Journal of Thrombosis and Haemostasis

Predictors of the post-thrombotic syndrome during long-term treatment of proximal deep vein thrombosis

Authors


S. R. Kahn, Center for Clinical Epidemiology and Community Studies, Sir Mortimer B. Davis Jewish General Hospital, 3755 Cote Ste. Catherine Rm. A-127, Montreal, Quebec H3T 1E2, Canada. Tel.: +1 514 340 8222, ext 4667; fax: +1 514 340 7564; e-mail: susan.kahn@mcgill.ca

Abstract

Summary. Background: The post-thrombotic syndrome is a chronic, poorly understood complication of deep venous thrombosis (DVT). Objectives: To evaluate predictors of the post-thrombotic syndrome, including intensity of long-term anticoagulation, and to assess the impact of the post-thrombotic syndrome on quality of life. Patients and methods: The setting was 13 Canadian hospitals and one US hospital. One hundred and forty-five patients with an unprovoked episode of proximal DVT who were initially treated with 3 months of conventional-intensity warfarin [target International Normalized Ratio (INR) of 2.5] then participated in a trial comparing two intensities of long-term warfarin therapy (target INR 2.5 vs. INR 1.7). Post-thrombotic syndrome was assessed at the end of the trial using a validated clinical scale. Generic and venous disease-specific quality of life was compared in patients with and without the post-thrombotic syndrome. Multivariable regression analyses were performed to identify predictors of the post-thrombotic syndrome and of its severity. Results: After an average follow-up of 2.2 years, the prevalence of post-thrombotic syndrome was 37% and of severe post-thrombotic syndrome was 4%. Quality of life was worse in patients with the post-thrombotic syndrome compared with patients who did not have it. The presence of factor (F)V Leiden or the prothrombin gene mutation was an independent predictor of both a lower risk (P = 0.006) and reduced severity (P = 0.045) of the post-thrombotic syndrome. Intensity of anticoagulation did not influence the risk of developing the post-thrombotic syndrome. Conclusions: The post-thrombotic syndrome is a frequent and burdensome complication of proximal DVT, even among patients maintained on long-term oral anticoagulation. While the presence of FV Leiden or prothrombin gene mutation appears to be associated with a reduced risk of post-thrombotic syndrome, this finding requires further evaluation in prospective studies.

Introduction

The post-thrombotic syndrome is a frequent, chronic complication of deep venous thrombosis (DVT). From the limited prospective data available, it is estimated that post-thrombotic syndrome develops in 20–40% of patients within 1–2 years after symptomatic DVT, and a severe form occurs in 5–10% of patients [1–3]. While recurrent, ipsilateral DVT increases the risk of developing post-thrombotic syndrome [1,3], it is not known whether other factors such as patient characteristics, intensity or duration of anticoagulant therapy or degree of resolution of the initial thrombus influence its development. Inability to predict who will develop the post-thrombotic syndrome has hampered progress in its prevention [4].

We recently completed the ELATE Study, a multicenter, double-blind, randomized trial that compared two intensities of warfarin therapy [target International Normalized Ratio (INR) 2.5 (range 2.0–3.0) vs. INR 1.7 (range 1.5–1.9)] for the long-term treatment of unprovoked venous thromboembolism (DVT or pulmonary embolism) in patients who had already completed at least 3 months of conventional-intensity (target INR 2.5) warfarin therapy [5]. This study provided us with an opportunity to evaluate predictors of the post-thrombotic syndrome, including the intensity of long-term anticoagulation, and to assess the impact of the post-thrombotic syndrome on health-related quality of life.

