Platelets play an important role in hemostasis and thrombosis and inhibitors of platelet function are important therapeutic agents (Chap. 134). Platelets adhere to exposed subendothelium, become activated, release contents of their dense and α granules, and form aggregates. Additional platelets from the circulating blood are then recruited by adenosine diphosphate (ADP), which is released from dense granules, and also by thromboxane A2 synthesized by activated platelets in the aggregate. Simultaneous with the initial platelet adhesion and aggregation, thrombin generation is initiated. The activated platelet phospholipid membrane is an effective surface for binding of coagulation factors to enhance the rate of thrombin generation. As thrombin is formed it activates additional platelets and also cleaves fibrinopeptides from fibrinogen to form fibrin in and around the platelet plug, consolidating it. The role of platelets in initiating thrombosis is greater in the arterial circulation than in the venous circulation because higher shear forces present in arteries activate platelets. Consequently, antiplatelet drugs are more effective in arterial than in venous thrombosis. Table 25–6 summarizes the types of drug, their use in clinical settings, their mechanism of action, and their dosages.
Table 25–6.Antiplatelet Agents by Mechanism of Action and Clinical Use ||Download (.pdf) Table 25–6. Antiplatelet Agents by Mechanism of Action and Clinical Use
|Agent and Indications ||Dosages |
|Cyclooxygenase inhibitors |
|Aspirin ||Coronary and cerebrovascular disease ||75–650 mg daily |
| ||VTE secondary prevention || |
|Agents that increase cAMP |
|Dipyridamole ||Coronary, cerebrovascular, peripheral arterial disease ||75–100 mg QID |
|Pentoxifylline ||Peripheral arterial disease ||400 mg BID |
|Cilostazol ||Peripheral arterial disease ||100 mg BID |
|ADP receptor blockers |
|Ticlopidine ||Cerebrovascular disease ||250 mg BID |
|Clopidogrel ||Coronary, cerebrovascular disease, PCI ||75 mg daily, loading dose 300 mg |
|Prasugrel ||ACS, PCI ||10 mg daily, 60-mg loading dose |
|Ticagrelor ||ACS ||90 mg BID, 180-mg loading dose |
|ADP mimetic |
|Cangrelor ||Not approved in United States at time of this writing || |
|αIIbβ3 inhibitors |
|Abciximab ||ACS, PCI ||0.25 mg/kg, then 10 mcg/kg/min |
|Eptifibatide ||ACS, PCI || |
ACS 180 mcg/kg, then 2 mcg/kg/min
PCI 180 mcg/kg, then 2 mcg/kg/min with 180 mcg/kg at 10 min
|Tirofiban ||ACS, PCI ||0.4 mcg/kg/min × 30 min, then 0.1 mcg/kg/min |
|Thrombin receptor blocker |
|Vorapaxar ||Coronary disease, peripheral arterial disease ||2.08 mg daily |
Cyclooxygenase (COX)-1 is an enzyme that is present in most cells. It converts arachidonic acid released from membrane phospholipids by phospholipase A2 or phospholipase C and diacylglycerol to prostaglandin (PG) G2 (Chap. 112). A peroxidase converts PGG2 to PGH2, which is then converted by thromboxane synthase in platelets to thromboxane A2. Thromboxane A2 is a potent activator of platelets. In endothelial cells, PGH2 is converted to prostacyclin, a potent inhibitor of platelet function, through an increase in intraplatelet cyclic adenosine monophosphate (cAMP).
Aspirin (acetylsalicylic acid) was recognized as an inhibitor of platelet function in the 1960s, although the mechanism of its action was unknown at that time. It prolonged the bleeding time in normal subjects slightly, although usually not out of the normal range, and its effect lasted for several days. It was demonstrated that acetylation of COX is important in platelet inhibition by aspirin. Because platelets cannot synthesize new COX, irreversible enzyme inhibition by aspirin means that inhibition persists for the life span of the platelet. Most cells have two forms of COX, known as COX-1 and COX-2. COX-1 is synthesized constitutively, whereas COX-2 is only synthesized under stress conditions. Both COX-1 and COX-2 are inhibited by aspirin and most nonsteroidal antiinflammatory drugs (NSAIDs), with aspirin acetylating both forms. The nonaspirin COX inhibitors are reversible inhibitors, so they are active only while in the circulation. It was thought initially that only COX-1 is found in platelets, but COX-2 has been detected in platelets and its effect is particularly apparent when there was a rapid platelet turnover. Because COX-1 is the major COX in platelets, COX-2–specific inhibitors have minimal effect on platelet function.
