- Email: [email protected]
Insufficient Recanalization of Thrombotic Venous Occlusion—Risk for Postthrombotic Syndrome
CLINICAL STUDY
Insufficient Recanalization of Thrombotic Venous Occlusion—Risk for Postthrombotic Syndrome Luka Jeraj, MD, Mateja Kaja Jezovnik, MD, PhD, and Pavel Poredos, PhD, MD ABSTRACT Purpose: To investigate the relationship between recanalization rate of occluded veins after deep venous thrombosis (DVT) and development of postthrombotic syndrome (PTS). Materials and Methods: Patients treated for DVT of the lower limbs were evaluated 12–36 months after acute DVT. Of 100 patients, 34 developed PTS, defined as Villalta score of 5. Symptoms and signs of PTS were assessed, and ultrasound examination of the veins was performed, checking for residual thrombus and presence of reflux. Results: Patients with PTS were older (64.0 y vs 55.5 y; P ¼ .007) and more frequently experienced recurrent DVT (15% vs 3%; P ¼ .030). Patients with PTS had a lower rate of recanalization. Patients with residual thrombus appeared to be at increased risk for PTS development compared with patients with total recanalization (odds ratio 6.0; 95% confidence interval, 1.7–21.9; P ¼ .006). No difference in the presence of reflux was observed. Conclusions: Incomplete or absent recanalization is associated with a higher incidence of PTS, probably as a consequence of deteriorated blood flow and increased venous pressure. This suggests early recanalization could improve the outcome of DVT treatment in selected patients.
ABBREVIATIONS DVT ¼ deep venous thrombosis, PTS ¼ postthrombotic syndrome
Postthrombotic syndrome (PTS) is a frequent chronic complication of deep venous thrombosis (DVT), affecting 20%–50% of patients with DVT within months to years after acute DVT. This syndrome is characterized by a combination of symptoms and signs, including leg heaviness, pain, edema, cramps, venous ectasia, hyperpigmentation, and venous ulceration. PTS severely affects the quality of life and increases health-related costs of patients with DVT. Many risk factors for PTS have been identified, such as elevated body mass index, older age, preexisting venous
From the Department of Vascular Disease (L.J., P.P.), University Medical Centre Ljubljana, Zalo ska cesta 7, Ljubljana 1000, Slovenia; and Center for Advanced Heart Failure (M.K.J.), University of Texas Health Science Center at Houston, Houston, Texas. Received January 5, 2017; final revision received and accepted March 21, 2017. Address correspondence to P.P.; E-mail: [email protected]
insufficiency, more proximal thrombosis, recurrent DVT of the same leg, and subtherapeutic anticoagulation (1). Treatment of DVT in the initial phase is based on anticoagulation, which prevents clot propagation. In selected cases, systemic or local thrombolysis is used (2). Thrombus evolution is a natural process, usually leading to recanalization of the affected veins (3). Although thrombus load is reduced by 50% in the first 3 months after acute DVT, some residual thrombus is still present 3 years after the diagnosis in half of the patients (4,5). Numerous studies have shown an increased incidence of recurrent DVT in patients with less efficient recanalization, seen as residual thrombosis (6,7). Data on the direct relationship between PTS and recanalization are scarce; however, they indicate an association between residual thrombosis and PTS (8). The aim of this study was to assess the prevalence of PTS in patients with a history of DVT and further evaluate its relationship to the recanalization rate of the affected veins.
