Additional benefits seen with ticagrelor may be due to the unique inhibition of nonplatelet P2Y12 receptors. These receptors are present in vascular smooth muscle and stimulate vasoconstriction. Systemically active drugs, such as ticagrelor, are able to penetrate the vascular wall, prevent vasospasm and aid in myocardial perfusion. Prodrugs, such as clopidogrel, have not been shown to inhibit these receptors potentially due to the physical and chemical properties of the metabolite.14
The pharmacokinetics of ticagrelor have been studied in healthy volunteers, those with ACS, and in patients with renal or hepatic insufficiency. Ticagrelor is an oral medication that demonstrates, at doses from 100 to 400 mg, rapid absorption without requiring metabolic activation. Hepatic cytochrome P450 3A generates an equally potent active metabolite, with plasma concentrations equalling one-third of the parent compound.14,16 Plasma concentrations of ticagrelor and its metabolite exhibit linear, dose-proportional pharmacokinetics that are stable and predictable at steady state.7,16 Nearly complete inhibition of platelet aggregation (IPA), 85% to 95%, is observed at 2 to 4 hours following oral administration of 100 mg twice daily. Increases in doses beyond 100 mg twice daily create only small additional increases in the IPA.7,17 Twelve hours after the last 90 or 100 mg dose, the IPA declines to 70% to 75% and is less than 50% by 24 hours postdose.7,18 By 3 days postdose, IPA is about 20%, which is comparable with the IPA for clopidogrel 5 days postdose.18 Ticagrelor has a half-life of 7 to 8.5 hours, with the metabolite lasting up to 12 hours. This, combined with its reversible binding to the ADP receptor, mandates twice daily dosing.7,17,18 The excretion of ticagrelor relies minimally on renal function, and very low levels (≤0.05%) of the parent compound and metabolite are found in the urine.19 Individuals with mild hepatic insufficiency have shown moderate increases in the levels of ticagrelor and the metabolite compared with controls. Nevertheless, these increases create no subsequent effects on the pharmacodynamics of the drug or clinical outcomes.20
PHARMACODYNAMICS AND PHARMACOKINETICS OF TICAGRELOR VERSUS THIENOPYRIDINES
Compared with clopidogrel, ticagrelor displays more consistent and superior platelet inhibition throughout therapy without an increased risk for bleeding.21 The antiplatelet effect of clopidogrel as compared with ticagrelor differs in the onset time, degree of platelet aggregation, receptor binding, and consistency of patient response (Table 1).7,11,12,17,18,22–24 Clopidogrel is a prodrug that is metabolized by 2 main pathways. The first is mediated by esterases that metabolize 85% of the parent compound into an inactive, unusable form.12,22 The second pathway is mediated by hepatic activation through 2 sequential enzymatic changes, one of which involves the P450 CYP2C19 isozyme, to create the active form. Maximal platelet aggregation is not seen for 4 to 8 hours after a loading dose of 300 to 600 mg and the average IPA does not exceed 40% to 60%.18,22 Patients who do not receive a loading dose reach maximum platelet inhibition in approximately 5 days.25 Furthermore, due to irreversible binding with the ADP receptor, antiplatelet effects are seen for the lifespan of the platelet, 7 to 10 days.22 Genetic variations in the P450 CYP2C19 isozyme can predispose individuals to greater bleeding risk or thrombosis with clopidogrel as well as create undesirable drug-drug interactions that may reduce the efficacy of clopidogrel.22,26 Approximately 15% to 30% of patients have been reported to be nonresponsive to clopidogrel. The frequencies for poor responders are approximately 2% for Whites, 4% for Blacks, and 14% for Chinese ethnicities.22 In addition, concomitant use of medications metabolized by the CYP2C19 isozyme, such as omeprazole, pharmacokinetically interact with clopidogrel and may considerably reduce the level of the active metabolite, and subsequently the amount of platelet inhibition.26 Ticagrelor does not require activation, therefore drug-drug interactions are less likely to interfere with antiplatelet effects and outcomes compared with clopidogrel.21
