Xarelto vs. Warfarin for DVT and PE: Now I’ll Have to Help Patients Choose

Late week the FDA approved Xarelto for the treatment of pulmonary embolus (PE), acute deep vein thrombosis (DVT), and prevention of recurrence or these conditions.  Now the decision on the use of Xarelto vs. warfarin will be one we have to discuss with patients who develop DVT or PE.  Up until now family physicians have had a bye much of the time so far in the decision on whether to use the new oral anticoagulant drugs including Xarelto and Pradaxa (rivaroxaban) or to choose the well established drug warfarin, because with their primary FDA indication for prevention of stroke due to non-valvular atrial fibrillation we’ve been able to defer this decision to our cardiology consultants in many cases.  Now with the FDA approval of Xarelto for the treatment of PE, DVT, and prevention of recurrent DVT and PE the responsibility of working with our patients to decide on the use of Xarelto vs. warfarin treatment is in our laps.  In most cases primary care physicians treat PE and DVT ourselves and don’t rely as much on specialist help.

In short these are high risk and high benefit medications.  The benefits are lowering risk of recurrent DVT and PE, which can cause death and much morbidity.  The risks are of life threatening bleeding complications. Nearly all exerts agree that with rare exceptions not using an anticoagulant for therapy of PE or acute DVT is simply unacceptable because the risk of death from PE or severe venous injury is too high.

Patients who develop a DVT in their lower extremity are at high risk of the clot in the DVT breaking loose and traveling through the venous system and the heart to lodge in the lung, a condition called a pulmonary embolus.  This can be fatal and is a relatively common cause of sudden unexpected death in otherwise young and healthy people. The standard of care for all of my 30 year medical career and prior has been immediate anticoagulation with heparin (either IV of subcutaneously with low molecular weight heparin) followed by oral anticoagulation with warfarin, an inhibitor of vitamin K dependent clotting factor production.

Use of warfarin is quite involved and has numerous drawbacks and risks.  These include taking into account that the effect of a given dose of warfarin is delayed by several days because of its mechanism of action as an inhibitor of the production of a clotting cascade factor.  Additionally many factors lead to a wide range and often changing dose of warfarin for a given individual.  These include intake of dietary vitamin K, a vast number of medication interactions, and a great deal of patient-to-patient variability in dosing requirements. This means that strict and ongoing monitoring of warfarin dosage and the lab metric used to measure the degree of anticoagulation called the INR is mandatory.  Studies have shown in the best of situations patients remain in the goal anticoagulation range only about 60% of the time.  When a patient is inadequately anti-coagulated on warfarin they are at higher risk of thrombotic events (recurrent DVT and PE or in the case of a-fib of stroke) and if over anti-coagulated they are at high risk of serious or life-threatening hemorrhage.

The use of the new oral anticoagulants that work directly on the clotting cascade make therapy potentially much simpler.  In the case of Xarelto, an inhibitor of factor 10a, the onset of adequate anticoagulation is very fast, within hours, and it has an approval from the FDA for the treatment of acute PE in lieu of heparin.  This has the advantage or eliminating the need for parenteral administration by the IV or subcutaneous route used for heparin, plus eliminating the need for titration of dosage and constant monitoring of the degree of anticoagulation for subsequent warfarin therapy.  It remains for  experts with better cost-benefit ratio analytic skills than me to decide if Xarelto is more or less expensive to use when taking into account the costs of monitoring warfarin use with frequent lab testing and clinic visits, vs the much higher cost of Xarelto vs warfarin to buy the drug.  The cost of Xarelto 20 mg at Costco is $261.80 / 30 tablets vs. warfarin generic 5 mg tablets at $5.90 / 30 pills (branded Coumadin is $48.29 / 30 pills.

Patients are likely to enjoy the simplicity of a fixed dose, once daily oral anticoagulant that does not require monitoring of anticoagulant effect.  The studies presented to the FDA to get approval showed non-inferiority of Xarelto when compared to low molecular weight heparin followed by warfarin therapy.  There was a non-significant trend toward lower bleeding rates,  all-cause death and recurrent DVT and a very slight non-significant trend toward higher PE rates in the Einstein DVT Evaluation study.

The big fear of use of directly acting anticoagulants like Xarelto is that their effect on coagulation is not immediately reversible with infusion of clotting factors as is the case in warfarin use.  If a patient has a life threatening bleed, or need for immediate life-saving surgery while on warfarin clotting factor infusion can lead to rapid reversal of the anticoagulation effect.  With drugs like Xarelto and Pradaxa because the drug remains in the patient’s bloodstream infusion additional clotting factors is ineffective.  Unlike Pradaxa which is less protein bound and felt to be dialyzable (35-60% of Pradaxa can be removed in 2-3 hours with dialysis) Xarelto is largely protein bound and less apt to benefit from use of hemodialysis for removal of the drug.  Fortunately the serum half life of Xarelto is relatively short at 5-9 hours so its effect will be largely gone from the body in about a day.

