Antiplatelet therapy in acute coronary syndromes

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CURE trial, aspirin was administered (in combination with clopidogrel) at doses ...... The ongoing TRILOGY ACS trial is comparing the use of pra- sugrel and ...
Review

Antiplatelet therapy in acute coronary syndromes Alberto Menozzi†, Daniela Lina, Giulio Conte, Francesco Mantovani & Diego Ardissino 1.

Introduction

2.

Aspirin

3.

P2Y12

Azienda Ospedaliero-Universitaria di Parma, Unita` Operativa di Cardiologia, Parma, Italy

ADP-receptor antagonists 4.

New targets for platelet

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inhibition: the role of PAR-1 inhibitors 5.

Glycoprotein IIb/IIIa inhibitors

6.

Conclusions

7.

Expert opinion

Introduction: Antiplatelet therapy is the cornerstone of treatment for patients with acute coronary syndromes in the acute phase and in long-term management. Over the last few years, new antiplatelet drugs have been developed and the therapeutic landscape has rapidly evolved. Areas covered: We review the available evidence and most recent data concerning all of the principal classes of antiplatelet agents, including aspirin, thienopyridines and glycoprotein IIb/IIIa inhibitors, as well the impact of the new drugs prasugrel and ticagrelor and the available data concerning cangrelor, elinogrel and PAR-1 inhibitors (still under development). Expert opinion: This review considers the management of antiplatelet therapy in the light of recent advances, highlighting how to identify patients who will receive the greatest benefit from the older and newer agents, and underscoring the importance of carefully balancing the risks of ischaemia and bleeding in order to improve clinical outcomes. Finally, the paper discusses the potential role of functional and genetic tests in guiding the choice of antiplatelet therapy in a future perspective of ‘personalised medicine’. Keywords: acute coronary syndromes, bleeding risk, clopidogrel, dual antiplatelet therapy, ischaemic risk, personalised medicine, pharmacogenomics, prasugrel, ticagrelor Expert Opin. Pharmacother. (2012) 13(1):27-42

1.

Introduction

Acute coronary syndromes (ACS) are life-threatening manifestations of atherosclerosis that are usually precipitated by acute thrombosis induced by a ruptured or eroded atherosclerotic plaque. Platelets play a key role in the development of ACS because plaque rupture is followed by platelet adhesion, activation and aggregation, leading to thrombus formation [1]. Antiplatelet therapy is therefore the cornerstone of medical treatment in patients with ACS, and is necessary in both the acute phase and long-term maintenance therapy. Platelets are activated via multiple pathways as their specific agonists, such as thromboxane-A2, adenosine diphosphate (ADP), thrombin or collagen may activate different surface receptors [2]. These receptors are the targets for antiplatelet drugs and a synergistic antiplatelet effect can be obtained by their simultaneous inhibition [3] (Figure 1). Aspirin is the first-choice antiplatelet treatment for all of the clinical manifestations of coronary artery disease (CAD); the current standard of care for all patients with ACS includes dual antiplatelet therapy with aspirin and an ADP-receptor antagonist in order to ensure the blockade of a second activation pathway [4-7]. Over the last few years, a number of clinical trials have investigated novel antiplatelet agents and others are currently ongoing. The aims of these trials are to obtain additional antagonists of the ADP receptor that are more effective than clopidogrel, and to target other pathways involved in platelet activation in order to ensure synergy with current therapies. As expected, these agents reduce the re-occurrence of ischaemia but are associated with an intrinsically increased risk of bleeding, a matter of major 10.1517/14656566.2012.642862 © 2012 Informa UK, Ltd. ISSN 1465-6566 All rights reserved: reproduction in whole or in part not permitted

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Antiplatelet therapy in acute coronary syndromes

Article highlights. .

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Antiplatelet therapy is the cornerstone of medical treatment in patients with acute coronary syndrome (ACS), and it is necessary in both the acute phase and long-term maintenance therapy. The current standard of care for patients with ACS includes dual antiplatelet therapy with aspirin and an adenosine diphosphate (ADP)-receptor antagonist. Clopidogrel is hampered by some substantial limitations. Prasugrel and ticagrelor have improved clinical outcomes compared with clopidogrel by reducing the reoccurrence of ischaemic events, but at the expense of an increased risk of bleeding. New promising agents, such as cangrelor, elinogrel and platelet PAR-1 receptor inhibitors, are under investigation. Given all the available drugs and their possible combinations, the selection of the optimal antiplatelet therapy in clinical practice should be based on the balance between the thrombotic and haemorrhagic risk in each individual patient. If platelet function and/or genotype-guided therapy will demonstrate to improve clinical outcome, it might lead to a paradigm shift in antiplatelet therapy bringing about the promise of ‘personalised medicine’.

This box summarises key points contained in the article.

concern because haemorrhagic complications are associated with adverse outcomes in patients with ACS [8]. This article provides an overview on the currently available antiplatelet agents and promising new drugs for the treatment of ACS that are in a late stage of clinical development. 2.

Aspirin

Aspirin irreversibly inhibits the platelet cyclo-oxygenase (COX)-1 enzyme, thus permanently reducing the transformation of arachidonic acid into thromboxane-A2, a potent inducer of platelet aggregation. In patients with acute myocardial infarction (MI), the use of aspirin is associated with an approximately 30% reduction in the relative risk (RR) of the cumulative incidence of vascular death, MI or stroke [9]. The role of aspirin in ACS and all clinical settings of CAD is well established, but there has been some debate concerning its optimal dose. Aspirin is efficacious at a wide range of doses, but the risk of bleeding seems to be dose-dependent [10]. In the CURE trial, aspirin was administered (in combination with clopidogrel) at doses ranging from 75 to 325 mg, and there was no evidence of any greater efficacy at the higher doses; however, the incidence of major bleeding increased with the dose, and was lowest at doses of up to 100 mg [11]. The CURRENT-OASIS 7 trial, which randomised 25,087 patients with ACS to low-dose (75 -- 100 mg/day) or high-dose aspirin (300 -- 325 mg/day), has recently provided a conclusive answer [12]. There was no difference in the rate of the cumulative 28

primary end point of cardiovascular death, MI or stroke or in TIMI (thrombolysis in myocardial infarction) major bleeding between the two doses, but high-dose aspirin was associated with a higher risk of minor bleeding (p = 0.04) and gastrointestinal bleeding (p = 0.05) [13]. Some data concerning possible aspirin ‘resistance’ have been reported; however, although some patients may be truly resistant because of cellular or genetic factors, the possible explanation in the majority of cases is aspirin underuse or malabsorption, or drug interactions [14]. Aspirin is recommended for all patients with an initial oral (possibly chewable) loading dose (LD) of 150 -- 300 mg or intravenous bolus of 250 -- 500 mg, followed by a long-term maintenance dose (MD) of 75 -- 100 mg/day [4,5]. 3.

