The Balance Between Anti-ischemic Efficacy and Bleeding Risk of Antithrombotic Therapy in Percutaneous Coronary Intervention: A

   ABSTRACT: Background. The development of newer and more potent antithrombotic agents and strategies has markedly reduced cardiovascular mortality and ischemic complications in patients with acute coronary syndromes and those undergoing percutaneous coronary intervention (PCI). With every approach to reduce coronary thrombosis, however, there is an accompanying risk of increasing bleeding complications elsewhere. Conversely, reducing bleeding complications may increase coronary thrombotic (ischemic) events. This is the Yin-Yang principle of antithrombotic therapy and strategies in PCI. Balancing both ends of the spectrum is essential, and an individualized approach to therapy is advocated. This article reviews the efficacy and bleeding risk profile of the different antithrombotic agents and strategies in PCI, including aspirin, thienopyridines, glycoprotein IIb/IIIa-inhibitors, heparin-based antithrombins, synthetic antithrombins and oral anticoagulants. Recommendations for reducing thrombotic and bleeding complications are also discussed. J INVASIVE CARDIOL 2010;22:284–292    Antithrombotic therapy has revolutionized the medical management of patients with acute coronary syndromes (ACS) as well as those undergoing percutaneous coronary intervention (PCI). In both situations, thrombus formation potentiated by plaque disruption, and in some situations, heightened thrombogenicity of the blood contribute to ischemic complications. The use of aspirin as an antithrombotic agent has markedly reduced cardiovascular mortality and ischemic complications. Over the past 20 years, the development of new antithrombotic medications and strategies has further reduced ischemic events. However, with every strategy to reduce thrombosis, there is always the possibility of increasing bleeding complications — a Yin-Yang analogy referring to opposing forces that are interconnected or interdependent in the natural world. In the case of PCI, decreasing thrombosis within the coronary vasculature may invariably result in bleeding in other vascular beds, and vice versa (Figure 1).    Clearly, thrombotic events increase morbidity and mortality from coronary intervention, leading to post-procedural myocardial infarction (MI) and cardiovascular mortality. Likewise, bleeding increases morbidity and mortality, and remains a leading cause of adverse events in PCI. This article reviews antithrombotic strategies in PCI (Table 1), with specific reference to the Yin and the Yang principle of these therapies, comparing the approaches that attempt to reduce thrombotic/ischemic complications but inadvertently increase bleeding events, or those that are intended to decrease hemorrhagic complications but consequently may increase coronary ischemic (thrombotic) risk. Measures to possibly reduce thrombotic complications in patients who are at particularly higher risk for recurrent ischemic events are discussed. Also explored are strategies in identifying the patients who are at higher risk of bleeding, as well as approaches to possibly reduce hemorrhagic adverse events during PCI, including prevention of vascular access-site complications.

Antiplatelet Therapy: Aspirin

   Aspirin versus placebo. Aspirin is an irreversible cyclooxygenase inhibitor that blocks platelet synthesis of thromboxane A2, thereby reducing platelet aggregation. Its efficacy for both primary¹ and secondary² prevention of cardiovascular events is well-established. Aspirin remains the cornerstone of antithrombotic therapy after MI and PCI. In patients with coronary artery disease (CAD), aspirin treatment, compared to placebo, was associated with significant proportional reductions in serious vascular events of 46% among patients with unstable angina and 33% (p 3 Aspirin therapy, however, was associated with a 1.7-fold increase in major bleeding events as compared to placebo.⁴    Low-dose versus high-dose aspirin. The optimal dose of aspirin is yet to be definitively resolved, but data from the Antithrombotic Trialists Collaboration (ATTC) meta analysis showed that in very low doses, the efficacy of aspirin appears to diminish, while at high doses, the bleeding complications increase. Aspirin in doses 5 This observation also applies in the setting of PCI, where the optimal effective dosage of aspirin remains largely undefined as well. In a large observational analysis of the patients who underwent PCI in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (PCI-CURE) study, moderate-dose aspirin (101–199 mg daily) was associated with a 28% (p = 0.37) reduction in 30-day cardiovascular events compared with low-dose aspirin ( 200 mg), however, were associated with worse clinical outcomes and a two-fold higher risk of major bleeding compared with low-dose aspirin.⁶    New data from the Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events study conducted by the Organization to Assess Strategies in Ischemic Syndromes (CURRENT-OASIS 7)⁷ regarding optimal aspirin dosing has recently been presented. In this trial of patients with ACS, there was no significant difference between low-dose (75–100 mg daily) or high-dose (300–325 mg daily) aspirin in terms of post-PCI death, MI or stroke (4.2% vs. 4.1%, respectively; p = 0.76), stent thrombosis (2.1% vs. 1.9%; p = 0.37), or major bleeding (2.3% vs. 2.3%, respectively; p = 0.71). However, in a subgroup analysis of patients who were taking high-dose clopidogrel, high-dose compared to low-dose aspirin was associated with significantly lower rates of ischemic events (3.8% vs. 4.5%, respectively; p = 0.043) without significantly increasing bleeding risk (2.4% vs. 2.7%, respectively; p = 0.099).    The current guidelines on post-PCI antiplatelet therapy recommend indefinite daily aspirin using lower doses (75–162 mg). Higher-dose aspirin (300–325 mg daily), however, is recommended during the early post-PCI period when the risk for stent thrombosis is highest. The recommended duration of high-dose aspirin therapy was based on clinical trial protocols, and varies according to stent type (minimum of 1 month for bare-metal, 3 months for sirolimus-eluting and 6 months for paclitaxel-eluting stents). Exception is made for patients at high risk of bleeding, where low-dose aspirin may be substituted.⁸

