Summary
Effective antagonism of the P2Y 12 platelet receptor is central to the treatment of acute coronary syndrome (ACS) patients, especially in the setting of percutaneous coronary intervention and stenting. According to consensus guidelines, early revascularization and intensive antiplatelet therapy are key to reducing the complications that arise from myocardial ischaemia and the recurrence of cardiovascular events. Until recently, clopidogrel was the key P2Y 12 antagonist advocated, but due to several limitations as an antiplatelet agent, newer drugs with more predictable, rapid and potent effects have been developed. Prasugrel and ticagrelor are now the recommended first-line agents in patients presenting with non-ST-segment elevation ACS and ST-segment elevation ACS, due to large-scale randomized trials that demonstrated net clinical benefit of these agents over clopidogrel, as stated in the European guidelines. Although no study has directly compared the two agents, analysis of the data to date suggests that certain patient types, such as diabetics, those with ST-segment elevation myocardial infarction or renal failure and the elderly may have a better outcome with one agent over the other. Further studies are needed to confirm these differences and answer pending questions regarding the use of these drugs to optimize efficacy while minimizing adverse events, such as bleeding. The aim of this review is to provide an overview of the current P2Y 12 receptor antagonists in the treatment of ACS, with a focus on issues of appropriate agent selection, timing of treatment, bleeding risk and the future role of personalized treatment using platelet function and genetic testing.
Résumé
L’inhibition effective du récepteur plaquettaire P2Y 12 est primordiale dans le traitement des patients présentant un syndrome coronaire aigu (SCA), en particulier lors de l’exécution d’une intervention coronaire percutanée (ICP) avec pose de stent. Selon les recommandations, une revascularisation précoce et un traitement antiplaquettaire intensif sont clés pour réduire les complications secondaires à l’ischémie myocardique et prévenir la récurrence d’événements cardiovasculaires. Jusqu’à un passé récent, clopidogrel a été le produit de référence pour inhiber le récepteur P2Y 12 , cependant, en raison d’un certain nombre de limitations de son action antiplaquettaire, de nouveaux agents, plus constants dans leur effet, plus rapides et plus puissants, ont été développés. Prasugrel et ticagrelor sont maintenant les molécules de première ligne recommandées chez les patients présentant un SCA sans sus-décalage du segment ST (NSTE-SCA) ou avec sus-décalage du segment ST (STE-SCA), en raison de l’existence de larges études randomisées ayant démontré un bénéfice clinique net de ces produits supérieur à clopidogrel, comme le mentionnent les recommandations européennes. Bien qu’aucune n’étude n’ait directement comparé les deux produits, à ce jour l’analyse des données suggère que certains profils de patients, comme les diabétiques, les patients avec un STEMI, les insuffisants rénaux ou les sujets âgés, tirent plus de bénéfice avec l’une ou l’autre des molécules. Des études supplémentaires sont nécessaires pour confirmer ces différences et répondre à des questions restées en suspens quant à l’utilisation optimale de ces produits, consistant à favoriser leur efficacité tout en réduisant leurs effets secondaires tels que les saignements. Le but de cette revue de la littérature est d’apporter une vue d’ensemble sur les molécules actuelles antagonistes du récepteur P2Y 12 dans le traitement du SCA, en insistant sur les problématiques concernant le choix approprié de la molécule, le moment de son administration, le risque de saignement et le rôle futur d’un traitement personnalisé grâce aux tests de fonction plaquettaire et génétiques.
Introduction
Acute coronary syndromes (ACSs) have a significant impact on health in the Western world, with an estimated burden of 1.5 million hospitalizations and 4.5 million emergency department visits per year attributed to ACSs in the USA . Despite advances in treatment, ACSs are associated with significant morbidity and mortality.
