Ann Thorac Surg 2000;70:S3-S8
© 2000 The Society of Thoracic Surgeons
Antiplatelet agents in cardiology: the choice of therapy
Steven R. Steinhubl, MDa
a Department of Cardiology, Wilford Hall Medical Center, Lackland AFB, Texas, USA
Address reprint requests to Dr Steinhubl, Department of Cardiology, Wilford Hall Medical Center, 2200 Bergquist Dr, Lackland AFB, TX 78236-5300
Presented at the "Managing the Patient Receiving Platelet Inhibitors in Cardiac Surgery" Roundtable Discussion, San Antonio, TX, Jan 22–23, 1999.
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Abstract
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Background. The platelet-rich, intracoronary thrombus is central to the pathogenesis of acute myocardial infarctions, unstable angina, and the majority of complications of percutaneous coronary interventions. Until recently, aspirin was the only antiplatelet agent available to help prevent or treat these events. Over the past several years, there has been a substantial expansion in our antiplatelet armamentarium as well as in our understanding of the clinical importance of antiplatelet therapy in limiting the complications of intracoronary thrombosis. Because of this, it is likely that over the coming years, the use of antiplatelet therapies will continue to expand, and it may not be unusual for a surgeon to encounter a patient being treated with two or even three platelet inhibitors.
Conclusions. This review will highlight the benefits and limitations of the currently available antiplatelet regimens: aspirin, thienopyridines (ticlopidine and clopidogrel), and the platelet glycoprotein IIb/IIIa inhibitors.
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Introduction
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If intraarterial thrombus formation could be prevented, the major sequelae of atherosclerotic heart disease (myocardial infarction, unstable angina, and sudden cardiac death) as well as the majority of complications of percutaneous interventions could be prevented. Arterial thrombi, in contrast to venous thrombi, are platelet rich, making antiplatelet therapy central to their prevention. Until recently, our antiplatelet armamentarium was limited to aspirin. Today, we have a much wider selection of antiplatelet agents from which to choose, allowing us to optimize antiplatelet protection in specific clinical scenarios. Of course, the clinical benefits of platelet inhibition must be weighed against the associated risk of both surgical and nonsurgical hemorrhage.
As our treatment choices for the prevention of intraarterial thrombosis grow, surgeons will encounter patients being treated with more than just aspirin more frequently. An understanding of the reasoning behind the choice of an antiplatelet regimen is important for optimizing the patient’s surgical and nonsurgical care. This review will summarize the clinical data supporting the use of an antiplatelet agent or a combination of antiplatelet agents in various clinical settings.
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Intracoronary thrombosis
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Intracoronary thrombosis begins with the disruption of the endothelial monolayer, either spontaneously or because of a mechanical device such as a balloon or stent, leading to a monolayer of platelets adhering to the newly exposed subendothelium (Fig 1). Adhesion is mediated by the binding of platelets to normally hidden subendothelial glycoproteins such as von Willebrand’s factor, fibronectin, and collagen.
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Fig 1. Steps involved in intracoronary thrombus formation. Antiplatelet agents are shown in gray boxes by the specific processes they inhibit. (ADP = adenosine diphosphate; TXA2 = thromboxane A2.)
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The newly exposed collagen is also one of the stronger agonists of platelet activation, which causes the liberation of arachadonic acid and the eventual production of thromboxane A2. Platelet activation also initiates the platelet release reaction, which entails the freeing of prepackaged granules containing adenosine diphosphate (ADP), serotonin, fibrinogen, and other compounds that then promote further platelet activation. Once activated, a conformational change occurs in the platelet glycoprotein (GP) IIb/IIIa receptor, the exclusive mediator, and final common pathway of platelet aggregation, which allows for the formation of a platelet aggregate.
Thromboxane A2 and ADP released from the activated platelets leads to the activation of surrounding platelets, thereby amplifying the thrombotic process. The activated platelets accelerate the production of thrombin via the coagulation cascade, which then serves to stabilize the thrombus by the conversion of fibrinogen to fibrin as well as to potently promote further platelet activation.
