- Email: [email protected]
Outcome of Inferior Vena Cava and Noncaval Venous Leiomyosarcomas
Abstracts Gregory L. Moneta, MD, Section Editor
Factors Impacting on Patient Perception of Procedural Success and Satisfaction Following Treatment for Varicose Veins Onida S, Shalhoub J, Moore HM, et al. BJS 2016;103:382-90. Conclusions: Analysis of patient-reported outcome measures (PROMs) indicates treatment of varicose veins improves quality of life (QoL), and anxiety or depression. Perioperative and postoperative anxiety or depression scores impact patient-perceived success and satisfaction rates. Summary: Interventions for varicose veins are designed not only to correct underlining anatomical or hemodynamic disturbances but to improve well-being and QoL. In fact, there is increasing use of QoL measures as primary end points in clinic studies. However, the role of enhanced case selection using QoL assessment remains unclear. A high prevalence of undiagnosed depression has been documented in patients with varicose veins (Sritharan K et al, Eur J Vasc Endovasc Surg 2012;43:480-4). The purpose of this study was to examine PROMs for varicose vein intervention to characterize variables impacting patient perception of procedural success and satisfaction. A secondary aim was to assess effective intervention and self-reported anxiety and depression. This was a retrospective study to examine PROMs for varicose vein interventions focusing on factors that might predict patient reported perception of procedural success and satisfaction. Centrally compiled PROMs data for varicose vein procedures from 2009-2011 was obtained from the hospital episode statistics data warehouse for England. Data for 35,039 patient episodes (62.8% women) were available for analysis. Some 23.4% of patients reported a degree of anxiety or depression before treatment. A formal diagnosis of depression was present in 7.8%. QoL as measured by a generic QoL tool, EQ-5D3LTM index, a disease specific QoL tool, the Aberdeen Varicose Vein Questionnaire (AVVQ), improved after an intervention by 11.7% (0.77-0.86) and 40.1% (18.95-11.36) respectively. The most significant improvement was found in EQ-5D visual analog scale scores. There was a significant improvement in self-perceived anxiety or depression after the intervention (P < .001). Both preoperative and postoperative depression or anxiety had a statistically significant relationship with self-perceived success and satisfaction (both P < .001). Comment: The data indicate treatment for varicose veins improves individual’s levels of self-reported anxiety or depression. Patients with higher QoL had improved self-reported outcomes with treatment success and satisfaction following varicose vein interventions. On the other hand patients with high levels of anxiety and depression were significantly more likely to view treatment as unsuccessful and unsatisfactory. Since the primary motivation for varicose vein treatment is often to improve QoL, careful assessment of the patient’s pre-intervention QoL, and anxiety and depression levels may help with pre-intervention counseling to help the patient understand their likelihood of achieving significant symptomatic improvement following intervention for varicose veins.
Five-Year Results of a Randomized Clinical Trial of Conventional Surgery, Endovenous Laser Ablation and Ultrasound-Guided Foam Sclerotherapy in Patients With Great Saphenous Varicose Veins Van der Velden SK, Biemans AA, De Maeseneer MG, et al. BJS 2015;102:1184-94. Conclusions: Endovenous laser ablation (EVLA) and conventional surgery are more effective than ultrasound-guided foam sclerotherapy (UGFS) in ablation of the greater saphenous vein (GSV) 5 years after intervention. UGFS is associated with higher rates of GSV reflux and inferior quality of life compared with EVLA and conventional surgery. Summary: Current guidelines recommend endovenous thermal ablation as the treatment of choice for a refluxing saphenous vein but are based largely on studies with short or mid-term follow-up (Gloviczki P et al, J Vasc Surg 2011;53(Suppl):2S-48S). At this point, however, only two randomized trials, demonstrating similar recurrence rates after conventional surgery and EVLA of the GSV, have been published that have had at least 5 years of follow-up. The present study was designed to compare long term outcomes of conventional surgery, EVLA and UGFS five years after intervention.
