Curr Treat Options Cardio Med (2015) 17:23 DOI 10.1007/s11936-015-0383-0

Coronary Artery Disease (D Feldman and V Voudris, Section Editors)

Novel Antiplatelet Agents in Cardiovascular Medicine Rahil Rafeedheen, MD Kevin P. Bliden, MBA Fang Liu, MD Udaya S. Tantry, PhD Paul A. Gurbel, MD* Address * Sinai Center for Thrombosis Research, Sinai Hospital of Baltimore, 2401 W. Belvedere Ave., Baltimore, MD 21215, USA Email: [email protected]

* Springer Science+Business Media New York 2015

This article is part of the Topical Collection on Coronary Artery Disease Keywords Antiplatelet therapy I Aspirin I P2Y12 receptor inhibitor I Thrombin receptor I Intracellular signaling I PAR-1 inhibitors

Opinion statement Dual antiplatelet therapy with aspirin and a P2Y12 receptor blocker, particularly clopidogrel, has been the standard of therapy for secondary prevention in patients with acute coronary syndromes and patients treated with percutaneous coronary intervention. More potent P2Y12 inhibitors such as ticagrelor and prasugrel are associated with better pharmacodynamic effect and improved clinical outcomes but are associated with an increased risk of bleeding compared to clopidogrel. In addition, the observation of treatment failure in ~10 % of high-risk patients treated with aspirin and a potent P2Y12 inhibitor is another major concern. Personalized antiplatelet therapy based on therapeutic winnow concept for P2Y12 receptor blocker may facilitate the balance between reducing ischemic events and avoiding bleeding events, thereby improving net clinical outcome. New class of agents like vorapaxar has been approved by the FDA to reduce thrombotic events in patients with a history of myocardial infarction or with peripheral arterial disease. In addition, new P2Y12 receptor and protease-activated receptor (PAR)-1 receptor antagonists and agents targeting intracellular signaling downstream from G proteincoupled receptors are among the novel strategies under investigation to prevent arterial ischemic event occurrences.

Introduction Platelet-rich thrombus formation at the site of arterial plaque rupture, fissuring, or endothelial cell erosion is a

major cause of ischemic event occurrences including myocardial infarction (MI), stent thrombosis (ST), and

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ischemic stroke (IS) [1, 2]. Platelet activation and aggregation play a critical role in the development of latter atherothrombotic events. Therefore, antiplatelet therapy is an important strategy in the primary and secondary prevention of coronary artery disease (CAD) (Table 1).

Currently, the four different classes of antiplatelet agents available are cyclooxygenase-1 (COX-1) inhibitors, adenosine diphosphate receptor (P2Y12) inhibitors, thrombin receptor inhibitors, and glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors.

Dual antiplatelet therapy Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor blocker, particularly clopidogrel, has been the standard of therapy for secondary prevention in patients with acute coronary syndromes (ACSs) and patients treated with percutaneous coronary intervention (PCI). The latter two classes of antiplatelet agents inhibit platelet activation and aggregation through separate but complementary pathways. By irreversibly inhibiting the cycloxoygenase-1 (COX-1) enzyme, aspirin prevents thromboxane A2 generation and subsequent thromboxane A2 (TxA2)-induced platelet activation and aggregation. Aspirin is an established COX-1 inhibitor and a bedrock therapy for primary prevention [3]. However, recently, the FDA has reviewed the currently available data and does not believe the current evidence base that supports the general use of aspirin for primary prevention of MI and stroke. Specifically, FDA suggested that aspirin should not be routinely used for primary prevention due to serious risks including an increased risk of cerebral and gastrointestinal (GI) bleeding [4]. Continuous downstream signaling from the P2Y12 receptor is critical for sustained platelet activation and aggregation and the formation of a stable thrombus at the site of plaque rupture. Clopidogrel, prasugrel, and ticagrelor belong to the class of P2Y12 receptor inhibitors. Based on significantly reduced composite endpoint of death, MI, and stroke with clopidogrel plus aspirin therapy compared to aspirin monotherapy, a non-selective or one-size-fits-all DAPT is widely recommended to prevent recurrent ischemic events in patients with high-risk CAD [3]. However, subsequent pharmacodynamic studies reveled limitations of clopidogrel therapy such as a delayed antiplatelet response, overall modest degree of steady state platelet inhibition (∼30–50 %), response variability with substantial percentage of patients exhibiting either a limited or no response (clopidogrel nonresponsiveness or clopidogrel resistance), irreversible platelet inhibition, and inter-individual variability in the recovery of platelet function [5–7]. It was further demonstrated that nearly 35 % of patients have high on-treatment platelet reactivity during clopidogrel therapy (HPR), and HPR has been strongly associated with recurrent ischemic event occurrence in patients treated with PCI [6, 7]. The latter demonstration of HPR in clopidogrel-treated patients provided a strong rationale for the development of potent P2Y12 receptor blockers such as prasugrel and ticagrelor. Clopidogrel and prasugrel are thienopyridine prodrugs that require hepatic metabolism for conversion to an active metabolite. The active metabolite irreversibly binds to the platelet P2Y12 receptor and prevents platelet activation and aggregation induced by adenosine diphosphate (ADP) [8].

