Author + information
- Received June 7, 2014
- Revision received August 4, 2014
- Accepted August 26, 2014
- Published online December 23, 2014.
- Gilles Montalescot, MD, PhD∗∗ (, )
- Jean-Philippe Collet, MD, PhD∗,
- Patrick Ecollan, MD†,
- Leonardo Bolognese, MD‡,
- Jurrien ten Berg, MD, PhD§,
- Dariusz Dudek, MD, PhD‖,
- Christian Hamm, MD¶,
- Petr Widimsky, MD, DrSc#,
- Jean-François Tanguay, MD∗∗,
- Patrick Goldstein, MD††,
- Eileen Brown, PhD‡‡,
- Debra L. Miller, RN, RCIS‡‡,
- LeRoy LeNarz, MD‡‡,
- Eric Vicaut, MD, PhD§§,
- ACCOAST Investigators
- ∗ACTION Study Group, Institut de Cardiologie, UPMC Université Paris 6, INSERM UMRS-1166 Paris, Centre Hospitalier Universitaire Pitié-Salpêtriėre (AP-HP), Paris, France
- †ACTION Study Group, SMUR, Centre Hospitalier Universitaire Pitié-Salpêtriėre (AP-HP), Paris, France
- ‡Cardiovascular and Neurological Department, Azienda Ospedaliera, Arezzo, Italy
- §Department of Cardiology, St. Antonius Hospital, Nieuwegein, the Netherlands
- ‖Institute of Cardiology, Jagiellonian University Medical College, University Hospital, Krakow, Poland
- ¶Kerckhoff Heart and Thoraxcenter, Bad Nauheim and Medical Clinic I, University of Giessen, Giessen, Germany
- #Third Medical Faculty of Charles University and University Hospital Royal Vineyards, Prague, Czech Republic
- ∗∗Montreal Heart Institute, Montreal, Quebec, Canada
- ††SAMU and Emergency Department, Lille University Hospital, Lille, France
- ‡‡Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana
- §§ACTION Study Group, Methodology and Statistical Unit, Centre Hospitalier Universitaire Lariboisière (AP-HP), Université Paris 7, Paris, France
- ↵∗Reprint requests and correspondence:
Dr. Gilles Montalescot, Institut de Cardiologie, Pitié-Salpêtriėre University Hospital, 47, Boulevard de l’Hôpital, 75013 Paris, France.
Background After percutaneous coronary intervention (PCI) for non–ST-segment elevation myocardial infarction (NSTEMI), treatment with a P2Y12 antagonist with aspirin is recommended for 1 year.
Objectives The oral P2Y12 antagonists ticagrelor and prasugrel have higher recommendations than clopidogrel, but it is unknown if administration before the start of PCI is beneficial.
Methods In the randomized, double-blind 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) trial, 4,033 patients were diagnosed with NSTEMI and 68.7% underwent PCI; 1,394 received pre-treatment with prasugrel (30-mg loading dose), and 1,376 received placebo. At the time of PCI, patients who received pre-treatment with prasugrel received an additional 30-mg dose of prasugrel, and those who received placebo received a 60-mg loading dose of prasugrel. Primary efficacy was a composite of cardiovascular death, myocardial infarction, stroke, urgent revascularization, or glycoprotein IIb/IIIa bailout through 7 days from randomization. Investigators captured the presence of thrombus on initial angiography and during PCI.
Results The incidence of the primary endpoint through 7 days from randomization in the pre-treatment group versus the no pre-treatment group was 13.1% versus 13.1% (p = 0.93). Pre-treatment with prasugrel was not associated with decreases in any ischemic event, including total mortality. Patients with thrombus on angiography had a 3-fold higher incidence of the primary endpoint than patients without thrombus. There was no impact of pre-treatment with prasugrel on the presence of thrombus before PCI or on occurrence of stent thrombosis after PCI. There was a 3-fold increase in all non–coronary artery bypass graft Thrombolysis In Myocardial Infarction (TIMI) major bleeding and a 6-fold increase in non–coronary artery bypass graft life-threatening bleeding with pre-treatment with prasugrel; the same trends persisted in patients who had radial or femoral access even with use of a closure device.
