This cohort study investigates the outcomes and clinical characteristics of patients with isolated distal deep vein thrombosis compared with those with proximal deep vein thrombosis.
Key Points
Question
What are the clinical characteristics and outcomes of patients with isolated distal deep vein thrombosis (DVT) compared with those with proximal DVT?
Findings
Among 33 897 participants in this cohort study, patients with isolated distal DVT had a lower comorbidity burden and a lower risk of 90-day mortality (odds ratio, 0.47) and 1-year composite of pulmonary embolism or new venous thromboembolism (hazard ratio, 0.83).
Meaning
Isolated distal DVT compared with proximal DVT was associated with lower risk of adverse events; this association was likely multifactorial with contribution from comorbidity burden on all-cause mortality and a potential association of thrombus location with venous thrombosis outcomes.
Abstract
Importance
Insufficient data exist about the clinical presentation, short-term, and long-term outcomes of patients with isolated distal deep vein thrombosis (IDDVT), that is, thrombosis in infrapopliteal veins without proximal extension or pulmonary embolism (PE).
Objective
To determine the clinical characteristics, short-term, and 1-year outcomes in patients with IDDVT and to compare the outcomes in unadjusted and multivariable adjusted analyses with patients who had proximal DVT.
Design, Setting, and Participants
This was a multicenter, international cohort study in participating sites of the Registro Informatizado Enfermedad Tromboembólica (RIETE) registry conducted from March 1, 2001, through February 28, 2021. Patients included in this study had IDDVT. Patients with proximal DVT were identified for comparison. Patients were excluded if they had a history of asymptomatic DVT, upper-extremity DVT, coexisting PE, or COVID-19 infection.
Main Outcomes and Measures
Primary outcomes were 90-day and 1-year mortality, 1-year major bleeding, and 1-year venous thromboembolism (VTE) deterioration, which was defined as subsequent development of proximal DVT or PE.
Results
A total of 33 897 patients were identified with isolated DVT (without concomitant PE); 5938 (17.5%) had IDDVT (mean [SD] age, 61 [17] years; 2975 male patients [50.1%]), and 27 959 (82.5%) had proximal DVT (mean [SD] age, 65 [18] years; 14 315 male patients [51.2%]). Compared with individuals with proximal DVT, those with IDDVT had a lower comorbidity burden but were more likely to have had recent surgery or to have received hormonal therapy. Patients with IDDVT had lower risk of 90-day mortality compared with those with proximal DVT (odds ratio [OR], 0.47; 95% CI, 0.40-0.55). Findings were similar in 1-year unadjusted analyses (hazard ratio [HR], 0.52; 95% CI, 0.46-0.59) and adjusted analyses (HR, 0.72; 95% CI, 0.64-0.82). Patients with IDDVT had a lower 1-year hazard of VTE deterioration (HR, 0.83; 95% CI, 0.69-0.99). In 1-year adjusted analyses of patients without an adverse event within the first 3 months, IDDVT was associated with lower risk of VTE deterioration (adjusted HR, 0.48; 95% CI, 0.24-0.97). By 1-year follow-up, symptoms or signs of postthrombotic syndrome were less common in patients with IDDVT (47.6% vs 60.5%).
Conclusions and Relevance
Results of this cohort study suggest that patients with IDDVT had a less ominous prognosis compared with patients with proximal DVT. Such differences were likely multifactorial, including the differences in demographics, risk factors, comorbidities, particularly for all-cause mortality, and a potential association of thrombus location with VTE deterioration and postthrombotic syndrome. Randomized clinical trials are needed to assess the optimal long-term management of IDDVT.
Introduction
Isolated distal deep vein thrombosis (IDDVT), ie, thrombosis in the infrapopliteal veins without coexisting proximal DVT or pulmonary embolism (PE), accounts for 20% to 50% of all DVTs.1,2 The data related to clinical presentation and outcomes of patients with IDDVT are limited. Some studies suggest less ominous outcomes with IDDVT compared with proximal DVT. However, prior studies were from single institutions or included a small number of patients, were underpowered to differentiate the clinical presentation of patients with IDDVT and those with proximal DVT, and focused only on short-term outcomes.2,3,4,5,6 Limitations with our understanding of outcomes for IDDVT is also discussed in the practice guidelines.7,8 It remains uncertain whether there are true differences in mortality, venous thromboembolism (VTE) recurrences, and bleeding events among patients with IDDVT compared with proximal DVT and whether the potential differences attenuate after consideration of the demographics, comorbidities, and VTE risk factors.2,3,9,10,11 Addressing these gaps in knowledge has implications for prognostication, and may affect the downstream treatment or follow-up decisions.
The Registro Informatizado Enfermedad Tromboembólica (RIETE) is an ongoing prospective registry of patients with VTE. Using the data from RIETE, we sought to determine the clinical presentation and 90-day and 1-year outcomes in patients with IDDVT. We compared those findings against patients with proximal DVT in unadjusted and multivariable adjusted analyses.
Methods
Data Source and Patients
Details about the methodology of the RIETE registry have been described previously (eAppendix in Supplement 1).12,13 Currently, the RIETE registry includes over 200 enrolling centers from Africa, North and South America, Asia, and Europe. The RIETE registry enrolls consecutive patients with objectively confirmed VTE (DVT, PE, or both) with a minimum follow-up of 3 months. Many patients complete 1-year and 2-year follow-up. All patients provided written or verbal informed consent in line with institutional review board requirements from each participating center. Previous studies have shown that the RIETE population closely represents that of large administrative databases.14 This study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines.
