Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction 51 - ATLAS ACS 2-TIMI 51
Rivaroxaban is a novel oral anti-Xa antagonist, with demonstrated safety and efficacy, as compared with agents such as warfarin, in patients with atrial fibrillation and thromboembolism. The phase II ATLAS ACS–TIMI 46 trial noted that in patients with recent acute coronary syndrome (ACS), rivaroxaban, on a background of dual antiplatelet therapy with aspirin and clopidogrel, was associated with reasonable efficacy but increased bleeding as compared with placebo. Doses of 2.5 and 5 mg appeared to have the best risk:benefit ratio. The current trial is a phase III trial to assess the safety and efficacy of these two doses of rivaroxaban in patients with recent ACS and at high risk for recurrent ischemic events as compared with placebo.
Low doses of rivaroxaban would be superior, as compared with placebo, for secondary prevention in patients with recent ACS.
- Placebo Controlled
- Age >18 years old with recent acute ACS
- If younger than age 55, had to be either diabetic or prior MI
Number of enrollees: 15,526
Duration of follow-up: 31 months
Mean patient age: 61.8 years
Percentage female: 25%
- Platelet count <90,000 cm3
- Hemoglobin <10 g/dl
- Creatinine clearance <30
- Clinically significant gastrointestinal bleeding within 12 months
- Previous ICH
- Previous TIA/stroke in patients already on aspirin and clopidogrel
- Efficacy: Composite of CV death/MI/stroke
- Safety: TIMI major bleeding
- All-cause mortality
- Stent thrombosis
- TIMI minor bleeding
Patients with recent ACS were randomized in a 1:1:1 fashion to either rivaroxaban 2.5 mg daily, 5 mg daily, or placebo. Stratification was by thienopyridine use.
Aspirin (98.7%), thienopyridine (93%), statin (83.5%), beta-blockers (66.4%), angiotensin-converting enzyme inhibitors (39.4%)
A total of 15,526 patients were enrolled at 766 centers in 44 countries (5.5% in North America), 5,174 to rivaroxaban 2.5 mg, 5,176 to rivaroxaban 5 mg, and 5,176 to placebo. The mean duration of treatment with a study drug was 13.1 months. Baseline characteristics were similar between the two arms. About 37% of the patients were ≥65 years, 73% were White, 32% had diabetes mellitus, and 27% had a prior history of myocardial infarction (MI). The median body mass was 78 kg, with a median creatinine clearance of 85 ml/min. The index diagnosis was ST-segment elevation MI (STEMI) in 50%, non-STEMI in 26%, and unstable angina in 24%. About 61% underwent revascularization with either percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG).
Over a median follow-up of about 2 years, the primary endpoint of cardiovascular (CV) death/MI/stroke was significantly lower in the rivaroxaban arm, as compared with placebo (8.9% vs. 10.7%, hazard ratio [HR] 0.84, 95% confidence interval [CI] 0.74-0.96, p = 0.008), and among STEMI patients, the primary outcome was 8.4% vs. 10.6% (p = 0.019). The benefit on the primary endpoint was seen in both the 5 mg dose and the 2.5 mg dose individually (see below). Individual components including CV mortality (3.3% vs. 4.1%, p = 0.04) and MI (5.5% vs. 6.6%, p = 0.047) were also reduced; rates of stroke were similar (1.6% vs. 1.2%, p = 0.25). Stent thrombosis rates (2.3% vs. 2.9%, p = 0.02) were lower. The results were generally consistent across the subgroups tested, with the possible exception of a small subgroup of patients with previous stroke or transient ischemic attack. In the subgroup that underwent PCI (n = 9,631), ARC definite and probable stent thrombosis was significantly reduced with rivaroxaban (1.5% vs. 1.9%, p = 0.017).
The primary safety endpoint of non–CABG-related TIMI (Thrombolysis in Myocardial Infarction) major bleeding was significantly elevated in the rivaroxaban arm, as compared with placebo (2.1% vs. 0.6%, HR 3.96, 95% CI 2.46-6.38, p < 0.001). This major bleeding finding was true among all patients and also those with STEMI. Rates of TIMI minor bleeding (1.3% vs. 0.5%, p = 0.003) and intracranial hemorrhage (ICH) (0.6% vs. 0.2%, p = 0.0009) were also higher in the rivaroxaban arm. Bleeding appeared to be higher after 6 months, with numerically higher rates in patients with lower body weight and older age.
