Author + information
- Received February 1, 2013
- Revision received March 24, 2013
- Accepted March 26, 2013
- Published online July 23, 2013.
- C. Michael Gibson, MD∗,†∗ (, )
- Anjan K. Chakrabarti, MD∗,
- Jessica Mega, MD, MPH†,
- Christophe Bode, MD‡,
- Jean-Pierre Bassand, MD§,
- Freek W.A. Verheugt, MD, PhD⋮,
- Deepak L. Bhatt, MD, MPH†,¶,
- Shinya Goto, MD#,
- Marc Cohen, MD∗∗,
- Satishkumar Mohanavelu, MS†,
- Paul Burton, MD††,
- Gregg Stone, MD‡‡,
- Eugene Braunwald, MD†,
- ATLAS-ACS 2 TIMI 51 Investigators
- ∗Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
- †TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
- ‡Department of Cardiology and Angiology, University of Freiburg, Freiburg, Germany
- §University Hospital Jean Minjoz, Besançon, France
- ⋮OnzeLieveVrouweGasthuis, Amsterdam, the Netherlands
- ¶VA Healthcare System, Boston, Massachusetts
- #Department of Medicine (Cardiology), Tokai University School of Medicine, Isehara, Japan
- ∗∗Division of Cardiology, Newark Beth Israel Medical Center, Newark, New Jersey
- ††Janssen Research and Development, Titusville, New Jersey
- ‡‡Columbia University, New York, New York
- ↵∗Reprint requests and correspondence:
Dr. C. Michael Gibson, Beth Israel Deaconess Medical Center, 185 Pilgrim Road, Farr 319, Boston, Massachusetts 02215.
Objectives The aim of this study was to determine if rivaroxaban is associated with a reduction in stent thrombosis among patients with acute coronary syndromes (ACS) in the ATLAS-ACS 2 TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects With Acute Coronary Syndrome—Thrombolysis in Myocardial Infarction 51) trial.
Background Dual antiplatelet therapy (DAPT) has been the mainstay of efforts to prevent stent thrombosis. Because thrombin is a potent stimulant of platelet activation, we hypothesized that inhibition of thrombin generation via factor Xa inhibition may further reduce the risk of stent thrombosis.
Methods The ATLAS-ACS 2 TIMI 51 study was a placebo-controlled trial that randomly assigned 15,526 patients with recent ACS to receive twice-daily doses of either 2.5 mg or 5 mg of rivaroxaban or placebo for a mean of 13 months and up to 31 months.
Results Among patients who had a stent placed before or at the time of the index event, rivaroxaban significantly reduced independently adjudicated Academic Research Consortium definite and probable stent thrombosis in the pooled (1.9% vs. 1.5%; hazard ratio [HR]: 0.65; p = 0.017) and the 2.5 mg twice-daily (1.9% vs. 1.5%; HR: 0.61; p = 0.023) treatment groups when compared with placebo, with a trend toward a reduction in the 5 mg twice-daily treatment group (1.9% vs. 1.5%; HR: 0.70; p = 0.089). Among patients who received both aspirin and a thienopyridine (stratum 2), the benefit of rivaroxaban emerged during the period of active treatment with DAPT (HR: 0.68; 95% CI: 0.50 to 0.92, combined rivaroxaban group vs. placebo). Among stented patients who were treated with dual antiplatelet therapy, there was a mortality reduction among those treated with twice-daily rivaroxaban 2.5 mg (HR: 0.56; 95% CI: 0.35 to 0.89; p = 0.014).
Conclusions Among stented patients with ACS treated with DAPT, the administration of twice-daily rivaroxaban 2.5 mg was associated with a reduction in stent thrombosis and mortality. (An Efficacy and Safety Study for Rivaroxaban in Patients With Acute Coronary Syndrome; NCT00809965)
Percutaneous coronary intervention (PCI) is the predominant revascularization strategy in patients with acute coronary syndromes (ACS), and intracoronary stents have improved procedural success and decreased rates of angiographic restenosis compared with conventional balloon angioplasty (1). Although stents have led to improvements in target lesion revascularization rates, they have also been associated with stent thrombosis, a highly morbid complication (2).
The incidence of stent thrombosis is significantly reduced by the administration of dual antiplatelet therapy (DAPT), implicating platelet activation as an important mediator of this complication (3). Efforts to reduce stent thrombosis have therefore focused on minimizing the discontinuation of DAPT and identifying those patients who have a poor response to thienopyridine therapy (4).
