Tinzaparin in intermediate dose for the treatment of superficial vein thrombosis: Results from an observational multicenter study

Abstract

Objectives

Low-molecular-weight heparins are recommended in the treatment of superficial vein thrombosis but with low grade of evidence. This study was conducted to assess the treatment outcomes of acute superficial vein thrombosis with intermediate dose of Tinzaparin.

Methods

Retrospective analysis of records from outpatients over a period of 16 months treated in seven centers with Tinzaparin 0.5 ml (10,000 anti-Xa IU) once daily for a period that was at the treating physician’s discretion. All the patients were followed up for at least 12 weeks.

Results

A total of 296 patients (189 females, mean age 57.4 years) were included. Two thirds of the patients (191/296, 64.5%) received treatment for approximately five weeks (mean 36.9 days) and the remaining (105/296, 35.5%) for a shorter period (mean 16.2 days). There was no difference in patients’ characteristics between the two treatment duration groups. The presence of thrombus above the knee and restricted daily activity were associated with longer period of treatment. Only one case with minor bleeding was observed. Recurrence of thrombosis over a 12-week follow-up period occurred in 6% (superficial vein thrombosis in 14 (4.7%), deep vein thrombosis in 3 (1%) and thrombus extension in the superficial veins in 1 (0.3%)). Recurrence was not related to the duration of treatment.

Conclusions

Intermediate dose of Tinzaparin was an effective and safe treatment for superficial vein thrombosis in the setting of real world practice. Location of thrombus and status of patients’ mobilization were associated with longer duration of treatment. Future prospective randomized studies are needed to corroborate these findings.

Keywords

deep vein thrombosis low-molecular-weight heparin pulmonary embolism superficial vein thrombosis venous thromboembolism

Introduction

Superficial vein thrombosis (SVT) is a relatively common condition most frequently affecting patients with varicose veins (VVs).^1,2 The prevalence of SVT appears to be twofold higher compared to deep vein thrombosis (DVT) and pulmonary embolism (PE).³ In the past, it has been considered as a benign condition with low clinical importance; however, recent findings have demonstrated that SVT may cause or could coexist with DVT and/or PE in 6–53% and 1.5–33%, respectively. ^1,2 Besides these interesting observations, SVT has not been studied in a systematic manner.

The therapeutic goals of SVT include resolution of symptoms, prevention of thrombus extension, prevention of propagation of the thrombotic process into the deep vein system and prevention of recurrence.⁴ Various therapeutic approaches have been proposed; however, the majority of the studies evaluating the treatment of SVT are of poor methodological quality and thus the current recommendations with respect to treatment are weak.^5,6

Patients with SVT are commonly treated with low-molecular-weight heparin (LMWH) in prophylactic, intermediate or therapeutic dosages for treatment periods of 10–45 days. This practice is also reflected by current guidelines but with low grade of evidence.^5,6 The results of two randomized clinical trials of SVT treatment comparing different regimens of LMWH did not manage to clearly define which dose or treatment duration of LMWH is best in the reduction of symptomatic venous thromboembolism (VTE) development and/or recurrence.^7,8 Fondaparinux at prophylactic doses for 45 days is also recommended, although this guideline is based only on one randomized controlled study.⁹ Recently, oral administration of Rivaroxan 10 mg once a day for 45 days was demonstrated as not inferior to Fondaparinux for SVT treatment.¹⁰

Our study was conducted to evaluate, in the setting of the real word practice, the efficacy and safety of Tinzaparin in intermediate dose in patients with acute SVT of the lower limb.

Materials and methods

Patients and study design

A multicenter, non-interventional observational study, which analyzed the medical records of patients with SVT (involving the greater or small saphenous vein systems) of the lower limbs from seven vascular centers in Greece, was undertaken. We carefully selected those centers in Greece with similar treatment protocol for SVT. In particular, the use of intermediate doses of Tinzaparin (0.5 ml, 10,000 anti-Xa IU) once daily for at least 14 days, initial assessment with duplex scanning, detailed recording of demographic and clinical data, a policy to rescan with duplex their patients in a period of approximately 2 weeks from the initiation of treatment and finally to maintain records on their outcome for a period of approximately 12 weeks. Treatment duration was at the treating physician’s discretion. The use of elastic stockings and topical application of heparinoids or non-steroidal anti-inflammatory drugs were not considered as exclusion criteria.

