Novel Oral Antiplatelet Agents

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Abstract

One of the mainstays of the treatment of acute coronary syndromes is the interference of thrombus formation. Over the past few years, much research has been dedicated to understanding the cellular mechanisms involved in the development of thrombus. This research has resulted in the identification of new pharmacologic targets for drug advancement as well as the development of more sophisticated versions of previously existing medications. In this article, we review the literature on the newest advances in oral antiplatelet therapies.

Disclosure
The authors have no conflicts of interest to declare.
Correspondence
Robert P Giugliano, MD, SM, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115. E: rgiugliano@partners.org
Received date
27 June 2011
Accepted date
18 August 2011

Coronary artery disease remains the leading cause of death in the US and worldwide. Although the incidence of death due to coronary artery disease has declined over the last several years, the prevalence of coronary artery disease remains high, with the American Heart Association (AHA) estimating that over 81 million Americans suffer from cardiovascular disease and 2,200 people dying every day of this disease.1

One of the pivotal events in acute coronary syndrome (ACS) is the formation of a thrombus within a coronary artery, leading to ischaemia and infarction. Research has focused on identifying targets within the process of thrombus generation, with the aim of halting or even reversing the establishment of an occlusive thrombus. The first steps in the development of a thrombus are platelet activation and aggregation, and hence many research efforts have concentrated on the development of antiplatelet agents. This article will discuss the most recent additions to the antiplatelet therapies being used in the treatment of coronary artery disease.

Background

Platelet activation and aggregation play a significant role in the development of an acute vascular event. When injury to the vascular wall occurs (for example, from atherosclerotic plaque rupture), the subendothelial matrix is exposed, revealing von Willebrand factor (vWF) and other adhesive proteins. Platelets instantly adhere to vWF via the glycoprotein (GP) Ib/V/IX receptor, and this interaction sparks the release of various agonists, such as adenosine diphosphate (ADP), thromboxane A2 (TXA2) and thrombin, from secretory storage vesicles within the platelets.2,3 ADP attaches to the P2Y12 receptor on the platelet surface to effect further platelet activation, while thrombin amplifies platelet activation through interaction with G-protein-coupled protease-activated receptors (PARs).4 With the release of these agonists, the platelet activation effect is multiplied exponentially. With activation of a platelet, the GP IIb/IIIa receptor undergoes a conformational change, thereby allowing fibrinogen to bind to the platelet and cross-link adjacent platelets, resulting in the formation of a platelet plug.5

P2Y12 Receptor Antagonists

P2Y12 receptor antagonists act by blocking the interaction between ADP and P2Y12 receptors on the platelet surface, thereby inhibiting platelet activation. Currently available therapies fall under two different categories: thienopyridine inhibitors (for example, ticlopidine, clopidogrel and prasugrel) and non-thienopyridine inhibitors (for example, ticagrelor).

Clopidogrel

Clopidogrel is a thienopyridine derivative that acts to irreversibly bind to the P2Y12 receptor, thereby inhibiting platelet function. It is widely used in the treatment of ST-elevation myocardial infarctions (STEMIs), non-ST-elevation myocardial infarctions, stroke and peripheral arterial disease,6–11 and the combination of aspirin and clopidogrel is considered the standard of care to prevent recurrent thrombosis events after intracoronary stenting.12

While clopidogrel has been in use for over 10 years now, recent data regarding its dosing and metabolism have raised important clinical issues. The first clinical area of concern regards the modest and delayed antiplatelet effect associated with the originally recommended 300 mg loading dose of clopidogrel. Initial studies demonstrated that a loading dose of 300 mg resulted in an inhibition of ADP-stimulated platelet aggregation of only 40–50 % during the first six hours after administration of the drug.13

Furthermore, a post hoc analysis of the Clopidogrel for the reduction of events during observation (CREDO) trial showed a loading dose of 300 mg should be given at least 15 hours before percutaneous coronary intervention (PCI) in order to achieve the desired level of platelet inhibition.14 Certainly, this timeframe is unrealistic when a patient presents with ACS and urgent PCI is needed.

