Abstract
Dual antiplatelet therapy (DAPT), which includes the combination of aspirin and a P2Y12 platelet receptor inhibitor, is a well-established antiplatelet regimen in the treatment of patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Three P2Y12 inhibitor options (clopidogrel, prasugrel and ticagrelor) are currently available, all having different efficacy and safety profiles along with contrasting contraindications, special warnings and precautions for use. This review compares and contrasts the unique P2Y12 antagonists in the NSTE-ACS setting, covering the latest evidence and their optimal use.
Introduction
Platelet inhibition is crucial in the treatment of non-ST-segment elevation acute coronary syndrome (NSTE-ACS) to aid in the containment and stabilization of the platelet plug and thrombus. Furthermore, platelet inhibition is needed for percutaneous coronary intervention (PCI) which can produce further plaque trauma, platelet-dependent thrombosis and embolization into the coronary microcirculation [Gurbel et al. 2009; Heusch et al. 2009; Lansky and Stone, 2010; Brar et al. 2011; De Caterina et al. 2012]. Dual antiplatelet therapy (DAPT), which includes the combination of aspirin and a P2Y12 platelet receptor inhibitor, is a well-established antiplatelet regimen in the treatment of patients with NSTE-ACS as well as those treated by PCI. While aspirin has remained steadfast as the cornerstone of DAPT, the P2Y12 inhibitor drug class has gone through an evolution in recent years. Three P2Y12 inhibitor options are currently available, all having different efficacy and safety profiles along with contrasting contraindications, special warnings and precautions for use. This review seeks to inform practitioners on the key differences between available P2Y12 inhibitors in an effort to help them make therapeutic decisions for NSTE-ACS.
Clopidogrel
Although ticlopidine was the first P2Y12 inhibitor investigated in NSTE-ACS, it was replaced by clopidogrel because of adverse effects such as thrombotic thrombocytopenic purpura and neutropenia. Clopidogrel became a standard part of NSTE-ACS treatment when it was found to provide a 20% relative reduction in cardiovascular (CV) events when added to aspirin in the treatment of NSTE-ACS and a 27% relative reduction in CV events when added to aspirin for PCI [Yusuf et al. 2001; Steinhubl et al. 2002]. Despite the demonstrated ability of clopidogrel to improve NSTE-ACS and PCI outcomes, it has limitations that compromise its clinical utility. In fact, for all its widespread use, approximately 10% of patients on clopidogrel had recurrent CV events within 1 year of an NSTE-ACS event [Yusuf et al. 2001; Wiviott et al. 2007]. These events are potentially explained by clopidogrel’s modest and variable platelet inhibition and inconsistent bioavailability, as well as its slow and mutable metabolism [Norgard and Abu-Fadel, 2008].
The drug efflux transporter P-glycoprotein (encoded by the ABCB1 gene) dictates clopidogrel absorption. Polymorphisms of the ABCB1 gene can alter clopidogrel bioavailability and contribute to the interpatient pharmacokinetic and pharmacodynamic variability; however results of clinical studies have been inconsistent [Taubert et al. 2006; Simon et al. 2009; Mega et al. 2010; Wallentin et al. 2010; Price et al. 2012]. The majority of the absorbed clopidogrel is metabolized into inactive metabolites by de-esterification. The remaining 15% of clopidogrel is converted to its active metabolite by two-step cytochrome P450 (CYP) dependent oxidative process. CYP1A2, CYP3A4/CYP3A5, CYP2C9 and CYP2C19 are considered the main contributors to active metabolite formation. Acquired and genetic changes in CYP isozymes can alter clopidogrel’s pharmacokinetic and pharmacodynamic profile [Farid et al. 2007; Gladding et al. 2008; Mega et al. 2009; Simon et al. 2009; Boulenc et al. 2012].
When drug metabolism is slow, clopidogrel is inefficiently converted into its active form, resulting in a reduced pharmacodynamic response. Active metabolite generation and the degree to which clopidogrel inhibits platelet function vary widely from patient to patient, ranging from near-complete platelet inhibition to almost no inhibition with a roughly normal distribution [Serebruany et al. 2005]. Available data show that up to 30% of patients who receive the conventional dose of clopidogrel display an inadequate antiplatelet response, referred to as clopidogrel nonresponsiveness or high on-clopidogrel platelet reactivity [Gurbel et al. 2003; Snoep et al. 2007; Angiolillo, 2009].
