ABSTRACT: Early initiation of antiplatelet therapy in addition to aspirin is critical for all patients with acute coronary syndrome (ACS) due to improved short- and long-term outcomes. Thus, evidence-based practice guidelines for ACS management recommend early and intensive initiation of antiplatelet therapy with aspirin, clopidogrel, and/or glycoprotein (GP) IIb/IIIa inhibitors. Despite the comprehensive nature of current guidelines, several important clinical issues concerning the optimal initiation of antiplatelet therapy remain. This review addresses four of these clinical issues: When should GP IIb/IIIa inhibitors be initiated? When should clopidogrel be initiated? What is the optimal clopidogrel loading dose? How should antiplatelet therapy be approached in chronically anticoagulated patients?
J INVASIVE CARDIOL 2010;22:40–44
Key words: acute coronary syndrome; antiplatelet therapy; atherothrombosis; percutaneous coronary intervention
Acute coronary syndrome (ACS), including unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI), and ST-segment elevation myocardial infarction (STEMI),1 is commonly caused by plaque rupture with superimposed thrombus formation. Platelets play a central role in these pathological processes;2 therefore, antiplatelet therapy is a cornerstone treatment of both immediate and long-term ACS management. Antiplatelet agents currently available for ACS treatment are the cyclooxygenase-1 inhibitor aspirin, the P2Y12 receptor antagonists ticlopidine and clopidogrel, and the glycoprotein (GP) IIb/IIIa receptor antagonists abciximab, eptifibatide and tirofiban.
Early initiation of antiplatelet therapy is pivotal to improving the outcomes of all patients with ACS, regardless of the presence or absence of ST-segment elevation or the planned management strategy (i.e., medical management, fibrinolysis, coronary artery bypass graft [CABG], or percutaneous coronary intervention [PCI]). Due to the positive results of studies conducted from the early 1980s onward,3 initiation of aspirin during ACS has became standard clinical practice for all aspirin-tolerant patients.4,5 Based on their synergistic mechanisms of inhibiting platelet function, later studies were designed to assess whether adding P2Y12 or GP IIb/IIIa receptor antagonists to aspirin during the acute phase of ACS would further improve clinical outcomes. The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE)6,7 and CLopidogrel as Adjunctive ReperfusIon TherapY-Thrombolysis In Myocardial Infarction (CLARITY-TIMI) 288,9 trials showed that compared with aspirin monotherapy, dual antiplatelet therapy with aspirin and clopidogrel (300 mg loading dose followed by 75 mg/day maintenance dose) decreases the risk of adverse cardiovascular outcomes in all patients with ACS, regardless of their management strategy or whether they presented with UA/NSTEMI or STEMI. While dual therapy with aspirin and clopidogrel in patients with ACS does increase the risk of bleeding compared with aspirin alone, the overall benefit outweighs the risk.10
Numerous clinical trials have also demonstrated the efficacy of early GP IIb/IIIa inhibition in patients with ACS; however, as opposed to dual therapy with aspirin and clopidogrel, its benefit is dependent on the chosen management strategy and the patient’s risk level. In a meta-analysis of six clinical trials of patients with UA/NSTEMI not routinely scheduled for revascularization during study drug infusion, addition of a GP IIb/IIIa inhibitor significantly reduced the risk of death or myocardial infarction (MI).11 Subgroup analyses revealed that GP IIb/IIIa inhibitors were particularly effective in higher-risk patients.12 A similar relationship between treatment strategy and GP IIb/IIIa inhibition efficacy is also seen for patients with STEMI.13 High-risk patients with elevated troponin levels also benefit from triple antiplatelet therapy with aspirin, clopidogrel, and a GP IIb/IIIa inhibitor.14–16
Based on the results of such clinical studies, clinical practice recommendations/guidelines, such as the joint guidelines of the American College of Cardiology (ACC) and American Heart Association (AHA),4,5,17 recommend that antiplatelet therapy be initiated as soon as possible for all patients with ACS (Table). Despite these recommendations, important clinical questions about early antiplatelet therapy remain unanswered. This review addresses four of these clinical issues: When should GP IIb/IIIa inhibitors be initiated? When should clopidogrel be initiated? What is the optimal clopidogrel loading dose? How should antiplatelet therapy be approached in chronically anticoagulated patients?
