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Xarelto Joins the Rush to Novel New Anticoagulants

August 26, 2011

The recent FDA approval of Xarelto (generic name rivaroxiban)  as the first direct factor Xa inhibitor for prevention of deep vein thrombosis and pulmonary embolism in patients undergoing hip and knee replacement caught my eye as a family physician who anticipates outliving at least one of these joints.  In my community the standard of care for DVT prophylaxis with hip and knee replacement is post-op treatment with low molecular weight heparin in the hospital and short term oral anticoagulation with warfarin.

Use of warfarin requires careful monitoring of coagulation times to avoid either under treatment and risk of DVT or over treatment and risk of bleeding. Xarelto is approved to use at a fixed dose and does not require blood testing to monitor its effects.  Sounds good but as Paul Harvey always said stay tuned for the “rest of the story.”

Xarelto has been used in Canada and Europe for about 3 years so it is not expected that huge unexpected aftermarket risks will show up.  The original studies compared Xarelto to a fairly low dose of low molecular weight heparin The studies generally show that Xarelto is more effective at preventing DVT than the low dose enoxaparin (Lovenox).  In the U.S. the FDA approved dose for DVT prophylaxis is 30 mg twice daily of enoxaparin twice daily, not the 40 mg once daily used in the comparison trials.  It is not unexpected that Xarelto leads to less DVTs and more bleeding than the low dose enoxaparin. I would like to see a study comparing warfarin use with Xarelto in prophylaxis of DVT post lower extremity total joint replacement. If I were having my hip replaced tomorrow I’d pass on Xarelto given what I can see from the current studies.  I’ll keep an eye on future studies and clinical experience as my opinion may change with more studies and broad clinical experience.

Potentially more exciting is the very recent August 10, 2011 study in the NEJM where a very large cohort of patients with atrial fibrillation was treated with either Xarelto 20 mg daily or variably dosed warfarin.  The results were very promising; with clear cut non-inferiority of Xarelto when compared to warfarin, and a fair probability that Xarelto is superior at preventing stroke.  For the statisticians among readers the p-value for non-inferiority was <0.001 and the p-value for superiority was 0.12.  The 95% range of confidence is 0.74-1.03.  Total bleeding risk was equal at about 14-15% annual risk of bleeding annually in both treatment arms, and the risk of serious intracranial bleeding or death from bleeding significantly lower with Xarelto.  This sounds promising and when FDA approved for prevention of stroke in a-fib, which seems very probable, Xaralto is going to give Pradaxa a run for its money in the non-valvular a-fib market.  Xarelto promises to have similar benefits as Pradaxa in that it requires no anti-coagulation monitoring.  This is a big deal for a-fib patients where the duration of treatment is often many years.  The long-term hassle of constant blood monitoring of a condition where treatment is likely to go on indefinitely is significant.  The issue of monitoring coagulation status for just 10-35 days post operatively is much less onerous.  I anticipate a much higher level of excitement for xarelto for atrial fibrillation than for post operative DVT prophylaxis.

It appears that there may be more drug interaction issues with Xarelto than with Pradaxa.  Xarelto is extensively metabolized through the CYP 3A4 pathway, whereas Pradaxa has far less extensive hepatic metabolism and so less likelihood of patients being on drugs with the likelihood of interactions.  That alone may make Pradaxa easier to use in this group of patients who are often subject to polypharmacy.

Of further note there are multiple other novel anticoagulant drugs that are likely to be brought to market in the next year or two, and it is likely that each will find a niche.