Due to its requirement for CYP metabolism, clopidogrel is susceptible to drug interactions via CYP inhibitors and inducers. Clopidogrel efficacy is significantly reduced by CYP3A inhibitors (erythromycin, ketoconazole, itraconazole) and CYP2C19 inhibitors (omeprazole) [Suh et al. 2006; Farid et al. 2007; Gilard et al. 2008]. CYP3A inducers (rifampin, St John’s wort) and smoking (a known CYP1A2 inducer) have been shown to increase the antiplatelet activity of clopidogrel [Lau et al. 2004; Bliden et al. 2008; Gremmel et al. 2009; Lau et al. 2011].
Accumulating evidence has shown that patients with high on-clopidogrel platelet reactivity have an increased risk of atherothrombosis [Barragan et al. 2003; Blindt et al. 2007; Bonello et al. 2007; Frere et al. 2008]. Several assays to assess platelet reactivity each with separate cutoff values for high on-treatment platelet reactivity are used to monitor clopidogrel’s pharmacologic efficacy [Aradi et al. 2014]. Despite the absence of a universal definition of high on-clopidogrel platelet reactivity or the gold standard test to quantify it, thrombotic events (stent thrombosis in particular) occur more frequently in patients who have persistent high platelet reactivity while taking clopidogrel, suggesting that a poor response to clopidogrel is a major factor in thrombosis development [Stone et al. 2013]. Pharmacokinetic and pharmacodynamic benefits have been observed with a higher-than-standard clopidogrel dose [Angiolillo et al. 2004; Von Beckerath et al. 2005; Cuisset et al. 2006; Montalescot et al. 2006; L’Allier et al. 2008; Lemesle et al. 2009]. Pharmacokinetically, loading with clopidogrel 600 mg resulted in greater plasma concentrations of the active metabolite as compared with a 300 mg loading dose. However, plasma concentrations of the active metabolite were not further increased by doses >600 mg [Von Beckerath et al. 2005]. Pharmacodynamically, the 600 mg loading dose was associated with more rapid and higher levels of inhibition of platelet aggregation and greater reductions in platelet activation during the first several hours compared with a 300 mg dose of clopidogrel [Gurbel et al. 2005; Hochholzer et al. 2005; Von Beckerath et al. 2005]. A loading dose of 900 mg of clopidogrel did not provide any incremental benefit over a 600 mg loading dose [Von Beckerath et al. 2005; Montalescot et al. 2006].
Clinical studies investigating the clinical benefit of higher-than-standard clopidogrel loading doses have yielded mixed results, with some showing higher clopidogrel doses to be associated with a significant clinical benefit, whereas others have not [Patti et al. 2005; Cuisset et al. 2006; Montalescot et al. 2006; Bonello et al. 2008; Fefer et al. 2009; Mehta et al. 2010]. A meta-analysis of 7 studies that included 25,383 patients undergoing PCI demonstrated that intensified loading doses of clopidogrel (600 rather than 300 mg) reduced the rate of major adverse CV events at 30 days without an increase in rates of major bleeding [Siller-Matula et al. 2011]. The largest study to investigate this concept was the Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events–Seventh Organization to Assess Strategies in Ischemic Syndromes (CURRENT-OASIS 7) trial, which showed that a 7-day double-dose regimen of clopidogrel (loading dose of 600 mg on day 1, followed by 150 mg daily on days 2 to 7) did not reduce the rate of 30-day major adverse CV events compared with the standard dosing regimen (a loading dose of 300 mg on day 1, followed by 75 mg daily on days 2 through 7) (4.2% versus 4.4%; p = 0.30) [Mehta et al. 2010]. The study did, however, find benefit in a prespecified analysis of the large subset of patients (17,263 out of the 25,086 patients enrolled) who underwent PCI, including a 30% reduction in rates of stent thrombosis (1.6% double dose versus 2.3% standard dose; p < 0.001). The higher dose regimen offered no benefit in patients who did not undergo PCI. In the overall study, the double-dose clopidogrel group had a statistically significant higher rate of study defined major bleeding events compared with the standard-dose clopidogrel group [2.5% versus 2%; hazard ratio (HR) 1.24, 95% confidence interval (CI) 1.05–1.46; p = 0.01]. Study-defined major bleeding was higher in the double-dose clopidogrel group in the PCI subset (1.6% versus 1.1%; HR 1.41, 95% CI 1.09–1.83;p = 0.009).
Since pharmacodynamic response to clopidogrel predicts clinical benefit from the drug, a practical approach to using clopidogrel in preparation for PCI is to tailor the clopidogrel loading dose according to pharmacodynamic response using platelet function monitoring. In this approach, patients have their platelet reactivity measured 12 hours following the administration of a 600 mg clopidogrel loading dose. If a patient meets the criteria for clopidogrel nonresponsiveness, before undergoing PCI, he or she receives additional clopidogrel loading doses in 600 mg increments every 24 hours until a target clopidogrel response is achieved or up to a maximum of 2400 mg. At that point, the patient will undergo PCI.