Conclusions These findings support deferring treatment with prasugrel until a decision is made about revascularization in patients with NSTEMI undergoing angiography within 48 h of admission. (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 [ACCOAST]; NCT01015287)
Optimal antiplatelet therapy is necessary in patients undergoing percutaneous coronary intervention (PCI), although the intensity of treatment and timing of administration are not well defined and may vary according to the clinical presentation. Pre-treatment is defined as treatment administered before coronary angiography. Coronary angiography confirms the diagnosis, defines the coronary status, and provides an indication of the need for revascularization. The main goal of pre-treatment is effective platelet inhibition for patients who require PCI, which is generally performed immediately after coronary angiography. The downside of a systematic strategy of pre-treatment is that it can cause a high level of platelet inhibition in patients who need emergent coronary artery bypass graft (CABG) surgery or unnecessarily increase the risk of bleeding in patients who do not require any intervention.
In the contemporary era, in which patients have rapid access to the catheterization laboratory, randomized studies of pre-treatment strategies have failed to show a reduction of ischemic events and have reported serious safety issues when compared with strategies of selecting the same antiplatelet therapy once coronary angiography has been performed. This was shown with upstream glycoprotein (GP) inhibitors in non–ST-segment elevation acute coronary syndromes (NSTE-ACS) in the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) and EARLY-ACS (Early Glycoprotein IIb/IIIa Inhibition in Non–ST-Segment Elevation Acute Coronary Syndrome) trials, leading to a class III recommendation for pre-treatment with GP inhibitors in patients with NSTE-ACS (1,2). The deleterious effects of pre-treatment were also shown with clopidogrel in randomized studies evaluating stable or stabilized patients, leading to a class III recommendation for pre-treatment with clopidogrel in these patients (3–6). No randomized studies have evaluated routine pre-treatment versus no pre-treatment with clopidogrel or ticagrelor and invasive management in patients with NSTE-ACS. In contrast, pre-treatment with prasugrel was evaluated with patients with NSTE-ACS scheduled to undergo catheterization in the randomized, double-blind 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) trial, which revealed no additional efficacy benefit with routine pre-treatment with prasugrel compared with selective use of prasugrel at the time of PCI but showed an increase in the rate of major bleeding complications (7).
Intracoronary thrombus and thrombotic complications during PCI, in particular in patients with acute coronary syndrome, have been a concern and have led to the concept of pre-treatment with clopidogrel, a drug with a delayed onset of action (8). Although this strategy makes sense for patients undergoing PCI, it was never demonstrated in patients with NSTE-ACS who were invasively managed within 48 h of admission, as performed in contemporary practice. The ACCOAST-PCI study was a unique opportunity to evaluate this concept in the modern era, in which patients have rapid access to the catheterization laboratory, frequent radial access, and access to drug-eluting stents with modern pharmacological therapy, including prasugrel.
The ACCOAST-PCI study prospectively evaluated 2,770 patients undergoing PCI who were randomized to double-blind therapy with prasugrel or placebo at 171 centers in 19 countries (7). The inclusion and exclusion criteria for the ACCOAST trial have been described previously (7,9). Briefly, patients were eligible for inclusion if they had a diagnosis of NSTE-ACS with an elevated troponin level. Randomization was to take place as soon as possible after diagnosis and before the patients received a loading dose of clopidogrel or any dose of prasugrel or ticagrelor. Patients were to be scheduled to undergo coronary angiography within 2 to 48 h from randomization. The ACCOAST study design pre-specified the prospective capture on a specific part of the case report form and the presence of thrombus during the procedure, and additional analyses were performed in relationship to clinical outcomes.
In addition to aspirin, patients were randomly assigned to receive either prasugrel or matching placebo once admitted to the study site with a diagnosis of non–ST-segment elevation myocardial infarction (NSTEMI). In the pre-treatment arm, patients received a 30-mg loading dose of prasugrel and an additional 30-mg dose of prasugrel at the time of PCI once angiography confirmed the indication for PCI. In the no pre-treatment arm, the approved 60-mg loading dose of prasugrel was administered after angiography at the time of PCI.
The first open-label maintenance dose of prasugrel was administered 18 to 24 h after PCI. Patients received a 10-mg daily maintenance dose of prasugrel in combination with aspirin through the follow-up visit at 30 days. In patients who were 75 years of age or older and/or had body weight <60 kg, a 5-mg daily maintenance dose of prasugrel was administered.
