Ticagrelor: a P2Y 12

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1 For reprint orders, please contact Ticagrelor: a P2Y 12 antagonist for use in acute coronary syndromes Expert Rev. Clin. Pharmacol. 5(3), (2012) Yanushi Dullewe Wijeyeratne, Rashi Joshi and Stan Heptinstall* Cardiovascular Medicine, Queens Medical Centre, University of ottingham, ottingham, G7 2UH, UK *Author for correspondence: Tel.: Fax: s.heptinstall@nottingham.ac.uk Agents that inhibit platelet function are used routinely in the treatment and prevention of acute coronary syndromes. The main antiplatelet treatments used combine aspirin with one of the thienopyridine P2Y 12 antagonists, either clopidogrel or prasugrel. By blocking the synthesis of thromboxane A 2 in platelets and by blocking the effects of ADP, respectively, these agents reduce platelet activity, platelet aggregation and thrombus formation. Ticagrelor (marketed by AstraZeneca as Brilinta in the USA, and as Brilique or Possia in Europe) is a cyclopentyltriazolo-pyrimidine, a new chemical class of P2Y 12 antagonist that is now approved for use in the wide spectrum of acute coronary syndromes. In this article we provide an overview of ticagrelor. We discuss the differences in mode of action compared with other P2Y 12 antagonists, examine its pharmacodynamic, pharmacokinetic and safety profile, and summarize the various clinical trials that have provided information on its efficacy in combination with aspirin. Ticagrelor appears to overcome some of the difficulties that have been encountered with other antiplatelet treatments, clopidogrel in particular. Keywords: acute coronary syndrome antiplatelet therapy clopidogrel cyclopentyl-triazolo-pyrimidine P2Y 12 antagonists prasugrel thienopyridine thrombosis ticagrelor Coronary heart disease (CHD) is the most common cause of death in the UK and a chief cause of morbidity and mortality globally [101]. In the UK in 2009, heart and circulatory disease accounted for more than 180,000 deaths and CHD accounted for 17.4% of all deaths in males and 12.1% of all deaths in females in England and Wales [102]. In Scotland, the age-standardized mortality rate for the under 75 years age category for CHD was 49.0 per 100,000 population in 2010 [103]. Furthermore, in Europe cardiovascular disease accounts for more than 4.3 million deaths per year, making it the leading cause of early death [104]. In the USA, the overall prevalence of CHD was 6% in 2010, affecting nearly 20% of people over 65 years of age [1]. CHD creates a substantial healthcare and socioeconomic problem worldwide; in the UK alone, the direct cost to the healthcare system was 3.2 billion in 2006 [101]. Furthermore, despite mortality rates decreasing in recent years, morbidity from CHD is rising; in the EU, approximately 4.4 million people are gravely restricted in their activities of daily living due to CHD [2]. A late-stage manifestation of CHD is an acute coronary syndrome (ACS) or cardiovascular death. ACS encompasses a spectrum of disease processes with three key conditions along a continuum: unstable angina (UA); non-st-segment elevation myocardial infarction (STEMI); and ST-segment elevation myocardial infarction (STEMI). on-st elevation acute coronary syndromes (STE-ACS) encompass UA and STEMI. Early risk of death is highest for patients with STEMI, but the risk of death 6 months post-discharge is highest for STEMI [3]. The morbidity and mortality 5 years post-event are equally high in all three ACS conditions [4]. Studies indicate that ACS mortality rates double 1 year post-discharge from hospital [5], emphasizing that currently therapies for the post-acute management of ACS are still not optimum, and thus there exists a major need to improve the post-acute management of ACS. All three forms of ACS (UA, STEMI and STEMI) have a common underlying pathology of a disrupted atherosclerotic plaque leading to exposure of tissue factor and collagen, /ECP Expert Reviews Ltd ISS

2 Wijeyeratne, Joshi & Heptinstall thrombin generation, platelet activation and aggregation, and eventual thrombogenesis. UA and STEMI are generally associated with white, platelet-rich and only partially occlusive thrombus, whereas in STEMI the thrombus is stable and occlusive. Platelets are a fundamental element in the promotion of thrombogenesis, highlighting the necessity of antiplatelet therapy in the medical management and secondary prevention of ACS. Figure 1 illustrates the current management strategy employed in the UK for ACS [ ]. Antiplatelet therapy is imperative in both the short- and long-term management of ACS, and newer antiplatelet medication has the potential to improve current treatment. The aim of antiplatelet therapy is to reduce platelet aggregation and other aspects of platelet function that arise following platelet activation, thereby reducing thrombus formation. This, of course, must be balanced against any negative effect of antiplatelet therapy on bleeding. As well as being involved in thrombus formation, platelets are the means through which hemostatic plugs are formed, and both myocardial infarction (MI) and bleeding complications in ACS patients are independent predictors of subsequent mortality [6]. The antiplatelet agents that are currently most frequently used in patients with ACS are aspirin, which inhibits synthesis of thromboxane A 2 (TXA 2 ) in platelets, and drugs that act as antagonists of the action of ADP at the P2Y 12 receptor. The use of low-dose aspirin rather than higher doses is widely used in countries other than orth America in an attempt to avoid widespread inhibition of vascular prostaglandin synthesis, most STEMI Antiplatelet and add-on anti-ischemic/anticoagulant treatment Reperfusion therapy (first line: primary PCI) Alternatives (only in centers where primary PCI is unavailable): thrombolytics (if within thrombolysis time window); or rescue PCI if thrombolysis unsuccessful; or CABG UA/STEMI Antiplatelet and add-on anti-ischemic/anticoagulant therapy Reperfusion therapy (PCI or CABG) Long-term management (including use of antiplatelet therapy, statin, β-blocker, ACE inhibitor, cardiac rehabilitation and lifestyle changes) Figure 1. Initial and long-term management of acute coronary syndromes in the UK. ACE: Angiotensin-converting enzyme; CABG: Coronary artery bypass grafting; STEMI: on-st-segment