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84 THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 26, NO. 2, 2013 Review Article

P2Y12 inhibitors in acute coronary syndromes: Which and when?

PREM PAIS

ABSTRACT cascade is the key pathology. Since the patho- Acute coronary syndromes (ACS) are the commonest acute physiology in ACS involves activation and the coagulation manifestation of coronary artery disease and a major cause of cascade, medical strategy targets both these systems. The use of hospitalization and death. Plaque rupture and subsequent a single agent is insufficient to address the ‘hot plaque’ and thus platelet activation are the key factors in its pathogenesis. multiple agents are required. Drugs that target mainly the coagulation cascade include those that block either via Platelet inhibitors are crucial in the management of ACS. 3 (, low molecular weight heparin [LMWH], remains the standard antiplatelet but use of dual ), directly (, ) or by blocking antiplatelet drugs is beneficial in ACS. Platelet the action of (, ). inhibitors are an important group of antiplatelet compounds The antiplatelet drugs act by blocking various platelet receptors that can be combined with aspirin in the management of ACS. (Fig. 1) and when used in combination in ACS they can lead to P2Y12 inhibitors may belong to the or non- better outcomes with acceptable safety. Aspirin, the earliest used thienopyridine group of compounds. The former (, antiplatelet agent in ACS, causes reduced synthesis of ) combine irreversibly with the receptor and therefore A2 which is responsible for the platelet activation effect of have a prolonged duration of action. On the other hand, the collagen by inhibiting the cyclooxygenase . The P2Y12 non-thienopyridine compounds (, ) have a receptor inhibitors (, clopidogrel, prasugrel, ticagrelor, reversible action and hence a shorter duration of action. , elinogrel) block the effect of diphosphate Several new compounds in this group have become or are (ADP) which acts by activating this receptor, while GPIIb/IIIa likely to become available. The newer agents have a more receptor inhibitors (, and ) block uniform and complete antiplatelet effect and are much less the final common pathway which involves fibrinogen and results likely to be affected by genetic variability of CYP2C19 enzyme in cross-linking of . The last group is used mainly in activity compared with that of clopidogrel. Large phase 3 trials conjunction with invasive management of ACS. In the setting of have shown that ticagrelor and prasugrel reduce major ACS, inhibition of platelet aggregation is related to clinical cardiovascular events in ACS compared to clopidogrel when outcomes; therefore, greater inhibition with acceptable risk of given in addition to aspirin. This is accompanied by some increase in . Collagen This review discusses the properties, clinical profile and possible place of P2Y12 receptor inhibitors in clinical practice. Aspirin ADP Natl Med J India 2013;26:84–90 Thromboxane A2 ACUTE CORONARY SYNDROMES (ACS) AND THEIR MEDICAL MANAGEMENT P2Y12 receptor Acute ST elevation (STEMI), acute non-ST inhibitors elevation myocardial infarction (NSTEMI) and unstable angina GPIIb/IIIa activation (UA) are the most frequent acute presentations of ischaemic heart disease (IHD). They carry significant morbidity and mortality. In GPIIb/IIIa all three forms of ACS, plaque rupture followed by platelet receptor activation, aggregation and subsequent triggering of the inhibitors

Platelet aggregation Department of Medicine, Clinical Trials Division, St John’s Medical College, Bengaluru 5600334, Karnataka, India; [email protected] FIG 1. Site of action of antiplatelet drugs ADP © The National Medical Journal of India 2013 PAIS : P2Y12 INHIBITORS IN ACUTE CORONARY SYNDROMES 85 bleeding should lead to better clinical efficacy. Seminal trials1,2 over aspirin. The CAPRIE study9 showed a borderline reduction have shown that in ACS platelet aggregation should be blocked at (8%) in major adverse cardiovascular events (MACE) compared two sites. The current guidelines for management of ACS to aspirin, and the CHARISMA study10 showed no benefit of