P2Y12 ADP-receptor antagonists

ADP is released by activated platelets, red blood cells and damaged endothelial cells. The currently available ADP-receptor antagonists are ticlopidine, clopidogrel, prasugrel and ticagrelor. Cangrelor and elinogrel are currently being investigated. Ticlopidine, in addition to conventional aspirin therapy, has been studied in patients with unstable angina and (in place of oral anticoagulation) patients undergoing percutaneous coronary intervention (PCI), leading to a striking reduction in adverse ischaemic events, including subacute stent thrombosis [15,16]. The introduction of dual antiplatelet therapy with aspirin and a thienopyridine has been a fundamental step forward in integrating antiplatelet therapy and interventional cardiology, permitting the widespread use of PCI as a key treatment for CAD [13]. It has been found that clopidogrel is as efficacious as ticlopidine in preventing periprocedural ischaemic events and subacute stent thrombosis after PCI, and has a better safety profile [17]. At present, dual antiplatelet therapy with aspirin plus an oral ADP-receptor inhibitor is recommended for all patients with ACS during the acute phase and for 12 months thereafter, unless it is contraindicated (e.g., because of an excessive risk of bleeding) [4-7]. Clopidogrel Clopidogrel, an oral, irreversible thienopyridine inhibitor of the platelet P2Y12 ADP receptor, has been extensively studied in patients with ACS. The first clinical evidence of the benefit of clopidogrel in this setting came from the CURE trial, in which patients with non-ST-segment elevation (NSTE)-ACS were randomised to receive, in addition to aspirin, clopidogrel or placebo at an initial LD of 300 mg and MD of 75 mg for up to 12 months [18]. Clopidogrel reduced the primary combined end point of death, MI and stroke by 20% in the overall study population (9.3 vs. 11.4%; RR 0.80, 95% confidence interval (CI) 0.72 to 0.90; p < 0.001) and, importantly, this benefit was evident 24 h after drug administration and continued throughout the 12 months of the study. Among the approximately 20% of patients who underwent PCI, the 3.1

Expert Opin. Pharmacother. (2012) 13(1)

Menozzi, Lina, Conte, Mantovani & Ardissino

P2Y12 receptor Clopidogrel Ticagrelor Elinogrel Cangrelor

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GPIIBIIIA Abciximab Tirofiban Eptifibatide

Par-1 receptor Vorapaxar Atopaxar Tromboxane receptor Aspirin

Figure 1. Platelet activation mechanisms: receptors involved and their antagonists (aspirin is not a receptor blocker but an inhibitor of the formation of the receptor agonist thromboxane-A2).

benefit of clopidogrel pretreatment was significant before PCI and long-term treatment was associated with a 30% RR reduction after 1 year of follow-up (8.8 vs. 12.6%; RR 0.69, 95% CI 0.54 to 0.87; p = 0.002) [19]. In patients with ST-segment elevation MI (STEMI), two different trials (COMMIT/CCS-2 and CLARITY-TIMI 28) confirmed the superiority of dual antiplatelet therapy with aspirin and clopidogrel over aspirin alone (albeit not in the context of primary PCI) [20,21]. Limitations of clopidogrel Despite its undoubted efficacy in multiple groups of patients, clopidogrel has some substantial limitations. First of all, its slow onset of action means that maximum platelet inhibition occurs at least 6 h after a standard LD of 300 mg, and only after 3 -- 5 days at the standard daily oral dose of 75 mg, without a LD [22]. The reason for the slow onset of action lies in the complex metabolism of clopidogrel: as a pro-drug, it requires two-step biotransformation to its active metabolite by hepatic cytochrome P450 (CYP) [23]. This may be partially overcome by administering a higher LD because more rapid and potent platelet inhibition can be reached at a dose of 600 mg [24]. The second limitation is the slow reversal of platelet inhibition caused by clopidogrel irreversible binding to the ADP receptor, and at least 5 days are needed for the recovery of 3.1.1

platelet function after drug discontinuation [25]. This may be important in patients requiring urgent coronary artery bypass grafting (CABG) or non-cardiac surgery. Third, the platelet inhibition induced by clopidogrel is an average of about 30 -- 40% at steady state, mainly because of its poor bioavailability. After oral administration, about 50% of the drug is rapidly absorbed by gastrointestinal system, and then approximately 85% is hydrolysed and inactivated by circulating esterases: only the remaining 15% of the absorbed pro-drug is therefore available for metabolisation by hepatic CYP450 enzymes to the active metabolite [22]. Finally, there is considerable inter-patient variability in the response to clopidogrel across a normal distribution [26]. This phenomenon, which has been known for years but has only recently been partially elucidated, consists of persistently high platelet reactivity despite adequate treatment, and has been observed in 4 -- 30% of patients by means of light transmission aggregometry [27]. A number of studies have investigated the clinical implications of this individual variability, and a poor antiplatelet response (measured by means of functional tests) has been associated with an increased risk of the re-occurrence of ischaemic events [28,29]. In an attempt to overcome these limitations, the clinical impact of increasing the clopidogrel dose has been tested. The CURRENT-OASIS 7 trial was designed to determine whether doubling the loading and initial MD of clopidogrel

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Antiplatelet therapy in acute coronary syndromes

(a 600 mg LD, followed by 150 mg/day for 7 days) was superior to the standard-dose regimen in ACS patients referred for an early invasive strategy. In the overall cohort, there was no difference in the primary efficacy end point (cardiovascular death, MI or stroke at 30 days), but the higher doses led to an increase in bleeding [12]. However, in the pre-specified subgroup of patients undergoing PCI, there was a reduction in the rates of the primary end point and definite stent thrombosis, again at the cost of an increase in major bleeding (although intracranial, fatal or CABG-related bleeding did not increase) [30]. Mechanisms of clopidogrel response variability The biological basis of the variability in clopidogrel responsiveness is multifactorial, involving clinical, environmental, cellular and genetic factors, and is still not fully understood [27] (Table 1). It is thought that the most important factor is related to genetic polymorphisms affecting clopidogrel pharmacokinetics. Clopidogrel’s active metabolite is generated in the liver by means of a two-step process involving several CYP450 isoenzymes, mainly 2C19 and 3A4, and the genes encoding CYP enzymes are polymorphic, with common alleles leading to reduced function [31,32]. The active (wild-type) allele of CYP2C19 is designated *1, whereas *2, *3, *4, *5, *6, *7 and *8 are loss-of-function alleles, and *17 is a gain-offunction allele. More than one-third of Europeans and more than 40% of people of African and Asian ancestry carry at least one copy of these common polymorphisms [33]. CYP2C19*2 is the most frequent variant in the reducedfunction group, and encodes a non-functional protein [34]. Four clinical phenotypes have been identified on the basis of the number of active, loss-of-function or gain-of-function alleles in DNA: extensive metabolisers are subjects with two ‘normal’ alleles (i.e., *1/*1) (wild-type); intermediate metabolisers have one copy of a loss-of-function allele (*1/*2); poor metabolisers have two loss-of-function alleles (*2/*2) and ultrarapid metabolisers have at least one copy of the gain-of-function allele (*1/*17 or *17/*17) [34]. Accordingly, clopidogrel responsiveness should not be considered in a dichotomously (resistant vs. non-resistant), but as a continuous and variable parameter. Carriers of the reduced-function CYP2C19 alleles have lower levels of clopidogrel’s active metabolite, show diminished platelet inhibition and are at higher risk of major adverse cardiovascular events, including a threefold greater risk of stent thrombosis [35,36]. Conversely, the carriers of the gain-of-function CYP2C19*17 allele, who are ultrarapid metabolisers, show high levels of CYP activity, an enhanced response to clopidogrel, and greater platelet inhibition, and may therefore be at increased risk of bleeding [37]. However, the *2 and *17 variants are in linkage disequilibrium, and so it is not certain that the effects of *17 are independent of those of *2 [38]. The majority of the variations in platelet response to clopidogrel remain unexplained by the CYP2C19*2 genotype and are therefore presumably due to