This approach has been examined using the vasodilator-stimulated phosphoprotein (VASP) index to measure the clopidogrel response [Bonello et al. 2009]. The VASP index is a standardized, flow cytometric measurement of VASP phosphorylation, which is a marker for platelet reactivity and is capable of detecting a significant decrease of platelet reactivity in patients treated with clopidogrel [Barragan et al. 2003]. The VASP index, expressed as a mean percentage of platelet reactivity, is inversely correlated with clopidogrel efficiency. Clopidogrel nonresponsiveness was defined as a VASP index >50% and additional clopidogrel loading doses were administered to achieve a VASP index <50% before PCI was performed. The rate of stent thrombosis within 30 days of PCI was significantly reduced in patients who received VASP index-guided dosing compared with control subjects who did not (0.5% versus 4.2%; p = 0.01). VASP index-guided dosing was also associated with a significantly reduced risk of major adverse CV events, including CV death, myocardial infarction (MI) or urgent revascularization (0.5% versus 8.9%; p = 0.001), without significantly increasing the risk of major or minor bleeding (3.7% versus 2.8%; p = 0.08). The widespread use of this approach in clinical practice is limited by VASP assay expense and technical difficulty. Additionally, approximately 50% of the patients in the VASP-guided group required all 4 loading doses prior to PCI, which would delay the procedure for over 4 days and could add to hospital-related expenses.
Clopidogrel therapy guided by multiple-electrode aggregometry was also found to significantly reduce the risk of stent thrombosis compared with patients who received standard therapy (tailored 0% versus standard 5.3%, p = 0.03) [Hazarbasanov et al. 2012]. As opposed to the VASP assay approach, multiple electrode aggregometry was assessed once 24 hours after clopidogrel loading and patients with high on-clopidogrel platelet reactivity (>46 ohms/min) received one additional 600 mg loading dose following PCI and 150 mg/day thereafter for 1 month.
The clinical impact of the high loading dose and/or tailored clopidogrel dosing compared with new antiplatelet agents remains unclear. While a tailored approach to dosing clopidogrel in patients prior to PCI has been shown to be effective at reducing early rates of recurrent CV events and stent thrombosis, the question remains as to whether the approach is feasible in clinical practice.
As with the loading dose, higher-than-standard maintenance doses of clopidogrel (150 mg/day versus 75 mg/day) provide greater platelet inhibition [Angiolillo et al. 2007; Von Beckerath et al. 2007; Aleil et al. 2008; Angiolillo et al. 2008; Fontana et al. 2008; Gladding et al. 2008; Trenk et al. 2008]. However, greater platelet inhibition with higher-than-standard maintenance clopidogrel doses and platelet reactivity guided maintenance antiplatelet management has not been shown to improve clinical outcomes. The Gauging Responsiveness With a VerifyNow Assay–Impact on Thrombosis and Safety (GRAVITAS) trial found no improvement in clinical outcomes with high-dose clopidogrel (150 mg/day) when compared with standard-dose clopidogrel (75 mg/day) in clopidogrel resistant patients despite an improvement in on-treatment platelet reactivity [Price et al. 2011]. It is thought that the failure of the GRAVITAS trial is due to the disproportionate enrollment of nonemergent and lower risk patients, resulting in much lower event rates (2.3%) than predicted (predicted event rate 5%). In addition, the high-dose clopidogrel regimen continued to provide a variable and modest pharmacodynamic effect. In fact, high-dose clopidogrel successfully reduced on-treatment platelet reactivity to a level associated with lower CV event risk in 48% of patients, suggesting that the high-dose clopidogrel regimen may only provide ischemic benefit in some patients [Price et al. 2011]. This insufficient improvement in pharmacodynamic response may have been responsible for the lack of clinical effectiveness observed with the high-dose regimen. The Responsiveness to Clopidogrel and Stent- Related Events in Acute Coronary Syndromes (RECLOSE 2-ACS) trial showed a poor pharmacodynamic response to clopidogrel to be associated with increased event rates in patients with ACS undergoing PCI; however, increasing the clopidogrel dose in patients with a poor response was not associated with clinical benefits in these patients [Parodi et al. 2011].
