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ARISTOTLE: Major bleeding consequences similar between apixaban, warfarin
Major bleeding was associated with increased risk for death, ischemic stroke and MI, and the risk was similarly elevated regardless of treatment with warfarin or apixaban, according to new findings from the ARISTOTLE trial.
Researchers conducted an ancillary study from ARISTOTLE, the pivotal trial for apixaban (Eliquis, Bristol-Myers Squibb/Pfizer; n=18,201) to evaluate the clinical consequences of major bleeds and to compare the management and treatment effects of warfarin vs. apixaban.
The outcome of interest was International Society on Thrombosis and Hemostasis major bleeding, defined as overt bleeding accompanied by a ≥2 g/dL decrease in hemoglobin or a transfusion of at least two units of packed red cells occurring at a critical site or resulting in death.
Claes Held, MD, PhD, FACC, from the departments of medical sciences and cardiology, Uppsala Clinical Research Center, Uppsala University, Sweden, evaluated time to death, ischemic stroke or MI by Cox regression models. They evaluated the excess risk associated with bleeding by separate time-dependent indicators for intracranial hemorrhage and non-intracranial hemorrhage.
Major bleeding occurred in 4.7% of patients, of whom 14.9% died within 30 days of bleeding. Of those with intracranial hemorrhage, 43.2% died within 30 days, and of those with non-intracranial hemorrhage major bleeding, 9.2% died within 30 days.
Compared with no major bleeds, patients with major bleeds were older; had lower body weight; were more likely to have had a previous MI; were more likely to have had a previous stroke, transient ischemic attack or systemic embolism; were more likely to have had previous bleeding; were more likely to have impaired renal function; had higher CHADS2, CHA2DS2-VASc and HAS-BLED scores; and were more often treated with aspirin, clopidogrel or nonsteroidal anti-inflammatory drugs (P<.01 for weight and MI; P<.0001 for all others).
Risk for death was markedly increased within 30 days of an intracranial hemorrhage (HR=121.5; 95% CI, 91.3-161.8), as was risk for stroke or MI (HR=21.95; 95% CI, 9.88-48.81), according to the researchers. Risk for death, ischemic stroke or MI was increased approximately 12-fold within 30 days of a non-intracranial hemorrhage bleeding event.
Among those with major bleeds, 20.8% received vitamin K antagonists and/or related medications, and 37% received blood transfusions. Patients assigned warfarin were more likely to receive vitamin K antagonists and/or related medications and to have fresh frozen plasma transfusion compared with those assigned apixaban. There was no difference between the groups in rate of blood transfusion, they wrote.
In addition, the warfarin and apixaban groups had similar rates of 30-day mortality among those with major bleeding (HR=0.77; 95% CI, 0.537-1.103).
In the ARISTOTLE trial, patients assigned apixaban had a lower rate of overall bleeding vs. those assigned warfarin, which “is likely to explain the lower rate of mortality and stroke in the overall trial,” Held and colleagues wrote.
Disclosure: The study was funded by Bristol-Myers Squibb/Pfizer. Several researchers report financial relationships with pharmaceutical companies, including Bristol-Myers Squibb and Pfizer; see the full study for a list of the researchers’ relevant financial disclosures.