Stephan Moll, MD writes…
Occasionally, recurrent DVT or PE occur in spite of warfarin therapy, particularly in patients with (a) fluctuating and sub-therapeutic INRs, (b) lupus anticoagulant/ antiphospholipid antibody (APLA) syndrome or (c) cancer.
A. How common is it?
Warfarin failure occurs in approximately:
- 2-3 % of patients with previous unprovoked VTE over 1-4 years on treatment with warfarin [ref 1].
- 17 % of patients who had a VTE due to cancer over 6 months on treatment with warfarin [ref 2].
- Up to 11 % of patients with VTE due to lupus anticoagulant and antiphospholipid antibody syndrome over 2 ½ years on treatment with warfarin [ref 3].
B. Why did warfarin fail the patient?
a) Documenting VTE recurrence
If there is significant suspicion for recurrence of VTE in a patient with a history of VTE, a confirmatory radiologic study should be obtained [ref 4]: a Doppler ultrasound in case of suspicion for DVT, and a CTA or VQ scan to r/o recurrent PE.
b) Does the Doppler, CT or VQ truly show a new VTE?
Doppler ultrasounds in patients with previous DVT can be difficult to interpret. It may be difficult to tell an acute DVT from chronic changes, or a new DVT on top of preexisting chronic changes. Having a previous Doppler ultrasound for comparison can be helpful, and having an experienced ultrasound technologist and physician perform and read the study is important. Obtaining a D-dimer in these unclear situations can also be helpful: a positive D-dimer is one additional reason to believe that the patient does have a new clot; a negative D-dimer can be one of the reasons to conclude that the changes seen on ultrasound may not be acute [ref 4]. However, the D-dimer is unspecific and the results should, therefore, not be overvalued and not be the only reason to conclude that a patient does or does not have a new VTE.
c) What were the INRs in the preceding weeks?
Review of the INRs of the preceding weeks is helpful to determine whether the patient had sub-therapeutic INRs not just at the time when the recurrent clot was diagnosed, but also at the time of the onset of symptoms or even in the weeks before, when a subclinical VTE may already have started. Potential non-compliance needs to be assessed. It is noteworthy that a patient’s presenting INR at the time the new VTE is diagnosed does not necessarily reflect the anticoagulation level of preceding weeks: some patients are know to have been non-compliant with their warfarin intake, yet upon the onset of new DVT or PE symptoms “double up” on their warfarin dose and, thus, present with a therapeutic INR value.
d) Does the patient have a lupus anticoagulant?
The presence of a lupus anticoagulant can lead to inaccurate INR values: An INR may appear therapeutic by value, but may mostly be elevated due to the lupus anticoagulant effect, not the warfarin itself. A correlation of INR with factor II or chromogenic factor X activity may help clarify the reliability of the INR.
e) Does the patient have cancer?
The warfarin failure rate in patients with VTE and cancer is high – 17 % over 6 months per CLOT trial [ref 3]. Thus, in the patient who has a recurrent VTE in spite of therapeutic INRs, the suspicion for cancer is increased and appropriate work-up is indicated.
C. Treatment options
If the patient truly had a true “warfarin failure”, then treatment options are:
- Continue warfarin, but increase the target INR (to 3.0-4.0, for example)
- Switch to a different anticoagulant:
- Low molecular weight heparin
- Arixtra (fondaparinux)
- One of the new oral anticoagulants – Xarelto (rivaroxaban), Pradaxa (dabigatran) or Eliquis (apixaban)
Only in patients with cancer is LMWH known to be more effective than warfarin in preventing recurrent VTE. In non-cancer patients no data exist that any of these choices would be more effective than warfarin, or that one choice is better than any other. Thus, the best management approach is not known.
IVC filter placement is not a solution, as the filter itself will not prevent DVT progression or recurrence and a decision about a change in anticoagulation management will still have to be made.
D. Personal Approach
- Warfarin failure: My typical approach to a patient with “warfarin failure”, once I have considered the causes of warfarin failure discussed above, is to consider twice daily LMWH; after 3 months, once the acute thrombotic event has been appropriately treated, I may discuss a switch in management, such as (a) fondaparinux because of the convenience of once daily dosing, (b) a switch to warfarin with a higher target INR if the patient has a history of fairly stable INRs, or (c) possibly a switch to one of the new oral anticoagulants. However, at this point, while rivaroxaban’s performance in real world VTE patients outside of clinical trials is still becoming more clear, I would be somewhat hesitant to put the patient with true warfarin failure that was not due to fluctuating and sub-therapuetic INRs on Xarelto or one of the other new oral anticoagulants.New oral anticoagulant failure: In the studies that compared Xarelto to warfarin in the treatment of DVT and PE, recurrent VTE occurred in both treatment groups equally often, i.e. in 2-3 % of patients over a 1 year treatment period [ref 5,6]. If a patient who is being treated with one of the new oral anticoagulants has clearly documented recurrent VTE, then a treatment change seems appropriate. I would choose and discuss with the patient a switch to warfarin, long-term. However, it is not known how effective that is in preventing recurrences.
- Kearon C et al. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin for long-term prevention of recurrent venous thromboembolism. N Engl J Med. 2003 Aug 14;349(7):631-9.
- Crowther MA et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med. 2003 Sep 18;349(12):1133-8.
- Lee AY et al. Low-molecular weight heparin versus coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003 Jul 10;349(2):146-53.
- Bates SM et al. Diagnosis of DVT: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST 2012; 141(2)(Suppl):e351S–e418S.
- Buller HR et al. Oral rivaroxaban for the symptomatic venous thromboembolism. N Engl Med 2010;363:2499-510.
- Buller HR et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl Med 2012;366:1287-97.
Disclosures: I have consulted for Janssen, Boehringer-Ingelheim, Daiichi.
Last updated: March 6th, 2013