Another method of overcoming high on-clopidogrel platelet reactivity is to switch treatment from clopidogrel to one of the more potent P2Y12 antagonists [Payne et al. 2008; Angiolillo et al. 2010; Gurbel et al. 2010]. This concept was studied in the Testing Platelet Reactivity in Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel (TRIGGER-PCI) trial, in which a low risk group of patients with stable coronary artery disease who had undergone successful stenting and had high on-clopidogrel platelet reactivity were either treated with prasugrel or continued on the standard clopidogrel dose [Trenk et al. 2012]. Prasugrel improved platelet reactivity compared with clopidogrel, but there was no reduction in clinical outcomes. However, the study was halted prematurely due to very low event rates in both arms, even in patients who were hyporesponsive to clopidogrel and was underpowered to find clinical outcome differences. Consequently, routine platelet function monitoring to guide antiplatelet therapy should not be encouraged in low risk patients. Higher risk populations are likely more dependent on adequate inhibition of platelet reactivity. The prognostic utility of serial platelet function testing may become more evident in such a patient population. However, prospective clinical trials using on-treatment platelet reactivity to guide clinical decision making are needed to demonstrate the clinical benefits of this strategy before it can be implemented.
Genetic variation in the CYP isozymes is an important determinant of clopidogrel response. Studies have shown that carriers of a reduced function CYP2C19 allele (i.e. CYP2C19*2) have significantly lower levels of the active metabolite of clopidogrel, diminished platelet inhibition, and a higher rate of major adverse CV events [Mega et al. 2009; Simon et al. 2009]. The US Food and Drug Administration (FDA) added a boxed warning to clopidogrel labeling to inform practitioners that poor metabolizers of the drug may not receive its full benefits. Using commercially available CYP2C19 polymorphism testing, the decision to use clopidogrel would be dependent on the absence of a CYP2C19*2 allele.
It has been shown that there is strong and consistent association between the CYP2C19 genotype and on-treatment platelet reactivity in patients taking clopidogrel [Price et al. 2012]. However, genotype-guided strategy is unproven and it is important to consider the role of CYP2C19 as a single piece of a complicated puzzle. The response to clopidogrel depends on a complex interplay of phenotypic (e.g. spontaneous platelet reactivity, inflammatory status, acuity of the clinical presentation, age, and renal function) as well as genetic variables. One analysis showed that genetic causes account for only approximately 12% of the response variability to clopidogrel [Shuldiner et al. 2009]. The pharmacodynamic profiles of the third generation P2Y12 inhibitors, ticagrelor and prasugrel, are not affected by the CYP2C19 genotype. Thus, the use of either drug eliminates the need for genetic testing. It remains unknown whether genotype-guided antiplatelet therapy leads to improved outcomes.
While genotype-guided and platelet reactivity-guided clopidogrel therapy may be better than a one-dose-fits-all approach, a more plausible approach, at this time, may be the upfront use of the more potent antiplatelet agents, prasugrel or ticagrelor.
Prasugrel
Prasugrel is a thienopyridine prodrug like clopidogrel. It is rapidly and completely hydrolyzed by intestinal hydroxyesterases to an intermediate, which is metabolized to the active metabolite by a single step, primarily by CYP3A4 and CYP2B6, and to a lesser extent by CYP2C9 and CYP2C19 [Niitsu et al. 2005]. As a consequence, the metabolism of prasugrel into active form is more efficient compared with clopidogrel, a drug that requires a two-stage hepatic activation by CYP enzymes [Niitsu et al. 2005]. Unlike clopidogrel, prasugrel is not dramatically altered by genetic and acquired variations in CYP activity due to its efficient metabolism [Brandt et al. 2007; Farid et al. 2007; Farid et al. 2007; Farid et al. 2009; Mega et al. 2009; Varenhorst et al. 2009]. Drugs that induce or inhibit CYP enzymes have not been shown to significantly alter the antiplatelet effect of prasugrel[Rehmel et al. 2006; Farid et al. 2007; Farid et al. 2009]. Earlier and more extensive formation of prasugrel active metabolite results in greater and more rapid platelet inhibition compared with clopidogrel [Brandt et al. 2007; Payne et al. 2007; Sugidachi et al. 2007; Wallentin et al. 2007; Weerakkody et al. 2007; Weerakkody et al. 2007; Erlinge et al. 2008]. In addition, prasugrel has been shown to overcome high on-clopidogrel platelet reactivity [Brandt et al. 2007; Weerakkody et al. 2007; Weerakkody et al. 2007]. Nevertheless, variability in biological responsiveness is still present [Wallentin et al. 2008; Alexopoulos, 2012]. In one small study (n = 301), high on-prasugrel platelet reactivity was present in ~25% of ACS patients following a 60 mg loading dose and was associated with higher rates of recurrent thrombotic events 30 days after PCI [Bonello et al. 2011]. Additional studies have found that high on-prasugrel platelet reactivity is quite low after 2–4 weeks of maintenance therapy (0–6% depending on the assay) [Jernberg et al. 2006; Montalescot et al. 2010].
