The management of patients with acute coronary syndrome (ACS), whether in the initial or later stages of disease, is rooted firmly in three fundamental pathobiological constructs—atherosclerosis, thrombosis, and vascular repair. This chapter summarizes current knowledge of platelets and their pivotal role in ACS with particular emphasis on clinical phenotypes, the evolution of targeted pharmacotherapy, and management strategies for optimizing patient care.
Fundamental Platelet Biology
Hemostasis and pathologic thrombosis, both platelet and tissue factor-mediated events with life-sustaining and life-threatening potential respectively, depending on the site of occurrence, coexisting conditions, and presence or absence of fully functional regulatory pathways, are familiar to most clinicians. In contrast, platelet biology, including emerging evidence for distinct functional platelet populations and platelet-dependent paracrine effects, represents an opportunity for expanded understanding and translatability from the bench to the bedside.
Megakaryocytes
Platelet production begins with a common hematopoietic stem cell (reviewed in reference ), from which two distinct blood cell lines emerge—lymphoid (all types of leukocytes) and myeloid (erythrocytes and platelets). Polypoid megakaryocytes, regenerating in human bone marrow at a rate of 10 8 cells per day, are the immediate progenitors of platelets ( Fig. 20-1 ). Each megakaryocyte can, in turn, generate more than 500 platelets. The production of such a large number of cells at a rapid rate represents a teleologic advantage for hemostatic challenges.
Under the influence of thrombopoietin—a protein synthesized in the kidney, liver and bone marrow stroma—megakaryocytes undergo dramatic morphologic changes during a 4- to 10-hour process of platelet production. The sequence of events includes cytoplasmic pseudopod development, proplatelet formation, and release or “budding off” of platelets. In addition to thrombopoietin, megakaryocytes contain both proapoptotic and antiapoptotic factors that collectively serve as biological “thermostats” for the highly regulated transition from proplatelets to platelets. ,
Several proteins of physiologic relevance are selectively expressed during specific phases of platelet development. Commitment of myeloid precursors to the megakaryocyte cell line is indicated by the expression of CD61 (ß3) and increased CD41 expression. Expression of protease-activated receptors (PARs) is determined during megakaryocyte differentiation and maturation. Expression of α IIb /ß 3 , preceding that of glycoproteins Ib, V and IX, may play a pivotal role in proplatelet formation and release. Similarly, purinergic G protein–coupled P2Y 12 (P2Y12) receptors may also participate in early megakaryocyte development.
Platelet Populations and Subpopulations
Early clotting assays, which relied on platelet-rich plasma preparations, were characterized by considerable patient-to-platelet variability—a hint of things to come in the evolution of our understanding of platelet biology. The early work of Buckwalter, Blythe, and Brinkhous identified patient-specific variability in thrombin generation on platelet surfaces. Subsequent observations made by Bouchard and coworkers, Brummel and associates, and Monroe established the presence of individual differences in platelet activation, factor X binding, factor V binding, conversion of factor X to factor Xa and prothrombinase-mediated thrombin generation.
Recently, it has become increasingly clear that platelet functionality may not only differ between individuals, but within individuals as well—and not only within individuals but within developing clots themselves. Munnix and colleagues investigated the commitment of platelets to forming aggregates and stimulating coagulation—two highly specialized and distinct steps in thrombus formation. High-resolution 2-photon fluorescence microscopy revealed separate platelet populations under flow conditions—one consisted of aggregated platelets, while distinct patches of non-aggregated platelets displayed phosphatidylserine expression, increased binding of coagulation proteins, decreased α IIb ß 3 integrins, and reduced adhesion ( Fig. 20-2 ). A third group of platelets covered with serotonin-derivatized proteins, fibrin(ogen), and thrombospondin in association with granular proteins, such as von Willebrand factor (vWF), factor V, and fibronectin were also identified. The observations suggest that distinct clusters of platelets contribute to aggregate formation, while others participate solely in procoagulant activity.
Under normal conditions platelets circulate freely without significant interaction with other platelets or healthy vascular endothelium. In the presence of endothelial disruption or activation, whether from vascular injury, rupture of an atherosclerotic plaque or maladaptive signals, a chain of events ensues that leads to platelet-rich clot formation. , Depending on the initiating event, this may represent protective hemostasis, a vital step toward vascular repair, or pathologic vascular thrombosis causing an acute coronary syndrome or ischemic stroke. The causative events represent a complex series of integrated biochemical and cellular processes that can be divided into five functional categories: translocation (tethering), activation, secretion, adhesion, and aggregation and transformation.
Translocation (Tethering)
Following vascular injury with exposure of subendothelial surfaces, or on activated endothelial cells, platelets move rapidly on bound vWF because of interactions between vWF and the glycoprotein (GP) Ib-IX-V complex. This translocation, or transient arrest, is followed by platelet activation and ultimately tethering or arrest on the vascular wall through interaction of α IIb β 3 integrins with adhesive ligands including fibronectin, fibrinogen, and vWF (described in greater detail under Adhesion).
Activation
In vivo, platelet activation is typically initiated by collagen and thrombin; however, the binding of vWF to GPIb provokes platelet activation and subsequently leads to the activation and expression of α IIb ß 3 on the platelet surface. Under static conditions, collagen can capture and activate platelets without need for cofactors, but under flow conditions, such as those encountered within the coronary vascular bed, vWF is typically required. Four receptors participating in collagen binding have been identified on the surface of human platelets; two bind directly to collagen α 2 β 1 and GPVI, the other two bind collagen via collagen-bound vWF (α IIb β 3 and GPIb. , Two separate thrombin receptors have been identified on the platelet surface—a high-affinity receptor known as GPIbα and a moderate-affinity receptor known as the thrombin receptor. , Thrombin interacts with at least two sites on the thrombin receptor and cleaves the amino-terminal extension to expose a new amino terminus which acts as a tethered ligand, activating platelets by binding to a specific region on the same receptor. Activation by collagen or thrombin produces a platelet monolayer that supports further thrombin generation and the subsequent adhesion of activated platelets to each other.