We routinely screened for periprocedural increases in cardiac enzyme concentrations every 8 h over the first 24 h after PCI. Definitions of myocardial infarction used creatine kinase or creatine kinase-myocardial bands and depended on the clinical timing of the event in relation to the timing of the index event and PCI procedures (9). The definition of urgent revascularization was driven by recurrent signs of ischemia occurring after completion of PCI, leading to a new emergent revascularization (PCI or CABG surgery) of either the vessel dilated at the initial procedure or a vessel not initially dilated. The unplanned use of a GP IIb/IIIa inhibitor while waiting for coronary angiography/PCI, during PCI, or within 24 h after PCI was considered bailout. Investigators documented planned use of a GP IIb/IIIa inhibitor once randomization occurred or before PCI, and this was not considered a GP IIb/IIIa inhibitor bailout endpoint. If Thrombolysis In Myocardial Infarction (TIMI) flow grade 0 to 1 was identified during initial coronary angiography and before PCI that required use of a GP IIb/IIIa inhibitor, a GP IIb/IIIa inhibitor bailout endpoint was reported. Reasons for use of GP IIb/IIIa inhibitor bailout were recorded by the sites, and all cases of GP IIb/IIIa inhibitor bailout were adjudicated.
The primary endpoint was time to first occurrence of cardiovascular death, myocardial infarction, stroke, urgent revascularization, or GP IIb/IIIa inhibitor bailout through 7 days from randomization. Safety endpoints of TIMI major and minor bleeding were evaluated as not related to CABG surgery and all bleeding. Bleeding complications also were adjudicated according to STEEPLE (Safety and Efficacy of Enoxaparin in PCI) definitions (9). An independent endpoint adjudication committee adjudicated the endpoints.
Comparisons of efficacy were performed on the basis of time to first event, according to intention-to-treat principle (Online Appendix). Safety analyses were performed on all patients who took at least one dose of study drug. Primary efficacy analysis was on the basis of time from randomization to the first occurrence of the primary composite endpoint on the basis of a 2-sided log-rank test. Time-to-event analyses for efficacy and safety outcomes were performed through 7 and 30 days from randomization. Rates are expressed as Kaplan-Meier estimates. An estimated hazard ratio (HR) and 95% confidence interval (CI) were obtained from a Cox proportional hazards model, and a 2-sided p value was obtained by the log-rank test. A p value for efficacy and safety was considered statistically significant when <0.05. Comparisons between patients with and without thrombus on angiography were performed for efficacy outcomes. Additionally, a multivariate stepwise Cox proportional hazards model was performed for the primary efficacy outcome and TIMI major or minor bleeding to investigate which characteristics were independently associated with these outcomes.
Overall, 2,770 of the 4,033 patients (68.7%) in the ACCOAST trial underwent PCI through 7 days from randomization. Of these, 1,394 patients were assigned to pre-treatment with prasugrel and 1,376 patients were assigned to placebo at baseline. No patients were lost to follow-up (Figure 1). The median delay between randomization and PCI was 4.25 h. The 2 groups were balanced with respect to baseline characteristics (Online Table 1). By study design, all patients had an increase in troponin level at randomization; 33% of patients in both the prasugrel pre-treatment group and no prasugrel pre-treatment group had initial troponin levels ≥3 and <10 times the upper limit of normal, and 51% of patients in both the prasugrel pre-treatment group and no prasugrel pre-treatment group had initial troponin levels ≥10 times the upper limit of normal. Radial access was preferred in 43% of the PCI cohort. Among the patients who had femoral access, a closure device was used in 40%. The characteristics reflect a population that was enrolled before coronary angiography; 4% had left main PCI, 38% had multivessel PCI, 10% had dilation of the 3 vessels, and 13% had long lesions, defined as more than 30 mm of stents. Drug-eluting stents were used most of the time. Importantly, a thrombus was angiographically noted before the start of PCI in 20% and 22% of patients with and without pre-treatment with prasugrel, respectively (p = 0.21). The preferred anticoagulants were unfractionated and low-molecular-weight heparins. Planned and unplanned GP IIb/IIIa inhibitor therapy was used in 15% of patients, with only 5.2% in the prasugrel pre-treatment group and 5.5% in the no prasugrel pre-treatment group in bailout situations (not significant between groups). The duration of the PCI procedure was similar in both groups.
The incidence of the primary endpoint through 7 days from randomization was not different between the prasugrel pre-treatment group and the no prasugrel pre-treatment group (13.1% vs. 13.1%; p = 0.93) (Table 1). The main secondary endpoint of cardiovascular death, myocardial infarction, or stroke did not differ between the 2 groups (Central Illustration, Table 1). Pre-treatment with prasugrel was not associated with a decrease in any ischemic event, including total mortality and stent thrombosis (Table 1).