Prasugrel has not been directly compared with ticagrelor, though it demonstrates comparable IPA levels and a similar onset of action.18,24 Compared with clopidogrel, prasugrel is associated with a higher and more severe risk of bleeding.6 Prasugrel is also a prodrug that is initially hydrolyzed by esterases in the intestines and converted to the active metabolite through only a single step, primarily by CYP3A4. Its absorption and metabolism is rapid and the maximum platelet inhibition levels, after a loading dose of 60 mg, occur between 2 to 4 hours postdose, with an IPA of 75% to 85%. Prasugrel covalently binds to the ADP receptor and like clopidogrel, the duration of action lasts for the lifespan of the platelet, 7 to 10 days.24 Life-threatening, major, and fatal bleeds in clinical trials were statistically higher for prasugrel than clopidogrel. Further bleeding risks with prasugrel compared with clopidogrel are seen in those that weigh less than 60 kg or are more than 75 years of age, and the drug is therefore generally not recommended for use in these patients.6,24
The clinical trial portfolio for ticagrelor consists primarily of the following 2 studies: DISPERSE-2 (Dose Confirmation Study Assessing Antiplatelet Effects of AZD6140 versus Clopidogrel in Non-ST-segment Elevation Myocardial Infarction-2) and PLATO (The Study of Platelet Inhibition and Patient Outcomes). These studies have also given way to many subgroup analyses.
The DISPERSE-2 trial assessed the safety and efficacy of ticagrelor in 990 patients with non-ST-elevation ACS.27 In addition to receiving aspirin and other standard therapies (31% received a glycoprotein IIb/IIIa receptor antagonist), patients were randomized in double-blind manner to receive 1 of the following 3 treatments: (1) ticagrelor 90 mg twice daily, (2) ticagrelor 180 mg twice daily, or (3) clopidogrel 300 mg load followed by 75 mg once daily. Treatments were given for up to 3 months, and those randomized to receive ticagrelor were also subrandomized to receive or not receive a 270 mg load of ticagrelor. The primary outcome of total bleeding events in the first 4 weeks of treatment did not differ between the 3 treatment groups, although at 12 weeks, there was more minor bleeding with ticagrelor 180 mg twice daily (6.1%) compared with clopidogrel (1.3%; P = 0.01). The use of a loading dose of ticagrelor did not significantly affect bleeding rates. There were no differences in any of the clinical end points (all-cause death, cardiovascular death, myocardial infarction, stroke, recurrent ischemia) between the ticagrelor 90 mg and clopidogrel groups, although these were all secondary end points. The only statistically significant difference detected between the ticagrelor 180 mg and clopidogrel groups in terms of clinical end points was a slightly lower rate of myocardial infarction with ticagrelor at 4 weeks (1.0% vs. 3.5%; P = 0.047). The most common adverse event reported with ticagrelor was dyspnea, which occurred in 6.4% of patients taking clopidogrel, 15.8% of patients receiving 180 mg ticagrelor (P < 0.0002 vs. clopidogrel), and 10.5% of patient receiving 90 mg ticagrelor (P = 0.07 vs. clopidogrel). The 180 mg ticagrelor group also displayed a higher incidence of asymptomatic ventricular pauses compared with clopidogrel and the 90 mg ticagrelor group. In summary, DISPERSE-2 demonstrated that rates of bleeding and major adverse cardiovascular events were similar between the 90 mg twice-daily regimen of ticagrelor and clopidogrel. Although the 180 mg dosage of ticagrelor showed lower rates of myocardial infarction compared with clopidogrel, the higher rates of dyspnea and electrocardiographic disturbances led to the selection of the 90 mg twice-daily regimen for further clinical development in the PLATO trial.