The primary outcome was obliteration or absence of the treated GSV segment. Secondary outcomes were absence of GSV reflux and changes in chronic venous insufficiency quality of life questionnaire (CIVIQ) and EuroQol-5D scores. There were a total of 224 legs included in this study, 69 treated with conventional surgery, 78 with EVLA, and 77 with UGFS. 86.2 % (n ¼ 193) were evaluated at final follow-up. At 5 years, KaplanMeier estimates of obliteration or absence of the GSV were 85% (95% CI, 75%-92%), 77% (95% CI, 66%-86%) and 23% (95% CI, 14%-33%) in the conventional surgery, EVLA and UGFS groups respectively. Absence of above-knee GSV reflux was found in 85 (73-92), 82 (72-90) and 41 (3053) percent respectively. CIVIQ scores deteriorated over time in patients with the UGFS (0.98 increase per year, 95% CI 0.16-1.79), and were significantly worse than the EVLA group (0.44 decrease per year, 95% CI 1.22 to 0.35), P ¼ .013. CIVIQ scores for conventional surgery group did not differ from those in the EVLA and UGFS groups (0.44 increase per year, 95% CI 0.41 to 1.29). EuroQol-5D scores improved equally in all groups. Comment: Limitations of the study include patients in the EVLA group were younger that those in the other two groups and approximately 14% of patients were lost to follow-up at 5 years. Overall, however, the study suggests both conventional surgery and EVLA are better than UGFS for treatment of greater saphenous vein reflux. EVLA also provides better disease specific patient reported outcomes than UGFS. There are no significant differences between EVLA and conventional surgery in obliteration of the treated greater saphenous vein segments. Overall, the paper strongly suggests EVLA and conventional surgery are preferred over UGFS for treatment of GSV reflux.
Outcome of Inferior Vena Cava and Noncaval Venous Leiomyosarcomas Illuminati G, Pizzardi G, Calio F, et al. Surgery 2016;159:613-20. Conclusions: Inferior vena cava and non-inferior vena cava leiomyosarcomas (LMS) exhibit similar outcomes in terms of post-operative course and survival. Surgical resection associated with vascular reconstruction, if applicable, followed by radiation and chemotherapy may be curative and is associated with good functional results. Summary: LMS represents only about 5%-7% of all soft tissue sarcomas with origin from large vessels in 2% of cases (Gage MJ et al, Ann Surg Oncol 2012;19:3368-74). Venous LMS derived from smooth muscle cells arise from the inferior vena cava (IVC) in 60% of cases. LMS of arterial smooth muscle are rare compared to that of those involving the venous system. Overall, however, venous LMS is still a rare and often lethal disease. There are a number of single institution reports of IVC LMS. However, there is even more limited experience with non-IVC LMS because of greater rarity of this location of disease. Information on non-IVC LMS is mostly from single case reports or small institutional case series. In this paper the authors reviewed their results with a treatment of both IVC and non-IVC LMS to potentially further define differences in clinical outcomes and to assess best operative treatment. There were 27 patients undergoing operative resection of a venous LMS at the authors’ institution that were retrospectively reviewed and divided into two groups; IVC leiomyosarcomas (IVC-LMS, Group A, n ¼ 18), and non-IVC leiomyosarcomas (nonIVC-LMS, Group B, n ¼ 9). The primary end points were postoperative mortality and morbidity, disease-specific survival and, if applicable, patency of venous reconstructions. There was no postoperative mortality in either group. Postoperative morbidity was 28% in Group A and 11% in Group B (P ¼ .33). Mean duration of follow up was 16 months (range, 13-140 months). Disease specific survival was 60% in Group A and 75% in Group B at three years (P ¼ .48) and was 54% in Group A and 62% in Group B at five years (P ¼ .63). Seven grafts were occluded in Group A, 39%, and one of three occluded in Group B, 33% (P ¼ .85). Comment: The study shows results of resection of non-IVC and IVC-LMS are similar in terms of survival and postoperative outcome. This likely reflects similar biologic behavior of LMS irrespective of its primary site of venous origin. There were some long-term disease-free survivors in both groups. Predictors of long-term survival were curative resection with R0 margins and absence of metastatic disease at the time of surgery. It
535
536 Abstracts
JOURNAL OF VASCULAR SURGERY: VENOUS AND LYMPHATIC DISORDERS October 2016
appears that aggressive operative resection and venous reconstruction, if feasible, is indicated in cases without metastases at the time of referral and such treatment remains the only chance of cure and provides better control of local disease.
