Author + information
- Received October 5, 2015
- Revision received November 7, 2015
- Accepted November 8, 2015
- Published online February 16, 2016.
- Dominick J. Angiolillo, MD, PhDa,
- Francesco Franchi, MDa,
- Ron Waksman, MDb,
- Joseph M. Sweeny, MDc,
- Ganesh Raveendran, MDd,
- Renli Teng, PhDe,
- Yonggang Zhao, PhDe,
- Glenn Carlson, MDe,
- Naeem Khan, MDe and
- Roxana Mehran, MDc,∗ ()
- aUniversity of Florida College of Medicine−Jacksonville, Jacksonville, Florida
- bMedStar Washington Hospital Center, Washington, DC
- cIcahn School of Medicine at Mount Sinai, New York, New York
- dUniversity of Minnesota Medical School, Minneapolis, Minnesota
- eAstraZeneca, Wilmington, Delaware
- ↵∗Reprint requests and correspondence:
Dr. Roxana Mehran, Icahn School of Medicine at Mount Sinai, The Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai Medical Center, One Gustave L. Levy Place, Box 1030, New York, New York 10029-6574.
Background Many low-risk acute coronary syndrome (ACS) patients are not pre-treated with a P2Y12 receptor inhibitor, and percutaneous coronary interventions (PCIs) are often performed on an ad hoc basis in this population. Pharmacodynamic (PD) studies comparing ticagrelor versus clopidogrel in patients undergoing ad hoc PCI are lacking.
Objectives This study sought to assess PD effects of ticagrelor versus clopidogrel loading dose (LD) in the peri-procedural period among troponin-negative ACS patients undergoing ad hoc PCI.
Methods This was a prospective, open-label, randomized, multicenter, parallel-group, phase IV PD study. One hundred P2Y12 inhibitor-naïve patients presenting with biomarker-negative ACS and undergoing ad hoc PCI, on a background of aspirin therapy, were randomized to receive either ticagrelor 180 mg LD or clopidogrel 600 mg LD. Platelet reactivity (P2Y12 reaction units [PRU]; VerifyNow assay) was measured at 5 time points: pre-LD, at 0.5, 2, and 8 h post-LD, and at end of PCI. The primary endpoint was PRU levels 2 h post-LD; secondary endpoints included PRU levels at all other time points and inhibition of platelet aggregation; an exploratory analysis evaluated rates of high on-treatment platelet reactivity (HPR) (PRU >208).
Results At 2 h, PRU levels were significantly lower with ticagrelor versus clopidogrel (98.4 ± 95.4 vs. 257.5 ± 74.5; p < 0.001; primary endpoint). PRU levels diverged as early as 0.5 h post-LD, with significant differences observed by the end of PCI (mean 0.6 h post-LD) and maintained up to 8 h post-LD. HPR rates were also significantly reduced with ticagrelor compared with clopidogrel at the end of PCI (p = 0.030), and at 2 h (p < 0.001) and 8 h (p < 0.001) after LD.
Conclusions In low-risk ACS patients undergoing ad hoc PCI, ticagrelor LD provides more prompt and potent platelet inhibition, and lower HPR rates, compared with clopidogrel LD. (Ad Hoc Percutaneous Coronary Intervention Study in Acute Coronary Syndrome Patients: NCT01603082)
- cardiovascular diseases
- coronary artery disease
- platelet aggregation inhibitors
- platelet function tests
- platelet reactivity
Ticagrelor is an oral, direct-acting cyclopentyltriazolopyrimidine antiplatelet agent that binds reversibly to the platelet P2Y12 receptor (1). These characteristics both facilitate rapid onset of platelet inhibition and allow earlier recovery of platelet function compared with clopidogrel (2). The pivotal PLATO (PLATelet inhibition and patient Outcomes) study demonstrated that ticagrelor was more effective than clopidogrel for reduction of ischemic events, including cardiovascular mortality, in patients with acute coronary syndrome (ACS), both ST-segment elevation myocardial infarction (MI) and non−ST-segment elevation (NSTE)-ACS, whether managed conservatively or invasively (3). However, only 17% of ACS patients in PLATO were troponin-negative (i.e., unstable angina). Moreover, in line with practice guideline recommendations at the time of trial design, in the PLATO trial, initiation of P2Y12 receptor–inhibiting therapy was encouraged at the time of clinical presentation, before defining coronary anatomy (3).
