Acute and chronic vascular diseases continue to be significant causes of morbidity and mortality worldwide. According to the World Health Organization (WHO), ischemic heart disease and cerebrovascular disease (CVD) are the top two leading causes of death worldwide [1,2]. The American Heart Association (AHA) estimates that 81,100,000 (approximately one third) American adults have one or more types of cardiovascular disease with an estimated cost (direct and indirect) of $503.2 billion [3]. They estimate that each year 785,000 Americans will have a new heart attack and 795,000 will have a new or recurrent stroke [3].
While these conditions may manifest clinically in different vascular territories, such as the brain in CVD and the heart in coronary artery disease (CAD), and the legs primarily in peripheral arterial disease (PAD), they share common pathobiological pathways. One critical shared pathway in the development of acute vascular events is that of platelet activation and aggregation that leads to occlusive thrombus formation and downstream ischemia, which may clinically present as myocardial infarction, stroke, or acute limb ischemia. As such, therapies targeted at interrupting platelet activation and aggregation have been the subject of active development and research.
Aspirin has been shown to significantly reduce the risk of atherothrombotic events and has become the cornerstone of antiplatelet therapy in patients at risk of events [4-9]. High-risk patients, such as those with a history of acute coronary syndrome (ACS), have been shown to derive further benefit from the addition of a second antiplatelet therapy, primarily in the form of thienopyridines such as clopidogrel [10,11]. Even as more potent thienopyridines have been shown to further reduce the rate of recurrent events in high-risk patients, there remains a significant residual risk. In addition, more potent platelet inhibition to date has been associated with high rates of bleeding [11]. As a result, there is ongoing research focused on novel pathways in platelet inhibition intended to further reduce the risk of ischemic events while maintaining a safe bleeding profile [12]. This review will cover several commonly used oral antiplatelet agents, as well as therapies currently under investigation.
BACKGROUND
The primary function of platelets is to prevent hemorrhage. They are produced by megakaryocytes in the bone marrow and circulate in the blood for approximately 10 days [13]. When exposed to sites of injury, platelets initially respond by adherence through interaction of the glycoprotein (GP) Ib/V/IX receptor with Von Willebrand factor (VWF), its major ligand, as well as by collagen receptors on the platelet surface [13]. Autocrine and paracrine release of multiple mediators amplifies platelet activation and further recruits platelets into the formation of a hemostatic plug [13]. These mediators include adenosine 5′-diphosphate (ADP), thrombin, epinephrine, and thromboxane A2 and act through a variety of different platelet receptors (Figure 1) [14]. In addition to platelet activation, the release of autocrine mediators leads to activation of the coagulation cascade and conversion of prothrombin to thrombin [14,15]. Thrombin is important for both coagulation and platelet activation, and has multiple actions — cleaving fibrinogen to fibrin thereby stabilizing the forming thrombus, as well as activating the protease-activating thrombin receptor (PAR)-1, leading to further platelet activation [13,16].
 |
Figure 1. Current target receptors in antiplatelet therapy. |
The development of oral antiplatelet therapy has targeted specific pathways of activation. Treatment with aspirin inhibits the generation of thromboxane A2, while the thienopyridines inhibit ADP-induced activation of platelets by antagonism of the purigenic receptor P2Y12. Both of these agents have been shown to be effective in reducing ischemic events. In addition, oral agents antagonizing the GP IIb/IIIa receptor have been developed but were found to increase mortality and bleeding, thus these agents are not clinically available [17,18]. Currently, the activation of platelets by thrombin through G-protein-coupled protease-activated receptors (PARs) is an area of active research and development with compounds in phase III of testing [12,19,20].
The remainder of this review will be focused on discussing commonly used oral antiplatelet agents, their characteristics, and recent data impacting their use. It is important to note that while platelet aggregation testing has been developed along with oral antiplatelet agents, to date major randomized clinical trials evaluating the efficacy of these therapies have not directly incorporated this testing. As such, integration of platelet aggregation testing in determining optimal therapies in the current clinical care of patients is continuing to evolve.
ASPIRIN
Mechanism of action
Aspirin (Figure 2) inhibits platelet aggregation through irreversible inhibition by acetylation of cyclooxygenase-1 (COX-1) preventing formation of thromboxane A2, a promoter of platelet aggregation.
 |
Figure 2. The molecular structure of aspirin. |
Pharmacokinetics and pharmacodynamics
Salicylates are used for a wide variety of indications. Both aspirin (acetylsalicylic acid) and its metabolite, salicylic acid, have activity; however, aspirin is a more potent inhibitor of both prostaglandin synthesis and platelet aggregation due to the acetyl group which inactivates cyclooxygenase via acetylation. For acute and chronic coronary disease doses generally range between 75 and 325 mg [4,5,9]. Oral aspirin is well absorbed, although there is variability in the presence of enteric coating and food [21]. Platelet inhibition occurs between 1 to 7.5 min after ingestion depending on the form [22]. The half-life of salicylic acid (active compound) is approximately 6 h; however, aspirin-mediated platelet inhibition is irreversible for the life of the platelet [23,24]. Salicylic acid undergoes hydrolysis in the liver and its metabolites are excreted through the kidney [24,25]. It can also be dialyzed [26].
Drug interactions
There are a wide range of possible aspirin—drug interactions, including that with nonsteroidal anti-inflammatory agents as well as other antiplatelet agents; however, in general, aspirin is well tolerated in conjunction with other medications [25].
Side effects and contraindications
The primary side effects of aspirin include bleeding and gastrointestinal effects such as dyspepsia and ulcers [25]. Contraindications for aspirin include documented allergy, significant thrombocytopenia, and uncontrolled bleeding. Caution should be used in patients with renal dysfunction, bleeding disorders, and known peptic ulcer disease.
