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Prospective Randomized Study of Ultrasound-Guided Foam Sclerotherapy Combined with Great Saphenous Vein High Ligation in the Treatment of Severe Lower Extremity Varicosis
Journal of Vascular Surgery: Venous and Lymphatic Disorders
Abstracts
471
Volume 5, Number 3 restenosis >50% found on duplex imaging. Primary, primary assisted, and secondary patency rates were estimated with Kaplan-Meier methods with the log-rank test. Percutaneous recanalization was successful in 77 of 81 limbs (95.1%). Stents were deployed in all iliofemoral occlusions, with two stents in 63 lesions (77.8%) and three stents in 18 lesions (22.2%). Venous perforation occurred in 32 patients (37.4%) and was resolved in all cases after stent placement. Back pain occurred during balloon angioplasty (93.8%) and persisted after stent placement in 56.8% of patients. However, the symptoms were self-limiting without further therapy. QOL and Villalta scores were significantly improved during a median follow-up of 19 months (range, 1-38 months; P < .01). The 2-year primary, primary assisted, and secondary cumulative stent patency rates were 81.5%, 91.4%, and 93.8%, respectively. Active ulcers were present in 33 limbs, and the cumulative recurrence-free ulcer-healing rate was 81%. Comments: Exactly why the authors felt that the Wallstent was inadequate for iliofemoral vein stenting is unclear to me because many of us use it with acceptable results. Regardless, the results they report for the combination of stents used is quite acceptable, and patient drop out was minimal, as demonstrated by life-table analysis. Patient-specific end points are provided in addition to specifics of device performance. In patients with advanced venous disease and iliofemoral venous occlusion, percutaneous iliac vein stent recanalization is again demonstrated to be a valuable interventional treatment. Not placing the stents into the inferior vena cava more aggressively may ultimately be an issue because covering the entire area of stenosis without doing so is sometimes quite difficult. Failure to cover the entire lesion is a mode of failure noted by many investigators.
Low-Molecular-Weight Heparin Versus Vitamin K Antagonists for the Treatment of Cancer-Associated Thrombosis: A Cost-Effectiveness Analysis Connell NT, Abel GA, Connors JM. Thromb Res 2017;150:53-8. Conclusions: The findings in this study suggest that compared with low-molecular-weight heparin (LMWH), warfarin (vitamin K antagonist [VKA]) is a more cost-effective strategy to treat cancer-associated venous thromboemboli (VTE). Although LMWH is associated with a modest increase in life expectancy, this increase comes at significant cost. Summary: The authors proposed a Markov state-transition model to compare the cost-effectiveness of LMWH to VKA for the treatment of cancer-associated thrombosis from a United States perspective. Cycle length was 6 months, and four health states were possible: initial anticoagulation, extended anticoagulation, no anticoagulation, or deceased. During each cycle, the simulated patients could experience potential events, including recurrent VTE, death from recurrent VTE, major bleeding, death from major bleeding, minor bleeding, and death from any cause. Model inputs for various event probabilities, costs, and utilities were obtained from previous published literature and are detailed in the text. In addition, because multiple randomized controlled trials (RCTs) have evaluated LMWH vs VKA for cancer-associated thrombosis, a fixed-effects meta-analysis was performed to include all recent data. All-cause mortality came from a Cochrane review. The model cost inputs were taken from published literature regarding the wholesale acquisition costs as well as the cost of various complications. The laboratory monitoring costs reflects the Centers for Medicare & Medicaid Services fee schedule. All costs were inflated to 2014 estimates. Disutility rates come from noncancer-specific populations, as detailed in the text. The chosen LMWH was twice-daily enoxaparin. Microsimulation of 1000 trials was performed to calculate mean quality-adjusted life-years (QALYs) and the cost associated with the two anticoagulation strategies. The model accounts for the amount of life each patient gains during each simulation and at the same time keeps track of the total cost associated with the treatment and various outcomes. An incremental cost-effectiveness ratio is calculated by dividing the total costs by the QALYs gained. Separate sensitivity analyses were performed of various aspects of care variation. The meta-analysis estimated the pooled odds ratio for major bleeding from LMWH compared with VKA, which was similar at 1.097, whereas that for recurrent VTE favored LMWH at a ratio of 0.55. Analysis of the base-case scenario resulted in a mean cost of the VKA strategy as $6383.39 6 $5174.56 and for the LMWH strategy as $64,975.83 6 $34,743.63. The mean effectiveness of the VKA strategy was 1.19 QALYs