Concomitant activation of platelets with both collagen and thrombin yields a population of coated (collagen and thrombin-activated) platelets that are enriched in several membrane-bound, procoagulant proteins including thrombospondin, factor V, fibronectin, fibrinogen, and vWF.
The existence of coated platelets is important for several reasons. First, it emphasizes the dynamic nature of platelet activation, which differs according to the agonist(s) involved and local conditions. Second, it underscores that platelet activation is not an “all or none” phenomenon. Third, it highlights the rapidly evolving field of platelet biology with varying populations of cells possessing distinct properties for activation, aggregation, coagulation, protease assembly, and paracrine effects.
There are three main pathways of platelet activation: (1) activation of phosphatidylinositol-4,5-bisphosphate (PIP 2 ) and second messenger-mediated increase in cytosolic Ca 2+ concentration (resulting in integrin activation and thromboxane A 2 synthesis) and protein kinase C (resulting in protein phosphorylation); (2) activation of monomeric G proteins in the Rho and Rac families vital to platelet shape change, reorganization of the cytoskeleton, and microparticle formation; and (3) suppression of cyclic adenosine monophosphate (cAMP) synthesis by adenyl cyclase to release a protective mechanism against unnecessary platelet activation.
Secretion
Platelet activation prompts cytoskeleton rearrangements, membrane fusion, and secretion of contents from three different types of platelet storage granules: lysosomes, α-granules, and dense bodies. The lysosomes contain a number of acid hydrolases (cathepsins) that digest endocytosed materials and secretion occurs more slowly than does dense body or α-granule secretion.
The platelet α-granules are spherical bodies (300 to 500 nm in diameter) that contain platelet-specific proteins such as platelet-derived growth factor (PDGF), proteins involved in fibroblast proliferation such as connecting tissue activating peptide III (CTAP III) and the heparin neutralizing small protein platelet factor-4. Additionally, platelet α-granules contain a number of coagulation proteins including 20% to 25% of factor V. It has been demonstrated that platelet factor V is the major protein secreted and phosphorylated following α-thrombin stimulation. , Accordingly, platelet factor V is critical to the assembly of prothrombinase, which then generates additional thrombin. Alpha granules also contain protein S (the cofactor for protein C-mediated factor V and VIII inhibition) ; plasminogen activator inhibitor-1, which plays a contributing role in modulating local fibrinolytic potential ; and fibrinogen. Although meager in comparison with plasma levels, platelet fibrinogen is more highly concentrated, suggesting further that platelets provide a site for localizing hemostatic responses.
The platelet also contains a small number of electron-dense granules, referred to as dense bodies. They contain a large amount of nonmetabolic purines (adenosine diphosphate [ADP], guanosine diphosphate [GDP]) as well as divalent cations (Ca 2+ , Mg 2+ ), serotonin, and pyrophosphates. ADP secretion following platelet activation promotes recruitment and activation of additional platelets to the site of vascular injury.
Adhesion
Activated platelets adhere strongly to damaged, disrupted, or dysfunctional vascular endothelial cells. This is especially true in areas of exposed subendothelial collagen, lipid deposits and tissue factor, as found in eroded or ruptured atheromatous plaques. Initial coverage of the exposed site by platelets is mediated by several adhesive proteins that are recognized by specific platelet membrane glycoproteins ( Table 20-1 ). There is considerable redundancy and functional overlap, as several receptors may bind the same ligand and a specific receptor may respond to more than one ligand. Platelet surface receptors also include integrins. In contrast to transient adhesion, stable adhesion of platelets to subendothelial tissues requires binding of GPVI and integrin α 2 β 1 to collagen with augmentation provided by glycoprotein (GP) IIb/IIIa α IIb β 3 ), to immobilized vWF and fibrinogen, as well as binding of fibronectin to integrin α 5 β 3 . Under very high shear stress (>10,000 S −1 ), activation-independent platelet aggregation mediated by soluble vWF facilitates adhesion and precedes stable aggregation.
| Receptor | Ligand | Integrin Components | Biological Action |
|---|---|---|---|
| GPIa/IIa | Collagen | α 2 β 1 | Adhesion |
| GPIb/IX | von Willebrand factor | Adhesion | |
| GPIc/Iia | Fibronectin | α 5 β 1 | Adhesion |
| GPIIb/IIIa | Collagen | α IIb β 3 | Aggregation (secondary role in adhesion) |
| Fibrinogen | |||
| Fibronectin | |||
| Vitronectin | |||
| von Willebrand factor | |||
| GPIV | Thrombospondin | Adhesion | |
| (GPIIb) | Collagen | ||
| Vitronectin | Vitronectin | α v β 3 | Adhesion |
| Thrombospondin | |||
| VLA-6 | Laminin | α 6 β 1 | Adhesion |
| GPVI | Collagen | Adhesion |
Aggregation
An important “end result” of platelet translocation, activation, secretion and adhesion is aggregation, representing a final step toward thrombus growth and development. Adhesive ligands, primarily fibrinogen and vWF, bind via activated α IIb β 3 (also known as GP IIb/IIIa) receptors expressed on the surface membranes of adherent platelets. In a high shear-stress environment, the “bridging” effect of fibrinogen, which is required for stable platelet plug formation, occurs only after an initial tethering of vWF and GPIbα.
Though vWF and GP IIb/IIIa-mediated platelet aggregation can occur independently of platelet activation, it does so only within areas of very high shear stress, and typically yields an unstable aggregate. Accordingly, a pharmacologic approach to platelet inhibition that focuses on platelet activation (to one or more agonists of relevance through one or more key receptors) has the most sound and biologically-based rationale.