None of the authors have identified a conflict of interest. © SIR, 2017 J Vasc Interv Radiol 2017; ▪:1–4 http://dx.doi.org/10.1016/j.jvir.2017.03.031
MATERIALS AND METHODS This study included patients with a diagnosis of acute DVT of the lower limbs who underwent treatment in a single
2 ▪ Recanalization of Occluded Veins and Development of PTS
outpatient clinic. Consecutive male and female patients with acute iliofemoral, femoropopliteal, or popliteal thrombosis with or without calf involvement were included. Patients were excluded if they had active cancer, symptomatic peripheral arterial disease, or chronic inflammatory disease or were unwilling to participate in the study. Only patients treated with anticoagulation and compression were included; patients treated with thrombolytic therapy were excluded. All patients signed a consent form before inclusion in the study. The study was approved by the National Medical Ethics Committee. There were 100 patients with a mean age of 58.9 years (± 11.2) included; 57% were men. The location of DVT was iliofemoral in 23%, femoropopliteal in 44%, and popliteal (with or without calf involvement) in 33%. DVT was unprovoked in 59% and provoked in 41%. A concurrent pulmonary embolism was present in 10% of patients; 7% had a recurrent DVT. Of patients, 61% had been treated with rivaroxaban, and 39% received warfarin together with dalteparin for the first 5–7 days, after which dalteparin was discontinued. Median time of anticoagulation was 6 months. Most patients in both groups were using compression therapy daily at least 6 months after DVT diagnosis (95%), either compression stockings (78%) or compression bandages (22%). All patients were followed until the check-up performed in the period between 12 and 36 months after the acute episode of DVT. At that time, signs and symptoms of PTS were assessed by a single investigator (L.J.), and the Villalta score was calculated for each patient (9). A Villalta score 5 was considered to be PTS positive, whereas a Villalta score < 5 was considered to be PTS negative. Deep veins of the lower limbs were assessed with ultrasound using a 10-MHz probe (ProSound Ultra 7; Hitachi Aloka Medical, Ltd, Mitaka, Japan). Recanalization status was defined as complete recanalization if the vein was totally compressible to no more than 2 mm, partial recanalization if the vein was partially compressible, or absent recanalization if the vein was occluded and incompressible. The competence of the vein valve function was checked and was defined as incompetent if a reversal flow (reflux) was > 0.5 second.
Statistical Analysis Patients were divided into 2 groups based on development of PTS. Continuous variables with normal distribution, as determined by the Kolmogorov-Smirnov test, were expressed as means and standard deviations. Variables without normal distribution were expressed as median and interquartile range. Differences between groups in normally distributed variables were analyzed using a t test for unpaired data, and a Mann-Whitney U test was used for the others. Categorical variables were expressed as percentages; c2 test was used to test differences between the groups. Variables with significant or near-significant values were analyzed using univariate logistic regression. A P value < .05 was considered significant. All statistical
Jeraj et al ▪ JVIR
Table 1. Demographic Characteristics of Patients and Type of Acute DVT Characteristic Age, y†
PTS-Positive* (n ¼ 34) 64.0 (58–71)
PTS-Negative (n ¼ 66)
P
55.5 (49–67)
.007‡ .062
Sex Male
15 (44%)
42 (64%)
Female
19 (56%)
24 (36%)
BMI, kg/m2†
28.6 (25.6–33.9) 28.7 (24.6–30.9) .421
Hypertension
16 (47%)
21 (32%)
.135
Hyperlipidemia Smoker
12 (35%) 7 (21%)
26 (39%) 12 (18%)
.689 .771
.593
Venous segment affected Iliofemoral
9 (26%)
14 (21%)
16 (47%)
28 (42%)
9 (26%)
24 (36%)
4 (12%)
6 (9%)
.673
Unprovoked
21 (62%)
38 (58%)
.687
Provoked
13 (38%)
28 (42%)
Recurrent DVT
5 (15%)
2 (3%)
Femoropopliteal Popliteal with/ without calf Concurrent pulmonary embolism Type of DVT
.030‡
BMI ¼ body mass index; DVT ¼ deep venous thrombosis; PTS ¼ postthrombotic syndrome. *PTS-positive patients are patients with Villalta score 5. † Median (interquartile range), Mann-Whitney U test. ‡ Statistically significant.
analyses were performed with IBM SPSS Statistics for Windows Version 23.0 (IBM Corp, Armonk, New York).
RESULTS Patients were assessed for the presence of PTS 12–36 months after acute DVT (median 23 months). Of 100 patients, 34 developed PTS. These patients were older and more frequently had a recurrent DVT (Table 1). Most patients with PTS had a mild form (Villalta score ¼ 5–9), whereas 15% developed a moderate form, and 3% developed a severe form. Compared with patients without PTS, patients who developed PTS had a lower percentage of completely recanalized veins (9% vs 38%) and a higher percentage of both no recanalization (24% vs 6%) and partial recanalization (68% vs 56%). However, there was no statistically significant difference in the presence of reflux between the groups (Table 2). In the logistic regression analysis, residual thrombus in the vein showed an odds ratio of 6.0 for PTS development compared with complete recanalization (Table 3).
