Author + information
- Received May 1, 2013
- Accepted October 1, 2013
- Published online March 25, 2014.
- David J. Whellan, MD∗∗ (, )
- Pierluigi Tricoci, MD, PhD†,
- Edmond Chen, MD‡,
- Zhen Huang, MS†,
- David Leibowitz, MD§,
- Pascal Vranckx, MD‖,
- Gregary D. Marhefka, MD∗,
- Claes Held, MD, PhD¶,
- Jose C. Nicolau, MD, PhD#,
- Robert F. Storey, MD, DM∗∗,
- Witold Ruzyllo, MD††,
- Kurt Huber, MD‡‡,
- Peter Sinnaeve, MD, PhD§§,
- A. Teddy Weiss, MD§,
- Jean-Pierre Dery, MD‖‖,
- David J. Moliterno, MD¶¶,
- Frans Van de Werf, MD§§,
- Philip E. Aylward, MD##,
- Harvey D. White, DSc∗∗∗,
- Paul W. Armstrong, MD†††,
- Lars Wallentin, MD, PhD¶,
- John Strony, MD‡,
- Robert A. Harrington, MD‡‡‡ and
- Kenneth W. Mahaffey, MD‡‡‡
- ∗Division of Cardiology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania
- †Duke Clinical Research Institute, Durham, North Carolina
- ‡Merck Sharp & Dohme Corp., Whitehouse Station, New Jersey
- §Heart Institute, Hadassah–Hebrew University Medical Center, Jerusalem, Israel
- ‖Thoraxcentre, Rotterdam, the Netherlands
- ¶Department of Medical Sciences, Uppsala Clinical Research Center, Uppsala, Sweden
- #Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil
- ∗∗Department of Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom
- ††Department of Coronary Artery Disease and Cardiac Catheterization Laboratory, Institute of Cardiology, Warsaw, Poland
- ‡‡3rd Department of Medicine, Cardiology and Emergency Medicine, Wilhelminen Hospital, Vienna, Austria
- §§Department of Cardiology, University of Leuven, Leuven, Belgium
- ‖‖Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec City, Québec, Canada
- ¶¶Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky, Lexington, Kentucky
- ##South Australian Health and Medical Research Institute, Flinders University and Medical Centre, Adelaide, Australia
- ∗∗∗Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand
- †††Division of Cardiology, University of Alberta, Edmonton, Alberta, Canada
- ‡‡‡Department of Medicine, Stanford University, Stanford, California
- ↵∗Reprint requests and correspondence:
Dr. David J. Whellan, Division of Cardiology, Thomas Jefferson University Hospital, 1015 Chestnut Street, Suite 317, Philadelphia, Pennsylvania 19107.
Objectives This study evaluated effects of protease-activated receptor-1 antagonist vorapaxar (Merck, Whitehouse Station, New Jersey) versus placebo among the TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) study patients with non–ST-segment elevation acute coronary syndromes undergoing coronary artery bypass grafting (CABG).
Background Platelet activation may play a key role in graft occlusion, and antiplatelet therapies may reduce ischemic events, but perioperative bleeding risk remains a major concern. Although the TRACER study did not meet the primary quintuple composite outcome in the overall population with increased bleeding, an efficacy signal with vorapaxar was noted on major ischemic outcomes, and preliminary data suggest an acceptable surgical bleeding profile. We aimed to assess efficacy and safety of vorapaxar among CABG patients.
Methods Associations between treatment and ischemic and bleeding outcomes were assessed using time-to-event analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the Cox hazards model. Event rates were estimated using the Kaplan-Meier method.
Results Among 12,944 patients, 1,312 (10.1%) underwent CABG during index hospitalization, with 78% on the study drug at the time of surgery. Compared with placebo CABG patients, vorapaxar-treated patients had a 45% lower rate of the primary endpoint (i.e., a composite of death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization during index hospitalization) (HR: 0.55; 95% CI: 0.36 to 0.83; p = 0.005), with a significant interaction (p = 0.012). The CABG-related Thrombolysis In Myocardial Infarction major bleeding was numerically higher with vorapaxar, but not significantly different between vorapaxar and placebo (9.7% vs. 7.3%; HR: 1.36; 95% CI: 0.92 to 2.02; p = 0.12), with no excess in fatal bleeding (0% vs. 0.3%) or need for reoperation (4.7% vs. 4.6%).
