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Current concepts in antiplatelet therapy for cardiovascular disease
Arturo Martinez, PA-C, MPASMr. Martinez works in the Division of Cardiothoracic Surgery, Cedars-Sinai Medical Center, Los Angeles, Calif. The author has indicated no relationships to disclose relating to the content of this article.Studies have shown that survival improves when newer antiplatelet drugs are used in patients who have had an acute coronary event.
Each year approximately 1.5 million people in the United States have an acute myocardial infarction (MI); as many as 300,000 die before reaching the hospital, and an additional 200,000 die within a month, often in the first 24 hours, either from the initial MI or from reinfarction.1 The activation and progression of the platelet-rich environment of intracoronary thrombus formation are central to the pathogenesis of acute MI, unstable angina, and some complications of percutaneous coronary interventions (PCIs) and bypass surgery. To understand the effects of the various platelet inhibitors, clinicians must first understand this activation and progression. Pathophysiology of coronary thrombosisThe fibrotic organization of coronary thrombosis, which contributes to the atherosclerotic process, was first suggested by von Rokitansky in the mid 19th century and later by Duguid in the 1940s.2,3 Angiography, angioscopy, and other experimental technologies have documented that the disruption of small platelet and fibrin-rich atherosclerotic plaques, with subsequent mural thrombosis and fibrotic organization of the thrombus, contributes to the progression of coronary atherosclerosis.4,5 Disruption of these atherosclerotic plaques, with resultant intraluminal thrombosis, plays a fundamental role in the pathogenesis of unstable angina, acute MI, and sudden death. Formation of platelet and fibrin-rich thrombi, usually secondary to atherosclerotic plaque disruption, is also involved in the development of the acute coronary syndromes. Atherosclerosis progresses through three phases: atheroma formation, sclerosis, and thrombosis. Atheroma formation results from the accumulation of lipids on the vessel wall. Sclerosis occurs as the vessel reacts to the lipid accumulation by forming a fibromuscular cap, resulting in an atherosclerotic plaque. Thrombosis occurs when the fibrous cap ruptures and exposes the lipid core to the bloodstream.4,5 This plaque disruption initiates platelet activation. Platelet activation and fibrin formation in thrombogenesisAn arterial thrombus develops in three stages: platelet adhesion, platelet aggregation, and activation of clotting mechanisms. Platelets tend to adhere to damaged or disrupted endothelial surfaces, such as ulcerated plaques, or to an artificial surface, such as a prosthetic heart valve or vascular prosthetic graft. In platelet adhesion, the platelet membrane is altered after coming in contact with a surface, and the platelet attaches to and spreads across the surface.6 Platelet adhesion appears to be determined by two factors: • The physiologic mechanisms of rapid blood flow—which permits nonspecific contact of the platelet with the damaged or disrupted endothelial surface or with the artificial surface—and red cells pushing the platelets toward the periphery, increasing platelet–vessel wall contact • Exposure of collagen fibers and von Willebrand's factor (vWF) to blood circulation, which specifically causes platelets to attach firmly to and spread across the surface.7 The importance of vWF in the initiation and progression of the atherosclerotic plaque is further substantiated by findings in pigs with homozygous von Willebrand's disease. Animals without vWF are notably resistant both to spontaneous atherosclerosis and to atherosclerosis induced by a diet high in cholesterol.8,9 In platelet aggregation, the second stage of arterial thrombus formation, the platelet mass builds as platelets adhere to one another. Platelet aggregation seems to depend primarily on an increase in cytoplasmic calcium, which in turn appears to be mediated by other processes involving adenosine diphosphate (ADP), thromboxane A2 (TXA2), and platelet stimulation by extrinsic stimuli.7,10-12 Cytoplasmic concentration of platelet calcium also plays a role, and in pathologic situations, as when an atherosclerotic plaque ruptures, extrinsic factors may be much more potent than the physiologic low concentrations of ADP and TXA2 in triggering calcium release and platelet aggregation; these extrinsic factors are exposed collagen from the vessel wall, thrombin resulting in the activation of the intrinsic and extrinsic coagulation systems, large amounts of ADP released from erythrocytes (hemorrhage with lysis), and, presumably, platelet activating factor (PAF) released from the neighboring cells. 