Shorter Anticoagulation an Option for Young Patients With Provoked VTE

For patients younger than 21 who have provoked venous thromboembolism (VTE), shortening the length of anticoagulation to prevent a recurrent event is no worse than using it for the standard 3 months, the randomized Kids-DOTT trial shows.

One-year cumulative rates of symptomatic recurrent VTE and clinically relevant bleeding were low overall—0.70% or less—and similar when comparing 6-week and 3-month durations of anticoagulation, which was low-molecular-weight heparin (LMHW) in the majority of patients. Shorter therapy was noninferior to the standard length in an analysis that accounted for the opposing risks of recurrent VTE and bleeding.

“After completing the first 6 weeks of anticoagulant therapy, if the repeat scan shows that the blood clot is not completely blocking all blood flow through that venous system, then for most patients the treatment could be stopped at that point rather than continuing on for the total 3 months’ duration based on the findings of this trial,” Neil Goldenberg, MD, PhD (Johns Hopkins All Children’s Hospital, St. Petersburg, FL), told TCTMD.

The findings, which were published in the January 11, 2022, issue of JAMA and first presented during the International Society on Thrombosis and Haemostasis (ISTH) meeting last summer, wouldn’t apply to patients with active cancer or pulmonary embolism, who were excluded from the trial, but they would be generalizable to the “vast majority” of young patients with provoked VTE, Goldenberg said.

There are implications here for getting young people back to their usual activities more quickly, which is especially important in the context of the ongoing obesity epidemic, he indicated. “Being off of anticoagulant medication makes that return to normal life, return to play, and return to school and other activities much more feasible.”

Kids-DOTT

Standard of care for patients with provoked VTE—regardless of age—has been a 3-month course of anticoagulation, although the optimal treatment length for patients younger than 21 had never been studied in a clinical trial, Goldenberg said. “Since 2008, clinical practice guidelines for pediatric venous thromboembolism treatment have suggested a 6-week course of antithrombotic therapy as an alternative to 3 months, while emphasizing the need for definitive evidence,” he and his colleagues note in their paper.

Being off of anticoagulant medication makes that return to normal life, return to play, and return to school and other activities much more feasible. Neil Goldenberg

The Kids-DOTT trial, conducted at 42 centers across five countries, was designed to meet that need, enrolling 417 patients younger than 21 with acute provoked VTE; the most common factors associated with VTE were placement of a central venous catheter, infection, and recent trauma or surgery. Patients who did not have persistent antiphospholipid antibodies and who had clots that were resolved or not completely occlusive on repeat imaging at 6 weeks were randomized to stop anticoagulation at that point or to continue for the full 3 months. Anticoagulation involved LMWH in more than 80% of patients.

The primary analysis assessed the noninferiority of shorter-duration versus standard-length anticoagulation in the per protocol population using a bivariate method that reflects the trade-off between symptomatic recurrent VTE and clinically relevant bleeding. “The bivariate method provides a structure, or construct, where you can look at those two things simultaneously as you do as a physician or patient when considering [the need to be on] anticlotting medication,” Goldenberg explained.

Overall, 297 patients (median age 8.3 years; 49% female) were included in the main analysis. The Kaplan-Meier estimate for the 1-year cumulative incidence of adjudicated symptomatic recurrent VTE was 0.66% with 6-week anticoagulation and 0.70% for 3-month treatment, whereas the corresponding rates of clinically relevant bleeding were 0.65% and 0.70%. The results demonstrated the noninferiority of shortened therapy, with similar findings in an intention-to-treat analysis.

Total adverse events were seen in 26% of patients in the 6-week group and 32% in the 3-month group; the most common event was fever (1.9% vs 3.4%). There were no cases of heparin-induced thrombocytopenia. None of the eight deaths in the trial—four in each arm—were considered related to the study intervention.

Although direct oral anticoagulants (DOACs), which have become increasingly used in this population in recent years, were prescribed for just a handful of Kids-DOTT participants, the investigators point out that rates of symptomatic recurrent VTE and bleeding observed in the study were similar to those seen in the more-recent EINSTEIN-Junior and DIVERSITY trials. These evaluated rivaroxaban (Xarelto; Bayer/Janssen) and dabigatran (Pradaxa; Boehringer Ingelheim), respectively, in comparable populations.

“Taken together, data from these recent RCTs suggest that the risks of recurrent venous thromboembolism and clinically relevant bleeding events in young patients receiving anticoagulation for the treatment of acute venous thromboembolism are lower than previously reported from observational studies—particularly among patients with provoked venous thromboembolism,” Goldenberg et al write. “This may reflect experience gained in pediatric venous thromboembolism management and improved ability to distinguish provoked from unprovoked venous thromboembolism in children and young adults.”

Moreover, they say, the low rates of recurrent VTE observed overall “serve to further support the clinical appropriateness of shortening the duration of anticoagulant therapy for provoked venous thromboembolism in patients younger than 21 years of age.”

Time to Change Practice?

In an accompanying editorial, Benoît Mâsse, PhD, Nancy Robitaille, MD, and Jacques Lacroix, MD (University of Montreal, Canada), say the Kids-DOTT results “suggest that 6 weeks of anticoagulant therapy should be considered for standard treatment in children and adolescents after a provoked venous thromboembolism.” They note, however, that additional studies are needed to confirm the findings in patients with active cancer or pulmonary embolism, and caution against making changes to the management of patients with unprovoked VTE or older patients.

Some people are already using the shorter duration, but [the trial] will strengthen their belief that it was the right thing to do, and I hope that other people that are still using anticoagulation for 3 months will change their mind. Jacques Lacroix

Speaking with TCTMD, Lacroix said that the statistical approach used by the investigators to assess noninferiority is valid, but noted that “it cannot be applied in all instances”—for example, when there aren’t any serious safety concerns to weigh against the efficacy of a therapy. “The statistical approach . . . is I think applicable only when the issues of safety and efficacy are quite equal, quite similar,” he commented.

As for the impact of the trial, Lacroix predicted it will change how some clinicians are treating patients with provoked VTE. “Some people are already using the shorter duration, but [the trial] will strengthen their belief that it was the right thing to do, and I hope that other people that are still using anticoagulation for 3 months will change their mind,” he said, adding that future studies are needed to see how the trial results are being adopted.

Goldenberg predicted, too, that the results would change practice, noting that there are already indications that physicians in some parts of the world have shortened the duration of anticoagulation in this population in response to the initial presentation of the results at the ISTH meeting last year.

The similarity in the rates of recurrent VTE and bleeding seen in Kids-DOTT when compared with the DOAC trials “suggests that these findings . . . on duration of therapy are likely to apply to all of the different classes of anticoagulants that we use,” he said, “But it’s important that we continue to observe real-world data in the future to see that the low rates of recurrent VTE and bleeding associated with shortened therapy really are borne out in real-world practice moving forward.”