Patients’ inclusion and exclusion criteria adopted in our search of the medical records are summarized in Table 1. The collected data included patients’ demographics (age, sex and body mass index), comorbidities and risk factors (previous VTE events, VVs, mobilization status, SVT complications along with treatment characteristics and outcome). We kept for analysis only the records of those patients which could provide our preselected data over a period of 16 months. The study protocol was approved by the institutional review board of each hospital.

Table 1.

Inclusion and exclusion criteria.

Inclusion criteria

• Outpatients ≥18 years

• Symptomatic SVT of the leg, as confirmed by imaging methods

• Thrombus extension of at least 5 cm

• Duration of symptoms ≤10 days prior to diagnosis

Exclusion criteria

• Any PE or DVT within last six months before inclusion

• SVT associated with sclerotherapy or placement of an intravenous catheter in the past one month

• SVT closer than 3 cm to the SFJ or SPJ

• BMI > 35 kg/m²

• Patients receiving medication that affect blood coagulation, e.g., acetylosalicylic acid, vitamin K antagonists, dextrane

• Major surgery within last three months before inclusion

• Patients subjected to spinal or epidural anesthesia within 48 h prior to study inclusion

• Patients experienced cerebral bleeding, trauma and/or recently underwent CNS surgery within last one month before inclusion

CNS: central nervous system; DVT: deep vein thrombosis; PE: pulmonary embolism; SFJ: saphenofemoral junction; SPJ: saphenopopliteal junction; SVT: superficial vein thrombosis.

A duplex ultrasound (DUS) was performed for the confirmation of diagnosis and estimation of the thrombotic process. SVT was diagnosed when superficial veins were not compressible under the probe. Furthermore, DUS was used to estimate the extent of thrombus and to exclude the presence of DVT. At visit 2, approximately two weeks later, details on the results of the second DUS and the clinical status were recorded. At 12 weeks, the data available from the physical or phone contact with the patients were collected from the records.

Outcomes measures and definitions

The primary end point of the study was the composite of death of any cause, symptomatic DVT and/or PE, extension of thrombus towards the saphenofemoral (SFJ) or saphenopopliteal junction (SPJ), or recurrence of SVT up to week 12 in patients with SVT treated with intermediate dose of Tinzaparin. SVT extension was defined as proximal progression of the initial thrombus by at least 2 cm and within ≤3 cm to the SFJ or SPJ. Recurrence was defined as a new thrombus located in a different superficial vein and not directly contiguous with the initial thrombus, or located in the same superficial vein but in a distance of at least 10 cm from the initial thrombus area. DVT was defined as a previously compressible deep vein that was no longer compressible under the probe. For documentation of PE, helical computed tomography scan of the lungs with intravenous administration of the contrast agent was required.

Secondary objectives were the evaluation of treatment duration with respect to the presence of each component of primary efficacy outcome and the evaluation of treatment safety (bleeding complications, heparin-induced thrombocytopenia (HIT) and other adverse events). Major bleeding was defined as a decrease of hemoglobin of ≥2 g/dl⁻¹, or if was leading to a transfusion or if was fatal. Minor bleeding was defined in all other cases. HIT was defined as a 50% decrease in the platelet count compared with the initial values after the initiation of treatment with LMWH.

Statistical analysis

Sample size estimation was based on the objective of the study which was to collect information about complications or recurrence of SVT. Therefore, the study should be adequately powered to detect at least one event of low frequency. Published data from randomized trials reported as low frequencies 2% and 1%. With 230 patients there was a 90% probability to observe at least one adverse event with incidence 1% and 99% probability to observe at least one adverse event with incidence 2%.¹¹ Thus with 230 patients included, there will be adequate power to observe rare events.

By including 250 patients, the study sample size would be safeguarded against an anticipated incomplete follow-up of 10%. In addition, the sample size should be able to provide adequate accuracy for the estimation of the relative frequency of patient characteristics and clinical variables. Since it was reasonable to expect that the majority of the parameters of interest would be in the range 10–30% (or 70–90%), a sample size of 250 patients provided 95% confidence interval of size ±3.7% – ±5.7% (where ±3.7% and ±5.7% corresponded to 10% and 30%, respectively). However, the number of 250 patients would be the minimum required in order to fulfill the study objectives. As this is a retrospective study, the inclusion of all the patients attending the study sites was pursued.