Recent clinical trial findings
A strong body of literature supports aspirin as an antiplatelet agent for patients at risk of vascular events or with established vascular disease [4,5,7-9]. In stable coronary heart disease, it has been observed that a low dose of aspirin (50-100 mg/d) is as effective as high doses but is associated with a low rate of major bleeding [27]. The use of aspirin in ACS is widely accepted and supported by guidelines; however, the optimal dosing has not been definitively established. Current guidelines recommend an initial dose between 162 and 325 mg, with a maintenance dose between 75 and 162 mg [4,5,7-9]. High doses are recommended (162 to 325 mg) if a patient is treated with percutaneous coronary intervention (PCI) and stenting with duration dependent on stent type [28].
The Clopidogrel optimal loading dose Usage to Reduce Recurrent EveNTs-Organization to Assess Strategies in Ischemic Syndromes (CURRENT-OASIS 7) trial examined low- versus high-dose aspirin in one arm of its factorial design [29]. The trial was a 2x2 factorial, open-label, randomized trial to determine the optimal clopidogrel and aspirin dosing in patients with ACS who presented within 24 h of ischemic symptoms [29]. Patients were randomized to either high-dose (300-325 mg) or low-dose (75-100 mg) aspirin daily for 30 days and in addition were randomized to either double-dose or standard-dose clopidogrel. The primary outcome was the composite of cardiovascular death, myocardial infarction, or stroke over 30 days.
A total of 25,087 patients were enrolled in the OASIS-7 trial with PCI performed in approximately 70%. Preliminary results showed the presence of significant interaction for the primary end point between high-dose and low-dose aspirin and double-dose and standard-dose clopidogrel groups (p = .043, Table 1) [29]. Between the two-aspirin dose strata, there were no differences in rates of the primary end point between high-dose and low-dose aspirin overall (4.2 vs. 4.4%, hazard ratio [HR] 0.96, 95% confidence interval [CI] 0.85 - 1.08, p = .47), or in the 17,232 patients who underwent PCI (4.2 vs 4.1%, HR 0.98, 95% CI 0.74 - 1.13, p = .76). Rates of stent thrombosis also were similar between the two aspirin dose groups (2.1 vs 1.9%, p = .37). While there was no difference in major bleeding (2.3 vs 2.3%), it should be noted that there was a trend toward more gastrointestinal bleeding with high-dose aspirin compared to low-dose aspirin (0.38 vs. 0.24%, p = .051) [29].
 |
TABLE 1. Comparison of current and novel P2Y12 inhibitors |
There was a significant interaction between aspirin dose and clopidogrel dosing with a benefit of high-dose clopidogrel seen only in the high-dose aspirin group [29]. This makes interpretation of this trial complex. While the authors concluded that there was no significant difference in efficacy or bleeding between the aspirin dose arms, the clinical significance of the observed interaction is not clear and warrants further investigation.
P2Y12 INHIBITORS
ADP is a potent activator of platelets that acts through the purigenic receptor P2Y12 on the platelet surface ultimately leading to activation of the GP IIb/IIIa complex [13]. Thienopyridines selectively and irreversibly inhibit the binding of ADP to its platelet receptor, thereby blocking activation of platelets. In addition, novel nonthienopyridine P2Y12 inhibitors are currently under investigation [30]. Table 1 summarizes basic attributes of currently used P2Y12 inhibitors including the thienopyridines clopidogrel and prasugrel, as well as the investigational nonthienopyridine P2Y12 inhibitor ticagrelor. Table 2 summarizes results of recent clinical trials of P2Y12 inhibitors in patients with ACS. A growing body of literature supports the use of P2Y12 inhibitors in addition to aspirin in patients at risk of atherothrombotic disease; however, understanding the differences between agents and indications, as well as careful patient selection, is important to ensure appropriate use [10,11,30,31].
 |
TABLE 2. Efficacy and safety: results from recent major trials of P2Y12 inhibitors in ACS |
CLOPIDOGREL
Clopidogrel (Figure 3) is a thienopyridine that has largely supplanted its predecessor, ticlopidine, in many parts of the world due to its improved tolerability and safety profile. Clopidogrel is approved for use across the spectrum of acute and chronic symptomatic vascular disease including ACS, stroke, and PAD [10,31,32]. Currently debated topics with regard to clopidogrel use center on its variability in interpatient antiplatelet effect in the setting of drugs or genetic variants, its optimal dosing in patients with ACS, and optimal duration of therapy. New data providing insight with regard to these topics are highlighted later.
 |
Figure 3. The molecular structure of clopidogrel. |
Pharmacokinetics and dosing
Clopidogrel is given orally and can be given as a loading dose or maintenance dose. It is 50% bioavailable and is metabolized by hepatic hydrolysis with ultimate excretion through the urine and feces. The elimination half-life of the active metabolite (thiol derivative) is rapid; however, its antiplatelet effect is irreversible for the life of the platelet. There is no dose adjustment necessary in renal or hepatic dysfunction.
Clopidogrel is a prodrug relying on metabolism in the liver for conversion of its active metabolite. Initial work showed clopidogrel reached a maximum inhibition of ADP-induced platelet aggregation of 40 to 50% at 2 to 5 h after a loading dose of 300 to 400 mg or after 3 to 7 days of 75 mg daily [33]. Appreciation of interpatient variability of clopidogrel antiplatelet effects has led to the investigation of higher doses of clopidogrel in an attempt to minimize hyporesponsiveness, particularly in high-risk patients such as those with non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Studies have demonstrated that ADP-induced platelet aggregation and expression of P-selectin were significantly lower in patients receiving 600 mg compared to those receiving 300 mg (p <.0001), with an associated reduction in recurrent CV events (5 vs 12%, p = .035) [34-36]. It should be noted, however, that even a 600-mg loading dose may require up to 8 h to achieve 50% steady state inhibition of ADP-induced platelet aggregation [37].
