10.4081/btvb.2022.20
While on conventional anticoagulation, up to 50% of patients with one or more episodes of proximal deep vein thrombosis (DVT) can develop post-thrombotic (PTS) manifestations. The potential strategies for PTS prevention are the treatment of acute DVT with catheter-directed thrombolysis (CDT), the use of elastic compression stockings (ECS) and that of the direct oral anticoagulants (DOAC) in place of vitamin K antagonists (VKA) for the initial and long-term treatment of DVT. Based on the results of three randomized clinical trials, CDT cannot be recommended on a routine basis because of its invasiveness, the associated risk of major bleedings and the uncertainty about its efficacy. According to the results of a placebo-controlled randomized clinical trial, ECS are no longer recommended for PTS prevention on a routine basis. However, based on the results of a recent subanalysis of a prospective cohort study, patients with residual vein thrombosis and/or popliteal valve reflux at three months are likely to benefit from ECS for at least six months. Finally, following the demonstration that the inadequacy of VKA therapy plays a key role in the PTS development, several retrospective and prospective studies have shown that the use of DOACs for the initial and long-term treatment of DVT in place of VKAs reduces the risk of PTS by approximately 50%. In conclusion, the availability of DOACs and the potential of ECS in selected patients with proximal DVT are expected to play a key role for decreasing the rate and the severity of PTS in the forthcoming years.
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Paolo  Prandoni
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Bleeding, Thrombosis and Vascular Biology
direct oral anticoagulants
New perspectives for prevention of the post-thrombotic syndrome
Text.Serial.Journal
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Narrative Reviews
2022-03-22
2022-02-10
2022-03-22
2022-05-02
Bleed Thromb Vascul Biol
Paolo  Prandoni
2022/03/22
10.4081/btvb.2022.20
Arianna Anticoagulazione Foundation, Bologna
2785-5309
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direct oral anticoagulants
en
;368:699-708.
New perspectives for prevention of the post-thrombotic syndrome
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1
                                                                                                      NARRATIVE REVIEW

New perspectives for prevention of the post-thrombotic syndrome
Paolo Prandoni

Arianna Anticoagulazione Foundation, Bologna, Italy



ABSTRACT
    While on conventional anticoagulation, up to 50% of patients with one or more episodes of proximal deep vein thrombosis (DVT)
can develop post-thrombotic (PTS) manifestations. The potential strategies for PTS prevention are the treatment of acute DVT with
catheter-directed thrombolysis (CDT), the use of elastic compression stockings (ECS) and that of the direct oral anticoagulants (DOAC)
in place of vitamin K antagonists (VKA) for the initial and long-term treatment of DVT. Based on the results of three randomized
clinical trials, CDT cannot be recommended on a routine basis because of its invasiveness, the associated risk of major bleedings and
the uncertainty about its efficacy. According to the results of a placebo-controlled randomized clinical trial, ECS are no longer recom-
mended for PTS prevention on a routine basis. However, based on the results of a recent subanalysis of a prospective cohort study, pa-
tients with residual vein thrombosis and/or popliteal valve reflux at three months are likely to benefit from ECS for at least six months.
Finally, following the demonstration that the inadequacy of VKA therapy plays a key role in the PTS development, several retrospective
and prospective studies have shown that the use of DOACs for the initial and long-term treatment of DVT in place of VKAs reduces
the risk of PTS by approximately 50%. In conclusion, the availability of DOACs and the potential of ECS in selected patients with




                                                                                                     ly
proximal DVT are expected to play a key role for decreasing the rate and the severity of PTS in the forthcoming years.




                                                                                            on
                                                                           DVT, in most patients they develop within the first six
EPIDEMIOLOGY AND RISK FACTORS                                              months.1,2 They are expected to increase the health care


                                                                                       e
    Post-thrombotic syndrome (PTS) is a chronic compli-                    costs, the total per-patient cost being almost 50% higher
                                                                                us
cation of deep vein thrombosis (DVT) of the lower ex-                      than that of DVT patients without PTS.3
tremities that develops in a substantial proportion of                          Based on the results of several prospective cohort
                                                                           al
patients following one or more episodes of proximal DVT                    studies, the development of long-term sequelae arising
despite adequate anticoagulant treatment.1,2 PTS manifes-                  after an episode of proximal DVT is expected to occur in
                                                                 ci


tations range from mild symptoms to debilitating com-                      40-50% of patients receiving conventional anticoagula-
                                                               er



plaints, such as skin induration, intractable edema and                    tion, and in approximately 8-10% is serious enough to se-
skin ulcers. They are generally aggravated by standing or                  verely impair patients’ quality of life.1,2,4,5
                                                              m




walking, while tend to improve with rest and leg eleva-                         Factors that were generally found to be associated
tion. Although PTS may occur within two years after                        with an increased rate of PTS at time of presentation with
                                                   om