Dual Antiplatelet Therapy: Thienopyridines

   Aspirin monotherapy versus dual antiplatelet therapy. Thienopyridine derivatives (e.g., ticlopidine, clopidogrel) irreversibly inhibit platelet adenosine diphosphate receptors, diminishing the platelet aggregation response to adenosine diphosphate released from activated platelets. Aspirin and thienopyridine derivatives have complementary antiplatelet effects, and dual therapy leads to a greater antithrombotic effect at the expense of increased bleeding risk. In the Stent Anticoagulation Restenosis Study (STARS), patients who underwent PCI were assessed for clinical events reflecting stent thrombosis including death, target-lesion revascularization, angiographically evident thrombosis or MI within 30 days. In this trial, adverse clinical outcomes were observed in 3.6% of patients assigned to receive aspirin alone, as opposed to 0.5% assigned to receive both aspirin and ticlopidine (p 9 Dual antiplatelet therapy hence became the standard of care after PCI. In the same study, hemorrhagic complications occurred in 1.8% of patients who received aspirin alone, compared to 5.5% who received combination aspirin and ticlopidine (p = 0.02).    Similarly, in the PCI-CURE substudy of the CURE trial, combination therapy with aspirin and clopidogrel was associated with a 30% reduction in cardiovascular death, MI or urgent target-vessel revascularization compared with aspirin monotherapy in patients who underwent PCI.¹⁰ At low doses of aspirin, there was no significant difference in the rates of bleeding complications between combination aspirin-clopidogrel therapy and aspirin monotherapy, although significantly fewer patients in the dual-antiplatelet therapy group received concomitant glycoprotein (GP) IIb/IIIa inhibitor treatment. At higher doses of aspirin, however, major bleeding was seen in 4.5% in the dual-antiplatelet therapy group as compared with 3.3% (p = 0.02) of patients in the monotherapy group.¹¹    The antithrombotic efficacy of ticlopidine and clopidogrel is generally similar. However, ticlopidine is less well-tolerated and is associated with higher rates of discontinuance.^12,13 As a result, clopidogrel has become the preferred thienopyridine derivative used in clinical practice.¹⁴    Low-dose versus high-dose clopidogrel. The CURRENT- OASIS 7 trial⁷ compared standard-dose (300 mg load, then 75 mg daily) with double-dose clopidogrel (600 mg load, then 150 mg daily for 1 week, then 75 mg daily) among patients with ACS. In patients undergoing PCI, the study found that rates cardiovascular death, MI or stroke were significantly lower in those given double-dose (3.9%) compared with standard-dose clopidogrel (4.5%; p = 0.036). Stent thrombosis was also significantly reduced by 42% with double-dose clopidogrel. The greater antithrombotic efficacy of higher-dose clopidogrel was accompanied, however, by a significant 25% higher major bleeding risk.    The current guidelines for PCI in ACS recommend a clopidogrel loading dose of 300–600 mg, acknowledging that the optimal dose has not yet been established. While it is known that even higher loading doses (900 mg or higher) provide faster and greater antiplatelet effects, a consensus among experts regarding this issue has not been reached, as the safety profile of such strategy is yet to be defined.¹⁵    Short-term versus long-term clopidogrel therapy. The PCI- CURE trial compared short-term (4 weeks) with long-term (8 months average) clopidogrel treatment in patients with ACS undergoing PCI. In this study, the rate of death, MI or urgent revascularization was 30% lower with long-term (4.5%) compared with short-term (6.4%; p = 0.03) thienopyridine therapy. Major bleeding rates were similar between groups, although minor bleeding complications were significantly higher with long-term therapy (3.5% vs. 2.1%, respectively; p = 0.03).¹⁶    Likewise, the Clopidogrel for the Reduction of Events During Observation (CREDO) trial randomized patients undergoing PCI into treatment with either short-term (4-week course) or sustained (1-year course) clopidogrel therapy. At 1 year, sustained clopidogrel therapy resulted in a 27% relative reduction in the combined risk of death, MI or stroke compared with short-term therapy (p = 0.02). Also, early administration of clopidogrel at least 6 hours be- fore PCI was associated with a 39% relative risk reduction in short- term death, MI or urgent target-vessel revascularization (p =0.05).¹⁷ The tradeoff was a higher rate of major bleeding events with sustained clopidogrel therapy (5.6%) compared with short- term treatment (3.9%; p = 0.07), most notably in the rates of major gastrointestinal bleeding (1.4% vs. 0.3%, respectively; p = 0.01).¹⁸    Recommendations by expert panels regarding the duration of post-PCI thienopyridine therapy have been modified a few times, reflecting dynamic attempts at balancing antithrombotic efficacy with bleeding complications. The latest guidelines propose that clopidogrel 75 mg daily should be given for at least 12 months (and up to 15 months) to patients who received a stent (either bare-metal or drug-eluting). Earlier discontinuation of the thienopyridine may be considered for safety concerns if the risk of bleeding outweighs the antithrombotic benefits.¹⁵    Clopidogrel and fibrinolytic therapy. Among patients with ST-elevation MI treated with fibrinolysis and aspirin who subsequently underwent PCI, pretreatment with clopidogrel was associated with lower mortality in the Clopidogrel As Adjunctive Reperfusion Therapy – Thrombolysis in Myocardial Infarction (CLARITY-TIMI) 28 study.¹⁹ Among patients randomized to pre-treatment with clopidogrel, PCI was associated with significantly lower mortality than medical therapy alone (1.3% vs. 2.8%, re- spectively; p = 0.04). In contrast, PCI was associated with a higher mortality rate among patients randomized to placebo (2.6% vs. 1.7%; p = 0.24). Although major bleeding event rates were similar, patients treated with clopidogrel had higher rates of minor bleeding compared to placebo (1.9% vs. 0.9%, respectively; p = 0.08).    The newer thienopyridines. Prasugrel is a new thienopyridine that inhibits adenosine diphosphate-induced platelet aggregation more rapidly, more consistently and to a greater extent than clopidogrel in healthy volunteers and in patients with CAD.²⁰ In the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction (TRITON–TIMI 38), patients who underwent PCI had a significant 19% risk reduction in cardiovascular death, non-fatal MI or non-fatal stroke when treated with prasugrel as compared with clopidogrel, regardless of the type of coronary stent used (9.7% vs. 11.9%, respectively; p = 0.0001). Prasugrel was also associated with a 52% risk reduction in stent thrombosis irrespective of stent type (1.13% vs. 2.35%, respectively; p 21 Both the loading and maintenance doses of prasugrel were superior to those of clopidogrel for the reduction of ischemic events in PCI. This benefit is somewhat negated, however, by a 39% increased risk of major bleeding with prasugrel compared to clopidogrel (1.71% vs. 1.23%, respectively; p = 0.036).²²    Ticagrelor is a novel, reversible adenosine diphosphate receptor inhibitor that has a more rapid onset and more pronounced platelet inhibition than clopidogrel. The Platelet Inhibition and Patient Outcomes (PLATO) trial²³ compared ticagrelor and clopidogrel for the prevention of cardiovascular events in patients with ACS. At 1 year, cardiovascular death, MI or stroke had occurred in 9.8% of patients receiving ticagrelor as compared with 11.7% of those receiving clopidogrel — a significant 16% relative risk reduction; p 15 Expert consensus regarding the use of ticagrelor in PCI has yet to be published.

