ACUTE CORONARY SYNDROMES | REVIEW

The Antiplatelet Journey Thus Far:

Focus On New Oral P2Y12 Inhibitors

Morten Würtz, MD, Erik Lerkevang Grove, MD, PhD, & Steen Dalby Kristensen, MD, DMSc, FESC* Department of Cardiology, Aarhus University Hospital, Skejby, Denmark.

Received 5/9/2011, Reviewed 29/9/2011, Accepted 30/11/2011 Key words: acute coronary syndromes, antiplatelet agents, , , , DOI: 10.5083/ejcm.20424884.62

ABSTRACT CORRESPONDENCE

Platelets are pivotal in the pathophysiology of acute coronary syndromes; the leading cause of death Steen Dalby Kristensen, worldwide. The use of antiplatelet agents in the treatment of acute coronary syndromes has reduced MD, DMSc, FESC Department of Cardiology, morbidity and mortality substantially. Thus, aspirin has been a cornerstone in the treatment of acute Aarhus University Hospital, coronary syndromes for years. However, during the last decade the P2Y12 inhibitor clopidogrel has Skejby Brendstrupgaardsvej 100, accompanied aspirin to further improve clinical outcomes. P2Y12 inhibitors are antiplatelet agents 8200 Aarhus, Denmark preventing the binding of diphosphate to P2Y12 receptors on the surface thus inhibiting platelet aggregation. Phone: +45 78 45 20 30 Fax: +45 78 45 22 60 Recently, the emergence of two new P2Y12 inhibitors, prasugrel and ticagrelor, has challenged the E-mail: [email protected] role of clopidogrel. Similar to clopidogrel, prasugrel is a prodrug that needs hepatic conversion to its active metabolite to provide irreversible P2Y12 inhibition. In contrast, ticagrelor is a direct-acting FUNDING allosteric P2Y12 antagonist inhibiting the P2Y12 reversibly. Both drugs provide a better pro- The authors are supported by tection against cardiovascular outcomes than clopidogrel as evidenced by large clinical trials. This the Danish Research Agency benefit might partly reflect the rapid onset of action and the pronounced antiplatelet effect of these (grant 2101-05-0052 to Drs. drugs compared to clopidogrel. So far, no direct comparison of prasugrel and ticagrelor has been Würtz, Grove, and Kristensen), performed, but ongoing trials will provide data to clarify the clinical role of these drugs. Aarhus University (Dr. Würtz), and The A.P Møller Foundation for the Advancement of Medical The present review outlines the key milestones of the history of P2Y12 inhibitors and provides an up- Science (Dr. Kristensen). to-date overview and comparison of the clinical applicability of these drugs.

DISCLOSURES Dr. Kristensen has received lecture fees from AstraZeneca and acute coronary syndromes Circulating platelets constantly interact with and Eli Lilly. Funding for this the vascular endothelium, but remain inactive article was provided by Acute coronary syndromes (ACS) are the leading due to the inhibitory action of e.g. nitric oxide AstraZeneca. The authors cause of death worldwide and one of the main and prostacyclin produced by endothelial cells. maintained full control of the reasons for hospital admissions in developed Upon endothelial injury, the subendothelium is content and writing of the countries. ACS thus represent a major public exposed to the stream and the circulating manuscript. AstraZeneca health concern. platelet pool. This, in turn, promotes the release provided medical accuracy review of the final draft. of mediators and cytokines that lead to the acti- Platelets play a pivotal role in the pathophysi- vation of receptors responsible for adhesion and ology of ACS. They are small anuclear cell frag- aggregation, such as the P2Y12, thromboxane ACKNOWLEDGEMENTS ments, measuring 2-3 μm, produced in the A2 and glycoprotein IIb/IIIa receptors. The authors appreciate the bone marrow as a result of the fragmentation input of Sami A. Omar, MBBS, of megakaryocytes. The life span of a platelet is Activation of these receptors induces platelet MRCP, St Thomas’s Hospital, about 7-10 days, and around 1011 platelets are aggregation, temporarily sealing the breach in Kings College University, produced every day (1). Platelets also play an im- the vessel wall. Aggregated platelets provide a London and Ami Richards, Editor, Healthcare Bulletin in platform on which fibrin is incorporated once portant role in normal haemostasis and healing the preparation of the processes. the full cascade has been activated. manuscript Regeneration of the damaged tissue is facili- tated through the release of platelet growth fac- tors. Once the healing process is complete the clot is broken down and reabsorbed (2;3).