Bailout use of GP IIb/IIIa inhibitors was infrequent (5% of patients) and did not differ between the 2 randomized groups (Table 1). Four of those 10 patients received GP IIb/IIIa inhibitors because of a slow flow before PCI was started, and the other 6 patients received GP IIb/IIIa inhibitors because of a slow flow or another complication during PCI. There was no difference between the prasugrel pre-treatment group and the no prasugrel pre-treatment group regarding the use of GP IIb/IIIa inhibitors either before or during PCI. The reasons for bailout use of GP IIb/IIIa inhibitors are reported in Online Table 2.
The baseline characteristics of patients with and without thrombus on angiography are shown in Online Table 3 and do not appear to differ. However, patients who had thrombus on angiography had a 3-fold higher incidence of 7-day and 30-day primary endpoints than patients without thrombus on angiography (Online Table 4). Surprisingly, there was no impact on the rate of definite or probable stent thrombosis in patients with thrombosis seen on angiography versus patients with thrombus not seen on angiography (Online Table 4). The results of the multivariate analysis indicated that thrombus on angiography was highly predictive of the primary efficacy outcomes (HR: 2.61 [95% CI: 2.09 to 3.25]; p < 0.001), adjusting for all other known significant predictors. Additional significant predictors included length of procedure (HR: 1.88 [95% CI: 1.49 to 2.36]; p < 0.001), number of lesions (HR: 1.24 [95% CI: 1.10 to 1.39]; p < 0.001), maximum length of stent (HR: 1.19 [95% CI: 1.04 to 1.35]; p = 0.005), and CRUSADE risk score (HR: 1.01 [95% CI: 1.00 to 1.02]; p = 0.023) (for every 1-point increase in CRUSADE risk score, the risk increases 1%) but not other baseline demographic and clinical characteristics or GRACE score.
The incidence of TIMI major bleeding through 7 days from the first loading dose was significantly higher with pre-treatment with prasugrel (Table 2); this was also true for TIMI major or minor bleeding (Central Illustration, Table 2). There was a 3-fold increase in non-CABG major bleeding and a 6-fold increase in non-CABG life-threatening bleeding events (Table 2). The most common locations of TIMI major bleeding through 7 days were vascular access sites (n = 9), gastrointestinal (n = 5), pericardial (n = 4), and retroperitoneal (n = 4). The incidence of TIMI minor bleeding events was also increased with pre-treatment with prasugrel (28 [2.01%] vs. 9 [0.65%]). Through 30 days, there were no additional vascular access site or retroperitoneal TIMI major bleeds, but there were 4 additional gastrointestinal bleeds and an additional pericardial major bleed. Rates of total transfusions were significantly higher in patients who received pre-treatment with prasugrel at 7 and 30 days (Table 2).
Rates of TIMI major bleeding were higher in patients who received pre-treatment with prasugrel with both radial and femoral access. Through 7 days, TIMI major bleeding events in patients with radial access were numerically higher with pre-treatment with prasugrel (4 vs. 1; HR: 3.82 [95% CI: 0.43 to 34.15]; p = 0.197). Through 7 days, TIMI major or minor bleeding events in patients with radial access was also numerically higher with pre-treatment with prasugrel (7 [1.15%] vs. 2 [0.34%]; HR: 3.35 [95% CI: 0.70 to 16.10]; p = 0.109). Through 7 days, TIMI major bleeding events in patients with femoral access and use of a closure device were numerically higher with pre-treatment with prasugrel (6 vs. 2; p = 0.180). Through 7 days, TIMI major or minor bleeding events in patients with femoral access and a closure device were higher with pre-treatment with prasugrel (18 [5.84%] vs. 3 [1.03%]; HR: 5.81 [95% CI: 1.71 to 19.7]; p = 0.001). Fourteen of the 18 TIMI major or minor bleeding locations were at the vascular access site or retroperitoneal. Through 7 days, TIMI major bleeding events in patients with femoral access and without a closure device were numerically higher with pre-treatment with prasugrel (9 [1.90%] vs. 4 [0.80%]; HR: 2.40 [95% CI: 0.74 to 7.79]; p = 0.132). TIMI major or minor bleeding events in patients with femoral access without a closure device were higher with pre-treatment with prasugrel (22 [4.65%] vs. 11 [2.20%]; HR: 2.16 [95% CI: 1.05 to 4.45]; p = 0.033). Thirteen of the 22 TIMI major or minor bleeding events with pre-treatment with prasugrel were at the vascular access site or retroperitoneal bleeding. Multivariate analysis for TIMI major bleeding identified femoral (vs. radial) access (HR: 3.01 [95% CI: 1.13 to 8.00]; p = 0.027) and treatment group (HR: 2.77 [95% CI: 1.16 to 6.60]; p = 0.022) as the 2 strongest independent correlates of bleeding complications.
