Title: Ticagrelor: Pharmacokinetics, Pharmacodynamics, Clinical Efficacy, and Safety
Abstract: Pharmacotherapy: The Journal of Human Pharmacology and Drug TherapyVolume 34, Issue 10 p. 1077-1090 Review of TherapeuticsOpen Access Ticagrelor: Pharmacokinetics, Pharmacodynamics, Clinical Efficacy, and Safety Paul P. Dobesh, Corresponding Author Paul P. Dobesh College of Pharmacy, University of Nebraska Medical Center, Omaha, NebraskaAddress for correspondence: Paul P. Dobesh, Associate Professor of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center, 986045 Nebraska Medical Center, Omaha, NE 68198-6045; e-mail: [email protected] for more papers by this authorJulie H. Oestreich, Julie H. Oestreich College of Pharmacy, University of Nebraska Medical Center, Omaha, NebraskaSearch for more papers by this author Paul P. Dobesh, Corresponding Author Paul P. Dobesh College of Pharmacy, University of Nebraska Medical Center, Omaha, NebraskaAddress for correspondence: Paul P. Dobesh, Associate Professor of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center, 986045 Nebraska Medical Center, Omaha, NE 68198-6045; e-mail: [email protected] for more papers by this authorJulie H. Oestreich, Julie H. Oestreich College of Pharmacy, University of Nebraska Medical Center, Omaha, NebraskaSearch for more papers by this author First published: 28 August 2014 https://doi.org/10.1002/phar.1477Citations: 109AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract Dual antiplatelet therapy, composed of aspirin plus a P2Y12-receptor antagonist, is the cornerstone of treatment for patients with acute coronary syndrome (ACS). A number of U.S. Food and Drug Administration–approved P2Y12-receptor antagonists are available for treating patients with ACS, including the thienopyridine compounds clopidogrel and prasugrel. Ticagrelor, the first of a new class of antiplatelet agents, is a noncompetitive, direct-acting P2Y12-receptor antagonist. Unlike the thienopyridine compounds, ticagrelor does not require metabolism for activity. Also, whereas clopidogrel and prasugrel are irreversible inhibitors of the P2Y12 receptor, ticagrelor binds reversibly to inhibit receptor signaling and subsequent platelet activation. In pharmacodynamic studies, ticagrelor demonstrated faster onset and more potent inhibition of platelet aggregation than clopidogrel. These properties of ticagrelor may contribute to reduced rates of thrombotic outcomes compared with clopidogrel, as demonstrated in a phase III clinical trial. However, in addition to bleeding, distinctive adverse effects of this new chemical entity have not been reported with the thienopyridine P2Y12-receptor inhibitors. Although ticagrelor represents an advancement in P2Y12-receptor inhibition therapy, a thorough understanding of this compound as an antiplatelet therapy remains to be elucidated. In the United States, over a million people are diagnosed annually with acute coronary syndrome (ACS).1 ACS consists of non–ST-segment elevation (NSTE) ACS and ST-segment elevation myocardial infarction (STEMI); NSTE ACS consists of unstable angina or non–ST-segment elevation myocardial infarction. Due to the central role of platelets in the pathophysiology of arterial thrombosis, antiplatelet therapy is critical for the acute and chronic treatment of patients with ACS. Dual antiplatelet therapy with aspirin and the P2Y12-receptor antagonist clopidogrel demonstrated significant benefit over aspirin alone in patients with NSTE ACS in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial in 2001.2 Since that time, dual antiplatelet therapy has been considered the standard of care for patients with ACS and has been incorporated into current treatment guidelines.3-5 Despite the widespread use of clopidogrel, there is a rate of recurrent cardiovascular (CV) events of at least 10% within 1 year of an ACS event.2 These events are potentially explained by issues related to clopidogrel including variability in antiplatelet response, pharmacogenomic influences, and drug interactions.6-8 The P2Y12-receptor inhibitor prasugrel overcame a number of limitations of clopidogrel