CardioExchange Archive

On Thursday the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 9-1 in favor of approval for Daiichi Sankyo’s edoxaban (Savaysa). The outcome will likely result in a drug that will be on the market, but that few physicians will prescribe until further studies are performed.

Edoxaban will almost certainly become the fourth new oral anticoagulant (NOAC) to receive FDA approval. (The others are dabigatran [Pradaxa, Boehringer Ingelheim], rivaroxban [Xarelto, Johnson & Johnson], and apixaban [Eliquis, Pfizer and BristolMyers Squibb].)

The indication under discussion was for the use of edoxaban to reduce the risk of stroke and systemic embolic events (SEE) in patients with non-valvular atrial fibrillation (NVAF). The panel spent the day trying to interpret the pivotal Engage AF-TIMI 48 trial. At first glance this should have been an easy task, since the trial clearly met its predetermined endpoint and demonstrated that both low-dose and high-dose edoxaban were noninferior to warfarin.

The problems emerged when a troubling subgroup analysis from the trial found that all of the benefit for edoxaban occurred in the large group of patients who had impaired renal function. Stroke reduction in patients with renal impairment (and therefore higher circulating levels of the drug) was highly significant while there was a trend toward harm in the group with normal renal function. In general the FDA does not place a lot of weight on a subgroup analysis like this, but both the FDA reviewers and the panel members felt that this was a biologically plausible phenomenon that could have important clinical implications.

With a 9-1 vote the panel clearly supported approval of the drug but had a hard time advising the FDA about how it should be labelled. Panel members discussed future trials that would adjust the dose based on renal function or, possibly, limiting the indication to patients with impaired renal function.

Panel member Sanjay Kaul sent the following statement:

The committee struggled with the core issue for discussion around the subgroup of patients with normal renal function where the benefit-risk balance was not optimal. Decisions based on subgroup analysis can be potentially treacherous at times, however, there were elements in the evidence base that made the results relatively credible. Given the size of the subset, the FDA was concerned about the potential public health impact of approving the drug in patients with normal renal function. Majority of the panel agreed with their assessment. There is no unique advantage that this drug offers that is not seen with approved existing therapies. Approvability is less of an issue relative to clinical acceptability and marketability being the fourth kid on the block.”

Based on results of the Hokusai-VTE trial, edoxaban is also being reviewed by the FDA for the treatment of symptomatic venous thromboembolism in patients with deep vein thrombosis and/or pulmonary embolism.