0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Review Article |

Antiplatelet Agents in the Perioperative Period FREE

James M. O’Riordan, MD; Ronan J. Margey, MB; Gavin Blake, MD; P. Ronan O’Connell, MD
[+] Author Affiliations

Author Affiliations: Departments of Surgery (Drs O[[rsquo]]Riordan and O[[rsquo]]Connell) and Cardiology (Drs Margey and Blake), Mater Misericordiae University Hospital, and School of Medicine and Medical Science, University College Dublin (Drs O[[rsquo]]Riordan and O[[rsquo]]Connell), Dublin, Ireland.


Arch Surg. 2009;144(1):69-76. doi:10.1001/archsurg.144.1.69.
Text Size: A A A
Published online

Objective  To determine the use of the 3 major classes of antiplatelet drugs (aspirin, thienopyridines, and glycoprotein IIb/IIIa inhibitors), their management in the perioperative period, and the risks associated with premature withdrawal.

Data Sources  We reviewed the PubMed, EMBASE, and Cochrane databases using the terms antiplatelet agents in the perioperative period, antiplatelet agents and management of bleeding, drug-eluting stents and stent thrombosis, substitutes for antiplatelet agents, and premature withdrawal of antiplatelet agents.

Study Selection  Randomized, double-blind, placebo-controlled trials; prospective observational studies; review articles; clinical registry data; and guidelines of professional bodies pertaining to antiplatelet agents were included.

Data Extraction and Synthesis  Two researchers independently read the selected abstracts and selected the studies that matched the inclusion criteria. Any discordance between the 2 researchers was resolved by discussion so that 99 articles were finally included.

Conclusions  Aspirin use should not be stopped in the perioperative period unless the risk of bleeding exceeds the thrombotic risk from withholding the drug. With the exception of recent drug-eluting stent implantation, clopidogrel bisulfate use should be stopped at least 5 days prior to most elective surgery. Use of glycoprotein IIb/IIIa inhibitors must be discontinued preoperatively for more than 12 hours to allow normal hemostasis. Premature withdrawal of antiplatelet agents is associated with a 10% risk of all vascular events. Following drug-eluting stent implantation, withdrawal is associated with stent thrombosis and potentially fatal consequences. No definitive guidelines exist to manage patients who are actively bleeding while taking these drugs.

Figures in this Article

Platelets play a central role in atherosclerotic plaque disruption and subsequent thrombus formation.1,2 Understanding the processes of platelet activation and aggregation has led to the widespread use of antiplatelet therapies in cardiovascular disease.

Aspirin is the most widely prescribed antiplatelet drug.3 More powerful new antiplatelet agents are superior in patients with recent myocardial infarction, ischemic stroke, or symptomatic peripheral arterial disease.4,5 Coadministration of 2 antiplatelet agents, such as aspirin and clopidogrel bisulfate, enhances platelet inhibition, as each binds to a different receptor.6

Advances in interventional cardiology have resulted in a growing population of patients taking antiplatelet agents following percutaneous coronary intervention (PCI).7,8 New technologies, such as drug-eluting stents (DESs)9 and drug-coated balloon angioplasty,10 have increased patency rates at 1 year and reduced the levels of neointimal hyperplasia and stent restenosis compared with balloon angioplasty alone11 and bare-metal stenting (BMS).12 Drug-eluting stents are currently used in the majority of patients undergoing PCI.13 Glycoprotein (Gp) IIb/IIIa inhibitors, such as ReoPro (Eli Lilly and Company, Indianapolis, Indiana, and Centocor, Horsham, Pennsylvania) (abciximab), are used as an adjunct to PCI for the prevention of cardiac ischemic complications.14

Most general surgeons are familiar with warfarin as an anticoagulant and perioperative management in terms of elective heparin bridging or reversal. However, many are unfamiliar with newer antiplatelet agents, the guidelines for antiplatelet therapy following PCI and acute coronary syndrome (ACS), and the serious consequences associated with premature withdrawal of these agents. A recent audit among vascular surgeons in the United Kingdom showed wide variation in practice with no consensus with regard to thienopyridine use and major vascular surgical procedures.15 Similarly, Joseph et al16 showed a lack of consensus with regard to stopping clopidogrel use in the perioperative period among orthopedic surgeons.

The decision to stop antiplatelet medication administration in the perioperative period may be simple if the thrombotic risk is overwhelming and the bleeding risk negligible. The situation is however frequently more complex and a risk-benefit assessment must be undertaken. The aims of this article were to review the pharmacokinetics of the 3 major classes of antiplatelet drugs (aspirin, thienopyridines, and Gp IIb/IIIa inhibitors), the current indications for their use, the management of bleeding while taking these antiplatelet agents, and the consequences of premature withdrawal of antiplatelet therapy.

PubMed, EMBASE, and the Cochrane medical databases were searched using the broad terms antiplatelet agents in the perioperative period, antiplatelet agents and management of bleeding, drug-eluting stents and stent thrombosis, substitutes for antiplatelet agents, and premature withdrawal of antiplatelet agents. Other search strategies included using key words such as “aspirin or clopidogrel or abciximab or Gp IIb/IIIa inhibitors” and “bleeding, guidelines, reversal” and “drug-eluting stents, drug-coated balloon angioplasty.” In addition, the references of articles retrieved were searched for relevant articles not already identified. Studies were included if they were randomized, double-blind, placebo-controlled trials; prospective observational studies; review articles; clinical registry data; or if they represented guidelines of professional bodies pertaining to antiplatelet agents. Case reports and data derived from abstracts were excluded and the search was limited from 1978 onward when coronary angioplasty and stenting were introduced.

From the initial search results, 121 studies were identified from the title as being of relevance to the study. Two researchers (J.M.O’R. and R.J.M.) independently read the abstracts and selected studies that matched the inclusion criteria. Any discordance between the 2 researchers was resolved by discussion. A total of 99 articles were finally included.

The current uses of oral antiplatelet agents are presented in Table 1, derived from the recommendations of the American College of Chest Physicians.17

Table Graphic Jump LocationTable 1. Principal Indications for Oral Antiplatelet Agentsa
ASPIRIN

Aspirin or acetylsalicylic acid is the most widely prescribed antiplatelet drug since the first randomized trial showed a link between aspirin and reduced risk of myocardial infarction.19 Aspirin works by irreversibly acetylating serine 529 of cyclooxygenase (COX) 1, resulting in inhibition of thromboxane A2 release from platelets and prostacyclin from endothelial cells.20 Thromboxane A2 stimulates platelet activation, whereas prostacyclin inhibits platelet activation. Because platelets are unable to generate significant amounts of new COX, the effects of aspirin-induced COX-1 inhibition last for the lifetime of the platelet. In contrast, endothelial cells recover normal function shortly after exposure to aspirin; therefore, aspirin is an antithrombotic agent.

The benefits of aspirin were first recognized in the ISIS-2 trial.21 In high-risk patients, aspirin reduced the risk of a serious thrombotic event by approximately 25%. However, 10% to 20% of patients treated with aspirin following an arterial thrombotic event subsequently have a further arterial thrombotic event.22,23 Aspirin alone is not sufficient to prevent stent thrombosis in the initial phase poststenting. This prompted development of adjunctive antithrombotic therapy.

THIENOPYRIDINES

Thienopyridines act by covalently binding to a cysteine residue of the P2Y12 platelet receptor (Figure 1). Consequently, platelets are affected for the remainder of their life span (7-10 days).24 Ticlopidine hydrochloride has been superseded by clopidogrel because clopidogrel has a faster onset of action and fewer adverse effects.25,26 The role of clopidogrel in relation to PCI has now been defined.7,2732 The CURE33 study was the first major trial that demonstrated the benefit of adding clopidogrel to aspirin (additional 10% relative risk reduction) rather than using aspirin alone in patients with non–ST-segment elevation ACS or unstable angina. Patients who are resistant to aspirin (up to 10%) have higher rates of cardiovascular events. It is these patients who benefit most from combination therapy.

Place holder to copy figure label and caption
Figure 1.

Mode of action of the 3 main types of antiplatelet agents (thienopyridines [eg, clopidogrel], aspirin, and glycoprotein [Gp] IIb/IIIa inhibitors) in relation to inhibition of platelet function. ADP indicates adenosine triphosphate.

