Association of Successful Ultrasound-Accelerated Catheter-Directed Thrombolysis with Postthrombotic Syndrome: A Post Hoc Analysis of the CAVA TrialFunding The trial was funded by a grant from ZonMw (The Netherlands Organisation for Health Research and Development, project number 171101001) and BTG-Interventional Medicine. Additional funding was provided by the board of the Maastricht University Medical Centre.
20 February 2020
06 May 2020
30 June 2020 (online)
Background The CAVA trial did not show the anticipated risk reduction for postthrombotic syndrome (PTS) after thrombus removal via additional ultrasound-accelerated catheter-directed thrombolysis (UACDT) in patients with acute iliofemoral deep vein thrombosis (IFDVT). Difficulties in achieving an effective degree of recanalization through thrombolysis may have influenced outcomes. We therefore assessed whether successful UACDT (restored patency ≥ 90%) did reduce the development of PTS.
Methods This CAVA trial post hoc analysis compared the proportion of PTS at 1-year follow-up between patients with successful UACDT and patients that received standard treatment only. In addition, clinical impact as well as determinants of successful thrombolysis were explored.
Results UACDT was initiated in 77 (50.7%) patients and considered successful in 41 (53.2%, interrater agreement κ = 0.7, 95% confidence interval 0.47–0.83). PTS developed in 15/41 (36.6%) patients in the successful UACDT group versus 33/75 (44.0%) controls (p = 0.44). In this comparison, successful UACDT was associated with lower Venous Clinical Severity Score (3.50 ± 2.57 vs. 4.82 ± 2.74, p = 0.02) and higher EuroQOL-5D (EQ-5D) scores (40.2 ± 36.4 vs. 23.4 ± 34.4, p = 0.01). Compared with unsuccessful UACDT, successful UACDT was associated with a shorter symptom duration at inclusion (p = 0.05), and higher rates of performed adjunctive procedures (p < 0.001) and stent placement (p < 0.001).
Conclusion Successful UACDT was not associated with a reduced proportion of PTS 1 year after acute IFDVT compared with patients receiving standard treatment alone. There was, however, a significant reduction in symptom severity and improvement of generic quality of life according to the EQ-5D. Better patient selection and optimization of treatment protocols are needed to assess the full potential of UACDT for the prevention of PTS.
Trial Registration Number ClinicalTrials.gov number, NCT00970619.
Keywordsdeep vein thrombosis - postthrombotic syndrome - thrombolysis - thrombolytic agents - vascular patency - quality of life
* Emeritus professor of venous surgery.
- 1 Prandoni P, Lensing AW, Prins MH. , et al. The impact of residual thrombosis on the long-term outcome of patients with deep venous thrombosis treated with conventional anticoagulation. Semin Thromb Hemost 2015; 41 (02) 133-140
- 2 Kahn SR, Shrier I, Julian JA. , et al. Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis. Ann Intern Med 2008; 149 (10) 698-707
- 3 Schulman S, Lindmarker P, Holmström M. , et al. Post-thrombotic syndrome, recurrence, and death 10 years after the first episode of venous thromboembolism treated with warfarin for 6 weeks or 6 months. J Thromb Haemost 2006; 4 (04) 734-742
- 4 Baglin T, Douketis J, Tosetto A. , et al. Does the clinical presentation and extent of venous thrombosis predict likelihood and type of recurrence? A patient-level meta-analysis. J Thromb Haemost 2010; 8 (11) 2436-2442
- 5 Stain M, Schönauer V, Minar E. , et al. The post-thrombotic syndrome: risk factors and impact on the course of thrombotic disease. J Thromb Haemost 2005; 3 (12) 2671-2676
- 6 Tick LW, Doggen CJ, Rosendaal FR. , et al. Predictors of the post-thrombotic syndrome with non-invasive venous examinations in patients 6 weeks after a first episode of deep vein thrombosis. J Thromb Haemost 2010; 8 (12) 2685-2692
- 7 Tick LW, Kramer MH, Rosendaal FR, Faber WR, Doggen CJ. Risk factors for post-thrombotic syndrome in patients with a first deep venous thrombosis. J Thromb Haemost 2008; 6 (12) 2075-2081
- 8 Appelen D, van Loo E, Prins MH, Neumann MH, Kolbach DN. Compression therapy for prevention of post-thrombotic syndrome. Cochrane Database Syst Rev 2017; 9: CD004174
- 9 Kearon C, Akl EA, Ornelas J. , et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016; 149 (02) 315-352
- 10 Amin EE, Bistervels IM, Meijer K. , et al. Reduced incidence of vein occlusion and postthrombotic syndrome after immediate compression for deep vein thrombosis. Blood 2018; 132 (21) 2298-2304
- 11 Watson L, Broderick C, Armon MP. Thrombolysis for acute deep vein thrombosis. Cochrane Database Syst Rev 2016; 11: CD002783
- 12 Comerota AJ, Paolini D. Treatment of acute iliofemoral deep venous thrombosis: a strategy of thrombus removal. Eur J Vasc Endovasc Surg 2007; 33 (03) 351-360
- 13 Enden T, Kløw NE, Sandvik L. , et al; CaVenT study group. Catheter-directed thrombolysis vs. anticoagulant therapy alone in deep vein thrombosis: results of an open randomized, controlled trial reporting on short-term patency. J Thromb Haemost 2009; 7 (08) 1268-1275
