Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 10/12/14 For personal use only.
Review
Contemporary antiplatelet therapy in patients undergoing percutaneous coronary intervention Expert Rev. Cardiovasc. Ther. 12(4), 463–474 (2014)
Shaun Bhatty1, Asghar Ali1,2, Ranjith Shetty1, Kevin F Sumption1,2, Michael J Cowley1 and Ion S Jovin*1,2 1 Department of Internal Medicine, Cardiovascular Division, Virginia Commonwealth University Health System/Medical College of Virginia, Richmond, VA, USA 2 Department of Internal Medicine, Cardiovascular Division, McGuire Veterans Administration Medical Center, Richmond, VA, USA *Author for correspondence: Tel.: +1 804 675 5448 Fax: +1 804 675 5450 [email protected]
The proper use of antiplatelet agents in the cardiac catheterization laboratory is important for ensuring optimal results in patients undergoing percutaneous revascularization. Understanding the mechanisms by which these drugs exerts their effects is important for both interventional and non-interventional cardiologists. The effects of these agents on platelet function can be assessed and monitored using a variety of commercially available laboratory assays but so far these tests have not been adopted in routine clinical practice. Currently, aspirin, thienopyridines and glycoprotein IIb/IIIa inhibitors are the primary types of antiplatelet drugs being utilized. The use of these drugs and of several newer antiplatelet drugs in the treatment of patients undergoing percutaneous revascularization in the cardiac catheterization laboratory will be discussed, especially in the light of the recently published guidelines. KEYWORDS: antiplatelet agents • cyclopentyltriazolopyrimidines aspirin • percutaneous intervention • thienopyridines
Every year, several hundred thousand percutaneous coronary intervention (PCI) procedures are performed in patients with acute coronary syndrome (ACS) and stable angina. PCI requires the use of antiplatelet and anticoagulant therapies to reduce the risk of adverse cardiovascular events. However, these therapies carry a significant risk of bleeding. Finding the balance between limiting adverse cardiovascular events and the risk of significant hemorrhage is an ongoing challenge. A thorough understanding of how currently available antiplatelet agents work and how they can be applied in an evidence-based way can improve patient outcomes in the cardiac catheterization laboratory. Hemostasis
Hemostasis describes a complex series of events that help to maintain the integrity of blood vessel walls when they become damaged and the processes involved occur somewhat simultaneously [1]. This process is initiated by exposure of circulating blood to extravascular proteins [2]. The four phases in the hemostatic process are: initiation and formation of the platelet plug, further amplification of clotting by the coagulation cascade, termination of the clotting process informahealthcare.com
10.1586/14779072.2014.901149
and degradation of the clot by fibrinolysis. The formation of the platelet plug is initiated when circulating platelets are recruited to the site of vascular injury and become activated. Collagen and thrombin are potent platelet activators while adenosine diphosphate (ADP) and epinephrine are weaker activating agents. Activated platelets undergo a series of four processes: adhesion, aggregation, secretion and procoagulant activity. When platelets adhere to subendothelial collagen and von Willebrand factor (vWF), a variety of chemical mediators are released from their granules and include: ADP, thomboxane A2, serotonin, fibronectin, fibrinogen and growth factors. These substances then recruit neighboring platelets leading to aggregation and also may function as vasoconstrictors. During platelet aggregation, fibrinogen binds to its platelet receptor, the glycoprotein (GP) IIb/ IIIa integrin resulting in platelet crosslinking. The GP IIb/IIIa complex is involved in two signaling pathways that lead directly to platelet aggregation. In ‘inside-out signaling’, after the platelet is stimulated, the GP IIb/IIIa complex undergoes a conformational change resulting in a stronger affinity for fibrinogen. In ‘outside-in signaling’, the cytosolic portion of the activated
2014 Informa UK Ltd
ISSN 1477-9072
463
Review
Bhatty, Ali, Shetty, Sumption, Cowley & Jovin
