review

Changing paradigms in the management of deep vein thrombosis Kathryn J. Lang,1 Prakash Saha,2 Lara N. Roberts1 and Roopen Arya1 1

King’s Thrombosis Centre, King’s College Hospital NHS Foundation Trust, and 2Guy’s Hospital, Guy’s and St. Thomas’ NHS Foundation Trust, London, UK

Summary In adults diagnosed with deep vein thrombosis (DVT), challenges remain in the management of the acute event whilst remaining alert to long-term morbidity. The addition of non-vitamin K antagonist oral anticoagulants (NOACs) to the pharmacopoeia represents the first of a number of recent advancements in the management of DVT. Worldwide, uptake of these agents has been avid, although drug selection, reversal and chronic treatment effects continue to be controversial areas. Multi-centre studies to evaluate the impact of NOACs on long-term outcomes, including thrombosis recurrence and post-thrombotic syndrome (PTS), are ongoing. Validation of tools capable of predicting PTS would enable patient selection for early aggressive intervention, such as local thrombolysis. Such interventional strategies are gaining momentum as initial approaches and would benefit from large randomized controlled trials. Keywords: anticoagulation, deep vein thrombosis, non-vitamin K antagonist oral anticoagulant(s), post-thrombotic syndrome, thrombolysis. Management of deep vein thrombosis (DVT) remained unchanged for many years, confined largely to a combination of vitamin K antagonist (VKA) therapy and compression hosiery. Whilst a significant healthcare burden, an accurate measure of the true incidence of venous thromboembolism (VTE) remains elusive as variations in healthcare data, as well as a trend away from post-mortem examinations, contribute to a fundamental lack of data. Three large-scale registry studies have reported the incidence of DVT to be between 0
93 and 1
48 per 1000 population (Oger, 2000; Naess et al, 2007; Spencer et al, 2009), The study reported by Oger (2000), comprising 342 000 patients in western France, found the combined incidence of DVT and pulmonary

Correspondence: Dr Kathryn Lang, Department of Haematological Medicine, King’s College Hospital NHS Foundation Trust, Denmark Hill, London SE5 9RS, UK. E-mail: [email protected]

First published online 19 April 2015 doi: 10.1111/bjh.13431

embolism (PE) in patients over the age of 75 years to be much higher, at 1 in 100. One-year mortality following a diagnosis of DVT is reported as between 9
7% and 14
6% (Heit et al, 1999; Naess et al, 2007; Kobberøe Søgaard et al, 2014). Danish registry data shows mortality at 30 d post-DVT to be 3% vs. 0
4% across the same period in a control cohort (Kobberøe Søgaard et al, 2014). The same study showed that patients with ‘classic’ risk factors (malignancy, recent surgery, trauma) had markedly elevated 30-d mortality rates with pre-existing comorbidity shown not to contribute significantly to this excess (Kobberøe Søgaard et al, 2014). PE is the best recognized complication of DVT and would contribute to the observed excess mortality. Important but less common acute complications include paradoxical embolism, causing cryptogenic embolic stroke (Cramer et al, 2004), and the limb-threatening condition, phlegmasia cerulea dolens (Perkins et al, 1996). Burgeoning pharmacological options have driven a renaissance in the field. Rivaroxaban was the first non-vitamin K antagonist oral anticoagulant (NOAC) to be licensed for the treatment of acute VTE in 2012 (http://www.xarelto.com/ html/downloads/2015-01_XRL_SPC_Jan2015_F1_low.pdf). Large randomized controlled trials of NOACs have demonstrated both universal non-inferiority to standard therapy in the treatment and prevention of thrombosis recurrence and an advantageous safety profile when compared with VKAs (Schulman et al, 2009; Bauersachs et al, 2010a; Agnelli et al, 2013; B€ uller et al, 2013). NOACs appear to ensure early and consistent attainment of anticoagulation during the crucial first month of treatment, as opposed to the often-variable anticoagulation intensity in the early phase of warfarin initiation. Could the NOACs reduce long-term morbidity for patients with DVT and, if so, which agent should we choose? Whilst the initial treatment of DVT focuses on prevention of clot propagation with anticoagulation, delayed venous recanalization and residual thrombosis may result in valvular incompetence, venous hypertension and subsequent postthrombotic syndrome (PTS) (Gonzalez-Fajardo et al, 2008). PTS is well-described and has significant morbidity and healthcare-associated costs (Prandoni, 2012; Roberts et al, 2014). Valve damage and subsequent incompetence is not, ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 162–174