Hence, researchers have recently investigated the effects of higher loading doses of clopidogrel. The Assessment of the best loading dose of clopidogrel to blunt platelet activation, inflammation and ongoing necrosis (ALBION) trial demonstrated that 600 mg of clopidogrel resulted in faster and higher levels of platelet inhibition.15 These promising results prompted the evaluation of more rapid and intense platelet inhibition, with the hope that this would translate into improved clinical outcomes. The Clopidogrel optimal loading doses to reduce recurrent events/optimal antiplatelet strategy for interventions (CURRENT-OASIS-7) trial randomised 25,087 patients with unstable angina or non-ST-elevation ACS (NSTE-ACS) to receive either a high-dose regimen of clopidogrel (600 mg loading dose with 150 mg maintenance dose for one week followed by 75 mg indefinitely) or a low-dose standard regimen (300 mg loading dose with 75 mg maintenance dose).16 Although there was no difference in the primary endpoint (combination of cardiovascular death, recurrent myocardial infarction [MI] and stroke at 30 days) between the high-dose and low-dose regimens (4.2 % versus 4.4 %; p=0.76),17 there were significant differences noted between the two regimens when the post hoc subgroup of patients who received PCI was analysed.17,18 Among the 17,232 patients who received PCI, not only was there a lower rate of the primary endpoint in the group that received the high-dose regimen (4.5 % versus 3.9 %; p=0.039), but there was also a lower rate of stent thrombosis in that group as well (1.3 % versus 0.7 %; p=0.0001). However, these benefits were seen in the presence of a small but significant increase in thrombolysis in MI (TIMI)-defined major bleeding with the high-dose regimen (1.6 % versus 1.1 %; p=0.009). The results of this trial suggest that higher loading doses of clopidogrel followed by higher initial maintenance doses result in better clinical outcomes in patients undergoing PCI for treatment of NSTE-ACS or unstable angina. Although the dose itself certainly influences the effectiveness of clopidogrel, the metabolism of clopidogrel also affects the degree of platelet inhibition. Clopidogrel is a pro-drug that is metabolised to its active form by the CYP450 system of enzymes in the liver. Recent studies have demonstrated that 25–30 % of the population have a genetic variant of CYP2C19, which is one of the isoenzymes within the CYP450 enzyme family. When carriers of this genetic variant are treated with clopidogrel, lower levels of the active metabolite are generated. This results in lower levels of platelet inhibition and increased ischaemic events, including stent thrombosis.19–21

Besides genetic variants, it has been suggested that some drugs, such as proton pump inhibitors (PPIs), may affect clopidogrel metabolism. Initial data on this drug–drug interaction were derived from retrospective analyses of large registries; the results suggested that patients treated with both clopidogrel and a PPI had worse outcomes than patients treated with clopidogrel alone.22 Further investigation revealed that some PPIs, such as omeprazole, act as inhibitors of CYP2C19, and this finding led to the concern that the combination of PPIs and clopidogrel may lead to competitive metabolism of the two drugs by CYP2C19, with the unfortunate result that the conversion of clopidogrel to its active metabolite would be decreased.

Initial small studies corroborated this hypothesis and demonstrated that the combination of PPIs and clopidogrel led to decreased levels of platelet inhibition compared with clopidogrel alone.23 Nevertheless, subsequent larger-scale studies have failed to demonstrate worse clinical outcomes as a result of this biological interaction. A post hoc analysis of a cohort of patients from the Trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-TIMI (TRITON-TIMI 38) showed no difference in clinical outcomes in patients who received PPIs and clopidogrel compared with patients who received clopidogrel alone.24 The Clopidogrel and the optimization of gastrointestinal events (COGENT) trial randomised 3,627 patients undergoing PCI to receive either a combination pill of clopidogrel and omeprazole or clopidogrel alone.25 There was no difference in the primary endpoint (a composite of cardiovascular death, non-fatal MI, recurrent PCI, ischaemic stroke or coronary artery bypass surgery) between the two groups. Omeprazole did, however, reduce gastrointestinal bleeding complications. While these findings are certainly reassuring regarding the use of PPIs and clopidogrel together, extra care should still be taken when prescribing both of these drugs to a patient with a recent stent.