For the current investigation, we focused on patients with IDDVT (ie, those with infrapopliteal DVT in the absence of coexisting proximal DVT or coexisting PE) enrolled in the RIETE registry between March 1, 2001, through February 28, 2021. We compared patients with IDDVT with patients with proximal DVT. We excluded patients with asymptomatic DVT or upper-extremity DVT and patients who had coexisting PE. In addition, we excluded patients with DVT in the setting of COVID-19 infection because the clinical characteristics and outcomes of those patients may be different from other patient groups.15,16,17 We determined the demographics, comorbidities, and treatments in patients with IDDVT. We compared them against patients with proximal DVT.
Outcomes
Short-term outcomes included 30-day and 90-day all-cause mortality, PE-related mortality, and major bleeding. Bleeding was considered as major if it was overt and required a transfusion of 2 or more units of blood, involved a critical site (retroperitoneal, spinal, or intracranial), or was fatal.12 This definition closely resembles that of the International Society on Thrombosis and Haemostasis for major bleeding.18 Long-term outcomes included mortality, VTE deterioration (defined as subsequent development of proximal DVT, or PE, including fatal PE), and major bleeding. We assessed for signs or symptoms of postthrombotic syndrome according to the Villalta score in patients with available follow-up. This outcome has been available in the RIETE registry since 2009.
Statistical Analysis
Comparison of categorical variables between those with IDDVT and proximal DVT was done via χ2 tests. We used the t test or its nonparametric counterparts for comparison of continuous variables between the 2 groups. One-year outcomes were assessed via survival analysis to account for censored information. For each specific outcome, censoring occurred only by the end of 1-year follow-up, by reaching the outcome of interest, or on loss to follow-up.
It was prespecified to run multivariable models to determine if differences existed in the outcomes of patients with IDDVT compared with proximal DVT; if differences did exist, we prespecified to determine they were driven by the demographics, comorbidities, and VTE risk factors. For that purpose, we used multivariable logistic regression analysis for short-term (90-day) outcomes and adjusted hazard models for 1-year outcomes. Variables were preselected by clinical consensus for multivariable adjustment and included age, sex, history of diabetes, anemia, chronic lung disease, active cancer, recent surgery (defined as surgery within 2 months before the index VTE event), immobility (defined as bed rest for at least 4 days within the prior 2 months), creatinine clearance, and use of anticoagulation.
RIETE is not an interventional study. The duration of anticoagulation may be variable based on patients’ clinical status and decisions by the treating clinicians. In the absence of contraindications, patients with acute VTE are routinely treated at least for 90 days. For short-term (90-day) outcomes, adjustment in multivariable analyses for use of anticoagulation was operationalized by a dichotomous variable, indicating whether anticoagulation was interrupted for 2 or more consecutive days until the end of the 90-day follow-up period or reaching the end point in each patient. For adjustment for multivariable analyses of 1-year outcomes, a different variable was operationalized. By 1-year follow-up, patients may have continued the anticoagulation indefinitely without any interruptions, they may have received at least 3 months of anticoagulation and stopped anticoagulation permanently thereafter, or they may have had a more complex sequence of events (eg, intermittent initiation and discontinuation). Therefore, for multivariable adjustment, a 3-category categorical variable was used.
Because reaching the end point was distinct for mortality and nonmortality outcomes, one such variable was created per each outcome. For 1-year all-cause mortality, Cox proportional hazards models were used. For 1-year PE-related mortality, VTE deterioration, and major bleeding, Fine-Gray models were implemented to account for the competing risk of event other than the outcomes of interest. A 2-sided P value < .05 was considered significant. Data analyses were performed using SPSS for SP Release, version 20 (SPSS Inc) and Stata, version 15.1 (StataCorp).
Results
We identified a total of 33 897 patients with isolated DVT, of whom 5938 (17.5%) had IDDVT (mean [SD] age, 61 [17] years; 2975 male patients [50.1%]; 2963 female patients [49.9%]), and 27 959 (82.5%) had proximal DVT (mean [SD] age, 65 [18] years; 14 315 male patients [51.2%]; 13 644 female patients [48.8%]) (eFigure 1 in Supplement 1). Patients with IDDVT were less likely to have chronic lung disease (410 [6.9%] vs 2432 [8.7%]), prior stroke (153 of 3633 [4.2%] vs 1038 of 17 583 [5.9%]), prior VTE (843 [14.2%] vs 4697 [18.8%]), or cancer (724 [12.2%] vs 4697 [16.8%]) than those with proximal DVT but more likely to have had recent surgery (1692 [15.6%] vs 2572 [9.2%]) or estrogen/hormone therapy use (395 of 2926 [13.5%] vs 1400 of 14 433 [9.7%]) (Table; eTable 1 in Supplement 1).