When Should Glycoprotein IIb/IIIa Inhibitors Be Initiated?
The administration of aspirin to all patients with ACS without a contraindication as soon as possible following presentation is a well-established practice.4,5 However, the optimal timing of GP IIb/IIIa inhibitor and clopidogrel initiation remains controversial. Clinical trials suggest that in order to achieve the best clinical outcomes, GP IIb/IIIa inhibitors should be initiated prior to catheterization18 and continued during PCI.12 Additionally, GP IIb/IIIa inhibitors, particularly eptifibatide and tirofiban, may be given to patients who might require CABG, as they are not likely to increase the risk of bleeding due to the loss of their antiplatelet effect 4–6 hours after infusion is discontinued.19 Even if abciximab is given to a patient who requires urgent CABG, surgery may be initiated soon after therapy discontinuation, as platelet transfusion can be used to combat any postoperative bleeding that may develop.19 These results suggest that if a GP IIb/IIIa inhibitor is to be used, infusion should be initiated as soon as possible.4,20 One exception is if PCI will be delayed by > 24 hours after GP IIb/IIIa infusion. In this case, eptifibatide and tirofiban are the preferred GP IIb/IIIa inhibitors, as patients who received abciximab > 24 hours before PCI had increased mortality compared with those who received abciximab When Should Clopidogrel Be Initiated?
Based on results of several trials, guidelines recommended that patients receive a loading dose of clopidogrel to promote more rapid platelet inhibition than the 75 mg/day maintenance dose.4-9,23 These trials also support provision of the loading dose prior to diagnostic angiography. For example, the risk reduction associated with early clopidogrel and aspirin administration in the CURE trial was irrespective of a hospital’s capacity for diagnostic angiography or future invasive procedures.7
Despite this favorable evidence, clopidogrel is often withheld until after diagnostic angiography is performed, or when the physician is confident the patient will not require CABG, as clopidogrel increases the risk of bleeding when given within 5 to 7 days of CABG.7,23,24 However, the practice of delayed clopidogrel initiation may be to the detriment of patients who undergo PCI, as clinical trial evidence indicates that 300 mg clopidogrel pretreatment provides significant benefit only when administered at least 6 hours prior to intervention.7,23 While physicians should certainly be cognizant of the increased bleeding risk associated with clopidogrel use prior to CABG, such pretreatment has also been shown to reduce the risk of ischemic events in these patients.25,26 Furthermore, registry data show that only 4–12% of patients with ACS undergo CABG,27 and only 0.3–0.6% do so emergently.28 Thus, the majority of patients with ACS would benefit from upstream clopidogrel initiation. Indeed, recently published guidelines from the European Association for Cardio-thoracic Surgery suggest that clopidogrel should not be withheld from patients with ACS even if future CABG is possible.29 If necessary, CABG can be successfully performed within 5 days of clopidogrel cessation with the conscientious application of a bleeding management algorithm.30 Reflecting the available evidence, the updated UA/NSTEMI recommendations note that an experienced surgeon may elect to perform CABG without clopidogrel washout if the bleeding risk is considered acceptable,4 while the STEMI recommendations indicate clopidogrel washout may be forgone if the urgency for revascularization outweighs the incremental risk of bleeding (Table).5 While some surgeons advocate the use of commercially available point-of-care tests of platelet function to determine a patient’s risk of bleeding, the clinical utility of this technique has not been clearly established and cannot be recommended at this time.