Platelet Autocrine and Paracrine Properties
Platelet-mediated thrombosis is the end result of a well-characterized series of events that include platelet translocation, activation, secretion, adhesion, and aggregation. While each step is vital to the overall process, platelet secretion represents a highly relevant component for two reasons. First, it is responsible for several sustaining autocrine circuits ( Fig. 20-3 ). Second, secretion is responsible for platelet-mediated paracrine effects that contribute to cellular proliferation and vascular repair, among other things.
The importance of understanding fundamental platelet biology, from the perspectives of hemostasis and thrombosis and vascular repair, must not be underestimated. The development of increasingly potent platelet-directly therapies, and a more widely prevalent trend in clinical practice to continue therapy for years at a time, introduces the potential for not only cumulative hemostatic challenges but a new category of vascular disorders, stemming from drug-mediated alterations in physiologic vascular repair.
Arterial Thrombosis Phenotype in Acute Coronary Syndrome
The development of flow altering blood clots is a distinguishing feature in ACS and requires an integrated series of events that involve tissue-factor–bearing clots, platelets, and coagulation proteins.
A cell-based model of coagulation establishes a physiologic, integrated, and functional view of complex biochemical events occurring on cellular (or other biological) surfaces, rather than distinct and relatively independent cascades that may be operational in static fluid systems ( Fig. 20-4 ). It also provides a scientific foundation for understanding the importance of specific platelet binding sites for coagulation proteases, , the nonhemostatic roles of coagulation factors (which include vessel wall inflammation and cellular proliferation), the dynamic nature of cellular interactions, and the inter-individual variability of platelet procoagulant activity (and thrombotic potential).
According to the cell-based model of coagulation, initiation takes place on intact cells or cellular fragments (monocytes, macrophages, neutrophils, activated endothelial cells, smooth muscle cells, apoptotic cells, platelet microparticles, circulating vesicles) bearing the transmembrane glycoprotein tissue factor. Exposed tissue factor binds and fully activates coagulation factor (f) VII, which subsequently activates fIX and fX (which then activates fV), generating a small amount of thrombin from prothrombin (fII). In the priming or amplification phase, surface-bound thrombin activates platelets (bioamplification), as well as fV, fXI, and fVIII (cleaving the latter from vWF). fXIa generates additional fIXa (whose action is accelerated by fVIIIa), whereas fVa accelerates (and amplifies) the action of fXa. During the propagation phase, fIXa binds to activated platelets, causing further fX activation. The complexing of fXa and fVa to membrane surfaces leads to a burst of thrombin generation. Thrombin’s major hemostatic roles include the conversion of soluble fibrinogen into a tridimensional network of fibrin (coagulation), the activation of platelets through at least two different G protein-coupled PARs (PAR 1 and PAR 4), and the constriction of endothelium-denuded vessels.
Thrombus growth in rapidly flowing blood is closely linked to the presence of soluble and surface-bound vWF. This multimeric protein not only acts as a bridge for the initial tethering and translocation of platelets to subendothelial collagen (via platelet GPIb), but also induces the surface expression of platelet GP IIb/IIIa (α IIb ß 3 ), leading to the stable adhesion and subsequent aggregation of activated platelets to newly formed and polymerizing fibrin strands.
Termination, elimination, and stabilization of coagulation through cell surface processes are vital for understanding potential dysregulated systems that typify atherothrombotic vascular disease. At least four plasma proteins participate in the initial termination of coagulation: tissue factor pathway inhibitor (TFPI)—released by endothelial cells and platelets, inhibiting tissue factor, fVIIa and fXa; antithrombin III—inhibits thrombin, fIXa, fXa, fXIa, and the fVIIa-tissue factor complex; protein C, a vitamin K-dependent inhibitor of fVa and fVIIIa, activated by the thrombin/thrombomodulin complex; and protein S—a cofactor in protein C-mediated fVa and fVIIIa inhibition. Activated platelets release protease nexin II, an inhibitor of soluble-phase fXIa.
Elimination of fibrin deposits (fibrinolysis) is closely linked to fibrin itself. At the thrombus surface, fibrin attracts plasminogen and tissue plasminogen activator (t-PA) to its lysine residues, whereas single-chain urokinase plasminogen activator (scu-PA) binds to plasminogen. While t-PA converts plasminogen to plasmin, the latter converts scu-PA to urokinase plasminogen (u-PA), which produces additional plasmin from plasminogen.
Stabilization of coagulation counteracts fibrinolysis through thrombin-activated fXIIIa, which converts loosely interlaced fibrin into a tightly knitted aggregate; thrombin-activatable fibrinolysis inhibitor (TAFI), which is activated to TAFIa (when exposed to the thrombin-thrombomodulin complex) and removes lysine residues from fibrin, impairing fibrin’s capacity to bind plasminogen and t-PA; plasminogen activator inhibitor type 1 (PAI-1), a rapid and irreversible inhibitor of t-PA and u-PA, released by endothelial cells and platelets; and the high-affinity plasmin inhibitor, alpha-2 antiplasmin .
Translating Platelet Biology and Pathobiology of Acute Coronary Syndromes to Pharmacotherapy
The pivotal role of platelets in the pathobiology of ACS provides a strong rationale for platelet-directed pharmacotherapy as a mainstay of treatment.
Aspirin
Aspirin, a prototypic platelet antagonist developed more than a century ago, is hydrolyzed rapidly after ingestion to salicylate and acetate. Aspirin irreversibly acetylates cyclooxygenase (COX), attenuating prostaglandin metabolism and the subsequent production of thromboxane A 2 within platelets.
About 80% to 90% of aspirin is absorbed through the gastrointestinal tract after oral ingestion. A much smaller proportion, 20% to 40%, is absorbed after rectal administration. Once absorbed, salicylate is detected within serum 5 to 30 minutes later, with peak concentrations attained typically within 2 hours. Enteric coating delays both absorption and time to peak concentration by 3- to 4-fold. The elimination half-life of salicylate is 15 to 20 minutes; however, COX inhibitory effects are sustained for the platelets’ life-span (7 ± 2 days).
