Rivaroxaban Doesn't Increase Post-ACS Bleeding vs Aspirin: GEMINI-ACS-1 Trial

Deborah Brauser

March 19, 2017

WASHINGTON, DC — The risk for increased bleeding is similar whether patients with acute coronary syndrome (ACS) are treated with a P2Y12 inhibitor plus either the Xa inhibitor rivaroxaban (Xarelto, Bayer/Janssen) or aspirin, new research suggests[1].

The GEMINI-ACS-1 phase 2 study of more than 3000 patients showed that 5% of those receiving standard dual antiplatelet therapy (DAPT) of aspirin and a P2Y12 inhibitor for more than a year had TIMI clinically significant bleeding not related to CABG (the primary end point)—as did those receiving low dose rivaroxaban in place of aspirin.

These results continued to be similar even when types of P2Y12 inhibitor were compared.

"This showed that aspirin could, at least potentially, be substituted if the outcomes are good. That said, this wasn't an outcomes trial; that still needs to be done," lead author Dr E Magnus Ohman (Duke University School of Medicine, Durham, NC) told heartwire from Medscape.

Ohman presented the study results here at the American College of Cardiology (ACC) 2017 Scientific Sessions, with simultaneous publication in the Lancet.

"We now have a list of medications that are helpful for patients with acute myocardial infarction. The question is: How much bleeding are we willing to allow? And how much bleeding is potentially risky? Hitting that right mix is what this GEMINI study is all about," commented ACC 2017 cochair Dr Jeffrey Kuvin (Dartmouth-Hitchcock Medical Center, Lebanon, NH).

"The data from this study show that there's noninferiority between the different algorithms that they chose in this population," said Kuvin, who was not involved with the research. "However, it's important to treat each patient as an individual who has individual risks of bleeding."

Dr E Magnus Ohman

Reevaluating Standard Treatment

DAPT consisting of aspirin and a P2Y12 inhibitor "is the standard antithrombotic treatment" for ACS, although about 10% of patients have a major CV event during follow-up, note the investigators. Rivaroxaban has been shown to decrease both mortality and ischemic event risks when added as a third prong to DAPT, but it's also associated with increased bleeding.

For the current study, the researchers enrolled 3037 ACS patients (75% men; 93% white; mean age 57.0 years) from 21 countries between April 2015 and October 2016.

After being on stable DAPT for at least 48 hours, all were randomly assigned to receive for at least 6 months 2.5 mg of rivaroxaban twice daily plus a P2Y12 inhibitor (n=1519) or 100 mg of aspirin per day plus a P2Y12 inhibitor (n=1518). The two types of P2Y12 inhibitors taken by the patients were ticagrelor (Brilinta, AstraZeneca) 75 mg daily (n=1704) and clopidogrel 90 mg twice daily (n=1333), which were not randomized.

The full therapeutic regimens began within 10 days after admission for the index ACS (mean time 5.5 days), and the mean treatment duration was 291 days.

The hazard ratio (HR) for the primary end point was a nonsignificant 1.09 between the treatment groups (95% CI 0.80–1.50, P=0.58).

In the P2Y12-inhibitor–based subgroups, the HR for the primary end point was higher for those receiving ticagrelor vs those receiving clopidogrel, but this was not significant—even when researchers also assessed for rivaroxaban or aspirin use.

"Hypotheses Generating"

TIMI major and minor bleeding, GUSTO life-threatening or severe bleeding, and BARC 3a and higher bleeding were all not significantly different between the groups, although rivaroxaban had numerically higher rates in each category.

In addition, International Society on Thrombosis and Hemostasis (ISTH) major bleeding was significantly higher in the rivaroxaban vs aspirin groups (2.0% vs 1.1%, respectively, HR 1.83; P=0.04).

In exploratory analyses, an ischemic composite end point of CV death, MI, stroke, or stent thrombosis occurred in 5% and 4.7% of the treatment groups, respectively (HR 1.06). But Ohman noted that the ischemic assessments were underpowered.

Based on the overall findings, "and the unmet need for improved treatments in the post–acute coronary syndromes setting, further testing of the efficacy and safety of this novel dual pathway antithrombotic regimen in an adequately powered trial should be considered," write the investigators.

Dr Ohman added that because this was a phase 2 trial, "the results are hypotheses generating." When asked after his presentation if a phase 3 trial is now in the works, he replied that "that would certainly be nice." However, nothing definite is currently planned.

Change to the Status Quo?

In an accompanying editorial[2], Drs Paul A Gurbel and Udaya S Tantry (Innova Heart and Vascular Institute, Falls Church, VA) note that "the cornerstone" to ACS treatment was firmly placed by the ISIS-2 trial, when it compared aspirin with placebo. But now, GEMINI-ACS-1 is attempting to replace that cornerstone.

"The investigators and sponsor should be congratulated for conducting thoughtful and exciting research," they write.

But although the primary end point did not differ significantly between the groups, "almost all bleeding metrics were nonsignificantly lower with aspirin and a 50% increased bleed rate with rivaroxaban cannot be excluded."

In addition, they note that numerically, if not significantly, the lowest composite ischemic end point came with ticagrelor plus aspirin (3.9% vs 4.7% when it was with rivaroxaban).

"Thus, it might be premature to believe that a low-dose Xa inhibitor on top of a P2Y12 inhibitor can be effective and safe therapy for most stabilized patients with [ACS]. The totality of the evidence of GEMINI-ACS-1 favors aspirin," write the editorialists, adding that more convincing research is needed.

Dr Jeffrey Kuvin

"This was a study looking at two treatment regimens and asking which one is better or which one is worse, in terms of bleeding in a high-risk population. I think we need to use this evidence, but really drill down how it's going to affect our patient care," Kuvin added to heartwire .

In other words, he's not yet ready to say it's time to throw out aspirin. "The data are intriguing, and I think they're thought-provoking. The take-home message is that we now have an expansive list of antithrombotic and anticoagulant medications that we can utilize in patients. But the question remains: in whom do we utilize these and in what combinations?"

During the postpresentation discussion, panelist Dr Karol E Watson (University of California, Los Angeles Medical School) noted that, based on the findings, "it does seem that the status quo will not be changing."

"With this being a phase 2 trial, it should not inform practice," agreed Ohman. "This is just a stepping-stone to try to better define how we can go forward with combinations of therapy in the future."

The study was funded by Janssen Research & Development and Bayer. Ohman has received institutional research grants from Janssen Pharmaceuticals, Daiichi-Sankyo, and Gilead Sciences, as well as consulting fees from Abbott Vascular, Abiomed, AstraZeneca, Bayer, Biotie, Boehringer Ingelheim, Daiichi-Sankyo, Medscape, Merck, St Jude Medical, Stealth Peptides, and the Medicines Company. Disclosures for the coauthors are listed in the paper. Gurbel has received consulting honoraria from AstraZeneca, Boehringer, Merck, Janssen, Bayer, and Haemonetics; has received research grants from Haemonetics, DCRI, Merck, the National Institutes of Health, Bayer, Medimmune, and Coramed; and has patents on platelet-function testing. Tantry and Kuvin have reported no relevant financial relationships. Watson has served as an advisor or consultant for GlaxoSmithKline, Merck, and Quest Diagnostics.

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