Article
Reference
Long-term risk of postthrombotic syndrome after symptomatic distal deep vein thrombosis: The CACTUS-PTS study
GALANAUD, Jean-Philippe, et al.
Abstract
After a proximal lower limb deep vein thrombosis (DVT; involving popliteal veins or above), up to 40% of patients develop postthrombotic syndrome (PTS) as assessed by the Villalta scale (VS). Poor initial anticoagulant treatment is a known risk factor for PTS. The risk of developing PTS after isolated distal DVT (infra-popliteal DVT without pulmonary embolism), and the impact of anticoagulant treatment on this risk, are uncertain.
GALANAUD, Jean-Philippe, et al . Long-term risk of postthrombotic syndrome after symptomatic distal deep vein thrombosis: The CACTUS-PTS study. Journal of Thrombosis and
Haemostasis , 2020, vol. 18, no. 4, p. 857-864
DOI : 10.1111/jth.14728 PMID : 31899848
Available at:
http://archive-ouverte.unige.ch/unige:155639
Disclaimer: layout of this document may differ from the published version.
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J Thromb Haemost. 2020;18:857–864. wileyonlinelibrary.com/journal/jth
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857 Received: 11 September 2019|
Accepted: 31 December 2019DOI: 10.1111/jth.14728
O R I G I N A L A R T I C L E
Long-term risk of postthrombotic syndrome after symptomatic distal deep vein thrombosis: The CACTUS-PTS study
Jean-Philippe Galanaud
1,2| Marc Righini
3| Lorris Le Collen
1| Aymeric Douillard
4| Helia Robert-Ebadi
3| Daniel Pontal
1| David Morrison
5| Marie-Thérèse Barrellier
6| Antoine Diard
7| Hervé Guénnéguez
8| Dominique Brisot
9| Pascale Faïsse
10|
Sandrine Accassat
11| Myriam Martin
12| Aurélien Delluc
13,14| Susan Solymoss
15| Jeannine Kassis
16| Marc Carrier
14| Isabelle Quéré
1| Susan R. Kahn
101Department of Vascular Medicine, Montpellier University Hospital and University of Montpellier, Montpellier, France
2Department of Medicine, Sunnybrook Health Sciences Centre and University of Toronto, Toronto, ON, Canada
3Division of Angiology and Hemostasis, Faculty of Medicine, Geneva University Hospital, Geneva, Switzerland
4Clinical Research and Epidemiology Unit, University Hospital, Montpellier, France
5Department of Medicine and Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada
6Vascular Medicine Unit, Caen University Hospital, Caen, France
7Vascular Medicine Office, Langoiran, France
8Clinique Mégival, St Aubin sur Scié, France
9Vascular Medicine Unit, Clinique du Parc, Castelnau Le Lez, France
10Vascular Medicine Physician, Alès, France
11Clinical Investigation Centre, Saint Etienne University Hospital, Saint Etienne, France
12Vascular Medicine Physician, Annecy, France
13Department of Medicine, Brest University Hospital, Brest, France
14Department of Medicine, Ottawa Hospital Research Institute at the University of Ottawa, Ottawa, ON, Canada
15Division of Hematology, St Mary’s Hospital, Montreal, QC, Canada
16Division of Hematology, Hôpital Rosemont-Maisonneuve, Montréal, QC, Canada
© 2020 International Society on Thrombosis and Haemostasis Manuscript handled by: John-Bjarne Hansen
Final decision: John-Bjarne Hansen, 31 December 2019 Correspondence
Jean-Philippe Galanaud, Division of General Internal Medicine, University of Toronto, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON, M4N 3M5 Canada.
Email: Jean-Philippe.Galanaud@sunnybrook.
ca
Funding Information
ISTH Presidential Fund, Canadian Institute of Health Research (MOP-119524), Programme Hospitalier de Recherche Clinique, and the Swiss National Science Foundation.
Abstract
Background: After a proximal lower limb deep vein thrombosis (DVT; involving popliteal veins or above), up to 40% of patients develop postthrombotic syndrome (PTS) as assessed by the Villalta scale (VS). Poor initial anticoagulant treatment is a known risk factor for PTS.
The risk of developing PTS after isolated distal DVT (infra-popliteal DVT without pulmo- nary embolism), and the impact of anticoagulant treatment on this risk, are uncertain.