Reduced Plasma Fibrin Clot Permeability and Susceptibility to Lysis Are Associated With Increased Risk of Post-Thrombotic Syndrome Siudut J, Grela M, Wypasek E, et al. J Thromb Haemost 2016;14:784-93. Conclusions: Formation of more compact fibrin clots displaying impaired susceptibility to lysis predisposes to post-thrombotic syndrome (PTS). Summary: PTS is the most common late complication of venous thromboembolism (VTE). Recurrent ipsilateral deep venous thrombosis (DVT) is a strong risk factor for PTS as is older age, obesity and proximal DVT. Fibrin clot structure and end-function including lysability is influenced by inflammatory states, medications, genetic factors and polymorphisms of various coagulation proteins. There is growing evidence that clots composed of compact fibrin networks are resistant to fibrinolysis and predispose patients to residual vein obstruction following VTE (Undas A et al, Throm Research 2012;130:e184-7). The authors hypothesized that a pro-thrombotic clot phenotype would be associated with a future risk of PTS. They investigated plasma clot characteristics and their determinants in DVT patients in relationship to the occurrence of PTS during followup. Plasma fibrin clot permeability (Ks) and lysability were investigated in a cohort of 197 consecutive patients aged 18e65 years recruited 3 months following a first-ever DVT. Patients with severe thrombophilia or comorbidities known to adversely affect clot phenotype were ineligible. During a 1year follow-up, PTS, as determined by the Villalta-scale, developed in 48 patients (24%). These patients were characterized by a lower clot permeation co-efficients (Ks), an indicator of pore size, prolonged fibrin clot lysis times (CLT) and slower release of D-dimer from clots (D-Drate), as well as higher plasma D-dimer, C-reactive protein and thrombin-activatable fibrinolysis inhibitor (TAFI) levels. There were no PTS associated differences in fibrinogen, thrombin generation, factor 8, other fibrinolysis proteins and the quality of anti-coagulation observed. Ks (r ¼ 0.71), CLT (r ¼ 0.45), D-Drate (r ¼ 0.30) and TAFI activity (r ¼ 0.3) all were associated with the Villalta-score (all P < .05). Recurrent VTE occurred most commonly in PTS patients during follow-up and these 26 (13.2%) patients had lower Ks, longer CLTs and lower D-Drate, (all P < .05). Independent predictors in a multivariant model adjusted for age, body mass index, fibrinogen and glucose showed that plasma D-dimer, Ks, D-Drate, tissue plasminogen activator and TAFI activity were all independent predictors of PTS. PTS was associated with more unfavorable clot variables including 18.5% Ks, 11.7% longer CLT and 6.9% lower D-Drate. Comment: The authors have shown that a pro-thrombotic plasma fibrin clot phenotype characterized by lower clot permeability predisposes patients to development of PTS. It appears denser fiber networks result in clot structures relatively resistant to tPA induced lysis, impaired vein recanalization and increasing outflow resistance, venous hypertension and finally PTS. The data may also provide some insight into why some DVTs undergo complete lysis while others only lyse partially or not at all. Resolution of thrombi following DVT and subsequent development of PTS appears to be a balance between pro-thrombotic activity and the phenotype of the clot formed. Basically, not all clots are the same and some are more resistant to fibrinolysis than others. This is likely, at least in part, due to the density of the clot and its fibrin network.
Sulodexide for the Prevention of Recurrent Venous Thromboembolism: The Sulodexide in Secondary Prevention of Recurrent Deep Vein Thrombosis (SURVET) Study: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial Andreozzi GM, Bignamini AA, Davi G, et al. Circulation 2015;132:1891-7. Conclusions: Sulodexide after discontinuation of anticoagulant treatment reduces risk of venous thromboembolism (VTE) recurrence in patients with unprovoked VTE, with no apparent increased risk of bleeding. Summary: Recurrent VTE particularly after an unprovoked VTE event is common and risk remains high for many years with approximately 20% of patients having a recurrence within 2 years after discontinuation of treatment with a vitamin K antagonist (Schulman S et al, N Engl J Med 1995;332:1661-5). Risk of recurrence can be decreased with continued warfarin administration but at an increased risk of bleeding.