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Aspirin
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Aspirin has been available commercially for over 100 years and was the first pharmaceutical agent available in a pill form. Interestingly, the dose of aspirin in this pill (5 grains or approximately 325 mg) was based on the optimal mixture of cornstarch and acetylsalicylic acid that could be compressed into a pill.
The clinical benefits of aspirin therapy in the prevention of thrombotic complications of cardiovascular disease have been well documented [1]. Among all subgroups of patients, treatment with aspirin decreases the risk of a vascular event by approximately 25% compared with placebo. The level of absolute benefit is greatest in patients at highest risk for a vascular event, eg, those with acute myocardial infarction or unstable angina patients, and least in low-risk subgroups such as recipients of primary prevention. This 25% reduction in vascular events from aspirin highlights the importance of antiplatelet therapy for the prevention of cardiovascular morbidity and mortality and makes aspirin the most cost-effective pharmacologic intervention available today. Now that other short-term and long-term antiplatelet therapies are available, however, it is important to evaluate, not why aspirin decreases events by 25%, but rather why it does not prevent vascular events in 75% of the at-risk population.
Because of the variability inherent in any biologic system, practitioners typically expect interpatient variability in response to pharmacologic interventions such as antihypertensives. Yet all patients have been assumed to achieve similar antithrombotic protection with a set dose of aspirin. This assumption is partially related to the difficulty associated with measuring a specific patient’s response to aspirin therapy. A number of studies, involving a total of 975 patients and using different methods for determining response to aspirin, have identified a substantial degree of interpatient variability [2–10] (Table 1). The clinical importance of this variability has been evaluated in one study involving 180 stroke victims [3]. The investigators measured each patient’s response to 1,500 mg aspirin daily before discharge and found one-third to be nonresponders. After 2 years of clinical follow-up, major end points occurred in 40% of aspirin nonresponders compared with only 4.4% of aspirin responders (p < 0.0001).
Aspirin resistance, optimal aspirin dosing, and a potential negative impact of aspirin on treatment with angiotensin-converting enzyme inhibitors (all concerns with the exclusive use of aspirin for prevention of vascular events) are subjects of ongoing evaluation [11–13]. Although aspirin has been the cornerstone of antithrombotic therapy for preventing vascular events for the past several decades, current and future research will help identify the individuals and clinical scenarios in which antiplatelet protection beyond that provided by aspirin alone is needed.
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Thienopyridines (ticlopidine and clopidogrel)
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Clopidogrel and ticlopidine are structurally identical thienopyridines except for the addition of a carboxymethyl side group in clopidogrel. Both agents irreversibly inhibit ADP-induced platelet aggregation and ADP-mediated amplification of other platelet agonists by selectively binding to adenylate cyclase-coupled ADP receptors on the platelet surface [14]. Although on a molar basis clopidogrel has a greater platelet inhibitory effect than ticlopidine, standard dosing of 75 mg daily was determined based on equivalency with the platelet inhibitory effects of chronic daily therapy with 500 mg of ticlopidine [15].
Clinical trials demonstrating the prevention of thrombotic complications of vascular disease by the ADP receptor antagonists ticlopidine and clopidogrel have confirmed the pathophysiologic role of ADP-induced platelet activation and aggregation in humans. Two studies of long-term therapy with ticlopidine in patients after a neurologic event, as well as a large study with clopidogrel in patients with any atherosclerotic disease, have consistently demonstrated a significant benefit of these agents compared with placebo and aspirin [16–18]. Similar protection by ticlopidine from adverse cardiac events in the setting of percutaneous coronary intervention (PCI) was also demonstrated in early studies [19]. The use of these agents in PCIs, however, did not gain full prominence until, when combined with aspirin, they were shown to reduce significantly the risk of stent thrombosis compared with a warfarin-based anticoagulant regimen [20]. The Stent Anticoagulation Restenosis Study (STARS) randomized 1,653 patients to one of three antithrombotic regimens after "optimal" stenting (aspirin alone, aspirin plus warfarin, and aspirin plus ticlopidine). The results of STARS demonstrated the benefits of antiplatelet therapy compared with anticoagulant therapy and confirmed the need for dual antiplatelet therapy with both ticlopidine and aspirin [21]. The clinical benefit of combination therapy with aspirin and an ADP receptor antagonist is likely from a synergistic platelet inhibitory effect of these agents. Studies of both ticlopidine and clopidogrel, along with aspirin, in different animal models and ex vivo human studies, have consistently demonstrated a synergistic antiplatelet effect [22–24].