but has a similar chemical structure (thienopyridine). Prasugrel must be activated through metabolism to provide antiplatelet effects, although the clinical relevance of this process remains unknown.9 However, ticagrelor is the first U.S. Food and Drug Administration–approved agent of a new class of antiplatelet agents—cyclopentyltriazolopyrimidines—and has distinct pharmacologic properties compared with those of the thienopyridines. Mechanism of Action and Chemical Properties Ticagrelor is an orally administered direct-acting P2Y12-receptor antagonist.10, 11 In vitro studies have demonstrated that ticagrelor binds reversibly and noncompetitively to the P2Y12 receptor at a site distinct from that of the endogenous agonist adenosine diphosphate (ADP).10 In contrast, the thienopyridine compounds clopidogrel and prasugrel (Figure 1) bind irreversibly to the P2Y12 receptor for the life of the platelet.12 Figure 1Open in figure viewerPowerPoint Chemical structures of the thienopyridine compounds prasugrel and clopidogrel. The development of ticagrelor began by leveraging the structure of adenosine triphosphate, which is an endogenous antagonist of the P2Y12 receptor (Figure 2). Prior to the development of ticagrelor, cangrelor was identified as a potent and selective P2Y12-receptor antagonist (Figure 2). Currently, cangrelor is being developed for intravenous administration. To identify orally active derivatives, the structure of cangrelor was altered by replacing the purine with a triazolopyrimidine heterocycle as well as substitutions at other key locations.13, 14 As a result, the compound AZD6140 (ticagrelor) was identified to possess acceptable affinity and metabolic stability.14 Figure 2Open in figure viewerPowerPoint Chemical structures of adenosine triphosphate (ATP), ticagrelor, and cangrelor. Pharmacokinetics In healthy subjects, ticagrelor is rapidly absorbed, with a median time to peak concentration (Tmax) of 2–3 hours after multiple twice/day oral dosing. Similarly, the median Tmax for one active metabolite of ticagrelor, AR-C124910XX, is ~2.5–4 hours.15 After absorption, ticagrelor and AR-C124910XX are highly bound to plasma proteins (more than 99.8%) and largely restricted to the plasma space.16, 17 The absolute bioavailability of ticagrelor is estimated at 36%, and the steady-state volume of distribution of ticagrelor is 88 L.18 Unlike clopidogrel and prasugrel, ticagrelor is not a prodrug and does not require metabolic activation for antiplatelet activity.19 Still, ticagrelor is extensively metabolized, with ticagrelor and its active and approximately equipotent metabolite composing the major circulating components in the plasma.17 Exposure to the active metabolite AR-C124910XX, formed through cytochrome P450 (CYP) 3A4- and 3A5-mediated metabolism, is approximately a third that of ticagrelor.15, 17, 21, 22 Ticagrelor and AR-C124910XX exhibit predictable linear pharmacokinetics in healthy volunteers as well as in patients with atherosclerosis, stable coronary artery disease (CAD), and ACS.15, 21-24 After multiple twice/day doses of ticagrelor in healthy volunteers, the mean elimination half-lives for ticagrelor and AR-C124910XX were 6.7–9.1 hours and 7.5–12.4 hours, respectively.15 After administration of radiolabelled ticagrelor in healthy subjects, the mean radioactivity recovery was 58% in feces and 27% in urine.17 Levels of unchanged ticagrelor and AR-C124910XX in urine were less than 0.05%, suggesting that renal excretion plays a relatively minor role in the elimination of ticagrelor and AR-C124910XX.17 As expected, severe renal impairment does not significantly affect the pharmacokinetics, pharmacodynamics, or safety of ticagrelor and AR-C124910XX.25 However, exposure to ticagrelor and AR-C124910XX was modestly increased in patients with mild hepatic impairment, although there were no subsequent effects on pharmacodynamics or tolerability.26 Based on these findings, no dosage adjustment is considered necessary in either of these patient groups. However, there are no pharmacodynamic data on the use of ticagrelor in patients with moderate or severe hepatic