Methods: Long-term follow-up of CACTUS double-blind trial comparing 6 weeks of s.c. nadroparin (171 IU/kg/d) versus s.c. placebo for a first symptomatic isolated distal DVT. At least 1 year after randomization, patients had a PTS assessment in clinic or by phone using the VS.
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GALANAUD etAL.1 | INTRODUCTION
After a proximal lower limb deep vein thrombosis (DVT; involving popliteal veins or above), up to 40% of patients develop postthrom- botic syndrome (PTS).1 PTS is a burdensome and chronic condition that significantly reduces quality of life (QOL) of affected individu- als and is the main predictor of increased health-care costs after a DVT.2
Anticoagulant treatment influences the risk of PTS after proxi- mal DVT. Proximal DVT patients treated with warfarin are at higher risk of developing PTS if they have subtherapeutic international normalized ratio (INR) tests more than half of the time during the initial 3 months of treatment of DVT (compared to patients who have better INR control), or compared to patients treated with extended low molecular weight heparin (LMWH) or direct oral anticoagulants (DOAC).3-6 Given the absence of other simple and effective measures to prevent PTS, optimal anticoagulation con- stitutes an easy and effective way to reduce the risk of PTS after a DVT.2,7
After an isolated distal DVT (infra-popliteal DVT without pulmo- nary embolism, referred to as distal DVT throughout this article), the risk of developing PTS and the impact of anticoagulant treatment on this risk are uncertain. As distal DVT is frequent and accounts for up to half of all lower limb DVT,8-11 this is an important knowledge gap.
Furthermore, whether distal DVT needs to be treated with thera- peutic anticoagulation is still debated and anticoagulant treatment is not routinely recommended in international guidelines.12-17 Thus, in clinical practice, not all patients with distal DVT are offered ther- apeutic anticoagulation, which could have an impact on their risk of developing future PTS.
With this perspective, we conducted a preplanned long-term follow-up of patients who participated in the compression versus
anticoagulant treatment and compression in symptomatic calf thrombosis diagnosed by ultrasound (CACTUS) trial18 to assess the risk of PTS after a first symptomatic distal DVT and the im- pact of therapeutic anticoagulation on this risk (CACTUS-PTS study).
2 | METHODS
2.1 | CACTUS trial
The CACTUS trial was an international (Canada, France, Switzerland) randomized placebo-controlled trial comparing a 6-week course of therapeutic dose LMWH (nadroparin 171 UI/kg daily subcutaneously) versus placebo in outpatients with a first symptomatic distal DVT.
The study protocol has been extensively described elsewhere.18 Main exclusion criteria were previous history of DVT or PE, concomitant proximal DVT or PE, distal DVT involving the calf trifurcation, active cancer, and indication for anticoagulant treatment at prophylactic or Results: After a median follow-up of 6 years, PTS was present in 30% (n = 54) of the 178 patients who had a PTS assessment. PTS was moderate or severe in 24% (n = 13) of cases. There was no statistically significant difference in prevalence of PTS in the nadroparin versus placebo groups (29% versus 32%, P = .6), except in patients without evidence of primary chronic venous insufficiency (9% versus 24%, P = .04). Rates of venous thromboembolism recurrence during follow-up in the nadroparin and placebo groups were, respectively, 8% (n = 7) and 14% (n = 13; P = .2).
Conclusion: After a first isolated distal DVT, the risk of PTS is substantial but much lower than that reported after proximal DVT. Anticoagulation with nadroparin doesn't provide any clear benefit to prevent PTS, except in patients without preexist- ing chronic venous insufficiency. Anticoagulation might be associated with a lower risk of venous thromboembolism recurrence.
K E Y W O R D S
clinical trial, deep vein thrombosis, epidemiology; anticoagulant, low molecular weight heparin, postthrombotic syndrome
Essentials
• After a distal deep vein thrombosis (DVT), risk of post- thrombotic syndrome (PTS) is uncertain.
• Long-term follow-up of CACTUS RCT compared 6 weeks of placebo versus nadroparin to treat distal DVT.
• After 6 years of follow-up, 30% of patients had PTS that was moderate or severe in 24% of cases.