Triple Antiplatelet Therapy: Glycoprotein IIb/IIIa Inhibitors

   Dual versus triple antiplatelet therapy. The GP IIb/IIIa complex is a receptor for fibrinogen as well as von Willebrand factor, fibronectin and vitronectin, and is the final common final pathway for platelet aggregation. In an attempt to achieve maximal platelet inhibition during PCI, adjunctive use of GP IIb/IIIa inhibitor therapy has been added to the standard aspirin and thienopyridine regimen to improve ischemic outcomes, especially in high-risk settings.    In the second Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR- REACT 2) trial,²⁴ the benefit of adjunctive abciximab was compared with placebo in patients with ACS undergoing PCI who were pretreated with aspirin, clopidogrel and heparin. Abciximab therapy was found to be associated with a significant 25% risk reduction in death, MI or urgent target-vessel revascularization compared with placebo, especially in patients with elevated cardiac biomarkers (13.1% vs. 18.3%, respectively; p = 0.02). There was no significant difference reported in the rate of major or minor bleeding between the dual-and triple-antiplatelet strategies, but those who received abciximab had a 21% higher incidence of minor bleeding and a 20% higher transfusion rate.    The Bavarian Reperfusion Alternatives Evaluation-3 (BRAVE-3) trial²⁵ evaluated upstream GP IIb/IIIa inhibitor theapy using abciximab compared to placebo in patients with MI undergoing PCI. The addition of abciximab to standard dual-antiplatelet therapy did not significantly reduce infarct size, clinical events or major hemorrhagic complications compared with placebo. It was, however, associated with higher rates of minor bleeding (3.7% vs. 1.8%, respectively; p = 0.08) and thrombocytopenia (6% vs. 0%, respectively; p = 0.03).    Upstream versus deferred GP IIb/IIIa inhibitor therapy. In an attempt to decrease bleeding complications from antithrombotics during ACS therapy, a strategy has been explored where GP IIb/IIIa inhibitor treatment was given in the cardiac catheterization laboratory only to those undergoing PCI. The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) Timing trial²⁶ assigned patients with ACS to administration of a GP IIb/IIIa inhibitor either immediately upon randomization (upstream strategy) or during cardiac catheterization just prior to performing PCI (deferred strategy), and compared the rates of ischemic events. The strategy of deferring GP IIb/IIIa inhibitors and selectively using them only during PCI did result in a significant reduction in major bleeding (4.9% vs. 6.1%, respectively; p = 0.009). Accompanying this reduced bleeding rate, however, was a slightly higher rate of ischemic events noted in the deferred compared with the upstream strategy (7.9% vs. 7.1%, respectively; p = 0.13).    The strategies of upstream versus delayed GP IIb/IIIa inhibition in ACS were also compared in the Early Glycoprotein IIb/IIIa Inhibition in Non–ST-Segment Elevation Acute Coronary Syndrome (EARLY-ACS) trial, where the agent eptifibatide was given provisionally only to those undergoing PCI in the delayed strategy group. In the study, early administration of eptifibatide resulted in a nonsignificant reduction in rates of mortality or MI compared with the delayed strategy (11.2% vs. 12.3%, respectively; p = 0.08). However, upstream GP IIb/IIIa inhibition was associated with significantly higher rates of major bleeding (2.6% vs. 1.8%, respectively; p = 0.02) compared with provisional administration.²⁷    The current guidelines on ACS state that an upstream strategy of giving GP IIb/IIIa inhibitors early prior to cardiac catheterization is reasonable for patients with non-ST-elevation ACS who have high-risk thrombotic features and a relatively low bleeding risk. Upstream administration of GP IIb/IIIa inhibitors prior to PCI, however, is of unclear benefit in patients with ST-elevation MI, and is not recommended for routine therapy.¹⁵    Bolus-only versus standard infusion of GP IIb/IIIa inhibitor. The Evaluation of 7E3 for the Prevention of Ischemic Complications (EPIC) trial found that in high-risk patients undergoing balloon angioplasty, the addition of the GP IIb/IIIa-inhibitor abciximab to aspirin and heparin therapy resulted in a significant 35% reduction in ischemic events compared to placebo (12.8% vs. 8.3%, respectively; p = 0.008), in exchange for a 2-fold increase in major bleeding risk (14% vs. 7%, respectively; p 28 The same study also compared standard bolus-with-infusion and bolus-only strategies of abciximab administration during PCI. While the bolus-only strategy was associated with less frequent bleeding complications (11% vs. 14%; p-value not reported [NR]) and thrombocytopenia (3% vs. 5.2%; p = NR), the standard abciximab infusion strategy, on the other hand, was associated with lower rates of death, MI and urgent intervention (7.6% vs. 10.6%; p = NR).²⁹Interestingly, with the addition of clopidogrel pretreatment in patients undergoing uncomplicated PCI, the Early Discharge After Transradial Stenting of Coronary Arteries (EASY) trial found no significant differences in antithrombotic efficacy and bleeding complications in the bolus-only strategy compared with standard abciximab infusion.