significance is not completely understood [9]. Aspirin and a P2Y12 inhibitor as dual antiplatelet therapy in PCI patients ADP were shown to be cost-effective with prasugrel and ticagrelor alternatives to use ADP receptor instead of clopidogrel. These new agents PAR-1 antagonist (P2Y12) are thought to be cost-effective as well, but there are no studies that have compared Aspirin them against each other for cost–effectiveArachidonic acid ness. There is also limited understanding PAR-1 Cyclooxygenase-1 of cost–effectiveness of GP IIa/IIIb inhibiProstaglandin G2/H2 tors for present-day PCI because of Thrombin changes in the guidelines of their use in ACS patients [10]. The oral agents, which Thromboxane A2 PAR-4 are approved or are in clinical development, inhibit activation of the platelets, while the GP IIb/IIIa inhibitors block aggregation of the platelets. Prasugrel and GP IIb-IIIa receptor ticagrelor are approved for use in ACS patients only, due to which cost–effectiveness analyzes of these agents against clopiFibrinogen dogrel are limited to this clinical situation GP IIb-IIIa inhibitors only. Pretreatment of non-ST segment elevaFigure 1. Antiplatelet agents and their receptors. Acetylsalicylic acid (aspirin) acts on cyclooxygenase to inhibit thromboxane A2 synthesis. Thienopyridines, cangrelor tion ACS patients with prasugrel prior to and ticagrelor act on the purinergic receptor P2Y12, which also binds ADP. GP IIb/IIIa undergoing PCI increased major bleeding inhibitors act on the fibrinogen receptor. The newer PAR1 agonist acts on the events and life-threatening bleeding events thrombin receptor. without any reduction in the postADP: Adenosine diphosphate; GP: Glycoprotein; PAR: Protease activated receptor. intervention ischemic events [11]. Clopidogrel as pretreatment therapy for ACS GP IIb/IIIa complex binds to the platelet cytoskeleton in order patients undergoing PCI has shown to have reduced coronary to mediate platelet spreading and clot retraction [3]. Platelets also events without any reduction in major bleeding events or mortalpossess procoagulant activity by allowing enzyme complexes in ity [12]. Administration of a 300 mg loading dose of clopidogrel the clotting cascade to assemble on the platelet surface, thereby 6–24 h prior to PCI in comparison with administering the loadincreasing reaction velocity. ing dose at the time of PCI has been shown to have lower rates of coronary events, major bleeding events and overall mortality [13]. Antiplatelet therapy Cytochrome P-450 enzyme is needed to convert clopidogrel The goal of antiplatelet therapy is to reduce platelet activation, into its active metabolite. Patients with reduced function thereby decreasing the incidence of cardiovascular events such CYP2C19 alleles have reduced platelet inhibition, which results as recurrent ischemia and myocardial infarction (MI), while in increased cardiovascular events in patients with ACS with or minimizing the risk of bleeding. FIGURE 1 shows the site of action without PCI and can serve as a prognostic indicator in young of antiplatelet agents. Antiplatelet agents exert their effects by patients [14–16]. inhibiting a variety of different platelet activators [4]. Aspirin, thienopyridines and GP IIb/IIIa inhibitors are the three pri- Platelet function testing mary classes of commonly used antiplatelet agents. Aspirin irre- Platelet function assays can help monitor response to various versibly inhibits the release of thromboxane A2 from platelets types of antiplatelet therapy. They are useful in evaluating and prostacyclin from endothelial cells. Thienopyridines inhibit platelet reactivity and platelet responsiveness, but the correlaADP from binding to its platelet surface P2Y receptor. GP IIb/ tions with clinical end points are not well established and vary IIIa receptor inhibitors prevent fibrinogen from binding to its among different tests. platelet surface integrin, a key step in platelet aggregation. AntiThe gold standard for platelet function testing is turbidimetplatelet regimen recommendations in patients undergoing PCI ric platelet aggregometry. This type of assay measures platelet are based on the disease status and are different for patients aggregation that occurs as a result of GP IIb/IIIa receptor who have stable coronary artery disease (CAD), non-ST seg- activation in platelet-rich plasma [17,18]. In platelet aggregomement elevation ACS or ST segment elevation MI [5–8]. Aspirin try, samples are exposed to an agonist (ADP or arachidonic and thienopyridine resistance has been reported, but its acid) and the increase in light transmittance resulting from
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 10/12/14 For personal use only.