ISSN 2042-4884

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Despite their key role in haemostasis, platelets may cause tissue Furthermore, as platelets are anuclear they are unable to regener- damage once activated inappropriately. In particular, platelet ag- ate , which is why the inhibition persists for the entire life gregation is harmful in the lumen of a coronary artery already span of the platelet (6). Aspirin has been proven to reduce morbid- partly obstructed by the intraluminal extension of an atheroma- ity and mortality in the context of secondary prevention, whereas tous plaque. Rupture of an unstable plaque may have fatal conse- its benefit in primaryprevention is a modest reduction of vascular quences. The exposure of the lipid-rich centre of the plaque leads events although offset by the increased risk of major bleeding(8) . to the activation of platelets potentially initiating a platelet acti- vation cascade. If platelet activation continues it may occlude the Clopidogrel vessel and compromise blood flow to the part of the myocardium distal to the occlusion. Eventually, this results in myocardial injury Clopidogrel is a second generation . It is a prodrug, and necrosis (2). which is well absorbed from the gut, but requires activation in the liver through the cytochrome P450 (CYP) system. The active metab- Although activation, adhesion and aggregation of platelets are olite of clopidogrel inhibits the ADP receptor-mediated platelet ag- necessary components during normal vascular healing processes, gregation pathway. The need for activation partly accounts for the inhibiting their function is potentially beneficial. Sufficient inhibi- delayed onset of its antiplatelet effect. This delay can be reduced by tion of platelet aggregation is one of the main goals in the pharma- the use of higher doses of clopidogrel (9). cological management of ACS, and current guidelines advocate the use of dual antiplatelet therapy (4;5). The prevailing dual antiplatelet CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) strategy is the use of aspirin and clopidogrel. However, new potent was a landmark trial, which established clopidogrel as a corner- drugs have recently been introduced and may serve clinicians as stone in dual antiplatelet therapy and affirmed that increased strong alternatives to the traditional regimen for dual antiplatelet platelet inhibition entails a reduction in cardiovascular events (10). therapy. Important differences between currently available anti- platelet drugs are outlined in Table 1. CURE was a randomised, double-blind, placebo-controlled trial in which a total of 12,562 ACS patients were included most being Aspirin treated conservatively rather than invasively. Only patients without ST-segment elevation being hospitalised within 24 hours of symp- Aspirin (acetylsalicylic acid) was the first major drug used in the tom onset were included. setting of preventive antiplatelet therapy. Aspirin inhibits plate- let aggregation by reducing thromboxane A2 production. This is The study was later refined to only include patients with either elec- achieved through the acetylation of the cyclooxygenase(COX)-1 trocardiographic changes consistent with cardiac ischaemia and/or leading to its permanent deactivation and inability to pro- elevation in cardiac biomarkers suggestive of myocardial necrosis. duce the platelet activator thromboxane A2. Aspirin has a rapid on- All patients were randomly assigned to either clopidogrel (300 mg set of action, and the maximum effect is achieved within one hour loading dose followed by 75 mg daily) or placebo on top of aspi- of administration (6). In healthy individuals, a single dose of 20 mg, rin (75-325 mg daily). Treatment was continued for 3 to 12 months 325 mg and 600 mg leads to inhibition of COX function by 34%, (mean duration 9 months). 89% and 95%, respectively (7).

Residual platelet function results from the continued stimulation of aggregation through COX-1 independent pathways mediated by (ADP) and thrombin.

Table 1: Characteristics of oral antiplatelet drugs.

