Reducing post-thrombotic syndrome using PMT

Early thrombus removal strategies in iliofemoral DVT reduce the incidence of post-thrombotic syndrome, but further work is needed to determine whether a quality of life benefit is conferred

Andrew Busuttil MD MRCS

Joseph Shalhoub BSc MBBS MRCS FHEA PhD

Alun Davies MA DM DSc FRCS FHEA FEBVS FACPH

Section of Vascular Surgery

Department of Surgery & Cancer,

Imperial College London, 

4 East Charing Cross Hospital, London, UK

The treatment of deep venous thrombosis (DVT) is undergoing a shift in priorities. The mortality related to DVT, in most instances due to pulmonary embolism (PE), has seen a sharp fall since the introduction of anticoagulants and has remained relatively stable since.1 As patients live longer after having had a DVT, the long-term effects of DVT have come into focus.

The post-thrombotic syndrome (PTS) represents the symptoms and signs individuals can experience following a DVT, and is seen in up to 30% of patients who have had a DVT.2 Two implicated pathophysiological processes are centred around the inflammatory response generated by the presence of a thrombus. This results in scarring of valves leading to impaired valvular function and venous reflux, and if thrombus resolution is incomplete, venous outflow obstruction ensues. Both these circumstances result in venous hypertension, which may manifest as limb swelling, skin changes, discomfort, aching and itching, pain on walking (venous claudication) and ulceration. PTS presents with varying degrees of severity and varying impacts on individuals’ quality of life (QoL).3

It is estimated that approximately 2% of the annual healthcare budgets of developed countries is spent on treating chronic venous insufficiency (CVI).4 PTS, as a cause of secondary CVI, is considerably more common than primary CVI. When considering the burden of lower limb ulceration secondary to PTS, including direct and indirect costs to the health service and the quality of life implications to individuals, efforts have been aimed at trying to reduce the incidence of PTS following DVT.5

Taking into account the aetiology of secondary PTS, early thrombus removal strategies have been developed to attenuate the haemodynamic and inflammatory consequences of deep venous clot burden. This concept is not a new one, with open venous thrombectomy being performed since the 1960s. Whereas technical success was high, the morbidity associated with the procedure, in particular when compared with oral anticoagulants, and the lack of large randomised controlled trials meant that this procedure is rarely performed in modern practice.1

The advent of pharmacotherapeutics such as streptokinase and, later, recombinant tissue plasminogen activator, led to their widespread use via a systemic route of administration. Early trials examining the long-term outcome of iliofemoral DVT patients being treated with systemic thrombolytic agents, reported mixed degrees of success. Whilst thrombus resolution rates were improving dramatically, complications related to systemic lysis made the procedure a risky one. A number of case series reported fatal intracranial haemorrhages and bleeding complications and this quickly resulted in systemic thrombolysis falling out of favour.1

Analysing the morbidity and mortality from this treatment modality, one could deduce that patient selection was not optimal and doses of thrombolytic agent were very high. This paved the way for the development of catheter-directed thrombolysis (CDT) and pharmacomechanical thrombolysis (PMT) which facilitated early thrombus removal with fewer adverse effects.

Current guidance

The UK National Institute of Health and Care Excellence (NICE),6 the US Society for Vascular Surgery (SVS), the American Venous Forum (AVF)7 and American College of Chest Physicians (ACCP)8 have all issued extensive guidance on the management of venous thromboembolism pertaining to the iliofemoral system, incorporating recent trials and methods of treatment.

The overall consensus from NICE and the SVS/AVF is that patients with iliofemoral DVT should be considered for CDT if the following criteria are met:

• Symptoms are less than 14 days in duration
• Premorbid mobility is good
• Patient life expectancy is expected to be greater than 1 year
• Risk of bleeding is low and the patient does not have contraindications to thrombolytic therapy
• First episode DVT

The current ACCP recommendation is that proximal DVTs should be treated with oral anticoagulation in the traditional fashion, suggesting that the patients who would benefit from CDT would be the ones who attach a higher value to the prevention of PTS and would not be concerned about the high cost, complexity and the risk of bleeding. The group reporting the ACCP guidance cites the evidence in relation to CDT as being Grade 2C (weak recommendation and poor evidence to support this). This is a change from their 2008 guidance document,9 which recommended CDT where the facilities are available.

The level of evidence upon which the guidance from each of the three groups has been based is not level 1, despite being derived from randomised control trials. The majority of the recommendations are listed as Grade 2C.

With regard to the timing of early thrombus removal, it is thought that procedures carried out within 14 days of the development of symptoms have a higher success rates, as thrombus is likely to be softer and less organised. However trials such as the CaVenT study10 included patients who experienced symptoms for up to 21 days. The on-going ATTRACT11 trial is including patients who have had symptoms for up to 14 days. The evidence for the timing for thrombus removal is not robust and further work is needed in order to clarify this.

Techniques available for PMT

PMT was developed to reduce the dose of lytic agent and to in turn lower the number and severity of bleeding complications, shorten the intensive care, high dependency and overall hospital inpatient stay and improve thrombus clearance. PMT has proven to be safe and not to cause additional injury to the venous valves when compared to CDT alone. PMT has resulted in a reduction in intensive care unit length of stay (0.6 days versus 2.4 days, p<0.04), a reduced overall hospitalisation length of stay (4.6 days versus 8.4 days, p<0.020),10 and a significant decrease the cost. 