Platelet P2Y12 Receptor Antagonists
The physiologic significance of the P2Y12 interaction with ADP is borne out by the success of P2Y12 blockers in reducing the risk of cardiovascular events. Though platelet P2Y12 receptor antagonists are often considered collectively as a single drug class, differences ranging from location of receptor binding site, metabolism, biological half-life, off-target effects, reversibility, and potential drug-drug interactions are evident ( Table 20-2 ).
| P2Y12 Antagonist | Dosing | Metabolism | Pharmacokinetics | Adverse Events | Reference |
|---|---|---|---|---|---|
| Thienopyridines | |||||
| Ticlopidine |
|
|
|
| , |
| Clopidogrel |
|
|
|
| |
| Prasugrel * |
|
|
|
| |
| ATP Analogue | |||||
| Cangrelor † |
| • Reversible inhibition |
|
| |
| Cyclopentyl-triazolo-pyrimidines | |||||
| Ticagrelor |
|
|
|
| |
Ticlopidine
Ticlopidine hydrochloride is an oral 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno-(3,2-c)-pyridine hydrochloride that, like all thienopyridines, irreversibly prevents ADP binding to the platelet P2Y12 receptor. Following oral administration, ticlopidine is extensively metabolized in the liver to at least 20 different metabolites. The active metabolite UR-4501 was isolated from rats administered ticlopidine, tested against human platelets in vitro, and may account for the pharmacodynamic activity of ticlopidine.
Ticlopidine displays nonlinear pharmacokinetics, and drug clearance decreases substantially on repeat dosing with steady-state plasma concentrations reached 14 to 21 days after daily dosing (250 mg twice daily). Thus, doses greater than 250 mg twice daily have minimal additional effect on platelet inhibition, but do increase the occurrence of adverse effects including neutropenia, agranulocytosis, aplastic anemia, and thrombotic thrombocytopenic purpura (TTP). In healthy volunteers, ADP-induced platelet aggregation is diminished 4 days after oral drug initiation, reaching a maximal effect after 8 to 11 days.
Clopidogrel
Clopidogrel, (+)-(S)-methyl 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridine-5(4H)-yl)-acetate sulfate, is another oral thienopyridine derivative. Following oral administration, clopidogrel must be transformed in the liver to its active metabolite, which contains a free thiol group that forms a disulfide bridge with P2Y12 extracellular cysteine residues.
Pharmacokinetic data are based on the inactive metabolite of clopidogrel. This carboxylic acid derivative, representing 85% of the circulating drug-related compounds in plasma, has no effect on platelet aggregation and has a half-life of about 8 hours. The elimination half-life of the active metabolite has not been determined in vivo , but is assumed to be relatively short. Dose-dependent inhibition of ADP-induced platelet aggregation is observed 2 hours after clopidogrel administration and reaches a steady-state within 3 to 7 days with daily dosing. When clopidogrel is given as a 600-mg loading dose, it achieves its mean peak antiplatelet effect 3 to 8 hours after administration.
Prasugrel
The most recent thienopyridine to be clinically investigated is prasugrel, 2-acetoxy-5-(a-cyclopropylcarbonyl-2-fluoro-2-fluorobenzyl-4,5,6,7-tetrahydrothieno [3,2-c]pyridine. In contrast to clopidogrel and ticlopidine, which require two-step cytochrome P-450 oxidation for generation of their active metabolites, prasugrel requires only one step, leading to a 10-fold higher plasma concentration. Human carboxylesterases, found in the liver and gastrointestinal tract, efficiently mediate the conversion of prasugrel to its active metabolite, providing an explanation for the rapid achievement of maximum plasma concentrations following oral administration. Prasugrel, given at doses of 10 and 20 mg once daily, achieves a robust degree of ADP-induced platelet inhibition beginning at 15 minutes, with peak response within 2 hours of administration of a 40- or 60-mg loading dose and steady-state platelet aggregation inhibition by day 3.
Cangrelor
Cangrelor, N6 [-2-methylthio]-2-[3,3,3-trifluoropropylthio]-5′-adenylic acid, was developed as an intravenous, selective, and reversible P2Y12 receptor antagonist and does not require hepatic conversion to an active metabolite. It is chemically similar to adenosine triphosphate (ATP) and is considered an ATP analogue. Following intravenous administration, cangrelor is metabolized primarily in the liver with a mechanism of plasma clearance determined by dephosphorylation and vascular surface (endothelial cell) endonuclease activity. Following an intravenous infusion of 4 hours’ duration, plasma elimination causes a rapid decline in cangrelor concentrations, with an initial half-life of less than 5 minutes.
In phase II studies of cangrelor administered at rates of 1, 2, and 4 µg/kg/minute to patients undergoing percutaneous coronary intervention (PCI), impedance-determined platelet aggregation in response to 3 µM ADP was inhibited by 94%, 87% and 99%, respectively, 15 minutes after drug administration. A return toward baseline platelet aggregation occurred 15 minutes after drug cessation in the 1 and 2 µg/kg/minute dosing arms but required 30 to 60 minutes for those patients in the 4 µg/kg/minute group.
Ticagrelor
Ticagrelor, is a cyclopentyltriazolopyrimidine (CTEP), a new class of P2Y12 inhibitors. Its molecular structure is 6-[2-(3,4-difluorophenyl)cyclopropyl-1-yl]amino-2-propylthio-9ß-D-ribofuranosyl-9H-purine. It is an oral and reversible derivative of cangrelor that similarly does not require hepatic conversion to an active metabolite, although one of its metabolites (AR-C12490XX) is also pharmacologically active.
Ticagrelor and AR-C12490XX show linear dose-response relationships, with a mean time to maximal inhibition of platelet aggregation of 2 to 4 hours following 100 mg twice daily, 200 mg twice daily, and 400 mg once daily dosing. On average, the degree of platelet inhibition in response to 20 µM ADP is 80% to 90% with the highest doses.