New non-VKA oral anticoagulants for extended duration treatment have an efficacy noninferior to VKA and generally decreased rates of bleeding. Sulodexide is a glycosaminoglycan with anti-thrombotic and profibrinolytic activities (Coccheri S et al, Drug Des Devel Ther 2014;8:49-65) and is associated with negligible bleeding risk (Errichi BM et al, Angiology 2004;55:243-9). Pharmacological and clinical profiles suggest Sulodexide may have a role in prevention of recurrent VTE following discontinuation of oral anticoagulation. The aim of this trial was to verify the efficacy and safety of Sulodexide in prevention of recurrent VTE after the end of VKA treatment in patients with a first unprovoked VTE. This was a multicenter, double-blind study of 615 patients with a first ever unprovoked VTE who had completed 3-12 months of oral anticoagulant treatment. Patients were randomly assigned to Sulodexide lipasemic units twice daily or placebo for 2 years in addition to elastic stockings. Primary efficacy outcome was recurrence of VTE. Major or clinically relevant bleeding was the primary safety outcome. VTE recurred in 15 of 307 patients who received Sulodexide and in 30 of 308 patients who received placebo (HR, 0.49; 95% CI, 0.27-0.92; P ¼ .02). An analysis in which lost to follow-up was assigned to failure yielded a risk ratio among the treated to control subjects of 0.54 (95% CI, 0.35-0.85; P ¼ .009). There were no major bleeding episodes. Two patients in each group had a clinically relevant bleeding episode and adverse events were similar in the two groups. Comment: Results of this study are similar to those of trials performed with aspirin (WARFASA and ASPIRE; Becattini C et al, N Engl J Med 2012;366:1959-67, and Brighton TA et al, N Engl J Med 2012;367:1979-87). Similarly, results reported with the new oral anticoagulants such as Apixaban, Dabigatran or Rivaroxaban also showed favorable results in decreasing recurrent VTE but at the expense of increased bleeding. Future studies should focus on whether similar effects can be obtained after treatment of index events with non VKA oral anticoagulants, possible summation effects with aspirin, and whether there are specific subgroups more likely to benefit from Sulodexide or from other treatments.
Unprovoked Venous Thromboembolism and Subsequent Cancer Risk: A Population-Based Cohort Study Sun LM, Chung WS, Lin CL, et al. J Thromb Haemost 2016;14:495-503. Conclusions: Unprovoked venous thromboembolism (VTE) is associated with a consistently high risk of subsequent cancer diagnosis particularly within the first 6 months after VTE. Summary: Age standardized incidence rates of first time VTE range from 71-117 cases per 100,000 population (Anderson FA Jr et al, Arch Int Med 1991;151:933-8, and White RH, Circulation 2003;107:14-8). Cancer patients represent 20% of all patients diagnosed with VTE (Caine GJ et al, Neoplasia 2002;4:465-73). The authors conducted a population based cohort study to determine association between unprovoked VTE and subsequent cancer in Taiwan. The hypothesis was that unprovoked VTE patients have a higher risk of subsequent overall and site specific cancer development. In addition, the authors wished to determine whether the increase risk was more evident in short-term or in long-term follow-up. They obtained data on 27,751 patients diagnosed with unprovoked VTE between January 1, 1998 and December 31, 2008 in Taiwan. For their comparison group they identified 4 people without unprovoked VTE who were propensity matched with each unprovoked VTE patient according to age, sex and index year. Cox proportional hazards regression models were employed to determine the effects of unprovoked VTE on cancer risk. Overall, cancer risk were significantly higher in the unprovoked VTE group than the comparison group (adjusted HR, 2.26; 95% CI, 2.16-2.37). The increased risk was observed in both men and women in various age groups. Patients in the unprovoked VTE group also showed a significantly increased risk of cancer at all site specific cancer sites. Analysis stratified according to follow-up duration revealed that significant differences were more evident between the two groups over a follow-up duration of <0.5 years than in over a follow-up duration of $3 years. One-year mortality risk of cancer patients with unprovoked VTE was significantly higher than that for cancer patients in the non-VTE group. Comment: The study suggests VTE can be an indicator of an occult malignancy and that such occult malignancies are most likely to be discovered within the first 6 months after the VTE diagnosis. The study, of course, does not tell us whether a work up for a potential occult malignancy in all patients with “idiopathic” VTE would be beneficial in earlier diagnosis of malignancy. Also, it is unclear whether an earlier diagnosis would improve cancer related prognosis and whether the development of VTE as manifestation of malignancy is associated with a more aggressive malignant process or a malignant process that is already metastasized subclinically at the time of the VTE diagnosis.