Graphic Jump Location

Clopidogrel use must be continued postinsertion of BMS for at least 4 weeks. Among patients presenting with an ACS, both the PCI-CURE31 and CREDO7 trials support long-term therapy post-PCI with BMS for 1 year. In the era of DES implantation, the current Food and Drug Administration recommendation is also to continue taking both antiplatelet agents for at least 1 year. Discontinuation prior to completing 1 year of therapy is considered premature withdrawal. The CHARISMA trial,30 which examined lower-risk patients who had not had a cardiovascular event or undergone PCI, showed no benefit of clopidogrel use in addition to aspirin in the context of primary prevention.34,35

Gp IIb/IIIa INHIBITORS

The Gp IIb/IIIa inhibitors form the third major class of antiplatelet agents. The Gp IIb/IIIa receptors are present on resting platelets and undergo a conformational change on activation. They link to fibrinogen to form bridges between activated platelets (Figure 1), leading to the formation of platelet thrombi. Direct inhibitors of the Gp IIb/IIIa receptor have been tested in patients admitted with an ACS, patients receiving thrombolytic therapy for acute myocardial infarction, and patients undergoing PCI.14,36 Aspirin and heparin have always been administered in addition to Gp IIb/IIIa inhibitors in these settings.

There are 2 categories of Gp IIb/IIIa inhibitors. The first (eg, tirofiban hydrochloride and eptifibatide) are competitive inhibitors of the Gp IIb/IIIa receptor, with a short half-life of up to 2 hours. The second group (eg, abciximab) are monoclonal antibodies directed against the Gp IIb/IIIa receptor. Abciximab, a chimeric (human/murine) IgG Fab fragment, produces almost irreversible inhibition. It takes more than 12 hours after stopping an infusion for the relative occupancy of the Gp IIb/IIIa receptors to decrease by 50%.37

Five major randomized trials3842 have demonstrated the efficacy of Gp IIb/IIIa inhibitors in the setting of PCI and ACS and they are increasingly used as an adjunct for the prevention of cardiac ischemic complications. Table 2 summarizes the characteristics of the main antiplatelet agents.

Table Graphic Jump LocationTable 2. Characteristics of the Main Antiplatelet Agentsa
DUAL ANTIPLATELET/ TRIPLE ANTIPLATELET THERAPY

The current European and American guidelines43,44 recommend dual antiplatelet therapy (aspirin plus clopidogrel) for all patients who present with non–ST-segment elevation ACS. High-risk patients (with recurrent ischemia, ST-segment depression, elevated troponin levels, and diabetes mellitus) may also in addition receive a Gp IIb/IIIa receptor inhibitor.45

BLEEDING AND ANTIPLATELET THERAPIES

Antiplatelet drugs predispose to bleeding.46 Coadministration of different antiplatelet therapies with different modes of action increases the risk of bleeding. The most common site of spontaneous bleeding in patients treated with clopidogrel or aspirin is the gastrointestinal tract. Bleeding is also common at arterial puncture sites in patients undergoing PCI or coronary artery bypass surgery.4750 Clopidogrel has been referred to as the “surgeon's headache” in reference to its propensity to cause bleeding.51 Retroperitoneal bleeding is not uncommon with clopidogrel whereas intracerebral bleeding is uncommon but is associated with the highest mortality.4,33,52

The definition of bleeding differs greatly between randomized trials that looked at antiplatelet therapies.5355 Eikelboom and Hirsh56 summarized the incidence of major bleeding in randomized trials of clopidogrel or clopidogrel-containing dual antiplatelet therapy based on the International Society on Thrombosis and Haemostasis53 definition of bleeding. They found the absolute increase in major bleeding with clopidogrel compared with placebo or control was approximately 1%. Adding clopidogrel to aspirin increased the relative risk of bleeding by up to 50%. Bleeding secondary to antiplatelet therapy was independently predictive of adverse clinical outcomes, including myocardial infarction, stroke, and death.57,58

There are no specific guidelines concerning treatment of bleeding in patients taking antiplatelet drugs. The general principles of management of major bleeding also apply to patients who bleed during clopidogrel, aspirin, or abciximab treatment (Figure 2). The antiplatelet effect of clopidogrel may be reversed with platelet transfusions.59 Other treatments include administration of antifibrinolytic agents, such as aprotinin,6064 desmopressin acetate,65,66 and recombinant factor VIIa.67 It is unclear whether these agents should be given prophylactically during urgent surgery or only be administered when bleeding arises. In a randomized trial of patients undergoing urgent coronary artery bypass graft, Akowuah et al64 found that continuing aspirin and clopidogrel therapy with intraoperative aprotinin administration was associated with reduced postoperative blood loss and transfusion requirements compared with stopping the antiplatelet treatment 5 days preoperatively but without giving intraoperative aprotinin.

Place holder to copy figure label and caption
Figure 2.

Algorithm for the management of bleeding for patients taking clopidogrel bisulfate. This should only be used as a guideline and specific management depends on clinical circumstances. Similar principles could be applied to the other antiplatelet agents. d/w Indicates discussed with; DDAVP, desmopressin acetate; PCI, percutaneous coronary intervention; and +/−, plus or minus.

Graphic Jump Location
PREMATURE WITHDRAWAL OF ANTIPLATELET AGENTS

Oral antiplatelet agent compliance and premature interruption are of great concern to cardiologists; however, there is little evidence to guide management in the perioperative period. Premature or inappropriate discontinuation of antiplatelet therapy can have serious and sometimes fatal outcomes.68 Collet et al69 found that oral antiplatelet withdrawal was an independent risk factor for death among 1358 consecutive patients admitted with an ACS. A recent meta-analysis by Burger et al70 found that single oral antiplatelet interruption may account for 10% of all vascular events whatever the arterial bed.

Interruption of oral antiplatelet therapy within the first month following BMS insertion has been reported to be associated with death rates of 25% to 50%.71 In patients who have had a DES inserted, 8 studies have reported premature interruption of oral antiplatelet therapy as one of the highest risk factors for delayed stent thrombosis.7279 Daemen et al80 have recently suggested that late stent thrombosis is also encountered, with no evidence of diminution up to 3 years postinsertion of a DES.

Withdrawal of antiplatelet agents may induce a rebound or prothrombotic effect.79,81 In perioperative patients, this added risk as well as the underlying risk of thromboembolism associated with surgery could be responsible for the high rates of thrombosis seen in patients who stop taking antiplatelet agents before major surgical procedures, particularly after PCI. Recent American guidelines identify the risk of stent thrombosis from premature antiplatelet drug discontinuation in patients receiving DES at up to 29% with resultant risk of acute myocardial infarction or death.82

SUBSTITUTES TO ORAL ANTIPLATELET AGENTS

There are no clinically useful alternatives to oral antiplatelet agents whereby a drug with a shorter half-life could be substituted prior to surgery.83,84 There is also no literature to support the use of therapeutic heparin as an alternative.71 Therapeutic doses of heparin given preoperatively in patients undergoing cardiac surgery have been found to significantly increase the rate of bleeding and need for reexploration.85

ASPIRIN IN THE PERIOPERATIVE PERIOD

Most surgeons advise patients to stop taking aspirin at least 7 to 10 days preoperatively. The French Society of Anesthesiology and Intensive Care in 2001 questioned this policy because of a reported increased incidence of myocardial infarction86 and recommended that aspirin use should not be stopped in the perioperative period unless the risk of hemorrhagic complications related to a specific procedure appeared to be greater than the increase in thrombotic/cardiovascular risk from withholding the drug. The same group also estimated the bleeding risks associated with perioperative antiplatelet therapy with regard to specific surgical procedures based on the available evidence87 (Table 3). Bélisle and Hardy,88 in a review of 50 articles that included more than 10 000 patients undergoing cardiac surgery from 70 centers, found that postoperative blood loss increased by only 300 mL on average for patients taking aspirin, with no associated increase in transfusion requirements.

Table Graphic Jump LocationTable 3. Bleeding Risk Associated With Different Surgical Procedures With Regard to Antiplatelet Therapies87,a

Evaluation of the bleeding risk is sometimes difficult depending on the type of surgery. There are confounding factors (eg, being elderly or obese, having heart failure or renal failure) that are associated with both bleeding and ischemic events.71 Neilipovitz et al89 looked at perioperative aspirin use in peripheral vascular surgery and found a decreased perioperative mortality rate and an increased life expectancy in those who continued to take aspirin in the perioperative period, with a corresponding increase in non–life-threatening hemorrhagic complications. The ASPIRIN trial (Antiplatelet Strategies in the Perioperative Period in Patients at Risk of Ischaemic Events) is an ongoing multicenter trial comparing low-dose aspirin therapy vs placebo during the perioperative period in patients with documented symptomatic stable coronary artery disease undergoing noncardiac surgery. This study may provide definitive guidelines for patients taking aspirin in the perioperative period.