Review however, an inevitable consequence of thrombosis. Although clot lysis and vein recanalization is estimated to occur in more than 90% of proximal DVTs by 12 months, patients with shorter natural recanalization times have an improved clinical outcome (Franzeck et al, 1997). Rapid and durable lysis is, however, more likely with surgical methods of clearance (Marder et al, 1977; Franzeck et al, 1996; Harenberg et al, 2002; Puskas et al, 2007), resulting in a lower residual thrombotic burden and a 21% relative reduction in rates of PTS (Watson et al, 2014). It remains unclear whom catheterdirected thrombolysis (CDT) and other invasive therapies for DVT will most benefit. Ongoing management of patients with DVT includes the identification and attenuation of risk factors for thrombosis. While decisions regarding duration of anticoagulation are individualized to each patient (taking into account the circumstances of the thrombotic event), the optimum duration of anticoagulation has yet to be elucidated. Thrombosis recurrence occurs in 20–30% after 5 years following unprovoked DVT (Hansson et al, 2000; Schulman et al, 2006; Prandoni et al, 2007) with attendant cumulative morbidity. Although a number of methods for the prediction of recurrence have been proposed, including measurement of Ddimers, quantification of residual thrombosis by ultrasonography and clinical risk scoring, or through a combination of several measures (Rodger et al, 2008; Cosmi et al, 2010a; Siragusa et al, 2011; Tosetto et al, 2012; Eichinger et al, 2014), to date, none have been prospectively validated. A combination of increased recognition amongst clinicians and clear public health interest in reducing the rate of chronic complications has driven developments in both scoring systems for the prediction and initial treatments aimed at reducing long-term adverse outcomes. This review evaluates the shifting paradigm in the treatment of DVT, from the current focus on acute treatment to new and emerging options that seek to minimize early morbidity and mortality and optimize long-term outcomes for patients.

Diagnostic algorithms and modalities Guidelines published by the National Institute of Health and Clinical Excellence (NICE) and the American College of Chest Physicians (ACCP) recommend compression ultrasonography (CUS) for the diagnosis of DVT (Bates et al, 2012; NICE Guidelines, 2012). Bilateral scanning is usually unnecessary as patients rarely have a DVT in the contralateral asymptomatic leg, with studies suggesting that confining scanning to a symptomatic leg would miss DVT in only 0
8% of cases (Strothman et al, 1994; Pennell et al, 2008). Controversy exists in the optimum management of patients with high pre-test probability subsequently found to have negative or inconclusive CUS. National guidelines (Bates et al, 2012; NICE Guidelines, 2012) recommend serial CUS in this circumstance (where D-dimer is positive or not performed), although meta-analysis of 4731 patients with a ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 162–174

single negative whole leg CUS found a subsequent VTE rate of only 0
57% (range, 0
25–0
89%) at 3 months follow-up (Johnson et al, 2010). A single instance of whole leg CUS can therefore adequately rule out DVT without the need for serial ultrasonography (Horner et al, 2014). Alternative imaging modalities for diagnosis of DVT include magnetic resonance direct thrombin imaging (MRDTI), magnetic resonance venography (MRV) and plethysmography. Tan et al (2014) showed that MRDTI is a highly accurate technique for imaging and can determine the age of the thrombosis, but this highly specialized technique is unlikely to progress to routine clinical care (Kelly et al, 2003). The PIOPED III (Prospective Investigation of Pulmonary Embolism Diagnosis III) researchers found that noncontrast magnetic resonance angiography (MRA) in isolation for the detection of DVT yielded a sensitivity of 78% with a specificity of 99% (Stein et al, 2010). When MRV and MRA were combined, sensitivity and specificity rose to 92% and 96% respectively, though technical inadequacy affected more than half of scans (Stein et al, 2010). Computerized strain gauge plethysmography (CSGP) is an older technique employing a pressurized cuff around the thigh, providing an indirect measure of venous outflow against venous capacitance and providing an operator-independent measure of presence or absence of thrombosis. False positive results are possible where there is external compression, such as from masses or venous congestion (Locker et al, 2006). The appeal is clear in that outpatient management can be facilitated and hastened by a diagnostic algorithm that reduces the need for radiology services; however it remains a controversial technique and studies combining CSGP with risk scoring systems are able only to achieve sensitivity of 52
8% and a negative predictive value of 86
7%. CSGP performs slightly better in its sensitivity for above knee thrombosis (73
7%) than below-knee (29
4%) (Siau et al, 2010). Reliable identification of patients with high pre-test probability of DVT who warrant referral for imaging is desirable. The Wells’ score is widely used but remains user-dependent and can over-predict thrombosis in less experienced hands (Wells et al, 1997; Penaloza et al, 2013). A later modification of the Wells’ score, the so-called two level test, used negative D-dimer results to safely omit ultrasonography from 38% of low-risk cases and only 0
4% of this group went on to develop VTE (Wells et al, 2003). As an alternative to the Wells’ score, the simplified Primary Care Rule has been developed using multivariate analysis of clinical and laboratory features of 1295 patients referred from primary care for ultrasound investigation (Oudega et al, 2005). This method uses point-of-care D-dimer testing. Validation of the score, performed in Dutch primary care facilities in 2009 showed that only 1
4% of patients developed VTE during 3 months of follow-up, comparing favourably with similar prediction rules (Buller et al, 2009). Direct comparison of the two scores showed a statistically significant (P < 0
001) tendency to over-prediction 163

