Enormous Rivaroxaban Study Stopped Early For ‘Overwhelming Efficacy’

(Updated)

–Oral anticoagulant reduced CV events in patients with coronary and peripheral disease.

The very large COMPASS study has been stopped early for “overwhelming efficacy,” according to a press release issued by Bayer AG and Janssen, manufacturers of rivaroxaban (Xarelto).

The phase 3 trial randomized 27,402 patients with coronary artery disease (CAD) and peripheral artery disease (PAD) 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. The primary endpoint of the study was the first occurrence of either MI, stroke, or CV death. The DMC said the trial had reached its prespecified criteria for superiority.

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.

COMPASS is the first new oral anticoagulant to be studied in this patient population, the announcement said. 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.”

COMPASS is the second successful 27,000 patient cardiovascular study to be announced in less than a week. On February 2 Amgen reported that the FOURIER trial with the PCSK9 inhibitor evolocumab (Repatha) had successfully met its primary endpoint.

Update:

Ethan Weiss (UCSF) tweeted out his thoughts about the trial. I asked him to summarize his thoughts for CardioBrief:

“We have known for 15 years that adding oral anticoagulants in high risk (ACS or secondary prevention patients) reduces events. It comes at cost of bleeding. This was seen clearly in WARIS II and in TIMI51. In WARIS II, the INR was high. In TIMI51, 93% of patients were on P2Y12 antagonists. So here, they set up a trial to test the lower dose rivaroxaban (2.5mg BID) + asa versus the higher dose (5mg BID) without asa versus aspirin alone. Again and importantly, P2Y12 use was excluded. The devil will be in the details. I am not at all surprised there was efficacy. We have seen that twice. The big question is, does removal of P2Y12 antagonist confer lower risk of bleeding?

So when we see, we will be left with an interesting set of questions. Assuming (big assumption) there is no significant bleeding in at least the 2.5 riva bid + asa arm versus ASA alone, here are the big ones:

  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?

I don’t know. I am very curious to see how this plays out. It might be that this proves to be a more efficacious and even safer option than aspirin and P2Y12 in higher risk people. As always, need to see the data!

 

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