J Thromb Thrombolysis DOI 10.1007/s11239-014-1119-9
Comparison of platelet inhibition by prasugrel versus ticagrelor over time in patients with acute myocardial infarction Leor Perl • Noa Zemer-Wassercug • Eldad Rechavia • Muthiah Vaduganathan Katia Orvin • Adaya Weissler-Snir • Hila Lerman-Shivek • Ran Kornowski • Eli I. Lev
•
Ó Springer Science+Business Media New York 2014
Abstract High on-treatment platelet reactivity (HTPR) despite use of P2Y12 antagonists is associated with adverse cardiac events. The long-term variability in response to prasugrel and ticagrelor is unclear. Our aim was to assess residual platelet reactivity (PR) and rates of HTPR during treatment with prasugrel versus ticagrelor in patients with myocardial infarction (MI). 114 patients with MI treated with percutaneous coronary intervention (PCI) were included. Sixty-two patients were treated with prasugrel (mean age 58 ± 8 years, 21 % women, 29 % diabetes), and 52 patients with ticagrelor (mean age 63 ± 9, 19 % women, 37 % diabetes). Patients were tested for PR at 2–4 days and 30 days post-PCI, using the VerifyNow P2Y12 assay and the multiple-electrode aggregometry. Our results show a higher residual PR in patients treated with prasugrel than those treated with ticagrelor (VerifyNow: 65.4 ± 60.6 vs. 26.0 ± 24.2 P2Y12 reaction units, p \ 0.001 at 2–4 days, and 67.3 ± 62.5 vs. 21.1 ± 26.1, p \ 0.001 at follow-up). HTPR rates were higher in the prasugrel group (8.1–11.3 % vs. none with ticagrelor in the early test, and L. Perl N. Zemer-Wassercug E. Rechavia K. Orvin A. Weissler-Snir R. Kornowski E. I. Lev (&) Department of Cardiology, Rabin Medical Center, Jabotinski st. 39, 49100 Petah Tiqwa, Israel e-mail: [email protected] L. Perl N. Zemer-Wassercug E. Rechavia K. Orvin A. Weissler-Snir R. Kornowski E. I. Lev The Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel M. Vaduganathan Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA H. Lerman-Shivek Clinical Pharmacy Department, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel
8.7–10.9 % vs. none with ticagrelor at follow-up). In conclusion, in patients with MI undergoing PCI, treatment with ticagrelor resulted in greater platelet inhibition and lower HTPR rates compared with prasugrel, up to 30 days after the event. Keywords Prasugrel Ticagrelor Platelet reactivity Acute myocardial infarction
Introduction Clopidogrel therapy is limited by wide variability in response and relatively frequent high on-treatment platelet reactivity (HTPR), which are clearly associated with adverse cardiovascular events [1–4]. The new platelet P2Y12 receptor inhibitors, prasugrel and ticagrelor, have been shown to have more predictable pharmacokinetics and enhanced pharmacodynamic platelet inhibitory effects, with significantly lower rates of HTPR compared with clopidogrel [5]. These superior pharmacodynamic properties have translated to beneficial clinical outcomes, specifically in reducing the risk of ischemic events in patients with acute coronary syndromes (ACS) [6, 7]. Contrary to the initial reports of consistent and effective platelet inhibition achieved by both prasugrel and ticagrelor, recent studies report a significant proportion of patients demonstrate HTPR after treatment with these new agents, with a seemingly higher level of HTPR with prasugrel [8– 13]. However, there is limited data comparing platelet inhibition and variability in response to prasugrel and ticagrelor over time in patients with myocardial infarction (MI). Our aim was therefore to examine residual platelet reactivity (PR) and rates of HTPR up to 1 month of treatment with prasugrel versus ticagrelor in patients with MI who underwent percutaneous coronary intervention (PCI).
123
L. Perl et al.
Materials and methods
VerifyNow P2Y12
Patients
VerifyNow P2Y12 (Accumetrics, San Diego, CA) is a rapid platelet-function cartridge-based assay designed to directly measure drug effect on the P2Y12 receptor. The assay contains 20 lmol adenosine-diphosphate and 22 nmol prostaglandin E1 to reduce the activation contribution from adenosine-diphosphate binding to P2Y12 receptors. Fibrinogen-coated microparticles are used in the VerifyNow P2Y12 cartridge to bind to available platelet receptors. The VerifyNow instrument measures platelet-induced aggregation as an increase in light transmittance and is expressed in P2Y12 reaction units. With this assay, a higher P2Y12 reaction units reflects greater adenosine-diphosphate-mediated PR.
All patients, aged 18–75, undergoing urgent PCI for MI in the Rabin Medical Center (Petah-Tikva, Israel) were considered for study participation. Patients with specific contraindications to prasugrel treatment, including the elderly ([75 years), the underweight (\60 kg), or patients with a history of prior stroke or transient ischemic attack, or to ticagrelor treatment, including symptomatic bradycardia and severe chronic pulmonary disease were not approached. Other exclusion criteria included hemodynamic instability, thrombocytopenia (\100,000 cells/mm3), anemia (hemoglobin \ 10 g/dL) and renal failure (creatinine [2.5 mg/dL). Study protocol Patients were treated with either prasugrel 60 mg or ticagrelor 180 mg before or immediately after the cardiac catheterization. They also received aspirin 325 mg in the same setting before catheterization. According to the therapeutic protocol of our medical center, patients with STEMI were mainly treated with prasugrel, and patients with non-ST-segment elevation MI were mainly treated with ticagrelor. After PCI, patients received daily prasugrel 10 mg or ticagrelor 90 mg twice daily for a year thereafter (in addition to aspirin 100 mg daily). Adjunctive treatment during PCI (heparin, bivalirudin and/or the glycoprotein IIB-IIIA inhibitor eptifibatide) was given according to physician discretion. PCI was performed according to standard practice guidelines with choice of catheters, balloons and stents according to the attending’s discretion. Patients were tested at two time points: (1) 2–4 days postPCI just prior to hospital discharge and (2) 30-days postPCI. At each time-point, PR was determined using the VerifyNow P2Y12 assay and the Multiplate analyzer. Blood tests were drawn 2–3 h after the administration of the last maintenance dose of the study medication. Multiple electrode aggregometry Platelet function was tested in whole blood on an impedance aggregometer, the Multiplate analyzer (MultiplateÒ Analyzer, Roche, Munich, Germany). After diluting the sample with normal saline (0.9 %), 6.4 lM/L adenosinediphosphate was added to separate test corvettes. Multiple electrode aggregometry results were recorded as aggregation units continuously for at least 6 min. Area under the curve was calculated and expressed as aggregation units*min.
123
Definition of HTPR Rates of HTPR despite P2Y12 inhibitor therapy were determined according to recently published definitions of HTPR for clopidogrel for both platelet function assays ([46 AU for multiple electrode aggregometry and [208 P2Y12 reaction units for VerifyNow) [1, 14, 15]. It should be noted that both these assays correlate well with light transmission aggregometry for various P2Y12 inhibitors [16, 17]. Statistical analysis Data are presented as mean ± standard deviation. Descriptive scatter plots of the distribution of antiplatelet responses to prasugrel and ticagrelor were presented separately at both timepoints. Kolmogorov–Smirnoff algorithm testing was utilized to test for normality of the distribution. Since the distribution was normal, unpaired two-sided Student’s t tests were used for comparisons of PR between the groups. v2 tests were utilized to compare HTPR rates between the two agents at different timepoints, and Spearman’s rank test to assess for correlation between treatment and rate of HTPR. In order to compare variability in response to treatment, the Brown-Forsythe test was used. Analyses were performed using SPSS version 22 (SPSS, Inc. Chicago, Illinois). Statistical significance was set at p \ 0.05. The study protocol was approved by the Ethics Committee of Rabin Medical Center and is in accordance to the Declaration of Helsinki. All patients were recruited from Rabin Medical Center between from February 2012 to October 2013, after obtaining explicit informed consent.