recommend the use of aspirin with a P2Y12 inhibitor in most using dual antiplatelet agents (aspirin and clopidogrel) over patients, with additional use of GPIIb/IIIa receptor inhibitor in aspirin alone in stable coronary artery disease. However, in ACS patients undergoing percutaneous coronary intervention (PCI).3 the role of clopidogrel is different. The CURE study,1 a placebo- controlled, double-blind study showed that in NSTEMI ACS the Aspirin addition of clopidogrel to aspirin reduced adverse events Aspirin has been in use for over a century for its anti-inflammatory (combination of cardiovascular death, non-fatal MI and non-fatal effects. Thirty years ago, it was discovered to have, in low doses, ) from 11.4% to 9.3%. This 20% relative risk reduction an antiplatelet effect by blocking the cyclooxygenase enzyme. (RRR) was homogeneous among all subgroups, i.e. even patients Aspirin is rapidly absorbed and inhibits platelet aggregation in with no ST depression or enzyme elevation benefited. However, about 60 minutes, but it has a relatively weak antiplatelet effect. this benefit came at the cost of increased bleeding—a 34% About one-third of patients are resistant to the effect of aspirin. (p=0.003) increase in major bleeds in the clopidogrel arm although Nevertheless, clinical trials of aspirin in ACS clearly showed that there was no significant increase in life-threatening bleeds. it reduced vascular mortality and recurrent myocardial infarction In the subgroup of participants in the CURE trial undergoing (MI). The ISIS 2 study4 showed a 23% reduction of vascular PCI (PCI-CURE)11 the benefit increased further (MACE reduced mortality among patients with STEMI given 162.5 mg of aspirin by 35% at 30 days and 28% at one year) with no increase in major alone and 42% reduction when given with compared bleeds. Subsequently, the CLARITY and COMMIT trials2,12 to placebo. A meta-analysis of trials of aspirin in ACS involving showed that the benefit of adding clopidogrel to aspirin was true 95 000 individuals in primary prevention trials and 17 000 in for STEMI even when many patients were treated with secondary prevention trials5 showed a 20% reduction of serious . In both the CURE and CLARITY trials, a loading vascular events. In view of this, low-dose aspirin remains the key dose of 300 mg clopidogrel followed by 75 mg daily was used in the management of ACS and should always be used unless there while in the COMMIT study from China the same daily dose was is a specific contraindication. used but with no loading dose. The CLARITY trial, like the CURE trial, reported a 20% reduction in the composite end-point of P2Y12 RECEPTOR INHIBITORS cardiovascular death, non-fatal MI and non-fatal stroke while About a decade after aspirin came to be used as an antiplatelet COMMIT with a large sample size of over 45 000 participants agent, a new class of such agents, the , was intro- reported a smaller but still highly significant reduction of 9%. The duced. Ticlopidine was the first such agent to be used in clinical lack of a loading dose in COMMIT could have been responsible practice.6 This group of drugs blocks platelet activation through for this smaller effect. ADP by blocking the platelet P2Y12 receptor. Ticlopidine was The antiplatelet effect of clopidogrel can be quite variable and found to cause bone marrow suppression in a few patients resulting the drug needs to be used in larger doses in critical situations such in leucopenia and occasionally thrombotic thrombocytopenic as ACS where PCI is intended. The CURRENT-OASIS 7 study13,14 purpura.7 It has been largely replaced by clopidogrel, the second compared two dosing regimens of clopidogrel—high dose (600 agent in this class. In the past 5 years large clinical trials have been mg loading dose, 150 mg daily for 7 days followed by 75 mg daily) conducted with newer P2Y12 inhibitors which are now entering with low dose (300 mg loading dose followed by 75 mg daily) in the market. This review focuses on the P2Y12 inhibitors especially patients with ACS where PCI was intended. All patients received clopidogrel, prasugrel and ticagrelor and their place in the clinical aspirin too in one of two