data
While the above data were obtained outside the peri- from a study of 165 patients undergoing 182 general thoracic
procedural area, similar outcomes have also been recorded surgery procedures while on DAPT showed that these patients
perioperatively.127 A population cohort study of 8000 patients exhibited an increased rate of transfusion with no increase in
undergoing major elective procedures who had BMS or DES mortality compared with patients off DAPT.144
placed up to 10 yr prior concluded that the fewest complica- Patients on DAPT undergoing orthopaedic surgery (especial-
tions occurred when the patient underwent surgery between ly patients undergoing hip and knee replacement) have an in-
6 months and 1 yr after DES placement.128 crease in bleeding complications and increased risk of
As a result, it is still unclear what is the optimal duration of transfusion in the operating theatre or in the first 24 h after op-
DAPTand timing of surgery. The key to these questions is the in- eration.145 Another study concluded that stopping clopidogrel
dividual risk for delayed stent endothelialization. Several clinic- 5 days before operation might decrease the risk of complica-
al predictors for delayed endothelialization and thrombosis of tions, although mortality is not influenced.146 These findings
DES have been identified: presence of ACS, treatment of bifur- are in contrast with data from patients undergoing hip fracture
cating lesions, presence of multiple and overlapping stents, left surgeries, who demonstrate no increase in transfusion require-
ventricular ejection fraction ,30%, renal insufficiency, and ments when taking clopidogrel.147 148

Perioperative management of antiplatelet therapy BJA
Urological surgery, with the exception of transurethral at high risk of cardiovascular complications undergoing elect-
resection of prostate, can be safely performed while on ive surgeries, the procedure should be postponed until the
DAPT.149 151 However, customary practice among urologists required period of DAPT has been fulfilled.
is to stop DAPT before cystoprostatectomy or nephrectomy In urgent cases that cannot be postponed until the recom-
due to concerns of increased bleeding.152 mended period of DAPT has been completed, different thera-
In patients undergoing intra-abdominal surgery, data peutic strategies have been proposed. If the bleeding risk is
suggest that these operations can be safely performed while low, the surgical procedure can be performed while the
continuing DAPT.153 patient continues DAPT. If the bleeding risk is intermediate,
A comprehensive meta-analysis including 99 randomized, the ADP inhibitor should be discontinued before operation
double-blind, placebo-controlled trials, prospective obser- and ASA continued. When patients at high risk of cardiovascu-
vational studies, review articles, and clinical registry data lar events undergo procedures with a high risk of bleeding,