THIENOPYRIDINES IN THE PERIOPERATIVE PERIOD

Because clopidogrel is seen as a more powerful antiplatelet agent than aspirin, most surgeons advise discontinuation prior to surgery. The timing of surgery is often dictated by the clinical circumstances in which clopidogrel has been prescribed. Clopidogrel therapy is advised for at least 4 weeks after placement of a BMS. If early surgery is undertaken with premature discontinuation of clopidogrel, the incidence of thrombotic complications and/or hemorrhagic events is extremely high.90,91 As a result, elective surgery should be postponed for a period of 1 to 3 months following placement of a BMS.86

A recent Science Advisory from the American Heart Association, American College of Cardiology, and the American College of Surgeons82 emphasizes the importance of 12 months of dual antiplatelet therapy postinsertion of DES because of the risk of late stent stenosis due to delayed endothelialization. Elective procedures for which there is significant risk of perioperative or postoperative bleeding should be postponed until patients have completed an appropriate course of thienopyridine therapy. Howard-Alpe et al92 and Brilakis et al93 have highlighted the increased risk of stent thrombosis after noncardiac surgery post–DES insertion. This risk is increased if surgery is performed early after stenting and particularly if dual antiplatelet therapy is discontinued.

Collet and Montalescot,71 based on guidelines from the French Society of Anesthesiology and Intensive Care, have suggested an algorithm for patients receiving dual antiplatelet therapy after insertion of a DES who require surgery. This involves the surgeon and anesthesiologist assessing the bleeding risk, the cardiologist evaluating the risk of stent thrombosis, and all 3 devising an individual management plan. For example, if there is a major risk of both stent thrombosis and bleeding, surgery should be postponed for at least 6 to 12 months post-DES. If this is not possible, aspirin use should be continued and clopidogrel therapy stopped 5 days before surgery. If the bleeding risk is small and there is a major risk of stent thrombosis, then antiplatelet agents should be continued in the perioperative period.

Full recovery of platelet function requires complete replacement of exposed platelets. However, hemostatic competence does not require 100% of all circulating platelets to be functioning normally. The CURE trial33 found that clopidogrel therapy could be discontinued at least 5 days prior to coronary artery bypass graft with no increased bleeding complications. Hence, for the majority of cases, stopping clopidogrel therapy at least 5 days preoperatively will allow adequate hemostatic function prior to most surgical procedures.18

Gp IIb/IIIa INHIBITORS IN THE PERIOPERATIVE PERIOD

The combined results of the EPILOG and EPISTENT trials showed no significant increase in transfusion rates and major blood loss in patients treated with the Gp IIb/IIIa inhibitor abciximab compared with placebo.94 However, the numbers of patients were small and those undergoing coronary artery bypass graft were operated on more than 12 hours after the administration of abciximab. Gammie et al95 showed that if abciximab was given within 12 hours of surgery, the rate of transfusion and hemorrhagic risk increased. With regard to the other Gp IIb/IIIa inhibitors (eg, eptifibatide and tirofiban), their half-lives are shorter than abciximab; hence, stopping the infusion of the drug just before surgery will allow the drug effect to disappear when the surgery is finished.96,97 Until further studies are performed, the recommendations for patients treated with Gp IIb/IIIa inhibitors undergoing cardiac surgery should also apply to patients undergoing noncardiac surgery.

Surgeons are increasingly confronted by patients prescribed antiplatelet drugs.98 There is a delicate balance between ischemic risk from stopping use of these drugs and bleeding risk from continuing use.87 No randomized data exist in noncardiac surgery patients.99 The ischemic risk needs to be evaluated by a cardiologist and consensus reached as to the appropriate timing of surgery and when or if the antiplatelet medication should be stopped.71 There is little evidence-based guidance on restarting therapy; however, it would appear prudent to limit the interruption of antiplatelet therapy to as short a time as possible.

Communication with the cardiologist in the perioperative period is important in evaluating the risk associated with stopping the antiplatelet drug therapy but also in influencing the type of stent inserted into a patient for a particular surgical procedure.92,93 Insertion of a BMS that requires 4 weeks' minimum antiplatelet treatment may stabilize the patient from a cardiac viewpoint and allow surgery to proceed within a reasonable time frame.

Premature withdrawal of antiplatelet medications must be understood as being a significant cause of morbidity and mortality.6870 A perceived risk of bleeding events often leads to antiplatelet medications being stopped, but in many cases, the interruption is unjustified. Management of a patient who is bleeding while taking antiplatelet agents, such as clopidogrel, depends on the site and extent of bleeding. Multidisciplinary consultation should be considered with regard to discontinuation of antiplatelet agents, platelet transfusion, and the use of other agents, such as desmopressin acetate, recombinant factor VIIa, and aprotinin.

Elective surgery after coronary stenting should be deferred until use of antiplatelet agents can be safely stopped. The literature supports the view that emergency surgery soon after coronary stenting is associated with adverse outcomes with increased rates of stent thrombosis. If emergency surgery is necessary, the actions of antiplatelet agents, such as clopidogrel, can be reversed with platelet transfusions. Close liaison between surgery and cardiology is essential to minimize both the adverse cardiac risk and surgical risk in this group of patients.

Correspondence: P. Ronan O’Connell, MD, Surgical Professorial Unit, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland (ronan.oconnell@ucd.ie).

Accepted for Publication: November 9, 2007.

Author Contributions:Study concept and design: O’Riordan and O’Connell. Acquisition of data: O’Riordan and Margey. Analysis and interpretation of data: O’Riordan, Margey, Blake, and O’Connell. Drafting of the manuscript: O’Riordan and O’Connell. Critical revision of the manuscript for important intellectual content: O’Riordan, Margey, Blake, and O’Connell. Statistical analysis: O’Riordan. Administrative, technical, and material support: O’Riordan, Margey, and O’Connell. Study supervision: Blake and O’Connell.

Financial Disclosure: None reported.

