Venous Thromboembolism - Management Follow Up

Monitoring

DVT and Acute Pulmonary Embolism

Provoked VTE with persistent risk factors and a second episode of unprovoked VTE have the highest recurrence rates at 1 year and 5 years after stopping anticoagulation therapy. The rate of recurrent VTE is approximately 10% during the first year and 30% after 5 years, and approximately 40% in 10 years in patients with unprovoked DVT. Other strong risk factors for recurrence include a pulmonary embolism, proximal DVT, or a previous VTE. A high (>8%/year) risk for long-term recurrence is seen in patients with active cancer, antiphospholipid antibody syndrome, and ≥1 prior VTE episodes without a transient factor.  

Cumulative VTE risk over 5 years is as follows:

• Low risk (<14%): Transient risk factors (eg surgery, Estrogen therapy)
• Intermediate risk (14-30%): Non-surgical transient risk factors (eg leg injury, significant medical illness, travel associated)
• High risk (>30%): Unprovoked VTE

Recurrences tend to develop in a similar site to the initial episode, with more proximal VTE having higher recurrences rates. Risk factors for recurrent VTE in patients with calf DVT include age >50 years old, male sex, multiple unilateral thromboses, bilateral DVT, unprovoked DVT, and cancer. 

Risk factors for proximal extension of distal DVT favoring anticoagulation include D-dimer ≥500 ng/mL, non-minor symptoms, unprovoked event, extensive thrombosis involving multiple veins, persistent or non-reversible risk factors (eg active cancer, prolonged immobility), prior DVT or pulmonary embolism, and inpatient status. The risk of proximal extension or pulmonary embolism in patients with distal DVT without anticoagulation is >10%.   

Factors favoring surveillance of distal DVT include D-dimer level <500 ng/mL, no or minor symptoms, absence of high-risk features of proximal extension, minor thrombosis in the muscular veins, high risk of or contraindications to bleeding and patient preference.

Patients with acute pulmonary embolism are recommended to follow up at or before 3 months after diagnosis to discuss the duration of anticoagulation, review the need for further testing, and assess for persistent pulmonary embolism-related symptoms. They have a high frequency (20-50%) of symptomatic extension of thrombus and/or recurrent VTE and therefore require long-term anticoagulant treatment. Patients who have experienced an acute pulmonary embolism should be assessed at every follow-up visit for at least 1 year for pulmonary embolism-related symptoms and functional limitations, in order to screen for chronic thromboembolic pulmonary disease (CTEPD) or other potential causes of dyspnea and reduced functional capacity. 

Extended anticoagulation treatment should be considered in the following patients with an index pulmonary embolism episode: Have no identifiable major reversible risk factor or with a minor transient risk factor; and those with a persistent risk factor other than antiphospholipid antibody syndrome.  

Patients receiving extended treatment should be followed up at least annually and checked for the presence of bleeding and recurrent VTE, changes in hepatic or renal function, adherence to therapy, treatment preferences, and new drug interactions.

If anticoagulation treatment failure occurs, check the patient's adherence to therapy, check for malabsorption or treatment suspension for a planned procedure, increase the anticoagulant dose or administration frequency or switch to an anticoagulant with a different mechanism of action, and address other causes of hypercoagulability.  

A CTPA or V/Q scan is recommended to objectively confirm or exclude the diagnosis of recurrent or breakthrough pulmonary embolism: 

• If a patient has a recurrent pulmonary embolism while adherent with therapeutic-intensity anticoagulation, it is reasonable to switch to a different drug class rather than continuing the same class
• If a patient has a documented recurrent acute pulmonary embolism while adherent with a reduced-dose DOAC, it is reasonable to escalate to a full-dose DOAC within the same class
• For patients with cancer who experience a recurrent pulmonary embolism despite LMWH therapy, it is reasonable to increase the LMWH dose by 20-25% to prevent future pulmonary embolism recurrences

A pulmonary rehabilitation program is reasonable for patients in whom CTEPD has been excluded but who have ongoing dyspnea and/or functional impairment despite ≥3 months of therapeutic anticoagulation after an acute pulmonary embolism to improve symptoms and exercise tolerance. For patients with acute pulmonary embolism and no identifiable provoking factors, perform a thorough history and physical examination and ensure completion of age-appropriate cancer screening to evaluate for occult malignancy.

LMWH  

Treatment options for patients with recurrent VTE unresponsive to vitamin K antagonist therapy or for those with breakthrough VTE during vitamin K antagonist therapy. The dose may be increased if there is treatment failure to present the dose.  

For patients with pulmonary embolism and cancer, LMWH is preferred over vitamin K antagonists and should be used for the first 6 months of long-term anticoagulant therapy. After which, these patients should receive oral anticoagulant therapy indefinitely or until the cancer has resolved.  