Use of a higher clopidogrel loading dose, which is discussed in more depth later in this review, may also impact the timing of clopidogrel initiation. Evidence from several clinical trials14,31,32 and an unselected PCI cohort33 suggests that use of a 600 mg clopidogrel loading dose may preclude the need for extended clopidogrel pretreatment prior to PCI. If true, this might allow clopidogrel to be initiated after coronary angiography, thus avoiding the potential excess bleeding in patients who need urgent CABG, while preserving the benefit for patients who require PCI.
What Is the Optimal Clopidogrel Loading Dose?
While the use of a clopidogrel loading dose is well established, the optimal dosing strategy that provides the most benefit to the patient is not. Several ex-vivo platelet aggregation studies have shown that compared with a 300 mg clopidogrel loading dose, 600 mg more rapidly and intensely inhibits platelet aggregation.34–36 Based on the results of initial studies in which a 900 mg clopidogrel loading dose did not significantly decrease platelet aggregation compared with a 600 mg dose,36,37 it was hypothesized that 600 mg is the maximally absorbable clopidogrel dose. However, a more recent study suggests that this may not be true as the provision of two 600 mg clopidogrel loading doses given within 18–24 hours significantly decreased platelet aggregation compared with a single 600 mg dose.38
Additional insight into the optimal clopidogrel dosing strategy is provided by trials that evaluated clinical efficacy. In the Antiplatelet therapy for the Reduction of MYocardial Damage During Angioplasty (ARMYDA)-2 trial, a 600 mg clopidogrel loading dose was shown to significantly decrease the 30-day risk of death, MI or target vessel revascularization without increasing the risk of bleeding in patients with UA/NSTEMI undergoing PCI when compared to the standard 300 mg dose.37 In a large, retrospective cohort study of 4,105 consecutive patients with coronary artery disease who underwent PCI, a 600 mg clopidogrel loading dose was associated with better in-hospital and 1-month clinical outcomes and did not increase the risk of in-hospital bleeding compared with a 300 mg dose.39 Upon multivariate analysis, the 600 mg clopidogrel loading dose was associated with a significant 37% reduction in the risk of major adverse coronary events at 1 month. Results of a retrospective analysis of patients with stable angina undergoing PCI did not show a reduction in cardiovascular events with a 600 mg loading dose,40 suggesting that a higher loading dose may be more beneficial for acute patients. Similarly, results of a meta-analysis of ten studies comprising 1,567 patients who received either a clopidogrel loading dose of 300 mg or > 300 mg suggested that the highest risk patients derived the most benefit from higher loading doses.41
As a direct result of the observation that not all patients respond equally to clopidogrel, Bonello and colleagues explored adjusting the pre-PCI clopidogrel loading dose based on each patient’s level of platelet reactivity, as measured by the vasodilator-stimulated phosphoprotein index.42,43 As a component of these studies, patients were randomized to receive platelet reactivity-guided clopidogrel dosing up to 2,400 mg. Patients who received platelet reactivity-guided clopidogrel dosing prior to PCI experienced significantly fewer adverse coronary events, including stent thrombosis, at 1 month compared with those who received a single 600 mg clopidogrel loading dose.42,43 Notably, the risk of bleeding was not increased in patients who received larger clopidogrel doses. While these results suggest that large clopidogrel loading doses given to the appropriate patients effectively improve patient outcomes without compromising safety, additional data from ongoing studies is necessary before such large doses become standard clinical practice.
Current ACC/AHA guidelines reflect the uncertainty surrounding the clopidogrel loading dose for patients with ACS. For example, a 600 mg clopidogrel loading dose is recommended prior to or at the time of PCI for all patients without a high risk of bleeding not receiving fibrinolytic therapy within the preceding 12–24 hours.17 The UA/NSTEMI recommendations indicate the optimal loading dose is unknown, and that a 600 mg loading dose may be considered,4 while the STEMI recommendations maintain a recommendation of 300 mg.5 Results of the ongoing Clopidogrel optimal loading dose Usage to Reduce Recurrent EveNTs-Organization to Assess Strategies in Ischemic Syndromes (CURRENT-OASIS) 7 clinical trial will likely clarify the safety and efficacy of a 600 mg clopidogrel loading dose,44 and hopefully reduce the controversy in this area.