doses (300–325 mg or 75–100 mg). management of ACS. While in the entire study population there was no significant The P2Y12 receptor plays a key role in activation of platelets. reduction in MACE (hazard ratio [HR] 0.95, 95% CI 0.83–1.06) Its activation by ADP leads to platelet degranulation, aggregation, or cardiovascular death (HR 0.95, 95% CI 0.81–1.13), in patients procoagulant activity and platelet–leucocyte interaction leading who actually underwent PCI there was a significant reduction to conversion of monocytes to macrophages and release of (15%) in MACE (HR 0.86, 95% CI 0.74–0.99) and a 46% cytokines.8 These actions are blocked by the P2Y12 inhibitors. reduction in definite stent thrombosis (HR 0.54, 95% CI 0.39– Based on their molecular structure, P2Y12 inhibitors are classified 0.74) but not in cardiovascular death alone (HR 0.96, 95% 0.79– as being thienopyridine or non-thienopyridine. Drugs in the 1.19) in patients receiving the higher dose of clopidogrel (Table thienopyridine group (ticlopidine, clopidogrel and recently II). This benefit of the higher dose came at a cost of a 39% increase prasugrel) bind to the P2Y12 receptor irreversibly and hence have in major bleeds. Following OASIS 7, it seems reasonable to use a prolonged action. A second and newer group of P2Y12 inhibitors the higher dose regimen in patients with ACS undergoing PCI but is the non-thienopyridine compounds (ticagrelor and cangrelor). not in others. It is yet unclear how long the higher maintenance Unlike the thienopyridine compounds, the non-thienopyridine dose of 150 mg should be continued. In OASIS 7 it was given for compounds bind reversibly to the P2Y12 receptor and therefore have a shorter duration of action. In the case of ticagrelor, the duration of action is about 3 days and in the case of cangrelor it is TABLE I. Characteristics of thienopyridine and non-thienopyridine about an hour (Table I). Ticagrelor has recently been licensed in antiplatelet compounds Europe and is being actively reviewed for licensing by the Food • Thienopyridine compounds (irreversible binding to P2Y12 receptor) and Drugs Administration (FDA) in the USA and the Drug Clopidogrel: Slow onset of action, slow offset of action Controller General of India (DCGI) in India. Prasugrel: Fast onset of action, slow offset of action • Non-thienopyridine compounds (reversible binding to P2Y12 receptor) Clopidogrel Ticagrelor: Fast onset of action, fast offset of action In stable IHD, clopidogrel does not seem to have a major advantage Cangrelor: Very fast onset of action, very fast offset of action 86 THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 26, NO. 2, 2013

TABLE II. Comparison of high-dose versus low-dose clopidogrel in patients undergoing percutaneous coronary intervention (PCI): Data from CURRENT-OASIS7 study13,14 Event All patients PCI No PCI RR (95% CI) RR (95% CI) RR (95% CI) Major adverse cardiovascular events* 0.94 (0.83–1.06) 0.86 (0.74–0.99) 1.14 (0.92–1.40) Cardiovascular death 0.95 (0.81–1.13) 0.96 (0.77–1.19) 0.99 (0.70–1.39) Definite stent thrombosis – 0.54 (0.39–0.74) – Major bleeding 1.24 (1.05–1.46) 1.39 (1.07–1.81) 1.09 (0.88–1.35) RR relative risk CI confidence interval * major adverse cardiovascular events (composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke) a week before reverting to a dose of 75 mg a day. The ARMYDA- could be used to tailor the dose of clopidogrel. All subjects were 4 and -515,16 studies did not find any benefit of reloading with given a loading dose of 600 mg of clopidogrel. Platelet function another 600 mg in patients who were already on clopidogrel. was tested using a point-of-care device (VerifyNow) 12–24 hours However, these studies were underpowered. Based on these after PCI. Those with platelet reactivity >230 units were studies the American College of Cardiology (ACC)/American randomized to either 75 mg or 150 mg of clopidogrel daily for 6 Heart Association (AHA) guidelines3 recommend that 75 mg oral months. In studying the whole cohort there was a 68% non- clopidogrel should be given to all patients with STEMI (ACS) significant trend to increased events in patients with persistent regardless of reperfusion