Prasugrel

Although clopidogrel had been shown to be effective in treating ACS, the development of P2Y12 receptor antagonists that would be more potent, have a faster onset of action, and whose activation would not be as susceptible to common genetic variants in the population ensued. Prasugrel is a third-generation irreversible P2Y12 receptor blocker, which has been approved by the US Food and Drug Administration (FDA) for the treatment of ACS. Initial studies in animals showed that prasugrel was 10 times more potent in dose-related platelet inhibition than clopidogrel,26 and initial small studies in humans confirmed the superiority of prasugrel in platelet inhibition when compared with clopidogrel.27 A standard loading dose of prasugrel (60 mg) results in peak platelet inhibition within two hours,28 compared with the six to eight hours needed to achieve the same level of platelet inhibition with 600 mg of clopidogrel.29 Thus prasugrel had a more favourable profile for use prior to PCI, since greater levels of platelet inhibition could be achieved more rapidly, and hence the patient would be at lower risk of stent thrombosis or other cardiovascular events.

An important step in testing whether prasugrel was superior to clopidogrel was to evaluate the degree of platelet inhibition in patients undergoing PCI with prasugrel compared with high-dose clopidogrel. The Prasugrel in comparison to clopidogrel for inhibition of platelet activation and aggregation-TIMI (PRINCIPLE-TIMI 44) trial randomised 201 patients undergoing planned PCI for stable coronary artery disease to receive either prasugrel (loading dose of 60 mg daily with maintenance dose of 10 mg daily) or clopidogrel (loading dose of 600 mg daily with maintenance dose of 150 mg daily).30 Levels of inhibition of platelet aggregation were subsequently tested six hours after the loading dose and 14 days after consistent treatment with the maintenance dose. Compared with clopidogrel, prasugrel resulted in greater levels of inhibition of platelet aggregation both after the initial loading dose (74.8 % versus 31.8 %; p<0.0001) and after treatment with the maintenance dose (61.3 % versus 46.1 %; p<0.0001).

The next step was to evaluate whether this greater degree of platelet inhibition translated into improved clinical outcomes. The TRITON-TIMI 38 took over 13,000 patients who were planned for PCI, including 10,000 patients with moderate-to-high risk NSTE-ACS and 3,000 patients with STEMI, and randomised these patients to receive aspirin in combination with either prasugrel (60 mg loading dose with 10 mg daily maintenance dose) or standard-dose clopidogrel (300 mg loading dose with 75 mg daily maintenance dose).31 Patients who received prasugrel had a 19 % reduction in the incidence of the primary endpoint (a composite of cardiovascular death, MI and stroke) compared with patients who received clopidogrel (9.9 % versus 12.1 %; p<0.001) (see Figure 1).

Subgroup analyses from the TRITON-TIMI 38 demonstrated that the benefits of prasugrel extended to several particular patient populations. Patients receiving prasugrel had better outcomes regardless of the use or disuse of GP IIb/IIIa inhibitors than patients receiving clopidogrel (interaction p=0.83).32 Furthermore, in a post hoc analysis, patients with diabetes mellitus had a greater reduction in cardiovascular events when treated with prasugrel compared with clopidogrel (12.2 % versus 17.0 %; p<0.001).33 Within the group of patients receiving prasugrel, those with diabetes derived a greater clinical benefit from the drug than those without diabetes – in particular, the rate of MI decreased by 40 % in diabetic patients compared with 18 % in non-diabetic patients (p=0.02).

Both patients who received stents and those who did not benefited from prasugrel. In stented patients, prasugrel was associated with a 52 % reduction in the rate of stent thrombosis (1.1 % versus 2.4 %; p<0.001).34 There was no significant difference in cardiovascular death or in the primary endpoint (a composite of cardiovascular death, non-fatal MI or stroke) between prasugrel and clopidogrel in patients not receiving stents; however, there was a trend suggesting that prasugrel reduced the rate of non-fatal MI (9.1 % versus 13.5 %; p=0.11) and there was a significant reduction in the rate of target vessel revascularisation with prasugrel as opposed to clopidogrel (4.0 % versus 10.1 %; p=0.009).36

