You are on page 1of 15

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

doi:10.1093/bja/aet402

CARDIOVASCULAR

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: adriana.oprea@yale.edu

Downloaded from http://bja.oxfordjournals.org/ at Louisiana State University School of Veterinary Medicine Library on April 2, 2014
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.
For Permissions, please email: journals.permissions@oup.com
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

Downloaded from http://bja.oxfordjournals.org/ at Louisiana State University School of Veterinary Medicine Library on April 2, 2014
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:


Clopidogrel
Thrombin Ticlopidine
ADP Prasugrel
2
TxA Ticagrelor
P2 ADP Cangrelor
abg Y
2
a
g b g
a b
P2

Thrombin a ADP
Y1

TxA2 b g

Intracellular
signalling ADP
activation
TxA2
GPIIb/IIIa inhibitors:
Thromboxane abciximab
synthesis inhibitor: eptifibatide
aspirin Platelet tirofiban
GP IIb/IIIa
GP la/IIa
GP VI GP IB-IX-V

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.

i4
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

Downloaded from http://bja.oxfordjournals.org/ at Louisiana State University School of Veterinary Medicine Library on April 2, 2014
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
exist.37
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
inhibition
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

i5
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

Downloaded from http://bja.oxfordjournals.org/ at Louisiana State University School of Veterinary Medicine Library on April 2, 2014
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
Pharmacology
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

i6
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

Downloaded from http://bja.oxfordjournals.org/ at Louisiana State University School of Veterinary Medicine Library on April 2, 2014
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

i7
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

Downloaded from http://bja.oxfordjournals.org/ at Louisiana State University School of Veterinary Medicine Library on April 2, 2014
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
Risks
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
Endoscopy
Eye anterior chamber
Dental extraction and surgery
Intermediate Frequently required Visceral surgery
Cardiovascular surgery
Major orthopaedic surgery
Otolaryngology
Urological surgery
Reconstructive surgery
High Possible bleeding in a closed space Intracranial neurosurgery
Spinal canal surgery
Eye posterior chamber surgery

i8
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

Downloaded from http://bja.oxfordjournals.org/ at Louisiana State University School of Veterinary Medicine Library on April 2, 2014
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

Bridging
therapy

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.

i9
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
events.118
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

Downloaded from http://bja.oxfordjournals.org/ at Louisiana State University School of Veterinary Medicine Library on April 2, 2014
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

i10
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,

Downloaded from http://bja.oxfordjournals.org/ at Louisiana State University School of Veterinary Medicine Library on April 2, 2014
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

i11
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 http://bja.oxfordjournals.org/ 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
Funding
Patient Receiving Antithrombotic or Thrombolytic Therapy The authors received no funding.
and the 2010 Guidelines of the European Society of Anaesthe-
siology, neuraxial and peripheral blocks can be safely per- References
formed while on ASA therapy. In contrast, due to concerns of 1 Tendera M, Wojakowski W. Role of antiplatelet drugs in the preven-
spinal/epidural haematoma for neuraxial blocks or bleeding tion of cardiovascular events. Thromb Res 2003; 110: 3559
in non-compressible spaces for certain peripheral nerve 2 World Health Organization. Top 10 causes of death. 2013.
blocks, such anaesthetic procedures should be avoided in Available at http://who.int/mediacentre/factsheets/fs310/en/
patients on ADP inhibitors.172 In order to diminish this risk, (accessed 29 August 2013)
the European Society of Anaesthesiology guidelines recom- 3 Hall R, Mazer CD. Antiplatelet drugs: a review of their pharmacol-
mend a drug-free period of 7 10 days for clopidogrel and pra- ogy and management in the perioperative period. Anesth Analg
2011; 112: 292318
sugrel and at least a 5 day cessation of ticagrelor.173 Several
4 Meadows TA, Bhatt DL. Clinical aspects of platelet inhibitors and
case reports comment on the safe placement of epidural
thrombus formation. Circ Res 2007; 100: 126175
catheters or spinal nerve stimulators in patients at high risk
5 Anitua E, Andia I, Ardanza B, Nurden P, Nurden AT. Autologous pla-
of cardiovascular events. In these patients bridging with eptifi- telets as a source of proteins for healing and tissue regeneration.
batide replaced the ADP inhibitor and normal platelet function Thromb Haemost 2004; 91: 415
was documented 8 h after GP IIb/IIIa inhibitor infusion discon- 6 Buller HR, Ten Cate T. Coagulation and platelet activation path-
tinuation and before the regional technique.174 175 For patients ways. A review of the key components and the way in which
at high risk of cardiovascular events who have stopped antipla- these can be manipulated. Eur Heart J 1995 (Suppl. L); 16: 8 10
telet agents for the recommended period of time before oper- 7 Kirkby NS, Lundberg MH, Chan MV, et al. Blockade of the purinergic
ation, single-shot techniques might be preferable as opposed P2Y12 receptor greatly increases the platelet inhibitory actions of
nitric oxide. Proc Natl Acad Sci USA 2013; 110: 15782 7
to catheter-based modalities.176
8 Kaplan ZS, Jackson SP. The role of platelets in atherothrombosis.
Hematology Am Soc Hematol Educ Program 2011; 2011: 51 61
Conclusions 9 Gawaz M, Langer H, May AE. Platelets in inflammation and athero-
Antiplatelet agents represent a quintessential therapy in pre- genesis. J Clin Invest 2005; 115: 337884
venting and treating cardiovascular events. Currently, with an 10 De Meyer SF, Vanhoorelbeke K, Broos K, Salles II, Deckmyn H. Anti-
increasing patient population requiring antiplatelet therapy platelet drugs. Br J Haematol 2008; 142: 51528
in conjunction with an increase in the number of interventional 11 Costopoulos C, Niespialowska-Steuden M, Kukreja N, Gorog DA.
Novel oral anticoagulants in acute coronary syndrome. Int J
procedures, the anaesthesia community is frequently faced
Cardiol 2013; 167: 2449 55
with the need to manage various antiplatelet regimens perio-
12 Roth GJ, Majerus PW. The mechanism of the effect of aspirin on
peratively.
human platelets. I. Acetylation of a particulate fraction protein.
In general, antiplatelet agents used for primary prevention J Clin Invest 1975; 56: 62432
or for AF can be safely discontinued before surgery. On the 13 Patrignani P, Filabozzi P, Patrono C. Selective cumulative inhibition
other hand, recent data suggest that, with few exceptions, pro- of platelet thromboxane production by low-dose aspirin in healthy
ceeding with surgery on DAPT is a relatively safe alternative. In subjects. J Clin Invest 1982; 69: 136672

