Recurrent VTE Despite Anticoagulation

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While recurrent venous thromboembolism is rare, it presents a unique challenge to emergency physicians seeking to understand the breadth of available anticoagulants. Here’s an essential run-down. 

43-year-old woman with a history of pulmonary embolism (PE) and antiphospholipid antibody syndrome taking rivaroxaban presented to the ED with shortness of breath, hemoptysis, and pleuritic chest pain. Chest CT demonstrated multiple PEs.

A 38-year-old man with an unknown type of thrombophilia came to the ED after experiencing 36 hours of inability to speak. He has a complex history of multiple PEs, DVT’s, STEMI with stent placement, and stroke. Historically, treatment with warfarin was not successful and he was most recently switched to apixiban. A new stroke was evident on the non-contrast CT.

The Problem
Recurrent venous thromboembolism (VTE) despite therapeutic anticoagulation is rare (about 2% in patients compliant with treatment) [4] and can occur regardless of the type of anticoagulant used. Recurrent symptoms of chest pain or dyspnea in patients on active anticoagulation cause understandable patient anxiety and result in ED visits to  “rule out PE.” Symptoms typically lead to confirmatory testing in the ED, using Doppler venous ultrasound, or more often, chest CT angiography. While there is no gold standard to help emergency providers make a clinical diagnosis, a better understanding of the pharmacology of anticoagulants can help in decision-making.

Conventional anticoagulants, such as Vitamin K antagonists (VKA), heparin, and low molecular weight heparins (LMWH) have solid track records in the management of (VTE), even in the most complex of patients. Disadvantages, including need for frequent monitoring, narrow therapeutic indices, drug-drug interactions, and adverse effects have led to the use of direct oral anticoagulant (DOAC) agents for VTE. Dabigatran, a direct thrombin inhibitor, and the factor Xa inhibitors (FXaI’s) apixaban, rivaroxaban, and edoxaban are all effective agents for VTE. DOACs carry the potential benefits of minimal monitoring, fixed dosing, wide therapeutic indices, and seemingly, fewer drug-drug interactions than occur with VKAs. Despite the advantages, DOACs carry the risk of treatment failure, particularly with compromised or inconsistent patient compliance and bleeding events [1].

There is little information regarding the relative efficacy of VKAs compared to DOACs for VTE. Trials published to date have largely been non-inferiority studies, rather than equivalency or superiority studies. Thus, determination of the ideal agent for each individual patient is based on the judgment and rationale of the individual physician, even in the setting of recurrent thrombosis [1,2].

Pharmacology and Pharmacokinetics
The pharmacokinetic and pharmacodynamic properties of the VKAs and DOACs are summarized in Table 1 (below), along with lab assays utilized in qualitative measurement. Due to the short half-life of the DOACs in comparison to VKAs, consistent patient compliance is critical, as protection from stroke and VTE can be compromised with the omission of a single dose of these agents. In instances of impaired renal function, DOAC half-lives prolong significantly and can lead to drug accumulation and the potential for bleeding. Obtain a careful medical history before prescribing DOACS for VTE. Avoid concomitant use of dabigatran with strong P-glycoprotein inducers and concomitant use of all factor Xa inhibitors with P-glycoprotein inducers and CYP 3A4 inducers. Dual P-gp and CYP 3A4 inducers (Table 1) present the highest risk of reducing therapeutic anticoagulation levels for DOAC patients and include: barbiturates, imidazole antifungals (i.e. ketoconazole), HIV protease inhibitors, carbamazepine, dexamethasone, phenytoin, rifampin, and St. John’s Wort [3].

The quantitative plasma concentration thresholds beyond which a patient would be at risk of thrombosis have not been established for any DOACs. Dabigatran causes dose-dependent prolongation in PT and aPTT, but these assays only indicate the presence of dabigatran, not its effectiveness. The ecarin clotting time (ECT) gives a more precise anticoagulant effect, but is not readily available in the ED.  For the FXaI’s, a standard anti-Factor Xa assay calibrated to UFH or LMWH can qualitatively assess anticoagulation, but it may only be available in tertiary care centers [1,3,4].