Thienopyridines Ticagrelor Cangrelor
464
Expert Rev. Cardiovasc. Ther. 12(4), (2014)
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 10/12/14 For personal use only.
Antiplatelet therapy in the cath lab
platelet–platelet aggregation is measured. This type of test can be used to monitor platelet responsiveness to aspirin, thienopyridines or GP IIb/IIIa inhibitors. Many of these tests have numerous limitations, including: high cost, variable reproducibility, the need for larger sample volumes with longer processing times and complex sample preparation. One promising point-of-care test that avoids many of these drawbacks is the VerifyNow test. This is a simple, rapid test that can be performed on whole blood using a small sample that requires no preparation. It can be used to assess platelet responsiveness to agents in the three primary classes of antiplatelet drugs. There are several other tests that can be used to measure platelet sensitivity to aspirin, thienopyridines and GP IIb/IIIa inhibitors and include: Plateletworks, the Thromboelastograph Platelet Mapping System, the Impact Cone and Platelet Analyzer and the Platelet Function Analyzer-100. Plateletworks measures platelet aggregation in whole blood. The Thromboelastograph Platelet Mapping System is a point-of-care test that uses whole blood to assess platelet clot formation and clot lysis by measuring the platelet contribution to clot strength. This test can assess antiplatelet drugs in the three primary classes, but has been studied less extensively than other testing methods. The Impact Cone and Platelet Analyzer assess shear-induced platelet adhesion. It uses whole blood, requires low sample volumes and needs no sample preparation. However, it is not a widely available test and is not recommended for monitoring the response to GP IIb/IIIa inhibitors. The Platelet Function Analyzer-100 is a simple, rapid, point-of-care test that uses low sample volumes of whole blood. There is no sample preparation required. This assay measures the in vitro cessation of high-shear blood flow by the platelet plug. It is dependent on vWF and hematocrit levels and it is not a good tool for monitoring thienopyridines [18], but is suitable to test the antiplatelet effects of aspirin. The multiplate analyzer is a good test to evaluate the antiplatelet effects of both aspirin and clopidogrel [19]. Patients with reduced function CYP2C19 allele have decreased antiplatelet activity and higher rates of events on therapy with thienopyridines; they have increased platelet aggregation and platelet reactivity index on testing [20]. Plasma platelet miRNA (miR-126) levels may have a potential to be used as a marker to predict major adverse cardiovascular events in 12 months time or bleeding events in 6 months time [21]. Some cardiac catheterization laboratories have one or more point-of-care assays and use them for monitoring patients’ platelet reactivity after PCI, but the tests have not gained widespread usage. Point-of-care monitoring of platelet function to optimize antiplatelet therapy in patients who receive coronary stents does not offer an advantage over those who are not monitored and at the same time there are no significant differences in major bleeding events between these two groups [22]. The bleeding complications as a result of antiplatelet therapy in elderly patients, in patients requiring double antiplatelet therapy along with full-dose anticoagulation and in low-risk ACS patients need further studies [23]. However, even if the utility of tailoring antiplatelet therapy is questionable, there is still an opportunity to use platelet function tests informahealthcare.com
Review
to understand the efficacy of therapy, the variability of therapy, the appropriate timing of therapy and to predict poor outcomes [24]. High on-treatment platelet reactivity to ADP and low on-treatment platelet reactivity to ADP predict adverse events like thrombotic events and bleeding events, respectively, which will allow for defining the therapeutic window for antiplatelet therapy [25,26]. In a study by Breet et al., the platelet function tests were limited in their accuracy and for predicting bleeding events [27]. Aspirin
Aspirin is an irreversible inhibitor of cyclooxygenase-1, a cyclooxygenase-1 enzyme. This enzyme catalyzes the conversion of arachidonic acid to prostaglandin H2 within platelets. Ultimately, this pathway produces thromboxane A2, a potent platelet aggregator and vasoconstrictor and is depicted in FIGURE 1. By preventing thromboxane A2 production, aspirin irreversibly inhibits platelet function and aggregation [9,28]. Aspirin also diminishes endothelial vasodilation as the pathway-mediated production of prostacyclin is also inhibited. The cyclooxygenase-1 inhibition of thromboxane production persists for the duration of the platelet itself, typically between 7 and 10 days. However, aspirin’s effect is transient in endothelial cells, which enables the recovery of vasodilatory function [29]. Aspirin has a multitude of beneficial effects on cardiac outcomes. It has been shown to reduce the incidence of MI in patients hospitalized with unstable angina, as well as reducing non-fatal MI or death from CAD [30,31]. In patients with an acute MI, aspirin therapy for 1 month resulted in a significant reduction in non-fatal MI [31]. Serious bleeding is the major risk of aspirin therapy with dose-dependent side effects [32]. Lower daily doses of aspirin (50 ml/min
Elective PCI with stent placement Tirofiban
ACS without thienopyridine ACS with thienopyridine STEMI
Class I, LOE A Class IIa, LOE B Class IIa, LOE B Class IIa, LOE B
LD: 0.4 mg/kg/min for 30 min followed by MD: 0.1 mg/kg/min for 48 h Reduce maintenance dose by 50% in patients with eCrCl 300 s. However, this came at a cost of a significant increase in bleeding [79]. Expert Rev. Cardiovasc. Ther. 12(4), (2014)
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 10/12/14 For personal use only.