Like warfarin, Xarelto has a number of drug-drug interactions.  With Xarelto these are primarily with drugs metabolized using the CYP-450 3A4/5 pathway.  This includes especially the macrolide antibiotics like erythromycin, Biaxin(clarithromycin) and Zithromax (axithromycin), many of the calcium channel blockers like verapamil and diltiazem, the anti-arrythmic amiodarone, the axole antifungal drugs like ketoconazole and sporinox, the anticonvulsant carbamazepine, and numerous herbal supplements, especially St. John’s Wort.  This list is not even close to complete, and physicians and patients will need to be diligent in looking for drug-drug interactions when using Xarelto.  This is a well known problem with warfarin, so this is not a bigger or smaller concern, just one where we will need to learn new drug-drug interactions.

So who is a good and who is a bad candidate for use of Xarelto for treatment of PE and prevention of recurrent PE and DVT?  This is a relatively new question, and I’m sure more information will come over time to help us with this decision.  Right now there is not really any data to tell us that Xarelto is superior to warfarin from either a safety or efficacy standpoint.  Therefore the decision will be made primarily using patient preference and physician comfort and preference as the deciding factors. I’ll use these as pros and cons in making the decision:

Xarelto Pros Xarelto Cons Warfarin Pros Warfarin Cons
Convenience: No need for regular INR testing, once daily fixed oral dosing Potentially less reversible in the case of a major bleeding complication Long experience with this drug Inconvenient, requires frequent lab testing to assure appropriate dosing
Appears to be as safe and effective as warfarin New drug, maybe issues will come up in post market analysis Inexpensive to buy the drug Expensive to monitor use of the drug
Alleviates need for initial use of parenteral heparin therapy and transition to oral warfarin High cost of the oral medication Reversible with clotting factor use in emergent situations, or with vitamin K administration in less urgent situations Dietary effects on efficacy (variation in dietary vitamin K intake can affect the degree of anticoagulation)
Much less concern regarding dietary effects on efficacy Numerous drug-drug interactions, though maybe less than common than with warfarin they may be more insidious as no test for efficacy of Xarelto is used Well known risks of bleeding relatively shield physicians from legal liability if the drug is used with standard monitoring. Many drug-drug interactions are commonly encountered in clinical use
With any new drug liability of physicians prescribing the drug are less clear, and with anticoagulant use there is a high risk/high benefit situation

Overall I anticipate strongly considering Xarelto in patients who can afford to buy the medication, who value the convenience of less rigorous monitoring and who I anticipate are at relatively low risk of bleeding complications.  I’ll lean toward warfarin use in patients for whom the month-to-month cost of Xarelto is a problem, who are more comfortable with the long-standing experience of warfarin use, and whom I feel are at higher risk of central nervous system or gastrointestinal bleeding.  This last issue, bleeding risk, is one where I plan to watch closely the aftermarket experience, as if Xarelto proves safer than  warfarin this balance may change.

9 Responses to Xarelto vs. Warfarin for DVT and PE: Now I’ll Have to Help Patients Choose

  1. Dr. Pullen says:

    Dave C: There is some evidence that Xarelto may be slightly safer than warfarin. I don’t think it’s good or bad. Either is an option for most patients. You need to discuss with your doctor or get a formal second opinion if you are concerned. DrP.

  2. dave.c says:

    30 year old male,with left below knee amputation for 10 years.developed dvt few days ago and currently bein treated with xarelto. My dr wouldn’t even consider warfarin, good idea? ?or bad

  3. Dr. Pullen says:

    Cathi: Glad you found it helpful. Thanks. DrP.

  4. Cathi Keller says:

    Very interesting reading. I’ve had 2 episodes of PE and now am on life-long warfarin. I hate the monthly testing and the bouncing around on the dosing. I plan to talk w/ my Dr. about Xarelto and seeing if that could be of use to me. i also hate not being about to have certain foods because they interact w/ warfarin. I love green leafy veggies and miss having them as part of my regular diet. Thanks again for a very informative article.

  5. David Merz says:

    A nice summary. Thank you. Of course anecdotal, nevertheless powerful. A 44 yr old on Xarelto who develops GI bleed, consumes 45 U blood products, and dies, as no antidote. Key point of studies is their non inferiority target, met, of course. Troubling to me is that in most instances warfarin dosing was done by clinician, while there are software programs that outperform clinicians in achieving target INRs, and would expect would be the best system to which to compare these new agents in terms of non inferiority. Surely I have seen catastrophes with warfarin, but the coagulopathy is reversible, and in large part avoidable using the computer-driven dosing.

  6. Dr. Pullen says:

    Kellie: I’ll try to put up a post on DVT sometime soon. Thanks. DrP.

  7. Kellie says:

    Thanks for the helpful info. Sadly, this was a choice I had to make. I am interested in learning more about how to treat and prevent DVT.

  8. Dr. Pullen says:

    PhilM: I’m not aware of warfarin leading to artery hardening as a likely side effect, and do not find it listed for Xarelto. DrP.

  9. PhilM says:

    This was an interesting read. Thanks for the post.

    One of the problems with Warfarin, I understand, is artery hardening. Does Xarelto share this trait with Warfarin as well?

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