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Table 1. Current and novel antiplatelet agents Antiplatelet agent Cyclooxygenase-1 and thromboxane A2 receptor inhibitors 1. Aspirin (acetyl salicylic acid)

2. Terutroban

3. Picotamide

4. Ridogrel

5. Terbogrel 6. Ramatroban P2Y12 receptor Inhibitors 1. Ticlopidine 2. Clopidogrel

3. Prasugrel

4. Ticagrelor

5. Elinogrel 6. Cangrelor

7. AZD1283 8. Diadenosine 5′,5″″ -P1,P4-dithio-P2, P3-chloromethylenetetraphosphate (Ap4A) Protease-activated receptor-1 (PAR-1, thrombin receptor) inhibitors 1. Vorapaxar 2. PZ128

Properties

Target population

- Cyclooxygenase-1 inhibitor - Irreversible indictor - Orally active agent - Thromboxane A2 receptor inhibitor - Orally active agent

- Primary and secondary prevention of cardiovascular disease patients

- Thromboxane A2 receptor and thromboxane A2 synthase inhibitor - Orally active agent - Thromboxane A2 receptor and thromboxane A2 synthase inhibitor - Orally active agent - Thromboxane A2 receptor inhibitor - Orally active agent - Thromboxane A2 receptor inhibitor - Orally active agent - Oral, irreversible, prodrug - Oral, irreversible, prodrug - Better safety profile compared to ticlopidine - Oral, irreversible, prodrug - Superior pharmacodynamic and clinical efficacy compared to clopidogrel - Orally active, reversibly binding, agent - Superior pharmacodynamic and clinical efficacy compared to clopidogrel - Both oral and intravenous, reversible agent - Intravenous, reversible agent - Rapid onset and offset of pharmacodynamic effects - Unknown - Unknown

- Orally active with slow dissociation from the receptor - A pepducin (lipidated peptide) that specifically targets the cytoplasmic surface of PAR-1 receptors

- Cardiovascular disease patients (discontinued in Europe and the USA) - Cardiovascular disease patients - Peripheral arterial disease patients - Cardiovascular disease patients

- Cardiovascular disease patients - Cardiovascular disease patients

- Secondary prevention of coronary artery disease patients - Secondary prevention of coronary artery disease patients - Secondary prevention of coronary artery disease patients - Secondary prevention of coronary artery disease patients - Discontinued due to side effects - Coronary artery disease patients undergoing percutaneous coronary intervention - Coronary artery disease patients - Coronary artery disease patients

- Coronary artery disease patients - Coronary artery disease patients undergoing percutaneous coronary intervention

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Table 1. (Continued) Antiplatelet agent

Properties

Target population

- Intravenous, reversible agent with fast onset and offset of action Collagen receptor inhibitors 1. Revacept Platelet intracellular signaling targets 1. AZD6482

2. YM-254890

- Glycoprotein (GP)VI receptor inhibitor - Orally active agent

- Coronary artery disease patients

- PI3Kβ inhibitor - Rapid onset and short half-life. - Reversible agent - Gq inhibitor