The PLATO trial is the centerpiece study for the ticagrelor clinical trial program. This double-blind study randomized 18,624 patients with an ACS, with symptom onset within the previous 24 hours to either ticagrelor (180 mg load followed by 90 mg twice daily) or clopidogrel (300–600 mg load followed by 75 mg once daily), in addition to aspirin and other standard therapies.28 The primary efficacy end point (death from vascular causes, myocardial infarction, or stroke) occurred in 9.8% of patients receiving ticagrelor and 11.7% of patients taking clopidogrel (hazard ratio: 0.84; 95% confidence interval: 0.77–0.92; P < 0.001). A breakdown of the components of the primary end point showed significantly lower rates of vascular death (4.0% vs. 5.1%; P = 0.001) and myocardial infarction (5.8% vs. 6.9%; P = 0.005) with ticagrelor, although rates of stroke were not statistically different between the 2 groups (1.5% ticagrelor, 1.3% clopidogrel; P = 0.22). All-cause mortality was also less with ticagrelor (4.5% vs. 5.9%; P < 0.001). The primary safety end point of any major bleeding event was similar between the ticagrelor (11.6%) and clopidogrel (11.2%) groups (P = 0.43), although noncoronary artery bypass graft (CABG)-related bleeds were higher with ticagrelor (4.5% vs. 3.8%; P = 0.03). In addition, rates of fatal intracranial bleeds, although low, were more common with ticagrelor (0.1% vs. 0.01%; P = 0.02), whereas rates of fatal non-intracranial bleeds were higher with clopidogrel (0.3% vs. 0.1%; P = 0.03). The most common adverse effect with ticagrelor in this study was dyspnea, which was experienced by 13.8% of patients taking ticagrelor (0.9% discontinued treatment) versus 7.8% of patients (0.1% discontinued) taking clopidogrel (P < 0.001). Although there were also more frequent episodes of ventricular pauses ≥3 seconds with ticagrelor during the first week of treatment compared with clopidogrel (5.8% vs. 3.6%, P = 0.01), by 30 days the differences were not statistically significant (2.1% vs. 1.7%).
A number of subgroup analyses emanated from PLATO. These analyses involved patients with diabetes,29 those with chronic kidney disease,19 those suffering from an ST-segment elevation ACS,30 and those undergoing a planned invasive strategy for ACS.31 The results seen in these various subgroups were generally the same as those in the parent PLATO trial in terms of clinical efficacy and major bleeding rates. However, one subgroup analysis of the PLATO data suggested that patients enrolled in that trial from the United States (n = 1413) fared worse with ticagrelor compared with clopidogrel (hazard ratio: 1.27 for US patients (P = 0.146); hazard ratio for non-US patients = 0.81; P < 0.0001 (Fig. 3). 32 In PLATO, only 2 other countries displayed a hazard ratio ≥1.27: Australia (n = 92) and Taiwan (n = 83). A Food and Drug Administration (FDA) review of the data could not uncover an explanation for this geographic phenomenon, although the raw PLATO data show that the use of aspirin dosages ≥300 mg per day were much more common in the United States compared with the rest of the world.32 Although the aspirin dosage seems to be a prime suspect in explaining the geographic disparity in results, a definitive explanation remains elusive. Nonetheless, the PLATO data are continuing to be meticulously reviewed by the FDA, which on December 17, 2010 denied approval of ticagrelor in the US pending additional analyses from this study.
Although a direct comparison of ticagrelor with prasugrel does not exist, an indirect comparison of these 2 drugs has been performed through a meta-analysis.33 This meta-analysis compared the results of the following 3 trials: DISPERSE-2, PLATO, and TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes By Optimizing Platelet Inhibition with Prasugrel), with a total of 32,893 patients. The results demonstrated that both ticagrelor and prasugrel were superior to clopidogrel in terms of efficacy without any significant difference in stroke or major bleeding. A comparison of ticagrelor and prasugrel yielded similar clinical efficacy, although the risk of stent thrombosis was less with prasugrel (odds ratio: 0.64; 95% confidence interval: 0.43–0.93; P = 0.02). However, the risk of major bleeding (overall and CABG-related) was less with ticagrelor compared with prasugrel with a similar risk of non-CABG-related major bleeding. Although this meta-analysis suggests generally comparable efficacy and safety between prasugrel and ticagrelor, the limitations of an indirect meta-analysis are many and these results should not serve as a substitute for those of a well-controlled clinical trial.
