CHAPTER 131 ANTIPLATELET THERAPY
CHAPTER 131 ANTIPLATELET THERAPY
HARVEY J. WEISS
Inhibitors of Thromboxane A2 Synthesis or Binding
Prostaglandin I2 and Analogues
Ticlopidine and Clopidogrel
Inhibitors of the Platelet GPIIB/IIIA Receptor
Other Antiplatelet Agents
Antiplatelet Drugs in Clinical Medicine
Ischemic Heart Disease
Valvular Heart Disease
Peripheral Vascular Disease
Small Vessel Thrombotic Diseases (Microangiopathies)
Other Arterial Thrombotic Disorders
The properties that make platelets useful in promoting the arrest of bleeding also lead them to be deposited as thrombi in blood vessels and on the surfaces of heart valves, artificial membranes, and prosthetic devices. In addition, substances produced or stored in platelets, when secreted, may be involved in vasospasm and proliferative responses, atherogenesis, and inflammation. Aspirin, the thienopyridine derivatives ticlopidine and clopidogrel, and a number of platelet glycoprotein (GP) IIb/IIIa receptor antagonists have been demonstrated to be efficacious in preventing and/or treating thrombotic vascular disease.
Acronyms and abbreviations that appear in this chapter include: ADP, adenosine diphosphate; AMIS, Aspirin in Myocardial Infarction Study; CABS, coronary artery bypass surgery; CAPRIE, Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events; CAPTURE, Chimeric 7E3 Antiplatelet in Unstable angina Refractory to standard treatment; CAST, Chinese Acute Stroke Trial; CATS, Canadian-American Ticlopidine Study; COX, cyclooxygenase; cyclic AMP (cAMP), cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; EPA, eicosapentaenoic acid; EPIC, Evaluation of 7E3 for the Prevention of Ischemic Complications; EPILOG, Evaluation of PTCA to Improve Long-term Outcome by c7E3 GPIIb/IIIa receptor blockade; EPISTENT, Evaluation of IIb/IIIa Platelet Inhibitor for Stenting; GP, glycoprotein; IMPACT II, Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis; ISIS-2, Second International Study of Infarct Survival; ISIS-3, Third International Study of Infarct Survival; IST, International Stroke Trial; KGD sequence, lysine-glycine-aspartic acid sequence; NO, nitric oxide; NSAIDs, non-steroidal anti-inflammatory drugs; PARAGON, Platelet IIb/IIIa Antagonist for the Reduction of Acute coronary syndrome events in a Global Organization Network; Paris II, Second Persantine Aspirin Reinfarction Study; PCI, percutaneous coronary interventions; PDGF, platelet-derived growth factor; PG, prostaglandin; PGE1, prostaglandin E1; PGHS-1, PGH-synthase; PGI2, prostacyclin; PRISM, Platelet Receptor Inhibition in Ischemic Syndrome Management; PRISM-PLUS, Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms; PTCA, percutaneous transluminal coronary angioplasty; PURSUIT, Platelet IIb/IIIa Underpinning the Receptor for Suppression of Unstable Ischemia Trial; RAPPORT, ReoPro and Primary PTCA Organization and Randomized Trial; RESTORE, Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis; RGD sequence, arginine-glycine-aspartic acid sequence; RINDs, reversible ischemic neurologic deficits; TASS, Ticlopidine Aspirin Stroke Study; TIAs, transient ischemic attacks; TxA2, thromboxane A2.
The term “antiplatelet” has no precise meaning at present. It has been used to describe drugs that inhibit platelet activation in vitro, modify experimentally induced thrombosis, prolong the survival of radioactively labeled platelets, or interfere with some presumed platelet-mediated pathologic processes. Drugs possessing these properties are shown in Table 131-1. The first part of this chapter will describe these agents, their mechanisms of action, and their pharmacology. The second part will describe the clinical application of these agents.
TABLE 131-1 ANTIPLATELET DRUGS USED IN CLINICAL MEDICINE
Following early observations that aspirin (acetylsalicylic acid) ingestion can result in a mild hemostatic defect and prolong the bleeding time,1,2 studies in the late 1960s demonstrated that a single, oral dose of the drug inhibited collagen-induced platelet aggregation and secondary aggregation responses to weak agonists such as ADP and epinephrine for about 7 days, whereas sodium salicylate was without effect.3 The aspirin effect corresponded roughly to the platelet life span and suggested that aspirin induced an irreversible inhibitory effect on platelet function through some mechanism involving the acetyl group.3 Subsequent studies demonstrated that, in platelets, aspirin inhibits the conversion of arachidonic acid to prostaglandins1,2,4 and thromboxane A2 (TxA2),5 one of the most potent platelet aggregating agents that has been described.6 In platelets, arachidonate is released from phospholipids in the platelet membrane, principally through the action of phospholipase A2, in response to a variety of agonists7,8 and 9 (see Chap. 111). Arachidonic acid is then converted to prostaglandin (PG) H2 by the enzyme PGH-synthase, PGHS-1, also referred to as cyclooxygenase (COX-1).9,10 The latter is a homodimeric, heme-containing protein with two catalytic activities, one of which (COX) cyclizes arachidonate to PGG2, while the other (peroxidase) catalyzes a two-electron reduction of PGG2 to PGH2.10,11 and 12 The latter endoperoxide is then converted to TxA2 by a specific isomerase called thromboxane synthase.9,10 Aspirin selectively blocks the cyclooxygenase (but not the peroxidase) activity of COX-1 by irreversibly acetylating the hydroxyl group12,13 of a crucial serine at position 530 (Ser530) or 529 (Ser529) in sheep14 or human15 platelets, respectively. Since the platelet is an anucleate cell, containing only a small amount of mRNA derived from megakaryocytes, it is unable to replace the irreversibly inactivated COX-1 through new protein synthesis, thereby accounting for the permanence of the “aspirin effect” on prostaglandin synthesis12 and platelet function.3 Although it was initially believed that serine 529/530 could be the active site within COX-1, later studies identified this site as tyrosine 38516,17 and showed that the covalent binding of aspirin to Ser529/530 has the effect of sterically hindering the access of arachidonate to the tyrosine residue responsible for initiating catalysis.16,18 Aspirin, as well as other salicylates, can also inhibit a second PGH-synthase isoenzyme, COX-2,16 that is undetectable in most mammalian tissues (including platelets), but whose expression can be induced in monocytes and other cells in response to inflammatory and mitogenic mediators.10 The concentration of aspirin required for inhibiting COX-2 is considerably higher than that required for inhibiting COX-1, which explains why the antiplatelet/antithrombotic dose of aspirin is so much lower than the anti-inflammatory dose.10,16
The antiplatelet effects of aspirin are complicated by its capacity for blocking the cyclooxygenase activity in endothelial cells, thereby inhibiting the conversion of endoperoxides to PGI2 (prostacyclin).19 The latter eicosanoid can interact with a receptor on the surface of platelets and initiate a series of changes that increase the intracellular concentration of cyclic-AMP, thereby inhibiting platelet aggregation7,19 (see Chap. 111). In contrast to platelets, inhibition of endothelial cell cyclooxygenase is not permanent, because these cells can synthesize new enzymes, and recovery of PGI2 production by cultured umbilical vein endothelial cells has been observed 2 h after aspirin treatment.20
The ability of aspirin to inhibit (irreversibly) the formation of both platelet TxA2 (a potential prothrombotic agent) and endothelial cell PGI2 (a potential antithrombotic agent) has raised the question of whether there is a dose of aspirin that will suppress TxA2 synthesis without inhibiting the production of PGI2. It is assumed that, if such a dose exists, it will be the optimum “antithrombotic” dose. However, several aspects of this question are unresolved. First, there is no convincing evidence that blocking the production of PGI2 is prothrom-botic. In addition, even if the preservation of PGI2 production were desirable, a dose of aspirin that optimally inhibits the production of TxA2 without affecting PGI2 has not been found.21 In addition, when PGI2 production was assessed by measuring the amount of a stable metabolite, 6-keto-1a, that is produced locally at the site of acute injury, as in a bleeding time wound, PGI2 production was markedly inhibited by daily aspirin doses as low as 30 mg per day.22 A controlled-release formulation of aspirin has been reported that inhibited thromboxane synthesis with only minimal inhibition of basal or bradykinin-induced PGI2 production.23 This effect is based on the observation that aspirin is rapidly deacetylated in the liver; therefore, aspirin absorbed in the stomach and intestine can acetylate platelets in the portal circulation before it is metabolized in the liver. The endothelial cells in the systemic circulation are not exposed to aspirin, but rather salicylate, which cannot acetylate cyclooxygenase. Whether this approach will also preserve local PGI2 production at sites of injury remains to be determined.