• Anticoagulants didn't prevent PTS except in patients without preexisting venous insufficiency.
therapeutic doses. All patients were advised to wear elastic compres- sion stockings (ECS) daily. Between February 2008 and November 2014, 259 patients were enrolled and 252 analyzed in intention-to- treat analysis. The main results of the trial were that nadroparin was not statistically superior to placebo in reducing the risk of proximal DVT or PE during 42 days follow-up (3% versus 5%, risk difference –2.1%, [95% confidence interval –7.8 to 3.5]; P = .5), and was associ- ated with a statistically significant higher risk of bleeding (4% versus 0%, risk difference 4.1% [0.4-9.2]; P = .03).18 These results helped to inform the American College of Chest Physicians (ACCP) guidelines statement that in patients with distal DVT at low risk of proximal ex- tension, the benefit of systematically treating patients with therapeu- tic anticoagulation is uncertain13 and that ultrasound surveillance is a safe alternative.
2.2 | CACTUS-PTS study
In 2011, it was decided to perform a long-term follow-up of patients enrolled in the main CACTUS trial, namely the CACTUS-PTS study.
The primary objective of this add-on study was to assess the long- term risk of PTS after distal DVT and the impact of anticoagulation on this risk. Secondary objectives included assessment of PTS se- verity category, rates of death and of VTE recurrence, and generic and venous disease-specific QOL in patients treated with nadro- parin or with placebo. This add-on study was funded by a grant from the Canadian Institutes of Health Research. It is registered in ClinicalTrials.gov (NCT00421538) and was approved by the research ethics boards at all participating centers.
All patients recruited in the CACTUS trial were invited to partici- pate. Patients who had been enrolled in the CACTUS trial before the CACTUS-PTS study was started were contacted by phone and asked if they were willing to participate. For patients recruited in the main CACTUS trial after the CACTUS-PTS study was initiated, consent to participate in this long-term follow-up was obtained at time of obtaining consent for the main trial.
Long-term follow-up consisted of a clinical visit performed once, at least 1 year after the index distal DVT event. The follow- ing information was collected and entered in an electronic case re- port form: use of compression stockings, any use of anticoagulant treatment, suspected or confirmed VTE recurrence, new diagnosis of cancer, or death (by family or physician report) since day 90 postrandomization (end of follow-up for main CACTUS trial). In ad- dition, an assessment for PTS and its severity was performed, and patients were asked to complete generic and venous disease-spe- cific QOL questionnaires. If a patient agreed to participate but was unable to attend the follow-up visit in person, a phone follow-up was performed by a physician or study nurse. The same informa- tion was collected as for the in-person follow-up visit, except that QOL was not assessed.
The primary outcome was the prevalence of PTS at follow-up.
Secondary outcomes include severity of PTS; QOL scores; over- all rates of VTE recurrence and death; and comparison of rates
of PTS, VTE recurrence, and QOL scores between patients as- signed to nadroparin versus placebo for their initial distal DVT event.
2.3 | Assessment of outcomes
As recommended by the International Society on Thrombosis and Haemostasis and the American Heart Association, PTS was as- sessed using the Villalta scale.19,20 PTS was considered to be pre- sent if the Villalta score (VS) was >4 in the leg ipsilateral to the index DVT. PTS was considered to be mild, moderate, or severe if the VS was 5-9, 10-15, or >15 and/or presence of a venous ulcer, respectively. In-person clinical assessment to determine the VS was done by a trained research nurse or a vascular medicine phy- sician, with the symptoms component of the VS assessed by the patient. In the case of a phone follow-up visit, PTS was assessed using the validated patient-reported Villalta scale.21 Quality of life was measured using validated generic (SF-36) and venous-disease specific (VEINES-QOL/Sym) questionnaires.23,24 Both patients and investigators were unaware of patients’ CACTUS trial treat- ment allocation group (ie, nadroparin or placebo injections). For all cases of VTE recurrence, new cancer, or death, medical re- cords were reviewed, and events were adjudicated by the study's adverse events committee.
2.4 | Statistical analyses
The CACTUS-PTS study sample size was determined by recruit- ment in the main CACTUS trial.18 We hypothesized that the rate of PTS after distal DVT would be 50% lower than after proximal DVT, and that anticoagulant treatment would reduce the risk of PTS by 50% (14% versus 27%).3,6,25 Anticipating that 380 CACTUS patients would undergo long-term follow-up, the study's statis- tical power to show a statistically and clinically significant re- duction in PTS from 27% to 14% with nadroparin (13% absolute difference; number needed to treat [NNT] = 8) is >85% (two-tailed α ≤ 0.05).