How Should Antiplatelet Therapy Be Initiated in Chronically Anticoagulated Patients?
Combined antiplatelet and anticoagulant therapy with aspirin, clopidogrel, and heparin is standard for patients with high-risk ACS upon initial presentation through hospital discharge or surgery.4 However, approximately 5–7% of patients with ACS, including those with atrial fibrillation, prosthetic heart valves or a history of thromboembolism, require long-term oral anticoagulation and are already anticoagulated.45,46 As elderly patients are more likely to have such indications, the aging of the population guarantees there will be a significant increase in the number of patients with ACS who, upon presentation, are already taking an oral anticoagulant.
There are several issues to consider when evaluating the management of these patients. The increased risk of bleeding in the elderly is important, as they are the most likely to have ACS complicated by atrial fibrillation.47 Other characteristics associated with an increased risk of bleeding include renal failure, peptic ulcer disease, cerebrovascular disease and diabetes mellitus.48 Data on the management of antiplatelet therapy in the chronically anticoagulated patient who presents with ACS is limited, primarily because such patients are usually excluded from clinical trials. Limited available data show that despite higher risk, chronically anticoagulated patients are less likely than those not anticoagulated to receive acute antithrombotic therapy, including aspirin, clopidogrel, heparin and GP IIb/IIIa inhibitors, less likely to receive the recommended dosages of acute medications, and less likely to undergo invasive procedures.45
In the absence of substantive data assessing the optimal management of chronically anticoagulated patients, the following recommendations may be considered. Physicians should not add another anticoagulant (e.g., heparin or low-molecular-weight heparin) without discontinuing oral anticoagulation unless a patient has a very low risk of bleeding;49 however, if the presenting indication dictates this addition, it should be used for as short a period of time as possible. If feasible and appropriate, PCI in anticoagulated patients should proceed through the radial artery using the smallest caliber catheter/stent system to minimize bleeding, and bare-metal stents should be used rather than drug-eluting stents to minimize the need for long-term dual-antiplatelet therapy.46,50,51 As determined by an assessment of the patient’s stroke risk, the physician should re-evaluate the need for anticoagulation and, if possible, discontinue it.46,50–52 For example, although chronic anticoagulation is recommended over the combination of aspirin and clopidogrel in patients with atrial fibrillation due to its superior efficacy in preventing vascular events,53 there would appear to be limited stroke risk when oral anticoagulation is replaced by aspirin plus clopidogrel for short periods of time (e.g., 3 months following PCI with bare-metal stent implantation).54
Conclusions
Early initiation of antithrombotic therapy in patients with ACS is critical to improving patient outcomes; as such, the ACC/AHA evidence-based recommendations for UA/NSTEMI, STEMI, and PCI contain guidelines regarding the use of early and aggressive antiplatelet therapy with aspirin, clopidogrel, and GP IIb/IIIa inhibitors.4,5,17 However, several issues are not clearly addressed in current guidelines, including questions of when to initiate GP IIb/IIIa therapy, when to initiate clopidogrel therapy, what the optimal clopidogrel loading dose should be, and how antiplatelet therapy should be used in chronically anticoagulated patients. Future comparative studies addressing a 600 mg clopidogrel loading dose will be important in determining optimal antiplatelet therapy strategies for patients with ACS. In addition, the recently approved antiplatelet agent prasugrel will undoubtedly further change the landscape as knowledge about its use accumulates. Further evaluation of combination antiplatelet-anticoagulant therapy is necessary to clarify treatment of those patients with ACS who present with indications for long-term anticoagulation. In the absence of clear recommendations from clinical practice guidelines, physicians should use available clinical evidence and assess risks of thrombosis, thromboembolism and bleeding to make educated decisions on the optimal use of antiplatelet therapy for their patients.
