Prescribing options in the case of anticoagulation failure in deep vein thrombosis

Here’s how readers responded to a You Make the Call question about a patient’s prescribing options for failed anticoagulation in a case of deep vein thrombosis.

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It is clearly a failure of apixaban. As in any other rare case of failure of anticoagulant therapy, provided the chosen drug was effectively administrated, my main concern is to diagnose the condition that leads to recurrence. Given the age of this patient, I would try to disclose an occult neoplasm and antiphospholipid syndrome. If the patient is stable, I would switch to enoxaparin 1 mg/kg three times a day until the workup is complete. Lupus anticoagulant can be a problem to study while on unfractionated heparin, but enzyme-linked immunosorbent assays can be of value in this situation.

Jorge David Korin, MD
Buenos Aires, Argentina

Is this failure of novel oral anticoagulant (NOAC)? Yes. Is there any data to suggest switching to another NOAC? No. What are the prescribing options? Warfarin with international normalized ratio (INR) control or low-molecular-weight heparin (LMWH).

Giuseppe Avvisati, MD, PhD
Rome, Italy

I would not classify this as a failure of direct oral anticoagulant (DOAC) as the pulmonary embolism (PE) occurred within only three days of diagnosis of deep vein thrombosis (DVT). In this case, I would switch to therapeutic LMWH for one week, and then return to a DOAC thereafter, assuming that the patient is not on any medications that interact with a DOAC that would lower the effectiveness of apixaban, and that his body weight is less than 120 kg.

Dimitri Scarvelis, MD
Ontario, Canada

First of all, there is no data to support changing to a NOAC. The underlying question is whether there is failure of the NOAC. The dyspnea may be related to pain. There was no mention of hypoxia, which would be more concerning. Heparin is not a good idea because it is difficult to get patients into the therapeutic range. LMWH would have been a better idea; it is more reliable and a readily bioavailable drug. The only reason to use heparin would be if you thought this patient would benefit from thrombolysis and needed to stop the heparin. I would consider a month of lovenox, and would go back to a NOAC.

Lorinda A Coombs, PhDc, RN
University of California San Francisco
San Francisco, CA

I have two identical cases, which occurred three days apart. Both cases were in young women who presented with acute DVT and significant local symptoms. Both progressed after starting appropriate rivaroxaban 15 mg orally twice a day.

In retrospect, I suspect that both patients had a partial heterozygote antithrombin deficiency that was acutely exacerbated by their DVT. Consequently, at time of presentation, they likely had a profound antithrombin 3 deficiency, leading to failure of therapy of a direct oral anti-10 A inhibitor.

I intend to start these patients on a direct oral thrombin inhibitor for the first month to bypass this potential therapeutic failure.

Maroun Hayek, MD
Delta Cancer Institute
Greenville, MS

Switch back to warfarin while we can test for NOAC resistance.

Balbina Gutierrez Gurrola
UMAE Hospital De Especialidades CMN
Puebla, Mexico

There is no data suggesting that switching to another NOAC will be better for the patient.

In those cases, I change to warfarin with an INR of 3.0 to 3.5. Lovenox 1 mg/kg every 12 hours or 1.5 mg/kg every 24 hours is an alternative if the patient accepts daily injections.

William Caceres, MD
Universidad Central del Caribe School of Medicine
San Juan, Puerto Rico

Symptomatic PE shortly after starting treatment for proximal DVT is not common, but neither is it rare; nor is it usually a cause for alarm. It is usually just part of the natural course of DVT/PE. Therapeutic anticoagulation nearly always prevents further thrombosis, although this doesn’t happen instantly (“it takes time to stop a moving freight train”).

Three possibilities can account for early diagnosis of PE in patients on treatment for a DVT:

  1. Mechanical break-off of some of the leg thrombus: PE comes from proximal DVT – anticoagulation stops further thrombus growth within a short time, but some of the DVT can still break off and cause symptomatic PE in the few days after starting treatment.
  2. Fragmentation of a PE that was already there when anticoagulation started. Remember that about half of patients with a proximal DVT already have a silent PE – some of these will fragment and then produce symptoms in the few days after starting treatment.
  3. True failure of anticoagulation and development of new or worsening of DVT leading to new PE. This is most likely to occur in patients with very thrombogenic cancers (such as non-small cell lung cancer [NSCLC]) or in patients with really active antiphospholipid antibody syndrome (APLAS).

What I would do in such a case:

  1. Consider whether the patient has features of a scary malignancy or obvious APLAS. However, I would not do thrombophilia testing or search for occult malignancy. You already know he doesn’t have NSCLC.
  2. Provide REASSURANCE,
  3. Absolutely no inferior vena cava filter!
  4. Switch the patient back to apixaban 10 mg twice daily. Switching to another DOAC or to LMWH or warfarin is not rational in this context.

Bill Geerts, MD
Sunnybrook Health Sciences Centre
Toronto, Canada

I would switch to warfarin. It is cheap and easily monitored. It has a long history of safe use.

Paul H. Duffey, MD
Tucson, AZ

I believe this represents a failure of apixaban, and I would favor switching to a direct thrombin inhibitor such as dabigatran.

Marcus P. Porcelli, MD
Somerset, NJ

Don’t think it represents failure since the PE was probably extant at the diagnosis of DVT. I would not change the treatment yet and would transition back to orals once stable.

Gilbert Nyamuswa, MD
Henderson, NV

I would assume this was all a single event and that he likely had the pulmonary embolism when the DVT was found, but that he was not exhibiting symptoms, so there was no reason for them to have done the CT scan during the first visit. I do not think this is a failure of apixaban, and I think the patient should continue with apixaban.

Rana Mansour Bilbeisi, DO
St. John Macomb-Oakland Hospital
Warren, MI

Patient had a 50 percent chance of having PE at presentation. I do not regard these early events as a treatment failure. My approach is to convert to therapeutic LMWH for an arbitrary period of 3-4 weeks and then re-initiate the original therapy. There is no evidence that changing to an alternative oral target specific OAC or warfarin is advantageous.

I’m not sure what you mean by family thrombophilia, but if this means other family members have spontaneous VTE, then I would be interested in the specifics.

I always think about underlying cancer in middle-aged patients presenting with spontaneous proximal DVT.

Paul Ockelford, MD
Auckland, New Zealand

I would discontinue DOAC and return to enoxaparin or warfarin with a higher INR. We continue to learn DOAC’s pharmacokinetics, which are less effective in cancer-associated thrombophilia or primary disorders. Rivaroxaban apparently is more indicated in cancer and concomitant VTE.

Manuel F. Gonzalez, MD
Sumter, SC

The patient’s PE three days after DVT presentation in my opinion would not represent treatment failure on apixaban. My approach would be to treat with enoxaparin for 30 days and switch back to apixaban.  Not aware of any data supporting other NOACs to be better or worse.

One could consider testing drug levels (for NOAC or LMWH), though the data here is also far from definitive in guiding treatment options.

Garry Schwartz, MD
Northeast Oncology Associates
Raleigh, NC