7,13,14 It has been suggested that PAF in the platelet serves as a third independent pathway of platelet activation and that the powerful effects of collagen and thrombin are more dependent on this pathway than on the activation of the ADP- and TXA2-related pathways. In either case, these powerful extrinsic aggregating factors may explain in part why platelet inhibitor drugs may be inefficient in preventing some arterial thrombotic phenomena.15 Furthermore, platelet aggregation and the subsequent generation of thrombin may be activated by circulating catecholamines, which may be a link between stressful situations and the development of arterial thrombosis. There is also increasing evidence of an enhanced thrombogenicity in cigarette smokers and in people with a strong family history of coronary disease, as well as in people with hyperlipidemia and diabetes.1 During the processes of platelet adhesion and aggregation, the clotting mechanism may be activated and thrombin generated, further promoting platelet aggregation. Most important, these processes lead to the polymerization of fibrin, which maintains the stability and fixation of the arterial thrombus. Fate of the thrombusReviewing the role of platelets in thrombus formation and the subsequent growth of the atherosclerotic plaque by the release of chemical mediators raises a question as to the fate of the thrombus. An arterial thrombus usually results in a subclinical mural thrombus, an acute or subacute thrombotic occlusion, or an acute embolus. Subclinical mural thrombi are probably the most common result and consist of a partial thrombotic obstruction of the vascular lumen that is insufficient to cause clinical symptoms. These thrombi tend to occur over an ulcerated atherosclerotic plaque, such as in the coronary or carotid arteries, or on an artificial surface, such as a prosthetic heart valve. Although such thrombi can totally or partially disappear in situ by lysis or embolization,10 they may persist as a continuous aggregation of platelets and eventually undergo phagocytosis, endothelialization, and atherogenic transformation.10,16 Such atherogenic transformation of arterial thrombi would likely accelerate to atherosclerosis in some patients. Thrombotic occlusion describes an arterial thrombus that suddenly occludes the vascular lumen totally or subtotally, resulting in acute or subacute manifestations. The vascular conditions under which these occlusive thrombi develop, as well as their fate, are similar to those of subclinical mural thrombotic obstruction. Classic examples are a thrombotic coronary artery occlusion resulting in an acute MI, a femoral artery thrombotic occlusion leading to acute or subacute pain and pallor of the affected extremity, and a Björk-Shiley valve thrombotic obstruction resulting in entrapment of the disk, leading to acute or subacute heart failure. The syndrome of coronary artery occlusion associated with spasm is controversial. This syndrome may be the result of platelet activation with the release of TXA2, which is a potent vasoconstrictor, although there is evidence that vascular spasm may be the cause rather than the consequence of platelet activation and thrombotic occlusion in this setting.17 Acute embolization describes a thrombus at a site in the arterial system, particularly the subclinical mural or partially obstructive type of thrombus that dislodges and embolizes to a distal artery or arteries. The acute embolization can result from forces of blood flow dislodging large masses of thrombi (macroembolism) and lead to a stroke or an occlusion of a limb artery; this typically occurs in patients who have ulcerated thromboatherosclerotic carotid arteries, an ulcerated abdominal aorta, or a prosthetic heart valve.7 Acute embolization can also result from digestion of fibrin in the thrombus by the fibrinolytic enzymatic system, causing small platelet masses (microembolism) to form; this process can be clinically apparent if the site is vitally important, as with transient ischemic attacks in patients with carotid atherosclerotic disease.18,19 Pathways of platelet activationScientific investigation of platelet receptors has produced a wealth of knowledge on the structure and function of the three principal