Azlina Amir Abbas, Chee Ken Chan, Cihan Ay, Mikel Sadek.

Response/Recommendation: Despite the lack of evidence in the literature to establish a role for thrombolysis in patients with postoperative venous thromboembolism (VTE), there is a potential role for thrombolysis among select patients. Thrombolysis should be considered, with attention to iatrogenic bleeding and hematoma risk, among postoperative patients in the following circumstances:

1. Limb threatening deep venous thrombosis (DVT) with acute limb ischemia (e.g., phlegmasia cerulea dolens).
2. For selected patients at low risk for bleeding with symptomatic DVT involving the iliofemoral veins and at higher risk for severe post thrombotic syndrome (PTS).

Strength of Recommendation: Consensus.

Rationale: Treatment of VTE has seen advances with the introduction of newer anticoagulants over the years. Nevertheless, despite newer therapeutical modalities, studies have reported that up to 60% of patients with VTE suffer from PTS, with up to 10% suffering severe PTS¹. PTS is a chronic debilitating condition resulting from incomplete clot dissolution causing venous obstruction and valvular reflux, leading to venous hypertension^2,3. These in turn may lead to limb swelling, pain, pigmentation, and development of venous ulcers.

There is some evidence that thrombolysis reduces the risk of developing PTS in patients with VTE, thereby improving quality of life^4,5. The aims of thrombolysis in acute VTE are to reduce thrombus burden, restore patency of the vein, and thereby prevent venous congestion⁴. Options for removal of the thrombus include:

1. Systemic thrombolysis: patients receive intravenous infusion of thrombolytic agents resulting in clot lysis. Commonly used agents include streptokinase, urokinase and alteplase⁶.
2. Catheter directed thrombolysis (CDT): delivery of a thrombolytic drug through a multiple side hole catheter positioned directly into the thrombosed vein⁷. It results in more directed thrombolysis and is used mainly for DVT alone.
3. Pharmacomechanical catheter directed thrombolysis (PCDT): procedures combining the use of lytic infusion for thrombolysis with adjunctive catheter-based devices to promote mechanical removal of thrombus⁷. Adjunctive procedures include balloon maceration, catheter aspiration, suction thrombectomy, percutaneous transluminal balloon venoplasty, stent placement, intravascular ultrasound, or some combination thereof. Some of the novel technologies use mechanical thrombectomy exclusively, thereby reducing the need for lytic agents and theoretically reducing the bleeding risk.

As the effect of thrombolysis is to remove blood clots, the main concern with thrombolytic therapy in all patients, especially post-operative, is that of major bleeding. Patients should be risk-stratified to determine those who would likely benefit from invasive treatment. Among the factors clinicians should consider are:

• Estimated risk of bleeding.
• Clinical severity of DVT.
• Anatomic extent of DVT.
• General medical evaluation including life-expectancy baseline ambulatory capacity and comorbidities.

To date, there have been 4 randomized clinical trials (RCT) examining the effectiveness of early thrombus removal strategies:

• TORPEDO (Thrombus Obliteration by Rapid Percutaneous Endovenous Intervention in Deep Venous Occlusion)⁸.
• CaVENT (Catheter-Directed Venous Thrombolysis in Acute Iliofemoral Vein Thrombosis)⁹.
• ATTRACT (Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis)¹⁰.
• CAVA (CAtheter Versus Anticoagulation Alone for Acute Primary Iliofemoral DVT)¹¹.

The RCT compared anticoagulation alone as standard treatment arm versus CDT (CaVENT and TORPEDO), PCDT (ATTRACT), or ultrasound accelerated CDT (CAVA). The important outcome measures from these trials are summarized:

1. PTS rates: The CaVENT and TORPEDO trials reported a significant reduction in incidence of PTS, but the ATTRACT and CAVA trials did not detect a significant difference in PTS rates between the intervention and control group, although the ATTRACT trial did report a significant reduction in moderate-severe PTS at 24 months.
2. Major bleeding: The CaVENT, ATTRACT and CAVA trial investigators reported an increased incidence of major bleeding in the intervention groups compared to the control groups. The TORPEDO trial investigators did not observe this in their study and postulated that it might be due to the lower doses of tissue plasminogen activator (tPA) and heparin used compared to other studies.
3. Recurrent VTE: The incidence of recurrent VTE was significantly reduced in the TORPEDO trial, and this benefit extended beyond 2.5 years. However, the ATTRACT trial reported no difference in recurrent VTE rates at 2-year follow-up.
4. Quality of life (QOL): The ATTRACT, CaVenT, and CAVA trials did not report a significant difference in quality-of-life scores between the 2 groups. Understandably, patients who had more severe PTS reported worse QOL scores.