Results Baseline characteristics Sixty-two patients with STEMI or recent MI were treated with prasugrel and 52 patients with non-STEMI or recent
Response to prasugrel versus ticagrelor over time Table 1 Population baseline characteristics
Variable
Prasugrel n = 62
Ticagrelor n = 52
p value
\0.001
Clinical characteristics Age (years)
57.5 ± 7.6
63.2 ± 8.8
Female (%)
13 (21.0)
10 (19.2)
0.793
Body mass index (kg/m2)
28.6 ± 4.8
28.0 ± 4.7
0.446
Type 2 diabetes mellitus (%)
17 (27.4)
19 (36.5)
0.311
Hypertension (%)
27 (43.5)
33 (63.5)
0.035
Smoking (%)a
32 (51.6)
18 (34.6)
0.067
Family history of CAD (%)
18 (29.0)
9 (17.3)
0.148
Hyperlipidemia (%)
37 (59.7)
33 (63.5)
0.632
Prior MI (%)
13 (21.0)
7 (13.5)
0.299
Prior CABG surgery (%)
4 (6.5)
3 (5.8)
0.948
Hemoglobin (g/dL)
11.9 ± 1.8
12.1 ± 1.9
0.371
Platelets (x103 per mm3)
248.2 ± 71.4
239.4 ± 68.2
0.412
Mean platelet volume (fl) creatinine (mg/dL)
9.3 ± 1.1 1.22 ± 0.6
9.1 ± 1.1 1.24 ± 0.7
0.665 0.433
White blood cell (x103 per mm3)
10.8 ± 1.6
10.1 ± 2.5
0.108
Troponin T (ng/mL)
1.1 ± 0.9
0.8 ± 0.7
0.137
Creatine phosphokinase (U/L)
409.8 ± 303.2
348.1 ± 296.9
0.339
LAD (%)
30 (48.4)
25 (48.1)
0.310
RCA (%)
15 (24.2)
12 (23)
CX (%)
8 (12.9)
4 (7.7)
Multiple vessel (%)
9 (14.5)
11 (21.2)
DES (%)
43 (65.2)
39 (75.0)
Glycoprotein IIB-IIIA inhibitors (%)
4 (6.5)
6 (11.5)
0.293
Statins (%)
58 (93.5)
52 (100)
0.072
b-Blockers (%)
51 (82.2)
44 (84.6)
0.691
ACE inhibitors/ARB (%)
57 (91.9)
46 (94.2)
0.701
Proton pump inhibitors (%)
33 (53.2)
20 (38.5)
0.117
Laboratory findings
Categorical variables are expressed as n (%), while continuous variables are expressed as mean ± standard deviation CAD coronary artery disease, MI myocardial infarction, CABG coronary artery bypass graft surgery, STEMI STelevation myocardial infarction, LAD left anterior descending artery, RCA right coronary artery, CX circumflex artery, DES drug eluting stent, ACE angiotensin-converting enzyme, ARB angiotensin receptor blockers a
Includes current and former smokers
Percutaneous intervention
0.227
Treatment at discharge
MI were treated with ticagrelor. Of these, 46 patients (74.2 %) were available for 1 month follow-up in the prasugrel group and 40 (76.9 %) in the ticagrelor group. Table 1 describes the baseline characteristics of the two cohorts. Patients in the ticagrelor group were older (63.2 ± 8.8 vs. 57.5 ± 7.6 years, p \ 0.001) and had higher rates of hypertension (63.5 vs. 43.5 %, p = 0.035). Of the 62 patients in the prasugrel group, two were not diagnosed as STEMI, but as recent MI. In the ticagrelor group, one patient was diagnosed with transient STEMI. One other patient was regarded as a recent MI. Residual platelet reactivity during treatment with prasugrel versus ticagrelor Figures 1 and 2 juxtapose the early (day 2–4) and mid-term (day 30) PR in response to prasugrel and ticagrelor
treatment, displayed as scatterplot comparisons according to VerifyNow P2Y12 reaction units (Fig. 1) and multiple electrode aggregometry (Fig. 2). At both time points, and using both assays, patients treated with prasugrel had higher mean PR than patients treated with ticagrelor (VerifyNow: 65.4 ± 60.6 with prasugrel vs. 26.0 ± 24.2 P2Y12 reaction units with ticagrelor, p \ 0.001 at the early test, and 67.3 ± 62.5 vs. 21.1 ± 26.1, respectively, p \ 0.001 for the follow-up test. Multiple electrode aggregometry: 19.6 ± 18.0 vs. 8.5 ± 6.0, respectively, p \ 0.001, at the early time point, and 21.3 ± 16.9 vs. 15.6 ± 11.1, respectively, p = 0.08, for the follow-up test). Intra-group comparison of PR at the follow-up versus the early time points showed no difference in the prasugrel (p = 0.88 for P2Y12 reaction units, p = 0.34 for multiple electrode aggregometry), or the ticagrelor groups (p = 0.18 for P2Y12 reaction units, p = 0.29 for multiple electrode aggregometry).
123
L. Perl et al. Table 2 Rates of HTPR PR Test
Prasugrel
Ticagrelor
p value
PRU early
8.1 %
0%
0.036
PRU follow-up
8.7 %
0%
0.056
MEA early
11.3 %
0%
0.012
MEA follow-up
10.9 %
0%
0.032
HTPR high-on-treatment platelet reactivity, PR platelet reactivity, PRU P2Y12 reaction units, MEA multiple electrode aggregometry
Fig. 1 Platelet Reactivity according to the P2Y12 reaction units. Scatter plots of platelet reactivity during prasugrel and ticagrelor treatment at the 2 time-points. Data is provided for the VerifyNow P2Y12 P2Y12 reaction units at day 2–4 post-PCI (n = 62 for prasugrel and n = 52 for ticagrelor) and day 30 post-PCI (n = 46 for prasugrel and n = 40 for ticagrelor). PCI percutaneous coronary intervention, PRU P2Y12 reaction units
HTPR at either time-point. Thus, rates of HTPR were higher in the prasugrel group compared to the ticagrelor group (Table 2). To correct for the effect of different baseline characteristics, we have conducted a logistic regression analysis for the following potential confounders: Age, sex, body mass index, diabetes, hypertension, smoking, white blood cell count, troponin levels, treatment with statins, and proton pump inhibitors. Even after multivariate adjustment, ticagrelor was associated with reduced rates of HTPR compared to prasugrel (results not shown). A moderate correlation was shown between the treatment with prasugrel and the rate of HTPR based on the VerifyNow assay (Spearman’s rho correlation coefficients 0.377, p \ 0.001 for the early and 0.413, p \ 0.001 for the late). For the multiple electrode aggregometry, the respective results were 0.364, p \ 0.001, and 0.377, p \ 0.001). Variability in residual PR during treatment with prasugrel versus ticagrelor The degree of variability in residual PR was compared between the two groups at both time points. According to the VerifyNow P2Y12 reaction units values, variability was significantly greater in the prasugrel cohort compared to the ticagrelor cohort at the early time-point (F-value 6.17; p \ 0.0001) and follow-up test (F-value 5.71; p \ 0.0001). Safety
Fig. 2 Platelet Reactivity according to the multiple electrode aggregometry. Scatter plots of platelet reactivity during prasugrel and ticagrelor treatment at the 2 time-points. Data is provided for the multiple electrode aggregometry at day 2–4 post-PCI (n = 62 for prasugrel and n = 52 for ticagrelor) and day 30 post-PCI (n = 46 for prasugrel and n = 40 for ticagrelor). PCI percutaneous coronary intervention, MEA multiple electrode aggregometry
Rates of HTPR Rates of HTPR among the two groups and at the 2 time points are presented in Table 2. In the prasugrel group, 8–11 % of patients exhibited HTPR at the early time-point, depending on the assay used, and 9–11 % at the later timepoint. In the ticagrelor group none of the patients exhibited
123
Among the patients treated with ticagrelor, two stopped taking the medication due to bleeding episodes (one had suffered from upper gastrointestinal bleeding and another had new-onset iron deficiency anemia that resolved with cessation of therapy). In the prasugrel group, there were no bleeding events reported. Importantly, there were also no ischemic events during the follow-up period in either group.
