CAVA (Ultrasound-Accelerated Catheter-Directed Thrombolysis on Preventing Post-Thrombotic Syndrome) Trial: Long-Term Follow-Up Results

Pascale Notten, André A E A de Smet, Lidwine W Tick, Marlène H W van de Poel, Otmar R M Wikkeling, Louis-Jean Vleming, Ad Koster, Kon-Siong G Jie, Esther M G Jacobs, Harm P Ebben, Michiel Coppens, Hugo Ten Cate, Cees H A Wittens, Arina J Ten Cate-Hoek, Pascale Notten, André A E A de Smet, Lidwine W Tick, Marlène H W van de Poel, Otmar R M Wikkeling, Louis-Jean Vleming, Ad Koster, Kon-Siong G Jie, Esther M G Jacobs, Harm P Ebben, Michiel Coppens, Hugo Ten Cate, Cees H A Wittens, Arina J Ten Cate-Hoek

Abstract

Background The CAVA (Ultrasound-Accelerated Catheter-Directed Thrombolysis Versus Anticoagulation for the Prevention of Post-Thrombotic Syndrome) trial did not show a reduction of post-thrombotic syndrome (PTS) after additional ultrasound-accelerated catheter-directed thrombolysis in patients with acute iliofemoral deep vein thrombosis at 1-year follow-up. This prespecified analysis of the CAVA trial aimed to determine the impact of additional thrombolysis on outcomes of PTS at long-term follow-up. Methods and Results Patients aged 18 to 85 years with a first-time acute iliofemoral deep vein thrombosis were included and randomly assigned (1:1) to either standard treatment plus ultrasound-accelerated catheter-directed thrombolysis or standard treatment alone. The primary outcome was the proportion of PTS (Villalta score ≥5 on 2 occasions ≥3 months apart or venous ulceration) at the final follow-up visit. Additionally, PTS according to the International Society on Thrombosis and Haemostasis (ISTH) consensus definition was assessed to allow external comparability. Major bleedings were the main safety outcome. At a median follow-up of 39.0 months (interquartile range, 23.3-63.8), 120 patients (79.8%) participated in the final follow-up visit: 62 from the intervention group and 58 from the standard treatment group. PTS developed in 19 (30.6%) versus 26 (44.8%) patients, respectively (odds ratio [OR], 0.54; 95% CI, 0.26 to 1.15 [P=0.11]), with an absolute difference between groups of -14.2% (95% CI, -32.0% to 4.8%). Using the ISTH consensus definition, a significant reduction in PTS was observed (29 [46.8%] versus 40 [69.0%]) (OR, 0.40; 95% CI, 0.19-0.84 [P=0.01]) with an absolute difference between groups of -22.2% (95% CI, -39.8% to -2.8%). No new major bleedings occurred following the 12-month follow-up. Conclusions The impact of additional ultrasound-accelerated catheter-directed thrombolysis on the prevention of PTS was found to increase with time. Although this study was limited by its sample size, the overall findings indicate a reduction of mild PTS without impact on quality of life. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00970619.

Keywords: Iliofemoral deep vein thrombosis; catheter‐directed thrombolysis; long‐term follow‐up; post‐thrombotic syndrome; quality of life.

Conflict of interest statement

Dr Coppens reports grants and personal fees from Bayer Daiichi Sankyo, CSL Behring; grants from Boehringer Ingelheim, Pfizer, Bristol‐Meyers Squibb, and Sanquin Blood Supply; and personal fees from Sobi, NovoNordisk, and UniQure, outside the submitted work. Dr ten Cate reports personal fees and other from Bayer; other from Pfizer and Coagulation profile; and personal fees from LEO Pharma, Gideon Pharmaceuticals, and Alveron Pharma, outside the submitted work. Dr Wittens reports grants from BTG International Group during the conduct of the study. None of the above‐mentioned organizations had any involvement in the design, conduct, analysis, or report of the study data. The remaining authors have no disclosures to report.

Figures

Figure 1. Trial profile.
Figure 1. Trial profile.