Qualitative data were reported as numbers and percentages.
Quantitative data were reported as medians with interquartile ranges. Differences between treatment groups were assessed with Chi square or Fisher exact tests.
Prespecified sensitivity analyses were performed in two sub- groups: patients without significant contralateral venous insuffi- ciency (defined as a VS < 5 in the leg contralateral to index DVT) as an indicator of absence of primary venous insufficiency, and patients who had an in-person PTS assessment.
To assess predictors of PTS, we performed conditional logistic regression models adjusted on age and sex. The following baseline variables were entered into the model: age, sex, body mass index, DVT location (deep calf vein versus muscular vein distal DVT), number of thrombosed veins, presence of varicose veins, D-dimer
860
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GALANAUD etAL.levels at time of DVT event (analyzed as a continuous variable; type of assay used left at each center's discretion as per CACTUS trial's protocol), as well as treatment allocation group (nadroparin versus placebo), compression stockings use (yes versus no), antiplatelet or anticoagulant drugs use, use of nonsteroidal anti-inflammatory drugs, and VTE recurrence during follow-up.
QOL scores were calculated using established scoring algo- rithms and analyzed using Wilcoxon Mann-Whitney tests; score differences on the order of 3-4 points were considered clinically important.23,26
All statistical tests were two-sided and significance was set at P ≤ .05. Analyses were done with SAS version 7.1.
3 | RESULTS
Among the 252 patients analyzed in the modified intention-to- treat analysis of the CACTUS trial, 178 patients had a PTS as- sessment, which occurred during an in-person clinic visit in 68%
(n = 111) of patients (Figure 1). Among patients assessed for PTS, 87 had been randomized to nadroparin and 91 to placebo. PTS was assessed at a median of 6.4 years (interquartile range [IQR]
4.4-7.5) in the nadroparin group and 6.2 years (IQR 4.4-7.4) in the placebo group.
3.1 | Characteristics of the population assessed for PTS
Characteristics of the study population assessed for PTS, shown in Table 1, were well balanced between treatment groups. Age was higher in patients who attended the in-person follow-up visit compared to the phone follow-up visit (63 years versus 55 years, respectively). However, there were no differences in other baseline characteristics (sex, body
mass index, varicose veins, unprovoked versus provoked DVT, deep calf vein versus muscular vein thromboses) between patients who had an in-person or a phone PTS assessment. Varicose veins at baseline were more prevalent in patients who had a PTS assessment versus no PTS assessment (21% versus 12%) (Table S1 in supporting information).
There were no differences in other baseline characteristics.
3.2 | Postthrombotic syndrome (PTS)
Fifty-four (30%) patients had PTS at follow-up. PTS was mild, mod- erate, and severe in 76%, 11%, and 13% of cases, respectively. There was no difference between treatment groups in the prevalence or severity of PTS (Table 2).
Sensitivity analyses showed that in the subgroup of patients without contralateral chronic venous insufficiency, patients in the nadroparin arm had a significantly lower prevalence of PTS than those in the placebo arm (9% versus 24%, P = .04).
No differences in prevalence of PTS were found in patients as- sessed at in-person visits versus phone visits (P = 1.0).
3.3 | Predictors of PTS
Women had a higher prevalence of PTS than men (odds ratio [OR] = 3.4 [1.7-6.6]), as did patients with varicose veins (OR = 2.4 [1.1-4.9]). Initial anticoagulation (ie, allocation to nadroparin versus placebo), age, body mass index, DVT location, and VTE recurrence, among other tested variables, were not associated with a signifi- cantly different prevalence of PTS.
3.4 | VTE recurrence
Twenty patients (11%) experienced at least one VTE recurrence (SVT, DVT, or PE) during follow-up (Table 3). VTE recurrence oc- curred in 8% (n = 7) in the nadroparin and 14% (n = 13) in the placebo groups (P = .2). No proximal DVT or PE occurred after 90 days.
3.5 | Other outcomes
Three (2%) patients, all in the nadroparin group, died during follow- up. Eight (4%) patients had a new diagnosis of cancer, five in the na- droparin group and three in the placebo group.