- Coronary artery disease patients

- Coronary artery disease patients

Prasugrel Prasugrel, a third-generation thienopyridine, produces a more rapid and superior platelet inhibition as compared to clopidogrel [9, 10]. Compared to clopidogrel therapy, prasugrel therapy is associated with lesser influence of single nucleotide polymorphisms of cytochrome P450 (CYP) isoenzymes associated with the metabolism of prasugrel and lesser interactions with other drugs metabolized by same CYP isoenzymes, resulting in lesser inter-individual variation in its antiplatelet effect and lower prevalence of HPR [10]. In the TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel–Thrombolysis In Myocardial Infarction) trial, 13,608 patients with acute coronary syndromes undergoing PCI were treated with prasugrel versus clopidogrel on top of aspirin for 12 months. Overall, prasugrel therapy demonstrated a significant reduction in the primary endpoint of cardiovascular death, non-fatal MI, or non-fatal strokes (7.4 vs. 9.7 %, hazard ratio (HR)=0.81, p=0.0004) [11•]. Importantly, there was a 24 % relative reduction in MI and a 52 % reduction in stent thrombosis with prasugrel therapy, but no significant difference in cardiovascular death or overall mortality. However, prasugrel therapy was associated with 32 % relative increase in non-coronary artery bypass grafting (CABG) thrombolysis in myocardial infarction (TIMI) major bleeding events (2.4 vs. 1.8 %, HR=1.32, p=0.03). A favorable clinical benefit/risk profile with prasugrel therapy was observed in patients with ST segment elevation myocardial infarction (STEMI) or diabetes as compared to overall population [12•]. There are significant observations in some subgroups that influenced the recommendations and prasugrel’s use in clinical practice. Based on higher risk for serious bleeding complications including intracranial hemorrhage and lower efficacy compared to overall population, prasugrel therapy is not recommended in patients with a history of stroke or transient ischemic attack. Adverse outcomes of prasugrel outweighed the benefits in certain groups of patients including older patients above 75 years, patients who weigh G60 kg, and patients with a prior history of stroke or transient ischemic attack. A maintenance dose of 5 mg has been approved by the FDA in patients who weigh G60 kg due to a potential increased risk of bleeding, although the

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effectiveness and safety of the 5-mg dose have not been studied prospectively. In patients aged ≥75 years, prasugrel is generally not recommended because of the increased risk of fatal and intracranial bleeding. In a sub-analysis of TRITON-TIMI trial, irrespective glycoprotein (GP)IIb/ IIIa inhibitors’ use, prasugrel therapy was associated with significant reduction in the risk of cardiovascular events and the adjunctive use of GPIIb/IIIa inhibitors did not increase the relative risk of bleeding with prasugrel as compared to clopidogrel [13]. In the TRILOGY-ACS (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel– Thrombolysis In Myocardial Infarction) trial, prasugrel therapy was compared to clopidogrel therapy in 9326 patients with ACS managed medically without revascularization. There were no differences in the primary endpoint of 17month cardiovascular death, MI, or stroke among patients under the age of 75 years between prasugrel and clopidogrel groups (13.9 vs. 16.0 %) and also in the Global Use of Strategies to Open Occluded Arteries (GUSTO) severe and TIMI bleeding. At this time, prasugrel is not recommended for the treatment of ACS managed without revascularization [14]. In the ACCOAST (A Comparison of Prasugrel at PCI or Time of Diagnosis of Non-ST Elevation Myocardial Infarction) trial, the timing of prasugrel administrations immediately at the time of diagnosis versus before initiation of PCI was compared in 4033 non-STEMI (NSTEMI) patients. In this trial, there was no difference in the composite endpoint of cardiovascular death, MI, stroke, or urgent revascularization, but an increased risk of bleeding (pretreatment (2.6 %) vs. no pretreatment (1.4 %)) was associated with early prasugrel administration with more major and life-threatening bleeding complications not related to CABG surgery in the pretreatment group [15].

Ticagrelor Ticagrelor (AZD6140), a cyclopentyltriazolopyrimidine derivative, is an oral, reversibly binding, direct-acting P2Y12 inhibitor [16]. Pharmacodynamic studies involving stable CAD patients demonstrated that ticagrelor therapy was associated with a rapid onset of action, a greater level of inhibition that persisted during maintenance therapy, a more rapid offset of pharmacodynamic action compared with clopidogrel, and a greater platelet inhibition compared with clopidogrel in both clopidogrel responders and nonresponders [17, 18]. The PLATO (a study of PLATelet inhibition and patient Outcomes) trial was a phase III randomized, multicenter, double-blind study designed to evaluate the efficacy of ticagrelor compared with clopidogrel for the prevention of vascular events and death in patients with ACS (n=18,624). Ticagrelor therapy was associated with a significant reduction in the primary efficacy endpoint of cardiovascular death, MI, or stroke compared to clopidogrel at 30 days (4.8 vs. 5.4 %, p=0.045), and the superiority of ticagrelor was maintained throughout 12 months with a 16 % relative risk reduction (9.8 vs. 11.7 %, HR=0.84, pG0.001). Cardiovascular death (5.1 % clopidogrel and 4.0 % ticagrelor, p= 0.001) and MI (6.9 % clopidogrel and 5.8 % ticagrelor, p=0.005) but not stroke (1.5 vs. 1.3 %, p=0.22) were significantly reduced by ticagrelor treatment. The mortality benefit seen with ticagrelor is unique among other antiplatelet agents undergoing trials. There was a 33 % reduction in definite stent thrombosis

