DEEP VEIN THROMBOSIS

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• In the U.S., an estimated 900,000 people (0.1 - 0.3% of the adult population) develop a VTE each year. An individual's risk for DVT depends on a number of risk factors that are often identifiable. [33]

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• Overview
• A deep vein thrombosis (DVT) is a blood clot that forms in the deep veins of the leg. DVTs can cause pain and swelling in the affected extremity, but more importantly, pieces of the clot can break off and travel to the lungs, where it becomes a pulmonary embolism (PE). DVTs are treated with anticoagulation to prevent their extension and hasten their dissolution.

• DVT location
• Proximal DVT - DVT located in the veins of the thigh (femoral vein, deep femoral vein, common femoral vein, iliac veins, popliteal vein)
• Distal DVT - DVT located in the veins of the calf (anterior tibial vein, posterior tibial vein, peroneal vein)
• Illustration of deep veins of the leg


• In a study of 189 patients with a symptomatic DVT, 88% had a proximal DVT, and 12% had an isolated distal DVT. Of the patients with a proximal DVT, 99% had an associated distal DVT. As for the natural course of untreated isolated distal DVTs, 15 - 25% will extend into the proximal veins, typically within 2 weeks. [6,7,10]
• The table below shows the location of proximal DVTs diagnosed with venography in 166 consecutive patients with suspected VTE

• Reference [7]

DVT location in 166 patients with a proximal DVT diagnosed by venography
Location of DVT	% of patients
Popliteal	10%
Popliteal and femoral	42%
Popliteal, femoral, and common femoral	5%
All proximal veins	35%
Common femoral +/- femoral or iliac	8%

• Pulmonary embolism risk
• The risk of developing a PE from an untreated DVT is unknown, as most DVT patients are anticoagulated, and withholding treatment would be considered unethical. In one study, the 3-year incidence of a PE after isolated DVT was 5.1%; however, the study did not distinguish between patients who received long-term anticoagulation and those who did not. PEs can also be asymptomatic and go undetected. In one study, 40% of DVT patients without PE symptoms had evidence of PE on ventilation-perfusion lung scanning. [1]

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• Previous pulmonary embolism or DVT
• Age (1 in 10,000 annually before 40, rising to 6 in 1000 annually by age 80) [34]
• Cancer
• Cigarette smoking [3]
• First-degree relative with history of unprovoked VTE - the younger the age of the relative when the VTE occurred, the higher the risk [17]
• Human immune globulin products (ex. IVIG, Gamimune®, Sandoglobulin®, Polygam®) [15]
• Hypercoagulable disorders
• Immobilization for an extended period (ex. travel, surgery, hospitalization)
• Estrogen-containing medications (e.g. oral contraceptives, hormone replacement, SERMs) - see also hormone therapy after VTE [3]
• Obesity
• Peripherally inserted central catheters (PICC lines) [21]
• Ponatinib (Iclusig®) [16]
• Pregnancy
• Superficial vein thrombosis (SVT) - in one study, 2.5% of patients with an SVT developed a DVT within 3 months of SVT diagnosis; the incidence of PE was 0.9% during the same period. At 5 years, the risk of VTE was 5-fold higher in SVT patients compared to unaffected patients. [18]

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• Overview
• Recommendations for providing extended anticoagulation after a DVT are based on whether the DVT is considered provoked or unprovoked. In general, these terms have the following meanings:
• Provoked DVT - DVT with a preceding identifiable risk factor
• Unprovoked DVT - DVT with no preceding identifiable risk factor


• Significant provoking risk factors are not consistently defined across the medical literature. For example, in some studies, oral contraceptive use is considered a significant provoking factor, while in others, it is not. The same goes for pregnancy and a list of other conditions. [11]
• The 2021 ACCP VTE recommendations define two categories of provoking risk factors that are used to make extended anticoagulation recommendations. Those categories are described in the table below, along with major risk factors used in the Wells score.

• References [4,31]

ACCP 2021 DVT Risk Factor Categories
DVT provoked by a major transient risk factor Surgery with general anesthesia for greater than 30 minutes Confinement to bed in hospital (only bathroom privileges) for at least 3 days with an acute illness Cesarean section
DVT provoked by a minor transient risk factor Surgery with general anesthesia for less than 30 minutes Admission to hospital for less than 3 days with an acute illness Confinement to bed out of hospital for at least 3 days with an acute illness Leg injury associated with reduced mobility for at least 3 days Estrogen therapy (OCPs or HRT) Pregnancy and the six weeks after delivery
Major risk factors in the Wells score Active cancer Paralysis or recent immobilization of the lower extremity (this could include prolonged travel) Recently bedridden for ≥ 3 days, or major surgery within previous 12 weeks

