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Comparison of double (360 mg) ticagrelor loading dose with standard (60 mg) prasugrel loading dose in ST-elevation myocardial infarction patients: The Rapid Activity of Platelet Inhibitor Drugs (RAPID) primary PCI 2 study
Comparison of double (360 mg) ticagrelor loading dose with standard (60 mg) prasugrel loading dose in ST-elevation myocardial infarction patients: The Rapid Activity of Platelet Inhibitor Drugs (RAPID) primary PCI 2 study Guido Parodi, MD, a Benedetta Bellandi, MD, a Renato Valenti, MD, a Angela Migliorini, MD, a Rossella Marcucci, MD, b Nazario Carrabba, MD, a Letizia Giurlani, MD, a Gian Franco Gensini, MD, a,b,c Rosanna Abbate, MD, b and David Antoniucci, MD a Florence, Italy
Background In ST-elevation myocardial infarction (STEMI) patients, residual platelet reactivity soon after a loading dose (LD) of prasugrel or ticagrelor is higher than that reported for healthy volunteers or subjects with stable coronary artery disease; and the majority of primary percutaneous coronary intervention (PPCI) procedures with bivalirudin monotherapy are performed without proper platelet inhibition. However, ticagrelor LD is just the daily dose, whereas prasugrel LD is 6-fold the long-term daily dose. We hypothesized that an increased ticagrelor LD may result in a faster and more effective platelet inhibition as compared with the standard prasugrel LD. Methods Fifty patients with STEMI, pretreated with intravenous aspirin, undergoing PPCI were randomized to receive prasugrel 60-mg LD (n = 25) or ticagrelor 360-mg LD (n = 25). Residual platelet reactivity was assessed by VerifyNow at baseline and 1, 2, 4, and 12 hours after drug LD. Results At the time of LD, 90% of enrolled patients had an aspirin reactivity unit value b550. P2Y12 reaction units 1 hour after the LD (study primary end point) were 236 (129-289) and 248 (115-304) in the prasugrel and ticagrelor group, respectively (P = .899). High residual platelet reactivity (P2Y12 reaction units ≥240) was found in 43% and 56% of patients (P = .386) at 1 hour and in 30% and 32% of patients (P = .907) at 2 hours, respectively. There was no significant difference in bleeding, arrhythmias, or dyspnea episodes in the 2 groups. Conclusions In patients with STEMI undergoing PPCI, double (360 mg) ticagrelor LD failed to achieve a faster and more intense platelet inhibition as compared with the standard prasugrel LD. Intravenously administered aspirin allowed to achieve a very early inhibition of acid arachidonic pathway. (Am Heart J 2014;0:1-6.)
Current guidelines recommend prasugrel or ticagrelor therapy in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). 1,2 In STEMI patients, residual platelet reactivity soon after a loading dose (LD) of these new
From the aDepartment of Heart and Vessels, Careggi Hospital, Florence, Italy, bDepartment of Clinical and Experimental Medicine, University of Florence, Florence, Italy, and cDon Carlo Gnocchi Foundation, Florence, Italy. RCT# NCT01805570. Authorship: All authors had access to data and a role in writing the article. Submitted October 16, 2013; accepted March 17, 2014. Reprint requests: Guido Parodi, MD, PhD, FESC, Department of Cardiology, Careggi Hospital, Viale Pieraccini 17, I-50134, Florence, Italy. E-mail: [email protected] http://dx.doi.org/10.1016/j.ahj.2014.03.011 0002-8703/ © 2014, Mosby, Inc.
antiplatelet agents is higher than that reported for healthy volunteers or subjects with stable coronary artery disease; and the majority of PPCI procedures with bivalirudin monotherapy are performed without proper platelet inhibition. 3–5 A several-hour vulnerable window of suboptimal antithrombotic therapy exists in which STEMI patients are at high risk of thrombotic events. In particular, in the RAPID study, 60-mg prasugrel LD, despite being adsorbed as a prodrug, showed to be noninferior as compared with 180-mg ticagrelor LD in reducing the primary end point of the study of residual platelet reactivity 2 hours after drug administration. 5 However, we can argue that ticagrelor LD is just the daily dose, whereas prasugrel LD is 6-fold the long-term daily dose. Previous studies showed that ticagrelor administered orally was safe and well tolerated in healthy subjects at doses up to 400 mg/d. 6 Moreover, in the DISPERSE 2
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Figure 1
Patient flow and study design. Number of patients screened and finally enrolled in each study arm (upper panel). Sampling schedule (lower panel).
Trial, a ticagrelor 270-mg LD and a subsequent 360-mg daily dose (180 mg bid) was not associated with a significant increase in major bleeding events as compared with standard ticagrelor administration. 7 Since ticagrelor antiplatelet effect is dose dependent, 8 we hypothesized that an increased ticagrelor LD may result in a faster and more effective platelet inhibition as compared with the standard prasugrel LD. Thus, in the RAPID 2 study, we compared a double (360 mg) ticagrelor LD with a standard (60 mg) prasugrel LD regarding their effect in P2Y12 platelet receptor inhibition.
Methods Study design The RAPID 2 study was a randomized, 2-arm, prospective study. The study was approved by the local ethical committee. All patients gave informed consent. The study complies with the Declaration of Helsinki. The study flowchart is reported in Figure 1.