impairment; therefore, use should be avoided in these patients. It is also important to note that data are not available on the clinical response to ticagrelor in patients with hepatic impairment and ACS. Notably, a phase II study demonstrated that prior clopidogrel dosing or responder status does not affect the pharmacokinetics of ticagrelor.23 Pharmacodynamics Inhibition of platelet aggregation (IPA) stimulated by ADP is a commonly used pharmacodynamic parameter for P2Y12-receptor antagonists. In this section, we refer to final platelet aggregation observed at the end of platelet response (i.e., 6 min), rather than maximal extent of platelet aggregation.27 The IPA by ticagrelor has been examined in several populations. For example, in healthy volunteers, single doses of ticagrelor (100–400 mg) were associated with a rapid (2 hrs), dose-dependent, and near-complete inhibition of 20-μM ADP-induced platelet aggregation.22 In a multiple-dose study in healthy volunteers, IPA gradually decreased with declining plasma concentrations from ~12 hours after dosing, indicating that ticagrelor-associated IPA is concentration dependent and slowly reversible. Ticagrelor is only approved for twice/day dosing because this strategy showed greater and more consistent IPA than once/day dosing (50–600 mg) (Table 1).15 In another study of healthy volunteers, the effect of age and sex on the pharmacodynamics of ticagrelor was assessed.28 Elderly and younger volunteers of both sexes received a single dose of ticagrelor 200 mg. Notably, elderly subjects had higher ticagrelor exposure compared with younger subjects, and women had higher exposure than men. The maximal concentration was significantly increased by 61% in young women, 73% in elderly men, and 148% in elderly women compared with young men. Interestingly, the elderly subjects with the highest ticagrelor exposure also had the lowest IPA, suggesting that platelets are less sensitive in the elderly. Despite these differences, no adjustment in ticagrelor dose is recommended based on age or sex because IPA was substantial in all groups examined (higher than 90% at 4 and 8 hrs after dosing). Table 1. Final Percentage of Mean Inhibition of Platelet Aggregation over Time in Healthy Subjects Receiving Multiple Doses of Ticagrelor15 Treatment regimen Final percentage of inhibition of platelet aggregation (%) 4 hrs 8 hrs 12 hrs 24 hrs Ticagrelor once/day 50 mg (n=7) 94.0 ± 6.0 72.0 ± 31.5 62.0 ± 33.2 14.0 ± 13.2 100 mg (n=7) 99.0 ± 2.5 95.0 ± 5.0 89.0 ± 9.3 57.0 ± 28.9 200 mg (n=14) 99.0 ± 1.2 95.0 ± 6.3 95.0 ± 8.2 76.0 ± 26.7 300 mg (n=7) 100.0 ± 0.2 97.0 ± 5.1 93.0 ± 8.6 82.0 ± 13.2 400 mg (n=6) 97.0 ± 4.2 95.0 ± 6.8 91.0 ± 10.8 90.0 ± 11.8 600 mg (n=6) 99.0 ± 1.9 97.0 ± 4.9 96.0 ± 4.7 91.0 ± 11.0 Ticagrelor twice/day 50 mg (n=14) 95.0 ± 10.8 90.0 ± 20.0 87.0 ± 23.9 79.0 ± 29.6 100 mg (n=13) 97.0 ± 7.9 95.0 ± 10.9 93.0 ± 15.8 93.0 ± 10.8 200 mg (n=13) 98.0 ± 4.8 98.0 ± 3.7 96.0 ± 6.4 97.0 ± 6.8 300 mg (n=7) 100.0 ± 0.0 100.0 ± 0.0 99.0 ± 1.1 100.0 ± 0.0 Clopidogrel once/day 75 mg (n=14) 90.0 ± 21.1 82.0 ± 26.4 83.0 ± 22.5 77.0 ± 27.4 Placebo once/day (n=23–39) 7 ± 7.4 8 ± 8.8 8 ± 12.0 5 ± 6.5 Data are mean ± SD percentages. Key Pharmacokinetic and Pharmacodynamic Trials Ticagrelor was first evaluated in patients with stable CAD in the Dose Confirmation Study Assessing Anti-Platelet Effects of AZD6140 versus Clopidogrel in Non–ST-Segment Elevation Myocardial Infarction (DISPERSE) trial.21 In this randomized, double-blind, parallel-group study, 200 patients with stable CAD who were currently taking aspirin were administered either ticagrelor or clopidogrel for 28 days. The pharmacokinetics, pharmacodynamics, and safety of ticagrelor were evaluated for four different dose regimens—50 mg twice/day, 100 mg twice/day, 200 mg twice/day, or 400 mg/day—compared with clopidogrel 75 mg/day. The highest doses of ticagrelor (100 mg and 200 mg twice/day, and 400 mg/day) achieved peak IPA within 2–4 hours and comparable IPA at steady state (~90–95%) (Table 2). Conversely, ticagrelor 50 mg twice/day and clopidogrel 75 mg/day (without a loading dose) resulted in a slower onset