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• Symptoms
• Common symptoms of DVT are listed below. It's important to note that DVTs may also be asymptomatic and discovered incidentally on imaging for other indications.
• Symptoms of DVT include:
• Pain in the affected leg
• Swelling in the affected leg
• Dilated superficial veins (nonvaricose) in the affected leg

• Physical exam findings
• Localized tenderness along distribution of deep vein system
• Swelling of affected leg
• Dilated superficial veins (nonvaricose) in the affected leg
• Calf swelling ≥ 3 cm larger than that of the unaffected leg (measured 10 cm below the tibial tuberosity)

• Ultrasound
• Lower extremity ultrasound (US) is the preferred method for diagnosing DVT. When venography is used as the reference standard, US has a sensitivity of 97% for proximal DVT and 71% for distal DVT. Specificity is greater than 90%. [32]

• D-dimer
• D-dimer, a degradation product of fibrin cross-linking whose levels rise during clot formation (see coagulation cascade illustration), can be helpful in diagnosing a DVT. An elevated D-dimer is sensitive for a DVT, but not specific, as a number of other conditions can cause elevations (e.g. advanced age, cancer, pregnancy, recent surgery). Therefore, a normal D-dimer essentially rules out a DVT in many patients, while a high level is nonspecific and requires further testing.

• Age-adjusted D-dimer
• D-dimer levels rise naturally with age, so older patients have higher levels. In most laboratories, the upper limit of normal for a D-dimer is 500 mcg/L (0.500 mg/L). Studies have found that using age-adjusted cutoff levels in patients 50 and older increases the specificity of the test without sacrificing sensitivity, and some experts argue that age-adjusted levels should be the standard. [PMID 26320520, PMID 23645857, PMID 24643601].
• The formula for calculating an age-adjusted level is as follows:
• Age-adjusted D-dimer cutoff = patient's age (if 50 or older) X 10 mcg/L [Online calculator]

• DVT Diagnostic Algorithm
• STEP 1 - Use Wells score to determine patient's risk of DVT

• If both legs are symptomatic, use more symptomatic leg
• Reference [4]

Wells score
Finding / History	Points
Active cancer (treatment ongoing, administered within previous 6 months or palliative)	+1
Paralysis or recent immobilization of the lower extremity	+1
Recently bedridden for ≥ 3 days, or major surgery within previous 12 weeks	+1
Localized tenderness along distribution of deep vein system	+1
Swelling of entire leg	+1
Calf swelling ≥ 3 cm larger than that of the unaffected leg (measured 10 cm below the tibial tuberosity)	+1
Pitting edema confined to affected leg	+1
Dilated superficial veins on affected leg (nonvaricose)	+1
Previously documented DVT	+1
Alternative diagnosis at least as probable as DVT	-2

• STEP 2 - Determine probability of DVT

• Reference [4]

Wells Score	DVT probability
≤ 0	Low probability
1 - 2	Intermediate probability
≥ 3	High probability

• STEP 3 - Based on the patient's probability, do the following:

• Reference [3,4]

Probability	Testing
High probability	Perform ultrasound
Intermediate or low probability	Order D-dimer If D-dimer is elevated, order ultrasound If D-dimer is normal, DVT unlikely [3,4]

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• DVT treatment is divided into three phases:
• Initiation phase (5 - 10 days) - period where the patient is quickly anticoagulated to prevent clot expansion
• Treatment phase (3 months) - continued anticoagulation to prevent clot expansion and promote dissolution
• Extended phase (beyond 3 months) - extended anticoagulation to prevent reoccurrence in appropriate patients

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• Initiation phase (5 - 10 days)
• In the initiation phase, patients are quickly anticoagulated to stop the clot from spreading. For many years, warfarin, which takes 3 - 5 days to become therapeutic and requires coverage with quick-acting injectable therapy during that time, was the only oral anticoagulant available. Rivaroxaban and apixaban, two newer DOACs, have a rapid onset of action and do not require injections during the first days of use. Two other DOACs, dabigatran and edoxaban, are FDA-approved for treatment after 5 - 10 days of parenteral therapy.