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Curr Treat Options Cardio Med (2015) 17:23 associated with ticagrelor therapy (1.3 vs. 1.9 %, HR=0.67, p=0.02). Benefits associated with ticagrelor versus clopidogrel was consistent regardless of whether the management strategy selected upfront was invasive or conservative, including age, risk factors, body weight, prior medical history (including TIA or stroke), type of ACS, and genotype [11•]. However, clinical benefit associated with ticagrelor treatment was absent in patients with unstable angina and, most importantly, among the North American patient population enrolled in the PLATO trial. The latter has been attributed to the concomitant use of high-dose aspirin (9100 mg/day). Therefore, a low-dose aspirin (G100 mg/day) with ticagrelor has been recommended. Ticagrelor is associated with bradycardia and ventricular pauses, and therefore, caution needs to be exercised while using concomitant atrioventricular nodal blocking agents. Dyspnea is another main concern, and in PLATO, 14.5 % of patients (n=1339) during ticagrelor therapy and 8.7 % of patients (n=798) during clopidogrel therapy developed dyspnea [19]. In a recent study of 1826 patients with ongoing STEMI of G6-h duration, prehospital (in the ambulance) versus in-hospital (in the catheterization lab) treatment with ticagrelor was studied. This study revealed that pre-hospital ticagrelor administration appeared to be safe in STEMI patients but was not associated with improved pre-PCI coronary reperfusion [20•].

Personalized antiplatelet therapy Although clopidogrel has been a widely recommended P2Y12 receptor blocker, major pharmacodynamic limitations such as slow onset of action and presence of HPR phenotype in 35 % of clopidogrel-treated patients with its independent association with post-PCI ischemic event occurrences provided a strong rationale to treat high-risk HPR patients with more potent P2Y12 blockers such as prasugrel and ticagrelor. In the multinational prospective registry study, ADAP T-DES (Assessment of Dual AntiPlatelet Therapy with Drug-Eluting Stents), which involved 98500 patients (~50 % of patients with ACS), 43 % of patients met the criteria of HPR (9208 P2Y12 reaction units (PRU)) which was independently associated with the risk of definite/probable stent thrombosis at 0– 30 days (HR=3.90, pG0.0001), 30 days–1 year (HR=1.55, p=0.23), and 2 years (HR=1.84, p=0.009); 9208 PRU identified the risk for definite/probable ST in 35 % of patients. The relationship between HPR and ischemic event occurrences was more pronounced in patients with ACS compared to patients with stable CAD (adjusted HR=2.60, pG0.005, and adjusted HR=1.44, p=0.47, respectively). In addition, HPR was inversely associated with bleeding [21, 22]. These observations provided a strong rationale for the periprocedural measurement of platelet reactivity during clopidogrel therapy and to treat high-risk patients with HPR with higher-dose clopidogrel, prasugrel, or ticagrelor to improve clinical outcomes. However, randomized trials of personalizing P2Y12 receptor blocker therapy based on platelet function testing have failed to demonstrate that personalized antiplatelet therapy is effective in reducing ischemic event occurrences. The potential reason is that the latter randomized trials enrolled low-risk patients and mainly used high-dose clopidogrel to improve clinical outcomes. A reasonable strategy is to assess platelet function in high-risk clopidogreltreated patients and use more potent P2Y12 receptor therapy selectively in the

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patient with HPR. However, it should be noted that clopidogrel is effective in patients without HPR (i.e., 65 % of patients) and the latter low-risk patients can be optimally treated with less expensive generic clopidogrel. Furthermore, unselected therapy with the new P2Y12 receptor blockers is associated with increased bleeding. In addition, the therapeutic window concept for the P2Y12 receptor blocker therapy may facilitate the balance between reducing ischemic events and avoiding bleeding events, thereby improving net clinical outcome [23].