Methods

Consecutive patients with one or more episodes of unprovoked symptomatic venous thromboembolism (proximal DVT or pulmonary embolism) who had completed 3 or more months of conventional-intensity (target INR 2.5) warfarin therapy were potentially eligible for the ELATE study [5]. Patients were excluded if they had other indications for warfarin, a contraindication to long-term warfarin therapy, a known antiphospholipid antibody, an allergy to contrast medium, or a life expectancy of < 2 years. Eligible, consenting patients were randomly assigned to either long-term conventional-intensity (target INR of 2.5) or low-intensity (target INR of 1.7) warfarin therapy. Patients, clinical centers, the coordinating center, the monitoring committee and the central adjudication committee for outcomes were unaware of treatment allocation (i.e. blinded design). The primary outcomes of interest for the ELATE study, which have previously been published, were symptomatic recurrent venous thromboembolism and bleeding [5].

To be considered for this substudy, patients had to have had (i) symptomatic proximal DVT (with or without pulmonary embolism) as their index event; and (ii) completed 3–4 months of conventional intensity warfarin therapy before enrollment in the ELATE trial. This ensured that substudy patients had a similar duration of initial conventional-intensity warfarin therapy, and allowed us to examine whether subsequent intensity of long-term warfarin therapy (i.e. low vs. conventional intensity) influenced the development of the post-thrombotic syndrome.

Outcome measures

At completion of the ELATE trial, each leg was assessed using a clinical scale developed by Villalta that grades the severity of five leg symptoms (pain, cramps, heaviness, pruritus and paresthesia) and six signs (edema, skin induration, hyperpigmentation, venous ectasia, redness, pain during calf compression), from 0 to 3 [6]. A Villalta score of 5 or higher is classified as the presence of the post-thrombotic syndrome. A score of 15 or higher, or the presence of a venous ulcer, is classified as severe post-thrombotic syndrome. Study personnel who examined the patients were unaware of their thrombophilia status, number of prior venous thromboembolic episodes and treatment allocation group (i.e. intensity of long-term warfarin).

General and venous disease-specific quality of life were assessed using the Short-Form Health Survey-36 (SF-36) [7] and the Venous Insufficiency Epidemiological and Economic Study-Quality of Life/Symptoms measure (VEINES-QOL/Sym) [8], respectively. The SF-36 is the current generic gold standard measure of physical [SF-36 Physical Component Score (PCS)] and mental [SF-36 Mental Component Score (MCS)] quality of life. The VEINES-QOL is a validated questionnaire that measures venous symptoms and limitations in daily activities and psychological impact of venous disease. VEINES-Sym is a validated subscale of the VEINES-QOL that measures venous symptoms. For all quality of life measures, lower scores indicate poorer quality of life.

Statistical analysis

Both legs were evaluated, but only the leg that had the index DVT was used in the analysis to assess for the presence and severity of post-thrombotic syndrome. If the index event was bilateral proximal DVT, the leg with the higher Villalta score was used. Comparisons between patients with and without the post-thrombotic syndrome were made using Fisher's exact test or Student's t-test, as appropriate. Ninety-five percent confidence intervals (CI) for proportions, and for differences of proportions, were calculated using the Wilson score method. In all cases, a statistically significant finding was defined as a two-sided P-value of ≤ 0.05. Logistic regression analysis was used to evaluate the association between post-thrombotic syndrome and the following predictor variables: age, sex, body mass index (BMI), intensity of long-term warfarin therapy, previous episode(s) of venous thromboembolism, duration of follow-up, factor (F)V Leiden or the prothrombin gene mutation, and presence of residual DVT at the time of randomization (defined as lack of full compressibility of the popliteal or femoral vein on venous ultrasound). Predictors achieving statistical significance were reported as an odds ratio (OR) with an associated 95% CI. Multiple linear regression was used to evaluate predictors of post-thrombotic syndrome severity among study patients. The modeling process used backward elimination to select the final model. Wherever possible, first-order interactions were also investigated.

