Superficial Vein Thrombosis: To Anticoagulate or not to Anticoagulate?

We posted a poll on twitter on 2/15/24 asking the following question:

• There was a pretty even split between options!
• Most respondents chose to anticoagulate, though there was no clear consensus on the type of anticoagulant or the duration of anticoagulation.
• As we will see in this topic, clinical practice guidelines would favor anticoagulating this patient with either fondaparinux or rivaroxaban for 45 days.

Q: Why should we consider anticoagulating patients with superficial vein thrombosis (SVT) of the leg?
A: To prevent occurrence extension into the deep vein system, resulting in DVT and PE¹

Guideline recommendations for treating patients with SVT of the leg depend on:

• The proximity of the clot is to the junction with the deep vein
• The length of the clot
• Whether there are:
  • Severe symptoms
  • Higher than normal risk factors for extension

Recommendations are summarized in the three graphics below and then detailed in the text:

Bottom line: With the exception of SVT < 5 cm in length and occurring> 3 cm away from the junction with the deep veins, patients with SVT should receive anticoagulation for 45 days – 3 months (the duration depends on proximity to the junction with the deep veins and the patient’s underlying prothrombotic risk factors) to reduce risk of DVT/PE using either fondaparinux 2.5 mg daily or rivaroxaban 10 mg daily, both being preferable to LMWH.

Description:

• Superficial vein thrombosis (SVT) – sometimes called superficial vein thrombophlebitis² refers to the presence of thrombus and inflammation of the superficial vein, characterized by painful/tender, warm, erythematous, and palpable cord-like structure along the course of a superficial vein.
• Usually affects the lower limbs, though may affect any superficial vein in the body, including upper extremifies, chest or abdomen.
• Two thirds of cases are seen in females.
• Three quarters occur in an existing varicose vein.
• Greater saphenous vein involvement in 60-80% of affected individuals.³
• 20%-25% of patients with SVT have deep vein thrombosis (DVT) or pulmonary embolus (PE) at time of diagnosis.
• Generally a benign, self-limited disorder, though thrombus in a superficial leg vein may propagate into the deep vein system, causing DVT and even PE.⁴
• Treatment is aimed at relieving local symptoms and preventing thromboembolic complications.
• Current guideline recommendations apply to lower extremity SVT; optimal treatment of SVT in other sites is not well established.

Definitions:

• Phlebitis refers to the presence of inflammation within a vein.
• Thrombosis indicates the presence of clot within the vein.
• Superficial phlebitis denotes the presence of pain and inflammation involving a vein in the absence of thrombus.
• Superficial thrombophlebitis or superficial vein thrombosis refers to concomitant inflammation and thrombosis of vein.⁵

Classification:

• According to absence or presence of varicose veins:
  • Varicose vein (V)-SVT:⁶
    • Thrombosis in varicose vein associated with sterile inflammation of vein wall.
    • Occurs in great saphenous vein, small saphenous vein, or collateral varicose veins.
    • Much more common than non-varicose vein-SVT.
    • Pathogenesis includes stasis of blood flow and vessel wall damage.
  • Non-varicose vein (NV)-SVT:
    • Miscellaneous causes.
    • Occurs in any superficial vein.
    • Either thrombosis or inflammation may predominate.
    • Pathogenesis includes stasis of blood flow, vessel wall damage, and/or hypercoagulability.
• According to whether or not there is an underlying condition:
  • Primary SVT – inflammation of vein wall and surrounding tissues in the absence of an obvious underlying disease.
  • Secondary SVT – inflammation of vein wall is associated with a chronic inflammatory process or systemic disease including:
    • Thromboangiitis obliterans (Buerger disease)
    • Behcet disease
    • Antiphospholipid syndrome
    • Systemic lupus erythematosus (SLE)
    • Malignancy
• Other specific types of SVT include:
  • Thrombophlebitis migrans:
    • Inflammation of vein wall travels proximally and distally on superficial vein
    • Occurs in Behcet disease and malignancy
  • Trousseau syndrome – recurrent, migratory SVT secondary to malignancy, particularly adenocarcinoma of pancreas
  • Thrombophlebitis saltans:
    • Inflammation of vein wall jumps from 1 vein to another
    • Occurs in Behcet disease
  • Mondor disease:
    • SVT affecting the superficial veins of the breasts, groin, or penis
    • Review of Mondor disease can be found in Intern Med 2018 Sep 15;57(18):2607
  • Infusion thrombophlebitis – associated with catheter insertion, venipuncture, IV drug infusion.