elevation myocardial infarction; PCI: Percutaneous coronary intervention; STEMI: ST-segment elevation myocardial infarction; UA: Unstable angina. of which (prostaglandin I 2, prostaglandin D 2, prostaglandin E 1 and prostaglandin E 2 ) are natural inhibitors of platelet function. Higher doses of aspirin are still used in orth America, although this may be changing (see below). Platelets are activated by a wide variety of molecules including thrombin, collagen, TXA 2 and ADP, all of which activate platelets through particular receptors on the surface of platelets (Figure 2). TXA 2 is synthesized by platelets following activation by agents such as collagen and thrombin, and contributes to the overall activation process through interaction with a receptor on platelets known as the TP receptor. ADP is also released from secretory granules in platelets in response to collagen and thrombin, and similarly contributes to the overall activation process. In addition, ADP can arise from the breakdown of ATP to ADP by ectonucleotidases. ATP is secreted with ADP from platelets and can also be released from other cells, particularly red cells, following cell damage. ADP interacts with two purinergic receptors on the platelet surface known as the P2Y 1 receptor and the P2Y 12 receptor, and both of these are needed for platelets to be fully activated by the ADP. Together, TXA 2 and ADP promote the direct platelet-activating effects of thrombin and collagen, resulting in platelet aggregation, platelet leukocyte interactions, platelet microparticle production and, ultimately, thrombus formation. Aspirin blocks TXA 2 production through an irreversible effect at the cyclo-oxygenase enzyme in platelets, and the thienopyridines clopidogrel and prasugrel act as P2Y 12 antagonists and block the action of ADP at the P2Y 12 receptor (Figure 3). Overview of the market The P2Y 12 antagonist clopidogrel is in widespread clinical use (along with low-dose aspirin) for the treatment of ACS. Prasugrel has been shown to give greater and more consistent platelet inhibition than clopidogrel. Ticagrelor (marketed by AstraZeneca as Brilinta in the USA, and in Europe as Brilique or Possia ) is the newest P2Y 12 antagonist to be licensed, and is the first reversibly-binding P2Y 12 antagonist. Other P2Y 12 antagonists are also in development, which include cangrelor, an agent being developed for intravenous use, and elinogrel, another reversible direct-acting P2Y 12 antagonist that is currently undergoing Phase II trials (Table 1) [7]. Other drug approaches in preventing thrombogenesis include the use of glycoprotein (GP)IIb/IIIa antagonists. These block platelet aggregation by preventing platelet platelet crosslinking, by fibrinogen, of activated GPIIb/IIIa molecules on adjacent platelets. Meanwhile, new agents that block the effects of thrombin at the PAR-1 receptor (the main receptor for thrombin on human 258 Expert Rev. Clin. Pharmacol. 5(3), (2012)

3 Ticagrelor: a P2Y 12 antagonist for use in acute coronary syndromes Drug Profile platelets) are under investigation as anti-thrombotic agents, as are direct inhibitors of thrombin production. The latter also reduce fibrin formation via interference with the coagulation cascade [8]. As mentioned above, the antiplatelet agents that are most commonly administered to patients with ACS are low-dose aspirin in combination with clopidogrel. GPIIb/IIIa antagonists are sometimes used as additional therapy during acute coronary interventions. However, there is a problem that is commonly referred to as nonresponse, low response or variable response to one or other of aspirin or clopidogrel. An under-response to aspirin is, in fact, relatively uncommon, although there are patients who apparently take aspirin in whom platelet function is less inhibited compared with other patients [9]. On the other hand, underresponse to clopidogrel in patients with ACS is very common and up to 50% of treated patients retain high levels of platelet reactivity [9]. Furthermore, the residual platelet activity does appear to contribute to a continued high risk of recurrent thrombotic events [10]. The thienopyridine clopidogrel is a prodrug that requires conversion to its active metabolite following oral administration before its inhibitory effect on platelets is realized. Actually, most of the drug is converted into an inactive metabolite and generation of the active metabolite is slow; it takes many hours for its desired effect to be realized even after administration of a high dose (600 mg) of the drug. Also, the degree of inhibition of platelet function differs in different people, related to differences in the amount of active metabolite generated. This is in part determined by genetic polymorphisms of the CYP450 cytochrome, including a reduced-function allele of the CYP2C19 gene [7]. The way in which the active metabolite of clopidogrel interacts with the P2Y 12 receptor also has consequences for the overall effects of the drug. Clopidogrel s active metabolite binds irreversibly to the receptor, rendering it incapable of interacting with ADP. This results in only a gradual recovery of platelet function after drug withdrawal commensurate with complete replacement of platelets via the natural process of removal and production, a process that takes up to 10 days. The irreversible nature of the drug s action raises concerns for increased procedure-related bleeding risk on treatment. Current practice is to stop the drug 5 7 days before surgery, which means that there is a period of inadequate platelet inhibition during that time. This may be associated with an increased cardiovascular morbidity [11]. Prasugrel is now available for use in some patients with ACS. Although remarkably similar to clopidogrel in its chemical structure, prasugrel differs from clopidogrel in that its active metabolite is the major product of its metabolism, whereas with clopidogrel some 85% of the drug ends up as an inactive metabolite. Thus, prasugrel provides more rapid, efficient and consistent inhibition of platelet function. Following demonstration of enhanced clinical benefit compared with clopidogrel in the TRITO-TIMI 38 trial [12], prasugrel is now licensed for use in ACS patients with STEMI undergoing percutaneous coronary intervention (PCI) [109]. Prasugrel, like clopidogrel, has an irreversible mode