Net clinical outcome analyses of acute coronary syndrome (ACS) mingle fatal or irreversible events with survivable or reversible events that vary significantly in clinical impact.
Objectives
A comparison of efficacy and safety limited to fatal or irreversible ischemic and adverse or seriously harmful events is one way to assess net clinical outcome and risk-benefit overall, given the fact that these events have a similar clinical impact.
Methods
In 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) trial of rivaroxaban in the secondary prevention of events among patients with ACS treated with aspirin plus clopidogrel or ticlopidine (clopidogrel/ticlopidine) or aspirin alone, fatal and irreversible efficacy events including nonbleeding cardiovascular death, myocardial infarction, and ischemic stroke were compared to fatal or irreversible safety events, including fatal and intracranial bleeding.
Results
Rivaroxaban, 2.5 mg orally twice per day, in patients treated with aspirin and clopidogrel/ticlopidine was associated with 115 (95% confidence interval [CI]: 18 to 212) fewer fatal or irreversible ischemic events (663 for placebo vs. 548 for therapy) and 10 (95% CI: −11 to 32) additional fatal or irreversible seriously harmful events (33 vs. 23 for placebo) per 10,000 patient-years of exposure. Taken together, there would be 105 (95% CI: 6 to 204) fatal or irreversible events prevented per 10,000 patient-years of exposure to rivaroxaban compared with placebo, with 11 (10 of 115) fatal or irreversible ischemic events prevented for each fatal or irreversible seriously harmful event caused. If only nonbleeding cardiovascular death is included as a fatal or irreversible event, then 95 events would be prevented per 10,000 patient-years of exposure in the group taking 2.5 mg orally twice per day.
Conclusions
Both fatal or irreversible ischemia and bleeding are clinically significant events that can be compared to assess the net clinical outcomes associated with therapy. Rivaroxaban therapy at an oral dose of 2.5 mg twice daily in patients treated with aspirin and clopidogrel is associated with a net reduction in fatal or irreversible events. (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction [ATLAS ACS 2-TIMI 51]; NCT00809965)
ATLAS ACS 2-TIMI 51 was supported by Johnson & Johnson and Bayer Healthcare. Dr. Gibson has received funding through his institution from Johnson & Johnson and Bayer Healthcare; and has received grants and honoraria from Bayer, Johnson & Johnson, and Portola. Dr. Levitan is an employee of Janssen Research and Development; and holds stock in Janssen, Baxter International, Inc., Pharmaceutical Holdrs Trust, and Zimmer Holdings, Inc. Drs. Yuan and Lee are employees of Janssen Research and Development. Dr. Braunwald, Ms. Murphy, and the TIMI Study Group have received research grants from Johnson & Johnson and Daiichi-Sankyo. Dr. Braunwald has received speakers honoraria from Daiichi-Sankyo and Bayer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