pathways of platelet agonism: the TXA2, ADP, and thrombin pathways. Antiplatelet therapy has concentrated traditionally on the TXA2 and ADP pathways. Drugs that affect these pathways include aspirin and the thienopyridines ticlopidine (Ticlid) and clopidogrel (Plavix). Interest has shifted recently to developing agents that affect the glycoprotein (GP) IIb/IIIa receptor, which, as a consequence of platelet activation, is converted from its inactive to its active form. This conversion is caused by a conformational change.20 Irrespective of the different modes of platelet activation, all pathways ultimately converge on the GP IIb/IIIa receptor, activating its ligand-binding function in this final and common pathway of platelet aggregation. A single molecule of plasma fibrinogen binds to two activated GP IIb/IIIa receptor molecules belonging to adjacent platelets. Multiple aggregation reactions between adjacent platelets lead to the formation of "white" clots (platelet-rich thrombi), and the process continues as previously described. A brief history of antiplatelet therapy in CVDAspirin Salicin, the active ingredient in willow bark, is a bitter glycoside. In 1829, Henri Leroux refined the extraction of salicin from willow bark and demonstrated its antipyretic effects.21 The pharmaceutical chemist Felix Hoffman, of the Bayer company of Germany, promoted acetylsalicylic acid, which was shown to have anti-inflammatory and analgesic properties. Acetylsalicylic acid was introduced into clinical medicine at the turn of the last century under the name aspirin.21,22 Its platelet inhibitory effect was not discovered until the late 1960s,23 and more than 30 years ago this property was linked to the irreversible inhibition of the cyclooxygenase enzyme responsible for the synthesis of eicosanoids.24 In platelets, aspirin prevents the formation of TXA2, one of the substances that induces platelet aggregation.24 Because platelets are unable to generate new cyclooxygenase, inhibition of the enzyme persists for the lifetime of the cell, about 10 days. In vascular endothelial cells, aspirin prevents the synthesis of prostacyclin, which inhibits platelet aggregation.25 Since endothelial cells can recover cyclooxygenase synthesis, however, the inhibitory effect of aspirin is shorter.26,27 In the late 1960s, almost as soon as aspirin's properties as an inhibitor of platelet aggregation had been discovered, its potential role in the prevention of coronary thrombosis was anticipated. During the 1970s, however, hope dwindled because the role of thrombosis as the cause of acute MI was questioned: clinical trials of platelet inhibitors for the prevention of recurrent coronary events showed only limited benefits. These trials were ultimately deemed to have been poorly organized and their results unreliable. Subsequently, with the revived appreciation of the importance of platelets and thrombosis in arterial disease and with better-designed clinical trials involving patients with overt atherosclerotic disease, the effectiveness of antithrombotic therapy with aspirin was convincingly demonstrated.27-38 Studies have included patients with coronary artery disease, ischemic stroke, and transient ischemic attacks; patients undergoing coronary angioplasty; and patients with nonvalvular atrial fibrillation, peripheral vascular disease, prosthetic heart valves, and venous thrombosis. Four large, randomized, placebo-controlled, double-blinded studies examined the use of aspirin administration in unstable angina. • In the 1983 Veterans Administration Cooperative Study, 1,266 men with unstable angina were randomized to receive buffered aspirin (325 mg/d) or placebo for 12 weeks.27 During the treatment period, the incidence of death and acute MI was reduced from 10.1% to 5% in the aspirin-treated group, a risk reduction of 51%, and the overall benefits of aspirin were maintained during the 1-year follow-up period. • In the Canadian Multicenter Trial reported in 1985, 555 patients (73% male) with unstable angina were randomly selected to receive aspirin, 1,300 mg/d, sulfinpyrazone, 800 mg/d, both, or placedo.28 After 18 months, the incidence of death and MI in the aspirin-treated groups was reduced from 17% to 8.6%, a risk reduction of 49%; sulfinpyrazone conferred no benefit.29 • In the Montreal Heart Institute Study, 479 patients (71% men) with unstable angina were randomly selected to receive aspirin, 325 mg twice a day, IV heparin, both, or placebo. After a mean of 6 days, final therapeutic decisions for individual