Review using the Wells’ score, with 55% referred for ultrasonography compared with 51% using the Primary Care Rule. Subsequently, DVT occurred in low-risk patients at an incidence of 1
6% with the Wells’ score and 1
4% with the Primary Care Rule (Velde et al, 2011). The three scoring systems are summarized in Table I. D-dimer quantification above the upper limit of normal independently correlates with increased risk of both VTE and all-cause mortality (Halaby et al, 2014). Both qualitative and quantitative D-dimer assays can add specificity to clinical risk scores; 3-month follow-up of 5000 patients assessed as having a low probability of DVT using Wells’ score and the SimpliRED D-dimer assay found a 0
5% incidence of VTE. Using ELISA D-dimer quantification the same group found the VTE rate in negative patients to be 0
4% (Fancher et al, 2004). Deep vein thrombosis is 10 times more common in elderly patients, but DVT risk scoring systems using D-dimer often fail to correct for the effect of age. An age-dependent cut-off for positive D-dimer results can appropriately exclude a greater proportion of patients, reducing unnecessary radiological investigation (Schouten et al, 2012) and an upper limit of normal set as age 910 lg/l for patients over the age of 50 years has been suggested. If the limit is set at >750 lg/l for patients over 60 years, subset analysis shows that, for patients aged 70–80 years, 45
9% can be re-categorized as low risk versus 30
6% using the conventional cut-off. For those aged over 80 years, 33
9% are deemed low-risk for VTE versus 21% using conventional benchmarks (Schouten et al, 2012). Similar age-adjusted cut-offs show that 51% of patients could be excluded compared with 42% at conventional levels (Douma et al, 2012).

Neither clinical risk prediction tools nor biochemical markers are sensitive enough in isolation; a prospectively validated combination is still required.

Optimizing the treatment of DVT Shifting focus in healthcare systems has driven a move toward multidisciplinary and outpatient management of DVT. Nurse-led clinics and ambulatory models of care are becoming standard and early mobilization is encouraged. Management of DVT requires adequate intensity of anticoagulation, to prevent clot propagation and reduce risks of systemic clot embolization and early recurrence, with the ongoing of treatment defined by patient and disease factors. While the option of traditional therapy with initial parenteral anticoagulant therapy followed by treatment with VKAs remains, both clinical trial evidence and patient preference are driving a move toward the use of the NOACs in VTE.

The NOAC era of VTE treatment The advent of NOAC therapy for VTEs has revolutionized the field. Since the first agent was licensed in the UK for the acute and ongoing treatment of VTE in 2012, the pharmacopoeia has expanded to encompass four agents: rivaroxaban (Bayer Healthcare, Berlin, Germany), dabigatran (Boehringer Ingelheim, Berlin, Germany) and apixaban (Pfizer, Princeton, NJ, USA/Bristol-Myers Squibb, New York City, NY, USA) are all licensed in Europe, and a fourth agent, edoxaban (Daiichi Sankyo, Tokyo, Japan) was recently demonstrated to be non-inferior to conventional anticoagulation with enoxap-

Table I. Comparison of clinical risk scores for the diagnosis of DVT. Original Wells Score (Wells et al, 1997)

 ≥3 points = high risk  1–2 points = Intermediate risk  18 years, 25% diagnosed with PE alone 8240 patients, >18 years, 40% had a primary diagnosis of PE

Recurrence or VTErelated death: 2
3% vs. 2
7% Recurrent symptomatic VTE: 3
2% vs. 3
5%

Major: 1
6% vs. 1
9% Non-major: 5
6% vs. 8
8% (P = 0
002) Major: 0
8% vs. 1
2% (P = 0
21) Non-major: 7
3% vs. 7% Major: 0
6% vs. 1
8% Non-major: 3
7% vs. 7
9% Major: 1
4% vs. 1
6% (P = 0
35 for superiority) Non-major: 7
2% vs. 8
9% (P = 0
004 for superiority)

Adverse events leading to discontinuation of study drug 9% vs. 6
8%

4
9% vs. 4
7%

6
1% vs. 7
4%

3
9% vs. 3
7%

RE-COVER, Efficacy and Safety of Dabigatran Compared to Warfarin for 6 Month Treatment of Acute Symptomatic Venous Thromboembolism study; EINSTEIN, Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients with Acute Symptomatic Deep Vein Thrombosis; AMPLIFY, Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy; HOKUSAI, Edoxaban versus Warfarin for the Treatment of Symptomatic Venous Thromboembolism; LMWH, low molecular weight heparin; PE, pulmonary embolism; DVT, deep vein thrombosis; VTE, venous thromboembolism. *All thrombosis endpoints showed non-inferiority of the investigational agent versus warfarin to P < 0
001. ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 162–174

