Anti-thrombotic management in interventional cardiology

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1 Chapter 8 Anti-thrombotic management in interventional cardiology James Tcheng, Steve Kindsvater Introduction Since the dawn of the interventional age, the need for anti-thrombotic therapy during percutaneous coronary intervention (PCI) has been considered a given. To mitigate the potential for intra-procedural thrombosis, Andreas Gruentzig administered unfractionated heparin in the very first PCI procedure in Aspirin was recognized as a mainstay of therapy in the early 1980s. Another decade would elapse, however, before systematic evaluations of anti-thrombotic strategies identified new therapeutics that could further improve outcomes of PCI beyond that achieved with aspirin and heparin. Over the past two decades, literally thousands of papers had been authored evaluating antithrombotic therapies in PCI. Most of these reports represent small steps, or in some cases missteps, in the understanding and use of anti-platelet and anti-thrombin agents as adjuncts to PCI. A few studies stand out for their contributions to our understanding of basic principles, or because they resulted in paradigm shifts in our therapeutic strategies. We believe the following papers represent these best of the best. Where is the body of evidence today? By coupling the absolutes of molecular science with the powers of observations across hundreds of thousands of patients, our understanding of the anti-thrombotic environment can perhaps best be summarized diagrammatically (Figure 1). There is a complex interplay between the classic coagulation cascade and platelet activity that leads to thrombosis. Interruption of the coagulation cascade (left side of panel) is best accomplished relatively late in the pathway, either by inhibition of factor Xa, the factor Xa V calcium complex, or at the level of thrombin. While unfractionated heparin has traditionally been the therapeutic mainstay, both enoxaparin or bivalirudin are in positions to (and arguably should) replace heparin today during PCI. The platelet, on the other hand, turns out to be much more difficult to address (right side of panel). Platelet activity can be divided into four different Coagulation cascade Enoxaparin Unfractional Heparin Fondaparinux Bivalirudin Hirudin Argatroban Ximelagatran Intrinsic, extrinsic pathways Plasma clotting cascade Prothrombin Factor Xa Antithrombin III Figure 1 Sites of anti-thrombotic drug action. Thrombin Fibrinogen Thrombolytics Aspirin Platelet agonists Thromboxane A 2 ADP Conformational activation of GPIIb/IIIa Platelet aggregation Fibrin Thrombus Platelet cascade Ticlopidine Clopidogrel GPIIb/IIIa inhibitors

2 Anti-thrombotic management in interventional cardiology functions: adhesion, activation, secretion, and aggregation. Both aspirin and the thienopyridines (ticlopidine and clopidogrel) target pathways that lead to platelet activation (and consequent secretion), and indirectly reduce (but do not eliminate) the capacity of platelets to aggregate. On the other hand, the glycoprotein IIb/IIIa (GP IIb/IIIa) receptor blockers prevent platelet aggregation, but they do not inhibit activation (or secretion). Thus the paradox is that inhibition of the final common pathway leading to platelet aggregation (with a GP IIb/IIIa inhibitor) is not sufficient to completely inhibit platelet function; in other words, the elaboration of vasoactive substrates and pro-inflammatory cytokines can occur despite treatment with these powerful agents. So where does this leave us? In the words of baseball great Casey Stengel, It s easy to get good players. Getting em to play together that s the hard part. Even today, the ideal regimen has not been defined. As many of these agents are costly, and all increase bleeding, each patient must be approached individually. Therapeutic decisions depend on striking a balance among efficacy, safety, and cost/cost-effectiveness. There does not appear to be a single cookbook approach that can be universally applied. It would seem appropriate for lower-risk patients (those unlikely to develop a thrombotic complication) to be managed with less aggressive regimens, while higher-risk patients deserve the multifaceted, multiple therapeutic target approach. The direction of future research will thus include the continued development and evaluation of new therapeutics along with efforts to fine tune the inherent complexity of multiple pathways, multiple agents, and multiple opportunities in defining and determining optimal strategies. 164

3 Classic Papers in Coronary Angioplasty Title 1 Author Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high risk coronary angioplasty Califf RM, for the EPIC (Evaluation of 7E3 for the Prevention of Ischemic Complications) Study Group Reference N Engl J Med 1994; 330: Abstract BACKGROUND: Platelets are believed to play a part in the ischemic complications of coronary angioplasty, such as abrupt closure of the coronary vessel during or soon after the procedure. Accordingly, we evaluated the effect of a chimeric monoclonal-antibody Fab fragment (c7e3 Fab) directed against the platelet glycoprotein IIb/IIIa receptor, in patients undergoing angioplasty who were at high risk for ischemic complications. The receptor is the final common pathway for platelet aggregation. METHODS: In a prospective, randomized, double-blind trial, 2099 patients treated at 56 centers received a bolus and an infusion of placebo, a bolus of c7e3 Fab and an infusion of placebo, or a bolus and an infusion of c7e3 Fab. They were scheduled to undergo coronary angioplasty or atherectomy in high-risk clinical situations involving severe unstable angina, evolving myocardial infarction, or high-risk coronary morphologic characteristics. The primary study end point consisted of any of the following: death, nonfatal myocardial infarction, unplanned surgical revascularization, unplanned repeat percutaneous procedure, unplanned implantation of a coronary stent, or insertion of an intraaortic balloon pump for refractory ischemia. The numbers of end-point events were tabulated for 30 days after randomization. RESULTS: As compared with placebo, the c7e3 Fab bolus and infusion resulted in a 35 percent reduction in the rate of the primary end point (12.8 vs. 8.3 percent, p 0.008), whereas a 10 percent reduction was observed with the c7e3 Fab bolus alone (12.8 vs percent, p 0.43). The reduction in the number of events with the c7e3 Fab bolus and infusion was consistent across the end points of unplanned revascularization procedures and nonfatal myocardial infarction. Bleeding episodes and transfusions were more frequent in the group given the c7e3 Fab bolus and infusion than in the other two groups. CONCLUSIONS: Ischemic complications of coronary angioplasty and atherectomy were reduced with a monoclonal antibody directed against the platelet IIb/IIIa glycoprotein receptor, although the risk of bleeding was increased. Summary The EPIC (Evaluation of 7E3 for the Prevention of Ischaemic Complications) study was a multicentre, randomized, parallel group, placebo-controlled trial of 2099 patients undergoing percutaneous coronary intervention (PCI) who were felt to be at high risk for developing a thrombosis-mediated ischaemic complication. Treatment with a bolus plus infusion of the glycoprotein IIb/IIIa (GP IIb/IIIa) blocker abciximab (ReoPro) reduced the 30-day incidence of major adverse cardiac events (death, myocardial infarction (MI), or urgent revascularization) by 35% (12.8% vs. 8.3%, p 0.009). This was accomplished mainly by a reduction in MI (8.6% vs. 165

