1. In this prospective cohort study, isolated distal deep vein thrombosis (IDDVT) was linked to lower all-cause mortality and fewer venous thromboembolism (VTE) deterioration events compared to proximal deep vein thrombosis (DVT). However, there was no significant difference between patients with IDDVT and proximal DVT in major bleeding events at 1 year.

2. Mortality related to pulmonary embolism (PE) was low in short- and long-term follow-up of patients with IDDVT.

Evidence Rating Level: 2 (Good)

Study Rundown: Isolated distal deep vein thrombosis (IDDVT), defined in this study as thrombosis in the infrapopliteal veins without co-existing proximal deep vein thrombosis (DVT) or pulmonary embolism (PE), accounts for approximately 20-50% of all DVTs. Evidence suggests worse outcomes in patients with proximal DVT versus IDDVT in all-cause mortality, VTE recurrences, and major bleeding events. However, prior literature on the topic is sparse, relying on single-center studies, studies that had small sample sizes or those that only focused on short-term outcomes. Thus, there remains a lack of high-quality evidence about the outcomes following IDDVT versus proximal DVT, and further research into this may aid prognostication, as well as aid downstream decisions surrounding treatment and follow-up. This study used data from the Registro Informatizado Enfermedad Tromboembólica (RIETE), a prospective registry of patients with venous thromboembolism (VTE), which includes over 200 enrolling centers from Africa, North and South America, Asia, and Europe. Categorical variables were compared between the IDDVT group and the proximal DVT group using chi-squared tests, while continuous variables were compared using the t-test or its nonparametric counterparts. Multivariable models were used to determine if differences between the two groups were driven by demographics, comorbidities, and VTE risk factors; multivariable logistic regression analysis used for short-term outcomes and adjusted hazard models used for long-term outcomes. Through the registry, 33,897 patients were identified to have isolated DVT, with 5,938 (17.5%) cases of IDDVT and 27,959 (82.5%) cases of proximal DVT. With respect to short-term outcomes, all-cause mortality at 30- and 90-day follow-up was lower in the IDDVT group versus the proximal DVT group, even after multivariable adjustment. Furthermore, major bleeding was less frequent in the IDDVT group versus the proximal DVT group at 30 days and 90 days. In the long term, all-cause mortality continued to be lower in the IDDVT group versus the proximal DVT group, and this difference again persisted after multivariable adjustment. VTE deterioration events at 1 year, defined as subsequent development of proximal DVT or PE, was significantly more frequent in the proximal DVT group when compared to the IDDVT group. There was no significant difference between the two groups in major bleeding events at 1 year after multivariable adjustment. A major strength of this study was the large patient population recruited from numerous different centers, minimizing the effect of type II error. In terms of limitations, baseline characteristics were not controlled between the groups, and differences in patient comorbidities likely contributed to outcomes such as all-cause mortality, given that fatal PE was an infrequent cause of death. The findings of this prospective cohort study provide insight into the differences in outcomes between proximal and IDDVT in both the short and long term and may guide further research into optimal management of DVT overall as well as management of subtypes of DVT.

Click to read the study in JAMA Cardiology

Relevant Reading: Comparison of the clinical history of symptomatic isolated distal deep-vein thrombosis vs. proximal deep vein thrombosis in 11086 patients

In depth [prospective cohort study]: This study analyzed patients with IDDVT and proximal DVT from the RIETE registry, from March 1, 2002, to February 28, 2021. The RIETE registry enrolled consecutive patients with objectively confirmed VTE with a minimum of 3 month follow up. Included in this study were patients that had isolated distal DVT or proximal DVT. Excluded were patients with asymptomatic DVT, upper extremity DVT, co-existing PE, and COVID-19. A total of 33,897 patients were identified to have isolated DVT, with 5,938 (17.5%) cases of IDDVT and 27,959 (82.5%) cases of proximal DVT. Treatment patterns were analyzed, and most patients (99.8%) received anti-coagulation treatment, most commonly low molecular weight heparin. With respect to short-term outcomes, the IDDVT group had a significantly lower risk of 30-day all-cause mortality when compared to the proximal DVT group (odds ratio [OR], 0.39; 95% CI, 0.30-0.51; p<0.001), and this difference persisted after multivariable adjustment. At 90 days, this difference was again present in all-cause mortality (OR, 0.47; 95% CI, 0.40-0.55; p<0.001), but there was no significant difference between the two groups in total number of PE-related deaths (p=0.23). Major bleeding was significantly less frequent in the IDDVT than the proximal DVT group after multivariable analysis at both 30 days (p=.009) and at 90 days (OR, 0.64; 95% CI, 0.48-0.86; p=.01). With respect to long-term outcomes, the IDDVT group had a lower hazard for all-cause mortality than the proximal DVT group (hazard ratio [HR], 0.52; 95% CI, 0.46-0.59; p<0.001). Of note, after 1 year, there were only 3 PE-related deaths (0.05%) in the IDDVT group. With regards to VTE deterioration events, these events were less frequent in the IDDVT versus the proximal DVT group (4.5% vs 6.8%; HR 0.83; 95% CI, 0.69-0.99; p=.04) at 1 year follow-up. Patients with IDDVT were at lower risk than patients with proximal DVT for major bleeding events at 1 year, but this difference was no longer significant after multivariable analysis. With respect to secondary outcomes, signs and symptoms of post-thrombotic syndrome were less likely to be present in the IDDVT group than the proximal DVT group at 1 year follow up. Overall, this cohort study suggests that patients with IDDVT were linked with less all-cause mortality, VTE deterioration events, and major bleeding events when compared to patients with proximal DVT.

Image: PD

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