DISCUSSION The main finding of this study is an association between vein recanalization in the chronic phase of DVT and the
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3
Table 2. Recanalization and Reflux of Deep Veins of the Lower Limbs 12–36 Months* after Acute DVT PTS-Positive† (n ¼ 34)
PTS-Negative (n ¼ 66)
P
3 (9%)
25 (38%)
.002‡
Partial
23 (68%)
37 (56%)
Absent
8 (24%)
4 (6%)
14 (41%)
21 (32%)
Recanalization Complete
Reflux
.353
DVT ¼ deep venous thrombosis; PTS ¼ postthrombotic syndrome. *Median 23 months. † PTS-positive patients are patients with Villalta score 5. ‡ Statistically significant.
Table 3. Logistic Regression of Variables Associated with Development of Postthrombotic Syndrome Variable Age, y
OR (95% CI)
P
1.06 (1.02–1.11)
.006*
Female sex
2.2 (0.95–5.15)
.064
Recurrent DVT
5.5 (1.01–30.1)
.049*
Residual thrombus
6.0 (1.7–21.9)
.006*
CI ¼ confidence interval; DVT ¼ deep venous thrombosis; OR ¼ odds ratio. *Statistically significant.
development of PTS. Patients who did not develop PTS had a significantly higher rate of recanalization after acute DVT. Recanalization of veins affected by DVT is a natural process that enables the venous lumen to be reestablished and blood flow to be improved; it can be seen 6 weeks after acute DVT (10). Thrombolysis and recanalization take several months to years to develop after acute DVT (5,6,11,12). Endogenous fibrinolysis, together with coagulation activity, probably plays the most important role in the recanalization process (13,14). Residual thrombus in the vein affected by acute DVT is associated with a higher incidence of venous reflux, whereas early resolution of the thrombus helps preserve venous valve integrity (15,16). Residual thrombus and vein wall damage have also been shown to be risk factors for recurrent DVT (6,7). Despite abundant research on venous recanalization, only limited data about the direct relationship between PTS and recanalization are available. Vein valve damage and increased venous pressure (as a consequence of chronic vein occlusion) are among the underlying mechanisms of PTS development (1). Therefore, an absence of complete recanalization is most likely associated with a higher risk for PTS development, as shown in this study. Residual thrombus, which includes partial and absent recanalization, had an odds ratio of 6.0 for PTS development compared with total recanalization. Prandoni et al (8) showed a connection between PTS and vein abnormalities, residual vein thrombosis and valve incompetence, which is in line with results
of the present study. Tick et al (17) showed similar findings. These studies focused on recanalization in the first months after acute DVT, whereas the present study assessed late recanalization. In addition to anticoagulation, thrombolytic therapy can be used for DVT treatment in some instances, particularly treatment of extensive proximal DVT (1,18). A metaanalysis of 17 studies with 1,103 participants showed that patients with DVT treated with (mostly systemic) thrombolysis had increased vein patency and higher rate of total recanalization compared with patients treated with standard anticoagulation. However, despite selecting patients with low bleeding risk, bleeding complications were more common in patients treated with thrombolysis (19). As opposed to systemic drug administration, catheter-directed thrombolysis is currently preferred, as it may reduce the risk of systemic bleeding (19). Several small randomized trials showed that catheter-directed thrombolysis could better preserve venous patency as opposed to standard anticoagulation (20,21). The randomized ATTRACT trial comprising 692 patients was finished more recently (22); results presented at the Society of Interventional Radiology (SIR) 2017 Annual Scientific Meeting indicate that pharmacomechanical PCT might lower the rate of moderate and severe forms of PTS but without lowering the total incidence of PTS (S. Vedantham, MD, FSIR, unpublished data, 2017). Together with results of the present study and others that showed a correlation between the recanalization rate and PTS development, these observations suggest catheterdirected thrombolysis could prove to be a useful tool in PTS prevention in selected patients. Some small trials also showed promising results of venous stent placement in patients with established PTS, improving the patency of insufficiently recanalized veins (23–25). Some known risk factors, such as older age and recurrent DVT, were confirmed in this study. A trend of higher incidence of PTS in female patients was seen; however, it was not statistically significant. The influence of sex on the development of PTS is not clear, with different studies showing an inconsistent relationship; the prevailing opinion is that there is no strong connection between PTS and sex. There was no significant correlation with the location of the thrombus. According to recent findings, compression stockings might not be effective in PTS prevention (26); they are recommended for symptom reduction when PTS is already present and are effective in acute DVT symptom reduction (1). Almost all patients in both groups were regularly using compression therapy for at least 6 months after the acute DVT. Limitations of this study include a relatively small number of patients and limited follow-up time. The limited follow-up could lead to underdiagnosed severe forms of PTS, which can develop over the course of years in patients with initially mild forms (4). However, most cases of PTS manifest during the first year after acute DVT (27). In conclusion, the absence of recanalization is associated with a higher incidence of PTS, probably as a consequence
4 ▪ Recanalization of Occluded Veins and Development of PTS
Jeraj et al ▪ JVIR
of vein wall damage and increased venous pressure caused by chronic vein occlusion. As PTS can severely decrease quality of life, early thrombus resolution could improve the outcome of DVT treatment in selected patients.
newly proposed vein diameter variation index. Ann Vasc Surg 2014; 28: 1751–1760. Killewich LA, Macko RF, Cox K, et al. Regression of proximal deep venous thrombosis is associated with fibrinolytic enhancement. J Vasc Surg 1997; 26:861–868. Meissner MH, Zierler BK, Bergelin RO, Chandler WL, Strandness DE. Coagulation, fibrinolysis, and recanalization after acute deep venous thrombosis. J Vasc Surg 2002; 35:278–285. Meissner MH, Manzo RA, Bergelin RO, Markel A, Strandness DE Jr. Deep venous insufficiency: the relationship between lysis and subsequent reflux. J Vasc Surg 1993; 18:596–605; discussion 606–608. O’shaughnessy AM, Fitzgerald DE. The patterns and distribution of residual abnormalities between the individual proximal venous segments after an acute deep vein thrombosis. J Vasc Surg 2001; 33:379–384. Tick LW, Doggen CJM, Rosendaal FR, et al. Predictors of the postthrombotic syndrome with non-invasive venous examinations in patients 6 weeks after a first episode of deep vein thrombosis. J Thromb Haemost 2010; 8:2685–2692. Sharafuddin MJ, Sun S, Hoballah JJ, Youness FM, Sharp WJ, Roh B-S. Endovascular management of venous thrombotic and occlusive diseases of the lower extremities. J Vasc Interv Radiol 2003; 14:405–423. Watson L, Broderick C, Armon MP. Thrombolysis for acute deep vein thrombosis. Cochrane Database Syst Rev 2016; 11:CD002783. Vedantham S. Interventional approaches to deep vein thrombosis. Am J Hematol 2012; 87(Suppl 1):S113–S118. Enden T, Haig Y, Kløw N-E, et al. Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial. Lancet 2012; 379:31–38. Vedantham S, Goldhaber SZ, Kahn SR, et al. Rationale and design of the ATTRACT Study: a multicenter randomized trial to evaluate pharmacomechanical catheter-directed thrombolysis for the prevention of postthrombotic syndrome in patients with proximal deep vein thrombosis. Am Heart J 2013; 165:523–530.e3. Nayak L, Hildebolt CF, Vedantham S. Postthrombotic syndrome: feasibility of a strategy of imaging-guided endovascular intervention. J Vasc Interv Radiol 2012; 23:1165–1173. Ruihua W, Xin W, Guang L, et al. Technique and clinical outcomes of combined stent placement for postthrombotic chronic total occlusions of the iliofemoral veins. J Vasc Interv Radiol 2017; 28:373–379. Ye K, Lu X, Jiang M, et al. Technical details and clinical outcomes of transpopliteal venous stent placement for postthrombotic chronic total occlusion of the iliofemoral vein. J Vasc Interv Radiol 2014; 25: 925–932. Kahn SR, Shapiro S, Wells PS, et al. Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial. Lancet 2014; 383:880–888. Roumen-Klappe EM, den Heijer M, Janssen MCH, van der Vleuten C, Thien T, Wollersheim H. The post-thrombotic syndrome: incidence and prognostic value of non-invasive venous examinations in a six year follow-up study. Thromb Haemost 2005; 94:825–830.