Discussion In the present study, we have shown that in patients with MI undergoing PCI, both new antiplatelet agents are
Response to prasugrel versus ticagrelor over time
associated with effective platelet inhibition and low HTPR rates. However, ticagrelor treatment was associated with greater platelet inhibition, reflected by lower residual PR and lower HTPR rates, compared with prasugrel, up to 30 days after the MI and PCI. Recently, Bonello et al. [8] reported that about 25 % of patients with ACS treated with prasugrel had HTPR 6–12 h after the loading dose, and that these patients were at higher risk of MACE after PCI. This report was followed by several studies in the setting of STEMI that demonstrated relatively high rates of HTPR for both new agents, in the early hours after the acute event [9, 10]. We recently reported an HTPR rate of about 10 % with prasugrel therapy up to a month after STEMI [11]. There is paucity of pharmacodynamic data comparing the two new agents. The RAPID (Rapid Activity of Platelet Inhibitor Drugs) primary PCI study had shown similar antiplatelet effects of prasugrel and ticagrelor in STEMI patients 2 h after loading [10]. Alexopoulos et al. [12] have shown that in patients with ACS demonstrating HTPR while on clopidogrel (24 h post-PCI), ticagrelor treatment was associated with significantly greater platelet inhibition compared with prasugrel, although both agents seemed to effectively overcome HTPR. Similarly, a recent study tested the effects of ticagrelor and prasugrel up to 18 h after loading in diabetic patients with ACS, and showed lower PR levels and a trend towards lower rates of HTPR with ticagrelor [13]. The results of our study are in accordance with the studies by Alexopoulos et al. [9] and Laine et al. [13], but extends their findings at the early phase after loading, to follow-up of PR over time. We have examined the antiplatelet effects of prasugrel and ticagrelor up to 30-days after MI, while earlier pharmacodynamic studies examined mainly the effects of these drugs in the early period after STEMI, and found that the full inhibitory effects of both agents are initially attenuated in the first hours of STEMI [9, 10]. In these prior studies, there were no differences in the effectiveness of the two agents at the early hours after the MI and PCI [9, 10]. However, the phamacodynamic differences between the drugs may take time to develop. In the study by Alexopoulos et al. [9], at day 5 after ACS, PR was lower with ticagrelor than prasugrel, consistent with our findings. Overall, we did not observe any cases of HTPR during ticagrelor treatment, and roughly a 10 % HTPR rate during prasugrel treatment. Although the HTPR rate for prasugrel is low, its occurrence has been associated with adverse clinical outcomes [8]. The mechanism of HTPR despite prasugrel therapy remains elusive. We have recently shown that in STEMI patients treated with prasugrel, levels of reticulated platelets are correlated with a reduced response to therapy [11]. Reticulated platelets contain mRNA and
can express increased amounts of adenosine-diphosphate receptors and intra-granular proteins [18]. These intrinsic platelet products may explain the observed increased reactivity and reduced responsiveness to several antiplatelet drugs in ACS [19, 20]. In addition, recent studies have demonstrated specific genetic influences on the antiplatelet effects of prasugrel. Cuisset et al. [21] have shown that PR during prasugrel therapy is influenced by the genetic polymorphisms of the CYP2C19*2 and *17 alleles in patients with ACS treated with PCI. Another study by Franken et al. [22] had demonstrated low platelet responsiveness in patients treated with prasugrel after PCI who carry the CYP2C9*2 and CYP2B6*6 polymorphisms. However, other studies did not find such a genetic influence on prasugrel [23, 24]. Nevertheless, since the antiplatelet effect of ticagrelor does not appear to be affected by CYP2C19*2 or other polymorphisms [25, 26], these genetic variations may partly explain the disparity between platelet response to therapy with prasugrel and ticagrelor. Furthermore, in contrast to theinopyridines, the activity of ticagrelor does not rely on hepatic activation or metabolism, rather ticagrelor uniquely utilizes a non-active binding site on the P2Y12 receptor allowing for allosteric inhibition. Thus, specific mutations in the active site of the adenosine-diphosphate receptor may more prominently influence prasugrel or clopidogrel efficacy than ticagrelor. Despite the adverse outcomes in patients with HTPR receiving prasugrel [8], it is yet to be shown that the enhanced platelet inhibition rates by ticagrelor leads to better clinical outcomes. Increased risk of bleeding events in patients with more pronounced platelet inhibition is a particular hazard, as shown in previous studies examining such differences in patients undergoing PCI and treated with clopidogrel [27]. In addition, strategies of tailoring antiplatelet therapy according to PR testing have so far not shown to improve prognosis [14, 28]. Large studies, designed to assess clinical outcomes in patients treated with prasugrel and ticagrelor according to PR, are warranted. The major limitation of our study is the comparison of PR and antiplatelet effects between two different groups of patients: mainly STEMI patients in the prasugrel group versus largely non-STEMI patients in the ticagrelor group. Patients with STEMI may have distinct platelet protein responses which may induce platelet hyper-reactivity [18]. Furthermore, the patients presenting with STEMI were taken more urgently to the catheterization laboratory to undergo primary PCI. However, the tests for PR were performed after an interval of several days up to a month post-PCI, thus potentially minimizing the differential acute stress-related effects between the two groups. Nevertheless, it is still possible that the higher HTPR rates in the prasugrel group, especially early after the acute MI, may
123
L. Perl et al.
have been partly related to platelet hyper-reactivity surrounding the acute STEMI event. It should also be noted that patients in the ticagrelor group were older and in general a higher-risk population, as is often observed in non-STEMI cohorts. In general, older patients have been shown to have higher PR and lower response to antiplatelet agents [29–31]. Despite these high-risk characteristics, patients in the ticagrelor group had, in fact, lower PR rates at both time-points, and no cases of HTPR at all, emphasizing the anti-platelet efficacy of the drug. The use of glycoprotein IIb-IIIa inhibitor was also more frequent in the ticagrelor group than the prasugrel group, albeit not reaching statistical significance (11.5 vs. 6.5 %; p = 0.293). Nevertheless, these differences in rates of HTPR between the two treatment groups persisted even after multivariate adjustment for potential confounders. An additional limitation is the lack of baseline PR levels (before drug treatment), due to the study design. Finally, the relatively small size of the study groups, and the significant rate of patients lost to follow-up (16 in the prasugrel and 12 in the ticagrelor group), may have introduced additional bias into the study results. Nevertheless, we believe the significant differences in rates of HTPR and PR levels observed in this study are of importance, despite these limitations. Future studies, such as the ISAR-REACT 5 [32], will assess whether ticagrelor is superior to prasugrel in patients with ACS and planned invasive strategy in terms of clinical outcomes.
3.
4.
5.
6.
7.
8.
9.
Conclusion In patients with MI undergoing PCI, both prasugrel and ticagrelor exerted potent antiplatelet effects, with low rates of HTPR, up to 30-days after the event. However, ticagrelor treatment was associated with lower rates of HTPR and lower residual PR compared with prasugrel.
10.
The authors declare that they have no conflict
11.
Conflict of interest of interest.
References 12. 1. Bonello L, Tantry US, Marcucci R, Blindt R, Angiolillo DJ, Becker R, Bhatt DL, Cattaneo M, Collet JP, Cuisset T, Gachet C, Montalescot G, Jennings LK, Kereiakes D, Sibbing D, Trenk D, Van Werkum JW, Paganelli F, Price MJ, Waksman R, Gurbel PA, Working Group on High On-Treatment Platelet Reactivity (2010) Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 56:919–933 2. Brar SS, ten Berg J, Marcucci R, Price MJ, Valgimigli M, Kim HS, Patti G, Breet NJ, DiSciascio G, Cuisset T, Dangas G (2011)
123
13.
Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention. A collaborative meta-analysis of individual participant data. J Am Coll Cardiol 58:1945–1954 Parodi G, Marcucci R, Valenti R, Gori AM, Migliorini A, Giusti B, Buonamici P, Gensini GF, Abbate R, Antoniucci D (2011) High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI. JAMA 306:1215–1223 Sofi F, Marcucci R, Gori AM, Giusti B, Abbate R, Gensini GF (2010) Clopidogrel non-responsiveness and risk of cardiovascular morbidity.An updated meta-analysis. Thromb Haemost 103:841–848 Jernberg T, Payne CD, Winters KJ, Darstein C, Brandt JT, Jakubowski JA, Naganuma H, Siegbahn A, Wallentin L (2006) Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease. Eur Heart J 27:1166–1173 Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA, PLATO Investigators (2009) Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 361:1045–1057 Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM, TRITON-TIMI 38 Investigators (2007) Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 357:2001–2015 Bonello L, Pansieri M, Mancini J, Bonello R, Maillard L, Barnay P, Rossi P, Ait-Mokhtar O, Jouve B, Collet F, Peyre JP, Wittenberg O, de Labriolle A, Camilleri E, Cheneau E, Cabassome E, Dignat-George F, Camoin-Jau L, Paganelli F (2011) High ontreatment platelet reactivity after prasugrel loading dose and cardiovascular events after percutaneous coronary intervention in acute coronary syndromes. J Am Coll Cardiol 58:467–473 Alexopoulos D, Xanthopoulou I, Gkizas V, Kassimis G, Theodoropoulos KC, Makris G, Koutsogiannis N, Damelou A, Tsigkas G, Davlouros P, Hahalis G (2012) Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with STsegment-elevation myocardial infarction. Circ Cardiovasc Interv 5:797–804 Parodi G, Valenti R, Bellandi B, Migliorini A, Marcucci R, Comito V, Carrabba N, Santini A, Gensini GF, Abbate R, Antoniucci D (2013) 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 61:1601–1606 Perl L, Lerman-Shivek H, Rechavia E, Vaduganathan M, Leshem-Lev D, Zemer-Wassercug N, Dadush O, Codner P, Bental T, Battler A, Kornowski R, Lev EI (2014) Response to prasugrel and levels of circulating reticulated platelets in patients with st-segment elevation myocardial infarction. J Am Coll Cardiol 63(6):513–517 Alexopoulos D, Galati A, Xanthopoulou I, Mavronasiou E, Kassimis G, Theodoropoulos KC, Makris G, Damelou A, Tsigkas G, Hahalis G, Davlouros P (2012) Ticagrelor versus prasugrel in acute coronary syndrome patients with high on-clopidogrel platelet reactivity following percutaneous coronary intervention: a pharmacodynamic study. J Am Coll Cardiol 60:193–199 Laine M, Fre`re C, Toesca R, Berbis J, Barnay P, Pansieri M, Michelet P, Bessereau J, Camilleri E, Ronsin O, Helal O, Paganelli F, Dignat-George F, Bonello L (2013) Ticagrelor versus prasugrel in diabetic patients with an acute coronary syndrome.A pharmacodynamic randomised study. Thromb Haemost 111(2):273–278
Response to prasugrel versus ticagrelor over time 14. Price MJ, Angiolillo DJ, Teirstein PS, Lillie E, Manoukian SV, Berger PB, Tanguay JF, Cannon CP, Topol EJ (2011) Platelet reactivity and cardiovascular outcomes after percutaneous coronary intervention: a time-dependent analysis of the gauging responsiveness with a Verifynow P2Y12 assay: impact on Thrombosis and Safety (GRAVITAS) trial. Circulation 124:1132–1137 15. Tantry US, Bonello L, Aradi D, Price MJ, Jeong YH, Angiolillo DJ, Stone GW, Curzen N, Geisler T, Ten Berg J, Kirtane A, SillerMatula J, Mahla E, Becker RC, Bhatt DL, Waksman R, Rao SV, Alexopoulos D, Marcucci R, Reny JL, Trenk D, Sibbingc D, Gurbel PA, Working group on on-treatment platelet reactivity (2013) Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding. J Am Coll Cardiol 62(24):2261–2273 16. Jakubowski JA, Payne CD, Li YG, Brandt JT, Small DS, Farid NA, Salazar DE, Winters KJ (2008) The use of the VerifyNow P2Y12 point-of-care device to monitor platelet function across a range of P2Y12 inhibition levels following prasugrel and clopidogrel administration. Thromb Haemost 99:409–415 17. Park Y, Jeong YH, Kim IS, Yun SE, Kwon TJ, Hwang SJ, Kwak CH, Hwang JY (2012) The concordance and correlation of measurements by multiple electrode and light transmittance aggregometries based on the pre-defined cutoffs of high and low ontreatment platelet reactivity. Platelets 23:290–298 18. Ault KA, Rinder HM, Mitchell J, Carmody MB, Vary CP, Hillman RS (1992) The significance of platelets with increased RNA content (reticulated platelets). A measure of the rate of thrombopoiesis. Am J Clin Pathol 98:637–646 19. Parguin˜a AF, Grigorian-Shamagian L, Agra RM, Lo´pez-Otero D, Rosa I, Alonso J, Teijeira-Ferna´ndez E, Gonza´lez-Juanatey JR, ´ (2011) Variations in platelet proteins associated with Garcı´a A ST-elevation myocardial infarction: novel clues on pathways underlying platelet activation in acute coronary syndromes. Arterioscler Thromb Vasc Biol 31:2957–2964 20. Parguin˜a AF, Grigorian-Shamajian L, Agra RM, Teijeira-Ferna´ndez E, Rosa I, Alonso J, Vin˜uela-Rolda´n JE, Seoane A, Gonza´lez-Juanatey JR, Garcı´a A (2010) Proteins involved in platelet signaling are differentially regulated in acute coronary syndrome: a proteomic study. PLoS One 5:e13404. doi:10.1371/journal. pone.0013404 21. Cuisset T, Loosveld M, Morange PE, Quilici J, Moro PJ, Saut N, Gaborit B, Castelli C, Beguin S, Grosdidier C, Fourcade L, Bonnet JL, Alessi MC (2012) CYP2C19*2 and *17 alleles have a significant impact on platelet response and bleeding risk in patients treated with prasugrel after acute coronary syndrome. J Am Coll Cardiol Intv 5:1280–1287 22. Franken CC, Kaiser AF, Kruger JC, Overbeck K, Mugge A, Neubauer H (2013) Cytochrome P450 2B6 and 2C9 genotype polymorphism–a possible cause of prasugrel low responsiveness. Thromb Haemost 110:131–140 23. Varenhorst C, James S, Erlinge D, Brandt JT, Braun OO, Man M, Siegbahn A, Walker J, Wallentin L, Winters KJ, Close SL (2009) Genetic variation of CYP2C19 affects both pharmacokinetic and pharmacodynamic responses to clopidogrel but not prasugrel in
24.
25.
26.
27.
28.
29.
30.
31.
32.
aspirin-treated patients with coronary artery disease. Eur Heart J 30:1744–1752 Brandt JT, Close SL, Iturria SJ, Payne CD, Farid NA, Ernest CS 2nd, Lachno DR, Salazar D, Winters KJ (2007) Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost 5(12):2429–2436 Tantry US, Bliden KP, Wei C, Storey RF, Armstrong M, Butler K, Gurbel PA (2010) First analysis of the relation between CYP2C19 genotype and pharmacodynamics in patients treated with ticagrelor versus clopidogrel: the ONSET/OFFSET and RESPOND genotype studies. Circ Cardiovasc Genet 3:556–566 Wallentin L, James S, Storey RF, Armstrong M, Barratt BJ, Horrow J, Husted S, Katus H, Steg PG, Shah SH, Becker RC, Investigators PLATO (2010) Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet 376:1320–1328 Sibbing D, Schulz S, Braun S, Morath T, Stegherr J, Mehilli J, Scho¨mig A, von Beckerath N, Kastrati A (2010) Antiplatelet effects of clopidogrel and bleeding in patients undergoing coronary stent placement. J Thromb Haemost 8(2):250–256 Collet JP, Cuisset T, Range´ G, Cayla G, Elhadad S, Pouillot C, Henry P, Motreff P, Carrie´ D, Boueri Z, Belle L, Van Belle E, Rousseau H, Aubry P, Monse´gu J, Sabouret P, O’Connor SA, Abtan J, Kerneis M, Saint-Etienne C, Barthe´le´my O, Beygui F, Silvain J, Vicaut E, Montalescot G, ARCTIC Investigators (2012) Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med 367(22):2100–2109 Cuisset T, Quilici J, Grosdidier C, Fourcade L, Gaborit B, Pankert M, Molines L, Morange PE, Bonnet JL, Alessi MC (2011) Comparison of platelet reactivity and clopidogrel response in patients B75 years versus [75 years undergoing percutaneous coronary intervention for non-ST-segment elevation acute coronary syndrome. Am J Cardiol 108(10):1411–1416 Silvain J, Cayla G, Hulot JS, Finzi J, Kerneis M, O’Connor SA, Bellemain-Appaix A, Barthe´le´my O, Beygui F, Collet JP, Montalescot G (2012) High on-thienopyridine platelet reactivity in elderly coronary patients: the SENIOR-PLATELET study. Eur Heart J 33(10):1241–1249 Vaturi M, Vaduganathan M, Bental T, Solodky A, Kornowski R, Lev EI (2013) Relation of aspirin response to age in patients with stable coronary artery disease. Am J Cardiol 112(2):212–216 Schulz S, Angiolillo DJ, Antoniucci D, Bernlochner I, Hamm C, Jaitner J, Laugwitz KL, Mayer K, von Merzljak B, Morath T, Neumann FJ, Richardt G, Ruf J, Scho¨mig G, Schu¨hlen H, Schunkert H, Kastrati A, Intracoronary Stenting and Antithrombotic Regimen: rapid Early Action for Coronary Treatment (ISAR-REACT) 5 Trial Investigators (2014) Randomized comparison of ticagrelor versus prasugrel in patients with acute coronary syndrome and planned invasive strategy–design and rationale of the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISARREACT) 5 trial. J Cardiovasc Transl Res 7(1):91–100