of action and so, again, the recovery of platelet function following drug withdrawal remains very slow indeed. Another consideration is the increased risk Collagen or thrombin Fibrinogen + Receptors Active GPIIb/IIIa Aggregation ADP ADP receptors P2Y 1 and P2Y 12 ADP TXA 2 TXA 2 TP receptor Figure 2. Simplified diagram of the pathways involved in platelet activation and aggregation, highlighting the roles of thromboxane A 2 and ADP. A purple arrow indicates a positive event and a black arrow indicates a transfer from inside to outside the cell. TXA 2 : Thromboxane A 2. of major bleeding that was seen in the TRITO-TIMI 38 trial in the patients taking prasugrel [12]. It is against this background that ticagrelor has emerged on the scene. Ticagrelor is the latest P2Y 12 antagonist to come on the market for use in patients with ACS. It was formerly known as AZD6140. It is the first in class of a new type of P2Y 12 antagonist known as cyclopentyl-triazolo-pyrimidines. The parent drug is direct-acting, which means that metabolic conversion to an active metabolite is not a requisite for the action of ticagrelor, although an active metabolite is formed and contributes in part to its clinical effects. This means that the effect Collagen or thrombin Fibrinogen + GPIIb/IIIa antagonists P2Y 12 antagonists Receptors Active GPIIb/IIIa Aggregation ADP ADP receptors P2Y 1 and P2Y 12 ADP TXA 2 TXA 2 TP receptor Aspirin Figure 3. Inhibition of platelet activation and aggregation by aspirin, P2Y 12 antagonists and glycoprotein IIb/IIIa antagonists. A purple arrow indicates a positive event, a black arrow indicates a transfer from inside to outside the cell, and a red line indicates inhibition of a particular pathway. GP: Glycoprotein; TXA 2 : Thromboxane A

4 Wijeyeratne, Joshi & Heptinstall Table 1. Differences in mode of action of P2Y 12 antagonists that are currently available or at a late stage of development. Drug Action Reversibility Onset Offset Inhibition of platelet function Variability of effect Clopidogrel Prodrug Irreversible Slow Slow Partial Variable Prasugrel Prodrug Irreversible Fast Slow More complete Less variable Ticagrelor Direct Reversible Fast Faster More complete Less variable Cangrelor Direct Reversible Immediate Very rapid More complete Less variable of ticagrelor on platelets is independent of genetic polymorphisms of the CYP450 cytochrome. Another difference compared with clopidogrel is that ticagrelor (and its metabolite) binds reversibly to the receptor rather than irreversibly. Ticagrelor is presented as round, biconvex yellow, film-coated tablets containing 90 mg of active substance in an immediaterelease form. Chemistry Ticagrelor s systematic name is (1S,2S,3R,5S)-3-[7-{[(1R,2S)- 2-(3,4-dif luorophenyl) cyclopropyl]amino}-5-(propylthio)- 3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane-1,2-diol. Its molecular weight is 523. Its structure, together with those of its major metabolites, is depicted in Figure 4. Pharmacodynamics Pharmacodynamic, pharmacokinetic, efficacy and safety data on ticagrelor were obtained through a series of Phase I and II studies, and also a large Phase III study. Ticagrelor acts as an antagonist at P2Y 12 receptors on platelets with high affinity (K i : 2.0 nm), and is thus a potent inhibitor of platelet activation by ADP [110]. Unlike clopidogrel and prasugrel, which interact with the receptor covalently and irreversibly, ticagrelor binds reversibly to the receptor. It does not compete directly with ADP at the ADP binding site but occupies an adjacent binding site and acts in an allosteric way, resulting in a reversible conformational change of the receptor [13]. The effects of ticagrelor on platelet function are evident both in vitro and in vivo. Since its major circulating metabolite AR-C124910XX also acts as a P2Y 12 antagonist, this also contributes to the effects of ticagrelor following its administration to animals and to man [14]. The P2Y 12 receptor is not widely expressed in cells and tissues other than platelets, although it does appear to be present in the spinal cord, brain, microglia, vascular smooth muscle cells, lymphocytes, CD34 + stem cells and pancreatic islets. On vascular smooth muscle cells ticagrelor has been shown to inhibit ADP-induced vasoconstriction, which theoretically could add to the antiplatelet effects of the drug in reducing thrombosis and ischemia [15,16]. Ticagrelor has some affinity (K i : 104 nm) for the adenosine A3 receptor but the in vitro and ex vivo data do not provide a clear conclusion as to whether the interaction of ticagrelor with the adenosine A3 receptor is agonistic or antagonistic [110]. Ticagrelor has been demonstrated to inhibit adenosine uptake into human erythrocytes, which could be relevant to ACS. ormally, any adenosine generated in the blood is rapidly taken up into erythrocytes (and other cells) and thereby removed. However, an increase in coronary blood flow was demonstrated experimentally in the presence of ticagrelor following induction of adenosine release via temporary occlusion of the coronary artery and by local administration of adenosine via a direct infusion. Similar results were obtained using dipyridamole, another inhibitor of adenosine uptake [17]. Furthermore, there is very recent evidence of ticagrelor inducing the release of ATP from human erythrocytes [18]. Released ATP would be rapidly converted to ADP, then to AMP and then adenosine via enzymes present on leukocytes and endothelial cells and within the blood plasma. Thus, in theory at least, increased adenosine production could occur through this HO H F H F HO H 2 O S F HO S F O S HO OH HO OH HO OH Ticagrelor AR-C124910XX AR-C133913XX Figure 4. Ticagrelor and its metabolites. 260 Expert Rev. Clin. Pharmacol. 5(3), (2012)