Badimon  LBadimon  JJVilahur  GSegales  ELlorente  V Pathogenesis of the acute coronary syndromes and therapeutic implications. Pathophysiol Haemost Thromb 2002;32 (5-6) 225- 231
PubMed Link to Article
Troxler  MDickinson  KHomer-Vanniasinkam  S Platelet function and antiplatelet therapy. Br J Surg 2007;94 (6) 674- 682
PubMed Link to Article
Elwood  PMorgan  GBrown  GPickering  J Aspirin for everyone older than 50? BMJ 2005;330 (7505) 1440- 1441
PubMed Link to Article
CAPRIE Steering Committee, A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348 (9038) 1329- 1339
PubMed Link to Article
Cannon  CPCAPRIE Investigators,Walker  PJ Effectiveness of clopidogrel versus aspirin in preventing acute myocardial infarction in patients with symptomatic atherothrombosis (CAPRIE TRIAL). Am J Cardiol 2002;90 (7) 760- 762
PubMed Link to Article
Ibanez  BVilahur  GBadimon  JJ Pharmacology of thienopyridines: rationale for dual pathway inhibition. Eur Heart J Suppl 2006;8 ((suppl G)) G3- G9
Link to Article
Steinhubl  SRBerger  PBMann  JT  III  et al. CREDO Investigators, Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002;288 (19) 2411- 2420
PubMed Link to Article
Gregorini  LMarco  JFajadet  J  et al.  Ticlopidine and aspirin pretreatment reduces coagulation and platelet activation during coronary dilation procedures. J Am Coll Cardiol 1997;29 (1) 13- 20
PubMed Link to Article
Spaulding  CHenry  PTeiger  E  et al.  Sirolimus-eluting versus uncoated stents in acute myocardial infarction. N Engl J Med 2006;355 (11) 1093- 1104
PubMed Link to Article
Scheller  BHehrlein  CBocksch  W  et al.  Treatment of coronary in-stent restenosis with a paclitaxel-coated balloon catheter. N Engl J Med 2006;355 (20) 2113- 2124
PubMed Link to Article
Grüntzig  ARSenning  ASiegenthaler  WE Nonoperative dilatation of coronary-artery stenosis: percutaneous transluminal coronary angioplasty. N Engl J Med 1979;301 (2) 61- 68
PubMed Link to Article
Serruys  PWStrauss  BHBeatt  KJ  et al.  Angiographic follow-up after placement of a self-expanding coronary-artery stent. N Engl J Med 1991;324 (1) 13- 17
PubMed Link to Article
Merritt  JCBhatt  DL The efficacy and safety of perioperative antiplatelet therapy. J Thromb Thrombolysis 2004;17 (1) 21- 27
PubMed Link to Article
 Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization: the EPILOG investigators. N Engl J Med 1997;336 (24) 1689- 1696
PubMed Link to Article
Smout  JStansby  G Current practice in the use of antiplatelet agents in the perioperative period by UK vascular surgeons. Ann R Coll Surg Engl 2003;85 (2) 97- 101
PubMed Link to Article
Joseph  JJPillai  ABramley  D Clopidogrel in orthopaedic patients: a review of current practice in Scotland. Thromb J 2007;56
PubMed Link to Article
Schünemann  HJCook  DGrimshaw  J  et al.  Antithrombotic and thrombolytic therapy: from evidence to application: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126 (3) ((suppl)) 688S- 696S
PubMed Link to Article
Lecompte  THardy  JF Antiplatelet agents and perioperative bleeding. Can J Anaesth 2006;53 (6) ((suppl)) S103- S112
PubMed Link to Article
Elwood  PCCochrane  ALBurr  ML  et al.  A randomized controlled trial of acetyl salicylic acid in the secondary prevention of mortality from myocardial infarction. Br Med J 1974;1 (5905) 436- 440
PubMed Link to Article
Patrono  CColler  BFitzgerald  GAHirsh  JRoth  G Platelet-active drugs: the relationships among dose, effectiveness, and side effects. Chest 2004;126 (3) ((suppl)) 234S- 264S
PubMed Link to Article
ISIS-2 (Second International Study of Infarct Survival) Collaborative group, Randomised trial of intravenous streptokinase, oral aspirin, or both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988;2 (8607) 349- 360
PubMed
Antithrombotic Trialists' Collaboration, Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324 (7329) 71- 86
PubMed Link to Article
Gaspoz  JMCoxson  PGGoldman  PA  et al.  Cost effectiveness of aspirin, clopidogrel, or both for secondary prevention of coronary artery disease. N Engl J Med 2002;346 (23) 1800- 1806
PubMed Link to Article
Kaushansky  K Thrombopoietin. N Engl J Med 1998;339 (11) 746- 754
PubMed Link to Article
Bertrand  MERupprecht  HJUrban  P Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS). Circulation 2000;102 (6) 624- 629
PubMed Link to Article
Müller  ISeyfarth  MRudiger  S  et al.  Effect of a high loading dose of clopidogrel on platelet function in patients undergoing coronary stent placement. Heart 2001;85 (1) 92- 93
PubMed Link to Article
Ringleb  PABhatt  DLHirsch  ATTopol  EJHacke  WCAPRIE Investigators, Benefit of clopidogrel over aspirin is amplified in patients with a history of ischaemic events. Stroke 2004;35 (2) 528- 532
PubMed Link to Article
Bhatt  DLChew  DPHirsch  ATRingleb  PAHacke  WTopol  EJ Superiority of clopidogrel versus aspirin in patients with prior cardiac surgery. Circulation 2001;103 (3) 363- 368
PubMed Link to Article
Bhatt  DLMarso  SPHirsch  ATRingleb  PAHacke  WTopol  EJ Amplified benefit of clopidogrel versus aspirin in patients with diabetes mellitus. Am J Cardiol 2002;90 (6) 625- 628
PubMed Link to Article
Bhatt  DLFox  KAHacke  W  et al. CHARISMA Investigators, Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354 (16) 1706- 1717
PubMed Link to Article
Mehta  SRYusuf  SPeters  RJ  et al.  Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358 (9281) 527- 533
PubMed Link to Article
Kastrati  AMehilli  JSchuhlen  H  et al.  A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel. N Engl J Med 2004;350 (3) 232- 238
PubMed Link to Article
Yusuf  SZhao  FMehta  SRChrolavicius  SToqnoni  GFox  KKClopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators, Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345 (7) 494- 502
PubMed Link to Article
Hamdalla  HSteinhubl  SR Clinical efficacy of clopidogrel across the whole spectrum of indications: percutaneous coronary intervention. Eur Heart J Suppl 2006;8 ((suppl G)) G20- G24
Link to Article
Boersma  EHarrington  RMoliterno  D A meta-analysis of all major randomized clinical trials. Lancet 2002;359 (9302) 189- 198
PubMed Link to Article
EPISTENT Investigators, Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein IIb/IIIa receptor blockade: the EPISTENT Investigators. Evaluation of platelet IIb/IIIa inhibitor for stenting. Lancet 1998;352 (9122) 87- 92
PubMed Link to Article
Tcheng  JEEllis  SGGeorge  BS  et al.  Pharmacodynamics of chimeric glycoprotein IIb/IIIa integrin antiplatelet antibody Fab 7E3 in high-risk coronary angioplasty. Circulation 1994;90 (4) 1757- 1764
PubMed Link to Article
ESPRIT Investigators, Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomized, placebo-controlled trial. Lancet 2000;356 (9247) 2037- 2044
PubMed Link to Article