Cangrelor A major limitation of the currently available oral P2Y12 receptor blocker is slow onset and slow offset of action with at least 5 days required to recover platelet function. In this line, an agent with rapid onset as well as rapid offset of action is desirable in high-risk patients undergoing PCI or surgery. Cangrelor is a parenteral ATP analog with a short half-life (3–6 min), rapid onset/offset of action, and dose-dependent and predictable pharmacodynamic effects [24]. Cangrelor directly, reversibly, and competitively inhibits ADP binding to the P2Y12 receptor. It was studied in the CHAMPION (Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition) trials for acute therapy in patients undergoing PCI [25–27]. In the CHAMPION-PCI trial, 8716 patients with stable angina, unstable angina, or NSTEMI were randomly assigned to receive a bolus and infusion of cangrelor (continued for 2 h or the duration of the PCI procedure, whichever was longer) followed by transition to clopidogrel or to receive clopidogrel 600 mg loading dose (LD) within 30 min of the start of PCI. In this trial, cangrelor therapy was associated with a similar rate of the primary endpoint of composite of death, MI, or ischemia-driven revascularization (IDR) at 48 h (7.5 vs. 7.1 %, odds ratio (OR)=1.05, p=0.59) but significantly increased risk of GUSTO severe or TIMI major bleeding and a trend toward increased ACUITY major bleeding (3.6 vs. 2.9 %, OR=1.26, p=0.06) compared to placebo. Importantly, the median time from hospital admission to PCI was only 6.3 h, and the latter may have reduced the specificity of postprocedure cardiac biomarkers to detect a true recurrent MI in patients who presented with an ACS [25]. In the CHAMPION-PLATFORM trial, 5362 patients with stable angina/ ischemia, unstable angina, or NSTEMI who had not been treated with a thienopyridine were randomly treated with a bolus and infusion of cangrelor within 30 min of PCI followed by transition to clopidogrel or to receive a clopidogrel 600 mg LD immediately after the procedure. Similar to the previous trial, there was no significant reduction in the rate of the primary endpoint of death, MI, or IDR at 48 h with cangrelor therapy (7.0 vs. 8.0 %, OR=0.87, p= 0.17). However, cangrelor therapy was associated with reduced prespecified secondary endpoints of stent thrombosis (0.2 vs. 0.6 %, OR=0.31, p=0.02), death from any cause (0.2 vs. 0.7 %, OR=0.33, p=0.02), and the post hoc exploratory endpoint of death, Q-wave MI, and IDR (0.9 vs. 1.6 %, p=0.02) [26]. Similarly, in a post hoc pooled analysis of the CHAMPION-PCI and CHAMPION-PLATFORM trials with the universal definition of MI, there was a significant reduction in the primary endpoint of death, MI, and IDR with cangrelor (OR=0.82, p=0.037) and a significant reduction in ST (OR=0.44, p= 0.018) [28]. The latter hypothesis-generating findings formed the basis for the CHAMPION-PHOENIX trial.

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In the CHAMPION-PHOENIX trial, 11,145 patients with stable CAD or ACS received either bolus and infusion of cangrelor followed by transition to clopidogrel or clopidogrel 300 or 600 mg loading dose (LD) [29]. Cangrelor therapy was associated with a significantly reduced primary efficacy endpoint, a composite of death, MI, IDR, or ST at 48 h (4.7 vs. 5.9 %, OR=0.78, p=0.005), driven by reductions in ST and MI. Furthermore, the benefits associated with cangrelor were consistent across the subgroups of stable CAD, NSTEMI, and STEMI (interaction, p=0.98), and whether the patient received clopidogrel 300 mg LD or 600 mg LD (interaction, p=0.61). In addition, the GUSTO severe bleeding was similar between groups [27]. Finally, in a patient-level, pooled meta-analysis of all the three phase III trials demonstrated that cangrelor therapy was associated with significantly reduced rate of the composite outcome of death, MI according to the universal definition, IDR, or ST at 48 h (3.8 vs. 4.7 %, p=0.0007) and that these results were maintained at 30 days. Furthermore, there was no significant increase in GUSTO-defined moderate-to-severe bleeding or the need for blood transfusion in patients treated with cangrelor [30]. Guidelines recommend that at least 5–7 days are required for platelet functional recovery after discontinuation of thienopyridines in patients undergoing CABG. The latter recommendation is a concern in surgical delays in patients with ACS. In the BRIDGE phase II trial, the utility of cangrelor for bridging thienopyridine-treated patients to CABG was evaluated in 210 patients with ACS or treated with a coronary stent and in those receiving a thienopyridine awaiting CABG surgery. In this study, a greater proportion of patients treated with cangrelor compared to placebo had low levels of platelet reactivity as measured by VerifyNow P2Y12 assay throughout the treatment period (99 vs. 19 %, pG0.001) and there were no significant differences in major bleeding prior to CABG or excessive CABG-related bleeding [31]. Cangrelor is still under evaluation by health authorities in several countries.

