Catheter directed thrombolysis for deep vein thrombosis in 2022: Rationale, evidence base and future directions.

INTRODUCTION: Catheter directed thrombolysis (CDT) has evolved as a treatment modality for patients diagnosed with proximal and caval deep vein thrombosis (DVT) and has shown to be superior in certain subset of patient population despite conflicting evidence as seen in the large 4 randomized controlled trials. RATIONALE FOR CDT IN ACUTE DVT PATIENTS: DVT adversely affects the quality of life and adds significantly to the treatment and hospitalization costs. CDT and pharmaco-mechanical catheter directed thrombolysis (PCDT) has been shown to accelerate symptom resolution, decrease symptom severity and decrease recurrence rates with successful procedures in certain patients. RANDOMIZED CLINICAL TRIALS (RCTS): Four RCTs have evaluated the use of CDT and PCDT in acute proximal DVT patients suggesting clinical benefit compared to anticoagulation alone. These trials suggested using CDT for proximal DVT patients with a lower bleeding risk as CDT may decrease PTS. Successful CDT treatment showed improvement in moderate to severe symptoms of post thrombotic syndrome (PTS). However, these studies have limitations including the use of non-standard techniques, different equipment and different endpoints. FUTURE DIRECTIONS AND CONCLUSION: Our goal is to highlight the factors which can potentially improve CDT outcomes in proximal DVT patients. Based on studies, patients with proximal DVT and a low bleeding risk may benefit from early CDT by decreased symptom severity of PTS, however, improvement in procedural technique, equipment and procedural success rates is necessary. With appropriate patient selection, and objective endpoints, we can further establish the benefit of CDT and PCDT in acute DVT patients.

Expedient Endovascular Hemorrhage Control During Anterior Lumbar Spinal Exposure Allows Procedural Completion in Rescued Patients.

OBJECTIVES: To propose a contemporary management strategy for venous injury during anterior lumbar spinal exposure that incorporates endovascular treatment. METHODS: Vein injuries suffered by patients treated in a single practice were reviewed. A treatment algorithm based on these experiences was formulated. RESULTS: Between 2015 and 2018, 914 patients received anterior access procedures for indicated lumbar interbody fusions. Of these patients, 15 (1.6%) suffered minor vascular injuries treated with manual pressure or suture repair. Four (0.4%) patients undergoing anterior lumbar spine surgery suffered major venous injuries, all of whom received the indicated spinal hardware following endovascular rescue. Primary repair was attempted in three patients before endovascular control and not at all in one. Vascular access was obtained via the bilateral femoral veins in 2 patients, unilateral femoral in one, and bilateral femoral plus right internal jugular vein in one. Stent choice included both uncovered (5, 63%) and covered stents (3, 38%). Deep venous thrombosis occurred in 2 patient's post-treatment. 1 DVT was encountered in the setting of a covered stent and 1 uncovered stent thrombosis was treated with catheter-directed lysis 4 weeks post-operatively. Ultimately, 3 patients were therapeutically anticoagulated. Mean follow-up is 13 months (range 1-36) with duplex ultrasounds available at 6 months or later in 3 of 4 patients. There is no evidence of post-thrombotic syndrome in the 2 patients that developed DVT's or in-stent stenosis in the 3 patients with available follow-up imaging. CONCLUSIONS: Endovascular techniques are important adjuncts when controlling large-volume hemorrhage associated with venous tears during anterior spinal exposure. Adequate direct compression allowing occlusion balloon inflation are key steps to reduce blood loss. Covered and uncovered stents are both appropriate choices to treat injuries. Patients must be anticoagulated post-operatively and surveilled for the sequelae of venous insufficiency. With expedient hemostasis, the indicated spinal surgery may be safely completed.

Meta-analyses of sulodexide and other drugs in prevention and treatment of post-thrombotic syndrome.