Primary mode Metabolism and Frequency of Drug of action platelet inhibition administration

Aspirin COX-1 inhibitor Prodrug, irreversible Daily

Clopidogrel ADP P2Y12 receptor Prodrug, irreversible Daily antagonist

Prasugrel ADP P2Y12 receptor Prodrug, irreversible Daily antagonist

Ticagrelor Allosteric ADP P2Y12 Direct-acting, reversible Twice daily receptor antagonist

ADP, adenosine diphosphate; COX, cyclooxygenase.

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The occurrences of the first primary endpoint, a composite of Prasugrel death, non-fatal (MI) and stroke, and of the second primary endpoint (the first primary in addition to refractory Prasugrel is a new thienopyridine agent. Like clopidogrel it requires ischaemia) were both significantly reduced in the clopidogrel arm activation to its active metabolite, which blocks the P2Y12 subtype (9.3% vs. 11.4%, p < 0.001; 16.5% vs. 18.8%, p < 0.001, respectively). of the ADP receptor. Accordingly, prasugrel is a prodrug, but it is Furthermore, there was a reduction in the incidence of secondary more efficiently converted to its active metabolite than clopidogrel. endpoints; severe ischaemia (2.8% vs. 3.8, p = 0.007), revascularisa- The metabolism is dependent on hepatic CYP enzymes as well as tion (20.8% vs. 22.7%, p = 0.03), and heart failure (3.7% vs. 4.4%, p intestinal carboxylesterases, but still, it has a more rapid onset of = 0.026). The benefits of dual antiplatelet therapy were apparent action and inhibits platelet aggregation stronger and more consis- within the first few hours after administration. These benefits, how- tently than clopidogrel. ever, were achieved at the cost of a significant increase in the num- ber of major bleeding events (3.7% vs. 2.7%, p = 0.001), although Thus, pharmacodynamic data suggest that the level of platelet in- this did not translate into a significant increase in life-threatening hibition attained 6 hours after the administration of clopidogrel bleeding (2.1% vs. 1.8%, p = 0.13) (10). can be achieved within 30 minutes with prasugrel (16). Moreover, the active metabolite of prasugrel inhibits ADP-induced platelet Once the benchmark of dual antiplatelet therapy in ACS was estab- aggregation with the same potency as that of clopidogrel in vitro, lished, the next question to arise was the optimal dosing required. but the in vivo differences in the metabolism of the drugs confer This question was addressed in the CURRENT-OASIS 7 trial (11;12); an approximately 12-fold greater exposure to prasugrel following a randomised, multinational, factorial trial evaluating the efficacy a loading dose of prasugrel (60 mg) compared to clopidogrel (300 of high- and low-dose antiplatelet therapy with aspirin and clopi- mg) (17). Also in terms of maintenance treatment, prasugrel (10 mg dogrel in patients with ACS treated with percutaneous coronary daily) provides a higher and more consistent level of platelet inhi- intervention (PCI). More than 25,000 patients were recruited on bition than clopidogrel even when using a relatively high dose of the basis of electrocardiographic changes suggestive of ischaemia clopidogrel (150 mg daily) (18). and/or raised levels of cardiac biomarkers. In view of these biochemical differences, the TRITON-TIMI 38 trial Around 17,000 of these patients were deemed suitable for PCI and (TRial to Assess Improvement in Therapeutic Outcomes by Optimiz- divided into four groups of 4,300 patients each. At first randomisa- ing Platelet InhibitioN with Prasugrel-Thrombolysis In Myocardial tion (double blind), patients were assigned to either high-dose (600 Infarction) was designed to compare the efficacy and safety of pra- mg loading dose followed by 150 mg daily for one week followed sugrel vs. clopidogrel in ACS patients planned