Results

Study patients

Of the 738 patients in the ELATE Study, 230 had symptomatic proximal DVT as their qualifying index event and were treated for 3–4 months before randomization, and hence, were eligible to participate in this substudy. Of these, 145 are included in this analysis, and 85 were not included for the following reasons: 24 were from two clinical centers that did not participate in this study, 13 had died, 10 had recurrent thrombotic events and were no longer being followed, nine declined participation, 16 agreed to participate but did not return to complete post-thrombotic syndrome assessments and 13 had incomplete data forms that precluded calculation of Villalta score. Characteristics of eligible patients who did, and did not, participate in the post-thrombotic syndrome substudy are shown in Table 1. Non-participants were more likely than participants to have had recurrent venous thromboembolism during follow-up (P = 0.001).

Table 1.  Characteristics of potentially eligible patients who did, and did not participate in the substudy
CharacteristicParticipants (n = 145)Non-participants (n = 85)
  1. CUS, Compression ultrasound; INR, International Normalized Ratio; VTE, venous thromboembolism. *P = 0.001.

Age (years):
 Mean (SD)59.1 (15.6)59.0 (16.2)
 Min–max18–8727–90
Female sex:
 No. (%)64 (44%)37 (44%)
Body mass index (kg m−2):(n = 141)(n = 80)
 Mean (SD)30.2 (5.7)29.6 (5.4)
 Min–max18.3–52.419.7–43.0
Previous episodes of VTE:
 No. (%)99 (68%)65 (76%)
Abnormal CUS of proximal deep veins at time of randomization:(n = 131)(n = 77)
 No. (%)74 (56%)42 (55%)
Target INR, low intensity (1.5–1.9):
 No. (%)67 (46%)49 (58%)
Follow-up (months):
 Mean (SD)26.4 (8.8)27.2 (9.8)
 Min–max13–431–42
VTE recurrence during follow-up*:
 No. (%)2 (1.4%)10 (12%)

Among participants, 143 patients had unilateral DVT (84 on the left side, and 59 on the right side) and two had bilateral DVT.

Prevalence and severity of the post-thrombotic syndrome

The mean interval between enrollment in the ELATE trial and assessment for the post-thrombotic syndrome was 2.2 years. At assessment, a Villalta score of ≥ 5 was obtained for 55 of 147 (37%) legs that had the index DVT (bilateral in one patient) and for 24 of 143 (17%) legs without DVT (P = 0.0001). Fifty-four (37%) patients satisfied our definition for the post-thrombotic syndrome (Villalta score of ≥ 5 in the same leg as the initial DVT) and six (4%) had severe post-thrombotic syndrome [score of ≥ 15 (four patients) or the presence of a venous ulcer (two patients)]. The mean Villalta score in patients with post-thrombotic syndrome was 8.8 (SD = 3.8) and in the subgroup of patients with severe post-thrombotic syndrome was 13.5 (SD = 6.2); the two patients with venous ulcers had scores of 6. Post-thrombotic syndrome was present in 29 of 83 (35%) patients who had a left-sided DVT compared with 25 of 62 (41%) patients who had a right-sided DVT (P = 0.49). This includes one patient with bilateral DVT and bilateral post-thrombotic syndrome. There was no difference in the severity of left-sided vs. right-sided post-thrombotic syndrome (data not shown).

Quality of life scores

Overall, patients defined as having the post-thrombotic syndrome had significantly lower generic and venous disease-specific quality of life scores than those without post-thrombotic syndrome (Fig. 1). Mean score differences were 3.1 (95% CI – 0.3, 6.5) for SF-36 MCS, 7.4 (95% CI 3.5, 11.3) for SF-36 PCS, 6.9 (5.2, 8.6) for VEINES-QOL, and 7.8 (5.9, 9.7) for VEINES-Sym. As a point of reference, 4–5 point differences in SF-36 scores between groups are considered clinically relevant [9].

Figure 1.

Generic and disease-specific quality of life scores in patients with and without the post thrombotic syndrome. SF-36 MCS (Mental Component Summary score) and SF-36 PCS (Physical Component Summary score) are generic quality of life measures. VEINES-QOL and VEINES-Sym are venous disease-specific quality of life measures. The VEINES-Sym is a validated subscale of the VEINES-QOL that measures venous symptoms. For all measures, lower scores indicate poorer quality of life. PTS, Post-thrombotic syndrome. Error bars represent 2 SEM.