(range 0.20-7.51), and for the LMWH strategy was 1.46 QALYs (range 0.20-9.03), resulting in a mean increase of 0.27 QALYs, or w14 weeks overall. The incremental cost-effectiveness ratio was approximately $217,007 per QALY. One sensitivity analysis revealed that the treatment with a VKA was always the preferred strategy at a willingness to pay threshold of $100,000 per QALY. At just below the $50,000 per QALY threshold often viewed as a reasonable cost for increased life extension, only use of VKA provides a positive net-monetary benefit to society. LMWH only becomes the preferred anticoagulation strategy when the wholesale acquisition cost is <$7177. Comments: This is a complex statistical exercise, which I would not pretend I understand in its entirety. Trusting the expertise of the authors, this study contradicts our current best practice with a Level I recommendation based on RCT results that LMWH prevents VTE recurrence better than VKAs. However, these RCTs provide no patient-centered quality of life evaluation or cost consideration. Our new payment structures are based on quality, which has as one large component: cost. What will ultimately drive best care may, in the future, use cost-analysis and will certainly use patient-focused outcomes to determine best care.
Prospective Randomized Study of UltrasoundGuided Foam Sclerotherapy Combined with Great Saphenous Vein High Ligation in the Treatment of Severe Lower Extremity Varicosis Yin H, He H, Wang M, Li Z, Hu Z, Yao C, et al. Ann Vasc Surg 2017;39:256-63. Conclusions: As a treatment of great saphenous vein (GSV) reflux with advanced clinical disease (C4-C6), ultrasound-guided foam sclerotherapy (UGFS) with GSV high ligation is noninferior to GSV high ligation, stripping, and stab phlebectomy or transilluminated powered phlebectomy (control group). Summary: This noninferiority study recruited clinical class C4 to C6 patients with primary superficial reflux between January 2012 and December 2014. Exclusion criteria were (1) previous intervention on the varicose veins by any technique; (2) ventricular or atrial septal defect; (3) previous deep veinous thrombosis; (4) pregnancy, malignant tumor, or severe cardiac, pulmonary, or renal diseases; (5) immobility or noncompliance with adjunctive compressive therapy; (6) primary deep vein insufficiency; or (7) other contraindications to the foam sclerosant. Based on defined average recurrence rates of w23% for each method, the authors estimated a total sample size of 138 to minimize type I and II error potential, but more were included to offset potential loss over time. Enlarged perforators in both groups were ablated by subfascial endoscopic perforator surgery (SEPS). In the UGFS group, the GSV was exposed and ligated, and then sclerosant foam was injected into the distal GSV via an 18-gauge needle, with filling of the GSV and varicose tributaries confirmed by ultrasound imaging. Additional foam was injected into residual patent varicose tributaries found by duplex imaging. The entire leg was pressure dressed with pads and elastic bandage for 24 hours, after which 30 to 40 mm Hg graduated stockings were substituted for 4 weeks and both day and night, and then only during the day for at least 2 more months. The control group underwent standard GSV high ligation and stripping to below the knee. Residual dilated GSV trunk and branch varicosities were removed with stab phlebectomy or the Trivex system (LeMaitre Vascular, Inc, Burlington, Mass). The leg was pressured bandaged for 72 hours, and then a class II elastic stocking was used during the day for at least 3 months. If the patient was clinical class C5 or C6, long-term compression was required. Follow-up was 1, 6, and 12 months with duplex imaging, Venous Clinical Severity Score, Aberdeen Varicose Vein Questionnaire, assessment of hemodynamic parameters, and physical examination. The cumulative reflux recurrence rate at the end of 12 months was the primary outcome defined as tortuous veins in the GSV area with diameter >3 mm and reflux time >0.5 seconds. Secondary outcomes were complications, remission of symptoms, disease-related quality of life, hemodynamic parameters, patient satisfaction, cost, and average operating and recovery times. The randomization process was computer generated. Of the 177 patients in the study, 82 were allocated to UGFS and 95 to the control group, of which 73 in the UGFS and 90 in the control groups received treatment. Complete data at study completion were available for 65 patients (89.0%) in the UGFS group and for 82.2% of patients in the control group. The groups had comparable baseline parameters. Average foam volume was 24.2, 27.7, and 29.3 mL in C4,