Patient population Fifty patients with STEMI pretreated by intravenous aspirin were randomized to receive prasugrel 60-mg LD (n = 25) or ticagrelor 360-mg LD (n = 25) before PPCI. The LD of prasugrel or ticagrelor was performed as soon as possible in the emergency department or in the catheterization laboratory. Dual-antiplatelet therapy (100 mg aspirin associated with 5 or
10 mg prasugrel or 180 mg ticagrelor) was recommended for 12 months. Study inclusion criteria were diagnosis of STEMI within 12 hours of symptoms onset and informed written consent. Exclusion criteria were (1) age b18 years; (2) active bleeding or bleeding diathesis; (3) any previous transient ischemic attack/ stroke; (4) administration in the week before the index event of clopidogrel, ticlopidine, prasugrel, ticagrelor, or warfarin; (5) known relevant hematological deviations; (6) life expectancy b1 year; and (7) known severe liver or renal disease. Concomitant medications: (a) Aspirin: intravenous 500-mg LD administered in the ambulance or at the patient’s home followed by 100-mg daily dose. (b) Bivalirudin: bolus 0.75 mg/kg followed by 1.75-mg/(kg h) infusion during PPCI. After PPCI, a bivalirudin infusion of 0.25 mg/(kg h) for 4 hours was performed in all the patients. (c) Unfractionated heparin use was discouraged. (d) Glycoprotein IIb/IIIa inhibitors were not allowed.
Platelet function tests Residual platelet reactivity was assessed at baseline (time of LD) and after 1, 2, 4, and 12 hours by VerifyNow for the assessment of P2Y12 reaction units (PRU) and aspirin reactivity units (ARU). Blood samples for platelet function analyses were collected from an antecubital vein at predefined time points into citrated tubes and processed within 1 hour by operators who were blinded to treatment. High residual platelet reactivity (HRPR) was defined as a PRU ≥ 240. 9 We also evaluated the number of patients with suboptimal platelet inhibition according to the recently proposed cutoff of 208. 10 Inhibition of platelet aggregation (IPA) was defined as the percentage
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Table I. Baseline characteristics of study patients and discharge therapy
Variable
Prasugrel 60-mg LD (n = 25)
Ticagrelor 360-mg LD (n = 25)
Age, y 67 ± 12 63 ± 11 Male gender 17 (71%) 15 (60%) Body mass index 26 ± 3 28 ± 7 Smoker 7 (29%) 14 (56%) Hypertension 11 (46%) 14 (56%) Dyslipidemia 6 (25%) 8 (32%) Diabetes mellitus 1 (4%) 3 (12%) Previous myocardial infarction 1 (4%) 3 (12%) Previous PCI 0 (0%) 4 (16%) Previous CABG 1 (4%) 0 (0%) Systolic blood pressure, mm Hg 145 ± 32 134 ± 21 Heart rate, beat/min 83 ± 26 83 ± 22 Left ventricular ejection fraction, % 44 ± 11 41 ± 10 Creatin kinase peak value, U/L 1809 ± 1391 2464 ± 2257 Time creatine kinase peak, h 7±3 7±4 Platelet count at admission, 10 9/L 238 ± 102 240 ± 51 Anterior infarct location 11 (46%) 15 (60%) Cardiogenic shock 1 (4%) 0 (0%) Thrombectomy 17 (71%) 18 (72%) Infarct artery stenting 25 (100%) 25 (100%) Morphine use 13 (54%) 9 (36%) Vomit 4 (17%) 5 (20%) UFH bolus before procedure 8 (32%) 9 (36%) Discharge therapy⁎ Aspirin 22 (88%) 22 (92%) ACE inhibitors 15 (60%) 19 (79%) β-blockers 19 (76%) 21 (87%) Statins 22 (88%) 24 (100%)
P .317 .426 .198 .058 .477 .588 .317 .317 .041 .302 .171 .965 .373 .707 .237 .928 .321 .302 .928 1 .201 .763 .765 .672 .146 .299 .080
CABG, Coronary artery bypass grafting; UFH, unfractionated heparin; ACE, angiotensin-converting enzyme. ⁎ One Ticagrelor group patient died before discharge.
decrease in aggregation values obtained at baseline and after treatment: 100 × (PRU baseline − PRU after drug)/PRU baseline. Low response to aspirin was defined as an ARU ≥550. 11
End points The primary study end point was residual platelet reactivity by PRU VerifyNow 1 hour after LD. Secondary end points were (1) the percentage of patients with an HRPR 1 hour after LD; (2) PRU at 2, 4, and 12 hours; (3) acute stent thrombosis; and (4) in-hospital Thrombolysis in Myocardial Infarction (TIMI) major or minor bleedings.
Sample size calculation The study is designed on the basis of the superiority principle: the primary end point for patients allocated to the ticagrelor group will be lower than that for patients allocated to the prasugrel group. We assumed that the primary end point (PRU) would be 110 ± 80 for the ticagrelor group and 175 ± 110 for the prasugrel group, which corresponds to a 30% PRU reduction with ticagrelor double LD. The planned enrolment of 50 patients provides 85% power for detecting this reduction at an α level of .05.
Statistical analysis Continuous data were expressed as mean ± standard deviation or medians (quartiles) as appropriate, and categorical data were expressed as proportions (percentage). Data were compared by means of the χ 2 test for categorical variables and unpaired t test or Mann-Whitney U test for continuous variables. To control for type I error in multiple comparisons, the Bonferroni-adjusted significance level was used for the 5 time points of PRU assessment. The multivariable analysis used to evaluate the independent contribution of clinical characteristics to HRPR at 1 hour was performed by the forward stepwise binary logistic regression analysis. The variables entered into the model were age (years), body mass index, diabetes mellitus, morphine use, and baseline PRU value. A significance of .05 was required for a variable to be included in the multivariate model, whereas .10 was the cutoff value for exclusion. Odds ratios (ORs) and 95% CI were calculated. A P value b .05 was considered statistically significant. All tests were 2-sided. Analyses were performed with SPSS 19 (IBM Corp, Somers, NY). The study was designed and sponsored by the investigators and supported by the “A.R. CARD” Foundation, Florence, Italy. No other extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this study, all study analysis, and the drafting and editing of the paper.