therapy and that it is reasonable to give high platelet reactivity. Although platelet reactivity was a 300 mg loading dose to those below 75 years of age. Pretreatment significantly reduced in patients receiving the higher dose of with a loading dose of 300–600 mg clopidogrel is recommended clopidogrel, the study could not show any clinical benefit of the before PCI. higher doses of clopidogrel. The reasons for this are unclear. The The major advantage of clopidogrel is that its strengths and authors hypothesized that perhaps platelet reactivity is a marker weaknesses are well known since it has been in use for over 15 but not necessarily the cause of higher events. The dose used may years. It has been shown in large clinical trials to reduce not have been high enough (although CURRENT showed definite cardiovascular events in acute and non-acute coronary artery benefit in cases of ACS undergoing PCI with 150 mg for just 7 disease, cerebrovascular disease and peripheral artery disease. days). The fact that all patients received a similar loading dose of Some areas of concern are its delayed onset of action, the variability 600 mg may have masked any effect of the difference in the in its antiplatelet effect and its long duration of action, increasing maintenance dose. Finally, including stable coronary artery disease the risk of bleeding due to coronary artery bypass graft (CABG) with ACS may have had an impact on the results. and non-CABG surgery. About 33% of patients on The irreversibility of clopidogrel action gives it a prolonged clopidogrel are ‘resistant’ and show only a low level of platelet antiplatelet effect until a new generation of platelets is developed. inhibition.17 One of the main reasons for the variability and This can lead to bleeding problems when surgery particularly delayed onset of action of clopidogrel is that it is a that CABG surgery is done in patients on the drug. Clopidogrel needs requires a two-step activation in the involving a series of to be discontinued at least 5 days before any major surgery. On the cytochrome P-450 (CYP) isoenzymes.18 This activation is other hand, the advantage of the prolonged action is that, even if susceptible to reduction in enzyme action caused by genetic a dose or two is missed, some antiplatelet effect remains. polymorphisms and to the effect of drug interaction when agents There has also been concern about the of with metabolism involving these isoenzymes are used clopidogrel in patients receiving the proton pump inhibitor concomitantly with clopidogrel. . Proton pump inhibitors can inhibit the CY2C19 that A reduced function allele of CYP2C19 is common and patients is required for the activation of clopidogrel. Some studies on with this allele have been shown to have a reduced area under the platelet aggregation have shown that use of clopidogrel with curve (AUC) of the active clopidogrel metabolite on omeprazole results in a reduction in the effect of clopidogrel in pharmacokinetic studies and reduced platelet aggregation on inhibiting platelet aggregation.23 The COGENT trial24 studied pharmacodynamic studies compared to those with an active 3873 patients on aspirin who were randomized to receive either a allele.19 In a study of 1477 patients with ACS and a planned PCI fixed-dose combination of clopidogrel 75 mg and omeprazole 20 treated with clopidogrel, over a year, there was a 50% increase in mg, or clopidogrel and placebo. The combination therapy group the composite of cardiovascular death, non-fatal MI and non-fatal had a 70% reduction in gastrointestinal bleeding (HR 0.30, stroke (relative risk [RR] 1.53, 95% CI 1.07–2.19, p=0.014) and p=0.001) and there was no increase in MACE (HR 0.99, p=0.96). a three-fold increase in stent thrombosis (RR 3.04, 95% CI 1.19– A cohort study of a general practice database of 24 471 patients 8.00, p=0.015) in those with the reduced function allele.20 This in Britain also did not find any clinical consequence of the use of increased event rate in those with this allele has also been proton pump inhibitors with clopidogrel.25 confirmed by a recently published meta-analysis.21 As a result in 2010, the US FDA required a black