This month, Kenneth A. Bauer, MD, discusses the duration of anticoagulation in a patient with ulcerative colitis and thrombosis.
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An 85-year-old man with a history of ulcerative colitis who was being treated with a tumor necrosis factor (TNF) inhibitor presented in June 2019 with phlegmasia cerulea dolens. He was found to have an iliofemoral deep vein thrombosis (DVT) and underwent catheter-directed thrombolysis with placement of a venous stent. He is currently on apixaban 5 mg orally twice per day and low-dose aspirin. He was not immobile prior to the development of the DVT and the only risk factor appears to be inflammatory bowel disease, although this is in remission. He has normal renal and hepatic function. I was considering reducing the dose of apixaban to 2.5 mg orally twice per day now that he is stable. The AMPLIFY-Extension trial was open to patients in whom physicians felt there was equipoise between continuing anticoagulation versus stopping it. Can we extrapolate those results to this setting where indefinite anticoagulation is likely warranted?
Following 3 to 6 months of anticoagulation, the decision as to whether to extend anticoagulation indefinitely in patients with a first episode of proximal DVT, pulmonary emboli (PE), or both continues to vex many clinicians. While the paradigm of dichotomizing patients into those with provoked (i.e., low recurrence risk) and unprovoked (i.e., high recurrence risk) events has utility in risk-stratifying patients, the reality is that there is a gradient of risk among “provocative” risk factors.1 Some of this stems from the multifactorial nature of venous thromboembolism (VTE) with regard to causation (i.e., the additive role of risk factors).
I approach such cases by first asking whether the patient warrants extended anticoagulation with any anticoagulant. This patient clearly had an unprovoked DVT and warrants consideration of extended anticoagulation despite his age and history of ulcerative colitis (which is itself a risk factor for VTE, especially when the patient‘s disease is active); this assumes he has not had a recent major bleed and is otherwise in good health (e.g., normal blood counts, liver tests, and renal function). From a bleeding standpoint, before considering further anticoagulation it is important that his ulcerative colitis be quiescent and that he not be at high risk for falls; consideration also should be given to stopping aspirin to lessen the risk of bleeding given that venous stents undergo endothelialization over time. The presence of a large clot burden at initial presentation, which was the case here, further strengthens my opinion that this patient should continue on anticoagulation. With respect to the recurrence risk in the placebo arm of the AMPLIFY Extension trial, it was similar to what has been reported for unprovoked VTE after an initial 6 to 12 months of anticoagulation in the literature (8.8% in the first year).2 Long-term studies have demonstrated a recurrence risk of about 25% at 4 years and 40% to 50% at 10 years.
The second question is which anticoagulant to employ. Given that warfarin has been shown to be more effective than rivaroxaban in patients with triple-positive antiphospholipid antibody syndrome, and antiphospholipid antibodies can be seen in patients with ulcerative colitis, I would exclude this possibility by obtaining levels of cardiolipin and β2-glycoprotein I antibodies. If the decision is made to employ an oral factor Xa inhibitor (apixaban or rivaroxaban), then one has the option of using a low-dose regimen (apixaban 2.5 mg orally twice per day rather than 5 mg, or rivaroxaban 10 mg orally once daily rather than 20 mg).2,3 There is relatively little evidence to guide the choice between doses and individualized decisions must take into account the risks of recurrence and bleeding. I tend not to reduce dose in patients whom I feel are at higher risk for recurrence (or potentially will have a severe outcome if they develop a recurrence); I also will generally not go to lower doses in those with higher body weights (i.e., >100 kg). Unless this patient has a low body weight (i.e., <60 kg), I would be inclined to continue apixaban 5 mg orally twice per day and not reduce the dose to 2.5 mg.
It is important to appreciate the limitations of the AMPLIFY Extension and EINSTEIN Choice trials.2,3 While the studies demonstrate a wide therapeutic window for apixaban and rivaroxaban dosing in the secondary prevention of VTE, it should not be inferred that there is no dose response with respect to efficacy or safety for these anticoagulants; the trials were not designed or powered to establish noninferiority for the low- and standard-dose regimens.1 It also should be noted that the patients in both trials had a low baseline bleeding risk, which contributed to the low bleeding rates observed with both the low- and standard-dose regimens.
- Lijfering WM, Timp JE, Cannegieter SC. Predicting the risk of recurrent venous thromboembolism; what the future might bring. J Thromb Haemost. 2019;17:1522-6.
- Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013;368:699-708.
- Weitz JI, Lensing AWA, Prins MH, et al. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med. 2017;376:1211-22.
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NEXT MONTH'S CLINICAL DILEMMA
I have a 45-year-old male patient with type 1 diabetes and ischemic cardiomyopathy who was referred for thrombocytosis. The highest platelet count recorded was 504,000 and the rest of his workup was normal, aside from a hemoglobin level of 13.7 g/dL , ferritin level of 19 ug/L, and iron saturation level of 21% . Since his diabetes was well treated for most of his life and the cardiomyopathy (ejection fraction of 35%) seemed less than what I would expect, and I was concerned about a myeloproliferative neoplasm (MPN), I did Tempus next-generation panel sequencing rather than single-gene sequencing for JAK2, CALR, and MPL to try to also capture DNMT3A, ASXL1, TET2, and so on. None of those were positive. He had a copy number loss in RUNX1 (but not RUNX1-EVT6 fusion) and a STAG2 loss of function at 3.9%, a gene that I had never heard of. Does this qualify as clonal hematopoiesis of indeterminate potential (CHIP), and might it explain his early coronary artery disease? Does he need a bone marrow biopsy to look for myelodysplastic syndromes (MDS), MPN, or MDS/MPN given his higher platelet count?
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