Conclusions In non–ST-segment elevation acute coronary syndrome patients undergoing CABG, vorapaxar was associated with a significant reduction in ischemic events and no significant increase in major CABG-related bleeding. These data show promise for protease-activated receptor 1 antagonism in patients undergoing CABG and warrant confirmatory evidence in randomized trials. (Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Acute Coronary Syndrome [TRA·CER] [Study P04736AM3]; NCT00527943)
Coronary artery bypass graft (CABG) surgery is the revascularization procedure of choice to treat patients with acute coronary syndromes (ACS) in whom coronary anatomy is not suitable for percutaneous coronary intervention. In CABG patients, subsequent ischemic events may originate in either grafts or in the native coronary artery. Asymptomatic graft occlusion occurs in up to 40% of patients within 1 year (symptomatic occlusion occurs in 3.4% of patients) and is associated with a mortality rate of up to 9% (1–3). Graft thrombosis is thought to be the leading mechanism of graft closure, and platelet activation may play a key role in both early and late graft occlusion (4–8). Aspirin improves early vein graft patency and ischemic outcomes, although significant aspirin resistance has been reported after CABG surgery, whereas its effect on long-term patency remains uncertain (9–12). Additional platelet inhibition through the P2Y12 receptor with clopidogrel in patients undergoing CABG after ACS was associated with reduced ischemic rates, but concerns regarding operative bleeding risk require pre-operative discontinuation and have hindered widespread adoption in the management of ACS patients undergoing CABG (13–18). Consequently, there is a lack of consensus regarding both clopidogrel use post-CABG and opportunities for novel therapeutic agents to fill the treatment gap in non–ST-segment elevation (NSTE) ACS patients undergoing CABG.
Thrombin generation increases during CABG surgery and persists afterward, potentially increasing the risk of thrombotic complications, including graft and native coronary artery thrombosis (19,20). Therefore, the blockade of the main platelet thrombin receptor, the protease-activated receptor (PAR)-1, could be a more specific strategy to reduce graft occlusion and native coronary thrombosis after CABG, thus preventing subsequent ischemic events. Vorapaxar (Merck, Whitehouse Station, New Jersey) is a selective, competitive, oral PAR-1 antagonist that inhibits thrombin-mediated platelet activation (21). In addition, in animal models, vorapaxar analogues did not increase surgical bleeding (22). In the TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) trial, among patients with NSTE ACS, vorapaxar did not significantly reduce a quintuple endpoint of cardiovascular (CV) death, myocardial infarction (MI), stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization, but it was associated with a reduction in the composite of CV death, MI, and stroke, largely due to a reduction of MI (23). Similarly, in a study of patients with chronic atherosclerotic disease, the rates of death, MI, and stroke were significantly reduced by vorapaxar (24). In both trials, vorapaxar was associated with a significant increase in major bleeding. We undertook a pre-specified analysis to assess the efficacy and safety of vorapaxar in TRACER patients undergoing CABG.
The analysis population includes patients who were randomized in the TRACER trial (n = 12,944), for which the primary results and study design have been published (23,25). Briefly, patients were enrolled if they presented with acute symptoms of coronary ischemia within 24 h before hospital presentation and with at least 1 of the following: cardiac troponin (I or T) or creatine kinase-myocardial band levels higher than the upper limit of normal, new ST-segment depression >0.1 mV, or transient ST-segment elevation (<30 min) of >0.1 mV in ≥2 contiguous leads. Patients were randomly assigned in a 1:1 ratio to receive vorapaxar (40-mg loading dose and 2.5-mg daily maintenance dose thereafter) or matching placebo with stratification according to intention to use a glycoprotein IIb/IIIa inhibitor (vs. none) and intention to use a parenteral direct thrombin inhibitor (vs. other antithrombins).
This analysis included patients who underwent CABG during index hospitalization after they were randomized and began the study drug. Because time to CABG may vary across centers, and because it may be local practice to discharge patients and then schedule CABG, we performed an additional analysis to include all CABG surgeries performed within 30 days of randomization.
The study protocol recommended that the study drug be continued during CABG. Temporary interruptions were defined as any disruption in study drug ≥2 days, but then resumed. Permanent discontinuation was definitive premature interruption of study treatment. For the efficacy endpoints, the accrual period was from CABG to the date of site notification of study termination. The endpoints for this analysis were: 1) the composite of CV death, MI, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization (primary); and 2) the composite of CV death, MI, or stroke (secondary) from the TRACER study.