Epidemiology:

• Women are affected more than men.
• Mean age is 60 years.
• Reported incidence of SVT:⁷
  • 0.3-0.6 per 1,000 person-years in younger patients
  • 0.7-1.5 per 1,000 person-years in older patients
• Yearly incidence rate is 0.64%.⁸
• SVT more commonly involves the great saphenous vein compared with the small saphenous vein.
• Prevalence 2-fold higher than that of deep vein thrombosis and pulmonary embolism combined.

Risk factors:

• The risk factors for SVT are similar to those for DVT, and include:⁹
  • Stasis of blood flow:
    • Varicose veins
    • Immobilization due to trauma or surgery
    • Pregnancy
  • Changes in vessel wall:
    • IV infusion
    • Trauma
    • Varicose veins and chronic vein insufficiency
    • Infection
    • Endothelial dysfunction, as occurs in Behcet syndrome
  • Primary hypercoagulable states:
    • Hereditary thrombophilia
    • Malignancy
    • Oral contraceptives
    • Pregnancy
  • Other risk factors:
    • Age
    • History of thrombosis 

Anatomy and pathophysiology:

• Superficial veins in lower extremity include:
  • Great saphenous
  • Anterior accessory saphenous
  • Small saphenous veins

Clinical presentation:

• Findings of acute SVT include those of:
  • Inflammation:¹⁰
    • Low-grade fever.
    • Erythema, warmth, and tenderness along vein (often dilated varicose vein).
    • Localized edema of the surrounding tissue.
    • Not usually associated with generalized edema of extremity, but if present, consider extension into the deep vein system.
  • Thrombus formation:
    • Palpable, cord-like structure along vein due to the presence of thrombus
• Primary SVT of legs more common than upper extremities:
  • 60%-80% are reported to be located in the greater saphenous vein.
  • 10%-20% are reported to be located in other veins of the legs.
  • Reported to be bilateral in 5%-10% of patients.

Diagnosis:

• Suspect SVT in patients with any of:
  • Findings of tender inflammation or palpable cord along superficial vein.
  • History of varicose veins.
  • History of recent immobilization, trauma, pregnancy, malignancy or other hypercoagulable risk factors.
• Confirm SVT with duplex ultrasound; unlike DVT, no recognized clinical scoring system for SVT.
• Given the high prevalence of concomitant proximal DVT in patients with SVT and the need to treat such patients with higher doses of anticoagulant therapy (i.e., therapeutic doses), patients with clinically suspected SVT above the knee should have ultrasonography to exclude proximal DVT.¹¹

Treatment (lower extremity SVT):