The greatly reduced rate of nonresponsiveness with prasugrel compared with clopidogrel is likely a very important factor in its superior clinical efficacy. Prasugrel was found to improve ischemic outcomes in the TRITON-TIMI 38 trial compared with clopidogrel in ACS patients who were referred for PCI but with more bleeding [Wiviott et al. 2007]. Prasugrel was associated with a significant 2.2% absolute reduction (number needed to treat = 46) and a 19% relative reduction in the primary efficacy endpoint, a composite of the rate of CV death, nonfatal MI, or nonfatal stroke during the follow-up period [Wiviott et al. 2007]. The primary efficacy endpoint occurred in 9.9% of patients receiving prasugrel and 12.1% of patients receiving clopidogrel (HR 0.81; 95% CI 0.73–0.90; p < 0.001). The difference in the primary endpoint was largely related to the difference in rates of nonfatal MI as the rates of CV death and nonfatal stroke were not significantly reduced by prasugrel relative to clopidogrel. Overall mortality was not significantly different between the two treatment groups. Rates of early and late stent thrombosis were significantly reduced with prasugrel overall (1.1% versus 2.4%; p < 0.001) in patients with drug-eluting stents and bare metal stents [Wiviott et al. 2008]. The benefits of prasugrel in preventing ischemic events emerged rapidly, as significant reductions in MI and stent thrombosis rates were seen within 72 hours of treatment initiation [Antman et al. 2008].
The downside to the increased platelet inhibition with prasugrel is an increased risk of major bleeding. In the TRITON-TIMI 38, there was a significant increase in the rate of non coronary artery bypass grafting (CABG) thrombolysis in myocardial infarction (TIMI) major bleeding [2.4% versus 1.8%; HR 1.32; 95% CI 1.03–1.68; p = 0.03; number needed to harm (NNH): 167]. This included a higher rate of life threatening (1.4% versus 0.9%; p = 0.01; NNH: 200) and fatal bleeding episodes (0.4% versus 0.1%; p = 0.002; NNH: 333). In addition to the greater antiplatelet effect of prasugrel, normalization of platelet reactivity after discontinuation is slower than with clopidogrel [Price et al. 2012]. This is of particular consequence for those patients requiring revascularization with CABG surgery as CABG-related major bleeding was increased nearly 5-fold with prasugrel compared with clopidogrel (13.4% versus 3.2%;p < 0.001; NNH: 10). Regardless, the clinical efficacy was in favor of prasugrel seeing that, for every 1000 patients, 23 MIs were prevented in those treated with prasugrel as compared with clopidogrel with an excess of 6 non-CABG related TIMI major hemorrhages [Wiviott et al. 2007].
While the TRITON-TIMI 38 trial demonstrated the efficacy of prasugrel in ACS patients who were referred for PCI, there are patients with ACS are treated medically without revascularization (approximately 20%) [Roe et al. 2012]. These patients were studied in the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trial [Roe et al. 2012]. Prasugrel did not reduce CV death, MI or stroke compared with clopidogrel and did not increase severe bleeding despite producing lower platelet reactivity.
Subgroup analyses of prasugrel studies suggest that there might be greater benefits or risks for specific groups. Such results must be interpreted with caution, especially because of the increased risk of false positive results arising from multiple post hoc analyses [Lagakos, 2006; Wang et al. 2007]. The benefit of prasugrel over clopidogrel was found to be greater in patients with diabetes, with a 30% relative risk reduction in CV death, MI or stroke (12.2% versus 17.0%; HR 0.70; 95% CI 0.58–0.85; p < 0.001; NNT 21) and no increase in major bleeding (2.6% versus 2.5%; HR 1.06; 95% CI 0.66–69; p = 0.29) [Wiviott et al. 2008]. Patients with diabetes mellitus are known to have enhanced platelet reactivity and a higher likelihood of high on-clopidogrel platelet reactivity, which may be the reason for the benefit from the more potent therapy [Angiolillo et al. 2011]. The benefit–risk ratio was found to be unfavorable for patients with a history of stroke or transient ischemic attack [Wiviott et al. 2007]. Increases in fatal and intracranial bleeding risk outweighed the ischemic benefits of prasugrel in this patient subgroup, which led to the addition of an absolute contraindication and box warning to the package insert. Additionally, prasugrel showed no net clinical benefit over clopidogrel in patients ⩾75 years old or with a body weight under 60 kg [Wiviott et al. 2007]. A pharmacokinetic substudy showed that these patients had higher levels of the active metabolite of prasugrel than other study subjects [Erlinge et al. 2012]. In these subjects, decreasing the maintenance dose of prasugrel to 5 mg reduced the levels of the active metabolite [Erlinge et al. 2012]. In medically managed ACS patients older than 75 years, 5 mg of prasugrel daily had a similar risk efficacy profile to 75 mg of clopidogrel daily [Roe et al. 2013].