While these studies demonstrated that prasugrel may be a more potent antiplatelet agent than clopidogrel, the theoretical concern arose as to whether it would fall victim to the same variability in platelet inhibition due to genetic variation in the CYP450 enzyme family that had plagued clopidogrel. Since prasugrel is transformed to its active metabolite via one CYP enzyme-mediated reaction, compared with the two CYP enzyme-mediated processes required for clopidogrel,28 some believed that prasugrel might not be as susceptible to individual variability. Further clinical studies have borne out this hypothesis. In a small study, Jernberg et al. randomised 101 patients with coronary artery disease to receive either prasugrel or clopidogrel for 28 days. Levels of platelet inhibition were measured throughout the course of the study and patients were defined as ‘non-responders’ if they did not achieve >20 % platelet inhibition. There was a significantly higher percentage of non-responders in the clopidogrel group as measured both after loading dose (52 % versus 3 %; p<0.0001) and at the end of a maintenance period of 28 days (45 % versus 0 %; p=0.0007).36 These findings were replicated in the PRINCIPLE-TIMI 44 study, in which it was noted that significantly fewer patients treated with prasugrel met criteria for thienopyridine hyporesponsiveness than patients treated with clopidogrel (0 % versus 49.4 % at six hours after dose; p<0.0001).30 A substudy of TRITON-TIMI 38 was performed, in which 1,466 patients treated with prasugrel also submitted blood for DNA testing to identify the presence of any of five known reduced-function alleles within the CYP gene family, with a particular focus on the reduced-function CYP2C19 allele. Within that group of patients, researchers showed that there was no difference in the composite rate of cardiovascular death, non-fatal MI and stroke between those who carried the CYP2C19 genotype and non-carriers (8.5 % versus 9.8 %; p=0.27),19 again suggesting that CYP genetic variants do not play a significant role in clinical outcomes in patients treated with prasugrel.

In summary, the results of recent studies involving prasugrel suggest that it is more efficacious than clopidogrel, both at a molecular level (as demonstrated by higher levels of platelet inhibition) and at a patient level (as demonstrated by improved clinical outcomes). Unfortunately, this increase in efficacy does have a price in the form of an increased bleeding risk. In the TRITON-TIMI 38, there was a significantly higher incidence of TIMI major bleeding with prasugrel than with clopidogrel (2.4 % versus 1.8 %; p=0.03), although there was no difference between the rates of intracranial haemorrhage (0.3 % versus 0.3 %; p=0.74).31 Given these findings, the investigators performed a series of post hoc analyses in an attempt to further identify which patients were at highest risk of an adverse outcome with prasugrel. Three subgroups of patients were identified as having either no net clinical benefit or even a net harm from treatment with prasugrel: patients with a history of prior stroke or transient ischaemic attack (hazard ratio 1.54; 95 % confidence interval [CI] 1.02–2.32; p=0.04); patients who were 75 years or older (hazard ratio 0.99; 95 % CI 0.81–1.21; p=0.92); and patients who weighed less than 60 kg (hazard ratio 1.03; 95 % CI 0.69–1.53; p=0.89). Based on these results, prasugrel is contraindicated in patients with a history of cerebrovascular events, and caution should be taken when administering this drug to patients aged 75 or older and patients weighing less than 60 kg. These findings are reflected in the recommendation that a lower dose (5 mg) of prasugrel be considered in selected patients who are at a higher risk of bleeding (e.g., the elderly or patients with low body weight).

Ticagrelor

Another limitation common to both prasugrel and clopidogrel is that they act irreversibly at the P2Y12 receptor site for the lifetime of the platelets (i.e., seven to 10 days), and this can lead to more difficulty in managing bleeding complications as well as the need to delay surgery in patients on these medications to reduce the risk of bleeding. Thus ticagrelor, a non-thienopyridine P2Y12 receptor inhibitor that reversibly blocks ADP binding to the P2Y12 receptor, thereby inhibiting platelet aggregation, is a welcome addition to the oral antiplatelet arsenal. Initial studies demonstrated that the mean time needed to achieve maximum platelet inhibition after ticagrelor administration was two hours compared with the 7.8 hours needed with clopidogrel.29 Furthermore, when compared with clopidogrel (300 mg loading dose followed by 75 mg daily), patients receiving a variety of doses of ticagrelor (90 mg twice daily or 180 mg twice daily) attained higher absolute levels of platelet inhibition both within four hours after the loading dose (p<0.001) and at 12 weeks after maintenance dosing (p<0.004).37 As would be expected given the reversibility of ticagrelor, the offset of platelet inhibition is also more rapid with ticagrelor than with clopidogrel. In the ONSET/OFFSET study, researchers found that, even though levels of platelet inhibition were higher with ticagrelor (95 %) than with clopidogrel (64 %), it took almost twice as long for those levels to decrease to 10 % in the clopidogrel group (109 hours versus 196 hours, respectively).29