• No consensus regarding optimal treatment.
• Most intervention studies have excluded patients with SVT that:
  • Extends to within 3 cm of the sapheno-femoral junction since these cases are considered to be equivalent to deep vein thrombosis (DVT) in terms of its risk of progression.
  • Is < 4-5 cm in length since these cases are considered minor and self-limiting, requiring symptomatic treatment alone.
• Goals of treatment include:
  • Symptomatic relief
  • Preventing extension of the SVT into the deep vein system
• Antibiotic therapy is generally not indicated unless there are signs of infection.¹²
• Expert opinion:
  • Di Nisio et al
    • Summary of a Cochrane review.
    • Twelve studies compared an active treatment with placebo or no treatment and 2 reported on venous thromboembolism (VTE) or ST extension or recurrence.
      • Low-molecular-weight heparin (LMWH):
        • In one trial (STENOX) LMWH was associated with lower rates of SVT extension or recurrence at both prophylactic doses (16/110) and therapeutic doses (16/106) vs placebo (37/112) without differences in symptomatic VTE and without major bleeding in any group.
        • In another trial, 30-day intermediate (i.e., dose between prophylactic and therapeutic) or therapeutic doses of LMWH were associated with lower VTE rates vs 10-day intermediate doses (4/219 vs 11/212) or prophylactic doses (2/81 vs 4/83) of LMWH without major bleeding in either group
        • In a third trial, 6-week prophylactic and intermediate doses of LMWH were associated with similar rates of symptomatic VTE (0/33 vs 1/35) and ST progression to VTE (1/33 vs 2/35) without major bleeding in either group.
      • One trial (CALIPSO) of 3002 patients with acute symptomatic ST demonstrated that 2.5 mg/d of fondaparinux administered subcutaneously for 45 days vs placebo was associated with lower rates of symptomatic VTE (3/1502 vs 20/1500; Table), ST extension (4/1502 vs 51/1500), ST recurrence (5/1502 vs 24/1500), and comparable rates of major bleeding (1/1499 vs 1/1488)
      • One trial (SURPRISE) of 472 patients with SVT given 2.5 mg/d of fondaparinux vs 10 mg/d of rivaroxaban reported similar rates of symptomatic VTE (1/236 vs 3/236; Table) without major bleeding in either group.
      • Conclusions:
        • Fondaparinux was associated with lower rates of VTE vs placebo without increases in major bleeding. Based on low-quality evidence, LMWH was associated with lower rates of ST extension or recurrence vs placebo but not VTE. Oral rivaroxaban requires further evaluation.
        • The present findings are only partly consistent with the guidelines from the American College of Chest Physicians, which suggests either a prophylactic dose of fondaparinux or a prophylactic dose of LMWH for 45 days to treat SVT. In contrast, data reported herein show no association of LMWH with prevention of VTE when used to treat SVT.
  • Up-to-Date:
    • For all patients with phlebitis, symptomatic care measures should be instituted and consist of extremity elevation, warm or cool compresses, compression stockings, and pain management.
    • A decision for anticoagulation is based on the patient’s risk for VTE, which can be stratified as low, intermediate, or elevated:
      • Low risk for VTE (uncomplicated SVT):¹³
        • Defined by both:
          • SVT remote from the saphenofemoral junction or saphenopopliteal junction, such as SVT involving the below-knee, rather than the above-knee great saphenous vein or focal SVT with axial vein involvement (≤5 cm in length).
          • Absence of medical risk factors for VTE.
        • We suggest supportive care as first-line therapy, rather than anticoagulation
      • Intermediate risk for VTE (uncomplicated SVT at intermediate risk for thromboembolism):¹⁴
        • Defined by both:
          • SVT in proximity (3 to 5 cm) to the deep venous system, particularly if involving the great or small saphenous vein; SVT that is more extensive with the affected vein segment ≥5 cm , rather than focal involvement; SVT that propagates with symptomatic care.
          • Absence of medical risk factors for VTE.
        • We suggest prophylactic anticoagulation for 45 days rather than supportive care alone, with either:
          • Fondaparinux
          • LMWH
          • UFH
          • DOAC
          • VKA
      • Elevated risk for VTE:
        • Defined by either of:
          • SVT identified initially or that subsequently propagates within 3 cm of the deep venous system, particularly if involving the great saphenous vein or small saphenous vein; SVT that propagates despite prophylactic anticoagulation; recurrent SVT after cessation of anticoagulation.
          • SVT in a patient with medical risk factors for VTE (eg, prior DVT, thrombophilia).
• Primary studies:
  • CALISTO¹⁵
    • Randomized, double-blind trial.
    • 3002 patients randomized to receive either for 45 days:
      • Fondaparinux, 2.5 mg SQ once daily