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3.1.2

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still unidentified and unmeasured factors, including possible additional genetic variants. In the PAPI (Pharmacogenomics of Antiplatelet Intervention) study of a homogeneous population of healthy Amish subjects, clopidogrel ADP-induced platelet aggregation was reduced in CYP2C19*2 allele carriers, thus showing a gene dosage effect; however, despite the relatively homogeneous population, the CYP2C19*2 genotype accounted for only 12% of the variability in clopidogrel response, whereas approximately 22% of the variation could be explained by age, body mass index (BMI) and lipid levels [39]. In addition to CYP2C19 genetic variants, other genetic polymorphisms influencing clopidogrel metabolism and clinical outcome have been identified in the ABCB1 gene, which encodes the efflux pump P-glycoprotein that regulates the intestinal absorption of clopidogrel [40], and in plasma paraoxonase-1 (PON1), a critical enzyme for clopidogrel bioactivation that determines the rate of active metabolite formation [41]. However, the findings concerning the PON1 enzyme are controversial because a subsequent study of a larger population found that PON1 polymorphisms did not influence platelet response or the risk of stent thrombosis in clopidogreltreated patients [42]. The knowledge that multiple singlenucleotide polymorphisms (SNPs) are associated with clopidogrel response variability may lead to them being combined into a panel in order to identify the patients at increased risk of recurrent adverse events. In 2010, on the basis of these data concerning genetic effects on metabolism, the Food and Drug Administration (FDA) added a boxed warning to the commercial label of clopidogrel that includes information about the reduced effectiveness of clopidogrel in poor metabolisers, the availability of tests to identify patients with genetic polymorphisms and the possibility of considering alternative treatment strategies. However, the FDA did not make any particular recommendation and left treating physicians to decide how to use this information and whether or not to undertake genetic testing [34]. Although it has been estimated that genetic factors are responsible for a large part of the individual variance in clopidogrel response, it is actually the result of the interaction of multiple factors, including also patient non-compliance, inappropriate dosing, higher pretreatment levels of platelet reactivity (i.e., patients with an increased BMI and diabetes mellitus), variable intestinal drug absorption and drug--drug interactions (strong inhibitors (such as ketoconazole) or inducers of CYP3A4 (such as rifampicin) may, respectively, reduce or increase the inhibitory effect of clopidogrel) [27]. In particular, proton pump inhibitors (PPIs) are metabolised by the hepatic CYP450 system, and it has been shown that omeprazole diminishes clopidogrel’s antiplatelet effect by inhibiting CYP2C19; this has led to concerns about the clinical impact of the interaction between PPIs and clopidogrel. Some retrospective analyses have found that patients treated with clopidogrel and PPIs are at higher risk of ischaemic events than those receiving clopidogrel alone, but other large-scale observational cohort studies and in post hoc

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Table 1. Factors influencing clopidogrel response variability. Genetic factors

Polymorphism Polymorphism Polymorphism Polymorphism

of of of of

CYP2C19 CYP3A4 ABCB1 PON1

Cellular factors

Reduced CYP3A metabolic activity Up-regulation of the P2Y12 pathway Up-regulation of the P2Y1 pathway Up-regulation of the P2Y-independent pathways (collagen, thromboxane-A2, thrombin) Increased ADP exposure Accelerated platelet turnover

Clinical factors

Poor compliance Underdosing Drug--drug interactions involving CYP450 isoenzymes Reduced intestinal absorption High BMI Diabetes mellitus ACS

ACS: acute coronary syndrome; ADP: adenosine diphosphate; BMI: body mass index.

analysis of the TRITON-TIMI 38 population have not confirmed the association between the use of PPIs and adverse outcomes [43,44]. Although its premature interruption meant that it was underpowered, the randomised COGENT trial, which tested omeprazole plus clopidogrel versus clopidogrel alone in patients receiving dual antiplatelet therapy, found that the routine use of omeprazole did not lead to any increase in ischaemic event rates, but reduced the rates of upper gastrointestinal bleeding [45]. There is still no conclusive clinical evidence that the co-administration of clopidogrel and PPIs increases the risk of ischaemic events. It has been recommended that PPIs are appropriate for use in patients on dual antiplatelet therapy at increased risk of gastrointestinal bleeding (a history of upper gastrointestinal tract bleeding, advanced age, the concomitant use of warfarin, steroids or non-steroidal anti-inflammatory drugs (NSAIDs) or Helicobacter pylori infection) [7-46]. Functional and genetic testing It has been clearly established that not all of the patients receiving clopidogrel benefit to the same extent and it has been shown that subjects with high on-treatment platelet reactivity at functional testing and those with a poor metaboliser genotype are at increased risk of ischaemic events. Platelet function and genetic testing might therefore lead to a paradigm shift in antiplatelet therapy. However, this is still speculative and, in the absence of any evidence of impact on clinical outcome, cannot be recommended for routine clinical decision making [34,47]. The main limitations of functional tests are the absence of a consensus regarding the most appropriate cut-off value for any one method 3.1.3

to predict the risk of cardiovascular or bleeding complications, and the only moderate correlation between the different assays [48]. Moreover, no large-scale clinical study has yet demonstrated that adjusting antiplatelet therapy on the basis of any of these cut-off values improves clinical outcomes. One strategy that has been evaluated has been to increase the dose on the basis of functional test results in order to improve the clinical efficacy of clopidogrel. In the GRAVITAS trial, an increased clopidogrel dose of 150 mg/day was compared with the standard regimen in patients showing persistently high platelet reactivity at functional testing. The occurrence of the composite primary end point (cardiovascular death, MI and stent thrombosis) was identical in the two groups, thus failing to demonstrate any improvement using this approach [49]. The TRIGGERPCI trial comparing prasugrel and clopidogrel in patients with stable CAD receiving PCI and high platelet reactivity has recently been halted because of the paucity of end points after a blinded preliminary analysis [50]. Similarly, the clinical usefulness of the available genetic tests is limited by various factors: the known genetic variants explain only a small part of the variation in platelet reactivity, the currently available commercial assays only cover a few variant alleles and the predictive capacity of genotyping is still quite weak, with limited sensitivity and specificity for detecting a high level of residual platelet activity [51]. The use of genotype-guided algorithms to tailor antiplatelet therapy on an individual basis has not yet been adequately tested in controlled trials, and so little is known about its possible impact on clinical outcomes. However, it is worth noting that the use of ticagrelor seems to be associated with better clinical outcome than clopidogrel, even in ‘good responders’ to clopidogrel [52]. New P2Y12 ADP-receptor antagonists: promises and challenges

