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- Platelet activation
- coronary intervention
- acute coronary syndrome
- antiplatelet treatment
- pharmacokinetics/pharmacodynamics
The management and prevention of arterial thrombosis has been transformed by the recognition of the role of platelets in this process and the development of effective antiplatelet drugs. The limited role of thromboxane A2 in platelet activation explains why aspirin therapy, which effectively inhibits release of thromboxane A2 by platelets, is insufficient in high risk conditions such as acute coronary syndromes (ACS) or percutaneous coronary intervention (PCI). The platelet P2Y12 receptor, one of two adenosine diphosphate (ADP) receptors on platelets, plays a central and unique role in platelet activation through amplifying the effects of numerous platelet agonists (figure 1).1 Platelet activation leads not only to aggregation but also to the release of pro-thrombotic and pro-inflammatory granule contents as well as the formation of thrombin. Strong amplification of all these platelet responses by P2Y12 explains why this receptor plays such an important part in thrombosis and haemostasis and is a successful target for antiplatelet drugs.
Limitations of clopidogrel
Clopidogrel is a second generation thienopyridine that transformed the safety and efficacy of PCI and improved the risk management of patients with ACS. Despite its success, there is now wide recognition of a number of limitations of clopidogrel in these clinical settings. The most important limitation is the wide variability between individuals in the pharmacodynamic response to clopidogrel relating to genetic variation and numerous other factors that affect the conversion of clopidogrel (a prodrug) to its active metabolite (box 1). Individuals with a poor or even absent pharmacodynamic response to clopidogrel have a higher risk of stent thrombosis, partly related to insufficient platelet inhibition and partly related to higher risk characteristics such as diabetes and chronic kidney disease that contribute both to ischaemic risk and to less effective conversion of clopidogrel to its active metabolite. Two further limitations of clopidogrel are: its relatively slow onset of action, which is of particular relevance in patients undergoing primary PCI for ST elevation myocardial infarction (STEMI) or proceeding rapidly to PCI for other reasons; and its irreversibility of action, which means that it takes 5–10 days for platelet function to recover after cessation of treatment while inhibited platelets are replaced in the circulation by newly formed platelets. These limitations have prompted the development of newer P2Y12 inhibitors.
Important factors influencing the pharmacodynamic response to clopidogrel
Age
Weight
Dose of clopidogrel
Disease states including diabetes mellitus, chronic kidney disease and heart failure
Genetic variation, particularly loss-of-function variants (*2-*8 alleles) in the cytochrome P450 (CYP) 2C19 gene
Drug–drug interactions including negative interaction with omeprazole
Unknown factors
Prasugrel, a more effective thienopyridine
Prasugrel is a new thienopyridine that is more effectively converted to its active metabolite compared to clopidogrel. Higher plasma concentrations of active metabolite explain why prasugrel has a faster onset of action and achieves higher mean levels of inhibition of platelet aggregation compared to clopidogrel, since the active metabolites of prasugrel and clopidogrel themselves have similar chemical structure and potency.2 This pharmacokinetic superiority of prasugrel circumvents the problem of variability seen with clopidogrel due to loss-of-function variants of the CYP2C19 gene, drug–drug interactions and other determinants of CYP activity, ensuring more consistent inhibition of platelet function as long as normal absorption occurs.