Results Baseline and procedural characteristics The 2 groups were well matched in all baseline characteristics (Table I), but there was a higher previous PCI rate in the ticagrelor group. The study drug LD was performed in 13 (26%) patients in the emergency department and in 37 (74%) patients in the catheterization laboratory, without differences between the 2 groups. Seventeen patients received 5,000 UI of unfractionated heparin in the ambulance or in the emergency department, with subsequent switching to bivalirudin. All, except for 2 patients who referred to be “allergic” to the drug, received intravenous aspirin before prasugrel or ticagrelor LD. Mean time between intravenous aspirin administration and prasugrel or ticagrelor LD was 51 ± 32 minutes. Residual platelet reactivity The 1-hour PRU assessment was performed after PPCI in all patients. One hour after LD, PRU values ranged from 3 to 400 (median value 243 [137-299]). There was no difference in PRU value at 1 hour between the prasugrel and ticagrelor groups: 236 (129-289) and 248 (115-304), respectively (P = .899): no significant PRU difference was observed between the 2 groups at any time point (Figure 2). We also calculated IPA values that are able to correct for potential differences in baseline PRU (Figure 3); no significant IPA difference was observed between the 2 groups at any time point. The percentage of HRPR patients at different time points in the prasugrel and ticagrelor groups is reported in Figure 4. The independent predictors of HRPR 1 hour after LD were morphine use (OR 4.49 [1.19-16.88], P = .026)
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Figure 3
600 500 ARU
400 300
60 mg Prasugrel LD 360 mg Ticagrelor LD
200 100
PRU
0 Baseline
1h
2h
4h
12 h
Kinetics of platelet inhibition over time. Residual platelet reactivity values assessed by PRU (lower curves) and ARU (upper curves) by VerifyNow at baseline and 1, 2, 4, and 12 hours after drug LD in patients treated by 60-mg prasugrel LD (Δ) or 360-mg ticagrelor LD (□). P value nonsignificant for all comparisons.
and baseline PRU value (OR 1.015 [1.00-1.03], P = .039). Five patients in each group showed very low (PRU ≤ 85) residual platelet reactivity 1 hour after LD
Aspirin effect assessment Baseline ARU ranged from 384 to 664 (median value: 452 [422-566]). The effect of intravenous aspirin LD assessed as ARU changes over time is reported in Figure 2 (upper curves). At each time point, about 90% of enrolled patients had an ARU value b 550 (Figure 5). In-hospital outcome The clinical events observed are reported in Table II. There was no difference in event rates between the 2 study drugs. In particular, bleeding events, bradyarrhythmias, contrast-induced nephropathy, transaminases elevation, and dyspnea were not significantly increased by a 360-mg ticagrelor LD. There were 2 deaths: one due to cardiac tamponade in the prasugrel group and one due to refractory heart failure in the ticagrelor group. No acute stent thrombosis occurred. No patient discontinued prasugrel or ticagrelor, whereas 3 patients withdrew aspirin during hospital stay because of bleeding events.
Discussion The study results can be summarized as follow: 1. An increased oral ticagrelor LD failed to achieve a faster and more intense platelet inhibition 1 hour after administration as compared with the standard prasugrel LD. 2. In patients with STEMI undergoing PPCI, double (360 mg) ticagrelor LD did not result in significant adverse effects.
Inhibition of Platelet Aggregation (%)
Platelet function test values (Units)
Figure 2
120 100 80 60 40 20 60 mg Prasugrel LD 360 mg Ticagrelor LD
0
1h
2h
4h
12 h
Inhibition of platelet aggregation over time. Inhibition of platelet aggregation by VerifyNow at baseline and 1, 2, 4, and 12 hours after drug LD in patients treated by 60-mg prasugrel LD (Δ) or 360-mg ticagrelor LD (□). P value nonsignificant for all comparisons.
3. Intravenously administered aspirin allowed to achieve a very early inhibition of the acid arachidonic pathway. According to the hypothesis that an increased ticagrelor LD might result in a faster and more effective platelet inhibition, we administered a double (360 mg) ticagrelor LD to STEMI patients undergoing PPCI. As previously documented in healthy subjects and in patients with acute coronary syndrome without ST-segment elevation, a 360-mg ticagrelor LD was well tolerated in our limited population of STEMI patients and did not result in excessive episodes of dyspnea or ventricular pauses as well as in unacceptable bleeding complication rate. However, the increased ticagrelor LD did not allow to achieve a higher platelet inhibition as compared with the standard 60-mg prasugrel LD within the first 12 hours after administration. One hour after the drug LD, about half of patients still presented HRPR despite the use of highly effective antiplatelet agents, whereas 2 hours after the LD, without any difference between the 60-mg prasugrel and 360-mg ticagrelor groups, a third of patients showed suboptimal platelet inhibition. The increased ticagrelor LD achieved similar residual platelet reactivity values as compared with prasugrel LD, and at least 3 hours was required to achieve an optimal platelet inhibition in most of the patients. Consistently with a recent nonrandomized study by Alexopoulos et al, 12 residual platelet reactivity values obtained by a double 360-mg ticagrelor LD were similar as compared with the values measured in patients enrolled in the RAPID 1 study who received a standard 180-mg ticagrelor LD. 5 Our data suggest that, in patients with STEMI, drug absorption plays a major role in the speed of action of the new oral antiplatelet agents. In such patients, hemodynamic disarrangement, systemic vasoconstriction,
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Patients with High Residual Platelet Reactivity %
100 90 80 70 60 50 40 30 20 10 0
60 mg Prasugrel LD 360 mg Ticagrelor LD
Baseline
1 hour 1 hour 2 hours (cut-off 208) (cut-off 240)
4 hours
12 hours
Patients with HRPR over time. The percentage of HRPR (PRU ≥240) patients at different time points in the prasugrel (green bars) and ticagrelor (orange bars) groups. P value nonsignificant for all comparisons.