to undergo PCI (19). by 75 mg daily) or low-dose dose (300 mg loading dose followed TRITON-TIMI 38 was a randomised, double-blind trial in which more by 75 mg daily) clopidogrel. At second randomisation (open label), than 13,500 aspirin-treated patients received either prasugrel (60 patients were assigned to either high-dose (300–325 mg daily) or mg loading dose followed by 10 mg daily) or clopidogrel (300 mg low-dose (300 mg followed by 75-100 mg daily) aspirin. loading dose followed by 75 mg daily). Treatment was continued for 6 to 15 months. CURRENT-OASIS 7 did not demonstrate a reduction in the primary outcome (death, MI or stroke at 30 days) in patients receiving high- The study demonstrated a significant reduction of the primary dose clopidogrel (4.2% vs. 4.4%, p = 0.3), but there was a significant endpoint (death, non-fatal MI and non-fatal stroke) in the prasug- reduction of the secondary endpoint of stent in the rel group compared to the clopidogrel group (9.9% vs. 12.1%, p < subgroup of patients undergoing PCI (1.6% vs. 2.3%, p = 0.001). 0.001), a benefit mainly driven by a reduction in non-fatal MI (7.3% This benefit, however, was obtained at the expense of more major vs. 9.5%, p < 0.001) and not by death (2.1% vs. 2.3%, p = 0.31) or bleeding (2.5% vs. 2.0%, p = 0.01). The dose of aspirin had no effect non-fatal stroke (1% in both groups, p = 0.93). Furthermore, there on the primary or secondary endpoints and no effect on bleeding was a significant reduction in the need for target vessel revasculari- rates (11). sation (3.7% vs. 2.5%, p < 0.001) and stent thrombosis with the use of prasugrel (2.4 vs. 1.1%, p < 0.001). However, the use of prasugrel The improved outcome in patients undergoing PCI obtained with conferred an increased incidence of non-coronary artery bypass the high-dose clopidogrel regimen were attributed to the more grafting (CABG) Thrombolysis In Myocardial Infarction (TIMI) ma- rapid onset of effect. Other concerns with clopidogrel are related to jor bleeding (2.4% vs. 1.8%, p = 0.03) and life-threatening bleeding its metabolism through the CYP system in the liver where the active (1.4% vs. 0.9%, p = 0.01) (19). metabolites are formed. In this regard, drug interactions between clopidogrel and proton pump inhibitors, especially omeprazole, and A post-hoc subgroup analysis recognised three specific groups other drugs that interfere with the CYP system might be important in which the benefit-to-harm risk profile differed from the overall (13;14). Another major concern was the emergent evidence of ge- study results. The first two groups included patients of 75 years or netic polymorphisms in the CYP system affecting the generation of older and patients with a body weight of less than 60 kg; these pa- the active metabolite and the platelet response to clopidogrel (15). tients had no overall benefit or harm. The third group, patients with a history of previous stroke or transient ischaemic attack (TIA), had In light of these concerns, it became apparent that better antiplate- an overall increase in adverse outcomes with no evidence of clini- let agents were needed. Recently, two new antiplatelet agents, cal benefit. In this group, the incidence of major bleeding was 2.3% prasugrel and ticagrelor, have been approved for clinical use. These with prasugrel vs. 0% in the equivalent group treated with clopido- drugs have improved pharmacodynamic capacities compared to grel (p = 0.02) (19). Accordingly, prasugrel should not be used in pa- clopidogrel and large clinical trials have documented their poten- tients with a history of previous stroke or TIA, and the dose should tial to improve cardiovascular outcome. be reduced to 10 mg/day in the elderly (≥75 years) and those with a body weight of less than 60 kg.