Ticagrelor, the first oral reversibly binding P2Y12 inhibitor
Ticagrelor belongs to a new chemical class (cyclopentyltriazolopyrimidine, CPTP) that evolved in the process of developing an orally active mimetic of adenosine triphosphate (ATP), the natural antagonist at the P2Y12 receptor. Unlike the thieno-pyridines, ticagrelor does not require metabolic activation for its inhibitory effects, although it does have a hepatic metabolite that is also an active inhibitor of P2Y12, and it binds reversibly to P2Y12, dissociating from the receptor when plasma concentrations fall. Since the plasma half-lives of ticagrelor and its active metabolite are 6–12 h, recovery of platelet function following cessation of administration is relatively rapid compared to that seen with thienopyridines, although it still takes more than 72 h for complete recovery to occur.3 Ticagrelor is administered twice daily in order to achieve consistent platelet inhibition over 24 h. A 180 mg loading dose of ticagrelor achieves a moderate level of P2Y12 inhibition at 30 min after dosing and a high level of inhibition by 1 h in patients with stable coronary artery disease.3 The onset of action seems similarly rapid in most ACS patients, although it is possible that occasionally absorption may be delayed in sick patients.4 Ticagrelor 90 mg twice daily achieves greater and more consistent inhibitory effects compared to clopidogrel in ACS patients, particularly when assessed by the VerifyNow P2Y12 assay (ticagrelor 31±32 P2Y12 reaction units (PRU) vs clopidogrel 196±95 PRU (mean±SD), 2–4 h post dose; p<0.0001) (figure 2).4
Prasugrel versus clopidogrel: more P2Y12 inhibition leads to fewer ischaemic events but more bleeding
The regimen of prasugrel selected for phase 3 development, 60 mg loading dose followed by 10 mg daily maintenance dose, was designed to provide rapid and consistently high level P2Y12 inhibition in the early high risk phase of PCI for ACS, followed by a lesser mean inhibitory effect during maintenance therapy that was still greater and more consistent than the mean effect of clopidogrel maintenance therapy. This regimen had shown promising signs of reduced incidence of stent thrombosis in the phase 2 study (JUMBO-TIMI 26). The phase 3 TRITON-TIMI 38 study compared the effects of this regimen of prasugrel with clopidogrel 300 mg loading dose followed by 75 mg daily maintenance dose in clopidogrel-naive patients who either had undergone coronary angio-graphy for non-ST elevation ACS (NSTE-ACS) or medically managed STEMI or were planned for primary PCI for acute STEMI. Patients were allowed to receive study drug after the PCI procedure had been performed, within 1 h after leaving the cardiac catheterisation laboratory, and only one-quarter of patients received study medication before PCI. Prasugrel proved to be superior to clopidogrel in preventing the combined primary end point of myocardial infarction, stroke, and cardiovascular death (HR 0.81, 95% CI 0.73 to 0.90; p<0.001) and stent thrombosis (2.4% vs 1.1%, HR 0.48; p<0.001).5 It is likely that the relatively low loading dose and timing of clopidogrel administration led to an exaggerated treatment effect since it has subsequently been established that a higher loading and maintenance regimen of clopidogrel (600 mg followed by 150 mg daily for 7 days) reduces the incidence of stent thrombosis and ischaemic events in patients managed by PCI compared to the standard 300 mg loading dose and 75 mg daily maintenance dose regimen.6 However, it is also likely that prasugrel would still prove more effective at preventing stent thrombosis than high dose clopidogrel, which is still associated with poor pharmacodynamic response in some patients.7
The greater inhibitory effect of prasugrel compared to clopidogrel was associated with an increased incidence of bleeding in TRITON (2.4% vs 1.8% non-coronary artery bypass graft surgery (CABG) TIMI major bleeding, HR 1.32, 95% CI 1.03 to 1.68; p=0.03), and the 0.3% excess of fatal bleeding with prasugrel (0.4% vs 0.1%; p=0.002) led to no overall benefit of prasugrel on cardiovascular death (2.1% vs 2.4%, HR 0.89, 95% CI 0.70 to 1.12; p=0.31). Patients with a prior history of stroke or transient ischaemic attack, body weight <60 kg or age ≥75 years were at higher risk of life threatening bleeding with prasugrel, and when these patients were excluded in a post-hoc analysis, the net clinical benefit was enhanced. Consequently prasugrel is contraindicated in those with a history of cerebrovascular disease and cautioned in those with body weight <60 kg or age ≥75 years, in whom a lower maintenance dose of 5 mg daily is suggested, on the basis of pharmacodynamic data only, if the relationship between ischaemic and bleeding risks is deemed appropriate. A relatively small proportion of patients underwent CABG surgery and there was a fourfold excess of major bleeding but lower mortality in the prasugrel treated patients. There was an excess of colonic neoplasia in the prasugrel group (13 vs 4 patients, p=0.03) which was deemed by the regulatory authorities to be likely due to chance, but warranting further assessment in subsequent studies. There were fewer cases of neutropenia in the prasugrel group (2 vs 10 patients, p=0.02).