5 Ticagrelor: a P2Y 12 antagonist for use in acute coronary syndromes Drug Profile mechanism. Inhibition of adenosine uptake by ticagrelor (possibly accompanied by increased adenosine production) could also explain the increased occurrence of dyspnea seen in clinical trials in which ticagrelor has been administered (see below) [19]. Such considerations would also predict increased inhibition of platelet aggregation by ticagrelor compared with other P2Y 12 antagonists that do not promote adenosine production or uptake, since adenosine is a powerful inhibitor of platelet aggregation in its own right. However, ticagrelor could not be demonstrated to enhance inhibition of platelet aggregation compared with results obtained using other P2Y 12 antagonists in measurements performed in whole blood (i.e., with erythrocytes present), despite clearly enhanced inhibition of platelet aggregation demonstrated using dipyridamole [20]. In such experiments ticagrelor behaves exactly like cangrelor and the prasugrel active metabolite, and no evidence of ticagrelor behaving differently to these other P2Y 12 antagonists has come to light. Such data argues against ticagrelor having additional effects on platelet function via an adenosine-related mechanism of action. Ticagrelor in the nanomolar range was shown to inhibit GPR17, a G-protein-coupled receptor activated by both uracil nucleotides and cysteinyl leukotrienes that may be involved in ischemic damage, and theoretically this could provide additional benefit to its antiplatelet effects [110]. The most interesting clinical pharmacodynamic data on ticagrelor has come from two Phase II dose-selection studies (DISPERSE and DISPERSE-2), two Phase II clinical pharmacology studies (OSET/OFFSET and RESPOD) and a Phase III trial in 18,000 patients with ACS (PLATO), all of which involved comparisons with clopidogrel. DISPERSE was a double-blind, parallel-group study performed in 200 patients with documented atherosclerotic disease [21]. Patients were randomized to receive one of three doses of ticagrelor twice daily (50, 100 or 200 mg twice daily), 400 mg ticagrelor once daily or clopidogrel 75 mg once daily for 28 days. All groups also received aspirin mg once daily. The pharmacodynamic effects of the administrations were assessed by measurement of ADP-induced platelet aggregation using optical aggregometry in platelet-rich plasma prepared from blood taken from the patients. All doses of ticagrelor from 100 mg and above rapidly and nearly completely inhibited ADP-induced platelet aggregation after initial dosing (day 1) and at days 14 and 28. On day 1, peak inhibition of platelet aggregation was observed 2 4 h postdose with ticagrelor and inhibition remained at this level during the entire treatment period. The lower dose of ticagrelor (50 mg twice daily) and also clopidogrel produced lower levels and variable degrees of inhibition throughout the dosing period. The inhibitory effects of ticagrelor on platelet aggregation declined after administration of the final dose consistent with its reversible nature but, after administration of the higher doses, platelet aggregation levels still remained higher than those for clopidogrel. During maintenance therapy with 100 and 200 mg ticagrelor twice daily, there was much less variation in inhibition of platelet aggregation in the individuals in taking the drug than was seen with 50 mg ticagrelor or clopidogrel. DISPERSE helped in dose selection for further clinical studies. The main goal of DISPERSE-2 was to compare the safety and initial efficacy of ticagrelor with clopidogrel in patients with STE- ACS [22]. Patients were randomized in a double-blind fashion to receive twice-daily ticagrelor 90 mg, ticagrelor 180 mg or a clopidogrel 300-mg loading dose followed by 75 mg once daily for up to 12 weeks. This was on top of standard therapy in these patients, which included low-dose aspirin. Half of the patients allocated to ticagrelor received a 270-mg loading dose. Patients randomized to receive clopidogrel were given a 300-mg loading dose unless they had already been treated with clopidogrel. Pharmacodynamic effects were measured in a substudy of 91 patients in which the antiplatelet effects of ticagrelor and clopidogrel were assessed, as well as the effects of ticagrelor in clopidogrel-pretreated patients [23]. Measurements of ADP-induced platelet aggregation were performed using optical aggregometry on day 1 and at 4-week intervals. All doses of ticagrelor produced rapid inhibition of platelet aggregation and exhibited greater mean inhibition of platelet aggregation than clopidogrel. During maintenance therapy, a similarly high degree of inhibition of platelet aggregation was consistently achieved. In addition, there was little variability in response in different individuals during maintenance therapy with ticagrelor, unlike the clopidogrel-treated group. Ticagrelor also further suppressed platelet aggregation in clopidogrel- pretreated patients, consistent with blockade of P2Y 12 receptors by ticagrelor that are not blocked by clopidogrel therapy. The aim of the OSET/OFFSET trial [24] was to measure both the onset and offset of platelet inhibition using the dose regimen for ticagrelor chosen for further clinical study following DISPERSE and DISPERSE-2 (i.e., a 180-mg loading dose followed by 90-mg twice-daily maintenance therapy). Here the effects of ticagrelor were compared with a higher loading dose of clopidogrel (600 mg) than used previously followed by 75 mg once daily. In this multicenter, randomized, double-blind study, 123 patients with stable coronary artery disease who were taking aspirin therapy ( mg/day) received ticagrelor (n = 57), clopidogrel (n = 54) or placebo (n = 12) for 6 weeks. Once again, greater inhibition of ADP-induced platelet aggregation occurred with ticagrelor than with clopidogrel at all time points following the loading dose and during maintenance therapy. Ticagrelor demonstrated a rapid onset of effect, with inhibition of platelet aggregation statistically significant at all times (0.5 h to maximum response at 8 h) with ticagrelor compared with clopidogrel. The rate of onset of inhibition over the first 2 h following the loading dose was more rapid with ticagrelor compared with clopidogrel, with most ticagrelor patients exhibiting a high degree of inhibition. In addition, a faster offset occurred with ticagrelor than with clopidogrel following drug withdrawal after 6 weeks of therapy; the slope of the offset curve of ticagrelor was significantly different from the offset curve of clopidogrel ( vs % per h; p < ). As mean inhibition of platelet aggregation was higher for ticagrelor 90 mg compared with clopidogrel 75 mg, inhibition was higher on ticagrelor than on clopidogrel before the 24-h time point and started to be significantly lower thereafter, with levels approaching baseline after 5 days for ticagrelor and 7 days 261