Kastrati  AMehilli  JNeumann  FJ  et al.  Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial. JAMA 2006;295 (13) 1531- 1538
PubMed Link to Article
Valgimigli  MPercoco  GBarbieri  D  et al.  The additive value of tirofiban administered with the high-dose bolus in the prevention of ischaemic complications during high-risk coronary angioplasty: the ADVANCE trial. J Am Coll Cardiol 2004;44 (1) 14- 19
PubMed Link to Article
Bonz  AWLengenfelder  BStrotmann  J  et al.  Effect of additional temporary glycoprotein IIb/IIIa receptor inhibition on troponin release in elective percutaneous coronary interventions after pretreatment with aspirin and clopidogrel (TOPSTAR trial). J Am Coll Cardiol 2002;40 (4) 662- 668
PubMed Link to Article
Topol  EJMoliterno  DJHerrmann  HC  et al.  Comparison of two platelet glycoprotein IIb/IIIa inhibitors, tirofiban and abciximab, for the prevention of ischaemic events with percutaneous coronary revascularization. N Engl J Med 2001;344 (25) 1888- 1894
PubMed Link to Article
Bertrand  MESimoons  MLFox  KA  et al.  Management of acute coronary syndromes: acute coronary syndromes without persistent ST segment elevation. Recommendations of the Task Force of the European Society of Cardiology. Eur Heart J 2000;21 (17) 1406- 1432
PubMed Link to Article
Braunwald  EAntman  EMBeasley  JW  et al.  ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol 2000;36 (3) 970- 1062
PubMed Link to Article
Bertrand  MEVan Belle  E Triple antiplatelet treatment in patients presenting with non-ST-segment elevation acute coronary syndromes. Eur Heart J Suppl 2006;8 ((suppl G)) G59- G63
Link to Article
Bracey  AWGrigore  AMNussmeier  NA Impact of platelet testing on presurgical screening and implications for cardiac and noncardiac surgical procedures. Am J Cardiol 2006;98 (10A) 25N- 32N
PubMed Link to Article
Kapetanakis  EIMedlam  DAPetro  KR  et al.  Effect of clopidogrel premedication in off-pump cardiac surgery: are we forfeiting the benefits of reduced hemorrhagic sequelae? Circulation 2006;113 (13) 1667- 1674
PubMed Link to Article
Kang  WTheman  TEReed  JF  IIIStoltzfus  JWeger  N The effect of preoperative clopidogrel on bleeding after coronary artery bypass surgery. J Surg Educ 2007;64 (2) 88- 92
PubMed Link to Article
Leong  JYBaker  RAShah  PJCherian  VKKnight  JL Clopidogrel and bleeding after coronary artery bypass graft surgery. Ann Thorac Surg 2005;80 (3) 928- 933
PubMed Link to Article
Chen  LBracey  AWRadovancevic  R  et al.  Clopidogrel and bleeding in patients undergoing elective coronary artery bypass grafting. J Thorac Cardiovasc Surg 2004;128 (3) 425- 431
PubMed Link to Article
Kapetanakis  EIMedlam  DABoyce  SW  et al.  Clopidogrel administration prior to coronary artery bypass grafting surgery: the cardiologist's panacea or the surgeon's headache? Eur Heart J 2005;26 (6) 576- 583
PubMed Link to Article
Chen  ZMPan  HCChen  YP  et al. COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial) Collaborative Group, Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomized placebo-controlled trial. Lancet 2005;366 (9497) 1607- 1621
PubMed Link to Article
Schulman  SKearon  CSubcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis, Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005;3 (4) 692- 694
PubMed Link to Article
The GUSTO Investigators, An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329 (10) 673- 682
PubMed Link to Article
Chesebro  JHKnatterud  GRoberts  R  et al.  Thrombolysis in Myocardial Infarction (TIMI) Trial, phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge. Circulation 1987;76 (1) 142- 154
PubMed Link to Article
Eikelboom  JWHirsh  J Bleeding and management of bleeding. Eur Heart J Suppl 2006;8 ((suppl G)) G38- G45
Link to Article
Rao  SVO’Grady  KPieper  KS  et al.  Impact of bleeding severity on clinical outcomes among patients with acute coronary syndromes. Am J Cardiol 2005;96 (9) 1200- 1206
PubMed Link to Article
Moscucci  MFox  KACannon  CP  et al.  Predictors of major bleeding in acute coronary syndromes: the Global Registry of Acute Coronary Events (GRACE). Eur Heart J 2003;24 (20) 1815- 1823
PubMed Link to Article
Vilahur  GChoi  BGZafar  MU  et al.  Normalisation of platelet reactivity in clopidogrel-treated subjects. J Thromb Haemost 2007;5 (1) 82- 90
PubMed Link to Article
Lindvall  GSartipy  UVan der Linden  J Aprotinin reduces bleeding and blood product use in patients treated with clopidogrel before coronary artery bypass grafting. Ann Thorac Surg 2005;80 (3) 922- 927
PubMed Link to Article
Levi  MCromheecke  MEde Jonge  E  et al.  Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints. Lancet 1999;354 (9194) 1940- 1947
PubMed Link to Article
Levy  JH Pharmacological preservation of the hemostatic system during cardiac surgery. Ann Thorac Surg 2001;72 (5) S1814- S1820
PubMed Link to Article
van der Linden  JLindvall  GSartipy  U Aprotinin decreases postoperative bleeding and number of transfusions in patients on clopidogrel undergoing coronary artery bypass graft surgery: a double-blind, placebo controlled, randomized clinical trial. Circulation 2005;112 (9) ((suppl)) I276- I280
PubMed Link to Article
Akowuah  EShrivastava  VJamnadas  B  et al.  Comparison of two strategies for the management of antiplatelet therapy during urgent surgery. Ann Thorac Surg 2005;80 (1) 149- 152
PubMed Link to Article
von Heymann  CSchoenfeld  HSpander  MZiemer  SGrubitzsch  HSpies  C Clopidogrel-related refractory bleeding after coronary artery bypass graft surgery: a rationale for the use of coagulation factor concentrates? Heart Surg Forum 2005;8 (1) E39- E41
PubMed Link to Article
Arom  KVEmery  RW Decreased postoperative drainage with addition of epsilon-aminocaproic acid before cardiopulmonary bypass. Ann Thorac Surg 1994;57 (5) 1108- 1112
PubMed Link to Article
Altman  RScazziota  ADe Lourdes Herrera  MGonzalez  C Recombinant factor VIIa reverses the inhibitory effect of aspirin or aspirin plus clopidogrel on in vitro thrombin generation. J Thromb Haemost 2006;4 (9) 2022- 2027
PubMed Link to Article
Collet  JPHimbert  FSteg  PG Myocardial infarction after aspirin cessation in stable coronary artery disease patients. Int J Cardiol 2000;76 (2-3) 257- 258
PubMed Link to Article
Collet  JPMontalescot  GBlanchet  B  et al.  Impact of prior use or recent withdrawal of oral antiplatelet agents on acute coronary syndromes. Circulation 2004;110 (16) 2361- 2367
PubMed Link to Article
Burger  WChemnitius  JMKneissl  GDRucker  G Low-dose aspirin for secondary cardiovascular prevention-cardiovascular risks after its perioperative withdrawal versus bleeding risks with its continuation—review and meta-analysis. J Intern Med 2005;257 (5) 399- 414
PubMed Link to Article
