Primary prevention
A large body of literature 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.[83][86][87] Such models include the Caprini RAM, the Geneva Risk Score, IMPROVE-RAM, IMPROVEDD (which included D-dimer), the Kucher Model, and the Padua Prediction Score.[88][89]
Prophylaxis
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 DVT 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). Recent studies have found that primary prevention improves with a multi-faceted approach including computer alerts.[90] Very-high-risk patients should receive both pharmacologic and mechanical prophylaxis if bleeding risk is low.[83][86][91][92] 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 (UFH), low molecular weight heparin (LMWH), and fondaparinux.
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Apixaban, rivaroxaban, dabigatran, aspirin, and vitamin K antagonists (usually warfarin) are also endorsed for VTE prophylaxis in patients undergoing joint replacement procedures, along with LMWH and fondaparinux.[91][93][94][95][96][97][98][99][100][101][102][103]
Specialist advice should be sought if a patient is at high risk of VTE during pregnancy or the postpartum period; there is uncertainty in current evidence about the risks and benefits of pharmacologic prophylaxis for these patients.[104]
Extended-duration pharmacologic prophylaxis
Extended-duration pharmacologic prophylaxis (i.e., continued prophylaxis after hospital discharge) may be appropriate in certain 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 LMWH.[86][91]
Five randomized trials enrolling over 40,000 patients have examined extended-duration prophylaxis following hospitalization for medical illness.[32][33][34][105] Regimens included LMWH or direct oral anticoagulants (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. A pooled analysis revealed that extended prophylaxis reduced symptomatic VTE or VTE-related death compared with standard of care (0.8% vs. 1.2%; risk ratio [RR] 0.61, 95% CI 0.44 to 0.83; P=0.002) but increased the risk of major or fatal bleeding (0.6% vs. 0.3%; RR 2.04, 95% CI 1.42 to 2.91; P <0.001).[106] 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. Currently in the US rivaroxaban is approved for extended-duration or post-discharge pharmacologic prophylaxis in select patients.[105][107][108]
In selected ambulatory patients receiving therapy for cancer, emerging evidence suggests that oral factor Xa inhibitor prophylaxis carries a favorable risk/benefit balance in reducing the risk for cancer-associated VTE versus associated major bleeding.[109]
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.[82] Elastic compression stockings may reduce the risk of VTE in patients with risk factors.[83][110]
Secondary prevention
The principal means of secondary prevention is the extended prescription (e.g., no planned stop date) of an anticoagulant. The American College of Chest Physicians (ACCP) guidelines recommend that the following patients are given extended-phase anticoagulation:[18]
Those with DVT who are diagnosed in the absence of transient provocation (unprovoked DVT or provoked by a persistent risk factor). These patients should be given a direct oral anticoagulant (DOAC).
Those with DVT who are diagnosed in the absence of a transient risk factor (unprovoked DVT or provoked by a persistent risk factor) who cannot receive a DOAC. These patients should be given a vitamin K antagonist (usually warfarin).
Extended-phase anticoagulation is not recommended in patients with DVT who are diagnosed in the context of a major or a minor transient risk factor.[18]
The ACCP guidelines recommend using reduced-dose apixaban or rivaroxaban for patients receiving apixaban or rivaroxaban; the choice of a particular drug and dose should consider the patient's body mass index, renal function, and adherence to the dosing regimen.[18] The decision to start or continue extended therapy should be based on patient preference and the predicted risk of recurrent venous thromboembolism (VTE) or bleeding.[18]
The continued use of extended-phase anticoagulation should be reassessed at least annually, as well as at any time there is a significant change in the patient's health status.[18]
The evidence to continue extended therapy beyond 4 years is uncertain. The ACCP recommends shared decision-making, taking into account the patient's values and preferences. Patients should be periodically reassessed for bleeding risk, burdens of therapy, and any change in values and preferences.[18]
If the decision is to stop extended-phase anticoagulation in patients with an unprovoked proximal DVT, the ACCP guidelines recommend aspirin (unless contraindicated) to prevent recurrent VTE.[18] The benefits of using aspirin should be balanced against the risk of bleeding and inconvenience of use.
Secondary prevention may also embrace interventions undertaken episodically, at times when thrombosis risk is elevated. Such interventions include assuring prophylaxis at the time of hospitalizations and surgeries, prophylactic measures during pregnancy and the postpartum period, and possibly prophylactic interventions during long-distance travel. Finally, maintenance of a healthy weight, regular exercise, avoidance of estrogens and smoking, and possibly use of a statin (when indicated for hyperlipidemia) may all reduce the risk of recurrent thrombosis.
Provoked DVT: there is consensus that patients who have an index DVT that occurs in the setting of a major transient provocation have a relatively low risk of developing recurrent VTE in the next 5 years, with estimates in the range of 15%.[18] In these patients, a time-limited course of anticoagulation of at least 3 months is suggested.[18] The presence of a hereditary thrombophilia does not alter this recommendation, and guidelines recommend against testing for thrombophilias in patients with a DVT occurring following a major transient provocation.[55][56] Guidelines differ on offering extended anticoagulation for VTE associated with minor transient provoking risk factors.[21][180]
Unprovoked (no identified risk factors) DVT: among patients who present with an idiopathic or unprovoked DVT, the 5-year recurrence rate is estimated to be approximately 30% or more.[18]
Cancer represents a persistent provocation for VTE until cured. Among patients who are diagnosed with DVT and have an active cancer (e.g., cancer under any form of active therapy or palliation) there is a very high risk for recurrent VTE, and indefinite anticoagulation is recommended. Guidelines have recommended using a DOAC, which is supported by randomized controlled trials and subsequent meta-analyses (e.g., apixaban, edoxaban, rivaroxaban), or low molecular weight heparin (LMWH) for at least the initial 6 months of therapy.[18][19][107][195][226][227][228][229][230]
Apixaban or LMWH is the preferred agent for patients with a higher risk of bleeding, especially those with gastrointestinal cancers. LMWH is preferred for patients with drug-drug interactions with apixaban, rivaroxaban, or dabigatran.[18][193][194][195]
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Beyond the treatment phase, therapy with a DOAC is associated with better outcomes when compared with warfarin.[265]
Many studies have attempted to identify subgroups of patients with unprovoked VTE who do not need to be treated indefinitely with oral anticoagulation. There is strong evidence that the risk of recurrent VTE is higher in the following patients: male sex; those with a diagnosis of a proximal DVT (versus isolated calf DVT); those with ultrasound evidence of residual clot; those who have an elevated D-dimer 1 month after stopping a 3- to 6-month course of oral anticoagulation; and those who had an unprovoked DVT.[18][41] Several risk assessment models have been developed for this purpose, including the DASH score, the Vienna Prediction Model, and the "Men Continue and HER-DOO2" model.[191] The latter model identifies a subset of women with low risk for recurrent VTE after an initial unprovoked event, and one prospective validation study of this model was published.[192]
In patients who do not use extended-phase anticoagulation, episodic use of prophylactic strategies should be employed at times of risk, such as surgery, hospitalization, and long-duration travel. Selected patients who become pregnant may require anticoagulant prophylaxis during pregnancy and 6 weeks postpartum. Lower doses of LMWH have been validated for this indication.[266]
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