Ticagrelor
Ticagrelor is the first of a new chemical class of antiplatelet agents called cyclopentyltriazolopyrimidines and has properties that distinguish it from the thienopyridines (Table 1). Ticagrelor directly and reversibly inhibits the P2Y12 receptor without first undergoing hepatic activation. As a result, it promptly achieves both a higher and a more consistent inhibition of platelet aggregation than clopidogrel and produces a significantly higher platelet inhibition than prasugrel [Gurbel et al. 2009; Alexopoulos et al. 2012]. The maximal antiplatelet effect of ticagrelor produces approximately 90% platelet inhibition and occurs approximately 2 hours following administration of the initial dose, whereas the maximal antiplatelet effect of clopidogrel generates approximately 60% platelet inhibition and occurs 6–8 hours after administration of the loading dose [Gurbel et al. 2009]. The reversible inhibition of adenosine diphosphate (ADP) receptors leads to a faster offset of action compared with clopidogrel, which necessitates twice-a-day ticagrelor dosing [Gurbel et al. 2009]. Although ticagrelor does not require metabolic activation, it is primarily metabolized by CYP3A4 into active and inactive metabolites [Zhou et al. 2011]. Thus, CYP3A4 inhibitors increase ticagrelor concentrations. Strong CYP3A4 inhibitors are contraindicated with ticagrelor and moderate inhibitors should be used with caution. Ticagrelor is also a substrate of P-glycoprotein and can significantly increase digoxin levels (75% increase in peak plasma concentration and 28% increase in area under the curve) [Teng and Butler, 2013]. Consequently, in patients on ticagrelor, digoxin concentrations should be monitored when initiating or changing ticagrelor therapy.
Antiplatelet pharmacology.
IPA, inhibition of platelet aggregation.
A unique characteristic of ticagrelor is its ability to increase plasma concentrations of adenosine [Bonello et al. 2014]. Adenosine is an endogenous molecule that may have beneficial effects in patients with ACS including cardioprotection, vasodilatation, inflammatory regulation and platelet function inhibition [Fredholm, 2007]. Ticagrelor prevents adenosine uptake by erythrocytes likely through the inhibition of the sodium-independent equilibrative nucleoside transporter 1 (ENT1) [Noji et al. 2004; Armstrong et al. 2014]. This effectively extends the halflife of adenosine, thereby increasing extracellular levels of locally produced endogenous adenosine. This action may be important in vessel damage or hypoxia, where increased adenosine levels may contribute to vasodilation, enhanced coronary blood flow and adenosine-mediated platelet inhibition [Nylander et al. 2013; Wittfeldt et al. 2013]. This suggests that ticagrelor may have a unique dual mode of action, with a primary effect mediated by P2Y12 antagonism complemented by a secondary effect mediated by adenosine uptake inhibition [Serebruany, 2011]. Additionally, increased endogenous adenosine may also have wide-ranging effects on other pathways involved in innate immunity and may have a protective effect against pulmonary injury [Storey et al. 2014].
The PLATO trial compared ticagrelor with clopidogrel in patients with acute coronary syndromes [Wallentin et al. 2009]. Ticagrelor was associated with a 1.9% absolute reduction (number needed to treat = 53) and 16% relative reduction in the primary efficacy endpoint, a composite of the rate of CV death, nonfatal MI or nonfatal stroke during the follow-up period. The primary efficacy endpoint occurred in 9.8% of patients receiving ticagrelor and 11.7% of patients receiving clopidogrel (HR 0.84; 95% CI 0.77–0.92; p < 0.001). This effect was independent of whether or not early revascularization was performed [Lindholm et al. 2014]. In addition, death from vascular causes was significantly reduced from 5.1% to 4.0% with ticagrelor (HR 0.79; 95% CI 0.69–0.91; p = 0.001) and MI from 6.9% to 5.8% (HR 0.84; 95% CI 0.75–0.95; p = 0.005). Ticagrelor’s benefits were observed regardless of prior therapy with clopidogrel. About 46% of patients randomized to ticagrelor were using clopidogrel while hospitalized before randomization.