6 Wijeyeratne, Joshi & Heptinstall for clopidogrel. This reflects the reversibility of inhibitory effects of ticagrelor following drug withdrawal, but also points out that return of platelet function to normal is still quite slow. The RESPOD study focused on measurements of platelet function performed in patients following change of drug treatment from clinical doses of clopidogrel to ticagrelor and vice versa [25]. Initially patients were also subgrouped into those deemed to be most responsive to clopidogrel and those deemed to be nonresponsive. Patients with stable coronary artery disease on aspirin therapy received a 300-mg loading dose of clopidogrel and the level of response was identified by optical aggregometry following platelet stimulation with ADP. onresponders (n = 41) and responders (n = 57) then randomly received clopidogrel (600/75 mg once daily) or ticagrelor (180/90 mg twice daily) for 14 days, following which all nonresponders switched treatment, half of the responders continued the same treatment and half of the responders switched treatment. The results demonstrated that inhibition of platelet aggregation was increased in clopidogrel nonresponders who were subsequently treated with ticagrelor, and thus that ticagrelor therapy overcomes nonresponsiveness to clopidogrel. In addition, switching to ticagrelor therapy significantly enhanced platelet inhibition in patients responsive to clopidogrel. The PLATO trial [26,27] was a major Phase III trial in over 18,000 patients with ACS, and it was the results of this trial that led to acceptance of the drug for clinical use. The clinical results of this major trial are discussed in detail below. As well as clinical outcomes, the PLATO trial was also used to generate pharmacodynamic data and, like DISPERSE 2, it did so via a platelet substudy [28]. The study involved randomizing patients with all forms of ACS to receive either clopidogrel ( mg loading dose followed by 75 mg once daily) or ticagrelor (180-mg loading dose followed by 90 mg twice daily). The antiplatelet effects of maintenance therapy were studied in 69 patients pre- and 2 4 h post-dose after at least 28 days. The effect of the loading dose was studied in 24 clopidogrelnaive patients. Once again, optical aggregometry was the main tool for assessment of the effects of the drugs on platelet function. Similar to previous results, ticagrelor at a dose of 90 mg twice daily achieved greater antiplatelet effect than standard dose clopidogrel both in the first hours of treatment and during maintenance therapy. The mean percentage aggregation response induced by ADP 20 µm at trough concentration of ticagrelor was 36 ± 12, compared with 48 ± 14 with clopidogrel (p < 0.001). At peak drug concentration, these values were 28 ± 10 and 44 ± 15%, respectively (p < ), and high platelet activity was seen more frequently with clopidogrel. Pharmacokinetics & metabolism In humans, ticagrelor undergoes rapid absorption, with peak plasma concentrations attained approximately 2 h after oral administration. The main metabolite AR-C124910XX (Figure 4), which has similar P2Y 12 antagonistic activity to that of the parent drug, is formed rapidly, attaining peak plasma concentrations 2 3 h after oral ticagrelor ingestion. It attains a concentration of approximately a third of that of the parent drug. Ticagrelor is metabolized mostly by CYP3A4 and 3A5 to AR-C124910XX (oxidative loss of the hydroxyethyl side chain) and also to the inactive AR C133913XX (loss of the difluorophenylcyclopropyl group, Figure 4). The plasma protein binding of ticagrelor and AR-C124910XX is very high ( 90%). The major route of excretion of ticagrelor and its metabolites is via the feces [14,29]. Renal impairment does not affect the clearance of ticagrelor [30]. The pharmacokinetics of ticagrelor were assessed in the DISPERSE study [21]. Pharmacokinetic data show that plasma concentrations of ticagrelor and its active metabolite AR-C124910XX were predictable following individual doses of ticagrelor up to 400 mg, although data do suggest some accumulation can occur following repeated administration of the higher doses tested. The distributions were not affected by sex or age. The terminal plasma half-life of ticagrelor and AR C133913XX are between 6 and 12 h. Ticagrelor can be administered either with or without food. In one study, administration with food has been shown to result in a 25% increase in ticagrelor exposure; however, that did not translate to a difference in the exposure to AR-C124910XX or in the extent of inhibition of platelet aggregation [29]. A subsequent randomized trial study that involved participants being given oral ticagrelor (single dose of 270 mg) either after a 10-h overnight fast or after a standard high-fat and high-calorie breakfast provided further evidence of the lack of a clinically significant food effect on the pharmacokinetics of ticagrelor [31]. One perceived drawback for clopidogrel is the interaction with proton pump inhibitors (PPIs), some of which interfere with the conversion of clopidogrel into the active metabolite responsible for inhibition of platelet function [32]. Since the antiplatelet effects of ticagrelor do not require conversion to an active metabolite, it was thought that no such interaction would occur with this drug. However, a recent analysis [33] of the relationship between PPI use and cardiovascular outcomes in ACS patients randomized to clopidogrel or ticagrelor in the PLATO trial revealed that the use of a PPI was independently associated with a higher rate of cardiovascular events in patients receiving either drug. Furthermore, there was a similar association between cardiovascular events and other non-ppi gastrointestinal drug treatment. It would seem, therefore, that patients who receive such treatments are already at increased risk irrespective of the type of antiplatelet agent they receive. The onset and magnitude of the inhibitory effect on platelet function appear to be related to plasma concentrations of ticagrelor and its metabolite given that the mean time to peak inhibition of platelet aggregation (2 4 h across ticagrelor doses) mirrored the mean t max of 2 3 h for both ticagrelor and its metabolite. However, at doses of ticagrelor above 100 mg when inhibition of platelet function is >90%, clearly no further inhibition of platelet function occurs, despite increased plasma levels of the drug and its metabolite at the higher drug doses used [23]. Taking data from all trials from which pharmacokinetic data have been obtained, it would appear that the pharmacokinetics of ticagrelor and AR-C124910XX are not clinically significantly influenced by smoking, weight or race. Slightly higher exposures have been noted in older people, but this is not considered to be clinically significant [111]. 262 Expert Rev. Clin. Pharmacol. 5(3), (2012)

