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Rivaroxaban for Pulmonary Embolism: One pill and done?

Posted Apr 03 2013 12:00am

With Dr. Jeff Tabas giving a lecture on the perennially hot topic of pulmonary embolism (PE) at the upcoming UCSF High Risk EM Conference ( main link , PDF  Brochure ) in San Francisco May 22-24, 2013, I thought I would get a sneak peak into his discussion points.


Rivaroxaban for Pulmonary Embolism: One pill and done?
By Prathap Sooriyakumaran, MD and Jeffrey Tabas, MD
UCSF-SFGH Emergency Medicine

Rivaroxaban (Xarelta) is a Xa inhibitor that seems to blow coumadin out of the water! Oral, fixed dose, no blood levels to monitor, and recently approved by the FDA for venous thromboembolism (VTE) treatment. Is it THAT good?

The FDA approval was largely based on EINSTEIN-PE , a randomized, open label study with 4,832 PE patients published in the NEJM in 2012. It compared rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once daily) to standard treatment (bridging enoxaparin plus coumadin for 3, 6 or 12 months). The results showed that rivaroxaban was as good as enoxaparin plus coumadin for safety and efficacy.


Should we use rivaroxaban for treatment of PE instead of coumadin with bridging enoxaparin? 

The data looks pretty good to us although with some important caveats.
  1. Almost all patients in the study who received rivaroxaban received low molecular weight heparin (LMWH) for 1 or 2 days, so it's not clear that it is OK to skip that initial anticoagulation with heparin. 
  2. There is always potential bias from the study of an expensive new proprietary product funded by the pharmaceutical company, especially in an open label, non-blinded study. Coumadin costs pennies and has been used for years. It is the target of all expensive anticoagulant studies. 
  3. We need to be aware of the exclusion criteria in the EINSTEIN-PE study, which included renal and liver disease, as well as severe hypertension (SBP > 180 or DBP > 110). 
  4. Remember that in the bleeding patient, we know how to reverse coumadin. Ribaroxaban is a more challenging issue. Eerenberg et al.  in Circulation showed that prothrombin complex concentrates (PCC) with factors 2, 7, 9 and 10 can reverse the effects of rivaroxaban on coagulation tests such as prothrombin time. However, they did not investigate the clinical efficacy of reversing the hemostatic effects with PCC. As Marlu et al. point out in a letter to Circulation in response to the Eerenberg paper, other agents that have had significant effects on improving coagulation tests have failed to be clinically effective in stopping bleeding. PCC products themselves cost thousands of dollars per dose. 




How much does rivaroxaban cost compared to standard treatment?
Our back-of-the-envelope calculation using online pharmacy costs is that rivaroxaban for 6 months is roughly 3-4 times the cost of warfarin + bridging enoxaparin, including lab costs.

Rivaroxaban
  • 6 month supply = $1,600

Coumadin
  • 6 month supply = $150
  • 7 day supply of Lovenox = $250
  • 5 INR checks = $110

Ultimate question Based on this information, which therapy would YOU choose for yourself, if faced with a diagnosis of PE?  

While acknowledging that further studies may change our knowledge of this medication significantly, based on current data, we would use it -- assuming we are not the ones paying for it!

If we were paying for it out of pocket, we think the benefit over coumadin is minimal and would choose coumadin. That being said, neither of the authors have had to be anticoagulated, so we can’t say for sure.

What would you do?

Drs. Sooriyakumaran and Tabas have no financial disclosures.

Reference
  1. EINSTEIN–PE Investigators, Büller HR, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012 Apr 5;366(14):1287-97. PMID: 2244929 3 .
  2. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011 Oct 4;124(14):1573-9. PMID: 21900088
  3. Marlu R, Hodaj E, Pernod G. Letter by Marlu et al regarding article, "reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects". Circulation. 2012 Apr 24;125(16):e615; author reply e616. PMID: 22529073
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