Patients with NSTEMI who are undergoing PCI theoretically represent the ideal population for pre-treatment with a P2Y12 antagonist because they have a thrombotic index event, their coronary anatomy is defined, and they have an indication of coronary stenting with dual antiplatelet therapy. However, our study showed that there was no additional benefit with pre-treatment with prasugrel compared with administration of prasugrel at the time of PCI to reduce the ischemic primary and main secondary endpoints in the NSTEMI population. Moreover, earlier administration of prasugrel was not associated with less thrombus burden at the time of the procedure, less stent thrombosis, or less urgent revascularization and did not decrease the use of GP inhibitors, which remained low in this double-blind study. In contrast, pre-treatment with prasugrel caused a significant excess of major bleeding complications, a risk not eliminated by radial access or the use of a closure device after femoral access. Pre-treatment with prasugrel was a strong correlate of major bleeding and major or minor bleeding independently of other variables, including vascular access.
The concept of pre-treatment with P2Y12 antagonists in patients with NSTE-ACS comes from the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) study, in which patients were managed conservatively with a further benefit suggested in the subgroup of 21% of patients who underwent PCI with or without stent implantation on average 6 days after randomization (10,11). The PCI meta-analysis, on the basis of the subsets of 2 randomized studies performed 15 years ago, showed a 22% relative risk reduction of major adverse cardiac events balanced with a 28% relative increase in major bleeding and no mortality benefit (5). Therefore, the potential benefit of pre-treatment with clopidogrel in patients with NSTE-ACS undergoing PCI is difficult to claim from these data and even more difficult to extend to modern practice, in which most patients are rapidly and invasively managed. The PCI cohort of patients enrolled in the ACCOAST study was a pre-specified subgroup that reflects modern practice of management of acute coronary syndrome, including early revascularization, and was larger than the PCI-CURE (Percutaneous Coronary Intervention in the Clopidogrel in Unstable Angina to Prevent Recurrent Events) cohort. Indeed, our patients were rapidly managed in the catheterization laboratory, with large use of radial access and closure devices; significant numbers of long lesions, left main, and multivessel stenting; and treatment with a predominance of drug-eluting stents. Although patients could undergo angiography up to 48 h from randomization, the median time to angiography was shorter, which is similar to what has been observed in contemporary studies of acute coronary syndrome (12–16).
The ACCOAST investigators noted prospectively the presence of thrombus on angiography because they were blinded to study drug, and 21% of patients were found to have an intracoronary thrombus. Visually, there was no patient characteristic, including the GRACE score or any coronary characteristic, that was predictive of the presence of thrombus in these patients who had a significant increase in troponin levels at admission. Pre-treatment with prasugrel did not reduce the presence of thrombus before the start of the PCI procedure and did not reduce the thrombotic complications during the procedure. However, the angiographic presence of thrombus drove the use of GP inhibitors (8-fold increase) and was associated with more frequent urgent revascularization (3-fold increase), more frequent myocardial infarctions (50% increase), and altogether a 2.5-fold increase in the incidence of the primary endpoint.
The multivariate analysis of the primary efficacy outcome concludes that lesion- or stent-related characteristics predict outcome, and the presence of thrombus was the stronger variable in this model. The ACCOAST study reinforces the role of angiography to diagnose NSTEMI, indicate the need for PCI, and avoid pre-treatment with prasugrel when it is not required. The ACCOAST-PCI study shows that there is no downside in waiting to provide prasugrel until after coronary angiography in patients who will need dual antiplatelet therapy for stenting. The angiogram provides additional information on the risk of the procedure and the prognosis for these patients. Although PCI was performed in patients who had an increase in troponin levels, with frequent long or multiple lesions and a high rate of thrombus-containing lesions, the rate of GP IIb/IIIa inhibitor use remained low and stent thrombosis was infrequent in both arms. This suggests that the strategy of prasugrel loading after angiography is not only safer but also effective in this population.