165

Review NOAC therapy, Holster et al (2013) showed the odds ratio (OR) overall for gastrointestinal bleeding in patients on NOACs to be 1
45 and 1
59 (compared to warfarin or LMWH) when treatment for VTE is considered separate to other indications though edoxaban appears to have a favourable profile in atrial fibrillation treatment with an OR of 0
31. Adherence is a further concern to some and though drug levels can be measured, there is as yet no satisfactory long-term measure of adherence to therapy. The lack of reversibility of NOACs continues to pose concerns for clinicians and patients although specific reversal agents are in development. Reversal of rivaroxaban effects on laboratory parameters has been demonstrated with prothrombin complex concentrate (PCC) in healthy volunteers, though the degree of reversal differs with each coagulation parameter measured: reversal of up to 50% of the anticoagulant effect is possible using four-factor PCC. This effect has not been replicated in human studies with the direct thrombin inhibitor dabigatran (Eerenberg et al, 2011; Perzborn et al, 2014). There is limited data to inform on the efficacy of PCC in the reversal of NOACs in bleeding individuals. Dabigatran is not protein bound and its elimination can be enhanced with haemodialysis (Bouchard et al, 2015). Specific antidotes are under development. Andexanet alfa (Portola Pharmaceuticals Inc., South San Francisco, CA, USA) is a modified recombinant factor Xa inhibitor reversal agent, it acts on both direct and indirect inhibitors of factor Xa (Lu et al, 2013). Andexanet alfa has been shown to dose-dependently decrease anti-Xa activity in both in vitro models of rivaroxaban, apixaban and betrixaban and in a phase III trial in healthy volunteers treated with apixaban (Mo & Yam, 2015). A further study in individuals with major bleeding whilst on factor Xa inhibitor is planned (clinicaltrials.gov: NCT02329327). Idarucizumab (BoehringerIngelheim) is a humanized monoclonal antibody fragment with specificity for dabigatran (Schiele et al, 2013). A global phase III clinical trial assessing its efficacy in patients on dabigatran with major bleeding is in progress (clinicaltrials.gov: NCT02104947), following experimental models showing a dose-dependent correction of clotting times (Mo & Yam, 2015; Siegal, 2015). As yet, no specific reversal agents are available for routine clinical use. Secondary prevention of VTE has been studied in extensions of the major VTE trials and variously compare NOAC treatment with warfarin and placebo. Compared with placebo, NOACs significantly reduced VTE recurrence from 7
24% to 1
32% (RR 0
17) (Kakkos et al, 2014). Although non-major bleeding was increased in the NOAC group (4
3% vs. 1
8%), net clinical benefit was in favour of NOACs over placebo, with a number needed-to-treat of 18. Economic analysis of the viability of extended prophylaxis with rivaroxaban for a 6- to 12-month period was favourable for the treatment group, despite the increased risk of bleeding (Coleman et al, 2014). Two independent randomized clinical trials (RCTs) investigating long term treatment with aspirin postanticoagulation [WARFASA [The Warfarin and Aspirin 166

study) and ASPIRE (Aspirin to Prevent Recurrent Venous Thromboembolism trial)] demonstrate that VTE recurrence can be reduced without concurrent increase in bleeding (Becattini et al, 2012; Brighton et al, 2012). Larger absolute risk reduction was seen in older patients and males across the combined results of the two studies (Simes et al, 2014). Whilst extended treatment is clearly beneficial in reducing recurrent VTE, excess bleeding rates must be taken into account. In some groups with a higher risk of bleeding, aspirin might be considered a suitable option. There is no validated tool for patients on NOACs, analogous to the HAS-BLED [Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile International Normalized Ratio (INR), Elderly, Drug] score for warfarin, widely used in atrial fibrillation (Lip et al, 2011) to predict bleeding risk in patients.

Interventional approaches Clot lysis has emerged as a potentially desirable outcome as demonstrable vessel recanalization is associated with statistically less venous hypertension, and subsequently less PTS after 1 year (Franzeck et al, 1996; Harenberg et al, 2002; Puskas et al, 2007). Successful transcatheter thrombolysis for acute thrombosis was first reported by Okrent et al (1991) following the recanalization of an acute iliofemoral DVT (IFDVT) in a young woman and various methods of surgical clot lysis have been described. The most common method currently used is catheter-directed thrombolytic infusion with or without pharmacomechanical adjuncts. In addition, angioplasty and stenting may be used in a subset of patients with either underlying stenosis, for example a May-Thurner’s lesion, or with a residual thrombosis. Despite these options, systematic methods for the reliable identification of patients who would benefit most from early intervention remain elusive. Though NICE and ACCP provide consensus guidelines, heterogeneous inclusion criteria are found in studies in exploring interventional approaches to DVT, such as first thrombosis, acute proximal DVT, >5 cm occlusive thrombus, symptoms for 6 months (Elsharawy & Elzayat, 2002; Baekgaard et al, 2010; Enden et al, 2012; Chandra et al, 2013). The majority of clinical trials require the presence of extensive thrombosis, and often include only cases of IFDVT, shown to be associated with higher rates of recurrence and long-term sequelae including PTS (Douketis et al, 2001). The TORPEDO (Thrombus obliteration by rapid percutaneous endovenous intervention in deep venous occlusion) study is one of the largest in support of early clot clearance by endovascular intervention using a variety of methods: 169 patients with proximal DVT were randomized equally to anticoagulation alone or endovascular intervention plus anticoagulation. Clinical assessment at 6 months showed significantly lower rates of PTS in the interventional group at 3
4% vs. 27
2% for anticoagulation alone, with reduced recurrence ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 162–174