and reduced IPA (68% for clopidogrel). Plasma concentrations for ticagrelor and AR-C124910XX were linear and dose proportional, and corresponded with IPA. The 100 mg twice/day regimen demonstrated peak blood levels of 800 ng/ml. Higher doses resulted in proportional increases in plasma concentrations without major changes in IPA (Table 2). Table 2. Pharmacokinetic and Pharmacodynamic Parameters of Ticagrelor at Day 14 of the DISPERSE Trial21 Parameter Ticagrelor 50 mg twice/day Ticagrelor 100 mg twice/day Ticagrelor 200 mg twice/day Ticagrelor 400 mg/day Clopidogrel 75 mg/day Tmax, hrs 2.5 (56) 2.8 (74) 2.6 (69) 2.4 (149) – Cmax, ng/ml 375 (50) 810 (41) 2278 (31) 3653 (41) – IPA, % 75 (55–84) 88 (82–95) 95 (86–100) 98 (88–100) 68 (44–81) Cmax = maximum concentration; DISPERSE = Dose Confirmation Study Assessing Anti-Platelet Effects of AZD6140 versus Clopidogrel in Non–ST-Segment Elevation Myocardial Infarction; IPA = inhibition of platelet aggregation; Tmax = time to reach maximum concentration. Data are mean (% coefficient of variation) for Tmax and Cmax, and median (interquartile range) for IPA. IPA refers to an estimation of final percentage of inhibition of platelet aggregation at 4 hours after dosing on day 14. From a safety perspective, bleeding times increased in all ticagrelor groups (14.8–23 min) compared with clopidogrel (10.5 min). Consistent with these findings, minor bleeding was more common with the three highest ticagrelor doses (44–51%) compared with either ticagrelor 50 mg twice/day (29%) or clopidogrel (32%). Also, one patient in the ticagrelor 400 mg/day group had a major bleeding event. The DISPERSE trial also identified an increased rate of dyspnea (10–20%) and elevated uric acid levels (by 5–10%) in the ticagrelor groups. Based on the superior antiplatelet effect compared with the 50 mg twice/day dose and the improved safety and tolerability compared with the 400 mg/day dose, the 100 mg and 200 mg twice/day doses were targeted for future study. After the DISPERSE trial findings, the formulation of ticagrelor was changed (the 100-mg tablet became 90 mg); therefore, the new corresponding doses of 90 mg and 180 mg twice/day were targeted in future studies. Following the DISPERSE trial, researchers initiated a follow-up study termed DISPERSE-2.29 The DISPERSE-2 trial was a randomized double-blind study conducted in 990 patients with NSTE-ACS. The primary end point of this trial was protocol-defined major or minor bleeding at 4 weeks. This end point was not significantly different between the ticagrelor 90 mg twice/day (9.8%), 180 mg twice/day (8.0%), and clopidogrel 75 mg/day (8.1%) groups (p=0.43 and p=0.96, respectively, vs clopidogrel). The rates of major bleeding were also not significantly different between groups. However, there was a trend for increased minor bleeding with ticagrelor 180 mg twice/day compared with clopidogrel (3.8% vs 1.3%, p=0.0504) at 4 weeks that was significant at 12 weeks (6.1% vs 1.3%, p=0.01). Furthermore, two fatal bleeds occurred in the ticagrelor 90-mg group. The rates of death or CV death were not significantly different among groups, but a trend for lower rates of myocardial infarction (MI) was identified among the ticagrelor groups compared with clopidogrel (3.8% for ticagrelor 90 mg vs 5.6% for clopidogrel, p=0.41; 2.5% for ticagrelor 180 mg vs 5.6% for clopidogrel, p=0.06). A substudy of DISPERSE-2 examined the pharmacodynamics of ticagrelor at doses of 90 mg and 180 mg twice/day compared with clopidogrel 75 mg/day for 12 weeks in clopidogrel-naive patients (clopidogrel 300-mg loading dose given; n=45) and clopidogrel pretreated patients (no clopidogrel loading dose given; n=44).24 Ticagrelor yielded greater and more consistent IPA than clopidogrel at 4 weeks and was associated with further suppression of platelet aggregation in patients pretreated with clopidogrel. As reported in the DISPERSE trial, the rates of dyspnea were higher in both ticagrelor groups of the DISPERSE-2 trial (10.5–15.8%) compared with clopidogrel (6.4%, p=0.07 and p<0.0002 for the ticagrelor 90 mg and 180 mg twice/day groups, respectively, vs