Many studies have addressed the question of whether there is a dose of aspirin that will result in the optimal inhibition of TxA2 production and platelet aggregation. When the TxA2 production has been assessed by measuring the concentration of a stable metabolite, TxB2, in clotted blood, daily aspirin doses (mg) were reported to inhibit serum TxB2 production as follows: 20 mg, 95 percent21; 30 mg, 94 percent24; 100 mg, 98 percent25; 100 mg, 95 percent26; and 325 mg, 91 percent.27 Thus, somewhere between 2 and 9 percent of serum TxB2 production was preserved with those dosage schedules, and therefore, it is theoretically possible that some TxA2 formation at sites of vascular injury, such as a ruptured atherosclerotic plaque, might still occur in patients receiving doses of aspirin sufficient to cause substantial, but incomplete, inhibition of its production.28 Although relatively low daily doses of aspirin will eliminate secondary platelet aggregation in response to epinephrine, the dose-response inhibitory effects of aspirin on platelets by other agonists may be significantly different in patients with vascular disease than in normal subjects.29 The current consensus is that clinically effective inhibition of platelet aggregation and thromboxane formation can be achieved as follows (loading dose, mg/daily maintenance dose, mg): 320/80–160,12 120/30–50,10 200–300/75–100.30 Whether these relatively low-dose schedules are universally applicable or might have to be modified in subgroups of patients with vascular disease, such as those with atherothrombosis in the cerebral circulation, is still the subject of some dispute (see later). Finally, the recent finding that a single 500-mg dose of aspirin may be required to block a newly described red cell–mediated, thromboxane A2–independent platelet reactivity could have implications for aspirin therapy in patients with vascular disorders.31
The possibility that aspirin, because of its platelet-inhibitory properties, might be useful as an antithrombotic agent has been studied in a variety of injury-induced thrombosis models in animals and found, in most cases, to confer some protection against thrombosis.1,2
In general, other nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit platelet aggregation and secretion32 through a mechanism similar to that of aspirin, i.e., through inhibition of platelet cyclooxygenase.1,2,33 Among NSAIDs, the prolonged inhibition of platelet function may be unique to aspirin. The effect of indomethacin, for example, is short-lived, and regardless of the size of the dose, inhibition is no longer detectable after 6 h.1,34
INHIBITORS OF THROMBOXANE A2 SYNTHESIS OR BINDING
Thromboxane synthase, the enzyme that catalyzes the synthesis of TxA2 from PGH2, is inhibited by a variety of pharmacologic agents, including prostaglandin endoperoxide analogues, imidazole and its derivatives, and pyridine and its derivatives1,6,7,34,35; administration of these compounds in human subjects can markedly reduce serum TxB2 levels.36 In theory, administration of these agents should block TxA2 synthesis and also promote the transfer of platelet-derived PGH2 to endothelial cells, where it could be utilized for production of PGI2.34,37 However, the value of the thromboxane synthase inhibitors that have been developed have been limited by their incomplete inhibition of TxA2 synthesis, as well as the proaggregatory effects of the prostaglandin endoperoxides that accumulate after their administration.34
Drugs have also been described that can block the receptor for TxA2, a cloned receptor that, on ligand stimulation, results in activation of phospholipase C.10 Although some of these TxA2 receptor antagonists, such as sulotroban and ifetroban, have shown antithrombotic activity in animal models of thrombosis,10,38 they have yielded disappointing results in phase II/III clinical trials.10,35 Drugs such as picotamide and ridogrel, which have the dual properties of blocking both thromboxane synthase and the TxA2 receptor have also been developed,10,35 based on experimental evidence suggesting a synergistic interaction between the two approaches.10 Their role(s) as clinical antithrombotic agents is unclear.
PROSTAGLANDIN I2 AND ANALOGUES
PGI2 (prostacyclin) is a potent inhibitor of platelet aggregation and platelet thrombus formation ex vivo, as well as a strong vasodilator (see above and Chap. 111). The inhibitory effects of PGI2, or its analogues, are due principally to their interaction with a receptor on the platelet surface that initiates a series of biochemical changes, mediated at least in part through G proteins, that increase the intraplatelet concentration of cyclic AMP, a potent inhibitor of several biochemical processes that are crucial for platelet activation (see Chap. 111). PGI2 may result in hypotension and gastrointestinal symptoms at doses that inhibit platelet function. More stable analogues of PGI2 (iloprost, cicaprost, beraprost) have been produced and shown to be potent inhibitors of platelet aggregation.11,34,35,39 The current status of prostacyclin analogues as antithrombotic agents has been recently reviewed.11,35 In general, their side effects have limited their effectiveness in preventing thrombosis.
Dipyridamole, a pyrimidopyrimidine compound with vasodilator properties, was introduced for the treatment of angina pectoris in 1961. Its antithrombotic properties were reported in 1968 when it was shown that the drug inhibited platelet-induced thromboembolism in the cerebrocortical blood vessels of rabbits.40 Similar results have been obtained in other experimental models, but negative results have also been reported.1,2,41 As discussed later, dipyridamole reduces the frequency of thromboembolism when administered with warfarin in patients with prosthetic heart valves.42 It has been administered in divided daily doses ranging from 75 to 400 mg. In general, platelet aggregation in platelet-rich plasma is not inhibited by dipyridamole, either when administered orally or when added in vitro in pharmacologic concentrations, although exceptions have been reported.1,2,41 However, the drug has been reported to inhibit platelet aggregation when studies are performed in the presence of erythrocytes by the technique of whole blood aggregometry.43
The basis for the antiplatelet and antithrombotic properties of dipyridamole is not clear.1,10,41,43 It inhibits phosphodiesterase and, in theory, could increase platelet cyclic AMP to levels at which it is inhibitory to platelet aggregation (see Chap. 111). Dipyridamole may also indirectly increase the plasma concentration of adenosine that is produced from damaged cells, such as erythrocytes, by inhibiting its subsequent uptake into cells, particularly erythrocytes and endothelial cells.1,43 This could explain why the drug inhibits platelet aggregation and thromboembolism under circumstances where erythrocytes may be damaged, as might occur in whole blood aggregometry tests and in patients with prosthetic heart valves.7
TICLOPIDINE AND CLOPIDOGREL
Ticlopidine and clopidogrel are structurally related thienopyridine derivatives that, after oral administration, specifically inhibit ADP-induced platelet aggregation.1,11,44,45,46,47,48 and 49 Neither drug is active in vitro, requiring metabolic activation by a liver cytochrome P 450 mechanism.44,50 The molecular characteristics of the active metabolites have not been clearly defined.10 After oral administration in humans, both drugs prolong the bleeding time (to a greater extent than aspirin)10,44,51 and inhibit platelet aggregation by ADP even at high agonist concentrations.1,44,47 Platelet aggregation by low, but not high, concentrations of collagen and thrombin are also inhibited by the drugs,11,44,47 suggesting that these inhibitory effects are probably due to a blockade of ADP-mediated amplification of the response to these agonists. Both ticlopidine52 and clopidogrel53 appear to exert their antiplatelet effects by inhibiting the binding of ADP to platelets. Recent studies using radiolabeled analogues of ADP (e.g., 3H-2-MeS-ADP) have shown that both ticlopidine and clopidogrel dramatically reduce the binding of ADP to a P2 purinergic receptor on platelets.53,54 and 55 The thienopyridine drugs do not inhibit platelet shape change or calcium influx.53 Therefore, the inhibited ADP receptor does not appear to belong to the ligand-gated ion channel or inotropic receptor designated as the P2X superfamily of purinergic receptors.56,57 Rather, both ticlopidine and clopidogrel selectively neutralize the ability of ADP to inhibit the increase in adenyl cyclase (and hence cyclic AMP) that occurs when platelets are exposed to agents such as PGE1.56,58 Thus, the thienopyridine drugs may bind to one of the subclasses of G-protein-coupled P2 receptors, or “metabotropic” superfamily, responsible for inhibition of stimulated adenyl cyclase activity in platelets.59 However, the exact relationship between inhibition of PGE1-stimulated adenyl cyclase and platelet aggregation by ADP remains to be clarified48 (see Chap. 111).