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Another subgroup analysis restricted to patients with diabetes If not already on aspirin they were given a loading dose of 300-325 showed that the reduction in the composite primary endpoint of mg. Patients were randomly assigned to either ticagrelor (180 mg cardiovascular death, nonfatal MI, and nonfatal stroke was signifi- loading dose followed by 90 mg twice daily) or clopidogrel (300 mg cant in both diabetic (14%) and non-diabetic (30%) patients (20). loading dose followed by 75 mg daily). Patients undergoing PCI af- Moreover, the incidence of major bleeding was similar among dia- ter randomisation received an additional dose of their study drug at betic patients, thus contrasting with the increased bleeding inci- the time of PCI: 300 mg of clopidogrel, at the investigator’s discre- dence seen with prasugrel in the non-diabetic patients. Overall, the tion, or 90 mg of ticagrelor for patients who were undergoing PCI net clinical benefit of prasugrel seems larger in ACS patients with more than 24 hours after randomisation (25). diabetes, and similar findings have been reported for a subgroup of ST-segment elevation MI (STEMI) patients (21). PLATO demonstrated a significant reduction in the occurrence of the primary endpoint (a composite of vascular death, MI or stroke) In TRITON-TIMI 38, all patients were scheduled for PCI, but another with the use of ticagrelor vs. clopidogrel (9.8% vs. 11.7%, p < 0.001). large trial is currently evaluating the effect of prasugrel in similar Furthermore, there was a significant reduction in the occurrence of patients not scheduled for PCI; TRILOGY ACS (the TaRgeted plate- the secondary endpoint (a composite of death from any cause, MI let Inhibition to cLarify the Optimal strateGy to medicallY manage and stroke) in the ticagrelor group (10.2% vs. 12.3%, p < 0.001), and Acute Coronary Syndromes) is a randomised, double-blind trial a significant reduction in a composite of death from any cause, MI planned to enrol 10,300 non-STEMI ACS patients within 10 days of and stroke in addition to recurrent ischaemia, TIA or other arterial presentation with either unstable angina or non-STEMI, who are thrombotic events (14.6% vs. 16.7%, p < 0.001). not intended to undergo revascularisation procedures for their in- dex event (22). In the ticagrelor group, a significant reduction in the incidence of MI alone was seen (5.8% vs. 6.9%, p = 0.005), and, importantly, the Ticagrelor rate of death from any cause was also reduced with ticagrelor (4.5% vs. 5.9%, p < 0.001). Moreover, death from vascular causes was re- Ticagrelor, an ATP analogue, is a reversible P2Y12 ADP receptor an- duced (4.0% vs. 5.1%, p = 0.001), whereas the incidence of stroke tagonist. Ticagrelor does not require metabolism in the liver, thus was not (1.5% vs. 1.3%, p = 0.22). These effects were evident at 30 leading to less inter-individual variability and more consistent days and were sustained during the entire study (25). platelet inhibition compared to clopidogrel. Furthermore, it has a more rapid onset and offset of action with more potent platelet in- Regarding safety, there were no significant difference between hibition than clopidogrel. A recent study demonstrated that plate- groups in terms of the occurrence of TIMI major bleeding (7.9% vs. let inhibition at 30 minutes with ticagrelor was equivalent to that 7.7%, p = 0.57), and there were no difference in the incidence of achieved with clopidogrel at 4 hours. At 1 hour after loading, the fatal or life-threatening bleeding (5.8% in both, p = 0.70). Ticagrelor degree of platelet inhibition with ticagrelor was greater than the conferred an increased incidence of non-CABG TIMI major bleeding maximal inhibition attained using clopidogrel, even though maxi- (4.5% vs. 3.8 %, p = 0.03) and intracranial bleeding as a whole (0.3% mal platelet inhibition with ticagrelor was not reached until 2 hours vs. 0.2%, p = 0.06), particularly fatal intracranial bleeding (0.1% vs. after administration. 0.01%, p = 0.02). In contrast, the occurrence of other types of fatal bleeding was reduced with ticagrelor (0.1% vs. 0.3%, p = 0.03) (25). Regarding offset, there was no significant difference in the extent Recent data have shown that treatment with ticagrelor results in a of platelet inhibition between ticagrelor and clopidogrel at 24 and significantly lower prevalence of high on-treatment platelet reac- 84 hours following the final dose, whereas ticagrelor provided sig- tivity than clopidogrel (26), and that ticagrelor overcomes low-re- nificantly lower inhibition of platelet aggregation than clopidogrel sponsiveness in patients with coronary artery disease treated with at 72 and 120 hours after the last dose (23). A recent study evaluated clopidogrel (27). and compared the pharmacodynamic properties of ticagrelor and clopidogrel in relation to CYP2C19 genotype. The study confirmed These findings are in line with the improved clinical outcome re- that the antiplatelet effect of clopidogrel is dependent on CYP2C19 ported from the PLATO trial (25) and may be explained by the phar- genotype, whereas this is not the case for ticagrelor (24). This lends macodynamic differences between the drugs. Moreover, a PLATO further support to the use of ticagrelor in patients carrying the loss- substudy revealed that the superiority of ticagrelor is present irre- of-function CYP2C19 alleles. spective of CYP2C19 and ABCB1 polymorphisms (28). Also, the sub- groups of STEMI patients (29) and patients undergoing CABG (30) To assess the effect of ticagrelor on clinical outcomes, the PLATO had benefit of ticagrelor compared to clopidogrel although not sta- trial (PLATelet inhibition and patient Outcomes) was designed as a tistically significant. Moreover, the excess benefit of ticagrelor was randomised, double-blind study comparing the efficacy and safety present whether patients were treated invasively or conservatively of ticagrelor and clopidogrel in patients with ACS (25). The diagno- (31). Finally, patients with impaired renal function appear to profit sis of ACS was evidenced by two of the following criteria; electro- particularly from ticagrelor (32). cardiographic changes suggestive of coronary ischaemia (unless it was ST-segment elevation with planned PCI; then this criterion alone did suffice), positive biomarkers consistent with myocardial DISCUSSION necrosis or one of a number of predefined risk factors. Furthermore, all patients were included in the study within 24 hours of symptom As platelets play an integral role in the pathophysiology of ACS, in- onset. A total of 18,624 patients were recruited and followed for up hibiting platelet activation and aggregation is a logical approach to 12 months. Most patients were treated with aspirin at a dose of when aiming to improve ACS outcome. Numerous pathways con- 75 mg to 100 mg daily. tribute to platelet activation, and several drugs have been devel- oped to inhibit these pathways and improve treatment of platelet- dependent thrombosis.