Review of DVT (14
8–2
3%) in surgically treated patients (Sharifi et al, 2010). Catheter-directed thrombolysis uses ultrasound-guided venous puncture with fluoroscopic imaging directing a multi-side-hole catheter into an intra-thrombus position allowing infusion of a thrombolytic agent. Regular venography is used to measure degree of clot dissolution (Baekgaard et al, 2010). In a Danish cohort of 103 patients treated with CDT, 62% had patent veins with competent valves and no evidence of PTS using the Clinical severity, (A)Etiology, Anatomy, Pathophysiology Classification criteria at 6 year follow-up (Baekgaard et al, 2010). A recent report of the open-label randomized controlled CaVenT (Catheter-directed thrombolysis versus standard treatment for acute Iliofemoral deep vein thrombosis) study randomized 209 patients to either CDT or anticoagulation alone. Of 108 control patients, 55
6% had evidence of PTS at 24 months follow-up compared with 41
1% in CDT-treated patients (P = 0
047). Iliofemoral patency at 6 months was 65
9% in CDT and 47
4% in controls (P = 0
012). The bleeding rate was 9%, largely at puncture sites and none were described as major (Enden et al, 2012). A number of pharmacomechanical adjuncts have been developed to help increase the efficacy of lytic therapy. These include those that use ultrasound to enhance the transport of a lytic agent, in which rotational devices are used to macerate the thrombus and rheolytic devices use high-pressure saline to create a pressure gradient to allow aspiration of thrombus into a catheter. Although these adjuncts may have potential at reducing the dose or length of time for lysis, there remains a paucity of long-term data and clinical trials are currently too small to justify their use routinely.

Early intervention, long-term improvements? Long-term follow up of patients treated with localized thrombolytic therapy is lacking in most major studies. A review of all types of thrombolysis shows a significant reduction of PTS in all groups to 43% vs. 64% in controls, though this remains excessive (Watson et al, 2014). Patients with IFDVT are more likely to derive benefit from interventional therapies, perhaps because of the greater thrombus burden in such cases and reduced recurrence rates, although this may also be attributable to a tendency to treat such patients with extended periods of anticoagulation. Stringent criteria are required to ascertain which patients are most likely to benefit from interventional approaches and to mitigate for the higher risk of bleeding. Certainly, interventional approaches are underused. US data revealed that whilst 26% of 90 618 patients with DVT would have been suitable for CDT, only 4
1% underwent the procedure (Bashir et al, 2014). UK data supports this finding; in one vascular unit only 15% of eligible patients with IFDVT were referred for vascular intervention (Saunders et al, 2013). Economic analysis shows increased healthcare-associated costs ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 162–174

and length of stay in patients undergoing CDT (Saunders et al, 2013; Bashir et al, 2014). This is likely to be a limiting factor in many healthcare economies. Further studies would benefit from standardized inclusion criteria and a consensus approach to measures both of clot lysis and post-procedural venous haemodynamics. Though long-term follow-up data is lacking, there appears to be a trend toward reduced rates of PTS in patients with iliofemoral thrombosis managed with interventional thrombolytic techniques. These treatments should, however, be used judiciously, as there remains a risk of haemorrhagic complications. Unanswered questions also remain as to the role of stenting following localized thrombolysis and whether the risk of procedure-related pulmonary embolization is enough to warrant routine use of inferior vena cava filter placement. The future of imaging in DVT. With interventional techniques for the treatment of IFDVT becoming increasingly available, there is a need for comprehensive imaging to enable pre-operative planning. Duplex ultrasonography has generally replaced contrast-enhanced venography for the diagnosis of DVT, but it is user-dependent and has limited sensitivity for the detection of thrombi within the deep veins of the pelvis. Computerized tomography (CT) venography is therefore most commonly used to assess thrombi in the abdomen and pelvis. Following the administration of contrast agent (preferentially into the veins of the foot), a significant venous filling defect can be demonstrated. Large doses of ionizing radiation are required, however, and the invasiveness of this method together with potential complications, including reactions to contrast media, limits its use in the initial assessment of DVT. Nevertheless, these images are easy to interpret and scans can be performed quickly in the emergency setting. Magnetic resonance imaging (MRI) can also be used for the diagnosis of DVT. Contrast-enhanced MRV with a Gadolinium-based blood pool agent has been shown to be effective in the detection of venous thrombi in the pelvis (Huang et al, 2013), while true fast imaging with steady-state precession is routinely used pre-operatively to show filling defects in the pelvic veins. This sequence requires no contrast agent (Cantwell et al, 2006). The main limitation to these and other current imaging methods is the lack of molecular information that can be obtained from individual scans. Thrombi with high fibrin content are most susceptible to thrombolytic therapy, while those that are predominantly collagenous will not lyse. An imaging technique that can stratify patients into those who would respond best to lysis is desirable and could help mitigate the risk of haemorrhagic complications. Nuclear medicine methods using radiolabelled peptides targeting fibrin and platelets have shown promise in the experimental setting (Houshmand et al, 2014). These can be coupled with CT and have potential to identify the location of acute or ‘active’ venous thrombi. MRI can also be used 167

