Cross-Over Trial of Febuxostat and Topiroxostat for Hyperuricemia With Cardiovascular Disease (TROFEO Trial)

Abstract

to reduce UA more potently than allopurinol, 7 while topiroxostat has a similar effect to allopurinol. 8 No study, however, has compared febuxostat with topiroxostat. Accordingly, a clinical study was conducted to compare febuxostat with topiroxostat and assess potential differences in efficacy (TopiROxostat and FEbuxostat in a randomized, Open-label, cross-over trial for hyperuricemia with cardiovascular disease (TROFEO trial). Methods Study ProtocolThe subjects were outpatients with cardiovascular disease and hyperuricemia in whom s-UA was controlled at ≤6 mg/dL by treatment with allopurinol or febuxostat. In this study, patients were randomized by the envelop method to receive treatment with either febuxostat (Teijin Pharma, Tokyo, Japan) or topiroxostat (Sanwa Kagaku Kenkyusho, Aichi, Japan and Fujiyakuhin, Saitama, Japan) for 6 months, after which they switched to the other medication for another 6 months. Baseline data were H yperuricemia was recently reported to be associated with hypertension, cardiovascular disease, and chronic kidney disease (CKD). 1,2 Allopurinol has long been regarded as a first-line drug for the treatment of hyperuricemia, but adverse reactions such as renal dysfunction, Stevens-Johnson syndrome, and hypersensitivity vasculitis have been reported with allopurinol, and it is not sufficiently effective in some cases. 3,4 In a comparative trial of febuxostat vs. allopurinol, we reported that febuxostat reduced serum uric acid (s-UA) earlier than allopurinol, had a stronger renoprotective effect than allopurinol, and also had superior antioxidant and anti-inflammatory effects. 5,6 Unlike allopurinol, febuxostat and topiroxostat (a novel xanthine oxidase reductase [XOR] inhibitor) have a non-purine structure and are mainly metabolized in the liver. In addition, these agents are excreted in both the urine and feces. Accordingly, their impact on the kidney is minimal, and dose adjustment depending on renal function is not required, in contrast to allopurinol. These 2 drugs have different dosing regimens (once daily for febuxostat vs. twice daily for topiroxostat) and febuxostat is reported Background: We previously reported that febuxostat was more effective for hyperuricemia than allopurinol. The efficacy, however, of topiroxostat (a novel xanthine oxidase reductase inhibitor similar to febuxostat), for hyperuricemia is unknown. Methods and Results:Patients with cardiovascular disease and hyperuricemia, in whom serum uric acid (s-UA) was controlled at ≤6 mg/dL, were eligible for enrollment. Fifty-five patients were randomized to receive either febuxostat or topiroxostat for 6 months and were switched to the other drug for the following 6 months. The primary endpoint was s-UA. Secondary endpoints included serum creatinine, estimated glomerular filtration rate, urinary albumin, cystatin-C, oxidized low-density lipoprotein, eicosapentaenoic acid/ arachidonic acid ratio, lipid biomarkers, high-sensitivity C-reactive protein and B-type natriuretic protein. Although s-UA level was similar for b...

Efficacy of uric acid‐lowering therapy on hypercholesterolemia and hypertriglyceridemia in gouty patients

“…To‐date, the effects of UA‐lowering drugs on blood lipids remain inconclusive. In animal experiments and clinical studies, conflicting data have been reported . Despite the negative results in Sezai's study, we can see a declining trend in the numerical value of triglycerides after 1 month when patients were treated with febuxostat .…”

The effects of topiroxostat on vascular function in patients with hyperuricemia

“…In a previous study, it showed tolerability and non‐inferior SUA‐lowering effect to allopurinol in hyperuricemic patients with or without gout . Furthermore, topiroxostat and febuxostat showed similar renal protective and anti‐inflammatory effects after 6‐month treatment in hyperuricemic patients with cardiovascular disease . In recent years, the organ protective effect of these novel XOR inhibitors has been suggested, which has gained considerable attention.…”

Changeover Trial of Febuxostat and Topiroxostat for Hyperuricemia with Cardiovascular Disease: Sub-Analysis for Chronic Kidney Disease (TROFEO CKD Trial)

“…The study result demonstrated that febuxostat caused greater and more rapid reduction of s-UA than topiroxostat, as well as an antioxidant effect superior to topiroxostat. 9) However, that study did not compare the two drugs in patients with CKD, so we performed a sub-analysis of CKD patients from the TROFEO trial in the present study (TROFEO CKD trial). All patients in TROFEO trial were those who underwent cardiovascular surgery.…”