Platelet Glycoprotein IIb/IIIa Receptor Antagonists
The α IIb /ß 3 receptor belongs to the integrin family of adhesion receptors that are found predominantly on the surface of platelets and megakaryocytes. This receptor is found in large numbers (80,000 copies per platelet) and consists structurally of a non-covalently linked heterodimer. GP IIb/IIIa receptor antagonists occupy the α IIb /β 3 receptor, inhibiting fibrinogen-mediated platelet aggregation. There are currently three intravenous platelet GP IIb/IIIa receptor antagonists that are used in clinical practice ( Table 20-3 ).
| Characteristics | Abciximab | Eptifibatide | Tirofiban |
|---|---|---|---|
| Type | Antibody | Peptide | Nonpeptide |
| Molecular weight (d) | ∼50,000 | ∼800 | ∼500 |
| Platelet-bound half-life | Long (hr) | Short (sec) | Short (sec) |
| Plasma half-life | Short (min) | Extended (2 hr) | Extended (2 hr) |
| Drug-to-GP IIb/IIIa receptor ratio | 1.5-2.0 | 250-2500 | >250 |
| 50% return of platelet function (without transfusion) | 12 hr | ∼4 hr | ∼4 h |
| Antagonist dosing | |||
| PCI | |||
| Bolus | 0.25 mg/kg | Double bolus 180 µg/kg/min(10 min apart) | 10 µg/kg |
| Infusion | 0.125 µg/kg/min for 12 hr | 2 µg/kg/min for 20-24 hr | 0.5 µg/kg/min |
| ACS | |||
| Bolus | Not recommended * | 180 µg/kg over 30 min | 0.4 µg/kg over 30 min |
| Infusion | 2 µg/kg/min up to 72 hr | 0.1 µg/kg/min for 48-108 hr | |
| Renal dysfunction | |||
| Creatinine clearance ≥50 mL/min | No adjustment required | 180 µg/kg over 30 min; 0.5 µg/kg/min infusion | 0.2 µg/kg over 30 min |
| Creatinine clearance <50 mL/min | Adjustment required ‡ | Contraindicated | 0.5 µg/kg/min infusion † |
* Use of abciximab for ACS in absence of planned PCI not recommended.
† Dose of tirofiban for patients with creatinine clearance < 30 mL/min. Experience limited.
Abciximab
Abciximab is the Fab fragment of the chimeric human-murine monoclonal antibody c7E3.
After an intravenous bolus, free plasma concentrations of abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second-phase half-life of 30 minutes, representing rapid binding to the platelet GP IIb/IIIa receptor. Abciximab remains in the circulation for 10 or more days in the platelet-bound state.
Pharmacodynamics
Intravenous administration of abciximab in doses ranging from 0.15 mg/kg to 0.3 mg/kg produces a rapid dose-dependent inhibition of platelet aggregation in response to ADP. At the highest dose, 80% of platelet GP IIb/IIIa receptors are occupied within 2 hours, and platelet aggregation, even with 20 µM of ADP, is completely inhibited. Sustained inhibition is achieved with prolonged infusions (12 to 24 hours), and low-level receptor blockade is present for 10 days after cessation of the infusion; however, platelet inhibition during infusions beyond 24 hours has not been well characterized. Platelet aggregation in response to 5 µM ADP returns to greater than or equal to 50% of baseline within 24 hours in most cases ( Fig. 20-5 ).
Tirofiban
Tirofiban, a synthetic 495-kd nonpeptide tyrosine derivative, is a selective competitive antagonist of the platelet GP IIb/IIIa receptor.
The pharmacokinetics of tirofiban are linear, and plasma concentrations are proportional to dose after intravenous infusions of 0.05 to 0.4 mg/kg/minute for 1 hour or 0.1 to 0.2 mg/kg/minute for 4 hours in healthy individuals. Concomitant administration of aspirin or clopidogrel does not affect pharmacokinetics.
Tirofiban is approximately 65% bound to plasma proteins, and binding is independent of drug concentrations over a wide range. The steady-state volume of distribution ranges from 22 to 42 L.
After intravenous administration, plasma concentrations of tirofiban decline in a biphasic manner. The half-life averages 1.5 to 2 hours. Clearance is predominantly (65% to 70%) through renal excretion, and metabolism of the drug is limited. Plasma clearance of tirofiban is 20% to 25% lower in older patients (≥65 years old) and can be reduced by 50% or more in patients with marked renal insufficiency (creatinine clearance <30 mL/minute). Drug clearance is not influenced by gender, race, or mild-to-moderate hepatic insufficiency. Tirofiban is removed to a variable degree by hemodialysis.
Pharmacodynamics
Tirofiban mimics the geometric stereotactic and conformational characteristics of the α IIb /β 3 receptor arginine-glycine-aspartic acid (RGD) sequence, interfering with fibrinogen surface binding and platelet aggregation.
Three doses of tirofiban were studied in phase I clinical trials: bolus dose of 5, 10, or 15 µg/kg followed by a continuous intravenous infusion of 0.05, 0.10, or 0.15 µg/kg/minute. A dose-dependent inhibition of ex vivo platelet aggregation was observed within several minutes of bolus administration with sustained inhibition during the maintenance infusion.
Plasma clearance of tirofiban is decreased substantially in patients with severe renal impairment (creatinine clearance <30 mL/minute), including patients requiring hemodialysis. These patients should receive half the usual infusion rate.
Eptifibatide
Eptifibatide, a synthetic cyclic heptapeptide, is a selective competitive antagonist of the platelet GP IIb/IIIa receptor.
The pharmacokinetics of eptifibatide are linear, and plasma concentrations are proportional to dose after intravenous administration of 90 to 250 µg/kg and infusions of 0.5 to 3 mg/kg/minute. Concomitant administration of aspirin or heparin does not influence the pharmacokinetics of eptifibatide. Dosing strategies, to include high-dose single bolus administration, have been investigated among patients with ACS.