Past practice guidelines emphasized the importance of early initiation of P2Y12-inhibiting therapy in ACS patients. More recently, including in the most recent guidelines (4–8), there is less certainty about the benefits of pre-treatment with P2Y12-inhibiting agents. In clinical practice, many patients, particularly those with low-risk, troponin-negative ACS, do not receive early treatment with a P2Y12 inhibitor, which is administered only after defining coronary anatomy (9). Furthermore, more than one-half of all elective percutaneous coronary intervention (PCI) procedures in the United States are performed on an ad hoc basis, immediately after diagnostic coronary angiography (10). This raises the question of the effectiveness of ticagrelor administered at the time of PCI. No previous study has specifically assessed the pharmacodynamic (PD) effects of ticagrelor compared with clopidogrel in patients undergoing ad hoc PCI. Therefore, the aim of the Ad-Hoc PCI Study was to evaluate the effect of ticagrelor versus clopidogrel loading dose (LD) on platelet reactivity in the peri-interventional period among troponin-negative ACS patients undergoing ad hoc PCI.
Study design and patient population
The Ad-Hoc PCI Study (NCT01603082) was a prospective, open-label, randomized, multicenter, parallel-group, phase IV PD study performed at 15 U.S. centers (Online Appendix). After diagnostic angiography, troponin-negative ACS patients undergoing ad hoc PCI were randomly assigned (1:1) to treatment with either ticagrelor 180 mg LD or clopidogrel 600 mg LD (Figure 1). All patients also received an LD of aspirin, as per institutional standards, and then 75 to 100 mg daily. Patients randomized to ticagrelor received a ticagrelor 90-mg maintenance dose 12 ± 1 h after the LD. Afterwards, antiplatelet treatment was left to the discretion of the treating physician. Study drug LD was administered in the catheterization laboratory after defining coronary anatomy and before starting PCI (before the guidewire passed the target lesion). Blood samples for platelet function testing were obtained at 5 time points: immediately before LD, then at 0.5, 2, and 8 h after LD, and at the end of PCI (when the guide catheter was removed at procedure completion). Access site, choice of anticoagulant, stent type, and procedural technique were at the physician’s discretion.
Members of the clinical staff who managed patient care were blinded to the study drug throughout the PCI procedure until final assessment of bleeding, approximately 1 h after sheath removal. Thereafter, the study became open-label, and the investigator could decide which antiplatelet treatment the patient should receive as part of ongoing clinical care. However, clinical staff performing PD assessments remained independent of other study-related activities to ensure that results remained blinded.
Male and female (post-menopausal or surgically sterile) patients who were ≥18 years of age were eligible for inclusion in the study if they had documented troponin-negative NSTE-ACS and were on aspirin as antiplatelet medication. NSTE-ACS was defined as the presence of cardiac ischemic symptoms with ischemic changes (but not ST-segment elevation) on electrocardiogram. However, normal electrocardiograms could be acceptable if the investigator considered an ACS presentation likely. A complete list of study inclusion and exclusion criteria is provided in the Online Appendix.
The study complied with the Declaration of Helsinki and with International Conference on Harmonization/Good Clinical Practice guidelines, and applicable regulatory requirements. Informed consent was obtained and documented for all patients before conducting any study-related procedures.
Platelet function was assessed using the VerifyNow P2Y12 assay (Accriva, San Diego, California). This is a turbidimetric-based optical detection system that measures platelet-induced aggregation as an increase in light transmittance and was used according to manufacturer’s instructions, as previously described (11). The assay reports results in P2Y12 reaction units (PRU). In a separate channel (BASE) of the cartridge, iso-thrombin receptor agonist peptide (TRAP) is used as an agonist, which provides a baseline value for platelet function, enabling assessment of device-defined percentage inhibition of platelet aggregation (IPA), measured as percent inhibition of P2Y12 receptor, without having to wean the patient off antiplatelet treatment.
Sample-size calculation and statistical analysis
The primary endpoint of our study was platelet reactivity 2 h after ticagrelor versus clopidogrel LD, measured as PRU level using VerifyNow. Assuming a standard deviation of 93 PRU on the basis of previous studies (2), a difference of 100 PRU should be detectable between groups with 40 patients, with 90% power and a 2-tailed alpha value of 0.05. However, assuming a potential increase in variability due to administration of study treatment in a supine position (12), a sample size of approximately 100 patients was assumed to be required.
