Anticoagulation not superior to placebo for calf DVT in low-risk patients, may increase bleeding risk
The randomized, double-blind, placebo-controlled trial examined a composite measure of extension of calf deep venous thrombosis (DVT) to proximal veins, contralateral proximal DVT, and symptomatic pulmonary embolism in a modified intention-to-treat population.
Treatment with a low-molecular-weight heparin was not superior to placebo in reducing the risk of proximal extension or venous thromboembolic events in low-risk outpatients with calf deep venous thrombosis (DVT), but it did increase the risk of bleeding, a study found.
Researchers conducted a randomized, double-blind, placebo-controlled trial among low-risk outpatients without active cancer or previous venous thromboembolic disease with a first acute symptomatic DVT in the calf at 23 university medical centers or community medical clinics in Canada, France, and Switzerland. DVT was established by whole-leg compression ultrasonography. Calf DVT was defined by the presence of an incompressible venous segment in deep calf veins (posterior tibial, peroneal, or anterior tibial) or muscular veins (gastrocnemius or soleus). Patients with a thrombus limited to superficial veins were not eligible.
Patients received either the low-molecular-weight heparin nadroparin (171 UI/kg, subcutaneously, once a day) or placebo (saline 0.9%, subcutaneously, once a day) for 42 days. All patients were prescribed compression stockings and followed for 90 days. (Nadroparin is not currently available in the United States.)
The primary efficacy outcome was a composite measure of extension of calf DVT to proximal veins, contralateral proximal DVT, and symptomatic pulmonary embolism at day 42 in the modified intention-to-treat population. The primary safety outcome was major or clinically relevant nonmajor bleeding at day 42. Results were published online Nov. 7 by The Lancet Haemotology.
Only half of the prespecified sample size was enrolled from February 2008 through November 2014, when the trial steering committee stopped the trial because of expiration of the study drug and slow recruitment. The intention-to-treat analysis population included 122 patients in the nadroparin group and 130 in the placebo group. There was no significant difference between the groups in the composite primary outcome, which occurred in 4 patients (3%) in the nadroparin group and in 7 (5%) in the placebo group (risk difference −2.1%; 95% CI, −7.8 to 3.5; P=0.54). Bleeding occurred in 5 patients (4%) in the nadroparin group and no patients in the placebo group (risk difference, 4.1%; 95% CI, 0.4% to 9.2%; P=0.0255). In the nadroparin group, 1 patient died from metastatic pancreatic cancer and 1 patient was diagnosed with heparin-induced thrombocytopenia type 2.
“The absence of serious thromboembolic events in the placebo group (no symptomatic pulmonary embolism at 6 weeks in 130 patients), combined with the significantly increased risk of bleeding in the nadroparin group is, in our view, a strong argument in favour of not systematically treating calf DVT with anticoagulants,” the authors wrote. “The net clinical benefit shows no clear advantage of anticoagulant therapy over placebo in our cohort of low-risk outpatients, in whom ultrasound surveillance seems to be a reasonable alternative to anticoagulant therapy. Avoidance of treating all calf DVTs with anticoagulants could be an important cost-saving strategy.”
An editorial stated that before rewriting the guidelines, generalizability of the trial needs to be considered.
Exclusion criteria in this trial reduced the patient population to a selected subgroup of patients without previous venous thromboembolism or other risk factors, the editorialist noted. While isolated calf venous thrombosis may be commonly seen in daily practice, trial recruitment was slow, an average of 1 patient every 7 months. This may have led to selection bias.
“Indeed, there exists a very low-risk subgroup of patients,” the editorial stated. “If clinicians would have felt comfortable enrolling a patient into [the current trial], they should not give this patient anticoagulation since it will do more harm than benefit. Obviously, this approach will guide treatment only in few patients with calf deep vein thrombosis, and so will not substantially reduce overtreatment. For all other patients, more research is needed.”