For bleeding endpoints, the accrual period was from CABG to the last dose of randomized treatment. The CABG-related major bleeding was defined according to the Thrombolysis In Myocardial Infarction (TIMI) criteria and was pre-specified as part of the TRACER trial event definition. To provide further detail, CABG-related major bleeding was defined as any hemorrhage meeting any of the following criteria: 1) fatal bleeding (i.e., bleeding that directly results in death); 2) perioperative intracranial bleeding; 3) reoperation after closure of the sternotomy incision to control bleeding; 4) transfusion of ≥5 U of whole blood or packed red blood cells within 48 h; or 5) chest tube output >2 l within 24 h. All efficacy and bleeding events in the TRACER study were systematically adjudicated by a central clinical events committee. All bleeding events were classified according to the TIMI and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) scales.
Associations between treatment assignments and outcomes were assessed using time-to-event analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression modeling, with the adjustment of randomization stratification factors and baseline covariates. Event rates were estimated by the Kaplan-Meier method. To test interaction, because patients had to be classified as either “CABG” or “no CABG” within a common time point (discharge from the index event), the event accrual period was from discharge to site notification. A sensitivity analysis was also carried out by including all events since randomization and accounting for propensity of having CABG.
The SAS version 9.3 (SAS Institute, Cary, North Carolina) was used to perform statistical analyses. The p values were not adjusted for multiple comparisons. The TRACER study was approved by an institutional review committee, and all patients gave informed consent.
In total, 1,312 (10.1%) of 12,944 patients enrolled in the TRACER trial underwent CABG surgery during the index hospitalization (vorapaxar n = 639; placebo n = 673). There were 1,510 patients who underwent CABG within 30 days of randomization (vorapaxar n = 750; placebo n = 760). The overall study population was followed for a median of 502 days (interquartile range [IQR]: 349 to 667 days). The 2 treatments arms were well balanced regarding baseline characteristics for patients undergoing CABG (Table 1).
Study treatment and concomitant antiplatelet agents
The median time to CABG in patients treated with vorapaxar was 120 h (IQR: 47 to 194 h) and with placebo was 119 h (IQR: 48 to 214 h) (Table 2). At randomization, there was a lower utilization of thienopyridine in patients later undergoing CABG (72% CABG vs. 89% no CABG), although use was similar between the vorapaxar and placebo groups. Before CABG, the study drug was interrupted in 23% of placebo patients and in 26% of vorapaxar patients. Among those who had the treatment withheld before surgery, the median time from last dose to CABG was 6 days (IQR: 4 to 8 days) for placebo and vorapaxar patients.
In those who underwent CABG, 39% in the placebo group and 38% in the vorapaxar group received clopidogrel within 5 days of CABG. Clopidogrel at discharge was used in 16% of placebo patients and in 19% of vorapaxar patients, which was much lower than among non-CABG patients (84.3% placebo; 84.9% vorapaxar).
Efficacy of vorapaxar in CABG patients
In patients undergoing CABG during index hospitalization (n = 1,312), the primary endpoint occurred in 43 patients in the vorapaxar group and in 70 patients in the placebo group (2-year Kaplan-Meier rates: 8.2% and 12.9%, respectively), corresponding to a 45% reduction (adjusted HR: 0.55; 95% CI: 0.36 to 0.83; p = 0.005) (Table 3). The reduction in events post-discharge was higher among patients who underwent CABG during index hospitalization (HR: 0.46; 95% CI: 0.28 to 0.77; p = 0.003) compared with those who did not undergo CABG during index hospitalization (HR: 0.97; 95% CI: 0.87 to 1.08; p = 0.59). There was a statistically significant interaction between CABG and vorapaxar (p = 0.012) (Fig. 1). All components of the primary endpoint were numerically lower with vorapaxar. When all patients who underwent CABG in the first 30 days after randomization were included, the effect on post-CABG events remained consistent, with a 48% reduction with vorapaxar (HR: 0.52; 95% CI: 0.36 to 0.76; p = 0.001), and the interaction between CABG and vorapaxar treatment effect on post-discharge events remained significant with groups defined at 30 days (p = 0.028).