Conformity to the normal distribution was evaluated for continuous variables with the Shapiro-Wilk test. For baseline characteristics, continuous variables are expressed as mean ± SD and categorical variables are expressed as frequencies and percentages. Chi-square tests or Fisher exact tests were used, where appropriate, to compare categorical variables between 2 groups.
Primary analysis of the difference between ticagrelor and clopidogrel in PRU at 2 h was analyzed using a 2-sample Student t test. Treatment level means and 2-sided 95% confidence intervals (CIs) were estimated. Two-sample Student t tests were also used to evaluate other intergroup comparisons. Repeated-measures analysis of variance, taking into account between- and within-subject variations, were conducted to evaluate the impact of the 2 different treatments on platelet reactivity across time points. Secondary endpoints included PRU levels at 0.5 h after dose, end of PCI, and 8 h after dose; percentage reduction from baseline in PRU; and percentage IPA from BASE channel. A key exploratory endpoint was percentage of patients with high on-treatment platelet reactivity (HPR), defined as PRU >208, according to consensus definitions (13). Sensitivity analyses were also performed on the primary endpoint time point (Online Table 1).
The PD population included all patients with PD data and without a major protocol deviation thought to significantly affect PD profiles. Patients with pre-LD PRU <150 were excluded from primary and secondary analyses. Patients with missing pre-dose PRU were included. The PD population was used for analysis of all PD variables. All patients who received at least 1 dose of study drug were included in the safety population. Erroneously treated patients (e.g., those randomized to 1 treatment, but actually given the other) were accounted for on the basis of actual treatment received. Safety was evaluated by assessment of adverse events (including bleeding), serious adverse events, physical examination, and vital signs. Adverse events were collected up to 14 days after completion of the study. Bleeding events were classified according to a modified CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) definition (14) (Online Appendix).
Between July 2012 and June 2014, of 343 patients screened, 100 were randomized to treatment with either ticagrelor (n = 51) or clopidogrel (n = 49) (Figure 2). All were included in the safety population, whereas the PD population consisted of 93 patients, 1 of whom (in the ticagrelor group) was excluded from the analyses because pre-dose PRU was <150. The PD population therefore comprised 92 patients (ticagrelor, n = 45; clopidogrel, n = 47). Baseline characteristics were similar between treatment groups, with the exception of prior coronary artery bypass graft, which was more common in the clopidogrel group (Table 1). Although considered to be at low risk in terms of their ACS diagnosis, the majority of patients had pre-existing cardiovascular risk factors, and more than a quarter of patients had a history of MI or prior PCI.
In the PD population, PRU levels at 2 h after LD were significantly lower with ticagrelor, compared with clopidogrel: 98.4 ± 95.4 versus 257.5 ± 74.5, a treatment difference of –159.1 (95% CI: –194.7 to –123.5; p < 0.001; primary endpoint) (Figure 3, Online Figure 1). Comparable results were achieved in all randomized patients with PRU values available at this time point (Online Table 2). Platelet reactivity across the study time points was overall lower in patients receiving ticagrelor compared with those receiving clopidogrel (p < 0.001). Analysis of PRU levels at the different time points showed a nonsignificant reduction of platelet reactivity at 0.5 h with ticagrelor, compared with clopidogrel. Significant differences (p < 0.05) between the treatment groups were observed at the end-of-PCI measurement (ticagrelor mean 0.6 ± 0.4 h from LD; clopidogrel mean 0.6 ± 0.3 h from LD); significant differences persisted up to the 8-h time point (p < 0.001) (Central Illustration).
Mean percentage reduction from baseline in PRU and mean percent IPA from BASE channel were also significantly greater with ticagrelor versus clopidogrel at the 2-h and 8-h time points (p < 0.001 for both) (Figure 4). In the case of IPA, the difference was statistically significant, even at 0.5 h after LD and at the end of PCI.
Exploratory analysis showed that significantly fewer ticagrelor-treated patients had HPR at the end of PCI (p = 0.030), and at 2 h (p < 0.001) and 8 h (p < 0.001) after LD, compared with clopidogrel-treated patients (Figure 5). Of note, at the 8-h time point, 53.3% of clopidogrel-treated patients still had HPR, compared with only 2.4% of ticagrelor-treated patients. Random-effects analysis of variance tests were performed to study the center effect for PRU at 2 h post-LD; neither center nor center-by-treatment interaction effects were statistically significant.