box warning to be added to the Prasugrel clopidogrel information leaflet to indicate that persons with ACS Prasugrel is a thienopyridine P2Y12 receptor inhibitor that has or those undergoing a PCI who have a reduced function allele of been licensed and marketed recently. It shares the class effect of CYP2C19 can have increased events while on the standard dose thienopyridines in being a non-reversible inhibitor of the P2Y12 of clopidogrel. Alternative treatment strategies may be considered receptor. In fact its duration of action is longer than that of where such patients are identified. The GRAVITAS trial22 in 2214 clopidogrel. However, it has a more rapid onset of action and more subjects with stable coronary artery disease or ACS undergoing uniform and complete inhibitory effect on the receptor. It requires PCI studied whether measuring the extent of platelet inhibition a one-stage activation that is much less dependent on the CYP PAIS : P2Y12 INHIBITORS IN ACUTE CORONARY SYNDROMES 87 enzyme and its action does not seem to be affected in patients who at a dose of 100 mg twice daily produced a uniform near 100% have a reduced function CYP2C19 allele. impaired platelet agreggability (IPA) while clopidogrel at a dose The definitive study on which prasugrel’s regulatory approval of 75 mg once daily produced 60% IPA.29 was based was the TRITON-TIMI 38 study.26 TRITON-TIMI 38 The pharmacodynamic sub-study from the DISPERSE trial was a double-blind, double-dummy, randomized of showed that 90 mg of ticagrelor b.i.d. produced a 75% inhibition patients with ACS (STEMI, NSTEMI and UA) and planned PCI; of platelet function while 75 mg of clopidogrel produced a 64% 13 600 patients were enrolled and randomized either to clopidogrel inhibition. Moreover, ticagrelor could produce an additional (300 mg loading dose/75 mg daily) or prasugrel (60 mg loading suppression of platelet function even in those patients previously dose/10 mg daily). All patients received aspirin. The median treated with clopidogrel.30 The ONSET–OFFSET study31 compared duration of follow-up was 14.5 months. The study reported a the pharmacodynamics of ticagrelor 180 mg followed by 90 mg significant 20% reduction in the composite of cardiovascular twice daily and clopidogrel 600 mg followed by 75 mg daily over death, non-fatal MI and non-fatal stroke with prasugrel compared 6 weeks on platelet aggregability in 123 patients with stable to clopidogrel. This applied equally to STEMI and NSTEMI ACS. coronary artery disease on aspirin. Ticagrelor produced The absolute risk reduction was 1.9% for NSTEMI and 2.4% for significantly greater IPA within 30 minutes, greater degree of STEMI. Stent thrombosis was reduced by over 50%. This benefit impairment of platelet function and faster return to baseline was seen both for drug-eluting stents (2.2% stent thrombosis rate platelet function compared with that of clopidogrel. with clopidogrel v. 0.8% with prasugrel, p<0.0001) and bare Early phase studies also showed some unusual symptoms in metal stents (2.3% stent thrombosis rate with clopidogrel v. 1.2% patients on ticagrelor. There was an increase in dyspnoea without with prasugrel, p=0.0014). However, these benefits came at the evidence of cardiac or pulmonary decompensation as well as cost of increased bleeding. Prasugrel led to significant increase in increased episodes of bradycardia.32,33 These symptoms do not both major (30% increase) and minor bleeds and in CABG surgery seem related to its antiplatelet effect but may be related to its and non-CABG surgery bleeding. CABG surgery-related major similarity in structure to adenosine. bleeding rate was 13.4% with prasugrel v. 3.2% with clopidogrel. The PLATO study34 was a phase 3 trial of ticagrelor in a broad In some subgroups excess bleeding nullified the benefit of range of ACS. It included patients with either STEMI or NSTEMI prasugrel—those >75 years of age, <60 kg in weight or those who and those managed with an invasive or conservative strategy. had had a stroke in the past. It would be wiser to avoid prasugrel However, the use of fibrinolytic therapy was a contraindication in such patients or to use a lower dose. On the