³⁰    The strategies of abbreviated (31    Facilitated PCI. It was previously theorized that combination therapy with GP IIb/IIIa inhibitors and thrombolytic agents would increase patency rates of coronary epicardial vessels and improve microvascular perfusion in acute MI, which would ultimately result in improved clinical outcomes in PCI. This hypothesis was tested in the Strategies for Patency Enhancement in the Emergency Department (SPEED/GUSTO 4) pilot trial,³² where combination abciximab and half-dose reteplase treatment (facilitated-PCI strategy) was compared with abciximab-only and reteplase-only therapies in patients with acute MI initially treated with pharmacologic reperfusion. There was a nonsignificant trend toward lower rates of death, MI and urgent revascularization in patients receiving facilitated PCI (5.9%) compared with those receiving reteplase alone (7.1%) and abciximab alone (8.1%; p = 0.89). This benefit, however, was counterbalanced by higher rates of major bleeding and transfusion requirement with combination therapy compared with reteplase-only and abciximab-only strategies (8.8% vs. 3.6% vs. 2.7%, respectively; p = 0.24).    To confirm such preliminary findings, the larger Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events (FI- NESSE) study³³ was conducted to compare the clinical effects of combination reteplase-abciximab-facilitated PCI, abciximab-facilitated PCI and primary PCI strategies on patients with acute MI. Significantly more patients had early ST-segment resolution with combination-facilitated PCI (43.9%) than with abciximab-facilitated PCI (33.1%; p = 0.01) or primary PCI (31.0%; p = 0.03). However, the mortality and cardiovascular event rates were not different among groups. Furthermore, non-intracranial bleeding complications were significantly more frequent with combination-facilitated (14.5%) compared with abciximab-facilitated (10.1%; p Antithrombin Therapy: Heparin     Unfractionated heparin. Unfractionated heparin (UFH), the prototypical antithrombin agent, is an essential component of early pharmacotherapy in ACS.³⁴ A pooled analysis of three randomized trials comparing treatment with heparin plus aspirin versus aspirin monotherapy estimated a 66% reduction in death or MI with adjunctive heparin therapy in patients with ACS. Another meta analysis of six randomized trials also demonstrated that the addition of heparin to aspirin reduced the rate of death or MI by 33% compared to aspirin therapy alone in patients with unstable angina. The enhanced antithrombotic efficacy with heparin, unfortunately, was accompanied by an increased risk of major bleeding (1.5% with combination therapy vs. 0.4% with aspirin alone).³⁵    Since the inception of angioplasty, periprocedural administration of antithrombin agents has been an integral component of PCI. With the intent to reduce bleeding complications, the possibility of performing PCI without periprocedural anticoagulation has recently been explored. The Reduction in Major and Minor Adverse Events With Eptifibatide-based Pharmacotherapy in Percutaneous Coronary Intervention (REMOVE) trial randomized a small number of patients undergoing elective PCI into standard treatment (heparin with triple-antiplatelet therapy using aspirin, clopidrogrel and the GP IIb/IIIa inhibitor eptifibatide) and triple-antiplatelet therapy without heparin. There indeed was a reduction in the bleeding index with omission of heparin compared with heparin-based PCI (3.0 vs. 3.9, respectively; p = 0.03). However, there was also a nonsignificant increase in the MI rate when heparin was not used in comparison to heparin use (17% vs. 13%, respectively; p = 0.54).³⁶    Unfractionated versus low-molecular-weight heparin. Low- molecular-weight heparin (LMWH) preparations have a higher anti-factor Xa/IIa ratio and more tissue factor pathway inhibition compared with UFH, resulting in a greater antithrombin activity. Also, the reduced binding of LMWH to plasma proteins is associated with high bioavailability after subcutaneous injection, a longer plasma half-life and a more predictable anticoagulant response, eliminating the need for frequent laboratory monitoring which is required during UFH infusions. The superiority of LMWH over UFH in reducing ischemic events has been well-documented in patients with ACS.³⁷    In the setting of PCI, the efficacy and bleeding outcomes with the LMWH enoxaparin was compared with UFH in the Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial of patients with ACS. The 30-day rates of death or MI were similar at 13.1% with enoxaparin and 14.2% with UFH (p = 0.289). Major bleeding in those undergoing PCI was significantly higher with enoxaparin (3.7%) compared with UFH (2.5%; p = 0.028), as was the need for transfusion. Bleeding rates also significantly increased with crossover from UFH to LMWH, and from LMWH to UFH.³⁸    However, in the Safety and Efficacy of Enoxaparin in PCI Patients (STEEPLE) trial of patients undergoing elective PCI, a single intravenous bolus of enoxaparin given at a lower dose (0.5 mg/kg) was associated with bleeding rates that were significantly lower compared to either UFH or enoxaparin bolus given at a higher dose (0.75 mg/kg).³⁹ Furthermore, in a meta-analysis of 13 trials comparing LMWH (in various dosing regimens) and UFH in patients undergoing PCI, UFH was actually associated with a higher risk of bleeding. UFH, however, was associated with a nonsignificant trend towards lower rates of death or urgent revascularization compared with LMWH, with similar rates of MI.⁴⁰