13.
14.
ACKNOWLEDGMENTS
15.
This study was supported by the Slovenian Research Agency.
16.
REFERENCES
17.
1. Kahn SR, Galanaud J-P, Vedantham S, Ginsberg JS. Guidance for the prevention and treatment of the post-thrombotic syndrome. J Thromb Thrombolysis 2016; 41:144–153. 2. Lang KJ, Saha P, Roberts LN, Arya R. Changing paradigms in the management of deep vein thrombosis. Br J Haematol 2015; 170:162–174. 3. Meissner MH, Caps MT, Bergelin RO, Manzo RA, Strandness DE. Propagation, rethrombosis and new thrombus formation after acute deep venous thrombosis. J Vasc Surg 1995; 22:558–567. 4. Baldwin MJ, Moore HM, Rudarakanchana N, Gohel M, Davies AH. Postthrombotic syndrome: a clinical review. J Thromb Haemost 2013; 11: 795–805. 5. Markel A, Meissner M, Manzo RA, Bergelin RO, Strandness DE. Deep venous thrombosis: rate of spontaneous lysis and thrombus extension. Int Angiol 2003; 22:376–382. 6. Prandoni P, Lensing AWA, Prins MH, et al. Residual venous thrombosis as a predictive factor of recurrent venous thromboembolism. Ann Intern Med 2002; 137:955–960. 7. Tan M, Mos ICM, Klok FA, Huisman MV. Residual venous thrombosis as predictive factor for recurrent venous thromboembolism in patients with proximal deep vein thrombosis: a systematic review. Br J Haematol 2011; 153:168–178. 8. Prandoni P, Frulla M, Sartor D, Concolato A, Girolami A. Vein abnormalities and the post-thrombotic syndrome. J Thromb Haemost 2005; 3: 401–402. 9. Villalta S, Bagatella P, Piccioli A, Lensing A, Prins M, Prandoni P. Assessment of validity and reproducibility of a clinical scale for the postthrombotic syndrome. Haemostasis 1994; 24:158. 10. van Ramshorst B, van Bemmelen PS, Hoeneveld H, Faber JA, Eikelboom BC. Thrombus regression in deep venous thrombosis. Quantification of spontaneous thrombolysis with duplex scanning. Circulation 1992; 86:414–419. 11. Jezovnik MK, Poredos P. Factors influencing the recanalisation rate of deep venous thrombosis. Int Angiol 2012; 31:169–175. 12. Brand~ ao GMS, Sobreira ML, Malgor RD, Rollo HA. Recanalization rates after acute deep vein thrombosis: a single-center experience using a
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Insufficient Recanalization of Thrombotic Venous Occlusion—Risk for Postthrombotic Syndrome Luka Jeraj, MD, Mateja Kaja Jezovnik, MD, PhD, and Pavel Poredos, PhD, MD ABSTRACT Purpose: To investigate the relationship between recanalization rate of occluded veins after deep venous thrombosis (DVT) and development of postthrombotic syndrome (PTS). Materials and Methods: Patients treated for DVT of the lower limbs were evaluated 12–36 months after acute DVT. Of 100 patients, 34 developed PTS, defined as Villalta score of 5. Symptoms and signs of PTS were assessed, and ultrasound examination of the veins was performed, checking for residual thrombus and presence of reflux. Results: Patients with PTS were older (64.0 y vs 55.5 y; P ¼ .007) and more frequently experienced recurrent DVT (15% vs 3%; P ¼ .030). Patients with PTS had a lower rate of recanalization. Patients with residual thrombus appeared to be at increased risk for PTS development compared with patients with total recanalization (odds ratio 6.0; 95% confidence interval, 1.7–21.9; P ¼ .006). No difference in the presence of reflux was observed. Conclusions: Incomplete or absent recanalization is associated with a higher incidence of PTS, probably as a consequence of deteriorated blood flow and increased venous pressure. This suggests early recanalization could improve the outcome of DVT treatment in selected patients.