Antiplatelet therapy in the cath lab
The EPILOG trial showed that abciximab therapy in conjunction with low-dose, weight-adjusted heparin conferred substantial clinical benefit without increased bleeding complications [80]. It also showed that the need for unplanned stent placement was reduced by treatment with abciximab and low-dose weightadjusted heparin. Due to the larger size of the molecule, abciximab is antigenic and carries the risk of rapid, acute thrombocytopenia [75,81]. Severe thrombocytopenia from abciximab occurs in less than 1% of patients and may occur after the first exposure as well as with repeated administration [82]. The half-life of abciximab is less than 30 min and platelet inhibition occurs rapidly after onset of infusion. The reversal of antiplatelet action is slow, and may take more than 12 h [83]. Platelet transfusion can reduce bleeding and is indicated for life-threatening bleeding, high-risk hemostatic impairment and confirmed platelet count
Review
Contemporary antiplatelet therapy in patients undergoing percutaneous coronary intervention Expert Rev. Cardiovasc. Ther. 12(4), 463–474 (2014)
Shaun Bhatty1, Asghar Ali1,2, Ranjith Shetty1, Kevin F Sumption1,2, Michael J Cowley1 and Ion S Jovin*1,2 1 Department of Internal Medicine, Cardiovascular Division, Virginia Commonwealth University Health System/Medical College of Virginia, Richmond, VA, USA 2 Department of Internal Medicine, Cardiovascular Division, McGuire Veterans Administration Medical Center, Richmond, VA, USA *Author for correspondence: Tel.: +1 804 675 5448 Fax: +1 804 675 5450 [email protected]
The proper use of antiplatelet agents in the cardiac catheterization laboratory is important for ensuring optimal results in patients undergoing percutaneous revascularization. Understanding the mechanisms by which these drugs exerts their effects is important for both interventional and non-interventional cardiologists. The effects of these agents on platelet function can be assessed and monitored using a variety of commercially available laboratory assays but so far these tests have not been adopted in routine clinical practice. Currently, aspirin, thienopyridines and glycoprotein IIb/IIIa inhibitors are the primary types of antiplatelet drugs being utilized. The use of these drugs and of several newer antiplatelet drugs in the treatment of patients undergoing percutaneous revascularization in the cardiac catheterization laboratory will be discussed, especially in the light of the recently published guidelines. KEYWORDS: antiplatelet agents • cyclopentyltriazolopyrimidines aspirin • percutaneous intervention • thienopyridines
Every year, several hundred thousand percutaneous coronary intervention (PCI) procedures are performed in patients with acute coronary syndrome (ACS) and stable angina. PCI requires the use of antiplatelet and anticoagulant therapies to reduce the risk of adverse cardiovascular events. However, these therapies carry a significant risk of bleeding. Finding the balance between limiting adverse cardiovascular events and the risk of significant hemorrhage is an ongoing challenge. A thorough understanding of how currently available antiplatelet agents work and how they can be applied in an evidence-based way can improve patient outcomes in the cardiac catheterization laboratory. Hemostasis
Hemostasis describes a complex series of events that help to maintain the integrity of blood vessel walls when they become damaged and the processes involved occur somewhat simultaneously [1]. This process is initiated by exposure of circulating blood to extravascular proteins [2]. The four phases in the hemostatic process are: initiation and formation of the platelet plug, further amplification of clotting by the coagulation cascade, termination of the clotting process informahealthcare.com
10.1586/14779072.2014.901149