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From the data outlined above, it is apparent that various strategies This might be a result of the more rapid offset of ticagrelor´s effect, of intense platelet inhibition do indeed improve clinical outcome. owing to the reversibility of the P2Y12 receptor inhibition provid- The combination of aspirin and clopidogrel set the benchmark for ed by this drug as demonstrated in patients with stable coronary dual antiplatelet therapy in the wake of the CURE study. However, artery disease (23). Similarly, the DISPERSE-2 study demonstrated concerns have emerged regarding the efficacy of clopidogrel due that patients undergoing CABG 1-5 days after stopping ticagrelor to its delayed onset of action, interaction with other drugs and a therapy had a numerically lower incidence of major bleeding than highly variable inter-individual platelet inhibitory effect. These patients treated with clopidogrel (36% vs. 64%) (36). Treatment with limitations have highlighted the need for new antiplatelet agents ticagrelor can be initiated prior to coronary angiography and may capable of overcoming the drawbacks of clopidogrel. Ideally, these be administered to patients who have already received clopidogrel. drugs should have a rapid onset of action and display a potent and There is no requirement to modify the dose according to age or more reliable antiplatelet effect. Furthermore, they should have a body weight. predictable and consistent antiplatelet effect in all individuals. Prasugrel and ticagrelor have emerged as potent and effective al- At first glance, examination of the data presented from TRITON-TIMI ternatives to clopidogrel in the management of ACS (4;5). So far, no 38 and PLATO suggests that prasugrel and ticagrelor meet the high direct comparison of these drugs has been performed. Currently, expectations as both drugs have a more rapid and pronounced an ongoing randomised crossover trial on ACS patients is compar- antiplatelet effect than clopidogrel. However, it is important to ing the efficacy of prasugrel and ticagrelor in terms of overcoming consider that TRITON-TIMI 38 was designed for patients scheduled high on-clopidogrel platelet reactivity (NCT01360437). Impor- for PCI. Additionally, the dose of clopidogrel used in this study was tantly, Bonello et al. recently demonstrated that the concern of on- lower than what is recommended by current guidelines (4). More- treatment platelet reactivity persists even with the new drugs. In over, as outlined above, in some specific patient groups prasugrel ACS patients treated with PCI, high on-prasugrel platelet reactivity is actually associated with an unfavourable benefit-to-harm risk was frequent (25,2%) and associated with an increased rate of car- profile. diovascular events (37).