Ticagrelor versus clopidogrel: reducing mortality in ACS
In the PLATO trial, ticagrelor 180 mg loading dose and 90 mg twice daily maintenance dose was compared with clopidogrel 300 mg loading dose followed by 75 mg daily for up to 12 months in 18 624 ACS patients with either moderate-to-high risk NSTE-ACS or STEMI planned for primary PCI.8 Ticagrelor treated patients received an additional 90 mg dose before PCI if more than 24 h after the initial loading dose, and clopidogrel treated patients could receive an additional 300 mg loading dose (total 600 mg) before PCI at the discretion of the physician or received no loading dose if already loaded with clopidogrel. Unlike the TRITON study, patients were uniformly required to receive study medication within 24 h of onset of chest pain, before any revascularisation procedure, and could be included if they had already received clopidogrel so that 46% of patients had been treated with clopidogrel before receiving study medication. For patients undergoing CABG surgery, the double-dummy study design allowed investigators to be advised to stop clopidogrel (or its placebo) 5 days before surgery but stop ticagrelor (or its placebo) 24–72 h before surgery, so that a greater proportion of ticagrelor treated patients stopped study medication within 5 days before surgery.
Ticagrelor proved more effective than clopidogrel in reducing the triple composite primary end point of cardiovascular death, myocardial infarction, and stroke, with the estimated annual rate being 9.8% for the ticagrelor group and 11.7% for the clopidogrel group (HR 0.84, 95% CI 0.77 to 0.92; p<0.001). Secondary end points were assessed according to a pre-specified hierarchical analysis and showed significant reductions also in myocardial infarction alone (HR 0.84, 95% CI 0.75 to 0.95; p<0.005) and cardiovascular death alone (HR 0.79, 95% CI 0.69 to 0.91; p<0.001). The Kaplan–Meier curves for all these end points diverged progressively and smoothly over time, out to 12 months, indicating that the benefit of ticagrelor over clopidogrel accrues progressively over this time course. Stroke was not significantly different between the groups (ticagrelor 1.5% vs clopidogrel 1.3%, HR 1.17, 95% CI 0.91 to 1.52; p=0.22) and there was a numerical excess of intracranial haemorrhage, including fatal intracranial haemorrhage, in the ticagrelor group. Total mortality was lower in the ticagrelor group (HR 0.78, 95% CI 0.69 to 0.89; p<0.001), as was definite stent thrombosis (HR 0.67, 95% CI 0.50 to 0.91; p<0.01). There was a consistent treatment effect across numerous subgroups including those intended for either invasive or conservative management at randomisation, patients over the age of 75 years or under 60 kg in body weight, patients with prior history of ischaemic stroke or transient ischaemic attack, patients with or without diabetes, and patients with STEMI.8–11 Clopidogrel treated patients with a loss-of-function allele in the CYP2C19 gene had a higher rate of ischaemic events in the first 30 days compared to those without such an allele, but the events rates beyond 30 days were not apparently affected by genetically predicted CYP2C19 metaboliser status and, as expected, event rates in the ticagrelor group were unaffected by CYP2C19 genotype.12 Consequently, ticagrelor was superior to clopidogrel regardless of CYP2C19 genotype.
