Anticoagulant transition plan reduced excess thrombotic, bleeding events

A transition plan developed for the ENGAGE-AF TIMI 48 trial was associated with reduced excess thrombotic and bleeding events in patients moved from one oral anticoagulant to another.

In the ROCKET AF trial of rivaroxaban (Xarelto, Janssen Pharmaceuticals) and the ARISTOTLE trial of apixaban (Eliquis, Bristol-Myers Squibb/Pfizer), researchers observed an excess of thrombotic and bleeding events in the 30 days after the trial when patients were transitioned from the blinded study drug to open-label antithrombotic therapy, according to the study background. When designing the ENGAGE-AF TIMI 48 trial of edoxaban (Savaysa, Daiichi Sankyo), researchers developed a comprehensive plan to transition patients from the blinded study drug to open-label antithrombotic therapy while minimizing the risks for stroke and bleeding.

All three trials evaluated novel oral anticoagulants compared with warfarin for prevention of stroke and systemic embolic events in patients with nonvalvular atrial fibrillation.

“Evidence-based guidance is needed in this area as patients in clinical practice are frequently switched from one anticoagulant to another before and after procedures when they develop side effects from a particular anticoagulant or need to switch due to changes in insurance coverage or are prescribed a necessary, but contraindicated, medication,” Christian T. Ruff, MD, MPH, from Brigham and Women’s Hospital and Harvard Medical School, and colleagues wrote.

Transition plan contents

According to the researchers, the transition plan consisted of:

Selection of the oral anticoagulant by the treating physician and patient.
A 14-day transition kit of modified-dose edoxaban for those randomized to edoxaban or matching placebo for those randomized to warfarin.
Early and frequent international normalized ratio (INR) testing, including at least three tests during the first 2 weeks.
The use of a vitamin K antagonist transition algorithm. All patients were followed for a minimum of 30 days after their end-of-trial visit.

At the end-of-trial visit, INR was measured and patients received a prescription for their open-label anticoagulant. The transition kit was provided to those transitioning to an open-label vitamin K antagonist such as warfarin and was continued until 14 days or achievement of INR ≥2. If INR ≥2 was not achieved at 14 days, the patient was continued on the transition kit with aggressive titration of warfarin or other vitamin K antagonist. INR measurements were conducted at days 4 to 6, 7 to 10, 11 to 14 and as often as needed to day 30.

For those transitioning to a novel oral anticoagulant, the transition kit was not given, and the novel oral anticoagulant was started the day after the end-of-trial visit if INR was <2, the researchers wrote. If INR was ≥2, the patients received an open label INR measurement on days 4 to 6 and if necessary every 1 to 4 days thereafter. Once the INR was <2, the patient was started on the novel oral anticoagulant.

Of the 13,642 patients taking the blinded study drug at the end of ENGAGE-AF TIMI 48, 68.2% were transitioned to an open-label vitamin K antagonist and 31.2% were transitioned to a novel oral anticoagulant; the others transitioned to antiplatelet therapy or no antithrombotic therapy, according to the researchers.

Ruff and colleagues observed seven strokes during the transition period in each of the three arms of the trial (warfarin arm, 1.9% per year; edoxaban high-dose arm, 1.89% per year; edoxaban low-dose arm, 1.85% per year). Eleven major bleeding events occurred in the warfarin arm (2.98% per year), 10 in the edoxaban high-dose arm (2.69% per year) and 18 in the edoxaban low-dose arm (4.76% per year).

In patients transitioned to a vitamin K antagonist, 85% had at least one INR ≥2 by day 14 and 99% did by day 30 after the transition, Ruff and colleagues found.

The plan “may provide reassurance that in clinical practice patients can be safely transitioned between a broad range of oral anticoagulants,” they wrote.

A new standard

“The impressive results reported by Ruff et al appear to set a new standard for the management of patients transitioning from [a novel oral anticoagulant] to open warfarin at the completion of blinded anticoagulation trials,” John W. Eikelboom, MBBS, and colleagues wrote in a related editorial. “Their data also provide several valuable insights into optimal management of patients who require interruption of anticoagulation in clinical practice.”

Eikelboom, of Hamilton General Hospital and McMaster University, Hamilton, Ontario, Canada, and colleagues wrote, however, that most patients in the ENGAGE-AF TIMI 48 trial switching from edoxaban to warfarin had a CHADS₂ score ≤3, so it is unclear how successful the bridging strategy might be in patients with higher CHADS₂ scores.

For more information:

Eikelboom JW. J Am Coll Cardiol. 2014;64:585-587.

Ruff CT. J Am Coll Cardiol. 2014;64:576-584.

Disclosure: The trial was funded by Daiichi Sankyo. See the full study for a list of the researchers’ relevant financial disclosures. See the full editorial for a list of the writers’ relevant financial disclosures.