Nephroprotective NOACs? Renal Dysfunction Not Infrequent Among A-fib Patients, but Some Agents Reduce Risk

Worsening renal function is not uncommon for patients with nonvalvular A-fib who are taking oral anticoagulants, but certain agents may be better able to lower the risks of adverse renal outcomes compared with warfarin, according to a new retrospective analysis.

Some “emerging data” have signaled that non-vitamin K antagonist oral anticoagulants (NOACs) might be linked to better preservation of kidney function versus warfarin, lead study author Xiaoxi Yao, PhD (Mayo Clinic, Rochester, MN), and colleagues point out in their paper published this week in the Journal of the American College of Cardiology.

Yet, “the nephroprotective effect of NOACs has remained largely speculative,” they add, “because no renal outcomes beyond [estimated glomerular filtration rate (eGFR)] decline were evaluated in the pivotal clinical trials, and some of the analyses were restricted to patients with long follow-up and could have underreported adverse renal outcomes as a result of early dropout.”

Teasing Out Differences

To determine the breadth of the issue and analyze the effects of several available anticoagulants—apixaban (Eliquis; Bristol-Myers Squibb), dabigatran (Pradaxa; Boehringer Ingelheim), rivaroxaban (Xarelto; Bayer/Janssen), and warfarin—the researchers linked numbers from a large US database to laboratory results from 9,769 patients with nonvalvular A-fib who started taking oral anticoagulation between October 2010 and April 2016. The average on-treatment follow-up was 10.7 months, during which an average of 2.5 creatinine values were determined.

The overall 2-year risks for a ≥ 30% decline in eGFR, doubling of serum creatinine, acute kidney injury, and kidney failure were 24.4%, 4.0%, 14.8%, and 1.7%, respectively. When patients treated with apixaban, dabigatran, and rivaroxaban were pooled, the NOACs were associated with reduced risks of a ≥ 30% decline in eGFR (HR 0.77; 95% CI 0.66-0.89), doubling of serum creatinine (HR 0.62; 95% CI 0.40-0.95), and acute kidney injury (HR 0.68; 95% CI 0.58-0.81) compared with warfarin.

Dabigatran was associated with lower risks of a ≥ 30% decline in eGFR (HR 0.71) and acute kidney injury (HR 0.55) than warfarin, and rivaroxaban was linked with lower risks of a ≥ 30% decline in eGFR (HR 0.73), doubling of serum creatinine (HR 0.46), and acute kidney injury (HR 0.69). However, there were no statistically significant differences in any renal outcome with apixaban versus warfarin.

Notably, renal function decline is “very common” in this patient group, Yao and colleagues write. “This observation underscores the need for periodic monitoring and comprehensive efforts to prevent and treat progressive CKD.”

When choosing an oral anticoagulant agent, physicians should consider the impact of the drug on subsequent renal function, they advise. More research is needed to see whether the impact on renal function decline is medication-specific, but “this finding does not suggest that dabigatran and rivaroxaban should be used in preference to apixaban,” the researchers stress.

The authors also point to their subgroup analysis, which hinted that patients on warfarin with an average international normalized ratio (INR) of greater than 3 were more likely to have an eGFR decline of at least 30%, doubling of serum creatinine, and acute kidney injury. “The renal benefits of NOACs appeared to be more evident in comparison with these patients. In recent years, point-of-care testing has become increasingly used to monitor INR, which could potentially improve the outcome in warfarin-treated patients,” they note.

“However, as observed in our study, in most cases, NOACs may still be associated with a lower (or numerically lower) risk of renal outcomes when compared with warfarin-treated patients with subtherapeutic or therapeutic INRs,” Yao et al continue. “This observation suggests that differential renal outcomes are not attributable solely to poor INR control with warfarin and that off-target effects of these agents may be at play.”

Are Laboratory Values Enough?

In an editorial accompanying the study, Michael Walsh, MD, PhD, and Stuart Connolly, MD (McMaster University, Hamilton, Canada), say that the paper is “very welcome as it further examines the question of whether [NOAC] use protects against the risk of chronic and acute kidney disease compared to [vitamin-K antagonists (VKAs)].”

The findings “broadly agree” with those from randomized controlled trials, Walsh and Connolly observe, but they “add a degree of refinement to the effect of [NOACs] on renal outcomes by showing consistency across a number of commonly accepted outcome definitions.”

Even if physicians accept the possibility that at a minimum dabigatran and rivaroxaban cause less renal dysfunction than warfarin, “there is still the question of whether the effect is meaningful,” the editorialists say. The reductions in eGFR decline, doubling of creatinine, and acute kidney injury seen in the study are “impressive” but not important to patients, they note. “They are simply worse laboratory values and some of them are only marginally and/or transiently worse values.”

“For patients who are happy with their warfarin treatment and not interested in a [NOAC] on the basis of [being] advantageous in terms of reduced risks of bleeding, or stroke, or in terms of convenience, it seems unlikely that the risk of slightly less normal laboratory measures will turn the tide for them,” Walsh and Connolly argue.

Today, it is “probably not broadly warranted” to switch patients on warfarin to a NOAC to preserve renal function, they conclude. “However, for patients at high risk of progressive loss of kidney function who do not have a contraindication to a [NOAC], the putative renal benefits are one more reason to choose a [NOAC] over a VKA.”