As had been seen previously over 4–12 weeks in the phase 2 study,13 there was no significant excess of PLATO defined major bleeding with ticagrelor compared to clopidogrel (11.6% vs 11.2%, HR 1.04; p=0.43) nor any difference in transfusion rates (both 8.9%). This was despite more rapid and greater, more consistent P2Y12 inhibition with ticagrelor compared to clopidogrel.4 This apparent paradox is explained by the fact that there was significantly more non-CABG related bleeding with ticagrelor (4.5% vs 3.8%, HR 1.19, 95% CI 1.02 to 1.38; p=0.03), but this was compensated for by a numerically lower rate of CABG related bleeding with ticagrelor (7.4% vs 7.9%, HR 0.95, 95% CI 0.85 to 1.06; p=0.32). One hypothetical explanation may be that more effective P2Y12 inhibition reduces the need for CABG surgery, as well as repeat PCI for stent thrombosis and/or reinfarction, and therefore reduces the number of cases exposed to the associated bleeding risk, but even a large study such as PLATO lacked the power to address this conclusively. However, this hypothesis is supported by the observation that there were numerically lower rates of coronary procedure related bleeding with ticagrelor (8.5% vs 9.2%) in the cohort of patients intended for invasive management at randomisation.9
In the PLATO trial, 1899 patients underwent CABG surgery following randomisation; of these, 1261 underwent this surgery within 7 days of receiving study medication, with 61% of the ticagrelor treated patients versus 50% of the clopidogrel treated patients stopping medication <5 days before surgery.14 There was no difference in the rates of major bleeding, transfusion or chest tube outputs in the two treatment groups, but there was a remarkable reduction in mortality in the ticagrelor group (4.7% vs 9.7%, HR 0.49, 95% CI 0.32 to 0.77; p<0.01). Subsequent to the PLATO study design, the ONSET-OFFSET study suggested that stopping ticagrelor 72 h before surgery is appropriate3 but the optimal strategy for discontinuing P2Y12 inhibitors before surgery remains to be determined.
Adverse effects of ticagrelor
A curious adverse effect of ticagrelor is the experience of dyspnoea which is generally mild or, less frequently, moderate in intensity and rarely severe.8 15 In the PLATO study, 13.8% of ticagrelor treated patients versus 7.8% of clopidogrel treated patients reported an adverse event of dyspnoea following randomisation (p<0.001).8 The episodes of dyspnoea of lesser severity tend to be well tolerated, not require discontinuation of ticagrelor, and resolve either spontaneously or following cessation of treatment.15 Only 0.9% of the ticagrelor treated patients in PLATO discontinued treatment as a result of dyspnoea.8 There was no evidence of loss of treatment effect in terms of reduced mortality for ticagrelor treated patients experiencing dyspnoea compared to those not reporting dyspnoea as an adverse event, suggesting that treatment should be continued if dyspnoea is tolerated.16 Alternatively, patients who cannot tolerate ticagrelor due to dyspnoea may be switched to a maintenance dose of either clopidogrel or prasugrel as appropriate. Ticagrelor related dyspnoea may often be distinguished from other causes of dyspnoea since it may be present as a mild sensation at rest and not affect exercise tolerance. Lack of wheezing or orthopnoea may also differentiate ticagrelor related dyspnoea from asthma, exacerbation of chronic obstructive pulmonary disease (COPD) or heart failure, and N-terminal pro-brain natriuretic peptide (NT-proBNP) values are not increased by ticagrelor.
Another adverse effect of ticagrelor is the increased frequency of ventricular pauses.8 13 This effect is seen more commonly early in the course of treatment and is predominantly due to increased incidence of sinoatrial pauses, particularly at night. There was no excess of bradycardia related clinical events in ticagrelor treated patients in the PLATO trial, including no difference in permanent pacemaker implantation; however, ticagrelor should be used with caution in those patients at increased risk of bradycardia and probably avoided in those with advanced sinoatrial disease not already treated with a permanent pacemaker. However, no adverse interactions between ticagrelor and rate limiting medications such as β-blockers and diltiazem were noted in the PLATO trial, even though it is recognised that diltiazem—a moderate CYP3A inhibitor—increases the plasma values and half-life of ticagrelor.
Creatinine concentrations increased after randomisation in both the ticagrelor and clopidogrel groups in the PLATO trial, but the percentage increase was significantly greater in the ticagrelor group (10% vs 8% at 1 month; p<0.001).8 There was no difference in creatinine values at 1 month after discontinuation of the study and no difference during the trial in renal adverse events considered by investigators to be related to the study medication. In fact, the absolute treatment effect of ticagrelor appeared greatest in those with chronic kidney disease, with lower rates of the ischaemic end points and a 4% absolute reduction in total mortality (HR 0.72, 95% CI 0.58 to 0.89) in those with an estimated creatinine clearance <60 ml/min/1.73 m2 body surface area.17
Ticagrelor is known to increase uric acid concentrations and should therefore be used with caution in patients with a history of gouty arthritis.