Elinogrel Elinogrel is a direct-acting, reversible P2Y12 inhibitor. ERASE MI (Early Rapid ReversAl of platelet thromboSis with intravenous Elinogrel before PCI to optimize reperfusion in acute Myocardial Infarction) trial demonstrated no increase in the rate of bleeding when evaluating the safety of escalating intravenous doses of elinogrel up to 40 mg versus clopidogrel alone before PCI [32]. Significant liver toxicity associated with its use resulted in discontinuation of the development of the drug.

Thrombin receptor antagonists Although ticagrelor and prasugrel are associated with better pharmacodynamic effect and improved clinical outcomes, they are associated with an increased risk of bleeding compared to clopidogrel. In addition, the observation of treatment failure in ~10 % of high-risk patients treated with aspirin and a potent P2Y12 inhibitor is another major concern. Inhibition of the interaction between thrombin and protease-activated receptor (PAR)-1 may further attenuate ischemic events in selected patients treated with DAPT.

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Vorapaxar Based on the core structure of himbacine, a natural product isolated from the bark of the Galbulimima baccata plant, vorapaxar (earlier known as SCH 530348), was discovered. Vorapaxar is a potent, selective, high-affinity, and orally active PAR-1 antagonist with very long dissociation kinetics. Vorapaxar administration was associated with a 980 % inhibition of thrombin receptoractivated peptide-induced platelet aggregation. In preclinical and phase I–II studies, the inhibition of thrombin-mediated platelet activation by a PAR-1 inhibitor, in general, has added to the antithrombotic efficacy of aspirin and clopidogrel without increasing bleeding [29]. In two phase III trials, TRACER (Thrombin-Receptor Antagonist Vorapaxar in Acute Coronary Syndromes) and TRA2P-TIMI 50 [Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA2P)–Thrombolysis in Myocardial Infarction (TIMI) 50] trials, vorapaxar was compared with placebo in addition to standard medical therapy (including patients on DAPT with aspirin and clopidogrel) [33, 34]. In the TRACER trial, vorapaxar was studied on top of standard antiplatelet therapy for the acute treatment of patients with NSTE-ACS (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) (n= 12,944). The study was prematurely stopped due to increased bleeding in the vorapaxar group. In the TRACER trial, vorapaxar did not significantly reduce the primary composite endpoint occurrence of cardiovascular death, MI, stroke, hospitalization for ischemia, or urgent revascularization (18.5 vs. 19.9 %; p= 0.07). There were a 1.35-fold increase in moderate and severe bleeding (7.2 vs. 5.2 %; pG0.001) and a 3.39-fold increase in intracranial hemorrhage with vorapaxar therapy (1.1 vs. 0.2 %, pG0.001) [33]. In the TRA20P-TIMI 50 trial, patients with a history of spontaneous MI or ischemic stroke within 2 weeks to 12 months or peripheral arterial disease (n=26,449) were treated with vorapaxar or placebo on top of standard medical care. The Data Safety Monitoring Board recommended that vorapaxar be discontinued in patients with prior stroke and in patients who suffered a stroke during the study because of an alarming rate of intracranial hemorrhage observed in patients with prior stroke treated with vorapaxar. Vorapaxar therapy was associated with a significantly lower rate of the composite endpoint occurrence of 3-year CV death, MI, or stroke (9.3 vs. 10.5 %, pG0.001), with an increase in the primary safety endpoint occurrence of GUSTO moderate or severe bleeding (4.2 vs. 2.5 %, pG0.001) and in intracranial hemorrhage (1.0 vs. 0.5 %; pG0.001) [34]. In the post-MI group of the TRA20P trial with no history of stroke or TIA (n=16,897, 64 % of the overall population), vorapaxar therapy was associated with a significant reduction in the composite endpoint occurrence of cardiovascular death, MI, and stroke (7.4 vs. 9.0 %, pG0.001) that was mainly attributed to a significant reduction in MI (4.6 vs. 5.7 %; pG0.001). There was an increase in the primary safety endpoint occurrence of GUSTO moderate or severe bleeding (3.0 vs. 2.0 %, pG0.001), major or minor TIMI bleeding (3.4 vs. 2.3 %; pG0.001), and a non-significantly increased rate of intracranial hemorrhage (0.5 vs. 0.4 %; HR=1.44; p=0.160) [35•]. Currently, vorapaxar has

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been approved to treat patients with MI and peripheral artery disease to reduce the risk of MI, stroke, CV death, and revascularization in both America and European countries.