Table. Demographic and Clinical Characteristics.
| Characteristic | No./total No. (%)a | |
|---|---|---|
| IDDVT (n = 5938) | Proximal DVT (n = 27 959) | |
| Female sex | 2963 (49.9) | 13 644 (48.8) |
| Male sex | 2975 (50.1) | 14 315 (51.2) |
| Age, mean (SD), y | 61 (17) | 65 (18) |
| BMI, mean (SD)b | 27.6 (5.2) | 27.8 (5.2) |
| Underlying conditions | ||
| Chronic lung disease | 410 (6.9) | 2432 (8.7) |
| Chronic heart failure | 238 (4.0) | 1146 (4.1) |
| Diabetes (n = 21 358) | 438/3655 (12.0) | 2761/17 703 (15.6) |
| Hypertension (n = 21 703) | 1476/3701 (39.9) | 8205/18 002 (45.6) |
| Prior myocardial infarction (n = 21 234) | 225/3641 (6.2) | 1059/17 593 (6.0) |
| Prior ischemic stroke (n = 21 216) | 153/3633 (4.2) | 1038/17 583 (5.9) |
| Recent major bleeding | 107 (1.8) | 531(1.9) |
| Anemia | 1692 (28.5) | 9897 (35.4) |
| Platelet count, mean (SD), cells per mL | 247 (91) | 234 (94) |
| Creatinine clearance, mean (SD), mL/min/1.73 m2 | 85 (39) | 79 (39) |
| Recent surgery | 1692 (15.6) | 2572 (9.2) |
| Recent immobility | 1384 (23.3) | 6794 (24.3) |
| Active cancer | 724 (12.2) | 4697 (16.8) |
| Prior VTE | 843 (14.2) | 4697 (16.8) |
| Pregnancy/puerperium (n = 16 462) | 58/2963 (2.0) | 536/13 644 (4.0) |
| Hormonal use among women (n = 17 369) | 395/2926 (13.5) | 1400/14 443 (9.7) |
| Symptoms | ||
| Pain (n = 33 297) | 5261/5807 (90.6) | 24 142/27 490 (87.8) |
| Swelling (n = 33 260) | 4958/5765 (86.0) | 26 033/27 495 (94.7) |
| Vital signs | ||
| SBP <90 mm Hg (n = 30 752) | 90/5057 (1.8) | 800/25 695 (3.1) |
| Heart rate >100 bpm (n = 29 874) | 380/4827 (5.7) | 2996/25 047 (8.7) |
| SaO2 < 90% (n = 2837) | 26/330 (7.9) | 174/2507 (6.9) |
Abbreviations: BMI, body mass index; bpm, beats per minute; DVT, deep vein thrombosis; IDDVT, isolated distal DVT; SaO2, oxygen saturation; SBP, systolic blood pressure; VTE, venous thromboembolism.
SI conversion factor: To convert creatinine clearance to milliliter per second per meter squared, multiply by 0.0167.
Values listed as No. (%) unless otherwise specified.
Calculated as weight in kilograms divided by height in meters squared.
Treatment Patterns
Most patients with IDDVT or proximal DVT were given anticoagulation treatment (33 843 of 33 897 [99.8%]), most commonly with low-molecular-weight heparins. No patients with IDDVT received fibrinolytic therapy. An inferior vena cava filter was used in 33 patients (0.6%) with IDDVT. Albeit used rarely, both therapies were more commonly used for patients with proximal DVT.
By 90-day follow-up, 90.9% of patients (5036 of 5541) with IDDVT and 97.0% of patients (25 027 of 25 792) with proximal DVT remained on anticoagulation. By 6-month and 1-year follow-up, the proportion of patients with IDDVT and proximal DVT who remained on anticoagulation were 69.1% (2215 of 3207) vs 83.4% (14 778 of 17 720) and 49.1% (817 of 1665) vs 64.2% (6453 of 10 047), respectively (Figure 1). Additional details are summarized in eTable 2 in Supplement 1.
Figure 1. Use of Anticoagulation in Patients With Isolated Distal Deep Vein Thrombosis (IDDVT) and Patients With Proximal DVT.
Short-term Mortality and Bleeding
At 30 days from enrollment, 64 patients (1.1%) with IDDVT died (95% CI, 0.9%-1.4%) compared with 760 patients (2.8%) with proximal DVT (95% CI, 2.6%-3.0%). Patients with IDDVT had a lower risk of 30-day all-cause mortality compared with those with proximal DVT (odds ratio [OR], 0.39; 95% CI, 0.30-0.51; P < .001). Results attenuated after multivariable adjustment (OR, 0.71; 95% CI, 0.51-0.97). Among patients with IDDVT, there were only 3 deaths (0.05%) from PE at 30-day follow-up (95% CI, 0.01%-0.1%).
By 90-day follow-up, 168 patients (2.9%) with IDDVT and 1642 patients (6.0%) with proximal DVT died. Therefore, patients with IDDVT had a lower risk of 90-day mortality compared with those with proximal DVT (OR, 0.47; 95% CI, 0.40-0.55; P < .001). Results were similar after multivariable adjustment (OR, 0.65; 95% CI, 0.55-0.73; P < .001). Among patients with IDDVT, the total number of PE deaths at 90 days was only 3 (0.05%). No significant difference in PE-related mortality was detected in patients with IDDVT compared with proximal DVT (OR, 0.49; 95% CI, 0.15-1.61; P = .23).
