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2276 Part XII: Hemostasis and Thrombosis Chapter 133: Venous Thrombosis 2277

therapy is appropriate and adhered to. The effectiveness and safety of whom the annual risk of bleeding, especially major bleeding, is similar
the DOACs compared with LMW heparin treatment in cancer patients or higher. However, if the risk of major bleeding is low, for example 1
with VTE has not been evaluated, and LMW heparin remains indicated percent per year or lower, then the annual risk of recurrent VTE of 3
for these patients. percent may not be sufficiently low to stop anticoagulation, especially
if the patient’s preference is on avoiding further recurrent VTE events.
Duration of Anticoagulant Therapy A variety of thrombophilic conditions have been identified and can
Anticoagulant treatment should be continued for at least 3 months in all be evaluated in the laboratory. These include deficiencies of the natu-
patients with VTE. 9,57,58,80 Stopping treatment at 4 to 6 weeks resulted in rally occurring inhibitors of coagulation such as antithrombin, protein
an increased incidence of recurrent VTE during the following 6 months C, and protein S; specific gene mutations including factor V Leiden
(absolute risk increase: 8 percent). 57, 80–82 In contrast, treatment for 3 to 6 and prothrombin 20210A; elevated levels of coagulation factor VIII;
months resulted in a low rate of recurrence during the following 1 to 2 and the presence of antiphospholipid antibodies (Chap. 131). The role
years (annual incidence 3 percent). 80–82 of the presence or absence of thrombophilia in guiding decisions about
The decision to stop anticoagulant therapy, or continue treatment duration of therapy has been controversial and is incompletely resolved.
after 3 months is influenced mainly by the patient’s clinical presentation Indefinite anticoagulant treatment should be considered in patients with
of thromboembolism as either “provoked,” which refers to VTE occur- a first episode of VTE and antiphospholipid antibodies or the presence
ring in association with known risk factors, or “unprovoked,” in which of one or a combination of the more potent thrombophilias (deficiency
identifiable risk factors for VTE are absent. Approximately 20 to 40 per- of antithrombin, protein C or protein S, homozygous factor V Leiden,
cent of all symptomatic patients present as unprovoked VTE. or prothrombin 20210A gene mutation, or one of these with a family
In patients with a first episode of DVT or PE provoked by a revers- history of VTE). Again, patient preference is important to the decision.
ible risk factor (e.g., surgery), treatment for 3 months is usually suffi- The DOACs have been evaluated by randomized trials for the
cient if the risk factor(s) is no longer present. If the risk factor(s) persist, extended treatment of patients with VTE who have completed an initial
for example prolonged immobility or cancer, treatment should be con- course of 6 months of anticoagulant therapy. 75,87–89 Most of the patients in
tinued until the risk factor is reversed. It has been a customary practice these trials had unprovoked VTE at their initial presentation and all had
to treat patients with PE for 6 months rather than 3 months, but the clinical equipoise about the benefit to risk tradeoff of receiving extended
clinical trials indicate there is little to no added benefit of doing so, with anticoagulant therapy. The results of the trials are consistent. The DOACs
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a small but additional risk of bleeding. Thus, for patients with DVT or produced 80 percent or greater reductions in the annual incidence of
PE provoked by a risk factor that has reversed, 3 months is sufficient and recurrent VTE of 7 to 9 percent per year in patients receiving placebo to
recommended over longer therapy. 57 approximately 2 percent per year in those given DOACs. 75,87–89 The rates of
Patients with a first episode of unprovoked VTE should be consid- major bleeding were 0.1 to 0.7 percent. Clinically relevant nonmajor bleed-
ered for indefinite anticoagulant therapy. 57,58 The term “indefinite” refers ing occurred in 3 to 4 percent of patients. 75,87–89 In the AMPLIFY Exten-
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to continued treatment without a scheduled stopping date; treatment sion trial, the rate of major bleeding for the 2.5 mg apixaban regimen was
may be stopped in the future if the patient’s risk-to-benefit profile or 0.2 percent per year, compared with 0.5 percent for placebo. The low rates
preference for continued treatment changes. The decision to stop or of major bleeding, coupled with the advantage of not requiring laboratory
continue anticoagulation after 3 months in patients with a first episode monitoring of the anticoagulant effect, will likely tip the balance in favor of
of unprovoked VTE should take into consideration the risk of recurrent extended treatment for more patients with unprovoked VTE.
VTE, the risk of bleeding, and patient preference. If indefinite antico- Aspirin has also been evaluated for the extended treatment of
agulant treatment is chosen, the risks and benefits of continuing such patients with a first episode of unprovoked VTE who have received a
treatment should be reassessed at periodic intervals. 57 course of 6 months or more of anticoagulant therapy. 90.91 Aspirin pro-
There has been significant research to develop strategies to aid the duced a statistically significant 42 percent RR reduction in recurrent
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clinician in assessing the risk of recurrent VTE in patients with unpro- VTE in one study (from 11.2 percent to 6.6 percent per year), and
voked VTE. The presence of residual DVT assessed by compression a nonsignificant (p = 0.09) 26 percent RR reduction in the second
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ultrasonography, elevated levels of plasma D-dimer after discontin- study (from 6.5 percent to 4.8 percent per year). The rates of major
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uing anticoagulant treatment, and male gender are associated with bleeding for aspirin (0.5 to 0.6 percent per year) were similar to pla-
an increased incidence of recurrent thromboembolism. The challenge, cebo. Although intuitive to the clinician, there is no data to indicate that
however, has been to identify the subgroup of patients with a sufficiently aspirin causes less major bleeding than the DOACs, although it is likely
low annual risk of recurrence to warrant stopping anticoagulant ther- that the efficacy for preventing recurrent VTE is significantly less (only
apy. Palaretti and colleagues evaluated an approach for patients with a about half as effective as the DOACs).
first episode of unprovoked VTE or VTE associated with a minor risk Oral anticoagulant treatment should be given indefinitely for most
factor (e.g., estrogens, pregnancy, or travel related thrombosis) which patients with a second episode of unprovoked VTE, 57,58,92 because stop-
combined evaluation of the presence or absence of residual thrombosis ping treatment at 3 to 6 months in these patients results in a high inci-
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by ultrasonography with serial D-dimer measurement to guide the deci- dence (21 percent) of recurrent VTE during the following 4 years. The
sion to stop or continue anticoagulant therapy. Patients in whom resid- risk of recurrent thromboembolism during 4-year followup was reduced
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ual vein thrombosis was absent after 3 months of treatment, or in those by 87 percent (from 21 percent to 3 percent) by continuing anticoagulant
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with residual vein thrombosis who had been treated for at least 1 year, treatment ; this benefit is partially offset by the risk of bleeding.
and who had serially negative D-dimer measurements for 3 months
after stopping vitamin K antagonist treatment, had an annual rate of Anticoagulant Therapy of Venous Thromboembolism in
recurrent VTE of 3 percent during followup off anticoagulant therapy; Cancer Patients
this compared to 0.7 percent per year in 373 patients who resumed anti- Use of LMW heparin for long-term treatment of VTE has been eval-
coagulation because of an elevated D-dimer measurement, and 8.8 per- uated in clinical trials. 67,68 The studies indicate that long-term treat-
cent per year among the 109 patients with elevated D-dimer who did ment with subcutaneous LMW heparin for 3 to 6 months is at least as
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not continue anticoagulant therapy. An annual risk of recurrent VTE effective as, and in cancer patients is more effective than, an oral vita-
of 3 percent may be low enough to discontinue therapy in patients in min K antagonist adjusted to maintain the INR between 2.0 and 3.0.

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