Both ticlopidine and clopidogrel have been found to inhibit experimentally induced thrombosis,11 and synergism with aspirin has been described in some studies.10 Because their effects on platelets are affected through active metabolites, there is a delay in the onset of effective treatment. Ticlopidine is usually administered orally in doses of 250 mg twice daily, and its full antiplatelet activity is only obtained after 5 to 7 days. When clopidogrel is administered to healthy volunteers in a dose of 50 to 100 mg daily, maximal steady-state inhibition of ADP-induced aggregation (»50–60 percent) is reached in 4 to 7 days.10,46,60 Besides diarrhea and rashes, more serious side effects of ticlopidine administration include neutropenia (1 percent of patients), which is usually reversible but occasionally accompanied by serious infection7; thrombocytopenia aplastic anemia61; and thrombotic thrombocytopenic purpura.62 A major advantage of clopidogrel is the relatively infrequent occurrence of serious side effects.60
INHIBITORS OF THE PLATELET GPIIB/IIIA RECEPTOR
Transformation of the platelet GPIIb/IIIa receptor to its high-affinity ligand binding state in activated platelets is the final common pathway by which all agonists act to initiate platelet aggregation (see Chap. 111). Platelets in which the receptor is either blocked or congenitally deficient on an inherited basis will not aggregate with any physiologic agonist, in contrast to the more limited inhibition obtained with aspirin or ticlopidine. Therefore, agents that can block the receptor function of GPIIb/IIIa may be useful in preventing platelet-induced thrombosis. This type of blockade has been achieved both with monoclonal antibodies directed against the GPIIb/IIIa complex and with a variety of peptide and nonpeptide antagonists of GPIIb/IIIa.
Monoclonal antibodies to GPIIb/IIIa markedly inhibit thrombus formation in a variety of animal models.7 In addition, these antibodies speed reperfusion of thrombosed coronary arteries and prevent reocclusion of the involved blood vessel in animal models of thrombolysis.7 The first antibody to be tested in human studies was a murine monoclonal antibody 7E363 in which the Fc region had been removed in order to prevent the removal of antibody-coated platelets by Fc receptors on macrophages. Because initial values in humans showed that this antibody was potentially immunogenic, a human-mouse chimeric antibody fragment (c7E3 Fab) was developed which consists of the variable regions of the mouse antibody joined to the constant regions of the human antibody.64 This antibody, now referred to as abciximab, inhibits platelet aggregation almost completely when 80 percent of the GPIIb/IIIa receptors are blocked and is a more potent inhibitor of platelet thrombus formation than aspirin.65 Abciximab, in addition to blocking the binding of adhesive proteins to GPIIb/IIIa, also binds to the avb3 vitronectin receptor that is present on endothelial and smooth muscle cells and has been implicated in the processes of cell adhesion, proliferation, and migration.66 Finally, abciximab also inhibits the prothrombinase activity of platelets,67,68 and this property could contribute further to its antithrombotic potential beyond its capacity for inhibiting platelet aggregation. The currently recommended dosing protocol is to administer an intravenous bolus of abciximab (0.25 mg/kg) followed by an infusion of 0.125 µg/kg/min (10 µg/min maximum) for 12 h.69 No allergic or anaphylactic reactions have been reported, but mild (<100,000 cells/µl) or severe (<50,000 cells/µl) thrombocytopenia has been reported in 2.5 to 5.6 percent and 0.9 to 1.6 percent, respectively, of patients in three clinical trials that have utilized abciximab.70
The GPIIb/IIIa receptor recognizes the arginine-glycine-aspartic acid (RGD) sequence contained in a number of adhesive molecules such as von Willebrand factor (see Chap. 111). RGD-containing low molecular weight peptides that compete with adhesive proteins for binding to GPIIb/IIIa have been isolated from the venom of several species of the viper family.10 These peptides, known as disintegrins, are likely to be immunogenic and have been used primarily to provide insight into the structural requirements for GPIIb/IIIa antagonism and to provide the basis for the design of synthetic low molecular weight antagonists. Although linear peptides based on the RGD sequence possess some inhibitory activity, cyclic RGD peptides are more resistant to enzymatic breakdown, have a higher affinity for GPIIb/IIIa, and are about 10 times more potent than linear analogues.11 One cyclic peptide inhibitor (eptifibatide) that has undergone clinical trials is based on a lysine-glycine-aspartic acid (KGD) rather than an RGD sequence71; it is a more specific inhibitor of the GPIIb/IIIa receptor than RGD-containing peptides.72
A variety of nonpeptide agents have been developed that mimic the structure and charge characteristics of the RGD sequence and thereby inhibit the binding of adhesive proteins to GPIIb/IIIa. These peptido-mimetic agents may have a longer survival time than peptide inhibitors72 and are potentially orally effective.9 Tirofiban, a tyrosine derivative,73 and lamifiban74 are two such small molecule peptidomimetic agents that have recently undergone clinical evaluation. Among agents that have been shown to be orally active, xemlofibin75 and sibrafiban76 have recently undergone clinical trials and others are currently under investigation.72,77,78 Thrombocytopenia has also been reported in a very small percentage of patients receiving these agents.