4 Anti-thrombotic management in interventional cardiology 5.2%, p 0.013), but was accompanied by a doubling in rates of major thrombolysis in myocardial infarction (TIMI) bleeding and blood transfusion requirements. Citation Count 1223 Related References 1. Gruentzig AR, King III SB, Schlumpf M, Siegenthaler W. Long-term follow-up after percutaneous transluminal coronary angioplasty: the early Zurich experience. N Engl J Med 1987; 316: Parisi AF, Folland ED, Hartigan P. A comparison of angioplasty with medical therapy in the treatment of single-vessel coronary artery disease. N Engl J Med 1992; 326: Detre KM, Holmes Jr DR, Holubkov R, et al. Incidence and consequences of periprocedural occlusion: the national heart, lung, and blood institute percutaneous transluminal coronary angioplasty registry. Circulation 1990; 82: Ellis SG, Roubin GS, King III SB, et al. Angiographic and clinical predictors of acute closure after native vessel coronary angioplasty. Circulation 1988; 77: Topol EJ, Ferguson JJ, Weisman HF, et al. for the EPIC Investigators. Long-term protection from myocardial ischemic events in a randomized trial of brief integrin beta3 blockade with percutaneous coronary intervention. JAMA 1997; 278: Key message In high-risk patients undergoing percutaneous revascularization, potent peri-procedural antiplatelet therapy with the GP IIb/IIIa antagonist abciximab reduces acute ischaemic events, primarily nonfatal MI and urgent repeat percutaneous or surgical revascularization, and this benefit is sustained up to 3 years. This reduction in ischaemic events is achieved at the cost of increased bleeding and need for transfusion. Why it s important Strengths The EPIC study was the first to demonstrate that the GP IIb/IIIa integrin was a logical clinical target for modulating the thrombosis cascade, and that potent blockade of this receptor during coronary intervention translated into improved clinical outcomes. Furthermore, benefit was imparted across the spectrum of major adverse cardiac events attributable to thrombosis (death, MI, and abrupt closure leading to repeat coronary revascularization). Prior to the EPIC study, acute vessel closure following angioplasty, often a thrombosis-mediated event, was a major cause of patient morbidity and mortality. This was the first major pharmacological breakthrough in PCI, and began the paradigm shift to focus on pharmacotherapies as critical adjuncts to PCI. This was a large, well-designed, prospective randomized trial with sufficient power and provided detailed data and results describing the advantages and disadvantages of abciximab therapy as an adjunct to PCI. The study spawned a series of sub-analyses, which further extended the knowledge base for use of this class of drugs. Weaknesses Patients with either ST elevation acute MI (n 42), or lesions within saphenous vein grafts (n 101) comprised only a small fraction of the trial. Lower-risk patients were excluded from 166

5 Classic Papers in Coronary Angioplasty the study, reducing the generalizability of the results. Intracoronary stents were placed for procedural failure of angioplasty in less than 2%, and the need for a stent was tracked as part of the composite primary endpoint. Relevance In managing the high-risk patient undergoing PCI, this trial highlighted the central role of platelets in precipitating complications of PCI. The bolus and infusion approach of abciximab, directed against the platelet GP IIb/IIIa receptor, improved procedural success rates and reduced acute ischaemic events. Furthermore, this benefit of abciximab occurred in the setting of concomitant aggressive anticoagulation with unfractionated heparin with pre-specified goals for the activated clotting time (ACT) of s. Despite dual anticoagulation and anti-platelet therapy, the rate of intracranial haemorrhage was not increased with the GP IIb/IIIa inhibitor. The results paved the way to acceptance of GP IIb/IIIa blockade as a mainstay of therapy in coronary intervention and the acute coronary syndromes. 167