• Early ambulation
• In the past, patients were often prescribed bed rest in the acute phase of a DVT because it was theorized that activity could disrupt the clot and cause pieces to break off. Studies have found this to be untrue, and patients should be encouraged to ambulate early and often if tolerated. [9]

• ACCP 2021 recommendations
• Factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) or dabigatran are preferred over warfarin. Parenteral therapy is not required with apixaban and rivaroxaban, whereas 5 to 10 days are recommended with dabigatran and edoxaban.
• Patients with distal DVT - see distal (calf) DVT
• Patients with antiphospholipid syndrome - warfarin (target INR 2.5) is preferred with initial parenteral therapy
• Patients with cancer - Factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) are preferred over LMWH. Edoxaban and rivaroxaban appear to be associated with a higher risk of GI major bleeding than LMWH in patients with cancer-associated thrombosis and a luminal GI malignancy, while apixaban does not. Apixaban or LMWH may be the preferred option in patients with luminal GI malignancies (see Cancer-associated VTE treatment) [31]

• ASH 2021 recommendations for patients with active cancer
• Apixaban, rivaroxaban, or LMWH is recommended for treatment during the first week [30]
• Studies
• Cancer-associated VTE treatment
• A study published in 2015 comparing tinzaparin, a LMWH, to warfarin in cancer patients with acute VTE found no significant difference between the therapies for recurrent VTE or major bleeding at 6 months. [PMID 26284719]

• Heparins
• Unfractionated heparin - typically referred to as "heparin" for short. Heparin works by activating antithrombin, which in turn, inhibits Factor IIa (thrombin) and Factor Xa (coagulation inhibition illustration). Heparin can be administered intravenously or subcutaneously and requires aPTT monitoring. It causes HIT in 1 - 5% of patients. [8]

• Low molecular weight heparin (LMWH) - LMWHs, also called "fractionated heparin," include enoxaparin (Lovenox®), dalteparin (Fragmin®), and tinzaparin (Innohep®). LMWHs are similar to heparin except that they consist of smaller molecules (hence "low molecular weight") because they have been fractionated (divided into parts). Like heparin, LMWHs work by stimulating antithrombin activity (see coagulation inhibition illustration). LMWHs are given by subcutaneous injection, and they do not require lab monitoring. Enoxaparin (Lovenox®), the most widely used LMWH, is dosed 1 mg/kg every 12 hours for VTE treatment and 40 mg once daily for VTE prevention. The risk of HIT with LMWH is 0.1 - 1.0%. [8]

• Fondaparinux (Arixtra®) - fondaparinux is a synthetic heparin derivative that activates antithrombin, but unlike heparins where Factor Xa and IIa are inhibited, only Factor Xa is inhibited when antithrombin is stimulated by fondaparinux (see coagulation inhibition illustration). Fondaparinux carries a negligible risk of HIT, and some experts recommend its use in HIT patients; however, it is not FDA-approved for this indication. Fondaparinux is administered once daily by subcutaneous injection and does not require lab monitoring. [8]

• Heparin-induced thrombocytopenia (HIT)
• Heparins can cause a syndrome called heparin-induced thrombocytopenia (HIT) that is marked by the development of antibodies to complexes of platelet factor 4 (PF4) and heparin. Anti-PF4 antibodies can activate platelets, causing thrombosis and platelet depletion. During HIT, platelet counts typically fall by 50% between 5 and 14 days after heparin initiation; patients with previous heparin exposure may see counts drop within 24 hours. If HIT is suspected, testing for anti-PF4 antibodies can be performed; however, a positive test has low specificity, as antibodies are present in up to 20% of heparin-exposed patients, but only a small fraction of these patients will develop HIT. To help make a diagnosis, a calculator has been developed that estimates the probability of HIT based on 4 findings (see 4Ts Score Calculator for HIT). HIT, which has a mortality of 5 - 10%, is treated by stopping heparin and switching to a non-heparin anticoagulant. [8,24]

• Non-heparins
• Argatroban - argatroban is a direct thrombin inhibitor FDA-approved for VTE treatment in patients with HIT syndrome. It is administered via continuous IV infusion and requires aPTT monitoring.
• Bivalirudin (Angiomax®) - bivalirudin is a direct thrombin inhibitor FDA-approved for use during PCI in patients with HIT syndrome. It is administered via continuous IV infusion and requires aPTT monitoring.

• Parenteral therapy treatment recommendations
• Patients with no history of HIT:
• LMWH or fondaparinux are preferred. Intravenous or subcutaneous unfractionated heparin may also be used.
• Therapy should last at least 5 days. See initiating warfarin for recommendations on dosing warfarin.
• Patients with ongoing HIT
• Direct thrombin inhibitor (argatroban)
• If cardiac surgery or PCI is needed, then use bivalirudin
• Patients with a history of HIT
• Fondaparinux [10]

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• Treatment phase (3 months)
• During the treatment phase, acute-phase anticoagulation is extended for a total of 3 months to facilitate clot reabsorption. Patients who received parenteral therapy during the acute phase are typically switched to oral therapy.