and degradation of the clot by fibrinolysis. The formation of the platelet plug is initiated when circulating platelets are recruited to the site of vascular injury and become activated. Collagen and thrombin are potent platelet activators while adenosine diphosphate (ADP) and epinephrine are weaker activating agents. Activated platelets undergo a series of four processes: adhesion, aggregation, secretion and procoagulant activity. When platelets adhere to subendothelial collagen and von Willebrand factor (vWF), a variety of chemical mediators are released from their granules and include: ADP, thomboxane A2, serotonin, fibronectin, fibrinogen and growth factors. These substances then recruit neighboring platelets leading to aggregation and also may function as vasoconstrictors. During platelet aggregation, fibrinogen binds to its platelet receptor, the glycoprotein (GP) IIb/ IIIa integrin resulting in platelet crosslinking. The GP IIb/IIIa complex is involved in two signaling pathways that lead directly to platelet aggregation. In ‘inside-out signaling’, after the platelet is stimulated, the GP IIb/IIIa complex undergoes a conformational change resulting in a stronger affinity for fibrinogen. In ‘outside-in signaling’, the cytosolic portion of the activated
2014 Informa UK Ltd
ISSN 1477-9072
463
Review
Bhatty, Ali, Shetty, Sumption, Cowley & Jovin
significance is not completely understood [9]. Aspirin and a P2Y12 inhibitor as dual antiplatelet therapy in PCI patients ADP were shown to be cost-effective with prasugrel and ticagrelor alternatives to use ADP receptor instead of clopidogrel. These new agents PAR-1 antagonist (P2Y12) are thought to be cost-effective as well, but there are no studies that have compared Aspirin them against each other for cost–effectiveArachidonic acid ness. There is also limited understanding PAR-1 Cyclooxygenase-1 of cost–effectiveness of GP IIa/IIIb inhibiProstaglandin G2/H2 tors for present-day PCI because of Thrombin changes in the guidelines of their use in ACS patients [10]. The oral agents, which Thromboxane A2 PAR-4 are approved or are in clinical development, inhibit activation of the platelets, while the GP IIb/IIIa inhibitors block aggregation of the platelets. Prasugrel and GP IIb-IIIa receptor ticagrelor are approved for use in ACS patients only, due to which cost–effectiveness analyzes of these agents against clopiFibrinogen dogrel are limited to this clinical situation GP IIb-IIIa inhibitors only. Pretreatment of non-ST segment elevaFigure 1. Antiplatelet agents and their receptors. Acetylsalicylic acid (aspirin) acts on cyclooxygenase to inhibit thromboxane A2 synthesis. Thienopyridines, cangrelor tion ACS patients with prasugrel prior to and ticagrelor act on the purinergic receptor P2Y12, which also binds ADP. GP IIb/IIIa undergoing PCI increased major bleeding inhibitors act on the fibrinogen receptor. The newer PAR1 agonist acts on the events and life-threatening bleeding events thrombin receptor. without any reduction in the postADP: Adenosine diphosphate; GP: Glycoprotein; PAR: Protease activated receptor. intervention ischemic events [11]. Clopidogrel as pretreatment therapy for ACS GP IIb/IIIa complex binds to the platelet cytoskeleton in order patients undergoing PCI has shown to have reduced coronary to mediate platelet spreading and clot retraction [3]. Platelets also events without any reduction in major bleeding events or mortalpossess procoagulant activity by allowing enzyme complexes in ity [12]. Administration of a 300 mg loading dose of clopidogrel the clotting cascade to assemble on the platelet surface, thereby 6–24 h prior to PCI in comparison with administering the loadincreasing reaction velocity. ing dose at the time of PCI has been shown to have lower rates of coronary events, major bleeding events and overall mortality [13]. Antiplatelet therapy Cytochrome P-450 enzyme is needed to convert clopidogrel The goal of antiplatelet therapy is to reduce platelet activation, into its active metabolite. Patients with reduced function thereby decreasing the incidence of cardiovascular events such CYP2C19 alleles have reduced platelet inhibition, which results as recurrent ischemia and myocardial infarction (MI), while in increased cardiovascular events in patients with ACS with or minimizing the risk of bleeding. FIGURE 1 shows the site of action without PCI and can serve as a prognostic indicator in young of antiplatelet agents. Antiplatelet agents exert their effects by patients [14–16]. inhibiting a variety of different platelet activators [4]. Aspirin, thienopyridines