i12
Perioperative management of antiplatelet therapy BJA
14 Awtry EH, Loscalzo J. Aspirin. Circulation 2000; 101: 120618 30 Brilakis ES, Patel VG, Banerjee S. Medical management after coron-
15 Cox D, Maree AO, Dooley M, Conroy R, Byrne MF, Fitzgerald DJ. Effect ary stent implantation: a review. J Am Med Assoc 2013; 310:
of enteric coating on antiplatelet activity of low-dose aspirin in 189 98
healthy volunteers. Stroke 2006; 37: 21538 31 Jolly SS, Pogue J, Haladyn K, et al. Effects of aspirin dose on ischae-
16 Bochner F, Williams DB, Morris PM, Siebert DM, Lloyd JV. Pharmaco- mic events and bleeding after percutaneous coronary interven-
kinetics of low-dose oral modified release, soluble and intraven- tion: insights from the PCI-CURE study. Eur Heart J 2009; 30: 900 7
ous aspirin in man, and effects on platelet function. Eur J Clin 32 Mehta SR, Bassand JP, Chrolavicius S, et al. Dose comparisons of
Pharmacol 1988; 35: 28794 clopidogrel and aspirin in acute coronary syndromes. N Engl J
17 Eikelboom JW, Hirsh J, Spencer FA, Baglin TP, Weitz JI. Antiplatelet Med 2010; 363: 93042
drugs: Antithrombotic Therapy and Prevention of Thrombosis, 9th 33 Mangano DT, Multicenter Study of Perioperative Ischemia Re-
ed: American College of Chest Physicians Evidence-Based Clinical search Group. Aspirin and mortality from coronary bypass
Practice Guidelines. Chest 2012; 141: e89119S surgery. N Engl J Med 2002; 347: 130917

Downloaded from http://bja.oxfordjournals.org/ at Louisiana State University School of Veterinary Medicine Library on April 2, 2014
18 Karha J, Rajagopal V, Kottke-Marchant K, Bhatt DL. Lack of effect of 34 Goldman S, Copeland J, Moritz T, et al. Improvement in early sa-
enteric coating on aspirin-induced inhibition of platelet aggrega- phenous vein graft patency after coronary artery bypass surgery
tion in healthy volunteers. Am Heart J 2006; 151: 976.e7 11 with antiplatelet therapy: results of a Veterans Administration Co-
19 Patrono C, Coller B, Dalen JE, et al. Platelet-active drugs: the rela- operative Study. Circulation 1988; 77: 1324 32
tionships among dose, effectiveness, and side effects. Chest 35 Hart RG, Halperin JL, McBride R, Benavente O, Man-Son-Hing M,
1998; 114: 470 88S Kronmal RA. Aspirin for the primary prevention of stroke and
20 Thrombosis prevention trial: randomised trial of low-intensity oral other major vascular events: meta-analysis and hypotheses.
anticoagulation with warfarin and low-dose aspirin in the primary Arch Neurol 2000; 57: 32632
prevention of ischaemic heart disease in men at increased risk. 36 Antithrombotic Trialists Collaboration. Collaborative meta-
The Medical Research Councils General Practice Research Frame- analysis of randomised trials of antiplatelet therapy for prevention
work. Lancet 1998; 351: 233 41 of death, myocardial infarction, and stroke in high risk patients. Br
21 Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive Med J 2002; 324: 71 86
blood-pressure lowering and low-dose aspirin in patients with 37 Brott TG, Halperin JL, Abbara S, et al. 2011 ASA/ACCF/AHA/AANN/
hypertension: principal results of the Hypertension Optimal Treat- AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS guideline on
ment (HOT) randomised trial. HOT Study Group. Lancet 1998; 351: the management of patients with extracranial carotid and verte-
175562 bral artery disease: executive summary. A report of the American
22 Raju N, Sobieraj-Teague M, Hirsh J, ODonnell M, Eikelboom J. Effect College of Cardiology Foundation/American Heart Association
of aspirin on mortality in the primary prevention of cardiovascular Task Force on Practice Guidelines, and the American Stroke Asso-
disease. Am J Med 2011; 124: 621 9 ciation, American Association of Neuroscience Nurses, American
23 Baigent C, Blackwell L, Collins R, et al. Aspirin in the primary and Association of Neurological Surgeons, American College of Radi-
secondary prevention of vascular disease: collaborative ology, American Society of Neuroradiology, Congress of Neuro-
meta-analysis of individual participant data from randomised logical Surgeons, Society of Atherosclerosis Imaging and
trials. Lancet 2009; 373: 1849 60 Prevention, Society for Cardiovascular Angiography and Interven-
tions, Society of Interventional Radiology, Society of NeuroInter-
24 US Preventive Services Task Force. Aspirin for the prevention of car-
ventional Surgery, Society for Vascular Medicine, and Society for
diovascular disease: U.S. Preventive Services Task Force recom-
Vascular Surgery. Circulation 2011; 124: 489 532
mendation statement. Ann Intern Med 2009; 150: 396404
38 McQuaid KR, Laine L. Systematic review and meta-analysis of
25 Mosca L, Benjamin EJ, Berra K, et al. Effectiveness-based guide-
adverse events of low-dose aspirin and clopidogrel in randomized
lines for the prevention of cardiovascular disease in women
controlled trials. Am J Med 2006; 119: 62438
2011 update: a guideline from the American Heart Association.
Circulation 2011; 123: 1243 62 39 He J, Whelton PK, Vu B, Klag MJ. Aspirin and risk of hemorrhagic
stroke: a meta-analysis of randomized controlled trials. J Am
26 Lewis HD, Davis JW, Archibald DG, et al. Protective effects of aspirin
Med Assoc 1998; 280: 19305
against acute myocardial infarction and death in men with un-
stable angina. Results of a Veterans Administration Cooperative 40 Mantz J, Samama CM, Tubach F, et al. Impact of preoperative
Study. N Engl J Med 1983; 309: 396403 maintenance or interruption of aspirin on thrombotic and bleed-
ing events after elective non-cardiac surgery: the multicentre, ran-
27 Anderson JL, Adams CD, Antman EM, et al. 2012 ACCF/AHA
domized, blinded, placebo-controlled, STRATAGEM trial. Br J
focused update incorporated into the ACCF/AHA 2007 guidelines
Anaesth 2011; 107: 899 910
for the management of patients with unstable angina/
non-ST-elevation myocardial infarction: a report of the American 41 Alghamdi AA, Moussa F, Fremes SE. Does the use of preoperative
College of Cardiology Foundation/American Heart Association aspirin increase the risk of bleeding in patients undergoing coron-
Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 61: ary artery bypass grafting surgery? Systematic review and
e179347 meta-analysis. J Card Surg 2007; 22: 247 56
28 OGara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guide- 42 Campbell CL, Smyth S, Montalescot G, Steinhubl SR. Aspirin dose
line for the management of ST-elevation myocardial infarction: for the prevention of cardiovascular disease: a systematic
executive summary: a report of the American College of Cardi- review. J Am Med Assoc 2007; 297: 201824
ology Foundation/American Heart Association Task Force on Prac- 43 Deray G, Bagnis C, Brouard R, et al. Clopidogrel activities in patients
tice Guidelines. J Am Coll Cardiol 2013; 61: 485 510 with renal function impairment. Clin Drug Investig 1998; 16:
29 Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three 319 28
antithrombotic-drug regimens after coronary-artery stenting. 44 Slugg PH, Much DR, Smith WB, Vargas R, Nichola P, Necciari J. Cir-
Stent Anticoagulation Restenosis Study Investigators. N Engl J rhosis does not affect the pharmacokinetics and pharmaco-
Med 1998; 339: 166571 dynamics of clopidogrel. J Clin Pharmacol 2000; 40: 396 401