In an ACS, acute atherosclerotic plaque rupture leads to platelet activation, adhesion and aggregation, which are vital factors in the early formation of a coronary thrombus . Antiplatelet agents that inhibit agonism by adenosine diphosphate (ADP) of the P2Y 12 platelet receptor are central to the prevention of complications and recurrent cardiovascular ischaemic events in patients with ACS and also post percutaneous coronary intervention (PCI) . Based on current European Society of Cardiology (ESC) and American Heart Association (AHA) guidelines , the diagnosis of ACS is further substratified into ST-segment elevation ACS (STE-ACS) and non-ST segment elevation ACS (NSTE-ACS). Dual antiplatelet therapy comprising aspirin and a P2Y 12 antagonist is currently recommended for the treatment of this clinical presentation.
Clopidogrel
Clopidogrel is a second-generation thienopyridine derivative that binds specifically and irreversibly to the platelet P2Y 12 purinergic receptor, inhibiting ADP-mediated platelet activation and aggregation . Clopidogrel is a prodrug that is metabolized to its active form in the liver. The reactive thiol group of the active metabolite of clopidogrel forms a disulphide bridge between one or more cysteine residues of the P2Y 12 receptor. This interaction is irreversible, accounting for the observation that platelets are inhibited, even if no active metabolite is detectable in plasma. Until recently, clopidogrel was the standard of care in dual antiplatelet therapy. However, clopidogrel has several limitations as an antiplatelet agent. Firstly, it has a delayed onset of action, which results in sub-optimal platelet inhibition at the time of urgent or early PCI. Secondly, the platelet inhibition due to clopidogrel is irreversible and there is interindividual variability in the recovery of platelet function, leading to higher bleeding risk for patients undergoing surgery, including coronary artery bypass graft (CABG). Thirdly, there is considerable interindividual variability in the pharmacodynamic response to the drug, with some patients being termed clopidogrel resistant or as having high on-treatment platelet reactivity (HPR). This is largely due to interindividual differences in the metabolism of the prodrug and has been correlated with increased risk of atherothrombotic events .
The CURE trial was the key landmark analysis that exemplified clopidogrel efficacy. In this study of 12,562 patients presenting with NSTE-ACS within 24 hours of symptom onset, clopidogrel 300 mg then 75 mg and aspirin was compared with aspirin alone. Clopidogrel resulted in a 20% relative risk reduction in the prevalence of the primary composite outcome of cardiovascular death, non-fatal myocardial infarction (MI) and stroke compared with aspirin monotherapy. This clinical benefit was also shown in patients presenting with ST-segment elevation myocardial infarction (STEMI) and treated with thrombolysis in the CLARITY-TIMI 28 trial, where there was a similar reduction in the occurrence of the clinical endpoint of cardiovascular death, myocardial infarction and recurrent ischaemia .
A higher loading dose (LD) of clopidogrel was assessed in ACS patients in the CURRENT-OASIS 7 trial, where 600 mg were administered on day 1, 150 mg on days 2–7 and 75 mg thereafter . There was overall no benefit for this strategy with respect to rate of occurrence of the primary outcome of cardiovascular death, myocardial infarction or stroke after 30 days (hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.83–1.06; P = 0.3). There was however a significant increase in the rate of bleeding in the high double-dose group (2.5%) compared with in the low-dose group (2.0%) (HR 1.24, 95% CI 1.05–1.46; P = 0.01). In a subgroup analysis of 17,263 patients who underwent PCI, the high dose appeared to have benefit in moderate-to-high-risk patients undergoing PCI, significantly decreasing the occurrence of the primary composite endpoint of myocardial infarction, stroke or cardiovascular death at 30 days (3.9% vs. 4.5%; HR 0.86, 95% CI 0.74–0.99; P = 0.039) ( Table 1 ). Further support for these findings was found in the COMMIT trial, which included a large number of patients with acute myocardial infarction ( n = 45,852) and demonstrated that 75 mg without LD within 24 hours of presentation produced a 9% proportional reduction in the occurrence of death, reinfarction or stroke .