Aspirin and several of the commonly used NSAIDs (e.g., indomethacin, ibuprofen, and naproxen) have similar in vitro effects on platelet function. Platelet aggregometry demonstrates that the second wave of aggregation induced by ADP or epinephrine in citrated platelet-rich plasma (PRP) is abolished after aspirin ingestion and that aggregation induced by low concentrations of collagen is markedly decreased. Arachidonic acid–induced aggregation is abolished after aspirin ingestion. Additionally, secretion of dense granule components (ADP, ATP, and serotonin) and of α-granule proteins by ADP, epinephrine, collagen, and arachidonic acid is inhibited in PRP after aspirin ingestion or with addition of indomethacin to PRP. Because of these in vitro effects of aspirin, the drug has been used extensively as an inhibitor of platelet function in vivo, with beneficial effects in primary and secondary prevention and in treatment of myocardial infarction (Chap. 135). Aspirin is also beneficial in stroke prevention with carotid artery disease and embolic stroke, although anticoagulation with warfarin or its analogues is generally more effective than aspirin in embolic stroke in most patients with a cardiac embolic source.107 Aspirin is less often used to prevent venous thrombosis, although two recent large randomized studies showed significant benefit for secondary prevention of recurrent VTE compared to placebo.108,109 Other drugs that inhibit COX-1 are not used to prevent either arterial or venous thrombosis.
A daily dose of 81 to 325 mg is recommended for most indications, as lower-dose aspirin appears as effective and may be associated with a lower risk of gastrointestinal bleeding than higher doses.110,111 Broadly, aspirin is currently recommended for primary and secondary prevention of a wide variety of atherosclerotic outcomes including stroke, myocardial infarction, and peripheral vascular disease.
DRUGS THAT MODULATE CYCLIC ADENOSINE MONOPHOSPHATE LEVELS
cAMP in platelets is formed from ATP by the action of adenylate cyclase and degraded by cAMP phosphodiesterase, and basal levels of cAMP in platelets are low. Elevated levels of intraplatelet cAMP are induced by inhibition of cAMP phosphodiesterase, or by stimulation of adenylate cyclase activity, resulting in inhibition of platelet activation through several pathways: (1) modulation of phosphorylation of specific proteins; (2) inhibition of several steps in metabolism of phosphoinositol phosphates; and (3) lowering of intracellular Ca2+, and accumulation of Ca2+ by platelet microsomes. Agents that inhibit the cAMP phosphodiesterase include theophylline, papaverine, and dipyridamole, as well as pentoxifylline and cilostazol. Several prostaglandins stimulate adenylate cyclase, including PGE1, PGD2, and PGI2 (prostacyclin). Drugs that elevate cAMP levels are dipyridamole, pentoxifylline, and cilostazol. Dipyridamole can be used alone or in combination with aspirin. A very large study of dipyridamole in combination with low-dose aspirin (25 mg) found the combination equivalently effective to clopidogrel for the secondary prevention of noncardioembolic stroke.112 Recent systematic reviews have also suggested that the combination of dipyridamole and aspirin is superior to aspirin alone for the prevention of cerebrovascular events.113
The other two phosphodiesterase inhibitors (pentoxifylline and cilostazol) are used primarily in patients with peripheral vascular disease. In addition to their inhibitory effect on platelets they may exert a beneficial effect on blood rheology and the microcirculation by increasing red cell deformability, thereby reducing blood viscosity. Cilostazol increases vascular endothelial growth factor levels, which may lead to an increase in collateral circulation. It has been shown to reduce risk of stroke in Asian populations,114,115 and increases walking distance in patients with peripheral vascular disease.116 Pentoxifylline inhibits vascular smooth-muscle cell proliferation and collagen synthesis, which may enhance vasodilation. Pentoxifylline probably is an effective treatment for ulcers associated with peripheral vascular disease; however, it is only modestly effective for treatment of peripheral vascular disease.117
ADENOSINE DIPHOSPHATE RECEPTOR BLOCKERS
The third class of platelet inhibitors is the ADP receptor blockers, which include thienopyridines (ticlopidine, clopidogrel, and prasugrel) and nonthienopyridines (ticagrelor and cangrelor). There are three ADP receptors on platelet membranes (Chap. 112), with the thienopyridines inhibiting one of them, the P2Y12 receptor. The inhibition of binding of ADP to the P2Y12 receptor results in inhibition of adenylate cyclase.