Factors Impacting on Patient Perception of Procedural Success and Satisfaction Following Treatment for Varicose Veins Onida S, Shalhoub J, Moore HM, et al. BJS 2016;103:382-90. Conclusions: Analysis of patient-reported outcome measures (PROMs) indicates treatment of varicose veins improves quality of life (QoL), and anxiety or depression. Perioperative and postoperative anxiety or depression scores impact patient-perceived success and satisfaction rates. Summary: Interventions for varicose veins are designed not only to correct underlining anatomical or hemodynamic disturbances but to improve well-being and QoL. In fact, there is increasing use of QoL measures as primary end points in clinic studies. However, the role of enhanced case selection using QoL assessment remains unclear. A high prevalence of undiagnosed depression has been documented in patients with varicose veins (Sritharan K et al, Eur J Vasc Endovasc Surg 2012;43:480-4). The purpose of this study was to examine PROMs for varicose vein intervention to characterize variables impacting patient perception of procedural success and satisfaction. A secondary aim was to assess effective intervention and self-reported anxiety and depression. This was a retrospective study to examine PROMs for varicose vein interventions focusing on factors that might predict patient reported perception of procedural success and satisfaction. Centrally compiled PROMs data for varicose vein procedures from 2009-2011 was obtained from the hospital episode statistics data warehouse for England. Data for 35,039 patient episodes (62.8% women) were available for analysis. Some 23.4% of patients reported a degree of anxiety or depression before treatment. A formal diagnosis of depression was present in 7.8%. QoL as measured by a generic QoL tool, EQ-5D3LTM index, a disease specific QoL tool, the Aberdeen Varicose Vein Questionnaire (AVVQ), improved after an intervention by 11.7% (0.77-0.86) and 40.1% (18.95-11.36) respectively. The most significant improvement was found in EQ-5D visual analog scale scores. There was a significant improvement in self-perceived anxiety or depression after the intervention (P < .001). Both preoperative and postoperative depression or anxiety had a statistically significant relationship with self-perceived success and satisfaction (both P < .001). Comment: The data indicate treatment for varicose veins improves individual’s levels of self-reported anxiety or depression. Patients with higher QoL had improved self-reported outcomes with treatment success and satisfaction following varicose vein interventions. On the other hand patients with high levels of anxiety and depression were significantly more likely to view treatment as unsuccessful and unsatisfactory. Since the primary motivation for varicose vein treatment is often to improve QoL, careful assessment of the patient’s pre-intervention QoL, and anxiety and depression levels may help with pre-intervention counseling to help the patient understand their likelihood of achieving significant symptomatic improvement following intervention for varicose veins.
Five-Year Results of a Randomized Clinical Trial of Conventional Surgery, Endovenous Laser Ablation and Ultrasound-Guided Foam Sclerotherapy in Patients With Great Saphenous Varicose Veins Van der Velden SK, Biemans AA, De Maeseneer MG, et al. BJS 2015;102:1184-94. Conclusions: Endovenous laser ablation (EVLA) and conventional surgery are more effective than ultrasound-guided foam sclerotherapy (UGFS) in ablation of the greater saphenous vein (GSV) 5 years after intervention. UGFS is associated with higher rates of GSV reflux and inferior quality of life compared with EVLA and conventional surgery. Summary: Current guidelines recommend endovenous thermal ablation as the treatment of choice for a refluxing saphenous vein but are based largely on studies with short or mid-term follow-up (Gloviczki P et al, J Vasc Surg 2011;53(Suppl):2S-48S). At this point, however, only two randomized trials, demonstrating similar recurrence rates after conventional surgery and EVLA of the GSV, have been published that have had at least 5 years of follow-up. The present study was designed to compare long term outcomes of conventional surgery, EVLA and UGFS five years after intervention.