other hand, TRITON for inclusion in the trial. The PLATO study randomized 18 624 confirmed that prasugrel retains its efficacy even in those with patients to either 180 mg loading dose of ticagrelor followed by reduced activity CYP2C19 allele. The event rate was similar in the 90 mg twice daily or to 300/600 mg of clopidogrel followed by 75 prasugrel arm for such patients while it was 53% higher in the mg daily. The study was continued for a median of 277 clopidogrel arm. If such patients could be identified, prasugrel days. It showed that patients randomized to ticagrelor had a would be especially beneficial for them. Another subgroup in significant 16% RRR in the composite of cardiovascular death, which prasugrel could be useful is those at high risk. In TRITON, non-fatal MI and non-fatal stroke (p=0.001). The use of ticagrelor patients with diabetes in the prasugrel arm had a highly significant was associated with a significant reduction in the pre-specified reduction in events (30%) with no increase in bleeding compared secondary end-point of MI (HR 0.84, 95% CI 0.75–0.95, p=0.005) to those in the clopidogrel arm. and cardiovascular death (HR 0.79, 95% CI 0.69–0.91, p=0.001). Prasugrel was approved by the US FDA in 2009 as an alternative The latter is a unique finding for not since aspirin has an antiplatelet to clopidogrel for patients with ACS who are to undergo PCI. The agent been shown to reduce mortality as an independent event. recommended dosage is a loading dose of 60 mg followed by a Neither CURE nor TRITON-TIMI 38 showed a significant maintenance dose of 10 mg daily (5 mg in those >75 years of age reduction in mortality (Table III). In PLATO, the rates of all-cause or <60 kg in weight). In patients with STEMI who are to be treated mortality were 4.5% with ticagrelor and 5.9% with clopidogrel— with thrombolytic therapy clopidogrel is preferred. Prasugrel a significant 22% RRR. The mechanism for this reduction in should be stopped 7 days earlier where CABG surgery is planned. mortality is unclear. It could be related to the increased antiplatelet For patients with ACS (without ST elevation) in whom medical effect without an increase in overall major bleeding (see below). management and not revascularization is planned, the TRILOGY It could also be related to the adenosine-like effect the molecule study27 did not show any benefit of prasugrel over clopidogrel. It has which also explains its unusual adverse symptoms of is known that smoking induces the effect of CYP 450. It is bradycardia and dyspnoea. In PLATO, ticagrelor also led to a 23% therefore of interest that an analysis of smokers in a cohort of patients undergoing PCI and the post hoc subgroup analysis of TRITON did not show any difference in outcome between smokers TABLE III. Clinical trial evidence of P2Y12 receptor inhibitors on and non-smokers—the benefits of prasugrel over clopidogrel clinical end-points in patients with acute coronary syndromes persisted.28 End-point Clopidogrel Prasugrel Ticagrelor Ticagrelor versus versus versus placebo clopidogrel clopidogrel Ticagrelor is a non-thienopyridine P2Y12 receptor inhibitor and (CURE)1 (TRITON)26 (PLATO)34 as such blocks this receptor reversibly. It has a rapid onset of action (within an hour) and a relatively quicker offset of its Total mortality 0.93 0.95 0.78* antiplatelet effects. It is a direct-acting drug that does not require Cardiovascular mortality 0.93 0.89 0.79* Major adverse cardiovascular 0.80* 0.81* 0.84* activation in the liver and hence its action is not affected in events† patients with the reduced activity CYP2C19 allele. Its platelet Major bleeding 1.38* 1.45* 1.04* inhibition effect is dose-dependent and is more complete than that All values are hazard ratios * p<0.05 † cardiovascular death, non-fatal myocardial 17 of clopidogrel. Phase 1 studies in humans showed that ticagrelor infarction and non-fatal stroke 88 THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 26, NO. 2, 2013 reduction in any stent thrombosis (p=0.01) and 33% reduction in volunteers, it causes near 100% inhibition of ADP-induced platelet definite stent thrombosis (p=0.009). The benefits were seen aggregation.36 