By contrast, in the PLATO study ticagrelor was used to treat all In conclusion, antiplatelet therapy remains a cornerstone in ACS patients presenting with ACS regardless of planned PCI or not. In treatment and has improved clinical outcome substantially. De- keeping with current guidelines, patients undergoing PCI were spite the advantage of clopidogrel as a part of a dual antiplatelet given high loading doses of antiplatelet treatment. Thus, they re- treatment strategy, this drug has important limitations. New drugs ceived an additional dose of the study drug at the time of PCI: 300 with more rapid and sustained action, more predictable function mg of clopidogrel or 90 mg of ticagrelor for patients undergoing and improved safety profiles are available heralding the advent of a PCI more than 24 hours after randomisation. Disadvantages of ti- new era in the treatment of ACS. cagrelor are the side effect of transient dyspnoea (33) and the need for twice daily dosing. REFERENCES The benefits derived from platelet inhibition in ACS are usually ob- (34) tained at the expense of an increased risk of bleeding . This is 1 Kaushansky K. Historical review: megakaryopoiesis and an important consideration given the increased mortality associ- thrombopoiesis. Blood 2008;111:981-6. ated with peri-interventional bleeding (35). However, there was no increase in the incidence of major bleeding events when compar- 2 Davi G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med 2007;357:2482-94. ing clopidogrel and ticagrelor whether employing the PLATO or the TIMI bleeding definitions. 3 Yeghiazarians Y, Braunstein JB, Askari A, Stone PH. Unstable angina pectoris. N Engl J Med 2000;342:101-14. This is in contrast to the comparison of clopidogrel and prasugrel, 4 Wijns W, Kolh P, Danchin N, Di MC, Falk V, Folliguet T, et al. in which the incidence of TIMI major bleeding was increased in Guidelines on myocardial revascularization: The Task Force on patients treated with prasugrel. However, in the PLATO study the Myocardial Revascularization of the European Society of number of non-CABG TIMI major bleeding was also significantly in- Cardiology (ESC) and the European Association for Cardio-Thoracic creased in the ticagrelor group confirming the dogma that stronger Surgery (EACTS). Eur Heart J 2010;31:2501-55. platelet inhibition provides a reduction in ischaemic events at the 5 Hamm CW, Bassand JP, Agewall S, Bax J, Boersma E, Bueno H, et al. cost of more spontaneous bleeding events. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The offset of action is another important aspect of antiplatelet The Task Force for the management of acute coronary syndromes agents used in the context of ACS, as a number of these patients (ACS) in patients presenting without persistent ST-segment elevation require CABG instead of PCI. Antiplatelet therapy is likely to either of the European Society of Cardiology (ESC). Eur Heart J 2011. delay surgery or precipitate bleeding-related complications. In TRI- 6 Patrono C, Garcia Rodriguez LA, Landolfi R, Baigent C. TON-TMI 38, a total of 368 patients underwent CABG. There was a Low-dose aspirin for the prevention of atherothrombosis. significant increase in the number CABG-related TIMI major bleed- N Engl J Med 2005;353:2373-83. (21) ing in the prasugrel group (13.4% vs. 3.2%, p < 0.001) . 7 Burch JW, Stanford N, Majerus PW. Inhibition of platelet prostaglandin synthetase by oral aspirin. J Clin Invest 1978;61:314-9. In the PLATO study, a total of 782 patients were triaged to CABG. In these patients, ticagrelor was associated with a slightly lower rate 8 Berger JS, Lala A, Krantz MJ, Baker GS, Hiatt WR. Aspirin for the of CABG-related TIMI major bleeding (5.3% vs. 5.8%, p = 0.32) (25). prevention of cardiovascular events in patients without clinical cardiovascular disease: A meta-analysis of randomized trials. Am Heart J 2011;162:115-24. 9 Savcic M, Hauert J, Bachmann F, Wyld PJ, Geudelin B, Cariou R. Clopidogrel loading dose regimens: kinetic profile of pharmacodynamic response in healthy subjects. Semin Thromb Hemost 1999;25 Suppl 2:15-9.

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