Secondary prevention
Secondary prophylaxis refers to preventing VTE recurrence. Risk of recurrent VTE in patients with a first episode of unprovoked VTE who completed at least 3 months of anticoagulant treatment has been estimated at 10% in the first year, 16% at 2 years, 25% at 5 years, and 36% at 10 years, with 4% of recurrent VTE events resulting in death.[152] When acute deep vein thrombosis (DVT) or pulmonary embolism (PE) is diagnosed, anticoagulant therapy is prescribed not only to treat local symptoms such as pain and swelling and to prevent extension of the DVT and/or PE, but also to provide secondary prophylaxis. Long-term prophylaxis is a term mainly used to describe the long-term (and often indefinite) use of therapeutic anticoagulation in patients with VTE who are at extremely high risk of recurrence if anticoagulation is stopped.
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This includes patients with thrombophilia, who have a 1.65 relative risk for recurrent VTE versus patients without thrombophilia, and patients with active cancer.[16][104]
The American College of Chest Physicians (ACCP) recommends offering extended-phase anticoagulation with a reduced-dose DOAC (apixaban or rivaroxaban) to patients with unprovoked VTE or those with VTE provoked by a persistent risk factor (e.g., active cancer or antiphospholipid syndrome).[153]
The American Society of Clinical Oncology advises the following treatment for patients with cancer with established VTE to prevent recurrence:[154]
Initial anticoagulation may involve low molecular weight heparin (LMWH), unfractionated heparin (UFH), fondaparinux, rivaroxaban, or apixaban. For patients initiating treatment with parenteral anticoagulation, LMWH is preferred over UFH for the initial 5-10 days, provided they do not have severe renal impairment (defined as creatinine clearance <30 mL/min).
For long-term prophylaxis (≥ 6 months), LMWH or direct oral anticoagulants (DOACs) (edoxaban, rivaroxaban, or apixaban) are preferred over vitamin K antagonists because of improved efficacy. There is a reduction in recurrent thrombosis but an increase in clinically relevant non-major bleeding risk with DOACs compared with LMWH. Caution with DOACs is therefore advised in gastrointestinal and genitourinary malignancies and other settings with high risk for mucosal bleeding.
Thrombophilia testing can be considered in select patients with established VTE, as a positive result can have bearing on the duration of anticoagulation treatment for secondary prophylaxis.[16]
In the US and Europe, the DOACs apixaban, dabigatran, and rivaroxaban are approved for the prevention of recurrent VTE. Edoxaban is also approved in Europe, but not the US, for this indication. Various studies have evaluated the use of DOACs for secondary thromboprophylaxis:
Rivaroxaban is the only DOAC to have been directly compared to aspirin for secondary prevention of VTE.[153] The EINSTEIN CHOICE trial randomised patients to 12 months of aspirin or rivaroxaban after completing 6-12 months of anticoagulation following acute VTE (provoked or unprovoked). This trial showed a 3% absolute risk reduction in recurrent VTE with rivaroxaban. However, 60% of the EINSTEIN CHOICE patients had provoked VTE, which is not the usual setting for extended secondary prophylaxis.[155] [
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A randomised, double-blind phase 3 trial involving patients with acute VTE found edoxaban to be non-inferior to warfarin for preventing recurrent VTE. Major bleeding events were similar for both drugs.[156]
Another trial found edoxaban to be non-inferior to dalteparin for the composite outcome of recurrent VTE or major bleeding in patients with cancer who had acute symptomatic or incidental VTE.[157]
In the AMPLIFY-EXT trial, a prophylactic dose of apixaban given as secondary prevention was as effective as a therapeutic dose to prevent VTE recurrence and mortality. This benefit occurred without an increased risk of major bleeding compared with placebo.[158]
Patient preference and predicted risk of recurrent VTE or bleeding should influence the decision to proceed with, or continue, extended-phase anticoagulation therapy. Patients who receive extended-phase anticoagulation should have this decision re-evaluated at least on an annual basis, and at times of significant change in health status. Extended-phase anticoagulation does not have a pre-defined stop date; there is limited evidence available to guide the decision about when (or if) anticoagulation should be ceased.[153]
In patients with unprovoked VTE who are stopping anticoagulant therapy (whether by their own choice or physician recommendation), aspirin can be offered as alternative (albeit less effective) secondary prophylaxis. The ACCP deem it preferable to no treatment. The benefits of aspirin need to be balanced against its side effects, particularly bleeding risk.[153]
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