123
Comparison of platelet inhibition by prasugrel versus ticagrelor over time in patients with acute myocardial infarction Leor Perl • Noa Zemer-Wassercug • Eldad Rechavia • Muthiah Vaduganathan Katia Orvin • Adaya Weissler-Snir • Hila Lerman-Shivek • Ran Kornowski • Eli I. Lev
•
Ó Springer Science+Business Media New York 2014
Abstract High on-treatment platelet reactivity (HTPR) despite use of P2Y12 antagonists is associated with adverse cardiac events. The long-term variability in response to prasugrel and ticagrelor is unclear. Our aim was to assess residual platelet reactivity (PR) and rates of HTPR during treatment with prasugrel versus ticagrelor in patients with myocardial infarction (MI). 114 patients with MI treated with percutaneous coronary intervention (PCI) were included. Sixty-two patients were treated with prasugrel (mean age 58 ± 8 years, 21 % women, 29 % diabetes), and 52 patients with ticagrelor (mean age 63 ± 9, 19 % women, 37 % diabetes). Patients were tested for PR at 2–4 days and 30 days post-PCI, using the VerifyNow P2Y12 assay and the multiple-electrode aggregometry. Our results show a higher residual PR in patients treated with prasugrel than those treated with ticagrelor (VerifyNow: 65.4 ± 60.6 vs. 26.0 ± 24.2 P2Y12 reaction units, p \ 0.001 at 2–4 days, and 67.3 ± 62.5 vs. 21.1 ± 26.1, p \ 0.001 at follow-up). HTPR rates were higher in the prasugrel group (8.1–11.3 % vs. none with ticagrelor in the early test, and L. Perl N. Zemer-Wassercug E. Rechavia K. Orvin A. Weissler-Snir R. Kornowski E. I. Lev (&) Department of Cardiology, Rabin Medical Center, Jabotinski st. 39, 49100 Petah Tiqwa, Israel e-mail: [email protected] L. Perl N. Zemer-Wassercug E. Rechavia K. Orvin A. Weissler-Snir R. Kornowski E. I. Lev The Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel M. Vaduganathan Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA H. Lerman-Shivek Clinical Pharmacy Department, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel
8.7–10.9 % vs. none with ticagrelor at follow-up). In conclusion, in patients with MI undergoing PCI, treatment with ticagrelor resulted in greater platelet inhibition and lower HTPR rates compared with prasugrel, up to 30 days after the event. Keywords Prasugrel Ticagrelor Platelet reactivity Acute myocardial infarction
Introduction Clopidogrel therapy is limited by wide variability in response and relatively frequent high on-treatment platelet reactivity (HTPR), which are clearly associated with adverse cardiovascular events [1–4]. The new platelet P2Y12 receptor inhibitors, prasugrel and ticagrelor, have been shown to have more predictable pharmacokinetics and enhanced pharmacodynamic platelet inhibitory effects, with significantly lower rates of HTPR compared with clopidogrel [5]. These superior pharmacodynamic properties have translated to beneficial clinical outcomes, specifically in reducing the risk of ischemic events in patients with acute coronary syndromes (ACS) [6, 7]. Contrary to the initial reports of consistent and effective platelet inhibition achieved by both prasugrel and ticagrelor, recent studies report a significant proportion of patients demonstrate HTPR after treatment with these new agents, with a seemingly higher level of HTPR with prasugrel [8– 13]. However, there is limited data comparing platelet inhibition and variability in response to prasugrel and ticagrelor over time in patients with myocardial infarction (MI). Our aim was therefore to examine residual platelet reactivity (PR) and rates of HTPR up to 1 month of treatment with prasugrel versus ticagrelor in patients with MI who underwent percutaneous coronary intervention (PCI).
123
L. Perl et al.
Materials and methods
VerifyNow P2Y12
Patients
VerifyNow P2Y12 (Accumetrics, San Diego, CA) is a rapid platelet-function cartridge-based assay designed to directly measure drug effect on the P2Y12 receptor. The assay contains 20 lmol adenosine-diphosphate and 22 nmol prostaglandin E1 to reduce the activation contribution from adenosine-diphosphate binding to P2Y12 receptors. Fibrinogen-coated microparticles are used in the VerifyNow P2Y12 cartridge to bind to available platelet receptors. The VerifyNow instrument measures platelet-induced aggregation as an increase in light transmittance and is expressed in P2Y12 reaction units. With this assay, a higher P2Y12 reaction units reflects greater adenosine-diphosphate-mediated PR.
All patients, aged 18–75, undergoing urgent PCI for MI in the Rabin Medical Center (Petah-Tikva, Israel) were considered for study participation. Patients with specific contraindications to prasugrel treatment, including the elderly ([75 years), the underweight (\60 kg), or patients with a history of prior stroke or transient ischemic attack, or to ticagrelor treatment, including symptomatic bradycardia and severe chronic pulmonary disease were not approached. Other exclusion criteria included hemodynamic instability, thrombocytopenia (\100,000 cells/mm3), anemia (hemoglobin \ 10 g/dL) and renal failure (creatinine [2.5 mg/dL). Study protocol Patients were treated with either prasugrel 60 mg or ticagrelor 180 mg before or immediately after the cardiac catheterization. They also received aspirin 325 mg in the same setting before catheterization. According to the therapeutic protocol of our medical center, patients with STEMI were mainly treated with prasugrel, and patients with non-ST-segment elevation MI were mainly treated with ticagrelor. After PCI, patients received daily prasugrel 10 mg or ticagrelor 90 mg twice daily for a year thereafter (in addition to aspirin 100 mg daily). Adjunctive treatment during PCI (heparin, bivalirudin and/or the glycoprotein IIB-IIIA inhibitor eptifibatide) was given according to physician discretion. PCI was performed according to standard practice guidelines with choice of catheters, balloons and stents according to the attending’s discretion. Patients were tested at two time points: (1) 2–4 days postPCI just prior to hospital discharge and (2) 30-days postPCI. At each time-point, PR was determined using the VerifyNow P2Y12 assay and the Multiplate analyzer. Blood tests were drawn 2–3 h after the administration of the last maintenance dose of the study medication. Multiple electrode aggregometry Platelet function was tested in whole blood on an impedance aggregometer, the Multiplate analyzer (MultiplateÒ Analyzer, Roche, Munich, Germany). After diluting the sample with normal saline (0.9 %), 6.4 lM/L adenosinediphosphate was added to separate test corvettes. Multiple electrode aggregometry results were recorded as aggregation units continuously for at least 6 min. Area under the curve was calculated and expressed as aggregation units*min.
123
Definition of HTPR Rates of HTPR despite P2Y12 inhibitor therapy were determined according to recently published definitions of HTPR for clopidogrel for both platelet function assays ([46 AU for multiple electrode aggregometry and [208 P2Y12 reaction units for VerifyNow) [1, 14, 15]. It should be noted that both these assays correlate well with light transmission aggregometry for various P2Y12 inhibitors [16, 17]. Statistical analysis Data are presented as mean ± standard deviation. Descriptive scatter plots of the distribution of antiplatelet responses to prasugrel and ticagrelor were presented separately at both timepoints. Kolmogorov–Smirnoff algorithm testing was utilized to test for normality of the distribution. Since the distribution was normal, unpaired two-sided Student’s t tests were used for comparisons of PR between the groups. v2 tests were utilized to compare HTPR rates between the two agents at different timepoints, and Spearman’s rank test to assess for correlation between treatment and rate of HTPR. In order to compare variability in response to treatment, the Brown-Forsythe test was used. Analyses were performed using SPSS version 22 (SPSS, Inc. Chicago, Illinois). Statistical significance was set at p \ 0.05. The study protocol was approved by the Ethics Committee of Rabin Medical Center and is in accordance to the Declaration of Helsinki. All patients were recruited from Rabin Medical Center between from February 2012 to October 2013, after obtaining explicit informed consent.