There have been relatively few contemporary studies examining oral anticoagulation and its role in the prevention of thrombotic complications of ACS and stent thrombosis (3,5). Rivaroxaban is an oral anticoagulant that directly and selectively inhibits factor Xa, interrupts the coagulation cascade, and thereby reduces the formation of thrombin. Inhibition of factor Xa is an attractive mechanistic target because thrombin generated on the surface of the activated platelet induces further platelet activation through the thrombin receptor (protease-activated receptor 1) to form a local positive-feedback loop (6). Indeed, rivaroxaban successfully inhibited high-shear–induced stent thrombosis in a porcine ex vivo model; when combined with DAPT, rivaroxaban reduced stent thrombus weight to a nearly undetectable limit of 2% (vs. 21% with DAPT alone) (7). It was therefore hypothesized that rivaroxaban administration is associated with a reduction in stent thrombosis, and this hypothesis was prospectively tested among patients with ACS randomized in the ATLAS-ACS 2 TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects With Acute Coronary Syndrome—Thrombolysis in Myocardial Infarction 51) trial.
The ATLAS-ACS 2 TIMI 51 trial (8,9) enrolled patients (≥18 years of age) who presented with symptoms suggestive of ACS. The present analysis was restricted to patients with a history of stent placement, including those receiving stents before study enrollment and those who received stents during the index PCI. Enrollment occurred within 7 days (median: 4.3 days) of hospital admission, and patients were randomly assigned in a 1:1:1 fashion to twice-daily administration of either 2.5 mg or 5.0 mg of rivaroxaban or placebo, with a maximum follow-up of 31 months.
All patients were to receive standard medical therapy at the enrolling physician's discretion at a dose recommended in either national or local guidelines. Stratum 1 was defined as those patients whom the enrolling physician chose to treat with aspirin alone, and stratum 2 was defined as those patients treated with aspirin plus a thienopyridine (8,9).
The primary efficacy endpoint of the ATLAS-ACS 2 TIMI 51 trial was a composite of death from cardiovascular causes, myocardial infarction, and stroke (ischemic, hemorrhagic, and stroke of uncertain cause) (8). Complete definitions of the endpoints have been reported previously (9). Stent thrombosis was a predefined endpoint reported by the enrolling physician and was independently adjudicated based upon the Academic Research Consortium (ARC) designations of definite, probable, or possible (2).
Efficacy analyses were performed using a modified intention-to-treat (mITT) approach, which has been described previously (8,9). Sensitivity efficacy analyses were conducted with the use of an ITT approach, which included all patients and all endpoint events occurring after randomization until the global treatment end date.
Hazard ratios (HR) with 2-sided 95% confidence intervals (CI) were used to compare the study groups. Rates of the endpoints were expressed as Kaplan-Meier estimates through 24 months. Results were examined according to major subgroups for general consistency of treatment effect, and interaction testing was performed.
Of the 15,342 patients included in the MITT analysis, 9,631 (63%) underwent PCI and had at least 1 stent inserted either before randomization or during their index event. Aside from a slightly greater age among rivaroxaban patients, there was no difference in baseline characteristics between stented patients randomly assigned to rivaroxaban versus placebo (Table 1).
ARC definite or probable (Fig. 1A) and ARC definite, probable, or possible (Fig. 1B) stent thrombosis were significantly reduced in the pooled group of all patients treated with rivaroxaban (both 2.5 mg and 5 mg twice-daily doses combined). There was also a reduction in definite stent thrombosis among all patients treated with rivaroxaban versus placebo (Fig. 2). This reduction achieved statistical significance when limited to those patients with ARC-defined definite or probable stent thrombosis in both the pooled (HR: 0.65; p = 0.017) and the rivaroxaban 2.5 mg twice-daily (HR: 0.61; p = 0.023) groups (Fig. 3).
The reduction in stent thrombosis with rivaroxaban (pooled doses) was consistent across a number of subgroups (Online Tables 1 and 2). There was homogeneity (p for interaction = 0.95) in the magnitude of the reduction in stent thrombosis among patients in whom a bare-metal stent was implanted (HR: 0.69; p = 0.042) and in whom a drug-eluting stent was implanted (HR: 0.68; p = 0.170). No significant reduction was noted in the small subgroup of patients who received a stent before randomization (Online Table 3).
In a landmark analysis, the magnitude of the treatment effect associated with rivaroxaban administration was fairly homogenous over time. Within 30 days of randomization, definite, probable, or possible stent thrombosis tended to be reduced in the pooled rivaroxaban group (HR: 0.65; 95% CI: 0.41 to 1.03; mITT and ITT p = 0.067). There was a comparable magnitude of reduction in the HR associated with rivaroxaban administration from 30 days to 2 years after enrollment (HR: 0.72; 95% CI: 0.46 to 1.13; mITT p = 0.154; ITT p = 0.081).
Among patients who received both aspirin and a thienopyridine (stratum 2), the benefit of rivaroxaban emerged during the period of active treatment with DAPT before any discontinuation of the thienopyridine (HR: 0.68; 95% CI: 0.50 to 0.92) in the combined rivaroxaban group versus placebo. There was a mortality reduction among those patients in stratum 2 treated with twice-daily rivaroxaban 2.5 mg (HR: 0.56; 95% CI: 0.35 to 0.89; mITT p = 0.014; ITT p = 0.039) (Fig. 4) but not twice-daily rivaroxaban 5 mg.