and GP IIb/IIIa inhibitors are the three pri- Platelet function testing mary classes of commonly used antiplatelet agents. Aspirin irre- Platelet function assays can help monitor response to various versibly inhibits the release of thromboxane A2 from platelets types of antiplatelet therapy. They are useful in evaluating and prostacyclin from endothelial cells. Thienopyridines inhibit platelet reactivity and platelet responsiveness, but the correlaADP from binding to its platelet surface P2Y receptor. GP IIb/ tions with clinical end points are not well established and vary IIIa receptor inhibitors prevent fibrinogen from binding to its among different tests. platelet surface integrin, a key step in platelet aggregation. AntiThe gold standard for platelet function testing is turbidimetplatelet regimen recommendations in patients undergoing PCI ric platelet aggregometry. This type of assay measures platelet are based on the disease status and are different for patients aggregation that occurs as a result of GP IIb/IIIa receptor who have stable coronary artery disease (CAD), non-ST seg- activation in platelet-rich plasma [17,18]. In platelet aggregomement elevation ACS or ST segment elevation MI [5–8]. Aspirin try, samples are exposed to an agonist (ADP or arachidonic and thienopyridine resistance has been reported, but its acid) and the increase in light transmittance resulting from
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 10/12/14 For personal use only.
Thienopyridines Ticagrelor Cangrelor
464
Expert Rev. Cardiovasc. Ther. 12(4), (2014)
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 10/12/14 For personal use only.
Antiplatelet therapy in the cath lab
platelet–platelet aggregation is measured. This type of test can be used to monitor platelet responsiveness to aspirin, thienopyridines or GP IIb/IIIa inhibitors. Many of these tests have numerous limitations, including: high cost, variable reproducibility, the need for larger sample volumes with longer processing times and complex sample preparation. One promising point-of-care test that avoids many of these drawbacks is the VerifyNow test. This is a simple, rapid test that can be performed on whole blood using a small sample that requires no preparation. It can be used to assess platelet responsiveness to agents in the three primary classes of antiplatelet drugs. There are several other tests that can be used to measure platelet sensitivity to aspirin, thienopyridines and GP IIb/IIIa inhibitors and include: Plateletworks, the Thromboelastograph Platelet Mapping System, the Impact Cone and Platelet Analyzer and the Platelet Function Analyzer-100. Plateletworks measures platelet aggregation in whole blood. The Thromboelastograph Platelet Mapping System is a point-of-care test that uses whole blood to assess platelet clot formation and clot lysis by measuring the platelet contribution to clot strength. This test can assess antiplatelet drugs in the three primary classes, but has been studied less extensively than other testing methods. The Impact Cone and Platelet Analyzer assess shear-induced platelet adhesion. It uses whole blood, requires low sample volumes and needs no sample preparation. However, it is not a widely available test and is not recommended for monitoring the response to GP IIb/IIIa inhibitors. The Platelet Function Analyzer-100 is a simple, rapid, point-of-care test that uses low sample volumes of whole blood. There is no sample preparation required. This assay measures the in vitro cessation of high-shear blood flow by the platelet plug. It is dependent on vWF and hematocrit levels and it is not a good tool for monitoring thienopyridines [18], but is suitable to test the antiplatelet effects of aspirin. The multiplate analyzer is a good test to evaluate the antiplatelet effects of both aspirin and clopidogrel [19]. Patients with reduced function CYP2C19 allele have decreased antiplatelet activity and higher rates of events on therapy with thienopyridines; they have increased platelet aggregation and platelet reactivity index on testing [20]. Plasma platelet miRNA (miR-126) levels may have a potential to be used as a marker to predict major adverse cardiovascular events