                                                                           an acute DVT are elderly age, varicose veins, obesity and
                                                                           the involvement of the most proximal venous segments;
                                             -c




  Correspondence: Paolo Prandoni, Arianna Anticoagulazione Foun-
                                                                           and those arising during the follow-up the persistence of
                                                                           residual vein thrombosis, the development of popliteal
                                    on




  dation, Via P. Fabbri 1/3, 40138 Bologna, Italy.
  Tel.: +39.340.2808202                                                    valve reflux, the inadequacy of anticoagulant therapy, and
  E-mail: prandonip@gmail.com
                                                                           the development of recurrent ipsilateral DVT.6 Addition-
                              N




  Kew words: Post-thrombotic syndrome, Deep vein thrombosis,               ally, baseline inflammatory markers elevation (such as C-
  Catheter-directed thrombolysis, Elastic compression stockings, An-       reactive protein and interleukin-6) at the time of the index
  ticoagulation, Vitamin K antagonists, Direct oral anticoagulants.        DVT, as well its persistency over the subsequent months
  Conflict of interest: The author declares no potential conflict of in-
                                                                           have been found to predict the development of PTS.7 In
  terest.                                                                  recent years, two scores have been derivate and validated,
                                                                           which have the potential to predict the development of
  Funding: None.
                                                                           PTS: the SOX PTS model generated from the SOX
  Received for publication: 10 February 2022.                              study,8,9 and the IDEAL PTS model, generated from the
  Accepted for publication: 8 March 2022.                                  IDEAL DVT study.10,11 They are displayed in Tables 1 and
                                                                           2, respectively. At present, however, the value of these
  This work is licensed under a Creative Commons Attribution Non-
  Commercial 4.0 License (CC BY-NC 4.0).
                                                                           scores is still uncertain, as are their implications for clin-
                                                                           ical practice.
  ©
   Copyright: the Author(s), 2022                                               The potential strategies for PTS prevention are essen-
  Licensee PAGEPress, Italy
                                                                           tially three: i) the treatment of acute DVT with catheter-
  Bleeding, Thrombosis and Vascular Biology 2022; 1:20
  doi:10.4081/btvb.2022.20                                                 directed thrombolysis (CDT); ii) the use of elastic
                                                                           compression stockings (ECS) in order to counteract the

                                              Bleeding, Thrombosis and Vascular Biology 2022; 1:20
                                     New perspectives for prevention of the post-thrombotic syndrome                             25



venous hypertension generated by residual vein thrombo-                 that CDT cannot be recommended on a routine basis be-
sis (RVT) and/or popliteal valve reflux (PVR); and iii) the             cause of its invasiveness, the associated risk of major
use of the novel direct oral anticoagulants (DOAC) in                   bleedings and the uncertainty about its efficacy. At pres-
place of vitamin K antagonists (VKA) for the initial and                ent, it can be considered only in patients with threatening
long-term treatment of DVT.                                             clinical presentation provided the ilio-femoral tract is in-
                                                                        volved and the bleeding risk is low, in centers where ad-
                                                                        equate expertise and resources are available.1,2
CATHETER-DIRECTED THROMBOLYSIS
     The earlier recanalization of obstructed vessels with
                                                                        ELASTIC COMPRESSION STOCKINGS
the use of thrombolytic drugs has long been advocated in
order to decrease the rate of PTS. Whether, however, this                   ECS have been used for decades in patients with DVT
strategy is associated with a favorable benefit/risk ratio is           with the aim of counteracting the venous hypertension
still uncertain. So far, the results of three randomized con-           generated by the vascular disorder and reducing leg
trolled clinical trials addressing the value of CDT have                edema. In two small, randomized studies, published 20
been published. In the ATTRACT study, by far the most                   years ago, the use of below-knee stockings for at least two
robust investigation, approximately 800 patients with                   years was found to reduce by approximately 50% the in-
proximal DVT were randomized to receive conventional                    cidence of PTS.18,19 By contrast, a recent large, double-




                                                                                         ly
anticoagulation alone or preceded by CDT.12 There was                   blind randomized clinical trial (the SOX study) failed to