Phase II trials evaluating ticagrelor yielded promising results regarding the safety of this agent even with its high potency. The Dose confirmation study assessing antiplatelet effects of AZD6140 versus clopidogrel in non-ST-segment elevation MI (DISPERSE-2) compared the safety of two different doses of ticagrelor (180 mg twice daily and 90 mg twice daily) with clopidogrel in 990 patients with NSTE-ACS. At four weeks, there was no difference in the rates of major or minor bleeding between either the 90 mg or 180 mg dose of ticagrelor and clopidogrel (7.1 %, 5.1 % and 6.9 %, respectively; p=0.91 and p=0.35, respectively, versus clopidogrel).38 However, there was an increased incidence of ventricular pauses (over 2.5 seconds) in patients taking 180 mg ticagrelor compared with those taking clopidogrel (9.9 % versus 4.3 %; p=0.01).

The Platelet inhibition and patient outcomes (PLATO) trial was the first large-scale trial to evaluate the effects of ticagrelor on clinical outcomes in patients with coronary artery disease. In this trial, 18,624 patients, who presented to hospital with either STEMI or NSTE-ACS, were randomised to receive either ticagrelor (180 mg loading dose with 90 mg twice daily as maintenance dosing) or clopidogrel (300–600 mg loading dose with 75 mg daily for maintenance dosing). At 12 months, patients receiving ticagrelor had a significantly lower incidence of the primary endpoint (a composite of cardiovascular death, MI or stroke) when compared with patients taking clopidogrel (9.8 % versus 11.7 %; p<0.001), as well as a significantly lower rate of all-cause mortality (4.5 % versus 5.9 %; p<0.001)39 (see Figure 2). This represents an unusual finding, since no other antiplatelet agent, with the exception of aspirin, has been shown to reduce mortality in ACS patients. Analyses of the subset of patients with ACS who were treated with an early invasive strategy also demonstrated the superiority of ticagrelor over clopidogrel (9 % versus 10.7 % incidence of primary endpoint; p=0.0025).40

With regard to the safety of ticagrelor, findings were consistent with the DISPERSE-2. There was no difference in overall major bleeding between the ticagrelor and clopidogrel groups (11.6 % versus 11.2 %; p=0.43), although there was an increase in major bleeding not associated with coronary artery bypass grafting with ticagrelor (4.5 % versus 3.8 %; p=0.03).40 Interestingly, the increase in bleeding associated with non-coronary artery bypass grafting surgery with ticagrelor use was similar in magnitude to non-coronary artery bypass grafting surgery bleeding observed with prasugrel in the TRITON-TIMI (2.4 % with prasugrel versus 1.8 % with clopidogrel; p=0.03).31 With regard to other side effects, there was a higher incidence of dyspnoea with ticagrelor (13.8 % versus 7.8 %; p<0.001) as well as a higher rate of ventricular pauses at one week (5.8 % versus 3.8 %; p=0.01),although this finding was not present at 30 days (2.1 % versus 1.7 %; p=0.52).40 There were no differences in syncope, pacemaker insertion or heart block between the two groups.