- 14 Parikh S, Motarjeme A, McNamara T. , et al. Ultrasound-accelerated thrombolysis for the treatment of deep vein thrombosis: initial clinical experience. J Vasc Interv Radiol 2008; 19 (04) 521-528
- 15 Motarjeme A. Ultrasound-enhanced thrombolysis. J Endovasc Ther 2007; 14 (02) 251-256
- 16 Notten P, Ten Cate-Hoek AJ, Arnoldussen CWKP. , et al. Ultrasound-accelerated catheter-directed thrombolysis versus anticoagulation for the prevention of post-thrombotic syndrome (CAVA): a single-blind, multicentre, randomised trial. Lancet Haematol 2020; 7 (01) e40-e49
- 17 Vedantham S, Goldhaber SZ, Julian JA. , et al; ATTRACT Trial Investigators. Pharmacomechanical catheter-directed thrombolysis for deep-vein thrombosis. N Engl J Med 2017; 377 (23) 2240-2252
- 18 Haig Y, Enden T, Grøtta O. , et al; CaVenT Study Group. Post-thrombotic syndrome after catheter-directed thrombolysis for deep vein thrombosis (CaVenT): 5-year follow-up results of an open-label, randomised controlled trial. Lancet Haematol 2016; 3 (02) e64-e71
- 19 Enden T, Haig Y, Kløw NE. , et al; CaVenT Study Group. 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 (9810): 31-38
- 20 Haig Y, Enden T, Slagsvold CE, Sandvik L, Sandset PM, Kløw NE. Determinants of early and long-term efficacy of catheter-directed thrombolysis in proximal deep vein thrombosis. J Vasc Interv Radiol 2013; 24 (01) 17-24 , quiz 26
- 21 Vedantham S, Sista AK, Klein SJ. , et al; Society of Interventional Radiology and Cardiovascular and Interventional Radiological Society of Europe Standards of Practice Committees. Quality improvement guidelines for the treatment of lower-extremity deep vein thrombosis with use of endovascular thrombus removal. J Vasc Interv Radiol 2014; 25 (09) 1317-1325
- 22 Kahn SR, Partsch H, Vedantham S, Prandoni P, Kearon C. ; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of post-thrombotic syndrome of the leg for use in clinical investigations: a recommendation for standardization. J Thromb Haemost 2009; 7 (05) 879-883
- 23 Kahn SR. Measurement properties of the Villalta scale to define and classify the severity of the post-thrombotic syndrome. J Thromb Haemost 2009; 7 (05) 884-888
- 24 Villalta SBP, Piccioli A, Lensing AW, Prins MH, Prandoni P. Assessment of validity and reproducibility of a clinical scale for the post-thrombotic syndrome. [Abstract]. Haemostasis 1994; 24: 158a
- 25 Rutherford RB, Padberg Jr FT, Comerota AJ, Kistner RL, Meissner MH, Moneta GL. Venous severity scoring: an adjunct to venous outcome assessment. J Vasc Surg 2000; 31 (06) 1307-1312
- 26 Aaronson NK, Muller M, Cohen PD. , et al. Translation, validation, and norming of the Dutch language version of the SF-36 Health Survey in community and chronic disease populations. J Clin Epidemiol 1998; 51 (11) 1055-1068
- 27 Brooks R. EuroQol: the current state of play. Health Policy 1996; 37 (01) 53-72
- 28 Bland JM, Dumville JC, Ashby RL. , et al. Validation of the VEINES-QOL quality of life instrument in venous leg ulcers: repeatability and validity study embedded in a randomised clinical trial. BMC Cardiovasc Disord 2015; 15: 85
- 29 van der Velden SK, Biemans AA, Nijsten T, Sommer A. Translation and validation of the Dutch VEINES-QOL/Sym in varicose vein patients. Phlebology 2014; 29 (04) 227-235
- 30 Lamping DL, Schroter S, Kurz X, Kahn SR, Abenhaim L. Evaluation of outcomes in chronic venous disorders of the leg: development of a scientifically rigorous, patient-reported measure of symptoms and quality of life. J Vasc Surg 2003; 37 (02) 410-419
- 31 Pollard CA. Preliminary validity study of the pain disability index. Percept Mot Skills 1984; 59 (03) 974
- 32 Strijkers RH, Arnoldussen CW, Wittens CH. Validation of the LET classification. Phlebology 2015; 30 (1, Suppl): 14-19
- 33 Norman GR, Sloan JA, Wyrwich KW. Interpretation of changes in health-related quality of life: the remarkable universality of half a standard deviation. Med Care 2003; 41 (05) 582-592
- 34 Walters SJ, Brazier JE. Comparison of the minimally important difference for two health state utility measures: EQ-5D and SF-6D. Qual Life Res 2005; 14 (06) 1523-1532
- 35 Petersohn S, Ramaekers BLT, Olie RH. , et al. Comparison of three generic quality-of-life metrics in peripheral arterial disease patients undergoing conservative and invasive treatments. Qual Life Res 2019; 28 (08) 2257-2279
- 36 Weinberg I, Vedantham S, Salter A. , et al; ATTRACT Trial Investigators. Relationships between the use of pharmacomechanical catheter-directed thrombolysis, sonographic findings, and clinical outcomes in patients with acute proximal DVT: results from the ATTRACT multicenter randomized trial. Vasc Med 2019; 24 (05) 442-451
- 37 White JM, Comerota AJ. Venous compression syndromes. Vasc Endovascular Surg 2017; 51 (03) 155-168
- 38 Comerota AJ, Grewal N, Martinez JT. , et al. Postthrombotic morbidity correlates with residual thrombus following catheter-directed thrombolysis for iliofemoral deep vein thrombosis. J Vasc Surg 2012; 55 (03) 768-773