• ACCP 2021 recommendations
• All patients should be treated for 3 months with the anticoagulant they received in the initiation phase [31]
• Patients with distal DVT - see distal (calf) DVT

• ASH 2021 recommendations for patients with active cancer
• First-line: apixaban, edoxaban, or rivaroxaban
• Second-line: LMWH
• Third-line: vitamin K antagonist [30]
• Studies
• Cancer-associated VTE treatment
• A study published in 2015 comparing tinzaparin, a LMWH, to warfarin in cancer patients with acute VTE found no significant difference between the therapies for recurrent VTE or major bleeding at 6 months. [PMID 26284719]

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• Extended phase (beyond 3 months)
• After 3 months of treatment, extended anticoagulation is used to prevent VTE recurrence, which can be as high as 8% in the first year after an unprovoked VTE. The 2021 ACCP recommendations for extended anticoagulation divide VTEs into the following three categories:
• VTE provoked by a major transient risk factor (see major and minor risk factor definitions)
• VTE provoked by a minor transient risk factor
• Unprovoked VTE or persistent risk factor (e.g. thrombophilia)

• ACCP 2021 recommendations
• See ACCP categories for definitions of major and minor transient risk factors
• Patients with a major or minor transient risk factor should not receive extended coagulation (A 2025 study found that extended anticoagulation was beneficial in some patients with provoked VTE. See provoked VTE with enduring risk factor)
• Patients with an unprovoked DVT or persistent risk factor (e.g. thrombophilia) should receive extended coagulation with a DOAC. If a DOAC cannot be used, a vitamin K antagonist should be offered. Patients with antiphospholipid syndrome should receive warfarin.
• Extended-phase apixaban dosing should be 2.5 mg twice daily, and extended-phase rivaroxaban dosing should be 10 mg once daily.
• In patients with an unprovoked proximal DVT or PE who stop anticoagulant therapy, taking low-dose daily aspirin may help to prevent VTE recurrence [31]
• A quantitative estimate of the risks and benefits of extended therapy is available here - risk-benefit estimation

• ASH 2021 recommendations for patients with active cancer
• Extended anticoagulation is recommended in all cancer patients with VTE
• Apixaban, edoxaban, rivaroxaban, or LMWH may be used [30]

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• Current treatment guidelines for provoked VTE recommend three months of anticoagulation. Extended anticoagulation beyond three months is typically reserved for patients with strong, persistent VTE risk factors, including active cancer or thrombophilia. The 2025 HI-PRO trial, detailed below, evaluated the effects of extended anticoagulation in patients with provoked VTE who had chronic minor risk factors.

• Summary
• In the HI-PRO trial, extended anticoagulation was superior to three months of anticoagulation in patients with provoked VTE who had minor chronic risk factors for recurrence. The first-year VTE recurrence rate in the placebo group was 10%, which is notably higher than the 1–6% rate observed in other studies enrolling patients with provoked VTE. The unexpectedly high placebo recurrence rate and the resulting clinical benefit from extended anticoagulation suggest that current risk stratification models may underestimate the impact of less significant chronic risk factors (e.g., cardiovascular disease) when determining the need for indefinite anticoagulation following a provoked VTE. One limitation of the study is the 12-month treatment duration, which may not reflect the full risks and benefits of lifelong anticoagulation. It will be interesting to see how future guidelines incorporate data from this study.

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• Distal (calf) DVT
• Distal DVTs (see location) do not pose a significant risk for pulmonary embolism, and they have a lower risk of recurrence (see distal DVT recurrence risk). If left untreated, approximately 15 - 25% of distal DVTs will extend into the proximal veins, typically within 2 weeks. [6,10]
• The ACCP recommends that patients with an isolated distal DVT without severe symptoms or risk factors for extension (see below) be monitored with ultrasound once weekly for 2 weeks. If any extension occurs, the DVT should be treated as a proximal DVT, even if it remains confined to the distal veins.
• STUDY
  A study published in 2016 compared LMWH to placebo in patients (n=152) with isolated calf DVT. The composite primary outcome of extension of calf DVT to proximal veins, contralateral proximal DVT, or symptomatic pulmonary embolism at day 42 occurred in 3% of the LMWH group and 5% of the placebo group (p=0.54). Bleeding events were significantly higher in the LMWH group. [PMID 27836513]
• Risk factors for extension and conditions that favor anticoagulation:
• Elevated D-dimer
• Blood clot that is extensive (> 5cm in length, involves multiple veins, > 7mm in diameter) or close to the proximal veins
• Unprovoked DVT
• Active cancer
• History of previous DVT
• Inpatient status
• COVID-19
• Highly symptomatic
• Patient prefers to avoid repeat imaging
• Factors that may favor serial ultrasound as opposed to anticoagulation
• Thrombosis is confined to the muscular veins of the calf (e.g. soleus, gastrocnemius)
• There is a high or moderate risk for bleeding
• Patient wishes to avoid anticoagulation [10,31]

• Recurrent DVT while taking anticoagulants
• Recurrent VTE while receiving anticoagulant therapy is rare, and affected patients should be evaluated for the following: (1) is the VTE truly a recurrent VTE, (2) anticoagulant compliance, (3) possibility of an underlying malignancy. The ACCP gives the following treatment recommendations:
• In patients receiving warfarin or a DOAC, switch to LMWH temporarily (defined as at least 1 month)
• In patients receiving long-term LMWH, increase the dose of LMWH by about one-quarter to one-third [22]

• Anticoagulant + antiplatelet therapy
• Patients with a DVT who have coronary artery disease have indications for both anticoagulation and antiplatelet therapy. Recommendations for antithrombotic therapy in these patients are provided at the links below.
• Antithrombotic therapy in acute coronary syndrome
• Antithrombotic therapy in chronic coronary disease

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• Inferior Vena Cava (IVC) filters
• IVC filters are devices placed in the inferior vena cava that capture venous blood clots, preventing them from reaching the lungs. They may be placed permanently or temporarily using retrievable filters.
• 2021 ACCP recommendations
• In patients with acute proximal DVT of the leg and a contraindication to anticoagulation, IVC filters are recommended
• IVC filters should not be added to anticoagulation [31]

• Thrombolysis
• Thrombolytic agents (e.g. alteplase, streptokinase), administered systemically or directly into a clot through a catheter, can be used to dissolve a DVT
• Small studies have suggested that thrombolysis may decrease the risk of post-thrombotic syndrome. However, a large study (N=692) published in 2017 found that adding catheter-directed thrombolysis to anticoagulation had no effect on the incidence of post-thrombotic syndrome, but it did increase the risk of major bleeding. [PMID 29211671]
• 2021 ACCP recommendations
• The ACCP does not recommend interventional (thrombolytic, mechanical, or pharmacomechanical) therapy for leg DVTs [31]

• Thrombectomy
• Blood clots can be removed from a vein through open surgery or mechanical aspiration with catheter-based devices
• 2021 ACCP recommendations
• The ACCP does not recommend interventional (thrombolytic, mechanical, or pharmacomechanical) therapy for leg DVTs [31]

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• Treatment
• Cancer-associated VTE has traditionally been treated with low molecular weight heparins like dalteparin. The studies below compared edoxaban and apixaban to dalteparin for VTE treatment in patients with cancer.

• RCT
  Apixaban vs Dalteparin for VTE in Patients with Cancer, NEJM (2020) [PubMed abstract]
• Design: Randomized controlled trial (N=1170 | length = 6 months) in patients with cancer who had symptomatic or incidental VTE
• Treatment: Apixaban 10 mg twice daily for 7 days then 5 mg twice daily vs Dalteparin 200 IU/kg once daily for one month then 150 IU/kg once daily
• Primary outcome: Objectively confirmed recurrent venous thromboembolism during the trial period
• Results:
• Primary outcome: Apixaban - 5.6%, Dalteparin - 7.9% (HR 0.63 95%CI [0.37 to 1.07])
• Major bleeding: Apixaban - 3.8%, Dalteparin - 4% (p=0.60)
• Findings: Oral apixaban was noninferior to subcutaneous dalteparin for the treatment of cancer-associated venous thromboembolism without an increased risk of major bleeding

• Professional recommendations
• ACCP and ASH DVT treatment recommendations
• ACCP and ASH PE treatment recommendations

• Summary
• In the two studies above, edoxaban and apixaban were noninferior to dalteparin for treating cancer-associated VTE. However, edoxaban caused more major bleeding events, which the authors note were mainly upper GI bleeds in patients with gastrointestinal cancer.
• Rivaroxaban has also been found to be noninferior to dalteparin in several small studies. [PMID 34627853, PMID 29746227]. A study (N=179) comparing 18 months of rivaroxaban treatment to 6 months in patients with acute low-risk pulmonary embolism found that 18 months was superior for preventing recurrent VTE at 18 months (5.6% vs 19.1%, p=0.01). [PMID 39556015]

• Cancer-associated VTE prevention in high-risk patients
• Malignancy is a major VTE risk factor, creating interest in the effects of routine thromboprophylaxis in cancer patients. Studies evaluating prophylactic heparin have had mixed results, and current guidelines do not recommend their use.
• A risk prediction tool called the Khorana score (scale 0 - 6 with higher scores indicating greater risk) has been developed to help identify high-risk patients. (Khorana score calculator) A score of 1 to 2 is intermediate risk, and 3 or higher is considered high risk. Studies have suggested that prophylaxis may benefit high-risk patients.
• The first two studies below compared apixaban and rivaroxaban to placebo for VTE prevention in cancer patients with Khorana scores of two or more. The third study compared apixaban 2.5 mg twice daily to apixaban 5 mg twice daily in patients with cancer-associated VTE who had completed at least 6 months of treatment.