      • Placebo
    • The primary efficacy outcome was a composite of death from any cause or symptomatic pulmonary embolism, symptomatic deep-vein thrombosis, or symptomatic extension to the saphenofemoral junction or symptomatic recurrence of superficial-vein thrombosis at day 47.
    • The main safety outcome was major bleeding. The patients were followed until day 77.
    • The primary efficacy outcome occurred in:
      • 13 of 1502 patients (0.9%) in the fondaparinux group
      • 88 of 1500 patients (5.9%) in the placebo group
    • The relative risk reduction in primary efficacy outcome was 85% with fondaparinux, 85% (P<0.001).
    • The incidence of each component of the primary efficacy outcome was significantly reduced in the fondaparinux group as compared with the placebo group, except for the outcome of death.
    • A total of 88 patients would need to be treated to prevent one instance of pulmonary embolism or deep-vein thrombosis.
    • Major bleeding occurred in one patient in each group.
    • The incidence of serious adverse events was 0.7% with fondaparinux and 1.1% with placebo.
    • Conclusions: Fondaparinux at a dose of 2.5 mg once a day for 45 days was effective in the treatment of patients with acute, symptomatic superficial-vein thrombosis of the legs and did not have serious side effects.
  • STENOX
    • Double-blind trial.
    • 427 patients older than 18 years with documented acute symptomatic superficial vein thrombosis of the legs were randomly assigned to receive one of:
      • Subcutaneous enoxaparin sodium, 40 mg
      • Subcutaneous enoxaparin, 1.5 mg/kg
      • Oral tenoxicam
      • Placebo
    • Primary efficacy outcome:
      • Deep venous thromboembolism between days 1 and 12
      • Symptomatic pulmonary embolism
    • Secondary efficacy outcomes:
      • Superficial vein thrombosis recurrence or extension
    • Incidence of deep venous thromboembolism between days 1 and 12:
      • Placebo group 5/112
      • 40-mg enoxaparin group 6/110
      • 1.5-mg/kg enoxaparin group 4/106
      • Tenoxicam group 4/99
    • Incidence of deep and superficial venous thromboembolism by day 12 was significantly reduced in all active treatment groups:
      • Placebo group 30.6%
      • 40-mg enoxaparin group 8.3%
      • 1.5-mg/kg enoxaparin group 6.9%
      • Tenoxicam group 14.9%
    • No death or major hemorrhage occurred during the study.
    • Conclusions: LMWH reduces the incidence of recurrence or the extension of superficial venous thrombosis. In the absence of a statistically significant reduction in the incidence of deep venous thromboembolic complications with a low-molecular-weight heparin, simple surveillance may remain the treatment of choice for superficial vein thrombosis. Treatment with a low-molecular-weight heparin should be evaluated further in the prevention of thromboembolic complications in patients with superficial vein thrombosis.
  • SURPRISE:
    • Open-label, masked endpoint, randomized, non-inferiority phase 3b trial.
    • Patients were:
      • 18 years or older with symptomatic superficial-vein thrombosis.
      • Eligible if they had symptomatic thrombosis (at least 5 cm in a supragenual superficial-vein segment) and at least one additional risk factor (older than 65 years, male sex, previous venous thromboembolism, cancer, autoimmune disease, thrombosis of non-varicose veins).
    • 472 patients randomly assigned to one of:
      • 10 mg oral rivaroxaban once a day for 45 days
      • 2·5 mg subcutaneous fondaparinux once a day for 45 days
    • Primary efficacy outcome was a composite of symptomatic deep-vein thrombosis or pulmonary embolism, progression or recurrence of superficial vein-thrombosis, and all-cause mortality at 45 days.
    • The main safety outcome was major bleeding.
    • Primary efficacy outcome occurred:
      • 3% in the rivaroxaban group
      • 2% in the fondaparinux group
      • Hazard ratio [HR] 1·9, 95% CI 0·6-6·4; p=0·0025 for non-inferiority
    • There were no major bleeds in either group.
    • Conclusions: Rivaroxaban was non-inferior to fondaparinux for treatment of superficial-vein thrombosis in terms of symptomatic deep-vein thrombosis or pulmonary embolism, progression or recurrence of superficial vein-thrombosis, and all-cause mortality, and was not associated with more major bleeding. Therefore, rivaroxaban could offer patients with symptomatic superficial-vein thrombosis a less burdensome and less expensive oral treatment option instead of a more expensive subcutaneous injection.
  • A systematic review and meta-analysis in 2019:
    • 17 articles, including 6,862 patients, were included in the meta-analysis.
    • Fondaparinux had the lowest event rate with 1.4 events per 100 patient-years of follow-up
    • Pooled event rates for DVT or PE ranged from 9.3 to 16.6 events per 100 patient-years across other treatment categories
