Caution needed over real-world NOAC study: experts


By Sunalie Silva

27 Oct 2016

Dabigatran (Pradaxa, Boehringer Ingelheim) may have a safety advantage over rivaroxaban (Xarelto, Bayer), say international experts after findings from the first ‘real world’ study comparing the two NOACS show that rivaroxaban was associated with a greater and more severe bleeding risk.

But Australian experts are cautious about drawing such prescriptive conclusions from an observational study.

Findings from the retrospective cohort study found no statistically significant difference in the rates of thromboembolic stroke between once-daily rivaroxaban and twice-daily dabigatran, but it did find significant increases in the rates of intracranial haemorrhage (ICH) as well as major extracranial bleeding including major gastrointestinal bleeding.

An accompanying editorial said that it had no hesitation in concluding that the findings “should lead us to prescribe dabigatran over rivaroxaban for patients with atrial fibrillation.”

Talking to the limbic head of the Haemostasis & Thrombosis Unit and Director of the Haemophilia Centre at The Alfred Hospital, Associate Professor Huyen Tran, said he is more conservative in his interpretation of the study.

“We have to be careful in terms of real world data – there’s a degree of uncertainty about compliance and other routine parameters, such as renal function … if patients that were prescribed rivaroxaban had worse kidney function for instance that could affect bleeding rates,” he said.

“So to say that one drug is superior over the other in terms of bleeding risk based on this study… I think that’s a big call.”

Electrophysiologist and arrhythmia specialist Dr Andrei Catanchin agreed that the editorial went too far in its interpretation of the findings.

“The wording of the trial and editorial is rather strong and a little provocative. I believe the findings clearly support the use of dabigatran [which is] useful for prescribers with doubts regarding its safety.

“While they may raise questions about the comparative safety profile of rivaroxaban, it is by no means an adequate comparison of the two. We would need much more real world data showing the same findings before we could draw these conclusions,” he said.

Researchers from the study, led by David Graham of the FDA’s office of Surveillance and Epidemiology in the Centre for Drug Evaluation and Research, retrospectively reviewed outcomes from more than 52,000 patients treated with a 150 mg twice-daily dose of dabigatran and over 66,000 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 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).

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 authors noted.

In a statement to the limbic a spokesperson for Bayer said the results of the analysis are in conflict with the pivotal ROCKET-AF trial, and all other studies and data that it is aware of.

According to Bayer the XANTUS (Xarelto for prevention of stroke in patients with atrial fibrillation) study published in 2015, which was the first prospective real-world study for a NOAC, included more than 6,500 patients treated with rivaroxaban and showed that rates of major bleeding and stroke with rivaroxaban were found to be low in routine clinical practice, with a ICH rate of 0.4%.

A spokesperson for BI said “the safety profile of dabigatran demonstrated in this study further supports the extensive comparative real world evidence for dabigatran.”

Meanwhile, the FDA has completed its safety review into rivaroxaban after serious concerns were raised about the pivotal ROCKET-AF trial, which found rivaroxaban was non inferior to warfarin.

New questions about the trial emerged last year when it was revealed that the point of care device used to measure the INR range in the warfarin group had been recalled due to unreliability in some patient populations.

Related story: The BMJ raises fresh concerns over ROCKET-AF

After conducting three analyses to assess the impact that this faulty monitoring device had on the ROCKET-AF study results. The Agency has determined that effects on strokes or bleeding, including intracranial bleeding, were minimal.

The FDA concluded on Tuesday that Xarelto is a safe and effective alternative to warfarin in patients with atrial fibrillation and does not require a change the rivaroxaban label product label.

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