patients were made on the basis of the results of cardiac catheterization. Aspirin significantly reduced the rate of MI by 72% compared to placebo, and heparin reduced the rate by 89%. Although there were no statistically significant differences among patients treated with aspirin, heparin, or the combination, there was a trend favoring the efficacy of heparin over that of aspirin.30 • In the European Research on Instability in Coronary Artery Disease (RISC) Group study, 794 men with unstable angina or non-Q wave myocardial infarction were randomly selected to receive aspirin, 75 mg/d for 3 months, IV heparin for 5 days, both, or neither. At 3 months, the risk of MI and death was significantly reduced by aspirin and even more with the combination of aspirin and heparin.31 The most convincing evidence of the efficacy of aspirin alone—without thrombolytic therapy—in acute evolving MI, came from the large-scale ISIS-2 (Second International Study of Infarct Survival) trial. Researchers randomized 17,187 patients within 24 hours of symptoms to treatment with IV streptokinase, 160 mg of aspirin orally for 30 days, both, or neither. In the group taking aspirin alone, there was a highly significant 23% reduction in mortality compared with the group taking neither streptokinase nor aspirin. The risk reduction for nonfatal reinfarction was 49%, and that for nonfatal stroke was 46%.32 Atherothrombosis is not only the basis of coronary disease leading to the need for coronary artery bypass graft (CABG) and percutaneous coronary angioplasty, but is also an important factor in the early complication rate of these interventions. Saphenous vein bypass disease can be divided into three phases: (1) early postoperative, with thrombotic occlusion within 1 month of surgery; (2) intermediate phase, within the first postoperative year, which is characterized by intimal hyperplasia resulting in a form of accelerated atherosclerosis that may have a superimposed thrombotic tendency; and (3) late phase, after the first postoperative year, composed of graft atherosclerosis similar to that affecting the native coronary arteries.33 The importance of platelets in the pathogenesis of thrombosis in this setting suggests that antiplatelet agents should inhibit thrombotic graft occlusion and decrease the frequency of late vein-graft atherosclerosis. In the Mayo Clinic trial on saphenous vein bypass grafting, patients received dipyridamole (Persantine), 75 mg three times a day, starting 7 hours after surgery and continuing for 1 year. There was no increased incidence of bleeding complications in the treatment group. Follow-up vein graft angiography 1 month after surgery showed a significant reduction in graft occlusion, from 10% to 2% per distal graft anastamosis and from 22% to 6% per patient.34,35 Other studies have convincingly demonstrated the importance of initiating platelet inhibitor therapy in the perioperative period, preferably before but not later than 48 hours after surgery.36-38 Thienopyridines Clopidogrel and ticlopidine are structurally identical to each other 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 ADP-coupled receptors on the platelet surface. Clinical trials demonstrating the prevention of thrombotic complications of vascular disease by these agents 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, consistently demonstrated a significant benefit of these agents compared with placebo and aspirin.39-41 Similar protection by ticlopidine from adverse cardiac events in the setting of percutaneous coronary intervention (PCI) was demonstrated in early studies.42 The use of these agents in PCIs, however, did not gain full acceptance until, when combined with aspirin, they were shown to reduce the risk of stent thrombosis compared with a warfarin-based anticoagulant regimen.43 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 with anticoagulant therapy and confirmed the value of dual antiplatelet therapy with both ticlopidine and aspirin.44 The clinical benefit of combination therapy with aspirin and an ADP receptor antagonist likely results 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.45-47 Although clopidogrel and ticlopidine provide similar levels of platelet inhibition with long-term therapy, clopidogrel appears to offer advantages over ticlopidine. When given as a 375-mg loading dose, clopidogrel has a much more rapid onset of action; steady state levels of platelet inhibition are achieved by 5 hours. Ticlopidine requires up to 7 days to achieve similar levels after a 