Strong CYP3A4 inhibitors such as ketoconazole greatly increase the plasma concentrations of ticagrelor and should not be co-administered with ticagrelor since this will increase the risk of adverse effects such as bleeding, dyspnoea, and ventricular pauses. Strong CYP3A4 inhibitors also notably attenuate the pharmacodynamic response to clopidogrel, thereby likely increasing the risk of ischaemic events, while the response to prasugrel is not significantly affected.
A new era in ACS pharmacotherapy
The success of ticagrelor in reducing mortality compared to standard treatment opens up a new era in ACS management, building on progress made in other aspects of ACS pharmacotherapy such as the adoption of safer anticoagulation regimens (notably fondaparinux at a dose used for prophylaxis against venous thromboembolism in place of enoxaparin at a dose used for treatment of venous thromboembolism), high dose statin regimens, and aldosterone antagonists for post-myocardial infarction heart failure. It also introduces further complexity related to the number of choices available in therapeutic decision making and future ACS guidelines will steer a course on how ticagrelor should be adopted into the antithrombotic armamentarium.
Although the Kaplan–Meier curves for ischaemic events and mortality continued to diverge out to 12 months in the PLATO trial, it has not been determined whether continuing ticagrelor beyond this time point (when clopidogrel is often discontinued) will lead to continued accrual of benefit. This issue will be addressed in the ongoing phase 3 PEGASUS-TIMI 54 study which will compare the efficacy and safety of the PLATO maintenance regimen of ticagrelor (90 mg twice daily) and a lower dose regimen of ticagrelor (60 mg twice daily) with placebo in higher risk patients with a history of myocardial infarction 1–3 years previously.
Other reversibly binding P2Y12 inhibitors in development
Cangrelor is a true analogue of ATP and is only active intravenously. It achieves steady state inhibition within 30 min of infusion or 2–3 min after a bolus dose and has a plasma half-life <10 min due to rapid hydrolysis of its triphosphate moiety. Consequently platelet function recovers in 1–2 h after cessation of infusion in patients with coronary artery disease.18 A limitation of cangrelor is that it blocks the binding of clopidogrel's active metabolite to the P2Y12 receptor and this complicates transition from cangrelor to clopidogrel.19 The phase 3 CHAMPION studies failed to show superiority of cangrelor and clopidogrel combinations over P2Y12 inhibitor regimens consisting only of clopidogrel, and a further phase 3 efficacy study, with modified end points, is in progress (CHAMPION PHOENIX). The short biological half-life of cangrelor makes it potentially suitable for bridging between cessation of oral inhibitors and performance of CABG, and this application is currently being studied in the BRIDGE study.
Elinogrel belongs to a further class of reversibly binding P2Y12 inhibitors that is available in both intravenous and oral formulations. It has a competitive inhibitory action at the receptor, compared to the non-competitive action of ticagrelor, and consequently it has much greater inhibitory effects on the platelet response to low concentrations of ADP compared to high concentrations of ADP. Like cangrelor, intravenous bolus administration allows rapid onset of action within minutes and, like both cangrelor and ticagrelor, it can induce dyspnoea that is usually mild and well tolerated.
Stent thrombosis and restenosis: a continuum?
While the critical role of platelets in stent thrombosis is well established, there remains uncertainty about the contribution of platelets to restenosis following PCI. However, it is known that platelets release pro-inflammatory mediators that are involved in vascular inflammation (figure 1). Recent preclinical studies have demonstrated how platelet mediated thrombosis following vascular injury can drive neointima formation, and the P2Y12 receptor plays a dominant role in this process.20 It appears that P2Y12 inhibitors, through preventing thrombus accumulation at the site of injury, may attenuate neointima formation if present at the time of injury and thereafter. This raises the hypothesis that effective P2Y12 inhibition covering the PCI procedure and sustained subsequently may play a role in reducing the incidence of restenosis. Further studies and analyses of registry data following implementation of more effective P2Y12 inhibitor regimens are warranted to explore this hypothesis.
