Lancet: Xarelto reduces major CV outcomes
Administration of the oral anticlotting drug rivaroxaban (Xarelto) to patients after an acute coronary syndrome, such as MI or unstable angina, reduces the incidence of stroke, further heart attack and death, according to the ATLAS ACS-TIMI 46 study reported in June 16 online in the Lancet.
Xarelto from Bayer HealthCare/Ortho-MacNeil Pharmaceutical inhibits factor Xa, which is involved in the blood clotting mechanism. In earlier studies, the drug proved to be effective in the prevention of venous thromboembolism in patients following orthopedic surgery. In this randomized, phase II trial, the researchers tested the safety and efficacy of rivaroxaban in subjects who had an ACS and aimed to find the most favorable dose and dosing regimen.
Jessica L. Mega, MD, from Brigham and Women's Hospital in Boston, and colleagues studied 3,491 patients from 297 sites in 27 countries, and participants were required to have symptoms suggestive of a coronary syndrome that lasted at least 10 minutes at rest. All of the patients were given standard background therapy of either aspirin (761 patients), or aspirin plus clopidogrel (2,730 patients).
Then, the researchers randomized patients 1:1:1 to receive either placebo or rivaroxaban (at doses 5 to 20 mg daily), given once daily or the same total daily dose given twice daily. The primary safety endpoint was clinically significant bleeding. The primary efficacy endpoint was death, MI, stroke or severe recurrent ischemia to the heart requiring intervention within six months.
The investigators found that the risk of clinically significant bleeding was increased by rixaroxaban in a dose-dependent manner. Compared with placebo, there was a 2.2 times increased risk with the 5 mg dose, which increased to five times for the 20 mg dose. Fewer patients given rivaroxaban reached the primary efficacy endpoint (5.6 vs. 7 percent compared to placebo), translating to a reduced risk of 21 percent. When examining just death, MI or stroke (the secondary endpoint), 3.9 percent of rivaroxaban patients experienced one of these events versus 5.5 percent with placebo--a reduced risk of 31 percent for patients given rivaroxaban. The most common adverse event was chest pain, experienced by approximately 10 percent of patients in both groups.
Based on their findings, the authors concluded that the use of an "oral factor Xa inhibitor in patients stabilized after an ACS increases bleeding in a dose-dependent manner and might reduce major ischemic outcomes. On the basis of these observations, a phase III study of low-dose rivaroxaban as adjunctive therapy in these patients is underway."
"In the ATLAS ACS-TIMI 46 study there was no suggestion of benefit in patients receiving dual antiplatelet therapy; robust clinical benefits without major increase in bleeding risk would need to be shown in the ongoing trials before this drug could be integrated into practice," wrote Kim Eagle, MD, and Hitinder S. Gurm, MD, from the University of Michigan Cardiovascular Center in Ann Arbor, in an accompanying commentary.
They also noted that although estimation of the drug's benefit in secondary prevention on the basis of the results of a dose-finding study would be premature, rivaroxaban could potentially displace intravenous anticoagulants for early management of these syndromes.
"This indication has not yet been assessed, and we hope that the drug's sponsors will actively pursue this hypothesis," they wrote.
Xarelto from Bayer HealthCare/Ortho-MacNeil Pharmaceutical inhibits factor Xa, which is involved in the blood clotting mechanism. In earlier studies, the drug proved to be effective in the prevention of venous thromboembolism in patients following orthopedic surgery. In this randomized, phase II trial, the researchers tested the safety and efficacy of rivaroxaban in subjects who had an ACS and aimed to find the most favorable dose and dosing regimen.
Jessica L. Mega, MD, from Brigham and Women's Hospital in Boston, and colleagues studied 3,491 patients from 297 sites in 27 countries, and participants were required to have symptoms suggestive of a coronary syndrome that lasted at least 10 minutes at rest. All of the patients were given standard background therapy of either aspirin (761 patients), or aspirin plus clopidogrel (2,730 patients).
Then, the researchers randomized patients 1:1:1 to receive either placebo or rivaroxaban (at doses 5 to 20 mg daily), given once daily or the same total daily dose given twice daily. The primary safety endpoint was clinically significant bleeding. The primary efficacy endpoint was death, MI, stroke or severe recurrent ischemia to the heart requiring intervention within six months.
The investigators found that the risk of clinically significant bleeding was increased by rixaroxaban in a dose-dependent manner. Compared with placebo, there was a 2.2 times increased risk with the 5 mg dose, which increased to five times for the 20 mg dose. Fewer patients given rivaroxaban reached the primary efficacy endpoint (5.6 vs. 7 percent compared to placebo), translating to a reduced risk of 21 percent. When examining just death, MI or stroke (the secondary endpoint), 3.9 percent of rivaroxaban patients experienced one of these events versus 5.5 percent with placebo--a reduced risk of 31 percent for patients given rivaroxaban. The most common adverse event was chest pain, experienced by approximately 10 percent of patients in both groups.
Based on their findings, the authors concluded that the use of an "oral factor Xa inhibitor in patients stabilized after an ACS increases bleeding in a dose-dependent manner and might reduce major ischemic outcomes. On the basis of these observations, a phase III study of low-dose rivaroxaban as adjunctive therapy in these patients is underway."
"In the ATLAS ACS-TIMI 46 study there was no suggestion of benefit in patients receiving dual antiplatelet therapy; robust clinical benefits without major increase in bleeding risk would need to be shown in the ongoing trials before this drug could be integrated into practice," wrote Kim Eagle, MD, and Hitinder S. Gurm, MD, from the University of Michigan Cardiovascular Center in Ann Arbor, in an accompanying commentary.
They also noted that although estimation of the drug's benefit in secondary prevention on the basis of the results of a dose-finding study would be premature, rivaroxaban could potentially displace intravenous anticoagulants for early management of these syndromes.
"This indication has not yet been assessed, and we hope that the drug's sponsors will actively pursue this hypothesis," they wrote.