472
Abstracts
Journal of Vascular Surgery: Venous and Lymphatic Disorders May 2017
C5, and C6 patients, respectively. SEPS was performed in w38% of both groups. At the end of 12 months, the cumulative reflux recurrence rate was 13.8% in the UGFS group and 13.5% in the control group (P ¼ .955). Respectively for the UGFS and control groups, minor complications (27.7% vs 21.6%; P ¼ .406) and major complications (3.1% vs 2.7%; P ¼.895) were not significantly different. Compared with baseline values, significant improvements of venous filling index, Venous Clinical Severity Score, and Aberdeen Varicose Vein Questionnaire scores after treatment were confirmed in both groups (P < .001) compared with baseline values. The average operating and recovery times were much shorter (38.3 vs 81.2 minutes and 5.4 vs 9.6 days, respectively; P < .001) and the average hospital cost was much lower (853 vs $1575; P < .001) in the UGFS group than in the control group. The patient satisfaction rate reached 92.3% in the UGFS group and 89.2% in the control group 12 months after the operation (P ¼ .270). All ulcers healed and did not recur in either group at 12 months.
Comments: This study was undertaken for some good reasons by the authors, polidocanol was approved in China (availability), and there is a need for a low-cost and less invasive alternative (current open operation is the lowest cost alternative) for the treatment of GSV and branch insufficiency. However, this article has several areas of potential bias that make it a less compelling randomized controlled trial to base overall recommends upon. The control group is not well standardized in terms of branch varicosities management, which could be stab phlebectomy or the Trivex method. The healing method of each could significantly affect the overall healing and patient perception of the procedure effect. Allowing SEPS before either intervention also adds bias, which could have been managed better. Finally, the 1-year follow-up is not sufficiently long to demonstrate the progressive diminishing benefits of UGFS, as noted by other investigators.
Abstracts
471
Volume 5, Number 3 restenosis >50% found on duplex imaging. Primary, primary assisted, and secondary patency rates were estimated with Kaplan-Meier methods with the log-rank test. Percutaneous recanalization was successful in 77 of 81 limbs (95.1%). Stents were deployed in all iliofemoral occlusions, with two stents in 63 lesions (77.8%) and three stents in 18 lesions (22.2%). Venous perforation occurred in 32 patients (37.4%) and was resolved in all cases after stent placement. Back pain occurred during balloon angioplasty (93.8%) and persisted after stent placement in 56.8% of patients. However, the symptoms were self-limiting without further therapy. QOL and Villalta scores were significantly improved during a median follow-up of 19 months (range, 1-38 months; P < .01). The 2-year primary, primary assisted, and secondary cumulative stent patency rates were 81.5%, 91.4%, and 93.8%, respectively. Active ulcers were present in 33 limbs, and the cumulative recurrence-free ulcer-healing rate was 81%. Comments: Exactly why the authors felt that the Wallstent was inadequate for iliofemoral vein stenting is unclear to me because many of us use it with acceptable results. Regardless, the results they report for the combination of stents used is quite acceptable, and patient drop out was minimal, as demonstrated by life-table analysis. Patient-specific end points are provided in addition to specifics of device performance. In patients with advanced venous disease and iliofemoral venous occlusion, percutaneous iliac vein stent recanalization is again demonstrated to be a valuable interventional treatment. Not placing the stents into the inferior vena cava more aggressively may ultimately be an issue because covering the entire area of stenosis without doing so is sometimes quite difficult. Failure to cover the entire lesion is a mode of failure noted by many investigators.