OTHER ANTIPLATELET AGENTS
Infusion of 60 to 100 g of dextran of Mr 66 to 72 kDa can increase the bleeding time and inhibit platelet reactivity in a variety of tests.1,2,41 The mechanism by which dextran inhibits platelet function is not clear, but could be related to alterations in the platelet membrane, to its interaction with plasma proteins that are necessary for platelet aggregation, or by transiently decreasing the plasma levels of von Willebrand factor.1,41 Antithrombotic properties have been described in numerous experimental and clinical studies.1,2,41
This uricosuric pyrazole compound related to phenylbutazone, when administered in divided oral doses of 800 mg per day or higher, is a competitive inhibitor of platelet cyclooxygenase.1,41,79 In addition to inhibiting experimentally induced platelet thrombi34 and normalizing platelet survival in patients with artificial heart valves,34 the drug has been reported to limit the extent of endothelial cell injury in several experimental models.1,41
FISH OILS AND n-3 FATTY ACIDS
The n-3 fatty acids (also referred to as omega-3 fatty acids), such as eicosapentaenoic acid (EPA) (C20:5 n-3) and docosahexaenoic acid (C22:6 n-3), are highly unsaturated fatty acids that, in platelets, compete with arachidonic acid for cyclooxygenase and result in the formation of thromboxane A3, a weak platelet agonist, rather than the strong agonist thromboxane A2.7,34,80 In addition, EPA results in the production in endothelial cells of PGI3, a potent platelet inhibitor.34 Supplementing an individual’s diet with n-3 fatty acids results in a prolongation of the bleeding time and decreased platelet aggregation, associated with decreased production of TxA2.7,34,80 Administration of diets rich in n-3 fatty acids produces antithrombotic effects in animal models of thrombosis,7 but the antithrombotic effects of such diets in humans have been questioned.10
Nitroglycerin, as well as other organic nitrate derivatives, inhibits platelet aggregation by ADP and other platelet agonists and reduces the extent of platelet-induced thrombus formation in experimental models.81 In humans, intravenously administered nitroglycerin and nitroprusside prolong the bleeding time and inhibit platelet aggregation ex vivo.7,81 Organic nitrates, such as the nitrovasodilators that have been used to lower blood pressure and relieve anginal attacks, are converted ultimately to nitric oxide (NO) (or an S-nitrosothiol congener thereof), thereby activating guanylate cyclase and resulting in an increase in intracellular cGMP, which is both a vasodilator and platelet inhibitor7,81 (see Chap. 111). NO may also exert a platelet inhibitory effect by activating endothelial cell cyclooxygenase, thereby promoting the release of the potent antiplatelet antagonist PGI2 (prostacyclin, see above).82
CALCIUM CHANNEL BLOCKERS
A rise in intracellular calcium concentration is required for platelet aggregation, secretion, and thromboxane A2 production (see Chap. 111). Current evidence suggests that, in platelets, calcium channels that are involved in calcium influx are not of the voltage-regulated type,83 but the matter is controversial.84 In general, calcium channel blocking agents have been more effective in inhibiting platelet activation in vitro than in vivo,85 and drug concentrations in plasma may be too low to be effective. The potential use of these agents as antithrombotic agents is unclear. In one study, oral verapamil, in a dose of 340 mg/d for 7 days, was reported to inhibit platelet thrombus formation ex vivo in patients with stable coronary disease.86
b-ADRENERGIC BLOCKING AGENTS
b-adrenergic blocking agents such as propranolol have been reported to reverse the enhanced ADP-induced aggregation observed in patients with angina pectoris,41,87 but whether this effect is related to nonspecific membrane effects of the drug rather than to b-adrenergic blockade is not clear.1,2,88 In some studies, administration of propranolol to healthy subjects had no significant effect on platelet aggregation,89 and in one study timolol (a nonselective beta-blocker) induced a significant increase in platelet aggregation and reduction in platelet cyclic AMP,90 whereas metoprolol had none of these effects.
Other drugs with antiplatelet properties that are used in clinical medicine include heparin and other antithrombins (see Chap. 132 and Chap. 133), vitamin E, serotonin antagonists, penicillin, other b-lactam antibiotics, and others.1,2,10
ANTIPLATELET DRUGS IN CLINICAL MEDICINE
The antiplatelet properties of drugs are frequently inferred from in vitro tests and experimental models that may not reflect accurately some, or even any, of the clinical events for which the drugs are used. A more rational basis for the clinical pharmacology of antiplatelet therapy will require further advances in understanding platelet activation mechanisms and the role of platelets in the various clinical conditions for which antiplatelet therapy may be useful. At present, a drug is usually chosen because it has been shown to have some antiplatelet property (as discussed above) in the hope that it will also prevent the (presumably) platelet-mediated clinical event or process. The topic has been the subject of many general reviews.1,2,7,9,10 and 11,34,35,91,92 and 93
ISCHEMIC HEART DISEASE
The clinical symptoms that are associated with a reduction of the blood supply to the heart are, in most cases, due either to the gradual narrowing of the atherosclerotic coronary arteries, or the abrupt reduction in flow due to a sudden further narrowing of a major coronary vessel by vasospasm or the deposition of an intraluminal platelet-fibrin thrombus.1,2,94 Thus, the efficacy of an antiplatelet agent in the syndromes associated with ischemic heart disease will depend on whether, and how, platelets contribute to the process, and the extent to which the drug modifies favorably the platelet activation mechanisms involved.
Platelets could play a role in the development of atherosclerosis by releasing mitogens, such as platelet-derived growth factor (PDGF), or vascular permeability factors, but their importance has not been established.7,94 Should platelets prove to be important, a useful antiplatelet drug would probably have to inhibit either platelet adhesion or the secretion of biologically active substances from adherent platelets. At present, there is no evidence that the progress of atherosclerosis can be favorably modified by any antiplatelet drug currently used in clinical medicine.
STABLE ANGINA PECTORIS
Stable angina is due primarily to increases in the myocardial oxygen demand beyond the capacity of the stenosed, atherosclerotic vessels to increase their delivery of oxygenated blood.94 Although some studies have suggested that platelet aggregation or release of vasospastic substances such as thromboxane A2 could play a role in precipitating anginal attacks,1,95,96 negative findings reported in other studies1,97,98 leave this question unresolved. In the U.S. Physicians’ Trial,99 aspirin did not affect favorably the anginal symptoms in a subset of men with this condition.100 However, in this trial,100 as well as in a study on 2035 patients who received a class III antiarrhythmic drug (sotalol) and either 75 mg of aspirin daily or a placebo, aspirin reduced the incidence of subsequent myocardial infarctions.101 Aspirin will reduce the frequency of acute thrombotic events in patients with ischemic heart disease (see below), but left unresolved is whether a more potent antiplatelet agent might affect favorably the symptoms of angina pectoris or the underlying atherosclerotic process.
ACUTE CORONARY SYNDROMES AND PERCUTANEOUS CORONARY INTERVENTIONS
Angiographic, angioscopic, and pathologic studies indicate that platelets play a role in acute or subacute syndromes associated with coronary atherosclerosis.102,103 In most cases, the thrombi formed in acute coronary syndromes are caused by the rupture of an atherosclerotic plaque,94 exposing tissue factor and platelet-reactive materials, such as collagen. The resultant platelet-fibrin thrombus accounts for the abrupt reduction in coronary blood flow, and the nature of the clinical event (unstable angina, non-Q-wave infarction, or Q-wave infarction) is probably determined by the degree of the occlusion, the distribution of the involved vessel, the presence of collateral blood vessels, and the reversibility of the obstruction. It is generally agreed that rupture of the plaque can promote the deposition of normal platelets, but it is uncertain whether hyperresponsive platelets constitute another risk factor in patients who are predisposed to acute coronary syndromes.1,2,7
Platelets also play a role in precipitating acute and subacute events associated with percutaneous coronary interventions (PCI) designed to improve blood flow in coronary arteries, such as balloon angioplasty (PTCA), atherectomy, and stenting. Thus, disruption of the atherosclerotic plaque during PTCA exposes prothrombotic material that probably accounts for a significant percentage of the abrupt closure that can occur shortly after the procedure34; the remainder is probably due to coronary mechanical occlusion secondary to dissection and flap formation. The mechanism promoting acute occlusion after percutaneous coronary revascularization is probably different from that involved in the late restenosis which may occur after these procedures.104 Although the mechanism responsible for late stenosis remains to be clarified, the liberation from platelets of growth factors (such as PDGF), GPIIb/IIIa-mediated platelet events involved in thrombin generation, and increased surface expression of the integrin avb3 on smooth muscle cells could all contribute to this process.104
An appreciation of the important role of platelets in the pathogenesis of acute coronary syndromes has led to the increasing use of antiplatelet agents in clinical cardiology.