adrenergic activation, polipharmacotherapy (including morphine use), abnormal muscular activity of the stomach and the intestines, and the high risk of vomit may have a significant impact on drug onset of action. Morphine use was confirmed to be able to delay oral antiplatelet agent onset of action and should be used with caution when rapid antiplatelet effect is required. 5 The fact that, in STEMI patients, gastrointestinal absorption is the major limitation to the speed of action of the orally administered antiplatelet agents was confirmed by the fact that intravenous aspirin allowed to achieve a very early inhibition of the acid arachidonic pathway. This specific type of delay in orally administered drug action cannot be overcome by increasing the dose of ticagrelor. Thus, intravenous antiplatelet agents such as glycoprotein IIb/IIIa receptor inhibitors or cangrelor should be considered in STEMI patients when early platelet inhibition is required. The STEMI guidelines of the European Society of Cardiology 1 recommend oral aspirin LD administration based on the result of the ISIS-2 study, 13 and intravenous aspirin should be considered only in patients unable to swallow. Meanwhile, the American College of Cardiology/ American Heart Association guidelines 2 recommend a 162- to 325-mg aspirin LD without specifying the route of administration. Our finding suggest that, given the potential variability in orally administered antiplatelet agents in STEMI patients, the intravenous administration guarantees a more predictable, rapid, and effective aspirin effect. In a recent study, aspirin pseudoresistance, resulting from delayed and reduced drug absorption, was found to be common in healthy volunteers who were screened for their response to a single oral dose of 325-mg enteric-coated aspirin. 14 Thus, there is the rationale to use aspirin intravenously not only in patients unable to swallow but probably in all STEMI patients when rapid platelet inhibition is desirable. However, directed comparison of intravenous and oral aspirin in STEMI patients is lacking.
Patients with High Aspirin Reaction Units (%)
Figure 5
Figure 4
100 90 80 70 60 50 40 30 20 10 0
60 mg Prasugrel LD 360 mg Ticagrelor LD
Baseline
1 hour
2 hours
4 hours
12 hours
Response to intravenous aspirin. The percentage of patients with high ARU (≥550) at different time points in the prasugrel (green bars) and ticagrelor (orange bars) groups. P value nonsignificant for all comparisons.
Our study must be evaluated in light of some limitations. First, the small sample size is certainly its most important limitation. However, we were able to enroll a prospective homogenous population of patients with STEMI that mirrors other similar studies; and clinical outcome data were reported only as indicative. The safety profile of ticagrelor 360-mg LD should be definitively tested in broader studies. Second, we evaluated residual platelet reactivity by only one test (VerifyNow) that was available in our hospital 7/7 days and 24/24 hours, allowing the enrollment of consecutive patients. Third, the PRU values were measured in STEMI patients treated with bivalirudin monotherapy; and it is unknown if they can be extrapolated to patients treated with different pharmacological strategies. Fourth, we did not choose for the primary end point the cutoff for high platelet reactivity that is currently recommended by updated consensus document. 10 However, our prespecified cutoff value of 240 was previously validated in a previous study from our institution. 9 Moreover, to evaluate impaired drug absorption, a pharmacokinetic analysis should have been performed. Fifth, intravenous aspirin dose used in this study was higher than the one recommended in the current guidelines. Finally, overfitting risk cannot be excluded in our multivariable model. These limitations notwithstanding, the present study provides several unique and potentially important insights in the treatment of STEMI patients by PPCI.
Acknowledgements We are indebted to the catheterization laboratory staff and the Intensive Cardiac Care Unit (ICCU) nurses for their precious help in collecting and processing blood samples. We are also very grateful to Fabio Torrini and Paola Baldini for their secretarial assistance.
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Table II. In-hospital outcomes Prasugrel 60 mg (n = 25) Death Reinfarction Stent thrombosis Stroke TIMI major bleeding TIMI minor bleeding Dyspnea Ventricular pauses N 3 s Contrast-induced nephropathy Serum GPT N 150 U/L
1 0 0 0 2 0 1 0 4
(4%) (0%) (0%) (0%) (8%) (0%) (4%) (0%) (16%)
0 (0%)
Ticagrelor 360 mg (n = 25) 1 0 0 0 1 2 4 1 1
(4%) (0%) (0%) (0%) (4%) (8%) (16%) (4%) (4%)
1 (4%)
P 1 1 1 1 .552 .149 .157 .312 .157
4.
5.
6.
.312
GPT, Glutamate-pyruvate transaminase.
7.
Disclosures Dr Parodi reported receiving consulting or lecture fees from Daiichi Sankyo/Eli Lilly, AstraZeneca, and The Medicine Company. Dr Marcucci received honoraria for lectures from Daiichi Sankyo/Eli Lilly and Merck Sharp Dohme. Dr Abbate reports receiving consulting fees from Eli Lilly; lecture fees from Instrumentation Laboratory and Sigma Tau; and research grant funding from Bayer, Boehringer Ingelheim, and Pfizer. Dr Antoniucci reported receiving consulting fees from Daiichi Sankyo/Eli Lilly and The Medicines Company, and serving on the advisory board of Cordis and CID. The other authors reported no disclosures.
10.
References
11.