The primary outcome was obliteration or absence of the treated GSV segment. Secondary outcomes were absence of GSV reflux and changes in chronic venous insufficiency quality of life questionnaire (CIVIQ) and EuroQol-5D scores. There were a total of 224 legs included in this study, 69 treated with conventional surgery, 78 with EVLA, and 77 with UGFS. 86.2 % (n ¼ 193) were evaluated at final follow-up. At 5 years, KaplanMeier estimates of obliteration or absence of the GSV were 85% (95% CI, 75%-92%), 77% (95% CI, 66%-86%) and 23% (95% CI, 14%-33%) in the conventional surgery, EVLA and UGFS groups respectively. Absence of above-knee GSV reflux was found in 85 (73-92), 82 (72-90) and 41 (3053) percent respectively. CIVIQ scores deteriorated over time in patients with the UGFS (0.98 increase per year, 95% CI 0.16-1.79), and were significantly worse than the EVLA group (0.44 decrease per year, 95% CI 1.22 to 0.35), P ¼ .013. CIVIQ scores for conventional surgery group did not differ from those in the EVLA and UGFS groups (0.44 increase per year, 95% CI 0.41 to 1.29). EuroQol-5D scores improved equally in all groups. Comment: Limitations of the study include patients in the EVLA group were younger that those in the other two groups and approximately 14% of patients were lost to follow-up at 5 years. Overall, however, the study suggests both conventional surgery and EVLA are better than UGFS for treatment of greater saphenous vein reflux. EVLA also provides better disease specific patient reported outcomes than UGFS. There are no significant differences between EVLA and conventional surgery in obliteration of the treated greater saphenous vein segments. Overall, the paper strongly suggests EVLA and conventional surgery are preferred over UGFS for treatment of GSV reflux.
Outcome of Inferior Vena Cava and Noncaval Venous Leiomyosarcomas Illuminati G, Pizzardi G, Calio F, et al. Surgery 2016;159:613-20. Conclusions: Inferior vena cava and non-inferior vena cava leiomyosarcomas (LMS) exhibit similar outcomes in terms of post-operative course and survival. Surgical resection associated with vascular reconstruction, if applicable, followed by radiation and chemotherapy may be curative and is associated with good functional results. Summary: LMS represents only about 5%-7% of all soft tissue sarcomas with origin from large vessels in 2% of cases (Gage MJ et al, Ann Surg Oncol 2012;19:3368-74). Venous LMS derived from smooth muscle cells arise from the inferior vena cava (IVC) in 60% of cases. LMS of arterial smooth muscle are rare compared to that of those involving the venous system. Overall, however, venous LMS is still a rare and often lethal disease. There are a number of single institution reports of IVC LMS. However, there is even more limited experience with non-IVC LMS because of greater rarity of this location of disease. Information on non-IVC LMS is mostly from single case reports or small institutional case series. In this paper the authors reviewed their results with a treatment of both IVC and non-IVC LMS to potentially further define differences in clinical outcomes and to assess best operative treatment. There were 27 patients undergoing operative resection of a venous LMS at the authors’ institution that were retrospectively reviewed and divided into two groups; IVC leiomyosarcomas (IVC-LMS, Group A, n ¼ 18), and non-IVC leiomyosarcomas (nonIVC-LMS, Group B, n ¼ 9). The primary end points were postoperative mortality and morbidity, disease-specific survival and, if applicable, patency of venous reconstructions. There was no postoperative mortality in either group. Postoperative morbidity was 28% in Group A and 11% in Group B (P ¼ .33). Mean duration of follow up was 16 months (range, 13-140 months). Disease specific survival was 60% in Group A and 75% in Group B at three years (P ¼ .48) and was 54% in Group A and 62% in Group B at five years (P ¼ .63). Seven grafts were occluded in Group A, 39%, and one of three occluded in Group B, 33% (P ¼ .85). Comment: The study shows results of resection of non-IVC and IVC-LMS are similar in terms of survival and postoperative outcome. This likely reflects similar biologic behavior of LMS irrespective of its primary site of venous origin. There were some long-term disease-free survivors in both groups. Predictors of long-term survival were curative resection with R0 margins and absence of metastatic disease at the time of surgery. It
535
536 Abstracts
JOURNAL OF VASCULAR SURGERY: VENOUS AND LYMPHATIC DISORDERS October 2016
appears that aggressive operative resection and venous reconstruction, if feasible, is indicated in cases without metastases at the time of referral and such treatment remains the only chance of cure and provides better control of local disease.