Rotational devices, such as the Amplatz Thrombectomy Device (Microvena, White Bear Lake, Minneapolis, USA), Straub Rotarex (Straub Medical, Wangs, Switzerland) and the Trerotola Percutaneous Thrombectomy Device (Arrow International, Reading, Philadelphia, USA) use a high velocity rotational helix or wire to fragment the thrombus.

Isolated pharmacomechanical thrombolysis with the Trellis-8 device (Covidien, Dublin, Ireland) uses a rotational sinusoidal wire between and proximal and distal balloon located 15–30cm apart in order to allow a more localised infusion of thrombolytic agent and reduce the risk of PE. Mechanical fragmentation is followed by aspiration. 

Rheolytic devices like Angiojet (Boston Scientific, Massachusetts, USA) deliver a high-pressure saline jet and rely on the Bernoulli principle for fragmentation of the thrombus and redirection of flow and debris into an outflow channel. The device, therefore, has two lumina: a central lumen for infusion and a larger outer lumen for aspiration.

Ultrasound-accelerated CDT is an alternative modality, which can be employed as an adjunct or as a standalone treatment. Ultrasound cavitation weakens the fibrin structure of thrombi and improves penetration of the lytic agent. The procedure length for ultrasound-accelerated CDT is approximately 6–43 hours. The benefits of this approach are shorter treatment duration, lower dose of lytic agent, reduced risk of PE and reduced intravenous contrast use.

Recent and ongoing trials

There have been a number studies looking into the safety and efficacy of early thrombus removal, but few that have followed patients up with regard to the long-term effects and benefits in relation to prevention of PTS.

The CaVenT study revealed that there is a 14.4% absolute risk reduction in PTS development in patients treated with either CDT or PMT for iliofemoral DVT at two years.10 This, coupled with a favourable safety profile, is prompting more and more units to offer early thrombus removal to patients fulfilling treatment criteria. One must consider the impact of adopting this management strategy on a health service. Patients with CDT have a longer inpatient stay, with the need for level 2 care during the lysis period. Comparatively, PMT requires less monitoring and, while the procedures do last longer, the inpatient stay is often shorter. Most healthcare providers and commissioners focus on cost effectiveness of procedures and, in the case of early thrombus removal, preventing PTS would be thought to improve quality of life substantially and potentially be accompanied by an attenuated cost of PTS care in the longer term.7

The CaVenT study was the first large randomised study to compare CDT to standard treatment alone and prove its safety and efficacy. The primary endpoint was the incidence of PTS at 24 months. The investigators showed a 14.4% absolute risk reduction of PTS (95% CI 0.2–27.9, p=0.047) for patients allocated thrombolytic therapy compared to the standard group, and the number needed to treat was seven (95% CI 4–502). Bleeding complications were higher in the CDT group (although no episodes of intracranial haemorrhage were reported). The mean in-hospital duration of CDT treatment was 2.4 days (and 1.1 days for standard treatment) and the average hospitalisation was 5.3 days for CDT while it was 4.2 days for standard treatment. Secondary endpoints evaluated in the study were quality of life, estimated by s EQ-5D and c VEINES-QOL/Sym instruments, sickness benefits as well as quality-adjusted life years (QALYs). QoL did not differ between the two groups. Cost estimation included hospital costs, treatments costs and transportation and it was found to be likely lower in the thrombolysis group.10,12

The ATTRACT (Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis)11 trial is a randomised multicentre trial, funded by the National Heart Lung and Blood Institute (NHLBI)/National Institutes of Health (NIH), which aims to evaluate the superiority of PMT +/- CDT to conventional medical treatment alone. The primary endpoint will be the incidence of PTS between six months and 24 months. Safety, imaging and cost effectiveness outcomes will also be recorded. ATTRACT is expected to determine the long-term clinical impact and socioeconomic impact of endovascular thrombolysis in proximal DVT.

The CAVA (CAtheter Versus Anticoagulation) trial is a randomised controlled Dutch multicentre trial comparing ultrasound-accelerated catheter-directed thrombolysis and standard anticoagulant therapy, with standard anticoagulant therapy alone, in acute primary iliofemoral DVT.

Other single arm studies are ongoing, using new devices or protocols. The SPADE study (Single Session Percutaneous Mechanical Thrombectomy for the Treatment of Iliofemoral Deep Vein Thrombosis: A Preliminary Evaluation), conducted by the Ottawa Hospital Research Institute, will compare a single PMT session using Angiojet without adjuvant thrombolysis to standard treatment. After the completion of the procedure patients are expected to remain in hospital for no more than six hours.

Further areas of research

Whilst results for the ATTRACT and CAVA trials are eagerly awaited, further study is needed into this treatment modality. A number of questions remain, namely with the use of adjuvant anticoagulants in particular the duration of treatment following such interventions. Whereas the general safety of the various procedures is acceptable, further work is needed to ascertain the need for perioperative inferior vena cava interruption, as to date only one randomised controlled trial has been performed looking into this.

Conclusion

Percutaneous endovenous treatment for acute DVT has risen in popularity but one must proceed with caution when considering patients for this treatment modality. The risks of bleeding, catheter related infections (if left indwelling) and the theoretical risk of intracranial haemorrhage have the potential to be devastating. Whilst undoubtedly thrombus resolution rates are better, if there is no improvement in quality of life outcomes at two years, it is clear that further work is needed in order to clarify the benefit expected by such procedures.

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