FREED: Febuxostat for Hyperuricemia May Shield Kidneys, CV Risk Unclear

August 29, 2018

MUNICH — Cutting elevated serum uric acid levels with febuxostat (Uloric, Takeda Pharmaceuticals) in patients with cardiovascular (CV) risk factors may protect the kidneys better than standard management, suggests a randomized trial, but one considered too small to be conclusive.

There was no sign that CV clinical outcomes, on their own, were any different between the febuxostat-based approach and the control treatment, which didn't include a placebo but did allow discretionary management with allopurinol, long the mainstay med for hyperuricemia.

Still, febuxostat-treated patients showed a significant reduction in the trial's primary clinical endpoint, a composite that ranged widely from CV and neurologic clinical events to renal functional deterioration, changes in laboratory markers, and aortic dissection.

Overwhelmingly in both treatment groups, renal dysfunction accounted for most events contributing to the composite primary endpoint. It was the only component to show a significant difference between the treatment groups, potentially suggesting a greater protective effect from febuxostat compared with standard care.

Both the newer drug and allopurinol are xanthine oxidase inhibitors used in patients with and at risk for gout. Febuxostat has been observed in earlier research to have greater selectively for uric acid than does allopurinol and to achieve lower uric-acid concentrations.

But the trial, called Febuxostat for Cerebral and Cardiorenovascular Events Prevention Study (FREED), raises cautions about the optimal degree of uric acid lowering. There were signs of a so-called J-curve for risk for clinical events by achieved serum uric acid level. The lowest risk was seen at intermediate concentrations compared with the lowest and the highest achieved levels, said Sunao Kojima, MD, PhD, Kawasaki Medical School, Okayama, Japan, when presenting FREED here at the European Society of Cardiology (ESC) Congress 2018.

The findings, he said, point to a benefit from febuxostat "for prevention of cerebral, cardiovascular, and renal events in elderly patients with hyperuricemia," although no reductions in hard clinical endpoints were seen.

Febuxostat also "may be expected to prevent the development and progression of chronic kidney disease." But "excessive" reductions in serum uric acid levels using the drug in such patients with CV risk factors should be avoided, Kojima said.

FREED's researchers and observers of the trial interpret its findings in light of earlier studies, especially the recent CARES trial, which directly compared febuxostat to allopurinol in high-CV-risk patients with gout and coronary, cerebrovascular, or peripheral vascular disease or diabetes with small-vessel disease. Patients in the febuxostat group compared with those receiving allopurinol showed an increase in CV deaths.

Taking FREED and CARES together, febuxostat seems to have a "neutral" effect on CV risk, FREED coinvestigator Kunihiko Matsui, MD, MPH, PhD, Kumamoto University, Japan, told | Medscape Cardiology.

But FREED is too small a study, with inadequate statistical power, to absolve febuxostat from CARES-related claims that it worsens CV risk, Matsui said. So those concerns persist.

He also pointed to the signal in FREED that excessive uric acid lowering, especially on the newer, more potent drug, may increase risk compared with more moderate reductions. That observation, despite the possible renal protective effect, suggests that clinicians should still heed cautions about febuxostat based on CARES and prefer allopurinol instead in patients with hyperuricemia and increased CV risk, Matsui said.

Barbara Casadei, MD, DPhil, University of Oxford, United Kingdom, agreed that there weren't enough patients or events in FREED to reliably dispute the concerns raised by CARES.

When interviewed, Casadei also seemed to question the strength of the trial's signs that febuxostat is renal protective. Renal function was tracked according to an array of indicators ranging from multiple laboratory markers to renal-associated death, she pointed out.

So the renal endpoint that contributed to the primary endpoint "was itself a composite," she said, and differences in individual components of composite endpoints are useful only in trials with lots of patients and endpoint-related events.

"Allopurinol is cheap and seems to be performing better according to the CARES study. So why would you want to use the more expensive drug?"

Cardiovascular risk was increased on febuxostat in CARES and not significantly increased in FREED, but "the number of events that were cardiovascular in CARES was an order of magnitude larger than was seen in FREED," pointed out Paul M. Ridker, MD, MPH, invited discussant, after Kojima's presentation of the study.