                                                                                  on
no difference at all between the two study groups in terms              confirm the advantage of stockings.20 Indeed, after two
of PTS development, as assessed with the Villalta scale,                years of follow-up there was no difference at all between
after two years. By converse, the use of CDT was associ-                the two study groups (each of them including approxi-


                                                                            e
ated with a significantly higher incidence of major bleed-            usmately 400 patients) in terms of PTS development, as as-
ing complications. However, in a prespecified subgroup                  sessed with the Ginsberg index and with the Villalta scale.
analysis the incidence of moderate/severe PTS was found                 Although, due to the unexpectedly low compliance (lower
to be lower in the subgroup of patients with ilio-femoral               than 50%), the conclusions of this study have generally
                                                               al

thrombosis.13 The results of the ATTRACT study are con-                 been criticized, most international guidelines do no longer
                                                    ci

sistent with those of two additional smaller clinical trials,           recommend the routine use of ECS besides conventional
the CAVENT14,15 and the DUTCH CAVA,16,17 and suggest                    anticoagulation in patients with proximal DVT.1,21 How-
                                                  er
                                                 m




Table 1. SOX PTS score for the prediction of PTS. A score ≥4 identifies patients at a higher risk of PTS.
                                       om




Features                                                                                            Score
BMI >35 kg/m2                                                                                          2
                                 -c




Iliac vein involvement                                                                                 1
                         on




Moderate (score 5-9) Villalta score at DVT presentation                                                1
Severe (score >10) Villalta score at DVT presentation                                                  2
PTS, post-thrombotic syndrome; DVT, deep vein thrombosis.
                   N




Table 2. IDEAL PTS score for the prediction of PTS. Baseline model: 0-2 points: 10%; 3-4 points: 20%; >5 points: 40%. After six
months: 0-2 points: 25%; 3-4 points: 45%; >5 points: 60%
Features                                                         Baseline score                        Score at six months
Age >56                                                                2                                       1
BMI >30 kg/m2                                                          2                                       1
Varicose veins                                                         4                                       3
Smoking                                                                1                                       1
Residual vein thrombosis                                               -                                       1
Female gender                                                          1                                        -
Ilio-femoral DVT                                                       1                                        -
Provoked DVT                                                           1                                        -
Previous DVT                                                           1                                        -
PTS, post-thrombotic syndrome; DVT, deep vein thrombosis.


                                          Bleeding, Thrombosis and Vascular Biology 2022; 1:20
26                                                        P. Prandoni




ever, elastic stockings are still commonly prescribed in           below 2.0 in more than 50% of time during the first three
clinical practice.22 In addition, following the publication        months of anticoagulation.28 By converse, the use of low-
of the OCTAVIA study, which failed to show the non-in-             molecular-weight heparin (LMWH) as a standalone ther-
feriority of a 1-year over a 2-year course of ECS,23 a meta-       apy in place of VKAs is associated with a lower risk of
analysis of all available controlled studies turned out to         PTS, most likely because of its strong anti-inflammatory
indicate a trend favoring the use of stockings.24                  properties coupled with a more stable anticoagulant
    In a systematic review and meta-analysis of 12 inves-          effect.29,30 A cohort study addressing value of an initial 3-
tigations, it was concluded that patients with RVT and/or          4 week period of LMWH therapy before shifting to con-
PVR, as assessed with ultrasonography at least six weeks           ventional DOAC treatment in patients reputed at a higher
after an acute DVT, exhibit a significantly higher risk of         risk of PTS is currently ongoing.30
subsequent PTS than those without these ultrasound find-               The DOACs have now become commercially avail-
ings.25 As each of these abnormalities, both alone and in          able worldwide. Because of their predictable pharmaco-
combination, can generate a longstanding venous hyper-             kinetics, they can be used in fixed dose, without
tension that may be counteracted by the compression ther-          laboratory monitoring, and result in a much more stable
apy, the conclusions of these investigators drew new               anticoagulation than that induced by VKAs.31 In addi-
attention on the potential of ECS in these two subgroups           tion, they have recently been found to restore the vein
of patients.                                                       patency more rapidly than VKA.32 Recently, the results




                                                                                            ly
    Therefore, we decided to explore retrospectively the           of a prospective multicenter Italian study have been pub-




                                                                                    on
risk of PTS in a broad number of almost 900 patients with          lished. The rate of PTS over a 2-year follow-up was cal-
proximal DVT, who had been recruited at our Institution            culated in more than 300 patients who had been treated
between 2003 and 2009 and were then followed up for                with DOACs (mostly rivaroxaban) and was compared



