Primary prevention
Evidence shows that the incidence of venous thromboembolism (VTE) can be reduced in the medically ill, surgical, and traumatic nonsurgical populations.
Risk stratification
Risk assessment models (RAMs) have been proposed to risk stratify patients for VTE and guide prophylactic strategies.[76][81] Externally validated models that improve rates of pharmacologic prophylaxis or clinical outcomes include the Kucher Model, the Padua Prediction Score, Caprini RAM, IMPROVE RAM, and the Geneva Risk Score.[82]
Early mobilization is recommended for all patients when feasible. Pharmacologic prophylaxis should be given to all hospitalized patients with an increased risk of VTE, a low bleeding risk, and no contraindications. Mechanical prophylaxis (generally with intermittent pneumatic compression devices) should be given to patients at risk for deep vein thrombosis but with a high risk for bleeding or a contraindication to pharmacologic prophylaxis. It is important to re-evaluate these patients frequently and begin pharmacologic prophylaxis if the bleeding risk or contraindication remits, or if the risk of VTE increases (e.g., placement of a central venous catheter while hospitalized).
Very high-risk patients should receive both pharmacologic and mechanical prophylaxis if bleeding risk is low.[76][81][83] Hospital-associated VTE rates are a publicly reported hospital quality measure in the US.
Pharmacologic prophylaxis
Options for pharmacologic prophylaxis for the medically ill and surgical populations include low-dose unfractionated heparin, low molecular weight heparin, and fondaparinux. Betrixaban, a direct oral anticoagulant (DOAC), is approved by the Food and Drug Administration for the prophylaxis of VTE in adults (with restricted mobility and other risk factors for VTE) hospitalized for an acute illness. Apixaban, rivaroxaban, dabigatran, aspirin, and vitamin K antagonists (warfarin) are approved for VTE prophylaxis in patients undergoing joint replacement procedures, along with low molecular weight heparin and fondaparinux.[83]
Emerging randomized controlled trial evidence suggests that apixaban may prevent VTE in intermediate-to-high risk ambulatory patients with cancer; risk of major bleeding with apixaban was, however, greater than with placebo.[84]
Extended duration pharmacologic prophylaxis
Extended-duration pharmacologic prophylaxis (i.e., continued prophylaxis after hospital discharge) may be appropriate in specific patient groups.
Patients undergoing hip or knee replacement or hip fracture surgery are suggested to continue prophylaxis for up to 10-35 days following surgery. Patients undergoing abdominal-pelvic surgeries for a malignancy are recommended a 28-day regimen of prophylactic low molecular weight heparin.[81][83]
A pooled analysis of five randomized trials (>40,000 patients) found that extended-duration prophylaxis following hospitalization for medical illness reduced symptomatic VTE or VTE-related death compared with standard of care (0.8% versus 1.2%, P=0.002), but increased the risk of major or fatal bleeding (0.6% versus 0.3%, P <0.001). Regimens included low molecular weight heparin or DOACs at a prophylactic-dose for 4-6 weeks following discharge. Inclusion criteria varied, but the most common reason for hospitalization across studies was heart failure.[85] Due to the very narrow margin of risks and benefits, further research is needed to appropriately select medical patients for extended prophylaxis following hospital discharge.
Long-distance travel
The routine use of pharmacologic prophylaxis in patients traveling long distances is not recommended but can be considered on a case-by-case basis. Elastic compression stockings may reduce the risk of VTE in these patients.[76]
Secondary prevention
The goal of extended-phase anticoagulant therapy (i.e., beyond the first 3 months and with no scheduled stop date) is secondary prevention of recurrent venous thromboembolism (VTE).
The American College of Physicians (ACCP) guidelines recommend that the following patients are given extended-phase anticoagulation:[21]
Those with PE diagnosed in the absence of transient provocation (unprovoked PE or PE provoked by a persistent risk factor). These patients should be given a direct-acting oral anticoagulant (DOAC)
Those with PE diagnosed in the absence of transient risk factor (unprovoked PE or PE provoked by a persistent risk factor) who cannot receive a DOAC. These patients should be given a vitamin K antagonist (VKA).
Extended-phase anticoagulation is not recommended in patients with PE diagnosed in the context of a major or a minor transient risk factor.[21]
The decision to start or continue extended therapy should be based on patient preference and the predicted risk of recurrent VTE or bleeding.[21]
Predictors for recurrence
Precise prediction of the risk for recurrent VTE after an initial event is challenging. The presence or absence of temporary provoking factors is the most potent predictor for recurrence. Patients with a major transient provocation (e.g. surgery) within the 3 months prior to the VTE event have the lowest risk for recurrence. Minor transient risk factors (e.g. medical hospitalization, estrogen use, long-haul travel) within 2 months of the diagnosis predict an intermediate risk for recurrence. Patients with no identifiable risk factor for VTE (i.e., unprovoked VTE) or a persisting provocation (e.g. cancer) are at high risk for recurrence.[20] Patients with recurrent unprovoked PE and proximal deep vein thrombosis are thought to be at an especially high risk for further recurrence.[174]
When assessing anticoagulant-related bleeding risk, the following factors should be considered: age >65 years (particularly >75 years), previous bleeding, cancer, renal failure, liver failure, thrombocytopenia, previous stroke, diabetes mellitus, anemia, antiplatelet therapy, poor anticoagulant control, comorbidity with reduced functional capacity, recent surgery, frequent falls, alcohol abuse, use of nonsteroidal anti-inflammatory drugs.[4] Patients with none of these risk factors are considered low risk; one risk factor renders a patient moderate risk; and two or more risk factors renders a patient high risk.
