Skip to main content

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


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 FDArecently 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
OutcomeRivaroxaban 2.5mg bidPlaceboHR (95% CI)p
CV death/MI/stroke8.710.60.81 (0.65–1.00)0.047
CV death2.54.20.60 (0.42–0.87)0.006
All-cause death3.04.70.63 (0.45–89)0.008
TIMI non-CABG major bleeding1.70.63.63 (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.

Comments

Post a Comment

Popular posts from this blog

Missing Data Lead FDA Panel to Vote Against Rivaroxaban for ACS May 23, 2012 (Updated May 24, 2012) (Silver Spring, Maryland) — The missing data issues plaguing the ATLAS ACS 2 TIMI 51 trial of the factor Xa inhibitor rivaroxaban (Xarelto, Bayer Healthcare/Janssen Pharmaceuticals) have prevented the drug from earning the endorsement of the FDA Cardiovascular and Renal Drugs Advisory Committee. At its May 23 meeting, the panel voted six to four (with one abstention) against recommending that the FDA approve rivaroxaban for reducing the risk of thrombotic cardiovascular events in patients with acute coronary syndrome or unstable angina in combination with aspirin, aspirin plus clopidogrel, or ticlopidine. Janssen's application is based on the results of the ATLAS ACS 2 phase 3 and the ATLAS ACS TIMI 46 phase 2 trial. The placebo-controlled ATLAS ACS 2 showed rivaroxaban reduced the risk of both all-cause and cardiovascular mortality while increasing the risk of bleeding and intracranial hemorrhage, but the studies were hindered by early patient withdrawals and missing data. We Don't Know What We're Missing Based on the ATLAS ACS 2 results, FDA reviewer Dr Karen Hicks recommended approval of rivaroxaban for the requested indications except all-cause mortality. However, another FDA reviewer, Dr Thomas Marciniak, was adamant that the trial results are not interpretable because about 12% of the patients had incomplete follow-up, far higher than the 1% to 1.5% differences in the end-point rates between rivaroxaban and placebo. A total of 1294 subjects discontinued the trial prematurely, and the company was only able to contact 183, of which 177 were confirmed to be alive. Because of the patient dropouts, the company adopted a "modified intention-to-treat analysis," whereby patients were observed for 30 days after randomization or the global end date for the trial, instead of observing all the patients until the end of the trial as the FDA originally suggested. Marciniak criticized the sponsor's efforts to follow the patients and said that three patient deaths not counted in the modified intention-to-treat analysis may just be the "tip of the iceberg." Because the percentage of patients whose ultimate vital status remains unknown is much greater than the reported differences in mortality rates, the claimed mortality benefits are not reliable. The majority of the panel sided with Marciniak. For example, Dr Sanjay Kaul (University of California, Los Angeles) voted "no" because "there was enough uncertainty in the quality and robustness of the data that dissuaded me from voting yes. . . . The 'missingness' of the data doesn't invalidate it, but it certainly makes it hard to infer [the conclusion]." Dr Steven Nissen (Cleveland Clinic, OH) said that the decision to use the modified intention-to-treat analysis had a "profound impact" on the interpretability of the data. "It's saying we don't care what happens after 30 days, [and] that colored the trial in ways we couldn't recover from." Given the risk of major bleeding, "I want to see better evidence that this strategy of adding an Xa inhibitor or a direct thrombin inhibitor or something else to a good antiplatelet agent is robustly better for the patient," Nissen said. He recommends that the companies run a new trial of the 2.5 twice-daily dose of rivaroxaban using a strict intention-to-treat approach, but, he said, "I don't expect the death benefit to be too robust." Several panelists said they were concerned that the patients who dropped out of the trial were disproportionately likely to have a bleeding event, which led them to quit the trial, or a "protopathic" event, as statistician Dr Scott Emerson (University of Washington, Seattle) put it. "We're worried that an impending event is what is changing their behavior. We see that all the time in clinical trials--that regularly measured end points do not pick up [all of] the events," he said. He said that since the company was only able to contact 183 of the over 1200 patients who dropped out, it is possible that the dropouts skew the outcomes comparison of the trial. "Differential event rates after dropout are the number-one thing we're afraid of, so you have to explore it" in a statistical sensitivity analysis of the potential impact of these unknown outcomes. "It would not surprise me if, at the end of the day, these data did not hold up under a proper sensitivity analysis," he said. "What I want to know is, among the people who had events, how differential was the follow-up, but I can tell you by just looking at it, there was a very slightly different amount of follow-up of the people in the treatment arm. But I don't know whether everyone in the treatment arm was cured and they were trekking in the Himalayas and everyone in the placebo arm went home to die. I don't know that that's not the case." Dr Maury Krantz (University of Colorado, Denver) voted in favor of approval but said he does not know how rivaroxaban would perform in general clinical practice, especially when used with aspirin and clopidogrel. "I felt very much torn by this. This isn't a simple paradigm shift. It means going to triple therapy, which is really a three-headed monster in many ways. I think that what you're going to see in practice, if this is not done carefully with the proper labeling and secondary studies, is really dramatic magnification of bleeding and perhaps minimization of the efficacy benefit."