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reported a 10% risk of vascular events after premature with- DAPT needs to be discontinued. Consideration should be
drawal of DAPT due to the life-threatening risk of ST. The given to replacing DAPT with a short-acting agent whose
study concluded that clopidogrel cannot be stopped in those effect on platelet function rapidly dissipates upon discontinu-
patients with a recently implanted DES.154 ation, known as bridging therapy (Fig. 2).
As noted above, all available evidence to date addresses
patients undergoing non-cardiac procedures while on DAPT
with ASA and clopidogrel. Perioperative data for patients on Bridging therapy
prasugrel and ticagrelor are lacking, probably due to their Bridging therapy with unfractionated or low molecular weight
recent availability on the market. heparin, similar to what is recommended for patients on war-
On the other hand, for patients on DAPT undergoing cardiac farin, has been considered. However, heparin has relatively
surgery, available evidence suggests that increased bleeding minor effects on platelets, and thus does not prevent a throm-
occurs if the ADP inhibitor is continued before operation. There- botic event.157 Therefore, despite being recommended as an
fore, current guidelines recommend stopping the ADP receptor alternative therapy by several societies, it does not seem to
inhibitor 5 days prior for clopidogrel and ticagrelor and 7 days be an appropriate choice.157
prior for prasugrel.55 56 155 Similar to ASA, patients at high risk Alternatively, bridging with short-acting GP IIb/IIIa inhibi-
of bleeding should have their DAPT therapy stopped before op- tors (tirofiban and eptifibatide) can be considered. While avail-
eration, if an appropriate amount of time has passed after able data are scarce and the ACC/AHA guidelines do not
stent insertion.110 mention bridging with GP IIb/IIIa inhibitors, the Society of
Thoracic Surgeons, ESC and Australia/ New Zealand guidelines
recommend such an approach in patients at high risk of cardio-
Management of DAPT in relation to the urgency of the vascular events.56 110 158 159 Several case reports and series
surgical procedure have described bridging therapy, and reported no increase in
While it is advisable to wait at least 46 weeks after BMS place- thrombotic or haemorrhagic events.160 163 Other studies on
ment and 612 months after DES placement, the urgency of patients undergoing non-cardiac surgery showed adequate
certain procedures sometimes takes priority. In emergent pro- protection against ST (at 30 days) with no cases of death or
cedures, there is not sufficient time to discontinue DAPT. Plate- MI and no increase in reoperation for bleeding.164 165
let transfusion can be given to counteract the effect of the However, a study of 67 patients who underwent non-cardiac
antiplatelet agents. Despite the theoretical efficacy of such a or cardiac surgery after DES implantation with preoperative
measure, newer evidence from the trauma literature suggests bridging with a GP IIb/IIIa inhibitor showed that ST can still
that platelet transfusions reverse the effect of ASA on throm- occur.166
bocytes but not that of clopidogrel.156 This can be explained The bridging protocols require discontinuing clopidogrel 5
by the plasma half-life of each drug. ASA has a short half-life days before the surgical procedure. Patients are started on an
and therefore has a low likelihood of affecting the transfused i.v. infusion of either tirofiban (0.4 mg kg21 bolus followed
platelets even if the drug was ingested within an hour of the by a maintenance infusion of 0.1 mg kg21 min21) or
surgical procedure. On the other hand, clopidogrel has a half- eptifibatide (2 mg kg21 min21). Tirofiban is stopped 36 h
life of 79 h so if the transfusion is administered within that and eptifibatide 412 h before the planned procedure.167 For
time frame, the new platelets will be affected by the available patients undergoing cardiac surgery, a small study of 19
circulating drug. Moreover, platelet transfusions can put the patients on bridging therapy with GP IIb/IIIa antagonists
patient at risk for ST. Therefore, the clinician should perform a reported increased incidence of bleeding during revasculariza-
risk benefit analysis before making this decision. tion surgery but no increase in ST.168
In patients at low risk of cardiovascular complications Another drug that appears useful as a bridging agent is can-
undergoing surgeries of low or intermediate bleeding risk grelor, studied in a prospective, randomized, double-blind,
(urgent or elective), ASA should be continued while discontinu- placebo-controlled, multicentre (BRIDGE) trial. While the trial
ing the ADP inhibitor. If the same patient population is under- was not powered to assess for MACE, it showed promising
going surgeries of high bleeding risk, then both the ADP results for patients undergoing CABG. These patients did not
inhibitor and ASA should be discontinued (Fig. 2). In patients demonstrate an increased rate of major bleeding before

BJA Oprea and Popescu

CABG surgery, but exhibited more minor postoperative bleed- situations of life-threatening bleeding, anaesthesiologists can
ing episodes. Cangrelor is not yet FDA approved.169 consider platelet transfusions. The more challenging cases are
those patients at high risk of cardiovascular events who are
Glycoprotein IIb/IIIa inhibitors undergoing procedures with a high risk of bleeding, and thus
are required to completely stop their antiplatelet medications.
Data for perioperative management of GP IIb/IIIa inhibitors in
In these situations, the perioperative team can consider using
non-cardiac surgery are derived mostly from small case series.
bridging therapies. Each patient has to be stratified according
In patients undergoing emergency or urgent CABG after treat-
to individual thrombotic and surgical bleeding risk. The peri-
ment with a GP IIb/IIIa inhibitor, abciximab was associated
operative team should all participate in the decision-making
with increased risk of haemorrhage and requirement of plate-
process by performing a thorough riskbenefit analysis of stop-
let transfusions if surgery is performed within 12 h of infusion
ping or continuing each type of antiplatelet agent.

Downloaded from at Louisiana State University School of Veterinary Medicine Library on April 2, 2014
discontinuation. Eptifibatide was associated with a similar
risk as placebo, even when surgery was performed within 2 h
of drug cessation. Limited data available for tirofiban show Authors contributions
that bleeding is not increased compared with ASA or A.D.O.: literature search, data collection, and writing up the first
heparin.170 Cessation of eptifibatide 4 h before surgery draft of the manuscript. W.M.P.: revision and editing of the
results in less bleeding and fewer transfusion requirements manuscript.
compared with stopping the infusion 2 h before surgery.171
Intraoperatively, antiplatelet agents represent a particular Declaration of interest
challenge for the anaesthesiologist when regional anaesthetic
None declared.
techniques are considered (see Banzon and colleagues, this
issue). According to the 2010 American Society of Regional An-
esthesia practice advisory on Regional Anesthesia in the
Patient Receiving Antithrombotic or Thrombolytic Therapy The authors received no funding.
and the 2010 Guidelines of the European Society of Anaesthe-
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