i13
BJA Oprea and Popescu

45 Martin MT, Spinler SA, Nutescu EA. Emerging antiplatelet therapies 61 Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to
in percutaneous coronary intervention: a focus on prasugrel. aspirin in patients with acute coronary syndromes without
Clin Ther 2011; 33: 425 42 ST-segment elevation. N Engl J Med 2001; 345: 494502
46 Small DS, Wrishko RE, Ernest CS, et al. Prasugrel pharmacokinetics 62 Sabatine MS, Cannon CP, Gibson CM, et al. Effect of clopidogrel
and pharmacodynamics in subjects with moderate renal impair- pretreatment before percutaneous coronary intervention in
ment and end-stage renal disease. J Clin Pharm Ther 2009; 34: patients with ST-elevation myocardial infarction treated with fibri-
585 94 nolytics: the PCI-CLARITY study. J Am Med Assoc 2005; 294:
47 Oprea AD, Popescu WM. ADP-receptor inhibitors in the peri- 122432
operative period: the good, the bad, and the ugly. J Cardiothorac 63 Steinhubl SR, Berger PB, Mann JT, et al. Early and sustained dual
Vasc Anesth 2013; 27: 77995 oral antiplatelet therapy following percutaneous coronary inter-
48 Bhatt DL. Prasugrel in clinical practice. N Engl J Med 2009; 361: vention: a randomized controlled trial. J Am Med Assoc 2002;
940 2 288: 241120