ABBREVIATIONS DVT ¼ deep venous thrombosis, PTS ¼ postthrombotic syndrome
Postthrombotic syndrome (PTS) is a frequent chronic complication of deep venous thrombosis (DVT), affecting 20%–50% of patients with DVT within months to years after acute DVT. This syndrome is characterized by a combination of symptoms and signs, including leg heaviness, pain, edema, cramps, venous ectasia, hyperpigmentation, and venous ulceration. PTS severely affects the quality of life and increases health-related costs of patients with DVT. Many risk factors for PTS have been identified, such as elevated body mass index, older age, preexisting venous
From the Department of Vascular Disease (L.J., P.P.), University Medical Centre Ljubljana, Zalo ska cesta 7, Ljubljana 1000, Slovenia; and Center for Advanced Heart Failure (M.K.J.), University of Texas Health Science Center at Houston, Houston, Texas. Received January 5, 2017; final revision received and accepted March 21, 2017. Address correspondence to P.P.; E-mail: [email protected]
insufficiency, more proximal thrombosis, recurrent DVT of the same leg, and subtherapeutic anticoagulation (1). Treatment of DVT in the initial phase is based on anticoagulation, which prevents clot propagation. In selected cases, systemic or local thrombolysis is used (2). Thrombus evolution is a natural process, usually leading to recanalization of the affected veins (3). Although thrombus load is reduced by 50% in the first 3 months after acute DVT, some residual thrombus is still present 3 years after the diagnosis in half of the patients (4,5). Numerous studies have shown an increased incidence of recurrent DVT in patients with less efficient recanalization, seen as residual thrombosis (6,7). Data on the direct relationship between PTS and recanalization are scarce; however, they indicate an association between residual thrombosis and PTS (8). The aim of this study was to assess the prevalence of PTS in patients with a history of DVT and further evaluate its relationship to the recanalization rate of the affected veins.
None of the authors have identified a conflict of interest. © SIR, 2017 J Vasc Interv Radiol 2017; ▪:1–4 http://dx.doi.org/10.1016/j.jvir.2017.03.031
MATERIALS AND METHODS This study included patients with a diagnosis of acute DVT of the lower limbs who underwent treatment in a single
2 ▪ Recanalization of Occluded Veins and Development of PTS
outpatient clinic. Consecutive male and female patients with acute iliofemoral, femoropopliteal, or popliteal thrombosis with or without calf involvement were included. Patients were excluded if they had active cancer, symptomatic peripheral arterial disease, or chronic inflammatory disease or were unwilling to participate in the study. Only patients treated with anticoagulation and compression were included; patients treated with thrombolytic therapy were excluded. All patients signed a consent form before inclusion in the study. The study was approved by the National Medical Ethics Committee. There were 100 patients with a mean age of 58.9 years (± 11.2) included; 57% were men. The location of DVT was iliofemoral in 23%, femoropopliteal in 44%, and popliteal (with or without calf involvement) in 33%. DVT was unprovoked in 59% and provoked in 41%. A concurrent pulmonary embolism was present in 10% of patients; 7% had a recurrent DVT. Of patients, 61% had been treated with rivaroxaban, and 39% received warfarin together with dalteparin for the first 5–7 days, after which dalteparin was discontinued. Median time of anticoagulation was 6 months. Most patients in both groups were using compression therapy daily at least 6 months after DVT diagnosis (95%), either compression stockings (78%) or compression bandages (22%). All patients were followed until the check-up performed in the period between 12 and 36 months after the acute episode of DVT. At that time, signs and symptoms of PTS were assessed by a single investigator (L.J.), and the Villalta score was calculated for each patient (9). A Villalta score 5 was considered to be PTS positive, whereas a Villalta score < 5 was considered to be PTS negative. Deep veins of the lower limbs were assessed with ultrasound using a 10-MHz probe (ProSound Ultra 7; Hitachi Aloka Medical, Ltd, Mitaka, Japan). Recanalization status was defined as complete recanalization if the vein was totally compressible to no more than 2 mm, partial recanalization if the vein was partially compressible, or absent recanalization if the vein was occluded and incompressible. The competence of the vein valve function was checked and was defined as incompetent if a reversal flow (reflux) was > 0.5 second.