| Endpoint (percentage of events) | CURRENT-OASIS 7 | TRITON-TIMI 38 (2007) | PLATO invasive (2009) | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Clopidogrel 600 mg | Clopidogrel 300 mg | HR (95% CI) | Prasugrel | Clopidogrel 300 mg | HR (95% CI) | Ticagrelor | Clopidogrel 300 mg | HR (95% CI) | |
| Primary endpoint a | 3.90 | 4.50 | 0.86 (0.74–0.99) | 9.90 | 12.10 | 0.81 (0.73–0.90) | 9.00 | 10.70 | 0.84 (0.75–0.94) |
| All-cause death | 1.90 | 2.10 | 0.94 (0.76–1.16) | 3.00 | 3.20 | 0.95 (0.78–1.16) | 3.90 | 5.00 | 0.81 (0.68–0.95) |
| Non-fatal myocardial infarction | 2.00 | 2.60 | 0.79 (0.64–0.96) | 7.30 | 9.50 | 0.76 (0.67–0.85) | 5.30 | 6.60 | 0.80 (0.69–0.92) |
| Non-CABG-related major bleeding b | 0.80 | 0.60 | 1.34 (0.94–1.91) | 2.40 | 1.80 | 1.32 (1.03–1.68) | 2.80 | 2.20 | 1.23 (0.98–1.55) |
a Death from cardiovascular causes, non-fatal MI, non-fatal stroke.
b According to Thrombolysis in Myocardial Infarction (TIMI) criteria.
Newer antiplatelet agents
To overcome the sub-optimal pharmacodynamic and pharmacokinetic profile of clopidogrel, new P2Y 12 inhibitors have been developed, which are more predictable and have a faster onset of action – characteristics that make them particularly attractive for PCI. Prasugrel and ticagrelor are two agents that are now recommended for the treatment of NSTE-ACS and STEMI based on evidence that has demonstrated a reduction in cardiovascular events compared with clopidogrel. Intravenous agents with reversible action, such as cangrelor, have also been developed, allowing an alternative route of administration and even more rapid onset and offset of action compared with oral agents.
Prasugrel
Prasugrel is a third-generation thienopyridine that has a similar mechanism of action to clopidogrel, in that its active form binds covalently to the P2Y 12 receptor via a disulphide bond, causing irreversible blockade for ADP binding. However, it has much more rapid and consistent inhibitory effects on platelet aggregation than clopidogrel, due to more efficient in vivo generation of its active metabolite . The prodrug is rapidly hydrolysed by carboxylesterases to a thiolactone, which is then efficiently converted to the active derivative via cytochrome P450 (CYP) isoenzymes (CYP3A4, CYP2B6 and CYP2C9) in a one-step process. CYP2C19 makes only a minor metabolic contribution . The esterase-mediated step for prasugrel occurs mainly in the intestine, as does the CYP-mediated oxidative step leading to the active metabolite formation. However, hydrolysis of clopidogrel by esterases in the intestine and/or liver leads to formation of an inactive metabolite, and conversion of the remaining clopidogrel to its active metabolite requires two CYP-mediated steps that occur mainly in the liver. The polymorphisms in CYP2C9, CYP2C19, CYP2C17 and ABCB1 that have an effect on clopidogrel do not significantly alter prasugrel clinical efficacy, pharmacokinetics or pharmacodynamics . The peak concentration of the active metabolite of prasugrel is achieved rapidly at 30 minutes and a maximum of 60–70% inhibition is usually achieved within 2–4 hours . For the STEMI population, recent studies have shown that optimal inhibition of platelet aggregation is reached 2–6 hours after LD administration and rarely before 1 hour .
The ACAPULCO trial specifically evaluated the pharmacodynamic effects of a 10 mg maintenance dose (MD) of prasugrel in 56 patients with unstable angina (UA)/non-ST-segment elevation myocardial infarction (NSTEMI), compared with a high MD of clopidogrel (150 mg daily) after a high LD (900 mg). Greater platelet inhibition with prasugrel 10 mg daily was observed over 14 days compared with clopidogrel 150 mg daily .
The pharmacodynamic benefit of prasugrel was further demonstrated in the OPTIMUS-3 study, when prasugrel was compared with high-dose clopidogrel in 35 patients with type 2 diabetes mellitus and coronary artery disease. Prasugrel was associated with greater platelet inhibition than clopidogrel at 4 hours post LD, as assessed using the VerifyNow assay (least squares mean 89.3% vs. 27.7%; P < 0.0001) and this was also seen for the MD at 7 days (61.8% vs. 44.2%; P < 0.0001) .