UNSTABLE ANGINA, NON-Q-WAVE MYOCARDIAL INFARCTION, AND PERCUTANEOUS CORONARY INTERVENTIONS
Aspirin Episodic increases in thromboxane A2 biosynthesis, as reflected by plasma measurements of thromboxane B2 in the coronary sinus or urinary 11-dehydro-thromboxane B2 and 2,3-dinor-thromboxane B2 excretion, have been reported in patients with unstable angina.105,106 The results of four randomized, placebo-controlled, double-blind trials demonstrated the beneficial effects of aspirin on patients with unstable angina. Treatment with aspirin in daily doses of 75 mg107 or 325 mg108 for 3 months; 650 mg for 3 to 9 days109; and 1300 mg for 24 months110 significantly reduced the incidence of both myocardial infarction and cardiac death by 50 to 70 percent and also reduced the symptoms of severe angina and the subsequent need for coronary revascularization.111 Meta-analysis of six unstable angina studies suggested an additional benefit from addition of heparin.112 Of interest, one study found that aspirin therapy in patients with unstable angina did not completely suppress the synthesis of TxA2, possibly reflecting extraplatelet sources.113
The incidence of acute thrombotic occlusions and Q-wave infarction after PCI can be reduced by aspirin, alone34,114 or in combination with dipyridamole.114 Aspirin alone appears to be as effective as a combination of aspirin and dipyridamole.115 Currently, the major use of aspirin in PCI is its administration, as adjunctive therapy, with heparin and more potent antiplatelet drugs (see below).
Ticlopidine When used to treat unstable angina, ticlopidine added to “conventional” therapy with drugs (b-blockers, calcium channel antagonists, and nitrates) that alone, or in combination, could have antiplatelet properties (see above) reduced the risk for nonfatal myocardial infarction (46 percent), nonfatal plus fatal myocardial infarction (53 percent), fatal myocardial infarction and vascular death (47 percent), and total vascular events (46 percent).116 However, its delayed onset of action (as long as 20–30 days116) is a very serious limitation in using ticlopidine as the sole drug to treat unstable angina. Ticlopidine, in combination with aspirin, has also been found to be superior to aspirin alone or conventional anticoagulation in preventing vascular complications after coronary stenting.49,117
GPIIb/IIIa Antagonists An increasing number of studies have reported on the efficacy of GPIIb/IIIa antagonists in favorably modifying the clinical course of patients with acute coronary syndromes, such as unstable angina and evolving myocardial infarction, or in preventing ischemic vascular complications after PCI (for reviews specific to these agents, see Refs. 9, 65, 77, 78, 118, 119 and 120). All patients in these studies received aspirin, and most received heparin. In the first major study [Evaluation of 7E3 for the Prevention of Ischemic Complications (EPIC)], abciximab, administered as a single bolus dose followed by a 12-h infusion, was found to reduce by 35 percent (P = 0.008) the primary end point of death, acute myocardial infarction, or urgent revascularization at 30 days in 2099 high-risk patients undergoing coronary angioplasty.119,121 The incidence of major bleeding events (14 percent) in the treated group was twice that in the controls. The benefits of abciximab treatment were maintained for 6 months, due principally to a decreased need for either repeat percutaneous intervention or coronary artery bypass surgery (CABS).122 The beneficial effect of therapy was still observable after 3 years.123 In a subsequent study (EPILOG) on 2792 lower-risk patients undergoing coronary intervention, abciximab reduced the incidence of primary end points by 55 percent (P < 0.001).124 The increase in major bleeding events associated with abciximab therapy in the EPIC study, which were principally at vascular access sites, was largely eliminated in EPILOG by reducing and weight-adjusting the dose of heparin and by removing the vascular sheath shortly after the procedure. The major studies through 1998 in which patients with acute coronary syndromes were given GPIIb/IIIa antagonists, with aspirin and heparin, are outlined in Table 131-2. The best results for reducing 30-day end points have been obtained with abciximab, which reduced the primary end points at 30 days by 35 percent in EPIC (P = 0.008),121 by 55 percent in EPILOG (P < 0.001),124 by 29 percent in the CAPTURE study of refractory unstable angina (P = 0.012),125 by 48 percent in the RAPPORT acute myocardial infarction/angioplasty study (P = 0.03),126 and by 51 percent in the EPISTENT elective stenting study (P = 0.001).127 A significant reduction, or trend in that direction, was also observed using eptifibatide in the IMPACT II all-risk coronary syndrome study (15 percent, P = 0.06)128 and the PURSUIT study on patients with unstable angina or non-Q-wave myocardial infarction (10 percent, P = 0.04).129 Similar trends were observed in patients receiving tirofiban in studies designated as RESTORE (16 percent, P = 0.16)130 and PRISM (7 percent, P = 0.34),131 and in patients entered into the PRISM-PLUS study132 who received heparin (17 percent, P = 0.03). In one study (PARAGON A), low-dose lamifiban (with or without heparin) reduced nonsignificantly (11 percent, P = 0.48) the 30-day end points, but significantly (23 percent, P = 0.027) the 6-month end points,133 and in one small Canadian study, lamifiban was strikingly effective in reducing end points (69 percent, P = 0.003).134
TABLE 131-2 GLYCOPROTEIN IIB/IIIA ANTAGONISTS IN ACUTE CORONARY SYNDROMES (ACS)*
A recent meta-analysis of 16 clinical studies that utilized GPIIb/IIIa antagonists in ischemic heart disease evaluated the odds ratios and benefits per 1000 patients in reducing significant end points at 48 to 96 hours, 30 days, and 6 months after beginning therapy.135 The results of this meta-analysis, summarized in Table 131-3, establish the important role of GPIIb/IIIa antagonists in managing patients with acute coronary syndromes. Whether the superior results obtained with abciximab to date are due to underdosing with the other inhibitors or to unique properties of abciximab, such as its ability to inhibit the avb3 vitronectin receptor (see above), remains to be determined. Further studies are also needed to determine the optimum duration of therapy with GPIIb/IIIa antagonists.
TABLE 131-3 CLINICAL BENEFITS FROM UTILIZING GPIIB/IIIA ANTAGONISTS IN ISCHEMIC HEART DISEASE*
The need and dosage requirement for heparin in association with GPIIb/IIIa antagonists requires further study. In two of the studies that used either tirofiban (PRISM PLUS)132 or eptifibatide (PURSUIT),136 failure to administer heparin concurrently with the GPIIb/IIIa antagonist may have been detrimental. The lower than “standard” dose of heparin in the EPILOG versus EPIC studies appears to have reduced bleeding without compromising the antithrombotic efficacy,124 but no studies using abciximab alone in acute coronary syndromes have been reported to date. Finally, the development of oral GPIIb/IIIa antagonists opens the possibility of achieving long-term platelet inhibition in patients with clinical syndromes associated with ischemic heart disease, and several early-phase trials with these agents (sibrafiban and xemilofiban) have been reported.137,138
ACUTE MYOCARDIAL INFARCTION
Antiplatelet Agents Alone In the ISIS-2 trial, which evaluated 17,187 patients, aspirin therapy (160 mg immediately and then daily for 1 month) for acute myocardial infarction decreased mortality and reinfarction when given alone, had an additive benefit when administered with streptokinase, and reduced the incidence of reinfarction that occurs after thrombolytic therapy.139 In fact, aspirin alone decreased 35-day mortality almost as much as streptokinase alone (23 percent vs 25 percent), and aspirin + streptokinase decreased mortality by 12 percent, suggesting an additive effect of using both drugs.139 The benefits were observed in both men and women.139 In the subsequent ISIS-3 trial, involving over 40,000 patients, no significant advantage of adding heparin to aspirin was observed.140 A summary of a meta-analysis141 of the effects of antiplatelet therapy in reducing the risks of a subsequent vascular event in patients with acute myocardial infarction is shown in Table 131-4. The major uses of antiplatelet agents in acute myocardial infarction have been their administration patients undergoing percutaneous coronary revascularization, as reviewed above, and in conjunction with thrombolytic therapy, reviewed below.