At 30-day follow-up, major bleeding was less frequent in patients with IDDVT compared with proximal DVT (0.6% vs 1.2%; OR, 0.51; 95% CI, 0.36-0.72; P < .001). The difference was attenuated but persisted after multivariable adjustment (OR, 0.60; 95% CI, 0.41-0.88; P = .009). Results were consistent at 90-day follow-up in bivariate (OR, 0.53; 95% CI, 0.40-0.71; P < .001) and multivariable analysis (OR, 0.64; 95% CI, 0.48-0.86; P = .01) (Figure 2).
Figure 2. All-Cause Death and Major Bleeding Outcomes at 90 Days.
Reference group (dotted vertical line) is proximal deep vein thrombosis. Point estimates are adjusted odds ratios (aORs), with 95% CIs shown in error bars.
One-Year Mortality, VTE Recurrence, and Bleeding
By 1-year follow-up, patients with IDDVT had a lower hazard for all-cause mortality (hazard ratio [HR], 0.52; 95% CI, 0.46-0.59; P < .001) (Figure 3A). After adjustment for demographics, comorbidities, and VTE risk factors, the association attenuated but persisted (adjusted HR [aHR], 0.72; 95% CI, 0.64-0.82). By 1-year follow-up, there were only 3 PE-related deaths (0.05%) in patients with IDDVT.
Figure 3. Cumulative Incidence Rate for All-Cause Mortality and Venous Thromboembolism (VTE) Deterioration.
A, All-cause mortality. B, VTE deterioration. DVT indicates deep vein thrombosis; HR, hazard ratio.
There were 246 VTE deterioration events (4.5%) (PE, PE-related mortality, or new proximal DVT) at 1-year follow-up in patients with IDDVT and 1688 events in patients with proximal DVT (6.8%; HR, 0.83; 95% CI, 0.69-0.99; P = .04) (Figure 3B). Findings were similar in multivariable analysis (aHR, 0.83; 95% CI, 0.69-1.00; P = .05).
In a prespecified multivariable 1-year analysis among patients without an adverse event within first 90 days, after adjustment for demographics, comorbidities, VTE risk factors, and use of anticoagulation, IDDVT compared with proximal DVT was associated with lower hazard for VTE deterioration (HR, 0.42; 95% CI, 0.21-0.84) (eFigure 2 in Supplement 1). Results remained consistent in multivariable analysis (aHR, 0.48; 95% CI, 0.24-0.97).
By 1-year follow-up, patients with IDDVT, compared with those with proximal DVT, were at lower risk for major bleeding (HR, 0.69; 95% CI, 0.50-0.94; P < .02). Results were no longer significant in multivariable analysis (aHR, 0.86; 95% CI, 0.64-1.16) (Figure 4).
Figure 4. All-Cause Death, Venous Thromboembolism (VTE), and Major Bleeding Outcomes at 1 Year.
Reference group (dotted vertical line) is proximal deep vein thrombosis. Point estimates are adjusted hazard ratios (aHRs), with 95% CIs shown in error bars.
Symptoms and Signs of Postthrombotic Syndrome
Symptoms or signs of postthrombotic syndrome were available among 2133 patients at 1-year follow-up. Patients with IDDVT were less likely to have a composite of postthrombotic syndrome signs or symptoms than those with proximal DVT (47.5% vs 59.5%; OR, 0.59; 95% CI, 0.43-0.82; P = .001). Eight patients with IDDVT and 61 patients with proximal DVT had venous ulcers at 1-year follow-up. At 2-year follow-up, signs and symptoms for postthrombotic syndrome were less frequent in patients with IDDVT compared with those who had proximal DVT (36.8% vs 62.5%; HR, 0.34; 95% CI, 0.20-0.59; P < .001).
Outcomes in Patients With IDDVT Who Did Not Receive Anticoagulation
We identified 47 patients with IDDVT who did not receive anticoagulation. Compared with patients who received anticoagulation, those who did not receive anticoagulation for IDDVT had a higher relative frequency of history of recent major bleeding (11.0% vs 1.7%). In patients who did not receive anticoagulation, 90-day all-cause and PE-related mortality rates were 4.25% (95% CI, 0.79%-13.36%) and 0% (95% CI, 0%-7.56%). The rate of 90-day VTE deterioration was 4.25% (95% CI, 0.79%-13.36%). These rates were not significantly different from those with IDDVT who were anticoagulated. No major bleeding events occurred in patients who did not receive anticoagulation.
One-Year and 2-Year Outcomes in Patients With IDDVT Who Discontinued Anticoagulation After the First 3 Months
Of 33 897 patients with DVT who survived the first 90 days after acute VTE, there were 1067 patients with IDDVT and 3486 patients with proximal DVT who permanently discontinued anticoagulation between days 91 and 180. Among such patients, those with IDDVT compared with those with proximal DVT had a lower hazard for all-cause mortality (HR, 0.26; 95% CI, 0.16-0.39; P < .001) and for VTE deterioration (HR, 0.38; 95% CI, 0.19-0.75; P = .005) at 1-year follow-up. By 1-year follow-up, symptoms or signs of postthrombotic syndrome were less common in patients with IDDVT (47.6% vs 60.5%). Results were similar at 2-year follow-up (eTable 3 in Supplement 1).