When analyzing the benefit by the dose of rivaroxaban, the greatest efficacy for reduction in ischemic endpoints was noted with the 2.5 mg daily dose. The primary endpoint was significantly lower in this arm as compared with placebo (9.1% vs. 10.7%, HR 0.84, 95% CI 0.72-0.97, p = 0.02). CV death was reduced by 34% (2.7% vs. 4.1%, p = 0.002) and all-cause mortality by 32% (2.9% vs. 4.5%, p = 0.002). In comparison, while the 5 mg daily dose was associated with a reduction in the primary endpoint (8.8% vs. 10.7%, p = 0.03), no reductions were noted in CV mortality (p = 0.63) or all-cause mortality (p = 0.66) as compared with placebo. Both doses had similar increases in non-CABG TIMI major bleeding as compared with placebo (1.8% vs. 0.6%, and 2.4% vs. 0.6%, respectively). However, the 2.5 mg dose had lower rates of TIMI minor bleeding as compared with the 5 mg dose (0.9% vs. 1.6%, p = 0.046), but not ICH (0.4% vs. 0.7%).
Premature drug discontinuation was noted in 26.9% of patients in the 2.5 mg daily arm, 29.4% in the 5 mg daily arm, and 26.4% in the placebo arm. About 94% of patients were compliant with the study drug at least 85% of the time. Alanine aminotransferase >3x the upper limit of normal occurred in 0.2% of patients in each arm.
The results of this trial indicate that the addition of very low dose rivaroxaban to dual antiplatelet therapy in patients hospitalized with a recent ACS (median duration of use 13.2 months) significantly reduced mortality and ischemic events (including stent thrombosis in patients undergoing PCI) for a median of 1.1 years as compared with placebo. There was, however, a significant increase in non–CABG-related TIMI major bleeding (fourfold increase) and ICH (threefold increase) with rivaroxaban. The best risk:benefit ratio appeared to be with the 2.5 mg daily dose. The results were materially similar among STEMI patients.
Rivaroxaban is a novel oral anti-Xa agent, which has been studied in various settings previously, such as the prevention of venous thromboembolism and stroke prophylaxis in patients with atrial fibrillation. It is currently Food and Drug Administration approved for both indications. A number of other oral anti-Xa agents have been similarly tested in these scenarios, with mostly positive results. However, no or limited benefit has been noted in ACS patients before with these patients. Apixaban was tested in the APPRAISE-1 (phase II) and -2 trials (phase III), which noted no significant improvement in ischemic outcomes, but an increase in bleeding with full-dose apixaban. Similarly, darexaban was tested in the RUBY-1 (phase II) trial, and showed a similarly elevated risk:benefit profile. Rivaroxaban itself was tested in the dose-ranging ATLAS ACS-TIMI 46 trial, and no significant reductions in ischemic endpoints were noted with higher bleeding, especially with the higher doses.
The current trial is thus the first reported successful trial (for ischemic endpoints) adding a low dose of an anticoagulant to dual antiplatelet therapy in patients with recent ACS. It is important to note, however, that this dose (2.5 mg bid) is one quarter the daily dose of the approved dose for anticoagulation of patients with atrial fibrillation (20 mg daily). Thus, the regimen tested is not “triple therapy” of full-dose anticoagulation and dual antiplatelet therapy. Almost all patients in this trial were either on clopidogrel or ticlopidine; concomitant use of even the low dose of rivaroxaban with prasugrel or ticagrelor is likely to be associated with higher bleeding, but would need to be further tested before considering that use. This trial cannot fully address the issue of how to manage patients who need anticoagulation for atrial fibrillation and dual antiplatelet therapy for a coronary stent. Future trials will be needed to define the optimal regimen for such patients.
Gibson CM, Chakrabarti AK, Mega J, et al., on behalf of the ATLAS ACS 2–TIMI 51 Investigators. Reduction of Stent Thrombosis in Patients With Acute Coronary Syndrome Treated With Rivaroxaban in ATLAS ACS 2–TIMI 51. J Am Coll Cardiol 2013;Apr 16:[Epub ahead of print].
Presented by Dr. J. Mega at the European Society of Cardiology Congress, Munich, Germany, August 27, 2012.
Mega JL, Braunwald E, Wiviott SD, et al., on behalf of the ATLAS ACS 2–TIMI 51 Investigators. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2011;Nov 13:[Epub ahead of print].
Armstrong PW, Harrington RA. Road mapping ATLAS ACS 2: are we there yet? Eur Heart J 2012;Jan 31:Epub ahead of print].
Presented by Dr. C. Michael Gibson at the American Heart Association Scientific Sessions, Orlando, FL, November 13, 2011.
Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Anticoagulation Management and ACS, Anticoagulation Management and Venothromboembolism, Aortic Surgery, Cardiac Surgery and Arrhythmias, Interventions and ACS, Interventions and Vascular Medicine
Keywords: Follow-Up Studies, Ischemic Attack, Transient, Morpholines, Thiophenes, Warfarin, Venous Thromboembolism, Ticlopidine, Creatinine, Azepines, United States Food and Drug Administration, Confidence Intervals, Benzamides, Pyridones, Myocardial Infarction, Stroke, Acute Coronary Syndrome, Body Weight, Piperazines, Pyrazoles, Stents, Percutaneous Coronary Intervention, Intracranial Hemorrhages, Secondary Prevention, Coronary Artery Bypass, Diabetes Mellitus
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