This increased platelet inhibition is seen even in regardless of an invasive or non-invasive strategy. In patients in those already receiving clopidogrel. However, so far clinical trial whom a conservative strategy was planned, compared to those on data have been disappointing. CHAMPION-PCI,37 a double- clopidogrel, those on ticagrelor had a 15% reduction in MACE blind, double-dummy trial randomized patients with ACS going (p=0.04), 24% reduction in cardiovascular death (p=0.02) and for PCI to cangrelor (bolus 30 µg/kg followed by an infusion of 25% reduction in total mortality (p=0.01). A pre-planned subgroup 4 µg/kg/hour) or clopidogrel 600 mg loading dose. Both arms analysis of PLATO showed that patients intended for medical were given clopidogrel after the PCI. At 48 hours, there was no management did not differ in outcome from the entire population.35 difference between the two arms as far as the primary end-point One would expect a drug with increased antiplatelet effect to was concerned (death, MI, ischaemia-driven revascularization result in increased bleeding. The results in PLATO showed that [IDR]). At the same time, there was an increase in bleeding with overall major bleeding was not significantly increased by ticagrelor cangrelor although there was no increase in the requirement for compared to clopidogrel (HR 1.04, 95% CI 0.95–1.13, p=0.43). transfusion. The BRIDGE trial38 recently published its results on However, on closer scrutiny, it was evident that major bleeding the use of cangrelor in the setting of CABG surgery. In this study, not related to surgery did in fact increase in the ticagrelor arm— 210 patients going for elective CABG surgery had their antiplatelet 4.5% v. 3.8%, p=0.03. However, CABG surgery-related bleeding medication discontinued 5–7 days before surgery. They were then was not increased and in fact it showed a trend towards reduction randomized to receive cangrelor or placebo infusion during these in the ticagrelor arm—7.4% v. 7.9%. The explanation for this days. Those receiving cangrelor were able to maintain over 60% could lie in the shorter duration of action of ticagrelor compared platelet inhibition with no significant increase in CABG-related to clopidogrel allowing more complete recovery of platelet function bleeding. The study was not powered to assess ischaemic or by the time of CABG surgery. However, there was a small increase mortality end-points. in intracranial bleeding with ticagrelor—0.3% v. 0.2%, p=0.06. Early phase studies had reported bradycardia and dyspnoea with Elinogrel ticagrelor, hence these were closely monitored in the PLATO study. Elinogrel is a direct-acting P2Y12 receptor inhibitor that is unique Episodes of bradycardia were assessed by Holter monitoring. In in being available in both i.v. and oral forms. This should give it patients receiving ticagrelor during the first week, 5.8% showed an advantage for use in both the acute setting in the catheterization ventricular pauses of over 3 seconds versus 3.6% of those receiving laboratory or in preparation for surgery. It has a reversible action, clopidogrel (p=0.01). By 30 days, the difference was no longer a half-life of 12–14 hours and no major interaction with CYP significant—2.1% and 1.7%, respectively (p=0.52). Bradycardia- agents or proton pump inhibitors. The INNOVATE-PCI39 trial, a related clinical events (pacemaker insertion and sudden death) were phase 2 trial of patients going for non-urgent PCI randomized not significantly different. In the case of syncope, there was a non- patients to either clopidogrel (300–600 mg loading dose followed significant trend towards increase in frequency in the ticagrelor arm by 75 mg daily) or 80 mg elinogrel i.v. followed by one of three (1.1% v. 0.8%, p=0.08). Patients with conduction defects and arms (50, 100 or 150 mg of elinogrel orally twice daily) for at least bradyarrythmias not protected by a pacemaker were excluded from 60 days. The 100 mg and 150 mg doses had greater platetet the trial and hence the effect of ticagrelor in this subgroup could not inhibitory effect than clopidogrel with no increase in bleeding. be assessed from the PLATO study. Some new receptor inhibitors are in the pipeline but are still far In the case of dyspnoea, symptomatic dyspnoea (13.8% v. from clinical use—protease-activated receptor (PAR) inhibitors 7.8%) and discontinuation of medication for dyspnoea (0.9% v. and compound E555. 