TABLE 131-4 ANTIPLATELET TRIALS IN CEREBROVASCULAR AND CARDIAC DISEASE
Antiplatelet Agents in Combination with Thrombolytic Therapy Successful reperfusion of acutely occluded coronary arteries with fibrinolytic agents has been estimated to occur in 75 to 90 percent of treated patients.7 Experimental evidence indicates that thrombi that are particularly rich in platelets, as may occur in some patients with myocardial infarction, are more resistant to lysis by thrombolytic agents7,142 and that enhanced lysis and perfusion may be achieved when a monoclonal antibody to GPIIb/IIIa is used in conjunction with fibrinolytic therapy.7,142 Platelets may also play a role in the reocclusion of a coronary artery that occurs after successful thrombolysis. Thrombolytic agents may paradoxically activate platelets by a variety of mechanisms, and the thrombi in reoccluded vessels may be particularly rich in platelets.7,142 In experimental models, reocclusion has been abolished by antiplatelet agents such as aspirin, PGI2, regimens that combine TxA2 receptor blockade and inhibition of thromboxane synthase, and glycoprotein GPIIb/IIIa antagonists.7,142 A meta-analysis of 32 studies of patients receiving thrombolytic therapy for acute myocardial infarction showed that the reocclusion rate assessed by angiography in 419 patients treated with aspirin was 11 percent compared with 25 percent in 513 patients without aspirin therapy (P < 0.001).143 Because of the positive results obtained in experimental models and the beneficial effects of aspirin, several clinical studies have addressed the question of whether more potent antiplatelet agents, notably GPIIb/IIIa antagonists, would help to speed reperfusion and favorably affect clinical end points in patients with acute myocardial infarction undergoing thrombolytic therapy. In several relatively small studies, both abciximab144 and eptifibatide145 have been reported to improve reperfusion at 90 min after instituting thrombolytic therapy. Whether this type of therapy will improve clinical end points remains to be determined.
SECONDARY PREVENTION STUDIES
These studies address the question of whether antiplatelet therapy will modify the clinical course, principally by reducing mortality and myocardial infarction, of patients who have already suffered one infarction. Conceptually, the question is similar to that raised in studying patients with unstable angina, since the mechanisms that are responsible for producing the acute events (myocardial infarction and sudden death) are probably similar in both syndromes. Table 131-5 outlines seven major randomized long-term studies146,147,148,149,150,151 and 152 with aspirin, or aspirin and dipyridamole, that have been carried out on a total of about 15,000 patients, in the majority men, who suffered one or more myocardial infarctions. These studies have differed from one another in some aspects of design that could affect the outcome, such as drug dosage, time of entry after myocardial infarction, and the decision as to whether to exclude from final analysis patients who withdrew from treatment or were otherwise deemed ineligible.1,153 The general design and overall results of these trials are summarized in Table 131-5 and have been reviewed in detail.1,154 Six of the trials tested aspirin alone, in a dose ranging from 300 to 1500 mg per day. In five of the studies, a trend favoring aspirin in reducing overall mortality by 17 to 30 percent was reported, but in no individual study was the reduction considered significant. In the largest study (AMIS), the mortality rate was greater (but not significantly) in the aspirin-treated group.149 In all six studies, as well as in the study utilizing aspirin plus dipyridamole only (Paris II), there was a trend toward a reduction in the incidence of nonfatal myocardial infarction. Analysis of the pooled data on the studies in which aspirin alone was tested showed a significant risk reduction with aspirin for total mortality (P < 0.03), all cardiovascular deaths (16 percent; P < 0.01), and fatal or nonfatal myocardial infarction (21 percent; P < 0.001).155
TABLE 131-5 SECONDARY PREVENTION TRIALS WITH ANTIPLATELET DRUGS
In 1988, the Antiplatelet Trialists’ Collaboration published a meta-analysis of randomized trials on patients who received antiplatelet therapy for various conditions, including secondary prevention after myocardial infarction.156 A summary of their subsequent meta-analysis141 of secondary prevention trials with all antiplatelet drugs, published in 1994, is shown in Table 131-4. For the 11 trials, involving almost 20,000 patients, allocation to antiplatelet treatment had no significant effect on nonvascular mortality, but reduced nonfatal myocardial infarction by 31 ± 6 percent, nonfatal stroke by 39 ± 11 percent, vascular death by 15 ± 5 percent, and death from any cause by 12 ± 5 percent, with corresponding benefits per 1000 patients treated of 18 ± 4, 6 ± 2, 13 ± 5, and 12 ± 5 respectively (Table 131-4). The weighted mean duration of antiplatelet therapy in these studies was 27 months, and allocation to antiplatelet therapy produced a highly significant reduction (2P < 0.00001) of about 36 per 1000 patients in the risk of suffering another vascular event, defined as myocardial infarction, stroke, or vascular death141 (Table 131-4). In separate analyses of the secondary prevention myocardial infarction trials, sulfinpyrazone may have been better than nontreatment, but a direct comparison with aspirin showed a trend favoring aspirin.156 There was no significant advantage to adding dipyridamole to aspirin, and no data for dipyridamole alone.156 Finally, no particular dose of aspirin between 300 and 1500 mg per day in the secondary prevention studies seemed to be more beneficial than any other dose.156
The secondary prevention Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial60 enrolled 19,185 patients and included, in approximately equal numbers, patients with a recent history of acute myocardial infarction or ischemic stroke, or symptomatic atherosclerotic peripheral vascular disease. After a mean follow-up of 1.9 years, the actuarial annual rate of the primary outcome events (ischemic stroke, myocardial infarction, or vascular death) was 5.83 percent in the aspirin-treated group and 5.32 percent in the clopidogrel-treated group. This was a relative risk reduction of 8.7 percent (95 percent confidence interval, 0.3–16.8, P = 0.043).157
PRIMARY PREVENTION STUDIES
The potential use of aspirin in the prophylaxis of myocardial infarction was suggested by early clinical observations158 and case-control studies.159 There have been two large trials employing aspirin in a population without a prior history of major vascular events, such as myocardial infarction or stroke. In one study, 22,071 male U.S. physicians received either a placebo or 325 mg of aspirin every other day.99 During 5 years of follow-up, aspirin reduced the incidence of myocardial infarction by 44 percent (P < 0.00001), but there was no reduction in overall mortality. In a smaller study employing 5139 male British physicians, 500 mg of aspirin daily did not reduce either total mortality or myocardial infarction.160 These studies have been reviewed in detail elsewhere,160 and a summary of a meta-analysis of the trials (which also included one much smaller study) is shown in Table 131-4. In one nonrandomized study of more than 87,000 American female nurses, aspirin dosage was noted, but not controlled. Aspirin consumption was associated with a 32 percent reduction in the incidence of first myocardial infarction, as compared with those who did not take aspirin (P = 0.0005).161 From all the above studies, a tentative conclusion is that aspirin may reduce the incidence of myocardial infarction in asymptomatic men and women, particularly in those over the age of 50 and with cardiovascular risk factors.93,162 A trend toward increased risk for hemorrhagic stroke in aspirin-treated patients was also suggested by these studies.93
CORONARY ARTERY BYPASS SURGERY (CABS)
The different mechanisms involved in early thrombotic occlusion (less than 1 month), occlusion during the first postoperative year, and closure during the 10 subsequent years after saphenous vein grafting or internal mammary artery bypass surgery for coronary artery disease have been reviewed.34,163 The incidence of early thrombosis after CABS can be significantly reduced with the use of antiplatelet agents (principally varying combinations of aspirin and dipyridamole) administered perioperatively, preferably before, but no later than 48 h after surgery.34,164,165 The improvement in graft patency with aspirin alone persists after 1 year.164 Ticlopidine has also been reported to improve graft patency in several studies.165 A meta-analysis of 20 studies utilizing various combinations of aspirin, dipyridamole, and ticlopidine has been published.166 Among patients who had CABS, allocation to a mean scheduled duration of 7 months of antiplatelet therapy was associated with prevention of occlusion in 92 (SD ± 15) patients per 1000 (21.1 percent of antiplatelet allocated patients versus 30.3 percent of corresponding controls).