Conclusions
P2Y12 inhibitors have transformed the efficacy of pharmacotherapy for ACS and PCI. New inhibitors, such as prasugrel and ticagrelor, that provide more consistently high levels of P2Y12 inhibition than clopidogrel, are more efficacious in the treatment and prevention of arterial thrombosis, at the expense of greater impairment of haemostasis. The reversibly binding P2Y12 inhibitor ticagrelor has demonstrated a unique, progressive reduction in mortality over 1 year compared to clopidogrel in moderate-to-high risk ACS patients without any increase in fatal bleeding, adding to the already established benefits of a range of pharmacological treatments in ACS. Further studies will explore the impacts of off-target effects of different P2Y12 inhibitors and assess the potential therapeutic role of high level P2Y12 inhibition across a broader range of indications.
New P2Y12 inhibitors: key points
The P2Y12 receptor pathway serves as a major amplification system in platelet function and platelet mediated thrombosis.
Clopidogrel: wide inter-individual variation in efficiency of active metabolite formation leads to limited efficacy in some individuals.
Prasugrel: more efficiently converted to its active metabolite than clopidogrel and achieves greater and more rapid mean platelet inhibition with consequent reduced risk of ischaemic events but higher risk of haemorrhage.
Ticagrelor: an oral, reversibly binding P2Y12 inhibitor that also achieves greater and more rapid platelet inhibition than clopidogrel and additionally has more rapid offset of effect; progressively reduces ischaemic events and total mortality compared to clopidogrel over 6–12 months in acute coronary syndrome patients without significantly increasing overall rates of major bleeding; generally well tolerated but adverse effects include increased risk of spontaneous bleeding, dyspnoea, ventricular pauses, and increases in serum uric acid and creatinine.
Other reversibly-binding P2Y12 inhibitors: cangrelor is an ultra-short acting intravenous inhibitor in phase 3 development; elinogrel is also in phase 2/3 development as both an oral and intravenous inhibitor.
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References
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- ↵Comprehensive comparison of the onset of action of clopidogrel and ticagrelor loading doses and offset following last maintenance dose.
- ↵Largest comparison of the inhibitory effects of ticagrelor and clopidogrel in patients with ACS.
- ↵TRITON-TIMI 38 study showing greater efficacy of prasugrel compared to clopidogrel.
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- ↵PLATO study showing greater efficacy of ticagrelor compared to clopidogrel including progressive reduction in cardiovascular mortality.
- ↵Clinical outcomes including stent thrombosis in patients planned for invasive management.
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- ↵Ticagrelor more efficacious than clopidogrel regardless of CYP2C19 genotype.
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- ↵Prospective study showing no adverse effect of ticagrelor on cardiac or pulmonary function despite an associated adverse effect of dyspnoea.
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- ↵Preclinical evidence of a potential role of the platelet P2Y12 receptor in restenosis.
Footnotes
Competing interests In compliance with EBAC/EACCME guidelines, all authors participating in Education in Heart have disclosed potential conflicts of interest that might cause a bias in the article. Professor Storey was an Executive Committee member and UK National Co-ordinating Investigator for the DISPERSE2 and PLATO studies and is an Executive Committee member and UK National Co-ordinating Investigator of the PEGASUS-TIMI 54 study and UK National Co-ordinating Investigator of the EPICOR, BRIDGE and ATLANTIC studies. He has received consultancy fees, honoraria and/or institutional research grants from AstraZeneca, Eli Lilly, Daiichi Sankyo, The Medicines Company, Novartis, Sanofi Aventis, Bristol Myers Squibb, GlaxoSmithKline, Eisai, Schering Plough, Merck, Teva, Dynabyte Accumetrics and Medscape and is Chair of the European Platelet Academy supported by unrestricted educational grants from Eli Lilly/Daiichi Sankyo and Accumetrics.
Provenance and peer review Commissioned; internally peer reviewed.