Low-Molecular-Weight Heparin Versus Vitamin K Antagonists for the Treatment of Cancer-Associated Thrombosis: A Cost-Effectiveness Analysis Connell NT, Abel GA, Connors JM. Thromb Res 2017;150:53-8. Conclusions: The findings in this study suggest that compared with low-molecular-weight heparin (LMWH), warfarin (vitamin K antagonist [VKA]) is a more cost-effective strategy to treat cancer-associated venous thromboemboli (VTE). Although LMWH is associated with a modest increase in life expectancy, this increase comes at significant cost. Summary: The authors proposed a Markov state-transition model to compare the cost-effectiveness of LMWH to VKA for the treatment of cancer-associated thrombosis from a United States perspective. Cycle length was 6 months, and four health states were possible: initial anticoagulation, extended anticoagulation, no anticoagulation, or deceased. During each cycle, the simulated patients could experience potential events, including recurrent VTE, death from recurrent VTE, major bleeding, death from major bleeding, minor bleeding, and death from any cause. Model inputs for various event probabilities, costs, and utilities were obtained from previous published literature and are detailed in the text. In addition, because multiple randomized controlled trials (RCTs) have evaluated LMWH vs VKA for cancer-associated thrombosis, a fixed-effects meta-analysis was performed to include all recent data. All-cause mortality came from a Cochrane review. The model cost inputs were taken from published literature regarding the wholesale acquisition costs as well as the cost of various complications. The laboratory monitoring costs reflects the Centers for Medicare & Medicaid Services fee schedule. All costs were inflated to 2014 estimates. Disutility rates come from noncancer-specific populations, as detailed in the text. The chosen LMWH was twice-daily enoxaparin. Microsimulation of 1000 trials was performed to calculate mean quality-adjusted life-years (QALYs) and the cost associated with the two anticoagulation strategies. The model accounts for the amount of life each patient gains during each simulation and at the same time keeps track of the total cost associated with the treatment and various outcomes. An incremental cost-effectiveness ratio is calculated by dividing the total costs by the QALYs gained. Separate sensitivity analyses were performed of various aspects of care variation. The meta-analysis estimated the pooled odds ratio for major bleeding from LMWH compared with VKA, which was similar at 1.097, whereas that for recurrent VTE favored LMWH at a ratio of 0.55. Analysis of the base-case scenario resulted in a mean cost of the VKA strategy as $6383.39 6 $5174.56 and for the LMWH strategy as $64,975.83 6 $34,743.63. The mean effectiveness of the VKA strategy was 1.19 QALYs
(range 0.20-7.51), and for the LMWH strategy was 1.46 QALYs (range 0.20-9.03), resulting in a mean increase of 0.27 QALYs, or w14 weeks overall. The incremental cost-effectiveness ratio was approximately $217,007 per QALY. One sensitivity analysis revealed that the treatment with a VKA was always the preferred strategy at a willingness to pay threshold of $100,000 per QALY. At just below the $50,000 per QALY threshold often viewed as a reasonable cost for increased life extension, only use of VKA provides a positive net-monetary benefit to society. LMWH only becomes the preferred anticoagulation strategy when the wholesale acquisition cost is <$7177. Comments: This is a complex statistical exercise, which I would not pretend I understand in its entirety. Trusting the expertise of the authors, this study contradicts our current best practice with a Level I recommendation based on RCT results that LMWH prevents VTE recurrence better than VKAs. However, these RCTs provide no patient-centered quality of life evaluation or cost consideration. Our new payment structures are based on quality, which has as one large component: cost. What will ultimately drive best care may, in the future, use cost-analysis and will certainly use patient-focused outcomes to determine best care.