USE IN PATIENTS WITH CLOPIDOGREL RESISTANCE
As mentioned above, individuals with genetic polymorphisms resulting in a reduced function CYP2C19 allele are more susceptible to clopidogrel resistance. Those with ACS and clopidogrel resistance are at high risk for serious ischemic and cardiovascular complications.34 The pharmacological and clinical effects of prasugrel in those with and without functional variants of the CYP enzymes have been assessed. Individuals treated with prasugrel, regardless of drug-metabolizing enzyme function, do not significantly differ in the levels of active metabolite or the amount of platelet inhibition induced by prasugrel.12 Furthermore, patients taking prasugrel with reduced-function polymorphisms do not differ in cardiovascular outcomes, such as myocardial infarction and stroke, compared with those without enzyme variants.34 As such, the effect of enzyme variation on pharmacological and clinical outcomes appears to be confined to patients taking clopidogrel. Prasugrel has antiplatelet activity that is not affected by genetic polymorphisms, and therefore would be an attractive alterative for those with clopidogrel resistance.12
The ability of ticagrelor to inhibit platelets has been compared with clopidogrel in patients who are either responsive or resistant to the effects of clopidogrel. Overall, it has been shown that anyone treated with ticagrelor demonstrates higher levels of platelet inhibition at any time point throughout the therapy compared with clopidogrel.23,35 Switching from clopidogrel to ticagrelor creates a rapid increase in IPA by approximately 30%, whereas switching from ticagrelor to clopidogrel is associated with a 30% reduction in platelet inhibition.23 Individuals who initially exhibit clopidogrel resistance and are treated with ticagrelor demonstrate a mean increase in IPA by up to 40%.23 This suggests that ticagrelor is able to overcome clopidogrel resistance and is equally effective regardless of clopidogrel response status. In addition, cardiovascular outcomes and risk of bleeding are similar between groups with and without a nonfunctional polymorphism when treated with ticagrelor.36 The capability of ticagrelor to consistently display antiplatelet effects may be due to its pharmacokinetic properties. It does not require hepatic activation, therefore its antiplatelet effects are not subject to interindividual genetic variations in P450 enzymes. The use of ticagrelor as antiplatelet therapy would decrease the cost, time, and inconvenience of genetic testing recommended with clopidogrel.36 From a pharmacokinetic and pharmacodynamic perspective, ticagrelor appears to be a superior alternative to clopidogrel due to its greater and more consistent antiplatelet activity, reversible antiplatelet effect, and ability to overcome clopidogrel resistance.23
On the basis of clinical trials, the most common adverse event consistently reported with ticagrelor was dyspnea. Dyspnea has been reported in up to 25% of patients taking ticagrelor, with a 6% absolute excess compared with clopidogrel.18,27,28 In one study, 50% of those who had initially reported dyspnea had resolution of the symptom within 24 hours with continued therapy.27 Discontinuation of ticagrelor due to complications of dyspnea occurred infrequently and was reported as low as <1%.28 The frequency of this side effect increases in a dose-dependent manner, with the mechanism being unknown. It is thought that dyspnea may be the result of ticagrelor having an off-target effect on adenosine reuptake. However, no adverse changes in cardiac or pulmonary function have been observed with ticagrelor-associated dyspnea.37 Bleeding complications were noted in a small group of patients taking ticagrelor, though the risk of minor, major, and fatal bleeds has not shown to significantly differ from clopidogrel.18,27,28 In one study, the incidence of intracranial bleeding, including fatal outcomes, was higher with ticagrelor as compared with clopidogrel. Furthermore, ticagrelor was reported to have a higher incidence of ventricular pauses in the first week of treatment as well as slightly increased levels of creatinine and uric acid.28 Other adverse events reported with frequency greater than clopidogrel were headache, nausea, dyspepsia, insomnia, dizziness, syncope, and hypotension.27 One interesting finding from the PLATO study was an increased incidence of gynecomastia with ticagrelor as compared with clopidogrel (0.16% vs. 0.03%; P = 0.0016).32 The etiology and significance of this finding is unknown, and it should be noted that the absolute number of events was very low and most reports of gynecomastia in PLATO were in patients already taking spironolactone.32