clopidogrel).29 Of the patients reporting dyspnea, 27% had resolution of symptoms within 24 hours while continuing therapy, and another 25% had relief after 24 hours, whereas 48% experienced symptoms during treatment lasting longer than 15 days. Diarrhea was also significantly more common in the ticagrelor 180-mg group compared with clopidogrel (7.4% vs 3.4%, p=0.02), and hypotension occurred more frequently in both ticagrelor groups (3.7% for the 180-mg group and 1.2% for the 90-mg group) compared with clopidogrel (0.6%; p=0.01 and p=0.004 for the ticagrelor 180-mg and 90-mg groups, respectively, vs clopidogrel). Patients treated with ticagrelor had higher rates of ventricular pauses greater than 2.5 seconds, but no corresponding significant difference in the rates of ventricular tachycardias; the ventricular pauses were significantly different in the ticagrelor 180-mg group. There were 4.9% of patients who experienced more than three episodes of ventricular pauses compared with 0.3% for clopidogrel (p<0.001). Due to the increased episodes of dyspnea and ventricular pauses in the ticagrelor 180-mg group, the 90-mg twice/day dose was selected for further investigation. To assess the pharmacodynamic response of ticagrelor, investigators designed a multicenter, randomized, double-blind assessment of the onset and offset of antiplatelet effects of ticagrelor compared with clopidogrel in patients with stable CAD: the ONSET/OFFSET trial.31 In this study, ticagrelor, at a loading dose of 180 mg followed by 90 mg twice/day, was compared with clopidogrel, at a loading dose of 600 mg followed by the standard maintenance dose of 75 mg/day, or placebo, for 6 weeks. Patients with stable CAD (n=123) achieved significantly greater IPA when treated with ticagrelor plus aspirin compared with clopidogrel plus aspirin, at 0.5, 1, 2, 4, 8, and 24 hours and 6 weeks after loading dose administration (p<0.0001 for all time points; Figure 3).31 Near maximal platelet inhibition (~80%) was achieved within 1 hour in the ticagrelor group, and peak IPA was achieved at 2 hours with ticagrelor compared with peak IPA at 7.8 hours with clopidogrel. Figure 3Open in figure viewerPowerPoint Final inhibition of platelet aggregation in patients with stable coronary artery disease who received ticagrelor (180-mg loading dose followed by a 90 mg twice/day maintenance dose), clopidogrel (600-mg loading dose followed by a 75-mg/day maintenance dose), or placebo for 6 weeks in the ONSET/OFFSET study. *p<0.0001; †p<0.005; ‡p<0.05.31 Consistent with its noncompetitive and reversible pharmacology, the rate of offset with ticagrelor was significantly faster compared with clopidogrel (p<0.0001; Figure 3). However, 4–5 days were still required for platelet reactivity to return to normal with ticagrelor. Although mean IPA was higher with ticagrelor than clopidogrel during the 6-week treatment period, mean IPA for both antiplatelet agents was similar at 24 hours after the last maintenance dose (58% for ticagrelor vs 52% for clopidogrel) when measured by using light transmittance aggregometry (Figure 3) and at 48 hours when measured by using the VerifyNow P2Y12 assay or the vasodilator-stimulated phosphoprotein phosphorylation assay. These findings suggest that patients treated with ticagrelor who are at steady state and miss a dose would have platelet inhibition similar to maximal pharmacodynamic response when using clopidogrel. Likewise, the risk of bleeding for ticagrelor is expected to remain higher than that for clopidogrel for at least 24–48 hours after the last dose. Bleeding events occurred more frequently in the ticagrelor group (28.1%) compared with the clopidogrel (13.0%) and placebo groups (8.3%) in the ONSET/OFFSET trial, but no major bleeding events were identified. One patient in the placebo group and four patients in the ticagrelor group discontinued study treatment due to adverse events. Three patients in the ticagrelor group withdrew from the study due to dyspnea. Likewise, dyspnea was significantly more common in patients treated with ticagrelor compared with clopidogrel (25% vs 4%, p<0.01). The pharmacodynamic