500-mg loading dose; thus, the pharmacodynamic advantage of clopidogrel over ticlopidine allows for earlier platelet inhibition at the time of increased risk for vascular events, such as during PCI or in the setting of an acute coronary syndrome. The results of the Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial (CURE), which evaluated clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevations, further validated the beneficial effects of combined antiplatelet therapy.47 GP IIb/IIIa inhibitors Because the GP IIb/IIIa receptor plays a key role in platelet-mediated thrombosis, inhibition of this receptor was expected to be a potent tactic for suppression of platelet aggregation and, consequently, of clot formation at the plaque injury site. Combination therapy using these new agents with heparin and aspirin has now emerged as a promising strategy for patients with acute coronary syndromes. Three GP IIb/IIIa inhibitors are available in the United States: abciximab (ReoPro), approved for use in patients undergoing PCI; eptifibatide (Integrilin), indicated for management of patients with non-ST-segment elevation acute coronary syndromes undergoing PCI; and tirofiban (Aggrastat), approved for use in patients with non-ST-segment elevation acute coronary syndromes. All three drugs bind to both resting and active forms of the receptor and therefore react with nonstimulated and stimulated platelets. Although all the GP IIb/IIIa inhibitors have a rapid onset of action, the return of platelet function to normal values after the drug is discontinued is slower with abciximab,48 an important factor when considering surgical intervention. These agents are administered IV with an initial bolus followed by constant infusion. The first large clinical trial of a GP IIb/IIIa inhibitor was the Evaluation of 7E3 in Preventing Ischemic Complications (EPIC) trial with abciximab, which enrolled 2,099 high-risk patients scheduled for PCI.49 Overall, patients receiving abciximab (bolus plus 12-hour infusion) had a significantly lower rate of the primary end point (death, MI, or urgent revascularization) at 30 days compared to placebo (8.3% vs 12.8%, P=.008).49 The beneficial effect of abciximab was maintained at the 3-year follow-up.50 The largest trial of a GP IIb/IIIa inhibitor to date, the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, evaluated the efficacy and safety of eptifibatide in 10,948 patients with moderate- to high-risk unstable angina or non-ST-segment elevation MI.51 Study drug infusions were administered until hospital discharge or initiation of CABG, for up to 72 hours. In patients who underwent PCI during the third day, infusions were continued for up to 24 hours after the procedure for a maximum of 96 hours. Decisions about the use and timing of invasive procedures were left to physician discretion. The treatment effect of eptifibatide was established during the first 72-hour median duration of infusion, with a reduction in the composite end point of death or MI from 7.6% in the placebo group to 5.9% in the eptifibatide group (P = .001).51 This benefit was fully sustained at 7 days (10.1% vs 11.6% in the placebo group, P = .016) and at 30 days (14.2% vs 15.7%, P = .042).51 A significant reduction was also observed at 6 months, as determined by the investigators (12.1% vs 13.6% in the placebo group, P = .21).52 Researchers in the Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis (RESTORE) studied the effect of tirofiban in a high-risk subset of patients undergoing coronary angioplasty and established a rational and well-tolerated dosing regimen for administration of the drug as adjunctive therapy in high-risk patients.53 Oral preparations of the GP IIb/IIIa inhibitors have also been evaluated but to date have not exhibited the promising results of the parenteral forms of these agents. ConclusionA greater selection of agents that act through various mechanisms has led to improvements in survival and long-term outcomes in patients undergoing PCI or presenting with an acute coronary syndrome. Further refinement of these therapies will likely allow for antiplatelet regimens to be individualized for specific patients and specific clinical situations. In the future, it may not be unusual for a patient to require an urgent surgical procedure while being treated with two or even three different antiplatelet agents, making it important for all involved to appreciate the potential risks associated with these interventions.
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