Residual Thrombosis: Still Relevant in the Direct Oral Anticoagulant (DOAC) Era?

The duration of anticoagulant treatment after venous thromboembolism continues to be matter of debate. In fact, venous thromboembolism is potentially life-threatening and tends to recur after an index episode; for this reason, venous thromboembolism has been regarded as a chronic disease for several decades.[ 1 ] Currently, the treatment of venous thromboembolism includes an initial phase aimed at treating the acute episode and an extended phase aimed at preventing recurrences. While the initial phase is mandatory in all patients, the extended phase should be reserved to patients with a substantial risk for recurrence and low risk of bleeding.[ 2 ] [ 3 ] [ 4 ] Indeed, potential risk factors for recurrence of venous thromboembolism have been investigated,[ 5 ] [ 6 ] and some conditions may be predisposing to the high long-term risk of cardiovascular events in this population.[ 7 ] Anticoagulant treatment is effective in reducing recurrent venous thromboembolism by over 90%, but it is associated with the risk for life-threatening and even fatal bleeding complications.[ 8 ] Indeed, the perceived risk of bleeding limits every-day life activities in a substantial proportion of patients during anticoagulant treatment. In addition, anticoagulant treatment may interfere with concomitant therapies, harm and discourage motherhood, and, in the event of vitamin K antagonists (VKAs), requires monitoring and dose adjustments. Thus, only patients with estimated risk for recurrence sufficiently high to warrant the risks and inconveniences of long-term anticoagulation should receive extended treatment. The assessment and mitigation of bleeding risk in venous thromboembolism has been the topic of a recent European and Asia-Pacific position paper.[ 9 ] Why does recurrent venous thromboembolism happen? Residual vein obstruction after proper anticoagulation has been claimed to be a predictor of recurrent venous thromboembolism.[ 10 ] Residual thrombi can be an easy substrate for thrombus growth and, perhaps, may suggest a peculiar prothrombotic phenotype. As an example, a more solid structure of the thrombus was hypothesized in carriers of the Leiden mutation of factor V after the observation of a lower risk of pulmonary embolism in patients with deep vein thrombosis.[ 11 ] In this view, the role of residual thrombi or emboli as predictors for recurrence has some biological plausibility. In a single-center, prospective study including consecutive patients with symptomatic proximal deep vein thrombosis described in the paper by Iding et al in this journal tested a management strategy with duration of anticoagulation tailored to residual thrombosis and to the setting of the thrombotic event (provoked or unprovoked).[ 12 ] Patients with persistent risk factors for venous thromboembolism were excluded from the study. The authors found no association between residual thrombosis and recurrent venous thromboembolism after adjusting for duration of anticoagulant therapy, unprovoked deep vein thrombosis, previous venous thromboembolism, venous insufficiency, and hypertension. Of course, it is conceivable that tailoring treatment duration has influenced the study results. In fact, a previous individual patient meta-analysis including a threefold larger population showed that early residual thrombosis is a predictor, albeit weak, of recurrence.[ 13 ] The management strategy tested by Iding et al tailored anticoagulation to residual thrombosis in both, patients treated for provoked and unprovoked deep vein thrombosis.[ 12 ] A large amount of data exist showing that the setting of index venous thromboembolism can be used to efficiently classify patients according to the risk for recurrence. The highest the attributable risk of the trigger condition for index venous thromboembolism (as major surgery and major trauma), the lower the risk for recurrent venous thromboembolism beyond discontinuation of anticoagulant treatment. In this view, 3 months of anticoagulant treatment is currently recommended for venous thromboembolism occurring after exposure to major transient risk factors.[ 2 ] [ 3 ] [ 4 ] About 40 to 60% of patients suffer from venous thromboembolism in the absence of identifiable risk factors. Whatever the definition we choose for these patients (idiopathic, unprovoked), they have a high risk for recurrent venous thromboembolism that continues beyond 3 months after the index episode[ 1 ] [ 14 ]; the risk is particularly high in the first 2 years after index venous thromboembolism then starts to decline and reaches a plateau, but never falls to zero. These patients are the main candidates for extended prevention of recurrences. Patients having venous thromboembolism in the context of minor transient risk factors (as minor trauma, short bed rest) represent a peculiar category as their risk of recurrence seems to be higher than that of patients having an event associated with major risk factors and lower than that of patients having an event not associated with identifiable risk factors. In the hypothesis of some unidentified prothrombotic phenotype, at times these patients have been considered for secondary prevention. By including patients treated for deep vein thrombosis associated with transient risk factors, Iding et al suggest that these patients could be candidates for further risk stratification.