Eptifibatide is approximately 25% bound to plasma proteins, principally albumin. The volume of distribution ranges from 185 to 260 mL/kg.
Plasma concentrations of eptifibatide decline in a biexponential manner after intravenous administration. The half-life ranges from 2.5 to 2.8 hours. Eptifibatide is eliminated by renal and nonrenal mechanisms. The drug undergoes deamination within plasma to a metabolite that is responsible for approximately 40% of the platelet inhibitory effects. Clearance of eptifibatide is proportional to body weight and creatinine clearance and inversely proportional to age. Renal clearance is responsible for 40% to 50% of total body clearance. Eptifibatide is removed to a variable degree by hemodialysis.
Pharmacodynamics
Early studies of patients undergoing PCI determined that bolus doses of 135 µg/kg or higher yielded greater than 80% inhibition of ADP-mediated platelet aggregation in most (75%) patients. A double bolus strategy (180 µg/kg, administered twice, 10 minutes apart) achieved maximal inhibition in a greater proportion of patients. Platelet aggregation returns to 50% of baseline 4 hours after infusion termination.
Dose adjustments have not been recommended with mild renal impairment (serum creatinine <2 mg/dL). Appropriate dosing of eptifibatide is based on creatinine clearance, a more accurate estimate of renal function than serum creatinine alone. Patients with a creatinine clearance of <50 mL/min should receive an infusion of 1 µg/kg/min representing a 50% reduction of the normal infusion. Eptifibatide should not be used in patients with dependence on renal dialysis.
Platelet-Directed Pharmacotherapy
Clinical Trials, Evidence, and Administration Strategies in Acute Coronary Syndromes
The contemporary management of patients with ACS has been summarized in recently published guidelines crafted by the American College of Cardiology, American Heart Association, and European Society of Cardiology , and by the American College of Chest Physicians.
Short-term Administration
Aspirin
International Studies of Infarct Survival (ISIS-2) was a randomized, placebo-controlled, blinded trial of short-term therapy with IV streptokinase (SK), oral aspirin (160 mg/d for 1 month), both or neither, among 17,187 patients with suspected myocardial infarction (MI). In addition to a 23% relative risk reduction (RRR) in 5-week vascular mortality among patients receiving SK, there was a 21% reduction among those receiving aspirin and a 40% reduction among those receiving a combination of SK and aspirin, which are all highly significant reductions. The early reduction in mortality with aspirin persisted when the patients were observed for a mean of 15 months. Aspirin reduced the risk of nonfatal reinfarction by 49% and nonfatal stroke by 46%. The increased rate of early nonfatal reinfarction noted when SK therapy was used alone is consistent with marked platelet activation after fibrinolytic therapy and was completely resolved when aspirin was added (3.8% vs. 1.3%; P < .001).
Aspirin added to the benefit of SK therapy in all groups examined. In particular, among patients younger than 70 years of age, the combination markedly reduced mortality from 23.8% to 15.8% ( P < .001) without increasing hemorrhage or stroke. Because of the overall poor prognosis among older individuals with acute MI, the absolute number of lives saved with aspirin and thrombolytic therapy increases with age (i.e . , 2.5 per 100 treated patients <60 years of age and 7 to 8 per 100 treated patients 60 years of age).
ISIS-2 showed that short-term aspirin therapy for MI decreases mortality and reinfarction, has benefits in addition to those of fibrinolysis, and reduces reinfarction after fibrinolytic therapy. Consequently, aspirin therapy for patients with acute MI should accompany fibrinolytic therapy. Although associated with an increased rate of minor bleeding from 1.9% to 2.5%, aspirin therapy was not associated with an increased risk of major bleeding, including hemorrhagic stroke. The benefit of aspirin, in contrast to that of SK, was independent of the time of onset of treatment. However, early administration seems prudent.
P2Y12 Receptor Antagonists
The CLARITY, TIMI, 28 , and COMMIT trials evaluated the addition of clopidogrel to antithrombotic therapy with aspirin, heparin, and a fibrinolytic agent. In the CLARITY trial, the addition of a loading dose of 300 mg of clopidogrel followed by 75 mg/day in 3491 patients younger than 75 years of age with acute ST-segment elevated myocardial infarction (STEMI) was associated with a significant 36% reduction in the composite primary end point of death, MI, or an occluded infarct-related coronary artery (95% confidence interval [CI]; 27%-47%; P < .001) at the time of angiography. The greatest effect of clopidogrel was on coronary occlusion; this trial did not demonstrate benefits on reducing either death or MI. The benefit did not come at the expense of increased bleeding despite the concomitant use of a fibrinolytic agent, aspirin, unfractionated heparin (UFH), or low-molecular-weight heparin (LMWH). In addition, the PCI-CLARITY subset of the trial demonstrated significantly better outcomes in the 1863 patients who underwent angioplasty after clopidogrel therapy.
The Chinese COMMIT trial of 45,852 patients with acute MI, half of whom received reperfusion therapy, demonstrated benefit from clopidogrel 75 mg/day compared with placebo; both groups received aspirin. The primary end point of death, MI, or stroke was reduced by 9% (10.1% vs. 9.3%, P = .002); mortality was reduced by 7% (8.1% vs. 7.5%, P = .03). Overall, when all transfused, fatal, or cerebral bleeds were considered together, there was no significant excess risk associated with the use of clopidogrel (134 [0.58%] clopidogrel vs. 125 [0.55%] placebo; P = .59). The average duration of treatment with clopidogrel for CLARITY and COMMIT was 16 days and 14 days, respectively.
Long-Term Administration
Aspirin
The Antiplatelet Trialists’ Collaboration update included 287 studies involving 135,640 high-risk (acute or previous vascular disease or another predisposing condition) patients in comparisons of antiplatelet therapy versus control and 77,000 similar patients in comparisons of different antiplatelet regimens. The analysis extended the direct evidence of benefit from platelet-directed therapy, predominantly with aspirin, to a much wider range of patients at high risk including those with ACS.