• RCT
  API-CAT - Reduced-dose Apixaban (2.5 mg BID) vs Full-dose Apixaban (5 mg BID) for Prevention of Recurrent Cancer-Associated VTE, NEJM (2025) [PubMed abstract]
• Design: Randomized, double-blind trial (N=1766 | length = 12 months) in patients with active cancer and proximal deep vein thrombosis or pulmonary embolism who had completed at least 6 months of anticoagulant therapy
• Treatment: Apixaban 2.5 mg twice daily vs Apixaban 5 mg twice daily
• Primary outcome: Fatal or nonfatal recurrent venous thromboembolism
• Results:
  • Primary outcome: Apixaban 2.5 mg - 2.1%, Apixaban 5 mg - 2.8% (p=0.001 for noninferiority)
  • Clinically relevant bleeding: Apixaban 2.5 mg - 12.1%, Apixaban 5 mg - 15.6% (p=0.03)
• Findings: Extended anticoagulation with reduced-dose apixaban was noninferior to full-dose apixaban for the prevention of recurrent venous thromboembolism in patients with active cancer.

• ASCO 2023 recommendations
• Routine pharmacologic thromboprophylaxis should not be offered to all outpatients with cancer
• High-risk outpatients with cancer (Khorana score of 2 or higher before starting a new systemic chemotherapy regimen) may be offered thromboprophylaxis with apixaban, rivaroxaban, or LMWH provided there are no significant risk factors for bleeding and no drug interactions. Consideration of such therapy should be accompanied by a discussion with the patient about the relative benefits and harms, drug cost, and duration of prophylaxis in this setting
• Patients with multiple myeloma receiving thalidomide- or lenalidomide-based regimens with chemotherapy and/or dexamethasone should be offered pharmacologic thromboprophylaxis with either aspirin or LMWH for lower-risk patients and LMWH for higher-risk patients [ASCO 2023 Guidelines]

• Summary
• In the AVERT trial, apixaban was superior to placebo in preventing VTE, but it had no effect on overall mortality and caused more major bleeding. In the CASSINI trial, rivaroxaban was not superior to placebo for preventing VTE or improving mortality. One weakness of both studies is that only a third of participants had a Khorana score of 3 or greater, meaning higher-risk patients were underrepresented. These two studies do not support routine thromboprophylaxis in cancer patients.
• In the API-CAT trial, apixaban 2.5 mg twice daily was noninferior to apixaban 5 mg twice daily for the prevention of recurrent VTE over 1 year. The 2.5 mg dose was associated with significantly fewer bleeding events.

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• Overall risk
• The risk of recurrent VTE is strongly tied to the presence or absence of a provoking risk factor. The first table below shows the 1-year risk of recurrence based on provoking risk factors in patients who received no extended anticoagulation. The second table gives cumulative incidences of recurrent VTE over 10 years in patients who discontinued anticoagulation after a first unprovoked VTE.

• Patients were treated with at least 3 months of anticoagulation
• Reference [11]

Recurrence rate in first year after stopping anticoagulation
Type of VTE	Recurrence
Provoked by surgery	1.0%
Provoked by nonsurgical risk factor	5.8%
Unprovoked VTE	7.9%

• Reference [25]

Cumulative recurrent VTE risk for patients who discontinued anticoagulation after a first unprovoked VTE
Time	VTE (Men)	VTE (Women)
2 years	18.3%	13.6%
5 years	28.6%	21.2%
10 years	41.2%	28.8%

• Recurrent VTE after stopping estrogen-containing OCPs
• A systemic review and meta-analysis published in 2022 examined the risk of recurrent VTE in women diagnosed with estrogen-provoked VTE. The review included 14 studies where women with a VTE thought to be provoked by an estrogen-containing OCP received acute treatment for at least 3 months and were then followed after they discontinued anticoagulation. The overall rate of recurrent VTE after stopping anticoagulation was 1.57% per year. In studies where all patients stopped hormonal use or were strongly encouraged to do so (N=8), the recurrence rate was 1.31% per year. The rate among studies that included patients with high-risk thrombophilias (N=4) was 1.95% per year, compared to 1.40% per year among studies that excluded these women. [PMID 35108438]
• Summary
• This observational study provides meaningful information on the risk of VTE recurrence in females who experience a VTE while taking estrogen-containing OCPs. OCP use is considered a minor transient risk factor in the most recent ACCP guidelines, and extended anticoagulation is not recommended. Given that the overall risk of recurrence in these women was 1.57% per year, this analysis supports their recommendation.

• Distal DVT
• The risk of VTE recurrence after an isolated distal DVT (see location) is lower than VTEs at other sites. Recurrence rates based on location after unprovoked VTEs in patients who did not receive long-term anticoagulation are provided in the table below.