                                                                               e
three years.26 In all patients the ultrasound assessment of        with that found in a historical cohort of more than 1000
RVT and/or PVR at three months had been performed
using a standardized procedure. Using predefined criteria,
                                                                        us
                                                                   patients who had been treated with VKAs and had been
                                                                   followed-up over time using an identical approach.26
patients were classified as those who used proper stock-           After adjusting for several unavoidable differences be-
                                                                 al
ings for at least 70% of daily time for at least one year          tween the two cohorts, DOACs were found to decrease
after the thrombotic episode (‘stockings’ group), and those
                                                     ci

                                                                   by more than 50% the risk of overall and severe PTS
who did not (‘no stockings’ group).27 The two groups were          over VKAs.33 According to the results of a recent meta-
                                                   er



virtually comparable in terms of baseline characteristics,         analysis of seven mostly retrospective investigations ad-
risk factors of venous thrombosis and risk factors of PTS.
                                                  m




                                                                   dressing the role of rivaroxaban and warfarin for
The findings were interesting. Indeed, while in patients           prevention of PTS, the incidence was found to be sig-
                                         om




with RVT and/or PVR the risk of PTS was high and was               nificantly lower among rivaroxaban recipients.34 The dif-
remarkably reduced by the proper use of stockings, in              ference was not only statistically significant but also
those free from vascular damage the risk of PTS was                clinically relevant, as it involved not only the rate of
                                    -c




lower and not impacted using stockings. Of the two vas-            mild and moderate PTS, but also that of the most severe
cular abnormalities, RVT was the one that impacted the             manifestations and that of skin ulcers.
                             on




study results most.27                                                  In addition to conferring a more stable anticoagulation
    Accordingly, the ultrasound detection of RVT (espe-            and to restoring the vein patency more quickly than the
                        N




cially if associated with PVR) three months after an               VKA, DOACs are expected to prevent the long-term re-
acute proximal DVT has the potential to identify patients          currences in a wide spectrum of patients with VTE. In-
at a higher risk of developing PTS and of benefiting               deed, based on the results of the Einstein Extension and
from ECS.                                                          Einstein Choice studies, rivaroxaban in either conven-
                                                                   tional or low doses is likely to protect from the risk of re-
                                                                   current DVT most DVT patients, virtually all but those
THE USE OF THE DIRECT ORAL                                         with major trauma/surgery.35 These results are consistent
ANTICOAGULANTS FOR THE INITIAL                                     with those shown by apixaban in the Amplify Extension
AND LONG-TERM TREATMENT OF PROXIMAL
                                                                   study.36 As recurrent ipsilateral DVT is by far the strongest
DEEP VEIN THROMBOSIS
                                                                   marker of PTS development,6 the long-term protection
    Among factors associated with an increased risk of             against DVT recurrences conferred by low-dose DOAC
PTS development, the inadequacy of VKA treatment is                in a wide spectrum of DVT patients is expected to result
likely to play a key role in the development of PTS. In-           in a substantial decrease of PTS development in compar-
deed, based on the results of a Dutch-Italian investigation        ison to the discontinuation of anticoagulation (as it was
conducted a few years ago, PTS is expected to develop              the case in the majority of VTE patients when VKAs were
three times more frequently in patients whose INR is               the only available resource).

                                     Bleeding, Thrombosis and Vascular Biology 2022; 1:20
                                  New perspectives for prevention of the post-thrombotic syndrome                                    27



                                                                           treatment for acute iliofemoral deep vein thrombosis (the
CONCLUSIONS                                                                CaVenT study): a randomised controlled trial. Lancet
                                                                           2012;379:31-8.
    In conclusion, the availability of DOACs for the initial
                                                                     15.   Haig Y, Enden T, Grøtta O, et al. Post-thrombotic syndrome
and long-term treatment of DVT and the potential of ECS                    after catheter-directed thrombolysis for deep vein thrombo-
in selected patients with proximal DVT are expected to                     sis (CaVenT): 5-year follow-up results of an open-label, ran-
play a key role for decreasing the rate and the severity of                domised controlled trial. Lancet Haematol 2016;3:e64-71.
PTS in the forthcoming years.                                        16.   Notten P, Ten Cate-Hoek AJ, Arnoldussen CWKP, et al. Ul-
                                                                           trasound-accelerated catheter-directed thrombolysis versus
                                                                           anticoagulation for the prevention of post-thrombotic syn-
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