Overall, 7705 (10.7%) serious vascular events occurred in 71,912 high-risk patients allocated antiplatelet versus an adjusted total of 9502 (13.2%) such events among 72,139 control patients (22% odds reduction; P = .0001). Antiplatelet therapy was associated with a highly significant 15% relative reduction in vascular deaths ( P = .0001) (similar across high- and low-risk groups), all-cause mortality ( P < .0001), nonfatal MI (34% odds reduction; P < .001), nonfatal MI or death from coronary heart disease (26% odds reduction; P < 0.001), and stroke (25% odds reduction; P < .001). Overall, the relative odds of experiencing a major extracranial hemorrhage was increased 60% with antiplatelet therapy (odds ratio, 1.6; P < .001). The increase in fatal hemorrhage was not significantly different from that for nonfatal hemorrhage, although only the excess of nonfatal hemorrhagic events achieved statistical significance.
The optimal dose of aspirin for the prevention of cardiovascular events has not been definitively established by directly comparing two different dosages in large clinical trials. The updated meta-analysis does, however, provide useful information on the effects of different doses of aspirin. Overall, among 3570 patients in three trials directly comparing aspirin doses (75 mg vs. <75 mg/day), there were significant differences in vascular events (two trials compared 75 to 325 mg/day aspirin vs. <75 mg/day and one trial compared 500 to 1500 mg of aspirin daily vs. <75 mg/day) favoring lower doses. Considering both direct and indirect comparisons of aspirin dose, vascular events were reduced 19% with 500 to 1500 mg/day, 26% with 160 to 325 mg/day, and 32% with 75 to 150 mg/day. These data provide indirect support for administration of an aspirin dose of 75 to 100 mg/day for cardiovascular disease treatment.
The benefit derived from antiplatelet therapy in patients with coronary artery disease (CAD), unstable angina (UA), acute MI, and previous MI is well established; additionally, the added benefit from multitargeted antiplatelet regimens, particularly among high-risk patients with non–ST-elevation myocardial infarction (NSTEMI) ACS, is now clearly established.
P2Y12 Receptor Antagonists
In the CURE trial, 12,562 patients with NSTEMI ACS were randomly assigned to receive clopidogrel (300 mg immediately followed by 75 mg/day) or placebo in addition to aspirin (75 to 325 mg/day) for 3 to 12 months. The first primary outcome, a composite of death from cardiovascular causes, nonfatal MI or stroke, occurred in 9.3% and 11.4% of patients given clopidogrel and placebo, respectively (relative risk [RR] 0.80; 95% CI, 0.72 to 0.90; P < .001). The compelling benefit in CURE is in reducing nonfatal MI (5.2% vs. 6.7%; RR, 0.77; 95% CI, 0.67 to 0.89); modest trends primarily (nonsignificant) suggested the possibility of small reductions in death (5.1% vs. 5.5%; RR, 0.93; 95% CI, 0.79 to 1.08), and stroke (1.2% vs.1.4%; RR 0.86; 95% CI, 0.63 to 1.18) with clopidogrel.
Significantly fewer patients in the clopidogrel group experienced recurrent angina (20.9% vs. 22.9%; RR, 0.91; 95% CI, 0.85 to 0.98; P = .01). The benefits of clopidogrel were consistent across a broad range of patient subsets including those with MI, ST-segment deviation, elevated cardiac biomarkers, diabetes mellitus, age older than 65 years, and high-risk features. Although the use of concomitant GP IIb/IIIa inhibitors was low in CURE, the treatment effect of clopidogrel was consistent among those receiving and not receiving the intravenous platelet inhibitors.
Major bleeding (defined as disabling hemorrhage, intraocular hemorrhage leading to visual loss, or bleeding requiring transfusion of at least 2 units of blood) was significantly more common in clopidogrel-treated patients (3.7% vs. 2.7%; RR, 1.38; 95% CI, 1.13 to 1.67; P = .001). Life-threatening bleeding (fatal hemorrhage or causing a reduction in hemoglobin of 5 g/dL or substantial hypotension requiring inotropic support, surgical intervention; symptomatic intracranial hemorrhage, or transfusing of 4 units of blood) was also more common, although the difference did not reach conventional levels of statistical significance (2.2% vs. 1.8%; RR, 1.21; 95% CI, 0.95 to 1.56). There was not an excess rate of fatal bleeding, bleeding that required surgical intervention, or hemorrhagic stroke. The number of patients requiring transfusion of 2 units of blood was higher in the clopidogrel group (2.8% vs. 2.2%; P = .02).
Compared with aspirin alone, there was an excess of minor and major bleeding with the combination of aspirin and clopidogrel in patients with NSTEMI in the CURE trial, although the incidence of life-threatening bleeding was not different between the two groups. Using the TIMI criteria for major bleeding, the rate of major bleeding with the combination of aspirin plus clopidogrel was similar to that with aspirin alone (1.1% and 1.2%, respectively; P = .70). Major or life-threatening bleeding in the PCI-CURE study was similar in the two groups, even in patients who received a GP IIb-IIIa inhibitor.
The rate of major bleeding with clopidogrel was higher early (within 30 days of randomization; 2.0% vs. 1.5%; RR, 1.31; 95% CI, 1.01 to 1.70) and also late (>30 days after randomization: 1.7% vs. 1.1%; RR, 1.48; 95% CI, 1.10 to 1.99). Bleeding associated with coronary artery bypass grafting (CABG) was particularly high among patients receiving clopidogrel within 5 days of surgery (9.6% vs. 6.3%; P = .06) but bleeding was not different between the groups when clopidogrel had been discontinued for more than 5 days. Overall, the risk of minor bleeding was significantly higher in patients treated with clopidogrel (5.1% vs. 2.4%; P = .001).
