Loading ...

Patients with advanced chronic kidney disease (CKD) gained no overall cardiovascular benefit from low-dose rivaroxaban in a large randomized trial, unlike the prevention advantage observed in other high-risk populations.

In the TRACK trial, 2.5 mg twice daily of the direct oral anticoagulant (DOAC) held no hint of reduction in the primary composite endpoint encompassing cardiovascular death, nonfatal myocardial infarction, stroke, or a peripheral artery disease event. The rivaroxaban group actually had a 22.6% rate compared with 20.7% in the placebo group over a median of 1.7 years in the trial (hazard ratio [HR], 1.09; 95% CI, 0.87-1.36; P = .46 ).

Rather, prophylaxis was associated with significantly more major bleeding — 8.8% vs 6.0% — the equivalent of 1.7 more events per 100 person-years (HR, 1.51; 95% CI 1.02-2.22; P = .04).

“Clinical decisions to prescribe anticoagulant treatments in these patients should be based on absolute risks rather than extrapolating evidence from general cardiology cohorts,” said Sunil V. Badve, PhD, of The George Institute for Global Health at the University of New South Wales in Sydney, Australia.

His group published the TRACK trial findings in JAMA in conjunction with presentation at the European Renal Association in Glasgow, Scotland.

Indeed, low-dose rivaroxaban plus aspirin reduced ischemic events and mortality to a degree that outweighed bleeding risks in the COMPASS trial among people with a history of coronary artery disease, ischemic stroke, or peripheral artery disease. The combination also showed cardiovascular risk reduction over aspirin alone in the VOYAGER PAD trial after lower extremity revascularization.

Patients with advanced CKD have a markedly higher risk for cardiovascular disease events than those in earlier stages of CKD but also a substantially elevated risk for major bleeding, which is further increased with anticoagulants, according to Badve.

“The pathophysiology of atherothrombosis and bleeding are different in these patients,” he said.

However, “all major previous cardiovascular outcome trials systematically excluded these patients,” he said. “Most clinicians who prescribe DOACs do so on the assumption that the evidence from general cardiology cohorts applies to advanced kidney disease.”

Nisha Bansal, MD, MAS, of the University of Washington in Seattle, and Wolfgang C. Winkelmayer, MD, of Baylor College of Medicine in Houston, called the findings a sign to pivot rather than dispense with anticoagulation altogether for this advanced CKD population.

“Does TRACK close the door on anticoagulation for cardiovascular protection in this population? Certainly not,” they wrote in an editorial accompanying the JAMA paper.

The results should “not be generalized to patients with advanced kidney disease who have specific indications for anticoagulant treatment, such as stroke prevention in atrial fibrillation,” they cautioned.

One limitation of TRACK was that it was terminated early, enrolling 1458 of the planned 1900 patients across 90 centers in 12 countries. While this reduced power to detect more modest benefits or subgroup effects, it was “an ambitious and impressive undertaking in a population that has been difficult to enroll in clinical trials,” the editorialists wrote.

Participants were adults with stage 4 or 5 CKD (estimated glomerular filtration rate ≤ 29 mL/min/1.73 m²) or dialysis-dependent kidney failure, who were considered at elevated cardiovascular risk due to coronary artery disease, peripheral artery disease, diabetes, a history of nonhemorrhagic and nonlacunar stroke, or aged 65 years or older.

Patients randomly assigned to receive rivaroxaban 2.5 mg twice daily rather than placebo showed no differences in the primary outcome across subgroups by age, sex, country, established cardiovascular disease, aspirin use, diabetes, dialysis dependence, or smoking status. Major bleeding risk, though, was elevated more with rivaroxaban in those 65 years or older (10% vs 5.6% on placebo) than in those younger than 65 years (7.3% vs 6.4%; P for interaction = .03).

No differences were seen favoring rivaroxaban across secondary outcomes including all-cause mortality (25.6% vs 23.0% on placebo; HR ,1.14; 95% CI, 0.92-1.40; P = .66) and individual components of the primary composite outcome.

The trial might have been hampered in finding a treatment signal due to the nearly one third of patients in the rivaroxaban group who permanently discontinued therapy prematurely — most often for patient preference and safety — and by inclusion of patients without established cardiovascular disease.

Heterogeneity in baseline aspirin use was also a concern, the editorialists said.

In the COMPASS trial, a rivaroxaban-only group showed no benefit whereas the combination with aspirin did. Only half of the TRACK trial patients were taking aspirin at baseline, “although subgroup analyses did not indicate any visible heterogeneity by baseline aspirin use, and a formal (underpowered) test for effect modification was not significant,” they wrote.

“Further, rivaroxaban is partially cleared by the kidneys,” Bansal and Winkelmayer wrote. “[I]t is unknown whether the dose used in patients with kidney disease is the same as those without kidney disease, which may have affected the safety of the medication.”

Despite these limitations, the trial showed that “rigorous, large-scale studies in advanced CKD are both feasible and essential,” the editorialists added. “More importantly, TRACK sets the direction for the questions that must be asked next, particularly regarding which patients are most likely to benefit (eg, those with established cardiovascular disease) and whether alternative oral anticoagulation strategies may prove more effective or safer in selected CKD populations.”

The study was supported by research grants from the NHMRC of Australia, the French Ministry of Health Programme Hospitalier de Recherche Clinique, and Deutsche Forschungsgemeinschaft. Bayer AG provided rivaroxaban and placebo tablets free of cost through the Investigator-Initiated Research Support Scheme.

Badve reported receiving personal fees and nonfinancial support to his institution from Bayer during the conduct of the study and personal fees to his institution from AstraZeneca, GSK, Vifor Pharma, Novo Nordisk, and Pfizer outside the submitted work.

Crystal Phend is an award-winning medical journalist with decades of experience reporting on clinical research and healthcare developments across specialties. When not walking the halls at a medical conference, she can be found on a keyboard in upstate New York.