The use of antiplatelet agents may increase perioperative bleeding in patients undergoing CABS. When administered preoperatively, aspirin produced a small but significant increase in drainage from the chest tube, in perioperative transfusion requirements, and in the reoperation rate, but there was no excess mortality due to bleeding complications.167 It has been suggested that starting antiplatelet therapy after invasive vascular procedures, including CABS, reduces the risk of bleeding while still preventing occlusion.166,168 In support of this concept, less bleeding (transfusion requirement, reoperation), but equivalent graft occlusion rates 8 days after surgery, was observed in patients who received aspirin (325 mg daily) 6 h after CABS compared with those whose therapy was started preoperatively.169
Extensive data on the use of antiplatelet drugs in patients receiving internal mammary artery grafts are not available. However, limited data suggests that the patency rates after 1 year are 92 to 100 percent, whether or not antiplatelet agents are used.165
VALVULAR HEART DISEASE
Because of the high risk of thromboembolism in patients receiving prosthetic heart valves, antithrombotic therapy is generally recommended for these patients. Anticoagulant therapy has been effective in reducing the incidence of thromboembolism, whereas antiplatelet therapy alone has not been effective.1,2,34,170 However, several studies have demonstrated that the addition of either aspirin (160 mg/d) or dipyridamole (400 mg/d) will confer additional protection in patients who suffer systemic thromboembolism despite adequate anticoagulation.1,2,34,170 For patients with prosthetic heart valves at high risk of thromboembolism, combined warfarin and aspirin therapy may be beneficial compared with warfarin alone.171 The possible use of antiplatelet agents in patients with rheumatic valvular disease (without prosthetic replacement), mitral valve prolapse, and other valvular disorders has been reviewed.172
There is some evidence that aspirin alone may be useful in reducing the incidence of thromboembolism in patients with atrial fibrillation (associated with both valvular and nonvalvular disorders),173 but this therapy should probably be reserved for patients who are unable to take adjusted-dose warfarin or for those in subgroups at a relatively low risk for stroke.174,175 In addition, the use of a regimen consisting of low-intensity, fixed-dose warfarin plus aspirin (325 mg per day) was found to be insufficient for stroke prevention in patients with atrial fibrillation at high risk for thromboembolism.176
Platelets are involved in the pathogenesis of ischemic syndromes involving the cerebral circulation.1,2,41 For example, patients with transient ischemic attacks (TIAs) frequently have ulcerated atherosclerotic lesions in the extracranial portion of the basilar or internal carotid arteries, and as early as the mid-1950s it was initially suggested that these attacks might be the result of microembolization from thrombi deposited on the lesions.177 More direct evidence came from observations of the passage of microemboli through the retinal arterioles during attacks of amaurosis fugax178 and the histological demonstration179 that some of these microemboli were composed of platelet aggregates. In addition, enhanced platelet activation occurs in some patients with transient ischemic attacks or after recovery from completed strokes.1,2 Since any large clinical study of cerebrovascular disease may contain patients with cerebral ischemia of varying etiologies, a method for identifying those whose symptoms are due to platelet emboli would be of great value.
The question of whether antiplatelet drugs can reduce the incidence of TIAs, strokes, and vascular deaths has been addressed in trials that studied patients with a previous history of TIAs and/or reversible ischemic neurologic deficits (RINDs) and/or strokes. These studies have varied in their size, inclusion criteria, drug dosage, and end points, as discussed in various reviews.1,34,91,92 and 93,180,181,182 and 183 The second meta-analysis of the Antiplatelet Trialists’ Collaboration (see above) is shown in Table 131-4.141 Patients with cerebrovascular symptoms were entered into 18 trials, 10 of which tested the efficacy of aspirin in daily doses ranging from 300 to 1500 mg per day. In some studies, dipyridamole or sulfinpyrazone, alone or in combination with aspirin, were also evaluated. Eleven studies entered patients with a prior myocardial infarction and nine entered patients with an acute infarction. The overall results of this analysis (summarized in Table 131-4) demonstrated the efficacy of antiplatelet therapy in preventing cerebrovascular events in patients with either prior cerebrovascular or cardiac events. For patients with prior cerebrovascular disease, the use of antiplatelet therapy resulted in a reduction in the odds ratio for non-fatal stroke by 23 ± 6 percent, for nonfatal myocardial infarction by 36 ± 11 percent, and for vascular death by 14 ± 7 percent, with corresponding benefits per 1000 patients treated of 20 ± 6, 9 ± 3, and 11 ± 6, respectively. All these reductions were highly significant. In early studies that utilized both aspirin and a combination of aspirin and dipyridamole, the addition of dipyridamole did not appear to confer any additional advantage in the cerebrovascular studies.156 However, the combination therapy was found to be more effective in a recent study that used low-dose aspirin (50 mg daily) and a high dose (400 mg daily) of a modified-release formulation of dipyridamole with improved bioavailability.184 Two studies have reported the beneficial effects of ticlopidine in stroke prevention.185,186 In one study (TASS), 3069 patients with TIAs or minor stroke received ticlopidine (500 mg) or aspirin (1300 mg) daily.185 Compared with aspirin, ticlopidine produced a significant relative risk reduction (12 percent) in the event rate for stroke or death and a 21 percent reduction for fatal or nonfatal stroke at 3 years. Subgroup analysis also showed a trend favoring ticlopidine in preventing transient ischemic attacks.186 In another study (CATS), treatment of patients with a recent ischemic stroke with ticlopidine (500 mg or placebo) resulted in a 30 percent reduction in stroke, myocardial infarction, or vascular death, with comparable results in males and females.187 A subgroup analysis of the CAPRIE study60 (see above) found that in patients with recent ischemic stroke, clopidogrel treatment was associated with a nonsignificant trend toward a lower annual rate of subsequent stroke, myocardial infarction, or vascular death compared with aspirin (7.15 percent vs 7.71 percent, P = 0.26).