"For major adverse cardiac events, where the numbers are far larger in CARES, we may still have to rely predominantly on those data, even though the data in FREED are reassuring for that endpoint," said Ridker, from Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts.

"On the other hand, I think FREED provides very important reassuring data, and in fact protective data, for the impact on renal impairment," he said. "This is a clinically important finding. Serum uric acid is a risk marker for renal decline, so this is a significant benefit for the slowing of renal disease, which could obviously have a huge impact for our patients."

In FREED, 1070 patients aged 65 years and older with serum uric acid levels greater than 7 to less than or equal or 9 mg/dL and one or more risk factors for cerebral, CV, or renal disease were randomly assigned to febuxostat or standard management.

The risk factors could include history of hypertension or type 2 diabetes, renal dysfunction (ie, estimated glomerular filtration rate ≥ 30 to < 60 mL/min per 1.73 m2) within prior 3 months, or history of cerebrovascular or CV disease prior to 3 months before enrollment.

The treatments consisted of febuxostat initially at 10 mg/d but escalated to 40 mg/d over 2 months or standard management without febuxostat but with discretionary allopurinol 100 mg/d if serum uric acid was elevated. Ultimately, 27.2% of patients in the latter group received allopurinol at that dosage.

Assigned therapy continued for 36 months; both were on top of lifestyle modification aimed at managing hyperuricemia.

There was no double-blinding to treatment, but endpoints were blindly adjudicated. The eclectic primary endpoint consisted of death due to CV or renal vascular disease; new or recurrent cerebrovascular disease including any ischemic or hemorrhagic stroke or transient ischemic attack; new or recurring nonfatal myocardial infarction or unstable angina; hospitalization for heart failure; arteriosclerotic disease requiring treatment, including aortic aneurysm or dissection, or arteriosclerosis obliterans; renal impairment, defined as incident microalbuminuria or mild proteinuria, progression to overt albuminuria or severe proteinuria, a twofold increase in serum creatinine levels, or progression to end-stage renal disease, or renal death; new-onset atrial fibrillation; or death from any other cause.

Secondary endpoints included those events individually and a "hard endpoint" composite of death from any cause or nonfatal cerebrovascular or coronary events.

Mean serum uric acid level at entry was 7.54 mg/dL in the febuxostat group and 7.50 mg/dL among controls. They plunged in the febuxostat group compared with the controls within the study's first 12 weeks, the separation remaining consistent throughout the trial's 36 months with final mean levels of 4.50 mg/dL and 6.76 mg/dL, respectively (P < .001).

Table. Outcomes at 36 Months in FREED

Endpoints Febuxostat (n = 537) (%) Standard Management (n = 533) (%) Hazard Ratio (95% Confidence Interval) P Value
Primary endpoint 23.3 28.7 0.75 (0.59 - 0.95) .017
Renal impairment 16.2 20.5 0.745 (0.562 - 0.987) .04
Death, cerebrovascular disease, nonfatal CAD 4.3 4.9 0.861 (0.492 - 1.506) .60


There were no significant differences between the two groups for the separate components of the primary endpoint, with the exception of renal impairment. Far and away, most of the events were renal: accounting for 87 of 125 events in the febuxostat group and 109 of 155 events in the standard management group.

In analyses by different levels of achieved serum uric acid levels in the two groups separately and both groups together, the primary-endpoint hazard ratio was lowest at achieved levels of greater than 5 to less than or equal to 6 mg/dL.

It was higher, sometimes significantly so, both at higher levels (at >7 mg/dL and at >6 to ≤7 mg/dL) and at lower levels (≤4 mg/dL and >4 to ≤5 mg/dL).

That suggests the greater effect of febuxostat on uric-acid lowering compared with allopurinol might turn out to be a disadvantage of the newer agent. Whether that's true, Matsui said, is one of the next challenges in this line of research.

FREED was funded by Teijin Pharma. Neither Kojima nor Matsui had disclosures. Casadei had no conflicts. Ridker discloses consulting for, receiving royalties from, or holding equity interest in Novartis; is listed as a coinventor on a patent held by his institution related to the use of inflammatory biomarkers licensed to Siemens; and has research contracts with Novartis, Kowa, and Pfizer.

European Society of Cardiology (ESC) Congress 2018. Hot Line Session 4. August 28, 2018.

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