Drug interactions
There are multiple potential drug interactions that may alter clopidgrel’s antiplatelet effect [25]. In addition, there are potential interactions between clopidogrel response and concomitant medications that modify cytochrome P450 (CYP) metabolism, important for conversion of the clopidogrel prodrug to its active metabolite, such as proton pump inhibitors (PPIs) [38,39]. Recent data with regard to this interaction are discussed later.
Side effects and contraindications
The principle side effect of clopidogrel is related to its antiplatelet effect and bleeding. In addition, thrombotic thrombocytopenic purpura has been reported with clopidogrel therapy [40].
Recent clinical trial findings
Variability in platelet inhibition resulting from administration of clopidogrel has been raised as a concern [34]. As noted earlier, one source of this variability appears to be related to the metabolism of the prodrug into its active metabolite by the CYP enzyme system. The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel—Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 trial randomized 13,608 patients presenting across the spectrum of ACS to either clopidogrel or prasugrel [11]. A subsequent analysis of reduced function CYP alleles performed within the clopidogrel stratum found that that carriers of at least one cytochrome P450 2C19 (CYP2C19) reduced function allele resulting in decreased function and were common (30% of the study population) [41]. In addition, carriers were found to have a 32.4% lower plasma exposure of the active metabolite of clopidogrel (p <.001), as well as a 53% higher rate of the primary composite end point of cardiovascular death, myocardial infarction, or stroke when compared to noncarriers (12.1 vs 8.0%, HR 1.53, 95% CI 1.07 - 2.19, p = .01) [41]. The clopidogrel arm of TRITON-TIMI 38 used clopidogrel 300-mg loading and 75 mg daily—the approved dosing regimen at that time [11].
The appreciation of interpatient variability in response to clopidogrel led to the hypothesis that high doses may overcome this lack of adequate antiplatelet effect. The CURRENT-OASIS 7 trial (described earlier) explored whether high dosing of clopidogrel is associated with reduced events compared to standard dosing with preliminary results presented earlier this year [29]. The primary analysis for this 2x2 factorial trial showed a significant interaction for the primary end point between low- and high-dose aspirin and standard- and double-dose clopidogrel groups (p = .043) [29]. Preliminary data presented at the European Society of Cardiology Scientific Sessions in 2009 revealed that patients randomized to high-dose aspirin had low rates of the primary end point on double-dose clopidogrel (3.8 vs 4.6%, relative risk [RR] 0.83, 95% CI 0.70 - 0.99, p = .036); however, this difference was not seen with double-dose versus standard-dose clopidogrel in the low-dose aspirin strata (4.5 vs 4.2%, RR 1.07, 95% CI 0.91 - 1.27, p = .42) [29]. When pooled across aspirin strata, there was no difference in the primary end point with double-dose versus standard-dose clopidogrel (4.2 vs 4.4%, HR 0.95, 95% CI 0.84 - 1.07, p = .37) [29].
In an unadjusted post-randomization analysis examining the 17,232 patients who underwent PCI, there were lower rates of the primary end point with double-dose compared with standard-dose clopidogrel (3.9 vs 4.5%) [29]. In patients not undergoing PCI, the rate of the primary end point did not favor double-dose clopidogrel (4.9 vs 4.2%) [29]. There were reductions in myocardial infarction (2.0 vs 2.6%) and definite or probable stent (1.6 vs 2.3%), with no difference in the rate of cardiovascular death [29].
There was an associated increase in CURRENT-OASIS 7 major bleeding with double-dose clopidogrel (2.5 vs 2.0%, HR 1.25, 95% CI 1.05 - 1.47, p = .01), but no differences in TIMI major bleeding, fatal bleeding, intracranial hemorrhage, or coronary artery bypass graft (CABG)-related major bleeding [29].
Other explanations for variable response to clopidogrel include modifications of CYP metabolism by concomitant medications. One commonly used group of medications raised as a potential concern is the PPI [38]. Omeprazole specifically has been evaluated as it has a more potent effect on P450 metabolism than other available PPIs such as pantoprazole. The Proton Pump Inhibitors And Clopidogrel Association (PACA) randomized trial was designed to evaluate this interaction. PACA randomized 104 ACS patients undergoing PCI to 20 mg daily of omeprazole or pantoprazole on background therapy of aspirin 75 mg and clopidogrel 150 mg [42]. The outcome of this trial was to determine differences in clopidogrel response (measured by platelet reactivity index vasoactive-stimulated phosphoprotein, PRI VASP) and platelet reactivity (measured by ADP-induced aggregation, ADP-Ag) at 1 month [42].
The investigators found that patients receiving pantoprazole had better platelet response to clopidogrel (PRI VASP 36 + 20% vs 48 + 17%, p = .007), with more clopidogrel nonresponders in the omeprazole group (44 vs 23%, p = .04) [42]. Interestingly, however, no significant difference in platelet reactivity was observed between the two groups (ADP-Ag 52 + 15% and 50 + 18%, p = .29) [42].
The authors conclude that these findings suggest pantoprazole may be preferred over omeprazole in patients receiving clopidogrel [42]. Differences in outcomes, however, were not measured making results difficult to apply directly to clinical care.
In the only prospective randomized trial able to evaluate this question, Clopidogrel and the Optimization of Gastrointestinal Events (COGENT) also found no association between PPI use and cardiovascular outcome [43]. Preliminary results for this trial, which was terminated prematurely due to lack of sufficient funding from the sponsor, were presented in 2009. A total of 3627 patients with ACS or receiving a coronary stent were randomized to either clopidogrel 75 mg with omeprazole 20 mg (single pill) or clopidogrel alone in addition to aspirin and were followed for a median of 133 days [43]. There were no differences observed between the groups in the rates of composite cardiovascular end points, myocardial infarction, or revascularization [43]. Of note, clopidogrel and omeprazole were integrated into a time-release formulation that is not currently available. Composite gastrointestinal events were significantly lower with omeprazole (HR 0.55, 95% CI 0.36 - 0.85, p = .007) [43]. Results of this study suggest that the use of a PPI in patients taking clopidogrel at high risk of bleeding is not only safe (no increase in cardiovascular events), but also possibly beneficial (fewer gastrointestinal complications).