6 Anti-thrombotic management in interventional cardiology Title 2 Author Standard versus low-dose weight-adjusted heparin in patients treated with the platelet glycoprotein IIb/IIIa receptor antibody fragment abciximab (c7e3 Fab) during percutaneous coronary revascularization Lincoff MA, for the PROLOG (Precursor to EPILOG [Evaluation in PTCA to Improve Long-term Outcome with abciximab glycoprotein IIb/IIIa blockade]) Investigators Reference Am J Cardiol 1997; 79: Abstract Summary Blockade of the platelet glycoprotein IIb/IIIa receptor by abciximab (c7e3 Fab) during coronary intervention reduces the incidence of ischemic complications, but has been associated with a doubling of the risk for bleeding complications. The present pilot study investigated whether modification of heparin dosing and/or early sheath removal would reduce the hemorrhagic complications associated with abciximab. One hundred three patients undergoing coronary intervention received abciximab (0.25 mg/kg bolus, 10 mg/min infusion for 12 hours) and aspirin and were randomized in a 2 2 factorial design to 1 of 2 weight-adjusted heparin doses and to 1 of 2 strategies for heparin discontinuation and vascular sheath removal. In the standard-dose heparin group, an initial bolus of 100 U/kg was administered to achieve a procedural activated clotting time (ACT) 300 seconds; in the low-dose heparin group, an initial bolus of 70 U/kg was administered without adjustment for ACT. In the late sheath removal arm, heparin infusion was continued for the 12-hour duration of the abciximab infusion, followed by sheath removal; in the early sheath removal group, heparin was stopped after the interventional procedure and sheaths were removed during the abciximab infusion. There were no apparent differences between patients randomized to the different treatment groups with regard to the occurrence of ischemic end points. Rates of bleeding and blood transfusion were reduced by low-dose heparin and early sheath removal and were lowest when both strategies were combined. Reduction and weight adjustment of heparin dose and early sheath removal in the setting of platelet inhibition with abciximab during coronary intervention may be useful in diminishing the incidence of hemorrhagic complications without loss of clinical efficacy. This study was a follow-on to the EPIC (Evaluation of 7E3 for the Prevention of Ischaemic Complications) trial, where a doubling in the rates of major bleeding and blood transfusions were observed with abciximab (ReoPro) treatment during high-risk percutaneous coronary intervention (PCI). In EPIC, bleeding correlated inversely with the activated clotting time and with body weight, which led to the hypothesis that less anticoagulation and/or early sheath removal would reduce bleeding without attenuating the benefits of glycoprotein IIb/IIIa (GP IIb/IIIa) blockade. In a randomized, parallel group, factorial design, 103 patients were randomized to late sheath removal after the completion of a 12 h abciximab and heparin infusion with either low- or highdose procedural heparin, or early sheath removal during the abciximab infusion (without further 168

7 Classic Papers in Coronary Angioplasty heparin by infusion) with either low- or high-dose procedural heparin. Bleeding complications and a composite endpoint of death, myocardial infarction, or urgent revascularization were tabulated at 7 days. The combined strategy of early sheath removal and low-dose heparin resulted in the lowest rate of bleeding without affecting the composite efficacy endpoint rate. Citation Count 79 Related References 1. The EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 1994; 330: The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med 1997; 336: Key message When using abciximab as an adjunct to coronary intervention, rates of bleeding and transfusion can be reduced by a strategy of lower-dose peri-procedural heparin without subsequent heparin by intravenous infusion, along with sheath removal shortly after completion of the procedure. Why it s important Strengths PROLOG, the pilot study to the larger EPILOG (Evaluation in PTCA to Improve Long-term Outcome with abciximab Glycoprotein IIb/IIIa blockade) study, demonstrated that sheath haemostasis could be achieved while the patient was receiving a continuous infusion of the GP IIb/IIIa blocker abciximab. It provided sufficient evidence that substantially lower doses of heparin could also be safely evaluated in the subsequent EPILOG study. This was a small, elegantly designed, prospective randomized pilot study which concisely demonstrated the safety of a strategy of reduced procedural and post-procedural use of heparin coupled with vascular sheath removal shortly after PCI. Weaknesses This trial was (by design) underpowered to show definitive differences in either efficacy or in haemorrhagic complications, and thus could not be considered definitive despite the compelling trends. The observations required a larger follow-up trial (EPILOG) to confirm the findings. Relevance Until the PROLOG study was conducted, the interventional community felt it to be heresy to substantially reduce heparin dosing during and after PCI. It was also unclear whether vascular haemostasis could be achieved with full GP IIb/IIIa blockade on board. PROLOG provided sufficient evidence to challenge conventional wisdom. This permitted the clinical trials community to move forward and conduct the definitive EPILOG trial. 169

8 Anti-thrombotic management in interventional cardiology Title 3 Author Randomized placebo-controlled and balloon-angioplastycontrolled trial to assess the safety of coronary stenting with use of glycoprotein IIb/IIIa blockade Topol EJ, for the EPISTENT (Evaluation of Platelet IIb/IIIa Inhibitor for Stenting) Investigators Reference Abstract Lancet 1998; 352: BACKGROUND: Coronary stenting with the use of heparin, aspirin, and ticopidine for thromboprophylaxis is performed in more than 500,000 patients per year worldwide. We did a randomized controlled trial to assess the role of platelet glycoprotein IIb/IIIa blockade for use in elective stenting. METHODS: At 63 hospitals in the USA and Canada, 2399 patients with ischemic heart disease and suitable coronary artery lesions were randomly assigned stenting plus placebo (n 809), stenting plus abciximab, a IIb/IIIa inhibitor (n 794), or balloon angioplasty plus abciximab (n 796). The primary endpoint was a combination of death, myocardial infarction, or need for urgent revascularization in the first 30 days. All patients received heparin, aspirin, and standard pharmacological therapy. FINDINGS: The primary endpoint occurred in 87 (10.8%) of 809 patients in the stent plus placebo group, 42 (5.3%) of 794 in the stent plus abciximab group (hazard ratio 0.48 [95% CI ] p 0.001), and 55 (6.9%) of 796 in the balloon plus abciximab group (0.63 [ ] p 0.007). The main outcomes that occurred less with abciximab were death and large myocardial infarction 7.8% in the placebo group, 3.0% for stent plus abciximab (p 0.001), and 4.7% for balloon angioplasty plus abciximab (p 0.01). Major bleeding complications occurred in 2.2% of patients assigned stent plus placebo, 1.5% assigned stent plus abciximab, and 1.4% assigned balloon angioplasty plus abciximab (p 0.38). INTERPRETATION: Platelet glycoprotein IIb/IIIa blockade with abciximab substantially improves the safety of coronary-stenting procedures. Balloon angioplasty with abciximab is safer than stenting without abciximab. Summary By 1996, coronary stenting had been adopted as the desired technique for percutaneous intervention. Standard pharmacological prevention of stent thrombosis included heparin, aspirin, and the thienopyridine ticlopidine. The investigators hypothesized that a platelet glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitor, superimposed on standard pharmacological prevention, would further improve outcomes in coronary stenting. In a multicentre, randomized, double-blind, controlled, parallel group trial, 2399 patients were assigned to stenting plus placebo, stenting plus abciximab, or balloon angioplasty plus abciximab. The composite primary endpoint of death, myocardial infarction, or urgent revascularization was tabulated at 30 days. The primary endpoint was lowest in the stent plus abciximab group (5.3%, hazard ratio 0.48, p 0.001) and was also reduced in the balloon angioplasty plus abciximab group (6.9%, hazard ratio 0.63, p 0.007), compared with the stent plus placebo group (10.8%). 170