3.6 | Quality of life scores
There was no difference in SF-36 scores (P = .5) or VEINES-QOL scores (P = .6) among patients treated with nadroparin versus placebo (Table 4). As expected, compared with patients without PTS, those F I G U R E 1 Study flow chart
Cactus Trial, patients randomized N = 259
3 lost to Follow-up 4 withdrew consent
48 lost to Follow-up 16 refused follow-up
7 died
3 developed dementia Cactus Trial, intention to treat analysis
N = 252
N = 188
N = 87 N = 91
Nadroparin Group Placebo Group Cactus-PTS study, primary outcome
analysis N = 178 patients Patients with long-term follow-up data
who developed PTS had significantly lower SF-36 scores (74 versus 52, P = .0001) and VEINES-QOL scores (53 versus 44, P = .0001).
4 | DISCUSSION
In this long-term follow-up study of patients with distal DVT who participated in the CACTUS trial, we found that 30% developed PTS, which was mild in 76% of patients. A 6-week course of therapeutic
nadroparin to treat the index distal DVT did not appear to reduce the risk of PTS, except in the subpopulation of patients without primary venous insufficiency.
To our knowledge, our study is the first to prospectively assess the risk of PTS in a large population (>100) of patients with a first symptomatic distal DVT followed in the long term. We found that after a median of 6 years after distal DVT, approximately one third of patients had PTS, which was mild in most (>75%) cases. This rate of PTS is lower than the rate of PTS after proximal DVT re- ported in recent studies with long-term follow-up (30%-70%).4,27 In the German TULIP PLUS registry, the rate of PTS at 3 years in the 64 patients with a first isolated distal DVT was lower than ours: 15.6%.28 However, this difference is fully explained by the fact that in TULIP PLUS registry, patients with preexisting chronic venous insufficiency were excluded. Indeed, when restricting our analysis to patients with a VS < 5 in the leg contralateral to DVT, our rate of PTS was identical: 16%. Taken together, our results and those of the TULIP PLUS registry demonstrate that the risk of developing PTS after a distal DVT is important, albeit lower than after proximal DVT.
We also found that generic and venous disease-specific QOL scores of distal DVT patients with PTS were significantly reduced to a degree that is clinically relevant (>3-4 points) compared with distal DVT patients who did not develop PTS.29 This shows that dis- tal DVT-related PTS is burdensome to patients and associated with significant morbidity.
We also assessed the effect of anticoagulation on the risk of de- veloping PTS after distal DVT. While there was no overall difference in the frequency of PTS in the nadroparin versus placebo groups, in the subgroup of patients without preexisting chronic venous
Total study population N = 178
Nadroparin group N = 87
Placebo group N = 91 Demographics and clinical characteristics
Female sex 86 (48) 42 (48) 44 (48)
Age at PTS assessment, years
59 (47-68) 61 (45-68) 58 (47-70)
BMI, kg/m2 25 (22-28) 25 (23-29) 25 (22-28)
Varicose veins 37 (21) 20 (23) 17 (19)
DVT characteristics
Unprovoked DVT 78 (44) 44 (48) 34 (39)
Deep calf vs muscular DVT
75 (42) 37 (41) 38 (44)
>1 thrombosed vein 23 (13) 12 (13) 11 (12)
ECS use
At 6-wk FU visit 151 (85) 71 (82) 80 (88)
At long-term FU visit 79 (63) 36 (57) 43(68)
Worn > 70% of the time 30 (39) 13 (37) 17 (40)
Note: Data are n (%), median (IQR), or n/N, unless indicated otherwise.
Abbreviations: BMI, body mass index (in Kg/m2); DVT, deep vein thrombosis; ECS, elastic compression stockings; FU, follow-up; IQR, interquartile range; PTS, postthrombotic syndrome.
TA B L E 1 Demographics and DVT characteristics of the 178 patients assessed for PTS in the whole CACTUS- PTS population and according to CACTUS trial treatment allocation group
TA B L E 2 Proportion of patients with PTS and severity of PTS at the long-term follow-up visit in the whole CACTUS-PTS population and according to initial CACTUS trial treatment allocation group
CACTUS- PTS population N = 178
Nadroparin group N = 87
Placebo group N = 91 P
value*
Postthrombotic syndrome
54 (30) 25 (29) 29 (32) .6
Villalta severity category Mild (score
5-9)
41 (23) 18 (21) 23 (25) .9
Moderate (score 10-14)
6 (3) 3 (3) 3 (3)
Severe (score > 14, ulcer)
7 (4) 4 (5) 3 (3)
Note: Data are n (%).