• Reference [27]

Cumulative recurrent VTE risk by initial VTE site in patients with first unprovoked VTE who did not receive long-term anticoagulation
Time	Distal DVT	Proximal DVT	PE
10 years	17%	37%	34%
20 years	30%	47%	44%

• Recurrent VTE after negative D-dimer
• D-dimer levels are useful in diagnosing a VTE. Some studies have shown they can also predict VTE recurrence, with elevated levels after VTE treatment indicating greater risk. The study below evaluated the utility of D-dimer testing to predict future VTE risk.

• OBS
  D-dimer testing to predict recurrent VTE in patients with first unprovoked VTE, Ann of IM (2015) [PubMed abstract]
• The study enrolled 410 adults with first unprovoked VTE who had completed 3 - 7 months of anticoagulation
• Patients had a D-dimer test during treatment, and if it was negative, anticoagulation was stopped. A second test was performed 1 month later, and if it was also negative, anticoagulation was held indefinitely (N=321). Recurrent VTE risk in patients with two negative tests is detailed in the table below, with women subdivided into whether their first VTE occurred during estrogen therapy (OCPs or HRT).

• Estrogen women were taking estrogen-containing OCPs or hormone replacement therapy when their first VTE occurred
• ^✝Five-year results were reported in a separate study [PMID 31033194]
• References [26,28]

Risk of recurrent VTE after negative D-dimer testing
Follow-up	Men	Non-estrogen Women	Estrogen Women
Average of 2.2 years	18.3%	11%	0%
Median of 5 years✝	29.7%	17%	2.3%

• Summary
• In the study above, D-dimer testing was not helpful in identifying patients at lower risk for VTE, as recurrence rates in negative patients were similar to those in untested populations.

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• ACCP risk-benefit estimation
• The ACCP published a table in their 2012 guidelines that estimates the risk and benefits of extended anticoagulation. Although the data has not been validated in a prospective study, it does offer a quantitative estimate of bleeding and recurrent VTE risk in patients treated with long-term anticoagulation.

• Categories of major bleeding risk:
• Low-risk: 0 risk factors
• Moderate-risk: 1 risk factor
• High-risk: ≥ 2 risk factors


• Risk factors for bleeding:
• Age > 65 years
• Age > 75 years (NOTE: An 80 year old would have 2 risk factors by age (> 65 and 75) and a 70 year old would have one risk factor by age)
• Previous bleeding
• Cancer
• Metastatic cancer (NOTE: A person with localized cancer would have one risk factor by cancer and a person with metastatic cancer would have 2 risk factors by cancer)
• Kidney failure
• Liver failure
• Low platelets (thrombocytopenia)
• Previous stroke
• Diabetes
• Anemia
• Antiplatelet therapy
• Poor anticoagulant control
• Comorbidity and reduced functional capacity
• Recent surgery
• Frequent falls
• Alcohol abuse [10]

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• See thrombophilia testing for recommendations on testing patients with VTE for hypercoagulable disorders

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• Up to 10% of patients with an unprovoked VTE are diagnosed with cancer within a year of their event. This association causes some providers to perform extensive cancer workups in affected patients. To test the validity of this approach, a study published in 2015 compared standard cancer screening to standard screening + CT of the abdomen/pelvis in patients with first unprovoked VTE.

• Summary
• The SOME study found no benefit of adding an abdominal and pelvic CT to standard cancer screening in patients with a first unprovoked VTE. It's unclear if an unprovoked VTE is a marker of increased cancer risk or if the higher incidence of cancer diagnosis after VTE is secondary to surveillance bias.

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• Overview
• A leg affected by a DVT may develop post-thrombotic syndrome, a condition marked by pain, swelling, heaviness, skin changes (brownish pigmentation), and in some cases, venous insufficiency with ulcers. Post-thrombotic syndrome affects up to a third of patients after their first DVT, typically within 2 years. Most cases are mild (minor leg swelling), while severe disease (intense pain and ulcers) is seen in about 8% of patients over 5 years of follow-up. [3,12]
• Small uncontrolled trials have suggested that compression stockings may help to prevent post-thrombotic syndrome. To assess these findings, the SOX trial detailed below compared compression stockings to placebo stockings in patients with first proximal DVT.