0.1%) were both significantly more in patients on ticagrelor compared with those on clopidogrel but the absolute numbers CLINICAL USE AND CHOICE OF were small. Both cangrelor and elinogrel are not yet available for clinical use. With the availability of prasugrel and shortly possibly of ticagrelor, OTHER P2Y12 ANTIPLATELET AGENTS (Table IV) it is worth discussing what place these newer agents will have in Cangrelor clinical practice. Cangrelor is an investigational, ultra-short-acting, non- In secondary prevention for patients with stable coronary artery thienopyridine P2Y12 platelet receptor inhibitor that has to be disease, either aspirin or clopidogrel would be appropriate. given intravenously. It is being tested as a bridge therapy in Considering cost, in those who tolerate aspirin it would be a patients with ACS being evaluated for CABG. It has a plasma reasonable choice. As of now there are no trials addressing the use half-life of 3–5 minutes with full recovery of platelet function of either clopidogrel or ticagrelor in emergency room settings. In within 60 minutes. Its metabolism is not dependant on renal or ACS being managed medically a combination of aspirin and hepatic function and it has no CYP 450 interactions. In normal clopidogrel (300 mg loading dose followed by 75 mg daily) would

TABLE IV. Properties of different P2Y12 receptor inhibitors Property P2Y12 receptor inhibitor Clopidogrel Prasugrel Ticagrelor Cangrelor Elinogrel Reversibility Irreversible Irreversible Reversible Reversible Reversible Formulation Oral Oral Oral Intravenous Intravenous and oral Onset 4–6 hours 1–2 hours 2–3 hours Immediate Immediate (i.v.) Half-life 5 days 5 days 12 hours 5 minutes Intravenous: 50 minutes Oral: 12 hours PAIS : P2Y12 INHIBITORS IN ACUTE CORONARY SYNDROMES 89 be appropriate. In medically managed patients, prasugrel has no in addition to aspirin in patients with acute coronary syndromes without ST-segment benefit over clopidogrel.27 On the other hand, the PLATO study elevation. N Engl J Med 2001;345:494–502. Erratum in: N Engl J Med 2001;345:1506. N Engl J Med 2001;345:1716. included patients in whom medical treatment was planned. A pre- 2 Sabatine MS, Cannon CP, Gibson CM, López-Sendón JL, Montalescot G, Theroux specified subgroup analysis of such patients showed that ticagrelor P, et al.; CLARITY-TIMI 28 Investigators. Addition of clopidogrel to aspirin and was superior to clopidogrel.35 Where fibrinolytic therapy is planned, fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med 2005;352:1179–89. a 300 mg loading dose of clopidogrel should be used and prasugrel 3 O’Connor RE, Brady W, Brooks SC, Diercks D, Egan J, Ghaemmaghami C, et al. and ticagrelor avoided. In patients with ACS with planned PCI, Part 10: Acute coronary syndromes: 2010 American Heart Association Guidelines aspirin can be combined with either clopidogrel 600 mg loading for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circula- tion 2010;122 (18 Suppl 3):S787–S817. Erratum in: Circulation 2012;125:e265. dose followed by 150 mg daily for a week and then 75 mg daily or Circulation 2011;123:e238. prasugrel 60 mg loading dose followed by 10 mg daily. Once it 4 ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. becomes available, ticagrelor 180 mg loading dose followed by 90 Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among mg twice daily would also be an option. Ticagrelor and prasugrel 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988;2: 349–60. may be considered particularly for high-risk patients with ACS 5 Trialists’ (ATT) Collaboration, Baigent C, Blackwell L, Collins R, (those with diabetes, triple-vessel disease, anterior wall MI) planned Emberson J, Godwin J, Peto R, et al. Aspirin in the primary and secondary prevention for PCI. of vascular disease: Collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009;373:1849–60. 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