    • Pooled event rate for no treatment/placebo was 10.5 events per 100 patient-years (95% CI, 3.0-22.0).
    • Major bleeding was low and similar across all treatment categories.
    • Heterogeneity was moderate to high for most pooled estimates.
    • Conclusion: While pooled event rates suggest that fondaparinux achieves the lowest rate of DVT or PE, low-quality evidence for other treatments prevents firm conclusions about the optimal treatment for SVT.
  • A Cochrane review in 2019:
    • 33 studies involving 7296 people with ST of the legs.
    • Treatment included:
      • Fondaparinux
      • Rivaroxaban
      • Low molecular weight heparin (LMWH)
      • Unfractionated heparin (UFH)
      • Non-steroidal anti-inflammatory drugs (NSAIDs)
      • Compression stockings
      • Topical, intramuscular, or intravenous treatment
      • Surgical interventions such as thrombectomy or ligation
    • Only a minority of trials compared treatment with placebo rather than an alternative treatment
    • Many studies were small and of poor quality.
    • In one large, placebo-controlled RCT (CALISTO) of 3002 participants, subcutaneous fondaparinux was associated with a significant reduction in symptomatic VTE (risk ratio (RR) 0.15), ST extension (RR 0.08), and ST recurrence (RR 0.21) relative to placebo. Major bleeding was infrequent in both groups with very wide CIs around risk estimate (RR 0.99).
    • In one RCT on 472 high-risk participants with SVT, fondaparinux was associated with a non-significant reduction of symptomatic VTE compared to rivaroxaban 10 mg (RR 0.33). There were no major bleeding events in either group.
    • In a placebo-controlled trial, both prophylactic and therapeutic doses of LMWH (prophylactic: RR 0.44; therapeutic: RR 0.46) and NSAIDs (RR 0.46) reduced the extension and recurrence of SVT in comparison to placebo, with no significant effects on symptomatic VTE or major bleeding.
    • Overall, topical treatments improved local symptoms compared with placebo, but no data were provided on the effects on VTE and ST extension.
    • Surgical treatment combined with elastic stockings was associated with a lower VTE rate and SVT progression compared with elastic stockings alone.
    • Conclusions: Prophylactic dose fondaparinux given for 45 days appears to be a valid therapeutic option for SVT of the legs for most people. The evidence on topical treatment or surgery is too limited and does not inform clinical practice about the effects of these treatments in terms of VTE. Further research is needed to assess the role of rivaroxaban and other direct oral factor-X or thrombin inhibitors, LMWH, and NSAIDs; the optimal doses and duration of treatment in people at various risk of recurrence; and whether a combination therapy may be more effective than single treatment. Adequately designed and conducted studies are required to clarify the role of topical and surgical treatments.
• Guidelines:
  • Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (2012):
    • In patients with SVT of the lower limb of at least 5 cm in length, we suggest the use of a prophylactic dose of fondaparinux or LMWH for 45 days over no anticoagulation (Grade 2B). Note: Patients who place a high value on avoiding the inconvenience or cost of anticoagulation and a low value on avoiding infrequent symptomatic VTE are likely to decline anticoagulation.
    • In patients with SVT who are treated with anticoagulation, we suggest fondaparinux 2.5 mg daily over a prophylactic dose of LMWH (Grade 2C).
  • Antithrombotic Therapy for VTE Disease: Second Update (2021) of the CHEST Guideline and Expert Panel Report
    • Although more expensive in some jurisdictions, anticoagulants have greater efficacy and similar safety when compared with conservative therapy and nonsteroidal anti-inflammatory medications.
    • The CALISTO study compared fondaparinux (2.5 mg/d for 45 days) with placebo in 3,000 patients with SVT (≥ 5 cm in length), and found that fondaparinux was effective at reducing VTE, recurrent SVT, extension of SVT, and the need for venous surgery, and was associated with a low risk of bleeding.
    • In an open-label RCT that enrolled 485 patients with SVT in a supragenual vein segment of at least 5 cm in length, subjects were randomized to fondaparinux 2.5 mg once daily or to rivaroxaban 10 mg once daily. Rivaroxaban met the prespecified margin for noninferiority in efficacy, with 3% vs 2% of patients experiencing progression of SVT, DVT, PE, or death.
    • Factors that favor the use of anticoagulant therapy in patients with SVT include the following:
      • Extensive SVT
      • Involvement above the knee, particularly if close to the saphenofemoral junction
      • Severe symptoms
      • Involvement of the greater saphenous vein
      • History of VTE or SVT
      • Active cancer
      • Recent surgery
    • Anticoagulant therapy generally is not used to treat SVT that occurs in association with an IV infusion (ie, infusion thrombophlebitis).