An updated meta-analysis by Broderick, et al.⁵, comparing thrombolytic strategies against standard anticoagulation for acute DVT of the lower limb reviewed 19 randomized controlled trials with 1,943 participants. The thrombolytic strategies included systemic, loco-regional, and CDT. Complete thrombolysis occurred more frequently in the thrombolysis group at early and intermediate follow-up, and no differences were found between the thrombolysis treatments at any time point. The thrombolysis group had increased bleeding complications compared to anticoagulation alone (6.7% vs. 2.2%), but no differences were detected between the different thrombolysis treatments.

It is important to note that these four trials and more recent meta-analysis all specifically excluded postoperative patients, thereby limiting applicability to postoperative orthopaedic patients. However, recent surgery is not generally considered an absolute contraindication to thrombolysis and is appropriate in the setting of active or high-risk limb ischemia. In reviewing the available literature on thrombolysis, the European Society for Vascular Surgery (ESVS) 2021 clinical practice guidelines on the management of VTE summarized by consensus that thrombolytic therapies should be limited to patients at the highest risk of developing PTS (i.e., extensive clot burden, including the iliofemoral level), with a high chance of technical success (i.e., within two weeks of onset and no obvious post-thrombotic lesions) and low bleeding risk⁷. The American Society of Hematology (ASH) 2020 guidelines for the management of VTE¹² similarly recommended that thrombolysis should be limited to patients with proximal DVT (iliofemoral veins), limb-threatening phlegmasia cerulea dolens, and pulmonary embolism (PE) with hemodynamic compromise and concomitant cardiopulmonary disease (submassive PE). Additionally, due to low certainty in the evidence of effect, CDT is considered superior to systemic thrombolysis for extensive DVT¹². The review specifically excluded postoperative patients.

References:

1. Sharma N, Bedi VS, Agarwal S, Yadav A, Satwik A, Agarwal D, et al. A comparison of pharmacomechanical catheter-directed thrombolysis versus anticoagulation alone in the prevention of postthrombotic syndrome following acute lower limb deep-vein thrombosis. Indian J Vasc Endovasc Surg 2019;6:248-55.
2. Tang A, Lakhter V, Zack CJ, Comerota AJ, Shah N, Zhao H, Bashir R. Contemporary nationwide trends and in-hospital outcomes of adjunctive stenting in patients undergoing catheter-directed thrombolysis for proximal deep venous thrombosis. J Vasc Surg Venous Lymphat Disord. 2021 Jan;9(1):62-72.e1. doi: 10.1016/j.jvsv.2020.04.034. Epub 2020 Jun 6. PMID: 32522616.
3. Abd El-Mabood ESA, Sorour WA. Acute iliofemoral deep vein thrombosis: does catheter-directed thrombolysis affect outcomes? Egypt J Surg 2020;39:325-37
4. Vedantham S, Piazza G, Sista AK, Goldenberg NA. Guidance for the use of thrombolytic therapy for the treatment of venous thromboembolism. J Thromb Thrombolysis. 2016;41(1):68-80. doi:10.1007/s11239-015-1318-z
5. Broderick C, Watson L, Armon MP. Thrombolytic strategies versus standard anticoagulation for acute deep vein thrombosis of the lower limb. Cochrane Database of Systematic Reviews 2021, Issue 1. Art. No.: CD002783. DOI: 10.1002/14651858.CD002783.pub5.
6. Martin C, Sobolewski K, Bridgeman P, Boutsikaris D. Systemic Thrombolysis for Pulmonary Embolism: A Review. P T. 2016;41(12):770-775.
7. Kakkos SK, Gohel M, Baekgaard N, Bauersachs R, Bellmunt-Montoya S, Black SA, Ten Cate-Hoek AJ, Elalamy I, Enzmann FK, Geroulakos G, Gottsäter A, Hunt BJ, Mansilha A, Nicolaides AN, Sandset PM, Stansby G, Esvs Guidelines Committee, de Borst GJ, Bastos Gonçalves F, Chakfé N, Hinchliffe R, Kolh P, Koncar I, Lindholt JS, Tulamo R, Twine CP, Vermassen F, Wanhainen A, Document Reviewers, De Maeseneer MG, Comerota AJ, Gloviczki P, Kruip MJHA, Monreal M, Prandoni P, Vega de Ceniga M. Editor’s Choice – European Society for Vascular Surgery (ESVS) 2021 Clinical Practice Guidelines on the Management of Venous Thrombosis. Eur J Vasc Endovasc Surg. 2021 Jan;61(1):9-82. doi: 10.1016/j.ejvs.2020.09.023. Epub 2020 Dec 15. PMID: 33334670.
8. Sharifi M, Bay C, Mehdipour M, Sharifi J; TORPEDO Investigators. Thrombus Obliteration by Rapid Percutaneous Endovenous Intervention in Deep Venous Occlusion (TORPEDO) trial: midterm results. J Endovasc Ther. 2012 Apr;19(2):273-80. doi: 10.1583/11-3674MR.1. PMID: 22545895.
9. Haig Y, Enden T, Grøtta O, Kløw NE, Slagsvold CE, Ghanima W, Sandvik L, Hafsahl G, Holme PA, Holmen LO, Njaaastad AM, Sandbæk G, Sandset PM; 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 Feb;3(2):e64-71. doi: 10.1016/S2352-3026(15)00248-3. Epub 2016 Jan 6. PMID: 26853645.
10. Vedantham S, Goldhaber SZ, Julian JA, Kahn SR, Jaff MR, Cohen DJ, Magnuson E, Razavi MK, Comerota AJ, Gornik HL, Murphy TP, Lewis L, Duncan JR, Nieters P, Derfler MC, Filion M, Gu CS, Kee S, Schneider J, Saad N, Blinder M, Moll S, Sacks D, Lin J, Rundback J, Garcia M, Razdan R, VanderWoude E, Marques V, Kearon C; ATTRACT Trial Investigators. Pharmacomechanical Catheter-Directed Thrombolysis for Deep-Vein Thrombosis. N Engl J Med. 2017 Dec 7;377(23):2240-2252. doi: 10.1056/NEJMoa1615066. PMID: 29211671; PMCID: PMC5763501.
11. Notten P, Ten Cate-Hoek AJ, Arnoldussen CWKP, Strijkers RHW, de Smet AAEA, Tick LW, van de Poel MHW, Wikkeling ORM, Vleming LJ, Koster A, Jie KG, Jacobs EMG, Ebben HP, Coppens M, Toonder I, Ten Cate H, Wittens CHA. Ultrasound-accelerated catheter-directed thrombolysis versus anticoagulation for the prevention of post-thrombotic syndrome (CAVA): a single-blind, multicentre, randomised trial. Lancet Haematol. 2020 Jan;7(1):e40-e49. doi: 10.1016/S2352-3026(19)30209-1. Epub 2019 Nov 27. PMID: 31786086.
12. Thomas L. Ortel, Ignacio Neumann, Walter Ageno, Rebecca Beyth, Nathan P. Clark, Adam Cuker, Barbara A. Hutten, Michael R. Jaff, Veena Manja, Sam Schulman, Caitlin Thurston, Suresh Vedantham, Peter Verhamme, Daniel M. Witt, Ivan D. Florez, Ariel Izcovich, Robby Nieuwlaat, Stephanie Ross, Holger J. Schünemann, Wojtek Wiercioch, Yuan Zhang, Yuqing Zhang; American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv 2020; 4 (19): 4693–4738. doi: https://doi.org/10.1182/bloodadvances.2020001830