Downloaded from http://bja.oxfordjournals.org/ at Louisiana State University School of Veterinary Medicine Library on April 2, 2014
49 Kowalczyk M, Banach M, Mikhailidis DP, Hannam S, Rysz J. Ticagre- 64 Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clo-
lora new platelet aggregation inhibitor in patients with acute pidogrel and aspirin followed by long-term therapy in patients
coronary syndromes. An improvement of other inhibitors? Med undergoing percutaneous coronary intervention: the PCI-CURE
Sci Monit 2009; 15: MS24 30 study. Lancet 2001; 358: 527 33
50 Anderson SD, Shah NK, Yim J, Epstein BJ. Efficacy and safety of tica- 65 Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopi-
grelor: a reversible P2Y12 receptor antagonist. Ann Pharmacother dogrel in patients with acute coronary syndromes. N Engl J Med
2010; 44: 524 37 2007; 357: 200115
51 Butler K, Teng R. Pharmacokinetics, pharmacodynamics, and 66 Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel
safety of ticagrelor in volunteers with severe renal impairment. in patients with acute coronary syndromes. N Engl J Med 2009;
J Clin Pharmacol 2012; 52: 1388 98 361: 104557
52 Capodanno D, Ferreiro JL, Angiolillo DJ. Antiplatelet therapy: new 67 Morrow DA, Wiviott SD, White HD, et al. Effect of the novel thieno-
pharmacological agents and changing paradigms. J Thromb pyridine prasugrel compared with clopidogrel on spontaneous
Haemost 2013; 11 (Suppl. 1): 31629 and procedural myocardial infarction in the Trial to Assess Im-
53 Norgard NB. Cangrelor: a novel P2Y12 receptor antagonist. Expert provement in Therapeutic Outcomes by Optimizing Platelet Inhib-
Opin Investig Drugs 2009; 18: 121930 ition with Prasugrel-Thrombolysis in Myocardial Infarction 38: an
application of the classification system from the universal defin-
54 Hamm CW, Bassand JP, Agewall S, et al. ESC guidelines for
ition of myocardial infarction. Circulation 2009; 119: 275864
the management of acute coronary syndromes in patients pre-
senting without persistent ST-segment elevation: the Task Force 68 Murphy SA, Antman EM, Wiviott SD, et al. Reduction in recurrent
for the management of acute coronary syndromes (ACS) in cardiovascular events with prasugrel compared with clopidogrel
patients presenting without persistent ST-segment elevation of in patients with acute coronary syndromes from the TRITON-TIMI
the European Society of Cardiology (ESC). Eur Heart J 2011; 32: 38 trial. Eur Heart J 2008; 29: 24739
29993054 69 Cannon CP, Harrington RA, James S, et al. Comparison of ticagrelor
55 Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative man- with clopidogrel in patients with a planned invasive strategy for
agement of antithrombotic therapy: Antithrombotic Therapy and acute coronary syndromes (PLATO): a randomised double-blind
Prevention of Thrombosis, 9th ed: American College of Chest Phy- study. Lancet 2010; 375: 283 93
sicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 70 Harrington RA, Stone GW, McNulty S, et al. Platelet inhibition with
141: e32650S cangrelor in patients undergoing PCI. N Engl J Med 2009; 361:
56 Wijns W, Kolh P, Danchin N, et al. Guidelines on myocardial revas- 231829
cularization. Eur Heart J 2010; 31: 2501 55 71 Bhatt DL, Lincoff AM, Gibson CM, et al. Intravenous platelet block-
57 Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI ade with cangrelor during PCI. N Engl J Med 2009; 361: 233041
guideline for percutaneous coronary intervention: a report of the 72 White HD, Chew DP, Dauerman HL, et al. Reduced immediate is-
American College of Cardiology Foundation/American Heart Asso- chemic events with cangrelor in PCI: a pooled analysis of the
ciation Task Force on Practice Guidelines and the Society for Car- CHAMPION trials using the universal definition of myocardial in-
diovascular Angiography and Interventions. Circulation 2011; farction. Am Heart J 2012; 163: 182 90.e4
124: e574651 73 Bhatt DL, Topol EJ. Scientific and therapeutic advances in antipla-
58 Rooke TW, Hirsch AT, Misra S, et al. 2011 ACCF/AHA focused update telet therapy. Nat Rev Drug Discov 2003; 2: 15 28
of the guideline for the management of patients with peripheral 74 Navarese EP, Verdoia M, Schaffer A, et al. Ischaemic and bleeding
artery disease (updating the 2005 guideline): a report of the complications with new, compared to standard, ADP-antagonist
American College of Cardiology Foundation/American Heart Asso- regimens in acute coronary syndromes: a meta-analysis of rando-
ciation Task Force on Practice Guidelines. Circulation 2011; 124: mized trials. QJM 2011; 104: 5619
202045 75 Pickard AS, Becker RC, Schumock GT, Frye CB. Clopidogrel-
59 Sacco RL, Diener HC, Yusuf S, et al. Aspirin and extended-release associated bleeding and related complications in patients under-
dipyridamole versus clopidogrel for recurrent stroke. N Engl J going coronary artery bypass grafting. Pharmacotherapy 2008; 28:
Med 2008; 359: 123851 376 92
60 Wann LS, Curtis AB, January CT, et al. 2011 ACCF/AHA/HRS 76 Hochholzer W, Wiviott SD, Antman EM, et al. Predictors of bleeding
focused update on the management of patients with atrial and time dependence of association of bleeding with mortality:
fibrillation (updating the 2006 guideline): a report of the insights from the Trial to Assess Improvement in Therapeutic Out-
American College of Cardiology Foundation/American Heart Asso- comes by Optimizing Platelet Inhibition with PrasugrelThromb-
ciation Task Force on Practice Guidelines. Circulation 2011; 123: olysis in Myocardial Infarction 38 (TRITON-TIMI 38). Circulation
104 23 2011; 123: 26819

i14
Perioperative management of antiplatelet therapy BJA
77 Goodnough LT, Smith PK, Levy JH, et al. Transfusion outcomes in 95 Biondi-Zoccai GG, Lotrionte M, Agostoni P, et al. A systematic
patients undergoing coronary artery bypass grafting treated review and meta-analysis on the hazards of discontinuing or not
with prasugrel or clopidogrel: TRITON-TIMI 38 retrospective data adhering to aspirin among 50,279 patients at risk for coronary
analysis. J Thorac Cardiovasc Surg 2013; 145: 1077 82.e4 artery disease. Eur Heart J 2006; 27: 2667 74
78 Cayla G, Cuisset T, Silvain J, et al. Prasugrel monitoring and bleed- 96 de Souza DG, Baum VC, Ballert NM. Late thrombosis of a
ing in real world patients. Am J Cardiol 2013; 111: 3844 drug-eluting stent presenting in the perioperative period. Anes-
79 Serebruany VL, Dinicolantonio JJ, Can MM, Pershukov IV, thesiology 2007; 106: 10579
Kuliczkowski W. Gastrointestinal adverse events after dual anti- 97 Artang R, Dieter RS. Analysis of 36 reported cases of late throm-
platelet therapy: clopidogrel is safer than ticagrelor, but prasugrel bosis in drug-eluting stents placed in coronary arteries. Am J
data are lacking or inconclusive. Cardiology 2013; 126: 35 40 Cardiol 2007; 99: 1039 43
80 Bhatt DL, Stone GW, Mahaffey KW, et al. Effect of platelet inhibition 98 Prevention of pulmonary embolism and deep vein thrombosis
with cangrelor during PCI on ischemic events. N Engl J Med 2013; with low dose aspirin: Pulmonary Embolism Prevention (PEP)