9 Classic Papers in Coronary Angioplasty Citation Count 838 Related References 1. Serruys PW, de Jaegere P, Kiemeneij F, et al. A comparison of balloon-expandable stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med 1994; 331: Fischman DL, Leon MB, Baim DS, et al. A randomized comparison of coronary stent placement and balloon angioplasty in the treatment of coronary artery disease. N Engl J Med 1994; 331: Lincoff MA, Califf RM, Moliterno DJ, for the EPISTENT Investigators. Complementary clinical benefits of coronary-artery stenting and blockade of platelet glycoprotein IIb/IIIa receptors. N Engl J Med 1999; 341: Topol EJ, Lincoff AM, Kereiakes DJ, for the EPISTENT Investigators. Multi-year follow-up of abciximab therapy in three randomized, placebo-controlled trials of percutaneous coronary revascularization. Am J Med 2002; 113: 1 6. Key message Even with stent implantation and aggressive anti-platelet therapy including aspirin and a thienopyridine, blockade of the platelet GP IIb/IIIa receptor with abciximab further reduces adverse cardiac events in patients undergoing placement of an intracoronary stent. This is accomplished primarily by reducing rates of death or large myocardial infarction (MI) (defined as new Q waves or creatinine kinase MB fraction greater than five times the upper limit of normal). Furthermore, balloon angioplasty plus abciximab is safer than the strategy of coronary stenting without the use of abciximab. Why it s important Strengths The BENESTENT and related studies had demonstrated the superiority of coronary stenting over balloon angioplasty primarily due to a reduction in the need for repeat revascularization. However, this benefit had come with a price tag, namely the problem of subacute stent thrombosis, occurring in 1 3% of patients. Furthermore, some in the interventional community did not believe platelet GP IIb/IIIa blockade to be relevant in the setting of stent implantation. EPISTENT (Evaluation of Platelet IIb/IIIa Inhibitor for Stenting) was the first to evaluate a GP IIb/IIIa receptor blocker, superimposed on the standard anti-thrombotic therapy, in patients undergoing elective coronary stenting, and demonstrated that abciximab reduced major events by more than 50% without an increase in bleeding complications. Furthermore, among 794 patients who received abciximab with stenting, there were no cases of sub-acute thrombosis. Lastly, the benefits of abciximab persisted at 6 months and at 1 year. A mortality benefit was also demonstrated at 1 year. EPISTENT was a well-designed, large, randomized, prospective trial with clearly defined and relevant clinical endpoints. The study addressed an issue of high clinical relevance, namely the utility of GP IIb/IIIa blockade following the paradigm shift from balloon to stent technologies during percutaneous coronary intervention (PCI). Weaknesses The number of patients undergoing vein graft angioplasty (n 51) was too small for definitive evaluation of this subgroup. Relevance of the MI component of the primary endpoint continues to be debated. 171

10 Anti-thrombotic management in interventional cardiology Relevance Simply put, EPISTENT ushered in a new standard of care for prevention of major adverse cardiovascular events with PCI. Potent anti-platelet therapy with abciximab during coronary stenting or angioplasty reduces the likelihood of patient death or large MI, without causing an excess in bleeding complications. 172