3.2

In an attempt to overcome the limitations of clopidogrel, new drugs are being developed that offer more potent and efficacious inhibition of the P2Y12 ADP receptor (Table 2). Prasugrel Prasugrel is an oral, irreversible thienopyridine inhibitor of the platelet P2Y12 ADP receptor and, like clopidogrel, a prodrug that is rapidly absorbed and requires in vivo metabolism to form its active metabolite. Prasugrel has a faster onset of action than clopidogrel, and leads to greater platelet inhibition with less variability of response [53]. This superiority is mainly due to its greater bioavailability, which is related to its simpler metabolism that allows the more rapid and extensive formation of its ex vivo clopidogrel-equipotent active metabolite [54]. Furthermore, the genetic polymorphisms that limit the effectiveness of clopidogrel do not seem to affect prasugrel [40]. Prasugrel is biotransformed in the liver by means of rapid hydrolysis by carboxylesterases and oxidation mainly by CYP3A and CYP2B6, with lesser contributions from CYP2C9 and CYP2C19 [55]. Peak concentrations of the active metabolite are reached 30 min after oral dosing, and maximum platelet 3.2.1

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Antiplatelet therapy in acute coronary syndromes

Table 2. Novel antiplatelet drugs.

Prasugrel Ticagrelor Cangrelor Elinogrel Vorapaxar Atopaxar

Target receptor

Pro-drug

Inhibition mode

Administration route

Pivotal clinical trials

Stage of development

P2Y12 P2Y12 P2Y12 P2Y12 PAR-1 PAR-1

Yes No No No No No

Irreversible Reversible Reversible Reversible Reversible Reversible

Oral Oral Parenteral Oral and parenteral Oral Oral

TRITON-TIMI 38 PLATO CHAMPION-PHOENIX INNOVATE-PCI TRACER LANCELOT

EMA- and FDA-approved EMA- and FDA-approved Ongoing Phase III Phase II completed Phase III completed Phase II completed

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EMA: European Medicines Agency; FDA: Food and Drug Administration; PAR-1: protease-activated receptor-1.

inhibition occurs about 2 h after a LD of 60 mg [56]. The Phase II PRINCIPLE-TIMI 44 trial compared prasugrel with a high LD (600 mg) and MD (150 mg) of clopidogrel in patients with stable CAD and planned PCI, and found that it led to significantly greater, faster and more consistent platelet inhibition [57]. The pharmacodynamic data showed that there was a significant difference in the inhibition of platelet aggregation between clopidogrel 600 mg and prasugrel 60 mg as early as 30 min after the LD, by which time the magnitude of the effect of prasugrel was similar to that obtained with clopidogrel after 2 -- 4 h; after 6 h, the degree of platelet inhibition was more than double that achieved by clopidogrel. Similarly, during the MD phase, prasugrel led to constantly greater inhibition of platelet aggregation [5,6]. Because of its irreversible blockade of the P2Y12 receptor, it takes 5 -- 9 days after the discontinuation of prasugrel before its effects are reversed [22]. The Phase III TRITON-TIMI 38 trial found that prasugrel was more efficacious than clopidogrel in a broad population of patients with STEMI or NSTE-ACS undergoing PCI [58]. The trial randomised 13,608 subjects to prasugrel (a 60 mg LD followed by a MD of 10 mg/day) or clopidogrel (a 300 mg LD followed by a MD of 75 mg/day), which were both administered with low-dose aspirin for 6 -- 15 months. The primary composite end point of cardiovascular death, MI and stroke occurred in fewer patients treated with prasugrel (9.9 vs. 12.1%; hazard ratio (HR) 0.81, 95% CI 0.73 to 0.90; p < 0.001), who also experienced a lower incidence of MI (7.4 vs. 9.7%; p < 0.001), urgent target vessel revascularisation (2.5 vs. 3.7%; p < 0.001) and stent thrombosis (1.1 vs. 2.4%; p < 0.001; Figure 2A). This beneficial effect was accompanied by increased bleeding, as prasugrel increased the risk of non-CABG-associated TIMI major bleeding (2.4 vs. 1.8%; p = 0.03), life-threatening bleeding (1.4 vs. 0.9%; p = 0.01) and fatal bleeding (0.4 vs. 0.1%; p = 0.002; Figure 2B). Importantly, the net clinical benefit including efficacy and safety end points was in favour of prasugrel, which prevented 23 non-fatal MI at the expense of five additional major bleeding events per 1000 treated patients. Post hoc subgroup analysis showed that the efficacy of prasugrel was offset by a higher risk of bleeding in three categories of patients: subjects aged 75 years or more and those weighing 32

less than 60 kg derived no net benefit from prasugrel (HR 0.99, 95% CI 0.81 to 1.21; p = 0.92, and HR 1.03, 95% CI 0.69 to 1.53; p = 0.89); and patients who had experienced a previous stroke or transient ischaemic attack (TIA) had a worse outcome than those treated with clopidogrel (HR 1.54, 95% CI 1.02 to 2.32; p = 0.04). Conversely, in the patients not falling into these three categories (those aged < 75 years, weighing > 60 kg and with no history of cerebral ischaemia), prasugrel was found to be more efficacious than clopidogrel in terms of the primary efficacy end point (8.3 vs. 11.0%; HR 0.74, 95% CI 0.66 to 0.84; p < 0.001) and, importantly, it led to a similar incidence of major bleeding [58]. Among the pre-specified subgroups, patients with diabetes mellitus and those with STEMI undergoing primary PCI obtained a considerable clinical benefit from prasugrel, with a large reduction in the rate of ischaemic events (12.2 vs. 17.0%; HR 0.70, 95% CI 0.58 to 0.85; p < 0.001) and no increase in bleeding risk (10.0 vs. 12.4%; HR 0.79, 95% CI 0.65 to 0.97; p = 0.02) [59,60]. On the basis of the results of the TRITON-TIMI 38 trial, prasugrel has been approved for clinical use in patients with ACS treated by PCI. However, it is contraindicated in patients with a history of stroke or TIA. In those aged ‡ 75 years or weighing < 60 kg, a lower MD of 5 mg may help to minimise the bleeding risk, and this reduced dose is currently being evaluated in terms of clinical end points [61,62]. TRILOGY-ACS is an ongoing trial comparing the relative efficacy and safety of prasugrel and clopidogrel in medically managed patients with highrisk NSTE-ACS [61]. This trial is clinically important because, despite the widespread use of coronary revascularisation procedures in patients with NSTE-ACS, a substantial proportion of them are not revascularised, including patients with contraindications to an invasive strategy (mainly because of co-morbidities such as kidney disease), others judged unsuitable for revascularisation mainly because of their anatomical characteristics or sub-critical coronary atherosclerosis, and those refusing to undergo an invasive procedure. It is estimated that the percentage of patients not receiving PCI or CABG is about 30 -- 50% [63,64]. Prasugrel is recommended for STEMI [4,6] and for NSTEACS patients undergoing PCI [5] without any contraindications or a high risk of life-threatening bleeding, once their coronary anatomy is known.