Although our study was pre-specified, its limitations include the fact that the original effects of randomization at entry into the trial are no longer present for the cohort of patients who have undergone PCI. To alleviate this issue, we presented the baseline characteristics of the patients, which were well balanced between the 2 groups. Moreover, it would be practically impossible to perform a randomized study of pre-treatment only in patients undergoing PCI, knowing that more than 90% of patients undergo ad-hoc PCI (in the same setting as angiography). Another limitation is the time frame from randomization to PCI (2 to 48 h), and our results apply only to patients with rapid access to the catheterization laboratory. The negative results from pre-treatment with prasugrel in the NSTEMI population in the ACCOAST study cannot be applied to the ST-segment elevation myocardial infarction population. The ATLANTIC (A 30 Day Study to Evaluate Efficacy and Safety of Pre-hospital vs. In-hospital Initiation of Ticagrelor Therapy in STEMI Patients Planned for Percutaneous Coronary Intervention [PCI]) trial (NCT01347580) will provide answers to the question of the use of pre-hospital treatment with a P2Y12 inhibitor in the ST-segment elevation myocardial infarction population (17). Finally, whether our conclusions can be extended to other oral P2Y12 antagonists will remain a matter of debate because no similar study has been performed in the same conditions with ticagrelor or clopidogrel. Considering the recent reappraisal of pre-treatment with clopidogrel, we advise caution with pre-treatment.
In patients with NSTEMI, our data support deferring a loading dose of prasugrel until a decision is made about revascularization. This strategy allows flexibility in the management of patients by providing prasugrel, with its rapid onset of action, to patients who proceed to PCI without risking bleeding complications in patients who do not proceed to PCI.
COMPETENCY IN MEDICAL KNOWLEDGE: Patients with NSTEMI and a thrombus burden face increased rates of adverse events compared with those without a thrombus burden.
COMPETENCY IN PATIENT CARE: Patients with NSTEMI face an increased risk of bleeding when pre-treated with a rapid-onset P2Y12 platelet inhibitor.
TRANSLATIONAL OUTLOOK: These results support delaying a loading dose of prasugrel until a decision is made about revascularization because of increases in all non-CABG major and life-threatening TIMI bleeding events without reduction of ischemic events associated with pre-treatment with prasugrel in patients with NSTEMI.
The trial was sponsored by Daiichi Sankyo Co., Ltd., and Eli Lilly and Company, and the coordinating center was the ACTION Study Group at the Institute of Cardiology of Pitié-Salpêtrière Hospital. Data were collected, managed, and analyzed by a clinical research organization contracted by the sponsors according to the protocol and a pre-defined statistical analysis plan.
Dr. Montalescot has received consulting fees from Bayer, Boehringer Ingelheim, CFR, Europa, GLG, Iroko Cardio International, Lead-Up, LLC, Luminex, McKinsey, Remedica, Servier, TIMI Group, WebMD, and Wolters; consulting fees and grant support from Bristol-Myers Squibb, AstraZeneca, Biotronik, Eli Lilly, The Medicines Company, Medtronic, Menarini, Sanofi, Pfizer, and Accumetrics; and grant support from Abbott Vascular, Daiichi Sankyo, Nanospheres, and Stentys. Dr. Collet has received research grants from Bristol-Myers Squibb, Sanofi, Eli Lilly, Guerbet Medical, Medtronic, Boston Scientific, Cordis, Stago, Centocor, Fondation de France, INSERM, Fédération Française de Cardiologie and Société Française de Cardiologie; consulting fees from Sanofi, Eli Lilly, and Bristol-Myers Squibb; and lecture fees from Bristol-Myers Squibb, Sanofi, and Eli Lilly.