Clinical characteristics associated with the post-thrombotic syndrome

The clinical characteristics of patients with and without the post-thrombotic syndrome are shown in Table 2. FV Leiden or the prothrombin gene mutation was significantly less frequent in patients with post-thrombotic syndrome compared with patients without post-thrombotic syndrome. Multivariate analyses confirmed that inherited thrombophilia was independently associated with a lower frequency of post-thrombotic syndrome (OR 0.33, 95% CI 0.15, 0.73, P = 0.006) and with reduced severity of post-thrombotic syndrome [1.6 point decrease (95% CI 0.06, 3.2, P = 0.045) in Villalta score if thrombophilia present] (Table 3). There was no statistical interaction between age, presence of these mutations, and development of the post-thrombotic syndrome. BMI was weakly predictive of post-thrombotic syndrome severity in the linear regression model [0.16 increase (95% CI 0.03, 0.29, P = 0.015) in Villalta score for each unit increase in BMI]. Neither the presence nor the severity of post-thrombotic syndrome was found to be associated with age, sex, previous episode(s) of venous thromboembolism or residual proximal DVT on ultrasound at randomization. Furthermore, neither target INR (i.e. 2.5 vs. 1.7) nor proportion of time with INR < 2.0 was associated with development of the post-thrombotic syndrome in any of the analyses.

Table 2.  Clinical characteristics of patients with and without the post-thrombotic syndrome
CharacteristicPTS n = 54No PTS n = 91Difference (95%CI)P-value
  1. PTS, Post-thrombotic syndrome; VTE, venous thromboembolism; FVL, factor V Leiden; PTm, prothrombin gene mutation; DVT, deep venous thrombosis; INR, International Normalized Ratio. *Samples not received at Central Laboratory for all patients as this was not a mandatory component of the ELATE Trial.

Age (years):
 Mean (SD)60.7 (13.8)58.1 (16.6)2.7 (− 2.6, 8.0)0.32
 Min–max26–8518–87  
Female sex:
 No. (%)27 (50%)37 (41%)9% (− 5, 23)0.27
Body mass index (kg m−2):(n = 53)(n = 88)  
 Mean (SD)31.0 (6.5)29.4 (5.3)1.6 (− 0.4, 3.7)0.11
 Min–max20.0–52.318.3–52.4  
Any previous episode of VTE:
 No. (%)36 (68%)63 (68%)0% (− 16, 14)1.0
Previous Episodes of VTE: no. (%)   
 018 (33%)29 (32%)  
 125 (46%)47 (51%) 0.47
 29 (17%)11 (12%)  
 3 +2 (4%)5 (5%)  
Thrombophilia (FVL or PTm)*:(n = 51)(n = 74)  
 No. (%)13 (25%)36 (49%)− 23% (− 36, −9)0.009
Follow-up (months):
 Mean (SD)27.0 (8.4)26.1 (9.1)1.0 (− 2.0, 4.0)0.53
 Min–max13–4313–43  
Residual deep venous thrombosis at time of randomization:(n = 50)(n = 81)  
 No. (%)29 (58%)45 (56%)2% (− 12, 17)0.78
Target INR, low intensity (1.5–1.9):
No. (%)23 (43%)44 (48%)− 6% (− 19, 8)0.50
Percent of time (months) INR < 2.0:    
 Mean (SD)46.2 (34.3)48.8 (33.8)− 2.7 (− 14.2, 8.9)0.65
 Min–max0–960–97  
Table 3.  Independent predictors of the post-thrombotic syndrome
Dependent variableLogistic regression Villalta score ≥ 5Linear regression Villalta score
  1. For explanation of the Villalta score, see Outcome measures.