Downloaded from http://bja.oxfordjournals.org/ at Louisiana State University School of Veterinary Medicine Library on April 2, 2014
368: 130313 trial. Lancet 2000; 355: 1295 302
81 Truong KM, Amankwa K, Kucukarslan S. Platelet glycoprotein IIb/ 99 Di Minno MN, Milone M, Mastronardi P, et al. Perioperative handling
IIIa-receptor inhibitors in patients with acute coronary syn- of antiplatelet drugs. A critical appraisal. Curr Drug Targets 2013;
dromes or undergoing percutaneous coronary interventions: a 14: 8808
review. Clin Ther 2001; 23: 1145 65 100 Nuttall GA, Horlocker TT, Santrach PJ, Oliver WC, Dekutoski MB,
82 Coller BS. Anti-GPIIb/IIIa drugs: current strategies and future Bryant S. Predictors of blood transfusions in spinal instrumen-
directions. Thromb Haemost 2001; 86: 427 43 tation and fusion surgery. Spine (Phila Pa 1976) 2000; 25:
83 Kohl DW, Slavik KJ, Kamath G, Lehr JM, McDonald MJ, Rubio F. High- 596 601
dose abciximab during coronary angioplasty in a patient with es- 101 Manning BJ, OBrien N, Aravindan S, Cahill RA, McGreal G,
sential thrombocytosis. J Invasive Cardiol 1998; 10: 173 6 Redmond HP. The effect of aspirin on blood loss and transfusion
84 Mascelli MA, Lance ET, Damaraju L, Wagner CL, Weisman HF, requirements in patients with femoral neck fractures. Injury
Jordan RE. Pharmacodynamic profile of short-term abciximab 2004; 35: 121 4
treatment demonstrates prolonged platelet inhibition with 102 Chassot PG, Marcucci C, Delabays A, Spahn DR. Perioperative anti-
gradual recovery from GP IIb/IIIa receptor blockade. Circulation platelet therapy. Am Fam Physician 2010; 82: 14849
1998; 97: 1680 8 103 Neilipovitz DT, Bryson GL, Nichol G. The effect of perioperative
85 Kereiakes DJ, Broderick TM, Roth EM, et al. Time course, magni- aspirin therapy in peripheral vascular surgery: a decision analysis.
tude, and consistency of platelet inhibition byabciximab, tirofiban, Anesth Analg 2001; 93: 57380
or eptifibatide in patients with unstable angina pectoris undergo- 104 Oscarsson A, Gupta A, Fredrikson M, et al. To continue or discon-
ing percutaneous coronary intervention. Am J Cardiol 1999; 84: tinue aspirin in the perioperative period: a randomized, controlled
391 5 clinical trial. Br J Anaesth 2010; 104: 30512
86 Vickers S, Theoharides AD, Arison B, et al. In vitro and in vivo studies 105 Antolovic D, Rakow A, Contin P, et al. A randomised controlled pilot
on the metabolism of tirofiban. Drug Metab Dispos 1999; 27: trial to evaluate and optimize the use of anti-platelet agents in the
13606 perioperative management in patients undergoing general and
87 Schneider DJ. Anti-platelet therapy: glycoprotein IIb IIIa antago- abdominal surgerythe APAP trial (ISRCTN45810007). Langen-
nists. Br J Clin Pharmacol 2011; 72: 67282 becks Arch Surg 2012; 397: 297 306
88 Arora RR, Rai F. Antiplatelet intervention in acute coronary syn- 106 Ghaffarinejad MH, Fazelifar AF, Shirvani SM, et al. The effect of pre-
drome. Am J Ther 2009; 16: e29 40 operative aspirin use on postoperative bleeding and perioperative
89 Sabatine MS, Jang IK. The use of glycoprotein IIb/IIIa inhibitors in myocardial infarction in patients undergoing coronary artery
patients with coronary artery disease. Am J Med 2000; 109: bypass surgery. Cardiol J 2007; 14: 4537
224 37 107 Thurston AV, Briant SL. Aspirin and post-prostatectomy haemor-
90 Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in rhage. Br J Urol 1993; 71: 5746
patients with acute coronary syndromes. The PURSUIT Trial Inves- 108 Korinth MC. Low-dose aspirin before intracranial surgeryresults
tigators. Platelet glycoprotein IIb/IIIa in unstable angina: receptor of a survey among neurosurgeons in Germany. Acta Neurochir
suppression using integrilin therapy. N Engl J Med 1998; 339: (Wien) 2006; 148: 1189 96
436 43 109 Burger W, Chemnitius JM, Kneissl GD, Rucker G. Low-dose aspirin
91 Memon MA, Blankenship JC, Wood GC, Frey CM, Menapace FJ. Inci- for secondary cardiovascular preventioncardiovascular risks
dence of intracranial hemorrhage complicating treatment with after its perioperative withdrawal versus bleeding risks with its
glycoprotein IIb/IIIa receptor inhibitors: a pooled analysis of continuationreview and meta-analysis. J Intern Med 2005;
major clinical trials. Am J Med 2000; 109: 2137 257: 399414
92 Angiolillo DJ, Sabate M, Fernandez-Ortiz A, Macaya C. Acute stent 110 Korte W, Cattaneo M, Chassot PG, et al. Peri-operative manage-
thrombosis after early withdrawal of platelet glycoprotein IIb/IIIa ment of antiplatelet therapy in patients with coronary artery
antagonists: potential rebound prothrombotic effect? Catheter disease: joint position paper by members of the working group
Cardiovasc Interv 2003; 58: 4814 on Perioperative Haemostasis of the Society on Thrombosis and
93 Diehl P, Halscheid C, Olivier C, Helbing T, Bode C, Moser M. Discon- Haemostasis Research (GTH), the working group on Perioperative
tinuation of long term clopidogrel therapy induces platelet Coagulation of the Austrian Society for Anesthesiology, Resuscita-
rebound hyperaggregability between 2 and 6 weeks post cessa- tion and Intensive Care (OGARI) and the Working Group Throm-
tion. Clin Res Cardiol 2011; 100: 765 71 bosis of the European Society for Cardiology (ESC). Thromb
94 Benzon HT, McCarthy RJ, Benzon HA, et al. Determination of re- Haemost 2011; 105: 743 9
sidual antiplatelet activity of clopidogrel before neuraxial injec- 111 Popescu WM. Perioperative management of the patient with a
tions. Br J Anaesth 2011; 107: 96671 coronary stent. Curr Opin Anaesthesiol 2010; 23: 109 15