Dr. Bolognese has received fees for board membership from Daiichi Sankyo and Eli Lilly; consulting fees from Daiichi Sankyo; and lecture fees from Daiichi Sankyo, Eli Lilly, Menarini, Abbott, AstraZeneca, and Iroko Cardio International. Dr. ten Berg has received fees for board membership from AstraZeneca; consulting fees from AstraZeneca, Eli Lilly, and Merck; and lecture fees from AstraZeneca and Eli Lilly. Dr. Dudek has received consulting and lecture fees from Abbott, Adamed, Adyton Medical Polska, Abiomed Europe, AstraZeneca, Biotronik, Balton, Bayer, Braun, BioMatrix, Boston Scientific, Boehringer Ingelheim, Bracco, Bristol-Myers Squibb, Comesa Polska, Cordis, Cook, Covidien Polska, DRG MedTek, Eli Lilly, EuroCor, Hammermed, GE Healthcare, GlaxoSmithKline, Inspire-MD, Iroko Cardio International, Medianet, Medtronic, The Medicines Company, Meril Life Sciences, Merck Sharp & Dohme, Orbus-Neich, Pfizer, Possis, ProCardia Medical, Promed, REVA Medical, Sanofi, Siemens, Solvay, Stentys, St. Jude Medical, Terumo, Tyco, and Volcano. Dr. Hamm has received payment for board membership from AstraZeneca, Medtronic, and Boehringer Ingelheim; consulting and lecture fees from Medtronic, Boehringer Ingelheim, Eli Lilly, The Medicines Company, Abbott Vascular, Bayer, Sanofi, Boston Scientific, Correvio, Roche Diagnostics, Pfizer, Cordis, Daiichi Sankyo, and GlaxoSmithKline; and lecture fees from AstraZeneca and Merck. Dr. Widimsky has received consulting and lecture fees from Eli Lilly and Daiichi Sankyo. Dr. Tanguay has received consulting fees from Eli Lilly, AstraZeneca, Abbott Vascular, Roche, and GlaxoSmithKline; lecture fees from Sanofi, Eli Lilly, AstraZeneca, Abbott Vascular, Pfizer, and Bristol-Myers Squibb; and grant support from Eli Lilly, AstraZeneca, Roche, Hexacath, Ikaria, Abbott Vascular, GlaxoSmithKline, Roche, and Sanofi. Dr. Goldstein has received fees for board membership from Boehringer Ingelheim, The Medicines Company, and Daiichi-Sankyo; consulting fees from Boehringer Ingelheim, Bayer, Sanofi, and AstraZeneca; lecture fees from Boehringer Ingelheim, The Medicines Company, Daiichi-Sankyo, Bayer, Sanofi, and AstraZeneca; payment for the development of educational presentations from Boehringer Ingleheim and AstraZeneca; and travel support from Boehringer Ingelheim, Daiichi-Sankyo, and Sanofi. Dr. Brown, Ms. Miller, and Dr. LeNarz are employees of and hold stock in Eli Lilly. Dr. Vicaut has received fees for board membership from CERC; consulting fees from Eli Lilly, Novartis, Pfizer, Sanofi, LFB, Abbott, Fresenius, Medtronic, and Hexacath; lecture fees from Novartis; and grant support from Sanofi, AstraZeneca, and Boehringer Ingelheim. Dr. Ecollan has reported that he has no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- coronary artery bypass graft
- confidence interval
- hazard ratio
- non–ST-segment elevation acute coronary syndrome
- non–ST-segment elevation myocardial infarction
- percutaneous coronary intervention
- Thrombolysis In Myocardial Infarction
- Received June 7, 2014.
- Revision received August 4, 2014.
- Accepted August 26, 2014.
- American College of Cardiology Foundation
- Widimsky P.,
- Motovská Z.,
- Simek S.,
- et al.,
- PRAGUE-8 Trial Investigators
- Di Sciascio G.,
- Patti G.,
- Pasceri V.,
- Colonna G.,
- Montinaro A.,
- ARMYDA-5 PRELOAD Investigators
- Bellemain-Appaix A.,
- O'Connor S.A.,
- et al.,
- ACTION Group
- Hamm C.W.,
- Bassand J.P.,
- Agewall S.,
- et al.,
- ESC Committee for Practice Guidelines
- Goto K.,
- Lansky A.J.,
- Nikolsky E.,
- et al.
- Montalescot G.,
- Bolognese L.,
- Dudek D.,
- et al.
- Yusuf S.,
- Zhao F.,
- Mehta S.R.,
- Chrolavicius S.,
- Tognoni G.,
- Fox K.,
- Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators
- Mehta S.R.,
- Yusuf S.,
- Peters R.J.,
- et al.,
- Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators
- Cannon C.P.,
- Harrington R.A.,
- James S.,
- et al.,
- PLATelet inhibition and patient Outcomes Investigators
- Montalescot G.,
- Lassen J.F.,
- Hamm C.W.,
- et al.