Antithrombin Therapy: Synthetic Agents

   Heparin versus bivalirudin. Bivalirudin is a synthetic, short-acting, direct antithrombin agent that binds specifically to thrombin at its active catalytic site. With the promise of reduced bleeding complications, bivalirudin is increasingly becoming a popular alternative anticoagulant to UFH in ACS therapy and PCI. Large randomized trials have consistently shown that the use of bivalirudin in PCI significantly reduced bleeding complications, without a significant increase in ischemic events compared to UFH.⁴¹ However, there has been a suggestion that bivalirudin monotherapy during PCI may augment specific thrombotic complications.    In the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE-2) trial, bivalirudin with provisional GP IIb/IIIa inhibition was compared with combination UFH-GP IIb/IIIa inhibition in patients undergoing PCI. In this study, the major bleeding rate was significantly reduced with bivalirudin (2.4% vs. 4.1%, respectively; p 42    Similar findings were noted in the ACUITY trial, which compared bivalirudin versus UFH or LMWH in patients with ACS undergoing PCI. Composite ischemic event rates were similar between the bivalirudin (19.4%) and heparin (17.8%) groups, while bleeding complications were reduced by 41% with bivalirudin. The rate of MI at 1 year, however, was somewhat higher in the bivalirudin group (9.1%) than in the heparin groups (7.8%; p = 0.06). Furthermore, in a subset of patients who were not pretreated with clopidogrel, bivalirudin monotherapy was associated with an almost 3-fold increase in death, MI or unplanned revascularization compared with combination heparin and GP IIb/IIIa inhibitor therapy (35.8% vs. 13.5%, respectively; p = NR).⁴³    Heparin versus fondaparinux. Fondaparinux is another synthetic, pure factor Xa inhibitor that selectively binds to antithrombin, causing rapid and predictable inhibition of factor Xa. Like enoxaparin, fondaparinux has linear pharmacokinetics with low interindividual and intraindividual variability, obviating the need for laboratory monitoring. Like bivalirudin, the potential for lower bleeding complications has made fondaparinux a viable alternative to heparin in ACS treatment and PCI. A small pilot trial, the Arixtra Study in Percutaneous Coronary Intervention: A Randomized Evaluation (ASPIRE), demonstrated that in patients undergoing PCI, fondaparinux treatment was associated with a nonsignificant 19% reduction in bleeding complications compared to UFH, with comparable efficacy outcomes.⁴⁴    The Fifth Organization to Assess Strategies in Ischemic Syndromes (OASIS-5) trial⁴⁵ compared fondaparinux and the LMWH enoxaparin in a large number of patients with ACS undergoing PCI. In this study, fondaparinux significantly reduced bleeding complications by half compared with enoxaparin (2.4% vs. 5.1%, respectively; p Antithrombin Therapy: Oral Anticoagulation    Warfarin post PCI. After stent implantation, the addition of the anticoagulant warfarin (a vitamin K antagonist) to aspirin therapy in patients who underwent PCI was associated with a significant 25% reduction in ischemic events compared with aspirin alone (2.7% vs. 3.6%, respectively; p = 0.001). This benefit was, however, negated by a 3-fold increase in major bleeding episodes (6.2% vs. 1.8%; p 9 Thienopyridine therapy, which is as- sociated with a superior reduction in both bleeding and ischemic cardiac events, has since supplanted warfarin as the main adjunct to aspirin in post-PCI antithrombotic therapy.⁴⁶ The use of anticoagulant therapy is generally avoided after PCI unless there is a concomitant condition requiring definitive anticoagulation (e.g., ST-elevation MI involving the proximal left anterior descending artery, severe systolic dysfunction, atrial fibrillation, venous thromboembolism, intracardiac thrombus, mechanical heart valves).    The current guidelines recommend all of the above antithrombin agents for potential use during PCI in ACS.¹⁵