• 2021 ACCP recommendations
• In patients with acute DVT of the leg, compression stockings are not recommended to prevent post-thrombotic syndrome [31]

• Summary
• The SOX trial found no benefit of compression stockings in preventing post-thrombotic syndrome. Compression stockings can be uncomfortable and hot to wear, and only about 56% of trial participants complied with the treatment.
• Catheter-directed thrombolysis (CDT) has also been proposed to decrease the risk of post-thrombotic syndrome. A large study (N=692) published in 2017 found that the addition of CDT to anticoagulation had no effect on the incidence of post-thrombotic syndrome, but it did increase the risk of major bleeding. [PMID 29211671]

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• Overview
• Superficial vein thrombosis is a blood clot in the veins underneath the skin. Leg varicose veins are the most common site, with the saphenous vein involved in about two-thirds of cases. In the past, SVT was considered a benign process and was either not treated or treated with aspirin. However, this thinking has changed as several studies have found that patients with SVT are at increased risk of VTE. In one study, patients with an SVT ≥ 5 cm in length had an accompanying proximal DVT in 10% of cases and a distal DVT in 13%. [4] Another study found that 2.5% of patients with an SVT were diagnosed with a DVT within 3 months. PE incidence was 0.9% over teh same period, and 5 years after SVT diagnosis, the risk of VTE was 5-fold higher compared to unaffected patients. [12]
• A study published in 2010 found that patients with an SVT (≥ 5 cm in length) treated with fondaparinux (2.5 mg once daily for 45 days) had a significantly lower risk of subsequent VTE (absolute risk reduction 5%). [PMID 20860504]


• 2021 ACCP SVT treatment recommendations
• In patients with SVT of the lower limb at increased risk for clot progression to VTE (see below), anticoagulation for 45 days is recommended
• Fondaparinux 2.5 mg once daily for 45 days is preferred over other anticoagulant regimens such as (prophylactic or therapeutic dose) LMWH
• In patients who refuse or are unable to use parenteral anticoagulation, rivaroxaban 10 mg daily is a reasonable alternative
• Risk factors for progression to VTE
• Extensive SVT (≥ 5 cm)
• 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 [31]

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• Overview
• While anticoagulants are the preferred therapy for preventing VTE, some patients are apprehensive about taking them. This was particularly true before DOACs, when warfarin, which often requires frequent labs and adjustments, was the only available drug. Aspirin is a weaker antithrombotic, but it carries a lower risk of bleeding and is very cheap, making it more acceptable to some patients.
• Two studies below, WARFASA and ASPIRE, compared aspirin to placebo for VTE prevention in patients with first episode of unprovoked VTE. A meta-analysis that combined results from these trials is also reviewed, along with a third study comparing aspirin to rivaroxaban in patients with provoked and unprovoked VTE.

• OBS
  Meta-analysis of WARFASA and ASPIRE Trials, NEJM (2012) [PubMed abstract]
• The authors of the ASPIRE study and the WARFASA study performed a pre-specified meta-analysis that combined the two studies
• Results of the meta-analysis showed the following:
• Aspirin reduced the relative risk of recurrent venous thromboembolism by 32% (HR 0.68, 95%CI [CI 0.51 - 0.90], p=0.007)
• There was no significant difference between the two groups in clinically relevant bleeding. Aspirin - 2.92%, Placebo - 1.97% (HR 1.47, 95%CI [0.70 - 3.08], p=0.31) [14]

• Summary
• The WARSAFA study found that aspirin significantly reduced the annual incidence of recurrent VTE compared to placebo (6.6% vs 11.2%, p=0.02), while the ASPIRE study did not (4.8% vs 6.5%, p=0.09). A meta-analysis that combined their results found that aspirin had an overall significant effect. Collectively, these studies show that aspirin lowers the annual absolute risk of VTE by about 2%.
• Not surprisingly, rivaroxaban was superior to aspirin in the EINSTEIN CHOICE trial

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• Overview
• Patients undergoing total hip or knee replacement surgery are at high risk for VTE, and postoperative anticoagulation with LMWHs or factor Xa inhibitors is recommended for 15 (knee) to 35 (hip) days.
• To determine if aspirin is a suitable alternative, the study below compared a full course of rivaroxaban to 5 days of rivaroxaban followed by aspirin in patients undergoing hip or knee arthroplasty

• Summary
• In the study above, five days of rivaroxaban followed by aspirin was noninferior to a full course of rivaroxaban for preventing VTE after hip and knee replacement surgery. Another study that compared aspirin to dalteparin in hip replacement surgery came to a similar conclusion. [PMID 23732713]

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• Overview
• Traumatic fractures increase the risk of VTE, particularly during the immediate post-fracture/operative phase. Professional guidelines recommend anticoagulation during this high-risk period, and low-molecular-weight heparins (LMWH) are typically used. Recent studies have suggested that aspirin may be equally effective and is preferred by patients due to its low cost and oral administration. The METRC study detailed below compared aspirin to enoxaparin for VTE prevention after traumatic fracture.

• Summary
• In the METRC study, aspirin was noninferior to enoxaparin for mortality and PE prevention in patients hospitalized with serious fractures. DVT incidence was significantly higher in the aspirin group, but only by 0.80%. Bleeding complications and other adverse events were similar between groups.

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