Penn State Hershey Medical Center, Penn State Heart and Vascular Institute, Hershey, Pennsylvania.
Editorial assistance (with searching the literature, coordinating revisions, and creating tables in preparation of this manuscript) was provided by Melanie Leiby, PhD, and funded by the Bristol-Myers Squibb/Sanofi Pharmaceutical Partnership. The author did not receive any compensation for this work.
Disclosure: Dr. Alagona has received speaker honoraria from Abbott Vascular and GlaxoSmithKline.
Manuscript submitted February 16, 2009, provisional acceptance given March 31, 2009, final version accepted August 7, 2009.
Address for correspondence: Peter Alagona, Jr., MD, Penn State Hershey Medical Center, Penn State Heart and Vascular Institute, 500 University Drive, Hershey, PA 17033. E-mail: palagona@hmc.psu.edu
1. Ramanath VS, Eagle KA. Evidence-based medical therapy of patients with acute coronary syndromes. Am J Cardiovasc Drugs 2007;7:95–116.
2. Meadows TA, Bhatt DL. Clinical aspects of platelet inhibitors and thrombus formation. Circ Res 2007;100:1261–1275.
3. Hennekens CH. Role of aspirin with thrombolytic therapy in acute myocardial infarction. Chest 1990;97(4 Suppl):151S–155S.
4. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction): Developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. Circulation 2007;116:e148–e304.
5. Antman EM, Hand M, Armstrong PW, et al. 2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: Developed in collaboration With the Canadian Cardiovascular Society endorsed by the American Academy of Family Physicians: 2007 Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction, writing on Behalf of the 2004 Writing Committee. Circulation 2008;117:296–329.
6. Mehta SR, Yusuf S, Peters 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;358:527–533.
7. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494–502.
8. Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005;352:1179–1189.
9. Sabatine MS, Cannon CP, Gibson CM, et al. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: The PCI-CLARITY study. JAMA 2005;294:1224–1232.
10. Bowry AD, Brookhart MA, Choudhry NK. Meta-analysis of the efficacy and safety of clopidogrel plus aspirin as compared to antiplatelet monotherapy for the prevention of vascular events. Am J Cardiol 2008;101:960–966.
11. Boersma E, Harrington RA, Moliterno DJ, et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: A meta-analysis of all major randomised clinical trials. Lancet 2002;359:189–198.
12. Roffi M, Chew DP, Mukherjee D, et al. Platelet glycoprotein IIb/IIIa inhibition in acute coronary syndromes. Gradient of benefit related to the revascularization strategy. Eur Heart J 2002;23:1441–1448.
13. De Luca G, Suryapranata H, Stone GW, et al. Abciximab as adjunctive therapy to reperfusion in acute ST-segment elevation myocardial infarction: A meta-analysis of randomized trials. JAMA 2005;293:1759–1765.
14. Kastrati A, Mehilli J, Neumann 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;295:1531–1538.
15. Rasoul S, Ottervanger JP, de Boer MJ, et al. A comparison of dual vs. triple antiplatelet therapy in patients with non-ST-segment elevation acute coronary syndrome: Results of the ELISA-2 trial. Eur Heart J 2006;27:1401–1407.
16. Iijima R, Ndrepepa G, Mehilli J, et al. Troponin level and efficacy of abciximab in patients with acute coronary syndromes undergoing early intervention after clopidogrel pretreatment. Clin Res Cardiol 2007;97:160–168.
17. King SB 3rd, Smith SC Jr, Hirshfeld JW Jr, et al. 2007 Focused Update of the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2007;117:261–295.
18. Montalescot G, Borentain M, Payot L, et al. Early vs late administration of glycoprotein IIb/IIIa inhibitors in primary percutaneous coronary intervention of acute ST-segment elevation myocardial infarction: A meta-analysis. JAMA 2004;292:362–366.