• Guidelines (cont’d)
  • European Society for Vascular Surgery (ESVS) 2023 Clinical Practice Guidelines on Antithrombotic Therapy for Vascular Diseases:
    • RCTs comparing anticoagulation with placebo have proved the effectiveness of anticoagulation in reducing thromboembolic events for SVT.
    • It is evident that there is heterogeneity in treatment type, intensity, and duration of anticoagulation, which precludes a formal meta-analysis.
    • Most studies were underpowered for the relatively rare outcomes of DVT and PE
    • Shorter duration of anticoagulation was associated with a higher risk of recurrent events
    • intermediate LMWH doses (between full anticoagulation and prophylactic, e.g., two thirds of the therapeutic dose) were better than prophylactic LMWH doses in preventing recurrent event.
    • In CALISTO randomized trial, fondaparinux achieved the lowest rate of recurrent VTE at 1.4 events per 100 patient years of follow up
    • The superiority of fondaparinux over LMWHs was recently shown in the INSIGHTS-SVT observational study where the composite primary outcome of symptomatic DVT, PE, and extension or recurrence of SVT at three months, adjusted by propensity score and for treatment duration was lower with fondaparinux compared with LMWH (4.4% vs. 9.6%)

• Guidelines (cont’d):
  • Thrombosis Canada:
    • Isolated SVT which extends to within 3 cm of the SFJ or SPJ is associated with a high risk of progression into the deep venous system. These patients should also receive therapeutic doses of anticoagulation for 3 months.
    • Isolated SVT ≥5 cm in length located >3 cm from the SFJ:
      • Should receive prophylactic doses of fondaparinux (2.5 mg SC daily) or rivaroxaban (10 mg PO daily) or prophylactic/intermediate doses of LMWH for 45 days.
      • Can also receive topical NSAIDs and/or compression therapy for symptomatic relief in conjunction with anticoagulation.
    • Isolated SVT <5 cm in length located >3 cm from the SFJ/SPJ
      • No severe symptoms or risk factors for extension:
        • Can be treated with oral or topical NSAIDs, compresses (warm or cool), and elevation for symptomatic relief. Compression stockings of appropriate length and tension can be considered if tolerable and no contraindications exist (e.g. known peripheral arterial disease).
      • Severe symptoms or risk factors for extension (prior history of DVT/PE or SVT, cancer, pregnancy, hormonal therapy, recent surgery or trauma):
        • Treatment with prophylactic doses of fondaparinux (2.5 mg SC daily), prophylactic doses of rivaroxaban (10 mg PO daily) or prophylactic/intermediate doses of LMWH (see Table 1) for up to 45 days can be considered.
    • SVT associated with IV cannulation is not generally treated with anticoagulation. Supportive measures such as warm compresses and topical NSAIDs can be considered for symptom relief.