Reduced Plasma Fibrin Clot Permeability and Susceptibility to Lysis Are Associated With Increased Risk of Post-Thrombotic Syndrome Siudut J, Grela M, Wypasek E, et al. J Thromb Haemost 2016;14:784-93. Conclusions: Formation of more compact fibrin clots displaying impaired susceptibility to lysis predisposes to post-thrombotic syndrome (PTS). Summary: PTS is the most common late complication of venous thromboembolism (VTE). Recurrent ipsilateral deep venous thrombosis (DVT) is a strong risk factor for PTS as is older age, obesity and proximal DVT. Fibrin clot structure and end-function including lysability is influenced by inflammatory states, medications, genetic factors and polymorphisms of various coagulation proteins. There is growing evidence that clots composed of compact fibrin networks are resistant to fibrinolysis and predispose patients to residual vein obstruction following VTE (Undas A et al, Throm Research 2012;130:e184-7). The authors hypothesized that a pro-thrombotic clot phenotype would be associated with a future risk of PTS. They investigated plasma clot characteristics and their determinants in DVT patients in relationship to the occurrence of PTS during followup. Plasma fibrin clot permeability (Ks) and lysability were investigated in a cohort of 197 consecutive patients aged 18e65 years recruited 3 months following a first-ever DVT. Patients with severe thrombophilia or comorbidities known to adversely affect clot phenotype were ineligible. During a 1year follow-up, PTS, as determined by the Villalta-scale, developed in 48 patients (24%). These patients were characterized by a lower clot permeation co-efficients (Ks), an indicator of pore size, prolonged fibrin clot lysis times (CLT) and slower release of D-dimer from clots (D-Drate), as well as higher plasma D-dimer, C-reactive protein and thrombin-activatable fibrinolysis inhibitor (TAFI) levels. There were no PTS associated differences in fibrinogen, thrombin generation, factor 8, other fibrinolysis proteins and the quality of anti-coagulation observed. Ks (r ¼ 0.71), CLT (r ¼ 0.45), D-Drate (r ¼ 0.30) and TAFI activity (r ¼ 0.3) all were associated with the Villalta-score (all P < .05). Recurrent VTE occurred most commonly in PTS patients during follow-up and these 26 (13.2%) patients had lower Ks, longer CLTs and lower D-Drate, (all P < .05). Independent predictors in a multivariant model adjusted for age, body mass index, fibrinogen and glucose showed that plasma D-dimer, Ks, D-Drate, tissue plasminogen activator and TAFI activity were all independent predictors of PTS. PTS was associated with more unfavorable clot variables including 18.5% Ks, 11.7% longer CLT and 6.9% lower D-Drate. Comment: The authors have shown that a pro-thrombotic plasma fibrin clot phenotype characterized by lower clot permeability predisposes patients to development of PTS. It appears denser fiber networks result in clot structures relatively resistant to tPA induced lysis, impaired vein recanalization and increasing outflow resistance, venous hypertension and finally PTS. The data may also provide some insight into why some DVTs undergo complete lysis while others only lyse partially or not at all. Resolution of thrombi following DVT and subsequent development of PTS appears to be a balance between pro-thrombotic activity and the phenotype of the clot formed. Basically, not all clots are the same and some are more resistant to fibrinolysis than others. This is likely, at least in part, due to the density of the clot and its fibrin network.
Sulodexide for the Prevention of Recurrent Venous Thromboembolism: The Sulodexide in Secondary Prevention of Recurrent Deep Vein Thrombosis (SURVET) Study: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial Andreozzi GM, Bignamini AA, Davi G, et al. Circulation 2015;132:1891-7. Conclusions: Sulodexide after discontinuation of anticoagulant treatment reduces risk of venous thromboembolism (VTE) recurrence in patients with unprovoked VTE, with no apparent increased risk of bleeding. Summary: Recurrent VTE particularly after an unprovoked VTE event is common and risk remains high for many years with approximately 20% of patients having a recurrence within 2 years after discontinuation of treatment with a vitamin K antagonist (Schulman S et al, N Engl J Med 1995;332:1661-5). Risk of recurrence can be decreased with continued warfarin administration but at an increased risk of bleeding.