19. De Carlo M, Maselli D, Cortese B, et al. Emergency coronary artery bypass grafting in patients with acute myocardial infarction treated with glycoprotein IIb/IIIa receptor inhibitors. Int J Cardiol 2008;123:229–233.
20. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction). Circulation 2004;110:e82–e292.
21. Simoons ML. Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularisation: The GUSTO IV-ACS randomised trial. Lancet 2001;357:1915–1924.
22. Keeley EC, Boura JA, Grines CL. Comparison of primary and facilitated percutaneous coronary interventions for ST-elevation myocardial infarction: Quantitative review of randomised trials. Lancet 2006;367:579–588.
23. Steinhubl SR, Berger PB, Mann JT 3rd, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: A randomized controlled trial. JAMA 2002;288:2411–2420.
24. Berger JS, Frye CB, Harshaw Q, et al. Impact of clopidogrel in patients with acute coronary syndromes requiring coronary artery bypass surgery: A multicenter analysis. J Am Coll Cardiol 2008;52:1693–1701.
25. Fox KA, Mehta SR, Peters R, et al. Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non-ST-elevation acute coronary syndrome: The Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) Trial. Circulation 2004;110:1202–1208.
26. McLean DS, Sabatine MS, Guo W, et al. Benefits and risks of clopidogrel pretreatment before coronary artery bypass grafting in patients with ST-elevation myocardial infarction treated with fibrinolytics in CLARITY-TIMI 28. J Thromb Thrombolysis 2007;24:85–91.
27. Kapetanakis EI, Medlam DA, Boyce 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;26:576–583.
28. Yang EH, Gumina RJ, Lennon RJ, et al. Emergency coronary artery bypass surgery for percutaneous coronary interventions: Changes in the incidence, clinical characteristics, and indications from 1979 to 2003. J Am Coll Cardiol 2005;46:2004–2009.
29. Dunning J, Versteegh M, Fabbri A, et al. Guideline on antiplatelet and anticoagulation management in cardiac surgery. Eur J Cardiothorac Surg 2008;34:73–92.
30. Chen L, Bracey AW, Radovancevic R, et al. Clopidogrel and bleeding in patients undergoing elective coronary artery bypass grafting. J Thorac Cardiovasc Surg 2004;128:425–431.
31. Kandzari DE, Berger PB, Kastrati A, et al. Influence of treatment duration with a 600-mg dose of clopidogrel before percutaneous coronary revascularization. J Am Coll Cardiol 2004;44:2133–2136.
32. Di Sciascio G, Patti G, Pasceri V, et al. ARMYDA-5 (Antiplatelet therapy for reduction of Myocardial damage during angioplasty) Study: Prospective, multicenter, randomized trial investigation influence on outcome of in-lab 600 mg clopidogrel loading vs 6-hour pre-PCI treatment — “ARMYDA-Preload”. Transcatheter Cardiovascular Therapeutics (TCT), Washington, D.C., October 20–25, 2007.
33. Hochholzer W, Trenk D, Frundi D, et al. Time dependence of platelet inhibition after a 600-mg loading dose of clopidogrel in a large, unselected cohort of candidates for percutaneous coronary intervention. Circulation 2005;111:2560–2564.
34. Montalescot G, Sideris G, Meuleman C, et al. A randomized comparison of high clopidogrel loading doses in patients with non-ST-segment elevation acute coronary syndromes: The ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) trial. J Am Coll Cardiol 2006;48:931–938.
35. Cuisset T, Frere C, Quilici J, et al. Benefit of a 600-mg loading dose of clopidogrel on platelet reactivity and clinical outcomes in patients with non-ST-segment elevation acute coronary syndrome undergoing coronary stenting. J Am Coll Cardiol 2006;48:1339–1345.
36. von Beckerath N, Taubert D, Pogatsa-Murray G, et al. Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel: Results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) Trial. Circulation 2005;112:2946–2950.
37. Patti G, Colonna G, Pasceri V, et al. Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention: Results from the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study. Circulation 2005;111:2099–2106.
