ATLAS ACS 2 TIMI 51: 2.5-mg Rivaroxaban Cuts Cardiac Events in STEMI

August 29, 2012

August 29, 2012 (Munich, Germany) — Results from the STEMI cohort of the ATLAS ACS 2 TIMI 51 trial have shown similar findings to the overall ACS population, with the 2.5-mg twice-daily dose of rivaroxaban (Xarelto, Bayer/Johnson & Johnson) showing better results than the 5-mg twice-daily dose.

Presenting the data at the European Society of Cardiology (ESC) 2012 Congress, Dr Jessica Mega (Brigham and Women's Hospital, Boston, US) noted that long-term anticoagulant therapy has been of particular interest in the STEMI population, and these patients were a prespecified subgroup in the ATLAS-2 TIMI51 study.

While the 2.5-mg dose of rivaroxaban did show an encouraging reduction in cardiac events in this population, the discussant of the STEMI analysis at the ESC meeting, Dr Andreas Zeiher (University of Frankfurt, Germany), suggested that there may be a relatively limited place for the drug in this indication at present.

Rivaroxaban is awaiting approval for the ACS indication based on the ATLAS ACS 2 TIMI51 results. The FDA recently requested additional data on missing patients.

The ATLAS ACS 2 TIMI 51 trial compared the two doses of the new anticoagulant with placebo on top of standard therapy in 15 526 ACS patients. Overall results, reported late last year, showed a reduction in cardiac events at the cost of an increase in major bleeding.

Zeiher noted that the results for the STEMI population could be superimposed on the global results in ACS patients. In addition, he observed that the placebo event rate in the STEMI group was "absolutely identical" to that in the overall ACS population, showing that once stabilized, STEMI and non-STEMI ACS patients carry identical risk during long-term follow-up.

Zeiher noted that, as in the overall trial, the 5-mg dose was associated with an unacceptable rate of bleeding, adding: "I think we have seen the end of the 5-mg dose."

Bleeding Increased With Time

While the 2.5-mg dose has a lower rate of bleeding than the 5-mg dose, Zeiher said that the linear relationship of bleeding with time was of concern. "What can we expect if we extend therapy?" he asked. He also pointed out that the efficacy curves diverged very early, and the risk reduction in cardiac events was, if anything, a little bit lower at 30 days than at the end of the study (two years). "So perhaps we could shorten duration of therapy," he suggested.

Where Will Rivaroxaban Fit in?

Zeiher said the data raised many clinical questions, the most important of which is where rivaroxaban would fit with regard to other agents in ACS. He pointed out that prasugrel (Effient, Lilly/Daiichi-Sanyo) and ticagrelor (Brilinta, AstraZeneca) are now the preferred antiplatelet agents to use in STEMI patients, but rivaroxaban was evaluated on top of clopidogrel in the ATLAS ACS 2 TIMI 51 trial. "Prasugrel and ticagrelor were not allowed in the trial because of concerns about bleeding risk. But we have to know if rivaroxaban in combination with these more potent antiplatelet agents will increase bleeding risk."

He further highlighted the fact that if the drug is approved for treatment in ACS, rivaroxaban will be on the market in three different doses for three different cardiovascular indications: AF at 20 mg a day; deep vein thrombosis/pulmonary embolism (DVT/PE) at 20 to 30 mg a day; and for ACS at 2.5 mg twice daily. "What would we do with a patient who comes in with ACS and has AF. Do we reduce dose to 2.5 mg bid? And how do we treat a patient who develops AF after MI?" he asked.

Already in the European STEMI Guidelines

He noted, however that the ATLAS ACS 2 data have already been incorporated into the new European STEMI guidelines. "The combination of aspirin plus prasugrel or ticagrelor is recommended with a level 1b level of evidence over aspirin plus clopidogrel, the regimen used in ATLAS ACS 2 trial. But rivaroxaban at the 2.5-mg twice-daily dose was given a class IIb recommendation for selected patients who do receive aspirin and clopidogrel for whatever reason if they are considered at low bleeding risk."

The current analysis focused on the 7817 STEMI patients in the trial. Results with the 2.5-mg dose showed a reduction in cardiac events, as well as cardiovascular death and all-cause death, at the cost of an increase in bleeding.

ATLAS2-TIMI51: Results in STEMI Patients at Two Years

Outcome Rivaroxaban 2.5mg bid Placebo HR (95% CI) p
CV death/MI/stroke 8.7 10.6 0.81 (0.65–1.00) 0.047
CV death 2.5 4.2 0.60 (0.42–0.87) 0.006
All-cause death 3.0 4.7 0.63 (0.45–89) 0.008
TIMI non-CABG major bleeding 1.7 0.6 3.63 (1.73–7.61) <0.001

Mega concluded that very low-dose rivaroxaban (2.5 mg twice daily) offers an effective strategy to reduce thrombotic events in patients following a STEMI.