Oral Anticoagulant

Treatment with oral anticoagulant is the preferred method of long-term management of most patients with pulmonary embolism. For patients with leg DVT or pulmonary embolism, DOACs are preferred over vitamin K antagonists for the first 3 months of long-term anticoagulant therapy. For patients with provoked proximal DVT, DOACs are preferred over vitamin K antagonists for the principal treatment phase. For patients with unprovoked proximal DVT, DOACs are recommended over LMWH followed by vitamin K antagonists for the principal treatment phase. For VTE patients with cancer, LMWH is preferred over vitamin K antagonists and DOACs are alternative agents. Adjusted doses of UFH or LMWH may be indicated for selected patients in whom oral anticoagulants are contraindicated or impractical.

Venous Thromboembolism - Management_Follow Up

• Continue for ≥3 months: First event with provoked risk factors, in cancer patients with symptomatic catheter-related thrombosis, patients with unprovoked proximal DVT with low to moderate bleeding risk, or patients with symptomatic distal DVT (provoked or unprovoked)
• Continue for ≥6 months: First episode, idiopathic VTE
• Continue for ≥12 months: Recurrent, idiopathic VTE or continuing risk factor
• Continue for 6-12 weeks: Symptomatic isolated calf vein thrombosis
• Consider for indefinite anticoagulation: Second episode of unprovoked pulmonary embolism, unprovoked proximal DVT, chronic risk factor (provoked non-surgical and non-reversible risk factors), or patients with pulmonary embolism and cancer without high bleeding risk

Extended anticoagulation beyond the initial 3-6 months for patients with pulmonary embolism:

• Patients continuing anticoagulation beyond 3-6 months: DOAC is preferred over a vitamin K antagonist to reduce bleeding risk
• Patients with cancer: A DOAC or LMWH is preferred over a vitamin K antagonist to reduce risk of recurrent VTE
• Patients without cancer but have contraindication to DOAC: Vitamin K antagonist is preferred over Aspirin or no therapy to reduce the risk of recurrent VTE
• Half-dose Apixaban or Rivaroxaban is recommended over full-dose therapy to reduce bleeding risk

Reduced dose of Apixaban or Rivaroxaban may be options for patients with unprovoked proximal DVT requiring extended anticoagulation for >6 months but without high risk of recurrence. Dabigatran is effective for extended anticoagulation therapy for VTE in patients with a high risk of recurrence. 

Warfarin  

An INR range of 2.0-3.0 is recommended for patients with VTE who will continue vitamin K antagonist therapy as extended anticoagulation after having completed the primary treatment.  

Aspirin  

Aspirin may be considered for the prevention of recurrent VTE in patients with unprovoked proximal DVT or pulmonary embolism who refused continued anticoagulant therapy. Low-dose Aspirin or Sulodexide may be considered for an extended VTE prophylaxis in patients who refuse, cannot tolerate or have contraindication to oral anticoagulation.  

For patients who sustained a VTE while taking Aspirin for primary cardiovascular disease prevention or for stable coronary artery disease, it is advised to suspend Aspirin while taking anticoagulant therapy.  

International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) Bleeding Risk  

IMPROVE is used to assess a confined patient’s risk for bleeding prior to initiation of therapy. A score of ≥7 signifies increased bleeding risk.

Monitoring during Anticoagulation Therapy  

Monitor patient for VTE recurrence, bleeding, adverse effects of medication, drug interactions and signs and symptoms of conditions that could alter the half-life of the anticoagulant used (eg kidney failure, weight loss or gain). INR should be checked at least weekly during the first several weeks of Warfarin therapy. If stable, monitor every 2 weeks then every 4 weeks as clinically appropriate. The target INR is 2.5 for most patients and 3.0 for patients with recurrent VTE. Regularly monitor therapeutic levels to ensure effective anticoagulation in patients weighing <50 kg or >120 kg. In patients with acute pulmonary embolism undergoing LMWH monitoring, a peak anti-Xa level should be measured 3-5 hours after an LMWH dose, once steady state has been reached after at least 3 doses. Peak levels are preferred over trough or random levels for the most accurate assessment of whether the patient is within the expected therapeutic range.
 
Monitoring without Anticoagulation Therapy  

Monitoring without anticoagulation therapy is recommended for patients with isolated distal leg DVT and no severe symptoms or risk factors for proximal extension, and those with high bleeding risk. Serial ultrasound imaging of both legs for 2 weeks is suggested.

Surveillance is recommended in patients with subsegmental pulmonary embolism and without proximal DVT and low risk of recurrence for VTE.