7 Ticagrelor: a P2Y 12 antagonist for use in acute coronary syndromes Drug Profile Clinical efficacy The trial that definitely established the efficacy of ticagrelor as a useful anti-thrombotic agent was the PLATO trial [26,27]. This Phase III trial in over 18,000 patients was designed to test the hypothesis that ticagrelor compared with clopidogrel will result in lower risk of recurrent thrombotic events in a broad patient population with ACS. It was an international, randomized, double-blind, event-driven trial on patients hospitalized for either STEMI with intended primary PCI, or for STE-ACS. Patients admitted with STE-ACS were included in the trial if they had two out of the following three criteria: ST changes on ECG, a positive biomarker, or one of several predefined risk factors. Ticagrelor was administered at a loading dose of 180 mg followed by 90 mg twice daily. Alternatively, clopidogrel was administered at a loading dose of mg followed by 75 mg once daily. Both treatments were in addition to aspirin. Treatment continued for 6 12 months. The primary efficacy variable was time to first occurrence of death from vascular causes, MI or stroke. The primary safety variable was major bleeding. At 12 months, the primary end point had occurred in 9.8% of patients receiving ticagrelor compared with 11.7% of patients receiving clopidogrel (hazard ratio: 0.84; 95% CI: ; p < 0.001). Treatment benefit of ticagrelor over clopidogrel on the primary outcome was seen at 30 days and persisted throughout the duration of the study (Figure 5). Predefined secondary end points also demonstrated significant benefit in favor of ticagrelor. There was a reduction in the rate of MI (5.8% in the ticagrelor group compared with 6.9% in the clopidogrel group; p = 0.005), stent thrombosis (1.3 vs 1.9%; p = 0.009) and rate of death from vascular causes (4.0 vs 5.1%; p = 0.001). o difference was seen in the rate of stroke between clopidogrel and ticagrelor (1.5 vs 1.3%; p = 0.22), although there were more hemorrhagic strokes in patients treated with ticagrelor (23 [0.2%] with ticagrelor vs 13 [0.1%] with clopidogrel; p = S). Of great interest was the observation that the rate of death from any cause was also reduced with ticagrelor (4.5 vs 5.9% with clopidogrel; p < 0.001). This had not been seen previously in any trial involving a P2Y 12 antagonist studied in comparison with clopidogrel. This observation has resulted in considerable debate as to the reasons for this particularly striking outcome of the PLATO trial [34 36]. o clear conclusion or consensus has yet been reached. There was no significant heterogeneity in outcome with regard to the primary end point between different subgroups of the PLATO study. However, the beneficial effects of ticagrelor were attenuated in patients who were underweight (defined as weighing less than the median weight for their sex; p = 0.04 for the primary end point Cumulative incidence of primary end point (%) At risk (n) Ticagrelor Clopidogrel in this subgroup), those not on lipid-lowering drugs (p = 0.04), and those enrolled from orth America (p = 0.045). The reasons for the orth American anomaly are unclear, and the lower efficacy observed could be due to chance alone [37]. One factor that has been given consideration, however, is that the high dose of aspirin (300 mg) given to patients in the orth American group may have influenced the efficacy of ticagrelor. Recent work has clearly demonstrated that P2Y 12 antagonists can markedly promote the inhibitory effects on platelet function of vascular prostaglandins such as prostaglandin I 2, prostaglandin D 2, and prostaglandins E 1 and E 2 [38 40]. Thus, the overall mechanistic benefit of a P2Y 12 antagonist may involve an interaction with such natural modulators of platelet function, rather than solely through P2Y 12 receptor blockade. A high dose of aspirin, compared with a lower dose, is more likely to inhibit the synthesis of vascular prostaglandins, and by doing so would reduce the overall mechanistic benefit of P2Y 12 blockade. This may have been more evident using ticagrelor than with clopidogrel, simply because the former is a stronger and more potent P2Y 12 antagonist. It should be noted that consideration of the impact of aspirin dose by the US FDA resulted in a warning that co-use of aspirin at doses greater than 100 mg/day may reduce ticagrelor s effectiveness [112,113]. Appropriate risk stratification and timely revascularization therapy is integral to the effective treatment of ACS. The PLATO- IVASIVE substudy [41] evaluated patients who were identified at randomization in the PLATO trial as needing invasive management either via PCI or coronary artery bypass grafting (CABG), although it must be noted that only 82 83% of these identified patients did in fact undergo revascularization therapy Clopidogrel 90 Ticagrelor p < Months Figure 5. Cumulative Kaplan Meier estimates from PLATO comparing ticagrelor and clopidogrel on the time to first occurrence of the primary efficacy end point: composite of death from vascular causes, myocardial infarction or stroke. Reproduced with permission from [27]