Prospective Randomized Study of UltrasoundGuided Foam Sclerotherapy Combined with Great Saphenous Vein High Ligation in the Treatment of Severe Lower Extremity Varicosis Yin H, He H, Wang M, Li Z, Hu Z, Yao C, et al. Ann Vasc Surg 2017;39:256-63. Conclusions: As a treatment of great saphenous vein (GSV) reflux with advanced clinical disease (C4-C6), ultrasound-guided foam sclerotherapy (UGFS) with GSV high ligation is noninferior to GSV high ligation, stripping, and stab phlebectomy or transilluminated powered phlebectomy (control group). Summary: This noninferiority study recruited clinical class C4 to C6 patients with primary superficial reflux between January 2012 and December 2014. Exclusion criteria were (1) previous intervention on the varicose veins by any technique; (2) ventricular or atrial septal defect; (3) previous deep veinous thrombosis; (4) pregnancy, malignant tumor, or severe cardiac, pulmonary, or renal diseases; (5) immobility or noncompliance with adjunctive compressive therapy; (6) primary deep vein insufficiency; or (7) other contraindications to the foam sclerosant. Based on defined average recurrence rates of w23% for each method, the authors estimated a total sample size of 138 to minimize type I and II error potential, but more were included to offset potential loss over time. Enlarged perforators in both groups were ablated by subfascial endoscopic perforator surgery (SEPS). In the UGFS group, the GSV was exposed and ligated, and then sclerosant foam was injected into the distal GSV via an 18-gauge needle, with filling of the GSV and varicose tributaries confirmed by ultrasound imaging. Additional foam was injected into residual patent varicose tributaries found by duplex imaging. The entire leg was pressure dressed with pads and elastic bandage for 24 hours, after which 30 to 40 mm Hg graduated stockings were substituted for 4 weeks and both day and night, and then only during the day for at least 2 more months. The control group underwent standard GSV high ligation and stripping to below the knee. Residual dilated GSV trunk and branch varicosities were removed with stab phlebectomy or the Trivex system (LeMaitre Vascular, Inc, Burlington, Mass). The leg was pressured bandaged for 72 hours, and then a class II elastic stocking was used during the day for at least 3 months. If the patient was clinical class C5 or C6, long-term compression was required. Follow-up was 1, 6, and 12 months with duplex imaging, Venous Clinical Severity Score, Aberdeen Varicose Vein Questionnaire, assessment of hemodynamic parameters, and physical examination. The cumulative reflux recurrence rate at the end of 12 months was the primary outcome defined as tortuous veins in the GSV area with diameter >3 mm and reflux time >0.5 seconds. Secondary outcomes were complications, remission of symptoms, disease-related quality of life, hemodynamic parameters, patient satisfaction, cost, and average operating and recovery times. The randomization process was computer generated. Of the 177 patients in the study, 82 were allocated to UGFS and 95 to the control group, of which 73 in the UGFS and 90 in the control groups received treatment. Complete data at study completion were available for 65 patients (89.0%) in the UGFS group and for 82.2% of patients in the control group. The groups had comparable baseline parameters. Average foam volume was 24.2, 27.7, and 29.3 mL in C4,
472
Abstracts
Journal of Vascular Surgery: Venous and Lymphatic Disorders May 2017
C5, and C6 patients, respectively. SEPS was performed in w38% of both groups. At the end of 12 months, the cumulative reflux recurrence rate was 13.8% in the UGFS group and 13.5% in the control group (P ¼ .955). Respectively for the UGFS and control groups, minor complications (27.7% vs 21.6%; P ¼ .406) and major complications (3.1% vs 2.7%; P ¼.895) were not significantly different. Compared with baseline values, significant improvements of venous filling index, Venous Clinical Severity Score, and Aberdeen Varicose Vein Questionnaire scores after treatment were confirmed in both groups (P < .001) compared with baseline values. The average operating and recovery times were much shorter (38.3 vs 81.2 minutes and 5.4 vs 9.6 days, respectively; P < .001) and the average hospital cost was much lower (853 vs $1575; P < .001) in the UGFS group than in the control group. The patient satisfaction rate reached 92.3% in the UGFS group and 89.2% in the control group 12 months after the operation (P ¼ .270). All ulcers healed and did not recur in either group at 12 months.
Comments: This study was undertaken for some good reasons by the authors, polidocanol was approved in China (availability), and there is a need for a low-cost and less invasive alternative (current open operation is the lowest cost alternative) for the treatment of GSV and branch insufficiency. However, this article has several areas of potential bias that make it a less compelling randomized controlled trial to base overall recommends upon. The control group is not well standardized in terms of branch varicosities management, which could be stab phlebectomy or the Trivex method. The healing method of each could significantly affect the overall healing and patient perception of the procedure effect. Allowing SEPS before either intervention also adds bias, which could have been managed better. Finally, the 1-year follow-up is not sufficiently long to demonstrate the progressive diminishing benefits of UGFS, as noted by other investigators.