Ocular bleeding risk lower for NOACs than warfarin, but effect is small

By Joan Stephenson

NEW YORK (Reuters Health) - Novel oral anticoagulants (NOACs) appear to reduce the risk of intraocular bleeding compared with warfarin, according to the authors of a systematic review and meta-analysis.

The absolute difference in risk reduction is small, however, and whether it’s clinically meaningful is uncertain.

In recent years, worldwide use of NOACs for patients with atrial fibrillation or venous thromboembolism has grown substantially. Several phase 3 randomized studies have demonstrated that compared with warfarin, NOACs have an equal or better efficacy in preventing blood clots, and they are also less likely to cause intracranial hemorrhage.

But whether NOACs are also associated with a lower risk of intraocular hemorrhage, an uncommon treatment-related event, has been less clear.

“An intraocular bleed can be a visually devastating event,” first author Dr. Michelle T. Sun, of the University of Adelaide’s South Australian Institute of Ophthalmology, told Reuters Health by email. “Blood thinners such as anticoagulants are used by patients for many conditions, and thus it is important to define the risk of intraocular bleeding associated with these agents.”

In their systematic review and meta-analysis, the researchers included 12 phase 3 randomized trials with more than 102,000 patients with atrial fibrillation or venous thromboembolism. Patients had been randomly assigned to receive a NOAC (dabigatran, rivaroxaban, apixaban, or edoxaban) or warfarin.

Randomization to NOACs “was associated with a 22% relative reduction in intraocular bleeding compared with warfarin” (risk ratio, 0.78), the researchers reported in JAMA Ophthalmology, online July 6.

Subgroup analysis also showed comparably lower intraocular bleeding risks for NOACs compared with warfarin, with similar benefits among patients treated for atrial fibrillation or venous thromboembolism and no significant differences related to type of NOAC.

“Our findings are particularly relevant to patients who are already at higher risk of intraocular bleeding, in particular those with exudative age-related macular degeneration, where a massive intraocular bleed can be a visually devastating event,” Dr. Sun said.

The findings “also raise the possibility that these newer agents may be advantageous in the perioperative period, where stopping and starting of warfarin can be very problematic,” she added.

However, despite a significant reduction in relative risk, intraocular bleeding occurs infrequently in patients treated with anticoagulants, and the reduction in absolute risk is small.

“The absolute risk decrease in intraocular bleeding association with (NOAC) use compared with warfarin was 0.8 bleeds per 1000 person-years,” the researchers note.

“That’s not really a clinically important difference,” Dr. James Douketis, of the division of hematology and thromboembolism at McMaster University in Hamilton, Ontario, Canada, told Reuters Health by phone.

“I would not choose a NOAC over warfarin to reduce the risk of intraocular hemorrhage based on that small, clinically insignificant - albeit statistically significant - difference,” said Dr. Douketis, who studies antithrombotic therapy, including risk factors for bleeding associated with antithrombotic treatment.

Dr. Douketis, who was not involved in the new meta-analysis, noted that some practice guidelines name NOACs as the first-line anticoagulation treatment because of their net clinical benefit compared with warfarin. That includes a small reduction in mortality and a small but clinically important reduction in intracranial hemorrhage, and efficacy that is as good, if not better, than that of warfarin.

“This is all apart from the convenience factor, but you have to factor in the cost issue, as well,” he said.

“I don’t think that warfarin is a bad drug, but if you’re going to use it, now you have to hold it to a higher standard,” Dr. Douketis explained. That means that to better match the efficacy and safety profile of the NOACs, clinicians have to ensure that patients taking warfarin have a time in therapeutic range of 70% to 80%, using “smarter” warfarin management, such as focusing on potential drug interactions, mitigating food and alcohol interactions, and taking comorbidities into account.

Dr. Douketis said he disagrees with the authors’ assertion that the findings imply a possible safety advantage for NOACs in perioperative management.

“You don’t want to say . . . we can assume that we can carry out intraocular surgery without interruption of these drugs,” he said. “There are no data to support that.”

As an example, he pointed to use of NOACs such as rivaroxaban (Xarelto) that have a very high and rapid peak effect. “You don’t want to be operating on someone a few hours after they take their Xarelto, because they’re going to have a very high peak anticoagulant effect,” he cautioned.

“So, I think we need data specific to intraocular surgery, or cataract surgery, before we can make any statements about safety (of NOACs) around eye surgeries or procedures,” he said.

The study had no commercial funding; one of the seven authors reported receiving lecture or travel funding from Boehringer-Ingelheim, which manufactures dabigatran.

SOURCE: https://bit.ly/2tbmf8F

JAMA Ophthalmol 2017.

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