11 Classic Papers in Coronary Angioplasty Title 4 Author Clinical pharmacology of higher dose eptifibatide in percutaneous coronary intervention (The PRIDE Study) Reference Tcheng JE, Talley JD, O Shea JC, et al. Am J Cardiol 2001; 88: Abstract This study describes the dose-exploration phase of the PRIDE trial, an investigation of the clinical pharmacology of higher dose eptifibatide in patients who underwent elective percutaneous coronary intervention (PCI). Outcomes of treatment with the platelet glycoprotein IIb/IIIa inhibitors were dependent upon proper dosing selection. In this multicenter, placebo-controlled clinical study, 127 patients were randomized 1:1:2:2 into 1 of the following treatment groups: placebo; eptifibatide as a 135 g/kg bolus followed by a 0.75 g/kg/min infusion; eptifibatide as a 180 g/kg bolus with a 2.0 g/kg/min infusion; or eptifibatide as a 250 g/kg bolus with a 3.0 g/kg/min infusion. Light transmission aggregometry was used to determine platelet aggregation in response to 20 M adenosine diphosphate, and platelet receptor occupancy was also determined. Eptifibatide exhibited linear pharmacokinetics over the dose range studied. Inhibition of platelet aggregation was greater in samples collected in sodium citrate compared with those collected in D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone [PPACK]. The 180/2.0 dosing regimen achieved 90% inhibition of platelet aggregation immediately (5 minutes) and at steady state (8 24 hours). At 1 hour, mean inhibition of platelet aggregation was 80%. Eptifibatide exhibited dose-dependent pharmacodynamics that were dependent upon choice of anticoagulant. A 180 g/kg bolus followed by a 2.0 g/kg/min infusion at steady state achieved 80% inhibition of platelet aggregation. With the single-bolus regimen, however, there was an early loss of the inhibition of platelet aggregation before steady state was reached. Additional dose-exploration studies may further optimize eptifibatide dosing. Summary In a series of seminal trials in coronary intervention, blockade of the glycoprotein IIb/IIIa (GP IIb/IIIa) receptor with abciximab was shown to reduce adverse cardiac event rates by 35 50%. A similar trial of eptifibatide (Integrilin), the IMPACT-II (Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis II) trial, showed only a marginal 14 22% benefit. The PRIDE trial was conducted to determine if the in vivo activity of eptifibatide might have been overestimated by the ex vivo assay conditions used to select the eptifibatide doses evaluated in IMPACT-II. Before elective percutaneous intervention, 127 patients were randomized to placebo or one of three combinations of an eptifibatide bolus and maintenance infusion. Samples were assayed for platelet aggregation (anticoagulants: sodium citrate and PPACK), receptor occupancy, and drug concentration. Clinical 30-day endpoints included bleeding complications, death, myocardial infarction, or urgent revascularization. Dose-dependent pharmacodynamics were observed, with citrate anticoagulation exaggerating the anti-platelet effects. The 180 g/kg bolus and 2.0 g/kg/min infusion achieved target 173

12 Anti-thrombotic management in interventional cardiology platelet inhibition, but was associated with an equilibration/volume of distribution dependent transient decrement in inhibition in the 1 4 h time window. Citation Count 20 Related References 1. The IMPACT-II Investigators. Randomized placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention. Lancet 1997; 349: Phillips DR, Teng W, Arfsten A, et al. Effect of calcium on GP IIb/IIIa interactions with integrilin-enhanced GP IIb/IIIa binding and inhibition of platelet aggregation by reductions in the concentration of ionized calcium in plasma anticoagulated with citrate. Circulation 1997; 96: The PURSUIT Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med 1998; 339: Key message The PRIDE study elegantly demonstrated that sodium citrate interferes with the assay for platelet aggregation in patients undergoing percutaneous coronary intervention (PCI), leading to an overestimation of the in vivo effects of eptifibatide. PRIDE suggested an appropriate dose of eptifibatide to achieve adequate platelet inhibition during the peri-pci period. The PRIDE study also underscored the critical need for physiologically relevant assay parametres in pharmacodynamic evaluations of agents prior to the design of pivotal clinical trials. Why it s important In evaluating eptifibatide as an adjunct to percutaneous intervention, the IMPACT-II trial documented a reduction in the rate of major adverse events by 22% at 30 days. Although statistically significant, the magnitude of the observed benefit was less than expected based upon comparable studies of other GP IIb/IIIa receptor blockers. The PRIDE study revealed that the IMPACT- II dose (135 g/kg bolus and 0.75 g/kg/min infusion) fell far short of its target of 80% inhibition of platelet aggregation. Furthermore, PRIDE showed that a 180 g/kg bolus and 2.0 g/kg/min infusion of eptifibatide, as used in the PURSUIT (Platelet IIb-IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy) trial, was similarly inadequate, leading to an early dip below the 80% platelet inhibition benchmark. This led to further modelling of eptifibatide pharmacodynamics, eventually identifying a 180 g/kg double bolus coupled with a 2.0 g/kg infusion as the optimal regimen. Strengths The PRIDE trial was a classic dose escalation, pharmacodynamic study with a novel twist (multiple anticoagulants and multiple platelet agonists) that assessed the effects of various doses of eptifibatide used in percutaneous intervention. Weaknesses None of the doses utilized in the PRIDE trial actually achieved the goal of greater than 80% inhibition of platelet aggregation throughout the study period. Further study and computer-assisted modelling was thus required to identify the proper dose. Nonetheless, PRIDE did provide a 174

13 Classic Papers in Coronary Angioplasty pharmacodynamic blueprint for a sufficiently potent eptifibatide dose which could be used in future trials. Relevance By demonstrating that the doses utilized in both the IMPACT-II and PURSUIT trials were too low, the PRIDE study underscored the importance of pharmacodynamic modelling. Furthermore, by providing a rationale for the marginal benefits observed in these two trials, PRIDE re-invigorated the debate that the platelet inhibition afforded by GP IIb/IIIa inhibitors might be a class effect. 175