OBJECTIVE: Post-thrombotic syndrome (PTS) is a common chronic complication of deep vein thrombosis. Elastic compression (ECS) is the common pillar for PTS prevention and treatment, while the pharmacological approach for PTS includes direct oral anticoagulants (DOACs) and venoactive drugs (VADs) for prevention and treatment, respectively. Sulodexide can be used both in long-term prevention and in the treatment of PTS. To better understand the efficacy of the main drugs used in the prevention (sulodexide or DOACs) and treatment of PTS (sulodexide or VADs), pairwise meta-analyses of observational studies and RCTs were conducted. MATERIALS AND METHODS: A literature search in MEDLINE, Embase, and Cochrane Library for observational studies and RCTs was performed. Incidence of PTS, reduction in PTS signs or symptoms and proportion of patients with complete venous ulcers healing were the primary outcomes for prevention and treatment of PTS, respectively. Fixed and Random effect model meta-analyses were performed. Heterogeneity and publication bias were assessed. R® software was used for the analysis. RESULTS: 893 articles were identified during the search. 8 observational studies (6 for DOACs and 2 for sulodexide) and 2 RCTs for sulodexide, out of the 11 studies included in the qualitative synthesis, were included for the prevention and treatment of PTS, respectively. Meta-analyses of observational studies showed an overall incidence of PTS of 15% (95% CI, 11-19) for sulodexide, and a 50% reduction of PTS signs and/or symptoms for rivaroxaban compared to warfarin (OR, 0.50; 95% CI, 0.38-0.65). The overall estimate of the two sulodexide RCTs showed a significant improvement in complete ulcer healing, with an OR of 2.32 (95% CI, 1.49-3.63). CONCLUSIONS: In prevention of PTS, sulodexide and rivaroxaban showed a low incidence and reduced risk of PTS respectively, while in PTS treatment, sulodexide was significantly effective in the complete ulcers healing. These results confirm the need to move from the traditional single-pillar approach with elastic compression stockings to a more effective multi-pillar approach, tailoring the treatment to each individual patient.

Less frequent post-thrombotic syndrome after successful catheter-directed thrombolysis for acute iliofemoral deep vein thrombosis.

Post-thrombotic syndrome (PTS) occurs in 20-50% of patients with proximal deep vein thrombosis (DVT). In this study, we aimed to identify potential markers of thrombolysis success at the early stage and to clarify the relationship between early thrombolysis success and subsequent PTS development in patients with acute DVT in the iliac vein. Fifty-two consecutive patients with acute iliofemoral DVT who were treated with catheter-directed thrombolysis (CDT) within 21 days of onset were enrolled. An infusion catheter with multiple side holes was placed to cover the thrombosed vessel entirely. Urokinase solution was administered either continuously or with the pulse-spray method at a dose of 480,000-720,000 IU/day over the course of 2-7 days. During CDT, unfractionated heparin (UFH) was infused simultaneously via the access sheath to prevent thrombus formation. Early success was defined as lysis grade ≥ 50% and restoration of forward flow. PTS was diagnosed based on the Villalta scale. Based on the lysis grading method, complete lysis (grade III) was achieved in 8 of 52 (16%) limbs. Lysis grade II (50-99%) was achieved in 35 of 52 (67%) limbs. Lysis grade I (< 50%) was achieved in 9 of 52 (17%) limbs. Therefore, grade II and grade III lytic outcomes (early success) were observed in 43 patients (83%). One-year clinical follow-up was performed for 43 patients (83%). PTS occurred in seven (16%) patients. Early success was more frequently observed in patients without PTS than in those with PTS (92% vs. 43%; P < 0.01). Early success was only significantly associated with PTS in the multivariate analysis. Patients with acute symptomatic iliofemoral DVT who had early success from CDT treatment during the acute phase less frequently progressed to PTS. Patients with early success tended to undergo the pulse-spray method and had a shorter interval from symptom onset to CDT. The use of pulse-spray method and early initiation of CDT since DVT onset were potential markers of thrombolysis success.