Rates of major bleeding were similar in the 2 groups (ticagrelor 11.6% and clopidogrel 11.2%; p = 0.43). However, ticagrelor was associated with a significantly higher rate of non-CABG major bleeding (4.5% versus 3.8%; p = 0.02) and nonprocedural major bleeding (3.1% versus 2.3%; p = 0.05) [Becker et al. 2011]. Importantly, bleeding causing or contributing to death did not differ between treatments [Varenhorst et al. 2014]. Unlike prasugrel, no specific subgroups have been identified as having an increased risk of bleeding with ticagrelor. Unique adverse effects of ticagrelor include dyspnea and ventricular pauses. These have been linked to ticagrelor’s augmentation of endogenous adenosine. Dyspnea occurs in up to 15% of patients within the first week of treatment, but rarely causes treatment discontinuation and the ventricular pauses have little to no clinical consequences [Wallentin et al. 2009; Scirica et al. 2011]. The administration of ticagrelor can cause a modest and reversible increase in serum uric acid. This may be caused by altered tubular secretion and/or increase in production [Butler and Teng, 2012]. There was also an increase in serum creatinine in ticagrelor patients compared with clopidogrel patients (10% versus 8% change from baseline; p < 0.001). The clinical significance of the increased levels of creatinine and uric acid has yet to be determined.
FDA approval of ticagrelor was initially delayed over concerns about a trend towards worse outcomes at North American sites, with the primary endpoint occurring in 11.9% of ticagrelor-treated patients compared with 9.6% of those on clopidogrel (HR 1.27; 95% CI 0.92–1.75; p = 0.15) [Mahaffey et al. 2011]. An analysis of the characteristics of patients based on geographical regions raised the possibility that it was differences in the aspirin dose that could play a role in the differential response to ticagrelor. Benefit from ticagrelor over clopidogrel was limited to patients taking under 100 mg of aspirin [Mahaffey et al. 2011]. The pharmacologic mechanism for this interaction has not been determined. Notwithstanding, lower dose of aspirin are recommended in most ACS patients because higher doses offer no extra efficacy regardless of the P2Y12 inhibitor used [Dinicolantonio et al. 2014].
Choice of P2Y12 inhibitor
Decisions about antiplatelet therapy must be made at several points during NSTE-ACS management: first medical contact, before catheterization, in the catheterization laboratory, and upon discharge. The initial choice of P2Y12 inhibitor is contingent on the chosen management strategy. For patients with definite or likely NSTE-ACS, two treatment strategies are used: (1) invasive strategy and (2) ischemia-guided strategy. The invasive strategy triages patients to coronary angiography to rapidly risk stratify them by assessing their coronary anatomy and promptly performing revascularization when appropriate. This strategy is subdivided into early (within 24 hours) and delayed (25–72 hours) angiography. The delayed strategy is reasonable in low to intermediate risk patients [Mehta et al. 2009]. The ischemia-guided strategy saves invasive procedures for patients who experience signs and symptoms of ischemia despite vigorous medical therapy.
Clopidogrel and ticagrelor were studied in all-inclusive trials and were found to have benefit in both invasively and medically managed NSTE-ACS patients [Yusuf et al. 2001; Lindholm et al. 2014]. Therefore, either clopidogrel or ticagrelor can be initiated at the time of presentation irrespective of treatment strategy. Current guidelines give preference to ticagrelor over clopidogrel as an initial antiplatelet and in medically managed NSTE-ACS patients [Amsterdam et al. 2014]. Prasugrel is only indicated in patients treated with PCI. Current evidence does not support the routine use of prasugrel before angiography or in medically managed patients [Wiviott et al. 2007; Roe et al. 2012; Montalescot et al. 2013]. Prasugrel was superior to clopidogrel only when administered to patients in whom coronary anatomy was known and were proceeding to PCI, but was not better than clopidogrel in patients who did not undergo revascularization [Wiviott et al. 2007; Roe et al. 2012]. Furthermore, the ACCOAST trial demonstrated that pretreatment with prasugrel before coronary angiography may not be necessary as it did not reduce the rate of major ischemic events but increased the rate of major bleeding complications compared with no pretreatment [Montalescot et al. 2013]. Pretreatment may not be needed due to the rapid onset of prasugrel and the low risk of ischemic complications observed in the interval between admission and catheterization [Mehta et al. 2009; Montalescot et al. 2009; Tricoci et al. 2012; Bhatt et al. 2013].