Several risk prediction models have attempted to identify patients with unprovoked and/or minor transient provocation who have a low risk of recurrent VTE. Of these, the HER-DOO2 model has been evaluated in a number of prospective clinical validation studies, and has been used to identify a subpopulation with a low risk of recurrence after stopping anticoagulation therapy (following completion of the treatment phase).[205]
Choice of agent
In patients who receive extended-phase anticoagulation therapy, there is usually no need to change the initial oral anticoagulant. ACCP guidelines recommend using reduced-dose apixaban or rivaroxaban for patients receiving apixaban or rivaroxaban; the choice of a particular drug and dose should take into account the patient’s body mass index, renal function, and expected adherence to the dosing regimen.[21]
Lower doses of both apixaban and rivaroxaban are similarly effective for extended-phase anticoagulant therapy, and are associated with a modest reduction in nonmajor bleeding compared with treatment doses.[21][206][207]
Evidence from studies of ≥6 months’ duration suggests that there are no significant differences in safety and efficacy between direct oral anticoagulants and conventional anticoagulation for the management of PE.[208][209]
[ 
]
[Evidence B]
The continued use of extended-phase anticoagulation should be reassessed at least annually, and at any time there is a significant change in the patient’s clinical status.[21] The evidence to continue extended therapy beyond 4 years is uncertain. ACCP guidelines recommend shared decision-making, taking into account the patient values and preferences.[21] Patients should be periodically reassessed for bleeding risk, burdens of therapy, and any change in values and preferences.
If the decision is to stop extended-phase anticoagulation, ACCP guidelines recommend giving aspirin (unless contraindicated) to prevent recurrent VTE.[21] The benefits of using aspirin should be balanced against risk of bleeding and inconvenience of use. Aspirin should not be considered a reasonable alternative for patients who are willing to undergo extended anticoagulation therapy, as aspirin is much less effective. The use of aspirin should always be reassessed when a patient stops anticoagulant therapy (because aspirin might have been stopped when anticoagulant therapy was started).[21]
Active cancer
For patients with active cancer, ACCP guidelines recommend apixaban, edoxaban, or rivaroxaban over low molecular weight heparin (LMWH) for extended-phase anticoagulation.[21] DOACs (particularly edoxaban and rivaxobaran) are associated with a higher risk of gastrointestinal bleeding than LMWH. In patients with luminal gastrointestinal cancer, the ACCP recommends apixaban or LMWH as preferred agents.[21]
[ ]
The American Society of Hematology (ASH) recommends using DOACs or LMWH for the extended phase; ASH acknowledges that this recommendation is conditional based on very low-certainty evidence.[166] Extended-phase anticoagulant therapy is recommended in these patients (i.e., no scheduled stop date) while cancer remains active.[4][21][166]
Pregnancy
Anticoagulant therapy should be administered for at least 6 weeks postpartum in women at high risk for postpartum VTE, and for a minimum overall treatment duration of 3 months from initial PE diagnosis.[4][169] LMWH is used during the antepartum as other anticoagulants, including VKAs, may cross the placenta with attendant risk of fetal adverse effects.[4][21]
Continued LMWH or VKAs are an option for breast-feeding mothers. DOACs are excreted in breast milk, and their use while breast-feeding is not recommended.[4]
Severe renal impairment
The ACCP recommends a VKA for patients with severe renal impairment (i.e., creatinine clearance <30 mL/minute).[21] Apixaban is also suitable for use in patients with severe renal dysfunction or end-stage renal disease, though evidence for use in this patient population is limited.[165]
Hepatic impairment and coagulopathy
ACCP guidelines recommend LMWH in this patient population.[21] Health professionals should refer to the label and/or local formularies before prescribing a direct-acting oral anticoagulant for a patient with hepatic impairment.
Antiphospholipid syndrome
In patients with antiphospholipid syndrome, the ACCP and the International Society on Thrombosis and Haemostasis guidelines recommend a VKA as the preferred therapy.[21][210]
Evidence from randomized controlled trials suggests that DOACs may not be as effective as VKAs for the treatment of thrombosis among patients with antiphospholipid syndrome. Therefore, the ACCP guidelines recommend that DOACs are avoided in these patients.[21]
Patients with recurrent VTE on anticoagulant therapy
Recurrent VTE is unusual among patients receiving therapeutic-dose anticoagulant therapy, with the exception of cancer (7% to 9% on-therapy recurrence with LMWH).[4][21][211] In addition to definitively establishing the presence of recurrent PE, consideration should be given to compliance with anticoagulant therapy or the presence of underlying malignancy.[21]
ACCP guidelines recommend a temporary switch to LMWH (for at least 1 month) for patients with recurrent PE who are thought to be compliant with a non-LMWH anticoagulant (or within the therapeutic range if receiving VKA therapy).[21] An increased dose of LMWH (one quarter to one third) is appropriate for patients with recurrent PE who have been receiving LMWH.[21]
Recurrent VTE following discontinuation of anticoagulant therapy
For patients who are no longer receiving anticoagulant therapy and experience a second PE with no identifiable risk factor (i.e., unprovoked), guidelines recommend the following anticoagulant treatment durations:[4][21]
Low or moderate bleeding risk: extended anticoagulant therapy with periodic reassessment to review risk-benefit ratio
High bleeding risk: stop anticoagulant therapy after 3 months.
Hereditary thrombophilia
While predictive of an initial VTE event, the presence of hereditary thrombophilia carries little risk prediction for recurrent VTE, and is not considered an important factor in determining whether a patient should continue anticoagulation for secondary prevention following the initial course of treatment.[21] Guidelines recommend against testing for hereditary thrombophilia in the presence of a strong transient risk factor (such as preceding surgery). A guideline from the American Society of Hematology outlines limited circumstances in which testing for individual (or a panel of) hereditary thrombophilias may have utility, and suggests the impact of the information on clinical decisions.[56][57]
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