Wednesday, April 25, 2012

The Demise of Protime Clinic?

The last remaining market for warfarin?
The final results of the EINSTEIN-PE trial were published in the New England Journal of Medicine this month.  EINSTEIN-PE was a randomized, open-label trial pitting rivaroxaban, a factor Xa inhibitor, against enoxaparin overlapping with warfarin (or other vitamin K antagonist) in adults with symptomatic pulmonary embolism.  The primary efficacy endpoint was recurrent venous thromboembolism.  

EINSTEIN-PE was a noninferiority study, which are all the rage these days.  Rivaroxaban would be deemed noninferior if the upper limit of the 95% confidence interval of the hazard ratio was 2 or less.  Put another way, rivaroxaban would be considered as good as warfarin as long as it was statistically unlikely to be more than twice as bad.  (Go ahead and thank us for clearing that up!)

Setting aside the "noninferiority" descriptor for a moment, let's take a look at the results:  1.8% of patients on warfarin had a recurrent VTE, compared to 1.8% of those on rivaroxaban, a non-significant difference.  Of course, with a negative study (i.e., one showing no difference in outcomes), you always want to look at the width of the 95% confidence interval, to make sure the trial wasn't simply underpowered.  The absolute risk reduction was 0.3% in favor of warfarin, with a pretty tight 95% CI of -0.5% to 1%.  (The authors don't report the data in terms of ARRs; I used an online calculator.)  Another way of stating the results:  Warfarin is unlikely to be more than 1% better than rivaroxaban, or, if you're a glass half-empty kind of person, rivaroxaban is unlikely to be more than 1% worse than warfarin in preventing recurrent VTE.  

The other major finding was that rivaroxaban had a lower rate of major bleeding of 1.1%, compared to 2.2% in the standard treatment group.  The investigators' definition of noninferiority is almost irrelevant.  Practically speaking, most doctors would agree that a drug with an almost equivalent rate of recurrent VTE and a decreased risk of major bleeding should be considered at least as good as standard therapy, especially without the added hassle of blood tests and dosage adjustments.

So why aren't more physicians hopping on the rivaroxaban bandwagon?  Don't worry, they will, but it will take time -- specifically, the amount of time it takes for rivaroxaban to go generic, or to drop in price.  We're talking about a medication that costs approximately $8 a day.  It's still not FDA-approved for treatment of VTE*, so it may not be covered by many insurance companies.

And what about rivaroxaban's other major competitor, the direct thrombin inhibitor, dabigatran?  There haven't been any head-to-head studies, and the pharmaceutical companies are smart enough not to fund one.  That said, I predict that rivaroxaban will end up trouncing dabigatran because 1) it doesn't have that pesky dyspepsia side effect and 2) you don't have to overlap it with heparin.  (RE-COVER, the trial comparing dabigatran to warfarin for VTE, used parenteral anticoagulation in both groups to maintain blinding, even though dabigatran has a fast onset of action.  Boehringer Ingelheim is probably kicking itself for being so scientifically rigorous.)

To all of you internists out there -- what's your first-line drug for venous thromboembolism?  And can anyone tell me what "EINSTEIN" stands for?

*Rivaroxaban is FDA-approved for the prevention of stroke in atrial fibrillation and DVT in post-orthopedic surgery patients.

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