Categorical data are presented as counts and corresponding percentages, whereas continuous data are presented as means and ranges. Time to event parameters were measured from the date of diagnosis and were estimated using Kaplan–Meier curves, while the log-rank test was used for assessing statistically significant differences. The chi-square test was used for testing categorical variables, significance was determined at the level of 5%, and all tests were two-sided. The statistical analysis was performed using SAS® software (SAS for Windows, version 9.3, SAS Institute Inc., Cary, NC).

Results

Between October 2014 and September 2015, a total of 296 patients (64% females) with SVT of the lower limbs from seven centers were identified through the medical records to fulfill the criteria set for inclusion in the study. Demographics and clinical characteristics of the patients are summarized in Table 2. The mean age of the patients was 57.4 ± 13.7 years (range, 27–87 years), whereas 50% of the patients was older than 60 years. Overweight or obese were 203 (68.5%), long-term immobility or restricted mobility was reported in 96 (32.4%), whereas VVs were present in 240 (81%) patients. Seventy-nine patients had experienced a VTE episode in at least six months from the index event with SVT to be the most common one (94%).

Table 2.

Demographics and clinical characteristics of the study population.

	N (%)
No	296
Age (years)	57.4 (27–87)
Female	189 (64%)
Male	107 (36%)
BMI
Normal
BMI ≤ 24.9 kg/m²	93 (31.5%)
Overweight
25 kg/m²≤ BMI ≤ 29.9 kg/m²	128 (43.2)
Obese
BMI ≥ 30 kg/m²	75 (25.3%)
Comorbidities	17 (5.7%)
CAD	3 (1%)
COPD	2 (0.6%)
Autoimmune disease	10 (3.4%)
Soft tissue infection	2 (0.6%)
Varicose veins	240 (81%)
Chronic or recent immobility	96 (32.4%)
Hospitalization	6 (2%)
Local trauma	7 (2.4%)
Sedentary life	22 (7.4%)
Long-haul flight	7 (2.4%)
Bed-ridden	16 (5.4%)
Long-term immobility	51 (17.2%)
History of VTE	79 (26.7%)
DVT	14 (4.8%)
PE	0
PTS	1 (0.4)
SVT	74 (25%)
Family history	2 (0.6%)

BMI: body mass index; CAD: coronary artery disease; COPD: chronic obstructive pulmonary disease; DVT: deep vein thrombosis; PE: pulmonary embolism; PTS: post-thrombotic syndrome; SVT: superficial vein thrombosis.

Mean time from visit 1 to visit 2 was 17 ± 7 days, whereas mean time between visit 2 and 3 was 70.7 ± 35.6 days. There was a decrease in mean thrombus length from visit 1 to visit 2, 97.2 ± 67.7 mm and 67.7 ± 63.8 mm, respectively.

Mean treatment duration was 29.9 days (range, 1–113 days). Two thirds of the patients (191/296, 64.5%) received treatment for approximately five weeks (mean 36.9 days) while the remaining one third (105/296, 35.5%) received treatment for a shorter period (mean 16.2 days). The reasons for treatment termination at the second visit were symptoms relief in 90 patients, patient’s decision in 3, treatment modification in 1 and minor bleeding (epistaxis) in 1 patient. Among 191 patients who continued the treatment after the second visit, 185 patients continued with the same regime and dose, 2 continued with the same regime but in higher dose due to DVT development, 1 patient received other regime due to DVT development and 3 patients also received other regime due to and persistent of symptoms. There was no difference in patients’ characteristics between the two treatment duration groups (Table 3). The presence of thrombus above the knee (p = 0.002) and restricted daily activity (p = 0.005) were the only factors associated with longer period of treatment (Table 3).

Table 3.

Patient’s characteristics in relation to treatment duration.

	≤2 weeks n (%)	>2 weeks n (%)	p value
No	30	266
BMI
Normal ≤ 24.9 kg/m²	10 (33.3%)	83 (30.9%)	0.83
Overweight/obese ≥ 25 kg/m²	20 (66.7%)	183 (69.1%)
Thrombus length
≤70 cm	20 (66.7%)	149 (56.2%)	0.33
>70 cm	10 (33.3%)	117 (43.9%)
Comorbidities
CAD/COPD	0	5 (1.8%)	1.00
Autoimmune disease	2 (6.7%)	8 (3%)	0.27
Soft tissue infection	0	2 (0.7%)	1.00
Varicose veins	22 (73.3%)	218 (81.9%)	0.22
Chronic or recent immobility
Hospitalization	1 (3.3%)	5 (1.8%)	0.47
Local trauma	0	7 (2.6%)	1.00
Sedentary life	3 (10%)	19 (7.1%)	0.47
Long-haul flight	0	7 (2.6%)	1.00
Bed-ridden	2 (6.7%)	14 (5.2%)	0.67
Long-term immobility	12 (40%)	39 (14.6%)	0.005
History of VTE
DVT	0	14 (5.2%)	0.37
PE	0	0
PTS	0	1 (0.3%)	1.00
SVT	5 (16.7%)	69 (25.9%)	0.37
Family history	0	2 (0.7%)	1.00
Thrombus location
Above the knee	18 (60%)	80 (30%)	0.002