8 Wijeyeratne, Joshi & Heptinstall This substudy showed reductions in the primary end point of cardiovascular death, MI or stroke (9.0 vs 10.7%; p = ), allcause death (3.9 vs 5.0%; p = ) and stent thrombosis (2.8 vs 3.8%; p = ) in patients who had planned revascularization therapy treated with ticagrelor compared with clopidogrel. Reperfusion therapy is also the mainstay of therapy for patients with STEMI. The PLATO-STEMI substudy [42] analyzed outcomes following the use of ticagrelor versus clopidogrel in 7544 patients who had ST elevation or left bundle branch block and planned PCI at randomization for the PLATO trial. Among patients who had a STEMI, the primary end point as defined in PLATO occurred in 9.4% of patients in the ticagrelor group compared with 10.8% of patients in the clopidogrel group. Although this difference had a hazard ratio of 0.87, it failed to reach statistical significance (p = 0.07). The incidence of cardiovascular death was 4.5% with ticagrelor, compared with 5.5% with clopidogrel in this subgroup of patients. Again, this difference was not statistically significant (p = 0.07). There was, however, a statistically significant reduction in all-cause mortality (5.0 vs 6.1%; p = 0.05) and a reduction in recurrent MI (4.7 vs 5.8%; p = 0.03), consistent with the overall PLATO results. In the PLATO-STEMI substudy, however, ticagrelor was associated with an increase in the risk of stroke (1.7 vs 1.0% in the clopidogrel group; p = 0.02). A prespecified ECG substudy of PLATO [43] showed that ticagrelor s effect on vascular death and MI within 1 year in patients who have had a STEMI is not associated with either the extent of baseline ST-segment shift or with residual ST changes at hospital discharge. This suggests that the main effects of ticagrelor may not relate to the rapidity or the completeness of acute reperfusion. This absence of an effect on ST resolution suggests that the benefits of ticagrelor are more likely via the prevention of further vascular events through more powerful platelet inhibition. The PLATO-CABG substudy [44] evaluated the efficacy and safety of ticagrelor compared with clopidogrel in over 1800 patients from the PLATO trial that underwent CABG. Ticagrelor was withheld for h prior to surgery, and clopidogrel was withheld for 5 days. The primary efficacy end point, as defined by PLATO, occurred in 10.6% of patients on ticagrelor, compared with 13.1% with clopidogrel. Although this difference was not statistically significant (p = 0.29), the results are in line with those of the main trial. Similarly, there was also no difference in the rate of MI or stroke at or after CABG with the two treatments. However, in patients undergoing CABG cardiovascular death was lower with ticagrelor (7.9 vs 4.1% with clopidogrel; p = 0.009). A benefit of ticagrelor on total mortality was also noted in this subgroup (4.7% total mortality with ticagrelor, compared with 9.7% with clopidogrel; p = 0.002), consistent with the overall trial results. In patients with ACS initially intended for noninvasive management, ticagrelor was shown to have greater benefit compared with clopidogrel, again consistent with the overall PLATO results. This indicates that ticagrelor improves cardiac outcomes in ACS patients regardless of the presence or absence of invasive reperfusion therapy [45]. Diabetes mellitus is a major risk factor for cardiovascular disease. The PLATO-DIABETES substudy [46] compared outcomes in patients with and without pre-existing diabetes mellitus who were enrolled in the PLATO trial. Consistent with the overall trial results, ticagrelor was noted to significantly reduce the primary composite end point (as defined by PLATO), all-cause mortality, MI and stent thrombosis in the larger subgroup of patients without diabetes; however, these benefits were not statistically significant in the smaller subgroup of patients with diabetes. It must be noted that the subgroup with diabetes comprised only 25% of all patients in the PLATO trial; hence, this retrospective subgroup analysis would have been underpowered to demonstrate statistical significance. The PLATO-REAL substudy [47] evaluated patients with chronic kidney disease (CKD) who were treated with ticagrelor. In this subgroup, ticagrelor was noted to be associated with a 4.7% absolute risk reduction in death from vascular causes, MI or stroke, and a 4.0% absolute risk reduction in mortality compared with clopidogrel. The results were 1 and 0.5%, respectively, for patients with better renal function, defined as creatinine clearance >60 ml/min (no statistically significant benefit in this analysis). Ticagrelor reduced the primary composite end point and total mortality consistently in patients with all stages of CKD, regardless of the cutoff value for CKD. However, the benefit was clearly greater in patients with more advanced CKD. It must be noted that the conclusions that can be inferred from the PLATO substudies are limited, being retrospective analyses of nonrandomized subgroups of patients from the parent trial. The substudy analyses could have been open to selection bias as well as survivor bias. Further prospective randomized control trials are needed to ascertain the observations made in the PLATO subgroup analyses. Although there are no head-to-head trials comparing ticagrelor with prasugrel, ticagrelor, like prasugrel [11], demonstrates greater efficacy than clopidogrel in preventing coronary thrombotic events. In addition, unlike prasugrel, ticagrelor shows benefit on overall mortality in patients with ACS compared with clopidogrel. Postmarketing surveillance Two further Phase III studies are in process to further evaluate the clinical efficacy of ticagrelor. CT [114] is another safety study in which 90 mg ticagrelor is administered twice daily with low-dose aspirin to Asian patients with ACS and a planned PCI, and is compared with 75 mg clopidogrel once daily, also with low-dose aspirin. A total of 800 subjects will be enrolled and the estimated completion date for the study is August PEGASUS is another major outcomes study in which 21,000 patients are being recruited 1 3 years after exhibiting ACS and randomized to receive one of 60 mg ticagrelor, 90 mg ticagrelor or placebo twice daily, all with mg aspirin once daily [115,116]. The aim of the study is to explore the benefits of ticagrelor beyond the point at which acute treatment would have normally ceased. The primary efficacy end point for PEGASUS will be time to first occurrence of any cardiovascular event including CV death, nonfatal MI or nonfatal stroke. The study is expected to run until February The results of this trial are eagerly awaited, particularly because current evidence is limited on the 264 Expert Rev. Clin. Pharmacol. 5(3), (2012)