In response to early signals raising the question of harm, the U.S. Food and Drug Administration (FDA) released a MedWatch Safety alert in November of 2009 stating,
…data show that when clopidogrel and omeprazole are taken together, the effectiveness of clopidogrel is reduced. Patients at risk for heart attacks or strokes who use clopidogrel to prevent blood clots will not get the full effect of this medicine if they are also taking omeprazole. Separating the dose of clopidogrel and omeprazole in time will not reduce this drug interaction [39].
What impact the final findings of COGENT (which have not yet been published in a peer-reviewed journal) will have on this cautionary statement, as well as subsequent iterations of clinical practice guidelines, is unclear [39].
PRASUGREL
A new more potent ADP receptor blocker, prasugrel (Figure 4), was recently approved for use in patients with ACS. Prasugrel, at a loading dose of 60 mg and maintenance dose of 10 mg daily, has been shown to provide faster onset and greater inhibition of P2Y12 receptor mediated platelet aggregation than clopidogrel given as a 600-mg loading dose and 75 mg daily [44,45]. The approval of this agent by the European Medicines Agency and FDA in 2009 postdates many of the most recent iterations of guidelines for treatment of patients with ACS. Some more recent releases, such as the 2009 update to the American College of Cardiology (ACC)/AHA ST-segment elevation myocardial infarction (STEMI) guidelines, have assigned the use of prasugrel as a class 1 indication in patients undergoing primary PCI or in patients receiving nonprimary PCI if they have not received fibrinolytic therapy and once the coronary anatomy is known [9]. Robust clinical trial data for patients with PAD only are not yet available and use of prasugrel in patients with history of stroke or transient ischemic attacks is contraindicated.
 |
Figure 4. The molecular structure of prasugrel. |
Pharmacokinetics
Prasugrel is given orally and is rapidly absorbed with greater than 79% bioavailability. It is converted to its active metabolite through rapid hydrolysis in the intestine by esterases followed by a single CYP-dependent step in the liver, unlike clopidogrel, which is metabolized by 2 consecutive CYP-dependent steps [44]. A single oral administration of prasugrel in rats produced a dose-related inhibition of platelet aggregation (IPA) that was approximately 10-fold more potent than that of clopidogrel [45]. Subsequent studies in humans have confirmed significantly increased potency of platelet inhibition when compared to clopidogrel [46]. Antiplatelet effects are evident at 30 min after dosing with >50% of ADP-induced platelet aggregation by 1 h with peak inhibition by 2 h (approximately 80%) and elimination half-life of the active metabolite of 7 to 8 h [44]. Platelet inhibition with this agent is irreversible, lasting the full duration of a platelets’ lifetime. After cessation of prasugrel, platelet aggregation will gradually return to baseline over 5 to 9 days, reflecting new platelet production [47]. There is no dose adjustment necessary in renal or hepatic dysfunction, although patients with severe hepatic dysfunction have not been studied in large clinical trials [11].
Drug interactions
The potential interactions between prasugrel response and concomitant medications that modify CYP metabolism have not been described for prasugrel. As with other antithrombotic agents, however, use of concomitant therapies that may theoretically increase the risk of bleeding should be used with caution [48].
Side effects and contraindications
Prasugrel carries an FDA Black Box warning for bleeding and specifically cautions against use in patients at risk for bleeding, including patients ≥75 years old, patients with low body weight (<60 kg), and patients otherwise at risk of bleeding [48]. Prasugrel is contraindicated in patients with a history of transient ischemic attacks or stroke due to increased risk of intracranial hemorrhage [48]. It is advised that prasugrel be held for at least 7 days before CABG [48].
Recent clinical trial findings
Prasugrel was studied in 13,608 patients presenting across the spectrum of ACS planned for an invasive approach in the TRITON-TIMI 38 trial [11]. Patients were randomized to prasugrel (60-mg loading dose followed by a 10-mg daily maintenance dose) or clopidogrel (300-mg loading dose followed by a 75-mg daily maintenance dose) and were followed for a median of 14.5 months [11]. Importantly, randomization did not occur until after coronary anatomy was known to be suitable for PCI and as such patients were not treated upstream, prior to angiography [11].
The primary end point, a composite of cardiovascular death, myocardial infarction, and stroke, was significantly reduced in patients randomized to prasugrel (9.9 vs 12.1%, HR 0.81, 95% CI 0.73 - 0.90, p <.001) [11]. In addition, prasugrel significantly reduced stent thrombosis (1.1 vs 2.4%, p <.001). Results were consistent in the subset of 3534 patients who presented with STEMI, with a reduction in the primary end point at 15 months (10 vs 12.4%, HR 0.79, 95% CI 0.65 - 0.97, p = .0221) [11].
This more potent P2Y12 inhibitor was associated with increased TIMI major bleeding (2.4 vs 1.8%, HR 1.32, 95% CI 1.03 - 1.68, p = .03) and fatal bleeding (0.4 vs 0.1%, p = .002), but no difference in intracranial hemorrhage (0.3 vs 0.3%, p = .74) [11].
Exploratory analyses identified 3 subgroups who did not benefit (or were harmed) by prasugrel use—patients with a history of stroke or transient ischemic attacks, patients ≥75 years of age, and patients weighing less than 60 kg (132 lb). These findings are reflected in the contraindications earlier [11].