The superior antiplatelet effect of prasugrel was further demonstrated in the phase II PRINCIPLE-TIMI (prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation – TIMI) 44 trial, which compared a 60 mg dose of prasugrel with a 600 mg LD of clopidogrel. Among patients planned for PCI, loading with prasugrel 60 mg resulted in greater platelet inhibition than a clopidogrel 600 mg LD. Daily maintenance therapy with prasugrel 10 mg resulted in a greater antiplatelet effect than clopidogrel 150 mg daily .
In addition, the safety of prasugrel was demonstrated in the JUMBO-TIMI (Joint Utilization of Medications to Block Platelets Optimally – Thrombolysis in Myocardial Infarction) phase II trial. This was a dose-ranging comparison of different prasugrel doses (7.5 mg, 10 mg and 15 mg) with clopidogrel . At 30 days, there was a numerically higher but not statistically significant rate of bleeding events (non-CABG Thrombolysis in Myocardial Infarction [TIMI] major + minor) in the prasugrel groups than in the clopidogrel group; access site bleeding was the most common type of bleeding observed.
The superior pharmacodynamic and pharmacokinetic profile of prasugrel has translated into clinical benefit compared with clopidogrel. The TRITON-TIMI 38 trial evaluated 13,608 patients with moderate-to-high-risk ACS, including 10,074 patients with UA or NSTEMI and 3534 patients with STEMI , who were planned to undergo PCI. Patients were randomized to receive a prasugrel 60 mg LD followed by 10 mg/day or clopidogrel 300 mg followed by 75 mg/day; for STEMI patients, the study drug was given as soon as possible, meaning that prasugrel could be given without knowledge of the coronary anatomy; for UA/NSTEMI patients, the study drug was given when the decision for PCI was made after the coronary angiogram. Patients continued therapy for 6–15 months after enrolment. Prasugrel was associated with a 19% reduced risk of occurrence of the primary endpoint (cardiovascular death, non-fatal myocardial infarction or non-fatal stroke) compared with clopidogrel and fewer ischaemic events, which translates to a number needed to treat of 46. This ischaemic benefit was counterbalanced by an increased risk of bleeding: among patients treated with prasugrel, 146 (2.4%) had at least one TIMI major haemorrhage that was not related to CABG, compared with 111 (1.8%) patients treated with clopidogrel (hazard ratio 1.32, 95% CI 1.03–1.68; P = 0.03), with a number needed to harm of 167; thus, the overall net clinical benefit of prasugrel was significant. The ischaemic benefit was mainly driven by a reduction in myocardial infarction and stent thrombosis, with overall reductions of 2.3% and 1.3%, respectively. No difference was observed in mortality ( Table 1 ).
Based mainly on the outcome of the TRITON trial, prasugrel was approved by the Food and Drug Administration (USA) in July 2009 and by the European Medicines Agency (Europe) in February 2009.
Ticagrelor
Ticagrelor (AZD6140) is the first of a new class of antiplatelet family called cyclopentyl-trazolo-pyrimidines (CPTPs) and is also the first oral reversible selective P2Y 12 receptor antagonist. Like the thienopyridines, ticagrelor binds the platelet P2Y 12 receptor to inhibit the prothrombotic effects of ADP. However, unlike the thienopyridines, this effect is non-competitive and reversible. Ticagrelor appears to act through an allosteric modulation site and exhibits a conformational change in the receptor by binding independently of ADP; it therefore does not prevent ADP binding but seems to have an effect on ADP receptor-induced signaling and platelet aggregation . Ticagrelor is a direct-acting compound and does not require metabolic activation, thus obviating any influence of the CYP pathway on the antiplatelet response. Moreover, CYP2C19 and ABCB1 genotypes, which are known to influence the effects of clopidogrel, did not influence the effect on ischaemic outcomes in ACS patients. When administered orally, the agent displays a linear pharmacokinetic profile and has a rapid onset of action. The maximum plasma concentration and maximum platelet inhibition are reached 1–3 hours after treatment . However, as with prasugrel, for the STEMI population, recent studies have shown that optimal inhibition of platelet aggregation is rarely reached before 1 hour and that the effects of ticagrelor and prasugrel on inhibition of platelet aggregation are similar . Ticagrelor has a relatively short half-life and an offset of action that is more rapid than clopidogrel, so it may be advantageous in clinical scenarios requiring rapid reversal of the antiplatelet effect (e.g. in patients requiring CABG). However, this pharmacodynamic profile could also put patients at risk of acute events, such as stent thrombosis, especially after drug-eluting stent implantation if they are not strictly compliant with therapy.