Collet  JPMontalescot  G Premature withdrawal and alternative therapies to dual oral antiplatelet therapy. Eur Heart J Suppl 2006;8 ((suppl G)) G46- G52
Link to Article
Ong  ATHoye  AAoki  J  et al.  Thirty-day incidence and six-month clinical outcome of thrombotic stent occlusion after bare-metal, sirolimus, or paclitaxel stent implantation. J Am Coll Cardiol 2005;45 (6) 947- 953
PubMed Link to Article
Park  DWPark  SWPark  KH  et al.  Frequency of and risk factors for stent thrombosis after drug-eluting stent implantation during long-term follow-up. Am J Cardiol 2006;98 (3) 352- 356
PubMed Link to Article
Urban  PGershlick  AHGuagliumi  G  et al.  Safety of coronary sirolimus-eluting stents in daily clinical practice: one-year follow-up of the e-Cypher registry. Circulation 2006;113 (11) 1434- 1441
PubMed Link to Article
Kuchulakanti  PKChu  WWTorguson  R  et al.  Correlates and long-term outcomes of angiographically proven stent thrombosis with sirolimus- and paclitaxel-eluting stents. Circulation 2006;113 (8) 1108- 1113
PubMed Link to Article
Jeremias  ASylvia  BBridges  J  et al.  Stent thrombosis after successful sirolimus-eluting stent implantation. Circulation 2004;109 (16) 1930- 1932
PubMed Link to Article
McFadden  EPStabile  ERegar  E  et al.  Late thrombosis in drug-eluting coronary stents after discontinuation of antiplatelet therapy. Lancet 2004;364 (9444) 1519- 1522
PubMed Link to Article
Iakovou  ISchmidt  TBonizzoni  E  et al.  Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293 (17) 2126- 2130
PubMed Link to Article
Ferrari  EBenhamou  MCerboni  PMarcel  B Coronary syndromes following aspirin withdrawal: a special risk for late stent thrombosis. J Am Coll Cardiol 2005;45 (3) 456- 459
PubMed Link to Article
Daemen  JWenaweser  PTsuchida  K  et al.  Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study. Lancet 2007;369 (9562) 667- 678
PubMed Link to Article
Angiolillo  DJFernandez-Ortiz  ABernardo  E  et al.  Clopidogrel withdrawal is associated with proinflammatory and prothrombotic effects in patients with diabetes and coronary artery disease. Diabetes 2006;55 (3) 780- 784
PubMed Link to Article
Grines  CLBonow  ROCasey  DE  et al.  Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians. Circulation 2007;115 (6) 813- 818
PubMed Link to Article
González-Correa  JAArrebola  MMMartin-Salido  EMunoz-Marin  Jde la Cuesta  FSDe La Cruz  JP Effects of dexibuprofen on platelet function in humans: comparison with low-dose aspirin. Anesthesiology 2007;106 (2) 218- 225
PubMed Link to Article
Samama  CM Preoperative nonsteroidal anti-inflammatory agents as substitutes for aspirin: already too late? Anesthesiology 2007;106 (2) 205- 206
PubMed Link to Article
McDonald  SBRenna  MSpitznagel  EL  et al.  Preoperative use of enoxaparin increases the risk of postoperative bleeding and re-exploration in cardiac surgery patients. J Cardiothorac Vasc Anesth 2005;19 (1) 4- 10
PubMed Link to Article
Samama  CMBastien  OForestier  F  et al.  Antiplatelet agents in the perioperative period: expert recommendations of the French Society of Anesthesiology and Intensive Care (SFAR) 2001-summary statement. Can J Anaesth 2002;49 (6) S26- S35
PubMed
Samama  CMDjoudi  RLecompte  TNathan-Denizot  NSchved  JF Perioperative platelet transfusion: recommendations of the Agence Francaise de Securite Sanitaire des Produits de Sante (AFSSaPS) 2003. Can J Anaesth 2005;52 (1) 30- 37
PubMed Link to Article
Bélisle  SHardy  JF Hemorrhage and the use of blood products after adult cardiac operations: myths and realities. Ann Thorac Surg 1996;62 (6) 1908- 1917
PubMed Link to Article
Neilipovitz  DTBryson  GLNichol  G The effect of perioperative aspirin therapy in peripheral vascular surgery: a decision analysis. Anesth Analg 2001;93 (3) 573- 580
PubMed Link to Article
Kałuza  GLJoseph  JLee  JRRaizner  MERaizner  AE Catastrophic outcomes of noncardiac surgery soon after coronary stenting. J Am Coll Cardiol 2000;35 (5) 1288- 1294
PubMed Link to Article
Wilson  SHFasseas  POrford  JL  et al.  Clinical outcome of patients undergoing non-cardiac surgery in the two months following coronary stenting. J Am Coll Cardiol 2003;42 (2) 234- 240
PubMed Link to Article
Howard-Alpe  GMde Bono  JHudsmith  LOrr  WPFoex  PSear  JW Coronary artery stents and non-cardiac surgery. Br J Anaesth 2007;98 (5) 560- 574
PubMed Link to Article
Brilakis  ESBanerjee  SBerger  PB Perioperative management of patients with coronary stents. J Am Coll Cardiol 2007;49 (22) 2145- 2150
PubMed Link to Article
Lincoff  AMLeNarz  LADespotis  GJ  et al.  Abciximab and bleeding during coronary surgery: results from the EPILOG and EPISTENT trials: improve long-term outcome with abciximab GP IIb/IIIa blockade. Evaluation of platelet IIb/IIIa inhibition in STENTing. Ann Thorac Surg 2000;70 (2) 516- 526
PubMed Link to Article
Gammie  JSZenati  MKormos  RL  et al.  Abciximab and excessive bleeding in patients undergoing emergency cardiac operations. Ann Thorac Surg 1998;65 (2) 465- 469
PubMed Link to Article
Bizzarri  FScolletta  STucci  E  et al.  Perioperative use of tirofiban hydrochloride (Aggrastat) does not increase surgical bleeding after emergency or urgent coronary artery bypass grafting. J Thorac Cardiovasc Surg 2001;122 (6) 1181- 1185
PubMed Link to Article
Dyke  CMBhatia  DLorenz  TJ  et al.  Immediate coronary artery bypass surgery after platelet inhibition with eptifibatide: results from PURSUIT. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrelin Therapy. Ann Thorac Surg 2000;70 (3) 866- 871
PubMed Link to Article
Meadows  TABhatt  DL Clinical aspects of platelet inhibitors and thrombus formation. Circ Res 2007;100 (9) 1261- 1275
PubMed Link to Article
Schouten  OPoldermans  D Cardiac risk in non-cardiac surgery. Br J Surg 2007;94 (10) 1185- 1186
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Mode of action of the 3 main types of antiplatelet agents (thienopyridines [eg, clopidogrel], aspirin, and glycoprotein [Gp] IIb/IIIa inhibitors) in relation to inhibition of platelet function. ADP indicates adenosine triphosphate.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Algorithm for the management of bleeding for patients taking clopidogrel bisulfate. This should only be used as a guideline and specific management depends on clinical circumstances. Similar principles could be applied to the other antiplatelet agents. d/w Indicates discussed with; DDAVP, desmopressin acetate; PCI, percutaneous coronary intervention; and +/−, plus or minus.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Principal Indications for Oral Antiplatelet Agentsa
Table Graphic Jump LocationTable 2. Characteristics of the Main Antiplatelet Agentsa
Table Graphic Jump LocationTable 3. Bleeding Risk Associated With Different Surgical Procedures With Regard to Antiplatelet Therapies87,a