Complete adverse events and serious adverse events are summarized in Online Table 3. There were no deaths or other adverse events leading to discontinuation of study drug. Three patients in the clopidogrel group (6.1%) had unstable angina versus none in the ticagrelor group; in 1 of these, PCI was performed. Chest pain was documented in 4 patients (7.8%) in the ticagrelor arm and 1 (2.0%) in the clopidogrel arm. Bleeding events considered related to study drug occurred in 4 (7.8%) ticagrelor-treated patients, 2 minor and 2 minimal, and in none of the clopidogrel-treated patients. Dyspnea was reported in 2 (3.9%) patients in the ticagrelor group and 1 (2.0%) in the clopidogrel group.
The present study is the first to compare the PD effects of ticagrelor versus clopidogrel in the setting of a prospective, randomized investigation specifically designed for low-risk troponin-negative ACS patients not pre-treated with a P2Y12 receptor inhibitor and undergoing ad hoc PCI immediately after defining coronary anatomy. Compared with clopidogrel LD, ticagrelor LD was associated with: 1) more prompt platelet inhibitory effects, with significant differences already seen by the end of PCI (0.6 h after LD); 2) more potent antiplatelet effects, with marked differences in absolute levels of platelet reactivity and measures of platelet inhibition at 2 h, which persisted up to 8 h after LD; and 3) reduced rates of HPR, known to be associated with ischemic events in PCI patients, by the end of PCI, with marked differences at 2 and 8 h after LD. Overall, these results confirm the superior PD potency of ticagrelor over clopidogrel and expand upon prior investigations conducted in different clinical settings (2,15–18) (Central Illustration).
Practice guidelines have traditionally advocated the importance of early initiation of P2Y12-inhibiting therapy in ACS patients. However, in recent years, the benefits of pre-treatment with P2Y12-inhibiting therapy have been largely debated, and most recent guidelines also provide less emphasis on timing of initiation of therapy (4–7,9,19,20). Accordingly, practice patterns on early initiation of P2Y12-inhibiting therapy vary across the globe, with patients in the United States less likely to be pre-treated compared with those in Europe (9,10). Indeed, risk of bleeding complications and potential for prolonged hospitalization, particularly in patients requiring surgical revascularization, are reasons for many clinicians to wait to define coronary anatomy before starting a P2Y12 receptor inhibitor. The shorter time frames from clinical presentation to the catheterization laboratory, as well as development of antiplatelet therapies with more prompt and potent effects, have further questioned the need for early initiation of P2Y12-inhibiting therapy (9,21). While early initiation of P2Y12-inhibiting therapy may safeguard patients from ischemic events in the early vulnerable period before and immediately after PCI, these events are less likely to occur in lower-risk settings, such as in troponin-negative ACS patients, as studied in this investigation. It may be argued that the PLATO biomarkers sub-study showed that there was less benefit of ticagrelor in the troponin-negative invasively managed population compared with those who were troponin-positive (22). However, this was a very small subset of the overall population studied (3.5%), and the total number of ischemic events was low, making this analysis underpowered to detect any clinical differences.
In patients undergoing PCI, achieving adequate platelet inhibition in the peri-procedural period is critical to reduce thrombotic complications (6,7). This was recently supported in a large-scale clinical investigation of P2Y12 inhibitor−naïve patients undergoing PCI in which cangrelor, a potent, fast-acting, intravenous P2Y12 inhibitor, was associated with a significant reduction in thrombotic complications compared with clopidogrel, irrespective of clinical indication (stable coronary artery disease, NSTE-ACS, ST-segment elevation−ACS) (23). The same study also showed that the benefit of cangrelor versus clopidogrel was enhanced in troponin-negative patients, even though the p value for interaction was not statistically significant with troponin-positive patients (23). However, that more potent oral P2Y12 receptor inhibitors (ticagrelor or prasugrel), known to have greater ischemic benefit over clopidogrel, were not used as a comparator represents a limitation to these findings (23).