Rivaroxaban administration is associated with a reduction in stent thrombosis defined using a variety of ARC definitions. The benefit of rivaroxaban when added to DAPT emerged early and was preserved over time. A priori it may have been hypothesized that rivaroxaban would reduce the risk of stent thrombosis following cessation of thienopyridine therapy. However, a key finding from the present study was that rivaroxaban reduced the risk of stent thrombosis during the period of active DAPT. It should be noted that the oral anticoagulant apixaban demonstrated a similar reduction in stent thrombosis in the APPRAISE-2 (Apixaban for Prevention of Acute Ischemic Events 2) study, but this reduction did not reach statistical significance because the study was stopped prematurely due to an increase in major bleeding events (10). A similar reduction in stent thrombosis was not reported with the thrombin receptor antagonist vorapaxar (11).
The underlying mechanism by which rivaroxaban reduces stent thrombosis when added to DAPT in animal and human studies is not known. It is not known whether the observed reduction in stent thrombosis in this study was mediated by a reduction in thrombin generation, which in turn directly mediates stent thrombosis, or if the reduction in stent thrombosis was mediated by a reduction in the stimulation of platelet aggregation because thrombin is a potent stimulant of platelets.
The factor Xa inhibitor rivaroxaban significantly reduced stent thrombosis in patients with ACS. The benefit emerged during the period of DAPT with aspirin plus a thienopyridine. The results of this analysis highlight the potential additive benefit of inhibiting thrombin generation over DAPT alone among stented patients.
The ATLAS-ACS 2 TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects With Acute Coronary Syndrome—Thrombolysis in Myocardial Infarction 51) study was supported by Johnson & Johnson and Bayer Healthcare. Dr. Gibson's institution receives funding from Johnson & Johnson and Bayer Healthcare, and Dr. Gibson has received grants from Abbott, Bayer, Genentech, Ikaria, Johnson & Johnson, Merck, and The sanofi-aventis Group; honoraria from Biogen Idec, Bristol-Myers Squibb, Daiichi Sankyo, CSL Behring, Cytori Therapeutics, Eli Lilly, GlaxoSmithKline, Genentech, Ischemix, Merck, Portola, Regado, The sanofi-aventis Group, The Medicines Company, and Medicure for consulting; and compensation for lectures and service on Speakers' Bureaus for Daiichi Sankyo and Eli Lilly. Dr. Mega has received research grant support from Johnson & Johnson, Bayer Healthcare, Bristol-Myers Squibb, The sanofi-aventis Group, Daiichi Sankyo, and Eli Lilly; research supplies from Accumetrics and Nanosphere; and honoraria for consulting from Merck, Janssen, and American Genomics. Dr. Bode has served as a speaker/advisor for AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Novartis, Pfizer, and The sanofi-aventis Group and has received grants for clinical research from Actavis, Astellas, Bayer, Eli Lilly, GlaxoSmithKline, Medtronic, Merck, and The sanofi-aventis Group. Dr. Bassand has served as a speaker/advisor for AstraZeneca, The sanofi-aventis Group, GlaxoSmithKline, Eli Lilly, and Bayer; has received honoraria for consulting from The sanofi-aventis Group and Bayer; and owns modest shares of GlaxoSmithKline, The sanofi-aventis Group, and Eli Lilly. Dr. Verheugt has received honoraria from Bayer Healthcare and Pfizer. Dr. Bhatt has served on advisory boards for Medscape Cardiology, the Boston VA Research Institute, the Society of Chest Pain Centers, and the American Heart Association Get With the Guidelines Science Subcommittee; received honoraria for consulting from the American College of Cardiology, the Duke Clinical Research Institute, Slack Publications, and WebMD; and received research grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, The sanofi-aventis Group, and The Medicines Company. Dr. Goto has received honoraria for consulting from Eisai, The sanofi-aventis Group, Otsuka, Bayer, Novartis, AstraZeneca, Astellas, Pfizer, Medtronics—Japan, Tanabe-Mitsubishi, Takeda, Daiichi Sankyo, Mochida, and Merck Sharp & Dohme, and research grants from The sanofi-aventis Group, Eisai, Boehringer Ingelheim, Otsuka, and Daiichi Sankyo. Dr. Burton is employed by Johnson & Johnson and owns stock in Johnson & Johnson. Dr. Stone serves as a consultant to Janssen, Bristol-Myers Squibb, The sanofi-aventis Group, Eli Lilly, Daiichi Sankyo, Abbott Vascular, Boston Scientific, and Medtronic. Dr. Braunwald and the TIMI Study Group have received research grants from Johnson & Johnson and Daiichi Sankyo. Dr. Braunwald has received honoraria for lectures at symposia sponsored by Daiichi Sankyo and Bayer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- acute coronary syndrome(s)
- dual antiplatelet therapy
- percutaneous coronary intervention
- Received February 1, 2013.
- Revision received March 24, 2013.
- Accepted March 26, 2013.
- American College of Cardiology Foundation
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