Efficacy outcomes

After 105 days of follow-up, 94.1% of patients were event free (Figure 1). Primary efficacy outcomes occurred in 18 (6%) patients. Recurrence of SVT occurred in 14 (4.7%) patients, DVT in 3 (1%) and thrombus extension in the superficial veins in 1 (0.3%) (Table 4). The average time to the event was 50.5 days. Recurrence was not related to duration of treatment as occurred in 5% of those with short treatment duration and in 8% of those with prolonged treatment (p = 0.46). No association was found between recurrence and the presence of VVs/venous valvular insufficiency (p = 0.1) (Figure 2), history of VTE events (p = 0.33) (Figure 3) or body weight (p = 0.31) (Figure 4). The majority of the events occurred after the fourth week (Table 5). Only one case with minor bleeding (epistaxis) was observed. No HIT or other adverse events were reported.

Figure 1.

Kaplan–Meier probability curves for primary efficacy outcome.

Table 4.

Efficacy outcomes.

	No (%)
SVT recurrence	14 (4.7%)
SVT extension to SFJ	1 (0.3%)
DVT	3 (1%)
Minor bleeding (epistaxis)	1 (0.3%)

DVT: deep vein thrombosis; SFJ: saphenofemoral junction; SVT: superficial vein thrombosis.

Figure 2.

Probability of VTE recurrence in relation to presence of VVs/vein reflux.

Figure 3.

Probability of VTE recurrence in relation to history of previous VTE events.

Figure 4.

Probability of VTE recurrence in relation to body weight.

Table 5.

Time to VTE recurrence.

	N (%) of events
Weekly event distribution
1st week	2 (11.1%)
2nd week	1 (5.6%)
>4th week	15 (83.3%)
Total	18

VTE: venous thromboembolism.

Discussion

In real world practice, it appears that there are various therapeutic approaches for the treatment of SVT.^12,13 Treatment with intermediate dose of LMWH is recommended but with low grade of evidence.⁶ In this multicenter, retrospective study, we investigated the efficacy of an intermediate dose of Tinzaparin for the treatment of SVT by reviewing the medical records of seven hospitals with the same approach to the management of SVT.

An important point remains the definition of what is LMWH intermediate dose. In general, it ranges from a 50 to 75% of the weight adjusted full treatment dose used for the treatment of DVT and/or PE. The intermediate dose of LMWH has been proposed on the assumption that prophylactic dose would not be sufficient to treat patients with SVT,⁸ while full treatment doses were not superior to intermediate ones in reducing the incidence of thrombus extension and recurrence of SVT in other studies.^8,13 In the practice for SVT treatment of the centers contributed in this study, a fixed intermediate dose of 0.5 ml (10,000 anti-Xa IU) once daily was used for at least 14 days.

Our study has some differences with respect to the other relevant studies (Table 6). In contrast to CALISTO study, we search the records only of non-hospitalized patients with an acute or recent SVT (<10 days). The SURPRISE study included patients with duration of symptoms ≤21 days prior to diagnosis and also patients treated for 3 days with therapeutic doses of anticoagulants from the index event.¹⁰ In STEFLUX study, patients with a history of DVT and/or PE within 6 months of the onset of index symptoms were included in the analysis.

Table 6.

Data presentation of the studies related to the treatment of SVT.