response of ticagrelor in clopidogrel nonresponders with stable CAD was assessed in a randomized, double-blind, crossover trial: the Response to Ticagrelor in Clopidogrel Nonresponders and Responders and Effect of Switching Therapies (RESPOND) trial.32 This study assessed the absolute change in maximal 20-μM ADP-induced platelet aggregation in nonresponders (absolute change 10% or lower; n=41) and responders (absolute change more than 10%; n=57). The effect of switching therapy was also examined. As expected, IPA significantly increased in clopidogrel nonresponders treated with a 180-mg loading dose of ticagrelor followed by 90 mg twice/day, compared with a 600-mg loading dose of clopidogrel followed by 75 mg/day (p=0.005; Figure 4A). Moreover, platelet aggregation decreased from 59% to 35% in patients who switched from clopidogrel to ticagrelor and increased from 36% to 56% in patients switched from ticagrelor to clopidogrel (p<0.0001 for both; Figure 4). Similar findings were identified in clopidogrel responders (Figure 4B). Therefore, the RESPOND trial helped confirm that patients can be switched from clopidogrel to ticagrelor without interruption of pharmacodynamic antiplatelet effect to obtain higher levels of platelet inhibition. Figure 4Open in figure viewerPowerPoint Maximum inhibition of platelet aggregation (IPA) in patients with stable coronary artery disease who were clopidogrel nonresponders (41 patients; panel A) and clopidogrel responders (57 patients; panel B) and were randomized to either ticagrelor (180-mg loading dose followed by 90 mg twice/day) or clopidogrel (600-mg loading dose followed by 75 mg once/day) for 14 days (period 1), then switched treatments (period 2; all nonresponders; half of responders). ADP = adenosine diphosphate. *p<0.0001; †p<0.001; ‡p<0.05.32 Clinical Efficacy The phase III clinical trial evaluating the efficacy and safety of ticagrelor in patients with ACS was the Platelet Inhibition and Patient Outcomes (PLATO) trial.30 Patients in this trial (n=18,624) who presented within 24 hours of an ACS event (NSTE ACS or STEMI) were randomized in a double-blinded fashion to a clopidogrel loading dose of 300 mg followed by 75 mg/day, or a loading dose of ticagrelor 180 mg followed by 90 mg twice/day, for at least 6 months and up to 12 months. An additional loading dose of clopidogrel 300 mg at the time of PCI was allowed at the investigator's discretion, as well as an additional loading dose of ticagrelor 90 mg if PCI occurred more than 24 hours after randomization. All patients also received aspirin unless tolerance to aspirin prevented its use. The primary efficacy end point of the trial was the composite of CV death, MI, and stroke. Patients randomized to ticagrelor demonstrated a significant 16% relative reduction in the primary end point compared with clopidogrel (hazard ratio [HR] 0.84, 95% confidence interval [CI] 0.77–0.92; Table 3). The benefit of ticagrelor over clopidogrel was evident within the first 30 days of treatment (4.8% vs 5.4%, p=0.045) and continued to increase from day 31 to day 360 (5.3% vs 6.6%, p<0.001). Therefore, the benefits demonstrated with ticagrelor in the PLATO trial were not just due to early potent antiplatelet therapy but also presumably due to maintained potent antiplatelet therapy. Table 3. Efficacy and Safety of Ticagrelor in the Phase III PLATO trial30 Outcome Ticagrelor group Clopidogrel group p value Primary efficacy outcome, % Cardiovascular death, myocardial infarction, and stroke 9.8 11.7 < 0.001 Secondary efficacy outcomes, % Cardiovascular death 4.0 5.1 0.001 Myocardial infarction 5.8 6.9 0.005 Stroke 1.5 1.3 0.22 Death from any cause 4.5 5.9 < 0.001 Stent thrombosis, definite 1.3 1.9 0.009 Stent thrombosis, probable or definite 2.2 2.9 0.02 Primary safety outcomes, % Total major bleeding, PLATO criteria 11.6 11.2 0.43 Total major bleeding, TIMI criteriaaa Major bleeding and major or minor bleeding according to TIMI criteria62 refer to nonadjudicated events analyzed with the use of a statistically programmed analysis in accordance with previously used definitions. 