The question remains whether the ACCOAST data analyzed the pretreatment strategy in general, or a pretreatment strategy with one specific drug? Ticagrelor also has a rapid onset of action but the question of whether ticagrelor pretreatment is necessary has not been addressed in clinical trials. The optimal timing of clopidogrel and ticagrelor administration remains unknown, but there are data to suggest that earlier is better [Serebruany, 2011]. It is presumed that prompt administration of clopidogrel or ticagrelor will diminish thrombus burden and stabilize unstable plaques, thereby reducing early ACS related adverse events and improving the safety of PCI (when needed) by reducing the risk of periprocedural ischemic complications. This is supported by data from the CURE trial, which showed the benefit of clopidogrel in NSTE-ACS was apparent within 24 hours of initiation and the CREDO trial, which showed that patients who received clopidogrel at least 6 hours before PCI had a relative reduction in the combined risk of death, MI or stroke [Steinhubl et al. 2002; Yusuf, 2003]. Additionally, a meta-analysis showed the administration of clopidogrel before PCI was associated with a lower risk of major cardiac events without increasing the risk of major bleeding [Bellemain-Appaix et al. 2012]. It is believed that delayed administration may increase patients’ vulnerability to thrombotic events during the interval before cardiac catheterization, particularly when there are delays between ACS presentation and the start of angiography. Consequently, many practitioners are inclined to initiate either clopidogrel or ticagrelor as soon as ACS is suspected.
The early administration strategy is hindered by the fact that approximately 5–15% of ACS patients will have a coronary anatomy that is more suitable for revascularization with CABG surgery [Steg et al. 2002; Stone et al. 2006; Ebrahimi et al. 2009]. Early P2Y12 inhibitor administration can delay CABG and/or increase the risk of CABG related bleeding [Mehta et al. 2006]. As a result, some practitioners defer P2Y12 inhibition until angiography rules out the need for CABG. This strategy is particularly acceptable when the time between admission and angiography is short. However, P2Y12 inhibitors may have differing safety profiles in CABG patients. Ticagrelor’s reversible inhibition and rapid pharmacodynamic offset may make it uniquely proficient in this population. Ticagrelor induces more extensive platelet inhibition but does not cause an increase in CABG-related bleeding compared with clopidogrel, even though the study protocol recommended ticagrelor to be withheld for 24–72 hours preceding surgery versus 5 days for clopidogrel [Wallentin et al. 2009]. In the subgroup of patients treated with CABG (n = 1899), 1261 patients were receiving either ticagrelor or clopidogrel ⩽7 days before surgery. Ticagrelor was associated with a substantial reduction in total and CV mortality compared with clopidogrel (4.7% versus 9.7%; HR 0.49; 95% CI 0.32–0.77; p = 0.0018 and 4.1% versus 7.9 %; HR 0.52, 95% CI 0.32–0.85; p = 0.009, respectively) without excess risk of CABG-related bleeding [Held et al. 2011]. Time from last intake of antiplatelet before surgery did not impact CABG-related bleeding. In fact, there was no difference in the PLATO study major/fatal/life-threatening CABG-related bleeding or GUSTO severe bleeds between ticagrelor and clopidogrel even when the antiplatelet was stopped 1 day before surgery [Held et al. 2011]. Prasugrel-associated bleeding risk, on the other hand, is particularly malignant (nearly five-fold higher than clopidogrel) in CABG patients, which provides further rationale that routine prasugrel pretreatment is not supported, but not needed [Wiviott et al. 2007].
In patients who undergo PCI, current guidelines give preference to ticagrelor or prasugrel over clopidogrel [Amsterdam et al. 2014]. The lack of a PCI indication at the early phase of hospitalization or initial presentation to a non PCI-capable hospital may lead to selection of clopidogrel initially. Switching from clopidogrel to prasugrel or ticagrelor leads to a reduction in platelet reactivity, and may be an effective and safe alternative for high risk patients better suited for more potent platelet inhibition [Angiolillo et al. 2010; Gurbel et al. 2010]. The clinical effect of switching on efficacy or safety has not been established by prospective trials. Ticagrelor and prasugrel have only been compared directly in pharmacodynamic studies [Alexopoulos et al. 2012]. Ticagrelor produces greater platelet inhibition; however, it is difficult to draw any clear conclusions as to whether pharmacodynamic differences translate into differences in clinical efficacy or safety and clinical decision making should not be influenced by these results. Until a head-to-head trial is completed, the choice between ticagrelor and prasugrel should be guided by NSTE-ACS management strategy, patient preference and the presence of contraindications.
Footnotes
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest statement
The authors declare no conflicts of interest in preparing this article.