i15
BJA Oprea and Popescu

112 Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and 128 Wijeysundera DN, Wijeysundera HC, Yun L, et al. Risk of elective
outcome of thrombosis after successful implantation of major noncardiac surgery after coronary stent insertion: a
drug-eluting stents. J Am Med Assoc 2005; 293: 212630 population-based study. Circulation 2012; 126: 135562
113 Ong AT, McFadden EP, Regar E, de Jaegere PP, van Domburg RT, 129 Dimitrova G, Tulman DB, Bergese SD. Perioperative management
Serruys PW. Late angiographic stent thrombosis (LAST) events of antiplatelet therapy in patients with drug-eluting stents. HSR
with drug-eluting stents. J Am Coll Cardiol 2005; 45: 208892 Proc Intensive Care Cardiovasc Anesth 2012; 4: 153 67
114 Priebe HJ. Triggers of perioperative myocardial ischaemia and in- 130 Grines CL, Bonow RO, Casey DE, et al. Prevention of premature dis-
farction. Br J Anaesth 2004; 93: 920 continuation of dual antiplatelet therapy in patients with coron-
115 Priebe HJ. Perioperative myocardial infarctionaetiology and pre- ary artery stents: a science advisory from the American Heart
vention. Br J Anaesth 2005; 95: 3 19 Association, American College of Cardiology, Society for Cardio-
116 Sharma AK, Ajani AE, Hamwi SM, et al. Major noncardiac surgery vascular Angiography and Interventions, American College of Sur-
following coronary stenting: when is it safe to operate? Catheter geons, and American Dental Association, with representation