Vorapaxar was also associated with lower occurrence of the key secondary endpoint (43 events; 2-year Kaplan-Meier rate of 8.2%) compared with placebo (58 events; 2-year Kaplan-Meier rate of 10.2%) in patients undergoing CABG (adjusted HR: 0.66; 95% CI: 0.43 to 1.01; p = 0.057). The reduction in post-discharge events was numerically higher among patients who underwent CABG (HR: 0.54; 95% CI: 0.31 to 0.94; p = 0.030) compared with those who did not undergo CABG (HR: 0.89; 95% CI: 0.78 to 1.01; p = 0.065). The interaction between randomized treatment and CABG was not statistically significant (p = 0.209) (Fig. 2). Results were comparable when all patients who underwent CABG in the first 30 days post-randomization were included (HR: 0.60; 95% CI: 0.40 to 0.88; p = 0.010).
The CABG-related TIMI major bleeding was not a statistically significant difference between vorapaxar and placebo, although it was numerically higher with vorapaxar (HR: 1.36; 95% CI: 0.92 to 2.02; p = 0.12), as it was for GUSTO severe bleeding related to CABG (HR: 1.35; 95% CI: 0.80 to 2.29; p = 0.26) (Table 4). The number of patients who required repeated surgery to control bleeding was similar between groups (vorapaxar n = 30 [4.7%]; placebo n = 31 [4.6%]). Fatal bleeding occurred in 2 placebo patients and in none of the vorapaxar patients. Among those who continued the study drug up to the time of surgery, TIMI major CABG-related bleeding occurred in 43 (8.0%) placebo patients and in 54 (11.0%) vorapaxar patients.
Among those who discontinued the randomized drug throughout CABG, TIMI major CABG-related bleeding occurred in 9 (7.3%) placebo patients and in 13 (9.3%) vorapaxar patients. Reoperation for bleeding in this subgroup was similar between the vorapaxar (n = 7 [5.0%]) and placebo (n = 7 [5.6%]) groups, and in the group of patients who continued the drug through the perioperative period (vorapaxar: n = 23 [4.6%]; placebo: n = 24 [4.4%]). In patients who received clopidogrel within 5 days of surgery (vorapaxar n = 242; placebo n = 263), TIMI major CABG-related bleeding occurred in 28 (11.6%) patients with vorapaxar and in 23 (8.7%) patients with placebo, and reoperation for bleeding occurred in 10 (4.1%) patients with vorapaxar and 13 (4.9%) patients with placebo. Among patients who received their last dose of clopidogrel ≥5 days before CABG (vorapaxar n = 214; placebo n = 231), TIMI major CABG-related bleeding occurred in 26 (12.1%) patients with vorapaxar and in 17 (7.4%) patients with placebo, and reoperation for bleeding occurred in 11 (5.1%) patients with vorapaxar and in 12 (5.2%) patients with placebo.
There was a mild excess in chest tube drainage in patients treated with vorapaxar versus placebo at 8 h (350 ml vs. 308 ml), at 24 h (635 ml vs. 580 ml), and total (830 ml vs. 780 ml).
When all CABG surgeries performed during the first 30 days from randomization were included, the results for CABG-related major bleeding were similar (Table 4).
Bleeding after discharge
In patients who underwent CABG during index hospitalization, bleeding after discharge increased with vorapaxar (Table 5). In the CABG population, GUSTO moderate or severe bleeding at 2 years was 4.0% with vorapaxar and 2.2% with placebo (HR: 1.60; 95% CI: 0.75 to 3.42). The TIMI major bleeding was infrequent in the CABG cohort, but increased with vorapaxar (2-year Kaplan-Meier rates of 1.4% with vorapaxar and 0.8% with placebo; HR: 1.83; 95% CI: 0.54 to 6.26). In the CABG cohort, there was 1 patient (0.2%) with intracranial hemorrhage who received vorapaxar and no intracranial hemorrhage with placebo. In the non-CABG population, the GUSTO moderate or severe bleeding rate at 2 years was 4.1% with vorapaxar and 2.8% with placebo (HR: 1.38; 95% CI: 1.09 to 1.75). There was no statistically significant interaction (p = 0.75).
In the TRACER study patients who underwent CABG, we observed that adding vorapaxar versus placebo to standard-of-care practices reduced the occurrence of the primary endpoint with an estimated relative hazard reduction of 45%. The improvement in the primary endpoint post-discharge for patients randomized to vorapaxar and undergoing CABG during index hospitalization appeared to be much stronger than that observed in the non-CABG cohort, a finding supported by a statistically significant interaction. In the CABG cohort, vorapaxar was also associated with a 34% reduction of CV death, MI, or stroke (a larger estimated effect than in the main TRACER study cohort), although the interaction was not statistically significant. There was a nonsignificant numerical increase in surgical bleeding with vorapaxar without increased occurrence of reoperations for bleeding. There was also an increase in non-CABG bleeding, which is consistent with the main results of the TRACER trial.