Although with long-term therapy clopidogrel and ticlopidine provide similar levels of platelet inhibition, clopidogrel appears to offer several advantages over ticlopidine. Clopidogrel, when given as a loading dose, has a much more rapid onset of action. When given as a 375-mg loading dose, steady-state levels of platelet inhibition are achieved by 5 hours [25]. On the other hand, ticlopidine requires up to 7 days to achieve similar levels after a 500-mg loading dose [26]. This pharmacodynamic advantage of clopidogrel over ticlopidine allows for earlier platelet inhibition at the time of an increased risk for vascular events: during PCI or in the setting of an acute coronary syndrome.
Another advantage of clopidogrel is a much lower incidence of side effects. In early clinical trials of ticlopidine, adverse events, mostly minor "nuisance" events, led to the discontinuation of its use in approximately 20% of patients [16, 17]. Of even greater concern, although much less common, are the blood dyscrasias associated with ticlopidine. Neutropenia (absolute neutrophil count < 1,200/mm3) has been reported in 2.4% of patients, and was severe (< 450/mm3) in 0.8%. Aplastic anemia, pancytopenia, thrombocytopenia, and thrombotic thrombocytopenic purpura (TTP) have also all been associated with ticlopidine treatment [27]. In stented patients treated with ticlopidine, TTP has been reported in 1 in 1,600 to 1 in 4,814 patients [28, 29].
Clinical safety data for clopidogrel come primarily from the 19,185-patient CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) trial [18]. Overall, the incidence of adverse events was similar in the clopidogrel- and aspirin-treated groups. Importantly, there was no significant difference in incidence of neutropenia in clopidogrel-treated patients compared with those receiving aspirin (0.10% vs 0.17%).
The recently reported CLASSICS (Clopidogrel Aspirin Stent International Cooperative Study) study compared ticlopidine and aspirin versus two regimens of clopidogrel and aspirin after stenting (American College of Cardiology, March 1999). Not unexpectedly, clopidogrel resulted in significantly fewer side effects than did ticlopidine, but with similar efficacy. Two other trials currently underway will explore the expanded use of the synergistic antiplatelet effects of clopidogrel and aspirin. The CREDO (Clopidogrel for Reduction of Events During extended Observation) trial will compare preloaded clopidogrel initiated before planned stenting, with clopidogrel begun at the time of the procedure. Both groups will also receive daily aspirin. Those randomized to the preload arm will continue treatment with aspirin and 75 mg of clopidogrel daily for 1 year instead of the routine 2- to 4-week course of dual therapy. The CURE (Clopidogrel in Unstable angina to prevent Recurrent ischemic Events) trial will evaluate the incidence of vascular death and nonfatal myocardial infarction (MI) in unstable angina patients randomized to either clopidogrel and aspirin or aspirin alone, also for 1 year. Based on the results of these and other trials, it is likely that a greater number of patients in the future will be receiving both aspirin and a thienopyridine for their long-term antiplatelet protection.
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Glycoprotein IIb/IIIa receptor antagonists
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Thromboxane A2, inhibited by aspirin, and ADP, inhibited by ticlopidine and clopidogrel, are only two of over 90 known agonists that can stimulate platelet aggregation. Thus, even with complete blockade of one or both of these pathways, platelet aggregates may still form. On the other hand, inhibition of the GP IIb/IIIa receptor prevents platelet aggregation irrespective of the agonist, making this an appealing target for antiplatelet therapy.