7.9 7.7 0.57 Total life-threatening or fatal bleeding, PLATO criteria 5.8 5.8 0.70 Secondary safety outcomes, % Non–CABG-related major bleeding, PLATO criteria 4.5 3.8 0.03 Non–CABG-related major bleeding, TIMI criteria 2.8 2.2 0.03 CABG-related major bleeding, PLATO criteria 7.4 7.9 0.32 CABG-related major bleeding, TIMI criteria 5.3 5.8 0.32 Major or minor bleeding, PLATO criteria 16.1 14.6 0.008 Major or minor bleeding, TIMI criteria 11.4 10.9 0.33 CABG = coronary artery bypass grafting; PLATO = Platelet Inhibition and Patient Outcomes; TIMI = Thrombolysis in Myocardial Infarction. a Major bleeding and major or minor bleeding according to TIMI criteria62 refer to nonadjudicated events analyzed with the use of a statistically programmed analysis in accordance with previously used definitions. The composite end point of CV death, MI, and stroke is a common end point in trials evaluating P2Y12 inhibitor therapy. However, a reduction in nonfatal MI is typically the driver of the overall benefit. Although the incidence of MI was significantly reduced by 16% with the use of ticagrelor in the PLATO trial (HR 0.84, 95% CI 0.75–0.95), there was also a significant 21% reduction in the incidence of CV death (HR 0.79, 95% CI 0.69–0.91; Table 3). Although the PLATO trial was not designed specifically as a mortality trial, a reduction in CV death has rarely been demonstrated with an oral antiplatelet agent.33 It is unknown if reduced CV death while taking ticagrelor is due to its more potent antiplatelet effect compared with clopidogrel or if it the result of an additional pharmacologic property of ticagrelor. Preclinical studies have demonstrated that ticagrelor can inhibit adenosine uptake by human erythrocytes and that ticagrelor can augment both endogenous and exogenous adenosine-induced coronary blood flow in a canine model.34 These findings have been confirmed in healthy volunteers, where ticagrelor augmented exogenous adenosine-induced coronary blood flow increases.35 Therefore, the mortality benefit demonstrated with the use of ticagrelor in the PLATO trial may be due to sustained and elevated adenosine levels in ischemic tissues leading to improved perfusion. Compared with clopidogrel, ticagrelor reduced thrombotic CV events in the PLATO trial, regardless of the management strategy. The magnitude of effect of ticagrelor was consistent between patients in whom an invasive strategy was planned (HR 0.84, 95% CI 0.75–0.94) and those assigned to a noninvasive medicinal strategy (HR 0.85, 95% CI 0.73–1.00).36, 37 Similar results were also demonstrated in the subgroup of patients with STEMI in whom primary percutaneous coronary intervention (PCI) was planned (n=7544; HR 0.87, 95% CI 0.75–1.01, p=0.07) and in patients who underwent coronary artery bypass grafting (CABG) surgery during the trial (planned or not) and who received their last dose of study drug within 7 days before surgery (n=1899; HR 0.84, 95% CI 0.60–1.16, p=0.29).38, 39 The PLATO trial allowed for a 300- or 600-mg loading dose of clopidogrel to be administered prior to PCI, with only 19.6% of patients in the clopidogrel group receiving the 600-mg dose.30 Therefore, there is concern that the clopidogrel group may have been at a disadvantage during the first few days of the trial because most patients did not receive the 600-mg clopidogrel loading dose. Although it will remain unknown how the outcomes may have been altered if all patients in the clopidogrel group would have received the 600-mg loading dose, two points should be considered. First, even with a 600-mg loading dose of clopidogrel, patients receiving ticagrelor 180 mg have significantly faster and more potent inhibition of platelet aggregation.31 Second, in the subgroup of patients receiving PCI, ticagrelor demonstrated similar efficacy in patients receiving less than a 600-mg loading dose of clopidogrel (HR 0.83, 95% CI 0.73–0.95) compared with those receiving 600 mg or more of clopidogrel (HR 0.87, 95% CI 0.69–1.10), with an interaction p value of 0.733.37 Therefore, the loading dose of clopidogrel did not appear to influence the outcomes of the PLATO trial. The consistency of the effects of