These results suggest that PAR-1 antagonism may be a viable therapeutic option to reduce recurrent ischemic events post-CABG. All components of the primary endpoint, including mortality, were numerically lower with vorapaxar after CABG, and the efficacy of vorapaxar seemed overall enhanced post-CABG. It is possible that PAR-1 activation is an important mechanism leading to graft failure. Particularly, increased thrombin generation after CABG may induce a higher susceptibility to the action of PAR-1 antagonists (26,27). Concomitant antiplatelet therapy might have also played a role. In fact, consistent with registry data, use of clopidogrel at discharge was much lower in CABG patients than in non-CABG patients (18% vs. 85%, respectively). It is possible that the effect of vorapaxar is stronger when added to aspirin only versus when added to aspirin and clopidogrel as triple oral antiplatelet therapy. It is interesting that vorapaxar was associated with a numerical reduction of urgent revascularization (not associated with an MI) in CABG patients, but not in non-CABG patients. Vorapaxar may affect the mechanism leading to urgent revascularization in CABG patients (e.g., graft failure), but not in non-CABG patients (e.g., in-stent restenosis, progression of pre-existing stenosis).
The use of antiplatelet therapy in addition to aspirin therapy is controversial due to the increased risk of bleeding that undermines the reduction in clinical events. In the CURE (Clopidogrel in Unstable angina to prevent Recurrent ischemic Events) trial (14), the reduction of CV death, MI, or stroke in the CABG cohort was consistent with the main CURE trial results. However, available evidence is controversial concerning a benefit in adding clopidogrel post-CABG to improve vein graft patency and CV events (28–30). Ticagrelor, a reversibly binding, direct-acting oral P2Y12 receptor antagonist, was associated with a 16% reduction in CV death, MI, or stroke, which was consistent overall with the main trial results, although ticagrelor appeared to have a more robust effect on mortality in the CABG cohort (15,16). The CABG bleeding rates were increased and comparable for both ticagrelor and clopidogrel (15,18). Based on these results, guidelines recommend withholding either ticagrelor or clopidogrel 5 days prior to CABG surgery (31). A third P2Y12 antagonist, prasugrel (vs. clopidogrel), was associated with significantly reduced mortality after adjusting for pre-operative risk in the few patients participating in the TRITON–TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis In Myocardial Infarction 38) trial who underwent follow-up CABG surgery (32). However, prasugrel requires an even longer interruption (7 days) before surgery, and the improved clinical outcomes with prasugrel need to be weighed against the substantial increased risk of CABG-related bleeding. In contrast, vorapaxar (or matching placebo) was to be continued perioperatively, as recommended by the TRACER study protocol.
In contrast with the main TRACER study results, in which there was a significant increase in major bleeding with vorapaxar, the perioperative safety profile of vorapaxar seemed acceptable in this analysis. In patients who received vorapaxar, there was a numerical increase in major CABG-related bleeding that did not meet statistical significance, a modest increase in chest tube drainage, and no trend indicating increased rates of reoperation to control bleeding. It is important to note that most CABG procedures were performed while vorapaxar was still active, unlike current recommendations for P2Y12 antagonists. In fact, 75% of patients in the vorapaxar group did not have interruption in study treatment before CABG. In addition, because the effect of duration of a single dose of vorapaxar is 2 to 3 weeks and the median time to CABG was only 120 h, even when the study drug was interrupted, it was still expected to be within its biological activity time frame. Our results confirm: 1) earlier findings that show no increase in surgical bleeding in an animal model with a vorapaxar analogue; and 2) preliminary results among 76 patients undergoing CABG in the phase II study, in which vorapaxar did not increase surgical bleeding (33). Overall, these data suggest the possibility of using vorapaxar during the perioperative period. The contrast between surgical and spontaneous bleeding effects of vorapaxar observed in this analysis could be related to different roles of PARs under different pathophysiologic circumstances.