New antiplatelet agents A better understanding of platelet receptors and their structures in the recent years lead to the development of newer antiplatelet agents. Among them are novel P2Y12 inhibitors (AZD1283), PAR-1 antagonist (PZ-128), thromboxane synthase inhibitors (terutroban), combined inhibitors of thromboxane synthase and thromboxane receptors (ridogrel and terbogrel), and GPVI inhibitors (revacept).

AZD1283 Ethyl 6-aminonicotinate acyl sulfonamides are novel series of P2Y12 antagonists that were discovered recently. Structure-activity relationship investigations demonstrated that the replacement of a 5-chlorothienyl with a benzyl substituent is associated with an increased antiaggregatory effect, whereas the introduction of substituents on the benzyl group led to higher microsomal clearance but not further increased in antiaggregatory potency. Among them, AZD1283 was associated with strongest inhibition of ADP-induced platelet aggregation, increased blood flow, and a therapeutic index of ≥10 in the separation of efficacy and bleeding time. Based on these results, AZD1283 has been selected for further clinical studies [36].

Diadenosine 5',5″″-P1,P4-dithio-P2,P3-chloromethylenetetraphosphate Diadenosine 5',5″″-P1,P4-dithio-P2,P3-chloromethylenetetraphosphate (Ap4A) is the member of dinucleoside polyphosphates that are stored in platelet dense granules and released upon activation in addition to ADP and ATP. It has been reported that Ap4A with the stereo configuration at P1 and P4 has strong plasma stability and inhibitory effect on P2Y12 and lesser effect on P2Y1. This compound remains under investigation [37].

PZ-128 The ability to rapidly and reversibly inhibit PAR-1 signaling using a parenteral strategy may be ideal in the high-risk patient undergoing PCI and may be associated with less bleeding risk in the setting of urgent surgery [38, 39]. PZ-128 is a pepducin (lipidated peptide) that specifically inhibits PAR-1. It targets the cytoplasmic surface of PAR-1 receptors and interrupts downstream signaling to internally located G proteins. The structure of PZ-128 was found to mimic the off state of the corresponding intracellular region of PAR-1 that is critical for coupling to G proteins. It has a fast onset of action and a short half-life and causes reversible inhibition of platelets as demonstrated in guinea pigs and primates, without any effect on other coagulation parameters. In animal models, it has not been associated with significant inhibition of either ADP or PAR-4 platelet responses (0–10 %) at any time point

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including at 1, 2, or 24 h. PZ-128 was shown to reach its maximal activity during (G15 min) and immediately after intravenous infusion and complete elimination from plasma within 24 h [40]. It is being studied in a phase I human study trial (NCT01806077).

COX-1 inhibition Terutroban is a selective TxA2 antagonist and has been shown to have similar levels of inhibition of platelet aggregation as aspirin, thus conferring its similar anti-thrombotic, anti-atherosclerotic, and antivasoconstrictive properties. In ex vivo models of thrombosis, it was shown to be superior to aspirin in its inhibition of platelet aggregation and thrombus formation [41]. In the PERFORM (Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic attack) trial, terutroban therapy was failed to meet criteria for noninferiority to aspirin in secondary prevention of cerebrovascular and cardiovascular events [42]. Picotamide, a thromboxane synthase inhibitor and a thromboxane receptor inhibitor, was studied in patients with diabetes mellitus and peripheral arterial disease comparing to aspirin, and it was demonstrated to reduce long-term overall mortality, but not on major cardiovascular events [43, 44]. Ridogrel, another combined inhibitor, in the RAPT (The Ridogrel Versus Aspirin Patency Trial), the efficacy and safety of ridogrel with aspirin as a conjunctive therapy for thrombolysis in patients with acute MI was studied. The latter trial failed to show the superiority of ridogrel compared to aspirin in enhancing the fibrinolytic efficacy of streptokinase [45]. Terbogrel is another combined inhibitor which is being studied for long-term antithrombotic therapy [46].