Statistical Analysis Patients were divided into 2 groups based on development of PTS. Continuous variables with normal distribution, as determined by the Kolmogorov-Smirnov test, were expressed as means and standard deviations. Variables without normal distribution were expressed as median and interquartile range. Differences between groups in normally distributed variables were analyzed using a t test for unpaired data, and a Mann-Whitney U test was used for the others. Categorical variables were expressed as percentages; c2 test was used to test differences between the groups. Variables with significant or near-significant values were analyzed using univariate logistic regression. A P value < .05 was considered significant. All statistical
Jeraj et al ▪ JVIR
Table 1. Demographic Characteristics of Patients and Type of Acute DVT Characteristic Age, y†
PTS-Positive* (n ¼ 34) 64.0 (58–71)
PTS-Negative (n ¼ 66)
P
55.5 (49–67)
.007‡ .062
Sex Male
15 (44%)
42 (64%)
Female
19 (56%)
24 (36%)
BMI, kg/m2†
28.6 (25.6–33.9) 28.7 (24.6–30.9) .421
Hypertension
16 (47%)
21 (32%)
.135
Hyperlipidemia Smoker
12 (35%) 7 (21%)
26 (39%) 12 (18%)
.689 .771
.593
Venous segment affected Iliofemoral
9 (26%)
14 (21%)
16 (47%)
28 (42%)
9 (26%)
24 (36%)
4 (12%)
6 (9%)
.673
Unprovoked
21 (62%)
38 (58%)
.687
Provoked
13 (38%)
28 (42%)
Recurrent DVT
5 (15%)
2 (3%)
Femoropopliteal Popliteal with/ without calf Concurrent pulmonary embolism Type of DVT
.030‡
BMI ¼ body mass index; DVT ¼ deep venous thrombosis; PTS ¼ postthrombotic syndrome. *PTS-positive patients are patients with Villalta score 5. † Median (interquartile range), Mann-Whitney U test. ‡ Statistically significant.
analyses were performed with IBM SPSS Statistics for Windows Version 23.0 (IBM Corp, Armonk, New York).
RESULTS Patients were assessed for the presence of PTS 12–36 months after acute DVT (median 23 months). Of 100 patients, 34 developed PTS. These patients were older and more frequently had a recurrent DVT (Table 1). Most patients with PTS had a mild form (Villalta score ¼ 5–9), whereas 15% developed a moderate form, and 3% developed a severe form. Compared with patients without PTS, patients who developed PTS had a lower percentage of completely recanalized veins (9% vs 38%) and a higher percentage of both no recanalization (24% vs 6%) and partial recanalization (68% vs 56%). However, there was no statistically significant difference in the presence of reflux between the groups (Table 2). In the logistic regression analysis, residual thrombus in the vein showed an odds ratio of 6.0 for PTS development compared with complete recanalization (Table 3).
DISCUSSION The main finding of this study is an association between vein recanalization in the chronic phase of DVT and the
Volume ▪ ▪ Number ▪ ▪ Month ▪ 2017
3
Table 2. Recanalization and Reflux of Deep Veins of the Lower Limbs 12–36 Months* after Acute DVT PTS-Positive† (n ¼ 34)
PTS-Negative (n ¼ 66)
P
3 (9%)
25 (38%)
.002‡
Partial
23 (68%)
37 (56%)
Absent
8 (24%)
4 (6%)
14 (41%)
21 (32%)
Recanalization Complete
Reflux
.353
DVT ¼ deep venous thrombosis; PTS ¼ postthrombotic syndrome. *Median 23 months. † PTS-positive patients are patients with Villalta score 5. ‡ Statistically significant.