References

    1. Kahn SR, Shrier I, Julian JA, Ducruet T, Arsenault L, Miron MJ, Roussin A, Desmarais S, Joyal F, Kassis J, et al. Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis. Ann Intern Med. 2008;149:698–707. DOI: 10.7326/0003-4819-149-10-200811180-00004.
    1. Schulman S, Lindmarker P, Holmstrom M, Larfars G, Carlsson A, Nicol P, Svensson E, Ljungberg B, Viering S, Nordlander S, 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;4:734–742. DOI: 10.1111/j.1538-7836.2006.01795.x.
    1. 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. DOI: 10.1002/14651858.CD004174.pub3.
    1. Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, Huisman M, King CS, Morris TA, Sood N, et al. Antithrombotic therapy for vte disease: chest guideline and expert panel report. Chest. 2016;149:315–352. DOI: 10.1016/j.chest.2015.11.026.
    1. Tick LW, Doggen CJ, Rosendaal FR, Faber WR, Bousema MT, Mackaay AJ, van Balen P, Kramer MH. 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;8:2685–2692. DOI: 10.1111/j.1538-7836.2010.04065.x.
    1. Roumen‐Klappe EM, den Heijer M, Janssen MC, 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. DOI: 10.1160/TH05-03-0146.
    1. Prandoni P, Lensing AW, Prins MH, Frulla M, Marchiori A, Bernardi E, Tormene D, Mosena L, Pagnan A, Girolami A. Below‐knee elastic compression stockings to prevent the post‐thrombotic syndrome: a randomized, controlled trial. Ann Intern Med. 2004;141:249–256. DOI: 10.7326/0003-4819-141-4-200408170-00004.
    1. Enden T, Haig Y, Kløw NE, Slagsvold CE, Sandvik L, Ghanima W, Hafsahl G, Holme PA, Holmen LO, Njaastad AM, 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. DOI: 10.1016/S0140-6736(11)61753-4.
    1. Kahn SR, Shbaklo H, Lamping DL, Holcroft CA, Shrier I, Miron MJ, Roussin A, Desmarais S, Joyal F, Kassis J, et al. Determinants of health‐related quality of life during the 2 years following deep vein thrombosis. J Thromb Haemost. 2008;6:1105–1112. DOI: 10.1111/j.1538-7836.2008.03002.x.
    1. Ten Cate‐Hoek AJ, Toll DB, Büller HR, Hoes AW, Moons KG, Oudega R, Stoffers HE, van der Velde EF, van Weert HC, Prins MH, et al. Cost‐effectiveness of ruling out deep venous thrombosis in primary care versus care as usual. J Thromb Haemost. 2009;7:2042–2049. DOI: 10.1111/j.1538-7836.2009.03627.x.
    1. Haig Y, Enden T, Grøtta O, Kløw NE, Slagsvold CE, Ghanima W, Sandvik L, Hafsahl G, Holme PA, Holmen LO, et al. 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:e64–e71. DOI: 10.1016/S2352-3026(15)00248-3.
    1. Vedantham S, Goldhaber SZ, Julian JA, Kahn SR, Jaff MR, Cohen DJ, Magnuson E, Razavi MK, Comerota AJ, Gornik HL, et al. Pharmacomechanical catheter‐directed thrombolysis for deep‐vein thrombosis. N Engl J Med. 2017;377:2240–2252. DOI: 10.1056/NEJMoa1615066.
    1. Strijkers RH, Arnoldussen CW, Wittens CH. Validation of the let classification. Phlebology. 2015;30:14–19. DOI: 10.1177/0268355515569133.
    1. Comerota AJ, Kearon C, Gu CS, Julian JA, Goldhaber SZ, Kahn SR, Jaff MR, Razavi MK, Kindzelski AL, Bashir R, et al. Endovascular thrombus removal for acute iliofemoral deep vein thrombosis. Circulation. 2019;139:1162–1173. DOI: 10.1161/CIRCULATIONAHA.118.037425.
    1. Notten P, Ten Cate‐Hoek AJ, Arnoldussen C, Strijkers RH, de Smet A, Tick LW, van de Poel MH, Wikkeling OR, Vleming LJ, Koster A, 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:e40–e49. doi: 10.1016/S2352-3026(19)30209-1.
    1. Notten P, Arnoldussen C, Brans R, de Smet AA, Tick LW, van de Poel MH, Wikkeling OR, Vleming LJ, Koster A, Jie KG, et al. Association of successful ultrasound‐accelerated catheter‐directed thrombolysis with post‐thrombotic syndrome: a post‐hoc analysis of the CAVA trial. Thromb Haemost. 2020;120:1188–1199. DOI: 10.1055/s-0040-1713171.
    1. Kahn SR, Partsch H, Vedantham S, Prandoni P, Kearon C. Definition of post‐thrombotic syndrome of the leg for use in clinical investigations: a recommendation for standardization. J Thromb Haemost. 2009;7:879–883. DOI: 10.1111/j.1538-7836.2009.03294.x.
    1. Villalta S, Bagatella P, 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.
    1. Rutherford RB, Padberg FT Jr, Comerota AJ, Kistner RL, Meissner MH, Moneta GL. Venous severity scoring: an adjunct to venous outcome assessment. J Vasc Surg. 2000;31:1307–1312. DOI: 10.1067/mva.2000.107094.
    1. Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non‐surgical patients. J Thromb Haemost. 2005;3:692–694. DOI: 10.1111/j.1538-7836.2005.01204.x.
    1. Aaronson NK, Muller M, Cohen PD, Essink‐Bot ML, Fekkes M, Sanderman R, Sprangers MA, te Velde A, Verrips E. 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;51:1055–1068. DOI: 10.1016/S0895-4356(98)00097-3.
    1. Brooks R. Euroqol: the current state of play. Health Policy. 1996;37:53–72. DOI: 10.1016/0168-8510(96)00822-6.
    1. Pollard CA. Preliminary validity study of the pain disability index. Percept Mot Skills. 1984;59:974. DOI: 10.2466/pms.1984.59.3.974.
    1. 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;29:227–235. DOI: 10.1177/0268355513476279.
    1. 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;37:410–419. DOI: 10.1067/mva.2003.152.
    1. Bland JM, Dumville JC, Ashby RL, Gabe R, Stubbs N, Adderley U, Kang'ombe AR, Cullum NA. 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. DOI: 10.1186/s12872-015-0080-7.
    1. Arnoldussen CW, Wittens CH. An imaging approach to deep vein thrombosis and the lower extremity thrombosis classification. Phlebology. 2012;27:143–148. DOI: 10.1258/phleb.2012.012s25.
    1. 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;14:1523–1532. DOI: 10.1007/s11136-004-7713-0.
    1. 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;41:582–592. DOI: 10.1097/01.MLR.0000062554.74615.4C.
    1. Porter JM, Moneta GL. Reporting standards in venous disease: an update. International Consensus Committee on Chronic Venous Disease. J Vasc Surg. 1995;21:635–645. DOI: 10.1016/S0741-5214(95)70195-8.

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