New non-VKA oral anticoagulants for extended duration treatment have an efficacy noninferior to VKA and generally decreased rates of bleeding. Sulodexide is a glycosaminoglycan with anti-thrombotic and profibrinolytic activities (Coccheri S et al, Drug Des Devel Ther 2014;8:49-65) and is associated with negligible bleeding risk (Errichi BM et al, Angiology 2004;55:243-9). Pharmacological and clinical profiles suggest Sulodexide may have a role in prevention of recurrent VTE following discontinuation of oral anticoagulation. The aim of this trial was to verify the efficacy and safety of Sulodexide in prevention of recurrent VTE after the end of VKA treatment in patients with a first unprovoked VTE. This was a multicenter, double-blind study of 615 patients with a first ever unprovoked VTE who had completed 3-12 months of oral anticoagulant treatment. Patients were randomly assigned to Sulodexide lipasemic units twice daily or placebo for 2 years in addition to elastic stockings. Primary efficacy outcome was recurrence of VTE. Major or clinically relevant bleeding was the primary safety outcome. VTE recurred in 15 of 307 patients who received Sulodexide and in 30 of 308 patients who received placebo (HR, 0.49; 95% CI, 0.27-0.92; P ¼ .02). An analysis in which lost to follow-up was assigned to failure yielded a risk ratio among the treated to control subjects of 0.54 (95% CI, 0.35-0.85; P ¼ .009). There were no major bleeding episodes. Two patients in each group had a clinically relevant bleeding episode and adverse events were similar in the two groups. Comment: Results of this study are similar to those of trials performed with aspirin (WARFASA and ASPIRE; Becattini C et al, N Engl J Med 2012;366:1959-67, and Brighton TA et al, N Engl J Med 2012;367:1979-87). Similarly, results reported with the new oral anticoagulants such as Apixaban, Dabigatran or Rivaroxaban also showed favorable results in decreasing recurrent VTE but at the expense of increased bleeding. Future studies should focus on whether similar effects can be obtained after treatment of index events with non VKA oral anticoagulants, possible summation effects with aspirin, and whether there are specific subgroups more likely to benefit from Sulodexide or from other treatments.
Unprovoked Venous Thromboembolism and Subsequent Cancer Risk: A Population-Based Cohort Study Sun LM, Chung WS, Lin CL, et al. J Thromb Haemost 2016;14:495-503. Conclusions: Unprovoked venous thromboembolism (VTE) is associated with a consistently high risk of subsequent cancer diagnosis particularly within the first 6 months after VTE. Summary: Age standardized incidence rates of first time VTE range from 71-117 cases per 100,000 population (Anderson FA Jr et al, Arch Int Med 1991;151:933-8, and White RH, Circulation 2003;107:14-8). Cancer patients represent 20% of all patients diagnosed with VTE (Caine GJ et al, Neoplasia 2002;4:465-73). The authors conducted a population based cohort study to determine association between unprovoked VTE and subsequent cancer in Taiwan. The hypothesis was that unprovoked VTE patients have a higher risk of subsequent overall and site specific cancer development. In addition, the authors wished to determine whether the increase risk was more evident in short-term or in long-term follow-up. They obtained data on 27,751 patients diagnosed with unprovoked VTE between January 1, 1998 and December 31, 2008 in Taiwan. For their comparison group they identified 4 people without unprovoked VTE who were propensity matched with each unprovoked VTE patient according to age, sex and index year. Cox proportional hazards regression models were employed to determine the effects of unprovoked VTE on cancer risk. Overall, cancer risk were significantly higher in the unprovoked VTE group than the comparison group (adjusted HR, 2.26; 95% CI, 2.16-2.37). The increased risk was observed in both men and women in various age groups. Patients in the unprovoked VTE group also showed a significantly increased risk of cancer at all site specific cancer sites. Analysis stratified according to follow-up duration revealed that significant differences were more evident between the two groups over a follow-up duration of <0.5 years than in over a follow-up duration of $3 years. One-year mortality risk of cancer patients with unprovoked VTE was significantly higher than that for cancer patients in the non-VTE group. Comment: The study suggests VTE can be an indicator of an occult malignancy and that such occult malignancies are most likely to be discovered within the first 6 months after the VTE diagnosis. The study, of course, does not tell us whether a work up for a potential occult malignancy in all patients with “idiopathic” VTE would be beneficial in earlier diagnosis of malignancy. Also, it is unclear whether an earlier diagnosis would improve cancer related prognosis and whether the development of VTE as manifestation of malignancy is associated with a more aggressive malignant process or a malignant process that is already metastasized subclinically at the time of the VTE diagnosis.