The two most recently developed and studied P2Y12 receptor antagonists, prasugrel and ticagrelor will be discussed later in the section “Emerging Platelet-Directed Pharmacotherapy.”
Dose of Aspirin with Combination Platelet-Directed Therapy
Long-term aspirin therapy is recommended for patients with CAD who undergo any revascularization procedure, including PCI. When aspirin is given in combination with other antiplatelet agents or with anticoagulants, it is reasonable to use a daily dose of 75 to 100 mg, rather than 325 mg, to minimize hemorrhagic risk.
The CURRENT-OASIS 7 trial randomized more than 25,000 patients with ACS to either low-dose aspirin (75-100 mg daily) or high-dose aspirin (300-325 mg daily for the first 7 days) and, in a separate randomization to either standard-dose lopidogrel (300 mg loading dose, followed by 75 mg daily on days 2-30) or high-dose clopidogrel (600 mg loading dose, followed by 150 mg daily on days 2-7). The primary outcome was the composite of death from cardiovascular causes, MI, or stroke at 30 days. In the overall cohort, which included 7855 patients who did not undergo PCI or in whom therapy was discontinued in anticipation of coronary artery bypass grafting, there was no significant difference in the primary outcome for high dose aspirin or high dose clopidogrel. Among the 17,232 patients who underwent PCI, high dose clopidogrel was associated with a significant reduction (15%) in the composite endpoint, driven in large part by a 22% reduction in the risk of MI. There was also a 42% reduction in the risk of definite start thrombosis. Severe bleeding and transfusions were increased by approximatedly 40% with high-dose clopidogrel compared to standard dosing. The overall benefit beyond 30 days is unknown (European Society of Cardiology, Barcelon, Spain, 2009).
A dose of 75 to 100 mg/day is supported by a post hoc analysis of data derived from the CURE study. Patients were classified into three aspirin-dose groups: less than 100 mg, 101 to 199 mg, and 200 mg. The combined incidence of cardiovascular death, MI, or stroke was reduced by clopidogrel regardless of aspirin dose, but the incidence of major bleeding increased with higher doses, both in patients randomized to aspirin plus placebo (1.9%, 2.8%, and 3.7%, respectively; P = .0001) and in those given aspirin plus clopidogrel (3.0%, 3.4%, and 4.9%, respectively; P = .0009).
Platelet-Directed Therapy Following Percutaneous Coronary Intervention
Extended treatment with the combination of aspirin and clopidogrel after PCI for an ACS or after elective angioplasty reduces the rate of ischemic events. The CREDO trial was a randomized, blinded, placebo-controlled trial conducted in 2116 patients undergoing elective PCI. Patients were randomly assigned to receive a 300-mg clopidogrel loading dose or placebo 3 to 24 hours before PCI. Thereafter, all patients received clopidogrel (75 mg/day) until day 28. From day 29 through 12 months, patients in the loading-dose group received clopidogrel (75 mg/day), while those in the control group received placebo. Both groups received aspirin throughout the study. The 12-month incidence of the composite of death, MI, or stroke in the intention-to-treat population was reduced by 26.9% in patients treated with long-term clopidogrel therapy ( P = .02). Drug-eluting stents (DES) were not yet available and therefore were not included in the study.
In the CREDO trial, major bleeding as defined by the TIMI criteria tended to be higher in the clopidogrel group than in those given placebo (8.8% and 6.7%, respectively; P = .07), although most of the major bleeding episodes were related to invasive procedure, such as CABG. Minor bleeding episodes were significantly more common with combination antiplatelet therapy in both the CURE and PCI-CURE studies. The CREDO trial did not find differences in minor bleeding between the two groups.
Stent Thrombosis Following Percutaneous Coronary Intervention
Although uncommon, stent thrombosis represents a severe complication of stent implantation with a high rate of morbidity (mostly MI) and mortality. Stent thrombosis can occur hours after placement (acute stent thrombosis), days thereafter (subacute stent thrombosis), or beyond 30 days (late stent thrombosis). Reports on the predictors of stent thrombosis following DES implantation have found that clinical (diabetes and renal failure), angiographic (bifurcation disease), and care (premature termination of antiplatelet therapy) characteristics are all associated with a higher risk of stent thrombosis. Impaired or delayed endothelialization, particularly with placement in the setting of an ACS, may also affect thrombosis occurrence.
Bare metal stent (BMS) thrombosis, with the introduction of combined therapy with aspirin and clopidogrel, occurs infrequently with most estimates being at less than 1% of patients, and is unusual after the first month. In contrast, stent thrombosis following DES, although less frequent with dual antiplatelet therapy, can occur months to years after implantation. In the PREMIER Registry, 500 DES-treated MI patients discharged from the hospital on aspirin and thienopyridine therapy were followed for 11 months. A total of 68 patients (13.6%) discontinued thienopyridine drugs within 30 days of hospital discharge, and on follow-up were more likely to die during the next 11 months (7.5% vs. 0.7%; adjusted hazard ratio, 9.0; 95% CI, 0.2 to 60.5; P < .0001) and to be rehospitalized (23% vs. 14%; adjusted hazard ratio, 1.5; 95% CI, 0.78 to 3.0; P = .08).
An observational study from the Duke Cardiovascular Database including 3165 patients receiving BMS and 1501 patients with DES who were event free (death, MI, revascularization) at 6 months and 12 months, were followed up and self-reported clopidogrel use was used to classify patients into four groups: BMS with clopidogrel, BMS without clopidogrel, DES with clopidogrel, and DES without clopidogrel. Among patients with BMS, clopidogrel did not influence the incidence of death or MI at 24 months; however, in patients with DES, continued use of clopidogrel was associated with lower rates of death (0% vs. 3.5%; 95% CI, 5.9 to 1.1%; P = .004) and death or MI (0.0% vs. 4.5%; 95% CI, 7.1 to 1.9; P < .001) ( Fig. 20-6 , left and right panels) .