It is possible that, during surgery, a high concentration of thrombin can increase activity of the PAR-4 receptor—which, in humans, requires higher concentrations of thrombin to be activated than PAR-1 does—therefore creating a “rescue” mechanism (34). Alternatively, thrombin generation during cardiopulmonary bypass surgery may cause platelet activation that leads to the desensitization of platelets and a reduction of platelet reactivity. By reducing perioperative, thrombin-mediated platelet activation, vorapaxar may prevent desensitization of platelets. Finally, it is possible that the PAR-1 receptor may have a more limited role in normal hemostasis after major vessel injury (35). Future analysis to also assess the safety of vorapaxar in the setting of noncardiac surgery will be helpful to further define how PAR-1 antagonism could be tolerated in the setting of surgical procedures.
The effect of vorapaxar on bleeding events (mostly representing spontaneous bleeding) after discharge in CABG patients is largely consistent with the overall TRACER study results, particularly in terms of a relative increase in bleeding. However, it is noteworthy that the absolute risk of bleeding is lower in CABG patients than in non-CABG patients, possibly due to the selection of candidates who undergo surgery and the lower concomitant use of clopidogrel. Therefore, the trade-off between efficacy and bleeding may be favorable to vorapaxar use in CABG patients, if the results of the present analysis are confirmed in a prospective randomized clinical trial.
Because the current analysis is not a randomized comparison of vorapaxar and placebo, the results have no immediate applicability in clinical practice and should be interpreted as hypothesis-generating. This is a pre-specified analysis of a post-randomization subgroup within a large clinical trial. Thus, we cannot rule out that study participation and study drug assignment may have influenced the choice of candidates for CABG, or that factors other than CABG itself may have influenced the results. It is important to note, however, that this was a double-blinded study and the time to CABG was short, so it is unlikely that there is bias of CABG referral based on treatment assignment. The vorapaxar and placebo groups were well balanced in the CABG and the non-CABG cohorts regarding baseline demographics. However, unmeasured confounders cannot be excluded with certainty.
Because the primary focus of the TRACER trial was not the evaluation of vorapaxar in patients undergoing CABG, data that may have improved our understanding of the underlying mechanism supporting these results—including the reason for patient referral to CABG, method for harvesting vein grafts, use of cardiopulmonary bypass circuit, or post-operative imaging of vein grafts—were not collected as part of the analysis (36,37). In particular, we did not collect imaging to assess graft failure; therefore, we are unable to provide a mechanistic explanation in support of the observed effect.
The CABG group represents 10% of the overall study population, and the study was not stratified by CABG. Some of the results and lack of statistical significance may have been influenced by insufficient power. No adjustment for multiple comparisons was performed so as not to reduce sensitivity in generating hypotheses.
In a large, nonrandomized cohort of patients with NSTE ACS who participated in the TRACER trial and subsequently underwent CABG, we have observed a marked reduction in the primary endpoint among patients assigned to vorapaxar and enhanced efficacy in comparison with the non-CABG cohort. The current analysis suggests that vorapaxar may have an acceptable safety profile for CABG-related bleeding. After discharge, rates of major bleeding were relatively low in CABG patients, but were increased with vorapaxar, consistent with the main trial. These results should be considered exploratory, yet they suggest that PAR-1 antagonism could be a potentially attractive strategy to reduce recurrent ischemic events in CABG patients, and this hypothesis warrants confirmatory evidence from future, appropriately designed, randomized clinical trials.
