Appeal type: Formulary Exception
Decision: Overturned

Diagnosis: Cardiac/Circulatory Problems. 
Treatment: Pharmacy/Prescription Drugs. 

The health plan denied the requested medication, Eliquis. 
The health plan's determination is overturned. 

The patient is a man with a history of nonischemic cardiomyopathy, heart transplantation and recurrent deep vein thrombosis. He is being treated with Tacrolimus to prevent transplant rejection. He has been taking Apixaban for prevention of recurrent venous thromboembolism. The medical necessity for Apixaban is at issue. 

I overturn, in whole the health plan's determination that Apixaban is not medically necessary. 

Apixaban, a direct oral anticoagulant, has been shown to result in significantly less bleeding than Warfarin and, in various reports, has been demonstrated to be superior to non-inferior to Warfarin in preventing recurrent VTE. In the study reported by Weycker that included 17,878 patients treated with Apixaban and the same number treated with Warfarin, incidence proportions for Apixaban versus Warfarin, respectively, were 1.7% versus 2.3% for major bleeding, 7.0% versus 9.4% for clinically relevant non-major bleeding and 2.3% versus 2.9% for recurrent venous thromboembolism (VTE). Thus, Warfarin would likely have more adverse effects in this patient, would not be expected to be more effective, and would possibly be less effective. In addition, given this patient's history of heart transplantation and the need for repeated invasive studies for surveillance for rejection, he would need frequent holding of Warfarin for several days before each procedure and would then require several days of therapy post-procedure for his international normalized ratio (INR) to become therapeutic. This would place him at increased risk for recurrent thromboembolism. Apixaban, on the other hand, could be held for just 24 hours pre-procedure and restarted afterwards, with almost immediate therapeutic effect. 
Rivaroxaban, like Apixaban, is a direct oral anticoagulant. While the efficacy and safety of the two agents have not been directly compared in a randomized controlled trial, in a retrospective study of 3,091 Apixaban users and 12,163 Rivaroxaban users, the crude incidence of recurrent venous thromboembolism was three per 100 person-years in the Apixaban group and seven per 100 person-years in the Rivaroxaban group. The incidence of major bleeding was three per 100 person-years in the Apixaban group and six per 100 person-years in the Rivaroxaban group. Thus, Apixaban appeared to be both safer and more effective than Rivaroxaban. In addition, an important consideration in this particular case is this man's concomitant use of Tacrolimus. There are limited data on the concurrent use of direct oral anticoagulants and calcineurin inhibitors, such as Tacrolimus. However, in the report by Vanhove, at al, 13/22 patients taking both Rivaroxaban and Tacrolimus, showed more than a 20% change in their Tacrolimus levels when the Rivaroxaban was started; the levels increased in 9/13 and decreased in the remaining 4. This degree of drug-drug interaction was not observed with Apixaban. Given the risk of drug toxicity, should the Tacrolimus level rise, as well as the potential for transplant rejection should the Tacrolimus level fall below the therapeutic range, the risk for adverse events is higher with Rivaroxaban than with Apixaban. This man has been stable on Apixaban for four years. Given the potential for harm if the drug were to be discontinued and Rivaroxaban substituted, it is this reviewer's opinion that Apixaban should be continued.