Abbreviation: PTS, postthrombotic syndrome.
*For comparison between nadroparin versus placebo groups.
862
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GALANAUD etAL.insufficiency, in whom clinical evidence of PTS likely represents
“true” PTS rather than a reflection of preexisting primary chronic venous insufficiency,30 anticoagulation significantly reduced the risk of developing PTS. However, as this was a secondary subanalysis on a small sample size, this result needs to be interpreted cautiously and merits further study.
Regarding VTE recurrence, we found that, in the long term, pa- tients who had been treated with anticoagulation had a twice lower risk of VTE recurrence than those who had been left untreated.
However, this result did not reach statistical significance. In addi- tion, it should be pointed out that all the VTE events adjudicated
more than 90 days after initial distal DVT were either distal DVT or superficial vein thromboses.
Our study has a number of strengths and limitations that should be acknowledged. Among the strengths, its multicenter, prospec- tive, and double-blinded design should be underlined. To our knowl- edge, CACTUS-PTS is thus far the largest study in terms of number of distal DVT patients assessed for PTS. We were also able, for the first time, to assess the impact of PTS on QOL after a distal DVT as well as the impact of anticoagulation versus no anticoagulation on the risk of PTS after distal DVT.
Among the limitations, we are aware that only 188 of the 252 pa- tients included in the intention to treat analysis of the main CACTUS trial underwent long-term follow-up (75%), and 178 (95%) of them were assessed for PTS. This is likely the consequence of attrition over our very long follow-up time and the fact that when this follow-up study was initiated, most patients had already completed the main CACTUS trial. CACTUS patients who underwent PTS assessment had a higher prevalence of varicose veins at baseline than those who did not. This may have led to a mild overestimate of our overall rate of PTS (at most by <3%) but has no impact on our main finding that anticoagulation with nadroparin does not provide any clear benefit to prevent PTS. Importantly all other baseline characteristics—eg, age, sex, body mass index, and distal DVT characteristics—of patients in- cluded in the CACTUS-PTS analysis were not different from those of patients that did not have a PTS assessment. Although our cohort of distal DVT patients is the largest to date to be assessed for PTS, due to the limited number of patients with PTS, we were unable to assess the impact of anticoagulation on PTS severity (ie, whether patients allocated to nadroparin had less severe PTS than those allocated to placebo, in all patients and in patients without preexisting primary chronic venous insufficiency). This limits the interpretation of our finding that anticoagulant treatment may prevent PTS in patients without preexisting primary venous insufficiency. Finally, as patients in both groups were prescribed ECS and that the vast majority of pa- tients (>80%) wore them for at least the first 6 weeks we were not able to adequately assess the impact of ECS on the development of PTS after distal DVT.
In conclusion, after a first isolated distal DVT, PTS develops in about one third of patients and is associated with reduced QOL.
Therapeutic anticoagulation of distal DVT for 6 weeks did not reduce the risk of PTS in the overall study population. However, it reduced the risk in patients without preexisting chronic venous insufficiency and may have led to a lower rate of VTE recurrence. Our results support the need for further research on the risks and benefits of anticoagulants for the treatment of distal DVT. They also suggest that inclusion of patients with significant preexisting venous insuffi- ciency should be carefully balanced when conducting interventional research on PTS.
ACKNOWLEDGMENTS
The CACTUS study was supported by a grant from The Swiss National Science Foundation (Grant no 3200B0-104172), a grant from the Programme Hospitalier de Recherche Clinique (French TA B L E 3 Rates of VTE recurrence (DVT, PE, and SVT) during
study follow-up* in the whole CACTUS-PTS population and according to initial CACTUS trial treatment allocation group
CACTUS-PTS population N = 178
Placebo group N = 91
Nadroparin group N = 87
P value Any VTE
recurrence
20 (11) 13 (14) 7 (8) .2
Deep VTE
recurrence 17 (10) 11 (12) 6 (7) .6
Proximal DVT or PE
6 (3) 3 (3) 3 (4)
Distal DVT 11 (6) 8 (9) 3 (4)
SVT 3 (2) 2 (2) 1 (1) 1.0
Note: Data are n (%).