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Menozzi, Lina, Conte, Mantovani & Ardissino

A. 15 p < 0.001

Clopidogrel

12.1

Prasugrel

p < 0.001

10 9.9 Percent

9.5 7.3

5 p < 0.001

p = 0.31 p = 0.93

2.4

2.1 1.0

0 Primary endpoint

B. 15

Cardiovascular death

Non fatal Stroke

Non fatal MI

1.1

1.0

Stent thrombosis

p < 0.001 Clopidogrel

Prasugrel

13.4

10 Percent

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2.4

p = 0.002 5

p = 0.03

5.0 p = 0.01 3.2

1.8

3.8

2.4 0.9

0 Non-CABG TIMI major bleeding

CABG-related TIMI major bleeding

1.4

Life-threatening bleeding

Major or minor TIMI bleeding

Figure 2. Major efficacy (panel A) and safety (panel B) end points after 15 months in the TRITON-TIMI 38 trial. The primary end point was the composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. Stent thrombosis was defined as definite or probable in accordance with the Academic Research Consortium. TIMI: thrombolysis in myocardial infarction criteria.

Ticagrelor Ticagrelor is an oral non-thienopyridine direct and reversible P2Y12 receptor antagonist. Unlike clopidogrel and prasugrel, it is not a pro-drug and therefore does not require metabolic activation [22]. Ticagrelor is characterised by a more rapid onset of action, relatively rapid reversibility and greater potency and consistency of platelet inhibition than clopidogrel: it leads to an average 50 -- 60% inhibition of ADPinduced maximum platelet aggregation 2 -- 4 h after a LD of 180 mg, and this level of inhibition is sustained by a MD of 90 mg b.i.d. [65]. 3.2.2

The ONSET/OFFSET trial compared the antiplatelet effects of ticagrelor and clopidogrel [66]. Aspirin-treated patients with stable CAD were randomised to receive a ticagrelor LD of 180 mg and a MD of 90 mg b.i.d., a clopidogrel LD of 600 mg and a MD of 75 mg/day or placebo for 6 weeks. The inhibition of platelet aggregation was greater in the ticagrelor group after 30 min (p < 0.0001) and at all timepoints during the 24 h after the LD and in the maintenance phase (p < 0.0001), more patients showed the onset of the antiplatelet effect within the first 2 h (p < 0.0001) and, 2 h after loading, more patients achieved 50 and 70% inhibition (p < 0001). After stopping

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Antiplatelet therapy in acute coronary syndromes

the study medication, more ticagrelor-treated patients showed offset 4 -- 72 h after the last dose (p < 0.0001) and, although the inhibition of platelet aggregation was not different between the two active treatment groups 24 or 48 h after the last dose, inhibition was lower in the ticagrelor group after 72 and 120 h (p < 0.05). The Phase III PLATO trial randomised 18,624 patients with STEMI or NSTE-ACS to ticagrelor (LD of 180 mg followed by 90 mg b.i.d.) or clopidogrel (LD of 300 -- 600 mg followed by 75 mg/day), in addition to aspirin [67]. The incidence of the primary end point, the composite of cardiovascular death, MI and stroke after 1 year of follow-up, was significantly reduced in the patients treated with ticagrelor (9.8 vs. 11.7%; HR 0.84, 95% CI 0.77 to 0.92; p < 0.001). Among the individual components of the primary end point, the rates of cardiovascular death and MI were lower in the ticagrelor group (p = 0.001 and p = 0.005, respectively), although there was no between-group difference in the rates of stroke (p = 0.22; Figure 3A). The difference in treatment effect was evident during the first 30 days of therapy and persisted throughout the study period. Although there was no difference in the overall rates of major bleeding between the ticagrelor and clopidogrel group (11.6 vs. 11.2%; p = 0.43), ticagrelor was associated with an higher rate of major bleeding unrelated to CABG (4.5 vs. 3.8%; p = 0.03), and a slightly lower rate of CABG-related major bleeding, although this last difference was not statistically significant (7.4 vs. 7.9%; p = NS; Figure 3B). One possible explanation of the 21% RR reduction in cardiovascular mortality obtained with ticagrelor may be the diminished risk of thrombotic events without a concomitant increase in the risk of bleeding (mortality benefit was particularly evident in patients undergoing CABG, in whom bleedings were dramatically reduced). Also, a potential off-target benefit of ticagrelor related to the inhibition of adenosine uptake into red blood cells, which may result in improved myocardial perfusion, may be considered [68]. All-cause mortality was lower in the ticagrelor group (4.5 vs. 5.9%; p < 0.001). However, as the pre-specified analyses of the PLATO trial involved a sequential hierarchical analysis of the secondary end points in which all-cause death came after stroke (the incidence of which was not significantly reduced), this finding should be interpreted with caution [67]. Importantly, the advantages of ticagrelor were seen regardless of whether invasive or non-invasive management was planned [69,70]. In the patients undergoing planned invasive treatment (PCI or CABG), ticagrelor led to a greater reduction in ischaemic events than clopidogrel (9.0 vs. 10.7%; HR 0.84, 95% CI 0.75 to 0.94; p = 0.0025) without any increase in major bleeding [69]. Furthermore, among the patients undergoing CABG, ticagrelor reduced the rate of all-cause death by 51% [71]. Subgroup analysis of the patients with STEMI undergoing primary PCI showed a 13% reduction in RR, in line with the overall effect of ticagrelor, without any increase in major 34

