Article In Brief
In a clinical trial, warfarin and dabigatran were equally safe and effective for cerebral venous thrombosis (CVT). None of 120 patients with CVT had a recurrent venous thrombotic event during about six months of treatment and only a few had bleeding.
Both dabigatran and warfarin appear to be safe and effective options for preventing recurrent venous thrombotic events (VTEs) in patients with cerebral venous thrombosis (CVT), a new open-label clinical trial found.
No matter which medication they received, none of the 120 CVT patients in the trial had a recurrent VTE during about six months of treatment and only a few had bleeding.
The study, called RE-SPECT CVT, was too small to demonstrate either noninferiority or superiority of either treatment, but lead study author José M. Ferro, MD, PhD, said the findings could be enough to convince more clinicians to start using dabigatran for anticoagulation in place of warfarin for their CVT patients.
“Both patients and doctors will prefer dabigatran for having less or no interactions with food and most medications and not needing periodic control with blood analysis and dose adjustments,” Dr. Ferro, professor of neurology and head of the department of neurosciences and mental health at Hospital Santa Maria in Lisbon, Portugal, said in an email to Neurology Today.
Considering the new findings, reported September 3 in JAMA Neurology, Dr. Ferro said his center is switching from dose-adjusted warfarin to dabigatran 150 mg twice daily to prevent secondary VTEs in CVT patients.
He and his colleagues pointed out in the study that CVT—a type of stroke caused by thrombosis in the dural sinus and/or cerebral veins—is rarely deadly (mortality is less than 5 percent), and about 75 percent of patients who survive make a full recovery. Survivors, however, face an increased risk of recurrent VTEs in the cerebral veins or dural sinuses, veins of the limbs, splanchnic veins, as well as pulmonary embolisms.
In observational studies, the risk of recurrent CVT was 1.5 per 100 persons per year and the risk of all VTEs was 2.0 to 4.1 per 100 persons per year, with most recurrences in the first months after the initial event, the paper noted. The recommended practice for preventing VTE recurrence after CVT is anticoagulation using vitamin K antagonists (such as warfarin) for variable periods, the study authors wrote, though that recommendation is based on an extrapolation of findings on preventing recurrent VTE in patients with deep vein thrombosis (DVT).
The study authors pointed out that direct non-vitamin K anticoagulants (such as dabigatran) are now changing anticoagulation practices, and dabigatran has been shown to be efficacious in stroke prevention in patients with atrial fibrillation, as well as for treatment and prevention of recurrent DVT and pulmonary embolism.
Study Design, Findings
The prospective, randomized open-label clinical trial was conducted at 36 tertiary medical centers in nine countries from December 2016 to June 2018.
The study recruited consecutive patients between the ages of 18 and 79 who had a diagnosis of CVT confirmed by MRI plus MR venography, CT plus CT venography, or intra-arterial venography. Patients were excluded if they could not swallow oral medication, if their CVT was associated with central nervous system infection or major head trauma, or if they had cancer, among other reasons. Patients with intracranial bleeding of the index CVT could participate.
Eligible patients were randomized 1:1 to either dabigatran (150 mg twice daily) or warfarin—at a dose adjusted to maintain an international normalized ratio (INR) between 2.0 and 3.0. Randomization occurred five to 15 days after initial acute treatment with unfractionated or low-molecular weight heparin. All randomized patients received at least one dose of their allotted medication. Eleven (9.2 percent) patients discontinued medication before 24 weeks, including seven (1.7 percent) on dabigatran and four (6.7 percent) on warfarin.
The primary outcome was a composite of patients with a new VTE or major bleeding during the study period. Secondary outcomes were cerebral venous recanalization and clinically relevant nonmajor bleeding events. (For more findings, see “By the Numbers: The RE-SPECT CVT Study”)
Among the study's limitations was that it was too small to determine whether one drug was better or worse than another. Because VTE after CVT is a rare occurrence to begin with, it would have taken a study with about 2,000 patients for significantly meaningful differences between the drugs to emerge.
The fact that the study was open-label could have created biases, including influencing post-randomization decisions as well as outcome reporting and evaluations. There was also some sample bias that could have affected the results. For instance, no comatose patients were included since patients had to be able to swallow a pill.
The researchers said the frequency of recurrent VTEs in their study was even “lower than expected.” They said that result could be due to excellent adherence to treatment and INR control, as well as the fact that the patients at highest risk for VTEs may have been excluded from participating because of the study's criteria.
Dr. Ferro said he and his research team hope to validate the study's findings through additional research.
Cheryl Bushnell, MD, MHS, professor of neurology and stroke division chief at Wake Forest Baptist Health, said the new study provides important information in spite of the fact that it was not designed to determine whether dabigatran, a newer drug, achieved better results than warfarin, which has a long track record as an anticoagulant.
“There are more studies with warfarin,” Dr. Bushnell said in an email interview with Neurology Today. “This is one of the first studies with dabigatran, so there is less confidence in the use of dabigatran.”
Dr. Bushnell also noted dabigatran carries a risk of gastrointestinal bleeding, “and that is always something to consider when prescribing.”
Still, Dr. Bushnell said the new findings will likely “change practice because dabigatran is an option to warfarin and is easier for patients to take—with no lag time and no monitoring.”
Brett L. Cucchiara, MD, associate professor of neurology at the University of Pennsylvania, said the study was needed. “This is a relatively rare disease so it's hard to study especially with a randomized trial,” he said. “I think the investigators should be congratulated for completing the trial even though it was small.”
Dr. Cucchiara said warfarin is a “complicated drug to use, and many people have been reluctant to use these newer agents without some higher-quality data specific to the [CVT] population.”
He said he hoped the new data would help reassure doctors and patients that dabigatran is an acceptable alternative to warfarin. He noted that he moved away from warfarin for CVT several years ago and instead prescribes the newer anticoagulants like apixaban and, to a lesser extent, dabigatran.
“One of the things that came from the study that was a little bit surprising was that the patients overall did very well, with a very low rate of recurrent events,” Dr. Cucchiara said, though he cautioned that the study included a highly selective population of patients.
Joshua Z. Willey, MD, assistant professor of neurology at Columbia University, said he will add the new findings to the “pros and cons” of treatment options that he discusses with every patient. Factors to be considered are lifestyle, diet, convenience, and cost of drugs, he said, as well as a drug's track record.
Dr. Willey said health care access is another consideration, especially since warfarin requires follow-up blood tests and possible dose adjustments.
“What is the patient's ability to access health care and will they be able to remain on their therapy for a lengthy period of time?” Dr. Willey said.
He said the encouraging news from the new study is that most CVT patients fared well during the six months of treatment no matter which blood thinner they took, though longer-term outcomes are needed.
“You have a clotted vein inside your head and that sounds pretty scary to the patient,” he said, and on top of that, the risks of being on a blood thinner can be worrisome for the patient. The new findings offer the reassurance, he said, that “patients overall tend to have good outcomes.”
Dr. Ferro reported receiving personal fees from Boehringer Ingelheim during the conduct of the study; personal fees from Bristol-Myers Squibb and Bayer outside the submitted work; and a grant for José Ferro Lab at Instituto de Medicina Molecular from Bayer. Dr. Willey reported no disclosures.