Discussion

   The enhancement of antithrombotic benefit is often associated with an increase in bleeding risk. The ideal antithrombotic agent in PCI is one that maximizes anti-ischemic efficacy and boosts favorable clinical outcomes, all while reducing bleeding risk. Unfortunately, this ideal antithrombotic agent is yet to be developed. Perhaps, the closest to such an ideal antithrombotic at the present may be bivalirudin. However, even this drug, while reducing bleeding events, has demonstrated prothrombotic “signals.”    There are patients who are at a higher risk of ischemic vascular events by virtue of their comorbid conditions. These include patients who have active malignancy, severe heart failure, peripheral artery disease, diabetes, thrombophilia and/or a history of prior PCI. Demographic factors predisposing to thrombotic complications after PCI include male gender, younger age, smoking and no previous aspirin use. Periprocedural predictors of thrombosis include off-label PCI indication, multivessel disease, moderate CAD proximal to a culprit lesion, left anterior descending artery disease, PCI of totally occluded vessels, bifurcation lesions, high thrombus burden, vein graft PCI, suboptimal PCI result, long total stent size, undersized stent and coronary dissection.^47,48 These individuals may require a more aggressive antithrombotic approach using more potent agents at higher therapeutic doses and employing more effective drug-combination strategies (Table 2a). Aside from drug-based therapy, mechanical techniques during PCI, such as catheter thrombus aspiration49 and use of distal protection devices,⁵⁰ may also reduce thrombotic events in high-risk settings.    On the other hand, there are patients whose bleeding risks out- weigh the potential rewards of an aggressive antithrombotic strategy. Major bleeding related to PCI is associated with a 3-fold increase in mortality risk.⁵¹ While studies have employed different definitions for bleeding, analysis of these trials as reported support the Yin-Yang paradigm. Predictors of major bleeding in PCI and ACS include older age, female gender, hypertension, chronic kidney disease, anemia, bleeding history, cardiogenic shock and use of an intra-aortic balloon pump.⁵²    A majority of bleeding events attributed to PCI result from vascular access-site hemorrhagic complications, especially those involving the femoral artery. In the OASIS-5 trial,⁴⁵ the rate of vascular access-site complications after PCI ranged from 3.2–8.1%, which accounted for up to 86% of the total bleeding events. In particular, patients with ACS who undergo early PCI have higher bleeding rates than those treated with an initial conservative approach.⁵³ Use of bare-metal stents, which generally require a shorter minimum duration of post-PCI thienopyridine therapy, should be considered. Utilizing a radial approach as opposed to femoral vascular entry during PCI may significantly reduce bleeding from access-site complications,⁵⁴ as do the use of smaller sheath sizes and timely sheath removal.⁵⁵    Additional steps to reduce vascular access-site bleeding include careful attention to the location of the femoral artery puncture. Access adjacent to the lower half of the femoral head, in most cases, allows for the puncture site to be in the common femoral artery below the inferior epigastric branch, which is the ideal sheath access site. Vascular closure devices have not been shown to reduce bleeding events in most studies, but certain devices have been shown to be more effective than others in preventing vascular complications.⁵⁶ We believe these closure devices should be utilized after PCI when the puncture site is optimal, as described above. Another technique that we have found useful in reducing groin complications is the micropuncture technique of vascular access, utilizing a fine 21-gauge needle with a 0.018′′ initial guidewire, as opposed to the standard large-bore, 18-gauge needle. Although presently not evidence- based, it is theorized that the finer profile of the micropuncture needle causes less trauma to the vessel and surrounding tissues than the large-bore needle, reducing the adverse consequences from errant arterial punctures. Randomized trials, however, are required to confirm this hypothesis.    Other sources of major hemorrhage (e.g., gastrointestinal, genitourinary, rhinopharyngeal, intracranial, etc.), however, remain unaffected by operational techniques in PCI. Therefore, individuals who are prone to bleeding would warrant a more conservative approach to antithrombotic therapy, and the careful selection of antiplatelet and anticoagulant agents that are associated with less bleeding tendencies is advocated. Therapeutic considerations that can be made to reduce hemorrhagic complications in these high-risk patients are outlined in Table 2b.    The acute coronary syndromes (ST-elevation and non-ST- elevation MI), as risk factors, are unique in that they are associated with both a heightened propensity for ischemic cardiovascular events and increased predilection to bleeding complications in PCI. This is a common dilemma that makes choosing a particular antithrombotic strategy particularly difficult. In these situations, the clinician should pay extra attention to closely weighing the individual’s overall risk profile before choosing either a more aggressive or a more conservative approach to antithrombosis.

Conclusion

   Antithrombotic therapy in ACS and PCI has evolved since the establishment of angioplasty as a viable treatment for CAD decades ago. Advances in the understanding of clotting and ischemic mechanisms have led to the development of more effective pharmacotherapeutic agents and strategies to reduce adverse cardiovascular events in PCI. However, the more potent agents are often associated with a higher bleeding risk, and vice-versa. The ideal antithrombotic drug — one with maximal antithrombotic properties while having the least hemorrhagic potential — is yet to be developed, and perhaps never will. As such, clinicians will continue to face the reality of the Yin and the Yang of PCI: that further attempts to reduce thrombotic coronary events may raise the risk of hemorrhagic complications in other vascular beds, and that the development of safer agents that reduce hemorrhagic complications may increase coronary thrombotic events. Balancing both ends of the spectrum with the proper antithrombotic strategy is essential, and an individualized approach to therapy cannot be overemphasized.

_________________________________________________ From the Cardiology Division, Department of Medicine, UCSF School of Medicine, Fresno MEP, Fresno, California. The authors report no conflicts of interest regarding the content herein. Manuscript submitted December 8, 2009, provisional acceptance given January 18, 2010, final version accepted February 17, 2010. Address for correspondence: John A. Ambrose, MD, FACC, UCSF-Fresno Division of Cardiology, CRMC 5th Floor, 2823 Fresno Street, Fresno CA 93721. E-mail: jamambrose@yahoo.com