Table 3. Logistic Regression of Variables Associated with Development of Postthrombotic Syndrome Variable Age, y
OR (95% CI)
P
1.06 (1.02–1.11)
.006*
Female sex
2.2 (0.95–5.15)
.064
Recurrent DVT
5.5 (1.01–30.1)
.049*
Residual thrombus
6.0 (1.7–21.9)
.006*
CI ¼ confidence interval; DVT ¼ deep venous thrombosis; OR ¼ odds ratio. *Statistically significant.
development of PTS. Patients who did not develop PTS had a significantly higher rate of recanalization after acute DVT. Recanalization of veins affected by DVT is a natural process that enables the venous lumen to be reestablished and blood flow to be improved; it can be seen 6 weeks after acute DVT (10). Thrombolysis and recanalization take several months to years to develop after acute DVT (5,6,11,12). Endogenous fibrinolysis, together with coagulation activity, probably plays the most important role in the recanalization process (13,14). Residual thrombus in the vein affected by acute DVT is associated with a higher incidence of venous reflux, whereas early resolution of the thrombus helps preserve venous valve integrity (15,16). Residual thrombus and vein wall damage have also been shown to be risk factors for recurrent DVT (6,7). Despite abundant research on venous recanalization, only limited data about the direct relationship between PTS and recanalization are available. Vein valve damage and increased venous pressure (as a consequence of chronic vein occlusion) are among the underlying mechanisms of PTS development (1). Therefore, an absence of complete recanalization is most likely associated with a higher risk for PTS development, as shown in this study. Residual thrombus, which includes partial and absent recanalization, had an odds ratio of 6.0 for PTS development compared with total recanalization. Prandoni et al (8) showed a connection between PTS and vein abnormalities, residual vein thrombosis and valve incompetence, which is in line with results
of the present study. Tick et al (17) showed similar findings. These studies focused on recanalization in the first months after acute DVT, whereas the present study assessed late recanalization. In addition to anticoagulation, thrombolytic therapy can be used for DVT treatment in some instances, particularly treatment of extensive proximal DVT (1,18). A metaanalysis of 17 studies with 1,103 participants showed that patients with DVT treated with (mostly systemic) thrombolysis had increased vein patency and higher rate of total recanalization compared with patients treated with standard anticoagulation. However, despite selecting patients with low bleeding risk, bleeding complications were more common in patients treated with thrombolysis (19). As opposed to systemic drug administration, catheter-directed thrombolysis is currently preferred, as it may reduce the risk of systemic bleeding (19). Several small randomized trials showed that catheter-directed thrombolysis could better preserve venous patency as opposed to standard anticoagulation (20,21). The randomized ATTRACT trial comprising 692 patients was finished more recently (22); results presented at the Society of Interventional Radiology (SIR) 2017 Annual Scientific Meeting indicate that pharmacomechanical PCT might lower the rate of moderate and severe forms of PTS but without lowering the total incidence of PTS (S. Vedantham, MD, FSIR, unpublished data, 2017). Together with results of the present study and others that showed a correlation between the recanalization rate and PTS development, these observations suggest catheterdirected thrombolysis could prove to be a useful tool in PTS prevention in selected patients. Some small trials also showed promising results of venous stent placement in patients with established PTS, improving the patency of insufficiently recanalized veins (23–25). Some known risk factors, such as older age and recurrent DVT, were confirmed in this study. A trend of higher incidence of PTS in female patients was seen; however, it was not statistically significant. The influence of sex on the development of PTS is not clear, with different studies showing an inconsistent relationship; the prevailing opinion is that there is no strong connection between PTS and sex. There was no significant correlation with the location of the thrombus. According to recent findings, compression stockings might not be effective in PTS prevention (26); they are recommended for symptom reduction when PTS is already present and are effective in acute DVT symptom reduction (1). Almost all patients in both groups were regularly using compression therapy for at least 6 months after the acute DVT. Limitations of this study include a relatively small number of patients and limited follow-up time. The limited follow-up could lead to underdiagnosed severe forms of PTS, which can develop over the course of years in patients with initially mild forms (4). However, most cases of PTS manifest during the first year after acute DVT (27). In conclusion, the absence of recanalization is associated with a higher incidence of PTS, probably as a consequence
4 ▪ Recanalization of Occluded Veins and Development of PTS
Jeraj et al ▪ JVIR
of vein wall damage and increased venous pressure caused by chronic vein occlusion. As PTS can severely decrease quality of life, early thrombus resolution could improve the outcome of DVT treatment in selected patients.
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This study was supported by the Slovenian Research Agency.
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