Overall increased efficacy of this agent over clopidogrel favors its use particularly in high-risk patients such as those with diabetes or those with history of stent thrombosis. In addition, drug metabolite levels and clinical outcomes do not appear to be affected by CYP genetic variants as has been shown with clopidogrel [49]. In correctly selected patients, prasugrel has been shown to provide significant benefit in the reduction of ischemic events over clopidogrel.
TICAGRELOR
Ticagrelor (Figure 5) is a novel, potent P2Y12 inhibitor. It is the first in the class of cyclopentyltriazolopyrimidines, which like thienopyridines block ADP-mediated platelet activation, but does so reversibly.
 |
Figure 5. The molecular structure of ticagrelor. |
Pharmacokinetics and pharmacodynamics
Ticagrelor is orally active without the need for activation. Plasma concentrations rise linearly and dose proportionally achieving steady state at day 14 [50]. Ticagrelor has been used in phase III studies as a 180-mg loading dose followed by 90 mg given twice daily [30]. At this dosing, the onset of antiplatelet effect with ticagrelor is seen within 30 min of loading with near maximal inhibition by 1 h. By 2 h after loading, 98% of patients given ticagrelor have >50% ADP-induced IPA and 90% had >70% IPA [37]. Due to its reversibility, the offset of platelet inhibition is faster than that observed with the thienopyridines. It has been observed that IPA after 3 days off ticagrelor is comparable to that for 5 days off clopidogrel, even though peak IPA is higher with clopidogrel [37]. IPA returns to baseline after 5 days off ticagrelor compared to 7 days off clopidogrel [37].
Drug interactions
As ticagrelor does not rely on activation in the intestine or liver, there are no drug interactions in this regard. It is a potent platelet inhibitor and as such similar possible interactions related to bleeding can be expected as with the thienopyridines.
Side effects and contraindications
In its completed phase III trial, the study of PLATelet inhibition and patient Outcomes (PLATO; described later) found that dyspnea was more common with the ticagrelor group than it was with the clopidogrel group (13.8 vs 7.8%); however, few patients discontinued the study drug because of dyspnea (<1% in both groups) [30]. In addition, there was a higher incidence of ventricular pauses on Holter monitoring in the first week, but not at day 30, with ticagrelor [30]. The two treatment groups did not differ significantly with respect to the incidence of syncope or pacemaker implantation. Overall, with ticagrelor discontinuation of the study drug due to adverse events occurred more frequently and the levels of creatinine and uric acid increased slightly more than they did with clopidogrel [30]. The clinical significance of these findings—if any—is unclear.
Recent clinical trial findings
Ticagrelor is not yet approved for use; however, recently published results from PLATO are promising. The PLATO trial randomized 18,624 patients with ACS to either ticagrelor (180-mg loading dose followed by 90 mg twice daily as maintenance) or clopidogrel (300-mg or 600-mg loading dose followed by 75 mg once daily as maintenance) in a double-blind fashion and followed them for a median of 277 days [30]. The primary end point was a composite of cardiovascular death, myocardial infarction, or stroke [30].
Treatment with ticagrelor significantly reduced the primary end point (9.8 vs 11.7%, HR 0.84, 95% CI 0.77 - 0.92, p <.001), as well as the individual components of cardiovascular death (4.0 vs 5.1%, p = .001) and myocardial infarction (5.8 vs 6.9%, p = .005), but not stroke (1.5 vs 1.3%, p = .22) [30].
All-cause mortality was reduced with ticagrelor (4.5 vs 5.9%, p <.001) [30]. Overall major bleeding was not increased with ticagrelor (11.6 vs 11.2%, p = .43), but major bleeding not associated with CABG was increased (4.5 vs 3.8%, p = .03) [30].
While these results, including a reduction in all-cause mortality, are very promising, integration of ticagrelor into treatment algorithms and guidelines for patients with ACS will depend on regulatory approval and ongoing analyses.
PROTEASE-ACTIVATING THROMBIN RECEPTOR-1 ANTAGONISTS
The importance of thrombin as a potent mediator of platelet activation is now appreciated. Human platelets express two thrombin receptors, PAR-1 and PAR-4; however, PAR-1 is the predominant receptor [13,51,52]. PAR-4 likely provides some redundancy [13,51]. PAR-1 is present on platelets, endothelial cells, and smooth muscle cells [51]. Thrombin binds to PAR-1 and irreversibly cleaves the amino terminus of the receptor [51,52]. The new amino terminus becomes a tethered ligand that undergoes a conformational change, folding back over the receptor to auto-activate the transmembrane protein [51,52]. Activation of the receptor initiates G-protein-coupled processes ultimately leading to cytoskeletal responses and platelet morphological changes, as well as increased intracellular calcium and decreased cyclic adenosine monophosphate (cAMP), respectively [13]. The result includes activation of the GP IIb/IIIa receptor, as well as release of further activators including ADP, serotonin, and thromboxane A2 [13]. Activated PAR-1 is rapidly uncoupled from signaling, internalized, and rapidly delivered to the lysosome for degradation [52].
Several PAR-1 inhibitors including peptide mimetic PAR-1 antagonists (eg, RWJ 58259), SCH 602539 (intravenous), and bicyclic amidine-based compounds (eg, E-5555) are currently under investigation. One compound, SCH 530348, is currently in phase III studies and as such will be discussed in further detail (Figure 6).
 |
Figure 6. The molecular structure of SCH 530348. |
Mechanism
SCH 530348 binds to the site of PAR-1 auto-activation, preventing the tethered ligand from interacting with the binding domain. This interaction of the thrombin receptor antagonist is therefore specific to the cellular actions of thrombin and does not interfere with thrombin’s role in the coagulation cascade. Other pathways of platelet activation, such as collagen-mediated platelet activation that is important for normal hemostasis, are unaffected. This has raised the hope of providing platelet inhibition to reduce ischemic events without associated excess bleeding [19].