1. Steering Committee of the Physicians' Health Study Research Group. Final report on the aspirin component of the ongoing Physicians' Health Study. N Engl J Med 1989;321:129–135.
2. Wallentin LC. Aspirin (75 mg/day) after an episode of unstable coronary artery disease: Long-term effects on the risk for myocardial infarction, occurrence of severe angina and the need for revascularization. Research Group on Instability in Coronary Artery Disease in Southeast Sweden. J Am Coll Cardiol 1991;18:1587–1593.
3. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Br Med J 2002;324:71–86.
4. The AAA Investigators. Aspirin for Asymptomatic Atherosclerosis. Presented at the Eu- ropean Society of Cardiology Annual Scientific Sessions, August 2009.
5. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71–86.
6. Jolly SS, Pogue J, Haladyn K, et al. Effects of aspirin dose on ischaemic events and bleeding after percutaneous coronary intervention: Insights from the PCI-CURE study. Eur Heart J 2009;30:900–907.
7. CURRENT OASIS 7 Investigators. Clopidogrel optimal loading dose Usage to Reduce Recurrent EveNTs – Organization to Assess Strategies in Ischemic Syndromes. Presented at the European Society of Cardioly Annual Scientific Sessions, August 2009.
8. King SB, Smith SC, Hirshfeld JW, 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 2008;117:172–209.
9. Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three antithrombotic- drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study In- vestigators. N Engl J Med 1998;339:1665–1671.
10. 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 interven- tion: The PCI-CURE study. Lancet 2001;358:527–533.
11. Jolly SS, Pogue J, Haladyn K, et al. Effects of aspirin dose on ischaemic events and bleeding after percutaneous coronary intervention: Insights from the PCI-CURE study. Eur Heart J 2009;30:900–907.
12. Bertrand M, Rupprecht H, Urban P, et al. Double-blind study of the safety of clopidogrelwith and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: The clopidogrel aspirin stent inter- national cooperative study (CLASSICS). Circulation 2000; 102:624–629.
13. Muller C, Buttner H, Petersen J, et al. A randomized comparison of clopidogrel and as- pirin versus ticlopidine and aspirin after the placement of coronary-artery stents. Circu- lation 2000;101:590–593.
14. Popma JJ, Berger P, Ohman EM, et al. Antithrombotic therapy during percutaneous coronary intervention: The Seventh ACCP Conference on Antithrombotic and Throm- bolytic Therapy. Chest 2004;126(3 Suppl):576S–599S.
15. Kushner FG, Hand M, Smith SC Jr, et al; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation My- ocardial Infarction (updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (updating the 2005 Guideline and 2007 Focused Update): A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2009;120:2271–2306.
16. Mehta SR, Yusuf S, Peters RJ, et al; the CURE Investigators. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percuta- neous coronary intervention: The PCI-CURE study. Lancet 2001;358:527–533.
17. Steinhubl S, Berger P, Mann J, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: A randomized controlled trial. JAMA 2002;288:2411–2420.
18. Aronow HD, Steinhubl SR, Brennan DM, Berger PB, Topol EJ; CREDO Investigators. Bleeding risk associated with 1 year of dual antiplatelet therapy after percutaneous coro- nary intervention: Insights from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial. Am Heart J 2009;157:369–374.
19. Gibson CM, Murphy SA, Pride YB, et al; TIMI Study Group. Effects of pretreatment with clopidogrel on nonemergent percutaneous coronary intervention after fibrinolytic administration for ST-segment elevation myocardial infarction: A Clopidogrel as Adjunc- tive Reperfusion Therapy-Thrombolysis in Myocardial Infarction (CLARITY-TIMI) 28 study. Am Heart J 2008;155:133–139.
20. Wiviott SD, Braunwald E, McCabe CH, et al; TRITON-TIMI 38 Investigators. Pra- sugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001–2015.
21. Wiviott SD, Braunwald E, McCabe CH, et al; TRITON-TIMI 38 Investigators. Inten- sive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary interven- tion and stenting in the TRITON-TIMI 38 trial: A subanalysis of a randomised trial. Lancet 2008;371:1353–1363.
22. Antman EM, Wiviott SD, Murphy SA, et al. Early and late benefits of prasugrel in pa- tients with acute coronary syndromes undergoing percutaneous coronary intervention: A TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Op- timizing Platelet InhibitioN with Prasugrel-Thrombolysis In Myocardial Infarction) analy- sis. J Am Coll Cardiol 2008;51:2028–2033.
23. Wallentin L, Becker RC, Budaj A, et al; the PLATO Investigators. Ticagrelor versus clopi- dogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045–1057.
24. Kastrati A, Mehilli J, Neumann FJ, et al; Intracoronary Stenting and Antithrombotic: Regimen Rapid Early Action for Coronary Treatment 2 (ISAR-REACT 2) Trial Investi- gators. 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.
25. Mehilli J, Kastrati A, Schulz S, et al; Bavarian Reperfusion Alternatives Evaluation-3 (BRAVE-3) Study Investigators. Abciximab in patients with acute ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention after clopi- dogrel loading: A randomized double-blind trial. Circulation 2009;119:1933–1940.
26. Stone GW, Bertrand ME, Moses JW, et al; ACUITY Investigators. Routine upstream initiation vs deferred selective use of glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: the ACUITY Timing trial. JAMA 2007;297:591–602.
27. Giugliano RP, White JA, Bode C, et al; EARLY ACS Investigators. Early versus delayed, provisional eptifibatide in acute coronary syndromes. N Engl J Med 2009;360:2176–2190.
28. The EPIC Investigators. Use of a monoclonal antibody directed against the platelet gly- coprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 7;330:956–961.
29. Marmur JD, Mitre CA, Barnathan E, Cavusoglu E. Benefit of bolus-only platelet glyco- protein IIb/IIIa inhibition during percutaneous coronary intervention: Insights from the very early outcomes in the Evaluation of 7E3 for the Prevention of Ischemic Complica- tions (EPIC) trial. Am Heart J 2006;152:876–881.
