FDA Approves Rivaroxaban for CV Event Reduction in CAD and PAD Patients

The US Food and Drug Administration (FDA) has added new indications for rivaroxaban (Xarelto; Bayer/Janssen) to include the treatment of patients with stable atherosclerotic vascular disease, both CAD and PAD, making the factor Xa inhibitor the first direct oral anticoagulant cleared for this use.

The expanded indications, announced Thursday by Janssen, are supported by the results of the 27,395-patient COMPASS trial, which had been stopped prematurely due to what the drug makers called “overwhelming efficacy.”

The main results of the trial showed that a combination of low-dose rivaroxaban (2.5 mg twice daily) and low-dose aspirin (100 mg/day) reduced the risk of a composite of cardiovascular death, MI, or stroke by an absolute 1.3% compared with low-dose aspirin alone, while increasing the risk of major bleeding by an absolute 1.2%. A net clinical benefit endpoint incorporating the most severe bleeds showed that the combination was superior to low-dose aspirin alone. Moreover, in the subgroup of patients with PAD, low-dose rivaroxaban and aspirin cut risks of major adverse limb events, major amputation, and a composite of major adverse cardiovascular and limb events.

Experts interviewed by TCTMD last year predicted that the trial would have a major impact, but they also noted some potential obstacles to implementing the approach studied in COMPASS, including clinical inertia, concerns about cost and bleeding, and a general lack of awareness of the findings among physicians.

Asked to comment on the FDA’s expansion of rivaroxaban’s indications, Erin Michos, MD (Johns Hopkins Medicine, Baltimore, MD), said she wasn’t surprised.

“The data from COMPASS were very compelling in my mind and really should get all of us to shift our focus in the management of chronic stable CAD or PAD from targeting ‘atherosclerosis’ to targeting ‘atherothrombosis,’” she told TCTMD in an email.

Michos pointed out that the combination of low doses of rivaroxaban and aspirin also lowered the risk of all-cause mortality by a relative 18% (though the difference fell short of the threshold for statistical significance used in the trial). “While this did come at the cost of an increased risk for bleeding, reduction in death matters. It’s meaningful,” she said.

As for integrating the approach into practice, Michos said she’d probably use it more in patients with combined CAD and PAD than in lower-risk patients with CAD alone, citing the relative dearth of targeted therapies for PAD.

But out-of-pocket costs for patients remain a concern, and physicians should not forget about all the other options currently available for secondary prevention in the excitement of a new approval, Michos said. Thus, patient selection is key.

“There is a sweet spot to figure out which types of patients will derive the most and the least benefit from adding antithrombotic therapy to their established secondary prevention regimen,” Michos said. “We have to have better tools (such as risk calculators) to identify those patients at greater risk for thrombosis events who would likely benefit versus those at greater risk for bleeding events who might be harmed.”

The new indication adds to several others already found on rivaroxaban’s label, including stroke prevention in nonvalvular A-fib, treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), reduction in risk of recurrent DVT and PE, and prophylaxis of DVT in patients undergoing knee or hip replacement surgery.

Rivaroxaban continues to be tested in various niches, falling flat in some. The drug was unsuccessful in the NAVIGATE ESUS trial of patients with embolic strokes of undetermined source and the COMMANDER HF trial of patients with heart failure and CAD but no A-fib. The GALILEO trial, which had been testing the rivaroxaban-based anticoagulation strategy in patients who had undergone successful TAVR, was stopped early because of an increased risk of all-cause mortality, thromboembolic events, and bleeding.