Risk of post-thrombotic syndrome after deep vein thrombosis treated with rivaroxaban versus vitamin-K antagonists: A systematic review and meta-analysis.

INTRODUCTION: Post-thrombotic syndrome (PTS) is a burdensome long-term complication of deep vein thrombosis (DVT). Recent studies have suggested that rivaroxaban may reduce PTS events compared to vitamin-K antagonists (VKAs). We, therefore, systematically reviewed available literature that compared rivaroxaban versus VKAs on the risk of PTS. MATERIALS AND METHODS: We conducted a systematic review and meta-analysis using PubMed, EMBASE and Cochrane Library for all related studies from inception until March 2020. Two reviewers independently screened studies, extracted data, and appraised the quality of included studies. The primary outcome was overall risk of PTS. The secondary outcomes were risks of each PTS category (mild, moderate, severe) and venous ulcer. RESULTS: Seven comparative studies, comprising 2364 participants, qualified for this meta-analysis. The use of rivaroxaban for DVT treatment was associated with a lower risk of PTS compared with conventional VKAs [pooled unadjusted odds ratio (OR): 0.53, 95%CI: 0.43-0.65, P < 0.00001]. This effect was maintained after adjustment of potential confounders (pooled adjusted OR: 0.44, 95%CI: 0.35-0.56, P < 0.00001). Furthermore, rivaroxaban therapy was found to be associated with reduced risk of mild PTS (OR: 0.64, 95%CI: 0.50-0.82, P = 0.0005), moderate PTS (OR: 0.64, 95%CI: 0.45-0.91, P = 0.01), and severe PTS (OR: 0.52, 95%CI: 0.33-0.82, P = 0.005). There was also a similar trend towards reduced risk for venous ulcer, albeit not statistically significant (OR: 0.41, 95%CI: 0.15-1.08, P = 0.07). CONCLUSION: In comparison to VKAs, the use of rivaroxaban for DVT treatment has the potential to reduce PTS events. However, well-designed studies with larger sample sizes are needed to corroborate these findings.

Rutosides for treatment of post-thrombotic syndrome.

