The Long-term Risk for Fatal Pulmonary Embolism after Discontinuing Anticoagulant Therapy for Venous Thromboembolism

Abstract & Commentary

By Harold L. Karpman, MD, FACC, FACP, Clinical Professor of Medicine, UCLA School of Medicine. Dr. Karpman reports no financial relationship to this field of study.

Synopsis: Patients with a first VTE event occurring in association with a reversible or time-limited risk factor should be treated with anticoagulants for at least three months, whereas patients with a first PE should be treated for at least six to 12 months; in fact, a case can be made for indefinite anticoagulant therapy in PE patients who have a great concern about recurrent PE and/or who are minimally concerned about the bleeding risk of anticoagulant therapy and the need for frequent determinations of the INR.

Source: Douketis JD, et al. Ann Inter Med. 2007;766-772.

When deciding whether to discontinue anticoagulant therapy for venous thromboembolism (VTE), the subsequent risk for fatal pulmonary embolism (PE) is obviously among the most important prognostic considerations since knowledge of the annual risk for fatal PE will undoubtedly influence any decision about discontinuing anticoagulation despite the low overall risk of fatal PE in these patients. The risk of fatal PE can be expressed in absolute terms or in conditional terms as the risk of fatality if recurrent disease occurs.1, 2

Douketis and his international (Canada, Sweden, Italy) colleagues performed a prospective cohort study at academic medical centers in an attempt to provide reliable and precise estimates of the annual risk for fatal PE and the case-fatality rate of disease recurrence if anticoagulation was discontinued and then they assessed these outcomes according to the initial presentation (deep venous thrombosis (DVT), PE, or both) and its etiology (secondary or idiopathic).3 They studied 2052 patients (1450 had DVT, 310 had PE, and 292 had DVT and PE) and determined the case-fatality rate of recurrent VTE, the incidence rates of any fatal PE and the rates of any definite or probable PE per 100 person-years of follow-up. The well defined and homogenous study population all had suffered a first episode of symptomatic VTE, had received similar initial anticoagulation and had completed, on average, six months of oral anticoagulant therapy. Careful follow-up revealed that in patients with a first episode of symptomatic VTE who had discontinued anticoagulant therapy, the risk for fatal PE was 0.19 to 0.49 events per 100 person-years and the case-fatality rate from recurrent VTE varied from 4% to 9%. This was contrasted with published data which reported that the annual risk for major hemorrhage if anticoagulation was continued at approximately 2%.

Commentary

Douketis and his associates3 have provided important information required by every clinician who treats patients with VTE or PE. The case-fatality rates which they carefully studied measures the clinical impact of disease recurrence if anticoagulation is discontinued, which can be compared with the case-fatality rate of bleeding if anticoagulation is continued.4,5 These findings become important when applied to advising patients with a first symptomatic VTE about their prognosis after discontinuing anticoagulation therapy6 The reported rate of fatal PE should reassure patients that their prognosis is good after stopping anticoagulation with a low (less than 1% per year) risk for future fatal PE that is further reduced if the initial VTE occurred after exposure to a transient risk factor or if they had already discontinued anticoagulants for more than one year. Of course, it should be recognized that these findings are less pertinent to patients with active cancer, permanent immobility, or high risk thrombophilia, who should not be identified with the study cohort because these patients usually receive lifelong anticoagulation therapy.6 A potential limitation of the Douketis study3 is that the duration of anticoagulant therapy was not standardized before entry into the inception cohort which theoretically could affect the incidence of fatal PE after anticoagulant treatment was stopped; however, in prespecified regression analyses, they found that the duration of anticoagulation, which ranged from three months to more than 12 months did not affect the incidence of fatal PE after discontinuation of therapy.

It has been demonstrated that the annual risk for disease recurrence if anticoagulation is discontinued is about 10%7 among patients with a first idiopathic VTE and that the annual risk for major bleeding if anticoagulation is continued is only about 2%.8 The calculated annual risk for death from bleeding is 0.16% to 0.18%, whereas the annual risk for death from recurrent VTE if anticoagulation is discontinued is 0.40 percent to 0.90% (ie, 10% recurrence risk times 4% to 9% case fatality rate), suggesting that the balance of risks seem to favor continuing anticoagulant therapy. However it is critically important to recognize that because the absolute difference in risk for death with either approach is extremely small, other individual patient factors (the D-dimer levels after discontinuing anticoagulant therapy,9 the estimated risk for nonfatal outcomes for example, postthrombotic syndrome, chronic pulmonary hypertension,10,11 and patient preferences) should be factored into the clinical decision about whether to continue or stop anticoagulants in each individual patient.

In summary, it would appear that the duration of the anticoagulant therapy in patients with VTE varies with the clinical setting as well as with patient preferences. Patients with a first VTE occurring in association with a reversible or time-limited risk factor should be treated with anticoagulants for at least three months whereas patients with a first PE should be treated for at least six to 12 months; in fact, a case can be made for indefinite anticoagulant therapy in PE patients who have a great concern about recurrent PE and/or who are minimally concerned about the bleeding risk of anticoagulant therapy and the need for frequent determinations of the INR. Finally, the results of the Douketis study3 would suggest that consideration should be given to continuing anticoagulants indefinitely in all patients with VTE; however, since the risk of death is extremely small whether or not anticoagulants therapy is continued after 3-12 months of therapy, clinical judgment will play an important role in the final decision.

References

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2. Douketis JD, et al. JAMA. 1998; 279:458-462.

3. Douketis JD, et al. Ann Inter Med. 2007;766-772.

4. Keeling D. Blood Rev. 2006;20:173-178.

5. Linkins LA, et al. Ann Inter Med. 2003;139:893-900.

6. Buller HR, et al. Chest. 2004;126:401S-428.

7. Ost D, et al. JAMA. 2005;294:706-715.

8. Palareti G et al. Lancet. 1996;348:423-428.

9. Palareti G et al. N Engl J Med. 2006; 355:1780-1789.

10. Pengo V, et al. N Engl J Med. 2004;350:2257-2264.

11. Douketis JD, et al. Arch Inter Med. 2000;160:3431-3436.