Discussion
In this large cohort study of patients with IDDVT treated with initial anticoagulation, PE-related mortality was rare in short-term and 1-year follow-up. All-cause mortality, VTE deterioration, and major bleeding events were less frequent in patients with IDDVT than in those who had proximal DVT. In addition, IDDVT was less likely to be associated with signs or symptoms of postthrombotic syndrome at 1-year follow-up. Nevertheless, 1 in every 22 patients with IDDVT had recurrent VTE at 1-year follow-up, and more than 45% had some form of signs or symptoms of postthrombotic syndrome.
We urge caution for appropriate interpretation of the study results. Patients with IDDVT had a lower burden of comorbidities and were more likely to have postoperative DVT than those with proximal DVT. Differences in outcomes for patients with IDDVT compared with proximal DVT may be related to inherent differences in the risk profile and characteristics in each group (ie, confounding), or a true difference as a result of the location of the DVT (IDDVT vs proximal DVT). For example, the difference in 1-year bleeding events in the 2 groups is implausible to be causal, and in fact, was no longer present after multivariable adjustment. This indicates the differences in patient profiles (confounding). In turn, the lower rate of VTE deterioration (composite of new PE, death from PE, or new proximal DVT) is plausible to be related to both patient profile (confounding) and the location of the DVT. For this outcome, the results remained consistent after multivariable analysis for demographics and comorbidities. In addition, among the small subgroup of patients with IDDVT who did not receive initial anticoagulation, no cases of PE-related mortality were identified. Adequately powered randomized clinical trials are required to understand if long-term management of IDDVT should be different from proximal DVT.19 With respect to mortality outcomes, considering that PE-related mortality was relatively infrequent, confounding is an important possibility. Although the results were significant in multivariable analyses, the association between location of DVT and mortality may arise from residual (unmeasured) confounding. Therefore, the differences in mortality rates should not be considered as causal, but rather, related to differences in patient characteristics for those who developed IDDVT compared with proximal DVT.
To our knowledge, very few other large-scale studies have assessed the risk factors and comorbidities in patients with IDDVT vs proximal DVT. In our study, patients with IDDVT had fewer comorbidities but were more likely to have had recent surgery, immobility, or use of hormonal therapy. Hormonal therapy, particularly estrogen-containing formulations, may be associated with increased risk of thrombotic events, such as VTE, and their indiscriminate use should be cautioned. Lower comorbidity burden in patients with IDDVT in RIETE is consistent with findings from the Global Anticoagulant Registry in the FIELD–Venous Thromboembolism (GARFIELD-VTE) registry9 and analyses from the RE-COVER trial participants.20 Nearly all patients in the current study underwent initial anticoagulant therapy, similar to the findings from the GARFIELD-VTE registry.9
Similarly, lower rate of short-term adverse events with IDDVT compared with proximal DVT is consistent with the results from GARFIELD-VTE.9 That study, similar to the current investigation, also showed a lower 1-year hazard for mortality (HR, 0.61; 95% CI, 0.48-0.77), recurrent VTE (HR, 0.76; 95% CI, 0.60-0.97), and bleeding (HR, 0.69; 95% CI, 0.57-0.84) in patients with IDDVT compared with those who had proximal DVT. The current investigation builds on prior studies in several ways. The current study had a larger patient population, making it possible to provide more reliable estimates. Further, unlike prior investigations, we were able to assess the association between IDDVT (vs proximal DVT) and outcomes in multivariable analyses. Some outcomes are implausible to have a causal association with IDDVT. For example, our results suggested the long-term lower risk of bleeding in patients with IDDVT compared with patients who had proximal DVT. This difference, however, was no longer significant after multivariable adjustment for demographics, comorbidities, and anticoagulant treatment.
With respect to subsequent VTE events, our findings are in agreement with the Xarelto for Long-term and Initial Anticoagulation in Venous Thromboembolism (XALIA) study, which included 1004 patients with IDDVT and 3098 with proximal DVT and the Optimisation de l’Interrogatoire pour la Maladie Thromboembolique Veineuse (OPTIMEV) study, including 259 patients with proximal DVT and 490 patients with IDDVT, both of which showed a lower risk of recurrent VTE in patients with IDDVT compared with proximal DVT.21,22 As a novel addition, in this study, we demonstrated that the lower hazard of VTE deterioration by 1-year follow-up persisted in multivariable analyses. We confirmed these findings with additional analyses among patients with IDDVT who discontinued anticoagulation after the first 3 months compared with patients with proximal DVT.
In additional prespecified analyses, this study showed that signs and symptoms of postthrombotic syndrome were less frequently observed in those with IDDVT compared with proximal DVT at 1-year and 2-year follow-up. These results are consistent with a recent analysis from the Compression vs Anticoagulant Treatment and Compression in Symptomatic Calf Thrombosis Diagnosed by Ultrasound (CACTUS) trial. That study of 178 participants showed that the risk of postthrombotic syndrome is substantial after IDDVT but much lower than that reported in patients with proximal DVT.23 Similarly, in a study of 135 patients with DVT, at 3-year follow-up, IDDVT was associated with lower risk of postthrombotic syndrome.24
Collectively, findings from this study have important implications. We found less ominous outcomes with IDDVT compared with proximal DVT. Further, we demonstrated that some of these differences stem from a lower burden of comorbidities, with outcomes such as long-term risk of major bleeding not having a significant difference once accounting for demographics and comorbidities. However, we also demonstrated a lower risk of long-term outcomes, such as signs or symptoms of postthrombotic syndrome, and a lower risk of VTE deterioration in patients with IDDVT compared with proximal DVT; this difference persisted in multivariable analyses. To our knowledge, these findings have not been reported in prior studies and are aligned with the judgment of clinicians who consider IDDVT as a lower-risk entity than proximal DVT. Results related to all-cause mortality, in contrast, are likely driven by the differences in patient characteristics (ie, residual confounding).