Review for molecular imaging. In particular, the fibrin-binding contrast agent EP-2104R has been shown in man to detect experimental thrombi that are susceptible to thrombolysis (Andia et al, 2014) and has demonstrated feasibility for the detection of DVT (Vymazal et al, 2009). Until these molecular probes become readily available, indirect measures of structure based on the paramagnetic properties of a thrombus can still be used. Magnetization transfer and diffusion weighted MRI sequences can characterize the changing protein content of a resolving murine thrombus (Phinikaridou et al, 2013), while a T1-mapping sequence based on the direct thrombus imaging technique first demonstrated by Moody (1997), appears to correlate with thrombus fibrin content and has utility in the identification of lysable experimental thrombi (Saha et al, 2013). Translation of these sequences into the clinic is one area of current research.

Predictors and modifiers of long-term outcome Recurrent thrombotic events and the pathological effects of altered venous haemodynamics are primary concerns in the long-term management of DVT. There is clinical need both to stratify patients into groups with unacceptably high risk of recurrence and those likely to suffer unacceptable levels of later morbidity, particularly with reference to the PTS: with this in mind, early and later treatments could then be tailored accordingly.

Prevention of recurrence Cumulative recurrence rates of VTE are reported between 13% and 26
4% of patients by 5 years following the index event (Beyth et al, 1995; Prandoni et al, 1997, 2007; Heit et al, 2000; Spencer et al, 2009; Baglin et al, 2010a). Absence of a provoking factor for DVT is associated with a hazard ratio (HR) of 2
30 for VTE recurrence with rates of 11
1% at 1 year and 30
3% (Prandoni et al, 2007; Baglin et al, 2010a). Rates of any VTE recurrence in distal DVT were 2
5- to 4-fold lower than patients with proximal DVT or PE (Baglin et al, 2010a; Kyrle & Eischer, 2013). Males have been shown to have an increased likelihood of recurrence after unprovoked DVT (30
7% vs. 8
5% in females, Kyrle et al, 2004).

Presence of heritable thrombophilia or strong family history of thrombosis have been shown in systematic reviews to have a modest effect on risk of recurrence, OR 1
41 (95% CI, 1
14–1
75) for F5 R506Q (factor V Leiden) heterozygosity and OR 1
72 (95% CI, 1
27–2
31) for the F2 G20210A (prothrombin gene mutation) (Ho et al, 2006). Thrombophilia testing to determine duration of anticoagulation is therefore not routinely recommended. Guidelines exhort that the presence of single copies of these polymorphisms do not justify extended duration anticoagulation (Baglin et al, 2010b). Attempts to define the optimum predictors of recurrence have reported varying degrees of concordance as to which factors constitute true risks. The Austrian study on recurrent venous thromboembolism (AUREC) found that patients with temporary risk factors were at a lower risk of recurrence: 2% at 1 year, 3% at 2 years and 6% 5 years after anticoagulation cessation (Kyrle & Eischer, 2013). Increasing age is a consistent risk factor for recurrence, though in a series of unprovoked VTEs the HR for advancing age over the 10-year study period was modest, at 1
09 per year, while stronger association could be shown for shorter duration of anticoagulation (HR 1
46) and presentation with DVT (HR 1
50) (Prandoni et al, 2007). The PROLONG (D-dimer testing to determine the duration of anticoagulation therapy) study showed that normal D-dimer after 1 month off anticoagulation was independently associated with a lower risk of VTE recurrence even when presence of comorbid disease was taken into account. Presence of comorbidity increased the risk of recurrence in patients with both normal (14
3% vs. 10
8%) and abnormal D-dimer (24
6% vs. 21
3%; Cosmi et al, 2010b) at mean follow-up of 30 months. Presence of ≥50% residual thrombus was strongly predictive of recurrence in one small series of patients with IFDVT (Aziz & Comerota, 2012). A number of scoring systems regarding recurrence for unprovoked VTE exist, including the DASH (D-dimer, age, sex, hormone use) score, the Vienna prediction model and HER-DOO2 (2 or more of the following variable: Hyperpigmentation, (O)Edema or Redness of either leg, D-dimer, Obestiy, Older age); these are summarized in Table III (Rodger et al, 2008; Tosetto et al, 2012; Eichinger et al, 2014). All were developed using multivariate regression analysis in cohorts at the point of discontinuation of anticoagulation to

Table III. Scoring systems to predict DVT recurrence in unprovoked VTE. Men continue and HER-DOO2 Score (Rodger et al, 2008)

DASH Score (Tosetto et al, 2012)

Hyperpigmentation, oedema or redness of either leg (+1) D-dimer ≥250 lg/l while taking warfarin (+1) Body mass index ≥30 (+1) Age ≥65 years (+1)

Positive D-dimer post-anticoagulation (+2) Age ≤50 years (+1) Male sex (+1) Hormone use at time of initial VTE [only in women] ( 2) Patients with a score ≤1 can be considered at low risk of recurrence

Males continue anticoagulation regardless of clinical characteristics; Women with 0 or 1 risk factors have low risk of recurrence

Vienna Prediction Model (Eichinger et al, 2014) Gender Location of first VTE D-dimer after anticoagulation

Risk of recurrence plotted on a nomogram

DVT, deep vein thrombosis; VTE, venous thromboembolism.