Ticlopidine was available for clinical use before clopidogrel. The Canadian American Ticlopidine Study was a randomized, placebo-controlled, double-blind study showing a 30 percent risk reduction for recurrent cardiovascular events with ticlopidine.118 A review of four trials of ticlopidine plus aspirin versus oral anticoagulants for coronary stenting showed benefit to the combination in terms of reduced risk of nonfatal myocardial infarction and revascularization at 30 days, combined negative events (mortality, myocardial infarction, revascularization at 30 days), and major bleeding, but increased the risk of thrombocytopenia and neutropenia.119
In clinical practice fear of toxicity has largely led ticlopidine to be abandoned in favor of clopidogrel. In a direct comparison of ticlopidine and clopidogrel in patients undergoing coronary stenting (CLASSICS trial), clopidogrel was associated with a significantly lower rate of major adverse events (4.6 percent vs. 9.1 percent).120 The first clinical trial of clopidogrel was the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial, a large randomized, blinded trial of clopidogrel versus aspirin in 19,000 patients at risk of ischemic events.121 Patients were enrolled after recent myocardial infarction (MI) or stroke, or if they had symptomatic peripheral arterial disease. The primary outcome was the occurrence of ischemic stroke, MI, or vascular death. With a mean followup of 1.91 years, there was a relative risk reduction of 8.7 percent in the clopidogrel group (p = 0.043). No major differences were noted in terms of safety. Clopidogrel is also used in acute coronary syndromes, based on studies like the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study, which showed a significant reduction in the combined end point of cardiovascular death, nonfatal MI, or stroke with clopidogrel and aspirin versus aspirin alone.122 Several studies have demonstrated the effectiveness of clopidogrel in patients undergoing percutaneous coronary intervention, and a recent meta-analysis of several large studies showed that clopidogrel treatment prior to intervention is associated with decreased incidence of major cardiac events (MI, stroke, urgent revascularization) compared to treatment after intervention.123 The degree of platelet inhibition after clopidogrel therapy varies. Larger loading doses of clopidogrel appear to reduce variability in response; the safety and efficacy of such doses are being compared in ongoing studies.124
Prasugrel is a “third-generation” P2Y12 blocking agent. Unlike clopidogrel it can be converted to its active metabolite via esterases present in either the liver or the gut. Like clopidogrel it irreversibly blocks the P2Y12 receptor.144 Evidence for the use of prasugrel comes predominately from one large study of prasugrel compared with clopidogrel. This study randomized 13,608 patients with moderate-to-high-risk acute coronary syndromes and who were scheduled to undergo percutaneous coronary intervention to receive prasugrel (a 60-mg loading dose and a 10-mg daily maintenance dose) or clopidogrel (a 300-mg loading dose and a 75-mg daily maintenance dose) for up to 15 months.125 Although prasugrel significantly reduced death from cardiovascular causes, nonfatal MI, and nonfatal stroke, it significantly increased all forms of bleeding, including major and fatal hemorrhage.
Ticagrelor is a member of the cyclopentyltriazolopyrimidines chemical class, a group of agents that reversibly inhibit the P2Y12 platelet receptor. Ticagrelor does not require hepatic activation and has a more rapid onset of action than clopidogrel. The PLATO trial was a large phase III randomized study comparing ticagrelor and aspirin (180 mg loading dose followed by 90 mg twice daily) to clopidogrel (300 to 600 mg dose followed by 75 mg daily) and aspirin for treatment of acute coronary syndrome.126 Patients receiving ticagrelor experienced the composite primary end point (death from vascular causes, MI, or stroke) less often than patients receiving clopidogrel (9.8 percent vs. 11.7 percent, hazard ratio [HR] 0.84) without a significant difference in the rates of major bleeding (11.6 percent vs. 11.2 percent).
Cangrelor, the first parenteral ADP receptor blocker, is not currently available for clinical use, but has been tested in three large randomized clinical trials of patients undergoing intracoronary stent implantation procedures. Advantages of this agent include parenteral administration, very rapid onset, and short half-life. The CHAMPION studies (PLATFORM,127 PCI,128 and PHOENIX129) compared cangrelor to clopidogrel or placebo in patients undergoing coronary interventions. Although only the PHOENIX trial showed a significant reduction (4.7 percent vs. 5.9 percent) in the 48-hour composite end point (death, MI, ischemia-driven revascularization, or stent thrombosis), in a pooled analysis of patient level data from the three CHAMPION trials cangrelor use was associated with a significant reduction in the primary efficacy end point compared to control (3.8 percent vs. 4.7 percent, OR 0.81).130
Fibrinogen binds specifically and saturably to the surface of activated platelets, and the αIIbβ3 complex is the fibrinogen receptor. This complex mediates platelet aggregation induced by all physiologic agonists. Fibrinogen binds only to the activated conformation of the receptor αIIbβ3. Monoclonal antibodies have been developed against αIIbβ3 complex on resting or activated platelets, which prevent aggregation by blocking ligand binding. Abciximab, is the Fab′2 fragment of a chimeric mouse–human antibody. Initial human pharmacodynamic studies were performed in patients with unstable angina and in patients undergoing high-risk coronary angioplasty, and dose-related inhibition of platelet function was found. No spontaneous bleeding was observed, despite prolongation of the template bleeding time. Because of the mouse component of abciximab, it may induce antimouse antibodies, preventing repeated use in patients.