Results Baseline characteristics Sixty-two patients with STEMI or recent MI were treated with prasugrel and 52 patients with non-STEMI or recent
Response to prasugrel versus ticagrelor over time Table 1 Population baseline characteristics
Variable
Prasugrel n = 62
Ticagrelor n = 52
p value
\0.001
Clinical characteristics Age (years)
57.5 ± 7.6
63.2 ± 8.8
Female (%)
13 (21.0)
10 (19.2)
0.793
Body mass index (kg/m2)
28.6 ± 4.8
28.0 ± 4.7
0.446
Type 2 diabetes mellitus (%)
17 (27.4)
19 (36.5)
0.311
Hypertension (%)
27 (43.5)
33 (63.5)
0.035
Smoking (%)a
32 (51.6)
18 (34.6)
0.067
Family history of CAD (%)
18 (29.0)
9 (17.3)
0.148
Hyperlipidemia (%)
37 (59.7)
33 (63.5)
0.632
Prior MI (%)
13 (21.0)
7 (13.5)
0.299
Prior CABG surgery (%)
4 (6.5)
3 (5.8)
0.948
Hemoglobin (g/dL)
11.9 ± 1.8
12.1 ± 1.9
0.371
Platelets (x103 per mm3)
248.2 ± 71.4
239.4 ± 68.2
0.412
Mean platelet volume (fl) creatinine (mg/dL)
9.3 ± 1.1 1.22 ± 0.6
9.1 ± 1.1 1.24 ± 0.7
0.665 0.433
White blood cell (x103 per mm3)
10.8 ± 1.6
10.1 ± 2.5
0.108
Troponin T (ng/mL)
1.1 ± 0.9
0.8 ± 0.7
0.137
Creatine phosphokinase (U/L)
409.8 ± 303.2
348.1 ± 296.9
0.339
LAD (%)
30 (48.4)
25 (48.1)
0.310
RCA (%)
15 (24.2)
12 (23)
CX (%)
8 (12.9)
4 (7.7)
Multiple vessel (%)
9 (14.5)
11 (21.2)
DES (%)
43 (65.2)
39 (75.0)
Glycoprotein IIB-IIIA inhibitors (%)
4 (6.5)
6 (11.5)
0.293
Statins (%)
58 (93.5)
52 (100)
0.072
b-Blockers (%)
51 (82.2)
44 (84.6)
0.691
ACE inhibitors/ARB (%)
57 (91.9)
46 (94.2)
0.701
Proton pump inhibitors (%)
33 (53.2)
20 (38.5)
0.117
Laboratory findings
Categorical variables are expressed as n (%), while continuous variables are expressed as mean ± standard deviation CAD coronary artery disease, MI myocardial infarction, CABG coronary artery bypass graft surgery, STEMI STelevation myocardial infarction, LAD left anterior descending artery, RCA right coronary artery, CX circumflex artery, DES drug eluting stent, ACE angiotensin-converting enzyme, ARB angiotensin receptor blockers a
Includes current and former smokers
Percutaneous intervention
0.227
Treatment at discharge
MI were treated with ticagrelor. Of these, 46 patients (74.2 %) were available for 1 month follow-up in the prasugrel group and 40 (76.9 %) in the ticagrelor group. Table 1 describes the baseline characteristics of the two cohorts. Patients in the ticagrelor group were older (63.2 ± 8.8 vs. 57.5 ± 7.6 years, p \ 0.001) and had higher rates of hypertension (63.5 vs. 43.5 %, p = 0.035). Of the 62 patients in the prasugrel group, two were not diagnosed as STEMI, but as recent MI. In the ticagrelor group, one patient was diagnosed with transient STEMI. One other patient was regarded as a recent MI. Residual platelet reactivity during treatment with prasugrel versus ticagrelor Figures 1 and 2 juxtapose the early (day 2–4) and mid-term (day 30) PR in response to prasugrel and ticagrelor
treatment, displayed as scatterplot comparisons according to VerifyNow P2Y12 reaction units (Fig. 1) and multiple electrode aggregometry (Fig. 2). At both time points, and using both assays, patients treated with prasugrel had higher mean PR than patients treated with ticagrelor (VerifyNow: 65.4 ± 60.6 with prasugrel vs. 26.0 ± 24.2 P2Y12 reaction units with ticagrelor, p \ 0.001 at the early test, and 67.3 ± 62.5 vs. 21.1 ± 26.1, respectively, p \ 0.001 for the follow-up test. Multiple electrode aggregometry: 19.6 ± 18.0 vs. 8.5 ± 6.0, respectively, p \ 0.001, at the early time point, and 21.3 ± 16.9 vs. 15.6 ± 11.1, respectively, p = 0.08, for the follow-up test). Intra-group comparison of PR at the follow-up versus the early time points showed no difference in the prasugrel (p = 0.88 for P2Y12 reaction units, p = 0.34 for multiple electrode aggregometry), or the ticagrelor groups (p = 0.18 for P2Y12 reaction units, p = 0.29 for multiple electrode aggregometry).
123
L. Perl et al. Table 2 Rates of HTPR PR Test
Prasugrel
Ticagrelor
p value
PRU early
8.1 %
0%
0.036
PRU follow-up
8.7 %
0%
0.056
MEA early
11.3 %
0%
0.012
MEA follow-up
10.9 %
0%
0.032
HTPR high-on-treatment platelet reactivity, PR platelet reactivity, PRU P2Y12 reaction units, MEA multiple electrode aggregometry
Fig. 1 Platelet Reactivity according to the P2Y12 reaction units. Scatter plots of platelet reactivity during prasugrel and ticagrelor treatment at the 2 time-points. Data is provided for the VerifyNow P2Y12 P2Y12 reaction units at day 2–4 post-PCI (n = 62 for prasugrel and n = 52 for ticagrelor) and day 30 post-PCI (n = 46 for prasugrel and n = 40 for ticagrelor). PCI percutaneous coronary intervention, PRU P2Y12 reaction units
HTPR at either time-point. Thus, rates of HTPR were higher in the prasugrel group compared to the ticagrelor group (Table 2). To correct for the effect of different baseline characteristics, we have conducted a logistic regression analysis for the following potential confounders: Age, sex, body mass index, diabetes, hypertension, smoking, white blood cell count, troponin levels, treatment with statins, and proton pump inhibitors. Even after multivariate adjustment, ticagrelor was associated with reduced rates of HTPR compared to prasugrel (results not shown). A moderate correlation was shown between the treatment with prasugrel and the rate of HTPR based on the VerifyNow assay (Spearman’s rho correlation coefficients 0.377, p \ 0.001 for the early and 0.413, p \ 0.001 for the late). For the multiple electrode aggregometry, the respective results were 0.364, p \ 0.001, and 0.377, p \ 0.001). Variability in residual PR during treatment with prasugrel versus ticagrelor The degree of variability in residual PR was compared between the two groups at both time points. According to the VerifyNow P2Y12 reaction units values, variability was significantly greater in the prasugrel cohort compared to the ticagrelor cohort at the early time-point (F-value 6.17; p \ 0.0001) and follow-up test (F-value 5.71; p \ 0.0001). Safety
Fig. 2 Platelet Reactivity according to the multiple electrode aggregometry. Scatter plots of platelet reactivity during prasugrel and ticagrelor treatment at the 2 time-points. Data is provided for the multiple electrode aggregometry at day 2–4 post-PCI (n = 62 for prasugrel and n = 52 for ticagrelor) and day 30 post-PCI (n = 46 for prasugrel and n = 40 for ticagrelor). PCI percutaneous coronary intervention, MEA multiple electrode aggregometry
Rates of HTPR Rates of HTPR among the two groups and at the 2 time points are presented in Table 2. In the prasugrel group, 8–11 % of patients exhibited HTPR at the early time-point, depending on the assay used, and 9–11 % at the later timepoint. In the ticagrelor group none of the patients exhibited
123
Among the patients treated with ticagrelor, two stopped taking the medication due to bleeding episodes (one had suffered from upper gastrointestinal bleeding and another had new-onset iron deficiency anemia that resolved with cessation of therapy). In the prasugrel group, there were no bleeding events reported. Importantly, there were also no ischemic events during the follow-up period in either group.