Study	Type	No patients	Inclusion criteria	Follow-up surveillance	Treatment	Primary outcome
SeVEN	Retrospective	296	Outpatients Duration of symptoms ≤10 days	DUS at 0 and 14 days, phone contact at 84 days	Intermediate dose of LMWH for at least 14 days	5% in short duration treatment 8% in prolonged
VESSALIO Study group⁷	Randomized	164	Outpatients Duration of symptoms ≤10 days	DUS at 0, 7, 30 and 90 days	Therapeutic dose of LMWH for 10 days followed by half dose LMWH for 20 days Prophylactic dose of LMWH for 30 days	7.2% 8.6%
CALISTO⁹	Randomized	3002	Hospitalized and non-hospitalized Duration of symptoms ≤21 days	DUS at 0	Fondaparinux 2.5 mg for 45 days Placebo	0.9% 5.9%
STEFLUX⁸	Randomized	664	Outpatients	DUS at 0 and 30 days and in clinical suspicion	Intermediate dose of LMWH for 10 days Intermediate dose of LMWH for 30 days Prophylactic dose of LMWH for 30 days	15.6% 1.8% 7.3%
SURPRISE¹⁰	Randomized	472	Hospitalized and non-hospitalized Duration of symptoms ≤21 days and patients treated for 3 days with therapeutic doses of anticoagulants	DUS at 0 days and in clinical suspicion, phone contact at 10 days, office visits at 45, 90 days	Fondaparinux 2.5 mg for 45 days Rivaroxaban 10 mg for 45 days	7% at 90 days 7% at 90 days

DUS: duplex ultrasound; LMWH: low molecular weight heparin; SVT: superficial vein thrombosis.

In our study, the majority of the patients were overweight, middle-aged women with a history of VVs. The mean age of our study population was 57 years, which was not different from other relevant studies.^2,14 As age increases, coagulation proteins increase too, without a proportional increase of anticoagulant factors.¹⁵ Obesity is also a risk factor for SVT,^16,17 as it predisposes to venous stasis and enhances thrombosis by increasing prothrombotic factors and impairing fibrinolytic activity.¹⁸ Although not significant, in our study a quarter of the patients experienced in the past (at least six months prior to index event) a VTE episode that was most commonly a SVT episode.

Two thirds of the patients in our study received treatment for approximately five weeks while in the remaining one third a shorter duration of treatment (about two weeks) sufficed for the resolution of symptoms. The only factors associated with prolonged treatment were the presence of thrombus above the knee and the restricted daily activity. SVT involving the great saphenous vein in the thigh is more likely to progress proximally.¹⁹ Also, restricted mobility has been reported as an independent risk factor for VTE development.^2,20

In our study, the observed primary efficacy end points were comparable to other studies.^7–10 In a randomized study that compared prophylactic doses of Nadroparin with body-weight-adjusted treatment doses once daily for one month, SVT progression and VTE complications were developed in 8.6% and 7.2%, respectively.⁷ The STEFLUX study, which compared different doses and treatment durations of Parnaparin, has reported that the incidence of symptomatic VTE was not different when intermediate or prophylactic doses were administered for 30 days. However, symptomatic VTE was reduced after 30-day treatment with intermediate doses compared to a 10-day treatment period.⁸ In addition, SVT extension at three months was significantly reduced when a 30-day treatment with intermediate dose was used compared to 30-day treatment with prophylactic dose or to 10-day treatment with intermediate dose.⁸ Unfortunately, the study was unable to determine the impact of the interventions on the most clinically important end points (DVT or PE) due to the low incidence and premature study termination.⁸

The CALISTO trial, a randomized trial comparing the effect of anticoagulant therapy versus placebo, has demonstrated that the administration of Fondaparinux 2.5 mg once daily for 45 days is an effective treatment.⁹ The primary efficacy outcome occurred in 0.9% of patients in the Fondaparinux group and 5.9% in the placebo group, while the rate of PE or DVT was 85% lower in the Fondaparinux group.⁹ Additionally, no difference was observed in major bleeding between the two groups.⁹ However, the lower rates in primary efficacy outcomes in CALISTO study as compared to our study and to other relevant ones should be attributed to the fact that it included only symptomatic VTE events and patients underwent DUS only at inclusion, thus making asymptomatic SVT extension and/or recurrence or DVT, to remain undiagnosed during follow up. Nevertheless, it should be acknowledged that CALISTO study was a randomized, blinded controlled study and therefore with stronger impact than our study. The SURPRISE trial, a recent randomized controlled trial comparing the effect of Rivaroxaban 10 mg versus Fondaparinux 2.5 mg both administered once daily for 45 days, demonstrated that Rivaroxaban was non-inferior to Fondaparinux.¹⁰ However, the primary efficacy outcomes after treatment discontinuation in patients receiving Fondaparinux was much higher than in CALISTO trial (7% vs. 1.2%) in the follow-up until day 90 and comparable to our study (6% vs. 7%). Similar to CALISTO trial, in the SURPRISE study no routine DUS was performed during follow-up visits, and objective testing was performed only in patients in whom an outcome event was suspected making asymptomatic forms of the thrombotic process to remain undiagnosed.