14 Anti-thrombotic management in interventional cardiology Title 5 Author Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomized, placebo-controlled trial Reference Abstract Summary Tcheng JE, for The ESPRIT Investigators Lancet 2000; 356: BACKGROUND: The platelet glycoprotein IIb/IIIa inhibitors, although effective in reducing ischemic complications of percutaneous coronary intervention, are used in few coronary stent implantation procedures. ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy) is a randomized, placebo-controlled trial to assess whether a novel, double-bolus dose of eptifibatide could improve outcomes of patients undergoing coronary stenting. METHODS: We recruited 2064 patients undergoing stent implantation in a native coronary artery. Immediately before percutaneous coronary intervention, patients were randomly allocated to receive eptifibatide, given as two 180 g/kg boluses 10 min apart and a continuous infusion of 2.0 g/kg/min for h, or placebo, in addition to aspirin, heparin, and a thienopyridine. The primary endpoint was the composite of death, myocardial infarction, urgent target vessel revascularization, and thrombotic bailout glycoprotein IIb/IIIa inhibitor therapy within 48 h after randomization. The key secondary endpoint was the composite of death, myocardial infarction, or urgent target vessel revascularization at 30 days. FINDINGS: The trial was terminated early for efficacy. The primary endpoint was reduced from 10.5% (108 of 1024 patients on placebo [95% CI %]) to 6.6% (69 of 1040 [ %]) with treatment (p ). The key 30-day secondary endpoint was also reduced, from 10.5% (107 of 1024 patients on placebo [ %]) to 6.8% (71 of 1040 [ %]; p ). There was consistency in reduction of events across all components of the composite endpoint and among the major subgroups. Major bleeding was infrequent but arose more often with eptifibatide than placebo (1.3%, 13 of 1040 [ %] vs. 0.4%, 4 of 1024 [ %]; p 0.027). INTERVENTION: Routine glycoprotein IIb/IIIa inhibitor pretreatment with eptifibatide substantially reduces ischemic complications in coronary stent intervention and is better than a strategy of reserving treatment to the bailout situation. The ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy) Trial evaluated a novel, higher-dose regimen of the glycoprotein IIb/IIIa (GP IIb/IIIa) receptor blocker eptifibatide (Integrilin) than had been studied in two previous pivotal trials. ESPRIT was a multicentre, randomized, double-blind, parallel group trial that recruited 2064 patients undergoing nonurgent percutaneous coronary intervention (PCI) to placebo or eptifibatide (two 180 g/kg boluses 10 min apart and a 2.0 g/kg/min h infusion) in addition to aspirin, unfractionated heparin, and a thienopyridine. Second and third generation stents were deployed in patients in ESPRIT. Endpoints included death, myocardial infarction (MI), and urgent revascularization at 48 h and 30 days, and bailout GP IIb/IIIa inhibitor therapy at 48 h. Eptifibatide treatment produced a significant 37% reduction in the 48 h primary endpoint which was maintained to 30 days and 1 year. 176

15 Classic Papers in Coronary Angioplasty Citation Count 262 Related References 1. The IMPACT-II Investigators. Randomized placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention. Lancet 1997; 349: The PURSUIT Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med 1998; 339: Tcheng JE, Talley JD, O Shea JC, et al. Clinical pharmacology of higher dose eptifibatide in percutaneous coronary intervention (the PRIDE study). Am J Cardiol 2001; 88: Topol EJ, for the EPISTENT Investigators. Randomized placebo-controlled and balloonangioplasty-controlled trial to assess the safety of coronary stenting with use of platelet glycoprotein IIb/IIIa blockade. Lancet 1998; 352: Key message The high-dose, double-bolus regimen of eptifibatide in planned coronary stent implantation produced clinically relevant and statistically significant reductions in ischaemic complications. This suggests a dose-dependent class effect to the benefit of platelet GP IIb/IIIa integrin blockade. Also, benefit was observed with eptifibatide therapy despite the relative maturity of stent technologies. Why it s important Strengths The ESPRIT dosing strategy achieved greater than 90% inhibition of GP IIb/IIIa receptors throughout the dosing period. The lower dose of eptifibatide used in the IMPACT-II (Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis II) trial (50 60% inhibition) reduced the composite of death, MI, or urgent revascularization from 11.6% to 9.1% (absolute difference 2.5%). In ESPRIT, high-dose eptifibatide reduced the composite endpoint from 10.5% to 6.9% ( 3.6%). Abciximab, the GP IIb/IIIa receptor from the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) trial, reduced the composite endpoint from 8.9% to 5.2% ( 3.7%). Taking trial differences into consideration, the findings of the ESPRIT trial are in accord with those of the EPISTENT trial, suggesting a class effect of the GP IIb/IIa receptor blockers. The ESPRIT trial was a large scale, well-designed, randomized, placebo-controlled trial. Weaknesses Emergency intervention patients (such as those with ongoing ischaemia or acute MI) were not included in the trial, nor were patients with a target lesion in a coronary bypass graft. A head-tohead comparison of eptifibatide to abciximab would have further advanced the field. Relevance Although prior trials had shown a clear benefit of abciximab in PCI, at the time of the ESPRIT trial abciximab was only utilized in 25% of cases, likely secondary to the high costs of this agent. The ESPRIT data suggested that the benefits during coronary stent implantation afforded by eptifibatide are a class effect (provided proper dosing is achieved) of the GP IIb/IIIa receptor blockers. The lower cost of eptifibatide, consequently, has led to this agent s emergence as the most common drug in its class utilized to improve the safety profile of coronary intervention procedures. 177