Downloaded from http://bja.oxfordjournals.org/ at Louisiana State University School of Veterinary Medicine Library on April 2, 2014
Cardiovasc Interv 2004; 63: 1415 from the American College of Physicians. J Am Dent Assoc 2007;
138: 6525
117 Di Minno MN, Prisco D, Ruocco AL, Mastronardi P, Massa S,
Di Minno G. Perioperative handling of patients on antiplatelet 131 Anderson MA, Ben-Menachem T, Gan SI, et al. Management of
therapy with need for surgery. Intern Emerg Med 2009; 4: antithrombotic agents for endoscopic procedures. Gastrointest
279 88 Endosc 2009; 70: 106070
118 Sambu N, Warner T, Curzen N. Clopidogrel withdrawal: is there a 132 Lillis T, Ziakas A, Koskinas K, Tsirlis A, Giannoglou G. Safety of dental
rebound phenomenon? Thromb Haemost 2011; 105: 21120 extractions during uninterrupted single or dual antiplatelet treat-
ment. Am J Cardiol 2011; 108: 9647
119 Fleisher LA, Beckman JA, Brown KA, et al. ACC/AHA 2007 guide-
lines on perioperative cardiovascular evaluation and care for non- 133 Abdel Samie A, Theilmann L. Endoscopic procedures in patients
cardiac surgery: executive summary: a report of the American under clopidogrel/dual antiplatelet therapy: to do or not to do?
College of Cardiology/American Heart Association Task Force on J Gastrointestin Liver Dis 2013; 22: 33 6
Practice Guidelines (Writing Committee to Revise the 2002 Guide- 134 Abdel Samie A, Stumpf M, Sun R, Theilmann L. Biliary-pancreatic
lines on Perioperative Cardiovascular Evaluation for Noncardiac endoscopic and surgical procedures in patients under dual anti-
Surgery) Developed in Collaboration with the American Society platelet therapy: a single-center study. Clin Endosc 2013; 46:
of Echocardiography, American Society of Nuclear Cardiology, 395 8
Heart Rhythm Society, Society of Cardiovascular Anesthesiolo- 135 Mason JO, Gupta SR, Compton CJ, et al. Comparison of hemor-
gists, Society for Cardiovascular Angiography and Interventions, rhagic complications of warfarin and clopidogrel bisulfate in
Society for Vascular Medicine and Biology, and Society for Vascular 25-gauge vitrectomy versus a control group. Ophthalmology
Surgery. J Am Coll Cardiol 2007; 50: 170732 2011; 118: 543 7
120 Pfisterer M, Nietlispach F, Jeger R, Kaiser C, BASKET Investigators. 136 Cook-Norris RH, Michaels JD, Weaver AL, et al. Complications of cu-
Drug-eluting coronary stents in clinical practice: lessons from the taneous surgery in patients taking clopidogrel-containing antico-
BAsel Stent Kosten-Effektivitats Trials (BASKET). A review of the agulation. J Am Acad Dermatol 2011; 65: 58491
BASKET trials. Swiss Med Wkly 2011; 141: w13263 137 Saadeh C, Sfeir J. Discontinuation of preoperative clopidogrel is
121 Eisenstein EL, Anstrom KJ, Kong DF, et al. Clopidogrel use and long- unnecessary in peripheral arterial surgery. J Vasc Surg 2013
term clinical outcomes after drug-eluting stent implantation. Advance Access published on 24 July 2013, doi: 10.1016/
J Am Med Assoc 2007; 297: 15968 j.jvs.2013.05.092
122 Park SJ, Park DW, Kim YH, et al. Duration of dual antiplatelet 138 Chechik O, Goldstein Y, Behrbalk E, Kaufman E, Rabinovich Y. Blood
therapy after implantation of drug-eluting stents. N Engl J Med loss and complications following carotid endarterectomy in
2010; 362: 1374 82 patients treated with clopidogrel. Vascular 2012; 20: 193 7
123 Gwon HC, Hahn JY, Park KW, et al. Six-month versus 12-month dual 139 Stone DH, Goodney PP, Schanzer A, et al. Clopidogrel is not asso-
antiplatelet therapy after implantation of drug-eluting stents: the ciated with major bleeding complications during peripheral arter-
Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After ial surgery. J Vasc Surg 2011; 54: 779 84
Stenting (EXCELLENT) randomized, multicenter study. Circulation 140 Cerfolio RJ, Minnich DJ, Bryant AS. General thoracic surgery is safe
2012; 125: 505 13 in patients taking clopidogrel (Plavix). J Thorac Cardiovasc Surg
124 Valgimigli M, Campo G, Monti M, et al. Short- versus long-term 2010; 140: 970 6
duration of dual-antiplatelet therapy after coronary stenting: a 141 Voltolini L, Rapicetta C, Luzzi L, et al. Lung resection for non-small
randomized multicenter trial. Circulation 2012; 125: 2015 26 cell lung cancer after prophylactic coronary angioplasty and stent-
125 Kim BK, Hong MK, Shin DH, et al. A new strategy for discontinuation ing: short- and long-term results. Minerva Chir 2012; 67: 7785
of dual antiplatelet therapy: the RESET Trial (REal Safety and Effi- 142 Sonobe M, Sato T, Chen F, et al. Management of patients with cor-
cacy of 3-month dual antiplatelet Therapy following Endeavor onary stents in elective thoracic surgery. Gen Thorac Cardiovasc
zotarolimus-eluting stent implantation). J Am Coll Cardiol 2012; Surg 2011; 59: 47782
60: 13408 143 Ceppa DP, Welsby IJ, Wang TY, et al. Perioperative management of
126 Wada T, Nakahama M, Toda H, et al. Dual antiplatelet patients on clopidogrel (Plavix) undergoing major lung resection.
therapy can be discontinued at three months after implantation Ann Thorac Surg 2011; 92: 1971 6
of zotarolimus-eluting stent in patients with coronary artery 144 Paul S, Stock C, Chiu YL, et al. Management and outcomes of
disease. ISRN Cardiol 2013; 2013: 518968 patients on preoperative Plavix (clopidogrel) undergoing general
127 Brotman DJ, Bakhru M, Saber W, et al. Discontinuation of antiplate- thoracic surgery. Thorac Cardiovasc Surg 2012; 61: 48995
let therapy prior to low-risk noncardiac surgery in patients with 145 Chechik O, Thein R, Fichman G, Haim A, Tov TB, Steinberg EL. The
drug-eluting stents: a retrospective cohort study. J Hosp Med effect of clopidogrel and aspirin on blood loss in hip fracture
2007; 2: 378 84 surgery. Injury 2011; 42: 1277 82

i16
Perioperative management of antiplatelet therapy BJA
146 Nandi S, Aghazadeh M, Talmo C, Robbins C, Bono J. Perioperative 163 Lizza BD, Kauflin MJ. Extended-infusion eptifibatide to prevent
clopidogrel and postoperative events after hip and knee arthro- stent thrombosis in a patient undergoing orthopedic surgery.
plasties. Clin Orthop Relat Res 2012; 470: 1436 41 Ann Pharmacother 2011; 45: e28
147 Collinge CA, Kelly KC, Little B, Weaver T, Schuster RD. The effects of 164 Marcos EG, Da Fonseca AC, Hofma SH. Bridging therapy for early
clopidogrel (Plavix) and other oral anticoagulants on early hip surgery in patients on dual antiplatelet therapy after drug-eluting
fracture surgery. J Orthop Trauma 2012; 26: 56873 stent implantation. Neth Heart J 2011; 19: 4127
148 Feely MA, Mabry TM, Lohse CM, Sems SA, Mauck KF. Safety of clopi- 165 Savonitto S, DUrbano M, Caracciolo M, et al. Urgent surgery in
dogrel in hip fracture surgery. Mayo Clin Proc 2013; 88: 149 56 patients with a recently implanted coronary drug-eluting stent:
149 Toepfer NJ, Baylor K, Henry Y, Simmons J, Berger PB. The effect of a phase II study of bridging antiplatelet therapy with tirofiban
antiplatelet and anticoagulant therapy on the clinical outcome of during temporary withdrawal of clopidogrel. Br J Anaesth 2010;
patients undergoing ureteroscopy. Urology 2013; 82: 7739 104: 28591
150 Eberli D, Chassot PG, Sulser T, et al. Urological surgery and antipla- 166 Alshawabkeh LI, Prasad A, Lenkovsky F, et al. Outcomes of a pre-