Abbreviations: DVT, deep vein thrombosis; PE, pulmonary embolism;
SVT, superficial vein thrombosis; VTE, venous thromboembolism.
*From randomization until the end of follow-up; Only the first VTE event is taken into account; one patient with proximal DVT later developed a distal DVT; no patient with first recurrence as a SVT later developed a DVT or PE.
TA B L E 4 General and disease-specific QOL scores of CACTUS patients according to treatment group and to the development of PTS
QOL measure Treatment group P value
Placebo group Nadroparin group
N = 50 N = 46
SF-36 67 (± 20) 64 (± 21) .5
N = 46 N = 36
VEINES-QOL 50 (± 7) 48 (± 9) .6
Patients with PTS
Patients without PTS
N = 37 N = 59
SF-36 52 (±16) 74 (±19) .0001
N = 37 N = 45
VEINES-QOL 44 (±7) 53 (±6) . 0001
Note: Values shown are mean score (±standard deviation).
Abbreviations: PTS, postthrombotic syndrome; QOL, quality of life.
Ministry of Health, PHRC 20051409), a grant from The Canadian Institutes of Health Research (MOP-119524), and a grant from The 2007 International Society on Thrombosis and Haemostasis (ISTH) Presidential Fund. The CACTUS-PTS add-on study was funded by the Canadian Institutes of Health Research (MOP-119524). Dr Kahn is a Tier 1 Canada Research Chair holder. Dr Galanaud was sup- ported by a grant from The French Society of Vascular Medicine. Drs.
Galanaud, Delluc, Carrier, Solymoss, Kassis, and Kahn are investiga- tors of the CanVECTOR Network, which receives grant funding from the Canadian Institutes of Health Research (Funding Reference: CDT- 142654). We would like to thank all the residents and physicians from the emergency departments and vascular medicine units of all partici- pating centers. We thank all investigators, study nurses, secretaries, and clinical research associates for their invaluable help. We also thank the Swiss Society of Angiology and the French Society for Vascular Medicine, as well as GlaxoSmithKline and Aspen Pharma, which pro- vided the study drug and Sigvaris, which provided ECS to CACTUS study Canadian patients. And last but not least, we would like to ex- press our gratitude to the patients who made the study possible by agreeing to participate to the trial.
CONFLIC T OF INTEREST
Jean-Philippe Galanaud, Susan R Kahn, Marc Righini, Isabelle Quéré, Lorris Le Collen, Aymeric Douillard, Helia Robert-Ebadi, Daniel Pontal, David Morrison, Marie-Thérèse Barrellier, Antoine Diard, Hervé Guénnéguez, Dominique Brisot, Pascale Faisse, Sandrine Accassat, Myriam Martin, Aurélien Delluc, Susan Solymoss, Jeannine Kassi,s and Marc Carrier state that they have no conflicts of interest in relation to this research.
AUTHOR CONTRIBUTIONS
Jean-Philippe Galanaud, Susan R Kahn, Marc Righini, and Isabelle Quéré: designed research, obtained funding, performed re- search, collected data, analyzed data, and wrote the paper; Lorris Le Collen, Aymeric Douillard, Helia Robert-Ebadi, Daniel Pontal, David Morrison, Marie-Thérèse Barrellier, Antoine Diard, Hervé Guénnéguez, Dominique Brisot, Pascale Faisse, Sandrine Accassat, Myriam Martin, Aurélien Delluc, Susan Solymoss, Jeannine Kassis, and Marc Carrier performed research, collected data, analyzed data, and approved the manuscript.
ORCID
Aurélien Delluc https://orcid.org/0000-0003-0227-1245 Susan R. Kahn https://orcid.org/0000-0002-5667-8916
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SUPPORTING INFORMATION
Additional supporting information may be found online in the Supporting Information section.
How to cite this article: Galanaud J-P, Righini M, Le Collen L, et al. Long-term risk of postthrombotic syndrome after symptomatic distal deep vein thrombosis: The CACTUS-PTS study. J Thromb Haemost. 2020;18:857–864. https ://doi.
org/10.1111/jth.14728
