The antithrombotic treatment of patients with acute coronary syndrome (ACS) has focused in the past on antiplatelet agents. Whereas recently, even stronger antiplatelet therapies, such as prasugrel or ticagrelor, have been developed, the rate of thrombotic events such as reinfarction, stent thrombosis or fatal thrombotic events remains a relevant clinical problem. Previous studies investigating prolonged anticoagulation beyond the administration of heparin or similar agents during the acute phase of ACS have not shown a clear benefit. Therefore, in clinical practice triple therapy encompassing two antiplatelet agents and an anticoagulant are only used in patients with an additional indication for anticoagulation such as atrial fibrillation or mechanical valves. 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) study investigating additional anticoagulation with low-dose rivaroxaban was published in the New England Journal of Medicine in January 2012.1
Study design and population
The ATLAS ACS 2-TIMI 51 study, a double-blind, placebo-controlled trial, included more than 15 000 patients with ST elevation myocardial infarction (STEMI; 50%), non-ST elevation myocardial infarction (NSTEMI; 26%) and unstable angina (UA; 24%). Rivaroxaban was used in a lower dose of 2 × 2.5 mg or 2 × 5 mg compared with previous studies such as the ROCKET AF (rivaroxaban once daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation) study investigating atrial fibrillation (once daily 20 mg). Rivaroxaban on top of standard care with dual antiplatelet treatment (aspirin 99% and thienopyridines 93%) was compared with placebo with standard care treatment. The median treatment duration was 31 months. Only patients without evidence of increased bleeding risk were included in the ATLAS ACS 2-TIMI 51 trial. Accordingly, only 9% of patients were 75 years of age or older and only 25% had reduced renal function. Of note, only 25% of patients were female. Sixty per cent of study patients underwent percutaneous coronary intervention or coronary-artery bypass grafting.
The combined primary efficacy endpoint cardiovascular mortality, myocardial infarction and stroke was significantly reduced by 16% (from 10.7% to 8.9% during 24 months) in the rivaroxaban arm. The effect was consistent with regard to relevant clinical baseline characteristics. Only patients with a prior stroke or transient ischaemic attack showed a trend for a worse outcome in the rivaroxaban group (P for interaction = 0.1). Also the secondary endpoint stent thrombosis, a potentially fatal event, was significantly reduced by 31% (from 2.9% to 2.3%). When analysing the two dosages of rivaroxaban separately a significant reduction of cardiovascular (P = 0.002) and all-cause mortality (P = 0.002) was observed with the lower dose of 2 × 2.5 mg rivaroxaban compared with placebo.
With regard to safety, rivaroxaban was associated with a rate of major bleeding (according to the TIMI definition) four times higher than placebo (2.1% vs 0.6%). Increased bleeding was observed with both dosages of rivaroxaban. In addition, the rate of intracerebral bleedings tripled in the rivaroxaban arm (0.6% vs 0.2%). However, the rate of fatal bleeding was not significantly higher with rivaroxaban (0.3% vs 0.2%, P = 0.66).
The additional and prolonged administration of rivaroxaban for > 2 years in patients with ACS showed increased efficacy compared with standard treatment with dual antiplatelet regimen only. Increased efficacy resulted in a reduction of mortality with the lower dosage of rivaroxaban. However, this was accompanied by a fourfold higher risk of major bleeding. Another study with the new oral anticoagulant apixaban was even stopped prematurely due to increased bleeding risk without improved efficacy.2 In contrast to the ATLAS ACS 2-TIMI 51 trial, this study did not reduce the dose of the new oral anticoagulant compared with the indication for atrial fibrillation.
Because of the strong increase in bleeding, patients who may benefit from increased efficacy with rivaroxaban 2 × 2.5 mg have to be selected carefully. Rivaroxaban could be a therapeutic option for young and otherwise healthy patients, without previous stroke or transient ischaemic attack, who have an increased risk of recurrence of coronary events such as stent thrombosis. An additional analysis of interventional data (e.g. type of stent) is warranted. Furthermore, the lack of the use of new antiplatelet agents in this study limits the generalizability of the data. Newer antiplatelet agents might be a safer option in patients at high risk for thrombotic events.