Docs Still in Dark on Anticoagulant Choice in Severe Kidney Disease

Newer nonvitamin K oral anticoagulants (NOACs) offer a significantly lower stroke risk and an overall more favorable risk profile than vitamin K antagonists, such as warfarin, in patients with early stage chronic kidney disease (CKD), suggests a systematic review.

However, the impact of the novel agents is unclear in patients with severe kidney disease.

Pooling results from 45 trials in more than 34,000 patients with CKD receiving anticoagulants, Sunil V. Badve, PhD, The George Institute for Global Health, UNSW Medicine, Newtown, New South Wales, Australia and colleagues, compared NOACs and vitamin K antagonists given for different indications.

Stressing that the research, published today in the Annals of Internal Medicine, is based on data "mostly from subgroups of large trials," Badve and colleagues found that, in CKD patients with atrial fibrillation (AF), NOACs were associated with a significant 21% reduction in the risk of stroke and systemic embolism versus vitamin K antagonists, and a potential 52% reduction in the risk of hemorrhagic stroke.

However, only the evidence in AF offers a high degree of certainty, they say.

The results suggest that patients with early CKD will "derive similar or greater benefit" from the use of NOACs compared with those without CKD, the authors conclude.

"However, evidence is insufficient to recommend widespread use of vitamin K antagonists or NOACs to improve clinical outcomes in patients with advanced CKD and dialysis-dependent ESRD," they stress.

All Risk and No Benefit in ESRD? Ongoing Trials Needed to Inform

Calling for "adequately powered randomized trials" of anticoagulants in patients with CKD, Badve and coauthors emphasize that "future trials should include not only participants with dialysis-dependent ESRD but also those with creatinine clearance less than 25 mL/min."

They nevertheless note the ongoing RENAL-AF trial, which is comparing apixaban with warfarin in participants with hemodialysis-dependent ESRD and AF, and AXADIA, which is looking at apixaban versus the vitamin K antagonist phenprocoumon in a similar patient population. Lastly, the AVKDIAL trial is examining warfarin versus no anticoagulation, also in those on dialysis with ESRD and AF.

In an accompanying editorial, Ainslie Hildebrand, MD, University of Alberta Edmonton, Canada, and colleagues call the new review "ambitious" and wonder whether — taking into account the "limitations of subgroup analysis" — there is "a level of renal dysfunction for which clinicians should apply greater caution in extrapolating these findings?"

They point to previous studies showing that the use of warfarin in patients with ESRD and AF has not reduced the risk of embolic stroke and has increased the risk of hemorrhagic stroke twofold.

And although the current results suggest that NOACs offer a "potential benefit" over vitamin K antagonists, a retrospective study of apixaban in patients with ESRD and AF indicates there may be no difference between the two classes in this very ill patient population, "raising concerns that these medications [NOACs] might be all risk and no benefit, at least for prophylaxis."

They echo the authors in underlining that the "highly anticipated" RENAL-AF and AXADIA trials "are required to prove efficacy."

"Until the results of these trials become available, the decision to use anticoagulant therapy in patients with end-stage kidney disease will continue to require an individualized approach that balances potential benefits and harms," Hildebrand and colleagues stress.

CKD Is Prothrombotic, but Patients Excluded From Anticoagulant Trials

The researchers explain that CKD is a "prothrombotic state" — the risks for venous thromboembolism (VTE) and AF are two to three times and 10 to 20 times greater in patients with CKD and ESRD, respectively, than in the general population, for example.

And the combination of CKD and AF increases the risk of stroke or systemic embolism, congestive heart failure, myocardial infarction, and all-cause death, while VTE in ESRD is linked to an increased bleeding and all-cause mortality risk.

So based on guidelines developed for the general population, most CKD patients require VTE prophylaxis during hospitalization and/or anticoagulation for their AF.

But AF patients with advanced CKD/ESRD are less likely to be prescribed oral anticoagulants than those with no or earlier stage CKD.

This, the authors suggest, "may be due to the increased risk for bleeding, uncertainty about potential benefits in this population, warfarin-associated calciphylaxis, and warfarin-related nephropathy."

The situation has been made worse by excluding patients with CKD from "nearly 90%" of anticoagulant trials.

For the current analysis, the team conducted a search of the MEDLINE, EMBASE, and Cochrane databases, as well as ClinicalTrials.gov to identify randomized controlled trials of NOACs and vitamin K antagonists for any indication in patients with CKD.

Trials Compared NOACs With Warfarin, LMWHs, Aspirin, and Placebo

The search yielded 45 trials involving 34,082 patients, "only eight [of which] included patients with ESRD (n = 685)," note the editorialists. Seven of these evaluated vitamin K antagonists for the prevention of access thrombosis, and one looked at the effect of vitamin K antagonists on hemostatic factors.

Patients receiving anticoagulation for AF (11 trials), thromboprophylaxis (six trials), prevention of dialysis access thrombosis (eight trials), and cardiovascular disease other than AF (nine trials) were included.

All but the eight trials involving patients with ESRD excluded those with a creatinine clearance less than 20 mL/min or an estimated glomerular filtration rate less than 15 mL/min/1.73m².

The trials could have been published up to February 2019 and were required to report efficacy or bleeding outcomes.

None of the AF trials included patients with dialysis-dependent ESRD.

Across all 45 trials, the median sample size was 276 and median follow-up was 12 months.

NOACs were compared with vitamin K antagonists in 15 trials, placebo in 10 trials, low molecular weight heparins (LMWHs) in five trials, and aspirin in four trials.

Vitamin K antagonists were compared with placebo in four trials, with no study medication in four trials, LMWHs in two trials, and aspirin in one trial.

The NOACs studied were rivaroxaban, dabigatran, apixaban, edoxaban, and betrixaban. Vitamin K antagonists were fixed-dose (1 or 2 mg) or low-intensity (target international normalized ratio [INR], 1.4-1.9) warfarin and adjusted-dose (target INR, 1.5-2.5 or 2-3) warfarin or acenocoumarol.

NOACs Reduce Stroke vs Warfarin in Patients With CKD and AF

The team reports that, in patients with CKD and AF, NOACs were associated with a reduced risk of stroke or systemic embolism compared with vitamin K antagonists, at a risk ratio (RR) of 0.79, for which the evidence had a high certainty.

NOACs were also associated with a reduced risk for hemorrhagic stroke versus vitamin K antagonists in patients with AF (RR, 0.48), although the evidence was only of moderate certainty.

However, compared with vitamin K antagonists, the effects of NOACs on recurrent VTE or VTE-related death were "uncertain" (RR, 0.72; 95% CI, 0.44 - 1.17; low-certainty evidence).

And in all trials combined, NOACs seemingly reduced major bleeding risk compared with vitamin K antagonists (RR, 0.75; CI, 0.56 - 1.01), but again, this was deemed "low-certainty evidence."

The team reiterates: "In early stage CKD, NOACs had a benefit–risk profile superior to that of vitamin K antagonists."

But for advanced CKD or ESRD, there was "scant" evidence "to establish benefits or harms of vitamin K antagonists or NOACs," they conclude.

No primary funding declared. Badve has reported receiving support from a John Chalmers Clinical Research Fellowship with the support of Servier from The George Institute for Global Health. Badve has reported receiving grants from the National Health and Medical Research Council of Australia, personal fees from Bayer and Amgen Australia, and nonfinancial support from Bayer during the conduct of the study. Disclosures for the other authors and editorialists are listed on the journal website.

Ann Intern Med. Published online July 15, 2019. Abstract, Editorial

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