1. Steg G, James SK, Atar D, et al. ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2012;33:2569-619. 2. O'Gara PT, Kushner FG, Ascheim DD, et al. ACCF/AHA guideline for the management of ST-elevation myocardial infarction: executive summary. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. AHA/ACC STEMI guidelines 2013. Circulation 2013;127:529-55. 3. Valgimigli M, Tebaldi M, Campo G, et al. Prasugrel versus tirofiban bolus with or without short post-bolus infusion with or without concomitant prasugrel administration in patients with myocardial infarction undergoing coronary stenting: the FABOLUS PRO
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(Facilitation through Aggrastat By drOpping or shortening Infusion Line in patients with ST-segment elevation myocardial infarction compared to or on top of PRasugrel given at loading dOse) trial. JACC Cardiovasc Interv 2012;5:268-77. Alexopoulos D, Xanthopoulou I, Gkizas V, et al. Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with ST-segment-elevation myocardial infarction. Circ Cardiovasc Interv 2012;5:797-804. Parodi G, Valenti R, Bellandi B, et al. Comparison of prasugrel and ticagrelor loading doses in ST-segment elevation myocardial infarction patients: RAPID (Rapid Activity of Platelet Inhibitor Drugs) primary PCI study. J Am Coll Cardiol 2013;61:1601-6. Teng R, Butler K. Pharmacokinetics, pharmacodynamics, tolerability and safety of single ascending doses of ticagrelor, a reversibly binding oral P2Y12 receptor antagonist, in healthy subjects. Eur J Clin Pharmacol 2012;66:487-96. Cannon CP, Husted S, Harrington RA, et al. Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non–ST-segment elevation acute coronary syndrome. J Am Coll Cardiol 2007;50: 1844-51. Husted Husted S, Emanuelsson H, Heptinstall S, et al. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J 2006;27:1038-47. Marcucci R, Gori AM, Paniccia R, et al. Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point-of-care assay: a 12-month follow-up. Circulation 2009;119:237-42. Tantry US, Bonello L, Aradi D, et al. Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding. J Am Coll Cardiol 2013;62:2261-73. Nielsen HL, Kristensen SD, Thygesen SS, et al. Aspirin response evaluated by the VerifyNow Aspirin System and light transmission aggregometry. Thromb Res 2008;123(2):267-73. Alexopoulos D, Gkizas V, Patsilinakos S, et al. Double vs standard loading dose of ticagrelor: onset of antiplatelet action in patients with STEMI undergoing primary PCI. J Am Coll Cardiol 2013;62:940-1. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet 1988;2:349-60. Grosser T, Fries S, Lawson JA, et al. Drug resistance and pseudoresistance: an unintended consequence of enteric coating aspirin. Circulation 2013;127:377-85.
Background In ST-elevation myocardial infarction (STEMI) patients, residual platelet reactivity soon after a loading dose (LD) of prasugrel or ticagrelor is higher than that reported for healthy volunteers or subjects with stable coronary artery disease; and the majority of primary percutaneous coronary intervention (PPCI) procedures with bivalirudin monotherapy are performed without proper platelet inhibition. However, ticagrelor LD is just the daily dose, whereas prasugrel LD is 6-fold the long-term daily dose. We hypothesized that an increased ticagrelor LD may result in a faster and more effective platelet inhibition as compared with the standard prasugrel LD. Methods Fifty patients with STEMI, pretreated with intravenous aspirin, undergoing PPCI were randomized to receive prasugrel 60-mg LD (n = 25) or ticagrelor 360-mg LD (n = 25). Residual platelet reactivity was assessed by VerifyNow at baseline and 1, 2, 4, and 12 hours after drug LD. Results At the time of LD, 90% of enrolled patients had an aspirin reactivity unit value b550. P2Y12 reaction units 1 hour after the LD (study primary end point) were 236 (129-289) and 248 (115-304) in the prasugrel and ticagrelor group, respectively (P = .899). High residual platelet reactivity (P2Y12 reaction units ≥240) was found in 43% and 56% of patients (P = .386) at 1 hour and in 30% and 32% of patients (P = .907) at 2 hours, respectively. There was no significant difference in bleeding, arrhythmias, or dyspnea episodes in the 2 groups. Conclusions In patients with STEMI undergoing PPCI, double (360 mg) ticagrelor LD failed to achieve a faster and more intense platelet inhibition as compared with the standard prasugrel LD. Intravenously administered aspirin allowed to achieve a very early inhibition of acid arachidonic pathway. (Am Heart J 2014;0:1-6.)
Current guidelines recommend prasugrel or ticagrelor therapy in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). 1,2 In STEMI patients, residual platelet reactivity soon after a loading dose (LD) of these new
From the aDepartment of Heart and Vessels, Careggi Hospital, Florence, Italy, bDepartment of Clinical and Experimental Medicine, University of Florence, Florence, Italy, and cDon Carlo Gnocchi Foundation, Florence, Italy. RCT# NCT01805570. Authorship: All authors had access to data and a role in writing the article. Submitted October 16, 2013; accepted March 17, 2014. Reprint requests: Guido Parodi, MD, PhD, FESC, Department of Cardiology, Careggi Hospital, Viale Pieraccini 17, I-50134, Florence, Italy. E-mail: [email protected] http://dx.doi.org/10.1016/j.ahj.2014.03.011 0002-8703/ © 2014, Mosby, Inc.
antiplatelet agents is higher than that reported for healthy volunteers or subjects with stable coronary artery disease; and the majority of PPCI procedures with bivalirudin monotherapy are performed without proper platelet inhibition. 3–5 A several-hour vulnerable window of suboptimal antithrombotic therapy exists in which STEMI patients are at high risk of thrombotic events. In particular, in the RAPID study, 60-mg prasugrel LD, despite being adsorbed as a prodrug, showed to be noninferior as compared with 180-mg ticagrelor LD in reducing the primary end point of the study of residual platelet reactivity 2 hours after drug administration. 5 However, we can argue that ticagrelor LD is just the daily dose, whereas prasugrel LD is 6-fold the long-term daily dose. Previous studies showed that ticagrelor administered orally was safe and well tolerated in healthy subjects at doses up to 400 mg/d. 6 Moreover, in the DISPERSE 2
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Figure 1
Patient flow and study design. Number of patients screened and finally enrolled in each study arm (upper panel). Sampling schedule (lower panel).
Trial, a ticagrelor 270-mg LD and a subsequent 360-mg daily dose (180 mg bid) was not associated with a significant increase in major bleeding events as compared with standard ticagrelor administration. 7 Since ticagrelor antiplatelet effect is dose dependent, 8 we hypothesized that an increased ticagrelor LD may result in a faster and more effective platelet inhibition as compared with the standard prasugrel LD. Thus, in the RAPID 2 study, we compared a double (360 mg) ticagrelor LD with a standard (60 mg) prasugrel LD regarding their effect in P2Y12 platelet receptor inhibition.