Nevertheless, the study also confirms that IDDVT is not entirely benign. Even in this population who received initial anticoagulation in more than 99% of participants, signs or symptoms of postthrombotic syndrome were present in more than 45% of patients. This is particularly concerning given that other than anticoagulation, no treatment has been proven to reduce the incidence of durable symptoms or the development of postthrombotic syndrome.25 In addition, although the rates of VTE deterioration were low in patients with IDDVT, compared with those who had proximal DVT, such events were not trivial. The annual incidence of VTE in the general population is estimated around 104 to 183 per 100 000 person-years, which is much lower than the 4.5% rate of VTE deterioration observed in our study. Although PE was rarely the cause of death in patients with IDDVT, it is still proportionally a more common cause of death in these patients compared with the average population.26
Strengths and Limitations
The current study should be considered in the context of its strengths and limitations. The strengths of this study included patient enrollment from a multinational registry representing small and large referral centers. The large pool of participants allowed for robust comparisons between those who had IDDVT and patients who had proximal DVT, without concern for type II error. Accounting for the competing risk of other events reduces the likelihood of biased estimates for nonmortality outcomes.
This study had several limitations. First, fewer patients had 1-year and 2-year follow-up data on postthrombotic syndrome, which is consistent with dropout in other long-term follow-up studies. However, there is no reason to suspect the follow-up duration was differential in those with IDDVT vs proximal DVT. As for other clinical outcomes, 90-day follow-up was available in all patients, whereas longer follow-up was encouraged but not mandatory in the RIETE registry. As a result of losses to follow-up for 1-year clinical outcomes, dedicated large-scale studies with long-term follow-up are needed to improve the certainty of the long-term findings that we reported. Second, the RIETE registry did not distinguish the subtype of distal DVTs (ie, muscular calf veins [soleus, gastrocnemius] compared with tibial and peroneal veins).8 Some prior studies failed to show a distinct pattern of subsequent outcomes based on the subtype of IDDVT.21 Third, the differences in some outcomes were implausible to be causal. For example, the difference in 1-year bleeding events was driven by the differences in patient characteristics and was no longer significant after multivariable adjustment. For all-cause mortality, considering that PE-related mortality was relatively infrequent in both groups, the difference is most likely attributable to differences in patient profile (ie, confounding). Fourth, this study was not designed as a comparative effectiveness analysis of various treatment strategies among patients with IDDVT.27,28 In our analyses, similar to those from the GARFIELD-VTE trial, the vast majority of patients with IDDVT received initial anticoagulation.9 Considering the findings of this study, future studies should determine whether formal incorporation of IDDVT in risk stratification models can affect patient outcomes. In addition, future trials are needed to better understand the optimal intensity and duration of anticoagulation in patients with IDDVT. Of note, no adequately powered randomized clinical studies have yet determined the role of direct oral anticoagulants in patients with IDDVT.29 Finally, routine screening was not a part of case ascertainment or identification of patients with VTE deterioration. Rather, such designations were based on signs and symptoms followed by objective testing at the discretion of treating clinicians. There are no large randomized clinical trials that have shown a net benefit for routine screening for DVT.30 As such, routine screening is not advised in most practice guidelines.31,32,33
Conclusions
In this large, longitudinal, multicenter cohort study, patients with IDDVT had less ominous short-term and 1-year adverse events, including mortality and signs or symptoms, for postthrombotic syndrome compared with those who had proximal DVT. These differences were multifactorial; some, such as VTE deterioration, were only partially related to lower burden of comorbidities in patients with IDDVT, persisted in multivariable analyses, and may be relevant for risk stratification and treatment decisions. Other differences, such as lower mortality rates in patients with IDDVT compared with proximal DVT, are most likely related to differences in measured and unmeasured patient characteristics.
