You Make the Call: How would you treat a patient with a history of bilateral PE and subsequent DVT? Free

Kenneth A. Bauer, MD 
Beth Israel Deaconess Medical Center 
Professor of Medicine 
Harvard Medical School 

CLINICAL DILEMMA

A 39-year-old female has a history of bilateral pulmonary embolism (PE) after taking oral contraceptive pills (OCPs), as well as a subsequent deep vein thrombosis (DVT) in the left calf after a long car ride. Given the recurrent event and her history of venous thromboembolism (VTE), would you treat with indefinite anticoagulation? For both provoked and unprovoked below-the-knee DVT, I typically treat for three months, but for recurrent, provoked below-the-knee DVT, what would you recommend? Could you treat either situation for three months, and use 5 mg of oral apixaban as prophylaxis prior to flying or long car rides? 

EXPERT OPINION

Based on the risk factors and comorbidities present at diagnosis of a first episode of VTE, the literature provides recurrence rates that aid in making decisions regarding the duration of anticoagulation. The risk is more difficult to determine in this patient who developed an isolated distal DVT (IDDVT) while off anticoagulation following a prior oral contraceptive-associated PE. When evaluating such patients, it is my practice to obtain additional history, including age at which the PE developed; how long she had been on the estrogen-containing OCPs; clot burden in the lungs; prior pregnancies or major surgeries; smoking; body mass index; duration of time between the thrombotic events; and the length of the car trip. It is also important to ascertain whether there is a family history of VTE, particularly among first-degree relatives. 

Following diagnosis of PE, this patient was appropriately treated with therapeutic anticoagulation for three months, and the OCP was discontinued; the recurrence risk is low (about 2% in the first year), and long-term anticoagulation is not recommended.¹ With regard to recurrent IDDVT, travel is a relatively weak risk factor. Based on data from case control studies, ten Wolde et al. found that the risk for developing a first VTE was only increased if travel time was greater than 10 hours (odds ratio = 2.5, 95% CI 1.0-6.2).² More importantly, a study found that proximal DVT or PE in association with air travel had a recurrence risk similar to unprovoked events.³ 

For patients diagnosed with a first symptomatic IDDVT, most clinicians recommend three months of therapeutic anticoagulation. The subsequent recurrence risk is about half that of a proximal DVT or PE, so long-term anticoagulation is not recommended.¹ A recently published study found that the one-, five-, and 10-year cumulative incidences of recurrent VTE following a first IDDVT were 5.6%, 14.7%, and 27.2%, respectively; the recurrence rates were higher for unprovoked than provoked IDDVT.⁴ Among the recurrent events, 29% were PE, and 33% were proximal DVT. However, a pooled analysis of 18 trials of patients with a first episode of unprovoked VTE in whom anticoagulant therapy was discontinued found that the recurrence risk following IDDVT was only 1.9% in the first year compared to 10.6% for patients with a proximal DVT.⁵ 

Patients with a second episode of VTE at low bleeding risk were historically placed on long-term anticoagulation. However, we now recognize that the recurrence risk is variable based on whether the initial or recurrent thrombotic events were unprovoked or provoked or if one of the events was an IDDVT. In one report, it was found that the cumulative incidence of recurrent VTE only increased from 22% after a first DVT to 28% after a second DVT.⁶ It is potentially relevant to this patient’s case to note that a prospective study of patients with a second VTE occurring more than one year after the first event had a recurrence rate of only 6% off anticoagulation.⁷ 

Given the variable recurrence rates in the literature for this patient, it is appropriate to discuss the benefits and risks of long-term anticoagulation with her, along with her preferences. Based on her history, I would counsel her that her cumulative recurrence risk may be 5% at one year and between 15% and 20% at five years in the absence of anticoagulation. As anticoagulation is highly effective in preventing recurrent VTE, it would be appropriate to place her on long-term anticoagulation if she valued prophylaxis and was at low bleeding risk. She appears to be an appropriate candidate for a low dose of an oral factor Xa inhibitor (either rivaroxaban 10 mg daily or apixaban 2.5 mg twice daily). If her two thrombotic events occurred one or more years apart and she did not want to commit to extended anticoagulation, it would be reasonable to have her stop anticoagulation. 

If long-term anticoagulation is not undertaken, she should be advised of the need for thromboprophylaxis following major surgery and during other periods of increased thrombotic risk, including pregnancy (using low-molecular-weight heparin [LMWH]). Given that travel is a very weak risk factor, I do not advise administration of a single dose of either LMWH or a direct oral anticoagulant just prior to long travel; rather, I advise patients to wear compression stockings and walk around the cabin at intervals while flying or ambulate during frequent rest breaks during long car travel. If patients are taking very long flights and are anxious about travel-associated VTE, I will occasionally prescribe a reduced dose of an oral factor Xa inhibitor for three days starting just prior to departure (though I acknowledge the absence of evidence for this approach). 

Finally, many young patients such as this woman with recurrent VTE will undergo evaluation for an underlying inherited or acquired prothrombotic disorder. In the absence of a strong family history of VTE, it has not been shown that the presence of most thrombophilic defects (save perhaps for persistently positive markers of antiphospholipid syndrome) should influence the decision regarding the need for long-term anticoagulation. 

References

1. ten Wolde M, Kraaijenhagen RA, Schiereck J, et al. Travel and the risk of symptomatic venous thromboembolism. Thromb Haemost. 2003;89(3):499-505. 
2. Ortel TL, Neumann I, Ageno W, et al. American Society of Hematology 2020 guidelines for the management of venous thromboembolism: treatment of deep venous thrombosis and pulmonary embolism. Blood Adv. 2020;4(19):4693-4738. 
3. Chua CC, Lim HY, Tracey M, et al. Retrospective evaluation of venous thromboembolism: are all transient provoking events the same? Eur J Haematol. 2017;99(1):18-26. 
4. Jørgensen CT, Tavoly M, Førsund E, et al. Incidence of bleeding and recurrence in isolated distal deep venous thrombosis: findings from the Venous Thrombosis registry in Østfold Hospital. J Thromb Haemost. 2023;21(10):2824-2832. 
5. Khan F, Rahman A, Carrier M, et al. Long term risk of symptomatic recurrent venous thromboembolism after discontinuation of anticoagulant treatment for first unprovoked venous thromboembolism event: systematic review and meta-analysis. BMJ. 2019;366:l4363. 
6. Hansson PO, Sörbo J, Eriksson H. Recurrent venous thromboembolism after deep vein thrombosis: incidence and risk factors. Arch Intern Med. 2000;160(6):769-774. 
7. van der Hulle T, Tan M, den Exter PL, et al. Recurrence risk after anticoagulant treatment of limited duration for late, second venous thromboembolism. Haematologica. 2015;100(2):188-193.