9 Ticagrelor: a P2Y 12 antagonist for use in acute coronary syndromes Drug Profile use of P2Y 12 inhibitor therapy after 1 year following an ACS. This trial could therefore provide useful information on whether a longer period of treatment is beneficial. It is however noted that the design of this trial is placebo-controlled. It does not use either clopidogrel or prasugrel to compare the treatment effects with ticagrelor. Safety & tolerability Ticagrelor is generally well tolerated. The most commonly reported adverse reactions include subcutaneous or dermal bleeding, bruising, epistaxis, gastrointestinal hemorrhage and dyspnea [111]. In the DISPERSE-2 study major or minor bleeding through 4 weeks was 8.1% in the clopidogrel group, 9.8% in the ticagrelor 90 mg group and 8.0% in the ticagrelor 180 mg group (p = 0.43 and p = 0.96, respectively, vs clopidogrel) [22]. The major bleeding rates were 6.9, 7.1 and 5.1%, respectively (p = 0.91 and p = 0.35, respectively, vs clopidogrel). In the PLATO trial overall there was no significant difference in the rate of major bleeding (PLATO definition of major bleeding) with ticagrelor compared with clopidogrel (11.6 vs 11.2%; p = 0.43) [25,26]. The incidence of intracranial bleeds was however higher in the ticagrelor group compared with clopidogrel (26 [0.3%] vs 14 [0.2%]; p = 0.06), including fatal intracranial bleeds (11 [0.1%] vs 1 [0.01%]; p = 0.02). However, the small numbers of events make the results difficult to interpret. A further detailed analysis of bleeding events in the PLATO trial has recently been made available [48]. There was no significant difference in the overall rate of major bleeding; however, non-cabg major bleeding in the ticagrelor- and clopidogreltreated groups (4.5 vs 3.8%; p = 0.02) and non-procedure-related major bleeding (3.1 vs 2.3%; p = 0.05) were more common in ticagrelor- treated patients. CABG-related bleeding rates were similar between ticagrelor and clopidogrel groups. As mentioned above, a notable side effect of ticagrelor is dyspnea, which was observed in 13.8% of patients treated with ticagrelor in PLATO. In total, 0.9% of patients in the ticagrelor group (compared with 0.1% in the clopidogrel group) discontinued the drug as a result of the dyspnea. The symptoms usually lasted less than 1 week after discontinuation of the drug. However, a pulmonary substudy that was conducted on 199 patients from the PLATO trial to identify effects of ticagrelor on pulmonary function did not show significant effects on various pulmonary function measures [49]. Pulmonary function parameters studied included blood oxygen saturation, spirometry, lung volumes (total lung capacity, functional residual capacity and residual volume), and diffusion capacity after patients were given ticagrelor (90 mg twice daily) or clopidogrel (75 mg daily) for days. It was concluded from this substudy that after a mean treatment of 31 days, ticagrelor did not affect pulmonary function compared with clopidogrel. There was no difference in the incidence of neoplasia arising during treatment between ticagrelor and clopidogrel, although the incidence of benign neoplasms was 0.2% in the ticagrelor group compared with 0.4% with clopidogrel (p = 0.02). The actual numbers of affected patients were small and it is possible that this difference was incidental. Gynecomastia was reported in 0.23% of patients on ticagrelor versus 0.05% of patients on clopidogrel. There were no other sex hormone-associated adverse reactions [117]. There was an increased incidence of asymptomatic ventricular pauses in the first week in patients treated with ticagrelor (5.8 vs 3.6% with clopidogrel; p = 0.01) [27]. This was similar to results from the DISPERSE-2 study, where in a post hoc analysis of continuous electrocardiograms, mostly asymptomatic ventricular pauses of >2.5 s were more common, especially in the ticagrelor 180 mg group (4.3, 5.5 and 9.9%, respectively; p = 0.58 and p = 0.01, respectively, vs clopidogrel) [22]. Serum creatinine levels increased slightly with ticagrelor (10 vs 8% with clopidogrel; p < at 1 month), and this difference was sustained at 12 months but became nonsignificant after discontinuation of therapy [27]. Serum uric acid levels were also seen to increase while on treatment with ticagrelor (14 vs 7% at 1 month; p < 0.001; difference sustained at 12 months), but there were no reports of any clinical consequences such as gout. The rise in uric acid with ticagrelor was partly reversible upon cessation of therapy at 12 months and the difference became nonsignificant. This modest and reversible increase in hyperuricemia has been confirmed in a subsequent study conducted in healthy volunteers [50], and may have been caused by altered tubular secretion and/or an increase in production of uric acid. It is interesting to note that uric acid is the final product of adenosine metabolism, but any association between uric acid and adenosine in ticagrelor-treated patients has not yet been demonstrated. Overall, there was a higher discontinuation rate of ticagrelor due to adverse effects in the PLATO trial compared with clopidogrel (7.4 vs 6.0%; p < 0.001) [27]. Ticagrelor is contraindicated in patients who are actively bleeding, who have a history of intracranial hemorrhage, or moderateto-severe hepatic impairment. Coadministration of ticagrelor with a strong CYP3A4 inhibitor (such as ketoconazole, clarithromycin and certain antiretroviral agents) is also contraindicated [118]. This is because of the role of the CYP3A4 enzyme in the formation of the ticagrelor active metabolite. Inhibition of CYP3A4 therefore affects the kinetic behavior of ticagrelor [51]. Ticagrelor should also be used with caution in patients receiving more than 40 mg simvastatin daily, owing to increased risk of statin-related adverse effects. In patients on digoxin for supraventricular arrhythmias or heart failure, digoxin levels should be monitored with initiation or change in ticagrelor therapy [117]. Regulatory affairs In September 2010, ticagrelor, in the form of Brilique 90-mg filmcoated tablets, was granted marketing authorization in Europe by the Committee for Medicinal Products for Human Use of the EMA. It stated that ticagrelor, coadministered with aspirin, is indicated for the prevention of atherothrombotic events in adult patients with ACS, which includes patients managed medically, as well as those who are managed with PCI or CABG [119]. The FDA approved ticagrelor for use in ACS in July This was, however, accompanied by the boxed warning that aspirin doses above 100 mg per day may decrease its effectiveness. In 265