May 182013
Apixaban (Eliquis) Prevents Recurrent DVT-PE Long-Term

People with unprovoked venous thromboembolic disease (pulmonary embolism or deep venous thrombosis, or DVT) are at high risk for recurrence, and current ACCP guidelines advise consideration of "indefinite" anticoagulation. Warfarin (Coumadin) is a wonder drug efficacy-wise, reducing the risk of pulmonary embolism and deep venous thrombosis by ~90%.

However, warfarin can be a nightmare for lifestyle (frequent monitoring) and side effects (bleeding). Because a lifetime on Coumadin is often considered overly dangerous or cumbersome, many people with DVT and PE are treated with warfarin for only 6-12 months, and then sent on their way. Unfortunately, up to one-third will eventually develop recurrent pulmonary embolism or DVT after stopping warfarin.

The newer anticoagulants dabigatran (Pradaxa, Boehringer Ingelheim), and the factor Xa inhibitors, apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) and rivaroxaban (Xarelto, Bayer/Johnson & Johnson) eliminate the need for laboratory monitoring, and probably have a lower bleeding risk than warfarin, making them much more patient-friendly. The perfect target market for these drugs, from Pharma's point of view, would be lifetime administration in people after DVT or PE (in addition to everyone with non-valvular atrial fibrillation).

In the February 21, 2013 New England Journal of Medicine, Bristol-Myers Squibb/Pfizer took a step toward realizing that vision, showing that apixaban (Eliquis) dramatically reduced the risk of recurrent DVT and PE when taken for 12 months after patients completed appropriate anticoagulation therapy for their original blood clots.

What They Did: Randomized 2,482 people to take apixaban (2.5 or 5 mg twice daily) or placebo for 12 months, after completing 6 to 12 months of Coumadin or apixaban for an initial DVT or PE (as part of the previous AMPLIFY trial).

What They Found: Of placebo-takers, 73 (8.8%) had recurrent symptomatic DVT or PE (including 7 deaths possibly due to PE, 0r 0.8%), but only 1.7% of those taking apixaban did (including 5 deaths, or 0.3%). Those taking apixaban also had a much lower incidence of a complex endpoint including other blood clots (stroke, MI) and death from any cause.

There was no excess major bleeding in those taking Eliquis compared to placebo (both were <0.5%). There was no difference in efficacy or risk of bleeding between the 2.5 mg and 5 mg doses of apixaban.

It's important to note that one-third of the patients in this trial never received any warfarin -- they got apixaban as initial and follow-up treatment. This would a priori slightly limit the trial's applicability to all "usual care" patients taking warfarin initially. But, authors stratified the trial according to this variable, and tell us there was no significant difference between the initial-warfarin and initial-apixaban subgroups.

What It Means: The long-term risks of recurrent pulmonary embolism and warfarin-induced bleeding are a two-headed bogeyman that haunts patients (and their pulmonologists) after an unprovoked PE. This trial's numbers look like a possible solution to that problem -- and some of the new generation anticoagulants seem almost as impressive at preventing stroke in people with atrial fibrillation. And all without the need for monitoring, and with a lower risk for intracranial hemorrhage. So why not put everyone with a history of unprovoked DVT, pulmonary embolism, or atrial fibrillation on a next-generation anticoagulant, for life?

In a word, rationing: prescribing apixaban to everyone with those conditions would cost about $10 billion a year, at current prices ($300 / month, with ~3.5 million affected in the U.S.) That notwithstanding, many insurers are covering these drugs, whose costs should be expected to fall eventually after their 7-year patent protection expires. Various cost comparisons assert that after factoring in the cost of monitoring with warfarin, the excess cost of the newer drugs is less.

While warfarin seems to carry an excess risk for catastrophic intracranial hemorrhage, its coagulopathy can be reversed with blood products. Rivaroxaban might be reversible with prothrombin complex (PCC, like fresh frozen plasma), but PCC hasn't yet been shown to work in people who hemorrhage while taking dabigatran or apixaban.

For comparison, good old aspirin (at 100 mg / day) reduced the risk of recurrent PE by ~60% compared to placebo (compared to an ~80% relative risk reduction by the newer anticoagulants in this and other trials), after completion of warfarin therapy for DVT or PE. Is the additional 20% risk reduction from newer anticoagulants worth their price, and the cost to "society"? I'll leave that up to you, your health plan administrator, and your friendly neighborhood medical ethicist (who these days, is also probably an accountant).

Giancarlo Agnelli, M.D et al. Apixaban for Extended Treatment of Venous Thromboembolism. N Engl J Med 2013; 368:699-708. 

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Taking Apixaban (Eliquis) after completing Coumadin prevents recurrent DVT/PE