References

Badimon  LBadimon  JJVilahur  GSegales  ELlorente  V Pathogenesis of the acute coronary syndromes and therapeutic implications. Pathophysiol Haemost Thromb 2002;32 (5-6) 225- 231
PubMed Link to Article
Troxler  MDickinson  KHomer-Vanniasinkam  S Platelet function and antiplatelet therapy. Br J Surg 2007;94 (6) 674- 682
PubMed Link to Article
Elwood  PMorgan  GBrown  GPickering  J Aspirin for everyone older than 50? BMJ 2005;330 (7505) 1440- 1441
PubMed Link to Article
CAPRIE Steering Committee, A randomized, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348 (9038) 1329- 1339
PubMed Link to Article
Cannon  CPCAPRIE Investigators,Walker  PJ Effectiveness of clopidogrel versus aspirin in preventing acute myocardial infarction in patients with symptomatic atherothrombosis (CAPRIE TRIAL). Am J Cardiol 2002;90 (7) 760- 762
PubMed Link to Article
Ibanez  BVilahur  GBadimon  JJ Pharmacology of thienopyridines: rationale for dual pathway inhibition. Eur Heart J Suppl 2006;8 ((suppl G)) G3- G9
Link to Article
Steinhubl  SRBerger  PBMann  JT  III  et al. CREDO Investigators, Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002;288 (19) 2411- 2420
PubMed Link to Article
Gregorini  LMarco  JFajadet  J  et al.  Ticlopidine and aspirin pretreatment reduces coagulation and platelet activation during coronary dilation procedures. J Am Coll Cardiol 1997;29 (1) 13- 20
PubMed Link to Article
Spaulding  CHenry  PTeiger  E  et al.  Sirolimus-eluting versus uncoated stents in acute myocardial infarction. N Engl J Med 2006;355 (11) 1093- 1104
PubMed Link to Article
Scheller  BHehrlein  CBocksch  W  et al.  Treatment of coronary in-stent restenosis with a paclitaxel-coated balloon catheter. N Engl J Med 2006;355 (20) 2113- 2124
PubMed Link to Article
Grüntzig  ARSenning  ASiegenthaler  WE Nonoperative dilatation of coronary-artery stenosis: percutaneous transluminal coronary angioplasty. N Engl J Med 1979;301 (2) 61- 68
PubMed Link to Article
Serruys  PWStrauss  BHBeatt  KJ  et al.  Angiographic follow-up after placement of a self-expanding coronary-artery stent. N Engl J Med 1991;324 (1) 13- 17
PubMed Link to Article
Merritt  JCBhatt  DL The efficacy and safety of perioperative antiplatelet therapy. J Thromb Thrombolysis 2004;17 (1) 21- 27
PubMed Link to Article
 Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization: the EPILOG investigators. N Engl J Med 1997;336 (24) 1689- 1696
PubMed Link to Article
Smout  JStansby  G Current practice in the use of antiplatelet agents in the perioperative period by UK vascular surgeons. Ann R Coll Surg Engl 2003;85 (2) 97- 101
PubMed Link to Article
Joseph  JJPillai  ABramley  D Clopidogrel in orthopaedic patients: a review of current practice in Scotland. Thromb J 2007;56
PubMed Link to Article
Schünemann  HJCook  DGrimshaw  J  et al.  Antithrombotic and thrombolytic therapy: from evidence to application: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126 (3) ((suppl)) 688S- 696S
PubMed Link to Article
Lecompte  THardy  JF Antiplatelet agents and perioperative bleeding. Can J Anaesth 2006;53 (6) ((suppl)) S103- S112
PubMed Link to Article
Elwood  PCCochrane  ALBurr  ML  et al.  A randomized controlled trial of acetyl salicylic acid in the secondary prevention of mortality from myocardial infarction. Br Med J 1974;1 (5905) 436- 440
PubMed Link to Article
Patrono  CColler  BFitzgerald  GAHirsh  JRoth  G Platelet-active drugs: the relationships among dose, effectiveness, and side effects. Chest 2004;126 (3) ((suppl)) 234S- 264S
PubMed Link to Article
ISIS-2 (Second International Study of Infarct Survival) Collaborative group, Randomised trial of intravenous streptokinase, oral aspirin, or both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988;2 (8607) 349- 360
PubMed
Antithrombotic Trialists' Collaboration, Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324 (7329) 71- 86
PubMed Link to Article
Gaspoz  JMCoxson  PGGoldman  PA  et al.  Cost effectiveness of aspirin, clopidogrel, or both for secondary prevention of coronary artery disease. N Engl J Med 2002;346 (23) 1800- 1806
PubMed Link to Article
Kaushansky  K Thrombopoietin. N Engl J Med 1998;339 (11) 746- 754
PubMed Link to Article
Bertrand  MERupprecht  HJUrban  P Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS). Circulation 2000;102 (6) 624- 629
PubMed Link to Article
Müller  ISeyfarth  MRudiger  S  et al.  Effect of a high loading dose of clopidogrel on platelet function in patients undergoing coronary stent placement. Heart 2001;85 (1) 92- 93
PubMed Link to Article
Ringleb  PABhatt  DLHirsch  ATTopol  EJHacke  WCAPRIE Investigators, Benefit of clopidogrel over aspirin is amplified in patients with a history of ischaemic events. Stroke 2004;35 (2) 528- 532
PubMed Link to Article
Bhatt  DLChew  DPHirsch  ATRingleb  PAHacke  WTopol  EJ Superiority of clopidogrel versus aspirin in patients with prior cardiac surgery. Circulation 2001;103 (3) 363- 368
PubMed Link to Article
Bhatt  DLMarso  SPHirsch  ATRingleb  PAHacke  WTopol  EJ Amplified benefit of clopidogrel versus aspirin in patients with diabetes mellitus. Am J Cardiol 2002;90 (6) 625- 628
PubMed Link to Article
Bhatt  DLFox  KAHacke  W  et al. CHARISMA Investigators, Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354 (16) 1706- 1717
PubMed Link to Article
Mehta  SRYusuf  SPeters  RJ  et al.  Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358 (9281) 527- 533
PubMed Link to Article
Kastrati  AMehilli  JSchuhlen  H  et al.  A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel. N Engl J Med 2004;350 (3) 232- 238
PubMed Link to Article
Yusuf  SZhao  FMehta  SRChrolavicius  SToqnoni  GFox  KKClopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators, Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345 (7) 494- 502
PubMed Link to Article
Hamdalla  HSteinhubl  SR Clinical efficacy of clopidogrel across the whole spectrum of indications: percutaneous coronary intervention. Eur Heart J Suppl 2006;8 ((suppl G)) G20- G24
Link to Article
Boersma  EHarrington  RMoliterno  D A meta-analysis of all major randomized clinical trials. Lancet 2002;359 (9302) 189- 198
PubMed Link to Article
EPISTENT Investigators, Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein IIb/IIIa receptor blockade: the EPISTENT Investigators. Evaluation of platelet IIb/IIIa inhibitor for stenting. Lancet 1998;352 (9122) 87- 92
PubMed Link to Article
Tcheng  JEEllis  SGGeorge  BS  et al.  Pharmacodynamics of chimeric glycoprotein IIb/IIIa integrin antiplatelet antibody Fab 7E3 in high-risk coronary angioplasty. Circulation 1994;90 (4) 1757- 1764
PubMed Link to Article
ESPRIT Investigators, Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomized, placebo-controlled trial. Lancet 2000;356 (9247) 2037- 2044
PubMed Link to Article
Kastrati  AMehilli  JNeumann  FJ  et al.  Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial. JAMA 2006;295 (13) 1531- 1538
PubMed Link to Article
Valgimigli  MPercoco  GBarbieri  D  et al.  The additive value of tirofiban administered with the high-dose bolus in the prevention of ischaemic complications during high-risk coronary angioplasty: the ADVANCE trial. J Am Coll Cardiol 2004;44 (1) 14- 19
PubMed Link to Article
Bonz  AWLengenfelder  BStrotmann  J  et al.  Effect of additional temporary glycoprotein IIb/IIIa receptor inhibition on troponin release in elective percutaneous coronary interventions after pretreatment with aspirin and clopidogrel (TOPSTAR trial). J Am Coll Cardiol 2002;40 (4) 662- 668
PubMed Link to Article
Topol  EJMoliterno  DJHerrmann  HC  et al.  Comparison of two platelet glycoprotein IIb/IIIa inhibitors, tirofiban and abciximab, for the prevention of ischaemic events with percutaneous coronary revascularization. N Engl J Med 2001;344 (25) 1888- 1894
PubMed Link to Article
Bertrand  MESimoons  MLFox  KA  et al.  Management of acute coronary syndromes: acute coronary syndromes without persistent ST segment elevation. Recommendations of the Task Force of the European Society of Cardiology. Eur Heart J 2000;21 (17) 1406- 1432
PubMed Link to Article
Braunwald  EAntman  EMBeasley  JW  et al.  ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol 2000;36 (3) 970- 1062
PubMed Link to Article
Bertrand  MEVan Belle  E Triple antiplatelet treatment in patients presenting with non-ST-segment elevation acute coronary syndromes. Eur Heart J Suppl 2006;8 ((suppl G)) G59- G63
Link to Article
Bracey  AWGrigore  AMNussmeier  NA Impact of platelet testing on presurgical screening and implications for cardiac and noncardiac surgical procedures. Am J Cardiol 2006;98 (10A) 25N- 32N
PubMed Link to Article
Kapetanakis  EIMedlam  DAPetro  KR  et al.  Effect of clopidogrel premedication in off-pump cardiac surgery: are we forfeiting the benefits of reduced hemorrhagic sequelae? Circulation 2006;113 (13) 1667- 1674
PubMed Link to Article
Kang  WTheman  TEReed  JF  IIIStoltzfus  JWeger  N The effect of preoperative clopidogrel on bleeding after coronary artery bypass surgery. J Surg Educ 2007;64 (2) 88- 92
PubMed Link to Article
Leong  JYBaker  RAShah  PJCherian  VKKnight  JL Clopidogrel and bleeding after coronary artery bypass graft surgery. Ann Thorac Surg 2005;80 (3) 928- 933
PubMed Link to Article
Chen  LBracey  AWRadovancevic  R  et al.  Clopidogrel and bleeding in patients undergoing elective coronary artery bypass grafting. J Thorac Cardiovasc Surg 2004;128 (3) 425- 431
PubMed Link to Article
Kapetanakis  EIMedlam  DABoyce  SW  et al.  Clopidogrel administration prior to coronary artery bypass grafting surgery: the cardiologist's panacea or the surgeon's headache? Eur Heart J 2005;26 (6) 576- 583
PubMed Link to Article
Chen  ZMPan  HCChen  YP  et al. COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial) Collaborative Group, Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomized placebo-controlled trial. Lancet 2005;366 (9497) 1607- 1621