In several studies the benefits from aspirin were confined to men, whereas this was not the case in other trials.188 Although the issue is not completely resolved, overall analysis of the various trials suggests that the benefits of aspirin are comparable in men and women.180,189 A second question pertains to the optimum dose of aspirin. The Antiplatelet Trialists’ meta-analysis of studies utilizing aspirin in daily doses ranging from 300 to 1300 mg,156 and two subsequently published trials of low-dose aspirin,190,191 suggested that daily aspirin doses of 75 to 300 mg are effective, and no differences in efficacy were found in one study that compared 300 mg with 1200 mg daily.192 However, the conclusion that dosage regimens of aspirin of 300 mg or less are as effective as those utilizing much higher doses (975 to 1300 mg) has been challenged,193 and several studies suggested that daily doses of aspirin in excess of 300 mg may be necessary to obtain maximum antiplatelet and antithrombotic effects in a, perhaps small, subgroup of patients.29,194,195 This conclusion has also been challenged.196
There have been two studies of the use of aspirin administered within 48 h of suspected acute ischemic stroke. The Chinese Acute Stroke Trial (CAST) enrolled 21,106 patients, half of whom received 160 mg of aspirin daily and the other half a placebo for up to 4 weeks,197 and the International Stroke Trial (IST) administered 300 mg of aspirin daily to a subgroup (n = 4858) of patients among a large study group (n = 19,438) in which the efficacy of heparin was also evaluated.198 The pooled results of the two studies indicated that aspirin produced a small, but significant, reduction of about 10 deaths or recurrent strokes per 1000 during the first few weeks.198
PERIPHERAL VASCULAR DISEASE
Ischemic symptoms in most patients with peripheral vascular disease are generally held to be the result of decreased blood flow consequent to occlusive atherosclerotic disease of large vessels. However, involvement of small vessels, through occlusions by platelet microaggregates, or through spasm produced by platelet-derived products, could also contribute to these symptoms. In addition, platelet-induced thrombosis probably plays a role in the acute, thromboembolic events that are frequent complications of peripheral vascular disease. The question of whether treatment with antiplatelet drugs, such as aspirin or ticlopidine, favorably affects the course of either peripheral atherosclerosis or its occlusive complications is unsettled.1,34,91,92,199 In the U.S. Physicians’ Trial, aspirin significantly reduced the need for peripheral arterial surgery, but did not affect the incidence of intermittent claudication,200 confirming the general impression199 that currently employed antiplatelet therapy may reduce the incidence of thrombotic complications in patients with peripheral vascular disease without affecting the basic disease process. Relief of clinical symptoms through the use of PGE1 or PGI2,1,91,201 or a PGI2 analogue (iloprost),39 has been reported, but further studies are needed. In addition, it is not clear whether beneficial effects are related to the platelet inhibitory, vasodilatory, or other properties of these drugs. In the CAPRIE study (see above), the subgroup of patients who appeared to derive the most benefit from clopidogrel (compared with aspirin) were those with symptomatic peripheral vascular disease.60
Although the role of antiplatelet therapy in preventing graft occlusion after peripheral artery reconstructive surgery is controversial, 199 meta-analysis165 suggests that vascular graft occlusions may be reduced by approximately one-third in aspirin-treated patients.202 One study reported improved patency of infrainguinal vein bypass grafts in patients treated with ticlopidine as compared with placebo.203
SMALL VESSEL THROMBOTIC DISEASES (MICROANGIOPATHIES)
Platelet-fibrin thrombi in the microcirculation are involved in the pathogenesis of some glomerular disorders, transplant rejection, and a variety of other conditions broadly classified as microangiopathies.1,2 In some experimental and clinical studies, the course of these disorders has been favorably influenced by antiplatelet drugs.
Platelet-fibrin thrombi play a role in the pathogenesis of membranoproliferative glomerulonephritis,1,2,91 and favorable results have been observed using combinations of dipyridamole, aspirin, and anticoagulants.1,2,91,92 Negative results with aspirin alone have also been reported.1,91 Antiplatelet agents may also modify or delay the rejection of renal allografts,1,2,91 but more data are necessary to support this conclusion. At present no definitive conclusions can be drawn about the efficacy of antiplatelet drugs in progressive renal disease.204
THROMBOTIC THROMBOCYTOPENIC PURPURA
Platelet microthrombi in this disorder are thought to form as a result of the presence of unusually large von Willebrand factor multimers that are released from injured endothelial cells, and not processed to smaller forms due to immune-mediated deficiency of a specific plasma protease activity (see Chap. 117). Although the efficacy of varying combinations of aspirin, dipyridamole, dextran, sulfinpyrazone, and PGI2 in modifying the course of this disorder has been suggested,1,205 the beneficial effect of antiplatelet agents (aspirin plus dipyridamole, in particular) has been challenged206; in some situations, such agents may significantly increase the risk of bleeding. Present evidence favors plasma exchange as the initial therapy of choice in this disorder (see Chap. 117).
Enhanced platelet activation is a contributing factor in the pathogen-esis of pregnancy-induced hypertension, an entity that encompasses a group of disorders previously designated as toxemia of pregnancy, preeclampsia, and eclampsia.207 Meta-analysis of early, relatively small clinical trials suggested that administration of low-dose aspirin (60–150 mg per day) during the second and third trimesters prevented preeclampsia in high-risk patients with no associated risk to the mother or fetus,207 but subsequent larger trials failed to confirm these findings.208 The question of whether properly selected subgroups of patients might benefit from aspirin therapy remains a subject of debate.209
OTHER ARTERIAL THROMBOTIC DISORDERS
In myeloproliferative disorders, particularly essential thrombocythemia, aspirin is effective in alleviating symptoms in the subgroup of patients with the syndrome of digital ischemia and spontaneous platelet aggregation (erythromelalgia).210 Whether antiplatelet agents (aspirin, in particular) are useful in preventing the more widespread thrombotic complications in these disorders is controversial,210,211 and reservations have been expressed concerning their use, particularly with regard to the increased predilection to hemorrhage210,212 (see Chap. 118). Antiplatelet therapy has also been used, with varying success, in managing patients with the lupus anticoagulant/“antiphospholid” syndrome, including those complications that occur during pregnancy213 (see Chap. 128). At present, aspirin is used primarily in combination with heparin during pregnancy, with warfarin used for most other thrombotic indications. Antiplatelet therapy has also been used in a variety of other disorders or clinical situations where platelet-induced thrombi may play a role, such as arteriovenous shunts and fistulas used in renal hemodialysis, vascular catheters, and extracorporeal devices used for cardiopulmonary bypass.1,2,91,165
Although platelets are more important in initiating arterial than venous thrombi1,2 (see Chap. 130), the differences in the pathophysiology of these two types of thrombi are not absolute. Early experimental and clinical evidence suggested that antiplatelet drugs (dextran, aspirin, aspirin plus dipyridamole, or sulfinpyrazone) might be useful in the prophylaxis of venous thrombosis,1,2,41 although the results were not conclusive. The most persuasive evidence for the efficacy of aspirin, administered in doses of 900 to 1300 mg per day, in preventing venographically documented venous thrombosis, has been obtained in patients undergoing hip surgery,1,93,214 particularly in reducing the risk of proximal vein thrombosis.93,215 A meta-analysis of 53 trials involving a total of 8400 patients who received an average of 2 weeks of antiplatelet therapy versus control in general orthopedic surgery, and 9 trials involving 600 patients with other conditions that predisposed them to venous thrombosis, was published in 1994.216 Overall, therapy produced a highly significant (2P < 0.0001) reduction in venous thrombosis (25 percent incidence in treatment vs 34 percent in the control group) and an even greater proportional reduction in pulmonary emboli (1.0 percent incidence in treatment vs 2.7 percent in the control group). The validity of recommending antiplatelet therapy as prophylaxis against venous thromboembolism based on this type of analysis has been challenged217 and defended.218
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn