More NOAC Comparisons See Higher Bleeding Risk With Rivaroxaban: Is the ‘Writing on the Wall’?

Evidence is mounting, albeit from observational studies, that while all of the non-vitamin K antagonist oral anticoagulants (NOACs) appear to have similar efficacy in terms of stroke reduction in atrial fibrillation, they may not be equivalent when it comes to safety.

One such study, appearing in JAMA Internal Medicine earlier this week, found no statistically significant difference in the rates of thromboembolic stroke between once-daily rivaroxaban (Xarelto; Janssen Pharmaceuticals) and twice-daily dabigatran (Pradaxa; Boehringer Ingelheim), but it did see significant increases in the rates of intracranial hemorrhage (ICH) as well as major extracranial bleeding.

A second study, published online in CHEST last week compared dabigatran, rivaroxaban, and apixaban (Eliquis; Bristol-Myers Squibb). Here again, all three drugs appeared to have similar effectiveness in terms of stroke or systemic embolism, but apixaban was associated with lower major bleeding risk versus the other two agents individually, while rivaroxaban was associated with an increased risk of major bleeding and ICH compared with dabigatran.

Speaking with TCTMD, Peter Noseworthy, MD (Mayo Clinic, Rochester, MN), lead author on the CHEST paper, observed: “These and other analyses are tending to show the similar effectiveness of the medications when they go head to head, so I don’t think it’s a matter of effectiveness as much as it appears to be a matter of safety.”

Several reports, however, “are starting to show a small signal for a poorer safety profile with rivaroxaban,” he said. “And I don’t think it’s so much that it’s a terrible medication—we’re seeing really small differences—but they are consistent and they are reproducible, and they are statistically significant enough that I think it may end up influencing physician choice between medications.”

On the Other Side of the Pond

The two new studies come close on the heels of an analysis by Danish researchers comparing dabigatran, rivaroxaban, apixaban, and warfarin. In that analysis, dabigatran and apixaban were associated with a significantly decreased risk of ICH compared with warfarin, but rivaroxaban was not, although all three NOACs were as effective as warfarin at reducing stroke in atrial fibrillation patients. Laila Stærk, MD (Herlev and Gentofte University Hospital, Denmark), who presented that data at the recent European Society of Cardiology Congress 2016, spoke about the new data with TCTMD today, choosing her words carefully.

“We know the limitations of registry studies, which include the possibility of unmeasured confounders,” Stærk observed. That said, she continued, “We are seeing a tendency—and we have seen it now in different countries—suggesting that maybe all NOACs are not the similar in terms of safety.”

The JAMA Internal Medicine paper was led by David Graham, MD, of the FDA’s office of Surveillance and Epidemiology in the Center for Drug Evaluation and Research. He and his colleagues retrospectively reviewed outcomes among more than 52,000 Medicare beneficiaries treated with a 150 mg twice-daily dose of dabigatran and over 66,000 Medicare patients treated with a 20 mg once-daily dose of rivaroxaban. Patients were propensity matched and followed for a mean of 108 days in the dabigatran group and 111 days in the rivaroxaban group.

Rivaroxaban was associated with numerically fewer thromboembolic strokes (HR 0.81, 95% CI 0.65-1.01) compared with dabigatran, but the rate of ICH was significantly higher (HR 1.65, 95% CI 1.20-2.26), as was the rate of major extracranial bleeds (HR 1.48, 95% CI 1.32-1.67). Of note, in patients 75 years or older with a CHADS₂ score greater than 2, rivaroxaban was associated with a significantly higher rate of all-cause death compared with dabigatran.

The CHEST paper, by Noseworthy et al, is the publication of data first presented at ACC 2016. As previously reported by TCTMD, Noseworthy and colleagues found that rivaroxaban was associated with a higher risk of major bleeding compared with dabigatran (HR 1.30; 95% CI 1.10-1.53) and apixaban was associated with lower risk versus either dabigatran (HR 0.50; 95% CI 0.36-0.70) or rivaroxaban (HR 0.39; 95% CI 0.28-0.54). For intracranial bleeding, the only between-drug difference to emerge was for rivaroxaban versus dabigatran (HR 1.79; 95% CI 1.12-2.86).

In both papers, the absolute difference in bleeding risk is low, Noteworthy stressed. “The difference in the event rate [in Graham et al’s paper] was one half of one percent or less in intracranial bleeding, so we’re talking about small differences. But there are 3 million people in the US with atrial fibrillation and we get most of them on anticoagulation, so these small differences can make a big difference in public health.”

Randomized Trial Data Lacking

To date there are no randomized head-to-head trials comparing the new agents, but that is about to change. Stærk told TCTMD that a new prospective, cluster randomized trial has just been announced in Denmark that will involve “almost all” hospitals in the country. Designed to run for 4 years, each hospital will just use one of the four approved NOACs (dabigatran, rivaroxaban, edoxaban [Savaysa; Daiichi Sankyo], and apixaban) for the period of 1 year, then the next the next year, and so forth. At the end of the 4-year period, every participating hospital will have 1 year’s experience with each of the approved NOACs, with follow-up to continue for several years thereafter. Dubbed DEN-NOAC, the trial will be led by Casper Bang, MD (Rigshospitalet, Copenhagen, Denmark).

In the meantime, Noseworthy believes the information coming out of observational studies may be starting to sway physician preferences.

“There are a lot of people doing comparative effective studies with these medications,” he said. “This population is a Medicare population, we’ve looked at privately insured populations, and other healthcare system databases will also be used. Probably over the next year or so a consensus will emerge and one or two drugs will likely be the winners.

“I think the writing is on the wall for rivaroxaban,” he continued, stressing though that more studies are needed.