[ 12 ] Risk stratification was initially proposed for patients suffering from venous thromboembolism not associated with identifiable risk factors but has been recently proposed also for patients having venous thromboembolism in the context of minor risk factors. Pursuing personalized medicine, several predictors have been proposed to stratify the risk for recurrence. Individual predictors were integrated in models and scores to estimate the individual risk for recurrence of venous thromboembolism and tailoring the duration of anticoagulation. Male gender, age, and D-dimer are usually included among the items of these models. The role of D-dimer-driven strategies has been recently dampened after a management study showed an approximately eightfold higher rate of symptomatic recurrence and major bleeding in patients treated for unprovoked venous thromboembolism who discontinued treatment due to normal D-dimer in comparison to patients extending with reduced doses of apixaban due to increased D-dimer (7.3 vs. 1.1%).[ 15 ] The question in clinical practice nowadays is whether risk stratification for recurrence is still relevant in the era of direct oral anticoagulants (DOACs). DOACs do not require monitoring or dose adjustment and, more important, are associated with approximately 50% the risk for major bleeding of VKAs. The results obtained with reduced doses of apixaban and rivaroxaban changed the paradigm for extended treatment of venous thromboembolism.[ 16 ] In fact, the reduction in the expected burden of anticoagulation could lead to reduce the threshold of estimated recurrence risk to candidate patients for extended prevention of recurrent venous thromboembolism. As of today, no large-scale study with long-term follow-up confirmed the results of randomized clinical trials with low-dose apixaban or rivaroxaban for secondary prevention of venous thromboembolism, but these regimens are widely used in clinical practice. In this scenario, definitively abandoning risk stratification could still be simplistic; in fact, continuing on DOAC, even at reduced doses, interferes with life-style (risk of traumatic bleeding, potential harms for the fetus) and adds costs to the patients and the health system. Due to the limited predictive value, residual thrombosis should probably not be used to select patients for extended prevention of recurrent venous thromboembolism. However, residual thrombi and emboli could represent a confounder when searching for recurrence. For this reason, venous ultrasound should be obtained at the time of treatment discontinuation in all patients treated for deep vein thrombosis to improve the accuracy in diagnosis of homolateral recurrence. To limit radiation exposure and adverse effects due to contrast medium, follow-up imaging should be limited to patients with persisting symptoms after index pulmonary embolism. Differently from isolated findings, residual thrombosis or emboli in the context of severe postthrombotic syndrome or postembolic pulmonary hypertension could turn in favor of extended prevention of recurrent venous thromboembolism. This claims for clinical trials and structured pathways for long-term management after venous thromboembolism in patients with sequaele.[ 2 ] [ 3 ] In addition to the absolute risk for recurrence, it should be noted that venous thromboembolism tends to recur with the clinical presentation of the index event, that means that deep vein thrombosis usually recurs as thrombosis and pulmonary embolism as emboli. This may impact the case fatality rate of recurrence after index deep vein thrombosis or index pulmonary embolism. With this in mind, withdrawal of anticoagulation is probably a reasonable option in all patients after a first episode of deep vein thrombosis in the absence of persistent major risk factors. Nevertheless, the role of patient preference is often advocated in decision making on extended prevention of recurrent venous thromboembolism.[ 17 ] Patients should be instructed on benefits and risks of venous thromboembolism and anticoagulant treatment, but physicians should give a clear opinion to each specific patient on what they believe is the better strategy. It should be clear that definite prolongations of anticoagulation beyond 3 months (i.e., additional 3 months, 9 months, etc.) only delay recurrences until treatment is discontinued. In conclusion, residual thrombosis should be assessed in all patients at the time of discontinuation of anticoagulant treatment to improve accuracy in diagnosis of recurrence. The role of residual thrombosis in decision making concerning the need for secondary prevention is limited outside the context of postthrombotic syndrome or chronic postembolic pulmonary hypertension. Additional data are advocated to better define the candidates and the strategies for secondary prevention of recurrent venous thromboembolism (NCT04168203, NCT04257487, NCT03285438). Publication History Received: 25 April 2023 Accepted: 24 May 2023 Accepted Manuscript online: 26 May 2023 Article published online: 24 July 2023 © 2023. Thieme. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany