Low-Dose NOACs Top Warfarin in Asian Patients in Everyday Practice, Retrospective Study Suggests

Dabigatran and rivaroxaban have superior efficacy and safety compared with warfarin in Taiwanese patients with A-fib, about 90% of whom receive low doses of the non-vitamin K antagonist oral anticoagulants (NOACs), a new study suggests. When compared with one another, the two agents generally yielded similar results.

“Either rivaroxaban or dabigatran may be a safer and more effective alternative to warfarin in Asian patients with [nonvalvular A-fib],” lead author Yi-Hsin Chan, MD (Chang Gung University, Taoyuan, Taiwan), and colleagues write in a study published in the September 27, 2016, issue of the Journal of the American College of Cardiology.

Commenting on the study for TCTMD, Jonathan Piccini, MD (Duke University, Durham, NC), said it was reassuring to see that outcomes in this real-world study were similar to those seen in the pivotal clinical trials of the NOACs. “And perhaps the best part of that is the fact that we continue to see lower rates of intracranial bleeding with those medications,” he said.

But, he added, there are limitations that need to be considered, including the lack of information on renal function and on the quality of warfarin therapy in the administrative dataset used in the analysis.

Moreover, he said, it’s difficult to discern why certain patients received low doses of the drugs and how they differed from those who received full doses.

“It’s commonly known that physicians often spare therapy due to bleeding concerns, when [it’s been shown] in study after study that the net clinical benefit weighs in favor of treatment,” Piccini said, noting that there is some evidence that outcomes are actually worse in patients who receive a reduced-dose NOAC when they should be receiving the full dose.

Discussing the potential impact of the current findings, he said the results are more applicable to clinicians practicing in East Asia than to those practicing in North America. The analysis “raises the question of whether we should have additional studies to refine what the best dose is for those specific patient populations,” Piccini said. “I think the study is interesting and makes a significant contribution to the literature, but the problem is we’re talking about a single country’s experience and we need to be very careful about generalizing it.”

Low-Dose NOACs Potent Enough?

The NOACs—which include dabigatran (Pradaxa; Boehringer Ingelheim), rivaroxaban (Xarelto; Janssen Pharmaceuticals), apixaban (Eliquis; Bristol-Myers Squibb), and edoxaban (Savaysa; Daiichi Sankyo)—have been shown to be at least as effective as warfarin for preventing thromboembolic events in patients with A-fib and to carry a lower risk of intracranial hemorrhage and a higher risk of GI bleeding.

But there is limited information about whether the effects are similar in Asians, who have a higher risk of intracranial hemorrhage when taking warfarin compared with non-Asians.

For the current study, Chan et al examined data from the Taiwan National Health Insurance Research Database on patients who started treatment for newly diagnosed A-fib between February and December 2013. The analysis included 3,916 patients taking rivaroxaban, 5,921 taking dabigatran, and 5,251 taking warfarin. Apixaban and edoxaban had not yet been approved.

After propensity-score adjustment, both rivaroxaban and dabigatran were associated with lower risks of ischemic stroke/systemic embolism, intracranial hemorrhage, and all-cause mortality compared with warfarin (P < 0.001 for all). Risks of acute MI and hospitalization for GI bleeding did not differ across groups, although the risk of hospitalization for major bleeding was lower with dabigatran versus warfarin (HR 0.65; 95% CI 0.48-0.88).

Most outcomes were similar when comparing rivaroxaban and dabigatran, with the exception of hospitalization for GI bleeding, which was more frequent with rivaroxaban (HR 1.60; 95% CI 1.11-2.51). That difference was no longer apparent in an on-treatment analysis, however.

The researchers also performed subgroup analyses to look at the impact of dosing. Low doses were used in 87% of patients taking rivaroxaban (10 to 15 mg/day) and in 90% of those taking dabigatran (110 mg twice daily). Safety and efficacy was better with the NOACs when low doses were used, but not when patients received standard doses.

The authors point to several factors to explain the extensive use of low-dose NOACs in Taiwan, including the lower body mass index of adults in that country compared with patients enrolled in the pivotal trials of the drugs, the use of lower doses to mimic the reduced INR ranges recommended for warfarin therapy in some Asian guidelines, cautious prescribing of standard doses in older patients with multiple comorbidities, and concern about the higher risk of vitamin K antagonist-related intracranial hemorrhage in Asian populations.

They say the current study is the largest yet to examine the efficacy of low-dose NOACs in Asians and shows that “low-dose NOACs may be potent enough at reducing thromboembolic events in Asians with low body mass.”

‘More Questions Than Answers’

In an accompanying editorial, Christian Ruff, MD, MPH (Brigham and Women’s Hospital, Boston, MA), says the study raises two important issues.

“The first is whether Asian patients with [A-fib] warrant modification of standard anticoagulant management compared with other populations because of a difference in their risk for thromboembolic and bleeding events and their response to treatment,” he writes. “The second involves the role, interpretation, and limitations of ‘real-world’ data.”

To that first point, Ruff says the study “helps us understand the implementation and impact of NOAC management in Asian patients as routinely practiced.”

But, he says, when it comes to assessing the effects of lower doses of NOACs on outcomes, there are challenges in interpreting retrospective, real-world data.

He notes that the results showing that low doses were superior to warfarin in terms of safety and efficacy conflict with clinical trial data in Asian patients, which show that only the higher dose of dabigatran (150 mg twice daily)—and not the lower dabigatran dose or full doses of the other NOACs—reduced ischemic stroke.

“Unfortunately, we cannot reconcile these differences, because the investigators do not provide any data on how well warfarin was used,” Ruff says.

He questions why the higher doses of dabigatran and rivaroxaban in the current study had efficacy comparable to that of warfarin when the lower doses yielded better outcomes.

“Is it because this study was underpowered with respect to the higher doses (< 10% of patients) or because the higher doses resulted in greater rates of drug discontinuation leading to loss of the protective effects of anticoagulation?” he wonders. “Again, we are missing details that are not available because of the limitations of data available in retrospective databases not designed to address these questions.”

He concludes by saying, “As is often the case with real-world data, we are often left with more questions than answers.”





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Todd Neale is the Associate News Editor for TCTMD and a Senior Medical Journalist. He got his start in journalism at …

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  • Chan Y-H, Kuo C-T, Yeh Y-H, et al. Thromboembolic, bleeding, and mortality risks of rivaroxaban and dabigatran in Asians with nonvalvular atrial fibrillation. J Am Coll Cardiol. 2016;68:1389-1401.

  • Ruff CT. The reality of “real-world” data: more questions than answers. J Am Coll Cardiol. 2016;68:1402-1403.

  • The study was supported by grants from the Ministry of Science and Technology and Chang Gung Memorial Hospital.
  • Chan reports no relevant conflicts of interest.
  • Ruff reports receiving consulting fees from Bayer, Daiichi Sankyo, Portola, and Boehringer Ingelheim and grant support through his institution from Daiichi Sankyo.
  • Piccini reports conducting research studies funded by Johnson &amp; Johnson and serving as a consultant to Pfizer/Bristol-Myers Squibb and Medtronic.