Risk and Evaluation
The recurrence rate of VTE on therapeutic doses of VKAs and DOACs in general, is approximately 2% [4]. Carefully review details of patient compliance when assessing recurrent VTE symptoms. One study reported that 17% of patients were noncompliant in the first three months of treatment, and compliance declined further over the next 6-12 months [5].

In the ED, for patients receiving DOACs who have prolonged ED stays for observation or admission, be sure to prescribe DOACs according to the patient’s dosing schedule, in order to prevent potential for VTE.

If possible, anti-Factor Xa assay, if available, can help determine if the patient is taking the drug—however  it would not necessarily exclude treatment failure. Next, determine if the patient’s symptoms truly represent recurrent VTE. D-dimer levels fall by about 25% within 24 hours of heparin administration [7], so a positive D-dimer assay is further evidence in support of recurrent VTE, while a negative result makes acute thrombosis less likely. Imaging with Doppler ultrasound or CT angiography is needed and should be compared with prior studies, if available.

Treatment and Management Considerations
In the ED, in the case of hemodynamically or clinically significant recurrent VTE, begin treatment with parenteral UFH or LMWH and obtain hematology consultation. 

Long-term management strategies include changing the patient to a different anticoagulant (i.e. DOAC to warfarin or warfarin to LMWH), increasing the intensity of anticoagulation with higher doses, or targeting a higher therapeutic INR for warfarin. These considerations are best managed by a hematologist [1,4].

Presuming adequate compliance, a primary concern is to determine the cause of the recurrence. Known causes of recurrent VTE on therapeutic anticoagulation include occult neoplasm, particularly myeloproliferative neoplasms, active antiphospholipid antibody syndrome (APLAS), and inconsistent medication adherence. The JAK2V617F mutation may be associated with increased risk of anticoagulation failure, even in the absence of malignancy [6]. Routine screening for JAK2V617F mutation in the absence of recurrent VTE or neoplasm has not yet proven beneficial.

Case Resolutions
The woman in our initial case study admitted that she periodically missed her doses of rivoxabaran. She was started on a heparin drip in the ED and admitted to the hospital for management of her PEs. A hematology consult confirmed the cause of recurrent PE was medication non-compliance. The man in our second case steadfastly insisted he had not missed a single dose of apixaban. With gentle and non-judgemental questioning, he finally admitted that he had trouble keeping track of his meds and couldn’t remember the last time he took his apixaban. With consideration of risks and benefits of anticoagulation despite a new stroke, heparin was started and the patient was admitted to the hospital. Hematology was consulted in the ED and planned to consider switching the patient to a once-a-day NOAC in hopes of enhancing compliance. 


REFERENCES

  1. Kazmi RS, Lwaleed BA. New anticoagulants: how to deal with treatment failure and bleeding complications. Br J Clin Pharmacol. 2011;72(4):593-603.
  2. Rankin J, Nagar M, Crosby J, et al. Possible failure of novel direct-acting oral anticoagulants in management of pulmonary embolism: a case report.  J Med Case Rep. 2016;10:346-51.
  3. Nutescu EA, Burnett A, Fanikos J, et al. A pharmacology of anticoagulants used in the treatment of venous thromboembolism. J Thromb Thrombolysis. 2016;41:15-31.
  4. van der Hulle T, Koolman J, den Exter PL, et al. Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost. 2014;12:320-328.
  5. Vora P, Soriano-Gabarro M, Suzart K, et al. Limited evidence on persistence with anticoagulants and its effect on the risk of recurrence of venous thromboembolism: a systematic review of observational studies. Patient Prefer Adherence. 2016;10:1657-1665.
  6. Ianotto JC, Chaveau A, Mottier D, et al. JAK2V617F and calreticulin mutations in recurrent venous thromboembolism: results from the EDITH prospective cohort. Ann Hematol. 2017;96:383-86.
  7. Linkins L-A, and Takach Lapner S ‘Review of D-Dimer testing: Good, Bad, and Ugly   Int J Lab Hem  2017:39 (Suppl 1): 98-103

ABOUT THE AUTHOR

Dr. Hatfield is a Lead Clinical Pharmacist Specialist, Emergency Medicine, at UNC Healthcare. She is an assistant professor of clinical education at UNC Eshelman School of Pharmacy.

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