Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. Warfarin Optimal Duration Italian Trial Investigators. Agnelli G, Prandoni P, Santamaria MG, Bagatella P, Iorio A, Bazzan M, Guazzaloca G, Bertoldi A, Tomasi A, Scannapieco G, Ageno W.
Overall Study Question
This open-label, multicenter trial was conducted to determine the clinical benefit of extending the three-month course of oral anticoagulant therapy for a first episode of idiopathic proximal deep vein thrombosis (DVT) to a treatment duration of one year. Patients between the ages of 18 and 85 were consecutively enrolled into the study after a first episode of symptomatic, idiopathic proximal DVT. After completing three months of uninterrupted therapy with warfarin or acenocoumarol (target INR 2.0-3.0), eligible patients were randomized to either discontinue oral anticoagulant therapy, or to continue it for an additional nine months. The primary outcome for this study was the symptomatic, objectively confirmed recurrence of venous thromboembolism during a minimum of two years of follow-up.
Are the Results of the Study Valid?
1. Was assignment of patients randomized?
Yes. Patients were randomized after three uninterrupted months of oral anticoagulant therapy without having a recurrence of thromboembolism or bleeding episode.
2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?
Yes. Two years of follow-up data for all 267 patients enrolled in the study was available. In addition, the primary analysis was performed on an intention-to-treat basis.
3. Were patients, their clinicians, and study personnel ‘blind’ to treatment?
No. This was an open-label trial. However, an independent, blinded adjudication committee reviewed all suspected outcome events (recurrent thromboembolism and bleeding episodes) and all deaths on the basis of predetermined objective criteria.
4. Were the groups similar at the start of the trial?
Unknown. The authors stated that the groups were similar at baseline, however they only provided summary information regarding sex, age and incidence of initial treatment use of low-molecular weight heparin by group. Although randomized, this was a small trial and some unspecified characteristics could be unbalanced between groups. Unspecified characteristics of interest include the incidence of DVT only at presentation, the number of patients with suspected or confirmed pulmonary embolism at presentation, and the frequency of patients with a family history of venous thromboembolism.
5. Aside from the experimental intervention, were the groups treated equally?
No. All patients were instructed to return for follow-up at 3, 6, and 12 months after randomization and every 6 months thereafter until study completion. Those patients assigned to 12 months of oral anticoagulant therapy were monitored in anticoagulant clinics associated with the study centers for an additional nine months of treatment. The frequency of monitoring was unspecified during this period. Those patients assigned to discontinue treatment after 3 months did not have this additional contact with study personnel. However, it is unlikely that bias was introduced as a result of this additional follow-up since the majority of episodes of recurrent venous thromboembolism (RVTE) were discovered after treatment was discontinued.
What were the Results?
1. How large was the treatment effect?
Recruitment was terminated prematurely when the results of a planned interim analysis indicated the treatment effect did not meet the a priori criterion for effectiveness. The intention-to-treat analysis revealed that 21 of the 134 patients assigned to 12 months of therapy experienced an episode of RVTE (15.7%, average follow-up, 37.8 months), as did 21 of the 133 patients who were assigned to the short course therapy treatment arm (15.8%, average follow-up, 37.2 months). The calculated relative risk was 0.99 (95% confidence interval (CI), 0.57 to 1.73). Per-protocol analysis yielded similar results: 18 of 115 (15.7%) patients assigned to 12 months of therapy , and 21 of 126 (16.7%) assigned to 3 months of therapy experienced RVTE (relative risk 0.94 (95% CI 0.54 to 1.67)). The average time from randomization to RVTE was 11.2 months for those patients assigned to the 3-month treatment arm and 16.0 months in those assigned to 12-month treatment arm.
Major bleeding was defined as: clinically overt and associated with either a decrease in the hemoglobin level of at least 2g/dL or the need for transfusion of >=2 units of red cells, if the bleeding episode was retroperitoneal or intracranial in nature, or if the episode warranted permanent discontinuation of the study drug. Four patients (3.0%) assigned to 12-month therapy experienced nonfatal episodes of major bleeding during oral anticoagulant therapy. None of these patients had an INR above 3.0 at the time of bleeding. Two patients (1.5%) assigned to 3-month therapy suffered fatal bleeding. One episode was an intracranial hemorrhage one month after discontinuation of oral anticoagulation, and the other was a gastrointestinal bleed that occurred 12 months after discontinuation.