30. Bertrand OF, Rodés-Cabau J, Larose E, et al. One-year clinical outcome after abciximab bolus-only compared with abciximab bolus and 12-hour infusion in the Randomized EArly Discharge after Transradial Stenting of CoronarY Arteries (EASY) Study. Am Heart J 2008;156:135–140.
31. Fung AY, Saw J, Starovoytov A, et al. Abbreviated infusion of eptifibatide after successful coronary intervention. The BRIEF-PCI (Brief Infusion of Eptifibatide Following Percu- taneous Coronary Intervention) randomized trial. J Am Coll Cardiol 2009;53:837–845.
32. Herrmann HC, Moliterno DJ, Ohman EM, et al. Facilitation of early percutaneous coro- nary intervention after reteplase with or without abciximab in acute myocardial infarction: Results from the SPEED (GUSTO-4 Pilot) Trial. J Am Coll Cardiol 2000;36:1489–1496.
33. Ellis SG, Tendera M, de Belder MA, et al; FINESSE Investigators. Facilitated PCI in pa- tients with ST-elevation myocardial infarction. N Engl J Med 2008;358:2205–2217.
34. Cohen M, Adams PC, Parry G, et al. Combination antithrombotic therapy in unstable rest angina and non-Q-wave infarction in nonprior aspirin users. Primary end points analysis from the ATACS trial. Antithrombotic Therapy in Acute Coronary Syndromes Research Group. Circulation 1994;89:81–88.
35. Oler A, Whooley MA, Oler J, Grady D. Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina. A meta-analysis. JAMA 1996;276:811–815.
36. Valencia R, Price MJ, Sawhney N, et al. Efficacy and safety of triple antiplatelet therapy with and without concomitant anticoagulation during elective percutaneous coronary intervention (the REMOVE trial). Am J Cardiol 2007;100:1099–1102.
37. Goodman SG, Cohen M, Bigonzi F, et al. Randomized trial of low molecular weight he- parin (enoxaparin) versus unfractionated heparin for unstable coronary artery disease: One-year results of the ESSENCE Study. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q Wave Coronary Events. J Am Coll Cardiol 2000;36:693–698.
38. White HD, Kleiman NS, Mahaffey KW, et al. Efficacy and safety of enoxaparin compared with unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention in the Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial. Am Heart J 2006;152:1042–1050.
39. Montalescot G, White HD, Gallo R, et al; STEEPLE Investigators. Enoxaparin versus unfractionated heparin in elective percutaneous coronary intervention. N Engl J Med 2006;355:1006–1017.
40. Dumaine R, Borentain M, Bertel O, et al. Intravenous low-molecular-weight heparins compared with unfractionated heparin in percutaneous coronary intervention: Quanti- tative review of randomized trials. Arch Intern Med 2007;167:2423–2430.
41. Lincoff AM, Bittl JA, Harrington RA, et al; REPLACE-2 Investigators. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glyco- protein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 ran- domized trial. JAMA 2003;289:853–863.
42. Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008;358:2218–2230.
43. White HD, Ohman EM, Lincoff AM, et al. Safety and efficacy of bivalirudin with and without glycoprotein IIb/IIIa inhibitors in patients with acute coronary syndromes un- dergoing percutaneous coronary intervention 1-year results from the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial. J Am Coll Cardiol 2008;52:807–814.
44. Mehta SR, Steg PG, Granger CB, et al; ASPIRE Investigators. Randomized, blinded trial comparing fondaparinux with unfractionated heparin in patients undergoing con- temporary percutaneous coronary intervention: Arixtra Study in Percutaneous Coronary Intervention: A Randomized Evaluation (ASPIRE) Pilot Trial. Circulation 2005;111:1390–1397.
45. Mehta SR, Granger CB, Eikelboom JW, et al. Efficacy and safety of fondaparinux versus enoxaparin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: Results from the OASIS-5 trial. J Am Coll Cardiol 2007;50:1742–1751.
46. Urban P, Macaya C, Rupprecht HJ, et al. Randomized evaluation of anticoagulation ver- sus antiplatelet therapy after coronary stent implantation in high-risk patients: The mul- ticenter aspirin and ticlopidine trial after intracoronary stenting (MATTIS). Circulation 1998;98:2126–2132.
47. van Werkum JW, Heestermans AA, Zomer AC, et al. Predictors of coronary stent throm- bosis: The Dutch Stent Thrombosis Registry. J Am Coll Cardiol 2009;53:1399–1409.
48. Mishkel GJ, Moore AL, Markwell S, Shelton ME. Correlates of late and very late throm- bosis of drug eluting stents. Am Heart J 2008;156:141–147.
49. Svilaas T, Vlaar PJ, van der Horst IC, et al. Thrombus aspiration during primary percu- taneous coronary intervention. N Engl J Med 2008;358:557–567.
50. Mauri L, Rogers C, Baim, DS. Devices for distal protection during percutaneous coronary revascularization. Circulation 2006;113:2651–2656.
51. Fuchs S, Kornowski R, Teplitsky I, et al. Major bleeding complicating contemporary pri- mary percutaneous coronary interventions-incidence, predictors, and prognostic impli- cations. Cardiovasc Revasc Med 2009;10:88–93.
52. Manoukian SV. Predictors and impact of bleeding complications in percutaneous coro- nary intervention, acute coronary syndromes, and ST-segment elevation myocardial in- farction. Am J Cardiol 2009;104(5 Suppl):9C–15C.
53. Cantor WJ, Mahaffey KW, Huang Z, et al. Bleeding complications in patients with acute coronary syndrome undergoing early invasive management can be reduced with radial access, smaller sheath sizes, and timely sheath removal. Cath Cardiovasc Interv 2006;69:73–83.
54. De Carlo M, Borelli G, Gistri R, et al. Effectiveness of the transradial approach to reduce bleedings in patients undergoing urgent coronary angioplasty with GP IIb/IIIa inhibitors for acute coronary syndromes. Catheter Cardiovasc Interv 2009;74:408–415.
55. Cannon CP, Weintraub WS, Demopoulos LA, et al; TACTICS-TIMI 18 Investigators. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med 2001;344:1879–1887.
56. Vaitkus PT. A meta-analysis of percutaneous vascular closure devices after diagnostic catheterization and percutaneous coronary intervention. J Invasive Cardiol 2004;16:243–246.