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The first large trial of a newer oral anticoagulant (NOAC) for prevention among coronary artery disease (CAD) and peripheral artery disease (PAD) -- the COMPASS study -- has been stopped early for "overwhelming efficacy," Bayer AG and Janssen, manufacturers of rivaroxaban (Xarelto), announced.
The phase III trial randomized 27,402 CAD and PAD patients to receive either rivaroxaban 2.5 mg twice daily in addition to aspirin 100 mg once daily, rivaroxaban 5 mg twice daily alone, or aspirin 100 mg once daily alone.
The trial was stopped a year ahead of its scheduled completion date following a recommendation by the Data Monitoring Committee. That committee said the trial reached its prespecified criteria for superiority on the primary endpoint of first occurrence of either MI, stroke, or cardiovascular death.
In an open-label extension trial, patients enrolled in the study will be offered rivaroxaban "owing to the magnitude of effect and the confirmation of the existing safety profile of rivaroxaban," the companies announced.
Full results of the study will be presented later this year at a major medical meeting.
"Although there are therapies that offer significant protection for patients with coronary or peripheral artery disease, a significant risk of heart attacks, stroke, or even death remains in these high-risk patients," said Salim Yusuf (McMaster University), principal investigator of the COMPASS study, in a press release issued when the trial was initiated. "This is therefore an important study, designed to investigate additional, potentially complementary, cardioprotective benefits for these patients."
Sanjay Kaul (Cedars Sinai) said that he is "not a big fan of stopping trials for efficacy unless there is a clear cut mortality benefit despite prespecified stopping rules." However, he pointed out that it is "not unreasonable" to stop this trial early since "there is already large safety data for rivaroxaban."
Ethan Weiss (UCSF) said the efficacy findings were not a surprise, since "we have known for 15 years that adding oral anticoagulants in high risk (ACS [acute coronary syndrome] or secondary prevention patients) reduces events. It comes at cost of bleeding. This was seen clearly in WARIS II and in TIMI51."
But, he said, "the devil will be in the details," particularly whether leaving a P2Y12 antagonist off the regimen will confer lower risk of bleeding. Other questions, with the big assumption that there's not significant bleeding risk in at least the lower rivaroxaban dose arm, are:
"1) How many patients will there who will meet these criteria? I.e., will there be a lot of people walking around out there off P2Y12 but meeting inclusion criteria here? Again, ACS and stable CAD + stent will be excluded for at least a year.
"2) Will doctors remember to add riva 2.5 to standard therapy in patients who have completed P2Y12 therapy or were not on it?
"3) Will this basically be a direct comparison to CHARISMA? And in this case, will the data be better for safety and efficacy?"