Taken together, these results on the safety and efficacy of ticagrelor suggest that it is a potent antiplatelet agent with a reasonable safety profile that should become an important agent in the treatment of ACS. Nevertheless, the drug has yet to obtain FDA approval and remains under review. The approval of ticagrelor has been slowed in part due to findings of significant geographic heterogeneity in the results of the PLATO trial, which demonstrated a slightly higher, albeit non-significant, rate of the primary endpoint in North America (11.9 % versus 9.6 %; p=non-significant). To address this concern, a large, multicentre, randomised controlled trial – Prevention with ticagrelor of secondary thrombotic events in high-risk patients with prior acute coronary syndrome-TIMI (PEGASUS-TIMI 54) – in which ticagrelor will be compared with placebo in patients with a history of cardiovascular disease, is currently under way and should provide substantial data regarding the safety and efficacy of ticagrelor.41 Of the 21,000 patients planned to be enrolled in the PEGASUS-TIMI 54 trial, approximately 20 % will be enrolled in the US.

Besides the clinical benefits of ticagrelor as demonstrated in the PLATO study, another advantage of ticagrelor over clopidogrel is that it does not require metabolic activation from the CYP450 enzyme system, which in theory would essentially eliminate the chance that genetic variants within the CYP450 family could lead to non-responders, as has been the case with clopidogrel. The Response to ticagrelor in clopidogrel non-responders and responders and effect of switching therapies (RESPOND) study was designed to directly assess whether patients who were non-responders to clopidogrel would have sufficient platelet inhibition with ticagrelor. Of the 98 patients enrolled in this study, 40 were identified as non-responders to clopidogrel using light transmittance aggregometry and 57 were classified as responders. Patients were randomly assigned to receive either clopidogrel or ticagrelor for the first two weeks of the study. At 14 days, all non-responders switched treatment and levels of platelet inhibition were evaluated. Among non-responders, inhibition of platelet aggregation was significantly higher in patients treated with ticagrelor than in patients treated with clopidogrel (p<0.05).42 Furthermore, in all patients, the levels of platelet inhibition increased significantly when patients were switched from clopidogrel to ticagrelor (35 % versus 59 %; p<0.0001). These results suggest that, similarly to prasugrel, patients who are non-responders to clopidogrel have an effective alternative treatment with ticagrelor.

Protease-activated Receptor-1 Antagonists

Over the last 10 years, the identification of a series of thrombin receptors on the platelet surface, known as protease-activated receptors (PARs), with PAR-1 being the principal receptor,43,44 has led to a new target for antiplatelet therapy. When thrombin binds to PAR-1, it causes a conformational change in the protein, which leads to the activation of a G-protein-mediated cascade of reactions that ultimately results in a morphological change in the platelet structure.2,44 The change in structure of the platelet sparks further release of platelet activators (e.g., ADP and TXA2) and also leads to the activation of the GP IIb/IIIa receptor (see Figure 3). Recently, compounds that act to specifically bind to, and inhibit the actions of, PAR-1 have been developed and investigated.

Vorapaxar

Vorapaxar is a low molecular weight competitive PAR-1 antagonist that interacts only with PAR-1 and thus has no effect on the other actions of thrombin (i.e., within the coagulation cascade). Initial animal studies demonstrated that vorapaxar can cause total inhibition of thrombin receptor agonist peptide (TRAP)-induced platelet aggregation.45 There was no evidence of an effect on the coagulation cascade with vorapaxar, as demonstrated by no changes in bleeding time, prothrombin time or activated partial thromboplastin time in these experiments.

Given that the drug seems to be a potent antiplatelet agent, phase II studies have been conducted to further evaluate its safety. In the Thrombin receptor antagonist PCI (TRA-PCI) study, over 1,000 patients who were undergoing non-urgent PCI were assigned to receive either vorapaxar at varying doses (loading doses of 10 mg, 20 mg or 40 mg and maintenance doses of 0.5 mg, 1.0 mg or 2.5 mg daily) or placebo in addition to standard aspirin and clopidogrel.46 Patients received standard anticoagulant therapy during PCI (unfractionated heparin, low molecular weight heparin, direct thrombin inhibitors). Patients who were planned for the use of GP IIb/IIIa inhibitors were excluded from the trial, although conditional use of the medication was allowed as needed. Measures of platelet inhibition were obtained and patients were monitored over the subsequent two months for evidence of bleeding. There was no difference in the rates of TIMI major or minor bleeding between the patients receiving any of the loading doses of vorapaxar (2 % for 10 mg versus 3 % for 20 mg versus 4 % for 40 mg versus 3 % with placebo; p=0.58) or any of the maintenance doses when compared with the patients receiving placebo (2 % for 0.5 mg versus 4 % for 1 mg versus 3 % for 2.5 mg versus 3 % with placebo; p=0.76). In testing for TRAP-mediated platelet aggregation, over 90 % of patients had achieved greater than 80 % platelet inhibition by two hours with the 40 mg loading dose of vorapaxar. At all of the maintenance doses, over 90 % of patients had greater than 80 % platelet inhibition both at the 30- and 60-day marks.

