In a new analysis comparing only clinically similar outcomes in patients with acute coronary syndrome, the addition of rivaroxaban to standard antiplatelet therapy resulted in 115 fewer fatal or irreversible ischemic events per 10,000 patient-years than placebo, at the expense of only 10 additional fatal or seriously harmful events.
This new interpretation of the ATLAS ACS 2-TIMI 51 trial (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction-51) suggests that the factor Xa inhibitor may still carve out a place for itself in ACS therapy, despite Food and Drug Administration rejections for this indication.
Not only did the survival benefit of rivaroxaban appear early in postevent treatment, it continued to protect patients over time, C. Michael Gibson, MD, and colleagues reported in the Journal of the American College of Cardiology.
“Time-to-event analysis demonstrated that the risk of fatal or irreversible harm remained low and constant over time, whereas reduction in fatal or irreversible ischemic events expanded,” wrote Dr. Gibson, professor of medicine at Beth Israel Deaconess Medical Center, Boston, and his coinvestigators. “By 720 days, a net of 142 fatal or irreversible events would have been prevented by 2.5-mg oral doses twice per day of rivaroxaban. Additional time-to-event sensitivity analyses demonstrated similar results, even when TIMI major bleeding was included as a fatal or irreversible event.”
In conducting the new analysis, Dr. Gibson and his team argued that the original interpretation of the results of ATLAS ACS 2-TIMI 51 lumped both fatal and nonfatal events together in composite endpoints, resulting in an inaccurate real-life picture of rivaroxaban’s therapeutic potential. “All types of events [were] weighted equally; for example, reversible nonintracranial hemorrhage, nonfatal bleeds that can be managed with supportive care, are weighted equally with death and disabling stroke. Second, stroke can be either hemorrhagic or ischemic, and the relative contributions of hemorrhagic or ischemic stroke may not be appropriately assigned to risk-versus-benefit categories in many analyses.”
The net result was that, while rivaroxaban did reduce the risk of the composite endpoint (cardiovascular death, MI, or stroke), the 1.7% absolute difference in cardiovascular mortality was almost completely offset by a 1.3% increase in major bleeding. However, most of those bleeds were reversible and nonfatal, associated with a drop in hemoglobin and/or blood transfusion. The drug did not increase the risk of fatal bleeding.
Giving equal statistical weight to clinically equal events provides a clearer focus, the investigators said.
“In this form of analysis, only fatal or irreversible events were included so that benefit and seriously harmful events of similar clinical impact were compared,” they wrote. “This is particularly important when the endpoints and analyses do not include measurements of subjective clinical impact such as utility measurements or preference weights. This approach also uses risk differences rather than relative measurements such as hazard ratios, so the number of events prevented and caused are clearly distinguished.”
ATLAS comprised more than 15,000 patients with ST-segment elevation MI, non-STEMI, or unstable angina. They were randomized to either rivaroxaban 2.5 mg orally twice per day, 5 mg orally twice per day, or to placebo, in addition to standard of care, which included low-dose aspirin. Patients were stratified by the optional use of clopidogrel/ticlopidine.
Dr. Gibson and his team reanalyzed the data by comparing outcomes they judged as having a similar clinical impact: fatal and irreversible cardiovascular death, MI, and ischemic stroke. They also assessed all bleeding, TIMI life-threatening bleeding, and TIMI major bleeding.
In this analysis, the 2.5-mg dose was associated with 115 fewer fatal or irreversible ischemic deaths per 10,000 patient-years of exposure than placebo (548 vs. 663 nonbleeding cardiovascular deaths, MIs, or ischemic strokes).
However, the same dose was also associated with 10 more excessive, fatal, or irreversibly serious harmful events, compared with placebo per 10,000 patient years (33 fatal bleeds or intracranial hemorrhage vs. 23 for placebo).
“Considered together, there would be 105 fatal or irreversible events prevented per 10,000 patient-years of exposure to 2.5 mg of rivaroxaban taken orally twice a day, compared with placebo. An alternate interpretation of the data is that there would be 11 [10 of 115] fatal or irreversible ischemic events prevented for each fatal or irreversible harmful event caused,” Dr. Gibson and his colleagues wrote.
The benefit held when the outcomes were individually reckoned as well. If periprocedural MIs were excluded, rivaroxaban would still prevent 115 fatal or irreversible ischemic events. If only nonbleeding cardiovascular death or ischemic strokes were included, then 90 fatal or irreversible events would be prevented. And if only nonbleeding cardiovascular death was included, then 95 events would be prevented per 10,000 patient-years of exposure in the group taking rivaroxaban 2.5 mg twice daily.
“In all cases, the fatal or irreversible events prevented are 9-11 times the fatal or irreversible seriously harmful events caused,” the investigators said.
ATLAS ACS 2-TIMI 51 was supported by Johnson & Johnson and Bayer Healthcare. Dr. Gibson has received institutional funding, grants, and honoraria from those companies and from Portola Pharmaceuticals.
SOURCE: Gibson CM et al. J Am Coll Cardiol. 2018;72:129-36.