BACKGROUND: Post-thrombotic syndrome (PTS) is a long-term complication of deep venous thrombosis (DVT) that is characterised by pain, swelling, and skin changes in the affected limb. One in three patients with DVT will develop post-thrombotic sequelae within five years. Rutosides are a group of compounds derived from horse chestnut (Aesculus hippocastanum), a traditional herbal remedy for treating oedema formation in chronic venous insufficiency (CVI). However, it is not known whether rutosides are effective and safe in the treatment of PTS. This is the second update of the review first published in 2013. OBJECTIVES: To determine the effectiveness (improvement or deterioration in symptoms) and safety of rutosides for treatment of post-thrombotic syndrome (PTS) in patients with DVT compared to placebo, no intervention, elastic compression stockings (ECS) or any other treatment. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 21 August 2018. SELECTION CRITERIA: Two review authors independently assessed studies for inclusion. Studies were included to allow the comparison of rutosides versus placebo or no treatment, rutosides versus ECS, and rutosides versus any other treatment. Two review authors extracted information from the trials. Disagreements were resolved by discussion. DATA COLLECTION AND ANALYSIS: Data were extracted using designated data extraction forms. The Cochrane 'Risk of bias' tool was used for all included studies to assist in the assessment of quality. Primary outcome measures were the occurrence of leg ulceration over time (yes or no) and any improvement or deterioration of post-thrombotic syndrome (yes or no). Secondary outcomes included reduction of oedema, pain, recurrence of DVT or pulmonary embolism, compliance with therapy, and adverse effects. All of the outcome measures were analysed using Mantel-Haenzel fixed-effect model odds ratios. The unit of analysis was the number of patients. We used GRADE to assess the quality of the evidence for each outcome. MAIN RESULTS: Ten reports of nine studies were identified following searching and three studies with a total of 233 participants met the inclusion criteria. Overall quality of evidence using the GRADE approach was low, predominantly due to the lack of both participant and researcher blinding in the included studies. The quality of the evidence was further limited as only three small studies contributed to the review findings. A subjective scoring system was used to obtain the symptoms of PTS so it was important that the assessors were blinded to the intervention. One study compared rutosides with placebo, one study compared rutosides with ECS and rutosides plus ECS versus ECS alone, and one study compared rutosides with an alternative venoactive remedy. Occurrence of leg ulceration was not reported in any of the included studies. There was no clear evidence to support a difference in PTS improvement between the rutosides or placebo/no treatment groups (OR 1.29, 95% CI 0.69 to 2.41; 164 participants; 2 studies; low-quality evidence); or between the rutosides and ECS groups (OR 0.80, 95% CI 0.31 to 2.03; 80 participants; 1 study ; low-quality evidence). Results from one small study reported less PTS improvement in the rutosides group compared to an alternative venoactive remedy (OR 0.18, 95% CI 0.04 to 0.94; 29 participants; 1 study; low-quality evidence). There was no clear evidence to support a difference in PTS deterioration when comparing rutosides with placebo/no treatment (OR 0.61, 95% CI 0.19 to 1.90; 80 participants; 1 study); with ECS (OR 0.61, 95% CI 0.19 to 1.90; 80 participants; 1 study); or an alternative venoactive remedy (OR 0.19, 95% CI 0.01 to 4.24; 29 participants; 1 study). No clear evidence of a difference in adverse effects between the rutosides and placebo/no treatment groups was seen ('mild side effects' reported in 7/41 and 5/42 respectively). In the study comparing rutosides with ECS, 2/80 could not tolerate ECS and 6/80 stopped medication due to side effects. The study comparing rutosides with an alternative venoactive remedy did not comment on side effects AUTHORS' CONCLUSIONS: There was no evidence that rutosides were superior to the use of placebo or ECS. Overall, there is currently limited low-quality evidence that 'venoactive' or 'phlebotonic' remedies such as rutosides reduce symptoms of PTS. Mild side effects were noted in one study. The three studies included in this review provide no evidence to support the use of rutosides in the treatment of PTS.

Venous Thrombosis and Post-Thrombotic Syndrome: From Novel Biomarkers to Biology.

Deep vein thrombosis (DVT) is a common disease that carries serious ramifications for patients, including pulmonary embolism and post-thrombotic syndrome (PTS). Although standard treatment for DVT is anticoagulation, this carries an added risk of bleeding and increased medication monitoring. Identifying those at risk for DVT and PTS can be difficult, and current research with murine models is helping to illuminate the biologic changes associated with these two disorders. Potential novel biomarkers for improving the diagnosis of DVT and PTS include ICAM-1, P-selectin, and cell-free DNA. Inhibition of factor XI, P- and E-selectin, and neutrophil extracellular traps holds promise for novel clinical treatment of DVT. Experimental research on PTS suggests potential cellular and mediator therapy targets of TLR9, MMP-2 and-9, PAI-1, and IL-6. Although many important concepts and mechanisms have been elucidated through research on DVT and PTS, more work must be done to translate experimental findings to the clinical arena. This review examines the currently used murine models of DVT, biomarkers involved in the pathophysiology and diagnosis of DVT and PTS, and potential pharmacologic targets for PTS treatment.

Postthrombotic Syndrome: Long-Term Sequela of Deep Venous Thrombosis.

Postthrombotic syndrome is a common long-term complication of proximal lower extremity deep venous thrombosis, which not only significantly affects the quality of life of patients but also imposes a substantial financial burden on our healthcare system. Due to limited awareness and inability of physicians to recognize and treat this condition early, its prevalence is steadily increasing. In this article, we review the pathophysiology, the risk factors involved, diagnostic workup, and the various management options available to treat this condition.