bleeding complications [72]. However, in the patients with a diagnosis of STEMI at presentation, there was only a trend towards a reduction in the primary end point (9.4 vs. 10.8%; HR 0.87, 95% CI 0.75 to 1.01; p = 0.07), while if the patients with a final diagnosis of STEMI were also included, the reduction was significant (9.3 vs. 11.0%; HR 0.85, 95% CI 0.74 to 0.97; p = 0.02). In the PLATO trial, ticagrelor was associated with peculiar side effects such as dyspnea (14.5 vs. 8.7%, p < 0.001) and bradyarrhythmias (0.9 vs. 0.1%, p < 0.001), which may limit its tolerability and lead to a higher rate of drug discontinuation in comparison with clopidogrel (7.4 vs. 6.0%, p < 0.001). Dyspnea was typically mild or moderate, the bradyarrhythmias were not associated with an increased risk of syncope or pacemaker implantation, and both tended to occur within the first few days of treatment [67]. It is worth noting that, like prasugrel, ticagrelor is not influenced by the genetic polymorphisms affecting clopidogrel (such as the CYP2C19 alleles or the ABCB1 genotype) because these proteins are not involved in its metabolism [52]. However, it has to be remembered that some drug--drug interactions can also occur with ticagrelor, such as in the case of the co-administration of strong CYP3A inhibitors or inducers [5]. In December 2010, the European Medicines Agency (EMA) approved ticagrelor for patients presenting with ACS regardless of whether they are managed medically or undergo PCI or CABG revascularisation. In the USA, the FDA has first requested further analyses of the PLATO data: this is widely believed to be due to an anomaly in the findings at the North American sites where, among the 1800 subjects enrolled, there was a statistically non-significant trend towards a worse outcome in the ticagrelor-treated patients, unlike in other geographical regions. One of the explanations put forward is that higher doses of aspirin were used in North America (up to 325 mg/day); other suggestions have included chance findings and different BMIs among North American patients [73]. In July 2011, FDA approved ticagrelor for the marketing in the USA with an accompanying boxed warning stating that use of ticagrelor with aspirin doses above 100 mg/day decreases the effectiveness of the medication [74]. Finally, ticagrelor is currently being investigated in the PEGASUS-TIMI 54 trial, in which patients with a previous ACS (12 -- 36 months before) are randomised to receive ticagrelor 60 or 90 mg twice daily, or placebo on top of aspirin (75 -- 150 mg). This study will examine the longterm efficacy and safety of ticagrelor after ACS (the primary end point will be the composite of cardiovascular death, nonfatal MI or stroke) in order to verify whether dual antiplatelet therapy beyond 12 months is beneficial [75]. The European guidelines currently recommend ticagrelor for STEMI and NSTE-ACS patients [5,6]. Cangrelor Like ticagrelor, cangrelor is a non-thienopyridine ADP-receptor antagonist, and a potent, parenteral, reversible and selective 3.2.3

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A. 15 Clopidogrel

p < 0.001

Ticagrelor

11.7 10 Percent

9.8

p = 0.005 p = 0.001 6.9

5

5.8

p = 0.02

5.1 4.0

p = 0.22 1.3

2.2

1.5

0 Primary endpoint

Cardiovascular death

Non fatal MI

Non fatal Stroke

Stent thrombosis

B. 15 Clopidogrel

p = 0.33

Ticagrelor

10.9

10 Percent

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2.9

p = 0.32

5

p = 0.03

2.2

5.8

11.4

p = 0.70

5.8

5.8

5.3

2.8

0 Non-CABG TIMI major bleeding

CABG-related TIMI major bleeding

Life-threatening bleeding

Major or minor TIMI bleeding

Figure 3. Major efficacy (panel A) and safety (panel B) end points after 12 months in the PLATO trial. The primary end point was the composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. Stent thrombosis was defined as definite or probable in accordance with the Academic Research Consortium. TIMI: thrombolysis in myocardial infarction criteria.

inhibitor of the P2Y12 receptor. It is only administered intravenously and does not require any further metabolism. After the administration of a bolus dose, the onset of action is immediate (within minutes) and platelet function normalises within 60 min of the discontinuation of the infusion [76]. Cangrelor has been evaluated in two Phase III studies: CHAMPION-PCI and CHAMPION-PLATFORM. Both were ended prematurely because the interim analysis did not reveal sufficient evidence of the drug’s clinical effectiveness. The CHAMPION-PCI trial enrolled 8716 patients: the large majority (85%) with ACS and a minority with stable angina (15%), who were all scheduled for PCI and receiving aspirin, and were randomised to receive cangrelor

followed by clopidogrel or clopidogrel alone [77]. Cangrelor (a 30 µg/kg bolus dose followed by a 4 µg/kg infusion) was started at the beginning of PCI, and administered for 2 -- 4 h (mean 2.1 h). A clopidogrel LD of 600 mg was given immediately after the end of the cangrelor infusion in the treatment arm and within 30 min of the start of the intervention in the control arm. The primary end point of the study (a composite of death from any cause, MI and ischaemia-driven revascularisation) occurred in the same proportion of patients in both arms (7.5 vs. 7.1% odds ratio (OR) 1.05, 95% CI 0.88 to 1.24; p = 0.59). The CHAMPION-PLATFORM trial enrolled 5362 patients with ACS or stable angina scheduled for PCI [78]. In

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Antiplatelet therapy in acute coronary syndromes

this trial, the control patients received the 600 mg LD of clopidogrel at the end of PCI (instead of within 30 min of the start of PCI as in the CHAMPION-PCI study) and only thienopyridine-naive patients were included, whereas the CHAMPION-PCI trial also enrolled patients receiving chronic treatment with clopidogrel. In this trial, the periprocedural use of cangrelor was not superior to placebo in reducing the 48-h primary end point of death, MI or ischaemia-driven revascularisation (7.0 vs. 8.0%; OR 0.87, 95% CI 0.71 to 1.07; p = 0.17), although there was a trend towards a 13% reduction in the RR of events and a lower incidence of death in the treatment arm. However, an exploratory analysis of the prespecified composite end point of all-cause death, showed that Q-wave MI and ischaemia-driven revascularisation (OR 0.72, 95% CI 0.52 to 0.98, p = 0.04) and all-cause death, Q-wave MI and stent thrombosis (OR 0.65, 95% CI 0.45 to 0.93, p = 0.02) were reduced in the cangrelor group after 48 h [78]. As some of the features of the design of these trials may account for the lack of evidence of the superior efficacy of cangrelor (including the definition of periprocedural MI), and because of the potential benefits of a potent, intravenously administered ADP-receptor antagonist (due to its rapid onset and offset of action), cangrelor is now being evaluated in the CHAMPION-PHOENIX trial, in which it is being compared with standard clopidogrel use in clopidogrel-naive patients undergoing PCI for stable or unstable CAD. The primary end point of this new study is the composite of allcause death, MI, ischaemia-driven revascularisation and stent thrombosis 48 h from randomization [79]. Elinogrel Elinogrel is a novel P2Y12 inhibitor that does not require metabolic activation and provides rapid, intense, competitive and reversible platelet inhibition. It is the first agent in this class to be developed in both intravenous and oral formulations. The safety and tolerability of adjunctive antiplatelet therapy with escalating intravenous doses of elinogrel in patients with STEMI undergoing primary PCI were evaluated in the pilot Phase IIA ERASE-MI trial [80]. It was found that treatment with a single intravenous bolus of elinogrel before primary PCI seemed to be feasible and well tolerated: the incidence of bleeding events was similar at all of the tested doses of elinogrel and placebo, and there were no differences in serious adverse events or ST-segment resolution. A second part of the trial was planned as a dose-confirmation study using the highest tolerated dose from the first part; however, as the sponsor prematurely discontinued the trial, it was never conducted. The safety and degree of platelet inhibition of elinogrel on top of aspirin in patients scheduled for non-urgent PCI was assessed in the Phase II INNOVATE-PCI trial, which randomised 652 patients to four treatment arms: a control group receiving clopidogrel 300 -- 600 mg followed by 75 mg/day, and three groups randomised to an 80 mg intravenous bolus of elinogrel followed by a 50, 100 or 150 mg oral dose twice 3.2.4

36

daily [81]. The results showed that, although elinogrel induced greater platelet inhibition than the standard doses of clopidogrel, there was no increase in TIMI major or minor bleeding in the periprocedural period or in the 120 days of follow-up. The trial was not powered for efficacy, but there were no differences in the clinical or biological efficacy end points across the treatment arms. These data support further investigations of this novel compound in patients with CAD, particularly those with ACS.