Methods Study design The RAPID 2 study was a randomized, 2-arm, prospective study. The study was approved by the local ethical committee. All patients gave informed consent. The study complies with the Declaration of Helsinki. The study flowchart is reported in Figure 1.
Patient population Fifty patients with STEMI pretreated by intravenous aspirin were randomized to receive prasugrel 60-mg LD (n = 25) or ticagrelor 360-mg LD (n = 25) before PPCI. The LD of prasugrel or ticagrelor was performed as soon as possible in the emergency department or in the catheterization laboratory. Dual-antiplatelet therapy (100 mg aspirin associated with 5 or
10 mg prasugrel or 180 mg ticagrelor) was recommended for 12 months. Study inclusion criteria were diagnosis of STEMI within 12 hours of symptoms onset and informed written consent. Exclusion criteria were (1) age b18 years; (2) active bleeding or bleeding diathesis; (3) any previous transient ischemic attack/ stroke; (4) administration in the week before the index event of clopidogrel, ticlopidine, prasugrel, ticagrelor, or warfarin; (5) known relevant hematological deviations; (6) life expectancy b1 year; and (7) known severe liver or renal disease. Concomitant medications: (a) Aspirin: intravenous 500-mg LD administered in the ambulance or at the patient’s home followed by 100-mg daily dose. (b) Bivalirudin: bolus 0.75 mg/kg followed by 1.75-mg/(kg h) infusion during PPCI. After PPCI, a bivalirudin infusion of 0.25 mg/(kg h) for 4 hours was performed in all the patients. (c) Unfractionated heparin use was discouraged. (d) Glycoprotein IIb/IIIa inhibitors were not allowed.
Platelet function tests Residual platelet reactivity was assessed at baseline (time of LD) and after 1, 2, 4, and 12 hours by VerifyNow for the assessment of P2Y12 reaction units (PRU) and aspirin reactivity units (ARU). Blood samples for platelet function analyses were collected from an antecubital vein at predefined time points into citrated tubes and processed within 1 hour by operators who were blinded to treatment. High residual platelet reactivity (HRPR) was defined as a PRU ≥ 240. 9 We also evaluated the number of patients with suboptimal platelet inhibition according to the recently proposed cutoff of 208. 10 Inhibition of platelet aggregation (IPA) was defined as the percentage
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Table I. Baseline characteristics of study patients and discharge therapy
Variable
Prasugrel 60-mg LD (n = 25)
Ticagrelor 360-mg LD (n = 25)
Age, y 67 ± 12 63 ± 11 Male gender 17 (71%) 15 (60%) Body mass index 26 ± 3 28 ± 7 Smoker 7 (29%) 14 (56%) Hypertension 11 (46%) 14 (56%) Dyslipidemia 6 (25%) 8 (32%) Diabetes mellitus 1 (4%) 3 (12%) Previous myocardial infarction 1 (4%) 3 (12%) Previous PCI 0 (0%) 4 (16%) Previous CABG 1 (4%) 0 (0%) Systolic blood pressure, mm Hg 145 ± 32 134 ± 21 Heart rate, beat/min 83 ± 26 83 ± 22 Left ventricular ejection fraction, % 44 ± 11 41 ± 10 Creatin kinase peak value, U/L 1809 ± 1391 2464 ± 2257 Time creatine kinase peak, h 7±3 7±4 Platelet count at admission, 10 9/L 238 ± 102 240 ± 51 Anterior infarct location 11 (46%) 15 (60%) Cardiogenic shock 1 (4%) 0 (0%) Thrombectomy 17 (71%) 18 (72%) Infarct artery stenting 25 (100%) 25 (100%) Morphine use 13 (54%) 9 (36%) Vomit 4 (17%) 5 (20%) UFH bolus before procedure 8 (32%) 9 (36%) Discharge therapy⁎ Aspirin 22 (88%) 22 (92%) ACE inhibitors 15 (60%) 19 (79%) β-blockers 19 (76%) 21 (87%) Statins 22 (88%) 24 (100%)
P .317 .426 .198 .058 .477 .588 .317 .317 .041 .302 .171 .965 .373 .707 .237 .928 .321 .302 .928 1 .201 .763 .765 .672 .146 .299 .080
CABG, Coronary artery bypass grafting; UFH, unfractionated heparin; ACE, angiotensin-converting enzyme. ⁎ One Ticagrelor group patient died before discharge.
decrease in aggregation values obtained at baseline and after treatment: 100 × (PRU baseline − PRU after drug)/PRU baseline. Low response to aspirin was defined as an ARU ≥550. 11
End points The primary study end point was residual platelet reactivity by PRU VerifyNow 1 hour after LD. Secondary end points were (1) the percentage of patients with an HRPR 1 hour after LD; (2) PRU at 2, 4, and 12 hours; (3) acute stent thrombosis; and (4) in-hospital Thrombolysis in Myocardial Infarction (TIMI) major or minor bleedings.
Sample size calculation The study is designed on the basis of the superiority principle: the primary end point for patients allocated to the ticagrelor group will be lower than that for patients allocated to the prasugrel group. We assumed that the primary end point (PRU) would be 110 ± 80 for the ticagrelor group and 175 ± 110 for the prasugrel group, which corresponds to a 30% PRU reduction with ticagrelor double LD. The planned enrolment of 50 patients provides 85% power for detecting this reduction at an α level of .05.