Discussion In the present study, we have shown that in patients with MI undergoing PCI, both new antiplatelet agents are
Response to prasugrel versus ticagrelor over time
associated with effective platelet inhibition and low HTPR rates. However, ticagrelor treatment was associated with greater platelet inhibition, reflected by lower residual PR and lower HTPR rates, compared with prasugrel, up to 30 days after the MI and PCI. Recently, Bonello et al. [8] reported that about 25 % of patients with ACS treated with prasugrel had HTPR 6–12 h after the loading dose, and that these patients were at higher risk of MACE after PCI. This report was followed by several studies in the setting of STEMI that demonstrated relatively high rates of HTPR for both new agents, in the early hours after the acute event [9, 10]. We recently reported an HTPR rate of about 10 % with prasugrel therapy up to a month after STEMI [11]. There is paucity of pharmacodynamic data comparing the two new agents. The RAPID (Rapid Activity of Platelet Inhibitor Drugs) primary PCI study had shown similar antiplatelet effects of prasugrel and ticagrelor in STEMI patients 2 h after loading [10]. Alexopoulos et al. [12] have shown that in patients with ACS demonstrating HTPR while on clopidogrel (24 h post-PCI), ticagrelor treatment was associated with significantly greater platelet inhibition compared with prasugrel, although both agents seemed to effectively overcome HTPR. Similarly, a recent study tested the effects of ticagrelor and prasugrel up to 18 h after loading in diabetic patients with ACS, and showed lower PR levels and a trend towards lower rates of HTPR with ticagrelor [13]. The results of our study are in accordance with the studies by Alexopoulos et al. [9] and Laine et al. [13], but extends their findings at the early phase after loading, to follow-up of PR over time. We have examined the antiplatelet effects of prasugrel and ticagrelor up to 30-days after MI, while earlier pharmacodynamic studies examined mainly the effects of these drugs in the early period after STEMI, and found that the full inhibitory effects of both agents are initially attenuated in the first hours of STEMI [9, 10]. In these prior studies, there were no differences in the effectiveness of the two agents at the early hours after the MI and PCI [9, 10]. However, the phamacodynamic differences between the drugs may take time to develop. In the study by Alexopoulos et al. [9], at day 5 after ACS, PR was lower with ticagrelor than prasugrel, consistent with our findings. Overall, we did not observe any cases of HTPR during ticagrelor treatment, and roughly a 10 % HTPR rate during prasugrel treatment. Although the HTPR rate for prasugrel is low, its occurrence has been associated with adverse clinical outcomes [8]. The mechanism of HTPR despite prasugrel therapy remains elusive. We have recently shown that in STEMI patients treated with prasugrel, levels of reticulated platelets are correlated with a reduced response to therapy [11]. Reticulated platelets contain mRNA and
can express increased amounts of adenosine-diphosphate receptors and intra-granular proteins [18]. These intrinsic platelet products may explain the observed increased reactivity and reduced responsiveness to several antiplatelet drugs in ACS [19, 20]. In addition, recent studies have demonstrated specific genetic influences on the antiplatelet effects of prasugrel. Cuisset et al. [21] have shown that PR during prasugrel therapy is influenced by the genetic polymorphisms of the CYP2C19*2 and *17 alleles in patients with ACS treated with PCI. Another study by Franken et al. [22] had demonstrated low platelet responsiveness in patients treated with prasugrel after PCI who carry the CYP2C9*2 and CYP2B6*6 polymorphisms. However, other studies did not find such a genetic influence on prasugrel [23, 24]. Nevertheless, since the antiplatelet effect of ticagrelor does not appear to be affected by CYP2C19*2 or other polymorphisms [25, 26], these genetic variations may partly explain the disparity between platelet response to therapy with prasugrel and ticagrelor. Furthermore, in contrast to theinopyridines, the activity of ticagrelor does not rely on hepatic activation or metabolism, rather ticagrelor uniquely utilizes a non-active binding site on the P2Y12 receptor allowing for allosteric inhibition. Thus, specific mutations in the active site of the adenosine-diphosphate receptor may more prominently influence prasugrel or clopidogrel efficacy than ticagrelor. Despite the adverse outcomes in patients with HTPR receiving prasugrel [8], it is yet to be shown that the enhanced platelet inhibition rates by ticagrelor leads to better clinical outcomes. Increased risk of bleeding events in patients with more pronounced platelet inhibition is a particular hazard, as shown in previous studies examining such differences in patients undergoing PCI and treated with clopidogrel [27]. In addition, strategies of tailoring antiplatelet therapy according to PR testing have so far not shown to improve prognosis [14, 28]. Large studies, designed to assess clinical outcomes in patients treated with prasugrel and ticagrelor according to PR, are warranted. The major limitation of our study is the comparison of PR and antiplatelet effects between two different groups of patients: mainly STEMI patients in the prasugrel group versus largely non-STEMI patients in the ticagrelor group. Patients with STEMI may have distinct platelet protein responses which may induce platelet hyper-reactivity [18]. Furthermore, the patients presenting with STEMI were taken more urgently to the catheterization laboratory to undergo primary PCI. However, the tests for PR were performed after an interval of several days up to a month post-PCI, thus potentially minimizing the differential acute stress-related effects between the two groups. Nevertheless, it is still possible that the higher HTPR rates in the prasugrel group, especially early after the acute MI, may
123
L. Perl et al.
have been partly related to platelet hyper-reactivity surrounding the acute STEMI event. It should also be noted that patients in the ticagrelor group were older and in general a higher-risk population, as is often observed in non-STEMI cohorts. In general, older patients have been shown to have higher PR and lower response to antiplatelet agents [29–31]. Despite these high-risk characteristics, patients in the ticagrelor group had, in fact, lower PR rates at both time-points, and no cases of HTPR at all, emphasizing the anti-platelet efficacy of the drug. The use of glycoprotein IIb-IIIa inhibitor was also more frequent in the ticagrelor group than the prasugrel group, albeit not reaching statistical significance (11.5 vs. 6.5 %; p = 0.293). Nevertheless, these differences in rates of HTPR between the two treatment groups persisted even after multivariate adjustment for potential confounders. An additional limitation is the lack of baseline PR levels (before drug treatment), due to the study design. Finally, the relatively small size of the study groups, and the significant rate of patients lost to follow-up (16 in the prasugrel and 12 in the ticagrelor group), may have introduced additional bias into the study results. Nevertheless, we believe the significant differences in rates of HTPR and PR levels observed in this study are of importance, despite these limitations. Future studies, such as the ISAR-REACT 5 [32], will assess whether ticagrelor is superior to prasugrel in patients with ACS and planned invasive strategy in terms of clinical outcomes.
3.
4.
5.
6.
7.
8.
9.
Conclusion In patients with MI undergoing PCI, both prasugrel and ticagrelor exerted potent antiplatelet effects, with low rates of HTPR, up to 30-days after the event. However, ticagrelor treatment was associated with lower rates of HTPR and lower residual PR compared with prasugrel.
10.
The authors declare that they have no conflict
11.
Conflict of interest of interest.
References 12. 1. Bonello L, Tantry US, Marcucci R, Blindt R, Angiolillo DJ, Becker R, Bhatt DL, Cattaneo M, Collet JP, Cuisset T, Gachet C, Montalescot G, Jennings LK, Kereiakes D, Sibbing D, Trenk D, Van Werkum JW, Paganelli F, Price MJ, Waksman R, Gurbel PA, Working Group on High On-Treatment Platelet Reactivity (2010) Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 56:919–933 2. Brar SS, ten Berg J, Marcucci R, Price MJ, Valgimigli M, Kim HS, Patti G, Breet NJ, DiSciascio G, Cuisset T, Dangas G (2011)
123
13.