In NSTE-ACS, use of prasugrel is recommended only after defining coronary anatomy, as studied in the TRITON−TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel−Thrombolysis In Myocardial Infarction 38) and ACCOAST (A Comparison of prasugrel at the time of percutaneous Coronary Intervention Or as pre-treatment At the time of diagnosis in patients with non-ST-segment elevation myocardial infarction) trials, whereas upstream administration is not recommended (class III), as this increases the risk of major bleeding complications without ischemic benefit, compared with in-lab treatment (24,25). In the PLATO trial, early initiation of P2Y12-inhibiting therapy was recommended, even before defining coronary anatomy (3). Accordingly, practice guidelines describe the benefits associated with ticagrelor therapy, as studied in PLATO (6,7). However, to date, there are no studies comparing the effectiveness of ticagrelor given upstream versus in-lab in NSTE-ACS. Moreover, there are no data comparing the effects of ticagrelor versus clopidogrel administered only after defining coronary anatomy among patients undergoing ad hoc PCI, which prompted this investigation. Our study was not designed to assess clinical events, but to provide PD data that may be informative for a patient population frequently encountered in clinical practice, but that was not adequately studied in PLATO.
Ticagrelor was confirmed to achieve prompt and potent platelet inhibitory effects. Notably, by the 8-h time point, more than one-half of clopidogrel-treated patients still had HPR, compared with <3% of those in the ticagrelor group. This finding is of potential clinical relevance because HPR status has been strongly associated with an increased risk of stent thrombosis and MI (26). In the ATLANTIC (Administration of Ticagrelor in the Cath Lab or in the Ambulance for New ST Elevation Myocardial Infarction to Open the Coronary Artery) trial, although pre-hospital ticagrelor LD did not improve pre-PCI coronary reperfusion (primary endpoint) compared with in-hospital ticagrelor LD in ST-segment elevation MI patients, it reduced the rates of definite stent thrombosis in the first 24 h and at 30 days (27). The PD sub-study confirmed that between-group differences in platelet inhibition did not begin to appear until after PCI, with maximal difference at 1 h post-PCI. Albeit not statistically significant, due to lack of power in this sub-study, this may contribute to the reduced early stent thrombosis rates, supporting the importance of achieving reduced levels of platelet reactivity after stent implantation (28).
Our study results are in line with and expand upon previous investigations comparing the PD effects of ticagrelor versus clopidogrel in different clinical settings. In patients with stable atherosclerosis not undergoing revascularization, escalating doses of ticagrelor achieved higher levels of platelet inhibition than clopidogrel 75 mg (without an LD), with an effect already evident at 2 h after administration and persistent at 28 days (15). This was confirmed in clopidogrel-naïve patients with NSTE-ACS, where a 270-mg LD of ticagrelor was associated with greater inhibition of adenosine diphosphate (ADP)−induced platelet aggregation at 2 h compared with a 300-mg LD of clopidogrel (16). In the ONSET/OFFSET study, a 180-mg LD of ticagrelor achieved more rapid and greater antiplatelet effects than a 600-mg LD of clopidogrel in patients with stable coronary artery disease (not in the setting of PCI); this was shown as early as 30 min after LD and was sustained during the maintenance phase of treatment (2). Similar findings were shown in the PD sub-study of the PLATO trial, in which a 180-mg LD of ticagrelor in clopidogrel-naïve patients was associated with lower levels of platelet reactivity compared with a 300- to 600-mg LD of clopidogrel at 2 h after administration (17). Pooled analysis of the ONSET/OFFSET and RESPOND (A Randomised, Double-Blind, Outpatient, Crossover Study of the Anti-platelet Effects of Ticagrelor Compared With Clopidogrel in Patients With Stable Coronary Artery Disease Previously Identified as Clopidogrel Non-responders or Responders) studies showed a markedly reduced rate of HPR after ticagrelor LD, compared with clopidogrel LD, as early as 30 min after the dose (18). The PD sub-study of the ACCOAST trial also showed a similar time course for reduction in platelet reactivity in ad hoc PCI patients treated with a 60-mg LD of prasugrel as we observed with ticagrelor in our own study (25). However, a direct comparison of these 2 agents in this clinical context is currently lacking.
Although we observed significant differences between clopidogrel and ticagrelor by the end of PCI in our study, rates of HPR were still high overall. This is also likely to be true in higher-risk ACS settings, such as in ST-segment elevation MI patients, characterized by a delay in onset of platelet inhibitory effects of several hours with oral antiplatelet agents, including ticagrelor and prasugrel, even with use of high-LD regimens (29,30). In this setting, crushing ticagrelor achieves faster platelet inhibition compared with whole tablets (31). Cangrelor may also represent an additional treatment alternative to achieve immediate platelet inhibition (32).