• Guidelines (cont’d):
  • British Committee for Standards in Haematology guidelines on the investigation and management of venous thrombosis at unusual sites:
    • Patients with lower limb SVT should have ultrasound assessment to exclude DVT, particularly if affecting the proximal long saphenous vein (1B).
    • Patients with confirmed SVT within 3 cm of the sapheno-femoral junction should be considered for therapeutic anticoagulation (2B).
    • Patients with SVT and risk factors for extension, recurrence or progression should be offered treatment with prophylactic doses of LMWH for 30 d or fondaparinux for 30–45 d (1B).
    • Other patients with SVT should be offered 8–12 d NSAIDs unless contraindicated (1A).
    • Investigation of patients with SVT for underlying thrombophilia is not routinely indicated, and should follow existing guideline criteria (1B).

Prognosis:

• In a Danish nationwide cohort of 10,973 patients diagnosed with a first-time SVT in Denmark between 1980 and 2012, most of whom did not receive anticoagulation, the incidence rate of VTE was 18.0 per 1000 patient-years During a median follow-up of 7 years. After adjustment for cancer, pregnancy, fracture, surgery, Charlson Comorbidity Index score, and autoimmune disease, this VTE incidence rate produced a hazard ratio (HR) of 11.3 (95% CI, 10.5-12.1) for DVT and 4.5 for PE (95% CI, 4.1-5.0) compared with the control group.¹⁶
• Another study found that a history of clinical SVT was associated with a 6.3-fold (95% confidence interval [CI] 5.0-8.0) increased risk of deep-vein thrombosis and a 3.9-fold increased risk of pulmonary embolism (95% CI 3.0-5.1).¹⁷
• In the Superficial Thrombophlebitis Treated by Enoxaparin (STENOX) trial, 427 patients with acute symptomatic SVT were randomly assigned to receive 40 mg enoxaparin sodium subcutaneously, 1.5 mg/kg enoxaparin subcutaneously, tenoxicam orally, or placebo once daily for 8 to 12 days. In the 112 patients with SVT who were treated with placebo only, thromboembolic complications occurred in 35% within 97 days and rates of DVT/PE were as high as 3.6% within the first 12 days.

Summary of primary data:

	Marchiori et al.	STENOX	VESALIO	CALISTO	SURPRISE
Patients	60	427	164	3002	472
Treatment	UFH	LMWH – low LMWH – high	LMWH – low LMWH – high	Placebo  Fondaparinux	Rivaroxaban  Fondaparinux
Duration of treatment	4 wk	2 wk	4 wk	6 wk	6 wk
Rate of DVT/PE during treatment, %	Low-dose UFH: 13.3  High-dose UFH: 0	Placebo: 3.6 Low-dose 0.9 High dose 2.8	Low dose 0 High dose 1.2	Placebo 1.3 Fonda 0.2	Riva 1.4 Fonda 0.4
Symptomatic SVT recurrence/ extension during treatment, %	Low dose UHF 23 High dose UHF 10	Placebo 24 Low dose 4.5 High dose 2.8	Low dose 1.2 High dose 0	Placebo 5.0 Fonda 0.6	Riva 1.7 Fonda 1.3
VTE rate until end of follow-up, %	Low dose UHF 20 High dose UHF 3.3	Placebo 4.5 Low dose 5.7 High dose 3.9	Low dose 2.5 High dose 1.48	Placebo 1.5 Fonda 0.3	Riva 2.5 Fonda 0.9
Symptomatic SVT recurrence/ extension until end of follow-up, %	Low dose UHF 36.7 High dose UHF 26.7	Placebo 27.7 Low dose 11 High dose 12.3	Low dose 1.2 High dose 1.2	Placebo 5.3 Fonda 0.9	Riva 4.4 Fonda 5.5

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