Impact of platelet reactivity on clinical outcomes after percutaneous coronary intervention. A collaborative meta-analysis of individual participant data. J Am Coll Cardiol 58:1945–1954 Parodi G, Marcucci R, Valenti R, Gori AM, Migliorini A, Giusti B, Buonamici P, Gensini GF, Abbate R, Antoniucci D (2011) High residual platelet reactivity after clopidogrel loading and long-term cardiovascular events among patients with acute coronary syndromes undergoing PCI. JAMA 306:1215–1223 Sofi F, Marcucci R, Gori AM, Giusti B, Abbate R, Gensini GF (2010) Clopidogrel non-responsiveness and risk of cardiovascular morbidity.An updated meta-analysis. Thromb Haemost 103:841–848 Jernberg T, Payne CD, Winters KJ, Darstein C, Brandt JT, Jakubowski JA, Naganuma H, Siegbahn A, Wallentin L (2006) Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease. Eur Heart J 27:1166–1173 Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA, PLATO Investigators (2009) Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 361:1045–1057 Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM, TRITON-TIMI 38 Investigators (2007) Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 357:2001–2015 Bonello L, Pansieri M, Mancini J, Bonello R, Maillard L, Barnay P, Rossi P, Ait-Mokhtar O, Jouve B, Collet F, Peyre JP, Wittenberg O, de Labriolle A, Camilleri E, Cheneau E, Cabassome E, Dignat-George F, Camoin-Jau L, Paganelli F (2011) High ontreatment platelet reactivity after prasugrel loading dose and cardiovascular events after percutaneous coronary intervention in acute coronary syndromes. J Am Coll Cardiol 58:467–473 Alexopoulos D, Xanthopoulou I, Gkizas V, Kassimis G, Theodoropoulos KC, Makris G, Koutsogiannis N, Damelou A, Tsigkas G, Davlouros P, Hahalis G (2012) Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with STsegment-elevation myocardial infarction. Circ Cardiovasc Interv 5:797–804 Parodi G, Valenti R, Bellandi B, Migliorini A, Marcucci R, Comito V, Carrabba N, Santini A, Gensini GF, Abbate R, Antoniucci D (2013) 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 61:1601–1606 Perl L, Lerman-Shivek H, Rechavia E, Vaduganathan M, Leshem-Lev D, Zemer-Wassercug N, Dadush O, Codner P, Bental T, Battler A, Kornowski R, Lev EI (2014) Response to prasugrel and levels of circulating reticulated platelets in patients with st-segment elevation myocardial infarction. J Am Coll Cardiol 63(6):513–517 Alexopoulos D, Galati A, Xanthopoulou I, Mavronasiou E, Kassimis G, Theodoropoulos KC, Makris G, Damelou A, Tsigkas G, Hahalis G, Davlouros P (2012) Ticagrelor versus prasugrel in acute coronary syndrome patients with high on-clopidogrel platelet reactivity following percutaneous coronary intervention: a pharmacodynamic study. J Am Coll Cardiol 60:193–199 Laine M, Fre`re C, Toesca R, Berbis J, Barnay P, Pansieri M, Michelet P, Bessereau J, Camilleri E, Ronsin O, Helal O, Paganelli F, Dignat-George F, Bonello L (2013) Ticagrelor versus prasugrel in diabetic patients with an acute coronary syndrome.A pharmacodynamic randomised study. Thromb Haemost 111(2):273–278
Response to prasugrel versus ticagrelor over time 14. Price MJ, Angiolillo DJ, Teirstein PS, Lillie E, Manoukian SV, Berger PB, Tanguay JF, Cannon CP, Topol EJ (2011) Platelet reactivity and cardiovascular outcomes after percutaneous coronary intervention: a time-dependent analysis of the gauging responsiveness with a Verifynow P2Y12 assay: impact on Thrombosis and Safety (GRAVITAS) trial. Circulation 124:1132–1137 15. Tantry US, Bonello L, Aradi D, Price MJ, Jeong YH, Angiolillo DJ, Stone GW, Curzen N, Geisler T, Ten Berg J, Kirtane A, SillerMatula J, Mahla E, Becker RC, Bhatt DL, Waksman R, Rao SV, Alexopoulos D, Marcucci R, Reny JL, Trenk D, Sibbingc D, Gurbel PA, Working group on on-treatment platelet reactivity (2013) Consensus and update on the definition of on-treatment platelet reactivity to adenosine diphosphate associated with ischemia and bleeding. J Am Coll Cardiol 62(24):2261–2273 16. Jakubowski JA, Payne CD, Li YG, Brandt JT, Small DS, Farid NA, Salazar DE, Winters KJ (2008) The use of the VerifyNow P2Y12 point-of-care device to monitor platelet function across a range of P2Y12 inhibition levels following prasugrel and clopidogrel administration. Thromb Haemost 99:409–415 17. Park Y, Jeong YH, Kim IS, Yun SE, Kwon TJ, Hwang SJ, Kwak CH, Hwang JY (2012) The concordance and correlation of measurements by multiple electrode and light transmittance aggregometries based on the pre-defined cutoffs of high and low ontreatment platelet reactivity. Platelets 23:290–298 18. Ault KA, Rinder HM, Mitchell J, Carmody MB, Vary CP, Hillman RS (1992) The significance of platelets with increased RNA content (reticulated platelets). A measure of the rate of thrombopoiesis. Am J Clin Pathol 98:637–646 19. Parguin˜a AF, Grigorian-Shamagian L, Agra RM, Lo´pez-Otero D, Rosa I, Alonso J, Teijeira-Ferna´ndez E, Gonza´lez-Juanatey JR, ´ (2011) Variations in platelet proteins associated with Garcı´a A ST-elevation myocardial infarction: novel clues on pathways underlying platelet activation in acute coronary syndromes. Arterioscler Thromb Vasc Biol 31:2957–2964 20. Parguin˜a AF, Grigorian-Shamajian L, Agra RM, Teijeira-Ferna´ndez E, Rosa I, Alonso J, Vin˜uela-Rolda´n JE, Seoane A, Gonza´lez-Juanatey JR, Garcı´a A (2010) Proteins involved in platelet signaling are differentially regulated in acute coronary syndrome: a proteomic study. PLoS One 5:e13404. doi:10.1371/journal. pone.0013404 21. Cuisset T, Loosveld M, Morange PE, Quilici J, Moro PJ, Saut N, Gaborit B, Castelli C, Beguin S, Grosdidier C, Fourcade L, Bonnet JL, Alessi MC (2012) CYP2C19*2 and *17 alleles have a significant impact on platelet response and bleeding risk in patients treated with prasugrel after acute coronary syndrome. J Am Coll Cardiol Intv 5:1280–1287 22. Franken CC, Kaiser AF, Kruger JC, Overbeck K, Mugge A, Neubauer H (2013) Cytochrome P450 2B6 and 2C9 genotype polymorphism–a possible cause of prasugrel low responsiveness. Thromb Haemost 110:131–140 23. Varenhorst C, James S, Erlinge D, Brandt JT, Braun OO, Man M, Siegbahn A, Walker J, Wallentin L, Winters KJ, Close SL (2009) Genetic variation of CYP2C19 affects both pharmacokinetic and pharmacodynamic responses to clopidogrel but not prasugrel in
24.
25.
26.
27.
28.
29.
30.
31.
32.
aspirin-treated patients with coronary artery disease. Eur Heart J 30:1744–1752 Brandt JT, Close SL, Iturria SJ, Payne CD, Farid NA, Ernest CS 2nd, Lachno DR, Salazar D, Winters KJ (2007) Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost 5(12):2429–2436 Tantry US, Bliden KP, Wei C, Storey RF, Armstrong M, Butler K, Gurbel PA (2010) First analysis of the relation between CYP2C19 genotype and pharmacodynamics in patients treated with ticagrelor versus clopidogrel: the ONSET/OFFSET and RESPOND genotype studies. Circ Cardiovasc Genet 3:556–566 Wallentin L, James S, Storey RF, Armstrong M, Barratt BJ, Horrow J, Husted S, Katus H, Steg PG, Shah SH, Becker RC, Investigators PLATO (2010) Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet 376:1320–1328 Sibbing D, Schulz S, Braun S, Morath T, Stegherr J, Mehilli J, Scho¨mig A, von Beckerath N, Kastrati A (2010) Antiplatelet effects of clopidogrel and bleeding in patients undergoing coronary stent placement. J Thromb Haemost 8(2):250–256 Collet JP, Cuisset T, Range´ G, Cayla G, Elhadad S, Pouillot C, Henry P, Motreff P, Carrie´ D, Boueri Z, Belle L, Van Belle E, Rousseau H, Aubry P, Monse´gu J, Sabouret P, O’Connor SA, Abtan J, Kerneis M, Saint-Etienne C, Barthe´le´my O, Beygui F, Silvain J, Vicaut E, Montalescot G, ARCTIC Investigators (2012) Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med 367(22):2100–2109 Cuisset T, Quilici J, Grosdidier C, Fourcade L, Gaborit B, Pankert M, Molines L, Morange PE, Bonnet JL, Alessi MC (2011) Comparison of platelet reactivity and clopidogrel response in patients B75 years versus [75 years undergoing percutaneous coronary intervention for non-ST-segment elevation acute coronary syndrome. Am J Cardiol 108(10):1411–1416 Silvain J, Cayla G, Hulot JS, Finzi J, Kerneis M, O’Connor SA, Bellemain-Appaix A, Barthe´le´my O, Beygui F, Collet JP, Montalescot G (2012) High on-thienopyridine platelet reactivity in elderly coronary patients: the SENIOR-PLATELET study. Eur Heart J 33(10):1241–1249 Vaturi M, Vaduganathan M, Bental T, Solodky A, Kornowski R, Lev EI (2013) Relation of aspirin response to age in patients with stable coronary artery disease. Am J Cardiol 112(2):212–216 Schulz S, Angiolillo DJ, Antoniucci D, Bernlochner I, Hamm C, Jaitner J, Laugwitz KL, Mayer K, von Merzljak B, Morath T, Neumann FJ, Richardt G, Ruf J, Scho¨mig G, Schu¨hlen H, Schunkert H, Kastrati A, Intracoronary Stenting and Antithrombotic Regimen: rapid Early Action for Coronary Treatment (ISAR-REACT) 5 Trial Investigators (2014) Randomized comparison of ticagrelor versus prasugrel in patients with acute coronary syndrome and planned invasive strategy–design and rationale of the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISARREACT) 5 trial. J Cardiovasc Transl Res 7(1):91–100
123