The first large clinical trial of abciximab was the Evaluation of c7E3 for the Prevention of Ischemic Complications (EPIC) trial,131 published in 1994, in which the drug was used in patients with high-risk coronary angioplasty. Abciximab reduced ischemic events after angioplasty when given together with heparin and aspirin, but it also increased the risk of bleeding. Subsequent studies of patients undergoing percutaneous coronary intervention, the Evaluation in PTCA to Improve Long-term Outcome with Abciximab GP IIb/IIIa (αIIbβ3) Blockade (EPILOG) study132 and EPISTENT trial,133 demonstrated efficacy in both low-risk and high-risk patients without any increase in major bleeding. Abciximab has also been tested in patients with acute ischemic stroke, but resulted in significant increase intracranial hemorrhage without any clinical efficacy so it has not been further pursued for this clinical indication.134
Other types of inhibitors of fibrinogen binding to platelets have also been developed. Those in clinical use are eptifibatide, a cyclic heptapeptide based on a rattlesnake venom peptide, and tirofiban, a nonpeptide derivative of tyrosine. Pharmacokinetic and pharmacodynamic studies in animals and humans showed a rapid onset of action, short plasma half-life, and rapid reversibility of action. The pharmacodynamics of eptifibatide are substantially altered by anticoagulants that chelate calcium, and pharmacokinetic modeling suggests that optimal dosing is obtained by giving a second bolus 10 minutes after the first bolus. Eptifibatide is not immunogenic.
The first major clinical trial of eptifibatide was the Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis (IMPACT) II trial in patients undergoing any kind of coronary intervention.135 There was a highly significant reduction in the composite end point of death, MI, coronary artery bypass grafting, repeat urgent or emergent coronary intervention, or stent placement for abrupt closure at 24 hours with both eptifibatide dosing arms. There was no increase in major bleeding. The effect was no longer significant at 30 days on intention-to-treat analysis.
Animal studies with tirofiban were performed in dogs. Dose-dependent inhibition of ex vivo platelet aggregation was achieved, with rapid reversibility at the end of the infusion. Electrically induced coronary artery thrombosis was markedly reduced by tirofiban infusion, without significant extension of the bleeding time. Pharmacokinetic and pharmacodynamic studies in humans showed that tirofiban provided a well-tolerated reversible means of inhibiting platelet function. Bleeding time was prolonged, and ADP-induced aggregation was blocked by at least 80 percent in normal volunteers. The plasma half-life was 1.6 hours. ADP- and collagen-induced platelet aggregation in normal volunteers returned to 55 percent and 89 percent of baseline, respectively, by 3 hours after the end of infusion. Similar results were found in a dose-ranging study in patients undergoing coronary angioplasty. Based on these results tirofiban has been extensively studied as an adjunct to therapies for patients with, or at risk of, acute coronary syndromes. Clinical results for patients treated with tirofiban have been reviewed.136
THROMBIN RECEPTOR BLOCKERS
Platelet activation occurs through a variety of cell surface receptors including the thrombin receptor, a potent platelet activator mediated by its binding to and cleaving the protease-activated receptor (PAR)-1. Vorapaxar is an irreversible PAR-1 thrombin receptor antagonist, which has been studied in two large phase III randomized studies. In the TRACER study 12,944 patients with non–ST elevation acute coronary syndromes were randomized to vorapaxar or placebo plus standard care.137 Vorapaxar use was associated with a significant reduction in death from cardiovascular causes (14.7 percent vs. 16.4 percent), but was also associated with a significant increase in major bleeding events, including intracranial hemorrhage (1.1 percent vs. 0.2 percent). The TRA 2P-TIMI 50 study randomized 26,449 patients with prior MI, stroke, or peripheral artery disease to vorapaxar versus placebo.138 This phase III study also demonstrated clinical efficacy with a reduction in death from cardiovascular cause (11.2 percent vs. 12.4 percent), but it was at the expense of increased major bleeding complications. Efforts are underway to identify subgroups that may have the greatest net benefit from vorapaxar. Atopaxar is a low-molecular-weight inhibitor of PAR-1, which has been studied in phase II trials of patients with acute coronary syndrome or high-risk coronary artery disease.139 These studies showed an increase in minimal bleeding events (16.4 percent vs. 4.5 percent) but no difference in clinically significant bleeding.