16 Anti-thrombotic management in interventional cardiology Title 6 Author Comparison of enoxaparin versus unfractionated heparin in patients with unstable angina pectoris/non-st-segment elevation acute myocardial infarction having subsequent percutaneous coronary intervention Reference Abstract Summary Fox KAA, Antman EM, Cohen M, Bigonzi F, for the ESSENCE/TIMI 11B Investigators Am J Cardiol 2002; 90: Patients with unstable angina or non-st-segment elevation myocardial infarction (MI) may undergo invasive revascularization procedures shortly after admission to hospital or after a brief period of stabilization. In the Thrombolysis in Myocardial Infarction (TIMI) 11B trial and Efficacy and Safety of Subcutaneous Enoxaparin in non-q-wave Coronary Events (ESSENCE) trial 1326 patients underwent percutaneous coronary intervention (PCI). A total of 924 patients underwent PCI during the initial hospitalization period, and of these, 445 patients did so while receiving treatment with unfractionated heparin (UFH) or the low-molecular-weight heparin, enoxaparin. This analysis compared efficacy and clinical events in the enoxaparin and UFH groups in patients who: (1) underwent PCI while on treatment versus those who did not, and (2) underwent PCI in hospital. We also compared those who did not undergo PCI. Treatment with enoxaparin (1 mg/kg given as twice daily subcutaneous injections) was beneficial and well tolerated in patients with unstable angina and non-st-segment elevation MI who underwent PCI. Compared with UFH, enoxaparin significantly reduced the likelihood of clinical events (death and nonfatal MI after PCI) in patients who underwent PCI after 1 year (p for in-hospital PCI); p for on-treatment PCI), with a trend toward a reduced event rate at 43 days. In addition, patients treated with enoxaparin who did not undergo PCI also showed a reduction in the risk of death, nonfatal MI, and urgent revascularization when compared with those treated with UFH (significant at 43 days, with a trend persisting at 1 year). Study limitations were that PCI was nonrandomized, the analysis was post hoc, and the sample size was relatively small. Nevertheless, in the absence of large clinical trials, this study suggests that treatment with enoxaparin was well tolerated, and exhibited a similar risk of major hemorrhage to UFH in patients who underwent PCI. The authors performed a post hoc, post-randomization meta-analysis of the Thrombolysis in Myocardial Infarction (TIMI) 11B and Efficacy and Safety of Subcutaneous Enoxaparin in non- Q-Wave Coronary Events (ESSENCE) trials to evaluate enoxaparin vs. unfractionated heparin in patients who underwent percutaneous coronary intervention (PCI) during the initial hospitalization. A total of 924 patients underwent PCI, and 445 of these patients underwent PCI while on treatment with randomized therapy (enoxaparin or unfractionated heparin). Death, myocardial infarction (MI), and urgent revascularization were tabulated at 43 days and 1 year. A 50% reduction in the rate of death or MI was seen at 1 year for those on therapy ; death or MI occurred in 4.98% (10/201) for enoxaparin vs % (32/244) for unfractionated heparin (UFH) (p 0.005). 178

17 Classic Papers in Coronary Angioplasty Citation Count 18 Related References 1. Cohen M, Demers C, Gurfinkel EP, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. The Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. N Engl J Med 1997; 337: Antman EM, McCabe CH, Gurfinkel EP, et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-q-wave myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) 11B trial. The TIMI 11B Investigators. Circulation 1999; 100: Young JJ, Keriakes DJ, Grines CL, et al. Low-molecular-weight heparin therapy in percutaneous coronary intervention: the NICE 1 and NICE 4 trials. J Invasive Cardiol 2003; 12(Suppl. E): E14 E Ferguson JJ. The use of enoxaparin and IIb/IIIa antagonists in acute coronary syndromes, including PCI: final results of the NICE-3 study. J Am Coll Cardiol 2001; 37(Suppl. A): 365A. 5. Bhatt DL, Lee BI, Casterella PJ, et al. Safety of concomitant therapy with eptifibatide and enoxaparin in patients undergoing percutaneous intervention. J Am Coll Cardiol 2003; 41: Key message Treatment with enoxaparin is safe and efficacious in patients with unstable angina and non- ST-elevation MI who undergo percutaneous intervention. In patients with an acute coronary syndrome, enoxaparin would appear to be at least as good, and perhaps better than heparin as an adjunct to PCI. Interestingly, the benefit of enoxaparin over unfractionated heparin did not become statistically significant until the period between 43 days and 1 year for the composite of death or MI or for the composite of death, MI, or urgent revascularization. Why it s important Strengths Regarding the pharmacological arsenal of anti-thrombotic agents to facilitate percutaneous intervention, much work has evaluated anti-platelet therapies including the glycoprotein IIb/IIIa inhibitors and the thienopyridines. Studies that directly challenge conventional wisdom that heparin anticoagulation is required are sparse. This post hoc analysis of the ESSENCE and TIMI 11B trials showed that the low-molecular-weight heparin, enoxaparin, was superior to heparin in the prevention of death, MI, or urgent revascularization at 1 year. Furthermore, the clinical efficacy of enoxaparin was achieved without an increase in major or minor haemorrhage. The TIMI 11B and ESSENCE trials were the pivotal head-to-head comparisons of enoxaparin and UFH in the treatment of acute coronary syndromes. The meta-analysis of the use of enoxaparin as an adjunct to PCI was powered sufficiently and had adequate long-term follow-up to show meaningful differences in patient outcomes. Weaknesses This was a retrospective meta-analysis of ESSENCE/TIMI 11B, where only a small percentage of patients underwent percutaneous intervention (13%). There was no randomization to receive or not receive percutaneous intervention, nor was the randomization performed at the time of 179

18 Anti-thrombotic management in interventional cardiology PCI. Also, there was no monitoring of levels of anticoagulation in the enoxaparin arm. The use of heparin during intervention confounded the data in 56 patients who had previously received enoxaparin. Relevance Various data support the use of low-molecular-weight heparin, particularly enoxaparin, in the medical management of the acute coronary syndromes. As the results of clinical trials emerge in routine clinical practice, cardiologists are ever more frequently confronted with the acute coronary syndrome patient receiving enoxaparin who subsequently require PCI. This analysis provides strong support for the use of low-molecular-weight heparin in percutaneous intervention and bridges the gap between the pre-intervention medical therapy of the acute coronary syndrome patient and management of anticoagulant therapy during PCI. Further guidance on this issue awaits the results of ongoing prospective, randomized trials. 180