168

ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 162–174

Review identify independent predictors of recurrence. There is overlap in the scores as to the inclusion of elevated D-dimer and male gender as positive predictors of recurrent thrombosis. Whilst prediction of recurrence is a clinical priority, there is currently no evidence to support the routine clinical use of such tools. Both the HERDOO2 and Vienna prediction models are currently undergoing prospective validation (Clinicaltrials.gov, NCT00967304 and NCT01972243). The ideal use of these scoring systems would be to determine an individualized duration of anticoagulation, but this remains a difficult area particularly as there is a lack of long-term data beyond 5–10 years following VTE. As has already been described, extended duration anticoagulation with NOACs or VKAs can reduce the risk of recurrence with attendant increased bleeding rates.

Post-thrombotic syndrome Post-thrombotic syndrome remains a common, under-recognized and poorly understood complication of DVT. The incidence of PTS following an episode of DVT is estimated at between 20% and 50% and severe PTS is found in 5–10% of cases (Schulman et al, 2006; De Wolf et al, 2012). Diagnosis and quantification of PTS is based on clinical scoring systems. The International Society for Thrombosis and Haemostasis recommends use of the Villalta scale for diagnosis and assessment of severity of PTS. Developed in 1996, the scale is validated as a tool which integrates both symptoms and clinical signs of venous stasis following DVT and is recommended by international guidelines as the most sensitive tool (Kahn, 2009). PTS is an independent predictor of poor quality of life and even mild PTS results in significantly lower than population norm QOL scores (Roberts et al, 2014). Post-thrombotic syndrome is defined by both clinical signs and symptoms: commonly, heaviness, ache, swelling or tingling in the affected limb and signs including oedema or skin changes including hyperpigmentation, venous eczema and venous ulceration (Kahn, 2011). Various scoring systems exist although the widely used Villalta score, taking account of both clinical features and symptoms, is perhaps the most well known. Its scoring is given in Table IV. The pathophysiology of PTS is poorly understood. Proposed mechanisms for venous hypertension include mechanical obstruction of venous valves and fibrosis, which can lead to reflux. Elevated hydrostatic pressures induce capillary leak and it has been postulated that persistent stasis within the microcirculation attracts neutrophils, fibrinogen and monocytes, as well as C-reactive protein, interleukin-6 and interleukin-8 [though no level of cytokine elevation has been shown to be statistically significant in established PTS (Bouman et al, 2014)], which add to the persistent inflammatory component in PTS and induce localized venous damage (Phillips & Sarkar, 2007). Various risk factors for PTS have been identified. Ipsilateral recurrent DVT is the strongest risk factor for the ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 170, 162–174

Table IV. Villalta scoring system (Villalta et al, 1994) for postthrombotic syndrome (PTS). Symptoms:

    

Pain Cramps Heaviness Paraesthesia Pruritus

Signs:

     

Pretibial oedema Skin induration Hyperpigmentation Redness Venous ectasia Pain on calf compression Venous ulcer (absent/present)

Scored based on severity (0–3 points per sign/symptom) PTS severity based on cumulative score: mild (5–9 points), moderate (10–14 points), severe (>15 points or presence of ulcer)

development of PTS (HR 6
4, CI 3
1–13
3) (Prandoni et al, 1996). Location of thrombosis at presentation correlates with later PTS, thrombosis of the common femoral or iliac vein being an independent predictor (2
23 increase in Villalta score versus calf vein thrombosis). Obesity is the only consistent variable (OR 2
6) of all the patient-related factors (Galanaud et al, 2013). Predictors of higher Villalta scores and PTS include early symptom severity at 1 month followup (1
97, 5
03, 7
00 additional Villalta scores for mild, moderate and severe, respectively) and previous ipsilateral thrombosis (1
78 increase in Villalta score, Kahn et al, 2008). D-dimer and clinical severity at presentation were significantly predictive for PTS, with adjusted ORs of 1
78 for every point increase in Villalta score and 2
71 for Ddimer > 1910 ng/ml (Roberts et al, 2013). Inadequate anticoagulation intensity in patients on VKA therapy is a risk factor, having an INR 20% of the time significantly increased the risk of developing PTS to 33
5% from 21
6% for those patients with more therapeutic time in range (Chitsike et al, 2012). As experience of NOACs grows, it will be of interest whether the consistency of anticoagulation intensity afforded by these agents will result in reduced PTS rates. The management of established PTS is heterogeneous and lacks evidence-based options. Compression hosiery has been a mainstay of PTS prevention and management for a number of years. The SOX study has been the best-designed RCT to investigate the benefit of compression hosiery in reduction of symptomatic PTS and found no difference between treatment group (14
2%) and controls (12
7%), although the study was limited by its definition of concordance. Further subgroup analysis of this trial also demonstrated no benefit for graduated compression stockings in the reduction of pain in the 2 months following the index 169