Predictors
Inherited thrombophilia (yes vs. no)OR = 0.33Coefficient = − 1.6
95% CI 0.15, 0.7395%CI −3.2, – 0.06
P = 0.006P = 0.045
Body mass index (kg m−2)OR = 1.06Coefficient = + 0.16
95% CI 0.99, 1.1395% CI 0.03, 0.29
P = 0.085P = 0.015

Discussion

We found that the post-thrombotic syndrome is a frequent complication of proximal DVT, even among patients maintained on long-term oral anticoagulation. The overall rate of 37% that we observed is higher than the rate of 22% at 2 years reported by Prandoni, who used the Villalta scale to diagnose the post-thrombotic syndrome [1]. The fact that all patients in our study had proximal DVT and many had a prior history of venous thromboembolism may explain the higher frequency of the post-thrombotic syndrome in this study. However, as only 11% (4%/37%) of those who developed the post-thrombotic syndrome in the current study were categorized as ‘severe’ compared with 27% of such patients in the study by Prandoni, in which anticoagulant treatment was stopped after 3 months, we cannot exclude that remaining on anticoagulant therapy reduced the severity of the syndrome.

Patients with post-thrombotic syndrome had worse quality of life than patients without post-thrombotic syndrome, with differences in disease-specific scores that were clinically significant and of a similar magnitude to those we reported in a separate population of DVT patients [10]. This finding, along with the substantial frequency of post-thrombotic syndrome in our study patients, confirms that that post-thrombotic syndrome causes substantial morbidity at both a patient and a population level.

We thought that a lower intensity of long-term anticoagulation might be associated with the development of the post-thrombotic syndrome. Having observed in the ELATE trial that low-intensity anticoagulation was associated with a higher frequency of recurrence, we considered that low-intensity therapy might also have been associated with a higher frequency of asymptomatic recurrent venous thrombosis (either small or larger veins) that could predispose to the post-thrombotic syndrome. However, our hypothesis was not confirmed. Further, ultrasound evidence of residual DVT 3–4 months after acute DVT did not appear to increase the risk of the post-thrombotic syndrome. Our observation that the post-thrombotic syndrome was less common in patients with FV Leiden or the prothrombin gene mutation was unexpected. While this finding may have occurred by chance, it may reflect true differences in the biology and natural history of thrombi that occur in patients with inherited thrombophilia compared with patients without inherited thrombophilia. For example, a recent review of seven primary studies reported that, among patients with venous thromboembolism, those with FV Leiden are half as likely to develop pulmonary embolism as those without FV Leiden [11]. It has also been reported that patients with symptomatic DVT who have FV Leiden have thrombi that are less extensive and less likely to involve the iliofemoral veins than those who do not have FV Leiden [12]. Hence, there may be a tendency for FV Leiden to predispose to smaller thrombi that are less likely to form emboli and to damage the venous valvular system (and thus induce post-thrombotic syndrome). In contrast to our finding, thrombophilia did not influence the risk of developing the post-thrombotic syndrome in a recent trial that evaluated graduated stockings in a heterogeneous group of patients with a first episode of proximal DVT [3]. However, the prevalence of thrombophilia was only 18% in that study, and associated hazard ratios were not reported.

Our finding that increased BMI was associated with the post-thrombotic syndrome has also been reported by others [13,14]. Although the explanation for this association is uncertain, obesity is known to be a risk factor for varicose veins and chronic venous insufficiency [15,16], and it is conceivable that excess body weight might increase venous pressure and promote valvular reflux in already compromised veins. The potential role of weight reduction in the prevention or management of the post-thrombotic syndrome should be evaluated.

Our study has a number of strengths including that: data were collected prospectively and systematically; the study population was well-defined; patients were recruited at multiple centers; there was blinded allocation of treatment group; study personnel who assessed patients for the post-thrombotic syndrome were unaware of thrombophilia status or compression ultrasound results; validated scales were used to define the presence and severity of the post-thrombotic syndrome [1,2,10] and to measure generic and disease-specific quality of life [8,9]; and the duration of follow-up (> 2 years) allowed sufficient time for the post-thrombotic syndrome to become apparent [1].