Elucidation of the function and structure of the GP IIb/IIIa receptor has led to the development of a number of antagonists, three of which currently have FDA approval for use in PCI, unstable angina, or both. All currently available agents must be given intravenously and are therefore used only in the inpatient setting. Abciximab (ReoPro; Centocor Inc, Malvern, PA), a chimeric Fab fragment formed by combining the murine variable region with the constant regions of human immunoglobin, was the first GP IIb/IIIa inhibitor developed and tested. Abciximab is unique among GP IIb/IIIa receptor antagonists in that it is a noncompetitive inhibitor of fibrinogen, binding with pharmacodynamics that are consistent with nearly irreversible occupation of the GP IIb/IIIa receptor [30]. Because of this property, recovery of platelet function occurs slowly, primarily because of the production of new platelets in the bone marrow. A second agent, eptifibatide (Integrilin; COR Therapeutics, South San Francisco, CA) is a competitive inhibitor of the GP IIb/IIIa receptor with a rapid onset of action and a short half-life. It is a cyclic heptapeptide with high specificity for GP IIb/IIIa receptor [31]. The third approved GP IIb/IIIa inhibitor is tirofiban (Aggrastat; Merck & Co, Inc, West Point, PA), which is a small nonpeptide molecule that also has a rapid onset of action and rapid reversal of effect after drug discontinuation. Whichever agent is used, to achieve nearly complete inhibition of platelet aggregation, 80% or more of a platelet’s ~80,000 GP IIb/IIIa receptors need to be blocked [32].
To date, randomized trials involving over 35,000 patients have evaluated the role of parenteral GP IIb/IIIa inhibitors in the setting of acute coronary syndromes or PCI. A recent metaanalysis of 16 of these trials involving 32,135 patients demonstrated a significant decrease in the risk of death or MI at all time points with the use of GP IIb/IIIa inhibitors [33]. At 30 days, the odds ratio was 0.76 (95% CI, 0.68 to 0.86), or 20 fewer deaths or MIs per 1,000 patients treated. Similar benefit was found whether the GP IIb/IIIa inhibitor was used in the setting of PCI or acute coronary syndrome. Although no trial has directly compared one GP IIb/IIIa inhibitor against another, indirect comparisons suggest that not all agents share similar efficacy when dosed as currently approved. In a recent comparison of all patients with the clinical diagnosis of unstable angina enrolled in the five large-scale trials of GP IIb/IIIa inhibitors in PCI, there was a substantially greater improvement with abciximab compared with eptifibatide and tirofiban (Table 2) [34]. Some of these trials involved early experience with GP IIb/IIIa inhibitors, however, and there are still a number of issues regarding the optimal dosing and duration of treatment with some.
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Table 2. Reduction in the Composite End Point of Death, Myocardial Infarction, and Urgent Revascularization in the Subgroup of Patients With Unstable Angina in Trials of GP IIb/IIIa Inhibitors in Percutaneous Coronary Intervention
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The two advances in interventional cardiology over the past 10 years that have most dramatically improved patient outcomes are coronary stents and GP IIb/IIIa inhibitors. The most recently completed trial of a GP IIb/IIIa inhibitor in PCI, the EPISTENT (Evaluation of Platelet IIb/IIIa Inhibitor for Stenting) trial, which evaluated the roles of stenting and abciximab, best highlights the importance of GP IIb/IIIa inhibitors in improving the safety and efficacy of PCI [35]. In this trial, 2,399 patients undergoing PCI were randomly assigned to stenting plus placebo, stenting plus abciximab, or balloon angioplasty plus abciximab. At 30 days, death or large myocardial infarction (defined as a fivefold increase in creatine kinase [CK] or its MB fraction) had occurred in 7.8% of the stent plus placebo group, 3.0% for stent plus abciximab (p < 0.001), and 4.7% for balloon angioplasty plus abciximab (p = 0.01). Not unexpectedly, stenting had its greatest impact on the incidence of clinical restenosis. At 6 months, the need for target vessel revascularization was 8.7% in the abciximab plus stent group, 10.6% in the placebo plus stent group, and 15.4% in those treated with abciximab plus balloon angioplasty [36]. Interestingly, abciximab treatment decreased the need for target vessel revascularization by over 50% (8.1% vs 16.6%; p = 0.021) among diabetic patients treated with stents [37]. Some of the most promising results to come from the EPISTENT trial are 1-year data showing that abciximab plus stenting was associated with a significant decrease in mortality compared with placebo plus stenting (1.0% vs 2.4%) (Scientific Sessions of the American Heart Association, unpublished data, 1998).
