Safety of Rivaroxaban Versus Acetylsalicylic Acid in Addition to Either Clopidogrel or Ticagrelor Therapy in Participants With Acute Coronary Syndrome - GEMINI-ACS-1

Nov 14, 2017
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Janssen Research & Development and Bayer AG.
Date Presented:
11/14/2017
Date Published:
03/18/2017
Date Updated:
11/14/2017
Original Posted Date:
03/18/2017
References

Contribution To Literature:

The GEMINI-ACS-1 trial showed that low-dose rivaroxaban (2.5 mg BID) does not result in higher bleeding compared with aspirin 100 mg daily in patients already on a P2Y12 inhibitor post-ACS.

Description:

The goal of the trial was to assess the safety of low-dose rivaroxaban 2.5 mg BID compared with aspirin in patients with recent acute coronary syndrome (ACS) also on a P2Y12 inhibitor.

Study Design

About 1-10 days following an ACS event, patients already on aspirin 100 mg were stratified by the treating physician to either clopidogrel 75 mg daily or ticagrelor 90 mg BID. In both strata, randomization was then performed in a 1:1 ratio to either continuing aspirin 100 mg daily (n = 1,518) or to rivaroxaban 2.5 mg BID (n = 1,519).

  • Total number of enrollees: 3,037
  • Duration of follow-up: 1 year
  • Mean patient age: 62 years
  • Percentage female: 25%

Inclusion criteria:

  • Randomization within 10 days of an ACS event
  • Patient age >18 years
  • Patients age <55 years required one of two enrichment criteria, either history of diabetes or prior myocardial infarction (MI)

Exclusion criteria:

  • History of active bleeding, intracranial bleeding, or significant gastrointestinal bleeding within 12 months
  • Estimated creatinine clearance <20 ml/min
  • Use of omeprazole (in clopidogrel strata)
  • Need for chronic full-dose anticoagulation
  • All patients were tested for P2Y12 metabolite status and results were provided to caring physician within 2 weeks of randomization to allow poor clopidogrel metabolizer patients to be switched

Other salient features/characteristics:

  • Percentage with ST-segment elevation MI (STEMI): 49%, non-STEMI: 40%
  • Mean time from hospitalization to randomization: 5.1 days
  • Mean GRACE score: 96
  • Percentage receiving catheterization: 94%; percutaneous coronary intervention: 87%; drug-eluting stent: 67.3%

Principal Findings:

Primary endpoint: TIMI non-CABG clinically significant bleeding for rivaroxaban vs. aspirin: 5.3% vs. 4.9%, p = 0.58

Secondary outcomes for rivaroxaban vs. aspirin:

  • TIMI major bleeding: 0.7% vs. 0.5%, p = 0.63
  • GUSTO moderate, severe, or life-threatening bleeding: 0.7% vs. 0.5%, p = 0.34
  • BARC 3a or higher bleeding: 1.4% vs. 0.9%, p = 0.13
  • Cardiovascular death/MI/stroke/definite stent thrombosis: 5.0% vs. 4.7%, p = 0.73
  • All-cause mortality: 1.4% vs. 1.5%, p = 0.88
  • All stent thrombosis: 1.1% vs. 1.1%, p = 0.86
  • No significant treatment interaction and P2Y12 inhibitor use for primary bleeding endpoint (p = 0.59) or ischemic endpoints (p = 0.39)

CYP2C19 clopidogrel metabolizer status: 34.4% were ultra-metabolizers, 37.8% extensive metabolizers, 24.5% intermediate metabolizers, and 3.2% reduced metabolizers. This information was provided to the enrolling investigators. Only 6.5% of patients had their P2Y12 inhibitor drug changed. Of these, two thirds were from ticagrelor to clopidogrel, mostly due to a nonbleeding adverse event. Among 20 patients with reduced metabolizer status in the clopidogrel-treated patients, 70% were switched to ticagrelor. Metabolizer status had no effect on ischemic or bleeding outcomes.

Interpretation:

The results of this phase II trial indicate that low-dose rivaroxaban (2.5 mg BID) does not result in higher bleeding compared with aspirin 100 mg daily in patients already on a P2Y12 inhibitor post-ACS. Ischemic endpoints were also similar, but the trial was not powered to assess these independently.

Switching of P2Y12 inhibitors was infrequent despite direct reporting of CYP2C19 metabolizer status to investigators, and in fact, was more commonly from ticagrelor to clopidogrel due to adverse events, rather than from clopidogrel to ticagrelor.

This trial adds to the growing body of literature suggesting a role for low-dose rivaroxaban in patients post-ACS. In the ATLAS-ACS 2-TIMI 51 trial, adding low-dose rivaroxaban to dual antiplatelet therapy (DAPT) resulted in lower ischemic events, but higher bleeding rates. This trial suggests that dropping aspirin (like in the WOEST trial) and adding low-dose rivaroxaban to a P2Y12 inhibitor has a similar bleeding profile to DAPT. The ischemic benefit will need to be tested in a larger phase III trial. Of note, the low-dose of rivaroxaban is currently not available in the United States.

References:

Presented by Dr. Matthew T. Roe at the American Heart Association Annual Scientific Sessions (AHA 2017), Anaheim, CA, November 14, 2017.

Ohman EM, Roe MT, Steg G, et al. Clinically significant bleeding with low-dose rivaroxaban versus aspirin, in addition to P2Y12 inhibition, in acute coronary syndromes (GEMINI-ACS-1): a double-blind, multicentre, randomised trial. Lancet 2017;389:1799-1808.

Presented by Dr. Erik M. Ohman at the American College of Cardiology Annual Scientific Session (ACC 2017), Washington, DC, March 18, 2017.

Keywords: AHA17, AHA Annual Scientific Sessions, ACC17, ACC Annual Scientific Session, Acute Coronary Syndrome, Adenosine, Angina, Unstable, Anticoagulants, Aspirin, Factor Xa Inhibitors, Hemorrhage, Myocardial Infarction, Secondary Prevention, Stents, Stroke, Thrombosis, Ticlopidine, Purinergic P2Y Receptor Antagonists


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