In a pharmacodynamics substudy of the PLATO study of 69 patients with ACS (to be discussed later), ticagrelor (180 mg LD, 90 mg twice-daily MD) exhibited greater inhibition of platelet aggregation than a standard regimen of clopidogrel (300–600 mg LD, 75 mg/day MD) within the first hours after LD and after 28 days of maintenance therapy .
In the RESPOND trial, ticagrelor was shown to overcome non-responsiveness to clopidogrel in patients with stable coronary artery disease. Patients who were deemed to be non-responders to clopidogrel ( n = 41) were treated with ticagrelor (180 mg LD/90 mg twice daily MD) and high-dose clopidogrel (600 mg LD/75 mg/day MD) in a 14-day two-way crossover design . Ticagrelor treatment resulted in a significantly greater reduction in platelet aggregation from baseline than high-dose clopidogrel.
Similarly to prasugrel, ticagrelor has shown clinical benefit in head-to-head phase II and III studies with clopidogrel in ACS, showing decreased incidence of adverse cardiac events with a higher rate of non-CABG related bleeding .
The PLATO study was the largest randomized study to compare ticagrelor with clopidogrel. In total 18,624 patients with ACS were included and randomized to either ticagrelor (180 mg LD, 90 mg twice daily thereafter) or clopidogrel (300–600 mg LD, 75 mg daily thereafter) . Treatment began within 24 hours of symptom onset and all patients were treated with aspirin therapy.
At 12-month follow-up, there was a 16% lower rate of the primary composite endpoint of cardiovascular mortality, myocardial infarction and stent thrombosis in patients receiving ticagrelor (9.8% vs. 11.7%; P < 0.001), which translates to a number needed to treat of 53. This improved outcome was driven by lower cardiovascular mortality, myocardial infarction and stent thrombosis. Again, this ischaemic benefit was balanced by increased bleeding. There was no increase in overall bleeding, but there was an increase in major non-CABG related bleeding with the PLATO definition (4.5% vs. 3.8%, respectively; P = 0.03) and the TIMI definition (2.8% vs. 2.2%; P = 0.025), with a number needed to harm of 167. Although this trial was not powered for mortality, there appeared to be a mortality rate benefit (4.5% with ticagrelor vs. 5.9% with clopidogrel) .
There was a surprising finding of increased risk of primary endpoint in ticagrelor-treated patients in the patients enrolled in the USA, which may be related to aspirin doses of > 300 mg in this patient group .
In a pre-specified analysis of PLATO, ticagrelor appeared to have an even more significant impact in chronic kidney disease patients, with a 21% reduction in occurrence of the primary endpoint and a 28% reduction in mortality without a significant increase in bleeding .
Apart from unresolved issues regarding differences in efficacy, ticagrelor has been reported to have a propensity to elevate uric acid and creatinine concentrations, increase ventricular pauses and cause dyspnoea.
Ticagrelor received regulatory approval in Europe in December 2010 and in the USA in July 2011.
Cangrelor
Cangrelor belongs to a family of ATP analogues that are relatively resistant to the breakdown of endonucleotidases; it does not require metabolic activation and acts as a reversible competitive antagonist on the P2Y 12 receptor. Administered intravenously rather than orally, cangrelor has a short half-life of < 5 minutes, with a rapid onset of effect, inhibiting platelets to a high degree, and a quick offset of effect with resolution of normal platelet function within an hour of cessation of treatment . With this pharmacokinetic profile, the major use for cangrelor is in the acute setting, where a rapid antiplatelet effect with minimal increase in bleeding is needed ( Table 2 ).