19 Classic Papers in Coronary Angioplasty Title 7 Author Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention (REPLACE-2 randomized trial) Reference Abstract Summary Lincoff AM, Bittl JA, Harrington RA, et al., for the REPLACE-2 Investigators JAMA 2003; 289: CONTEXT: The direct thrombin inhibitor bivalirudin has been associated with better efficacy and less bleeding than heparin during coronary balloon angioplasty but has not been widely tested during contemporary percutaneous coronary intervention (PCI). OBJECTIVE: To determine the efficacy of bivalirudin, with glycoprotein IIb/IIIa (GP IIb/IIIa) inhibition on a provisional basis for complications during PCI, compared with heparin plus planned GP IIb/IIIa blockade with regard to protection from periprocedural ischemic and hemorrhagic complications. DESIGN, SETTING, AND PARTICIPANTS: The Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial, a randomized, double-blind, active-controlled trial conducted among 6010 patients undergoing urgent or elective PCI at 233 community and referral hospitals in 9 countries from October 2001 through August INTERVENTIONS: Patients were randomly assigned to receive intravenous bivalirudin (0.75 mg/kg bolus plus 1.75 mg/kg per hour for the duration of PCI), with provisional GP IIb/IIIa inhibition (n 2999), or heparin (65 U/kg bolus) with planned GP IIb/IIIa inhibition (abciximab or eptifibatide) (n 3011). Both groups received daily aspirin and a thienopyridine for at least 30 days after PCI. MAIN OUTCOME MEASURES: The primary composite end point was 30-day incidence of death, myocardial infarction, urgent repeat revascularization, or in-hospital major bleeding; the secondary composite end point was 30-day incidence of death, myocardial infarction, or urgent repeat revascularization. RESULTS: Provisional GP IIb/IIIa blockade was administered to 7.2% of patients in the bivalirudin group. By 30 days, the primary composite end point had occurred among 9.2% of patients in the bivalirudin group vs. 10% of patients in the heparin-plus-gp IIb/IIIa group (odds ratio, 0.92; 95% confidence interval, ; p 0.32). The secondary composite end point occurred in 7.6% of patients in the bivalirudin vs. 7.1% of patients in the heparin-plus-gp IIb/IIIa groups (odds ratio, 1.09; 95% confidence interval ; p 0.40). Prespecified statistical criteria for non-inferiority to heparin plus GP IIb/IIIa were satisfied for both end points. In-hospital major bleeding rates were significantly reduced by bivalirudin (2.4% vs. 4.1%; p 0.001). CONCLUSIONS: Bivalirudin with provisional GP IIb/IIIa blockade is statistically not inferior to heparin plus planned GP IIb/IIIa blockade during contemporary PCI with regard to suppression of acute ischemic end points and is associated with less bleeding. In balloon angioplasty trials, bivalirudin was shown to have a favourable profile relative to heparin as a substitute anti-thrombin. The Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE) 2 was designed to test two hypotheses in contemporary stent 181

20 Anti-thrombotic management in interventional cardiology percutaneous coronary intervention (PCI): (1) that bivalirudin would prove superior to heparin in historical controls, and (2) that bivalirudin (with bailout use of a glycoprotein IIb/IIIa (GP IIb/IIIa) blocker) would be non-inferior to a combination of unfractionated heparin and a GP IIb/IIIa inhibitor. Patients undergoing PCI were randomized to the bivalirudin with bailout GP IIb/IIIa inhibitor therapy or heparin with planned GP IIb/IIIa inhibitor therapy. Only 7% of patients in the bivalirudin group received bailout GP IIb/IIIa inhibitor. All patients received aspirin and 85% were pretreated with a thienopyridine. At 30 days, death, myocardial infarction (MI), urgent revascularization, and major bleeding events were tabulated. There was less bleeding in the bivalirudin arm. Furthermore, bivalirudin was found to be noninferior to unfractionated heparin plus planned GP IIb/IIIa blockade during PCI. Citation Count 106 Related References 1. Xiao Z, Theroux P. Platelet activation with unfractionated heparin at therapeutic concentrations and comparisons with a low-molecular-weight heparin and with a direct thrombin inhibitor. Circulation 1998; 97: Bittl JA, Strony J, Brinker JA, et al. Treatment with bivalirudin (Hirulog) as compared with heparin during coronary angioplasty for unstable or postinfarction angina. N Engl J Med 1995; 333: Bittl JA, Chaitman BR, Feit F, Kimball W, Topol EJ, for the Bivalirudin Angioplasty Study Investigators. Bivalirudin vx heparin during coronary angioplasty for unstable or post-infarction angina: final report reanalysis of the Bivalirudin Angioplasty Study. Am Heart J 2001; 142: Antman EM. Should bivalirudin replace heparin during percutaneous coronary interventions? JAMA 2003; 289: Key message The direct thrombin inhibitor bivalirudin is a superior replacement to unfractionated heparin as an adjunct to PCI. Bleeding (both major and minor) is less common with bivalirudin, which makes bivalirudin particularly attractive in PCI patients who are at a high risk for bleeding. The strategy of bivalirudin with bailout GP IIb/IIIa inhibitor is non-inferior to the combination of unfractionated heparin plus a GP IIb/IIIa inhibitor in low-to-intermediate risk PCI patients, with the advantage of bivalirudin being imparted with reduced rates of bleeding (but not with improvements in efficacy). Why it s important Fundamentally, heparin is not a particularly good anti-thrombin. Also, despite their efficacy, the high cost of GP IIb/IIIa inhibitors and the risk of increased bleeding have limited their widespread use to approximately 50 60% of patients undergoing PCI. The REPLACE-2 trial established bivalirudin as an excellent replacement for heparin during PCI. In lower-risk patients, substitution of bivalirudin for GP IIb/IIIa inhibitors would result in lower rates of bleeding along with cost savings without compromising efficacy. Notably, bivalirudin has not been proven in higher-risk patients, including acute coronary syndrome patients and ST-elevation MI. Nonetheless, bivalirudin is an obvious choice for a PCI patient with heparin-induced thrombocytopenia or who is at high risk for bleeding complications. 182