There are also several limitations to our study. First, we cannot comment on whether use of elastic compression stockings influenced the development of post-thrombotic syndrome, as data on their use were not available. While we do not have reason to believe that stocking use would have differed according to assigned intensity of anticoagulation, as the ELATE trial was a blinded, randomized controlled trial, or according to thrombophilia status, as blood samples were analyzed centrally at the end of the ELATE trial, this is a potentially important limitation, as elastic compression stockings have been shown in two open-label clinical trials to reduce the incidence of the post-thrombotic syndrome [2,3]. Second, two-thirds of patients were noted to have had at least one episode of venous thromboembolism (which could include contralateral DVT, ipsilateral DVT or pulmonary embolism) before the thrombosis that qualified them for the current study (Table 2). Although we were able to determine that the post-thrombotic syndrome did not occur more often, or with greater severity, in this group of patients, details of previous episodes of thrombosis were not available to allow us to determine if the site or side of previous DVTs influenced our findings. We suspect that previous episodes of DVT contributed to the relatively high prevalence (i.e. 17%) of a Villalta score of ≥ 5 in patients' contralateral legs. Third, as venous thromboembolism recurrence was a primary endpoint of the ELATE Study and most such patients did not attend the final study visit, we could not assess the relation between recurrent ipsilateral DVT and development of the post-thrombotic syndrome. However, as only 3% of the ELATE study population had recurrent venous thromboembolism, and as recurrence was not associated with either the presence of thrombophilia or residual DVT at randomization [5], we believe that loss of these patients to the analysis is unlikely to have materially influenced our findings. Fourth, because central testing for thrombophilia was not a mandatory component of the ELATE Trial, we do not have complete data on thrombophilia status for all patients who participated in this study. Finally, as 10 of the 12 patients who had recurrent venous thromboembolism and who were eligible for our study could not be included in our analysis, and as recurrent ipsilateral DVT is an important risk factor for development of the post-thrombotic syndrome, our study may have underestimated the frequency of post-thrombotic syndrome.

We conclude that the post-thrombotic syndrome is a frequent complication of proximal DVT, even among patients maintained on long-term oral anticoagulation, and that it has a significant adverse impact on quality of life. While the presence of FV Leiden or prothrombin gene mutation appears to be associated with a reduced risk of developing post-thrombotic syndrome after proximal DVT, this finding should be considered preliminary and requires further evaluation in prospective studies.

Acknowledgements

The authors gratefully acknowledge the assistance of study personnel at the participating clinical centers. S.R.K. is supported by Fonds de la Recherche en Santé du Québec. C.K., M.A.C. and J.S.G. are supported by the Canadian Institutes of Health Research. P.W. holds a Canada Research Chair in thromboembolism. M.J.K. is supported by the University of Western Ontario. D.R.A. is supported by Dalhousie University. M.R. is supported by the Heart and Stroke Foundation of Canada. J.S.G. is supported by the Heart and Stroke Foundation of Ontario. The ELATE study was funded by the Canadian Institutes of Health Research. This study was funded, in part, by an unrestricted grant from AstraZeneca. The sponsor had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. A portion of this work was presented at the American Society of Hematology 45th Annual Meeting, San Diego, USA, December 2003.

Contribution of authors

S.R.K. conceived of the study idea and study analysis and drafted the paper. C.K. designed and conducted the original trial and provided input into the study design and analysis. J.A.J. helped plan and performed the data analysis. B.M-K. assembled the data. M.J.K., P.W., M.A.C., D.R.A., P.v.N., C.D., S.S., J.K., W.G., M.R., J.H. and J.S.G. were investigators of the original trial and provided patients for the study. All authors contributed to the writing of the paper and provided critical suggestions.

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