The TRACER trial was funded by Merck & Co., Inc. Dr. Whellan has received consultant honoraria from Novartis, POZEN, Terumo, and Medtronic; and he has received a research grant from Merck & Co., Inc., and Medtronic. Dr. Tricoci has received a consultant agreement and research grant from Merck & Co., Inc. Dr. Chen was an employee of Merck & Co., Inc. Dr. Held has received research support from Merck & Co., Inc., GlaxoSmithKline, AstraZeneca, and Bristol-Myers Squibb/Pfizer; has received institutional research grants from Schering-Plough/Merck Sharp & Dohme and Roche; has served on the advisory board for Pfizer and AstraZeneca; and has received lecture fees from AstraZeneca. Dr. Nicolau has received research grant support and consulting fees/honorarium from Merck & Co., Inc.; has board membership with AstraZeneca; has received research grant support and lecture fees, including service on speakers’ bureaus from AstraZeneca and Eli Lilly; and has received travel/accommodations/meeting expenses from AstraZeneca. Dr. Storey has received research grants from AstraZeneca, Eli Lilly/Daiichi Sankyo Alliance, Merck & Co., Inc., and Accumetrics; has served as a consultant for AstraZeneca, Eli Lilly, Daiichi Sankyo, Novartis, Merck & Co., Inc., Eisai, Sanofi-Aventis/Regeneron, Bristol-Myers Squibb, Roche, and Accumetrics; and has received honorarium from AstraZeneca, Eli Lilly, Daiichi Sankyo, Merck & Co., Inc., Accumetrics, Medscape, and Iroko. Dr. Ruzyllo has received honoraria for lectures and clinical studies from Bayer, Bristol-Myers Squibb/Pfizer, Merck & Co., Inc., Daiichi Sankyo, Eli Lilly, and Sanofi-Aventis. Dr. Huber has received honoraria for lectures and expert rounds from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Eli Lilly, Sanofi-Aventis, and The Medicines Company. Dr. Sinnaeve has received a research grant from AstraZeneca; has received advisory/speakers fees from Merck Sharp & Dohme, Merck & Co., Inc., Sanofi-Aventis, Bristol-Myers Squibb, Eli Lilly, Daiichi Sankyo, AstraZeneca, Boehringer Ingelheim, Pfizer, and Bayer; and has served on the advisory board of Merck Sharp & Dohme. Dr. Moliterno has received research support and consulting fees/honoraria from Merck & Co., Inc. Dr. Van de Werf has received a research grant from Merck Sharp & Dohme; has received research support from Merck & Co., Inc. and Boehringer Ingelheim; and has served as a consultant for and received lecture fees from AstraZeneca and Boehringer Ingelheim. Dr. Aylward has received research support from Merck & Co., Inc., AstraZeneca, Eli Lilly, and Bayer/Johnson & Johnson; has served as a consultant for AstraZeneca, Boehringer Ingelheim, Pfizer, Sanofi-Aventis, and Eli Lilly; and has received lecture fees from AstraZeneca, Boehringer Ingelheim, and Eli Lilly. Dr. White has received research support from Sanofi-Aventis, Eli Lilly, The Medicines Company, National Institutes of Health, Pfizer, Roche, Johnson & Johnson, Merck Sharpe & Dohme, AstraZeneca, GlaxoSmithKline, Daiichi Sankyo Pharma Development, and Bristol-Myers Squibb; and has served on advisory boards for Merck Sharpe & Dohme, and Regado Biosciences. Dr. Armstrong has received research support and consulting fees/honoraria from Merck Sharp & Dohme; has served as a consultant for Eli Lilly, Regado Biosciences, F. Hoffmann-La Roche Ltd., GlaxoSmithKline, Sanofi-Aventis, Takeda Pharmaceuticals, and Merck & Co., Inc.; has received a research grant from Schering-Plough Research Institute; and has received research support from Boehringer Ingelheim, Sanofi-Aventis Canada, GlaxoSmithKline, AstraZeneca, Regado Biosciences, Amylin, and Novartis. Dr. Wallentin has received research support and consulting fees/honoraria from Merck & Co., Inc.; has performed consultancy for Regado Biotechnologies, Portola, C.S.L. Behring, Athera Biotechnologies, Boehringer Ingelheim, AstraZeneca, GlaxoSmithKline, Bristol-Myers Squibb, and Pfizer; has received research support and lecture fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, and Schering-Plough; has received honoraria from Boehringer Ingelheim; and has received honoraria and travel support from AstraZeneca, Bristol-Myers Squibb, and Pfizer. Dr. Strony is an employee and stockholder of Merck & Co., Inc. Dr. Harrington’s disclosures are listed at: http://med.stanford.edu/profiles/medicine/frdActionServlet?choiceId=showCOIs&&fid=34240. Dr. Mahaffey’s full disclosures prior to August 1, 2013 are available at www.dcri.org; disclosures after August 1, 2013 are available at: http://med.stanford.edu/profiles/kenneth_mahaffey. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Dr. Chen is currently affiliated with Global Clinical Development, Bayer HealthCare Pharmaceuticals Inc., Whippany, New Jersey.
- Abbreviations and Acronyms
- acute coronary syndrome(s)
- coronary artery bypass grafting
- confidence interval
- hazard ratio
- interquartile range
- myocardial infarction
- non–ST-segment elevation
- protease-activated receptor
- Thrombolysis In Myocardial Infarction
- Received May 1, 2013.
- Accepted October 1, 2013.
- American College of Cardiology Foundation
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