Pharmacokinetics and pharmacodynamics
SCH 530348 was shown to have excellent bioavailability (86%) and no cytochrome P450 (CYP450) enzyme inhibition in human liver microsomes even at levels as high as 90 μM [53]. The compound is primarily metabolized and eliminated by biliary and gastrointestinal routes [53]. The terminal pharmacodynamic half-life is approximately 126 to 269 h [53]. Preclinical testing has suggested an excellent safety margin at the concentrations intended for human studies [53]. It causes no alteration in measures of coagulation, including the activated partial prothrombin time (aPTT), PT, or bleeding time [53]. Preclinical animal studies demonstrated that oral administration of SCH 530348 at a dose >0.1 mg/kg resulted in 100% inhibition of thrombin receptor agonist peptide (TRAP)-induced platelet aggregation for 24 h with partial recovery occurring at 48 h [53]. In subsequent studies using human platelet-rich plasma, SCH 530348 potently inhibited thrombin-mediated platelet aggregation with a 50% inhibitory concentration (IC50) of 47 nM and inhibited TRAP-induced platelet aggregation at an IC50 of 25 nM [53]. These effects were seen without changes to ADP, thromboxane A2, or collagen-induced platelet aggregation. The compound was found to be selective for PAR-1 when tested over a number of ion channels and receptors including PAR-4 receptor [53].
Drug interactions
Medications that are potent inducers or inhibitors of the CYP3A4 isoenzyme may alter drug levels [19].
Side effects and contraindications
While there is a theoretical risk of bleeding, early studies and a phase II study in patients having PCI did not show an increase in TIMI major plus minor bleeding when compared to placebo [54,55]. Other phase II studies have been reported to confirm a favorable safety profile [56,57]. Phase III trials are currently in progress [58,59].
Recent clinical trial findings
Phase II Studies
Three phase II studies of SCH 530348 have been completed with the largest being the Thrombin Receptor Antagonist—Percutaneous Coronary Intervention (TRA-PCI) trial [55]. This trial randomized in a 3:1 ratio 1030 patients undergoing nonurgent PCI or coronary angiography with planned PCI. Patients were to receive a loading dose (10 mg, 20 mg, or 40 mg) or placebo, and those treated with PCI were to continue maintenance dosing for 60 days [55]. During PCI, anticoagulant therapy was administered (unfractionated heparin, low-molecular weight heparin, or bivalirudin); however, planned GP IIb/IIIa antagonist use was prohibited. Provisional use of a GP IIb/IIIa antagonist for thrombotic complications was permitted. Of the 573 subjects who underwent PCI, over 95% received aspirin and clopidogrel (approximately one third received a 600-mg loading dose) [55]. The majority of patients achieved >80% inhibition of TRAP-induced platelet aggregation in 1-2 h after a 40-mg loading dose, and the maintenance dose led to a >80% sustained IPA in 100% of patients at 30 days and 60 days [55].
There was no increase in TIMI major or the combination of TIMI major or minor bleeding, in addition to dual antiplatelet therapy with aspirin and clopidogrel and compared with placebo. More patients randomized to SCH 530348 received blood transfusions (61 vs 46%, absolute rate difference 13.8%, 95% CI -10.2 - 37.8%). As a phase II study, this trial was not designed nor powered to evaluate clinical efficacy; however, numerically fewer patients treated with SCH 530348 experienced a death, major cardiac adverse event, or stroke at any dose (OR 0.67, 95% CI 0.33 - 1.34) compared with those receiving placebo [55]. Two additional phase II studies have supported this favorable safety [56,57].
Phase III Studies
Promising phase II data supported the development of two large phase III trials. These randomized, placebo-controlled trials of SCH 530348 are ongoing. The Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRA•CER) trial is enrolling 12,500 patients with NSTE-ACS and studying SCH 530348 with the administration of a loading dose followed by maintenance therapy (Figure 7) [59]. The Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2 P-TIMI 50) trial enrolled 26,450 patients in an evaluation of SCH 530348 for secondary prevention in patients with history of myocardial infarction, ischemic stroke, or symptomatic PAD and is currently in its follow-up phase (Figure 8) [12,58]. In both studies, SCH 530348 is being administered in combination with standard therapy for a minimum of 1 year. The combined experience from these studies is designed to include almost 40,000 patients.
 |
Figure 7. Schema for the phase III trial of SCH 530348 in acute coronary syndrome (ACS); the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRA•CER) trial. |
 |
Figure 8. Phase III trial of SCH 530348 in patients with atherosclerosis; the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2 P-TIMI 50) trail. |
SUMMARY
Vascular diseases are a leading cause of morbidity and mortality worldwide. While they have distinct clinical manifestations, their acute complications share common pathobiological processes. Platelet activation and aggregation are fundamental components in the development of acute atherothrombotic events. They have become targets for preventive therapies through a variety of mechanisms.
The addition of thienopyridines to aspirin has further reduced the rate of recurrent ischemic events in high-risk patients. There remains, however, residual risk associated with significant morbidity and mortality. In addition, incremental reductions in ischemic events though platelet inhibition have come at the expense of increased bleeding.
New generation agents with improved pharmacokinetic and pharmacodynamic properties, as well as novel therapies exploiting alternative pathways, hold promise for more effective platelet inhibition with improved safety profiles.