Downloaded from http://bja.oxfordjournals.org/ at Louisiana State University School of Veterinary Medicine Library on April 2, 2014
telet drugs after cardiac and cerebrovascular accidents. J Urol operative bridging strategy with glycoprotein IIb/IIIa inhibitors
2010; 183: 2128 36 to prevent perioperative stent thrombosis in patients with
151 Descazeaud A, Robert G, Lebdai S, et al. Impact of oral anticoagu- drug-eluting stents who undergo surgery necessitating interrup-
lation on morbidity of transurethral resection of the prostate. tion of thienopyridine administration. EuroIntervention 2013; 9:
World J Urol 2011; 29: 2116 204 11
152 Mukerji G, Munasinghe I, Raza A. A survey of the peri-operative 167 Huang PH, Croce KJ, Bhatt DL, Resnic FS. Recommendations for
management of urological patients on clopidogrel. Ann R Coll management of antiplatelet therapy in patients undergoing
Surg Engl 2009; 91: 31320 elective noncardiac surgery after coronary stent implantation.
Crit Pathw Cardiol 2012; 11: 17785
153 Illuminati G, Ceccanei G, Pacile AM, Pizzardi G, Palumbo P, Vietri F.
Dual antiplatelet treatment in patients candidates for abdominal 168 Ben Morrison T, Horst BM, Brown MJ, Bell MR, Daniels PR.
surgery. Ann Ital Chir 2014; 83: 2914 Bridging with glycoprotein IIb/IIIa inhibitors for periprocedural
management of antiplatelet therapy in patients with drug
154 ORiordan JM, Margey RJ, Blake G, OConnell PR. Antiplatelet
eluting stents. Catheter Cardiovasc Interv 2012; 79: 575 82
agents in the perioperative period. Arch Surg 2009; 144: 69 76
169 Angiolillo DJ, Firstenberg MS, Price MJ, et al. Bridging anti-
155 Hillis LD, Smith PK, Anderson JL, et al. 2011 ACCF/AHA guideline for
platelet therapy with cangrelor in patients undergoing cardiac
coronary artery bypass graft surgery: executive summary: a report
surgery: a randomized controlled trial. J Am Med Assoc 2012;
of the American College of Cardiology Foundation/American
307: 26574
Heart Association Task Force on Practice Guidelines. Circulation
2011; 124: 2610 42 170 Cheng DK, Jackevicius CA, Seidelin P, Feindel C, Rouleau JL.
Safety of glycoprotein IIb/IIIa inhibitors in urgent or emergency
156 Taylor G, Osinski D, Thevenin A, Devys JM. Is platelet transfusion ef-
coronary artery bypass graft surgery. Can J Cardiol 2004; 20:
ficient to restore platelet reactivity in patients who are responders
223 8
to aspirin and/or clopidogrel before emergency surgery? J Trauma
Acute Care Surg 2013; 74: 1367 9 171 Dyke CM, Jennings LK, Maier G, Andreou C, Daly R, Tamberella MR.
Preoperative platelet inhibition with eptifibatide during coronary
157 Darvish-Kazem S, Gandhi M, Marcucci M, Douketis JD. Periopera-
artery bypass grafting with cardiopulmonary bypass. J Cardiovasc
tive management of antiplatelet therapy in patients with a coron-
Pharmacol Ther 2007; 12: 5460
ary stent who need non-cardiac surgery: a systematic review of
clinical practice guidelines. Chest 2013 Advance Access published 172 Horlocker TT, Wedel DJ, Rowlingson JC, et al. Regional anesthesia
on 8 August 2013, doi: 10.1378/chest.13-0459 in the patient receiving antithrombotic or thrombolytic therapy:
American Society of Regional Anesthesia and Pain Medicine
158 Cardiac Society of Australia and New Zealand. Guidelines for the
Evidence-Based Guidelines (Third Edition). Reg Anesth Pain Med
management of antiplatelet therapy in patients with coronary
2010; 35: 64101
stents undergoing non-cardiac surgery. Heart Lung Circ 2010;
19: 2 10 173 Gogarten W, Vandermeulen E, Van Aken H, et al. Regional anaes-
thesia and antithrombotic agents: recommendations of the Euro-
159 Ferraris VA, Saha SP, Oestreich JH, et al. 2012 update to the Society
pean Society of Anaesthesiology. Eur J Anaesthesiol 2010; 27:
of Thoracic Surgeons guideline on use of antiplatelet drugs in
999 1015
patients having cardiac and noncardiac operations. Ann Thorac
Surg 2012; 94: 1761 81 174 Sisk J, Palma M, Cooper C, Eltahawy E, Atallah J. Use of eptifibatide
as a bridge antiplatelet agent for intrathecal drug delivery system
160 Chou S, Eshaghian S, Lamer A, Tran H, Dohad S, Kaul S. Bridging
placement. Pain Physician 2012; 15: 479 83
therapy in the perioperative management of patients with
drug-eluting stents. Rev Cardiovasc Med 2009; 10: 209 18 175 Bauer ME, Bauer ST, Rabbani AB, Mhyre JM. Peripartum manage-
ment of dual antiplatelet therapy and neuraxial labor analgesia
161 Rassi AN, Blackstone E, Militello MA, et al. Safety of bridging with
after bare metal stent insertion for acute myocardial infarction.
eptifibatide for patients with coronary stents before cardiac and
Anesth Analg 2012; 115: 6135
non-cardiac surgery. Am J Cardiol 2012; 110: 485 90
176 Popescu WM, Gusberg RJ, Barash PG. Epidural catheters and
162 Pickett AM, Taylor DA, Ackman ML. Prolonged infusion of eptifiba-
drug-eluting stents: a challenging relationship. J Cardiothorac
tide as bridge therapy between bare-metal stent insertion and
Vasc Anesth 2007; 21: 7013
cardiovascular surgery: case report and review of the literature.
Pharmacotherapy 2010; 30: 12733e
Handling editor: H. C. Hemmings

i17