New targets for platelet inhibition: the role of PAR-1 inhibitors

4.

Despite effective inhibition of the thromboxane-A2 and ADP-receptor pathways, platelets can still be activated by thrombin receptor stimulation [82]. Furthermore, from a clinical point of view, the recurrence of ischaemic events in patients with ACS remains significant despite the use of dual antiplatelet therapy; which is why new therapies have to be investigated [83]. It is possible to hypothesise that blocking the platelet thrombin receptor PAR-1 (protease-activated receptor-1) may lead to greater platelet inhibition. Preclinical observations indicate that selectively inhibiting PAR-1 receptor interferes with thrombin-induced platelet activation, but not with thrombin-mediated fibrin generation and coagulation, which are essential for haemostasis. This platelet inhibition strategy may reduce the suppression of normal haemostasis and lead to a favourable balance of antithrombotic efficacy and risk of bleeding [84]. Thrombin receptor antagonists are a novel class of antiplatelet agents that inhibit thrombin-mediated platelet activation. Two are currently under evaluation in clinical trials: vorapaxar and atopaxar, both of which are potent, oral, competitive and selective PAR-1 antagonists. The clinical development of vorapaxar is further advanced. The efficacy and safety of vorapaxar in addition to standard of care therapies are currently being evaluated in two Phase III trials: TRA-CER in the setting of high-risk ACS, and TRA-2P TIMI 50 for secondary prevention. TRA-CER was designed to compare vorapaxar (a LD of 40 mg followed by 2.5 mg/day for at least 1 year) administered from the acute phase on top of dual antiplatelet therapy with placebo in the prevention of ischaemic events (cardiovascular death, MI, stroke, recurrent ischaemia and urgent coronary revascularisation) in patients with NSTE-ACS [85]. The results of this trial, which enrolled about 13,000 subjects, are expected to be available shortly and will clarify the possible role of such agents in the field of ACS. The placebo-controlled TRA-2P TIMI 50 trial is evaluating vorapaxar 2.5 mg/day in the long-term treatment of up to 27,000 patients with established atherosclerotic disease (a history of MI or stroke, or existing peripheral arterial disease) receiving standard therapy [86]. It is worth noting that an observed increase in intracranial hemorrhage in patients

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with a history of stroke treated with vorapaxar has led to the discontinuation of the study treatment in patients with a history of ischaemic stroke or who suffer a stroke during the course of the trial [87]. Atopaxar has recently completed its Phase II evaluation with the J-LANCELOT and LANCELOT trials that included an ACS and a stable CAD substudy [88]. In the most recent LANCELOT-ACS trial, similar rates of CURE-defined and TIMI-defined bleeding were observed in the atopaxar and placebo groups, without any difference in the incidence of adverse ischaemic events [89]. However, some concerning signals were observed in the patients receiving atopaxar, such as an increase in the levels of liver transaminase enzymes [87]. 5.

Glycoprotein IIb/IIIa inhibitors

Glycoprotein (GP) IIb/IIIa inhibitors are potent parenteral antiplatelet agents that block fibrinogen-mediated platelet aggregation (oral inhibitors failed in clinical studies because of an excess of ischaemic and bleeding events, and were never approved for clinical use). Over the last 20 years, GPIIb/IIIa inhibitors have played a major role in the antithrombotic treatment of patients undergoing PCI, particularly in the setting of ACS. All three available drugs (abciximab, eptifibatide and tirofiban) have been found to be efficacious in high-risk ACS by reducing the number of major adverse cardiovascular events (especially periprocedural MI), although their use has been constantly associated with an increased risk of bleeding [90,91]. The balance between the anti-ischaemic benefit and bleeding risk was generally considered favourable, especially in higherrisk patients, in an era in which dual oral antiplatelet therapy was not the standard treatment and only a minority of patients were treated with clopidogrel. Their use has recently been more limited not only because of the widespread adoption of dual antiplatelet therapy, but also because of the increasing attention being placed on haemorrhagic risk as a result of the greater awareness of the impact of bleeding on patient prognosis [8]. The ISAR-REACT 2 trial confirmed the efficacy of GPIIb/ IIIa inhibitors on top of dual antiplatelet therapy in patients with troponin-positive NSTE-ACS undergoing PCI, by showing that abciximab reduces the recurrence of ischaemic events in patients pretreated with a 600 mg LD of clopidogrel (8.9 vs. 11.9%; RR 0.75, 95% CI 0.58 to 0.97; p = 0.03) [92]. More recently, attention has been focused on the optimal treatment timing by comparing ‘upstream’ (immediately after diagnosis and before coronary angiography) and ‘downstream’ (in the cath. lab., after coronary angiography) GPIIb/IIIa inhibitors use [93]. In the EARLY-ACS trial, the routine ‘upstream’ use of eptifibatide in patients with NSTE-ACS was associated with a non-significant difference in ischaemic events at the expense of an increased rate of major bleeding [94]. It is worth noting that, in the setting of NSTE-ACS, the recommendations for this class of drug differs between the

European Society of Cardiology (ESC) and American College of Cardiology Foundation (ACCF)/ American Heart Association (AHA) guidelines. While the European guidelines suggest withholding GPIIb/IIIa inhibitors until after angiography, except in case of ongoing ischaemia or when oral dual antiplatelet is not feasible (class IIA), the US guidelines recommend their ‘upstream’ use as an alternative to clopidogrel (class I) or in addition to clopidogrel (class IIA) in patients undergoing initial invasive strategy [5-7]. In patients with STEMI, in whom the efficacy of GPIIb/ IIIa inhibitors is firmly established because of the high thrombotic burden and the advantage of parenteral use in the emergency setting of primary PCI [4,6], the FINESSE trial found that ‘upstream’ abciximab showed no advantage over ‘downstream’ abciximab in terms of clinical outcomes, but increased bleeding rates [95]. Of note, both of the new ADP inhibitors prasugrel and ticagrelor are more efficacious than clopidogrel also in patients receiving GPIIb/IIIa inhibitors [67,96]. On the other hand, whether the use of GPIIb/IIIa inhibitors is beneficial in patients treated with prasugrel or ticagrelor is unknown and deserves further investigation. 6.