May 23, 2012   (Updated May 24, 2012)  (Silver Spring, Maryland)  —  The missing data issues plaguing the  ATLAS ACS 2 TIMI 51   trial of the factor Xa inhibitor  rivaroxaban  (Xarelto, Bayer Healthcare/Janssen Pharmaceuticals) have prevented the drug from earning the endorsement of the  FDA  Cardiovascular and Renal Drugs Advisory Committee. At its May 23 meeting , the panel voted six to four (with one abstention) against recommending that the FDA approve rivaroxaban for reducing the risk of thrombotic cardiovascular events in patients with acute coronary syndrome or unstable angina in combination with aspirin, aspirin plus  clopidogrel , or  ticlopidine . Janssen's application is based on the results of the ATLAS ACS 2 phase 3 and the  ATLAS ACS TIMI 46   phase 2 trial. The placebo-controlled ATLAS ACS 2 showed rivaroxaban reduced the risk of both all-cause and cardiovascular mortality while increasing the ri...
Post a Comment
Read more

Antidepressants Linked to Higher Diabetes Risk in Kids

Pediatric patients who use antidepressants may have an elevated risk for type 2 diabetes, the authors of a new study report. In a retrospective cohort study of more than 119,000 youths 5 to 20 years of age, the risk for incident type 2 diabetes was nearly twice as high among current users of certain types of antidepressants as among former users, Mehmet Burcu, PhD, and colleagues report in an article  published online October 16 in  JAMA Pediatrics . The risk intensified with increasing duration of use, greater cumulative doses, and higher daily doses of these antidepressants. The findings point to a growing need for closer monitoring of these products, including greater balancing of risks and benefits, in the pediatric population, the authors caution. They undertook the study because, despite growing evidence of an association between antidepressant use and an increased risk for type 2 diabetes in adults, similar research in pediatric patients was scarce. "To our know...
Post a Comment
Read more

EHR Work Measures Proposed to Address Burnout

Electronic health record (EHR) vendors should imbed metrics into their systems to measure how EHRs affect clinicians' work, experts write in a commentary  published online  October 10 in the  Annals of Internal Medicine . Yumi T. DiAngi, MD, a fellow in clinical informatics at Stanford University School of Medicine in Palo Alto, California, and colleagues propose six areas metrics should cover and recommended the creation of a "national council of clinicians" to design measures and create guidelines to address privacy and other issues. "The EHR, which was intended to improve patient care, has had the ironic and unintended consequence of impairing practice efficiency, largely because of poor design, a focus on regulatory reporting, and the burden placed on clinicians by data entry," they write. EHRs have also led to high levels of burnout as physicians' satisfaction in their work has declined, they note. To gain insight into the stresses that have pro...
Post a Comment
Read more