Review event (Kahn et al, 2014a). The ongoing IDEAL study will investigate whether tailoring compression stocking therapy to individual patients and symptoms would save costs and select for the most appropriate patients who would derive benefit. Results are expected in 2017 (Ten Cate-Hoek et al, 2014). Pharmacological therapies for PTS have been explored, however a 2013 Cochrane review found a lack of placebo-controlled trials in support of rutosides (Morling et al, 2013), compounds derived from horse chestnut and claimed as herbal remedies for the management of oedema and symptomatology in chronic venous disease. There is an urgent need for investigation of additional preventative and therapeutic approaches in PTS. A small feasibility study suggests exercise may reduce PTS (Kahn et al, 2011) and the EFFORT2 (Role of a Novel Exercise Program to Prevent Post-Thrombotic Syndrome) trial is an ongoing randomized controlled trial investigating the role of exercise in prevention of PTS (Clinicaltrials.gov, NCT02148029). Published evidence to support use of devices such as intermittent pneumatic compression and a portable calf compression device (Venowave) remains scant. Surgical options exist for the management of established PTS including venous stenting, bypass and venous valve reconstruction. The recent development of dedicated venous stents with the appropriate size, flexibility and crush resistance probably reflects a renewed appetite to treat patients with venous outflow obstruction. Single centre studies (Raju & Neglen, 2009) have shown potential for treatment, particularly when symptoms are severe and/or conventional therapy has failed but recommendation of any particular procedure is limited by lack of RCT data and the need for a specialist skill set, which may not be readily available. Discussion with local vascular surgeons is encouraged in the select group of patients with severe symptomatic PTS and the physiological reserve to tolerate and recuperate from these invasive procedures (Kahn et al, 2014b), though development of centralized specialist services for deep venous reconstruction is likely to yield better long-term results. Further research is also required to better identify those patients with functional outflow stenosis, which may contribute to PTS, as well as the ideal anticoagulation or antiplatelet strategy following venous intervention and the factors that relate to early or late stent occlusion.

It is widely expected that the use of VKAs will fall in the next 5 years though there will remain a population of patients in whom it will remain desirable to monitor anticoagulant intensity and adherence and, indeed, guidelines recommend a switch to VKAs in patients who experience recurrence while on NOAC therapy. Ongoing multi-centre post-marketing studies of the NOACs are likely to be instructive in choice of drug and will confirm whether the enhanced safety profile demonstrated in clinical trials applies to real-world patients. These drugs are also likely to become more acceptable to the practicing physician once reversal agents, currently in development, become available. Interventional management of DVT will remain a treatment for a subset of patients with iliac vein involvement. The reporting of large scale clinical trials such as the ongoing Dutch CAVA [Catheter Versus Anticoagulation Alone for Acute Primary (Ilio) Femoral DVT] trial (Clinicaltrials.gov, NCT00970619) and the multicentre US ATTRACT study (Clinicaltrials.gov, NCT00790335), may help to define the patient cohort whose risk of later morbidity from PTS is unacceptably high and would therefore be expected to derive the greatest benefit. Local surgical expertise will play a role in determining access, although national guidelines will serve to standardize public expectation. Even with interventional approaches, long term morbidity due to PTS and recurrent DVT remains high. Validation studies in progress on patient selection for extended anticoagulation following unprovoked VTE may lead to a more individualized approach to secondary VTE prevention. There is a need for further research to improve our understanding of PTS development and guide further preventative and therapeutic strategies for these patients to improve outcomes and patient quality of life.

Acknowledgement We are indebted to Professor Alberto Smith and Dr Jignesh Patel for their helpful comments in the preparation of this manuscript.

Author contributions Dr Lang, Mr Saha, Dr Roberts and Professor Arya co-authored this manuscript.

Conclusion

Disclosure of interests

Deep vein thrombosis remains an important diagnosis in worldwide healthcare, because associated morbidity is significant and it has high healthcare-related costs. The development and validation of prognostic scoring systems to better risk stratify patients with strong positive predictive power will allow more judicious use of diagnostic imaging techniques. As experience of NOACs grows, a selection of therapies will probably evolve to tailor the agent to individual patients.

Dr Lang has no disclosures; Mr Saha has received research funding from the National Institute of Health Research and The Academy of Medical Sciences and honoraria from Bayer; Dr Roberts has investigator-initiated research funding from Covidien, speaker fees from Covidien and Bayer and travel grants from Boehringer-Ingelheim; Professor Arya has received research support and honoraria from Bayer, Boehringer-Ingelheim, Covidien and Pfizer.

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Review

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