Additionally, the CALISTO study was criticized for its long treatment period that makes the treatment of any SVT to be not cost-effective. Probably, such long treatment could be reasonable only in patients with high thrombotic risk, in case of severe symptoms, thrombosis close to SFJ and in recurrent disease cases.²¹ It has been estimated that treatment with Fondaparinux would prevent 123 VTE events and two deaths in 10,000 patients with SVT and the probability that Fondaparinux to be cost-effective was 1% at a willingness to pay of 100,000$ per quality-adjusted life-years (QALY).²² Although oral Rivaroxaban is much cheaper and simpler than a subcutaneous injection of Fondaparinux once daily, a potential criticism for the treatment duration and cost-effectiveness remains for the SURPRISE trial too.

The STEFLUX trial showed that previous episode of VTE and/or SVT, a family history of VTE, obesity and absence of VVs are risk factors for recurrent events.⁸ Galanaud et al.²³ reported that the overall risk of recurrence is similar between SVT and proximal DVT patients and saphenian junction involvement (femoral or popliteal) represents an important factor for VTE recurrence whereas VVs status has a low impact on VTE recurrence.In another study,²⁴ the risk of recurrence, in patients with VVs after an episode of unprovoked SVT, increases in the presence of dislipidemia and mutations in Factor II (prothrombin). In our study, recurrence of SVT was not linked with the duration of treatment and was not associated with the body weight, the history of previous VTE events and the presence of VVs.

In our study, recurrence occurred in 5% among patients who received treatment for a shorter period and in 8% of the patients who received prolonged treatment. It should be noted that among patients who had an event, 66.7% had the event prior to treatment discontinuation and the event occurred on the fourth week from treatment initiation or later. Among patients with an event occurred after treatment discontinuation, more than 50% had the event on the third week or later. This observation indicates that prolonged treatment does not ensure better results on VTE events and contradicts with the assumption of the CALISTO study that prolonged administration of Fondaparinux for 45 days could improve results comparing to shorter treatment duration with LMWH.^7,9,25

The main limitations of our study are its retrospective nature and the potential selection bias. Additionally, it should be emphasized the potential bias in the treatment duration as it was at the treating physician’s discretion. Nevertheless, it represents the real world practice in centers with similar therapeutic approaches using the same anticoagulant agent. It is obvious that several issues about the treatment of SVT still require further investigation explaining the disparity in current practice.¹² Additionally, from the existing literature, a meta-analysis concerning the optimal regime and duration of SVT treatment is not possible as the quality of the studies is low and different therapeutic approaches have been used. Arguably, the treatment of SVT should not be uniform and probably it needs individualization according to location and length of thrombus, the etiology and risk factors of the patients.²⁶

Conclusions

In conclusion, our study indicates that Tinzaparin at intermediate dose is an effective and safe treatment for SVT. The location of thrombus and the status of patients’ mobility are factors associated with longer treatment duration. Future large prospective randomized studies are needed to corroborate these findings.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to research, authorship, and/or publications of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: LEO Pharmaceuticals Hellas S.A. provided funds for the preparation of CRF sheets according to the design of our study, secretariat assistance, data collection and statistical analysis.

Ethical approval

The study protocol was approved by the institutional review board of each hospital.

Guarantor

Authors’ contributions

AG was responsible for the concept, design, data analysis and review of the study. CK was responsible for the data collection, data analysis and writing. KMN, GG, CM, SV, GT, GP, KS, ML, MM, IT, SM and SK collected the data. All authors reviewed, amended and agreed the final draft. AG and CK drafted the manuscript.

Appendix 1

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Tinzaparin in intermediate dose for the treatment of superficial vein thrombosis: Results from an observational multicenter study—SeVEN study

Abstract

Objectives

Methods

Results

Conclusions

Keywords

Introduction

Materials and methods

Patients and study design

Outcomes measures and definitions

Statistical analysis

Results

Efficacy outcomes

Discussion

Conclusions

Footnotes

Declaration of Conflicting Interests

Funding

Ethical approval

Guarantor

Authors’ contributions

Appendix 1

References