Ticagrelor is a CYP450 substrate and as such, there is the potential for several drug-drug interactions. Ticagrelor has been shown to be a strong inhibitor of CYP3A5, a moderate inhibitor of CYP2C9 and CYP2D6, and a weak inhibitor of CYP3A4.32 In addition, ticagrelor and its active metabolite are both substrates and inhibitors of P-glycoprotein. Drug interactions of clinical significance include the CYP3A inhibitors ketoconazole and diltiazem, both of which have been shown to significantly increase ticagrelor plasma concentrations.32 Conversely and expectedly, the strong CYP3A inducer rifampin may significantly decrease plasma ticagrelor concentrations.32 As a P-glycoprotein substrate and inhibitor, ticagrelor has been shown to significantly increase plasma digoxin concentrations, which would necessitate monitoring of plasma drug concentrations with coadministration.32 Ticagrelor has been studied in combination with aspirin, atorvastatin, desmopressin, enoxaparin, heparin, midazolam, oral contraceptives, simvastatin, and tolbutamide without any clinically significant pharmacokinetic interactions.32
A recent and ongoing concern with the use of clopidogrel has been a potential interaction with proton-pump inhibitors, particularly omeprazole.38 This class of drugs has been shown to interfere with the formation of the active metabolite of clopidogrel by inhibition of the CYP2C19 isozyme, which has been shown to reduce the ability of clopidogrel to inhibit platelet aggregation, although an adverse effect on clinical outcomes has yet to be convicingly demonstrated. Nonetheless, the FDA has issued a statement that the concomitant use of clopidogrel with either omeprazole or esomeprazole should be avoided, but did not have enough data on the other proton-pump inhibitors to make any specific recommendations.39 Given the different pharmacokinetic profiles of prasugrel and ticagrelor, this potential drug-drug interaction seems to be of a lesser concern with ticagrelor. In clinical trials with ticagrelor, an interaction with proton-pump inhibitors was assessed as a group and also separately with omeprazole. These analyses demonstrated no meaningful effect on clinical outcomes when ticagrelor was given with omeprazole or other proton-pump inhibitors.32
CURRENT STATUS OF TICAGRELOR
Ticagrelor (Brilinta; AstraZeneca LP) is an investigational drug that is currently under review by the FDA and was recently (December 2010) approved for use in Europe. In July 2010, the FDA Cardiovascular and Renal Drugs Advisory Committee voted 7 to 1 in favor of approving ticagrelor for the treatment of ACS, but as mentioned above, in December 2010, the FDA did not approve ticagrelor for use in the US and appears to be delaying a final approval decision pending further analyses of PLATO study data. Although no specific reasons have been made publicly available by the FDA explaining the delay in deciding whether or not to approve ticagrelor in the US, it is widely speculated that one reason for this delay is the unexplained lack of efficacy of ticagrelor in the US population of the PLATO trial, as previously mentioned. Some speculate that the FDA might require a US-based trial in a US population that is sufficiently powered to determine if there truly is a geographic difference in response to the drug.40 If eventually approved and marketed, it has been estimated that peak sales of ticagrelor could reach 1.4 billion US dollars by 2017.40
Ticagrelor is a new oral antiplatelet drug that is in late stages of clinical development.41 It possesses many desirable characteristics in comparison with the thienopyridines clopidogrel and ticlopidine in terms of rapid, predictable, and reversible antiplatelet effects and clinical efficacy superior to clopidogrel without an excess of bleeding, unlike prasugrel. The main adverse effect seen with ticagrelor in clinical trials was dyspnea, which is of unknown etiology but only infrequently has led to drug discontinuation. Additional benefits of ticagrelor are its efficacy in patients unresponsive to clopidogrel and lack of interaction with proton-pump inhibitors. The unexplained lack of efficacy in the United States cohort of the PLATO trial is puzzling and is believed to be largely responsible for the delay by the FDA in deciding whether or not to approve ticagrelor in the United States. If the drug is ultimately approved, it has the potential to be a significant advance in the treatment of ACS.
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Keywords:© 2011 Lippincott Williams & Wilkins, Inc.
ticagrelor; P2Y12 antagonists; ADP receptor antagonists; AZD6140