Statistical analysis Continuous data were expressed as mean ± standard deviation or medians (quartiles) as appropriate, and categorical data were expressed as proportions (percentage). Data were compared by means of the χ 2 test for categorical variables and unpaired t test or Mann-Whitney U test for continuous variables. To control for type I error in multiple comparisons, the Bonferroni-adjusted significance level was used for the 5 time points of PRU assessment. The multivariable analysis used to evaluate the independent contribution of clinical characteristics to HRPR at 1 hour was performed by the forward stepwise binary logistic regression analysis. The variables entered into the model were age (years), body mass index, diabetes mellitus, morphine use, and baseline PRU value. A significance of .05 was required for a variable to be included in the multivariate model, whereas .10 was the cutoff value for exclusion. Odds ratios (ORs) and 95% CI were calculated. A P value b .05 was considered statistically significant. All tests were 2-sided. Analyses were performed with SPSS 19 (IBM Corp, Somers, NY). The study was designed and sponsored by the investigators and supported by the “A.R. CARD” Foundation, Florence, Italy. No other extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this study, all study analysis, and the drafting and editing of the paper.
Results Baseline and procedural characteristics The 2 groups were well matched in all baseline characteristics (Table I), but there was a higher previous PCI rate in the ticagrelor group. The study drug LD was performed in 13 (26%) patients in the emergency department and in 37 (74%) patients in the catheterization laboratory, without differences between the 2 groups. Seventeen patients received 5,000 UI of unfractionated heparin in the ambulance or in the emergency department, with subsequent switching to bivalirudin. All, except for 2 patients who referred to be “allergic” to the drug, received intravenous aspirin before prasugrel or ticagrelor LD. Mean time between intravenous aspirin administration and prasugrel or ticagrelor LD was 51 ± 32 minutes. Residual platelet reactivity The 1-hour PRU assessment was performed after PPCI in all patients. One hour after LD, PRU values ranged from 3 to 400 (median value 243 [137-299]). There was no difference in PRU value at 1 hour between the prasugrel and ticagrelor groups: 236 (129-289) and 248 (115-304), respectively (P = .899): no significant PRU difference was observed between the 2 groups at any time point (Figure 2). We also calculated IPA values that are able to correct for potential differences in baseline PRU (Figure 3); no significant IPA difference was observed between the 2 groups at any time point. The percentage of HRPR patients at different time points in the prasugrel and ticagrelor groups is reported in Figure 4. The independent predictors of HRPR 1 hour after LD were morphine use (OR 4.49 [1.19-16.88], P = .026)
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Figure 3
600 500 ARU
400 300
60 mg Prasugrel LD 360 mg Ticagrelor LD
200 100
PRU
0 Baseline
1h
2h
4h
12 h
Kinetics of platelet inhibition over time. Residual platelet reactivity values assessed by PRU (lower curves) and ARU (upper curves) by VerifyNow at baseline and 1, 2, 4, and 12 hours after drug LD in patients treated by 60-mg prasugrel LD (Δ) or 360-mg ticagrelor LD (□). P value nonsignificant for all comparisons.
and baseline PRU value (OR 1.015 [1.00-1.03], P = .039). Five patients in each group showed very low (PRU ≤ 85) residual platelet reactivity 1 hour after LD
Aspirin effect assessment Baseline ARU ranged from 384 to 664 (median value: 452 [422-566]). The effect of intravenous aspirin LD assessed as ARU changes over time is reported in Figure 2 (upper curves). At each time point, about 90% of enrolled patients had an ARU value b 550 (Figure 5). In-hospital outcome The clinical events observed are reported in Table II. There was no difference in event rates between the 2 study drugs. In particular, bleeding events, bradyarrhythmias, contrast-induced nephropathy, transaminases elevation, and dyspnea were not significantly increased by a 360-mg ticagrelor LD. There were 2 deaths: one due to cardiac tamponade in the prasugrel group and one due to refractory heart failure in the ticagrelor group. No acute stent thrombosis occurred. No patient discontinued prasugrel or ticagrelor, whereas 3 patients withdrew aspirin during hospital stay because of bleeding events.
Discussion The study results can be summarized as follow: 1. An increased oral ticagrelor LD failed to achieve a faster and more intense platelet inhibition 1 hour after administration as compared with the standard prasugrel LD. 2. In patients with STEMI undergoing PPCI, double (360 mg) ticagrelor LD did not result in significant adverse effects.
Inhibition of Platelet Aggregation (%)
Platelet function test values (Units)
Figure 2
120 100 80 60 40 20 60 mg Prasugrel LD 360 mg Ticagrelor LD
0
1h
2h
4h
12 h
Inhibition of platelet aggregation over time. Inhibition of platelet aggregation by VerifyNow at baseline and 1, 2, 4, and 12 hours after drug LD in patients treated by 60-mg prasugrel LD (Δ) or 360-mg ticagrelor LD (□). P value nonsignificant for all comparisons.
3. Intravenously administered aspirin allowed to achieve a very early inhibition of the acid arachidonic pathway. According to the hypothesis that an increased ticagrelor LD might result in a faster and more effective platelet inhibition, we administered a double (360 mg) ticagrelor LD to STEMI patients undergoing PPCI. As previously documented in healthy subjects and in patients with acute coronary syndrome without ST-segment elevation, a 360-mg ticagrelor LD was well tolerated in our limited population of STEMI patients and did not result in excessive episodes of dyspnea or ventricular pauses as well as in unacceptable bleeding complication rate. However, the increased ticagrelor LD did not allow to achieve a higher platelet inhibition as compared with the standard 60-mg prasugrel LD within the first 12 hours after administration. One hour after the drug LD, about half of patients still presented HRPR despite the use of highly effective antiplatelet agents, whereas 2 hours after the LD, without any difference between the 60-mg prasugrel and 360-mg ticagrelor groups, a third of patients showed suboptimal platelet inhibition. The increased ticagrelor LD achieved similar residual platelet reactivity values as compared with prasugrel LD, and at least 3 hours was required to achieve an optimal platelet inhibition in most of the patients. Consistently with a recent nonrandomized study by Alexopoulos et al, 12 residual platelet reactivity values obtained by a double 360-mg ticagrelor LD were similar as compared with the values measured in patients enrolled in the RAPID 1 study who received a standard 180-mg ticagrelor LD. 5 Our data suggest that, in patients with STEMI, drug absorption plays a major role in the speed of action of the new oral antiplatelet agents. In such patients, hemodynamic disarrangement, systemic vasoconstriction,
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Patients with High Residual Platelet Reactivity %
100 90 80 70 60 50 40 30 20 10 0
60 mg Prasugrel LD 360 mg Ticagrelor LD
Baseline
1 hour 1 hour 2 hours (cut-off 208) (cut-off 240)
4 hours
12 hours
Patients with HRPR over time. The percentage of HRPR (PRU ≥240) patients at different time points in the prasugrel (green bars) and ticagrelor (orange bars) groups. P value nonsignificant for all comparisons.