eAppendix. RIETE Group Information
eTable 1. Hormonal Therapy Among Women With DVT
eTable 2. Anticoagulation Status During the Study Period
eTable 3. Long-term Outcomes in Patients Who Received at Least 90 Days of Anticoagulation and Discontinued Between Days 91-180
eFigure 1. Study Flow Diagram
eFigure 2. Cumulative Incidence Rate for VTE Deterioration in Patients Who Did Not Have an Adverse Event in the First 90 Days
RIETE Investigators
References
- 1.Robert-Ebadi H, Righini M. Management of distal deep vein thrombosis. Thromb Res. 2017;149:48-55. doi: 10.1016/j.thromres.2016.11.009 [DOI] [PubMed] [Google Scholar]
- 2.Galanaud JP, Sevestre-Pietri MA, Bosson JL, et al. ; OPTIMEV-SFMV Investigators . Comparative study on risk factors and early outcome of symptomatic distal versus proximal deep vein thrombosis: results from the OPTIMEV study. Thromb Haemost. 2009;102(3):493-500. doi: 10.1160/TH09-01-0053 [DOI] [PubMed] [Google Scholar]
- 3.Galanaud JP, Quenet S, Rivron-Guillot K, et al. ; RIETE Investigators . Comparison of the clinical history of symptomatic isolated distal deep vein thrombosis vs proximal deep vein thrombosis in 11 086 patients. J Thromb Haemost. 2009;7(12):2028-2034. doi: 10.1111/j.1538-7836.2009.03629.x [DOI] [PubMed] [Google Scholar]
- 4.Spencer FA, Kroll A, Lessard D, et al. Isolated calf deep vein thrombosis in the community setting: the Worcester Venous Thromboembolism study. J Thromb Thrombolysis. 2012;33(3):211-217. doi: 10.1007/s11239-011-0670-x [DOI] [PubMed] [Google Scholar]
- 5.Brateanu A, Patel K, Chagin K, et al. Probability of developing proximal deep-vein thrombosis and/or pulmonary embolism after distal deep vein thrombosis. Thromb Haemost. 2016;115(3):608-614. doi: 10.1160/th15-06-0503 [DOI] [PubMed] [Google Scholar]
- 6.Porfidia A, Carnicelli A, Bonadia N, Pola R, Landolfi R. Controversies in venous thromboembolism: the unique case of isolated distal deep vein thrombosis. Intern Emerg Med. 2016;11(6):775-779. doi: 10.1007/s11739-016-1453-3 [DOI] [PubMed] [Google Scholar]
- 7.Mazzolai L, Aboyans V, Ageno W, et al. Diagnosis and management of acute deep vein thrombosis: a joint consensus document from the European Society of Cardiology working groups of aorta and peripheral circulation and pulmonary circulation and right ventricular function. Eur Heart J. 2018;39(47):4208-4218. doi: 10.1093/eurheartj/ehx003 [DOI] [PubMed] [Google Scholar]
- 8.Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149(2):315-352. doi: 10.1016/j.chest.2015.11.026 [DOI] [PubMed] [Google Scholar]
- 9.Schellong SM, Goldhaber SZ, Weitz JI, et al. Isolated distal deep vein thrombosis: perspectives from the GARFIELD-VTE registry. Thromb Haemost. 2019;119(10):1675-1685. doi: 10.1055/s-0039-1693461 [DOI] [PubMed] [Google Scholar]
- 10.Barco S, Corti M, Trinchero A, et al. Survival and recurrent venous thromboembolism in patients with first proximal or isolated distal deep vein thrombosis and no pulmonary embolism. J Thromb Haemost. 2017;15(7):1436-1442. doi: 10.1111/jth.13713 [DOI] [PubMed] [Google Scholar]
- 11.Krutman M, Kuzniec S, Ramacciotti E, et al. Rediscussing anticoagulation in distal deep venous thrombosis. Clin Appl Thromb Hemost. 2016;22(8):772-778. doi: 10.1177/1076029615627343 [DOI] [PubMed] [Google Scholar]
- 12.Bikdeli B, Jimenez D, Hawkins M, et al. ; RIETE Investigators . Rationale, design, and methodology of the Computerized Registry of Patients with Venous Thromboembolism (RIETE). Thromb Haemost. 2018;118(1):214-224. doi: 10.1160/TH17-07-0511 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Tzoran I, Brenner B, Papadakis M, Di Micco P, Monreal M. VTE Registry: what can be learned from RIETE? Rambam Maimonides Med J. 2014;5(4):e0037. doi: 10.5041/RMMJ.10171 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Guijarro R, Montes J, Sanromán C, Monreal M; RIETE Investigators . Venous thromboembolism in Spain: comparison between an administrative database and the RIETE registry. Eur J Intern Med. 2008;19(6):443-446. doi: 10.1016/j.ejim.2007.06.026 [DOI] [PubMed] [Google Scholar]
- 15.Bikdeli B, Madhavan MV, Jimenez D, et al. ; Global COVID-19 Thrombosis Collaborative Group; Endorsed by the ISTH, NATF, ESVM, and the IUA; Supported by the ESC Working Group on Pulmonary Circulation and Right Ventricular Function . COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-art review. J Am Coll Cardiol. 2020;75(23):2950-2973. doi: 10.1016/j.jacc.2020.04.031 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Bikdeli B, Madhavan MV, Gupta A, et al. ; Global COVID-19 Thrombosis Collaborative Group . Pharmacological agents targeting thromboinflammation in COVID-19: review and implications for future research. Thromb Haemost. 2020;120(7):1004-1024. doi: 10.1055/s-0040-1713152 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Fernández-Capitán C, Barba R, Díaz-Pedroche MDC, et al. Presenting characteristics, treatment patterns, and outcomes among patients with venous thromboembolism during hospitalization for COVID-19. Semin Thromb Hemost. 2021;47(4):351-361. doi: 10.1055/s-0040-1718402 [DOI] [PubMed] [Google Scholar]