38. L'Allier PL, Ducrocq G, Pranno N, et al. Clopidogrel 600-mg double loading dose achieves stronger platelet inhibition than conventional regimens: Results from the PREPAIR randomized study. J Am Coll Cardiol 2008;51:1066–1072.
39. Bonello L, Lemesle G, De Labriolle A, et al. Impact of a 600-mg loading dose of clopidogrel on 30-day outcome in unselected patients undergoing percutaneous coronary intervention. Am J Cardiol 2008;102:1318–1322.
40. Wolfram RM, Torguson RL, Hassani SE, et al. Clopidogrel loading dose (300 versus 600 mg) strategies for patients with stable angina pectoris subjected to percutaneous coronary intervention. Am J Cardiol 2006;97:984–989.
41. Lotrionte M, Biondi-Zoccai GG, Agostoni P, et al. Meta-analysis appraising high clopidogrel loading in patients undergoing percutaneous coronary intervention. Am J Cardiol 2007;100:1199–1206.
42. Bonello L, Camoin-Jau L, Arques S, et al. Adjusted clopidogrel loading doses according to vasodilator-stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: A multicenter randomized prospective study. J Am Coll Cardiol 2008;51:1404–1411.
43. Bonello L, Camoin-Jau L, Armero S, et al. Tailored clopidogrel loading dose according to platelet reactivity monitoring to prevent acute and subacute stent thrombosis. Am J Cardiol 2009;103:5–10.
44. Mehta SR, Bassand JP, Chrolavicius S, et al. Design and rationale of CURRENT-OASIS 7: A randomized, 2 x 2 factorial trial evaluating optimal dosing strategies for clopidogrel and aspirin in patients with ST and non-ST-elevation acute coronary syndromes managed with an early invasive strategy. Am Heart J 2008;156:1080–1088, e1081.
45. Wang TY, Chen AY, Peterson ED, et al. Impact of home warfarin use on treatment patterns and bleeding complications for patients with non-ST-segment elevation acute coronary syndromes: Observations from the CRUSADE quality improvement initiative. Eur Heart J 2008;29:1103–1109.
46. Helft G, Gilard M, Le Feuvre C, et al. Drug insight: Antithrombotic therapy after percutaneous coronary intervention in patients with an indication for anticoagulation. Nat Clin Pract Cardiovasc Med 2006;3:673–680.
47. De Servi S, Cavallini C, Dellavalle A, et al. Non-ST-elevation acute coronary syndrome in the elderly: Treatment strategies and 30-day outcome. Am Heart J 2004;147:830–836.
48. Buresly K, Eisenberg MJ, Zhang X, et al. Bleeding complications associated with combinations of aspirin, thienopyridine derivatives, and warfarin in elderly patients following acute myocardial infarction. Arch Intern Med 2005;165:784–789.
49. Becker RC, Meade TW, Berger PB, et al. The primary and secondary prevention of coronary artery disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133(6 Suppl):776S–814S.
50. Rubboli A, Verheugt FW. Antithrombotic treatment for patients on oral anticoagulation undergoing coronary stenting: A review of the available evidence and practical suggestions for the clinician. Int J Cardiol 2008;123:234–239.
51. Rubboli A, Di Pasquale G. Triple therapy of warfarin, aspirin and a thienopyridine for patients treated with vitamin K antagonists undergoing coronary stenting. A review of the evidence. Intern Emerg Med 2007;2:177–181.
52. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classification schemes for predicting stroke: Results from the National Registry of Atrial Fibrillation. JAMA 2001;285:2864–2870.
53. Connolly S, Pogue J, Hart R, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): A randomised controlled trial. Lancet 2006;367:1903–1912.
54. Karjalainen PP, Porela P, Ylitalo A, et al. Safety and efficacy of combined antiplatelet-warfarin therapy after coronary stenting. Eur Heart J 2007;28:726–732.