PubMed Link to Article
Schulman  SKearon  CSubcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis, Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005;3 (4) 692- 694
PubMed Link to Article
The GUSTO Investigators, An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329 (10) 673- 682
PubMed Link to Article
Chesebro  JHKnatterud  GRoberts  R  et al.  Thrombolysis in Myocardial Infarction (TIMI) Trial, phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge. Circulation 1987;76 (1) 142- 154
PubMed Link to Article
Eikelboom  JWHirsh  J Bleeding and management of bleeding. Eur Heart J Suppl 2006;8 ((suppl G)) G38- G45
Link to Article
Rao  SVO’Grady  KPieper  KS  et al.  Impact of bleeding severity on clinical outcomes among patients with acute coronary syndromes. Am J Cardiol 2005;96 (9) 1200- 1206
PubMed Link to Article
Moscucci  MFox  KACannon  CP  et al.  Predictors of major bleeding in acute coronary syndromes: the Global Registry of Acute Coronary Events (GRACE). Eur Heart J 2003;24 (20) 1815- 1823
PubMed Link to Article
Vilahur  GChoi  BGZafar  MU  et al.  Normalisation of platelet reactivity in clopidogrel-treated subjects. J Thromb Haemost 2007;5 (1) 82- 90
PubMed Link to Article
Lindvall  GSartipy  UVan der Linden  J Aprotinin reduces bleeding and blood product use in patients treated with clopidogrel before coronary artery bypass grafting. Ann Thorac Surg 2005;80 (3) 922- 927
PubMed Link to Article
Levi  MCromheecke  MEde Jonge  E  et al.  Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints. Lancet 1999;354 (9194) 1940- 1947
PubMed Link to Article
Levy  JH Pharmacological preservation of the hemostatic system during cardiac surgery. Ann Thorac Surg 2001;72 (5) S1814- S1820
PubMed Link to Article
van der Linden  JLindvall  GSartipy  U Aprotinin decreases postoperative bleeding and number of transfusions in patients on clopidogrel undergoing coronary artery bypass graft surgery: a double-blind, placebo controlled, randomized clinical trial. Circulation 2005;112 (9) ((suppl)) I276- I280
PubMed Link to Article
Akowuah  EShrivastava  VJamnadas  B  et al.  Comparison of two strategies for the management of antiplatelet therapy during urgent surgery. Ann Thorac Surg 2005;80 (1) 149- 152
PubMed Link to Article
von Heymann  CSchoenfeld  HSpander  MZiemer  SGrubitzsch  HSpies  C Clopidogrel-related refractory bleeding after coronary artery bypass graft surgery: a rationale for the use of coagulation factor concentrates? Heart Surg Forum 2005;8 (1) E39- E41
PubMed Link to Article
Arom  KVEmery  RW Decreased postoperative drainage with addition of epsilon-aminocaproic acid before cardiopulmonary bypass. Ann Thorac Surg 1994;57 (5) 1108- 1112
PubMed Link to Article
Altman  RScazziota  ADe Lourdes Herrera  MGonzalez  C Recombinant factor VIIa reverses the inhibitory effect of aspirin or aspirin plus clopidogrel on in vitro thrombin generation. J Thromb Haemost 2006;4 (9) 2022- 2027
PubMed Link to Article
Collet  JPHimbert  FSteg  PG Myocardial infarction after aspirin cessation in stable coronary artery disease patients. Int J Cardiol 2000;76 (2-3) 257- 258
PubMed Link to Article
Collet  JPMontalescot  GBlanchet  B  et al.  Impact of prior use or recent withdrawal of oral antiplatelet agents on acute coronary syndromes. Circulation 2004;110 (16) 2361- 2367
PubMed Link to Article
Burger  WChemnitius  JMKneissl  GDRucker  G Low-dose aspirin for secondary cardiovascular prevention-cardiovascular risks after its perioperative withdrawal versus bleeding risks with its continuation—review and meta-analysis. J Intern Med 2005;257 (5) 399- 414
PubMed Link to Article
Collet  JPMontalescot  G Premature withdrawal and alternative therapies to dual oral antiplatelet therapy. Eur Heart J Suppl 2006;8 ((suppl G)) G46- G52
Link to Article
Ong  ATHoye  AAoki  J  et al.  Thirty-day incidence and six-month clinical outcome of thrombotic stent occlusion after bare-metal, sirolimus, or paclitaxel stent implantation. J Am Coll Cardiol 2005;45 (6) 947- 953
PubMed Link to Article
Park  DWPark  SWPark  KH  et al.  Frequency of and risk factors for stent thrombosis after drug-eluting stent implantation during long-term follow-up. Am J Cardiol 2006;98 (3) 352- 356
PubMed Link to Article
Urban  PGershlick  AHGuagliumi  G  et al.  Safety of coronary sirolimus-eluting stents in daily clinical practice: one-year follow-up of the e-Cypher registry. Circulation 2006;113 (11) 1434- 1441
PubMed Link to Article
Kuchulakanti  PKChu  WWTorguson  R  et al.  Correlates and long-term outcomes of angiographically proven stent thrombosis with sirolimus- and paclitaxel-eluting stents. Circulation 2006;113 (8) 1108- 1113
PubMed Link to Article
Jeremias  ASylvia  BBridges  J  et al.  Stent thrombosis after successful sirolimus-eluting stent implantation. Circulation 2004;109 (16) 1930- 1932
PubMed Link to Article
McFadden  EPStabile  ERegar  E  et al.  Late thrombosis in drug-eluting coronary stents after discontinuation of antiplatelet therapy. Lancet 2004;364 (9444) 1519- 1522
PubMed Link to Article
Iakovou  ISchmidt  TBonizzoni  E  et al.  Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293 (17) 2126- 2130
PubMed Link to Article
Ferrari  EBenhamou  MCerboni  PMarcel  B Coronary syndromes following aspirin withdrawal: a special risk for late stent thrombosis. J Am Coll Cardiol 2005;45 (3) 456- 459
PubMed Link to Article
Daemen  JWenaweser  PTsuchida  K  et al.  Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study. Lancet 2007;369 (9562) 667- 678
PubMed Link to Article
Angiolillo  DJFernandez-Ortiz  ABernardo  E  et al.  Clopidogrel withdrawal is associated with proinflammatory and prothrombotic effects in patients with diabetes and coronary artery disease. Diabetes 2006;55 (3) 780- 784
PubMed Link to Article
Grines  CLBonow  ROCasey  DE  et al.  Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians. Circulation 2007;115 (6) 813- 818
PubMed Link to Article
González-Correa  JAArrebola  MMMartin-Salido  EMunoz-Marin  Jde la Cuesta  FSDe La Cruz  JP Effects of dexibuprofen on platelet function in humans: comparison with low-dose aspirin. Anesthesiology 2007;106 (2) 218- 225
PubMed Link to Article
Samama  CM Preoperative nonsteroidal anti-inflammatory agents as substitutes for aspirin: already too late? Anesthesiology 2007;106 (2) 205- 206
PubMed Link to Article
McDonald  SBRenna  MSpitznagel  EL  et al.  Preoperative use of enoxaparin increases the risk of postoperative bleeding and re-exploration in cardiac surgery patients. J Cardiothorac Vasc Anesth 2005;19 (1) 4- 10
PubMed Link to Article
Samama  CMBastien  OForestier  F  et al.  Antiplatelet agents in the perioperative period: expert recommendations of the French Society of Anesthesiology and Intensive Care (SFAR) 2001-summary statement. Can J Anaesth 2002;49 (6) S26- S35
PubMed
Samama  CMDjoudi  RLecompte  TNathan-Denizot  NSchved  JF Perioperative platelet transfusion: recommendations of the Agence Francaise de Securite Sanitaire des Produits de Sante (AFSSaPS) 2003. Can J Anaesth 2005;52 (1) 30- 37
PubMed Link to Article
Bélisle  SHardy  JF Hemorrhage and the use of blood products after adult cardiac operations: myths and realities. Ann Thorac Surg 1996;62 (6) 1908- 1917
PubMed Link to Article
Neilipovitz  DTBryson  GLNichol  G The effect of perioperative aspirin therapy in peripheral vascular surgery: a decision analysis. Anesth Analg 2001;93 (3) 573- 580
PubMed Link to Article
Kałuza  GLJoseph  JLee  JRRaizner  MERaizner  AE Catastrophic outcomes of noncardiac surgery soon after coronary stenting. J Am Coll Cardiol 2000;35 (5) 1288- 1294
PubMed Link to Article
Wilson  SHFasseas  POrford  JL  et al.  Clinical outcome of patients undergoing non-cardiac surgery in the two months following coronary stenting. J Am Coll Cardiol 2003;42 (2) 234- 240
PubMed Link to Article
Howard-Alpe  GMde Bono  JHudsmith  LOrr  WPFoex  PSear  JW Coronary artery stents and non-cardiac surgery. Br J Anaesth 2007;98 (5) 560- 574
PubMed Link to Article
Brilakis  ESBanerjee  SBerger  PB Perioperative management of patients with coronary stents. J Am Coll Cardiol 2007;49 (22) 2145- 2150
PubMed Link to Article
Lincoff  AMLeNarz  LADespotis  GJ  et al.  Abciximab and bleeding during coronary surgery: results from the EPILOG and EPISTENT trials: improve long-term outcome with abciximab GP IIb/IIIa blockade. Evaluation of platelet IIb/IIIa inhibition in STENTing. Ann Thorac Surg 2000;70 (2) 516- 526
PubMed Link to Article
Gammie  JSZenati  MKormos  RL  et al.  Abciximab and excessive bleeding in patients undergoing emergency cardiac operations. Ann Thorac Surg 1998;65 (2) 465- 469
PubMed Link to Article
Bizzarri  FScolletta  STucci  E  et al.  Perioperative use of tirofiban hydrochloride (Aggrastat) does not increase surgical bleeding after emergency or urgent coronary artery bypass grafting. J Thorac Cardiovasc Surg 2001;122 (6) 1181- 1185
PubMed Link to Article
Dyke  CMBhatia  DLorenz  TJ  et al.  Immediate coronary artery bypass surgery after platelet inhibition with eptifibatide: results from PURSUIT. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrelin Therapy. Ann Thorac Surg 2000;70 (3) 866- 871
PubMed Link to Article
Meadows  TABhatt  DL Clinical aspects of platelet inhibitors and thrombus formation. Circ Res 2007;100 (9) 1261- 1275
PubMed Link to Article
Schouten  OPoldermans  D Cardiac risk in non-cardiac surgery. Br J Surg 2007;94 (10) 1185- 1186
PubMed Link to Article

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 33

Related Content

Customize your page view by dragging & repositioning the boxes below.

See Also...
Articles Related By Topic
Related Collections
PubMed Articles
JAMAevidence.com

Users' Guides to the Medical Literature
Example 3