Collagen receptor inhibitors Initially, platelets adhere to the exposed collagen at the site of endothelial injury by binding to collagen receptors and undergo platelet activation. Particularly, platelet activation following collagen binding to GPVI receptor is more significant, leading to the release of secondary agonists such as TxA2 and ADP from platelets and amplification of platelet activation and aggregation. Therefore, targeting GPVI receptor is an attractive strategy that might obviate the increased risk of bleeding associated with current antiplatelet agents. A novel GPVI blocker, revacept (PR-15, dimeric GPVI-Fc), has been studied in recent years. In animal studies, the administration of revacept did not increase bleeding complications but inhibited platelet adhesion and aggregation to the injured vessel wall in vivo [47, 48]. In a rabbit model of atherosclerosis, 3-week repeated dosing of revacept was associated with significant improvement in endothelial function and significantly decreased vessel wall thickening. There was no influence of revacept on bleeding time alone or when administered with other antiplatelet drugs in mice [49]. In the first in-human study, once, intravenous infusion of revacept in healthy volunteers did not significantly affect the bleeding

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Curr Treat Options Cardio Med (2015) 17:23 time and ADP or TRAP-1 induced platelet aggregation but collageninduced platelet aggregation was dose-dependently inhibited up to 48 h at lower doses and for 7 days after higher doses [50].

Platelet intracellular signaling targets PI3Kβ inhibitors PI3Kβ inhibitors have been shown to inhibit in vitro platelet aggregation and also in vivo thrombus generation [51, 52]. AZD6482, a PI3Kβ inhibitor, was associated with a rapid onset of action and a short halflife in inhibiting platelet aggregation in animal models and humans. In addition, a 3-h parenteral infusion of AZD6482 in humans was well tolerated and unaccompanied by any change in bleeding time. However, the potential influence on insulin signaling is a major concern. It has been suggested that AZD6482 may be an effective reversible agent in the management of patients undergoing cardiopulmonary bypass surgery and stroke to inhibit platelet activation [53].

Gq inhibitors Although YM-254890, a novel inhibitor of Gq signaling, has been shown to inhibit ADP-induced platelet aggregation suggesting a potential clinical role for Gq signaling inhibitors, the latter approach may have adverse effects in multiple organs due to its widespread importance to many GPCR pathways [54].

Conclusions Treatment with aspirin and a P2Y12 receptor blocker has been a major strategy to treat patients with high-risk coronary artery disease. Aspirin is a bedrock antiplatelet agent in the secondary prevention of cardiovascular disease. So far, there are no credible alternatives to aspirin, although few novel agents are being studied. Regarding the P2Y12 receptor blocker, clopidogrel is widely used in the clinical practice. More potent P2Y12 receptor blockers such as prasugrel and ticagrelor are being increasingly used in high-risk patients in recent years. However, the cost and the increased risk of bleeding are major concerns. Therefore, the treatment with clopidogrel, prasugrel, or ticagrelor in selected patients based on platelet function is being examined, although initial personalized antiplatelet therapy trials are not promising. At this time, it is reasonable to select high-risk patients for treatment with clopidogrel versus prasugrel or ticagrelor based on the therapeutic window concept. The latter strategy will help to achieve maximum anti-ischemic benefits with a minimal risk of bleeding in addition to cost-saving by treating low-risk patients without HPR with clopidogrel. A ceiling of net clinical benefit associated with aspirin and potent P2Y12 receptor blockers indicates a potential need for targeting alternative platelet activation pathways. One pathway that most recently has been targeted is the thrombin-PAR-1 receptor by vorapaxar. Finally, experimental evidence supports a potential interaction between highdose aspirin and the most recently approved potent P2Y12 inhibitor

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ticagrelor, an effect that may be explained by the actions of PGI2 and ticagrelor.

Expert opinion Significant advances in the platelet receptor biology with a greater understanding of the mechanism of receptor signaling induced by important platelet agonists resulted in the development of many novel agents that can be introduced in the cardiovascular medicine. Future goal is to achieve maximum antiischemic benefit with a minimal risk of bleeding. Novel antiplatelet agents may help to achieve the latter goal. In addition, instead of the one-size-fits-all strategy of antiplatelet agents, the personalized approach will be studied and more widely adapted in the general practice in the next few years.

Compliance with Ethics Guidelines Conflict of Interest Rahil Rafeedheen, Kevin P. Bliden, Fang Liu, and Udaya S. Tantry, each declare no potential conflicts of interest. Dr Gurbel reports serving as a consultant/receiving honoraria from Daiichi Sankyo, Bayer, AstraZeneca, Merck, and Janssen; receiving grants from the National Institutes of Health, Daiichi Sankyo, CSL, AstraZeneca, Harvard Clinical Research Institute, Bayer, Haemonetics, Duke Clinical Research Institute, Sinnowa, Coramed and Accriva. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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