The present study was not designed to assess clinical events. Although reduced rates of HPR, as observed with ticagrelor therapy in this study, have been associated with reduced thrombotic complications, this investigation was not powered for ischemic events. Similarly, the lack of safety issues within our study should be considered as exploratory only. The safety and efficacy of ticagrelor in elective or urgent PCI, including high-risk patients, are currently being tested (NCT02270242). In our study, only thienopyridine-naïve patients were included; whether our results also apply to patients pre-treated with clopidogrel is unknown. In addition, the study did not address the issue of potential need for switching or reloading with P2Y12 inhibitors in some patients (33). Only 1 platelet function assay was used, and additional PD assays would have been useful to corroborate our study findings. Finally, although it is assumed that most patients received opiates in the catheterization laboratory, on the basis of standard local protocols for PCI, details specific to morphine use, such as timing of administration, which may affect absorption of oral antiplatelet agents, were not recorded (30). However, morphine use was low and not significantly different between treatment groups (11.8% vs. 18.4% with ticagrelor and clopidogrel, respectively; p = 0.41).
In low-risk ACS patients undergoing ad hoc PCI and receiving the P2Y12 antagonist immediately after coronary angiography, platelet reactivity was decreased to a greater extent at 2 h after ticagrelor LD, compared with clopidogrel LD, and was maintained up to the 8-h time point. The number of patients with HPR was significantly lower with ticagrelor than with clopidogrel. These results support that ticagrelor LD is more effective than clopidogrel LD for inhibition of platelet reactivity in the peri-intervention period in low-risk, troponin-negative ACS patients undergoing ad hoc PCI.
COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: Current practice guidelines recommend antiplatelet therapy with aspirin and a P2Y12 receptor antagonist for patients with low-risk ACS treated with PCI. In patients with unstable angina, ticagrelor has a more potent and faster antiplatelet effect than clopidogrel, with greater suppression of platelet reactivity 2 h after a loading dose is given following diagnostic coronary angiography and before PCI.
TRANSLATIONAL OUTLOOK: Prospective studies are needed to establish the optimal time to administer P2Y12 receptor antagonists in patients with unstable angina, once the results of diagnostic coronary angiography prompt a decision to perform PCI.
The authors thank the patients who participated in this study, and all the Ad-Hoc PCI Study Principal Investigators not listed as authors for their contributions to the study (Online Appendix).
For supplemental information as well as a table and figure, please see the online version of this article.
This study was supported by AstraZeneca. Medical writing support was provided by Liz Anfield, PrimeMedica Ltd., Knutsford, Cheshire, UK; and was funded by AstraZeneca.
Dr. Angiolillo has received consulting fees or honorarium from Sanofi, Eli Lilly, Daiichi-Sankyo, The Medicines Company, AstraZeneca, Merck, Abbott Vascular, and PLx Pharma; participated in review activities from CeloNova, Johnson & Johnson, and St. Jude Medical; and has received institutional payments for grants from GlaxoSmithKline, Eli Lilly, Daiichi-Sankyo, The Medicines Company, AstraZeneca, Janssen Pharmaceuticals, Inc., Osprey Medical, Inc., Novartis, CSL Behring, and Gilead. Dr. Waksman has received consulting fees or honoraria from AstraZeneca, Abbott Vascular, Boston Scientific, Medtronic Vascular, Biotronik, and Biosensors; and received institutional payments for investigator grants from AstraZeneca, Boston Scientific, Edwards Life Sciences, Medtronic Vascular, Biotronik, Biosensors, and Infraredx. Dr. Zhao is a consultant to AstraZeneca. Drs. Carlson, Teng, and Khan are employees of AstraZeneca. Dr. Mehran has received research grants from DSI/Eli Lilly, Bristol-Myers Squibb/Sanofi-Aventis, AstraZeneca, and The Medicines Company; and consulting or advisory board fees from AstraZeneca, CSL Behring, Janssen Pharmaceuticals, Inc., and Osprey Medical, Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Robert F. Storey, BM, DM, served as Guest Editor for this paper.
- Abbreviations and Acronyms
- acute coronary syndrome
- high on-treatment platelet reactivity
- inhibition of platelet aggregation
- loading dose
- non-ST–segment elevation acute coronary syndrome
- percutaneous coronary intervention
- P2Y12 reaction units
- Received October 5, 2015.
- Revision received November 7, 2015.
- Accepted November 8, 2015.
- 2016 American College of Cardiology Foundation
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