Another DOAC Fails in the Setting of Mechanical Heart Valves

The PROACT Xa trial has been halted prematurely after it was found that apixaban (Eliquis; Bristol Myers Squibb) carried a greater risk of blood clots leading to stroke when compared with warfarin in patients with the On-X mechanical aortic valve, device maker Artivion announced last week.

The trial’s data and safety monitoring board (DSMB) recommended the stoppage “due to lack of evidence supporting noninferiority of apixaban to warfarin for valve thrombosis and thromboembolism,” the company said.

In fact, “the DSMB found that blood clots, resulting in stroke, occurred more frequently in patients receiving apixaban and that continuing the trial was unlikely to achieve the primary endpoint while possibly exposing patients to increased risk.”

All patients assigned to apixaban, a factor Xa inhibitor, as part of PROACT Xa will be switched back to warfarin.

On Twitter, several physicians expressed disappointment with the result, but not necessarily surprise, as apixaban is not the first direct oral anticoagulant (DOAC) to unsuccessfully challenge warfarin in patients with mechanical heart valves. The phase II RE-ALIGN trial was stopped early after dabigatran (Pradaxa; Boehringer Ingelheim), a direct thrombin inhibitor, increased thromboembolic and bleeding risks relative to warfarin in that patient population.

“I thought it was going to be negative,” Isaac George, MD (NewYork-Presbyterian/Columbia University Irving Medical Center, New York, NY), tweeted about PROACT Xa. “It was a little hard to understand the trial design and the biologic basis.”

Iqbal Jaffer, MBBS, PhD (McMaster University, Hamilton, Canada), said “the concern isn’t with the science—it was well designed and considered.” But he suggested newer DOACs might have a better shot in the setting of mechanical heart valves. “I hold a lot of hope for [factor XI] inhibitors. Mechanistically, they make more sense.”