Venous thromboembolism (VTE) is a well-established complication of inflammatory bowel disease (IBD). IBD patients are at 3–4-fold higher risk of VTE compared to the general population, with lifetime cumulative risks approaching 30% by age 70 years.1, 2 The mortality following VTE in the IBD population has been reported to be as high as 22%.3, 4 Thus, a high index of suspicion and prompt treatment are critical in optimizing health outcomes following VTE. As in the general population, the mainstay of VTE treatment in those with IBD is anticoagulation therapy and, in select patients, use of thrombolytics. Because IBD patients frequently have active disease with gastrointestinal bleeding, there may be concerns regarding the safety of anticoagulation therapy. A meta-analysis of studies in which anticoagulation was used as primary treatment for IBD did not show increased risk of major bleeding.5 However, there remains a paucity of efficacy and safety data for treatment of VTE in the IBD population.
In this issue of Inflammatory Bowel Diseases, Tabibian and Streiff (Inflammatory Bowel Disease-associated Thromboembolism: A Systematic Review of Outcomes with Anticoagulation Versus Catheter-directed Thrombolysis) perform a systematic review of case reports and series describing outcomes of IBD patients who were treated for thromboembolism, of whom 35 received anticoagulation (AC) and 17 received IBD catheter-directed thrombolysis (CDT). In their analysis they found that all patients who were treated with CDT had at least partial resolution of symptoms compared to only three-quarters of those who received AC (P = 0.02), with a marginally significantly higher rate of radiologic resolution (100% versus 74%, P = 0.06). The authors did not show a statistically significant difference in treatment-related gastrointestinal (GI) or non-GI bleeding between those receiving AC and CDT.
Among the limitations of the study is the small sample size, which may have precluded the detection of differences in efficacy and especially hemorrhagic complications between the two treatment groups. The small sample size is further compounded by the heterogeneity of data collection and the site of thromboembolism, which affects severity and outcomes. Moreover, because case reports are more likely to be submitted and published if they describe successful interventions or significant complications, there is considerable potential for publication bias favoring positive studies—both beneficial outcomes and adverse events. The skewed publication of positive studies may have contributed to the greater symptomatic improvement observed in the CDT group relative to the AC group. Additionally, the published cases analyzed in this study overly select for atypical sites of thromboembolism, even though pulmonary embolism and lower extremity deep venous thrombosis account for more than 90% of IBD-related VTEs.2–4, 6 Thus, the effectiveness data from this systematic review may not be applicable to all types of VTEs.
Despite the above caveats, there are key points regarding the safety of VTE treatment that arise from this descriptive study in which 40% of subjects had hematochezia prior to treatment. First, the rate of hemorrhagic complication from CDT in this small case series does not appear to be higher than that reported in non-IBD patients.7–9 Given the small sample size, it is difficult to interpret whether it is higher than bleeding complications associated with AC. The data from this study lend additional support to the assumption that IBD patients, even in the presence of hematochezia, can be safely managed with AC or CDT as long as there is no massive, ongoing GI hemorrhage. The decision to treat with CDT or AC should be made on a case-by-case basis. Even in the general population, the mortality benefit of CDT over AC remains unclear.10, 11 CDT may be appropriate in individuals with more severe presentations of VTE such as pulmonary embolism with hemodynamic compromise or massive and proximal deep venous thrombosis with severe symptoms.12 Thus, until further safety and efficacy suggest otherwise, IBD patients with VTE should initially be managed similarly to non-IBD patients.
What the above systematic review does not address is the long-term management of VTE, which may require different consideration in the IBD population. Up to three-quarters of IBD patients presenting with VTE do not have any identifiable provoking factors.2, 6 Among those with unprovoked VTE, as many as a third will have a recurrent VTE event within 5 years, which reflects a 2.5-fold higher risk of recurrence compared to non-IBD patients following an initial VTE.6 In the general population, an initial unprovoked VTE prompts investigation for an underlying hypercoagulable state. In the absence of such conditions, anticoagulation is continued for at least 3 months, and long-term treatment is considered on an individual basis weighing the risk/benefit ratio.12 In the IBD population, the optimal duration of anticoagulation for unprovoked VTE is unknown. Between 55%–80% of IBD patients have active disease at the time of first VTE.2–4, 13 Furthermore, a recent population-based study from the U.K. showed that IBD patients were at highest risk of VTE relative to non-IBD patients during acute, moderate/severe flares of their disease and especially in the ambulatory setting when this relative risk was nearly 16-fold.14 In the same study, in a same given individual, the risk of VTE was 9-fold higher during acute flares relative to periods of remission.14 These cumulative data provide supporting evidence for the role of underlying active IBD as a precipitating factor for VTE. Thus, it would be reasonable to consider continuing anticoagulation for VTE in a patient with active IBD until clinical remission is achieved. It is not clear whether these patients would benefit from prophylactic or treatment doses of anticoagulation during future IBD flares, and such decisions should be considered on a case-by-case basis, ideally under consultation with a hematologist or thrombosis clinic. For IBD patients with unprovoked VTE while in clinical remission, the optimal duration of anticoagulation is unclear and is also usually addressed on an individual basis.
Although VTE is a well-established complication of IBD that is associated with high mortality, there is a paucity of clinical studies to drive evidence-based guidelines on how to optimally manage this condition in the IBD population. Treating physicians consequently adapt treatment paradigms developed for the general population and, in doing so, make assumptions regarding similar risk of hemorrhagic complications. This systematic review by Tabibian and Streiff does not definitively establish the safety of CDT in the IBD population. However, the data do support that IBD is not a contraindication for CDT and that the treatment modality is a viable option in appropriately selected IBD patients. The long-term management of VTE in the IBD population remains poorly addressed. Larger multicenter retrospective and prospective studies are needed to conduct a comparative assessment of the relative efficacy and safety of various treatment strategies with anticoagulation to optimize VTE-related long-term outcomes.