New Data for DOACs in Cerebral Venous Thrombosis

Abu Dhabi, UAE — New evidence supports the use of direct oral anticoagulants (DOACs) in the treatment of cerebral venous thrombosis (CVT) based on findings from a new prospective, observational study.

The DOAC-CVT study showed very similar rates of the primary endpoint — a composite of recurrent venous thrombosis and major bleeding with DOACs and vitamin K antagonists.

“Our results suggest that patients with CVT can be safely and efficaciously treated with DOACs,” said lead investigator, Anita van de Munckhof, MD, Amsterdam University Medical Center, Amsterdam.

The trial results were presented on October 25 at the 16th World Stroke Congress (WSC) 2024.

Few Randomized Trials 

CVT is a less common cause of stroke that primarily affects young people and, more often, women. The incidence is estimated at approximately 1.5 to 2 cases per 100,000 in the Western world, but in developing countries, especially India and Pakistan, it is much more common.

Although it is an ischemic disorder, CVT is also associated with bleeding. It is estimated that about 40% of patients can experience an intracerebral hemorrhage because of the increased venous pressure that builds up in the brain, complicating the treatment, which is mainly based on anticoagulation.

Patients are generally started on low-molecular weight heparin in the acute phase and then after several days switched to oral anticoagulation.

Vitamin K antagonists (warfarin) have been the main oral anticoagulants used in CVT, but now DOACs are starting to be used as an alternative treatment. However, there is very limited data on the use of DOACs for this indication, senior author of the DOAC-CVT trial, Jonathan Coutinho, MD, also from Amsterdam University Medical Center, told Medscape Medical News.

There have been a few studies, but they have been too small to be able to draw any firm conclusions. The largest randomized trial (RE-SPECT CVT) suggested similar outcomes with DOACs vs vitamin K antagonists but only included 120 patients.

“Because of the rarity of CVT and the low event rates, it’s very difficult to conduct a properly powered randomized controlled trial, and as a result, current international guidelines are careful in the recommendation on the use of DOACS in CVT or advise against their use,” van de Munckhof said.

Coutinho explained that given the challenges of securing funding for a large randomized trial, they opted for the next best option — a large, prospective comparative cohort study. Though observational, this study was carefully designed with a strong methodology, including thorough baseline measurements and well-defined outcomes that were adjudicated by a blinded committee.

Van de Munckhof said the DOAC-CVT trial was conducted to compare the safety and efficacy of DOACs vs vitamin K antagonists for the treatment of CVT in a setting that reflects the daily clinical practice.

The investigator-initiated study included 619 patients with radiologically confirmed CVT from 65 centers in 23 countries over five continents. The choice of oral anticoagulant treatment was at the discretion of the treating physician, with 401 patients given a DOAC and 218 a vitamin K antagonist.

Patients were excluded if they had a contraindication for the use of DOACs such as pregnancy or severe liver disease.

Large, Diverse Study

Study participants had a median age of 40 years, and almost two thirds were women, which van de Munckhof said was very representative of a CVT cohort. Patients in the DOAC group were less likely to come from middle income countries.

Risk factors did not differ between the two study groups. Patients in the DOAC group were less likely to have focal neurologic deficits at presentation, but important predictors for poor functional outcomes such as seizure, coma, or intracranial hemorrhage at presentation did not differ between the groups. About one third of patients had intracranial hemorrhage at baseline, which is also representative of CVT cohorts.

The vast majority of study participants received heparin first, and the mean time to initiation of oral anticoagulation was 6 days in both groups.

The study’s primary endpoint was a composite of symptomatic recurrent venous thrombosis or major bleeding events (International Society on Thrombosis and Hemostasis definition) at 6 months of follow-up. Weighted odds ratios were calculated using propensity score inverse probability weighting.

Results showed that the primary endpoint occurred in 3% of the DOAC group and 3.2% of the vitamin K antagonist group.

After correcting for the multiple cofounders, this gave a weighted odds ratio of 0.99 (95% CI, 0.37-3.38), showing no difference between the two groups.

Symptomatic recurrent venous thrombosis occurred in 1.5% of the DOAC group vs 1.4% of the vitamin K antagonist group, and major bleeding occurred in 1.5% of the DOAC group and 1.8% of the vitamin K antagonist group.

Mortality rates were low in both groups (0.7% DOAC vs 1.4% vitamin K antagonist), as were all other secondary outcome events, including clinically relevant nonmajor bleeds. The vast majority of patients had modified Rankin Scale (mRS) scores of 0-2, with mRS scores ≥ 3 occurring in 5.1% of DOAC patients and 7.4% of vitamin K antagonist patients. All these secondary outcomes were not statistically different.

Van de Munckhof noted that the strengths of the study included its large and diverse population, which encompassed the majority of patients diagnosed with CVT in the participating hospitals, along with complete baseline and follow-up data for almost all patients.

She cautioned that the study did not enroll many patients with antiphospholipid syndrome as warfarin has been shown to be superior to DOACs in this patient group.

Guideline Change Warranted? 

During the discussion period, chair of the WSC session, Werner Hacke, MD, Heidelberg University, Heidelberg, Germany, said the study was a “very well–performed observational study.” 

Another commentator said they hoped these findings would change current guidelines.

“The data is reassuring on all accounts, with similar rates across the board for both bleeding and thrombosis. I think this is the best data we’re going to get in CVT. So I think we now have enough evidence that these patients can be treated with either a vitamin K antagonist or a DOAC,” said Coutinho.

He said most physicians these days would probably choose a DOAC because of convenience, but vitamin K antagonists may still be used in lower-income countries because of costs or availability.

Coutinho noted that the most common DOAC used in the study was dabigatran, possibly because the RE-SPECT CVT trial was conducted with dabigatran. “But I would think any of the DOACs would be appropriate. I think it would be extremely unlikely that there would be any difference in effects between the DOACs.”

The DOAC-CVT study was funded by the Dutch Thrombosis Foundation. Van de Munckhof reported no disclosures. Coutinho received grants paid to his institution from Boehringer Ingelheim and Bayer.