- 18.Schulman S, Angerås U, Bergqvist D, Eriksson B, Lassen MR, Fisher W; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis . Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients. J Thromb Haemost. 2010;8(1):202-204. doi: 10.1111/j.1538-7836.2009.03678.x [DOI] [PubMed] [Google Scholar]
- 19.Bikdeli B, Tajrishi FZ, Sadeghipour P, et al. Efficacy and safety considerations with dose-reduced direct oral anticoagulants: a review. JAMA Cardiol. Published online June 1, 2022. doi: 10.1001/jamacardio.2022.1292 [DOI] [PubMed] [Google Scholar]
- 20.Schellong S, Ageno W, Casella IB, et al. Profile of patients with isolated distal deep vein thrombosis vs proximal deep vein thrombosis or pulmonary embolism: RE-COVERY DVT/PE study. Semin Thromb Hemost. 2021. doi: 10.1055/s-0041-1729169 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Galanaud JP, Sevestre MA, Genty C, et al. ; OPTIMEV-SFMV investigators . Incidence and predictors of venous thromboembolism recurrence after a first isolated distal deep vein thrombosis. J Thromb Haemost. 2014;12(4):436-443. doi: 10.1111/jth.12512 [DOI] [PubMed] [Google Scholar]
- 22.Ageno W, Mantovani LG, Haas S, et al. Patient management strategies and long-term outcomes in isolated distal deep vein thrombosis vs proximal deep vein thrombosis: findings from XALIA. TH Open. 2019;3(1):e85-e93. doi: 10.1055/s-0039-1683968 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Galanaud JP, Righini M, Le Collen L, et al. Long-term risk of postthrombotic syndrome after symptomatic distal deep vein thrombosis: the CACTUS-PTS study. J Thromb Haemost. 2020;18(4):857-864. doi: 10.1111/jth.14728 [DOI] [PubMed] [Google Scholar]
- 24.Hach-Wunderle V, Bauersachs R, Gerlach HE, et al. Postthrombotic syndrome 3 years after deep venous thrombosis in the Thrombosis and Pulmonary Embolism in Out-Patients (TULIPA) PLUS registry. J Vasc Surg Venous Lymphat Disord. 2013;1(1):5-12. doi: 10.1016/j.jvsv.2012.07.003 [DOI] [PubMed] [Google Scholar]
- 25.Kahn SR, Comerota AJ, Cushman M, et al. ; American Heart Association Council on Peripheral Vascular Disease, Council on Clinical Cardiology, and Council on Cardiovascular and Stroke Nursing . The postthrombotic syndrome: evidence-based prevention, diagnosis, and treatment strategies: a scientific statement from the American Heart Association. Circulation. 2014;130(18):1636-1661. doi: 10.1161/CIR.0000000000000130 [DOI] [PubMed] [Google Scholar]
- 26.Barco S, Mahmoudpour SH, Valerio L, et al. Trends in mortality related to pulmonary embolism in the European Region, 2000-15: analysis of vital registration data from the WHO mortality database. Lancet Respir Med. 2020;8(3):277-287. doi: 10.1016/S2213-2600(19)30354-6 [DOI] [PubMed] [Google Scholar]
- 27.Chopard R, Albertsen IE, Piazza G. Diagnosis and treatment of lower extremity venous thromboembolism: a review. JAMA. 2020;324(17):1765-1776. doi: 10.1001/jama.2020.17272 [DOI] [PubMed] [Google Scholar]
- 28.Righini M, Galanaud JP, Guenneguez H, et al. Anticoagulant therapy for symptomatic calf deep vein thrombosis (CACTUS): a randomised, double-blind, placebo-controlled trial. Lancet Haematol. 2016;3(12):e556-e562. doi: 10.1016/S2352-3026(16)30131-4 [DOI] [PubMed] [Google Scholar]
- 29.Galanaud JP, Trujillo-Santos J, Bikdeli B, et al. ; RIETE Investigators . Management of isolated distal deep vein thrombosis with direct oral anticoagulants in the RIETE registry. J Thromb Haemost. 2021;52(2):532-541. doi: 10.1007/s11239-020-02347-6 [DOI] [PubMed] [Google Scholar]
- 30.Schmidt B, Michler R, Klein M, Faulmann G, Weber C, Schellong S. Ultrasound screening for distal vein thrombosis is not beneficial after major orthopedic surgery: a randomized controlled trial. Thromb Haemost. 2003;90(5):949-954. [DOI] [PubMed] [Google Scholar]
- 31.Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2):e278S-e325S. doi: 10.1378/chest.11-2404 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2):e227S-e277S. doi: 10.1378/chest.11-2297 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Anderson DR, Morgano GP, Bennett C, et al. American Society of Hematology 2019 guidelines for management of venous thromboembolism: prevention of venous thromboembolism in surgical hospitalized patients. Blood Adv. 2019;3(23):3898-3944. doi: 10.1182/bloodadvances.2019000975 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eAppendix. RIETE Group Information
eTable 1. Hormonal Therapy Among Women With DVT
eTable 2. Anticoagulation Status During the Study Period
eTable 3. Long-term Outcomes in Patients Who Received at Least 90 Days of Anticoagulation and Discontinued Between Days 91-180
eFigure 1. Study Flow Diagram
eFigure 2. Cumulative Incidence Rate for VTE Deterioration in Patients Who Did Not Have an Adverse Event in the First 90 Days
RIETE Investigators