in 12 months time or bleeding events in 6 months time [21]. Some cardiac catheterization laboratories have one or more point-of-care assays and use them for monitoring patients’ platelet reactivity after PCI, but the tests have not gained widespread usage. Point-of-care monitoring of platelet function to optimize antiplatelet therapy in patients who receive coronary stents does not offer an advantage over those who are not monitored and at the same time there are no significant differences in major bleeding events between these two groups [22]. The bleeding complications as a result of antiplatelet therapy in elderly patients, in patients requiring double antiplatelet therapy along with full-dose anticoagulation and in low-risk ACS patients need further studies [23]. However, even if the utility of tailoring antiplatelet therapy is questionable, there is still an opportunity to use platelet function tests informahealthcare.com
Review
to understand the efficacy of therapy, the variability of therapy, the appropriate timing of therapy and to predict poor outcomes [24]. High on-treatment platelet reactivity to ADP and low on-treatment platelet reactivity to ADP predict adverse events like thrombotic events and bleeding events, respectively, which will allow for defining the therapeutic window for antiplatelet therapy [25,26]. In a study by Breet et al., the platelet function tests were limited in their accuracy and for predicting bleeding events [27]. Aspirin
Aspirin is an irreversible inhibitor of cyclooxygenase-1, a cyclooxygenase-1 enzyme. This enzyme catalyzes the conversion of arachidonic acid to prostaglandin H2 within platelets. Ultimately, this pathway produces thromboxane A2, a potent platelet aggregator and vasoconstrictor and is depicted in FIGURE 1. By preventing thromboxane A2 production, aspirin irreversibly inhibits platelet function and aggregation [9,28]. Aspirin also diminishes endothelial vasodilation as the pathway-mediated production of prostacyclin is also inhibited. The cyclooxygenase-1 inhibition of thromboxane production persists for the duration of the platelet itself, typically between 7 and 10 days. However, aspirin’s effect is transient in endothelial cells, which enables the recovery of vasodilatory function [29]. Aspirin has a multitude of beneficial effects on cardiac outcomes. It has been shown to reduce the incidence of MI in patients hospitalized with unstable angina, as well as reducing non-fatal MI or death from CAD [30,31]. In patients with an acute MI, aspirin therapy for 1 month resulted in a significant reduction in non-fatal MI [31]. Serious bleeding is the major risk of aspirin therapy with dose-dependent side effects [32]. Lower daily doses of aspirin (50 ml/min
Elective PCI with stent placement Tirofiban
ACS without thienopyridine ACS with thienopyridine STEMI
Class I, LOE A Class IIa, LOE B Class IIa, LOE B Class IIa, LOE B
LD: 0.4 mg/kg/min for 30 min followed by MD: 0.1 mg/kg/min for 48 h Reduce maintenance dose by 50% in patients with eCrCl 300 s. However, this came at a cost of a significant increase in bleeding [79]. Expert Rev. Cardiovasc. Ther. 12(4), (2014)
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 10/12/14 For personal use only.
Antiplatelet therapy in the cath lab
The EPILOG trial showed that abciximab therapy in conjunction with low-dose, weight-adjusted heparin conferred substantial clinical benefit without increased bleeding complications [80]. It also showed that the need for unplanned stent placement was reduced by treatment with abciximab and low-dose weightadjusted heparin. Due to the larger size of the molecule, abciximab is antigenic and carries the risk of rapid, acute thrombocytopenia [75,81]. Severe thrombocytopenia from abciximab occurs in less than 1% of patients and may occur after the first exposure as well as with repeated administration [82]. The half-life of abciximab is less than 30 min and platelet inhibition occurs rapidly after onset of infusion. The reversal of antiplatelet action is slow, and may take more than 12 h [83]. Platelet transfusion can reduce bleeding and is indicated for life-threatening bleeding, high-risk hemostatic impairment and confirmed platelet count