The encouraging results realized with short-term intravenous therapy with GP IIb/IIIa inhibitors both in the treatment of acute coronary syndromes and in the setting of PCI have led to the evaluation of extended therapy with several oral GP IIb/IIIa inhibitors. The use of these agents allows for the possibility of sustained inhibition of platelet aggregation and clinical stabilization of the culprit lesion. There are a number of oral GP IIb/IIIa antagonists undergoing evaluation, with several agents recently completing or still undergoing phase 3 testing. The results of phase 2 trials with these agents suggested that bleeding complications were frequent, with minor hemorrhagic events occurring in 30% of patients receiving certain dosing regimens [38]. Drug was discontinued in over half of patients with bleeding events. Therefore, successful treatment with these agents will require a careful balance of clinical efficacy and safety.
Preliminary results currently available from two phase 3 trials of oral agents have been disappointing. Because of safety concerns, the Data Safety Monitoring Board halted trial enrollment at 8,000 of a planned 12,000 in The OPUS/TIMI-16 (Orbofiban in Patients with Unstable coronary Syndromes/Thrombolysis in Myocardial Infarction) trial. Preliminary efficacy and safety results were recently presented at the 1999 American College of Cardiology Meeting. Surprisingly, both at 30 days and over the long term (median of 7 months), treatment with orbofiban was associated with a trend toward increased adverse cardiac events. The higher dosing regimen of orbofiban was also associated with a significant increase in major bleeding events compared with placebo (3.7% vs 1.9%). A second trial, the EXCITE (Evaluation of oral Xemilofiban in Controlling Thrombotic Events) trial, was a double-blind, placebo-controlled study of the efficacy and safety of xemilofiban when administered before, and for up to 6 months after, a percutaneous coronary revascularization procedure. Preliminary results from this trial, also presented at the 1999 American College of Cardiology Meeting, did not show a benefit of treatment with the oral GP IIb/IIIa inhibitor xemilofiban in this population.
Despite the significant improvement in outcome associated with the use of short-term parenteral GP IIb/IIIa inhibitors in various populations, there is much that still needs to be learned about these agents. The results of a number of ongoing trials will be critical in optimizing the use of these agents. Nonetheless, at the present time, it appears likely that GP IIb/IIIa inhibitors will be the primary agent in future antithrombotic treatment regimens of patients with ischemic heart disease.
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Conclusion
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Thanks to the development of more and better antiplatelet agents, we are now at the beginning of a new era in the treatment of ischemic heart disease. A greater selection of agents that act through various mechanisms has led to a significant improvement in the safety and long-term outcomes of patients undergoing PCI or presenting with an acute coronary syndrome. Thousands of lives have been saved yearly. Future refinement of these therapies will allow for antiplatelet regimens to be individualized for specific patients and specific clinical syndromes. Along with these more aggressive treatment regimens, however, comes the potential for increased hemorrhagic risk, especially in the surgical setting. In the months and years to come, it may not be unusual for a patient to require an urgent surgical procedure while being treated with two, or possibly three, different antiplatelet agents. Therefore, it is as important for the surgeon to understand the clinical benefits of antiplatelet therapy as it is for the cardiologist to appreciate the substantial risks associated with surgical bleeding. The mutual understanding of these issues will allow for optimal choice of antiplatelet therapies in patients with ischemic heart disease.
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Abstract
Introduction