REFERENCES
1. WHO. Atlas of heart disease and stroke. Geneva: World Health Organization, 2004.
2. WHO. Global burden of disease study. Geneva: World Health Organization, 2004.
3. WRITING GROUP MEMBERS; Lloyd-Jones D, Adams RJ, Brown TM, et al. Executive summary: heart disease and stroke statistics—2010 update. A report from the American Heart Association. Circulation 2010;121(7):948-954. [Medline]
4. Patrono C, Bachmann F, Baigent C, et al. Expert consensus document on the use of antiplatelet agents. The task force on the use of antiplatelet agents in patients with atherosclerotic cardiovascular disease of the European Society of Cardiology. Eur Heart J 2004;25(2):166-181. [Medline]
5. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non- ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (writing committee to revise the 2002 guidelines for the management of patients with unstable Angina/Non-ST-elevation myocardial infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll Cardiol 2007;50(7):e1-e157. [Medline]
6. Antman EM, Hand M, Armstrong PW, et al. 2007 focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association task force on practice guidelines: developed in collaboration with the Canadian Cardiovascular Society endorsed by the American Academy of Family Physicians: 2007 writing group to review new evidence and update the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction, writing on behalf of the 2004 writing committee. Circulation 2008;117(2):296-329. [Medline]
7. Task Force for Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of European Society of Cardiology, Bassand JP, Hamm CW, et al. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur Heart J 2007;28(13):1598-1660. [Medline]
8. Van de Werf F, Bax J, Betriu A, et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the task force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology. Eur Heart J 2008;29(23):2909-2945. [Medline]
9. Kushner FG, Hand M, Smith SC Jr, et al. 2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update): A report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. Circulation 2009;120(22):2271-2306. [Medline]
10. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without STsegment elevation. N Engl J Med 2001;345(7):494-502. [Medline]
11. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357(20):2001-2015. [Medline]
12. Morrow DA, Scirica BM, Fox KA, et al. Evaluation of a novel antiplatelet agent for secondary prevention in patients with a history of atherosclerotic disease: design and rationale for the thrombinreceptor antagonist in secondary prevention of atherothrombotic ischemic events (TRA 2 degrees P)-TIMI 50 trial. Am Heart J 2009;158(3):335-341.e3. [Medline]
13. Davi G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med 2007;357(24):2482-2494. [Medline]
14. Kulkarni S, Dopheide SM, Yap CL, et al. A revised model of platelet aggregation. J Clin Invest 2000;105(6):783-791. [Medline]
15. Schwertz H, Tolley ND, Foulks JM, et al. Signal-dependent splicing of tissue factor pre-mRNA modulates the thrombogenicity of human platelets. J Exp Med 2006;203(11):2433-2440. [Medline]
16. Offermanns S. Activation of platelet function through G proteincoupled receptors. Circ Res 2006;99(12):1293-1304. [Medline]
17. Serebruany VL, Malinin AI, Eisert RM, Sane DC. Risk of bleeding complications with antiplatelet agents: meta-analysis of 338,191 patients enrolled in 50 randomized controlled trials. Am J Hematol 2004;75(1):40-47. [Medline]
18. Chew DP, Bhatt DL, Sapp S, Topol EJ. Increased mortality with oral platelet glycoprotein IIb/IIIa antagonists: a meta-analysis of phase III multicenter randomized trials. Circulation 2001;103(2):201-206. [Medline]
19. Chackalamannil S. Thrombin receptor (protease activated receptor-1) antagonists as potent antithrombotic agents with strong antiplatelet effects. J Med Chem 2006;49(18):5389-5403. [Medline]
20. Jennings LK. Role of platelets in atherothrombosis. Am J Cardiol 2009;103(3 Suppl):4A-10A. [Medline]
21. Mason WD. Kinetics of aspirin absorption following oral administration of six aqueous solutions with different buffer capacities. J Pharm Sci 1984;73(9):1258-1261. [Medline]
22. Feldman M, Cryer B, Rushin K, Betancourt J. A comparison of every-third-day versus daily low-dose aspirin therapy on serum thromboxane concentrations in healthy men and women. Clin Appl Thromb Hemost 2001;7(1):53-57. [Medline]
23. Seymour RA, Williams FM, Ward A, Rawlins MD. Aspirin metabolism and efficacy in postoperative dental pain. Br J Clin Pharmacol 1984;17(6):697-701. [Medline]
24. Levy G, Tsuchiya T. Salicylate accumulation kinetics in man. N Engl J Med 1972;287(9):430-432. [Medline]
25. Hardman JG, Gilman AG, Limbird LE, Hardman JG, Gilman AG, Limbird LE, eds. Goodman and Gilman’s the Pharmacological Basis of Therapeutics, 9th ed. New York, NY: McGraw-Hill; 1996.
26. Kallen RJ, Zaltzman S, Coe FL, Metcoff J. Hemodialysis in children: technique, kinetic aspects related to varying body size, and application to salicylate intoxication, acute renal failure and some other disorders. Medicine (Baltimore) 1966;45(1):1-50. [Medline]
27. Berger JS, Brown DL, Becker RC. Low-dose aspirin in patients with stable cardiovascular disease: a meta-analysis. Am J Med 2008;121(1):43-49. [Medline]
28. King SB 3rd, Smith SC Jr, Hirshfeld JW Jr, et al. 2007 focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association task force on practice guidelines: 2007 writing group to review new evidence and update the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention, writing on behalf of the 2005 writing committee. Circulation 2008;117(2):261-295. [Medline]
29. Mehta SR, CURRENT OASIS 7: A 2X2 factorial randomized trial of optimal clopidogrel and aspirin dosing in patients with ACS undergoing an early invasive strategy with intent for PCI. Proceedings of the European Society of Cardiology 2009 Congress, August 30-September 2, 2009, Barcelona, Spain.
30. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361(11):1045-1057. [Medline]
31. Bhatt DL, Flather MD, Hacke W, et al. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol 2007;49(19):1982-1988. [Medline]
32. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE steering committee. Lancet 1996;348(9038):1329-1339. [Medline]
33. Savcic M, Hauert J, Bachmann F, Wyld PJ, Geudelin B, Cariou R. Clopidogrel loading dose regimens: kinetic profile of pharmacodynamic response in healthy subjects. Semin Thromb Hemost 1999;25(Suppl 2):15-19. [Medline]
34. Gurbel PA, Bliden KP, Hiatt BL, O’Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003;107(23):2908-2913. [Medline]
35. Matetzky S, Fefer P, Shenkman B, Varon D, Savion N, Hod H. Effectiveness of reloading to overcome clopidogrel nonresponsiveness in patients with acute myocardial infarction. Am J Cardiol 2008;102(5):524-529. [Medline]
36. Cuisset T, Frere C, Quilici J, et al. Benefit of a 600-mg loading dose of clopidogrel on platelet reactivity and clinical outcomes in patients with non-ST-segment elevation acute coronary syndrome undergoing coronary stenting. J Am Coll Cardiol 2006;48(7):1339-1345. [Medline]
37. Gurbel PA, Bliden KP, Butler K, et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation 2009;120(25):2577-2585. [Medline]
38. Ho PM, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 2009;301(9):937-944. [Medline]
39. U.S. Food and Drug Administration. Clopidogrel (marketed as Plavix) and Omeprazole (marketed as Prilosec) - Drug Interaction http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsForHumanMedicalProducts/ucm190848.htm. Accessed 12/15. U.S. Food and Drug Administration, 2009.
40. Bennett CL, Kim B, Zakarija A, et al. Two mechanistic pathways for thienopyridine-associated thrombotic thrombocytopenic purpura: a report from the SERF-TTP research group and the RADAR project. J Am Coll Cardiol 2007;50(12):1138-1143. [Medline]
41. Mega JL, Close SL, Wiviott SD, et al. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med 2009;360(4):354-362. [Medline]
42. Cuisset T, Frere C, Quilici J, et al. Comparison of omeprazole and pantoprazole influence on a high 150-mg clopidogrel maintenance dose the PACA (proton pump inhibitors and clopidogrel association) prospective randomized study. J Am Coll Cardiol 2009;54(13):1149-1153. [Medline]
43. Bhatt DL, ed. The COGENT Trial. Proceedings of the Transcatheter Cardiovascular Therapeutics Conference, September 24, 2009, San Francisco, California. 2009.
44. Payne CD, Li YG, Small DS, et al. Increased active metabolite formation explains the greater platelet inhibition with prasugrel compared to high-dose clopidogrel. J Cardiovasc Pharmacol 2007;50(5):555-562. [Medline]
45. Niitsu Y, Jakubowski JA, Sugidachi A, Asai F. Pharmacology of CS-747 (prasugrel, LY640315), a novel, potent antiplatelet agent with in vivo P2Y12 receptor antagonist activity. Semin Thromb Hemost 2005;31(2):184-194. [Medline]
46. Wallentin L, Varenhorst C, James S, et al. Prasugrel achieves greater and faster P2Y12 receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur Heart J 2008;29(1):21-30. [Medline]
47. Jakubowski JA, Payne CD, Weerakkody GJ, et al. Dosedependent inhibition of human platelet aggregation by prasugrel and its interaction with aspirin in healthy subjects. J Cardiovasc Pharmacol 2007;49(3):167-173. [Medline]
48. Eli Lilly I, IN. Product Information: EFFIENTTHE Oral Tablets, Prasugrel Oral Tablets. 2009.
49. Mega JL, Close SL, Wiviott SD, et al. Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes. Circulation 2009;119(19):2553-2560. [Medline]
50. Husted S, Emanuelsson H, Heptinstall S, Sandset PM, Wickens M, Peters G. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J 2006;27(9):1038-1047. [Medline]
51. Coughlin SR. Protease-activated receptors and platelet function. Thromb Haemost 1999;82(2):353-356. [Medline]
52. Coughlin SR. Thrombin signaling and protease-activated receptors. Nature 2000;407(6801):258-264. [Medline]
53. Chackalamannil S, Wang Y, Greenlee WJ, et al. Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity. J Med Chem 2008;51(11):3061-3064. [Medline]
54. Chintala M, Vemulapalli S, Kurowski S, et al. SCH 530348, a novel oral antiplatelet agent, demonstrated no bleeding risk alone or in combination with aspirin and clopidogrel in cynomolgus monkeys. Arterioscler Thromb Vasc Biol 2008;28:e138-e139. [pdf]
55. Becker RC, Moliterno DJ, Jennings LK, et al. Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomised, double-blind, placebocontrolled phase II study. Lancet 2009;373(9667):919-928. [Medline]
56. Goto S, Yamaguchi T, Ikeda Y, Yamaguchi H, Shimizu K, Jensen P. Phase II trial of the novel antiplatelet agent, SCH 530348, in Japanese patients with non-ST segment elevating acute coronary syndromes (NSTE ACS). Eur Heart J 2008;29(Abstr Suppl):829 (abstract P4767).
57. Shinohara Y, Goto S, Shimizu K, Jensen P. A Phase II safety study of novel antiplatelet agent, SCH 530348, in Japanese patients with prior ischemic stroke. Int J Stroke 2008;3(Suppl 1):139 (Abstract PO01-193).
58. U.S. National Library of Medicine. Trial to assess the effects of SCH 530348 in preventing heart attack and stroke in patients with atherosclerosis (TRAP 2 - TIMI 50) (Study P04737AM2)http://clinicaltrials.gov/ct2/show/NCT00526474. Accessed 07/2009. U.S. National Library of Medicine, 8600 Rockville Pike, Bethesda, MD 20894, June 17, 2009.
59. U.S. National Library of Medicine. Trial to assess the effects of SCH 530348 in preventing heart attack and stroke in patients with acute coronary syndrome (TRA•CER) (Study P04736AM1) http://www.clinicaltrials.gov/ct2/show/NCT00527943. Accessed 7/2009. U.S. National Library of Medicine, 8600 Rockville Pike, Bethesda, MD 20894, June 17, 2009.