adrenergic activation, polipharmacotherapy (including morphine use), abnormal muscular activity of the stomach and the intestines, and the high risk of vomit may have a significant impact on drug onset of action. Morphine use was confirmed to be able to delay oral antiplatelet agent onset of action and should be used with caution when rapid antiplatelet effect is required. 5 The fact that, in STEMI patients, gastrointestinal absorption is the major limitation to the speed of action of the orally administered antiplatelet agents was confirmed by the fact that intravenous aspirin allowed to achieve a very early inhibition of the acid arachidonic pathway. This specific type of delay in orally administered drug action cannot be overcome by increasing the dose of ticagrelor. Thus, intravenous antiplatelet agents such as glycoprotein IIb/IIIa receptor inhibitors or cangrelor should be considered in STEMI patients when early platelet inhibition is required. The STEMI guidelines of the European Society of Cardiology 1 recommend oral aspirin LD administration based on the result of the ISIS-2 study, 13 and intravenous aspirin should be considered only in patients unable to swallow. Meanwhile, the American College of Cardiology/ American Heart Association guidelines 2 recommend a 162- to 325-mg aspirin LD without specifying the route of administration. Our finding suggest that, given the potential variability in orally administered antiplatelet agents in STEMI patients, the intravenous administration guarantees a more predictable, rapid, and effective aspirin effect. In a recent study, aspirin pseudoresistance, resulting from delayed and reduced drug absorption, was found to be common in healthy volunteers who were screened for their response to a single oral dose of 325-mg enteric-coated aspirin. 14 Thus, there is the rationale to use aspirin intravenously not only in patients unable to swallow but probably in all STEMI patients when rapid platelet inhibition is desirable. However, directed comparison of intravenous and oral aspirin in STEMI patients is lacking.
Patients with High Aspirin Reaction Units (%)
Figure 5
Figure 4
100 90 80 70 60 50 40 30 20 10 0
60 mg Prasugrel LD 360 mg Ticagrelor LD
Baseline
1 hour
2 hours
4 hours
12 hours
Response to intravenous aspirin. The percentage of patients with high ARU (≥550) at different time points in the prasugrel (green bars) and ticagrelor (orange bars) groups. P value nonsignificant for all comparisons.
Our study must be evaluated in light of some limitations. First, the small sample size is certainly its most important limitation. However, we were able to enroll a prospective homogenous population of patients with STEMI that mirrors other similar studies; and clinical outcome data were reported only as indicative. The safety profile of ticagrelor 360-mg LD should be definitively tested in broader studies. Second, we evaluated residual platelet reactivity by only one test (VerifyNow) that was available in our hospital 7/7 days and 24/24 hours, allowing the enrollment of consecutive patients. Third, the PRU values were measured in STEMI patients treated with bivalirudin monotherapy; and it is unknown if they can be extrapolated to patients treated with different pharmacological strategies. Fourth, we did not choose for the primary end point the cutoff for high platelet reactivity that is currently recommended by updated consensus document. 10 However, our prespecified cutoff value of 240 was previously validated in a previous study from our institution. 9 Moreover, to evaluate impaired drug absorption, a pharmacokinetic analysis should have been performed. Fifth, intravenous aspirin dose used in this study was higher than the one recommended in the current guidelines. Finally, overfitting risk cannot be excluded in our multivariable model. These limitations notwithstanding, the present study provides several unique and potentially important insights in the treatment of STEMI patients by PPCI.
Acknowledgements We are indebted to the catheterization laboratory staff and the Intensive Cardiac Care Unit (ICCU) nurses for their precious help in collecting and processing blood samples. We are also very grateful to Fabio Torrini and Paola Baldini for their secretarial assistance.
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Table II. In-hospital outcomes Prasugrel 60 mg (n = 25) Death Reinfarction Stent thrombosis Stroke TIMI major bleeding TIMI minor bleeding Dyspnea Ventricular pauses N 3 s Contrast-induced nephropathy Serum GPT N 150 U/L
1 0 0 0 2 0 1 0 4
(4%) (0%) (0%) (0%) (8%) (0%) (4%) (0%) (16%)
0 (0%)
Ticagrelor 360 mg (n = 25) 1 0 0 0 1 2 4 1 1
(4%) (0%) (0%) (0%) (4%) (8%) (16%) (4%) (4%)
1 (4%)
P 1 1 1 1 .552 .149 .157 .312 .157
4.
5.
6.
.312
GPT, Glutamate-pyruvate transaminase.
7.
Disclosures Dr Parodi reported receiving consulting or lecture fees from Daiichi Sankyo/Eli Lilly, AstraZeneca, and The Medicine Company. Dr Marcucci received honoraria for lectures from Daiichi Sankyo/Eli Lilly and Merck Sharp Dohme. Dr Abbate reports receiving consulting fees from Eli Lilly; lecture fees from Instrumentation Laboratory and Sigma Tau; and research grant funding from Bayer, Boehringer Ingelheim, and Pfizer. Dr Antoniucci reported receiving consulting fees from Daiichi Sankyo/Eli Lilly and The Medicines Company, and serving on the advisory board of Cordis and CID. The other authors reported no disclosures.
10.
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