The favorable safety profile as well as laboratory evidence for potent antiplatelet activity paved the way for the development of two phase III trials, which are currently under way. The Thrombin receptor antagonist in secondary prevention of atherothrombotic ischemic events (TRA 2°P-TIMI 50) trial randomised over 25,000 patients with a history of MI, ischaemic stroke or peripheral arterial disease to receive either vorapaxar or placebo in combination with standard therapy for a minimum of one year.48 This trial is currently in its follow-up phase and is monitoring patients for the development of cardiovascular death, MI, stroke and urgent coronary revascularisation as well as for any bleeding complications. In addition, the Trial to assess the effects of vorapaxar in preventing heart attack and stroke in patients with acute coronary syndrome (TRA*CER) randomised 10,000 high-risk patients with NSTE-ACS to receive either vorapaxar or placebo in combination with standard medical therapy for at least one year, and followed patients to evaluate the occurrence of cardiovascular death, MI, stroke, recurrent ischaemia or urgent coronary revascularisation.49 Evaluation of both of these trials by the independent Drug Safety Monitoring Board has found an increase in intracranial haemorrhage in patients with a history of stroke, which resulted in the early closing of TRA*CER and an alteration of the TRA 2°P-TIMI 50 trial such that patients with a prior stroke were required to stop the study drug. Results for both of these studies are expected in late 2011 or early 2012 (see Figure 4).

Atopaxar

Atopaxar is another small molecule that acts to inhibit the binding of thrombin to PAR-1 on the platelet surface. Similarly to vorapaxar, this agent has been shown to inhibit TRAP-induced platelet aggregation in vitro.50 In addition, studies have also shown that this drug may also inhibit platelet activity beyond just PAR-1 antagonism. In plasma samples from healthy volunteers as well as volunteers with stable coronary artery disease, atopaxar mildly inhibited ADP-induced and collagen-induced platelet aggregation at a rate of 10–15 % (p<0.05), and these effects were still seen in patients pre-treated with either aspirin, clopidogrel, or a combination of both of these medications.49 These findings suggest that atopaxar may be useful as a sole agent or as an adjunct to conventional antiplatelet therapy with aspirin and clopidogrel, although the non-specific nature of the drug does have the potential to increase the risk of bleeding. Recently, the Lessons from antagonizing the cellular effects of thrombin-acute coronary syndromes (LANCELOT-ACS) phase II trial investigated the safety of atopaxar in patients with ACS as well as stable coronary artery disease, and found that atopaxar shows no significant increase in major bleeding when compared with placebo (3.08 % versus 2.17 %,respectively; p=0.63)51 although overall bleeding rates by CURE criteria did tend to be higher with atopaxar (3.9 % versus 0.6 %; p=0.03).51 Investigators were encouraged to see that major cardiac events were numerically, although not statistically, lower in subjects receiving atopaxar and that adverse effects (including gastrointestinal symptoms and liver function abnormalities) did not differ significantly between the two groups.51 Further larger-scale phase III trials are being organised to assess the true efficacy and safety of atopaxar.

Conclusions

Cardiovascular disease continues to be a major health concern both in the US and worldwide, and antiplatelet agents remain one of the cornerstones of treatment for both unstable and stable coronary artery disease. As the scientific and medical communities gain greater understanding of the development of acute thrombotic events at a molecular level, more potent and safer drugs are being developed that are aimed at novel targets within the process of thrombus formation. Since platelets play such a central role in thrombus formation, novel oral antiplatelet agents are among the most exciting therapies currently being developed in the field of atherothrombosis. Table 1 summarises the properties of these novel agents. As these new agents are tested and released onto the market when deemed safe and effective, hopefully patient outcomes in acute coronary syndromes will continue to improve.

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