Conclusions

Dual antiplatelet therapy with aspirin and clopidogrel has represented the standard of care for patients with ACS over the last decade. However, the reoccurrence of ischaemic events remains a major concern and indicates the need for alternative agents and targets. Prasugrel and ticagrelor have improved clinical outcomes by reducing the re-occurrence of ischaemic events, but at the expense of an increased risk of bleeding. In the light of these new advances, the role of GPIIb/IIIa inhibitors may need to be redefined. Other agents, such as cangrelor, elinogrel and platelet PAR-1 receptor inhibitors, are still under investigation. To optimise clinical outcomes, the choice of antiplatelet strategy must be based on balancing the risks of ischaemia and bleeding in each individual patient. The focus in the near future will be to identify how to realise the promise of ‘personalised medicine’ in the setting of ACS. 7.

Expert opinion

The ACS pharmaco-therapeutic arsenal has significantly expanded over recent years. Given the array of medications available and their possible combinations, it is becoming challenging to choose the optimal antiplatelet therapy in clinical practice. In patients with ACS, the selection of antiplatelet agents should be based on the thrombotic and haemorrhagic risk ratio, and consideration should also be given to the management strategy (initially invasive or conservative). Among the P2Y12 receptor antagonists, patients with STEMI undergoing

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primary PCI and diabetics, especially younger subjects, obtain considerable benefit from the use of prasugrel or ticagrelor because in these patients the more potent agents result in a greater efficacy in reducing ischaemic events without increasing the risk of bleeding. The more rapid onset of action of prasugrel and ticagrelor may also be particularly helpful in the emergency setting of primary PCI, and in patients with NSTE-ACS undergoing an early invasive strategy. Similarly, patients at higher risk of stent thrombosis (e.g., those with multiple drug-eluting stents or who have experienced thrombosis while taking clopidogrel) should receive the new P2Y12 receptor inhibitors. Clopidogrel is still the best option in patients at increased risk of bleeding, and especially in the elderly (who are a significant part of everyday clinical practice but definitely under-represented in randomised clinical trials). With regard to the different use of the new agents, prasugrel is currently confined to PCI-treated patients once their coronary anatomy is known, whereas ticagrelor can be administered as soon as a diagnosis of ACS is made. The ongoing ACCOAST trial is evaluating the ‘upstream’ use of prasugrel in patients with NSTE-ACS before coronary angiography [62]. Ticagrelor can also be used in the case of a conservative strategy, a treatment option that involves a substantial proportion of ACS patients. The ongoing TRILOGY ACS trial is comparing the use of prasugrel and clopidogrel in such patients. The benefit of prasugrel appears earlier in the periprocedural setting, and it may be preferable in the case of primary PCI, whereas the benefit of ticagrelor seems to increase over time. Another key point seems to be the different timing of the reversal of the antiplatelet action. The shorter period before the offset of ticagrelor may be an advantage in cases in which drug interruption may be required (i.e., patients at high risk of urgent cardiac or non-cardiac surgery); on the other hand, its short half-life and twice daily dose may require stricter compliance in order to avoid the risk of adverse events due to inappropriate drug interruption. In any case, it is recommended to withdraw ticagrelor 5 days before major surgery [5]. The side effects of ticagrelor (dyspnea and ventricular pauses) may limit its use in certain patients, such as those suffering from dyspnea because of heart failure or respiratory disease, or those with a history of syncope. Another challenging issue is the use of GPIIb/IIIa. Their role remains central in the setting of STEMI, especially in patients with a high thrombotic burden, recent symptom onset and low haemorrhagic risk. The provisional use at the time of angiography is advisable because this strategy is equally efficacious and associated with less bleeding (and also in relation to the availability of bivalirudin, which may guarantee better net clinical outcomes in patients at higher bleeding risk). In patients with NSTE-ACS, on top of oral dual antiplatelet therapy, the ‘downstream’ use of GPIIb/IIIa can be considered in selected patients with a high thrombotic risk (i.e., diabetics or those with an angiographically visible thrombus) and low bleeding risk. Their ‘upstream’

38

use (with tirofiban or eptifibatide) should be reserved to patients with ongoing ischaemia or at very high ischaemic risk (but without a high bleeding risk) awaiting a very early invasive strategy, although it may also be considered instead of an ADP-receptor blocker in clinically unstable patients who are likely to be candidates for urgent surgical revascularisation. Finally, in all patients, it is advisable to minimise bleeding risk and optimise outcomes by reducing the duration of infusion, carefully dosing heparin, and using the radial approach [97]. In the future, if cangrelor and elinogrel prove to be efficacious and are approved for clinical use, their intravenous administration may provide a further advantage in the acute phase because of their rapid onset and offset action. PAR-1 inhibitors are currently being evaluated during the acute phase and long-term management of ACS. Preclinical data suggest that PAR-1 is a very good antithrombotic target that has little effect on haemostasis. If PAR-1 inhibitors prove to be really effective in reducing ischaemic events without increasing bleeding, they can probably play a role on top of dual antiplatelet therapy in patients without a high haemorrhagic risk, and in combination with aspirin (as an alternative to ADP-receptor blockers) in patients at high haemorrhagic risk. For the development of this strategy, one key point will certainly be their positive or negative association with intracranial bleeding risk. A number of other significant questions concerning antiplatelet therapy remain to be answered, including the optimal management of patients who need to discontinue dual antiplatelet therapy before surgical procedures, and the very important question of the optimal duration of long-term dual antiplatelet therapy after ACS. Finally, platelet function and genetic testing could bring about the promise of ‘personalised medicine’ in the near future. This will be possible if antiplatelet therapy guided by functional and/or genetic tests is shown to improve clinical outcomes in comparison with the standard approach, and to be cost-effective (as generic clopidogrel will be on the market). Platelet function and genetic testing should therefore be prospectively investigated in order to determine whether they are stand-alone or complementary strategies [98,99]. Alternatively, with the availability of prasugrel and ticagrelor, which are more potent, effective and consistent antiplatelet agents, and are not influenced by genotype, the characterisation of clopidogrel responsiveness may become irrelevant or possibly only selectively applicable to patients who are candidates for clopidogrel treatment because of a high bleeding risk, in order to exclude the presence of a harmful genotype.

Declaration of interest The authors state no conflict of interest and have received no payment in preparation of this manuscript.

Expert Opin. Pharmacother. (2012) 13(1)

Menozzi, Lina, Conte, Mantovani & Ardissino

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Affiliation

Alberto Menozzi† MD PhD, Daniela Lina MD, Giulio Conte MD, Francesco Mantovani MD & Diego Ardissino MD † Author for correspondence Azienda Ospedaliero-Universitaria di Parma, Unita` Operativa di Cardiologia, via Gramsci 14, 43126 Parma, Italy Tel: +39 0521 704608 702070; Fax: +39 0521 702189; E-mail: [email protected]