2. How precise was the estimate of the treatment effect?
The confidence intervals are quite wide (95% CI 0.57 to 1.73 for the intention-to-treat analysis). This is probably reflective of the relatively small sample size. There does not appear to be a significant skew in the CI that would suggest a possible benefit in the treatment group.
Will the Results Help Me in Caring for My Patients?
1. Can the results be applied to my patient care?
The results of this study may be generalized to the majority of patients with a first episode of symptomatic idiopathic proximal DVT. The inclusion and exclusion criteria were not exceedingly restrictive. At the time of randomization, 290 consecutive patients met the inclusion criteria, and only 23 were excluded (including 6 who declined to consent), accounting for fewer than 10% of the total number of patients screened. As discussed previously, limited data describing the characteristics of the trial population were available. The average age of patients enrolled in this study (approximately 67 +/-7 years) appeared older than the average age of patients enrolled in another recent trial of anticoagulation in idiopathic venous thromboembolism (approximately 59 +/-16 years). The percentage of males in both trials was similar.
2. Were all clinically important outcomes considered?
Yes. Recurrent deep venous thromboembolism, major bleeding, and death were assessed. The location of the recurrent DVT events was not specified in the article. Venous thrombosis of the proximal veins of the legs carries a higher risk of developing pulmonary embolism than thrombosis of the distal veins. Personal communication with the authors reveals that all 16 RVTE that occurred in those patients receiving 12 months of treatment were proximal in nature. In the 3 month treatment group, 16 of 18 (89%) RVTE were proximal, including popliteal vein location while the remaining events were distally located. Exclusion of the two distal RVTE makes it even less likely that a potential treatment effect was missed.
3. Are the likely treatment benefits worth the potential harms and costs?
Unable to determine. For the first 12 months of the study, the treatment group experienced a reduction in the rate of RVTE. This was at the expense of twice the rate of major bleeding. During the follow-up period after discontinuation of extended anticoagulation, rates of RVTE were in fact higher in the group assigned to continue therapy. Considering that the patients assigned to the treatment group did not derive any sustained benefit, extending the duration of anticoagulation from three months to one year for a first episode of symptomatic idiopathic proximal DVT may not be worth the potential harms and costs for all patients. It appears that RVTE events were simply delayed with continued oral anticoagulant therapy, rather that reduced. In order to recommend continued therapy, the bleeding risks and risk of RVTE in individual patients must be considered.
The rates of major bleeding documented with anticoagulation therapy for RVTE in previous trials is 2-4%, while in the current trial the rate was 3%. Of note, none of the patients who experienced major bleeding events in this trial had INR values in excess of the therapeutic range. It is possible that even enhanced INR monitoring during long-term therapy may not prevent adverse bleeding events. It is this risk of major bleeding during long-term therapy that must be weighed against the consequences of RVTE.
The optimal duration of therapy with oral anticoagulants for patients with idiopathic venous thromboembolism has yet to be determined. Results from earlier studies have identified that this population is at increased risk of recurrent thromboembolism. The Sixth ACCP Consensus Conference on Antithrombotic Therapy recommends that “patients with a first episode of idiopathic RVTE should be treated for at least 6 months”, but it is not clear whether a longer duration of treatment would be advantageous for this high risk group.
Recently, Kearon et al compared an additional 24 months of warfarin therapy with placebo in patients with a first episode of idiopathic thromboembolism who had completed 3 months of initial anticoagulation. They demonstrated a 95 % reduction in the risk of recurrent thromboembolism in patients assigned to extended treatment with warfarin, but did not address whether this advantage would be maintained upon discontinuation of therapy. The current trial was designed to determine if the benefits of extended anticoagulation persists after therapy is discontinued. This trial supports the findings of Kearon et al in that RVTE rates were reduced while patients received continued anticoagulation therapy. However, the results were not maintained after discontinuation, suggesting that prolonging the course of anticoagulation simply delays recurrence until treatment is discontinued. The focus of future trials may need to shift from the determination of an optimal duration of therapy for all patients to the identification of those patients at increased risk of RVTE who would benefit from indefinite anticoagulation. Patients at highest risk of recurrence must be identified due to the risks, costs and inconvenience associated with long-term anticoagulation therapy.